Early reversible leukoencephalopathy and unilateral sixth cranial nerve palsy in mild COVID-19 infection.

OBJECTIVES: To provide new insights into neurological manifestations of COVID-19. We describe a patient with mild COVID-19 associated with diplopia from right sixth cranial nerve palsy and early diffuse leukoencephalopathy, successfully treated with intravenous methylprednisolone. METHODS: The patient was evaluated for diplopia that occurred 1 day after the onset of fever, myalgia, and headache. A complete neurological workup, including neurological examination, cerebrospinal fluid (CSF) analysis with viral polymerase chain reaction (PCR), serum autoimmune encephalitis, and anti-nerve antibodies and brain magnetic resonance imaging (MRI), was performed. RESULTS: Clinical examination revealed incomplete right sixth cranial nerve palsy. Brain MRI showed diffuse confluent fluid-attenuated inversion recovery (FLAIR) hyperintense white matter abnormalities, while CSF analysis showed mild hyperproteinorrachia (61 mg/dL) without pleocytosis. The patients were treated with high-dose intravenous methylprednisolone with rapid improvement of neurological symptoms and resolution of CSF and MRI abnormalities. DISCUSSION: Our report shows that COVID-19 may predominantly present with neurological symptoms; furthermore, it argues the notion of leukoencephalopathy as a typical feature of a severe case of the disease. Mechanisms underpinning neurological symptoms in COVID-19 still need to be elucidated; nonetheless, early recognition and prompt management may ensure their improvement or even complete recovery and are therefore recommended.

Epidemiology and seasonality of human parainfluenza serotypes 1-3 in Australian children.

BACKGROUND: Parainfluenza viruses are significant contributors to childhood respiratory illness worldwide, although detailed epidemiological studies are lacking. Few recent Australian studies have investigated serotype-specific PIV epidemiology, and there is a paucity of southern hemisphere PIV reports. We report age-stratified PIV hospitalisation rates and a mathematical model of PIV seasonality and dynamics in Western Australia (WA). METHODS: We used linked perinatal, hospital admission and laboratory diagnostic data of 469 589 children born in WA between 1996 and 2012. Age-specific rates of viral testing and PIV detection in hospitalised children were determined using person time-at-risk analysis. PIV seasonality was modelled using a compartmental SEIRS model and complex demodulation methods. RESULTS: From 2000 to 2012, 9% (n = 43 627) of hospitalised children underwent PIV testing, of which 5% (n = 2218) were positive for PIV-1, 2 or 3. The highest incidence was in children aged 1-5 months (PIV-1:62.6 per 100 000 child-years, PIV-2:26.3/100 000, PIV-3:256/100 000), and hospitalisation rates were three times higher for Aboriginal children compared with non-Aboriginal children overall (IRR: 2.93). PIV-1 peaked in the autumn of even-numbered years, and PIV-3 annually in the spring, whereas PIV-2 had inconsistent peak timing. Fitting models to the higher incidence serotypes estimated reproduction numbers of 1.24 (PIV-1) and 1.72 (PIV-3). CONCLUSION: PIV-1 and 3 are significant contributors towards infant respiratory hospitalisations. Interventions should prioritise children in the first 6 months of life, with respect to the observed autumn PIV-1 and spring PIV-3 activity peaks. Continued surveillance of all serotypes and investigation into PIV-1 and 3 interventions should be prioritised.

Inferring a complete genotype-phenotype map from a small number of measured phenotypes.

Understanding evolution requires detailed knowledge of genotype-phenotype maps; however, it can be a herculean task to measure every phenotype in a combinatorial map. We have developed a computational strategy to predict the missing phenotypes from an incomplete, combinatorial genotype-phenotype map. As a test case, we used an incomplete genotype-phenotype dataset previously generated for the malaria parasite's 'chloroquine resistance transporter' (PfCRT). Wild-type PfCRT (PfCRT3D7) lacks significant chloroquine (CQ) transport activity, but the introduction of the eight mutations present in the 'Dd2' isoform of PfCRT (PfCRTDd2) enables the protein to transport CQ away from its site of antimalarial action. This gain of a transport function imparts CQ resistance to the parasite. A combinatorial map between PfCRT3D7 and PfCRTDd2 consists of 256 genotypes, of which only 52 have had their CQ transport activities measured through expression in the Xenopus laevis oocyte. We trained a statistical model with these 52 measurements to infer the CQ transport activity for the remaining 204 combinatorial genotypes between PfCRT3D7 and PfCRTDd2. Our best-performing model incorporated a binary classifier, a nonlinear scale, and additive effects for each mutation. The addition of specific pairwise- and high-order-epistatic coefficients decreased the predictive power of the model. We evaluated our predictions by experimentally measuring the CQ transport activities of 24 additional PfCRT genotypes. The R2 value between our predicted and newly-measured phenotypes was 0.90. We then used the model to probe the accessibility of evolutionary trajectories through the map. Approximately 1% of the possible trajectories between PfCRT3D7 and PfCRTDd2 are accessible; however, none of the trajectories entailed eight successive increases in CQ transport activity. These results demonstrate that phenotypes can be inferred with known uncertainty from a partial genotype-phenotype dataset. We also validated our approach against a collection of previously published genotype-phenotype maps. The model therefore appears general and should be applicable to a large number of genotype-phenotype maps.

Modifications of sleep EEG induced by chronic vagus nerve stimulation in patients affected by refractory epilepsy.

OBJECTIVE: The aim of this study was to evaluate the impact of chronic vagus nerve stimulation (VNS) on sleep/wake background EEG and interictal epileptiform activity (IEA) of patients with medically refractory epilepsy. METHODS: From a broader sample of 10 patients subjected to baseline and treatment polysomnographies, spectral analysis and IEA count have been performed on 6 subjects' recordings, comparing the results by means of statistical analysis. RESULTS: An overall increase in EEG total power after VNS has been observed, more marked in NREM sleep; collapsing EEG power spectra into 5 frequency bands, we have found a statistically significant increase in delta and theta in NREM sleep, and of alpha in wakefulness and REM sleep. The incidence of IEA is diminished, although not significantly; only the duration of discharges is significantly diminished. CONCLUSIONS AND SIGNIFICANCE: Long-term VNS produces an enhancement in sleep EEG power of medically refractory epileptic patients. These results may be related to a better structured composition of EEG, and it is possible that chronic VNS may have a major role in enhancing the brain's ability to generate an electrical activity.

Chronic vagus nerve stimulation improves alertness and reduces rapid eye movement sleep in patients affected by refractory epilepsy.

OBJECTIVE: Our study aimed to evaluate the existence and entity of changes in sleep structure following vagus nerve stimulation in patients with refractory epilepsy. METHOD: A polysomnographic study was performed on the nocturnal sleep of 10 subjects with refractory epilepsy. Subjects were recorded both in baseline conditions and after chronic vagus nerve stimulation. Sleep parameters of the entire night were evaluated. Mean power value of slow-wave activity was computed in the first non-rapid eye movement sleep cycle. A sleep-wake diary evaluated quantity of both nocturnal and daytime sleep, while visual-analog scales assessed quality of sleep and wake. The differences between the 2 conditions underwent parametric and nonparametric statistical evaluation. RESULTS: Vagus nerve stimulation produced a significant reduction in REM sleep (in all subjects with vagus nerve stimulus intensity greater than 1.5 milliampere, but not in the only patient with a stimulus intensity less than 1.5 milliampere), along with an increase in the number of awakenings, percentage of wake after sleep onset, and stage 1 sleep. Data from a sleep-wake questionnaire show a decrease in both nocturnal sleep and daytime naps and an increased daytime alertness, while the quality of wakefulness is globally improved. Spectral analysis shows an enhancement of delta power during non-rapid eye movement sleep. CONCLUSIONS: Our data demonstrate major effects of vagus nerve stimulation on both daytime alertness (which is improved) and nocturnal rapid eye movement sleep (which is reduced). These effects could be interpreted as the result of a destabilizing action of vagus nerve stimulation on neural structures regulating sleep-wake and rapid eye movement/non-rapid eye movement sleep cycles. Lower intensity vagus nerve stimulation seems only to improve alertness; higher intensity vagus nerve stimulation seems able to exert an adjunctive rapid eye movement sleep-attenuating effect.