Interpretation of clinical trials comparing different drug regimens for Parkinson's disease (PD) is complicated by the different dose intensities used: higher doses of levodopa and, possibly, other drugs produce better symptomatic control but more late complications. To address this problem, conversion factors have been calculated for antiparkinsonian drugs that yield a total daily levodopa equivalent dose (LED). LED estimates vary, so we undertook a systematic review of studies reporting LEDs to provide standardized formulae. Electronic database and hand searching of references identified 56 primary reports of LED estimates. Data were extracted and the mean and modal LEDs calculated. This yielded a standardized LED for each drug, providing a useful tool to express dose intensity of different antiparkinsonian drug regimens on a single scale. Using these conversion formulae to report LEDs would improve the consistency of reporting and assist the interpretation of clinical trials comparing different PD medications.

Systematic review of levodopa dose equivalency reporting in Parkinson's disease

At no time in the past have the basic and clinical sciences applied to Parkinson's disease been so active. Experimental therapies under study at present promise to improve on the limitations of existing treatments. Future progress in understanding the causation and pathogenesis of the disorder will permit the development of new treatments that will slow, halt, or even reverse the currently inexorable progressive course of Parkinson's disease.

Parkinson's disease. Second of two parts.

High-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN-HFS) is the preferred surgical treatment for advanced Parkinson's disease. In the 15 years since its introduction into clinical practice, many studies have reported on its benefits, drawbacks, and insufficiencies. Despite limited evidence-based data, STN-HFS has been shown to be surgically safe, and improvements in dopaminergic drug-sensitive symptoms and reductions in subsequent drug dose and dyskinesias are well documented. However, the procedure is associated with adverse effects, mainly neurocognitive, and with side-effects created by spread of stimulation to surrounding structures, depending on the precise location of electrodes. Quality of life improves substantially, inducing sudden global changes in patients' lives, often requiring societal readaptation. STN-HFS is a powerful method that is currently unchallenged in the management of Parkinson's disease, but its long-term effects must be thoroughly assessed. Further improvements, through basic research and methodological innovations, should make it applicable to earlier stages of the disease and increase its availability to patients in developing countries.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(08)70291-6.pdf

Deep brain stimulation of the subthalamic nucleus for the treatment of Parkinson's disease

Hallucinations, mainly of a visual nature, are considered to affect about one-quarter of patients with Parkinson's disease. They are commonly viewed as a side-effect of antiparkinsonian treatment, but other factors may be involved. The aim of this study was to determine the phenomenology, prevalence and risk factors of hallucinations in Parkinson's disease. Two-hundred and sixteen consecutive patients fulfilling clinical criteria for Parkinson's disease were studied. Demographic and clinical variables were recorded, including motor and cognitive status, depressive symptoms and sleep-wake disturbances. Patients with and without hallucinations were compared using non-parametric tests, and logistic regression was applied to significant data. Hallucinations had been present during the previous 3 months in 39.8% of the patients, and fell into three categories: minor forms, consisting of a sensation of a presence (person), a sideways passage (commonly of an animal) or illusions were present in 25.5% of the patients (an isolated occurrence in 14.3%), formed visual hallucinations were present in 22.2% (isolated in 9.3%) and auditory hallucinations were present in 9.7% (isolated in 2.3%). Patients with minor hallucinations had a higher depression score than non-hallucinators but did not differ in other respects. Logistic regression analysis identified three factors independently predictive of formed visual hallucinations: severe cognitive disorders, daytime somnolence and a long duration of Parkinson's disease. These findings indicate that, when minor hallucinations are included, the total prevalence is much higher than previously reported. A simple side-effect of dopaminergic treatment is not sufficient to explain the occurrence of all visual hallucinations. The main risk factor in treated patients is cognitive impairment, although sleep-wake cycle disturbances, and possibly other factors related to the duration of the disease, act as cofactors.

/pdf/hallucinations-in-parkinson-s-disease-prevalence-3d2uc6a357.pdf

Hallucinations in Parkinson's disease: prevalence, phenomenology and risk factors.

To clarify the mechanism underlying improvement of parkinsonian signs by high-frequency electrical stimulation (HFS) of the subthalamic nucleus (STN), we investigated the effects of STN HFS on neuronal activity of the internal and external segment of the globus pallidus (GPi and GPe, respectively) in two rhesus monkeys rendered parkinsonian by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. A scaled-down version of the chronic stimulating electrode used in humans, consisting of four metal contacts 0.50 mm in length each separated by 0.50 mm, was implanted through a cephalic chamber targeting the STN. Histological reconstruction revealed that the cathode was located in the STN in both monkeys. Extracellular recordings from a total of 110 pallidal neurons during STN stimulation were performed. Poststimulus time histograms of single neurons triggered by 2 Hz STN stimulation pulses at 2.4–3.0 V revealed short-latency excitations at 2.5–4.5 and 5.5–7.0 msec after stimulation onset and inhibitions at 1.0–2.5, 4.5–5.5, and 7.0–9.0 msec for both GPe and GPi neurons. These short-latency responses were present with 136 Hz stimulation, at voltages effective for alleviation of parkinsonian signs, resulting in a significant increase in mean discharge rate and a stimulus-synchronized regular firing pattern. These results indicate that activation of the STN efferent fibers and resultant changes in the temporal firing pattern of neurons in GPe and GPi underlie the beneficial effect of HFS in the STN in Parkinson's disease and further support the role of temporal firing patterns in the basal ganglia in the development of Parkinson's disease and other movement disorders.

https://www.jneurosci.org/content/jneuro/23/5/1916.full.pdf

Stimulation of the Subthalamic Nucleus Changes the Firing Pattern of Pallidal Neurons

The aim of this study was to compare, retrospectively, the value of chronic bilateral stimulation of the internal globus pallidus (GPi) and the subthalamic nucleus (STN) in patients with young onset Parkinson's disease. We selected 13 consecutive patients with similar characteristics at the time of surgery: age at onset < 40 years, disabling motor fluctuations (Hoehn and Yahr stage 4 or 5 in off-drug phases) and levodopa-induced dyskinesias (LID). Eight patients were operated on in the STN and five in the GPi. The Unified Parkinson's Disease Rating Scale (UPDRS), timed motor tests and a LID scale were compared in on- and off-drug conditions before surgery and 6 months after surgery on stimulation using the chronic electrical parameters found to improve best the motor state of the individual patient, without adverse effects. In off-drug phases, the motor score of the UPDRS was improved by 71% with STN stimulation and by 39% with GPi stimulation on average. This difference was statistically significant (P < 0.05). Whereas rigidity and tremor showed good improvement in both groups, the decrease in the akinesia score was more pronounced in the STN group. In the STN group, the improvement of all motor symptoms was very close, or equal, to the best levodopa response. Thus the levodopa test was predictive of outcome. The improvement in off-drug period motor handicap allowed a decrease in the levodopa-equivalent dose only in the STN group (-56%). The voltage, frequency and pulse width used for chronic stimulation were lower in the STN group. In the on-drug phases there was a marked improvement in LID in the GPi group, as measured by the dyskinesias score during an acute levodopa test, whereas there was only a small decrease in the STN group (P < 0.05). However, in the long term, the reduction of levodopa dosage in the STN group led to an indirect reduction of LID similar to that in the GPi group during activities of everyday life. In conclusion, the overall results favour the neurosurgical treatment of Parkinson's disease by stimulating the STN rather than the GPi.

Subthalamic nucleus or internal pallidal stimulation in young onset Parkinson's disease.

Background: Repetitive behaviours (RB) in patients with Gilles de la Tourette syndrome (GTS) are frequent. However, a controversy persists whether they are manifestations of obssessive-compulsive disorder (OCD) or correspond to complex tics. Methods: 166 consecutive patients with GTS aged 15–68 years were recruited and submitted to extensive neurological, psychiatric and psychological evaluations. RB were evaluated by the YBOCS symptom checklist and Mini International Neuropsychiatric Interview (M.I.N.I), and classified on the basis of a semi-directive psychiatric interview as compulsions or tics. Results: RB were present in 64.4% of patients with GTS (107/166) and categorised into 3 major groups: a ‘tic-like’ group (24.3%–40/166) characterised by RB such as touching, counting, ‘just right’ and symmetry searching; an ‘OCD-like’ group (20.5%–34/166) with washing and checking rituals; and a ‘mixed’ group (13.2%–22/166) with both ‘tics-like’ and ‘OCD-like’ types of RB present in the same patient. In 6.3% of patients, RB could not be classified into any of these groups and were thus considered ‘undetermined’. Conclusions: The results confirm the phenomenological heterogeneity of RB in GTS patients and allows to distinguish two types: tic-like behaviours which are very likely an integral part of GTS; and OCD-like behaviours, which can be considered as a comorbid condition of GTS and were correlated with higher score of complex tics, neuroleptic and SSRIs treatment frequency and less successful socio-professional adaptation. We suggest that a meticulous semiological analysis of RB in GTS patients will help to tailor treatment and allow to better classify patients for future pathophysiologic studies. Trial Registration: ClinicalTrials.gov NCT00169351

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Repetitive behaviours in patients with Gilles de la Tourette syndrome: tics, compulsions, or both?

Early onset torsion dystonia are rare movement disorders. Molecular defect is known for only a subgroup, consisting of a unique and recurrent mutation in the TOR1A gene. We undertook a nationwide census of French TOR1A-mutation carriers and the assessment of clinical associated signs. Overall, 53 index cases and 104 relatives were studied and haplotypes linked to the mutation constructed. The previously reported Ashkenazi-Jewish haplotype was found in 11 families with the remainder carrying distinct haplotypes suggesting independent mutation events. This study demonstrates the scarcity of this disease in France with estimated disease frequency of 0.13:100,000 and mutation frequency of 0.17:100,000.

/pdf/is-the-early-onset-torsion-dystonia-eotd-linked-to-tor1a-17j3dz32o7.pdf

Jing Xie

Papers

Subthalamic nucleus or internal pallidal stimulation in young onset Parkinson's disease.

Repetitive behaviours in patients with Gilles de la Tourette syndrome: tics, compulsions, or both?

Is the early-onset torsion dystonia (EOTD) linked to TOR1A gene as frequent as expected in France?