Pulmonary Medicine

Neuromuscular Disorders Affecting the Thorax: Amyotrophic Lateral Sclerosis

What every physician needs to know:

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's Disease, is a progressive neurodegenerative disorder of upper and lower motor neurons that results in loss of strength of skeletal muscles, including respiratory muscles.

The most common presenting symptom (in 80% of patients) is progressive distal limb weakness. The next most common symptoms are bulbar in origin (in 20% of patients), with 25% having early involvement of bulbar muscles. There is a link between ALS and frontotemporal dementia so patients may present with cognitive dysfunction. Autonomic symptoms develop later in the course of the disease, and death is usually due to repeated respiratory infections and progressive respiratory failure.

Classification

Not applicable.

Are you sure the patient has ALS? What should you expect to find?

The clinical findings in ALS are due to involvement of specific groups of neurons:

  • Upper motor neuron (UMN) signs and symptoms include spasticity, hyperreflexia, bulbar signs and symptoms, and presence of the Babinski sign.

  • Lower motor neuron (LMN) signs and symptoms include weakness, muscle atrophy, hyporeflexia, and muscle fasciculations.

  • Acute respiratory failure and nocturnal hypoventilation may be presenting features (in 1-3%) because of early involvement of phrenic nerve neurons in the spinal cord; the onset of respiratory failure often constitutes the beginning of rapid clinical decline.

  • Clinical evolution reflects progressive UMN and LMN involvement over months. UMN involvement may be localized to one region of the spinal cord (e.g., bulbar, cervical, or lumbosacral areas).

The diagnosis of ALS is based on the EMG finding of fibrillation potentials (reflecting LMN involvement) in the absence of an alternative diagnosis; in 5-10% of cases, a positive family history for ALS is obtained.

Diagnostic criteria for ALS include:

  • Clinical, electrophysiological, and neuropathological evidence of lower motor neuron degeneration

  • Clinical evidence of upper motor neuron degeneration

  • Progressive spread of signs and symptoms

  • Absence of electrophysiological, pathological, and radiographic evidence of an alternate

  • disease process

Pulmonary function test (PFT) findings in ALS are summarized below:

  • PFT abnormalities are present early in the disease.

  • When the vital capacity (VC) is less than 50% predicted, respiratory symptoms are usually present.

  • When the VC is 25-30% predicted, the risk of respiratory failure and sudden death is significant.

  • The VC and maximal voluntary ventilation (MVV) decline progressively over time, the residual volume (RV) increases.

  • Maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) are decreased.

  • A MIP less than -60 cm H2O is essentially 100% sensitive for survival less than eighteen months.

  • The VC is the most specific test for predicting survival in ALS.

  • Total lung capacity (TLC) and functional residual capacity (FRC) remain relatively well preserved.

Radiographic assessment, including neuro-imaging, is not diagnostic in ALS; radiologic studies are used to rule out other disease processes. The MRI is usually normal.

Beware: there are other diseases that mimic ALS.

A number of disorders may mimic ALS; examples include:

  • Myasthenia gravis

  • Lambert-Eaton myasthenic syndrome

  • Lyme disease

  • Poliomyelitis and post-poliomyelitis

  • Heavy metal intoxication

  • Kennedy syndrome

  • Adult-onset Tay-Sachs disease

  • Hereditary spastic paraplegia

  • Multifocal neuropathy

  • Cervical spondylosis or extramedullary tumor with compressive radiculopathy and myelopathy

  • Inclusion body myositis

  • Progressive bulbar palsy

  • Progressive muscular atrophy

  • Motor neuron syndromes with lymphoproliferative disorders or other malignancies (e.g., lung, breast)

  • Thyrotoxic myopathy

How and/or why did the patient develop ALS?

The etiology of ALS is unknown. Ten to 15% of familial cases have a mutation in the gene encoding copper-zinc dismutase (a free oxygen radical scavenger), suggesting that neurons may be susceptible to oxidative stress. In addition, neurons may be sensitive to glutamate-induced cell membrane damage.

Which individuals are at greatest risk of developing ALS?

ALS is characterized by the following epidemiologic findings:

  • The incidence of the disease is 1-3/100,000.

  • No ethnic or racial predisposition has been described.

  • Males are more commonly affected than females before age 65 years; after age 65 years, men and women are equally affected.

  • The peak age of diagnosis is in the seventh and eighth decades; however, ALS may be diagnosed as early as the third decade.

  • The majority of cases are sporadic; in 5-10%, autosomal dominant inheritance is noted.

  • The five-year mortality is 80%; death is generally due to respiratory failure.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Additional laboratory studies may be helpful in establishing the diagnosis of ALS or in evaluating other diagnostic considerations:

  • Measurement of creatine phosphokinase (CPK) should be considered; in ALS, it may be elevated to 1,000 U/L.

  • A screen for heavy metal exposure should be done if there is a positive occupational history.

  • Genetic testing may be considered if a strong family history is present.

What imaging studies will be helpful in making or excluding the diagnosis of ALS?

Not applicable.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of ALS?

Pulmonary function test (PFT) findings in ALS are notable, and PFT abnormalities are present early in the disease.

The vital capacity (VC) is the most specific test for predicting survival in ALS. When the VC is less than 50% predicted, respiratory symptoms are usually present. When the VC is 25-30% predicted, the risk of respiratory failure and sudden death is significant. The VC and maximal voluntary ventilation (MVV) decline progressively over time, and the residual volume (RV) increases.

Maximal inspiratory pressure (MIP) and maximum expiratory pressure (MEP) fall. An MIP of less than -60 cm H2O is essentially 100% sensitive for survival of less than eighteen months. Total lung capacity (TLC) and functional residual capacity (FRC) remain relatively well preserved.

What diagnostic procedures will be helpful in making or excluding the diagnosis of ALS?

The diagnosis of ALS is made on clinical grounds, supported by electromyography (EMG) and nerve conduction studies (NCS):

  • The EMG shows evidence of diffuse acute and chronic denervation.

  • NCS usually demonstrates normal sensory and motor functions.

  • Compound motor action potential (CMAP) amplitudes may be decreased.

  • Decreased numbers of motor units are noted, although the finding is not specific to ALS.

  • Muscle biopsy demonstrates nonspecific findings of chronic denervation and reinnervation.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of ALS?

Physicians may screen for heavy metal exposure if there is a positive occupational history. Genetic testing may be considered if a strong family history is present. (Familial ALS accounts for ~10% of ALS cases.) Chronic denervation and reinnervation are nonspecific findings seen on muscle biopsy.

If you decide the patient has ALS, how should the patient be managed?

Management of ALS is based upon a comprehensive, multi-disciplinary approach. With development of respiratory symptoms and a moderate or rapid decline in lung function, non-invasive ventilation should be considered, as it decreases risk of death: Application of non-invasive ventilation when the FVC is less than 50% predicted or falls by more than 15% in three months results in a slower decline in lung function and decreased mortality. Noninvasive positive pressure ventilation improves quality of life when the technique is tolerated. Invasive ventilation may be used if long-term survival is the goal. Goals of care should be discussed early in the course of the diagnosis so the patient’s wishes can be honored.

In addition, administration of pneumococcal and influenza vaccines is important. Anti-glutamate therapy (Riluzole), which is the only treatment shown to prolong survival in ALS, should be considered.

Edaravone can also be considered. It is a free radical scavenger that reduces oxidative stress, one of the purported pathogenic mechanisms of ALS. FDA approval in the U.S. was granted in May 2017. Edaravone benefits patients most in early ALS and should be used as an adjunct to Riluzole.

Emergency management of the patient with ALS is focused on management of acute respiratory failure: In the absence of bulbar weakness, an initial trial of non-invasive ventilation should be considered. For patients with bulbar weakness and those with difficulty handling respiratory secretions during non-invasive ventilation, intubation is usually required.

What is the prognosis for patients managed in recommended ways?

ALS is progressive and incurable, with a median time from diagnosis to death of 3-5 years; 10% of patients may live beyond ten years.

What other considerations exist for patients with ALS?

An alternative diagnosis can be considered if

  • There is a relapsing, remitting course of ALS.

  • There are involuntary movements.

  • Ataxia is present.

  • EMG findings are not diffuse.

  • There is motor conduction block.

  • There are abnormal motor and conductions velocities and CMAPs.

Cognitive dysfunction does not necessarily rule out ALS. Frontotemporal dementia may be present, although it is usually mild. Family genetic counseling, advanced care planning, and other ancillary considerations should be made.

Ongoing trials are studying roles for heat shock proteins, gene therapy, and fast skeletal muscle troponin activator in the management of ALS. An updated list of drug trials can be found online from the ALS association, the Northeast ALS Consortium, and ClinicalTrials.gov

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