Close
New

Medscape is available in 5 Language Editions – Choose your Edition here.

 

Amyotrophic Lateral Sclerosis Medication

  • Author: Carmel Armon, MD, MSc, MHS; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE  more...
 
Updated: Mar 23, 2016
 

Medication Summary

The glutamate pathway antagonist riluzole is the only medication that has shown efficacy in extending life in amyotrophic lateral sclerosis (ALS). The American Academy of Neurology (AAN) guideline recommends that riluzole be offered to patients with ALS.[2]

A variety of other medications may be useful for relief of symptoms associated with ALS. These include the following:

  • Muscle relaxants to relieve spasticity
  • The combination of dextromethorphan and quinidine to decrease emotional lability of pseudobulbar affect
  • Anticholinergics and sympathomimetics for sialorrhea
  • Mucolytics for thickened secretions
  • Lorazepam for anxiety
  • Selective serotonin reuptake inhibitors (SSRIs) for depression
  • Nonsteroidal anti-inflammatory drugs (NSAIDs), tramadol (Ultram), ketorolac (Toradol), morphine (immediate or extended release), or transdermal fentanyl, for pain
Next

Neurologics, Others

Class Summary

Riluzole is thought to counteract excitatory amino acid (glutaminergic) pathways, noncompetitively block N-methyl-D-aspartate (NMDA)–mediated responses, and inactivate voltage-dependent sodium channels. Its exact mechanism of action in ALS is unknown.

Riluzole (Rilutek)

 

Riluzole (Rilutek)

Riluzole is a benzothiazole agent that is well absorbed, with average oral bioavailability of 60% and mean elimination half-life of 12 hours; steady state is reached within 5 days with multiple dose administration. Metabolism occurs in the liver (P450-dependent glucuronidation and hydroxylation), with 6 major and a few minor metabolites produced. The recommended dosage for riluzole is 50 mg twice daily. Riluzole is used for extension of time to death or tracheostomy.

Previous
Next

Skeletal Muscle Relaxants

Class Summary

These agents relieve spasticity and muscle spasms in patients with symptoms of limb stiffness.

Baclofen (Lioresal, Gablofen)

 

Baclofen is metabolized in the liver and excreted primarily in urine. This agent is not a controlled substance under the Drug Enforcement Administration (DEA).

Previous
Next

Alpha2 Adrenergic Agonists

Class Summary

Alpha2 adrenergic agonists decrease excitatory input to alpha motor neurons (which are a type of lower motor neuron [LMN]). Common alpha2 adrenergic effects include decrease release of acetylcholine and norepinephrine, contraction of sphincters in the gastrointestinal tract, and inhibition of lipolysis.

Tizanidine (Zanaflex)

 

Tizanidine is a centrally acting muscle relaxant metabolized in the liver and excreted in urine and feces. It is used in patients with predominantly upper motor neuron (UMN) involvement. It is not a DEA-controlled substance.

Previous
Next

NMDA Antagonists

Class Summary

The combination of dextromethorphan and quinidine is shown to decrease emotional lability of pseudobulbar affect (PBA).

Dextromethorphan and quinidine (Nuedexta)

 

Dextromethorphan is a sigma-1 receptor agonist and an uncompetitive NMDA receptor antagonist. Quinidine increases plasma levels of dextromethorphan by competitively inhibiting cytochrome P4502D6, which catalyzes a major biotransformation pathway for dextromethorphan. The mechanism by which dextromethorphan exerts therapeutic effects in patients with PBA is unknown.

This combination is indicated for PBA and symptoms associated with ALS (and multiple sclerosis) that result in involuntary, sudden, and frequent episodes of laughing and/or crying. It is available as a capsule containing dextromethorphan 20 mg and quinidine 10 mg.

Previous
 
Contributor Information and Disclosures
Author

Carmel Armon, MD, MSc, MHS Chair, Department of Neurology, Assaf Harofeh Medical Center, Tel Aviv University Sackler Faculty of Medicine, Israel

Carmel Armon, MD, MSc, MHS is a member of the following medical societies: American Academy of Neurology, Massachusetts Medical Society, American Academy of Sleep Medicine, American Stroke Association, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, American College of Physicians, American Epilepsy Society, American Medical Association, American Neurological Association, Sigma Xi

Disclosure: Received research grant from: Neuronix Ltd, Yoqnea'm, Israel.

Chief Editor

Nicholas Lorenzo, MD, MHA, CPE Founding Editor-in-Chief, eMedicine Neurology; Founder and CEO/CMO, PHLT Consultants; Chief Medical Officer, MeMD Inc

Nicholas Lorenzo, MD, MHA, CPE is a member of the following medical societies: Alpha Omega Alpha, American Association for Physician Leadership, American Academy of Neurology

Disclosure: Nothing to disclose.

Acknowledgements

Neil A Busis, MD Chief, Division of Neurology, Department of Medicine, Head, Clinical Neurophysiology Laboratory, University of Pittsburgh Medical Center-Shadyside

Neil A Busis, MD is a member of the following medical societies: American Academy of Neurology and American Association of Neuromuscular and Electrodiagnostic Medicine

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

References
  1. Brooks BR, Miller RG, Swash M, Munsat TL. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000 Dec. 1(5):293-9. [Medline].

  2. [Guideline] Miller RG, Jackson CE, Kasarskis EJ et al. Practice Parameter update: The care of the patient with amyotrophic lateral sclerosis: Drug, nutritional, and respiratory therapies (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2009. 73:1218-1226. [Medline]. [Full Text].

  3. [Guideline] Miller RG, Jackson CE, Kasarskis EJ, et al. Practice parameter update: The care of the patient with amyotrophic lateral sclerosis: multidisciplinary care, symptom management, and cognitive/behavioral impairment (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2009 Oct 13. 73(15):1227-1233. [Medline]. [Full Text].

  4. Hardiman O, van den Berg LH, Kiernan MC. Clinical diagnosis and management of amyotrophic lateral sclerosis. Nat Rev Neurol. 2011 Oct 11. 7(11):639-49. [Medline].

  5. King SJ, Duke MM, O'Connor BA. Living with amyotrophic lateral sclerosis/motor neurone disease (ALS/MND): decision-making about 'ongoing change and adaptation'. J Clin Nurs. 2009 Mar. 18(5):745-54. [Medline].

  6. Eisen A. Amyotrophic lateral sclerosis: A 40-year personal perspective. J Clin Neurosci. 2009 Apr. 16(4):505-12. [Medline].

  7. Phukan J, Hardiman O. The management of amyotrophic lateral sclerosis. J Neurol. 2009 Feb. 256(2):176-86. [Medline].

  8. Wijesekera LC, Leigh PN. Amyotrophic lateral sclerosis. Orphanet J Rare Dis. 2009 Feb 3. 4:3. [Medline]. [Full Text].

  9. Brooks BR. Managing amyotrophic lateral sclerosis: slowing disease progression and improving patient quality of life. Ann Neurol. 2009 Jan. 65 Suppl 1:S17-23. [Medline].

  10. Al-Chalabi A, Fang F, Hanby MF, Leigh PN, Shaw CE, Ye W, et al. An estimate of amyotrophic lateral sclerosis heritability using twin data. J Neurol Neurosurg Psychiatry. 2010 Dec. 81(12):1324-6. [Medline]. [Full Text].

  11. Hudson AJ. Clinical Neurology. The motor neuron diseases and related disorders. 1996. Vol. 4: 11-14.

  12. Kanouchi T, Ohkubo T, Yokota T. Can regional spreading of amyotrophic lateral sclerosis motor symptoms be explained by prion-like propagation?. J Neurol Neurosurg Psychiatry. 2012 Jul. 83(7):739-45. [Medline]. [Full Text].

  13. Renton AE, Majounie E, Waite A, Simón-Sánchez J, Rollinson S, Gibbs JR, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011 Oct 20. 72(2):257-68. [Medline]. [Full Text].

  14. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011 Oct 20. 72(2):245-56. [Medline]. [Full Text].

  15. Seeley WW, Crawford RK, Zhou J, Miller BL, Greicius MD. Neurodegenerative diseases target large-scale human brain networks. Neuron. 2009 Apr 16. 62(1):42-52. [Medline]. [Full Text].

  16. Armon C. What is ALS?. Bedlack RS, Mitsumoto H, Eds. Amyotrophic Lateral Sclerosis: A Patient Care Guide for Clinicians. New York: Demos Medical Publishing; 2012. 1-23.

  17. Ravits JM, La Spada AR. ALS motor phenotype heterogeneity, focality, and spread: deconstructing motor neuron degeneration. Neurology. 2009 Sep 8. 73(10):805-11. [Medline]. [Full Text].

  18. Armon C. Epidemiology of ALS/MND. Shaw P and Strong M, eds. Motor Neuron Disorders. Elsevier Sciences: 2003. 167-206.

  19. Armon C. ALS 1996 and Beyond: New Hopes and Challenges. A manual for patients, families and friends. Fourth Edition. California: Published by the LLU Department of Neurology, Loma Linda; 2007. [Full Text].

  20. Neary D, Snowden JS, Gustafson L, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology. 1998 Dec. 51(6):1546-54. [Medline].

  21. Clinical and neuropathological criteria for frontotemporal dementia. The Lund and Manchester Groups. J Neurol Neurosurg Psychiatry. 1994 Apr. 57(4):416-8. [Medline].

  22. Ravits JM, La Spada AR. ALS motor phenotype heterogeneity, focality, and spread: deconstructing motor neuron degeneration. Neurology. 2009 Sep 8. 73(10):805-11. [Medline]. [Full Text].

  23. Wijesekera LC, Mathers S, Talman P, Galtrey C, Parkinson MH, Ganesalingam J, et al. Natural history and clinical features of the flail arm and flail leg ALS variants. Neurology. 2009 Mar 24. 72(12):1087-94. [Medline]. [Full Text].

  24. Almeida V, de Carvalho M, Scotto M, Pinto S, Pinto A, Ohana B, et al. Primary lateral sclerosis: predicting functional outcome. Amyotroph Lateral Scler Frontotemporal Degener. 2013 Mar. 14(2):141-5. [Medline].

  25. Barber SC, Shaw PJ. Oxidative stress in ALS: key role in motor neuron injury and therapeutic target. Free Radic Biol Med. 2010 Mar 1. 48(5):629-41. [Medline].

  26. Strong MJ. Progress in clinical neurosciences: the evidence for ALS as a multisystems disorder of limited phenotypic expression. Can J Neurol Sci. 2001 Nov. 28(4):283-98. [Medline].

  27. Shaw PJ. Molecular and cellular pathways of neurodegeneration in motor neurone disease. J Neurol Neurosurg Psychiatry. 2005 Aug. 76(8):1046-57. [Medline]. [Full Text].

  28. Rothstein JD. Current hypotheses for the underlying biology of amyotrophic lateral sclerosis. Ann Neurol. 2009 Jan. 65 Suppl 1:S3-9. [Medline].

  29. Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993 Mar 4. 362(6415):59-62. [Medline].

  30. Shaw PJ, Ince PG, Falkous G, Mantle D. Oxidative damage to protein in sporadic motor neuron disease spinal cord. Ann Neurol. 1995 Oct. 38(4):691-5. [Medline].

  31. Simpson EP, Henry YK, Henkel JS, Smith RG, Appel SH. Increased lipid peroxidation in sera of ALS patients: a potential biomarker of disease burden. Neurology. 2004 May 25. 62(10):1758-65. [Medline].

  32. Mitsumoto H, Santella RM, Liu X, Bogdanov M, Zipprich J, Wu HC, et al. Oxidative stress biomarkers in sporadic ALS. Amyotroph Lateral Scler. 2008 Jun. 9(3):177-83. [Medline].

  33. Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. N Engl J Med. 1994 Mar 3. 330(9):585-91. [Medline].

  34. Lacomblez L, Bensimon G, Leigh PN, Guillet P, Meininger V. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II. Lancet. 1996 May 25. 347(9013):1425-31. [Medline].

  35. Neumann M, Sampathu DM, Kwong LK, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006 Oct 6. 314(5796):130-3. [Medline].

  36. Arai T, Hasegawa M, Akiyama H, et al. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun. 2006 Dec 22. 351(3):602-11. [Medline].

  37. Tan CF, Eguchi H, Tagawa A, et al. TDP-43 immunoreactivity in neuronal inclusions in familial amyotrophic lateral sclerosis with or without SOD1 gene mutation. Acta Neuropathol. 2007 May. 113(5):535-42. [Medline].

  38. Mackenzie IR, Bigio EH, Ince PG, et al. Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol. 2007 May. 61(5):427-34. [Medline].

  39. Sreedharan J, Blair IP, Tripathi VB, et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science. 2008 Mar 21. 319(5870):1668-72. [Medline].

  40. Kabashi E, Valdmanis PN, Dion P, et al. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet. 2008 May. 40(5):572-4. [Medline].

  41. Van Deerlin VM, Leverenz JB, Bekris LM, et al. TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol. 2008 May. 7(5):409-16. [Medline].

  42. Yokoseki A, Shiga A, Tan CF, et al. TDP-43 mutation in familial amyotrophic lateral sclerosis. Ann Neurol. 2008 Apr. 63(4):538-42. [Medline].

  43. Rutherford NJ, Zhang YJ, Baker M, et al. Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis. PLoS Genet. 2008 Sep 19. 4(9):e1000193. [Medline].

  44. Del Bo R, Ghezzi S, Corti S, et al. TARDBP (TDP-43) sequence analysis in patients with familial and sporadic ALS: identification of two novel mutations. Eur J Neurol. 2009 Jun. 16(6):727-32. [Medline].

  45. Hasegawa M, Arai T, Akiyama H, et al. TDP-43 is deposited in the Guam parkinsonism-dementia complex brains. Brain. 2007 May. 130:1386-94. [Medline].

  46. Schwab C, Arai T, Hasegawa M, Akiyama H, Yu S, McGeer PL. TDP-43 pathology in familial British dementia. Acta Neuropathol. 2009 Mar 13. [Medline].

  47. Geser F, Martinez-Lage M, Robinson J, et al. Clinical and pathological continuum of multisystem TDP-43 proteinopathies. Arch Neurol. 2009 Feb. 66(2):180-9. [Medline].

  48. Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science. 2009 Feb 27. 323(5918):1205-8. [Medline].

  49. Vance C, Rogelj B, Hortobagyi T, et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science. 2009 Feb 27. 323(5918):1208-11. [Medline].

  50. Simpson CL, Lemmens R, Miskiewicz K, Broom WJ, Hansen VK, van Vught PW, et al. Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration. Hum Mol Genet. 2009 Feb 1. 18(3):472-81. [Medline]. [Full Text].

  51. Padhi AK, Kumar H, Vasaikar SV, Jayaram B, Gomes J. Mechanisms of loss of functions of human angiogenin variants implicated in amyotrophic lateral sclerosis. PLoS One. 2012. 7(2):e32479. [Medline]. [Full Text].

  52. Armon C. An evidence-based medicine approach to the evaluation of the role of exogenous risk factors in sporadic amyotrophic lateral sclerosis. Neuroepidemiology. 2003 Jul-Aug. 22(4):217-28. [Medline].

  53. Armon C. Acquired nucleic acid changes may trigger sporadic amyotrophic lateral sclerosis. Muscle Nerve. 2005 Sep. 32(3):373-7. [Medline].

  54. Armon C. Smoking may be considered an established risk factor for sporadic ALS. Neurology. November 17, 2009. 73 (20):1693-1698. [Medline]. [Full Text].

  55. de Jong SW, Huisman MH, Sutedja NA, van der Kooi AJ, de Visser M, Schelhaas HJ, et al. Smoking, alcohol consumption, and the risk of amyotrophic lateral sclerosis: a population-based study. Am J Epidemiol. 2012 Aug 1. 176(3):233-9. [Medline].

  56. Esclaire F, Kisby G, Spencer P, Milne J, Lesort M, Hugon J. The Guam cycad toxin methylazoxymethanol damages neuronal DNA and modulates tau mRNA expression and excitotoxicity. Exp Neurol. 1999 Jan. 155(1):11-21. [Medline].

  57. Kisby GE, Standley M, Park T, et al. Proteomic analysis of the genotoxicant methylazoxymethanol (MAM)-induced changes in the developing cerebellum. J Proteome Res. 2006 Oct. 5(10):2656-65. [Medline].

  58. Ravits J, Paul P, Jorg C. Focality of upper and lower motor neuron degeneration at the clinical onset of ALS. Neurology. 2007 May 8. 68(19):1571-5. [Medline].

  59. Körner S, Kollewe K, Fahlbusch M, et al. Onset and spreading patterns of upper and lower motor neuron symptoms in amyotrophic lateral sclerosis. Muscle Nerve. 2011 May. 43(5):636-42. [Medline].

  60. Armon C. From clues to mechanisms: understanding ALS initiation and spread. Neurology. 2008 Sep 16. 71(12):872-3. [Medline].

  61. Frank SA. Evolution in health and medicine Sackler colloquium: Somatic evolutionary genomics: mutations during development cause highly variable genetic mosaicism with risk of cancer and neurodegeneration. Proc Natl Acad Sci U S A. 2010 Jan 26. 107 Suppl 1:1725-30. [Medline]. [Full Text].

  62. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011 Oct 20. 72(2):245-56. [Medline]. [Full Text].

  63. Renton AE, Majounie E, Waite A, Simón-Sánchez J, Rollinson S, Gibbs JR, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011 Oct 20. 72(2):257-68. [Medline]. [Full Text].

  64. Cooper-Knock J, Hewitt C, Highley JR, Brockington A, Milano A, Man S, et al. Clinico-pathological features in amyotrophic lateral sclerosis with expansions in C9ORF72. Brain. 2012 Mar. 135:751-64. [Medline]. [Full Text].

  65. Chiò A, Borghero G, Restagno G, Mora G, Drepper C, Traynor BJ, et al. Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72. Brain. 2012 Mar. 135:784-93. [Medline]. [Full Text].

  66. Byrne S, Elamin M, Bede P, Shatunov A, Walsh C, Corr B, et al. Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort study. Lancet Neurol. 2012 Mar. 11(3):232-40. [Medline]. [Full Text].

  67. Stewart H, Rutherford NJ, Briemberg H, Krieger C, Cashman N, Fabros M, et al. Clinical and pathological features of amyotrophic lateral sclerosis caused by mutation in the C9ORF72 gene on chromosome 9p. Acta Neuropathol. 2012 Mar. 123(3):409-17. [Medline]. [Full Text].

  68. Wijesekera LC, Mathers S, Talman P, Galtrey C, Parkinson MH, Ganesalingam J, et al. Natural history and clinical features of the flail arm and flail leg ALS variants. Neurology. 2009 Mar 24. 72(12):1087-94. [Medline].

  69. Al-Chalabi A, Lewis CM. Modelling the effects of penetrance and family size on rates of sporadic and familial disease. Hum Hered. 2011. 71(4):281-8. [Medline].

  70. Hanby MF, Scott KM, Scotton W, Wijesekera L, Mole T, Ellis CE, et al. The risk to relatives of patients with sporadic amyotrophic lateral sclerosis. Brain. 2011 Dec. 134:3454-7. [Medline]. [Full Text].

  71. Pasinelli P, Brown RH. Molecular biology of amyotrophic lateral sclerosis: insights from genetics. Nat Rev Neurosci. 2006 Sep. 7(9):710-23. [Medline].

  72. Fogh I, Rijsdijk F, Andersen PM, Sham PC, Knight J, Neale B, et al. Age at onset in sod1-mediated amyotrophic lateral sclerosis shows familiality. Neurogenetics. 2007 Aug. 8(3):235-6. [Medline].

  73. Ahmeti KB, Ajroud-Driss S, Al-Chalabi A, Andersen PM, Armstrong J, et al. The Algen Consortium. Age of onset of amyotrophic lateral sclerosis is modulated by a locus on 1p34.1. Neurobiol Aging. 2013 Jan. 34(1):357.e7-19. [Medline].

  74. Andersen PM, Al-Chalabi A. Clinical genetics of amyotrophic lateral sclerosis: what do we really know?. Nat Rev Neurol. 2011 Oct 11. 7(11):603-15. [Medline].

  75. Ferraiuolo L, Kirby J, Grierson AJ, Sendtner M, Shaw PJ. Molecular pathways of motor neuron injury in amyotrophic lateral sclerosis. Nat Rev Neurol. 2011 Nov. 7(11):616-30. [Medline].

  76. Wu CH, Fallini C, Ticozzi N, Keagle PJ, Sapp PC, Piotrowska K, et al. Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature. 2012 Aug 23. 488(7412):499-503. [Medline]. [Full Text].

  77. Andersen PM. Amyotrophic lateral sclerosis genetics with Mendelian inheritance. Brown RH Jr, Swash M and Pasinelli P, eds. Amyotrophic Lateral Sclerosis. 2nd edition. Informa healthcare; 2006. 187-207.

  78. Saeed M, Yang Y, Deng HX, et al. Age and founder effect of SOD1 A4V mutation causing ALS. Neurology. 2009 May 12. 72(19):1634-9. [Medline].

  79. Saito Y, Yokota T, Mitani T, et al. Transgenic small interfering RNA halts amyotrophic lateral sclerosis in a mouse model. J Biol Chem. 2005 Dec 30. 280(52):42826-30. [Medline].

  80. Al-Chalabi A, Jones A, Troakes C, King A, Al-Sarraj S, van den Berg LH. The genetics and neuropathology of amyotrophic lateral sclerosis. Acta Neuropathol. 2012 Sep. 124(3):339-52. [Medline].

  81. Arai T, Mackenzie IR, Hasegawa M, et al. Phosphorylated TDP-43 in Alzheimer's disease and dementia with Lewy bodies. Acta Neuropathol. 2009 Feb. 117(2):125-36. [Medline].

  82. Morita M, Al-Chalabi A, Andersen PM, Hosler B, Sapp P, Englund E, et al. A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia. Neurology. 2006 Mar 28. 66(6):839-44. [Medline].

  83. Vance C, Al-Chalabi A, Ruddy D, Smith BN, Hu X, Sreedharan J, et al. Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2-21.3. Brain. 2006 Apr. 129:868-76. [Medline].

  84. van Es MA, Veldink JH, Saris CG, Blauw HM, van Vught PW, Birve A, et al. Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nat Genet. 2009 Oct. 41(10):1083-7. [Medline].

  85. Shatunov A, Mok K, Newhouse S, Weale ME, Smith B, Vance C. Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries: a genome-wide association study. Lancet Neurol. 2010 Oct. 9(10):986-94. [Medline].

  86. Laaksovirta H, Peuralinna T, Schymick JC, Scholz SW, Lai SL, Myllykangas L. Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study. Lancet Neurol. 2010 Oct. 9(10):978-85. [Medline].

  87. Smith BN, Newhouse S, Shatunov A, Vance C, Topp S, Johnson L, et al. The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founder. Eur J Hum Genet. 2013 Jan. 21(1):102-8. [Medline]. [Full Text].

  88. Al-Sarraj S, King A, Troakes C, Smith B, Maekawa S, Bodi I, et al. p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS. Acta Neuropathol. 2011 Dec. 122(6):691-702. [Medline].

  89. Deng HX, Chen W, Hong ST, Boycott KM, Gorrie GH, Siddique N, et al. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature. 2011 Aug 21. 477(7363):211-5. [Medline]. [Full Text].

  90. Majoor-Krakauer D, Ottman R, Johnson WG, Rowland LP. Familial aggregation of amyotrophic lateral sclerosis, dementia, and Parkinson's disease: evidence of shared genetic susceptibility. Neurology. 1994 Oct. 44(10):1872-7. [Medline].

  91. Fallis BA, Hardiman O. Aggregation of neurodegenerative disease in ALS kindreds. Amyotroph Lateral Scler. 2009 Apr. 10(2):95-8. [Medline].

  92. Cruz DC, Nelson LM, McGuire V, Longstreth WT Jr. Physical trauma and family history of neurodegenerative diseases in amyotrophic lateral sclerosis: a population-based case-control study. Neuroepidemiology. 1999. 18(2):101-10. [Medline].

  93. Nelson LM, McGuire V, Longstreth WT Jr, Matkin C. Population-based case-control study of amyotrophic lateral sclerosis in western Washington State. I. Cigarette smoking and alcohol consumption. Am J Epidemiol. 2000 Jan 15. 151(2):156-63. [Medline].

  94. Kamel F, Umbach DM, Munsat TL, Shefner JM, Sandler DP. Association of cigarette smoking with amyotrophic lateral sclerosis. Neuroepidemiology. 1999. 18(4):194-202. [Medline].

  95. Gallo V, Bueno-De-Mesquita HB, Vermeulen R, Andersen PM, Kyrozis A, Linseisen J. Smoking and risk for amyotrophic lateral sclerosis: analysis of the EPIC cohort. Ann Neurol. 2009 Apr. 65(4):378-85. [Medline].

  96. Sutedja NA, Veldink JH, Fischer K, Kromhout H, Wokke JH, Huisman MH. Lifetime occupation, education, smoking, and risk of ALS. Neurology. 2007 Oct 9. 69(15):1508-14. [Medline].

  97. Weisskopf MG, O'Reilly EJ, McCullough ML, et al. Prospective study of military service and mortality from ALS. Neurology. 2005 Jan 11. 64(1):32-7. [Medline].

  98. Horner RD, Kamins KG, Feussner JR, et al. Occurrence of amyotrophic lateral sclerosis among Gulf War veterans. Neurology. 2003 Sep 23. 61(6):742-9. [Medline].

  99. Armon C. Occurrence of amyotrophic lateral sclerosis among Gulf War veterans. Neurology. 2004 Mar 23. 62(6):1027; author reply 1027-9. [Medline].

  100. Armon C. Excess incidence of ALS in young Gulf War veterans. Neurology. 2004 Nov 23. 63(10):1986-7; author reply 1986-7. [Medline].

  101. Coffman CJ, Horner RD, Grambow SC, Lindquist J. Estimating the occurrence of amyotrophic lateral sclerosis among Gulf War (1990-1991) veterans using capture-recapture methods. Neuroepidemiology. 2005. 24(3):141-50. [Medline].

  102. Horner RD, Grambow SC, Coffman CJ, et al. Amyotrophic lateral sclerosis among 1991 Gulf War veterans: evidence for a time-limited outbreak. Neuroepidemiology. 2008. 31(1):28-32. [Medline].

  103. Barth SK, Kang HK, Bullman TA, Wallin MT. Neurological mortality among U.S. veterans of the Persian Gulf War: 13-year follow-up. Am J Ind Med. 2009 Sep. 52(9):663-70. [Medline].

  104. Sutedja NA, Veldink JH, Fischer K, Kromhout H, Heederik D, Huisman MH, et al. Exposure to chemicals and metals and risk of amyotrophic lateral sclerosis: a systematic review. Amyotroph Lateral Scler. 2009 Oct-Dec. 10(5-6):302-9. [Medline].

  105. Popat RA, Van Den Eeden SK, Tanner CM, et al. Effect of reproductive factors and postmenopausal hormone use on the risk of amyotrophic lateral sclerosis. Neuroepidemiology. 2006. 27(3):117-21. [Medline].

  106. Beghi E, Logroscino G, Chiò A, Hardiman O, Millul A, Mitchell D, et al. Amyotrophic lateral sclerosis, physical exercise, trauma and sports: results of a population-based pilot case-control study. Amyotroph Lateral Scler. 2010 May 3. 11(3):289-92. [Medline]. [Full Text].

  107. Chiò A, Benzi G, Dossena M, Mutani R, Mora G. Severely increased risk of amyotrophic lateral sclerosis among Italian professional football players. Brain. 2005 Mar. 128:472-6. [Medline].

  108. Belli S, Vanacore N. Proportionate mortality of Italian soccer players: is amyotrophic lateral sclerosis an occupational disease?. Eur J Epidemiol. 2005. 20(3):237-42. [Medline].

  109. Armon C. Sports and trauma in amyotrophic lateral sclerosis revisited. J Neurol Sci. 2007 Nov 15. 262(1-2):45-53. [Medline].

  110. Chio A, Traynor BJ, Swingler R, eet al. Amyotrophic lateral sclerosis and soccer: a different epidemiological approach strengthen the previous findings. J Neurol Sci. 2008 Jun 15. 269(1-2):187-8; author reply 188-9. [Medline].

  111. Belli S, Vanacore N. Sports and amyotrophic lateral sclerosis. J Neurol Sci. 2008 Jun 15. 269(1-2):191; author reply 191-2. [Medline].

  112. Armon C. Amyotrophic lateral sclerosis and soccer: a different epidemiological approach strengthen the previous findings. J Neurol Sci. 2008. 269:188-189 (author reply).

  113. Armon C. Response to Belli and Vanacore. J Neurol Sci. 2008. 269:191192 (author reply).

  114. Chio A, Calvo A, Dossena M, Ghiglione P, Mutani R, Mora G. ALS in Italian professional soccer players: the risk is still present and could be soccer-specific. Amyotroph Lateral Scler. 2009 Aug. 10(4):205-9. [Medline].

  115. McKee AC, Gavett BE, Stern RA, Nowinski CJ, Cantu RC, Kowall NW, et al. TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J Neuropathol Exp Neurol. 2010 Sep. 69(9):918-29. [Medline]. [Full Text].

  116. Appel SH, Cwik VA, Day JW. Trauma, TDP-43, and amyotrophic lateral sclerosis. Muscle Nerve. 2010 Dec. 42(6):851-2. [Medline].

  117. Bedlack RS, Genge A, Amato AA, Shaibani A, Jackson CE, Kissel JT, et al. Correspondence regarding: TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J Neuropathol Exp Neurol 2010:69;918-29. J Neuropathol Exp Neurol. 2011 Jan. 70(1):96-7; author reply 98-100. [Medline].

  118. Armon C, Miller RG. Correspondence regarding: TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J Neuropathol Exp Neurol 2010:69;918-29. J Neuropathol Exp Neurol. 2011 Jan. 70(1):97-8; author reply 98-100. [Medline].

  119. Lehman EJ, Hein MJ, Baron SL, Gersic CM. Neurodegenerative causes of death among retired National Football League players. Neurology. 2012 Nov 6. 79(19):1970-4. [Medline].

  120. Armon C, Nelson LM. Is head trauma a risk factor for amyotrophic lateral sclerosis? An evidence based review. Amyotroph Lateral Scler. 2012 Jun. 13(4):351-6. [Medline].

  121. Peters TL, Fang F, Weibull CE, Sandler DP, Kamel F, Ye W. Severe head injury and amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2013 May. 14(4):267-72. [Medline].

  122. Kurland LT, Radhakrishnan K, Smith GE, Armon C, Nemetz PN. Mechanical trauma as a risk factor in classic amyotrophic lateral sclerosis: lack of epidemiologic evidence. J Neurol Sci. 1992 Dec. 113(2):133-43. [Medline].

  123. Savica R, Parisi JE, Wold LE, Josephs KA, Ahlskog JE. High school football and risk of neurodegeneration: a community-based study. Mayo Clin Proc. 2012. 87:335-340.

  124. Wicks P, Ganesalingham J, Collin C, Prevett M, Leigh NP, Al-Chalabi A. Three soccer playing friends with simultaneous amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2007 Jun. 8(3):177-9. [Medline].

  125. Whiting MG. Toxicity of Cycads: A Literature Review. Economic Botany. 1963. 68:270-302.

  126. Borenstein AR, Mortimer JA, Schellenberg GD, Galasko D. The ALS/PDC syndrome of Guam and the cycad hypothesis. Neurology. 2009 Feb 3. 72(5):473, 476; author reply 475-6. [Medline].

  127. Steele JC, McGeer PL. The ALS/PDC syndrome of Guam and the cycad hypothesis. Neurology. 2008 May 20. 70(21):1984-90. [Medline].

  128. Borenstein AR, Mortimer JA, Schofield E, et al. Cycad exposure and risk of dementia, MCI, and PDC in the Chamorro population of Guam. Neurology. 2007 May 22. 68(21):1764-71. [Medline].

  129. Cox PA, Banack SA, Murch SJ. Biomagnification of cyanobacterial neurotoxins and neurodegenerative disease among the Chamorro people of Guam. Proc Natl Acad Sci U S A. 2003 Nov 11. 100(23):13380-3. [Medline].

  130. Khabazian I. Isolation of various forms of sterol B-D-glucoside from the seed of Cycas circinalis: neurotoxicity and implications for the ALS-parkinsonian dementia complex. J Neurochem. 2002. 82:516-528.

  131. Chiò A, Mora G, Calvo A, Mazzini L, Bottacchi E, Mutani R. Epidemiology of ALS in Italy: a 10-year prospective population-based study. Neurology. 2009 Feb 24. 72(8):725-31. [Medline].

  132. Alonso A, Logroscino G, Jick SS, Hernán MA. Incidence and lifetime risk of motor neuron disease in the United Kingdom: a population-based study. Eur J Neurol. 2009 Jun. 16(6):745-51. [Medline].

  133. Johnston CA, Stanton BR, Turner MR, Gray R, Blunt AH, Butt D, et al. Amyotrophic lateral sclerosis in an urban setting: a population based study of inner city London. J Neurol. 2006 Dec. 253(12):1642-3. [Medline].

  134. Johnston CA, Stanton BR, Turner MR, Gray R, Blunt AH, Butt D, et al. Amyotrophic lateral sclerosis in an urban setting: a population based study of inner city London. J Neurol. 2006 Dec. 253(12):1642-3. [Medline].

  135. Cronin S, Hardiman O, Traynor BJ. Ethnic variation in the incidence of ALS: a systematic review. Neurology. 2007 Mar 27. 68(13):1002-7. [Medline].

  136. Zaldivar T, Gutierrez J, Lara G, Carbonara M, Logroscino G, Hardiman O. Reduced frequency of ALS in an ethnically mixed population: a population-based mortality study. Neurology. 2009 May 12. 72(19):1640-5. [Medline].

  137. Rojas-Garcia R, Scott KM, Roche JC, Scotton W, Martin N, Janssen A, et al. No evidence for a large difference in ALS frequency in populations of African and European origin: a population based study in inner city London. Amyotroph Lateral Scler. 2012 Jan. 13(1):66-8. [Medline].

  138. Sabel CE, Boyle PJ, Löytönen M, et al. Spatial clustering of amyotrophic lateral sclerosis in Finland at place of birth and place of death. Am J Epidemiol. 2003 May 15. 157(10):898-905. [Medline].

  139. Manjaly ZR, Scott KM, Abhinav K, Wijesekera L, Ganesalingam J, Goldstein LH, et al. The sex ratio in amyotrophic lateral sclerosis: A population based study. Amyotroph Lateral Scler. 2010 Oct. 11(5):439-42. [Medline].

  140. Kimura F, Fujimura C, Ishida S, et al. Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS. Neurology. 2006 Jan 24. 66(2):265-7. [Medline].

  141. Turner MR, Scaber J, Goodfellow JA, Lord ME, Marsden R, Talbot K. The diagnostic pathway and prognosis in bulbar-onset amyotrophic lateral sclerosis. J Neurol Sci. 2010 Jul 15. 294(1-2):81-5. [Medline].

  142. Murphy J, Henry R, Lomen-Hoerth C. Establishing subtypes of the continuum of frontal lobe impairment in amyotrophic lateral sclerosis. Arch Neurol. 2007 Mar. 64(3):330-4. [Medline].

  143. Phukan J, Elamin M, Bede P, Jordan N, Gallagher L, Byrne S, et al. The syndrome of cognitive impairment in amyotrophic lateral sclerosis: a population-based study. J Neurol Neurosurg Psychiatry. 2012 Jan. 83(1):102-8. [Medline].

  144. Elamin M, Phukan J, Bede P, Jordan N, Byrne S, Pender N, et al. Executive dysfunction is a negative prognostic indicator in patients with ALS without dementia. Neurology. 2011 Apr 5. 76(14):1263-9. [Medline].

  145. Chiò A, Logroscino G, Hardiman O, Swingler R, Mitchell D, Beghi E, et al. Prognostic factors in ALS: A critical review. Amyotroph Lateral Scler. 2009 Oct-Dec. 10(5-6):310-23. [Medline]. [Full Text].

  146. Kimura F, Fujimura C, Ishida S, Nakajima H, Furutama D, Uehara H et al. Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS. Neurology. 2006. 66:265-267.

  147. Armon C, Moses D. Linear estimates of rates of disease progression as predictors of survival in patients with ALS entering clinical trials. J Neurol Sci. 1998 Oct. 160 Suppl 1:S37-41. [Medline].

  148. Armon C, Graves MC, Moses D, Forté DK, Sepulveda L, Darby SM, et al. Linear estimates of disease progression predict survival in patients with amyotrophic lateral sclerosis. Muscle Nerve. 2000 Jun. 23(6):874-82. [Medline].

  149. Armon C, Brandstater ME. Motor unit number estimate-based rates of progression of ALS predict patient survival. Muscle Nerve. 1999 Nov. 22(11):1571-5. [Medline].

  150. Czaplinski A, Yen AA, Appel SH. Amyotrophic lateral sclerosis: early predictors of prolonged survival. J Neurol. 2006 Nov. 253(11):1428-36. [Medline].

  151. Roche JC, Rojas-Garcia R, Scott KM, Scotton W, Ellis CE, Burman R, et al. A proposed staging system for amyotrophic lateral sclerosis. Brain. 2012 Mar. 135:847-52. [Medline]. [Full Text].

  152. Kim WK, Liu X, Sandner J, Pasmantier M, Andrews J, Rowland LP, et al. Study of 962 patients indicates progressive muscular atrophy is a form of ALS. Neurology. 2009 Nov 17. 73(20):1686-92. [Medline]. [Full Text].

  153. Armon C, Schultz JD. Preferences of patients with ALS for accurate prognostic information. Presented at the annual meeting of the International Alliance of Motor Neuron Disease Associations. Philadelphia. December 2004. [Full Text].

  154. Armon C. ALS 1996 and Beyond: New Hopes and Challenges. A Manual for Patients, Families and Friends. Loma Linda University Department of Neurology, Loma Linda, California. Fourth Edition. 2007.

  155. Isaacs JD, Dean AF, Shaw CE, Al-Chalabi A, Mills KR, Leigh PN. Amyotrophic lateral sclerosis with sensory neuropathy: part of a multisystem disorder?. J Neurol Neurosurg Psychiatry. 2007 Jul. 78(7):750-3. [Medline]. [Full Text].

  156. Byrne S, Elamin M, Bede P, Hardiman O. Absence of consensus in diagnostic criteria for familial neurodegenerative diseases. J Neurol Neurosurg Psychiatry. 2012 Apr. 83(4):365-7. [Medline].

  157. Byrne S, Bede P, Elamin M, Kenna K, Lynch C, McLaughlin R, et al. Proposed criteria for familial amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2011 May. 12(3):157-9. [Medline].

  158. de Carvalho M, Dengler R, Eisen A, et al. Electrodiagnostic criteria for diagnosis of ALS. Clin Neurophysiol. 2008 Mar. 119(3):497-503. [Medline].

  159. Bromberg MB, Swoboda KJ, Lawson VH. Counting motor units in chronic motor neuropathies. Exp Neurol. 2003 Nov. 184 Suppl 1:S53-7. [Medline].

  160. Armon C, Brandstater ME. Motor unit number estimate-based rates of progression of ALS predict patient survival. Muscle Nerve. 1999 Nov. 22(11):1571-5. [Medline].

  161. Cedarbaum JM, Stambler N. Performance of the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) in multicenter clinical trials. J Neurol Sci. 1997 Oct. 152 Suppl 1:S1-9. [Medline].

  162. Cedarbaum JM, Stambler N, Malta E, et al. The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III). J Neurol Sci. 1999 Oct 31. 169(1-2):13-21. [Medline].

  163. Instructions for completing the ALSFRS-R. (ALS Functional Rating Scale). ALS Connection. [Full Text].

  164. [Guideline] Miller RG, Rosenberg JA, Gelinas DF, et al. Practice parameter: the care of the patient with amyotrophic lateral sclerosis (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology: ALS Practice Parameters Task Force. Neurology. 1999 Apr 22. 52(7):1311-23. [Medline]. [Full Text].

  165. Bedlack RS, Mitsumoto H, Eds. Amyotrophic Lateral Sclerosis: A Patient Care Guide for Clinicians. New York: Demos Medical Publishing; 2012.

  166. Amyotrophic Lateral Sclerosis Association. Available at http://www.alsa.org.

  167. Muscular Dystrophy Association. Available at http://als.mdausa.org/.

  168. Miller RG, Mitchell JD, Lyon M, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev. 2007 Jan 24. CD001447. [Medline].

  169. Bensimon G, Lacomblez L, Delumeau JC, Bejuit R, Truffinet P, Meininger V. A study of riluzole in the treatment of advanced stage or elderly patients with amyotrophic lateral sclerosis. J Neurol. 2002 May. 249(5):609-15. [Medline].

  170. Yanagisawa N, Tashiro K, Tohgi H, et al. Efficacy and safety of riluzole in patients with amyotrophic lateral sclerosis: double-blind placebo-controlled study in Japan. Igakuno Ayumi. 1997. 182:851-866. [Article in Japanese].

  171. Yanagisawa N, Shindo M. [Neuroprotective therapy for amyotrophic lateral sclerosis (ALS)]. Rinsho Shinkeigaku. 1996 Dec. 36(12):1329-30. [Medline].

  172. Armon C, Guiloff RJ, Bedlack R. Limitations of inferences from observational databases in amyotrophic lateral sclerosis: all that glitters is not gold. Amyotroph Lateral Scler Other Motor Neuron Disord. 2002 Sep. 3(3):109-12. [Medline].

  173. Bourke SC, Tomlinson M, Williams TL, Bullock RE, Shaw PJ, Gibson GJ. Effects of non-invasive ventilation on survival and quality of life in patients with amyotrophic lateral sclerosis: a randomised controlled trial. Lancet Neurol. 2006. 5:140-147. [Medline].

  174. Jackson CE, Gronseth G, Rosenfeld J, et al. Randomized double-blind study of botulinum toxin type B for sialorrhea in ALS patients. Muscle Nerve. 2009 Feb. 39(2):137-43. [Medline].

  175. Neppelberg E, Haugen DF, Thorsen L, Tysnes OB. Radiotherapy reduces sialorrhea in amyotrophic lateral sclerosis. Eur J Neurol. 2007 Dec. 14(12):1373-7. [Medline].

  176. Brooks BR, Thisted RA, Appel SH, et al. Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: a randomized trial. Neurology. 2004 Oct 26. 63(8):1364-70. [Medline].

  177. Pioro EP, Brooks BR, Cummings J, Schiffer R, Thisted RA, Wynn D. Dextromethorphan plus ultra low-dose quinidine reduces pseudobulbar affect. Ann Neurol. 2010 Nov. 68(5):693-702. [Medline].

  178. Baile WF, Buckman R, Lenzi R, Glober G, Beale EA, Kudelka AP. SPIKES-A six-step protocol for delivering bad news: application to the patient with cancer. Oncologist. 2000. 5(4):302-11. [Medline].

  179. VA Secretary Establishes ALS as a Presumptive Compensable Illness. September 23, 2008. VA Secretary Establishes ALS as a Presumptive Compensable Illness. September 23, 2008. [Full Text].

  180. Lo Coco D, Marchese S, Pesco MC, La Bella V, Piccoli F, Lo Coco A. Noninvasive positive-pressure ventilation in ALS: predictors of tolerance and survival. Neurology. 2006 Sep 12. 67(5):761-5. [Medline].

  181. Harding A. PET scans distinguish ALS patients from healthy controls. Reuters Health Information. March 11, 2014. [Full Text].

  182. Migliore L, Coppede F. Genetics, environmental factors and the emerging role of epigenetics in neurodegenerative diseases. Mutat Res. 2008 Oct 31. [Medline].

  183. Valdmanis PN, Rouleau GA. Genetics of familial amyotrophic lateral sclerosis. Neurology. 2008 Jan 8. 70(2):144-52. [Medline].

  184. Van Laere K, Vanhee A, Verschueren J, et al. Value of 18fluorodeoxyglucose-positron-emission tomography in amyotrophic lateral sclerosis: a prospective study. JAMA Neurol. 2014 Mar 10. [Medline].

  185. Brooks BR. 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 Jul. 124 Suppl:96-107. [Medline].

  186. de Carvalho M, Dengler R, Eisen A, England JD, Kaji R, Kimura J, et al. Electrodiagnostic criteria for diagnosis of ALS. Clin Neurophysiol. 2008 Mar. 119 (3):497-503. [Medline].

  187. Chiò A, Battistini S, Calvo A, Caponnetto C, Conforti FL, Corbo M, et al. Genetic counselling in ALS: facts, uncertainties and clinical suggestions. J Neurol Neurosurg Psychiatry. 2014 May. 85 (5):478-85. [Medline].

  188. Zu T, Gibbens B, Doty NS, Gomes-Pereira M, Huguet A, Stone MD, et al. Non-ATG-initiated translation directed by microsatellite expansions. Proc Natl Acad Sci U S A. 2011 Jan 4. 108 (1):260-5. [Medline].

  189. Zu T, Liu Y, Bañez-Coronel M, Reid T, Pletnikova O, Lewis J, et al. RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia. Proc Natl Acad Sci U S A. 2013 Dec 17. 110 (51):E4968-77. [Medline].

  190. Al-Chalabi A, Calvo A, Chio A, Colville S, Ellis CM, et al. Analysis of amyotrophic lateral sclerosis as a multistep process: a population-based modelling study. Lancet Neurol. 2014 Nov. 13 (11):1108-13. [Medline].

  191. Fournier CN, Gearing M, Upadhyayula SR, Klein M, Glass JD. Head injury does not alter disease progression or neuropathologic outcomes in ALS. Neurology. 2015 Apr 28. 84 (17):1788-95. [Medline].

  192. Woolley SC, Strong MJ. Frontotemporal Dysfunction and Dementia in Amyotrophic Lateral Sclerosis. Neurol Clin. 2015 Nov. 33 (4):787-805. [Medline].

 
Previous
Next
 
The 4 regions or levels of the body. Bulbar (muscles of the face, mouth, and throat); cervical (muscles of the back of the head and the neck, the shoulders and upper back, and the upper extremities); thoracic (muscles of the chest and abdomen and the middle portion of the spinal muscles); lumbosacral (muscles of the lower back, groin, and lower extremities).
The genetic/environmental/age- and time-dependent interactions hypothesis for amyotrophic lateral sclerosis (ALS). Risk factors operate upstream to a putative biochemical transformation (likely an acquired nucleic acid or protein change), which causes the appearance of altered proteins or nucleic acids or abnormal quantities of normal proteins or nucleid acids. These agents spread within the motor system and cause the downstream disintegration of the motor system and the downstream biochemical, histologic, and clinical consequences of ALS. (Adapted from Armon C. What is ALS? In: Amyotrophic Lateral Sclerosis: A Patient Care Guide for Clinicians. Bedlack RS, Mitsumoto H, Eds. Demos Medical Publishing, New York, 2012:1-23)
Muscle in nerve disease. Image courtesy of Dr. Friedlander, Associate Professor and Chair of Pathology at Kansas City University of Medicine and Biosciences.
Table 1. Familial Forms of ALS [74, 75, 76]
Gene Locus Protein Inheritance
SOD1



(ALS1)



21q22.11 Superoxide dismutase 1 (SOD1) AD*
ALS2 2q33 Alsin (ALS2) Juvenile/AR**
ALS3 18q21 Unknown AD
ALS4 9q34 SETX Juvenile/AD
ALSS 15q15 SPG11 Juvenile/AR
FUS (ALS6) 16p11.2 FUS AD
ALS7 20ptel-p13 Unknown AD
ALS8 20q13.3 VABP AD
ALS9 14q11.2 Angiogenin (ANG) AD
TARDBP (ALS10) 1p36.2 TAR DNA-binding protein (TARDBP) AD
ALS11 6q21 FIG4 AD
ALS12 10p13 OPTN AD; AR
ALS13 12q24 ATXN2 AD
ALSX Xp11 UBQLN2 X-linked
C9orf72 (ALS-FTD) 9q21-22 C9ORF72 AD
ALS-FTD 9p13.3 SIGMAR1 AD; Juvenile/AR
PFL1 17p13.2 Profilin 1 AD
*AD–autosomal dominant; **AR—autosomal recessive
Previous
Next
 
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.