Medical therapy and subthalamic deep brain stimulation in advanced Parkinson's disease: a different long-term outcome?

OBJECTIVES: Few clinical trials reported the comparative short-term efficacy of subthalamic nucleus deep brain stimulation (STN-DBS) versus medical therapy in advanced Parkinson's disease (PD). However, the comparative efficacy, safety and the potential disease-modifying effect of these treatments have not been investigated over a longer follow-up period. METHODS: In this study, we organised a 'retrospective control group' to compare medical and surgical therapies over a long-term period. We assessed a group of PD patients suitable for STN-DBS but successively treated with medical therapies for reasons not related to PD, and a group of similar consecutive STN-DBS patients. We thus obtained two groups comparable at baseline, which were re-evaluated after an average follow-up of 6 years (range 4-11). RESULTS: Patients treated with STN-DBS showed a long-lasting superior clinical efficacy on motor fluctuations, with a significant reduction in the average percentage of the waking day spent in 'OFF' and in the duration and disability of dyskinesia. Moreover, operated patients showed a better outcome in the activities of daily living in 'Medication-OFF' condition. On the other hand, a similar progression of motor score and cognitive/behavioural alterations was observed between the two groups, apart from phonemic verbal fluency, which significantly worsened in STN-DBS patients. CONCLUSIONS: To our knowledge, this is the first long-term comparison between medical and surgical therapies; a superior efficacy of STN-DBS was observed on motor disability, while no significant differences were observed in the progression of motor symptoms and, apart from phonemic verbal fluency, of neuropsychological alterations.

Subthalamic nucleus deep brain stimulation outcome in young onset Parkinson's disease: a role for age at disease onset?

BACKGROUND: Patients with young onset Parkinson's disease (YOPD) are often candidates for subthalamic nucleus-deep brain stimulation (STN-DBS). Nevertheless, few data have been reported on the long term STN-DBS clinical outcome of YOPD versus non-young onset Parkinson's disease (n-YOPD) patients. AIM: In this study, the issue of whether YOPD might represent a long term positive predictive factor for STN-DBS was addressed, comparing follow-up data for 20 YOPD and 40 n-YOPD patients (20 treated after <15 years of disease duration and 20 treated after ≥15 years of disease duration). MATERIALS AND METHODS: Mean scores for the Unified Parkinson's Disease Rating Scale (UPDRS) sections were compared 1 year, 5 years and, for 34 patients (12 YOPD and 22 n-YOPD), ≥7 years after surgery. Furthermore, a Cox proportional hazard regression model was used to determine the influence of age at PD onset, clinical phenotype, disease duration and duration of motor complications on the development of stimulation and medication resistant symptoms. RESULTS: YOPD patients showed a lower incidence of stimulation and medication resistant symptoms and a lower mortality rate; also, the tremor dominant clinical phenotype was associated with a lower risk of developing dementia, hallucinations and constipation. No significant differences in UPDRS scores were observed between n-YOPD patients treated after <15 years of PD and those treated after ≥15 years of PD. CONCLUSION: In this series of STN-DBS treated patients, YOPD was associated with a medium to long term lower incidence of stimulation and medication resistant symptoms.

Parkinson's disease progression at 30 years: a study of subthalamic deep brain-stimulated patients.

Clinical findings in Parkinson's disease suggest that most patients progressively develop disabling non-levodopa-responsive symptoms during the course of the disease. Nevertheless, several heterogeneous factors, such as clinical phenotype, age at onset and genetic aspects may influence the long-term clinical picture. In order to investigate the main features of long-term Parkinson's disease progression, we studied a cohort of 19 subjects treated with subthalamic nucleus deep brain stimulation after >20 years of disease, reporting clinical and neuropsychological data up to a mean of 30 years from disease onset. This group of patients was characterized by an early onset of disease, with a mean age of 38.63 years at Parkinson's disease onset, which was significantly lower than in the other long-term subthalamic nucleus deep brain stimulation follow-up cohorts reported in the literature. All subjects were regularly evaluated by a complete Unified Parkinson's Disease Rating Scale, a battery of neuropsychological tests and a clinical interview, intended to assess the rate of non-levodopa-responsive symptom progression. Clinical data were available for all patients at presurgical baseline and at 1, 3 and 5 years from the subthalamic nucleus deep brain stimulation surgical procedure, while follow-up data after >7 years were additionally reported in a subgroup of 14 patients. The clinical and neuropsychological performance progressively worsened during the course of follow-up; 64% of patients gradually developed falls, 86% dysphagia, 57% urinary incontinence and 43% dementia. A progressive worsening of motor symptoms was observed both in 'medication-ON' condition and in 'stimulation-ON' condition, with a parallel reduction in the synergistic effect of 'medication-ON/stimulation-ON' condition. Neuropsychological data also showed a gradual decline in the performances of all main cognitive domains, with an initial involvement of executive functions, followed by the impairment of language, reasoning and memory. Thirty years after the disease onset, most patients presented non-levodopa-responsive symptoms, although the effect of both subthalamic nucleus deep brain stimulation and dopaminergic therapies still showed significant efficacy on the main disease cardinal features. Nevertheless, compared with other subthalamic nucleus deep brain stimulation follow-up studies, which included patients with a shorter disease duration at the time of surgery, a higher prevalence of axial and non-levodopa-responsive symptoms was observed in the long-term evaluations, confirming that several complex aspects underlie the development of non-motor symptoms and other features of Parkinson's disease progression, even in patients with an early disease onset and a prior long-lasting response to dopaminergic therapies.

Comparison of subthalamic nucleus deep brain stimulation and Duodopa in the treatment of advanced Parkinson's disease.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) and levodopa/carbidopa enteral (Duodopa) infusion are two effective therapeutic options for the treatment of advanced Parkinson's disease (PD). METHODS: Retrospectively, this study compared the two procedures, evaluating 40 PD patients who underwent either STN-DBS or a percutaneous gastrostomy (PEG) for Duodopa infusion. Duodopa group comprised 20 patients, with a mean follow-up of ∼15 months, treated by Duodopa infusion rather than STN-DBS because of the presence of neurosurgical contraindications, age > 70 years-old, moderate cognitive impairment or patient's unwillingness to undergo neurosurgery. The STN-DBS group comprised 20 consecutive patients similar to the patients of the Duodopa group for age at the disease onset, age at the procedure, follow-up, and duration of motor complications. The only difference concerned neuropsychological functions, which were more impaired in the group of Duodopa patients. Clinical and neuropsychological data were compared at baseline and at follow-up for the two procedures. RESULTS: Both procedures showed a significant improvement in UPDRS-II, UPDRS-III, and UPDRS-IV and a considerable reduction in the percentage of waking day spent in "off," whereas only the STN-DBS group showed a significant improvement in dyskinesias duration and disability. STN-DBS was associated to a significant drop in the phonemic verbal fluency score, whereas Duodopa patients showed a milder worsening in this task. The procedure-related complications occurred more frequently with Duodopa. CONCLUSION: STN-DBS and Duodopa showed a significant efficacy on motor symptoms, activities of daily living, and motor complications. The group of Duodopa-treated patients developed more procedure-related complications.

Beyond nine years of continuous subthalamic nucleus deep brain stimulation in Parkinson's disease.

Deep brain stimulation of the subthalamic nucleus is an effective treatment for advanced Parkinson's disease. The benefits of bilateral subthalamic stimulation are well documented, and some studies reported outcomes with a follow-up of 5 to 6 years; nevertheless, few data are available beyond 5 years. We report a long-term prospective evaluation of 14 consecutive parkinsonian patients, treated by bilateral subthalamic stimulation for at least 9 years. Motor symptoms, activity of daily living, and motor complications were evaluated by means of the Unified Parkinson's Disease Rating Scale, while cognition and mood were assessed with a specific neuropsychological test battery; medication intake, stimulation parameters, comorbidity, and adverse events were also recorded. Patients were evaluated before surgery and at 1, 5, and ≥ 9 years after surgery. At last follow-up, deep brain stimulation significantly improved the motor score by 42% compared to baseline, whereas activities of daily living were no longer improved; there was a 39% reduction in the dosage of dopaminergic drugs and a 59% improvement of L-dopa-related motor complications. The neuropsychological assessment showed that 4 patients (29%) developed a significant cognitive decline over the follow-up period. These results indicate a persistent effect of deep brain stimulation of the subthalamic nucleus on the cardinal motor symptoms in advanced Parkinson's disease patients in the long-term; however, a worsening of patients' disability, mainly due to disease progression, was observed.

Asymptomatic deep venous thrombosis after deep brain stimulation for Parkinson disease.

BACKGROUND/AIMS: Patients with advanced Parkinson disease (PD) are at increased risk for asymptomatic leg deep venous thrombosis (DVT) because of severe motor fluctuations. Protracted immobility in the absence of antiparkinsonian therapy during stereotactic surgery may further increase the risk for venous thrombosis. Our aim was to determine the incidence of asymptomatic DVT of leg veins in PD patients undergoing subthalamic nucleus deep brain stimulation (STN-DBS). METHODS: 41 consecutive PD patients undergoing stereotactic surgery for STN-DBS were investigated by ultrasound compression sonography of leg veins and D-dimer measurement in the week preceding surgery. After surgery, D-dimer measurements were repeated and when the value exceeded the normal range, ultrasound compression sonography was repeated to confirm or exclude DVT. RESULTS: Doppler ultrasonographic examinations demonstrated that 2 patients (4.9%) developed asymptomatic DVT shortly after surgery (8.5 days) despite the fact that none of the 41 patients submitted to STN-DBS had DVT before surgery and that a specific prophylaxis was applied during surgery. CONCLUSIONS: Our data show that advanced PD patients are at risk for developing asymptomatic leg DVT following stereotactic surgery performed for STN-DBS. A strict clinical monitoring in the perioperative period is advisable in order to ensure early detection of DVT and prevent further thrombo-embolic complications.

Deep brain stimulation in Parkinson's disease: A multicentric, long-term, observational pilot study.

BACKGROUND: The impact of deep brain stimulation (DBS) on cognitive and urinary disorders, falls, and eventually hospitalizations and mortality in Parkinson's disease (PD) is still debated. OBJECTIVE: We compared the rates of dementia, mild cognitive impairment (MCI), urinary incontinence, nocturia, falls, hospitalizations, and mortality in a cohort of PD patients undergoing DBS with a cohort of medically-treated patients chosen as controls. METHODS: We conducted a retrospective pilot study in six Italian DBS centers. 91 PD patients receiving DBS and 91 age- and gender-matched controls receiving the best medical treatment alone with a minimum follow-up of one year were enrolled. Clinical data were collected from baseline to the last follow-up visit using an ad-hoc developed web-based system. RESULTS: The risk of dementia was similar in the two groups while patients in the surgical cohort had lower rates of MCI, urinary incontinence, nocturia, and falls. In contrast, the risk of hospital admissions related to PD was higher in the surgical cohort. However, when excluding hospitalizations related to DBS surgery, the difference between the two cohorts was not significant. The surgical cohort had a lower number of hospitalizations not related to PD. The risk of death was similar in the two groups. CONCLUSION: Despite a higher risk of hospitalization, patients receiving DBS had a lower rate of MCI, urinary incontinence, nocturia and falls, without evidence of an increased risk of dementia and mortality. Although these findings need to be confirmed in prospective studies, they seem to suggest that DBS may play a significant role in the management of non-motor symptoms and common complications of advanced PD.

Effects of intestinal Levodopa infusion on freezing of gait in Parkinson disease.

OBJECTIVE: To determine the impact of levodopa-carbidopa intestinal gel (LCIG) infusion on different subtypes of freezing of gait (FoG) classified according to levodopa responsiveness in advanced Parkinson disease (PD) patients. METHODS: We retrospectively assessed the presence and severity of FoG in 32 advanced PD patients based on the Unified PD Rating Scale (UPDRS) item 14 score. Different FoG subtypes were inferred from the score variation with oral dopaminergic medications. Modifications following long-term LCIG infusion were analysed. Motor symptoms and motor complications were assessed by UPDRS part III and IV respectively. RESULTS: FoG related UPDRS score varied from 2.6±0.9 in OFF condition to 0.9±0.8 in the ON condition at baseline and improved to 0.6±0.7 with LCIG infusion (p=0.027). After a mean of 2.59±1.12years of continuous LCIG infusion, Pseudo-ON-FoG improved to a greater extent with LCIG infusion than with oral therapy in 12 patients (38%) and equally well in 8 patients (25%), OFF-type-FoG was controlled equally well in 8 patients (25%) and worsened slightly in 3 patients (9%). Unresponsive-FoG, present in one patient (3%), was unmodified by LCIG infusion. CONCLUSIONS: Even though limited by the subjective simple measure of FoG, this study suggests that patients undergoing LCIG infusion maintain a good long-term control of FoG. Pseudo-on-FoG improves in a considerable percentage of patients and OFF-type-FoG remains well controlled with LCIG infusion. Further studies with a larger number of patients and objective measures of FoG are needed to confirm these findings.

A polysomnographic study in parkinsonian patients treated with intestinal levodopa infusion.

Sleep disorders are very common in advanced Parkinson's disease (PD) and have a significant negative impact on the quality of life of patients. Questionnaire-based studies suggest that sleep quality might improve following levodopa-carbidopa intestinal gel (LCIG) infusion. The objective of this study was to evaluate the impact of LCIG infusion and subsequent oral medication changes on polysomnography (PSG) and sleep symptoms in advanced PD patients. Eleven PD patients underwent PSG at baseline and after 3.8 ± 1.2 months of LCIG treatment. LCIG infusion therapy was halted during PSG. Patients were assessed with the Unified-PD-rating-Scale and completed the PD-Sleep-Scale-version-2 (PDSS-2), the Epworth Sleepiness Scale and the RBD single question. Subjective sleep quality improved in all patients. PSG showed a reduction of the number of awakenings in sleep, a trend towards a lower apnea-hypopnea index and no change in sleep latency, total sleep time and sleep efficiency. There was a positive correlation between the number of awakenings and PDSS-2 scores for "difficulty staying asleep", "muscle cramps of arms or legs" and "urge to move arms or legs". Motor complications and activities of daily living improved with LCIG. Subjective sleep quality improved significantly and the PSG study showed a less fragmented sleep pattern in advanced PD patients treated with LCIG infusion.

80 Hz versus 130 Hz subthalamic nucleus deep brain stimulation: effects on involuntary movements.

BACKGROUND: Subthalamic Nucleus Deep Brain Stimulation (STN-DBS) represents a valid therapeutic option for advanced Parkinson's disease (PD), leading to a significant amelioration of motor fluctuations and levodopa-induced involuntary movements (IM). This study address the issue of whether stimulation frequency may influence the control of IM in STN-DBS treated patients, comparing the effects of 80 Hz and 130 Hz STN-DBS frequencies in 10 parkinsonian patients with residual IM (dyskinesia in 6 cases and dystonia in 4 cases). METHODS: Patients were evaluated by means of the Rush Dyskinesias Rating Scale (blinded-video analysis) and Unified Parkinson's Disease Rating Scale at 4 different time-points: baseline, shortly after the switch of stimulation frequency from 130 Hz to 80 Hz, after 1 month and 12 months of chronic 80 Hz stimulation. RESULTS: IM improved in most subjects after the switch of stimulation frequency: dyskinesias improved in 6/6 subjects and dystonic features in 3/4 subjects after one month of 80 Hz stimulation. However, the 130 Hz STN stimulation was restored in 4 subjects during the following months, because of a gradual worsening of parkinsonian symptoms. A sustained efficacy on motor features and IM was observed with 80 Hz stimulation frequency in the remaining patients. CONCLUSIONS: In this limited cohort of STN-DBS patients, we observed an improvement of residual IM after the switch of stimulation frequency from 130 Hz to 80 Hz. However, a moderate worsening of parkinsonian symptoms was observed in a portion of patients, requiring to return at 130 Hz STN-DBS.

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 Parkinson's 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.

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 Parkinson's 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.