General Neurology

(Contributed by Lydia Sastre.)

(Contributed by Lydia Sastre.)

(Contributed by Lydia Sastre.)

(Contributed by Lydia Sastre.)

(Contributed by Lydia Sastre.)

(Contributed by Lydia Sastre.)

(A) Conjugate gaze in primary position. (B) Anisocoria (seen in uncal herniation ipsilateral to dilated pupil). (C) Rightward gaze deviation (ipsilateral to dysfunctional frontal eye fields). (D) Right internuclear ophthalmoplegia (localizes to ipsilateral medial longitudinal fasciculus). (E) Downward deviation (localizes to mesencephalic tegmentum). (Contributed by Dr. Paulina Henriquez Rojas.)

(Green) Rostral reticular formation and ascending pathways. (Orange) Target regions of the activating system (thalamus, basal forebrain, and hypothalamus). (Yellow) Caudal portion and descending pathways. (Contributed by Dr. Paulina Henriquez Rojas.)

(Contributed by Dr. Tamara Kaplan. From: Bashir A, Sizar O. Laxatives. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing, 2024.)

The image identifies the location of the striate cortex (V1), early occipital visual regions (V2, V3), and two parallel pathways. One that leads dorsally to the posterior parietal regions for the "where and visually-guided action" pathway and one that leads ventrally to posterior and inferior temporal regions for the "what" pathway. (Contributed by Dr. Victoria Pelak. Modified with permission from: Pelak VS. The clinical approach to the identification of higher-order visual dysfunction in neurodegenerative disease. Curr Neurol Neurosci Rep 2022;22[4]:229-42.)

(A) Macular OCT of central retinal vein occlusion shows thickening of the foveal region in cystoid macular edema. Small cystic spaces are evident in the outer plexiform layer, with loss of the normal foveal depression. The hyperreflectivity of the inner retina is due to ischemia. (B) Normal macular OCT. (Contributed by Dr. Prin Hantrakul.)

Dilated and tortuous retinal veins are seen along with scattered flame-shaped hemorrhages. The white patch temporal to the optic disc suggests secondary cilioretinal artery occlusion that occurred after the central retinal vein occlusion. (Contributed by Dr. Parin Hantrakul.)

The central retinal arteries and veins emerge from the optic nerve head. The normal ratio of artery and vein is 2:3. The fovea, seen as a yellow spot, is located between the superior and inferior temporal vascular arcades. (Contributed by Dr. Prin Hantrakul.)

A total of 13 studies were included in the analysis. Dots represent individual participant data, continuous lines represent means, and dashed lines represent 90% confidence intervals. The lower dashed line represents the lower limit of normal, and the upper dashed line represents the upper limit of normal at the respective altitude. The 90% confidence intervals were not corrected for possible confounders, such as age, sex, and body mass index. (Source: Forrer A, Gaisl T, Sevik A, et al. Partial pressure of arterial oxygen in healthy adults at high altitudes: a systematic review and meta-analysis. JAMA Netw Open 2023;6[6]:e2318036. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The size of each bubble is proportional to the standard error of each of the 51 studies shown in the figure. The 95% confidence interval (gray area) is the standard error of the estimate (ie, the standard error of the point estimation for one observation). (Source: Forrer A, Gaisl T, Sevik A, et al. Partial pressure of arterial oxygen in healthy adults at high altitudes: a systematic review and meta-analysis. JAMA Netw Open 2023;6[6]:e2318036. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Hu B, Gong M, Xiang Y, Qu S, Zhu H, Ye D. Mechanism and treatment of olfactory dysfunction caused by coronavirus disease 2019. J Transl Med 2023;21[1]:829. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Hu B, Gong M, Xiang Y, Qu S, Zhu H, Ye D. Mechanism and treatment of olfactory dysfunction caused by coronavirus disease 2019. J Transl Med 2023;21[1]:829. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(a) Supporting cells affect olfactory sensory neurons functions through tight junctions. (b) SARS-CoV-2 enters and damages olfactory sensory neurons. (c) Amplification of inflammatory factors leads to olfactory sensory neuron impairment. (Source: Hu B, Gong M, Xiang Y, Qu S, Zhu H, Ye D. Mechanism and treatment of olfactory dysfunction caused by coronavirus disease 2019. J Transl Med 2023;21[1]:829. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Blue: anterior cranial fossa; Green: middle cranial fossa. (Source: Edwards B, Wang JM, Iwanaga J, Loukas M, Tubbs RS. Cranial nerve foramina part I: a review of the anatomy and pathology of cranial nerve foramina of the anterior and middle fossa. Cureus 2018;10[2]:e2172. Creative Commons Attribution 3.0 Unported [CC BY 3.0] license, creativecommons.org/licenses/by/3.0.)

Abbreviations: CG: crista galli; CF: cribriform plate. (Source: Edwards B, Wang JM, Iwanaga J, Loukas M, Tubbs RS. Cranial nerve foramina part I: a review of the anatomy and pathology of cranial nerve foramina of the anterior and middle fossa. Cureus 2018;10[2]:e2172. Creative Commons Attribution 3.0 Unported [CC BY 3.0] license, creativecommons.org/licenses/by/3.0.)

(A) superior view; (B) oblique view. Abbreviations: OC: optic canal; SOF: superior orbital fissure; FR: foramen rotundum; FO: foramen ovale; FS: foramen spinosum. (Source: Edwards B, Wang JM, Iwanaga J, Loukas M, Tubbs RS. Cranial nerve foramina part I: a review of the anatomy and pathology of cranial nerve foramina of the anterior and middle fossa. Cureus 2018;10[2]:e2172. Creative Commons Attribution 3.0 Unported [CC BY 3.0] license, creativecommons.org/licenses/by/3.0. Figure edited by Dr. Douglas J Lanska.)

(Source: Lacey H, Oliphant H, Smith C, Koenig M, Rajak S. Topographical anatomy of the annulus of Zinn. Sci Rep 2022;12[1]:1064. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(a) Eye; (b) Optic nerve in the muscular cavity; (c) Optic nerve cut off outside the orbit; (d) The portion of the dura mater, which becomes the periosteum; (e) Levator palpebrae superioris cut off near its origin; (f) The superior oblique muscle bent by a pulley (the trochlea); (g) Superior rectus muscle; (h) Superior rectus muscle insertion; (i) Medial rectus muscle; (k) Each of the muscles just mentioned being connected to each other near the origin, so that it is clear from this that the levator palpebrae did not originally reach the sheath of the optic nerve, but that it was imposed on both muscles; (l) Inferior rectus muscle; (m) Lateral rectus muscle; (n) Superior head (lesser) of the lateral rectus muscle; (o) Inferior head of the lateral rectus muscle; (p) The interval between the two heads of the lateral rectus muscle.

(Source: Zinn JG. Descriptio anatomica oculi humani. Göttingen, B. Abrahami Vandenhoeck, 1780. Tab V, Figure 2. Public domain. Figure edited and labeling translated and updated from the original French labels by Dr. Douglas J Lanska.)

(a) The optic nerve was cut off near the entrance; (b) Septum bony between the optic foramen and the sphenoid [superior orbital] fissure rounded; (c) The dura mater is cut off, where it becomes the periosteum of the orbit; (d) Superior rectus muscle; (e) Levator palpebrae superioris; (f) Common tendon, from which the abductor, adductor, and depressor muscles (lateral rectus, medial rectus, and inferior rectus muscles) originate (annulus of Zinn); (g) The tendinous branches arising from the common ligament, going off to their muscles; (h) Lateral rectus muscle; (i) Inferior rectus muscle; (k) Medial rectus muscle.

(Source: Zinn JG. Descriptio anatomica oculi humani. Göttingen, B. Abrahami Vandenhoeck, 1780. Tab V, Figure 3. Public domain. Figure edited and labeling translated and updated from the original French labels by Dr. Douglas J Lanska.)

(Public domain.)

(a) Eye; (b) Optic nerve in the muscular cavity; (c) Optic nerve cut off outside the orbit; (d) The portion of the dura mater, which, having been severed from the optic nerve, leaves the opening of the orbit; (e) Levator palpebrae superioris, the levator of the upper eyelid, arising from the angle of the division of the dura mater, and terminating in the broad aponeurosis; (f) Superior rectus muscle "in large part the levator of the lid" (through a synkinesis); (g) The superior oblique muscle bent by a pulley (the trochlea); (h) Inferior oblique muscle insertion; (i) Inferior rectus muscle; (k) Lateral rectus muscle; (l) Superior head (lesser) of the lateral rectus muscle; (m) Inferior head of the lateral rectus muscle; (n) An interval between the two heads of the lateral rectus muscle, through which the collected nerves are transmitted in a bundle; (o) The first branch of the fifth nerve (V1); (p) Of this first branch of the fifth nerve (V1), the lacrimal branch was cut off; (q) Frontal branch of the fifth nerve (V1) cut off; (r) Nasal branch of the fifth nerve (V1); (s) Branch of the nasal shoot, which constitutes the longer root of the ophthalmic ganglion; (t) Oculomotor nerve; (u) Abducens nerve.

(Source: Zinn JG. Descriptio anatomica oculi humani. Göttingen, B. Abrahami Vandenhoeck, 1780. Tab V, Figure 1. Public domain. Figure edited and labeling translated and updated from the original French labels by Dr. Douglas J Lanska.)

(A) Eye; (B) Lacrimal gland; (C) Lateral rectus muscle; (D) Superior rectus muscle; (E) Levator palpebrae superioris; (F) Inferior rectus muscle; (G) Lateral rectus muscle; (H) Superior oblique muscle; (I) Trochlea; (K) Part of the inferior oblique muscle; (L) Internal carotid artery in the cavernous sinus; (M) Carotid penetrating into the cavity of the skull; (N) Ophthalmic artery arising from the internal carotid artery; (a) Optic nerve passing through its foramen; (b) Part of the fifth nerve in the cranial cavity; (c) Mandibular branch of the fifth nerve (V3); (d) Maxillary branch of the fifth nerve (V2); (e) Ophthalmic branch of the fifth nerve (V1); (f) Frontal branch of V1, divided again into two branches; (g) Nasal branch of V1 ; (h) Nasociliary branch of V1; (i) Lacrimal branch of V1; (k) Trochlear nerve; (l) Abducens nerve in the cavernous sinus; (n) Insertion of the abducens nerve into the lateral rectus muscle; (o) Trunk of the oculomotor nerve; (p) The superior, lesser branch of the oculomotor nerve; (q) Branches of the oculomotor nerve to the superior rectus muscle; (r) Branch of the oculomotor nerve to the levator palpebrae superioris; (s) The lower branch of the oculomotor nerve is larger; (t) Branch of the oculomotor nerve to the medial rectus muscle; (u) Branch of the oculomotor nerve to the inferior rectus muscle; (x) Branch of the oculomotor nerve to the inferior oblique muscle; (y) The ophthalmic (ciliary) ganglion, (a peripheral parasympathetic ganglion), loosened from its connection with the optic nerve, and rolled outwards. (The ciliary ganglion is situated near the apex of orbit between the optic nerve and lateral rectus muscle.); (z) The shorter root of the ophthalmic (ciliary) ganglion, from the inferior oblique nerve (Preganglionic parasympathetic fibers from the Edinger Westphal nucleus pass to the inferior oblique muscle branch of the oculomotor nerve to reach the ciliary ganglion, where preganglionic fibers synapse with postganglionic fibers. Postganglionic fibers pass through the short ciliary nerve to supply the pupillary sphincter and the ciliary muscle.)

Note: the numerals are omitted from this legend.

(Source: Zinn JG. Descriptio anatomica oculi humani. Göttingen, B. Abrahami Vandenhoeck, 1780. Tab VI, Figure 1. Public domain. Figure edited and labeling translated and updated from the original French labels by Dr. Douglas J Lanska.)

(A) The superior rectus is slightly rolled, so that the lower face, to which the nerve is inserted, is exposed; (B) Levator palpebrae superioris; (C) Superior oblique muscle; (D) Trochlea; (E) Portion of the medial rectus with a branch of the oculomotor nerve ; (F) Portion of the inferior rectus with the branch of the oculomotor nerve; (G) Lateral rectus muscle seen from the internal face; (H) Insertion of the inferior oblique muscle; (I) Portion of the upper eyelid; (a) Optic nerve; (b) Trochlear nerve (a portion cut off); (c) Abducens nerve inserted into the lateral rectus muscle; (d) Oculomotor nerve; (e) Superior branch of the oculomotor nerve; (f) Branch of the oculomotor nerve to the superior rectus muscle; (g) Branch of the oculomotor nerve to the levator palpebrae superioris; (h) Inferior branch of the oculomotor nerve; (i) Branch of the oculomotor nerve to the inferior rectus muscle; (k) Branch of the oculomotor nerve to the medial rectus muscle; (l) Branch of the oculomotor nerve to the inferior oblique muscle; (m) The frontal branch of the fifth pair of nerves (V1) was cut off; (n) The (external) nasal branch of the fifth pair of nerves (V1) was cut off; (o) Two ciliary nerves arise from the nasal cavity; (p) Ophthalmic (ciliary) ganglion lateral to the optic nerve; (s) Upper bundle of ciliary nerves composed of three nerves; (t) The lower bundle of ciliary nerves is larger; (u) The shoot of the ciliary nerves is bent outward and approaches the eye in a long loop.

Note: some small cap labels omitted.

(Source: Zinn JG. Descriptio anatomica oculi humani. Göttingen, B. Abrahami Vandenhoeck, 1780. Tab VI, Figure 2. Public domain. Figure edited and labeling translated and updated from the original French labels by Dr. Douglas J Lanska.)

Optic nerve (B) contained within the dural sheath and coursing through the common tendinous ring. Superior rectus (A), lateral rectus (D), levator palpebrae superioris (E), medial rectus (F), inferior rectus (G). Intra-orbital vessels (C).

(Source: Lacey H, Oliphant H, Smith C, Koenig M, Rajak S. Topographical anatomy of the annulus of Zinn. Sci Rep 2022;12[1]:1064. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(The right eyeball has been removed.) Common tendinous origin (A). Optic chiasm (B) with bilateral optic nerves extending from it. Muscular cone extending into orbit (C) top to bottom lateral rectus, superior rectus, medial rectus. (D) Levator palpebrae superioris, (E) superior rectus, (F) inferior rectus.

(Source: Lacey H, Oliphant H, Smith C, Koenig M, Rajak S. Topographical anatomy of the annulus of Zinn. Sci Rep 2022;12[1]:1064. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Optic nerve (ON); the ophthalmic artery (OA) is surrounded by oculomotor foramen structures (abducens nerve, nasociliaris nerve, two branches of oculomotor nerve); the skeletal muscle fibers of the extraocular muscles (M) are separated by thin layers of fibrous tissue (FT); the annular fibrous tissue (annulus of Zinn) is continuous with the skull base dura (D).

(Source: Lacey H, Oliphant H, Smith C, Koenig M, Rajak S. Topographical anatomy of the annulus of Zinn. Sci Rep 2022;12[1]:1064. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Major (F) and minor (E) head of the medial rectus. (A) Superior rectus, (B) optic nerve with surrounding dural sheath, (C) lateral rectus, (D) levator palpebrae superioris, (G) inferior rectus.

(Source: Lacey H, Oliphant H, Smith C, Koenig M, Rajak S. Topographical anatomy of the annulus of Zinn. Sci Rep 2022;12[1]:1064. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Upper head (D) and lower head (E). (A) Superior rectus, (B) levator palpebrae superioris, (C) eye, (F) common tendinous origin, (G) inferior rectus.

(Source: Lacey H, Oliphant H, Smith C, Koenig M, Rajak S. Topographical anatomy of the annulus of Zinn. Sci Rep 2022;12[1]:1064. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Dural sheath (A) shown continuing into the orbit anteriorly and posteriorly to unite with the common tendinous origin (B). Lateral rectus (C), inferior rectus (D).

(Source: Lacey H, Oliphant H, Smith C, Koenig M, Rajak S. Topographical anatomy of the annulus of Zinn. Sci Rep 2022;12[1]:1064. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The atypical muscle (marked by black asterisk) originates at the common tendinous ring (origin marked by black arrowhead) and passes laterally to the optic nerve (II) and the ophthalmic artery (OA). (a) Dissection of the specimen harvested from the right orbit. The lateral rectus muscle has been removed to expose the accessory muscle. (b) Dissection of the specimen harvested from the left orbit. One of the sub-branches derived from the inferior branch of the oculomotor nerve (IB) innervates the inferior slip of the accessory muscle (this small branch has been marked by a white arrowhead).

IR, inferior rectus muscle; IO, inferior oblique muscle; NIO, nerve to inferior oblique; SR, superior rectus muscle; III, oculomotor nerve.

(Source: Haładaj R, Wysiadecki G, Polguj M, Topol M. Bilateral muscular slips between superior and inferior rectus muscles: case report with discussion on classification of accessory rectus muscles within the orbit. Surg Radiol Anat 2018;40[7]:855-62. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Sagittal section of the specimen harvested from the right orbit. Lateral view. Thickening of both superior and inferior rectus muscles at the insertion point of the accessory muscle slips has been clearly visualized. Black asterisk marks the accessory muscle, black arrowhead marks the origin of the accessory muscle located at the common tendinous ring.

II, optic nerve; III, oculomotor nerve; IR, inferior rectus muscle; SR, superior rectus muscle; OA, ophthalmic artery.

(Source: Haładaj R, Wysiadecki G, Polguj M, Topol M. Bilateral muscular slips between superior and inferior rectus muscles: case report with discussion on classification of accessory rectus muscles within the orbit. Surg Radiol Anat 2018;40[7]:855-62. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(a) Part of the superior head of the right accessory rectus muscle. Fibers of striated skeletal muscle have been visualized (H&E stain, x10 objective). (b) Sample fibers of striated skeletal muscle obtained from the superior head of the right accessory rectus muscle. The striations of skeletal muscle tissue have been visualized (H&E stain, x40 objective). (c) Part of the inferior head of the right accessory rectus muscle shown near its origin from the inferior rectus muscle. Fibers of striated skeletal muscle as well as cross sections of small nerves (marked by white arrowheads) have been visualized (H&E stain, x10 objective). (d) Sample fibers of striated skeletal muscle obtained from the inferior head of the right accessory rectus muscle. The striations of skeletal muscle tissue have been visualized (H&E stain, x40 objective).

Abbreviations: An, anterior; Po, posterior.

(Source: Haładaj R, Wysiadecki G, Polguj M, Topol M. Bilateral muscular slips between superior and inferior rectus muscles: case report with discussion on classification of accessory rectus muscles within the orbit. Surg Radiol Anat 2018;40[7]:855-62. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(a) Part of the superior head of the left accessory rectus muscle (marked by grey arrowheads) shown at its origin from superior rectus muscle (SR) (H&E stain, x2 objective). Fibers of striated skeletal muscle and a cross-section of small nerve (marked by white arrowhead) have been visualized. (b) Part of the tendon with visible bundles of collagen fibers (tissue sample taken from the origin of the left accessory rectus muscle) (H&E stain, x40 objective). (c) Part of the inferior head of the left accessory rectus muscle (marked by black arrowheads) shown at its origin from the inferior rectus muscle (IR) (H&E stain, x2 objective). Fibers of striated skeletal muscle and cross-section of small nerve (marked by white arrowhead) have been visualized. (d) Sample fibers of striated skeletal muscle obtained from the inferior head of the left accessory rectus muscle. The striations of skeletal muscle tissue have been visualized (H&E stain, x40 objective).

Abbreviations: An, anterior; Po, posterior.

(Source: Haładaj R, Wysiadecki G, Polguj M, Topol M. Bilateral muscular slips between superior and inferior rectus muscles: case report with discussion on classification of accessory rectus muscles within the orbit. Surg Radiol Anat 2018;40[7]:855-62. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Variants of the supernumerary orbital muscles reported in the literature. For ease of comparison and increased transparency, the same side has been presented on all schemes. Terminology applied by Lüdinghausen and colleagues has been taken into account. (Lüdinghausen M, Miura M, Würzler N. Variations and anomalies of the human orbital muscles. Surg Radiol Anat 1999;21[1]:69-76.)

(a) Anatomical variation described in this report—an accessory muscle observed on a 68-year-old cadaver with no eye movement abnormalities reported in the medical history. The accessory muscle is divided into two delicate slips (heads): superior (marked by black asterisk)—forming a muscular bridge connected to the superior rectus muscle (SR); and inferior—corresponding to accessory rectus muscle (AR) and attached in the anterior half of the inferior rectus muscle (IR). (b) Supernumerary orbital muscle (AR) with a broad muscular bridge (marked by black asterisk) to the SR and attachment to the anterior part of the IR. The accessory muscle was well-separated from the IR. (c) Supernumerary orbital muscle (AR) with a thin muscular bridge (marked by black asterisk) to the SR and close attachment to the anterior part of the IR. Variants (b) and (c) were described by Lüdinghausen and colleagues on the adult cadaver with no problems with mobility of the eyeball in the medical history.

Abbreviation: II, optic nerve.

(Source: Haładaj R, Wysiadecki G, Polguj M, Topol M. Bilateral muscular slips between superior and inferior rectus muscles: case report with discussion on classification of accessory rectus muscles within the orbit. Surg Radiol Anat 2018;40[7]:855-62. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Schematic drawings simulating MRI or CT coronal scans demonstrating spatial organization of muscular structures within the orbit in the event of the presence of accessory (supernumerary) rectus muscles or muscular bands between superior and inferior rectus muscles. The drawings were prepared based on a comparison of different MRI scans presented by Khitri, Dremer, and Kighlinger and colleagues (Khitri and Dremer 2010; Kightlinger et al 2017).

(a) Complete muscular bridge seen between temporal edges of superior and inferior rectus muscles (marked by grey arrowheads). On drawing (b) only fragments of certain heads of the supernumerary rectus were captured (grey arrowheads). Abbreviations: IR, inferior rectus muscle; LR, lateral rectus muscle; LPS, levator palpebrae superioris muscle; MR, medial rectus muscle; SR, superior rectus; SO, superior oblique muscle; II, optic nerve.

(Source: Haładaj R, Wysiadecki G, Polguj M, Topol M. Bilateral muscular slips between superior and inferior rectus muscles: case report with discussion on classification of accessory rectus muscles within the orbit. Surg Radiol Anat 2018;40(7):855-62. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

References cited:
Khitri MR, Demer JL. Magnetic resonance imaging of tissues compatible with supernumerary extraocular muscles. Am J Ophthalmol 2010;150[6]:925-31.

Kightlinger BS, Saraf-Lavi E, Sidani C. Anomalous extraocular muscles: a case series of orbital bands connecting the superior rectus to inferior rectus. Neurographics 2017;7[2]:88-91.)

Selective injection of the external carotid artery demonstrates filling of the cavernous sinus (arrow) and retrograde drainage into the right superior ophthalmic vein (arrowhead).

(Source: Thinda S, Melson MR, Kuchtey RW. Worsening angle closure glaucoma and choroidal detachments subsequent to closure of a carotid cavernous fistula. BMC Ophthalmol 2012;12:28. Creative Commons Attribution 2.0 Generic [CC BY 2.0] license, creativecommons.org/licenses/by/2.0.)

External photographs of the right eye taken 1 month (top) and 2 months (bottom) after closure of an indirect carotid-cavernous fistula. (Top) External photograph showing corkscrew blood vessels. (Bottom) External photograph showing corkscrew blood vessels and iris pigment on the anterior capsule.

(Source: Thinda S, Melson MR, Kuchtey RW. Worsening angle closure glaucoma and choroidal detachments subsequent to closure of a carotid cavernous fistula. BMC Ophthalmol 2012;12:28. Creative Commons Attribution 2.0 Generic [CC BY 2.0] license, creativecommons.org/licenses/by/2.0.)

Fundus photographs of the right eye taken one month (top) and two months (bottom) after closure of a carotid-cavernous fistula. (Top) Fundus photograph showing intraretinal hemorrhages, tortuous retinal vessels, and choroidal detachments. (Bottom) Fundus photograph showing worsening choroidal detachments.

(Source: Thinda S, Melson MR, Kuchtey RW. Worsening angle closure glaucoma and choroidal detachments subsequent to closure of a carotid cavernous fistula. BMC Ophthalmol 2012;12:28. Creative Commons Attribution 2.0 Generic [CC BY 2.0] license, creativecommons.org/licenses/by/2.0.)

Neuro-ophthalmologic examination prior to treatment shows left palpebral ptosis, exotropia of the primary look of the left eye, and paresis of the third, fourth, and sixth left cranial nerves.

(Source: Mendez JA, Arias CR, Sanchez D, et al. Painful ophthalmoplegia of the left eye in a 19-year-old female, with an emphasis in Tolosa-Hunt syndrome: a case report. Cases J 2009;2:8271. Creative Commons Attribution 3.0 Unported [CC BY 3.0] license, creativecommons.org/licenses/by/3.0.)

Neuro-ophthalmologic examination after treatment shows improvement of the left palpebral ptosis and left eye movements after 72 hours of steroid treatment.

(Source: Mendez JA, Arias CR, Sanchez D, et al. Painful ophthalmoplegia of the left eye in a 19-year-old female, with an emphasis in Tolosa-Hunt syndrome: a case report. Cases J 2009;2:8271. Creative Commons Attribution 3.0 Unported [CC BY 3.0] license, creativecommons.org/licenses/by/3.0.)

Note that the internal carotid plexus accompanies the internal carotid artery in the cavernous sinus. It is composed of postganglionic sympathetic fibers ascending from the superior cervical ganglion, including fibers destined for the pupillary dilator muscle. Of the cranial nerves in the cavernous sinus, III, IV, V1, and V2 are located along the lateral wall, whereas VI passes more centrally and is, thus, more susceptible to damage from cavernous sinus pathology.

(Source: Kuybu O, Dossani RH. Cavernous sinus syndromes. In: StatPearls [Internet]. Treasure Island [FL]: StatPearls Publishing, 2024. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0. Edited by Dr. Douglas J Lanska.)

Legend: II, optic nerve; III, occulomotor nerve; IV, trochlear nerve; V1, ophthalmic division, trigeminal nerve; V2, maxillary division, trigeminal nerve; VI, abducens nerve; C, carotid artery.

(Courtesy of Dr. G Aaron Rogers, 2007. Creative Commons Attribution 2.5 Generic [CC BY 2.5] license, creativecommons.org/licenses/by/2.5. Edited by Dr. Douglas J Lanska.)

(Source: Courtesy of Anatomist90 [2011] via Wikimedia Commons. Creative Commons Attribution 3.0 Unported [CC BY 3.0] license, creativecommons.org/licenses/by/3.0.)

The left cavernous sinus is shown in red. The wall of the cavernous sinus has been removed on the right to show the internal carotid artery. Also, a portion of the skull has been removed on the right to show the contents of orbit. The levator palpebrae superioris and the superior rectus muscles have been resected.

(Source: Gray H, Lewis WH. Gray’s Anatomy of the Human Body. 20th edition. Philadelphia: Lea & Febiger, 1918. Public domain. Edited by Dr. Douglas J Lanska.)

Note that the vessels are also labeled with their diameters. The orientation box located in the top-left corner indicates the viewing direction (S superior) with arrows pointing toward left and anterior.

(Source: Nowinski WL, Thaung TS. A 3D stereotactic atlas of the adult human skull base. Brain Inform 2018;5[2]:1. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Of the cranial nerves in the cavernous sinus, III (oculomotor), IV (trochlear), V1 (ophthalmic nerve), and V2 (maxillary nerve) are located along the lateral wall, whereas VI (abducens, here written as "abducent") passes more centrally, and is, thus, more susceptible to damage from cavernous sinus pathology. Note also the proximity of the sphenoid sinus to the cavernous sinus.

(Source: Gray H, Lewis WH. Gray’s Anatomy of the Human Body. 20th edition. Philadelphia: Lea & Febiger, 1918. Public domain. Edited by Dr. Douglas J Lanska.)

Cranial nerves III and IV are illustrated passing lateral to the internal carotid artery with V1 and V2. The abducens nerve and the wall of the cavernous sinus are not shown. The optic nerve enters the orbit through the optic canal, whereas the superior and inferior branches of III, IV (and VI) along with branches of V1 enter the orbit through the superior orbital fissure.

(Source: Gray H, Lewis WH. Gray’s Anatomy of the Human Body. 20th edition. Philadelphia: Lea & Febiger, 1918. Public domain.)

Illustration by Ben Pansky. (Source: House EL, Pansky B. A functional approach to neuroanatomy. New York: McGraw-Hill Book Co., 1960, via Wikimedia Commons. Public domain. Edited by Dr. Douglas J Lanska.)

In the absence of a history of trauma, this is usually iatrogenic following infusions. The finding was clinically asymptomatic in this case. (Courtesy of Hellerhoff, 2023, via Wikimedia Commons. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Dural venous sinuses (blue); internal carotid artery (red). (Source: Sobotta J, McMurrich JP. Atlas and Text-book of Human Anatomy. Volume III. Vascular System, Lymphatic system, Nervous system, and Sense Organs. Philadelphia: W.B. Saunders, 1908. Public domain. Edited by Dr. Douglas J Lanska.)

Histopathology of a nasal biopsy in a woman with granulomatosis with polyangiitis causing cavernous sinus syndrome and diabetes insipidus (H&E stain, magnification X100). This condition was formerly called Wegener granulomatosis. Vertical arrows show granuloma. Horizontal left-facing arrow: necrosis. Horizontal right-facing arrow: angiitis with necrosis in vessel wall.

(Source: Peters JE, Gupta V, Saeed IT, Offiah C, Jawad AS. Severe localised granulomatosis with polyangiitis [Wegener's granulomatosis] manifesting with extensive cranial nerve palsies and cranial diabetes insipidus: a case report and literature review. BMC Neurol 2018;18[1]:59. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Coronal contrast-enhanced CT image of the skull base and neck (pre-cyclophosphamide treatment) in a woman with granulomatosis with polyangiitis causing cavernous sinus syndrome and diabetes insipidus. There is marked abnormal chronic inflammatory infiltration of the cavernous sinuses bilaterally (bold white arrow) and hypophyseal involvement (black arrow). Multiple lower cranial nerve palsies (Collet-Sicard syndrome) as a result of the skull base inflammatory involvement were evident on imaging, including right vocal cord palsy indicated by adducted right true vocal cord and enlarged right laryngeal ventricle (long white arrow).

(Source: Peters JE, Gupta V, Saeed IT, Offiah C, Jawad AS. Severe localised granulomatosis with polyangiitis [Wegener's granulomatosis] manifesting with extensive cranial nerve palsies and cranial diabetes insipidus: a case report and literature review. BMC Neurol 2018;18[1]:59. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Coronal T2-weighted MRI image of the skull base and neck (pre-cyclophosphamide treatment) in a woman with granulomatosis with polyangiitis causing cavernous sinus syndrome and diabetes insipidus. There is severe chronic inflammatory soft tissue abnormality affecting the cavernous sinuses and central and lateral skull base, including the left cavernous sinus, right sphenoid bone, and foramen rotundum (large black arrows). Secondary cranial nerve palsies are present. Palsy of the mandibular division of the right trigeminal nerve has resulted in atrophy of the right masticator space muscle, in comparison to the more normal muscle volume on the left (short white arrows). Lower cranial nerve palsies are demonstrated by atrophy of the right superior pharyngeal constrictor muscle (short black arrow) and sternocleidomastoid muscles (long white arrows).

(Source: Peters JE, Gupta V, Saeed IT, Offiah C, Jawad AS. Severe localised granulomatosis with polyangiitis [Wegener's granulomatosis] manifesting with extensive cranial nerve palsies and cranial diabetes insipidus: a case report and literature review. BMC Neurol 2018;18[1]:59. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Coronal contrast-enhanced fat-saturated T1-weighted MRI of the brainstem, skull base, and pituitary gland in a woman with granulomatosis with polyangiitis causing cavernous sinus syndrome and diabetes insipidus. There is pathological enhancement of the cavernous sinus, pituitary gland, and pituitary stalk (arrow). The abnormalities are nondiscrete and radiologically inconsistent with a microadenoma or invasive macro adenoma of the pituitary gland.

(Source: Peters JE, Gupta V, Saeed IT, Offiah C, Jawad AS. Severe localised granulomatosis with polyangiitis [Wegener's granulomatosis] manifesting with extensive cranial nerve palsies and cranial diabetes insipidus: a case report and literature review. BMC Neurol 2018;18[1]:59. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Dedicated thin-section coronal contrast-enhanced T1-weighted image of the pituitary in a woman with granulomatosis with polyangiitis causing cavernous sinus syndrome and diabetes insipidus. There is abnormal enhancement and thickening of the pituitary stalk as well as the cavernous sinus and pituitary parenchyma in more detail.

(Source: Peters JE, Gupta V, Saeed IT, Offiah C, Jawad AS. Severe localised granulomatosis with polyangiitis [Wegener's granulomatosis] manifesting with extensive cranial nerve palsies and cranial diabetes insipidus: a case report and literature review. BMC Neurol 2018;18[1]:59. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Dedicated thin-section sagittal contrast-enhanced T1-weighted image of the pituitary in a woman with granulomatosis with polyangiitis causing cavernous sinus syndrome and diabetes insipidus. There is abnormal generalized thickening and enhancement of the pituitary stalk (arrow) consistent with granulomatous infundibulitis.

(Source: Peters JE, Gupta V, Saeed IT, Offiah C, Jawad AS. Severe localised granulomatosis with polyangiitis [Wegener's granulomatosis] manifesting with extensive cranial nerve palsies and cranial diabetes insipidus: a case report and literature review. BMC Neurol 2018;18[1]:59. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Photograph demonstrating dilated left pupil and nasal deformity in a woman with granulomatosis with polyangiitis causing cavernous sinus syndrome and diabetes insipidus. This was taken after three pulses of intravenous methylprednisolone.

(Source: Peters JE, Gupta V, Saeed IT, Offiah C, Jawad AS. Severe localised granulomatosis with polyangiitis [Wegener's granulomatosis] manifesting with extensive cranial nerve palsies and cranial diabetes insipidus: a case report and literature review. BMC Neurol 2018;18[1]:59. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Axial intracranial contrast-enhanced T1-weighted MR image after six pulses of cyclophosphamide in a woman with granulomatosis with polyangiitis causing cavernous sinus syndrome and diabetes insipidus. There is reduction in the volume of abnormal cavernous sinus-enhancing chronic inflammatory tissue (arrows) compared with pre-treatment imaging.

(Source: Peters JE, Gupta V, Saeed IT, Offiah C, Jawad AS. Severe localised granulomatosis with polyangiitis [Wegener's granulomatosis] manifesting with extensive cranial nerve palsies and cranial diabetes insipidus: a case report and literature review. BMC Neurol 2018;18[1]:59. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

T1-weighted MRI in a man with a steroid-responsive cavernous sinus syndrome due to Rosai-Dorfman disease. There is asymmetry of the cavernous sinuses, with the left cavernous sinus larger than the right, and contrast enhancement of the left cavernous sinus (right).

(Source: Nóbrega PR, Rodrigues PG, de Sousa Pereira I, et al. Steroid responsive cavernous sinus syndrome due to Rosai-Dorfman disease: beyond Tolosa-Hunt syndrome--a case report. BMC Neurol 2021;21[1]:264 Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

MRI findings in a man with a steroid-responsive cavernous sinus syndrome due to Rosai-Dorfman disease. There is an extra-axial nodule in the left cerebellopontine angle cistern with isosignal in T1 and low signal in T2/FLAIR with homogeneous contrast enhancement, surrounded by cerebellar edema, with dural tail and no restricted diffusion (A, B, to G). In H and I there is a small extra-axial image with the same characteristics described above in the right temporal region.

(Source: Nóbrega PR, Rodrigues PG, de Sousa Pereira I, et al. Steroid responsive cavernous sinus syndrome due to Rosai-Dorfman disease: beyond Tolosa-Hunt syndrome--a case report. BMC Neurol 2021;21[1]:264 Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(A) At low magnification (H&E staining, 10x), there is fibrous and thickened dura mater (blue arrow) with extensive superficial infiltration by histiocytic cells (black arrow). (B) At intermediate magnification (H&E staining, 20x), there is extensive superficial meningeal infiltration by histiocytes (arrow); absence of cell atypias, malignant cells or meningothelial neoplasia. (C) Immunohistochemical staining for CD68 shows diffuse positivity in lesion cells, confirming the histiocytic aspect. (D) Immunohistochemical staining for S100 shows focal positivity in lesion cells, confirming the histiocytic aspect. Other reactions performed were negative: CD1a and ALK (not shown).

(Source: Nóbrega PR, Rodrigues PG, de Sousa Pereira I, et al. Steroid responsive cavernous sinus syndrome due to Rosai-Dorfman disease: beyond Tolosa-Hunt syndrome--a case report. BMC Neurol 2021;21[1]:264 Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

These images demonstrate the disappearance of the extra-axial nodules in the left cerebellopontine angle cistern and the right temporal region, as well as resolution of the cavernous sinus asymmetry.

(Source: Nóbrega PR, Rodrigues PG, de Sousa Pereira I, et al. Steroid responsive cavernous sinus syndrome due to Rosai-Dorfman disease: beyond Tolosa-Hunt syndrome--a case report. BMC Neurol 2021;21[1]:264 Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(a) Contrast-enhanced coronal T1 MRI of the first headache attack (left-sided headache) on December 12, 2020. The left cavernous sinus was enlarged and widened. The abnormal tissue strongly enhanced after intravenous injection of the contrast material. (b) Contrast-enhanced coronal T1 MRI of the second headache attack (right-sided headache) on January 10, 2021. The increased soft tissue shadows were present in cavernous sinuses bilaterally and were more pronounced on the right. (c) Axial sinus CT on January 14, 2021, shows inflammation of the right sphenoid sinus cavity. (d) One month after surgical and antibiotic therapy, MRI showed that the signal shadow of the cavernous sinus was less than before, although inflammation was still observed on the right side. (e-f) Two months after treatment, MRI showed a normal cavernous sinus and sphenoid sinus.

(Source: He W, Zhu Y, Zhang Y, Dong L, Zhou Z, Zhou J. A case report on recurrent alternating Tolosa-Hunt syndrome due to bacterial sphenoid sinusitis: rediscussing the diagnostic terminology and classification. BMC Neurol. 2023;23[1]:25. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Courtesy of Dr. Ahmed Muhammed, 2008. GNU Free Documentation License, Version 1.2. Enlarged and sharpened by Dr. Douglas J Lanska.)

(Courtesy of Jmarchin, 2023. Creative Commons Attribution 3.0 Unported [CC BY 3.0] license, creativecommons.org/licenses/by/3.0.) Enlarged and sharpened by Dr. Douglas J Lanska.)

(Source: Gray H, Lewis WH. Gray’s Anatomy of the Human Body. 20th edition. Philadelphia: Lea & Febiger, 1918. Public domain. Edited by Dr. Douglas J Lanska.)

Note: The labeling has been corrected from that in Gray's Anatomy (1918). Gray has mislabeled the projections from the Edinger-Westphal nucleus in the midbrain as sympathetic rather than parasympathetic fibers and had labeled the sympathetic fibers from the superior cervical ganglion as postganglionic fibers without noting that they were sympathetic.

(Source: Gray H, Lewis WH. Gray’s Anatomy of the Human Body. 20th edition. Philadelphia: Lea & Febiger, 1918. Public domain. Edited by Dr. Douglas J Lanska.)

(Source: Gray H, Lewis WH. Gray’s Anatomy of the Human Body. 20th edition. Philadelphia: Lea & Febiger, 1918. Public domain. Edited by Dr. Douglas J Lanska.)

The orientation box located in the top-left corner indicates the viewing direction (S superior) with arrows pointing toward left and anterior. Source: Nowinski and Thaung (2018). Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Skull base along with selected intracranial arteries (internal carotid artery, vertebral artery, basilar artery, middle cerebral artery [M1 and M2 segments], posterior cerebral artery [P1 and P2 segments] and circle of Willis) and selected extracranial arteries. The orientation box located in the top-left corner indicates the viewing direction (S superior) with arrows pointing toward left and anterior.

(Source: Nowinski WL, Thaung TS. A 3D stereotactic atlas of the adult human skull base. Brain Inform 2018;5[2]:1. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The orientation box located in the top-left corner indicates the viewing direction (S superior, A anterior, L left) with arrows pointing toward superior, left, and anterior. (Source: Nowinski WL, Thaung TS. A 3D stereotactic atlas of the adult human skull base. Brain Inform 2018;5[2]:1. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The orientation box located in the top-left corner indicates the viewing direction (S superior, P posterior, L left) with arrows pointing toward superior, left, and anterior.

(Source: Nowinski WL, Thaung TS. A 3D stereotactic atlas of the adult human skull base. Brain Inform 2018;5[2]:1. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The orientation box located in the top-left corner indicates the viewing direction (S superior, P posterior, L left), with arrows pointing toward superior, left, and anterior.

(Source: Nowinski WL, Thaung TS. A 3D stereotactic atlas of the adult human skull base. Brain Inform 2018;5[2]:1. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Legend: C, clinical picture; L, laboratory test results; I, imaging studies results; SURG, surgical treatment; ATM, antimicrobial therapy; iv, intravenously; ↑, elevated levels; 𝛾GT, gamma-glutamyl transferase; AF, alkaline phosphatase; PCR, a polymerase chain reaction.

(Source: Benites G, Urbančič J, Bardales C, Vozel D. Sinonasal orbital apex syndrome, Horner syndrome and pterygopalatine fossa infection: a case report and mini-review. Life (Basel) 2023;13(8):1658. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(A) axial CT shows the dehiscent lateral wall of the right sphenoid sinus (SS) and medial orbital apex (OA); (B) axial CT shows widened right Vidian canal (*), pterygopalatine fossa (**), and mucosal fossa (**) and mucosal thickening in the lateral recess (LR) of the sphenoid sinus; (C) sagittal CT shows eroded superior part of the right Vidian canal and mucosal thickening of the lateral recess of the sphenoid sinus; (D) coronal CT shows mucosal thickening in the right posterior ethmoid sinus and dehiscence of the medial orbital wall.

(Source: Benites G, Urbančič J, Bardales C, Vozel D. Sinonasal orbital apex syndrome, Horner syndrome and pterygopalatine fossa infection: a case report and mini-review. Life (Basel) 2023;13(8):1658. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(A) right sphenoid sinus (SS) after sphenoidotomy, with polypoid (P) mucosa on its lateral wall obstructing lateral recess of sphenoid sinus and microabscess (M) on the sphenoid sinus floor; (B) view after right-sided extended middle meatal antrostomy showing maxillary sinus (MS), sphenoethmoidectomy, and drainage of pus from the pterygopalatine fossa (PPF); (C) decompression and drainage of the orbital apex (OA); (D) right pterygopalatine fossa and orbital apex after the decompression and drainage.

(Source: Benites G, Urbančič J, Bardales C, Vozel D. Sinonasal orbital apex syndrome, Horner syndrome and pterygopalatine fossa infection: a case report and mini-review. Life (Basel) 2023;13(8):1658. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Courtesy of medical illustrator Patrick J. Lynch, 2021. Creative Commons Attribution 2.5 Generic [CC BY 2.5] license, creativecommons.org/licenses/by/2.5.)

(Source: Bardeleben KH, Haeckel EH. Atlas of Applied (Topographical) Human Anatomy for Students and Practitioners. [Translation of Atlas der Topographischen Anatomie des Menschen]. London: Rebman Limited; New York, Rebman Company, 1906. Public domain.)

(Source: Bardeleben KH, Haeckel EH. Atlas of Applied (Topographical) Human Anatomy for Students and Practitioners. [Translation of Atlas der Topographischen Anatomie des Menschen]. London: Rebman Limited; New York, Rebman Company, 1906. Public domain.)

(Source: Bardeleben KH, Haeckel EH. Atlas of Applied (Topographical) Human Anatomy for Students and Practitioners. [Translation of Atlas der Topographischen Anatomie des Menschen]. London: Rebman Limited; New York, Rebman Company, 1906. Public domain.)

Legend: 1, optic nerve; 2, optic artery; 3, common tendinous ring (annulus of Zinn); 4, lacrimal nerve (the smallest branch of V1); 5, frontal nerve (the largest branch of V1); 6, trochlear nerve (IV); 7, superior ophthalmic vein; 8, superior branch of the oculomotor nerve (III); 9, nasociliary nerve (branch of V1); 10, abducens nerve (VI); 11, lower branch of the oculomotor nerve (III); 12, inferior ophthalmic vein; 13, optic canal; 14, superior segment of the superior orbital fissure; 15, inferior segment of the superior orbital fissure.

(Courtesy of Wojtin, 2011. Creative Commons Attribution 3.0 Unported [CC BY 3.0] license, creativecommons.org/licenses/by/3.0. Illustration edited and legend translated and modified by Dr. Douglas J Lanska.)

As illustrated in the Latin edition of Schedel's Nuremberg Chronicle (1493), folio 113v. Hartmann Schedel (1440-1514) was a German historian, physician, humanist, and cartographer. The woodcut print was made in the workshop of German printmaker Michel Wolgemut (1434-1519). (Courtesy of the Rijkmuseum, Amsterdam. S. Emmering Bequest, Amsterdam. Public domain.)

Line engraving by P Galle, 1572. Philip (or Philips) Galle (1537-1612) was a Dutch publisher, designer, and engraver. (Courtesy of the Wellcome Collection, London, United Kingdom. Public domain.)

Reproduction of an oil painting by Ernest Board (1877-1934). (Courtesy of the Wellcome Collection, London, United Kingdom. Public domain.)

This image was prepared from an original photograph for a special museum exhibit. (From: Lanska DJ. Dissection of the Brain in Woodcut: A Visual Exploration of Renaissance Anatomy from Gersdorff to Vesalius. 23rd Annual Meeting of the International Society for the History of the Neurosciences. Dittrick Medical History Center, Case Western Reserve University, Cleveland, Ohio. June 20, 2018.)

This image was prepared from an original photograph for a special museum exhibit. (From: Lanska DJ. Dissection of the Brain in Woodcut: A Visual Exploration of Renaissance Anatomy from Gersdorff to Vesalius. 23rd Annual Meeting of the International Society for the History of the Neurosciences. Dittrick Medical History Center, Case Western Reserve University, Cleveland, Ohio. June 20, 2018.)

This image was prepared from an original photograph for a special museum exhibit. (From: Lanska DJ. Dissection of the Brain in Woodcut: A Visual Exploration of Renaissance Anatomy from Gersdorff to Vesalius. 23rd Annual Meeting of the International Society for the History of the Neurosciences. Dittrick Medical History Center, Case Western Reserve University, Cleveland, Ohio. June 20, 2018.)

Engraving by George Vertue (1684-1756) in 1742. (Courtesy of Llyfrgell Genedlaethol Cymru, the National Library of Wales. Public domain.)

(From Willis' Cerebri Anatome, 1664. Public domain.)

(Courtesy of the Wellcome Collection, London, United Kingdom. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

From Sömmerring's De Basi Encephali Et Originibus Nervorum Cranio Egredientium Libri Quinque: Cum IV. Tabulis Aeneis, 1778. The olfactory bulb and tract, the optic chiasm, and the third nerve (exiting the brainstem from the interpeduncular fossa) are evident. (Public domain.)

From Sömmerring’s De Basi Encephali Et Originibus Nervorum Cranio Egredientium Libri Quinque: Cum IV. Tabulis Aeneis, 1778. (Public domain.)

From Sömmerring’s De Basi Encephali Et Originibus Nervorum Cranio Egredientium Libri Quinque: Cum IV. Tabulis Aeneis, 1778. (Public domain.)

(Public domain.)

Engraving from Gowers’ A Manual of Diseases of the Nervous System, 1888. The cranial nerves are indicated by Roman numerals. Abbreviations: Th, thalamus; t c, tuber cinereum; h, pituitary body ("hypophysis cerebri"); P, peduncle; P V, pons varioli; a, corpora abicantia [sic]; Ce, cerebellum; pa, anterior pyramid; o, olivary body. (After Henle). (Public domain.)

(Source: W.R. Gowers. A Manual of Diseases of the Nervous System, 1888. Public domain.)

(1) Fibers to the ipsilateral lateral rectus in the abducens nerve. (2) Fibers to the contralateral medial rectus through the medial longitudinal fasciculus to the contralateral third nerve nucleus and then through the oculomotor nerve to the medial rectus. Thus, lesions to the sixth nerve nucleus typically produce an ipsilateral gaze palsy. Note that the medial longitudinal fasciculous is labeled as “p.h,f." for "posterior horizontal fibers." (Source: W.R. Gowers. A Manual of Diseases of the Nervous System, 1888. Public domain.)

Abbreviations and symbols: * commonly present; +/- variably present; C contralesional; CN cranial nerve; I internuclear; L left; N nuclear; R right; R/L bilateral; S supranuclear; V1 ophthalmic division of trigeminal nerve; V2 maxillary division of trigeminal nerve; V3 mandibular division of trigeminal nerve.

(Source: Plate 1 from Benjamin Franklin's Experiments and Observations on Electricity (1774) printed in London by F Newbery. Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain. Edited by Dr. Douglas J Lanska.)

An area of infarction is evident in the left lateral medulla. After the infarcted area has reached its greatest extent, it rapidly approaches its frontal pole, so that this section only shows the last remnants of the cerebral tip medioventrally from the nucleus solitarius, a uniformly light-colored area, which merges seamlessly into the normal surroundings. Only the lateral part of the dorsal reticular formation is directly destroyed at this level. All other changes concern secondary degenerations. Apart from a strong atrophy and fiber thinning within the ventral two-thirds of the crescent of the left spinal trigeminal tract and nucleus, a uniform yellow coloration is noticeable on the left half of the cross-section. The lateral section of this degeneration field is formed by the anterior spinocerebellar tract (ventral spinocerebellar tract; tractus spinocerebellaris ventralis; Gowers’ bundle), the medial section by the spinotectal fibers (spinomesencephalic fibers; fibrae spinotectales) and the spinothalamic tract (spinothalamicae, tract of Edinger). The fibers of the ventral trigeminal tract (ventral trigeminothalamic tract, anterior trigeminal tract, or anterior trigeminothalamic tract) are almost completely missing in their transverse course on the left and in their continuation on the right. (Source: Wallenberg A. Anatomischer Befund in einem als “acute Bulbär-aVection [Embolie der Art. cerebellar. post. inf. sinistr?]” bescreidenen Falle. Archiv für Psychiatrie und Nervenkrankheiten 1901;34:923-59. Edited by Dr. Douglas J Lanska.)

An area of infarction is evident in the left lateral medulla. This section contains the largest transverse diameter of the lateral medullary infarction. The softening focus has the shape of an irregular ellipse with the largest axis in the ventrolateral-dorsomedial direction. Among the involved areas mentioned by Wallenberg were the lateral half of the left dorsal accessory olivary nucleus; lateral reticular nucleus (nucleus lateralis medullae); cells of the reticular formation (formatio reticularis grisea); the nucleus ambiguus; internal arcuate fibers (fibrae arcuatae internae) from the nucleus cuneatus (Burdach nucleus); the ventral two-thirds of the spinal trigeminal tract and nucleus; vagus nerve fibers passing through the spinal trigeminal tract and nucleus; dorsal spinocerebellar fibers to the restiform body (corpus restiforme; inferior cerebellar peduncle); anterior spinocerebellar tract (ventral spinocerebellar tract; tractus spinocerebellaris ventralis; Gowers’ bundle); spinotectal fibers (spinomesencephalic fibers; fibrae spinotectales) and spinothalamic tract (spinothalamicae, tract of Edinger); rubrospinal tract (Monakow’s bundle); fibers descending from Deiters’ nucleus to the anterior column of the spinal cord; and anterior external arcuate fibers (ventral external arcuate fibers; fibrae arcuatae externae ventrales) from the right dorsal column nuclei (especially Goll’s) to the left restiform body (corpus restiforme; inferior cerebellar peduncle). (Source: Wallenberg A. Anatomischer Befund in einem als “acute Bulbär-aVection [Embolie der Art. cerebellar. post. inf. sinistr?]” bescreidenen Falle. Archiv für Psychiatrie und Nervenkrankheiten 1901;34:923-59. Edited by Dr. Douglas J Lanska.)

An area of infarction is evident in the left lateral medulla. The area of infarction extends further medially. Destroyed here are, in addition to the long (spinotectal and spinothalamic) tracts of the lateral medulla, the most lateral internal arcuate fibers (fibrae arcuatae internae), the cerebello-olivary fibers (fibrae cerebello-olivares), the dorsal and ventral spino-cerebellar tracts (fibrae spino-cerebellares dorsales et ventrales), the ventral two-thirds of the spinal trigeminal nucleus, lateral parts of the nucleus ambiguous near its caudal end and the nucleus lateralis medullae (nucleus reticularis lateralis), and finally the most caudal vagus fibers as they pass through the spinal trigeminal nucleus. The narrow, unmyelinated layer extending dorsally along the restiform body (corpus restiforme; inferior cerebellar peduncle) can be partly described as secondary degeneration. (Source: Wallenberg A. Anatomischer Befund in einem als “acute Bulbär-aVection [Embolie der Art. cerebellar. post. inf. sinistr?]” bescreidenen Falle. Archiv für Psychiatrie und Nervenkrankheiten 1901;34:923-59. Edited by Dr. Douglas J Lanska.)

An area of infarction is evident in the left lateral medulla. The area of infarction extends from the lateral surface inwards as far as the lateral internal arcuate fibers (fibrae arcuatae internae). In the dorsoventral direction, it covers the area between the dorsal marrow of the olive and the dorsal third of the left spinal trigeminal nucleus and tract. (Source: Wallenberg A. Anatomischer Befund in einem als “acute Bulbär-aVection [Embolie der Art. cerebellar. post. inf. sinistr?]” bescreidenen Falle. Archiv für Psychiatrie und Nervenkrankheiten 1901;34:923-59. Edited by Dr. Douglas J Lanska.)

From the 1901 autopsy of Adolf Wallenberg's 1895 case of lateral medullary syndrome. The left posterior inferior cerebellar artery (on the left side of the figure) is nearly occluded with a thrombus. (Source: Wallenberg A. Anatomischer Befund in einem als “acute Bulbär-aVection [Embolie der Art. cerebellar. post. inf. sinistr?]” bescreidenen Falle. Archiv für Psychiatrie und Nervenkrankheiten 1901;34:923-59. Edited by Dr. Douglas J Lanska.)

Areas of atherosclerotic plaque shown from the 1901 autopsy of Adolf Wallenberg's 1895 case of lateral medullary syndrome. (Source: Wallenberg A. Anatomischer Befund in einem als “acute Bulbär-aVection [Embolie der Art. cerebellar. post. inf. sinistr?]” bescreidenen Falle. Archiv für Psychiatrie und Nervenkrankheiten 1901;34:923-59. Edited by Dr. Douglas J Lanska.)

This drawing illustrated extensive atherosclerotic disease. (Source: Wallenberg A. Anatomischer Befund in einem als “acute Bulbär-aVection [Embolie der Art. cerebellar. post. inf. sinistr?]” bescreidenen Falle. Archiv für Psychiatrie und Nervenkrankheiten 1901;34:923-59. Edited by Dr. Douglas J Lanska.)

The double-hatched areas in the diagram indicate those regions where deeper pinpricks can still be felt as the head, and temperature differences of 30° to 40° C cannot be recognized. In the single but closely hatched areas, the tip and head can be perceived when pressed firmly, temperature differences of 20° to 30° C. Finally, in the more hatched areas, the sensitivity anomalies have almost disappeared (however, there are still clear differences compared to the same areas on the other side). (Source: Wallenberg A. Anatomischer Befund in einem als “acute Bulbär-aVection [Embolie der Art. cerebellar. post. inf. sinistr?]” bescreidenen Falle. Archiv für Psychiatrie und Nervenkrankheiten 1901;34:923-59. Edited by Dr. Douglas J Lanska.)

Sensation of pain or differentiation between the tip and head of a pin. The double-hatched areas indicate those regions where deeper pinpricks can still be felt as the head, and temperature differences of 30° to 40° C cannot be recognized. In the single but closely hatched areas, the tip and head can be perceived when pressed firmly, with temperature differences of 20° to 30° C. Finally, in the more hatched areas, the sensitivity anomalies have almost disappeared (however, there are still clear differences compared to the same areas on the other side). (Source: Wallenberg A. Anatomischer Befund in einem als “acute Bulbär-aVection [Embolie der Art. cerebellar. post. inf. sinistr?]” bescreidenen Falle. Archiv für Psychiatrie und Nervenkrankheiten 1901;34:923-59. Edited by Dr. Douglas J Lanska.)

Henry Hun's case of lateral medullary syndrome (1897), 4 years before the pathology from Wallenberg's case was published. Diagram of the nerve tracts and nuclei destroyed by the foci of softening. The sensory and coordinating fiber tracts are purposefully drawn out of their course in order that they shall not pass across the dark nuclei and thus lead to confusion. (Source: Hun H. Analgesia, thermic anaesthesia, and ataxia, resulting from foci of softening in the medulla oblongata and cerebellum, due to occlusion of the left inferior posterior cerebellar artery. A study of the course of the sensory and co-ordinating tracts in the medulla oblongata. N Y Med J 1897;65:513-9.)

Henry Hun's case of lateral medullary syndrome (1897), 4 years before the pathology from Wallenberg's case was published. Diagram of a section through the isthmus just above the junction of the medulla and pons. (Source: Hun H. Analgesia, thermic anaesthesia, and ataxia, resulting from foci of softening in the medulla oblongata and cerebellum, due to occlusion of the left inferior posterior cerebellar artery. A study of the course of the sensory and co-ordinating tracts in the medulla oblongata. N Y Med J 1897;65:513-9.)

Henry Hun's case of lateral medullary syndrome (1897), 4 years before the pathology from Wallenberg's case was published. Diagram of section of the medulla at the beginning of the sensory decussation. LTD, degenerated fibers of the descending cerebellar tract of Marchi; V, degenerated fibers of the descending root of the fifth nerve; S, substantia gelatinosa. (Source: Hun H. Analgesia, thermic anaesthesia, and ataxia, resulting from foci of softening in the medulla oblongata and cerebellum, due to occlusion of the left inferior posterior cerebellar artery. A study of the course of the sensory and co-ordinating tracts in the medulla oblongata. N Y Med J 1897;65:513-9. Edited by Dr. Douglas J Lanska.)

Henry Hun's case of lateral medullary syndrome (1897), 4 years before the pathology from Wallenberg's case was published. Diagram of the medulla at a level near the caudal end of the fourth ventricle. The shading represents the degenerated areas. (Source: Hun H. Analgesia, thermic anaesthesia, and ataxia, resulting from foci of softening in the medulla oblongata and cerebellum, due to occlusion of the left inferior posterior cerebellar artery. A study of the course of the sensory and co-ordinating tracts in the medulla oblongata. N Y Med J 1897;65:513-9.)

Henry Hun's case of lateral medullary syndrome (1897), 4 years before the pathology from Wallenberg's case was published. A section through the medulla oblongata at the level of the cochlear nerves. This shows degeneration of both anterior pyramids, especially of the right, and of the stratum zonale and hilum of each olive W and Z, also of the lateral portion of the left formatio reticularis and of the left corpus restiforme. The direct sensory cerebellar tract is represented by S, K, B; Deiters's nucleus by D, C; the descending vestibular olivary tract by y y; the descending vestibular spinal tract by x x; and the descending root of the fifth nerve by V Desc. (Source: Hun H. Analgesia, thermic anaesthesia, and ataxia, resulting from foci of softening in the medulla oblongata and cerebellum, due to occlusion of the left inferior posterior cerebellar artery. A study of the course of the sensory and co-ordinating tracts in the medulla oblongata. N Y Med J 1897;65:513-9. Edited by Dr. Douglas J Lanska.)

Henry Hun's case of lateral medullary syndrome (1897), 4 years before the pathology from Wallenberg's case was published. A section through the medulla oblongata at the level of the beginning of the sensory decussation. This shows degeneration of the fibers of the left descending root of the fifth nerve, V, while on the right side, these fibers are healthy, G. The substantia gelatinosa on the left side is not greatly degenerated. There is degeneration of the descending cerebellar tract of Marchi, L, T, and D, and of the right anterior pyramid. (Source: Hun H. Analgesia, thermic anaesthesia, and ataxia, resulting from foci of softening in the medulla oblongata and cerebellum, due to occlusion of the left inferior posterior cerebellar artery. A study of the course of the sensory and co-ordinating tracts in the medulla oblongata. N Y Med J 1897;65:513-9. Edited by Dr. Douglas J Lanska.)

Henry Hun's case of lateral medullary syndrome (1897), 4 years before the pathology from Wallenberg's case was published. A section through the medulla oblongata at a level near the caudal end of the fourth ventricle. This shows the undegenerated tracts of Flechsig and Gowers and degenerations in the lateral portion of the formatio reticularis on the left side, in the descending root of the left fifth nerve, surrounding both olives, and to a lesser degree in the right anterior pyramid. (Source: Hun H. Analgesia, thermic anaesthesia, and ataxia, resulting from foci of softening in the medulla oblongata and cerebellum, due to occlusion of the left inferior posterior cerebellar artery. A study of the course of the sensory and co-ordinating tracts in the medulla oblongata. N Y Med J 1897;65:513-9. Edited by Dr. Douglas J Lanska.)

Henry Hun's case of lateral medullary syndrome (1897), 4 years before the pathology from Wallenberg's case was published. Diagram of cerebellum, showing foci of softening in corpus dentatum. (Source: Hun H. Analgesia, thermic anaesthesia, and ataxia, resulting from foci of softening in the medulla oblongata and cerebellum, due to occlusion of the left inferior posterior cerebellar artery. A study of the course of the sensory and co-ordinating tracts in the medulla oblongata. N Y Med J 1897;65:513-9. Edited by Dr. Douglas J Lanska.)

Henry Hun's case of lateral medullary syndrome (1897), 4 years before the pathology from Wallenberg's case was published. Diagram of the right crus cerebri, showing the ascending degeneration in the “pes." (Source: Hun H. Analgesia, thermic anaesthesia, and ataxia, resulting from foci of softening in the medulla oblongata and cerebellum, due to occlusion of the left inferior posterior cerebellar artery. A study of the course of the sensory and co-ordinating tracts in the medulla oblongata. N Y Med J 1897;65:513-9.)

Henry Hun's case of lateral medullary syndrome (1897), 4 years before the pathology from Wallenberg's case was published. Diagram of focus of softening in the pons Varolii at a level just above the entrance of the fifth nerve. The area of softening is included within the dotted line a a a. (Source: Hun H. Analgesia, thermic anaesthesia, and ataxia, resulting from foci of softening in the medulla oblongata and cerebellum, due to occlusion of the left inferior posterior cerebellar artery. A study of the course of the sensory and co-ordinating tracts in the medulla oblongata. N Y Med J 1897;65:513-9.)

Henry Hun's case of lateral medullary syndrome (1897), 4 years before the pathology from Wallenberg's case was published. Diagram of the medulla near the lower level of the lesion, showing the nuclei destroyed by the focus of softening. The area of softening is included within the dotted line a a a. (Source: Hun H. Analgesia, thermic anaesthesia, and ataxia, resulting from foci of softening in the medulla oblongata and cerebellum, due to occlusion of the left inferior posterior cerebellar artery. A study of the course of the sensory and co-ordinating tracts in the medulla oblongata. N Y Med J 1897;65:513-9.)

Henry Hun's case of lateral medullary syndrome (1897), 4 years before the pathology from Wallenberg's case was published. Diagram of the medulla at the level of the greatest extent of the lesion, showing the nerve-fiber tracts destroyed by the latter. The area of softening is included within the dotted line a a a. (Source: Hun H. Analgesia, thermic anaesthesia, and ataxia, resulting from foci of softening in the medulla oblongata and cerebellum, due to occlusion of the left inferior posterior cerebellar artery. A study of the course of the sensory and co-ordinating tracts in the medulla oblongata. N Y Med J 1897;65:513-9.)

Henry Hun's case of lateral medullary syndrome (1897), 4 years before the pathology from Wallenberg's case was published. Diagram of the medulla near the lower level of the lesion, showing the nerve-fiber tracts destroyed by the latter. The area of softening is included within the dotted line a a a. (Source: Hun H. Analgesia, thermic anaesthesia, and ataxia, resulting from foci of softening in the medulla oblongata and cerebellum, due to occlusion of the left inferior posterior cerebellar artery. A study of the course of the sensory and co-ordinating tracts in the medulla oblongata. N Y Med J 1897;65:513-9.)

Henry Hun's case of lateral medullary syndrome (1897), 4 years before the pathology from Wallenberg's case was published. Represents a section through the medulla oblongata in a plane corresponding to the upper vagus or glossopharyngeal roots, and 2 or 3 mm candad to the plane of junction of the pons and medulla. The focus of softening is shown at X, and areas of degeneration are shown surrounding and within both olivary bodies. The section is not strictly transverse, the right side being slightly cephalad to the left. The anterior pyramids became detached from this section and are not represented. (Source: Hun H. Analgesia, thermic anaesthesia, and ataxia, resulting from foci of softening in the medulla oblongata and cerebellum, due to occlusion of the left inferior posterior cerebellar artery. A study of the course of the sensory and co-ordinating tracts in the medulla oblongata. N Y Med J 1897;65:513-9. Edited by Dr. Douglas J Lanska.)

(Source: Tilney F, Jelliffe SE, editors. Semi-centennial anniversary volume of the American Neurological Association 1875-1924. New York: American Neurological Association, 1924. The same photograph was also published in: Archambault L. Henry Hun: 1854-1924. Archives of Neurology and Psychiatry 1924;11[6]:711-5.)

Note the depressed left corner of the mouth and a flattening of the left nasolabial fold. "Complete paralysis of the left sixth and facial nerves (with inability to move the right eye towards the left) from an acute lesion on the left side of the pons. (Source: Gowers WR. A Manual of Diseases of the Nervous System. London: J & A Churchill, 1888.)

(Source: Revue annuelle illustrée des hôpitaux et hospices de la ville de Paris, 1922-1923. Paris: Edouard Ribaud, 1922-1923. Edited by Dr. Douglas J Lanska.)

Joseph Babinski (1857-1932) is supporting the patient with hysteria, Marie "Blanche" Wittman, while Jean-Martin Charcot (1825-1893) lectures. (Source: Musée d'histoire de la médecine, Paris. Public domain.)

(Source: Wellcome Collection, London, UK. Public domain.)

(Source: Photograph by E. Pirou, Paris. Courtesy of the Wellcome Collection, London, UK. Public domain mark. Edited by Dr. Douglas J Lanska.)

(Public domain.)

(Public domain.)

(Source: Courtesy of Robert Laureno MD. Edited by Dr. Douglas J Lanska.)

(Source: Tilney F, Jelliffe SE, editors. Semi-centennial anniversary volume of the American Neurological Association 1875-1924. New York: American Neurological Association, 1924.)

(Source: College of Physicians, Philadelphia. Courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. Public domain. Edited by Dr. Douglas J Lanska.)

The diagram was drawn by Dr. Nathan Beucler. (Source: Beucler N, Boissonneau S, Ruf A, Fuentes S, Carron R, Dufour H. Crossed brainstem syndrome revealing bleeding brainstem cavernous malformation: an illustrative case. BMC Neurol 2021;21[1]:204. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The responsible lesions for various brainstem syndromes are shown with colored ovals. The crossed neurologic symptoms observed in the Defoville (Foville) syndrome are shown in the lower pons. The diagram was drawn by Dr. Nathan Beucler. (Source: Beucler N, Boissonneau S, Ruf A, Fuentes S, Carron R, Dufour H. Crossed brainstem syndrome revealing bleeding brainstem cavernous malformation: an illustrative case. BMC Neurol 2021;21[1]:204. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Surgical sequences in a 65-year-old man with Defoville (Foville) syndrome caused by a medial pontine hematoma from a brainstem cavernous malformation. (A) Hockey stick fashion opening of the dura mater, discovering the cerebellar notch medially, and the left superior and inferior semilunar lobules. (B) The floor of the fourth ventricle appears after passing through the inferior medullary velum, and displays crucial anatomical landmarks including the striae medullares (SM), the infrafacial triangle (IFT) just above, and the hypoglossal triangle (HT) underneath. The exophytic hematoma appears on the left side at the level of the striae medullares. The cerebellar developmental venous anomaly (DVA) appears in blue under a thin layer of nervous tissue. (C) Evacuation of the pontine hematoma (H) at the level of the infrafacial triangle (IFT), just above the striae medullares (SM). The midline is marked with a dotted line. (D) En-bloc excision of the cavernous malformation (CAV) using a tumor’s clamp. (E) Resection cavity. (Source: Beucler N, Boissonneau S, Ruf A, Fuentes S, Carron R, Dufour H. Crossed brainstem syndrome revealing bleeding brainstem cavernous malformation: an illustrative case. BMC Neurol 2021;21[1]:204. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(A-C) T1-weighted sequence and (D) gradient-echo sequence. The cerebral MRI shows a brainstem cavernous malformation (A, white arrowhead), associated with a bilateral cerebellar developmental venous anomaly most prominent on the right side and draining into the vein of Galen (A-C, black arrowheads). The brainstem cavernous malformation was responsible for a medial pontine hematoma (B and D, black arrows). (Source: Beucler N, Boissonneau S, Ruf A, Fuentes S, Carron R, Dufour H. Crossed brainstem syndrome revealing bleeding brainstem cavernous malformation: an illustrative case. BMC Neurol 2021;21[1]:204. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Post-contrast T1-weighted sequence. A suboccipital telovelar approach was used to gain access to the rhomboid fossa (D). Then the infrafacial triangle was used as an entry point to the pons (C) to perform microsurgical excision of the BCM (A) and the pontine hematoma (B,C). The cerebellar developmental venous anomaly was left intact (A-D). (Source: Beucler N, Boissonneau S, Ruf A, Fuentes S, Carron R, Dufour H. Crossed brainstem syndrome revealing bleeding brainstem cavernous malformation: an illustrative case. BMC Neurol 2021;21[1]:204. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Note that he is pulling up on his pants to sustain holding his left leg off of the bed. (Source: Beucler N, Boissonneau S, Ruf A, Fuentes S, Carron R, Dufour H. Crossed brainstem syndrome revealing bleeding brainstem cavernous malformation: an illustrative case. BMC Neurol 2021;21[1]:204. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Note the black arrow showing the drift of the outstretched right arm. (Source: Beucler N, Boissonneau S, Ruf A, Fuentes S, Carron R, Dufour H. Crossed brainstem syndrome revealing bleeding brainstem cavernous malformation: an illustrative case. BMC Neurol 2021;21[1]:204. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Beucler N, Boissonneau S, Ruf A, Fuentes S, Carron R, Dufour H. Crossed brainstem syndrome revealing bleeding brainstem cavernous malformation: an illustrative case. BMC Neurol 2021;21[1]:204. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Beucler N, Boissonneau S, Ruf A, Fuentes S, Carron R, Dufour H. Crossed brainstem syndrome revealing bleeding brainstem cavernous malformation: an illustrative case. BMC Neurol 2021;21[1]:204. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Public domain.)

(Source: Zaorsky NG, Luo JJ. A case of classic Raymond syndrome. Case Rep Neurol Med 2012;2012:583123. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Zaorsky NG, Luo JJ. A case of classic Raymond syndrome. Case Rep Neurol Med 2012;2012:583123. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Brain MRI (3-Tesla) sagittal T1-weighted image from a 50-year-old man with classic Raymond syndrome. (Source: Zaorsky NG, Luo JJ. A case of classic Raymond syndrome. Case Rep Neurol Med 2012;2012:583123. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Brain MRI (3-Tesla) axial fluid-attenuated inversion recovery image from a 50-year-old man with classic Raymond syndrome. (Source: Zaorsky NG, Luo JJ. A case of classic Raymond syndrome. Case Rep Neurol Med 2012;2012:583123. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Brain MRI (3-Tesla) axial apparent diffusion coefficient image from a 50-year-old man with classic Raymond syndrome. (Source: Zaorsky NG, Luo JJ. A case of classic Raymond syndrome. Case Rep Neurol Med 2012;2012:583123. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Brain MRI (3-Tesla) axial diffusion-weighted image from a 50-year-old man with classic Raymond syndrome. (Source: Zaorsky NG, Luo JJ. A case of classic Raymond syndrome. Case Rep Neurol Med 2012;2012:583123. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Raymond F. Sur une variété particulière de paralysie alterne. In: E. Ricklin and A Souques, editors. Leçons sur les maladies du système nerveux [année 1894-1895] par F. Raymond. Première série. Paris: Octave Doin, 1896:365-83. Public domain.)

Raymond's original drawing of a cross-section of the caudal pons at the level where the abducens nerve fascicle traverses the basis pontis to enter the prepontine cistern. (Source: Raymond F. Sur une variété particulière de paralysie alterne. In: E. Ricklin and A Souques, editors. Leçons sur les maladies du système nerveux [année 1894-1895] par F. Raymond. Première série. Paris: Octave Doin, 1896:365-83. Public domain.)

(1) Motor cortex; (2) interhemispheric fissure; (3) anterior surface of the spinal cord; (4) corticobulbar fibers; (4') decussation of the corticobulbar fibers in the caudal pons (although Raymond localizes the decussation too far caudally) (Wolfe 1971); (5) bulbar nucleus and emerging nerve fibers; (6) corticospinal fibers; (6') decussation of the corticospinal fibers in the caudal medulla; (7) anterior horns of the spinal gray matter; (8) spinaI roots; (a) centrum semiovale; (b) internal capsule; (c) cerebral peduncle; (d) pons; (e) medulla; (f) spinal cord. (Source: Raymond F. Sur une variété particulière de paralysie alterne. In: E. Ricklin and A Souques, editors. Leçons sur les maladies du système nerveux [année 1894-1895] par F. Raymond. Première série. Paris: Octave Doin, 1896:365-83. Public domain.)

(Courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. Public domain.)

(Source: Photograph by Josef Löwy [1834-1902], Sport & Salon, December 27, 1902. Public domain.)

(Source: Bibliothèque interuniversitaire de Santé, Paris. Licence Ouverte/Open Licence.)

(Source: Wellcome Collection, London, UK. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Weltrundschau zu Reclams Universum. Leipzig: Philipp Reclam jun, 1913. Public domain.)

(Courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. Public domain.)

Sir Hermann David Weber was a German-born physician working in London, in 1902. Painting Hubert von Herkomer (1849-1914). (Courtesy of Bushey Museum and Art Gallery, Bushey, England. Public domain.)

In the schematic drawing, taste buds are indicated in brown. (Source: Illustration by Jonas Töle, 2014. Public domain dedication.)

(Source: Gray H, Lewis WH. Anatomy of the Human Body. Twentieth edition. Philadelphia and New York: Lea & Febiger, 1918. Public domain.)

Schematic drawing of a human fungiform papilla located on the tongue. Taste buds are indicated in brown. (Source: Illustration by Jonas Töle, 2014. Public domain dedication.)

Semidiagrammatic view of a portion of the mucous membrane of the tongue. Two fungiform papillae are shown. On some of the filiform papillae, the epithelial prolongations stand erect; in one they are spread out, and in three they are folded in. (Source: Gray H, Lewis WH. Anatomy of the Human Body. Twentieth edition. Philadelphia and New York: Lea & Febiger, 1918. Public domain.)

Magnified. (Source: Gray H, Lewis WH. Anatomy of the Human Body. Twentieth edition. Philadelphia and New York: Lea & Febiger, 1918. Public domain.)

(Source: Gray H, Lewis WH. Anatomy of the Human Body. Twentieth edition. Philadelphia and New York: Lea & Febiger, 1918. Public domain.)

A view of the right-sided middle ear space with the external ear canal, eardrum (tympanic membrane) and hearing bones (ossicles) removed, showing the course of the chorda tympani nerve. The observer is looking at the medial wall of the middle ear, as seen from a lateral viewpoint. The facial nerve is seen to pass horizontally in a path superior to the middle ear and then turn in an inferior direction and pass vertically posterior to the middle ear. The Eustachian tube extends anteriorly and is directed inferiorly as its path towards the throat (nasopharynx) extends further from the middle ear. The jugular fossa is inferior to the middle ear space. (Source: Illustration by Henry Vandyke Carter [1831-1897]. Gray H, Lewis WH. Anatomy of the Human Body. Twentieth edition. Philadelphia and New York: Lea & Febiger, 1918. Public domain.)

Scanning electron microscopic image by David Gregory and Debbie Marshall. (Courtesy of the Wellcome Collection, London, UK. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Scanning electron microscopic image by David Gregory and Debbie Marshall. (Courtesy of the Wellcome Collection, London, UK. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Scanning electron microscopic image by David Gregory and Debbie Marshall. (Courtesy of the Wellcome Collection, London, UK. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Scanning electron microscopic image by David Gregory and Debbie Marshall. (Courtesy of the Wellcome Collection, London, UK. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Dibner Library of the History of Science and Technology, Smithsonian Libraries. Public domain.)

(Courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. Public domain.)

From an album featuring portraits of all the members of the second chamber of the Swedish parliament elected in 1897. (Source: Wikimedia Commons. Public domain.)

The patient holds green spectacles in his left hand. The woman holds a cup with a spoon. Lettering: Der patient (Das Vertrauen). A patient (Confidence). (Source: F. Silber, Berlin, Germany. Courtesy of the Wellcome Library, London, UK. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

"Le docteur. _ Ah! ... si vous avez mangé du raisin tout s'explique: vous avez alors la maladie des pommes de terre dont le remède est encore inconnu ... tranquillisez-vous!" [“The doctor. _ Ah! ... if you have eaten grapes, everything is explained: you then have potato disease for which the cure is still unknown... don't worry!”]. (Courtesy of the Wellcome Library, London, UK. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0. Edited by Dr. Douglas J Lanska.)

A patient poking out his tongue and having his pulse taken by a physician. Watercolor by Cynicus. Martin Anderson (1854-1932), better known by his pseudonym Cynicus, was a Scottish artist, political cartoonist, postcard illustrator, and publisher. (Courtesy of the Wellcome Library, London, UK. Public domain.)

Photograph by Leopold Bude (1840-1907). (Source: University Archive of the Karl-Franzens University of Graz, Graz, Austria. Public domain.)

Painting by Carlo Cignani (1628-1719). (Source: Wikimedia Commons. Public domain.)

(Courtesy of the Bibliothèque interuniversitaire de Santé, Paris, France. Open License, version 1.0, fr.wikisource.org/wiki/Licence_Ouverte,_version_1.0.)

(Source: Wikimedia Commons. Public domain.)

Italian anatomist Giulio Casserio (Julius Casserius). (Courtesy of the Wellcome Library, London, UK. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Italian anatomist Giulio Cesare Casseri, also known as Julius Casserius, anatomist in Padua, possibly by Gijsbert van Veen, 1591. (Courtesy of the Rijkmuseum, Amsterdam, The Netherlands. Public domain.)

Cases selected were published since advent of CT in the mid-1970s (CT was introduced in the US in 1973), in English (not only as abstract), and met diagnostic criteria, including involvement of at least seven cranial nerves on one side, without long-tract signs, without increased intracranial pressure, and with evidence of skull erosion. Garcin sequence involves 7-11 cranial nerves on one side, whereas Garcin syndrome involves all 12. Documentation was often poor in these cases. Reported glossopharyngeal (CN IX) dysfunction is suspect in many, based on the inadequate documentation of how it was assessed; many seemed to believe that pharyngeal/gag abnormalities automatically indicated involvement of both cranial nerves IX and X. The Thakar (2012) case was included even though there was bilateral peripheral facial weakness. CNs = cranial nerves.

Under a magnification of 980X, this photomicrograph of a Gram-stained tissue sample, revealed the presence of mycelia from an unknown Mucor sp. fungal organism harvested from a patient ill with mucormycosis, otherwise known as zygomycosis. (Courtesy of the Public Health Image Library, Centers for Disease Control and Prevention. Photomicrograph by Dr. Lucille K. Georg, 1964. Public domain.)

Under a magnification of 945X, this photomicrograph of a hematoxylin-eosin (H&E) stained stomach tissue sample, revealed the presence of a mycelium from an unknown fungal organism, harvested from a patient ill with mucormycosis, otherwise known as zygomycosis. (Courtesy of the Public Health Image Library, Centers for Disease Control and Prevention. Photomicrograph by Dr. Lucille K. Georg, 1964. Public domain.)

This photomicrograph of a Giemsa-stained specimen, revealed the presence of a sporangium and its supportive columella from an unknown fungal organism in this mucosal tissue sample harvested from the ethmoid sinus of a patient ill with mucormycosis, otherwise known as zygomycosis. Rhinocerebral mucormycosis, also known as zygomycosis, is a rare disease caused by filamentous fungi that affect the nose, paranasal sinuses, and brain. (Courtesy of the Public Health Image Library, Centers for Disease Control and Prevention. Photomicrograph by Dr. Lucille K. Georg, 1964. Public domain.)

Under a magnification of 610X, this photomicrograph of a Gram-stained specimen, revealed the presence of a filamentous mycelium from a Rhizopus sp. fungal organism. The specimen was harvested from a patient ill with mucormycosis, otherwise known as zygomycosis. (Courtesy of the Public Health Image Library, Centers for Disease Control and Prevention. Photomicrograph by Dr. Lucille K. Georg, 1964. Public domain.)

Under a medium magnification, this photomicrograph of a hematoxylin-eosin (H&E)-stained specimen, revealed the presence of mycelial fungal filaments in this tissue sample, from a patient ill with mucormycosis (phycomycosis), otherwise known as a form of zygomycosis. (Courtesy of the Public Health Image Library, Centers for Disease Control and Prevention. Photomicrograph by Dr. Lucille K. Georg, 1968. Public domain.)

Intravascular large, irregular, non-septate hyphae; some with 90-degree branching from a patient with zygomycosis/mucormycosis. Source: Philip Kane, MD. Dr. Yale Rosen Atlas of Pulmonary Pathology | Flickr. Creative Commons Attribution 2.0 Generic [CC BY 2.0] license, creativecommons.org/licenses/by/2.0.)

Large, irregular, non-septate hyphae; some with 90-degree branching from a patient with zygomycosis/mucormycosis. Some hyphae are seen cut in cross section. Source: Dr. Yale Rosen Atlas of Pulmonary Pathology | Flickr. Creative Commons Attribution 2.0 Generic [CC BY 2.0] license, creativecommons.org/licenses/by/2.0.)

Large, irregular, non-septate hyphae; some with 90-degree branching from a patient with zygomycosis/mucormycosis. Some hyphae are seen cut in cross section. Source: Dr. Yale Rosen Atlas of Pulmonary Pathology | Flickr. Creative Commons Attribution 2.0 Generic [CC BY 2.0] license, creativecommons.org/licenses/by/2.0.)

Large, irregular, non-septate hyphae; some with 90-degree branching from a patient with zygomycosis/mucormycosis. Some hyphae are seen cut in cross section. Source: Dr. Yale Rosen Atlas of Pulmonary Pathology | Flickr. Creative Commons Attribution 2.0 Generic [CC BY 2.0] license, creativecommons.org/licenses/by/2.0.)

The pictures illustrate the non-septate, wide ribbon shape of mucormycotic hyphae observed in a potassium hydroxide (KOH 20%) preparation under 400x magnification. The arrows mark the rectangular divisions of hyphae. The outlines of mucormycotic hyphae were outlined by a white line. (Source: Yang H, Wang C. Looks like Tuberculous Meningitis, But Not: A Case of Rhinocerebral Mucormycosis with Garcin Syndrome. Front Neurol 2016;7:181. Slightly cropped from original. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The pictures illustrate the non-septate, wide ribbon shape of mucormycotic hyphae observed in a potassium hydroxide (KOH 20%) preparation under 400x magnification. The arrows mark the rectangular divisions of hyphae. (Source: Yang H, Wang C. Looks like Tuberculous Meningitis, But Not: A Case of Rhinocerebral Mucormycosis with Garcin Syndrome. Front Neurol 2016;7:181. Slightly cropped from original. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Under a magnification of 600X, this photomicrograph revealed ultrastructural morphology exhibited by an immature sporangium of the fungal organism, Rhizopus oryzae, also known as Rhizopus arrhizus var. delemar. This specimen was isolated from a patient with a case of phycomycosis (mucormycosis), a form of zygomycosis. (Courtesy of the Public Health Image Library, Centers for Disease Control and Prevention. Photomicrograph by Dr. Lucille K. Georg, 1968. Public domain.)

Under a magnification of 120X, this photomicrograph revealed ultrastructural morphology exhibited by a columella of the fungal organism, Rhizopus oryzae, also known as Rhizopus arrhizus var. delemar. This organism is known to be an opportunistic pathogen in humans causing the disease known as mucormycosis, otherwise known as zygomycosis. (Courtesy of the Public Health Image Library, Centers for Disease Control and Prevention. Photograph by Dr. Libero Ajello, 1964. Public domain.)

Under a magnification of 600X, this photomicrograph revealed ultrastructural morphology exhibited by an immature sporangium of the fungal organism, Rhizopus oryzae, also known as Rhizopus arrhizus var. delemar. This specimen was isolated from a patient with a case of phycomycosis (mucormycosis), a form of zygomycosis. (Courtesy of the Public Health Image Library, Centers for Disease Control and Prevention. Photomicrograph by Dr. Lucille K. Georg, 1968. Public domain.)

This image depicts an anterior view of a patient’s face, which displayed the morphologic changes in the facial symmetry due to a zygomycotic infection, caused by the fungal organism, Rhizopus arrhizus. Zygomycosis is also known as mucormycosis, and in this case, involved the patient’s right eye region causing a drooping of the upper eyelid (ptosis) and the right side of the face (peripheral facial paresis), and the expression of an ophthalmic exudate. (Courtesy of the Public Health Image Library, Centers for Disease Control and Prevention. Photomicrograph by Dr. Lucille K. Georg, 1967. Public domain.)

This patient presented with a rhinocerebral mucormycosis infection of her face, caused by the fungal organism, Rhizopus arrhizus. Note the left eye proptosis, as well as ocular misalignment. The patient is being asked to look to the right, demonstrating medial rectus weakness on the left. In combination with the clinical setting and the patient's ptosis, she probably had an oculomotor nerve palsy (among other cranial nerve deficits). (Courtesy of the Public Health Image Library, Centers for Disease Control and Prevention. Photograph by Dr. Libero Ajello, 1961. Public domain.)

Captured in a clinical setting, this patient presented with a rhinocerebral mucormycosis infection of her face, caused by the fungal organism, Rhizopus arrhizus. Note the left eye proptosis, with accompanying ptosis of the upper lid, and generalized palpebral swelling and erythema. Also note the decreased wrinkles on the left forehead and the depressed nasolabial fold and depressed corner of the mouth on the left, indicating left peripheral facial paresis. (Courtesy of the Public Health Image Library, Centers for Disease Control and Prevention. Photograph by Dr. Libero Ajello, 1961. Public domain.)

This patient presented with a case of a periorbital fungal infection known as mucormycosis, or phycomycosis, caused by a member of the order, Mucorales. Mucormycosis is a dangerous fungal infection usually occurring in the immunocompromised patient, affecting the regions of the eye and nose, and through its growth and destruction of the periorbital tissues can eventually invade the brain cavity. (Courtesy of the Public Health Image Library, Centers for Disease Control and Prevention. Photograph by Dr. Libero Ajello, 1961. Public domain.)

This image depicts an anterior view of a patient in Nigeria, ill with the fungal infection known as mucormycosis (phycomycosis), a form of zygomycosis. In this specific patient’s case, the disease was classified as rhino-phycomycosis, having affected the nose, nasal airways, and sinuses, as well as the subcutaneous tissues of the maxilla, and upper lip, producing the distorted facial symmetry you see in this view. (Courtesy of the Public Health Image Library, Centers for Disease Control and Prevention. Photomicrograph by Dr. Lucille K Georg, 1966. Public domain.)

Photograph reproduced from Piasecki E. Higiena Szkolna. Warszawa, Lublin, Wilno, Nasza Księgarnia, 1939. Also reproduced in (Cisińska A. Stanisław Kopczyński--internista i neurolog, pionier higieny szkolnej w Polsce [Stanisław Kopczyński, a specialist in internal medicine and neurology--pioneer of school sanitary sciences in Poland]. Pol Arch Med Wewn 2007;117(10):477-8.)

Photograph of the skull base at autopsy, showing the extent of tumor (fibrosarcoma) extension evident. The white line shows the location of the tumor (it was changed from the less obvious black line used in the original illustration). (Source: Yaver S. Sur un cas de sarcome de la base du crâne [In a case of skull base sarcoma]. Xe congrès international d'otologie, Paris, 19-22 juillet 1922.Tome II. Comptes-Rendus des Séances. Paris: Librairie Octave Doin, 1923:791-9.)

Schematic diagram of the extent of tumor (fibrosarcoma) extension evident by gross examination of the skull base at autopsy. (Source: Yaver S. Sur un cas de sarcome de la base du crâne [In a case of skull base sarcoma]. Xe congrès international d'otologie, Paris, 19-22 juillet 1922.Tome II. Comptes-Rendus des Séances. Paris: Librairie Octave Doin, 1923:791-9.)

Patient was unable to whistle due to left peripheral facial palsy. (Source: Yaver S. Sur un cas de sarcome de la base du crâne [In a case of skull base sarcoma]. Xe congrès international d'otologie, Paris, 19-22 juillet 1922.Tome II. Comptes-Rendus des Séances. Paris: Librairie Octave Doin, 1923:791-9.)

Ten weeks later after initial diplopia presentation the patient’s condition had progressed to include left ptosis, complete anesthesia of the entire left face and cornea, internal and external ophthalmoplegia of the left eye, left peripheral facial palsy, left-sided deafness, and partial paralysis of the soft palate and tongue on the left. Notice the obvious complete ptosis on the left, as well as more subtle lessening of forehead wrinkles on the left, and a slightly decreased corner of the mouth on that side. (Source: Yaver S. Sur un cas de sarcome de la base du crâne [In a case of skull base sarcoma]. Xe congrès international d'otologie, Paris, 19-22 juillet 1922.Tome II. Comptes-Rendus des Séances. Paris: Librairie Octave Doin, 1923:791-9.)

65-year-old man with complaints of diplopia showing normal gaze to the right. (Source: Yaver S. Sur un cas de sarcome de la base du crâne [In a case of skull base sarcoma]. Xe congrès international d'otologie, Paris, 19-22 juillet 1922.Tome II. Comptes-Rendus des Séances. Paris: Librairie Octave Doin, 1923:791-9.)

65-year-old man with complaints of diplopia showing impaired abduction of the left eye with gaze to the left, consistent with a left abducens nerve palsy. (Source: Yaver S. Sur un cas de sarcome de la base du crâne [In a case of skull base sarcoma]. Xe congrès international d'otologie, Paris, 19-22 juillet 1922.Tome II. Comptes-Rendus des Séances. Paris: Librairie Octave Doin, 1923:791-9.)

Yaver was one of the five founding members of the Turkish Otorhinolaryngology Society in İstanbul on May 8, 1930 (Tanyeri Y. The Foundation story of Turkish Archives of Otorhinolaryngology. Turkish Archives of Otorhinolaryngology 2015;53:1-3). (Source: KBB EFEMERASI (39) dr. sani yaver'den meslektaşına bilgi notu. Accessed January 28, 2024.)

"What is immediately striking in this patient is the right ptosis accompanying total right (peripheral) facial paralysis." (Contributed by Dr. Douglas Lanska.)

Cross section of the pons with Weigert-Pal staining. The tumor grew slowly, pushing back the different nerve bundles. (Contributed by Dr. Douglas Lanska.)

Note the tongue deviation to the left (left hypoglossal palsy) and the asymmetry of the palpebral fissures and nasolabial folds (left peripheral facial palsy). The right eye is not well visualized in this photograph, so no strabismus is shown although the patient was noted to have left abducens paresis. (Contributed by Dr. Douglas Lanska.)

(Source: Banque d'images de la Bibliothèque interuniversitaire de santé: CIPB1710. Licence Ouverte 1.0.)

A 64-year-old man with a sarcoma progressively eroding the left skull base and causing dysfunction of all cranial nerves on one side. Two extensions of the basilar tumor are shown by the dotted lines. (Contributed by Dr. Douglas Lanska.)

X-ray of the right petrous temporal bone in the Stenvers position enhanced with gouache (semi-schematic). Note the marked decalcification of the anterior 2/3 of the right petrous temporal bone. (Contributed by Dr. Douglas Lanska.)

X-rays of the left petrous temporal bone in the Stenvers position. This is actually a semi-schematic image that was enhanced with gouache (ie, opaque pigments ground in water and thickened with a gluelike substance). Note the erosion of the left petrous pyramid. (Contributed by Dr. Douglas Lanska.)

(Creative Commons Attribution 1.0 Generic [CC BY 1.0] license, creativecommons.org/licenses/by/1.0.)

(Source: L'informateur des aliénistes et des neurologistes. Paris: Delarue, 1923.)

(Source: Banque d'images de la Bibliothèque interuniversitaire de santé : CIPB1710. Licence Ouverte 1.0.)

Workers pose in 1891 with a 100-hp Westinghouse synchronous alternator at the Ames power plant located near Ophir, Colorado. At the time, it was the largest alternator Westinghouse made. It was used as a generator, connected by a belt drive to a 6-foot Pelton water wheel driven by water from the San Miguel River. It produced a 3000-volt, 133-Hertz, single-phase alternating current to drive a similar alternator connected by copper power lines 2.6 miles long that acted as a motor to drive a stamp mill at the Gold King Mine. It replaced an existing steam mill that was difficult to run because of a lack of timber to use as fuel. (Source: Wikimedia Commons. Public domain.)

U.S. Patent 373035 to George Westinghouse, 1887. (Source: Wikimedia Commons. Public domain.)

From an 1888 catalog. (Source: Wikimedia Commons. Public domain.)

(Source: Wikimedia Commons. Public domain.)

Nikola Tesla's AC dynamo-electric machine (AC electric generator) in an 1888 U.S. patent 390,721. (Source: Wikimedia Commons. Public domain.)

Drawing from an 1887 U.S. patent 381,968, illustrating the principle of Tesla's alternating current induction motor. (Source: Wikimedia Commons. Public domain.)

A drawing of Serbian-American electrical engineer Nikola Tesla illuminated by electrical discharges created by touching the high voltage terminal of his Tesla coil oscillator, from an illustration accompanying an 1894 interview with him in the New York World newspaper. A charismatic showman, during the period 1891-1894, Tesla gave a series of dramatic public demonstrations of the new technology of high-frequency, high-voltage electricity that made him internationally famous. He had discovered that the high-frequency current produced by his Tesla coil did not cause the sensation of electric shock that lower frequencies or direct current produced and, in fact, that currents lethal at lower frequencies could be passed through his body without apparent harm. During demonstrations, he would charge his body with hundreds of thousands of volts from his coils, causing a glowing corona discharge aura to surround his body, as shown here, and brush discharges to spark from his fingers. (Source: Arthur Brisbane, "Our Foremost Electrician" in New York World newspaper, Sunday, July 22, 1894, p 17. Public domain. Edited by Dr. Douglas J Lanska.)

Serbian-American inventor and electrical engineer Nikola Tesla. (Source: Photograph by Napoleon Sarony (1821-1896). Source: Wikimedia Commons. Public domain.)

Topsy elephant put to death by electrocution at "Luna Park," a Coney Island amusement park, in 1903. A press photograph from the January 4, 1903, electrocution of Topsy the elephant in an event to raise publicity about the opening of the new Coney Island amusement park "Luna Park," which was still under construction. The photograph was taken just when 6600 volts of electricity was turned on. Behind Topsy is the bridge over the lagoon of the "Shoot the Chutes" ride to an island in the middle. On the island is the unfinished "Electric Tower" with a sign advertising "OPENING MAY 2ND 1903 LUNA PARK $1,000,000 EXPOSITION, THE HEART OF CONEY ISLAND," and "FOUNDATION OF 200FT ELECTRIC TOWER" in the background. (Source: Wikimedia Commons. Public domain.)

Print shows New York politician John ("Honest John") Kelly trying to bring Tammany Hall back to life by turning an electrical apparatus labeled "Deal with the Republicans" connected to an "Anti-Monopoly" device, then with wires spelling "Patronage" to a rod held by a man dressed as a Native American lying in a coffin labeled "Tammany Died 1880"; the jolt of electricity knocks the moccasins off his feet. (Source: Political cartoon by Friedrich Graetz (c1849-c1913) from Puck 40(273), May 31, 1882. Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain. Edited by Dr. Douglas J Lanska.)

(Source: Wikimedia Commons. GNU Free Documentation License. Edited by Dr. Douglas J Lanska.)

Photolithography reproduction. US patent application 223898, Thomas Alva Edison, "Electric lamp." (Source: Wikimedia Commons. Public domain. Edited by Dr. Douglas J Lanska.)

(Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain.)

Illustration from the frontispiece of the 1831 edition. Steel engraving (993 x 71 mm) by Theodore Von Holst (1810-1844) for the revised edition of Frankenstein by Mary Shelley (1797-1851), published by Colburn and Bentley, London 1831. The novel was first published in 1818. (Source: Tate Britain. Courtesy of Wikimedia Commons. Public domain. Edited by Dr. Douglas J Lanska.)

Movieland Wax Museum in Niagara Falls, Canada. (Source: Photograph by Diego Torres Silvestre. Creative Commons Attribution 2.0 Generic [CC BY 2.0] license, creativecommons.org/licenses/by/2.0. Edited by Dr. Douglas J Lanska.)

Hand-colored lithograph. In an image inspired by Aldini's experiments, the Jacksonian editor Francis Preston Blair rises from his coffin, revived by a primitive galvanic battery. He is shown with two demons and another man (possibly Amos Kendall).

One demon cries in frustration: "There! We've lost him after all! See! They are bringing him to life again!" The other demon replies: "Lose him! ha ha! No, no, no, Horny. Rest you easy on that score. But can't you see that it's all for our gain that he should be galvanized into activity again? Where have we his equal on earth? especially since dear Amos, poor fellow, has got his hands so full, at the Post Office that he can't write for us as he used to. Show me another man that can lie like him. They talk of Croswell, but Harris is nothing to him. I doubt if I can beat him myself. Lose him! a good joke that!" The man standing nearby remarks: "Had I not been born insensible to fear, now should I be most horribly afraid. Hence! horrible shadows! unreal mockery. Hence! And yet it stays — can it be real [?] How it grins! Hoe malignity and venom are "blended in cadaverous [sic] union in its countenance! It must surely be "a galvanised" corpse. But what do I feel? The thing begins to draw me. I feel it plainly — and now it winks at me — Oh! I'm lost! I can't withstand it — I shall hug it! I shall hug it! — Oh yes I shall hug-hug-hug it..... [Faints, and falls on the neck of the Corpse.]

Credit: The Elisha Whittelsey Collection, The Elisha Whittelsey Fund and Harris Brisbane Dick Fund, by Exchange, 1970. (Source. The Metropolitan Museum of Art, New York. Public domain. Edited by Dr. Douglas J Lanska.)

Lithograph F Mauraisse (opera originale). Lithography by de Lemercier. (Source: Archivio storico dell'Accademia delle Scienze di Torino. Public domain.)

Stipple engraving by Italian reproductive engraver and etcher Luigi Schiavonetti (April 1, 1765-June 7, 1810) after Pierre-Noël Violet (1749-1819). (Courtesy of the Wellcome Collection, London, UK. Public domain. Edited by Dr. Douglas J Lanska.)

Stipple engraving by L Rados, 1828, after R Focosi. Volta is shown in his laboratory. A voltaic pile is in the background on the right. (Courtesy of the Wellcome Collection, London, UK. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0. Edited by Dr. Douglas J Lanska.)

(Courtesy of the Wellcome Collection, London, UK. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Courtesy of the Wellcome Collection, London, UK. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Courtesy of the Wellcome Collection, London, UK. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Courtesy of the Wellcome Collection, London, UK. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Courtesy of the Wellcome Collection, London, UK. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The plate is broken. (Courtesy of the Wellcome Collection, London, UK. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Plate electrical machine, believed to have been used by Luigi Galvani in some of his frog experiments (the glass plate is not the original). (Source: Courtesy of the Wellcome Collection, London, UK. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Luigi Galvani discovered that frog legs twitch when electricity is passed through the muscles, a phenomenon called galvanism that led to the subject of electrophysiology and treatment by electrotherapy. (Source: Wells DA. The Science of Common Things: a Familiar Explanation of the First Principles of Physical Science. New York: Ivison, Phinney, Blakeman, 1859. Public domain.)

Oil painting by an unidentified painter between the 18th century and 19th century. (Source: Wikimedia Commons. Public domain.)

(Source: Winkler JH. The Stärke der Elektischen Kraft des Wassers in gläsernen Gefässen. Leipzig: Breitkopf, 1746. Public domain. Edited by Dr. Douglas J Lanska.)

(Source: Benjamin Franklin's “Experiments and Observations on Electricity,” 1751-3:487. Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain. Edited by Dr. Douglas J Lanska.)

Detail of the engraving of Benjamin Franklin by James McArdell after a painting by Benjamin Wilson. The image has been rotated to allow easy readability. (Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain. Edited by Dr. Douglas J Lanska.)

Engraved by James McArdell (approximately 1729-1765). Benjamin Franklin, in a half-length portrait, stands facing slightly left, holding a book, "Electric Expts"; scientific instruments are to his left, and in the background, lightning strikes a village. From a painting by Benjamin Wilson. Franklin sat for Wilson, who also experimented with electricity, shortly after his arrival in London. He worked in London as a foreign diplomat representing the Pennsylvania Assembly. (Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain. Edited by Dr. Douglas J Lanska.)

Mezzotint engraving by Henry S Sadd, 184-. (Printed by W Neale. Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain. Edited by Dr. Douglas J Lanska.)

Painting by Charles E Mills between 1900 and 1920. (Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain. Edited by Dr. Douglas J Lanska.)

Published between 1874 and 1888. (Source: Engravings of the American Banknote Company. Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain. Edited by Dr. Douglas J Lanska.)

(Source: GBD 2021 Carbon Monoxide Poisoning Collaborators. Global, regional, and national mortality due to unintentional carbon monoxide poisoning, 2000-2021: results from the Global Burden of Disease Study 2021. Lancet Public Health 2023;8[11]:e839-49. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: GBD 2021 Carbon Monoxide Poisoning Collaborators. Global, regional, and national mortality due to unintentional carbon monoxide poisoning, 2000-2021: results from the Global Burden of Disease Study 2021. Lancet Public Health 2023;8[11]:e839-49. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

GBD=Global Burden of Diseases, Injuries, and Risk Factors Study. (Source: GBD 2021 Carbon Monoxide Poisoning Collaborators. Global, regional, and national mortality due to unintentional carbon monoxide poisoning, 2000-2021: results from the Global Burden of Disease Study 2021. Lancet Public Health 2023;8[11]:e839-49. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Error bars represent the 95% uncertainty interval. YLLs=years of life lost. (Source: GBD 2021 Carbon Monoxide Poisoning Collaborators. Global, regional, and national mortality due to unintentional carbon monoxide poisoning, 2000-2021: results from the Global Burden of Disease Study 2021. Lancet Public Health 2023;8[11]:e839-49. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

GBD=Global Burden of Diseases, Injuries, and Risk Factors Study. (Source: GBD 2021 Carbon Monoxide Poisoning Collaborators. Global, regional, and national mortality due to unintentional carbon monoxide poisoning, 2000-2021: results from the Global Burden of Disease Study 2021. Lancet Public Health 2023;8[11]:e839-49. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Global age-standardized mortality rate and number of deaths due to unintentional carbon monoxide poisoning, 2000 to 2021. Shading indicates the upper and lower limits of the 95% uncertainty intervals. (Source: GBD 2021 Carbon Monoxide Poisoning Collaborators. Global, regional, and national mortality due to unintentional carbon monoxide poisoning, 2000-2021: results from the Global Burden of Disease Study 2021. Lancet Public Health 2023;8[11]:e839-49. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Age-standardized rates of intentional carbon monoxide poisoning hospital admissions by region across all the population (left), and among females (center) and males (right) in England between 2002 and 2016. Standardized using the 2013 European Standard Population. (Source: Roca-Barceló A, Crabbe H, Close R, Fahie H, Leonardi GS, Piel FB. Spatial and temporal trends and risk factors for intentional carbon monoxide poisoning hospitalizations in England between 2002 and 2016. J Affect Disord 2023;329:168-75. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Distribution of cases of carbon monoxide poisoning by month (%) in Adiyaman, Turkey, from 2012 to 2022. (Source: Öz E, Küçükkelepçe O, Kurt O, Vural A. Carbon monoxide poisoning: beyond survival - mortality, morbidities, and risk factors, a Turkey sample. PeerJ 2023;11:e16093. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Distribution of cases and deaths from carbon monoxide poisoning by age (%) in Adiyaman, Turkey, from 2012 to 2022. (Source: Öz E, Küçükkelepçe O, Kurt O, Vural A. Carbon monoxide poisoning: beyond survival - mortality, morbidities, and risk factors, a Turkey sample. PeerJ 2023;11:e16093. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Treatment strategies fall into three categories: gas exchange, carbon monoxide scavenging, and pharmacological mitigation. Normobaric oxygen therapy, hyperbaric oxygen therapy, and isocapnic hyperpnea therapy rely on gas exchange in the lungs with accelerated carbon monoxide clearance driven by increased oxygen partial pressure or ventilation. In addition, extracorporeal membrane oxygenation facilitates carbon monoxide clearance via gas exchange in cases of extreme illness or lung damage, and extracorporeal removal of carbon monoxide with phototherapy facilitates this clearance through carbon monoxide photolysis. Carbon monoxide-scavenging therapeutics, including hemoprotein-based scavengers and small molecule-based scavengers, may directly sequester carbon monoxide from circulating hemoglobin (Hb) or cellular hemoproteins. These scavengers undergo rapid renal clearance to safely eliminate both scavenger molecules and carbon monoxide. Finally, pharmacological compounds are being explored to mitigate pathophysiological damage incurred during acute carbon monoxide poisoning (eg, steroids, anti-inflammatory drugs, and mitochondrial electron transport chain substrates). Abbreviations: ECCOR-P, extracorporeal removal of carbon monoxide with phototherapy; ECMO, extracorporeal membrane oxygenation; HBOT, hyperbaric oxygen therapy; IH, isocapnic hyperpnea; NBOT, normobaric oxygen therapy. (Source: Dent MR, Rose JJ, Tejero J, Gladwin MT. Carbon monoxide poisoning: from microbes to therapeutics. Annu Rev Med 2024;75:337-51. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

In circulating red blood cells, carbon monoxide binds to heme sites in hemoglobin, diminishing oxygen-carrying capacity and stabilizing the high-affinity R-state. In addition to binding hemoglobin in circulation, carbon monoxide may also bind myoglobin, causing a reduction in oxygen availability in tissue. In mitochondria, carbon monoxide may directly bind the heme a₃ site in complex IV of the mitochondrial electron transport chain, inhibiting the reduction of oxygen to water. This inhibition, coupled with reduced oxygen availability, leads to membrane depolarization, reduced ATP output, and accumulation of reducing equivalents in the electron transport chain. These reducing equivalents may react with oxygen to form superoxide (O₂^•−), which may propagate cellular damage directly or through conversion to other reactive oxygen species, such as hydrogen peroxide. Abbreviations: CO, carbon monoxide; CoQ, coenzyme Q/ubiquinone; Cyt c, cytochrome c; ETC, electron transport chain; H2O2, hydrogen peroxide; Hb-R, relaxed-state hemoglobin; Hb-T, tense-state hemoglobin; pO₂, partial pressure of oxygen. (Source: Dent MR, Rose JJ, Tejero J, Gladwin MT. Carbon monoxide poisoning: from microbes to therapeutics. Annu Rev Med 2024;75:337-51. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

In mitochondria, vitamin B12 deficiency impacts the enzyme L-methylmalonyl-CoA mutase (MUT). This deficiency not only disrupts the biosynthesis of crucial compounds but also triggers the accumulation of reaction intermediates that are potentially toxic at increased concentrations, leading to metabolic decompensation. The light green arrows highlight further biochemical implications resulting from vitamin B12 deficiency, potentially influencing molecular and cellular processes. (Source: Mathew AR, Di Matteo G, La Rosa P, et al. Vitamin B12 deficiency and the nervous system: beyond metabolic decompensation-comparing biological models and gaining new insights into molecular and cellular mechanisms. Int J Mol Sci 2024;25[1]:590. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The arrows in the "metabolism" part of the figure indicate an increase (if pointing upwards) or a decrease (if pointing downwards) in the metabolite or vitamin B12.

Abbreviations: HC, haptocorrin (probably more commonly known as R-protein or transcobalamin I); HCy, homocysteine; MMA, methylmalonic acid; TC, transcobalamin; TC-R, the transcobalamin receptor, CD320; VitB12, vitamin B12.

(Source: Mathew AR, Di Matteo G, La Rosa P, et al. Vitamin B12 deficiency and the nervous system: beyond metabolic decompensation-comparing biological models and gaining new insights into molecular and cellular mechanisms. Int J Mol Sci 2024;25[1]:590. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0. Note this figure was modified by Dr. Douglas J Lanska from the original, which was intended to compare divergent metabolic processes and uptake mechanisms of vitamin B12 across human, mouse, and zebrafish.)

In the cytoplasm, vitamin B12 deficiency impacts the enzyme methionine synthase (MTR). This deficiency not only disrupts the biosynthesis of crucial compounds but also triggers the accumulation of reaction intermediates that are potentially toxic at increased concentrations, leading to metabolic decompensation. Lightning bolt icons indicate the metabolic steps that might indirectly contribute to oxidative stress. The light green arrows highlight further biochemical implications resulting from vitamin B12 deficiency, potentially influencing molecular and cellular processes. (Source: Mathew AR, Di Matteo G, La Rosa P, et al. Vitamin B12 deficiency and the nervous system: beyond metabolic decompensation-comparing biological models and gaining new insights into molecular and cellular mechanisms. Int J Mol Sci 2024;25[1]:590. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Abbreviations: Ado-VitB12, adenosylcobalamin, also more fully 5′-deoxyadenosylcobalamin; Cubam R, cubam receptor, a multi-ligand receptor located in the terminal ileum, specializing in absorption of vitamin B12; FA, folic acid; HC, haptocorrin (probably more commonly known as R-protein or transcobalamin I); HCy, homocysteine; IF, intrinsic factor; M-CoA, methylmalonyl-CoA; MRP1, multidrug-resistant protein 1; MTR, methionine synthase; MUT, L-methylmalonyl-CoA mutase; TC, transcobalamin; VitB12, vitamin B12.

(Source: Mathew AR, Di Matteo G, La Rosa P, et al. Vitamin B12 deficiency and the nervous system: beyond metabolic decompensation-comparing biological models and gaining new insights into molecular and cellular mechanisms. Int J Mol Sci 2024;25[1]:590. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Nitrous oxide inactivates vitamin B12 by oxidation of the cobalt atom, leading to functional defects in vitamin B12 as a cofactor for the catabolism of homocysteine and methylmalonic acid. Thus, the circulating concentrations of methylmalonic acid and homocysteine are increased in N2O-induced vitamin B12 deficiency.

Abbreviations: AdB12, adenosyl-vitamin B12; CBS, cystathionine beta-synthase; MeB12, methyl-vitamin B12; MMCoAM, methylmalonyl- CoA mutase; MTR, methionine synthase; N2O, nitrous oxide; THF, 5-methyl tetrahydrofolate.

(Source: Leleu D, Denimal D. A case of functional vitamin B12 deficiency after recreational nitrous oxide use. Biochem Med [Zagreb] 2024;34[1]:010801. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Metabolic effects of metformin on gut bacteria to increase their vitamin B12 uptake, leading to increasing competition for available dietary vitamin B12 and ultimately to human vitamin B12 deficiency. In E. coli metformin inhibits the respiratory chain complex I, and vitamin B12 transport through the bacterial inner wall is blocked so that vitamin B12 accumulates in the periplasm. By contrast, in Bacteroides ovatus metformin upregulates respiratory chain complex V so that vitamin B12 can be transported across the inner membrane to the bacterial cytoplasm. (Source: Chen M, Shu Y, Li Q, et al. Bacteroides ovatus accelerates metformin-induced vitamin B12 deficiency in type 2 diabetes patients by accumulating cobalamin. NPJ Biofilms Microbiomes 2023;9[1]:51. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Slagboom TN, van Bunderen CC, De Vries R, Bisschop PH, Drent ML. Prevalence of clinical signs, symptoms and comorbidities at diagnosis of acromegaly: a systematic review in accordance with PRISMA guidelines. Pituitary 2023;26[4]:319-32. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Slagboom TN, van Bunderen CC, De Vries R, Bisschop PH, Drent ML. Prevalence of clinical signs, symptoms and comorbidities at diagnosis of acromegaly: a systematic review in accordance with PRISMA guidelines. Pituitary 2023;26[4]:319-32. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The numbers shown for each sign or symptom are: (N/N for weighted mean): weighted mean (range). (Source: Slagboom TN, van Bunderen CC, De Vries R, Bisschop PH, Drent ML. Prevalence of clinical signs, symptoms and comorbidities at diagnosis of acromegaly: a systematic review in accordance with PRISMA guidelines. Pituitary 2023;26[4]:319-32. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The numbers shown for each sign or symptom are: (N/N for weighted mean): weighted mean (range). (Source: Slagboom TN, van Bunderen CC, De Vries R, Bisschop PH, Drent ML. Prevalence of clinical signs, symptoms and comorbidities at diagnosis of acromegaly: a systematic review in accordance with PRISMA guidelines. Pituitary 2023;26[4]:319-32. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(A) and (B) illustrate, respectively, coronal T1-weighted post-contrast and T2-weighted MRI images at diagnosis showing a large homogeneous pituitary mass with intra- and suprasellar extension, compression, and upward stretching of the optic chiasm. In addition, there is a cavernous sinus extension and internal carotid artery compression. (C) is a sagittal T1-weighted MRI image showing a large homogeneous pituitary mass with partial hyperattenuated margins. (Source: Sada V, Puliani G, Feola T, et al. Tall stature and gigantism in transition age: clinical and genetic aspects-a literature review and recommendations. J Endocrinol Invest 2024;47[4]:777-93. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Sada V, Puliani G, Feola T, et al. Tall stature and gigantism in transition age: clinical and genetic aspects-a literature review and recommendations. J Endocrinol Invest 2024;47[4]:777-93. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Photograph of the American acromegalic giant Max Edmund Palmer (1927-1984, final height 224.8 cm) hospitalized at Charity Hospital in New Orleans because of an “infected toe,” January 4, 1952. Photograph from the private collection of Wouter W de Herder. (Source: de Herder WW, Raymond WA. Neuropathic foot ulcers in the tallest patients with acromegalic gigantism: a common and significant problem. Historical overview. Pituitary 2023;26[4]:333-9. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0. The photograph also appeared in “The Milwaukee Journal” on January 4, 1952, among other newspapers. Anonymous. Giant finds things difficult in hospital. Milwaukee: The Milwaukee Journal, January 4, 1952.)

Photograph of the American acromegalic giant Cecil Boling (1920-2000, final height 235 cm) learning to walk again on artificial legs (which reduced his height to 213 cm) at The University Hospital in Seattle, July 2, 1960. Photograph from the private collection of Wouter W de Herder. (Source: de Herder WW, Raymond WA. Neuropathic foot ulcers in the tallest patients with acromegalic gigantism: a common and significant problem. Historical overview. Pituitary 2023;26[4]:333-9. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0. The photograph also appeared in the newspaper “The Joplin Globe” on July 3, 1960, among other newspapers.)

Photographs of the left and right foot of the Icelandic acromegalic giant Johann Petursson (1913-1984, final height 220.5 cm), showing deformities and the situation after amputations of the third and fourth toes, because of recurrent ulcerations and infections. Photographs from the private collection of Warren A. Raymond. (Source: de Herder WW, Raymond WA. Neuropathic foot ulcers in the tallest patients with acromegalic gigantism: a common and significant problem. Historical overview. Pituitary 2023;26[4]:333-9. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Photograph of the American acromegalic giant Johann (John) Aasen (1890-1938, final height of 218.4 cm) while hospitalized in Lane Hospital in San Francisco because of recurrent bilateral foot ulcers, November 2, 1936. Recorded height at admission was 213.4 cm. Note the foot deformities (clawing toes). A penetrating ulcer on the bottom of the left foot is not shown. Photograph from the private collection of Warren A Raymond. (Source: de Herder WW, Raymond WA. Neuropathic foot ulcers in the tallest patients with acromegalic gigantism: a common and significant problem. Historical overview. Pituitary 2023;26[4]:333-9. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0. This photograph was also partly reproduced in: Gray H. The Minneapolis giant. Ann Intern Med 1937;10:1669-82.)

Photograph of the American acromegalic giant Robert Wadlow (1918-1940) from October 19, 1936, age 18 years and 8 months (height 255.9 cm, weight 197.7 kg), showing deformities of both legs (genu valga), knees and feet. Photograph from the private collection of Warren A. Raymond. (Source: de Herder WW, Raymond WA. Neuropathic foot ulcers in the tallest patients with acromegalic gigantism: a common and significant problem. Historical overview. Pituitary 2023;26[4]:333-9. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0. The bottom part of this photograph, only showing the legs, was also reproduced in: Daughaday WH. Extreme gigantism. Analysis of growth velocity and occurrence of severe peripheral neuropathy and neuropathic arthropathy [Charcot joints]. N Engl J Med 1977;297(23):1267-9.)

Schematic recording of the “cutaneous sensations” of the American acromegalic giant Robert Wadlow (1918-1940) from 25 March 1935, age 17 years and 1 month (height 244 cm, weight 170 kg) demonstrating sensory defects in the lower legs. Picture from the Barnes Hospital, St. Louis, MO medical file, private collection Warren A. Raymond. (Source: de Herder WW, Raymond WA. Neuropathic foot ulcers in the tallest patients with acromegalic gigantism: a common and significant problem. Historical overview. Pituitary 2023;26[4]:333-9. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

A woman pours a glass of brandy into the mouth of a child; a girl has fallen to the floor; men and women in the background show signs of being intoxicated, in the apparent belief that alcohol will prevent cholera. On the table is a huge bottle of brandy. (Source: Illustration by Robert Seymour [1798-1836], artist. London. August 1, 1831. Courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. Public domain. Edited by Dr. Douglas J Lanska.)

A man wearing a shop apron, coat, and top hat, and holding a bottle, is leaning against a building. To the left is a broadside advertising an alcoholic beverage, and far left is a door. Alcohol is being consumed to guard against cholera. (Source: P.C. Geissler, Nürnberg, [18--]. Courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. Public domain. Edited by Dr. Douglas J Lanska.)

(Source: OpenStax College. Anatomy & Physiology, Connexions Website: cnx.org/content/col11496/1.6. Jun 19, 2013. Creative Commons Attribution 3.0 Unported license, creativecommons.org/licenses/by/3.0/deed.en.)

The level of bicarbonate in the blood determines the severity of metabolic acidosis. (Source: Wikipedia user: MetabolicAcidosisExpert, 2019. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

A skeletal figure drinking a glass of toxic red chemicals, representing the death of civilization by chemical warfare. Drawn by Dutch painter, caricaturist, and editorial cartoonist Louis Raemakers (1869-1956) for The Century Magazine, Barron Collier Series of Patriotic Cartoons. (Source: U.S. Library of Congress, Prints and Photographs Division, Washington, D.C. Public domain.)

Drawn by Dutch painter, caricaturist, and editorial cartoonist Louis Raemakers (1869-1956) for The Century Magazine, Barron Collier Series of Patriotic Cartoons. (Source: U.S. Library of Congress, Prints and Photographs Division, Washington, D.C. Public domain.)

After a crayon drawing by Dutch painter, caricaturist, and editorial cartoonist Louis Raemakers (1869-1956). (Source: Wellcome Collection, London, UK. Wellcome Library no. 46015i (Photo number: V0018240). Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Colored chalk by Dutch painter, caricaturist and editorial cartoonist Louis Raemakers (1869-1956), 1916. (Source: Wellcome Collection, London, UK. Wellcome Library no. 46015i (Photo number: V0018240). Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Dutch painter, caricaturist and editorial cartoonist Louis Raemakers (1869-1956), between ca. 1915 and ca. 1920. (Source: U.S. Library of Congress, Prints and Photographs Division, Washington, D.C. Public domain.)

Pastel by Scottish artist A. Kirkpatrick Maxwell (1884-1975), ca. 1915. (Source: Wellcome Collection, London, UK. Wellcome Library no. 571751i. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Colored chalks by Dutch painter, caricaturist, and editorial cartoonist Louis Raemaekers (1869-1956), ca. 1918. The print of this composition was "Drawn specially for the Graphic"; it was published in the Graphic on August 3, 1918. (Source: Wellcome Collection, London, UK. Wellcome Library no. 46016i. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Color halftone printed in two colors after Scottish artist A. Kirkpatrick Maxwell (1884-1975), ca. 1917. The victim died 19 hours after exposure. Most of the pulmonary alveoli are filled with edema fluid, and the walls of the air sacs are ruptured in many places. The rounded edges of these torn walls can be recognized both in the areas of emphysema and in the parts that are flooded with edema fluid. The bronchus also is filled with edema fluid, but its lining is intact, and pus cells have not accumulated in the secretion. The blood vessels of the alveolar network are congested; although intravascular thrombosis is frequently found in these small vessels with phosgene poisoning, it is not present in this section. The main changes in the lung are: (1) congestion, and occasional thrombosis, of the network of pulmonary vessels; (2) abundant outpouring of inflammatory edema fluid both into the tissues and into the airspaces of the alveoli and bronchi; and (3) disruptive emphysema of the weakened lung tissue. The result of these changes is that the blood circulation through the lungs is impeded, and the respiratory exchange of gasses between the blood and the air in the lung is seriously diminished. In this era, before the development of respirators, a gassed man would be in danger of death by asphyxia so long as his lung was drowned in edema fluid. (Source: Wellcome Collection, London, UK. Wellcome Library no. 571919i. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Color halftone printed in two colors after Scottish artist A. Kirkpatrick Maxwell (1884-1975), ca. 1917. The victim died at the end of the second day (40 hours after exposure). The bronchiole is filled with fibrin and pus cells, and its lining epithelium has been destroyed. The inflammation has caused a characteristic ring of hemorrhage in the tissues around the bronchial tube, and infection is beginning to appear in the alveoli nearest to these inflamed tissues. There is no generalized pulmonary edema. The pathological changes in the bronchioles and in the alveoli are, therefore, in sharp contrast with those caused by phosgene. As infection spreads into the lung tissues, patches of septic bronchopneumonia and small abscesses develop, and these often excite a surrounding inflammatory edema. If the patient lives, his bronchial mucous membrane is slowly regenerated; and during this time, he is subject to reflex spasms of coughing or even to a protracted bronchitis. (Source: Wellcome Collection, London, UK. Wellcome Library no. 571919i. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Poison gas identification kits were issued to civil defense personnel during World War II. These individuals were usually ARP (Air Raid Precaution) wardens, and the kits trained them to identify a range of dangerous gases. This kit contains eight small, labeled, glass bottles and some sachets of chemicals in a leatherette case. The wider civilian population was issued gas masks as protection against potentially fatal gas attacks. They were also given pamphlets describing characteristic smells of different gases. Gas attacks were to be signaled by air raid wardens using large wooden rattles that produced a loud “clacking” sound. In the post-war period, many of these were used by football (soccer) fans around the country. Poison gases (eg, mustard gas) were used to great effect during World War I (1914-1918). They were outlawed in the Treaty of Versailles, which formally ended the conflict. Nevertheless, because the British expected the Germans to use chemical weapons against civilians during World War II, poison gas identification kits were developed, and the general public was supplied with gas masks. (Source: Courtesy of The Science Museum, London, UK, and the Wellcome Collection, London, UK. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Note the limited visibility that would be provided through the translucent eye ports and the canister at the end of the protruding snout that was intended to filter airborne chemical weapons. Poison gas was a new weapon during the First World War and was first used by the German Army in 1915. The British and French Armies soon followed suit. Fortunately, although good protective equipment was initially quite slow to develop, masks like this one eventually reduced poison gas to a major annoyance rather than the terrifying killer of the early attacks. Among the chemical weapons used was mustard gas, which caused burns to the skin and blindness. Phosgene gas was also used and was particularly dangerous as it is colorless and almost odorless; this gas affected the lungs and breathing and could also cause heart problems. (Source: Courtesy of The Science Museum, London, UK, and the Wellcome Collection, London, UK. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Note the limited visibility that would be provided through the translucent eye ports and the canister at the end of the protruding snout that was intended to filter airborne chemical weapons. Poison gas was a new weapon during the First World War and was first used by the German Army in 1915. The British and French Armies soon followed suit. Fortunately, although good protective equipment was initially quite slow to develop, masks like this one eventually reduced poison gas to a major annoyance rather than the terrifying killer of the early attacks. Among the chemical weapons used was mustard gas, which caused burns to the skin and blindness. Phosgene gas was also used and was particularly dangerous as it is colorless and almost odorless; this gas affected the lungs and breathing and could also cause heart problems. (Source: Courtesy of The Science Museum, London, UK, and the Wellcome Collection, London, UK. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Chart of war gases. Issued by the Ministry of Home Security. London: H.M. Stationary Office, 1942. Courtesy of the Wellcome Library, London, UK. Reference number: b15316890. Public domain.)

(Source: Waltenburg MA, Larson VA, Naor EH, et al. Notes from the field: botulism type B After intravenous methamphetamine use--New Jersey, 2020. MMWR Morb Mortal Wkly Rep 2020;69:1425-6. Public domain.)

Data are derived from routine, passive national surveillance. Data are presented as one trend line because the incidence and absolute case count trend lines are indistinguishable. (Source: Varma JK, Katsitadze G, Moiscrafishvili M, et al. Signs and symptoms predictive of death in patients with foodborne botulism--Republic of Georgia, 1980-2002. Clin Infect Dis 2004;39[3]:357-62. Public domain.)

The numbers indicated in the period ranges 1875 to 1936, 1940 to 1944, 1956 to 1970, and 1971 to 1977 are the annual mean values. Total cases (blue), type B botulism (green), type A botulism (red), type E botulism (purple), type F botulism (orange arrows). (Source: Rasetti-Escargueil C, Lemichez E, Popoff MR. Human Botulism in France, 1875-2016. Toxins [Basel]. 2020;12[5]:338. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Cases by epidemiologic week of symptom onset. (Source: Peak CM, Rosen H, Kamali A, et al. Wound botulism outbreak among persons who use black tar heroin - San Diego County, California, 2017-2018. MMWR Morb Mortal Wkly Rep 2019;67[5152]:1415-8. Public domain.)

(Source: Centers for Disease Control and Prevention; Peak CM, Rosen H, Kamali A, et al. Wound botulism outbreak among persons who use black tar heroin - San Diego County, California, 2017-2018. MMWR Morb Mortal Wkly Rep 2019;67[5152]:1415-8. Public domain.)

Botulism cases (n = 31) in a federal correctional facility, by reported date of hooch exposure and symptom onset. Hooch is defined as an illicitly made alcoholic beverage. First exposure is defined as the first exposure to hooch occurring during June 1-19, 2016. Date of exposure was unknown for two inmates. (Source: McCrickard L, Marlow M, Self JL, et al. Notes from the field: botulism outbreak from drinking prison-made illicit alcohol in a federal correctional facility--Mississippi, June 2016. MMWR Morb Mortal Wkly Rep 2017;65[52]:1491-2. Public domain.)

(rate/100,000 population) (Source: Leclair D, Fung J, Isaac-Renton JL, et al. Foodborne botulism in Canada, 1985-2005. Emerg Infect Dis 2013;19[6]:961-8. Public domain.)

(A) Length of hospitalization, (B) length of time in a special care unit. The box and whiskers represent the data as quartiles; the whiskers (vertical lines) represent the top and bottom values, the box represents the 1st (bottom) to 3rd (top) quartiles of values, and the horizontal line in the middle of the box represents the median. The circles indicate individual data points including outliers. A single outlier for time in special care occurred for serotype E. (Source: Harris RA, Tchao C, Prystajecky N, et al. Foodborne Botulism, Canada, 2006-2021. Emerg Infect Dis 2023;29[9]:1730-7. Public domain.)

(A) Number of cases from 1960 to 2021; (B) detail of number of cases from 2006 to 2021. Inset pie graphs represent the percentage of cases among non-Indigenous and Indigenous persons. (Source: Harris RA, Tchao C, Prystajecky N, et al. Foodborne Botulism, Canada, 2006-2021. Emerg Infect Dis 2023;29[9]:1730-7. Public domain.)

(Source: Centers for Disease Control and Prevention, 2003. Courtesy of Natural Resources Canada. Public domain.)

(Source: Centers for Disease Control and Prevention, 2001. Public domain.)

Postmortem cranial nerve tissue from a patient with asymmetric Type F botulism showing B-cell infiltration of nerve tissue. (Source: Filozov A, Kattan JA, Jitendranath L, et al. Asymmetric type F botulism with cranial nerve demyelination. Emerg Infect Dis 2012;18[1]:102-4. Public domain.)

Postmortem cranial nerve tissue from a patient with asymmetric Type F botulism showing CD68-positive myelinoklastic macrophages (original magnification ×400). (Source: Filozov A, Kattan JA, Jitendranath L, et al. Asymmetric type F botulism with cranial nerve demyelination. Emerg Infect Dis 2012;18[1]:102-4. Public domain.)

Postmortem cranial nerve tissue from a patient with asymmetric Type F botulism showing fragmentation of myelin sheaths and inflammatory infiltration of B and CD3+ T-cells within the nerve tissue (original magnification ×200). (Source: Filozov A, Kattan JA, Jitendranath L, et al. Asymmetric type F botulism with cranial nerve demyelination. Emerg Infect Dis 2012;18[1]:102-4. Public domain.)

(Source: Sobel J, Tucker N, Sulka A, McLaughlin J, Maslanka S. Foodborne botulism in the United States, 1990-2000. Emerg Infect Dis 2004;10[9]:1606-11. Public domain.)

Justinus Kerner published the first description of botulism. Lithograph 1841/1850. (Source: Universitätsbibliothek Leipzig. Public domain.)

Ida Bengtson on January 1, 1848. Dr. Bengtson was the first woman scientist in the Public Health Service. In 1937, she was transferred to Washington, D.C. Her former laboratory in the Public Health Service had become the Division of Infectious Diseases of the National Institute of Health. Bengtson was awarded the Typhus Medal in 1947 by the American Typhus Commission. Dr. Bengtson died in 1952, at the age of 71. (Source: Courtesy of the History Office, U.S. National Institutes of Health, Bethesda, Maryland. Public domain.)

Ida Bengtson was the first woman to be hired as a bacteriologist in the United States Hygienic Laboratory, now known as the National Institutes of Health. Half-length portrait while seated in United States Hygienic Laboratory's sterile room, transferring tissue cultures of Rocky Mountain spotted fever ca. 1938. (Source: Courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. NLM Image ID: B02711 Public domain.)

At her microscope, this historic image depicts bacteriologist Dr. Ida A. Bengtson (1881-1952), while at work in her laboratory. The photograph was taken from the U.S. Public Health Service records. Dr. Bengtson was particularly noted for her studies of bacterial toxins, especially her discoveries concerning the organism Clostridium botulinum. (Source: Public Health Image Library ID# 3606, Centers for Disease Control and Prevention, Atlanta, Georgia. Public domain.)

Belgian bacteriologist Émile van Ermengem discovered the bacterium that causes botulism, later named Clostridium botulinum. (Source: Van Loo, Florimond, Portret Van Emile-Pierre Van Ermengem [1851-1932], Hoogleraar Aan De Faculteit Geneeskunde Te Gent. Gand: Florimond Van Loo, 1897. Creative Commons Attribution-ShareAlike [CC BY-SA 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Photograph by Dr. VR Dowell Jr., Centers for Disease Control and Prevention, 1980. Public Health Image Library ID# 16681, Centers for Disease Control and Prevention, Atlanta, Georgia. Public domain.)

The white mouse depicted here was exhibiting neurologic deficits due to botulism toxicity during an in vitro botulism toxicity test. (Source: Photograph by Dr. Hatheway, Centers for Disease Control and Prevention, 1980. Public Health Image Library ID# 16186, Centers for Disease Control and Prevention, Atlanta, Georgia. Public domain.)

Under a low magnification of 1.9x, this image shows a close view of Clostridium botulinum, type-E bacterial colonies, which had formed on the surface of the egg yolk agar growth medium in this Petri dish culture plate, after undergoing a 48-hour incubation period. Note the opaque, opalescent nature exhibited by these characteristic type-E colonies. (Source: Photograph by Dr. Holdeman, Centers for Disease Control and Prevention, 1965. Public Health Image Library ID# 3871, Centers for Disease Control and Prevention, Atlanta, Georgia. Public domain.)

Photomicrograph showing the presence of Clostridium botulinum, type-A bacteria, that had been cultivated in this Gram-stained, thioglycollate broth specimen, having undergone a 48-hour incubation period, at a temperature of 35°C. Note that some of the organisms had entered their endospore phase, assuming the morphological shape of safety pins. (Source: Photograph by Dr. George Lombard, Centers for Disease Control and Prevention, 1978. Public Health Image Library ID# 3870, Centers for Disease Control and Prevention, Atlanta, Georgia. Public domain.)

Under a low magnification (5x), this image shows a close view of a Clostridium botulinum, type-A bacterial colony, which had formed on the surface of the blood agar growth medium in this Petri dish culture plate, after undergoing a 72-hour incubation period. (Source: Photograph by Dr. Holdeman, Centers for Disease Control and Prevention, 1965. Public Health Image Library ID# 3869, Centers for Disease Control and Prevention, Atlanta, Georgia. Public domain.)

Close view of the surface of a blood agar culture plate, which produced these colonies after having been inoculated with Clostridium botulinum, type-A, strain 2 bacteria and incubated for 48 hours. (Source: Photograph by Dr. Holdeman, Centers for Disease Control and Prevention, 1965. Public Health Image Library ID# 3868, Centers for Disease Control and Prevention, Atlanta, Georgia. Public domain.)

Jars containing contaminated Jalapeño peppers preserves, which were involved in an outbreak of botulism in Pontiac, Michigan in April 1977. (Source: Photograph by Dr. Chas Hatheway, Centers for Disease Control and Prevention, 1978. Public Health Image Library ID# 3355, Centers for Disease Control and Prevention, Atlanta, Georgia. Public domain.)

Photomicrograph depicts the presence of numerous Clostridium botulinum, type-A bacteria, which had been highlighted after they were processed using the Gram-stain technique. Note the Cl. botulinum endospores, which appeared shaped like tennis rackets. (Source: Photograph by Dr. George Lombard, Centers for Disease Control and Prevention, 1978. Public Health Image Library ID# 2132, Centers for Disease Control and Prevention, Atlanta, Georgia. Public domain.)

Photomicrograph depicting the presence of numerous Clostridium botulinum, type-A bacteria, which had been highlighted after they were processed using the Gram-stain technique. Note the Cl. botulinum endospores, which appeared shaped like bobby pins. (Source: Photograph by Dr. George Lombard, Centers for Disease Control and Prevention, 1978. Public Health Image Library ID# 2131, Centers for Disease Control and Prevention, Atlanta, Georgia. Public domain.)

Photomicrograph of a gentian violet-stained culture specimen revealing the presence of numerous gram-positive Clostridium botulinum, formerly known as Bacillus botulinus bacteria, and bacterial endospores. (Source: Centers for Disease Control and Prevention, 1979. Public Health Image Library ID# 2107, Centers for Disease Control and Prevention, Atlanta, Georgia. Public domain.)

This 6-week-old infant displayed a posture that was caused by botulinum toxin, which manifested as a marked loss of muscle tone, especially in the region of the head and neck. This toxin is made by the bacterium, Clostridium botulinum, and sometimes Cl. butyricum and Cl. baratii bacteria as well. These bacteria can be spread by food, and sometimes by other means, including potentially in bioterrorism. (Source: Public Health Image Library ID# 1935, Centers for Disease Control and Prevention, Atlanta, Georgia. Public domain.)

Photomicrograph depicting numerous Clostridium botulinum bacteria in their endospore stage, which had been highlighted after being processed using the malachite green staining method. The endospores appear as green spheres, whereas the bacilli themselves stain a purple color. (Source: Photography by Larry Stauffer, Oregon State Public Health Laboratory, 2002. Public Health Image Library ID# 1932, Centers for Disease Control and Prevention, Atlanta, Georgia. Public domain.)

Photomicrograph depicting numerous Clostridium botulinum bacteria in their endospore stage, which had been highlighted after being processed using the malachite green staining method. The endospores appear as green spheres, whereas the bacilli themselves stain a purple color. (Source: Photography by Larry Stauffer, Oregon State Public Health Laboratory, 2002. Public Health Image Library ID# 1931, Centers for Disease Control and Prevention, Atlanta, Georgia. Public domain.)

Close view of a Petri dish, which contained a growth medium of egg yolk agar that had been inoculated with Clostridium botulinum bacteria and subsequently incubated for a 72-hour period. Note the presence of the "lipase reaction," which manifests as a shiny margin that surrounds each colony. (Source: Photography by Larry Stauffer, Oregon State Public Health Laboratory, 2002. Public Health Image Library ID# 1930, Centers for Disease Control and Prevention, Atlanta, Georgia. Public domain.)

A mother is holding off a boa constrictor wrapped around her and her three small children. Flames surround them. A liquor store is in the background on the right. A still is behind them on the right, with the inscription "The worm of the still." (Source: Harper's Weekly 1887;31:760. Courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. Public domain.)

Carleton was the author of "The Serpent of the Still" (1906). (Source: The Magazine of Poetry 1890;2. Public domain.)

(Alcohol addiction) Two old men, one is leaning on a staff and the other is embracing a tankard; their unkempt appearance is indicative of the ravages of alcoholism. (Source: "Human passions delineated in above 120 figures...designed in the Hogarthian style.." by Tim Bobbin [ie, pseudonym of English caricaturist and satirical poet John Collier, 1708-1786] and engraved by Thomas Sanders. London, 1773. Courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. Public domain.)

(Alcohol addiction) Two men, one is happily embracing his tankard of liquor, the other is sad at having none. (Source: "Human passions delineated in above 120 figures...designed in the Hogarthian style.." by Tim Bobbin [ie, pseudonym of English caricaturist and satirical poet John Collier, 1708-1786] and engraved by Thomas Sanders. London, 1773. Courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. Public domain.)

Anti-alcohol poster sponsored by the U.S. National Institute on Alcohol Abuse and Alcoholism. (Source: Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain.)

Huge distillation apparatus; black men, representing the West Indies, distill sugar and molasses. At right representatives of agriculture, holding corn and barley, fall back in fear. Spirits representing the effects of alcohol emanate from a large vat. Artist Samuel De Wilde (1748-1832). Published by S Tipper, England, 1808. (Source: Courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. Public domain.)

Print shows an archway of the nine steps of a drunkard's progress, beginning with a man in fancy dress having "a glass with a friend" and then his gradual decline in society with poverty and disease, criminal activity, becoming a bum, and his eventual "death by suicide"; a weeping woman and child are under the archway. (Source: Lithograph published by N Currier, New York. Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain.)

(Source: Caasis and Lubrecht, New York, c1884. Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain.)

Print shows an archway of the nine steps of a drunkard's progress, beginning with a man in a fancy dress having "a glass with a friend" and then his gradual decline in society with poverty and disease, criminal activity, becoming a bum, and his eventual "death by suicide"; two men, one on horseback and another with sacks, are in foreground. (Source: EB and EC Kellogg, Hartford, Connecticut, c1846. Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain.)

Stereograph showing a studio scene of a policeman intervening in a fight, against a painted backdrop. By GW Edmondson, Plymouth, Richland County, Ohio, c1874? (Source: Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain.)

Illustration by British caricaturist and book illustrator George Cruikshank (1792-1878). A man, ruined by alcohol and placed in an institution, is huddled before a locked cage that protects a stove. He is visited by a son and daughter. Through a doorway, a wide-eyed maniac sits on the floor, and a man holding a key waits outside the door. (Source: Courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. Public domain.)

Two men and a woman are sitting around a small table on which is a large punch bowl; each is holding a glass. On the right is seated a fat man with both feet and his left hand bandaged. In the center, a young woman is holding her stomach. On the left, a man appears to be near death. The fat man with gout on the right claims that "PUNCH cures the GOUT," to which the woman adds "the COLIC," and the sickly man adds "and the TISICK." Note that "tisick" in British English is archaic for a splutter (a short explosive spitting or choking noise) or a cough. Cartoon by British caricaturist and printmaker James Gillray (1756-1815), who was famous for his etched political and social satires. (Source: Courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. Public domain.)

Two men and a woman are sitting around a table drinking to their health; the man on the right suffers from gout. The man on the left, holding a glass of alcohol, claims "This good Appetite gives [sic]." The woman in the middle, holding a glass of alcohol, adds, "Cures the vapors also." The snarling man on the right, also holding a glass of alcohol, asks, "Will it Cure the Cursed Pain I have got in my toe?" Artist William Heath (1795-1840), London, 1810. (Source: Courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. Public domain.)

The bum drinks the alcohol from the cigar lighter. A bowery is a city district known for cheap bars and derelicts. The Strobridge Lithographing Company, Cincinnati and New York. (Source: Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain.)

Two cartoon panels illustrate the effects of overindulging in alcohol. "Night" (left panel) depicts a laughing man with friends seated at a table set with decanters labeled "Port" and "Sherry," holding a goblet of wine in his raised right hand and fruit in his left hand. "Morning" (right panel) depicts the same man lying in bed tormented by two imp-like figures personifying wine; "Sherry" hammers the man's head while "Port" prods his stomach with a red-hot poker. This indicates some of the symptoms of a hangover: headache and nausea. Published by Thomas McLean in London in the 1830s. (Source: Courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. Public domain.)

Designed and engraved by John Warner Barber (1798-1885). Print shows a man identified as "King Alcohol" and a skeleton representing Death standing on barrels labeled "Strong Beer, Wines, Rum, Gin, Brandies, Whiskies, compounded liquors," with "social class" and "moderate drinkers" on the left, as well as the "suicide and murderous fighter," and on the right, the "dead and drunken," their broken families, ruined homes, and their graves. "Hope" at lower left mourns the "60,000 annually in the U.[S.] States." "King Alcohol" holds a tankard in his raised right hand with a snake coiled around his arm; printed above is a reference to Proverbs XXIII 32 ("In the end, it will bite like a snake and poison like a viper."). (Source: Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain.)

Drawing from between 1860 and 1902. Artist Thomas Nast (1840-1902). Forms part of the Cabinet of American illustration (Library of Congress). (Source: Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain.)

Motion picture poster for "Absinthe" shows a man seated, with hand on head, at table with three glasses of absinthe. Metropolitan Division, U.S. Lithograph Company. (Source: Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain.)

Anti-alcohol poster sponsored by the U.S. National Institute on Alcohol Abuse and Alcoholism, 1975. (Source: Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain.)

Painted by Francis William Edmonds (1806-1863) and engraved by Thomas Doney (active 1844-1852). Print showing a man in a woodworking shop sitting in front of a bottle of alcohol resting on a shelf in a window. (Source: Published by R.F. Fraser, New York, c1846. Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain.)

Anti-alcohol poster sponsored by the U.S. National Institute on Alcohol Abuse and Alcoholism, 1973. (Source: Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain.)

Death, appearing as a doctor with a top hat and cane, is standing before a stout man sitting in a chair. The man is holding a glass, and on the table next to him are the remnants of overindulgence. Cartoon by French artist Joseph Guillaume Bourdet (1799-1869), 183-. (Source: Courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. NLM Unique ID: 101393102. Public domain.)

From engraver and publisher Johann Theodor de Bry (1561-1623), after Nicolaas Braeu, after Flemish painter Karel van Mander (1548-1606), 1596. Title: [The epicurians celebrate this rite from a herd of swine]. From: Emblemata Saecularia [Secular emblems], 1596. A drunken young man lies vomiting in a ditch. He is held by his buddy, who points to two men carrying away a large barrel of beer in the background. Two sober barrel carriers are able to carry a full barrel of beer, while a drunkard cannot tolerate anything (anymore). The moral: beware of intemperate drinking with all the bad consequences that entails. Emblem No. 14 in Emblemata Saecularia (1596) and no. 35 in the second edition (1611). (Source: Courtesy of the Rijkmuseum, Amsterdam, The Netherlands. Object number RP-P-BI-5200. Public domain.)

Death is pouring alcohol down the throat of an alcoholic while another man next to him vomits from drinking too much. Copy of a print by German-Swiss painter and printmaker Hans Holbein the younger (c1497-1543) from 1538. First published in: Imagines mortis... (Images of death). Lyon: Johannes Frellon, 1547. (Source: Courtesy of the Rijkmuseum, Amsterdam, The Netherlands. Object number RP-P-OB-21.777[V]. Public domain.)

Anonymous, after George Cruikshank. Print against the abuse of alcoholic beverages, ca 1867-1868. Under a tree composed of liquor barrels and green snakes, all kinds of different people collect the poisonous drink in their glass. In the foreground, victims lie drunk or dead on the ground. In the background, a large laughing devil with the inscription “Strong drink / People's cancer.” (Source: Courtesy of the Rijkmuseum, Amsterdam, The Netherlands. Object number RP-P-1962-352. Public domain.)

People reaching for alcoholic drink falling from a pile of barrels of liquor likened to the upas tree; skeletons litter the ground. Alcohol is compared to the upas tree, a poisonous tree allegedly fatal to approach with sap that is used as arrow poison. Colored etching by British caricaturist and book illustrator George Cruikshank (1792-1878), c1842. (Source: Courtesy of the Wellcome Library, London, UK. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

A large bottle labeled "Absinthe" leans to one side. Death sits on the bottle and pours alcohol into a goblet held by a man while dangling a spider over the man's head. Acts of insanity, murder, and suicide resulting from alcoholism are depicted. (Source: Harper's Weekly 1883;27:592. Courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. Public domain. Figure edited by Dr. Douglas Lanska.)

Sitting under grapevines heavy with fruit is Podagra who, though looking like the wise philosopher, personifies the excess represented by Venus and Bacchus who are sitting beside him. Note the cane for Podagra (gout) and the large glass of alcohol (presumably wine) for Bacchus. (Source: From the frontispiece of Scriptum apologetico-politicum de podagra oder das so benahmte ... Zipperlein (1687) by Johann Andreas Schlegel [fl 1657-1681]. Courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. Public domain. Figure edited and cropped by Dr. Douglas Lanska.)

"Commit him for manslaughter in the greatest degree." Shows an unhappy bottle of rum in a prison yard with a chain on its ankle carrying two buckets of water. (Source: Harper's Weekly 1874;18:264. Courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. Public domain. Figure edited by Dr. Douglas Lanska.)

Experienced Party: "No, it isn't regular drinking that hurts a man; it's this way you fellers have of drinking between drinks." (Source: Harper's Weekly 1865;9:32. Courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. Public domain. Figure edited by Dr. Douglas Lanska.)

(Source: Harper's Weekly 1870;14:344. Courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. Public domain.)

Man with bottle in his back pocket looking at his black eye in mirror. Stereo image by Ingersoll View Company, St Paul, Minnesota, c1902. (Source: Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain.)

Man with a black eye and a bottle in back pocket, in a stuporous condition looking into mirror. Stereo image by Ingersoll View Company, St Paul, Minnesota, c1902. (Source: Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain.)

(A) The sleeve gastrectomy (SG) group included 12 women, and the control group included nine women. (B and D) Area under the curve (AUC) for concentration-time curves for both groups. Whiskers indicate the standard error of the mean. The "a" indicates that the AUC value for the sleeve gastrectomy group was significantly different from the control group at p<.05. (C) Sleeve gastrectomy and control group participants were matched on time-to-peak blood alcohol concentrations (BAC). Analysis was conducted among seven women from each group. (E and F) Individual BAC curves. (Source: Seyedsadjadi N, Acevedo MB, Alfaro R, et al. Site of alcohol first-pass metabolism among women. JAMA Netw Open 2022;5[3]:e223711. Erratum in: JAMA Netw Open 2022;5[4]:e2212773. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Average annual number of deaths from excessive alcohol use by age group and period among males (A) and females (B). Deaths from excessive alcohol use includes all decedents whose deaths were attributed to conditions that were fully caused by alcohol use, alcohol-related acute causes of death that involved binge drinking, and alcohol-related chronic conditions that involved medium (females: more than one but less than two drinks; males: more than two but less than four drinks) or high (females: more than two drinks; males: more than four drinks) daily average drinking levels. (Source: Esser MB, Leung G, Sherk A, et al. Estimated deaths attributable to excessive alcohol use among U.S. adults aged 20 to 64 years, 2015 to 2019. JAMA Netw Open 2022;5[11]:e2239485. Public domain.)

Estimated percentage of total deaths attributable to excessive alcohol use among adults aged 20 to 49 years, United States, 2015 to 2019. (Source: Esser MB, Leung G, Sherk A, et al. Estimated deaths attributable to excessive alcohol use among U.S. adults aged 20 to 64 years, 2015 to 2019. JAMA Netw Open 2022;5[11]:e2239485. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The Nystagmocatcher can be coupled to any commercially available smartphone. It is placed in front of the eye, and a video recording can be made with the smartphone. (Source: Melliti A, van de Berg M, van de Berg R. Capturing nystagmus during vertigo attacks using a smartphone: adherence, characteristics, pearls and pitfalls. J Neurol 2023;270[12]:6044-56. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The three panels show heart rate (HR) and blood pressure (BP) for vasovagal syncope (left, VVS), initial orthostatic hypotension (middle, iOH), and psychogenic pseudosyncope (right, PPS). Orange bars represent the duration of apparent loss of consciousness (LOC). The upward arrows indicate head-up tilt for vasovagal syncope and active standing for initial orthostatic hypotension. Downward arrows indicate tilt down for vasovagal syncope and falling for initial orthostatic hypotension. The vertical scales for heart rate and blood pressure are the same for the vasovagal syncope, initial orthostatic hypotension, and psychogenic pseudosyncope panels, but the time scale differs. Loss of consciousness in vasovagal syncope is accompanied by low heart rate and low blood pressure. In initial orthostatic hypotension, it is accompanied by low blood pressure and normal or high heart rate. In psychogenic pseudosyncope, apparent loss of consciousness is accompanied by normal to high heart rate and blood pressure. The blood pressure nadir of vasovagal syncope usually occurs many minutes after assuming the upright position, whereas this is a matter of seconds in initial orthostatic hypotension. (Source: Stewart JM, van Dijk JG, Balaji S, Sutton R. A framework to simplify paediatric syncope diagnosis. Eur J Pediatr 2023;182[11]:4771-80. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Comparison of lesion morphology of “iron dot” lesions in Susac syndrome (bottom) and multiple sclerosis (top). The figure illustrates differences in morphology on 7T T2*w images between “iron dots” in Susac syndrome (red arrows) and the central vein sign (white and black arrow) as well as T2*w hypointense core lesions (blue arrows with zoom) in multiple sclerosis. T2*-weighted imaging is an MRI sequence to quantify observable or effective T2 (T2* or "T2-star"); in this sequence, hemorrhages and hemosiderin deposits become hypointense (Chavhan GB, Babyn PS, Thomas B, Shroff MM, Haacke EM. Principles, techniques, and applications of T2*-based MR imaging and its special applications. Radiographics 2009;29[5]:1433-49). All exemplary T2*w images in the bottom are from different patients with Susac syndrome. Note that the “iron dots” in Susac syndrome (red arrows) appear punctate and sharply delineated on T2*w. In contrast, the T2*w hypointense core lesions (blue arrows with zoom) in multiple sclerosis often appear just slightly less hyperintense on T2*w in comparison to other multiple sclerosis lesions. Only when the lesion is viewed on strongly susceptibility-weighted sequences (right) does a rather diffuse signal loss become apparent. The central vein sign in multiple sclerosis also appears as a point-like, pronounced hypointensity on T2*w images when the slice plane is perpendicular to the long axis of the multiple sclerosis lesion (white arrow). However, if the slice plane is parallel to the long axis of the lesion, the central vein sign can be recognized as a straight line running through the center of multiple sclerosis lesions (black arrow). (Source: Strunk D, Sinnecker T, Kleffner I, et al. Central intra-lesional iron deposits as a possible novel imaging marker at 7 Tesla MRI in Susac Syndrome: an exploratory study. BMC Med Imaging 2024;24[1]:4. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Callosal “iron dot” lesions (indicated by red arrows) on 7T quantitative T1 maps (left) and 3D T2* weighted (right) sequences. (Source: Strunk D, Sinnecker T, Kleffner I, et al. Central intra-lesional iron deposits as a possible novel imaging marker at 7 Tesla MRI in Susac Syndrome: an exploratory study. BMC Med Imaging 2024;24[1]:4. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

"Iron dot” lesion in the left frontal lobe on 3D T2*-weighted (T2*w) coronal (top left), sagittal (lower left), and axial (right) 7 Tesla MRI sequences. T2*-weighted imaging is an MRI sequence to quantify observable or effective T2 (T2* or "T2-star"); in this sequence, hemorrhages and hemosiderin deposits become hypointense (Chavhan GB, Babyn PS, Thomas B, Shroff MM, Haacke EM. Principles, techniques, and applications of T2*-based MR imaging and its special applications. Radiographics 2009;29[5]:1433-49). Note the strong but punctate and sharply delineated intralesional signal loss. This type of intralesional T2*w signal loss differs from that of more recent multiple sclerosis lesions where central T2*w hypointensities appear larger and are more diffuse. They are also distinct from (enlarged) venules present in multiple sclerosis lesions as “iron dot” lesions do not show a tubular appearance following the course of a vessel. (Source: Strunk D, Sinnecker T, Kleffner I, et al. Central intra-lesional iron deposits as a possible novel imaging marker at 7 Tesla MRI in Susac Syndrome: an exploratory study. BMC Med Imaging 2024;24[1]:4. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(A) Optical coherence tomography infrared image of the right eye shows inferior retinal branch involvement (black arrows); the black arrows on the right of the image show occlusion, whereas on the left there is incomplete occlusion. (B) Fundus fluorescein angiography, late phase of the left eye in the same patient seen in A. There is arteriolar wall hyper-fluorescence seen along with frank leakage. (C) Late phase of fundus fluorescein angiography of the left eye demonstrates the requirement for peripheral views to gauge the extent of the retinal vascular involvement. (D) Late phase of fundus fluorescein angiography of the right eye shows superior arterial tree involvement in the same patient. (Source: Bose S, Papathanasiou A, Karkhanis S, et al. Susac syndrome: neurological update [clinical features, long-term observational follow-up and management of sixteen patients]. J Neurol 2023;270[12]:6193-206. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Algorithm for diagnosis, treatment, and monitoring of Susac syndrome. (Source: Bose S, Papathanasiou A, Karkhanis S, et al. Susac syndrome: neurological update [clinical features, long-term observational follow-up and management of sixteen patients]. J Neurol 2023;270[12]:6193-206. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Brain histology at higher magnification shows microangiopathy with thickening of arteriolar wall and a sparse perivascular lymphocytic infiltrate (arrow). (Source: Bose S, Papathanasiou A, Karkhanis S, et al. Susac syndrome: neurological update [clinical features, long-term observational follow-up and management of sixteen patients]. J Neurol 2023;270[12]:6193-206. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Brain histology shows multiple microinfarcts (arrows) in the cerebral cortex. Abbreviation: H&E, hematoxylin and eosin staining. (Source: Bose S, Papathanasiou A, Karkhanis S, et al. Susac syndrome: neurological update [clinical features, long-term observational follow-up and management of sixteen patients]. J Neurol 2023;270[12]:6193-206. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Sagittal T2-weighted MRI shows central callosal lesions. (Source: Bose S, Papathanasiou A, Karkhanis S, et al. Susac syndrome: neurological update [clinical features, long-term observational follow-up and management of sixteen patients]. J Neurol 2023;270[12]:6193-206. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Coronal FLAIR MRI sequence shows callosal, periventricular, and thalamic lesions. (Source: Bose S, Papathanasiou A, Karkhanis S, et al. Susac syndrome: neurological update [clinical features, long-term observational follow-up and management of sixteen patients]. J Neurol 2023;270[12]:6193-206. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Auger CA, Perosa V, Greenberg SM, van Veluw SJ, Kozberg MG. Cortical superficial siderosis is associated with reactive astrogliosis in cerebral amyloid angiopathy. J Neuroinflammation 2023;20[1]:195. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Comparison of axial MRI on days 0 and 14 in a 74-year-old, right-handed man, with no past medical history or vascular comorbidities and no prior head trauma, who presented with sudden left arm weakness, paresthesias, word-finding difficulties, and involuntary movements of the fingers. (A) Susceptibility-weighted imaging and (B) T2*-weighted imaging on days 0 and 14, respectively. On A there is very faint superficial siderosis in the central sulcus, which is much more pronounced at the last examination (B). Both MRIs were performed on the same 3 Tesla scanner. (Source: Andersen NH, Blauenfeldt RA, Mikkelsen R, Simonsen CZ. Preceding symptoms and temporal development of cortical superficial siderosis in cerebral amyloid angiopathy: a case report. BMC Neurol. 2023;23[1]:252. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Comparison of axial MRI on days 0 and 14 in a 74-year-old, right-handed man, with no past medical history or vascular comorbidities and no prior head trauma, who presented with sudden left arm weakness, paresthesias, word-finding difficulties, and involuntary movements of the fingers. MRI on days 0 (A-C) and 14 (D-F). (A and D) Diffusion-weighted imaging shows a hyperintense lesion in relation to the right lateral ventricle (dotted circle). (B and F) FLAIR. (C and F) Susceptibility-weighted imaging reveals multiple cortical microbleeds in the same area (solid circle). Both MRIs were performed on the same 3 Tesla scanner. (Source: Andersen NH, Blauenfeldt RA, Mikkelsen R, Simonsen CZ. Preceding symptoms and temporal development of cortical superficial siderosis in cerebral amyloid angiopathy: a case report. BMC Neurol. 2023;23[1]:252. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

MRI in a 27-year-old woman with right-sided headache and sensory Jacksonian seizures demonstrates a hyperintense cortical lesion in the right postcentral parietal area on (a) axial T2-weighted and (b) axial FLAIR images (arrow), with (c) signal loss and “blooming” of the central vein on axial T2*-weighted image (arrow) without cortical superficial siderosis. (d,e) Circumscribed peripheral contrast enhancement in an axial post-contrast T1-weighted image (arrow) and (f) restricted diffusion of the thrombus on axial diffusion-weighted imaging. (Source: Weidauer S, Neuhaus E, Hattingen E. Cerebral superficial siderosis: etiology, neuroradiological features and clinical findings. Clin Neuroradiol 2023;33[2]:293-306. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Acute cortical subarachnoid hemorrhage on (b) axial FLAIR, (c) axial susceptibility-weighted, and (d) axial diffusion-weighted images (arrow). (a, e) Enlarged perivascular spaces on axial T2-weighted images (arrow). (b, f) Focal gliosis on axial FLAIR (arrowhead). (c, g) Multiple microbleeds, cortical superficial siderosis, and residual atypical intracerebral bleeding in the left frontal area (arrowhead) on axial susceptibility-weighted images. (Source: Weidauer S, Neuhaus E, Hattingen E. Cerebral superficial siderosis: etiology, neuroradiological features and clinical findings. Clin Neuroradiol 2023;33[2]:293-306. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

CT and MRI in a 74-year-old woman suffering from recurrent cortical subarachnoid hemorrhage in cerebral amyloid angiopathy. (a-d) The first cortical subarachnoid hemorrhage in the right frontal area on (a) axial CT (arrow) with (b) sulcal hyperintense signal changes on FLAIR image (arrow) and (c, d) sulcal signal loss on T2*-weighted images (arrow) with additional cortical superficial siderosis on the left (arrowhead). (e-g) The second cortical subarachnoid hemorrhage in the paramedian left frontal area on (e) axial FLAIR and (g) axial T2*-weighted image (arrowhead). (f, g) Note the characteristic bilinear track-line appearance of cortical superficial siderosis in the chronic stage on T2*-weighted images (arrow). (h-k) The third cortical subarachnoid hemorrhage in the left frontodorsal area on (h) axial CT (arrow) with (i-k) signal loss on susceptibility-weighted imaging (arrow) and progressive cortical superficial siderosis bilaterally. (Source: Weidauer S, Neuhaus E, Hattingen E. Cerebral superficial siderosis: etiology, neuroradiological features and clinical findings. Clin Neuroradiol 2023;33[2]:293-306. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Axial post-contrast T1-weighted MRI in the lower cervical area showing inhomogeneous contrast enhancement (arrow) in a 59-year-old man suffering from progressive gait ataxia within 6 months and traumatic nerve root injury C7 and C8 30 years previously. (Source: Weidauer S, Neuhaus E, Hattingen E. Cerebral superficial siderosis: etiology, neuroradiological features and clinical findings. Clin Neuroradiol 2023;33[2]:293-306. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Enlarged empty nerve root pouches (arrows) in the lower cervical area on the left on sagittal T2*-weighted MRI in a 59-year-old man suffering from progressive gait ataxia within 6 months and traumatic nerve root injury C7 and C8 30 years previously. (Source: Weidauer S, Neuhaus E, Hattingen E. Cerebral superficial siderosis: etiology, neuroradiological features and clinical findings. Clin Neuroradiol 2023;33[2]:293-306. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Enlarged empty nerve root pouches (arrows) on the left at C7 and C8 on sagittal T2*-weighted MRI in a 59-year-old man suffering from progressive gait ataxia within 6 months and traumatic nerve root injury C7 and C8 30 years previously. (Source: Weidauer S, Neuhaus E, Hattingen E. Cerebral superficial siderosis: etiology, neuroradiological features and clinical findings. Clin Neuroradiol 2023;33[2]:293-306. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Sagittal susceptibility-weighted imaging of the spinal cord in a 73-year-old woman with a ventral dural defect at the level of the second thoracic vertebra with spontaneous intracranial hypotension and recurrent subarachnoid bleeding over more than 10 years. Extensive spinal superficial siderosis (arrows) and ventral epidural fluid collection at the upper thoracic level (arrowheads). (Source: Weidauer S, Neuhaus E, Hattingen E. Cerebral superficial siderosis: etiology, neuroradiological features and clinical findings. Clin Neuroradiol 2023;33[2]:293-306. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Superficial siderosis of the spinal cord on sagittal T2*-weighted images (arrows) in a 59-year-old man suffering from progressive gait ataxia within 6 months and traumatic nerve root injury C7 and C8 30 years previously. (Source: Weidauer S, Neuhaus E, Hattingen E. Cerebral superficial siderosis: etiology, neuroradiological features and clinical findings. Clin Neuroradiol 2023;33[2]:293-306. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

MRI in a 77-year-old woman with progressive hearing loss, gait ataxia, visual disturbances, and visual hallucinations over 6 months due to classical infratentorial superficial siderosis. Axial T2*-GRE (a-f) showing superficial siderosis of the upper cervical spinal cord (a, arrow), cranial nerve VIII but sparing cranial nerve VII (b; arrowhead, arrow), the cerebellum and mesencephalon (c, d; arrow), the medial Sylvian fissure (e, arrow) and of the medial occipital lobes (f, arrow).

Abbreviation: T2*-GRE multi-echo gradient recalled echo T2*-weighted imaging (Tang MY, Chen TW, Zhang XM, Huang XH. GRE T2∗-weighted MRI: principles and clinical applications. Biomed Res Int 2014;2014:312142).

(Source: Weidauer S, Neuhaus E, Hattingen E. Cerebral superficial siderosis: etiology, neuroradiological features and clinical findings. Clin Neuroradiol 2023;33[2]:293-306. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

MRI sequences from a 61-year-old man with superficial siderosis due to ongoing hemorrhage from a melanoma metastasis in the right frontal cortex. In T2*-GRE (f) and susceptibility-weighted imaging (b, g), superficial siderosis is revealed by dark rims on the surface of affected structures, eg, the mesencephalon (arrow), with susceptibility-weighted imaging being more sensitive. Minimum intensity projections of susceptibility-weighted images (c, h) further enhance the conspicuousness of superficial siderosis. In addition, a filtered phase image of susceptibility-weighted imaging (a) can be used to distinguish paramagnetic (hemorrhage/iron, dark here) from diamagnetic substances (calcification, bright here), as they have opposite signal intensities. In general, susceptibility effects are more pronounced on images acquired at 3T (f-j) than on images acquired at 1.5T (a-e). Whereas at 3T a hypointense rim around the mesencephalon is seen in T2-weighted and FLAIR images (i, j; arrow), superficial siderosis is almost undetectable at 1.5T in T2-weighted and FLAIR images (d, e; arrow). (a-e) 1.5T; (a-c) susceptibility-weighted imaging, TR/alpha 52ms/20°, 4 echoes TE1 = 12 ms, deltaTE = 11 ms; (d) T2, TR/TE/alpha = 5762 ms/110 ms/90°; (e) FLAIR, TR/TE/TI/alpha = 11000 ms/140 ms/2800 ms/90°; (f-j) 3 T; (f) T2*-GRE, TR/TE/alpha=631ms/20ms/20°; (g, h) susceptibility-weighted imaging, TR/TE/alpha=27ms/20ms/15°; (i) T2, TR/TE/alpha=4980ms/92ms/150°, (j) FLAIR: TR/TE/TI/alpha = 8500 ms/81 ms/2440 ms/150°. TR repetition time, TE echo time, TI inversion time, α flip angle.

Abbreviation: T2*-GRE multi-echo gradient recalled echo T2*-weighted imaging (Tang MY, Chen TW, Zhang XM, Huang XH. GRE T2∗-weighted MRI: principles and clinical applications. Biomed Res Int 2014;2014:312142).

(Source: Weidauer S, Neuhaus E, Hattingen E. Cerebral superficial siderosis: etiology, neuroradiological features and clinical findings. Clin Neuroradiol 2023;33[2]:293-306. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Microscopic examination of CSF in a 59-year-old man suffering from progressive gait ataxia within 6 months and traumatic nerve root injury C7 and C8 30 years previously. (Source: Weidauer S, Neuhaus E, Hattingen E. Cerebral superficial siderosis: etiology, neuroradiological features and clinical findings. Clin Neuroradiol 2023;33[2]:293-306. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

CSF is from a 73-year-old woman with a ventral dural defect at the level of the second thoracic vertebra with spontaneous intracranial hypotension and recurrent subarachnoid bleeding over more than 10 years. (Source: Weidauer S, Neuhaus E, Hattingen E. Cerebral superficial siderosis: etiology, neuroradiological features and clinical findings. Clin Neuroradiol 2023;33[2]:293-306. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Auburn-colored CSF from a 73-year-old woman with a ventral dural defect at the level of the second thoracic vertebra with spontaneous intracranial hypotension and recurrent subarachnoid bleeding over more than 10 years. (Source: Weidauer S, Neuhaus E, Hattingen E. Cerebral superficial siderosis: etiology, neuroradiological features and clinical findings. Clin Neuroradiol 2023;33[2]:293-306. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

CT scan of the hypopharynx and oropharynx in a 26-year-old man following a direct lightning strike on the head image shows obstruction with a complete narrowing of the supraglottic space: edema of vocal cords (black lines) and soft tissue behind the thyroid cartilage (black stars). (Source: Pizzi B, Petrucci E, Marinangeli F. Emergency cricothyrotomy in a harsh environment: a case report of complete airway obstruction following a lightning strike. A A Pract 2023;17(6):e01688. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Burn injuries on the left side of the neck (black line) following a direct lightning strike on the head of a 26-year-old man. (Source: Pizzi B, Petrucci E, Marinangeli F. Emergency cricothyrotomy in a harsh environment: a case report of complete airway obstruction following a lightning strike. A A Pract 2023;17(6):e01688. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Prominent interstitial hemorrhage was present only in sections from areas of punctate burning from arcing. Superficial skin loss is noted. (Source: Byard RW. Lichtenberg figures-morphological findings. Forensic Sci Med Pathol 2023;19(2):269-72. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Histological examination revealed no interstitial hemorrhage, inflammation or epidermal, dermal or subcutaneous injuries. The only findings were subtle dermal capillary dilatation, contrasting with adjacent normal skin. (Source: Byard RW. Lichtenberg figures-morphological findings. Forensic Sci Med Pathol 2023;19(2):269-72. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Also present in this area and extending into adjacent skin where there were no Lichtenberg figures were numerous punctate burns associated with subcutaneous hemorrhage. (Source: Byard RW. Lichtenberg figures-morphological findings. Forensic Sci Med Pathol 2023;19(2):269-72. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Byard RW. Lichtenberg figures-morphological findings. Forensic Sci Med Pathol 2023;19(2):269-72. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Abbreviations: 1,25DHD: 1,25 dihydroxy vitamin D; Ca-R: calcium receptor; CKD: chronic kidney disease; FGF-23: fibroblast growth factor-23; FGFR: fibroblast growth factor receptor; iPh: inorganic phosphate; PTH: parathyroid hormone; SHP: secondary hyperparathyroidism; VDR: vitamin D receptor. (Source: Habas E Sr, Eledrisi M, Khan F, Elzouki AY. Secondary hyperparathyroidism in chronic kidney disease: pathophysiology and management. Cureus 2021;13[7]:e16388. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Parathyroid hormone (PTH) synthesis or secretion can be decreased in the chief cell of the parathyroid gland by different mechanisms: (1) increased extracellular calcium concentrations by activation of the calcium-sensing receptor (CaSR); (2) activation of the fibroblast growth factor (FGF)/alpha-Klotho receptor complex by FGF23; and (3) activation of the retinoid X receptor (RXR)/vitamin-D-receptor complex by 1,25-dihydroxyvitamin D. In bone, PTH acts on osteoblasts to secrete receptor activator of nuclear factor kappa-B ligand (RANKL), which acts on osteocytes to release calcium, thereby increasing extracellular calcium. FGF23 is released by the osteocytes in response to increased extracellular phosphate concentration, which acts on the FGF/alpha-Klotho receptor complex in the parathyroid gland and decreases synthesis of PTH mRNA and PTH secretion. PTH acts on the kidney to decrease the reabsorption of phosphate and increase the absorption of calcium, thereby increasing serum calcium and decreasing serum phosphate concentrations. PTH acts on 1-alpha-hydroxylase in the kidney to convert 25-hydroxyvitamin D to active 1,25-dihydroxyvitamin D, which increases both calcium and phosphate absorption and interacts with the RXR/vitamin-D-receptor complex in the parathyroid gland to suppress PTH mRNA. (Source: English KA, Lines KE, Thakker RV. Genetics of hereditary forms of primary hyperparathyroidism. Hormones [Athens] 2024;23[1]:3-14. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Abbreviations: 1,25-DOH-Vit-D: 1,25 dihydroxy hydroxycholecalciferol; 25-OH-Vit-D: 25 monohydroxy hydroxycholecalciferol; CKD: chronic kidney disease; FGF: fibroblast factor; PTH: parathyroid hormone; Vit D: vitamin D. (Source: Habas E Sr, Eledrisi M, Khan F, Elzouki AY. Secondary hyperparathyroidism in chronic kidney disease: pathophysiology and management. Cureus 2021;13[7]:e16388. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

In familial hypocalciuric hypercalcemia (FHH) types 1-3, inactivating mutations in CaSR, GNA11, or AP2S1 lead to loss of function of signaling through the CaSR pathway and, therefore, require higher extracellular calcium concentrations (red arrow) to suppress PTH secretion. These germline genetic changes affect all parathyroid cells. (Source: English KA, Lines KE, Thakker RV. Genetics of hereditary forms of primary hyperparathyroidism. Hormones [Athens] 2024;23[1]:3-14. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Mutual activation of microglia and astrocytes and the release of inflammatory factors, such as tumor necrosis factor alpha (TNF-a) and interleukin 1 beta (IL-1b). The release of inflammatory factors promotes the expression of the GluN1 and GluN2 subunits of the N-methyl-D-aspartic acid receptors (NMDAR) in postsynaptic neurons, allowing the binding of excitatory neuronal glutamate (Glu) and NMDAR released from presynaptic neurons and the inward flow of calcium ions (Ca²⁺) to act on neuronal synaptic plasticity by regulating the long-term potentiation (LTP) and MAPK/ERK phosphorylation pathways (also known as the Ras-Raf-MEK-ERK pathway, a chain of proteins in the cell that communicates a signal from a cell surface receptor to the DNA in the nucleus of the cell) through calmodulin-dependent kinase II (CaMKII). The release of inflammatory factors, on the other hand, directly promotes the development of neuroinflammation in the brain, secondary to the death of dopaminergic neurons, which leads to the development of Parkinson disease and the development of levodopa-induced dyskinesia (LID) in patients with Parkinson disease after years of L-DOPA administration by exacerbating the inflammatory response in the brain tissue and, thus, creating a vicious circle. (Source: Zhang J, Luo L, Long E, Chen L. Neurotoxicity induced by taxane-derived drugs: analysis of the FAERS database 2017-2021. Expert Opin Drug Saf 2023;22[8]:715-24. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Both microglia and astrocytes have differentiated pro-inflammatory phenotypes that are neurotoxic and injurious to dopaminergic neurons, whereas the neuroprotective phenotypes are neuroprotective and protective of dopaminergic neurons. Under certain specific circumstances, the pro-inflammatory and anti-inflammatory phenotypes of microglia can be switched. Pro-inflammatory microglia secrete interleukin-1 alpha (IL-1a), interleukin 1 beta (IL-1b), tumor necrosis factor-alpha (TNF-a), and complement component 1q (C1q), which can convert astrocytes to a pro-inflammatory phenotype. Pro-inflammatory astrocytes secrete IL-1b, TNF-a, granulocyte-macrophage colony-stimulating factor (GM-CSF), and chemokine C-C motif ligand 2 (CCL2), which in turn activate pro-inflammatory microglia. The phenotypic transition of astrocytes remains to be clarified. Dashed lines with question marks indicate possible relationships, but evidence of a direct association is lacking. (Source: Zhang J, Luo L, Long E, Chen L. Neurotoxicity induced by taxane-derived drugs: analysis of the FAERS database 2017-2021. Expert Opin Drug Saf 2023;22[8]:715-24. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Astrocyte-mediated neuroinflammation and neuroprotective mechanisms in the pathogenesis of Parkinson disease. On exposure to inflammatory stimuli, astrocytes become activated A1 phenotype. A1 phenotype astrocytes secrete pro-inflammatory factors, such as interleukin 1 beta (IL-1b), tumor necrosis factor-alpha (TNF-a), and other inflammatory factors, which further induce neuroinflammation and neurotoxicity mechanisms in the human brain, damaging dopaminergic neurons. A1 phenotype astrocytes secrete pro-inflammatory factors, such as IL-1b, TNF-a, and other inflammatory factors. On the other hand, the neuroprotective mechanism of activated A2 phenotype astrocytes against Parkinson disease includes the release of anti-inflammatory cytokines into the brain as well as the upregulation of neuroprotective trophic factors, anti-inflammatory cytokines including transforming growth factor beta (TGF-β), which inhibit persistent neuroinflammation and, thus, protect dopaminergic neurons. Disease occurs when this balance in the organism is disrupted. (Source: Zhang J, Luo L, Long E, Chen L. Neurotoxicity induced by taxane-derived drugs: analysis of the FAERS database 2017-2021. Expert Opin Drug Saf 2023;22[8]:715-24. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Microglia-mediated neuroinflammation and neuroprotective mechanisms in the pathogenesis of Parkinson disease. Microglia turns into an activated M1 phenotype when exposed to stimuli, such as infection, trauma, and intoxication. M1 phenotype microglia secrete pro-inflammatory factors, which further induce neuroinflammatory and neurotoxic mechanisms in the human brain through processes such as enhanced phagocytic activity and increased interleukin 1 beta (IL-1b), tumor necrosis factor-alpha (TNF-a), and reactive oxygen species (ROS) generation, damaging dopaminergic neurons. On the other hand, the presence and stimulation of anti-inflammatory factors can lead to an activated M2 phenotype. The neuroprotective mechanism of M2 microglia against Parkinson disease involves the release of anti-inflammatory cytokines into the brain and the upregulation of neuroprotective trophic factors. The anti-inflammatory cytokines include interleukin 4 (IL-4), interleukin 10 (IL-10), and so on, which inhibit persistent neuroinflammation and consequently protect the dopaminergic neurons. Disease occurs when this balance in the organism is disrupted. (Source: Zhang J, Luo L, Long E, Chen L. Neurotoxicity induced by taxane-derived drugs: analysis of the FAERS database 2017-2021. Expert Opin Drug Saf 2023;22[8]:715-24. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Axial FLAIR sequence 6 months after symptom onset in osmotic demyelination syndrome showing resolving hyperintensity in the hand knob area. (Source: Siranart N, Nakaphan P, Viarasilpa V, Anukoolwittaya P, Hemachudha P. Hand knob sign in osmotic demyelinating syndrome. BMC Neurol 2024;24[1]:83. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Axial FLAIR sequence 6 months after symptom onset in osmotic demyelination syndrome showing resolving hyperintensity in the basal ganglia bilaterally. (Source: Siranart N, Nakaphan P, Viarasilpa V, Anukoolwittaya P, Hemachudha P. Hand knob sign in osmotic demyelinating syndrome. BMC Neurol 2024;24[1]:83. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Axial FLAIR sequence 6 months after symptom onset in osmotic demyelination syndrome showing resolving hyperintensity in the pons. (Source: Siranart N, Nakaphan P, Viarasilpa V, Anukoolwittaya P, Hemachudha P. Hand knob sign in osmotic demyelinating syndrome. BMC Neurol 2024;24[1]:83. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Axial FLAIR sequence 3 weeks after symptom onset in osmotic demyelination syndrome showing a homogenous region of hyperintensity in the central pons. (Source: Siranart N, Nakaphan P, Viarasilpa V, Anukoolwittaya P, Hemachudha P. Hand knob sign in osmotic demyelinating syndrome. BMC Neurol 2024;24[1]:83. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Axial FLAIR sequence 3 weeks after symptom onset in osmotic demyelination syndrome showing hyperintensity in the precentral gyri bilaterally, including the hand knob area ("hand knob sign"). (Source: Siranart N, Nakaphan P, Viarasilpa V, Anukoolwittaya P, Hemachudha P. Hand knob sign in osmotic demyelinating syndrome. BMC Neurol 2024;24[1]:83. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Diffusion-weighted imaging (DWI) at onset of symptoms in osmotic demyelination syndrome showing symmetrical increased signal intensity in the lentiform and caudate nuclei bilaterally. (Source: Siranart N, Nakaphan P, Viarasilpa V, Anukoolwittaya P, Hemachudha P. Hand knob sign in osmotic demyelinating syndrome. BMC Neurol 2024;24[1]:83. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Axial FLAIR sequence at onset of symptoms in osmotic demyelination syndrome showing symmetrical increased signal intensity in the lentiform and caudate nuclei bilaterally. (Source: Siranart N, Nakaphan P, Viarasilpa V, Anukoolwittaya P, Hemachudha P. Hand knob sign in osmotic demyelinating syndrome. BMC Neurol 2024;24[1]:83. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Diffusion-weighted imaging (DWI) showing hyperintense signal in the central pons consistent with central pontine myelinolysis in a 46-year-old man with hyperosmolar hyperglycemia. (Source: Qu HL, Sun XY, Dai YJ. Central pontine myelinolysis: a rare finding in hyperosmolar hyperglycemia. Front Neurol 2023;14:1216328. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.) Figure edited by Dr. Douglas Lanska (cropping and removal of red color cast).

Axial FLAIR sequence showing hyperintense signal in the central pons consistent with central pontine myelinolysis in a 46-year-old man with hyperosmolar hyperglycemia. (Source: Qu HL, Sun XY, Dai YJ. Central pontine myelinolysis: a rare finding in hyperosmolar hyperglycemia. Front Neurol 2023;14:1216328. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.) Figure edited by Dr. Douglas Lanska (cropping and removal of red color cast).

Axial T2-weighted sequence showing hyperintense signal in the central pons consistent with central pontine myelinolysis in a 46-year-old man with hyperosmolar hyperglycemia. (Source: Qu HL, Sun XY, Dai YJ. Central pontine myelinolysis: a rare finding in hyperosmolar hyperglycemia. Front Neurol 2023;14:1216328. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.) Figure edited by Dr. Douglas Lanska (cropping and removal of red color cast).

(Source: Qu HL, Sun XY, Dai YJ. Central pontine myelinolysis: a rare finding in hyperosmolar hyperglycemia. Front Neurol 2023;14:1216328. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Axial T1-weighted sequence showing hypointense signal in the central pons consistent with central pontine myelinolysis in a 46-year-old man with hyperosmolar hyperglycemia. (Source: Qu HL, Sun XY, Dai YJ. Central pontine myelinolysis: a rare finding in hyperosmolar hyperglycemia. Front Neurol 2023;14:1216328. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.) Figure edited by Dr. Douglas Lanska (cropping and removal of red color cast).

"Piglet" (or "piglet face") sign of the upper pons in FLAIR MRI sequence (red circle). In the ʺpiglet faceʺ sign, the pons takes on a distinctive resemblance to the snout of a piglet, whereas the internal carotid arteries and the fourth ventricle form, respectively, the eyes and mouth. (Source: Koul P, Harjpal P, Raghumahanti R. Osmotic demyelination syndrome: a rare clinical image. Diagnostics [Basel] 2023;13[21]:3393. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

"Piglet" (or "piglet face") sign of the upper pons in an axial T2-weighted MRI sequence (green circle). In the ʺpiglet faceʺ sign, the pons takes on a distinctive resemblance to the snout of a piglet, whereas the internal carotid arteries and the fourth ventricle form, respectively, the eyes and mouth. (Source: Koul P, Harjpal P, Raghumahanti R. Osmotic demyelination syndrome: a rare clinical image. Diagnostics [Basel] 2023;13[21]:3393. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Trident-shaped appearance (trident sign or omega sign) of central pons in an axial T2-weighted image (blue arrow) in osmotic demyelination syndrome. The characteristic “trident”-shaped appearance is attributed to the involvement of the transverse pontine fibers and relative sparing of the descending corticospinal tracts. (Source: Koul P, Harjpal P, Raghumahanti R. Osmotic demyelination syndrome: a rare clinical image. Diagnostics [Basel] 2023;13[21]:3393. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Axial diffusion-weighted image (DWI) showing hyperintensity of the central pons in (orange arrow) in osmotic demyelination syndrome. (Source: Koul P, Harjpal P, Raghumahanti R. Osmotic demyelination syndrome: a rare clinical image. Diagnostics [Basel] 2023;13[21]:3393. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

This 40-year-old woman with chronic alcoholism presented with intractable headache for 3 days and progressively worsening unsteady gait requiring a wheelchair to ambulate. Electrolyte levels were normal. Central pontine myelinolysis and extrapontine myelinolysis were attributed to alcohol withdrawal. Other MRI sequences (not shown) showed heterogenous high-T2 signal abnormality within the central pons, extending into the bilateral cerebral peduncles and the medullary pyramids. Source: (Source: Jamil M, Salam A, Joseph Benher BM, Rehman S, Jamil J, Suleyman G. A case of alcohol withdrawal-induced central and extrapontine myelinolysis. Cureus 2023;15[7]:e41640. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

CT scan of the head showing scattered areas of reduced density in the subcortical white matter, including the frontal lobes and right parietal lobe, consistent with extrapontine myelinolysis. This 40-year-old woman with chronic alcoholism presented with intractable headache for 3 days and progressively worsening unsteady gait requiring a wheelchair to ambulate. Electrolyte levels were normal. Central pontine myelinolysis and extrapontine myelinolysis were attributed to alcohol withdrawal. (Source: Jamil M, Salam A, Joseph Benher BM, Rehman S, Jamil J, Suleyman G. A case of alcohol withdrawal-induced central and extrapontine myelinolysis. Cureus 2023;15[7]:e41640. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

This 40-year-old woman with chronic alcoholism presented with intractable headache for 3 days and progressively worsening unsteady gait requiring a wheelchair to ambulate. Electrolyte levels were normal. Central pontine myelinolysis and extrapontine myelinolysis were attributed to alcohol withdrawal. (Source: Jamil M, Salam A, Joseph Benher BM, Rehman S, Jamil J, Suleyman G. A case of alcohol withdrawal-induced central and extrapontine myelinolysis. Cureus 2023;15[7]:e41640. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Sagittal FLAIR sequence showing a hyperintense lesion in the central pons in a patient with central pontine myelinolysis secondary to hyperglycemia. (Source: Sun WP, Wang YD, Gao S, Wang YF, Li DW. A rare presentation of central pontine myelinolysis secondary to hyperglycaemia. BMC Endocr Disord 2023;23[1]:106. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.) Figure edited by Dr. Douglas Lanska (removal of red color cast).

Axial T2‐weighted MRI showing a hyperintense lesion in the central pons in a patient with central pontine myelinolysis secondary to hyperglycemia. (Source: Sun WP, Wang YD, Gao S, Wang YF, Li DW. A rare presentation of central pontine myelinolysis secondary to hyperglycaemia. BMC Endocr Disord 2023;23[1]:106. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.) Figure edited by Dr. Douglas Lanska (cropping and removal of red color cast).

Axial FLAIR sequence showing a hyperintense lesion in the central pons in a patient with central pontine myelinolysis secondary to hyperglycemia. (Source: Sun WP, Wang YD, Gao S, Wang YF, Li DW. A rare presentation of central pontine myelinolysis secondary to hyperglycaemia. BMC Endocr Disord 2023;23[1]:106. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.) Figure edited by Dr. Douglas Lanska (cropping and removal of red color cast).

Axial T1‐weighted MRI showing a mildly hypointense lesion in the central pons in a patient with central pontine myelinolysis secondary to hyperglycemia. (Source: Sun WP, Wang YD, Gao S, Wang YF, Li DW. A rare presentation of central pontine myelinolysis secondary to hyperglycaemia. BMC Endocr Disord 2023;23[1]:106. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.) Figure edited by Dr. Douglas Lanska (cropping and removal of red color cast).

Axial FLAIR MRI demonstrating moderately homogeneous signal enhancement bilaterally symmetrical in the basal ganglia with symmetrical foci of enhancement in the posterior thalami typical for extrapontine myelinolysis. (Source: Dimitrov G, Naeva D, Duparinova R, Stratieva S, Manev V, Prinova K. Osmotic demyelination syndrome amidst COVID-19: a case report with literature review. Neurologia [Engl Ed] 2024;39[2]:213-7. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Axial FLAIR MRI demonstrating a centrally located area of increased signal in the pons typical for pontine myelinolysis. (Source: Dimitrov G, Naeva D, Duparinova R, Stratieva S, Manev V, Prinova K. Osmotic demyelination syndrome amidst COVID-19: a case report with literature review. Neurologia [Engl Ed] 2024;39[2]:213-7. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Subsequent endoscopy showed chronic gastritis. (Source: Romero Calvo L, Garcia-Blanco MJ, Valenzuela F, Álvarez Granda J. Osmotic demyelination syndrome in a normonatremic patient under treatment with proton pump inhibitors. Cureus 2023;15[8]:e44472. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Coronal T2-weighted MRI sequence showing a hyperintense lesion in the central pons in a normonatremic woman with severe hypomagnesemia. (Source: Romero Calvo L, Garcia-Blanco MJ, Valenzuela F, Álvarez Granda J. Osmotic demyelination syndrome in a normonatremic patient under treatment with proton pump inhibitors. Cureus 2023;15[8]:e44472. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Axial T2-weighted MRI sequence showing a hyperintense lesion in the central pons in a normonatremic woman with severe hypomagnesemia. (Source: Romero Calvo L, Garcia-Blanco MJ, Valenzuela F, Álvarez Granda J. Osmotic demyelination syndrome in a normonatremic patient under treatment with proton pump inhibitors. Cureus 2023;15[8]:e44472. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Axial FLAIR MRI sequence showing a hyperintense lesion in the central pons in a normonatremic woman with severe hypomagnesemia. (Source: Romero Calvo L, Garcia-Blanco MJ, Valenzuela F, Álvarez Granda J. Osmotic demyelination syndrome in a normonatremic patient under treatment with proton pump inhibitors. Cureus 2023;15[8]:e44472. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Axial T1-weighted MRI sequence showing a hypointense lesion in the central pons in a normonatremic woman with severe hypomagnesemia. (Source: Romero Calvo L, Garcia-Blanco MJ, Valenzuela F, Álvarez Granda J. Osmotic demyelination syndrome in a normonatremic patient under treatment with proton pump inhibitors. Cureus 2023;15[8]:e44472. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Cranial MRI of a 66-year-old woman with hypopituitarism due to Sheehan syndrome more than 30 years earlier after her last delivery was complicated by postpartum hemorrhage. The images show an empty sella turcica (arrows) with pituitary tissue compressed against the sellar floor with lateral stalk deviation. (Source: Vasconcelos AL, Pinto Ribeiro R, Claúdio Ferreira P, Maciel J, Araújo R. A case report of Sheehan syndrome: a rare cause of hypopituitarism. Cureus 2024;16(2):e53544. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

A 66-year-old woman with hypopituitarism due to Sheehan syndrome more than 30 years earlier after her last delivery was complicated by postpartum hemorrhage. The patient's legs show a complete absence of hair, suggesting that androgen deficiency due to secondary adrenal insufficiency, as well as hypothyroidism and hypogonadism, could be present. (Source: Vasconcelos AL, Pinto Ribeiro R, Claúdio Ferreira P, Maciel J, Araújo R. A case report of Sheehan syndrome: a rare cause of hypopituitarism. Cureus 2024;16(2):e53544. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

A 66-year-old woman with hypopituitarism due to Sheehan syndrome more than 30 years earlier after her last delivery was complicated by postpartum hemorrhage. She has pale skin but reddish eye mucosa. A marked wrinkling around the eyes and forehead is evident. Dry and weak hair is also partially seen. These findings raised concerns about cortisol and thyroid hormone deficiencies. (Source: Vasconcelos AL, Pinto Ribeiro R, Claúdio Ferreira P, Maciel J, Araújo R. A case report of Sheehan syndrome: a rare cause of hypopituitarism. Cureus 2024;16(2):e53544. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Serum thyroglobulin variation following the initiation of radioiodine and sorafenib treatments after total thyroidectomy in a 74-year-old man with diffuse follicular variant papillary thyroid cancer metastatic to the pituitary. Abbreviation: RAI, radioactive iodine (also called radioiodine or I-131). (Source: Kırkgöz T, Gürsoy S, Acar S, et al. Genetic diagnosis of congenital hypopituitarism in Turkish patients by a target gene panel: novel pathogenic variants in GHRHR, GLI2, LHX4, and POU1F1 genes. Arch Endocrinol Metab 2023;68:e220254. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

From a 74-year-old man with diffuse follicular variant papillary thyroid cancer metastatic to the pituitary. The thyroid capsule was not observed over the right thyroid lobe. The tumor was extrathyroidal. The right internal jugular vein was obliterated. (Source: Kırkgöz T, Gürsoy S, Acar S, et al. Genetic diagnosis of congenital hypopituitarism in Turkish patients by a target gene panel: novel pathogenic variants in GHRHR, GLI2, LHX4, and POU1F1 genes. Arch Endocrinol Metab 2023;68:e220254. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Positron emission tomographic images show increased fluoro-deoxyglucose uptake in the left ninth rib in a 74-year-old man with diffuse follicular variant papillary thyroid cancer metastatic to the pituitary. (Source: Kırkgoz T, Gürsoy S, Acar S, et al. Genetic diagnosis of congenital hypopituitarism in Turkish patients by a target gene panel: novel pathogenic variants in GHRHR, GLI2, LHX4, and POU1F1 genes. Arch Endocrinol Metab 2023;68:e220254. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Positron emission tomographic images show increased fluoro-deoxyglucose uptake in one of the pulmonary metastatic nodules in a 74-year-old man with diffuse follicular variant papillary thyroid cancer metastatic to the pituitary. (Source: Kırkgöz T, Gürsoy S, Acar S, et al. Genetic diagnosis of congenital hypopituitarism in Turkish patients by a target gene panel: novel pathogenic variants in GHRHR, GLI2, LHX4, and POU1F1 genes. Arch Endocrinol Metab 2023;68:e220254. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Positron emission tomographic images show increased fluoro-deoxyglucose uptake in the thyroid gland with substernal extension in a 74-year-old man with diffuse follicular variant papillary thyroid cancer metastatic to the pituitary. (Source: Kırkgöz T, Gürsoy S, Acar S, et al. Genetic diagnosis of congenital hypopituitarism in Turkish patients by a target gene panel: novel pathogenic variants in GHRHR, GLI2, LHX4, and POU1F1 genes. Arch Endocrinol Metab 2023;68:e220254. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Sagittal neck computed tomography images with contrast show deviated trachea and obliterated internal jugular vein in a 74-year-old man with diffuse follicular variant papillary thyroid cancer metastatic to the pituitary. Abbreviations: A: anterior; R: right side; Tr: thyroid gland; T: trachea. (Source: Kırkgöz T, Gürsoy S, Acar S, et al. Genetic diagnosis of congenital hypopituitarism in Turkish patients by a target gene panel: novel pathogenic variants in GHRHR, GLI2, LHX4, and POU1F1 genes. Arch Endocrinol Metab 2023;68:e220254. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Axial neck computed tomography images with contrast show deviated trachea and obliterated internal jugular vein in a 74-year-old man with diffuse follicular variant papillary thyroid cancer metastatic to the pituitary. Abbreviations: A: anterior; R: right side; Tr: thyroid gland; T: trachea. (Source: Kırkgoz T, Gürsoy S, Acar S, et al. Genetic diagnosis of congenital hypopituitarism in Turkish patients by a target gene panel: novel pathogenic variants in GHRHR, GLI2, LHX4, and POU1F1 genes. Arch Endocrinol Metab 2023;68:e220254. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Coronal neck CT images with contrast show deviated trachea, obliterated internal jugular vein, and substernal extension of the thyroid in a 74-year-old man with diffuse follicular variant papillary thyroid cancer metastatic to the pituitary. Abbreviations: A: anterior; R: right side; Tr: thyroid gland; T: trachea. (Source: Kırkgöz T, Gürsoy S, Acar S, et al. Genetic diagnosis of congenital hypopituitarism in Turkish patients by a target gene panel: novel pathogenic variants in GHRHR, GLI2, LHX4, and POU1F1 genes. Arch Endocrinol Metab 2023;68:e220254. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Coronal T1-weighted pituitary MRI showing pituitary mass with invasion of the right cavernous sinus (curved white arrow) and optic chiasm compression (short white arrows) in a 74-year-old man with diffuse follicular variant papillary thyroid cancer metastatic to the pituitary. (Left) postcontrast; (right) precontrast. (Source: Kırkgöz T, Gürsoy S, Acar S, et al. Genetic diagnosis of congenital hypopituitarism in Turkish patients by a target gene panel: novel pathogenic variants in GHRHR, GLI2, LHX4, and POU1F1 genes. Arch Endocrinol Metab 2023;68:e220254. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Sagittal T1-weighted pituitary MRI shows pituitary mass with suprasellar extension (thick white arrows) in a 74-year-old man with diffuse follicular variant papillary thyroid cancer metastatic to the pituitary. (Left) precontrast; (right) postcontrast. (Source: Kırkgöz T, Gürsoy S, Acar S, et al. Genetic diagnosis of congenital hypopituitarism in Turkish patients by a target gene panel: novel pathogenic variants in GHRHR, GLI2, LHX4, and POU1F1 genes. Arch Endocrinol Metab 2023;68:e220254. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

T1-weighted cranial MRI shows significant regression of pituitary fossa lesion 1 year after parathyroidectomy in a 47-year-old woman with a large osteoclastoma of the sphenoid bone, invading the pituitary fossa, causing hypopituitarism. (Source: Bandeira L, de Oliveira LB, de Lima MV, Rêgo D, Griz L, Bandeira F. Hypopituitarism due to a large osteoclastoma arising from the sphenoid bone invading the pituitary fossa in a patient with parathyroid carcinoma. Case Rep Endocrinol 2023;2023:8274108. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

T1-weighted cranial MRI shows an infiltrative lesion compromising the bony segments of the skull and face in a 47-year-old woman with a large osteoclastoma of the sphenoid bone, invading the pituitary fossa, causing hypopituitarism. (Source: Bandeira L, de Oliveira LB, de Lima MV, Rêgo D, Griz L, Bandeira F. Hypopituitarism due to a large osteoclastoma arising from the sphenoid bone invading the pituitary fossa in a patient with parathyroid carcinoma. Case Rep Endocrinol 2023;2023:8274108. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

T1-weighted cranial MRI shows the presence of a 3.1 cm lesion invading the pituitary fossa in a 47-year-old woman with a large osteoclastoma of the sphenoid bone, invading the pituitary fossa, causing hypopituitarism. (Source: Bandeira L, de Oliveira LB, de Lima MV, Rêgo D, Griz L, Bandeira F. Hypopituitarism due to a large osteoclastoma arising from the sphenoid bone invading the pituitary fossa in a patient with parathyroid carcinoma. Case Rep Endocrinol 2023;2023:8274108. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

T2-weighted cranial MRI shows the presence of a 3.1 cm lesion invading the pituitary fossa in a 47-year-old woman with a large osteoclastoma of the sphenoid bone, invading the pituitary fossa, causing hypopituitarism. (Source: Bandeira L, de Oliveira LB, de Lima MV, Rêgo D, Griz L, Bandeira F. Hypopituitarism due to a large osteoclastoma arising from the sphenoid bone invading the pituitary fossa in a patient with parathyroid carcinoma. Case Rep Endocrinol 2023;2023:8274108. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

X-ray from a 47-year-old woman with a large osteoclastoma of the sphenoid bone, invading the pituitary fossa, causing hypopituitarism. (Source: Bandeira L, de Oliveira LB, de Lima MV, Rêgo D, Griz L, Bandeira F. Hypopituitarism due to a large osteoclastoma arising from the sphenoid bone invading the pituitary fossa in a patient with parathyroid carcinoma. Case Rep Endocrinol 2023;2023:8274108. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The functional mechanism under deafferentation (ie, blindness in this context) is that false sensory data become overly influential, overriding the results of data comparison and expectancies to become incorporated into a hallucinatory perception. The hallucinated perception is replaced by a veridical one when the strength of the false sensory evidence reduces, or expectancies and data comparison override it. False sensory data results from hyperexcitability and spontaneous activation of the primary visual cortex caused by chronic loss of visual input. Green shading indicates which aspects of the framework are mapped to in each model, with the green text indicating the specific effects on functions. (Source: Collerton D, Barnes J, Diederich NJ, et al. Understanding visual hallucinations: a new synthesis. Neurosci Biobehav Rev 2023;150:105208. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Descending influences are shown in blue, and ascending are shown in red. Horizontal influences are in green. The grey blur over memory, context, emotion, and intention indicates that these factors interact to create complex expectancies. Linking arrows show the specific relationships between concepts while recognizing that the influence of these varies dynamically. The level of detail for each function reflects the need to incorporate distinctions in existing theories; thus, perception and attention are much more fractionated than memory or context. Expectancies act to bias perception and can be conceptualized as brain states that reflect prior information about what is possible or probable in the forthcoming sensory environment, ie, what is expected to be seen in that context (Parr T, Rees G, Friston KJ. Computational neuropsychology and Bayesian inference. Front Hum Neurosci 2018;12:61.). Predictions of sensory-level data are central to state models; in contrast, trait models emphasize higher-order expectances that develop from an interaction between (1) memories of past similar visual environments (memory expectancies), (2) the current visual context (context expectancies), (3) future intentions and motivations (intentional and motivational expectancies), and (4) emotions (emotional expectancies). Emphasizing the circular interactions between these functions, the visual context is created from inputs arising from current visual (and other sensory) perceptions. In addition to their direct role in modifying predicted data, expectancies also indirectly affect sensory data gathering and processing via attention. (Source: Collerton D, Barnes J, Diederich NJ, et al. Understanding visual hallucinations: a new synthesis. Neurosci Biobehav Rev 2023;150:105208. Creative Commons Attribution [CC BY] license.)

Ten-second EEG epoch tracing with longitudinal bipolar montage and central leads showing focal slowing over the left temporal region (encased in the blue box). (Source: Sy AJ, Gochioco DC. Charles Bonnet syndrome as sequelae of occipital lobe infarct with hemorrhagic conversion: a case report. Cureus 2023;15[12]:e50472. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Cranial T2 FLAIR MRI showing a subacute hemorrhagic infarct involving the left posteromedial temporal and left occipital lobes and, to a lesser extent, the left posterior thalamus. (Source: Sy AJ, Gochioco DC. Charles Bonnet syndrome as sequelae of occipital lobe infarct with hemorrhagic conversion: a case report. Cureus 2023;15[12]:e50472. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

OS (left eye) showing right visual field loss (area in black); OD (right eye) showing right visual field loss (area in black). (Source: Sy AJ, Gochioco DC. Charles Bonnet syndrome as sequelae of occipital lobe infarct with hemorrhagic conversion: a case report. Cureus 2023;15[12]:e50472. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Cranial gradient echo (GRE) MRI showing a subacute hemorrhagic infarct involving the left posteromedial temporal and left occipital lobes and, to a lesser extent, the left posterior thalamus. (Source: Sy AJ, Gochioco DC. Charles Bonnet syndrome as sequelae of occipital lobe infarct with hemorrhagic conversion: a case report. Cureus 2023;15[12]:e50472. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

A model of a perception process in the predictive processing framework in which a prediction is sent to the model of perception, which, in turn, passes down an expected perception that is contrasted with sensory input to generate a prediction error. This prediction error goes up to the perceptual model and, in turn, changes predictions about environmental states. (Source: Schmid FR, Kriegleder MF. Explanatory power by vagueness. Challenges to the strong prior hypothesis on hallucinations exemplified by the Charles-Bonnet-Syndrome. Conscious Cogn 2024;117:103620. Creative Commons Attribution [CC BY] license.)

A model of a perception process in the predictive processing framework in which a prediction is sent to the model of perception, which, in turn, passes down an expected perception that is contrasted with sensory input to generate a prediction error. This prediction error goes up to the perceptual model and, in turn, changes predictions about environmental states. (Source: Schmid FR, Kriegleder MF. Explanatory power by vagueness. Challenges to the strong prior hypothesis on hallucinations exemplified by the Charles-Bonnet-Syndrome. Conscious Cogn 2024;117:103620. Creative Commons Attribution [CC BY] license.)

T2 FLAIR-weighted sagittal image 7 months after metastasis resection shows the resection cavity, with slight enhancement at the margins, and the adjacent sub-/epidural collection. (Source: Ovchinnikov A, Andereggen L, Rogers S, Gschwind M. Visual hallucinations after resection of cerebral metastases: two patients with complex phantom images. Strahlenther Onkol 2024. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

T1-weighted contrast-enhanced axial MRI 7 months after metastasis resection shows the resection cavity, with slight enhancement at the margins. (Source: Ovchinnikov A, Andereggen L, Rogers S, Gschwind M. Visual hallucinations after resection of cerebral metastases: two patients with complex phantom images. Strahlenther Onkol 2024. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

T2 FLAIR-weighted axial image 7 months after metastasis resection shows the resection cavity, with slight enhancement at the margins, and the adjacent sub-/epidural collection. (Source: Ovchinnikov A, Andereggen L, Rogers S, Gschwind M. Visual hallucinations after resection of cerebral metastases: two patients with complex phantom images. Strahlenther Onkol 2024. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Sagittal T1-weighted contrast-enhanced MRI at time of diagnosis shows a slightly hypointense, ring-enhancing, and partially cystic mass with marked perilesional edema. There was a minor midline shift. (Source: Ovchinnikov A, Andereggen L, Rogers S, Gschwind M. Visual hallucinations after resection of cerebral metastases: two patients with complex phantom images. Strahlenther Onkol 2024. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Sagittal T2 fluid-attenuated inversion recovery (FLAIR)-weighted MRI sequence at time of diagnosis depicts a left occipital paramedian iso- to hypointense lesion. (Source: Ovchinnikov A, Andereggen L, Rogers S, Gschwind M. Visual hallucinations after resection of cerebral metastases: two patients with complex phantom images. Strahlenther Onkol 2024. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Sagittal T2 fluid-attenuated inversion recovery (FLAIR)-weighted MRI sequence at time of diagnosis depicts a left occipital paramedian iso- to hypointense lesion. (Source: Ovchinnikov A, Andereggen L, Rogers S, Gschwind M. Visual hallucinations after resection of cerebral metastases: two patients with complex phantom images. Strahlenther Onkol 2024. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Case timeline for a 74-year-old man who presented with a right homonymous hemianopia and persistent left-temporal headache. (Source: Ovchinnikov A, Andereggen L, Rogers S, Gschwind M. Visual hallucinations after resection of cerebral metastases: two patients with complex phantom images. Strahlenther Onkol 2024. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Magnified view of period corresponding to tetrodotoxin (TTX) accumulation in bivalves at selected shellfish representative monitoring sites in 2016. The plot shows satellite-derived daily mean sea-surface temperature (SST) values between May and July 2016 at sites with TTX (red dots) and without TTX (blue dots). The dashed vertical lines represent the onset of TTX accumulation on 21st June and when maximum TTX concentrations were recorded (4th July). (Source: Dhanji-Rapkova M, Teixeira Alves M, Triñanes JA, et al. Sea temperature influences accumulation of tetrodotoxin in British bivalve shellfish. Sci Total Environ 2023;885:163905. Creative Commons Attribution [CC BY] license.)

Daily continuous sea-surface temperature (SST) changes at selected shellfish representative tetrodotoxin (TTX) monitoring sites in the United Kingdom where TTX-positive or TTX-negative bivalves were recovered in 2016. Satellite-derived SST from 2016 using (A) daily mean SST and (B) "SST Difference" data sets. "SST Difference" values were determined by subtracting the lowest daily mean SST value from the daily mean SST values at each site. Significant interactions were found between time and TTX status for both data sets. (Source: Dhanji-Rapkova M, Teixeira Alves M, Triñanes JA, et al. Sea temperature influences accumulation of tetrodotoxin in British bivalve shellfish. Sci Total Environ 2023;885:163905. Creative Commons Attribution [CC BY] license.)

Sea-surface temperature characteristics of selected shellfish representative tetrodotoxin (TTX) monitoring sites in the United Kigndom where TTX-positive or TTX-negative bivalves were recovered in 2016. Box and whisker plots showing median (horizontal line), mean (diamond) and 1st and 3rd quartiles for satellite-derived sea surface temperature (SST) from 2016, based on (A) daily mean SST and (B) "SST difference" data sets. "SST difference" values were determined by subtracting the lowest daily mean SST value from the daily mean SST values at each site. (Source: Dhanji-Rapkova M, Teixeira Alves M, Triñanes JA, et al. Sea temperature influences accumulation of tetrodotoxin in British bivalve shellfish. Sci Total Environ 2023;885:163905. Creative Commons Attribution [CC BY] license.)

Tetrodotoxin (TTX) concentrations in bivalves and sea-surface temperature (SST) over multiple years. The data were collected from selected shellfish representative monitoring sites in the United Kingdom. (Source: Dhanji-Rapkova M, Teixeira Alves M, Triñanes JA, et al. Sea temperature influences accumulation of tetrodotoxin in British bivalve shellfish. Sci Total Environ 2023;885:163905. Creative Commons Attribution [CC BY] license.)

A summary of the ecology of tetrodotoxin (TTX) in bivalve mollusks in the United Kingdom. (Source: Dhanji-Rapkova M, Teixeira Alves M, Triñanes JA, et al. Sea temperature influences accumulation of tetrodotoxin in British bivalve shellfish. Sci Total Environ 2023;885:163905. Creative Commons Attribution [CC BY] license.)

(Source:Public domain.)

This figure provides an overview of existing hormonal therapies, their benefits, risks, and potential challenges. (Source: van Lohuizen R, Paungarttner J, Lampl C, MaassenVanDenBrink A, Al-Hassany L. Considerations for hormonal therapy in migraine patients: a critical review of current practice. Expert Rev Neurother 2023;24[1]:1-21. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

In this figure, serum levels of hormones and their effect on the endometrium over the course of the menstrual cycle are depicted, as well as the concurrence of fluctuations in the incidence of migraine attacks in women with menstrual migraine. Lasting around 28 days, the cycle starts with the release of follicle stimulating hormone, stimulating the growth of ovarian follicles. The maturation of these follicles leads to an increasing production of estradiol, which triggers a surge in luteinizing hormone and causes ovulation. After ovulation, the ruptured follicle transforms into the corpus luteum, which produces progesterone and prepares the endometrium for possible fertilization. If fertilization does not occur, the corpus luteum breaks down progesterone and estradiol levels drop, which triggers menstruation and the start of a new menstrual cycle. The decline of estradiol ("estradiol-withdrawal") is thought to precipitate migraine without aura in women with menstrual migraine.

Sources:
Reddy N, Desai MN, Schoenbrunner A, Schneeberger S, Janis JE. The complex relationship between estrogen and migraines: a scoping review. Syst Rev 2021a;10[1]:72.
van Lohuizen R, Paungarttner J, Lampl C, MaassenVanDenBrink A, Al-Hassany L. Considerations for hormonal therapy in migraine patients: a critical review of current practice. Expert Rev Neurother 2023;24[1]:1-21.
Martin VT, Lipton RB. Epidemiology and biology of menstrual migraine. Headache 2008;48 Suppl 3:S124-30.
MacGregor EA, Okonkwo R, Detke HC, Polavieja P, Fernandes MS, Pavlovic JM. Effect of galcanezumab in women with episodic migraine meeting criteria for menstrually related migraine: a post hoc analysis of EVOLVE-1 and EVOLVE-2. Headache 2024;64[2]:179-87.

(Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Innervation of the heart includes the afferent (sensory) neurons (green) that transmit information from baroreceptors in the heart to the spinal cord and brain, and efferent (motor) neurons that innervate the heart. These efferent motor neurons comprise the cardiac autonomic nervous system and include the sympathetic (purple) and parasympathetic (yellow) neurons. Depending on the location of neuronal cell bodies of each neuron type, cardiac innervation is divided into intrinsic and extrinsic elements. Intracardiac vagal innervation (pink) originates in the brain and relays information into the heart, whereas vagal neurons (yellow) synapse with secondary interneurons (pink) to activate the parasympathetic tone. The cell bodies of interconnecting neurons and other neural elements all cluster into the ganglionated plexi (small dark dots) in specific cardiac locations with diverse densities.

Abbreviations: Ao, aorta; IVC, inferior vena cava; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle; SVC, superior cava.

(Source: Yarkoni M, Rehman WU, Bajwa A, Yarkoni A, Rehman AU. Ganglionated plexus ablation procedures to treat vasovagal syncope. Int J Mol Sci 2023;24[17]:13264. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

A three-dimensional representation of four anatomical ganglionated plexus locations. White (anterior) and grey (posterior) circles indicate ganglionated plexus areas within the heart. (1) The right anterior ganglionated plexus (RAGP) is located on the posterior superior surface of the right atrium, adjacent to the junction of the superior vena cava (SVC) and right atrium, close to the right superior pulmonary vein (RSPV). (2) The left superior ganglionated plexus (LSGP) is located on the posterior surface of the left atrium between the left pulmonary veins (PVs). (3) The right inferior ganglionated plexus (RIGP) is located on the posterior surface of the right atrium, adjacent to the interatrial groove. (4) The left inferior ganglionated plexus (LIGP) is located on the posterior medial surface of the left atrium, close to the left inferior pulmonary vein (LIPV). (5) The left lateral ganglionated plexus (LLGP, not shown) is located in the area around the ligament of Marshall and can be viewed with a left lateral view. (Source: Yarkoni M, Rehman WU, Bajwa A, Yarkoni A, Rehman AU. Ganglionated plexus ablation procedures to treat vasovagal syncope. Int J Mol Sci 2023;24[17]:13264. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Several etiopathogenic mechanisms have been proposed to explain the responsiveness of some neonatal seizures to pyridoxine, and particularly to its active form, pyridoxal 5′ phosphate (PLP). PLP acts as a cofactor of several enzymes, such as glutamic acid decarboxylase (GAD), which regulates the synthesis of the inhibitory neurotransmitter gamma-amino butyric acid (GABA) from the excitatory neurotransmitter glutamate (GLUT); consequently, a reduction of PLP may lower GABA and raise GLUT, decreasing the seizure threshold. PLP is also involved in the synthesis of serine and glycine; a reduction of PLP may cause lower levels of these two amino acids, which is associated with epileptic phenotypes. SHMT is involved in the metabolic pathway, eventually leading to the formation of 5-methyltetrahydrofolate (5-mTHF), the main circulating form of folate, a reduction of which has been reported in some patients suffering from pyridoxine-dependent epilepsies. Furthermore, the reduction of 5-mTHF may be associated with oxidative stress, with excessive production of reactive oxygen species (ROS), possibly a consequence of low levels of pyridoxine, an antioxidant. ROS contribute to the peroxidation of several molecules, also affecting ion channels, potentially including KCNQ2. PLP also acts as an antagonist of specific ion channels with a possible anticonvulsant effect, so low pyridoxine levels may have a convulsant effect in part through action on these ion channels: this may apply to KCNQ2 (potassium voltage-gated channel subfamily Q member 2). Finally, some antiepileptic drugs may contribute to the depletion of pyridoxine and, indirectly, hyperhomocysteinemia, which is known to lower the seizure threshold. (Source: Amore G, Butera A, Spoto G, et al. KCNQ2-related neonatal epilepsy treated with vitamin B6: a report of two cases and literature review. Front Neurol 2022;13:826225. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Courtesy of the Florida Fish and Wildlife Conservation Commission. Public domain.)

Brevetoxin B, a group of neurotoxins isolated from the marine dinoflagellate Karenia brevis (formerly Gymnodinium breve).

Brevetoxin-2 (PbTx-2) R = -CH2C(=CH2)CHO
Brevetoxin-3 (PbTx-3) R = -CH2C(=CH2)CH2OH
Brevetoxin-5 (PbTx-5) R = -CH2C(=CH2)CH2OH, OH in position 37 is acetylated
Brevetoxin-6 (PbTx-6) like PbTx-2, epoxide in position 27-28
Brevetoxin-8 (PbTx-8) R = -CH2COCH2Cl
Brevetoxin-9 (PbTx-9) R = -CH2CH(CH3)CH2OH

(Source: Public domain.)

Brevetoxin A, a group of neurotoxins isolated from the marine dinoflagellate Karenia brevis (formerly Gymnodinium breve).

Brevetoxin-1 (PbTx-1) R = -CH2C(=CH2)CHO
Brevetoxin-7 (PbTx-7) R = -CH2C(=CH2)CH2OH
Brevetoxin-10 (PbTx-10) R = -CH2CH(-CH3)CH2OH

(Source: Public domain.)

(Public domain.)

(Public domain.)

Pictured is Dr. Anton as a professor in Graz, Austria, circa 1890. (Public domain.)

Diagram illustrating the time course of the disease. Abbreviations: PTA, pure-tone average; R, right; L, left; MRI, magnetic resonance imaging; MCP, middle cerebellar peduncle. (Source: Yuan Z, Xiang L, Liu R, Yue W. Case report: bilateral sudden deafness in acute middle cerebellar peduncle infarction: central or peripheral? Front Med [Lausanne] 2023;10:1174512. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Brain and neck computed tomography angiography revealed occlusion of the bilateral vertebral artery V3 segment, proximal V4 segment, and anterior inferior cerebellar artery bilaterally, as well as severe stenosis of the distal left vertebral artery V4 segment. (Source: Yuan Z, Xiang L, Liu R, Yue W. Case report: bilateral sudden deafness in acute middle cerebellar peduncle infarction: central or peripheral? Front Med [Lausanne] 2023;10:1174512. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Brain and neck computed tomography angiography revealed occlusion of the bilateral vertebral artery V3 segment, proximal V4 segment, and anterior inferior cerebellar artery bilaterally, as well as severe stenosis of the distal left vertebral artery V4 segment. (Source: Yuan Z, Xiang L, Liu R, Yue W. Case report: bilateral sudden deafness in acute middle cerebellar peduncle infarction: central or peripheral? Front Med [Lausanne] 2023;10:1174512. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Ten days after hospitalization, diffusion-weighted MRI showed new hyperintense foci at the middle cerebellar peduncle bilaterally. (Source: Yuan Z, Xiang L, Liu R, Yue W. Case report: bilateral sudden deafness in acute middle cerebellar peduncle infarction: central or peripheral? Front Med [Lausanne] 2023;10:1174512. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Third day, diffusion-weighted MRI showed hyperintense foci in the cerebellum bilaterally. (Source: Yuan Z, Xiang L, Liu R, Yue W. Case report: bilateral sudden deafness in acute middle cerebellar peduncle infarction: central or peripheral? Front Med [Lausanne] 2023;10:1174512. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Ten days after hospitalization, diffusion-weighted MRI showed new hyperintense foci at the middle cerebellar peduncle bilaterally. (Source: Yuan Z, Xiang L, Liu R, Yue W. Case report: bilateral sudden deafness in acute middle cerebellar peduncle infarction: central or peripheral? Front Med [Lausanne] 2023;10:1174512. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Third day, diffusion-weighted MRI showed hyperintense foci in the cerebellum bilaterally. (Source: Yuan Z, Xiang L, Liu R, Yue W. Case report: bilateral sudden deafness in acute middle cerebellar peduncle infarction: central or peripheral? Front Med [Lausanne] 2023;10:1174512. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The electrocochleogram showed the binaural SP/AP (summating potential/action potential) ratio in the normal range at 90 dBnHL (decibel normal hearing level), with the left ear SP/AP ratio 0.33 and the right ear SP/AP ratio 0.25. (Source: Yuan Z, Xiang L, Liu R, Yue W. Case report: bilateral sudden deafness in acute middle cerebellar peduncle infarction: central or peripheral? Front Med [Lausanne] 2023;10:1174512. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Pure tone audiogram after 3-month follow-up showing moderately severe to severe hearing loss in both ears with pure tone averages (PTA) of 67 dB on the right and 73 dB on the left. (Source: Yuan Z, Xiang L, Liu R, Yue W. Case report: bilateral sudden deafness in acute middle cerebellar peduncle infarction: central or peripheral? Front Med [Lausanne] 2023;10:1174512. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Pure-tone audiogram on admission showing profound sensorineural hearing loss in both ears with pure-tone averages (PTA) of 112 dB on the right and 115 on the left. (Source: Yuan Z, Xiang L, Liu R, Yue W. Case report: bilateral sudden deafness in acute middle cerebellar peduncle infarction: central or peripheral? Front Med [Lausanne] 2023;10:1174512. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Combined activation map of auditory processing in a 29-year-old right-handed man with bihemispheric cardioembolic infarcts in the middle cerebral artery territories. Activation map contrasting language conditions relative to rest for the two "spoken narrative" and "slow spoken narrative" paradigms, where only activation in a given voxel across all three paradigms is shown. The activation maps are overlain on coronal slices in two-slice increments from T1-weighted structural imaging spanning the length of Heschl's gyri bilaterally. Slices with activation of Heschl's gyri in a given hemisphere are denoted with arrows. The lesion mask (unsmoothed to allow for fine-grained interpretation of the activation patterns relative to structural damage) is depicted in blue. Left is left. Abbreviation: HG = Heschl's gyri. (Source: Casilio M, Kasdan AV, Schneck SM, et al. Situating word deafness within aphasia recovery: a case report. Cortex 2024;173:96-119. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Activation maps for the narrative paradigms in a 29-year-old right-handed man with bihemispheric cardioembolic infarcts in the middle cerebral artery territories. (A-B) Activation maps contrasting language conditions relative to matched perceptual conditions for the written narrative and slow written narrative paradigms. (C-D) Activation maps contrasting language conditions relative to matched perceptual conditions for the spoken narrative and slow spoken paradigms. The activation map from the repeated spoken narrative paradigm obtained during the second scanning session is not depicted because it is identical to the one obtained during the first scanning session. The smoothed lesion mask is depicted in blue. The color bar reflects the percentile range a t statistic fell within for a given voxel (lower % indicates greater statistical significance). Left is left. (Source: Casilio M, Kasdan AV, Schneck SM, et al. Situating word deafness within aphasia recovery: a case report. Cortex 2024;173:96-119. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Activation maps for the adaptive word paradigms in a 29-year-old right-handed man with bihemispheric cardioembolic infarcts in the middle cerebral artery territories. (A-C) Activation maps contrasting language conditions relative to matched perceptual conditions. The color bar reflects the percentile range a thresholded t statistic fell within for a given voxel (lower % indicates greater statistical significance). The smoothed lesion mask is depicted in blue. Left is left. (Source: Casilio M, Kasdan AV, Schneck SM, et al. Situating word deafness within aphasia recovery: a case report. Cortex 2024;173:96-119. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Lesion-delineated structural scan in a 29-year-old right-handed man with bihemispheric cardioembolic infarcts in the middle cerebral artery territories. Axial slices are presented at five-slice intervals from T1-weighted scans spanning the extent of his lesions, which are delineated in blue (unsmoothed to allow for fine-grained review of structural damage). Left is left. (Source: Casilio M, Kasdan AV, Schneck SM, et al. Situating word deafness within aphasia recovery: a case report. Cortex 2024;173:96-119. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Model of hypothesized processes that underly spoken language comprehension. Boxes and connecting arrows in blue depict linguistic processes, whereas boxes and arrows in gray show auditory processes. This model is a simplified modification of the model proposed by Whitworth in 2013 and is designed to also express interaction among processes (Dell et al 1997; Levelt et al 1999; Whitworth et al 2013). Components of this model were ultimately derived from German neurologist and psychiatrist Karl Kleist (1879-1960) (Kleist 1962), a student of German neurologist, psychiatrist, and neuropathologist Carl Wernicke (1848-1905). Kleist's work can be understood within the historical connectionist model of language processing (Wernicke 1874; Lichtheim 1885). To show this direct comparison, lettering in the top-right corner of the boxes corresponds to those used by German physician and pioneering aphasiologist Ludwig Lichtheim (1845-1928) in 1885, as does the color-coding of the boxes and connecting arrows described above (ie, those outlined in blue represent centers and pathways that result in select aphasia syndromes if damaged). (Source: Casilio M, Kasdan AV, Schneck SM, et al. Situating word deafness within aphasia recovery: a case report. Cortex 2024;173:96-119. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

References cited:
Dell GS, Schwartz MF, Martin N, Saffran EM, Gagnon DA. Lexical access in aphasic and nonaphasic speakers. Psychol Rev 1997;104[4]:801-38.
Kleist K. Sensory aphasia and amusia: the myeloarchitectonic basis. Oxford: Pergamon Press, 1962.
Levelt WJ, Roelofs A, Meyer AS. A theory of lexical access in speech production. Behav Brain Sci 1999;22[1]:1-38; discussion 38-75.
Lichtheim L. On aphasia. Brain 1885;7:433-84. Wernicke C. Der aphasische symptomencomplex. Breslau: Cohn and Weigert, 1874.
Whitworth A, Webster J, Howard D. A Cognitive Neuropsychological Approach To Assessment And Intervention In Aphasia: A Clinician's Guide. 2nd ed. Hove [England]: Psychology Press, 2013.

Normal pure-tone audiogram results from an audiological evaluation approximately 1 month after stroke onset. (Source: Casilio M, Kasdan AV, Schneck SM, et al. Situating word deafness within aphasia recovery: a case report. Cortex 2024;173:96-119. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Representative axial slices from diffusion-weighted MRI obtained approximately 3 days after stroke onset show bilateral middle cerebral artery infarcts, most likely from a cardioembolic source. Images were warped to standardized space. Left is left. (Source: Casilio M, Kasdan AV, Schneck SM, et al. Situating word deafness within aphasia recovery: a case report. Cortex 2024;173:96-119. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Systemic administration (intravenous) targets the central and the peripheral nervous system and is the only effective route to target the large and anatomically complex muscle tissue effectively. Intrathecal administration allows targeting of the brain, spinal cord, and peripheral nerves, whereas administration through unique anatomical locations, including directly to the brain parenchyma, facilitates specific targeting of the CNS. (Contributed by Dr. Rotem Orbach. Created with BioRender.com.)

Cell transduction with a transgene of interest or a gene editing machinery can be achieved through viral or nonviral vectors, in vivo or ex vivo. (Contributed by Dr. Rotem Orbach. Created with BioRender.com.)

The figure illustrates the main approaches for DNA- and RNA-directed therapies. (Contributed by Dr. Rotem Orbach. Created with BioRender.com.)

The context around treatment modulates several biochemical pathways across different diseases and systems, and these pathways are the same as those modulated by drugs. The involvement of serotonin [5-hydroxytryptamine, 5-HT] receptors in hormonal responses and depression is not definitive. CCK, cholecystokinin; IL-2, interleukin-2; IFNγ, interferon- γ; COX, cyclooxygenase; NSAID, non-steroid anti-inflammatory drugs. (Contributed by Dr. Aziz Shaibani.)

Classification of spinal stenosis based on the morphology of the dural sac on MRI. (Contributed by Dr. Kourosh Rezania.)

A 19-year-old patient developed cardiac arrest. When extubated, she was noted to be cortically blind. Diffusion-weighted MRI and corresponding ADC map (6 days after cardiac arrest) showed evidence for extensive predominantly cortical diffusion restriction most prominent in the right occipital cortex and bilateral basal ganglia. (Contributed by Dr.Sangeeta Khanna.)

(Contributed by Dr. Jonathan Trobe.)

(Source: Courtesy of ZEISS Microscopy, Jena, Germany. Creative Commons Attribution-Share Alike 2.0 Generic [CC BY] license, creativecommons.org/licenses/by-sa/2.0/deed.en.)

(Source: Wikimedia Commons. Public domain.)

In the mammalian nose, odorants are detected by odorant receptors (ORs) in a combinatorial fashion: one odorant can activate multiple odorant receptors, and each odorant receptor can detect more than one odorant. (a) When the combinatorial code was first established, each odorant receptor was tested against a given concentration of a single odorant, and only agonist interactions were analyzed. (b) Recent studies that analyzed the responses of odorant receptors to specific odorants presented as part of odor mixtures found that odorants, in addition to their agonist role, can also serve as modulators (antagonists, inverse agonists, partial agonists, and synergistic ligands) to odorant receptor activity. A “No odorant” condition depicts the activation profile of odorant receptors 1 to 6 in the absence of any odorant. Note: An inverse agonist binds to the same receptor as an agonist but brings about the opposite response to that of an agonist, whereas an antagonist binding to such a receptor will disrupt the interaction and the function of both the agonist and the inverse agonist at the receptor. (Source: Kurian SM, Naressi RG, Manoel D, Barwich AS, Malnic B, Saraiva LR. Odor coding in the mammalian olfactory epithelium. Cell Tissue Res 2021;383[1]:445-56. Creative Commons Attribution 4.0 International [CC BY] license, creativecommons.org/licenses/by/4.0.)

Recent single-cell RNA-sequencing experiments showed that most intact odorant receptors (ORs) are expressed in the olfactory epithelium across a large dynamic range, with only a minority being expressed at very high levels. As measured by single-cell RNA-sequencing, the abundance level of a given odorant receptor in the olfactory epithelium correlates perfectly with the number of olfactory sensory neurons expressing it. The arrow depicts the position of the last odorant receptors plotted. (Source: Kurian SM, Naressi RG, Manoel D, Barwich AS, Malnic B, Saraiva LR. Odor coding in the mammalian olfactory epithelium. Cell Tissue Res 2021;383[1]:445-56. Creative Commons Attribution 4.0 International [CC BY] license, creativecommons.org/licenses/by/4.0.)

In the nose, each mature olfactory sensory neuron (mOSN) expresses one allele of a single odorant receptor (OR) gene. This type of expression became known in the field as the "one neuron - one receptor" rule. (Source: Kurian SM, Naressi RG, Manoel D, Barwich AS, Malnic B, Saraiva LR. Odor coding in the mammalian olfactory epithelium. Cell Tissue Res 2021;383[1]:445-56. Creative Commons Attribution 4.0 International [CC BY] license, creativecommons.org/licenses/by/4.0.)

Expression patterns of odorant receptors in the olfactory epithelium. In the nose, mature olfactory sensory neurons expressing the same odorant receptors gene are stochastically distributed within a spatially restricted area of the olfactory epithelium, also known as a “zone.” Early studies identified four nonoverlapping odorant receptor expression zones, but later studies identified as many as nine to 12 partially overlapping zones. In the schematic, the four nonoverlapping odorant receptor expression zones (blue, red, yellow, and green colors) are shown: left panel, lateral view of the olfactory mucosa; right panel, a coronal section of the olfactory mucosa (including the respiratory epithelium, in grey). (Source: Kurian SM, Naressi RG, Manoel D, Barwich AS, Malnic B, Saraiva LR. Odor coding in the mammalian olfactory epithelium. Cell Tissue Res 2021;383[1]:445-56. Creative Commons Attribution 4.0 International [CC BY] license, creativecommons.org/licenses/by/4.0.)

The major cell types of the mammalian olfactory mucosa. In mammals, the olfactory mucosa is composed of the olfactory epithelium and a submucosa. The olfactory epithelium is a pseudostratified epithelium composed mainly of sustentacular cells (SUCs), globose basal cells (GBCs), horizontal globose cells (HBCs), immature olfactory sensory neurons (iOSNs), and mature olfactory sensory neurons (mOSNs). The olfactory ensheathing cells (OECs) are an important cell type populating the submucosa. (Source: Kurian SM, Naressi RG, Manoel D, Barwich AS, Malnic B, Saraiva LR. Odor coding in the mammalian olfactory epithelium. Cell Tissue Res 2021;383[1]:445-56. Creative Commons Attribution 4.0 International [CC BY] license, creativecommons.org/licenses/by/4.0.)

Each olfactory receptor neuron expresses one olfactory receptor, which responds to different odorants. Odorant molecules bind to olfactory receptors on cilia. Olfactory receptors activate olfactory receptor neurons, which transduce the input signal into action potentials. Glomeruli generally receive input from olfactory receptors of one specific type and connect to the principal neurons of the olfactory bulb and mitral and tufted cells. Legend: (MT) mitral/tufted. (OB) Olfactory bulb. (OR) Olfactory receptors. (ORN) Olfactory receptor neuron (also called OSN, olfactory sensory neuron). (Source: Wikimedia Commons, derived from: Auffarth B, Kaplan B, Lansner A. Map formation in the olfactory bulb by axon guidance of olfactory neurons. Front Syst Neurosci 2011;5:84. Creative Commons Attribution 3.0 Unported [CC BY 3.0] license, creativecommons.org/licenses/by/3.0/deed.en.)

Cajal drawing showing the olfactory cortex layers. Legend: (A) Olfactory fibers layer. (B) Plexiform layer. (C) Layer of polymorphic superficial cells. (D) Layer of the pyramids. (E) Deep polymorphous cells. (b) Bifurcation of axons. (Source: Ramón y Cajal S. Estudios sobre la corteza cerebral humana. IV. Estructura de la corteza cerebral olfativa del hombre y mamíferos. Trab Lab Invest Biol 1901;1:1-140. Instituto Cajal, Madrid, Spain. See: Figueres-Oñate M, Gutiérrez Y, López-Mascaraque L. Unraveling Cajal's view of the olfactory system. Front Neuroanat 2014;8:55. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/4.0.)

Olig2 (oligodendrocyte progenitors, red), S100β (astrocytes, green), and myelin binding protein (MBP, gray). Nuclei labeled with Hoechst (blue). (Source: Figueres-Oñate M, Gutiérrez Y, López-Mascaraque L. Unraveling Cajal's view of the olfactory system. Front Neuroanat 2014;8:55. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/4.0.)

Cajal drawing of an olfactory bulb section of a month-old rat. Weigert-Pal method. Legend: (A) Layer of the glomeruli. (B) Lower molecular layer. (C) Mitral layer. (D) Higher molecular layer. (E) Coating the grains. (a) Myelin fiber corresponding to the cylinder-axis of mitral cells. (b) Cylinder-axis of mitral cells. (c) Core fiber from within the glomeruli. (d) Bundles of fibers in the layer of grains. (e) Thin horizontal strands from the higher molecular area. (f) Mitral cells. (g) Glomerulus. (Source: Ramón y Cajal, 1890. Instituto Cajal, Madrid, Spain. See: Figueres-Oñate M, Gutiérrez Y, López-Mascaraque L. Unraveling Cajal's view of the olfactory system. Front Neuroanat 2014;8:55. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/4.0.)

Fernando de Castro (1896-1918) drawing illustrating the glomerular layer of the adult dog stained by the Cajal’s gold chloride sublimate method. Legend: (g) Intraglomerular fibrous elements. (a) Radioglomerular corpuscles. (f) Fibrous cells are located superficial to the molecular zone, displaying most of their extensions oriented toward the deepest layers. Note numerous nuclei located in this region, corresponding to Cajal’s adendritic glia. (Source: De Castro, 1920. Instituto Cajal, Madrid, Spain. See: Figueres-Oñate M, Gutiérrez Y, López-Mascaraque L. Unraveling Cajal's view of the olfactory system. Front Neuroanat 2014;8:55. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/4.0.)

Fernando de Castro (1896-1918) drawing of human olfactory bulb stained with Cajal’s gold chloride sublimate method. Legend: (A) Superficial substratum of the molecular layer with numerous cephalopodic cells. (B) Deep substratum. (C) Mitral cell layer. (D) Grains layer. (Source: De Castro, 1920. Instituto Cajal, Madrid, Spain. See: Figueres-Oñate M, Gutiérrez Y, López-Mascaraque L. Unraveling Cajal's view of the olfactory system. Front Neuroanat 2014;8:55. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/4.0.)

Cajal drawing of an olfactory bulb section from a several-day-old cat. Legend: (A) Glomerular layer. (B) Outer plexiform layer. (C) Mitral cell layer. (D) Inner plexiform layer. (D) Grains layer. (E) White matter. (a) Terminal arborization of an olfactory fiber. (b) Glomerulus with several endings. (c) Mitral plume. (d) Tufted cells. (Source: Ramón y Cajal S. Estudios sobre la corteza cerebral humana. IV. Estructura de la corteza cerebral olfativa del hombre y mamíferos. Trab Lab Invest Biol 1901;1:1-140. Instituto Cajal, Madrid, Spain. See: Figueres-Oñate M, Gutiérrez Y, López-Mascaraque L. Unraveling Cajal's view of the olfactory system. Front Neuroanat 2014;8:55. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/4.0.)

Drawing by Cajal’s disciple Tomás Blanes Viale (1878-1900), showing periglomerular cells of a cat glomerular layer. Legend: (A) Cell branching into three glomeruli. (B-D) Biglomerular cells. (C-E) Monoglomerular cells. (a) Axon. (Source: Blanes T. Sobre algunos puntos dudosos de la estructura del bulbo olfatorio. Rev Trimest Microgr 1898;3:99-127. Instituto Cajal, Madrid, Spain. See: Figueres-Oñate M, Gutiérrez Y, López-Mascaraque L. Unraveling Cajal's view of the olfactory system. Front Neuroanat 2014;8:55. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/4.0.)

Coronal section of a mouse olfactory bulb stained with hematoxylin and eosin and showing the different layers described by Cajal in previous figure (“Rabbit olfactory bulb, frontal section”). Legend: EPL: External plexiform layer; GcL: Granular and white matter layer; GL: Glomerular layer; IPL: Inner plexiform layer; MCL: Mitral cells layer; ONL: Olfactory nerve layer. (Source: Ramón y Cajal S. Estudios sobre la corteza cerebral humana. IV. Estructura de la corteza cerebral olfativa del hombre y mamíferos. Trab Lab Invest Biol 1901;1:1-140. Instituto Cajal, Madrid, Spain. Figueres-Oñate M, Gutiérrez Y, López-Mascaraque L. Unraveling Cajal's view of the olfactory system. Front Neuroanat 2014;8:55. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/4.0.)

Cajal's drawing of the frontal section of the rabbit olfactory bulb, showing the layered distribution of cells. Legend: (1) Olfactory nerve layer. (2) Glomerular layer. (3) External plexiform layer. (4) Mitral cells layer. (5) Inner plexiform layer. (6) Granular and white matter layer. (a) Peripheral tufted cells, (b) middle; (c) internal (d) short axon cells. (Source: Ramón y Cajal S. Estudios sobre la corteza cerebral humana. IV. Estructura de la corteza cerebral olfativa del hombre y mamíferos. Trab Lab Invest Biol 1901;1:1-140. Instituto Cajal, Madrid, Spain. Figueres-Oñate M, Gutiérrez Y, López-Mascaraque L. Unraveling Cajal's view of the olfactory system. Front Neuroanat 2014;8:55. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/4.0.)

Axonal arborizations of olfactory sensory neuron axons in several glomeruli stained with the Golgi method. (Source: Figueres-Oñate M, Gutiérrez Y, López-Mascaraque L. Unraveling Cajal's view of the olfactory system. Front Neuroanat 2014;8:55. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/4.0.)

Cajal's schematic drawing of the mammal’s olfactory system. Legend: (A) Olfactory lobe. (B) Olfactory bulb’s glomerular layer. (C) Cribriform plate. (D) Olfactory epithelium or nasal mucosa. (a) Supporting cells. (b) Olfactory sensory neurons. (Source: Ramón y Cajal S. Nuevo concepto de la Histología de los centros nerviosos. Conferencia III. Rev Cienc Méd Barc 1892;18:457-76. Instituto Cajal, Madrid, Spain. See also: Figueres-Oñate M, Gutiérrez Y, López-Mascaraque L. Unraveling Cajal's view of the olfactory system. Front Neuroanat 2014;8:55. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/4.0.)

Immunohistochemistry for the Tuj1 marker in mouse olfactory epithelium shows both mature and immature olfactory sensory neurons. (Source: Figueres-Oñate M, Gutiérrez Y, López-Mascaraque L. Unraveling Cajal's view of the olfactory system. Front Neuroanat 2014;8:55. Photomicrograph by Albert Blanchart. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/4.0.)

Olfactory epithelium labeled E18 cells after in-utero electroporation of an EGP-expressing plasmid injected into the olfactory placode at E14 (green). Hoechst (blue). Sagittal mouse section. a-e, n correspond to the counterpart structures labeled by Cajal in previous figure (“Cell types and their morphologies in the olfactory epithelium”). Legend: Olfactory sensory neurons components: (n) nucleus, (b) dendrite, (c) apical cilia, (a) axon, (d) olfactory sensory neuron axons bundle, (e) supporting or sustentacular cell. (Source: Figueres-Oñate M, Gutiérrez Y, López-Mascaraque L. Unraveling Cajal's view of the olfactory system. Front Neuroanat 2014;8:55. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/4.0.)

Cajal drawing illustrating the cell types and their morphologies in the olfactory epithelium. Legend: Olfactory sensory neuron components: (n) nucleus, (b) dendrite, (c) apical cilia, (a) axon, (d) olfactory sensory neuron axons bundle, (e) supporting or sustentacular cell. The drawing shows the handwriting of Cajal with specific instructions for the required reduction publication factor in the margins. (Source: Instituto Cajal, Madrid, Spain. Figueres-Oñate M, Gutiérrez Y, López-Mascaraque L. Unraveling Cajal's view of the olfactory system. Front Neuroanat 2014;8:55. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/4.0.)

Olfactory sensory neurons (green) at E17, labeled after in-utero electroporation of an EGP-expressing plasmid into the olfactory placode at E11. Nuclei counterstained with Hoechst (blue). Sagittal mouse brain section. (Source: Figueres-Oñate M, Gutiérrez Y, López-Mascaraque L. Unraveling Cajal's view of the olfactory system. Front Neuroanat 2014;8:55. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/4.0.)

Immunohistochemical staining for Dab1 protein (reelin signaling mediator, green) and Map2a,b protein (microtubule-associated protein, red) on mouse olfactory bulb sections at P3. Nuclei counterstained with Hoechst (blue). Legend: (D) Olfactory nerve layer. (E) Olfactory glomerular layer. (F) External plexiform layer. (G) Mitral cell body layer. (H) Internal plexiform layer. (I) Granule layer. (Source: Martín-López E, Blanchart A, De Carlos JA, López-Mascaraque L. Dab1 (Disable homolog-1) reelin adaptor protein is overexpressed in the olfactory bulb at early postnatal stages. PLoS One 2011;6[10]:e26673. See also: Figueres-Oñate M, Gutiérrez Y, López-Mascaraque L. Unraveling Cajal's view of the olfactory system. Front Neuroanat 2014;8:55. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/4.0.)

Cajal’s diagram outlining the circuitry and the trajectory of the nerve impulse (1894). The trajectory of the nerve impulse is shown by arrows. (A) Bipolar cells of the olfactory mucosa. (B) Olfactory glomeruli. (C) Mitral cells. (D) Grains. (E) External root (lateral olfactory tract). (F) Olfactory cortex. (a) Small tufted cell. (b) Main dendrite of a mitral cell. (c) Terminal branch of a grain. (e) Recurrent collaterals of a mitral cell. (g) Surface triangular cells of the olfactory cortex. (h) Epithelial cells of the nasal mucosa. (Source: Ramón y Cajal S. Croonian Lecture: la fine structure des centres nerveux. Proc R Soc Lond 1894;55:444-68. Instituto Cajal, Madrid, Spain. See: Figueres-Oñate M, Gutiérrez Y, López-Mascaraque L. Unraveling Cajal's view of the olfactory system. Front Neuroanat 2014;8:55. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/4.0.)

Cartoon of the olfactory system by Santiago Ramón y Cajal (1894). (Source: Instituto Cajal, Madrid, Spain. Figueres-Oñate M, Gutiérrez Y, López-Mascaraque L. Unraveling Cajal's view of the olfactory system. Front Neuroanat 2014;8:55. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/4.0.)