Amyotrophic lateral sclerosis overview
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Differentiating Amyotrophic lateral sclerosis from other Diseases |
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Diagnosis |
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamadmostafa Jahansouz M.D.[2]
Historical Perspective
For the first time ALS was identified as a specific disease by Jean Martin Charcot, a French neurologist working in Paris in 1869s, and thus is still sometimes called Charcot’s disease in some countries such as France. He described and diagnosed the first cases of ALS as a specific neurological disease associated with a distinct pathology. Studies conducted between 1865 to 1869 by Charcot and his colleague Joffroy found that lesions within the lateral column in the spinal cord resulted in chronic progressive paralysis and contractures (no atrophy of muscles), while lesions of the anterior horn of the spinal cord resulted in paralysis without contractures (with atrophy of muscles). These findings supported his hypothesis at the time that the motor component of the spinal cord consisted of a two-part system, and that the location of the lesion results in a varying clinical presentation. While the term amyotrophic lateral sclerosis was not offered by Charcot until 1874 when his lectures were compiled into a collection of his work titled “Oeuvres Completes,” ALS is still referred to as Charcot’s disease in many parts of the world. While numerous molecular and genetic discoveries have allowed for a greater understanding of this disease, his original descriptions of the associated clinical and pathological findings of ALS have remained virtually unaltered. Lou Gehrig was a famous baseball player for the New York Yankees. He was one of the most talented baseball players of all time; yet he is also remembered for ALS, the disease that took his life (June 2, 1941) and still bears his name as its eponym.
Classification
ALS is classified into three general groups, familial ALS, sporadic ALS and Guamanian ALS.
Pathophysiology
The cause of ALS is not known. An important step toward answering that question came in 1993 when scientists discovered that mutations in the gene that produces the Cu/Zn superoxide dismutase (SOD1) enzyme were associated with some cases (approximately 20%) of familial ALS. This enzyme is a powerful antioxidant that protects the body from damage caused by superoxide, a toxic free radical. Free radicals are highly reactive molecules produced by cells during normal metabolism. Free radicals can accumulate and cause damage to DNA and proteins within cells. Although it is not yet clear how the SOD1 gene mutation leads to motor neuron degeneration, researchers have theorized that an accumulation of free radicals may result from the faulty functioning of this gene. Current research, however, indicates that motor neuron death is not likely a result of lost or compromised dismutase activity, suggesting mutant SOD1 induces toxicity in some other way (a gain of function)
Causes
Scientists have not found a definitive cause for ALS and the onset of the disease has been linked to several factors, including: a virus; exposure to neurotoxins or heavy metals; DNA defects; immune system abnormalities; and enzyme abnormalities. There is a known hereditary factor in familial ALS (FALS); however, there is no known hereditary component in the 90-95% cases diagnosed as sporadic ALS.
Differentiating Amyotrophic lateral sclerosis from Other Diseases
Conditions that are commonly mistaken for or difficult to differentiate from ALS are multifocal motor neuropathy with conduction block, cervical spondylotic myelopathy, Kennedy disease (KD), and Post-polio syndrome (PPS). Differentiating multifocal motor neuropathy from ALS is especially important, as patients with this neuropathy may benefit from intravenous immunoglobulin treatment, where ALS patients do not. PPS presents with focal muscle weakness that very slowly progresses to other muscle groups over many years, and does not usually cause death. Patients who present with chronic respiratory muscle weakness should have a thorough evaluation to rule out ALS, as the onset of these symptoms are found in about 3% of ALS patients.
Epidemiology and Demographics
Between 1 to 2 people per 100,000 develop ALS each year . ALS most commonly strikes people between 40 and 60 years of age, but younger and older people can also develop the disease. Men are affected slightly more often than women. Although there have been reports of several "clusters" including three American football players from the San Francisco 49ers, three soccer-playing friends in the south of England, and reports of conjugal (i.e., husband and wife) cases in the south of France, these are statistically plausible chance events. Although many authors consider ALS to be caused by a combination of genetic and environmental risk factors, so far the latter have not been firmly identified, other than a higher risk with increasing age.
Risk Factors
Common risk factors in the development of amyotrophic lateral sclerosis include: Smoking, oxidative stress, heavy metals, chemical exposure (pesticides, fertilizers, herbicides, insecticides, and formaldehyde), Radiation, Diet (high level of glutamate and fat can have adverse effects on ALS patients while Omega 3 fatty acids, Vitamin E, and fiber can have defensive impact.) and genetic causes. Among all the heavy metals that might be associated with ALS, lead exposure seems to be studied the most possibly due to the ALS-like symptoms experienced by people exposed to high concentrations of lead.
Screening
There is insufficient evidence to recommend routine screening for amyotrophic lateral sclerosis.
Natural History, Complications, and Prognosis
The symptoms of Amyotrophic lateral sclerosis usually develop in the fifth decade of life. Only 5% of the cases have an onset <30 years of age. With the progression of ALS, patients develop the distinctive feature of a combination of upper motor and LMN degeneration signs within the same CNS region. Common complications of ALS include: Dyspnea, Orthopnea, Hypoventilation, Pneumonia, cognitive dysfunction, weight loss, which is an indicative of a poor prognosis. The main cause of death in ALS is respiratory failure as the result of pulmonary complications. Prognosis is generally poor, and the 30 months survival rate of patients withALS is approximately 5%. Only 20% of the patients survive between 5 and 10 years after symptoms onset. Reduced survival to the disease is related to the older age of symptom onset, early respiratory muscle dysfunction, and bulbar onset disease. On the other hand, limb-onset disease, younger age at presentation of the disease and longer diagnostic delay are independent predictors of prolonged survival. Some ALS subtypes vary according to prognosis. LMN form of ALS, which includes flail-limb variant and PMA, shows a slower progression than other forms of ALS. A prognosis of 2–4 years is seen in the pure bulbar palsy phenotype, which usually affects women older than 65 years of age. In this type of ALS, the disease remains localized to the oropharyngeal musculature and UMN features predominate.
Diagnosis
Diagnostic Study of Choice
Equal emphasis on both electromyogram (EMG) and clinical abnormalitie are the gold standard method for the diagnosis of amyotrophic lateral sclerosis. EMG and nerve conduction studies are most sensitive to detecting the disease and can quantify its trademark characteristic of LMN degeneration. Magnetic resonance imaging (MRI) studies of the brain and spinal cord are the most useful neuroimaging technique in ALS mainly to exclude syndromes that mimic ALS.
History and Symptoms
The onset of ALS may be so subtle that the symptoms are frequently overlooked. The earliest symptoms are obvious weakness and/or muscle atrophy. This is followed by twitching, cramping, or stiffness of affected muscles; muscle weakness affecting an arm or a leg; and/or slurred and nasal speech. The twitching, cramping, etc. associated with ALS is a result of the dying muscle, therefore these symptoms without clinical weakness or atrophy of affected muscle is likely not ALS.
Physical Examination
ALS begins in the limbs, usually the arms, in about two-thirds of patients. The first symptoms are most often unilateral and focal. As limb function deteriorates, patients become dependent on caregivers. Physical examination of patients with amyotrophic lateral sclerosis is usually remarkable for: Fasciculation, cramps, muscle atrophy, marked weakness, spasticity, hyperreflexia, weakness, positive Babinski sign, positive Hoffmann sign, foot drop, difficulty walking, abnormal gait patterns, dropped head, trophied fasciculating tongu, nystagmus in advanced disease, abnormal extra-ocular movements, symmetric chest expansion or decreased chest expansion , displaced point of maximal impulse (PMI) and heart murmurs. Sphincter and sensory functions are usually, but not always, spared. Eye movements are preserved until advanced stages. Abdominal examination of patients with ALS is usually normal. Back examination of patients with ALS is usually normal. Urinary retention is common in patients with ALS. Urological evaluation is indicated in ALS patients with prominent spasticity.
Laboratory Findings
Typical labs drawn in patients with ALS are: Erythrocyte sedimentation rate, serum and urine protein electrophoresis, thyroid function tests, serum calcium and phosphate measurements, and CSF analysis. Heavy metal screening is indicated in patients with a potential history of exposure. B-hexaminidase subunits alpha and beta activity should be tested in Ashkenazi Jews because deficiency in this enzyme mimics ALS, but in reality is the rare autosomal recessive genetic disorder, Tay-Sachs. Other clinical laboratory tests that may be abnormal in otherwise typical case of ALS include: Muscle enzymes (serum creatine kinase [unusual above ten times upper limit of normal , ALT, AST, LDH), serum creatinine (related to loss of skeletal muscle mass), Hypochloremia, increased bicarbonate (related to advanced respiratory compromise, elevated CSF protein (uncommonly more than 100 mg/dl).
Electrocardiogram
There are no specific ECG findings associated with amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis can cause non-specific ECG abnormalities that mimic coronary syndromes including: S-T elevation, T wave inversion, Q-T prolongation. Patients with advanced amyotrophic lateral sclerosis may experience loss of heart rate variability and enhanced vasomotor responses and atrioventricular heart block..
MRI
Magnetic resonance imaging (MRI) studies of the brain and spinal cord are the most useful neuroimaging technique in ALS mainly to exclude syndromes that mimic ALS. New chromosome 9p-linked frontotemporal dementia (FTD)-ALS shows a distinct pattern of brain atrophy and neuropathological findings that can help differentiate from classical ALS. Other findings on MRI suggestive of [disease name] include: hyperintensity in the corticospinal tracts (specificity <70% and sensitivity <40%) in T2, hypointensity in the precentral gyrus bilaterally, known as the "motor band sign" in GRE/SWI, decreased NAA, decreased glutamate, increased choline and increased myo-inositol in MR spectroscopy.
Treatment
Medical Therapy
Riluzole is believed to reduce damage to motor neurons by decreasing the release of glutamate. Clinical trials with ALS patients showed that riluzole prolongs survival by several months, and may have a greater survival benefit for those with a bulbar onset. The drug also extends the time before a patient needs ventilation support. Riluzole does not reverse the damage already done to motor neurons, and patients taking the drug must be monitored for liver damage and other possible side effects. However, this first disease-specific therapy offers hope that the progression of ALS may one day be slowed by new medications or combinations of drugs.
Surgery
Not only urgical intervention is not recommended for the management of amyotrophic lateral sclerosis, the site of surgery before ALS onset correlates with the region of onset of ALS. Patients with slower disease progression are at an increased risk of undergoing surgery, probably as part of initial difficulty in diagnosis.