Dopamine agonists versus levodopa monotherapy in early Parkinson's disease for the potential risks of motor complications: A network meta-analysis.

BACKGROUND: Compared with levodopa, dopamine agonists (DAs) as initial treatment are associated with lower incidences of motor complications in early Parkinson's disease (PD). There is no strong evidence that a given DA is more potent in lower incidences of motor complications than another. OBJECTIVE: We performed a network meta-analysis of levodopa versus DAs as monotherapy in early PD to access the risk of motor complications. METHODS: Databases were searched up to June 2022 for eligible RCTs. Levodopa and four DAs (pramipexole, ropinirole, bromocriptine and pergolide) were investigated. The incidences of motor complications and efficacy, tolerability and safety outcomes were analyzed. RESULTS: Nine RCTs (2112 patients) were included in the current study. The surface under the cumulative ranking curve (SUCRA) indicated that levodopa ranked first in the incidence of dyskinesia (0.988), followed by pergolide, pramipexole, ropinirole, and bromocriptine (0.704, 0.408, 0.240, 0.160). Pramipexole was least prone to wearing-off (0.109) and on-off fluctuation (0.041). Levodopa performed best in improvements of UPDRS-II, UPDRS-III, and UPDRS-II + III (0.925, 0.952, 0.934). Bromocriptine ranked first in total withdrawals and withdrawals due to adverse events (0.736, 0.751). Four DAs showed different adverse events profiles. CONCLUSION: In the two non-ergot DAs, ropinirole is associated with a lower risk of dyskinesia while pramipexole is associated with lower risks of wearing-off and on-off fluctuations. Our research may facilitate head-to-head research, larger sample sizes, long following-up time RCTs to confirm the findings of this network meta-analysis.

Determinants of Low Body Mass Index in Patients with Parkinson's Disease: A Multicenter Case-Control Study.

BACKGROUND: In Parkinson's disease (PD) patients, the factors related to weight loss remain unclear. OBJECTIVE: To investigate determinants of low body mass index (BMI) in PD patients. METHODS: We identified factors associated with low BMI in PD patients in a multicenter case-control study. A total of 435 PD patients and 401 controls were included. RESULTS: The mean BMI was significantly lower in PD patients than in controls (22.0±3.4 kg/m2 vs. 25.4±4.3 kg/m2), with an adjusted odds ratio (AOR) of 3.072 (95% CI, 2.103-4.488; p < 0.001) for low BMI (<22 kg/m2) in PD. Compared to the high-BMI PD group (>22 kg/m2), the low-BMI PD group (<22 kg/m2) had more women; a longer disease duration; higher revised Movement Disorder Society Unified PD Rating Scale (MDS-UPDRS) II and IV scores; an increased levodopa equivalent dose (LED); and increased constipation, visual hallucination, dysphagia, dyskinesia and wearing off rates. There were no between-group differences in depression, anhedonia, apathy, sleep problems and daytime sleepiness. Multivariable analysis showed that visual hallucination (AOR, 2.408; 95% CI, 1.074-5.399; p = 0.033) and the MDS-UPDRS IV (AOR, 1.155; 95% CI, 1.058-1.260; p = 0.001) contributed to low BMI after controlling for clinical factors. In a second model, visual hallucination (AOR, 2.481; 95% CI, 1.104-5.576; p = 0.028) and dyskinesia (sum of the MDS-UPDRS 4.3-4.6) (AOR, 1.319; 95% CI, 1.043-1.668; p = 0.021) significantly contributed to low BMI. CONCLUSION: PD patients were 3 times more likely than healthy controls to have a low BMI. Motor complications, particularly dyskinesia, and visual hallucination were significantly associated with low BMI in PD patients.

Levodopa-responsive retrocollis on the background of choreic dyskinesia.

Purpose/aim: Retrocollis can substantially disturb the daily living of individuals with Parkinson's disease (PD). Clinician often encounter the difficulty in managing the retrocollis. Materials and Methods: We describe a patient with PD who presented with choreic dyskinesia and levodopa-responsive retrocollis. Results: The patient had dyskinesia and the off periods, and received levodopa (700 mg, 14 times/day). The patient received levodopa-carbidopa intestinal gel (LCIG) treatment. After several months, the patient complained of difficulty in swallowing and speech due to severe retrocollis. Thirty minutes following a fast levodopa infusion of LCIG, the retrocollis improved. As a result, a frontal view was obtained, and her talking abilities showed improvement. Conclusions: Severe retrocollis can be superimposed on choreic dyskinesia, and it was likely to increase during the off periods. Duodenal levodopa infusion may reduce the severity of retrocollis.

Pseudohernia abdominal como complicación infrecuente de herpes zóster cutáneo: reporte de un caso / Abdominal pseudohernia as a complication infrequent cutaneous herpes zoster: report of a case

Una de las infecciones virales más comunes -sobretodo en personas de mayor edad- es el Herpes Zóster (HZ). Su característica clínica, hace sospechar al médico de forma temprana, para otorgar un tratamiento adecuado y oportuno. Dentro de las complicaciones más frecuentes se encuentran las sensitivas, como la neuralgia postherpética.1 Sin embargo, existen un grupo de complicaciones motoras de menor incidencia, como lo es la Pseudohernia abdominal. Ésta corresponde a una paresia segmentaria, que se manifiesta como una protrusión de la pared abdominal sin un defecto real, que aumenta con maniobras de valsalva.1 Generalmente se puede presentar en hombres, mayores de 60 años, inmunosuprimidos o con neoplasias hematológicas.1,2,3 El diagnóstico es clínico, aunque se puede confirmar con estudio imagenológico, que evidencie una musculatura de la pared abdominal adelgazada con respecto a la contralateral y que descarta un orificio herniario por un defecto estructural. 2 La electromiografía también puede jugar un rol al evidenciar anormalidades en la conducción nerviosa. 2 La pseudohernia por HZ tiene un buen pronóstico en la mayoría de los pacientes con recuperación completa: entre 2-18 meses. 3 Su principal riesgo es la pseudobstrucción intestinal, que se puede manifestar como constipación.2,4 En el siguiente reporte de caso, se analiza a la pseudohernia abdominal como complicación motora infrecuente del HZ y sus características.

One of the most common viral infections -especially in elderly- is Herpes Zoster (HZ). Its clinical characteristic makes the doctor suspect early, to grant adequate and timely treatment. Among the most frequent complications are the sensitive ones, such as postherpetic neuralgia1 . However, there is a group of motor complications of lower incidence, such as abdominal pseudohernia. This corresponds to a segmental paresis, which manifests as a protrusion of the abdominal wall without a real defect that increases with valsalva maneuvers1 . It can generally present in men, older than 60 years, immunosuppressed or with hematological neoplasms1,2,3, The diagnosis is clinical, although it can be confirmed with an imaging study, which shows a thinner abdominal wall musculature with regard to the contralateral wall, and which rules out a hernial orifice due to a structural defect2 . Electromyography can also play a role in show abnormalities in nerve conduction2 . HZ pseudohernia has a good prognosis in most patients with complete recovery: between 2-18 months.3 Its main risk is intestinal pseudoobstruction, which can manifest as constipation2,4. In the following case report, abdominal pseudohernia is analyzed as a rare motor complication of HZ and its characteristics.

Putaminal Dopamine Turnover in de novo Parkinson's Disease Predicts Later Neuropsychiatric Fluctuations but Not Other Major Health Outcomes.

BACKGROUND AND OBJECTIVE: To investigate the predictive value of striatal dopamine turnover in patients with de novo Parkinson's disease (PD) for later occurrence of major non-motor health outcomes. METHODS: This retrospective, observer-blinded cohort study followed up 29 patients with de novo PD for a median of 10.7 years, who completed 18Fluorodopa PET imaging to measure striatal effective distribution volume ratio (EDVR, inverse of dopamine turnover) prior to antiparkinsonian treatment. Outcomes were assessed with a battery of non-motor, health-related quality-of-life and non-motor fluctuation (WOQ-19) measures and survival. RESULTS: During follow-up, 52% of patients developed wearing-off, 43% neuropsychiatric fluctuations, 35% sensory fluctuations, 32% dementia, 46% depression, 30% psychosis, and PD-related mortality was 26%. Patients with wearing-off and neuropsychiatric fluctuations showed significantly lower baseline EDVR (higher dopamine turnover) in the putamen but not in the caudate nucleus than those without these fluctuations. Consistently, baseline EDVR in the putamen predicted development of wearing-off and neuropsychiatric fluctuations with a lower risk with higher EDVR (lower dopamine turnover), whereas EDVR in caudate nucleus did not correlate with these fluctuations. No relationships were observed between baseline PET measures and the presence of other major health outcomes including survival. CONCLUSIONS: Lower putaminal dopamine turnover in de novo PD is associated with reduced risk for later neuropsychiatric fluctuations comprising a disease-intrinsic predisposing factor for their development, similar as reported for levodopa-induced motor complications. Striatal (putaminal/caudate) dopamine turnover is not predictive for other long-term major health outcomes. These results should be treated as hypothesis generating and require confirmation.

The Characteristics of Patients Associated With High Caregiver Burden in Parkinson's Disease in Singapore.

Introduction: Given the complex multitude of Parkinson's disease (PD) symptoms, caregiving for PD patients can be highly demanding. Our study was aimed to investigate the characteristics of PD patients related to different levels of caregiver burden. Methods: This cross-sectional study recruited 104 idiopathic PD patient-caregiver pairs. Patients were evaluated on motor, non-motor symptoms, and quality of life (QoL). Caregiver burden was quantified using Zarit Burden Inventory and subsequently stratified into 3 subgroups. Statistical analysis was performed to identify differences in the no-or little, mild-moderate, and high caregiver burden subgroups. Results: The mean disease duration was significantly longer in the high caregiver burden group compared to no-or little group (9.63 vs. 5.17 years; p-value 0.003). The mean levodopa equivalent daily dose (LEDD) and mean total UPDRS Part IV scores (UPDRS4) were significantly higher in the high caregiver burden group compared to no-or little group (p-value 0.011 and 0.004, respectively). The high caregiver burden group had significantly higher median QoL scores (PDQ-39) for PD patients for domain 2 (ADL, p-value 0.005), domain 4 (stigma, p-value 0.005), and domain 6 (cognition, p-value 0.002) compared to no-or little group. Conclusion: Greater caregiver burden was observed in PD patients with more prolonged disease duration, higher LEDD to control motor symptoms as well as greater levodopa related motor complications. Further studies on potential interventions to mitigate or delay levodopa related motor complications may reduce caregiver burden. Marked worsening in patient's QoL, specifically ADL, stigma and cognition in the high compared to no-or little caregiver burden group suggests the possible utility of monitoring these factors for early identification of increasing caregiver stress and burden.

Efficacy and motor complications of original and generic levodopa in Parkinson's disease treatment.

BACKGROUND: In general, a generic drug is considered interchangeable with the original formulated drug. In Parkinson's disease (PD), generic drug use remains debated. This study was aimed to investigate whether the generic drug was as effective as the original in improving the symptoms of PD and the prevalence of motor complications. METHODS: This study was a multicenter cohort study of patients with PD enrolled from three northeast hospitals in Thailand between February 2013 and February 2014. The patients were categorized into original and generic levodopa groups. The clinical characteristics, efficacy, and motor complications were compared between the groups. RESULTS: There were 400 eligible patients. Of these, 327 patients (81.75%) met the study criteria and were classified as the original levodopa group (200 patients, 61.16%) and the generic levodopa group (127 patients, 38.84%). The average age of all patients with PD was 65 years. The duration of PD and the modified Hoehn-Yahr stages were not different between the groups. The total doses of original and generic levodopa-equivalent doses were significantly different (199.97±127.08 versus 305.58±138.27 mg; P-value <0.001) and the actual doses were 198.10±117.92 versus 308.85±139.40 mg (P-value <0.001). Approximately 80% of patients with PD in both groups had good responses (P-value >0.999), but the development of motor complications was significantly greater in the original than in the generic group. CONCLUSION: Generic levodopa was effective in improving the symptoms of PD. The prevalence of motor complications in the original compound group, at a lower dose of levodopa equivalent, was higher than in the generic group.

L-Dopa induced dyskinesias in Parkinsonian mice: Disease severity or L-Dopa history.

In Parkinson's disease, the efficacy of l-Dopa treatment changes over time, as dyskinesias emerge with previously beneficial doses. Using MitoPark mice, that models mitochondrial failure in dopamine (DA) neurons and mimics the progressive loss of dopamine observed in Parkinson's disease, we found that the severity of DA denervation and associated adaptations in striatal neurotransmission at the time of initiation of l-Dopa treatment determines development of l-Dopa induced dyskinesias. We treated 20-week, and 28-week old MitoPark mice with l-Dopa (10mg/kg i.p. twice a day) and found locomotor responses to be significantly different. While all MitoPark mice developed sensitization to l-Dopa treatment over time, 28-week old MitoPark mice with extensive striatal DA denervation developed abnormal involuntary movements rapidly and severely after starting l-Dopa treatment, as compared to a more gradual escalation of movements in 20-week old animals that started treatment at earlier stages of degeneration. Our data support that it is the extent of loss of DA innervation that determines how soon motor complications develop with l-Dopa treatment. Gene array studies of striatal neurotransmitter receptors revealed changes in mRNA expression levels for DA, serotonin, glutamate and GABA receptors in striatum of 28-week old MitoPark mice. Our results support that delaying l-Dopa treatment until Parkinson's disease symptoms become more severe does not delay the development of l-Dopa-induced dyskinesias. MitoPark mice model genetic alterations known to impair mitochondrial function in a subgroup of Parkinson patients and provide a platform in which to study treatments to minimize the development of dyskinesia.

REM sleep behavior disorder: association with motor complications and impulse control disorders in Parkinson's disease.

OBJECTIVE: Clinical phenotypes such as old age, longer disease duration, motor disability, akineto-rigid type, dementia and hallucinations are known to be associated with REM sleep behavior disorder (RBD) in Parkinson's disease (PD). However, the relationship between motor fluctuations/impulse control and related behaviors (ICRB) and RBD is not clear. We designed this study to elucidate the clinical manifestations associated with RBD to determine the implications of RBD in PD. DESIGN: In a cross-sectional study, a total of 994 patients with PD were interviewed to determine the presence of RBD and their associated clinical features including motor complications and ICRB. RESULTS: Of the 944 patients, 578 (61.2%) had clinical RBD. When comparing the clinical features between patients with RBD (RBD group) and without RBD (non-RBD group), older age, longer disease duration, higher Hoehn and Yahr stage (H&Y stage), higher levodopa equivalent daily dose (LEDD), and the existence of wearing off, dyskinesia, freezing, and ICRB, especially punding, were associated with the RBD group compared to the non-RBD group (P < .05 in all). Multivariate analysis showed that motor complications including wearing off, peak dose dyskinesia, and diphasic dyskinesia were the only relevant factors for RBD after adjusting for age and disease duration. CONCLUSION: Motor complications and ICRB are more frequent in patients with RBD than in patients without RBD. In addition, motor complications are related to RBD even after adjusting for age and disease duration.

Diagnosis and treatment of impulse control disorders in patients with movement disorders.

Impulse control disorders are a psychiatric condition characterized by the failure to resist an impulsive act or behavior that may be harmful to self or others. In movement disorders, impulse control disorders are associated with dopaminergic treatment, notably dopamine agonists (DAs). Impulse control disorders have been studied extensively in Parkinson's disease, but are also recognized in restless leg syndrome and atypical Parkinsonian syndromes. Epidemiological studies suggest younger age, male sex, greater novelty seeking, impulsivity, depression and premorbid impulse control disorders as the most consistent risk factors. Such patients may warrant special monitoring after starting treatment with a DA. Various individual screening tools are available for people without Parkinson's disease. The Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease has been developed specifically for Parkinson's disease. The best treatment for impulse control disorders is prevention. However, after the development of impulse control disorders, the mainstay intervention is to reduce or discontinue the offending anti-Parkinsonian medication. In refractory cases, other pharmacological interventions are available, including neuroleptics, antiepileptics, amantadine, antiandrogens, lithium and opioid antagonists. Unfortunately, their use is only supported by case reports, small case series or open-label clinical studies. Prospective, controlled studies are warranted. Ongoing investigations include naltrexone and nicotine.

Effect of NR2B antagonist on behavior and related signal proteins in a rat model of levodopa-induced motor complications / 中华行为医学与脑科学杂志

ObjectiveTo investigate the role of N-methyl-D-aspartate receptor subunit 2B (NR2B) antagonist CP-101.606 in behaviour and expression of related signal proteins in a rat model of levodopa-induced motor complications.MethodsThe hemi-parkinsonian rat model was produced by injecting stereotaxically 6-OHDA to right medial forebrain bundle.Then,rats were intraperitoneally treated with levodopa (50 mg/kg with benserazide 12.5 mg/kg,twice daily) for 22 days.On 23th day,rats received CP-101.606 before levodopa administration.Rotational duration was estimated.After sacrificed,phosphorylated NR2B and Ca2+/calmodulin-dependent protein kinase Ⅱ (CaMKⅡ) and glutamate receptor 1 ( GluR1S831 ) were observed by western blot.ResultsThe results showed that NR2B antagonist CP-101.606 reversed the levodopa-induced shortened rotational duration.Chronic levodopa treatment increased abundance of the phosphorylated NR2B and downstream related signal proteins CaMKⅡ and GluR1S831 to (145.3±6.5)％ and (132.5±5.7)％ and (105.6±6.3)％,respectively.Moreover,CP-101.606 could reduce hyperphosphorylation of NR2B and CaMKⅡ and GluR1 S831 to (102 ± 4.9 )％,(98.4±3.9)％ and (49.5 ± 4.2 )％,respectively.ConclusionsThese results indicate that the enhancement of N-methyl-D-aspartate (NMDA) receptor function mediated by NR2B phosphorylation contribute to development of motor complications,through a mechanism that involved the downstream signal mediators of NMDA receptor overactivation.Pharmaceuticals which act to inhibit NR2B may be useful in the treatment of the motor complications in parkinsonian patients.

The research on the property of GluR1 subunit in rat models of motor complication of Parkinson' s disease after CaMKⅡ inhibitor KN-93 treatment / 中华行为医学与脑科学杂志

Objective To investigate the alteration of phosphorylated GluR1Ser831 and behavioural effects in a rat model of levodopa-induced motor complications after Ca2 +/calmodulin-dependent protein kinase Ⅱ (CaMKⅡ) inhibitor KN-93 treatment. Methods The hemi-parkinsonian rat model was produced by injecting stereotaxically 6-OHDA to right medial forebrain bundle. Then, rats were intraperitoneally treated with levodopa ( 50 mg/kg with benserazide 12.5 mg/kg,twice daily) for 22 days. On day 23 ,rats received KN-93 before levodopa administration. Rotational duration was estimated. After sacrificed, subcellualr distribution of GluR1 and phosphorylated GluR1Ser831 were observed by western blot. Results The study showed that CaMKⅡ inhibitor KN-93 prolonged rotational duration. Moreover, KN-93 could regulate subcellular distribution of GluR1 and reduce hyperphosphorylation of GluR1 Ser831, which was closely associated with levodopa-induced motor complications. The expression of membrane GluR1 and phosphorylated GluR1Ser831 was (83.4 ±4.2)% and (47.2 ±5.2)% ,respectively. Conclusions These results indicated that activation of CaMKⅡ contributed to development of motor complications, through a mechanism that involved an increase in phosphorylated GluR1 Ser831. Pharmaceuticals which act to inhibit CaMKⅡ may be useful in the treatment of the motor complications in parkinsonian patients.