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Neuropathy with anti-disialosyl IgM antibodies and multifocal persistent motor conduction blocks
  1. R Ahdab1,
  2. J P Lefaucheur1,
  3. D Malapert2,
  4. E Touze3,
  5. C Caudie4,
  6. C André5,
  7. A Créange2
  1. 1
    Service de Physiologie—Explorations Fonctionnelles, Hôpital Henri Mondor, Assistance Publique—Hôpitaux de Paris, Université Paris XII, Créteil, France
  2. 2
    Service de Neurologie, Hôpital Henri Mondor, Créteil, France
  3. 3
    Service de Neurologie, Hôpital Sainte-Anne, Paris, France
  4. 4
    Service d’Immunologie, Hôpital Neurologique, Hospices Civils de Lyon, Lyon, France
  5. 5
    Service d’Immunologie Biologique, Hôpital Henri Mondor, Créteil, France
  1. Professor J-P Lefaucheur, Service Physiologie, Explorations Fonctionnelles, Hôpital Henri Mondor, 51 avenue de Lattre de Tassigny, 94010 Créteil cedex, France; jean-pascal.lefaucheur{at}hmn.ap-hop-paris.fr

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In 1985, circulating IgM antibodies reacting with NeuAc(alpha2–8)NeuAc(alpha2–3)Gal-configured disialosyl gangliosides (including GD1b, GD3, GT1b, and GQ1b) were first described in a patient with chronic sensory neuropathy.1 The typical clinical picture of anti-disialosyl-associated neuropathy comprises marked sensory ataxia, areflexia, a relatively preserved motor function excepting ophtalmoplegia and a chronic or relapsing course.2 In half of the cases, IgM antibodies are also cold agglutinins, fulfilling all the conditions for the chronic ataxic neuropathy, ophthalmoplegia, monoclonal IgM protein, cold agglutinins and disialosyl antibodies (CANOMAD) syndrome. We report two patients with a chronic or relapsing sensory neuropathy and ophtalmoplegia associated with anti-disialosyl IgM antibodies who developed asymmetrical motor weakness related to multifocal persistent conduction blocks, an unusual feature in this context.

Patient 1

A 39-year-old woman presented with gait ataxia and paraesthesias in the left foot. Paraesthesias spread up to both legs, and then to both hands within a year. Over the following year, ataxia worsened, and distal weakness appeared in the lower limbs, predominating on the left side. Clinical examination showed decreased sensation to all modalities in all four extremities, gait ataxia, dorsal and plantar flexion weakness, and absent tendon reflexes in the lower limbs. Six years after disease onset, she developed right hand and proximal lower limb weakness. Three years later, she presented with a right-sided ptosis and diplopia with both vertical and horizontal components secondary to partial third cranial nerve palsy. Other cranial nerves were intact. Meanwhile, gait and limb ataxia continued to worsen. Serum protein electrophoresis and immunofixation disclosed an IgM Kappa monoclonal protein (9 g/l). Circulating anti-GD1b, GD3, GQ1b and GT1b IgM antibodies were found by immunodot. Serum did not react to other gangliosides, including GM1. There were no cold agglutinins. Several neurophysiological examinations were undertaken at various intervals in the course of the disease. They disclosed persistent motor conduction blocks that were, according to validated criteria,3 4 definite and probable for the right and left median nerves at the forearm, and possible for the right radial nerve at the arm, the left ulnar nerve at the forearm and the left tibial nerve at the leg (fig 1). SNAPs were absent in the four limbs. Twenty-five years into her illness, the patient is left with horizontal and vertical diplopia, tingling involving the palms, the soles, and the legs up to the knees, severe gait impairment, ataxia and diffuse weakness predominating in the lower limbs, but she is still able to walk with assistance. She receives periodic infusions of intravenous immunoglobulins (IVIgs), resulting in unequivocal but transient motor improvement with modest effects on gait and diplopia. Azathioprine and methotrexate did not provide any significant clinical benefit.

Figure 1

Motor nerve conduction studies. Definite (***), probable (**) and possible (*) conduction blocks are indicated with the value of negative peak amplitude decrement (temporal dispersion in parentheses) of the compound muscle action potentials in the given limb segment.

Patient 2

A man in his early 60s man presented with diplopia and gait ataxia that spontaneously resolved within 2 weeks. The following year, right peripheral facial nerve palsy occurred. While facial palsy slowly resolved with steroid treatment, the patient reported recurrence of gait ataxia, paraesthesias of the four extremities and writing difficulties. Neurological examination showed decreased sensation to all modalities in the face, fingers and toes with diffuse areflexia, impaired joint position sense, gait and limb ataxia, but no motor deficit. Four years later, he developed right distal upper-limb motor weakness and left foot drop, while gait ataxia and writing difficulties progressively worsened. Serum protein electrophoresis and immunofixation disclosed a biclonal IgM Kappa protein (3 g/l). Circulating anti-GD1b IgM antibodies were found by immunodot. Serum did not react to other gangliosides, including GM1. There were no cold agglutinins. Repeated neurophysiological examinations showed persistent conduction blocks that were definite for the right ulnar nerve at the forearm, probable for the left peroneal nerve at the leg and possible for the left tibial nerve at the leg (fig 1). SNAP amplitudes were markedly reduced in the four limbs. Eight years after disease onset, the patient has widespread disabling paraesthesias at the four extremities, ataxia, writing difficulties and distal left lower limb weakness. He receives periodic IVIg infusions with modest overall improvement.

Discussion

Both patients were characterised by chronic or relapsing severe sensory neuropathy affecting the four limbs, ophtalmoparesis and circulating anti-disialosyl IgM antibodies. If not for the absence of cold agglutinins, the clinical and biological picture was consistent with the diagnosis of CANOMAD.2 In this context, the presence of multifocal persistent motor conduction blocks associated with asymmetrical motor weakness was unusual.

In the literature, electrophysiological features of CANOMAD include diffuse demyelinating neuropathy, axonal sensory and motor neuropathy, or isolated sensory findings.2 Three patients with motor conduction block in one median nerve have been reported.2 However, the overall electrophysiological picture was suggestive of widespread demyelination, as evidenced by prolonged distal motor and F-wave latencies and slowing of conduction velocity in various territories. Whether or not the conduction blocks were persistent was not mentioned.

In our patients, clinical and electrophysiological findings resemble those of the Lewis–Sumner variant of chronic inflammatory demyelinating neuropathy (CIDP), a multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) with multifocal conduction blocks and other features of demyelination.5 Multifocal conduction blocks are also observed in multifocal motor neuropathy (MMN) that can be differentiated from MADSAM by the absence of sensory signs and the presence of anti-GM1 antibodies in a substantial number of cases.5 In our patients, as in MMN, motor weakness paralleled conduction blocks in the absence of more widespread demyelinating features. However, the patients also showed diffuse, symmetrical SNAP alteration and anti-disialosyl, but no anti-GM1 antibodies. These findings associated with an IgM monoclonal gammopathy helped us to identify our cases as CANOMAD syndromes.

The presence of chronic or relapsing sensory neuropathy with ophtalmoparesis leads one to suspect the diagnosis of CANOMAD and to screen for monoclonal paraprotein and anti-disialosyl antibodies. According to our observations, this should be the case even when asymmetrical motor weakness and multifocal persistent motor conduction blocks are also present. Actually, CANOMAD may fall into the category of asymmetrical, multifocal forms of CIDP (MADSAM-like). Fine antibody specificities likely explain the heterogeneity of anti-disialosyl-associated neuropathies. Considerable effort is made to define subcategories of anti-ganglioside antibodies, improving understanding of their pathophysiological involvement and clinical correlates. One pragmatic impact of the present observations would be to consider IVIgs as the first-line agent in CANOMAD, at least in the case of MADSAM-like presentation.

REFERENCES

Footnotes

  • Competing interests: None.

  • Patient consent: Obtained.

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