Sasha Zivkovic's research while affiliated with Yale University and other places

Hereditary neuropathies are typically associated with an early onset of symptoms, but same types of neuropathies may also manifest late, after the age 50 years. A 62-year-old African American woman presented with a 6-year history of gait unsteadiness and has been using a walker since the age 57 years after an unwitnessed fall. Gradual worsening of walking difficulties was later followed by decreased dexterity. The family history was negative for neuromuscular disorders, including neuropathy. On examination, the patient had both distal and proximal weakness with distal sensory loss to all modalities and hyporeflexia. Charcot Marie Tooth Examination Score was 12. Previous electrodiagnostic testing at the age 60 years showed severe sensorimotor demyelinating polyneuropathy with bilateral severe carpal tunnel syndrome. Genetic testing showed a homozygous pathogenic mutation in SH3TC2 gene (c.2860C>T; p.Arg954*), associated with CMT4C. CMT4C is the most common recessive demyelinating sensorimotor polyneuropathy and overall comprises 0.4%–1.7% of all patients with Charcot–Marie–Tooth disease. It is more common in French Canadians and Spanish Roma and in recent natural history study; only 1 of 56 patients was African American. This report demonstrates sporadic occurrence of CMT4C in other ethnic groups as well.

Transthyretin amyloidosis (ATTR) is a condition defined by accumulation of insoluble transthyretin amyloid deposits in multiple organs, especially in the peripheral nerve and heart muscle. ATTR may result from transthyretin mutations (variant ATTR or ATTRv) or may occur with normal transthyretin genotype (wild type ATTR or ATTRwt). ATTRwt was previously known as “senile amyloidosis” and causes cardiomyopathy which may lead to heart failure with a preserved ejection fraction, affecting predominantly elderly men. The exact prevalence of ATTRwt in the general population remains unclear, but its occurrence may be underestimated in women. It was observed that a proportion of ATTRwt cardiomyopathy patients may develop slowly progressing neuropathy that is milder and indolent in comparison with typical progressive neuropathy associated with ATTRv. Furthermore, the causality of neuropathy is often uncertain in patients with ATTRwt. Neuropathy symptoms, including distal sensory loss, unsteadiness and (neuropathic) pain are common in elderly patients with multiple potential causes, and as ATTRwt patients are typically older, relatively high prevalence of peripheral neuropathy is expected with frequent comorbidities. Relatively high prevalence of ATTRwt in elderly population contrasts few documented cases of neuropathy caused by ATTRwt, and there is uncertainty whether ATTRwt neuropathy is an infrequent occurrence or a significant manifestation of multisystemic ATTRwt. We review neurologic and musculoskeletal manifestations of ATTRwt and present clinical features of a single center cohort of ATTRwt patients with suspected peripheral neuropathy.

Purpose of Review The purpose of this review is to summarize currently available and developing diagnostic and treatment options for hereditary transthyretin amyloid polyneuropathy. Transthyretin amyloidosis (ATTR) predominantly manifests with cardiomyopathy and/or peripheral neuropathy, but amyloid deposits may be found in other organs or tissues. Recent Findings Currently available treatments include transthyretin gene silencers (for hereditary ATTR peripheral neuropathy only) and transthyretin stabilizers (tafamidis for ATTR cardiomyopathy in the USA, and for both hereditary ATTR peripheral neuropathy and ATTR cardiomyopathy in Europe, Japan, Brazil, and some other countries), and liver transplantation. Gene silencers stop the progression of hereditary ATTR peripheral neuropathy in most patients, and transthyretin stabilizers reduce hospitalizations and mortality in patients with ATTR cardiomyopathy. The use of liver transplantation for ATTR has declined with the availability of more effective therapies, and shortage of available allografts. On the horizon are new treatments already in clinical trials including new gene silencers and gene editing agents, new transthyretin stabilizers, and amyloid removal treatments. Summary Recently approved treatments for ATTR have changed its natural history, and additional medications may get approved in the near future. Early diagnosis is still essential to improve treatment outcomes. New management strategies may include combinations of gene silencers, transthyretin stabilizers, gene editing, and amyloid removal agents, but the cost may become the limiting factor.

Objective: To investigate cerebrospinal fluid findings in relation to clinical and electrodiagnostic subtypes, severity, and outcome of Guillain-Barré syndrome based on 1500 patients in the International GBS Outcome Study. Methods: Albuminocytological dissociation was defined as an increased protein level (>0.45 g/L) in absence of elevated white cell count (<50 cells/µL). We excluded 124 (8%) patients due to other diagnoses, protocol violation or insufficient data. CSF was examined in 1231 patients (89%). Results: In 846 (70%) patients CSF examination showed albuminocytological dissociation, which increased with time from weakness onset: ≤4 days 57%, >4 days 84%. High CSF protein levels were associated with a demyelinating subtype, proximal or global muscle weakness and a reduced likelihood of being able to run at week 2 (OR: 0.42 (95% CI 0.25-0.70; p = 0.001) and week 4 (OR: 0.44 (95% CI 0.27-0.72; p = 0.001). Patients with the Miller Fisher syndrome, distal predominant weakness and normal or equivocal nerve conduction studies were more likely to have lower CSF protein levels. CSF cell count was <5 cells/µL in 1005 patients (83%), 5-49 cells/µL in 200 patients (16%) and ≥50 cells/µL in 13 patients (1%). Interpretation: Albuminocytological dissociation is a common finding in Guillain-Barré syndrome, but normal protein levels do not exclude this diagnosis. High CSF protein level is associated with an early severe disease course and a demyelinating subtype. Elevated CSF cell count, rarely ≥50 cells/µL, is compatible with GBS after thorough exclusion of alternative diagnoses. Classification of evidence: This study provides Class IV evidence that CSF albuminocytologic dissociation (defined by the Brighton Collaboration) is common in patients with GBS.

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.

The clinical course of neuromuscular disorders (NMDs) can be affected by infections, both in immunocompetent individuals, and in those with reduced immunocompetence due to immunosuppressive/immunomodulating therapies. Infections and immunizations may also trigger NMDs. There is a potential for reduced efficacy of immunizations in patients with reduced immunocompetence. The recent vaccination program for Coronavirus Disease‐ 2019 (COVID‐19) raises several questions regarding the safety and efficacy of this vaccine in individuals with NMDs. In this Practice Statement, we address the role of vaccine‐preventable infections in NMDs and the safety and efficacy of immunization in individuals with NMDs, with emphasis on vaccination against COVID‐19.

Objective To collect preliminary data on the effects of mexiletine on cortical and axonal hyperexcitability in sporadic amyotrophic lateral sclerosis (ALS) in a phase 2 double‐blind randomized controlled trial. Methods Twenty ALS subjects were randomized to placebo and mexiletine 300 mg or 600 mg daily for 4 weeks and assessed by transcranial magnetic stimulation and axonal excitability studies. The primary endpoint was change in resting motor threshold (RMT). Results RMT was unchanged with 4 weeks of mexiletine (combined active therapies) as compared to placebo, which showed a significant increase (p=0.039). Reductions of motor evoked potential (MEP) amplitude (p=0.013) and accommodation half‐time (p=0.002), secondary outcome measures of cortical and axonal excitability, respectively, were also evident at 4 weeks on mexiletine. Conclusions The relative stabilization of RMT in the treated subjects was unexpected and could be attributed to unaccounted sources of error or chance. However, a possible alternative cause is neuromodulation preventing an increase. The change in MEP amplitude and accommodation half‐time supports the reduction of cortical and axonal hyperexcitability with mexiletine. This article is protected by copyright. All rights reserved.