The Neurological Manifestations of Post-Acute Sequelae of SARS-CoV-2 infection.

PURPOSE OF REVIEW: Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global health challenge. This review aims to summarize the incidence, risk factors, possible pathophysiology, and proposed management of neurological manifestations of post-acute sequelae of SARS-CoV-2 infection (PASC) or neuro-PASC based on the published literature. RECENT FINDINGS: The National Institutes of Health has noted that PASC is a multi-organ disorder ranging from mild symptoms to an incapacitating state that can last for weeks or longer following recovery from initial infection with SARS-CoV-2. Various pathophysiological mechanisms have been proposed as the culprit for the development of PASC. These include, but are not limited to, direct or indirect invasion of the virus into the brain, immune dysregulation, hormonal disturbances, elevated cytokine levels due to immune reaction leading to chronic inflammation, direct tissue damage to other organs, and persistent low-grade infection. A multidisciplinary approach for the treatment of neuro-PASC will be required to diagnose and address these symptoms. Tailored rehabilitation and novel cognitive therapy protocols are as important as pharmacological treatments to treat neuro-PASC effectively. With recognizing the growing numbers of COVID-19 patients suffering from neuro-PASC, there is an urgent need to identify affected individuals early to provide the most appropriate and efficient treatments. Awareness among the general population and health care professionals about PASC is rising, and more efforts are needed to understand and treat this new emerging challenge. In this review, we summarize the relevant scientific literature about neuro-PASC.

Peripheral Nervous System Manifestations Associated with COVID-19.

PURPOSE OF REVIEW: The present review discusses the peripheral nervous system (PNS) manifestations associated with coronavirus disease 2019 (COVID-19). RECENT FINDINGS: Nerve pain and skeletal muscle injury, Guillain-Barré syndrome, cranial polyneuritis, neuromuscular junction disorders, neuro-ophthalmological disorders, neurosensory hearing loss, and dysautonomia have been reported as PNS manifestations in patients with COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19. COVID-19 has shown syndromic complexity. Not only does SARS-CoV-2 affect the central nervous system but also it involves the PNS. The PNS involvement may be due to dysregulation of the immune system attributable to COVID-19. Here we review the broad spectrum of PNS involvement of COVID-19.

Correction to: Central Nervous System Manifestations Associated with COVID-19.

The original version contained incorrect formatting of Dr. Napolis. His first name should be Mario and his last name should be Di Napoli.

Central Nervous System Manifestations Associated with COVID-19.

PURPOSE OF REVIEW: Coronavirus disease 2019 (COVID-19) has become a global health crisis of our time. The disease arises from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that binds to angiotensin-converting enzyme 2 (ACE2) receptors on host cells for its internalization. COVID-19 has a wide range of respiratory symptoms from mild to severe and affects several other organs, increasing the complexity of the treatment. There is accumulating evidence to suggest that SARS-CoV-2 can target the nervous system. In this review, we provide an account of the COVID-19 central nervous system (CNS) manifestations. RECENT FINDINGS: A broad spectrum of the CNS manifestations including headache, impaired consciousness, delirium, loss of smell and taste, encephalitis, seizures, strokes, myelitis, acute disseminated encephalomyelitis, neurogenic respiratory failure, encephalopathy, silent hypoxemia, generalized myoclonus, neuroleptic malignant syndrome and Kawasaki syndrome has been reported in patients with COVID-19. CNS manifestations associated with COVID-19 should be considered in clinical practice. There is a need for modification of current protocols and standing orders to provide better care for COVID-19 patients presenting with neurological symptoms.

Copy number variant study of bipolar disorder in Canadian and UK populations implicates synaptic genes.

Genome-wide single nucleotide polymorphism (SNP) data from 936 bipolar disorder (BD) individuals and 940 psychiatrically healthy comparison individuals of North European descent were analyzed for copy number variation (CNV). Using multiple CNV calling algorithms, and validating using in vitro molecular analyses, we identified CNVs implicating several candidate genes that encode synaptic proteins, such as DLG1, DLG2, DPP6, NRXN1, NRXN2, NRXN3, SHANK2, and EPHA5, as well as the neuronal splicing regulator RBFOX1 (A2BP1), and neuronal cell adhesion molecule CHL1. We have also identified recurrent CNVs on 15q13.3 and 16p11.2-regions previously reported as risk loci for neuropsychiatric disorders. In addition, we performed CNV analysis of individuals from 215 BD trios and identified de novo CNVs involving the NRXN1 and DRD5 genes. Our study provides further evidence of the occasional involvement of genomic mutations in the etiology of BD, however, there is no evidence of an increased burden of CNVs in BD. Further, the identification of CNVs at multiple members of the neurexin gene family in BD individuals, supports the role of synaptic disruption in the etiology of BD.

Tumor-related epilepsy and epilepsy surgery.

Tumor-related epilepsy (TRE) is a major etiologic category of epilepsy. TRE is heterogeneous, and the epidemiology, pathology, pathophysiology, clinical features, treatment, and outcomes vary accordingly. In addition, treatment imperatives vary between almost purely epilepsy considerations and those that are primarily oncologic. Often, there is no clear separation of imperatives, and there is a relatively scant evidence base that underpins management decisions in such cases. Given a diverse molecular as well as clinical landscape and the rapid pace with which new knowledge accrues, there are relatively few recent literature resources on TRE that provide neurologists, neurosurgeons, epileptologists, and oncologists with an up-to-date, state-of-the-art review of the field in all of its important aspects. The proceedings of the Sixth International Epilepsy Colloquium in Cleveland in Ohio, U.S.A., in May 2013 on Tumoral Epilepsy and Epilepsy Surgery address, at least in part, several TRE aspects crucial to modern epilepsy and oncology practice.

Sudden unexpected death in epilepsy or voodoo heart: analysis of heart/brain connections.

Sudden unexpected death in epilepsy (SUDEP) affects up to 5000 patients a year in the United States alone. The exact pathophysiologic processes of are unknown. Profound autonomic dysregulation driving cardiac and respiratory dysfunction is likely. Available evidence from monitored deaths suggests that fatal tachyarrhythmias are not primarily responsible although near deaths due to ventricular arrhythmias have been reported. Genetic "neuro-cardiac" channelopathies affecting brain function, central respiratory processes, and cardiac rhythm have been hypothesized. These, as well as serotonergic mechanisms affecting brainstem homeostasis of cardiac and respiratory function are important areas of current and future SUDEP research.

Association of Guillain-Barre syndrome with COVID-19 infection: An updated systematic review.

OBJECTIVE: The systematic review aimed to determine demographic characteristics, clinical features, lab evaluation, management and complications of the studies focusing on Guillain-Barre syndrome (GBS) as a sequele of novel coronavirus (COVID-19) infection. METHODS: After protocol registration, PubMed, Web of Science and Cumulative Index to Nursing & Allied Health Literature (CINHAL) databases were searched for relevant articles using MeSH key-words and imported into referencing/review softwares. The data, regarding demographic and clinical characteristics, diagnostic workup and management, was analyzed in International Business Machines (IBM) Statistics SPSS 21. Many statistical tests, such as t-test and the Mann-Whitney U test, were used. P < 0.05 was considered significant. RESULTS: We identified 64 relevant articles. The mean age of the patients was 56 ± 16 years; the majority were males (64.9%). Among the neurological findings, paresthesia was the most typical symptom (48.9%). Most of the patients had been diagnosed by reverse transcriptase-polymerase chain reaction (RT-PCR) (69.2%). Two-third of the patients received immunoglobulins (IVIg) (77.7%). Although functions recovered in most patients, there were four patients with facial diplegia during follow-up (4.26%). Acute inflammatory demyelinating polyneuropathy (AIDP) was more likely to be associated with paresis of the lower extremity (p < 0.05) and higher levels of glucose on cerebrospinal fluid (CSF) analysis (p < 0.05). These patients were more likely to receive IVIg (p < 0.05) and develop respiratory insufficiency, subsequently (p < 0.05). CONCLUSIONS: GBS is being recognized as one of the many presentations of the COVID-19 infection. Although the common form is AIDP that might lead to complications, other variants are possible as well, and more studies are needed to focus on those subvariants.

Attention-deficit/hyperactivity disorder (ADHD) association with the DAT1 core promoter -67 T allele.

Association between attention deficit hyperactivity disorder (ADHD) and the 10-repeat allele of a polymorphism (a 40 bp variable number of tandem repeats) in the dopamine transporter gene (DAT1) has been reported by several groups. In this study, we examined whether either allele of the DAT1 core promoter -67 functional polymorphism is associated with ADHD in a case/control study. The allele and genotype frequencies of the polymorphism were studied in 110 patients and 120 controls, which were matched on the basis of sex, age and ethnicity. The genotype frequencies in the patients group were as follows: AA 19.2%; AT 65.2%; TT 15.4% vs. the genotype frequencies in the control group: AA 47.5%; AT 43.3%; TT 9.2% [chi2=20.73, df=2, P

Primary dystonias and genetic disorders with dystonia as clinical feature of the disease.

Dystonia is probably the most common form of movement disorder encountered in the clinical practice. It is characterized by sustained muscle contractions, usually producing twisting and repetitive movements or abnormal postures or positions. Dystonias can be classified in several ways, including primarily by the clinical phenomenology or by the underlining etiology, in particular to understand if the presentation is genetically determined. By advances of genetics, including contemporary genomic technologies, there is a growing understanding of the molecular underpinnings of genetically determined dystonias. The intricacy of information requires a user friendly, novel database that may efficiently serve clinicians to inform of advances of the field and to diagnose and manage these often complex cases. Here we present an up to date, comprehensive review - in tabulated formats - of genetically determined primary dystonias and complex Mendelian disorders with dystonia as central feature. The detailed search up to December 24, 2012, identified 24 hereditary primary dystonias (DYT1 to DYT 25) that are mostly monogenic disorders, and a larger group (>70) of genetic syndromes in which dystonia is one of the characteristic clinical features. We organized the findings not only by individual information (name of the conditions, pattern of inheritance, chromosome and gene abnormality, clinical features, relevant ancillary tests and key references), but also provide symptom-oriented organization of the clinical entities for efficient inquiries.

Ten Years' Follow-Up of a Family With Myokymia and Muscle Cramps Without Ataxia.

We report 10 years' follow-up of the previously described family with a novel mutation of the KCNA1 gene. The family consisted of 3 affected boys (first seen at ages 3, 11, and 12) and their affected mother and asymptomatic father and sister. They clinically presented with diffuse myokymia, muscle cramps, and lower limb spasticity without ataxia, but episodic ataxia developed later during adolescence and early adulthood. Long-term follow-ups of families with known KCNA1 gene mutation are rarely mentioned in the literature. Treatment with carbamazepine, 600 to 800 mg daily resulted in cessation of muscle cramps and marked improvement of lower leg symptoms. In the youngest child, after 2 years carbamazepine had to be changed to oxcarbazepine because of side effects. Carbamazepine and oxcarbazepine are both effective in treatment of symptoms related to KCNA1 gene mutation. Symptoms will reoccur if treatment is stopped and there is variability of symptom severity between family members.

Sialorrhea: anatomy, pathophysiology and treatment with emphasis on the role of botulinum toxins.

Sialorrhea or excessive drooling is a major issue in children with cerebral palsy and adults with neurodegenerative disorders. In this review, we describe the clinical features, anatomy and physiology of sialorrhea, as well as a review of the world literature on medical treatment using Yale University's search engine; including but not limited to Medline and Erasmus. Level of drug efficacy is defined according to the guidelines of American Academy of Neurology. Current medical management is unsatisfactory. Topical agents (scopolamine and tropicamide) and oral agents (glyccopyrolate) combined render a level B evidence (probably effective); however, this treatment is associated with troublesome side effects. Double-blind and placebo-controlled studies of botulinum toxin (BoNT) provide a level A evidence for type B (two class I studies; effective and established) and both overall and individual B level of evidence for OnabotulinumtoxinA (A/Ona) and AbobotulinumtoxinA (A/Abo); these are probably effective. For IncobotulinumtoxinA (A/Inco), the level of evidence is U (insufficient) due to lack of blinded studies. Side effects are uncommon; transient and comparable between the two types of toxin. A clinical note at the end of this review comments on fine clinical points. Administration of BoNTs into salivary glands is currently the most effective way of treating sialorrhea.

Hyperhidrosis: anatomy, pathophysiology and treatment with emphasis on the role of botulinum toxins.

Clinical features, anatomy and physiology of hyperhidrosis are presented with a review of the world literature on treatment. Level of drug efficacy is defined according to the guidelines of the American Academy of Neurology. Topical agents (glycopyrrolate and methylsulfate) are evidence level B (probably effective). Oral agents (oxybutynin and methantheline bromide) are also level B. In a total of 831 patients, 1 class I and 2 class II blinded studies showed level B efficacy of OnabotulinumtoxinA (A/Ona), while 1 class I and 1 class II study also demonstrated level B efficacy of AbobotulinumtoxinA (A/Abo) in axillary hyperhidrosis (AH), collectively depicting Level A evidence (established) for botulinumtoxinA (BoNT-A). In a comparator study, A/Ona and A/Inco toxins demonstrated comparable efficacy in AH. For IncobotulinumtoxinA (A/Inco) no placebo controlled studies exist; thus, efficacy is Level C (possibly effective) based solely on the aforementioned class II comparator study. For RimabotulinumtoxinB (B/Rima), one class III study has suggested Level U efficacy (insufficient data). In palmar hyperhidrosis (PH), there are 3 class II studies for A/Ona and 2 for A/Abo (individually and collectively level B for BoNT-A) and no blinded study for A/Inco (level U). For B/Rima the level of evidence is C (possibly effective) based on 1 class II study. Botulinum toxins (BoNT) provide a long lasting effect of 3-9 months after one injection session. Studies on BoNT-A iontophoresis are emerging (2 class II studies; level B); however, data on duration and frequency of application is inconsistent.