Type of stroke after transient monocular blindness or retinal infarction of presumed arterial origin

Background

Retinal infarction and transient monocular blindness (TMB) are associated with an increased risk of future ischaemic stroke. Little information is available on the type of subsequent ischaemic strokes that may occur (anterior or posterior circulation and small vessel or large vessel).

Aim

To analyse the type of stroke after TMB.

Methods

Patients with transient or permanent retinal ischaemia were selected from three prospective studies: the Dutch TIA Trial, the Dutch Amaurosis Fugax Study and the European/Australian Stroke Prevention in Reversible Ischaemia Trial. On follow‐up the type of stroke was classified according to the supply territory and the type of vessel involved.

Results

654 patients were included. During a mean follow‐up of 5.2 years, 42 patients were found to have had a cerebral or retinal infarct, of which 27 occurred in the carotid territory ipsilateral to the symptomatic eye, 9 in the territory of the contralateral carotid artery and 6 were infratentorial strokes. Thirty patients had a large‐vessel infarct, four had a small‐vessel infarct and eight had a retinal infarct. Characteristics associated with a notable increased risk for subsequent stroke or retinal infarction were age ⩾65 years, a history of stroke, a history of intermittent claudication, diabetes mellitus, Rankin score ⩾3, more than three attacks of retinal ischaemia and any degree of ipsilateral carotid stenosis on duplex ultrasonography observation.

Conclusion

Ischaemic strokes after TMB or retinal infarction were found to be mainly large‐vessel infarcts in the territory of the ipsilateral carotid artery. TMB and retinal infarction are probably manifestations of large‐vessel disease.Transient monocular blindness (TMB) is caused by temporary ischaemia of the retina in one eye, secondary to transient occlusion of a retinal artery, hypoperfusion or vasospasm.¹ TMB is a risk factor for subsequent ischaemic stroke,² but this risk is lower than after transient ischaemic attacks of the brain.^3,4,5,6 The annual incidence of ischaemic stroke after TMB or retinal infarcts in unselected patients ranges between 2.0% and 2.8%,^2,3,4,7,8,9 and increases up to 8.4% in the presence of high‐grade stenosis of the ipsilateral carotid artery.⁵ That TMB often occurs in patients with atherosclerotic lesions of the carotid artery^3,6,10,11,12 suggests that it should be regarded as a manifestation of large‐vessel atherosclerosis. But, even among patients with stenosis of the internal carotid artery, the risk for subsequent stroke is lower in patients with TMB than in those who have had a cerebral transient ischaemic attack,^5,6 which may indicate a difference in pathophysiological background between hemispheric and retinal ischaemia. Patients who have had a transient ischaemic attack or non‐disabling ischaemic stroke caused by large‐vessel disease are more likely to have subsequent large‐vessel stroke during follow‐up.¹³ If TMB is considered to be a manifestation of large‐vessel disease, the subsequent ischaemic stroke may be large‐vessel ischaemic stroke. To date, no information is available on whether brain infarcts after TMB are caused by small‐vessel or by large‐vessel disease, and whether subsequent ischaemic strokes occur mainly in the ipsilateral or also in the contralateral hemisphere, or in the vertebrobasilar territory. Given the low incidence of recurrent stroke after TMB, many patients have to be followed up for a long time for a meaningful analysis. We aimed to analyse the type of subsequent ischaemic stroke in patients with TMB or retinal infarction, to obtain more insight into the pathophysiology of retinal ischaemia, especially with respect to the type of vascular disease.     

Interleukin 10, monocytes and increased risk of early infection in ischaemic stroke

Background and purpose

: The pathophysiology of stroke‐associated infection (SAI) is uncertain. The cytokine profile and peripheral white cell response were assessed in patients with or without SAI.

Methods

The incidence of SAI was assessed in 110 patients with ischaemic stroke allocated antibiotic prophylaxis or placebo within 24 h of clinical onset. Peripheral white cell counts, interleukin (IL)6, tumour necrosis factor (TNF)α and IL10 were measured in plasma.

Results

17 (15%) patients developed infection and showed time‐dependent increases of total white cell count, neutrophils, monocytes, lymphocytes, IL6 and IL10, whereas TNFα and the TNFα/IL10 ratio decreased. In logistic regression, IL10 (odds ratio (OR) 1.08, 95% confidence interval (CI) 1.01 to 1.16), monocyte count (OR 1.42, 95% CI 1.08 to 1.87) and National Institute for Health Stroke Survey score on admission (OR 1.17, 95% CI 1.05 to 1.31) were independent predictors of systemic infection.

Conclusions

SAI is associated with stroke severity, excessive IL10‐mediated response and an increased number of circulating monocytes. These results support the finding that acute ischaemic brain injury triggers a blood‐borne anti‐inflammatory response that decreases the antimicrobial drive of the immune system.Stroke‐associated infection (SAI) has been reported in 21–65% of patients with stroke.^1,2,3,4 A high rate of infection, despite avoidance of invasive manoeuvres³ or prophylactic antibiotics,⁵ suggests that a brain‐mediated immunodepressive state can be an independent contributor to SAI, as recently suggested in a mouse model of transient focal brain ischaemia,⁶ and in patients with brain trauma or neurosurgery.⁷ Several cytokines may increase soon after stroke onset in patients and affect clinical outcome.^8,9 Cytokines are essential mediators in the cross‐talk between the brain and the immune system to maintain homoeostasis,¹⁰ and acute brain injury may facilitate a cytokine‐mediated systemic inflammatory response syndrome, activate neuroimmune pathways, such as the hypothalamic–pituitary–adrenal axis, or the autonomic nervous system,¹¹ and decrease the competence of the immune system.¹² Proinflammatory cytokines released by the injured brain tissue may also transfer to the plasma and set off a compensatory anti‐inflammatory response syndrome that will re‐establish homeostasis only if the degree of proinflammatory and anti‐inflammatory responses is proportionate.¹² Here, our findings support the notion that in patients with acute ischaemic stroke, brain injury may set off a blood‐borne response that decreases the antimicrobial drive of the immune system.     

A randomised pilot study to assess the efficacy of an interactive, multimedia tool of cognitive stimulation in Alzheimer's disease

Objective

To determine the usefulness of an interactive multimedia internet‐based system (IMIS) for the cognitive stimulation of Alzheimer''s disease.

Methods

This is a 24‐week, single‐blind, randomised pilot study conducted on 46 mildly impaired patients suspected of having Alzheimer''s disease receiving stable treatment with cholinesterase inhibitors (ChEIs). The patients were divided into three groups: (1) those who received 3 weekly, 20‐min sessions of IMIS in addition to 8 h/day of an integrated psychostimulation program (IPP); (2) those who received only IPP sessions; and (3) those who received only ChEI treatment. The primary outcome measure was the Alzheimer''s Disease Assessment Scale‐Cognitive (ADAS‐Cog). Secondary outcome measures were: Mini‐Mental State Examination (MMSE), Syndrom Kurztest, Boston Naming Test, Verbal Fluency, and the Rivermead Behavioral Memory Test story recall subtest.

Results

After 12 weeks, the patients treated with both IMIS and IPP had improved outcome scores on the ADAS‐Cog and MMSE, which was maintained through 24 weeks of follow‐up. The patients treated with IPP alone had better outcome than those treated with ChEIs alone, but the effects were attenuated after 24 weeks. All patients had improved scores in all of the IMIS individual tasks, attaining higher levels of difficulty in all cases.

Conclusion

Although both the IPP and IMIS improved cognition in patients with Alzheimer''s disease, the IMIS program provided an improvement above and beyond that seen with IPP alone, which lasted for 24 weeks.Alzheimer''s disease is the most frequent form of dementia in elderly people,^1,2 and its current treatment includes cholinesterase inhibitors (ChEIs),^3,4,5 and n‐methyl‐d‐aspartate receptor blockers (eg, memantine).⁶ However, symptomatic treatment often entails non‐pharmacological treatments as well, and adequate dementia management requires a wide range of intervention to help maximise the patient''s independence, increase their self‐confidence and relieve burden to the care giver.Current symptomatic treatment of Alzheimer''s disease can improve cognition and functionality.^3,4,5,6 However, before the emergence of these drugs, non‐pharmacological treatments had already been evaluated and cognitive stimulation had been found to be potentially beneficial for patients with dementia.^7,8,9 Although these non‐pharmacological treatments do not always seem efficacious, methodological problems may limit the validity of some studies.¹⁰ A recent Cochrane review¹¹ emphasised caution when interpreting the results of non‐pharmacological treatments, but suggested that certain cognitive domains could, in fact, benefit from these types of interventions.Clinical and laboratory studies have shown that mental and physical activity can positively influence cognition in normal elderly people and people with dementia. Education¹² and lifestyle choices (eg, occupation and leisure activities)^13,14,15 can modulate the risk of developing dementia, and psychomotor stimulation improves cognition in patients with Alzheimer''s disease.^16,17 Environmental enrichment can improve cognition in transgenic mice.^18,19 Despite the continued deposition of β‐amyloid, exercise can increase the levels of brain‐derived neurotrophic factor²⁰ and may reduce amyloid burden.²¹Despite the progressive nature of the degenerative process, patients with Alzheimer''s disease also seem to retain the physiological capacity to alter brain structure and function. Recent studies have shown cognitive plasticity and learning potential not only in patients with Alzheimer''s disease but also in healthy elders.^22,23 Positron emission tomography studies that used activation paradigms^24,25 have found that people with Alzheimer''s disease have a greater activation than those without dementia in the brain regions usually associated with memory tasks, as well as in the frontal lobes that were activated only with increasing difficulty of tasks. Pathological studies conducted on biopsy specimens of patients with Alzheimer''s disease with mild or moderate dementia have shown increased synaptic contact size.²⁶ Thus, the brain may be able to compensate during the early stages of Alzheimer''s disease, suggesting that there may be some utility to non‐pharmacological adjunctive interventions.Although studies on cognitive stimulation show that it is possible to stimulate the memory of patients with Alzheimer''s disease, the results are often modest. Because of methodological limitations, there is a need to conduct more randomised‐controlled trials with larger samples to validate this therapeutic approach. Computerised systems²⁷ and internet‐based distance programs offer one potential mechanism by which non‐pharmacological cognitive stimulation can be conducted in patients with dementia. In this study, we evaluated an interactive multimedia internet‐based system (IMIS) as an adjunct to ChEI treatment and classic psychostimulation treatment.     

Effects of apolipoprotein E genotype on outcome after ischaemic stroke, intracerebral haemorrhage and subarachnoid haemorrhage

Background

Rodent models of acute ischaemic stroke and head injury suggest that apolipoprotein E (APOE) genotype influences neuronal repair, regeneration and survival after brain injury. Possession of an APOE ε4 allele is associated with poor outcome after head injury in clinical studies. APOE might therefore influence outcome after acute stroke in humans.

Objective and methods

To comprehensively search, identify, assess and carry out meta‐analyses of studies reporting on the association between APOE and the combined outcome of death or dependency, or death alone, several months after ischaemic stroke, intracerebral haemorrhage (ICH) or subarachnoid haemorrhage (SAH).

Results

Main analyses included data from nine studies on 2262 patients (1453 with ischaemic stroke, 199 with ICH and 610 with SAH). Overall, ε4+ genotypes were not significantly associated with risk of death or dependency several months after stroke. However, there was significant heterogeneity between studies, and between the three pathological types of stroke. ε4+ genotypes were associated with increased death or dependency after SAH (relative risk (RR) 1.40, 95% confidence interval (CI) 1.06 to 1.84), with a trend towards a similar association with ICH (RR 1.38, 95% CI 0.99 to 1.92), but not with ischaemic stroke (RR 0.98, 95% CI 0.85 to 1.12). Results were similar for death alone.

Conclusions

APOE may differentially affect outcome after the three main pathological types of stroke. Further, large studies are needed to confirm or refute these findings, and to assess the possibility of an interaction between the effects of APOE and age.In contrast with the many studies assessing the role of various candidate genes in the causation of stroke and its subtypes,^1,2,3 the role of genetic factors influencing outcome after acute stroke has been relatively little studied in humans.^4,5 However, studies on animal models of stroke comparing outcomes among genetically manipulated animals with those among wild‐type animals suggest that this should be a promising subject, which may ultimately improve our understanding of the pathways of neuronal protection and recovery, and even lead to new therapeutic insights.^4,6The apolipoprotein E gene (APOE) is one of the most widely studied genes in vascular and neurodegenerative diseases. Its protein product is a 34‐kDa glycoprotein with three common isoforms, E2, E3 and E4, encoded by the alleles ε2, ε3 and ε4, respectively, giving rise to six genotypes, the ε3/ε3 genotype occurring in about 50–66% of people in most populations.⁷ APOE has a major role in lipid redistribution, which is important for membrane maintenance and repair in the brain, and in the regulation of synaptic remodelling during or after brain injury.^6,8,9,10,11 Rodent models of head injury and ischaemic stroke suggest that APOE influences neuronal repair, regeneration and survival after brain injury.^6,11 In clinical studies, possession of an APOE ε4 allele is associated with poor outcome after head injury.⁵ These observations suggest that APOE might influence outcome after acute stroke in humans, but clinical studies have produced conflicting results.⁵Here, we use systematic review and meta‐analysis methods to assess the effect of APOE on outcome after the three main pathological types of acute stroke: ischaemic stroke, intracerebral haemorrhage (ICH) and subarachnoid haemorrhage (SAH).     

Carotid body autotransplantation in Parkinson disease: a clinical and positron emission tomography study

Background

Carotid body (CB) glomus cells are highly dopaminergic and express the glial cell line derived neurotrophic factor. The intrastriatal grafting of CB cell aggregates exerts neurotrophic actions on nigrostriatal neurons in animal models of Parkinson disease (PD).

Objective

We conducted a phase I–II clinical study to assess the feasibility, long term safety, clinical and neurochemical effects of intrastriatal CB autotransplantation in patients with PD.

Methods

Thirteen patients with advanced PD underwent bilateral stereotactic implantation of CB cell aggregates into the striatum. They were assessed before surgery and up to 1–3 years after surgery according to CAPIT (Core Assessment Programme for Intracerebral Transplantation) and CAPSIT‐PD (Core Assessment Programme for Surgical Interventional Therapies in Parkinson''s Disease) protocols. The primary outcome measure was the change in video blinded Unified Parkinson''s Disease Rating Scale III score in the off‐medication state. Seven patients had ¹⁸F‐dopa positron emission tomography scans before and 1 year after transplantation.

Results

Clinical amelioration in the primary outcome measure was observed in 10 of 12 blindly analysed patients, which was maximal at 6–12 months after transplantation (5–74%). Overall, mean improvement at 6 months was 23%. In the long term (3 years), 3 of 6 patients still maintained improvement (15–48%). None of the patients developed off‐period dyskinesias. The main predictive factors for motor improvement were the histological integrity of the CB and a milder disease severity. We observed a non‐significant 5% increase in mean putaminal ¹⁸F‐dopa uptake but there was an inverse relationship between clinical amelioration and annual decline in putaminal ¹⁸F‐dopa uptake (r = −0.829; p = 0.042).

Conclusions

CB autotransplantation may induce clinical effects in patients with advanced PD which seem partly related to the biological properties of the implanted glomus cells.Parkinson disease (PD) is a progressive neurodegenerative disorder of unknown aetiology. Its main pathological hallmark is the degeneration of midbrain dopaminergic neurons projecting to the striatum, although other neuronal systems are also affected.¹ Current pharmacological and surgical therapies are symptomatically effective but their long term utility is limited because of disease progression.^2,3 Therefore, there is a need for neuroprotective and/or neurorestorative therapies capable of arresting or reversing the neurodegenerative process.Over the past two decades, cell replacement therapies have been tested in PD patients with the objective of restoring the striatal dopaminergic deficit.⁴ Transplantation of fetal mesencephalic neurons, the most frequently used technique, can increase the striatal dopamine storage, but does not always produce the expected clinical benefit and may induce disabling off‐medication dyskinesias.^5,6 Thus it appears that the ectopic placement of dopamine secreting cells in the striatum is not the ideal approach to compensate for progressive nigrostriatal neuronal loss.⁷ Given this scenario, the clinical applicability of other transplantation procedures based on a similar rationale (eg, intrastriatal grafting of porcine mesencephalic neurons, retinal pigment epithelial cells or stem cell derived dopaminergic neurons) is, for the moment, uncertain.More recently, other strategies aiming to protect or restore the nigrostriatal pathway have emerged. Glial cell line derived neurotrophic factor (GDNF) has been shown to exert neuroprotective and neurorestorative actions in animal models of PD.^8,9,10 The clinical efficacy of GDNF has been assayed in clinical trials, but the method of delivery is a critical issue. Whereas intraventricular administration failed to induce clinical benefit,¹¹ intraputaminal infusion showed promising results,^12,13 although a placebo controlled trial using this route has been halted because of lack of efficacy and safety concerns about recombinant human GDNF administration.¹⁴ Other alternative methods being tested experimentally in parkinsonian animals include in vivo gene therapy using GDNF encoding viral vectors^15,16,17 and the intrastriatal grafting of recombinant GDNF producing cell lines.^18,19,20,21 Carotid body (CB) glomus cells are neural crest derived dopaminergic cells that express high levels of GDNF. Glomus cell GDNF production is resistant to 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine administration, and maintained in aged rodents or after intrastriatal grafting.^22,23 The survival rate of these cells after transplantation (>70%) is particularly high as hypoxia stimulates their growth and function. Moreover, CB grafts performed in young rats remain active for the entire animal lifespan.^22,23 Transplantation of CB cell aggregates has been shown to induce a neurotrophic mediated recovery in animal models of PD^{22,23,24,25,26,27} and stroke.^28,29We conducted a phase I–II video blinded clinical study to assess the long term safety, clinical and neurochemical effects of intrastriatal CB autotransplantation in patients with advanced PD. In a pilot report of our first six patients, we showed this procedure to be feasible.³⁰ Here we report the clinical outcomes and prognostic factors in the whole study (n = 13), as well as ¹⁸F‐dopa positron emission tomography (PET) outcomes in a subgroup of patients (n = 7).     

Differences in circadian variation of cerebral infarction, intracerebral haemorrhage and subarachnoid haemorrhage by situation at onset

Background

The precise time of stroke onset during sleep is difficult to specify, but this has a considerable influence on circadian variations of stroke onset.

Aim

To investigate circadian variations in situations at stroke onset—that is, in the waking state or during sleep—and their differences among subtypes.

Methods

12 957 cases of first‐ever stroke onset diagnosed from the Iwate Stroke Registry between 1991 and 1996 by computed tomography or magnetic resonance imaging were analysed. Circadian variations were compared using onset number in 2‐h periods with relative risk for the expected number of the average of 12 2‐h intervals in the waking state or during sleep in cerebral infarction (CIF), intracerebral haemorrhage (ICH) and subarachnoid haemorrhage (SAH).

Results

ICH and SAH showed bimodal circadian variations and CIF had a single peak in all situations at onset, whereas all three subtypes showed bimodal circadian variations of stroke onset in the waking state only. These variations were different in that CIF showed a bimodal pattern with a higher peak in the morning and a lower peak in the afternoon, whereas ICH and SAH had the same bimodal pattern with lower and higher peaks in the morning and afternoon, respectively.

Conclusions

Sleep or status in sleep tends to promote ischaemic stroke and suppress haemorrhagic stroke. Some triggers or factors that promote ischaemic stroke and prevent haemorrhagic stroke in the morning cause different variations in the waking state between ischaemic and haemorrhagic stroke.Stroke occurrence shows chronobiological variations,¹ such as circannual variations, circaseptan variations and circadian variations. Various patterns have been reported but no conclusions have yet been reached on circadian variations. The circadian variations of stroke onset may differ according to subtype or reporter, and are classified as cerebral infarction (CIF) with a single peak^2,3,4,5,6 or double peaks,^7,8 subarachnoid haemorrhage (SAH) with a single peak⁹ or double peaks,^{6,10,11,12,13,14} and intracerebral haemorrhage (ICH) with double peaks.^6,10,12 Most previous studies have not treated the three major subtypes simultaneously. Only three reports^6,7,8 discussed all the three subtypes, but the number of cases of ICH, especially of SAH, was too small for investigation of circadian variation. This may have led to differences in the conceived patterns of circadian variation. Large numbers of cases in population‐based samples are required to investigate and compare the circadian variations of stroke onset among subtypes. For investigation of the triggers and risk factors of stroke onset, it is necessary to determine the circadian variations of stroke onset with precise times. The precise time of stroke onset during sleep is difficult to specify, but this has a considerable influence on circadian variations of stroke onset.We investigated circadian variation in stroke onset by situations at onset in CIF, ICH and SAH in a Japanese population, by using stroke registry data. We also investigated the differences in circadian variations, triggers and risk factors among subtypes.     

Functional status and use of healthcare facilities in long-term survivors of transient ischaemic attack or minor ischaemic stroke

Background

Stroke may have a major effect on survivors and on the healthcare system.

Aims

To study the functional status and use of healthcare facilities in long‐term survivors of a transient ischaemic attack (TIA) or minor ischaemic stroke (MIS) and evaluate associations with baseline and follow‐up characteristics.

Methods

Follow‐up of patients who had participated in the Dutch TIA Trial or the European Atrial Fibrillation Trial was extended to a mean period of 15.6 years. Patients were interviewed through a postal questionnaire (n = 468) and a sample of this group was also interviewed at home (n = 198). Demographic data, information on comorbidity, functional status (Barthel Index, Frenchay Activities Index and modified Rankin Scale) and use of healthcare facilities were recorded.

Results

About one third of the survivors interviewed at home experienced any residual disability and 26% were moderately to severely handicapped. Factors associated with poor functional status were advanced age and the presence of any infarct on a baseline computed tomography scan, the recurrence of a new major stroke or the presence of comorbidity of locomotion. One third of survivors used any kind of professional care, which was predominantly related to the functional status at follow‐up.

Conclusions

Recurrent stroke and the presence of comorbidity of locomotion are important determinants of long‐term disability of survivors of a TIA or an MIS, which, in turn, is strongly associated with the long‐term use of professional care. The need for measuring comorbidity with regard to functional status is recommended in research on stroke outcome.As mortality due to stroke decreases, the number of stroke survivors increases, and this is likely to have a growing effect on the healthcare system. Patients with no or minor sequelae from a transient ischaemic attack (TIA) or minor ischaemic stroke (MIS) are usually discharged home and are less often studied than those with a major stroke. From a previous study, however, we learnt that these patients with a “minor stroke” are exposed to a continuous high risk of recurrent major events (stroke, myocardial infarction or vascular death) even in the long term.¹ Information on functional status long after a TIA or an MIS has occurred is scarce. The few studies that followed up patients for more than 10 years describe survival and, in some cases, the risk of new events.^1,2,3,4 Assessing activities and participation of these patients is important in determining quality of life⁵ and use of healthcare facilities.⁶Previous studies on long‐term functioning of patients with stroke applied only the Barthel Index and the (modified) Rankin Scale (mRS),^7,8 or no standardised instruments at all.^9,10,11,12 The Barthel Index and mRS measure important dimensions of stroke‐related constraints of activity, but both have definite limitations. The Barthel Index measures only the basic activities of daily living in the home and has a profound ceiling effect, especially in people with mild or moderate stroke, whereas the mRS predominantly reflects physical dependence and does not explicitly assess psychosocial functioning.To clarify the factors that improve or deteriorate functional capacity, it is important to differentiate the effects of stroke from those of ageing.¹⁰ It is well known that patients with stroke, who are often elderly people, experience much comorbidity,¹³ but to what extent that is related to functioning in patients with stroke has not been well explored.Our main objectives were (1) to describe the functional status and use of healthcare facilities of long‐term (>10‐year) survivors of a TIA or an MIS and (2) to identify associations with baseline and follow‐up characteristics (including comorbidity).     

Long term follow-up of the first 70 operated adults in the Goteborg Epilepsy Surgery Series with respect to seizures, psychosocial outcome and use of antiepileptic drugs

Objective

To compare long term (10 years) seizure outcome, psychosocial outcome and use of antiepileptic drugs (AED) with the 2 year follow‐up in adults after resective epilepsy surgery.

Methods

All adults (n = 70) who underwent resective epilepsy surgery from 1987 to 1995 in the Göteborg Epilepsy Surgery Series were included. Fifty‐four had undergone temporal lobe resections and 16 extratemporal resections (12 frontal). A cross‐sectional follow‐up in the form of a semistructured interview was performed in late 2003.

Results

Mean follow‐up was 12.4 years (range 8.6–16.2). Of the 70 patients (51% males), five (7%) were dead (three as a result of non‐epilepsy related causes). Of the 65 patients interviewed, 38 (58%) were seizure‐free at the long term follow‐up: 65% of the patients with temporal lobe resections and 36% of the patients with extratemporal resections. Of the 35 patients who were seizure‐free at the 2 year follow‐up, 3 (9%) had seizures at the long term follow‐up. Of the 30 patients who had seizures at the 2 year follow‐up, 6 (20%) were seizure‐free at the long term follow‐up. Of all 65 patients, 45 (69%) had the same seizure status as the 2 year follow‐up. Sixteen (25%) had an improved seizure status and 4 (6%) had a worsened status. Of the seizure‐free patients, 11 (29%) had ceased taking AED, 28 (74%) were working and 25 (66%) had a driving license.

Conclusions

Adult patients who are seizure‐free 2 years after resective epilepsy surgery are most likely to still be seizure‐free 10 years later. Most are working and have obtained a driving license.Epilepsy surgery is a well established treatment for medically intractable epilepsy.^1,2 The ultimate aims of epilepsy surgery are to reduce the frequency and intensity of seizures and thereby to improve quality of life. Most studies of the effectiveness of epilepsy surgery have focused on seizure outcome of anterior temporal lobe resections 1–2 years after surgery. One randomised controlled study² and multiple clinical series have shown that approximately two thirds of patients become free of seizures with impairment of awareness. It has also been shown that quality of life scores improve after temporal lobe resection, especially in seizure‐free patients who also have a trend towards better social function (see Engel et al,³ Jones et al⁴ and Malmgren et al⁵).Concern has been raised about the long term seizure outcome of epilepsy surgery. Several studies have described late seizure recurrences after initial success, sometimes but not always related to discontinuation of antiepileptic drugs (AED).^6,7,8 On the other hand, it has been suggested that seizure outcome at 2 years after surgery in patients subjected to temporal lobectomy predicts the long term outcome.^6,9,10,11,12However, there are only a few studies concerning long term outcome beyond 5 years (ie, presenting data with 10 years of follow‐up).¹³ Most have only included patients subjected to temporal lobectomy and very little is known about the long term seizure outcome for patients who have undergone other resection types.Patients'' aims for epilepsy surgery are, however, not limited to seizure relief. The five commonest aims for patients during presurgical evaluation cited in the study by Taylor et al¹⁴ were: desire for work, driving of motor vehicles, independence, socialising and freedom from drugs (see also Gilliam et al¹⁵). Psychosocial outcomes (eg, employment status, educational status and driving a vehicle) are seldom reported in long term studies. Of the few studies reporting psychosocial aspects, the average follow‐up time is no more than 5 years and most of them have only included patients subjected to temporal lobectomy^4,16,17,18 (see Guldvog et al¹⁹).The Göteborg Epilepsy Surgery Series is a multidisciplinary prospective follow‐up of all patients subjected to epilepsy surgery in Göteborg since its start in 1987. We have previously described the 2 year outcome regarding alterations in seizure frequency,²⁰ general cognitive function, and memory²¹ and psychiatric morbidity²² in the first 70 consecutive operated adults. The aim of this study was to compare the long term (>10 years) outcome concerning seizure status, psychosocial issues and use of AED with the 2 year follow‐up in these well characterised 70 adults.     

Botulinum toxin for writer's cramp: a randomised, placebo-controlled trial and 1-year follow-up

Background

Botulinum toxin type A (BoNT‐A) has become the treatment of choice for most types of focal dystonia.

Objective

To investigate the efficacy of BoNT‐A injections in patients with writer''s cramp in a double‐blind, randomised, placebo‐controlled trial and to evaluate the follow‐up results.

Methods

Forty participants were randomised to treatment with either BoNT‐A or placebo injections in two sessions. Trial duration was 12 weeks. The primary outcome measure was the patients'' choice to continue with the treatment, despite its possible disadvantages. Secondary outcome measures included several clinical rating scales on the levels of impairment and disability. Assessments were made at baseline and 2 months (secondary outcomes) and 3 months (primary outcome). Duration of follow‐up was 1 year.

Results

39 patients completed the trial. Fourteen of 20 patients (70%) receiving BoNT‐A reported a beneficial effect and chose to continue treatment, versus 6 of 19 patients (31.6%) in the placebo group (p = 0.03). The changes on most of the clinical rating scales were significantly in favour of BoNT‐A. Side effects reported were hand weakness, which was mostly mild and always transient, and pain at the injection site. After 1 year, 20 of 39 patients were still under treatment with a positive effect.

Conclusion

Treatment with BoNT‐A injections led to a significantly greater improvement compared with placebo, according to patients'' opinion and clinical assessment scales. Weakness in the hand is an important side effect of BoNT‐A injections, but despite this disadvantage, most patients preferred to continue treatment. About 50% of our patients were still under treatment after 1 year.Writer''s cramp is a task‐specific, focal hand dystonia. It is characterised by involuntary, repetitive or sustained contractions of finger, hand or arm muscles that occur during writing and produce abnormal postures or movements that interfere with normal handwriting.^1,2,3,4 Two categories are recognised: simple writer''s cramp, in which dystonic posturing of the hand and arm occurs only during writing, and complex or dystonic writer''s cramp, in which the condition manifests also during other manual tasks and sometimes with spontaneous abnormal posturing.^1,2,5 In most patients, no specific cause can be identified. Although the prevalence is relatively low, varying from 3 to 7/100 000,^6,7,8 writer''s cramp may be responsible for considerable morbidity in terms of working impairment, pain, embarrassment, low self‐esteem and poor social interaction.Therapeutic recommendations have included physical treatment, postural and writing re‐education exercises, relaxation techniques, hypnosis, biofeedback, use of special writing devices, acupuncture and transcranial magnetic stimulation, but most of the patients do not obtain satisfactory and sustained benefit.^9,10,11,12 Some patients learn to write with their non‐dominant hand, but there is a 25% chance that this hand will become afflicted with the same problem.¹³ Drug treatment has been disappointing so far.^3,9,14 The use of splints or braces and constraint‐induced movement treatment may occasionally be helpful, but it is not clear if they produce sustained relief.^15,16,17 There is presently only limited experience with stereotactic neurosurgical procedures for focal hand dystonia.^18,19 The treatment of dystonic syndromes such as blepharospasm and cervical dystonia has been much improved by the introduction of botulinum toxin as a therapeutic agent.^20,21 When botulinum toxin is injected into muscles, the toxin produces local chemodenervation by interfering with the release of acetylcholine from the presynaptic nerve terminal.⁴ However, there are also several drawbacks. Firstly, the effects of botulinum toxin type A (BoNT‐A) are not permanent, lasting for only approximately 3 months; thus, regular injections are required. Secondly, inconvenient muscle weakness interfering with other non‐writing activities may occur.²² Regarding the treatment of writer''s cramp, three randomised, double‐blind, placebo‐controlled studies have been undertaken, however, with small numbers of patients, different methods and inconclusive results.^23,24,25We performed a randomised, double blind, placebo‐controlled trial in 40 patients with writer''s cramp, to assess whether the benefits of BoNT‐A treatment outweigh its disadvantages. The trial duration was 12 weeks and thereafter patients were followed for 1 year.     

Diffusion anisotropy of the cervical cord is strictly associated with disability in amyotrophic lateral sclerosis

Background

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with severe cervical cord damage due to degeneration of the corticospinal tracts and loss of lower motor neurones. Diffusion tensor magnetic resonance imaging (DT MRI) allows the measurement of quantities reflecting the size (such as mean diffusivity) and orientation (such as fractional anisotropy) of water‐filled spaces in biological tissues.

Methods

Mean diffusivity and fractional anisotropy histograms from the cervical cord of patients with ALS were obtained to: (1) quantify the extent of tissue damage in this critical central nervous system region; and (2) investigate the magnitude of the correlation of cervical cord DT MRI metrics with patients'' disability and tissue damage along the brain portion of the corticospinal tracts. Cervical cord and brain DT MRI scans were obtained from 28 patients with ALS and 20 age‐matched and sex‐matched controls. Cord mean diffusivity and fractional anisotropy histograms were produced and the cord cross‐sectional area was measured. Average mean diffusivity and fractional anisotropy along the brain portion of the corticospinal tracts were also measured.

Results

Compared with controls, patients with ALS had significantly lower mean fractional anisotropy (p = 0.002) and cord cross‐sectional area (p<0.001). Mean diffusivity histogram‐derived metrics did not differ between the two groups. A strong correlation was found between mean cord fractional anisotropy and the ALS Functional Rating Score (r = 0.74, p<0.001). Mean cord and brain fractional anisotropy values correlated moderately (r = 0.37, p = 0.05).

Conclusions

Cervical cord DT MRI in patients with ALS allows the extent of cord damage to be graded. The conventional and DT MRI changes found are compatible with the presence of neuroaxonal loss and reactive gliosis, with a heterogeneous distribution of the pathological process between the brain and the cord. The correlation found between cord fractional anisotropy and disability suggests that DT MRI may be a useful adjunctive tool to monitor the evolution of ALS.Amyotrophic lateral sclerosis (ALS) is the most common adult‐onset motor neurone disease, characterised by a progressive and simultaneous degeneration of upper and lower motor neurones.^1,2 In its typical form, the disease begins either in one limb or with a combination of bulbar and corticobulbar symptoms, and continues with progressive weakness of the bulbar, limb, thoracic and abdominal musculature.^1,2 By using a variety of conventional magnetic resonance imaging (MRI) sequences, several studies^{3,4,5,6,7,8,9,10,11,12,13,14,15} have shown changes in signal intensity along the brain portion of the corticospinal tracts, particularly in the posterior limb of the internal capsule and cerebral peduncles, varying between 25% and 80%. Reduced magnetisation transfer ratios in the internal capsule^8,11 and N‐acetylaspartate levels in the motor cortex^13,16,17 of patients with ALS have also been observed. However, none of these studies has reported a correlation between such magnetic resonance abnormalities and the degree of disability.^{8,11,13,16,17}Diffusion‐tensor magnetic resonance imaging (DT MRI) enables the random diffusional motion of water molecules to be measured and thus provides quantitative indices of the structural and orientational features of the central nervous system (CNS).¹⁸ DT MRI has been used to assess quantitatively the tissue damage of the brain portion of the corticospinal tracts in ALS,^{12,19,20,21,22,23} and all studies have shown increased mean diffusivity (indicating a loss of structural barriers limiting the motion of water molecules) and decreased fractional anisotropy (indicating a loss of tissue organisation). However, brain DT MRI studies also resulted in heterogeneous clinicopathological correlations, as some authors found a moderate correlation between brain DT MRI metrics and the severity of disability,^12,21,23 but others did not.¹⁹ In the past few years, DT MRI has also been used successfully to grade the extent of cervical cord damage associated with demyelinating conditions.^24,25,26Considering that the cervical cord in ALS is one of the most affected portions of the CNS (owing to the combined presence of neuronal loss in the anterior horns of the grey matter and degeneration of the corticospinal tracts), we obtained mean diffusivity and fractional anisotropy histograms of the cervical cord from patients with ALS with the following aims: (1) to quantify the extent of tissue damage in this critical CNS region; and (2) to investigate the magnitude of the correlation of cervical cord DT MRI metrics with patients'' disability and tissue damage along the brain portion of the corticospinal tracts.     

Improvement of gait by chronic, high doses of methylphenidate in patients with advanced Parkinson's disease

Background

Therapeutic management of gait disorders in patients with advanced Parkinson''s disease (PD) can sometimes be disappointing, since dopaminergic drug treatments and subthalamic nucleus (STN) stimulation are more effective for limb‐related parkinsonian signs than for gait disorders. Gait disorders could also be partly related to norepinephrine system impairment, and the pharmacological modulation of both dopamine and norepinephrine pathways could potentially improve the symptomatology.

Aim

To assess the clinical value of chronic, high doses of methylphenidate (MPD) in patients with PD having gait disorders, despite their use of optimal dopaminergic doses and STN stimulation parameters.

Methods

Efficacy was blindly assessed on video for 17 patients in the absence of l‐dopa and again after acute administration of the drug, both before and after a 3‐month course of MPD, using a Stand–Walk–Sit (SWS) Test, the Tinetti Scale, the Unified Parkinson''s Disease Rating Scale (UPDRS) part III score and the Dyskinesia Rating Scale.

Results

An improvement was observed in the number of steps and time in the SWS Test, the number of freezing episodes, the Tinetti Scale score and the UPDRS part III score in the absence of l‐dopa after 3 months of taking MPD. The l‐dopa‐induced improvement in these various scores was also stronger after the 3‐month course of MPD than before. The Epworth Sleepiness Scale score fell dramatically in all patients. No significant induction of adverse effects was found.

Interpretation

Chronic, high doses of MPD improved gait and motor symptoms in the absence of l‐dopa and increased the intensity of response of these symptoms to l‐dopa in a population with advanced PD.The significant, long‐term benefits of dopaminergic treatment¹ and bilateral stimulation of the subthalamic nucleus (STN)² have been well documented for limb‐related syndromes in patients with advanced Parkinson''s disease (PD). However, after several years of disease progression (and regardless of the ongoing treatment), axial signs in general and gait disorders in particular (including reduced step length, freezing and postural instability) become more prominent and lead to falls and even institutionalisation. Therapeutic management of the condition is disappointing, since dopaminergic treatments and STN stimulation are more effective for other limb‐related parkinsonian signs than for gait disorders as such.^2,3 However, an interesting therapeutic approach could involve the combined modulation of l‐dopa bioavailability (to potentiate the partial dopa‐sensitivity of gait disorders) and the non‐dopaminergic system, particularly the norepinephrine system, which has been previously suspected to be involved in gait disorders.^4,5 This “norepinephrine hypothesis” could explain the positive results on freezing of gait observed in some open‐label studies on small populations of patients with advanced PD using the synthetic norepinephrine precursor l‐threo‐dihydroxyphenylserine^6,7 or tinazidine, an α‐2 adrenergic agonist.⁴ However, these results have never been confirmed—probably because l‐threo‐dihydroxyphenylserine is a weak precursor of norepinephrine and only slightly influences striatal, extracellular dopamine levels.⁸Methylphenidate (MPD, Ritalin) is an amphetamine‐like psychomotor stimulant, which influences both the dopaminergic and norepinephrine systems. Indeed, MPD inhibits the dopamine transporter (DAT), particularly in the striatum.⁹ The DAT is one of the most important determinants of extracellular dopamine concentrations, as demonstrated in DAT knock‐out mice.¹⁰ Through inhibition of the DAT, MPD blocks presynaptic dopamine re‐uptake.¹¹ To a lesser extent, MPD also influences the norepinephrine system through presynaptic norepinephrine transporter inhibition.^11,12,13 Hence, by targeting the DAT and the norepinephrine transporter, MPD might disperse dopamine widely and consign dopamine storage and release to regulation by norepinephrine neurones as well as by dopaminergic neurones.¹³ Effects of MPD may be mediated by restoration of the dopaminergic/norepinephrine neurotransmitter balance.^13,14A pilot study on five patients with PD with motor fluctuations showed that low doses of MPD (0.2 mg/kg) combined with l‐dopa led to greater peak right‐hand tapping speed.¹⁵ The effects of doses of up to 0.4 mg/kg of MPD were also assessed in a double‐blind, placebo‐controlled procedure; MPD seemed to lack an effect when given alone but did potentiate the effects of l‐dopa on walking speeds and dyskinesia.⁹ Recently, positive effects on gait speed, fall risk and attention were demonstrated in an open‐label study using an acute, low dose (20 mg) of MPD.¹⁶ It therefore seemed interesting to determine whether higher doses and longer‐term treatment could improve the MPD‐induced partial response for gait disorders. Indeed, up to 70% of the dopamine nerve terminals (and consequently 70% of DAT activity) are lost in severe PD.¹⁷ An oral dose of 0.25 mg/kg MPD may only occupy half of the striatal DATs in humans,¹² whereas oral doses of 0.5–0.8 mg/kg allow a higher occupancy and lead to high extracellular dopamine concentrations.^13,18,19 Moreover, high doses of MPD could also increase the norepinephrine properties of MPD.Our research hypothesis was the improvement of gait by MPD. The aim of this study was to assess the clinical value of a high‐dose, 3‐month course of MPD (1 mg/kg) in STN‐stimulated patients with advanced PD (free of motor fluctuations) having gait disorders despite their use of optimal dopaminergic doses and STN stimulation parameters. The primary outcome measure was the completion time in the Stand–Walk–Sit (SWS) Test.²⁰ Efficacy was blindly assessed on video in the absence of l‐dopa and then again after acute administration of the latter drug, to assess the potential norepinephrine and/or dopaminergic effects of MPD on gait speed and step length.     

Sleep-disordered breathing after stroke: a randomised controlled trial of continuous positive airway pressure

Background

Sleep‐disordered breathing (SDB) is common after stroke, but it is unclear whether it should be treated.

Objective

To conduct a randomised controlled trial of continuous positive airway pressure (CPAP) after stroke.

Methods

Patients with stroke with ⩾30 apnoeas and hypopnoeas per hour ((A+H)/h) with predominant obstructive sleep apnoea or hypopnoea were randomised to either CPAP treatment or conservative treatment for 8 weeks. Outcomes were measured blind to treatment allocation at 8 weeks and 6 months after the stroke. The primary outcome was physical function on the Nottingham Extended Activities of Daily Living Scale.

Results

Of 658 patients with stroke screened, only 71 (10.7%) were eligible and consented to a sleep study 14–19 days after stroke. 66 patients completed the sleep study (21 women; mean age 72 years), 33 (50%) had ⩾30 (A+H)/h that were predominantly obstructive. 15 were randomised to CPAP treatment and 15 to conventional treatment. Despite intensive efforts, objective use of CPAP was poor, averaging 1.4 h a night. CPAP treatment resulted in no significant improvements (p>0.1) in the primary outcome or in neurological function or sleepiness, and in poorer health status on some measures.

Conclusions

This trial showed no benefit from CPAP treatment, the relevance of the observed detrimental effects is questionable. Even in our highly selected patients with stroke, use of CPAP was poor. At present, CPAP treatment should be advocated for patients with stroke only if they have symptoms of SDB.In the past decade, a link between stroke and sleep‐disordered breathing (SDB) has been recognised. Longitudinal studies have shown that people with SDB have a greater risk of stroke,¹ although this relationship is partly explained by the association between SDB, obesity and hypertension. SDB is also common after stroke^2,3,4,5 and has been associated with poor outcomes.^6,7,8,9,10 Continuous positive airway pressure (CPAP) treatment improves daytime function,¹¹ blood pressure¹² and cerebral blood flow¹³ in stroke‐free people with SDB and may reduce their risk of cardiovascular event.¹⁴ The question then arises whether CPAP treatment in patients with stroke with SDB might improve outcomes. Martinez‐Garcia et al¹⁵ showed that patients with SDB after stroke who complied with CPAP use had fewer vascular events during follow‐up than those who did not. To reliably determine whether CPAP use improves outcome, however, we need to conduct randomised controlled trials (RCTs). There have been few trials of CPAP use for SDB in patients with stroke, and only one entailed random allocation to CPAP use or control.¹⁶We conducted an RCT in patients with stroke with SDB to examine whether CPAP use is beneficial. Specifically, we hypothesised that nasal CPAP use might improve sleepiness, fatigue, cognitive function and mood in patients with stroke with SDB, we also postulated that nasal CPAP might make this group more compliant with rehabilitation and stabilise circadian blood pressure in the recovery phase of stroke; thus CPAP use would result in better functional outcome.     

Trunk performance after stroke: an eye catching predictor of functional outcome

Background and aim

Trunk performance is an important predictor of functional outcome after stroke. However, the percentage of explained variance varies considerably between studies. This may be explained by the stroke population examined, the different scales used to assess trunk performance and the time points used to measure outcome. The aim of this multicentre study was to examine the predictive validity of the Trunk Impairment Scale (TIS) and its subscales when predicting the Barthel Index score at 6 months after stroke.

Methods

A total of 102 subjects were recruited in three European rehabilitation centres. Participants were assessed on admission (median time since stroke onset 20 days) and 6 months after stroke. Correlation analysis and forward stepwise multiple regression analysis were used to model outcome.

Results

The best predictors of the Barthel Index scores at 6 months after stroke were total TIS score (partial R² = 0.52, p<.0001) and static sitting balance subscale score (partial R² = 0.50, p<.0001) on admission. The TIS score on admission and its static sitting balance subscale were stronger predictors of the Barthel Index score at 6 months than the Barthel Index score itself on admission.

Conclusions

This study emphasises the importance of trunk performance, especially static sitting balance, when predicting functional outcome after stroke. The TIS is recommended as a prediction instrument in the rehabilitation setting when considering the prognosis of stroke patients. Future studies should address the evolution of trunk performance over time and the evaluation of treatment interventions to improve trunk performance.Although the age specific incidence of major stroke has fallen over the past few years,¹ it is still the main cause of long term disability in adults, with a growing number of survivors being dependent for activities of daily living (ADL).^2,3 Frequently identified variables predicting ADL after stroke are age and initial severity of motor and functional deficits.⁴ Trunk performance has also been identified as an important independent predictor of ADL after stroke.^5,6,7,8,9 However, based on multiple regression analyses, the reported variance of functional outcome after stroke explained by trunk performance ranges from 9% to 71%.^5,6,7,8,9 Differences in reported variance could be explained by the stroke population included, the various scales used to measure trunk performance and the time points used to measure outcome.Previous studies evaluating the predictive validity of trunk performance after stroke were performed in a single rehabilitation setting, warranting caution when generalising results.^5,6,7,8,9,10 Clinical tools used to assess trunk performance are the Trunk Control Test,^5,6,10 trunk control items of the Postural Assessment Scale for Stroke patients^7,8 and trunk assessment of Fujiwara et al.⁹ A limitation of the first two tests is that they both have a ceiling effect, which makes their use less suitable in long term outcome studies.^5,11,12,13 Furthermore, the trunk control items of the Trunk Control Test and Postural Assessment Scale for Stroke patients are largely comparable with the items of the trunk measure of Fujiwara et al.⁹ All previously mentioned clinical tools include items in the supine position which involve rolling as well as only basic balance movements in sitting. Finally, with the exception of the trunk control items of the Postural Assessment Scale for Stroke patients,⁸ no study has evaluated the prognostic value of trunk performance when predicting functional outcome at 6 months after stroke.The Trunk Impairment Scale (TIS) for patients after stroke was designed to measure ADL related selective trunk movements rather than participation of the trunk in gross transfer movements.¹⁴ The TIS assesses static and dynamic sitting balance and trunk coordination. Reliability, validity, measurement error, internal consistency and discriminant ability of the TIS have been reported elsewhere.^14,15 The TIS has no ceiling effect in subacute and chronic stroke patients and already appeared to be strongly related to measures of gait, balance and functional ability in a cross sectional study.¹² To the best of our knowledge, the predictive value of the TIS and its subscales has not been evaluated. Including age and other measures of motor and functional performance could provide a useful combination of variables predicting outcome after stroke. The Barthel Index score is a widely accepted measure in stroke rehabilitation research and assesses functional milestones in stroke recovery. Predicting Barthel Index scores at 6 months after stroke based on measurements taken on admission to a rehabilitation centre would further establish the importance of trunk performance when predicting long term outcome after stroke. Experts in the field of neurological rehabilitation have addressed the trunk as the central key point of the body.¹⁶ Proximal stability of the trunk is a prerequisite for distal head and limb movement and therefore expected to be related to functional ADL.In summary, there is still a lack of clarity regarding the importance of trunk performance in functional outcome after stroke. Scales which have been used in previous studies have important statistical limitations and are likely to be a comprehensive measure of motor performance of the trunk. Therefore, the aim of this multicentre study was to examine the predictive validity of the TIS and its subcomponents, together with other known predictors, in predicting functional outcome measured as a Barthel Index score at 6 months after stroke.     

Cognitive outcome 5 years after bilateral chronic stimulation of subthalamic nucleus in patients with Parkinson's disease

Aim

To assess the long‐term cognitive and behavioural outcome after bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) in patients affected by Parkinson''s disease, with a 5‐year follow‐up after surgery.

Methods

11 patients with Parkinson''s disease treated by bilateral DBS of STN underwent cognitive and behavioural assessments before implantation, and 1 and 5 years after surgery. Postoperative cognitive assessments were carried out with stimulators turned on.

Results

A year after surgery, there was a marginally significant decline on a letter verbal fluency task (p = 0.045) and a significant improvement on Mini‐Mental State Examination (p = 0.009). 5 years after surgery, a significant decline was observed on a letter verbal fluency task (p = 0.007) and an abstract reasoning task (p = 0.009), namely Raven''s Progressive Matrices 1947. No significant postoperative change was observed on other cognitive variables. No patient developed dementia 5 years after surgery. A few days after the implantation, two patients developed transient manic symptoms with hypersexuality and one patient developed persistent apathy.

Conclusion

The decline of verbal fluency observed 5 years after implantation for DBS in STN did not have a clinically meaningful effect on daily living activities in our patients with Parkinson''s disease. As no patient developed global cognitive deterioration in our sample, these findings suggest that DBS of STN is associated with a low cognitive and behavioural morbidity over a 5‐year follow‐up, when selection criteria for neurosurgery are strict.Chronic bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective neurosurgical procedure for treatment of motor symptoms in patients with advanced Parkinson''s disease, who cannot be satisfactorily treated with pharmacological treatments. The safety of this procedure has been investigated by several studies, which have assessed the effects of STN DBS on cognition and behaviour.^1,2,3 Some investigations have also attempted to distinguish between the cognitive effects of surgical intervention and those of DBS of STN in itself.^4,5,6,7All neuropsychological investigations in patients treated by STN DBS showed a postoperative decline of verbal fluency, whereas less consistent effects have been reported on other cognitive tasks in different studies. A postoperative decline of episodic verbal memory, which was detectable 3 months after surgery, has been reported in some investigations.^6,8Different effects of STN DBS on various frontal cognitive functions have been described. STN stimulation may impair response‐inhibition performance on the interference task of the Stroop test, as compared with the off‐stimulation condition.^5,7,9 A positron emission tomography study showed that such impaired performance on the Stroop test in the on‐stimulation condition is associated with decreased activation in both the right anterior cingulate cortex and the right ventral striatum.⁹ Conversely, short‐term STN stimulation may improve performance on cognitive flexibility tasks, including random number generation⁷ and the Modified Wisconsin Card Sorting Test (MWCST).⁵Various behavioural effects have been described in patients with Parkinson''s disease treated by STN DBS. Some studies reported cases of depression¹⁰ or increased apathy,¹¹ whereas cases of mania were described in other studies^12,13,14 and an improvement of depression¹ or apathy¹⁵ was also found.The long‐term cognitive and behavioural effects of bilateral STN DBS were investigated in 70 patients with Parkinson''s disease followed up for 3 years.¹¹ In this study, a decline of verbal fluency, an improvement of depression and an increased apathy were observed 3 years after surgery. Some patients showed behavioural changes (aggressive behaviour, hypomania, depression and psychosis), which were mostly transient. Recently, the long‐term outcome of bilateral DBS of STN was investigated in a multicentre study conducted in 49 patients with Parkinson''s disease followed up for 3 or 4 years.¹⁶ This study showed that stimulation of the STN induced a significant improvement in Parkinsonian motor symptoms and activities of daily living 3–4 years after surgery. Among the adverse events, the authors reported memory decline or psychiatric disturbances (including hallucinations, delirium, depression, apathy and anxiety), which occurred in about 30% of the patients.In two recent investigations, the long‐term outcome of bilateral DBS of STN was investigated in patients with a 5‐year follow‐up.^17,18 In one study conducted on 49 patients with Parkinson''s disease,¹⁷ cognitive performance was assessed by means of the Mattis Dementia Rating Scale (MDRS)¹⁹ and a frontal‐lobe score.⁴ Five years after surgery, there was a marked improvement of both motor function, while off drugs, and activities of daily living, a statistical trend towards a decline on the MDRS (reflecting the appearance of progressive dementia in three patients between the third and the fifth postoperative years) and a significant decline in the average frontal‐lobe score. Another study carried out on 37 patients with Parkinson''s disease¹⁸ also assessed cognitive performance by means of MDRS¹⁹ and a frontal score.²⁰ Five years after the implantation, there was an improvement in Parkinsonian motor symptoms and activities of daily living and a reduction of levodopa‐related motor complications and levodopa daily doses. However, a significant decline in cognitive performance was detected on the MDRS and the frontal score.To our knowledge, no extensive neuropsychological data have been reported so far in patients with a follow‐up >3 years. The aim of the present study was to assess the long‐term cognitive and behavioural outcome after bilateral DBS of the STN in a series of patients followed up for 5 years after surgery.     

Co-occurrence of affective and schizophrenia spectrum disorders with PINK1 mutations

Objective

To investigate a possible association of mutations in the PTEN‐induced putative kinase 1 (PINK1) gene with psychiatric disorders in a large family with monogenic parkinsonism.

Method

20 members of a family (4 homozygous, 11 heterozygous and 5 non‐mutation carriers) were investigated for the presence of psychiatric disorders using the structured clinical interview for Diagnostic and Statistical Manual of Mental Disorders, 4^th edition (DSM‐IV); information on three additional heterozygous mutation carriers was obtained according to the family history research diagnostic criteria.

Results

We found predominantly affective and schizophrenia spectrum disorders in 11 (61%) of the 18 mutation carriers and in 1 (20%) of the 5 mutation‐negative cases.

Conclusions

First, affective and psychotic symptoms may be part of the phenotypic spectrum or even the sole manifestation of PINK1 mutations. Second, patients with familial movement disorders associated with psychiatric conditions may serve as a valuable study population to explore (genetic) causes of neuropsychiatric disease.In patients with Parkinson''s disease (PD), a wide range of psychiatric disorders has been described including depression (20–50%),¹ psychosis (15–40%),^2,3 anxiety disorder (20–40%) and cognitive impairment (20%).² Psychiatric disorders may be the first or even the only manifestation in carriers of Parkin gene mutations, the most‐frequent known cause of early‐onset parkinsonism (EOP).⁴ Likewise, psychiatric problems have been reported in patients and their motor‐asymptomatic relatives with mutations in the recently detected PTEN‐induced kinase 1 (PINK1) gene, the second‐commonest cause of EOP.^5,6,7,8,9Two homozygous mutations in the PINK1 gene were initially described in three consanguineous families with EOP.⁶ The frequency of PINK1 mutations ranges from 1% to 8% in patients with PD of different ethnicities who are often selected for young age of onset and for family history (for review see Klein and Schlossmacher¹⁰). Most of the currently described mutations are localised near or within the functional serine/threonine kinase domain of PINK1 and are expected to result in a loss‐of‐function effect in vivo. Wild‐type PINK1 functions as a protein kinase that is mainly located within the mitochondria.Although PINK1‐associated parkinsonism is generally considered an autosomal recessive condition, a growing body of evidence has been accumulating that supports the notion of a single heterozygous mutation conferring disease susceptibility in at least a subset of patients.^6,8,9,10,11Currently, no studies have systematically assessed psychiatric symptoms in monogenic EOP. To investigate this possible association, we evaluated a large family with EOP with PINK1 mutations for the presence of psychiatric disorders.     

Intake of polyunsaturated fatty acids and vitamin E reduces the risk of developing amyotrophic lateral sclerosis

Background

To assess whether the premorbid dietary intake of fatty acids, cholesterol, glutamate or antioxidants was associated with the risk of developing amyotrophic lateral sclerosis (ALS).

Methods

Patients referred to our clinic during 2001–2002, who had definite, probable or possible ALS according to El Escorial criteria, without a familial history of ALS, were asked to participate in a case–control study (132 patients and 220 healthy controls). A food‐frequency questionnaire was used to assess dietary intake for the nutrients of interest. Multivariate logistic regression analysis was performed with adjustment for confounding factors (sex, age, level of education, energy intake, body mass index and smoking).

Results

A high intake of polyunsaturated fatty acid (PUFA) and vitamin E was significantly associated with a reduced risk of developing ALS (PUFA: odds ratio (OR) = 0.4, 95% confidence interval (CI) = 0.2 to 0.7, p = 0.001; vitamin E: OR = 0.4, 95% CI = 0.2 to 0.7, p = 0.001). PUFA and vitamin E appeared to act synergistically, because in a combined analysis the trend OR for vitamin E was further reduced from 0.67 to 0.37 (p = 0.02), and that for PUFA from 0.60 to 0.26 (p = 0.005), with a significant interaction term (p = 0.03). The intake of flavonols, lycopene, vitamin C, vitamin B₂, glutamate, calcium or phytoestrogens was not associated with the risk of developing ALS.

Conclusion

A high intake of PUFAs and vitamin E is associated with a 50–60% decreased risk of developing ALS, and these nutrients appear to act synergistically.Sporadic amyotrophic lateral sclerosis (ALS) probably develops through the combined effects of several modifying genes and environmental factors.¹ Despite several studies that investigated environmental exposures in relation to ALS, age, gender and smoking are the only established risk factors.² Several, not mutually exclusive, pathological processes may contribute to motor neurone death in ALS in a so‐called convergence model,³ including oxidative stress, mitochondrial dysfunction, protein misfolding, axonal strangulation, apoptosis, inflammation, glutamate excitotoxicity and defects in neurotrophin biology. Nutrients are factors that could influence these processes and thereby the risk of developing ALS or its clinical expression.ALS was previously found to be positively associated with intake of glutamate,⁴ fat,⁴ fish⁵ and milk,^6,7 and inversely associated with intake of lycopene,⁸ dietary fibre,⁴ bread and pasta.⁹ Two other studies, however, failed to establish the relationship with milk.^10,11 Several of these studies included only small samples of patients (<25),^5,6,9 or investigated nutrition as one of many environmental factors, thus increasing the likelihood of chance findings.^{5,6,7,9,10,11} Furthermore, most studies did not account for the possible influence of clinical onset preceding the diagnosis^{5,6,7,8,9,10,11} or adjust for possible confounders including total energy intake, body mass index (BMI), sex, smoking and education.^{5,6,7,9,10,11}One study found an association between intake of total fat and ALS, although this was not hypothesised beforehand.⁴ This finding is of interest considering the observed associations of intake of saturated and unsaturated fatty acids and cholesterol with other neurodegenerative diseases.¹² In this case–control study, therefore, we examined the possible association between premorbid dietary intake of fatty acids, cholesterol, glutamate, phytoestrogens, calcium and anti‐oxidants and the risk of developing ALS, adjusting for confounding factors.     

Moderate therapeutic efficacy of positron emission tomography-navigated repetitive transcranial magnetic stimulation for chronic tinnitus: a randomised, controlled pilot study

Background

Tinnitus has been shown to respond to modulations of cortical activity by high‐frequency and low‐frequency repetitive transcranial magnetic stimulation (rTMS).

Objective

To determine the tinnitus‐attenuating effects of a 2‐week daily regimen of rTMS, navigated to the maximum of tinnitus‐related increase in regional cerebral blood flow.

Methods

Six patients with chronic tinnitus were enrolled in this sham‐controlled crossover study and treated with 2×2 weeks of suprathreshold 1 Hz rTMS (30 min) applied to the region with maximal tinnitus‐related increase in regional cerebral blood flow delineated by functional imaging with [¹⁵O]H₂O positron emission tomography and a control area. Tinnitus‐related distress was assessed before and after each treatment and 2 weeks after the end of the 4‐week course of stimulation using a validated tinnitus questionnaire. Additional self‐assessment scores of tinnitus change, loudness and annoyance were obtained.

Results

In five of six patients, rTMS induced greater reduction of the tinnitus questionnaire score than sham stimulation. In two patients, all parameters measured (tinnitus change score, tinnitus loudness, tinnitus annoyance) showed unequivocal improvement. At the group level, the degree of response in the tinnitus questionnaire score was correlated with tinnitus‐associated activation of the anterior cingulate cortex. Two weeks after the final stimulation, tinnitus had returned to baseline in all patients but one.

Conclusion

Tinnitus can be attenuated by low‐frequency rTMS navigated to each person''s maximum tinnitus‐related cortical hyperactivity. The effects are only moderate; interindividual responsiveness varies and the attenuation seems to wear off within 2 weeks after the last stimulation session. Notably, tinnitus‐related anterior cingulate cortex activation seems to predict the response to rTMS treatment.Tinnitus is the phantom perception of sound or noise in the absence of an auditory stimulus and is a common symptom of disorders of the auditory system.¹ Its chronic form affects between 5% and 15% of the general population.² In 1–3% of the population, it causes severe impairment of the quality of life.^3,4 In most cases, tinnitus is associated with hearing loss that is often induced by noise exposure or is age related.¹ Nevertheless, currently no specific pharmacological treatments are available that provide a replicable, long‐term effect on tinnitus superior to placebo. The use of antidepressants, anticonvulsants and benzodiazepines may offer relief to some patients, but these treatments are largely considered palliative rather than curative. Hearing aids or electronic devices, producing a white noise that covers up the annoying perception, can be of help.^5,6 The combination of noise generators and counselling is called “tinnitus retraining therapy” and is often used in the management of chronic tinnitus.⁷ Although psychology‐based strategies effectively support the habituation and adaptation to tinnitus,⁸ the development of treatments is constrained by the limited pathophysiological knowledge.In recent years, it has become widely accepted that maladaptive changes of central information processing are critically involved in tinnitus perception and generation. Particularly, studies on positron emission tomography (PET) have provided evidence for an association between tinnitus and activation of areas involved in the perception and processing of sounds and speech.^9,10 In these studies, regional cerebral blood flow (rCBF) during tinnitus perception was contrasted with rCBF when tinnitus was transiently reduced by lidocaine injection,^9,11,12 oral facial movements¹³ or gaze.^10,14 These data indicate that tinnitus corresponds to abnormally high levels of regional cortical activity, which would increase and decrease with tinnitus loudness. This is in line with animal studies indicating a reduction of intracortical inhibition due to deafferentation.^15,16 Nevertheless, imaging studies alone cannot warrant the behavioural relevance of the associated activation.In the initial studies on transcranial magnetic stimulation (TMS), these areas were subjected to short trains of repetitive transcranial magnetic stimulation (rTMS), interfering with the neuronal activity in underlying areas.^17,18 Indeed, a short‐lasting decrease in tinnitus was observed, providing evidence for the critical role of cortical auditory and association areas in tinnitus perception. In contrast with short trains of high‐frequency rTMS, low‐frequency rTMS is suited to induce a longer‐lasting decrease in cortical activity in the stimulated area, as shown in the motor cortex.¹⁹ We have previously shown that this kind of stimulation can reduce tinnitus in a dose‐dependent manner for up to 30 min.¹² However, the clinical use of rTMS in tinnitus would require a persistent reduction in tinnitus loudness and its associated distress. A prior series of experiments has provided initial evidence for the efficacy and practicability of this treatment strategy. Repeated sessions of rTMS directed towards the auditory cortex were applied over 1 week in a placebo‐controlled, crossover design.^20,21 After real rTMS, Kleinjung et al²¹ reported a reduction of the mean tinnitus score by 7.5% (compared with baseline). Interestingly, after 6 months the reduction was even more pronounced (12%).The aim of this study was to test whether a 2‐week series of low‐frequency rTMS, guided to each patient''s maximum of tinnitus‐related cortical activity as assessed by [¹⁵O]H₂O PET, can induce a lasting suppression of tinnitus compared with the control stimulation of a non‐cortical site eliciting equivalent noise and sensations.     

A population-based study of depressive symptoms in multiple sclerosis in Stockholm county: association with functioning and sense of coherence

Objectives

To explore and analyse the prevalence of depressive symptoms in people with multiple sclerosis (PwMS), taking into account disease‐related and sociodemographic factors, and also to analyse the association between depressive symptoms and functioning (tested and self‐reported) and sense of coherence (SOC), respectively.

Methods

Home visits were made to a population‐based sample of 166 PwMS. Data were obtained from structured, face‐to‐face interviews using the Beck Depression Inventory (BDI), the Sickness Impact Profile (SIP) and the SOC scale. A range of tests were also carried out for analyses of different aspects of functioning such as cognitive function, walking capacity and manual dexterity, and structured interviews examined activities of daily living and frequency of social/lifestyle activities.

Results

19% (28/149) of the people were depressed (BDI ⩾13). Depressive symptoms were associated with worse self‐reported functioning on the SIP and with poor memory function, but not with any of the other tests of functioning. Depressive symptoms were associated with weak SOC, but not with any of the disease‐related or sociodemographic factors studied.

Conclusion

The prevalence of depressive symptoms in a population‐based sample of PwMS is high. Given the serious nature of depression and its association with worse self‐reported functioning and weak SOC, attention to, and treatment of, mental‐health problems and depression are strongly indicated in the clinical management of multiple sclerosis.Few population‐based studies of depression have been conducted on multiple sclerosis,^1,2,3,4,5 although many reports of depression and its correlation with numerous variables in clinical samples of people with multiple sclerosis (PwMS) have been published. The population‐based studies have all reported a high prevalence of depression^1,2,3,4,5 despite using different methods of data collection.Depressive symptoms are reported to be associated with decreases in functioning.⁶ In multiple sclerosis, it has been reported that depressed PwMS perform worse than the non‐depressed in evaluations of cognitive function,⁷ but there are conflicting reports.⁵ Depressive symptoms in PwMS are also associated with worse self‐reported functioning and health‐related quality of life scores,⁸ and depressed PwMS have been shown to be more likely to perceive their disability as being greater than their doctors'' perception.⁹ It is therefore important to consider different aspects of functioning when evaluating the presence of depression in PwMS.In the salutogenic model, proposed by Antonovsky,¹⁰ health is described as a continuum between ease and disease rather than as the binary opposite of disease; the model is thus appropriate for studying people afflicted with chronic disorders. Sense of coherence (SOC) refers to “general resistance resources”—capacities that facilitate coping with stressors and thereby improve health.¹⁰ The SOC describes the degree to which a person views the world as meaningful, comprehensible and manageable.¹⁰ SOC has been studied in several patient groups^11,12 including those with multiple sclerosis.^13,14 Weak SOC has been found to be associated with a higher prevalence of depression in studies of people with chronic diseases, such as rheumatoid arthritis,¹⁵ but this has not been explored in PwMS.Certain inconsistencies were observed in previously presented results on depression and its association with disease‐related and sociodemographic factors.^1,2,3,4,5 On account of differences in healthcare systems and policies, the results from population‐based studies of depression and functioning in other countries may not easily be extrapolated to Swedish conditions.We have conducted a cross‐sectional, population‐based study of PwMS in Stockholm county, to comprehensively describe and analyse their functioning and health (the Stockholm MS Study). In this report from the Stockholm MS Study, the aim was to explore the prevalence of depressive symptoms, taking into account disease‐related and sociodemographic factors, and also to analyse the association between depressive symptoms and functioning (tested and self‐reported) and SOC, respectively.     

Deep-brain stimulation: long-term analysis of complications caused by hardware and surgery--experiences from a single centre

Objective

To determine the surgery‐related and hardware‐related complications of deep‐brain stimulation (DBS) at a single centre.

Methods

262 consecutive patients (472 electrodes) operated for DBS in our department from February 1996 to March 2003 were retrospectively analysed to document acute adverse events (30 days postoperatively). The data of 180 of these patients were additionally revised to assess long‐term complications (352 electrodes, mean follow‐up 36.3 (SD 20.8) months).

Results

The frequency of minor intraoperative complications was 4.2% (11/262 patients). Transient (0.2%) or permanent (0.4%) neurological deficits, and in one case asymptomatic intracranial haemorrhage (0.2%), were registered as acute severe adverse events caused by surgery. Among minor acute complications were subcutaneous bleeding along the extension wire (1.2%) and haematoma at the pulse generator implantation site (1.2%). Skin infection caused by the implanted material was registered in 15 of 262 patients (5.7%). The infection rate during the first observation period was 1.5% (4/262 patients) and the late infection rate was 6.1% (11/180 patients). Partial or complete removal of the stimulation system was necessitated in 12 of 262 (4.6%) patients because of skin infection. During the long‐term observation period, hardware‐related problems were registered in 25 of 180 (13.9%) patients.

Conclusions

Stereotactic implantation of electrodes for DBS, if performed with multiplanar three‐dimensional imaging and advanced treatment planning software, is a safe procedure with no mortality and low morbidity. The main causes for the patients'' prolonged hospital stay and repeated surgery were wound infections and hardware‐related complications.During the past 10 years, worldwide, a growing number of patients with movement disorders have been treated with deep‐brain stimulation (DBS). The most frequent indications were Parkinson''s disease, tremor and dystonia. At present, new indications such as obsessive–compulsive disorders (OCD), Gilles‐de‐la‐Tourette syndrome, severe depression or epilepsy are under investigation.^1,2,3,4,5DBS is now considered to modulate the functional units of the CNS, serving as a permanent and lifelong treatment. Therefore, a realistic analysis of complications should not be restricted to acute hardware‐related and surgery‐related adverse events, but should also document problems occurring in the long term. In the literature, a reasonably high number of publications have already dealt with the adverse events associated with DBS. Only a few studies, however, analysed a larger number of patients (n>50),^{6,7,8,9,10,11} and some of this work considered only one possible source for complications, either surgery^6,10 or the implanted hardware.^8,9 In this article, we present a comprehensive analysis of 262 patients of a single centre (Department of Stereotaxy and Functional Neurosurgery, University of Cologne, Cologne, Germany).     

Symptomatic intracranial haemorrhage after intra-arterial thrombolysis in acute ischaemic stroke: assessment of 294 patients treated with urokinase

Background

The PROACT II trial showed that intra‐arterial thrombolysis (IAT) is effective for treatment of acute ischaemic stroke attributable to M1 and M2 segment occlusions. Incidence of symptomatic intracranial haemorrhage (sICH) was 10%.

Objective

: To evaluate the risk and predictors of sICH after IAT by using urokinase in a large number of patients presenting with the whole spectrum of cerebral vessel occlusions.

Methods

294 patients with stroke treated with intra‐arterial urokinase were retrospectively analysed. The risk of sICH as well as bleeding characteristics were assessed. Demographic and radiological data, time to treatment, urokinase dose, recanalisation rates, stroke aetiology and severity were analysed for predictors.

Results

sICH occurred in 14 of 294 (4.8%) patients. The median National Institute of Health Stroke Scale score of all patients was 15. All but one sICH were located in the infarcted brain tissue, and no sICH occurred in patients with peripheral vessel occlusions (M3 or M4 segments of the middle cerebral artery). Poor collaterals (p = 0.001), early signs of ischaemia on computed tomography (p = 0.003), higher urokinase dose (p = 0.019), lower recanalisation rate (p = 0.02) and higher diastolic blood pressure on admission (p = 0.04) were found to be correlated with sICH on univariate analysis. On multivariate analysis, poor collaterals (p = 0.004), urokinase dose (p = 0.021) and early signs on computed tomography (p = 0.026) remained predictors of sICH.

Conclusions

With regard to the whole spectrum of cerebral vessel occlusions, an incidence of <5% sICH after IAT is distinctly low. This result underlines the important role of IAT in the treatment of acute stroke.The aim of treatment in acute ischaemic stroke is revascularisation as fast as possible. For this purpose, both intravenous thrombolysis (IVT) and intra‐arterial thrombolysis (IAT) have proved to be effective.^1,2,3,4,5 The most devastating complication of both treatments is intracranial haemorrhage (ICH). ICH is categorised into haemorrhagic transformation, which is usually petechial and asymptomatic, and parenchymal haematomas without deterioration and those with clinical deterioration. Those with clinical deterioration are referred to as symptomatic ICH (sICH), which is associated with an increased mortality and occurs spontaneously in 0.6–4% of patients with ischaemic strokes. Thrombolysis increases the risk of sICH. Current literature reports wide ranges of incidence—for example, 3.3–21.2% for IVT and 0–14.3% for IAT.^{1,3,6,7,8,9,10,11,12,13,14}The largest IAT series was the PROACT II trial reporting on a defined subgroup of patients with stroke (n = 180) exclusively with M1 and M2 segment occlusions of the middle cerebral artery (MCA).³This study was conducted to evaluate the risk of sICH in the whole spectrum of patients with large cerebral artery occlusions treated with IAT. Characteristics of patients with sICH were assessed and predictors analysed.