Neurological manifestations of COVID-19: available evidences and a new paradigm.

The recent pandemic outbreak of coronavirus is pathogenic and a highly transmittable viral infection caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2). In this time of ongoing pandemic, many emerging reports suggested that the SARS-CoV-2 has inimical effects on neurological functions, and even causes serious neurological damage. The neurological symptoms associated with COVID-19 include headache, dizziness, depression, anosmia, encephalitis, stroke, epileptic seizures, and Guillain-Barre syndrome along with many others. The involvement of the CNS may be related with poor prognosis and disease worsening. Here, we review the evidence of nervous system involvement and currently known neurological manifestations in COVID-19 infections caused by SARS-CoV-2. We prioritize the 332 human targets of SARS-CoV-2 according to their association with brain-related disease and identified 73 candidate genes. We prioritize these 73 genes according to their spatio-temporal expression in the different regions of brain and also through evolutionary intolerance analysis. The prioritized genes could be considered potential indicators of COVID-19-associated neurological symptoms and thus act as a possible therapeutic target for the prevention and treatment of CNS manifestations associated with COVID-19 patients.

Effect of External Positive and Negative Pressure on Venous Flow in an Experimental Model.

OBJECTIVE: Positive external pressure is said to decrease transmural pressure; negative pressure in the pleural cavity is widely believed to result in negative pressure in systemic chest veins. The discrepancy between erect column height and foot venous pressure has been explained on this basis. METHODS: These core concepts rest on static closed models that may not be appropriate. This study examined the effects of external pressures in a dynamic open model that may better reflect in vivo conditions. Flow in a Penrose drain enclosed in a chamber that could be positively or negatively pressurized was used. Input and output reservoirs with pressures in the physiological range provided flow. Flow and pressure were monitored in horizontal and erect models with modifications to suit particular experiments. RESULTS: The discrepancy between foot venous pressure and erect venous column height was shown in this experimental model to be a result of two flows in opposite directions (superior and inferior vena cavae) meeting at the zero reference level at the heart; the upper column pressure therefore does not register at the foot. Positive external pressure results in slowing of velocity with conversion to pressure. Internal and transmural pressures therefore do not decrease. Negative external pressure has only a marginal effect on flow; importantly, internal pressure does not become negative. In an experimental set-up it was shown that negative pressure in chest veins was not necessary for air embolism to occur. CONCLUSION: Persistent negative pressure in systemic chest veins probably does not occur. The reason for the discrepant foot venous pressure is likely to be a result of dynamic flow and not negative pressure in chest veins. External positive pressure results in slowing of velocity but the transmural pressure remains largely unchanged.

Scuba Diving-Induced Inner-Ear Pathology: Imaging Findings of Superior Semicircular Canal and Tegmen Tympani Dehiscence.

BACKGROUND Superior semicircular canal dehiscence is an inner-ear pathology which presents with vertigo, disequilibrium, and hearing loss. Although the exact etiology of superior semicircular canal dehiscence is unknown, it is thought that an increase in middle-ear pressure disrupts a thin overlying temporal bone. Superior semicircular canal dehiscence is frequently seen in association with dehiscence of the tegmen tympani, which overlies the middle ear. Here, we present a case report of a 52-year-old Puerto Rican man with vertigo, dizziness, vomiting, and mild hearing loss associated with superior semicircular canal and tegmen tympani dehiscence after performing improper scuba diving techniques. CASE REPORT A 52-year-old Puerto Rican man presented to the emergency department with vertigo, dizziness, vomiting, and mild hearing loss in the right ear. The symptoms began shortly after scuba diving with inadequate decompression techniques on ascent. He was treated with recompression therapy with mild but incomplete improvement in symptoms. Bilateral temporal magnetic resonance imaging was suggestive of segmental dehiscence of the right superior semicircular canal and tegmen tympani. High-resolution computed tomography of the temporal bone confirmed right superior semicircular canal and tegmen tympani dehiscence with an intact left inner ear. CONCLUSIONS The increased inner-ear pressure that occurs during scuba diving can lead to dehiscence of the superior semicircular canal and tegmen tympani, causing vertigo and hearing loss. Performance of improper diving techniques can further increase the risk of dehiscence. Therefore, appropriate radiologic evaluation of the inner ear should be performed in such patients.

Posterior Inferior Cerebellar Artery Aneurysm Shaped Like a "Calabash Gourd" and Mimicking a Tumor.

Posterior inferior cerebellar artery aneurysms are likely to be fusiform, yet they hardly enlarge to mimic a tumor in the posterior fossa on radiology. They constitute about 3%-4% of all cerebral aneurysms. A 65-year-old woman presented with tremor in her right upper limb for 1 year and intermittent dizziness for 8 months. Interestingly, magnetic resonance imaging revealed 2 unanimously enhanced masses like mother and daughter located in the right cerebellum hemisphere. The lesion was resected via surgery, and histopathology established the diagnosis of an aneurysm. Her tremor and dizziness subsided 3 months after the surgery, and at her 2-year follow-up she was well with no further neurologic deficits.

Clinical characteristics of cervicogenic-related dizziness and vertigo.

Cervical vertigo has long been a controversial entity and its very existence as a medical entity has advocates and opponents. Supporters of cervical vertigo claim that its actual prevalence is underestimated due to the overestimation of other diagnostic categories in clinics. Furthermore, different pathophysiological mechanisms have been attributed to cervical vertigo. Here the authors discuss the clinical characteristics of rotational vertebral artery vertigo, postwhiplash vertigo, proprioceptive cervical vertigo, and cervicogenic vertigo of old age. A clinical entity named subclinical vertebrobasilar insufficiency appears in the context of cervical osteoarticular changes. Migraine-associated vertigo may explain why some patients suffering from cervical pain have vertigo while others do not.

[Application of vestibular rehabilitation with an introduction session in patients with chronic dizziness].

Pharmacological and non-pharmacological approaches are the treatment options for dizzy patients. Vestibular exercises are a potential treatment option for intractable dizzy patients who do not respond to conventional drug therapy. The retention rate of exercises is quite important for a successful outcome. We organized vestibular exercise courses to improve the retention rate in the outpatient groups; these courses comprised introduction sessions with a clinical psychologist and rehabilitation sessions with a clinical technologist. It is unclear whether the effects of vestibular rehabilitation are based on the improvement of the psychological parameters of vestibular function. Therefore, we evaluated the functional mechanism of vestibular rehabilitation by using questionnaires and balance function tests. Our study comprised 16 patients with chronic dizziness. The patients performing the self-administered home-based vestibular exercise courses were supervised in small groups. The patients were taught that the exercises were to be performed 4 times a day at their respective homes. The symptoms of dizziness were evaluated using the Japanese version of the dizziness handicap inventory (DHI). Anxiety and depression levels were assessed using a set of psychological questionnaires. The static and dynamic balance function was assessed using static posturography and foam posturography and by measuring the time required for performing a certain series of eye-head movement protocols at the initial visit, before rehabilitation, and 2 and 3 months after rehabilitation. Of 16 patients, 15 could successfully complete the study (93.8%). The DHI score significantly improved 1 month after the rehabilitation, whereas anxiety and depression levels did not improve. The results of static and foam posturography as well as the time required for the eye-head movements also significantly improved. The improvement in the DHI scores was not associated with psychological changes, but with the improvement in the static and dynamic balance function.

Effect of repositioning maneuver type and postmaneuver restrictions on vertigo and dizziness in benign positional paroxysmal vertigo.

INTRODUCTION: To compare the efficiency of Epley (Ep) and Sémont-Toupet (ST) repositioning maneuvers and to evaluate postmaneuver restriction effect on short-term vertigo and dizziness after repositioning maneuvers by an analog visual scale (VAS) in benign positional paroxysmal vertigo (BPPV). MATERIAL AND METHODS: 226 consecutive adult patients with posterior canal BPPV were included. Patients were randomized into 2 different maneuver sequence groups (n = 113): 2 ST then 1 Ep or 2 Ep then 1 ST. Each group of sequence was randomized into 2 subgroups: with or without postmaneuver restrictions. Vertigo and dizziness were assessed from days 0 to 5 by VAS. RESULTS: There was no difference between vertigo scores between Ep and ST groups. Dizziness scores were higher in Ep group during the first 3 days but became similar to those of ST group at days 4 and 5. ST maneuvers induced liberatory signs more frequently than Ep (58% versus 42% resp., P < 0.01, Fisher's test). After repositioning maneuvers, VAS scores decreased similarly in patients with and without liberatory signs. Postmaneuver restrictions did not influence VAS scores. CONCLUSION: Even if ST showed a higher rate of liberatory signs than Ep in this series, VAS scores were not influenced by these signs.

Geriatric conditions develop in middle-aged adults with diabetes.

BACKGROUND: Geriatric conditions, collections of symptoms common in older adults and not necessarily associated with a specific disease, increase in prevalence with advancing age. These conditions are important contributors to the complex health status of older adults. Diabetes mellitus is known to co-occur with geriatric conditions in older adults and has been implicated in the pathogenesis of some conditions. OBJECTIVE: To investigate the prevalence and incidence of geriatric conditions in middle-aged and older-aged adults with diabetes. DESIGN: Secondary analysis of nationally-representative, longitudinal health interview survey data (Health and Retirement Study waves 2004 and 2006). PARTICIPANTS: Respondents 51 years and older in 2004 (n=18,908). MAIN MEASURES: Diabetes mellitus. Eight geriatric conditions: cognitive impairment, falls, incontinence, low body mass index, dizziness, vision impairment, hearing impairment, pain. KEY RESULTS: Adults with diabetes, compared to those without, had increased prevalence and increased incidence of geriatric conditions across the age spectrum (p< 0.01 for each age group from 51-54 years old to 75-79 years old). Differences between adults with and without diabetes were most marked in middle-age. Diabetes was associated with the two-year cumulative incidence of acquiring new geriatric conditions (odds ratio, 95% confidence interval: 1.8, 1.6-2.0). A diabetes-age interaction was discovered: as age increased, the association of diabetes with new geriatric conditions decreased. CONCLUSIONS: Middle-aged, as well as older-aged, adults with diabetes are at increased risk for the development of geriatric conditions, which contribute substantially to their morbidity and functional impairment. Our findings suggest that adults with diabetes should be monitored for the development of these conditions beginning at a younger age than previously thought.

Population pharmacokinetic model development and its relationship with adverse events of oxcarbazepine in adult patients with epilepsy.

This study aimed to develop a pharmacokinetic (PK) model of oxcarbazepine (OXC) and analyse the relationship between monohydroxylated derivative (MHD), an active metabolite of OXC, and the adverse events of OXC. We obtained 711 OXC samples from 618 patients with epilepsy who were enrolled in the Epilepsy Registry Cohort of Seoul National University Hospital from February 2011 to January 2014. The plasma PK model was developed using a nonlinear mixed-effect modelling method with NONMEM (ver 7.3). A one-compartment model with a first-order absorption model and proportional residual error adequately described the MHD concentration-time profiles. The only covariate incorporated for CL/F and V/F was body weight. Of the 447 patients analysed, 28 (6.26%) had dose-related adverse events (DRAEs), which were dizziness, somnolence, headache, and diplopia. For DRAE occurrence, the cut-off values of the MHD trough and AUC were 12.27 mg/L (specificity 0.570, sensitivity 0.643) and 698.5 mg h/L (specificity, sensitivity 0.571), respectively. Multivariate analysis showed the sole dizziness symptom was significantly associated with both the MHD trough and the AUC (p = 0.013, p = 0.038, respectively). We newly developed a population PK model using sparse sampling data from patients with epilepsy, and the model better reflects the actual clinical situation.

Case Report: Encephalitis Caused by Balamuthia mandrillaris in a 3-Year-Old Iranian Girl.

It is about half a century since free-living amoebae were recognized as pathogenic organisms, but there is still much we should learn about these rare fatal human infectious agents. A recently introduced causative agent of granulomatous amoebic encephalitis, Balamuthia mandrillaris, has been reported in a limited number of countries around the world. A 3-year-old girl was referred to our tertiary hospital because of inability to establish a proper diagnosis. She had been experiencing neurologic complaints including ataxia, altered level of consciousness, dizziness, seizure, and left-sided hemiparesis. The patient's history, physical examination results, and laboratory investigations had led to a wide differential diagnosis. Computed tomography (CT) scan and magnetic resonance imaging analyses revealed multiple mass lesions. As a result, the patient underwent an intraoperative frozen section biopsy of the brain lesion. The frozen section study showed numerous cells with amoeba-like appearances in the background of mixed inflammatory cells. Medications for free-living amoebic meningoencephalitis were administered. PCR assay demonstrated B. mandrillaris as the pathogenic amoeba. Unfortunately, the patient died 14 days after her admission. To our knowledge, this is the first report of B. mandrillaris meningoencephalitis in the Middle East and the first time we have captured the organism during a frozen-section study.

Hereditary Angioedema Type 1 with Recurrent Dizziness.

A 41-year-old woman presented with recurrent dizziness. After an attack of dizziness, she felt edematous sensations in her hands. However, according to photographs taken during the attack, the edema on the back of the patient's hands and fingers appeared mild. Laboratory examinations revealed a low C4 and C1 inhibitor (INH) activity. A direct sequencing analysis of C1INH revealed a pathogenic gene mutation. Based on these results, she was diagnosed with hereditary angioedema (HAE) type 1. These findings indicate that HAE can cause recurrent dizziness, and it should therefore be included in the differential diagnosis in patients with recurrent neurologic symptoms, even in the absence of severe edema.

Diffusion tensor imaging in orthostatic tremor: a tract-based spatial statistics study.

OBJECTIVE: The pathogenesis of orthostatic tremor (OT) is unknown. We investigated OT-related white matter changes and their correlations with scores from a neuropsychological testing battery. METHODS: Diffusion tensor imaging measures were compared between 14 OT patients and 14 age- and education-matched healthy controls, using whole-brain tract-based spatial statistics analysis. Correlations between altered diffusion metrics and cognitive performance in OT group were assessed. RESULTS: In all cognitive domains (attention, executive function, visuospatial ability, verbal memory, visual memory, and language), OT patients' cognitive performance was significantly worse than that of healthy controls. OT patients demonstrated altered diffusivity metrics not only in the posterior lobe of the cerebellum (left cerebellar lobule VI) and in its efferent cerebellar fibers (left superior cerebellar peduncle), but also in medial lemniscus bilaterally (pontine tegmentum), anterior limb of the internal capsule bilaterally, right posterior limb of the internal capsule, left anterior corona radiata, right insula, and the splenium of corpus callosum. No relationship was found between diffusion measures and disease duration in OT patients. Diffusion white matter changes, mainly those located in right anterior limb of the internal capsule, were correlated with poor performance on tests of executive function, visuospatial ability, verbal memory, and visual memory in OT patients. INTERPRETATION: White matter changes were preferentially located in the cerebellum, its efferent pathways, as well as in the pontine tegmentum and key components of the frontal-thalamic-cerebellar circuit. Further work needs to be done to understand the evolution of these white matter changes and their functional consequences.

Oxidative Stress in Cerebral Small Vessel Disease Dizziness Patients, Basally and After Polyphenol Compound Supplementation.

BACKGROUND: Leukoaraiosis (LA) is a common radiological finding in elderly, frequently associated with several clinical disorders, including unexplained dizziness. The pathogenesis of LA is multifactorial, with a dysfunction of cerebral microcirculation resulting in chronic hypoperfusion and tissue loss, with oxidative stress involved in this cascade. OBJECTIVE: The aim of this study was to analyse some oxidative stress biomarkers in a cohort of LA patients. METHOD: Fifty-five consecutive patients (33 males, median age 75 years) with LA were recruited. In a subgroup of 33 patients with LA and unexplained dizziness, we have then performed an open study to evaluate if 60-day supplementation with a polyphenol compound may modify these biomarkers and influence quality of life, analysed with the Dizziness Handicap Inventory (DHI) scale. RESULTS: At baseline, blood oxidative stress parameters values were outside normal ranges and compared to matched healthy controls. After the two months supplementation, we observed a significant decrement of advanced oxidation protein products values and a significant improvement of DHI. CONCLUSION: Oxidative stress biomarkers may be useful to detect redox imbalance in LA and to provide non-invasive tools to monitor disease status and response to therapy.

Cervical Intervertebral Disc Degeneration Contributes to Dizziness: A Clinical and Immunohistochemical Study.

OBJECTIVES: Dizziness often happens in patients with chronic neck pain with only cervical disc degeneration but without cervical radiculopathy or myelopathy. We prospectively selected a series of patients who showed cervical disc degeneration with concomitant chronic neck pain and intractable dizziness who did not respond to conservative treatment to test a new diagnostic method for this dizziness, to analyze the results of anterior cervical discectomy and fusion (ACDF) surgery based on the test, and to explore its pathogenesis. METHODS: Seventy-seven patients who had a transient neck pain and dizziness relief after injection of bupivacaine into a suspected disc were included in the study. In total, 52 underwent ACDF as surgery group, and 25 refused surgery and accepted conservative treatments as conservative group from June, 2015 to October, 2016 with subsequent follow-up to 1 year. The outcomes were visual analogue scale for neck pain, Neck Disability Index, and intensity and frequency of dizziness. During ACDF, the 72 specimens of degenerative cervical discs were collected to determine the innervation in degenerative cervical discs immunohistochemically. RESULTS: After surgery, the patients experienced a significant reduction in neck pain and dizziness. Symptomatic relief in surgery group was obviously better than conservative group at each time point of follow-up (P = 0.001). Ruffini corpuscles and substance P-positive free nerve fibers were obviously increased in the number and deeply ingrown into the inner degenerative cervical discs. CONCLUSIONS: Current clinical and immunohistochemical studies strongly suggest that chronic neck pain and intractable dizziness in this series of patients stem from the degenerative cervical discs.

Predicting continued dizziness after an acute peripheral vestibular disorder.

OBJECTIVE: To identify individuals at risk of developing ongoing dizziness 3 months after an acute peripheral vestibular disorder episode, which is usually functionally compensated or even healed within a few weeks. METHODS: In a prospective longitudinal study, we assessed fear of bodily sensations and cognitions related to anxiety at the time of hospital admission and 3 months later in 43 patients with an episode of vestibular neuritis (VN) or benign paroxysmal positional vertigo (BPPV). All participants were assessed for mental disorders using a structured clinical interview. RESULTS: Only the interaction between fear of bodily sensations within the first 2 weeks after admission and the type of vestibular disorder predicted the extent of dizzy complaints 3 months later; this accounts for 21% of the variance in a multiple regression analysis. Specifically, the prediction was valid only in patients with VN but not in patients with BPPV. Further analysis demonstrated that the interaction was not due to the peripheral vestibular disorder per se but rather determined by the initial severity of dizziness, which was significantly different in BPPV and VN patients. CONCLUSIONS: The present study demonstrates that, for the development of persistent psychogenic dizziness after a peripheral vestibular disorder, the fear of bodily sensations is only relevant in interaction with the initial severity of dizziness experienced during the acute organic episode. To prevent development of persistent psychogenic dizziness, we feel that our results indicate the need to screen patients with vestibular disorders for at-risk status and offer them psychological support to deal with their symptoms.

The relationship between cerebral T2 hyperintensity and fixation suppression of vestibulo-ocular reflex in elderly patients with dysequilibrium symptoms.

OBJECTIVES: To evaluate the relationship between cerebral T2 hyperintensity on MRI and visual suppression of vestibulo-ocular reflex (VOR) in elderly patients with dysequilibrium symptoms. METHODS: Eighty-nine elderly patients with no MRI abnormalities in the infratentorial region aged 60-89 years complaining dysequilibrium symptoms were studied. Cases with whom a definitive diagnosis of peripheral or central disease could be established were not included. T2 hyperintense lesions in the cerebrum: basal ganglia, subcortical white matter and periventricular white matter were evaluated. VOR in darkness and fixation-suppressed VOR using pseudo-sinusoidal rotation stimuli were recorded to calculate visual suppression rate. Correlation between visual suppression rate and semi-quantitative scores for severity of T2 hyperintensity in the cerebrum was investigated. RESULTS: Patients with T2 hyperintensity in the cerebrum exhibited significantly lower visual suppression rate than those without lesions in the cerebrum. Multiple regression analysis showed that visual suppression rate was significantly and negatively correlated with severity of lesions in the basal ganglia, but not with patient age, severity of subcortical white matter lesions, or that of periventricular white matter lesions. CONCLUSIONS: In elderly patients with dizziness with a non-specific history and otoneurological findings, fixation suppression of vestibular nystagmus was associated with T2 hyperintensities in the basal ganglia.

The impact of diabetes on mobility, balance, and recovery after repositioning maneuvers in individuals with benign paroxysmal positional vertigo.

AIM: The prevalence of benign paroxysmal positional vertigo (BPPV) is higher in people with type 2 diabetes (DM). The impact of DM on mobility, balance, and management of BPPV is unknown. This prospective study compared symptom severity, mobility and balance before and after the canalith repositioning maneuver (CRM) in people with posterior canal BPPV canalithiasis, with and without DM. METHODS: Fifty participants, BPPV (n=34) and BPPV+DM (n=16) were examined for symptom severity (dizziness handicap inventory, DHI), mobility (functional gait assessment, FGA), and postural sway (using an accelerometer in five conditions) before and after the CRM. The number of maneuvers required for symptom resolution was recorded. RESULTS: At baseline, no differences in DHI or FGA scores were seen between groups, however, people with BPPV+DM had higher sway velocity in the medio-lateral direction in tandem stance (p<0.01). After treatment, both groups improved in DHI and FGA scores (p<0.01), with no differences between groups. Decrease in sway velocity in the mediolateral direction (p=0.003) were seen in tandem stance in persons with BPPV+DM. There were no differences between the groups in the number of CRMs provided. CONCLUSIONS: This pilot study showed no differences in symptom severity, mobility deficits or efficacy of CRM treatments in people with posterior canal BPPV canalithiasis with and without DM. Future studies examining the impact of the severity and duration of diabetes, as well as the influence of diabetic peripheral neuropathy on functional performance are essential.

Interobserver agreement in magnetic resonance brain and neck imaging.

AIM: To investigate the interobserver reliability of brain and neck magnetic resonance imaging (MRI) in older community subjects previously recruited to a case-control study of dizziness. METHODS: Subjects aged over 65 years were identified through a local survey and advertising. Several investigations were performed, including MRI of the head and neck using a Siemens 1.5 Tesla machine. Images were coded independently by two consultant neuroradiologists. Interobserver agreement was calculated using kappa statistics. RESULTS: Of the 246 participants, scans from 84 dizzy subjects and 79 non-dizzy subjects were available for coding by two neuroradiologists. Agreement was "fair" for cerebral atrophy, "good" for white matter lesions (WML) in the cerebral hemispheres, and moderate for WML in the posterior fossa. Agreement for cervical spine disease ranged from "moderate" (severity of cord compression) to "poor" (vertebral artery occlusion). CONCLUSION: Interobserver variability in the evaluation of brain and cervical cord MRI was substantial. The development of standardized scores, particularly for disease of the cervical cord, may improve interobserver reliability.