Neuromuscular Disorders

(Contributed by Dr. Leo Wang.)

(Contributed by Dr. Leo Wang.)

This is an x-ray of a young child with idiopathic infantile scoliosis. Genetic testing and MRI scans of the brain and spinal cord were normal. He had a right thoracic curve with a Cobb angle measuring 53.7 degrees. Despite Risser casting, his scoliosis has progressed severely. (Contributed by Dr. Daniel Bonthius.)

AP spinal x-ray of a 2-year-old boy with infantile scoliosis, following placement of MAGEC (MAGnetic Expansion Control) rods, spanning from T4 to L3. Screws are inserted into the vertebral pedicles bilaterally. Following placement of the hardware, the patient's scoliotic curve was reduced and stabilized. (Contributed by Dr. Daniel Bonthius.)

Share of 1-year-olds who have received the third dose of polio-containing vaccine. This may be either the oral or the inactivated polio vaccine. (Source: Dattani S, Spooner F, Ochmann S, Roser M. Polio. First published in November 2017, and last updated in May 2024. Available at: ourworldindata.org/polio. Accessed May 2024. Based on U.S. Public Health Service, U.S. Centers for Disease Control and Prevention, and World Health Organization. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The reported figures include both wild- and vaccine-derived type polio infections that occurred indigenously and as imported cases. (Source: Dattani S, Spooner F, Ochmann S, Roser M. Polio. First published in November 2017, and last updated in May 2024. Available at: ourworldindata.org/polio. Accessed May 2024. Based on U.S. Public Health Service, U.S. Centers for Disease Control and Prevention, and World Health Organization. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Some cases of paralytic polio arise from vaccine-derived strains that have reverted to a form that can cause disease. There are three vaccine-derived strains of paralytic polio: VDPV1, 2, and 3. This shows cases of circulating vaccine-derived polioviruses. (Source: Dattani S, Spooner F, Ochmann S, Roser M. Polio. First published in November 2017, and last updated in May 2024. Available at: ourworldindata.org/polio. Accessed May 2024. Based on U.S. Public Health Service, U.S. Centers for Disease Control and Prevention, and World Health Organization. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Some cases of paralytic polio arise from vaccine-derived strains that have reverted to a form that can cause disease. The total number of cases across all three vaccine-derived strains is shown. (Source: Dattani S, Spooner F, Ochmann S, Roser M. Polio. First published in November 2017, and last updated in May 2024. Available at: ourworldindata.org/polio. Accessed May 2024. Based on U.S. Public Health Service, U.S. Centers for Disease Control and Prevention, and World Health Organization. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Estimates of the total number of paralytic polio cases due to wild polioviruses and vaccine-derived polioviruses. (Source: Dattani S, Spooner F, Ochmann S, Roser M. Polio. First published in November 2017, and last updated in May 2024. Available at: ourworldindata.org/polio. Accessed May 2024. Based on data from the World Health Organization and Duintjer Tebbens RJ, Pallansch MA, Cochi SL, et al. Economic analysis of the global polio eradication initiative. Vaccine 2010;29[2]:334-43. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Annual reported cases of polio that led to paralysis of the infected person. It includes both wild and vaccine-derived polioviruses. (Source: Dattani S, Spooner F, Ochmann S, Roser M. Polio. First published in November 2017, and last updated in May 2024. Available at: ourworldindata.org/polio. Accessed May 2024. Based on data from the World Health Organization and Global Polio Eradication Initiative. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Annual number of reported cases of paralytic polio per million people. This includes all reported cases from wild polioviruses and vaccine-derived polioviruses. (Source: Dattani S, Spooner F, Ochmann S, Roser M. Polio. First published in November 2017, and last updated in May 2024. Available at: ourworldindata.org/polio. Accessed May 2024. Based on data from the World Health Organization and population data based on various sources. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Countries are considered endemic if they have indigenous cases of polio from wild polioviruses.

Note: The following countries eradicated polio before 1960 but are hard to see on the map: Nauru (1910), Tuvalu (1936), Palau (1940), American Samoa, Niue and Tokelau (1950), Cayman Islands (1958), and Andorra and Cook Islands (1959).

(Source: Dattani S, Spooner F, Ochmann S, Roser M. Polio. First published in November 2017, and last updated in May 2024. Available at: ourworldindata.org/polio. Accessed May 2024. Based on data from the Global Polio Eradication Initiative. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Countries with wild poliovirus transmission are considered endemic. Countries are shown as polio-free (not certified) if they have demonstrated the absence of wild poliovirus transmission. When all countries in a World Health Organization region have recorded 0 cases for 3 consecutive years while meeting surveillance targets, the region can be certified as polio-free.

Note: The country Nauru already eradicated polio in 1910, which explains the starting date of this map. The first "larger" countries' eradication of polio can be seen after 1960.

(Source: Dattani S, Spooner F, Ochmann S, Roser M. Polio. First published in November 2017, and last updated in May 2024. Available at: ourworldindata.org/polio. Accessed May 2024. Based on data from the Global Polio Eradication Initiative. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

This includes reported cases of paralytic polio from any wild poliovirus strain (WPV1, WPV2, WPV3).

Note: The last case of WPV2 was reported in 1999, whereas the last case of WPV3 was reported in 2012. Cases shown since 2013 were all caused by WPV1.

(Source: Dattani S, Spooner F, Ochmann S, Roser M. Polio. First published in November 2017, and last updated in May 2024. Available at: ourworldindata.org/polio. Accessed May 2024. Based on data from the World Health Organization. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(A) 2000, (B) 2014, (C) 2016, and (D) 2023. Abbreviations: IPV, inactivated poliovirus vaccine; fIPV, fractional-dose inactivated poliovirus vaccine.

Note: Fractional-dose IPV can reduce the cost of polio immunization in campaigns. Two doses of fIPV can induce nearly 100% immunity if given in the appropriate schedule, whereas only using 40% of a full dose of IPV.

(Source: Sutter RW, Eisenhawer M, Molodecky NA, Verma H, Okayasu H. Inactivated poliovirus vaccine: recent developments and the tortuous path to global acceptance. Pathogens 2024;13[3]:224.) IPV introduction date: WHO Immunization, immunizationdata.who.int. Accessed on December 17, 2023. fIPV countries: Macklin GR, Mach O. Fractional-dose IPV in polio eradication. Lancet Infect Dis 2021;21[8]:1061-2. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The funding given by each donor group to the Global Polio Eradication Initiative. This data is expressed in U.S. dollars, adjusted for inflation. Note: This data is expressed in constant 2021 US dollars.

(Source: Dattani S, Spooner F, Ochmann S, Roser M. Polio. First published in November 2017, and last updated in May 2024. Available at: ourworldindata.org/polio. Accessed May 2024. Based on data from the International Monetary Fund [via World Bank] and Global Polio Eradication Initiative. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Dattani S, Spooner F, Ochmann S, Roser M. Polio. First published in November 2017, and last updated in May 2024. Available at: ourworldindata.org/polio. Accessed May 2024. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Controlling the disease can have lower costs in the short term, but the cumulative costs can quickly overtake those of eradication. (Source: Roser M, Ochmann S, Behrens H, Ritchie H, Dabonaite B. Eradication of diseases: which diseases could we eradicate in our lifetimes and how? First published in June 2014 and last revised in January 2024. Available at: ourworldindata.org/eradication-of-diseases. Accessed May 2024. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0 by Max Roser.)

Abbreviations: cVDPV, circulating vaccine-derived poliovirus; mOPV2, monovalent oral polio vaccine type 2; NID, national immunization day; sNID, supplemental national immunization day. (Source: Tegegne AA, Anyuon AN, Legge GA, et al. A circulating vaccine-derived poliovirus type 2 outbreak in a chronic conflict setting: a descriptive epidemiological study in South Sudan - 2020 to 2021. BMC Infect Dis 2023;23[1]:816. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Abbreviations: AFP, acute flaccid paralysis; NPAFP, nonpolio acute flaccid paralysis; WHO, World Health Organization.

Notes:
(1) The number of NPAFP cases per 100,000 children younger than 15 years of age per year. NPAFP cases are cases of AFP determined not to be polio on further case investigation and stool testing. The threshold of two or more NPAFP cases indicating that AFP surveillance is sufficiently sensitive to detect circulating polio is based on a background rate of AFP due to etiologies other than polioviruses.

(2) Surveillance targets are two or more NPAFP cases per 100,000 persons younger than 15 years of age per year and 80% or more of persons with AFP having two stool specimens collected within 14 days of paralysis onset, 24 or more hours apart, and received in good condition (ie, without leakage or desiccation) by a WHO-accredited laboratory via reverse cold chain (storing and transporting samples at recommended temperatures from the point of collection to the laboratory).

(3) The 2023 priority countries include the following: African Region (21): Angola, Botswana, Burkina Faso, Burundi, Cameroon, Central African Republic, Chad, Democratic Republic of the Congo, Ethiopia, Equatorial Guinea, Kenya, Madagascar, Malawi, Mali, Mozambique, Niger, Nigeria, South Sudan, Tanzania, Zambia, and Zimbabwe; Eastern Mediterranean Region (five): Afghanistan, Pakistan, Somalia, Sudan, and Yemen; South-East Asia Region (one): Indonesia; and Western Pacific Region (one): Papua New Guinea.

(4) NPAFP rate is difficult to interpret when the population younger than 15 years of age is below 100,000.

(5) Dotted and dashed lines on maps represent approximate border lines for which there might not yet be full agreement.

(Source: Kishore N, Krow-Lucal E, Diop OM, et al. Surveillance to track progress toward polio eradication - worldwide, 2022-2023. MMWR Morb Mortal Wkly Rep 2024;73[13]:278-85. Public domain.)

Abbreviation: WPV1, wild poliovirus type 1. (Source: Geiger K, Stehling-Ariza T, Bigouette JP, et al. Progress toward poliomyelitis eradication - Worldwide, January 2022-December 2023. MMWR Morb Mortal Wkly Rep 2024;73[19]:441-446. Public domain.)

Data current as of May 5, 2023. Abbreviation: WPV1, wild poliovirus type 1. (Source: Lee SE, Greene SA, Burns CC, Tallis G, Wassilak SG, Bolu O. Progress toward poliomyelitis eradication - worldwide, January 2021-March 2023. MMWR Morb Mortal Wkly Rep 2023;72[19]:517-22. Public domain.)

(Source: Bammeke P, Adamu US, Bolu O, et al. Descriptive epidemiology of poliomyelitis cases due to wild poliovirus type 1 and wild poliovirus type 3 in Nigeria, 2000-2020. Pan Afr Med J 2023;45[Suppl 2]:4. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Abbreviations: AFP, acute flaccid paralysis; NPAFP, nonpolio acute flaccid paralysis; WHO, World Health Organization.

Notes:
(1) Targets: two or more NPAFP cases per 100,000 persons younger than 15 years of age per year and 80% or more of persons with AFP having two stool specimens collected within 14 or fewer days of paralysis onset and 24 or more hours apart and received in good condition (ie, without leakage or desiccation) by a WHO-accredited laboratory via reverse cold chain (storing and transporting samples at recommended temperatures from the point of collection to the laboratory).

(2) Priority countries by region in 2022 included the following: African Region (24): Angola, Benin, Burkina Faso, Cameroon, Central African Republic, Chad, Côte d’Ivoire, Democratic Republic of the Congo, Equatorial Guinea, Ethiopia, Guinea, Guinea-Bissau, Kenya, Madagascar, Malawi, Mali, Mozambique, Niger, Nigeria, South Sudan, Tanzania, Togo, Zambia, and Zimbabwe; Eastern Mediterranean Region (7): Afghanistan, Iraq, Pakistan, Somalia, Sudan, Syria, and Yemen; South-East Asia Region (1): Burma (Myanmar); and Western Pacific Region (2): Papua New Guinea and the Philippines.

(3) NPAFP rate is difficult to interpret when the population aged younger than 15 years is less than 100,000.

(Source: Stehling-Ariza T, Wilkinson AL, Diop OM, et al. Surveillance to track progress toward poliomyelitis eradication - worldwide, 2021-2022. MMWR Morb Mortal Wkly Rep 2023;72[23]:613-20. Public domain.)

(Source: Al-Qassimi MA, Al Amad M, Al-Dar A, Al Sakaf E, Al Hadad A, Raja'a YA. Circulating vaccine-derived poliovirus type 2 outbreak and response in Yemen, 2021-2022, a retrospective descriptive analysis. BMC Infect Dis 2024;24[1]:321. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Abbreviation: cVDPV2, circulating vaccine-derived poliovirus type 2. (Source: Al-Qassimi MA, Al Amad M, Al-Dar A, Al Sakaf E, Al Hadad A, Raja'a YA. Circulating vaccine-derived poliovirus type 2 outbreak and response in Yemen, 2021-2022, a retrospective descriptive analysis. BMC Infect Dis 2024;24[1]:321. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Abbreviations: cVDPV2, circulating vaccine-derived poliovirus type 2; WPV1, wild poliovirus type 1. (Source: Mbaeyi C, Baig S, Safdar RM, et al. Progress toward poliomyelitis eradication - Pakistan, January 2022-June 2023. MMWR Morb Mortal Wkly Rep 2023;72[33]:880-5. Public domain.)

Observed incidence and median (95% CI) pre-vaccination incidence based on the main and sensitivity analyses, Sweden 1910- to 2019. Gray-shaded areas represent pre-vaccination periods. CI, confidence interval. (Source: Martin LJ, Galanis I, Lepp T, Lindstrand A. Estimated number of reported vaccine-preventable disease cases averted following the introduction of routine vaccination programs in Sweden, 1910-2019. Eur J Public Health 2023;33[6]:1188-93. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0. Modified by Dr. Douglas J Lanska to show only poliomyelitis cases with legend, whereas the original also showed curves for pertussis, measles, and mumps, and the legend was not connected with the poliomyelitis curve.)

Abbreviation: WPV1, wild poliovirus type 1. (Source: Mbaeyi C, Baig S, Safdar RM, et al. Progress toward poliomyelitis eradication - Pakistan, January 2022-June 2023. MMWR Morb Mortal Wkly Rep 2023;72[33]:880-5. Public domain.)

Major risk factors for poliovirus transmission include poor sanitation and hygiene conditions, high population density, and tropical or subtropical climate. (A) Polioviruses infect humans by the fecal-oral route. This acid-resistant virus can travel through the stomach (pH: 1–2) and reach the intestine. (B) Once in the intestine (pH: 7.3–7.7), the poliovirus (WPV or OPV) meets the commensal microbiota and the first antiviral defense, such as the mucus layer, protective peptides, immune cells expressing CD103 and KLRG1 and is able to bind the E-cadherin found at the surface of epithelial cells (Devaux and Raoult 2018; Devaux et al 2019). However, the interaction of poliovirus capsid with lipopolysaccharide of bacteria enhances virion stability and receptor attachment (Robinson et al 2014). (C) The polioviruses which manage to pass the first barrier of defense encounter a second barrier which is the intestinal epithelium, protecting the host against intruder transmigration. On this intestinal epithelium, polioviruses found their CD155 receptor on M cells. (D) Simplified model of replication cycle of polioviruses.

(Source: Devaux CA, Pontarotti P, Levasseur A, Colson P, Raoult D. Is it time to switch to a formulation other than the live attenuated poliovirus vaccine to prevent poliomyelitis? Front Public Health 2024;11:1284337. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

References cited:
Devaux CA, Mezouar S, Mege JL. The E-cadherin cleavage associated to pathogenic bacteria infections can favor bacterial invasion and transmigration, dysregulation of the immune response and cancer induction in humans. Front Microbiol 2019;10:2598.
Devaux CA, Raoult D. The microbiological memory, an epigenetic regulator governing the balance between good health and metabolic disorders. Front Microbiol 2018;9:1379.
Robinson CM, Jesudhasan PR, Pfeiffer JK. Bacterial lipopolysaccharide binding enhances virion stability and promotes environmental fitness of an enteric virus. Cell Host Microbe 2014;15(1):36-46.

The viruses were replicated either in vivo on monkey (MK) or mouse (Mo) or in vitro. The in vitro cultures used cells from different tissues (cynomolgus monkey kidney cells, rhesus monkey testicular or skin tissues). At the different stages of the selection, the strains were tested for neurovirulence in cynomolgus monkeys inoculated intraspinally, and those possessing the least residual neurovirulence were selected. Culture on chik (Chik) embryos was also used for other strains (CHAT and Cox) replicated in vivo in humans (Hu) and was used for selection of the CHAT strain. Large batches of the three types of Sabin OPVs were produced using cultures of monkey kidney cells transformed by the SV40 susceptible to poliovirus infection and replication.

Abbreviations: Hu, human; MK, monkey; Mo, mouse; OPV, oral poliovirus vaccine.

(Source: Devaux CA, Pontarotti P, Levasseur A, Colson P, Raoult D. Is it time to switch to a formulation other than the live attenuated poliovirus vaccine to prevent poliomyelitis? Front Public Health 2024;11:1284337. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Upper panel) Mahoney virus. P1 is the precursor of the capsid proteins; P2 and P3 are the precursors of the noncapsid proteins. The genome segment from nucleotide 743 to 3,832 encodes a polyprotein precursor amino acids 1 to 1,030. Noncoding region = NCR (also designed UTR for untranslated region); nuclotide = nt.

(Middle panel) Sabin OVP1 strain. The complete nucleotide sequence of the attenuated Sabin OPV1 compared with the WPV Mahoney strain (Nomoto et al 1982) identified 57 base substitutions to be scattered all over the genome. Of these, 21 were missense mutations (red triangle) resulting in amino acid changes in some viral proteins, especially in the NH2-terminal half of the VP1 capsid protein, involved in attenuation (each mutation indicated by a red star). The location of the principal nucleotide substitutions leading to the attenuated phenotype is indicated in blue (A480G, G935U, U2438A, G2795A, and C2879U for the Sabin OPV1).

(Lower panel) Location of the principal nucleotide substitutions leading to the attenuated phenotype of Sabin OPV2 and OPV3 (the other substitutions are not shown).

Abbreviations: NCR, noncoding region; nt, nucleotide; OPV1, OPV2, OPV3, oral live-attenuated poliovirus vaccine types 1, 2, and 3; P1, the precursor of the capsid proteins; P2 and P3, precursors of the non-capsid proteins (also designed UTR for untranslated region); WPV, wild poliovirus.

(Source: Devaux CA, Pontarotti P, Levasseur A, Colson P, Raoult D. Is it time to switch to a formulation other than the live attenuated poliovirus vaccine to prevent poliomyelitis? Front Public Health 2024;11:1284337. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Reference cited:
Nomoto A, Omata T, Toyoda H, et al. Complete nucleotide sequence of the attenuated poliovirus Sabin 1 strain genome. Proc Natl Acad Sci U S A 1982;79(19):5793-7.

Data derived from WHO HQ as of February 27, 2024. Abbreviations: AFP, acute flaccid paralysis; cVDPV, circulating vaccine-derived poliovirus; WPV, wild-type poliovirus. (Source: Lopez Cavestany R, Eisenhawer M, Diop OM, Verma H, Quddus A, Mach O. The last mile in polio eradication: program challenges and perseverance. Pathogens 2024;13[4]:323. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Clinical acute flaccid paralysis (AFP) and environmental surveillance (ES) poliovirus detections are depicted. On the left, there is a per-country list of the latest detections of AFP and ES. Data source: from WHO HQ as of February 27, 2024; figure adapted from internal WHO HQ figures; map creation April 5, 2024; map produced by WHO GIS Centre for Health, DNA/DDI. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. (Source: Lopez Cavestany R, Eisenhawer M, Diop OM, Verma H, Quddus A, Mach O. The last mile in polio eradication: program challenges and perseverance. Pathogens 2024;13[4]:323. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Abbreviations: IPV, inactivated poliovirus vaccine, containing formalin-killed virus, developed by U.S. physician and virologist Jonas Salk (1914-1995) and licensed for use in 1955; OPV, oral poliovirus vaccine containing live-attenuated poliovirus, was developed by Polish-American microbiologist Albert Sabin (1906-1993). (Source: Lopez Cavestany R, Eisenhawer M, Diop OM, Verma H, Quddus A, Mach O. The last mile in polio eradication: program challenges and perseverance. Pathogens 2024;13[4]:323. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The figure depicts the use of Sabin OPV (mOPV2 and tOPV) for outbreak response and introduction of nOPV2 in March 2021. The data are from July 1, 2016 to December 31, 2023.

Abbreviations: cVDPV2, type 2 circulating vaccine-derived type 2 monovalent oral poliovirus vaccine; tOPV, trivalent oral poliovirus vaccine; bOPV, bivalent oral poliovirus vaccine; mOPV2, type 2 monovalent oral poliovirus vaccine; nOPV2, novel type 2 oral poliovirus vaccine.

(Source: Lopez Cavestany R, Eisenhawer M, Diop OM, Verma H, Quddus A, Mach O. The last mile in polio eradication: program challenges and perseverance. Pathogens 2024;13[4]:323. Based on a figure from: Bandyopadhyay AS, Zipursky S. A novel tool to eradicate an ancient scourge: the novel oral polio vaccine type 2 story. Lancet Infect Dis 2023;23[2]:e67-71. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(A) Humoral immunity. (B) Mucosal immunity. Abbreviations: IPV, inactivated poliovirus vaccine; fIPV, fractional-dose inactivated poliovirus vaccine; mos, months; OPV, oral polio vaccine; wks, weeks; yr, year. (Source: Sutter RW, Eisenhawer M, Molodecky NA, Verma H, Okayasu H. Inactivated poliovirus vaccine: recent developments and the tortuous path to global acceptance. Pathogens 2024;13[3]:224. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Abbreviations: cVDPV2, circulating vaccine-derived poliovirus type 2; IPV, inactivated poliovirus vaccine; SIA, supplementary immunization activity. (Source: Sutter RW, Eisenhawer M, Molodecky NA, Verma H, Okayasu H. Inactivated poliovirus vaccine: recent developments and the tortuous path to global acceptance. Pathogens 2024;13[3]:224. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Muscle ultrasound of a 61-year-old man with Hoffmann syndrome showing normal to slightly increased echogenicity of the calf muscles. (Source: Winter S, Heiling B, Eckardt N, Kloos C, Axer H. Hoffmann's syndrome in the differential workup of myopathic complaints: a case report. J Med Case Rep 2023;17[1]:473. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

MRI of a 61-year-old man with Hoffmann syndrome shows muscular hypertrophy of the lower extremities but no signs of myositis or myopathy (ie, no gadolinium enhancement, edema, or fatty degeneration). (Source: Winter S, Heiling B, Eckardt N, Kloos C, Axer H. Hoffmann's syndrome in the differential workup of myopathic complaints: a case report. J Med Case Rep 2023;17[1]:473. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Calf muscles of a 61-year-old man with Hoffmann syndrome showing apparent hypertrophy. (Source: Winter S, Heiling B, Eckardt N, Kloos C, Axer H. Hoffmann's syndrome in the differential workup of myopathic complaints: a case report. J Med Case Rep 2023;17[1]:473. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Abbreviations: PTH, parathyroid hormone; PTH1R, type 1 PTH receptor; PTHrP, parathyroid hormone-related protein.

(Source: Srisuwarn P, Disthabanchong S. Role of parathyroid hormone and parathyroid hormone-related protein in protein-energy malnutrition. Front Biosci [Landmark Ed] 2023;28[8]:167. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(A) Amino acid sequences of the N-terminal region of PTH and PTHrP. The shared sequences with PTH are indicated by dark purple circles on PTHrP. (B) Binding of PTH and PTHrP to a G-protein-coupled receptor. (C) The two principal signaling pathways of PTH1R: the cyclic adenosine monophosphate and phosphatidylinositol pathways.

Abbreviations: ATP, adenosine triphosphate; CREB, cAMP response element binding protein; DAG, diacylglycerol; IP3, inositol 1,4,5 trisphosphate; PIP2, phosphatidylinositol 1,4,5 trisphosphate; PLC, phospholipase C; PKA, protein kinase A; PKC, protein kinase C; PTH, parathyroid hormone; PTH1R, type 1 PTH receptor; PTHrP, parathyroid hormone-related protein.

(Source: Srisuwarn P, Disthabanchong S. Role of parathyroid hormone and parathyroid hormone-related protein in protein-energy malnutrition. Front Biosci [Landmark Ed] 2023;28[8]:167. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Kidney and bone are the traditional targets of this hormone. When calcium levels in the blood decrease, parathyroid glands release PTH, which promotes calcium mobilization from bone, reabsorption in the kidney, and absorption in the small intestine, via activation of vitamin D. Since PTH receptors have been found in skeletal muscle, it is possible that PTH may also have an effect in that tissue. Legend: PTH, parathyroid hormone. (Source: Romagnoli C, Brandi ML. Muscle physiopathology in parathyroid hormone disorders. Front Med [Lausanne] 2021;8:764346. Creative Commons Attribution [CC-BY] license, creativecommons.org/licenses/by/2.0.)

Legend: PTH, parathyroid hormone. (Source: Jan de Beur SM, Minisola S, Xia WB, et al. Global guidance for the recognition, diagnosis, and management of tumor-induced osteomalacia. J Intern Med 2023;293[3]:309-28.)

Figure adapted from:
Minisola S, Peacock M, Fukumoto S, et al. Tumour-induced osteomalacia. Nat Rev Dis Primers 2017;3:17044.
Courbebaisse M, Lanske B. Biology of fibroblast growth factor 23: from physiology to pathology. Cold Spring Harb Perspect Med 2018;8[5]:a031260.
Saraff V, Nadar R, Högler W. New Developments in the treatment of X-linked hypophosphataemia: implications for clinical management. Paediatr Drugs 2020;22[2]:113-21. Creative Commons Attribution [CC-BY] license, creativecommons.org/licenses/by/2.0.

Legend: 1,25(OH)2D, 1,25-dihydroxyvitamin D; 25(OH)D, 25-hydroxyvitamin D; ALP, alkaline phosphatase; FGF23, fibroblast growth factor 23; PTH, parathyroid hormone. (a) Perform genetic testing before imaging in children, young adults, or those with suggestive family history. (b) Perform genetic testing in adults without family history and negative functional imaging. (Source: Jan de Beur SM, Minisola S, Xia WB, et al. Global guidance for the recognition, diagnosis, and management of tumor-induced osteomalacia. J Intern Med 2023;293[3]:309-28.)

Figure adapted from:
Minisola S, Peacock M, Fukumoto S, et al. Tumour-induced osteomalacia. Nat Rev Dis Primers 2017;3:17044.
Courbebaisse M, Lanske B. Biology of fibroblast growth factor 23: from physiology to pathology. Cold Spring Harb Perspect Med 2018;8[5]:a031260.
Saraff V, Nadar R, Högler W. New Developments in the treatment of X-linked hypophosphataemia: implications for clinical management. Paediatr Drugs 2020;22[2]:113-21. Creative Commons Attribution [CC-BY] license, creativecommons.org/licenses/by/2.0.)

Legend: 1,25(OH)2D, 1,25-dihydroxyvitamin D; FGF23, fibroblast growth factor 23; NPT2, type II sodium phosphate cotransporter; PMT, phosphaturic mesenchymal tumor. (Source: Jan de Beur SM, Minisola S, Xia WB, et al. Global guidance for the recognition, diagnosis, and management of tumor-induced osteomalacia. J Intern Med 2023;293[3]:309-28.)

Figure adapted from:
Minisola S, Peacock M, Fukumoto S, et al. Tumour-induced osteomalacia. Nat Rev Dis Primers 2017;3:17044.
Courbebaisse M, Lanske B. Biology of fibroblast growth factor 23: from physiology to pathology. Cold Spring Harb Perspect Med 2018;8[5]:a031260.
Saraff V, Nadar R, Högler W. New Developments in the treatment of X-linked hypophosphataemia: implications for clinical management. Paediatr Drugs 2020;22[2]:113-21. Creative Commons Attribution [CC-BY] license, creativecommons.org/licenses/by/2.0.

Transaxial (A), sagittal (B), and coronal (C) perspectives, showing (arrows) focal area of increased radiotracer concentration in the right side of the neck at the level of C5-C7 vertebra suggestive of parathyroid adenoma or carcinoma. Delayed static image of Tc-99m sestamibi parathyroid scintigraphy (D), showing (arrow) persistent focal activity in the abovementioned area. Legend: SPECT-CT: single-photon emission computed tomography-computed tomography. (Source: Huq MR, Hossain A, Hannan MA, Anwar MB, Khan AM. Proximal myopathy with hypercalcemic crisis and papillary thyroid carcinoma in a 38-year-old female. Cureus 2021;13[12]:e20700. Creative Commons Attribution [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(A) Right side: an irregular hypoechoic nodular lesion (arrows), measuring approximately 17 × 14 mm with foci of calcification, in the upper pole of the right lobe of the thyroid gland suggestive of adenoma or carcinoma of the parathyroid gland. (B) Left side: No abnormalities were found. (Source: Huq MR, Hossain A, Hannan MA, Anwar MB, Khan AM. Proximal myopathy with hypercalcemic crisis and papillary thyroid carcinoma in a 38-year-old female. Cureus 2021;13[12]:e20700. Creative Commons Attribution [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Variation of iPTH levels over time (days). Legend: iPTH: intact parathyroid hormone. (Source: Huq MR, Hossain A, Hannan MA, Anwar MB, Khan AM. Proximal myopathy with hypercalcemic crisis and papillary thyroid carcinoma in a 38-year-old female. Cureus 2021;13[12]:e20700. Creative Commons Attribution [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Variation of calcium levels (mg/dL) over time (days). (Source: Huq MR, Hossain A, Hannan MA, Anwar MB, Khan AM. Proximal myopathy with hypercalcemic crisis and papillary thyroid carcinoma in a 38-year-old female. Cureus 2021;13[12]:e20700. Creative Commons Attribution [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Dematapitiya C, Perera C, Pathmanathan S, et al. Parathyroid carcinoma during pregnancy: a novel pathogenic CDC73 mutation - a case report. BMC Endocr Disord 2022;22[1]:259. Creative Commons Attribution 4.0 International [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Dematapitiya C, Perera C, Pathmanathan S, et al. Parathyroid carcinoma during pregnancy: a novel pathogenic CDC73 mutation - a case report. BMC Endocr Disord 2022;22[1]:259. Creative Commons Attribution 4.0 International [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Dematapitiya C, Perera C, Pathmanathan S, et al. Parathyroid carcinoma during pregnancy: a novel pathogenic CDC73 mutation - a case report. BMC Endocr Disord 2022;22[1]:259. Creative Commons Attribution 4.0 International [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Dematapitiya C, Perera C, Pathmanathan S, et al. Parathyroid carcinoma during pregnancy: a novel pathogenic CDC73 mutation - a case report. BMC Endocr Disord 2022;22[1]:259. Creative Commons Attribution 4.0 International [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Legend: PTH = Parathyroid Hormone; Ca2+ = Calcium; cAMP = Cyclic Adenosine Mono Phosphate. (Source: Dawale K, Agrawal A. Parathyroid hormone secretion and related syndromes. Cureus 2022;14[10]:e30251. Diagram by Ketaki Dawale. Creative Commons Attribution [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Lumbar spine MRI revealing H-shaped vertebrae and fatty changes in the posterior paraspinal muscles (arrow), abnormal bone marrow signal intensity of the spine associated with metabolic disease. (Source: Alarfaj HM, Alrasheed WY, Alsulaiman SA, Almulhem FT, Almaideni MF, Alkuwaity KW. A case report of severe osteomalacia in a young patient after bariatric surgery. Cureus 2021;13[12]:e20198. Creative Commons Attribution [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Pelvic computed tomography revealing a diffuse prominent trabeculation of the bone associated with osteopenia and minimal expansion as well as multiple old fractures associated with pelvic deformity due to very soft bones (arrow). This is consistent with severe osteomalacia. (Source: Alarfaj HM, Alrasheed WY, Alsulaiman SA, Almulhem FT, Almaideni MF, Alkuwaity KW. A case report of severe osteomalacia in a young patient after bariatric surgery. Cureus 2021;13[12]:e20198. Creative Commons Attribution [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Pelvic radiograph showing generalized reduced bone density consistent with metabolic disease with healed bilateral proximal femoral fractures in the varus position (arrows). (Source: Alarfaj HM, Alrasheed WY, Alsulaiman SA, Almulhem FT, Almaideni MF, Alkuwaity KW. A case report of severe osteomalacia in a young patient after bariatric surgery. Cureus 2021;13[12]:e20198. Creative Commons Attribution [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Chest radiograph showing healed right-sided multiple rib fractures (arrow). (Source: Alarfaj HM, Alrasheed WY, Alsulaiman SA, Almulhem FT, Almaideni MF, Alkuwaity KW. A case report of severe osteomalacia in a young patient after bariatric surgery. Cureus 2021;13[12]:e20198. Creative Commons Attribution [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Right shoulder radiograph showing a healed right proximal humerus fracture in the varus position with a deformed scapular neck consistent with an old fracture (arrows). (Source: Alarfaj HM, Alrasheed WY, Alsulaiman SA, Almulhem FT, Almaideni MF, Alkuwaity KW. A case report of severe osteomalacia in a young patient after bariatric surgery. Cureus 2021;13[12]:e20198. Creative Commons Attribution [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Left shoulder radiograph showing reduced bone density with a healed left clavicular fracture and a healed proximal humerus fracture (arrows). (Source: Alarfaj HM, Alrasheed WY, Alsulaiman SA, Almulhem FT, Almaideni MF, Alkuwaity KW. A case report of severe osteomalacia in a young patient after bariatric surgery. Cureus 2021;13[12]:e20198. Creative Commons Attribution [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0.)

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

This 2000 photograph depicted a sign displayed in Gorakhpur, India, which advertised a Pulse Polio Vaccination Program that had been scheduled to take place on February 27, 2000, the main purpose of which was to vaccinate children up to 5 years of age against polio. (Source: CDC/Chris Zahniser BSN RN MPH. Zahniser was a "Stop Transmission of Polio" (STOP) team member and photographer, who was assigned to the state of Uttar Pradesh in northern India. U.S. Centers for Disease Control and Prevention, Public Health Image Library. Public domain.)

Scene at a Birmingham, Alabama airport, where the Alabama National Guard was preparing to fly polio vaccine to Haleyville during the polio epidemic of 1963. (Source: CDC/Mr. Stafford Smith, 1963. U.S. Centers for Disease Control and Prevention, Public Health Image Library. Public domain.)

Images like this were used to encourage individuals to receive polio vaccinations, which were made available in April 1955. (Source: CDC. U.S. Centers for Disease Control and Prevention, Public Health Image Library. Public domain.)

A young girl receiving her Salk polio vaccination in her left upper arm. The girl was among local residents who had lined up at this mobile polio vaccination clinic. This photograph was taken in 1963, when the U.S. was shifting from the killed-virus Salk vaccine to the oral attenuated Sabin vaccine. (Source: CDC, 1963. U.S. Centers for Disease Control and Prevention, Public Health Image Library. Public domain.)

A Pakistani Field Epidemiology Training Program (FETP) 2nd cohort resident, (Dr. Muhammad Dawood Kasi) administering oral polio vaccine (OPV) to unvaccinated children in the union council locality of Kharotabad, Balochistan, Pakistan, during the July 2011, polio campaign. The FETP trains workers on the ground to help countries build sustainable capacity for detecting and responding to health threats. The program develops in-country expertise so that disease outbreaks can be detected locally and prevented from spreading. (Source: CDC/Tamkeen Ghafoor, Pakistan. U.S. Centers for Disease Control and Prevention, Public Health Image Library. Public domain.)

A Somali mother holding her child steady, while a "Stop Transmission of Polio" (STOP) worker administered the oral polio vaccine to the young infant. WHO and UNICEF, working in conjunction with national Ministries of Health, request skilled short-term consultants, who can provide field support to immunization programs. STOP participants are descendants of the "smallpox warriors" of the 1970s. (Source: CDC/Shurram Shahzad, Somalia, 2014. Stop Transmission of Polio (STOP) Program. U.S. Centers for Disease Control and Prevention, Public Health Image Library. Public domain.)

A young girl receiving her polio immunization by way of an orally administered sugar cube at a Dekalb County, Georgia, well-child clinic. (Source: CDC/Meredith Hickson, 1977. U.S. Centers for Disease Control and Prevention, Public Health Image Library. Public domain.)

A young child being supported by a healthcare worker atop a clinic table. Although the child looks to be old enough to be able to walk on his own, after having acquired poliomyelitis, the resulting lower limb paralysis prevented him from supporting his own weight. (Source: PAHO/WHO, 1989. U.S. Centers for Disease Control and Prevention, Public Health Image Library. Public domain.)

The child pictured here in this 2000 photograph, held by her father, had been diagnosed with acute flaccid paralysis, 2 months prior to being photographed. The father was bringing his child to a physician for a follow-up evaluation. Since its inception in the fall of 1998, the "Stop Transmission of Polio" (STOP) immunization initiative teams have worked in over 50 countries. In the first years of the program, most STOP team members worked primarily to bolster acute flaccid paralysis surveillance, support National Immunization Days, and conduct polio case investigation and follow-up. (Source: CDC/Chris Zahniser BSN RN MPH, 2000. Zahniser was a Stop Transmission of Polio [STOP] team member and photographer, who was assigned to the state of Uttar Pradesh in northern India. U.S. Centers for Disease Control and Prevention, Public Health Image Library. Public domain.)

This 1963 poster featured what at that time, was the Communicable Disease Center’s (CDC) national symbol of public health, the "Wellbee," who was reminding the public to "be well, be clean, WASH YOUR HANDS". CDC used Wellbee in a comprehensive marketing campaign that included newspapers, posters, leaflets, radio, and television, as well as personal appearances at public health events. Wellbee’s first assignment was to sponsor the Sabin type II oral polio vaccine (OPV) campaigns across the United States. Later, Wellbee’s character was incorporated into other health promotion campaigns. CDC's name changed in 1970 from the Communicable Disease Center to the Center for Disease Control, and in 1992 to the Centers for Disease Control and Prevention. (Source: CDC/Mary Hilpertshauser, 1963. U.S. Centers for Disease Control and Prevention, Public Health Image Library. Public domain.)

This 1963 poster featured what at that time, was the Communicable Disease Center’s (CDC) national symbol of public health, the "Wellbee," who was reminding the public to "be well, be clean, WASH YOUR HANDS." CDC used Wellbee in a comprehensive marketing campaign that included newspapers, posters, leaflets, radio, and television, as well as personal appearances at public health events. Wellbee’s first assignment was to sponsor the Sabin type II oral polio vaccine (OPV) campaigns across the United States. Later, Wellbee’s character was incorporated into other health promotion campaigns. CDC's name changed in 1970 from the Communicable Disease Center to the Center for Disease Control, and in 1992 to the Centers for Disease Control and Prevention. (Source: CDC/Mary Hilpertshauser, 1963. U.S. Centers for Disease Control and Prevention, Public Health Image Library. Public domain.)

This 1964 poster featured what at that time, was the Communicable Disease Center’s (CDC) national symbol of public health, the "Wellbee," who was reminding the public to "be well, be clean, WASH YOUR HANDS." CDC used Wellbee in a comprehensive marketing campaign that included newspapers, posters, leaflets, radio, and television, as well as personal appearances at public health events. Wellbee’s first assignment was to sponsor the Sabin type II oral polio vaccine (OPV) campaigns across the United States. Later, Wellbee’s character was incorporated into other health promotion campaigns. CDC's name changed in 1970 from the Communicable Disease Center to the Center for Disease Control, and in 1992 to the Centers for Disease Control and Prevention. (Source: CDC/Mary Hilpertshauser, 1964. U.S. Centers for Disease Control and Prevention, Public Health Image Library. Public domain.)

Dr. Joseph Oren, Chief of the CDC Poliomyelitis Surveillance Unit, was examining the child, who was displaying signs of respiratory weakness. A suction machine was being used, in conjunction with a tracheostomy tube to help in suctioning sputum build-up from the lungs. (Source: CDC, 1960. U.S. Centers for Disease Control and Prevention, Public Health Image Library. Public domain.)

Aerial view of a long line of people waiting for their polio vaccinations. The line surrounded the city auditorium in San Antonio, Texas. (Source: CDC/Mr. Stafford Smith, 1962. U.S. Centers for Disease Control and Prevention, Public Health Image Library. Public domain.)

Physical therapist assisting two polio-stricken children that were holding on to a handrail, while they exercised their lower limbs, by keeping a beach ball suspended between their upper bodies. (Source: CDC/Charles Farmer, 1963. U.S. Centers for Disease Control and Prevention, Public Health Image Library. Public domain.)

Scanning electron microscopic (SEM) image depicted a number of round, polio virions, or virus particles, scattered on a background plane. (Source: CDC. U.S. Centers for Disease Control and Prevention, Public Health Image Library. Public domain.)

Latin-American nurse performing a neurologic examination on a boy with residua of poliomyelitis. Note the severe atrophy of muscles in both lower legs and the callouses over the knees and possible effusion of the knee joint, indicating that the boy ambulated by crawling. (Source: PAHO/WHO, 1989. U.S. Centers for Disease Control and Prevention, Public Health Image Library. Public domain.)

This mother was cradling her child, as he received an oral polio vaccine, which would prevent the baby from acquiring the highly infectious disease poliomyelitis (polio), caused by the poliovirus. Beginning in 1988, the efforts of the World Health Organization (WHO), Rotary International, the U.S. Centers for Disease Control and Prevention (CDC), and UNICEF, through the Global Polio Eradication Initiative, led to the realistic possibility of global eradication of this viral disease. (Source: PAHO/WHO, 1989. This image is from the 1989 Pan American Health Organization (PAHO) Polio Eradication Field Guide. U.S. Centers for Disease Control and Prevention, Public Health Image Library. Public domain.)

Healthcare worker supporting an infant, who was at an age when he should have been able to walk, however, poliomyelitis caused lower limb weakness that made him unable to support his own weight. (Source: PAHO/WHO, 1989. Unidentified Latin-American country. U.S. Centers for Disease Control and Prevention, Public Health Image Library. Public domain.)

Photomicrograph of a spinal cord tissue sample at higher magnification in the region of the anterior horn, revealing polio type III degenerative changes. (Source: CDC/Dr. Karp, Emory University, 1964. U.S. Centers for Disease Control and Prevention, Public Health Image Library. Public domain.)

Photomicrograph of a spinal cord tissue sample at low magnification in the region of the anterior horn, revealing polio type III degenerative changes. (Source: CDC/Dr. Karp, Emory University, 1964. U.S. Centers for Disease Control and Prevention, Public Health Image Library. Public domain.)

(Source: CDC, 1961. U.S. Centers for Disease Control and Prevention, Public Health Image Library. Public domain.)

Transmission electron microscopic image depicting numerous, round, poliovirus type-1 virions, which measure 20-30nm in diameter, and exhibit icosahedral symmetry. (Source: CDC/ Dr. Joseph J. Esposito; F. A. Murphy, 1971. U.S. Centers for Disease Control and Prevention, Public Health Image Library. Public domain.)

Two workers standing beside a cart loaded with boxes containing poliovirus vaccine, produced at the time by the Wyeth pharmaceutical company. (Source: CDC/ Mr. Stafford Smith, 1963. U.S. Centers for Disease Control and Prevention, Public Health Image Library. Public domain.)

(1) First, poliovirus binds to the cell surface macromolecule CD155, which functions as the receptor. (2) Uncoating the viral RNA is mediated by receptor-dependent destabilization of the virus capsid. (3) Cleavage of the viral protein VPg is performed by a cellular phosphodiesterase, and translation of the viral RNA occurs by a cap-independent (IRES-mediated) mechanism. (4) Proteolytic processing of the viral polyprotein yields mature structural and non-structural proteins. (5) The positive-sense RNA serves as the template for complementary negative-strand synthesis, thereby producing a double-stranded RNA (replicative form, RF). (6) Initiation of many positive strands from a single negative strand produces the partially single-stranded replicative intermediate (RI). (7) The newly synthesized positive-sense RNA molecules can either serve as templates for translation or (8) associate with capsid precursors to undergo encapsidation and induce the maturation cleavage of VP0, which ultimately generates progeny virions. (9) Lysis of the infected cell results in release of infectious progeny virions. (Source: De Jesus NH. Epidemics to eradication: the modern history of poliomyelitis. Virol J 2007;4:70. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/2.0.)

This genomic region has been divided into six domains (I to VI), of which domain I constitutes the cloverleaf and the remaining domains comprise the internal ribosome entry site (IRES). Spacer sequences without complex secondary structure exist between the cloverleaf and the IRES (nt 89-123) and between the IRES and the initiation codon (nt 620-742). Mutations in the 5'NTR of the Sabin poliovirus type 1, 2, and 3 vaccine strains localizing to nucleotides 480 (A to G), 481 (A to G), and 472 (C to U), respectively (each denoted by a star), confer attenuation in the CNS and deficient replication in neuroblastoma cells as well as reduced viral RNA translation efficiency. (Source: De Jesus NH. Epidemics to eradication: the modern history of poliomyelitis. Virol J 2007;4:70. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/2.0.)

After binding to cell-surface receptors, poliovirus (160S) undergoes conformational changes of the capsid to the 135S form. The 135S particles are then internalized by an actin- and tyrosine kinase-dependent, but clathrin- and caveolin-independent, mechanism. The release of the viral genome takes place only after internalization from an endocytotic compartment localized within 100-200 nm of the plasma membrane. On release of the RNA genome, the empty capsid (80S) is transported away along microtubules. (Source: Brandenburg B, Lee LY, Lakadamyali M, Rust MJ, Zhuang X, Hogle JM. Imaging poliovirus entry in live cells. PLoS Biol 2007;5[7]:e183. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/2.0.)

This transmission electron microscopic image reveals ultrastructural features exhibited by numerous icosahedral-shaped poliovirus particles. (Source: CDC/ Dr. Fred Murphy, Sylvia Whitfield (1975). U.S. Centers for Disease Control and Prevention, Public Health Image Library. Public domain.)

The poliovirus genome consists of a single-stranded, positive-sense polarity RNA molecule, which encodes a single polyprotein. The 5' non-translated region (NTR) harbors two functional domains, the cloverleaf and the internal ribosome entry site (IRES), and is covalently linked to the viral protein VPg. The 3'NTR is polyadenylated. (Source: De Jesus NH. Epidemics to eradication: the modern history of poliomyelitis. Virol J 2007;4:70. Creative Commons Attribution License [CC BY], creativecommons.org/licenses/by/2.0.)

Sullivan (A), Orange (B), Rockland (C), Kings and Queens (D), and Nassau (E) counties, New York. Abbreviation: PV2 = poliovirus type 2. Sampling sites are sewersheds defined as the community area served by a wastewater collection system. Sub-sewersheds are upstream sampling locations within a larger sewershed. In July 2022, paralytic poliomyelitis resulting from infection with vaccine-derived PV2 was confirmed in an unvaccinated adult resident of Rockland County, New York. A single large-volume sample from a sub-sewershed serving parts of Kings and Queens counties tested positive for the PV2 genetically linked to the virus isolated from the patient. (Source: Ryerson AB, Lang D, Alazawi MA, et al. Wastewater testing and detection of poliovirus type 2 genetically linked to virus isolated from a paralytic polio case - New York, March 9-October 11, 2022. MMWR Morb Mortal Wkly Rep 2022;71[44]:1418-24. Public domain.)

Wastewater polio test results, by jurisdiction (N = 1,053)--13 counties in New York and New York City, March 9-October 11, 2022. Abbreviation: PV2 = poliovirus type 2. Sampling sites are sewersheds defined as the community area served by a wastewater collection system. Testing was conducted to determine if a sample was negative or positive for PV2, and if positive for PV2, whether the PV2 was genetically linked to an unvaccinated paralytic poliomyelitis patient from Rockland County, New York identified in July 2022. Some samples had sequencing insufficient to determine relation to the Rockland County patient (ie, linkage to patient unknown). Indeterminate results are excluded from this figure. Indeterminate results include those from samples that tested positive using real-time reverse transcription polymerase chain reaction but not enough viral material was available to complete sequencing. Specimens pending sequencing results are also excluded. Number of samples in each jurisdiction include New York City (408) and the following New York counties: Rockland (124), Putnam (20), Orange (280), Nassau (85), Sullivan (21), Westchester (83), Suffolk (14), and Ulster (18). (Source: Ryerson AB, Lang D, Alazawi MA, et al. Wastewater testing and detection of poliovirus type 2 genetically linked to virus isolated from a paralytic polio case - New York, March 9-October 11, 2022. MMWR Morb Mortal Wkly Rep 2022;71[44]:1418-24. Public domain.)

cVDPVs are genetically linked VDPV2 isolates for which there is evidence of person-to-person transmission in the community. Total cases by period: January-June 2021 = one WPV1 and 42 cVDPV2, July-December 2021 = three WPV1 and one cVDPV2, and January-September 2022 = two WPV1 and zero cVDPV2. Abbreviations: cVDPV2 = circulating vaccine-derived poliovirus type 2; WPV1 = wild poliovirus type 1. (Source: Mohamed A, Akbar IE, Chaudhury S, et al. Progress toward poliomyelitis eradication--Afghanistan, January 2021-September 2022. MMWR Morb Mortal Wkly Rep 2022;71[49]:1541-6. Public domain.)

The number of cases of WPV1 and cVDPV2 were 90 and 351, respectively. cVDPVs are genetically linked VDPV2 isolates for which there is evidence of person-to-person transmission in the community. Abbreviations: cVDPV2 = circulating vaccine-derived poliovirus type 2; WPV1 = wild poliovirus type 1. (Source: Mohamed A, Akbar IE, Chaudhury S, et al. Progress toward poliomyelitis eradication--Afghanistan, January 2021-September 2022. MMWR Morb Mortal Wkly Rep 2022;71[49]:1541-6. Public domain.)

Abbreviations: cVDPV2 = circulating vaccine-derived poliovirus type 2; WPV1 = wild poliovirus type 1. (Source: Mbaeyi C, Baig S, Safdar MR, et al. Progress toward poliomyelitis eradication--Pakistan, January 2021-July 2022. MMWR Morb Mortal Wkly Rep 2022;71[42]:1313-8. Public domain.)

Abbreviations: cVDPV2 = circulating vaccine-derived poliovirus type 2; WPV1 = wild poliovirus type 1. (Source: Mbaeyi C, Baig S, Safdar MR, et al. Progress toward poliomyelitis eradication--Pakistan, January 2021-July 2022. MMWR Morb Mortal Wkly Rep 2022;71[42]:1313-8. Public domain.)

Abbreviation: WPV1 = wild poliovirus type 1. (Source: Lee SE, Greene SA, Burns CC, Tallis G, Wassilak SG, Bolu O. Progress toward poliomyelitis eradication--worldwide, January 2021-March 2023. MMWR Morb Mortal Wkly Rep 2023;72[19]:517-22. Public domain.)

Electrocardiogram of an adolescent following the treatment of thyrotoxic periodic paralysis, showing near resolution of U waves and normal sinus rhythm. U waves are still seen in leads V2, V3, V4, and V5. (Source: Yoon SH, Raza H. Thyrotoxic periodic paralysis: the peril of potassium replacement. Cureus 2022;14[12]:e32926. Creative Commons Attribution [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Electrocardiogram of an adolescent in the setting of thyrotoxic periodic paralysis with hypokalemia (1.7 mEq/L), showing sinus tachycardia (110 beats per minute), inverted T wave (green arrow), and prominent U wave (red arrow). (Source: Yoon SH, Raza H. Thyrotoxic periodic paralysis: the peril of potassium replacement. Cureus 2022;14[12]:e32926. Creative Commons Attribution [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Electrocardiogram of a 22-year-old man with thyrotoxic periodic paralysis complicated by syncope. His initial electrocardiogram during an episode showed sinus bradycardia (55 bpm) with incomplete right bundle branch block, and after intravenous atropine this evolved to an accelerated junctional rhythm, a corrected QT interval of 614ms, and an incomplete right bundle branch block. After treatment with intravenous potassium and intravenous magnesium due to his prolonged QT interval, his symptoms resolved completely within 12 hours. Most of his electrocardiogram changes resolved after correction of his hypokalemia, leaving normal sinus rhythm with a first-degree atrioventricular block. (Source: Dosu A, Gupta M, Walsh O, Makan J. Thyrotoxic periodic paralysis: case presentation with tetraparesis and cardiac dysrhythmia. Cureus 2022;14[9]:e29759. Creative Commons Attribution [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Initial electrocardiogram of a 22-year-old man with thyrotoxic periodic paralysis during an episode complicated by syncope. The electrocardiogram shows sinus bradycardia (55 bpm) with incomplete right bundle branch block. (Source: Dosu A, Gupta M, Walsh O, Makan J. Thyrotoxic periodic paralysis: case presentation with tetraparesis and cardiac dysrhythmia. Cureus 2022;14[9]:e29759. Creative Commons Attribution [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Electrocardiogram of a 45-year-old woman with thyrotoxic periodic paralysis during an episode, showing normal sinus rhythm with no ST elevation and positive U waves. (Source: Kaeley N, Ameena SM, Silpa S, Gangdev AM, Rajta M. Thyrotoxic periodic paralysis: an unusual cause of quadriparesis. Cureus 2022;14[9]:e29355. Creative Commons Attribution [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Dystroglycan is a transmembrane protein connecting the cell to extracellular ligands, such as laminin. Alpha- and beta-dystroglycan (DG) are shown in purple. The site of action of each glycosyltransferase mutated in dystroglycanopathies is indicated at the respective bonds on the functional glycan. Abbreviations: Man= mannose, GlcNac=N-acetylglucosamine, GalNac=N-acetylgalactosamine, Gal=galactose, RboP=ribitol phosphate, Xyl=xylose, GlcA=glucuronic acid. (The figure was partially created with BioRender. Contributed by Dr. Maria Chiara Manzini.)

(A) Typical patient with proximal muscle weakness and diffuse erythematous rash visible at the right knee and both arms. (B) Typical Gottron rash at the knuckles of the interphalangeal joints, sparing the phalanges. (C) Subcutaneous calcifications in the elbow protruding to the skin. (Contributed by Dr. Marinos Dalakas.)

(A) Cross-section of an H&E-stained muscle biopsy demonstrates the classic perifascicular atrophy (layers of atrophic fibers at the periphery of the fascicle) with necrosis and some inflammatory infiltrates (H&E stain ×100.) (B) Deposition of complement (membranolytic attack complex in green) on the endothelial cell wall of endomysial vessels (stained in red with a lectin Ulex Europaeus) leads to destruction of endothelial cells (confirmed in orange based on the superimposition of red on green). Consequently, in the muscles of patients with dermatomyositis, (C) the density of the endomysial capillaries (in red) is reduced, especially at the periphery of the fascicle, with dilatation of the lumen of the remaining capillaries in an effort to compensate for the ischemic process (x560). (Dalakas MC. Polymyositis, dermatomyositis and inclusion body myositis. In: Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J, editors. Harrison’s principles of internal medicine. 19th edition. New York: McGraw-Hill, 2015b:2195-202.)

Activation of complement C3 is an early event leading to formation of C3b, C3bNEO, and membrane attack complexes, which are deposited on the endothelial cell wall of the endomysial capillaries and result in destruction of capillaries, ischemia, or microinfarcts, most prominently in the periphery of the fascicles, and perifascicular atrophy. Cytokines released by activated complement lead to activation of CD4+ T cells, macrophages, B cells, and CD123+ plasmacytoid dendritic cells; enhance the expression of vascular cell adhesion molecules (VCAM) and intercellular adhesion molecule (ICAM) on the endothelial cell wall; and facilitate lymphoid cell transmigration to endomysial tissue by their integrins, late activation antigen-4, and lymphocyte function–associated antigen-1, which bind VCAM and ICAM. The perifascicular regions contain fibers in a state of remodeling and regeneration (expressing TGF-beta, NCAM, Μi-2), cell-stress (expressing HSP 70,90), immune activation (expressing MHC-1, chemokines, STAT-1), and molecules associated with innate immunity (such as MxA, ISG15, Rig-1). The role of innate immunity in inflammation and perifascicular atrophy is clearly secondary to hypoxic and ischemic damage sensed by the retinoic acid-inducible gene-1 (Rig-1) signaling, which, in turn, leads to auto-amplification of the local inflammation via beta-interferon. Abbreviations: ICAM-1, intercellular adhesion molecule-1; LFA-1, lymphocyte function–associated antigen 1; MAC, membrane attack complex; MaC-1, macrophage 1 antigen; MxA, myxovirus (influenza virus) resistance protein 1; NO, nitrous oxide; STAT-1, signal transducer and activator of transcription protein 1; TGF-beta, transforming growth factor-beta; TNF-alpha, tumor necrosis factor-alpha; VCAM-1, vascular cell adhesion molecule-1; VLA-1, very late antigen-1. (Contributed by Dr. Marinos Dalakas.)

Effect of IVIg on the skin manifestations (Gottron rash) and muscle strength of patients with dermatomyositis based on the first and pivotal placebo-controlled study. (Dalakas MC, Illa I, Dambrosia JM, et al. A controlled trial of high-dose intravenous immunoglobulin infusions as treatment for dermatomyositis. N Engl J Med 1993;329:1993-2000.) Not only do the active reddish lesions (top) improve, but the old grayish discolorations and mechanics hands (bottom) improve as well, allowing for the patient to fix her nails after many years of severe disease. Improvement in strength can be impressive and even allow wheelchair-bound patients to walk. (Contributed by Dr. Marinos Dalakas.)

IVIg inhibits complement at the C3a level (1, arrow) 2 days after the infusion (2) and intercepts the formation of MAC. As a result, MAC is not detected in the repeated muscle biopsies of the improved patients anymore (3a, 3b). The interception of MAC allows the restoration of the endomysial microvasculature, neovascularization (3c, 3d) and resolution of the perifascicular atrophy (3e, 3f). (Contributed by Dr. Marinos Dalakas.)

Patterns of muscle weakness in inclusion body myositis. (A) Wasting of the forearm muscles (*) with difficulty making a grip. (B) Quadriceps atrophy (*). (C) “Locking up” of the knee to avoid falls and use of a cane. (D) Dysphagia in a patient who has to use a special cup to avoid tilting the head backwards when he tries to swallow. (Contributed by Dr. Marinos Dalakas.)

(A) Cross-sections of H&E-stained muscle biopsies demonstrate scattered inflammatory foci with lymphocytes invading or surrounding healthy-appearing muscle fibers combined with autophagic vacuoles with bluish-red material in areas not invaded by T cells and chronic myopathic features (increased connective tissue, atrophic and hypertrophic fibers). (B) In clinical inclusion body myositis, there is inflammation without vacuoles. (C) Characteristic in typical inclusion body myositis are COX-negative fibers and (D) crystal violet-positive congophilic amyloid deposits within the vacuoles. (Contributed by Dr. Marinos Dalakas.)

MHC-1/CD8 complex in inclusion body myositis. (A) The cells surrounding or invading healthy muscle fibers are CD8+T cells, seen in green, immunostained with an anti-CD8+ monoclonal antibody (x640). (B) There is also widespread expression of MHC-1, seen in green (x350), even in fibers not invaded by T cells. (C) The characteristic MHC-1/CD8 complex is shown based on the superimposition of red/green on the autoinvasive CD8+ cells (orange) and the MHC-1 (green) expression on both the muscle fibers and the T cells. (Contributed by Dr. Marinos Dalakas.)

In humans, upper motor neurons (blue) descend from the motor cortex and project onto the brainstem and spinal cord via the corticospinal tract. These corticospinal neurons form a monosynaptic pathway (in primates and humans) that innervates lower motor neurons (orange), which in turn transmit motor signals to effector muscles. Together this forms the motor circuitry within humans. Neurophysiological impairments leading to amyotrophic lateral sclerosis can arise in the corticospinal tract at various loci. In amyotrophic lateral sclerosis, cortical dysfunction ranges from hyperexcitability (increased excitability) as a result of increased excitatory signaling or reduced inhibition, disruption of synaptic vesicle dynamics, and impaired synaptic plasticity that also extends to cortico-hippocampal connections. Within the corticospinal tract, upper motor neurons are vulnerable to synaptic loss and dendrite pathology including loss of dendritic spines that may arise from increased hyperexcitability. In a feedforward mechanism of dysfunction, degeneration of lower motor neurons is mediated, at least in part, via glutamate-mediated excitotoxicity whereby, cortical dysfunction precedes that of lower motor neurons, potentially causing further neurophysiological impairments and injury in lower motor neurons. (Reproduced with author permission from: Pasniceanu IS, Atwal MS, Souza CD, et al. Emerging mechanisms underpinning neurophysiological impairments in C9ORF72 repeat expansion-mediated amyotrophic lateral sclerosis/frontotemporal dementia. Front Cell Neurosci 2021;15: 784833.)

The interaction between dipeptide repeat polypeptides (DPRs), tethering of mitochondria to the endoplasmic reticulum by the VAPB-PTPIP51 tethering proteins, calcium and glycogen synthase beta gene (GSK-3b), resulting in impaired synaptic function and neurodegeneration in C9orf72 mutations ALS-FTD. (Contributed by Dr. Peter K Panegyre.)

Three modes of action currently link phase separation to pathology with the potential to serve as pathways for intervention. (A) The phase boundary, a metric for the propensity to phase-separate, is defined by the saturation concentration and the relative interaction strengths between molecules. (B) Material properties of condensed phases include viscoelasticity, reversibility of exchange, and the dynamics and mobility of molecules within and across droplets. (C) Fiber formation may be nucleated within droplets, potentially giving rise to pathology. These three modes of action, which are sensitive to disease-associated conditions, highlight distinct avenues for regulation and therapeutic targeting of liquid phase separation in disease. (Reproduced with author permission from: Elbaum-Garfinkle, S. Matter over mind: Liquid phase separation and neurodegeneration. J Biol Chem 2019;294(18):7160-68.)

If a polio patient's diaphragm was compromised, the early treatment was use of the iron lung, a form of negative pressure ventilator. (Photo ID: NPC 3631. Source collection: OHA 250: New Contributed Photographs. Repository: National Museum of Health and Medicine, Otis Historical Archives.)

An Emerson Respirator, also known as an iron lung, was a machine that enabled a person to breathe on their own when muscle control had been lost (often due to poliomyelitis). It used negative pressure ventilation to induce inhalation. (Photo ID: NCP 4145. Source Collection: OHA 250: New Contributed Photographs Collection. Repository: National Museum of Health and Medicine, Otis Historic Archives. Creative Commons Attribution 2.0 Generic License [CC BY 2.0], https://creativecommons.org/licenses/by/2.0.)

(Creator: U.S. Air Force. File name: 244001_1370. Citation: Mayor John F Collins records, Collection #0244.001, City of Boston Archives, Boston. Creative Commons Attribution 2.0 Generic License [CC BY 2.0], https://creativecommons.org/licenses/by/2.0.)

(Photo by Don Pinder. Courtesy of the Florida Keys Public Library. Creative Commons Attribution 2.0 Generic License [CC BY 2.0], https://creativecommons.org/licenses/by/2.0.)

(Source: Oakenroad. Creative Commons Attribution 2.0 Generic License [CC BY 2.0], https://creativecommons.org/licenses/by/2.0.)

Late stage, extreme atrophy of the lower portion of the trunk, the pelvic region, and the legs; marked pes varus, right side. (Source: Bing R. A textbook of nervous diseases for students and practising physicians in thirty lectures. Authorized translation by Charles L Allen. New York: Rebman Co, 1921.)

(Source: Bing R. A textbook of nervous diseases for students and practising physicians in thirty lectures. Authorized translation by Charles L Allen. New York: Rebman Co, 1921.)

(Source: Bing R. A textbook of nervous diseases for students and practising physicians in thirty lectures. Authorized translation by Charles L Allen. New York: Rebman Co, 1921.)

The images are from Plate 539 in Muybridge’s Animal Locomotion (Muybridge E. Animal locomotion: an electrophotographic investigation of consecutive phases of animal movements, 1872-1885. Philadelphia: University of Pennsylvania, 1887). The boy was photographed by English-American photographer Eadweard Muybridge (1830-1904) and American neurologist Francis Xavier Dercum (1856-1931) in 1885. (Public domain. Courtesy of the Boston Public Library and available either through Wikimedia Commons or Digital Commonwealth Massachusetts Collections Online.)

For details, see:
Lanska DJ. The Dercum-Muybridge collaboration for sequential photography of neurologic disorders. Neurology 2013;81:1550-4.
Lanska DJ. The Dercum-Muybridge collaboration and the study of pathologic gaits using sequential photography. J Hist Neurosci 2016a;25:23-38.
Lanska DJ. A human quadrupedal gait following poliomyelitis: From the Dercum-Muybridge collaboration (1885). Neurology 2016b;86:872-6.

Note the accentuated anterior pelvic tilt and lumbar lordosis producing a swayback posture, the marked atrophy of the leg muscles, and the back-kneeing (genu recurvatum). The images are from Plate 539 in Muybridge’s Animal Locomotion (Muybridge E. Animal locomotion: an electrophotographic investigation of consecutive phases of animal movements, 1872-1885. Philadelphia: University of Pennsylvania, 1887). The boy was photographed by English-American photographer Eadweard Muybridge (1830-1904) and Francis Xavier Dercum (1856-1931) in 1885. (Public domain. Courtesy of the Boston Public Library and available either through Wikimedia Commons or Digital Commonwealth Massachusetts Collections Online.)

For details, see:
Lanska DJ. The Dercum-Muybridge collaboration for sequential photography of neurologic disorders. Neurology 2013;81:1550-4.
Lanska DJ. The Dercum-Muybridge collaboration and the study of pathologic gaits using sequential photography. J Hist Neurosci 2016a;25:23-38.
Lanska DJ. A human quadrupedal gait following poliomyelitis: From the Dercum-Muybridge collaboration (1885). Neurology 2016b;86:872-6.

Case of Hans Spitzy (1912). "Handwalker" girl, 7 years of age. All of the muscles in both legs, except the iliopsoas of each side, are paralyzed. The child can get around only by crawling. Duration of paralysis was 5 years. (Source: Spitzy H. Surgical measures in diseases of nervous origin. [Translated by Carl G Leo-Wolf]. In: Pfaundler M, Schlossmann A, editors. The diseases of children: a work for the practising physician. [English translation edited by Henry LK Shaw and Linnæus la Pétra]. Volume 5. Philadelphia and London: JB Lippincott Co, 1912:322-3.)

Case of Austrian orthopedist Hans Spitzy (1912). "The patient can walk a little in erect posture after arthrodesis in both knees. To prevent post-operative curvature [of the legs] she wears celluloid braces (for 2 years)." (Source: Spitzy H. Surgical measures in diseases of nervous origin. [Translated by Carl G Leo-Wolf]. In: Pfaundler M, Schlossmann A, editors. The diseases of children: a work for the practising physician. [English translation edited by Henry LK Shaw and Linnæus la Pétra]. Volume 5. Philadelphia and London: JB Lippincott Co, 1912:322-3.)

Case of German orthopedist Oskar Vulpius (1915). Boy using a hands-and-knees crawl: infantile spinal paralysis (handwalker) (observation of Professor O Vulpius, Heidelberg). (Source: Ibrahim J. Poliomyelitis anterior acuta [acute spinal infantile paralysis]. In: Burr CW, editor. Text-book on nervous diseases. Philadelphia: P Blakiston’s Son & Co, 1915:793-810. See also: Lanska DJ. A human quadrupedal gait following poliomyelitis: From the Dercum-Muybridge collaboration [1885]. Neurology 2016;86:872-6.)

Case of Swiss neurologist Robert Bing (1921). Boy using a hands-and-feet bear crawl: infantile spinal paralysis. So-called "handwalker" as a result of severe dorsal and lumbar poliomyelitis. Note the marked atrophy in the pelvic girdle and leg muscles. (Source: Bing R. A textbook of nervous diseases for students and practising physicians in thirty lectures. Authorized translation by Charles L Allen. New York: Rebman Co, 1921. See also: Lanska DJ. A human quadrupedal gait following poliomyelitis: From the Dercum-Muybridge collaboration [1885]. Neurology 2016;86:872-6.)

Case of Austrian pediatrician Heinrich Lehndorff (1908). Poliomyelitis in a 7-year-old child. Severe paralysis of both legs. Flexion contracture in the hip joint, severe lordosis of the lumbar spine. "Hand walkers." [Case] of Dr. H[einrich] Lehndorff in the Carolinen Children's Hospital in Vienna. Note also the accentuated anterior pelvic tilt, which, in combination with the accentuated lumbar lordosis, produces a swayback posture; the marked atrophy of the leg muscles; and the back-kneeing (genu recurvatum). (Sources: Zappert J. Die Epidemie der Poliomyelitis acuta epidemica. [Heine-Medinsche. Krankheit] in Wien und Nieder-Oester reich. Jahre 1908. Oppenheim H. Text-book of nervous disease for physicians and students: authorized translation by Alexander Bruce. 5th edition. Edinburgh: Otto Schultze & Co, 1911;1:209. See also: Lanska DJ. A human quadrupedal gait following poliomyelitis: From the Dercum-Muybridge collaboration [1885]. Neurology 2016;86:872-6.)

Case of Austrian pediatrician Heinrich Lehndorff (1908). Note the extreme lumbar lordosis, reflecting a combination of weakness and hip contractures.

Sources:
Zappert J. Die Epidemie der Poliomyelitis acuta epidemica. [Heine-Medinsche. Krankheit] in Wien und Nieder-Oester reich. Jahre 1908.
Oppenheim H. Text-book of nervous disease for physicians and students: authorized translation by Alexander Bruce. 5th edition. Edinburgh: Otto Schultze & Co, 1911;1:209.

See also: Lanska DJ. A human quadrupedal gait following poliomyelitis: From the Dercum-Muybridge collaboration [1885]. Neurology 2016;86:872-6.

Late-stage, carmine preparation from the spinal cord of a 76-year-old man. The cells of the anterior horn, still recognizable microscopically, are brought out by retouching. (Source: Bing R. A textbook of nervous diseases for students and practising physicians in thirty lectures. Authorized translation by Charles L Allen. New York: Rebman Co, 1921.)

Poliomyelitis acuta having run its course. Section of the lumbar cord; staining according to Weigert. Narrowing of the left half of the spinal cord section; atrophy and sclerosis of the anterior horn; degeneration of the anterior roots on the left side. (From Schmaus). (Source: Ibrahim J. Poliomyelitis anterior acuta [acute spinal infantile paralysis]. In: Burr CW, editor. Text-book on nervous diseases. Philadelphia: P Blakiston’s Son & Co, 1915:793-810.)

HQ=headquarters. (Composite image prepared by Dr. Douglas J Lanska from publicly available information on Wikimedia Commons.)

This includes all reported cases of wild polioviruses and vaccine-derived polioviruses. (Source: Dattani S, Spooner F, Ochmann S, Roser M. Polio. Published online at OurWorldInData.org 2017, last revised 2022. Retrieved from: https://ourworldindata.org/polio. Creative Commons Attribution 4.0 International License [CC BY 4.0], https://creativecommons.org/licenses/by/4.0.)

Shown is the "base case" reported by Duintjer Tebbens and colleagues. (Sources: Dattani S, Spooner F, Ochmann S, Roser M. Polio. Published online at OurWorldInData.org 2017, last revised 2022. Retrieved from: https://ourworldindata.org/polio. Duintjer Tebbens RJ, Pallansch MA, Cochi SL, et al. Economic analysis of the global polio eradication initiative. Vaccine 2010;29[2]:334-43. Creative Commons Attribution 4.0 International License [CC BY 4.0], https://creativecommons.org/licenses/by/4.0. Reformatted and rearranged from original by Dr. Douglas J Lanska, but data remain unchanged.)

Reported cases of polio underestimate actual cases because people with acute flaccid paralysis may not be detected and tested for poliovirus in time. (Source: Dattani S, Spooner F, Ochmann S, Roser M. Polio. Published online at OurWorldInData.org 2017, last revised 2022. Retrieved from: https://ourworldindata.org/polio. Creative Commons Attribution 4.0 International License [CC BY 4.0], https://creativecommons.org/licenses/by/4.0.)

With the Global Polio Eradication Initiative (GPEI), 105 countries received support for surveillance, childhood immunizations, and campaigns to control outbreaks. (Sources: Thompson KM, Kalkowska DA. An updated economic analysis of the global polio eradication initiative. Risk Anal 2021b;41[2]:393-406. Dattani S, Spooner F, Ochmann S, Roser M. Polio. Published online at OurWorldInData.org 2017, last revised 2022. Retrieved from: https://ourworldindata.org/polio. Creative Commons Attribution 4.0 International License [CC BY 4.0], https://creativecommons.org/licenses/by/4.0.)

World Health Organization data as of August 25, 2020. Abbreviations: bOPV, bivalent oral poliovirus vaccine; mOPV, monovalent oral poliovirus vaccine; tOPV, trivalent OPV; WHA, World Health Assembly; WHO, World Health Organization. (Source: Modlin JF, Bandyopadhyay AS, Sutter R. Immunization against poliomyelitis and the challenges to worldwide poliomyelitis eradication. J Infect Dis 2021;224[12 Suppl 2]:S398-404.)

Data as of May 20, 2014. (Source: Moturi EK, Porter KA, Wassilak SG, et al. Progress toward polio eradication--worldwide, 2013-2014. MMWR Morb Mortal Wkly Rep 2014;63[21]:468-72.)

Other countries include Cameroon (n = 5), Equatorial Guinea (n = 5), Ethiopia (n = 1), Iraq (n = 2), Somalia (n = 5), and Syria (n = 1). (Source: Morales M, Tangermann RH, Wassilak SG. Progress toward polio eradication - worldwide, 2015-2016. MMWR Morb Mortal Wkly Rep 2016;65[18]:470-3.)

Data as of May 3, 2019. (Source: Greene SA, Ahmed J, Datta SD, et al. Progress toward polio eradication - worldwide, January 2017-March 2019. MMWR Morb Mortal Wkly Rep 2019;68[20]:458-62.)

Data as of August 3, 2021. Abbreviation: WPV1 = wild poliovirus type 1. (Source: Bigouette JP, Wilkinson AL, Tallis G, Burns CC, Wassilak SGF, Vertefeuille JF. Progress toward polio eradication - worldwide, January 2019-June 2021. MMWR Morb Mortal Wkly Rep 2021;70[34]:1129-35.)

Data as of May 5, 2022. Abbreviation: WPV1 = wild poliovirus type 1. (Source: Rachlin A, Patel JC, Burns CC, et al. Progress toward polio eradication - worldwide, January 2020-April 2022. MMWR Morb Mortal Wkly Rep 2022;71[19]:650-5.)

This includes reported cases of paralytic polio from any wild poliovirus strain (WPV1, WPV2, WPV3). As can be seen, the predominant type of circulating vaccine-derived poliovirus (cVDPV) was type 2 (cVDPV2). (Source: Dattani S, Spooner F, Ochmann S, Roser M. Polio. Published online at OurWorldInData.org 2017, last revised 2022. Retrieved from: https://ourworldindata.org/polio. Creative Commons Attribution 4.0 International License [CC BY 4.0], https://creativecommons.org/licenses/by/4.0.)

Data as of March 24 to 27, 2020. Abbreviations: cVDPV1 = cVDPV type 1; cVDPV2 = cVDPV type 2. (Source: Alleman MM, Jorba J, Greene SA, et al. Update on vaccine-derived poliovirus outbreaks--worldwide, July 2019 to February 2020. MMWR Morb Mortal Wkly Rep 2020;69[16]:489-95.)

Data as of November 9, 2021. Abbreviations: cVDPV = circulating vaccine-derived poliovirus; cVDPV1 = cVDPV type 1; cVDPV2 = cVDPV type 2; cVDPV3 = cVDPV type 3. (Source: Alleman MM, Jorba J, Greene SA, et al. Update on vaccine-derived poliovirus outbreaks--worldwide, July 2019 to February 2020. MMWR Morb Mortal Wkly Rep 2020;69[16]:489-95.)

Courtesy of Ondrej Mach and Ajay Kumar Goel, World Health Organization. Abbreviations: AFP, acute flaccid paralysis; bOPV, bivalent oral poliovirus vaccine; cVDPV, circulating vaccine-derived poliomyelitis; ES, environmental surveillance; WHO, World Health Organization. (Source: Modlin JF, Bandyopadhyay AS, Sutter R. Immunization against poliomyelitis and the challenges to worldwide poliomyelitis eradication. J Infect Dis 2021;224[12 Suppl 2]:S398-404.)

Note that in 2017 the graphs for wild-type type 1 and cVDPV cross over so that cVDPV exceeds the number of wild-type cases. (Figure prepared by Dr. Douglas J Lanska from data from the Centers for Disease Control and Prevention and the World Health Organization.)

(Sources: CDC; Dauer CC. Incidence of poliomyelitis in the United States in 1945. Public Health Rep [1896] 1946;61:915-21. Original image was not quite square; this has been corrected by Dr. Douglas J Lanska.)

(Figure prepared by Dr. Douglas J Lanska. Source for plotted data: U.S. Census Bureau. No. HS-18. Specified reportable diseases--cases per 100,000 population: 1912 to 2001. Statistical abstract of the United States, 2003. Available at: https://www2.census.gov/library/publications/2004/compendia/statab/123ed/hist/hs-18.pdf.)

Abbreviations: ED = emergency department; VDPV2 = type 2 vaccine-derived poliovirus. Wastewater, also referred to as sewage, includes water from household or building use (eg, toilets, showers, and sinks) that can contain human fecal waste and water from non-household sources (eg, rain and industrial use). Note that more than one positive wastewater sample might have been collected on the same day in Rockland County or Orange County. (Source: Link-Gelles R, Lutterloh E, Schnabel Ruppert P, et al. Public health response to a case of paralytic poliomyelitis in an unvaccinated person and detection of poliovirus in wastewater--New York, June to August 2022. MMWR Morb Mortal Wkly Rep 2022;71[33]:1065-8.)

(A) Tibial F wave study showing normal F waves. The solid horizontal line denotes normal F wave duration in the superimposed waves (settings gain 200 microvolt/division, time base 20 ms/division). (B) Tibial F wave study showing stimulus induced after discharges with F waves being obscured. The solid horizontal line denotes stimulus induced after discharge duration of 140 ms (settings gain 200 microvolt/division, time base 20 ms/division). (Figure reprinted with permission from: Nair AV, Mani A, Vijayaraghavan A, et al. Utility of stimulus induced after discharges in the evaluation of peripheral nerve hyperexcitability: old wine in a new bottle? J Peripher Nerv Syst 2021;26:90-8.)

Note the decrementing response. The top is recorded with a long sweep speed of 100 milliseconds per division, whereas the insert is at a regular sweep speed of 10 milliseconds per division. Note the very high frequency (150 to 250 Hz) repetitive discharge of a single motor unit. (Image used with permission from: Preston DC, Shapiro BE. Electromyography and neuromuscular disorders: clinical-electrophysiological correlations. Elsevier Saunders: London, 2013.)

Note that myokymic discharge is shown in a long sweep speed of 200 milliseconds per division. Note that the number of potentials often changes from one burst to another, varying in this example from four to seven potentials. (Contributed by Dr. Bashar Katirji.)

(Figure reprinted with permission from: Termsarasab T, Thammongkolchai T, Katirji B. Stiff person syndrome and related disorders. Springer: New York, 2020.)

A total of 91 cases of wild poliovirus type 1 (WPV1) and 71 cases of vaccine-derived poliovirus type 2 (VDPV2) were reported from January 2016 to July 2020, with a marked exacerbation in 2020 (data as of August 29, 2020). Abbreviations: aVDPV2 = ambiguous vaccine-derived poliovirus type 2; cVDPV2 = circulating vaccine-derived poliovirus type 2; WPV1 = wild poliovirus type 1. aVDPVs are isolates with no evidence of person-to person transmission or from persons with no known immunodeficiency; cVDPVs are isolates for which there is evidence of person-to-person transmission in the community. (Source: U.S. Centers for Disease Control and Prevention. Martinez M, Akbar IE, Wadood MZ, Shukla H, Jorba J, Ehrhardt D. Progress toward poliomyelitis eradication - Afghanistan, January 2019-July 2020. MMWR Morb Mortal Wkly Rep 2020;69(40):1464-8.)

During 2019, 147 WPV1 cases were reported in Pakistan, more than 12 times the 12 reported cases during 2018. Since the detection of the first cVDPV2 case in July 2019 through September 15, 2020, 81 cases were reported. Abbreviations: cVDPV2 = circulating vaccine-derived poliovirus type 2; WPV1 = wild poliovirus type 1. cVDPVs are isolates for which there is evidence of person-to-person transmission in the community. (Source: U.S. Centers for Disease Control and Prevention. Hsu CH, Rehman MS, Bullard K, Jorba J, et al. Progress toward poliomyelitis eradication - Pakistan, January 2019-September 2020. MMWR Morb Mortal Wkly Rep 2020;69(46):1748-52.)

EMG of calf muscles showed low-amplitude, short-duration motor unit action potentials (MUAPs) suggestive of a myopathic disorder. (Courtesy of: Gupta M, Singh R, Lehl SS. Reversible calf pseudohypertrophy in a young male. Research 2014;1:901. Creative Commons Attribution License CC BY. Image cropped and edited by Douglas J Lanska MD to correct focus and exposure.)

Pseudohypertrophy of calf muscles in a man with Hoffmann syndrome. (Courtesy of: Gupta M, Singh R, Lehl SS. Reversible calf pseudohypertrophy in a young male. Research 2014;1:901. Creative Commons Attribution [CC BY] license.)

Schematic representation of the main lipid disorders that affect the skeletal muscle cell. ATP: adenosine triphosphate, CACT: carnitine-acylcarnitine translocase, CPTI: carnitine palmitoyltransferase I, CPT II: carnitine palmitoyltransferase II, ETF: electron transfer flavoprotein, ETFDH: electron transfer flavoprotein dehydrogenase, FADH2: flavin adenine dinucleotide, FFA: free fatty acids, IMM: internal mitochondrial membrane, LCFAT: long-chain fatty acid transporter, MCAD: medium-chain acyl-CoA dehydrogenase, MTP: mitochondrial trifunctional protein, NADH: nicotinamide adenine dinucleotide, OCTN2: organic cation/carnitine transporter 2, OMM: outer mitochondrial membrane, SCAD: short-chain acyl-CoA dehydrogenase, TCA: tricarboxylic acid, VLCAD: very long-chain acyl-CoA dehydrogenase. (Contributed by Dr. Ezequiel Piccione.)

Clinical, laboratory, and treatment highlights of lipid disorders with episodic symptomatology. CPTII: carnitine palmitoyltransferase II, DHA: docosahexaenoic acid, LPIN1: phosphatidic acid phosphorylase 1, MTP: mitochondrial trifunctional protein, VLCAD: very long-chain acyl-CoA dehydrogenase. (Contributed by Dr. Ezequiel Piccione.)

Clinical differences between the classic lipid storage myopathies. CoQ10: coenzyme Q10, MCT: medium-chain triglycerides. (Contributed by Dr. Ezequiel Piccione.)

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.)

(Contributed by Dr. Simona Treidler.)

(Contributed by Dr. Simona Treidler.)

(Contributed by Dr. Simona Treidler.)

(Contributed by Dr. Simona Treidler.)

(Contributed by Dr. Simona Treidler.)

(Contributed by Dr. Simona Treidler.)

Midsagittal image shows hypoplasia of the cerebellar vermis and ventral pons with characteristic brainstem kink. (Contributed by Dr. Peter Barth.)

T1-weighted inversion recovery MRI of a 4-month-old male with severe hydrocephalus due to Walker-Warburg syndrome. In this section, the border between cortex and adjacent white matter is irregular because of the irregular structure of the neocortex, a characteristic of cobblestone malformation. (Contributed by Dr. Peter Barth.)

Polish-American virologist Albert Sabin (1906-1993) developed the first effective trivalent live-attenuated (oral) poliovirus vaccine. (Contributed by Dr. Douglas Lanska. Source: Woodward T. The Armed Forces Epidemiological Board: its first fifty years. Falls Church, VA: Office of the Surgeon General, Department of the Army, 1990. Public domain photograph of a U.S. Army soldier taken in the course of the person’s official duties.)

O’Connor was Chairman of the National Foundation for Infantile Paralysis that funded the development and testing of polio vaccines, including the Salk killed virus vaccine. He was also later Chairman and President of the American Red Cross (1944-1949) and the League of Red Cross Societies (1945-1950). (Contributed by Dr. Douglas Lanska. Source: Red Cross and Red Crescent Movement History. http://www.redcross.int/en/history/not_oconnor.asp [Accessed 4-23-2017]. Used with permission.)

This cartoon helps to illustrate the rules of mitochondrial genetics, including the exclusive contribution of the oocyte’s mitochondria to the zygote (maternal inheritance), heteroplasmy (oversimplified by showing entire mitochondria as wild-type or mutated), and mitotic segregation, leading to one heteroplasmic and two homoplasmic cells in the third cell generation. For simplicity, the relative sizes of the oocyte and the sperm have not been respected. (Contributed by Dr. Salvatore DiMauro.)

This full-term newborn boy’s mother has the more usual later onset form of the disease. The boy has the characteristic facial diplegia with an inverted V-shaped upper lip, generalized hypotonia and weakness, and multiple joint contractures involving ankles, hips, and interphalangeal joints of the fingers. (Reproduced with permission from: Sarnat HB, O’Connor T, Byrne PA. Clinical effects of myotonic dystrophy on pregnancy and the neonate. Arch Neurol 1976;33:459-65. Copyrighted 1976, American Medical Assoc.)

The vaporizer and entire setup is displayed. Three baths can be bubbled with halothane for the halothane contracture test. The other three baths can only be bubbled with O2 CO2. The latter are used for the caffeine contracture test. (Contributed by Dr. Jordan Miller.)

Thyroid acropachy. (Source: Fred HL, van Dijk HA. Images of memorable cases: case 144. OpenStax 2008.) (Creative Commons Attribution 4.0 License.)

Pretibial myxedema. (Source: Fred HL, van Dijk HA. Images of memorable cases: case 144. OpenStax 2008.) (Creative Commons Attribution 4.0 License.)

Pseudohypertrophy of the right calf in a man with Hoffmann syndrome. (Source: Fred HL, van Dijk HA. Images of memorable cases: case 119. OpenStax 2008.) (Creative Commons Attribution 4.0 License.)

Calf pseudohypertrophy in the same boy with Kocher-Debré-Sémelaigne syndrome. (Source: Shaw C, Shaw P. Kocher-debre-semelaigne syndrome: hypothyroid muscular pseudohypertrophy—a rare report of two cases. Case Rep Endocrinol 2012;2012:153143.) (Creative Commons Attribution License.)

Facial features in a man with Hoffmann syndrome. (Source: Fred HL, van Dijk HA. Images of memorable cases: case 119. OpenStax 2008.) (Creative Commons Attribution 4.0 License.)

A ten-year-old boy with pseudomuscular hypertrophy in Kocher-Debré-Sémelaigne syndrome. (Source: Shaw C, Shaw P. Kocher-debre-semelaigne syndrome: hypothyroid muscular pseudohypertrophy—a rare report of two cases. Case Rep Endocrinol 2012;2012:153143.) (Creative Commons Attribution License.)

A 9-year-old girl with pseudomuscular hypertrophy in Kocher-Debré-Sémelaigne syndrome. (Source: Shaw C, Shaw P. Kocher-debre-semelaigne syndrome: hypothyroid muscular pseudohypertrophy—a rare report of two cases. Case Rep Endocrinol 2012;2012:153143.) (Creative Commons Attribution License.)

Facial features in the same girl with Kocher-Debré-Sémelaigne syndrome. (Source: Shaw C, Shaw P. Kocher-debre-semelaigne syndrome: hypothyroid muscular pseudohypertrophy—a rare report of two cases. Case Rep Endocrinol 2012;2012:153143.) (Creative Commons Attribution License.)

Histology of “struma lymphomatosa” (Hashimoto thyroiditis). Legend: (a) Lymphoid follicle; (b) Degenerated thyroid follicle; (c) Giant cells; (d) Hyperplastic interstitium with prominent round-cell (lymphocytic) infiltration. (Source: Hashimoto H. Zur Kenntnis der lymphomatösen Veränderung der Schilddrüse (Struma lymphomatosa). Archiv für Klinische Chirurgie (Berlin) 1912;97:219-48.) (Public domain.)

British surgeon William Miller Ord MRCS (1834-1902). (Source: Anonymous. William Miller Ord, M.D., F.R.C.P. Lond. Br Med J 1902;1(2160):1315-7. Public domain.)

English physician Caleb Hillier Parry (1755-1822) gave one of the earliest accounts of exophthalmic goiter. (Source: Hull G. Caleb Hillier Parry 1755-1822: a notable provincial physician. J R Soc Med 1998;91(6):335-8. Courtesy of Wikimedia Commons. Public domain.)

Suggested workup scheme for cases of rhabdomyolysis. (Zutt R, van der Kooi AJ, Linthorst GE, Wanders RJ, de Visser M. Rhabdomyolysis: review of the literature. Neuromuscul Disord 2014;24(8):651-9.)

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.)

Paraffin transverse sections stained with hematoxylin-eosin show normal muscle architecture, no connective tissue proliferation, necrosis, or regeneration, and two populations of fibers by size. Magnification of A is x100, and magnification of B is x250. (Contributed by Dr. Harvey Sarnat.)

Courtesy of the U.S. National Library of Medicine. Public domain.