Neuromuscular Diseases of the Older Adult

Janaka K. Seneviratne

Mark A. Ross

MOTOR NEURON DISEASE

DEFINITION OF TERMS

Motor neuron disease (MND) refers to a group of disorders resulting from dysfunction and death of motor neurons. Although the pathologic changes in MND are well known, the underlying etiology remains poorly understood. It is likely that common pathogenetic mechanisms cause the different forms of MND and other neurodegenerative diseases. The clinical manifestations of MND depend on the degree of upper motor neuron (UMN) and lower motor neuron (LMN) involvement and the specific regions of the nervous system involved. There are four main clinical categories seen in MND (22).

Amyotrophic lateral sclerosis (ALS): UMN and LMN findings
Primary lateral sclerosis (PLS): Only UMN findings
Progressive muscle atrophy (PMA): Only LMN findings
Progressive bulbar palsy (PBP): Only bulbar findings

CLINICAL FEATURES

Clinical features define the different categories of MND. ALS is the most common form of MND. The diagnosis of ALS requires both UMN and LMN findings. The other types of MND, which do not meet the definition of ALS, are initially viewed as tentative diagnostic considerations because of the high likelihood that additional clinical signs will develop as the disease progresses over time. Patients with only LMN findings are diagnosed with PMA, and those with purely UMN findings are diagnosed with PLS. Patients with PBP can have either UMN or LMN findings but do not have sufficient abnormalities to meet the criteria for ALS.

Amyotrophic Lateral Sclerosis

ALS is by far the most common form of MND. The diagnosis is established by clinical criteria that require progressive muscle weakness with both UMN and LMN findings on examination and no alternative explanation after a thorough investigation. The disease typically begins with slowly progressive focal muscle weakness.

Early in the diagnostic evaluation, the motor manifestations may be exclusively UMN, exclusively LMN, or any combination of both. However, both UMN and LMN signs must be present to meet the criteria for diagnosis. As the illness progresses, there is worsening of motor function in affected regions and spread to previously unaffected regions (3).

The LMN signs are muscle weakness, atrophy, and fasciculations. Muscle atrophy is a major contributing factor to the weight loss that regularly occurs in ALS patients. Careful inspection of muscles may be necessary to observe fasciculations. Obesity or edema may completely obscure fasciculations and may even mask muscle atrophy. Muscle cramps are common and may precede other symptoms.

The UMN signs are weakness, spasticity, hyperreflexia, and pathologic reflexes. The pattern of UMN muscle weakness typically affects antigravity muscles. Prominent spasticity can significantly impair motor function despite relatively preserved strength. Many patients do not develop severe spasticity and may simply have hyperreflexia or pathologic reflexes as UMN manifestations. Reflexes that are considered pathologic include the Babinski sign and either clonus or spread of reflexes to other muscles. Reflex spread may be vertical, as with the brachioradialis reflex spreading to the biceps, or horizontal, such as the crossed adductor reflex. Other pathologic reflexes include the jaw jerk, hyperactive gag reflex, and the presence of the superficial abdominal reflex.

Weakness begins in the limbs in 60% to 75% of cases. Either the arms or legs may be initially involved. The weakness often begins asymmetrically in a single limb. Rarely, it may affect the arm and leg on one side at onset, creating a hemiparetic pattern.

Onset with bulbar muscle weakness is the second most common presentation, which may occur in 25% to 40% of patients. Bulbar involvement can begin with dysarthria or dysphagia, but dysarthria is much more common as an initial symptom. Dysarthric speech may result from either UMN or LMN dysfunction or a combination of both. Dysarthric speech
due to UMN disease is often characterized as strained or strangulated speech. Dysarthria due to LMN disease is described as slurred speech. Dysphagia is usually first noted as difficulty swallowing liquids. As dysphagia progresses, patients develop difficulty swallowing solid foods. Patients observe choking on thin liquids and foods with particulate consistencies. UMN bulbar signs include hyperactive gag reflex and jaw jerk. Clinical manifestations of LMN bulbar dysfunction include tongue atrophy and tongue fasciculations.

Another common feature of ALS patients with bulbar involvement is emotional lability. This has been called pseudobulbar palsy or pseudobulbar affect. This term refers to a change in emotional expression, such that patients lose the ability to inhibit strong emotions. Consequently, patients display either crying or laughing in situations that formerly would not have prompted such emotional release. This may be an important clue to the illness because this emotional lability is not seen in other neuromuscular disorders causing bulbar dysfunction.

Rarely, respiratory muscle weakness causing dyspnea can be the initial manifestation of ALS. More often, respiratory muscle weakness develops gradually as the patient develops progressive limb weakness. Respiratory muscle failure is the usual cause of death and the reason for the poor prognosis with ALS. There is great variability of survival in ALS, with some patients progressing rapidly to death within 1 year of symptom onset and others surviving for 10 to 20 years. The average survival ranges from 3 to 4 years from the time of diagnosis.

Although ALS is often considered to be a purely motor disorder, some patients develop additional neurologic manifestations. Dementia may occur, and recent studies have suggested that frontotemporal type dementia may be much more common than previously recognized. Sensory symptoms are never a prominent feature of the illness, but many patients may have minor sensory complaints. Autonomic involvement is uncommon, but many patients have problems with constipation, and occasionally, patients develop urinary incontinence.

Primary Lateral Sclerosis

PLS is a gradually progressive form of MND with UMN findings. Some patients develop limited electromyographic evidence of LMN involvement but not sufficient evidence of LMN involvement to meet criteria for ALS. As in ALS, the diagnosis requires thorough investigation to exclude other conditions that could cause UMN disease. Many patients with an initial provisional diagnosis of PLS later develop progressive LMN disease and meet the criteria for ALS (4,31). The most common initial presentation of PLS is asymmetrical spastic leg weakness. The second most common clinical presentation is bulbar dysfunction. Patients with PLS may develop upper extremity weakness and spasticity as the illness progresses, but upper extremity onset is uncommon. Bladder function is usually preserved in PLS. Cognitive function is generally preserved in PLS, although some studies have indicated mild frontal lobe dysfunction (5). The progression of PLS is much slower than ALS, and consequently, the prognosis is much better. In reported series, patients with PLS have died from causes other than PLS.

Progressive Muscular Atrophy

PMA is the term used to describe MND when only LMN involvement is present. Patients with progressive LMN disease require thorough evaluation for other conditions that might cause this clinical presentation. Examples include spinal root disorders, multifocal motor neuropathy, inflammatory myopathy, and viral disorders such as West Nile virus and poliomyelitis. Patients with PMA generally have a slower course than patients with ALS and are less likely to develop bulbar involvement. Most patients initially diagnosed as having PMA will later develop UMN signs and meet criteria for ALS.

Progressive Bulbar Palsy

PBP is a form of MND primarily affecting the bulbar muscles. The disorder begins with bulbar dysfunction with symptoms of dysarthria or dysphagia. Most patients who begin with bulbar disease ultimately go on to develop the typical clinical picture of ALS. Those rare patients who remain with an exclusively bulbar illness without progression to ALS are regarded as having PBP.

EPIDEMIOLOGY IN OLDER ADULTS

The annual incidence of ALS is one to two per 100,000 population, with a prevalence rate of four to six cases per 100,000. ALS is an adult illness, with the average age of onset in the mid-50s and the peak age of incidence in the age range of 50 to 75 years (22,26). The male-to-female ratio is 1.5:1 up to age 70 and 1:1 afterwards. Due to progression of muscle weakness leading to respiratory failure, the average period of survival from diagnosis is 3 to 4 years. Rarely, patients may survive for >10 years. Factors that favor relatively longer survival include young age of onset (<45 years), onset in limb muscles, male gender, and a longer period from symptom onset to diagnosis (33). Of the different categories of MND, ALS has the worst prognosis. Although the other categories of MND have a better prognosis than ALS, it is not possible to be certain of the prognosis or estimate survival for an individual patient with one of the other forms of MND.

The frequency of PLS has been estimated to be roughly 2% to 10% of all cases of MND, with most series showing a rate of <5%. Onset is usually in the fifth decade or later. Both PMA and PBP are infrequent, with each category making up <5% of all cases of MND.

PATHOLOGY

The primary pathology of MND involves degeneration and death of motor neurons. The pathology is similar in the different clinical subtypes of MND. The major pathologic change is loss of motor neurons and resultant gliosis. In forms of MND with UMN involvement, there is evidence of corticospinal tract degeneration. Even some patients with PMA who have no clinical evidence of UMN involvement have been found to have corticospinal tract degeneration at postmortem examination. Such findings have reinforced the concept that the different forms of MND are all variations within the broad spectrum of neurodegenerative disease (4,31).

Neuronal pathology in MND includes chromatolysis, increased lipofuscin, neurofilament accumulation, and ubiquitinated inclusions. Additional pathologic findings include Bunina bodies (34), Lewy-like inclusions, and Hirano bodies.

ETIOLOGY

The cause of MND remains undetermined. Hereditary forms of MND provide evidence that genetic factors can either cause or contribute to the illness. Roughly 10% of ALS cases are familial, with most having an autosomal dominant inheritance pattern. Roughly 20% of familial cases are due to mutations in the superoxide dismutase 1 (SOD1) gene. The sporadic and familial forms have similar pathology and clinical features, although several unique clinical presentations are associated with specific SOD1 mutations.

The most common SOD1 mutation variant seen in North America is the A4V variant. This name describes an alanine substitution for valine at codon 4. This variant accounts for roughly half of the SOD1 cases in North America and is clinically characterized by an exclusively LMN illness. This disorder is rapidly progressive, with a survival time of 1 year or less. Another important SOD1 mutation is the D90A variant, which manifests as a predominantly UMN illness with survival >10 years.

The precise mechanisms by which SOD1 mutations lead to MND remain unknown. However, studies from the transgenic mouse model have indicated that the fundamental problem is a gain of an undetermined toxic function rather than an inability to scavenge free radicals (10).

In addition to a genetic basis for MND, other pathogenetic mechanisms that have been considered include toxin exposure (25), viral illness (18), and autoimmune illness. Multiple pathogenic processes have been considered, including mitochondrial dysfunction, protein aggregation (35), oxidative stress (30), disrupted cytoskeleton and impaired axonal transport, and glutamate excitotoxicity (29).

Exposure to toxins may play a role in MND pathogenesis. Several studies have demonstrated an association between exposure to heavy metals such as lead and mercury and MND (23). Although motor neuron degeneration has been associated with significant exposure to heavy metals, this does not appear to be a contributing factor in typical cases of ALS or other forms of MND.

Disorders such as poliomyelitis and West Nile virus complicated by encephalomyelitis provide examples in which motor neuron loss clearly occurs as a complication of a viral illness. Although theoretically attractive, no conclusive association between viral infection and MND has been determined. Efforts to detect viral pathogens including polio virus have not been successful. MND has been reported to occur as a rare consequence of HIV infection (18), but such an association is not clearly established in the majority of cases.

DIAGNOSIS

No specific diagnostic test exists for ALS or the other categories of MND. Consequently, the diagnosis of MND is established by clinical criteria, with diagnostic tests performed primarily to exclude other conditions that may have similar features. It is standard clinical practice to perform thorough diagnostic testing before reaching the conclusion that a patient has MND. Routine tests include laboratory studies, electromyography (EMG), and selected imaging studies of the central nervous system. The purpose of such testing is to determine whether any alternative condition or combination of conditions could possibly account for the clinical phenotype of MND. If an alternative condition can be identified, then the clinician must weigh the evidence for the alternative condition against the possibility of MND.

Laboratory Studies

Laboratory studies are primarily obtained to search for conditions that may, at times, mimic ALS or other forms of MND. Another reason for obtaining laboratory studies is that MND is a chronic progressive illness and there may be systemic complications that need to be monitored with laboratory studies.

Laboratory studies that are commonly assessed for patients suspected of having ALS include complete blood count, chemistry panel, sedimentation rate, thyroid-stimulating hormone, vitamin B₁₂ level, rapid plasma reagent, antinuclear antibody, and serum
immunofixation electrophoresis. For patients with disease onset at age <40 years, it is common to evaluate the hexosaminidase A level. For patients with a history of exposure to heavy metals, a 24-hour urine collection for heavy metal testing is preformed. A variety of other laboratory tests may be ordered depending on individual case circumstances.

Electromyography

EMG studies are routinely performed as part of the diagnostic evaluation of patients suspected of having MND. The results of EMG studies are integrated with the information obtained through clinical history, physical examination, laboratory studies, and radiologic studies.

EMG studies are critically important for the diagnosis of MND for several reasons. First, EMG studies can reveal evidence of a pathophysiologic process other than motor neuron degeneration, which would completely change the suspected diagnosis. Examples include peripheral neuropathy, such as multifocal motor neuropathy (20); a myopathic process, such as inflammatory myopathy; or a neuromuscular junction transmission disorder, such as myasthenia gravis (MG) or Lambert-Eaton myasthenic syndrome (LEMS). Each of these conditions can mimic ALS, and in some cases, EMG studies may provide the critical clue when the diagnosis is not otherwise suspected.

The EMG studies also provide information about the degree and distribution of LMN abnormalities. There may be times when LMN involvement is not readily apparent on the clinical examination and EMG studies resolve this question. Finding widespread fibrillation potentials can substantiate the diagnosis of ALS or PMA, and the absence of widespread fibrillation potentials can support a diagnosis of PLS or PBP.

Nerve conduction studies may be normal in MND or may show low-amplitude compound muscle action potentials (CMAPs) reflecting loss of motor axons. Repetitive nerve stimulation (RNS) studies may show a decremental response in some patients with ALS.

The EMG findings on needle examination in ALS include fibrillation potentials, fasciculation potentials, and neurogenic motor unit potential changes. Reduced recruitment of motor unit potentials is common. If reinnervation of muscle fibers has occurred, the motor unit potentials become complex with large-amplitude, long-duration, and excessive polyphasia. Such motor unit potentials often show instability with variation in amplitude while firing. This reflects blocking or failure of action potentials from some muscle fibers due to recently formed and immature neuromuscular junctions.

If EMG studies are performed relatively early in the course of the patient’s symptomatic illness, there may not be sufficient LMN abnormalities to be certain of the diagnosis. In this case, it is best to repeat the studies in several months because more abnormalities develop with time.

Neuroimaging Evaluation

Magnetic resonance imaging (MRI) studies of the brain and cervical spinal cord are frequently performed when the diagnosis of MND is suspected. The main purpose of these studies is to exclude other diseases of the central nervous system that could explain UMN findings. In most patients with MND, the brain and cervical spine MRI studies do not reveal abnormalities that can explain the clinical features. MRI studies of the cervical spine are commonly performed to evaluate for cervical spine abnormalities, which at times may mimic ALS. The combination of cervical spinal stenosis and multilevel cervical radiculopathies can produce both UMN and LMN signs that mimic ALS. Brain MRI studies are performed to evaluate for structural abnormalities or diseases of the brain that could explain the patient’s UMN signs.

Conventional MRI studies using long T2-weighted or fluid-attenuated inversion recovery (FLAIR) sequences may show hyperintense signal changes in the corticospinal tract at the level of the posterior limb of the internal capsule or cerebral peduncles in some ALS patients (11).

Newer MRI techniques, such as magnetization transfer and diffusion tensor imaging, are being investigated for the potential of better demonstration of abnormal signal within the corticospinal tracts in patients with MND.

DIAGNOSTIC CRITERIA

Despite the lack of specific diagnostic tests for MND, diagnostic criteria for ALS have been developed based on clinical features. The criteria commonly used for research studies are the Revised El Escorial Criteria. These criteria require the basic features of UMN and LMN signs, progression of the illness as manifested by spread of physical signs over time, and exclusion of other disorders that could mimic ALS.

The El Escorial Criteria are based on division of the central nervous system into four anatomic regions: the brainstem and cervical, thoracic, and lumbosacral spinal regions. Each region is assessed for UMN and LMN signs, and the combination of findings is used to place the patient into a category of diagnostic certainty (Table 25-6). The criteria were created for the purpose of standardizing enrollment of ALS patients onto research studies. The current standard for clinical trials in ALS is to limit eligibility for enrollment to those patients with
definite and probable ALS. Although these categories require clinical evidence of more extensive disease, the term “diagnostic certainty” may be somewhat misleading. There is no evidence that patients who do not meet criteria for definite or probable ALS are less likely to have the diagnosis. Furthermore, there is no evidence that the category of diagnostic certainty is predictive of prognosis. The fact that roughly 10% of ALS patients die of the illness without ever having documented clinical signs to meet criteria for probable or definite ALS underscores the limitations of these criteria.

Table 25-6. Revised El Escorial Criteria for ALS

ALS Diagnostic Category	Criteria
Definite ALS	UMN and LMN signs in 3 regions
Definite Familial ALS	UMN and LMN signs in 1 region plus DNA evidence of familial ALS
Probable ALS	UMN and LMN signs in 2 regions (with some UMN signs rostral to LMN signs)
Probable ALS, laboratory supported	UMN and LMN signs in 1 region or UMN signs in ≥ 1 region plus
	EMG evidence of LMN signs in ≥ 2 limbs
Possible ALS	UMN and LMN signs in 1 region
From Brooks BR, Miller RG, Swash M, et al. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000;5:293-299.