Continued benefit of nusinersen initiated in the presymptomatic stage of spinal muscular atrophy: 5-year update of the NURTURE study.

INTRODUCTION/AIMS: NURTURE (NCT02386553) is an open-label study of nusinersen in children (two SMN2 copies, n = 15; three SMN2 copies, n = 10) who initiated treatment in the presymptomatic stage of spinal muscular atrophy (SMA). A prior analysis after ~3 y showed benefits on survival, respiratory outcomes, motor milestone achievement, and a favorable safety profile. An additional 2 y of follow-up (data cut: February 15, 2021) are reported. METHODS: The primary endpoint is time to death or respiratory intervention (≥6 h/day continuously for ≥7 days or tracheostomy). Secondary outcomes include overall survival, motor function, and safety. RESULTS: Median age of children was 4.9 (3.8-5.5) y at last visit. No children have discontinued the study or treatment. All were alive. No additional children utilized respiratory intervention (defined per primary endpoint) since the prior data cut. Children with three SMN2 copies achieved all World Health Organization (WHO) motor milestones, with all but one milestone in one child within normal developmental timeframes. All 15 children with two SMN2 copies achieved sitting without support, 14/15 walking with assistance, and 13/15 walking alone. Mean Hammersmith Functional Motor Scale Expanded total scores showed continued improvement. Subgroups with two SMN2 copies, minimum baseline compound muscle action potential amplitude ≥2 mV, and no baseline areflexia had better motor and nonmotor outcomes versus all children with two SMN2 copies. DISCUSSION: These results demonstrate the value of early treatment, durability of treatment effect, and favorable safety profile after ~5 y of nusinersen treatment. Inclusion/exclusion criteria and baseline characteristics should be considered when interpreting presymptomatic SMA trial data.

Changes in spatiotemporal gait parameters following intravenous immunoglobulin treatment for chronic inflammatory demyelinating polyneuropathy.

INTRODUCTION: Gait impairment is a common presenting symptom in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). However, gait parameters have not previously been evaluated in detail as potential independent outcome measures. METHODS: We prospectively measured changes in spatiotemporal gait parameters of 20 patients with CIDP at baseline and following treatment with intravenous immunoglobulin (IVIG), using GAITRite® a computerized walkway system with embedded sensors. RESULTS: Overall, study patients showed significant improvements in gait velocity, cadence, stride length, double support time, stance phase, and swing phase following IVIG treatment. Mean changes in velocity, stance phase, and swing phase, exhibited the greatest statistical significance among the subgroup that exhibited clinically meaningful improvement in Inflammatory Neuropathy Cause and Treatment disability score, Medical Research Council sum score, and grip strength. CONCLUSIONS: Assessment of gait parameters, in particular velocity, step phase and swing phase, is a potentially sensitive outcome measure for evaluating treatment response in CIDP. Muscle Nerve 56: 732-736, 2017.

Comparison of 2-limb versus 3-limb electrodiagnostic studies in the evaluation of chronic inflammatory demyelinating polyneuropathy.

INTRODUCTION: European Federation of Neurological Societies/Peripheral Nerve Society electrodiagnostic (EDx) criteria for the definite diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) require the presence of demyelinating findings (DF) in at least 2 nerves. Data are lacking, however, regarding the optimal number of nerves to test. METHODS: We retrospectively reviewed EDx data from 53 patients with CIDP and compared the number of DF found on 2- and 3-limb testing. RESULTS: A median of 3 (range 2-5) DF were found on 2-limb testing compared with 5 (range 4-7) DF when 3 limbs were evaluated. Two-limb EDx studies were sufficient to diagnose definite CIDP in 92.3% of typical, 84.2% of asymmetric, and 66.7% of distal phenotypes. Testing a third limb increased diagnostic certainty in 11 patients (20.8%) to definite CIDP. CONCLUSIONS: Three-limb testing may increase diagnostic sensitivity of definite CIDP, especially in patients with atypical phenotypes. Larger prospective studies are needed to better assess the benefit of performing 3-limb EDx studies.

Follow-up nerve conduction studies in CIDP after treatment with IGIV-C: Comparison of patients with and without subsequent relapse.

INTRODUCTION: Electrodiagnostic studies (EDX) are not performed routinely before treatment suspension in CIDP, and no data exist regarding their value in predicting clinical relapse. METHODS: Serial EDX (baseline and after IGIV-C therapy) were analyzed from subjects in the ICE clinical trial who responded to IGIV-C treatment and were subsequently re-randomized to placebo in an extension phase. Comparisons were made between subjects who relapsed and those who did not. RESULTS: A total of 55% (6/11) of the Relapse group had an increase in total number of demyelinating findings (DF) versus 8% (1/13) in the No Relapse group (P = 0.023). In the Relapse group, 100% had ≥ 1 new DF and 73% (8/11) had ≥ 4 new DF versus 60% (8/13) and 8% (1/13), respectively, in the No Relapse group. CONCLUSIONS: An increased total number of DF or the occurrence of ≥ 4 new DF may indicate a higher risk of clinical relapse after treatment cessation in IGIV-C-responsive patients.

Peripheral neuropathies of rheumatologic disease and gluten-related disorders.

Peripheral nervous system disease is a common and often debilitating feature of many systemic rheumatologic disorders. Such involvement takes many forms, reflecting the variety of underlying pathophysiology, though most patients present with painful multifocal neuropathy (usually vasculitic) or a distal sensory more than motor peripheral neuropathy (sometimes vasculitic and nearly always axonal). The presence of peripheral nervous system involvement is often an early signal of the generalization of inflammatory disease in blood vessels or extravascular tissues, though peripheral neuropathy is not itself an independent predictor of mortality. Nonetheless, progressive multifocal neuropathy, motor neuropathy, small fiber neuropathy, and sensory neuronopathy should be treated early and aggressively with immunosuppression (or the gluten-free diet in appropriate situations) to limit morbidity. Given the rapidly evolving therapeutic landscape, partnership with a rheumatologist is essential. Treatment is usually sustained for 1 to 2 years, and remission is possible in many cases within 6 to 12 months, with variable rates of relapse and treatment resistance. Patients should be meticulously monitored for relapse with serial laboratory testing, electrodiagnostic studies, and clinical examination. Functional rating scores, such as the neuropathy impairment scale and the total neuropathy score are useful for longitudinal assessment.

A Post-Marketing Surveillance Study of Nusinersen for Spinal Muscular Atrophy in Routine Medical Practice in China: Interim Results.

INTRODUCTION: Spinal muscular atrophy (SMA) is a rare, autosomal recessive, neuromuscular disease that leads to progressive muscular weakness and atrophy. Nusinersen, an antisense oligonucleotide, was approved for SMA in China in February 2019. We report interim results from a post-marketing surveillance phase 4 study, PANDA (NCT04419233), that collects data on the safety, efficacy, and pharmacokinetics of nusinersen in children with SMA in routine clinical practice in China. METHODS: Participants enrolled in PANDA will be observed for 2 years following nusinersen treatment initiation. The primary endpoint is the incidence of adverse events (AEs)/serious AEs (SAEs) during the treatment period. Efficacy assessments include World Health Organization (WHO) Motor Milestones assessment, the Hammersmith Infant Neurological Examination (HINE), and ventilation support. Plasma and cerebrospinal fluid (CSF) concentrations of nusinersen are measured at each dose visit. RESULTS: Fifty participants were enrolled as of the January 4, 2023, data cutoff: 10 with infantile-onset (≤ 6 months) and 40 with later-onset (> 6 months) SMA. All 50 participants have received at least one dose of nusinersen; 6 have completed the study. AEs were experienced by 45 (90%) participants and were mostly mild/moderate; no AEs led to nusinersen discontinuation or study withdrawal. Eleven participants experienced SAEs, most commonly pneumonia (n = 9); none were considered related to study treatment. Stability or gain of WHO motor milestone was observed and mean HINE-2 scores improved in both subgroups throughout the study. No serious respiratory events occurred, and no permanent ventilation support was initiated during the study. Pre-dose nusinersen CSF concentrations increased steadily through the loading-dose period, with no accumulation in plasma after multiple doses. CONCLUSION: Nusinersen was generally well tolerated with an acceptable overall safety profile, consistent with the known safety of nusinersen. Efficacy, safety, and nusinersen exposure are consistent with prior observations. These results support continuing PANDA and evaluation of nusinersen in Chinese participants with SMA. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04419233.

Gender Differences in Skin Biopsy Findings in Small Fiber Neuropathy: A Retrospective Chart Review.

OBJECTIVES: To determine whether there are gender differences in the clinical presentation or skin biopsy measures of nerve fiber density in patients with small fiber neuropathy (SFN). METHODS: Retrospective chart review of subjects with suspected SFN. RESULTS: Of 218 cases (137 women and 81 men) with suspected SFN, 96 (44%), including 63% of the men and 33% of the women (P < 0.05), had low epidermal nerve fiber density (ENFD) or sweat gland nerve fiber density (SGNFD). There were no differences in the clinical presentation between men and women. In those with abnormal findings, low ENFD alone was more frequent in women than men (51.1% vs. 7.8%, P < 0.05), whereas abnormal SGNFD alone was more frequent in men than women (68.6% vs. 11.1%, P < 0.05). Both SGNFD and ENFD were low in 23.5% of men and 33.3% of women. Skin biopsy findings were independent of clinical presentation or etiology. CONCLUSIONS: The clinical presentation of SFN is similar in men and women. In skin biopsy studies, low ENFD is more common in women and low SGNFD in men.

Rare myelin protein zero sequence variant in late onset CMT1B.

Myelin protein zero (MPZ) mutations cause demyelinating neuropathies that range from severe neonatal to milder adult forms. We report a 65-year-old woman with slowly progressive leg weakness starting at 47. Examination revealed distal weakness and atrophy in all extremities, impaired light touch in both feet and pin perception to proximal calves, absent leg reflexes, and unsteady gait. Electrodiagnostic studies revealed a severe sensorimotor polyneuropathy with conduction velocities of 25 m/s - to normal. The conduction velocities in the upper 20's were seen in lower extremities with severe reduction of the corresponding compound muscle action potential amplitudes. She had a MPZ mutation with A-C transversion (nucleotide: 116, codon: 10, histidine-to-proline). Her sister has an identical mutation, with high arches, distal leg weakness, decreased vibration sensation in toes and ankle areflexia. Nerve conduction studies revealed a moderate-severe sensorimotor polyneuropathy with nerve conduction velocities of 36 m/s - to normal. Their mother had an abnormal gait and conduction velocities of 29-30 m/s. A third sister is clinically and genetically unaffected. One report has previously described four patients with this mutation with similar clinical and electrodiagnostic features. In patients tested for possible CMT, the frequency of MPZ His-Pro codon 10 substitutions was 0.11% (27 of 24,076 alleles).

Abnormal Nutritional Factors in Patients Evaluated at a Neuropathy Center.

Abnormal concentrations of nutritional factors were found in 24.1% of 187 patients with neuropathy who were newly seen at our academic neuropathy referral center over a 1-year period. All patients presented with sensory axonal or small fiber neuropathy. In 7.3%, they were present in association with at least one other identifiable cause for neuropathy. Elevated levels of pyridoxal phosphate or mercury occurred more frequently than deficiencies in vitamins B1, B12, or B6. The nutritional abnormalities are amenable to correction by dietary intervention.

Small-fiber neuropathy/neuronopathy associated with celiac disease: skin biopsy findings.

BACKGROUND: Celiac disease (CD) is increasingly recognized in North America and is associated with a peripheral neuropathy. OBJECTIVE: To report the clinical characteristics and skin biopsy results in patients with CD and small-fiber neuropathy symptoms. DESIGN: Case series. SETTING: Academic peripheral neuropathy clinic. PATIENTS: Eight patients with CD and neuropathy symptoms. Intervention Three-millimeter punch biopsy using the panaxonal marker protein gene product 9.5 to assess epidermal nerve fiber (ENF) density and a gluten-free diet. MAIN OUTCOME MEASURE: Clinical data and ENF density. RESULTS: All patients had asymmetric numbness and paresthesias. Three had more prominent involvement of hands than feet, and 3 had facial numbness. Celiac disease was diagnosed in 5 after their neuropathy began. The following serum antibody levels were elevated: tissue transglutaminase (n = 6), IgA gliadin (n = 4), and IgG gliadin (n = 7). Results of nerve conduction studies were normal in 7 patients. One patient had mildly reduced sural amplitudes. The ENF density was reduced in 5 patients. The ENF density was at the low limit of the normal range in 3 additional patients, 2 of whom had morphologic changes in axons. Three patients had decreased ENF density at the thigh or forearm, which was more severe than at the distal leg, compatible with a non-length-dependent process. Four reported improvement with a gluten-free diet. One had no improvement after 4 months. Symptoms developed in 2 while receiving a gluten-free diet. CONCLUSIONS: Patients with CD may have a neuropathy involving small fibers, demonstrated by results of skin biopsy. The pattern of symptoms, with frequent facial involvement and a non-length-dependent pattern on skin biopsy findings, suggests a sensory ganglionopathy or an immune-mediated neuropathy. Improvement of symptoms in some patients after initiating a gluten-free diet warrants further study.

Comparison of electrodiagnostic abnormalities and criteria in a cohort of patients with chronic inflammatory demyelinating polyneuropathy.

BACKGROUND: Current electrodiagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP) are research oriented favoring specificity over sensitivity. Application of such criteria in clinical practice may miss the diagnosis in potentially treatable patients. OBJECTIVES: To analyze the electrophysiologic abnormalities in a cohort of patients with clinically defined CIDP, to compare these data with published electrodiagnostic criteria, and to identify a set of abnormalities that is shared by all patients with CIDP. DESIGN: Retrospective medical record review. SETTING: Academically based neuromuscular clinic. Patients Fifteen patients with clinically diagnosed relapsing sensorimotor CIDP. INTERVENTIONS: Administration of intravenous immunoglobulin or prednisone. MAIN OUTCOME MEASURES: Electrodiagnostic studies. RESULTS: All patients had electrodiagnostic abnormalities in at least 3 nerves with possible partial conduction block or demyelinating range abnormalities in at least 1 nerve. The diagnostic sensitivities of 5 published CIDP criteria were as follows: the Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force (40%), Saperstein et al (47%), Nicolas et al (53%), Hughes et al for the Inflammatory Neuropathy Cause and Treatment Group (60%), and Thaisetthawatkul et al (70%). CONCLUSIONS: Current electrodiagnostic criteria for CIDP are insensitive and may fail to diagnose the condition in a substantial number of patients. More inclusive criteria that allow identification of patients in routine clinical practice are needed.

Etanercept (Enbrel) therapy for chronic inflammatory demyelinating polyneuropathy.

Patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and/or variants who were refractory or intolerant of standard therapies were treated with etanercept, 25 mg twice per week. Ten patients underwent treatment, and manual muscle strength, sensory thresholds and functional abilities were tested prior to and 4-6 months after initiating therapy. Three patients had significant improvement and three others had possible improvement. Based on these preliminary observations, treatment with etanercept may be considered in patients with CIDP, who cannot undergo standard therapies, although its efficacy in CIDP needs to be examined in a double-blinded, controlled clinical trial.

Small fiber abnormalities in skin biopsies of patients with benign fasciculations.

OBJECTIVE: To determine whether patients with benign fasciculations have evidence for axonal loss in skin biopsies. METHODS: Epidermal sensory and sweat gland nerve fiber densities were quantified in skin biopsies of 11 patients with benign fasciculations and no other known cause for neuropathy. RESULTS: Nine of the 11 patients (82%) had significantly reduced epidermal or sweat gland nerve fiber densities at the calf or thigh, in comparison with control values. CONCLUSIONS: The presence of reduced epidermal and sweat gland nerve fiber density indicates the presence of axonal loss in patients with benign fasciculations.

Prolongation of the tibialis anterior CMAP duration in chronic inflammatory demyelinating polyneuropathy.

OBJECTIVE: To assess the duration of the distal compound muscle action potential (dCMAP) recording from the tibialis anterior (TA) as a supportive electrodiagnostic feature in chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: We performed peroneal motor conduction studies with recording from the TA in 35 CIDP patients, 30 normal controls, and 21 disease controls. The normal cut-off for the TA dCMAP duration was determined to be 14 ms. RESULTS: Prolonged TA dCMAP durations were detected in 34% of CIDP patients (12/35) and in 33% (2/6) of patients in whom only one demyelinating lesion was identified by conventional motor conduction studies. Prolonged TA dCMAP durations were present in 28% (5/18) of patients with normal duration dCMAPs recorded from the abductor hallucis (AH) and in 42% (5/12) of patients with normal duration dCMAPs recorded from the extensor digitorum brevis (EDB). In patients with AH or EDB dCMAP amplitudes <1 mV, TA dCMAP durations were prolonged in 28% and 23% of patients, respectively. CONCLUSIONS: Determination of TA dCMAP duration appears to be useful for detecting demyelination in CIDP, especially when there is significant coexisting axon loss. SIGNIFICANCE: In patients with potential CIDP and limited electrodiagnostic abnormalities by routine studies, the finding of additional demyelinating findings, such as increased TA dCMAP duration, could allow for improved diagnostic sensitivity.

Differential gene expression in chronic inflammatory demyelinating polyneuropathy (CIDP) skin biopsies.

Gene expression analysis previously identified molecular markers that are up-regulated in sural nerve biopsies from patients with chronic inflammatory demyelinating polyneuropathy (CIDP). To determine whether the same or additional genes are also up-regulated in skin, we applied gene microarray profiling and quantitative real-time PCR (qPCR) analysis to skin punch biopsies from patients with CIDP and controls. Five genes, allograft inflammatory factor 1 (AIF-1), lymphatic hyaluronan receptor (LYVE-1/XLKD1), FYN binding protein (FYB), P2RY1 (purinergic receptor P2Y, G-protein-coupled, 1), and MLLT3 (myeloid/lymphoid or mixed-lineage leukemia translocated to, 3), all associated with immune cells or inflammatory processes, were elevated in punch skin biopsies from patients with CIDP as compared to normal subjects or patients with Charcot-Marie-Tooth Type 1 (CMT1). The average fold change of the 5 genes over normal expression, as determined by qPCR, was significantly elevated in skin biopsies from patients with CIDP in comparison to CMT1 or diabetic neuropathy, and similar to that seen in Lyme disease. The findings indicate the presence of inflammatory changes in the skin of patients with CIDP.

Demyelinating neuropathy in patients with hepatitis C virus infection.

Infection with hepatitis C virus (HCV) can be associated with demyelinating polyneuropathy that may be responsive to immunomodulatory therapy. In this case report series, we review four patients (all male, ages 47-60 years) with HCV and demyelinating polyneuropathy. Two of the four patients were diagnosed with HCV during the course of initial neuropathy evaluation. All patients had sensory loss, absent/diminished reflexes, lower extremity weakness (except for one patient), and demyelinating electrodiagnostic features. Three patients had polyclonal hypergammaglobulinemia and one patient had IgM monoclonal gammopathy. Intravenous immunoglobulin resulted in improvement in three patients; one patient had no benefit from rituximab therapy, but his symptoms have been stable. Demyelinating neuropathy may develop in patients with HCV unrelated to antiviral therapy. Immunomodulatory therapy may be beneficial in some cases. Testing for HCV should be considered, especially in patients with hypergammaglobulinemia or IgM monoclonal gammopathy.