Jens Carsten Möller

The REM sleep behavior disorder screening questionnaire--a new diagnostic instrument.

Many patients with assumed idiopathic REM sleep behavior disorder (RBD) may actually represent an early clinical manifestation of an evolving neurodegenerative disorder, such as the α‐synucleinopathies, Parkinsons disease or multiple system atrophy. Early detection of these patients is clinically relevant for long‐term prospective as well as future neuroprotective studies. For this purpose, we validated a 10‐item patient self‐rating questionnaire (maximum total score 13 points) covering the clinical features of RBD. The RBD screening questionnaire (RBDSQ) was applied to 54 patients with polysomnographically confirmed RBD (29 men; mean age 53.7 ± 15.8 years), 160 control subjects (81 men; mean age 50.8 ± 15.5 years) in whom RBD was excluded by history and polysomnography (PSG, control group 1) and 133 unselected healthy subjects (58 men; mean age 46.9 ± 12.3 years; no PSG, control group 2). In most subjects (n = 153) of control group 1, other sleep‐wake disturbances were present. The mean RBDSQ score in the RBD group was 9.5 ± 2.8 points compared with 4.6 ± 3.0 points in control group 1 (P < 0.0001). Considering an RBDSQ score of five points as a positive test result, we found a sensitivity of 0.96 and a specificity of 0.56. The RBDSQ poorly discriminated patients with the most challenging differential diagnoses such as sleepwalking or epilepsy. In control group 2, the mean RBDSQ score (2.02 ± 1.78) was significantly lower than in the RBD group (P < 0.0005), revealing a specificity of 0.92. Due to its high sensitivity, the RBDSQ appears to be particularly useful as a screening tool.

Driving in Parkinson's disease : Mobility, accidents, and sudden onset of sleep at the wheel

Only few studies have addressed driving ability in Parkinsons disease (PD) to date. However, studies investigating accident proneness of PD patients are urgently needed in the light of motor disability in PD and—particularly—the report of “sleep attacks” at the wheel. We sent a questionnaire about sudden onset of sleep (SOS) and driving behavior to 12,000 PD patients. Subsequently, of 6,620 complete data sets, 361 patients were interviewed by phone. A total of 82% of those 6,620 patients held a driving license, and 60% of them still participated in traffic. Of the patients holding a driving license, 15% had been involved in and 11% had caused at least one accident during the past 5 years. The risk of causing accidents was significantly increased for patients who felt moderately impaired by PD, had an increased Epworth Sleepiness Scale (ESS) score, and had experienced SOS while driving. Sleep attacks at the wheel usually occurred in easy driving situations and resulted in typical fatigue‐related accidents. Those having retired from driving had a more advanced (subjective) disease severity, higher age, more frequently female gender, an increased ESS score, and a longer disease duration. The study revealed SOS and daytime sleepiness as critical factors for traffic safety in addition to motor disabilities of PD patients. The results suggest that real sleep attacks without any prior sleepiness are rare. However, our data underline the importance of mobility for patients and the need for further studies addressing the ability to drive in PD.

Pain sensitivity and descending inhibition of pain in Parkinson’s disease

Background: Patients suffering from Parkinson’s disease (PD) often complain about painful sensations. Recent studies detected increased subjective pain sensitivity and increased spinal nociception, which appeared to be reversible by dopaminergic treatment. Possibly, reduced descending pain inhibition contributes to this finding. Objective: Subjective pain thresholds as well as nociceptive reflex thresholds were investigated to isolate potential loci of the pathophysiological changes within the pain pathway. In addition, the diffuse noxious inhibitory control (DNIC) system as one form of descending control was assessed. Method: 15 patients with PD and 18 controls participated in the study. Electrical and heat pain thresholds as well as the nociceptive flexion reflex (NFR) thresholds were determined. Thereafter, the electrical pain thresholds were measured once during painful heat stimulation (conditioning stimulation) and twice during innocuous stimulation (control stimulation). Results: Patients with PD exhibited lower electrical and heat pain thresholds as well as lower NFR thresholds. Suppression of the electrical pain thresholds during painful heat stimulation (conditioning stimulation) compared with control stimulation did not differ significantly between the groups. No differences in the thresholds between patients with PD with and without clinical pain were seen. Conclusions: Finding the NFR threshold to be decreased in addition to the decreased electrical and heat pain thresholds indicates that the pathophysiological changes either already reside at or reach down to the spinal level. Reduced activation of the DNIC system was apparently not associated with increased pain sensitivity, suggesting that DNIC-like mechanisms do not significantly contribute to clinical pain in PD.

Predictors of sudden onset of sleep in Parkinson's disease.

With respect to the ongoing discussion of “sleep attacks” in Parkinsons disease (PD), we sought to estimate the prevalence of sudden onset of sleep (SOS) with and without preceding sleepiness in PD, to identify associated factors, and to define the role of antiparkinsonian medication in SOS. We sent a questionnaire about SOS, sleep behaviour, and medication to 12,000 PD patients. The response rate was 63%, from which 6,620 complete data sets could be analysed. A total of 42.9% of our population reported SOS, 10% of whom never experienced sleepiness before the appearance of SOS (4.3% of all), and we identified the administration of all dopaminergic drugs as a risk factor for SOS. However, SOS occurred earlier after introduction of nonergoline dopamine agonists (DA) and was more strongly associated with nonergoline DA in younger patients (below 70 years) with a shorter disease duration (up to 7 years) but, actually, medication was less efficient in predicting SOS than most other factors considered such as higher age, male sex, longer disease duration, and the report of sleep disturbances. This survey strongly suggests that SOS is a multifactorial phenomenon. Some subgroups are at particular risk of experiencing SOS under nonergoline DA, especially at the beginning of this therapy. Our results support the current notion that SOS, in part, can be attributed to PD‐specific pathology because disease duration and subjective disease severity have been shown to be predictors of SOS. We recommend the development of a standardised question to recognise SOS and to facilitate the comparison of prevalence estimates.

Validation of the “L-DOPA test” for diagnosis of restless legs syndrome

We developed and validated a standardized test procedure to evaluate the accuracy of the supportive diagnostic criterion “response to dopaminergic treatment” in restless legs syndrome (RLS). Forty‐eight patients who fulfilled at least three of the four essential criteria for RLS, thus including uncertain clinical cases for a nonexpert, were recruited. Patients received a preliminary diagnosis of RLS or non‐RLS. All patients underwent a polysomnography (PSG) and were then asked to perform the diagnostic L‐DOPA test at home, which consisted in the application of one single dose of 100/25 mg L‐DOPA/benserazide and a subsequent observational period of 2 hours. Before, and in 15‐minute intervals after, drug intake, the patients rated the severity of the “symptoms in the legs” and the “urge to move the legs” using a 100‐mm visual analogue scale. Considering a 50% improvement as a positive test result, we found a sensitivity of 88% (“symptoms in the legs”) and 80% (“urge to move the legs”) with a specificity of 100% for both test items. A rate of 90% or 83% of all patients could be correctly diagnosed by the L‐DOPA test. Both scales were able to predict the response to dopaminergic agents in the subsequent course of the treatment by 100%. The periodic leg movements arousal index as assessed by polysomnography was less appropriate for the prediction of the correct diagnosis. We recommend the L‐DOPA test for diagnostic decision making in all patients with an unclear RLS diagnosis according to the essential diagnostic criteria of the International RLS Study Group.

Restless Legs Syndrome (RLS) and Parkinson's disease (PD)—Related disorders or different entities?

The relationship between Restless Legs Syndrome (RLS) and Parkinsons disease (PD) is still controversial. Most genetic, pathological, and imaging data argue against a close association of these two disorders. Still, many studies reported an increased prevalence of RLS in PD patients. These studies are difficult to interpret because the current diagnostic criteria for RLS have not been validated in PD patients. Although many PD patients suffer from motor restlessness due to parkinsonism and may thus mimic RLS, the risk for (secondary) RLS in PD patients is probably slightly increased. This review provides an overview of the current pertinent literature and discusses the possible association between RLS and PD.

Assessment of idiopathic rapid-eye-movement sleep behavior disorder by transcranial sonography, olfactory function test, and FP-CIT-SPECT

Idiopathic rapid‐eye‐movement (REM) sleep behavior disorder (iRBD) has been suggested to be a risk factor for subsequent development of neurodegenerative disorders, especially Parkinsons disease (PD) and other α‐synucleinopathies. At present, it is not possible to predict whether or not an iRBD patient will eventually develop PD. Here, we report 5 iRBD patients who underwent a test battery comprising a neurological examination (including UPDRS rating), mini mental state examination testing, transcranial sonography, olfactory function testing, and presynaptic dopamine transporter imaging with FP‐CIT‐SPECT. Our preliminary data show the diverse pattern of individual combinations of pathological findings when a multimodal assessment approach is applied in this patient group. Large‐size longitudinal studies in iRBD patients are required to evaluate the usefulness of diagnostic tests to identify the subgroup of iRBD patients that is prone to develop PD.

Pharmacotherapy of Parkinson’s disease in Germany

AbstractTreatment standards or guidelines have been developed for most features of Parkinson’s disease (PD). However, data on the actual treatment that is put into practice are scarce. In 2000, a nationwide survey on the topic of sudden onset of sleep (SOS) in PD was initiated among the members of the German patient support group (deutsche Parkinson–Vereinigung, dPV). A part of this mailed questionnaire survey covering the antiparkinsonian and concomitant medication of the participants is presented here. This study analyses data sets from more than 6,500 PD patients. The mean dopaminergic dose was equivalent to 599 ± 387 mg levodopa/die. The most frequently administered drugs were levodopa (94.2 %), dopamine agonists (DA) (71.7 %), amantadine (40.1 %), selegiline (27.6 %), entacapone (20.4 %), budipine (12.3 %), and anticholinergics (11.8 %). Costs of pharmacotherapy were estimated to be approximately € 399 million/year in Germany. PD drug therapy in general strongly depended on age, disease duration, and the level of care. The treatment guidelines were apparently not consistently followed underlining the need for their continuous propagation throughout the medical community. In addition our data suggest that non–motor symptoms in PD are not adequately treated and that concomitant sedative medication contributes to the occurrence of SOS.

The alpha-synuclein gene in multiple system atrophy

Background: The formation of α-synuclein aggregates may be a critical event in the pathogenesis of multiple system atrophy (MSA). However, the role of this gene in the aetiology of MSA is unknown and untested. Method: The linkage disequilibrium (LD) structure of the α-synuclein gene was established and LD patterns were used to identify a set of tagging single nucleotide polymorphisms (SNPs) that represent 95% of the haplotype diversity across the entire gene. The effect of polymorphisms on the pathological expression of MSA in pathologically confirmed cases was also evaluated. Results and conclusion: In 253 Gilman probable or definite MSA patients, 457 possible, probable, and definite MSA cases and 1472 controls, a frequency difference for the individual tagging SNPs or tag-defined haplotypes was not detected. No effect was observed of polymorphisms on the pathological expression of MSA in pathologically confirmed cases.

Pain sensitivity and clinical progression in Parkinson's disease.

Pain sensitivity in Parkinsons disease is known to be altered in an L‐dopa‐dependent manner with increased spinal nociception and experimental pain perception in the medication‐defined “off” state. As Parkinsons disease‐related pain can be an early symptom in Parkinsons disease, the present study aimed to investigate experimental pain sensitivity and spinal nociception during clinical progression. The nociceptive flexion reflex as a marker of spinal nociception as well as electrical and heat pain thresholds were assessed during the medication‐defined “off” state in 29 patients with Parkinsons disease divided into 3 severity groups (according to their Unified Parkinsons Disease Rating Scale motor score) and compared with 27 healthy elderly subjects. Parkinsons disease‐related pain was also quantified. Data provided evidence that spinal nociception and pain sensitivity are preserved during the early phase of Parkinsons disease. Following increased spinal nociception (F1,36 = 6.838, P = .013), experimental thermal and electrical pain sensitivity were augmented during the course of Parkinsons disease (F1,34 = 5.397, P = .014; F1,34 = 6.038, P = 0.053), whereas spinal nociception further increased (F1,34 = 5.397, P < .001). Increased experimental pain sensitivity was observed in patients exhibiting Parkinsons disease‐related pain. Spinal alterations either on the local level or induced by diminished dopaminergic descending inhibition probably led to increased pain sensitivity in later stages. Because Parkinsons disease‐related pain is correlated with experimental pain sensitivity these 2 observations likely reflect a causal relation.