Introduction to ALS

Amyotrophic Lateral Sclerosis (ALS): The Diagnosis and Treatment of this Debilitating Disease

Article originally published in Geriatrics and Aging
Originally published in: Volume 3, Number 9, November 2000, Pages 26, 27

In 1869, french neurologist Jean-Martin Charcot first described a rapidly progressive, fatal neuromuscular disease. This disease, amyotrophic lateral sclerosis, or Lou-Gehrig's disease, is a neurodegenerative disorder that affects the patient's motor neurons; typically the patient is paralyzed or deceased within 2 to 5 years of the initial diagnosis. Currently, approximately 3000 Canadians suffer from this tragic disease.

Andrew Eisen MD, FRCPC
Professor and Head, Division of
Neurology, University of British Columbia,
Head of the Neuromuscular Diseases Unit,
Vancouver General Hospital

Amyotrophic lateral sclerosis (ALS) is a prototypic neurodegeneration of the aging nervous system. It has a worldwide incidence of about 2 per 100,000 members of the population and a prevalence of 4&endash;7 per 100,000. As is true of both Parkinson's and Alzheimer's disease, the incidence of ALS is increasing proportional to the increasing longevity of the population. Information regarding the specific incidence of ALS in the elderly (aged 75 years and older) is sparse. The apparent decrease in incidence of this disease in patients older than 70 years reflects mortality from competing diseases in later life.

The etiopathogenesis of ALS is complex and multi-factorial. To gain insight into this complex disease, the physician must understand the genetics of normal aging, the mechanisms that determine selective neuronal vulnerability, the molecular biology of cellular demise and the environmental factors that potentially contribute to its development. Aging is associated with the formation of free radicals that cause injury to mitochondrial DNA (mtDNA). This injury is greatest in cells, such as neurons, that are irreversibly differentiated. The neurons that are particularly susceptible are those that utilize high levels of oxygen: Examples of these include the corticomotoneurons in the brain and the anterior horn cells in the spinal cord, both of which are selectively involved in ALS.

About 5-10 % of the cases of ALS are hereditary and about 20% of these have a mutation of the superoxide-dismutase (SOD1) gene. Other candidate genes relevant to ALS are actively being sought and include genes that are involved in the assembly of neurofilaments and in the transport of glutamate.

Presently, there is no specific biological marker for ALS and the diagnosis depends upon the recognition of a characteristic clinical constellation that is supported by electrophysiological findings. The recently developed El Escorial criteria are used to classify the diagnosis of ALS as possible, probable or definite. A middle aged patient who presents with a combination of painless and progressive, but asymmetrical, muscle weakness with wasting, fasciculation (and cramps), in a multimyotomal distribution that is associated with upper motor neuron signs, a normal sensory examination, and normal sphincter and ocular function, almost always has ALS. Similar signs and symptoms may result from a cervical cord syndrome; therefore, the physician must exclude other possible causes, which include syringomyelia, arteriovenous malformations, spinal cord tumour and cervical spondylotic myelopathy. The last disorder is by far the most common and can cause difficulties with diagnosis, as some degree of degenerative disc disease invariably occurs with this disease at an age when ALS has its greatest frequency.

Free Radical Damage to Motor Neurons
Reactive oxygen species (ROS), or free radicals, are generated as a result of metabolic processes. These free radicals have at least one unpaired electron, which renders them chemically unstable and highly reactive with other molecules in the body. Mitochondrial DNA (mtDNA) is located near the inner mitochondrial membrane, and lacks advanced DNA repair mechanisms, making mtDNA particularly susceptible to damage from ROS. Cells respond to oxidative damage by neutralizing free radicals through antioxidant enzymes, such as superoxide dismutase (SOD) and catalase. Eventually, damage accumulates due to the inability of cells to repair damage as quickly as it arises.

Differential Diagnosis of ALS
To confirm a diagnosis of ALS, electromyography, which includes conduction studies of various types, needle EMG, and tests that employ transcranial magnetic stimulation of the motor cortex, are very helpful. Nerve conduction studies are essential to exclude some of the disorders that mimic ALS but which have a better prognosis or are treatable. Examples of 'mimicking' disorders include motor neuropathy with conduction block and Kennedy's syndrome. In ALS, the needle EMG is frequently abnormal in clinically strong limbs that also have normal muscle bulk. As 58% of anterior horn cells can be lost before weakness or muscle wasting occur, the demonstration of abnormalities in strong muscles can help to identify widespread disease. Needle EMG is also helpful for the documentation of early diaphragmatic disease, which may be an indication for instituting bimodal passive airway pressure (BIPAP).

Multifocal motor neuropathy
A diagnosis of multifocal motor neuropathy with persistent conduction block [MMN] can only be confirmed through the use of motor conduction studies. It is similar to ALS in that it affects patients in the same age range, and it predominantly affects males. Clinical evaluations will reveal that the weak or paretic limb is usually of normal muscle bulk, but fasciculations (and cramping) are frequent. Two major features can be used to distinguish this disease from ALS: Fasciculations in the weak or paretic limb are in a peripheral nerve distribution and not in a myotomal distribution as is the case in ALS. In addition, in multifocal motor neuropathy the tendon reflexes in the weak limb are usually depressed, whereas in ALS they are often increased. In some cases of motor neuropathy with conduction block, magnetic resonance imaging (MRI) can be used to visualize the thickening of the brachial plexus.

Kennedy's disease
Patients with Kennedy's disease [spino- bulbar muscular atrophy] also suffer from symptoms that closely resemble those of ALS. Fasciculation is often profuse, and bulbar muscles are involved. However, this disease is sex linked and only affects the lower motor neuron. Clinical clues to Kennedy's syndrome are the absence of reflexes, the symmetry of the neurological deficit and the presence of gynaecomastia. In Kennedy's disease, sensory nerve action potentials are distinctive in that they are either very small or absent. A mutation of the androgen receptor gene linked to chromosome Xq21-22 is specific for this disorder.

Other similar presentations
Several other clinical clues should raise the concern that a patient does not have ALS. These include symmetrical wasting and weakness of the muscles, and symmetrical depression, or loss, of deep tendon reflexes with associated weakness. Inclusion body myositis (IBM), or less frequently painless polymyositis, are both associated with diffuse muscle weakness and variable wasting, which occurs most frequently in elderly patients. Chronic inflammatory demylinating polyneuropathy (CIPD) is also often painless and lacks significant sensory abnormalities. Deep tendon reflexes are diffusely absent.

Diagnosis of ALS
Upper motor neuron deficit is essential for the diagnosis of ALS but can be difficult to determine, particularly in a weak and wasted limb. There is a need to develop adequate methodology that can verify the presence of the upper motoneuron component in ALS. Such techniques are becoming available and include functional magnetic resonance imaging (fMRI), imaging with positron emission tomography [PET1] and magnetic resonance spectroscopy [1HMRS]. These techniques have demonstrated that the cortical abnormalities in ALS extend beyond the motor cortex. Various neurophysiologic methods employing transcranial magnetic stimulation (TMS) indicate that the motor cortex is hyper-excitable early in the course of ALS. This is probably related to glutamate toxicity.

Several clinical features are inconsistent with a diagnosis of ALS, including sensory dysfunction, sphincter impairment, autonomic dysfunction, abnormalities of eye movements, movement disorders and cognitive dysfunction. However, there are well-documented cases of patients with ALS having one or more of these "exceptions". An interesting example is that of bladder dysfunction, which is phenotypically characteristic of the aspartate to alanine mutation (D90A) mutation of the Cu/Zn SOD1. Overt clinical dementia occurs in less than 5% of ALS patients but, using formal psychometric testing, as many as 35% of patients show some evidence of cognitive impairment. Neuropsychological testing, imaging studies and neuropathological data, indicate that the dementia associated with ALS is typically of the "frontal lobe type", and differs from Alzheimer's dementia.

TABLE 1 Presenting complaints of ALS (listed in approximate order of their frequency)

Clumsy hand Hoarse voice (dysarthria) Shoulder dysfunction Weak foot (foot drop) Difficulty walking (spastic gait) Exercise intolerance Fasciculation Respiratory insufficiency Cognitive impairment

The presenting clinical features of ALS are readily misinterpreted [see table 1]. Some early symptoms may be ignored in elderly and frail subjects, as they may incorrectly be considered a manifestation of normal aging. Examples include exercise intolerance, a weak voice, decreasing respiratory reserve, walking difficulty, and clumsiness of hand function.

Primary lateral sclerosis (PLS) predominantly affects the upper motor neuron, presenting with slowly progressive spinobulbar spasticity. Histopathology reveals the exclusive loss of precentral pyramidal neurons that predominantly affect the large pyramidal Betz cells in layer V, and degeneration of the secondary pyramidal tract. The nosological status of PLS and its relationship to ALS is uncertain, but the general consensus is that PLS represents one end of the spectrum of ALS. This is exemplified by descriptions of classical ALS developing many years after the onset of PLS.

Management of ALS
Numerous clinical trials in ALS have been undertaken over the last decade, but only the drug rilutek, a glutamate antagonist, has been formally approved for its treatment. Recommended dosage is 50 mg twice daily, and this results in a modest retardation of the disease progression. It is doubtful that a single agent will ever be able to arrest further neuronal loss and promote regeneration in ALS. Therapeutic success will most likely result from a combination of medications. Poly-therapies might include the use of glutamate antagonists, antioxidants (particularly those that protect mitochondrial repair systems), anti-apoptotic agents, conventional and less conventional growth factors such as the immunophillins, agents that promote neurofilamentous integrity, and finally, anti-inflammatories. Each one of these drugs combats a different aspect of the terminal cascade of events in ALS.

Alleviation of the symptoms and other supportive measures are imperative in the treatment of ALS. This is best achieved through a multi-disciplinary team approach. To improve the patient's quality of life, expertise is required in respiratory function, nutrition, and rehabilitative and occupational measures. In addition, social work and counseling are important, especially with regards to end-of-life decisions. In North America, the use of bimodal passive airway pressure (BIPAP), which actively assists the inspiratory phase of respiration, is rapidly becoming standard care for ALS patients. Most patients develop confidence with the use of this device within a short period of time. Another commonplace therapy is enteral nutrition delivered via percutaneous endoscopically placed gastrostomy (PEG). If they are commenced in a timely fashion, both PEG and BIPAP are associated with a significant increase in the survival of patients with ALS. Excessive salivation and thickened mucous are major problems for patients suffering from ALS. Increased salivation can be treated by use of a transdermal patch containing scopolamine, which is applied twice weekly. A recent unpublished trial, which investigated the effects of small dose radiation on the submandibular glands in 18 ALS patients with excessive salivation, noted that 11 of these had more than 3 months of marked relief [Eisen personal communication]. A home suction machine is usually required when excess salivation is more persistent.

Thickened mucous is less frequently a problem and can be managed by use of a mucolytic agent, such as mucomyst, in a dose of 1-2 cc twice daily.

Summary
ALS is a complex, multi-factorial disease. It is likely that multiple genes are involved in its pathogenesis. This makes treatment of the disease difficult, but fortunately, also widens the possibilities for developing an appropriate therapy. Currently, the need for polytherapy to alleviate the symptoms of patients who suffer from ALS is fully recognized, and research efforts are being directed at trials using potentially useful drug combinations. It can be anticipated that the impact of this approach will result in increased longevity, and an improvement in the quality of life, for those who are stricken with this disease.

Further reading

1. Andersen PM, Forsgren L, Binzer M, Nilsson P, et al., (1996). Autosomal recessive adult-onset amyotrophic lateral sclerosis associated with homozygosity for AsP90A1a CuZn-superoxide dismutase mutation: a clinical and genealogical study of 36 patients. Brain; 119:1153-1172.
2. Armon C, Kurland LT, Daube JR, O'Brien P (1991)., Epidemiologic correlates of sporadic amyotrophic lateral sclerosis. Neurology; 41:1077-1084.
3. Bensimon G, Lacombiez L, Meininger V, and the ALS/Riluzole Study Group., (1994). A controlled trial of riluzole in amyotrophic lateral sclerosis. NEJM;330:585-591.
4. Bolton CF, Grand'maison F, Parkes A, Shkrum M., (1992). Needle electromyography of the diaphragm. Muscle & Nerve;15:678-681.
5. Bouche P, Moulonguet A,Younes-Chennoufi AB, et al., (1995). Multifocal motor neuropathy with conduction block: a study of 24 patients. J Neurol Neurosurg Psychiatry;59:38-44.
6. Brown RH Jr., (1996).Superoxide dismutase and familial amyotrophic lateral sclerosis: New insights into mechanisms and treatments. Ann. Neurol. 39: 145-146.
7. Brooks BR., (1994). World Federation of Neurology Sub Committee on Neuromuscular Diseases. El Escorial criteria for the diagnosis of amyotrophic lateral sclerosis J Neurol Sci;124 Suppl:96-107.
8. Chancellor AM, Hendry A, Caird FI, Warlow CP, Weir AI., (1993). Motor neuron disease: a disease of old age. Scottish Med J; 38:178-182.
9. Eisen A., (1995). Amyotrophic lateral sclerosis is a multifactorial disease. Muscle & Nerve;18:741-752.
10. Eisen A, Krieger C. Amyotrophic Lateral Slclerosis: A synthesis of Research and Clinical Practice. Cambridge University Press; 1998; pp303
11. Eisen A, Weber M. Treatment of amyotrophic lateral sclerosis. Drugs & Aging 1999; 14:173-196.
12. Eisen A. Motor neurone disease (amyotrophic lateral sclerosis) In: OXFORD TEXTBOOK OF GERIATRIC MEDICINE Evans JG, Williams TF, Beattie BL, Michel J-P, Wilcock GK (Eds); Oxford University Press, 2000, pp 789-797.
13. Hopkins LC, Tatarian GT, Pianta TF., (1996). Management of ALS: Respiratory care. Neurology; 47(Suppl 2):S123-S125.
14. Kasarskis EJ, Neville HE., (1996). Management of ALS: Nutritional care. Neurology; 47(Suppl 2):S118-S120.
15. Lacomblez L, Bensimon G, Leigh PN, Guillet P, Meinninger V and the ALS/Riluzole Study group-II., (1996). A dose-ranging study of riluzole in amyotrophic lateral sclerosis. Lancet; 347:1425-1431.
16. Leigh PN., (1994). Pathogenic mechanisms in amyotrophic lateral sclerosis and other motor neuron disorders. In:Neurodegenerative Diseases, Calne DB (Ed), WB Saunders Co;pp473-488.
17. Lillienfeld DE, Chan E, Ehland J, et al., (1989). Rising mortiality from motoneuron disease in the USA, 1982-84. Lancet;1:710-712.
18. Radunovic A, Leigh PN., (1996). Cu/Zn superoxide dismutase gene mutations in amyotrophic lateral sclerosis: correlation between genotype and clinical features. J Neurol Neurosurg Psychiatry; 61:565-572.