Treatment Of Multifocal Motor Neuropathy Research Articles

Use of Health Technology Assessment for the Continued Funding of Health Technologies: The Case of Immunoglobulins for the Management of Multifocal Motor Neuropathy.

Funding decisions for many health technologies occur without undergoing health technology assessment (HTA), in particular, without assessment of cost effectiveness (CE). Immunoglobulins in Australia are an interesting case study because they have been used for a long time for various rare disorders and their price is publicly available. Undertaking an HTA enables us to assess CE for an intervention for which there is limited clinical and economic evidence. This study presents a post-market review to assess the CE of immunoglobulins for the treatment of multifocal motor neuropathy (MMN) compared with best supportive care. A Markov model was used to estimate costs and quality-adjusted life-years (QALYs). Input sources included randomised controlled trials, single-arm studies, the Australian clinical criteria for MMN, clinical guidelines, previous Medical Services Advisory Committee (MSAC) reports and inputs from clinical experts. Sensitivity analyses were conducted to assess the uncertainty and robustness of the CE results. The cost per patient of treating MMN with immunoglobulin was AU$275,853 versus AU$26,191when no treatment was provided, with accrued QALYs of 6.83 versus 6.04, respectively. The latter translated into a high incremental cost-effectiveness ratio (ICER) of AU$317,552/QALY. The ICER was most sensitive to the utility weights and the price of immunoglobulins. MSAC advised to continue funding of immunoglobulins on the grounds of efficacy, despite the high and uncertain ICER. Beyond the ICER framework, other factors were acknowledged, including the high clinical need in a patient population for which there are no other active treatments available. This case study highlights the challenges of conducting HTA for already funded interventions, and the efficiency trade-offs required to fund effective high-cost therapies in rare conditions.

Multifocal motor neuropathy.

Multifocal motor neuropathy (MMN) has specific clinical and electrophysiologic features but can be difficult to diagnose if cases are not typical. Intravenous immunoglobulin (IVIg) remains the core initial and long-term treatment. In this review, recent advances in the diagnosis, monitoring and treatment of MMN are discussed. The pathology of MMN likely depends on immune-mediated attack of the nodes of Ranvier and paranodal regions leading to conduction block. Antiganglioside antibodies are present in over 50% of patients. The sensitivity of antibody detection can be improved by testing for GM1/galactocerebroside (GM1/GalC) complexes. Complement activation plays a key role in the pathophysiology of MMN. Subcutaneous immunoglobulins are an efficacious alternative to IVIg for maintenance therapy in MMN. Complement inhibitor eculizumab may be a potential future treatment, but further studies are necessary. The European Federation of Neurological Societies (EFNS)/Peripheral Nerve Society (PNS) guidelines for the diagnosis of MMN are currently widely used but probably need revision. Nerve ultrasound and plexus/nerve MRI can be helpful in diagnostic dilemmas. Monitoring of disease and response to treatment may improve using disease-specific evaluation scales such as MMN-Rasch-built overall disability scale. Further research into the pathophysiology of MMN is necessary to direct future treatment strategies.

Subcutaneous versus intravenous immunoglobulin for chronic autoimmune neuropathies: A meta-analysis.

High-dose intravenous immunoglobulin (IVIg) is an evidence-based treatment for multifocal motor neuropathy (MMN) and chronic inflammatory demyelinating polyneuropathy (CIDP). Recently, subcutaneous immunoglobulin (SC-Ig) has received increasing attention. We performed a meta-analysis of reports of efficacy and safety of SC-Ig versus IVIg for inflammatory demyelinating polyneuropathies. A total of 8 studies comprising 138 patients (50 with MMN and 88 with chronic CIDP) were included in the meta-analysis. There were no significant differences in muscle strength outcomes in MMN and CIDP with Sc-Ig (MMN: effect size [ES] = 0.65, 95% confidence interval [CI] = -0.31-1.61; CIDP: ES = 0.84, 95% CI = -0.01-1.69). Additionally SC-Ig had a 28% reduction in relative risk (RR) of moderate and/or systemic adverse effects (95% CI = 0.11-0.76). The efficacy of SC-Ig is similar to IVIg for CIDP and MMN and has a significant safety profile. Muscle Nerve 55: 802-809, 2017.

Subcutaneous immunoglobulin for treatment of multifocal motor neuropathy.

Subcutaneous immunoglobulin (SCIg) has been used for treatment of immune neuropathies. We evaluated the safety and efficacy of 1.53:1 SCIg to intravenous immunoglobulin (IVIg) in individuals receiving <2 g/kg IVIg per month and 1:1 in individuals receiving 2 g/kg per month for treatment of multifocal motor neuropathy (MMN) in an open-label, 6-month trial. Medical Research Council sum score, grip strength, modified Guy's Upper Limb Neurological Disability score, Health Utility Index Quality of Life score, and immunoglobulin levels were evaluated at baseline and at 3 and 6 months. Eleven men and 4 women, aged 31-82 years, were enrolled. Eleven patients completed the program with minor localized reactions and high satisfaction. Three of 6 patients receiving less than 1.53:1 replacement developed intolerable weakness by month 3, and 1 exited after developing erythema and elevated transaminase levels. Patients with MMN tolerate SCIg infusion with maintained strength, but some patients may develop increasing weakness and merit close monitoring. Muscle Nerve 54: 856-863, 2016.

Immunosuppressant and immunomodulatory treatments for multifocal motor neuropathy.

Multifocal motor neuropathy (MMN) is characterised by progressive, predominantly distal, asymmetrical limb weakness and usually multiple partial motor nerve conduction blocks. Intravenous immunoglobulin (IVIg) is beneficial but the role of immunosuppressive agents is uncertain. This is an update of a review first published in 2002 and previously updated in 2003, 2005, 2008 and 2011. To assess the effects of immunosuppressive agents for the treatment of multifocal motor neuropathy. On 22 September 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, EMBASE and LILACS for trials of MMN. We also searched two trials registers for ongoing studies. We planned to include randomised controlled trials (RCTs) and quasi-RCTs. We considered prospective and retrospective case series and case reports in the Discussion. Two review authors searched the titles and abstracts of the articles identified and extracted the data independently. Only one RCTof an immunosuppressive or immunomodulatory agent has been performed in MMN. This study randomised 28 participants and showed that mycophenolate mofetil, when used with IVIg, did not significantly improve strength, function or reduce the need for IVIg. No serious adverse events were observed. The study was deemed at low risk of bias. We summarised the results of retrospective and prospective case series in the discussion. According to moderate quality evidence, mycophenolate mofetil did not produce significant benefit in terms of reducing need for IVIg or improving muscle strength in MMN. Trials of other immunosuppressants should be undertaken.

High dose steroid and acute visual loss: case report and discussion on acute central serous chorioretinopathy in elderly

Central serous chorioretinopathy (CSCR) is one of sight-threatening side effects of systemic steroids. Although it is uncommon, CSCR seriously threatens the patient’s vision and it has the potential for permanent visual morbidity. This article reports about a 54-year-old Malay gentleman who developed central vision loss after received a course of oral prednisolone 50 mg/day for a month period for the treatment of multifocal motor neuropathy. His vision recovered 1 year after cessation of steroid as the CSCR resolved. However, subjectively the visual quality is poor. Steroids in any route of administration can induce CSCR and it must be used with precaution especially in the elderly. Although resolutions are usually spontaneous after cessation of steroid, chronic and recurrent CSCR can lead to irreversible visual impairment. Judicious use of systemic steroids, early detection and prompt co-management with the treating physician can help prevent permanent visual disturbance.

Multifocal motor neuropathy: a review of pathogenesis, diagnosis, and treatment.

Multifocal motor neuropathy (MMN) is an uncommon, purely motor neuropathy associated with asymmetric deficits with predilection for upper limb involvement. Even in the early descriptions of MMN, the associations of anti-GM1 antibodies and robust response to immunomodulatory treatment were recognized. These features highlight the likelihood of an underlying autoimmune etiology of MMN. The clinical presentation of MMN can closely mimic several neurological conditions including those with more malignant prognoses such as motor neuron disease. Therefore early and rapid recognition of MMN is critical. Serological evidence of anti GM-1 antibodies and electrodiagnostic findings of conduction block are helpful diagnostic clues for MMN. Importantly, these diagnostic features are not universally present, and patients lacking these characteristic findings can demonstrate similar robust response to immunodulatory treatment. In the current review, recent research in the areas of diagnosis, pathogenesis, and treatment of MMN and needs for the future are discussed. The characteristic findings of MMN and treatment implications are reviewed and contrasted with other mimicking disorders.

Treatment of Multifocal Motor Neuropathy

Multifocal motor neuropathy (MMN) is a treatable immune disorder of the peripheral nerves that is characterized clinically by slowly progressive or stepwise asymmetric distal > proximal, upper > lower limb weakness in multiple motor nerve distributions; electrophysiologically by multifocal motor demyelination, specifically partial motor conduction block; laboratory evidence of high serum anti-GM1 IgM antibodies; and remarkable treatment response to intravenous immunoglobulin (IVIG). IVIG has become the treatment of choice, and the U.S. Food and Drug Administration (FDA) has approved Gammagard Liquid 10% [immune globulin infusion (human)] as a treatment for multifocal motor neuropathy (MMN). Response to IVIG in MMN is dose- and frequency-dependent, most patients needing high (2g/kg) and frequent (every 4-8weeks) doses for several years. Over time, response to IVIG may decrease despite higher and more frequent dosing of IVIG treatment. Subcutaneous immunoglobulin (dose equivalent to IVIG) given in weekly fashion has recently been used with equal efficacy and fewer side effects. There are some case reports and non-randomized trials suggesting variable results from therapeutic or adjunctive use of other immunosuppressive or immunomodulatory agents such as cyclophosphamide, cyclosporine, methotrexate, azathioprine, interferon beta-1a, and rituximab. Of these, cyclophosphamide and rituximab are the only immune treatments that have shown some benefits in case reports. One randomized controlled trial of mycophenolate mofetil used as adjunctive agent did not prove efficacious in altering the disease course. Although MMN, like chronic inflammatory demyelinating polyneuropathy (CIDP), is a chronic immune-mediated demyelinating neuropathy, the use of corticosteroids and plasma exchange - two other therapies used in CIDP - is not beneficial for MMN. Further investigations are warranted to evaluate the immunopathogenesis of MMN and to explore options for dose, frequency, and duration of IVIG treatment as well as the use of alternative immunomodulatory agents either as primary therapeutic or adjunctive agents.

Multifocal motor neuropathy

Multifocal motor neuropathy (MMN) remains a difficult issue for neurologists, as its clinical and electrophysiological presentation may be atypical, and because no alternative treatment to periodic immunoglobulin infusions has been assessed in its long-term management. This review intends to summarize the most recent advances in the diagnosis and treatment of MMN. Recent reports have focused on atypical onset and unusual clinical presentation. Several sophisticated electrophysiological techniques, as triple stimulation, may help establish the presence of conduction blocks, as well as MRI findings. A recent immunological study focused on the detection of serum IgM binding to NS6S heparin disaccharide. In another research article, it was proposed that the use of combinatorial glycoarray or ELISA may increase the diagnostic sensitivity of antiglycolipid antibody testing. Subcutaneous immunoglobulin may represent an interesting alternative option to intravenous immunoglobulin. Lastly, recently reported open-label clinical trials with complement inhibitors and anti-CD20 monoclonal antibody may constitute a first step for further developments. Diagnostic criteria for MMN are well established, but challenging situations still occur. Progresses in neurophysiologic and other laboratory tests may help in clarifying doubtful diagnoses. Current research into the pathophysiology of MMN is required to determine the future treatment targets.

A Phase III, Randomized, Placebo-Controlled Study of the Efficacy and Safety of 10% Liquid Intravenous Immunoglobulin (IGIV) for the Treatment of Multifocal Motor Neuropathy (MMN)

tube irritation during daily activities such as suction, transfer. Patient 2 showed reflex cough and abnormal posturing due to tube irritation. They underwent granulation removal and stomaplasty for making permanent tracheostoma after 60, 22, 12 months of the first conventional tracheostomy. Setting: Tertiary care hospital Results or Clinical Course: For all three patients, no early and late complications occurred, and airway patency was well maintained. Frequency of suction, sudden spasticity increase, reflex cough were reduced, and airway hygiene was improved after the permanent tracheostoma. All three caregivers reported the reduced difficulty and anxiety and also their satisfaction after the procedure. Discussion: Permanent tracheostoma establishes a short, skinlined, noncollapsing, nonstenosing, self-sustaining passage between the trachea and the external environment, and is not supported by a tube, vent, or stent. The benefit of this tube-free, permanent tracheostoma is that the patients are free of risk for complication caused by tracheostomy tube itself, such as tube displacement, tube obstruction, granuloma, tracheal stenosis. This method is a useful alternative way to make long-term ventilatory bypass without tuberelated complications in the chronic disease such as obstructive sleep apnea, bilateral vocal cord paralysis, laryngotracheal stenosis, chronic pulmonary disease, laryngeal cancer. It is the first report of successful permanent tracheostoma in chronic brain injured patients with long-term tracheostomy, who had cognitive deficit, and weakness of four extremities, and poor head and neck control due to their quadriplegic status. Conclusions: Permanent tracheostoma can be considered a useful alternative way for chronic brain injured patients with long-term tracheostomy.

Multifocal motor neuropathy

Multifocal motor neuropathy (MMN) is a chronic immune-mediated neuropathy that is particular for its asymmetric, multifocal, purely motor clinical presentation, often related to the distribution of individual nerves. Upper limbs are usually primarily and more severely affected, but lower limbs may be involved during the course of the disease. The hallmark of the disease is the presence, in electrophysiological studies, of persistent conduction blocks in the affected motor nerves, located outside the usual sites of nerve compression, contrasting with normal sensory nerve conduction velocities. The most typical laboratory finding is the presence of high levels of serum IgM antibodies to the ganglioside GM1, and less frequently to asialo-GM1, GD1a or GM2. These striking features may help distinguishing this neuropathy from both motor neuron disease and other chronic immune-mediated neuropathies. Several randomized controlled trials (RCT) have established the efficacy of high-dose intravenous immunoglobulin (IVIg), as well as subcutaneous immunoglobulin (SCIg). However, this therapy has a short-lasting effect, and need to be maintained with periodic infusions. This disappointing status has led to the search of other immune therapies whose efficacy has not been so far confirmed in RCT. This review intends to summarize current contents in the diagnosis and the treatment of MMN.

Immune Pathogenesis and Treatment of Multifocal Motor Neuropathy

Multifocal motor neuropathy (MMN) is a rare, probably immune-mediated chronic disorder characterized by asymmetric distal limb weakness and conduction block. The exact pathogenesis of MMN is still unclear, but IgM anti-GM1 antibodies, which can be detected in sera from approximately half of all MMN patients, are thought to play an important role. Treatment with intravenous immunoglobulin (IVIG) is effective in the vast majority of patients, but, despite IVIG maintenance treatment, many patients experience a slowly progressive decline in muscle strength. In this review we will summarize the results from studies on pathogenesis. We will discuss current treatment strategies of MMN and how insight into MMN pathogenesis may translate into novel therapies in the future.

Efficacy, Safety, and Tolerability of Intravenous Gammaglobulin (IGIV, 10%) in a Phase 3, Randomized, Placebo-Controlled, Cross-Over Trial for the Treatment of Multifocal Motor Neuropathy (MMN) (PL02.002)

Efficacy, Safety, and Tolerability of Intravenous Gammaglobulin (IGIV, 10%) in a Phase 3, Randomized, Placebo-Controlled, Cross-Over Trial for the Treatment of Multifocal Motor Neuropathy (MMN) (PL02.002)

The Long-term Treatment of Multifocal Motor Neuropathy with Intravenous Immunoglobulin

Multifocal motor neuropathy (MMN) is a rare, purely motor neuropathy. It is a progressive disorder, most patients eventually developing severe fatigue and weakness in the arm muscles that severely impair daily functioning and quality of life. Unlike other motor neuropathies such as motor neurone disease, MMN is treatable with regular infusions of intravenous immunoglobulin (IVIg). Four double-blind, randomised, placebo-controlled studies have shown that in the short term, IVIg significantly improves muscle strength and disability in more than 70 % of patients. The 11 observational studies reviewed in this article confirm that long-term maintenance treatment with IVIg maintains clinical improvement compared to pre-treatment baseline in most patients. Infusions are generally well tolerated, but regular monitoring and re-evaluation of the IVIg maintenance regimen is essential, as most patients need progressive increases in dosage or reduced intervals between infusions to maintain their response to treatment. In the absence of accepted predictive markers, maintenance IVIg should be individualised, based on each patient’s initial response, disability and the interval between the first infusion and decline in muscle strength.

Immunotherapy of multifocal motor neuropathy

Introduction: Multifocal motor neuropathy (MMN) is an immune-mediated disease, which usually runs a chronic course. Current treatments are aiming at modulation of the immune response to maintain functional status. Although patients can remain stable with prolonged maintenance intravenous immunoglobuin (IVIg) treatment, most patients slowly deteriorate over many years despite increasing IVIg doses.Areas covered: The paper identifies studies since 1985 for patients with MMN. Randomised and non-randomized studies examining the effects of any therapeutic agent were selected, to give a full overview of the different treatments for MMN. The review provides a treatment algorithm together with our views on current treatments, ongoing trials and possible directions for further research.Expert opinion: IVIg remains the only proven treatment for MMN, although questions around dosages and duration of treatment remain. The presence of an effective therapy for MMN should not discourage but stimulate further research into alternative treatments as ongoing axonal damage results in increasing impairment in patients with MMN.

European Federation of Neurological Societies/Peripheral Nerve Society Guideline on management of multifocal motor neuropathy. Report of a Joint Task Force of the European Federation of Neurological Societies and the Peripheral Nerve Society – first revision

A European Federation of Neurological Societies/Peripheral Nerve Society consensus guideline on the definition, investigation, and treatment of multifocal motor neuropathy (MMN) was published in 2006. The aim is to revise this guideline. Disease experts considered references retrieved from MEDLINE and Cochrane Systematic Reviews published between August 2004 and July 2009 and prepared statements that were agreed to in an iterative fashion. The Task Force agreed on Good Practice Points to define clinical and electrophysiological diagnostic criteria for MMN, investigations to be considered, and principal recommendations for treatment.

Subcutaneous immunoglobulin therapy for the treatment of multifocal motor neuropathy: a case report

Multifocal motor neuropathy (MMN) is a rare immune-mediated disease characterized by slowly progressive, asymmetric, predominantly distal weakness of one or more limbs without sensory loss. The first line of treatment is high-dose intravenous immunoglobulins (IVIg). Subcutaneous immunoglobulins (SCIg)already approved for the treatment of primary immune deficiency have recently been proposed also for the treatment of disimmune peripheral neuropathies such as MMN, and a few trials were performed to see if patients receiving immunomodulatory doses of IVIg could be treated equally well with SCIg. We describe a patient affected by MMN who was included in a protocol of treatment with SCIg for a period of 6months. He successfully responded to treatment with a stabilization of strength. The patient is still treated with SCIg even after the end of the protocol. This is the first description of an Italian case of a patient affected by MMN successfully treated with SCIg.

Interferon beta‐1a as adjunctive treatment for multifocal motor neuropathy: an open label trial

Interferon beta‐1a as adjunctive treatment for multifocal motor neuropathy: an open label trial

Treatment of multifocal motor neuropathy with immunoglobulin: does route of administration matter?

Treatment of multifocal motor neuropathy with immunoglobulin: does route of administration matter?

Subcutaneous versus intravenous immunoglobulin in multifocal motor neuropathy: a randomized, single‐blinded cross‐over trial

For treatment of multifocal motor neuropathy (MMN), we hypothesized that (i) infusion of equivalent dosages of subcutaneous immunoglobulin (SCIG) is as effective as intravenous immunoglobulin (IVIG) and that (ii) subcutaneous infusion at home is associated with a better quality of life. In a randomized single-blinded cross-over study, nine IVIG responsive patients were allocated to receive either SCIG or IVIG for a period equivalent to three IVIG treatment intervals and, subsequently, crossed over to the other treatment. Primary end-points were (i) dynamometric strength of affected muscles and (ii) the SF-36 quality of life questionnaire. The two treatments were equally effective, the mean change in muscle strength after SCIG being 3.6% (95% CI -3.6% to 10.9%) vs. 4.3% (-1.3% to 10.0%) after IVIG (P = 0.86). One patient had sustained erythema and oedema at the injection sites for a few weeks. All other adverse effects during SCIG were mild and transient. No differences between treatments of health-related quality of life occurred. In MMN, short-term subcutaneous infusion of immunoglobulin is feasible, safe and as effective as intravenous infusion. Subcutaneous administration is an alternative option that adds flexibility to the treatment schedule.