Amyotrophic lateral sclerosis: Clinical heterogeneity and approaches to classification

Amyotrophic lateral sclerosis (ALS) is a clinically and pathogenically heterogenic disease. Clinical heterogeneity refers to the initial localization of the pathological process, the variability of the combination of signs of upper and lower motor neuronal damage, the age of the onset, the rate of progression, hereditary predisposition, and the presence of non-motor clinical manifestations. A large number of forms of the disease are described (primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, flail-arm syndrome, and others), which in some cases can be considered as independent diseases due to the localization of the pathological process, disease course and prognosis. In recent years, convincing evidences of the genetic and pathogenetic heterogeneity of ALS have also been obtained. Large heterogeneity makes it difficult to create a unified classification of ALS. Formal classifications used, for example, in the diagnostic criteria of El Escorial or the International Classification of Diseases of the 10th revision, do not take into account many of the important features of the disease. The article describes the clinical heterogeneity of ALS. The proposed classifications are compared. A new classification system that taking into account various features of the disease and can improves understanding of the diversity of ALS is described.

1. Bäumer D., Talbot K., Turner M. R. Advances in motor neurone disease. J R Soc Med 2014;107(1):14–21. DOI: 110.1177/0141076813511451. PMID: 24399773.

2. Couratier P., Corcia P., Lautrette G. et al. Epidemiology of amyotrophic lateral sclerosis: a review of literature. Rev Neurol(Paris) 2016;172(1):37–45. DOI: 110.1016/j.neurol.2015.11.002. PMID: 26727307.

3. Завалишин И. А., Переседова А. В. Этапы разработки проблемы БАС.

4. В кн.: Боковой амиотрофический склероз. Под. ред. И. А. Завалишина. М.: Евразия+, 2007. С. 9–27. [Zavalishin I. A., Peresedova A. V. Stages of the ALS problem development. In: Amyotrophic lateral sclerosis. Ed. I.A. Zavalishin. Moscow: Evraziya+, 2007. Pp. 9–27. (In Russ.)].

5. Eisen A. A. Historical aspects

6. of motor neuron diseases. Handb Clin Neurol 2007;82:1–11. DOI: 110.1016/S0072–9752(07)80004–2. PMID: 18808886.

7. Wechsler I. S., Brody S. The problem of primary lateral sclerosis. J Am Med Assoc 1946;130:1195–8. PMID: 21022534.

8. Brain W. R. Diseases of the nervous system. London: Oxford University Press, 1933.

9. Справочник по формулированию клинического диагноза болезней нервной системы. Под ред. В. Н. Штока,

10. О. С. Левина. М.: Медицинское информационное агентство, 2006. C. 149–152. [Reference book on formulation of clinical diagnosis of nervous system diseases. Eds.: V. N. Shtok, O. S. Levin. Moscow: Meditsinskoe informatsionnoe agentstvo, 2006. Pp. 149–152. (In Russ.)].

11. Al-Chalabi A., Hardiman O., Kiernan M. C. et al. Amyotrophic lateral sclerosis: moving towards a new classification system. Lancet Neurol 2016;15(11):1182–94. DOI: 110.1016/S1474–4422(16)30199–5. PMID: 27647646.

12. Swinnen B., Robberecht W. The phenotypic variability of amyotrophic lateral sclerosis. Nat Rev Neurol 2014;10(11):661–70. DOI: 110.1038/nrneurol.2014.184. PMID: 25311585.

13. Завалишин И. А., Стойда Н. И., Шитикова И. Е. Клиника, классификация, диагностика. В кн.: Боковой амиотрофический склероз. Под. ред.

14. И. А. Завалишина. М.: Евразия+, 2007. С. 51–131. [Zavalishin I. A., Stoyda N. I., Shitikova I. E. Clinical picture, classification, diagnosis. In: Amyotrophic lateral sclerosis. Ed. I.A. Zavalishin. Moscow: Evraziya+, 2007. Pp. 51–131. (In Russ.)].

15. Хондкариан О. А., Бунина Т. Л., Завалишин И. А. Боковой амиотрофический склероз. М.: Медицина, 1978. 264 c. [Khondkarian O. A., Bunina T. L., Zavalishin I. A. Amyotrophic lateral sclerosis. Moscow: Meditsina, 1978. 264 p. (In Russ.)].

16. Sabatelli M., Conte A., Zollino M. Clinical and genetic heterogeneity

17. of amyotrophic lateral sclerosis. Clin Genet 2013;83(5):408–16. DOI: 110.1111/cge.12117. PMID: 23379621.

18. Hu M. T., Ellis C. M., Al-Chalabi A. et al. Flail arm syndrome: a distinctive variant of amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 1998;65(6):950–1. PMID: 9854987.

19. Jawdat O., Statland J. M., Barohn R. J. et al. Amyotrophic lateral sclerosis regional variants(brachial amyotrophic diplegia, leg amyotrophic diplegia, and isolated bulbar amyotrophic lateral sclerosis). Neurol Clin 2015;33(4):775–85. DOI: 110.1016/j.ncl.2015.07.003. PMID: 26515621.

20. Su X. W., Broach J. R., Connor J. R. et al. Genetic heterogeneity of amyotrophic lateral sclerosis: implications for clinical practice and research. Muscle Nerve 2014;49(6):786–803. DOI: 110.1002/mus.24198. PMID: 24488689.

21. Al-Chalabi A., van den Berg L. H., Veldink J. Gene discovery in amyotrophic lateral sclerosis: implications for clinical management. Nat Rev Neurol 2017;13(2): 96–104. DOI: 110.1038/nrneurol.2016.182. PMID: 27982040.

22. Turner M. R., Swash M. The expanding syndrome of amyotrophic lateral sclerosis: a clinical and molecular odyssey. J Neurol Neurosurg Psychiatry 2015;86(6):667–73. DOI: 110.1136/jnnp-2014-308946. PMID: 25644224.

23. Chiò A., Calvo A., Moglia C. et al. Phenotypic heterogeneity of amyotrophic lateral sclerosis: a population based study. J Neurol Neurosurg Psychiatry 2011;82(7):740–6. DOI: 110.1136/jnnp.2010.235952. PMID: 21402743.

24. Ravits J. M., La Spada A. R. ALS motor phenotype heterogeneity, focality, and spread: deconstructing motor neuron degeneration. Neurology 2009;73:805–11. DOI: 110.1212/WNL.0b013e3181b6bbbd. PMID: 19738176.

25. Попова Л. М. Амиотрофический боковой склероз в условиях продленной жизни. М.: Медицина, 1998. 144 с. [Popova L. M. Amyotrophic lateral sclerosis and prolonged life. Moscow: Meditsina, 1998. 144 p. (In Russ.)].

26. Shoesmith C. L., Findlater K., Rowe A., Strong M. J. Prognosis of amyotrophic lateral sclerosis with respiratory onset. J Neurol Neurosurg Psychiatry 2007;78(6):629–31. DOI: 110.1136/jnnp.2006.103564. PMID: 17088331.

27. Brooks B. R., Miller R. G., Swash M. et al. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2000;1(5):293–9. PMID: 11464847.

28. Ince P. G., Evans J., Knopp M. et al. Corticospinal tract degeneration

29. in the progressive muscular atrophy variant of ALS. Neurology 2003;60(8):1252–8. PMID: 12707426.

30. Floyd A. G., Yu Q. P., Piboolnurak P. Transcranial magnetic stimulation in ALS: utility of central motor conduction tests. Neurology 2009;72(6):498–504. DOI: 110.1212/01.wnl.0000341933.97883.a4. PMID: 19204259.

31. Kim W. K., Liu X., Sandner J. et al. Study of 962 patients indicates progressive muscular atrophy is a form of ALS. Neurology 2009;73(20):1686–92. DOI: 110.1212/WNL.0b013e3181c1dea3. PMID: 19917992.

32. Бакулин И. С., Червяков А. В., Захарова М. Н. и др. Возможности навигационной транскраниальной магнитной стимуляции в сложных диагностических случаях вовлечения верхнего мотонейрона: клиническое наблюдение. Нервно-мышечные болезни 2015;(2):32–7. [Bakulin I. S., Chervyakov A. V., Zakharova M. N. et al. Navigated transcranial magnetic stimulation possibilities in difficult diagnostic cases upper motor

33. neuron lesions – case report. Nervno-myshechnye bolezni = Neuromuscular Diseases 2015;(2):32–7. (In Russ.)]. DOI: 110.17 650/2222-8721-2015-5-2-32-37.

34. Visser J., van den Berg-Vos R. M., Franssen H. et al. Disease course and prognostic factors of progressive muscular atrophy. Arch Neurol 2007;64(4):522–8. DOI: 110.1001/archneur.64.4.522. PMID: 17420313.

35. Agosta F., Al-Chalabi A., Filippi M. et al. The El Escorial criteria: strengths and weaknesses. Amyotroph Lateral Scler Frontotemporal Degener 2015; 16(1–2):1–7. DOI: 110.3109/21678421.2014.964258. PMID: 25482030.

36. Hübers A., Hildebrandt V., Petri S. et al. Clinical features and differential diagnosis of flail arm syndrome. J Neurol 2016;263(2):390–5. DOI: 110.1007/s00415-015-7993-z. PMID: 26705123.

37. Wijesekera L. C., Mathers S., Talman P.

38. et al. Natural history and clinical features of the flail arm and flail leg ALS variants. Neurology 2009;72(12):1087–94. DOI: 110.1212/01.wnl.0000345041.83406. a2. PMID: 19307543.

39. Gamez J., Cervera C., Codina A. Flail arm syndrome of Vulpian – Bernhart’s form of amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2009;67(2):258. PMID: 10475767.

40. Vucic S., Kiernan M. C. Abnormalities in cortical and peripheral excitability

41. in flail arm variant amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2007;78(8):849–52. DOI: 110.1136/jnnp.2006.105056. PMID: 17210625.

42. Singer M. A., Statland J. M., Wolfe G. I. et al. Primary lateral sclerosis. Muscle Nerve 2007;35(3):291–302. DOI: 110.1002/mus.20728. PMID: 17212349.

43. Swash M., Desai J., Misra V. P. What is primary lateral sclerosis? J Neurol Sci 1999;170(1):5–10. PMID: 10540029.

44. Gordon P. H., Cheng B., Katz I. B. et al. Clinical features that distinguish PLS, upper motor neuron-dominant ALS, and typical ALS. Neurology 2009;72(22):1948–52. DOI: 110.1212/WNL.0b013e3181a8269b. PMID: 19487653.

45. Gastaut J. L., Bartolomei F. Mills’ syndrome: ascending(or descending) progressive hemiplegia: a hemiplegic form of primary lateral sclerosis? J Neurol Neurosurg Psychiatry 1994;57(10):1280–1. PMID: 7931406.

46. Statland J. M., Barohn R. J., McVey A. L. et al. Patterns of weakness, classification of motor neuron disease, and clinical diagnosis of sporadic amyotrophic lateral sclerosis. Neurol Clin 2015;33(4):735–48. DOI: 110.1016/j.ncl.2015.07.006. PMID: 26515618.

47. Orban P., Devon R. S., Hayden M. R., Leavitt B. R. Juvenile amyotrophic lateral sclerosis. Handb Clin Neurol 2007;82:301–12. PMID: 18808900.

48. Flor-de-Lima F., Sampaio M., Nahavandi N. et al. Alsin related disorders: literature review and case study with novel mutations. Case Rep Genet 2014;2014:691515. DOI: 110.1155/2014/691515. PMID: 25302125.

49. Hirano M., Quinzii C. M., Mitsumoto H. et al. Senataxin mutations and amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2011;12(3):223–7. DOI: 110.3109/17482968.2010.545952. PMID: 21190393.

50. Zou Z. Y., Liu M. S., Li X. G., Cui L. Y. Mutations in SOD1 and FUS caused juvenile-onset sporadic amyotrophic lateral sclerosis with aggressive progression. Ann Transl Med 2015;3(15):221. DOI: 110.3978/j.issn.23055839.2015.09.04. PMID: 26488017.

51. Pupillo E., Messina P., Logroscino G. et al. Long-term survival of amyotrophic lateral sclerosis: a population-based study. Ann Neurol 2014;75(2):287–97. DOI: 110.1002/ana.24096. PMID: 24382602.

52. Абрамычева Н. Ю., Лысогорская Е. В., Шпилюкова Ю. С. и др. Молекулярная структура бокового амиотрофического склероза в российской популяции. Нервно-мышечные болезни 2016;6(4):21–7. [Abramycheva N. Yu., Lysogorskaya E. V., Shpilyukova Yu. S. et al. Molecular structure of amyotrophic lateral sclerosis in Russian population. Nervno-myshechnye bolezni = Neuromuscular Diseases 2016;6(4):21–7. (In Russ.)]. DOI: 110.17650/2222-8721-2016-6-4-21-27.

53. Knibb J. A., Keren N., Kulka A. et al. A clinical tool for predicting survival

54. in ALS. J Neurol Neurosurg Psychiatry 2016;87(12):1361–7. DOI: 110.1136/jnnp-2015-312908. PMID: 27378085.

55. Testa D., Lovati R., Ferrarini M. et al. Survival of 793 patients with amyotrophic lateral sclerosis diagnosed over a 28-year period. Amyotroph Lateral Scler Other Motor Neuron Disord 2004;5(4):208–12. PMID: 15799548.

56. Woolley S. C., Strong M. J. frontotemporal dysfunction and dementia in amyotrophic lateral sclerosis. Neurol Clin 2015;33(4):787–805. DOI: 110.1016/j.ncl.2015.07.011. PMID: 26515622.

57. Achi E. Y., Rudnicki S. A. ALS and frontotemporal dysfunction: a review. Neurol Res Int 2012;2012:806306. DOI: 110.1155/2012/806306. PMID: 22919484.

58. Desai J., Swash M. Extrapyramidal involvement in amyotrophic lateral sclerosis: backward falls and retropulsion. J Neurol Neurosurg Psychiatry 1999;67(2):214–6. PMID: 10406993.

59. Manno C., Lipari A., Bono V. et al. Sporadic Parkinson disease and amyo-trophic lateral sclerosis complex(Brait– Fahn–Schwartz disease). J Neurol Sci 2013;326(1–2):104–6. DOI: 110.1016/ j.jns.2013.01.009. PMID: 23380453.

60. Gamez J., Corbera-Bellalta M., Mila M. et al. Chorea-ballism associated with familial amyotrophic lateral sclerosis. A clinical, genetic, and neuropathological study. Mov Disord 2008;23(3):434–8. DOI: 110.1002/mds.21856. PMID: 18072201.

61. Sadeghian H., O’Suilleabhain P. E., Battiste J. et al. Huntington chorea presenting with motor neuron disease. Arch Neurol 2011;68(5):650–2. DOI: 110.1001/archneurol.2011.76. PMID: 21555641.

62. Isaacs J. D., Dean A. F., Shaw C. E. et al. Amyotrophic lateral sclerosis with sensory neuropathy: part of a multisystem disorder? J Neurol Neurosurg Psychiatry 2007;78(7):750–3. DOI: 110.1136/jnnp.2006.098798. PMID: 17575021.

63. Brooks B. R. El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. Subcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases and the El Escorial “Clinical limits of amyotrophic lateral sclerosis” workshop contributors. J Neurol Sci 1994;124:96–107. PMID: 7807156.

64. de Carvalho M., Dengler R., Eisen A. et al. Electrodiagnostic criteria for diagnosis of ALS. Clin Neurophysiol 2008;119(3):497–503. DOI: 110.1016/j.clinph.2007.09.143. PMID: 18164242.

65. Kraemer M., Buerger M., Berlit P. Diagnostic problems and delay of diagnosis in amyotrophic lateral sclerosis. Clin Neurol Neurosurg 2010;112(2):103–5. DOI: 110.1016/j.clineuro.2009.10.014. PMID: 19931253.

66. Roche J. C., Rojas-Garcia R., Scott K. M. et al. A proposed staging system for amyotrophic lateral sclerosis. Brain 2012;135(Part 3): 847–52. DOI: 110.1093/brain/awr351. PMID: 22271664.