Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial.

BACKGROUND: The balance of risk and benefit from early neurosurgical intervention for conscious patients with superficial lobar intracerebral haemorrhage of 10-100 mL and no intraventricular haemorrhage admitted within 48 h of ictus is unclear. We therefore tested the hypothesis that early surgery compared with initial conservative treatment could improve outcome in these patients. METHODS: In this international, parallel-group trial undertaken in 78 centres in 27 countries, we compared early surgical haematoma evacuation within 12 h of randomisation plus medical treatment with initial medical treatment alone (later evacuation was allowed if judged necessary). An automatic telephone and internet-based randomisation service was used to assign patients to surgery and initial conservative treatment in a 1:1 ratio. The trial was not masked. The primary outcome was a prognosis-based dichotomised (favourable or unfavourable) outcome of the 8 point Extended Glasgow Outcome Scale (GOSE) obtained by questionnaires posted to patients at 6 months. Analysis was by intention to treat. This trial is registered, number ISRCTN22153967. FINDINGS: 307 of 601 patients were randomly assigned to early surgery and 294 to initial conservative treatment; 298 and 291 were followed up at 6 months, respectively; and 297 and 286 were included in the analysis, respectively. 174 (59%) of 297 patients in the early surgery group had an unfavourable outcome versus 178 (62%) of 286 patients in the initial conservative treatment group (absolute difference 3·7% [95% CI -4·3 to 11·6], odds ratio 0·86 [0·62 to 1·20]; p=0·367). INTERPRETATION: The STICH II results confirm that early surgery does not increase the rate of death or disability at 6 months and might have a small but clinically relevant survival advantage for patients with spontaneous superficial intracerebral haemorrhage without intraventricular haemorrhage. FUNDING: UK Medical Research Council.

Long-term incidence of depression and predictors of depressive symptoms in older stroke survivors.

BACKGROUND: Depression is common and an important consequence of stroke but there is limited information on the longer-term relationship between these conditions. AIMS: To identify the prevalence, incidence and predictors of depression in a secondary-care-based cohort of stroke survivors aged over 75 years, from 3 months to up to 10 years post-stroke. METHOD: Depression was assessed annually by three methods: major depression by DSM-IV criteria, the self-rated Geriatric Depression Scale (GDS) and the observer-rated Cornell scale. RESULTS: We found the highest rates, 31.7% baseline prevalence, of depressive symptoms with the GDS compared with 9.7% using the Cornell scale and 1.2% using DSM-IV criteria. Incidence rates were 36.9, 5.90 and 4.18 episodes per 100 person years respectively. Baseline GDS score was the most consistent predictor of depressive symptoms at all time points in both univariate and multivariate analyses. Other predictors included cognitive impairment, impaired activities of daily living and in the early period, vascular risk factor burden and dementia. CONCLUSIONS: Our results emphasise the importance of psychiatric follow-up for those with early-onset post-stroke depression and long-term monitoring of mood in people who have had a stroke and remain at high risk of depression.

Long term incidence of dementia, predictors of mortality and pathological diagnosis in older stroke survivors.

Greater understanding of the risk factors and mechanisms of incident dementia in stroke survivors is needed for prevention and management. There is limited information on the long-term consequences and forms of incident dementia in older stroke survivors. We recruited 355 patients aged >75 years from hospital-based stroke registers into a longitudinal study 3 months after stroke. At baseline none of the patients had dementia. Patients were genotyped for apolipoprotein E and assessed annually for cognition and development of incident dementia over up to 8 years of follow-up. The effect of baseline vascular risk factors upon incidence of dementia and mortality were estimated by Cox proportional regression analyses adjusted for age and gender. Standard neuropathological examination was performed to diagnose the first 50 cases that came to autopsy. We found that the median survival from the date of the index stroke was 6.72 years (95% confidence intervals: 6.38-7.05). During the follow-up of a mean time of 3.79 years, 23.9% of subjects were known to have developed dementia and 76.1% remained alive without dementia or died without dementia. The incidence of delayed dementia was calculated to be 6.32 cases per 100 person years whereas that for death or dementia was 8.62. Univariate and multivariate regression analyses showed that the most robust predictors of dementia included low (1.5 standard deviations below age-matched control group) baseline Cambridge Cognitive Examination executive function and memory scores, Geriatric Depression Scale score and three or more cardiovascular risk factors. Autopsy findings suggested that remarkably ≥ 75% of the demented stroke survivors met the current criteria for vascular dementia. Demented subjects tended to exhibit marginally greater neurofibrillary pathology including tauopathy and Lewy bodies and microinfarcts than non-demented survivors. Despite initial improvements in cognition following stroke in older stroke survivors, risk of progression to delayed dementia after stroke is substantial, but is related to the presence of vascular risk factors. Careful monitoring and treatment of modifiable vascular risk factors may be of benefit in preventing post-stroke dementia in the general population.

Surgical Trial In Traumatic intraCerebral Haemorrhage (STITCH): a randomised controlled trial of Early Surgery compared with Initial Conservative Treatment.

BACKGROUND: While it is accepted practice to remove extradural (EDH) and subdural haematomas (SDH) following traumatic brain injury, the role of surgery in parenchymal traumatic intracerebral haemorrhage (TICH) is controversial. There is no evidence to support Early Surgery in this condition. OBJECTIVES: There have been a number of trials investigating surgery for spontaneous intracerebral haemorrhage but none for TICH. This study aimed to establish whether or not a policy of Early Surgery for TICH improves outcome compared with a policy of Initial Conservative Treatment. DESIGN: This was an international multicentre pragmatic parallel group trial. Patients were randomised via an independent telephone/web-based randomisation service. SETTING: Neurosurgical units in 59 hospitals in 20 countries registered to take part in the study. PARTICIPANTS: The study planned to recruit 840 adult patients. Patients had to be within 48 hours of head injury with no more than two intracerebral haematomas greater than 10 ml. They did not have a SDH or EDH that required evacuation or any severe comorbidity that would mean they could not achieve a favourable outcome if they made a complete recovery from their head injury. INTERVENTIONS: Patients were randomised to Early Surgery within 12 hours or to Initial Conservative Treatment with delayed evacuation if it became clinically appropriate. MAIN OUTCOME MEASURES: The Extended Glasgow Outcome Scale (GOSE) was measured at 6 months via a postal questionnaire. The primary outcome was the traditional dichotomised split into favourable outcome (good recovery or moderate disability) and unfavourable outcome (severe disability, vegetative, dead). Secondary outcomes included mortality and an ordinal assessment of Glasgow Outcome Scale and Rankin Scale. RESULTS: Patient recruitment began in December 2009 but was halted by the funding body because of low UK recruitment in September 2012. In total, 170 patients were randomised from 31 centres in 13 countries: 83 to Early Surgery and 87 to Initial Conservative Treatment. Six-month outcomes were obtained for 99% of 168 eligible patients (82 Early Surgery and 85 Initial Conservative Treatment patients). Patients in the Early Surgery group were 10.5% more likely to have a favourable outcome (absolute benefit), but this difference did not quite reach statistical significance because of the reduced sample size. Fifty-two (63%) had a favourable outcome with Early Surgery, compared with 45 (53%) with Initial Conservative Treatment [odds ratio 0.65; 95% confidence interval (CI) 0.35 to 1.21; p = 0.17]. Mortality was significantly higher in the Initial Conservative Treatment group (33% vs. 15%; absolute difference 18.3%; 95% CI 5.7% to 30.9%; p = 0.006). The Rankin Scale and GOSE were significantly improved with Early Surgery using a trend analysis (p = 0.047 and p = 0.043 respectively). CONCLUSIONS: This is the first ever trial of surgery for TICH and indicates that Early Surgery may be a valuable tool in the treatment of TICH, especially if the Glasgow Coma Score is between 9 and 12, as was also found in Surgical Trial In spontaneous intraCerebral Haemorrhage (STICH) and Surgical Trial In spontaneous lobar intraCerebral Haemorrhage (STICH II). Further research is clearly warranted. TRIAL REGISTRATION: Current Controlled Trials ISRCTN 19321911. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 70. See the NIHR Journals Library website for further project information.

Early Surgery versus Initial Conservative Treatment in Patients with Traumatic Intracerebral Hemorrhage (STITCH[Trauma]): The First Randomized Trial.

Intraparenchymal hemorrhages occur in a proportion of severe traumatic brain injury TBI patients, but the role of surgery in their treatment is unclear. This international multi-center, patient-randomized, parallel-group trial compared early surgery (hematoma evacuation within 12 h of randomization) with initial conservative treatment (subsequent evacuation allowed if deemed necessary). Patients were randomized using an independent randomization service within 48 h of TBI. Patients were eligible if they had no more than two intraparenchymal hemorrhages of 10 mL or more and did not have an extradural or subdural hematoma that required surgery. The primary outcome measure was the traditional dichotomous split of the Glasgow Outcome Scale obtained by postal questionnaires sent directly to patients at 6 months. The trial was halted early by the UK funding agency (NIHR HTA) for failure to recruit sufficient patients from the UK (trial registration: ISRCTN19321911). A total of 170 patients were randomized from 31 of 59 registered centers worldwide. Of 82 patients randomized to early surgery with complete follow-up, 30 (37%) had an unfavorable outcome. Of 85 patients randomized to initial conservative treatment with complete follow-up, 40 (47%) had an unfavorable outcome (odds ratio, 0.65; 95% confidence interval, CI 0.35, 1.21; p=0.17), with an absolute benefit of 10.5% (CI, -4.4-25.3%). There were significantly more deaths in the first 6 months in the initial conservative treatment group (33% vs. 15%; p=0.006). The 10.5% absolute benefit with early surgery was consistent with the initial power calculation. However, with the low sample size resulting from the premature termination, we cannot exclude the possibility that this could be a chance finding. A further trial is required urgently to assess whether this encouraging signal can be confirmed.

Update on the Surgical Trial in Lobar Intracerebral Haemorrhage (STICH II): statistical analysis plan.

BACKGROUND: Previous studies had suggested that the outcome for patients with spontaneous lobar intracerebral haemorrhage (ICH) and no intraventricular haemorrhage (IVH) might be improved with early evacuation of the haematoma. The Surgical Trial in Lobar Intracerebral Haemorrhage (STICH II) set out to establish whether a policy of earlier surgical evacuation of the haematoma in selected patients with spontaneous lobar ICH would improve outcome compared to a policy of initial conservative treatment. It is an international, multi-centre, prospective randomised parallel group trial of early surgery in patients with spontaneous lobar ICH. Outcome is measured at six months via a postal questionnaire. RESULTS: Recruitment to the study began on 27 November 2006 and closed on 15 August 2012 by which time 601 patients had been recruited. The protocol was published in Trials (http://www.trialsjournal.com/content/12/1/124/). This update presents the analysis plan for the study without reference to the unblinded data. The trial data will not be unblinded until after follow-up is completed in early 2013. The main trial results will be presented in spring 2013 with the aim to publish in a peer-reviewed journal at the same time. CONCLUSION: The data from the trial will provide evidence on the benefits and risks of early surgery in patients with lobar ICH. TRIAL REGISTRATION: ISRCTN: ISRCTN22153967.

Surgical trial in traumatic intracerebral hemorrhage (STITCH(Trauma)): study protocol for a randomized controlled trial.

BACKGROUND: Intracranial hemorrhage occurs in over 60% of severe head injuries in one of three types: extradural (EDH); subdural (SDH); and intraparenchymal (TICH). Prompt surgical removal of significant SDH and EDH is established and widely accepted. However, TICH is more common and is found in more than 40% of severe head injuries. It is associated with a worse outcome but the role for surgical removal remains undefined. Surgical practice in the treatment of TICHs differs widely around the world. The aim of early surgery in TICH removal is to prevent secondary brain injury. There have been trials of surgery for spontaneous ICH (including the STICH II trial), but none so far of surgery for TICH. METHODS/DESIGN: The UK National Institutes of Health Research has funded STITCH(Trauma) to determine whether a policy of early surgery in patients with TICH improves outcome compared to a policy of initial conservative treatment. It will include a health economics component and carry out a subgroup analysis of patients undergoing invasive monitoring. This is an international multicenter pragmatic randomized controlled trial.Patients are eligible if: they are within 48 h of injury; they have evidence of TICH on CT scan with a confluent volume of attenuation significantly raised above that of the background white and grey matter that has a total volume >10 mL; and their treating neurosurgeon is in equipoise.Patients will be ineligible if they have: a significant surface hematoma (EDH or SDH) requiring surgery; a hemorrhage/contusion located in the cerebellum; three or more separate hematomas fulfilling inclusion criteria; or severe pre-existing physical or mental disability or severe co-morbidity which would lead to poor outcome even if the patient made a full recovery from the head injury.Patients will be randomized via an independent service. Patients randomized to surgery receive surgery within 12 h. Both groups will be monitored according to standard neurosurgical practice. All patients have a CT scan at 5 days (+/-2 days) to assess changes in hematoma size. Follow-up is by postal questionnaire at 6 and 12 months. The recruitment target is 840 patients. TRIAL REGISTRATION: Current Controlled Trials ISRCTN19321911.

Surgical trial in lobar intracerebral haemorrhage (STICH II) protocol.

BACKGROUND: Within the spectrum of spontaneous intracerebral haemorrhage there are some patients with large or space occupying haemorrhage who require surgery for neurological deterioration and others with small haematomas who should be managed conservatively. There is equipoise about the management of patients between these two extremes. In particular there is some evidence that patients with lobar haematomas and no intraventricular haemorrhage might benefit from haematoma evacuation. The STICH II study will establish whether a policy of earlier surgical evacuation of the haematoma in selected patients will improve outcome compared to a policy of initial conservative treatment. METHODS/DESIGN: An international multicentre randomised parallel group trial. Only patients for whom the treating neurosurgeon is in equipoise about the benefits of early craniotomy compared to initial conservative treatment are eligible. All patients must have a CT scan confirming spontaneous lobar intracerebral haemorrhage (≤1 cm from the cortex surface of the brain and 10-100 ml in volume). Any clotting or coagulation problems must be corrected and randomisation must take place within 48 hours of ictus. With 600 patients, the study will be able to demonstrate a 12% benefit from surgery (2p < 0.05) with 80% power.Stratified randomisation is undertaken using a central 24 hour randomisation service accessed by telephone or web. Patients randomised to early surgery should have the operation within 12 hours. Information about the status (Glasgow Coma Score and focal signs) of all patients through the first five days of their trial progress is also collected in addition to another CT scan at about five days (+/- 2 days). Outcome is measured at six months via a postal questionnaire to the patient. Primary outcome is death or severe disability defined using a prognosis based 8 point Glasgow Outcome Scale. Secondary outcomes include: Mortality, Rankin, Barthel, EuroQol, and Survival. TRIAL REGISTRATION: ISRCTN: ISRCTN22153967.

Incidence and prediction of falls in dementia: a prospective study in older people.

BACKGROUND: Falls are a major cause of morbidity and mortality in dementia, but there have been no prospective studies of risk factors for falling specific to this patient population, and no successful falls intervention/prevention trials. This prospective study aimed to identify modifiable risk factors for falling in older people with mild to moderate dementia. METHODS AND FINDINGS: 179 participants aged over 65 years were recruited from outpatient clinics in the UK (38 Alzheimer's disease (AD), 32 Vascular dementia (VAD), 30 Dementia with Lewy bodies (DLB), 40 Parkinson's disease with dementia (PDD), 39 healthy controls). A multifactorial assessment of baseline risk factors was performed and fall diaries were completed prospectively for 12 months. Dementia participants experienced nearly 8 times more incident falls (9118/1000 person-years) than controls (1023/1000 person-years; incidence density ratio: 7.58, 3.11-18.5). In dementia, significant univariate predictors of sustaining at least one fall included diagnosis of Lewy body disorder (proportional hazard ratio (HR) adjusted for age and sex: 3.33, 2.11-5.26), and history of falls in the preceding 12 months (HR: 2.52, 1.52-4.17). In multivariate analyses, significant potentially modifiable predictors were symptomatic orthostatic hypotension (HR: 2.13, 1.19-3.80), autonomic symptom score (HR per point 0-36: 1.055, 1.012-1.099), and Cornell depression score (HR per point 0-40: 1.053, 1.01-1.099). Higher levels of physical activity were protective (HR per point 0-9: 0.827, 0.716-0.956). CONCLUSIONS: The management of symptomatic orthostatic hypotension, autonomic symptoms and depression, and the encouragement of physical activity may provide the core elements for the most fruitful strategy to reduce falls in people with dementia. Randomised controlled trials to assess such a strategy are a priority.

Subjectively reported sleep quality and excessive daytime somnolence in Parkinson's disease with and without dementia, dementia with Lewy bodies and Alzheimer's disease.

OBJECTIVE: We compared subjective sleep quality and excessive daytime somnolence (EDS) in controls, Parkinson's disease with (PDD) and without dementia (PD), dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). We investigated whether sleep dysfunction and EDS associate with motor phenotype in PD, PDD and DLB. METHOD: Assessments included the Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI). RESULTS: EDS was more frequent in PD, DLB and PDD patients than in AD. PDD, PD and DLB patients also had worse sleep quality when compared with AD and controls. Baseline postural instability-gait difficulty (PIGD) motor phenotype in PDD was associated with a higher ESS score and frequency of EDS, but this association was lost at two years. PSQI scores did not differ between PIGD dominant and non-dominant PD, PDD and DLB patients. CONCLUSION: EDS and poor sleep quality are greater in PD, PDD and DLB, compared with AD. The dissociation of EDS and motor phenotype suggests their pathophysiology is anatomically and/or temporally distinct.

Characteristics of visual hallucinations in Parkinson disease dementia and dementia with lewy bodies.

OBJECTIVE: Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB) have overlapping clinical and pathologic features. Recurrent visual hallucinations (RVH) are common in both disorders. The authors have compared details of hallucination characteristics and associated neuropsychiatric features in DLB and PDD. METHODS: This is a descriptive, cross-sectional study using the Institute of Psychiatry Visual Hallucinations Interview (IP-VHI) to explore self-reported frequency, duration, and phenomenology of RVH in PDD and DLB. The caregivers' ratings of hallucinations and other neuropsychiatric features were elicited with the Neuropsychiatric Inventory (NPI). RESULTS: Fifty-six patients (35 PDD; 21 DLB) with RVH were assessed. Hallucination characteristics were similar in both disorders. Simple hallucinations were rare. Most patients experienced complex hallucinations daily, normally lasting minutes. They commonly saw people or animals and the experiences were usually perceived as unpleasant. NPI anxiety scores were higher in PDD. Neuropsychiatric symptoms coexisting with hallucinations were apathy, sleep disturbance, and anxiety. CONCLUSIONS: Patients with mild to moderate dementia can provide detailed information about their hallucinations. Characteristics of RVH were similar in PDD and DLB, and phenomenology suggests the involvement of dorsal and ventral visual pathways in their generation. The coexistence of RVH with anxiety, apathy, and sleep disturbance is likely to impair patients' quality of life and may have treatment implications.

A comparison of the efficacy of donepezil in Parkinson's disease with dementia and dementia with Lewy bodies.

BACKGROUND: Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB) overlap in phenomenology and neurochemical deficits. We hypothesised they would not differ in their response to the cholinesterase inhibitor donepezil. METHODS: We recruited 70 subjects, 30 DLB and 40 PDD, in an open label study to compare the efficacy of donepezil in these two patient groups. They were assessed at baseline, 4, 12 and 20 weeks. The main outcome measures were the Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI) and motor sub-section of the Unified Parkinson's Disease Rating Scale (UPDRS III). RESULTS: PDD patients were younger than DLB and had more severe parkinsonism at baseline. The groups were similar on all other variables of interest. By 20 weeks the mean MMSE score increased by 3.9 points in the DLB group and by 3.2 points in PDD. The mean NPI score reduced by 14.6 points for DLB and 12.0 points for PDD. These treatment effects were all significant compared to baseline (p < 0.001) but there were no significant between-group treatment differences (MMSE p = 0.56, NPI p = 0.39). UPDRS III motor scores did not change significantly from baseline values in either group. Although adverse effects were common (69%) they were usually mild and 64 patients (91%) completed the study. The four patients who did withdraw with adverse effects all had a PDD diagnosis. CONCLUSIONS: Donepezil produced similar improvements in cognition and behaviour in DLB and PDD. This supports the hypothesis that the two disorders are closely related clinically and neurobiologically. Larger scale, placebo controlled clinical trials are needed to provide an evidence base to guide the clinical use of cholinesterase inhibitors in Lewy body disease.

Extrapyramidal features in Parkinson's disease with and without dementia and dementia with Lewy bodies: A cross-sectional comparative study.

Risk factors predicting an increased risk of dementia in Parkinson's disease (PD) are not fully established. The dementia associated with PD (PDD) closely resembles dementia with Lewy bodies (DLB). Based upon a high frequency of non-dopaminergic mediated clinical features in DLB, we predicted that a motor subtype comprising postural instability and balance problems would be more common in PDD. We examined extrapyramidal, cognitive, and affective features in 38 PD, 43 PDD, and 26 DLB patients in a cross-sectional study design. Motor subtype was subdivided into postural-instability gait difficulty (PIGD) or tremor (TD) dominant. The PIGD-subtype was more common in PDD (88% of cases) and DLB (69% of cases) groups compared with the PD group (38% of cases), in which TD and PIGD sub-types were more equally represented (P < 0.001). Although the mean depression scores overall were modest, PDD patients scored significantly higher than PD, but not DLB patients (Cornell; P = 0.006, and Geriatric Depression scale, GDS-15; P = 0.001), while within the PD group, those patients with a PIGD subtype had greater depression scores than the TD subtype (GDS-15; P < 0.05). We conclude that non-dopaminergic motor features are frequent in PDD. Neurodegeneration within the cholinergic system is likely to mediate many of these motor problems, as well as playing a significant role in determining the neuropsychiatric symptomatology of both PDD and DLB.