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Electrodiagnosis of Motor Neuron Disease

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Electrodiagnosis of Motor Neuron Disease Electrodiagnosis of Motor Neuron Disease Anuradha Duleep, MD*, Jeremy Shefner, MD, PhD KEYWORDS Motor neuron disease Amyotrophic lateral sclerosis Awaji criteria Electrodiagnosis KEY POINTS 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 electrodiag- nosis of all motor neuron disease. Electrodiagnostic testing in ALS should be guided by the clinical manifestations noted on physical examination. 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 cate- gories of the revised El Escorial criteria. 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 reinner- vation. 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 inci- dence of approximately 1.5 per 100,000, with a male/female ratio of approximately 1.5.1 Although occasional patients present before the age of 25, the incidence increases after age 40 and does not clearly decline in the elderly population.2 Approx- imately 10% of cases are familial and include autosomal recessive, X-linked, and Dr Shefner receives research funding from NIH, ALSA, MDA, ALS Therapy Alliance, Biogen-Idec, Sanofi Aventis, Neuraltus. He receives personal compensation as an Editor for UpToDate, and as a consultant for Trophos, ISIS, Glaxo SmithKline, Biogen-Idec, Cytokinetics. No disclosures (Anuradha Duleep). Department of Neurology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA * Corresponding author. E-mail address: [email protected] Phys Med Rehabil Clin N Am 24 (2013) 139–151 http://dx.doi.org/10.1016/j.pmr.2012.08.022 pmr.theclinics.com 1047-9651/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved. 140 Duleep & Shefner autosomal-dominant patterns, with autosomal-dominant being most common.3 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.4,5 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.6 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, agricul- tural or factory work, and periods of heavy muscle use, but a definite causal relation- ship with any one factor has not been established.7,8 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.9–12 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.13,14 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.15,16 Mitochondrial dysfunction has been noted early in genetic models, and likely plays a role in the disease pathway.17 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.18 This leads to increased intracellular calcium, which trig- gers damage to mitochondria and nucleic acids, and ultimately neuronal death. Protein misaggregation has been noted pathologically, and several recently discovered caus- ative 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.19,20 Because these genes have a major role in RNA traf- ficking, impairment of this function has been suggested as a potential cause of ALS.21 Riluzole (Rilutek), which reduces glutamate-induced excitotoxicity, is the only drug that has been shown to affect the course of ALS.22,23 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 cranio- bulbar, 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.24 Electrodiagnosis of Motor Neuron Disease 141 Clinical features resulting from loss of LMNs are flaccid weakness, muscle atrophy, hyporeflexia, muscle cramps, and fasciculations, which may be visible as brief twitch- ing 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 find- ings 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.25 This may manifest as subtle impairment of language, judgment, or personality.26 Mutations involving certain genes, including TDP-43, FUS, and C9orf72, are associated with a higher likelihood of cognitive impairment.27–29 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. 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 Feder- ation of Clinical Neurophysiology.30 Using EMG to uncover subclinical LMN dysfunction in the form of active denervation with compensatory chronic reinnervation in the same muscle can change the diag- nosis of ALS from “Clinically Possible ALS” to “Laboratory Supported Clinically Prob- able 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 “Labo- ratory Supported Clinically Probable ALS” requires a demonstration of LMN by phys- ical 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.
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