Comparison of patients with biopsy positive and negative primary angiitis of the central nervous system.

OBJECTIVE: There is limited evidence on when to obtain a central nervous system (CNS) biopsy in suspected primary angiitis of the central nervous system (PACNS). Our objective was to identify which clinical and radiological characteristics were associated with a positive biopsy in PACNS. METHODS: From the multicenter retrospective Cohort of Patients with Primary Vasculitis of the CNS (COVAC), we included adults with PACNS based on a positive CNS biopsy or otherwise unexplained intracranial stenoses with additional findings supportive of vasculitis. Baseline findings were compared between patients with a positive and negative biopsy using logistic regression models. RESULTS: 200 patients with PACNS were included, among which a biopsy was obtained in 100 (50%) and was positive in 61 (31%). Patients with a positive biopsy were more frequently female (OR 2.90, 95% CI 1.25-7.10, p = 0.01) and more often presented with seizures (OR 8.31, 95% CI 2.77-33.04, p < 0.001) or cognitive impairment (OR 2.58, 95% CI 1.11-6.10, p = 0.03). On imaging, biopsy positive patients more often had non-ischemic parenchymal or leptomeningeal gadolinium enhancement (OR 52.80, 95% CI 15.72-233.06, p < 0.001) or ≥ 1 cerebral microbleed (OR 8.08, 95% CI 3.03-25.13, p < 0.001), and less often had ≥ 1 acute brain infarct (OR 0.02, 95% CI 0.004-0.08, p < 0.001). In the multivariable model, non-ischemic parenchymal or leptomeningeal gadolinium enhancement (aOR 8.27, 95% CI 1.78-38.46), p < 0.01) and absence of ≥ 1 acute brain infarct (aOR 0.13, 95% CI 0.03-0.65, p = 0.01) were significantly associated with a positive biopsy. CONCLUSIONS: Baseline clinical and radiological characteristics differed between biopsy positive and negative PACNS. These results may help physicians individualize the decision to obtain a CNS biopsy in suspected PACNS.

Three-month functional outcomes following endovascular thrombectomy during the first wave of the COVID-19 pandemic: a Canadian single-center cohort study.

BACKGROUND: The COVID-19 pandemic has disrupted acute stroke care logistics, including delays in hyperacute management and decreased monitoring following endovascular therapy (EVT). We aimed to assess the impact of the pandemic on 90-day functional outcome among patients treated with EVT. METHODS: This is an observational cohort study including all patients evaluated for an acute stroke between March 30, 2020 and September 30, 2020 (pandemic cohort) and 2019 (reference cohort) in a high-volume Canadian academic stroke center. We collected baseline characteristics, acute reperfusion treatment and management metrics. For EVT-treated patients, we assessed the modified Rankin score (mRS) at 90 days. We evaluated the impact of the pandemic on a 90-day favourable functional status (defined as mRS 0-2) and death using multivariable logistic regressions. RESULTS: Among 383 and 339 patients included in the pandemic and reference cohorts, baseline characteristics were similar. Delays from symptom onset to evaluation and in-house treatment were longer during the early first wave, but returned to reference values in the subsequent months. Among the 127 and 136 EVT-treated patients in each respective cohort, favourable 90-day outcome occurred in 53/99 (53%) vs 52/109 (48%, p=0.40), whereas 22/99 (22%) and 28/109 (26%, p=0.56) patients died. In multivariable regressions, the pandemic period was not associated with 90-day favourable functional status (aOR 1.27, 95% CI 0.60 to 2.56) or death (aOR 0.74, 95% CI 0.33 to 1.63). CONCLUSION: In this single-center cohort study conducted in a Canadian pandemic epicenter, the first 6 months of the COVID-19 pandemic did not impact 90-day functional outcomes or death among EVT-treated patients.

Predictors and clinical impact of infarct progression rate in the ESCAPE-NA1 trial.

BACKGROUND: Determining infarct progression rate in acute ischemic stroke (AIS) is important for patient triage, treatment decision-making, and outcome prognostication. OBJECTIVE: To estimate infarct progression rate in patients with AIS with large vessel occlusion (LVO) and determine its predictors and impact on clinical outcome. METHODS: Data are from the ESCAPE-NA1 Trial. Patients with AIS with time from last known well to randomization <6 hours and near-complete reperfusion following endovascular treatment were included. Infarct growth rate (mL/h) was estimated by dividing 24 hour infarct volume (measured by non-contrast CT or diffusion-weighted magnetic resonance imaging) by time from last known well to reperfusion. Multivariable linear regression was used to assess the association of patient baseline variables with log-transformed infarct progression rate. The association of infarct progression rate and good outcome (modified Rankin Scale score 0-2) was determined using multivariable logistic regression. RESULTS: Four hundred and nine patients were included in the study. Median infarct progression rate was 4.74 mL/h (IQR 1.25-14.84). Collateral status (ß: -0.81 (95% CI -1.20 to -0.41)), Alberta Stroke Program Early CT Score (ASPECTS, ß: -0.34 (95% CI -0.46 to -0.23)), blood glucose(ß: 0.09 (95% CI 0.02 to 0.16)), and National Institutes of Health Stroke Scale (NIHS score (ß: 0.07 (95% CI 0.04 to 0.10)) were associated with log-transformed infarct progression rate. Clinical and imaging baseline variables explained 23% of the variance in infarct progression rate. Infarct progression rate was significantly associated with good outcome (aOR per 1 mL/h increase: 0.96 (95% CI 0.95 to 0.98)). CONCLUSION: In this sample of patients presenting within the early time window with LVO and near-complete recanalization, infarct progression rate was significantly associated with good outcome. A significant association between ASPECTS, collateral status, blood glucose, and NIHSS score was observed, but baseline imaging and clinical characteristics explained only a small proportion of the interindividual variance. More research on measurable factors affecting infarct growth is needed.

Canadian Stroke Best Practice Recommendations: Secondary Prevention of Stroke Update 2020.

The 2020 update of the Canadian Stroke Best Practice Recommendations (CSBPR) for the Secondary Prevention of Stroke includes current evidence-based recommendations and expert opinions intended for use by clinicians across a broad range of settings. They provide guidance for the prevention of ischemic stroke recurrence through the identification and management of modifiable vascular risk factors. Recommendations address triage, diagnostic testing, lifestyle behaviors, vaping, hypertension, hyperlipidemia, diabetes, atrial fibrillation, other cardiac conditions, antiplatelet and anticoagulant therapies, and carotid and vertebral artery disease. This update of the previous 2017 guideline contains several new or revised recommendations. Recommendations regarding triage and initial assessment of acute transient ischemic attack (TIA) and minor stroke have been simplified, and selected aspects of the etiological stroke workup are revised. Updated treatment recommendations based on new evidence have been made for dual antiplatelet therapy for TIA and minor stroke; anticoagulant therapy for atrial fibrillation; embolic strokes of undetermined source; low-density lipoprotein lowering; hypertriglyceridemia; diabetes treatment; and patent foramen ovale management. A new section has been added to provide practical guidance regarding temporary interruption of antithrombotic therapy for surgical procedures. Cancer-associated ischemic stroke is addressed. A section on virtual care delivery of secondary stroke prevention services in included to highlight a shifting paradigm of care delivery made more urgent by the global pandemic. In addition, where appropriate, sex differences as they pertain to treatments have been addressed. The CSBPR include supporting materials such as implementation resources to facilitate the adoption of evidence into practice and performance measures to enable monitoring of uptake and effectiveness of recommendations.

Management and outcome of patients with acute ischemic stroke and tandem carotid occlusion in the ESCAPE-NA1 trial.

BACKGROUND: The optimal treatment and prognosis for stroke patients with tandem cervical carotid occlusion are unclear. We analyzed outcomes and treatment strategies of tandem occlusion patients in the ESCAPE-NA1 trial. METHODS: ESCAPE-NA1 was a multicenter international randomized trial of nerinetide versus placebo in 1105 patients with acute ischemic stroke who underwent endovascular treatment. We defined tandem occlusions as complete occlusion of the cervical internal carotid artery (ICA) on catheter angiography, in addition to a proximal ipsilateral intracranial large vessel occlusion. Baseline characteristics and outcome parameters were compared between patients with tandem occlusions versus those without, and between patients with tandem occlusion who underwent ICA stenting versus those who did not. The influence of tandem occlusions on functional outcome was analyzed using multivariable regression modeling. RESULTS: Among 115/1105 patients (10.4%) with tandem occlusions, 62 (53.9%) received stenting for the cervical ICA occlusion. Of these, 46 (74.2%) were stented after and 16 (25.8%) before the intracranial thrombectomy. A modified Rankin Score (mRS) of 0-2 at 90 days was achieved in 82/115 patients (71.3%) with tandem occlusions compared with 579/981 (59.5%) patients without tandem occlusions. Tandem occlusion did not impact functional outcome in the adjusted analysis (OR 1.5, 95% CI 0.95 to 2.4). Among the subgroup of patients with tandem occlusion, cervical carotid stenting was not associated with different outcomes compared with no stenting (mRS 0-2: 75.8% vs 66.0%, adjusted OR 2.0, 95% CI 0.8 to 5.1). CONCLUSIONS: Tandem cervical carotid occlusion in patients with acute large vessel stroke did not lower the odds of good functional outcome in our study. Functional outcomes were similar irrespective of the management of the cervical ICA occlusion (stenting vs not stenting).

Assessment of Discrepancies Between Follow-up Infarct Volume and 90-Day Outcomes Among Patients With Ischemic Stroke Who Received Endovascular Therapy.

Importance: Some patients have poor outcomes despite small infarcts after endovascular therapy (EVT), while others with large infarcts do well. Understanding why these discrepancies occur may help to optimize EVT outcomes. Objective: To validate exploratory findings from the Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times (ESCAPE) trial regarding pretreatment, treatment-related, and posttreatment factors associated with discrepancies between follow-up infarct volume (FIV) and 90-day functional outcome. Design, Setting, and Participants: This cohort study is a post hoc analysis of the Safety and Efficacy of Nerinetide in Subjects Undergoing Endovascular Thrombectomy for Stroke (ESCAPE-NA1) trial, a double-blind, randomized, placebo-controlled, international, multicenter trial conducted from March 2017 to August 2019. Patients who participated in ESCAPE-NA1 and had available 90-day modified Rankin Scale (mRS) scores and 24-hour to 48-hour posttreatment follow-up parenchymal imaging were included. Exposures: Small FIV (volume ≤25th percentile) and large FIV (volume ≥75th percentile) on 24-hour computed tomography/magnetic resonance imaging. Baseline factors, outcomes, treatments, and poststroke serious adverse events (SAEs) were compared between discrepant cases (ie, patients with 90-day mRS score ≥3 despite small FIV or those with mRS scores ≤2 despite large FIV) and nondiscrepant cases. Main Outcomes and Measures: Area under the curve (AUC) and goodness of fit of prespecified logistic models, including pretreatment (eg, age, cancer, vascular risk factors) and treatment-related and posttreatment (eg, SAEs) factors, were compared with stepwise regression-derived models for ability to identify small FIV with higher mRS score and large FIV with lower mRS score. Results: Among 1091 patients (median [IQR] age, 70.8 [60.8-79.8] years; 549 [49.7%] women; median [IQR] FIV, 24.9 mL [6.6-92.2 mL]), 42 of 287 patients (14.6%) with FIV of 7 mL or less (ie, ≤25th percentile) had an mRS score of at least 3; 65 of 275 patients (23.6%) with FIV of 92 mL or greater (ie, ≥75th percentile) had an mRS score of 2 or less. Prespecified models of pretreatment factors (ie, age, cancer, vascular risk factors) associated with low FIV and higher mRS score performed similarly to models selected by stepwise regression (AUC, 0.92 [95% CI, 0.89-0.95] vs 0.93 [95% CI, 0.90-0.95]; P = .42). SAEs, specifically infarct in new territory, recurrent stroke, pneumonia, and congestive heart failure, were associated with low FIV and higher mRS scores; stepwise models also identified 24-hour hemoglobin as treatment-related/posttreatment factor (AUC, 0.92 [95% CI, 0.90-0.95] vs 0.94 [95% CI, 0.91-0.96]; P = .14). Younger age was associated with high FIV and lower mRS score; stepwise models identified absence of diabetes and higher baseline hemoglobin as additional pretreatment factors (AUC, 0.76 [95% CI, 0.70-0.82] vs 0.77 [95% CI, 0.71-0.83]; P = .82). Absence of SAEs, especially stroke progression, symptomatic intracerebral hemorrhage, and pneumonia, was associated with high FIV and lower mRS score2; stepwise models also identified 24-hour hemoglobin level, glucose, and diastolic blood pressure as posttreatment factors associated with discrepant cases (AUC, 0.80 [95% CI, 0.74-0.87] vs 0.79 [95% CI, 0.72-0.86]; P = .92). Conclusions and Relevance: In this study, discrepancies between functional outcome and post-EVT infarct volume were associated with differences in pretreatment factors, such as age and comorbidities, and posttreatment complications related to index stroke evolution, secondary prevention, and quality of stroke unit care. Besides preventing such complications, optimization of blood pressure, glucose levels, and hemoglobin levels are potentially modifiable factors meriting further study.

Discrepancy between post-treatment infarct volume and 90-day outcome in the ESCAPE randomized controlled trial.

BACKGROUND: Some patients with ischemic stroke have poor outcomes despite small infarcts after endovascular thrombectomy, while others with large infarcts sometimes fare better. AIMS: We explored factors associated with such discrepancies between post-treatment infarct volume (PIV) and functional outcome. METHODS: We identified patients with small PIV (volume ≤ 25th percentile) and large PIV (volume ≥ 75th percentile) on 24-48-h CT/MRI in the ESCAPE randomized-controlled trial. Demographics, comorbidities, baseline, and 24-48-h stroke severity (NIHSS), stroke location, treatment type, post-stroke complications, and other outcome scales like Barthel Index, and EQ-5D were compared between "discrepant cases" - those with 90-day modified Rankin Scale(mRS) ≤ 2 despite large PIV or mRS ≥ 3 despite small PIV - and "non-discrepant cases". Multi-variable logistic regression was used to identify pre-treatment and post-treatment factors associated with small-PIV/mRS ≥ 3 and large-PIV/mRS ≤ 2. Sensitivity analyses used different definitions of small/large PIV and good/poor outcome. RESULTS: Among 315 patients, median PIV was 21 mL; 27/79 (34.2%) patients with PIV ≤ 7 mL (25th percentile) had mRS ≥ 3; 12/80 (15.0%) with PIV ≥ 72 mL (75th percentile) had mRS ≤ 2. Discrepant cases did not differ by CT versus MRI-based PIV ascertainment, or right versus left-hemisphere involvement (p = 0.39, p = 0.81, respectively, for PIV ≤ 7 mL/mRS ≥ 3). Pre-treatment factors independently associated with small-PIV/mRS ≥ 3 included older age (p = 0.010), cancer, and vascular risk-factors; post-treatment factors included 48-h NIHSS (p = 0.007) and post-stroke complications (p = 0.026). Absence of vascular risk-factors (p = 0.004), CT-based lentiform nucleus sparing (p = 0.002), lower 24-hour NIHSS (p = 0.001), and absence of complications (p = 0.013) were associated with large-PIV/mRS ≤ 2. Sensitivity analyses yielded similar results. CONCLUSIONS: Discrepancies between functional ability and PIV are likely explained by differences in age, comorbidities, and post-stroke complications, emphasizing the need for high-quality post-thrombectomy stroke care. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT01778335.

Acute carotid stenting in patients undergoing thrombectomy: a systematic review and meta-analysis.

BACKGROUND: The benefit of acute carotid stenting compared with no acute stenting on clinical outcomes among patients with tandem lesions (TL) undergoing endovascular thrombectomy (EVT) remains unknown. METHODS: We conducted a a systematic review and meta-analysis of studies comparing acute carotid stenting versus no stenting among TL patients undergoing EVT with regards to 90 day modified Rankin Scale (mRS) score, symptomatic intracerebral hemorrhage (sICH), and mortality. Four reviewers screened citations for eligibility and two assessed retained studies for risk of bias and data extraction. A random effects model was used for the synthesis of aggregated data. RESULTS: 21 studies (n=1635 patients) were identified for the systematic review; 19 were cohort studies, 1 was a post-hoc analysis of an EVT trial, and 1 was a pilot randomized controlled trial. 16 studies were included in the meta-analysis. Acute stenting was associated with a favorable 90 day mRS score: OR 1.43 (95% CI 1.07, 1.91). No significant heterogeneity between studies was found for this outcome (I2=17.0%; χ2=18.07, p=0.26). There were no statistically significant differences for 3 month mortality (OR 0.80 (95% CI 0.50, 1.28)) or sICH (OR 1.41 (95% CI 0.91, 2.19)). CONCLUSIONS: This meta-analysis suggests that among TL patients undergoing EVT, acute carotid stenting is associated with a greater likelihood of favorable outcome at 90 days compared with no stenting.

Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial.

BACKGROUND: Nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, is a neuroprotectant that is effective in preclinical stroke models of ischaemia-reperfusion. In this trial, we assessed the efficacy and safety of nerinetide in human ischaemia-reperfusion that occurs with rapid endovascular thrombectomy in patients who had an acute ischaemic stroke. METHODS: For this multicentre, double-blind, randomised, placebo-controlled study done in 48 acute care hospitals in eight countries, we enrolled patients with acute ischaemic stroke due to large vessel occlusion within a 12 h treatment window. Eligible patients were aged 18 years or older with a disabling ischaemic stroke at the time of randomisation, had been functioning independently in the community before the stroke, had an Alberta Stroke Program Early CT Score (ASPECTS) greater than 4, and vascular imaging showing moderate-to-good collateral filling, as determined by multiphase CT angiography. Patients were randomly assigned (1:1) to receive intravenous nerinetide in a single dose of 2·6 mg/kg, up to a maximum dose of 270 mg, on the basis of estimated or actual weight (if known) or saline placebo by use of a real-time, dynamic, internet-based, stratified randomised minimisation procedure. Patients were stratified by intravenous alteplase treatment and declared endovascular device choice. All trial personnel and patients were masked to sequence and treatment allocation. All patients underwent endovascular thrombectomy and received alteplase in usual care when indicated. The primary outcome was a favourable functional outcome 90 days after randomisation, defined as a modified Rankin Scale (mRS) score of 0-2. Secondary outcomes were measures of neurological disability, functional independence in activities of daily living, excellent functional outcome (mRS 0-1), and mortality. The analysis was done in the intention-to-treat population and adjusted for age, sex, baseline National Institutes of Health Stroke Scale score, ASPECTS, occlusion location, site, alteplase use, and declared first device. The safety population included all patients who received any amount of study drug. This trial is registered with ClinicalTrials.gov, NCT02930018. FINDINGS: Between March 1, 2017, and Aug 12, 2019, 1105 patients were randomly assigned to receive nerinetide (n=549) or placebo (n=556). 337 (61·4%) of 549 patients with nerinetide and 329 (59·2%) of 556 with placebo achieved an mRS score of 0-2 at 90 days (adjusted risk ratio 1·04, 95% CI 0·96-1·14; p=0·35). Secondary outcomes were similar between groups. We observed evidence of treatment effect modification resulting in inhibition of treatment effect in patients receiving alteplase. Serious adverse events occurred equally between groups. INTERPRETATION: Nerinetide did not improve the proportion of patients achieving good clinical outcomes after endovascular thrombectomy compared with patients receiving placebo. FUNDING: Canadian Institutes for Health Research, Alberta Innovates, and NoNO.

Primary angiitis of the central nervous system: neurologic deterioration despite treatment.

Primary angiitis of the central nervous system (PACNS) is an idiopathic vasculitis confined to the central nervous system. In children with PACNS, small-vessel (SV) involvement is characterized clinically by progressive neurologic symptoms, multifocal lesions on brain imaging, occasional pseudo-tumor presentation, and normal angiogram results in most patients. Small case series of patients with SV PACNS with short follow-up usually reveal favorable outcomes in children treated with immunosuppressive therapy. We report here the cases of 3 children with biopsy-confirmed SV PACNS and long-term follow-up who developed different patterns of neurologic deterioration despite immunosuppressive therapy. One patient had transient ischemic attacks shortly after initiation of corticosteroid treatment. Early ischemic events probably result from residual thrombogenicity or residual inflammation of recently affected vessels, which supports the use of antiplatelet agents and suggests potential benefits of stronger immunosuppressive therapy. In contrast, the other 2 patients had later neurologic deterioration after corticosteroid withdrawal, which suggests failure of initial immunosuppressant treatment and the need for stronger agents, longer treatment duration, or both. All patients responded to long-term treatment with corticosteroids combined with cytotoxic agents. This particular combination is probably indicated in many cases of SV PACNS, including those with neurologic deterioration that occurs during maintenance corticotherapy or after corticosteroid withdrawal. In 1 case, SV PACNS recurred several years after discontinuation of combination therapy. Long-term relapses may reflect intrinsic predispositions to SV PACNS rather than treatment failure. These cases highlight different chronological patterns of neurologic deterioration despite immunosuppressive therapy, which supports the relevance of monitoring clinical, laboratory, and radiologic responses to treatment and of long-term follow-up of patients with SV PACNS.

Intravenous thrombolysis for acute ischaemic stroke in young adult patients.

BACKGROUND: Intravenous tissue plasminogen activator (IV tPA) has been studied primarily in patients over age 50. We sought to describe baseline differences in adult patients < or = 50 years-old taken from a large prospective cohort of acute stroke patients treated with intravenous tPA (IV tPA) and to determine whether outcomes differed for this population. METHODS: Data (n = 1120) prospectively collected from the Canadian Alteplase for Stroke Effectiveness Study (CASES) were reviewed and patients aged < or = 50 years-old (n = 99) were compared with those aged > 50 years (n = 1021) with regards to baseline characteristics, symptomatic intracerebral haemorrhage (sICH), functional outcome at 90 days and death. RESULTS: Nine percent of patients were < or = 50 years-old. Among patients aged < or = 50 years, 40.4% were women and median age was 42 +/- 6.1 years (range 20 to 50). They had significantly more current cigarette use but fewer other vascular risk factors than older patients (p < 0.05) and their baseline median NIHSS score was lower (13 versus 15, P = 0.001). Although this group was more likely to have a favourable 90-day outcome, multivariable regression confirmed that age < or = 50 years, while independently associated with a decreased risk of death (RR 0.36, 95% CI 0.14 to 0.95), was not itself predictive of favourable 90-day outcome or decreased risk of sICH. CONCLUSIONS: Adult patients < or = 50 years-old had fewer medical co-morbidities and a modestly lower baseline median NIHSS score than their older counterparts. Age < or = 50 years was independently associated with a decreased risk of death but not with favourable outcome or risk of sICH.

Fibromuscular dysplasia with carotid artery dissection presenting as an isolated hemianopsia.

BACKGROUND: Internal carotid artery (ICA) dissection is a well-known cause of anterior circulation stroke, but its association with posterior circulation stroke has been less commonly reported. The latter situation can arise when there is persistent fetal circulation of the posterior cerebral artery and has, to our knowledge, never been reported in the setting of fibromuscular dysplasia (FMD) involving the ICA. METHODS: A 52-year-old man awoke with severe headache and noted visual loss. Examination confirmed a congruous left homonymous hemianopsia. A head computed tomography scan revealed an acute right posterior parietal infarct. Carotid ultrasonography demonstrated complete occlusion of the right ICA. Conventional angiography confirmed this and was diagnostic of FMD with dissection. A right-sided persistent fetal circulation was also noted. Magnetic resonance imaging revealed right parietal and right occipital infarctions. RESULTS: The patient received ASA and clopidogrel and his visual deficit resolved within days. One year later, he remained asymptomatic and there was no suggestion of FMD in other vascular beds. CONCLUSIONS: Although infrequently reported, carotid disease, including dissection, can be responsible for posterior circulation infarcts. Cervical artery dissection can be related to underlying arteriopathies such as FMD, which must be differentiated from vasculitis and vasospasm.

Neuromyelitis optica with hypothalamic involvement.

We describe two cases of neuromyelitis optica (NMO) with clinical and radiographically confirmed features of hypothalamic involvement, in the absence of other parenchymal brain lesions. Their course is otherwise typical of Devic's form of NMO. A review of the literature identifies additional cases of NMO in which clinical features attributable to under-recognized dysfunction of the hypothalamic-pituitary axis were present. We propose that the currently accepted criteria for the diagnosis of NMO could be revisited to recognize the possibility of lesions developing within hypothalamic structures.