Individualized immunoglobulin therapy in chronic immune‐mediated peripheral neuropathies*

Despite the well‐recognized importance of immunoglobulin therapy individualization during the treatment of chronic inflammatory demyelinating polyneuropathy (CIDP), the pathway to best achieve optimization is unknown. There are many pharmacokinetic and immunobiologic variables that can potentially influence the appropriateness of any individual therapy. Although identification of specific autoantibodies and their targets has only been accomplished in a minority of patients with CIDP, already the diagnostic and treatment implications of specific autoantibody detection are being realized. Individual variability in IgG pharmacokinetic properties including IgG catabolic rates and distribution, as well as the IgG level necessary for disease control also require consideration during the optimization process. For optimization to be successful there must be a measure of treatment response that has a clinically meaningful interpretation. There are currently available well‐defined and validated clinical assessment tools and outcome measures that are well suited for this purpose. While there remains much to learn on how best to manipulate immunopathology and immunoglobulin pharmacokinetics in the most favorable way, there currently exists an understanding of these principles to a degree sufficient to begin to develop rational and evidence‐based treatment optimization strategies.     

Chronic dysimmune neuropathies: Beyond chronic demyelinating polyradiculoneuropathy

The spectrum of chronic dysimmune neuropathies has widened well beyond chronic demyelinating polyradiculoneuropathy (CIDP). Pure motor (multifocal motor neuropathy), sensorimotor with asymmetrical involvement (multifocal acquired demylinating sensory and motor neuropathy), exclusively distal sensory (distal acquired demyelinating sensory neuropathy) and very proximal sensory (chronic immune sensory polyradiculopathy) constitute the variants of CIDP. Correct diagnosis of these entities is of importance in terms of initiation of appropriate therapy as well as prognostication of these patients. The rates of detection of immune-mediated neuropathies with monoclonal cell proliferation (monoclonal gammopathy of unknown significance, multiple myeloma, etc.) have been facilitated as better diagnostic tools such as serum immunofixation electrophoresis are being used more often. Immune neuropathies associated with malignancies and systemic vasculitic disorders are being defined further and treated early with better understanding of the disease processes. As this field of dysimmune neuropathies will evolve in the future, some of the curious aspects of the clinical presentations and response patterns to different immunosuppressants or immunomodulators will be further elucidated. This review also discusses representative case studies.     

Efficacy and tolerability of different brands of intravenous immunoglobulin in the maintenance treatment of chronic immune‐mediated neuropathies

High‐dose intravenous immunoglobulin (IVIg) is effective in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN). Not all brands of IVIg are however licensed for these neuropathies. We reviewed six patients with CIDP and seven with MMN treated with maintenance therapy with IVIg from 2009 to 2013. In all patients, we measured the Medical Research Council (MRC) and Overall Neuropathy Limitation Scale (ONLS) scores before each infusion, registered the monthly dose and brand of IVIg, and recorded adverse events. Patients were treated for 25–60 months (mean 49 months) alternating different brands of IVIg including IgVena, Gammagard, Kiovig, and Flebogamma. Minor and transient side effects were equally observed with each brand. No difference in the MRC or ONLS scores was observed in relation to the brand of IVIg used. Chronic maintenance treatment with IVIg in patients with MMN and CIDP was not associated with a different tolerability or efficacy despite the use of different brands of IVIg.     

Current treatments of chronic immune‐mediated demyelinating polyneuropathies

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multifocal motor neuropathy (MMN), and anti–myelin‐associated glycoprotein (anti‐MAG) neuropathy are three demyelinating acquired neuropathies, with distinct responses to immunotherapy. In placebo‐controlled, double‐blind, randomized trials, intravenous immunoglobulin (IVIg) has been effective for CIDP and MMN, and plasmapheresis has been effective for CIDP. Corticosteroids have been beneficial in controlled trials for CIDP. Other agents, including cyclophosphamide, rituximab, azathioprine, cyclosporine, interferons, fludarabine, mycophenolate mofetil, and etanercept, have been reported to benefit some patients with inflammatory demyelinating neuropathies in case series and case reports. This review examines the use and toxicity associated with these immunotherapy medications in treating patients with chronic immune‐mediated demyelinating neuropathies. Muscle Nerve, 2009     

Nerve ultrasound score in distinguishing chronic from acute inflammatory demyelinating polyneuropathy

ObjectiveAim of this study was to develop and evaluate the applicability of an ultrasound score (Bochum ultrasound score – BUS) in distinguishing chronic (CIDP) from acute inflammatory demyelinating polyneuropathy (AIDP).Methods

• •Step 1: For the development of BUS 75 healthy-controls, 20 CIDP, 20 AIDP patients underwent US 4.55 ± 3.5 and 3.4 ± 2.91 years, respectively after onset. After comparing the distribution pattern and frequency of pathological US changes between the two study groups, we developed BUS, summarizing the cross sectional area (CSA) of: (1) the ulnar nerve in Guyons’ canal, (2) the ulnar nerve in upper-arm, (3) the radial nerve in spiral groove, (4) the sural nerve between the gastrocnemius muscle.
• •Step 2: The BUS underwent blinded evaluation in further 10 CIDP, 21 AIDP patients 3.8 ± 2.7 and 2.3 ± 1.5 years, respectively after onset.
• •Step 3: The BUS underwent blinded, prospective evaluation in 8 patients with acute/subacute polyradiculoneuropathy (5 CIDP, 3 AIDP) 2.6 ± 1.8 weeks after onset.

ResultsThe BUS showed a sensitivity of 90% and specificity of 90.4% (positive predictive value, PPV = 81.8%; negative predictive value, NPV = 95%) in distinguishing CIDP from AIDP, when they showed no differences in disease duration (p = 0.0551).In addition, the BUS distinguished subacute-CIDP from AIDP with a sensitivity of 80%, specificity of 100% (PPV = 100%, NPV = 75%).ConclusionThe BUS seems to allow a reliable distinction of CIDP from AIDP.SignificanceThe BUS may be helpful in distinguishing subacute-CIDP from AIDP.     

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

Introduction: 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. Methods: We performed a meta‐analysis of reports of efficacy and safety of SC‐Ig versus IVIg for inflammatory demyelinating polyneuropathies. Results: 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). Conclusions: 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     

Lewis–sumner syndrome of pure upper‐limb onset: Diagnostic,prognostic, and therapeutic features

We studied two 16‐year‐old males with juvenile muscular atrophy of the distal arm, “Hirayama disease,” resulting in asymmetric atrophy and weakness of the distal upper extremities. Pathogenic theories include a compressive myelopathy with or without ischemia, and occasional cases are accounted for by genetic mutations. To specifically address the ischemia hypothesis we performed spinal angiography and epidural venography. Neck flexion during spinal angiography showed a forward shift of a nonoccluded anterior spinal artery without impedance to blood flow. Epidural venography demonstrated engorgement of the posterior epidural venous plexus without obstruction to venous flow. The findings do not support large vessel obstruction as a contributory factor. The Hirayama hypothesis continues to best explain the disease pathogenesis: neck flexion causes tightening of the dura and intramedullary microcirculatory compromise with resultant nerve cell damage. The age‐related factor can most likely be accounted for by a growth imbalance between the vertebral column and the cord/dural elements. Resolution of progression is associated with cessation of body growth, after which the symptoms plateau or modestly improve. Muscle Nerve 40: 206–212, 2009     

Nerve ultrasound in a case of multifocal motor neuropathy without conduction block

Introduction: Multifocal nerve enlargements and ultrastructural changes either corresponding or not to sites of existing conduction blocks have been described in demyelinating polyneuropathies using multiple imaging techniques. Methods: Using the emerging technique of peripheral nerve ultrasonography we investigated the peripheral nerves of a patient with multifocal motor neuropathy (MMN) without conduction block. Results: In this case of MMN without conduction blocks we found multifocal nerve enlargements in the ultrasonography and electrodiagnostic signs of acute and chronic denervation associated with positive anti‐GM1 IgM antibodies. Conclusions: This case shows that nerve ultrasound can be a complementary tool for diagnosing multifocal motor neuropathy without typical electrodiagnostic features. Muscle Nerve 52 : 294–299, 2015     

Early neurophysiological evolution of chronic inflammatory demyelinating polyneuropathy in a patient with Hashimoto's thyroiditis

A patient with a known history of hypothyroidism due to Hashimoto's thyroiditis presented with a subacute, progressive sensorimotor deficit that affected the upper limbs predominantly. The electrophysiological findings progressively evolved from multifocal motor conduction block to multifocal demyelinating sensory and motor nerve involvement with conduction block, and finally to findings fulfilling the diagnostic criteria of chronic inflammatory demyelinating polyneuropathy (CIDP). The patient did not respond adequately to intravenous immunoglobulin, whereas oral prednisone led to fast and complete recovery. This report discusses the evolution of early findings of CIDP, as well as its coexistence with Hashimoto's thyroiditis.     

Management challenges for chronic dysimmune neuropathies during the COVID-19 pandemic

Since March 2020, the COVID-19 pandemic has led to the need to re-think the delivery of services to patients with chronic dysimmune neuropathies. Telephone/video consultations have become widespread but have compounded concerns about objective evaluation. Therapeutic decisions need, more than ever before, to be considered in the best interests of both patients, and society, while not denying function-preserving/restoring treatment. Immunoglobulin therapy and plasma exchange, for those treated outside of the home, expose patients to the hazards of hospital or outpatient infusion centers. Steroid therapy initiation and continuation pose increased infectious risk. Immunosuppressant therapy similarly becomes highly problematic, with the risks of treatment continuation enhanced by uncertainties regarding duration of the pandemic. The required processes necessitate considerable time and effort especially as resources and staff are re-deployed to face the pandemic, but are essential for protecting this group of patients and as an integral part of wider public health actions.     

Nerve size in chronic inflammatory demyelinating neuropathy varies with disease activity and therapy response over time: A retrospective ultrasound study

Introduction: Nerves are often enlarged in chronic inflammatory demyelinating polyneuropathy (CIDP). In this investigation we studied changes with treatment over time. Methods: We retrospectively compared serial ultrasound measurements of median and ulnar nerve size with clinical and electrodiagnostic evaluations in 23 CIDP subjects. We defined remission as stable clinical improvement on low or decreasing amounts of medication. Results: Nerves were normal at last follow‐up more often in subjects who achieved remission than in those who did not (10 of 13 vs. 0 of 10, P = 0.0001). Nerves were normal or smaller (>30% reduction) more often in subjects whose grip strength improved or remained strong compared those whose grip strength weakened (12 of 16 vs. 0 of 3, P = 0.04), and in subjects whose demyelinating electrodiagnostic features resolved compared with those whose demyelination persisted (7 of 7 vs. 6 of 12, P = 0.04). Over time, nerve size decreased more in subjects with baseline nerve enlargement who achieved remission than in those who did not (?41% vs. 7%, P = 0.04). Conclusion: In CIDP, enlarged nerves normalized or decreased with remission. Muscle Nerve 50 : 733–738, 2014