Article Text


Sensory predominant neuropathy with GM1 antibodies, conduction blocks, and orbital pseudotumour
  1. Department of Neurology, Innsbruck University Clinic, Austria
  1. Dr S Kiechl, Department of Neurology, Innsbruck University Clinic, Anichstr 35, A-6020 Innsbruck, Austria. email: STEFAN.KIECHL{at}UIBK.AC.AT

Statistics from

Two male patients developed multifocal sensory neuropathy with high titre IgM anti-GM1 antibodies (up to 1: 64 000) and infiltrative orbitopathy. Nerve conduction studies showed multiple motor conduction blocks and evidence of a similar phenomenon in sensory nerves. Both patients deteriorated after corticosteroid administration but benefited substantially from intravenous immunoglobulin therapy. Our findings suggest the existence of a predominantly sensory subtype of multifocal motor neuropathy (MMN) and challenge the postulated motor specificity of anti-GM1 antibodies.

Anti-GM1 antibodies have been implicated in the aetiology of multifocal motor neuropathy (MMN) and are assumed to be specific for this disease when occurring at high titres.1 2 We report on two patients with high titre IgM anti-GM1 antibodies and electrophysiological features typical of MMN presenting with severe sensory neuropathy.

Patient 1 was a man who developed asymmetric numbness of limbs and difficulty in performing fine motor movements around the age of 55. Sensory deficits showed a multifocal pattern (multiple mononeuropathy) and involved proximal limb regions, trunk, and face. The course of illness was steadily deteriorating with some episodes of prominent disease progression usually preceded by minor infections. After 10 years he was unable to write, needed assistance for dressing and walking, and complained of diplopia. Neurological examination showed profound loss of all sensory modalities in the arms and legs and pseudoathetosis of the fingers and wrist. Deep tendon reflexes were preserved and muscle strength was normal. The patient showed marked protrusion and downwards and outwards deviation of the left eye with a complex impairment of all eye movements.

Patient 2, a 68 year old man, reported an insidious onset and gradual worsening of asymmetric sensory loss and painful patchy dysaesthesia. At a neurological examination 15 years after disease onset, pinprick sensation, vibration, and proprioception were prominently affected in his arms and legs. There was severe ataxia of gait. Postural maintenance and voluntary movements strongly depended on visual guidance. Muscle strength was normal except for slight bilateral paresis of the tibialis anterior and intrinsic hand muscles (4+/5 MRC scale). There was no evidence of autonomic nerve or pyramidal tract dysfunction. Tendon reflexes were absent. The patient had an incomplete left side third nerve paresis and ipsilateral visual loss.

General physical examination was normal in both patients, as were repeated screenings for neoplastic and connective tissue diseases. Enzyme linked immunosorbent assays (ELISAs)3 showed IgM antibody activity against GM1, asialo-GM1, and GD1b, presumably recognising the Gal(β1–3)GalNAc group (table). Clonality of ganglioside antibodies was not investigated. Serum immunoelectrophoresis did not show monoclonal gammopathy. All the following laboratory indices were normal or negative: creatine phosphokinase, erythrocyte sedimentation rate, renal and liver function, antinuclear antibodies, thyroxin, vitamins B1, B6, B12, folic acid, urine porphobilinogen, and serum cryoglobulins. Cerebrospinal fluid was acellular with 52 mg/dl and 90 mg/dl protein, respectively (normal <50 mg/dl).

Ganglioside antibody patterns and electrophysiological characteristics

Nerve conduction studies showed multifocal slowing of motor nerve conduction velocities and F wave latencies (table). Despite near normal muscle strength we found motor conduction blocks at sites not prone to compression. Sensory nerve potentials could not be elicited in the median, ulnar, radial, or sural nerves. Electromyography showed fibrillation activity, generalised fasciculations, and features of chronic neurogenic damage. Magnetic resonance imaging of the brain, spinal cord, and dorsal nerve roots did not show relevant abnormalities. Both patients had non-progressive orbital infiltration with slight gadolinium enhancement suggestive of ectopic lymphoproliferative tissue. Lesion extension was most pronounced at the apex orbitae and fissura orbitalis superior and caused compression of the left optic and oculomotor nerves in one patient and mechanical interference with eye movement in the other. Analogous orbital infiltration has been described in patients with paraproteinemic neuropathies and antibody mediated autoimmune diseases such as myasthenia.

Administration of methylprednisolone at dosages of 40 to 60 mg/day was followed by marked deterioration of sensory ataxia in both patients. By contrast, substantial and rapid benefit was achieved by means of intravenous immunoglobulin (IVIg) therapy (0.4 g/kg body weight/day for five consecutive days). Gait normalised, fine motor movements and ophthalmoplegia markedly improved, and motor conduction blocks partially resolved. In addition, low amplitude sensory nerve action potentials reoccurred.

In the literature, there is circumstantial evidence of a pathogenic role of high titre IgM anti-GM1 antibodies in the mediation of motor conduction blocks in MMN.1 2Often, the antibody attack is directed at the Gal(β1–3)GalNAc epitope of GM1. This carbohydrate group, however, is also an obligatory constituent of GD1b (cross reactivity), which was implicated in the aetiology of sensory neuropathies. GD1b distributes on human dorsal root ganglion cells and paranodal myelin and shows comparable immunostaining with anti-GM1 antibodies with Gal(β1–3)GalNAc specificity and antibodies to disialosyl residues of GD1b.4This and various other findings challenge a motor specificity of anti-GM1 antibodies and, instead, suggest a vulnerability of part of the sensory system. Actually, nerve conduction studies in previous series of patients with MMN showed numerous sensory abnormalities, as did pathological evaluations of sensory nerve biopsy specimens.5 6 7 We report on a predominantly sensory variant of MMN found in two male patients. Both had IgM anti-GM1 and antiasialo-GM1 antibodies at titres high enough to be assumed specific for MMN.1 2Despite near normal muscle strength both of our patients had multiple motor conduction blocks. Rapid clinical improvement after IVIg therapy despite a more than 10 year history of illness tempts us to speculate on a similar phenomenon in sensory nerves (sensory conduction block).

Good response to therapy argues against a pathogenetic significance of high titre GD1b antibodies in patient 2, because the rare GD1b associated sensory axonal neuropathy (sensory ganglionopathy) is mostly irreversible. In addition, this patient showed multiple conduction blocks and slowing of nerve conduction velocities rather than predominantly axonal damage and had no monoclonal gammopathy, which is usually present in cases with the GD1b associated neuropathy.

We propose that multifocal neuropathies with conduction blocks and high titre anti-GM1 antibodies have a clinical range from predominantly sensory to predominantly motor variants and suggest that all these variants be subsumed under the term “multifocal motor-sensory neuropathy (MMSN)”. This concept is of clinical relevance in that all phenotypes share the same therapeutic peculiarities including good response to IVIg and ineffectiveness (most cases) or even unfavourable effects of corticosteroids, which are first line drugs in the treatment of other immune neuropathies. Our report aims to increase awareness for sometimes prominent sensory involvement in MM(S)N and to facilitate early and accurate diagnosis in such patients.


View Abstract

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.