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  Disease summary:

  
  
  
  
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    Amyotrophic lateral sclerosis (ALS) is a progressive paralytic and fatal neurodegenerative disease affecting motor neurons in the brain and spinal cord.

    
    
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    Epidemiology: The prevalence of ALS has been estimated up to 2.7 to 7.4 per 100,000 with an annual incidence of 1.5 to 2.7 per 100,000. There is a male predominance of 1.5:1 and the average age of onset for sporadic ALS is between 55 and 75 years. Familial onset is noted to occur at a younger age, approximately 45 to 50, although this varies between genes. After the age of 70, the gender incidence is equal.

    
    
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    Prognosis: The average life expectancy after diagnosis is between 2 and 5 years. However, this is highly variable and up to 10% survive for at least 10 years and 5% survive over 20 years. Older-onset patients and those with initial respiratory involvement or bulbar forms of the disease tend to have a worse prognosis.

    
    
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    Clinical presentation: ALS is well known as a condition with a relentless progression of asymmetric muscular weakness and atrophy. The presentation varies widely depending on the region affected and the predominance of either upper or lower motor neuron (LMN) findings.

    
    
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    Anatomic involvement: Anatomic involvement of ALS includes primarily the motor neurons of the corticospinal tract in the brain and spinal cord as well as the anterior horn cells. A strong glial reaction typically surrounds the affected upper and lower motor neurons and degenerating descending tracts of ALS patients.

  
  
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  Differential diagnosis:

  
  
  
  
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    It is highly important to recognize potentially treatable conditions that may mimic ALS.

    
    
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    Upper motor neuron presentation: Differential diagnoses include any condition affecting central nervous system (CNS) motor systems such as hereditary spastic paraplegia, spinocerebellar ataxias, tumors, cervical disc disease, demyelinating conditions, strokes, myelopathic conditions, and other forms of degenerative diseases.

    
    
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    Lower motor neuron presentation: Differential diagnoses include any condition affecting the lower motor neuron including focal nerve injuries, mononeuropathies, radiculopathies, plexopathies, and other conditions affecting the anterior horn cells (viral infections, spinal muscular atrophy, and Kennedy disease). Myopathies, primarily adult onset, may often be initially considered as well. Peripheral nerve disorders such as multifocal motor neuropathy, chronic inflammatory demyelinating polyneuropathy and Charcot-Marie-Tooth disease could be mistaken for ALS at the outset.

    
    
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    Bulbar presentation: Myasthenia gravis should always be considered in patients with a strict bulbar presentation. Any other causes of cranial nerve palsies, dysarthria, or dysphagia may be of consideration.

  
  
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  Monogenic forms:

  
  
  
  
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    ALS is a genetically heterogeneous disease (Table 130-1).

  
  
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  Family history:

  
  
  
  
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    Approximately 90% of ALS cases are sporadic and 10% familial. Mode of inheritance can be autosomal dominant (most common), recessive (usually juvenile onset) or X-linked dominant (adult or juvenile onset).

  
  
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  Twin studies:

  
  
  
  
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    There is evidence for concordance among twins, but conclusions may be limited by the small numbers of patients included in these studies.

  
  
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  Environmental factors:

  
  
  
  
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    Cigarette smoking and battlefield exposure have been reported as risk factors.

  
  
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  Genome-wide associations:

  
  
  
  
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    Many genetic associations have been reported although very few have been validated. The validated ones include PON gene cluster polymorphisms and ATXN2 intermediate length polyglutamine expansions. In a recent meta-analysis, a locus at 1p34.1 was associated with age at onset. Testing for single-nucleotide polymorphisms (SNPs) is not yet clinically validated to diagnose ALS.

  
  
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  Pharmacogenomics:

  
  
  
  
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    Although data are limited, slow and fast metabolizers of riluzole have been reported.

Diagnostic Criteria for ALS

Despite advancements in the diagnosis of many neurologic conditions, ALS remains a diagnosis of exclusion without specific biomarkers or definitive tests. A progressive spread of upper and LMN signs and symptoms are required. The diagnosis of ALS requires

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   the presence of

   
   

   (A:1) Evidence of LMN degeneration by clinical, electrophysiologic, or neuropathologic examination

   
   

   (A:2) Evidence of upper motor neuron (UMN) degeneration by clinical examination

   
   

   (A:3) Progressive spread of symptoms or signs within a region or to other regions, as determined by history or examination, together with

   
   

   the absence of

   
   

   (B:1)Electrophysiologic and pathologic evidence of other disease processes that might explain the signs of LMN and/or UMN degeneration

   
   

   (B:2)Neuroimaging evidence of other disease processes that might explain the observed clinical and electrophysiologic signs

Diagnostic Categories