›

Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic Lateral Sclerosis (ALS)

Sections





Sections




Overview

Here, we'll learn about Amyotrophic Lateral Sclerosis (ALS), which is the most common motor neuron disease.

As background, let's list the key motor neuron disorders.

Motor Neuron Diseases

  • Amyotrophic lateral sclerosis (ALS), which is a mixed UMN (corticospinal tract) and LMN (anterior horn cell) disorder.
  • Primary lateral sclerosis, which is the prototypical pure upper motor neuron disorder, which is most easily thought of as pure UMN ALS.
  • Progressive muscular atrophy, which is the prototypical pure lower motor neuron disorder, which is most easily thought of as pure LMN ALS (although patients can develop upper motor neuron disease).
  • Spinal muscular atrophy, which encompasses most childhood-onset, genetic motor neuron disease.
  • Poliomyelitis, which is the prototypical infectious myelitis with motor neuron pathology, primarily.

Consider that all the disorders described can have bulbar disease as a major or eventual feature of the disease.

Neuroanatomy Background

Spinal Cord Anatomy

Before we address the diseases, let's review the general anatomy of the spinal cord.

Gray Matter

The gray matter horns – from posterior to anterior:

  • Dorsal (aka posterior) horn comprises sensory nuclei.
  • Intermediate zone comprises autonomic and spinocerebellar nuclei.
  • Ventral (aka anterior) horn comprises motor nuclei.
  • The fasciculus proprius surrounds the gray matter.

White Matter

  • The lateral corticospinal tract lies within the lateral white matter column (the lateral funiculus).
  • The posterior funiculus carries large proprioceptive sensory afferents for movement and position sensation.
  • The anterior funiculus carries small, thermoceptive and nociceptive sensory afferents for pain and temperature sensation, respectively.

Nerve Roots

  • Motor neuron sends motor fibers out via ventral root.
  • The dorsal root receives sensory fibers.
    • We show the bulbous dorsal root ganglion (DRG), which houses the primary sensory neuron, which is pseudounipolar: it sends fibers both towards the spinal cord and also toward the periphery.
  • Where the roots merge, they form the mixed spinal nerve

Amyotrophic lateral sclerosis (ALS)

ALS Overview

With that anatomy as a background, let's address amyotrophic lateral sclerosis (ALS).

Key Clinical Features of ALS

The average age of onset is ~ 55 years old (but it can present at a wide range of ages) and that the average life expectancy from the time of diagnosis is ~ 3 years.

Diagnosis requires clinical evidence of UMN & LMN signs plus EMG evidence of acute and chronic denervation in multiple myotomes (muscle groups innervated by a single spinal nerve) in 3 regions (cervical, thoracic, lumbosacral, or cranial).

Mixed Upper & Lower Motor Neuron Disease

Indicate that it is a mixed pattern of upper and lower motor neuron disease. The name, itself, which can help remind us of this:

  • Amyotrophic means muscle atrophy, which is the key clinical finding in lower motor neuron disease.
  • Lateral sclerosis refers to the degenerative changes that occur in the lateral corticospinal tracts within the spinal cord; they key pathological cause of upper motor neuron disease.

Clinical-Anatomical Changes

Anterior horn cell degeneration causes lower motor neuron findings.

Lateral corticospinal tract pathology causes upper motor neuron findings.

Although we are focused on spinal cord changes, show degenerative changes within a brainstem, as well because bulbar weakness is a key component of ALS.

Clinical Features of UMN & LMN Disease

Let's use a table to review the clinical exam features of these UMN and LMN injury types based on muscle tone, muscle stretch reflexes, and the presence or absence of pathological reflexes, which will help us categorize findings in ALS.

UMN Disease

  • In upper motor neuron disease, indicate that there is spastic muscle tone, that the reflexes are hyperactive (possibly with clonus), and that pathologic reflexes (eg the Babinski sign) are present.
  • Indicate that there is characteristic stiffness and slowness of movement.
    • We'll see that spasticity is the key findings in the pure upper motor neuron disorders (eg hereditary spastic paraparesis) more so than muscle weakness.

LMN Disease

  • In lower motor neuron disease, indicate that there is flaccid muscle tone, that the reflexes are hypoactive (or absent), and that pathologic reflexes are absent.
  • Indicate that there is characteristic muscle atrophy, fasciculations, and muscle cramps.
    • Consider that the term flaccid paralysis is often used to describe the lower motor neuron diseases (eg poliomyelitis).

Pattern of Weakness in ALS

Now, let's illustrate some key features of ALS.

Head

  • Draw a head and show weakness of the pharyngeal region. The dysarthric pattern of speech in ALS is one of its most recognizable symptoms.
  • Indicate that there is characteristic preservation of extraocular muscle strength, which helps distinguish ALS from myasthenia gravis wherein asymmetric ptosis is the most common presenting feature.

Body

  • Show focal asymmetric weakness via wrist drop, foot drop, and thigh wasting.
    • Unlike myasthenia gravis and the inflammatory myopathies, ALS typically presents with an asymmetric, focal pattern of weakness and only later becomes confluent.
    • Note that it can present in a myriad of different ways, including isolated bulbar dysfunction or isolated limb dysfunction. Imagine that it can present with degeneration of pretty much any pool of motor neurons and thus it can manifest in a variety of ways. Those presenting patterns are beyond the scope of this tutorial but include:
      "progressive bulbar palsy": isolated bulbar weakness at onset, "respiratory-onset": early diaphragmatic involvement; "flail arm syndrome" (aka brachial amyotrophic diplegia) or "flail leg syndrome": symmetric, proximal weakness; "dropped head syndrome": neck extensor weakness.
  • Finally, draw a thoracic cage and show weakness of the diaphragm.
    • Indicate respiratory failure from diaphragm denervation, which is the leading cause of death in ALS.

Histopathology of ALS

Cytoplasmic inclusions are the key histopathological finding in ALS

  • Draw a motor neuron and within it, draw Bunina bodies: eosinophilic cytoplasmic inclusions. They are filled with a ubiquitin-negative, amorphous, electron-dense material.
  • Although historically, Bunina bodies are the key pathologic marker in ALS, ubiquitin aggregates with TDP-43 positivity have since been found to be the most commonly identified abnormal cytoplasmic inclusions.
    • TDP-43 normally localizes to the nucleus but in ALS it aggregates in the cytoplasm (just like in frontotemporal dementia, which helps link the disorders). Note that many other protein components to ubiquitin have been identified.
  • It is believed that the pathological changes in ALS are, at least in part, secondary to aggregation of misfolded proteins, which disrupt normal cell functioning; impaired protein degradation; impaired cellular transport; and RNA toxicity.

Other Clinical Considerations in ALS

  • Bladder dysfunction and/or sensory loss should bring the diagnosis into question.
  • Co-occuring ALS with frontotemporal dementia can occur (TDP-43 positivity is a shared feature). In this setting, dementia may begin in tandem with weakness or precede it.

ALS Genetics

  • ~ 10% of ALS is familial ALS.
  • SOD1 gene mutation is found in is found in ~ 10% of familial ALS but only ~ 1.5% of sporadic ALS.
  • TDP-43 + inclusions are NOT found in this form of ALS, thus it doesn't represent the classic phenotype.
  • To date, the most impactful gene mutation to be discovered is C9orf72, which is found in ~ 40% of familial ALS, ~ 5-10% of sporadic ALS, and is the major cause of frontotemporal dementia.

Laboratory Work-up for ALS Differential Dx

The following labs are commonly performed to look for other key causes of weakness:

  • Metabolic panel to look for electrolyte disturbance.
  • Creatine kinase to look for myopathy.
  • B12 and copper to look for subacute combined degenerative myelopathy.
  • GM-1 antibody to look for multifocal motor neuropathy (which we address in part 2).
  • SPEP/Immunofixation panel to look for monoclonal gammopathy.

Treatment

Disease-Modifying Treatments

No curative treatment exists for ALS. The following are considered life prolonging (disease-modifying) agents.

Riluzole

Riluzole is believed to modify disease progression through a variety of mechanisms including reduction of glutamate excitotoxicity and release, as well as actions on NMDA and voltage-gated sodium channels.

Riluzole provides a 2 to 3 month survival benefit (according to a 2012 Cochrane Review) but subsequent articles suggest that certain patient populations may experience significantly longer benefit.

Riluzole dosing is given at 50 mg PO BID.

Key side effects include GI, especially liver dysfunction, and rarely neutropenia.

Edaravone

Edaravone is a free-radical scavenger that is used to reduce oxidative stress, an important pathophysiological mechanism in ALS.

Its efficacy is not well established but it likely, at least marginally, slows disease progression.

Edaravone has both oral and IV formulations.

Key side effects include injection-site reactions, ataxia, headache, and allergic reactions especially in asthmatics.

Tofersen (for SOD1 gene mutation ALS)

Tofersen is used to inhibit SOD1 through gene-silencing mechanisms, thus, it is used exclusively in SOD1 gene mutation ALS patients.

It's ultimate benefit remains to be fully determined but refer to this 2022 New England Journal of Medicine article for details "Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS".

Board Review

Getting ready for boards? Review these concise, bulleted high yield reviews for your exam.

USMLE & COMLEX-USA

Internal Medicine

Neurology

PA

NP

References

  • Bangham, C. R M. "HTLV-1 Infections." Journal of Clinical Pathology 53, no. 8 (August 1, 2000): 581–86. https://doi.org/10.1136/jcp.53.8.581.
  • Beilke, Mark A. "Retroviral Coinfections: HIV and HTLV: Taking Stock of More Than a Quarter Century of Research." AIDS Research and Human Retroviruses 28, no. 2 (February 2012): 139–47. https://doi.org/10.1089/aid.2011.0342.
  • Brugman, Frans, Jan H. Veldink, Hessel Franssen, Marianne de Visser, J. M. B.Vianney de Jong, Carin G. Faber, Berry H. P. Kremer, et al. "Differentiation of Hereditary Spastic Paraparesis From Primary Lateral Sclerosis in Sporadic Adult-Onset Upper Motor Neuron Syndromes." Archives of Neurology 66, no. 4 (April 1, 2009). https://doi.org/10.1001/archneurol.2009.19.
  • Chen, Yating, Peng Luo, Zhongli Li, Hengping Hu, Duobin Wu, Tingting Xu, Xingzuo Wang, and Haiting Xie. "Kennedy Disease with Difficulty in Differential Diagnosis: A Case Report." Medicine 96, no. 19 (May 2017): e6792. https://doi.org/10.1097/MD.0000000000006792.
  • Fan, Hueng-Chuen, Li-Ing Ho, Ching-Shiang Chi, Shyi-Jou Chen, Giia-Sheun Peng, Tzu-Min Chan, Shinn-Zong Lin, and Horng-Jyh Harn. "Polyglutamine (PolyQ) Diseases: Genetics to Treatments." Cell Transplantation 23, no. 4–5 (2014): 441–58. https://doi.org/10.3727/096368914X678454.
  • Fischbeck, Kenneth H. "Spinal and Bulbar Muscular Atrophy Overview." Journal of Molecular Neuroscience : MN 58, no. 3 (March 2016): 317–20. https://doi.org/10.1007/s12031-015-0674-7.
  • Garg, Nidhi, Susanna B Park, Steve Vucic, Con Yiannikas, Judy Spies, James Howells, William Huynh, et al. "Differentiating Lower Motor Neuron Syndromes." Journal of Neurology, Neurosurgery & Psychiatry 88, no. 6 (June 2017): 474–83. https://doi.org/10.1136/jnnp-2016-313526.
  • Gendelman, Howard E., and Igor Grant. The Neurology of AIDS. Oxford University Press, USA, 2011.
  • Goutman, Stephen A. "Diagnosis and Clinical Management of Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders." CONTINUUM: Lifelong Learning in Neurology 23, no. 5 (October 2017): 1332. https://doi.org/10.1212/CON.0000000000000535.
  • Howard, Robin S. "Poliomyelitis and the Postpolio Syndrome." BMJ : British Medical Journal 330, no. 7503 (June 4, 2005): 1314–18.
  • Lawson, Victoria H, and W David Arnold. "Multifocal Motor Neuropathy: A Review of Pathogenesis, Diagnosis, and Treatment." Neuropsychiatric Disease and Treatment 10 (April 5, 2014): 567–76. https://doi.org/10.2147/NDT.S39592.
  • Leis, A. Arturo, and Dobrivoje S. Stokic. "Neuromuscular Manifestations of West Nile Virus Infection." Frontiers in Neurology 3 (March 21, 2012). https://doi.org/10.3389/fneur.2012.00037.
  • Maloney, J.A., D.M. Mirsky, K. Messacar, S.R. Dominguez, T. Schreiner, and N.V. Stence. "MRI Findings in Children with Acute Flaccid Paralysis and Cranial Nerve Dysfunction Occurring during the 2014 Enterovirus D68 Outbreak." American Journal of Neuroradiology 36, no. 2 (February 2015): 245–50. https://doi.org/10.3174/ajnr.A4188.
  • Manzano, Raquel, Gianni Sorarú, Christopher Grunseich, Pietro Fratta, Emanuela Zuccaro, Maria Pennuto, and Carlo Rinaldi. "Beyond Motor Neurons: Expanding the Clinical Spectrum in Kennedy's Disease." Journal of Neurology, Neurosurgery & Psychiatry 89, no. 8 (August 2018): 808–12. https://doi.org/10.1136/jnnp-2017-316961.
  • Matsuura, Eiji, Satoshi Nozuma, Yuichi Tashiro, Ryuji Kubota, Shuji Izumo, and Hiroshi Takashima. "HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP): A Comparative Study to Identify Factors That Influence Disease Progression." Journal of the Neurological Sciences 371 (December 2016): 112–16. https://doi.org/10.1016/j.jns.2016.10.030.
  • Mehndiratta, Man Mohan, Prachi Mehndiratta, and Renuka Pande. "Poliomyelitis." The Neurohospitalist 4, no. 4 (October 2014): 223–29. https://doi.org/10.1177/1941874414533352.
    ———. "Poliomyelitis." The Neurohospitalist 4, no. 4 (October 2014): 223–29. https://doi.org/10.1177/1941874414533352.
  • Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND) Cochrane Database Syst Rev. 2012;(3):CD001447.
  • Miller TM, Cudkowicz ME, Genge A, et al. Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. N Engl J Med 2022; 387:1099.
  • Olindo, Stephane, Severine Jeannin, Martine Saint-Vil, Aissatou Signate, Mireille Edimonana-Kaptue, Julien Joux, Harold Merle, et al. "Temporal Trends in Human T-Lymphotropic Virus 1 (HTLV-1) Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) Incidence in Martinique over 25 Years (1986-2010)." Edited by Yoshihisa Yamano. PLOS Neglected Tropical Diseases 12, no. 3 (March 19, 2018): e0006304. https://doi.org/10.1371/journal.pntd.0006304.
  • Rinaldi, Carlo, Laura C. Bott, and Kenneth H. Fischbeck. "Muscle Matters in Kennedy's Disease." Neuron 82, no. 2 (April 16, 2014): 251–53. https://doi.org/10.1016/j.neuron.2014.04.005.
  • Serrao, Mariano, Martina Rinaldi, Alberto Ranavolo, Francesco Lacquaniti, Giovanni Martino, Luca Leonardi, Carmela Conte, et al. "Gait Patterns in Patients with Hereditary Spastic Paraparesis." Edited by Andrea Macaluso. PLOS ONE 11, no. 10 (October 12, 2016): e0164623. https://doi.org/10.1371/journal.pone.0164623.
  • Shoseyov, David, Tali Cohen-Kaufman, Isabella Schwartz, and Sigal Portnoy. "Comparison of Activity and Fatigue of the Respiratory Muscles and Pulmonary Characteristics between Post-Polio Patients and Controls: A Pilot Study." PLOS ONE 12, no. 7 (July 27, 2017): e0182036. https://doi.org/10.1371/journal.pone.0182036.
  • "Spinal Muscular Atrophy." NORD (National Organization for Rare Disorders) (blog). Accessed November 14, 2018. https://rarediseases.org/rare-diseases/spinal-muscular-atrophy/.
  • Visser, Jeldican, Renske M. van den Berg-Vos, Hessel Franssen, Leonard H. van den Berg, John H. Wokke, J. M. Vianney de Jong, Rebecca Holman, Rob J. de Haan, and Marianne de Visser. "Disease Course and Prognostic Factors of Progressive Muscular Atrophy." Archives of Neurology 64, no. 4 (April 1, 2007): 522–28. https://doi.org/10.1001/archneur.64.4.522.