Case 19

Published on 03/03/2015 by admin

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Last modified 03/03/2015

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Case 19

HISTORY AND PHYSICAL EXAMINATION

Progressive weakness developed over 7 months in the left hand of a 53-year-old right-handed woman. Initially, she noted that she had difficulty picking up small objects, buttoning shirts, or pulling snaps. This worsened and she recently has been unable to use her left hand to assist during meals. The weakness had not affected her left upper arm and her right upper extremity was normal. She denied any limb or neck pain, numbness, or cramps. She denied any bulbar, ocular, cognitive, or sphincteric symptoms.

Her medical history was relevant for diabetes mellitus since 45 years of age, hypertension, and cigarette smoking. She takes insulin injections and furosemide. There is no family history of neuromuscular disorder.

On examination, she had normal mental status and cranial nerves. There was no facial weakness, neck weakness, or tongue atrophy or fasciculations. She had slight atrophy of all intrinsic muscles of the left hand only. No fasciculations were observed. Tone was normal. There was moderate weakness that was restricted to the left upper extremity muscles. Manual muscle examination, using Medical Research Council (MRC) grading (1 to 5), showed the following:

• Hand grip 4-/5

• Interossei 4-/5

• Long finger flexors 4/5

• Long finger extensors 4/5

• Wrist extensors 4+/5

• Wrist flexors 4+/5

• Elbow flexion 5-/5

• Elbow extension 5-/5

• Shoulder abduction 5-/5

Deep tendon reflexes were pathologically brisk in both upper extremities, but knee jerks were normal and ankle jerks were absent. Jaw jerk was brisk. She had a right Babinski sign and bilateral Hoffmann signs. Sensory examination was normal to all modalities. Results of gait and cerebellar examinations were normal.

The patient was evaluated by a neurologist who found normal x-rays of the cervical spine. Magnetic resonance imaging of the cervical spine revealed mild disk bulging at C3–C4 and C5–C6. An electrodiagnostic (EDX) study of the left upper extremity, done 3 months after onset of symptoms, revealed fibrillations and large motor units in left C7-, C8-, T1-innervated muscles, with normal sensory and motor nerve conduction studies. Because of progressive left hand weakness, the patient was referred for a repeat EDX examination 7 months after the onset of symptoms.

Please now review the Nerve Conduction Studies and Needle EMG tables.

QUESTIONS

1. The aforementioned EDX findings can be seen with all of the following except:

A. Widespread polyradiculopathy.

B. Diffuse anterior horn cell disease.

C. Axonal motor neuropathy.

D. Diabetic distal polyneuropathy.

2. Diffusely low-amplitude compound muscle action potentials (CMAPs) may be caused by all of the following except:

B. Amyotrophic lateral sclerosis (ALS).

C. Duchenne muscular dystrophy.

D. Lambert-Eaton myasthenic syndrome.

E. Widespread polyradiculopathy.

3. In a patient with diffuse degenerative spine disease, the presence of fibrillations in the upper and lower limbs, as well as the tongue and masseter muscles, is diagnostic of ALS:

4. A patient with weakness in the right hand has fibrillation potentials in the right C5 through T1 roots, with normal left upper limb, lower limbs, thoracic paraspinal and bulbar muscles. These findings rule out ALS:

Case 19: Nerve Conduction Studies

Case 19: Needle EMG

EDX FINDINGS AND INTERPRETATION OF DATA

Pertinent EDX findings in this patient include:

1. Normal sensory nerve action potentials (SNAPs) throughout, including all sensory amplitudes, distal latencies, and conduction velocities.

2. Low-amplitude (or absent) median and ulnar CMAPs, recording the thenar and hypothenar muscles, bilaterally and asymmetrically (worse on the left), with borderline distal latencies, conduction velocities, and F-wave latencies, and no conduction blocks.

These two findings are suggestive of a cervical intraspinal canal lesion, affecting the lower C8/T1 roots or cord segments bilaterally, worse on the left, and producing axonal loss. The slight slowing of motor distal latencies and conduction velocities, and F wave latencies, with values not lower than 70 to 80% of the normal limit, is compatible with an axonal loss lesion, and reflects relative loss of the large, fast-conducting motor fibers. Normal ulnar SNAPs, which derive their fibers from C8 roots, are evidence in support of a preganglionic lesion (i.e., a lesion of the lower cervical roots or cord).

3. Low left peroneal CMAP, recording the extensor digitorum brevis (EDB), with normal latency and conduction velocity.

This, when added to the aforementioned findings, might suggest a diffuse intraspinal canal disease, which extends to the lumbosacral roots or cord. However, it should be remembered that selective atrophy of the extensor digitorum brevis is a common finding, of no definite clinical significance; thus, a low-amplitude CMAP, recording EDB, does not automatically indicate a pathologic process at the L5 root, S1 root, or peroneal nerve.

4. On needle examination, it is clear that the disorder is much more diffuse than can be determined either clinically or by nerve conduction studies. Fibrillation potentials, reduced recruitment, and reinnervated long-duration polyphasic motor unit action potentials (MUAPs) are detected diffusely. Fasciculation potentials are not prominent, seen primarily in asymptomatic limbs. Axonal loss is widespread, affecting muscles of multiple roots and multiple nerve distribution in multiple extremities. The needle EMG findings also mirror the weakness and CMAP abnormalities; they are worst in the left upper extremity, and they are early and subtle in the other three limbs.

In summary, using strict EDX definitions, the findings are pathognomonic of a diffuse pathologic process that involves all ventral roots or spinal cord segments and produces axonal loss, worse in the left cervical myotomes, with evidence of prominent active (ongoing) denervation. These findings may result from an active polyradiculopathy (such as carcinomatous meningitis), a diffuse myelopathy, or rapidly progressive motor neuron disease (such as amyotrophic lateral sclerosis). Obviously, this EDX study is most compatible with ALS in this patient due to the associated upper motor neuron findings, as well as the lack of pain or any other sensory manifestations. The extensive denervation seen in this patient is not consistent with diabetic distal sensorimotor polyneuropathy, because of the predominant loss of motor units in the upper extremities, the marked asymmetry, and the preservation of all the SNAPs. Finally, cool extremities result in high (not low) CMAP and SNAP amplitudes with slow latencies.

DISCUSSION

Pathology and Etiology

Amyotrophic lateral sclerosis (ALS), a term first coined by Charcot in 1875, is the prototypical disease among disorders of the motor neuron. It is a relentlessly progressive and fatal neurodegenerative disorder caused by loss of both upper motor neurons (UMN) and lower motor neurons (LMN). ALS is usually sporadic while 5 to 10% of cases are familial, usually following an autosomal dominant inheritance pattern.

The pathology of sporadic ALS is represented by the selective loss of motor neurons in the spinal cord and brain stem, and cortical motor neurons (Betz cells). Classic findings on spinal cord sections include the loss of anterior horns, with degeneration of the pyramidal tracts (crossed and uncrossed) and dramatic preservation of the dorsal columns and spinocerebellar tracts. Although all motor neurons ultimately degenerate, there is relative sparing of the oculomotor nuclei in the brain stem and Onuff nucleus in the lumbosacral cord. Microscopically, there is, in addition to the loss of anterior horn motor neurons, frequent accumulation of neurofilaments in surviving neurons and dilatation of axons (“spheroids”). The pathologic findings in familial ALS are identical to those in the sporadic form, except that Lewy-like bodies frequently are identified in surviving motor neurons.

Amyotrophic lateral sclerosis is a fatal disorder of unknown etiology. It is likely that there are initiating and propagating factors that lead to motor neuron cell death. Currently, there are five major hypotheses about the development of ALS, although many theories are interrelated:

1. The excitatory amino acid hypothesis. This theory suggests that glutamate excitotoxicity could contribute to neuronal cell loss. It implies that excessive synaptic glutamate, caused in part by its insufficient clearance due to the loss of glutamate transport (likely astroglial-specific), is followed by increased cytosolic calcium, which activates motor neuron cell death.

2. The oxidative stress hypothesis. This theory suggests that increased free radicals lead to neuronal death. It is supported by the discovery that a subset of patients with familial ALS have a mutation in SOD1, the gene that encodes copper-zinc superoxide dismutase (Cu, Zn SOD). This cytoplasmic enzyme, present in all neurons and glia, “dismutes” superoxide into molecular oxygen and hydrogen peroxide, which is catalyzed further into water. How mutation of human Cu, Zn SOD might cause degeneration of motor neurons is unclear. Hypotheses include (1) the generation of hydroxyl radical (HO) from hydrogen peroxide, (2) the release of free copper, which could promote free radical damage to the membranes, or (3) the formation of a nitronium-like intermediate with peroxynitrite, resulting in the nitration of tyrosine residues in critical proteins.

3. The neurofilament poisoning hypothesis. This theory proposes that neurofilament gene mutation results in disorganization and/or decreased transport of neurofilaments, leading to accumulation of axonal neurofilaments, neuronal dysfunction, and degeneration.

4. The immune hypothesis. Certain antibodies directed against the motor neuron population may be found in ALS patients and animal models. Antiganglioside antibodies, especially anti-GM1, are occasionally detected in ALS sera usually in medium titers. These antibodies are present in high titer in acute motor axonal neuropathy (AMAN), and multifocal motor neuropathy with conduction block. Antibodies to – and L-type calcium channels, present in the sera of some patients with ALS, results in increased calcium entry into the cell, leading to degeneration. The lack of response to various immunomodulatory treatments, including intravenous immunoglobulin, cyclophosphamide, and corticosteroids, is perhaps the most telling that there is no convincing evidence of conventional autoimmunity in ALS.

5. The viral hypothesis. HIV and HTLV1 infections may cause ALS-like syndromes, but neither viruses have been shown to cause ALS. However, the possibility of an unconventional infection, such as prions, cannot be excluded.

Clinical Features

Amyotrophic lateral sclerosis, also known as motor neuron disease, Lou Gehrig disease, or maladie de Charcot, occurs in a fairly uniform distribution worldwide with no true differences in geographical incidence, except for small clusters in Guam, the Kii peninsula of Japan, and West New Guinea. The worldwide incidence of ALS is 0.6 to 2.6 per 100 000 population, and its lifetime risk is 1 in 1000. Since 5 to 10% of ALS cases are dominantly inherited, the risk to siblings of a patient with ALS is approximately 2.5 to 5%. The disorder affects both sexes, with a slight preponderance to males. The mean age of onset is 55 years, with a wide range from 17 to 77 years. The illness is fatal within 5 years in 80% of patients; however, some survive as long as 20 years. Patients with initial weakness in the bulbar muscles and older patients have a poorer prognosis for survival. Most patients with ALS die of respiratory failure and fewer than 10% of ALS patients in the United States choose long-term mechanical ventilation to sustain their lives.

More than two-thirds of patients with ALS present with weakness, atrophy, or both. The weakness involves one arm, one leg, or asymmetrically both legs in almost half of patients, while generalized weakness, bilateral upper extremities, or unilateral hemiparesis are less common. Bulbar manifestations are present at onset in a quarter of patients. Fasciculations, cramps, shortness of breath, head drop, or weight loss are rare initial presentations. UMN findings include weakness, spasticity, hyperreflexia, and Babinski and Hoffman signs. LMN findings are usually more pronounced and include weakness, muscle atrophy, fasciculations, and hyporeflexia. Bulbar manifestations in ALS typically include dysarthria, dysphagia, sialorrhea, aspiration, and pseudobulbar affect (inappropriate, spontaneous, forced laughing, crying, or yawning).

A typical patient with ALS is a man in his fifties in whom asymmetrical weakness and atrophy of the muscles develop in one limb, usually those in one hand or one foot. The weakness progresses over time to adjacent myotomes in the same limb and thence to the contralateral limb or the other limb on the same side. The weakness ultimately generalizes to involve all limb, bulbar and respiratory muscles. At its advanced stage, there is usually generalized diffuse muscular atrophy and weakness, fasciculations, spasticity with hyperreflexia, and possibly dysphagia and dysarthria. In typical ALS, there is sparing of sphincteric function, eye movement, sensory function, and cognitive capability.

The diagnosis of ALS is based on the presence of a progressive disorder with the characteristic combination of upper and lower motor neuron involvement. Many criteria have been proposed but most are inadequate, particularly those pertaining to early diagnosis and the definition of upper motor neuron involvement. Among them, the revised El Escorial diagnostic criteria currently are the most widely accepted for the diagnosis of ALS (Table C19-1).

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