AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Amyotrophic lateral sclerosis (ALS) is a disease of unknown cause characterized by slowly progressive degeneration of upper motor neurons (UMNs) and lower motor neurons (LMNs). The UMN findings include hyperreflexia and spasticity. They result from degeneration of the lateral corticospinal tracts in the spinal cord. The LMN findings include weakness, atrophy, and fasciculations. They are a direct consequence of muscle denervation. ALS is eventually fatal because of respiratory muscle weakness. Aspiration pneumonia and medical complications of immobility contribute to morbidity.

Because Charcot made the first clinical description in the 1860s, the disease is named for him in Europe. In the United States, the disease often is called Lou Gehrig disease after the baseball legend who died from ALS in 1941.

For a related CME activity, see CME - Diagnosis and Treatment of Bulbar Symptoms in Amyotrophic Lateral Sclerosis.

Pathophysiology

No single cause for ALS explains its entire pathology; indeed, there may be multiple causes resulting in phenotypic similarity. While ALS is ultimately a diffuse disease, onset is often focal and asymmetric. At onset, bulbar motor neurons can be involved, resulting in bulbar weakness (progressive bulbar palsy), or spinal cord anterior horn cells can be affected, resulting in limb weakness (spinal muscular atrophy). When upper motor neuron involvement of bulbar muscles occurs, a syndrome of pseudobulbar palsy results, causing spastic dysarthria, dysphagia, and emotional incontinence. Upper motor neuron involvement of spinal cord tracks results in spastic weakness of the limbs (primary lateral sclerosis). Later, spread to other motor areas produces the classic combination of upper and lower motor neuron dysfunction recognized as ALS.

Five to 10% of patients with ALS have a family history following an autosomal dominant pattern of inheritance. About 20% of these patients have a mutation of the superoxide dismutase 1 (SOD1) enzyme. This mutation is believed to make a defective protein that is toxic to motor nerve cells. The SOD1 mutation, however, accounts for only 1 or 2 percent of ALS cases, or 20 percent of the familial (inherited) cases. This enzyme functions as an antioxidant. Glutamate toxicity, mitochondrial dysfunction, and autoimmunity all may play a role in causation.

Frequency

United States

Approximately 5,600 people in the United States are diagnosed with ALS each year. The incidence of ALS (2 per 100,000 people) is 5 times higher than Huntington disease and about equal to multiple sclerosis. It is estimated that as many as 30,000 Americans may have the disease at any given time.

Mortality/Morbidity

ALS is a fatal disease. Median survival is 3-5 years. However, longer survival is not rare. About 30% of patients with ALS live 5 years after diagnosis, and about 10-20% survive for greater than 10 years. Long-term survival is associated with a younger age at onset, being male, and limb rather than bulbar symptom onset. There are rare reports of spontaneous remission.¹

Sex

Incidence is higher in men than in women, with a male-to-female ratio of 1.6:1.

Age

Onset usually occurs in patients aged 40-60 years. Mean age of onset of sporadic ALS is 56 years; mean age of onset of familial ALS is 46 years.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

The diagnosis of ALS is primarily clinical. Electrodiagnostic testing contributes to the diagnostic accuracy. ALS can be differentiated from stroke or trauma due to the subacute or chronic progression of symptoms. When focal limb weakness occurs, ALS is differentiated from a root or peripheral nerve lesion by the lack of pain or sensory symptoms. While ALS is a slowly progressive disease, a precipitous event may occur to bring the patient to the ED.

• Bulbar symptoms: The patient's family first notices slurring of words or choking during a meal. An aspiration event or acute respiratory symptoms of air hunger occur.
• Extremity weakness: The patient notices wrist drop interfering with his or her work performance. Or, the patient may find reduced finger dexterity, cramping, stiffness, and weakness or wasting of intrinsic hand muscles. Less frequently, the patient may develop foot drop resulting in a fall or sprain.
• Fasciculations may present early on the disease, particularly in the tongue.

Physical

Lower motor neuron signs include weakness, atrophy, fasciculations, and depressed reflexes. Fasciculations are observed with the muscle at rest.

Upper motor neuron signs include an upper motor neuron pattern of weakness (greatest in the extensors of the arm and flexors of the leg), spastic bulbar and limb muscles, hyperreflexia, and extensor plantar responses. A hyperreflexic jaw jerk helps to confirm upper motor neuron involvement causing dysarthria and dysphagia.

Tendon reflexes are paradoxically brisk.

In patients with pseudobulbar palsy, emotional incontinence may cause the patient to over-react to sad or funny things. The patient is aware of the lack of control. Cognitive impairment, if present, most often is observed in patients with bulbar involvement.

Muscle cramps are common for patients with lower motor neuron involvement, while patients with upper motor neuron dysfunction can have clonus or painful extensor spasms.

Ocular, sensory, or autonomic dysfunction occurs only very late in the disease course, usually in patients living with ventilatory support.

The key finding in an involved limb is the combination of lower and upper motor neuron dysfunction with a weak, atrophic, fasciculating muscle occurring in combination with increased tone and hyperreflexia.

• Lower motor neuron signs include atrophy and fasciculations.
• Upper motor neuron (ie, corticospinal tract) signs include spasticity and hyperactive tendon reflexes and may include the Babinski sign.
• No loss of anal sphincter tone occurs. Cardiac and smooth muscle are not involved.
• The course is progressive, and initial symptoms primarily are those of weakness.
• Weakness often is asymmetric and begins in the legs, arms, or oropharyngeal muscles with approximately equal frequency. Masticatory weakness occurs late. Ultimately, weakness becomes symmetrical.
• Ocular musculature is not involved.
• Muscle atrophy and weight loss almost always are recognized by the time the patient seeks medical treatment.
• Fasciculations may be quite widespread and active. Surprisingly, the patient often ignores this symptom.
• Patients may have inappropriately active tendon reflexes and weak, wasted, twitching muscles.
• Muscle cramps are common.
• Dysarthria, exaggeration of motor expressions, and emotional lability (pseudobulbar affect) may occur when the disease process involves the corticobulbar projections to the brainstem.
• Decubitus ulcers are rare.
• Hypoxia or cardiac arrhythmias are the most common cause of death in patients with ALS. The primary cause of death among patients electing to use ventilatory support is pulmonary infection.

Causes

The specific cause is unknown. Recent evidence suggests the existence of clusters of cases. Further evaluation of clusters may provide epidemiologic data associated with causes.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

For patients with a new focal presentation, the differential diagnoses by region include the following:

• Upper motor neuron bulbar signs - Brainstem lesions including syrinx, mass, stroke, and demyelination forms or other degenerative diseases
• Lower motor neuron bulbar signs - Cranial nerve palsies
• Limb upper motor neuron signs - Cervical myelopathy, cord tumor, hereditary spastic paraparesis, transverse myelopathy, HIV-related myelopathy, syrinx
• Limb lower motor neuron signs - Radiculopathy, plexopathy, neuropathy

• Upper motor neuron signs - Compressive myelopathy, syrinx
• Lower motor neuron signs - Chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor, toxic, or metabolic neuropathies or myopathies such as inclusion body myositis or polymyositis

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• No specific laboratory test identifies ALS.

Imaging Studies

• Magnetic resonance imaging of the brain and spinal cord is performed to exclude conditions that might stimulate this condition such as multiple sclerosis, brainstem strokes, and tumors.
• Magnetic resonance spectroscopy is also being used, but it has a high false-negative rate.

Other Tests

• ALS does not lend itself to a quick definitive diagnosis. Often, neurologists need many months to exclude all other possible diagnoses in a patient presenting with upper and lower motor neuron signs.
• Nerve conduction studies can assess conduction amplitude and velocity of sensory and motor neurons, but the utility of this test has not yet been determined definitively for ALS.
• Electromyography shows fibrillation and fasciculations. The motor units are polyphasic and have high amplitude and long duration.
• Other laboratory studies sometimes ordered in the evaluation of a patient with possible ALS include anti-GM1 antibodies, as these can be seen in patients with multifocal motor neuropathy with conduction block. Vitamin B-12 and folate, HIV testing, Lyme serology, and CPK determinations may also be performed. CPK level can be elevated in ALS, but it is obviously not diagnostic.
• ALS research has expanded, and some research is showing that ALS may share common biological mechanisms with Alzheimer disease, Parkinson disease, and other neurodegenerative diseases. Collaborative research is increasing.²

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Emergency Department Care

Emergency physicians should be familiar with this disease and should consider the diagnosis in patients with only motor syndromes.

• Patients initially are cared for symptomatically, and emotional support should be available to the patient and family. Discussion of a new diagnosis of ALS in the ED is inappropriate before further evaluation occurs.
• If a living will or a declaration for a natural death is in place, keep patients comfortable and do not intubate.
• Complications, such as infections, deep vein thrombosis, or respiratory insufficiency, should be managed appropriately.

Consultations

Refer patients to a neurologist experienced in the diagnosis and treatment of neuromuscular diseases.

• Refer to a pulmonologist if respiratory failure is imminent and patient wishes allow.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Treatment of pneumonia or urosepsis initially involves empiric use of a relatively broad-spectrum antibiotic or antibiotics effective against probable pathogens, after appropriate cultures and specimens for laboratory evaluation have been obtained. These medications may include cephalosporins, fluoroquinolones, vancomycin, penicillins, and aminoglycosides.

Drug Category: Amyotrophic Lateral Sclerosis Agent

These agents may inhibit the release of neurotransmitters.

Drug Category: Antispasticity agents

Treatment of spasticity is not specific for ALS.

Drug Category: Cholinergic agents

For patients with ALS who may have secondarily impaired neuromuscular junction transmission.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Physical and occupational therapy and speech pathology consultations assist the patient in maintaining strength, daily living activities, and communication skills.
• When forced vital capacity (FVC) reaches about 50% of predicted levels, supplemental respiratory support may be needed. (The first symptom may be disturbed sleep.) Use of noninvasive positive pressure ventilation improves quality of life; further respiratory deterioration may necessitate tracheostomy and ventilator support.
• Patients with progressive weight loss, symptomatic dysphagia, or aspiration should be considered for percutaneous gastrostomy placement. Risk of percutaneous endoscopic gastrostomy (PEG) placement increases with declining respiratory function. PEG is best placed before FVC falls to less than 50% of predicted levels.
• Advance directives should be addressed by the patient's neurologist early in the course and should be discussed at regular intervals. Hospice referral may be appropriate to aid in care during the terminal phase of the disease.

Further Outpatient Care

• Early in the treatment course, encourage patients to continue routine activities.
• Patients are best cared for in a designated ALS center. Many mechanical aids can help overcome disabilities.
• Patients' length of survival and quality of life are enhanced by night-time breathing assistance early in the course of the disease and by aggressive application of alternate feeding options to ensure good nutrition once swallowing becomes difficult.³

In/Out Patient Meds

• Medications are patient specific.

Complications

• Pneumonia
• Urosepsis
• Constipation
• Depression
• Muscle cramps
• Immobility-related problems

Prognosis

• ALS is a fatal disease. Younger patients may have a slower rate of progression. Patients with bulbar onset, particularly the lower motor neuron type, have a poorer prognosis.

Patient Education

• Patients with ALS are eligible for participation in a Muscular Dystrophy Association clinic.
• Informational web sites include the following:
• • Muscular Dystrophy Association
  • ALS Association of America
  • National Institute of Neurological Disorders and Stroke (NINDS)
• For excellent patient education resources visit eMedicine's Brain and Nervous System Center. Also, see eMedicine's patient education articles Amyotrophic Lateral Sclerosis (Lou Gehrig Disease) and Advance Directives.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Refer patients to a neurologist. In a patient with an established diagnosis of ALS, follow advance directives.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Amyotrophic lateral sclerosis (ALS) patient using eye-gaze computer device to conduct business and communicate.
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Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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2. Hudson AJ. The motor neuron diseases and related disorders. In: Clinical Neurology. Vol. 4. 1996:11-14.
3. 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. Sep 12 2006;67(5):761-5. [Medline].
4. Abramowitz M. Riluzole for amyotrophic lateral sclerosis. Med Lett Drugs Ther. 1995;37.
5. Carter GT, Miller RG. Comprehensive management of amyotrophic lateral sclerosis. Phys Med Rehabil Clin N Am. Feb 1998;9(1):271-84, viii-ix. [Medline].
6. Eisen A, Schulzer M, MacNeil M, et al. Duration of amyotrophic lateral sclerosis is age dependent. Muscle Nerve. Jan 1993;16(1):27-32. [Medline].
7. Goldblatt D. Caring for patients with amyotrophic lateral sclerosis. In: Smith RA, ed. Handbook of Amyotrophic Lateral Sclerosis. Marcel Dekker;1992. [Medline].
8. Gourie-Devi M, Nalini A, Subbakrishna DK. Temporary amelioration of symptoms with intravenous cyclophosphamide in amyotrophic lateral sclerosis. J Neurol Sci. Sep 10 1997;150(2):167-72. [Medline].
9. Gubbay SS, Kahana E, Zilber N, et al. Amyotrophic lateral sclerosis. A study of its presentation and prognosis. J Neurol. 1985;232(5):295-300. [Medline].
10. Househam E, Swash M. Diagnostic delay in amyotrophic lateral sclerosis: what scope for improvement?. J Neurol Sci. Nov 1 2000;180(1-2):76-81. [Medline].
11. Jablecki CK, Berry C, Leach J. Survival prediction in amyotrophic lateral sclerosis. Muscle Nerve. Oct 1989;12(10):833-41. [Medline].
12. Kaufmann P, Pullman SL, Shungu DC, et al. Objective tests for upper motor neuron involvement in amyotrophic lateral sclerosis (ALS). Neurology. May 25 2004;62(10):1753-7. [Medline].
13. 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. Apr 22 1999;52(7):1311-23. [Medline].
14. Sabel CE, Boyle PJ, Loytonen M. Spatial clustering of amyotrophic lateral sclerosis in Finland at place of birth and place of death. Am J Epidemiol. May 15 2003;157(10):898-905. [Medline].
15. Shefner JM. Amyotrophic lateral sclerosis. In: Gilchrist JM, ed. Prognosis in Neurology. Boston: Butterworth-Heinemann; 1998:135-138.
16. Tandan R. Disorders of the upper and lower motor neurons. In: Bradley WG, Daroff RB, Fenichel GM, Marsden CD, eds. Neurology in Clinical Practice. Boston: Butterworth-Heinemann; 1996:1823-1852.
17. Tandan R, Bradley WG. Amyotrophic lateral sclerosis: Part 1. Clinical features, pathology, and ethical issues in management. Ann Neurol. Sep 1985;18(3):271-80. [Medline].

Article Last Updated: Jul 17, 2008