To Örebro University

Importance: There are limited data concerning the risk of metabolic and cardiovascular disorders among individuals with Tourette syndrome (TS) or chronic tic disorder (CTD).

Objective: To investigate the risk of metabolic and cardiovascular disorders among individuals with TS or CTD over a period of 40 years.

Design, Settings, and Participants: This longitudinal population-based cohort study included all individuals living in Sweden between January 1, 1973, and December 31, 2013. Families with clusters of full siblings discordant for TS or CTD were further identified. Data analyses were conducted from August 1, 2017, to October 11, 2018.

Exposures: Previously validated International Classification of Diseases diagnoses of TS or CTD in the Swedish National Patient Register.

Main Outcomes and Measures: Registered diagnoses of obesity, dyslipidemia, hypertension, type 2 diabetes, and cardiovascular diseases (including ischemic heart diseases, arrhythmia, cerebrovascular diseases and transient ischemic attack, and arteriosclerosis).

Results: Of the 14 045 026 individuals in the cohort, 7804 individuals (5964 males [76.4%]; median age at first diagnosis, 13.3 years [interquartile range, 9.9-21.3 years]) had a registered diagnosis of TS or CTD in specialist care. Of 2 675 482 families with at least 2 singleton full siblings, 5141 families included siblings who were discordant for these disorders. Individuals with TS or CTD had a higher risk of any metabolic or cardiovascular disorders compared with the general population (hazard ratio adjusted by sex and birth year [aHR], 1.99; 95% CI, 1.90-2.09) and sibling controls (aHR for any disorder, 1.37; 95% CI, 1.24-1.51). Specifically, individuals with TS or CTD had higher risks for obesity (aHR, 2.76; 95% CI, 2.47-3.09), type 2 diabetes (aHR, 1.67; 95% CI, 1.42-1.96), and circulatory system diseases (aHR, 1.76; 95% CI, 1.67-1.86). The risk of any cardiometabolic disorder was significantly greater in males than in females (aHR, 2.13; 95% CI, 2.01-2.26 vs aHR, 1.79; 95% CI, 1.64-1.96), as was the risk of obesity (aHR, 3.24; 95% CI, 2.83-3.70 vs aHR, 1.97; 95% CI, 1.59-2.44). The risks were already evident from childhood (the groups were significantly different by age 8 years) and were significantly reduced with the exclusion of individuals with comorbid attention-deficit/hyperactivity disorder (aHR, 1.52; 95% CI, 1.42-1.62), while excluding other comorbidities did not significantly affect the results. Compared with patients with TS or CTD who were not taking antipsychotics, patients with a longer duration of antipsychotic treatment (>1 year) had significantly lower risks of metabolic and cardiovascular disorders.

Conclusions and Relevance: The findings of this study suggest that TS and CTD are associated with a substantial risk of metabolic and cardiovascular disorders. The results highlight the importance of carefully monitoring cardiometabolic health in patients with TS or CTD across the lifespan, particularly in those with comorbid attention-deficit/hyperactivity disorder.

Key Points: QuestionHow do levels of neurofilament light in cerebrospinal fluid (cNfL) compare between neurological conditions and with healthy controls?

Findings: Among 10 059 individuals in this systematic review and meta-analysis, cNfL was elevated in most neurological conditions compared with healthy controls, and the magnitude of the increase varies extensively. Although cNfL overlaps between most clinically similar conditions, its distribution did not overlap in frontotemporal dementia and other dementias or in Parkinson disease and atypical parkinsonian syndromes.

Meaning: The cNfL is a marker of neuronal damage and may be useful to differentiate some clinically similar conditions, such as frontotemporal dementia from Alzheimer disease and Parkinson disease from atypical parkinsonian syndromes.

This systematic review and meta-analysis assesses the associations of age, sex, and diagnosis with neurofilament light in cerebrospinal fluid and evaluates its potential in discriminating clinically similar conditions.

Importance: Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date.

Objectives: To assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions.

Data Sources: PubMed was searched for studies published between January 1, 2006, and January 1, 2016, reporting cNfL levels (using the search terms neurofilament light and cerebrospinal fluid) in neurological or psychiatric conditions and/or in HC.

Study Selection: Studies reporting NfL levels measured in lumbar CSF using a commercially available immunoassay, as well as age and sex.

Data Extraction and Synthesis: Individual-level data were requested from study authors. Generalized linear mixed-effects models were used to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels, with cohort of origin modeled as a random intercept.

Main Outcome and Measure: The cNfL levels adjusted for age and sex across diagnoses.

Results: Data were collected for 10059 individuals (mean [SD] age, 59.7 [18.8] years; 54.1% female). Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n=2795), dementias and predementia stages (n=4284), parkinsonian disorders (n=984), and HC (n=1332). The cNfL was elevated compared with HC in a majority of neurological conditions studied. Highest levels were observed in cognitively impaired HIV-positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% of diagnoses, including HC, multiple sclerosis, Alzheimer disease (AD), and Parkinson disease (PD), cNfL was higher in men than women. The cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC. The cNfL overlapped in most clinically similar diagnoses except for FTD and iHIV, which segregated from other dementias, and PD, which segregated from atypical parkinsonian syndromes.

Conclusions and Relevance: These data support the use of cNfL as a biomarker of neuroaxonal damage and indicate that age-specific and sex-specific (and in some cases disease-specific) reference values may be needed. The cNfL has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.

IMPORTANCE Brain injury affects neurologic function and quality of life in survivors after cardiac arrest. OBJECTIVE To compare the effects of 2 target temperature regimens on long-term cognitive function and quality of life after cardiac arrest. DESIGN, SETTING, AND PARTICIPANTS In this multicenter, international, parallel group, assessor-masked randomized clinical trial performed from November 11, 2010, through January 10, 2013, we enrolled 950 unconscious adults with cardiac arrest of presumed cardiac cause from 36 intensive care units in Europe and Australia. Eleven patients were excluded from analysis for a total sample size of 939. INTERVENTIONS Targeted temperature management at 33 degrees C vs 36 degrees C. MAIN OUTCOMES AND MEASURES Cognitive function was measured by the Mini-Mental State Examination (MMSE) and assessed by observers through the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Patients reported their activities in daily life and mental recovery through Two Simple Questions and their quality of life through the Medical Outcomes Study 36-Item Short Form Health Survey, version 2. RESULTS In the modified intent-to-treat population, including nonsurvivors, the median MMSE score was 14 in the 33 degrees C group (interquartile range [IQR], 0-28) vs 17 in the 36 degrees C group (IQR, 0-29) (P = .77), and the IQCODE score was 115 (IQR, 79-130) vs 115 (IQR, 80-130) (P = .57) in the 33 degrees C and 36 degrees C groups, respectively. The median MMSE score for survivors was within the reference range and similar (33 degrees C group median, 28; IQR, 26-30; vs 36 degrees C group median, 28; IQR, 25-30; P = .61). The median IQCODE score was within the minor deficit range (33 degrees C group median, 79.5; IQR, 78.0-85.9; vs 36 degrees C group median, 80.7; IQR, 78.0-86.9; P = .04). A total of 18.8% vs 17.5% of survivors reported needing help with everyday activities (P = .71), and 66.5% in the 33 degrees C group vs 61.8% in the 36 degrees C group reported that they thought they had made a complete mental recovery (P = .32). The mean (SD) mental component summary score was 49.1 (12.5) vs 49.0 (12.2) (P = .79), and the mean (SD) physical component summary score was 46.8 (13.8) and 47.5 (13.8) (P = .45), comparable to the population norm. CONCLUSIONS AND RELEVANCE Quality of life was good and similar in patients with cardiac arrest receiving targeted temperature management at 33 degrees C or 36 degrees C. Cognitive function was similar in both intervention groups, but many patients and observers reported impairment not detected previously by standard outcome scales.

Importance: Severe forms of Tourette syndrome or chronic tic disorder (TS/CTD) may involve repeated head jerking. Isolated case reports have described a spectrum of severe neck disorders in individuals with TS/CTD. However, the nature and prevalence of cervical spine disorders in TS/CTD are unknown.

Objective: To establish if TS/CTD are associated with an increased risk of cervical spine disorders and related neurological complications compared with individuals from the general population.

Design, Setting, and Participants: All individuals born from 1973 to 2013 and living in Sweden between 1997 and 2013 were identified. Individuals with a record of TS/CTD diagnosed in specialist settings were matched on age, sex, and county of birth with 10 unexposed individuals randomly selected from the general population. Cox proportional hazards regression models were used to estimate the risk of vascular and nonvascular cervical spine disorders among exposed individuals, compared with unexposed individuals. Models were adjusted for other known causes of cervical spine injury. Data were analyzed from March 19 to May 16, 2021.

Exposures: International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnoses of TS/CTD in the Swedish National Patient Register.

Main Outcomes and Measures: Records of cervical vascular disorders (ie, aneurysm, cerebral infarction, transitory cerebral ischemia) and cervical nonvascular disorders (ie, spondylosis, cervical disc disorders, fractures of the cervical spine, cervicalgia) and cervical surgeries. Covariates included rheumatic disorders, traffic injuries, fall- or sport-related injuries, and attention-deficit/hyperactivity disorder comorbidity.

Results: A total of 6791 individuals with TS/CTD were identified (5238 [77.1%] were male; median [interquartile] age at first diagnosis, 15.6 [11.4-23.7] years) and matched to 67 910 unexposed individuals. Exposed individuals had a 39% increased risk of any cervical spine disorder (adjusted hazard ratio, 1.39; 95% CI, 1.22-1.59). Adjusted hazard ratios for cervical vascular and nonvascular disorders were 1.57 (95% CI, 1.16-2.13) and 1.38 (95% CI, 1.19-1.60), respectively. Risks were similar among men and women.

Conclusions and Relevance: Individuals with severe TS/CTD are at increased risk of cervical spine disorders. These outcomes are relatively rare but may lead to persistent disability in some individuals and thus require close monitoring to facilitate early interventions.

Importance: One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design.

Objective: To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates.

Design, Setting, and Participants: This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria.

Exposures: Alzheimer disease biomarkers detected on PET or in CSF.

Main Outcomes and Measures: Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations.

Results: Among the 19 097 participants (mean [SD] age, 69.1 [9.8] years; 10 148 women [53.1%]) included, 10 139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P = .04). Gaussian mixture modeling-based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P = .004), subjective cognitive decline (9%; 95% CI, 3%-15%; P = .005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P = .004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, -2% to 9%; P = .18).

Conclusions and Relevance: This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies.

Importance: There is little evidence to guide the choice of antiseizure medication (ASM) for patients with poststroke epilepsy. Theoretical concerns about detrimental effects of ASMs on survival exist. Enzyme-inducing drugs could interfere with secondary stroke prevention. The US Food and Drug Administration recently issued a safety announcement about the potential proarrhythmic properties of lamotrigine.

Objective: To investigate whether mortality varies with specific ASMs among patients with poststroke epilepsy.

Design, Setting, and Participants: A cohort study was conducted using individual-level data from linked registers on all adults in Sweden with acute stroke from July 1, 2005, to December 31, 2010, and subsequent onset of epilepsy before December 31, 2014. A total of 2577 patients receiving continuous ASM monotherapy were eligible for the study. Data were analyzed between May 27, 2019, and April 8, 2021.

Exposures: The dispensed ASM (Anatomical Therapeutic Chemical code N03A) determined exposure status, and the first dispensation date marked the start of treatment.

Main Outcomes and Measures: The primary outcome, all-cause death, was analyzed using Cox proportional hazards regression with carbamazepine as the reference. Cardiovascular death (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes I0-I99 as the underlying cause) was assessed using Fine-Gray competing risk regression models.

Results: A total of 2577 patients (1400 men [54%]; median age, 78 years [IQR, 69-85 years]) were included. The adjusted hazard ratio of all-cause death compared with carbamazepine was 0.72 (95% CI, 0.60-0.86) for lamotrigine, 0.96 (95% CI, 0.80-1.15) for levetiracetam, 1.40 (95% CI, 1.23-1.59) for valproic acid, 1.16 (95% CI, 0.88-1.51) for phenytoin, and 1.16 (95% CI, 0.81-1.66) for oxcarbazepine. The adjusted hazard ratio of cardiovascular death compared with carbamazepine was 0.76 (95% CI, 0.61-0.95) for lamotrigine, 0.77 (95% CI, 0.60-0.99) for levetiracetam, 1.40 (95% CI, 1.19-1.64) for valproic acid, 1.02 (95% CI, 0.71-1.47) for phenytoin, and 0.71 (95% CI, 0.42-1.18) for oxcarbazepine.

Conclusions and Relevance: This cohort study's findings suggest differences in survival between patients treated with different ASMs for poststroke epilepsy. Patients receiving lamotrigine monotherapy had significantly lower mortality compared with those receiving carbamazepine. The opposite applied to patients prescribed valproic acid, who had a higher risk of cardiovascular and all-cause death. Levetiracetam was associated with a reduced risk of cardiovascular death compared with carbamazepine, but there was no significant difference in overall mortality.

Importance: Although highly effective disease-modifying therapies for multiple sclerosis (MS) have been associated with an increased risk of infections vs injectable therapies interferon beta and glatiramer acetate (GA), the magnitude of potential risk increase is not well established in real-world populations. Even less is known about infection risk associated with rituximab, which is extensively used off-label to treat MS in Sweden.

Objective: To examine the risk of serious infections associated with disease-modifying treatments for MS.

Design, Setting, and Participants: This nationwide register-based cohort study was conducted in Sweden from January 1, 2011, to December 31, 2017. National registers with prospective data collection from the public health care system were used. All Swedish patients with relapsing-remitting MS whose data were recorded in the Swedish MS register as initiating treatment with rituximab, natalizumab, fingolimod, or interferon beta and GA and an age-matched and sex-matched general population comparator cohort were included.

Exposures: Treatment with rituximab, natalizumab, fingolimod, and interferon beta and GA.

Main Outcomes and Measures: Serious infections were defined as all infections resulting in hospitalization. Additional outcomes included outpatient treatment with antibiotic or herpes antiviral medications. Adjusted hazard ratios (HRs) were estimated in Cox regressions.

Results: A total of 6421 patients (3260 taking rituximab, 1588 taking natalizumab, 1535 taking fingolimod, and 2217 taking interferon beta/GA) were included, plus a comparator cohort of 42 645 individuals. Among 6421 patients with 8600 treatment episodes, the mean (SD) age at treatment start ranged from 35.0 (10.1) years to 40.4 (10.6) years; 6186 patients were female. The crude rate of infections was higher in patients with MS taking interferon beta and GA than the general population (incidence rate, 8.9 [95% CI, 6.4-12.1] vs 5.2 [95% CI, 4.8-5.5] per 1000 person-years), and higher still in patients taking fingolimod (incidence rate, 14.3 [95% CI, 10.8-18.5] per 1000 person-years), natalizumab (incidence rate, 11.4 [95% CI, 8.3-15.3] per 1000 person-years), and rituximab (incidence rate, 19.7 [95% CI, 16.4-23.5] per 1000 person-years). After confounder adjustment, the rate remained significantly higher for rituximab (HR, 1.70 [95% CI, 1.11-2.61]) but not fingolimod (HR, 1.30 [95% CI, 0.84-2.03]) or natalizumab (HR, 1.12 [95% CI, 0.71-1.77]) compared with interferon beta and GA. In contrast, use of herpes antiviral drugs during rituximab treatment was similar to that of interferon beta and GA and lower than that of natalizumab (HR, 1.82 [1.34-2.46]) and fingolimod (HR, 1.71 [95% CI, 1.27-2.32]).

Conclusions and Relevance: Patients with MS are at a generally increased risk of infections, and this differs by treatment. The rate of infections was lowest with interferon beta and GA; among newer treatments, off-label use of rituximab was associated with the highest rate of serious infections. The different risk profiles should inform the risk-benefit assessments of these treatments.

Importance: Tic disorders are associated with multiple social adversities, but little is known about the experience of violent assault (including sexual assault) and criminality in this group.

Objective: To establish if Tourette syndrome (TS) and chronic tic disorder (CTD) are associated with an increased risk of experiencing violent assault and criminal convictions.

Design, Setting, and Participants: In this cohort study, all individuals living in Sweden at any time between January 1, 1973, and December 31, 2013, were identified from Swedish nationwide health and administrative registers. Cox proportional hazards regression models were used to estimate the risk of violent assault and criminal convictions among people with TS or CTD, compared with the general population and unaffected full siblings. Data analyses were conducted between September 1 and October 22, 2021.

Exposures: The Swedish version of the International Classification of Diseases, Eighth Revision (ICD-8), ICD-9, and ICD-10 diagnoses of TS or CTD in the Swedish National Patient Register.

Main Outcomes and Measures: Records of sexual and nonsexual violent assault and death due to violent assaults were obtained from the National Patient Register and the Cause of Death Register, respectively. Convictions for violent and nonviolent criminal offenses were obtained from the Crime Register. Covariates included sex and birth year.

Results: The study cohort included 13 819 284 individuals living in Sweden between 1973 and 2013. A total of 7791 individuals with TS or CTD were identified (median [IQR] age at first diagnosis, 13.4 [10.0-21.8] years; 5944 [76%] male). Compared with unaffected individuals from the general population, people with TS or CTD had a 2-fold increased risk of experiencing any violent assault (sexual and nonsexual) (adjusted hazard ratio [aHR], 2.21; 95% CI, 2.00-2.43), a 3-fold increased risk of violent convictions (aHR, 3.13; 95% CI, 2.92-3.36), and a 1.6-fold increased risk of nonviolent crime convictions (aHR, 1.62; 95% CI, 1.54-1.71). Among people with TS or CTD, 37.0% (114 of 308; 95% CI, 31.6%-42.4%) of individuals who had experienced violent assault also had a violent crime conviction, compared with 17.9% (16 067 of 89 920; 95% CI, 17.6%-18.1%) in the general population. Exclusion of individuals with attention-deficit/hyperactivity disorder and substance use disorders partially attenuated the associations. Similarly, within-sibling models attenuated but did not eliminate the associations (any violent assault: aHR, 1.32; 95% CI, 1.08-1.61; violent crime: aHR, 2.23; 95% CI, 1.86-2.67; nonviolent crime: aHR, 1.34; 95% CI, 1.20-1.50).

Conclusions and Relevance: Results of this cohort study suggest that most individuals with TS or CTD are not assaulted nor are perpetrators of crime. However, individuals with TS or CTD diagnosed in specialist settings were more likely to both experience violent assault and be perpetrators of violence compared with the general population. The risk was highest in individuals with comorbid attention-deficit/hyperactivity disorder and substance use disorders. The increased risk found in specialty clinics will need to be better understood in the general population.

Importance: To our knowledge, it is unknown whether a prehospital stroke triage system combining symptom severity and teleconsultation could accurately select patients for primary stroke center bypass and hasten delivery of endovascular thrombectomy (EVT) without delaying intravenous thrombolysis (IVT).

Objective: To evaluate the predictive performance of the newly implemented Stockholm Stroke Triage System (SSTS) for large-artery occlusion (LAO) stroke and EVT initiation. Secondary objectives included evaluating whether the Stockholm Stroke Triage System shortened onset-to-puncture time for EVT and onset-to-needle time (ONT) for IVT.

Design, Setting, and Participants: This population-based prospective cohort study conducted from October 2017 to October 2018 across the Stockholm region (Sweden) included patients transported by first-priority ("code stroke") ambulance to the hospital for acute stroke suspected by an ambulance nurse and historical controls (October 2016-October 2017). Exclusion criteria were in-hospital stroke and helicopter or private transport. Of 2909 eligible patients, 4 (0.14%) declined participation.

Exposures: Patients were assessed by ambulance nurses with positive the face-arm-speech-time test or other stroke suspicion and were evaluated for moderate-to-severe hemiparesis (≥2 National Institutes of Health stroke scale points each on the ipsilateral arm and leg [A2L2 test]). If present, the comprehensive stroke center (CSC) stroke physician was teleconsulted by phone for confirmation of stroke suspicion, assessment of EVT eligibility, and direction to CSC or the nearest primary stroke center. If absent, the nearest hospital was prenotified.

Main Outcomes and Measures: Primary outcome: LAO stroke. Secondary outcomes: EVT initiation, onset-to-puncture time, and ONT. Predictive performance measures included sensitivity, specificity, positive and negative predictive values, the overall accuracy for LAO stroke, and EVT initiation.

Results: We recorded 2905 patients with code-stroke transports (1420 women [49%]), and of these, 323 (11%) had A2L2+ teleconsultation positive results and were triaged for direct transport to CSC (median age, 73 years [interquartile range (IQR), 64-82 years]; 55 women [48%]). Accuracy for LAO stroke was 87% (positive predictive value, 41%; negative predictive value, 93%) and 91% for EVT initiation (positive predictive value, 26%; negative predictive value, 99%). Endovascular thrombectomy was performed for 84 of 323 patients (26%) with triage-positive results and 35 of 2582 patients (1.4%) with triage-negative results. In EVT cases with a known onset time (77 [3%]), the median OPT was 137 minutes (IQR, 118-180; previous year, 206 minutes [IQR, 160-280]; n = 75) (P < .001). The regional median ONT (337 [12%]) was unchanged at 115 minutes (IQR, 83-164; previous year, 115 minutes [IQR, 85-161]; n = 360) (P = .79). The median CSC IVT door-to-needle time was 13 minutes (IQR, 10-18; 116 [4%]) (previous year, 31 minutes [IQR, 19-38]; n = 45) (P < .001).

Conclusions and Relevance: The Stockholm Stroke Triage System, which combines symptom severity and teleconsultation, results in markedly faster EVT delivery without delaying IVT.

Importance: The influence of Tourette syndrome and chronic tic disorders on academic performance has not been objectively quantified.

Objective: To investigate the association of Tourette syndrome and chronic tic disorders with objectively measured educational outcomes, adjusting for measured covariates and unmeasured factors shared between siblings and taking common psychiatric comorbidities into account.

Design, Setting, and Participants: A population-based birth cohort consisting of all individuals born in Sweden from 1976 to 1998 was followed up until December 2013. Individuals with organic brain disorders, mental retardation, and 2 foreign-born parents were excluded. We further identified families with at least 2 singleton full siblings and families with siblings discordant for Tourette syndrome or chronic tic disorders.

Exposures: Previously validated International Classification of Diseases diagnoses of Tourette syndrome or chronic tic disorders in the Swedish National Patient Register.

Main Outcomes and Measures: Eligibility to access upper secondary school after compulsory education, finishing upper secondary school, starting a university degree, and finishing a university degree.

Results: Of the 2 115 554 individuals in the cohort, 3590 had registered a diagnosis of Tourette syndrome or a chronic tic disorder in specialist care (of whom 2822 [78.6%] were male; median [interquartile] age at first diagnosis, 14.0 [11-18] years). Of 726 198 families with at least 2 singleton full siblings, 2697 included siblings discordant for these disorders. Compared with unexposed individuals, people with Tourette syndrome or chronic tic disorders were significantly less likely to pass all core and additional courses at the end of compulsory school (odds ratios ranging from 0.23 [95% CI, 0.20-0.26] for the handcraft textile/wood course to 0.36 [95% CI, 0.31-0.41] for the English language course) and to access a vocational program (adjusted OR [aOR], 0.31; 95% CI, 0.28-0.34) or academic program (aOR, 0.43; 95% CI, 0.39-0.47) in upper secondary education. Individuals with the disorders were also less likely to finish upper secondary education (aOR, 0.35; 95% CI, 0.32-0.37), start a university degree (aOR, 0.41; 95% CI, 0.37-0.46), and finish a university degree (aOR, 0.39; 95% CI, 0.32-0.48). The results were only marginally attenuated in the fully adjusted sibling comparison models. Exclusion of patients with neuropsychiatric comorbidities, particularly attention-deficit/hyperactivity disorder and pervasive developmental disorders, resulted in attenuated estimates, but patients with Tourette syndrome or chronic tic disorders were still significantly impaired across all outcomes.

Conclusions and Relevance: Help-seeking individuals with Tourette syndrome or chronic tic disorders seen in specialist settings experience substantial academic underachievement across all educational levels, spanning from compulsory school to university, even after accounting for multiple confounding factors and psychiatric comorbidities.

Importance: Posttraumatic stress disorder (PTSD) has been associated with increased risk for dementia. Less is known, however, about other stress-related disorders and their associations with neurodegenerative diseases.

Objective: To examine the association between stress-related disorders and risk for neurodegenerative diseases.

Design, Setting, and Participants: This population-matched and sibling cohort study was conducted in Sweden using data from nationwide health registers, including the Swedish National Patient Register. Individuals who received their first diagnosis of stress-related disorders between January 1, 1987, and December 31, 2008, were identified. Individuals who had a history of neurodegenerative diseases, had conflicting or missing information, had no data on family links, or were aged 40 years or younger at the end of the study were excluded. Individuals with stress-related disorders were compared with the general population in a matched cohort design; they were also compared with their siblings in a sibling cohort. Follow-up commenced from the age of 40 years or 5 years after the diagnosis of stress-related disorders, whichever came later, until the first diagnosis of a neurodegenerative disease, death, emigration, or the end of follow-up (December 31, 2013), whichever occurred first. Data analyses were performed from November 2018 to April 2019.

Exposures: Diagnosis of stress-related disorders (PTSD, acute stress reaction, adjustment disorder, and other stress reactions).

Main Outcomes and Measurements: Neurodegenerative diseases were identified through the National Patient Register and classified as primary or vascular. Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis were evaluated separately. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) with 95% CIs after controlling for multiple confounders.

Results: The population-matched cohort included 61 748 exposed individuals and 595 335 matched unexposed individuals. A total of 44 839 exposed individuals and their 78 482 unaffected full siblings were included in the sibling cohort analysis. The median (interquartile range) age at the start of follow-up was 47 (41-56) years, and 24 323 (39.4%) of the exposed individuals were male. The median (interquartile range) follow-up was 4.7 (2.1-9.8) years. Compared with unexposed individuals, individuals with a stress-related disorder were at an increased risk of neurodegenerative diseases (HR, 1.57; 95% CI, 1.43-1.73). The risk increase was greater for vascular neurodegenerative diseases (HR, 1.80; 95% CI, 1.40-2.31) than for primary neurodegenerative diseases (HR, 1.31; 95% CI, 1.15-1.48). A statistically significant association was found for Alzheimer disease (HR, 1.36; 95% CI, 1.12-1.67) but not Parkinson disease (HR, 1.20; 95% CI, 0.98-1.47) or amyotrophic lateral sclerosis (HR, 1.20; 95% CI, 0.74-1.96). Results from the sibling cohort corroborated results from the population-matched cohort.

Conclusions and Relevance: This study showed an association between stress-related disorders and an increased risk of neurodegenerative diseases. The relative strength of this association for vascular neurodegenerative diseases suggests a potential cerebrovascular pathway.

IMPORTANCE: Earlier research on celiac disease (CD) and neuropathy has been hampered by the use of inpatient data, low study power, and lack of neuropathic characteristics.

OBJECTIVE: To examine the relative risk and absolute risk of developing neuropathy in a nationwide population-based sample of patients with biopsy-verified CD.

DESIGN, SETTING, AND PARTICIPANTS: Between October 27, 2006, and February 12, 2008, we collected data on small-intestinal biopsies performed at Sweden's 28 pathology departments between June 16, 1969, and February 4, 2008. We compared the risk of neuropathy in 28 232 patients with CD (villous atrophy, Marsh 3) with that of 139 473 age-and sex-matched controls. Cox proportional hazards regression estimated hazard ratios (HRs) and 95% CIs for neuropathy defined according to relevant International Classification of Diseases codes in the Swedish National Patient Register (consisting of both inpatient and outpatient data).

MAIN OUTCOMES AND MEASURES: Neuropathy in patients with biopsy-verified CD.

RESULTS: Celiac disease was associated with a 2.5-fold increased risk of later neuropathy (95% CI, 2.1-3.0; P < .001). We also found an increased risk (with results reported as HRs [95% CIs]) of chronic inflammatory demyelinating neuropathy (2.8; 1.6-5.1; P = .001), autonomic neuropathy (4.2; 1.4-12.3; P = .009), and mononeuritis multiplex (7.6; 1.8-32.4; P = .006), but no association between CD and acute inflammatory demyelinating polyneuropathy (0.8; 0.3-2.1; P = .68).

CONCLUSIONS AND RELEVANCE: We found an increased risk of neuropathy in patients with CD. This statistically significant association in a population-based sample suggests that CD screening should be completed in patients with neuropathy.

Importance: A head computed tomography (CT) with positive results for acute intracranial hemorrhage is the gold-standard diagnostic biomarker for acute traumatic brain injury (TBI). In moderate to severe TBI (Glasgow Coma Scale [GCS] scores 3-12), some CT features have been shown to be associated with outcomes. In mild TBI (mTBI; GCS scores 13-15), distribution and co-occurrence of pathological CT features and their prognostic importance are not well understood.

Objective: To identify pathological CT features associated with adverse outcomes after mTBI.

Design, Setting, and Participants: The longitudinal, observational Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study enrolled patients with TBI, including those 17 years and older with GCS scores of 13 to 15 who presented to emergency departments at 18 US level 1 trauma centers between February 26, 2014, and August 8, 2018, and underwent head CT imaging within 24 hours of TBI. Evaluations of CT imaging used TBI Common Data Elements. Glasgow Outcome Scale-Extended (GOSE) scores were assessed at 2 weeks and 3, 6, and 12 months postinjury. External validation of results was performed via the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. Data analyses were completed from February 2020 to February 2021.

Exposures: Acute nonpenetrating head trauma.

Main Outcomes and Measures: Frequency, co-occurrence, and clustering of CT features; incomplete recovery (GOSE scores <8 vs 8); and an unfavorable outcome (GOSE scores <5 vs ≥5) at 2 weeks and 3, 6, and 12 months.

Results: In 1935 patients with mTBI (mean [SD] age, 41.5 [17.6] years; 1286 men [66.5%]) in the TRACK-TBI cohort and 2594 patients with mTBI (mean [SD] age, 51.8 [20.3] years; 1658 men [63.9%]) in an external validation cohort, hierarchical cluster analysis identified 3 major clusters of CT features: contusion, subarachnoid hemorrhage, and/or subdural hematoma; intraventricular and/or petechial hemorrhage; and epidural hematoma. Contusion, subarachnoid hemorrhage, and/or subdural hematoma features were associated with incomplete recovery (odds ratios [ORs] for GOSE scores <8 at 1 year: TRACK-TBI, 1.80 [95% CI, 1.39-2.33]; CENTER-TBI, 2.73 [95% CI, 2.18-3.41]) and greater degrees of unfavorable outcomes (ORs for GOSE scores <5 at 1 year: TRACK-TBI, 3.23 [95% CI, 1.59-6.58]; CENTER-TBI, 1.68 [95% CI, 1.13-2.49]) out to 12 months after injury, but epidural hematoma was not. Intraventricular and/or petechial hemorrhage was associated with greater degrees of unfavorable outcomes up to 12 months after injury (eg, OR for GOSE scores <5 at 1 year in TRACK-TBI: 3.47 [95% CI, 1.66-7.26]). Some CT features were more strongly associated with outcomes than previously validated variables (eg, ORs for GOSE scores <5 at 1 year in TRACK-TBI: neuropsychiatric history, 1.43 [95% CI .98-2.10] vs contusion, subarachnoid hemorrhage, and/or subdural hematoma, 3.23 [95% CI 1.59-6.58]). Findings were externally validated in 2594 patients with mTBI enrolled in the CENTER-TBI study.

Conclusions and Relevance: In this study, pathological CT features carried different prognostic implications after mTBI to 1 year postinjury. Some patterns of injury were associated with worse outcomes than others. These results support that patients with mTBI and these CT features need TBI-specific education and systematic follow-up.