PATTERNS OF NERVE CONDUCTION ABNORMALITIES IN POEMS SYNDROME

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1 ABSTRACT: Polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome is a rare cause of demyelinating and axonal neuropathy. POEMS syndrome and chronic inflammatory demyelinating polyneuropathy (CIDP) cause peripheral nerve demyelination, and the electrodiagnostic findings may therefore be similar, but the two disorders are distinct. To elucidate the electrodiagnostic features of POEMS syndrome, we reviewed nerve conduction studies of 8 patients, and compared their results with those in 42 patients with CIDP. The patients with POEMS syndrome showed (1) slowing of nerve conduction that was more predominant in the intermediate than distal nerve segments, (2) rare conduction block (6% of the tested nerves), and (3) more severe attenuation of compound muscle action potentials in the lower than upper limbs. Findings in the CIDP patients were characterized by multifocal conduction slowing that was occasionally dominant distally, frequent conduction block (44% of tested nerves), and less discrepancy between upper and lower limb nerves. The pattern of nerve conduction abnormalities differs between these disorders. Recognition of these typical patterns may be helpful for early diagnosis of POEMS syndrome Wiley Periodicals, Inc. Muscle Nerve 26: , 2002 PATTERNS OF NERVE CONDUCTION ABNORMALITIES IN POEMS SYNDROME JIA-YING SUNG, MD, SATOSHI KUWABARA, MD, KAZUE OGAWARA, MD, KAZUAKI KANAI, MD, and TAKAMICHI HATTORI, MD Department of Neurology, Chiba University School of Medicine, Inohana, Chuo-Ku, Chiba , Japan Accepted 28 March 2002 Polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome is an unusual multisystem disease, and the rare cause of demyelinating and axonal polyneuropathy. 3,8,10,11 Recent studies suggest that vascular endothelial growth factor, which is probably secreted by plasma cells, plays an important role in the pathogenesis of this disorder, and that increased vascular permeability may account for symptoms such as edema, pleural effusion, ascites, and skin pigmentation. 4,21 However, the cause of the peripheral neuropathy has not been elucidated. According to the research criteria for the diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) of the American Academy of Abbreviations: CIDP, chronic inflammatory demyelinating polyneuropathy; CMAP, compound muscle action potential; CMT, Charcot-Marie- Tooth disease; POEMS, polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes; TLI, terminal latency index; VEGF, vascular endothelial growth factor Key words: axonal degeneration; chronic inflammatory demyelinating polyneuropathy; demyelination; nerve conduction study; POEMS syndrome Correspondence to: S. Kuwabara; kuwabara@med.m.chibau.ac.jp 2002 Wiley Periodicals, Inc. Published online 5 June 2002 in Wiley InterScience (www. interscience.wiley.com). DOI /mus Neurology, 1 POEMS syndrome is regarded as a disease that can be concurrent with CIDP. 15 However, the prognosis, outcome, and pathological findings in POEMS syndrome differ from those of CIDP. 7,11,19 POEMS syndrome is a potentially life-threatening disease with multi-organ involvement; Nakanishi et al. 11 reported that 34 of 58 Japanese patients with POEMS syndrome died after a mean survival period of 33 months, and that heart failure or intractable pleural effusion or ascites due to increased vascular permeability was the cause of death in most cases. Long-term chemotherapy with melphalan may improve the outcome of patients with POEMS syndrome. 7 Both CIDP and POEMS syndrome cause peripheral nerve demyelination, 2,17 and the electrodiagnostic findings may therefore be similar. To investigate whether POEMS syndrome is associated with particular patterns of nerve conduction abnormalities, and whether such patterns differ from those of CIDP, we compared the findings on nerve conduction studies in patients with POEMS syndrome and CIDP. MATERIALS AND METHODS Subjects. Between 1990 and 2000 at the Chiba University Hospital, eight patients (five women and Nerve Conduction in POEMS Syndrome MUSCLE & NERVE August

2 three men) were diagnosed as having POEMS syndrome. Their mean age was 51 years (range, years). Seven of these patients had all five features of the syndrome; the remaining patient lacked M protein but had hepatosplenomegaly, foot edema, pleural effusion, ascites, and skin pigmentation. Clinical details and outcomes of the patients have been described elsewhere. 7 Forty-two patients with CIDP, whose condition fulfilled the research criteria formulated by the American Academy of Neurology, 1 and seven patients with genetically-confirmed Charcot-Marie-Tooth disease type 1a (CMT1a), served as neurological controls during the same study period. Two of the 42 CIDP patients had M protein (monoclonal gammopathy of undetermined significance). Normal data on nerve conduction study parameters were obtained from 101 healthy subjects (mean age, 49 years; range, years), who provided informed consent, with the approval of the local ethics committee. Electrophysiology. Motor nerve conduction studies of the median, ulnar, and tibial nerves were performed using conventional procedures. F waves were recorded after distal stimulation, and 16 to 32 consecutive responses were analyzed. Conduction block in the forearm segments of the median and ulnar nerves was defined as >20% decrease in amplitude of compound muscle action potential (CMAP) without >15% increase in CMAP duration. 1 For distal latency, conduction velocity, and minimal F-wave latency, we defined a value beyond 2.5 SD from the control mean as abnormal. For CMAP amplitude, we defined the presence of abnormality as amplitude falling below 2.5 SD of the mean of the logarithmically transformed amplitudes of the normal controls. Terminal latency index (TLI) 16 was used to compare the extent of conduction slowing in the distal and intermediate segments of the median and ulnar nerves, and calculated with the following formula: TLI = terminal distance (mm)/[distal latency (ms) conduction velocity (m/s)]. Terminal distance was measured from the recording electrode on the abductor pollicis brevis or abductor digiti minimi to the stimulus site at the wrist. For statistical analysis, differences within each group were tested with the Mann Whitney U test or Fisher s exact probability test, using the Statecel software for Windows 98 (OMS Co. Ltd., Tokyo, Japan). RESULTS Routine Nerve Conduction Parameters. Results of the median and tibial motor nerve conduction studies are shown in Figure 1. In patients with POEMS syndrome, distal latencies were mildly longer than those in normal subjects but significantly shorter than in patients with CIDP or CMT1a. In contrast, nerve conduction velocities were similarly decreased and F-wave latencies were similarly prolonged in the POEMS and CIDP groups. Nerve conduction slowing was most severe in patients with CMT1a in all nerve segments. Prolonged distal latency was significantly less frequent in POEMS syndrome (38% of the nerves tested; P < 0.05) than in CIDP (76%) or CMT1a (100%), whereas the frequency of slowed conduction velocity was similar in POEMS syndrome (88%), CIDP (76%), and CMT1a (100%). These data suggest that in patients with POEMS syndrome, conduction slowing was more prominent in the intermediate nerve segments (forearm or leg segment) than in the distal nerve segments. To confirm this, terminal latency index was analyzed. Terminal Latency Index. Figure 2 shows the TLI of the median and ulnar nerves in normal subjects and in the patient groups. TLIs were significantly greater for the POEMS group than for normal subjects or patients with CIDP or CMT1a. These results confirmed that conduction slowing is predominant in the intermediate nerve segments in POEMS syndrome. CMAP Amplitudes. Figure 3 shows median and tibial CMAP amplitudes after distal stimulation, and the tibial/median CMAP amplitude ratio. In patients with POEMS syndrome, CMAP amplitudes decreased mildly in the median nerve and severely in the tibial nerve. Tibial CMAPs were not recordable in six of the eight patients with POEMS syndrome. In order to evaluate the relative severity of decrease in CMAP amplitude in the two nerves, we calculated the tibial/median CMAP amplitude ratio (tibial CMAP amplitude after ankle stimulation/median CMAP amplitude after wrist stimulation). The ratio was significantly smaller for patients with POEMS syndrome than for normal subjects or patients with CIDP or CMT1a, suggesting that decreases in tibial CMAP were disproportionally prominent in POEMS syndrome. Conduction Block. The presence of conduction block between the wrist and elbow in the median and ulnar nerves was examined. Results of tibial 190 Nerve Conduction in POEMS Syndrome MUSCLE & NERVE August 2002

3 FIGURE 1. Results of median and tibial nerve conduction studies. POEMS, polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes; CIDP, chronic inflammatory demyelinating polyneuropathy; CMT, Charcot-Marie-Tooth disease 1a. Error bars indicate standard error. nerve studies could not be analyzed because of the absence of the distal CMAP in most of the patients with POEMS syndrome. Conduction block was found in 1 of the 16 nerves (6%) of patients with POEMS syndrome, and 37 of the 84 nerves (44%) of CIDP patients. The frequency of conduction block was significantly higher in the CIDP group than the POEMS syndrome group (P = 0.01). FIGURE 2. Terminal latency index. Abbreviations as in Figure 1. Error bars indicate standard error. DISCUSSION We found a number of differences in the pattern of nerve conduction abnormalities in POEMS syndrome and CIDP. First, conduction slowing was more prominent in the intermediate than distal nerve segments in POEMS syndrome, whereas demyelination in CIDP was distributed multifocally and involved both the distal and intermediate nerve segments. Second, conduction block was much less frequent in POEMS syndrome. Finally, in POEMS syndrome, lower limb nerves were more severely involved than upper limb nerves, in contrast to CIDP. The distal nerve terminals, as well as the nerve roots, are regions where the blood nerve barrier is anatomically deficient, 13 and they therefore are preferentially affected in immune-mediated demyelinating neuropathies such as CIDP, Guillain Barré syndrome, and neuropathy with antibody against myelin-associated glycoprotein. 5 The reverse pattern (i.e., sparing of the distal nerve segments) was found in patients with POEMS syndrome. This suggests that mechanisms other than antibody- or cell-mediated immune responses are responsible for the neuropathy in POEMS syndrome. Similarly, in most axonal neuropathies, dying-back or Wallerian degeneration is the main pathophysiology, and the distal nerve terminals are affected earlier and more severely than the intermediate segments. Dying-back degenera- Nerve Conduction in POEMS Syndrome MUSCLE & NERVE August

4 FIGURE 3. Amplitudes of distally evoked compound muscle action potential in median and tibial nerve studies, and tibial/median ratio. Abbreviations as in Figure 1. Error bars indicate standard error. tion is unlikely to account for nerve damage in POEMS syndrome. We therefore speculate that the slowing of nerve conduction predominant in the intermediate nerve segments is characteristic of the syndrome. The significantly greater TLIs seen in our patients with POEMS syndrome support this particular pattern of distribution of conduction slowing. Conduction block is one of the diagnostic hallmarks in acquired demyelinating neuropathies. We found conduction block frequently in our CIDP patients, but rarely in patients with POEMS syndrome. Profound conduction slowing in the intermediate or proximal nerve segments (decrease in conduction velocity and prolongation of F-wave latency) found in POEMS syndrome suggested peripheral nerve demyelination, which is consistent with the results of previous pathological studies demonstrating extensive demyelinating changes in this syndrome. 2,6,14 The less frequent conduction block in POEMS syndrome might be explained by the more diffusely distributed demyelinating changes along the nerves, in contrast to the focally accentuated lesions seen in CIDP. One of the electrodiagnostic features of POEMS syndrome in the present study was markedly attenuated or absent CMAPs in tibial nerve studies, even when the amplitude of median or ulnar CMAPs was normal. The reduction of tibial CMAP amplitudes was probably caused by axonal loss, which is consistent with the muscle atrophy occurring in the distal lower limbs in this disorder. 11 A sural nerve study of POEMS syndrome 12 showed prominent axonal loss and attenuation. Sobue et al. 17 examined the distribution of pathological changes along the nerves in POEMS syndrome. Segmental demyelination associated with excessive myelin outfolds was the most common feature, and demyelinating changes were more prominent in the proximal nerve trunk and the spinal roots than in the distal nerve segments. They also found severe axonal loss in the lower limb nerves, and speculated that segmental pathology, probably demyelination, occurred in the nerve trunk or in the proximal portion. Our findings are consistent with these pathological changes, and suggest some nerve length-dependent factors associated with the pathophysiology of nerve damage in POEMS syndrome. Marked increase in the serum level of cytokines or matrix metalloproteinases, 9 especially of the vascular endothelial growth factor (VEGF), have been reported in patients with POEMS syndrome, and VEGF can be used as diagnostic marker of this syndrome. 4,18,20,21 Because prognoses and optimal treatments may differ between POEMS syndrome and CIDP, recognition of the pattern of nerve conduction abnormalities found in our patients, as well as serum VEGF levels, may be helpful for early diagnosis of this particular syndrome. REFERENCES 1. Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force. Research criteria for diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Neurology 1991;41: Adams D, Said G. Ultrastructural characterisation of the M protein in nerve biopsy of patients with POEMS syndrome. J Neurol Neurosurg Psychiatry 1998;64: Nerve Conduction in POEMS Syndrome MUSCLE & NERVE August 2002

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