Obsessive compulsive symptoms in bipolar disorder patients: a comorbid disorder or a subtype of bipolar disorder?

概述

在过去十年中，人们越来越关注同时符合两种或两种以上精神障碍诊断标准的患者。上述共病情况之一就是双相障碍合并强迫症，这在以双相障碍为主要诊断的患者中比较常见。但是，关于这种共病的诊断和治疗的研究很少，在中国尤为如此。现有的研究主要集中在小样本的横断面研究，因此它们在对理解这种共病情况的病因和病程作用有限。对有限的文献进行回顾发现这是双相障碍中一种相对严重的、难治性的亚型，只有少数情况可以被认为是一种共病障碍。要阐明这种共病的病因、预后以及合适的治疗方法，则需要大样本的前瞻性研究。

中文全文

本文全文中文版从2015年10月26日起在http://dx.doi.org/10.11919/j.issn.1002-0829.215091可供免费阅览下载 The Forum by Peng and Jiang[1] highlights the lack of literature about comorbid bipolar disorder and obsessive compulsive (OCD) disorder. To provide a preliminary summary of the available English-language literature, a search of PubMed using three relevant keywords (‘bipolar disorder’, ‘obsessive compulsive disorder’, and ‘comorbidity’) was conducted in July 2015. Only a few of the 176 papers retrieved by this search were directly related to the topic of interest: most of the relevant papers described the incidence and clinical features of comorbid bipolar disorder and OCD in relatively small samples of patients; some discussed the etiology and treatment of the comorbid condition; and a few reported on prospective, multi-center studies with relatively large samples. Bipolar-OCD comorbidity was first reported in a 1995 study from Germany[2] which found that more than half of all patients with bipolar disorder had experienced other mental disorders, including OCD, during the course of the bipolar disorder. The study reported that the prevalence of comorbid OCD was higher in patients with unipolar depression than among patients with bipolar disorder. A subsequent systematic review[3] of 64 relevant articles in 2014 reported that from 11 to 21% of persons with bipolar disorder experience comorbid OCD at some time during the course of their bipolar disorder. Most reports indicate that comorbid OCD exacerbates the symptoms of bipolar disorder and makes the diagnosis and treatment of bipolar disorder more difficult. Compared to OCD patients and bipolar disorder patients without other comorbid conditions, bipolar patients with comorbid OCD have: a) higher rates of obsessive ideas about sex and religion and lower rates of ritual checking;[4] b) higher rates of substance abuse (including use of alcohol, sedatives, caffeine, etc.);[5,6] more episodes of depression, higher rates of suicide, and more frequent admissions to hospitals;[7] and d) more chronic episodes and residual symptoms.[8,9] There were no differences between bipolar patients with and without comorbid OCD in age, gender, education, marital status, age of onset of bipolar disorder, personality, prevalence of psychotic symptoms or rapid cycling, history of suicide attempts, the type of initial bipolar episode (i.e., depressed or manic), and the type of episode that was most prevalent throughout the course of bipolar disorder.[9] The systematic review by Amerio and colleagues[3] found that compared to bipolar patients without comorbid OCD, patients with bipolar disorder with comorbid OCD were more likely to experience OCD symptoms during an affective disorder episode (75% v. 3%), had a higher mean (sd) number of depressive episodes (8.9 [4.2] v. 4.1 [2.7] episodes), and were more likely to experience an antidepressant-induced manic episode (39% v. 9%). They also found that among patients with comorbid bipolar disorder and OCD, OCD symptoms were more like to occur during depressive episodes than manic episodes (78% v. 64%). Based on their findings, these authors argue that the obsessive-compulsive symptoms observed in these patients were secondary to bipolar disorder, not a co-occurring independent disorder.[3] Following this logic, I recommend that the occurrence of obsessivecompulsive symptoms during the depressive (or manic) episodes of a bipolar disorder should not be sufficient to merit a diagnosis of comorbid bipolar disorder and OCD; this comorbid diagnosis should be restricted to situations in which a patient with bipolar disorder also meets the full OCD symptomatic and duration criteria when the patient is not experiencing a depressive or manic episode. There are only a few articles about the possible etiology of bipolar-OCD comorbidity. A long-term family study based on a multi-generational dataset[10] (cases registered from January 1969 to 2009 included 19, 814 with OCD, 58, 336 with schizophrenia, 48, 180 with bipolar disorders, and 14, 904 with schizoaffective disorder) found familial associations among individuals with bipolar disorder, OCD, and schizophrenia spectrum disorders. There are also few reports about the long-term prognosis of comorbid bipolar disorder and OCD. One study[11] that followed 20 patients with bipolar disorder without comorbid disorders and 20 patients with comorbid bipolar disorder and OCD for 4 years found no significant differences in the long-term outcomes between the two groups. The treatment of bipolar-OCD comorbidity is difficult because the use of antidepressants to treat obsessive compulsive disorder may induce manic episodes. The existing literature about the treatment is primarily composed of case reports, retrospective cross-sectional studies, and a few treatment studies with small samples. A recent systematic review that combined the results of four treatment studies[12] found that 42% of patients with comorbid bipolar disorder and OCD were simultaneously treated with multiple mood stabilizers and another 10% needed combined treatment with mood stabilizers and anti-psychotic medications. One of the four studies reported that the combined use of antidepressants and mood stabilizers was effective and another study reported that some patients benefitted from the combined use of mood stabilizers and psychological therapy.[11] Based on currently available information, I recommend that patients with comorbid bipolar disorder and OCD be initially treated with mood stabilizers; if mono-therapy with mood stabilizers is ineffective, adjunctive treatment with selective serotonin reuptake inhibitor antidepressants (which are less likely to induce mania) should be considered. In my opinion, the basic treatment for bipolar-OCD is mood stabilizers and could be combined with antidepressants if the patients do not respond to the single treatment (ineffective). Despite ongoing debates about the etiology, diagnosis, and treatment of comorbid bipolar disorder and OCD, the clinicians who regularly treat bipolar patients need more high-quality, evidence-based information to improve their identification and management of this relatively severe and refractory subgroup of bipolar patients. Well-designed prospective studies with relatively large samples that are specifically focused on this important subgroup of bipolar disorder patients are needed.     

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

Background

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

Methods

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

Results

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

Conclusion

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

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.     

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.     

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.     

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.     

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).     

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     

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.     

Fatigue and activity dependent changes in axonal excitability in amyotrophic lateral sclerosis

Background

While patients with amyotrophic lateral sclerosis (ALS) may complain of fatigue, the underlying mechanisms appear complex, with dysfunction of central and peripheral nervous systems independently reported as contributing factors. The aim of the present study was to further delineate the mechanisms underlying increased fatigability in ALS by measuring activity dependent changes in axonal excitability following a maximum voluntary contraction (MVC).

Methods

Nerve excitability changes were recorded before and after an MVC of the abductor pollicis brevis in 16 patients with ALS and 25 controls.

Results

In patients with ALS, there was a greater increase in threshold (36.5 (5.9)%; controls 19.6 (3.5)%; p<0.05) as a result of MVC, with reduction in the amplitude of the compound muscle action potential generated by a submaximal stimulus (ALS 49 (7.6)%; controls 41.0 (5.4)%). These changes were associated with an increase in superexcitability (ALS 65.1 (25.4)%; controls 42.3 (5.7)%) and reduction in strength–duration time constant (ALS 20 (4.9)%; controls 10 (2.5)%; p<0.01), indicative of axonal hyperpolarisation. The increase in threshold was more pronounced in patients with ALS with predominantly lower motor neuronal involvement.

Conclusions

Higher firing rates of surviving motor axons attempting to compensate for neurogenic weakness are likely to explain the greater activity dependent changes in ALS. As such, the present study suggests a further peripheral factor underlying the development of fatigue in ALS.Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that affects motor neurones in the spinal cord, brainstem and motor cortex.^1,2 The consequences of this neurodegeneration are motor deficits in the limbs, bulbar and respiratory muscles.³ Although the mechanisms of neuronal dysfunction, and ultimately the development of symptoms in ALS, remain unknown, glutamate excitotoxicity,^4,5,6 increased levels of inducible nitric oxide synthase levels⁴ and, in cases of inherited ALS, oxidative stress secondary to mutations in the superoxide dismutase‐1 gene, have been proposed.^7,8,9,10Increased fatigability, defined as an inability to sustain a predictable maximal force during voluntary contraction, is a common symptom of ALS.^11,12,13 The mechanisms underlying fatigue in ALS are complex, and contributions from both the central and peripheral nervous systems have been reported.^11,12 Central fatigue refers to a reduced excitatory drive to motor neurones, secondary to central nervous system dysfunction, resulting in incomplete motor unit recruitment and submaximal motor unit discharge rates. In contrast, peripheral fatigue typically refers to impaired muscle activation, caused by dysfunction at or below the anterior horn cell.^13,14 Perhaps somewhat counterintuitively, fatigue in ALS appears to be independent of muscle strength and disease severity.^15,16 Regardless of the underlying mechanism, fatigue in ALS severely impacts on the patient''s quality of life.^15,16The ability to sustain a motor output may be assessed by measuring changes in axonal membrane threshold following a voluntary contraction. Specifically, in peripheral nerves, voluntary contraction activates the axonal membrane Na⁺/K⁺ pump,¹⁷ which attempts to return the resting membrane potential to baseline after contraction has ceased,^18,19,20,21 resulting in activity dependent hyperpolarisation. The magnitude of activity dependent hyperpolarisation is determined by the impulse load²² and, in neurological diseases where the safety margin for impulse conduction has been reduced as occurs for instance in demyelinating neuropathy, may be sufficient to induce conduction failure.^23,24,25 In an attempt to further delineate the mechanisms underlying fatigability and weakness in ALS, the present study measured activity dependent changes in axonal excitability induced by voluntary contraction.