Chronic Inflammatory Demyelinating Polyneuropathy with

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1 CASE REPORT Chronic Inflammatory Demyelinating Polyneuropathy with Multiple Hypertrophic Nerves in Intracranial, and Intra- and Extra-Spinal Segments Masaaki Niino, Sachiko Tsuji and Kunio Tashiro Hypertrophic nerves have occasionally been seen in chronic inflammatory demyelinating polyneuropathy (CIDP), but most are in the cauda equina. Wereport a case with CIDPin whom magnetic resonance imaging (MRI) with gadolinium diethylene triamine penta-acetic acid (Gd- DTPA) enhancement demonstrated hypertrophy of various peripheral nerves including multiple cranial nerves. Interestingly, none showed neurological signs corresponding to the lesions, except for clinical signs consistent with CIDP. MRIcan be useful for the detection of silent, but abnormal nerve involvement in CIDP. (Internal Medicine 38: , 1999) Key words: nerve hypertrophy, magnetic resonance imaging (MRI), onion bulb formation Introduction Enlargement of the peripheral nerves has been reported in a variety of congenital and acquired neuropathies, for which the term "hypertrophic neuritis" has generally been used (1). Chronic inflammatory demyelinating polyneuropathy (CIDP) is now a well-established neurological disorder, the criteria of which has been proposed by the American Academy of Neurology (2). In CIDP, widespread nerve enlargement may occur (1); most are found in the lumbar region including the cauda equina (3-6). However, a few cases have shown hypertrophy of the cranial nerves (4, 7). Here, a patient with CIDP is presented, in whommagnetic resonance imaging (MRI) showed massive nerve root hypertrophy, including the gadolinium diethylene triamine penta-acetic acid (Gd-DTPA) enhancement of multiple cranial nerves. For editorial comment, see also p 384. Case Report A 29-year-old man noticed slowly progressive muscle weakness and numbness of the bilateral lower limbs since age 17, followed by muscle atrophy and sensory disturbance of the lower extremities by age 27. He became unable to climb up the stairs, and visited our neurology department. There was no family history suggestive of polyneuropathy. General physical examination on admission was within normal limits. Neurologically, mentation was normal, and mild bilateral facial paralysis was seen on the cranial nerve examination. In the upper extremities, strength was normal but moderate atrophy of the intrinsic hand muscles was noted. The lower extremities were hypotonic, and muscle weakness and atrophy were noted both proximally and distally, and much more severe in the distal part of legs with pes cavus. The deep tendon reflexes were diminished in the upper extremities and absent in the lower extremities with silent plantar responses. Mild stocking type sensory disturbance and markedly diminished vibration and position sense in both legs were noted. Romberg's sign was positive. Nerve trunks were not enlarged on palpation. Coordination was intact. He was able to stand with some difficulty and walk with severe steppage gait. There was no autonomic dysfunction. The results of hemogramand urinalysis were normal. Serum chemistries were within normal limits with no evidence of serum cryoglobulin, M-protein, or Bence Jones protein in his urine. The glucose tolerance test was normal. Vitamin Bl was within normal limit. Autoantibody screenings, including anti-gm- 1 antibody, were negative. Molecular genetic studies disclosed absence of 17pl l.2 duplication. Cerebrospinal fluid showed 1 lymphocyte per microliter, and protein and immunoglobulin G (IgG) levels were markedly elevated at 315 and mg/dl (IgG/albumin index 3.4), respectively. Motor nerve From the Department of Neurology, Hokkaido University School of Medicine, Sapporo Received for publication July 25, 1998; Accepted for publication January 14, 1999 Reprint requests should be addressed to Dr. Masaaki Niino, the Department of Neurology, Hokkaido University School of Medicine, Kita- 1 5 Nishi-7, Kita-ku, Sapporo, Hokkaido

2 Nnnoet al Table 1. MCVStudies before and One Month after Steroid Therapies CMAP:compound muscle action potential, Amp: amplitude, W: wrist stimulation, E: elbow stimulation, Dur: duration, MCV:motor conduction velocity. conduction velocities in bilateral median and ulnar nerves were severely reduced with conduction block and no temporal dispersion (Table 1), and compound muscle action potentials (CMAP)could not be elicited by stimulation to the bilateral tibial and peroneal motor nerves. No sensory nerve action potentials in median, ulnar and sural nerves were obtained. The facial nerve conduction times recorded from just below the ear to the orbicularis oculi muscles were severely delayed bilaterally (right 9.7 msec, left 8.0 msec). Latencies of blink reflex were prolonged bilaterally (right Rl : 24.8 msec, R2: 59.8 msec ; leftrl: 26.0msec, R2: 58.1 msec ; normalrange : Rl msec, R msec) and brainstem auditory evoked potentials (BAEP) showed prolonged interpeak intervals between I and III (right 2.94 msec, left 2.97 msec; normal range: msec). Visual evoked potentials (VEP) were normal. MRI of the brain showed marked hypertrophy of the cranial nerves V, VI, VII and VIII bilaterally. There was enhancement with Gd- DTPAof the cranial nerves III, V, VI and VIII (Fig. 1). MRI showed hypertrophy of many nerve roots, and at the C6-C7 level, massively hypertrophied nerve roots were compressing the spinal cord (Fig. 2A, B, C). Intercostal nerves were enlarged with enhancement of the peripheral segments (Fig. 3), and the cauda equina was severely hypertrophic (Fig. 4). A right sural nerve biopsy disclosed severe loss of myelinated fibers, occasional onion bulb formation and slight edema under perineurium, without inflammatory cell infiltration (Fig. 5). Prednisolone at an initial dose of 60 mg daily was started, with diminished numbness of the lower extremities and a mild increase in the strength of the legs. Motor nerve conduction velocities showed little improvement in one month, but the CMAPof the right ulnar nerve with elbow stimulation improved markedly, from 0.6 mvto 4.5 mv(table 1). The sensory nerve action potentials at bilateral median and ulnar nerves, previously unobtainable, were evoked (median nerves; right 25.3 m/sec, left 27.2 m/sec : ulnar nerves; right 28.6 m/sec, left 25.3 m/sec). However, the hypertrophy of nerves on MRIwas unchanged during the follow-up period of 6 months. Figure 1. Tl-weighted cranial MRI after the injection of Gd-DTPAin coronal section; cranial nerves VI (arrows) and V2 (heads arrow) are enlarged (TR= 600 ms, TE=14 ms). Discussion Our patient had a long-standing sensory-motor neuropathy of 1 2 years' duration, without apparent inheritance. Polyneuropathy associated with paraproteinemia, collagen disease, vitamin B 1 deficiency, and diabetic mellitus were excluded by laboratory studies. The important differential diagnoses include HMSNtype I and type III. No family history, the absence of 17pl l.2 duplication, and clinical and electrophisiological re- 446

3 CIDP with Multiple Hypertrophic Nerves Figure 2. MRimages showing massively hypertrophied nerve roots compressing spinal cord at the C6-C7 level (arrows): (A) (sagittal image, TR=500 ms, TE=12 ms), (B) (axial image at C6/7 level, TR=600 ms, TE=15 ms), (C) (axial image at C6/7 level, TR=4,500 ms, TE=96 ms). generalized limb and truncal weakness from childhood. The present patient had normal motor development during child- hood, and his neurological signs and symptoms started in adulthood. His clinical signs, symptoms and laboratory data were compatible with CIDP defined by the American Academy of Neurology (2). The widespread nerve enlargement has been reported in CIDP, but usually occurring in the cauda equina (3-6). The present case showed marked hypertrophy of not only the cauda equina, but also the cervical and thoracic nerve roots, intercostal nerves and cranial nerves. Symondsand Blackwood reported a case of spinal cord compression by root hypertrophy with Babinski's sign (9). In our case, although definite cord compression was seen on MRI,no neurological evidence was noted indicating cord involvement. The nerve hypertrophy in CIDP is chiefly attributable to the proliferation of Schwanncells caused by repeated demyelination and remyelination (10). The mucopolysaccharides in the endoneurium as secondary products associated with nerve degeneration ( 1 1) and edema (12) may also be contributed to nerve swelling in CIDP. In other reports, neither onion bulb formation nor inflammatory findings was detected in the sural nerves, sponses for steroid therapy may favor the diagnosis for CIDP while remarkable onion bulb formation and inflammatory cell over HMSNtype I. In HMSNtype III, a remarkable increase infiltration were present in the hypertrophied nerves (13, 14). in the protein content of the cerebrospinal fluid (CSF) may be In the right sural nerve of the present case, severe loss of mypresent (8), and clinically, gait is severely impaired because of elinated fibers with slight proliferation of interstitial tissue and Figure 3. Tl-weighted axial image after the injection of GdDTPAat Th7 level shows intercostal nerves with enlargement and peripheries of nerves are slightly enhanced with Gd-DTPA (arrows) (TR= 660 ms, TE=15 ms). Internal Medicine Vol. 38, No. 5 (May 1999) 447

4 Niino et al Figure 5. 1 fi section of right sural nerve biopsy (toluidine blue, x230). Severe loss of myelinated fibers and slight edema under the perineurium are present without inflammatory cell infiltration. Figure 4. T2-weighted sagittal image shows hypertrophy of the cauda equina (TR=2,052.5 ms, TE=70 ms). edema were present, suggesting that the hypertrophy of the nerves in our case might be associated with onion bulb formation. Prednisolone, plasma exchange, intravenous immune globulin and cyclosporine are choices of therapy for CIDP, but most have not been proven to be effective for nerve hypertrophy (4, 5), except for a case report stating steroid responsiveness (12). The present patient was treated with oral prednisolone with someclinical improvement, but no improvementfor hypertrophy of peripheral nerves including cranial nerves was noted. The cranial nerve involvement was clinically detected in the facial nerves, and was supported by the prolonged facial nerve conduction time and blink reflexes. Involvement of other cranial nerves was suggested by the results of BAEPsand MRI. Schady et al reported enlargement of the cranial nerves VII and the cauda equina (4), and Castillo and Mukherji showed enlargement and contrast enhancementof the cranial nerves III, V, VI, VII, VIII, IX, X and XI on MRI (6). In anotherreport of CIDP, the enhancement of cranial nerve VIII was reported (7), and abnormal enhancement of the cauda equina was also reported (3). In our case, cranial nerves V, VI, VII and VIII were thickened, with Gd-DTPAenhancement of the cranial nerves III, V, VI and VIII. The mechanism for enhancement seen with inflammatory processes is considered to be due to breakdown of the blood-nerve barrier (15, 16). In 66% of patients with CIDP, a slow monophasic progressive course was observed (17), as seen in our case. Nerve hypertrophy, the mild response to steroid therapy and absent inflammatory cell infiltration in the sural nerve biopsy in our patient might be explained by his long-standing progressive course. Although the enlargement and enhancement of peripheral nerves and cranial nerves in CIDP have been reported by several others (3-7, 9, 10), to our knowledge, this is the first report to demonstrate the enlargement of multiple cranial nerves, together in the multiple nerve roots and intercostal nerve in the same patient. Multiple hypertrophic nerves in the intracranial, and intra- and extra-spinal segments might be identified by neuroimaging studies, without the corresponding clinical signs and symptoms. Acknowledgements: This work was supported in part by a grant for Ministry of Education (No ). References 1 ) Thomas PK, Lascelles RG, Stewart G. Hypertrophic neuropathy, in: Handbook of Clinical Neurology, Vinken PJ, Bruyn GW, Eds. Vol 21, System Disorders and Atrophies. Elsevier/North Holland Amsterdam, 1975: ) Research criteria for diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Report from an Ad Hoc Subcommittee of the 448

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