Amyotrophic Lateral Sclerosis
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[edit] Amyotrophic Lateral Sclerosis
T. Jock Murray
William Pryse-Phillips
Amyotrophic lateral sclerosis (ALS) is also called the motor neuron disease, or Lou Gehrig's disease after the baseball player who died of the disease in 1941 (Box 170-1). In ALS, the anterior horn cells and corticospinal tracts are usually affected at many levels, although a few patients have clinical manifestations of involvement at only one level.
| Box 170-1 - Who Was Lou Gehrig? |
| ALS has become known to the public as Lou Gehrig's disease. Lou Gehrig was one of the greatest baseball players of all time, a New York Yankee from 1923 to 1939, until his career was stopped by a progressive neurologic disease. Nicknamed “the Iron Man,” the “Iron Horse,” and “the Pride of the Yankees,” he was on his way to surpassing Babe Ruth for many records when his game seemed to go into a slump, starting in 1938 and noticed by all in 1939. In an emotional tribute to his impressive career and his stature as a respected sportsman, he told a packed Yankee Stadium that he felt he was the luckiest man alive. Although the illness took his life in June 1941 at the age of 38, he has become the symbol not only for ALS but also for hope and strength by those who suffer with the disease. |
According to the pattern of involvement, different names have been employed, e.g., progressive muscular atrophy (anterior horn cell degeneration only); primary lateral sclerosis (pyramidal tract degeneration only); progressive bulbar palsy (brainstem motor nuclear degeneration); and pseudobulbar palsy. The most common picture, however, is a mixture of these features: the patient has both upper and lower motor neuron signs and symptoms often with bulbar involvement as well. Because the disease eventually generalizes to involve both upper and lower motor neurons at both cranial and spinal levels, many authors use the term ALS for all forms. At death, some patients who have had clinical evidence of degeneration at only one level may show pathologic changes at other levels not evident clinically.
[edit] PATHOLOGY
The pathologic features are primarily degeneration of motor cells in the spinal cord, brainstem, and to a lesser extent the cerebral cortex, with secondary degeneration of pyramidal tracts. The anterior horn cells and pyramidal tracts are more or less severely affected; the cellular destruction is greatest in the cervical and lumbar regions of the cord (Fig. 170-1). There is some diffuse loss of myelin in all areas of the spinal cord except the posterior columns, but the loss in the pyramidal tracts is striking, giving the cord a characteristic picture on myelin staining.
In the brainstem, degeneration occurs in the motor nuclei of the cranial nerves but the three oculomotor nuclei are spared; this feature is worthy of careful investigation, as we might learn more about this enigmatic disease from the few nuclei that are never involved than the many that usually are. Degeneration is found in the pyramidal tracts and sometimes in other fiber tracts in the brainstem. Pyramidal degeneration can be traced into the internal capsule in about one-half of cases, and in one-third the number of Betz cells in the motor cortex is decreased and there is a variable loss of medium-sized motor cortical cells.
[edit] CLINICAL FEATURES
The overall incidence of ALS is 2 per 100,000 population. The onset is usually between the ages of 50 and 70 years, and twice as many men develop the disease as women. The disease appears as a dominant character in some families. It accounts for 1 in 1000 deaths.
Although ALS is a disease of the motor neurons and the findings are entirely motor, secondary degeneration in nerves and muscles may give rise to vague pains and paresthesias in a quarter of the patients, particularly at the onset of the disease, but the clinical findings will be entirely motor. Most patients first notice weakness in their legs or arms, sometimes mentioning atrophy as well but seldom commenting on fasciculations (Box 170-2).
| Box 170-2 - Signs and Symptoms of ALS |
Lower Motor Signs
|
In progressive muscular atrophy the clinical features are those of degeneration of the anterior horn cells of the spinal cord. The patient notes weakness in the hands and legs, and on examination is found to have atrophy of the small muscles of the hands and of the more distal muscles of the arms and legs. Fasciculations can be seen in these areas and often over the shoulder girdle, trunk, tongue, and face as well. Although about 20% of patients show this picture at the onset, in only 8% does it remain as a “pure form” throughout the course of the disease. Other causes that must be ruled out include hexosaminidase A deficiency, multifocal motor neuropathy, and inherited adult-onset spinal muscular atrophies (Box 170-3).
| Box 170-3 - Conditions That May Mimic ALS |
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In primary lateral sclerosis the manifestations are of pyramidal tract degeneration, with weakness and spasticity of the legs and later of the arms. Hyperactive muscle stretch reflexes including the jaw jerk, palmomental and pouting reflexes, and Hoffmann's and Babinski's signs are commonly found. This is a difficult diagnosis, however, as many more common causes of paraplegia must first be excluded. Although the existence of this rare form has been disputed, cases have been confirmed by autopsy.
In progressive bulbar palsy the degeneration is primarily of the motor nuclei of the brainstem. The patient complains of slurred speech and later has difficulty in swallowing and coughing, so aspiration is a constant danger. There are atrophy and fasciculations of the tongue, poor palatal movement, and sometimes fasciculations and weakness of the facial muscles. Although less than 10% of cases have pure progressive bulbar palsy, most ALS patients show some bulbar involvement eventually. Pseudobulbar palsy can also occur with signs of spastic weakness of the bulbar muscles, but no evidence of an upper motor neuron lesion elsewhere.
Amyotrophic lateral sclerosis (ALS) is the term applied to the most common form, in which there is evidence of both anterior horn cell and pyramidal degeneration, usually at both bulbar and spinal levels. On examination these patients have atrophy, weakness, and fasciculations in their limbs, indicating a lower motor neuron lesion, combined with hyperactive reflexes and Babinski's signs. It is this combination of upper and lower motor neuron signs in all limbs that is the hallmark of ALS.
[edit] FAMILIAL ALS
In a small number of cases (5% to 10%) there is a positive family history of ALS. One in five of those have a defective superoxide dismutase 1 (SOD1) gene. The pattern of inheritance is autosomal dominant with penetrance of up to 90% by age 70. The clinical picture is similar to sporadic ALS except that the male to female ratio is 1:1, whereas there are more males in the sporadic form, and this form occurs 10 years earlier on average. A rare juvenile-onset familial form has also been described in African families.
[edit] DIAGNOSTIC CRITERIA
The El Escorial ALS Diagnostic Criteria (1994) tried to refine the diagnosis. The system recognizes that the problem involves the peripheral and central nervous system (CNS) in four regions: bulbar, cervical, thoracic, and lumbosacral. To make the diagnosis of ALS the following should be present:
- Progression of disease (confirmed by examinations 6 months apart).
- Clinical and/or electrical evidence of involvement of two regions (probable ALS) or three or four regions (definite ALS).
- No other disease that could mimic the presentation (seeBox 170-3).
[edit] ASSOCIATED DISEASES
ALS has been associated with recurrent hypoglycemia, hyperthyroidism, poliomyelitis, and carcinoma, and it has also been reported in pregnancy and after gastrectomy. ALS has also been associated with acromegaly, electric shock injury, and heavy metal poisoning. With most of these conditions, the association is rare and probably coincidental. However, malignant tumors, particularly carcinoma of the lung, have been noted in about 10% of the patients. An ALS-like syndrome (postpolio syndrome) sometimes occurs many years after an episode of poliomyelitis, but this syndrome is unrelated and is much more benign. An ALS syndrome with associated parkinsonism and dementia occurs on the island of Guam.
[edit] COURSE AND PROGNOSIS
The course of the disease is variable, but the average life expectancy is 3.5 years from onset; only 20% survive over 5 years. We have seen patients who died in as short a time as 9 months, and others who had a slow course over 15 to 20 years and more, with long periods without change. To some extent, survival depends on the type of ALS but there is great variation even within the same type.
Although bulbar palsy is regarded as an ominous form of the disease, some patients survive for up to 15 years, while in contrast, other patients with this form of the disorder may die within months of developing brainstem symptoms. In general, those with bulbar palsy have a more rapid course than those with primary lateral sclerosis, in whom the prognosis is markedly better.
[edit] DIFFERENTIAL DIAGNOSIS
ALS must be differentiated from other conditions that produce a combination of upper and lower motor neuron lesions. The most obvious of these are disorders of the cervical cord, such as skull base deformities, syringomyelia, cord tumors, and cervical spondylosis. In such cases, however, there should not be any evidence of anterior horn cell involvement in the legs or trunk, but only in the upper limbs. Any signs of disease due to a lesion above the foramen magnum (such as bulbar signs or V or VII nerve involvement) would rule out a cervical cause.
Lower motor neuron lesions may be predominant with spinal arachnoiditis (usually syphilitic) and radiculitis, cervical ribs, and peripheral nerve lesions, including the postpolio syndrome previously mentioned. Weakness and wasting are typical of all forms of hereditary motor neuropathy, some of which occur first in adult life, and in hereditary motor and sensory neuropathy. The same findings, although without fasciculations, are also seen in primary muscle disease, rheumatoid arthritis, and myotonic dystrophy. If there is doubt about evidence of anterior horn cell disease in the trunk or legs, electromyography (EMG) should be able to demonstrate that which cannot be seen clinically.
[edit] LABORATORY STUDIES
Although the diagnosis is usually evident clinically, there are a few investigations that can be used to confirm the diagnosis or to rule out other diseases or associated disease. Nerve conduction studies yield results that are normal or only slightly slowed, making demyelinating neuropathies unlikely. EMG shows evidence of denervation and reduced numbers of motor unit potentials among which are giant units and polyphasic potentials, as well as fasciculations. The cerebrospinal fluid (CSF) protein is elevated, in the range of 45 to 95 mmol/L in one-third of cases. Decreased urinary creatinine and increased urinary creatine levels are found but are not useful diagnostic tests. Muscle biopsy demonstrates the characteristic features of a neurogenic muscular atrophy but is seldom needed, unless a condition such as inclusion body myositis is suspected.
Investigations should be undertaken to rule out underlying malignancy if there is any atypical feature on examination or investigation, such as marked slowing of motor nerve conduction velocities. Cervical myelopathy can look like ALS if cord compression is combined with root involvement. The lower motor neuron findings are only in the arms, an important diagnostic feature, and this situation can be confirmed by imaging of the cervical cord and using EMG to show fasciculations in the legs. Most other mimics can be excluded by history (hereditary neuropathy; prior gastrectomy, polio, or electrical injury); by examination (hyperthyroidism, acromegaly); or by laboratory tests (lead or other metal poisoning, recurrent hypoglycemia, hexosaminidase deficiency, and anti-GM1 ganglioside antibody if multifocal neuropathy is suspected).
[edit] MANAGEMENT
Treatment of this disease is disappointing, despite some new agents that may make a slight difference in the course of the progression. Riluzole (Rilutek), a glutamate-blocking agent, has shown a statistical improvement in the rate of progression, but this is of minor clinical significance since the difference translates to a prolongation of death by 3 months or so. Despite its minor effect, the release of this drug, the first to make any difference in the disease, has had a much greater effect on the sense of hope for these patients, who have had little before. A number of other agents are under study, but none as yet has shown much promise. With such first steps, however, there is always the hope of the next steps.
Other studies have suggested some effect from brain-derived neurotrophic factor (BDNF), insulin-like growth factor (IGF-1), and gabapentin, but further trial and experience are required to assess whether they have any place in the treatment of this disease.
Despite limited therapy for the underlying disease, help with the major symptoms of ALS can be offered in the following, which outlines some of the approaches to symptomatic therapy:
[edit] Slurring, Choking, and Drooling.
Anticholinergics can dry secretions, and paradoxically, neostigmine may be helpful to increase muscle power temporarily. The patient should decide how liquid his food should be, and how large the mouthfuls. Cricopharyngeal myotomy can be performed to aid swallowing.
[edit] Involuntary Limb Jerks.
Phenytoin, carbamazepine, baclofen, and clonazepam may be helpful.
[edit] Cramps and Aching Limb Pains.
Quinine, phenytoin, or carbamazepine may be helpful, but major pain is usually not a problem.
[edit] Insomnia and Problems Turning in Bed.
Special beds can be leased or borrowed. Family and friends may organize a roster of people to sleep over, sparing the spouse from waking every 3 hours to turn the patient.
[edit] Frustration and Boredom.
Family and volunteers can be mobilized from neighborhood groups, such as church or social groups, to visit to talk, listen, play cards, turn pages or read, or just to be there for a while. Occupational therapists can advise on a number of communications aids.
[edit] Motility and Posture.
Occupational therapy assessment can be arranged for the home environment, providing rails, hoists, or supports; eliminating stairs where possible; and advising on helpful devices for feeding, shaving, dressing, recreation, and ambulation. Posture may be improved with a collar, a brace, or spring-loaded splints.
[edit] Leg Swelling.
The legs should be elevated, and elastic stockings used if leg swelling is a problem. Avoid using diuretics for leg swelling.
[edit] Cachexia.
As mentioned, swallowing can be improved, but a nasogastric tube may become necessary when weakness and atrophy advance. Gastrotomy can be used but often just adds misery to the last days of the patient.
[edit] Constipation.
Constipation is due to weak abdominal muscles and reduced activity. Bulk purgatives, laxatives, and enemas are helpful. Avoid manual evacuations if possible.
[edit] Sexual Frustration.
Sexual frustration is common and is not often discussed. The clinician should do so freely and without embarrassment with both the patient and spouse; the problems are mainly matters of method. The partner may need counseling to understand that he or she needs to take the active role and to learn effective techniques that overcome weakness and muscle spasms.
[edit] Pneumonia.
Respiratory infections become a risk as chest movement is restricted and the patient is bedridden. Treatment is as for any patient, but there comes a time when this may fail because of the respiratory failure.
[edit] Respiratory Failure.
When there are early signs of respiratory failure the patient may be made more comfortable, especially at night, by noninvasive positive pressure ventilation (NIPPV) methods such as bi-level positive air pressure (BiPAP). Tracheotomy and machine ventilation may become necessary. The clinician should not embark on measures that only prolong distress, unless the patient clearly wishes to prolong the course of the disease. With a tracheostomy and ventilator the patient may have a year of passive, uncommunicating existence, and that may be important to him or her, but many do not wish this. It is crucial to determine if the patient is willing to accept this state well before it occurs, by means of early discussions and by having a living will. The patient should appoint a trusted person to act with power of attorney on his or her behalf.
Management of problems such as these demands a team approach, but the team has to be led by someone who can identify the needs, prescribe for them, and coordinate their delivery. Ideally, that person should be a physician but a rehabilitation specialist is not always available. The patient's primary care physician is perhaps best of all for he or she is available, knows the family, and can properly take the responsibility for relieving the symptoms and suffering during the course of the disease. The primary care physician can comfort the patient to the end.
[edit] The Multidisciplinary Approach
The management of an ALS patient through the course of the disease requires many professionals with diverse backgrounds and skills, each bringing important components to the overall care (Table 170-1).
Table 170-1 Multidisciplinary Approach to ALS Care
| Problem | Approach |
|---|---|
| Weakness | Physical therapy |
| Exercise program | |
| Ambulation | Braces and walking aids |
| Battery-operated scooter or wheelchair | |
| Depression | Physician counseling |
| Antidepressants | |
| Psychiatrist or psychologist | |
| Family counseling | |
| Activities of daily living | Occupational therapist |
| Adaptive devices | |
| Home assistance | Home health aids |
| Health service agencies | |
| Swallowing difficulty | Swallowing evaluation |
| Speech pathologist or physical therapist | |
| Surgical gastrostomy | |
| Pulmonary failure | Periodic forced vital capacity measurement |
| Positive pressure ventilation | |
| Tracheostomy and ventilator | |
| Advanced directives | Durable power of attorney for health care |
| Living will | |
| Pain | Analgesics and physical therapy |
| Antispasticity agents |
At the outset the primary care physician should recognize that the patient has a progressing neurologic disease and refer the patient to a neurologist for confirmation of the diagnosis. The neurologist is responsible for the neurologic assessment and the EMG tests that confirm the diagnosis. The neurologist is often the best person to explain the diagnosis, the nature of the disease and its meaning to the life of the patient, and expectations for the future. The neurologist will usually administer the initial treatments, explain research on therapies, and explain the availability of any clinical trials. There may be a multidisciplinary ALS clinic in the area to begin to coordinate the care.
The nurse coordinator in the ALS clinic is usually responsible for coordinating care and involvement of other health professionals, but in other settings where such a clinic is not available the primary care physician usually is responsible for this role. Other professionals who are needed as the disease progresses are a physical therapist, an occupational therapist, a dietitian, a speech pathologist, and a social worker. Since the weakness affects pulmonary function, a pulmonologist becomes very important. A counselor and spiritual advisor may be needed, if wished by the patient and family, and early involvement is recommended in most instances.
[edit] End-of-Life Care
Every patient with ALS and their families have to come to grips with the many end-of-life decisions that confront them. These include the need to get the many events in life in order, come to terms with relationships, and decide how forthcoming disabilities will be handled. Should a ventilator be used if it just prolongs the inevitable? If it is used, will there be other decisions about how and who would discontinue the ventilator at the end? When nursing care increases, will care be at home or in a nursing facility? Should there be an advance directive? A living will? Power of attorney? Patients may raise the question of suicide or assisted suicide, and the physician should be comfortable not only talking about these issues but also calling on others who may have more expertise and experience in discussing these issues. It makes things more difficult for the patient and family if the physician avoids these sensitive areas and talks only about the disease and medical management.
Further information can be found at The ALS Association, 21021 Ventura Blvd, Suite 321, Woodlawn Hills, California 91364-2206, USA.
In addition, information on ALS resources can be found in the Cleveland Clinic ALS Care Manual, 1996; write to the ALS Coordinator, CCF—Department of Neurology, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
A group of acknowledged experts on ALS (Mitsumoto et al) prepared a state-of-the-art summary of ALS for the continuing education program of the American Academy of Neurology, which was extensively used in the preparation of this chapter. See Additional Readings for details.
[edit] ADDITIONAL READINGS
- BR Brooks: El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. J Neurol Sci 1994; 124 (suppl):96 - 107.
- H Mitsumoto FH Norris Amyotrophic lateral sclerosis: a comprehensive guide to management. New York: Demos Publications; 1994:
- H Mitsumoto, VA Cwik, H Neville,et al.: Motor neuron diseases: CONTINUUM. Am Acad Neurol 1997; 3:48 - 77.
- H Mitsumoto, DA Chad, EP Pioro: Amyotrophic lateral sclerosis Philadelphia: F.A. Davis Co.; 1996:
- Rowland LP Amyotrophic lateral sclerosis and other motor neuron diseases. New York: Raven Press; 1991:
- DB Williams, AJ Windebank: Motor neuron disease (amyotrophic lateral sclerosis). Mayo Clin Proc 1991; 66:54 - 82.
- EC Yuen, WC Mobley: Therapeutic potential of neurotrophic factors for neurological disorders. Ann Neurol 1996; 40:346 - 354.
