Dyskinesia Research Articles

Novel formulations and modes of delivery of levodopa.

Ever since its early clinical use in the 1960s, levodopa has remained the gold standard of symptomatic efficacy in the drug treatment of Parkinson's disease (PD). Motor response fluctuations and drug-induced dyskinesias seriously compromise the unparalleled symptomatic efficacy of l-dopa during long-term treatment. Discontinuous drug delivery resulting from the short half-life of l-dopa and erratic gastrointestinal absorption plays a major role in the pathophysiology of these motor complications. Several approaches to improve the pharmacokinetics and ways of administration of l-dopa are in different stages of clinical development and include novel formulations as well as nonoral routes of drug delivery. IPX066 is a novel extended-release l-dopa capsule that has successfully completed phase III clinical trials while the l-dopa prodrug XP21279 and a gastric retention formulation ("accordion pill") are in earlier phases of clinical development. Novel enzyme inhibitors enhancing l-dopa efficacy and half-life are also still being developed, including a novel catechol-O-methyltransferase inhibitor with once-daily pharmacokinetics, and there are studies testing the effects of increasing the dose of amino acid decarboxylase inhibitors given concomitantly with l-dopa. Intrajejunal infusion of a gel formulation of l-dopa/carbidopa is in clinical use in Europe, and its efficacy to smooth out motor fluctuations has recently been shown in a randomized, controlled trial. Subcutaneous and intrapulmonal delivery routes of l-dopa have reached phase III of clinical development. After more than 50 years of clinical use, l-dopa not only remains the gold standard of symptomatic efficacy, but it also remains a drug in active clinical development.

Bilateral subthalamic stimulation for advanced Parkinson disease: early experience at an Eastern center.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) can improve the life quality of patients with advanced Parkinson disease (PD). However, previous studies have stemmed mainly from Western centers. Present study analyzed the 6-month outcomes of bilateral STN-DBS therapy that were observed during a 9-year period at a Taiwanese institute. We retrospectively reviewed 72 consecutive patients, whose mean disease history was 8 years when they underwent surgery. The median "drug-off" Hoehn and Yahr stage was 3. The STN was targeted using T2-weighted magnetic resonance imaging and electrophysiological guidance. The over-time mean differences in the Unified PD Rating Scale (UPDRS) scores and daily levodopa-equivalent dose (LED) were assessed using the repeated measurements ANOVA at 3 and 6 months relative to those of presurgical drug-off baseline. At 6 months postsurgery, the mean UPDRS total, Part II and Part III subscores significantly decreased by 27, 30 and 25 %, respectively, with clinically high effect size. Tremors were markedly (66 %) ameliorated. Moreover, problems of akinesia, rigidity, and locomotion were significantly improved by 20 %. The mean daily LED needs decreased by 25 %; thus, drug-induced dyskinesia was markedly (80 %) diminished. STN-DBS therapy could provide similarly effective impacts to Eastern and Western PD patients. Preoperative optimal selection of patients and postoperative delicate programming ensure a better surgical improvement.

Total sacrectomy via posterior approach for malignant sacral tumors

Objective To investigate the surgical indication,approach,resection methods and complications of total sacrectomy via posterior approach for primary malignant sacral tumors involving high level (S1,S2).Methods 5 cases of primary malignant sacral tumors treated by total sacrectomy via posterior approach and iliolumbar reconstruction from March 2010 to March 2011 were analyzed retrospectively.There were 3 males and 2 females.The mean age was 41,ranging from 32 to 55.The imageology examination showed osteolytic destruction,among which there were 4 cases of obvious soft tissue mass,1 case of obvious sacral foramina expansion with bone damage.MRI showed 1 case of the tumors in S1-S5,1 case of the tumors in S1 、S2,1 case of the tumors in S1-S3.The smallest tumor was 9.2 cm×7.6 cm×4.1 cm,while the largest was 22.0 cm× 19.0 cm× 16.0 cm.Preoperative TTNB were done on the 5 patients.Pathological diagnosis:2 cases of chordoma,1 case of malignant neurilemmoma,1 case of chondrosarcoma and 1 case of malignant hemangioendothelioma.5 patients had sacrococcygeal pain or lumbocrural pain before the surgery.Visual analogue scale (VAS):2 cases of 2,2 cases of 6 and 1 case of 8.Ilium stability reconstructions were all performed on 5 patients with spine pedicle screw-rod system.Results The mean operation time was 6.5 hours (range,4.5-11 hours),with the mean intraoperative blood loss of 3 700 ml (range,2 000-7 200 ml).There was no perioperative death.The mean follow-up time was 17 months (range,9-23 months).There were 2 cases of wound complications 2 weeks after surgery and healed by second intention with washing and drainage after debridement.There was no deep infection.1 case of rectal injury,which was performed with colostomy during the operation,and stoma returned 12 weeks after surgery.4 cases of sciatic nerve symptom of lower limbs and plantar flexion dyskinesia after bilateral S1 nerve roots resection.The patients walked with ankle brace fixed after the surgery.There was 1 case of implant breakage and no obvious spine down.5 patients had functional disability in sphincter after surgery.1 case of hemangioendothelioma recurred locally 9 months later.Local radiotherapy was performed since there was no reoperation indication.The patient is currently on the 13th month follow-up and survives with tumors.Compared with combined approach,the selection of posterior approach alone has relatively strict surgery indications.Conclusion Total sacrectomy via posterior approach is an effective way to treat the primary high-level malignant sacral tumors.The good surgical resection boundary is important to achieve the good oncology prognosis.The occurrence rate of postoperative complication is high,which has great influence on patients' postoperative neurological function. Key words: Sacrum; Bone neoplasms; Surgical procedures, operative

Current therapy for Parkinson's disease

The main goal of therapy for Parkinson's disease (PD) is to correct dopamine deficiency in the nigrostriatal system. Levodopa preparations and dopamine receptor agonists (DRAs) that are prescribed with regards to patient age and disease severity are mainly used now. Notwithstanding the fact that levodopa preparations are the gold standard of therapy, their long-term use gives rise to complications as motor fluctuations and drug-induced dyskinesias. The currently available DRAs are the drugs of choice for the therapy of early-stage PD as they are as effective as levodopa preparations. In extensive-stage PD, DRAs are used to enhance the therapy and correction of developed motor fluctuations and dyskinesias. Pramipexole is one of the most commonly used representatives of non-ergoline DRAs. The paper analyzes the efficacy of the medication used as both monotherapy and part of combined therapy, its effect on tremor and depression in PD. A novel extended-release formulation of pramipexole is considered separately. Both immediate- and extended-release pramipexole formulations contain the same active ingredient and have the same dopamine-receptor interaction profile, but differ in the tablet release rate of the active ingredient. The advantages of the novel formulation are its more steady-state plasma concentration and 24-hour action, which ensures continuous dopaminergic stimulation of postsynaptic receptors to prevent and treat already developed motor complications. The once-daily extended-release formulation of the drug makes its treatment regimen easier and patient compliance higher.

The relationship between tumor location of low-grade gliomas and motor dysfunction: a neuroimaging analysis

Objective To explore the relationship between tumor location of low grade gliomas in motor area and motor dysfunction by drawing the dyskinesia risk map.Methods All of images of patient were registered to T1 weighted brain atlas (MNI152; Montreal Neurological Institute),calculating the overlay layer of motor dysfunction account for the total number of overlay for each voxel,in order to draw the dyskinesia risk map.Results The dyskinesia risk map was acquired by quantitive neuroimage analysis.The medial part of the hand knot had more effects on motor strength than the lateral part.The risk values of the lateral part of hand knot and secondary motor areas were lowest.From the lateral part to the medial,the risk values increased gradually from 40％ to 80％.Conclusions The dyskinesia risk map could demonstrate the relationship between low grade gliomas in motor area and motor dysfunction effectively,and predictively evaluate the motor dysfunction. Key words: Low-grade gliomas; Motor area; Muscle strength; Magnetic resonance imaging

Evaluation of the volume and volume fraction of the lateral ventricles in the Parkinsonism

Parkinson’s disease (PD) commonly begins in late middle age and the course is slowly progressive. Ventricular enlargement, a nonspecific measure of brain atrophy, has been associated with PD. The aim of this study is to perform the measurements of the cerebral hemispheres and lateral ventricles using magnetic resonance imaging (MRI) in combination with the stereology, to detect structural alterations in the Parkinsonism. 19 controls (9 female; 10 male) and 18 Parkinson’s disease (8 female; 10 male) were participated. Structural MRI was done for both groups using a Siemens 1.5 Tesla scanner. The DICOM images were analyzed using the Image software. The planimetry technique was done for assessment of the cut surface areas of the coronal sections. The volume and volume fractions of the lateral ventricles were estimated. The mean volumes of the right and left cerebral hemispheres in control and patient groups were 608.96 cm 3 , 606.94 cm 3 , and 603.41 cm 3 , 604.27 cm 3 , respectively. The mean volume fractions of the right and left cerebral hemispheres were 50.07%, 49.93% and 49.99%, 50.01%, respectively. The volume and volume fraction of the right and left lateral ventricles in control and patient groups were; 12.82 cm 3 , 2.08%, 14.76 cm 3 , 2.42%, and 16.75 cm 3 , 2.88%, 17.40 cm 3 , 2.98%, respectively. There were no statistically significant differences between the patients and the controls for the volume and volume fraction of the hemispheres and the ventricles (p≥0.05), except for the volume fraction of the hemispheres in the females (p≤0.05). The significant different in the volume fraction of the right and left cerebral hemispheres between control and patient females, which related to that the women experience more frequent dyskinesia or bad reactions to PD medications. The finding of asymmetrical lateral ventricular enlargement following the same pattern as motor asymmetry in PD.

Abnormal expression of connexin 36 plays a role in the pathogenesis of levodopa induced dyskinesia in rat model of Parkinson’ s disease

Objective To explore whether gap junction disturbances are involved in the pathogenesis of levodopa-induced dyskinesia (LID). Methods The hemi-parkinsonian (PD) rat was treated intraperitoneally with L-dopa methylester (20 mg/kg) and benserazid (10 mg/kg) for 21 days and abnormal involuntary movement was evaluated to establish LID rat model. The experimental animals were divided into three groups: LID group, PD group and normal control group，respectively．The behavior responses of intraperitoneal injection of different doses of carbenoxolon and intracerebroventricular injection of quinine were observed to estimate the effects of gap junctional blockade on the abnormal involuntary movement (AIM) in the rat model of LID. Double immunofluorescence labeling was used to analyze the expression of connexin 36 (Cx36) in enkephalin positive medium spiny neurons and parvalbumin (PV) positive interneurons in the striatum. Western blottings was used to observe the expression of Cx36 in the striatum and moter cortex. Results Behavioral characteristics indicated that high dose of carbenoxolone (>60 mg/kg) intraperitoneal injection and intracerebroventricular injection of quinine (0.5，1.0，2.0 μmol/L, >2.5 μmol/L) could decrease the AIM score of LID rats. Western blotting indicated that expression of Cx36 in lesioned striatum and motor cortex of LID rat model was 219.56%±18.12% and 226.03%±16.33%, respectively, which induced a significant upregulation in comparison with the normal control group (104.05%±3.82%, t=15.389, P<0.01; 105.27%±2.82%，t=8.074, P<0.01) and untreated PD group (119.31%±8.92%, t=13.356, P<0.01; 138.20%±17.88%, t=5.872, P<0.01). Double immunofluorescence labeling staining revealed that Cx36 expression was increased in Enk-positive striatum neurons in LID model (57.59%±5.36%) compared with that in normal control group (32.67%±4.22%) and PD group (37.24%±0.86%, F=78.060, P<0.01). The expression of Cx36 in PV-positive interneurons was also elevated in LID group (68.49%±11.60%) in comparison with normal control group (40.43%±2.30%) and PD group (31.92%±5.68%, F=39.567, P<0.01). Conclusions The Cx36 expression is generally increased in lesioned striatum and motor cortex of LID rat model. In the striatum, the up-regulation of Cx36 is specifically observed in Enk-positive striatum neurons and in PV-positive interneurons. The dyskinesia behavior of LID rats can be significantly reduced by treatment with gap junction blockade. All these results suggest that gap junction dysfunction may play an important role in the pathogenesis of LID. Key words: Parkinson disease; Dyskinesias; Connexins; Gap junctions; Disease models, animal

P305: Electrophysiological implementation for the prevention and management of Levodopa induced dyskinesia in Parkinson’s disease

P305: Electrophysiological implementation for the prevention and management of Levodopa induced dyskinesia in Parkinson’s disease

Role for the nicotinic cholinergic system in movement disorders; therapeutic implications.

A large body of evidence using experimental animal models shows that the nicotinic cholinergic system is involved in the control of movement under physiological conditions. This work raised the question whether dysregulation of this system may contribute to motor dysfunction and whether drugs targeting nicotinic acetylcholine receptors (nAChRs) may be of therapeutic benefit in movement disorders. Accumulating preclinical studies now show that drugs acting at nAChRs improve drug-induced dyskinesias. The general nAChR agonist nicotine, as well as several nAChR agonists (varenicline, ABT-089 and ABT-894), reduces l-dopa-induced abnormal involuntary movements or dyskinesias up to 60% in parkinsonian nonhuman primates and rodents. These dyskinesias are potentially debilitating abnormal involuntary movements that arise as a complication of l-dopa therapy for Parkinson's disease. In addition, nicotine and varenicline decrease antipsychotic-induced abnormal involuntary movements in rodent models of tardive dyskinesia. Antipsychotic-induced dyskinesias frequently arise as a side effect of chronic drug treatment for schizophrenia, psychosis and other psychiatric disorders. Preclinical and clinical studies also show that the nAChR agonist varenicline improves balance and coordination in various ataxias. Lastly, nicotine has been reported to attenuate the dyskinetic symptoms of Tourette's disorder. Several nAChR subtypes appear to be involved in these beneficial effects of nicotine and nAChR drugs including α4β2*, α6β2* and α7 nAChRs (the asterisk indicates the possible presence of other subunits in the receptor). Overall, the above findings, coupled with nicotine's neuroprotective effects, suggest that nAChR drugs have potential for future drug development for movement disorders.

Adaptive Gene Regulation in the Striatum of RGS9-Deficient Mice

BackgroundRGS9-deficient mice show drug-induced dyskinesia but normal locomotor activity under unchallenged conditions.ResultsGenes related to Ca2+ signaling and their functions were regulated in RGS9-deficient mice.ConclusionChanges in Ca2+ signaling that compensate for RGS9 loss-of-function can explain the normal locomotor activity in RGS9-deficient mice under unchallenged conditions.SignificanceIdentified signaling components may represent novel targets in antidyskinetic therapy. The long splice variant of the regulator of G-protein signaling 9 (RGS9-2) is enriched in striatal medium spiny neurons and dampens dopamine D2 receptor signaling. Lack of RGS9-2 can promote while its overexpression prevents drug-induced dyskinesia. Other animal models of drug-induced dyskinesia rather pointed towards overactivity of dopamine receptor-mediated signaling. To evaluate changes in signaling pathways mRNA expression levels were determined and compared in wild-type and RGS9-deficient mice. Unexpectedly, expression levels of dopamine receptors were unchanged in RGS9-deficient mice, while several genes related to Ca2+ signaling and long-term depression were differentially expressed when compared to wild type animals. Detailed investigations at the protein level revealed hyperphosphorylation of DARPP32 at Thr34 and of ERK1/2 in striata of RGS9-deficient mice. Whole cell patch clamp recordings showed that spontaneous synaptic events are increased (frequency and size) in RGS9-deficient mice while long-term depression is reduced in acute brain slices. These changes are compatible with a Ca2+-induced potentiation of dopamine receptor signaling which may contribute to the drug-induced dyskinesia in RGS9-deficient mice.

Dopamine Pumps for Parkinson Disease: Has the Time Come?

Oral treatments for Parkinson disease (PD) are limited mainly by the association with motor fluctuations and dyskinesia, leading to burgeoning interest in better, more continuous delivery strategies for advanced PD. In the trial, researchers tested the safety and efficacy of an intrajejunal levodopa–carbidopa intestinal gel infusion strategy that is investigational in the U.S. The manufacturer-sponsored, randomized, double-blind, double-dummy, double-titration trial was conducted at 26 centers in Germany, New Zealand, and the U.S. All participants underwent placement of a percutaneous gastrojejunostomy tube and were …

Clinical characteristics of primary ciliary dyskinesia

To analyze the clinical characteristics of primary ciliary dyskinesia(PCD) so as to improve the diagnostic level of this rarely seen disease. Ten patients with PCD were retrospectively reviewed, the medical history, symptoms, signs, lung CT or chest X-ray, rhino-sinus CT scan, nasal nitric oxide (NO) levels, nasal ciliary ultrastructure, DNAH5 and DNAH11 genetic mutation, as well as treatment outcome were analyzed. All 10 patients had recurrent chronic sinusitis, otitis media, bronchitis/bronchiectasis since childhood. Nine cases with translocation of heart and big vessels were diagnosed as Kartagener syndrome. One woman was suffering from barrenness and one man sterility after marriage for long time without birth control. Nasal NO levels were significantly lower in 2 patients with PCD but it was almost normal in one patient. Ciliary ultrastructure investigated by transmission electron microscope were almost normal in 4 cases without missing of inner or outer dynein arms. Two cases taking exome capture sequencing showed that mutations happened in DNAH5 and DNAH11. Five subjects underwenting sanger sequencing on 6 common exon fragments of DNAH5 and DNAH11 did not show any abnormality. Ten cases took medication therapy, while 5 patients once underwent functional endoscope sinus surgery. All of the 10 patients had improvement of their symptoms and signs after treatment. The PCD is so rare in clinic that it is easily misdiagnosed. Clinical characteristics, nasal NO levels, ciliary ultrastructure and genetic testing are significant for clinical diagnosis.

New perspectives in non-oral drug delivery in Parkinson's disease: Highlights of a satellite symposium held at the XX world congress on Parkinson's disease and related disorders, Geneva, Switzerland, 8-11 December 2013

Oral therapies, including levodopa, dopamine agonists and monoamine oxidase type B (MAO-B) inhibitors, form the mainstay of medical treatment for Parkinson's disease (PD). However, over time, chronic treatment with multiple daily doses of oral agents is often associated with the development of motor fluctuations and dyskinesias. Alternative methods of dopaminergic drug delivery, particularly if they bypass the gastrointestinal system, may be of value for PD patients who have developed motor complications despite optimised oral therapy, in particular those with gastrointestinal absorption issues, including gastroparesis. This satellite symposium, held at the XX World Congress on Parkinson's Disease and Related Disorders, Geneva, Switzerland, from 8-11 December 2013, was chaired by Professor Werner Poewe (Austria) and Professor Andrew Lees (UK) and discussed recent evidence regarding the benefits of using non-oral drug-delivery strategies with therapies such as subcutaneous apomorphine. Beginning with the history of apomorphine and its well-established use in PD both as an intermittent injection and a continuous infusion, the presenters set out the evidence for its efficacy in managing both motor and non-motor symptoms in PD. The significance of gastrointestinal involvement in PD and how this may influence responses to oral medications was also reviewed. Interim results from the ongoing Apokyn for Motor IMProvement of Morning AKinesia Trial (AM IMPAKT) study of the use of subcutaneous apomorphine in PD patients with morning akinesia were also presented and the continuing main role of apomorphine in the treatment of PD was discussed, including the selection of the most appropriate patients for this effective yet underused therapy.

Pharmacovigilance for psychiatrists: An introduction.

Byline: Ravi. Rajkumar, George. Melvin Patients with psychiatric disorders are often managed with pharmacotherapy. Because of the chronic and relapsing nature of some of these disorders, most practice guidelines recommend that medications should be continued for several months or years. [sup][1],[2],[3] As a result, patients are at risk of experiencing a variety of adverse drug reactions (ADRs). At times, these ADRs can be life-threatening (such as neuroleptic malignant syndrome) [sup][4] or disabling (such as drug-induced tardive dyskinesia). [sup][5] It is important for psychiatrists to be aware of the processes involved in identifying and reporting ADRs, especially those that are new or unrecognized. These processes form the basis for the medical discipline of pharmacovigilance. Pharmacovigilance has been defined by the World Health Organization (WHO) as the science and activities related to the detection, assessment, understanding, and prevention of adverse drug effects. [sup][6] As such, pharmacovigilance is not a specialist activity: It is one that must be carried out by all those involved in caring for patients on medication, including doctors, nurses, and pharmacists. [sup][7],[8] The birth of pharmacovigilance has a close relationship to psychiatry. In the 1960s, thalidomide was widely used in several countries to treat insomnia during pregnancy - a common problem affecting many women. It was soon noticed by physicians that babies exposed to the drug in utero developed congenital malformations, and it was this tragedy - related to a drug that was marketed as a safe sedative - that was the beginning of the field of pharmacovigilance. [sup][9] This relationship has continued to the present day. In a recent review of nine major ADRs reported in Europe from 1995 to 2008, two of them involved psychotropics - seizures with bupropion, and suicidality in children taking SSRI antidepressants. [sup][10] While the latter was identified by a re-analysis of data from the pharmaceutical industry, the former was identified through physician reports. In an analysis of ADRs reported to the FDA between 1998 and 2005, many of the frequently implicated drugs were psychotropics [sup][11] - antipsychotics (clozapine, olanzapine, risperidone), antidepressants (duloxetine, sertraline, paroxetine, bupropion), mood stabilizers (carbamazepine, valproate, lamotrigine), and even anti-ADHD medication (atomoxetine). Now, as then, clinicians have a key role in identifying and reporting new or serious adverse drug effects. Why is Pharmacovigilance Important in Psychiatry? Pharmacovigilance activities are an important part of medical practice in general. A meta-analysis found that around 5% of hospitalizations in a general medical setting are due to adverse drug effects. [sup][12] A study in a general hospital in France found that 3% of new admissions were due to ADRs, and 6.6% of patients developed a significant ADR during their hospital stay. [sup][13] However, there are four reasons why this field is of special importance to psychiatrists. First, pharmacotherapy is the principal modality of management in several psychiatric disorders. Most drugs used in psychiatry are frequently associated with ADRs. Often, patients do not respond to initial drug therapy, and may require several trials of different medications. [sup][14],[15] Some patients may require a combination of various drugs - polypharmacy - which can increase the risk of adverse effects or drug interactions. [sup][16] Second, most clinical trials of psychotropics are conducted in ideal conditions - patients are selected according to stringent criteria, and comorbid medical conditions are usually excluded. These trials also tend to be short-term, lasting for a few weeks or months. By contrast, the patients we encounter in practice often have more complex presentations and comorbid medical illnesses, and they remain under our care for longer periods of time. …

LEVODOPA–INDUCED MOTOR COMPLICATIONS IN AN INCIDENT PARKINSON'S DISEASE COHORT

BackgroundLevodopa is the mainstay of treatment for Parkinson's disease (PD) but is associated with potentially-disabling drug-induced motor fluctuations and dyskinesias. Previous studies have suggested that both of these complications develop...

Recent advances of paroxysmal kinesigenic dyskinesia

Paroxysmal kinesigenic dyskinesia (PKD) is the most frequently described subtype of paroxysmal dyskinesias.The precipitating factor is usually sudden movement or startle.Clinically, PKD cases suffer involuntary movements including unilateral or bilateral chorea, athetosis, dystonia or ballismus, with preserved consciousness.Family history is commonly noted in idiopathic PKD, but sporadic cases are also reported.Familial PKD is inherited in an autosomal dominant fashion with incomplete penetrance.To date, 2 loci 16p11-q12 and 16q13-q22 have been mapped to PKD, although a 3rd locus is also suspected.PRRT2, which was located in 16p12.1, was recently identified as causative gene of PKD.However, culprit genes in the other 2 loci remain to be investigated.The potential mechanism of PKD remains largely unclear and the role of mutant PRRT2 in the pathogenesis of PKD is still unknown.In this review, the recent advances of PKD were summarized and hypothesis regarding the mechanisms of PKD was put up, which may make significant contributions to the diagnosis and treatment of PKD. Key words: Paroxysmal kinesigenic dyskinesia; Causative gene; PRRT2

Melatonin synergizes with low doses of L‐DOPA to improve dendritic spine density in the mouse striatum in experimental Parkinsonism

The dopamine precursor, L-3,4-dihydroxyphenylalanine (L-DOPA), is the preferred drug for Parkinson's disease, but long-term treatment results in the drug-induced dyskinesias and other side effects. This study was undertaken to examine whether melatonin could potentiate low dose L-DOPA effects in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced experimental parkinsonism. Mice were treated with the parkinsonian neurotoxin, MPTP, and different doses of melatonin and low doses of L-DOPA. Behavior, striatal histology, and dopamine metabolism were evaluated on the 7th day. MPTP-induced striatal dopamine loss was not modified by melatonin administration (10-30mg/kg; i.p. at 10-hr intervals, 6 times; or at 2-hr intervals, by day). However, low doses of L-DOPA (5mg/kg, by oral gavage) administered alone or along with melatonin (10mg/kg, i.p.) twice everyday for 2days, 10hr apart, after two doses of MPTP significantly attenuated striatal dopamine loss and provided improvements in both catalepsy and akinesia. Additionally, Golgi-impregnated striatal sections showed preservation of the medium spiny neurons, which have been damaged in MPTP-treated mouse. The results demonstrated that melatonin, but not L-DOPA, restored spine density and spine morphology of medium spiny neurons in the striatum and suggest that melatonin could be an ideal adjuvant to L-DOPA therapy in Parkinson's disease, and by the use of this neurohormone, it is possible to bring down the therapeutic doses of L-DOPA.

Application of VEEG+SEMG in diagnosing different motor seizure types

To explore the value of video-electroencephalography plus surface electromyography (VEEG+SEMG) in providing theoretic rationales for clinical diagnosis of different motor seizure types and differentiating the application value of paroxysmal diseases. A total of 116 suspected and repetitive motion epileptics underwent VEEG+SEMG from 2009 to 2012. According to their clinical features, different muscles were selected to record electromyography (EMG) under different activations and stimulations (bodily movement and posture activation, touching, sound stimulus, tapping tendons and arms straight test, etc) and monitor their seizure states. Among 68 patients, 567 attacks were recorded, including 443 epileptic seizures in 41 patients (229 epileptic mycological seizures in 22 patients, 95 tonic seizures in 8, 118 epileptic spasms in 10 and 1 atonic seizure in 1). The average durations of different epileptic motor seizures were (0.16 ± 0.04), (2.9 ± 2.4), (1.4 ± 0.8) and 2 s respectively. Their features of ictal EEG and SEMG varied.Non-epileptic seizures were recorded, including 43 non-epileptic myoclonus (NEMS) in 2 patients 81 PKD in 25. The primary differential diagnoses of epileptic motor seizures were NEMS and paroxysmal kinesigenic dyskinesia (PKD). VEEG+SEMG is a reliable tool for diagnosing different types of epileptic seizures and differentiating among paroxysmal diseases.

Research progress and diagnostic strategy of genetic pathogenesis of dystonia

Dystonia is a syndrome of abnormal involuntary movements that are repetitive, twisting or patterned, and can result in abnormal postures. Genetic factors play an important role in the pathogenesis of dystonia. To date, at least 20 dystonic syndromes have been distinguished on a genetic basis ( DYT1-21 , except DYT14 ), 10 of which have had clear causing genes. Recently, major discoveries have appeared in the genetic field: mutations in the transcription factor THAP1 and DNA replication factor CIP1-interacting zinc finger protein 1 ( CIZ1 ) have been linked to adult-onset primary dystonia; proline-rich transmembrane protein 2 ( PRRT2 ) has been tied to paroxysmal kinesigenic dyskinesia; DYT14 has been redefined as DYT5 due to a deletion mutation in guanosine triphosphate cyclohydrolase 1 ( GCH1 ). In addition, the existing diagnostic algorithms for dystonic syndromes rely on the clinicians' experience, without a streamlined diagnostic pathway. Non-specialist clinicians and neurologists may, therefore, find diagnosis of dystonic syndromes difficult. This review focuses on the molecular and phenotypic features of the hereditary dystonias, with emphasis on recent advances. Also an eight-question approach is proposed in this review to inform specialists and general neurologists on the appropriate diagnostic test for each patient with a possible dystonic syndrome.

Advances in molecular genetic studies of primary dystonia

Dystonias are heterogeneous hyperkinetic movement disorders characterized by involuntary muscle contractions which result in twisting, repetitive movements and abnormal postures. In recent years, there was a great advance in molecular genetic studies of primary dystonia. This paper will review the clinical characteristics and molecular genetic studies of primary dystonia, including early-onset generalized torsion dystonia ( DYT1 ), whispering dysphonia ( DYT4 ), dopa⁃responsive dystonia ( DYT5 ), mixed-type dystonia ( DYT6 ), paroxysmal kinesigenic dyskinesia ( DYT10 ), myoclonus⁃dystonia syndrome ( DYT11 ), rapid-onset dystonia parkinsonism ( DYT12 ), adult-onset cervical dystonia ( DYT23 ), craniocervical dystonia ( DYT24 ) and primary torsion dystonia ( DYT25 ).