Acute disseminated encephalomyelitis: a follow-up study in Taiwan

Background

Acute‐disseminated encephalomyelitis (ADEM) is a demyelinating disorder of the central nervous system, whose epidemiology, clinical presentations and functional outcome are incompletely understood in Asian populations.

Objective

To assess the clinical presentations, predisposing factors and functional outcome of ADEM in Taiwan.

Methods

50 patients initially diagnosed with ADEM (male, 19; female, 31) were enrolled from 1991 to 2005. Diagnosis of ADEM or multiple sclerosis was established during a follow‐up period of 2–120 months. 8 adult patients were noted to have taken the immunomodulatory drug, levamisole, within 3 months before onset of symptoms. The remaining 42 patients (male, 17; female, 25) were categorised by age as children (<16 years, n = 12), young adults (16–49 years, n = 21) and elderly adults (⩾50 years, n = 9). The clinical manifestations, predisposing factors and radiological findings were compared between different age groups and adult patients with or without levamisole use. Functional outcome was compared by a log‐rank test.

Results

Preceding upper respiratory tract infection was evident in 21 (50%) patients and only one young‐adult patient had received Rubella vaccine immunisation. The frequency of fever was higher in children (p = 0.04) and psychiatric symptoms were more prevalent in elderly patients (p = 0.03). Functional recovery was faster in children than in adults (p = 0.002). Initial Expanded Disability Status Scale score (odds ratio (OR) 1.9, p = 0.03) and no fever (OR 0.04, p = 0.06) were associated with poor outcome (modified Rankin scale ⩾2). After a mean (SD) follow‐up of 31.8 (9.9) months, 4 (9.5%) patients developed multiple sclerosis (3 (25%) children, 1 (4.7%) young adult, p = 0.03). The neurological disability, radiological and cerebrospinal fluid findings did not differ between patients with and without levamisole use. One elderly adult patient previously receiving levamisole developed multiple sclerosis of relapse‐remitting type after a mean follow‐up period of 36.9 months.

Conclusion

The clinical presentations, functional outcome and risk of developing multiple sclerosis differed between different age groups. Functional recovery was faster in children than in adults. Poor functional outcome was related to initial high Expanded Disability Status Scale score and absence of fever.Acute disseminated encephalomyelitis (ADEM) is a monophasic inflammatory demyelinating disorder of the central nervous system (CNS). Pathogenesis is suspected to be an autoimmune response to myelin, which is triggered by infection or immunisation via molecular mimicry.^1,2 Thus, ADEM may be the clinical counterpart to experimental allergic encephalomyelitis (EAE).³ The exact incidence is not known, but it was reported that the incidence of ADEM among persons aged <20 years residing in San Diego County, California was approximately 0.4/10⁵/year.⁴ More studies have been conducted in paediatric populations than in elderly adults and most reported series were Caucasians.^5,6,7,8 Few large series of ADEM have been published in Asian populations.⁹We thus assessed the precipitating factors, clinical presentations, cerebrospinal fluid (CSF) and radiological findings, and long‐term outcome in a cohort of ethnic Taiwanese patients with ADEM in different age groups, and attempted to determine the prognostic factors for poor functional outcome.     

Anti-aquaporin 4 antibody in Japanese multiple sclerosis: the presence of optic spinal multiple sclerosis without long spinal cord lesions and anti-aquaporin 4 antibody

Background

Anti‐aquaporin 4 (AQP4) antibodies were found in patients with neuromyelitis optica (NMO) and Japanese optic–spinal multiple sclerosis (OSMS).

Objective

To review the clinical features and investigate anti‐AQP4 antibodies of Japanese patients with multiple sclerosis (MS), with or without long spinal cord lesions (LCL).

Methods

Anti‐AQP4 antibodies were examined in the sera of 128 consecutive Japanese patients by the immunofluorescence method using AQP4 transfected cells.

Results

The 45 LCL‐MS patients included 28 with a long spinal cord lesion extending contiguously over three vertebral segments on sagittal T2 weighted images (long T2 lesion) and 17 with segmental cord atrophy extending more than three vertebral segments. We identified 25 patients with anti‐AQP4 antibody with LCL and anti‐AQP4 antibody. Anti‐AQP4 antibody was found in 12/17 (70.6%) LCL‐MS patients with segmental cord atrophy, and in 13/28 (46.4%) LCL‐MS patients without segmental long cord atrophy (p = 0.135, Fisher''s exact test). Seropositive MS patients with LCL had more relapses than seronegative patients (p = 0.0004, Mann–Whitney U test). 9 patients with OSMS were negative for anti‐AQP4 antibody who did not show LCL.

Conclusion

These results suggest that an anti‐AQP4 antibody is found not only in MS patients with long T2 lesions but also in patients with segmental cord atrophy extending more than three vertebral segments. It is a marker of LCL‐MS showing frequent exacerbations. Japanese OSMS cases comprised those that were identical to NMO cases and those that were more closely related to classic MS.Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system. Japanese MS patients have been classified into two phenotypes: classic MS (CMS) and optic–spinal MS (OSMS).¹ OSMS has been recognised since the 1950s.² Patients with OSMS have symptoms and MRI findings in which the main lesions are confined to the optic nerve and spinal cord. In patients with OSMS, there is a higher female/male ratio; neuropathologically necrotic lesions; pleocytosis with a predominance of polymorphonuclear cells and a low frequency of oligoclonal IgG bands in CSF; a high incidence of autoantibodies in sera; long spinal cord lesions (LCL) extending more than three vertebral segments in MRI scans; and an association with a human leucocyte antigen class II allele (DPB1*0502).³Neuromyelitis optica (NMO) has been described as Devic disease, but its clinical definition has frequently been revised.⁴ LCL extending contiguously over three vertebral segments on sagittal T2 weighted images (long T2 lesion) is a disease marker. Current NMO criteria include unilateral optic neuritis, no restriction on onset of optic neuritis and myelitis, relapsing course and brain involvement.^4,5 Recent NMO criteria stress the presence of both brain MRI abnormalities that do not meet diagnostic criteria for MS and NMO‐IgG,⁴ a highly specific biomarker of NMO,⁶ and its target antigen is the aquaporin 4 (AQP4) water channel.⁷The incidence of NMO‐IgG seropositivity in Japanese patients with OSMS (6/11 cases, 54%) was similar to that in NMO (33/45, 73%), and OSMS was thought to be the same disease.⁶ However, in that study,⁶ the Japanese OSMS patients had been selected using 1999 NMO criteria (Fujihara K, personal communication) that are not the same as the clinical definition of OSMS widely used in Japan.⁸ Their recent report showed that serum NMO‐IgG was found in 12 of 19 patients with OSMS (63%).⁹ We established an AQP4 antibody assay system and identified nine seropositive MS patients with LCL‐MS.¹⁰     

Cerebrospinal fluid beta-amyloid 1-42 concentration may predict cognitive decline in older women

Background

Low levels of cerebrospinal fluid (CSF) β‐amyloid 1–42 (Aβ42) and high total tau (T‐tau) are diagnostic for manifest Alzheimer''s disease. It is not known, however, whether these biomarkers may be risk indicators for cognitive decline in otherwise healthy older people.

Methods

The longitudinal relationship between CSF markers, Aβ42 and T‐tau, measured in 1992, and change in Mini‐Mental State Examination (ΔMMSE) score between 1992 and 2002 were investigated in 55 women (aged 70–84 years, mean (SD) MMSE score = 28.3 (1.5)), who were participants in the Prospective Population Study of Women in Gothenburg, Sweden. These women did not have dementia when they experienced lumbar puncture in 1992–3.

Results

Over the 8‐year follow‐up period, ΔMMSE (range =  +3 to −21 points) was correlated with Aβ42 (Spearman''s r = 0.40, p = 0.002), such that lower levels of Aβ42 were related to greater decline. This was also observed after excluding 4 women who developed dementia between 1992 and 2002 (Spearman''s r = 0.34, p = 0.019). A multivariate logistic regression model predicting a decline of ⩾5 points on the MMSE (observed in six women), or a risk of developing dementia over the 8‐year follow‐up period (observed in four women), including age, education, Aβ42 and T‐tau as covariates, showed that Aβ42 was the sole predictor of significant cognitive decline or dementia (OR per 100 pg/ml Aβ42 = 2.24, 95% CI 1.19 to 4.22, p = 0.013).

Conclusions

Low levels of CSF Aβ42 may predict cognitive decline among older women without dementia.Alzheimer''s disease (AD) is rapidly increasing with advancing age, with reported prevalence estimates of 30% at age 85 years, and as high as 50% at age 95 years.¹ AD is expected to reach epidemic proportions between 2010 and 2050, when the number of people with the disease is projected to be more than double. Juxtaposed against this harrowing background is the fact that risk indicators for AD in healthy older people are lacking.β‐amyloid 1–42 (Aβ42) and total tau (T‐tau) are two known biomarkers of manifest AD that are detectable in cerebrospinal fluid (CSF). Low levels of CSF Aβ42 and high levels of CSF T‐tau in cases of AD have been described in both clinical and population‐based samples.^2,3,4,5,6 Aβ42 is the 42‐amino acid fragment of amyloid precursor protein. It accumulates in the brain and is the principal component of senile plaques. Aβ42 in CSF has been suggested to reflect the deposition of β‐amyloid in senile plaques, with lower levels excreted to the CSF. T‐tau is a microtubule‐associated protein that, on hyperphosphorylation, is the primary component of neurofibrillary tangles in AD.⁷ T‐tau in CSF has been suggested to reflect neuronal and axonal degeneration in AD and/or the formation of neurofibrillary tangles.⁷ Thus, both these markers potentially reflect central pathogenic processes in a brain with AD. In addition, clinical evidence is accumulating that low levels of CSF Aβ42 and high levels of T‐tau may also be useful for predicting progression of mild cognitive impairment (MCI) to AD.⁸Despite known associations between CSF Aβ42 and T‐tau, and manifest AD, little is known about the utility of these biomarkers as risk indicators of cognitive decline in healthy older people who are representative of the population. Thus, we investigated whether lower CSF Aβ42 and higher CSF T‐tau predict cognitive decline, as measured using change in Mini‐Mental State Examination (ΔMMSE) score over 8 years, in a population‐based sample of older women aged 70–84 years.     

Diffusion weighted imaging in ataxic hemiparesis

Objective

Ataxic hemiparesis (AH) is a well recognised lacunar syndrome involving homolateral ataxia with accompanying corticospinal tract impairment. Most previous studies of lesion location in AH did not use diffusion weighted MRI (DW MRI). The purpose of this study was to use DW MRI to evaluate the radiological correlation in patients presenting with AH.

Methods

Retrospectively, we studied 29 patients with AH using DW MRI.

Results

All patients were scanned within 4 days of onset. Acute infarction was identified in 28 of 29 (97%) patients. A single lesion was identified in 26 patients: pons (n = 8), internal capsule (n = 6), corona radiata (n = 2), distended internal capsule from corona radiate (n = 7), frontal subcortical area (n = 1) and precentral with or without postcentral gyrus (n = 2). Two lesions were found in two patients: in the pons and corpus callosum of one patient, and in the corona radiata and subcortical white matter of the other.

Conclusions

AH is mainly caused by pontine or internal capsule/corona radiata lesions. It also occurs in the precentral gyrus, including the precentral knob, with or without postcentral gyrus lesions. Fibres of the fronto‐ponto‐cerebellar system may originate from the frontal cortex, including the precentral gyrus, probably near the pyramidal tract. Damage at this location may cause AH.Ataxic hemiparesis (AH) was first reported by Fisher et al, who initially described and named this syndrome which consists of a combination of homolateral ataxia and crural paresis.^1,2 He later renamed it “ataxic hemiparesis”, signifying any combination of weakness and incoordination out of proportion to weakness on the same side of the body. The lesion topography of AH is known to be located in the pons, internal capsule, thalamus or corona radiata.^{3,4,5,6,7,8,9,10} The subcortical white matter and the cerebral cortex have also been implicated but only rarely. Most previous reports of the location of AH were based on CT or conventional MRI, not on diffusion weighted MRI (DW MRI). The purpose of this study was to use DW MRI to evaluate the radiological correlation in patients with presenting AH. We provide DW MRI data from our institution for the acute phases of 29 cases of AH.     

Thrombolytic therapy for acute ischaemic stroke in octogenarians: selection by magnetic resonance imaging improves safety but does not improve outcome

Background

Owing to the fear of an increased bleeding risk, thrombolytic therapy is withheld from many patients with acute stroke >80 years of age.

Objective

To analyse the risk for symptomatic intracranial haemorrhage (sICH), morbidity and mortality after thrombolytic therapy in octogenarians focusing, in particular, on whether patients selected using magnetic resonance imaging (MRI) had a better risk:benefit ratio.

Methods

The prospectively collected single‐centre data of all patients treated with systemic thrombolytic therapy for acute ischaemic stroke since 1998 (n = 468) were reviewed, and patients ⩾80 years (n = 90) were compared with those aged <80 years (n = 378). In addition, the group of octogenarians was analysed with respect to initial imaging modality.

Results

The overall rate of sICH in the octogenarians was 6.9%, compared with 5.3% in younger patients (p = 0.61). In older patients selected by computed tomography, the rate of sICH was 9.4%; no patient selected by MRI had sICH (p = 0.10). Mortality in the octogenarians selected by computed tomography was 29.7% after 3 months as compared with 26.9% in the patients selected by MRI (p = 1.0). 20.3% of the octogenarians selected by computed tomography and 15.4% of those selected by MRI had a favourable outcome (modified Rankin scale ⩽1) after 3 months (p = 0.77).

Conclusion

Compared with younger patients, octogenarians do not have an increased risk of sICH. The use of MRI to select octogenarians for thrombolytic therapy seemed to decrease the risk of sICH, but did not influence the overall outcome after 3 months.The incidence of stroke increases steeply with age. In a population‐based survey, incidence of a first‐ever stroke was around 0.8 per 1000 population per year in people aged <75 years as compared with 14 per 1000 population per year in those aged 75–84 years and 29 per 1000 population per year in those aged >85 years.¹ With respect to changes in the population''s age structure in the industrialised world, the number of acute vascular events in elderly people will almost double in the course of the next 25 years.¹ Furthermore, age is an independent predictor for poor outcome after ischaemic stroke. Older patients, especially those aged >80 years, have a higher in‐hospital mortality risk and a favourable functional outcome is less likely.² Intravenous thrombolysis with recombinant tissue‐type plasminogen activator (rt‐PA) is the only approved therapy for patients with acute ischaemic stroke. However, the European and Australian rt‐PA stroke trials excluded patients >80 years of age.^3,4,5 Older patients were only allowed to be enrolled in the National Institute of Neurological Disorders and Stroke (NINDS) rt‐PA stroke study, but a mean age of 69 years in this trial shows that few patients >80 years of age were actually included.⁶ Owing to the lack of knowledge about the safety and efficacy of thrombolysis in this age group from randomised trials, the European Medicines Evaluation Agency (EMEA) recommends that rt‐PA not be used in patients with ischaemic stroke aged >80 years.⁷In the past few years, it has become increasingly popular to select patients for thrombolytic therapy using multiparametric magnetic resonance imaging (MRI) techniques. Our objective was to analyse the morbidity, mortality and risk for symptomatic intracranial haemorrhage (sICH) after thrombolytic therapy in octogenarians, focusing in particular on whether the risk:benefit ratio was higher in patients selected by MRI.     

Antimyelin antibodies and the risk of relapse in patients with a primary demyelinating event

Aim

To investigate whether the presence of serum antibodies against myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP) in patients with a clinically isolated syndrome (CIS) predicts the interval to develop more frequently and earlier a first relapse (clinically definite multiple sclerosis: CDMS) than seronegative patients.

Methods

Sera from 45 patients with a CIS and positive intrathecal IgG‐synthesis were retrospectively tested for the presence of IgM antibodies against both MOG and MBP. Antibodies were detected by immunoblot using recombinant MOG (1–125) and human MBP antigen preparations. Clinical follow ups were performed retrospectively by telephone interviews and documented neurological examination.

Results

Using the Cox proportional hazards model there was no significant increased risk for developing CDMS in anti‐MOG and anti‐MBP positive patients compared with negative. However regarding the median of the time span between CIS and CDMS over the whole follow up, antibody positive patients (MOG/MBP +/+) developed significantly earlier relapses (median 5.5 months (range 3–20)) than the antibody negative ones (median 25.0 months (range 7–43); p<0.006). On testing sera from 56 apparently healthy students, quite high frequencies of anti‐MOG and anti‐MBP antibodies (21% and 28% respectively) were detected. This limited specificity of anti‐MOG and anti‐MBP antibodies has been seen earlier and restricts their diagnostic relevance in MS despite their role as a predictor of relapses after a CIS.

Conclusions

This study confirms previous data only in a subanalysis indicating that patients with positive anti‐MOG/MBP antibodies develop earlier relapses than patients who are antibody negative. However, the authors could not verify that the presence of these antibodies anticipates the overall risk of developing CDMS—according to study criteria—after a first demyelinating event within the study period of 21–106 months (mean 60 (SD 25)).Multiple sclerosis (MS) is a common inflammatory neurological disease, predominantly affecting young adults.¹ It usually starts with a clinically isolated syndrome (CIS), caused by an inflammatory demyelinating lesion of the central nervous system. About 30% of patients with a CIS exhibit a second demyelinating event with dissemination within 12 months, leading to the diagnosis of clinically definite multiple sclerosis (CDMS).^2,3,4The pathogenesis of MS is not completely understood. Apart from the evidence that myelin‐specific T cell responses are crucial to disease pathogenesis, it is suggested that B cells and autoantibodies may also play a major role in the process of demyelination.^5,6,7,8According to a recent study by Berger et al,⁹ seropositivity for myelin oligodendrocyte glycoprotein (MOG) and/or myelin basic protein (MBP) in patients with a CIS was associated with a markedly increased risk of a first relapse during the study follow up (mean 50.9, range 12–96). In the present study, the incidence of anti‐MOG and anti‐MBP IgM antibodies was investigated retrospectively in a cohort of patients with a CIS. The main issue of this study was to investigate whether MOG and MBP positive CIS patients develop more frequently and earlier a first relapse than seronegative patients. In addition, to further examine the diagnostic specificity of these antibodies, incidences of MOG and MBP antibodies were analysed in a group of healthy individuals not suffering from any inflammatory disease.     

Focal cortical dysplasia: long term seizure outcome after surgical treatment

Background

Studies of long term outcome after epilepsy surgery for cortical malformations are rare. In this study, we report our experience with surgical treatment and year to year long term outcome for a subgroup of patients with focal cortical dysplasia (FCD).

Methods

We retrospectively analysed the records of 49 patients (females n = 26; males n = 23; mean age 25 (11) years) with a mean duration of epilepsy of 18 years (range 1–45). Preoperative MRI, histological results based on the Palmini classification and clinical year to year follow‐up according to the International League Against Epilepsy (ILAE) classification were available in all patients.

Results

98% of patients had a lesion on preoperative MRI. In addition to lobectomy (n = 9) or lesionectomy (n = 40), 14 patients had multiple subpial transections of the eloquent cortex. The resected tissue was classified as FCD type II b in 41 cases with an extratemporal (88%) and FCD type II a in 8 cases with a temporal localisation (100%). After a mean follow‐up of 8.1 (4.5) years, 37 patients (76%) were seizure free, a subgroup of 23 patients (47%) had been completely seizure free since surgery (ILAE class 1a) and 4 patients (8%) had only auras (ILAE class 2). Over a 10 year follow‐up, the proportion of satisfactory outcomes decreased, mainly within the first 3 years. During long term follow‐up, 48% stopped antiepileptic drug treatment, 34% received a driver''s license and 57% found a job or training.

Conclusion

Surgical treatment of epilepsy with FCD is not only successful in the short term but also has a satisfying long term outcome which remains constant after 3 years of follow‐up but is not associated with better employment status or improvement in daily living.With the development of high resolution MRI in the past decade, cortical malformations have been detected more often in patients with drug resistant epilepsy.^1,2 Visualisation by MRI has aided diagnosis and surgical treatment of the largest group of cortical malformations (ie, the focal cortical dysplasias (FCDs)). Successful short term follow‐up with seizure free rates of 40–86% were described in several studies^{3,4,5,6,7,8,9} but only a few focused on long term outcome.^10,11,12 Most of these studies did not analyse subgroups of patients with the same histopathology, as other malformations or low grade gliomas were also included. The Engel classification,¹³ and not the newer International League Against Epilepsy (ILAE) classification,¹⁴ was used to describe the seizure outcome in all studies, and a year to year follow‐up, important for the long term course of these patients, was not included.The first aim of this study was a reclassification of all FCD cases according to the new Palmini classification¹⁵ to define a homogenous histopathological group. The second aim was to analyse the year to year long term outcome with respect to seizures according to the ILAE classification, antiepileptic drug (AED) use and socioeconomic outcome (eg, driving license and employment status).     

Cortical cholinergic denervation is associated with depressive symptoms in Parkinson's disease and parkinsonian dementia

Aim

To investigate the relationship between ratings of depressive symptoms and in vivo cortical acetylcholinesterase (AChE) activity in subjects with Parkinson''s disease (PD) and parkinsonian dementia (PDem).

Methods

Subjects (with PD, n = 18, including subjects with PDem, n = 6, and normal controls, n = 10) underwent [¹¹C]methyl‐4‐piperidinyl propionate AChE positron emission tomography imaging and clinical assessment including the Cornell Scale for Depression in Dementia (CSDD).

Results

Subjects with PD and PDem had higher scores on the CSDD compared with normal controls: 7.3 (5.4) and 2.8 (2.6), respectively (F = 6.9, p = 0.01). Pooled analysis demonstrated a significant inverse correlation between cortical AChE activity and CSDD scores: R = −0.5, p = 0.007. This correlation remained significant after controlling for Mini‐Mental State Examination scores.

Conclusion

Depressive symptomatology is associated with cortical cholinergic denervation in PD that tends to be more prominent when dementia is present.Depression is a frequent non‐motor manifestation of Parkinson''s disease.¹ The pathophysiology of depression in PD is complex and probably related to the dysfunction of several neurotransmitter systems, including serotonin, dopamine and norepinephrine.² However, a recent meta‐analysis of depression treatment studies in PD found less benefit from typical antidepressant treatment, particularly selective serotonin reuptake inhibitors, than seen in elderly patients without PD.³ A recent study on acute tryptophan depletion also failed to identify a specific serotonergic vulnerability for depression in PD.⁴ Dopaminergic denervation is unlikely to play a major role in depression, as antidepressant effects of levodopa treatment in PD are generally modest.⁵A relatively unique feature of depression in PD is that mood disturbance is associated with a quantitative but not qualitative worsening of cognitive deficits.⁶ This modulatory effect of depression on cognitive impairment in PD suggests that a common mechanism might underlie both types of symptoms. We recently reported in vivo findings of more severe cholinergic denervation in parkinsonian dementia (PDem) compared with Alzheimer''s disease,⁷ and cholinergic degeneration may play a significant role in the cognitive decline in PD.⁸ This raises the question of whether depression in PD is, at least in part, associated with cholinergic hypofunction.     

Validation of the nerve axon reflex for the assessment of small nerve fibre dysfunction

Objective

To validate nerve–axon reflex‐related vasodilatation as an objective method to evaluate C‐nociceptive fibre function by comparing it with the standard diagnostic criteria.

Methods

Neuropathy was evaluated in 41 patients with diabetes (26 men and 15 women) without peripheral vascular disease by assessing the Neuropathy Symptom Score, the Neuropathy Disability Score (NDS), the vibration perception threshold (VPT), the heat detection threshold (HDT), nerve conduction parameters and standard cardiovascular tests. The neurovascular response to 1% acetylcholine (Ach) iontophoresis was measured at the forearm and at both feet by laser flowmetry. An age‐matched and sex‐matched control group of 10 healthy people was also included.

Results

Significant correlations were observed between the neurovascular response at the foot and HDT (r_s = −0.658; p<0.0001), NDS (r_s = −0.665; p<0.0001), VPT (r_s = −0.548; p = 0.0005), tibial nerve conduction velocity (r_s = 0.631; p = 0.0002), sural nerve amplitude (r_s = 0.581; p = 0.0002) and autonomic function tests. According to the NDS, in patients with diabetes who had mild, moderate or severe neuropathy, a significantly lower neurovascular response was seen at the foot than in patients without neuropathy and controls. A neurovascular response <50% was found to be highly sensitive (90%), with a good specificity (74%), in identifying patients with diabetic neuropathy.

Conclusion

Small‐fibre dysfunction can be diagnosed reliably with neurovascular response assessment. This response is already reduced in the early stages of peripheral neuropathy, supporting the hypothesis that small‐fibre impairment is an early event in the natural history of diabetic neuropathy.Diabetic neuropathy includes nerve fibres with both small and large diameter.¹ Small‐fibre neuropathy remains a diagnostic challenge because currently available techniques are not objective, have a high variability and are not routinely applied.^2,3 Consequently, the diagnosis of small‐fibre neuropathy can easily be missed.Assessment of nerve–axon reflex‐related vasodilatation, or neurovascular response, has been proposed as an objective method to quantify C‐nociceptive fibre function.⁴ Activation of peripheral C‐fibres by different noxious stimuli, or activation experimentally by acetylcholine (Ach), leads to the conduction of the impulse, both orthodromically to the spinal cord and antidromically to other branches of the same C‐fibres, which then release vasodilating neuropeptides. This vasodilative response is part of Lewis''s triple anti‐inflammatory response.⁵This neurovascular response is impaired in patients with diabetic neuropathy.⁶ Moreover, local anaesthesia markedly reduces the neurovascular response in controls and patients with diabetes without peripheral neuropathy, whereas in patients with diabetic peripheral neuropathy, the already low neurovascular response at the foot does not decrease further after the induction of local anaesthesia.⁷As all previous findings indicate that C‐fibre function is the main determinant of the neurovascular response, it is reasonable to hypothesise that the assessment of this response may be used as a surrogate measure of C‐fibre integrity. The aim of the present study was therefore to validate the neurovascular response for the assessment of small‐fibre function by comparing it with the currently used techniques.     

Endothelial cell activation markers and delayed cerebral ischaemia in patients with subarachnoid haemorrhage

Background

Endothelial cell activation may be connected with the pathogenesis of delayed cerebral ischaemia (DCI) after subarachnoid haemorrhage (SAH).

Aim

To assess the relationship between serial concentrations of circulating markers of endothelial cell activation (soluble intercellular adhesion molecule‐1, soluble platelet selectin (sP‐selectin), soluble endothelial selectin, ED1‐fibronectin, Von Willebrand Factor (VWF) and VWF propeptide) and development of DCI.

Methods

687 blood samples were collected from 106 consecutive patients admitted within 72 h after onset of SAH. Changes in levels were analysed in the last sample before and in the first sample after the onset of DCI (n = 30), and in subgroups with DCI occurring within 24 h after treatment of the aneurysm (n = 12) or unrelated to treatment of the aneurysm (n = 18). Patients without DCI (n = 56) served as controls.

Results

Concentrations of sP‐selectin, but not of the other markers, were found to increase considerably after DCI unrelated to treatment of the aneurysm (increase 25 ng/ml, 95% CI 8 to 43), whereas they tended to decrease in the control patients without DCI (decrease 13 ng/ml, 95% CI −28 to 2.4). Surgery was found to profoundly influence the levels of the markers irrespective of the occurrence of DCI.

Conclusion

The rise in sP‐selectin level during DCI is suggested to be the result of platelet activation, as levels of the other markers of endothelial cell activation were not increased after DCI unrelated to treatment. Whether a causal role of platelet activation is implicated in the development of DCI should be determined in further studies in which the relationship between concentrations of markers and treatment is taken into account.Endothelial cell activation may have a role in the pathogenesis of delayed cerebral ischaemia (DCI) after subarachnoid haemorrhage (SAH).^1,2 Activated endothelial cells express several receptors on their cell membrane. The inflammatory cell adhesion molecules intercellular adhesion molecule‐1 (ICAM‐1), P (platelet)‐selectin and E (endothelial)‐selectin participate in rolling, firm adhesion and transmigration of leucocytes along the vessel wall. ICAM‐1 is constitutively expressed in low quantities on leucocytes, fibroblasts, epithelial cells and endothelial cells. Its expression increases on stimulation by cytokines.³ E‐selectin is found only on activated endothelium. P‐selectin is a membrane molecule of the α granules in platelets and of the endothelial Weibel–Palade bodies and is expressed on the cell membrane on activation of endothelial cells.⁴ ED1‐fibronectin (ED1‐fn) is an adhesive glycoprotein that is synthesised in endothelial cells. The ED1 domain is included in fibronectin molecules in pathological conditions of the vessel wall.⁵ Von Willebrand Factor (VWF) is a large adhesive glycoprotein participating in the adhesion of platelets. It is produced and released by vascular endothelial cells and, in much smaller amounts, by platelets. VWF is a marker of both acute and chronic endothelial cell activation. A recently developed assay is the measurement of VWF propeptide, which may serve as a marker of acute endothelial cell activation.⁶The synthesis of VWF propeptide is linked with the synthesis of VWF, but its plasma half life is shorter than that of VWF.We studied the relationship between serial concentrations of circulating markers of endothelial cell activation (soluble (s) ICAM‐1, sP‐selectin, sE‐selectin, ED1‐fn, VWF and VWF propeptide) and development of DCI in patients with SAH.     

Anti-ganglioside complex antibodies in Miller Fisher syndrome

Background

Some ganglioside complexes (GSCs) are target antigens for serum antibodies in patients with Guillain–Barré syndrome (GBS). Anti‐GSC antibodies may be associated with particular clinical features of GBS.

Objective

To investigate antibodies to GSCs in the sera of patients with Miller Fisher syndrome (MFS) characterised by elevation of the IgG anti‐GQ1b antibody.

Results

In all, 7 of 12 (58%) consecutive patients with MFS were found to have IgG antibodies to GSCs containing GQ1b, of whom 5 had IgG antibodies to GQ1b‐GM1 complex (GQ1b/GM1) and 2 had antibodies to GQ1b/GD1a; 4 of 5 patients without sensory symptoms had anti‐GQ1b/GM1 antibodies.

Conclusions

At least three different specificities in MFS‐associated antibodies, GQ1b‐specific, anti‐GQ1b/GM1‐positive and anti‐GQ1b/GD1a‐positive, were observed. In patients with MFS not only GQ1b itself but also clustered epitopes of GSCs, including GQ1b, may be considered to be prime target antigens for serum antibodies. A tendency to escape sensory disturbances is shown by anti‐GQ1b/GM1‐positive MFS.We recently reported that some ganglioside complexes (GSCs) are target antigens for serum antibodies in patients with Guillain–Barré syndrome (GBS), an acute immune‐mediated polyradiculoneuropathy, and suggested that anti‐GSC antibodies may be associated with particular clinical features of GBS.¹ Because glycolipids including gangliosides tend to form clustered complexes with cholesterols in lipid rafts in the plasma membrane,² anti‐GSC antibodies are likely to cause nerve dysfunction through binding to GSCs in lipid rafts in neuronal membranes.Miller Fisher syndrome (MFS) is characterised by a clinical triad of ophthalmoplegia, ataxia and areflexia, and is considered to be a variant of GBS.³ The presence of the IgG anti‐GQ1b antibody in serum is an excellent diagnostic marker for MFS.⁴ This antibody often cross reacts with GT1a^4,5 and is pathophysiologically associated with ophthalmoplegia or ataxia in MFS and GBS.^5,6,7 Thus, MFS is a clinically and serologically well‐defined syndrome with a pathophysiological mechanism similar to that of GBS, which suggests that patients with MFS may also have anti‐GSC antibodies. Here, we examined the serum samples of patients with MFS and found antibodies specific for a mixture of two gangliosides, including GQ1b or GT1a.     

Unexplained syncope—is screening for carotid sinus hypersensitivity indicated in all patients aged >40?years?

Objective

To determine the frequency, age distribution and clinical presentation of carotid sinus hypersensitivity (CSH) among 373 patients (age range 15–92 years) referred to two autonomic referral centres during a 10‐year period.

Methods

Carotid sinus massage (CSM) was performed both supine and during 60° head‐up tilt. Beat‐to‐beat blood pressure, heart rate and a three‐lead electrocardiography were recorded continuously. CSH was classified as cardioinhibitory (asystole ⩾3 s), vasodepressor (systolic blood pressure fall ⩾50 mm Hg) or mixed. All patients additionally underwent autonomic screening tests for orthostatic hypotension and autonomic failure.

Results

CSH was observed in 13.7% of all patients. The diagnostic yield of CSM was nil in patients aged <50 years (n = 65), 2.4% in those aged 50–59 years (n = 82), 9.1% in those aged 60–69 years (n = 77), 20.7% in those aged 70–79 years (n = 92) and reached 40.4% in those >80 years (n = 57). Syncope was the leading clinical symptom in 62.8%. In 27.4% of patients falls without definite loss of consciousness was the main clinical symptom. Mild and mainly systolic orthostatic hypotension was recorded in 17.6%; evidence of sympathetic or parasympathetic dysfunction was found in none.

Conclusions

CSH was confirmed in patients >50 years, the incidence steeply increasing with age. The current European Society of Cardiology guidelines that recommend testing for CSH in all patients >40 years with syncope of unknown aetiology may need reconsideration. Orthostatic hypotension was noted in some patients with CSH, but evidence of sympathetic or parasympathetic failure was not found in any of them.Unexplained syncope is a common medical problem. In our series of 641 patients with recurrent syncope, a definite diagnosis could not be established in 28%, despite an extensive diagnostic investigation.¹ This is consistent with the literature, where figures range from 13% to 42% depending on populations studied and diagnostic algorithms used.²Carotid sinus hypersensitivity (CSH) refers to the occurrence of asystole ⩾3 s (cardioinhibitory CSH), a fall in systolic blood pressure of ⩾50 mm Hg (vasodepressor CSH) or both (mixed CSH), after carotid sinus massage (CSM). In patients with syncope of unknown origin and CSH on CSM, carotid sinus syndrome (CSS) is usually diagnosed, although the phenomenon of CSH has also been observed in up to 35% of asymptomatic older people in a recent study and there is no consistent definition of CSS in the literature.^3,4,5,6 To avoid confusion we will therefore refer to CSH instead of CSS throughout this paper, being well aware that the frequency of CSH may exceed that of CSS.CSH is a recognised cause of recurrent syncope and is increasingly recognised as accounting for unexplained falls in elderly people.^7,8 The diagnostic yield of CSM in patients >65 years presenting with syncope or unexplained falls was up to 45%, in studies by Kenny et al.^8,9,10 Subsequent studies that also included younger patients >50 or 60 years, however, have found lower prevalence rates of CSH, in the range of 17–21%.^11,12,13 Indeed, CSH was found to be rare in patients <50 years in a recent study by Puggioni et al,¹⁴ namely 4% in those aged <41 years and 11% in those aged 41–50 years.Despite these figures, the current European Society of Cardiology (ESC) guidelines still recommend testing for CSH in all patients >40 years who have unexplained syncope after basic evaluation consisting of history, physical examination including orthostatic blood pressure measurements and standard electrocardiography (ECG).^15,16 More data on the diagnostic yield of CSM in populations including patients <50 years of age are therefore needed to estimate the yield and thus cost effectiveness of these guidelines.In this study, we evaluated the results of CSM performed during a 10‐year period in two autonomic referral centres with an extensive regional and national patient‐referral base. We determined the frequency and clinical characteristics, especially the age distribution, of patients with CSH. Additionally, we analysed the detailed cardiovascular autonomic function tests of all patients with CSH, with an emphasis on the presence of orthostatic hypotension and evidence for autonomic failure, as it has been suggested that these coexist with CSH^7,8,17 and may cause or contribute to syncope.     

Cueing training in the home improves gait-related mobility in Parkinson's disease: the RESCUE trial

Objectives

Gait and mobility problems are difficult to treat in people with Parkinson''s disease. The Rehabilitation in Parkinson''s Disease: Strategies for Cueing (RESCUE) trial investigated the effects of a home physiotherapy programme based on rhythmical cueing on gait and gait‐related activity.

Methods

A single‐blind randomised crossover trial was set up, including 153 patients with Parkinson''s disease aged between 41 and 80 years and in Hoehn and Yahr stage II–IV. Subjects allocated to early intervention (n = 76) received a 3‐week home cueing programme using a prototype cueing device, followed by 3 weeks without training. Patients allocated to late intervention (n = 77) underwent the same intervention and control period in reverse order. After the initial 6 weeks, both groups had a 6‐week follow‐up without training. Posture and gait scores (PG scores) measured at 3, 6 and 12 weeks by blinded testers were the primary outcome measure. Secondary outcomes included specific measures on gait, freezing and balance, functional activities, quality of life and carer strain.

Results

Small but significant improvements were found after intervention of 4.2% on the PG scores (p = 0.005). Severity of freezing was reduced by 5.5% in freezers only (p = 0.007). Gait speed (p = 0.005), step length (p<0.001) and timed balance tests (p = 0.003) improved in the full cohort. Other than a greater confidence to carry out functional activities (Falls Efficacy Scale, p = 0.04), no carry‐over effects were observed in functional and quality of life domains. Effects of intervention had reduced considerably at 6‐week follow‐up.

Conclusions

Cueing training in the home has specific effects on gait, freezing and balance. The decline in effectiveness of intervention effects underscores the need for permanent cueing devices and follow‐up treatment. Cueing training may be a useful therapeutic adjunct to the overall management of gait disturbance in Parkinson''s disease.In neurological patients, Parkinson''s disease is the most common disorder leading to gait disturbance and falls.¹ Despite advances in pharmacological treatments and surgical techniques, gait and balance deficits still persist and are associated with loss of independence, immobility and high cost for healthcare systems.² Therefore, the development of rehabilitation approaches that work in conjunction with current treatment is important to manage these problems.Recent systematic reviews concluded that evidence available was insufficient to support or refute the efficacy of physiotherapy in Parkinson''s disease or to support the use of one form of physiotherapy over another.^3,4 Some studies had methodological problems. However, reviewers did comment that the efficacy of physiotherapy was improved by the addition of cueing techniques. Cueing is defined as using external temporal or spatial stimuli to facilitate movement (gait) initiation and continuation. Recent reviews on cueing suggest that it can have an immediate and powerful effect on gait performance in people with Parkinson''s disease, indicating improvements in walking speed, step length and step frequency.^5,6 The influence of cueing has mainly been studied in single‐session experiments in laboratory settings.^7,8,9,10,11 Results show a short‐term correction of gait and gait initiation, and suggest that carry‐over to uncued performance and its generalisation to activities of daily living (ADL) is limited. Using cues in a therapeutic setting is more complex, as the “modality” of cue delivery (visual, auditory or somatosensory) and the cue “parameter” selected for movement correction (frequency or size of step) have to be adapted to the needs of the patient. Apart from two limited studies on the retention effects of cues, to date no work has evaluated the clinical application and prolonged training effects of cues in the home to improve walking in a functional context.^12,13 Furthermore, improved mobility with cues may have an adverse effect by distracting attention, increasing the risk of falling.^14,15The primary objective of this study was to investigate the efficacy of a home‐based cueing programme on parameters of gait, gait‐related activity and health‐related quality of life in people with Parkinson''s disease. We hypothesised that a 3‐week period of home‐based cueing training would result in measurable improvements of selected gait parameters immediately after treatment, but that these effects might decrease after 6 weeks without cueing.     

Non-infectious fever in the neurological intensive care unit: incidence, causes and predictors

Background and objective

Non‐infectious causes of fever are often considered in critical neurological patients but their true significance has not been formally studied. The aim of this study was to evaluate the incidence, causes and predictors of fever in patients with acute neurological/neurosurgical disease and no documented infection.

Methods

Prospective data collection of consecutive patients admitted to the neurological intensive care unit (NICU) of an academic medical centre for more than 48 h was carried out. Fever was defined as body temperature ⩾101°F (38.3°C) documented on at least one measurement for 2 consecutive days. Patients were enrolled only if a diagnostic workup, including cultures of ⩾2 body samples, was performed before antibiotic use. Febrile patients with no proven evidence of infection were considered to have non‐infectious fever.

Results

93 patients were included in the final analysis. Fever was non‐infectious in 31 patients (33%). There were no differences between the infectious and non‐infectious fever groups in terms of age, use and duration of invasive catheters, daily duration of fever and number of days with fever. Documented infections tended to be more common among febrile patients with traumatic brain injury (52% vs 36%; p = 0.06). Non‐infectious fever was more frequent among patients with subarachnoid haemorrhage (48% vs 18%; p = 0.01) in whom it was associated with vasospasm (p = 0.03) and symptomatic vasospasm (p = 0.05). Non‐infectious fever started earlier (mean 2.6 vs 4 days; p = 0.007) and onset of fever within the first 72 h of admission predicted negative evaluation for infection (p = 0.01). Subarachnoid haemorrhage and fever onset within the first 72 h were independent predictors of non‐infectious fever on multivariable analysis.

Conclusions

Fever in the absence of documented infections occurs commonly in the NICU, especially among patients with subarachnoid haemorrhage and vasospasm. Early onset of fever predicts a non‐infectious cause.Between one‐quarter¹ and more than one‐half^2,3,4 of patients admitted to the neurological intensive care unit (NICU) develop fever. The cause of fever in these patients often remains unexplained. As hyperthermia is strongly detrimental for the recovery of the acutely injured brain^5,6,7,8,9 and contributes to an increase in the length of stay in the NICU,^4,10 timely and accurate diagnosis of the cause of fever in the NICU is crucial.Infections are the most common causes of fever in the NICU population but they are only documented in half of all febrile patients.¹ Central fever related to loss of the physiological regulation of body temperature by the hypothalamus is often proposed as a possible cause for persistent fever in acute neurological patients with no evidence of infection. There are no current means to confirm the diagnosis of central fever. Thus we can only assess its frequency by studying patients in whom fever remains unexplained after thorough investigations for infectious and other non‐infectious causes.The objective of this study was to determine the incidence, causes and predictors of non‐infectious fever in patients with acute neurological disease.     

Accuracy of the bedside head impulse test in detecting vestibular hypofunction

Objective

To determine the accuracy of the bedside head impulse test (bHIT) by direct comparison with results from the quantitative head impulse test (qHIT) in the same subjects, and to investigate whether bHIT sensitivity and specificity changes with neuro‐otological training.

Methods

Video clips of horizontal bHIT to both sides were produced in patients with unilateral and bilateral peripheral vestibular deficits (n = 15) and in healthy subjects (n = 9). For qHIT, eye and head movements were recorded with scleral search coils on the right eye and the forehead. Clinicians (neurologists or otolaryngologists) with at least 6 months of neuro‐otological training (“experts”: n = 12) or without this training (“non‐experts”: n = 45) assessed video clips for ocular motor signs of vestibular deficits on either side or of normal vestibular function.

Results

On average, bHIT sensitivity was significantly (t test: p<0.05) lower for experts than for non‐experts (63% vs 72%), while bHIT specificity was significantly higher for experts than non‐experts (78% vs 64%). This outcome was a consequence of the experts'' tendency to accept bHIT with corresponding borderline qHIT values as still being normal. Fitted curves revealed that at the lower normal limit of qHIT, 20% of bHIT were rated as deficient by the experts and 37% by the non‐experts.

Conclusions

When qHIT is used as a reference, bHIT sensitivity is adequate and therefore clinically useful in the hands of both neuro‐otological experts and non‐experts. We advise performing quantitative head impulse testing with search coils or high speed video methods when bHIT is not conclusive.The Halmagyi–Curthoys head impulse test is, at present, the only bedside examination that allows identification of the side of a unilateral hypofunction of the peripheral vestibular system.¹ Head impulses are rapid, passive, unpredictable rotations of the head relative to the trunk. The patient is asked to fix upon a target straight ahead, usually the nose of the examiner, while the examiner turns the patient''s head in the plane of a pair of semicircular canals. The rotations are of low amplitude (10–20°) but of high acceleration (10000°/s²). If the peripheral vestibular system is intact and the vestibulo‐ocular reflex (VOR) operates normally, the patient''s eyes keep their fixations approximately on target (ie, gaze is held relatively stable in space). If not (ie, in the case of a reduced gain of the VOR towards the side of the head impulse), a reflexive saccade back to the examiner''s nose is performed after the end of the head thrust. This corrective saccade indicates a peripheral vestibular hypofunction on the side towards which the preceding head rotation occurred, provided ocular motor function is intact.Head impulses mainly drive the short latency, oligosynaptic VOR pathways from the semicircular canals to the extraocular muscles. Polysynaptic pathways via the cerebellum are less efficient in transmitting such high acceleration vestibular stimuli. The oligosynaptic pathways show distinct non‐linear properties in that the contribution of the signals from the excited semicircular canals to the ocular motor response is greater than the contribution of the signals from the inhibited semicircular canals. This principle, known as Ewald''s second law,² is probably the result of a non‐linear pathway, which during high accelerations is driven into inhibitory cut‐off on the side of inhibited semicircular canals.^3,4 In the case of unilateral peripheral vestibular hypofunction, Ewald''s second law results in an asymmetric gain of the VOR (ie, the gain during high acceleration head rotations towards the lesioned side is lower than towards the healthy side).⁵Halmagyi and Curthoys¹ as well as Foster and colleagues⁶ have shown surpassing accuracy of the bedside head impulse test (bHIT) in patients with complete unilateral vestibular loss. In these patients, both sensitivity and specificity reached 100% with reference to a control group of healthy subjects. In patients with partial vestibular deficits, however, the sensitivity of bHIT is considerably lower, because residual peripheral function results in a smaller gain asymmetry of the VOR. In a general clinical population of patients without and patients with significant asymmetries in caloric testing (canal paresis factor >25%), bHIT sensitivity was approximately 35% and bHIT specificity 95%.^7,8,9 Direct comparison of bHIT with caloric testing, however, is problematic, as head impulses and caloric irrigation probe different frequencies of the VOR. Moreover, central compensation mechanisms in response to a peripheral vestibular deficit are frequency dependent and more often incomplete for higher (head impulses) than for lower frequencies (caloric irrigation).^10,11,12,13Considering these problems of correctly appraising the clinical usefulness of bHIT by caloric testing, we set out to better determine the accuracy of bHIT by comparing it directly with head impulse testing that is assessed quantitatively from simultaneous recordings of eye and head movements with search coils. The result of this quantitative head impulse test (qHIT) was compared with the clinicians'' evaluations of bHIT (presented on video clips) in the same patients. We further asked whether the sensitivities and specificities of bHIT differed depending on the clinicians'' neuro‐otological training.     

Influence of cognitive impairment on the institutionalisation rate 3 years after a stroke

Background and purpose

Pre‐existing cognitive decline and new‐onset dementia are common in patients with stroke, but their influence on institutionalisation rates is unknown.

Objective

To evaluate the influence of cognitive impairment on the institutionalisation rate 3 years after a stroke.

Design

(1) The previous cognitive state of 192 consecutive patients with stroke living at home before the stroke (with the Informant Questionnaire on COgnitive Decline in the Elderly (IQCODE)), (2) new‐onset dementia occurring within 3 years and (3) institutionalisation rates within 3 years in the 165 patients who were discharged alive after the acute stage were prospectively evaluated.

Results

Independent predictors of institutionalisation over a 3‐year period that were available at admission were age (adjusted odds ratio (adjOR) for 1‐year increase  = 1.08; 95% confidence interval (CI) 1.03 to 1.15), severity of the neurological deficit (adjOR for 1‐point increase in Orgogozo score = 0.97; 95% CI 0.96 to 0.99) and severity of cognitive impairment (adjOR for 1‐point increase in IQCODE score = 1.03; 95% CI 1 to 1.06). Factors associated with institutionalisation at 3 years that were present at admission or occurred during the follow‐up were age (adjOR for 1‐year increase = 1.17; 95% CI 1.07 to 1.27) and any (pre‐existing or new) dementia (adjOR = 5.85; 95% CI 1.59 to 21.59), but not the severity of the deficit of the neurological deficit.

Conclusion

Age and cognitive impairment are more important predictors of institutionalisation 3 years after a stroke than the severity of the physical disability.Institutionalisation after a stroke increases with the severity of the neurological deficit, increasing age, female gender, low socioeconomic level, marital status and poor social environment.^1,2,3,4,5,6Dementia is common after a stroke,⁷ leading to autonomy loss.⁸ Pre‐existing dementia is present in up to 16% of patients with stroke,^9,10,11,12 and post‐stroke de mentia (PSD) occurs in up to one third.⁷ Several studies have found a link between cognitive impairment and institutionalisation after a stroke,^1,2,3,4,5 but they had several methodological limitations: (1) cross‐sectional studies were performed in long‐term stroke survivors and did not take into account patients who had been institutionalised but died before the study⁶; (2) there was no systematic cognitive assessment¹³ or only a Mini Mental State Examination,¹⁴ which is not appropriate for patients with stroke; and (3) most studies included only patients recruited in rehabilitation centres, leading to selection bias.^1,2,3,4,5 To our knowledge, no study has prospectively evaluated the influence of pre‐existing cognitive impairment and PSD on the institutionalisation rate after a stroke.The aim of this study was to evaluate the influence of the previous cognitive state and new‐onset dementia on the institutionalisation rate 3 years after a stroke.     

Abnormal breathing patterns in stroke: relationship with location of acute stroke lesion and prior cerebrovascular disease

Objective

To determine whether central periodic breathing (CPB) is associated with acute involvement of any particular part of the brain, or the extent of total damage in patients with acute stroke.

Methods

CPB was identified using portable monitoring equipment in patients with stroke on admission. A neuroradiologist classified acute stroke lesions and prior cerebrovascular disease on brain images.

Results

Among 134 patients with acute stroke, those with CPB were more likely to have a large acute stroke lesion in a cerebral hemisphere (p = 0.01) and more mass effect (p = 0.03). There was no association between CPB and severe prior cerebrovascular disease on imaging (p = 0.76).

Conclusion

CPB is related to the acute (not old) lesions, particularly large acute cerebral hemispheric lesions with mass effect. A relationship between lesions in any discrete brain location (unilateral or bilateral) and CPB could not be shown.Central periodic breathing (CPB), including Cheynes–Stokes respiration, during wakefulness has been reported to occur in 53% of patients with acute stroke.¹ Limited information suggests a possible relationship between the site and size of the stroke lesion and the presence of CPB. Previous studies suggested that the presence of bilateral hemispheric or brain stem stroke lesions might be crucial for the presence of CPB after stroke.^2,3 However, these were small studies (n = 28, n = 49) predating computed tomography, which found that hospitalised patients with intermittent CPB during wakefulness had bilateral hemispheric or brain stem lesions on autopsy. More recent studies have failed to find any association between the location of brain lesion on imaging and CPB while patients were awake¹ (n = 32) or asleep^4,5 (n = 93, n = 39).We reported previously that CPB was associated with a poor functional outcome at 3 months after stroke, even after accounting for clinical stroke severity, but the mechanism linking CPB with poor outcome was unclear.⁶ Therefore, we aimed to determine, using data from the same cohort, whether CPB was related to features of the acute stroke lesion on brain imaging or to prior cerebrovascular disease (ie, previous infarcts, haemorrhages and/or periventricular white matter lesions (PVWML)/leucoaraiosis).     

Increased cerebrospinal fluid and serum levels of S100B in first-onset schizophrenia are not related to a degenerative release of glial fibrillar acidic protein, myelin basic protein and neurone-specific enolase from glia or neurones

Objective

To assess levels of glial fibrillar acidic protein (GFAP), myelin basic protein (MBP), neurone‐specific enolase (NSE) and S100B in patients with first‐onset schizophrenia.

Method

We investigated CSF and serum samples from 12 patients with first‐onset schizophrenia and from 17 control subjects by ELISA (GFAP, MBP) or immunoluminometric sandwich assays (NSE, S100B).

Results

Patients with schizophrenia had significantly higher levels of S100B in CSF (p = 0.004; 2.73 (SD 0.80) v 1.92 (0.58) μg/l) and serum (p = 0.032; 0.09 (0.03) v 0.08 (0.02) μg/l) in comparison with those in the matched control group. No diagnosis‐dependent differences of protein concentration were seen for GFAP, MBP and NSE.

Discussion

Our finding of increased levels of S100B in patients with schizophrenia without an indication for significant glial (GFAP, MBP) or neuronal (NSE) damage may be interpreted as indirect evidence for increased active secretion of S100B during acute psychosis.S100B is a calcium‐binding, growth‐regulating secretory protein that is expressed particularly in brain tissue and mediates the interaction among glial cells and between glial cells and neurones. Nanomolar levels of S100B protein stimulate neurite growth and promote neurone survival, whereas micromolar levels result in the opposite effects and can even induce neuronal apoptosis.¹ S100B expression in the central nervous system has been found in astrocytes, oligodendrocytes, ependyma and a few neurones.^2,3,4Increased levels of S100B in cerebrospinal fluid (CSF) and serum have been reported in various neuropsychiatric diseases, including acute phases of schizophrenia.^{5,6,7,8,9,10,11} High levels of S100B were considered to be a biomarker for astrocytic damage or dysfunction in schizophrenia. However, this assumption has not been proved yet, as only one study on S100B in CSF and no histological study has been published on this topic.⁹The aim of this study was to replicate the findings of Rothermundt et al⁹ on S100B expression in the CSF, and to identify whether there is an indication for astrocytic, oligodendrocytic or neuronal damage in acute schizophrenia, leading to increased levels of S100B in CSF and serum. We investigated non‐secretory glial and neuronal proteins in CSF and serum to clarify this question. Glial fibrillar acidic protein (GFAP), myelin basic protein (MBP) and neurone‐specific enolase (NSE) are well‐established markers to identify the brain compartment involved in neuropsychiatric disorders.^12,13 We hypothesised that there would be increased CSF levels of GFAP, MBP or NSE in cases of astrocytic, oligodendrocytic or neuronal damage, whereas unchanged levels of these proteins and increased levels of S100B in the CSF would be indicative of an increased active secretion of S100B during acute schizophrenia.     

Thrombolysis in patients older than 80 years with acute ischaemic stroke: Canadian Alteplase for Stroke Effectiveness Study

Background

The benefit of intravenous tissue plasminogen activator (tPA) given within 3 h of acute ischaemic stroke to patients over 80 years of age is uncertain.

Aim

To examine the clinical characteristics and complications and the predictors of outcome after intravenous tPA treatment in patients aged ⩾80 years.

Methods

Data (n = 1135) prospectively collected from the Canadian Alteplase for Stroke Effectiveness Study were reviewed and patients aged ⩾80 years (n = 270) treated with intravenous tPA for acute ischaemic stroke were compared with those aged <80 years (n = 865).

Results

The risk of symptomatic intracerebral haemorrhage did not differ between patients aged ⩾80 years and <80 years (4.4% (95% CI 2.3 to 7.6) v 4.6% (95% CI 3.3 to 6.2), p = 1.0). Favourable outcome, defined as a modified Rankin Score of 0–1 at 90 days, was seen in 26% of patients aged ⩾80 years and in 40% of those <80 (p<0.001). The following baseline characteristics were found to be more common in those aged ⩾80 years than in those aged <80 years: atrial fibrillation (37% v 18%; p<0.001); congestive heart failure (11% v 6%; p = 0.004); hypertension (59% v 48%; p = 0.002); and severity of stroke with a median National Institutes of Health Stroke Scale (NIHSS) score of 16 v 14 (p = 0.004). In the multivariable logistic regression analysis, age ⩾80 years, stroke severity, baseline Alberta Stroke Program Early CT Score and glucose level were found to be the major independent predictors of outcome.

Conclusion

In carefully selected elderly patients, the use of intravenous tPA was not found to be associated with an increased risk of symptomatic intracerebral haemorrhage. Age‐related differences were seen in the clinical characteristics and outcome in the elderly population.Thirty per cent of strokes occur in patients aged ⩾80 years but the role of intravenous thrombolysis in this age group is not well defined.¹ No randomised trials have focused specifically on elderly patients with acute ischaemic stroke. Recent studies analysed the risks and outcome of using intravenous tissue plasminogen activator (tPA) in elderly people and reported no increase in the risk of intracerebral haemorrhage, but the outcomes were not as favourable as in younger patients.^2,3 The number of patients studied, however, was very small, thereby preventing definitive conclusions from being drawn.People older than 80 years represent the fastest growing segment of the population in developed countries,⁴ and in view of the increased incidence of stroke with advancing age, stroke‐related disability is expected to increase.^5,6,7 We sought to examine the clinical characteristics, complications and predictors of outcome in patients aged ⩾80 years who were treated with intravenous tPA.