Dirk C.G. Straver

Multifocal motor neuropathy: diagnosis, pathogenesis and treatment strategies.

Multifocal motor neuropathy (MMN) is a rare inflammatory neuropathy characterized by slowly progressive, asymmetric distal limb weakness without sensory loss. The clinical presentation of MMN may mimic amyotrophic lateral sclerosis, other variants of motor neuron disease, or chronic inflammatory demyelinating polyneuropathy with asymmetric onset. Differentiation is important, as these diseases differ in prognosis and treatment. The electrophysiological finding of conduction block in the absence of abnormalities in sensory nerves is the hallmark of MMN, but can be difficult to detect. Intravenous immunoglobulin is efficacious in most patients, but long-term maintenance therapy does not prevent slowly progressive axonal degeneration. Moreover, cyclophosphamide, although effective, has substantial adverse effects, and the efficacy of other immunosuppressive drugs, including rituximab, is not established. The underlying pathological mechanisms of MMN are unclear, but IgM autoantibodies against the ganglioside GM1 may cause changes in nodal and perinodal structures that compromise nerve conduction. Further elucidation of the disease mechanisms may ultimately lead to improved treatment strategies. In this Review, we discuss the diagnostic criteria for MMN, and provide an update on the current understanding of MMN pathogenesis. We also describe available treatments and promising new therapeutic strategies.

Cold paresis in multifocal motor neuropathy

Increased weakness during cold (cold paresis) was reported in single cases of multifocal motor neuropathy (MMN). This was unexpected because demyelination is a feature of MMN and symptoms of demyelination improve, rather than worsen, in cold. It was hypothesized that cold paresis in MMN does not reflect demyelination only, but may indicate the existence of inflammatory nerve lesions with permanently depolarized axons that only just conduct at normal temperature, but fail at lower temperatures. We investigated symptoms of cold paresis in 50 MMN patients, 48 chronic inflammatory demyelinating polyneuropathy (CIDP) patients, 35 progressive spinal muscular atrophy (PSMA) patients, and 25 chronic idiopathic axonal polyneuropathy patients. We also investigated symptoms of increased weakness during warmth (heat paresis). Cold paresis was reported more often than heat paresis. Cold paresis was most frequently reported in MMN. Multivariate analysis indicated that MMN patients had a 4- to 6-fold higher risk of reporting cold paresis than CIDP or PSMA patients. Because cold paresis is not consistent with demyelination, the lesions in MMN may involve other mechanisms than demyelination only. In conclusion, symptoms of cold paresis are common in peripheral nervous system disorders, particularly in MMN. This supports the above-described hypothesis.

Pathophysiology of immune-mediated demyelinating neuropathies--Part II: Neurology.

In the second part of this review we deal with the clinical aspects of immune‐mediated demyelinating neuropathies. We describe the relationship between pathophysiology and symptoms and discuss the pathophysiology of specific disease entities, including Guillain–Barré syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, anti–myelin‐associated glycoprotein neuropathy, and POEMS syndrome. Muscle Nerve 49: 4–20, 2014

Spinal arteriovenous shunts presenting as intracranial subarachnoid haemorrhage.

BackgroundIn approximately 5% of patients with intracranial subarachnoid haemorrhage (SAH), the cause is another than a ruptured aneurysm or perimesencephalic haemorrhage. One of these causes is a spinal arteriovenous shunt (SAVS). The aim of this study was to investigate the characteristics of patients with SAVS who present with intracranial SAH without symptoms and signs suggesting a spinal cause.MethodsWe systematically reviewed the literature and searched the SAH database of the University Medical Center Utrecht, The Netherlands, for patients with SAVS presenting with intracranial SAH and studied the characteristics of patients with SAVS whose clinical presentation mimicked intracranial SAH caused by rupture of a saccular aneurysm.ResultsThirty-five patients were identified after a review of the literature. In our SAH database, comprising 2142 patients included in the period 1985–2004, we found one patient (0.05%, 95 % CI 0.006–0.3%). SAH due to SAVS occurred at any age (4–72 years). The SAVS was located at the craniocervical junction in 14 patients, at the cervical level in 11, and at the thoracolumbar level in the remaining 11 patients. The majority of patients (n = 26, 72%) had no disabling deficits at discharge or follow-up.ConclusionRupture of a SAVS presenting as intracranial SAH is rare and can occur at any age. The SAVS can be located not only at the craniocervical junction or cervical level but also in the thoracolumbar region. Most patients with SAVS presenting as intracranial SAH have a good recovery.

Activity-dependent conduction block in multifocal motor neuropathy

Previous studies suggested that activity‐dependent conduction block (CB) contributes to weakness in multifocal motor neuropathy (MMN). Obtaining more robust evidence for activity‐dependent CB is important because it may be a novel target for treatment strategies. We performed nerve conduction studies in 22 nerve segments of 19 MMN patients, before and immediately after 60 seconds of maximal voluntary contraction (MVC) of the relevant muscle. We employed supramaximal electrical stimulation, excluded nerves with marked axonal loss, and adopted criteria for activity‐dependent CB. Per segment, the segmental area ratio [area proximal compound muscle action potential (CMAP)/area distal CMAP] was calculated and, per nerve, total area ratio (area CMAP at Erbs point/area distal CMAP) was obtained. MVC induced no changes in mean area ratios and induced no activity‐dependent CB. In segments with CB before MVC, the MVC induced increased duration prolongation. In MMN, MVC induced temporal dispersion but no activity‐dependent CB. Muscle Nerve, 2011

MMN: From Immunological Cross-Talk to Conduction Block

Multifocal motor neuropathy (MMN) is a rare inflammatory neuropathy characterized by progressive, asymmetric distal limb weakness and conduction block (CB). Clinically MMN is a pure motor neuropathy, which as such can mimic motor neuron disease. GM1-specific IgM antibodies are present in the serum of approximately half of all MMN patients, and are thought to play a key role in the immune pathophysiology. Intravenous immunoglobulin (IVIg) treatment has been shown to be effective in MMN in five randomized placebo-controlled trials. Despite long-term treatment with intravenous immunoglobulin (IVIg), which is efficient in the majority of patients, slowly progressive axonal degeneration and subsequent muscle weakness cannot be fully prevented. In this review, we will discuss the current understanding of the immune pathogenesis underlying MMN and how this may cause CB, available treatment strategies and future therapeutic targets.

Activity-dependent conduction block in chronic inflammatory demyelinating polyneuropathy

Previous studies suggested that activity-dependent conduction block (CB) contributes to weakness in chronic inflammatory demyelinating polyneuropathy (CIDP). These studies, however, investigated only one nerve segment per patient, employed cervical magnetic stimulation which may be submaximal, included nerves with extremely low compound muscle action potentials (CMAPs) which precludes assessment of CB, and lacked predefined criteria for activity-dependent CB. Obtaining more robust evidence for activity-dependent CB is important because it may be treated pharmacologically. We investigated 22 nerve segments in each of 18 CIDP patients, employed supramaximal electrical stimulation, excluded nerves with markedly reduced CMAPs, and adopted criteria for activity-dependent CB. Each nerve was tested before and immediately after 60 s of maximal voluntary contraction (MVC) of the relevant muscle. Per nerve segment we calculated segmental area ratio: (area proximal CMAP)/(area distal CMAP). Per nerve we calculated total area ratio: (area CMAP evoked at Erbs point)/(area most distally evoked CMAP). MVC induced no change in mean area ratios and no activity-dependent CB according to our criteria, except for one segment. MVC induced increases in distal and proximal CMAP area and duration. In segments with demyelinative slowing, MVC induced an increase in CMAP duration prolongation. Thus, in CIDP, muscle activity induces virtually no CB, but it may increase temporal dispersion of nerve action potentials.

Symptoms of activity-induced weakness in peripheral nervous system disorders

Activity‐induced weakness was reported in multifocal motor neuropathy (MMN) and chronic inflammatory demyelinating polyneuropathy (CIDP). This was attributed to activity‐dependent conduction block (CB) arising in demyelinated axons. It is not known if activity‐induced weakness is common, nor if it is specific for MMN and CIDP. We, therefore, carried out an investigation by questionnaire in 64 MMN patients, 52 CIDP patients, 48 progressive spinal muscular atrophy (PSMA) patients, and 30 normal subjects. Subjects were asked if they experienced an increase in weakness when performing 10 common tasks. The percentage of tasks causing activity‐induced weakness was higher in the patient groups than in the normal subjects (p < 0.001). The risk of activity‐induced weakness exceeding that in normal subjects was sixfold higher for each patient group when adjusted for sex, age, and a fatigue score. With further adjustment for scores of weakness and axon loss, no significant differences were found between the patient groups. In conclusion, activity‐induced weakness is frequently reported in MMN and CIDP. It is, however, not specific for these neuropathies as PSMA patients reported it to the same extent.

P12-19 Cold paresis in multifocal motor neuropathy

Somatosensory evoked potentials that change during the evolution of the disease. Conclusions: Like in other types of Guillain Barré syndrome, we need to perform almost two neurophysiological examinations to define the distribution and degree of neurological impairment that in our Miller Fisher Syndrome patients is defined as a sensory demyelinating neuropathy or polyradiculoneuropathy with good recovery.

P12-18 Exercise-induced weakness in demyelinating neuropathies

Somatosensory evoked potentials that change during the evolution of the disease. Conclusions: Like in other types of Guillain Barré syndrome, we need to perform almost two neurophysiological examinations to define the distribution and degree of neurological impairment that in our Miller Fisher Syndrome patients is defined as a sensory demyelinating neuropathy or polyradiculoneuropathy with good recovery.