Maurizio Zibetti

Duodenal levodopa infusion for advanced Parkinson's disease: 12‐month treatment outcome

We assessed prospectively clinical and quality of life changes in 9 patients with Parkinsons disease (PD; H&Y ≥ 3) with severe motor fluctuations and dyskinesia who started continuous daily levodopa duodenal infusion through percutaneous endoscopic gastrostomy. Seven patients completed the follow‐up period. Duration of “off” periods and time with disabling dyskinesia shortened significantly in all patients (P < 0.01). Total daily dose of levodopa infused did not differ from baseline equivalents. There were significant improvements in UPDRS‐II (activities of daily living) and ‐IV (motor complications) in the “on” condition (P < 0.02), and in four PDQ‐39 domains (mobility, activities of daily living, stigma, bodily discomfort; P < 0.05). Two patients withdrew for adverse events. Our results demonstrate that a satisfactory therapeutic window can be achieved and maintained for several months in advanced PD patients.

Pain as a nonmotor symptom of Parkinson disease: evidence from a case-control study

OBJECTIVE To determine whether pain is more frequent among people with Parkinson disease (PD) than among age-matched controls. DESIGN Case-control study. PATIENTS AND METHODS Logistic regression models taking into account type of pain, time between pain and PD onset, and possible confounders were used to compare 402 PD patients with 317 age-matched healthy control subjects. RESULTS The overall frequency of pain was significantly greater in PD patients than in controls (281 [69.9%] vs 199 [62.8%]; P = .04), mainly because the healthy control group lacked dystonic pain. Conversely, the frequency of nondystonic pain was similar among PD patients and controls (267 [66.4%] vs 199 [62.8%]; P = .28). Nevertheless, we observed a significant association between PD and nondystonic pain, beginning after the onset of parkinsonian symptoms (odds ratio, 2.1; 95% confidence interval, 1.4-2.9). Cramping and central neuropathic pain were more frequent among PD patients than controls. About one-quarter of patients who experienced pain reported pain onset before starting antiparkinsonian therapy. CONCLUSION These data support the hypothesis that pain begins at clinical onset of PD or thereafter as a nonmotor feature of PD.

Chronic Deep Brain Stimulation of the Subthalamic Nucleus for Parkinson’s Disease: Effects on Cognition, Mood, Anxiety and Personality Traits

Objective: To evaluate modifications occurring in cognitive functions and behavioural aspects in a group of 72 consecutive patients with Parkinson’s disease (PD) 15 months after bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN). Methods: 72 consecutive PD patients bilaterally implanted for DBS of the STN were evaluated before and after surgery with a mean follow-up of 15 months. A neuropsychological assessment was performed to evaluate reasoning (Raven Colour Matrices), memory (Bisyllabic Word Repetition Test, Corsi’s Block-Tapping Test, Paired-Associate Learning) and frontal executive functions (Trail Making Test Part B, Nelson Modified Card Sorting Test, phonemic and category verbal fluency tasks). Mood and suicidal ideation were evaluated using the Beck Depression Inventory (BDI). Anxiety was measured by means of the State-Trait Anxiety Inventory and personality traits were evaluated with the Structured Clinical Interview for the DSM-III-R Axis II Disorders (SCID-II). Assessment of thought disorders and apathy was based on subitems of the Unified Parkinson’s Disease Rating Scale. Results: The comparisons between pre- and postoperative neuropsychological test scores showed a significant worsening only in phonemic and semantic verbal fluency tasks, while fewer errors were found in the Nelson Modified Card Sorting Test. Globally, behavioural assessment evidenced a small improvement in mood, as assessed by the BDI, in obsessive-compulsive and paranoid personality traits (SCID-II). Thought disorders worsened while suicidal ideation, anxiety and apathy showed no postoperative modifications. The analysis of individual outcomes (±1 SD criterion) evidenced a relevant postoperative cognitive decline in 3 patients out of 65 (4.5%). Moreover, following implantation, 1 patients exhibited psychosis (1.5%), 2 patients experienced a clinically relevant worsening of depressive symptoms (3%), 7 patients showed an increase in anxiety (12%) and 3 patients a worsening in depression and anxiety symptoms (3%). On the contrary, 12 patients (20%) showed a relevant improvement in mood and 14 patients (23%) a relevant reduction of anxiety symptoms after the surgery. Conclusions: The present study confirms that STN DBS is cognitively safe since the only relevant change observed was a mild decrease in verbal fluency tasks. Globally, a small postoperative improvement was found in the BDI, and in two SCID-II subscales concerning obsessive-compulsive and paranoid personality traits, even though postoperative behavioural disturbances can occur in individual patients.

Duodenal levodopa infusion improves quality of life in advanced Parkinson's disease.

Background: A significant percentage of patients with Parkinson’s disease (PD) continue to experience motor fluctuations and dyskinesias despite the association of dopamine agonists and levodopa with COMT or MAO-B inhibitors. The use of apomorphine infusion is limited by compliance while deep brain stimulation is feasible only for a small number of patients mostly because of age constraints. Objective: To assess prospectively the effectiveness of duodenal levodopa infusion on quality of life as well as motor features in patients with advanced PD. In all but 1 case levodopa infusion was stopped at nighttime. Methods: We report the outcome of 22 PD patients, followed for up to 2 years, who were on continuous duodenal levodopa/carbidopa infusion through percutaneous endoscopic gastrostomy. Results: We found a significant reduction in ‘off’ period duration as well as dyskinesia severity (Unified Parkinson’s Disease Rating Scale part IV, items 33 and 39). There was significant improvement in the 39-item Parkinson’s Disease Quality of Life Questionnaire as well as in the Unified Parkinson’s Disease Rating Scale part II up to the 2-year follow-up. Five patients withdrew: 2 for poor compliance and 3 for adverse events (1 was related to percutaneous endoscopic gastrostomy). Conclusions: These results demonstrate significant clinical improvements in quality of life and activities of daily living consistent with the occurrence of a satisfactory therapeutic response and a reduction in dyskinesia severity.

Motor and Nonmotor Symptom Follow-Up in Parkinsonian Patients after Deep Brain Stimulation of the Subthalamic Nucleus

Objective: To evaluate motor and nonmotor symptoms in patients with Parkinson’s disease undergoing bilateral deep brain stimulation of the subthalamic nucleus (STN DBS). Methods: Thirty-six consecutive patients receiving bilateral STN stimulation implants were evaluated preoperatively as well as 12 and 24 months after surgery. Motor symptoms were assessed through the Unified Parkinson’s Disease Rating Scale (UPDRS). Data concerning nonmotor symptoms were collected from items of the UPDRS and 2 additional questions from clinical charts regarding constipation and urological dysfunction. Results: STN DBS was effective in controlling motor symptoms; concerning nonmotor symptoms, sleep quality and constipation improved after surgery as compared to baseline. Salivation, swallowing and sensory complaints were ameliorated to a comparable degree by the medication on state, whether preoperatively or postoperatively. With a lower dose of dopaminergic medication, however, the medication on state appeared to be a much larger percentage of the day postoperatively. No significant variations were detected in intellectual impairment, depression, thought disorders, motivation, falling unrelated to freezing, nausea, orthostatic hypotension and urological dysfunction. Conclusions: STN DBS effectively controls motor symptoms, while nonmotor features of advanced Parkinson’s disease patients are mostly unchanged after surgery, even though some specific aspects, notably sleep complaints and constipation, are ameliorated.

Long-term outcome of subthalamic nucleus DBS in Parkinson's disease: from the advanced phase towards the late stage of the disease?

BACKGROUND Deep Brain Stimulation of the Subthalamic Nucleus (STN-DBS) is an effective treatment for Parkinsons disease (PD), but only few studies investigated its long-term efficacy. Furthermore, little is known about the role of PD-subtype on STN-DBS long-term outcome. OBJECTIVE To report the results of a long-term follow-up (mean 11 years, range 10-13) on 26 patients bilaterally implanted in two centres. METHODS Patients were assessed preoperatively and 1, 5 and 11 years after the implant by the Unified Parkinsons Disease Rating Scale (UPDRS) and a battery of neuropsychological tests. Stimulation parameters, drugs dosages, non-motor symptoms and adverse events were also recorded. RESULTS At 11 years, stimulation significantly improved the motor symptoms by 35.8%, as compared to the preoperative off-state. Motor complications were well controlled, with a 84.6% improvement of dyskinesias and a 65.8% improvement of motor fluctuations. Despite this, the UPDRS-II-on score worsened by 88.5%, mainly for the worsening of poorly levodopa-responsive symptoms. More than 70% of the patients performed in the normal range in most of the neuropsychological tests, despite the development of dementia in 22.7%. Age at disease onset, axial subscore in off-condition and presence of REM behaviour disorder at baseline were found to be associated with a higher risk of developing disability over time. CONCLUSIONS Our study confirms the long-term safety and efficacy of STN-DBS in PD. Nevertheless, the functionality of patients worsens over time, mainly for the onset and progression of levodopa-resistant and non-motor symptoms. The role of PD-subtype seems to be relevant in the long-term outcome.

Transient effects of 80 Hz stimulation on gait in STN DBS treated PD patients: A 15 months follow-up study

BACKGROUND Subthalamic nucleus deep brain stimulation (STN DBS) is an effective therapeutic option for advanced Parkinsons disease (PD). Nevertheless, some patients develop gait disturbances despite a persistent improvement of PD segmental symptoms. Recent studies reported that stimulation of STN with low frequencies produced a positive effect on gait disorders and freezing episodes. OBJECTIVE To evaluate the effects of 80 Hz stimulation frequency on gait in PD patients undergoing STN DBS and to determine whether such effects are maintained over time. METHODS We evaluated 11 STN DBS treated PD patients who had developed gait impairment several years after surgery. Gait was assessed by means of the Stand-Walk-Sit (SWS) test. Motor symptoms and activities of daily living were evaluated through the Unified PD Rating Scale (UPDRS). The stimulation frequency was switched from 130 Hz to 80 Hz, adapting the voltage to maintain the same total delivered energy. Patients were assessed at baseline and 3 hours after switching the stimulation frequency to 80 Hz. Follow-up evaluations were carried out after 1, 5, and 15 months. The clinical global improvement scale was rated at every follow-up visit. RESULTS A significant improvement of gait (SWS test) was evident immediately after switching the stimulation frequency to 80 Hz, with no deterioration of PD segmental symptoms. However, gait improvement was no longer detectable by the SWS test at follow-up evaluations 1, 5, and 15 months later. Three patients were switched back to 130 Hz because of unsatisfactory control of motor symptoms. Of the eight patients maintained at 80 Hz up to 15 months, five showed a global improvement and three showed no change. CONCLUSIONS Stimulation frequency at 80 Hz has an immediate positive effect on gait in STN DBS treated patients; however, the objective gait improvement is not maintained over time, limiting the use of this frequency modulation strategy in the clinical setting.

Neuropathy and levodopa in Parkinson's disease: Evidence from a multicenter study

The objectives of this study were to evaluate the risk of neuropathy in patients with Parkinsons disease (PD) and to evaluate the role of levodopa exposure as a potential risk factor. A multicenter study of 330 patients with PD and 137 healthy controls with a comparable age distribution was performed. With respect to levodopa exposure, 144 patients had long exposure (≥3 years) to levodopa (LELD), 103 patients had short exposure (<3 years) to levodopa (SELD), and 83 patients had no exposure to levodopa (NOLD). Nerve function was evaluated using the reduced total neuropathy score. Right sural sensory antidromic and peroneal motor nerve conduction studies were performed by neurophysiologists who were blinded to the existence of neuropathy clinical features or PD treatment. Overall, 19.40% of patients in the LELD group, 6.80% in the SELD group, 4.82% in the NOLD group, and 8.76% in the control group were diagnosed with neuropathy (axonal, predominantly sensory). Multivariate logistic analysis indicated that the risk of neuropathy was not influenced by disease duration, severity, or sex. The risk of neuropathy increased by approximately 8% for each year of age (P < 0.001; odds ratio [OR], 1.08; 95% confidence interval [CI], 1.037‐1.128). The risk of neuropathy was 2.38 higher in the LELD group than in the control group (P = 0.022; OR, 2.38; 95% CI, 1.130‐5.014). In a comparison between patients with and without neuropathy (Students t test), the levodopa dose was higher (P < 0.0001), serum vitamin B12 levels were lower (P = 0.0102), and homocysteine levels were higher (P < 0.001) in the patients with neuropathy. Our results demonstrate that the duration of exposure to levodopa, along with age, is the main risk factor for the development of neuropathy. Screening for homocysteine and vitamin B12 levels and clinical‐neurophysiological monitoring for neuropathy may be advisable in patients with PD who are receiving treatment with levodopa.

Levodopa/carbidopa intestinal gel infusion in advanced Parkinson's disease: a 7-year experience

Levodopa/carbidopa intestinal gel (LCIG) infusion is nowadays becoming an established therapeutic option for advanced Parkinsons disease (PD) patients with fluctuating symptoms unresponsive to conventional oral treatment. As the implementation of LCIG therapy is increasing, there is a need for safety and efficacy data from current clinical practice.

Neuropsychological changes 1-year after subthalamic DBS in PD patients: A prospective controlled study ☆

OBJECTIVE This study aimed at investigating the neuropsychological effect of DBS of the Subthalamic Nucleus in patients with advanced Parkinsons disease (PD). METHODS A standardized neuropsychological test battery, assessing reasoning, memory and executive functions, was administered to 27 PD patients who underwent DBS-STN (DBS group) and to a matched control group of 31 PD patients under optimal medical treatment (MED group). Patients were evaluated at baseline and at the end of 1 year. RESULTS Change score analysis (T1 minus T0 scores) demonstrated a significant decline in phonemic verbal fluency in the DBS group compared with the MED group (p < 0.005), while there were no significant changes between the two groups for the other cognitive tests. Single cases analysis by means of multivariate normative comparisons revealed that 4 out of 27 DBS patients (15%) showed cognitive deterioration one year post surgery. These patients were significantly more compromised from a motor standpoint (UPDRS, section III) than the 23 DBS PD patients who had no cognitive decline post surgery. CONCLUSION Results of this prospective controlled-study showed that phonemic verbal fluency declined one year after DBS-STN, while the other cognitive domains did not change significantly. Nevertheless, single case analysis highlighted the fact that a subgroup comprising 15% of DBS-STN patients (4/27) showed significant cognitive decline 1 year after surgery.