R.M. van den Berg-Vos, M.D.
Clinical features
MMN is clinically characterised by a slowly progressive, asymmetrical, predominantly distal weakness that develops insidiously or in a stepwise manner over several years. The commonest presenting clinical features are wrist drop, foot drop and grip weakness. Symptoms and signs of distal muscles prevail for a long time. In our recent study of 38 patients, 22 had onset of disease in the arms. In 14 of the 16 patients with onset in the legs, the arms were also affected at a later stage and in five of these, weakness in the arms predominated.14 Proximal muscle weakness in deltoid and biceps muscles has been described. Single cases of cranial nerve involvement have been reported.15 Sensory disturbances are absent or minimally present. Fasciculation and cramps are present in about two-thirds of the patients. Tendon reflexes are usually reduced in affected regions.
We studied the clinical, laboratory and electrophysiological characteristics of 37 patients presenting with muscle weakness and atrophy of the limbs and electrophysiological features compatible with demyelination. Based on these findings, we have proposed a set of clinical, laboratory and electrophysiological criteria for the diagnosis of MMN, which has been verified by follow-up and response to treatment with intravenous immunoglobulins (IVIg).16 Using these criteria, 21 patients were diagnosed as definite MMN (17 responders), seven patients as probable MMN (5 responders) and nine as possible MMN (1 responder). Age at onset, the number of affected limb regions and the number of patients with creatine kinase (CK) >180 U/L were significantly lower in responders than in non-responders. Elevated anti-GM1 antibodies and definite conduction block were found significantly more often in responders. The proposed diagnostic criteria (see table) may be useful in clinical practice and therapeutic trials.
Natural course and prognosis
The majority of patients with MMN respond to IVIg treatment. A prospective study on the natural course of MMN is therefore not feasible. In retrospective studies we and others have shown that the disease runs a slowly progressive course, although most patients are impaired in their daily life by reduced dexterity in manual activities.14,54. Occasionally, a step-wise55,56 or spontaneously remitting course1,57 have been described.
In our retrospective study of 38 patients with MMN, with disease durations ranging from 6 months to 34 years, disease severity was assessed by determining muscle weakness, disability, conduction block, and distal and proximal compound muscle action potential (CMAP)- amplitude. As indicator for an ongoing immune-mediated process, the response to one course of IVIg treatment was measured in 34 patients and associated with disease severity. With increasing disease duration, weakness and disability became significantly more severe, and the distal and proximal CMAP-amplitude decreased significantly. The number of conduction blocks was significantly higher in patients with a disease duration longer than 10 years than in those affected less than 10 years. Thirty of the 34 patients responded to IVIg treatment. Non-responsiveness to IVIg was not associated with any of the disease variables. Severe and widespread weakness was significantly associated with a good response on the MRC-sumscore. The good response to IVIg treatment in patients with severe and prolonged disease indicates that progression may be the result of an ongoing immune-mediated process.
Epidemiology
The incidence and prevalence of MMN are unknown, but probably low. In the literature one MMN patient for every 50 patients with ALS51, a disease with a reported incidence of 1.5 -2 :100.00052,53, has been described. In the Netherlands, we estimate the number of patients with MMN at approximately 100, giving a prevalence of 0.7: 100.000. With an approximate ratio of 2.6 : 1, men are more frequently affected than women.8 The mean age at onset is 40 years, with a range of 20 – 65 years.16
Differential diagnosis
The differential diagnosis of MMN includes (lower) motor neuron disease ((L)MND)17,18 on one hand and demyelinating neuropathies on the other. In some patients MMN may appear similar to amyotrophic lateral sclerosis (ALS) with predominantly lower motor neuron signs and axonal changes on nerve conduction studies. The rapidly progressive disease course and the presence -or development during the disease course- of upper motor neuron signs as hyperreflexia, spasticity and/or bulbar signs may point to a diagnosis of ALS. The difference with LMND may be more difficult as a subgroup of patients with adult-onset, sporadic LMND may have a benign disease course. The clinical phenotype of several subtypes may be helpful in differentiating from MMN. Recently, we have classified these patients according to the pattern of muscle weakness in the following subtypes, which may help differentiating : ‘slowly progressive spinal muscular atrophy (SMA)’ with generalized weakness, ‘distal SMA’ with symmetrical, distal weakness more in legs than arms, ’segmental distal SMA’ with asymmetrical weakness predominantly in distal muscle groups in arms and ’segmental proximal SMA’ with asymmetrical weakness predominantly in proximal muscle groups in arms.19 The finding of persistent motor nerve conduction block on nerve conduction studies outside nerve compression sites and/or a positive titer of anti-GM1 antibodies and/or increased signal intensities on T2-weighted MR images of the brachial plexus (see later) are helpful in differentiating MMN from LMND.
Within the demyelinating neuropathies it is important to differentiate MMN from chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal inflammatory demyelinating neuropathy (MIDN). In CIDP proximal, symmetrical weakness and generalized areflexia are common, whereas weakness in MMN is asymmetrical and distal and reflexes are only lowered or absent in affected limbs. The remitting and relapsing course of CIDP is uncommon in MMN. Sensory signs and symptoms in CIDP often occur, and patients with MMN rarely have sensory symptoms at clinical and electrophysiological examination. However, there are patients with a purely motor form of CIDP, in whom weakness is often predominantly proximal and symmetrical. On nerve conduction studies motor CB is found in both CIDP and MMN, but other features of demyelination such as slowed conduction velocities and prolonged distal latencies are more prominent in CIDP. In previous studies several patients have been described who have an asymmetric sensory or sensorimotor demyelinating neuropathy which has several features in common with CIDP or MMN, but who do not exactly fulfill the diagnostic criteria for these diseases. We reported several patients and proposed to call this neuropathy MIDN.13 MIDN is suggested by the finding of asymmetrical weakness and/or sensory symptoms that remain localized in one arm for several years, neuropathic pain, focal nerve tenderness or even a palpable supraclavicular or popliteal mass. The latter may result in consideration of non-immunological diseases such as tumours or neurofibromatosis and often a long diagnostic delay and late treatment. Nerve conduction studies are helpful in differentiating from MMN as we found decreased distal SNAP amplitudes in all patients. Patients with MIDN may benefit from treatment with corticosteroids, whereas patients with MMN do not, or may even deteriorate.20
Ancillary investigations
| Evidence of motor conduction block (CB) is considered to be the electrodiagnostic hallmark of MMN. CB has been defined as a reduction in the amplitude or area of the compound muscle action potential (CMAP) obtained by proximal versus distal stimulation of motor nerves exceeding the CMAP reduction caused by increased temporal dispersion in demyelinating disorders or polyphasic motor-unit potentials in axonal degeneration.21 The degree of CMAP reduction which is necessary to diagnose CB varies considerably from author to author. Our criterion for definite CB (area reduction P/D at least 50%) is based on the finding that computer simulation of temporal dispersion of biphasic MUPs yields an area reduction P/D of no more than 50%.22 With more polyphasic MUPs, the CMAP reduction P/D is possibly greater.23 Therefore many studies require that temporal dispersion, as measured by duration prolongation P/D, has to be limited.23-25We did not include this in our criteria, because temporal dispersion was reduced by warming.26 Warming for at least 30 min in water at 37o C yields a nerve temperature close to 37o C 27,28 and improves the detection of CB by reducing temporal dispersion. 26,29 and inducing CB in demyelinating neuropathy 27,30 but not in axonal neuropathy.31 To minimize underdiagnosis of mild CB we defined a criterion for probable CB, i.e. amplitude reduction P/D of at least 30% in an arm nerve.32,33 In a study of diagnostic criteria for MMN (see above), we found that 17 of 21 patients (81%) with definite motor conduction block and five of seven patients (71%) with probable motor conduction block responded favourably to IVIg). Only one of nine patients (11%) showing features compatible with demyelination other than conduction block showed a favourable response.16 These non-responding patients with a progressive disease course were probably suffering from LMND rather than MMN. These findings stress the importance of careful electrophysiological analysis in the search for conduction block in all patients with pure lower motor neuron syndromes. Nevertheless, we also demonstrated that clinical and laboratory features may contribute to a diagnosis of MMN.16 For example, we observed increased signal intensities on T2-weighted MR images of the brachial plexus34 in approximately one-third of patients with MMN.16 These abnormalities have also been observed in patients with CIDP34, monoclonal gammopathy of undetermined significance35, but not in LMND. |
| Pathogenesis and etiology At present the pathogenesis of MMN is not known, but there is some evidence, mostly based on the clinical improvement in immunological therapies and the frequent asssociation with anti-glycolipid antibodies, that the disease is immune-mediated.{VANDENBERGVOSRM2003A} The precise mechanisms and the target antigens of this immune response have not yet, however, been elucidated. The frequent occurrence of IgM anti-GM1 ganglioside antibodies, in 20 to 80% of patients with MMN36,37, has favoured the hypothesis that the ganglioside GM1 may be the target of this immune response. Gangliosides are indeed highly concentrated in the nervous system. The carbohydrate structures of gangliosides share structural similarities with bacterial lipopolysaccharide. The possibility of an association between MMN and C. Jejuni infection by the mechanism of molecular mimicry has been raised in three patients with high titres of anti-GM1 antibodies after C. Jejuni enteritis in whom a diagnosis of MMN was considered.38-40 A recent study did not, however, reveal high titers of anti-C. jejuni antibodies in 20 patients with MMN.41 The conduction abnormalities in MMN suggest dysfunction at the nodes of Ranvier. Binding experiments with cholera toxin have shown that binding sites for the Gal (b1-3)GalNac disccharide moieties of GM1 are present at the level of the nodes of Ranvier, compact or outer myelin, and at axonal membranes.42 Moreover, the sparse pathological studies in MMN have demonstrated IgM deposits and complement activation at the nodes of Ranvier 43-45 Thus, anti-GM1 antibodies could trigger an inflammatory process which damages both myelin and axons. It is also possible that IgM anti-GM1 antibodies, or other at present unidentified antibodies, could hamper Schwann cell processes in recognizing axonal membrane components and thus interfere with remyelination, leading to persistent conduction block and a primary progressive disease course with few signs of remission. Another indication of an ongoing immunological process is the finding of a persistent impairment of the blood-nerve barrier in MMN.46 In addition, IgM antibodies could through complement activation also cause ion channel dysfunction at the nodes of Ranvier.42,47 In our study on the distribution of electrophysiological abnormalities in patients with MMN, we found a preferential localization of demyelinating features in the nerves of the arms, whereas axonal loss was demonstrated more frequently in longer nerves, usually occurring in the nerves of the legs.48 The preferential localization of demyelination in the nerves of the arms may explain the greater improvement in muscle strength in the arms compared to the legs following IVIg treatment in MMN. These differences in findings prompt the suggestion that nerves of the arms are more vulnerable to demyelination, and nerves of the legs more vulnerable to axonal loss.49 The results of our long-term IVIg maintenance treatment study further support different disease mechanisms in nerves of the arms and legs.50 The disease mechanisms remyelination and reinnervation were predominantly observed in nerves with conduction block, whereas axonal loss was more often observed in nerves without conduction block. This latter group mainly consisted of nerves of the legs. These observations also favour a more primary role for axonal degeneration in the pathophysiology of MMN than was previously presumed. In addition, differences in ion channel distributions between, for example, nerves of the arms and of the legs might explain a greater susceptibility to conduction block of arm nerves in MMN. Attempts to confirm these findings should be carried out by future prospective studies combining nerve conduction studies and concentric needle EMG analysis. These could provide further insight into the relation between the mechanisms of demyelination and axonal loss in MMN. |
Therapy
Based on the assumption that MMN may be immune-mediated, several immune therapies have been used. Prednisolone and plasma exchange are ineffective in most patients with MMN.20,58 Of the immunosuppressants, only cyclophosphamide seems to be consistently effective.3,59 Unfortunately, the considerable side effects of cyclophosphamide, especially the increased risk of the development of neoplasms60-62, may limit its utility. More recently, various open and placebo-controlled studies have shown that treatment with high-dose IVIg leads to improvement of muscle strength in patients with MMN.55,63-66 As the effect of IVIg treatment only lasts for a number of weeks, IVIg maintenance treatment is necessary to maintain the effect on muscle strength in most patients and has been shown to be effective over a period of several years.67,68As IVIg maintenance treatment is expensive, and the frequent infusions may be burdensome to patients, it is important to know whether IVIg maintenance treatment is effective in the long-term. We performed a long-term follow-up study of 11 patients with MMN, who received IVIg maintenance treatment for a period of 4 – 8 years.50 During follow-up, the frequency and dosage of IVIg infusions, muscle strength (MRC grading and hand-held dynamometry of a selection of weak muscle groups), systematic electrophysiological studies, and upper and lower limb disability were assessed. The frequency and dosage of IVIg infusions ranged from one infusion every 1 to 7 weeks and an average dosage of 7 to 48 g per week. Muscle strength improved significantly within three weeks of the start of IVIg treatment, and was still significantly better at the last follow-up examination than before treatment, even though it decreased slightly, and significantly, during follow-up. Upper limb disability was significantly better after the first full course of IVIg than before treatment. Conduction block disappeared in six nerve segments but new conduction block appeared in eight nerve segments during the follow-up period. Changes consistent with improvement (‘remyelination’ or ‘reinnervation’) occurred in 13 nerves during follow-up and changes consistent with worsening (‘demyelination’ or ‘axon loss’) occurred in 14 nerves. Electrophysiological changes consistent with improvement were significantly associated with the presence of conduction block before IVIg treatment. Thus, IVIg maintenance treatment has a beneficial long-term effect on muscle strength and upper limb disability but may not prevent a slight decrease in muscle strength. The electrophysiological findings imply that IVIg treatment favourably influenced mechanisms of remyelination or reinnervation but that axon loss cannot be prevented.50 Patients who do not respond to immunoglobulins may benefit from interferon-b1A.69,70 However, a double-blind controlled study with interferon-b1A has not yet been performed. Mycophenolate mofetil is a newly developed immunosuppressant which has been approved for use in the prophylaxis of organ rejection in patients receiving allogeneic organ transplantation. It is given orally and has less severe side-effects than the older immunosuppressant agents.71,72 We are planning to study whether add-on treatment with mycophenolate mofetil allows for a > 50% reduction in maintenance IVIg dose in a double-blind placebo-controlled study in patients with MMN.
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