Clinical Vignette

A 62-year-old female first noted difficulty walking over uneven ground. Progressive painless weakness developed over the course of the next 6 months; initially this affected the left leg more than the right, resulting in a number of falls. By the time she was evaluated by a neurologist, she could no longer cut her own food or clip her own finger nails. She denied any pain, sensory disturbance or change in her ability to think, speak, swallow, or breathe.

Etiology, Genetics, and Pathogenesis

The cause of sporadic ALS is unknown. As with other neurodegenerative diseases, it is hypothesized that ALS may result from the dual insult of genetic susceptibility and environmental injury. Attempts to identify predisposing mutations and potential toxic or infectious agents have been unsuccessful to date.

It has been long recognized that a small percentage of patients (fALS) have an autosomal dominant pattern of Mendelian inheritance. A major breakthrough in our understanding of familial ALS took place in 1991 with the identification of cytosolic copper-zinc superoxide dismutase (SOD1) gene mutations on chromosome 21q22.11 in affected individuals in some families. This represents the most frequently identified form of fALS. SOD1 is a free radical scavenger. Recognition of the SOD1 mutation led to the hypothesis that SOD1-fALS was mediated by free radical toxicity. However, SOD1 knock-out mouse with no SOD1 protein do not develop motor neuron disease. In contrast, heterozygote mice become symptomatic and die from a paralyzing disorder. It is thought that SOD1 mutations may injure neurons through conformational changes in the SOD1 protein.

Particularly intriguing has been the recognition of the phenotypic heterogeneity in SOD1 fALS (Table 67-1). About 114 pathologic mutations have been identified within the five exons of the SOD1 gene; each of these mutations may produce a distinct phenotype. The most common mutation found in North America is an alanine for valine (A4V) substitution at codon 4; this typically produces a lower motor neuron dominant phenotype (LMN-D) with a life expectancy approximating 1 year. Table 67-1 summarizes the phenotypic heterogeneity that results from different SOD1 mutations. SOD1 mutations are not fully penetrant. It is estimated that individuals carrying the mutation have an 80% chance of developing disease by age 85 years. SOD1 mutations constitute 20–25% of all individuals with fALS. Other fALS genotypes are listed in Table 67-2. Some of these mutations produce a predominantly lower motor neuron (LMN) or upper motor neuron (UMN) disorder and more closely resemble the phenotypes of spinal muscular atrophy or hereditary spastic paraparesis, respectively.

Table 67-1 Phenotypic Variation in SOD1 fALS

Phenotype	SOD 1 Mutation
Lower motor neuron predominant	A4V, L84V, D101N
Upper motor neuron predominant	D90A
Slow progression (>10-year survival)	G37R, G41D, G93C, L144S, L144F
Fast progression (<2-year survival)	A4T, N86S, L106V, V148G
Late onset	G85R, H46R
Early onset	G37R, L38V
Female predominant	G41D
Bulbar onset	V148I
Low penetrance	D90A, I113T
Posterior column involvement	E100G

Mutations that may produce both a frontotemporal lobar degeneration and motor neuron disease occur on chromosomes 9p13.2-21.3, 9q21-q22, and 17q21. A recently identified fALS mutation occurs in the TAR DNA-binding protein, 43 (TDP-43) gene. Non-amyloid, structurally modified TDP-43 has been recognized as a major constituent of the ubiquitinated inclusions found in cortical neurons of patients with both sporadic (s) and familial (f) forms of frontotemporal lobar degeneration (FTD).

There are many proposed mechanisms for motor neuron death in sALS, including excitotoxicity secondary to glutamate, free radical–mediated oxidative cytotoxicity, mitochondrial dysfunction, protein aggregation, cytoskeletal abnormalities, aberrant activation of cyclo-oxygenase, impaired axonal transport, activation of inflammatory cascades, and apoptosis. Why the motor neurons and corticospinal/bulbar tracts are vulnerable in a selective manner remains unknown. Why the disease begins focally and progresses in a regional fashion is also unknown. One putative hypothesis is that misfolded, toxic protein aggregates may proselytize normal protein in adjacent neurons, analogous to mechanisms proposed for prion diseases.

Whatever the mechanism, ALS is pathologically characterized by loss of myelinated fibers in the corticospinal and corticobulbar pathways (see Fig. 67-2) and loss of motor neurons within the anterior horns of the spinal cord and many motor cranial nerve nuclei. Even in individuals with predominantly UMN or LMN involvement clinically, pathologic involvement of both systems is seen. Patients with associated FTD have preferential lobar atrophy and neuronal loss from these portions of the brain (Fig. 67-3). As a result of anterior horn cell loss, ventral roots become atrophic in comparison to sparing of their dorsal root counterparts (Fig. 67-4). Anterior horn cell loss occurs within virtually all levels of the spinal cord with selective sparing of the third, fourth, and sixth cranial nerves, and Onuf’s nucleus within the anterior horn of sacral segments 2–4. There is also cell preservation within the intermediolateral cell columns.

The majority of sALS patients will be found to have ubiquitinated inclusions and Bunina bodies within the central nervous system. The latter are dense granular intracytoplasmic inclusions within motor neurons considered specific for ALS. Additionally in ALS with FTD, spongiform changes of the first and second layers of the frontal cortex have been described.

Clinical Presentations

The diagnosis of ALS remains a clinical endeavor. EMG and nerve conduction studies and measurements of ventilatory capacity are routinely obtained in ALS suspects. These tests are done to provide diagnostic support for diffuse LMN and ventilatory muscle involvement respectively. Other testing is done with the primary intent of identifying or excluding differential diagnostic considerations. SOD1 mutational analysis provides diagnostic proof in patients with suggestive family histories. Although a small percentage (2%) of seemingly sALS patients will be found to have SOD1 mutations, mutational analysis is not routinely recommended in this population.

The presenting features of ALS are quite variable. Typically, the patient seeks medical care when his or her weakness begins to affect activities of daily living (Fig. 67-5). It is not uncommon for ALS to be misdiagnosed initially and the time between symptom onset and diagnosis is usually months. Unfortunately, there is a tendency to misdiagnose ALS as a potentially treatable nerve, nerve root, or spinal cord compressive syndrome or orthopedic condition. A significant percentage of ALS patients may undergo unnecessary surgeries. It should be emphasized that progressive weakness and atrophy in the absence of pain and sensory symptoms rarely represents a surgically treatable condition.

The exclusive motor involvement and the chronologic course serve to distinguish ALS from other neurologic disease. Simultaneous involvement of both UMNs and LMNs and progression both within and outside of the originally involved regions is necessary for a definite clinical diagnosis. LMN involvement may be documented by clinical, electrodiagnostic, or pathologic (muscle biopsy) means. UMN involvement is currently defined by clinical criteria alone. Classic ALS is usually an easy diagnosis for an experienced neurologist. Diagnosis may be delayed in patients with limited clinical evidence of the LMN or UMN involvement, slow disease progression, and confounding neurologic signs from unrelated problems such as sensory loss from mononeuropathies, radiculopathies, and polyneuropathies.

The signature of anterior horn cell loss is painless weakness and atrophy, hypoactive or absent deep tendon reflexes, and fasciculations. Atrophy is best appreciated when it is focal, in contrast to normal muscle bulk elsewhere. It may be difficult to distinguish atrophy from LMN disease resulting from the atrophy of disuse, particularly in the elderly. Suppressed deep tendon reflexes may also be difficult interpret as they may represent a normal variant. In ALS, muscle weakness due to LMN dysfunction occurs in a segmental (myotomal) distribution and spreads in a regional fashion. As an example, a patient with ALS and hand weakness may have all hand muscles innervated by C8–T1 roots affected. Weakness occurring in a nerve distribution should lead to consideration of a different disorder, for example, multifocal motor neuropathy.

Fasciculations seen in many muscles in multiple limbs are ominous and are strongly suggestive of a motor neuron disease. Fasciculations that occur infrequently, or repetitively in one area, are more likely to have a benign origin, particularly in the absence of weakness or atrophy. The absence of fasciculations does not eliminate ALS. They may not be readily visible because of prominent subcutaneous tissue. Physicians often initially recognize fasciculations, although the patient in retrospect may recall that they were present for some time. Muscle cramping is a common, albeit nonspecific, manifestation of motor neuron disease. The initiation of cramps during manual muscle testing is common in ALS.

What constitutes clinical signs of corticospinal or corticobulbar tract pathology may be more ambiguous. Spasticity represents a definite UMN sign; Babinski signs if unequivocal are confirmatory of UMN disease. Unfortunately, Babinski signs may not be elucidated in many ALS patients as a result of LMN toe extensor weakness. The Hoffman sign is generally indicative of UMN involvement of the arms, particularly if asymmetric. Hyperactive deep tendon reflexes, particularly with sustained clonus, indicate UMN involvement. The term relative UMN sign has been used to describe the presence of a deep tendon reflex in a weak and atrophic muscle. Reflex spread also implicates UMN disease; finger flexion (C8) occurring in response to brachioradialis tendon percussion (C6), and activation of the contralateral thigh adductors when the insertions of the ipsilateral thigh adductors are percussed (crossed adduction) are two notable examples of this phenomenon. Motor impairment in UMN disease typically results in slowness and incoordination. UMN weakness occurs in a specific pattern: the elbow, wrist, and finger extensors are weaker than their flexor counterparts in the upper extremity whereas conversely, hip and knee flexors and foot dorsiflexors and evertors are weaker in the lower limb.

Tongue atrophy, fasciculation, and weakness are perhaps the most frequently occurring and recognized manifestations of LMN involvement of cranial nerves. It is important to observe for fasciculations when the tongue is relaxed on floor of the mouth (Fig. 67-6). Tremulousness of the tongue with attempted protrusion may be readily misinterpreted as representing fasciculations. Weakness of both facial and jaw muscles may occur in ALS but they are usually subtle. Weakness of neck extension and neck flexion is common in ALS, and head drop may be a rare presenting feature (Fig. 67-7). Neck drop is commonly associated with posterior neck discomfort and is typically relieved when the neck is supported. Notable for their absence are ptosis and ophthalmoparesis, and symptoms related to sight, hearing, taste, smell, and facial sensation.

Upper motor neuron signs and symptoms in the bulbar region may be more difficult to characterize. The presence of a jaw jerk or snout reflex is considered an indicator of corticobulbar tract dysfunction. An exaggerated gag reflex has a similar implication. One common manifestation of central nervous system involvement in ALS is a pseudobulbar affect, that is, the tendency to laugh in the absence of happiness and cry in the absence of sadness. The pathologic substrate of this phenomenon is incompletely understood.

Symptoms related to disordered ventilation occur most commonly in the latter stages of ALS but may be the presenting manifestation in approximately 1% of patients. The inability to generate a robust cough, sniff, or sneeze is due to the inability to generate sufficient intrathoracic pressures due to LMN weakness of the internal intercostal or abdominal muscles. Orthopnea implicates diaphragmatic insufficiency due to anterior horn cell disease in the upper segments (C3–C5) of the cervical cord. Paradoxical abdominal movement, that is, outward (rather than the normal inward) movement of the abdominal wall during inspiration, is a helpful clinical sign. Disordered sleep is probably a common manifestation of impaired nocturnal ventilation, and early morning headache represents a fairly ominous indicator of nocturnal carbon dioxide retention.

As previously mentioned, clinical involvement of extraocular muscles and external urethral and rectal sphincters never occurs in ALS. ALS patients with UMN dominant disease may complain of urinary urgency. Traditionally, ALS is considered to be a painless disease. However, discomfort due to impaired mobility, spasticity, and cramping may be prominent. Immobilized upper extremities commonly result in painful adhesive capsulitis of the shoulders. Alteration in gait mechanics from leg weakness may put inordinate stress on the back, hips and knees, potentially exacerbating preexisting degenerative joint disease.

Behavioral and cognitive abnormalities in ALS have been recognized since the 19th century but may be obscured by dysarthria, or blamed on coexisting depression. The frontotemporal dementia (FTD) associated with ALS may precede, coincide, or follow signs and symptoms of motor neuron disease. It may occur in both sporadic and familial disease, and it is now estimated that 20% of ALS patients will fulfill criteria for FTD. The cognitive changes are most prominent in the domain of executive dysfunction and language. Disorganization, impaired planning, mental inflexibility, nonfluent progressive aphasia (word finding), and fluent semantic dementia (word meaning) may dominate the clinical picture. Tests of verbal fluency provide a sensitive screening method. Normal patients should be able to generate at least 11 words in 1 minute in a defined category, for example, fruits. Behavioral difficulties are typically displayed in social and interpersonal realms. Patients lose the ability to appreciate nonverbal cues as well as the insight to interpret them. Patients may also become withdrawn, disinhibited, and depressed.

The classification of ALS and related motor neuron disease remains confusing. Many would suggest that the standard is based on histopathologic examination, demonstrating degeneration restricted to anterior horn cells, motor cranial nerve nuclei in the pons and medulla, and corticospinal and corticobulbar tracts, with or without the addition of ubiquitinated inclusions and Bunina bodies. The major problem with this approach of course is the impracticality of using autopsy as a diagnostic tool. An additional hurdle is the potential histopathologic involvement of other nonmotor neurologic systems, most notably the association with frontotemporal dementia. Diagnostic dilemmas occur when the course is slow, or when either UMN or LMN signs do not develop until late in the course. Less typical phenotypes of ALS have often been referred to by other names. Progressive bulbar palsy refers to motor neuron disease that initially exclusively affects bulbar function, typically speech and swallowing. Approximately a quarter of ALS patients, often older women, present in this manner. They may have both UMN and/or LMN features confined to lower cranial nerves. Eventually, the vast majority develops limb involvement and incontrovertible ALS.

Of the approximately two-thirds of patients who present with limb-onset disease, about a third will have predominantly or exclusively LMN features. Sporadic cases of pure lower motor neuron disease have been historically referred to as progressive muscular atrophy (PMA). Most PMA patients will develop UMN features, leaving little doubt that they have ALS. There are patients with PMA who progress more slowly than ALS and never develop UMN signs. Some of these patients, usually men, develop profound weakness that is restricted to either the upper or lower extremities for years before progressing to other regions. These syndromes have been referred to as bibrachial amyotrophic diplegia (BAD) and lower extremity amyotrophic diplegia (LAD), respectively. These designations have little practical value other than to alert clinicians that such atypical presentations exist.

The opposite end of the phenotypic spectrum is the patient with UMN predominant disease. Five percent or less of MND patients will present in this manner. Signs and symptoms typically begin in the legs but may start in the arms or bulbar regions. Exclusive UMN disease has historically been referred to as primary lateral sclerosis (PLS). PLS often has a much more protracted course than full-blown ALS. Most series report an average life expectancy of 7–14 years. A certain percentage of patients with PLS eventually develop clinical and electrodiagnostic evidence of LMN disease, and therefore it would be logical to consider PLS as a subtype of ALS until evidence suggests otherwise. PLS patients who devolve into ALS typically do so within 4 years of onset.

The El Escorial criteria were developed in 1990 in El Escorial, Spain, and were modified in 1998 in Airlie House, Virginia, in an attempt to develop consensus criteria for the research diagnosis of ALS. Definite diagnosis according to these criteria requires both UMN and LMN clinical findings in three of the four body regions (cranial, cervical, thoracic, and lumbosacral). In addition to a definite ALS category, there are probable, possible, and laboratory-supported probable ALS categories. The former two are based solely on clinical criteria, whereas the latter allows for consideration of electrodiagnostic evidence of denervation as a surrogate for clinical evidence of LMN disease. In most cases, an experienced neurologist will recognize the inevitability of the ALS diagnosis long before these criteria are fulfilled. Even more dissuasive is the recognition that approximately a quarter of ALS patients will succumb to their disease without fulfilling these criteria.

Differential Diagnosis

The differential diagnosis of ALS is largely that of other disorders of anterior horn cells, myopathies, disorders of neuromuscular transmission, motor predominant polyneuropathies and myelopathies (Table 67-3). With bulbar onset and predominantly LMN features, myasthenia gravis, inflammatory myopathy particularly inclusion body myositis, X-linked bulbospinal muscular atrophy (Kennedy disease), oculopharyngeal muscular dystrophy, multiple cranial neuropathies, or infiltrative head and neck cancers are the primary considerations. Of these, myasthenia gravis (MG) deserves the most attention. Clues favoring a diagnosis of MG include a weak tongue without atrophy or fasciculations, absence of UMN signs, and presence of ptosis or ophthalmoparesis. Dysphagia, usually without dysarthria, may rarely be the initial or most prominent symptom of the inflammatory myopathies. The pattern of limb weakness, the absence of fasciculations, and UMN signs in these disorders provides distinction from ALS. X-linked bulbospinal muscular atrophy or Kennedy disease may have early or prominent weakness of the throat, tongue, or jaw muscles often associated with fasciculation and may therefore easily be confused with bulbar ALS. A slower evolution of symptoms, the pattern of limb weakness, and the presence of gynecomastia and sensory abnormalities are distinctive features from ALS. Oculopharyngeal muscular dystrophy (OPMD) may be confused with bulbar ALS, although the course of OPMD is typically much longer, with a positive family history and prominent ptosis and ophthalmoplegia on examination. Multiple cranial neuropathies from chronic meningitis (e.g., cancer, sarcoidosis) are usually associated with sensory dysfunction.

The differential diagnosis of head drop includes chronic inflammatory demyelinating neuropathy, radiation neuropathy, MG, and a wide variety of myopathies, for example, acid maltase deficiency, inflammatory myopathies, primary paraspinal myopathy, mitochondrial myopathy, and adult-onset nemaline myopathy. In addition, the dropped head syndrome may be mimicked by anterocollis resulting from multiple system atrophy and other extrapyramidal disorders. Neuromuscular causes of ventilatory failure in adults include a number of neuropathic disorders, for example, infectious disorders such as poliomyelitis and West Nile virus, Guillain–Barré syndrome, critical illness myoneuropathy, toxic neuropathies, and bilateral phrenic neuropathies. Severe hypophosphatemia and hypokalemia may result in ventilatory muscle weakness. In addition, disorders of neuromuscular transmission and some myopathies may progress to ventilatory insufficiency. MG, botulism and rare envenomations may be associated with diaphragmatic weakness. Acid maltase deficiency can affect ventilation early in the course. The dystrophinopathies, limb girdle dystrophy, myotonic muscular dystrophy, and adult-onset nemaline myopathy may progress to ventilatory failure.

In most series, multifocal motor neuropathy (MMN) is the entity most likely to be confused with LMN presentations of ALS. The distinction is important as MMN represents a potentially treatable disorder. The weakness of MMN occurs in an individual nerve distribution rather than in the myotomal pattern of ALS. Unfortunately, as the disease progresses, the confluence of deficits may preclude the identification of this distinctive multifocal neuropathy pattern. In addition, in keeping with its initial demyelinating pathophysiology, MMN often produces weakness in the absence of atrophy. The clinician may have to rely on electrodiagnostic or serologic testing, and a therapeutic trial of intravenous immunoglobulin to make a confident diagnosis.

Another disorder that may be mistaken as LMN predominant ALS is IBM. IBM presents with asymmetric painless weakness in older males that may affect distal as well as proximal muscles. Wrist and finger flexors, foot dorsiflexors, and quadriceps are often weak. The slow progression and the typical pattern of weakness help distinguish IBM from ALS. The juvenile segmental form of spinal muscular atrophy (Hirayama disease) may be difficult to initially distinguish from ALS. This is a slowly progressive and self-limited LMN disorder affecting young adult men with initial involvement of C8–T1 hand and forearm muscles unilaterally.

Benign fasciculations tend to occur repetitively in a single region of a single muscle over the course of a few seconds to minutes and then disappear. The calves and the orbicularis oculi tend to be particularly affected. Patients may seek medical attention for fasciculations that they describe as being widespread and pervasive. Their examination demonstrates no pathologic alterations in muscle strength, bulk, or tone and no reflex abnormalities. In this context, particularly with a normal EMG examination, the patient can be reassured.

UMN presentations of ALS affecting the limbs have a more extensive differential diagnosis. Cervical spondylotic myelopathy is a major differential diagnostic consideration, particularly in individuals presenting with LMN signs in the arms and UMN features in the legs. The presence of sensory and bladder symptoms and imaging should help distinguish this disorder from ALS. Other causes of myelopathy including ischemic (e.g., dural vascular malformations of the spinal cord), infectious, and inflammatory causes of myelopathy also remain considerations.

The differential diagnosis of ALS also uncommonly includes a number of hereditary and degenerative disorders. Of these, hereditary spastic paraparesis is potentially the most confounding, particularly in those individuals in whom there is no family history. Slow progression, the high arched feet, loss of large fiber sensory perception in the feet, and sparing of upper extremity and bulbar function are distinguishing features. An ALS-like syndrome may occur in certain individuals with hexosaminidase deficiency, typically in compound heterozygotes. A motor neuron syndrome may also accompany the spinocerebellar atrophies, particularly type III (Machado–Joseph disease) or occasionally in prion disorders such as Creutzfeldt–Jakob and Gerstmann–Straussler–Scheinker disease. Polyglucosan disease is a rare heritable disorder of glycogen metabolism that may produce cognitive and genitourinary issues in addition to a motor neuropathy.

Finally, certain toxic, metabolic, infectious, immune-mediated, and paraneoplastic conditions have been reported to mimic ALS. Lead toxicity, hyperthyroidism and parathyroidism, HIV, Lyme disease, and lymphoma are the most notable of these. Recently, serum copper deficiency has been reported as a potential ALS mimic and should receive consideration in anyone with an ALS-like syndrome with unexplained sensory complaints.

Diagnostic Approach

There is no perfect algorithm in the evaluation of an ALS suspect. In a patient with LMN and UMN features that have progressed in a typical pattern and time course, the diagnosis is indisputable. In most cases where ALS is suspected, tests are ordered guided by the clinician’s index of suspicion (Table 67-4). In large part, these tests are done to exclude considerations other than ALS.

Virtually every ALS patient undergoes electromyography and nerve conduction studies, collectively referred to as electrodiagnosis (EDX) (Table 67-5). The goal of EDX in ALS is to confirm a pattern of active denervation, chronic denervation, and fasciculation potentials in multiple muscles innervated by multiple segments in multiple regions. According to the modified El Escorial EDX criteria, a definite diagnosis of ALS requires evidence of active denervation (fibrillation potentials and positive sharp waves) in at least three of the following four body regions: cranial, cervical, thoracic, and lumbosacral. In the limbs, at least two different muscles belonging to different nerve and root innervations need to be affected. Involvement in a single cranial muscle is sufficient to satisfy that region’s requirements. Thoracic paraspinal muscles are particularly helpful as they are uncommonly denervated in non-ALS disorders. Fasciculation potentials are a supportive but not mandatory electrodiagnostic feature. Features that would suggest an alternative diagnosis that might mimic ALS need to be excluded; examples include abnormal sensory conductions in Kennedy syndrome, decremental response to repetitive stimulation consistent with myasthenia, conduction block suggestive of multifocal motor neuropathy, or small motor unit potentials suggestive of a myopathy such as IBM. Finally EX may offer insight into the rate of progression, that is, active denervation without chronic denervation and reinnervation, motor unit variability, and a rapid decline in motor unit estimation being electrodiagnostic indicators of a rapidly progressive course.

Table 67-5 Electrodiagnostic Features of EMG

Pattern of abnormalities	Multisegmental in multiple regions (cranial–cervical–thoracoabdominal–lumbosacral)
Motor conductions	↓ or normal CMAP amplitudes depending on severity, relative preservation of conduction velocities, and distal latencies
Sensory conductions	Normal
F waves and H reflexes	F waves normal or absent, M response of H reflex reduced in amplitude, absent or normal depending on severity. Latencies preserved
Slow repetitive stimulation	May demonstrate decremental response
Spontaneous activity (EMG)	Fibrillation potentials and positive waves necessary for diagnosis, complex repetitive, myotonic, myokymic, and neuromyotonic discharges uncommon and should lead to alternative considerations
MUP morphology	Typically long duration, high amplitude with instability if sought for
MUP recruitment	MUP recruitment reduced, MUP activation may be reduced as well with prominent UMN component.

CMAP, compound muscle action potential; MUP, motor unit potential.

MR imaging of the brain should be strongly considered in any patient with a bulbar presentation without limb involvement to identify brainstem parenchymal, meningeal, or cranial nerve disorders. Imaging of the cervical and/or thoracic cord would be indicated in patients with predominantly UMN limb involvement without bulbar signs. Lumbosacral MRI with gadolinium enhancement is indicated in purely LMN syndromes affecting the lower extremities to evaluate for conus medullaris or cauda equina pathology. MRI, positron emission tomography (PET) or single-photon emission computed tomographic (SPECT) imaging may support preferential atrophy or hypometabolism of the anterior brain in individuals suspected of having FTLD.

It is important to recognize that elevated serum creatine kinase levels are not specific for myopathy. Approximately two thirds of ALS patients will have creatine kinase elevations, typically in the 300–500 U/L range but occasionally as high as 1000 or more. Antibodies directed at the GM1 ganglioside are found in high titer in 30–80% of patients with MMN. They are typically ordered in patients with LMN syndromes without cranial nerve or UMN findings. Serologic tests for myasthenia, typically acetylcholine receptor binding, may be obtained in patients with bulbar presentations. Other tests, listed in Table 67-4, are used more judiciously in the appropriate clinical context. Many patients with ALS inquire about the possibility of Lyme disease, and Lyme serologies are frequently ordered to lessen these concerns. HIV testing is not done in suspected ALS unless the clinical context would suggest an increased probability of infection. Historically, screening for heavy metals, thyroid and parathyroid disorders, and occult neoplasia was emphasized. Serum copper, ceruloplasmin, and zinc levels should be considered in any patient with weakness and unexplained sensory symptoms.

Testing for the five commercially available fALS genetic tests is performed in patients with suspected ALS in whom there have been other affected family members. Genetic testing is not recommended in apparent sporadic ALS patients unless there are mitigating circumstances. With a known SOD1 mutation in the proband, testing in an asymptomatic family member should only be done after detailed counseling.

Muscle biopsy is rarely done in ALS suspects except to exclude IBM or other myopathies that might mimic ALS. Pulmonary function tests are used to monitor disease progression; forced vital capacity and inspiratory pressure measurements are obtained both in the sitting and supine positions. Forced vital capacity of less than 50% of predicted suggests a 6-month life expectancy and along with a negative inspiratory force of <60 cm H₂O or PCO₂ of >40 mm Hg are indications for the use of positive airway pressure equipment.

Management and Therapy

Management of ALS includes disease-specific treatments, symptomatic and supportive treatments, as well as adequate education and counseling. These are summarized in Table 67-6 and are elaborated on in two of the reviews listed in the bibliography. Rilutek is the only FDA-approved and effective pharmacologic agent identified to date. Unfortunately, it prolongs life expectancy on average by 10% without noticeable improvement in function or sense of well-being. Its cost is substantial, and it should be prescribed only after the patient has been informed of its benefits and drawbacks. Patients should be encouraged to participate in clinical trials when available. Many ALS patients utilize alternative health measures. Patients should be informed that any treatment biologically active enough to help is also biologically capable of harm. It is not uncommon for patients to ask for medications that have been touted, but unproven to be effective. If these agents are to be studied in clinical trials, clinicians should discourage their use outside of the trial so as to not subvert enrollment in and/or the integrity of the trial.

Table 67-6 Therapeutic Considerations in ALS

Problem	Potential Prescription
ALS	Riluzole 50 mg bid
ALS	Clinical trials
Sialorrhea (excessive thin secretions)	Glycopyrrolate Tricyclic antidepressants Robinul Botulinum toxin Atropine Salivary gland radiation Scopolamine Chorda tympani section

Secretion clearance (thick secretions) Pseudobulbar affect Depression Laryngospasm Neck drop Cervical collar (headmaster) Communication Hypoventilation Contractures Tripping from foot drop Ankle–foot orthoses Falling secondary to quadriceps weakness Reduced bed mobility Hospital bed with side-rails and/or trapeze Bathroom safety and functionality House accessibility Improved ADLs Dysphagia—malnutrition Constipation Urinary urgency Tolterodine Cramps Safety

An important aspect of the management of ALS patients and their families is the provision of reliable education. It is important to discuss end-of-life issues with a patient at some point before a ventilatory crisis occurs or the ability to communicate is lost. Until an effective treatment is found, the primary goals in ALS management are to provide symptom relief and to maintain independent and safe function. In the later stages of disease, the primary goal shifts to maintenance of comfort. Table 67-6 provides a list of many of these potential interventions (Fig. 67-8). In our clinic, we focus on symptoms referable to the following domains: pain, sleep, psychosocial issues, speech and swallowing, ventilation, motor function, and miscellaneous issues. As mentioned above, pain occurs commonly in this disease. Prophylactic range of motion should be applied to immobilized body parts. Analgesics including opioids may be required. Impaired sleep has many potential causes in an ALS patient, including discomfort secondary to immobility or cramping, depression, impaired ventilation and bathroom requirements, each of which may be have to be identified and addressed separately.

Future Directions

Current ALS research is focusing on the identification of biomarkers in ALS that might allow for improved classification of the motor neuron diseases, earlier and more precise identification of ALS patients, and potential insights into critical pathophysiological mechanisms. In addition, scientists are currently attempting to identify susceptibility genes that would potentially provide additional clues for disease origins and mechanisms. Although stem cell biology offers the hope of replacing degenerating motor neurons, ultimately, identifying the root causes of ALS and eliminating them will provide a realistic means by which to cure this devastating disease.