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Necrotising vasculitis with conduction block in mononeuropathy multiplex with cold agglutinins
  1. R OTSUKA,
  2. F UMEHARA,
  3. K ARIMURA,
  4. Y MARUYAMA,
  5. Y ARIMURA,
  6. M OSAME
  1. The Third Department of Internal Medicine, Kagoshima University School of Medicine, Sakuragaoka 8–35–1 Kagoshima, Japan
  1. Dr R Otsuka, The Third Department of Internal Medicine, Kagoshima University School of Medicine, Sakuragaoka 8–35–1 Kagoshima, Japan. Telephone 0081 99 275 5332; fax 0081 99 265 7164; email reika{at}med4.kufm.kagoshima-u.ac.jp

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Cold agglutinins are cold reactive autoantibodies that have haemolytic effects on red blood cells mediated via complement fixation. Neuropathy associated with cold agglutinins has been described,1-5 however, details of its pathomechanism are unclear. Here, we report the clinical, electrophysiological, and pathological findings of a mononeuropathy multiplex in a patient with cold agglutinins, who responded very well to plasmapheresis.

A 72 year old man was admitted with a 1 month history of progressing dysaesthesia and weakness of the limbs. He had no anaemia, jaundice, hepatosplenomegaly, or lymphadenopathy. Cranial nerves and the cerebellum were not involved. There was severe weakness and atrophy of bilateral thenar, interossei, and plantar muscles with severe dysaesthesia of both palms and plantaris. Pin prick and light touch were reduced as well as position and vibratory sensation in both hands and feet. Deep tendon reflexes were hypoactive. Babinski’s sign was negative.

Laboratory investigation showed a raised erythrocyte sedimentation rate: 52 mm/hour (normal <10) and serum C reactive protein: 1.8 mg/dl (normal; < 0.5). Blood cell counts were within normal limits. The following were normal or negative; IgG, IgA, IgE, IgM, M-protein, direct and indirect Coombs tests, cryoglobulin, antibodies to mycoplasma, myelin associated glycoprotein, gangliosides (GM1, GD1b, asialo-GM1, GT1b, GQ1b, Gal-C), P-ANCA, and C-ANCA. The CSF was normal. Titre of cold agglutinins was detectable at 1:1024 at 4°C (normal; <1:256). The patient’s serum agglutinated adult group OI-red blood cells, but not Oi-red blood cells or human cord red blood cells, signifying cold agglutinins with I specificity. Immunoelectrophoresis of the eluate confirmed IgM composition.

The initial nerve conduction study showed severe diminution or absence of compound muscle action potentials (CMAPs) with mildly diminished conduction velocities. F wave latencies were mildly prolonged. There were no evoked sensory nerve action potentials (SNAPs) in median, ulnar, and sural nerves bilaterally. Electromyographic studies of the affected muscles showed moderate neurogenic changes, but there were no fibrillation potentials except in the left anterior tibialis muscle. Sural nerve biopsy was performed. Epineurial vessels were surrounded by mononuclear cell infiltrates (figure A). Some vessels had focal necrosis of their wall. The small vessels in the endoneurium and epineurium showed slugging of red blood cells. The densities of large and small myelinated fibres were markedly decreased (diameter<5 μm: 1504/mm2, diameter >5 μm:708/mm2, total: 2212/mm2)(figure B). Teased fibre analysis showed that 90% of the fibres were undergoing axonal degeneration.

(A) Sural nerve (toluidine blue staining) showing epineurial vessel surrounded by mononuclear cell infiltrates. Note fibrin deposition (arrow) and necrosis in media. (bar=20 μm). (B) Most of myelinated fibres are undergoing axonal degeneration. Many macrophages containing myelin debris infiltrate the endoneurium. (bar=30 μm).

Oral prednisolone (30–50 mg/day) for 4 weeks reduced the erythrocyte sedimentation rate and C reactive protein, but not the serum titre of cold agglutinins; neither was there any improvement of symptoms. He received massive dose intravenous corticosteroid therapy. This moderately improved the muscle strength and sensory disturbance. Follow up nerve conduction studies (71 days after the initial study) suggested conduction block of the right median nerve on the forearm (CMAP, duration at the wrist: 2.76 mV, 8.4 ms; CMAP, duration at the elbow: 1.87 mV, 8.8 ms), whereas CMAP could not be elicited in the initial study. We adapted the following criteria to define conduction block: <15% change in duration and >20% fall in negative peak amplitude between proximal and distal sites by percutaneous supramaximal stimulation of motor nerves. As the conduction block might delay smooth recovery of symptoms, Double filtration plasmapheresis was performed four times. After the second plasmapheresis, dysaesthesia and muscle strength improved remarkably.The titre of cold agglutinins was reduced to 1:64. The motor nerve conduction velocity (MCV) of the right median nerve likewise improved (pretreatment; 40.0 m/s, post-treatment; 57.0 m/s). Double filtration plasmapheresis was followed by oral azathioprine (50 mg/day) with tapering of steroid. He was discharged on prednisolone (20 mg/day). In the subsequent 4 years, he has had mild exacerbation of dysaesthesia that responded to intermittent steroid therapy.

Characteristic features of the present case are as follows: (1) subacute onset of mononeuropathy multiplex; (2) necrotising vasculitis with marked loss of myelinated fibres; (3) probable conduction block in the median nerve; (4) increased concentrations of serum titres of cold agglutinin; and (5) marked response to plasmapheresis. Extensive investigation for other causes of neuropathy was negative except for an increased serum concentration of cold agglutinins, which strongly suggests that cold agglutinins may play an important part in the induction of neuropathy in this case.

Six patients with neuropathy associated with cold agglutinins have been reported1-5 including our patient. Cold agglutinins are cold reactive autoantibodies that react with the antigenic determinant termed I/i or Pr present on glycoproteins and glycolipids in erythrocyte membranes. Arai et al 1 reported a case of polyneuropathy and IgMκ M proteinemia with anti-Pr2 CA activity. IgM M protein cross reacted with sialosyl paragloboside, GT1b, GD1a, GD1b, GM3, and GD3 present in myelin and in endothelial cells of the peripheral nervous system. It has been speculated that anti-Pr2 IgM protein induced immune mediated damage to vascular endothelium and peripheral nervous system myelin. A similar pathomechanism has been postulated in the other cases.2-3 However, necrotising vasculitis has never been reported in neuropathy with cold agglutinins. This is the first demonstration of vasculitic neuropathy with cold agglutinins. Although the mechanism for neuropathy with cold agglutinins is unknown, mechanisms similar to those in cryoglobulinaemic neuropathy have been postulated.4 The hypotheses are (1) immunologically mediated demyelination; (2) ischaemic injury secondary to slugging or agglutination of red blood cells in the vasa nervorum; and (3) an associated vasculitis. In the present case, we have confirmed the necrotising vasculitis and probable conduction block. Pathophysiological explanations for association of vasculitis and conduction block may be as follows. Firstly, conduction block may occur as a consequence of nerve ischaemia due to small vessel occlusion. There have been reports of conduction block occurring in vasculitic neuropathy which support this possibility. Secondly, humoral factors including cold agglutinins may induce immune mediated demyelination in the peripheral nervous system. Taken together, neuropathy with cold agglutinins may involve immunologically mediated demyelination, microcirculation occlusion, and vasa nervorum vasculitis. The diversity of pathomechanisms may come from the difference target antigens recognised by cold agglutinins. Plasmapheresis proved effective in all cases. These findings strongly suggest that humoral factors including cold agglutinins may play an important part in the induction of neuropathy with cold agglutinins. We recommend plasmapheresis as first choice treatment for neuropathy associated with cold agglutinins.

Acknowledgments

We thank Dr Gerard Salazar for critical reading of the manuscript, Ms M Teshima and N Hirata for their technical assistance, Dr S Kusunoki (Department of Neurology, Institute for Brain research, University of Tokyo) for analyses of antibodies to gangliosides, and Mr H Moug (Division of Blood Transfusion Medicine, University of Kagoshima) for characterization of cold agglutinin.

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