Amyotrophic lateral sclerosis (ALS; Lou Gehrig’s disease; Charcot's disease)

• Disease Site
• Incidence
• Predisposing Factors
• Natural History
• Clinical History
• Clinical Examination
• General Investigation
• Specific Investigations
• Prognosis
• References

Disease Site

Amyotrophic lateral sclerosis (ALS) is a type of motor neuron disease that attacks the neurons responsible for controlling voluntary muscles. Movement occurs when upper motor neurons send messages to neurons in the spinal cord (lower motor neurons). The lower motor neurons relay these messages to the specific muscles that then carry out the movement.
In ALS, both upper and lower motor neurons are affected. When these neurons degenerate or die, they cease to send messages to muscles. This results in gradual weakness, atrophy and fasciculations in the muscles that lose functioning ability. Eventually, all voluntary movement is lost and the muscles become paralysed.
Charcot was the first to clinically describe this condition in the 1860s, and as a result, the disease was named after him. In the US, the disease is often called Lou Gehrig disease after the baseball legend who died from ALS in 1941.

Incidence

ALS is the most common type of adult-onset motor neuron disease. The prevalence of the disease in the United States is 20,000.⁸
ALS occurs worldwide, without predilection for races and ethnic backgrounds. The most common age of onset is between 40 and 60 years of age, but younger and older people also can develop the disease. Men are affected more often than women, with a male to female ratio of 1.6:1.¹
In the Western Pacific region (Guam, Papua New Guinea), there is an increased incidence that in many cases is associated with Parkinsonism and dementia.

Predisposing Factors

The exact aetiology of ALS is unknown.

• 5-10% of cases are inherited or familial. In these cases, there is an associated autosomal dominant mutation (chromosome 21q22.1);
• 90-95% of cases are sporadic. Suggested contributory factors include sulfur containing toxins, excess glutamate, free radicals, viruses (enteroviruses, retroviruses) and autoimmune factors;⁷
• 10% of cases are familial and the disease is transmitted in an autosomal dominant fashion.

Natural History

ALS involves both upper and lower motor neurons and presents as an idiopathic, progressive degeneration of anterior horn cells and their associated neurons resulting in progressive muscle weakness, atrophy, and fasciculations. ALS is characterised by atrophy of muscle fibres, which are denervated as their corresponding anterior horn cells degenerate. The motor neurons in the anterior and lateral columns of the spinal cord degenerate and are replaced by fibrous astrocytes (gliosis).
Onset of symptoms tends to be gradual. 70% of patients present initially with progressive and asymmetric limb weakness. This often begins as a foot drop or difficulty with fine hand movements. Localised muscle pain over several weeks may indicate the onset of weakness and atrophy; pain may be severe in later stages of disease. When muscles in the diaphragm and chest wall fail, patients are unable to breathe without ventilatory support. Respiratory failure is the most common cause of death in patients with ALS, usually occurring within 3 to 5 years from the onset of symptoms. Although the usual course is relentlessly progressive with a 50% mortality rate within three years from onset, it can sometimes be protracted.⁹
There is currently no cure for ALS.
Complications include aspiration pneumonia, loss of mobility (and sequelae such as pressure sores), and loss of independence.

Clinical History

With a complete history, ALS can be differentiated from stroke or trauma due to the subacute or chronic progression of symptoms. When focal limb weakness occurs, ALS is distinguished from a specific nerve problem by the lack of pain or sensory symptoms. While ALS is a slowly progressive disease, a precipitous/traumatic event may occur to bring the patient to the ED. Patients may report difficulty in swallowing, chewing, coughing, breathing and talking if there is involvement of the higher centres. Involvement of the limbs is characterised by weakness, stiffness, cramping, loss of co-ordination and wasting of the muscles. Patients may notice problems with lifting, climbing stairs and walking.⁵

Clinical Examination

A neurological examination indicates weakness, often beginning in one limb or in proximal groups (such as shoulders or hips). There may be muscle tremors, spasms, twitching, or muscle atrophy (loss of tissue). Atrophy and twitching of the tongue are common. Usually, there is no significant change in sensation. The gait may be stiff or clumsy. Reflexes may be abnormal, including loss of the gag reflex. Some patients have “emotional incontinence” in which it is hard to control crying or laughing.

General Investigation

• Blood investigations: Full blood count (FBC), ESR, CK, lead levels, thyroid function tests, syphilis and HIV serology, arterial blood gases (ventilatory failure late in disease);
• Needle EMG and nerve conduction studies are the tests of choice for confirming the diagnosis of ALS. Typically, the conduction velocity of sensory fibres is unchanged. EMG often reveals chronic partial denervation in clinically unaffected muscles, with spontaneous fasciculations and fibrillation potentials;
• An MRI brain scan is indicated for patients with suspected bulbar involvement to exclude a brainstem lesion. High signal intensity of the intracranial corticospinal tract on T1-weighted images may reflect the severe pathological changes of the upper motor neurons in ALS;¹⁰
• Lung function tests;
• Neuropsychological testing may reveal frontal lobe impairment;
• PET.

Specific Investigations

There are no specific tests that diagnose ALS.

Prognosis

Median survival from time of diagnosis is 3-5 years. However, there have been a few reports of the stabilisation or even regression of the condition. 25% of patients survive 5 years or longer. Favourable prognostic indicators include early age of onset and progressive muscle atrophy.

References

1. Clem K, Morgenlander JC. Amyotrophic lateral sclerosis [online]. Omaha, NE: eMedicine; 2004 [cited 29 December 2005]. Available from: URL link
2. Goldblatt D. Caring for patients with amyotrophic lateral sclerosis. In: Smith RA (ed). Handbook of Amyotrophic Lateral Sclerosis. New York, NY: Marcel Dekker; 1992. [Book]
3. Gourie-Devi M, Nalini A, Subbakrishna DK. Temporary amelioration of symptoms with intravenous cyclophosphamide in amyotrophic lateral sclerosis. J Neurol Sci. 1997;150(2):167-72. [Abstract]
4. Hankey G, Wardlaw J. Clinical Neurology. New York, NY: Demos Medical Publishing; 2002. [Book]
5. Braunwald E, Fauci AS, Kasper DL, et al. Harrison’s Principles of Internal Medicine (15th edition). New York: McGraw-Hill Publishing; 2001. [Book]
6. Mitsumoto H. Riluzole: What is its impact in our treatment and understanding of amyotrophic lateral sclerosis? Ann Pharmacother. 1997;31(6):779-81. [Abstract]
7. Facts about amyotrophic lateral sclerosis (ALS) [online]. Tucson, AZ: Muscular Dystrophy Association; 2005 [cited 29 December 2005]. Available from: URL link
8. Amyotrophic lateral sclerosis fact sheet [online]. Bethesda, MD: National Institute of Neurological Disorders and Stroke; 2005 [cited 29 December 2005]. Available from: URL link
9. Tandan R, Bradley WG. Amyotrophic lateral sclerosis: Part 1. Clinical features, pathology, and ethical issues in management. Ann Neurol. 1985;18(3):271-80. [Abstract]
10. Waragai M. MRI and clinical features in amyotrophic lateral sclerosis. Neuroradiology. 1997;39(12):847-51. [Abstract]