Electrodiagnostic subtyping in Guillain-Barré syndrome patients in the International Guillain-Barré Outcome Study.

BACKGROUND AND PURPOSE: Various electrodiagnostic criteria have been developed in Guillain-Barré syndrome (GBS). Their performance in a broad representation of GBS patients has not been evaluated. Motor conduction data from the International GBS Outcome Study (IGOS) cohort were used to compare two widely used criterion sets and relate these to diagnostic amyotrophic lateral sclerosis criteria. METHODS: From the first 1500 patients in IGOS, nerve conduction studies from 1137 (75.8%) were available for the current study. These patients were classified according to nerve conduction studies criteria proposed by Hadden and Rajabally. RESULTS: Of the 1137 studies, 68.3% (N = 777) were classified identically according to criteria by Hadden and Rajabally: 111 (9.8%) axonal, 366 (32.2%) demyelinating, 195 (17.2%) equivocal, 35 (3.1%) inexcitable and 70 (6.2%) normal. Thus, 360 studies (31.7%) were classified differently. The areas of differences were as follows: 155 studies (13.6%) classified as demyelinating by Hadden and axonal by Rajabally; 122 studies (10.7%) classified as demyelinating by Hadden and equivocal by Rajabally; and 75 studies (6.6%) classified as equivocal by Hadden and axonal by Rajabally. Due to more strictly defined cutoffs fewer patients fulfilled demyelinating criteria by Rajabally than by Hadden, making more patients eligible for axonal or equivocal classification by Rajabally. In 234 (68.6%) axonal studies by Rajabally the revised El Escorial (amyotrophic lateral sclerosis) criteria were fulfilled; in axonal cases by Hadden this was 1.8%. CONCLUSIONS AND DISCUSSION: This study shows that electrodiagnosis in GBS is dependent on the criterion set utilized, both of which are based on expert opinion. Reappraisal of electrodiagnostic subtyping in GBS is warranted.

Anti-MAG neuropathy: historical aspects, clinical-pathological correlations, and considerations for future therapeutical trials.

BACKGROUND: Patients with anti-MAG neuropathy present with distal demyelinating polyneuropathy, IgM monoclonal gammopathy, and elevated titers of anti-MAG antibodies. OBJECTIVE: This paper reviews what is known about the clinical presentation, course, pathophysiology, and treatment of anti-MAG neuropathy, with considerations for the design of therapeutic trials. METHODS: A literature review of the medical and scientific literature related to anti-MAG neuropathy, and the design of therapeutic clinical trials in peripheral neuropathy. RESULTS: Anti-MAG neuropathy can remain indolent for many years but then enter a progressive phase. Highly elevated antibody titers are diagnostic, but intermediate titers can also occur in chronic inflammatory demyelinating polyneuropathy (CIDP). The peripheral nerves can become inexcitable, thereby masking the demyelinating abnormalities. There is good evidence that the anti-MAG antibodies cause neuropathy. Reduction of the autoantibody concentration by agents that target B-cells was reported to result in clinical improvement in case series and uncontrolled trials, but not in controlled clinical trials, probably due to inadequate trial design. CONCLUSION: We propose that therapeutic trials for anti-MAG neuropathy include patients with the typical presentation, some degree of weakness, highly elevated anti-MAG antibody titers, and at least one nerve exhibiting demyelinating range abnormalities. Treatment with one or a combination of anti-B-cell agents would aim at reducing the autoantibody concentration by at least 60%. A trial duration of 2 years may be required to show efficacy. The neuropathy impairment score of the lower extremities (NIS-LL) plus the Lower Limb Function (LLF) score would be a suitable primary outcome measure.

ANTECEDENTES: Pacientes com neuropatia anti-MAG apresentam polineuropatia desmielinizante distal, gamopatia monoclonal IgM e títulos elevados de anticorpos anti-MAG. OBJETIVO: Este artigo revisa o que se sabe sobre a apresentação clínica, curso, fisiopatologia e tratamento da neuropatia anti-MAG, com considerações para o desenho de ensaios terapêuticos. MéTODOS: Revisão bibliográfica da literatura médica e científica relacionada à neuropatia anti-MAG e desenho de ensaios clínicos terapêuticos em neuropatia periférica. RESULTADOS: A neuropatia anti-MAG pode permanecer indolente durante muitos anos, mas depois entra numa fase progressiva. Títulos de anticorpos altamente elevados são diagnósticos, mas títulos intermediários também podem ocorrer na polineuropatia desmielinizante inflamatória crônica (CIDP). Os nervos periféricos podem tornar-se inexcitáveis, mascarando, assim, as anomalias desmielinizantes. Há boas evidências de que os anticorpos anti-MAG causam a neuropatia. Foi relatado que a redução da concentração de autoanticorpos por agentes direcionados às células B resultou em melhora clínica em séries de casos e ensaios não controlados, mas não em ensaios clínicos controlados, provavelmente devido ao desenho inadequado dos ensaios. CONCLUSãO: Propomos que os ensaios terapêuticos para neuropatia anti-MAG incluam pacientes com apresentação típica, algum grau de fraqueza, títulos de anticorpos anti-MAG altamente elevados e pelo menos um nervo exibindo anormalidades na faixa desmielinizante. O tratamento com um ou uma combinação de agentes anticélulas B teria como objetivo reduzir a concentração de autoanticorpos em pelo menos 60%. Pode ser necessária uma duração de ensaio de 2 anos para demonstrar eficácia. A pontuação de comprometimento da neuropatia das extremidades inferiores (NIS-LL) mais a pontuação da função dos membros inferiores (LLF) seria uma medida de resultado primário adequada.

Diagnosis and treatment of hereditary transthyretin amyloidosis with polyneuropathy in the United States: Recommendations from a panel of experts.

Hereditary transthyretin (ATTRv; v for variant) amyloidosis is a rare, multisystem, progressive, and fatal disease in which polyneuropathy is a cardinal manifestation. Due to a lack of United States (US)-specific guidance on ATTRv amyloidosis with polyneuropathy, a panel of US-based expert clinicians convened to address identification, monitoring, and treatment of this disease. ATTRv amyloidosis with polyneuropathy should be suspected in unexplained progressive neuropathy, especially if associated with systemic symptoms or family history. The diagnosis is confirmed through genetic testing, biopsy, or cardiac technetium-based scintigraphy. Treatment should be initiated as soon as possible after diagnosis, with gene-silencing therapeutics recommended as a first-line option. Consensus is lacking on what represents "disease progression" during treatment; however, the aggressive natural history of this disease should be considered when evaluating the effectiveness of any therapy.

Acute/chronic inflammatory polyradiculoneuropathy.

Autoimmune neuropathy may present acutely or with a more progressive and/or relapsing and remitting course. Acute inflammatory neuropathy or Guillain-Barré syndrome (GBS) has variable presentations but by far the most common is acute inflammatory demyelinating polyradiculoneuropathy which is characterized by rapidly progressive proximal and distal symmetric weakness, sensory loss, and depressed reflexes. The most common chronic autoimmune neuropathy is chronic inflammatory demyelinating polyradiculoneuropathy, which in its most typical form is clinically similar to acute inflammatory demyelinating polyradiculoneuropathy (proximal and distal symmetric weakness, sensory loss, and depressed reflexes) but differs in that onset is much more gradual, i.e., over at least 8 weeks. While the majority of GBS cases result from a postinfectious activation of the immune system, presumably in a genetically susceptible host, less is understood regarding the etiopathogenesis of chronic inflammatory demyelinating polyradiculoneuropathy. Both acute and chronic forms of these inflammatory neuropathies are driven by some combination of innate and adaptive immune pathways, with differing contributions depending on the neuropathy subtype. Both disorders are largely clinical diagnoses, but diagnostic tools are available to confirm the diagnosis, prognosticate, detect variant forms, and rule out mimics. Given the autoimmune underpinnings of both disorders, immunosuppressive and immunomodulating treatments are typically given in both diseases; however, they differ in their response to treatment.

Updated consensus statement: Intravenous immunoglobulin in the treatment of neuromuscular disorders report of the AANEM ad hoc committee.

Intravenous immune globulin (IVIG) is an immune-modulating biologic therapy that is increasingly being used in neuromuscular disorders despite the paucity of high-quality evidence for various specific diseases. To address this, the AANEM created the 2009 consensus statement to provide guidance on the use of IVIG in neuromuscular disorders. Since then, there have been several randomized controlled trials for IVIG, a new FDA-approved indication for dermatomyositis and a revised classification system for myositis, prompting the AANEM to convene an ad hoc panel to update the existing guidelines.New recommendations based on an updated systemic review of the literature were categorized as Class I-IV. Based on Class I evidence, IVIG is recommended in the treatment of chronic inflammatory demyelinating polyneuropathy, Guillain-Barré Syndrome (GBS) in adults, multifocal motor neuropathy, dermatomyositis, stiff-person syndrome and myasthenia gravis exacerbations but not stable disease. Based on Class II evidence, IVIG is also recommended for Lambert-Eaton myasthenic syndrome and pediatric GBS. In contrast, based on Class I evidence, IVIG is not recommended for inclusion body myositis, post-polio syndrome, IgM paraproteinemic neuropathy and small fiber neuropathy that is idiopathic or associated with tri-sulfated heparin disaccharide or fibroblast growth factor receptor-3 autoantibodies. Although only Class IV evidence exists for IVIG use in necrotizing autoimmune myopathy, it should be considered for anti-hydroxy-3-methyl-glutaryl-coenzyme A reductase myositis given the risk of long-term disability. Insufficient evidence exists for the use of IVIG in Miller-Fisher syndrome, IgG and IgA paraproteinemic neuropathy, autonomic neuropathy, chronic autoimmune neuropathy, polymyositis, idiopathic brachial plexopathy and diabetic lumbosacral radiculoplexopathy.

Hyaluronidase-facilitated subcutaneous immunoglobulin 10% as maintenance therapy for chronic inflammatory demyelinating polyradiculoneuropathy: The ADVANCE-CIDP 1 randomized controlled trial.

BACKGROUND AND AIMS: ADVANCE-CIDP 1 evaluated facilitated subcutaneous immunoglobulin (fSCIG; human immunoglobulin G 10% with recombinant human hyaluronidase) efficacy and safety in preventing chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) relapse. METHODS: ADVANCE-CIDP 1 was a phase 3, double-blind, placebo-controlled trial conducted at 54 sites in 21 countries. Eligible adults had definite or probable CIDP and adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability scores of 0-7 (inclusive), and received stable intravenous immunoglobulin (IVIG) for ≥12 weeks before screening. After stopping IVIG, patients were randomized 1:1 to fSCIG 10% or placebo for 6 months or until relapse/discontinuation. fSCIG 10% was administered at the same dose (or matching placebo volume) and interval as pre-randomization IVIG. The primary outcome was patient proportion experiencing CIDP relapse (≥1-point increase in adjusted INCAT score from pre-subcutaneous treatment baseline) in the modified intention-to-treat population. Secondary outcomes included time to relapse and safety endpoints. RESULTS: Overall, 132 patients (mean age 54.4 years, 56.1% male) received fSCIG 10% (n = 62) or placebo (n = 70). CIDP relapse was reduced with fSCIG 10% versus placebo (n = 6 [9.7%; 95% confidence interval 4.5%, 19.6%] vs n = 22 [31.4%; 21.8%, 43.0%], respectively; absolute difference: -21.8% [-34.5%, -7.9%], p = .0045). Relapse probability was higher with placebo versus fSCIG 10% over time (p = .002). Adverse events (AEs) were more frequent with fSCIG 10% (79.0% of patients) than placebo (57.1%), but severe (1.6% vs 8.6%) and serious AEs (3.2% vs 7.1%) were less common. INTERPRETATION: fSCIG 10% more effectively prevented CIDP relapse than placebo, supporting its potential use as maintenance CIDP treatment.

Leptomeningeal Disease Secondary to Thr60Ala Transthyretin Amyloidosis: Case Report and Review of the Literature.

A 31-year-old woman with transthyretin (TTR) amyloidosis secondary to a Thr60Ala mutation developed recurrent stroke-like episodes with fluctuating mental status. Evaluation for stroke and seizures was unrevealing. She was found to have leptomeningeal contrast enhancement on magnetic resonance imaging, which was confirmed to be CNS TTR amyloidosis on histopathology following brain and dura biopsy. While leptomeningeal disease has rarely been known to be associated with TTR amyloidosis, this is the first documented case of leptomeningeal disease secondary to a Thr60Ala mutation in the TTR gene. A literature review of TTR amyloidosis is presented with special focus on the treatment of leptomeningeal TTR amyloidosis.

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.

Liver-directed drugs for transthyretin-mediated amyloidosis.

Transthyretin-mediated amyloidosis (ATTR) is a rare, under-recognized, progressively debilitating, fatal disease caused by the aggregation and extracellular deposition of amyloid transthyretin (TTR) fibrils in multiple organs and tissues throughout the body. TTR is predominantly synthesized by the liver and normally circulates as a homotetramer, while misfolded monomers aggregate to form amyloid fibrils. One strategy to treat ATTR amyloidosis is to reduce the amount of TTR produced by the liver using drugs that directly target the TTR mRNA or gene. This narrative review focuses on how TTR gene silencing tools act to reduce TTR production, describing strategies for improved targeted delivery of these agents to hepatocytes where TTR is preferentially expressed. Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), termed RNA silencers, cause selective degradation of TTR mRNA, while a TTR gene editing tool reduces TTR expression by introducing nonsense mutations into the TTR gene. Two strategies to facilitate tissue-specific delivery of these nucleic acid-based drugs employ endogenous receptors expressed by hepatocytes. Lipid nanoparticles (LNPs) that recruit apolipoprotein E support low-density lipoprotein receptor-mediated uptake of unconjugated siRNA and are now used for CRISPR gene editing tools. Additionally, conjugating N-acetylgalactosamine (GalNAc) moieties to ASOs or siRNAs facilitates receptor-mediated uptake by the asialoglycoprotein receptor. In summary, ATTR is a progressive disease with various clinical manifestations due to TTR aggregation, deposition, and amyloid formation. Receptor-targeted ligands (eg, GalNAc) and nanoparticle encapsulation (eg, LNPs) are technologies to deliver ASOs, siRNAs, and gene editing tools to hepatocytes, the primary location of TTR synthesis.

Long-term efficacy and safety of inotersen for hereditary transthyretin amyloidosis: NEURO-TTR open-label extension 3-year update.

BACKGROUND: Hereditary transthyretin amyloidosis (hATTR/ATTRv) results from the deposition of misfolded transthyretin (TTR) throughout the body, including peripheral nerves. Inotersen, an antisense oligonucleotide inhibitor of hepatic TTR production, demonstrated a favorable efficacy and safety profile in patients with the polyneuropathy associated with hATTR in the NEURO-TTR (NCT01737398) study. We report longer-term efficacy and safety data for inotersen, with a median treatment exposure of 3 years. METHODS: Patients who satisfactorily completed NEURO-TTR were enrolled in its open-label extension (OLE) study. Efficacy assessments included the modified Neuropathy Impairment Score + 7 (mNIS + 7), Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) questionnaire total score, and the Short Form 36 (SF-36v2) Health Survey Physical Component Summary score. Safety and tolerability were also assessed. Efficacy is reported for patients living in Europe and North America (this cohort completed the study approximately 9 months before the remaining group of patients outside these regions); safety is reported for the full safety dataset, comprising patients living in Europe, North America, and Latin America/Australasia. This study is registered with ClinicalTrials.gov, identifier NCT02175004. RESULTS: In the Europe and North America cohort of the NEURO-TTR study, 113/141 patients (80.1%) completed the study, and 109 patients participated in the OLE study. A total of 70 patients continued to receive inotersen (inotersen-inotersen) and 39 switched from placebo to inotersen (placebo-inotersen). The placebo-inotersen group demonstrated sustained improvement in neurological disease progression as measured by mNIS + 7, compared with predicted worsening based on projection of the NEURO-TTR placebo data (estimated natural history). The inotersen-inotersen group demonstrated sustained benefit, as measured by mNIS + 7, Norfolk QoL-DN, and SF-36v2, compared with estimated natural history as well as compared with the placebo-inotersen group. With a maximum exposure of 6.2 years, inotersen was not associated with any additional safety concerns or increased toxicity in the OLE study. Platelet and renal monitoring were effective in reducing the risk of severe adverse events in the OLE study. CONCLUSION: Inotersen treatment for > 3 years slowed progression of the polyneuropathy associated with hATTR, and no new safety signals were observed.

Randomized Phase 2 Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease.

OBJECTIVE: To determine whether locally acting ACE-083 is safe, well tolerated, and increases muscle volume, motor function, and quality of life (QoL) in adults with Charcot-Marie-Tooth disease (CMT) type 1. METHODS: This phase 2 study enrolled adults with CMT1 or CMTX (N=63). Part 1 was open-label and evaluated safety and tolerability of different dose levels of ACE-083 for use in Part 2. Part 2 was a randomized, placebo-controlled, 6-month study of 240 mg/muscle ACE-083 injected bilaterally in the tibialis anterior muscle, followed by a 6-month, open-label extension in which all patients received ACE-083. Pharmacodynamic endpoints included total muscle volume (TMV; primary endpoint), contractile muscle volume (CMV), and fat fraction. Additional secondary endpoints included 6-minute walk test, 10-meter walk/run, muscle strength, and QoL. Safety was assessed with treatment-emergent adverse events (TEAEs) and clinical laboratory tests. RESULTS: In Part 1 (n=18), ACE-083 was generally safe and well tolerated at all dose levels, with no serious AEs, TEAEs ≥Grade 3, or death reported. In Part 2 (n=45 enrolled, n=44 treated), there was significantly greater change in TMV with ACE-083 compared with placebo (LS mean difference: 13.5%; p = 0.0096). There was significant difference between ACE-083 and placebo for CMV and change in ankle dorsiflexion strength. Fat fraction and all other functional outcomes were not significantly improved by ACE-083. Moderate-to-mild injection-site reactions were the most common TEAEs. CONCLUSIONS: Despite significantly increased TMV and CMV, patients with CMT receiving ACE-083 in tibialis anterior muscles did not demonstrate greater functional improvement compared with those receiving placebo. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that intramuscular ACE-083 is safe, well tolerated, and increases total muscle volume after 6 months of treatment in adults with CMT1 or CMTX.

Electrodiagnosis of Guillain-Barre syndrome in the International GBS Outcome Study: Differences in methods and reference values.

OBJECTIVE: To describe the heterogeneity of electrodiagnostic (EDx) studies in Guillain-Barré syndrome (GBS) patients collected as part of the International GBS Outcome Study (IGOS). METHODS: Prospectively collected clinical and EDx data were available in 957 IGOS patients from 115 centers. Only the first EDx study was included in the current analysis. RESULTS: Median timing of the EDx study was 7 days (interquartile range 4-11) from symptom onset. Methodology varied between centers, countries and regions. Reference values from the responding 103 centers were derived locally in 49%, from publications in 37% and from a combination of these in the remaining 15%. Amplitude measurement in the EDx studies (baseline-to-peak or peak-to-peak) differed from the way this was done in the reference values, in 22% of motor and 39% of sensory conduction. There was marked variability in both motor and sensory reference values, although only a few outliers accounted for this. CONCLUSIONS: Our study showed extensive variation in the clinical practice of EDx in GBS patients among IGOS centers across the regions. SIGNIFICANCE: Besides EDx variation in GBS patients participating in IGOS, this diversity is likely to be present in other neuromuscular disorders and centers. This underlines the need for standardization of EDx in future multinational GBS studies.

Surveillance for disease progression of transthyretin amyloidosis after heart transplantation in the era of novel disease modifying therapies.

BACKGROUND: Heart Transplantation (HT) is a rational therapy for advanced transthyretin cardiac amyloidosis (ATTR-CA), but the impact of ongoing amyloid deposition is not well defined. We evaluated a cohort of patients who underwent HT for ATTR-CA to determine the incidence of de novo or progression of post-HT ATTR deposition. METHODS: All patients who were followed post-HT for ATTR-CA at our center were included. Baseline demographics and post-HT manifestations of TTR deposition were collected. All patients completed the Composite Autonomic Symptom Score (COMPASS-31 quantifies autonomic symptoms, with a higher score [0-100] indicating more severe autonomic dysfunction) and Polyneuropathy Disability Score (PND, range from 0 [asymptomatic] to IV [confined to wheelchair/bed]) questionnaires. RESULTS: Twelve patients (5 wild-type, 7 variant [6 p.Val142Ile, 1 p.Thr80Ala]) were included. Mean age at HT was 64.6 (SD: 4.8) years, 83.3% male, and 50% Black. At a median of 4.0 years (IQR 2.4, 5.9) post-HT, 8 patients had symptoms of ATTR deposition (5 with gastrointestinal involvement, 4 orthopedic and 4 neurologic), with 4 patients having ≥2 body systems involved. There were no patients with recurrent cardiac involvement. Median COMPASS-31 score was 17.3 (IQR 11.3, 23.5) at 3.9 years (IQR 2.4, 5.9) post-HT. Four patients had a PND score of stage 1 (sensory disturbance), 1 patient was stage 2 (impaired walking) and 1 patient stage 3b (required a walking aid). CONCLUSIONS: More than 50% of patients had evidence of progressive or de novo ATTR deposition post-HT, impairing quality of life despite a well-functioning cardiac allograft. These observations highlight an unmet need to establish the role of formal surveillance and treatment of TTR using TTR disease-modifying therapies, which may maintain or improve quality of life post-HT for ATTR-CA.

A double-blind, placebo-controlled, randomized trial of PXT3003 for the treatment of Charcot-Marie-Tooth type 1A.

BACKGROUND: Charcot-Marie-Tooth disease type 1A (CMT1A) is a rare, orphan, hereditary neuromuscular disorder with no cure and for which only symptomatic treatment is currently available. A previous phase 2 trial has shown preliminary evidence of efficacy for PXT3003 in treating CMT1A. This phase 3, international, randomized, double-blind, placebo-controlled study further investigated the efficacy and safety of high- or low-dose PXT3003 (baclofen/naltrexone/D-sorbitol [mg]: 6/0.70/210 or 3/0.35/105) in treating subjects with mild to moderate CMT1A. METHODS: In this study, 323 subjects with mild-to-moderate CMT1A were randomly assigned in a 1:1:1 ratio to receive 5 mL of high- or low-dose PXT3003, or placebo, orally twice daily for up to 15 months. Efficacy was assessed using the change in Overall Neuropathy Limitations Scale total score from baseline to months 12 and 15 (primary endpoint). Secondary endpoints included the 10-m walk test and other assessments. The high-dose group was discontinued early due to unexpected crystal formation in the high-dose formulation, which resulted in an unanticipated high discontinuation rate, overall and especially in the high-dose group. The statistical analysis plan was adapted to account for the large amount of missing data before database lock, and a modified full analysis set was used in the main analyses. Two sensitivity analyses were performed to check the interpretation based on the use of the modified full analysis set. RESULTS: High-dose PXT3003 demonstrated significant improvement in the Overall Neuropathy Limitations Scale total score vs placebo (mean difference: - 0.37 points; 97.5% CI [- 0.68 to - 0.06]; p = 0.008), and consistent treatment effects were shown in the sensitivity analyses. Both PXT3003 doses were safe and well-tolerated. CONCLUSION: The high-dose group demonstrated a statistically significant improvement in the primary endpoint and a good safety profile. Overall, high-dose PXT3003 is a promising treatment option for patients with Charcot-Marie-Tooth disease type 1A.

Neurologic Safety Monitoring of COVID-19 Vaccines: Lessons From the Past to Inform the Present.

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered a global effort to rapidly develop and deploy effective and safe coronavirus disease 2019 (COVID-19) vaccinations. Vaccination has been one of the most effective medical interventions in human history, although potential safety risks of novel vaccines must be monitored, identified, and quantified. Adverse events must be carefully assessed to define whether they are causally associated with vaccination or coincidence. Neurologic adverse events following immunizations are overall rare but with significant morbidity and mortality when they occur. Here, we review neurologic conditions seen in the context of prior vaccinations and the current data to date on select COVID-19 vaccines including mRNA vaccines and the adenovirus-vector COVID-19 vaccines, ChAdOx1 nCOV-19 (AstraZeneca) and Ad26.COV2.S Johnson & Johnson (Janssen/J&J).

Mononeuropathy Multiplex After COVID-19.

OBJECTIVES: COVID-19 is a novel coronavirus that emerged in 2019 and is responsible for a global pandemic. Numerous neurologic manifestations have been described in the literature regarding COVID-19, but most studies are focused on the central nervous system. The authors have noted an association between prior COVID-19 infection and the development of a systemic neuropathy that manifests with asymmetric sensorimotor loss in the peripheral nervous system. We describe 4 cases of mononeuropathy multiplex that were diagnosed after COVID-19 infection. METHODS: All patients included were treated for severe COVID-19 infection at New York Presbyterian Hospital and subsequently referred to the Columbia Peripheral Neuropathy Center for persistent neuropathy. RESULTS: Patient history, COVID-19 disease course, and mononeuropathy multiplex diagnostic evaluation of the 4 patients are recounted. CONCLUSIONS: We postulate a connection between COVID-19 and the development of mononeuropathy multiplex with implications in prognostication, rehabilitation strategies, and future treatments.