~~~~~~~
~
~
We have carried out a long-term study of lesions found in a man who had a demyelinating disease of both central and peripheral nervous systems. During the 10 years of his clinical course, he suffered from optic neuritis, multifocal myelitis, and chronic multifocal demyelinating neuropathy, with persistent conduction block. Our study revealed that both central and peripheral nervous system demyelination occurred repeatedly and simultaneously. Key words: demyelinating neuropathy, chronic multifocal conduction block multiple sclerosis useless hand syndrome magnetic resonance imaging MUSCLE & NERVE 14:953-959 1991
CHRONIC MULTIFOCAL DEMYELlNATlNG NEUROPATHY ASSOCIATED WITH CENTRAL NERVOUS SYSTEM DEMYELlNATlON MUTSUO NAGANUMA, MD, KOHJI SHIMA MD, AKlHlSA MATSUMOTO, MD, and KUNIO TASHIRO MD
Many reports have been published concerning clinical and pathophysiological studies of lesions in demyelinating diseases with combined involvement of central and p r i p h e r a l nervous systems (CNS and PNS),'6,20, PNS lesions in multiple sclerosis, and CNS lesions in acute or chronic inflammatory demyelinating polyradiculoneuropathy (AIDP or CIDP). It was, however, only in the cases of AIDP, that attention was paid to the simultaneous occurrence of demyelinations in both nervous systems, and analyzed prospectively with magnetic resonance ima ing (MRI) and/or electrophysiological studies. 13,18,25,26 Lewis et al. reported 5 cases of chronic multifocal demyelinating neuropathy (CMDN) with persistent conduction block (CB).I4 Because 2 of
From the Department of Neurology, Sapporo Minami National Hospital, Sapporo, Japan (Drs. Naganuma, Shima, and Matsumoto), and Department of Neurology, Hokkaido University School of Medicine, Sapporo, Japan (Dr. Tashiro). Acknowledgments: The authors thank Dr. A. Ohnishi for his evaluation of the pathology of the sural nerve, and for his comments on our work. The authors also thank Dr. K. Miyasaka for his evaluation of the MRI findings. Address reprint requests to Mutsuo Naganuma, MD, Department of Neurology, Hokkaido University School of Medicine, N-15 W-7, Sapporo, Hokkaido, Japan. Accepted for publication September 17, 1990.
CCC 0148- 639X/91/01001953- 07 $04.00 0 1991 John Wiley & Sons, Inc.
Chronic Multifocal Dernyelinating Neuropathy
the cases had optic neuritis, they emphasized that the demyelinating lesion was not always restricted to the PNS. By extensive electrophysiological, pathological, and radiological studies during 3 exacerbations over 4 years, we found multifocal demyelination repeatedly and simultaneously in both the CNS and PNS. CASE REPORT
At the age of 26, in August 1980, our patient suddenly developed partial loss of vision in his left eye. T w o days later, painful dysesthesia attacked his legs, but disappeared in a few days. On initial admission to our hospital 2 weeks later, he had a central scotoma and papilledema in his left eye, loss of knee and achilles tendon reflexes, decreased vibration and position sense in his legs, and a positive Romberg sign. After 3 months of parenteral prednisolone therapy, most of these neurological signs had disappeared, except for reduced visual acuity. Five years later, in December 1985, he gradually developed weakness of his legs, especially of his left knee. Two months later, he noted weakness and tightness of his extremities, predominantly on the right side. Furthermore, tingling and numbness began to develop gradually in the distal part of the lower extremities, slowly spreading up over his body. When he was admitted for
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the second time in April 1986, he had mild weakness of right upper and lower extremities, generalized areflexia, a positive right Babinski sign, a left-side dominant superficial sensory disturbance over his body and extremities, a marked loss of both position and vibratory sensation below the pelvis and in the ulnar aspect of his right hand, and a positive Romberg sign. Hematological and serological tests all fell within normal limits. CSF analysis showed a protein level of 67 mg/dL, 7 cells/mm3, and no myelin basic protein (MBP). MRI with 0.5 T, T R 2000 ms, and T E 80 ms demonstrated a region of abnormally high signal in the spinal cord on the right at C6. (Fig. 1A) Using a steroid pulse therapy (20 mg/kg of methylprednisolone was given intravenously once a day for 3 days) followed by oral prednisolone (1 mg/kg per day for 1 week with a gradual tapering dosage) most of his symptoms and signs had disappeared within the next 2 months. He was discharged with only a mild loss of vibration sense and generalized areflexia. In October 1986, 4 months after discharge, numbness developed in his feet bilaterally, and
gradually rose to his pelvis; similar numbness then began to develop in his hands and spreaded to his neck. He also complained of dysesthesia over the left side of his chest and face. When he was admitted for the third time in January 1987, he had decreased sensation over the left side of his face corresponding to the distribution of the trigeminal nerve, weakness and pseudo-athetotic involuntary movements of the hands, generalized areflexia, hyperalgesia of the extremities and paresthesia below his neck, profound loss of both position and vibratory sensation in his upper extremities with distal predominance, and mild loss of vibratory sensation in the lower extremities. CSF analysis showed a protein level of 56 mg/dL, 1 cell/mm3, no MBP, and 3 oliogoclonal IgG bands (OCB). There was no laboratory evidence of syphilis, diabetes mellitus, porphyria, dysglobulinemia, collagen vasculitis, or infections from human immunodeficiency virus type I or 111. Metrizamide C T myelography showed focal swelling of the upper cervical spinal cord (Fig. 1B). After repetition of steroid pulse therapy, most of his symptoms and signs gradually
A
C
0
D
FIGURE 1. MRI (0.5 T, TR 2000 ms, TE 80 ms) during the second admission showed a region of abnormally high signal in the spinal cord on the right at C6 (A). Metrizamide CT myelography during the third admission showed focal swelling in the spinal cord at C3 (6). MRI (1.5 T, TR 3000 ms, TE 30 ms) during the fourth admission showed a region of abnormally high signal in the spinal cord on the right posterolateral at C6 (C), and on the dorsal columns at C3 with no focal swelling (D).
954
Chronic Multifocal Demyelinating Neuropathy
MUSCLE & NERVE
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disappeared during the following 3 months, except for hypalgesia below the knees. From about one year after discharge, he sometimes complained of double vision, numbness of the right side of his face, weakness of his right arm, pain and weakness of his right lower leg, and a tight band-like feeling in his chest. In March 1989, he complained of numbness and weakness of the ulnar side of his left hand. In May, he felt weakness of his left lower leg. When he was admitted for the fourth time in June 1989, he had generalized areflexia, weakness of right hand muscles innervated by the median and ulnar nerves, weakness of right foot flexor muscles and left foot extensor muscles, superficial sensory disturbance over the ulnar aspect of both his upper extremities, mild loss of vibration and position sense of lower extremities, and positive Romberg sign. CSF analysis showed a protein level of 119 mg/dL; 5 cells/mm3. MRI with 1.5 T, TR 3000 ms, and TE 30 ms, showed a region of abnormally high signal in the spinal cord on the posterior column at C3 and T1, and on the posterolateral at C6 with no focal swelling. (Fig. 1C and 1D) After oral prednisolone therapy, he again im-
proved gradually, and was discharged 3 months later with little clinical disturbance. MATERIALS AND METHODS
Electrophysiological studies were performed using an electromyographer (Medelec, Sanei, Japan) and signal processor (Evomatic, DISA, Denmark). Motor nerve conduction studies were performed by percutaneous supramaximal nerve stimulation at bilateral median, ulnar, tibial, and peroneal nerves. l 2 Compund muscle action potentials (CMAP) were recorded using surface electrodes. We used Lewis’ criteria to judge CB; the negative peak area of the CMAP by proximal stimulation was less than 60% of the area obtained by distal stimulation. l4 F-wave latencies were determined as the average of 10 responses recorded at bilateral median, ulnar, and tibial nerves following the stimulation at elbows and knees. Sensory nerve action potentials (SNAPS) were recorded antidromically by using surface ring electrodes on the fingers or surface electrodes and on the feet at bilateral median, ulnar, and sural nerves. We recorded blink responses by stimulating the supraorbital nerve, and by recording the
Before therapy Recorded from hypothenar muscle
Stimulated at the :
w1
After therapy
A
w1
w2
w2
w3
w3
w4
El E2 E3 Distance of each point is 2.5cm
Maximum NCV (Wl-El)= 43.8 m/s Area Ratio (ElIW1)< 0.08
, 10ms
_11 mV i
Maximum NCV (Wl-El) = 42.5 m/e 0.41 Area Ratio (Ei/Wi)=
,
1 Oms 12 mV t
FIGURE 2. Compound muscle action potentials in the right ulnar nerve during the third admission. Before the therapy, partial conduction block with marked temporal dispersions was noted between W3 to E3, especially at E l . Maximum NCV was only slightly reduced because of preservation of fastest nerve fibers. After the therapy, temporal dispersions were improved but partial conduction block was still remained. W1 was at 7 cm proximal from the recording electrode, E2 was at cubita! tunnel groove. NCV: nerve conduction velocity. Area: area of negative peak@).
Chronic Multifocal Demyelinating Neuropathy
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responses of the orbicularis oculi muscles bilaterally. Somatosensory evoked potentials (SSEPs) were elicited by electrical stimulation of the median nerves at the wrists and, were recorded at scalp.6 A sural nerve was biopsied at a site posterior to the left lateral malleolus. T h e specimen of the nerve was processed for light and electron microscopy and for teased nerve fiber preparation. RESULTS
The first electrophysiological examination was carried out after the steroid treatment during the
second admission (Table 1). Clinically, the patient recovered almost completely, however, he was left with multifocal lesions with CB, temporal dispersion (TD), and decreased nerve conduction velocity (NCV). Proximal NCVs judged by F-wave studies revealed a slowing of all the nerves of the upper extremities, while in the lower extremities, they remained normal. As for the distal part of the nerves, partial CBs were detected in the right median, bilateral ulnar, and left tibia1 nerve, while left peroneal nerves were diffusely affected. N% of SSEPs were detected. SNAPS of the sural nerve could not be clearly elicited.
Table 1. Electrophysiological study: second, third, and fourth admission dates Second
6120186 Steroid therapy Nerve Median
+
+
NVC
Parameter
Normal Range
R
L
M
Amp DL NCV TD DL NCV Amp DL NCV N20
23.5123.5 58.8154.2 248.0 (-I--) 227 256.0 2161219 57.9153.5 253.0 521.3
0.112.3' 22.314.3 10.8
3.813.8 8.013.4 50.0
Amp DL NCV TD DL NCV Amp DL NCV
22.7122.8 57.5153.4 254
1.514.9t 7.613.0 45.6
Amp DL NCV TD DL NCV
225122.9 ~15.11~6.0 241 .O
(+++I+-)
(++I*)
548.0 244.0
37.6 52.2
41.4 46.0
Amp DL NCV TD
22.51225 512.9155.5 240.0
0.210.4 16.215.6 29.3 (++I+)
ND ND ND ND
Amp DL NCV
24.9 52,l 241.3
ND ND ND
ND ND ND
F S
SSEP M
Ulnar
F S
M
Tibia1
F Peroneal
M
Sural
S
All data other than NCV are expressed as data of proximalldistal (PID, elbowlwrist, kneelankle) stimulation, M = motor, f = Lwave. S = sensory, SSEP = somatosensory evoked potenbal (N20, recorded at C4'. ms), Amp = amplitude (mV for M-NCV, pV for S-NCV), DL = distal latency (ms, msl14 cm for sural N), NCV = nerve conduction velocity
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Chronic Multifocal Demyelinating Neuropathy
(+I-.)
43.0 33.4 ND14.5 ND13.0 ND
21.2
(-I-)
30.5 40.9 1.213.0 12.114.2 37.5 21 .o
527 255.0
45.6 26.1
2 15/218 26.9123.1 253.0
ND12.0 ND13.8 ND
1.416.4t 8.713.2 41.8 (&I-.) 35.0 35.0 0.3125 9.814.4 40.7
0.610.6 15.817.8 41.8
2.317.7t 17.419.6 39.7
(-1-1
(-1-1
(-I-)
(++I+)
(mls), ND = not detected, TD = temporal dispersion (- none, 2 minimal, + mild, + + moderate, + + + severe, B = biopsied) *Conduction block wlth area ratio (PlD) < 0 6 and duration ratio (PID) sl 15
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The next electrophysiological examination was carried out 6 months later, before the steroid therapy, during the third admission. Although the amplitudes, distal latencies, maximum NCVs of most of the motor nerves, and the distal part of the sensory nerve conductions in the upper extremities had improved, we failed to detect SSEPs bilaterally, and the right ulnar nerve had been more damaged than before. We recorded CMAPs serially from the wrist to the elbow inch by inch along this nerve (Fig. 2). The maximum NCV was only slightly reduced in spite of the severe TDs because of the preservation of the fastest-conduct-
ing fibers. A partial CB began at the middle of the forearm with severe TD. After the steroid therapy, the degree of CBs and TDs was greatly reduced, but the patient still suffered from the partial CB. T h e delayed left R1 latency (18.5 ms) of the blink response returned to normal (10.5 ms). SNAPS were easily elicited in the sural nerve. The final electrophysiological examination, during the fourth admission, revealed that most of the sensory and motor nerves were more disturbed than the previous visit, both proximally and distally. It was particularly clear in the left ulnar and median, bilateral tibial, and left peroneal
Third 1114/87
Fourth 7/7/89
R
L
+
-
R
R
L
2.0/4.2* 11.813.8 26.3 (*I?) 30.0 43.9 NDI10.0 ND13.7 ND ND
4.516.7 7.313.3 45.5 (*I*) 26.0 51.4 2.519.0 7.813.4 47.7 ND
2.214.4 10.414.2 35.5 (*I-) 28.5 54.0 ND15.0 NDl4.0 ND ND
1.213.1* 12.615.8 35.3 (+I?) 40.2 34.4 NDIl .O ND15.4 ND ND
0.7/3.6$ 10.213.9 33.3 (+++It) ND ND ND11.O ND15.2 ND ND
0.317.2$ 7.812,9 43.8 (+++I?) 50.0 21.9 ND ND ND
2.718.6-t 7.212.9 48.8 (*I*) 32.0 40.0 2.515.0 8.013.2 50.0
2.116.3t 8.513.2 42.5 (*I-) 34.0 36.0 ND13.0 ND13.2 ND
1.014.9 9.614.4 42.3 (&I-) 37.0 34.0 NDl2.0 ND16.2 ND
1.6/4.9$ 14.213.8 24.0 (+ + +I?) ND* ND ND11.O ND16.6 ND
3.6110.9t 14.815.4 38.2 (++I-) 40.0 46.0
1.417.7t 12.815.4 44.7 (++I?) 41.6 44.0
2.1110.5t 14.415.6 42.6 (+I-) 41 .O 44.2
0.3/3.8$ 18.919.4 25.2 (+++I-) ND* ND
0.2/3.3$ 16.215.1 31.5 (+++I+) 47.5 40.5
3.615.4 14.014.7 33.9 (&I-)
0.2/1.1* 16.815.3 25.2 (+I-)
1.514.5t 13.815.0 39.8 (*I-)
0.611.5 14.218.0 47.5 (*I?)
NDll.8-f ND17.6 ND (ND/+)
1.o 3.4 ND
ND ND ND
5.0 3.0 42.8
2.5 8.4 ND
B B B
tConduction block with area ratio (PIO) < 0.6 and duration ratio (PlO) >1.15. #A nerve region which was judged to have a definite new demyelinating lesion. Normal range: upper or lower limit (average f 2 SO) from the data."
Chronic Multifocal Demyelinating Neuropathy
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nerves, in which TDs were more prominent than in other nerves. The partial CB in the left ulnar and tibia1 nerves persisted during the second to third admission, and in the right median nerve throughout the examination. Sural nerve biopsy was carried out during the third admission before the steroid therapy. Though larger myelinated fibers decreased moderately, we found no evidence of inflammation or demyelination. DISCUSSION
On his first admission, the patient had acute retrobulbar optic neuritis and, from the clinical point of view, a large-fiber polyneuropathy of the lower extremities and possible demyelinating posterior column myelopathy. On the second admission, he had a demyelinating cervical myelopathy which manifested the Brown- SCquard syndrome and generalized multifocal demyelinating neuropathy. On the third admission, he had trigeminal neuropathy, mononeuropathy of right ulnar nerve, and a demyelinating posterior column lesion of the upper cervical spinal cord, manifesting the useless hand syndrome. On the fourth admission, he had generalized multifocal demyelinating neuropathy with a clinical picture of mononeuropathy multiplex, and possible demyelinating posterior column myelopathy. Except at the onset, most of his symptoms and signs were mild and developed slowly. In each exacerbation, signs and symptoms improved coincident with steroid therapy, and near total recovery was achieved. Although electrophysiological study results indicated the presence of CMDN with persistent CB, it was sometimes difficult for us to determine clinically whether or not he was suffering from CMDN. Simultaneous demyelinating lesions of the spinal cord and slow development of signs and symptoms made it difficult to discriminate between central and peripheral nerve lesions. Pathology of the sural nerve ruled out the possibility of systemic and nonsystemic vasculitic neuropathy. l o Normal teased nerve fibers suggested that there had been no previous demyelinating episode, at least in the biopsied portion of the nerve. The loss of the myelinated fibers was derived from a more proximal lesion. Different patterns in the distribution of conduction failure were observed during the 3 examinations. At second admission, lesions were distributed multifocally along the length of the nerves in the upper extremities, but were predominantly dis-
958
Chronic Multifocal Demyelinating Neuropathy
tal in the lower extremities. During the third admission, the only new lesion was found in the distal part of the right ulnar nerve. During the fourth admission, generalized multifocal lesions were detected. This kind of hetero eneity has been reported in patients with CIDP.2 f It is known that the degree of CB, not the slowing of conduction, correlates best with the clinical impairment.' However, during recovery, a partial CB was still present even in the nerve when muscular weakness was equivocal. Absence of clinical weakness in muscles innervated by partially blocked nerve has been reported in an experimental model,21and in a patient with AIDP.2 During his third admission, our patient developed the useless hand syndrome, in which the arm loses all deep sensation including vibration and position sense, and becomes useless because of the profound sensory loss and sensory ataxia. This syndrome is characteristic of multiple sclerosis and is usually unilateral, however, when bilateral, it can be remarkably symmetrical," as if it were a PNS disorder. It is almost impossible for us to explain these symptoms and signs by a large-fiber sensory neuronopathy or gangli~nopathy,~ because most of the electrophysiological data, apart from the SSEP, showed improvement, and because of the favorable response to the steroid therapy. They may, on the other hand, be explained by the posterior column lesion located in the spinal cord at C3 on MRI if we postulate that the demyelinating process had begun in the middle of the posterior column, and then spread centrifugally to the lateral portion.15 Symmetry of symptoms and signs is a typical f e a t ~ r ebut , ~ cases present with mononeuritis multiplex, are recognized in CIDP. 14,23 Asbury3 classified asymmetric and multifocal neuropathic disorders which present a picture of mononeuropathy multiplex into 2 categories: an axonal neuropathy associated with vasculitis, and a CMDN with CB. Two different forms of CMDN have been reported: a pure motor form resembling motor neuron disease, 19727 and an asymmetric sensory-motor form. 1,4,7,14,17,22,29 In our patient, both CNS and PNS demyelinations were multifocal in time and space, occurred simultaneously, developed either acutely or slowly, and improved satisfactorily coincident with steroid therapy. These findings suggest that both CNS and PNS demyelinations may occur repeatedly and simultaneously as a result of common immunopathogenic mechanisms.
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REFERENCES 1. Adams RD, Asbury AK, Michelsen JJ: Multifocal pseudohypertrophic neuropathy. Trans Am Neurol Assoc
1965;90:30-34. 2. Albers JW: Inflammatory demyelinating polyradiculoneuropathy, in Brown WF, Bolton CF (eds): Clinical Electromyography. Boston, Butterworths, 1987, pp 209-244. 3. Asburv AK. Gilliatt RW: The clinical amroach to neuroDathy, h Asbury AK, Gilliat RW (eds): bkipheral Nerve D k orders. Boston, Butterworths, 1984, pp 1-20. 4. Baba M, Narita S, Takebe K, Matsunaga M, Komori T: Chronic relapsing demyelinating neuropathy of multiple mononeuropathy type. Clin Neurol (Tokyo) 1985;23:575580. 5. Barohn RJ, Kissel JT, Warmolts JR, Mendell JR: Chronic inflammatory demyelinating polyradiculoneuropathy: clinical characteristics, course, and recommendations for diagnostic criteria. Arch Neurol 1989;46:878-884. 6. Bradley WG, Kessel RS: Short-latency somatosensory evoked potentials. AAEE glossary of terms in clinical electromyography, 2nd ed. Muscle Nerve 1987;10(suppl):G26. 7. Bradley WG, Bennett RK, Good P, Little B: Proximal chronic inflammatory polyneuropathy with multifocal conduction block. Arch Neurol 1988;45:451-455. 8 . Brown WF, Feasby TE: Conduction block and denervation in Guillain-Barre polyneuropathy. Bruin 1984; 107:219239. 9. Dalakas MC: Chronic idiopathic ataxic neuropathy. Ann Neurol 1986;19:545-554. 10. Dyck PJ, Benstead TJ, Conn DL, Stevens JC, Windebank Bruin AJ: Nonsystemic vasculitis neuropathy. 1987;110:843-854. 1 1 . Hashimoto SA, Paty DW: Diagnosis of multiple sclerosis, in Cotsonas NJ (ed): Multiple Sclerosis. Disease-a-Month. Chicago, Year Book Medical, 1986, pp 549-562. 12. Kimura J (ed): Electrodiagnosis in Diseases of Nerve and Muscle, Principles and Practice, 2nd ed. Philadelphia, F.A. Davis, 1989. 13. Lassmann H, Budka H, Schnaberth G: Inflammatory dernyelinating polyradiculitis in a patient with multiple sclerosis. Arch Neurol 1981;38:99- 102. 14. Lewis RA, Sumner AJ, Brown MJ, Asbury AK: Multifocal demyelinating neuropathy with persistent conduction block. Neurology (NU) 1982;32:958-964. 15. McDonald WI: The pathophysiology of multiple sclerosis, in McDonald WI, Silberberg DH (eds): Multiple Sclerosis. Boston, Butterworths, 1986, pp 112- 133. 16. Mendell JR, Kolkin S, Kissel JT, Weiss KL, Chakeres DW, Rammohan KW: Evidence for central nervous system de-
Chronic Multifocal Dernyelinating Neuropathy
myelination in chronic inflammatory demyelinating polyradiculoneuropathy. Neurology 1987;37:1291- 1294. 17. Nukada H, Pollock M, Haas LF: Is ischemia implicated in chronic multifocal demyelinating neuropathy? Neurology 1989;39:106- 110. 18. Pall HS, Williams AC: Subacute polyradiculopathy with oDtic and auditory nerve involvement. Arch Neurol 1$87;44:885-887. ' 19. Parry GJ, Clarke S: Multifocal acquired demyelinating neuropathy masquerading as motor neuron disease. Muscle Nerve 1988;11:103-107. 20. Rubin M, Karpati G, Carpenter S: Combined central and peripheral myelinopathy. Neurology 1987;37:1287- 1290. 21. Saida K, Sumner AJ, Saida T, Brown MJ, Silberberg DH: Antiserum-mediated demyelination: relationship between remyelination and functional recovery. Ann Neural 1980;8:12-24. 22. Sakai N, Saida T, Ichikawa K, Kageyama Y , Komure 0: Chronic demyelinative encephalomyeloneuritis: a new disease or a combination of CIDP and MS? Clin Neurol (Tokyo) 1989;30:30-37. 23. Sumner AJ: Chronic demyelinating neuropathy, in Asbury AK, Gilliat RW (eds): Peripheral Nerve Disorders. Boston, Butterworths, 1984, pp 46-57. 24. Thomas PK, Walker RWH, Rudge P, Morgan-Hughes JA, King RHM, Jacobs J M , Mills KR, Ormerod IEC, Murray NMF, McDonald WI: Chronic demyelinating peripheral neuropathy associated with multifocal central nervous system demyelination. Brain 1987;110:53-76. 25. Toshniwal P: Demyelinating optic neuropathy with MillerFisher syndrome: the case for overlap syndromes with central and peripheral demyelination. J Neurol 1987;234:353358. 26. Uncini A, Treviso M, Basciani, Onofrj M, Gambi D: Associated central and peripheral demyelination: an electrophysiological study. J Neurol 1988;235:238-240. 27. Van den Bergh P, Logigian EL, Kelly JJ: Motor neuropathy with multifocal conduction blocks. Muscle Nerve 1989;11:26-31. 28. Van der Meche FGA, Vermeulen M, Busch HFM: Chronic inflammatory demyelinating polyneuropathy: conduction failure before and during immunologlobulin or plasma therapy. Brain 1989;112:1563- 1571. 29. Waddy HM, Misra VP, King RHM, Thomas PK, Middleton L, Ormerod IEC: Focal cranial nerve involvement in chronic inflammatory demyelinating polyneuropathy: clinical and MRI evidence of peripheral and central lesions. J Neurol 1989;236:400-405,
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~
~
We have carried out a long-term study of lesions found in a man who had a demyelinating disease of both central and peripheral nervous systems. During the 10 years of his clinical course, he suffered from optic neuritis, multifocal myelitis, and chronic multifocal demyelinating neuropathy, with persistent conduction block. Our study revealed that both central and peripheral nervous system demyelination occurred repeatedly and simultaneously. Key words: demyelinating neuropathy, chronic multifocal conduction block multiple sclerosis useless hand syndrome magnetic resonance imaging MUSCLE & NERVE 14:953-959 1991
CHRONIC MULTIFOCAL DEMYELlNATlNG NEUROPATHY ASSOCIATED WITH CENTRAL NERVOUS SYSTEM DEMYELlNATlON MUTSUO NAGANUMA, MD, KOHJI SHIMA MD, AKlHlSA MATSUMOTO, MD, and KUNIO TASHIRO MD
Many reports have been published concerning clinical and pathophysiological studies of lesions in demyelinating diseases with combined involvement of central and p r i p h e r a l nervous systems (CNS and PNS),'6,20, PNS lesions in multiple sclerosis, and CNS lesions in acute or chronic inflammatory demyelinating polyradiculoneuropathy (AIDP or CIDP). It was, however, only in the cases of AIDP, that attention was paid to the simultaneous occurrence of demyelinations in both nervous systems, and analyzed prospectively with magnetic resonance ima ing (MRI) and/or electrophysiological studies. 13,18,25,26 Lewis et al. reported 5 cases of chronic multifocal demyelinating neuropathy (CMDN) with persistent conduction block (CB).I4 Because 2 of
From the Department of Neurology, Sapporo Minami National Hospital, Sapporo, Japan (Drs. Naganuma, Shima, and Matsumoto), and Department of Neurology, Hokkaido University School of Medicine, Sapporo, Japan (Dr. Tashiro). Acknowledgments: The authors thank Dr. A. Ohnishi for his evaluation of the pathology of the sural nerve, and for his comments on our work. The authors also thank Dr. K. Miyasaka for his evaluation of the MRI findings. Address reprint requests to Mutsuo Naganuma, MD, Department of Neurology, Hokkaido University School of Medicine, N-15 W-7, Sapporo, Hokkaido, Japan. Accepted for publication September 17, 1990.
CCC 0148- 639X/91/01001953- 07 $04.00 0 1991 John Wiley & Sons, Inc.
Chronic Multifocal Dernyelinating Neuropathy
the cases had optic neuritis, they emphasized that the demyelinating lesion was not always restricted to the PNS. By extensive electrophysiological, pathological, and radiological studies during 3 exacerbations over 4 years, we found multifocal demyelination repeatedly and simultaneously in both the CNS and PNS. CASE REPORT
At the age of 26, in August 1980, our patient suddenly developed partial loss of vision in his left eye. T w o days later, painful dysesthesia attacked his legs, but disappeared in a few days. On initial admission to our hospital 2 weeks later, he had a central scotoma and papilledema in his left eye, loss of knee and achilles tendon reflexes, decreased vibration and position sense in his legs, and a positive Romberg sign. After 3 months of parenteral prednisolone therapy, most of these neurological signs had disappeared, except for reduced visual acuity. Five years later, in December 1985, he gradually developed weakness of his legs, especially of his left knee. Two months later, he noted weakness and tightness of his extremities, predominantly on the right side. Furthermore, tingling and numbness began to develop gradually in the distal part of the lower extremities, slowly spreading up over his body. When he was admitted for
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the second time in April 1986, he had mild weakness of right upper and lower extremities, generalized areflexia, a positive right Babinski sign, a left-side dominant superficial sensory disturbance over his body and extremities, a marked loss of both position and vibratory sensation below the pelvis and in the ulnar aspect of his right hand, and a positive Romberg sign. Hematological and serological tests all fell within normal limits. CSF analysis showed a protein level of 67 mg/dL, 7 cells/mm3, and no myelin basic protein (MBP). MRI with 0.5 T, T R 2000 ms, and T E 80 ms demonstrated a region of abnormally high signal in the spinal cord on the right at C6. (Fig. 1A) Using a steroid pulse therapy (20 mg/kg of methylprednisolone was given intravenously once a day for 3 days) followed by oral prednisolone (1 mg/kg per day for 1 week with a gradual tapering dosage) most of his symptoms and signs had disappeared within the next 2 months. He was discharged with only a mild loss of vibration sense and generalized areflexia. In October 1986, 4 months after discharge, numbness developed in his feet bilaterally, and
gradually rose to his pelvis; similar numbness then began to develop in his hands and spreaded to his neck. He also complained of dysesthesia over the left side of his chest and face. When he was admitted for the third time in January 1987, he had decreased sensation over the left side of his face corresponding to the distribution of the trigeminal nerve, weakness and pseudo-athetotic involuntary movements of the hands, generalized areflexia, hyperalgesia of the extremities and paresthesia below his neck, profound loss of both position and vibratory sensation in his upper extremities with distal predominance, and mild loss of vibratory sensation in the lower extremities. CSF analysis showed a protein level of 56 mg/dL, 1 cell/mm3, no MBP, and 3 oliogoclonal IgG bands (OCB). There was no laboratory evidence of syphilis, diabetes mellitus, porphyria, dysglobulinemia, collagen vasculitis, or infections from human immunodeficiency virus type I or 111. Metrizamide C T myelography showed focal swelling of the upper cervical spinal cord (Fig. 1B). After repetition of steroid pulse therapy, most of his symptoms and signs gradually
A
C
0
D
FIGURE 1. MRI (0.5 T, TR 2000 ms, TE 80 ms) during the second admission showed a region of abnormally high signal in the spinal cord on the right at C6 (A). Metrizamide CT myelography during the third admission showed focal swelling in the spinal cord at C3 (6). MRI (1.5 T, TR 3000 ms, TE 30 ms) during the fourth admission showed a region of abnormally high signal in the spinal cord on the right posterolateral at C6 (C), and on the dorsal columns at C3 with no focal swelling (D).
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Chronic Multifocal Demyelinating Neuropathy
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disappeared during the following 3 months, except for hypalgesia below the knees. From about one year after discharge, he sometimes complained of double vision, numbness of the right side of his face, weakness of his right arm, pain and weakness of his right lower leg, and a tight band-like feeling in his chest. In March 1989, he complained of numbness and weakness of the ulnar side of his left hand. In May, he felt weakness of his left lower leg. When he was admitted for the fourth time in June 1989, he had generalized areflexia, weakness of right hand muscles innervated by the median and ulnar nerves, weakness of right foot flexor muscles and left foot extensor muscles, superficial sensory disturbance over the ulnar aspect of both his upper extremities, mild loss of vibration and position sense of lower extremities, and positive Romberg sign. CSF analysis showed a protein level of 119 mg/dL; 5 cells/mm3. MRI with 1.5 T, TR 3000 ms, and TE 30 ms, showed a region of abnormally high signal in the spinal cord on the posterior column at C3 and T1, and on the posterolateral at C6 with no focal swelling. (Fig. 1C and 1D) After oral prednisolone therapy, he again im-
proved gradually, and was discharged 3 months later with little clinical disturbance. MATERIALS AND METHODS
Electrophysiological studies were performed using an electromyographer (Medelec, Sanei, Japan) and signal processor (Evomatic, DISA, Denmark). Motor nerve conduction studies were performed by percutaneous supramaximal nerve stimulation at bilateral median, ulnar, tibial, and peroneal nerves. l 2 Compund muscle action potentials (CMAP) were recorded using surface electrodes. We used Lewis’ criteria to judge CB; the negative peak area of the CMAP by proximal stimulation was less than 60% of the area obtained by distal stimulation. l4 F-wave latencies were determined as the average of 10 responses recorded at bilateral median, ulnar, and tibial nerves following the stimulation at elbows and knees. Sensory nerve action potentials (SNAPS) were recorded antidromically by using surface ring electrodes on the fingers or surface electrodes and on the feet at bilateral median, ulnar, and sural nerves. We recorded blink responses by stimulating the supraorbital nerve, and by recording the
Before therapy Recorded from hypothenar muscle
Stimulated at the :
w1
After therapy
A
w1
w2
w2
w3
w3
w4
El E2 E3 Distance of each point is 2.5cm
Maximum NCV (Wl-El)= 43.8 m/s Area Ratio (ElIW1)< 0.08
, 10ms
_11 mV i
Maximum NCV (Wl-El) = 42.5 m/e 0.41 Area Ratio (Ei/Wi)=
,
1 Oms 12 mV t
FIGURE 2. Compound muscle action potentials in the right ulnar nerve during the third admission. Before the therapy, partial conduction block with marked temporal dispersions was noted between W3 to E3, especially at E l . Maximum NCV was only slightly reduced because of preservation of fastest nerve fibers. After the therapy, temporal dispersions were improved but partial conduction block was still remained. W1 was at 7 cm proximal from the recording electrode, E2 was at cubita! tunnel groove. NCV: nerve conduction velocity. Area: area of negative peak@).
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responses of the orbicularis oculi muscles bilaterally. Somatosensory evoked potentials (SSEPs) were elicited by electrical stimulation of the median nerves at the wrists and, were recorded at scalp.6 A sural nerve was biopsied at a site posterior to the left lateral malleolus. T h e specimen of the nerve was processed for light and electron microscopy and for teased nerve fiber preparation. RESULTS
The first electrophysiological examination was carried out after the steroid treatment during the
second admission (Table 1). Clinically, the patient recovered almost completely, however, he was left with multifocal lesions with CB, temporal dispersion (TD), and decreased nerve conduction velocity (NCV). Proximal NCVs judged by F-wave studies revealed a slowing of all the nerves of the upper extremities, while in the lower extremities, they remained normal. As for the distal part of the nerves, partial CBs were detected in the right median, bilateral ulnar, and left tibia1 nerve, while left peroneal nerves were diffusely affected. N% of SSEPs were detected. SNAPS of the sural nerve could not be clearly elicited.
Table 1. Electrophysiological study: second, third, and fourth admission dates Second
6120186 Steroid therapy Nerve Median
+
+
NVC
Parameter
Normal Range
R
L
M
Amp DL NCV TD DL NCV Amp DL NCV N20
23.5123.5 58.8154.2 248.0 (-I--) 227 256.0 2161219 57.9153.5 253.0 521.3
0.112.3' 22.314.3 10.8
3.813.8 8.013.4 50.0
Amp DL NCV TD DL NCV Amp DL NCV
22.7122.8 57.5153.4 254
1.514.9t 7.613.0 45.6
Amp DL NCV TD DL NCV
225122.9 ~15.11~6.0 241 .O
(+++I+-)
(++I*)
548.0 244.0
37.6 52.2
41.4 46.0
Amp DL NCV TD
22.51225 512.9155.5 240.0
0.210.4 16.215.6 29.3 (++I+)
ND ND ND ND
Amp DL NCV
24.9 52,l 241.3
ND ND ND
ND ND ND
F S
SSEP M
Ulnar
F S
M
Tibia1
F Peroneal
M
Sural
S
All data other than NCV are expressed as data of proximalldistal (PID, elbowlwrist, kneelankle) stimulation, M = motor, f = Lwave. S = sensory, SSEP = somatosensory evoked potenbal (N20, recorded at C4'. ms), Amp = amplitude (mV for M-NCV, pV for S-NCV), DL = distal latency (ms, msl14 cm for sural N), NCV = nerve conduction velocity
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Chronic Multifocal Demyelinating Neuropathy
(+I-.)
43.0 33.4 ND14.5 ND13.0 ND
21.2
(-I-)
30.5 40.9 1.213.0 12.114.2 37.5 21 .o
527 255.0
45.6 26.1
2 15/218 26.9123.1 253.0
ND12.0 ND13.8 ND
1.416.4t 8.713.2 41.8 (&I-.) 35.0 35.0 0.3125 9.814.4 40.7
0.610.6 15.817.8 41.8
2.317.7t 17.419.6 39.7
(-1-1
(-1-1
(-I-)
(++I+)
(mls), ND = not detected, TD = temporal dispersion (- none, 2 minimal, + mild, + + moderate, + + + severe, B = biopsied) *Conduction block wlth area ratio (PlD) < 0 6 and duration ratio (PID) sl 15
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The next electrophysiological examination was carried out 6 months later, before the steroid therapy, during the third admission. Although the amplitudes, distal latencies, maximum NCVs of most of the motor nerves, and the distal part of the sensory nerve conductions in the upper extremities had improved, we failed to detect SSEPs bilaterally, and the right ulnar nerve had been more damaged than before. We recorded CMAPs serially from the wrist to the elbow inch by inch along this nerve (Fig. 2). The maximum NCV was only slightly reduced in spite of the severe TDs because of the preservation of the fastest-conduct-
ing fibers. A partial CB began at the middle of the forearm with severe TD. After the steroid therapy, the degree of CBs and TDs was greatly reduced, but the patient still suffered from the partial CB. T h e delayed left R1 latency (18.5 ms) of the blink response returned to normal (10.5 ms). SNAPS were easily elicited in the sural nerve. The final electrophysiological examination, during the fourth admission, revealed that most of the sensory and motor nerves were more disturbed than the previous visit, both proximally and distally. It was particularly clear in the left ulnar and median, bilateral tibial, and left peroneal
Third 1114/87
Fourth 7/7/89
R
L
+
-
R
R
L
2.0/4.2* 11.813.8 26.3 (*I?) 30.0 43.9 NDI10.0 ND13.7 ND ND
4.516.7 7.313.3 45.5 (*I*) 26.0 51.4 2.519.0 7.813.4 47.7 ND
2.214.4 10.414.2 35.5 (*I-) 28.5 54.0 ND15.0 NDl4.0 ND ND
1.213.1* 12.615.8 35.3 (+I?) 40.2 34.4 NDIl .O ND15.4 ND ND
0.7/3.6$ 10.213.9 33.3 (+++It) ND ND ND11.O ND15.2 ND ND
0.317.2$ 7.812,9 43.8 (+++I?) 50.0 21.9 ND ND ND
2.718.6-t 7.212.9 48.8 (*I*) 32.0 40.0 2.515.0 8.013.2 50.0
2.116.3t 8.513.2 42.5 (*I-) 34.0 36.0 ND13.0 ND13.2 ND
1.014.9 9.614.4 42.3 (&I-) 37.0 34.0 NDl2.0 ND16.2 ND
1.6/4.9$ 14.213.8 24.0 (+ + +I?) ND* ND ND11.O ND16.6 ND
3.6110.9t 14.815.4 38.2 (++I-) 40.0 46.0
1.417.7t 12.815.4 44.7 (++I?) 41.6 44.0
2.1110.5t 14.415.6 42.6 (+I-) 41 .O 44.2
0.3/3.8$ 18.919.4 25.2 (+++I-) ND* ND
0.2/3.3$ 16.215.1 31.5 (+++I+) 47.5 40.5
3.615.4 14.014.7 33.9 (&I-)
0.2/1.1* 16.815.3 25.2 (+I-)
1.514.5t 13.815.0 39.8 (*I-)
0.611.5 14.218.0 47.5 (*I?)
NDll.8-f ND17.6 ND (ND/+)
1.o 3.4 ND
ND ND ND
5.0 3.0 42.8
2.5 8.4 ND
B B B
tConduction block with area ratio (PIO) < 0.6 and duration ratio (PlO) >1.15. #A nerve region which was judged to have a definite new demyelinating lesion. Normal range: upper or lower limit (average f 2 SO) from the data."
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nerves, in which TDs were more prominent than in other nerves. The partial CB in the left ulnar and tibia1 nerves persisted during the second to third admission, and in the right median nerve throughout the examination. Sural nerve biopsy was carried out during the third admission before the steroid therapy. Though larger myelinated fibers decreased moderately, we found no evidence of inflammation or demyelination. DISCUSSION
On his first admission, the patient had acute retrobulbar optic neuritis and, from the clinical point of view, a large-fiber polyneuropathy of the lower extremities and possible demyelinating posterior column myelopathy. On the second admission, he had a demyelinating cervical myelopathy which manifested the Brown- SCquard syndrome and generalized multifocal demyelinating neuropathy. On the third admission, he had trigeminal neuropathy, mononeuropathy of right ulnar nerve, and a demyelinating posterior column lesion of the upper cervical spinal cord, manifesting the useless hand syndrome. On the fourth admission, he had generalized multifocal demyelinating neuropathy with a clinical picture of mononeuropathy multiplex, and possible demyelinating posterior column myelopathy. Except at the onset, most of his symptoms and signs were mild and developed slowly. In each exacerbation, signs and symptoms improved coincident with steroid therapy, and near total recovery was achieved. Although electrophysiological study results indicated the presence of CMDN with persistent CB, it was sometimes difficult for us to determine clinically whether or not he was suffering from CMDN. Simultaneous demyelinating lesions of the spinal cord and slow development of signs and symptoms made it difficult to discriminate between central and peripheral nerve lesions. Pathology of the sural nerve ruled out the possibility of systemic and nonsystemic vasculitic neuropathy. l o Normal teased nerve fibers suggested that there had been no previous demyelinating episode, at least in the biopsied portion of the nerve. The loss of the myelinated fibers was derived from a more proximal lesion. Different patterns in the distribution of conduction failure were observed during the 3 examinations. At second admission, lesions were distributed multifocally along the length of the nerves in the upper extremities, but were predominantly dis-
958
Chronic Multifocal Demyelinating Neuropathy
tal in the lower extremities. During the third admission, the only new lesion was found in the distal part of the right ulnar nerve. During the fourth admission, generalized multifocal lesions were detected. This kind of hetero eneity has been reported in patients with CIDP.2 f It is known that the degree of CB, not the slowing of conduction, correlates best with the clinical impairment.' However, during recovery, a partial CB was still present even in the nerve when muscular weakness was equivocal. Absence of clinical weakness in muscles innervated by partially blocked nerve has been reported in an experimental model,21and in a patient with AIDP.2 During his third admission, our patient developed the useless hand syndrome, in which the arm loses all deep sensation including vibration and position sense, and becomes useless because of the profound sensory loss and sensory ataxia. This syndrome is characteristic of multiple sclerosis and is usually unilateral, however, when bilateral, it can be remarkably symmetrical," as if it were a PNS disorder. It is almost impossible for us to explain these symptoms and signs by a large-fiber sensory neuronopathy or gangli~nopathy,~ because most of the electrophysiological data, apart from the SSEP, showed improvement, and because of the favorable response to the steroid therapy. They may, on the other hand, be explained by the posterior column lesion located in the spinal cord at C3 on MRI if we postulate that the demyelinating process had begun in the middle of the posterior column, and then spread centrifugally to the lateral portion.15 Symmetry of symptoms and signs is a typical f e a t ~ r ebut , ~ cases present with mononeuritis multiplex, are recognized in CIDP. 14,23 Asbury3 classified asymmetric and multifocal neuropathic disorders which present a picture of mononeuropathy multiplex into 2 categories: an axonal neuropathy associated with vasculitis, and a CMDN with CB. Two different forms of CMDN have been reported: a pure motor form resembling motor neuron disease, 19727 and an asymmetric sensory-motor form. 1,4,7,14,17,22,29 In our patient, both CNS and PNS demyelinations were multifocal in time and space, occurred simultaneously, developed either acutely or slowly, and improved satisfactorily coincident with steroid therapy. These findings suggest that both CNS and PNS demyelinations may occur repeatedly and simultaneously as a result of common immunopathogenic mechanisms.
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October 1991
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Chronic Multifocal Dernyelinating Neuropathy
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