Neurological and Head/Eyes/Ears/Nose/Throat Manifestations of COVID-19: A Systematic Review and Meta-Analysis.

BACKGROUND/OBJECTIVE: Coronavirus disease 2019 (COVID-19) has been associated with various neurological and atypical head/eyes/ears/nose/throat (HEENT) manifestations. We sought to review the evidence for these manifestations. METHODS: In this systematic review and meta-analysis, we compiled studies published until March 31, 2021 that examined non-respiratory HEENT, central, and peripheral nervous system presentations in COVID-19 patients. We included 477 studies for qualitative synthesis and 59 studies for meta-analyses. RESULTS: Anosmia, ageusia, and conjunctivitis may precede typical upper/lower respiratory symptoms. Central nervous system (CNS) manifestations include stroke and encephalopathy, potentially with brainstem or cranial nerve involvement. MRI studies support CNS para-/postinfectious etiologies, but direct neuroinvasion seems very rare, with few cases detecting Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in the CNS. Peripheral nervous system (PNS) manifestations include muscle damage, Guillain-Barre syndrome (GBS), and its variants. There was moderate-to-high study heterogeneity and risk of bias. In random-effects meta-analyses, anosmia/ageusia was estimated to occur in 56% of COVID-19 patients (95% CI: 0.41-0.71, I2:99.9%), more commonly than in patients without COVID-19 (OR: 14.28, 95% CI: 8.39-24.29, I2: 49.0%). Neurological symptoms were estimated to occur in 36% of hospitalized patients (95% CI: 0.31-0.42, I2: 99.8%); ischemic stroke in 3% (95% CI: 0.03-0.04, I2: 99.2%), and GBS in 0.04% (0.033%-0.047%), more commonly than in patients without COVID-19 (OR[stroke]: 2.53, 95% CI: 1.16-5.50, I2: 76.4%; OR[GBS]: 3.43,1.15-10.25, I2: 89.1%). CONCLUSIONS: Current evidence is mostly from retrospective cohorts or series, largely in hospitalized or critically ill patients, not representative of typical community-dwelling patients. There remains a paucity of systematically gathered prospective data on neurological manifestations. Nevertheless, these findings support a high index of suspicion to identify HEENT/neurological presentations in patients with known COVID-19, and to test for COVID-19 in patients with such presentations at risk of infection.

Prevalence of mild behavioral impairment in mild cognitive impairment and subjective cognitive decline, and its association with caregiver burden.

BACKGROUND: Mild behavioral impairment (MBI) describes later life acquired, sustained neuropsychiatric symptoms (NPS) in cognitively normal individuals or those with mild cognitive impairment (MCI), as an at-risk state for incident cognitive decline and dementia. We developed an operational definition of MBI and tested whether the presence of MBI was related to caregiver burden in patients with subjective cognitive decline (SCD) or MCI assessed at a memory clinic. METHODS: MBI was assessed in 282 consecutive memory clinic patients with SCD (n = 119) or MCI (n = 163) in accordance with the International Society to Advance Alzheimer's Research and Treatment - Alzheimer's Association (ISTAART-AA) research diagnostic criteria. We operationalized a definition of MBI using the Neuropsychiatric Inventory Questionnaire (NPI-Q). Caregiver burden was assessed using the Zarit caregiver burden scale. Generalized linear regression was used to model the effect of MBI domains on caregiver burden. RESULTS: While MBI was more prevalent in MCI (85.3%) than in SCD (76.5%), this difference was not statistically significant (p = 0.06). Prevalence estimates across MBI domains were affective dysregulation (77.8%); impulse control (64.4%); decreased motivation (51.7%); social inappropriateness (27.8%); and abnormal perception or thought content (8.7%). Affective dysregulation (p = 0.03) and decreased motivation (p=0.01) were more prevalent in MCI than SCD patients. Caregiver burden was 3.35 times higher when MBI was present after controlling for age, education, sex, and MCI (p < 0.0001). CONCLUSIONS: MBI was common in memory clinic patients without dementia and was associated with greater caregiver burden. These data show that MBI is a common and clinically relevant syndrome.

Utility of the Canadian Treatment Optimization Recommendations (TOR) in MS care.

OBJECTIVES: Criteria for Treatment Optimization Recommendations (TOR) for patients with multiple sclerosis (MS) identify suboptimal response to disease-modifying treatment (DMT). The Canadian TOR (CanTOR) were used to indicate recommendations for treatment switches or treatment maintenance based on relapse, disease progression and magnetic resonance imaging (MRI) criteria in patients. We assessed concordance between the TOR and clinicians' decisions regarding treatment response and identified prevalence of patients with MS receiving DMT meeting medium/high levels of concern according to TOR. METHODS: Prospective baseline and end-of-study assessments of patients with relapsing-remitting MS (RRMS) or clinically isolated syndrome were conducted in this open-label, 12-month, Phase IV, observational Canadian study. RESULTS: Data were reported for 184 patients (female 72%, mean age 39 years) of which 96% had RRMS. The TOR criteria identified 19 (10.3%) patients with suboptimal response to treatment. Twelve patients had ≥1 high level of concern. Two patients had ≥2 medium levels of concern. Concordance between TOR and clinician decision in maintaining treatment was 95.3%. Where treatment change was recommended by the TOR, concordance was 29.4%. Clinicians identified the TOR as the principal reason for changing treatment in 50.0% of cases where the TOR identified suboptimal response. The TOR were considered useful by 70.6% of clinicians when treatment optimization was recommended and by 55.3% when maintaining treatment was recommended. CONCLUSIONS: The TOR criteria can identify suboptimal response in this patient cohort. Concordance between TOR and clinician decision was high when maintaining treatment was recommended. Usefulness of the TOR was most apparent when treatment optimization was recommended.

A pragmatic dementia risk score for patients with mild cognitive impairment in a memory clinic population: Development and validation of a dementia risk score using routinely collected data.

Introduction: This study aimed to develop and validate a 3-year dementia risk score in individuals with mild cognitive impairment (MCI) based on variables collected in routine clinical care. Methods: The prediction score was trained and developed using data from the National Alzheimer's Coordinating Center (NACC). Selection criteria included aged 55 years and older with MCI. Cox models were validated externally using two independent cohorts from the Prospective Registry of Persons with Memory Symptoms (PROMPT) registry and the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Results: Our Mild Cognitive Impairment to Dementia Risk (CIDER) score predicted dementia risk with c-indices of 0.69 (95% confidence interval [CI] 0.66-0.72), 0.61 (95% CI 0.59-0.63), and 0.72 (95% CI 0.69-0.75), for the internally validated and the external validation PROMPT, and ADNI cohorts, respectively. Discussion: The CIDER score could be used to inform clinicians and patients about the relative probabilities of developing dementia in patients with MCI.

Complications in MS patients after CCSVI procedures abroad (Calgary, AB).

BACKGROUND: The "chronic cerebrospinal venous insufficiency" or "CCSVI" hypothesis, namely that multiple sclerosis (MS) is caused by abnormalities in the azygous and internal jugular veins with subsequent alterations in venous hemodynamics in the central nervous system, has been a dominant topic in MS care in Canada over the past year. Although there is no methodologically rigorous evidence to support this hypothesis presently, a considerable number of MS patients have undergone endovascular CCSVI procedures. Such procedures include angioplasty or stent placement in jugular and azygous veins. The safety and efficacy of these procedures is unknown, but not without risk. METHODS: Chart and patient review of five patients with confirmed MS followed in Calgary were undertaken after patients came to medical attention by referral or admission secondary to complications believed to be associated with CCSVI procedures. RESULTS: Complications upon investigation and review included internal jugular vein stent thrombosis, cerebral sinovenous thrombosis, stent migration, cranial nerve injury and injury associated with venous catheterization. CONCLUSIONS: As the debate about CCSVI and its relationship to MS continues, the complications and risks associated with venous stenting and angioplasty in jugular and azygous veins are becoming clearer. As increasing numbers of MS patients are seeking such procedures, these five cases represent the beginning of a wave of complications for which standardized care guidelines do not exist. Our experience and that of our colleagues will be used to develop guidelines and strategies to monitor and manage these patients as their numbers increase.

Pilot study of minocycline in relapsing-remitting multiple sclerosis.

BACKGROUND: Current multiple sclerosis (MS) treatment is only partially effective and not all patients respond well. The goal in this study was to evaluate minocycline for its safety, tolerability, and MRI impact as a potential therapy over 36 months after a three month run-in in ten relapsing-remitting (RR) MS patients. METHODS: Clinical assessments were at three month intervals until six months, then at six month intervals. Three Tesla MRI was performed monthly during the run-in and first six months of treatment, then at 12, 24, and 36 months. RESULTS: Treatment was safe and well tolerated. Annualized relapse rate was 1.2 during the run-in and 0.25 during treatment. The proportion of active scans was lower during the first six months of treatment (5.6%, p < 0.001) and during the extension (8.7%, p = 0.002) than during the run-in (47.5%). Consistent with these outcomes, mean T2 lesion volume remained stable over three years and percent brain volume change was reduced during year three (-0.37%) of minocycline treatment. CONCLUSIONS: This trial is limited by small sample and no control group but suggests that minocycline is safe and potentially beneficial in RRMS. This supports further investigation of its efficacy.

The syndrome of stroke-like migraine attacks after radiation therapy associated with prolonged unresponsiveness in an adult patient.

INTRODUCTION: The syndrome of stroke-like migraine attacks after radiation therapy (SMART) is an extremely rare complication of cerebral irradiation. It is characterized by reversible episodic neurological dysfunction, commonly associated with headaches and occasionally with seizures, occurring years after cranial radiotherapy. Approximately a dozen cases have been reported in adult patients to date. CASE REPORT: In 1997, a 48-year-old man underwent resection of a right cerebellar metastasis from renal cell carcinoma, followed by whole-brain irradiation. Two years later he began experiencing recurrent episodes of headache associated with reversible left hemiparesis, dysphasia, visual field defects, and confusion. Over subsequent years these episodes increased in frequency, and in 2009 and 2010 the patient experienced 2 episodes associated with seizures and characterized by severe depression in level of consciousness (GCS 5); the latter of these was particularly prolonged, with neurological recovery requiring almost 6 months. Cortical and leptomeningeal gadolinium enhancement was demonstrated on magnetic resonance imaging during the second episode. Repeated electroencephalography studies did not demonstrate any epileptiform activity, and extensive workup including brain biopsy failed to identify any neoplastic, vascular, or infective pathology. The diagnosis of SMART syndrome was therefore made. CONCLUSIONS: Reduced level of consciousness of such severity and duration as observed here has not previously been described in SMART syndrome. This report, however, suggests that an excellent prognosis can be expected even in cases of prolonged unresponsiveness. The pathogenic mechanisms of SMART syndrome remain unclear, but may involve pathways common to both migraine and epilepsy.

The promise of futility trials in neurological diseases.

Double-blinded randomized controlled trials (RCTs) have contributed much important evidence to guide treatment decisions in neurology. RCTs are relatively straightforward to conduct, provided that they investigate common diseases, have clearly defined outcome measures, and are of short duration. In neurology, however, many diseases are uncommon, have no consensus outcome measures, and develop over decades. Basic research into neurological diseases continues to identify candidate therapies faster than they can be tested for their clinical utility, leading to a 'translational gap'. Futility trials were initially developed in oncology to efficiently test candidate therapies in phase II trials. As single-arm unblinded studies, futility trials are relatively easy to conduct, and they generally require smaller sample sizes than RCTs. In this article, we discuss futility models, highlighting their advantages as well as challenges to their application in several neurological diseases, including Parkinson disease, stroke and multiple sclerosis.

Long-term persistence with injectable therapy in relapsing-remitting multiple sclerosis: an 18-year observational cohort study.

Disease modifying therapies (DMTs) reduce the frequency of relapses and accumulation of disability in multiple sclerosis (MS). Long-term persistence with treatment is important to optimize treatment benefit. This long-term, cohort study was conducted at the Calgary MS Clinic. All consenting adults with relapsing-remitting MS who started either glatiramer acetate (GA) or interferon-ß 1a/1b (IFN-ß) between January 1st, 1996 and July 1st, 2011 were included. Follow-up continued to February 1st, 2014. Time-to-discontinuation of the initial and subsequently-prescribed DMTs (switches) was analysed using Kaplan-Meier survival analyses. Group differences were compared using log-rank tests and multivariable Cox regression models. Analysis included 1471 participants; 906 were initially prescribed GA and 565 were initially prescribed IFN-ß. Follow-up information was available for 87%; 29 (2%) were lost to follow-up and 160 (11%) moved from Southern Alberta while still using DMT. Median time-to-discontinuation of all injectable DMTs was 11.1 years. Participants with greater disability at treatment initiation, those who started treatment before age 30, and those who started between 2006 and 2011 were more likely to discontinue use of all injectable DMTs. Median time-to-discontinuation of the initial DMT was 8.6 years. Those initially prescribed GA remained on treatment longer. Of 610 participants who discontinued injectable DMT, 331 (54%) started an oral DMT, or a second-line DMT, or resumed injectable DMT after 90 days. Persistence with injectable DMTs was high in this long-term population-based study. Most participants who discontinued injectable DMT did not remain untreated. Further research is required to understand treatment outcomes and outcomes after stopping DMT.

Treatment optimization in multiple sclerosis.

The treatment of multiple sclerosis has finally become possible with the advent of the current disease-modifying therapies (DMTs) that have had a significant impact on those living with this disease. Though demonstrating clear efficacy on a number of short-term outcome measures, unfortunately, these agents are not "cures" and many patients with multiple sclerosis continue to experience disease activity in spite of treatment. Clinicians are becoming more comfortable initiating therapy with DMTs, but it is now important to focus attention on monitoring the results of the chosen therapy and deciding whether or not a patient is responding well to treatment. At present, however, clinicians lack criteria for defining optimal versus suboptimal responses to DMTs as well as evidence-based guidelines on how to improve treatment outcomes. Using a recently published model as a framework, The Canadian Multiple Sclerosis Working Group developed practical recommendations on how neurologists can assess the status of patients on DMTs and decide when it may be necessary to modify treatment in order to optimize outcomes. The Canadian Multiple Sclerosis Working Group's recommendations are based on monitoring relapses, neurological progression and MRI activity. Other possible causes of suboptimal treatment responses or treatment failure are also considered.

Calgary experience with West Nile virus neurological syndrome during the late summer of 2003.

BACKGROUND: Between August 25 and September 25, 2003 seven patients with West Nile virus neurological manifestations were identified through the hospital neurology consultation services in Calgary, Alberta, Canada. Three of the seven patients were treated with interferon alpha-2b (IFN alpha-2b). In this report we document the clinical characteristics of these seven cases. METHODS: Clinical and laboratory information was obtained from a retrospective review of patient hospital and clinic charts. Patients were included if they had serological evidence of West Nile virus infection and had clinical evidence of aseptic meningitis, encephalomyelitis, cerebellar syndrome or motor neuronopathy. Three patients received a treatment course of three million units IFN alpha-2b, administered by subcutaneous injection once per day for 14 days. RESULTS: Four patients had cerebellar signs without change in consciousness, two had both encephalitis and neuromuscular weakness, and one patient had focal lower motor neuron arm weakness. The mean age was 52 (range 24 - 73). All patients had flu-like illness and fever as presenting symptoms and six had severe headaches. Two patients were immunocompromised prior to infection. Two patients with cerebellar signs (one with opsoclonus-myoclonus) improved spontaneously and exhibited only mild residual deficits on discharge. The other two patients with cerebellar findings developed brainstem involvement, one coinciding with and one subsequent to the cerebellar symptoms. Within one week of treatment with IFN alpha-2b these latter two patients showed marked improvement. One patient with encephalitis and neuromuscular weakness, was treated with IFN alpha-2b and subsequently recovered. INTERPRETATION: In this case review of seven patients, multiple neurological symptoms occurred in each patient and the neurological presentation was varied. Four patients had predominant cerebellar findings and one patient had opsoclonus-myoclonus, not previously reported. The marked improvement in three patients who received IFN alpha-2b raises preliminary optimism towards this potential treatment.

Herpes encephalitis presenting with an opercular syndrome and epilepsia partialis continua.

OBJECTIVES: The opercular syndrome is a rare form of pseudobulbar palsy that is characterized by automatic-voluntary dissociative weakness of the face in addition to weak masticatory and pharyngeal muscles. It is typically seen in the setting of an acute stroke or in association with various congenital malformations of the cortex. It has also been described rarely in association with herpes encephalitis but with an abnormal cerebrospinal fluid (CSF) cell count. METHODS: We report on a 65-year-old-man with an opercular syndrome associated with epilepsia partialis continua (EPC) secondary to acute herpes simplex virus encephalitis despite an initial near normal CSF analysis. RESULTS: Initial EEG was unremarkable while CSF analysis revealed changes suggestive of a traumatic tap. An opercular syndrome was diagnosed based on the classic presentation of dysarthria, facial diplegia, and hypersalivation, with corresponding MRI brain changes in the operculum. During admission, EPC developed, with continuous right facial twitching and an electroencephalographic correlate in the left centrotemporal region. The EPC initially responded to intravenous lorazepam. Phenytoin was then added for seizure prophylaxis. Herpes virus DNA was later on detected in the CSF. The patient improved with antiviral treatment except for very mild residual dysarthria. CONCLUSION: Neurologists should be aware of the possible predilection of the herpes simplex virus for the opercular area and the need to empirically treat for herpes encephalitis even in the setting of near normal initial CSF studies in patients with a suggestive clinical presentation.