eMedicine Specialties > Neurology > Neuromuscular Diseases

Amyotrophic Lateral Sclerosis

Carmel Armon, MD, MSc, MHS, Professor of Neurology, Tufts University School of Medicine; Chief, Division of Neurology, Baystate Medical Center

Updated: Jun 29, 2009

Introduction

Background

Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease of the motor neuron system. In its classic form, it affects motor neurons at 2 or more levels supplying multiple regions of the body. It affects lower motor neurons that reside in the anterior horn of the spinal cord and in the brain stem; corticospinal upper motor neurons that reside in the precentral gyrus; and, frequently, prefrontal motor neurons that are involved in planning or orchestrating the work of the upper and lower motor neurons.¹

Loss of lower motor neurons leads to progressive muscle weakness and wasting (atrophy). Loss of corticospinal upper motor neurons may produce stiffness (spasticity), abnormally active reflexes, and pathological reflexes. Loss of prefrontal neurons may result in special forms of cognitive impairment that include, most commonly, executive dysfunction, but may also include an altered awareness of social implications of an individual’s circumstances and, consequently, maladaptive social behaviors.² In its fully expressed forms, the prefrontal dysfunction meets established criteria for frontotemporal dementia.^3,4 See eMedicine article Frontotemporal Dementia.

The classic form of sporadic ALS usually starts as dysfunction or weakness in one part of the body and spreads gradually within that part and then to the rest of the body. Ventilatory failure results in death, on average, 3 years after the onset of focal weakness. ALS is also known as motor neurone disease (MND), Charcot’s disease, and Lou Gehrig disease.

The term classic amyotrophic lateral sclerosis is reserved for the form of disease that involves upper and lower motor neurons. If only lower motor neurons are involved, the disease is called progressive muscular atrophy (PMA). Although many patients with PMA have a course indistinguishable from that of classic ALS, others have a course that may be longer. When only upper motor neurons are involved, the disease is called primary lateral sclerosis (PLS). (See eMedicine article Primary Lateral Sclerosis.) The course of PLS is different from that of ALS, and is usually measured in decades. Rarely, the disease is restricted to bulbar muscles, and called progressive bulbar palsy (PBP). Most patients who present with initial involvement of bulbar muscles evolve to classic ALS.

Worldwide, ALS occurs sporadically in 90-95% of cases and with Mendelian patterns of heredity (familial ALS [FALS]) in 5-10% of cases. Most familial ALS is inherited in an autosomal dominant pattern.¹ Approximately 20% of cases with familial ALS are due to a mutation in the Cu, Zn superoxide dusmutase 1 (SOD1) gene; however, its phenotype is of lower motor neuron disease.⁵ More than 100 mutations in the SOD1 gene have been reported. In the United States, 50% of mutant SOD1 ALS patients have an alanine-to-valine mutation in codon 4 of the gene (A4V mutation); their survival is on average 12 months from disease onset.⁶

Three Western Pacific foci of increased incidence have been found in Guam, in western New Guinea, and in the Kii peninsula in Japan.¹

Pathophysiology

In 2006, ubiquinated inclusions containing pathologic forms of TAR DNA-binding protein-43 (TDP-43) were identified in the cytoplasm of motor neurons of patients with sporadic ALS and in a subset of patients with frontotemporal dementia.^7,8 TDP-43 is an RNA processing protein. It is normally found mainly in the nucleus. Shortly after their identification, TDP-43 positive inclusions were identified in patients with non-SOD1 FALS^9,10 , and mutations in the gene on chromosome 1 coding for TDP-43 were identified in patients with sporadic and familial ALS^{11,12,13,14,15,16} .

Mutations in the TDP-43 gene account for 5% of patients with FALS. TDP-43 inclusions have been found in more than 90% of patients with sporadic ALS, in patients with Guamanian parkinsonism-dementia complex¹⁷ and in patients with familial British dementia.¹⁸ A review of the continuum of multisystem TDP-43 proteinopathies concluded that the phenotypic expression is linked to the specific cells that are affected by the proteinopathy.¹⁹

In February of 2009, 2 groups^20,21 reported that mutations in the gene for another RNA processing protein, fused in sarcoma/translated in liposarcoma (FUS/TLS) (located on chromosome 16), cause ALS-6, an autosomal dominant form of FALS. Patients with the FUS/TLS mutations have cytoplasmic inclusions containing FUS/TLS but not TDP-43. Usually, FUS/TLS is concentrated in the nucleus. Mutations in FUS/TLS account for 4% of patients with FALS. These observations have placed derangements of RNA metabolism at the core of current thinking with regard to the pathophysiology of most types of ALS.

Prior to the recent observations implicating TDP-43 and FUS/TLS pathology in ALS, much of the information had been derived from studies in transgenic mice carrying the human SOD1 mutation.²² Mutant SOD1 exerts its effect through “gain of function” (ie, toxicity that is not related to loss of its natural activity). Oxidative damage, mitochondrial dysfunction, caspase-mediated cell death (apoptosis), defects in axonal transport, growth factor expression, glial cell pathology, and glutamate excitotoxicity may all mediate the pathways, causing cell death in ALS.²²

Inferences from animal models, including transgenic models of familial disease, to sporadic human disease are tenuous, at best. However, recognition of the role of glutamate excitotoxicity in sporadic disease and in animal models paved the way to the testing and approval of riluzole, the only treatment that has been shown to ameliorate the course of sporadic ALS, extending life by 2-3 months.^23,24

In contrast to these advances in understanding the pathophysiology of ALS, the mechanisms that lead to disease onset, which may be distinguished by use of term pathogenesis, remain unknown.

Assuming that the abnormal gene or gene product plays a role in triggering disease onset in FALS and may have a role in disease propagation is reasonable. However, having an abnormal gene is neither a necessary nor a sufficient condition for developing ALS since not all familial gene carriers develop the disease and the normalcy of these genes does not prevent development of sporadic ALS. Additional factors must be postulated to intervene between birth and disease onset even in patients with FALS who develop the disease, because the disease does not appear to start at birth. ALS should not be considered a single disease entity, but rather a clinical diagnosis for different pathophysiological cascades that share the common consequence that they cause preferential progressive loss of motor neurons.

Making the distinction between pathogenesis and pathophysiology matters because the mechanisms underlying each of these stages are probably different, and, therefore, interfering with those mechanisms likely requires different approaches. Prevention of ALS requires modifying or removing factors that are part of disease pathogenesis. A precondition is identifying probable risk factors for ALS.²⁵  Mechanism-specific treatments directed at the processes that cause the disease to evolve after it has expressed itself sufficiently to be diagnosed may, at best, have an ameliorative effect. Treatments that halt the spread of the disease may be more effective than those that try to salvage affected motor neurons. Adaptive treatments directed at the clinical manifestations of the disease are the mainstay of contemporary treatment of ALS. The author has hypothesized that acquired nucleic acid changes trigger disease onset in sporadic ALS.²⁶

Loss of motor neurons bridges disease pathophysiology and its clinical expression. When advanced, this results in the characteristic picture seen in a cross section of the spinal cord. At the level of the muscle, loss of discrete lower motor neurons results in loss of innervation of individual motor units. Early in the disease, surviving nerve fibers establish connections and reinnervate motor units that have lost their connection to axons that have died; as a result, larger motor units are formed. These large motor units manifest in histological stains as type grouping (see Media file 3). They also have special characteristics on electromyographic testing. Later in the disease, when the motor neurons that supply the large motor units die, group atrophy ensues.

Muscle in nerve disease. Image courtesy of Dr. Friedlander, Associate Professor and Chair of Pathology at Kansas City University of Medicine and Biosciences.

Frequency

United States

The incidence of ALS in populations of European descent is approximately 2 per 100,000 population per year. The lifetime risk for developing ALS for individuals aged 18 years has been estimated to be 1 in 350 for men and 1 in 420 for women.²⁷ These estimates are close to those reported from 2 European databases, using different methods.^28,29

Average disease duration from clinical onset is 3 years. Therefore, disease prevalence is estimated at 6 per 100,000 population.

International

European, age-adjusted incidence data are similar to those in the US population of European descent.²⁸ Most variability between countries has been attributed to different age composition or differences in case finding. However, recent data suggest that there may be ethnic variability in disease incidence^30,31 that may not be explained entirely by differences in case finding, with lower incidence in nonwhites or individuals of mixed ethnicity. This area merits further study.

Mortality/Morbidity

• Average disease duration from clinical onset to death is 3 years.
• Younger onset age and limb onset are favorable prognostic factors.
• Some ALS variants have a more extended course.
• Some forms of familial ALS have a course that is faster than average, and some have a course slower than average.

Race

In the United States, ALS affects whites more often than nonwhites; the white-to-nonwhite ratio is 1.6:1.³⁰ Uncertainty surrounds this finding; is it true or due to reduced case-finding in non-whites. See also International.

Sex

Men are affected more frequently than women. The male-to-female ratio is approximately 1.5:1.0.¹

Age

The incidence of ALS increases with age. Average age of onset is 65 years. Different series report peak incidence in those aged 75-85 years, but whether the peak is a true peak or due to less complete case findings in older patients is uncertain.

Clinical

History

ALS may be suspected whenever an individual develops loss of function or gradual, slowly progressive, painless weakness in 1 or more regions in the body, without changes in the ability to feel, and no other cause immediately evident. ALS is more likely to be suspected based on clinical presentation alone when the disease is more widespread, (ie, when more parts of the body are involved, and when upper and lower motor neuron signs are present together in more regions of the body). When the disease has progressed far in its course and involves many parts of the body, it may be possible to make the diagnosis based on the way the patient looks and on the findings on the neurologic examination. However, when a patient presents with the first symptoms, making the diagnosis is not straightforward.²

Physical

The symptoms that some patients with ALS may experience and the signs that are found on their neurologic examination are summarized below. Not all patients experience all symptoms or have all signs. While the symptoms of motor dysfunction are best recognized, affecting all patients with ALS, a fair proportion of patients also experience emotional and special cognitive difficulties that are part of the disease. These difficulties may adversely affect the patients’ ability to plan and relate appropriately to others. Their interactions with caregivers and their willingness to accept treatment recommendations are impaired, and their prognosis is worse than of unaffected patients.²

• Upper or lower motor neuron dysfunction
  • Weakness (However, classic ALS weakness is usually due to lower motor neuron dysfunction or loss)
  • Muscle cramps
  • Difficulties with speech and swallowing
  • Unsteadiness
• Upper motor neuron dysfunction
  • Stiffness (spasticity)
  • Tendon reflexes which are brisk or spread abnormally
  • Presence of abnormal reflexes
  • Loss of dexterity in the presence of normal strength
• Lower motor neuron dysfunction
  • Twitching muscles (fasciculations)
  • Reduction of muscle bulk (atrophy)
  • Foot drop
  • Breathing difficulties
• Emotional symptoms
  • Involuntary laughing or crying
  • Depression
• Special cognitive changes

Diagnosis of ALS

The World Federation of Neurology (WFN) has developed an algorithm that combines the clinical findings and, in some cases, electrophysiologic findings, to express in each patient the degree of involvement by ALS at the time of the examination (the El Escorial criteria).³² The WFN uses adjectives that in usual speech imply a degree of certainty. However, when these criteria are applied to patients with ALS, the adjectives need to be understood as reflective of the degree of clinical involvement, particularly if no alternative diagnosis has been found and the disease has progressed out of a single limb.
 
For the diagnosis of ALS, the WFN criteria require all of the following:

• Evidence of upper motor neuron findings 
• Evidence of lower motor neuron findings
• Evidence of progression (within the site of onset and beyond the site of onset)

Alternative causes for this presentation and findings need to be excluded.
 
For the purpose of applying the WFN criteria, 4 regions or levels of the body are recognized (see Media file 1):²

• Bulbar - Muscles of the face, mouth, and throat
• Cervical - Muscles of the back of the head and the neck, shoulders, and upper back, and the upper extremities
• Thoracic - Muscles of the chest and abdomen and the middle portion of the spinal muscles
• Lumbosacral - Muscles of the lower back, groin, and lower extremities

The 4 regions or levels of the body. Bulbar (muscles of the face, mouth, and throat); cervical (muscles of the back of the head and the neck, the shoulders and upper back, and the upper extremities); thoracic (muscles of the chest and abdomen and the middle portion of the spinal muscles); lumbosacral (muscles of the lower back, groin, and lower extremities)

The qualifying term possible is applied to the diagnosis of ALS when both upper and lower neuron involvement at one level is seen. The term laboratory-supported probable ALS is used when upper motor neurons are involved at one level and electrophysiologic evidence of lower motor neurons are involved in more than 1 limb. The qualifying term probable is applied when upper and lower motor neuron involvement is seen at 2 levels, and the term definite ALS is used when the involvement is at 3 or more levels of the body. If something other than ALS can be explained for the patient’s symptoms and findings, then these terms do not apply.

Recently, a group of experts proposed to revise the WFN criteria further, primarily by giving equal weight to clinical and electrophysiologic evidence of denervation.³³ However, even when there is no uncertainty, this system still retains use of the term probable ALS, which denotes uncertainty. There are other differences between this system and the previous one, and for now the author believes forgoing the use of the revised WFN criteria is premature.³²  

Patients with a family history of Mendelian ALS are considered to have definite ALS as soon as any evidence of motor neuron disease arises that cannot be accounted for by an alternative explanation, regardless of the extent of involvement.
 
Patients with definite, probable, and laboratory-supported probable ALS are considered eligible for inclusion in clinical trials of disease-modifying treatments. Most patients with possible ALS progress to more extensive disease, but because it is not possible to predict who will not progress, they have not been included in clinical trials.
 
The term suspected ALS is given special meaning in the WFN classification system. The term is applied to patients with a pure upper motor neuron presentation, particularly if it is too early to diagnose them with primary lateral sclerosis, and to patients with a pure lower motor neuron presentation (particularly early in their presentation) if there is uncertainty if they will remain pure lower motor neuron and thus might be diagnosed more precisely as having progressive muscular atrophy.
 
From a practical standpoint, patients with primary lateral sclerosis have a course that is measured in decades (approximately 20 y). See eMedicine article Primary Lateral Sclerosis. Some patients with a predominantly upper motor neuron form of ALS may have a longer course than those with classical ALS.³⁴
 
Most patients with progressive muscular atrophy have a course indistinguishable from that of patients with classical ALS (except for the absence of upper motor neuron findings). Some patients may have a longer course, particularly those with "flail arm" or "flail leg" syndromes.³⁵ Since the distinction between a diagnosis of PMA and laboratory-supported possible ALS hinges on the identification of 1 upper motor neuron sign, at some point in the patient’s disease, this distinction may prove to be of greater significance to researchers than to clinicians and patients, for whom rate of progression is the factor that determines the patients’ course and outcome.
 
Patients with progressive bulbar palsy (PBP) may be classified while the disease is restricted to the bulbar region as suspected ALS if only upper or lower motor abnormalities are evident, and as possible ALS if there is upper and lower involvement. When neurophysiologic or clinical spread beyond the bulbar level is evident, the condition would be reclassified as probable, laboratory-supported probable, or definite ALS.

In day-to-day practice, clinicians will inevitably use the term suspected ALS whenever they suspect ALS, regardless of the extent of clinical involvement at the time, and may or may not use the WFN qualifiers when they conclude that the patient has the disease.

Causes

Sporadic amyotrophic lateral sclerosis

The causes of sporadic ALS are considered to be unknown, but we are getting closer to understanding them. Interactions between genetic, environmental, and age-dependent risk factors have been hypothesized to trigger disease onset.

Malignant biochemical transformation hypothesis. Risk factors operate up-stream to a putative malignant biochemical transformation, which causes the appearance of endogenous ALS-specific toxins. These putative toxins spread, behaving like a metastasizing biochemical malignancy, and cause the downstream biochemical, histologic and clinical consequences of ALS. (Adapted from Armon C. ALS: Clinical and Epidemiologic Clues to Pathogenesis. In: Neurobiology of ALS. Course Syllabus, 51st Annual Meeting. American Academy of Neurology, 1999.)

(i) the results could have been influenced by ascertainment bias because they were based on just seven additional cases of ALS among Gulf War veterans in a study of 2.5 million participants; and
(ii) the mortality rate of Gulf War veterans due to ALS has not yet been found to be elevated."

Differential Diagnoses

Other Problems to Be Considered

Brainstem syndromes
Cervical disk syndromes
Paraneoplastic neuropathy
Tay-Sachs/GM₂ gangliosidosis disease (late onset)

At times, the early presentation of the conditions listed above may overlap that of amyotrophic lateral sclerosis (ALS). ALS can be diagnosed, and the alternatives can be excluded through appropriate evaluation (see Workup). When ALS is expressed fully, it usually cannot be mistaken for anything else.

Workup

Laboratory Studies

Nerve Conduction Studies and Needle Electromyography

Nerve conduction studies and needle electromyography are useful for confirming the diagnosis of ALS and for excluding peripheral look-alikes.

The characteristic lower motor neuron features of ALS are decreased amplitudes of compound muscle action potentials with normal conduction velocities, absence or little involvement of sensory nerves, and a mixed pattern of acute denervation and chronic reinnervation of muscles in the distribution of multiple roots at multiple levels. These features are present abundantly in advanced disease but may be sparse early on. 

Other disease processes that may be suggested by their characteristic electrophysiologic presentation include the following: 

• Multifocal motor mononeuropathy may be suggested by presence of the following:
  • Motor conduction block in multiple nerves
  • Motor conduction velocities less than 70% of the lower limit of normal, and distal motor latencies greater than 30% of the upper limits of normal values
• Chronic inflammatory demyelinating polyradiculoneuropathy may be suggested by the features listed above, together with the following:
  • Low sensory nerve action potential amplitudes with slow conduction if not attributable to entrapment syndromes or known concomitant pathology, such as diabetes
  • F-wave or H-wave latencies greater than 30% above established normal values
• A generalized axonal sensorimotor peripheral neuropathy may be suggested if motor and sensory fibers appear affected equally without excessive slowing, or if sensory fibers are affected more than motor fibers, recognizing that mild sensory abnormalities may be found occasionally in patients with ALS without sensory symptoms, and that the lower limits of normal in those aged 60 years or older are lower than those for younger individuals.
• Myasthenia gravis may be suggested by compound muscle action potential decrements greater than 20% on repetitive stimulation of motor nerves.
• Inclusion body myositis may be suggested by a characteristic pattern of distribution of affected muscles and by a mixed pattern of large and small motor unit potentials on needle examination.
• Other myopathies may also be suggested if small rapidly firing motor unit potentials are found, rather than those characteristic of a neurogenic process.
• Primary lateral sclerosis may be suggested if there is no lower motor neuron involvement, particularly if that remains the case 3 years (or more conservatively, 5 years) after clinical onset of disease.
• Monomelic amyotrophy may be suggested if no evidence of disease is found outside 1 limb several years after its onset.

Electrophysiological features compatible with upper motor neuron involvement include the following:

• Increase of up to 30% in central motor conduction time determined by cortical magnetic stimulation. However, central electrophysiologic studies are currently not part of the routine evaluation of patients with ALS because whether emergence of central studies abnormalities precedes that of clinical signs of upper motor neuron involvement has not been determined.
• Low or irregular firing rates of motor unit potentials on maximal effort may be seen during routine needle examination. However, this feature is nonspecific as it may be seen in other settings if patients find it hard to activate specific muscles.

Motor unit number estimation

Motor unit number estimation (MUNE) is a nerve conduction study technique that can quantify the numbers of motor units innervating an individual muscle.⁸³ It may be used to help with the diagnostic process in rare cases where clinical or electrodiagnostic lower motor neuron involvement cannot be shown otherwise. For example, the author encountered an individual with rapidly progressive upper motor neuron disease in whom muscle denervation could not be demonstrated clinically or on routine electromyography, and in whom MUNE showed numbers below the lower limit of normal in distal upper and lower extremity muscles, establishing the diagnosis as ALS; but such situations must be rare.

MUNE may be used to separate patients into faster and slower progressive groups.⁸⁴ However, other measures of disease progression that are easier to obtain, such as the ALSFRS-R, may serve this purpose, and patients the author has surveyed have reflected ambivalence or reluctance to receive prognostic information early in the course of the disease when such information is of greatest relevance.⁸⁵ While MUNE is appealing as a quantifiable, physiologic measure of disease progression that is independent of patient effort, the error inherent in the estimation process precludes its use as the primary measure of efficacy of putative, mechanism-specific interventions to slow disease progression

Other laboratory studies need to be tailored to the clinical circumstances, in search of treatable look-alikes.

• The author suggests serum protein electrophoresis and immunoelectrophoresis; HIV1/2, RPR, TSH and T4, PTH, B ₁₂ , and occasionally B ₁ .
• In patients with pure lower motor neuron disease, anti GM1 antibodies should be included.
• If myasthenia gravis is under consideration, antiacetylcholine receptor antibodies and anti-muscle specific kinase (MuSK) antibodies.
• Urinary 24-hour collections for heavy metals may be requested if there is reason to suspect that recent exposure is producing a reversible ALS look-alike.
• In patients with FALS, genetic testing may be requested after appropriate counseling. The results of genetic testing may affect not only the patient, but family members.
• Tests for the SOD1 gene and for the gene causing Kennedy disease are available commercially. Patients with other forms of familial ALS may be referred for further information to centers with a research interest in FALS.
• Hexosaminidase A in urine may be checked when adult Tay-Sachs is suspected strongly.
• Lyme disease serology may be considered if clinical data suggest that the patient had untreated Lyme disease. The author’s infectious diseases colleagues assure him that history, rather than laboratory testing, drives the diagnosis.

Imaging Studies

Imaging studies need to be tailored to the clinical presentation.

Brain or spinal MRI may be done to rule out structural lesions that might account for early clinical features, but they may not be necessary when the patient presents with advanced disease.

CT with myelography may be needed in patients in whom an MRI cannot be performed safely (eg, because of presence of a pacemaker, an implantable defibrillator, or metal fragments).

Procedures

Muscle biopsy is needed only rarely and may be considered if the presentation is atypical. This will confirm the presence of signs of denervation and reinnervation or may lead to an alternative diagnosis. Presence of small angular fibers is consistent with neurogenic atrophy (denervation) and fiber type grouping is consistent with reinnervation.

Histologic Findings

Muscle biopsy shows small angular fibers that are consistent with neurogenic atrophy (denervation) and fiber type grouping that is consistent with reinnervation.

Staging

Progression of amyotrophic lateral sclerosis

ALS is expected to progress within the area first affected and then to adjacent contiguous regions. As it progresses, patients’ function and independence diminish. When ventilator muscles are affected, patients may be supported using noninvasive or invasive measures. The majority of patients die of ventilatory failure, most having chosen not to opt for long-term invasive mechanical ventilation. Less than 5% of patients die of other causes, such as a heart attack, a serious infection, or blood clots that migrate to the lungs.
 
Patients progress at their own pace and their symptoms depend on the muscles affected. Regular monitoring of their course assists in directing their treatment.
 
Standardized assessment of patients with ALS was facilitated by the development of the ALS Functional Rating Scale, a 10-item standardized questionnaire.⁸⁶ It was revised to give greater weight to respiratory involvement and became the 12-item ALSFRS-R,^87,88 which is used extensively.

Functions mediated by cervical, trunk, lumbosacral, and respiratory muscles are each assessed by 3 items. Each item is scored from 0 to 4, with 4 reflecting no involvement by the disease and 0 reflecting maximal involvement. The item scores are added to give a total. In general terms, a score above 40 reflects minimal-to-mild impact of disease, a score between 39 and 30 reflects mild-to-moderate impact, a score under 30 show moderate-to severe-impact, and a score under 20 is advanced disease. These qualifiers are generalizations, and for individual patients, loss of only 8-10 points on the ALSFRS-R may have severe implications, for example, if respiratory function or bulbar functions bear the brunt of the losses. A minor limitation of the scale is that it has a floor effect in terms of measuring disease progression in quadriparetic, ventilator-dependent patients.
 
Most physicians caring for patients with ALS use a measure of their breathing ability to follow the course of their disease. Of the tests of pulmonary function, vital capacity is used most commonly. Additional measures, such as maximal inspiratory and expiratory pressures, may provide earlier evidence of dysfunction. Comparison of vital capacity in the upright and supine positions may also provide an earlier indication of weakening ventilatory muscle strength.

Treatment

Medical Care

Treatment of amyotrophic lateral sclerosis (ALS) may be divided broadly into education, mechanism-specific treatment, and adaptive or supportive treatment.^2,89 Patient education can be enhanced by referral to multidisciplinary clinics with specialists with special interest in ALS, by reading educational materials prepared for patients and families by national organizations in the US^90,91 and other countries or by individual experts² , and by participating in local support groups.

Outpatient care

Most of the care of patients with ALS may be delivered in the outpatient setting, and often guidance can be provided by a neurologist or physiatrist with special interest in the disease. Multidisciplinary clinics can provide "one-stop shopping" for patients, where patients can receive all assessments and recommendations in the course of a single visit. Most multidisciplinary clinics provide a combination of on-site and off-site services. While this is a highly effective method of delivering care to patients with ALS, it may not be available in all venues because adequate patient volume and usually some nonclinical (ie, philanthropic) support is required to sustain it. Some patients find full-day assessments exhausting, and for them more frequent, but shorter, visits are more acceptable. The patients’ primary care providers have an important role in the care of patients with ALS, and in some settings the PCP may be able to coordinate all the patients’ care.

Noninvasive ventilatory support

Noninvasive ventilatory support has been shown to improve patients’ quality of life and to extend life when applied as patients begin to experience the early effects of ventilatory failure, including early features of disruption of sleep, and is probably more effective in terms of life extension, than all other treatments. Overnight polysomnography may identify disruption of the contiguity of sleep, one of the early consequences of ventilatory failure that may precede frank apneas, hypopneas, or nocturnal oxygen desaturation.

Surgical Care

Many patients are not interested in surgical interventions; their wishes need to be ascertained and respected. Since patients may change their mind, periodic reassessment is reasonable but needs to be done with sensitivity.

Invasive ventilatory support, requiring tracheostomy, may be considered in patients who present with respiratory failure who are largely intact otherwise, in patients who want to be maintained using long-term invasive ventilatory support as their disease progresses, or in very rare patients in whom secretions cannot be managed otherwise.

Placement of a feeding gastrostomy may be considered in patients who cannot maintain adequate caloric intake due to swallowing difficulties.

Consultations

Consultants are best used within the multidisciplinary model based on patients’ preferences and need to complement the range of services that the patients’ primary care providers and primary neurologists or physiatrists can provide directly.

• Physical and occupational therapists help the patient adapt to loss of function, provide exercises to maximize existing function and ameliorate spasticity, identify safety concerns and advise how to circumvent, and help patients select and learn to use assistive devices, including, as the disease advances, a customized wheel chair.
• Speech therapist advises on adaptation to swallowing difficulties, and, as speech fails, on use of communication devices.
• Respiratory therapist assists with learning to use noninvasive ventilation support and, if needed, advises on secretion management, suctioning equipment, and selection of a cough assistive device.
• Dietician or nutritionist evaluates caloric intake and advises how to optimize it, particularly if intake is declining. They may be able to provide guidance regarding nutritional supplementation.
• Pulmonologist, if needed, assesses for tracheostomy and manages ventilator, tracheostomy, and complications (such as infections) if this treatment is selected.
• Gastroenterologist or surgeon advises and performs PEG placement and advises on its care and maintenance.
• Visiting nurse assesses patients’ in-home needs and helps quantify the need for and time the introduction of personal care assistants (home health care aides) and other home-based therapies.
• Hospice service provides the framework for in-home end-of-life care, or helps with alternative arrangements.
• Spiritual (religious) services, if elected by patients, usually connect with the resource of their choice.
• Alternative therapies (frequently elected by patients), if not unsafe or exorbitantly priced, may be a reasonable approach to giving patients a sense of some control, may confer on them a feeling of calm, and thus be of benefit, in subjective terms. Since most, if not all, alternative therapies have not been tested against placebo controls, traditional medicine cannot provide blanket recommendations, but practitioners may be able to be supportive, if circumstances permit, of specific patient choices.
• Psychiatrist/psychologist/counselors: While many patients and families might benefit from such support, the author has seen it used mainly by individuals who had already used these options prior to disease onset, or who had these options offered within the multidisciplinary model of care.

Diet

Patients’ appetite tends to decline as the disease progresses, and their ability to swallow may become impaired.

Consultations with a dietician or nutrititionist and a speech therapist may be requested to assist the patient in compensating for these losses. Dietary supplements may be used to assure adequate caloric intake.

Consultation with a gastroenterologist (or surgeon) may be requested if PEG placement is being considered.

Activity

Initially, no activity restriction is necessary. However, patients should not overexert themselves to the point of fatigue or pain. Patients should maintain a regular exercise regimen if their degree of weakness allows. Patients need to realize that their muscle reserve will diminish before overt sustained weakness will appear, and in most cases  they should avoid endurance exercises (repetitions). The chief goals of activity are maintenance of range of motion of all joints, prevention of painful contractures, and maintenance of tone and strength of muscles not yet or minimally affected by the disease.

As disease progresses, patients may become unstable and at risk of falls and may need to be counseled to use assistive devices or not transfer without appropriate support. If they reach a point when they cannot manage a vehicle safely, including in emergencies, they need to be counseled to stop driving. Some states require mandatory reporting by practitioners.

Medication

Glutamate pathway antagonist riluzole is the only medication that has shown efficacy in extending life in ALS. Compared with placebo, riluzole may prolong median tracheostomy-free survival by 2-3 months in patients younger than 75 years with definite or probable ALS with disease duration under 5 years who have an FVC of greater than 60%.⁹² This conclusion is based on 2 double-blinded, randomized, placebo-controlled clinical trials.^23,24 A third clinical trial⁹³ in patients who were ineligible to participate in the second pivotal clinical trial²⁴ did not show efficacy, possibly due to low power (small number of patients included relative to the magnitude of the possible effect). A fourth clinical trial conducted in Japan⁹⁴ did not show efficacy,⁹⁵ and the details have not been published in the English literature. 

The Cochrane review pooled the data from the first three clinical trials,^23,24,93 but not the fourth.⁹⁴ The statistical significance of the data for efficacy, using the pooled data from the first 3 trials is P=0.056. Subsequent reports have claimed greater efficacy for riluzole in clinical practice than in the clinical trials. 

The relevance of these claims has been challenged.⁹⁶ They pit Class IV Evidence against Class I Evidence, which is contrary to the usual evidence-based approach to judge treatment efficacy. Patients with ALS who have depression, frontotemporal dementia, or a milder level of frontal impairment are now recognized as less likely to accept treatment recommendations and have a poorer prognosis. Failure to accept riluzole treatment is a marker for a risk factor for poor survival, not its cause. Furthermore, registries in place since before the introduction of riluzole show no overall extension of survival of patients with ALS.

Symptomatic treatments

• Antispasticity agents may be used to treat limb stiffness.
• Antisiallorea treatments include anticholinergics, sympathomimetics, botulinum toxin type B, and salivary gland irradiation.
• Anticholinergics such as amitriptyline (25-50 mg qhs) or trihexyphenidyl (Artane) (0.5-2.0 mg prn) may be administered as tolerated (patient experience).
• Efficacy of botulinum toxin type B injections, 2500 units to the salivary glands (double-blinded, placebo-controlled trial)⁹⁷ and salivary gland radiation 7.5 Gy (Case series with standardized outcome measure)⁹⁸ has been reported.
• Sympathomimetics such as pseudoephedrine may be tried if tolerated. 30-60 mg may be administered as needed or in the extended release formulations, 120-240 mg/d may be used (patient experience).
• Mucolytics, such as guaifenesin may be used to make thickened secretions thinner (patient experience). Adequate hydration and humidification of room air may prove helpful and are recommended. 
• Mechanical suction devices may be needed to remove secretions.
• When using antidepressants, SSRIs work best (eg, citalopram 10-40 mg/d; patient experience). If the desired benefit is not achieved with one agent, another may be tried.
• A common anxiolytic used is lorazepam (0.5-1.0 mg as needed; patient experience). There is potential for respiratory depression with benzodiazepines and careful titration is needed.
• If analgesics are needed, tramadol Hcl (Ultram), ketorolac tromethamine (Toradol), morphine (IR, ER), or fentanyl patch may be considered. Respiratory depression with opiates may occur. Careful titration, starting with low doses, is needed.
• A combination of dextromethorphan and quinidine has shown efficacy in ameliorating involuntary laughter and crying (the expression of pseudobulbar affect)⁹⁹ but has not received FDA approval for this indication, pending results of additional studies.

Glutamate pathway antagonist

Riluzole is thought to counteract excitatory amino acid (glutaminergic) pathways, but exact mechanism of action in ALS unknown.

Riluzole (Rilutek)

Benzothiazole agent that is well absorbed, with average oral bioavailability of 60% and mean elimination half-life of 12 h; steady state reached within 5 d with multiple dose administration; metabolism occurs in liver (P 450-dependent glucuronidation and hydroxylation); 6 major and a few minor metabolites produced.

Dosing

Adult

50 mg PO bid

Pediatric

Not established

Interactions

Metabolized primarily by liver isoenzyme CYP₁ A₂; other agents also metabolized via this enzymatic pathway (ie, theophylline, caffeine) may affect rate of elimination

Contraindications

Documented hypersensitivity, liver disease with elevations in liver function tests

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Use caution in patients with concomitant liver or renal insufficiency

Antispastic agents

These agents relieve spasticity and muscle spasms in patients with symptoms of limb stiffness.

Baclofen (Lioresal)

Metabolized in liver and excreted primarily in urine; not a DEA-controlled substance.

Dosing

Adult

5 mg PO tid; not to exceed 80 mg/d

Pediatric

Not established

Interactions

May interact with alcohol, antipsychotics, MAOIs, narcotics, antipsychotics, tricyclic antidepressants, oral hypoglycemics, or insulin

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Use with caution in patients with seizure disorder or impaired renal function; serious reactions include somnolence and stupor, cardiovascular collapse, seizures, and respiratory depression; common adverse effects include headaches, dizziness, blurred vision, slurred speech, rash, weight gain, pruritus, constipation, increased perspiration; exercise caution in prescribing to patients already experiencing such symptoms; excessive dosing may lead to weakness

Tizanidine (Zanaflex)

Centrally acting muscle relaxant metabolized in liver and excreted in urine and feces; used in patients with predominantly UMN involvement; not a DEA-controlled substance.

Dosing

Adult

4-8 mg PO q8h prn; not to exceed 36 mg/d

Pediatric

Not established

Interactions

May interact with alcohol (to increase somnolence, stupor) and oral contraceptives (to decrease its clearance); can increase hypotensive effects when administered concurrently with diuretics

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Use with caution in elderly patients and in patients with impaired renal function; serious reactions include hallucinations, severe bradycardia, and liver toxicity; more common adverse effects include dryness of mouth, somnolence and sedation, dizziness, malaise, constipation, increased spasms, and hypotension

Follow-up

Further Inpatient Care

Inpatient care may be needed temporarily for patients with amyotrophic lateral sclerosis (ALS) who decompensate in the outpatient setting, for example due to pneumonia, or those who reach critical ventilatory failure without having appropriate ventilatory support in place and without having made end-of-life decisions (advance directives) declining such ventilatory support and electing comfort measures instead.

Deterrence/Prevention

Smoking is the only probable risk factor for ALS.^25,45 Smoking avoidance may result in a decrease in age-specific incidence of ALS. However, if more patients at risk for developing the disease survive to each age due to reduced mortality from other smoking related diseases, such as cancer and cardiovascular diseases, this presumptive benefit of smoking cessation may not be realized fully. Furthermore, as the population survives to older ages (in which age-specific incidence of disease is higher) crude incidence of ALS may increase.

Individuals with a gene for FALS may benefit from genetic counseling if they wish to minimize the risk of transmitting the gene to the next generation.

Complications

• Progressive inability to perform activities of daily living (ADLs), including handling utensils for self-feeding
• Deterioration of ambulation
• Aspiration pneumonia
• Respiratory insufficiency
• Complications from being wheelchair-bound or bedridden, including decubitus ulcers and skin infections (While rare in patients with ALS, these complications can emerge if appropriate padding is not used.)
• Deep vein thromboses and pulmonary emboli (These complications are rare in patients with ALS, but have been encountered with greater frequency in the active treatment arm of some clinical trials.)

Prognosis

Patients with ALS survive on average 3 years from disease onset. Patients with some variants of the disease may have a longer course. Patients who are younger or with limb onset survive longer on average. The most effective predictor of survival is the rate of observed disease progression. Estimates derived as a ratio, where loss according to various measures serves as the numerator and time elapsed from disease onset to the time of measurement serves as the denominator may also provide more individualized prognostic information.
 
Patients the author has surveyed have indicated ambivalence about being offered individualized information early in the course of the disease (when it may matter most).⁸⁵  The author does not offer patients individualized prognostic information when he sees them first. When patients do request it, he asks them to consider the possible implications of the answers they might receive and then they can ask him again at a subsequent visit.

Patient Education

• ALS Association, Living With ALS Manuals
• Muscular Dystrophy Association: MDA ALS Caregiver’s Guide
• Armon C. ALS 1996 and Beyond: New Hopes and Challenges. A manual for patients, families and friends. Fourth Edition. 2007. Published by the LLU Department of Neurology, Loma Linda, California.
• Doctor's Guide, patient resources: ALS (Lou Gehrig's Disease)
• ALS newsletter of the Muscular Dystrophy Association
• eMedicine's Brain and Nervous System Center
• eMedicine's patient education article Amyotrophic Lateral Sclerosis (Lou Gehrig Disease)

Miscellaneous

Medicolegal Pitfalls

• Patients are eligible for social security and Medicare benefits once they are diagnosed with ALS, without the waiting period required of other patients with chronic diseases. Patients should be advised to apply early.
• Since September 2008, ALS has been considered a service-connected conditions for US Veterans, and they are eligible for care and benefits. Eligible patients should be advised to apply early. Volunteers from local branches of veterans organization may be able to assist in preparing the application and moving it rapidly through the approval process.
• End of life issues may be discussed and clarified early. However, this may not work well for some patients. The physician should be aware of the individual state laws that regulate these issues, encourage, if appropriate for the patient, completion of advance directives, and document the patient’s preferences in the medical records, whether formal advance directives have been written or not.
• For patients with limited access to home-based resources, social service professionals may be able to assist with placement.
• Local branches of advocacy organizations (ALSA and MDA) may be excellent resources to inform patients of what is available to them locally.
• Patients will have decreasing ability to sign documents or to mobilize themselves for taking care of personal affairs. Some may benefit from legal advice. The earlier they do so the better, but they may need to recover from the initial shock of the diagnosis.
• All patients will become at risk for falls as the disease progresses: they should be informed and cautioned gently. Most patients tend to sustain several falls before they relinquish the independent activities that led to the falls.
• All patients will become unable to drive as their disease progresses. They need to be alerted. Most tend to be gracious about quitting before their driving results in injury. Some states require mandatory reporting by practitioners to the Department of Motor Vehicle Affairs.

Special Concerns

• Support groups are available to patients in many communities.
• Burnout of the primary caregiver needs to be anticipated and avoided by assuring that the primary caregiver is not the only caregiver.
• Patients with ALS may wish to help with the search for treatments for the disease through participation in clinical trials. They should be encouraged to focus on trials that have been listed with the ALS Association and with ClinicalTrials.gov, a registry of federally and privately supported clinical trials conducted in the United States and around the world.
• Patients often request prescription of available pharmaceuticals for off-label use in the hope of slowing disease progression. Since all such pharmaceuticals, so far, have either made patients worse when tested in double-blinded placebo-controlled studies or have had no benefit, this is not something that can be recommended.

Multimedia

Media file 1: The 4 regions or levels of the body. Bulbar (muscles of the face, mouth, and throat); cervical (muscles of the back of the head and the neck, the shoulders and upper back, and the upper extremities); thoracic (muscles of the chest and abdomen and the middle portion of the spinal muscles); lumbosacral (muscles of the lower back, groin, and lower extremities)

Media file 2: Malignant biochemical transformation hypothesis. Risk factors operate up-stream to a putative malignant biochemical transformation, which causes the appearance of endogenous ALS-specific toxins. These putative toxins spread, behaving like a metastasizing biochemical malignancy, and cause the downstream biochemical, histologic and clinical consequences of ALS. (Adapted from Armon C. ALS: Clinical and Epidemiologic Clues to Pathogenesis. In: Neurobiology of ALS. Course Syllabus, 51st Annual Meeting. American Academy of Neurology, 1999.)

Media file 3: Muscle in nerve disease. Image courtesy of Dr. Friedlander, Associate Professor and Chair of Pathology at Kansas City University of Medicine and Biosciences.

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Keywords

amyotrophic lateral sclerosis, ALS, Lou Gehrig disease, Lou Gehrig's disease, Charcot disease, Charcot's disease, motor neuron disease

Contributor Information and Disclosures

Author

Carmel Armon, MD, MSc, MHS, Professor of Neurology, Tufts University School of Medicine; Chief, Division of Neurology, Baystate Medical Center
Carmel Armon, MD, MSc, MHS is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, American College of Physicians, American Epilepsy Society, American Medical Association, American Neurological Association, American Stroke Association, Massachusetts Medical Society, Movement Disorders Society, and Sigma Xi
Disclosure: Nothing to disclose.

Medical Editor

Donald B Sanders, MD, EMG Laboratory Director, Professor of Medicine (Neurology), Division of Neurology, Duke University Medical Center
Donald B Sanders, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Neurological Association, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Neil A Busis, MD, Chief, Division of Neurology, Department of Medicine, Head, Clinical Neurophysiology Laboratory, University of Pittsburgh Medical Center-Shadyside
Neil A Busis, MD is a member of the following medical societies: American Academy of Neurology and American Association of Neuromuscular and Electrodiagnostic Medicine
Disclosure: Nothing to disclose.

CME Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Nicholas Y Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants
Nicholas Y Lorenzo, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Neurology
Disclosure: Nothing to disclose.

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• Mitsumoto H, Przedborski S, Gordon PH, eds. Amyotrophic Lateral Sclerosis. Taylor and Francis. 2006.
• Miller RG, Gelinas D, O'Connor P. Amyotrophic Lateral Sclerosis. AAN Press. Demos 2004.

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