Objective To systematically describe central (CNS) and peripheral (PNS) nervous system complications in hospitalized COVID-19 patients. Methods We conducted a prospective, consecutive, observational study of adult patients from a tertiary referral center with confirmed COVID-19. All patients were screened daily for neurological and neuropsychiatric symptoms during admission and discharge. Three-month follow-up data were collected using electronic health records. We classified complications as caused by SARS-CoV-2 neurotropism, immune-mediated or critical illness-related. Results From April to September 2020, we enrolled 61 consecutively admitted COVID-19 patients, 35 (57%) of whom required intensive care (ICU) management for respiratory failure. Forty-one CNS/PNS complications were identified in 28 of 61 (45.9%) patients and were more frequent in ICU compared to non-ICU patients. The most common CNS complication was encephalopathy (n = 19, 31.1%), which was severe in 13 patients (GCS ≤ 12), including 8 with akinetic mutism. Length of ICU admission was independently associated with encephalopathy (OR = 1.22). Other CNS complications included ischemic stroke, a biopsy-proven acute necrotizing encephalitis, and transverse myelitis. The most common PNS complication was critical illness polyneuromyopathy (13.1%), with prolonged ICU stay as independent predictor (OR = 1.14). Treatment-related PNS complications included meralgia paresthetica. Of 41 complications in total, 3 were para/post-infectious, 34 were secondary to critical illness or other causes, and 4 remained unresolved. Cerebrospinal fluid was negative for SARS-CoV-2 RNA in all 5 patients investigated. Conclusion CNS and PNS complications were common in hospitalized COVID-19 patients, particularly in the ICU, and often attributable to critical illness. When COVID-19 was the primary cause for neurological disease, no signs of viral neurotropism were detected, but laboratory changes suggested autoimmune-mediated mechanisms.

IMPORTANCE Prolonged neuropsychiatric and cognitive symptoms are increasingly reported in patients after COVID-19, but studies with well-matched controls are lacking.OBJECTIVE To investigate cognitive impairment, neuropsychiatric diagnoses, and symptoms in survivors of COVID-19 compared with patients hospitalized for non-COVID-19 illness. DESIGN, SETTING, AND PARTICIPANTSThis prospective case-control study from a tertiary referral hospital in Copenhagen, Denmark, conducted between July 2020 and July 2021, followed up hospitalized COVID-19 survivors and control patients hospitalized for non-COVID-19 illness, matched for age, sex, and intensive care unit (ICU) status 6 months after symptom onset. EXPOSURES Hospitalization for COVID-19.MAIN OUTCOMES AND MEASURES Participants were investigated with the Mini-International Neuropsychiatric Interview, the Montreal Cognitive Assessment (MoCA), neurologic examination, and a semi-structured interview for subjective symptoms. Primary outcomes were total MoCA score and new onset of International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) psychiatric diagnoses. Secondary outcomes included specific psychiatric diagnoses, subjective symptoms, and neurologic examination results. All outcomes were adjusted for age, sex, ICU admission, admission length, and days of follow-up. Secondary outcomes were adjusted for multiple testing. RESULTS A total of 85 COVID-19 survivors (36 [42%] women; mean [SD] age 56.8 [14] years) after hospitalization and 61 matched control patients with non-COVID-19 illness (27 [44%] women, mean age 59.4 years [SD, 13]) were enrolled. Cognitive status measured by total geometric mean MoCA scores at 6-month follow-up was lower (P = .01) among 95% CI, 95% CI,). The cognitive status improved substantially (P = .004), from 19.2 (95% CI, 15.2-23.2) at discharge to 26.1 (95% CI, 23.1-29.1) for 15 patients with COVID-19 with MoCA evaluations from hospital discharge. A total of 16 of 85 patients with COVID-19 (19%) and 12 of 61 control patients (20%) had a new-onset psychiatric diagnosis at 6-month follow-up, which was not significantly different (odds ratio, 0.93; 95% CI, 0.39-2.27; P = .87). In fully adjusted models, secondary outcomes were not significantly different, except anosmia, which was more common after COVID-19 (odds ratio, 4.56; 95% CI, 1.52-17.42; P = .006); but no longer when adjusting for multiple testing. CONCLUSIONS AND RELEVANCEIn this prospective case-control study, cognitive status at 6 months was worse among survivors of COVID-19, but the overall burden of neuropsychiatric and neurologic signs and symptoms among survivors of COVID-19 requiring hospitalization was comparable with the burden observed among matched survivors hospitalized for non-COVID-19 causes.

ObjectiveTo systematically describe CNS and PNS complications in hospitalized COVID-19 patients.MethodsWe conducted a prospective, consecutive, observational study of adult patients from a tertiary referral center with confirmed COVID-19. All patients were screened daily for neurological and neuropsychiatric symptoms during admission, at discharge and at 3-month follow-up. We classified complications as caused by SARS-CoV-2 neurotropism, immune-mediated or critical illness-related.ResultsFrom April-September 2020, we enrolled 61 consecutively admitted COVID-19 patients, 35 (57%) of whom were referred to ICU for respiratory failure. Evaluation revealed a higher frequency of CNS/PNS symptoms in ICU patients compared to non-ICU patients. The most common CNS complication was encephalopathy (n=22, 36.1%), which was severe in 13 patients (GCS≤12), including 8 with akinetic mutism. Length of ICU admission was an independent predictor of encephalopathy (OR=1.23). Other CNS complications included ischemic stroke, a biopsy-proven acute necrotizing encephalitis, and transverse myelitis. The most common PNS complication was critical illness polyneuromyopathy (13.1%), with prolonged ICU stay as independent predictor (OR=1.14). Treatment-related PNS complications included meralgia paresthetica. Of 41 complications in total, 3 were classified as para/post-infectious. The remainder included cases secondary to critical illness or other causes (n=34) or without sufficient investigations (n=4). Cerebrospinal fluid was negative for SARS-CoV-2 RNA in all 5 patients investigated.ConclusionsCNS/PNS complications were common in hospitalized COVID-19 patients, particularly in ICU patients, and often attributable to critical illness. In cases with COVID-19 as the primary cause for neurological disease, there were no signs of viral neurotropism, but laboratory changes suggested autoimmune-mediated mechanisms.

Background: As of October 2020, COVID-19 has caused 1,000,000 deaths worldwide. However, large-scale studies of COVID-19 mortality and new-onset comorbidity compared to individuals tested negative for COVID-19 and individuals tested for influenza A/B are lacking. We investigated COVID-19 30-day mortality and new-onset comorbidity compared to individuals with negative COVID-19 test results and individuals tested for influenza A/B.Methods and findings: This population-based cohort study utilized electronic health records covering roughly half (n = 2,647,229) of Denmark's population, with nationwide linkage of microbiology test results and death records. All individuals ≥18 years tested for COVID-19 and individuals tested for influenza A/B were followed from 11/2017 to 06/2020. Main outcome was 30-day mortality after a test for either COVID-19 or influenza. Secondary outcomes were major comorbidity diagnoses 30-days after the test for either COVID-19 or influenza A/B. In total, 224,639 individuals were tested for COVID-19. To enhance comparability, we stratified the population for in- and outpatient status at the time of testing. Among inpatients positive for COVID-19, 356 of 1,657 (21%) died within 30 days, which was a 3.0 to 3.1-fold increased 30-day mortality rate, when compared to influenza and COVID-19-negative inpatients (all p < 0.001). For outpatients, 128 of 6,263 (2%) COVID-19-positive patients died within 30 days, which was a 5.5 to 6.9-fold increased mortality rate compared to individuals tested negative for COVID-19 or individuals tested positive or negative for influenza, respectively (all p < 0.001). Compared to hospitalized patients with influenza A/B, new-onset ischemic stroke, diabetes and nephropathy occurred more frequently in inpatients with COVID-19 (all p < 0.05).Conclusions: In this population-based study comparing COVID-19 positive with COVID-19 negative individuals and individuals tested for influenza, COVID-19 was associated with increased rates of major systemic and vascular comorbidity and substantially higher mortality. Results should be interpreted with caution because of differences in test strategies for COVID-19 and influenza, use of aggregated data, the limited 30-day follow-up and the possibility for changing mortality rates as the pandemic unfolds. However, the true COVID-19 mortality may even be higher than the stated 3.0 to 5.5-fold increase, owing to more extensive testing for COVID-19.

Functional MRI (fMRI) and EEG may reveal residual consciousness in patients with disorders of consciousness (DoC), as reflected by a rapidly expanding literature on chronic DoC. However, acute DoC is rarely investigated, although identifying residual consciousness is key to clinical decision-making in the intensive care unit (ICU). Therefore, the objective of the prospective, observational, tertiary center cohort, diagnostic phase IIb study ‘Consciousness in neurocritical care cohort study using EEG and fMRI’ (CONNECT-ME, NCT02644265) was to assess the accuracy of fMRI and EEG to identify residual consciousness in acute DoC in the ICU. Between April 2016 and November 2020, 87 acute DoC-patients with traumatic or non-traumatic brain injury were examined with repeated clinical assessments, fMRI and EEG. Resting-state EEG and EEG with external stimulations were evaluated by visual analysis, spectral band analysis and a Support Vector Machine (SVM) consciousness classifier. In addition, within- and between-network resting-state connectivity for canonical resting-state fMRI networks were assessed. Next, we used EEG and fMRI data at study enrollment in two different machine-learning algorithms (Random Forest and SVM with a linear kernel), to distinguish patients in a minimally conscious state or better (≥MCS) from those in coma or unresponsive wakefulness state (≤UWS), at time of study enrollment and at ICU-discharge (or before death). Prediction performances were assessed with area under the curve (AUC). Of 87 DoC-patients (mean age, 50.0 ± 18 years, 43% women), 51 (59%) were ≤ UWS and 36 (41%) were ≥ MCS at study enrollment. Thirty-one (36%) patients died in the ICU, including 28 who had life-sustaining therapy withdrawn. EEG and fMRI predicted consciousness levels at study enrollment and ICU-discharge, with maximum AUCs of 0.79 (95% CI 0.77-0.80) and 0.71 (95% CI 0.77-0.80), respectively. Models based on combined EEG and fMRI features predicted consciousness levels at study enrollment and ICU-discharge with maximum AUCs of 0.78 (95% CI 0.71-0.86) and 0.83 (95% CI 0.75-0.89), respectively, with improved positive predictive value and sensitivity. Overall, both machine-learning algorithms (SVM and Random Forest) performed equally well. In conclusion, we suggest that acute DoC prediction models in the ICU be based on a combination of fMRI and EEG features, regardless of the machine-learning algorithm used.

BackgroundPalbociclib is a selective well-tolerated antineoplastic drug used in the treatment of advanced HER2-negative, estrogen-receptor positive breast cancer that has shown significant improvement in progression-free survival. We present a patient that developed severe rhabdomyolysis with tetra-affection and loss of gait after initiating the first cycle of Palbociclib concomitantly with Simvastatin 40 mg treatment.Case presentationA 71-year-old woman with metastatic breast cancer developed tetraparesis and near fatal rhabdomyolysis after initiation of first cycle Palbociclib. For 10 years prior to this treatment, the patient had been treated with Simvastatin without myalgia or other neuromuscular complaints prior to the first cycle of Palbociclib. The patient was admitted at the neurology department, where Palbociclib and Simvastatin were discontinued. The patient was aggressively hydrated and treated with intravenous immunoglobulin therapy with slowly remission and finally regaining independent gait function. Evaluation showed a negative myositis antibody work-up. Muscle magnetic resonance imaging showed edema in multiple foci, but skeletal muscle biopsy did not show necrosis. Post discharge genetic analysis showed single heterozygosity for nucleotide polymorphism rs4149056.ConclusionWe present a patient who developed severe rhabdomyolysis induced by a combination of Palbociclib and Simvastatin treatment. Rhabdomyolysis was most likely induced by toxic plasma concentrations of Simvastatin due to Palbociclibs inhibition of the CYP3A4 enzyme in combination with a decreased hepatic uptake of Simvastatin due to single nucleotide polymorphism rs4149056. The study underscores that combining Simvastatin and Palbociclib should be done cautiously and genetic testing of the rs4149056 SNP is warranted. If present, Simvastatin should be discontinued or replaced with a lesser myopathic statin in regard to patients risk of cardiovascular events.

OBJECTIVE:To determine the clinical and laboratory features of immune checkpoint inhibitor (ICPI)-associated autoimmune encephalitis (ICPI-AIE), an increasingly recognized adverse event with ICPI treatment.METHODS.We searched PubMed, The Cochrane Library and Embase for ICPI-AIE cases from the first description in 2015 until 01/2020 using standard bibliographic measures including PRISMA guidelines and pre-registration with PROSPERO (CRD42019139838).RESULTS.Thirty-nine studies met inclusion criteria, resulting in 54 ICPI-AIE patients (mean age 58.6 years; 43% females). Common cancers included melanoma (30%) and non-small cell lung cancer (30%). Brain metastases were found in 16 patients (30%). The most frequent ICPI was nivolumab (61%). Onset of ICPI-AIE occurred after a median of 3.5 treatment cycles, but very early and late presentations were common. Non-limbic AIE was roughly twice as frequent as limbic AIE (p<0.05). The most common laboratory abnormalities included bitemporal FLAIR lesions on MRI, continuous slow waves and diffuse slowing on EEG, and monocytic pleocytosis on cerebrospinal fluid analysis. Of note, intraneuronal antibodies were more frequent than neuronal surface antibodies, and a significant predictor for lack of improvement after 1st line immunotherapy (p<0.05).CONCLUSIONS.ICPI-AIE consists of a heterogenous group of conditions. Neurologists will likely encounter ICPI-AIE more often in the future, but important unresolved questions include the exact pathophysiological mechanisms, the epidemiology and the best treatment approaches associated with ICPI-AIE.

Background Climate change, including global warming, will cause poorer global health and rising numbers of environmental refugees. As neurological disorders account for a major share of morbidity and mortality worldwide, global warming is also destined to alter neurological practice; however, to what extent and by which mechanisms is unknown. We aimed to collect information about the effects of ambient temperatures and human migration on the epidemiology and clinical manifestations of neurological disorders. Methods We searched PubMed and Scopus from 01/2000 to 12/2020 for human studies addressing the influence of ambient temperatures and human migration on Alzheimer’s and non-Alzheimer’s dementia, epilepsy, headache/migraine, multiple sclerosis, Parkinson’s disease, stroke, and tick-borne encephalitis (a model disease for neuroinfections). The protocol was pre-registered with PROSPERO (2020 CRD42020147543). Results Ninety-three studies met inclusion criteria, 84 of which reported on ambient temperatures and nine on migration. Overall, most temperature studies suggested a relationship between increasing temperatures and higher mortality and/or morbidity, whereas results were more ambiguous for migration studies. However, we were unable to identify a single adequately designed study addressing how global warming and human migration will change neurological practice. Still, extracted data indicated multiple ways by which these aspects might alter neurological morbidity and mortality soon. Conclusion Significant heterogeneity exists across studies with respect to methodology, outcome measures, confounders and study design, including lack of data from low-income countries, but the evidence so far suggests that climate change will affect the practice of all major neurological disorders in the near future. Adequately designed studies to address this issue are urgently needed, requiring concerted efforts from the entire neurological community.