Effect of hematin in porphyric neuropathy.

Early, intravenous administration of hematin in a patient with acute intermittent porphyria and severe quadriparesis may have produced partial but remarkable improvement of neuropathy, and resulted in simultaneous decline of porphyrin precursors in the blood. Intermittent, biweekly hematin infusions given 1 month after the onset of the porphyric relapse had no effect on recovery of the residual neuropathy. We believe hematin may be effective in the treatment of porphyric neuropathy, if administered before irreversible neuronal damage has occured.     

Porphyric neuropathy and hereditary delta-aminolevulinic acid dehydratase deficiency in an adult

A man without a history of porphyric attacks developed a subacute motor neuropathy at the age of 63. At the same time the first signs of a myeloproliferative disorder were found. He had a homozygous deficiency of erythrocyte delta-aminolevulinic acid dehydratase (ALA-D) with autosomal recessive inheritance. Treatment with parenteral glucose and with hematin had a beneficial influence on the plasma ALA levels. The finding of a motor neuropathy with increased plasma levels of ALA but not of porphobilinogen (PBG) supports the potential role of ALA in the pathogenesis of porphyric neuropathy.     

Long term follow up of multifocal motor neuropathy with conduction block under treatment.

Eighteen patients (15 men, three women; age range 30 to 71 years, mean 45.8 years) with multifocal motor neuropathy treated with high dose intravenous immunoglobulin (IVIg) were evaluated for nine to 48 months (mean follow up 25.3 months). The median time between onset of multifocal motor neuropathy and treatment was 5.8 years. The dose of IVIg was 0.4 g/day for three to five days. The interval between each treatment was determined for each patient by the evaluation of the effect of the first course. Muscle strength was evaluated by a computerised analyser. Clinical improvement was seen in 12 patients treated with IVIg (67%). Isometric strength increased from 32% to 97% (mean 54.5%) of the initial value. Functional scales corroborated these findings. No clear predictive factors of response to IVIg was found except the presence of high titres of IgM anti-GM1 antibodies. Often, patients needed repeated courses of IVIg to maintain the improvement. In two patients, IVIg infusions were stopped without signs of relapse after one year. Four patients were initially treated with prednisone (1 mg/kg/day), without any clear improvement. Five patients with no response to IVIg or who were IVIg dependent were treated with cyclophosphamide, but only one showed improvement. These results show the long term benefits and safety of IVIg in multifocal motor neuropathy but also the transient effect of this expensive treatment in most patients.     

A family with IVIg-responsive Charcot–Marie–Tooth disease

We report a family of intravenous immunoglobulin (IVIg)-responsive X-linked Charcot–Marie–Tooth disease Type 1 (CMT1X) with a novel gap junction protein 1 mutation. Two of three siblings in the family complained of subacute motor and sensory impairment, and their symptoms improved after the administration of IVIg. Additional IVIg treatment also resulted in similar improvement. The other also showed a mild improvement on IVIg. It has been suggested that an immune-mediated process is involved in the progression of neuropathy in CMT1X. The finding in our report provides evidence of susceptibility to immune-mediated demyelinating neuropathy in some form of CMT1X. Superimposed demyelinating neuropathy as well as a gradual deterioration of neuropathy over decades can be a clinical manifestation of CMT1X.     

Multifocal motor neuropathy

PURPOSE OF THIS REVIEW: To conduct a critical review of recent studies on the clinical and therapeutic aspects of multifocal motor neuropathy, and to analyse their implications for patient management. RECENT FINDINGS: Recent studies have contributed to defining the specific position of multifocal motor neuropathy within the spectrum of chronic immune-mediated polyneuropathies. One study compared features of this condition with multifocal acquired demyelinating sensory and motor neuropathy, while others have focused on pathological alterations at the site of conduction blocks. A further study described six new cases of multifocal acquired motor neuropathy, which should be considered as a variant of multifocal motor neuropathy. Several Cochrane reviews and review articles have shown evidence of the efficacy of intravenous immunoglobulins in the treatment of multifocal motor neuropathy. The issue of long-term intravenous immunoglobulins in multifocal motor neuropathy, however, has yielded controversial results. Two studies have shown progressive motor deterioration in most patients, correlated with electrophysiological signs indicative of axonal degeneration, while a third study found signs of sustained clinical and electrophysiological improvement after a mean follow up of 7.25 years. SUMMARY: Multifocal motor neuropathy is a distinct clinical entity that differs from chronic inflammatory demyelinating polyradiculoneuropathy and multifocal acquired demyelinating sensory and motor neuropathy, although they share some electrophysiological characteristics. Although the aetiology remains unsolved, frequent association with high-titer antibodies against ganglioside GM1, together with an often positive response to intravenous immunoglobulins further support an autoimmune mechanism. New therapeutic strategies are required, however, that focus on the effects and the costs of treatment over long-term follow up.     

Beneficial effect of rituximab monotherapy in multifocal motor neuropathy

Multifocal motor neuropathy (MMN) is a chronic, pure motor, asymmetric neuropathy for which intravenous immunoglobulin (IVIg) is widely regarded as first-line treatment. Rituximab is a monoclonal antibody against CD20+ cells that causes prolonged B cell depletion, a well-tolerated therapy currently explored in several immune-mediated neurologic disorders. We report three patients with MMN, who had become increasingly less responsive to IVIg but showed sustained clinical improvement following rituximab monotherapy. We provide a review of the literature on rituximab for MMN and conclude that rituximab may represent an efficacious, well-tolerated and cost-effective therapeutic option for MMN patients with declining response to IVIg.     

Childhood-onset multifocal motor neuropathy with conduction blocks

Multifocal motor neuropathy (MMN) is an acquired disorder with onset in adulthood. The authors describe a patient with a slowly progressing distal upper limb motor neuropathy since age 6 years, in whom definite conduction blocks in upper limbs, outside common entrapment sites, and no sensory involvement were consistent with MMN. IV immunoglobulin treatment produced marked muscle strength improvement and conduction block disappearance. MMN diagnosis should also be considered in childhood.     

Axonal multifocal motor neuropathy without conduction block or other features of demyelination

BACKGROUND: Conduction block is considered an essential finding for the distinction between motor neuropathies and lower motor neuron disorders. Only a small number of reports describe patients with multifocal motor neuropathies who lack overt conduction block, although in these cases other features of demyelination still suggest the presence of a demyelinating disorder. In contrast, a purely axonal multifocal motor neuropathy has not been described. METHODS: This report describes nine patients with slowly or nonprogressive multifocal motor neuropathies who had purely axonal electrodiagnostic features. RESULTS: GM1 antibodies titers were normal in all nine cases. Six patients were treated with either prednisone or IV immunoglobulin and three showed convincing improvement. CONCLUSIONS: These findings suggest an immune-mediated motor neuropathy with axonal electrophysiologic features that appears to be distinct from both multifocal motor neuropathy and established motor neuron disorders.     

Amyloid-like IgM deposition neuropathy with multiple mononeuropathies and generalized neuropathy

Amyloid-like IgM deposition neuropathy is a distinct entity in the setting of IgM monoclonal gammopathy in which endoneurial perivascular entire IgM-particle accumulation leads to a painful sensory followed by motor peripheral neuropathy. We report a 77-year-old man presenting with progressive multiple mononeuropathies starting with painless right foot drop. Electrodiagnostic studies showed severe axonal sensory-motor neuropathy superimposed by multiple mononeuropathies. Laboratory investigations were remarkable for biclonal gammopathy of IgM kappa, IgA lambda and severe sudomotor and mild cardiovagal autonomic dysfunction. A right sural nerve biopsy showed multifocal axonal neuropathy, prominent microvasculitis, and prominent large endoneurial deposits of Congo-red negative amorphous material. Laser dissected mass spectrometry-based proteomics identified IgM kappa deposit without serum amyloid-P protein. This case has several distinctive features, including motor preceding sensory involvement, prominent IgM-kappa proteinaceous deposits replacing most of the endoneurium, a prominent inflammatory component, and improvement of motor strength after immunotherapy.     

Rituximab in chronic immune mediated neuropathies: a systematic review

Chronic immune mediated neuropathy is a heterogenous group of peripheral nerve diseases, encompassing chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), autoimmune nodopathy, multifocal motor neuropathy (MMN), and anti-myelin-associated glycoprotein (MAG) neuropathy. Rituximab (RTX) is a chimeric monoclonal antibody targeting the CD20 antigen, which has been used in the treatment of autoimmune neuropathies, although the efficacy of RTX remains unclear. A literature search was performed using Medline, Embase and Cochrane Register for studies between 2000 and 2021 using the search terms “Chronic inflammatory demyelinating polyneuropathy” OR “Multifocal motor neuropathy” OR “Myelin associated glycoprotein” OR “Distal acquired demyelinating neuropathy” OR “Multifocal acquired demyelinating sensory and motor neuropathy” OR “demyelinating neuropathy” AND “Rituximab”. Twenty-three studies were included, of which two were randomised controlled trials, 6 prospective studies and 15 retrospective studies. RTX was effective in 63% of CIDP patients, 48% of anti-MAG neuropathy, and 96% of patients with autoimmune nodopathy. Neurophysiological improvement was evident in 58% of CIDP and 40% of anti-MAG neuropathy patients. Low rates of serious adverse events (2.6%) were observed. These results indicate that RTX has potential as a treatment in immune mediated polyneuropathy, although the quality of evidence supporting its use it poor. Randomized controlled trials are required to reliably establish the efficacy and safety of RTX. Trial registration number: CRD42020179666.     

Pure motor demyelinating neuropathy: deterioration after steroid treatment and improvement with intravenous immunoglobulin.

Within one month of starting oral prednisolone treatment weakness unexpectedly increased in four patients aged 34 to 75 years with purely motor forms of acquired chronic demyelinating neuropathy. By contrast, steroids produced the expected improvement in 11 other patients with symmetric sensorimotor chronic inflammatory demyelinating polyneuropathy. Two of the patients with purely motor demyelinating neuropathy were subsequently treated with high dose IVIg (0.4 g/kg/day for five days) with prompt improvements in strength measurements and motor nerve conduction. Thus IVIg seems to be the treatment of choice and steroids should be used with extreme caution, if at all, in patients with purely motor forms of acquired demyelinating polyneuropathy.     

Peripheral neuropathy associated with; plasma cell dyscrasia: a clinical and electrophysiological follow-up study

Thirteen patients with polyneuropathy associated with plasma cell dyscrasia had serial electrophysiological studies. Five patients with monoclonal IgG had motor and/or sensory symptoms of which 4 correlated with slow motor and sensory nerve conduction. The 4 patients with monoclonal IgM reactive with myelin-associated glycoprotein (MAG), had predominantly motor symptoms, demyelination in the nerve biopsy and slow motor and sensory nerve conduction. Four patients with monoclonal IgM without anti-MAG activity had mainly sensory symptoms, axonal neuropathy on nerve pathology and slow or absent sensory nerve conduction. After treatment with plasmapheresis and chemotherapy 9 patients improved clinically and 4 were unchanged. Criteria for electrophysiologic improvement were presence of sensory or motor responses that were absent before treatment, conduction velocity increased by more than 10 m/s and increase of amplitude by more than 100%. Electrophysiological studies showed improvement in 7, were unchanged in 4, and worse in 2. Sensory velocities in ulnar and sural nerves were significantly improved following treatment (P less than 0.002) and the same trend was noted for the sensory velocity in the median nerve (P less than 0.19). We conclude that nerve conduction studies in combination with clinical examinations are useful in documenting the effects of treatment in these neuropathies.     

Minocycline with aspirin: a therapeutic approach in the treatment of diabetic neuropathy

Enhanced production of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in diabetes leads to degradation of extracellular matrix in blood vessels and leads to complications of diabetes. In the present study, we have targeted MMP-2 and MMP-9 overactivation in diabetic neuropathy using a known MMP-2 and MMP-9 inhibitor, minocycline, with a non-selective COX inhibitor, aspirin. Streptozotocin-induced diabetic neuropathy was carried out in male Wistar rats and monitored by measuring the sensory nerve conduction velocity (SNCV), motor nerve conduction velocity (MNCV), tail flick latency and hot plate latency. Three weeks of treatment with a combination of minocycline and aspirin showed significant improvement in SNCV, MNCV, hot plate latency and tail flick latency when compared with diabetic control. The results of the present study suggest that MMP-2 and MMP-9 inhibition in the presence of COX inhibitor prevents the development of experimental diabetic neuropathy in rats and can be a potential approach for the treatment.     

High-dose intravenous immunoglobulin therapy improved muscle strength in a patient with multifocal motor neuropathy and antibodies against the glycolipid LK1

We report improvement in muscle strength in a patient with multifocal motor neuropathy (MMN) when given high-dose intravenous immunoglobin (i.v.-Ig) treatment. The patient had asymmetrical limb weakness, atrophy and absent or weak reflexes, but no sensory disturbances. Neurography showed multiple conduction blocks in peripheral motor nerves but no sensory nerve abnormalities. Serum and anti-GM1 antibodies were not found, however, the patient had serum antibodies against the glycolipid LK1, an epitope found both in glycolipid and also in some glycoproteins in peripheral nerve myelin. Muscle strength improved 5 days after i.v.-Ig therapy, and lasted about 10 weeks. Repeated courses of treatment resulted in similar improvement. This is, to our knowledge, the first patient reported with MMN found to have antibodies against the glycolipid LK1.     

AAEM case report #30: Multifocal motor neuropathy

A 73-year-old man with a 16-year history of fasciculations and 15 years of weakness in his right arm was diagnosed with focal motor neuron disease. After 10 years of purely motor symptoms, he developed mild parasthesias although his sensory examination remained normal. Reflexes were reduced or absent in the weak muscles but were normal elsewhere. Nerve conduction was studied in nerves innervating weak muscles and showed severe motor conduction block. Sensory nerve conduction studies were minimally abnormal, showing reduced amplitudes with normal velocities. Based on the clinical picture and the presence of severe motor conduction block, the patient was diagnosed with multifocal motor neuropathy. Treatment with high-dose intravenous immunoglobulin was given with significant improvement in strength and partial resolution of the conduction block. As this case demonstrates, this treatable disorder may occasionally be mistaken for motor neuron disease although the resemblance is only superficial, and it should never be mistaken for amyotrophic lateral sclerosis. Multifocal motor neuropathy is an inflammatory, demyelinating neuropathy which, like chronic inflammatory demyelinating polyneuropathy (CIDP), is probably immune-mediated. It differs from typical CIDP by virtue of a marked predilection for motor axons, a strikingly restricted distribution, and a protracted course. Treatment with high-dose intravenous immunoglobulin is frequently helpful, but other forms of immune manipulation are less effective. © 1996 Gareth J. Parry, MD, FRACP. Published by John Wiley & Sons, Inc.     

Chronic relapsing brachial plexus neuropathy with persistent conduction block

Idiopathic brachial plexus neuropathy (BPN) is an immune-mediated disorder characterized by an acute onset of painful weakness in one or both upper extremities. The course is usually monophasic with gradual improvement over months; however, occasionally BPN can recur. Electrophysiologic studies suggest the pathogenesis is primarily axonal in the majority of cases. We descibe an unusual case of BPN in which the patient had a chronic and relapsing course of painless weakness associated with conduction blocks and other electrophysiologic features of demyelination across the brachial plexus. The patient improved following treatment with intravenous immunoglobulin. The neuropathy falls within the spectrum of chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy. © 1997 John Wiley & Sons, Inc. Muscle Nerve 20: 1303–1307, 1997     

多灶性运动神经病的临床特征及治疗

目的:分析多灶性运动神经病(MMN)的临床特征及治疗方法。方法:回顾性分析24例多灶性运动神经病患者的临床资料。结果:24例MMN表现为进行性、非对称性肢体运动无力,以远端为重,伴或不伴感觉障碍。部分患者抗-GM1抗体滴度升高。10例应用激素治疗,8例无效;20例应用免疫球蛋白(IVIg)治疗,15例有效。结论:MMN是一种以运动神经受累为主的不对称性周围神经病,临床症状和体征是诊断MMN的基础,免疫学检查发现抗-GM1抗体滴度升高支持诊断,但与临床症状和体征并非完全相关,免疫球蛋白(IVIg)治疗有效。     

Predominantly sensory neuropathy in patients with AIDS and AIDS-related complex

The most common type of peripheral neuropathy associated with human immunodeficiency virus (HIV) infection, predominantly sensory neuropathy, affects 10-30% of patients with acquired immunodeficiency syndrome (AIDS). From 40 individuals with peripheral neuropathy and HIV infection, we have identified 26 patients with this syndrome. All had constitutional symptoms when neuropathic symptoms developed; 20 had AIDS and six had AIDS-related complex. The most common complaint was pain on the soles. Paresthesias were frequent and usually involved the entire foot. Signs of peripheral neuropathy were present in all; the most frequent finding was absent or reduced ankle reflexes. Electrophysiologic studies revealed abnormal sensory and motor conduction, studies suggesting a dying-back axonopathy. Over time, the neuropathy progressed in all except one patient with ARC, who had spontaneous subjective improvement. Tricyclic antidepressants provided partial symptomatic relief. In three patients, the neuropathy did not change during azidothymidine treatment. Predominantly sensory neuropathy in HIV infection appears to be a distal axonal degeneration primarily involving sensory neurons. The mechanism is unknown, but the neuropathy is associated with the late manifestations of HIV infection.     

Long-term follow-up of multifocal motor neuropathy with conduction block under intravenous immunoglobulin

INTRODUCTION: Multifocal motor neuropathy with conduction block is an immune-mediated motor neuropathy, which usually responds to intravenous immunoglobulin. However, efficacy of long-term intravenous immunoglobulin is controversial. Our aim was to establish the long-term effects of intravenous immunoglobulin therapy on clinical and neurophysiological outcome measures and to determine the criteria predicting a good response to long-term intravenous immunoglobulin treatment. METHODS: We retrospectively included all multifocal motor neuropathy with conduction blocks patients followed for at least 4 years who received intravenous immunoglobulin therapy. We compared clinical data, MRC sumscores and electrophysiological data between the first and the last examination in the department. RESULTS: Seventeen patients were followed for an average of 8 years (range 4 to 18 years). At last examination, weakness remained asymmetric, predominant in the upper limbs, with a peripheral nerve distribution. At last examination, 3 patterns of evolution was seen: 6/17 patients had muscle strength improvement and need no more intravenous immunoglobulin therapy, 6/17 had initial improvement but became intravenous immunoglobulin dependent and 5/17 did not respond to intravenous immunoglobulin. MRC sumscores, number of conduction blocks and distal compound muscle action potential amplitudes were comparable between the first and the last examination (p>0.05). Improvement of MRC sumscores was not correlated with the clinical, biological and electrophysiological data that we analysed: age, gender, duration of disease, time from onset to intravenous immunoglobulin therapy, number of involved nerves, number of affected limbs, presence of muscle atrophy, MRC sumscores at diagnosis, number of conduction blocks, mean amplitude of the motor evoked potentials, presence of anti-GM1 antibodies, titers and IgM or IgG type of anti-GM1 antibodies. CONCLUSIONS: In this study, one third of multifocal motor neuropathy with conduction blocks patients have clinical improvement at last examination and need no more treatment, one third are intravenous immunoglobulin dependent and one third have never responded to intravenous immunoglobulin. Electrophysiological data are comparable between the first and the last examination. No predictive factor has been disclosed for long-term response to intravenous immunoglobulin.     

Treatment of multifocal motor neuropathy with interferon-beta1A

ARTICLE ABSTRACT: Nine patients with multifocal motor neuropathy who had previously responded favorably to IV immunoglobulins (IVIg) were treated with interferon-beta1a. Muscle strength and disability were evaluated. In six patients there was no effect of treatment. Four patients deteriorated in such a way that IVIg had to be restarted during the study. Three patients showed an improvement that was more pronounced than on IVIg. These patients had a shorter disease duration and were less affected clinically and electrophysiologically than those who did not respond.