Developmental delay in Rett syndrome: data from the natural history study

Background

Early development appears normal in Rett syndrome (OMIM #312750) and may be more apparent than real. A major purpose of the Rett Syndrome (RTT) Natural History Study (NHS) was to examine achievement of developmental skills or abilities in classic and atypical RTT and assess phenotype-genotype relations in classic RTT.

Methods

Developmental skills in four realms, gross and fine motor, and receptive and expressive communication from initial enrollment and longitudinal assessments for up to 7 years, were assessed from 542 females meeting criteria for classic RTT and 96 females with atypical RTT divided into two groups: 50 with better and 46 with poorer functional scores. Data were analyzed for age at acquisition and loss of developmental features and for phenotype-genotype effects. Acquired, lost, and retained skills were compared between classic RTT and atypical RTT with better or poorer functional scores using Fisher''s Exact test. To examine if the mean total score from the Motor Behavioral Assessment during follow-up differed for acquiring a skill, we used a generalized estimating equation assuming compound symmetry correlation structure within a subject. A general linear model was used to examine whether the mean age of acquisition or loss of a developmental skill differed by mutation type. P values <0.05 were considered significant and were two-sided without adjustment for multiple testing. Statistical analyses utilized SAS 9.3 (SAS Institute, Cary, NC, USA).

Results

Early developmental skills or abilities were often acquired albeit later than normal. More complex motor and communication acquisitions were delayed or absent. Clinical severity was less in those achieving the respective skill. Individuals with R133C, R294X, and R306C point mutations and 3′ truncations tended to have better developmental outcomes.

Conclusions

Early developmental skills were acquired by many, but clear differences from normal emerged, particularly in skills expected after age 6 months. When comparing clinical severity, greater acquisition of specific skills was associated with specific mutations, confirming the impression that these mutations confer milder developmental abnormalities. These data may serve for planning and interpretation of early intervention studies in RTT.

Trial registration

This NHS study, clinicaltrials.gov ({"type":"clinical-trial","attrs":{"text":"NCT00296764","term_id":"NCT00296764"}}NCT00296764), represents the largest group of RTT participants assessed repeatedly by direct examination.     

Meaningful word acquisition is associated with walking ability over 10 years in Rett syndrome

PurposeTo investigate walking ability in Japanese patients with Rett syndrome (RTT).MethodsWalking ability was assessed in 100 female Japanese patients with RTT using univariate and multivariate analysis in all age groups, and in patients over 10 years of age. We analyzed walking ability and confounding factors including prenatal-perinatal histories, developmental milestones, somatic and head growth, anthropometric data, body mass index, age of loss of purposeful hand use, age at onset of stereotypic hand movement, history of autistic behavior, age at regression, presence or absence of seizures, and the results of MECP2 genetic examination from the Japanese Rett syndrome database.ResultsUnivariate analysis revealed that acquisition of walking in all age groups was significantly correlated with the acquisition of meaningful words, microcephaly, and crawling (P < 0.0001, P = 0.005, P < 0.0001, respectively). Univariate analysis revealed that walking ability over 10 years of age was significantly correlated with acquisition of meaningful words, microcephaly, and body mass index (P < 0,0001, P = 0.005, P = 0.0018, respectively). MECP2 mutations R306C, R133C, and R294X were significantly associated with different acquisition of crawling (P = 0.004) and walking (P = 0.01). Multivariate analysis revealed that only acquisition of meaningful words was significantly correlated with walking ability over 10 years of age. This trend excluded the genetic effects of R306C, R133C, and R294X.ConclusionsMeaningful word acquisition was robustly associated with walking ability over 10 years. Prognosis of walking ability may be predicted by the acquisition of meaningful words. This information is potentially useful for early intervention and the planning of comprehensive treatment for young children with RTT.     

Pediatric Stroke Clinical Pathway Improves the Time to Diagnosis in an Emergency Department

BackgroundIdentified barriers to the diagnosis of pediatric stroke include delays in provider recognition and definitive neuroimaging (magnetic resonance imaging). Clinical pathways are recommended to address these barriers; yet few studies have evaluated their impact. Our aim is to describe the effect of a pediatric stroke clinical pathway on the diagnosis of stroke in patients presenting with focal neurological dysfunction to a pediatric emergency department.MethodsThe pediatric stroke clinical pathway was implemented in our level 1 pediatric emergency department in June 2014 for children aged one month to 18 years. Demographic and clinical data were collected for patients ultimately diagnosed with stroke using the pediatric stroke clinical pathway and compared with data collected on patients diagnosed with stroke before implementation of the pediatric stroke clinical pathway.ResultsThe pediatric stroke clinical pathway was activated for 36 patients. Stroke was diagnosed in 11 patients (33%), of whom 55% were male with a median age 11 ± 7 years. Focal deficits (82%) and headache (55%) were common presenting complaints. There was a significant improvement in the median time to magnetic resonance imaging from arrival to the emergency department (before implementation of the pediatric stroke clinical pathway: 17 hours [interquartile range 6, 22] versus after implementation of the pediatric stroke clinical pathway: four hours [interquartile range 3, 12]; P = 0.02).ConclusionsThe pediatric stroke clinical pathway improved time to definitive diagnosis and streamlined the care provided to children presenting to the pediatric emergency department with focal neurological dysfunction.     

The course of awake breathing disturbances across the lifespan in Rett syndrome

Rett syndrome (RTT), an X-linked dominant neurodevelopmental disorder caused by mutations in MECP2, is associated with a peculiar breathing disturbance exclusively during wakefulness that is distressing, and can even prompt emergency resuscitation. Through the RTT Natural History Study, we characterized cross sectional and longitudinal characteristics of awake breathing abnormalities in RTT and identified associated clinical features. Participants were recruited from 2006 to 2015, and cumulative lifetime prevalence of breathing dysfunction was determined using the Kaplan-Meier estimator. Risk factors were assessed using logistic regression. Of 1205 participants, 1185 had sufficient data for analysis, including 922 females with classic RTT, 778 of whom were followed longitudinally for up to 9.0?years, for a total of 3944 person-years. Participants with classic or atypical severe RTT were more likely to have breathing dysfunction (nearly 100% over the lifespan) compared to those with atypical mild RTT (60–70%). Remission was common, lasting 1?year on average, with 15% ending the study in terminal remission. Factors associated with higher odds of severe breathing dysfunction included poor gross and fine motor function, frequency of stereotypical hand movements, seizure frequency, prolonged corrected QT interval on EKG, and two quality of life metrics: caregiver concern about physical health and contracting illness. Factors associated with lower prevalence of severe breathing dysfunction included higher body mass index and head circumference Z-scores, advanced age, and severe scoliosis or contractures. Awake breathing dysfunction is common in RTT, more so than seizures, and is associated with function, quality of life and risk for cardiac dysrhythmia.     

Lennox–Gastaut syndrome in south Iran: Electro-clinical manifestations

PurposeLennox–Gastaut syndrome (LGS) is an uncommon epileptic encephalopathy. In this study, we tried to determine the clinical and EEG characteristics of patients with LGS in south Iran.MethodsIn this retrospective study, all patients with a clinical diagnosis of LGS were recruited at the outpatient epilepsy clinic at Shiraz University of Medical Sciences from 2008 through 2012. Age, gender, age at seizure onset, seizure type(s), epilepsy risk factors, EEG and imaging findings of all patients were registered routinely.ResultsDuring the study period, 2500 patients with epilepsy were registered at our epilepsy clinic. One-hundred and thirty-five patients (5.4%) were diagnosed as having LGS. Age of onset (mean ± standard deviation) was 3.2 ± 3.8 years. In 14 (10.4%) patients, age of onset was above 8 years. Eighty-three patients (61.5%) were male and 52 (38.5%) were female. The most common seizure type was tonic, followed by generalized tonic–clonic and myoclonic seizures. The most common EEG finding was slow spike-wave complexes. The most common abnormal MRI finding was brain atrophy.ConclusionLGS is an uncommon epileptic encephalopathy characterized by multiple seizure types, a specific electroencephalographic pattern and psychomotor retardation, beginning in childhood. However, variants of this classical triad including atypical EEG findings, normal psychomotor function, and late-onset disease could be seen in some patients. These atypical findings in a patient with typical history for LGS should not deter from the correct diagnosis. The mainstay for making a correct syndromic diagnosis is a detailed clinical history.     

The value of video-EEG monitoring to diagnose juvenile myoclonic epilepsy

ObjectiveA diagnostic accuracy of conventional electroencephalography (EEG) is approximately 50% at best. We aimed to determine the accuracy of video-EEG monitoring (VEM) for a correct diagnosis and the feasibility of its clinical application. The data from all 55 patients (M:F = 31:24) with juvenile myoclonic epilepsy (JME) who underwent VEM were reviewed according to the clinical history, brain imaging and video-EEG findings.ResultsAge at seizure onset ranged from 10 to 25 (15.5 ± 2.7 years). The age at VEM ranged from 15 to 46 (21.8 ± 5.8 years) and 57% (29/51) showed seizures. Of those, 20 patients (69%) showed myoclonic jerks alone, whereas 3 (10%) showed generalized seizures alone. Both of these conditions were observed in 6 patients (21%). Interictal abnormalities alone without clinical seizures were detected in 16 patients (31%). Atypical semiologies such as asymmetric myoclonus or versive seizures were observed in 18 patients (35%) during video monitoring. Interestingly three patients complained of visual aura on history. The duration of VEM ranged from 1 to 6 days (1.8 ± 1.1). Overall, 88% of patients showed an EEG abnormality with/without seizure, concordant with JME. Among 10 patients with a normal conventional EEG before VEM, 9 showed interictal or ictal EEG abnormalities during approximately 1-day of VEM.ConclusionsVEM for 1 or 2 days is appropriate for making a correct diagnosis of JME, especially in patients having an atypical semiology and a normal result on the conventional EEG.     

Genetic and clinical variations in a Norwegian sample diagnosed with Rett syndrome

Background and purposeRett syndrome (RTT) is a neurodevelopmental disorder mainly caused by mutations in MECP2. The diagnostic criteria of RTT are clinical; mutations in MECP2 are neither diagnostic nor necessary, and a mutation in another gene does not exclude RTT. We attempted to correlate genotype and phenotype to see if there are significant clinical associations.MethodsAll available females diagnosed with RTT in Norway were invited to the study. Parents were interviewed, the girl or woman with RTT examined and medical records reviewed. All diagnoses were revisited according to the current diagnostic criteria and exome-based sequencing analyses were performed in individuals without an identified causative mutation. Participants were categorized according to genotypes and RTT diagnosis. Individuals with RTT with and without mutations in MECP2 were compared.ResultsNinety-one individuals were included. A presumed causative mutation was identified in 86 individuals, of these, mutations in MECP2 in 77 individuals and mutations in SMC1A, SYNGAP1, SCN1A, CDKL5, FOXG1 or chromosome 13q in nine. Seventy-two individuals fulfilled the diagnostic criteria for classic and 12 for atypical RTT. Significant differences in early development, loss of hand use and language, intense eye gaze and the presence of early onset epilepsy were revealed in individuals with RTT according to their MECP2 genotypic status.ConclusionUsing the current diagnostic criteria, genetic and clinical variation in RTT is considerable. Significant differences between individuals with RTT with and without MECP2 mutations indicate that MECP2 is a major determinant for the clinical phenotype in individuals with RTT.     

Paroxysmal limb dystonias associated with GABBR2 pathogenic variant: A case-based literature review

BackgroundDe novo mutations in the GABBR2 (Gamma-Aminobutyric acid Type B Receptor Subunit 2) gene have recently been reported to be associated with a form of early-infantile epileptic encephalopathy (EIEE59; OMIM# 617904), as well as a Rett syndrome (RTT)-like disorder defined as a neurodevelopmental disorder with poor language and loss of hand skills (NDPLHS; OMIM# 617903).MethodsWe describe a pediatric case carrying a de novo GABBR2 pathogenic variant and showing a phenotype encompassing RTT, epilepsy, generalized hypotonia with a paroxysmal limb dystonia.ResultsA 11-year-old girl, born to non-consanguineous parents after an uneventful pregnancy, had developmental delay and generalized hypotonia. At age 3.5 months she presented with infantile spasms with an electroencephalographic pattern of hypsarrhythmia. After treatment with clonazepam and prednisolone, she became seizure-free with a slow background electrical activity. Brain magnetic resonance imaging was normal. Paroxysmal dystonic posturing of the extremities, especially the upper limbs, have been observed since the age of 3 years. Motor stereotypies, non-epileptic episodes of hyperventilation and breath-holding were also reported. The girl suffered from feeding difficulties requiring gastrostomy at the age of 8. Exome sequencing (ES) revealed a de novo GABBR2 pathogenic variant (NM_005458:c.G2077T:p.G693W).ConclusionParoxysmal limb dystonias, especially in the context of neurodevelopmental disorder featuring epilepsy, generalized hypotonia and RTT-like features should lead to the suspect of GABBR2 mutations.     

Shared pattern of impaired social communication and cognitive ability in the youth brain across diagnostic boundaries

BackgroundAbnormalities in brain structure are shared across diagnostic categories. Given the high rate of comorbidity, the interplay of relevant behavioural factors may also cross these classic boundaries.MethodsWe aimed to detect brain-based dimensions of behavioural factors using canonical correlation and independent component analysis in a clinical youth sample (n = 1732, 64 % male, age: 5–21 years).ResultsWe identified two correlated patterns of brain structure and behavioural factors. The first mode reflected physical and cognitive maturation (r = 0.92, p = .005). The second mode reflected lower cognitive ability, poorer social skills, and psychological difficulties (r = 0.92, p = .006). Elevated scores on the second mode were a common feature across all diagnostic boundaries and linked to the number of comorbid diagnoses independently of age. Critically, this brain pattern predicted normative cognitive deviations in an independent population-based sample (n = 1253, 54 % female, age: 8–21 years), supporting the generalisability and external validity of the reported brain-behaviour relationships.ConclusionsThese results reveal dimensions of brain-behaviour associations across diagnostic boundaries, highlighting potent disorder-general patterns as the most prominent. In addition to providing biologically informed patterns of relevant behavioural factors for mental illness, this contributes to a growing body of evidence in favour of transdiagnostic approaches to prevention and intervention.     

Delayed episodic memory recall after one week is associated with executive functions and divided attention in pediatric epilepsy patients

AimRecent studies suggest that although children with epilepsy may show normal learning and memory performance, accelerated long-term forgetting (ALF) may become evident over time. Our study examined associations between delayed episodic memory performance (recall 1-week after learning) and executive functions.MethodA consecutive sample of children with a diagnosis of idiopathic epilepsy with focal or generalized seizures, without morphologic or metabolic abnormalities (n = 20, mean age: 11.70 years) was compared to an IQ-matched healthy control group (n = 20, mean age: 11.55 years). We also assessed parents’ and children’s rating of forgetting in everyday life and explored its association with delayed episodic memory recall.ResultsSimilar to results from recent studies of pediatric patients with temporal lobe epilepsy or genetic generalized epilepsy, our pediatric epilepsy patients showed a significantly elevated recall loss over time, although verbal learning, immediate and 30-minute recall was comparable to the matched control group. Additionally, delayed memory recall in patients was moderately associated with their subjective rating of forgetting, as well as with executive functions (verbal fluency and switching) and divided attention.InterpretationWe assume that executive functions play a crucial role in deep memory encoding, facilitating stronger and more enduring memory traces. Given that approximately 20% of epilepsy patients – compared to a healthy reference sample – had a significantly reduced delayed recall and due to the clinical relevance of long-term memory, age-appropriate standard norms for free memory recall after 1-week are desirable.     

Medium-term prognosis of an incident cohort of parkinsonian patients compared to controls

BackgroundThe best data on prognosis comes from population-based incident cohorts but few such cohorts exist for Parkinson's disease and atypical parkinsonism.MethodsThe PINE study is a prospective follow-up study of an incident cohort of people with degenerative or vascular parkinsonism and age-sex matched controls. Participants have annual follow-up from diagnosis until death with review of primary/secondary care records and linkage to the UK death register. Data are collected on survival, disability (dependency on others for activities of daily living) and institutionalization. Research criteria are used to guide the clinical diagnosis, which is updated annually. We compared all-cause mortality, disability and institutionalization in patients (subdivided by diagnosis) and controls, adjusted for important confounders.Results323 incident parkinsonian patients (199 Parkinson's disease, 124 atypical parkinsonism, mean age at diagnosis 75yrs) and 262 controls (mean age 75yrs) had 1349 and 1334 person-years follow-up respectively (maximum follow-up 10 years). All outcomes were worse in parkinsonian patients than controls, especially in atypical parkinsonism (adjusted mortality hazards ratios Parkinson's disease 2.49, 95%CI 1.72–3.58, atypical parkinsonism, 6.85, 95%CI 4.78–9.81). Median survival times for Parkinson's disease and atypical parkinsonism were 7.8 and 2.7 years respectively but were very age-dependent. At three years the rates of death or dependency were controls 21%, Parkinson's disease 46%, atypical parkinsonism 96% whilst overall institutionalization rates were 5%, 15% and 55% respectively.ConclusionThe prognosis of Parkinson's disease and atypical parkinsonism in this unselected incident cohort was significantly worse than previously reported. This has important implications for patient management.     

Adaptive behavior profiles in young children with autism spectrum disorder diagnosed under DSM-5 criteria

BackgroundThis study explored adaptive behavior profiles in a clinical sample of well-characterized children aged one to three years with ASD.MethodProfiles were compared to a sample of children with non-ASD developmental delays. Cluster analyses were performed to determine whether differences in adaptive skills effectively distinguished children with ASD from other young children presenting for assessment due to behavioral or other concerns, but who received other non-ASD diagnoses.ResultsA profile of motor > daily living > socialization > communication skills was found in both children with ASD and children with non-spectrum diagnoses, showing that this profile is not unique to young children with ASD. A two-group cluster solution was found which differentiated children by developmental functioning level rather than by diagnosis.DiscussionThe results of this study provide support for two developmental profiles for adaptive functioning in children with ASD: an average to borderline delayed profile and a borderline to more severely delayed profile that may remain stable or worsen over time. They additionally highlight the importance of delivering early targeted interventions to children with ASD who have greater deficits in adaptive functioning due to their association with poorer long-term outcomes.     

Time to hospital presentation following intracerebral haemorrhage: Proportion of patients presenting within eight hours and factors associated with delayed presentation

PurposeProlonged time to diagnosis of primary intracerebral haemorrhage (ICH) can result in delays in obtaining appropriate blood pressure control, reversal of coagulopathy or surgical intervention in select cases. We sought to characterise the time to diagnosis in a cohort of patients with ICH and identify factors associated with delayed diagnosis.MethodologyThe stroke database of our hospital was retrospectively reviewed to identify patients presenting to our hospitals emergency department with ICH over two years (January 2017-December 2018.) Data collected included demographics (age and sex), comorbidities, anticoagulation status, clinical scores (NIHSS, GCS, ICH score), and imaging (anatomical site, haematoma size). Time from symptom onset to diagnosis and hospital presentation were recorded. Factors associated with diagnosis >8 h post ictus were assessed using a univariate and then multivariable analysis.Results235 patients were identified with 125 males (53%) and a median age of 76 (range 40-98). For the 200 patients that initially presented to our hospital, median time to presentation was 179 min (IQR 77-584 min), and median time from ictus to imaging diagnosis was 268 min (IQR 114-717 min). 139 (70%) presented within 8 h of symptom onset, and 129 (65%) patients had imaging of the brain performed within 8 h of symptom onset. Factors associated with presentation >8 h post symptom onset included wake up stroke (OR 5.31, 95% confidence interval (CI) 2.36-11.96, p < 0.0001) and age (OR 1.04, 95% CI 1.01-1.08, p = 0.01). Patients with hemiplegia were less likely to present >8 h following ictus (OR 0.41, 95% CI 0.21-0.84, p = 0.01).ConclusionsThe majority of patients with ICH presented within 8 h of ictus. Cases of delayed diagnosis involved patients who had not incurred hemiplegia.     

Syndrome of Electrical Status Epilepticus During Sleep: Epileptic Encephalopathy Related to Brain Development

BackgroundEpileptic encephalopathy with electrical status epilepticus during sleep is an age-related and self-limited disorder. The present study analyzed the etiology, demographics, and pathogenesis of patients with electrical status epilepticus during sleep to provide information on the diagnosis and therapy of this syndrome.MethodsThe etiologies of epileptic encephalopathy with electrical status epilepticus during sleep in patients admitted in Chinese People's Liberation Army General Hospital from 2009 to 2014 were retrospectively analyzed. Patients were classified into the genetic, structural-metabolic, and unknown groups according to the etiology. Demographics and clinical characteristics of all the patients were then analyzed and compared among groups.ResultsThe etiologies of epileptic encephalopathy with electrical status epilepticus during sleep in 75 patients mainly included benign childhood epilepsy with centrotemporal spikes, Landau-Kleffner syndrome, polymicrogyria, and migration disorders. Age at onset of epilepsy did not show a specific pattern, but age at onset of epileptic encephalopathy with electrical status epilepticus during sleep was concentrated at age 6-9 years. The mean age at onset of epilepsy in the genetic group was significantly older than that in the structural-metabolic group (P < 0.05). Age at onset of epileptic encephalopathy with electrical status epilepticus during sleep did not significantly differ between the two groups.ConclusionsElectrical status epilepticus during sleep is an epileptic encephalopathy related to brain development and presents an age-dependent occurrence.     

Diagnosis and Outcomes of Late-Onset Wilson's Disease: A National Registry-Based Study

Background

Wilson's disease (WD) is usually diagnosed in children and young adults; limited data exist on late-onset forms.

Objective

The aim was to characterize the clinical and paraclinical presentations, therapeutic management, and outcomes in patients with late-onset WD.

Methods

Patients diagnosed with WD after age 40 years were identified from the French Wilson's Disease Registry (FWDR). Clinical, laboratory, and imaging findings and treatment were reported at diagnosis and last follow-up.

Results

Forty-five patients were identified (median age: 49, range: 40–64) and placed in three groups according to their clinical presentation: neurological (n = 20, median diagnostic delay: 20 months), hepatic (n = 13, diagnostic delay: 12 months), and family screening (n = 12), all confirmed genetically. Six neurological patients had an atypical presentation (1 torticollis, 2 writer's cramps, 2 functional movement disorders, and 1 isolated dysarthria), without T2/fluid-attenuated inversion recovery brain magnetic resonance imaging (MRI) hyperintensities; 5 of 6 had no Kayser–Fleischer ring (KFR); 5 of 6 had liver involvement. In the neurological group, 84% of patients improved clinically, and 1 developed copper deficiency. In the hepatic group, 77% had cirrhosis; 6 patients required liver transplantation. In the screened group, 43% had mild liver involvement; 3 were not treated and remained stable; 24-h urinary copper excretion was normal in 33% of patients at diagnosis.

Conclusions

In the FWDR, late-onset forms of WD affect 8% of patients, mostly with neurological presentations. Thirty percent of the neurological forms were atypical (isolated long-lasting symptoms, inconspicuous brain MRI, no KFR). With personalized treatment, prognosis was good. This study emphasized that WD should be suspected at any age and even in cases of atypical presentation. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

Single gene,two diseases,and multiple clinical presentations: Biotin–thiamine-responsive basal ganglia disease

AimTo present seven new genetically confirmed cases of biotin–thiamin-responsive basal ganglia disease (BTBGD) with different clinical and brain magnetic resonance imaging (MRI) characteristics.Material and methodsGenetic variants, clinical presentations, brain MRI findings, treatment response, and prognosis of seven selected patients with BTBGD, diagnosed with SLC19A3 mutations were described.ResultsAmong seven patients diagnosed with BTBGD, two had early infantile form, four had classic childhood form, and one was asymptomatic. Four different homozygous variants were found in the SLC19A3. Two patients with early infantile form presented with encephalopathy, dystonia, and refractory seizure in the neonatal period and have different variants. Their MRI findings were similar and pathognomonic for the early infantile form. Three siblings had same variants: one presented seizure and encephalopathy at the age of 4 months, one presented seizure at 14 years, and another was asymptomatic at 20 years. Only one of them had normal MRI findings, and the others MRI findings were similar and suggestive of the classic form. Other two siblings; one of them presented with developmental delay, seizure, and dystonia at 18 months and the other presented with subacute encephalopathy and ataxia at 20 months. Their MRI findings were also similar and suggestive of the classic form.ConclusionBTBGD may present with dissimilar clinical characteristics or remain asymptomatic for a long time period even in a family or patients with same variants. Brain MRI patterns may be important for the early diagnosis of BTBGD that would save children’s lives.     

Factors affecting the outcome of delayed intravenous thrombolysis (> 4.5 hours)

IntroductionEvidence of the intravenous tissue plasminogen activator (tPA) efficacy beyond the 4.5 hours window is emerging. We aim to study the factors affecting the outcome of delayed thrombolysis in patients of clear onset acute ischemic stroke (AIS).MethodsData of patients with AIS who received intravenous thrombolytic after 4.5 hours were reviewed including: demographics, risk factors, clinical, laboratory, investigational and radiological data, evidence of mismatch, treatment type and onset, National Institutes of Health Stroke Scale (NIHSS) score at baseline, 24 hours, 7 days after thrombolysis and before discharge, and 3 months follow-up modified Rankin Scale (mRS).ResultsWe report 136 patients treated by intravenous tPA between 4.53 and 19.75 hours with average duration of 5.7 h. The ASPECT score of our patients was ≥ 7. Sixty-four cases showed intracranial arterial occlusion. Perfusion mismatch was detected in 117 (84.6%) patients, while clinical imaging mismatch was detected in 19 (15.4%). Early neurological improvement after 24 hours occurred in 114 (83.8%) patients. At 90 days, 91 patients (67%) achieved good outcome (mRS 0–2), while 45 (33%) had bad outcome (mRS 3–6). Age, endovascular treatment, NIHSS, AF, and HT were significantly higher in the bad outcome group. Age (P = 0.001, OR: 1.099, 95% CI: 1.042–1.160) and baseline NIHSS were predictive of the poor outcome (P = 0.002, OR: 1.151, 95% CI: 1.055–1.256). The best cutoff value of age was 72.5 with AUC of 0.76, sensitivity 73.3% and specificity 60.4%. While for NIHSS at admission, the cutoff value of 7 showed the best results with AUC of 0.73, sensitivity 71.1% and specificity 63.7%. Combination of age and admission NIHSS raised the sensitivity and specificity to 84.4% and 63.7%, respectively.ConclusionIncreased age and admission NIHSS may adversely affect the outcome of delayed thrombolysis and narrow the eligibility criteria. Age and baseline NIHSS based stratification of the patients may provide further evidence as regards the efficacy of the delayed thrombolysis.     

Clinical description of the broad range of neurological presentations of COVID-19: A retrospective case series

BackgroundNeurological disorders associated with SARS-CoV-2 infection represent a clinical challenge because they encompass a broad neurological spectrum and may occur before the diagnosis of COVID-19.MethodsIn this monocentric retrospective case series, medical records from patients with acute neurological disorders associated with SARS-CoV-2 infection from medicine departments of an academic center in Paris area were collected between March 15^th and May 15^th 2020. Diagnosis of SARS-CoV-2 was ascertained through specific RT-PCR in nasopharyngeal swabs or based on circulating serum IgG antibodies.ResultsTwenty-six patients diagnosed with SARS-CoV-2 infection presented with neurological disorders: encephalitis (N = 8), encephalopathy (N = 6), cerebrovascular events (ischemic strokes N = 4 and vein thromboses N = 2), other central nervous system (CNS) disorders (N = 4), and Guillain-Barré syndrome (N = 2). The diagnosis of SARS-CoV-2 was delayed on average 1.6 days after the onset of neurological disorder, especially in case of encephalitis 3.9 days, encephalopathy 1.0 day, and cerebrovascular event 2.7 days.ConclusionsOur study confirms that COVID-19 can yield a broad spectrum of neurological disorders. Because neurological presentations of COVID-19 often occur a few days before the diagnosis of SARS-COV-2 infection, clinicians should take preventive measures such as patient isolation and masks for any new admission to avoid nosocomial infections. Anti-SARS-CoV2 antibody detection in RT-PCR SARS CoV-2 negative suspected cases is useful to confirm a posteriori the diagnosis of atypical COVID-19 presentations.     

The role of age on tau PET uptake and gray matter atrophy in atypical Alzheimer's disease

IntroductionLittle is known about the role of age on neurodegeneration and protein deposition in atypical variants of Alzheimer's disease (AD).MethodsRegional tau and β-amyloid positron emission tomography standard uptake value ratios and gray matter volumes were calculated in a cohort of 42 participants with atypical AD. The relationship between regional metrics and age was modeled using a Bayesian hierarchical linear model.ResultsAge was strongly associated with tau uptake across all cortical regions, particularly parietal, with greater uptake in younger participants. Younger age was associated with smaller parietal and lateral temporal volumes. Regional β-amyloid differed little by age. Age showed a stronger association with tau than volume and β-amyloid in all cortical regions. Age was not associated with cognitive performance.DiscussionAge is an important determinant of severity of cortical tau uptake in atypical AD, with young participants more likely to show widespread and severe cortical tau uptake.     

Clinical milestones in Parkinson's disease: A 7-year population-based incident cohort study

IntroductionClinical staging of Parkinson's disease (PD) is important for patient management and prognosis. The non-motor and functional features visual hallucinations, recurrent falls, dementia and nursing home placement are currently not included in clinical staging schemes, but have been suggested as clinical milestones with important prognostic implications in advanced PD. In this study, we sought to evaluate the potential of these four milestone events for clinical staging and prognosis during the early years of the disease.MethodsWe recruited 185 patients with incident PD and monitored prospectively every six months through seven years for emergence and consequences of four clinical milestones.ResultsOne or more milestones were reached in 53.0%. Of the patients who reached the milestones, visual hallucinations appeared after a median of 3.3 (interquartile range 1.3–4.9) years from diagnosis, recurrent falls after 3.8 (2.8–5.2) years, dementia after 4.0 (2.1–4.8) years and nursing home placement after 5.4 (3.9–6.7) years. Presence of any milestone was associated with occurrence of other milestones (relative risks 1.9–6.3; all p ≤ 0.001). Experiencing two or more milestones increased the risk of death during the study (relative risk 2.7, p = 0.03).ConclusionsIn early PD, visual hallucinations, recurrent falls, dementia and nursing home placement appear closely interrelated, possibly reflecting a shared neuropathological disease stage. All events convey important and sinister information on PD status and prognosis and are relatively easily accessible during routine clinical consultations. Therefore, they appear highly useful as clinical PD milestones and could possibly be incorporated into a novel disease rating scale.