Effects of DBS,premotor rTMS,and levodopa on motor function and silent period in advanced Parkinson's disease

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a widely used and highly effective treatment for patients with advanced Parkinson's disease (PD). Repetitive TMS (rTMS) applied to motor cortical areas has also been shown to improve symptoms in PD and modulate motor cortical excitability. Here, we compared clinical and neurophysiological effects of STN stimulation with those of 1 Hz rTMS given to the dorsal premotor cortex (PMd) and those following intake of levodopa in a group of PD patients with advanced disease. Ten PD patients were studied on 2 consecutive days before and after surgery. Clinical effects were determined using the UPDRS motor score. Motor thresholds, motor‐evoked potential (MEP) amplitudes during slight voluntary contraction, and the cortical silent periods (SP) were measured using TMS. Before surgery effects of levodopa and 1 Hz PMd rTMS and after surgery those of STN stimulation with or without additional levodopa were determined. Levodopa significantly improved clinical symptoms and increased the SP duration. STN stimulation improved clinical symptoms without changing the SP duration. In contrast, 1 Hz PMd rTMS was not effective clinically but normalized the SP duration. Whereas levodopa had widespread effects at different levels of an abnormally active motor network in PD, STN stimulation and PMd rTMS led to either clinical improvement or SP normalization, i.e., only partially reversed abnormal motor network activity. © 2009 Movement Disorder Society     

Long term treatment and disease severity change brain responses to levodopa in Parkinson's disease

OBJECTIVES: Degeneration of nigrostriatal neurons and subsequent striatal dopamine deficiency produce many of the symptoms of Parkinson disease (PD). Initially restoration of striatal dopamine with oral levodopa provides substantial benefit, but with long term treatment and disease progression, levodopa can elicit additional clinical symptoms, reflecting altered effects of levodopa in the brain. The authors examined whether long term treatment affects the brain's response to levodopa in the absence of these altered clinical responses to levodopa. METHODS: Positron emission tomography (PET) measurements were used of brain-blood flow before and after an acute dose of levodopa in three groups: PD patients treated long term with levodopa without levodopa induced dyskinesias, levodopa naive PD patients, and controls. RESULTS: It was found that the PD group treated long term responded to acute levodopa differently from controls in left sensorimotor and left ventrolateral prefrontal cortex. In both regions, the treated PD group had decreased blood flow whereas the control group had increased blood flow in response to levodopa. Levodopa naive PD patients had little or no response to levodopa in these regions. Within the treated PD group, severity of parkinsonism correlated with the degree of abnormality of the sensorimotor cortex response, but not with the prefrontal response. CONCLUSIONS: It is concluded that long term levodopa treatment and disease severity affect the physiology of dopaminergic pathways, producing altered responses to levodopa in brain regions associated with motor function.     

Onset of dyskinesia with adjunct ropinirole prolonged‐release or additional levodopa in early Parkinson's disease

Levodopa‐induced dyskinesia can result in significant functional disability and reduced quality of life in patients with Parkinson's disease (PD). The goal of this study was to determine if the addition of once‐daily ropinirole 24‐hour prolonged‐release (n = 104) in PD patients not optimally controlled with levodopa after up to 3 years of therapy with less than 600 mg/d delays the onset of dyskinesia compared with increasing doses of levodopa (n = 104). During the study, 3% of the ropinirole prolonged‐release group (mean dose 10 mg/d) and 17% of the levodopa group (mean additional dose 284 mg/d) developed dyskinesia (P < 0.001). There were no significant differences in change in Unified Parkinson's Disease Rating Scale activities of daily living or motor scores, suggesting comparable efficacy between the two treatments. Adverse events were comparable in the two groups with nausea, dizziness, insomnia, back pain, arthralgia, somnolence, fatigue, and pain most commonly reported. Ropinirole prolonged‐release delayed the onset of dyskinesia with comparable efficacy to increased doses of levodopa in early PD patients not optimally controlled with levodopa. © 2010 Movement Disorder Society     

Effect of histamine H2 receptor antagonism on levodopa–induced dyskinesia in the MPTP‐macaque model of Parkinson's disease

Levodopa‐induced motor complications, including dyskinesia and wearing off, are troublesome side effects of treatment and impair quality of life in Parkinson's disease (PD) patients. The use of nondopaminergic agents as adjuncts to levodopa are potential options for managing these problems. Here, we asses the ability of the clinically available, selective histamine H₂ antagonist, famotidine (1, 3, and 30 mg/kg) to treat levodopa‐induced dyskinesia and wearing off in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐macaque model of PD. Famotidine (3 mg/kg) increased peak activity, enhanced peak anti‐parkinsonian action (1 and 3 mg/kg), and extended duration of action (3 mg/kg, by 38%) of a low dose of levodopa (compared to low dose levodopa alone). Enhancement of anti‐parkinsonian actions of low dose levodopa by famotidine (3 mg/kg) was associated with only mild, nondisabling dystonia. Famotidine had no effect on the anti‐parkinsonian actions of high dose levodopa (compared to high dose levodopa alone). However, famotidine (1, 3, and 30 mg/kg) had a significant effect on chorea, but not dystonia, induced by high dose levodopa (compared to high dose levodopa alone). Famotidine increased high dose levodopa–induced “good quality” on time, i.e., on time not associated with disabling dyskinesia, by up to 28% (compared to high dose levodopa alone). In conclusion, famotidine, a drug currently available for use in the clinic, can enhance the peak‐dose anti‐parkinsonian actions and extend total duration of action of a low dose of levodopa, without producing disabling dyskinesia. Furthermore, in combination with a higher dose of levodopa, famotidine can reduce peak‐dose levodopa‐induced chorea and improve the quality of on‐time. © 2010 Movement Disorder Society     

Opposite effects of one session of 1 Hz rTMS on functional connectivity between pre-supplementary motor area and putamen depending on the dyskinesia state in Parkinson's disease

ObjectiveTo explore the effects of low-frequency repetitive transcranial magnetic stimulation (LF rTMS) on cortico-striatal-cerebellar resting state functional connectivity in Parkinson’s disease (PD), with and without dyskinesias.MethodsBecause there is increasing evidence of an involvement of the pre-supplementary motor area (pre-SMA) in the pathophysiology of levodopa induced dyskinesias, we targeted the right pre-SMA with LF rTMS in 17 PD patients. We explored the effects of one sham-controlled LF rTMS session on resting state functional connectivity of interconnected brain regions by using functional MRI, and how it is modified by levodopa. The clinical effect on motor function and dyskinesias was documented.ResultsAs expected, one LF rTMS session did not alleviate dyskinesias. However, real, and not sham LF rTMS significantly increased the functional connectivity with the right putamen in patients with dyskinesias. In patients without dyskinesias, the real LF rTMS session significantly decreased functional connectivity in the right putamen and the cerebellum. We found no effects on functional connectivity after levodopa ingestion.ConclusionOne session of 1 Hz rTMS has opposing effects on pre-SMA functional connectivity depending on the PD patients' dyskinesia state.SignificancePatients dyskinesias state determines the way LF rTMS affects functional connectivity in late stage PD.     

Levodopa normalizes exercise related cortico-motoneuron excitability abnormalities in Parkinson's disease.

OBJECTIVES: To measure exercise induced changes in cortico-motoneuron excitability in Parkinson's disease (PD) before and after levodopa. METHODS: Transcranial magnetic stimulation was delivered at 10% above resting motor threshold in 9 PD and 8 control subjects. Each subject performed repetitive isometric wrist extension at 50% of the baseline maximal voluntary contraction (MVC) for 30s with 3s rest between extensions until fatigued, defined as the inability to generate force at more than 25% of the baseline MVC. We recorded motor evoked potentials (MEPs) from the resting extensor carpi radialis muscle before (baseline), during, and after fatiguing exercise. Baseline electromyographic activity was closely monitored. We compared absolute MEP amplitudes between PD and controls, before and after levodopa, during baseline, exercise, and recovery periods. We correlated absolute MEP amplitudes with an objective measure of fatigability. RESULTS: PD subjects in the "off" state had increased absolute MEP amplitudes compared with controls. The effect was present in all 3 exercise periods. These differences disappeared after levodopa. Post-exercise facilitation was clear for PD subjects before and after levodopa, but post-exercise depression was not significant. Absolute MEP amplitude showed negative correlation with objective fatigability for PD subjects before levodopa. CONCLUSIONS: Levodopa normalized the increased cortico-motoneuron excitability in PD patients before, during, and after fatiguing exercise. SIGNIFICANCE: This study demonstrated the abnormal cortico-motoneuron excitability associated with motor fatigue in PD.     

The effect of peripheral enzyme inhibitors on levodopa concentrations in blood and CSF

Levodopa combined with a dopa‐decarboxylase inhibitor, such as carbidopa, shifts the metabolism to the COMT pathway. Adding the peripheral acting COMT inhibitor entacapone provides improvement for patients with PD suffering from motor fluctuations. We studied the effects of the enzyme inhibitors entacapone and carbidopa on the levodopa concentrations in CSF and in blood. Five PD patients with wearing‐off underwent lumbar drainage and intravenous microdialysis. Samples were taken 12 h daily for 3 days. Day 1; intravenous levodopa was given, day 2; additional oral entacapone 200 mg tid, day 3; additional oral entacapone 200 mg tid and carbidopa 25 mg bid. Levodopa in CSF and in dialysates was analysed. The AUC for levodopa increased both in blood and CSF when additional entacapone was given alone and in combination with carbidopa. The C_max of levodopa in both CSF and blood increased significantly. Additional entacapone to levodopa therapy gives an increase of C_max in CSF and in blood. The increase is more evident when entacapone is combined with carbidopa. © 2010 Movement Disorder Society     

Treatment of early Parkinson's disease

Levodopa is still the most effective therapeutic agent for the treatment of Parkinson's disease (PD). Initially, levodopa provides a stable therapeutic response but, during long-term treatment its beneficial effect declines and a gradually increasing number of patients experience fluctuations in motor response. Therefore, in the management of PD it is important to minimise the risks for the development of motor fluctuations. In this context, recent double-blind long-term studies have confirmed the earlier results, suggesting that it appears advisable to initiate dopaminergic treatment in early PD by initially using a dopamine agonist and by adding levodopa when the benefit is no longer adequate with dopamine agonist alone. Another alternative would be to start with selegiline alone, then depending on the disability of the patient, add a dopamine agonist and finally levodopa.     

Early versus delayed initiation of entacapone in levodopa‐treated patients with Parkinson’s disease: a long‐term,retrospective analysis

Background: We analysed data from three clinical trials in Parkinson’s disease (PD) patients with wearing‐off to determine whether early enhancement of levodopa therapy with entacapone can lead to better long‐term outcomes than delayed entacapone treatment. Methods: Post‐hoc analysis of pooled data from three randomized, double‐blind, placebo‐controlled studies and their long‐term, open‐label extension phases. In all three studies, patients on levodopa/dopa‐decarboxylase inhibitor (DDCI) were first randomized to entacapone (‘early‐start’ group) or placebo (‘delayed‐start’ group) for the initial 6‐month double‐blind phase, after which all patients received open‐label levodopa/DDCI and entacapone treatment for up to 5 years. Results: A total of 488 PD patients with wearing‐off were included in the analysis. A statistically significant benefit of early initiation of levodopa/DDCI and entacapone was found, with an improvement in Unified Parkinson’s Disease Rating Scale Part III (motor) score of ?1.66 (95% confidence intervals [?3.01, ?0.31]) points compared with the delayed‐start treatment group (P < 0.05). Levodopa/DDCI and entacapone therapy was well tolerated. There was no excess of dyskinesia in the early‐start group. Conclusions: These data suggest that early rather than delayed addition of entacapone to levodopa/DDCI in PD patients with wearing‐off provides a modest clinical benefit over levodopa/DDCI that is maintained for up to 5 years.     

Clinical effects of repetitive transcranial magnetic stimulation versus acute levodopa challenge in Parkinson's disease

We studied the short-term clinical effects of 10-Hz repetitive transcranial magnetic stimulation (rTMS) of the motor hand area contralateral to the more affected limb in 12 non-fluctuating, for at least 12 hours drug free patients with Parkinson's disease (PD). We investigated the efficacy of rTMS in combination with a levodopa challenge test design under double-blind, placebo controlled conditions. Significant reductions of UPDRS III motor scores showed the treatment conditions: placebo/rTMS, levodopa/sham stimulation and levodopa/rTMS. A more detailed evaluation of arm symptoms contralateral to the stimulated brain region showed even more pronounced effects for the three conditions. There were significant differences between the mean response of the UPDRS III arm scores to the four test conditions. In conclusion our study demonstrates short-term beneficial effects of 10-Hz rTMS on motor symptoms in PD patients. A release of endogenous dopamine in subcortical structures, i.e. putamen, in response to rTMS is the most likely mechanism of action.     

Large differences in levodopa dose requirement in Parkinson’s disease: men use higher doses than women

Background and purpose: The characteristics of levodopa dosing are not well described in the literature. The aims were to investigate the use of levodopa in a nationwide Swedish survey and to study the characteristics of low‐dose and high‐dose patients with Parkinson’s disease (PD) in a university hospital. Methods: Patients with ≥ 1 and ≥ 2 purchases of levodopa during 2007 were selected from the prescribed drug register. Daily levodopa doses were estimated. Records of 504 patients with PD who visited the neurology clinic at Uppsala University Hospital during 2006–2007 were examined to select a low‐dose group (≤ 400 mg levodopa daily, n = 21) and a high‐dose group (≥ 1200 mg daily, n = 26) with at least 5 years of PD duration. Results: In total, 33 534 levodopa users with ≥ 1 levodopa purchase were found. Daily levodopa dose range was large; median daily dose was 465 mg for men and 395 mg for women (P < 0.0001). Almost half (46%) of the patients used < 400 mg levodopa daily. Significantly, more men were treated with doses ≥ 1200 mg daily. Dose and age correlated negatively (P < 0.0001). Patients with high dose at 5 years PD duration continuously increased their dosage the following years, whereas low‐dose patients did not. The occurrence of dyskinesias was about the same in both groups despite the large difference in levodopa dose. Conclusions: We conclude that the levodopa requirement in PD ranges considerably, and that men use higher levodopa dose than women. Levodopa requirement is constant during the progression of the disease in low‐dose patients but increases in high‐dose patients.     

Levodopa in the treatment of Parkinson's disease

Levodopa is the most efficacious drug to treat the symptoms of Parkinson's disease (PD) and is widely considered the "gold standard" by which to compare other therapies, including surgical therapy. Response to levodopa is one of the criteria for the clinical diagnosis of PD. A major limiting factor in levodopa therapy is the development of motor complications, namely dyskinesias and motor fluctuations. The ELLDOPA study was designed to determine if levodopa affected the progression of PD. This double-blind randomized study showed that the subjects treated with levodopa for 40 weeks had less severe parkinsonism than the placebo treated subjects even after a 2-week washout of medications, with the highest dose group showing the greatest benefit. Thus, levodopa may actually have neuroprotective value, but the result was not conclusive of slowing disease progression, because the same result could have arisen from a very long-lasting symptomatic benefit of levodopa.     

Levodopa in the treatment of Parkinson's disease: current controversies.

Levodopa is the most effective symptomatic agent in the treatment of Parkinson's disease (PD) and the "gold standard" against which new agents must be compared. However, there remain two areas of controversy: (1) whether levodopa is toxic, and (2) whether levodopa directly causes motor complications. Levodopa is toxic to cultured dopamine neurons, and this may be a problem in PD where there is evidence of oxidative stress in the nigra. However, there is little firm evidence to suggest that levodopa is toxic in vivo or in PD. Clinical trials have not clarified this situation. Levodopa is also associated with motor complications. Increasing evidence suggests that they are related, at least in part, to the short half-life of the drug (and its potential to induce pulsatile stimulation of dopamine receptors) rather than to specific properties of the molecule. Treatment strategies that provide more continuous stimulation of dopamine receptors provide reduced motor complications in MPTP monkeys and PD patients. These studies raise the possibility that more continuous and physiological delivery of levodopa might reduce the risk of motor complications. Clinical trials to test this hypothesis are underway. We review current evidence relating to these areas of controversy.     

Pramipexole combined with levodopa improves motor function but reduces dyskinesia in MPTP‐treated common marmosets

Reduced expression of dyskinesia is observed in levodopa‐primed MPTP‐treated common marmosets when dopamine agonists are used to replace levodopa. We now investigate whether a combination of the D‐2/D‐3 agonist pramipexole and levodopa also reduces dyskinesia intensity while maintaining the reversal of motor disability. Drug naïve, non‐dyskinetic MPTP‐treated common marmosets were treated daily for up to 62 days with levodopa (12.5 mg/kg plus carbidopa 12.5 mg/kg p.o. BID) or pramipexole (0.04–0.3 mg/kg BID) producing equivalent reversal of motor disability and increases in locomotor activity. Levodopa alone resulted in marked dyskinesia induction but little or no dyskinesia resulted from the administration of pramipexole. From day 36, some animals were treated with a combination of levodopa (3.125–6.25 mg/kg plus carbidopa 12.5 mg/kg p.o. BID) and pramipexole (0.1–0.2 mg/kg p.o. SID). This improved motor disability to a greater extent than occurred with levodopa alone. Importantly, while dyskinesia was greater than that produced by pramipexole alone, the combination resulted in less intense dyskinesia than produced by levodopa alone. These results suggest that pramipexole could be administered with a reduced dose of levodopa to minimize dyskinesia in Parkinson's disease while maintaining therapeutic efficacy. © 2010 Movement Disorder Society     

Levodopa response in long-term bilateral subthalamic stimulation for Parkinson's disease.

Subthalamic nucleus deep brain stimulation (STN-DBS) is effective in advanced Parkinson's disease (PD), but its effects on the levodopa response are unclear. We studied the levodopa response after long-term STN-DBS, STN-DBS efficacy and predictive value of preoperative levodopa response to long-term DBS benefit in 33 PD patients with bilateral STN-DBS. Patients were assessed using the Unified Parkinson's Disease Rating Scale preoperatively (with and without medications) and postoperatively (without medications or stimulation, with only medications or stimulation, and with both medications and stimulation). Levodopa response significantly decreased postoperatively by 31.1% at 3 years and 32.3% at 5 years, possibly related to the reduction in medication requirement, direct STN stimulation effect or PD progression. STN-DBS alone significantly improved motor scores (37.2% at 3 years and 35.1% at 5 years) and activities of daily living scores (27.1% at 3 years and 19.2% at 5 years). Anti-PD drugs were significantly reduced by 47.9% at 3 years and 39.8% at 5 years. However, the magnitude of the preoperative response to levodopa did not predict DBS benefit at 3 and 5 years.     

Impairments of speed and amplitude of movement in Parkinson's disease: A pilot study

Bradykinesia, characterized by slowness and decreased amplitude of movement, is often considered the most important deficit in Parkinson's disease (PD). The current clinical rating of bradykinesia in PD, based on the motor subscale of the Unified Parkinson's disease Rating Scale (UPDRS‐III), does not individually weigh the impairments in speed and amplitude of rapid alternating movements. We sought to categorize movement in PD to determine whether speed and amplitude have different relationships to current measures of motor impairment and disability. Categories of speed and amplitude (normal, slow/low, and very‐slow/very‐low) were ascertained using an electromagnetic tracking device. Amplitude was disproportionally more affected than speed in the “off” state. UPDRS‐III and the Schwab & England disability scale were worst in patients with very impaired amplitude and best in patients with normal amplitude. A similarly graded relationship was not found for categories of speed impairment. The examiner clinical global impression of change mirrored “off” state amplitude but not speed categories. Levodopa, however, normalized speed to a greater extent than amplitude. Our observations suggest that amplitude and speed impairments may be associated with different functional aspects in PD and deserve separate clinical assessment. © 2009 Movement Disorder Society     

Effect of controlled‐release levodopa on the microstructure of sleep in Parkinson’s disease

Background: Dopamine is an important neurotransmitter in the regulation of the sleep–wake cycle, and parkinsonian patients suffer from prominent sleep abnormalities. Hence, the question arises whether the disrupted sleep pattern in Parkinson’s disease (PD) is responsive to dopaminergic treatment. Methods: Thirty‐two patients (18 women, 45–82 years old; mean 61 ± 8 years) with dopamine‐responsive, akinetic‐rigid PD, not taking neuroleptic medication or suffering from dementia were randomized into two groups. Both groups had to withhold their usual dopaminergic medication after noon. At bedtime, one group received 200 mg controlled‐release (CR) levodopa/carbidopa, whilst the other group spent the night in the ‘off’‐state. Polysomnographic recordings were obtained in all patients and 16 age‐matched, healthy controls. Results: Compared to healthy controls, patients with PD suffered from significantly decreased total sleep time, REM sleep and slow wave sleep (SWS), whilst the time spent awake was increased. The administration of levodopa/carbidopa CR had no impact on any of these variables. Conclusion: Levodopa/carbidopa CR has previously been found effective for treating night‐time akinesia, but according to this study, it has no impact on the altered sleep structure in PD.     

Bursts of high-frequency repetitive transcranial magnetic stimulation (rTMS), together with lorazepam,suppress seizures in a rat kainate status epilepticus model

BackgroundStatus epilepticus (SE) is a condition of prolonged or recurrent and often drug-resistant seizures where nonsedating SE therapy remains an important unmet need. Repetitive transcranial magnetic stimulation (rTMS) is emerging as a means to suppress seizures but has not been extensively studied in models.ObjectivesWe aimed to test the antiepileptic potential of high-frequency rTMS in SE. As a step toward eventual coupling of rTMS with antiepileptic pharmacotherapy, we also tested whether high-frequency rTMS in combination with a low (ineffective but less likely to cause a side effect) lorazepam dose is as effective as a full lorazepam dose in suppressing seizures in a rat SE model.MethodsEEG was recorded to measure epileptic spike frequency in the rat kainate SE model. Epileptic spikes were counted before, during, and after either high-frequency rTMS treatment alone or high-frequency rTMS treatment in combination with lorazepam, a firstline SE treatment.ResultsWe found that rTMS alone decreases epileptic spike frequency only acutely. However, combinatory treatment with half-dose lorazepam together with rTMS was as effective as a full lorazepam dose.ConclusionWe report that high-frequency rTMS has modest antiepileptic potential alone but acts in complement with lorazepam to suppress seizures.     

重复经颅磁刺激治疗帕金森病2年随访

目的随访观察重复经颅磁刺激(r TMS)治疗帕金森病(PD)患者的疗效。方法应用统一PD评分量表第Ⅲ部分(UPDRSⅢ)、Hoehn-Yahr(H-Y)分级、PD非运动症状(NMS)筛查问卷(NMSQ)、PD睡眠量表(PDSS)、汉密尔顿抑郁量表(HAMD)、汉密尔顿焦虑量表(HAMA)和简易智能量表(MMSE)对37例应用药物和r TMS治疗的PD患者(r TMS+药物组)及45例单纯药物治疗的PD患者(药物组)在基线和2年随访末的运动症状(MS)和非运动症状(NMS)进行评估,对比分析两组患者病情进展。结果 r TMS+药物组2年随访末H-Y分级较基线显著升高(P 0.05);药物组2年随访末UPDRSⅢ、H-Y分级、HAMD、HAMA评分及左旋多巴等效剂量(LED)较基线均显著升高(P 0.05);对两组2年随访末的症状进行比较,药物组的UPDRSⅢ、H-Y分级、HAMD评分及LED较r TMS+药物组升高显著(P 0.05)。结论规律的r TMS辅助常规抗PD药物治疗可减缓PD进展,优于单纯抗PD药物治疗。     

Effect of levodopa on pain threshold in Parkinson's disease: a clinical and positron emission tomography study.

Patients suffering from Parkinson's disease (PD) frequently experienced painful sensations that could be in part due to central modification of nociception. We compared pain threshold before and after administration of levodopa in PD patients and in controls, and investigated cerebral activity with positron emission tomography (PET) during experimental nociceptive stimulation. Pain threshold was determined using thermal stimulation during two randomized conditions: off and on. We performed H(2) (15)O PET analysis of regional cerebral blood flow on subjects while they received alternate randomized noxious and innocuous stimuli during off and on conditions. In off condition, pain threshold in nine PD patients was significantly lower than in nine controls. Administration of levodopa significantly raised pain threshold in PD patients but not in controls. During off condition, there was a significant increase in pain-induced activation in right insula and prefrontal and left anterior cingulate cortices in PD compared to control group. Levodopa significantly reduced pain-induced activation in these areas in PD. This study shows that pain threshold is lower in PD patients but returns to normal ranges after levodopa administration. Moreover, PD patients have higher pain-induced activation in nociceptive pathways, which can be reduced by levodopa.