Persistent post-COVID-19 neuromuscular symptoms.

Neuromuscular symptoms may develop or persist after resolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Besides residual sensorimotor symptoms associated with acute neuromuscular complications of coronavirus disease-2019 (COVID-19), such as Guillain-Barré syndrome, critical illness neuromyopathy, and rhabdomyolysis, patients may report persistent autonomic symptoms, sensory symptoms, and muscle symptoms in the absence of these acute complications, including palpitations, orthostatic dizziness and intolerance, paresthesia, myalgia, and fatigue. These symptoms may be associated with long COVID, also known as post-COVID-19 conditions or postacute sequelae of SARS-CoV-2 infection, which may significantly impact quality of life. Managing these symptoms represents a challenge for health-care providers. Recent advances have identified small-fiber neuropathy as a potential etiology that may underlie autonomic dysfunction and paresthesia in some long COVID patients. The pathogenic mechanisms underlying myalgia and fatigue remain elusive and need to be investigated. Herein we review the current state of knowledge regarding the evaluation and management of patients with persistent post-COVID-19 neuromuscular symptoms.

Small fiber neuropathy associated with SARS-CoV-2 infection.

INTRODUCTION/AIMS: The development and persistence of neurological symptoms following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is referred to as "long-haul" syndrome. We aimed to determine whether small fiber neuropathy (SFN) was associated with SARS-CoV-2 infection. METHODS: We retrospectively studied the clinical features and outcomes of patients who were referred to us between May 2020 and May 2021 for painful paresthesia and numbness that developed during or after SARS-CoV-2 infection and who had nerve conduction studies showing no evidence of a large fiber polyneuropathy. RESULTS: We identified 13 patients, Eight women and five men with age ranging from 38-67 y. Follow-up duration ranged from 8 to 12 mo. All patients developed new-onset paresthesias within 2 mo following SARS-CoV-2 infection, with an acute onset in seven and co-existing autonomic symptoms in seven. Three patients had pre-existing but controlled neuropathy risk factors. Skin biopsy confirmed SFN in six, all of whom showed both neuropathy symptoms and signs, and two also showed autonomic dysfunction by autonomic function testing (AFT). Of the remaining seven patients who had normal skin biopsies, six showed no clinical neuropathy signs and one exhibited signs and had abnormal AFT. Two patients with markedly reduced intraepidermal nerve fiber densities and one with normal skin biopsy had severe and moderate coronavirus disease 2019 (COVID-19); the remainder experienced mild COVID-19 symptoms. Nine patients received symptomatic neuropathy treatment with paresthesias controlled in seven (77.8%). DISCUSSION: Our findings suggest that symptoms of SFN may develop during or shortly after COVID-19. SFN may underlie the paresthesias associated with long-haul post-COVID-19 symptoms.

MRI negative myelopathy post mild SARS-CoV-2 infection: vasculopathy or inflammatory myelitis?

Since the onset of the COVID-19 pandemic, there have been rare reports of spinal cord pathology diagnosed as inflammatory myelopathy and suspected spinal cord ischemia after SARS-CoV-2 infection. Herein, we report five cases of clinical myelopathy and myeloradiculopathy in the setting of post-COVID-19 disease, which were all radiographically negative. Unlike prior reports which typically characterized hospitalized patients with severe COVID-19 disease and critical illness, these patients typically had asymptomatic or mild-moderate COVID-19 disease and lacked radiologic evidence of structural spinal cord abnormality. This case series highlights that COVID-19 associated myelopathy is not rare, requires a high degree of clinical suspicion as imaging markers may be negative, and raises several possible pathophysiologic mechanisms.

Severe rapidly progressive Guillain-Barré syndrome in the setting of acute COVID-19 disease.

There is concern that the global burden of coronavirus disease of 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection might yield an increased occurrence of Guillain-Barré syndrome (GBS). It is currently unknown whether concomitant SARS-CoV-2 infection and GBS are pathophysiologically related, what biomarkers are useful for diagnosis, and what is the optimal treatment given the medical comorbidities, complications, and simultaneous infection. We report a patient who developed severe GBS following SARS-CoV-2 infection at the peak of the initial COVID-19 surge (April 2020) in New York City and discuss diagnostic and management issues and complications that may warrant special consideration in similar patients.

Diabetic Neuropathy.

Diabetes mellitus is becoming increasingly common worldwide. As this occurs, there will be an increase in the prevalence of known comorbidities from this disorder of glucose metabolism. One of the most disabling adverse comorbidities is diabetic neuropathy. The most common neuropathic manifestation is distal symmetric polyneuropathy, which can lead to sensory disturbances, including diminished protective sense, making patients prone to foot injuries. However, focal, multifocal, and autonomic neuropathies are also common. Diabetic nerve pain and Charcot osteoarthropathy are advanced neuropathic conditions that portend a severe deterioration in quality of life. To combat these symptoms, along with glycemic control and establishment of health care systems to educate and support patients with the complexities of diabetes, there are pharmacologic remedies to ameliorate the neurologic symptoms. Several guidelines and review boards generally recommend the use of tricyclic antidepressants, serotonin/norepinephrine-reuptake inhibitors, α-2-delta ligands, and anticonvulsants as medications to improve painful diabetic neuropathy and quality of life.

Healthcare utilization impacts of an eConsult program for headache at an academic medical center.

INTRODUCTION: Interprofessional consultations ("eConsults") can reduce healthcare utilization. However, the impact of eConsults on healthcare utilization remains poorly characterized among patients with headache. METHODS: We performed a retrospective, 1:1 matched cohort study comparing patients evaluated for headache via eConsult request or in-person referral at the Mount Sinai Health System in New York. Groups were matched on clinical and demographic characteristics. Our primary outcome was one or more outpatient headache-related encounters in 6 months following referral date. Secondary outcomes included one or more all-cause outpatient neurology and headache-related emergency department (ED) encounters during the same period. We used univariable and multivariable logistic regression to model associations between independent variables and outcomes. RESULTS: We identified 74 patients with headache eConsults who were matched to 74 patients with in-person referrals. Patients in the eConsult group were less likely to achieve the primary outcome (29.7% vs 62.2%, P < 0.0001) or have an all-cause outpatient neurology encounter (33.8% vs 79.7%, P < 0.0001) than patients in the comparison group. Both groups did not significantly differ by headache-related ED encounters. In multivariable analyses, patients in the eConsult group had significantly lower odds of having one or more headache-related or all-cause neurology encounters than patients in the comparison group (odds ratio (OR) 0.3, 95% confidence interval (CI) 0.1-0.6; OR 0.1, 95% CI 0.1-0.3, respectively). DISCUSSION: In comparison to in-person referrals, eConsult requests for headache were associated with reduced likelihood of outpatient neurology encounters in the short-term but not with differential use of headache-related ED encounters. Larger-scale, prospective studies should validate our findings and assess patient outcomes.

Acute Cerebellitis and Myeloradiculitis Associated With SARS-CoV-2 Infection in Common Variable Immunodeficiency-A Case Report.

The role of the adaptive immune system in mediating COVID-19 is largely unknown. Therefore, it is difficult to predict the clinical course in patients with common variable immunodeficiency (CVID), a disease characterized by dysfunctional lymphocytes and impaired antibody production. We report a case of SARS-CoV-2 infection presenting as isolated neurological symptoms in a patient with CVID. The patient subsequently improved following steroids, intravenous immunoglobulin, and convalescent plasma (CP). The latter has been shown to be safe and efficacious in treating COVID-19 in patients with primary immunodeficiency. Recent data suggest that the mechanism of CNS injury in COVID-19 may be due to immunological dysregulation rather than direct viral-mediated injury. This case exemplifies the complex interaction between the brain, the immune system, and the SARS-CoV-2 virus.

The electrophysiological effects of cardiac glycosides in human iPSC-derived cardiomyocytes and in guinea pig isolated hearts.

BACKGROUND/AIMS: Monitoring changes in the field potential (FP) of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) following compound administration has been proposed as a novel screening tool to evaluate cardiac ion channel interactions and QT liability. Here we extended the use of FP to evaluate the pharmacological and toxicological properties of cardiac glycosides. METHODS: FPs were recorded using microelectrode arrays (MEAs) in spontaneously beating hiPSC-CMs. The in vitro effects of ouabain and digoxin on FPs were compared with data generated on hemodynamic and ECG parameters in guinea pig Langendorff hearts. RESULTS: In hiPSC-CMs, ouabain and digoxin reduced Na(+)-spike amplitude, shortened FP duration (FPD), increased Ca(2+)-wave amplitude, and dose-dependently induced arrhythmic beats. The ouabain-induced changes observed in hiPSC-CMs correlated well with the effects seen in isolated hearts which revealed QT shortening, enhancement of contractility, and arrhythmogenesis. Nifedipine, an L-type Ca(2+) channel blocker, reduced Ca(2+)-wave amplitude and FPD in hiPSC-CMs, and led to parallel effects of decreased ventricular contractility and shortened QT interval in isolated hearts. Further, nifedipine attenuated the Ca(2+)-peak amplitude and proarrhythmic effect of both glycosides. These results suggested that FPD and Ca(2+)-wave amplitude are comparable surrogates of QT interval and contractility of intact hearts, respectively. CONCLUSION: hiPSC-CMs reflect similar cardiac pharmacology as seen in isolated cardiac preparations and thus are a suitable model in study of the pharmacology and toxicology of cardioactive ion channel and transporter modulators.

Management of Neuropathic Pain in the Geriatric Population.

Neuropathic pain is common in the geriatric population. Diagnosis requires a thorough history and physical examination to differentiate it from other types of pain. Once diagnosed, further workup is required to elucidate the cause, including potential reversible causes of neuropathy. When treating neuropathic pain in the elderly, it is important to consider patients' comorbidities and other medications to avoid drug-drug interactions and iatrogenic effects given the physiologic changes of drug metabolism in the elderly. Nonsystemic therapies and topical medications should be considered. Systemic medications should be started at low dose and titrated up slowly with frequent monitoring for adverse effects.

A critical review of the capsaicin 8% patch for the treatment of neuropathic pain associated with diabetic peripheral neuropathy of the feet in adults.

INTRODUCTION: Diabetes is an increasingly prevalent disorder affecting nearly 1-in-5 adults, of which half will experience diabetic peripheral neuropathy (DPN) and a quarter will suffer from diabetic peripheral nerve pain (DPNP), severely impacting quality of life. The currently approved treatment options are typically centrally acting agents whose use is limited by systemic effects and drug interactions. The capsaicin 8% dermal patch was recently approved by the U.S. FDA for the treatment of DPNP. AREAS COVERED: The authors review the available literature regarding the use of high-concentration capsaicin 8% patch for the treatment of diabetic peripheral neuropathy and neuropathic pain and discuss implementing its use in clinical practice. EXPERT OPINION: The high-concentration capsaicin 8% patch is an effective and well-tolerated treatment option for treating DPNP. Capsaicin 8% patch may be used alone or in combination with other oral therapies and can provide rapid and sustained neuropathic pain relief following a single application and is safe and effective when used long term.

Variant Median Nerve Anatomy: Ultrasound Evidence of a Pseudoconduction Block.

INTRODUCTION: A conduction block at a noncompressible site warrants further investigation. METHODS AND MATERIALS: A 36-year-old woman with a history of Hodgkin lymphoma and chemotherapy-induced polyneuropathy developed bilateral hand numbness and paresthesias. Workup revealed bilateral carpal tunnel syndrome and an apparent superimposed conduction block of the median nerve in the forearm. Given the history of cancer, there was concern for an infiltrative or an immune-mediated process. RESULTS: Neuromuscular ultrasound demonstrated that the median nerve descended the upper extremity along an atypical path, deep along the posteromedial aspect of the upper arm, and relatively medially in the forearm. Ultrasound-directed nerve stimulation revealed there was no conduction block. This anatomical variant has been rarely described and has not been reported previously to mimic conduction block or been documented via ultrasound. CONCLUSIONS: This case demonstrates that neuromuscular ultrasound may supplement the electrodiagnostic study and limit confounding technical factors because of rare anatomic variation.

A Case of Elsberg Syndrome in the Setting of Asymptomatic SARS-CoV-2 Infection.

ABSTRACT: Elsberg syndrome is a rare cause of lumbosacral radiculitis with concomitant thoracic and lumbosacral myelitis that can be seen after an acute or reactivated viral infection. After the initial coronavirus surge in New York City, a 68-year-old man developed progressive lower extremity weakness and a defined sensory level at the lower abdomen. He had highly elevated SARS-CoV-2 IgG antibodies despite an absence of preceding COVID-19 symptoms. Serial electrodiagnostic testing revealed absent lower extremity late responses, with otherwise normal distal sensorimotor conductions. Electromyography revealed active neurogenic changes and reduced motor unit recruitment in the L3-L4 myotomes. Treatment with methylprednisolone and intravenous immunoglobulin was followed by minimal clinical improvement but re-emergence of the lower extremity late responses on electrodiagnostic testing. We report here, to the best of our knowledge, the first case of suspected COVID-19-associated Elsberg syndrome, which expands the spectrum of neuromuscular manifestations associated with SARS-CoV-2 infection and sheds light on ways to approach diagnostic and treatment options for these patients.

Safety of Therapeutic Plasma Exchange for the Treatment of Guillain-Barré Syndrome in Polycythemia Vera.

Polycythemia vera (PV) is a risk factor for systemic thromboses and ischemic stroke. This has been attributed to blood hyperviscosity, the result of increased blood cell production. Intravenous immunoglobulin, which is indicated for the treatment of numerous hematologic and neurological conditions also causes increased serum viscosity and has been associated with ischemic strokes in the setting of PV. Here we report a case of a 70-year-old man with prior stroke and PV who developed Guillain-Barré syndrome, an acute inflammatory demyelinating disorder of peripheral nerves causing ascending paresis, numbness, and paresthesia, who was treated safely with therapeutic plasma exchange. Plasma exchange may be preferable to administration of intravenous immunoglobulin for treatment of various medical conditions in patients with comorbid PV.

Refining the human iPSC-cardiomyocyte arrhythmic risk assessment model.

Human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) are capable of detecting drug-induced clinical arrhythmia, Torsade de Pointes (TdP), and QT prolongation. Efforts herein employ a broad set of structurally diverse drugs to optimize the predictive algorithm for applications in discovery toxicology and cardiac safety screening. The changes in the beat rhythm and rate of a confluent monolayer of hiPS-CMs by 88 marketed and 30 internal discovery compounds were detected with real-time cellular impedance measurement and quantified by measures of arrhythmic beating (IB20, lowest concentration inducing ≥ 20% arrhythmic [irregular, atypical] beats in 3 consecutive 20-s sweeps, and predicted proarrhythmic score [PPS]-IB20) or changes in beat rate (BR20, the lowest concentration inducing a reduction in beat rate of ≥ 20% at 3 consecutive sweeps compared with the time-matched vehicle control group, and PPS-BR20). Drug-induced arrhythmic beats and reductions in beat rates are predictive of clinical arrhythmia and QT prolongation, respectively. A threshold of ≤ 10 µM for class determination results in 82% in vitro-in vivo concordance for TdP prediction and 91% sensitivity for non-TdP arrhythmia detection, or 83% and 91% if clinically efficacious plasma (effective serum therapeutic concentration [C eff]) values are incorporated. This human cardiomyocyte arrhythmic risk (hCAR) model provides greater predictivity for torsadogenicity in humans compared with either human ether-a-go-go-related gene (hERG) inhibition (75%) or QT prolongation (81%). The concordance of beat rate reductions to predict clinical QT prolongation is 86%, or 87% when C eff is considered, which is greater than a hERG signal (80%). Further, arrhythmic beats resulting from cytotoxicity were identified by a distinct arrhythmic beating pattern, which occurred after the onset of cytolethality. This hCAR assay showed increased performance over existing preclinical tools in predicting clinical QT prolongation, arrhythmia, and TdP. Thus, hiPS-CMs are a relevant cell system to improve evaluating cardiac safety liabilities of drug candidates.

The effects of jaspamide on human cardiomyocyte function and cardiac ion channel activity.

Jaspamide (jasplakinolide; NSC-613009) is a cyclodepsipeptide that has antitumor activity. A narrow margin of safety was observed between doses required for efficacy in mouse tumor models and doses that caused severe acute toxicity in rats and dogs. We explored the hypothesis that the observed toxicity was due to cardiotoxicity. Jaspamide was tested in a patch clamp assay to determine its effect on selected cardiac ion channels. Jaspamide (10 µM) inhibited Kv1.5 activity by 98.5%. Jaspamide also inhibited other channels including Cav1.2, Cav3.2, and HCN2; however, the Kv11.1 (hERG) channel was minimally affected. Using spontaneously contracting human cardiomyocytes derived from induced pluripotent stem cells, effects on cardiomyocyte contraction and viability were also examined. Jaspamide (30 nM to 30 µM) decreased cardiomyocyte cell indices and beat amplitude, putative measurements of cell viability and cardiac contractility, respectively. Concentration-dependent increases in rhythmic beating rate were noted at ≤ 6 h of treatment, followed by dose-dependent decreases after 6 and 72 h exposure. The toxic effects of jaspamide were compared with that of the known cardiotoxicant mitoxantrone, and confirmed by multiparameter fluorescence imaging analysis. These results support the hypothesis that the toxicity observed in rats and dogs is due to toxic effects of jaspamide on cardiomyocytes.

Estimating the risk of drug-induced proarrhythmia using human induced pluripotent stem cell-derived cardiomyocytes.

Improved in vitro systems for predicting drug-induced toxicity are needed in the pharmaceutical and biotechnology industries to decrease late-stage drug attrition. One unmet need is an early screen for cardiotoxicity, which accounts for about one third of safety-based withdrawn pharmaceuticals. Herein, the first published report of a high-throughput functional assay employing a monolayer of beating human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) is described, detailing a model that accurately detects drug-induced cardiac abnormalities. Using 96-well plates with interdigitated electrode arrays that assess impedance, the rhythmic, synchronous contractions of the iPSC-CMs were detected. Treatment of the iPSC-CMs with 28 different compounds with known cardiac effects resulted in compound-specific changes in the beat rate and/or the amplitude of the impedance measurement. Changes in impedance for the compounds tested were comparable with the results from a related technology, electric field potential assessment obtained from microelectrode arrays. Using the results from the set of compounds, an index of drug-induced arrhythmias was calculated, enabling the determination of a drug's proarrhythmic potential. This system of interrogating human cardiac function in vitro opens new opportunities for predicting cardiac toxicity and studying cardiac biology.

Long-term impact of radiation on the stem cell and oligodendrocyte precursors in the brain.

BACKGROUND: The cellular basis of long term radiation damage in the brain is not fully understood. METHODS AND FINDINGS: We administered a dose of 25Gy to adult rat brains while shielding the olfactory bulbs. Quantitative analyses were serially performed on different brain regions over 15 months. Our data reveal an immediate and permanent suppression of SVZ proliferation and neurogenesis. The olfactory bulb demonstrates a transient but remarkable SVZ-independent ability for compensation and maintenance of the calretinin interneuron population. The oligodendrocyte compartment exhibits a complex pattern of limited proliferation of NG2 progenitors but steady loss of the oligodendroglial antigen O4. As of nine months post radiation, diffuse demyelination starts in all irradiated brains. Counts of capillary segments and length demonstrate significant loss one day post radiation but swift and persistent recovery of the vasculature up to 15 months post XRT. MRI imaging confirms loss of volume of the corpus callosum and early signs of demyelination at 12 months. Ultrastructural analysis demonstrates progressive degradation of myelin sheaths with axonal preservation. Areas of focal necrosis appear beyond 15 months and are preceded by widespread demyelination. Human white matter specimens obtained post-radiation confirm early loss of oligodendrocyte progenitors and delayed onset of myelin sheath fragmentation with preserved capillaries. CONCLUSIONS: This study demonstrates that long term radiation injury is associated with irreversible damage to the neural stem cell compartment in the rodent SVZ and loss of oligodendrocyte precursor cells in both rodent and human brain. Delayed onset demyelination precedes focal necrosis and is likely due to the loss of oligodendrocyte precursors and the inability of the stem cell compartment to compensate for this loss.