Amyotrophic Lateral Sclerosis (ALS)

History

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder involving the neurons of the motor system in the brain and spinal cord. The disorder was first described by Ran in 1850. This description was then expanded in 1873 by Charcot, who emphasized the involvement of the corticospinal tracts. In the United States, ALS is often referred to as Lou Gehrig's Disease, after the famous ball player who was stricken by the disease in the midst of his career. In Europe the term Motor Neuron Disease is preferred, although this term can also be used to designate the class of disorders of which ALS is only one entity. Other disorders which fall under the category of motor neuron disease include primary lateral sclerosis, spinal muscular atrophy, and progressive bulbar palsy.

Clinical Presentation

Epidemiology

The sporadic type of ALS has an annual incidence of 0.4 - 2 per 100,000, and a prevalence of 4 per 100,000. The median age of onset is 55-66. Onset before age 20 is rare, although does occur. There is a male preponderance, with a male to female ratio of 1.5 - 1.8:1. A familial type of ALS, 5-10% of all cases, has also been described (see Genetics below). Familial ALS is genetically determined, is inherited in an autosomal dominant fashion, and does not follow the epidemiology described above for sporadic ALS.

Finally, there are certain geographic regions with a particularly high incidence of ALS, specifically Guam and the Kii Peninsula in Japan. In Guam, ALS occurs frequently as part of a syndrome, which includes dementia and parkinsonism; and is associated pathologically with neurofibrillary tangles (which are also found in Alzheimer's disease). This higher incidence does not appear to be due to familial ALS or en environmental factor, such as an infective agent, but is thought to be due to higher susceptibility to the disease by the islands native population.

Clinical Features

The primary symptom of ALS is progressive weakness. The weakness usually begins in the legs and more commonly distally than proximally, but the location of onset is highly variable. In some patients the first sign of weakness is difficulty swallowing or eating due to involvement of the tongue or pharyngeal muscles (bulbar onset ALS). Eventually the weakness spreads to involve all four extremities, the muscles of the trunk and abdomen, and the bulbar muscles of the face, mouth, and throat. Muscles of eye movement and bowel or bladder sphincters are not affected in ALS, and their involvement should bring the diagnosis into question.

Involved muscles also show both upper and lower motor neuron findings, which is the hallmark of the disease. Upper motor neuron findings include spasticity and hyperreflexia. Lower motor neuron findings consist of fasciculations(muscle twitching) and atrophy. In addition to bowel and bladder function and oculomotor function, sensation, coordination, and cognition are also spared.

The course of ALS is one of relentless progression and spread. There are only rare cases of stabilization of symptoms. Reported cases of recovery may have actually been cases of viral infection similar to polio, and not true ALS. Patients < 65 years old at onset have a 50% mortality after 3 years, 20% live > 5 years, 10% live > 10 years, and few may live up to 20 years. When the disease onset is > 65 years old, there is a 50% mortality after 2 years. Death from ALS results from weakness of the respiratory muscles. When patients reach the stage where they can no longer breath on their own, they are faced with the choice of either indefinite mechanical ventilation, or imminent death.

Pathophysiology

The weakness and atrophy of ALS results from progressive degeneration of motor neurons in the spinal cord, brain stem, and motor cortex. As anterior horn cells (motor neurons whose cell bodies reside in the anterior horn of the spinal cord) die, the muscle fibers they innervate become weak, fasciculate, and eventually atrophy. Sometimes neighboring axons from other anterior horn cells will sprout collateral branches to innervate the isolated muscle fibers, but these anterior horn cells are destined to eventually die as well. Why the motor neurons begin to die is still unknown. Recent evidence, however, have implicated glutamate excitotoxicity, free radical toxicity, and mitochondrial dysfunction as possible mechanisms, and this is an area of active research.

Diagnosis

The diagnosis of ALS is based primarily on clinical presentation, with supportive data from electrodiagnostic, imaging, and laboratory studies. In 1994, the World Federation of Neurology published the El Escorial criteria for the diagnosis of ALS. They defined three categories of certainty based on clinical signs:

  • Clinically Definite ALS: Upper and lower motor neuron signs in three or more regions. Regions are defined as bulbar, cervical, thoracic, or lumbar.
  • Clinically Probable ALS: Upper and lower motor neuron findings in two regions or having upper motor neuron findings anatomically rostral (above) lower motor neuron findings. (therefore increased reflexes in the arms with wasting and fasciculations in the legs would qualify, but not the other way around.)
  • Clinically Possible ALS: Upper and lower motor neuron findings in one region or lower motor neuron findings above upper motor neuron findings

In addition to the motor neuron signs as defined above, the diagnosis is supported by the spread of signs and symptoms from one region to another with a linear increase in severity. The diagnosis of ALS should be questioned if sensory, cerebellar, oculomotor, or bowel or bladder symptoms are present. The laboratory studies below are helpful in confirming the diagnosis, and ruling out other possible diagnoses.

  • Blood tests - CPK may be normal or moderately elevated (2-3 times normal) in ALS. CPK may be ordered to rule out muscle disease, which is some cases can cause a high elevation of CPK. Other studies which are ordered to rule out diseases which can mimic some of the findings of ALS include B12, Lyme titers or western blot, Anti-GM1 antibody titers, and serum protein electrophoresis.
  • Electromyography (EMG) - the presence of fibrillations and positive waves (together referred to as spontaneous activity) and decreased recruitment in a muscle qualify as lower motor neuron findings, and can be used to upgrade the probability of the diagnosis based on the El Escorial criteria outlined above.
  • MRI of the spine - Mutifocal spine disease can mimic the findings of ALS and therefore should be ruled out with an anatomical study.
  • Muscle Biopsy - Not routinely performed, but is done in selected cases where the diagnosis is problematic. In ALS, a muscle biopsy will show neurogenic atrophy.
  • Genetic Testing - If familial ALS is suspected, then DNA testing for the SOD1 mutation can be performed.

Related Disorders

There are several closely related disorders which may be confused with ALS. Primary Lateral Sclerosis (PLS) is also a disease marked by progressive weakness due to the dying off of motor neurons. It can be distinguished from ALS, however, by the presence of only upper motor neuron signs, therefore there are no fasciculations and atrophy is less severe. Multifocal Motor Neuropathy is a disorder of motor nerves, and therefore results in weakness with predominantly lower motor neuron signs, and will also have abnormal nerve conduction studies. Adult Spinal Muscular Atrophy results from death of only the anterior horn cells (the lower motor neuron), and therefore has only lower motor neuron findings. Progressive Bulbar Atrophy is essentially ALS which remains isolated to the bulbar muscles. Whether this is truly a separate disease or just part of the spectrum of ALS is a matter of debate.

Genetics

Familial ALS accounts for 5-10% of ALS cases. Of familial ALS cases, 20% are associated with mutation of the SOD1 gene (21q) for cytosolic copper/zinc superoxide dismutase, which plays a role in free radical homeostasis. Free radicals have been identified as an important mechanism of cell damage and death. 50 different SOD1 mutations have been identified in different familial pedigrees. Familial ALS is inherited in an autosomal dominant fashion, therefore only one parent need carry the gene in order to pass on the disease to their children.

Treatment

Maintaining the highest level of function and comfort is an important goal in the management of patients with ALS. Physical therapy for mobility, ambulation, prevention of contractures, occupational therapy, and activities of daily living is essential. Patients should also be evaluated for proper orthotic devices, such as ankle-foot orthosis, and assistive devices, such as walkers and when necessary wheelchairs. Pulmonary evaluation including pulmonary function tests should be done early to obtain a baseline which can be followed as the disease progresses. If bulbar symptoms are present, even if mild, then a swallowing and nutritional evaluation should be obtained.

Personal and family counseling should be offered to the patient when appropriate. From the moment of diagnosis, patients will need a great deal of support. They will also need to be counseled by their physician and other health care professionals on the difficult issues which must eventually be faced, including mechanical ventilation, feeding tube placement, the need for a living will, and occupational issues.

Drug Treatment

Riluzole (Rilutek TM) is the first and only drug to receive FDA approval for the treatment of ALS. Clinical trials in America and Europe have shown a significant prolongation of tracheostomy-free survival (about 20%) in ALS patients taking riluzole compared to those taking placebo. Riluzole is a glutamate release inhibitor and it is thought that it works in ALS by decreasing glutamate mediated motor neuron cell death. The dose is 50mg po BID (twice daily). Doctors must follow CBC (complete blood count) and LFT's (liver function tests) every month for 3 months then every 3 months for 9 months.

Research

US and European studies have been completed testing Myotrophin (IGF-1, Insulin-like Growth Factor -1) in ALS. As the name implies, IGF-1 is a growth factor which is hoped will prolong survival of motor neurons in ALS. The results are conflicting and therefore have not been convincing enough to earn FDA approval. The FDA did approve the drug for further investigational use. More recently, however (May 8, 1997), the FDA, in a 6-3 vote, decided against approval for Myotrophin. Although clinical trials with Myotrophin are still ongoing, the future of this drug in ALS treatment seems bleak.

In a small clinical trial, Neurontin (gabapentin) showed a trend towards improvement in ALS patients, but did not reach statistical significance, and therefore was deemed a negative study. A larger trial of Neurontin in ALS proved negative. Therefore, although Neurontin is also a glutamate inhibitor, it did not prove effective in the treatment of ALS.

A clinical trial of Topamax (topiramate) in the treatment of ALS is just being completed (Summer 2001). Topamax is already FDA approved for the adjunctive treatment of partial epilepsy and therefore is available by prescription. Topamax antagonizes kainate activation of the alpha-amino-3-hydroxy- 5-methyl-4-isoxazole-propionic acid (AMPA) glutamatergic excitatory amino acid receptor, and therefore has antiglutamate activity, as does Rilutek. Results of this trial are expected in the Fall of 2001. A clinical trial of Celebrex (celecoxib) will be underway in the Fall of 2001.

Celebrex is a Cox-2 inhibitor used to treat pain and inflammation. Cox-2 inhibitors work by decreasing prostaglandin synthesis, which is hoped will both decrease glutamate release and free radical production. Celebrex is an approved drug and is therefore available by prescription, but the study will use a much higher dose than standard therapy.

There is also an ongoing trial of creatine in the treatment of ALS. Creatine is a protein supplement available over the counter. Animal data suggests that it can slow the progression of ALS, however there is currently no human data available, at least until the results of the ongoing trial are available. The presumed mechanism of action of creatine is mitochondrial stabilization. The recommended dose is 2gm BID (twice daily) and the major side effect is kidney damage from protein overload. This can be avoided by keeping well hydrated by drinking large amounts of fluid.

Several agents have been studied recently and found to have no clinical benefit for ALS patients. They include CNTF, and most recently BDNF (brain derived neurotrophic factor). Other agents under study include GDNF and Procysteine. There is anecdotal evidence to suggest other agents as possibly useful in ALS, but sufficient clinical trials have not yet been completed. They include some antioxidants (Vitamin E, Vitamin C, and Beta Carotene), Branched- Chain Amino Acids (BCAA's), NMDA (N-methyl, D-aspartate) Inhibitors, Dextromethorphan, IVIG (intravenous immune globulin), calcium channel blockers (nimodipine), and some chemotherapeutic agents (Cytoxan and total lymphoid irradiation).

Support Groups

Muscular Dystrophy Association (MDA)
National Headquarters
3300 East Sunrise Drive
Tucson, Arizona 85718
Phone: 1-800-572-1717

The MDA supports research and patient care for over 40 diseases, including ALS. They can put patients and families in touch with local chapters and support groups.

Amyotrophic Lateral Sclerosis Association (ALSA)
21021 Ventura Boulevard
Suite 321
Woodland Hills, CA 91364
Phone: (818) 340-7500 or (800) 782-4747
Fax: (818) 340-2060

ALSA is dedicated to supporting research into the cause and cure for ALS as well as patient support.

Internet Links to other ALS sites:

Disclaimer

This page is intended for educational purposes only, to provide an overview of ALS for patients, their families, and health care providers. It is not intended to recommend any specific treatment, nor should it be used as a guide for self-treatment. Patients with ALS should consult their physician before making any changes to their treatment regimen.