Electrodiagnostic testing has proved useful in helping to establish the diagnosis of amyotrophic lateral sclerosis by eliminating possible disease mimics and by demonstrating abnormalities in body areas that are clinically unaffected. Electrodiagnosis begins with an understanding of the clinical features of the disease, because clinical correlation is essential. To improve the sensitivity of the electrophysiologic evaluation, the Awaji criteria have been proposed as a modification to the revised El Escorial criteria. Although techniques to evaluate corticomotor neuron abnormalities and to quantify lower motor neuron loss have been developed, they remain primarily research techniques and have not yet influenced clinical practice.
Key points
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ALS, a relentlessly progressive disorder of upper and lower motor neurons and the most common form of motor neuron disease, is examined here as a model for the electrodiagnosis of all motor neuron disease.
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Electrodiagnostic testing in ALS should be guided by the clinical manifestations noted on physical examination.
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The most sensitive and specific criteria for the diagnosis of ALS are the principles of the revised El Escorial criteria combined with the Awaji modifications to the diagnostic categories of the revised El Escorial criteria.
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Nerve conduction study and needle electromyography remain the most important diagnostic testing for ALS. The former is used primarily to help rule out other disorders, and the latter to establish evidence for widespread active denervation and chronic reinnervation.
Clinical features of amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of upper motor neurons (UMN) and lower motor neurons (LMN). It has a worldwide incidence of approximately 1.5 per 100,000, with a male/female ratio of approximately 1.5. Although occasional patients present before the age of 25, the incidence increases after age 40 and does not clearly decline in the elderly population. Approximately 10% of cases are familial and include autosomal recessive, X-linked, and autosomal-dominant patterns, with autosomal-dominant being most common. The first causative mutation reported was a point mutation in the gene that encodes SOD1; since this discovery in 1993, more than 75 other mutations have been described. Most recently, a hexanucleotide repeat expansion of the chromosome 9 open reading frame 72 (C9orf72) gene has been described, and is likely to be the most common mutation in familial cases with or without frontotemporal dementia. A total of 90% of cases of ALS remain sporadic or idiopathic.
The only clear risk factor is increasing age, but this is too nonspecific to be clinically useful. Sporadic ALS has been linked to cigarette smoking, military service, agricultural or factory work, and periods of heavy muscle use, but a definite causal relationship with any one factor has not been established. Multiple genetic risk factors have been identified in sporadic ALS, including duplication of the survival motor neuron 1 gene and trinucleotide repeat expansion of the ataxin 2 gene. Hexanucleotide repeat expansions of the C9orf72 gene are not only associated with familial ALS, but may be found in approximately 5% to 7% of apparently sporadic cases.
The cause of sporadic ALS is unknown, and many of the multiple genetic defects that cause ALS do so in a manner that is still obscure. The finding that mutations in SOD1 cause ALS has raised the question of the role of oxidative stress in ALS, because SOD1 is a ubiquitous free radical scavenger in neural and nonneural tissue. However, it is clear that SOD1 mutations cause disease as a result of a toxic gain of function, rather than reduction of activity of the SOD1 protein. Mitochondrial dysfunction has been noted early in genetic models, and likely plays a role in the disease pathway. Excitotoxicity by excessive activation of glutamate receptors has been shown in a variety of models, caused at least in part by reduction in glutamate uptake in areas of the brain damaged by ALS. This leads to increased intracellular calcium, which triggers damage to mitochondria and nucleic acids, and ultimately neuronal death. Protein misaggregation has been noted pathologically, and several recently discovered causative mutations in the genes for fused in sarcoma (FUS), TAR DNA binding protein-43 (TDP-43), and potentially C9orf72 result in abnormal protein being deposited in the cytoplasm of motor neurons. Because these genes have a major role in RNA trafficking, impairment of this function has been suggested as a potential cause of ALS.
Riluzole (Rilutek), which reduces glutamate-induced excitotoxicity, is the only drug that has been shown to affect the course of ALS. Death usually occurs through respiratory muscle insufficiency or complications from dysphagia, with a median survival from time of diagnosis of 3 to 5 years. Approximately 10% of patients with ALS may live beyond 10 years, but the relentlessly progressive nature of this disease, the significant morbidity, and impact on family and society is common to all.
The clinical presentation of ALS is varied, given the number of body segments and predominance of UMN versus LMN symptoms and signs that are possible. We speak of ALS affecting four body segments, referring to motor neurons involved in a craniobulbar, cervical, thoracic, or lumbosacral distribution. A fundamental quality of ALS is the presence of UMN and LMN findings that spread without remission to ultimately involve multiple body segments, often in a predictable pattern. UMN findings include muscle spasticity, defined as increased tone in the muscle that renders it resistant to stretch and causes stiff and slow movement with little weakness, and heightened deep tendon reflexes. An interesting feature of UMN dysfunction is pseudobulbar affect. This manifests with sudden outbursts of involuntary laughter or crying that is often excessive or incongruent to mood, caused by loss of voluntary cortical inhibition to brainstem centers that produce the facial and respiratory functions associated with those behaviors, through bilateral corticobulbar lesions, or through interruption of corticocerebellar control of affective displays.
Clinical features resulting from loss of LMNs are flaccid weakness, muscle atrophy, hyporeflexia, muscle cramps, and fasciculations, which may be visible as brief twitching under the skin or in the tongue. LMN loss in axial muscles may result in abdominal protuberance or impaired ability to hold the body or head upright against gravity. LMN loss to the diaphragm results in dyspnea or orthopnea that usually disturbs sleep. Flaccid weakness affecting bulbar muscles may present as slurred, nasal, or hoarse speech; dysphagia; or drooling. The initial clinical presentation of ALS may start in any body segment, and may manifest as UMN, LMN, or both, with a pattern of spread from one body segment to others that is often predictable. In time, UMN and LMN findings develop in the same body segment, if they did not start concurrently. Asymmetric limb weakness, often distal with hand weakness or foot drop, is the initial presentation in 80% of patients, with bulbar symptoms, such as dysarthria or dysphagia, in most of the rest.
Extraocular motor neurons are spared until very late in the disease. Autonomic symptoms are not typical, but multifactorial constipation and urinary urgency from a spastic bladder may occur late in the course. Sensory symptoms, such as distal limb paresthesias, may occur in 20% of patients, but usually with a normal clinical sensory examination. Cognitive symptoms in the form of frontotemporal dementia or dysfunction may be present in anywhere from 15% to 50% of patients. This may manifest as subtle impairment of language, judgment, or personality. Mutations involving certain genes, including TDP-43, FUS, and C9orf72, are associated with a higher likelihood of cognitive impairment.
Clinical features of amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of upper motor neurons (UMN) and lower motor neurons (LMN). It has a worldwide incidence of approximately 1.5 per 100,000, with a male/female ratio of approximately 1.5. Although occasional patients present before the age of 25, the incidence increases after age 40 and does not clearly decline in the elderly population. Approximately 10% of cases are familial and include autosomal recessive, X-linked, and autosomal-dominant patterns, with autosomal-dominant being most common. The first causative mutation reported was a point mutation in the gene that encodes SOD1; since this discovery in 1993, more than 75 other mutations have been described. Most recently, a hexanucleotide repeat expansion of the chromosome 9 open reading frame 72 (C9orf72) gene has been described, and is likely to be the most common mutation in familial cases with or without frontotemporal dementia. A total of 90% of cases of ALS remain sporadic or idiopathic.
The only clear risk factor is increasing age, but this is too nonspecific to be clinically useful. Sporadic ALS has been linked to cigarette smoking, military service, agricultural or factory work, and periods of heavy muscle use, but a definite causal relationship with any one factor has not been established. Multiple genetic risk factors have been identified in sporadic ALS, including duplication of the survival motor neuron 1 gene and trinucleotide repeat expansion of the ataxin 2 gene. Hexanucleotide repeat expansions of the C9orf72 gene are not only associated with familial ALS, but may be found in approximately 5% to 7% of apparently sporadic cases.
The cause of sporadic ALS is unknown, and many of the multiple genetic defects that cause ALS do so in a manner that is still obscure. The finding that mutations in SOD1 cause ALS has raised the question of the role of oxidative stress in ALS, because SOD1 is a ubiquitous free radical scavenger in neural and nonneural tissue. However, it is clear that SOD1 mutations cause disease as a result of a toxic gain of function, rather than reduction of activity of the SOD1 protein. Mitochondrial dysfunction has been noted early in genetic models, and likely plays a role in the disease pathway. Excitotoxicity by excessive activation of glutamate receptors has been shown in a variety of models, caused at least in part by reduction in glutamate uptake in areas of the brain damaged by ALS. This leads to increased intracellular calcium, which triggers damage to mitochondria and nucleic acids, and ultimately neuronal death. Protein misaggregation has been noted pathologically, and several recently discovered causative mutations in the genes for fused in sarcoma (FUS), TAR DNA binding protein-43 (TDP-43), and potentially C9orf72 result in abnormal protein being deposited in the cytoplasm of motor neurons. Because these genes have a major role in RNA trafficking, impairment of this function has been suggested as a potential cause of ALS.
Riluzole (Rilutek), which reduces glutamate-induced excitotoxicity, is the only drug that has been shown to affect the course of ALS. Death usually occurs through respiratory muscle insufficiency or complications from dysphagia, with a median survival from time of diagnosis of 3 to 5 years. Approximately 10% of patients with ALS may live beyond 10 years, but the relentlessly progressive nature of this disease, the significant morbidity, and impact on family and society is common to all.
The clinical presentation of ALS is varied, given the number of body segments and predominance of UMN versus LMN symptoms and signs that are possible. We speak of ALS affecting four body segments, referring to motor neurons involved in a craniobulbar, cervical, thoracic, or lumbosacral distribution. A fundamental quality of ALS is the presence of UMN and LMN findings that spread without remission to ultimately involve multiple body segments, often in a predictable pattern. UMN findings include muscle spasticity, defined as increased tone in the muscle that renders it resistant to stretch and causes stiff and slow movement with little weakness, and heightened deep tendon reflexes. An interesting feature of UMN dysfunction is pseudobulbar affect. This manifests with sudden outbursts of involuntary laughter or crying that is often excessive or incongruent to mood, caused by loss of voluntary cortical inhibition to brainstem centers that produce the facial and respiratory functions associated with those behaviors, through bilateral corticobulbar lesions, or through interruption of corticocerebellar control of affective displays.
Clinical features resulting from loss of LMNs are flaccid weakness, muscle atrophy, hyporeflexia, muscle cramps, and fasciculations, which may be visible as brief twitching under the skin or in the tongue. LMN loss in axial muscles may result in abdominal protuberance or impaired ability to hold the body or head upright against gravity. LMN loss to the diaphragm results in dyspnea or orthopnea that usually disturbs sleep. Flaccid weakness affecting bulbar muscles may present as slurred, nasal, or hoarse speech; dysphagia; or drooling. The initial clinical presentation of ALS may start in any body segment, and may manifest as UMN, LMN, or both, with a pattern of spread from one body segment to others that is often predictable. In time, UMN and LMN findings develop in the same body segment, if they did not start concurrently. Asymmetric limb weakness, often distal with hand weakness or foot drop, is the initial presentation in 80% of patients, with bulbar symptoms, such as dysarthria or dysphagia, in most of the rest.
Extraocular motor neurons are spared until very late in the disease. Autonomic symptoms are not typical, but multifactorial constipation and urinary urgency from a spastic bladder may occur late in the course. Sensory symptoms, such as distal limb paresthesias, may occur in 20% of patients, but usually with a normal clinical sensory examination. Cognitive symptoms in the form of frontotemporal dementia or dysfunction may be present in anywhere from 15% to 50% of patients. This may manifest as subtle impairment of language, judgment, or personality. Mutations involving certain genes, including TDP-43, FUS, and C9orf72, are associated with a higher likelihood of cognitive impairment.
Electrodiagnosis
ALS is a clinical diagnosis, but is supported by electrophysiologic study, which can either help to rule out other possible diagnoses or show characteristic abnormalities in body areas not yet clinically affected. The electrophysiologic studies that are in common practice, such as needle electromyography (EMG) and nerve conduction studies (NCS), directly identify LMN pathology, and at best may suggest UMN pathology by the observation of decreased activation on EMG. How do needle EMG and nerve conduction testing, together referred to as electrodiagnostic testing (EDX), support the diagnosis of ALS? EDX primarily helps rule out other causes of similar symptoms ( Table 1 ) and uncovers subclinical LMN loss, which can speed time to diagnosis and increase diagnostic sensitivity.
| Disease | Presentation | Distinguishing Features | Role of Electrodiagnostic Testing |
|---|---|---|---|
| Cervical radiculomyelopathy | LMN dysfunction at the level of stenosis with UMN findings below | Neck pain and radicular sensory symptoms in arms | No EMG findings in bulbar or thoracic paraspinal muscles |
| Concomitant cervical and lumbar stenosis | Like cervical radiculomyelopathy, but with LMN findings also in lumbosacral myotomes | Neck and back pain, radicular sensory symptoms in the arms and legs | No EMG findings in bulbar or thoracic paraspinal muscles |
| Benign fasciculation syndrome | Frequent fasciculations, diffuse or focal; cramps | Normal neurologic examination | No EMG findings other than fasciculation potentials |
| Multifocal motor neuropathy with conduction block | LMN limb weakness, often upper extremities | Not myotomal, often in patients younger than 45 yr old | Conduction block in motor nerve NCS nonentrapment sites |
| Inflammatory myopathies | LMN limb weakness, dysphagia | IBM: finger flexor, quadriceps weakness Polymyositis or dermatomyositis: proximal muscle weakness | Fibrillation potentials/positive sharp waves; small amplitude and short duration motor unit potentials and occasionally neuropathic MUPs (IBM only) with normal or early recruitment |
Review of the diagnostic criteria for ALS illustrates the importance of uncovering subclinical LMN loss with EDX, particularly with EMG. The El Escorial World Federation of Neurology criteria, first proposed in 1994 and revised in 2000 ( Tables 2 and 3 ), is still in effect, with two key modifications proposed in December 2006 during a consensus conference in Awaji-shima, Japan, sponsored by the International Federation of Clinical Neurophysiology.
| Presence | Absence |
|---|---|
| Evidence of LMN degeneration by clinical, electrophysiologic, or neuropathologic examination | Electrophysiologic or pathologic evidence of another disease process that might explain the signs of LMN or UMN degeneration |
| Evidence of UMN dysfunction by clinical examination | Evidence of another disease process by neuroimaging that might explain the observed clinical and electrophysiologic signs |
| Progressive spread of symptoms or signs within a region or to other regions, as determined by history, physical examination, or electrophysiologic tests |
| Category of ALS | UMN Findings Body Segments a on Physical Examination | LMN Findings Body Segments on Physical Examination | Additional Tests | ||
|---|---|---|---|---|---|
| Clinically definite | 3 | + | 3 | ||
| Clinically probable | 2 Some UMN signs rostral to the LMN signs | + | 2 | ||
| Clinically probable Laboratory supported | 1 At least 1 | + OR + | 1 0 | + + | Acute and chronic denervation in at least two limbs by EMG |
| Clinically possible | 1 At least 2 | + OR | 1 0 | ||
| Definite familial Laboratory supported | 1 | + | 1 | + | Documented genetic mutation |
a Body segments are craniobulbar, cervical, thoracic, and lumbosacral.
Using EMG to uncover subclinical LMN dysfunction in the form of active denervation with compensatory chronic reinnervation in the same muscle can change the diagnosis of ALS from “Clinically Possible ALS” to “Laboratory Supported Clinically Probable ALS.” A limitation of the revised El Escorial criteria is that it is not sufficient to demonstrate LMN dysfunction by EMG alone in a limb, but that the category of “Laboratory Supported Clinically Probable ALS” requires a demonstration of LMN by physical examination in one limb. Another limitation is that the revised El Escorial criteria restricts EMG evidence of acute denervation to fibrillations or positive sharp waves, which may not be as demonstrable in bulbar muscles and those muscles of normal bulk and strength. These limitations have contributed to the fact that 22% of patients die from ALS without being assigned a level of certainty about the disease higher than the “Clinically Possible ALS” category.
To increase the sensitivity for detection of a probable or definite diagnosis of ALS, the Awaji criteria were recently proposed ( Table 4 ). Using these criteria, EMG findings of LMN dysfunction, specifically active denervation with chronic reinnervation in a muscle, are assigned equal diagnostic significance to the findings of LMN dysfunction on physical examination. This eliminates the need for the category of “Laboratory Supported Clinically Probable ALS” and is based on the observation that EMG is an extension of the physical examination in detecting features of denervation and reinnervation.
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