Sebastian Paus

Sleep attacks, daytime sleepiness, and dopamine agonists in Parkinson's disease

To study the putative association of dopamine agonists with sleep attacks in patients with Parkinsons disease (PD) and their relation to daytime sleepiness, we performed a survey of 2,952 PD patients in two German counties. In 177 patients, sudden, unexpected, and irresistible sleep episodes while engaged in some activity were identified in a structured telephone interview. Ninety‐one of these patients denied the occurrence of appropriate warning signs. A total of 133 patients (75%) had an Epworth Sleepiness Scale (ESS) score >10; 65 (37%) >15. Thirty‐one patients (18%) had an ESS score ≤10 and yet experienced sleep attacks without warning signs. Thus, although a significant proportion of patients at risk for sleep attacks might be identified using the ESS, roughly 1% of the PD patient population seems to be at risk for sleep attacks without appropriate warning signs and without accompanying daytime sleepiness. Sleep attacks occurred with all dopamine agonists marketed in Germany (α‐dihydroergocryptine, bromocriptine, cabergoline, lisuride, pergolide, pramipexole, ropinirole), and no significant difference between ergot and nonergot drugs was evident. Levodopa (L‐dopa) monotherapy carried the lowest risk for sleep attacks (2.9%; 95% confidence interval [CI], 1.7–4.0%) followed by dopamine agonist monotherapy (5.3%; 95% CI, 1.5–9.2%) and combination of L‐dopa and a dopamine agonist (7.3%; 95% CI, 6.1–8.5%). Neither selegeline nor amantadine or entacapone appeared to influence the occurrence of sleep attacks. A high ESS score, intake of dopamine agonists, and duration of PD were the main influencing factors for the occurrence of sleep attacks. The odds ratio for dopamine agonist therapy was 2.9 compared to 1.9 with L‐dopa therapy and 1.05 for a 1‐year‐longer disease duration.

Bright light therapy in Parkinson's disease: a pilot study.

Several observations suggest a beneficial effect of melatonin antagonism for Parkinsons disease (PD). Although bright light therapy (BLT) suppresses melatonin release and is an established treatment for depression and sleep disturbances, it has not been evaluated in PD. We examined effects of BLT on motor symptoms, depression, and sleep in PD in a randomized placebo‐controlled double‐blind study in 36 PD patients, using Parkinsons Disease Rating Scale (UPDRS) I–IV, Becks Depression Inventory, and Epworth Sleepiness Scale. All patients received BLT for 15 days in the morning, 30 min daily. Illuminance was 7.500 lux in the active treatment group and 950 lux in the placebo group. Although group differences were small, BLT led to significant improvement of tremor, UPDRS I, II, and IV, and depression in the active treatment group but not in the placebo group. It was very well tolerated. Follow up studies in more advanced patient populations employing longer treatment durations are warranted.

Modulation of the cerebello-thalamo-cortical network in thalamic deep brain stimulation for tremor: a diffusion tensor imaging study.

BACKGROUND Deep brain stimulation alleviates tremor of various origins. Several regions like the ventralis intermediate nucleus of thalamus, the caudal zona incerta, and the posterior subthalamic region are generally targeted. Previous work with fiber tractography has shown the involvement of the cerebello-thalamo-cortical network in tremor control. OBJECTIVE To report the results of a prospective trial in a group of patients with tremor who underwent post hoc tractographic analysis after treatment with traditional thalamic deep brain stimulation. METHODS A total of 11 patients (aged 64 ± 17 years, 6 male) were enrolled (essential tremor [6], Parkinson tremor [3], and myoclonic tremor in myoclonus dystonia [2]). Patients received 1 (3 patients), 2 (7 patients), or 3 (1 patient) quadripolar electrodes. A 32-direction diffusion tensor magnetic resonance imaging sequence was acquired preoperatively. Tractography was processed postoperatively for evaluation and the dentato-rubro-thalamic tract (DRT) was individually tracked. Electrode positions were determined with helical computed tomography. Electric fields (EFs) were simulated according to individual stimulation parameters in a standardized atlas brain space (ICBM-MNI 152). RESULTS Tremor was reduced in all patients (69.4% mean) on the global (bilateral) tremor score. Effective contacts were located inside or in proximity to the DRT. In moderate tremor reduction (2 patients), the EFs were centered on its anterior border. In good and excellent tremor reduction (9 patients), EFs focused on its center. CONCLUSION Deep brain stimulation of the cerebello-thalamo-cortical network reduces tremor. The DRT connects 3 traditional target regions for deep brain stimulation in tremor disease. Tractography techniques can be used to directly visualize the DRT and, therefore, optimize target definition in individual patients.

Dopamine D3 receptor variant and tardive dyskinesia

Abstract In the search for genetic factors contributing to tardive dyskinesia, dopamine receptor genes are considered major candidates. The dopamine D3 receptor is of primary interest as dopamine D3 receptor knock-out mice show locomotor hyperactivation resembling extrapyramidal side-effects of neuroleptic treatment. Furthermore, Steen and colleagues (1997) recently reported an association between tardive dyskinesia and a dopamine D3 receptor gene variant.In the present study we tried to replicate this finding. We investigated 157 patients with schizophrenia or schizoaffective disorder receiving long-term neuroleptic medication who never or persistently displayed tardive dyskinesia. As advanced age is a main risk factor for tardive dyskinesia, we also compared older patients with a long duration of schizophrenia not displaying tardive dyskinesia to younger patients with a shorter duration of the illness displaying tardive dyskinesia. However, we found no evidence that the dopamine D3 receptor gene is likely to confer susceptibility to the development of tardive dyskinesia.

Transcriptional profiling in human epilepsy: expression array and single cell real-time qRT-PCR analysis reveal distinct cellular gene regulation.

Highly parallel expression monitoring by microarrays is a powerful tool to study human brain disorders. In contrast to various nonneuronal tissues, the CNS is composed of a multitude of different cell types. Changed mRNA levels in neuropathological conditions may simply reflect altered tissue composition, rather than specific gene transcription regulation. Therefore, it is crucial, to supplement expression array data of histologically heterogeneous brain samples with a detailed analysis at the cellular level. Here, we have used a two-step approach to identify specific changes in hippocampal gene expression in patients with a hippocampal seizure focus (TLE) and marked neuronal damage. Using comparative expression array hybridization, 21 genes appeared to be differentially regulated. Expression alterations of a subset of these genes, i.e. (up-regulation of ataxin-3 and glial fibrillary acid protein (GFAP) as well as down-regulation of calmodulin) was confirmed in an extended series of individuals by real-time quantitative RT-PCR (qRT-PCR). In order to determine the cellular localization of these mRNAs, we performed real-time qRT-PCR of individual laser-microdissected neurons and glial cells. While ataxin-3 was expressed only in hippocampal neurons, GFAP was detected in reactive astrocytes. The differential calmodulin expression found on the tissue level was not observed in mRNA analyses from single neurons, suggesting that lower calmodulin mRNA levels are a consequence of segmental cell loss and do not indicate reduced cellular expression. Ataxin-3 has been related to neuronal maintenance. Its functional role for TLE has to be further evaluated.

Association study of dopamine D2, D3, D4 receptor and serotonin transporter gene polymorphisms with sleep attacks in Parkinson's disease.

Sleep attacks are a common yet only recently recognized phenomenon in patients with Parkinson’s disease (PD). Initially reported to occur only with particular dopamine agonists, sleep attacks have been observed with all dopaminergic drugs.1–3 In the majority of affected patients, sleep attacks are a stable phenomenon and occur with and without excessive daytime sleepiness.2 Presence or absence of warning signs preceding a sleep attack have received particular interest, as sleep attacks without warning signs might be especially dangerous. It is conceivable that intrinsic variations of the sleep regulating systems in interaction with dopaminergic drugs may provoke the occurrence of sleep attacks. To test if genetic variants of the different dopamine receptors or the serotonin transporter contribute to the etiology of sleep attacks, we examined four known polymorphisms of the genes for dopamine receptors 2, 3, and 4 (DRD2 141C del/ins; DRD2 TaqIA; DRD3 Ser9Gly; DRD4 48 base pair [bp] repeat), and the 5-HTTLPR polymorphism in the serotonin transporter gene (SERT) in a community based case control study. We found an association between sleep attacks without warning signs and the DRD4*2 (short) allele.

Meningioma of the optic nerve sheath: treatment with hydroxyurea

The best treatment of optic nerve sheath meningiomas remains controversial. Recent reports have emphasised the efficacy of fractionated stereotactic or conformal radiotherapy, and some clinicians favour this approach instead of surgery or observation.1,2 On the other hand, a beneficial effect of hydroxyurea on unresectable, residual, and recurrent meningiomas has been reported in various series.3–5 We report a patient with a meningioma of the optic nerve sheath and nearly complete visual loss who was successfully treated with hydroxyurea alone. A 46 year old woman presented with painless and progressive right sided visual failure for two years. On admittance, visual acuity of the right eye was 0.05. In addition, there was an afferent pupillary defect, and swelling of the optic disc. Otherwise, the neurological examination was normal. Cranial magnetic resonance imaging (MRI) revealed a homogeneously enhancing, fusiform tumour (5 × …

Schizophrenia and the serotonin transporter gene.

&NA; A case control study was conducted among cases with schizophrenia (DSM IV criteria) and screened adult controls from three cohorts. Bi‐allelic polymorphisms in the promoter region of the serotonin transporter gene (5‐HTT) were examined in conjunction with those of the serotonin 5‐HT2a receptor (HTR2). No significant association with 5‐HTT was detected among US Caucasians (n = 207), African‐Americans (n = 84) or Caucasians from Sweden (n = 221). However, survival analysis suggested an association with the age at onset among the Swedish cases. The association should be considered tentative as it was not evident in the smaller US samples. The following exploratory analyses among the US samples were also not significant: associations with subgroups of patients based on familiality or response to medications, or altered risk due to the joint effects of 5‐HTT and HTR2 genotypes. Psychiatr Genet 8:207‐212

The DRD2 TaqIA polymorphism and demand of dopaminergic medication in Parkinson's disease

Previous studies have demonstrated that the TaqIA polymorphism of the D2 dopamine receptor gene (DRD2) is associated with response to dopaminergic and antidopaminergic treatment in Parkinsons disease (PD) and schizophrenia, respectively. We tested whether the TaqIA genotype in PD is responsible for demand of dopaminergic medication, measured in total dopaminergic load per year of disease, in a large scale association study based on the gene bank of the German Competence Network on Parkinsons disease. Regression analysis yielded no significant differences between the TaqIA genotypes. We conclude that the DRD2 TaqIA polymorphism alone has no pivotal role for interindividual variability of dopaminergic requirement in PD. We propose a practicable system of measuring dopaminergic treatment for future pharmacogenetic studies in PD.

Lack of association between the interleukin-1 alpha (-889) polymorphism and early-onset Parkinson's disease

An increasing number of studies have shown that an inflammatory process is part of Parkinsons disease (PD) brain pathology. Interleukin-1 (IL-1) is a multifunctional cytokine and is considered to contribute to several inflammatory diseases. Recently, we detected an associated risk in a subgroup of PD patients with a disease onset < 50 years and a C to T transition in the IL-1alpha promoter (-889). One-hundred-seventy-six German PD patients (42.1 +/- 6.4 years; 42.4% male) and 170 unrelated age-matched control individuals (40.4 +/- 8.7 years; 57.6% male) were investigated for the presence of the IL-1alpha (-889C/T) polymorphism. No significant difference in the allelic distribution of the analyzed IL-1alpha polymorphism has been found between PD and controls. We conclude that the C/T polymorphism in the IL-1alpha promoter region at -889 does not increase the risk to develop PD.