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.     

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.     

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.     

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.     

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.     

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).     

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     

Gender differences in Parkinson's disease

Objective

To investigate gender differences in basic disease characteristics, motor deterioration and nigrostriatal degeneration in Parkinson''s disease (PD).

Methods

We studied 253 consecutive PD patients who were not receiving levodopa or dopamine agonists (disease duration ⩽10 years). We investigated the influence of gender and oestrogen status on: (1) age at onset, (2) presenting symptom, (3) severity and progression of motor symptoms (Unified Parkinson''s Disease Rating Scale III (UPDRS‐III) scores) and (4) amount and progression of nigrostriatal degeneration ([¹²³I]FP‐CIT single photon emission computed tomography measurements).

Results

Age at onset was 2.1 years later in women (53.4 years) than in men (51.3 years). In women, age at onset correlated positively with parity, age at menopause and fertile life span. Women more often presented with tremor (67%) than men (48%). Overall, patients presenting with tremor had a 3.6 year higher age at onset and a 38% slower UPDRS‐III deterioration. Mean UPDRS‐III scores at disease onset were equal for both genders, as was the rate of deterioration. Women had a 16% higher striatal [¹²³I]FP‐CIT binding than men at symptom onset and throughout the course of PD.

Conclusions

Our results suggest that, in women, the development of symptomatic PD may be delayed by higher physiological striatal dopamine levels, possibly due to the activity of oestrogens. This could explain the epidemiological observations of a lower incidence and higher age at onset in women. Women also presented more often with tremor which, in turn, is associated with milder motor deterioration and striatal degeneration. Taken together, these findings suggest a more benign phenotype in women with PD.There are several indications of gender differences in Parkinson''s disease (PD). Epidemiological studies have shown that both incidence and prevalence of PD are 1.5–2 times higher in men than in women.^1,2,3,4,5,6 Furthermore, in 6 out of 8 incidence studies mentioning gender specified age at onset, onset in women was slightly later than in men (by a mean of 2.2 years (range 1–4)).⁷ After progression into the clinical phase of the disease, women had better Unified Parkinson''s Disease Rating Scale (UPDRS) motor scores⁸ but a greater prevalence of dyskinesias^8,9 compared with men (at a disease duration of more than 5 years). Furthermore, men reported several parkinsonian symptoms more frequently than women when asked at a disease duration of 9 years.¹⁰ Gender differences in the earlier stage of PD, before initiation of dopamine agonists or levodopa, have not been investigated.The reported gender differences reflecting distinct time periods—before and after symptom onset—could be related to the different levels of circulating oestrogens in men and women. Several findings indicate that oestrogens may play a role in PD. In animal models of PD, oestrogens had a neuroprotective effect when administered prior to or coinciding with a toxic insult.^11,12,13 Secondly, the dopaminergic neurons in the substantia nigra and the striatal dopamine content were more vulnerable to chemical lesioning at dioestrus (low oestrogen) than at pro‐oestrus (high oestrogen).¹⁴ However, the possibly beneficial effects of oestrogens suggested by these reports could not be confirmed in humans. Postmenopausal oestrogen use in women was associated with both higher, lower and equal risks of PD.^15,16,17 Furthermore, trials of postmenopausal oestrogen supplementation, which started after symptom onset, did not affect parkinsonian symptoms.^18,19 However, women who had undergone ovariectomy or hysterectomy had an increased risk of PD.^20,21 Thus the precise nature and extent of gender differences and the role of oestrogens in PD remain unclear.Here we investigated whether and how gender affects both the preclinical and clinical disease stages, reflected by (1) the age of PD onset, (2) the presenting symptom, (3) the severity and progression of motor symptoms assessed with UPDRS derived variables and (4) the amount and progression of nigrostriatal degeneration assessed using [¹²³I]FP‐CIT single photon emission computed tomography (SPECT).     

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.     

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.     

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.     

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).     

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.     

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.     

Anterior-medial thalamic lesions in dementia: frequent, and volume dependently associated with sudden cognitive decline

Background

The anterior‐medial thalamus (AMT), which is associated with memory processing, is severely affected by Alzheimer''s disease pathology and, when damaged, can be the sole cause of dementia.

Objective

To assess the frequency of magnetic resonance imaging (MRI) hyperintensities affecting the AMT, and their relationship with sudden cognitive decline.

Methods

205 consecutive participants from a university cognitive neurology clinic underwent clinical evaluation, neuropsychological testing and quantitative MRI.

Results

AMT hyperintensities >5 mm³ occurred in 0 of 34 normal controls but were found in 5 of 30 (17%) participants with cognitive impairment with no dementia (CIND), 9 of 109 (8%) patients with probable Alzheimer''s disease, 7 of 17 (41%) with mixed disease and 8 of 15 (53%) with probable vascular dementia (VaD). AMT hyperintensities occurred more often in participants with stepwise decline than in those with slow progression (χ² = 31.7; p<0.001). Of the 29 people with AMT hyperintensities, those with slow progression had smaller medial temporal width (p<0.001) and smaller anterior‐medial thalamic hyperintensities (p<0.001). In a logistic regression model, both variables were significant, and the pattern of decline was correctly classified in 86% of the sample (Cox and Snell R² = 0.56; p<0.001). Those with AMT hyperintensities >55 mm³ were likely to have stepwise decline in cognitive function regardless of medial temporal lobe width; in contrast, those with smaller AMT hyperintensities showed a stepwise decline only in the absence of medial temporal lobe atrophy. All patients with VaD had left‐sided AMT hyperintensities, whereas those with CIND had right‐sided AMT hyperintensities.

Conclusions

AMT hyperintensities >55 mm³ probably result in symptomatic decline, whereas smaller lesions may go unrecognised by clinicians and radiologists. Only half of those with AMT hyperintensities had diagnoses of VaD or mixed disease; the other AMT hyperintensities occurred in patients diagnosed with Alzheimer''s disease or CIND. These silent hyperintensities may nevertheless contribute to cognitive dysfunction. AMT hyperintensities may represent a major and under‐recognised contributor to cognitive impairment.Dementia caused solely by cerebrovascular disease is rare. In a large memory clinic autopsy series of over 1900 people with dementia, only six had infarcts without any Alzheimer''s disease neuropathology,¹ and all six people had infarctions affecting at least one of three key areas: the thalamus, the medial temporal lobe and the frontal cortex.¹ Although the medial temporal lobe has long been appreciated as a site of strategic importance for dementia, the involvement of the thalamus is less frequently assessed. The anterior nucleus of the thalamus is part of a cortical network, including the hippocampus, anterior cingulate and mamillary bodies, which mediates memory processing.^2,3,4,5 Infarcts to the anterior and dorsomedial thalamus are associated with memory impairment in animal studies,⁶ human case reports^7,8,9,10 or series.^{1,11,12,13,14} One indication that thalamic infarcts may be important in dementia populations comes from the Nun Study, which found that people with infarcts to the basal ganglia, thalamus and deep white matter exhibited dementia with less Alzheimer''s disease neuropathology than in those without infarcts.¹⁵Despite this finding, and despite the appreciated role of anterior‐medial thalamic (AMT) infarcts in causing isolated cases of amnesia or dementia in stroke populations,^11,12,13,16 the frequency and consequences of thalamic lesions in a large sample of people with cognitive impairment have not been evaluated. In this study, we quantified hyperintensities on magnetic resonance images (MRI) in the anterior‐medial thalamus in a cognitive neurology clinic sample. We determined the frequency and volumes of thalamic hyperintensities and whether these hyperintensities were associated with sudden changes in cognitive status defined by clinical history.     

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.     

Focal cortical dysplasia: long term seizure outcome after surgical treatment

Background

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

Methods

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

Results

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

Conclusion

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

Quantitative gait dysfunction and risk of cognitive decline and dementia

Background

Identifying quantitative gait markers of preclinical dementia may lead to new insights into early disease stages, improve diagnostic assessments and identify new preventive strategies.

Objective

To examine the relationship of quantitative gait parameters to decline in specific cognitive domains as well as the risk of developing dementia in older adults.

Methods

We conducted a prospective cohort study nested within a community based ageing study. Of the 427 subjects aged 70 years and older with quantitative gait assessments, 399 were dementia‐free at baseline.

Results

Over 5 years of follow‐up (median 2 years), 33 subjects developed dementia. Factor analysis was used to reduce eight baseline quantitative gait parameters to three independent factors representing pace, rhythm and variability. In linear models, a 1 point increase on the rhythm factor was associated with further memory decline (by 107%), whereas the pace factor was associated with decline on executive function measured by the digit symbol substitution (by 29%) and letter fluency (by 92%) tests. In Cox models adjusted for age, sex and education, a 1 point increase on baseline rhythm (hazard ratio (HR) 1.48; 95% CI 1.03 to 2.14) and variability factor scores (HR 1.37; 95% CI 1.05 to 1.78) was associated with increased risk of dementia. The pace factor predicted the risk of developing vascular dementia (HR 1.60; 95% CI 1.06 to 2.41).

Conclusion

Our findings indicate that quantitative gait measures predict future risk of cognitive decline and dementia in initially non‐demented older adults.Dementia is widely recognised as a global public health problem. There is increasing evidence that subtle clinical and physiological abnormalities precede the diagnosis of dementia by many years.¹ Identifying early markers of dementia may help identify high risk elderly patients for further evaluation and interventions. We previously reported in another cohort (Bronx Ageing Study)² that clinical gait abnormalities predicted risk of non‐Alzheimer''s dementia in older adults. While an integral aspect of patient evaluation, clinical gait assessments have several limitations. Most assessment protocols are not standardised or validated. Most gait abnormalities are mild,³ and detection is dependent on the examiner''s expertise. Clinicians may use the presence of gait abnormalities to assign dementia subtypes raising issues of diagnostic circularity.^2,4 Quantitative gait assessments, independent of clinical diagnosis, may help avoid these shortcomings.It has been reported that slowing of gait may precede development of cognitive impairment.^5,6,7,8 However, gait is a complex motor behaviour with many measurable facets besides velocity, and with an intricate relationship to different aspects of cognition.⁹ Moreover, single gait variables are often highly correlated with one another so that their independent effects on risk of cognitive decline and dementia may be hard to observe while adjusting for other gait variables. To address this issue, we used factor analysis to identify independent gait domains derived from quantitative assessments.^9,10 Gait variability has been linked to multiple adverse outcomes in older adults, including Alzheimer''s disease.^11,12 However, its role in predicting dementia is not established. Hence we included gait variability measures in our analyses.Based on our and other studies^2,5,6,7,8,9 we hypothesised that quantitative gait assessments may help reveal subtle alterations in brain function early in the course of the dementia. Our aim was to examine the relationship of quantitative gait parameters with decline in general and specific cognitive domains in a population of non‐demented older adults. We also studied whether quantitative gait parameters could predict risk of incident dementia. Identifying quantitative gait markers of preclinical dementia may provide new insights into early biological stages of dementia, improve diagnosis and risk assessment procedures, and facilitate development of novel preventive strategies.     

The patient knows best: significant change in the physical component of the Multiple Sclerosis Impact Scale (MSIS-29 physical)

Aim

The aims of this study were to determine the reliability, responsiveness and minimally important change score of the Multiple Sclerosis Impact Scale (MSIS)‐29 physical using the Expanded Disability Status Scale (EDSS) as an anchor measure.

Methods

214 patients with multiple sclerosis (MS) (EDSS 0–8.5) had concurrent MSIS‐29 and EDSS assessments at baseline and at up to 4 years of follow‐up.

Results

116 patients had unchanged EDSS scores. Stability of the MSIS‐29 physical (mean change 0.1 points) was better in the 85 patients with EDSS 0–5.0 than in the 31 patients with EDSS 5.5–8.5 in whom the MSIS‐29 physical score fell by 8 points, a response shift phenomenon. A floor effect for the MSIS‐29 was observed in 5% of stable patients at both time points. 98 patients experienced EDSS change with moderately strong statistically significant correlations between change scores in the EDSS and the MSIS‐29 physical (r = 0.523, p<0.0001). Effect sizes for MSIS‐29 physical change were moderate to large. Using receiver operating characteristic curves, the MSIS‐29 change score which produced a combination of optimal sensitivity and specificity was chosen for both EDSS ranges. For EDSS range 5.5–8, a change score of 8 had a sensitivity of 87% and specificity of 67%. For EDSS 0–5.0, a change score of 7 had a sensitivity of 78% and a specificity of 51%.

Conclusions

The MSIS‐29 physical performs well over time, and is suitable for use in trials; a minimal change score of 8 points in the MSIS‐29 is clinically significant.In the past 10 years, patients'' perspectives on the effect of multiple sclerosis (MS) on their well being has been addressed by the development of a number of disability and quality of life (QoL) self report scales.^1,2,3 The properties of such new MS scales have been examined using the Expanded Disability Status Scale (EDSS)⁴ or the Multiple Sclerosis Functional Composite (MSFC)⁵ as comparators. Surprisingly, despite moderately good cross sectional correlations, the longitudinal correlations of change scores have been weak.^6,7,8 Part of this difficulty might relate to relatively short periods of follow‐up or differing perceptions between the patient and the neurologist as to whether change had taken place.⁶ This discrepancy might in part be accounted for by a phenomenon called “response shift” which is well recognised in QoL studies but has not been addressed in MS self report literature.⁹The multiple sclerosis impact scale (MSIS‐29) is a psychometrically designed patient reported measure of the effect of MS on activities of daily living³; it has been validated in a number of patient groups and shows responsiveness to change in patients treated with steroid therapy for relapses and in the rehabilitation setting.^{10,11,12,13,14} There are two parts to the scale: one part (questions 1–20) addresses physical impact and is termed MSIS‐29 physical; the other part (questions 21–29) relates to psychological concerns and is termed MSIS‐29 psychological. The stability, sensitivity to change and minimally important change of the MSIS‐29 physical using repeated assessments in patients with accumulating disability in MS over years has not been established. Responsiveness to change is an important aspect of scale performance, particularly in its possible use as an endpoint in drug trials. The concept of minimally important change in the MSIS‐29 is important in both the clinical setting and in research studies; it is necessary to know whether a change in the MSIS‐29 score reported by the patient is clinically relevant.The aims of this study were to examine the reliability of the MSIS‐29 physical over 4 years in patients with stable disease (absence of relapses and unchanged EDSS scores) and to examine the long term responsiveness to change of the MSIS‐29 physical in patients with worsening EDSS scores. In addition, we aimed to determine minimally important change in the MSIS‐29 physical score using the EDSS as an anchor measure over a 4 year period in patients with EDSS scores 0–8.5.     

The effect of the apolipoprotein E gene polymorphisms and haplotypes on behavioural and psychological symptoms in probable Alzheimer's disease

Background

Patients with Alzheimer''s disease and dementia commonly suffer from behavioural and psychological symptoms of dementia (BPSD). A genetic component to BPSD development in Alzheimer''s disease has been demonstrated. Several studies have investigated whether the exon 4 ε2/ε3/ε4 haplotype of the apolipoprotein E (APOE) gene is associated with BPSD, with variable results.

Objective

We investigated the exon 4 polymorphisms and extended this study to include promoter polymorphisms and the resultant haplotypes across the gene.

Methods

Our large independent cohort of 388 patients with longitudinal measures of BPSD assessed by the Neuropsychiatric Inventory was used to analyse whether any of these variants were associated with the presence of BPSD.

Results

We revealed several significant relationships before correction for multiple testing. The exon 4 haplotype was associated with hallucinations and anxiety, A‐491T with irritability, T‐427C with agitation/aggression and appetite disturbances, and T‐219C with depression. Haplotype analyses of all variants did not reveal any statistically significant findings.

Conclusions

Our data and a review of previous studies showed a diversity of relationships, suggesting that these findings might be due to chance and so collectively do not support a role for the APOE gene in BPSD.Many patients with dementia display behavioural and psychological symptoms of dementia (BPSD). Unlike cognitive decline, BPSD do not continuously exist in a patient once they have occurred. Genetic determinants of BPSD in Alzheimer''s disease have been proposed from studies on families.^1,2,3 It has been hypothesised that the genes that increase the risk for Alzheimer''s disease may also determine the presence of BPSD.⁴ The ε4 allele of the apolipoprotein E (APOE) gene is the only risk factor robustly associated with Alzheimer''s disease. However, previous investigations on APOE have produced inconsistent findings on BPSD, with some researchers reporting associations with a variety of different symptoms and alleles^{4,5,6,7,8,9,10,11,12,13,14,15,16} (summarised in the table provided online at http://jnnp.bmjjournals.com/supplemental), whereas others find no relevant relationships.^{17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33} We used a large independent clinical cohort of patients with Alzheimer''s disease, with longitudinal data on BPSD to further extend these studies, and additionally investigated promoter polymorphisms of APOE, which have been shown to independently incur risk of Alzheimer''s disease in some studies.³⁴