Peripheral Neuropathies

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.

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.)

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.)

MRI of the head/ internal auditory canal with gadolinium demonstrated asymmetrical enhancement of the tympanic and mastoid segments of the left facial nerve and both internal auditory canals. (Source: Sheik-Ali S, Jiang Y, Nasef H, Sproson E, Tuohy O. Bilateral sequential Ramsay Hunt syndrome in an immunocompromised adult: a rare entity. Ann R Coll Surg Engl 2024;106[2]:197-9 Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Extensive vesicular eruption involving the left pinna and external auditory canal, with an associated necrotic focus in the conchal bowl and subsequent blistering. (Source: Sheik-Ali S, Jiang Y, Nasef H, Sproson E, Tuohy O. Bilateral sequential Ramsay Hunt syndrome in an immunocompromised adult: a rare entity. Ann R Coll Surg Engl 2024;106[2]:197-9 Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Abbreviations: CCL18: chemokine ligand 18; ERT: enzyme replacement therapy; GauSS-I: Gaucher Severity Score Index for type I patients; GD-DS3: Gaucher disease type I severity scoring system; IV: intravenous; Lyso-Gb1/Lyso-GL1: glucosylsphingosine; MDT: multidisciplinary team; NSAIDS: non-steroidal anti-inflammatory drugs; PARC: pulmonary and activation-regulated chemokine; SRT: substrate reduction therapy; SSI: severity score index; TDS: three times daily; Tx: treatment.

(Adapted from: Torralba-Cabeza MÁ, Olivera-González S, Sierra-Monzón JL. The importance of a multidisciplinary approach in the management of a patient with type I Gaucher disease. Diseases 2018;6[3]:69.)

(Source: Louw VJ, Fraser I, Giraldo P. Management goals of type 1 Gaucher disease in South Africa: an expert Delphi consensus document on good clinical practice. PLoS One 2023;18[8]:e0290401. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Treatments are shown at the top. Neurologic findings and laboratory data are depicted in the middle and lower schemes, respectively. Abbreviations: ACE, angiotensin-converting enzyme; TRACP-5b, tartrate-resistant acid phosphatase 5b. (Source: Higashi K, Sonoda Y, Kaku N, et al. Rapid and long-lasting efficacy of high-dose ambroxol therapy for neuronopathic Gaucher disease: a case report and literature review. Mol Genet Genomic Med 2024;12[4]:e2427. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Sagittal T1-weighted (left) and axial fluid-attenuated inversion recovery (FLAIR, middle) image on day 24 of admission. No parenchymal lesion was detected in the FLAIR image at 3 months after discharge (right). (Source: Higashi K, Sonoda Y, Kaku N, et al. Rapid and long-lasting efficacy of high-dose ambroxol therapy for neuronopathic Gaucher disease: a case report and literature review. Mol Genet Genomic Med 2024;12[4]:e2427. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

May-Grunwald-Giemsa staining for Gaucher cells (arrows) in the bone-marrow smear. Scale, 10 μm. (Source: Higashi K, Sonoda Y, Kaku N, et al. Rapid and long-lasting efficacy of high-dose ambroxol therapy for neuronopathic Gaucher disease: a case report and literature review. Mol Genet Genomic Med 2024;12[4]:e2427. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Left) When self-amplifying RNA (saRNA) is injected and delivered into cells, the translation of replicase takes place. The replicase uses the saRNA as a template and makes a negative saRNA strand, which in turn serves as a template for self-amplification by the replicase. Replicase recognizes sub-genomic promoter in the negative strand, so sgRNA is synthesized. Consequently, high levels of glucocerebrosidase are produced. (Right) When the mRNA is injected and delivered into the cells, it is translated into glucocerebrosidase protein. Ultimately, the glucocerebrosidase produced breaks down the GlcCer into glucose and ceramide leading to the normal condition.

Abbreviations: saRNA, self-amplifying RNA; mRNA, messenger RNA; sgPr, sub-genomic promoter; GD, Gaucher disease; GCase, glucocerebrosidase; GlcCer, glucosylceramide.

(Source: Feng S, Rcheulishvili N, Jiang X, et al. A review on Gaucher disease: therapeutic potential of β-glucocerebrosidase-targeted mRNA/saRNA approach. Int J Biol Sci 2024;20[6]:2111-29. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Normally, GBA1 is transcribed into mRNA, which is subsequently exported from the nucleus to the endoplasmic reticulum where glucocerebrosidase is synthesized. Glucocerebrosidase binds to LIMP-2, which is essential for the regulation of glucocerebrosidase transport from the endoplasmic reticulum through the Golgi apparatus (where the glucocerebrosidase protein undergoes maturation) to the lysosomes. The binding occurs at a neutral pH, and dissociation takes place within the acidic lysosomal environment. In the lysosome, with the support of its essential co-factor saposin C, glucocerebrosidase catalyzes the hydrolysis of GlcCer into glucose and ceramide. Due to a GBA1 mutation in Gaucher disease, the mutant glucocerebrosidase produced is a target for endoplasmic reticulum-associated degradation and proteasomal breakdown. Mutant glucocerebrosidase is unable to reach the lysosome, causing accumulation of GlcCer within the lysosomal compartment. The upregulated levels of intracellular GlcCer promote the formation of toxic soluble alpha-synuclein assemblies, exacerbating a pathogenic cycle by impairing the maturation of lysosomes and inhibiting the activity of functional glucocerebrosidase. This impairment results in further GlcCer accumulation and augmented alpha-synuclein formation due to its hampered degradation, leading to the release of inflammatory cytokines. The enzyme, known as GBA2 (the so-called second glucocerebrosidase), transforms GlcSph (also known as lyso-GlcCer) into sphingosine, which subsequently undergoes phosphorylation, resulting in the production of sphingosine-1-phosphate. Enhanced inflammatory response, along with the associated pathophysiology, contributes to bone fragility, lowering the erythrocyte and platelet levels and reducing lung function, and may also lead to neurodegeneration. Black arrows represent reactions that proceed normally. Broken red arrows indicate the normal reactions that do not occur. Solid red arrows denote the harmful reactions that do take place.

Abbreviations: GD, Gaucher disease; GCase, glucocerebrosidase; LIMP-2, lysosomal integral membrane protein 2; ER, endoplasmic reticulum; ERAD, endoplasmic reticulum-associated degradation; GlcCer, glucosylceramide; α-Syn, α-synuclein; GBA2, β-glucocerebrosidase 2; S1P, sphingosine-1-phosphate; lyso-GlcCer, lyso-glucosylceramide.

(Source: Feng S, Rcheulishvili N, Jiang X, et al. A review on Gaucher disease: therapeutic potential of β-glucocerebrosidase-targeted mRNA/saRNA approach. Int J Biol Sci 2024;20[6]:2111-29. 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.)

In a patient with Gaucher disease type 1 (GBA1 genotype p.Asn409Ser/c.217delC mutations), MRI revealed diffuse bone marrow signal abnormality throughout the left femur consistent with avascular osteonecrosis. (Source: Basiri M, Ghaffari ME, Ruan J, et al. Osteonecrosis in Gaucher disease in the era of multiple therapies: biomarker set for risk stratification from a tertiary referral center. Elife 2023;12:e87537. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

A few months after initial MRI, the patient developed avascular osteonecrosis in the right femur. (Source: Basiri M, Ghaffari ME, Ruan J, et al. Osteonecrosis in Gaucher disease in the era of multiple therapies: biomarker set for risk stratification from a tertiary referral center. Elife 2023;12:e87537. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The 3D MRI rendering shows a tick (arrow) on the surface of the head. (Source: Sarwar Z, Osborne AF, Shah C, Rathore MH. Neuroimaging in tick paralysis: looking outside the box. Infect Dis Rep 2022;14(6):837-40. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Sagittal T1-weighted MRI of the brain shows a tick in the occipital region (arrow). (Source: Sarwar Z, Osborne AF, Shah C, Rathore MH. Neuroimaging in tick paralysis: looking outside the box. Infect Dis Rep 2022;14(6):837-40. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Axial T1-weighted MRI of the brain at the level of the medulla shows a normal appearance of the medulla and the cerebellum. However, on closer inspection, there is a small, isointense area (arrow) seen attached to the skin in the occipital region on the right side. (Source: Sarwar Z, Osborne AF, Shah C, Rathore MH. Neuroimaging in tick paralysis: looking outside the box. Infect Dis Rep 2022;14(6):837-40. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Sarwar Z, Osborne AF, Shah C, Rathore MH. Neuroimaging in tick paralysis: looking outside the box. Infect Dis Rep 2022;14(6):837-40. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0. Image cropped from original.)

(Source: Cooperrider J, Kriegler J, Yunus S, Wilson R. A survey-based study examining differences in perception of postural orthostatic tachycardia syndrome between patients and primary care physicians. Cureus 2022;14[10]:e30167. Creative Commons Attribution [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Follow up at 3 months in a 27-year-old woman with granulomatous cheilitis. (Source: Tummidi S, Nagendran P, Anthony ML, Ramani RJ, Shankaralingappa A, Gopinath H. Granulomatous cheilitis of Miescher: a rare entity. BMC Womens Health 2023;23[1]:118. Creative Commons Attribution 4.0 International [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0. The image has been cropped from the original.)

Follow up at 1 month in a 27-year-old woman with granulomatous cheilitis. (Source: Tummidi S, Nagendran P, Anthony ML, Ramani RJ, Shankaralingappa A, Gopinath H. Granulomatous cheilitis of Miescher: a rare entity. BMC Womens Health 2023;23[1]:118. Creative Commons Attribution 4.0 International [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0. The image has been cropped from the original.)

Photomicroscopy of a biopsy from a 27-year-old woman who presented with a 3-month history of unrelenting upper lip swelling. The noncaseating granuloma is comprised of epithelioid cells, with a sprinkling of lymphocytes, histocytes, and multinucleated giant cells (red arrow) (H&E x 40). (Source: Tummidi S, Nagendran P, Anthony ML, Ramani RJ, Shankaralingappa A, Gopinath H. Granulomatous cheilitis of Miescher: a rare entity. BMC Womens Health 2023;23[1]:118. Creative Commons Attribution 4.0 International [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0. The image has been cropped from the original.)

Photomicroscopy of a biopsy from a 27-year-old woman who presented with a 3-month history of unrelenting upper lip swelling. The noncaseating granuloma is comprised of epithelioid cells, with a sprinkling of lymphocytes, histocytes, and multinucleated giant cells (red arrow) (H&E x 40). (Source: Tummidi S, Nagendran P, Anthony ML, Ramani RJ, Shankaralingappa A, Gopinath H. Granulomatous cheilitis of Miescher: a rare entity. BMC Womens Health 2023;23[1]:118. Creative Commons Attribution 4.0 International [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0. The image has been cropped from the original.)

Photomicroscopy of a biopsy from a 27-year-old woman who presented with a 3-month history of unrelenting upper lip swelling. A few dilated lymphatics (green arrow) are seen adjacent to the granuloma along with mild perivascular lymphoplasmacytic cuffing (H&E x 40). The noncaseating granuloma is comprised of epithelioid cells, with a sprinkling of lymphocytes, histocytes (orange arrow), and multinucleated giant cells. (Source: Tummidi S, Nagendran P, Anthony ML, Ramani RJ, Shankaralingappa A, Gopinath H. Granulomatous cheilitis of Miescher: a rare entity. BMC Womens Health 2023;23[1]:118. Creative Commons Attribution 4.0 International [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0. The image has been cropped from the original.)

Photomicroscopy of a biopsy from a 27-year-old woman who presented with a 3-month history of unrelenting upper lip swelling. The biopsy shows mucosal lining with parakeratotic stratified squamous epithelium. Mid dermis with presence of noncaseating granuloma (H&E ×10). (Source: Tummidi S, Nagendran P, Anthony ML, Ramani RJ, Shankaralingappa A, Gopinath H. Granulomatous cheilitis of Miescher: a rare entity. BMC Womens Health 2023;23[1]:118. Creative Commons Attribution 4.0 International [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0. The image has been cropped from the original.)

Non-tender diffuse swollen and firm upper lip and perioral area with areas of scaling in a 27-year-old woman who presented with a 3-month history of this problem. Biopsy from the lesion was consistent with granulomatous cheilitis. (Source: Tummidi S, Nagendran P, Anthony ML, Ramani RJ, Shankaralingappa A, Gopinath H. Granulomatous cheilitis of Miescher: a rare entity. BMC Womens Health 2023;23[1]:118. Creative Commons Attribution 4.0 International [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0. The image has been cropped from the original.)

Photograph shows the fissured tongue in a 38-year-old woman referred by her dentist for evaluation of recurrent swelling of the lower lip along with left hemifacial palsy. She was diagnosed with Melkersson-Rosenthal syndrome based on its three clinical features: recurrent facial palsy, orofacial swelling, and fissured tongue. (Source: Aoun G, Skandri N, Ghattas H, Maksoud C. Melkersson-Rosenthal syndrome in a 38-year-old female patient: a rare case with complete triad. Cureus 2022;14[7]:e27427. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0. The image has been cropped from the original.)

Photograph shows swelling of the lower lip in a 38-year-old woman referred by her dentist for evaluation of recurrent swelling of the lower lip along with left hemifacial palsy. She was diagnosed with Melkersson-Rosenthal syndrome based on its three clinical features: recurrent facial palsy, orofacial swelling, and fissured tongue. (Source: Aoun G, Skandri N, Ghattas H, Maksoud C. Melkersson-Rosenthal syndrome in a 38-year-old female patient: a rare case with complete triad. Cureus 2022;14[7]:e27427. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0. The image has been cropped from the original.)

The blink reflex test reveals absent responses of ipsilateral R1 and R2 and contralateral R2 at stimulation of the right supraorbital nerve. (Source: Hwang YS, Kim YS, Shin BS, Kang HG. Two cases of Ramsay-Hunt syndrome following varicella zoster viral meningitis in young immunocompetent men: case reports. BMC Neurol 2023;23[1]:43. Creative Commons Attribution 4.0 International [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The blink reflex test reveals absent responses of ipsilateral R1 and R2 and contralateral R2 at stimulation of the right supraorbital nerve. (Source: Hwang YS, Kim YS, Shin BS, Kang HG. Two cases of Ramsay-Hunt syndrome following varicella zoster viral meningitis in young immunocompetent men: case reports. BMC Neurol 2023;23[1]:43. Creative Commons Attribution 4.0 International [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Internal auditory canal (IAC) MRI image of a patient with herpes zoster oticus. The post-contrast 3D T1-weighted image shows contrast enhancement in the left vestibulocochlear nerve (small arrow) and the dura of the left IAC (large arrow). (Source: Lee J, Choi JW, Kim CH. Features of audio-vestibular deficit and 3D-FLAIR temporal bone MRI in patients with herpes zoster oticus. Viruses 2022;14[11]:2568. Creative Commons Attribution 4.0 International [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Internal auditory canal MRI image of a patient with herpes zoster oticus. The post-contrast 3D T1-weighted image shows that the labyrinthine segment of the left facial nerve is enhanced (arrow). (Source: Lee J, Choi JW, Kim CH. Features of audio-vestibular deficit and 3D-FLAIR temporal bone MRI in patients with herpes zoster oticus. Viruses 2022;14[11]:2568. Creative Commons Attribution 4.0 International [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Contrast‐enhanced T1‐weighted MRI of the brain showing enhancement in the right facial nerve (white arrows). (Source: Hwang YS, Kim YS, Shin BS, Kang HG. Two cases of Ramsay-Hunt syndrome following varicella zoster viral meningitis in young immunocompetent men: case reports. BMC Neurol 2023;23[1]:43. Creative Commons Attribution 4.0 International [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The facial nerve conduction study reveals a prolonged terminal latency and reduced compound muscle action potential amplitude upon direct stimulation of the right facial nerve. NCV = nerve conduction velocity. (Source: Hwang YS, Kim YS, Shin BS, Kang HG. Two cases of Ramsay-Hunt syndrome following varicella zoster viral meningitis in young immunocompetent men: case reports. BMC Neurol 2023;23[1]:43. Creative Commons Attribution 4.0 International [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Pure-tone audiometry revealing both increased air and bone conduction thresholds without an air-bone gap in the right ear, consistent with predominantly high-frequency sensorineural hearing loss. (Source: Hwang YS, Kim YS, Shin BS, Kang HG. Two cases of Ramsay-Hunt syndrome following varicella zoster viral meningitis in young immunocompetent men: case reports. BMC Neurol 2023;23[1]:43. Creative Commons Attribution 4.0 International [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Vesicles noted along the medial aspect of the antihelix of the right ear (arrow). (Source: Gillette BT, Heilbronn CM. A rare case of vocal cord paralysis in the setting of Ramsay Hunt syndrome. Cureus 2023;15[3]:e36027. Creative Commons Attribution [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Initial onset of Ramsay Hunt syndrome. Right facial palsy presented as an asymmetric mouth and incomplete closure of the right eye. The patient received a Grade V score on the House-Brackmann Facial Paralysis Scale. (Source: Chou CC, Lo YT, Su HC, Chang CM. Fear of falling as a potential complication of Ramsay Hunt syndrome in older adults: a case report. BMC Geriatr 2022;22[1]:901. Creative Commons Attribution 4.0 International [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0. The image was cropped from the original.)

Pure-tone audiogram showing right-sided sensorineural hearing loss of 43 dB PTA (pure-tone average) in a 42-year-old woman with herpes zoster oticus, delayed facial nerve palsy, and cranial polyneuropathy. (Source: Al-Ani RM. Ramsay Hunt syndrome with cranial polyneuropathy and delayed facial nerve palsy: a case report. Cureus 2022;14[7]:e27434. Creative Commons Attribution 4.0 International [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Right peripheral facial nerve paralysis with flattening of the nasolabial fold, drop of the oral angle, and reduced wrinkles on the forehead in a 42-year-old woman with herpes zoster oticus, delayed facial nerve palsy, and cranial polyneuropathy. (Source: Al-Ani RM. Ramsay Hunt syndrome with cranial polyneuropathy and delayed facial nerve palsy: a case report. Cureus 2022;14[7]:e27434. Creative Commons Attribution 4.0 International [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Vesicular eruption of the right auricle (A), external auditory canal, and tympanic membrane (B) in a 42-year-old woman with herpes zoster oticus, delayed facial nerve palsy, and cranial polyneuropathy. (Source: Al-Ani RM. Ramsay Hunt syndrome with cranial polyneuropathy and delayed facial nerve palsy: a case report. Cureus 2022;14[7]:e27434. Creative Commons Attribution 4.0 International [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Three-dimensional rendering of glucocerebrosidase with catalytic residues highlighted. (Illustration by Samschrnbrg1 on March 9, 2018. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0. Figure edited by Dr. Douglas J Lanska.)

Three-dimensional rendering of human glucocerebrosidase with three distinct domains highlighted in different colors. (Illustration by Samschrnbrg1 on March 7, 2018. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0. Figure edited by Dr. Douglas J Lanska.)

Hematoxylin and eosin stain. Necrotic bone is characterized histomorphologically by a lack of osteocytes in the lacunae. (Photomicrograph by Nephron in May 2011 via Wikimedia Commons. Creative Commons Attribution 3.0 Unported [CC BY 3.0] license, creativecommons.org/licenses/by/3.0.)

Hematoxylin and eosin stain. Necrotic bone is characterized histomorphologically by a lack of osteocytes in the lacunae. (Photomicrograph by Nephron in May 2011 via Wikimedia Commons. Creative Commons Attribution 3.0 Unported [CC BY 3.0] license, creativecommons.org/licenses/by/3.0.)

Hematoxylin and eosin stain. Necrotic bone is characterized histomorphologically by a lack of osteocytes in the lacunae. (Photomicrograph by Nephron in May 2011 via Wikimedia Commons. Creative Commons Attribution 3.0 Unported [CC BY 3.0] license, creativecommons.org/licenses/by/3.0.)

Thudichum isolated and characterized numerous compounds of the brain, such as cephalin, sphingomyelin, galactose, lactic acid, and sphingosine. In 1884, he explained his findings in a publication titled "A Treatise on the Chemical Constitution of the Brain," a book that was widely criticized in the scientific community (Thudichum 1884). After his death, Thudichum's discoveries were realized to be important scientific contributions to the study of the chemical and molecular composition of the brain.

Reference: Thudichum JL. A Treatise on the Chemical Constitution of the Brain: Based Throughout upon Original Researches. London : Bailliere, Tindall, and Cox, 1884.

(Source: Courtesy of the US National Library of Medicine. Public domain.)

A chamber and the cells it contains, high magnification (x330). Drawing by Gaucher for his thesis. (Source: Gaucher E. De l'epithélioma primitif de la rate: hypertrophie idiopathique de la rate sans leucémie. Paris: Octave Doin, 1882.)

Drawing by Gaucher for his thesis. "We see the hyperplastic connective tissue and the compartments they limit filled with epithelial cells. – In a, a bloody effusion." (Magnification x60). (Source: Gaucher E. De l'epithélioma primitif de la rate: hypertrophie idiopathique de la rate sans leucémie. Paris: Octave Doin, 1882.)

Drawing by Gaucher for his thesis. "We see in a, in one of the compartments, a bloody effusion. The section is limited on the right by the thickened outer fibrous envelope. In the large fibrous spans, we see sclerotic vessels." (Magnification x60). (Source: Gaucher E. De l'epithélioma primitif de la rate: hypertrophie idiopathique de la rate sans leucémie. Paris: Octave Doin, 1882.)

(Source: National Institutes of Health. Public domain.)

(Image by WillowW on May 19, 2006, via Wikimedia Commons. Creative Commons Attribution 3.0 Unported [CC BY 3.0] license, creativecommons.org/licenses/by/3.0.)

Mallory's aniline blue connective tissue stain (x560). Marked longitudinal fibrillation of the cytoplasm of the Gaucher cells. (Source: Bloom W. Splenomegaly [type Gaucher] and lipid-histiocytosis [type Niemann]. Am J Pathol 1925;1[6]:595-626.9.)

Hemalum and eosin stain (x240). Mayer’s hemalum solution for nuclear staining and eosin solution for counterstaining. (Source: Bloom W. Splenomegaly [type Gaucher] and lipid-histiocytosis [type Niemann]. Am J Pathol 1925;1[6]:595-626.9.)

Mutated GCase or decreased levels of GCase cause a slowdown of alpha-synuclein degradation with the resulting formation of alpha-synuclein oligomers and fibrils (Cullen et al 2011; Yap et al 2011; Murphy et al 2014). Glucosylceramide stabilizes the alpha-synuclein oligomers (Mazzulli et al 2011), which are able to bind to the mutated glucocerebrosidase molecules and inhibit the enzymatic activity of glucocerebrosidase, further decreasing enzyme activity (Mazzulli et al 2011; Yap et al 2013a; 2015). These impaired lysosomes show impaired chaperone-mediated autophagy and autophagosome fusion. This results in an increased accumulation of alpha-synuclein in the cytoplasm, forming insoluble aggregates that ultimately form Lewy bodies. These aggregates block trafficking of GCase from the endoplasmic reticulum (ER) to the Golgi (Siebert et al 2014). Mutant GCase is retained in the endoplasmic reticulum, which causes ER stress and evokes the ER stress response (unfolded protein response) (Horowitz et al 2016). Saposin C can have a modulating effect on this by binding to Gcase, thus, maintaining its activity (Yap et al 2013b; Gruschus et al 2015).

References:
Cullen V, Sardi SP, Ng J, et al. Acid β-glucosidase mutants linked to Gaucher disease, Parkinson disease, and Lewy body dementia alter alpha-synuclein processing. Ann Neurol 2011;69(6):940-53.
Gruschus JM, Jiang Z, Yap TL, et al. Dissociation of glucocerebrosidase dimer in solution by its co-factor, saposin C. Biochem Biophys Res Commun 2015;457(4):561-6.
Horowitz M, Elstein D, Zimran A, Goker-Alpan O. New directions in Gaucher disease. Hum Mutat 2016;37(11):1121-36.
Mazzulli JR, Xu YH, Sun Y, et al. Gaucher disease glucocerebrosidase and alpha-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 2011;146:37-52.
Murphy KE, Gysbers AM, Abbott SK, et al. Reduced glucocerebrosidase is associated with increased alpha-synuclein in sporadic Parkinson's disease. Brain 2014;137(Pt 3):834-48.
Siebert M, Sidransky E, Westbroek W. Glucocerebrosidase is shaking up the synucleinopathies. Brain 2014;137(Pt 5):1304-22.
Yap TL, Gruschus JM, Velayati A, et al. Alpha-synuclein interacts with glucocerebrosidase providing a molecular link between Parkinson and Gaucher diseases. J Biol Chem 2011;286(32):28080-8.
Yap TL, Gruschus JM, Velayati A, Sidransky E, Lee JC. Saposin C protects glucocerebrosidase against α-synuclein inhibition. Biochemistry 2013b;52(41):7161-3.
Yap TL, Jiang Z, Heinrich F, et al. Structural features of membrane-bound glucocerebrosidase and alpha-synuclein probed by neutron reflectometry and fluorescence spectroscopy. J Biol Chem 2015;290(2):744-54.
Yap TL, Velayati A, Sidransky E, Lee JC. Membrane-bound alpha-synuclein interacts with glucocerebrosidase and inhibits enzyme activity. Mol Genet Metab 2013a;108(1):56-64.

(Source: Stirnemann J, Belmatoug N, Camou F, et al. A review of Gaucher disease pathophysiology, clinical presentation, and treatments. Int J Mol Sci 2017;18[2]:441. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Normally, GCase interacts with its substrate glucosylceramiide (GlcCer) as well as monomers of alpha-synuclein in lysosomes, facilitating the breakdown of both at acidic pH. (Source: Stirnemann J, Belmatoug N, Camou F, et al. A review of Gaucher disease pathophysiology, clinical presentation, and treatments. Int J Mol Sci 2017;18[2]:441. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

LIMP-2 is a lysosomal membrane protein (LMP) whose highly glycosylated intra-lysosomal part protects the lysosome’s membrane. LIMP-2 anomalies can induce a phenotype rather than GD3 (Gonzalez A, Valeiras M, Sidransky E, Tayebi N. Lysosomal integral membrane protein-2: a new player in lysosome-related pathology. Mol Genet Metab 2014;111[2]:84-91).

(Source: Stirnemann J, Belmatoug N, Camou F, et al. A review of Gaucher disease pathophysiology, clinical presentation and treatments. Int J Mol Sci 2017;18[2]:441. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0. Figure modified by Dr. Douglas J Lanska.)

Protein maturation takes place in the Golgi apparatus; the transport and delivery of GCase to lysosomes require a particular molecule, LIMP-2, which allows GCase to reach the lysosome where the acidic pH breaks the molecular link (Gonzalez A, Valeiras M, Sidransky E, Tayebi N. Lysosomal integral membrane protein-2: a new player in lysosome-related pathology. Mol Genet Metab 2014;111[2]:84-91).

(Source: Stirnemann J, Belmatoug N, Camou F, et al. A review of Gaucher disease pathophysiology, clinical presentation and treatments. Int J Mol Sci 2017;18[2]:441. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0. Figure modified by Dr. Douglas J Lanska.)

The expression of GCase varies from one cell type to another and depends on the tissue. In a mouse model of GCase deficiency (red cross), GlcCer is transformed via an alternative ceramidase pathway into glucosylsphingosine (red arrow), which is degraded by cytoplasmic GCase2 (GBA2 gene), active at a neutral pH, to sphingosine-1-phosphate (S1P), a very active metabolite (Mistry PK, Liu J, Sun L, et al. Glucocerebrosidase 2 gene deletion rescues type 1 Gaucher disease. Proc Natl Acad Sci U S A 2014;111[13]:4934-9).

Abbreviations: GCase, glucocerebrosidase; GlcCer, glucosylceramide; S1P, sphingosine-1-phosphate.

(Source: Stirnemann J, Belmatoug N, Camou F, et al. A review of Gaucher disease pathophysiology, clinical presentation and treatments. Int J Mol Sci 2017;18[2]:441. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(x60) Gaucher cells infiltrate various organs (eg, bone marrow, spleen, and liver) and are responsible for major signs of the disease). (Courtesy of Fabrice Camou and Rachid Seddik. Source: Stirnemann J, Belmatoug N, Camou F, et al. A review of Gaucher disease pathophysiology, clinical presentation and treatments. Int J Mol Sci 2017;18[2]:441. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(x60) Gaucher cells infiltrate various organs (eg, bone marrow, spleen, and liver) and are responsible for major signs of the disease). (Courtesy of Fabrice Camou and Rachid Seddik. Source: Stirnemann J, Belmatoug N, Camou F, et al. A review of Gaucher disease pathophysiology, clinical presentation and treatments. Int J Mol Sci 2017;18[2]:441. Creative Commons Attribution [CC BY] License, https://creativecommons.org/licenses/by/4.0.)

(Source: Stirnemann J, Belmatoug N, Camou F, et al. A review of Gaucher disease pathophysiology, clinical presentation and treatments. Int J Mol Sci 2017;18[2]:441. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0. Figure modified by Dr. Douglas J Lanska.)

Horizontal axis shows time in years after presentation of Gaucher disease. (Source: D'Amore S, Page K, Donald A, et al. In-depth phenotyping for clinical stratification of Gaucher disease. Orphanet J Rare Dis 2021;16[1]:431. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Controlling for gender, the hazard or risk of having a first fragility fracture after presentation of Gaucher disease was greater in patients who had splenectomy (hazard ratio of 2.83 [95% CI 1.33–5.99; p = 0.01]). Horizontal axis shows years after presentation with Gaucher disease. (Source: D'Amore S, Page K, Donald A, et al. In-depth phenotyping for clinical stratification of Gaucher disease. Orphanet J Rare Dis 2021;16[1]:431. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Horizontal axis shows years after presentation with Gaucher disease. (Source: D'Amore S, Page K, Donald A, et al. In-depth phenotyping for clinical stratification of Gaucher disease. Orphanet J Rare Dis 2021;16[1]:431. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

H-shaped vertebrae of the thoracic spine consistent with osteonecrosis. (Source: D'Amore S, Page K, Donald A, et al. In-depth phenotyping for clinical stratification of Gaucher disease. Orphanet J Rare Dis 2021;16[1]:431. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Prominent thoracic kyphosis and exaggerated lumbar lordosis with minimal lumbar curve. (Source: D'Amore S, Page K, Donald A, et al. In-depth phenotyping for clinical stratification of Gaucher disease. Orphanet J Rare Dis 2021;16[1]:431. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Extensive osteonecrosis of the right femoral head, which shows marked flattening with complete loss of joint space. (Source: D'Amore S, Page K, Donald A, et al. In-depth phenotyping for clinical stratification of Gaucher disease. Orphanet J Rare Dis 2021;16[1]:431. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Gross expansion and coarse trabeculation of the left femur. (Source: D'Amore S, Page K, Donald A, et al. In-depth phenotyping for clinical stratification of Gaucher disease. Orphanet J Rare Dis 2021;16[1]:431. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Generalized osteopenia and lytic areas in humeri. (Source: D'Amore S, Page K, Donald A, et al. In-depth phenotyping for clinical stratification of Gaucher disease. Orphanet J Rare Dis 2021;16[1]:431. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Generalized osteopenia and lytic areas in mid shafts of both femora and tibiae. Erlenmeyer flask deformity of both femurs, also known as metaphyseal flaring. (Source: D'Amore S, Page K, Donald A, et al. In-depth phenotyping for clinical stratification of Gaucher disease. Orphanet J Rare Dis 2021;16[1]:431. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Generalized osteopenia and lytic areas in iliac wings and mid shafts of both femora. Pathological fractures both upper femora. (Source: D'Amore S, Page K, Donald A, et al. In-depth phenotyping for clinical stratification of Gaucher disease. Orphanet J Rare Dis 2021;16[1]:431. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Glucosylceramides and galactosylceramides are hydrolyzed respectively by glucocerebrosidase (also named glucosylceramidase; the GBA gene encoding lysosomal glucocerebrosidase is associated with Gaucher disease) and galactosylceramidase (encoded by the GALC gene; that deficiency causes Krabbe disease) to regenerate ceramides. Ceramides are further deacetylated to sphingosines that can be broken down or recycled for sphingolipid synthesis by the salvage pathway.

Abbreviations and chromosomal locations of the responsible genes: ARSA arylsulfatase A (22q13.33); B4GALNT1 beta-1,4-N-acetyl- galactosaminyltransferase 1 (12q13.3); GAL3ST1 galactose-3-O-sulfotransferase 1 (22q12.2); GALC galactosylceramidase (14q31.3); GBA glucosylceramidase beta also named GBA1 (1q22); GBA2 glucosylceramidase beta 2 (9p13.3); GBA3 glucosylceramidase beta 3 (4p15.2); GLA galactosidase alpha (Xq22.1); GLB1 galactosidase beta 1 (3p22.3); SM4s 3-sulfo-GalCer (also known as sulfatide, galactocerebroside, 3-O-sulfogalactosylceramide, SGalCer, and SGC); ST3GAL6 ST3 beta-galactoside alpha-2,3- sialyltransferase 6 (3q12.1); UGT8 UDP glycosyltransferase 8 (4q26).

(Source: Belarbi K, Cuvelier E, Bonte MA, et al. Glycosphingolipids and neuroinflammation in Parkinson's disease. Mol Neurodegener 2020;15[1]:59. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

This diagram shows the metabolic loci for Fabry disease, metachromatic leukodystrophy, Krabbe disease, Gaucher disease, Sandhoff disease, Sialidosis, Tay Sachs disease/Sandhoff disease/GM2 gangliosidosis AB variant, and GM1 gangliosidosis. The nomenclature for gangliosides and the components are based on those of Svennerholm (1963) and IUPAC-IUBMB Joint Commission on Biochemical Nomenclature (IUPAC-IUB Joint Commission on Biochemical Nomenclature 1997; Chester 1997). Glycosphingolipids belonging to the asialo-series, ganglio-series, lacto/neo-lacto-series and globo/iso-globo-series are colored in brown, blue, purple and green, respectively. Lysosomal glycosphingolipid storage disorders resulting from an enzyme defect are indicated in brackets and in red in the figure.

Abbreviations and chromosomal locations of the responsible genes: A4GALT alpha 1,4- galactosyltransferase (22q13.2); ARSA arylsulfatase A (22q13.33); B3GALT4 beta-1,3-galactosyltransferase 4 (6p21.32); B4GALNT1 beta-1,4-N-acetyl- galactosaminyltransferase 1 (12q13.3); B4GALT6 beta-1,4-galactosyltransferase 6 (18q12.1); GAL3ST1 galactose-3-O-sulfotransferase 1 (22q12.2); GALC galactosylceramidase (14q31.3); GBA glucosylceramidase beta also named GBA1 (1q22); GBA2 glucosylceramidase beta 2 (9p13.3); GBA3 glucosylceramidase beta 3 (4p15.2); GLA galactosidase alpha (Xq22.1); GLB1 galactosidase beta 1 (3p22.3); HEXA hexosaminidase subunit alpha (15q23); HEXB hexosaminidase subunit beta (5q13.3); NEU1 neuraminidase 1 (6p21.33); NEU2 neuraminidase 2 (2q37.1); NEU3 neuraminidase 3 (11q13.5); NEU4 neuraminidase 4( 2q37.3); SM4s 3-sulfo-GalCer (also known as sulfatide, galactocerebroside, 3-O-sulfogalactosylceramide, SGalCer, and SGC); ST3GAL1 ST3 beta-galactoside alpha-2,3-sialyltransferase 1 (8q24.22); ST3GAL2 ST3 beta-galactoside alpha-2,3-sialyltransferase 2 (16q22.1); ST3GAL5 ST3 beta-galactoside alpha-2,3-sialyltransferase 5 (2p11.2); ST3GAL6 ST3 beta-galactoside alpha-2,3- sialyltransferase 6 (3q12.1); ST6GALNAC6 ST6 N-acetylgalactosaminide alpha-2,6-sialyltransferase 6 (9q34.11); ST8SIA1 ST8 alpha-N-acetyl- neuraminide alpha-2,8-sialyltransferase 1 (12p12.1); ST8SIA3 ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 3 (ST8SIA3, 18q21.31); ST8SIA5 ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 5 (18q21.1); UGCG UDP-glucose ceramide glucosyltransferase (9q31.3); UGT8 UDP glycosyltransferase 8 (4q26).

References:
Chester MA. IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). Nomenclature of glycolipids--recommendations 1997. Eur J Biochem 1998;257(2):293-8.
IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). Nomenclature of glycolipids recommendations 1997. J Mol Biol. 1999;286(3):963-70.
Svennerholm L. Chromatographic separation of human brain gangliosides. J Neurochem 1963;10:613–23.

(Source: Belarbi K, Cuvelier E, Bonte MA, et al. Glycosphingolipids and neuroinflammation in Parkinson's disease. Mol Neurodegener 2020;15[1]:59. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Glycosphingolipids are composed of a sphingosine, a fatty acid chain (these two forming a ceramide) and a carbohydrate moiety (X). The fatty acid attached to the sphingosine may vary in chain length and in degree of unsaturation and/or hydroxylation. (Source: Belarbi K, Cuvelier E, Bonte MA, et al. Glycosphingolipids and neuroinflammation in Parkinson's disease. Mol Neurodegener 2020;15[1]:59. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Ceramide, glucosylceramide shift between the Golgi apparatus and lysosomes. Ceramides (Cer), generated in the endoplasmic reticulum (ER), are transported to the Golgi apparatus, where UDP-glucosylceramide synthase (UGCG synthase) converts Cer to glucosylceramide (GC) on the cytosolic side of the Golgi (Halter et al 2007; Hanada 2010). After, GC is transported back into the ER. To transport ceramide to lysosome, GS, GCase, and saposin C (reaction facilitator) are embedded within intralysosomal membrane where cleavage of the lipid tail will occur (Tamargo et al 2012). Eliglustat inhibits UGCG synthase. Ambroxol increases GCase enzyme activity.

References:
Halter D, Neumann S, van Dijk SM, et al. Pre- and post-Golgi translocation of glucosylceramide in glycosphingolipid synthesis. J Cell Biol 2007;179(1):101-15.
Hanada K. Intracellular trafficking of ceramide by ceramide transfer protein. Proc Jpn Acad Ser B Phys Biol Sci 2010;86(4):426-37.
Tamargo RJ, Velayati A, Goldin E, Sidransky E. The role of saposin C in Gaucher disease. Mol Genet Metab 2012;106(3):257-63.

(Source: Ivanova MM, Dao J, Kasaci N, et al. Cellular and biochemical response to chaperone versus substrate reduction therapies in neuropathic Gaucher disease. PLoS One 2021;16[10]:e0247211. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Classification of mild type 1, severe type 1, and neuronopathic Gaucher disease (nGD) was based on genotypes. Glucosylsphingosine (lyso-Gb1) levels of subjects with wild-type GBA1 were considered to be the control.

Abbreviations: lyso-Gb1, glucosylsphingosine; nGD, neuronopathic Gaucher disease; NS, non-significant. Black dots represent the outliers.

(Source: Dinur T, Bauer P, Beetz C, et al. Gaucher disease diagnosis using Lyso-Gb1 on dry blood spot samples: time to change the paradigm? Int J Mol Sci 2022;23[3]:1627. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Revel-Vilk S, Fuller M, Zimran A. Value of glucosylsphingosine (Lyso-Gb1) as a biomarker in Gaucher disease: a systematic literature review. Int J Mol Sci 2020;21[19]:7159. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0. See also: Aerts JM, Kuo CL, Lelieveld LT, et al. Glycosphingolipids and lysosomal storage disorders as illustrated by Gaucher disease. Curr Opin Chem Biol 2019;53:204-15. Figure modified by Dr. Douglas J Lanska.)

(n = 19) (Source: Mengel E, Gaedeke J, Gothe H, et al. The patient journey of patients with Fabry disease, Gaucher disease and mucopolysaccharidosis type II: a German-wide telephone survey. PLoS One 2020;15[12]:e0244279. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Circles represent females and squares males. Filled symbols indicate affected family members and clear symbols unaffected members. Double lines in the pedigree represent a consanguineous marriage. Asterisks indicate individuals for whom a DNA sample is available, and an arrow indicates the sample selected for exome sequencing. Below each family member the PSAP c.1076A>C genotype is displayed. (Source: Liaqat K, Hussain S, Acharya A, et al. Phenotype expansion for atypical Gaucher disease due to homozygous missense PSAP variant in a large consanguineous Pakistani family. Genes (Basel) 2022;13[4]:662. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(a) MRI should include sagittal T1-weighted scan of the spine and T1-weighted scan of the head of the femur. (b) DXA should include spine and total body Z-scores, which require comparison with age- and gender-specific norms. (c) If baseline results are normal there is no need for follow-up within 6 months. (d) The recommended frequency is every 12 months for nonsymptomatic patients not receiving ERT, every 6 months for patients receiving ERT who are not yet meeting therapeutic goals, and every 6 to 12 months for patients receiving ERT who are meeting therapeutic goals. (e) The recommended frequency is every 24 months for nonsymptomatic patients not receiving ERT, every 12 months for patients receiving ERT who are not yet meeting therapeutic goals, and every 12 to 24 months for patients receiving ERT who are meeting therapeutic goals. (f) The recommended frequency for DXA is every 24 to 36 months, or less frequently if deemed appropriate based on clinical course and response to treatment.

Abbreviations: DXA, dual-energy x-ray absorptiometry; ERT, enzyme replacement therapy; GD1, Gaucher disease type 1; GD3, Gaucher disease type 3; HRQoL, health-related quality of life; lyso-Gb1, glucosylsphingosine; MRI, magnetic resonance imaging; PedsQL, Pediatric Quality of Life Inventory; PT, prothrombin time; PTT, partial thromboplastin time; SF-36, 36-item Short-Form Health Survey.

(Source: Weinreb NJ, Goker-Alpan O, Kishnani PS, et al. The diagnosis and management of Gaucher disease in pediatric patients: Where do we go from here? Mol Genet Metab 2022;136[1]:4-21. Adapted from: Kaplan P, Baris H, De Meirleir L, et al. Revised recommendations for the management of Gaucher disease in children. Eur J Pediatr 2013;172[4]:447-58. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Weinreb NJ, Goker-Alpan O, Kishnani PS, et al. The diagnosis and management of Gaucher disease in pediatric patients: Where do we go from here? Mol Genet Metab 2022;136[1]:4-21. Adapted from: Kishnani PS, Al-Hertani W, Balwani M, et al. Screening, patient identification, evaluation, and treatment in patients with Gaucher disease: results from a Delphi consensus. Mol Genet Metab. 2022;135[2]:154-62. Abbreviations: GCase, glucocerebrosidase; GD, Gaucher disease. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(a) Dysphagia, apnea, difficulty with secretions. (b) Progressive. (c) Avascular necrosis, osteopenia, pathologic fractures. Presenting signs and symptoms of Gaucher disease are summarized Gary and colleagues; some would only be expected for specific Gaucher disease subtypes (eg, overt neurologic symptoms only expected in GD2 and/or GD3) (Gary SE, Ryan E, Steward AM, Sidransky E. Recent advances in the diagnosis and management of Gaucher disease. Expert Rev Endocrinol Metab 2018;13[2]:107-18.).

Abbreviations: GD, Gaucher disease; LAL, lysosomal acid lipase; LSD, lysosomal storage disease.

(Source: Weinreb NJ, Goker-Alpan O, Kishnani PS, et al. The diagnosis and management of Gaucher disease in pediatric patients: Where do we go from here? Mol Genet Metab 2022;136[1]:4-21. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The infant’s epidermal detachment ("collodion baby") is characteristic of perinatal Gaucher disease type 2. (Source: Sugiura T, Fujiwara A, Yo T, et al. Gaucher disease carrier with gestational thrombocytopenia and anemia: a case report. J Med Case Rep 2022;16[1]:203. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The infant’s epidermal detachment ("collodion baby") is characteristic of perinatal Gaucher disease type 2. (Source: Sugiura T, Fujiwara A, Yo T, et al. Gaucher disease carrier with gestational thrombocytopenia and anemia: a case report. J Med Case Rep 2022;16[1]:203. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

P = pathogenic, LP = likely pathogenic, UOA = urine organic acids, VLCFA = very long chain fatty acids. (From: Vanderver A, Bernard G, Helman G, et al. Randomized clinical trial of first-line genome sequencing in pediatric white matter disorders. Ann Neurol 2020;88(1):264-73.)

(Contributed by Deepa Rajan MD.)

The EULAR-Sjögren Syndrome Task Force Group therapeutic algorithm for central nervous system involvement is based on the type of neurologic manifestation. The authors suggested that corticosteroids plus cyclophosphamide could be the first- and second-line therapeutic approach in patients with CNS vasculitis and neuromyelitis optica spectrum disorder but that corticosteroids should be rapidly tapered with the aim of decreasing the risk of severe infection. Rituximab or/plus plasma exchanges may also be recommended for the treatment of this manifestation, especially in patients with severe or refractory disease, but its use is currently limited by the lack of US Food and Drug Administration or European Medicines Agency approval for these indications. When lymphocytic meningitis does not respond to symptomatic treatment, the same therapeutic algorithm should be followed. (Ramos-Casals M, Brito-Zerón P, Bombardieri S, et al. EULAR recommendations for the management of Sjogren's syndrome with topical and systemic therapies. Ann Rheum Dis 2020;79(1):3-18.)

The EULAR-Sjögren Syndrome Task Force Group recommended general sequential use of the 3 main categories of immunosuppressive agents in Sjögren syndrome based on a similar approach to that reported for other systemic autoimmune disease, such as systemic lupus erythematosus or vasculitis, with no controlled studies supporting this approach in Sjögren syndrome. The immunosuppressive approaches traditionally used in multineuritis and axonal polyneuropathy (predominantly vasculitis related) are high dose of glucocorticoids as first-line treatment and oral immunosuppressive agents or rituximab as second-line. In refractory cases, cyclophosphamide or plasma exchanges are recommended as rescue therapy. Azathioprine and mycophenolate mofetil may be used in lieu of cyclophosphamide or following cyclophosphamide as “remission maintenance” agents, although neither medication has been evaluated for this purpose in formal clinical trials. In cases in which the axonal polyneuropathy is sensory, first-line treatment will be symptomatic, but in refractory cases, motor involvement, ganglionopathy, and or chronic inflammatory demyelinating polyneuropathy, EULAR Task Force Group recommend intravenous immunoglobulins 0.4 to 2 g/kg for 5 days as first-line treatment and methylprednisolone pulses as second-line or cyclophosphamide pulses 0.5 g/15 day (maximum 6 pulses) as rescue therapy. (Ramos-Casals M, Brito-Zerón P, Bombardieri S, et al. EULAR recommendations for the management of Sjogren's syndrome with topical and systemic therapies. Ann Rheum Dis 2020;79(1):3-18.)

This video clip demonstrates proximal and distal leg muscle weakness and atrophy in two patients of diabetic amyotrophy. (Video used with permission from the Nerve and Muscle Center of Texas.)

Map of the range of the Australian paralysis tick (Ixodes holocyclus). (Courtesy of Wikimedia Commons. Creative Commons Attribution 3.0 Unported [CC BY 3.0] license, creativecommons.org/licenses/by/3.0.)

Detailed distribution map of the Australian paralysis tick (Ixodes holocyclus). Image by FHS Roberts (1970). (Courtesy of Wikimedia Commons. With permission.)

Comparison of the stages of engorgement of the Ixodes holocyclus tick (Australian paralysis tick). Although these pictures are not to the same scale, the scutum can be used to compare the relative sizes because the size of the “shield” (scutum) does not change as the female tick engorges. Photographs by Commonsource (2010). (Courtesy of Wikimedia Commons. Creative Commons Attribution 3.0 Unported [CC BY 3.0] license, creativecommons.org/licenses/by/3.0.)

An engorged female Haemophysalis longicornis tick (also called the Bush tick in Australia). This is not the Australian paralysis tick (Ixodes holocyclus), but is shown for comparison with Ixodes holocyclus. Unlike Ixodes holocyclus, all pairs of legs of Haemaphysalis longicornis are of the same shade, the legs are finer, the mouthparts are much shorter, and the shield is rounded. Photographs by Commonsource (2002). (Courtesy of Wikimedia Commons. Creative Commons Attribution 3.0 Unported [CC BY 3.0] license, creativecommons.org/licenses/by/3.0.)

Ixodes holocyclus ticks before and after feeding (shown on the palm of a human hand). These ticks were picked off of koalas in the Koala Hospital in Port Macquarie, New South Wales, Australia. The small tick had not yet started feeding, whereas the other had probably been at work for a couple of days. The amount of blood inside the larger tick is approximately 5 milliliters. Photograph by Bjørn Christian Tørrissen (January 14, 2009). (Courtesy of Wikimedia Commons. Creative Commons Attribution 3.0 Unported [CC BY 3.0] license, creativecommons.org/licenses/by/3.0.)

A moderately engorged Ixodes holocyclus tick attached to a severely paralyzed dog. Photograph by Commonsource (1998). (Courtesy of Wikimedia Commons. Creative Commons Attribution 3.0 Unported [CC BY 3.0] license, creativecommons.org/licenses/by/3.0.)

A fully engorged adult female Ixodes holocyclus tick showing the darker first and fourth pairs of legs. Photograph by Commonsource (2002). (Courtesy of Wikimedia Commons. Creative Commons Attribution 3.0 Unported [CC BY 3.0] license, creativecommons.org/licenses/by/3.0.)

(Courtesy of the U.S. Centers for Disease Control and Prevention. Public domain.)

A female Ixodes holocyclus tick (the so-called Australian paralysis tick) at an early stage of attachment on human skin. Photograph by Kevin Broady. (Courtesy of Wikimedia Commons. Creative Commons Attribution 3.0 Unported [CC BY 3.0] license, creativecommons.org/licenses/by/3.0.)

A female Ixodes holocyclus tick (the so-called Australian paralysis tick) photographed against lined paper for an indication of size. The tick was removed from the coat of a dog that had been in the bush. Photography by AY Arktos (November, 2005) at Batemans Bay, New South Wales, Australia. (Courtesy of Wikimedia Commons. Creative Commons Attribution 2.5 Generic [CC BY 2.5] license, creativecommons.org/licenses/by/2.5.)

A male American dog tick, Dermacentor variabilis, on a human finger (dorsal view). Photograph by Jerry Kirkhart, Los Osos, California (2009). (Courtesy of Wikimedia Commons. Creative Commons Attribution 2.0 International [CC BY 2.0] license, creativecommons.org/licenses/by/2.0.)

Note that larvae have six legs, whereas nymphs and adults have eight legs. (Courtesy of the Public Health Image Library, Centers for Disease Control and Prevention. Public domain.)

(Courtesy of the U.S. Centers for Disease Control and Prevention. Public domain.)

Girl with tick attached behind ear and otherwise obscured by hair. Note the swollen lymph node on neck below. Photograph by Bernard Hudson. (Courtesy of Wikimedia Commons. Creative Commons Attribution 3.0 Unported [CC BY 3.0] license, creativecommons.org/licenses/by/3.0.)

By compressing the mouthparts (and not the body of the tick) one avoids squeezing more allergens, toxins, and infectious micro-organisms into the host. Illustration by Commonsource (2005). (Courtesy of Wikimedia Commons. Creative Commons Attribution 3.0 Unported [CC BY 3.0] license, creativecommons.org/licenses/by/3.0.)

The life cycle of a 3-host tick may take 1 to 2 years, depending on whether the tick can find a suitable host between life stages. (1) Female tick lays eggs on ground. (2) The 6-legged larva feeds on small mammals and then drops off to the ground and molts. (3) The 8-legged nymph feeds on a small mammal and then drops off to the ground and molts. (4) Eight-legged adult ticks feed and mate on a larger mammal (including livestock and pets) and then drop off to the ground, where females begin to develop eggs. Illustration by Scott Charlesworth, Purdue University, Medical Entomology Extension. (Source: Department of Entomology, University of Wisconsin-Madison. Courtesy of Wikimedia Commons. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Image demonstrates reduced intraepidermal nerve fiber density with rare remaining nerve fibers. (Courtesy of Dr. Kurenai Tanji.)

Skin biopsy cryosection, stained with PGP 9.5 stain for epidermal nerve fibers. Image demonstrates normal intraepidermal nerve fiber staining. (Courtesy of Dr. Kurenai Tanji.)

A 22-year-old female spent 20 hours in an immobile recumbent state and was found to have bilateral leg weakness. Electromyography localized the lesions to the sciatic nerves bilaterally, and subsequent computerized tomography of the pelvis demonstrated marked hypodensity with interspersed hyperdense regions indicating hemorrhage within the gluteal muscles bilaterally, with the areas of necrosis surrounded by solid arrows bilaterally. (Contributed by Dr. Cory Toth.)

14-year-old daughter of index case with Melkersson-Rosenthal syndrome, showing lingua plicata (fissured tongue). (Source: Jasinska D, Boczon J. Melkersson-Rosenthal syndrome as an early manifestation of mixed connective tissue disease. Eur J Med Res 2015;20:100.) (Courtesy of Creative Commons Attribution 4.0 International License.)

38-year-old woman with Melkersson-Rosenthal syndrome, showing facial diparesis and inability to smile. (Source: Jasinska D, Boczon J. Melkersson-Rosenthal syndrome as an early manifestation of mixed connective tissue disease. Eur J Med Res 2015;20:100.) (Courtesy of Creative Commons Attribution 4.0 International License.)

38-year-old woman with Melkersson-Rosenthal syndrome, showing lingua plicata (fissured tongue). (Source: Jasinska D, Boczon J. Melkersson-Rosenthal syndrome as an early manifestation of mixed connective tissue disease. Eur J Med Res 2015;20:100.) (Courtesy of Creative Commons Attribution 4.0 International License.)

The androgen receptor protein has three major domains: (1) an N-terminal trans-activating domain, (2) a DNA-binding domain, and (3) a ligand-binding domain. The N-terminal domain contains the polyglutamine tract, where the major transactivating function occurs. The DNA binding domain (DBD) contains zinc finger structures that facilitate androgen receptor binding to DNA. The ligand binding domain in the C-terminus also contains minor transactivating function. (Contributed by Dr. Cory Toth.)

(A) C3d deposition on internodal axolemma (arrows). (B) Macrophage in the periaxonal space and lying adjacent to an axon. (C) Left fiber: macrophage (M) surrounding a shrunken but intact axon (A) inside normal-appearing myelin sheath. Right fiber: axon has completely degenerated, and macrophage (M) is occupying its position with normal-appearing myelin sheath. (Contributed by Dr. Kazim Sheikh.)

(A) Deposition of C3d at the nodes of Ranvier (arrows). (B) Macrophages overlying and inserting processes at the nodes of Ranvier (arrow). (C) Normal node of Ranvier (arrow). (D) Lengthening of the node (arrow) with overlying macrophages (arrowhead). (Contributed by Dr. Kazim Sheikh.)

Examples of median nerve conduction studies demonstrating demyelinating features. (Contributed by Dr. Betty Soliven.)