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Amyotrophic Lateral Sclerosis: Current Understanding.

It was the eminent French neurologist Charcot who first described motor neuron disease (MND) in 1874 (Swash, 2000). Since his thorough and valid description, MND, or amyotrophic lateral sclerosis (ALS) as he termed it, remains an enigma (Mitsumoto, 1994). It is a degenerative disorder of the upper and lower motor neurons. Muscular weakness, atrophy, and corticospinal tract signs resulting from degeneration of the motor neurons in the spinal cord, brainstem, and cerebral cortex are the characteristic features of the disease (Rowland, 1982). The terms ALS and MND are often used interchangeably.

The term motor neuron disease was introduced by Brain (1962) in recognition of the relationship between progressive muscular atrophy, amyotrophic lateral sclerosis, and progressive bulbar palsy, as shown by the differing patterns of involvement of upper and lower motor neurons and muscle wasting in these syndromes (Swash, 2000; Swash & Desai, 2000). This term MND has become commonly used in the United Kingdom, while ALS is the preferred term in other European countries and the United States (Rowland, 1982).

Idiopathic MND is sometimes used to describe all primary degenerative lower motor neuron and all upper motor neuron disorders (Swash, 2000). The term other motor neuron diseases describes those disorders that share a clinical association and mimic the syndrome (Table 1). These disorders are sometimes viewed as a causative factor in the development of ALS (Swash & Schwartz, 1995). The most common of the motor neuron disease syndromes in adults, ALS results in degeneration of the nerve and tracts in the spinal cord. Degeneration is most severe in the motor fibers that maintain muscle tone and control the speed and precision of skilled movements such as dexterity (Tandan, 1994).
Table 1. The Motor Neuron Diseases

 Other Motor
Idiopathic Motor Neuron Diseases Neuron Diseases

Amyotrophic lateral sclerosis (ALS) Excitotoxin-induced
Progressive bulbar palsy (PBP) Western Pacific ALS
Primary lateral sclerosis (PLS) Lathyrism
Progressive muscular atrophy (PMA) Viral and immunological
Familial amyotrophic lateral sclerosis (FALS) Poliomyelitis
Juvenile amyotrophic lateral sclerosis Creutzfeldt-Jakob
Madras motor neuron disease disease
Monomelic motor neuron disease AIDS
 Post-encephalitis
 myelopathy
 Herpes zoster
 myelitis
 Other viruses
 System degeneration
 Spino-cerebellar
 degeneration
 Shy-Drager syndrome
 Olivoponto-cerebellar
 degeneration
 Joseph-Machado
 disease
 Huntington's disease
 Heavy metal poisoning
 Lead and other
 heavy metals
 Mercury
 Manganese
 Others
 Electric shock
 Lightning injuries
 Post-irradiation
 syndrome


ALS is a fatal progressive degenerative disease resulting in relentlessly progressive weakness and wasting of voluntary muscles, affecting a combination of the upper motor neurons in the motor cortex and the lower motor neurons in the brainstem and spinal cord. This combined loss of function in upper and lower motor neurons causes a mixture of spastic paralysis and flaccid muscular weakness and wasting (Campbell & Enderby, 1984). The disease process appears to spare the sensory, autonomic, and oculomotor neurons (Choi, 1992). Thus patients retain control of their bladder, bowels, and eye movements until late in the progress of the disease.

This article offers a comprehensive overview of ALS and discusses current information on the genetic and environmental factors associated with the disease, including the excitatory neurotransmitter glutamate and its role in the pathogenesis of ALS. Until recently the only treatment and management options available for ALS were symptomatic treatment. With the increase in knowledge of the mechanism of neuronal death and increasing research efforts, we have seen the emergence of the drug riluzole, the only disease-specific treatment to date that offers some hope to patients suffering from this devastating disease.

Incidence

It is estimated that ALS occurs at an annual rate of about 3 cases per 100,000 of the general population (Kondo, 1995). This incidence rate appears to be uniform throughout the world. As a heterogeneous problem, ALS can be subclassified into sporadic, familial, and endemic categories (Shibata et al., 1999). About 90% of ALS patients are classified as sporadic, while the rest are familial. Approximately 20% of familial ALS (FALS) cases are associated with mutations of the copper/zinc superoxide dismutase-1 gene (SOD-1) (Lyons, Gralla, & Valetine, 1999; Rosen et al., 1993). Superoxide dismutase is an antioxidative metallo-proteinase enzyme that catalyzes the reaction of the superoxide radical ([O.sub.2]) with the hydrogen anion (H+) to produce hydrogen peroxide ([H.sub.2][O.sub.2]) and molecular [O.sub.2] (Young & Penney, 1992). This gene is encoded on chromosome 21, and the SOD-1 mutation in FALS is inherited by autosomal dominant transmission (Anderson, 2000; Mulder, Kurland, Offord, & Beard, 1986). Other FALS subgroups have been described, as follows:

* Autosomal recessive, linked to chromosome 2q33-35 (Hantati et al., 1994)

* Autosomal dominant, linked to chromosome 9q34 (Chance et al., 1998)

* Autosomal recessive, linked to chromosome 15q12-21 (Hantati et al., 1997)

* Chromosome X-linked dominant (the genes encoded by these chromosomes have not yet been identified).

Clinical Features

ALS is a disease that usually affects adults, particularly those in the latter half of life (Bradley, 1994). The symptoms and signs are usually slowly progressive, advancing over months or years to produce weakness, cramping, fatigue, fasciculations in the limb and tongue muscles, dysarthria, dysphagia, and dyspnoea. About 40%-60% of ALS patients present with initial symptoms in an arm and about 20% in a leg (Tyler & Shefner, 1991). Difficulty performing fine tasks, such as buttoning shirts, or weakness when picking up objects or carrying heavy loads are common presenting complaints.

Others are gait disturbance, tripping when walking or running, difficulty negotiating curbs, dragging of a foot, difficulty climbing stairs, or getting out of chairs (Mitsumoto, 1997).

Bulbar symptoms may be the presenting symptoms, but more often develop during the course of the disease. Approximately 20%-25% of patients present with bulbar symptoms, including dysarthria, dysphagia, and drooling, or with complaints about their voice or tongue. The voice may be raspy hoarse or weak and may sound nasal (Belsh, 1996). Speech is often strained, slurred, and monotonous. The tongue movements are often slow with weak protrusion. Bulbar symptoms are a more common presenting feature in women than in men and are also more common in older patients. Of those who experience disease onset after 70 years of age, 34%-55% present with bulbar symptoms (Mitsumoto, 1997). Bulbar involvement leads to difficulty speaking and swallowing and is often closely correlated with weakness in respiratory muscles and reduced vital capacity (Swash, 2000).

Articulation and mastication become progressively impaired as the disease progresses. This severely disabling and embarrassing condition results from the lack of spontaneous automatic swallowing to clear saliva in the mouth; the amount of saliva secreted is not increased (Charchafflie, Fernandez, Perec, Gonzales, & Marzi, 1974; Goode & Smith, 1970). Impaired mastication and difficulty swallowing may result in aspiration of oral contents into the airway. Patients may be unable to complete the oral phase of swallowing, so that the bolus becomes pooled between the gums and cheeks. Liquids are especially difficult to swallow and may regurgitate through the nose. Eventually, attempting to swallow may trigger coughing. This may be a warning that serious swallowing difficulties are imminent. When the cough reflex is weakened by flaccid paralysis of the pharynx, larynx, and respiratory muscles, aspiration of food and saliva into the airway becomes inevitable (Mitsumoto, 1994).

The continuous physical deterioration involves a number of losses for the patient with ALS. These can best be described as loss of mobility, loss of occupation, loss of role in family, and loss of future.

As a result of these losses, the patient undergoes distinct psychological phases characterized by anxiety, shock, acknowledgment, reconciliation, and parting (Stylsvig et al., 2000). These symptoms need to be managed with a high degree of sensitivity and professionalism by the patient's care groups, because the disease is progressive and these disabilities worsen with time. The Aarhus University ALS Care group proposes an interdisciplinary-care model based on a close connection between physical symptoms and psychological conditions, because the timing-of-care provision is crucial if maximum benefits are to be received by patients (Stylsvig et al.).

Disease Onset

Disease onset is difficult to determine. Early clinical manifestations develop gradually, in what can be described as a preclinical phase, over several years (Swash & Ingram, 1988). ALS affects motor neurons in four different anatomic regions of the body: bulbar, cervical, thoracic, and lumbosacral. The bulbar region includes the jaw, face palate, tongue and larynx, all of which are controlled by the lower cranial nerves. The cervical region includes the neck, arms, hands, and diaphragm. The thoracic region includes the back and abdomen, and the lumbosacral region includes the lower back, buttocks, legs, and feet.

The site of onset is generally classified as limb or bulbar and is an important determinant in survival. Bulbar involvement implies a poor prognosis and shorter life expectancy, but limb onset has a better outcome. Those who present with bulbar symptoms tend to die earlier than those who initially presented with limb onset. Patients whose initial presentation was weakness of respiratory muscles have the worst prognosis (Louwerse, Visser, Bossuyt, Weverling, & The Netherlands ALS Consortium, 1997). Patients with predominant upper limb or bulbar involvement often have weak respiratory muscles. The cough is weak and the ability to sniff vigorously is reduced (Swash, 2000). This results in breathlessness on minimal exertion, especially when there is weakness of the diaphragm. Poor nocturnal sleep, excessive daytime sleepiness, headache on awakening, and excessive nocturnal sweating are features of early respiratory failure.

Risk Factors

The role of environmental factors contributing to or influencing the etiology of ALS has been a controversial issue since the disease was first described in the 19th century (Mitchell, 2000). Several associated risk factors for ALS have been postulated. In a study by Gunarsson, Bodin, Soderfeldt, & Axelson (1992), patients with ALS had more exposure to welding and soldering than controls. The inhalation of lead vapor was suggested as a potential risk factor. Agricultural employment and exposure to chemicals also might be important. Several studies suggest an association with ALS (Choi, 1992; Gunnarsson, Lygner, Veiga-Cabo, & de Pedro-Questa, 1996; Holloway & Emery, 1982; Rosati et al., 1977). However, this association was evident only among male patients. Electrical trauma also has been suggested as a cause in a few cases. However, it is clear that electrical injury does not induce a true progressive motor neuron disease syndrome (Mitchell, 2000).

Age, sex, and mechanical injuries are the three most common risk factors that play a role in disease development (Kondo, 1995). Age is the strongest known risk factor in both sexes. The incidence rates rise sharply from about age 50 to 80 years. The reasons for this trend are still unknown. However, the aging process is assumed to be a factor in all neurodegenerative conditions (Kondo, 1995). Gender is a particular factor in ALS, because there is a striking male predominance that is unique among the neurodegenerative diseases. The number of men developing the disease is 1.5 times higher than that for women. The reasons for this are unknown. One reason may be that men are more likely to sustain physical injury, another suspected risk factor for ALS (Kondo, 1995).

Pathogenesis

The cause of ALS is unknown, but there is evidence that excitotoxic damage to the motor neurons may play an important role in the disease pathogenesis (Choi, 1992; Rothstein, 1995; Shaw, 1994). Glutamate concentration is elevated in the blood and cerebrospinal fluid of many patients with ALS (O'Brien & Fischbach, 1986; Plaitakis, Constantakakis, & Smith, 1988), and the excitatory neurotransmitter glutamate appears to plays a role in its pathogenesis. This may be due to a defect in transport proteins, because glutamate transport is selectively impaired in motor areas of the brain and spinal cord in patients with ALS (Rothstein, 1995, 1996; Rothstein, Martin, & Kuncl, 1992; Rothstein et al., 1995). There is the possibility that multiple insults may lead to a common pathway of motor neuron death. However, other investigators have found that abnormalities in glutamate transporter protein activity are not unique to ALS (Choi, 1992; Ince, Eggett, & Shaw, 1997; Tyler & Shefner, 1991).

The normal process of glutamatergic neurotransmission involves the release of glutamate from presynaptic neuronal terminals and activation of receptors on the postsynaptic membranes. The excitatory signal is terminated by active removal of glutamate from the synaptic cleft by several types of glutamate reuptake transporter proteins, which are located on both neurons and perisynaptic astrocytes (Ince, Eggett, & Shaw, 1997). Glutamate, released into the synaptic deft, can stimulate a number of postsynaptic receptors before being actively removed by glutamate transporters located on glial cells. In the glial cells, glutamate is converted to glutamine by the enzyme glutamine synthetase and returned to the presynaptic neuron where glutaminase converts glutamine back to glutamate (Laake, Slyngstad, Haug, & Ottersen, 1995). The binding of glutamate to calcium causes the glutamate receptors to open their calcium channels, thus allowing an influx of calcium into the cytosol (Rothstein, Martin, & Kuncl, 1992). This elevated cytosol calcium concentration is considered part of the mechanism of cell death in ALS.

Glutamic acid is the major excitatory neurotransmitter in the brain and accounts for approximately one-third of all rapid excitatory synapses in the central nervous system. Glutamatergic input to motor neurons comes from the descending corticospinal pathways (Young & Penney, 1992; Young, Penney, Dauth, Bromberg, & Gilman, 1983) and from the spinal cord excitatory interneurons (O'Brien & Fischback, 1986). Glutamic acid released from glutamatergic nerve terminals in response to depolarization crosses the synaptic cleft and acts on postsynaptic receptors. This physiologic process is part of the normal neurotransmitter function of glutamate in rapid, excitatory synaptic transmission. This function may be impaired in ALS. Under certain conditions a high concentration of glutamic acid can accumulate in the synaptic cleft and trigger an excitatory process (Meldrum & Garthwaite, 1990; Young et al., 1983). This results in excessive stimulation of excitatory amino acid receptors on the postsynaptic cell membrane and leads to excessive entry of sodium and calcium ions into the cell, causing a disturbance in ionic homeostasis.

Management and Treatment of ALS

There is no known cure for ALS. Management should be focused on providing comprehensive and holistic care, with a view to maintaining the patient's functional independence for as long as possible (Gutmann & Mitsumoto, 1996). The drug riluzole has demonstrated neuroprotective effects in ALS and is the only disease-specific treatment available to date. Riluzole has been approved by the National Institute for Clinical Excellence in the United Kingdom for use in the treatment of ALS, and it is recommended that it be made available to all patients with the disease deemed likely to benefit from it by their neurologist. The recommended adult dose is 50 mg twice a day. In two randomized placebo-controlled, doubleblind trials, riluzole showed the ability to slow the rate of deterioration in muscle strength and increase the survival rate in patients with ALS. In a number of experimental models of excitotoxic and degenerative motor neuron diseases, riluzole has inhibited the presynaptic release of glutamate and reduced the extent of neuronal damage (Estevez, Stutzmann, & Barbeito, 1995; Herbert et al., 1994; Neatherlin, 1998).

ALS is a complex disease in which neurons are subjected to a variety of insults, for example, from genetic mutations, unidentified environmental factors, and glutamate excitotoxicity. A combination of these thus far largely unrecognized factors makes it unlikely that a single therapeutic compound will be used to treat the disease. A cocktail of therapeutic agents, yet to be formulated, may have to be employed to combat the disease. This combination might include antiglutamate preparations, antioxidants, and a variety of neurotrophic factors (Eisen & Weber, 1999). Some therapeutic agents in these classes, for example, gabapentin, neurotrophic factors, and antioxidants, have been tested in clinical trials in patients with ALS, but the results have not been encouraging. For example, gabapentin, a drug with antiepileptic and antiglutamate properties, showed neuroprotective effects in aminal models of ALS (Gurney et al., 1999). However, this positive effect was not significant in patients with ALS (Shaw, 1999).

The use of neurotrophic factors as therapeutic agents to prevent neuronal cell atrophy and death in neurodegenerative diseases, such as Parkinson's disease (PD), Huntington's disease (HD), and ALS, is a novel approach. Neurotrophic factors have the potential to protect diseased and injured neurons from dying, induce neuronal sprouting, and increase neuronal metabolism and function (Connor & Dragunow, 1998). Neurotrophic factors are polypeptides that interact with specific cellular receptors leading to biological responses, including proliferation, differentiation, and changes in cell motility and structure. They promote survival of neurons (Semkova & Kreiglstein, 1999). Neurotrophic factors can protect neurons under acute conditions (Bohn, 1999). Decreased neurotrophic support for neurons is associated with neuronal death and, perhaps, the appearance of neurodegenerative diseases.

Nerve growth factor (NGF) is of special interest in neurodegenerative diseases because of its neuroprotective properties. It is thought to promote survival of motor neurons (Altman, 1992; Oppenheim, 1991; Shaw, 1999). The basis of neuroprotection is to try to achieve long-term benefits for the patient, such as increased life expectancy and improved quality of life, by delaying the onset of major neurodegenerative symptoms. Several clinical trials involving NGF have been conducted with discouraging results. Their therapeutic administration appears to be complicated because of their chemical properties. Neurotrophic factors are large protein molecules that cannot easily cross the blood brain barrier and do not distribute normally after systemic administration (Semkova & Kreiglstein, 1999). The main problem is finding a route of administration for NGF that reaches motor neurons in sufficient concentration to exert therapeutic effect (Shaw).

Alternative Treatments

There are numerous examples of unorthodox treatment regimes for ALS, ranging from megadose vitamin treatment, pancreatic enzymes, wheat germ, snake venom, to bee pollen. These approaches are costly and have not been uniformly studied. Their use may have a negative emotional effect on patients and their families and can seriously deplete financial resources (Glasberg, 1994). Because of the nature of the disease and the fear and hopelessness it generates in its victims, all claims of successful therapeutic intervention must be based on objective scientific assessment, rather than on anecdote. The use of antioxidants has widely been advocated on an experimental basis as an alternative form of treatment for delaying the onset of symptoms of ALS. While approaches like these have not proven to be of benefit to patients, they may offer support, encouragement, and hope in an otherwise bleak situation for patients (Swash & Schwartz, 1995).

Symptomatic Treatment

Management of ALS is mainly symptomatic, and because the disease is progressive, this symptomatic management must be ongoing and reviewed at intervals to ensure appropriateness of treatment. Symptoms include weakness, fatigue, cramps, spasms, spasticity, sleep disturbance, sialorrhea, laryngospasm, jaw quivering, and clenching, gastroesophageal reflux, nasal congestion, constipation, depression, anxiety, dysphagia, dysarthia, and dyspnea. Each problem can be actively treated. Table 2 provides a list of commonly use medication for specific symptoms of ALS.
Table 2. Commonly Used Medications for Symptomatic Treatment in ALS

 Treatment

 Symptom Drug

Anxiety or agitation Lorazepam
Cramp, spasm Baclofen
 Intrathecal baclofen
 Tizanidine

Depression or anxiety Sertraline
 Fluoxetine
 Paroxetine

Dyspnea Bupropion
 Morphine sulphate elixir, 20 mg/ml

Excessive crying or laughing Amitriptyline
 Fluoxetine
 Paroxetine

Jaw quivering or jaw clenching Clonazepam
 Diazepam
 Lorazepam

Laryngospasm Clonazepam
 Diazepam
 Lorazepam

Nausea Prochloperazine

Terminal management Lorazepam
 Morphine sulphate elixir 20 mg/ml
 Morphine via subcutaneous pump
 Bolus

Pain Ibuprofen
 Morphine sulphate elixir 20 mg/ml

Sleep disturbance Amtriptyline
 Sertraline
 Temazepam
 Zolpidem
 Trazodone

Sialorrhea Amitriptyline
 Glycopyrrolate
 Scopalamine

Urinary urgency/frequency Oxybutynin

 Treatment

 Symptom Dosage

Anxiety or agitation 0.5-3 mg t.i.d. p.r.n.
Cramp, spasm 10-20 mg q.i.d. p.r.n.

 slow increase to 8 mg t.i.d

Depression or anxiety 50-100 mg at night
 10-40 mg each morning
 10-40 mg at night

Dyspnea 100-150 mg b.i.d.
 0.5-2 mg dose

Excessive crying or laughing 10-75 mg daily
 10-40 mg daily
 10-40 mg daily

Jaw quivering or jaw clenching 0.5 mg t.i.d. p.r.n.
 2.5-5 mg b.i.d.-q.i.d. p.r.n.
 0.5-1 mg, 8 hourly p.r.n.

Laryngospasm 0.5 mg
 2.5-5 mg b.i.d.-q.i.d. p.r.n.
 0.5-1.0 mg p.r.n.

Nausea 5-10 mg t.i.d. p.r.n.

Terminal management 1-3 mg t.i.d.
 0.5-2 mg dose
 1-5 mg/hr
 0.5-2 mg every 15 min t.i.d.

Pain 200-800 mg
 0.5-2 mg

Sleep disturbance 25-75 mg at bedtime
 50-100 mg at bedtime
 7.5-30 mg at bedtime
 5-10 mg at bedtime
 50 mg at bedtime

Sialorrhea 10-25 mg t.i.d. p.r.n.
 1-2 mg q.i.d. p.r.n.
 0.125 mg t.i.d. p.r.n.

Urinary urgency/frequency 5 mg daily or t.i.d. p.r.n.


ALS challenges a person's ability to control his or her body and maintain independence. Symptom management should aim at providing comfort and dignity for patients who will find themselves having to unlearn personal control and return to a state of almost complete dependence as the disease progresses.

Weakness

The most common presentation of ALS, occurring in approximately 40% of patients, is progressive weakness and wasting of muscles of an upper limb, usually commencing in the hand. The muscles of the thenar eminence are commonly involved with loss of abduction and opposition of the thumb (Campbell & Enderby, 1984). This causes impairment of pinch grip between thumb and index finger, resulting in loss of fine finger control. The patient experiences difficulty in picking up small objects and in dressing, especially in buttoning clothing. There is also difficulty in writing with the dominant hand. As the disease progresses and these difficulties worsen, the patient loses the ability to use his or her hands and becomes completely dependent on others to perform the most basic activities of daily living.

A rehabilitation specialist may actively pursue compensatory methods to maximize function at all stages of the disease. Devices should be versatile enough to be adapted for long-term use and to perform more complex function as the disease progresses. For example, introducing assist devices early during the course of the disease allows patients time to become familiar with them. Occupational therapists can provide assistive devices tailored to meet individual needs that maintain independence with activities of daily living, such as dressing feeding, transferring, and maintaining hygiene (Giagheddu et al., 1983).

The physiotherapist must become involved at the earliest possible stage to maintain muscle integrity. Patients should be taught exercises to maintain the full range of motion and to minimize contractures and joint pain. Physiotherapists and occupational therapists are invaluable in assessing and teaching transfer techniques that maximize safety and enhance confidence for both patient and carers. Falls are frequent occurrences among ALS patients and can affect a patient's confidence. Walkers can compensate for weakened trunk and leg muscles, help prevent falls, and permit continued ambulation. Manual and motorized wheelchairs will continue to provide ambulation when walkers are no longer useful. Wheelchairs must be adapted to suit a patient's specific needs and provided early before limb weakness and muscle wasting ensue to give patients time to develop familiarity. The wheelchair should be equipped with a head support, reclining back, gel air cushions, adjustable arm supports, and a variety of controls to provide independence at home.

Muscle Cramps and Fatigue

As motor neurons die, the remaining neurons are burdened with the extra workload of sending signals to activate the muscle fibers in enlarged motor units formed by terminal axonal sprouting. This overburdens motor neurons, leading to muscle fatigue and exhaustion--a common feature of ALS. Patients should be encouraged to pace themselves in a manner to avoid exhaustion and conserve energy.

Cramps are caused by a brief contraction of a weakened muscle as a result of an explosive overactivity of motor nerves or of the muscle fibers themselves. They can be extremely painful and can interfere with activities such as walking. The management of cramps should include the avoidance of strenuous exercise and over exertion of weakened muscles. Stretching of the muscle can be effective in eliminating cramps. In severe cases medication can be used to alleviate the symptoms. Drugs such as quinine sulfate, dantrolene, clonazepam, lorazepam, diphenyhydantoin, and gabapentin are sometimes prescribed. Often, however, a simple drink of tonic water, which contains quinine, is a useful remedy.

Insomnia and Dyspnea

Sleep disturbance is a common occurrence in ALS that can lead to depression, fatigue, and anxiety (Giagheddu et al., 1983). Obstructive apnea, hypopnea, and an increase in airway resistance are factors that can lead to insomnia in ALS. Positioning in bed is important in ALS management. Patients often find the position that is most comfortable, but as a general rule, especially for patients with bulbar and respiratory involvement, sleeping with the head of the bed elevated is recommended. This helps prevent periodic upper airway obstruction and aspiration of saliva during sleep and also helps to prevent microarousals due to hypoventilation (Glasberg, 1984; Guilleminault et al., 1992). These disturbances in sleep patterns can result in daytime fatigue. Many patients find sleeping medication useful.

Dyspnea may have many causes in ALS; reversible causes must always be sought and treated where appropriate (Giagheddu et al., 1983). Dyspea is due to ALS progression and chronic hypoventilation and tends to occur during sleep. Patients may complain of bad dreams and experience anxiety attacks and daytime sleepiness (Guilleminault et al., 1992). Chronic nighttime hypoventilation can be treated successfully in many patients by using nocturnal noninvasive ventilatory support (Schiffman & Belsh, 1989), such as mouth intermittent positive pressure ventillation or nasal intermittent positive pressure ventillation (Cazzoli & Oppenheimer, 1996). However, as patients become unable to tolerate face masks and manage upper airway secretions, more invasive methods such as tracheostomy should be discussed. Although the emotional costs of invasive ventilatory support are high, quality of life is reported as satisfactory (Cazzoli & Oppenhemer).

Dysphagia and Sialorrhea

Progressive weakness of the oropharyngeal muscles causes difficulty in drinking and swallowing. In addition, there is a loss of coordination of the tongue, which can cause difficulty in propelling solids and liquids around the mouth and then back toward the pharynx. Sialorrhea causes significant social stress and is of major importance to patients. Saliva production is actually decreased in patients with ALS (Charchafflie, Fernandez, Perec, Gonzales, & Marzi, 1974; Goode & Smith, 1970). The problem of excess saliva is therefore not a problem of overproduction but of decreased clearance (Chance et al., 1998). Saliva is not swallowed automatically, and repeated volitional swallowing is required to compensate for the lack of automatic action. Pooling of saliva and food particles into the pharynx may cause choking and carry the risk of aspiration of these secretions into the lungs, resulting in aspiration pneumonia.

When aspiration becomes a serious risk, dysphagia results in weight loss, or eating a meal becomes an additional cause of fatigue, a percutaneous endoscopic gastrostomy (PEG) should be considered. Patients may be inclined to avoid eating and drinking in an attempt to avoid the distress, and this further contributes to the patient's overall weight loss and weakness. A conservative approach includes finding an optimum feeding position and diet. Simple routines may be most effective in increasing confidence, facilitating nutrition, and reducing anxiety. The use of a PEG will resolve most of the patient's eating and drinking problems. However, some patients consider a PEG to be unnatural because it bypasses the taste aspect of a food. Nonetheless, there is no reason why a person with a PEG should not taste food even when he or she cannot swallow it.

For the control of excessive saliva, a wide range of anticholinergic drugs is available (Newall, Orser, & Hunt, 1996; Norris, Smith, & Denys, 1985; Schrank, Kostopoulos, & Jost, 2000). These can be administered orally, intramuscularly, in the form of dermal patches, or subcutaneously via a 24-hour pump, depending on the patient's choice and therapeutic effectiveness. The use of glycopyrulate, benstropine, transdermal hyocine, atropine, or amitriptyline for daytime and nighttime are recommended (Miller et al., 1999; Schrank, Kostopoulos, & Jost, 2000). Other techniques such as head positioning, reduction of spasticity, suctioning, and surgical transposition of the salivary duct to the back of the throat also are used to manage the secretions (Hewer, 1995). Some of these methods carry a high risk of failure because they have a tendency to thicken the secretions and cause further complications (Newall, Orser, & Hunt). More specialized techniques, such as the use of botulinum toxin injected into the parotid and submaxillary salivary glands (Bushara, 1997; Geiss et al., 2000), may provide more acceptable relief.

Prognosis/Mortality

ALS is a disease that brings a predictable decline in motor function. The disease inexorably progresses with increasing physical disability. This is accompanied by emotional and almost inevitable financial hardship. Sensory, autonomic, and oculomotor neurons are almost completely unaffected, while most aspects of mental function, especially personality and intellect, usually remain intact. Age and site of onset at diagnosis appear to be the most powerful predictors of survival. Prognosis worsens with advancing age. The prognosis is to an extent determined by the delay in diagnosis from the first symptom; in most countries this is about 1 year.

Patients who were diagnosed before 40 years of age or with limb onset presentation had a median survival of 5 years, compared to those older than 60 years of age, whose median survival was 1 year (Louwerse, Visser, Bossuyt, Weverling, & The Netherlands ALS Consortium, 1997). The median duration from diagnosis of ALS to death ranges from 1 to 3 years (Geiss et al., 2000; Norris, Shepherd, & Denys, 1993). Patients with bulbar symptoms tend to die earlier than limb onset patients. Patients with initial weakness in respiratory muscles without limb or bulbar symptoms had the worst prognosis--a median survival of only 2 months (Louwerse, Visser, Bossuyt, Weverling, & The Entherlands ALS Consortium). The most important cause of respiratory failure and hypoventilation is the loss of negative intrathoracic pressure, normally carried out by the diaphragm (DeCarvalho et al., 1996), and ALS patients progress to respiratory insufficiency and death as a result of weakness and fatigue of respiratory muscles. Because riluzole is probably most effective when given early in the course of the disease, early diagnosis is of paramount importance (Househam & Swash, 2000; Swash, 1998).

Summary

ALS is a fatal degenerative disease resulting in relentlessly progressive weakness and wasting of voluntary muscles, affecting a combination of the upper motor neurons in the motor cortex and the lower motor neurons in the brainstem and spinal cord. This combined loss of function causes a mixture of spastic paralysis and flaccid muscular weakness and wasting. ALS can be subclassified into sporadic, familial, and endemic categories. About 90% of ALS patients have the sporadic form, while the rest have FALS. Approximately 20% of familial cases are associated with mutations of the copper/zinc superoxide dismutase-1 gene (SOD-l). This gene is encoded on chromosome 21.

The cause of ALS is unknown. Several risk factors are thought to contribute to the etiology of ALS, including exposure to welding and sodering, exposure to agrochemicals, and electrical trauma. Excitotic damage to motor neurons by the excitatory neurotransmitter glutamate appears to play a role in its pathogenesis. The only disease-specific treatment available to date is riluzole, and the management of ALS remains mainly symptomatic. ALS is a complex disease in which neurons are subjected to a variety of insults. It may be that a cocktail of therapeutic agents, yet to be formulated, may have to be employed to combat this devastating disease.

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Questions or comments about this article may be directed to: Thompson Charles, RN MSc, Department of Neurology, The Royal London Hospital, Whitechapel, London E1 1BB, England. He is a research nurse at The Royal London Hospital.

Michael Swash, MD FRCP FRCPath, is a professor of neurology in the department of neurology, The Royal London Hospital.
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