Central nervous system complications associated with SARS-CoV-2 infection: integrative concepts of pathophysiology and case reports.

Coronavirus disease 2019 (COVID-19) is a highly infectious pandemic caused by a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It frequently presents with unremitting fever, hypoxemic respiratory failure, and systemic complications (e.g., gastrointestinal, renal, cardiac, and hepatic involvement), encephalopathy, and thrombotic events. The respiratory symptoms are similar to those accompanying other genetically related beta-coronaviruses (CoVs) such as severe acute respiratory syndrome CoV (SARS-CoV) and Middle East Respiratory Syndrome CoV (MERS-CoV). Hypoxemic respiratory symptoms can rapidly progress to Acute Respiratory Distress Syndrome (ARDS) and secondary hemophagocytic lymphohistiocytosis, leading to multi-organ system dysfunction syndrome. Severe cases are typically associated with aberrant and excessive inflammatory responses. These include significant systemic upregulation of cytokines, chemokines, and pro-inflammatory mediators, associated with increased acute-phase proteins (APPs) production such as hyperferritinemia and elevated C-reactive protein (CRP), as well as lymphocytopenia. The neurological complications of SARS-CoV-2 infection are high among those with severe and critical illnesses. This review highlights the central nervous system (CNS) complications associated with COVID-19 attributed to primary CNS involvement due to rare direct neuroinvasion and more commonly secondary CNS sequelae due to exuberant systemic innate-mediated hyper-inflammation. It also provides a theoretical integration of clinical and experimental data to elucidate the pathogenesis of these disorders. Specifically, how systemic hyper-inflammation provoked by maladaptive innate immunity may impair neurovascular endothelial function, disrupt BBB, activate CNS innate immune signaling pathways, and induce para-infectious autoimmunity, potentially contributing to the CNS complications associated with SARS-CoV-2 infection. Direct viral infection of the brain parenchyma causing encephalitis, possibly with concurrent neurovascular endotheliitis and CNS renin angiotensin system (RAS) dysregulation, is also reviewed.

Practice Update: Review of Anticonvulsant Therapy.

Since 2010, the Food and Drug Administration has approved the use of four new anti-epilepsy drugs (AEDs) for the treatment of epilepsy in the USA: clobazam (Onfi), ezogabine (Potiga), perampanel (Fycompa), and eslicarbazepine (Aptiom) as well as two extended release formulations, topiramate ER (Qudexy XR and Trokendi) and oxcarbazepine ER (Oxtellar). This not only provides practitioners ample choice to match medication profiles to their patients' preferences and co-morbidities better, but also challenges us to be proficient in the use of all. In addition to providing a brief overview of these new medications and of the current medical management of epilepsy, this review discusses new data regarding vitamin D and AED-related osteoporosis, pregnancy registries, suicidality, marijuana-related compounds for epilepsy, and the recently published guidelines on the approach and management of a first unprovoked seizure in adults and guidelines for when to stop AEDs.

Ictal fear: Associations with age, gender, and other experiential phenomena.

PURPOSE: The aim of this study was to determine the relationship of fear to other auras and to gender and age using a large database. METHODS: The Epilepsy Phenome/Genome Project (EPGP) is a multicenter, multicontinental cross-sectional study in which ictal symptomatology and other data were ascertained in a standardized series of questionnaires then corroborated by epilepsy specialists. Auras were classified into subgroups of symptoms, with ictal fear, panic, or anxiety as a single category. RESULTS: Of 536 participants with focal epilepsy, 72 were coded as having ictal fear/panic/anxiety. Reviewing raw patient responses, 12 participants were deemed not to have fear, and 24 had inadequate data, leaving 36 (7%) of 512 with definite ictal fear. In univariate analyses, fear was significantly associated with auras historically considered temporal lobe in origin, including cephalic, olfactory, and visceral complaints; déjà vu; and derealization. On both univariate and multivariate stepwise analyses, fear was associated with jamais vu and auras with cardiac symptoms, dyspnea, and chest tightening. Expressive aphasia was associated with fear on univariate analysis only, but the general category of aphasias was associated with fear only in the multivariate model. There was no age or gender relationship with fear when compared to the overall population with focal epilepsy that was studied under the EPGP. Patients with ictal fear were more likely to have a right hemisphere seizure focus. CONCLUSIONS: Ictal fear was strongly associated with other auras considered to originate from the limbic system. No relationship of fear with age or gender was observed.

EEG Abnormalities and Their Radiographic Correlates in a COVID-19 Inpatient Cohort.

Background and Objectives: To identify the prevalence of EEG abnormalities in patients with coronavirus disease 2019 (COVID-19) with neurologic changes, their associated neuroimaging abnormalities, and rates of mortality. Methods: A retrospective case series of 192 adult COVID-19-positive inpatients with EEG performed between March and June 2020 at 4 hospitals: 161 undergoing continuous, 24 routine, and 7 reduced montage EEG. Study indication, epilepsy history, intubation status, administration of sedatives or antiseizure medications (ASMs), metabolic abnormalities, neuroimaging pathology associated with epileptiform abnormalities, and in-hospital mortality were analyzed. Results: EEG indications included encephalopathy (54.7%), seizure (18.2%), coma (17.2%), focal deficit (5.2%), and abnormal movements (4.6%). Epileptiform abnormalities occurred in 39.6% of patients: focal intermittent epileptiform discharges in 25.0%, lateralized periodic discharges in 6.3%, and generalized periodic discharges in 19.3%. Seizures were recorded in 8 patients, 3 with status epilepticus. ASM administration, epilepsy history, and older age were associated with epileptiform abnormalities. Only 26.3% of patients presented with any epileptiform abnormality, 37.5% with electrographic seizures, and 25.7% patients with clinical seizures had known epilepsy. Background findings included generalized slowing (88.5%), focal slowing (15.6%), burst suppression (3.6%), attenuation (3.1%), and normal EEG (3.1%). Neuroimaging pathology was identified in 67.1% of patients with epileptiform abnormalities, over two-thirds acute. In-hospital mortality was 39.5% for patients with epileptiform abnormalities and 36.2% for those without. Risk factors for mortality were coma and ventilator support at time of EEG. Discussion: This article highlights the range of EEG abnormalities frequently associated with acute neuroimaging abnormalities in COVID-19. Mortality rates were high, particularly for patients in coma requiring mechanical ventilation. These findings may guide the prognosis and management of patients with COVID-19 and neurologic changes.

Misdiagnosis of epileptic seizures as manifestations of psychiatric illnesses.

BACKGROUND: Epileptic seizures may be misdiagnosed if they manifest as psychiatric symptoms or seizures occur in patients with known psychiatric illness. METHODS: We present clinical profiles of six patients with epilepsy (three male, mean age 39 ± 12 years) that presented with prominent psychiatric symptoms. RESULTS: Two patients had pre-existing psychiatric illnesses. Three patients were initially diagnosed with panic attacks, two with psychosis, and one with schizophrenia. Five patients had temporal lobe epilepsy (TLE) while the sixth patient was subsequently found to have absence status epilepticus (SE). Cranial computed tomogram (CT) including contrast study was unremarkable in five patients and showed post-traumatic changes in one patient. Cranial magnetic resonance imaging (MRI) revealed dysembryoplastic neuroepithelial tumour (DNET) in one patient, cavernous hemangioma in one, and post-traumatic changes plus bilateral mesial temporal sclerosis in another patient but it was normal in two TLE patients. Routine electroencephalography (EEG) revealed absence SE in one patient but it was non-diagnostic in the TLE patients. Video-EEG telemetry in the epilepsy monitoring unit (EMU) was necessary to establish the diagnosis in four TLE patients. None of the patients responded to medications aimed at treating psychiatric symptoms alone. Two patients required surgery while the other four required treatment with anti-epileptic drugs. All the patients had favorable response to the treatment of their epilepsy. CONCLUSIONS: This case series illustrates that epileptic patients may experience non-convulsive seizures that might be mistaken as primary psychiatric illnesses. In this subset of patients, evaluation by an epileptologist, MRI of the brain, and/or video-EEG telemetry in an EMU was necessary to confirm the diagnosis of epilepsy if routine EEGs and cranial CT are normal.

Obstructive Sleep Apnea: Cognitive Outcomes.

There is a strong association between obstructive sleep apnea (OSA) and cognitive dysfunction. Executive function, attention, verbal/visual long-term memory, visuospatial/constructional ability, and information processing are more likely to be affected, whereas language, psychomotor function, and short-term memory are less likely to be affected. Increased accumulation of Aß2-amyloid in the brain, episodic hypoxemia, oxidative stress, vascular inflammation, and systemic comorbidities may contribute to the pathogenesis. Patients with OSA should have cognitive screening or formal testing, and patients with cognitive decline should have testing for OSA. Treatment with continuous positive airway pressure may improve cognitive symptoms in the patient with OSA.

The impact of medications and medical comorbidities on sexual function in people with epilepsy.

OBJECTIVE: People with epilepsy experience increased rates of sexual dysfunction, often affecting quality of life. Sexual dysfunction may result from the underlying disorder, antiseizure or other medications, or comorbid psychosocial factors. This study evaluated the incidence and clinical associations of sexual dysfunction in adult epilepsy patients. METHODS: 89 epilepsy patients 18 years and older admitted to the New York University Comprehensive Epilepsy Center epilepsy monitoring unit between 2016 and 2018 completed a survey on sexual functioning. The survey included demographic, clinical, and sexual functioning information with a validated measure of sexual function (the Arizona Sexual Experiences Scale (ASEX). RESULTS: Of 89 surveys completed, 15 (16.9 %) patients had discussed sexual functioning with a medical professional and 20 (22.5 %) reported sexual dysfunction. For the group, the mean ASEX score was 13.6 (SD 4.8). 59 (66.3 %) participants reported not being asked about sexual health by their doctor or nurse practitioner in the last year. The two independent predictors of sexual dysfunction were self-identifying as overweight/obese (OR 6.1, CI 1.4-26.5, P = 0.02) or taking strong enzyme-inducing antiseizure medications (OR 7.8, CI 1.4-44.9, P = 0.02). Other factors such as age, relationship status, duration of epilepsy, the presence of depression or anxiety, cardiovascular risk factors, and opioid/stimulant use, did not predict sexual dysfunction. SIGNIFICANCE: Our study showed that sexual dysfunction is common in epilepsy patients but infrequently discussed by medical professionals. Two modifiable risk factors, being overweight or taking strong enzyme-inducing antiseizure medications, were independently associated with sexual dysfunction, suggesting interventions to potentially improve sexual health.

Update on anticonvulsant drugs.

In 2009, the US Food and Drug Administration approved three medications for the treatment of epilepsy: rufinamide, lacosamide, and vigabatrin. In addition, extended-release formulations of lamotrigine and levetiracetam were approved recently. When added to the dozen medications for treating epilepsy, the choice is a luxury in terms of additional options, but also a challenge for practitioners to use them all with expertise. Recently, there has been much interest surrounding medications for epilepsy and their possible association with osteoporosis, safety during pregnancy, biological equivalence to generic versions, and possible association with higher rates of suicidality. This review discusses these issues and provides a current overview for the medical management of epilepsy.

Application of RNS in refractory epilepsy: Targeting insula.

Although responsive neurostimulation (RNS) is approved for treatment of resistant focal epilepsy in adults, little is known about response to treatment of specific cortical targets. We describe the experience of RNS targeting the insular lobe. We identified patients who had RNS implantation with at least one electrode within the insula between April 2014 and October 2015. We performed a retrospective review of preoperative clinical features, imaging, electrocardiogram (EEG), intraoperative electrocorticography (ECoG), and postoperative seizure outcome. Eight patients with at least 6 months of postimplant follow-up were identified. Ictal localization was inconclusive with MRI or scalp EEG findings. Intracranial EEG monitoring or intraoperative ECoG demonstrated clear ictal onsets and/or frequent interictal discharges in the insula. Four patients demonstrated overall 50-75% reduction in seizure frequency. Two patients did not show appreciable seizure improvement. One patient has experienced a 75% reduction of seizure frequency, and another is nearly seizure free postoperatively. There were no reported direct complications of insular RNS electrode placement or stimulation, though two patients had postoperative complications thought to be related to craniotomy (hydrocephalus and late infection). Our study suggests that insular RNS electrode placement in selected patients is relatively safe and that RNS treatment may benefit selected patients with insular epilepsy.

Management of Tiny Meningiomas: To Resect or Not Resect.

Meningiomas are most often benign primary intracranial tumors that are frequently found incidentally on imaging. Larger sized meningiomas may present with symptoms such as seizures and headaches. Smaller meningiomas are commonly asymptomatic and usually observed with serial imaging. We present two female patients, both of whom were found to have very small left frontal meningiomas that marginated Broca's area. The first patient in this case series experienced episodes resembling seizures which consisted of weakness, vision loss, and slurred speech, as well as subtle language dysfunction in her day-to-day conversations. The second patient presented with headaches and an enlarging meningioma. Both meningiomas were surgically resected and the patients' symptoms resolved. Small meningiomas should not be overlooked as they may very well be the source of neurologic symptoms.

Which EEG patterns warrant treatment in the critically ill? Reviewing the evidence for treatment of periodic epileptiform discharges and related patterns.

Continuous electroencephalographic monitoring in critically ill patients has improved detection of nonconvulsive seizures and periodic discharges, but when and how aggressively to treat these electrographic patterns is unclear. A review of the literature was conducted to understand the nature of periodic discharges and the strength of the data on which management recommendations have been based. Periodic discharges are seen from a wide variety of etiologies, and the discharges themselves are electrographically heterogeneous. This spectrum suggests a need to consider these phenomena along a continuum between interictal and ictal, but more important clinically is the need to consider the likelihood of neuronal injury from each type of discharge in a given clinical setting. Recommendations for treatment are given, and a modification to current criteria for the diagnosis of nonconvulsive seizures is suggested.

Auras in generalized epilepsy.

OBJECTIVE: We studied the frequency of auras in generalized epilepsy (GE) using a detailed semistructured diagnostic interview. METHODS: In this cross-sectional study, participants with GE were drawn from the Epilepsy Phenome/Genome Project (EPGP). Responses to the standardized diagnostic interview regarding tonic-clonic (grand mal) seizures were then examined. This questionnaire initially required participants to provide their own description of any subjective phenomena before their "grand mal seizures." Participants who provided answers to these questions were considered to have an aura. All participants were then systematically queried regarding a list of specific symptoms occurring before grand mal seizures, using structured (closed-ended) questions. RESULTS: Seven hundred ninety-eight participants with GE were identified, of whom 530 reported grand mal seizures. Of these, 112 (21.3%) reported auras in response to the open-ended question. Analysis of responses to the closed-ended questions suggested that 341 participants (64.3%) experienced at least one form of aura. CONCLUSIONS: Auras typically associated with focal epilepsy were reported by a substantial proportion of EPGP subjects with GE. This finding may support existing theories of cortical and subcortical generators of GE with variable spread patterns. Differences between responses to the open-ended question and closed-ended questions may also reflect clinically relevant variation in patient responses to history-taking and surveys. Open-ended questions may underestimate the prevalence of specific types of auras and may be in part responsible for the underrecognition of auras in GE. In addition, structured questions may influence participants, possibly leading to a greater representation of symptoms.

Imaging P-glycoprotein function in rats using [(11)C]-N-desmethyl-loperamide.

OBJECTIVE: One mechanism that may be responsible for drug resistance in epilepsy is the upregulation of P-glycoprotein (P-gp), a drug efflux pump, at the epileptogenic focus. In this study, we sought to evaluate the potential of a recently developed P-gp PET radiotracer, [(11)C]N-desmethyl-loperamide ([(11)C]dLop), for measuring P-gp function in the rat brain. METHODS: The precursor to [(11)C]dLop was synthesized in two steps from commercially available starting materials and subsequently radiolabeled in one step using [(11)C]methyl iodide. [(11)C]dLop was then administered to two groups of rats, controls (n = 4) and those treated with a P-gp inhibitor (n = 8). Cyclosporin A (CsA, 50 mg/kg, n = 3) and tariquidar (TQ, 20 mg/kg, n = 5) were both used as P-gp inhibitors. MicroPET brain scans were performed for 120 min with arterial blood sampling. A one-tissue compartment model was used to estimate the distribution volume of radiotracer as the outcome measure of P-gp function. RESULTS: Plasma levels of parent [(11)C]dLop decreased rapidly to <0.1 mean standardized uptake value (SUV) at 60 min. In controls, brain uptake of [(11)C]dLop was very low (<0.1 mean SUV). In contrast, the mean SUVs were significantly higher in rats treated with CsA (0.51) or TQ (0.22). Estimation of distribution volumes was stable by 70 min. Estimated distribution volumes were significantly larger after P-gp inhibition (CsA = 7.3, TQ = 4.7) compared to controls (no inhibitor = 2.1). CONCLUSIONS: The rat brain demonstrates significantly increased uptake of [(11)C]dLop after P-gp inhibition. [(11)C]dLop is a substrate of P-gp, and will serve as a promising radiotracer for studying P-gp function in the future.