Associations of Cerebral Small Vessel Disease and Chronic Kidney Disease in Patients With Acute Intracerebral Hemorrhage: A Cross-Sectional Study.

BACKGROUND AND OBJECTIVES: Chronic kidney disease (CKD) may be associated with the pathogenesis and phenotype of cerebral small vessel disease (SVD), which is the commonest cause of intracerebral hemorrhage (ICH). The purpose of this study was to investigate the associations of CKD with ICH neuroimaging phenotype, volume, and location, total burden of small vessel disease, and its individual components. METHODS: In 2 cohorts of consecutive patients with ICH evaluated with MRI, we investigated the frequency and severity of CKD based on established Kidney Disease Improving Global Outcomes criteria, requiring estimated glomerular filtration rate (eGFR) measurements <60 mL/min/1.732 ≥ 3 months apart to define CKD. MRI scans were rated for ICH neuroimaging phenotype (arteriolosclerosis, cerebral amyloid angiopathy, mixed location SVD, or cryptogenic ICH) and the presence of markers of SVD (white matter hyperintensities [WMHs], cerebral microbleeds [CMBs], lacunes, and enlarged perivascular spaces, defined according to the STandards for ReportIng Vascular changes on nEuroimaging criteria). We used multinomial, binomial logistic, and ordinal logistic regression models adjusted for age, sex, hypertension, and diabetes to account for possible confounding caused by shared risk factors of CKD and SVD. RESULTS: Of 875 patients (mean age 66 years, 42% female), 146 (16.7%) had CKD. After adjusting for age, sex, and comorbidities, patients with CKD had higher rates of mixed SVD than those with eGFR >60 (relative risk ratio 2.39, 95% CI 1.16-4.94, p = 0.019). Severe WMHs, deep microbleeds, and lacunes were more frequent in patients with CKD, as was a higher overall SVD burden score (odds ratio 1.83 for each point on the ordinal scale, 95% CI 1.31-2.56, p < 0.001). Patients with eGFR ≤30 had more CMBs (median 7 [interquartile range 1-23] vs 2 [0-8] for those with eGFR >30, p = 0.007). DISCUSSION: In patients with ICH, CKD was associated with SVD burden, a mixed SVD phenotype, and markers of arteriolosclerosis. Our findings indicate that CKD might independently contribute to the pathogenesis of arteriolosclerosis and mixed SVD, although we could not definitively account for the severity of shared risk factors. Longitudinal and experimental studies are, therefore, needed to investigate causal associations. Nevertheless, stroke clinicians should be aware of CKD as a potentially independent and modifiable risk factor of SVD.

Statin Therapy for Secondary Prevention in Ischemic Stroke Patients With Cerebral Microbleeds.

BACKGROUND AND OBJECTIVES: The association between statin use and the risk of intracranial hemorrhage (ICrH) following ischemic stroke (IS) or transient ischemic attack (TIA) in patients with cerebral microbleeds (CMBs) remains uncertain. This study investigated the risk of recurrent IS and ICrH in patients receiving statins based on the presence of CMBs. METHODS: We conducted a pooled analysis of individual patient data from the Microbleeds International Collaborative Network, comprising 32 hospital-based prospective studies fulfilling the following criteria: adult patients with IS or TIA, availability of appropriate baseline MRI for CMB quantification and distribution, registration of statin use after the index stroke, and collection of stroke event data during a follow-up period of ≥3 months. The primary endpoint was the occurrence of recurrent symptomatic stroke (IS or ICrH), while secondary endpoints included IS alone or ICrH alone. We calculated incidence rates and performed Cox regression analyses adjusting for age, sex, hypertension, atrial fibrillation, previous stroke, and use of antiplatelet or anticoagulant drugs to explore the association between statin use and stroke events during follow-up in patients with CMBs. RESULTS: In total, 16,373 patients were included (mean age 70.5 ± 12.8 years; 42.5% female). Among them, 10,812 received statins at discharge, and 4,668 had 1 or more CMBs. The median follow-up duration was 1.34 years (interquartile range: 0.32-2.44). In patients with CMBs, statin users were compared with nonusers. Compared with nonusers, statin therapy was associated with a reduced risk of any stroke (incidence rate [IR] 53 vs 79 per 1,000 patient-years, adjusted hazard ratio [aHR] 0.68 [95% CI 0.56-0.84]), a reduced risk of IS (IR 39 vs 65 per 1,000 patient-years, aHR 0.65 [95% CI 0.51-0.82]), and no association with the risk of ICrH (IR 11 vs 16 per 1,000 patient-years, aHR 0.73 [95% CI 0.46-1.15]). The results in aHR remained consistent when considering anatomical distribution and high burden (≥5) of CMBs. DISCUSSION: These observational data suggest that secondary stroke prevention with statins in patients with IS or TIA and CMBs is associated with a lower risk of any stroke or IS without an increased risk of ICrH. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with IS or TIA and CMBs, statins lower the risk of any stroke or IS without increasing the risk of ICrH.

CADMUS: A Novel MRI-Based Classification of Spontaneous Intracerebral Hemorrhage Associated With Cerebral Small Vessel Disease

BACKGROUND AND OBJECTIVES: Cerebral small vessel disease (SVD) is the major cause of intracerebral hemorrhage (ICH). There is no comprehensive, easily applicable classification of ICH subtypes according to the presumed underlying SVD using MRI. We developed an MRI-based classification for SVD-related ICH. METHODS: We performed a retrospective study in the prospectively collected Swiss Stroke Registry (SSR, 2013-2019) and the Stroke InvestiGation in North And central London (SIGNAL) cohort. Patients with nontraumatic, SVD-related ICH and available MRI within 3 months were classified as Cerebral Amyloid angiopathy (CAA), Deep perforator arteriopathy (DPA), Mixed CAA-DPA, or Undetermined SVD using hemorrhagic and nonhemorrhagic MRI markers (CADMUS classification). The primary outcome was inter-rater reliability using Gwet's AC1. Secondary outcomes were recurrent ICH/ischemic stroke at 3 months according to the CADMUS phenotype. We performed Firth penalized logistic regressions and competing risk analyses. RESULTS: The SSR cohort included 1,180 patients (median age [interquartile range] 73 [62-80] years, baseline NIH Stroke Scale 6 [2-12], 45.6% lobar hematoma, systolic blood pressure on admission 166 [145-185] mm Hg). The CADMUS phenotypes were as follows: mixed CAA-DPA (n = 751 patients, 63.6%), undetermined SVD (n = 203, 17.2%), CAA (n = 154, 13.1%), and DPA (n = 72, 6.3%), with a similar distribution in the SIGNAL cohort (n = 313). Inter-rater reliability was good (Gwet's AC1 for SSR/SIGNAL 0.69/0.74). During follow-up, 56 patients had 57 events (28 ICH, 29 ischemic strokes). Three-month event rates were comparable between the CADMUS phenotypes. DISCUSSION: CADMUS, a novel MRI-based classification for SVD-associated ICH, is feasible and reproducible and may improve the classification of ICH subtypes in clinical practice and research.

Prevalence, patterns, and predictors of patient-reported non-motor outcomes at 30 days after acute stroke: Prospective observational hospital cohort study.

BACKGROUND: Adverse non-motor outcomes are common after acute stroke and likely to substantially affect quality of life, yet few studies have comprehensively assessed their prevalence, patterns, and predictors across multiple health domains. AIMS: We aimed to identify the prevalence, patterns, and the factors associated with non-motor outcomes 30 days after stroke. METHODS: This prospective observational hospital cohort study-Stroke Investigation in North and Central London (SIGNAL)-identified patients with acute ischemic stroke or intracerebral hemorrhage (ICH) admitted to the Hyperacute Stroke Unit (HASU) at University College Hospital (UCH), London, between August 1, 2018 and August 31, 2019. We assessed non-motor outcomes (anxiety, depression, fatigue, sleep, participation in social roles and activities, pain, bowel function, and bladder function) at 30-day follow-up using the Patient-Reported Outcome Measurement Information System-Version 29 (PROMIS-29) scale and Barthel Index scale. RESULTS: We obtained follow-up data for 605/719 (84.1%) eligible patients (mean age 72.0 years; 48.3% female; 521 with ischemic stroke, 84 with ICH). Anxiety (57.0%), fatigue (52.7%), bladder dysfunction (50.2%), reduced social participation (49.2%), and pain (47.9%) were the commonest adverse non-motor outcomes. The rates of adverse non-motor outcomes in ⩾ 1, ⩾ 2 and ⩾ 3 domains were 89%, 66.3%, and 45.8%, respectively; in adjusted analyses, stroke due to ICH (compared to ischemic stroke) and admission stroke severity were the strongest and most consistent predictors. There were significant correlations between bowel dysfunction and bladder dysfunction (κ = 0.908); reduced social participation and bladder dysfunction (κ = 0.844); and anxiety and fatigue (κ = 0.613). We did not identify correlations for other pairs of non-motor domains. CONCLUSION: Adverse non-motor outcomes were very common at 30 days after stroke, affecting nearly 90% of evaluated patients in at least one health domain, about two-thirds in two or more domains, and almost 50% in three or more domains. Stroke due to ICH and admission stroke severity were the strongest and most consistent predictors. Adverse outcomes occurred in pairs of domains, such as with anxiety and fatigue. Our findings emphasize the importance of a multi-domain approach to effectively identify adverse non-motor outcomes after stroke to inform the development of more holistic patient care pathways after stroke.

The impact of the UK COVID-19 pandemic on patient-reported health outcomes after stroke: a retrospective sequential comparison.

BACKGROUND AND PURPOSE: The COVID-19 pandemic and related social isolation measures are likely to have adverse consequences on community healthcare provision and outcome after acute illnesses treated in hospital, including stroke. We aimed to evaluate the impact of the COVID-19 pandemic on patient-reported health outcomes after hospital admission for acute stroke. METHODS: This retrospective study included adults with acute stroke admitted to the University College Hospital NHS Foundation Trust Hyperacute Stroke Unit. We included two separate cohorts of consecutively enrolled patients from the same geographical population at two time points: 16th March-16th May 2018 (pre-COVID-19 pandemic); and 16th March-16th May 2020 (during the COVID-19 pandemic). Patients in both cohorts completed the validated Patient Reported Outcomes Measurement Information System-29 (PROMIS-29 version 2.0) at 30 days after stroke. RESULTS: We included 205 patients who were alive at 30 days (106 admitted before and 99 admitted during the COVID-19 pandemic), of whom 201/205 (98%) provided patient-reported health outcomes. After adjustment for confounding factors, admission with acute stroke during the COVID-19 pandemic was independently associated with increased anxiety (ß = 28.0, p < 0.001), fatigue (ß = 9.3, p < 0.001), depression (ß = 4.5, p = 0.002), sleep disturbance (ß = 2.3, p = 0.018), pain interference (ß = 10.8, p < 0.001); and reduced physical function (ß = 5.2, p < 0.001) and participation in social roles and activities (ß = 6.9, p < 0.001). CONCLUSION: Compared with the pre-pandemic cohort, patients admitted with acute stroke during the first wave of the COVID-19 pandemic reported poorer health outcomes at 30 day follow-up in all domains. Stroke service planning for any future pandemic should include measures to mitigate this major adverse impact on patient health.

Sequential fluctuating paraneoplastic ocular flutter-opsoclonus-myoclonus syndrome and Lambert-Eaton myasthenic syndrome in small-cell lung cancer.

Paraneoplastic cerebellar degeneration may occur in association with Lambert-Eaton myasthenic syndrome (LEMS), but to our knowledge, the co-occurrence of paraneoplastic opsoclonus-myoclonus syndrome and LEMS has not been previously reported. A 67-year-old woman presented with a complex partial seizure and evolving ocular flutter, opsoclonus, myoclonus and 'cerebellar' signs, all of which improved spontaneously within 6 weeks. Approximately 8 weeks after symptom onset, the patient became encephalopathic, she had a further complex partial seizure, and she became areflexic with potentiation of deep tendon reflexes. Radiological, bronchoscopic and histological investigations revealed small-cell lung cancer, and neurophysiological investigations confirmed a diagnosis of LEMS. High-titre anti-P/Q-type voltage-gated calcium-channel antibodies were identified in the serum, which increased as the signs of opsoclonus and myoclonus resolved. The encephalopathy and clinical features of LEMS responded dramatically to chemotherapy and radiotherapy. Spontaneous improvement of paraneoplastic opsoclonus-myoclonus syndrome may occur, and this syndrome may occur in association with LEMS. Antivoltage-gated calcium-channel antibodies are not implicated in the pathogenesis of paraneoplastic opsoclonus-myoclonus syndrome.

Proton MR spectroscopy of metabolite concentrations in temporal lobe epilepsy and effect of temporal lobe resection.

PURPOSE: To use proton Magnetic Resonance Spectroscopy (MRS) to measure in vivo temporal lobe GABA and glutamate plus glutamine (GLX) concentrations in patients with temporal lobe epilepsy (TLE) attributable to unilateral hippocampal sclerosis (HS) before and following anterior temporal lobe resection (ATLR). METHODS: We obtained quantitative short echo time MRS in both temporal lobes of 15 controls and 16 patients with TLE and HS, and repeat spectra in 10 patients after ATLR. We measured the concentrations of N-acetyl aspartate+N-acetyl aspartyl-glutamate (NAAt), creatine plus phosphocreatine (Cr), and glutamate+glutamine (GLX) using a metabolite-nulled sequence designed to minimize macromolecule artifact. GABA concentrations were measured using a previously described double quantum filter. RESULTS: In patients with TLE, NAAt/Cr was reduced in ipsilateral and contralateral temporal lobes. No significant variation in GLX/Cr or GABA+/Cr was evident in any group although GABA+/Cr was highest in the ipsilateral temporal lobe in TLE. After ATLR there was a trend to normalization of NAAt/Cr in the contralateral temporal lobe but no change in individual metabolite concentrations, GLX/Cr or GABA+/Cr compared to pre-surgery levels. DISCUSSION: Temporal lobe epilepsy was associated with bilateral reduction in NAAt/Cr but not significant abnormality in GABA+/Cr or GLX/Cr. Normalization of NAAt/Cr in the contralateral temporal lobe was seen following successful ATLR.

The effect of epileptic seizures on proton MRS visible neurochemical concentrations.

PURPOSE: To investigate post-ictal changes in cerebral metabolites. METHODS: We performed a longitudinal quantitative proton magnetic resonance spectroscopy (MRS) study in 10 patients with epilepsy and 10 control subjects. The patients were studied on two occasions: immediately following a seizure, and on a second occasion at least 7h after the most recent seizure. Each study measured N-acetyl aspartate plus N-acetyl aspartyl glutamate (NAAt), Creatine plus phosphocreatine (Cr), Choline containing compounds (Cho) and glutamate plus glutamine (GLX) concentrations using a short-echo time sequence (TE=30ms), and NAAt, Cr and lactate using a second sequence with longer echo time (TE=144ms). The control group was studied on two occasions using the same sequences. RESULTS: No inter-scan differences were observed for the control group. NAAt and NAAt/Cr levels were lower in the patient group at both measured TEs but did not change significantly between studies. The ratio of Cr at TE 144ms to TE 30ms (Cr(144)/Cr(30)) and GLX/Cr were higher and Cho lower in the post-ictal scan compared to the inter-ictal study. Change in Cr(144)/Cr(30) and NAAt(144)/Cr(144) correlated with the post-ictal interval. Lactate measurement at longer TE was not informative. DISCUSSION: Proton MRS is sensitive to metabolite changes following epileptic seizures within the immediate post-ictal period. The ratio Cr(144)/Cr(30) is the most sensitive measure of metabolic disturbance and is highest in the post-ictal period but appears to normalise within 2h of the most recent seizure.

The effect of sodium valproate on proton MRS visible neurochemical concentrations.

The effect of the antiepileptic medication sodium valproate (VPA) on the concentrations of cerebral metabolites was studied longitudinally in ten patients with epilepsy using proton magnetic resonance spectroscopy (MRS). Myo-inositol was found to be lower while taking VPA, although no relationship between the change in metabolite concentration, VPA dose or seizure control was observed. MRS findings should be interpreted in the light of administered medications.

Proton magnetic resonance spectroscopy of malformations of cortical development causing epilepsy.

PURPOSE: To use proton magnetic resonance spectroscopy (MRS) to measure concentrations of gamma-aminobutyric acid (GABA) and glutamate plus glutamine (GLX) in adult patients with refractory epilepsy associated with malformations of cortical development (MCD). METHODS: We used MRS to measure N-acetyl aspartate (NAA), creatine plus phosphocreatine (Cr) and choline containing compounds (Cho), as well as GLX, and GABA. Fifteen patients with epilepsy attributable to MCD and 15 healthy controls were studied. Nine of the MCD group had heterotopia and six had polymicrogyria. Quantitative short echo time MRS [echo time (TE)=30 ms, repetition time (TR)=3000 ms] was performed in the MRI evident MCD and in the occipital lobes of the control group and the concentrations of NAA, Cr, Cho, and GLX were measured. GABA plus homocarnosine (GABA+) was measured in the same regions using a double quantum filter. RESULTS: The dominant abnormalities in the patient group were elevation of Cho and GLX and reduction in NAAt compared to the control group. The ratios GLX/NAAt and GABA+/Cr were also increased in the patient group whilst the ratio NAAt/Cr was decreased. NAAt was significantly lower in polymicrogyria than heterotopia. CONCLUSIONS: Large cortical malformations had abnormal levels of both GLX and GABA+/Cr. Low NAAt and high Cho were also observed. These results indicate that MCD show spectroscopic features of primitive tissue and abnormal metabolism of both inhibitory and excitatory neurotransmitters.

Long-term retention rates of new antiepileptic drugs in adults with chronic epilepsy and learning disability.

We compared the long-term retention rates of several newly licensed antiepileptic drugs (AEDs) in a residential community of adults with chronic epilepsy and learning disability. Data relating to duration of therapy, maximum dose, and tolerability of six new AEDs-gabapentin (GBP), lamotrigine (LTG), levetiracetam (LEV), oxcarbazepine (OXC), tiagabine (TIA), and topiramate (TPM)-were collected. Drug retention at 2 years was 85% (OXC), 57% (LTG), 56% (LEV), 45% (TPM), 24% (TIA) and 15% (GBP). OXC was used mainly as a substitute for carbamazepine. LTG, LEV, and TPM were all associated with retention rates higher than those of GBP or TIA. TPM had the highest rate of adverse event development at the maximum tried dose (60%), whereas LEV had the lowest (16%). Experience from this single epilepsy community study indicated limited impact for GBP or TIA but higher retention of OXC, LEV, LTG, and TPM in patients with chronic epilepsy and learning disability.

High-resolution diffusion tensor imaging of the hippocampus in temporal lobe epilepsy.

PURPOSE: To assess the quantitative diffusion characteristics of the hippocampus with high-resolution diffusion tensor imaging (DTI) in temporal lobe epilepsy (TLE). METHODS: Thirteen controls and seven unilateral TLE patients (six with hippocampal sclerosis, one with normal magnetic resonance imaging (MRI)) were scanned with DTI using a zonally magnified oblique multislice echo planar imaging (ZOOM-EPI) acquisition. Fractional anisotropy (FA) and mean diffusivity (MD) were measured in the hippocampi. RESULTS: The mean hippocampal MD ipsilateral to the seizure focus was higher than the contralateral MD in patients (p<0.05) and the mean MD in controls (p<0.001). Hippocampal FA ipsilateral to the seizure focus was lower than the mean FA in controls (p<0.05). MD asymmetry indexes were significantly different between the patient and control groups (p<0.01). All six individual HS patients had ipsilateral hippocampal MD >or=2 standard deviations (S.D.) above the control mean. The patient with normal structural MRI had bilaterally low hippocampal FA and high MD. DISCUSSION: High-resolution DTI identifies lateralizing abnormalities of MD and FA in TLE patients. This quantitative data on hippocampal integrity may assist in evaluating TLE patients with normal MRI, and in longitudinal studies.

Magnetisation transfer ratio of choline is reduced following epileptic seizures.

The purpose of this study was to characterise the concentration and magnetisation transfer ratio (MTR) of brain metabolites following epileptic seizures. Magnetic resonance spectroscopy was performed in 10 patients with temporal or extra-temporal lobe epilepsy as soon as possible after a seizure, with a second interictal scan between 1 and 3 days after the postictal scan and 10 healthy controls were scanned twice. Voxels (26 +/- 2 mL) were placed in the frontal lobe in all patients and controls, on the side of seizure focus in the patient group. Spectra were obtained using a modified PRESS sequence (TE 30 ms, TR 3 s, with three hard pulses offset from the water frequency by 2,500 Hz for MT presaturation). Mean metabolite concentrations and median metabolite MTRs of N-acetylaspartate (NAA), creatine, choline (Cho), myo-inositol (Ins) and glutamate plus glutamine were compared between the first and second scans in each group. A significant decrease in the MTR of Cho was seen postictally in the patient group, but the metabolite concentrations showed no significant difference between interictal and postictal scans and in the control group there was no difference between the two scans. Inter-group comparison showed significantly reduced concentrations of NAA and Ins in the patients. Reduced MTR of Cho indicates a shift from a bound to a more mobile fraction. These changes might indicate membrane perturbation in areas of seizure spread.

Magnetization transfer effect on human brain metabolites and macromolecules.

A pulse sequence was implemented to observe the magnetization transfer (MT) effect on metabolites, water, and macromolecules in human frontal lobes in vivo at 1.5 Tesla. Signals were compared following the application of three hard pulses of 0.745 muT amplitude, applied at frequency offsets of either 2500 Hz or 30 kHz, preceding a conventional point-resolved spectroscopy (PRESS)-localized acquisition with an echo time (TE) of 30 ms and repetition time (TR) of 3 s. This gave an MT effect on water in vivo of 46%, while direct saturation by the MT pulses at 2.5 kHz offset was confirmed to be under 4% for all metabolites. We observed significant MT saturation in vivo for N-acetylated compounds, choline (Cho), myo-inositol, and lactate (Lac); a trend of an effect on glutamate + glutamine (Glx); and the typically observed effect on creatine (Cr). No significant MT effect was seen on the macromolecule signal, which was observed using metabolite nulling.

Cardiac arrhythmias in focal epilepsy: a prospective long-term study.

BACKGROUND: Patients with epilepsy are at risk of sudden unexpected death. Neurogenic cardiac arrhythmias have been postulated as a cause. Electrocardiograms (ECG) can be monitored by use of an implantable loop recorder for up to 18 months. We aimed to determine the frequency of cardiac arrhythmias in patients with refractory focal seizures over an extended period. METHODS: 20 patients received an implantable loop recorder at one hospital in the UK. Devices were programmed to record automatically if bradycardia (<40 beats per min) or tachycardia (>140 beats per min) were detected. Additionally, in the event of a seizure, patients and relatives could initiate ECG recording with an external activator device. Data were analysed at regular intervals and correlated with seizure diaries. FINDINGS: More than 220000 patient-hours were monitored over 24 months, during which ECGs were captured on implantable loop recorders in 377 seizures. One patient withdrew from the study. In 16 patients, median heart rate during habitual seizures exceeded 100 beats per min. Ictal bradycardia (<40 beats per min) was rare, occurring in eight (2.1%) recorded events, in seven patients. Four patients (21%) had bradycardia or periods of asystole with subsequent permanent pacemaker insertion. Three of these four (16% of total) had potentially fatal asystole. INTERPRETATION: Clinical characteristics of patients with peri-ictal cardiac abnormalities are closely similar to those at greatest risk of sudden unexpected death in epilepsy. Asystole might underlie many of these deaths, which would have important implications for the investigation of similar patients and affect present cardiac-pacing policies.