A Practical Guide to Identify Patients With Multifocal Motor Neuropathy, a Treatable Immune-Mediated Neuropathy.

Multifocal motor neuropathy (MMN) is a rare immune-mediated motor neuropathy characterized by asymmetric weakness that preferentially affects distal upper limb muscles. The clinical features of MMN may be difficult to differentiate from motor neuron disease. Other conditions that may be mistaken for MMN include inclusion body myositis, chronic inflammatory demyelinating polyradiculoneuropathy, hereditary neuropathy with liability to pressure palsy, focal neuropathies, and radiculopathies. A key distinguishing electrophysiologic feature of MMN is the motor nerve conduction block located at noncompressible sites. MMN is a treatable neuropathy; therefore it is important that primary care physicians are aware of the features of the disease to identify potential patients and make referrals to a neuromuscular specialist in a timely manner. This review provides an overview of the disease, highlights key differential diagnoses, and describes available treatment options for patients with MMN.

Subcutaneous batoclimab in generalized myasthenia gravis: Results from a Phase 2a trial with an open-label extension.

OBJECTIVES: To assess the safety, tolerability, and key pharmacodynamic effects of subcutaneous batoclimab, a fully human anti-neonatal Fc receptor monoclonal antibody, in patients with generalized myasthenia gravis and anti-acetylcholine receptor antibodies. METHODS: A Phase 2a, proof-of-concept, randomized, double-blind, placebo-controlled trial is described. Eligible patients were randomized (1:1:1) to receive once-weekly subcutaneous injections of batoclimab 340 mg, batoclimab 680 mg, or matching placebo for 6 weeks. Subsequently, all patients could enter an open-label extension study where they received batoclimab 340 mg once every 2 weeks for 6 weeks. Primary endpoints were safety, tolerability, and change from baseline in total immunoglobulin G, immunoglobulin G subclasses, and anti-acetylcholine receptor antibodies at 6 weeks post-baseline. Secondary endpoints included changes from baseline to 6 weeks post-baseline for Myasthenia Gravis Activities of Daily Living, Quantitative Myasthenia Gravis, Myasthenia Gravis Composite, and revised 15-item Myasthenia Gravis Quality of Life scores. RESULTS: Seventeen patients were randomized to batoclimab 680 mg (n = 6), batoclimab 340 mg (n = 5), or placebo (n = 6). Batoclimab was associated with significantly greater reductions in total immunoglobulin G and anti-acetylcholine receptor antibodies from baseline to 6 weeks post-baseline than placebo. Reductions in immunoglobulin G subclasses were generally consistent with total immunoglobulin G. While clinical measures showed directionally favorable improvements over time, the study was not powered to draw conclusions about therapeutic efficacy. No safety issues were identified. INTERPRETATION: The safety profile, pharmacodynamics, and preliminary clinical benefits observed in this study support further investigation of subcutaneous batoclimab injections as a potential patient-administered therapy for seropositive generalized myasthenia gravis.

Anti-myelin-associated glycoprotein neuropathy: Where do we stand?

Myelin-associated glycoprotein (MAG) is a transmembrane glycoprotein concentrated in periaxonal Schwann cell and oligodendroglial membranes of myelin sheaths that serves as an antigen for immunoglobulin M (IgM) monoclonal antibodies. Individuals who harbor anti-MAG antibodies classically develop a progressive autoimmune peripheral neuropathy characterized clinically by ataxia, distal sensory loss, and gait instability, and electrophysiologically by distally accentuated conduction velocity slowing. Although off-label immunotherapy is common, there are currently no proven effective disease-modifying therapeutics, and most patients experience slow accumulation of disability over years and decades. The typically slowly progressive nature of this neuropathy presents unique challenges when trying to find effective anti-MAG therapeutic agents. Drug development has also been hampered by the lack of validated outcome measures that can detect clinically meaningful changes in a reasonable amount of time as well as by the lack of disease activity biomarkers. In this invited review, we provide an update on the state of clinicometric outcome measures and disease activity biomarkers in anti-MAG neuropathy. We highlight the insensitivity of widely used existing clinicometric outcome measures such as the Inflammatory Neuropathy Cause and Treatment (INCAT) disability score as well as the INCAT sensory subscore in anti-MAG neuropathy, referencing the two previous negative randomized controlled clinical trials evaluating rituximab. We then discuss newly emerging candidate therapeutic agents, including tyrosine kinase inhibitors and enhanced B-cell-depleting agents, among others. We conclude with a practical approach to the evaluation and management of anti-MAG neuropathy patients.

CIDP prognosis in patients with IVIG treatment-related fluctuations.

INTRODUCTION/AIMS: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired immune-mediated peripheral nerve disorder with variable prognosis and long-term dependence on immunotherapy. Frequent assessment of grip strength can be a useful tool to identify intravenous immunoglobulin (IVIG) treatment-related fluctuations (TRFs) and optimize IVIG treatment in real-time, but the long-term implications of TRFs are unknown. We aimed to explore the impact that real-time TRFs had on long-term CIDP prognosis, strength impairment, and disability. METHODS: This retrospective observational cohort study analyzed standard of care clinical and treatment outcomes in patients who participated in a published prospective study of intra-IVIG-cycle grip strength quantification. Patients were analyzed based upon the presence or absence of TRFs, as determined in the initial prospective study. RESULTS: Data were available for 23 CIDP patients with a mean follow-up period of 44.7 mo. There were no differences in baseline or follow-up strength, disability, or IVIG usage in patients with a low number of fluctuations compared to those with a high number of fluctuations. In both groups, drug-free remission was achieved in about one-third of patients. DISCUSSION: TRFs are important to identify in order to optimize treatment in real time, but poorly predict long-term disease activity status. The presence of minor TRFs are unlikely to result in substantial accumulation of disability over time. Periodic IVIG optimization trials using objective outcomes are encouraged in all CIDP patients receiving chronic IVIG treatment as a means to identify the lowest effective IVIG dose and frequency.

Diagnosis of chronic inflammatory demyelinating polyneuropathy.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a chronic immune-mediated peripheral form of polyneuropathy. No reliable diagnostic biomarkers are available by which to make the diagnosis of CIDP. As a result, diagnosis of the condition can be challenging. Many patients are not recognized early in the disease course, and on the other end of the spectrum both establishing early and accurate diagnosis as well as avoiding misdiagnosis and overtreatment. Identification of the hallmark clinical, electrophysiological, and laboratory features of the disease are critical to facilitate rapid diagnosis, while an understanding of diagnostic pitfalls can help prevent misdiagnosis. Since the original description of CIDP in the 1970s, over 15 sets of diagnostic criteria have been proposed. The criteria published in 2021 by the European Academy of Neurology / Peripheral Nerve Society (EAN/PNS) were developed for use during routine clinical care and are available in the public domain. These criteria provide clinicians with an invaluable resource by which the data collected during the evaluation of the patient with possible CIDP can be interpreted. One point of importance that bridges diagnosis to treatment is objectification of the treatment response. Interpretation of how patients respond to treatment drives both long-term treatment paradigms and the diagnosis at which these treatments are aimed. Although no approach is perfect, utilization of strength impairment and disability outcomes in clinical practice can help unravel the difficulties in interpreting response to treatment. Just as improvement in these outcomes is considered diagnostically supportive, the absence of objective benefit argues against it and should prompt reconsideration of a CIDP diagnosis.

Treatment of chronic inflammatory demyelinating polyneuropathy.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a chronic peripheral polyneuropathy that results in disability through immune-mediated nerve injury, but which not uncommonly has residual and irreversible neurological deficits after the active inflammatory component of the disorder has been treated. Management of the condition entails addressing both the abnormal immune activity that drives ongoing or active deficits while also managing residual symptoms through supportive interventions. Immune-based treatments are grounded in several important principles. First, early treatment is guided by evidence-based, proven-effective therapies that sequentially escalate depending on the response. Second, optimization or personalization of first-line treatments is needed to understand the ideal dose for any given patient, and whether long-term treatment is needed at all. Third, although many immunosuppressive agents may be utilized in nonresponding patients or when intravenous immunoglobulin (IVIg)/corticosteroid-sparing intervention is desired, all are unproven and require a delicate balance between risk, cost, and unknown likelihood of benefit that is tailored to each individual patient's unique circumstances. There is no reliable disease activity biomarker that can be used to guide treatment---a reality that makes it very challenging to optimize treatment to individual patient needs. Serial clinical assessments are key to understanding the value of continued immunotherapy or if long-term therapy is needed at all. Regardless of the immunotherapy status of a patient, equally important is addressing residual deficits through supportive interventions, including physical therapy, adaptive equipment, pain management, and emotional support.

A longitudinal evaluation of fatigue in chronic inflammatory demyelinating polyneuropathy.

BACKGROUND AND AIMS: Fatigue is a common but poorly understood complaint in patients with immune-mediated polyneuropathies. We sought to evaluate changes in fatigue over 1 year in a cohort of chronic inflammatory demyelinating polyneuropathy (CIDP) patients and to correlate changes in fatigue with changes in disability and quality of life. Investigation into other factors that may contribute to fatigue with a particular interest in the role other chronic disease states may play was also performed. METHODS: Fifty patients with CIDP who satisfied the 2010 EFNS/PNS diagnostic criteria were followed over the period of 1 year at three tertiary care centers in Serbia. Assessments of disability, quality of life, and patient perception of change and fatigue were collected at two time points 12 months apart. Comorbidities, treatment regimens, and sedating medication use was collected. RESULTS: Disability, quality of life, and patient perception of change showed statistically significant correlations with change in fatigue (p < .01). Increased levels of fatigue were noted in patients who used sedating medications (p = .05) and who had a comorbid chronic medical condition (p = .01). INTERPRETATION: Worsening fatigue correlates over time with increased disability and worse quality of life. Fatigue is not specific to CIDP, but is common in many chronic medical conditions and with the use of sedating medications. Our findings support the importance of identifying and supportively managing fatigue in patients with CIDP, but cautions against considering fatigue as a CIDP diagnostic symptom or using fatigue to justify immunotherapy utilization.

European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.

OBJECTIVE: To revise the 2010 consensus guideline on chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). METHODS: Seventeen disease experts, a patient representative, and two Cochrane methodologists constructed 12 Population/Intervention/Comparison/Outcome (PICO) questions regarding diagnosis and treatment to guide the literature search. Data were extracted and summarized in GRADE summary of findings (for treatment PICOs) or evidence tables (for diagnostic PICOs). RESULTS: Statements were prepared according to the GRADE Evidence-to-Decision frameworks. Typical CIDP and CIDP variants were distinguished. The previous term "atypical CIDP" was replaced by "CIDP variants" because these are well characterized entities (multifocal, focal, distal, motor, or sensory CIDP). The levels of diagnostic certainty were reduced from three (definite, probable, possible CIDP) to only two (CIDP and possible CIDP), because the diagnostic accuracy of criteria for probable and definite CIDP did not significantly differ. Good Practice Points were formulated for supportive criteria and investigations to be considered to diagnose CIDP. The principal treatment recommendations were: (a) intravenous immunoglobulin (IVIg) or corticosteroids are strongly recommended as initial treatment in typical CIDP and CIDP variants; (b) plasma exchange is strongly recommended if IVIg and corticosteroids are ineffective; (c) IVIg should be considered as first-line treatment in motor CIDP (Good Practice Point); (d) for maintenance treatment, IVIg, subcutaneous immunoglobulin or corticosteroids are recommended; (e) if the maintenance dose of any of these is high, consider either combination treatments or adding an immunosuppressant or immunomodulatory drug (Good Practice Point); and (f) if pain is present, consider drugs against neuropathic pain and multidisciplinary management (Good Practice Point).

Outcome measures and biomarkers in chronic inflammatory demyelinating polyradiculoneuropathy: from research to clinical practice.

Introduction: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune-mediated syndrome characterized clinically by weakness and/or numbness that evolves over 2 months or more. The heterogeneity of clinical features necessitates an individualized approach to disease monitoring that takes lessons learned from clinical trials and applies them to clinical practice.Areas covered: This review discusses the importance of clinimetrics and biomarkers in CIDP diagnosis and disease monitoring. Highlighted are the challenges of defining responses to immunotherapy, the usefulness, and limitations of utilizing evidence-based clinical outcome measures during routine clinical care, and the evolving understanding of how diagnostic and disease activity biomarkers may reshape our treatment and disease monitoring paradigms.Expert opinion: Although disability and impairment outcome measures are commonly used in CIDP to indicate disease status, the nonspecific nature of these metrics limits the ability to attribute a change in any given metric to a change in CIDP. This interpretive challenge may be magnified by inconsistencies in the direction of change as well as a strong placebo effect. There is a need to improve our understanding of minimally important changes in existing outcome measures as a means to personalize treatment and to better assess disease activity status with biomarker discovery.

European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.

To revise the 2010 consensus guideline on chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Seventeen disease experts, a patient representative, and two Cochrane methodologists constructed 12 Population/Intervention/Comparison/Outcome (PICO) questions regarding diagnosis and treatment to guide the literature search. Data were extracted and summarized in GRADE summary of findings (for treatment PICOs) or evidence tables (for diagnostic PICOs). Statements were prepared according to the GRADE Evidence-to-Decision frameworks. Typical CIDP and CIDP variants were distinguished. The previous term "atypical CIDP" was replaced by "CIDP variants" because these are well characterized entities (multifocal, focal, distal, motor, or sensory CIDP). The levels of diagnostic certainty were reduced from three (definite, probable, possible CIDP) to only two (CIDP and possible CIDP), because the diagnostic accuracy of criteria for probable and definite CIDP did not significantly differ. Good Practice Points were formulated for supportive criteria and investigations to be considered to diagnose CIDP. The principal treatment recommendations were: (a) intravenous immunoglobulin (IVIg) or corticosteroids are strongly recommended as initial treatment in typical CIDP and CIDP variants; (b) plasma exchange is strongly recommended if IVIg and corticosteroids are ineffective; (c) IVIg should be considered as first-line treatment in motor CIDP (Good Practice Point); (d) for maintenance treatment, IVIg, subcutaneous immunoglobulin or corticosteroids are recommended; (e) if the maintenance dose of any of these is high, consider either combination treatments or adding an immunosuppressant or immunomodulatory drug (Good Practice Point); and (f) if pain is present, consider drugs against neuropathic pain and multidisciplinary management (Good Practice Point).

Patient Preferences for Subcutaneous versus Intravenous Administration of Treatment for Chronic Immune System Disorders: A Systematic Review.

BACKGROUND: For many chronic immune system disorders, the available treatments provide several options for route of administration. The objective of this systematic literature review is to inform discussions about therapy choices for individual patients by summarizing the available evidence regarding the preferences of patients with chronic immune system disorders for intravenous (IV) or subcutaneous (SC) administration. METHODS: Searches of the MEDLINE, Embase and Cochrane Library databases were conducted using terms designed to capture studies reporting patient preferences between IV and SC therapy published in English. Relevant studies were limited to those in which mode of administration, including treatment frequency and setting, was the main difference between comparators. RESULTS: In total, 49 studies were included in the review. Among 18 studies that compared IV and SC immunoglobulin therapy, 16 found patients to prefer the SC administration route. The results of the 31 studies comparing IV infusion and SC injection of non-immunoglobulin therapies were mixed, with patients favoring SC administration in 20, IV infusion in seven, and having no overall preference in four. Patient experience had a strong effect on preferences, with treatment-experienced patients preferring their current administration route in most studies. Patients preferring SC administration tended also to prefer treatment at home, mainly due to the convenience and comfort of home treatment and the avoidance of having to attend hospital. By contrast, patients preferring IV infusion tended to cite the lower treatment frequency and a dislike of self-injecting, and preferred hospital treatment, mainly due to the presence of healthcare professionals and resulting feelings of safety. CONCLUSION: In general patients with chronic immune system disorders tend to be more likely to choose SC administration than IV infusion, but preferences may vary according among individuals. These findings may assist discussions around appropriate treatment choices for each patient.

Misdiagnosis and diagnostic pitfalls of chronic inflammatory demyelinating polyradiculoneuropathy.

BACKGROUND AND PURPOSE: The aim of this study was to determine the frequency of over- and underdiagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and to identify related diagnostic pitfalls. METHODS: We conducted a retrospective study in Dutch patients referred to the Erasmus University Medical Centre Rotterdam between 2011 and 2017 with either a diagnosis of CIDP or another diagnosis that was revised to CIDP. We used the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) 2010 diagnostic criteria for CIDP to classify patients into three groups: overdiagnosis, underdiagnosis, or confirmed diagnosis of CIDP. Clinical and laboratory features and treatment history were compared between groups. RESULTS: A referral diagnosis of CIDP was revised in 32% of patients (31/96; overdiagnosis). Of 81 patients diagnosed with CIDP, 16 (20%) were referred with another diagnosis (underdiagnosis). In the overdiagnosed patients, 20% of muscle weakness was asymmetric, 48% lacked proximal muscle weakness, 29% only had distal muscle weakness, 65% did not fulfil the electrodiagnostic criteria for CIDP, 74% had an elevated cerebrospinal fluid (CSF) protein level, and 97% had another type of neuropathy. In the underdiagnosed patients, all had proximal muscle weakness, 50% had a clinically atypical CIDP, all fulfilled the electrodiagnostic criteria for CIDP, and 25% had an increased CSF protein level. CONCLUSION: Over- and underdiagnosis of CIDP is common. Diagnostic pitfalls include lack of attention to proximal muscle weakness as a diagnostic hallmark of CIDP, insufficient recognition of clinical atypical phenotypes, overreliance on CSF protein levels, misinterpretation of nerve conduction studies and poor adherence to electrodiagnostic criteria, and failure to exclude other causes of polyneuropathy.

Quantifying Treatment-Related Fluctuations in CIDP: Results of the GRIPPER Study.

OBJECTIVE: The objective of this study was to explore the extent of IV immunoglobulin (IVIG) treatment-related fluctuations (TRFs) by using home collection of daily grip strength in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and to use that information to develop evidence-based treatment optimization strategies. METHODS: This prospective observational study included 25 patients with well-defined CIDP. Participants recorded grip strength daily for 6 months. Disability and gait metrics were collected weekly. Serum immunoglobulin G levels were obtained at peak, trough, and midcycle IVIG intervals. Day-to-day grip strength changes <10% were considered random. To identify patients with TRFs, 3-day averaged grip strength was calculated on each consecutive day after an IVIG infusion. TRFs were defined as ≥10% 3-day averaged grip strength difference compared to the pre-IVIG baseline. RESULTS: Participants successfully recorded grip strength on all but 9% of recordable days. Twelve patients (48%) were classified as low/no fluctuaters and 13 (52%) as frequent fluctuaters. In the frequent fluctuating group, grip strength improved over 1 week and thereafter was relatively stable until the third week after infusion. Grip strength was significantly correlated with measures of disability. CONCLUSIONS: Grip strength collection by patients at home is reliable, valid, and feasible. A change in grip strength by ≥10% is a useful, practical, and evidence-based approach that may be used to identify clinically meaningful TRFs. From these data, we propose a treatment optimization strategy for patients with CIDP on chronic IVIG that may be applied to routine clinic care during both face-to-face and virtual video or telephone patient encounters. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02414490.

A Global Survey of Disease Burden in Patients Who Carry a Diagnosis of Chronic Inflammatory Demyelinating Polyneuropathy.

INTRODUCTION: The extent to which work productivity, emotional well-being, social interactions, and family life are impacted in patients who self-identify as having chronic inflammatory demyelinating polyneuropathy (CIDP) is not well characterized. METHODS: Data from an online survey of 595 individuals with self-reported CIDP, recruited by the Guillain-Barré syndrome (GBS)/CIDP Foundation, were used to assess disease and treatment burden. A total of 37% of patients were classified as "likely", 34% as "somewhat likely", and 28% as "unlikely" CIDP. RESULTS: Of ten symptoms that patients with CIDP may experience, each symptom was experienced by 77-94% of "likely", 79-96% of "somewhat likely", and 66-91% of "unlikely" patients. In "likely" CIDP patients 44% stopped working because of their symptoms and 24% moved to a new home. The most common treatments were intravenous immunoglobulin (IVIg) infusion and corticosteroids. IVIg was associated with venous access issues and work/school absenteeism. CONCLUSIONS: CIDP diagnostic confirmation was not performed in any of the survey respondents. Our results do not add any knowledge on the diagnosis or treatment of CIDP. Our findings do provide insight into the symptoms that patients that think they have CIDP or have been told they have CIDP experience, explores how patients that are labeled as having CIDP view treatment expectations, and highlights how these symptoms affect home and work life. We hope that the findings are constructively used to get patients the services they need to improve quality of life, maintain employment, and ensure a safe home environment regardless of diagnostic accuracy.

Fatigue in chronic inflammatory demyelinating polyneuropathy.

INTRODUCTION: In this study we aimed to better understand fatigue in chronic inflammatory demyelinating polyneuropathy (CIDP) as it relates to disease activity status. METHODS: Patients with probable or definite CIDP were stratified into active CIDP or CIDP in remission. Assessments of fatigue, physical impairment, disability, sleepiness, sleep quality, and depression were collected. RESULTS: Of the 85 patients included in the study, 46 (54%) had active disease, whereas 39 (46%) were in remission. Fatigue was substantial in both groups, but was more severe in the active group. Use of sedating medications was a major contributor to fatigue. Sleep quality was poor in both groups, whereas depression more commonly affected those with active CIDP. Inflammatory Neuropathy Cause and Treatment disability, poor sleep quality, and higher level of depression had the greatest effect on fatigue severity. DISCUSSION: Fatigue is common in CIDP regardless of the disease activity state. Minimizing sedating medications, improving sleep quality, and managing depression may improve CIDP-associated fatigue.

Monitoring Clinical Course and Treatment Response in Chronic Inflammatory Demyelinating Polyneuropathy During Routine Care: A Review of Clinical and Laboratory Assessment Measures.

Importance: Identifying clinical change in many neurologic diseases, including chronic inflammatory demyelinating polyneuropathy (CIDP), can be challenging. At the same time, how change is defined heavily influences a patient's diagnostic and treatment pathway. It can be especially problematic when equivocal subjective observations are interpreted as clinically meaningful and then used to make diagnostic and treatment decisions. Change in clinical trials is strictly defined by a preselected metric, but there is a perception that formal outcomes collection during routine clinical care is neither feasible nor necessary. Given the importance placed on how change is interpreted, there is a need to select assessments that can be applied to routine care that are representative of the neurologic disease state. Observations: For an outcome measure to be useful during clinical trials, it must have good reliability, validity, be responsive to change, and have clinical meaning. To be useful during routine clinical care, the assessment must additionally be easy to collect without the need for extensive training or equipment and should provide an immediately available result that can be rapidly quantified and interpreted. Chronic inflammatory demyelinating polyneuropathy is clinically heterogeneous and so is best evaluated with a diverse group of assessment tools. Assessing strength impairment, disability, and quality of life is ideally suited for everyday practice when caring for patients with CIDP. While electrophysiologic studies, imaging, cerebrospinal fluid, and nodal/paranodal antibodies can provide diagnostic data, they are less practical and helpful longitudinal assessment tools. Conclusions and Relevance: Sound clinimetric outcome measures in CIDP are widely available and have the potential to help clinicians objectify treatment response and disease progression. Such data are critically important when justifying the need for ongoing or periodic immunotherapy, documenting relapse or deterioration, or providing reassurance of disease improvement, stability, or remission.