A simple tool to identify elderly patients with a surgically important acute subdural haematoma.

OBJECTIVES: ASDH in the elderly is a common and increasing problem, and differs in its pathophysiology from ASDH in younger people. Admitting doctors may have difficulty identifying those elderly patients whose lesions may benefit from surgery. The objective of this study was to determine whether simple neuroradiological measurements could identify those patients, who need urgent neurosurgical referral for consideration for surgery. DESIGN: A retrospective cohort study. PARTICIPANTS: All patients aged 65 years or greater referred to Salford Royal Foundation Trust with the diagnosis of ASDH between 01/01/2008 and 31/12/2011. METHODS: The initial presenting CT brain scans were reviewed. The linear dimensions, degree of midline shift and haematoma volume (using ABC/2 method) of all scans were measured and recorded. All presenting radiology was also assessed by a consultant neurosurgeon blind to clinical and CT scan measurement data and patients were categorised as having "surgical" lesions or not. Receiver operating characteristic (ROC) curves were generated and cut point value for 100% sensitivity and specificity were tabled to assess which combination of scan parameters best predicted a "surgical" ASDH. RESULTS: 212/483 patients were considered to have a 'surgical' lesion. All 'surgical' lesions had a volume of >35ml (range 35-435), maximum thickness of ≥10mm (range 10-49) and 99% had midline shift ≥1mm (range 0-32). The best predictor of a 'surgical' lesion was a combination of maximum haematoma thickness and midline shift which offered 100% (95% CI 98.3-100) sensitivity with 83% (95% CI 77.6-87) specificity. CONCLUSION: Surgically relevant cases of ASDH in the elderly can be reliably and objectively identified by two easily performed scan measurements, haematoma thickness and midline shift. If used in routine practice, these measurements could clarify those patients who may need urgent neurosurgical referral and might avoid unnecessary transfer to neurosurgical units in this cohort.

Pitfalls in microdialysis methodology: an in vitro analysis of temperature, pressure and catheter use.

Microdialysis of macromolecules within the brain provides a unique insight into physiological and pathological processes occurring within an otherwise inaccessible cranial cavity. The physically restricted nature of the intracranial compartment may present wider variations of pressure and temperature than those experienced in the rest of the body. In this study we attempted to determine the effect of variation of temperature and pressure on a cytokine recovery in vitro. Our results demonstrate that the wide variation of recovery attributable to different catheter use outweighed any effects caused by temperature or pressure. Investigators performing cytokine microdialysis using the CMA 71 system should be aware of the wide inter-catheter variability and potential effects of temperature on recovery.

Stroke thrombolysis: where are we and where are we going?

Stroke is an important cause of death and disability throughout the world. Most strokes are ischaemic, caused by thrombotic or embolic occlusion of blood vessels. The advent of thrombolysis for acute ischaemic stroke has revolutionised the treatment of acute stroke in the developed world. The benefit of thrombolysis in acute stroke is very time-dependent, with the greatest benefit achieved when administered within 90 minutes of ictus, but trials demonstrating some benefit up to 4.5, and possibly 6 hours. This has revolutionised stroke treatment, with redesign of clinical pathways to try to ensure patients with suspected stroke reach a hospital with a thrombolysis service as quickly as possible. Clinical stroke services need to ensure that all acute stroke patients can be scanned, treated and admitted to stroke units without delay. Future research needs to address the prevention and better management of complications, such as secondary intracerebral haemorrhage and angioedema. In addition, the evidence base for direct intra-arterial intervention such as thrombectomy needs to be established.

Rapid brain penetration of interleukin-1 receptor antagonist in rat cerebral ischaemia: pharmacokinetics, distribution, protection.

BACKGROUND AND PURPOSE: Limited data on the brain penetration of potential stroke treatments have been cited as a major weakness contributing to numerous failed clinical trials. Thus, we tested whether interleukin-1 receptor antagonist (IL-1RA), established as a potent inhibitor of brain injury in animals and currently in clinical development, reaches the brain via a clinically relevant administration route, in experimental stroke. EXPERIMENTAL APPROACH: Male, Sprague-Dawley rats [either naïve or exposed to middle cerebral artery occlusion (MCAo)] were given a single s.c. dose of IL-1RA (100 mg*kg(-1)). The pharmacokinetic profile of IL-1RA was assessed in plasma and CSF up to 24 h post-administration. Brain tissue distribution of administered IL-1RA was assessed using immunohistochemistry. In a separate experiment, the neuroprotective effect of the single s.c. dose of IL-1RA in MCAo was assessed versus a placebo control group. KEY RESULTS: A single s.c. dose of IL-1RA reduced damage caused by MCAo by 33%. This dose resulted in sustained, high concentrations in plasma and CSF, penetrated brain tissue exclusively in areas of blood-brain barrier breakdown and co-localized with morphologically viable neurones. CSF concentrations did not reflect massive parenchymal infiltration of IL-1RA in MCAo animals compared to naïve. CONCLUSIONS AND IMPLICATIONS: These data are the first to show that a potential treatment for stroke, IL-1RA, rapidly reaches salvageable brain tissue via an administration route that is clinically relevant. This allows confidence that IL-1RA, as a candidate for further clinical development, is able to confer its protective actions both peripherally and centrally.

Prognosis in patients with transient ischaemic attack (TIA) and minor stroke attending TIA services in the North West of England: the NORTHSTAR Study.

BACKGROUND: The ABCD2 score predicts stroke risk within a few days of transient ischaemic attack (TIA). It is not clear whether the predictive value of the ABCD2 score can be generalised to UK TIA services, where delayed presentation of TIA and minor stroke are common. We investigated prognosis, and the use of the ABCD2 score, in patients attending TIA services in the North West of England with a diagnosis of TIA or minor stroke. METHODS: 711 patients with TIA or minor stroke were prospectively recruited from five centres (median duration from index event to recruitment 15 days). The primary outcome was the composite of incident TIA, stroke, acute coronary syndrome or cardiovascular death at the 3 month follow-up. Prognostic factors were analysed using Cox proportional hazards regression. RESULTS: The primary outcome occurred in 126 (18%) patients. Overall, there were 30 incident strokes. At least one incident TIA occurred in 100 patients (14%), but only four had a subsequent stroke. In multifactorial analyses, the ABCD2 score was unrelated to the risk of the primary outcome, but predicted the risk of incident stroke: score 4-5: hazard ratio (HR) 3.4 (95% CI 1.0 to 12); score 6-7: HR 4.8 (1.3 to 18). Of the components of the ABCD2 score, unilateral motor weakness predicted both the primary outcome (HR 1.8 (1.2 to 2.8)) and stroke risk (HR 4.2 (1.3 to 14)). CONCLUSIONS: In patients attending typical NHS TIA services, the risk of incident stroke was relatively low, probably reflecting delays to assessment. Current provision of TIA services, where delayed presentation to "rapid access" TIA clinics is common, does not appear to provide an appropriate setting for urgent evaluation, risk stratification or timely secondary prevention for those who may be at highest risk.

Deglutitive laryngeal closure in stroke patients.

BACKGROUND: Dysphagia has been reported in up to 70% of patients with stroke, predisposing them to aspiration and pneumonia. Despite this, the mechanism for aspiration remains unclear. AIMS: To determine the relationship between bolus flow and laryngeal closure during swallowing in patients with stroke and to examine the sensorimotor mechanisms leading to aspiration. METHODS: Measures of swallowing and bolus flow were taken from digital videofluoroscopic images in 90 patients with stroke and 50 healthy adults, after repeated volitional swallows of controlled volumes of thin liquid. Aspiration was assessed using a validated Penetration-Aspiration Scale. Oral sensation was also measured by electrical stimulation at the faucial pillars. RESULTS: After stroke, laryngeal ascent was delayed (mean (standard deviation (SD)) 0.31 (0.06) s, p<0.001), resulting in prolongation of pharyngeal transit time (1.17 (0.07) s, p<0.001) without a concomitant increase in laryngeal closure duration (0.84 (0.04) s, p = 0.9). The delay in laryngeal elevation correlated with both the severity of aspiration (r = 0.5, p<0.001) and oral sensation (r = 0.5, p<0.001). CONCLUSIONS: After stroke, duration of laryngeal delay and degree of sensory deficit are associated with the severity of aspiration. These findings indicate a role for sensorimotor interactions in control of swallowing and have implications for the assessment and management of dysphagia after stroke.

A randomised phase II study of interleukin-1 receptor antagonist in acute stroke patients.

OBJECTIVES: The cytokine interleukin (IL)-1 mediates ischaemic brain damage in rodents. The endogenous, highly selective, IL-1 receptor antagonist (IL-1ra) protects against ischaemic cerebral injury in a range of experimental settings, and IL-1ra causes a marked reduction of cell death when administered peripherally or at a delay in transient cerebral ischaemia. We report here the first randomised, double blind, placebo controlled trial of recombinant human IL-1ra (rhIL-1ra) in patients with acute stroke. METHODS: Patients within 6 hours of the onset of symptoms of acute stroke were randomised to rhIL-1ra or matching placebo. Test treatment was administered intravenously by a 100 mg loading dose over 60 seconds, followed by a 2 mg/kg/h infusion over 72 h. Adverse events and serious adverse events were recorded for up to 3 months, serial blood samples were collected for biological markers up to 3 months, and 5-7 day brain infarct volume was measured by computed tomography. RESULTS: No adverse events were attributed to study treatment among 34 patients randomised. Markers of biological activity, including neutrophil and total white cell counts, C reactive protein, and IL-6 concentrations, were lower in rhIL-1ra treated patients. Among patients with cortical infarcts, clinical outcomes at 3 months in the rhIL-1ra treated group were better than in placebo treated. CONCLUSIONS: These data suggest that rhIL-1ra is safe and well tolerated in acute stroke. In addition, rhIL-1ra exhibited biological activity that is relevant to the pathophysiology and clinical outcome of ischaemic stroke. Our findings identify rhIL-1ra as a potential new therapeutic agent for acute stroke.

Dementia with Lewy bodies studied with positron emission tomography.

OBJECTIVE: To report a case initially fulfilling the clinical criteria for probable Alzheimer disease, although later clinical features suggested dementia with Lewy bodies. Oxygen 15-labeled positron emission tomograms revealed a pattern of hypometabolism characteristic of Alzheimer disease. At post mortem, there was no evidence of the pathological features of Alzheimer disease, but diffuse cortical Lewy bodies were seen in the pigmented brainstem nuclei and cerebral cortex. DESIGN: A case report. SETTING: Tertiary referral center. PATIENT: A 65-year-old white man presented with a 3-year history of memory loss and language difficulties. RESULTS: Oxygen 15-labeled positron emission tomograms revealed hypometabolism in the frontal, temporal, and parietal lobes, more severe on the left than right. Metabolism in the left caudate was just outside the 95% reference range. Occipital metabolism was normal. CONCLUSIONS: Positron emission tomographic studies have been reported to show occipital hypometabolism in dementia with Lewy bodies, in addition to the characteristic posterior bitemporal biparietal pattern of Alzheimer disease. We suggest that although this finding may favor a diagnosis of dementia with Lewy bodies, it is not necessary for diagnosis.

The Oxfordshire Community Stroke Project classification in the early hours of ischemic stroke and relation to infarct site and size on cranial computed tomography.

BACKGROUND AND PURPOSE: The Oxfordshire Community Stroke Project (OCSP) classification clinically subdivides cerebral infarction into total anterior circulation (TACS), partial anterior circulation (PACS), posterior circulation (POCS) and lacunar (LACS) syndromes. We compared the OCSP classification in patients presenting within 12 hours of onset of stroke with infarct site and size on computed tomography (CT) brain scan at 5 to 7 days. METHODS: OCSP classification was prospectively assigned by 1 of 3 observers in 43 patients presenting within 12 hours of stroke. CT brain scan was performed on admission to exclude primary intracerebral hemorrhage. Repeat CT brain scan at 5 to 7 days was used to classify recent visible infarction as total anterior circulation infarction (TACI), partial anterior circulation infarction (PACI), lacunar circulation infarction (LACI), or posterior circulation infarction (POCI). For each OCSP subtype, sensitivity and specificity were calculated by using CT classification as a standard. RESULTS: Median (range) interval from onset of stroke symptoms to OCSP classification was 5.0 (1.5, 11.75) hours. Thirty-seven patients had ischemic stroke, with recent visible infarction in 34 (92%). Sensitivity and specificity of each OCSP subtype was TACS (0.80, 0.82), PACS (0.56, 0.79), LACS (0.33, 0.88), and POCS (1.00, 0.97). Overall, 65% of OCSP subtypes assigned were correct when compared to CT classification. CONCLUSIONS: In this small study, we have shown that the OCSP classification within 12 hours of ischemic stroke onset compares with CT classification at 5 to 7 days. Larger studies are required to evaluate the validity of the OCSP classification in the early hours of ischemic stroke in guiding appropriate patient selection for acute stroke therapy and interventions.

Post stroke shoulder pain: more common than previously realized.

Stroke is a common disease often requiring rehabilitation, which may be prolonged by shoulder pain. The true incidence of post stroke shoulder pain has not been fully evaluated. In order to establish this, we undertook a prospective study of 123 consecutive patients with a diagnosis of acute stroke during a 6-month period. Patients were assessed by interview, full rheumatological and neurological examination, 14 days post stroke, for a history of shoulder pain according to predetermined criteria. In addition, Barthel Index, HAD score and pain scores were also recorded. Twenty-five percent of patients developed shoulder pain within 2 weeks of their stroke. There was a statistically significant association with ipsilateral sensory impairment (p < 0.005), abnormal rheumatological examination (p < 0.001) and depression score (p < 0.005). We conclude that post stroke shoulder pain is more common than previously realized and in addition to abnormal shoulder joint examination may also be associated with upper limb sensory impairment. Thorough neurological examination is required to detect sensory loss and hence establish patients at risk. This is probably best done by a structured proforma.

The unreliability of clinical measures of muscle tone: implications for stroke therapy.

BACKGROUND: the central tenet of the neurofacilitatory approach to stroke therapy is that muscle tone needs to be normal before normal movement can occur. A reliable clinical measure of the full spectrum of muscle tone is needed to test: (i) the purported relationship between muscle tone, other motor impairments and disability, and (ii) the effectiveness of stroke therapy to restore movement. AIM: the purpose of the study was to test the inter-rater reliability of clinical categorization of muscle tone (spastic/normal/flaccid) and also a visual analogue scale with anchor points of 'lowest tone possible' (score 0) and 'highest tone possible' (score 100). METHODS: four independent raters assessed tone of elbow flexors and knee extensors of 14 stroke rehabilitation inpatients using the categorical scale. Six independent raters assessed tone of elbow flexors and knee extensors of 25 chronic stroke patients and two healthy volunteers using the visual analogue scale. All assessment orders were randomized. RESULTS: both scales were unreliable, with K coefficients for the categorical scale ranging from -0.046 to 0.56 for the categorical scale, and intra-class correlation coefficients for the visual analogue scale of 0.595 for elbow flexors and 0.451 for knee extensors. Assessment order effects for the visual analogue scale were non-significant for elbow flexors (P= 0.545) and knee extensors (P= 0.911). CONCLUSIONS: these results, and those of earlier studies, suggest that clinical measures of muscle tone are consistently unreliable. Systematic investigation of the therapy rationale for planning and evaluating treatment is required before relevant clinical measures can be developed.

Progressive frontal gait disturbance with atypical Alzheimer's disease and corticobasal degeneration.

OBJECTIVES: The clinical neuropsychological, neuroradiological, and neuropathological description of two patients presenting with a frontal gait disturbance. METHODS: Clinical case note review, neuropsychological assessment, functional imaging with (15)O(2) and (18)F-fluorodopa PET, and neuropathology. RESULTS: Both patients presented with frontal gait impairment and only later developed more widespread cognitive impairment. In both cases (15)O(2) PET disclosed focal hypometabolism in the medial frontal lobes and in one patient (18)F-fluorodopa uptake into the caudate and putamen was normal. The neuropathological examination in one patient showed Alzheimer's histopathology together with large swollen eosinophilic neurons characteristic of corticobasal degeneration, which were particularly prominent in the medial frontal lobes. CONCLUSION: Focal degeneration of the medial frontal lobes may present as an isolated gait disturbance and should be considered in the differential diagnosis of patients who present without an obvious structural abnormality on neuroimaging.

Progressive loss of speech output and orofacial dyspraxia associated with frontal lobe hypometabolism.

Three patients are described with slowly progressive loss of speech and dysarthria associated with orofacial dyspraxia, initially with intact written language, who subsequently developed more widespread cognitive abnormalities. Positron emission tomography (PET) revealed bifrontal hypometabolism in all of the patients, most marked in the inferior and lateral portions of both frontal lobes, with some extension into the parietal and temporal cortices in one case. These patients may represent a further example of focal progressive cortical degeneration.

Clinical and positron emission tomographic studies in the 'extrapyramidal syndrome' of dementia of the Alzheimer type.

Extrapyramidal signs, particularly rigidity and tremor, have been reported in a proportion of patients with dementia of the Alzheimer type. To test the hypothesis that these extrapyramidal signs are similar clinically and neurochemically to the extrapyramidal signs of Parkinson's disease, a group of 20 patients satisfying clinical criteria for probable Alzheimer's disease were studied and assessed clinically for the presence of rigidity, tremor, and bradykinesia. In those patients with extrapyramidal signs, qualitative differences were observed between the signs in these patients and in subjects with Parkinson's disease. Fifteen of 20 patients underwent fluoro-18-dopa scans, which showed no significant difference in fluoro-18-dopa uptake into the caudate and putamen between normal subjects and the rigid and nonrigid patients with Alzheimer's disease, in contrast to the marked reduction in fluoro-18-dopa uptake into the putamen that is observed in Parkinson's disease. This provides clinical and in vivo neurochemical support for the hypothesis that extranigral factors may be involved in the pathogenesis of rigidity in Alzheimer's disease.

Progressive degeneration of the right temporal lobe studied with positron emission tomography.

A 79 year old man with a twelve year progressive history of prosopagnosia and recent naming difficulty, in whom other intellectual skills were preserved, is described. Positron emission tomography (PET) revealed an area of right temporal lobe hypometabolism, with an additional area of less severe hypometabolism at the left temporal pole. This may represent an example of progressive focal cortical degeneration similar to that associated with primary progressive dysphasia, but affecting the right temporal lobe.