Blinded evaluation confirms long-term asymmetric effect of unilateral thalamotomy or subthalamotomy on tremor in Parkinson's disease.

In the past, stereotactic surgery was a regular treatment for prominent unilateral tremor in Parkinson's disease (PD), but follow-up studies were usually short-term and always unblinded. We examined 17 PD patients in long-term follow-up (mean, 10.9 years after surgery) and used videotapes and the Unified Parkinson's Disease Rating Scale to blindly compare tremor ipsilateral and contralateral to the side of surgery. Since the patients were specifically selected for stereotactic surgery because of asymmetric tremor, and the surgical side chosen was contralateral to the predominant tremor, a sign of long-term efficacy would be current postoperative reversal of tremor side predominance. Upper extremity tremor was significantly better contralateral to the surgery compared with the ipsilateral side. We conclude that stereotactic surgery improved the absolute magnitude of tremor or ameliorated its rate of progression. Since asymmetric bradykinesia and dyskinesia were not a prerequisite for the choice of surgical side, we cannot make any conclusion about long-term impact of surgery on these features.     

双侧丘脑底核电刺激改善帕金森病患者关期运动障碍以及安全性评估

目的:探讨双侧丘脑底核电刺激(STN-DBS)改善帕金森病(PD)患者"关"期运动障碍疗效和安全性评估。方法:对接受双侧STN-DBS治疗的57例PD患者进行前瞻性研究。分别在术后1年和3年,应用UPDRS和Schwab&England评分对患者进行"关"期运动功能以及安全性评估。结果:与术前比较,在"关"期评分中,术后1年患者的运动功能评分改善60%;术后3年改善51%;除语言改善不明显外,震颤、肌肉强直、运动不能以及姿势稳定性等均有较大改善。术后3年多巴胺类药物的服用剂量、左旋多巴所致运动障碍的持续时间和严重程度都有明显减轻(P<0.001)。术后1年日常生活能力改善61%,术后3年改善50%。严重的不良事件为1例丘脑出血。结论:双侧STN-DBS治疗显著改善PD患者"关"期运动障碍,安全性好。     

Unilateral subthalamic nucleus deep brain stimulation contralateral to thalamic stimulation in Parkinson disease

The effects of unilateral subthalamic nucleus (STN) stimulation contralateral to thalamic stimulation in Parkinson disease (PD) have not been previously reported. We are reporting a patient who developed left arm tremor in 1994, at age 62, as her first PD symptom. She underwent right thalamic DBS surgery in 1999 that resulted in complete resolution of left arm tremor. Her PD symptoms progressed and she developed severe motor fluctuations and disabling dyskinesias. In 2003, she underwent left STN electrode implantation. Left STN stimulation improved contralateral motor scores in the medication OFF state, and allowed for reduced medication doses and less dyskinesia. However, there was no significant improvement in activities of daily living (ADL), motor scores in the medication ON state, gait, or postural stability.     

Accuracy of objective ambulatory accelerometry in detecting motor complications in patients with Parkinson disease

Shortcomings of existing assessment methods in Parkinson disease (PD) have led to the development of continuous ambulatory multichannel accelerometry for the assessment of the core features of PD. Although measures for hypokinesia, bradykinesia, and tremor have been validated in groups of patients with PD, it is unclear whether this method is able to detect "on" with or without dyskinesias, and "off" in individual PD patients. This study therefore addressed the accuracy of objective ambulatory accelerometry in detecting motor complications in 15 PD patients, using a self-assessment scale as gold standard. Measures for hypokinesia, bradykinesia, and tremor showed limited sensitivity (0.60-0.71) and specificity (0.66-0.76) for motor complications in individual PD patients. In the group of PD patients, comparing the "on" with the "off" state yielded statistically significant differences for tremor only. Objective dyskinesia measures correlated with time spent with dyskinesias (r = 0.89). Although validated for the measurement of hypokinesia, bradykinesia, and tremor, continuous ambulatory multichannel accelerometry currently cannot detect "on" and "off" in individual PD patients.     

Thalamic deep brain stimulation: comparison between unilateral and bilateral placement

BACKGROUND: Unilateral thalamic deep brain stimulation (DBS) is accepted as an effective treatment for essential tremor (ET) and the tremor of Parkinson disease (PD). There are, however, relatively little data concerning bilateral thalamic DBS and no thorough comparisons between the 2 methods. METHODS: To assess the relative benefit of a staged second contralateral DBS placement in patients with PD and ET, we compared preoperative baseline assessments with those at 3 months after the initial implantation, and again at 3 months after the second contralateral implantation. The assessments included the Unified Parkinson's Disease Rating Scale for patients with PD (n = 8) and a modified Unified Tremor Rating Assessment for patients with ET (n = 13). The design included open and blinded (unknown activation status) assessments. RESULTS: Overall, after the second implantation, all specific measures assessing tremor contralateral to that side improved in patients with PD and ET, generally without sacrificing those contralateral to the first side implantation. Midline tremors (face and head) improved only after the second side implantation. In patients with ET, functional and subjective scores tended to further improve after the second placement; however, patients with PD had less subjective improvement. Hand tremor scores in patients with ET randomized to "on" stimulation improved from 6.7 +/- 0.9 to 1.3 +/- 1.2 (P<.005). The scores of patients with PD randomized to on stimulation improved from 9.3 +/- 1.0 to 1.0 +/- 0.5. (Data are given as mean +/- SD.) Tremor scores did not change from baseline in those patients randomized to "off" stimulation in either group. Adverse events related to stimulation increased after the second implantation in both groups. CONCLUSIONS: Bilateral thalamic DBS is more effective than unilateral DBS at controlling bilateral appendicular and midline tremors of ET and PD. Despite this, overall functional disability only improved in patients with ET, possibly secondary to more problematic adverse events in patients with PD, especially balance problems. Bilateral DBS should be considered when unilateral DBS does not offer satisfactory benefit, especially in patients with ET.     

Current surgical treatments for Parkinson's disease and potential therapeutic targets

Currently, the most common surgical treatment for Parkinson's disease is deep brain stimulation(DBS). This treatment strategy is typically reserved for bradykinesia, rigidity and tremor in patients who no longer respond to medication in a predictable manner or who suffer medication-induced dyskinesias. In addition to DBS, ablative procedures like radiofrequency, radiosurgery and focused ultrasound are also utilized for select tremor symptoms. In this review, we discuss evolving surgical techniques, targets, and emerging technology. In addition, we evaluate potential paradigm shifts in treatment, including gene therapy, immunotherapy and cell transplantation. While these new techniques and treatment options are still in their infancy, advances in Parkinson's disease treatment are rapidly expanding.     

Comparison of Contralateral Pallidotomy vs. Pallidal Stimulation After Prior Unilateral Pallidotomy for Parkinson’s Disease

Objectives: Pallidal stimulation and pallidotomy are known to improve the symptoms of Parkinson's disease (PD). However, it is not known which modality produces greater benefit in patients who have already undergone unilateral pallidotomy. It is also suggested that the original pallidal surgery provides a greater benefit than subsequent pallidal surgery. The aim of this study was to analyze which modality produced greater PD symptom improvement in patients with a prior pallidotomy and whether the chronological order of the pallidal surgery influenced the size of the improvement. Methods: Five patients who had undergone a prior unilateral pallidotomy for PD were studied. Because of ongoing Parkinsonian symptoms, all patients subsequently underwent contralateral pallidal surgery, either a further pallidotomy or pallidal stimulation. All surgeries were performed by a single functional neurosurgeon and the patients prospectively assessed and scored at routine follow‐ups. Paired‐sample t‐tests were used to detect differences in outcomes after first and second surgeries. Results: Two patients underwent pallidal stimulation and three underwent a second pallidotomy. Mean follow‐up was 13.5 months and 12.3 months, respectively. Greater percentage improvements in the majority of scores were found after pallidal stimulation compared with a second pallidotomy, namely Unified Parkinson's Disease Rating Scale (UPDRS) II off (25.22% vs. −3.27%), UPDRS III off (36.15% vs. 5.21%), rigidity (58.34% vs. 11.54%), tremor (5.56% vs. −30.48%), bradykinesia (48.55% vs. −2.23%), gait composite (16.52% vs. −51.79%), dyskinesia duration (83.33% vs. 66.67%), dyskinesia disability (100% vs. 66.67%), speech (10% vs. −50%), and the proportion of the day spent in the “off” state (50% vs. 25%). Comparing outcomes after the first surgery to those after the second surgery, statistical differences were found in dyskinesia duration improvement and ipsilateral dyskinesia improvement after the second surgery (p < 0.004 and p = 0.021, respectively). Conclusions: Pallidal stimulation produced greater symptom improvement than a second pallidotomy and subsequent surgery did not produce inferior results to the original pallidal surgery.     

Acute and chronic effects of anteromedial globus pallidus stimulation in Parkinson''s disease

OBJECTIVE: To evaluate the effects of acute and chronic stimulation in the anteromedial part of the globus pallidus internus (GPi) on the symptoms of patients with Parkinson's disease. METHODS: Six patients with severe Parkinson's disease (Hoehn and Yahr stage 4-5 in "off" drug condition) with motor fluctuations and levodopa induced dyskinesia (LID) were operated on. Chronic electrodes were implanted in the anteromedial GPi bilaterally in five patients and unilaterally in one patient. The effect of stimulation via the four contacts for each electrode (n=11) was assessed postoperatively on the contralateral parkinsonian signs in the off condition and on the contralateral and ipsilateral LID in the "on" condition. The core assessement program for intracerebral transplantation protocol was performed before surgery and then 1, 3, and 6 months after surgery in on and off conditions and in on and off stimulation conditions. RESULTS: Stimulation performed postoperatively showed a significant improvement (p<0.05) by 47% (contralateral rigidity) and 32% (contralateral bradykinesia) when stimulation was applied through the distal contact. Levodopa induced dyskinesias were improved by 95% (contralateral LID) and by 66% (ipsilateral LID) when stimulation was applied through the distal contact. Six months after the surgery, GPi stimulation in the off condition led to a mean improvement in the motor score of UPDRS by 36%. The mean daily duration in the off state decreased by 52% (p<0.05). The mean duration of LIDs decreased by 68% (p<0.05) and their severity by 53% (p<0.05). CONCLUSION: Chronic stimulation in the anteromedial GPi shows that this is a safe and effective treatment for advanced Parkinson's disease with benefit sustained for at least 6 months.     

Long-term evaluation of bilateral fetal nigral transplantation in Parkinson disease

BACKGROUND: Parkinson disease (PD) is associated with a progressive loss of nigrostriatal dopamine neurons. Medication therapy provides adequate control of symptoms for several years, but long-term treatment is complicated by progressive disability and the development of motor fluctuations and dyskinesias. In animal models of PD, fetal nigral transplants have been shown to survive grafting into the striatum, provide extensive striatal reinnervation, and improve motor function. In patients with PD, cell survival and clinical benefit have been observed following fetal nigral grafting, but results have been inconsistent. OBJECTIVE: To evaluate the safety and efficacy of bilateral fetal nigral transplantation into the postcommissural putamen in patients with advanced PD complicated by motor fluctuations and dyskinesias. PATIENTS AND METHODS: Six patients with advanced PD underwent bilateral fetal nigral transplantation. Each patient received solid grafts derived from donors aged 6 1/2 to 9 weeks after conception stereotactically implanted into the postcommissural putamen using 3 to 4 donors per side. Cyclosporine was administered for approximately 6 months to provide immune suppression. Clinical evaluations included the Unified Parkinson's Disease Rating Scale (UPDRS), Schwab-England Activities of Daily Living Scale, and timed tests of motor function conducted during both the "off' and "on" states at baseline and at 1, 3, 6, 9, 12, 18, and 24 months following transplantation. Percentage of time off and percentage of time on with and without dyskinesia were recorded at half-hour intervals using home diaries during the week prior to each evaluation. 18F-fluorodopa positron emission tomographic scans were performed at baseline, and at 6 months and 1 year following transplantation. RESULTS: Patients have been followed up for a mean+/-SD of 20.5+/-5.5 months. Complications related to surgery were mild and transient. Activities of daily living, motor, and total (activities of daily living plus motor) UPDRS scores during the off state improved significantly (P<.05, Wilcoxon signed rank test) at final visit in comparison with baseline. Mean total UPDRS off score improved 32%, and each patient experienced at least a 19% improvement. Mean percentage of time on without dyskinesia during the waking day improved from 22% to 60% (P<.05). Mean putamenal fluorodopa uptake on positron emission tomography increased significantly at 6 and 12 months in comparison with baseline (P<.001, 2-tailed t test). This increase correlated with clinical improvement. Two patients died 18 months after transplantation from causes unrelated to the surgical procedure. In both cases, histopathological examination showed robust survival of tyrosine hydroxylase immunoreactive cells and abundant reinnervation of the postcommissural putamen. CONCLUSIONS: Fetal nigral tissue can be transplanted into the postcommissural putamen bilaterally in patients with advanced PD safely and with little morbidity. In this open-label pilot study we observed consistent long-term clinical benefit and increased fluorodopa uptake on positron emission tomography. Clinical improvement appears to be related to the survival and function of transplanted fetal tissue.     

Deep brain stimulation for the treatment of Parkinson's disease.

Deep brain stimulation (DBS) is increasingly accepted as an adjunct therapy for Parkinson's disease (PD). It is considered a surgical treatment alternative for patients with intractable tremor or for those patients who are affected by long-term complications of levodopa therapy such as motor fluctuations and severe dyskinesias. Thalamic stimulation in the ventral intermediate nucleus (Vim) leads to a marked reduction of contralateral tremor but has no beneficial effect on other symptoms of Parkinson's disease. The subthalamic nucleus (STN) and the internal segment of the globus pallidus (GPi) are targeted for the treatment of advanced Parkinson's disease. Several studies have proven the efficacy of STN-DBS and GPi-DBS in alleviating off motor symptoms and dyskinesias. Sub-thalamic nucleus deep brain stimulation is currently considered superior to GPi-DBS because the antiakinetic effect seems to be more pronounced, allows a more marked reduction of antiparkinsonian medication, and requires less stimulation energy. More recently, however, a number of reports on possible psychiatric and behavioral side effects of STN-DBS have been a matter of concern. Given the chronic nature of PD and the noncurative approach of DBS, both targets will need to be reevaluated on the basis of their long-term efficacy and their impact on quality of life. Despite the rapidly increasing numbers of DBS procedures, surprisingly few controlled clinical trials are available that address important clinical issues such as: When should DBS be applied during the course of disease? Which patients should be selected? Which target should be considered? Which guidelines should be followed during postoperative care? Here is summarized the available evidence on DBS as a therapeutic tool for the treatment of Parkinson's disease and the current state of debate on open issues.     

The oscillatory activity in the Parkinsonian subthalamic nucleus investigated using the macro-electrodes for deep brain stimulation.

OBJECTIVES: To investigate the oscillatory activity in the Parkinsonian subthalamic nucleus using the macro-electrodes for deep brain stimulation. METHODS: During bilateral deep brain stimulating electrode implantation, spontaneous and evoked field potentials were recorded from the subthalamic nucleus (STN) in two patients with Parkinson's disease (PD) during spontaneous resting tremor, passive manipulation of the wrist, and following electrical stimulation of the contralateral STN. RESULTS: Frequency analysis of the STN field potentials recorded during spontaneous resting tremor showed significant coherence with electromyographic activity in the contralateral arm, suggesting a close involvement of the STN in the generation of resting tremor in PD. The STN responded to passive movement of the contralateral wrist, but not to ipsilateral movement. High frequency (100 Hz) electrical stimulation of the STN induced tremor (4 Hz) in both forearms, and also oscillation of the contralateral STN (4 Hz). In contrast, low frequency (5 Hz) stimulation induced contralateral arrhythmic involuntary movement (3 Hz), but without altering the contralateral STN activity. CONCLUSIONS: We propose that the functional connection between the STN and arm muscles is mainly contralateral, but cross talk may occur between bilateral STN via a frequency-dependent pathway.     

脑深部电刺激治疗帕金森病和特发性震颤的近期和远期疗效

自1987年以后,脑深部电刺激(deep brain stimulation,DBS)成为治疗难治性帕金森病和特发性震颤的主要外科手段。刺激的靶点最先为丘脑腹侧中间核(nucleus ventero-intermedius,Vim)。由于Vim DBS只能缓解震颤,而对于帕金森病的其他核心症状以及多巴长期应用后的不良反应,如运动波动和异动症疗效不显著,1990年后治疗PD的靶点转移到丘脑底核(subthalamic nucleus,STN)和苍白球内侧部(interal globus pallidus,GPi),上述问题在这两个靶点得到显著改善。Vim DBS仍然为治疗特发性震颤的位点。本文就这3个靶点的持续电刺激在治疗帕金森病和特发性震颤的近期和远期疗效等进行评述。     

Thalamic deep brain stimulation: effects on the nontarget limbs.

Unilateral thalamic ventral intermediate (VIM) deep brain stimulation (DBS) is now accepted as an effective treatment for essential tremor (ET) and tremor related to Parkinson's disease (PD). The effects of unilateral placement on the side ipsilateral to the surgical site have not been carefully evaluated. To systematically assess the effects ipsilateral to the surgical side and to determine the effects of device inactivation on the baseline tremor, we evaluated tremor in 73 patients approximately 3 months after their unilateral thalamic placement. Assessment included blinded and unblinded ratings using the Unified Parkinson's Disease Rating Scale for PD patients and a modified Tremor Rating Scale in ET patients. All measures of tremor contralateral to the implantation site improved significantly and robustly in both PD and ET. Implantation did not worsen tremor by any measure on the ipsilateral side. There was mild ipsilateral improvement as measured by lower observed tremor scores in ET (6.0 +/- 1.8 to 5.0 +/- 1.9, P < 0.005), but not PD. There was no rebound augmentation of tremor in either hand after the devices were deactivated in either group. We conclude that VIM DBS may mildly improve ipsilateral ET, and that concerns about meaningful ipsilateral tremor augmentation after device deactivation are not warranted.     

Electrophysiological confirmation of the zona incerta as a target for surgical treatment of disabling involuntary arm movements in multiple sclerosis: use of local field potentials.

Lesioning or chronic deep brain stimulation (DBS) of the nucleus ventralis intermedius results in abolition of tremor in the contralateral limbs in Parkinson's disease (PD) and also in essential tremor. Recently, chronic DBS of the subthalamic nucleus has also proved to be very effective in reducing contralateral limb tremor in PD. These targets have been less effective in controlling the complex limb tremor often seen in multiple sclerosis (MS). Consequently, other targets have been sought in cases of MS with tremor. We describe a patient with MS with disabling proximal and distal involuntary arm movements in whom we were able to obtain sustained control of contralateral arm tremor and achieve functional improvement of the affected arm by chronic DBS of the region of the zona incerta. We also highlight the important role played by local field potentials recorded from the brain, with simultaneous recording of corresponding EMGs, in target localisation.     

Lesion of thalamic centromedian--parafascicular complex after chronic deep brain stimulation

A patient with PD who exhibited disabling tremor and prominent dyskinesia underwent deep brain stimulation (DBS) of the left thalamic ventral intermediate nucleus. The electrode migrated and was replaced but with suboptimal clinical response. Two years later, postmortem analysis found the second electrode tip had entered the thalamic centromedian-parafascicular complex. There was a small thalamotomy and cell loss exceeding that found in PD. Thalamic damage may occur in association with DBS for PD.     

双侧丘脑底核脑深部刺激术治疗帕金森病13例报告

目的 探讨双侧丘脑底核（STN）脑深部刺激术（DBS）治疗帕金森病的临床经验。方法 从2002年到2005年共完成了13例帕金森病的双侧丘脑底核DBS，根据STN解剖学定位，靶点的理论坐标值是X=11-13mm，Y=0-2mm，Z=0-4mm，通过立体定向技术在双侧丘脑底核植入刺激电极，并于锁骨下方植入脑深部电刺激器。结果 随访时间为6个月到3年，3例震颤为主病人的症状完全缓解，即震颤完全消失；僵直和运动迟缓为主要症状者的症状缓解程度达90％以上，其中以四肢肌肉僵直的效果较好，运动迟缓也有明显缓解，但是有1例病人双侧肢运动协调性差。所有患者植物神经功能症状有较明显改善，如便秘、流涎、出汗和浮肿等均有改善。结论 DBS治疗帕金森病，是帕金森病治疗的一个里程碑似的进步。它可以明显地缓解帕金森病的主要症状和体征，对运动迟缓、僵直和震颤等均有较理想的效果。     

Treatment of advanced Parkinson's disease by unilateral posterior GPi pallidotomy: 4-year results of a pilot study.

To assess the long-term outcome following unilateral pallidotomy for advanced Parkinson's disease, we performed nonblinded Core Assessment Program for Intracerebral Transplantations protocol assessments in 10 of the original 15 patients in our pilot study for 4 years following surgery. Although Unified Parkinson's Disease Rating Scale motor examination scores returned to baseline levels at 3 and 4 years, most patients continued to show sustained improvements in contralateral tremor, akinesia, and drug-induced dyskinesias. Contralateral tremor was absent at 4 years in all seven patients with preoperative tremor. Contralateral "off" arm movement times (averaged for three tasks) decreased by 37% at 1 year and by 30% at 4 years. Contralateral dyskinesia scores improved by 82% at 1 year and by 64% at 4 years. In contrast, after reaching speeds equal to the contralateral side at 1 year, ipsilateral "off" movement times increased by 13% over baseline levels at 4 years. Although most gait and postural stability measures showed modest initial improvement followed by a return to baseline values, "on" stand-walk-sit task performance declined significantly at 4 years. Despite the restriction of our surgeries to one side and the expected natural progression of Parkinson's disease, the results of patient self-assessments suggest that 4 years after unilateral pallidotomy, most patients continue to experience a quality of life above preoperative levels.     

Deep brain stimulation and medication for parkinsonian tremor during secondary tasks.

This study examined the efficacy of subthalamic nucleus (STN), deep brain stimulation (DBS), and medication for resting tremor during performance of secondary tasks. Hand tremor was recorded using accelerometry and electromyography (EMG) from 10 patients with Parkinson's disease (PD) and ten matched control subjects. The PD subjects were examined off treatment, on STN DBS, on medication, and on STN DBS plus medication. In the first experiment, tremor was recorded in a quiet condition and during a cognitive task designed to enhance tremor. In the second experiment, tremor was recorded in a quiet condition and during isometric finger flexion (motor task) with the contralateral limb at 5% of the maximal voluntary contraction (MVC) that was designed to suppress tremor. Results showed that: (1) STN DBS and medication reduced tremor during a cognitive task that exacerbated tremor, (2) STN DBS normalized tremor frequency in both the quiet and cognitive task conditions, whereas tremor amplitude was only normalized in the quiet condition, (3) a secondary motor task reduced tremor in a similar manner to STN DBS. These findings demonstrate that STN DBS still suppresses tremor in the presence of a cognitive task. Furthermore, a secondary motor task of the opposite limb suppresses tremor to levels comparable to STN DBS.     

Early morning off-medication dyskinesias, dystonia, and choreic subtypes

BACKGROUND: Abnormal involuntary movements (dyskinesias) are common in patients with Parkinson disease (PD) as a consequence of the disease and dopaminergic replacement therapy. Early morning off-medication choreic dyskinesias have been recently reported after fetal dopaminergic cell transplantations in patients with advanced PD. OBJECTIVE: To determine the frequency and severity of the early morning off-medication dyskinesias in consecutive patients with advanced PD and an insufficient response to medical management before they undergo neurosurgery. METHODS: Consecutive patients with advanced idiopathic PD were examined and videotaped before undergoing neurosurgery that included pallidotomy, fetal transplantation, or deep brain stimulation. The examination took place in the morning in the practically defined off state, at least 12 hours after the last dose of dopaminergic drugs. Parkinson disease was characterized using the Unified Parkinson's Disease Rating Scale and the Hoehn and Yahr stage. Dyskinesias were rated with the Abnormal Involuntary Movements Scale and the Rush Dyskinesia Rating Scale. Patients' characteristics and medications were compared using the Wilcoxon rank sum and the Fisher exact tests. RESULTS: Of 68 consecutive patients (44 [65%] men and 24 [35%] women), 11 (16%) had early morning off-medication dyskinesia, with a 95% upper confidence limit of 24%. Focal dystonia was the most common off-medication dyskinesia, and occurred in 10 patients (15%), with a 95% upper confidence limit of 22%; and off-choreic dyskinesia occurred in 1 patient (1.5%), with a 95% upper confidence limit of 4%. There was no difference in PD medications between the patients with and those without dyskinesias. CONCLUSIONS: The most common form of off-medication dyskinesia seen in patients with advanced PD is dystonia. Early morning off-medication choreic dyskinesias are rare but do occur in patients with advanced PD before surgical intervention. The presence and type of off-medication dyskinesias should be monitored in clinical and surgical studies in patients with PD as part of the safety and evaluation of clinical benefits.     

A home diary to assess functional status in patients with Parkinson's disease with motor fluctuations and dyskinesia

In clinical trials for patients with Parkinson's disease (PD) with motor fluctuations, efficacy is generally ascribed to an intervention if motor function is significantly improved or if "off" time is significantly reduced. However, we have argued that patients might not be improved if off time is reduced only to the extent that unwanted dyskinesia is increased. Therefore, a home diary should include an assessment of dyskinesia to provide an accurate reflection of clinical status over a period of time. We undertook two studies to develop a home diary to assess functional status in patients with PD with motor fluctuations and dyskinesia. In both studies, patients concurrently completed a test and a reference diary. In Study I, we evaluated the impact of different severities of dyskinesia on patient-defined functional status. There were 1,149 evaluable half-hour time periods from 24 patients; 94.3% of off time was considered "bad" time and 90.2% of "on" time without dyskinesia, 72.6% of on time with mild dyskinesia, 43.0% of on time with moderate dyskinesia, and 15.2% of on time with severe dyskinesia was considered "good" time. In Study II, we evaluated a new home diary designed to separate dyskinesia that had a negative impact on patient-defined functional status from dyskinesia that did not. There were 816 evaluable time periods from 17 patients; 84.9% of off time and 89.9% of on time with troublesome dyskinesia was considered bad time while 85.5% of on time without dyskinesia and 93.8% of on time with nontroublesome dyskinesia was considered good time. With this diary (Diary II), the effect of an intervention can be expressed as the change in off time and the change in on time with troublesome dyskinesia (bad time). The sum can be used as an outcome variable and compared to baseline or across groups. In evaluating the efficacy of an intervention, assessment of change in off time and change in on time with troublesome dyskinesia provides a more accurate reflection of clinical response than change in off time alone.