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.     

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).     

Hippocampal volume and subcortical white matter lesions in late life depression: comparison of early and late onset depression

Background

Reduced hippocampal volume and increased prevalence of subcortical white matter lesions are associated with both recurrent early onset depression (EOD) and late onset depression (LOD). It is not clear whether these two factors differentially affect the age of onset of first depression. Therefore, we wished to investigate the relationship between age of first depression onset and hippocampal volume, with adjustment for subcortical white matter lesions.

Methods

MRI brain scans were used to compare hippocampal volumes and white matter lesions between age matched female patients (>60 years) with recurrent EOD and LOD and healthy controls.

Results

When comparing the three groups and adjusting for age, the Mini‐Mental State Examination score, total brain volume and total hippocampal volume were significantly smaller in patients with EOD compared with controls (5.6 vs 6.1 ml; p = 0.04). The prevalence of larger subcortical white matter lesions was higher in patients with LOD compared with patients with EOD (47% vs 8%; p = 0.002). Patients with LOD did not differ in hippocampal volume from patients with EOD or from controls.

Conclusions

In late life depression, age of first depression onset may distinguish between different independent neuropathological mechanisms. A small hippocampus volume may be a neuranatomical marker of EOD depression and larger subcortical white matter lesions could be an intermediate between cerebrovascular disease and LOD.Reduced hippocampal volume in late life depression (depression in those aged ⩾60 years) is associated with a chronic intermittent illness course.^1,2,3,4 Accordingly, older patients with recurrent early onset depression (EOD, first onset of depression before 60 years) would therefore have smaller hippocampal volumes compared with patients with late onset depression (LOD, first onset of depression at age 60 years or after) because of the longer duration of the disease. However, two recent studies showed smaller hippocampal volumes in patients with LOD compared with those with EOD.^5,6The latter observation could have been confounded by the increased prevalence of subcortical white matter lesions among patients with LOD^7,8,9 as these lesions may be related to hippocampal atrophy.^10,11,12 Therefore, in the current study we wished to investigate the relationship between age of onset of depression and hippocampal volume, with adjustment for subcortical white matter lesions, in elderly (⩾60 years) patients with chronic recurrent EOD and patients with LOD.     

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.     

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.     

Levodopa raises objective pain threshold in Parkinson's disease: a RIII reflex study

Background

Patients suffering from Parkinson''s disease (PD) describe painful sensations that could be related to neuropathic pain. Experimental data have indicated the involvement of basal ganglia and dopaminergic pathways in central nociceptive processing.

Aim

The objective of this study was to assess and compare the effect of levodopa on the objective pain threshold in patients with PD and healthy subjects.

Methods

The objective pain threshold was assessed by the nociceptive flexion reflex (RIII) in 13 PD patients and 10 healthy subjects. Patients and healthy subjects were evaluated under two randomised conditions: with levodopa (ON) and without (OFF).

Results

Levodopa significantly increased the RIII threshold of PD patients (6.9 (1.2) mA in the OFF condition vs 8 (1.1) mA in the ON position; p = 0.02). RIII threshold was significantly lower in PD patients than in healthy subjects in the OFF condition (6.9 (1.2) mA vs 9.7 (3.4) mA; p = 0.02). RIII threshold did not change after levodopa administration in healthy subjects.

Conclusion

These results provide evidence of a dopaminergic modulation of objective pain threshold in PD patients. In addition, the decrease in RIII threshold in PD patients, in the OFF condition, compared with controls, confirms the existence of an objective pain perception disturbance in PD.Pain is recognised as a feature of Parkinson''s disease (PD) and is reported by 40–75% of patients with PD.¹ Painful sensations are various (musculoskeletal, neuropathic pain) and may be present at any stage of the disease.^2,3Several anatomical, electrophysiological and pharmacological arguments are in favour of the involvement of the basal ganglia and dopaminergic pathways in central nociceptive processing.⁴There are only a few controversial studies on pain perception in PD. The pain threshold of patients with PD has been found to be lower than, higher than or equal to that of healthy subjects.^5,6,7 Recently, Djaldetti et al have shown that patients with PD have a lower subjective heat pain threshold than healthy subjects.⁸ To our knowledge, the effect of levodopa has only been assessed on the subjective pain threshold. Using two different experimental thermal stimulations (cold pressor test and thermotest with Peltier effect), we have previously shown that acute administration of levodopa significantly raised the subjective pain threshold of patients with PD.^9,10The nociceptive flexion reflex (RIII), a polysynaptic reflex, has been described as a useful tool for objectively investigating the pain threshold and its pharmacological modulation by analgesic drugs in normal subjects.^11,12The primary aim of the present study was to compare the effects of levodopa on objective pain threshold (RIII reflex) in pain free patients with PD and in healthy subjects. A secondary objective was to compare such parameters between these two groups.     

Case control study of diffusion tensor imaging in Parkinson's disease

Background

Preliminary work has shown that diffusion tensor MRI (DTI) may contribute to the diagnosis of Parkinson''s disease (PD).

Objectives

We conducted a large, prospective, case control study to determine: (1) if fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values on DTI in the basal ganglia and substantia nigra are different between patients with PD and healthy controls; and (2) the predictive value of these parameters and their clinical utility.

Methods

DTI imaging was carried out in patients with PD and controls. FA and ADC values were obtained from various brain structures on the DTI scan using the diffusion tensor taskcard. The structures studied were: caudate, putamen, globus pallidus, thalamus and substantia nigra.

Results

151 subjects (73 PD patients, 41 men, 32 women; mean age 63.6 years) and 78 age and sex matched control subjects were studied. The FA value of the substantia nigra in patients with PD was lower compared with controls (0.403 vs 0.415; p = 0.001). However, no significant differences were demonstrated for FA or ADC values of other structures. Multiple regression analysis revealed that the clinical severity of PD correlated inversely with the FA value in the substantia nigra in patients with PD (regression coefficient −0.019). No single FA value had both a high positive and negative predictive power for PD.

Conclusions

We demonstrated in a large, prospective, case control study that the FA value in the substantia nigra on DTI was lower in PD compared with healthy controls, and correlated inversely with the clinical severity of PD. Further longitudinal studies would be helpful to assess the clinical utility of serial FA measurements of the substantia nigra in objective quantification of disease progression and monitoring of the therapeutic response.The diagnosis of Parkinson''s disease (PD) is usually made clinically, based on the presence of rest tremor, bradykinesia and rigidity.^1,2 However, in select cases, the diagnosis may not be clear, especially in patients without tremor. Large community based studies have also shown that there is considerable difficulty in diagnosing parkinsonism or PD among elderly subjects in clinical practice.^3,4 Subtle signs of parkinsonism can be detected on clinical examination in approximately 30% of apparently healthy community based elderly cohorts.^4,5,6Diffusion tensor imaging (DTI) is an MRI technique that can indirectly evaluate the integrity of white matter tracts by measuring water diffusion and its directionality in three dimensions.⁷ The magnitude (diffusivity) and directionality (anisotropy) of water molecular displacement by diffusion in the brain can be quantified by the apparent diffusion coefficient (ADC) and fractional anisotropy (FA), respectively.^{8,9,10,11,12,13,14,15} Studies have revealed age related declines in white matter FA of normal healthy adults in whom volume loss may not even be evident.^12,15,16 DTI changes have also been reported in structures with relatively low inherent anisotropy, such as the thalamus and putamen.^11,12,17A small pilot study reported lower FA values in the nigrostriatal projection of patients with PD.¹⁸ Another group showed that ADC values in the basal ganglia and substantia nigra were no different between patients with PD and controls.^19,20 To our knowledge, correlation of FA and ADC values on DTI with clinical severity, and determination of positive and negative predictive values of DTI parameters have not been demonstrated for PD. Hence, we conducted a large, prospective, case control study to determine the clinical utility of FA and ADC values on DTI in distinguishing patients with PD from healthy controls.     

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.     

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.     

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.     

Cerebral venous thrombosis and plasma concentrations of factor VIII and von Willebrand factor: a case control study

Background

High plasma concentrations of factor VIII (FVIII) and von Willebrand factor (VWF) have been recently associated with a moderately increased risk of venous thrombosis, but their roles in cerebral sinus and venous thrombosis (CSVT) have not been addressed. To determine whether elevation of FVIII and VWF is more frequent in CSVT, we analysed plasma levels of FVIII and VWF in a case control study.

Methods

The study population consisted of 25 consecutive patients (of whom nine were excluded) admitted for CSVT to the Department of Neurology, Amiens University Hospital, France, from January 1997 to December 2002, for a general screening for thrombophilia. Sixty‐four healthy subjects matched for age and sex formed the group control.

Results

Mean FVIII (CSVT: 167.3 (SD 48.8) IU/dl; control group: 117.9 (39.8) IU/dl; p = 0.001) and VWF levels (CSVT: 165.4 (76.5)%; control group: 108.5 (27.8)%; p = 0.01) were significantly higher in the CSVT group. Using the 95th percentile of the control group as the cut off value, elevated FVIII (>190 IU/dl) occurred in 25% (4/16) (p = 0.005) and elevated VWF (>168%) in 37.5% (6/16) of patients with CSVT (p<0.001). Using previously reported cut off values (>150 IU/dl or >150%) showed the same results (FVIII: p = 0.005; VWF: p = 0.009).

Conclusion

Our study suggests that elevation of plasma factor VIII levels is the most common prothrombotic risk factor for CSVT. Elevation of VWF is also associated with an increased risk of CSVT but its effect seems to be partly mediated through FVIII.Cerebral sinus and vein thrombosis (CSVT) is a rare localisation of venous thromboembolic disease. It generally occurs in young or middle‐aged adults and accounts for approximately 1% of strokes.¹ Many coagulation disorders have been associated with CSVT.^2,3,4Several prospective studies showed that high concentrations of factor VIII (FVIII) are associated with a moderately increased risk of venous thromboembolism (VTE).^5,6 The role of increased levels of von Willebrand Factor (VWF) in VTE remains unclear.^5,7 Recent studies suggest that the effect of VWF is fully explained by FVIII concentrations.⁵ Indeed, the ABO blood group, which regulates plasma concentrations of both FVIII and VWF, may also play a role in susceptibility to thrombosis.^8,9,10The increased risk of VTE with elevated levels of FVIII or VWF has been observed in previous studies.^5,6,7,11 However, they did not specifically include patients with CSVT^7,9 or they were incomplete.¹²The aim of our study was to assess plasma levels of FVIII, VWF and other thrombophilic factors in patients with CSVT in a case control study.     

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.     

Apolipoprotein E epsilon4 and impaired episodic memory in community-dwelling elderly people: a marked sex difference. The Hordaland Health Study

Background

Among elderly people without dementia, the apolipoprotein E ε4 allele (APOE4) has been associated with cognitive deficit, particularly in episodic memory, but few reports are available on whether this association differs by sex.

Methods

In a community‐dwelling Norwegian cohort of 2181 elderly people (55% women), aged 70–74 years, episodic memory was examined in relation to sex and APOE4 zygosity, with the Kendrick Object Learning Test (KOLT).

Results

Possession of at least one APOE4 allele had a modest, detrimental effect on episodic memory in women, whereas in men, heterozygotes were unaffected and homozygotes had markedly lower scores across the distribution of KOLT scores. This sex difference was found consistently in all analyses: on comparing means and medians, examining trends across quintiles, and studying the distribution of scores and the risk of cognitive impairment. Results were broadly similar when adjusted for known determinants of cognition and also when severely impaired participants were excluded. The adjusted odds ratio (OR) of cognitive impairment in women was shown to be 1.8 (95% confidence interval (CI): 1.1 to 2.8) for heterozygotes and 1.1 (0.3 to 3.7) for homozygotes; the adjusted OR in men was observed to be 1.1 (0.6 to 2.1) for heterozygotes and 10.7 (4.7 to 24) for homozygotes.

Conclusions

Although the harmful effect of APOE4 on episodic memory was modest in women, the risk was found to occur in about 30%. APOE4 was observed to have a dramatic effect on episodic memory in men, but only in homozygotes, who comprised about 3% of men: the whole male homozygous group showed a marked shift to lower memory scores.Age and the apolipoprotein E ε4 allele (APOE4) are the most important known risk factors for sporadic Alzheimer''s disease. The disease is thought to have a long presymptomatic phase,¹ which suggests that APOE4 starts exerting its detrimental effects in the preclinical phase. Most studies on elderly people without dementia have found that the APOE4 allele is associated with various cognitive deficits,^{2,3,4,5,6,7,8,9,10,11,12,13,14} particularly in memory.^2,3,4,5,6,7 A recent meta‐analysis of more than 20 000 people concluded that this allele was associated with poorer performance on tests of global cognitive functioning, episodic memory and executive functioning.¹⁵The association of APOE4 with Alzheimer''s disease varies with sex.^{16,17,18,19,20} The meta‐analysis by Farrer et al²⁰ found that APOE4 homozygosity affords a high risk of Alzheimer''s disease for both men and women, but that a single copy of the allele confers a greater risk on women than on men. A similar sex difference related to APOE4 has been found in the degree of hippocampal atrophy in a cohort with mild cognitive impairment.²¹ We may therefore expect to find an effect related to sex of the APOE4 allele in cognitive tests in elderly people without dementia. Two studies^3,22 that have reported an influence of sex on this relationship found a stronger effect of APOE4 in women.^3,22In this study, we investigated whether sex influences the relationship between APOE alleles and episodic memory in community‐dwelling elderly people. We selected episodic memory because memory deficit is a hallmark of Alzheimer''s disease. Tests of episodic memory have been found to be particularly effective in identifying people at risk.^23,24 We compared the influence of sex in our cohort with that found on the risk of Alzheimer''s disease. We studied a relatively large group of 2181 people from western Norway.     

Progression of non-age-related callosal brain atrophy in multiple sclerosis: a 9-year longitudinal MRI study representing four decades of disease development

Background

In multiple sclerosis (MS), multiple periventricular lesions are commonly the first findings on MRI. However, most of these MS lesions are clinically silent. The brain atrophy rate has shown better correlation to physical disability, but it is not clear how atrophy develops over decades. Corpus callosum forms the roof of the third and lateral ventricles. The corpus callosum area (CCA) in a midsagittal image is age independent in a normal adult population up to the seventh decade; therefore it can be used as a marker for non‐age‐related, pathological brain atrophy.

Objectives

To investigate whether and how CCA decreases in size over time in patients with MS.

Methods

In a clinical observational study, 37 patients with MS with a wide range of disease duration at baseline (1–33 years) were followed. Three different MS courses were represented. The mean of individual MRI follow‐up was 9 years. Multiple sclerosis severity score (MSSS) was also applied to evaluate disability at baseline and after 9 years of follow‐up.

Results

A significant decrease in CCA over 9 years (p<0.001) and a persisting association between CCA and the disability status were found. The atrophy rate was similar ever four decades of MS for all MS courses. The mean annual CCA decrease was 9.25 mm² (1.8%). Surprisingly, atrophy rate did not correlate with sex, disease duration, age at MS onset or MS course.

Conclusions

Serial evaluations of CCA might be a robust method in monitoring a non‐age‐related decrease in CCA, reflecting progression of irreversible destructive changes in MS.Multiple sclerosis (MS) is a complex inflammatory disease of the brain and spinal cord,^1,2,3 which leads to a well‐documented early irreversible atrophy.^4,5,6 The main neuroimaging modality used to monitor MS development is MRI, which can visualise both lesions and atrophy. In follow‐up examinations of patients with MS, the correlation between clinical development and extent of MRI findings is generally poor, which is sometimes referred to as “the clinicoradiological paradox”.⁷In contrast with focal MS lesions, atrophy measures of the brain or spinal cord have been regarded as a better predictor of the disability progression in MS.^2,5,8,9,10 However, some reports also show non‐significant correlation between disability and atrophy.^{11,12,13,14,15,16} Focal MS lesions visualised on MRI have a characteristic pattern of oval‐shaped, typically periventricular white matter changes, often located in the corpus callosum. Atrophy of the corpus callosum is common in MS. However, pathological changes in the corpus callosum might develop independently of focal T2‐weighted lesions.¹⁷The corpus callosum, consisting of 2×10⁸ axons in a healthy person, forms the roof of the third and lateral ventricles and has a central role for interhemispheric communication.¹⁸ The corpus callosum area (CCA) is normally resistant to age‐related shrinkage between the third and the seventh decades of life.^19,20 Atrophy of the corpus callosum correlates to other measures of brain atrophy such as widening of third and lateral ventricles.¹ Pelletier et al²¹ reported a persisting association between CCA and disability, as assessed by the Expanded Disability Status Scale (EDSS) in a 5‐year longitudinal study of patients with relapsing–remitting multiple sclerosis (RRMS). Schreiber et al²² reported CCA in patients with MS to be associated with EDSS. In contrast, Barkhof et al²³ reported a lack of correlation between CCA and EDSS. Simon et al¹ found a slight correlation between CCA and EDSS at baseline, but on follow‐up there was no significant correlation between the significant CCA decrease and EDSS change.The corpus callosum atrophy rate has not been reported for different disease durations, sex or types of MS course in longitudinal studies.²¹ The starting point for prospective, longitudinal MRI studies is often close to the time of diagnosis of MS, focusing on the early years of the disease.We followed a patient cohort for 9 years. Disease duration at baseline was widespread (range 1–33 years), giving us the possibility of an overview of disease development over four decades. Our first aim was to study the rate at which the callosal atrophy developed. Second, we wanted to study the correlation between the atrophy rate and disability changes. The third aim was to study the association between CCA and disability at baseline and at the end of the study. The fourth aim was to investigate the association of the atrophy rate to sex, MS course (course at the end of study), disease duration and age at onset.     

A randomised controlled trial of a home based exercise programme to reduce the risk of falling among people with Parkinson's disease

Objective

To evaluate the effectiveness of a personalised home programme of exercises and strategies for repeat fallers with Parkinson''s disease (PD).

Method

Patients with a confirmed diagnosis of idiopathic PD, independently mobile, living at home in the community, experiencing more than one fall in the previous 12 months and with intact gross cognitive function were invited to participate in this randomised controlled trial. Usual care was compared with a personalised 6 week, home based exercise and strategy programme. The primary outcomes were rates of falling at 8 weeks and 6 months. Whether participants had repeat fallen, nearly fallen or experienced injurious falls were also examined. Functional Reach, the Berg Balance Test, PD Self‐assessment Scale and the Euro Quol were rated by a blinded assessor.

Results

Participants were randomised to the exercise (n = 70) and control (n = 72) groups. There was a consistent trend towards lower fall rates in the exercise group at both 8 weeks and 6 months and lower rates of injurious falls needing medical attention at 6 months. Lower rates of repeat near falling were evident for the exercise group at 8 weeks (p = 0.004) and 6 months (p = 0.007). There was a positive effect of exercises at 6 months on Functional Reach (p = 0.009) and quality of life (p = 0.033). No significant differences were found on other secondary outcomes measures.

Conclusion

There was a trend towards a reduction in fall events and injurious falls with a positive effect of exercises on near falls and quality of life.Postural instability and falls among people with Parkinson''s disease (PD) are common. In contrast with the estimated one‐third of the healthy population over 65 years who experience a fall,¹ two‐thirds of people living in the community with PD will have fallen in the previous 12 months² and those who have fallen two or more times in the previous year are likely to fall again in the next 3 months.³ As falls following PD can be injurious,⁴ prevention is important but postural instability is difficult to treat with medication. Physiotherapy may provide effective treatment for people with PD but two Cochrane reviews in 2001 on the general physical management of people with PD concluded there was insufficient evidence to support or refute the efficacy of physiotherapy or one form of physiotherapy over another for people with PD, and highlighted the need for more randomised controlled trials to test standard physiotherapy.^5,6 Most of the trials included in the systematic reviews recruited less than 20 subjects, and the use of poor research design and methodology was a common finding of the reviewers.Review of the literature on falls management among the general elderly population confirms that multidisciplinary fall prevention programmes can be beneficial for elderly people.^7,8 The most effective intervention was a multifactorial fall risk assessment and management programme. Exercise programmes, such as moderate intensity muscle strengthening and balance training, individually prescribed at home by a trained health professional, have been shown to be effective in reducing fall frequency among the elderly population living in the community.^7,8,9,10,11The purpose of this trial was to evaluate the effectiveness of a personalised home based exercise programme (activities selected from a menu of muscle strengthening, stretches, balance retraining and cognitive movement strategies for learning and compensating), administered by a physiotherapist for reducing fall events among people with PD. The research question addressed was: do repeat fallers with PD, who participate in an exercise programme of strength, balance training and strategies, experience fewer falls, near falls or injuries than those who do not?     

Pain as the only symptom of cervical artery dissection

Background

Headache or neck pain is a frequent symptom of spontaneous cervical artery dissection (sCAD).

Patients and methods

Patients were drawn from an ongoing hospital‐based registry of consecutive cases diagnosed with sCAD. Only patients with isolated pain were included in this series. Pain topography, dynamics, severity and quality, imaging findings and outcome were analysed.

Results

20 of 245 (8%) patients with sCAD presented with pain as the only symptom (mean (SD) age 39 (8) years; 14 (70%) women). Of them, 12 had vertebral artery dissection, 3 had internal carotid dissection and 5 had multiple dissections. The median delay from symptom onset to diagnosis was 7 days (range 4 h to 29 days). 6 patients presented with headache, 2 with neck pain and 12 with both. Onset of headache was progressive in 6, acute in 8 and thunderclap‐type in 4 patients; neck pain was progressive in 7 and acute in 7. Headache was throbbing in 13 and constrictive in 5 patients; neck pain was throbbing in 4 and constrictive in 10. Pain was unilateral in 11 and bilateral in 9. Pain was different from earlier episodes in all but one case. All patients were pain free at 3 months.

Conclusion

Pain may be the only symptom in sCAD, even when multiple arteries are dissected. Pain topography, dynamics, quality and intensity were heterogeneous. Data from this study lend support to recommendations favouring imaging studies of the cervical arteries in patients with new‐onset unexplained headache or neck pain.Spontaneous cervical artery dissection (sCAD) is a well‐recognised cause of stroke, particularly in the young, with a wide spectrum of clinical presentations.^1,2 Patients may present with local manifestations, ischaemic signs or both. The typical clinical manifestations of spontaneous vertebral artery dissections (sVADs) are thought to be occipital headache, posterior neck pain or both, as well as posterior circulation ischaemia or subarachnoid haemorrhage (SAH).^3,4,5 Patients with spontaneous internal carotid artery dissection (sICAD) mainly present with ipsilateral anterior headache or neck pain, Horner''s syndrome, cranial nerve palsies and retinal or cerebral ischaemia.^2,6Pain is the most frequent local symptom and often the initial manifestation of sCAD. However, it has rarely been reported as the only symptom of sCAD.^{7,8,9,10,11,12} Therefore, to determine patterns of pain that could raise suspicion about sCAD, we analysed patients with sCAD, who presented with only headache or neck pain.     

Estimated life expectancy of Parkinson's patients compared with the UK population

Objective

To calculate the best possible estimates for age specific life expectancy (LE) and anticipated age at the time of death (AAD) in patients with Parkinson''s disease (PD) compared with the general population in the UK. These may be of greater value to patients than standardised mortality ratios (SMRs), which are usually reported in studies on mortality in PD.

Methods

A literature review identified articles with data on age stratified life expectancy or SMRs to calculate estimations of LE using the Gompertz function and data on mortality and LE in the UK from the Office of National Statistics and Actuarial Department for the year 2003.

Results

Two UK studies and four from Western Europe were used to estimate LE and AAD for patients with PD from SMRs. The mean LEs of patients with PD compared with the general population were: 38 (SD 5) years for onset between 25 and 39 years compared with 49 (SD 5) years; 21 (SD 5) years for onset between 40 and 64 years compared with 31 (SD 7) years; and 5 (SD 4) years for onset age ⩾65 years compared with 9 (SD 5) years. The average AAD of patients with PD with onset between 25 and 39 years was 71 (SD 3) years and considerably lower than that of the general population (82 (SD 2) years). The difference between average AAD for older individuals with PD (onset ⩾65 years) and the general population was smaller, with an AAD of approximately 88 (SD 7) years compared with 91 (SD 5) years.

Conclusions

The calculations showed that LE and AAD in PD are reduced for all onset ages but this reduction is greatest in individuals with a young onset. While the results are average estimates, these can provide useful indications of LE and AAD.Parkinson''s disease (PD) is a neurodegenerative disorder with an average onset of approximately 60 years, but some patients have a much earlier onset. PD is associated with increased mortality compared with the general population, with an ongoing debate on the influence of dopaminergic treatment on mortality rates.^1,2,3,4,5Although some papers reported survival time,⁶ comparison of mortality rates between patients with PD and the general population is usually presented using the standardised mortality ratio (SMR). The SMR allows for comparison between population groups with different demographics and life expectancies. This ratio is however of limited value in advising patients and their families on their prognosis. In addition, limited information is available on the comparative general survival and life expectancy in young versus older onset PD.We therefore undertook an analysis of published data on mortality in PD to calculate estimates of life expectancy (LE; anticipated mean remaining time to live) based on SMRs and the most recent UK actuary data, and to compare LE in patients with PD by age group.     

Prospective comparison of acute confusion severity with duration of post-traumatic amnesia in predicting employment outcome after traumatic brain injury

Background

Measurement of the duration of post‐traumatic amnesia (PTA) is common practice, serving as an important index of the severity of traumatic brain injury (TBI) and a predictor of functional outcome. However, controversy exists regarding the nature of PTA; some studies indicate that it is a confusional state with symptoms that extend beyond disorientation and amnesia.

Objective

To evaluate the contribution of the severity of acute confusion 1 month after TBI to prediction of employment at 1 year after injury, comparing it with PTA duration.

Methods

Prospective study involving 171 participants with complete data, who met the study criteria, from 228 consecutive TBI Model System admissions. Outcome measures included weekly administration of the Delirium Rating Scale‐Revised‐98 (DelRS‐R98) to measure the severity of acute confusion. Evaluations closest to 1 month after injury were used for study purposes. Duration of PTA was defined as the interval from injury until two consecutive Galveston Orientation and Amnesia Test scores of ⩾76 were obtained within a period of 24–72 h. Univariable and multivariable logistic regression were used to predict employment status at 1 year after injury.

Results

Age, education and DelRS‐R98 were significant predictors accounting for 34% of outcome variance. Individuals with greater confusion severity at 1 month after injury, older age and lower levels of education were less likely to be employed at 1 year after injury. Severity of confusion was more strongly associated with employment outcome (r_s = −0.39) than was PTA duration (r_s = −0.34).

Conclusions

In addition to demographic indices, severity of acute confusion makes a unique contribution to predicting late outcome after TBI.Impaired consciousness represents the clinical hallmark of non‐penetrating traumatic brain injury (TBI).^1,2 Individuals with mild TBI may experience a brief period of confusion, while others with greater injury severity may become comatose followed by prolonged confusion with amnesia.² This transitory state of impaired consciousness is commonly referred to as post‐traumatic amnesia (PTA). Determination of the duration of PTA is important as it yields an index of injury severity and is one of the best predictors of recovery and functional outcome.^3,4,5,6,7 Prospective evaluation of PTA is common practice in rehabilitation settings, largely because it provides an ongoing index of the patient''s progress³ and suitability for neuropsychological testing.^7,8Historically, investigations of PTA primarily focus on the disorientation and amnestic aspects of impaired consciousness after TBI, yet other neurobehavioral manifestations commonly occur. Stuss et al found that attentional disturbance is a key aspect of impaired consciousness among confused patients with TBI.⁹ They noted similarities between post‐traumatic impaired consciousness and delirium, a confusional state in which attentional deficits are commonly observed. They further proposed that the term “post‐traumatic confusional state” replace the more commonly used “post‐traumatic amnesia” as PTA less accurately represents cognitive impairments after TBI.⁹ Similarly, Nakase‐Thompson et al and later Sherer et al studied confusion among neurorehabilitation admissions with TBI and found that traditional measures of PTA did not adequately reflect the range of observed neurobehavioral impairments.^10,11 In addition to attentional, orientation and memory impairments, prevalent manifestations found among confused patients after TBI included sleep–wake cycle disturbance, decreased daytime arousal, fluctuation in cognitive and behavioural symptom severity, motor agitation, affective lability, and perceptual and thought process abnormalities.^10,11Studies addressing PTA as a predictor of outcome typically examine duration; that is, the time elapsed from injury until meeting a criterion for return of orientation and/or memory.^12,13,14,15 Important methodological limitations exist, however, in the determination of PTA duration.^3,16,17 While the early stages of PTA are easily recognised, identifying the end point is more challenging.^16,17,18 In some cases, patients are no longer available for determination of PTA emergence, having been transferred to home or another setting. Conversely, PTA resolution may occur prior to the initial evaluation, requiring retrospective estimation. Furthermore, different PTA measures may yield discrepant PTA duration recordings in the same patient, raising questions of test validity.^3,17,19,20 As duration of PTA is influenced by injury severity, evaluating the severity of confusion at a set time after injury potentially reduces the confounding influence of evaluation results with those of duration of TBI recovery.In an effort to clarify the relevance of severity, rather than duration of confusion symptoms, after TBI on functional outcome, we examined the predictive utility of a measure that encompasses many aspects of neurobehavioral impairment associated with acute confusion. We hypothesised that a rating scale that evaluates the range and severity of behavioural, cognitive and physiological changes associated with early confusion will provide unique utility in predicting late functional outcome. Moreover, clinicians caring for persons with TBI whose contacts with patients are too limited in time to permit determination of PTA duration could still have useful prognostic information. This study primarily aimed to examine the nature and severity of acute confusion utilising a common measure in the delirium literature, the Delirium Rating Scale‐Revised‐98 (DelRS‐R98),²¹ at 1 month after TBI, and its relationship to employment outcome at 1 year after injury. The second aim was to compare the functional prognostic value of the 1 month DelRS‐R98 with that of PTA duration, as assessed by the Galveston Orientation and Amnesia Test (GOAT),²² a common measure of PTA.^16,19     

Psychiatric disorders in preclinical Huntington's disease

Background

Psychiatric symptoms are a common feature of Huntington''s disease (HD) and often precede the onset of motor and cognitive impairments. However, it remains unclear whether psychiatric changes in the preclinical period result from structural change, are a reaction to being at risk or simply a coincidental occurrence. Few studies have investigated the temporal course of psychiatric disorder across the preclinical period.

Objectives

To compare lifetime and current prevalence of psychiatric disorder in presymptomatic gene carriers and non‐carriers and to examine the relationship of psychiatric prevalence in gene carriers to temporal proximity of clinical onset.

Methods

Lifetime and current psychiatric histories of 204 at risk individuals (89 gene carriers and 115 non‐carriers) were obtained using a structured clinical interview, the Composite International Diagnostic Interview. Psychiatric disorders were classified using both standardised diagnostic criteria and a more subtle symptom based approach. Follow‐up of gene carriers (n = 51) enabled analysis of the role of temporal proximity to clinical onset.

Results

Gene carriers and non‐carriers did not differ in terms of the lifetime frequency of clinical psychiatric disorders or subclinical symptoms. However, gene carriers reported a significantly higher rate of current depressive symptoms. Moreover, the rate of depression increased as a function of proximity to clinical onset.

Conclusions

Affective disorder is an important feature of the prodromal stages of HD. The findings indicate that depression cannot be accounted for by natural concerns of being at risk. There is evidence of a window of several years in which preclinical symptoms are apparent.Huntington''s disease (HD) is an inherited neurodegenerative disorder, characterised by motor dysfunction, cognitive impairment and psychiatric disturbance. HD is associated with a wide range of psychiatric disturbances, including affective disorders,^1,2,3 irritability,^4,5,6 apathy^1,3,6 and psychosis.^4,7,8 Both major depression^1,2,4,9 and more subtle mood disturbances¹⁰ have been reported to predate clinical onset, conventionally defined by onset of motor symptoms. However, the basis for psychiatric symptoms remains unclear. Depression has been observed to occur up to 20 years before the onset of motor symptoms,^9,11 raising the possibility that psychiatric symptoms are an early indicator of HD and result from incipient neurodegenerative changes. However, the finding that psychiatric symptoms tend to cluster in certain HD families might indicate that psychiatric changes have a genetic basis and reflect a “switching on” of the HD gene early in life.^2,8 High rates of psychiatric disturbance have also been observed in HD family members who do not carry the genetic mutation,^9,10 raising the alternative possibility that affective changes arise in response to emotional stressors, such as being at risk, or the burden of growing up in a family with affected members. A more thorough understanding of the underlying basis of psychiatric changes in preclinical gene carriers is crucial, as future therapeutic strategies are most likely to target such individuals.Previous psychiatric studies of at risk individuals have yielded inconsistent results. Earlier studies reported high lifetime rates of psychiatric disorder in preclinical gene carriers (eg, 18% major affective disorder),² whereas more recent studies indicate little difference between rates for gene carrier and non‐carrier groups.^10,12,13,14 A number of factors may account for these discrepancies. The majority of earlier reports were limited to retrospective observation of affected individuals and therefore lacked appropriate controls.^4,5 The advent of predictive testing has enabled direct comparison of at risk individuals who have the HD mutation and those who do not, thereby controlling for social and environmental factors.^10,12,13,14 Whereas the majority of earlier studies lacked standardised assessment criteria,^4,7 more recent studies have utilised operational diagnostic criteria, although these have in turn been criticised for failing to detect the more subtle psychiatric disturbances that can occur in HD.^3,15Few studies have taken account of the temporal distance to onset of motor symptoms. It is now well established that the clinical onset of HD is typically preceded by a prodromal period of several months or years during which non‐specific mild neurological signs arise intermittently.¹⁶ The difficulty in establishing exact dates of onset for retrospective cases may have led to the inclusion in earlier studies of individuals who were already in the early stages of HD. Studies of presymptomatic individuals have typically recruited participants without motor signs, who may have been further from clinical onset.The present study is a double blind comparison of lifetime and current prevalence of psychiatric disorders in preclinical gene carriers and non‐carriers, using a combination of standardised psychiatric diagnostic criteria and a more subtle symptom based approach. Follow‐up of gene carriers has enabled analysis of the role of temporal proximity to clinical onset.     

Clinicopathological concordance and discordance in three monozygotic twin pairs with familial Alzheimer's disease

Aim

Neuropathological examination of both individuals in a monozygotic (MZ) twin pair with Alzheimer''s disease (AD) is rare, especially in the molecular genetic era. We had the opportunity to assess the concordance and discordance of clinical presentation and neuropathology in three MZ twin pairs with AD.

Methods

The MZ twins were identified and characterised by the University of Washington Alzheimer''s Disease Research Center. We reviewed the available clinical and neuropathological records for all six cases looking specifically for concordance and discordance of clinical phenotype, neuritic amyloid plaques (NP), neurofibrillary tangles (NFT) and Lewy related pathology (LRP).

Results

Discordance in age of onset for developing AD in the MZ twins varied from 4 to 18 years. Clinical presentations also differed between twins. One twin presented with a dementia with Lewy Body clinical syndrome while the other presented with typical clinical AD. Neuropathology within the MZ twin pairs was concordant for NP and NFT, regardless of duration of disease, and was discordant for LRP. This difference was most marked in the late onset AD twin pair. One pair was found to have a mutation in presenilin‐1 (PS1) (A79V) with remarkably late onset in a family member.

Conclusions

MZ twins with AD can vary considerably in age of onset, presentation and disease duration. The concordance of NP and NFT pathological change and the discordance of LRP support the concept that, in AD, the former are primarily under genetic control whereas the latter (LRP) is more influenced by disease duration and environmental factors. The A79V mutation in PS1 can be associated with very late onset of dementia.Alzheimer''s disease (AD) is the most common neurodegenerative disorder causing dementia in the elderly. AD has typically been divided into early onset (EOAD, onset <60 years) and late onset (LOAD, onset ⩾60 years). LOAD occurs in the majority (>95%) of patients with AD¹ while EOAD accounts for a small proportion of patients (<5%). Demarcation of familial LOAD/EOAD is not absolute as approximately 25% of families with familial LOAD will have members with EOAD, accounting for about 6% of all affected cases.²The cause of AD is unknown in the majority of cases. The most powerful risk factors for developing LOAD are age, a positive family history and APOE genotype.³Specific mendelian genetic factors have also been identified in patients who develop familial EOAD, namely mutations in presenilin 1 (PS1),⁴ presenilin 2 (PS2)⁵ and amyloid precursor protein.⁶ PS1 mutations are the most frequent pathogenic mutation in EOAD.⁷Genetic variation influences a number of aspects of clinical phenotype in patients affected by AD,¹ with modelling suggesting that environmental factors are also important in determining development of dementia.⁸ Monozygotic (MZ) twins provide a unique insight into the relationship between genetic programming and environmental factors impacting on that programming. Twin studies suggest a polygenic multifactorial mode of inheritance¹ and heritability for (LO)AD, being somewhere between 58% and 79%.⁹ Concordance rates in MZ twins can be as high as 61%,⁹ with concordance rates increasing with increasing duration of follow‐up.¹⁰ In a recent identical twin study, the environmental risk factors that predicted the development of (LO)AD were a history of tooth loss before 35 years (presumably reflecting childhood deprivations) and low educational attainment.¹¹Neuritic amyloid plaques (NP) and neurofibrillary tangles (NFT) are the neuropathological hallmarks of AD, with NFT composed of the microtubule associated protein tau. Alpha‐synuclein (SNCA) is a major component of Lewy related pathology (LRP, including inclusions and neuritic pathological change) and is a presynaptic protein which may be involved in synaptic function.¹² LRP is a pathological hallmark of “idiopathic” Parkinson''s disease but it can also be found in up to 60% of sporadic AD and approximately 5% of elderly, non‐parkinsonian individuals.¹³There are few data in the literature on the concordance of neuropathology in MZ twins with AD. To our knowledge, only three case reports that included neuropathology of both twins in a pair with AD have been published^14,15,16 and these were before the advent of beta amyloid, tau and SNCA immunohistochemistry and genetic testing. Age at onset of AD in two of these case reports (age of onset 34¹⁴ and 50 years¹⁶) raises the possibility that specific genetic mutations could have been responsible for the disease. Other reports of neuropathology in affected twins have included only one autopsy per twin pair¹⁷ or have not commented on neuropathology details.¹⁰ We are unaware of any case reports of autopsies in both twins of a MZ pair with a PS1 mutation.We had the unique opportunity of identifying three kindreds with affected MZ twin pairs, in which neuropathology was available in all six cases and one pair had a mutation in PS1. This allowed us to review the clinical information, genetic status and detailed neuropathology on all six subjects to assess the concordance and discordance for all of these variables.