~
~~~~
A patient in whom multiple sclerosis (MS) was ultimately diagnosed presented with a lower motor neuron syndrome involving 1 hand, with EMG evidence of denervation. Twelve other patients were subsequently identified with definite MS and asymmetric hand atrophy. These patients were studied clinically and electrophysiologically.Evidence of chronic and ongoing denervation was noted in the hands of 12 of the 13 patients; in only 3 patients could the EMG abnormalities be accounted for by peripheral nerve lesions. Thus, lesions resulting in lower motor neuron damage may occur in the central nervous system in MS patients. We suggest that demyelination in the region of the ventral root exit zone may account for these findings. 0 1992 John Wiley & Sons, Inc.
Key words: multiple sclerosis denervation peripheral nerve MUSCLE & NERVE 15:1265-1270 1992
LOWER MOTOR NEURON DYSFUNCTION IN PATIENTS WITH MULTIPLE JEREMY M. SHEFNER, MD, PhD, GLENN A. MACKIN, MD, and DAVID M. DAWSON, MD
T h e patchy demyelination that is a hallmark of multiple sclerosis (MS) is traditionally considered to be limited to the central nervous system, sparing myelin produced by Schwann cells. Studies of peripheral sensory and motor conduction usually report normal findings, with occasional abnormalities caused by superimposed entrapment neuropathies.' Even in patients presenting with muscle atrophy, EMG and nerve conduction studies have been normaLg Recently, however, one of us encountered a patient whose initial complaint was of focal hand weakness and atrophy, with clear EMG evidence of denervation. This patient eventually developed signs and symptoms typical of MS. His clinical course prompted a search for other patients with hand muscle atrophy within a population of patients being treated at a large MS clinic. This report discusses the clinical and electrophysiologic findings in 13 such patients.
From the Neurology Division and the Center for Neurologic Diseases, Brigham and Women's Hospital; Spinal Cord Injury Service and Neurology Service, West Roxbury-Brockton VA Medical Center; and the Longwood Neurological Training Program, Harvard Medical School, Boston, Massachusetts. Address reprint requests to Dr. Jeremy Shefner, Neurology Division, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 021 15 Accepted for publication April 2, 1992. CCC 0148-639X/92/111265-06 0 1992 John Wiley & Sons, Inc
Hand Atrophy in MS Patients
CASEREPORT
A 41-year-old man (patient 4 in Table 1) presented with a 2-month history of tingling, numbness, and weakness of the left hand. He had also noted some numbness and stiffness of the left side of his trunk and leg and a pressure sensation along the rib cage. His gait was subjectively mildly unsteady. Initial examination showed striking weakness of the left hand affecting intrinsic muscles. There was also some weakness of finger extension, but proximal strength was intact. All reflexes were normal except for the left triceps jerk, which was absent. Both plantar responses were extensor. No sensory loss could be documented. Cervical plain films were normal, as were head C T scan, cervical myelogram, and postmyelogram metrizamide CT scan. EMG showed fibrillation potentials in the tongue and left hand, and changes in motor unit morphology suggestive of chronic denervation (i.e., enlarged, prolonged, often polyphasic units) in many muscles of the left and right arms, as well as the left leg. Nerve conduction studies of the left median, ulnar, and sural nerves were normal. The patient's left arm weakness improved gradually to normal over 6 months, as did his lower extremity sensory symptoms and gait difficulties. Extensor plantar responses persisted. Eighteen months after presentation, visual-evoked potential studies were normal, while somatosensory-evoked
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responses from left tibia1 nerve stimulation showed a significant delay. MRI of the cervical spine showed an area of increased T-2 signal in the lower cervical area. MRI of the head showed two focal areas of increased T-2 signal, one near the right frontal horn and another adjacent to the right lateral ventricle. The patient remained stable for approximately 5 years, then experienced increasing weakness of his left leg over 1 week. Exam was unchanged except for spastic weakness of his left leg. Prednisone 60 mgld was prescribed, with dramatic improvement over 7 days. Repeat EMG/NCS study showed normal upper and lower nerve conduction studies, and no spontaneous activity in the tongue, paraspinal muscles, or extremities, but abnormalities consistent with chronic denervation in both hands, the left forearm, and bilateral C-7T-1 paraspinal regions. MATERIALS AND METHODS Patient Population. Patients were recruited from the MS clinic at the Brigham and Women's Hospital. All had a diagnosis of definite MS, according to the criteria of Poser et a1.l' Patients were recruited for study if significant hand atrophy was noted, as defined by a difference in hand circumference of more than 1 cm measured at the midmetacarpal level. Weakness of the atrophic hand was not required, nor was sensory loss. In patients who appeared to have bilateral hand atrophy, data from the most affected hand is included in this study. 'Thirteen patients were identified who fulfilled the above criteria. There were 9 men and 4 women, with ages ranging from 20 to 66 years. Duration since disease diagnosis ranged from 1 month to 30 years. Three patients had received no treatment at the time of study, while 10 patients had had one or more courses of corticosteroids, 7 patients had been treated with cyclophosphamide, and 1 patient had been treated with methotrexate. Seven of the 13 patients were moderately or severely weak in the atrophic hand; 1 patient was stronger in that hand than on the contralateral side. Four patients could walk unassisted, 5 patients required a cane, and 4 patients were wheelchair bound. Other abnormalities included hemiataxia (1 patient), afferent pupillary defect (2 patients), intranuclear ophthalmoplegia (3 patients). MRI of the cervical spine was obtained on 9 of the 13 patients; in 6 cases, results were either normal or not relevant in making a diagnosis of hand atrophy. However, in 3 cases, MRI disclosed
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a white matter lesion within the lower cervical spinal cord. Electrophysiological Studies. All patients underwent median and ulnar nerve conduction studies of the most affected hand, using standard techniques. The contralateral hand was also studied in most cases. Temperature of the limb was controlled within 34" to 36°C using a feedbackcontrolled infrared heating lamp. Compound motor action potentials (CMAPs) were recorded using surface electrodes from the abductor pollicis brevis (APB) muscle for median nerve study and the abductor digiti quinti (ADQ) muscle for the ulnar nerve. Median and ulnar F waves were also obtained. Orthodromic sensory potentials were recorded using surface electrodes at the wrist with stimulation of digit 2 for median nerve study and digit 5 for the ulnar nerve. Near-nerve study of a sural nerve was also performed for most patients. A complete description of the stimulus and recording methods is presented e l ~ e w h e r e . ~Me.'~ dian and ulnar distal motor latencies, motor and sensory conduction velocities, compound motor and sensory action potential amplitudes, and F-wave latencies were compared against agedependent normal values. Sural nerve amplitudes and conduction velocities were also compared to age-dependent normal values." Electromyography was carried out using concentric electrodes. In the most affected hand, median and ulnar innervated intrinsic hand muscles were studied; in most cases, forearm muscles innervated by C6-8 myotomes were also tested. In 8 patients, the contralateral arm was also studied. Paraspinal muscles were tested in 4 patients. Muscles were studied in the standard manner. For each muscle, one to four needle insertions were made; for each insertion, four electrode penetrations were made, each at right angles to the others. The presence or absence of abnormal spontaneous activity was determined, and motor unit action potential (MUAP) amplitude, duration, and number of phases was assessed. For each muscle studied, MUAPs were determined to be either normal or enlarged and/or prolonged, suggesting chronic neurogenic change.
RESULTS
Results of electrophysiological study are summarized in the Tables 1 and 2. EMG findings are shown only from intrinsic hand muscles; results from other muscles are reported in the text. Me-
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Table 1. Results of electrophysiological studies on MS patients with hand atrophy. Patients with normal nerve conduction studies. Patient #
NCS abnormalities, most affected hand
1
None
2
None
3 4
None None
5
None
6
None
EMG summary, most affected hand
Other studies
Fibrillations (fibs.) in APB, ADQ, MUAPs prolonged in APB, ADQ. Fibs. in APB, ADO, MUAPs prolonged, enlarged in APB. MUAPs prolonged, enlarged in APB, ADQ. Fibs. in APB, ADQ, MUAPs prolonged, enlarged in APB. ADQ. Fibs. in APB, ADQ, MUAPs prolonged in APB, ADQ. MUAPs prolonged in APB, prolonged, enlarged in ADQ.
Sural NCS: dec min CV. Fibs. in cervical paraspinals Sural NCS: dec max CV, dec min CV. Fibs. in cervical paraspinals. Fibs. in cervical paraspinals Sural NCS: normal. MUAPs prolonged, enlarged in cervical paraspinals.
Sural NCS: dec min CV
NCS nerve conduction studies, APE abductor pollicis brews, ADQ abductor digiti quint!, MUAP motor unit action potential, dec decreased min CV minimum Conduction velocity, and max CV maximum conduction velocity
dian and ulnar nerve conduction studies were within normal limits for patients 1 to 6 (‘Table 1); however, EMG showed fibrillation activity and/or evidence of motor unit remodelling in both median and ulnar distribution muscles. In all 6 patients, EMG also revealed ongoing and/or chronic
denervation in other upper extremity muscles. The primarily C-8 innervated flexor pollicis longus (FPL) was abnormal in all 6 patients, while muscles innervated by C-7 [such as extensor digitorum communis (EDC) and triceps] were denervated in patients 1, 3, 4, and 6. In all patients ex-
Table 2. Results of electrophysiological studies on MS patients with hand atrophy. Patients with nerve conduction abnormalities.
Patient #
NCS abnormalities, most affected hand
EMG summary, most affected hand
Other studies
Patients with nerve conduction abnormalities insufficient to account for EMG 7 Median: prolonged DML. Fibrillations (fibs.) in APB; MUAPs prolonged, enlarged in APB, ADQ. 8 Median: dec SAP amp. Fibs. in ADQ; MUAPs prolonged, enlarged in APB, ADQ. Fibs. in APB, ADQ: MUAPs Ulnar: dec MCV at elbow, dec 9 prolonged, enlarged in APB. SAP amp. Patients with nerve conduction abnormalities sufficient to account for EMG Fibs. in APB, ADQ; MUAPs Median: prolonged DML, F, dec 10 prolonged, enlarged in APB, SAP amp. ADQ. Ulnar: prolonged DML, F, dec MCV at elbow, dec SAP amp. 11 Median: prolonged DML, dec Fibs in ADQ; MUAPs prolonged, enlarged in APB, ADQ. SAP amp. Ulnar: prolonged DML. Fibs in APB, ADO; MUAPs Median: prolonged DML, F, dec 12 prolonged, enlarged in APB, CMAP arnp, dec SAP arnp. ADQ. Ulnar: prolonged DML, F. dec CMAP amp, dec MCV at elbow Patient with normal EMG, abnormal nerve conduction studies 13 Median: prolonged DML, dec EMG normal. MCV, dec SAP amp. Ulnar: prolonged DML, dec MCV
Sural NCS: dec min CV
Sural NCS: normal. Sural NCS: dec min CV
Sural NCS dec amp, dec min CV Contralateral hand worse NCS abnormalities, only mild EMG abnormalities Sural NCS dec amp
Sural NCS: dec min CV.
Sural NCS: dec amp
DML. distal motor latency; SAP. sensory action potential; MCV: motor conduction velocity; CMAP: compound motor action potential; F: F wave; and amp. ampktude.
Hand Atrophy in MS Patients
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cept for patient 4, who showed a diffuse pattern of chronic denervation, EMG of muscles innervated primarily by C-5 and C-6 were normal. Paraspinal EMG was performed in patients 1 to 4; fibrillation potentials were seen in the lower cervical paraspinal regions in patients 1 to 3, while paraspinal MUAPs were prolonged and enlarged in patient 4, when studied 5 years after his initial presentation (see Case Report). In 3 of 4 patients, sural nerve study showed normal amplitudes and maximum conduction velocity, providing further evidence against a significant polyneuropathy. Thus, the EMG and nerve conduction abnormalities in patients 1 to 6 are most consistent with lesions at the root or anterior horn cell level, rather than focal or generalized neuropathy. In patients 7 to 9 (Table 2), abnormalities were noted in median and ulnar nerve conduction studies, but were insufficient to account for the EMG findings. The only nerve conduction abnormalities seen in patients 7 and 8 were mild prolongation of median distal motor latency (patient 7) and reduced median sensory action potential amplitude (patient 8). In both patients, EMG was limited to intrinsic hand muscles, but clear evidence for denervation was found in both median and ulnar muscles. In patient 9, deriervation was noted in the APB, ADQ, FPL, and EDC, while nerve conduction abnormalities were limited to a probable ulnar neuropathy at the elbow. In 8 patients, EMG and nerve conduction findings coincided, suggesting that peripheral nerve abnormalities could account for the denervation seen in distal hand muscles. Patients 10 and 11 showed evidence of mild generalized neuropathies, with abnormalities noted in median and ulnar nerves as well as either decreased sural CSAP amplitude or conduction velocity. EMG showed denervation in both median and ulnar innervated hand muscles, as well as ulnar innervated forearm muscles in patient 10. In patient 12, nerve conduction studies suggested both a carpal tunnel syndrome and an ulnar neuropathy at the elbow; EMG showed denervation in intrinsic hand muscles, but the EDC was normal. In patient 13, EMG of distal hand muscles was normal in the presence of significant hand atrophy. For this patient, nerve conduction studies suggested both median and ulnar nerve lesions, but EMG showed no evidence of denervation. For this patient, EMG was performed only on intrinsic hand muscles.
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Hand Atrophy in MS Patients
DISCUSSION
In this study, patients were selected for evaluation because of asymmetric hand atrophy. EMG showed signs of denervation in both median and ulnar innervated muscles in I 2 of 13 patients. In 8 of the 12 patients showing denervation of hand muscles, forearm muscles innervated by C-8/T-1 roots were also studied and showed denervatiori as well. Nerve conduction study revealed a variety of abnormalities, suggesting that the denervation found on EMG could be caused by one or more of several mechanisms. In 6 patients, including the patient discussed in the Case Report, no evidence of either focal or significant generalized peripheral neuropathy was found. If a peripheral nerve lesion is not responsible for the denervation seen on needle exam, an intrinsic lesion of the spinal cord must be considered. A lesion of multiple sclerosis located at the exit zone of the lower cervical ventral roots could cause a pure motor deficit such as that seen in these patients; the lesion cannot be purely demyelinating, because the EMG findings imply that some degree of axonal damage has occurred. While a lesion confined to this area may well be too small to be resolved given current imaging techniques, 3 patients did have MRI scans showing lesions in the lower cervical region. It is irnportant to note that none of the other 6 patients studied with cervical MRI showed evidence of cervical root compression on their scans. The patient discussed in the Case Report obviously did not present in a typical manner for multiple sclerosis. His initial presentation involved primarily lower motor neuron abnormalities; EMG showed ongoing and chronic denervation in three limbs, as well as fibrillations in the tongue. However, his subsequent course was quite typical of multiple sclerosis, with evolving upper motor neuron abnormalities, a long latent period, and then an exacerbation that was well treated with prednisone. A definite explanation for this patient’s diffuse lower motor neuron abnormalities is not available. However, it seems possible that his initial presentation was due to a diffuse, predominantly spinal white matter lesion involving ventral root exit zones quite widely. The abnormalities in the tongue could have been due to a parallel process in the brainstem. Upon repeat EMG 5 years later, only mild evidence of chronic denervation was noted in bilateral extremity and paraspinal muscles innervated by the lower cervical roots. Processes that result in reduced numbers of
MUSCLE & NERVE
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motor axons within a peripheral nerve often will be reflected in a reduced compound motor action potential when that nerve is stimulated. This is frequently the case in radiculopathies, as well as degenerative diseases such as amyotrophic lateral sclerosis. However, if a disease process is slowly progressive in its course, loss of axons can be at least partially compensated for by terminal sprouting of the remaining axons. This will result in an increase in the size of existing motor units and a relative preservation of the amplitude of the compound muscle action potential. Obviously, if this preservation were complete, there would be no loss of muscle fibers and therefore no hand atrophy. The normal compound motor action potential amplitude in the context of moderate atrophy most likely reflects both ongoing reinnervation as well as the large variability of the normal range of motor action potential amplitudes. The lack of clear weakness in 3 of 13 patients with mild atrophy also demonstrates the wide range of normality in the clinical examination. The presence of fibrillation potentials has been noted in some patients with cervical spinal cord injuries in myotomes far distal to the area of injury (e.g., refs. 3 and 6 ) , raising the possibility that this electrical activity may be caused by an upper motor neuron lesion. In patients with multiple sclerosis who have multiple central nervous system lesions, the same possibility exists. However, the incidence of multiple compressive neuropathies in the spinal cord- injured population is very high,I4 and it is likely that the fibrillations noted in muscles remote from the area of injury are simply a result of axon loss from superimposed neuropathy. In our patients, chronic neurogenic change reflected in enlarged, prolonged motor units was seen just as frequently as fibrillation potentials, making the possibility that these abnormalities are due to upper motor neuron damage even less likely. The occurrence of muscle atrophy in patients with MS has been noted previously, with evidence of focal wasting found in 6% and 7% of patients in two series.’.” There has been no clear consensus, however, regarding the etiology of focal atrophy. Fisher et al.7 found that nerve conduction studies, as well as EMG, tended to be normal in their patients, and concluded that hand wasting was likely to be the result of CNS disease above the level of the anterior horn cell. However, their criteria for subject inclusion were different than in the present study. In contrast, autopsy studies have found a variety of anterior horn cell lesions
Hand Atrophy in MS Patients
in areas of the spinal cord projecting to atrophic muscles.538In addition, EMG abnormalities consistent with denervation were reported in 3 patients with focal hand atrophy.‘ In 6 of our patients, upper extremity nerve conduction abnormalities were found in conjunction with EMG evidence of denervation in intrinsic hand muscles. In 3 of these patients, the abnormalities did not involve both ulnar and median nerves and so could not account for EMG findings, while 3 patients had evidence of combined median and ulnar lesions. Multiple compressive neuropathies are common in any population where movements are impaired and there is loss of muscle bulk. They have been reported previously in multiple sclerosis patients,“ as well as in other immobilizing conditions such as spinal cord injury. It is possible that a more generalized neuropathy may account for the EMG abnormalities seen in some patients. Sural nerve study showed reduced amplitude or maximum conduction velocity in 4 patients. In addition, minimum conduction velocity was reduced in 7 of the 11 patients studied. This is consistent with a prior study showing that mild peripheral nerve abnormalities were present in many patients with MS.I5 The reason for the disparity between our results and those reported by Fisher et al.7 is unclear. Disease duration was quite similar for both groups, being 8.9 years for our patients and 9.3 years in the Fisher et al. series. One possible difference is that weakness was well correlated with atrophy for patients reported by Fisher et al., while 6 of 13 patients in our series had either mild or no weakness. This difference may reflect a different underlying mechanism for the hand atrophy in the two groups. In summary, MS patients may display focal intrinsic hand muscle atrophy either early or late in the course of their disease. This atrophy usually reflects denervation, and may be secondary either to focal peripheral neuropathies or to motor neuron damage within the spinal cord.
’
REFERENCES 1. Blaik Z, McCarry J. Daura R: Peripheral neuropathy in spinal cord injured patients. Eleclromyogr Clin Neurophysiol 1989;29:469-472. 2. Bonduelle M, Bouygues P, Chaumont P: Amyotrophies e l abolition des reflexes dans la sclerose en plaque. Sem Hop Paris 1964; 13:B 14- 82 1. 3. Brandstater ME, Dinsdale SM: Electrophysiological studies in the assessment of spinal cord lesions. Arch Phys Med Rehabil 1976:57:70-74.
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4. Buchthal F, Rosenfalck A, Behse F: Sensory potentials of normal and diseased nerves, in Dyck PI, Thomas PK, Lambert EH, Bunge R (eds): Peripherul Neuroputhy. Philadelphia, WB Saunders, 1984, p p 981-1015. 5. Davison C, Goodhart SP, Lander J : Multiple sclerosis and amyotrophies. Arch Neurol Psychiatry 1934;31:270-289. 6. Di Benedetto M: Electrodiagnostic phenomena observed in patients with spinal cord lesions. Electromyoffr Clin Neurophysiol 1977; 17:205-220. 7 . Fisher M, Long R, Drachman D: Hand muscle atrophy in multiple sclerosis. Arch Neurol 1983;409:811-815. 8. Friedman AP, Davison C: Multiple sclerosis with late onset of symptoms. Arch Neural Psychiatry 1945;54:348-360. 9. Hasson J , Terry R, Zimmerman H: Peripheral neuropathy in multiple sclerosis. Neurology 1958;8:503-5 10. 10. Horowitz S, Krarup C: Conduction studies in 139 normal
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sural nerves. Electroencephalogr Clin Nturaphysiol 1987; 66:S47. 11. Kurtzke JF, Beebe GW, Nagler B, et al.: Studies on the natural history of multiple sclerosis. Actu Neural Scand 1972;48: 19-46. 12. Poser CM, Paty D, Scheinberg L, et al.: New diagnostic criteria for multiple sclerosis. Ann Neural 1983;13:227-231. 13. Shefner JM, Buchthal F, Krarup C: Slowly conducting myelinated fibers in peripheral neuropathy. Muscle Nerve 1991; 14:534-542. 14. Shefner JM, T u n C: Clinical neurophysiology of focal spinal cord injury. Neural Clin 1991;9:671-678. 15. Shefner 1M, Carter IL, Krarup C: Peripheral sensory abnormalities in patients with mGltiple scle'rosis. Muscle kerve 1992;15:73- 76.
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~~~~
A patient in whom multiple sclerosis (MS) was ultimately diagnosed presented with a lower motor neuron syndrome involving 1 hand, with EMG evidence of denervation. Twelve other patients were subsequently identified with definite MS and asymmetric hand atrophy. These patients were studied clinically and electrophysiologically.Evidence of chronic and ongoing denervation was noted in the hands of 12 of the 13 patients; in only 3 patients could the EMG abnormalities be accounted for by peripheral nerve lesions. Thus, lesions resulting in lower motor neuron damage may occur in the central nervous system in MS patients. We suggest that demyelination in the region of the ventral root exit zone may account for these findings. 0 1992 John Wiley & Sons, Inc.
Key words: multiple sclerosis denervation peripheral nerve MUSCLE & NERVE 15:1265-1270 1992
LOWER MOTOR NEURON DYSFUNCTION IN PATIENTS WITH MULTIPLE JEREMY M. SHEFNER, MD, PhD, GLENN A. MACKIN, MD, and DAVID M. DAWSON, MD
T h e patchy demyelination that is a hallmark of multiple sclerosis (MS) is traditionally considered to be limited to the central nervous system, sparing myelin produced by Schwann cells. Studies of peripheral sensory and motor conduction usually report normal findings, with occasional abnormalities caused by superimposed entrapment neuropathies.' Even in patients presenting with muscle atrophy, EMG and nerve conduction studies have been normaLg Recently, however, one of us encountered a patient whose initial complaint was of focal hand weakness and atrophy, with clear EMG evidence of denervation. This patient eventually developed signs and symptoms typical of MS. His clinical course prompted a search for other patients with hand muscle atrophy within a population of patients being treated at a large MS clinic. This report discusses the clinical and electrophysiologic findings in 13 such patients.
From the Neurology Division and the Center for Neurologic Diseases, Brigham and Women's Hospital; Spinal Cord Injury Service and Neurology Service, West Roxbury-Brockton VA Medical Center; and the Longwood Neurological Training Program, Harvard Medical School, Boston, Massachusetts. Address reprint requests to Dr. Jeremy Shefner, Neurology Division, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 021 15 Accepted for publication April 2, 1992. CCC 0148-639X/92/111265-06 0 1992 John Wiley & Sons, Inc
Hand Atrophy in MS Patients
CASEREPORT
A 41-year-old man (patient 4 in Table 1) presented with a 2-month history of tingling, numbness, and weakness of the left hand. He had also noted some numbness and stiffness of the left side of his trunk and leg and a pressure sensation along the rib cage. His gait was subjectively mildly unsteady. Initial examination showed striking weakness of the left hand affecting intrinsic muscles. There was also some weakness of finger extension, but proximal strength was intact. All reflexes were normal except for the left triceps jerk, which was absent. Both plantar responses were extensor. No sensory loss could be documented. Cervical plain films were normal, as were head C T scan, cervical myelogram, and postmyelogram metrizamide CT scan. EMG showed fibrillation potentials in the tongue and left hand, and changes in motor unit morphology suggestive of chronic denervation (i.e., enlarged, prolonged, often polyphasic units) in many muscles of the left and right arms, as well as the left leg. Nerve conduction studies of the left median, ulnar, and sural nerves were normal. The patient's left arm weakness improved gradually to normal over 6 months, as did his lower extremity sensory symptoms and gait difficulties. Extensor plantar responses persisted. Eighteen months after presentation, visual-evoked potential studies were normal, while somatosensory-evoked
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responses from left tibia1 nerve stimulation showed a significant delay. MRI of the cervical spine showed an area of increased T-2 signal in the lower cervical area. MRI of the head showed two focal areas of increased T-2 signal, one near the right frontal horn and another adjacent to the right lateral ventricle. The patient remained stable for approximately 5 years, then experienced increasing weakness of his left leg over 1 week. Exam was unchanged except for spastic weakness of his left leg. Prednisone 60 mgld was prescribed, with dramatic improvement over 7 days. Repeat EMG/NCS study showed normal upper and lower nerve conduction studies, and no spontaneous activity in the tongue, paraspinal muscles, or extremities, but abnormalities consistent with chronic denervation in both hands, the left forearm, and bilateral C-7T-1 paraspinal regions. MATERIALS AND METHODS Patient Population. Patients were recruited from the MS clinic at the Brigham and Women's Hospital. All had a diagnosis of definite MS, according to the criteria of Poser et a1.l' Patients were recruited for study if significant hand atrophy was noted, as defined by a difference in hand circumference of more than 1 cm measured at the midmetacarpal level. Weakness of the atrophic hand was not required, nor was sensory loss. In patients who appeared to have bilateral hand atrophy, data from the most affected hand is included in this study. 'Thirteen patients were identified who fulfilled the above criteria. There were 9 men and 4 women, with ages ranging from 20 to 66 years. Duration since disease diagnosis ranged from 1 month to 30 years. Three patients had received no treatment at the time of study, while 10 patients had had one or more courses of corticosteroids, 7 patients had been treated with cyclophosphamide, and 1 patient had been treated with methotrexate. Seven of the 13 patients were moderately or severely weak in the atrophic hand; 1 patient was stronger in that hand than on the contralateral side. Four patients could walk unassisted, 5 patients required a cane, and 4 patients were wheelchair bound. Other abnormalities included hemiataxia (1 patient), afferent pupillary defect (2 patients), intranuclear ophthalmoplegia (3 patients). MRI of the cervical spine was obtained on 9 of the 13 patients; in 6 cases, results were either normal or not relevant in making a diagnosis of hand atrophy. However, in 3 cases, MRI disclosed
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Hand Atrophy in MS Patients
a white matter lesion within the lower cervical spinal cord. Electrophysiological Studies. All patients underwent median and ulnar nerve conduction studies of the most affected hand, using standard techniques. The contralateral hand was also studied in most cases. Temperature of the limb was controlled within 34" to 36°C using a feedbackcontrolled infrared heating lamp. Compound motor action potentials (CMAPs) were recorded using surface electrodes from the abductor pollicis brevis (APB) muscle for median nerve study and the abductor digiti quinti (ADQ) muscle for the ulnar nerve. Median and ulnar F waves were also obtained. Orthodromic sensory potentials were recorded using surface electrodes at the wrist with stimulation of digit 2 for median nerve study and digit 5 for the ulnar nerve. Near-nerve study of a sural nerve was also performed for most patients. A complete description of the stimulus and recording methods is presented e l ~ e w h e r e . ~Me.'~ dian and ulnar distal motor latencies, motor and sensory conduction velocities, compound motor and sensory action potential amplitudes, and F-wave latencies were compared against agedependent normal values. Sural nerve amplitudes and conduction velocities were also compared to age-dependent normal values." Electromyography was carried out using concentric electrodes. In the most affected hand, median and ulnar innervated intrinsic hand muscles were studied; in most cases, forearm muscles innervated by C6-8 myotomes were also tested. In 8 patients, the contralateral arm was also studied. Paraspinal muscles were tested in 4 patients. Muscles were studied in the standard manner. For each muscle, one to four needle insertions were made; for each insertion, four electrode penetrations were made, each at right angles to the others. The presence or absence of abnormal spontaneous activity was determined, and motor unit action potential (MUAP) amplitude, duration, and number of phases was assessed. For each muscle studied, MUAPs were determined to be either normal or enlarged and/or prolonged, suggesting chronic neurogenic change.
RESULTS
Results of electrophysiological study are summarized in the Tables 1 and 2. EMG findings are shown only from intrinsic hand muscles; results from other muscles are reported in the text. Me-
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Table 1. Results of electrophysiological studies on MS patients with hand atrophy. Patients with normal nerve conduction studies. Patient #
NCS abnormalities, most affected hand
1
None
2
None
3 4
None None
5
None
6
None
EMG summary, most affected hand
Other studies
Fibrillations (fibs.) in APB, ADQ, MUAPs prolonged in APB, ADQ. Fibs. in APB, ADO, MUAPs prolonged, enlarged in APB. MUAPs prolonged, enlarged in APB, ADQ. Fibs. in APB, ADQ, MUAPs prolonged, enlarged in APB. ADQ. Fibs. in APB, ADQ, MUAPs prolonged in APB, ADQ. MUAPs prolonged in APB, prolonged, enlarged in ADQ.
Sural NCS: dec min CV. Fibs. in cervical paraspinals Sural NCS: dec max CV, dec min CV. Fibs. in cervical paraspinals. Fibs. in cervical paraspinals Sural NCS: normal. MUAPs prolonged, enlarged in cervical paraspinals.
Sural NCS: dec min CV
NCS nerve conduction studies, APE abductor pollicis brews, ADQ abductor digiti quint!, MUAP motor unit action potential, dec decreased min CV minimum Conduction velocity, and max CV maximum conduction velocity
dian and ulnar nerve conduction studies were within normal limits for patients 1 to 6 (‘Table 1); however, EMG showed fibrillation activity and/or evidence of motor unit remodelling in both median and ulnar distribution muscles. In all 6 patients, EMG also revealed ongoing and/or chronic
denervation in other upper extremity muscles. The primarily C-8 innervated flexor pollicis longus (FPL) was abnormal in all 6 patients, while muscles innervated by C-7 [such as extensor digitorum communis (EDC) and triceps] were denervated in patients 1, 3, 4, and 6. In all patients ex-
Table 2. Results of electrophysiological studies on MS patients with hand atrophy. Patients with nerve conduction abnormalities.
Patient #
NCS abnormalities, most affected hand
EMG summary, most affected hand
Other studies
Patients with nerve conduction abnormalities insufficient to account for EMG 7 Median: prolonged DML. Fibrillations (fibs.) in APB; MUAPs prolonged, enlarged in APB, ADQ. 8 Median: dec SAP amp. Fibs. in ADQ; MUAPs prolonged, enlarged in APB, ADQ. Fibs. in APB, ADQ: MUAPs Ulnar: dec MCV at elbow, dec 9 prolonged, enlarged in APB. SAP amp. Patients with nerve conduction abnormalities sufficient to account for EMG Fibs. in APB, ADQ; MUAPs Median: prolonged DML, F, dec 10 prolonged, enlarged in APB, SAP amp. ADQ. Ulnar: prolonged DML, F, dec MCV at elbow, dec SAP amp. 11 Median: prolonged DML, dec Fibs in ADQ; MUAPs prolonged, enlarged in APB, ADQ. SAP amp. Ulnar: prolonged DML. Fibs in APB, ADO; MUAPs Median: prolonged DML, F, dec 12 prolonged, enlarged in APB, CMAP arnp, dec SAP arnp. ADQ. Ulnar: prolonged DML, F. dec CMAP amp, dec MCV at elbow Patient with normal EMG, abnormal nerve conduction studies 13 Median: prolonged DML, dec EMG normal. MCV, dec SAP amp. Ulnar: prolonged DML, dec MCV
Sural NCS: dec min CV
Sural NCS: normal. Sural NCS: dec min CV
Sural NCS dec amp, dec min CV Contralateral hand worse NCS abnormalities, only mild EMG abnormalities Sural NCS dec amp
Sural NCS: dec min CV.
Sural NCS: dec amp
DML. distal motor latency; SAP. sensory action potential; MCV: motor conduction velocity; CMAP: compound motor action potential; F: F wave; and amp. ampktude.
Hand Atrophy in MS Patients
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cept for patient 4, who showed a diffuse pattern of chronic denervation, EMG of muscles innervated primarily by C-5 and C-6 were normal. Paraspinal EMG was performed in patients 1 to 4; fibrillation potentials were seen in the lower cervical paraspinal regions in patients 1 to 3, while paraspinal MUAPs were prolonged and enlarged in patient 4, when studied 5 years after his initial presentation (see Case Report). In 3 of 4 patients, sural nerve study showed normal amplitudes and maximum conduction velocity, providing further evidence against a significant polyneuropathy. Thus, the EMG and nerve conduction abnormalities in patients 1 to 6 are most consistent with lesions at the root or anterior horn cell level, rather than focal or generalized neuropathy. In patients 7 to 9 (Table 2), abnormalities were noted in median and ulnar nerve conduction studies, but were insufficient to account for the EMG findings. The only nerve conduction abnormalities seen in patients 7 and 8 were mild prolongation of median distal motor latency (patient 7) and reduced median sensory action potential amplitude (patient 8). In both patients, EMG was limited to intrinsic hand muscles, but clear evidence for denervation was found in both median and ulnar muscles. In patient 9, deriervation was noted in the APB, ADQ, FPL, and EDC, while nerve conduction abnormalities were limited to a probable ulnar neuropathy at the elbow. In 8 patients, EMG and nerve conduction findings coincided, suggesting that peripheral nerve abnormalities could account for the denervation seen in distal hand muscles. Patients 10 and 11 showed evidence of mild generalized neuropathies, with abnormalities noted in median and ulnar nerves as well as either decreased sural CSAP amplitude or conduction velocity. EMG showed denervation in both median and ulnar innervated hand muscles, as well as ulnar innervated forearm muscles in patient 10. In patient 12, nerve conduction studies suggested both a carpal tunnel syndrome and an ulnar neuropathy at the elbow; EMG showed denervation in intrinsic hand muscles, but the EDC was normal. In patient 13, EMG of distal hand muscles was normal in the presence of significant hand atrophy. For this patient, nerve conduction studies suggested both median and ulnar nerve lesions, but EMG showed no evidence of denervation. For this patient, EMG was performed only on intrinsic hand muscles.
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DISCUSSION
In this study, patients were selected for evaluation because of asymmetric hand atrophy. EMG showed signs of denervation in both median and ulnar innervated muscles in I 2 of 13 patients. In 8 of the 12 patients showing denervation of hand muscles, forearm muscles innervated by C-8/T-1 roots were also studied and showed denervatiori as well. Nerve conduction study revealed a variety of abnormalities, suggesting that the denervation found on EMG could be caused by one or more of several mechanisms. In 6 patients, including the patient discussed in the Case Report, no evidence of either focal or significant generalized peripheral neuropathy was found. If a peripheral nerve lesion is not responsible for the denervation seen on needle exam, an intrinsic lesion of the spinal cord must be considered. A lesion of multiple sclerosis located at the exit zone of the lower cervical ventral roots could cause a pure motor deficit such as that seen in these patients; the lesion cannot be purely demyelinating, because the EMG findings imply that some degree of axonal damage has occurred. While a lesion confined to this area may well be too small to be resolved given current imaging techniques, 3 patients did have MRI scans showing lesions in the lower cervical region. It is irnportant to note that none of the other 6 patients studied with cervical MRI showed evidence of cervical root compression on their scans. The patient discussed in the Case Report obviously did not present in a typical manner for multiple sclerosis. His initial presentation involved primarily lower motor neuron abnormalities; EMG showed ongoing and chronic denervation in three limbs, as well as fibrillations in the tongue. However, his subsequent course was quite typical of multiple sclerosis, with evolving upper motor neuron abnormalities, a long latent period, and then an exacerbation that was well treated with prednisone. A definite explanation for this patient’s diffuse lower motor neuron abnormalities is not available. However, it seems possible that his initial presentation was due to a diffuse, predominantly spinal white matter lesion involving ventral root exit zones quite widely. The abnormalities in the tongue could have been due to a parallel process in the brainstem. Upon repeat EMG 5 years later, only mild evidence of chronic denervation was noted in bilateral extremity and paraspinal muscles innervated by the lower cervical roots. Processes that result in reduced numbers of
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motor axons within a peripheral nerve often will be reflected in a reduced compound motor action potential when that nerve is stimulated. This is frequently the case in radiculopathies, as well as degenerative diseases such as amyotrophic lateral sclerosis. However, if a disease process is slowly progressive in its course, loss of axons can be at least partially compensated for by terminal sprouting of the remaining axons. This will result in an increase in the size of existing motor units and a relative preservation of the amplitude of the compound muscle action potential. Obviously, if this preservation were complete, there would be no loss of muscle fibers and therefore no hand atrophy. The normal compound motor action potential amplitude in the context of moderate atrophy most likely reflects both ongoing reinnervation as well as the large variability of the normal range of motor action potential amplitudes. The lack of clear weakness in 3 of 13 patients with mild atrophy also demonstrates the wide range of normality in the clinical examination. The presence of fibrillation potentials has been noted in some patients with cervical spinal cord injuries in myotomes far distal to the area of injury (e.g., refs. 3 and 6 ) , raising the possibility that this electrical activity may be caused by an upper motor neuron lesion. In patients with multiple sclerosis who have multiple central nervous system lesions, the same possibility exists. However, the incidence of multiple compressive neuropathies in the spinal cord- injured population is very high,I4 and it is likely that the fibrillations noted in muscles remote from the area of injury are simply a result of axon loss from superimposed neuropathy. In our patients, chronic neurogenic change reflected in enlarged, prolonged motor units was seen just as frequently as fibrillation potentials, making the possibility that these abnormalities are due to upper motor neuron damage even less likely. The occurrence of muscle atrophy in patients with MS has been noted previously, with evidence of focal wasting found in 6% and 7% of patients in two series.’.” There has been no clear consensus, however, regarding the etiology of focal atrophy. Fisher et al.7 found that nerve conduction studies, as well as EMG, tended to be normal in their patients, and concluded that hand wasting was likely to be the result of CNS disease above the level of the anterior horn cell. However, their criteria for subject inclusion were different than in the present study. In contrast, autopsy studies have found a variety of anterior horn cell lesions
Hand Atrophy in MS Patients
in areas of the spinal cord projecting to atrophic muscles.538In addition, EMG abnormalities consistent with denervation were reported in 3 patients with focal hand atrophy.‘ In 6 of our patients, upper extremity nerve conduction abnormalities were found in conjunction with EMG evidence of denervation in intrinsic hand muscles. In 3 of these patients, the abnormalities did not involve both ulnar and median nerves and so could not account for EMG findings, while 3 patients had evidence of combined median and ulnar lesions. Multiple compressive neuropathies are common in any population where movements are impaired and there is loss of muscle bulk. They have been reported previously in multiple sclerosis patients,“ as well as in other immobilizing conditions such as spinal cord injury. It is possible that a more generalized neuropathy may account for the EMG abnormalities seen in some patients. Sural nerve study showed reduced amplitude or maximum conduction velocity in 4 patients. In addition, minimum conduction velocity was reduced in 7 of the 11 patients studied. This is consistent with a prior study showing that mild peripheral nerve abnormalities were present in many patients with MS.I5 The reason for the disparity between our results and those reported by Fisher et al.7 is unclear. Disease duration was quite similar for both groups, being 8.9 years for our patients and 9.3 years in the Fisher et al. series. One possible difference is that weakness was well correlated with atrophy for patients reported by Fisher et al., while 6 of 13 patients in our series had either mild or no weakness. This difference may reflect a different underlying mechanism for the hand atrophy in the two groups. In summary, MS patients may display focal intrinsic hand muscle atrophy either early or late in the course of their disease. This atrophy usually reflects denervation, and may be secondary either to focal peripheral neuropathies or to motor neuron damage within the spinal cord.
’
REFERENCES 1. Blaik Z, McCarry J. Daura R: Peripheral neuropathy in spinal cord injured patients. Eleclromyogr Clin Neurophysiol 1989;29:469-472. 2. Bonduelle M, Bouygues P, Chaumont P: Amyotrophies e l abolition des reflexes dans la sclerose en plaque. Sem Hop Paris 1964; 13:B 14- 82 1. 3. Brandstater ME, Dinsdale SM: Electrophysiological studies in the assessment of spinal cord lesions. Arch Phys Med Rehabil 1976:57:70-74.
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4. Buchthal F, Rosenfalck A, Behse F: Sensory potentials of normal and diseased nerves, in Dyck PI, Thomas PK, Lambert EH, Bunge R (eds): Peripherul Neuroputhy. Philadelphia, WB Saunders, 1984, p p 981-1015. 5. Davison C, Goodhart SP, Lander J : Multiple sclerosis and amyotrophies. Arch Neurol Psychiatry 1934;31:270-289. 6. Di Benedetto M: Electrodiagnostic phenomena observed in patients with spinal cord lesions. Electromyoffr Clin Neurophysiol 1977; 17:205-220. 7 . Fisher M, Long R, Drachman D: Hand muscle atrophy in multiple sclerosis. Arch Neurol 1983;409:811-815. 8. Friedman AP, Davison C: Multiple sclerosis with late onset of symptoms. Arch Neural Psychiatry 1945;54:348-360. 9. Hasson J , Terry R, Zimmerman H: Peripheral neuropathy in multiple sclerosis. Neurology 1958;8:503-5 10. 10. Horowitz S, Krarup C: Conduction studies in 139 normal
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sural nerves. Electroencephalogr Clin Nturaphysiol 1987; 66:S47. 11. Kurtzke JF, Beebe GW, Nagler B, et al.: Studies on the natural history of multiple sclerosis. Actu Neural Scand 1972;48: 19-46. 12. Poser CM, Paty D, Scheinberg L, et al.: New diagnostic criteria for multiple sclerosis. Ann Neural 1983;13:227-231. 13. Shefner JM, Buchthal F, Krarup C: Slowly conducting myelinated fibers in peripheral neuropathy. Muscle Nerve 1991; 14:534-542. 14. Shefner JM, T u n C: Clinical neurophysiology of focal spinal cord injury. Neural Clin 1991;9:671-678. 15. Shefner 1M, Carter IL, Krarup C: Peripheral sensory abnormalities in patients with mGltiple scle'rosis. Muscle kerve 1992;15:73- 76.
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