Carla Piano

Motor and cognitive outcome in patients with Parkinson's disease 8 years after subthalamic implants.

Deep brain stimulation of the subthalamic nucleus represents the most important innovation for treatment of advanced Parkinsons disease. Prospective studies have shown that although the beneficial effects of this procedure are maintained at 5 years, axial motor features and cognitive decline may occur in the long term after the implants. In order to address some unsolved questions raised by previous studies, we evaluated a series of 20 consecutive patients who received continuous stimulation for 8 years. The overall motor improvement reported at 5 years (55.5% at Unified Parkinsons Disease Rating Scale-motor part, P < 0.001 compared with baseline) was only partly retained 3 years later (39%, P < 0.001, compared with baseline; -16.5%, P < 0.01, compared with 5 years), with differential effects on motor features: speech did not improve and postural stability worsened (P < 0.05). The preoperative levodopa equivalent daily dose was reduced by 58.2% at 5 years and by 60.3% at 8 years. In spite of subtle worsening of motor features, a dramatic impairment in functional state (-56.6% at Unified Parkinsons Disease Rating Scale-Activities of Daily Living, P < 0.01) emerged after the fifth year of stimulation. The present study did not reveal a predictive value of preoperative levodopa response, whereas few single features at baseline (such as gait and postural stability motor scores and the preoperative levodopa equivalent daily dose) could predict long-term motor outcome. A decline in verbal fluency (slightly more pronounced than after 5 years) was detected after 8 years. A significant but slight decline in tasks of abstract reasoning, episodic memory and executive function was also found. One patient had developed dementia at 5 years with further progression at 8 years. Executive dysfunction correlated significantly with postural stability, suggesting interplay between axial motor deterioration and cognition. Eight years after surgery, no significant change was observed on scales assessing depression or anxiety when compared with baseline. At 8 years, there was no significant increase of side-effects when compared with 5-year follow-up. In conclusion, deep brain stimulation of the subthalamic nucleus is a safe procedure with regard to cognitive and behavioural morbidity over long-term follow-up. However, the global benefit partly decreases later in the course of the disease, due to progression of Parkinsons disease and the appearance of medication- and stimulation-resistant symptoms.

The role of small intestinal bacterial overgrowth in Parkinson's disease

Parkinsons disease is associated with gastrointestinal motility abnormalities favoring the occurrence of local infections. The aim of this study was to investigate whether small intestinal bacterial overgrowth contributes to the pathophysiology of motor fluctuations. Thirty‐three patients and 30 controls underwent glucose, lactulose, and urea breath tests to detect small intestinal bacterial overgrowth and Helicobacter pylori infection. Patients also underwent ultrasonography to evaluate gastric emptying. The clinical status and plasma concentration of levodopa were assessed after an acute drug challenge with a standard dose of levodopa, and motor complications were assessed by Unified Parkinsons Disease Rating Scale–IV and by 1‐week diaries of motor conditions. Patients with small intestinal bacterial overgrowth were treated with rifaximin and were clinically and instrumentally reevaluated 1 and 6 months later. The prevalence of small intestinal bacterial overgrowth was significantly higher in patients than in controls (54.5% vs. 20.0%; P = .01), whereas the prevalence of Helicobacter pylori infection was not (33.3% vs. 26.7%). Compared with patients without any infection, the prevalence of unpredictable fluctuations was significantly higher in patients with both infections (8.3% vs. 87.5%; P = .008). Gastric half‐emptying time was significantly longer in patients than in healthy controls but did not differ in patients based on their infective status. Compared with patients without isolated small intestinal bacterial overgrowth, patients with isolated small intestinal bacterial overgrowth had longer off time daily and more episodes of delayed‐on and no‐on. The eradication of small intestinal bacterial overgrowth resulted in improvement in motor fluctuations without affecting the pharmacokinetics of levodopa. The relapse rate of small intestinal bacterial overgrowth at 6 months was 43%.

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.

Botulinum toxin A versus B in sialorrhea: A prospective, randomized, double-blind, crossover pilot study in patients with amyotrophic lateral sclerosis or Parkinson's disease†

Background: Either botulinum toxins (BoNTs) A and B have been used for improving drooling in different neurological conditions. Methods: Consecutive patients affected by Amyotrophic Lateral Sclerosis (ALS) or Parkinsons Disease (PD) accompanied by severe drooling were randomized to receive botulinum neurotoxin type A (BoNT‐A) or B (BoNT‐B) injections into the salivary glands. Following the first treatment, when sialorrhea returned to baseline (at least three months after the first injection), subjects were re‐treated with the other serotype. Ultrasound‐guided injections into parotid and submandibular glands were bilaterally performed: total doses were 250 U BoNT‐A (Dysport) and 2500 U BoNT‐B (Neurobloc). Objective (cotton roll weight) and subjective (ad hoc clinical scales) evaluations were performed at baseline, after 1 and 4 weeks, and every 4 weeks until drooling returned to baseline. Results: Twenty‐seven patients (15 ALS and 12 PD) were enrolled, fourteen completed the study. BoNT‐A and BoNT‐B treatments gave both subjective and objective improvements in all patients. The latency was significantly shorter after BoNT‐B treatments (3.2 ± 3.7 days) compared to BoNT‐A (6.6 ± 4.1 days; P = 0.002). The mean benefit duration was similar at 75 and 90 days for BoNT‐A and BoNT‐B, respectively (P = NS). The only toxin‐related side effect was a change to saliva thickness. Conclusions: Either 250 U Dysport or 2500 U Neurobloc have similar effectiveness and safety in controlling sialorrhea. BoNT‐B has a shorter latency and comparable duration. Cost analysis, considering the doses used in this study protocol favored BoNT‐B treatment.

Mutation screening of the DYT6/THAP1 gene in Italy

Mutations in the THAP1 gene on chromosome 8p21‐p22 (DYT6 locus) have been recently reported as causative of autosomal dominant primary torsion dystonia (PTD) in four Amish–Mennonite families and in 12 additional probands of different ancestry. We sequenced the THAP1 gene in 158 patients with DYT1‐negative PTD who had onset of symptoms below 30 years and/or positive family history. One sporadic Greek male patient, aged 57 years, was found to carry a novel heterozygous missense variant in THAP1 exon 3 (p.Cys170Arg), of likely pathogenic significance. This subject first presented with right writers cramp at age of 10 years and, subsequently, developed left arm dystonia and an extremely severe left laterocollis, without further spreading to other body districts. Our findings expand the genotypic spectrum of THAP1 and strengthen the association with upper body involvement, including the cranial and cervical districts that are usually spared in DYT1‐PTD.

The long-term effect of tetrabenazine in the management of Huntington disease

Objectives: To enhance the knowledge on the long-term efficacy and safety of tetrabenazine (TBZ) in managing chorea. Methods: We analyzed 68 Huntington disease patients (mean disease duration, 55.8 ± 34.7 months) who had been treated with TBZ for a mean period of 34.4 ± 25.2 months (median, 34 months; mode, 48 months; range, 3-104 months). We measured the variation from pretreatment of the motor score of Unified Huntingtons Disease Rating Scale at the first follow-up visit and at the latest. Results: Mean Unified Huntingtons Disease Rating Scale-chorea underscore at the time of the pretreatment visit was 10.4 ± 4.1 (range, 0-28). At the first follow-up, 9.7 ± 7.8 months after the prescription of TBZ (mean dose, 35.3 ± 14.7 mg), mean score of chorea was 8.2 ± 4.1 (−21% compared with baseline), whereas at the latest follow-up visit (mean dose, 57.5 ± 14.7 mg), it was 9.5 ± 5.0 (9%). During the follow-up, the clinical benefit persisted, but the magnitude was reduced despite a progressive increase of the doses (up to 60%). Motor improvement was not influenced by sex, or doses or duration of therapy; age at onset was the only predictor of a good outcome. Five patients (7%) did not gain any improvement, and TBZ was discontinued. There were 2 withdrawals because of side effects; 34 patients reported at least 1 side effect. Conclusions: Tetrabenazine was well tolerated and produced long-term improvement of motor symptoms in Huntington disease patients, although a slight reduction of benefit occurred during the course of treatment. Abbreviations: HD, Huntington disease, TBZ, tetrabenazine

Novel mutations in SPG11 cause hereditary spastic paraplegia associated with early-onset levodopa responsive parkinsonism

Background: Autosomal recessive hereditary spastic paraplegia with thin corpus callosum is a neurodegenerative disorder characterized by spastic paraparesis, cognitive impairment, and peripheral neuropathy. The neuroradiologic hallmarks are thin corpus callosum and periventricular white matter changes. Mutations in the SPG11 gene have been identified to be a major cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and recently also proven to be responsible for juvenile parkinsonism associated with spastic paraplegia.

Effects of stimulation of the subthalamic nucleus on naming and reading nouns and verbs in Parkinson's disease.

UNLABELLED An impairment for verbs has been described in patients with Parkinsons disease (PD), suggesting that a disruption of frontal-subcortical circuits may result in dysfunction of the neural systems involved in action-verb processing. A previous study suggested that deep brain stimulation (DBS) of the subthalamic nucleus (STN) during verb generation may affect the ability to select from many competing lexical alternatives. In this study, 12 PD patients who had undergone bilateral STN DBS and completed an 8-year follow-up and 14 matched normal controls were administered action and object naming tasks and verb and noun reading tasks. Their responses were recorded using a microphone, resulting in a signal that marked the onset of the verbal response and allowed to measure response times (RTs). Accuracy was scored manually. RESULTS Overall performance in naming (independently of stimulation): In naming task controls were faster and more accurate than PD patients. In both groups, performance (accuracy and RTs) was worse on action naming than object naming. PD patients were significantly slower than controls in naming actions. Effect of stimulation: Compared with the OFF stimulation condition, in ON stimulation condition PD patients showed improved performance on object and action naming tasks (increased accuracy, faster RTs), with a decreased number of semantic errors. Some evidence also emerged that action naming in the ON stimulation condition improved more than object naming. On noun and verb reading tasks, although accuracy was at ceiling in both groups and no significant difference was observed in RTs for nouns and verbs, PD patients were slower than controls. CONCLUSIONS Our findings suggest that STN DBS may improve lexical search in PD patients. We hypothesize that STN stimulation may facilitate the motor components involved in naming and reading tasks (increased speed of speech onset), resulting in shorter RTs in both naming and reading and, to some extent, in increased accuracy in naming due to fewer omissions (no response within the 7500 ms time limit). However, to account for greater accuracy in naming due to decreased number of semantic errors in the ON stimulation condition, we hypothesize that STN stimulation restores the activity of the corticostriatal circuits involved in selection processes of a target word among different alternatives.

Polysomnographic Findings and Clinical Correlates in Huntington Disease. A Cross-sectional Cohort Study.

STUDY OBJECTIVES To evaluate the sleep pattern and the motor activity during sleep in a cohort of patients affected by Huntington disease (HD). DESIGN Cross-sectional cohort study. SETTING Sleep laboratory. PATIENTS Thirty HD patients, 16 women and 14 men (mean age 57.3 ± 12.2 y); 30 matched healthy controls (mean age 56.5 ± 11.8 y). INTERVENTIONS Subjective sleep evaluation: Epworth Sleepiness Scale (ESS); Berlins Questionnaire, interview for restless legs syndrome (RLS), questionnaire for REM sleep behavior disorder (RBD). Clinical evaluation: disease duration, clinical severity (unified Huntington disease motor rating scale [UHDMRS]), genetic tests. Laboratory-based full-night attended video-polysomnography (V-PSG). MEASUREMENTS AND RESULTS The duration of the disease was 9.4 ± 4.4 y, UHMDRS score was 55.5 ± 23.4, CAG repeats were 44.3 ± 4.1. Body mass index was 21.9 ± 4.0 kg/m(2). No patients or caregivers reported poor sleep quality. Two patients reported symptoms of RLS. Eight patients had an ESS score ≥ 9. Eight patients had high risk of obstructive sleep apnea. At the RBD questionnaire, two patients had a pathological score. HD patients, compared to controls, showed shorter sleep, reduced sleep efficiency index, and increased arousals and awakenings. Four patients presented with sleep disordered breathing (SDB). Periodic limb movements (PLMs) during wake and sleep were observed in all patients. No episode of RBD was observed in the V-PSG recordings, and no patients showed rapid eye movement (REM) sleep without atonia. The disease duration correlated with ESS score (P < 0.02). UHMDRS correlated positively with the ESS score (P < 0.005), and negatively with the percentage of REM sleep. CONCLUSIONS Patients with Huntington disease showed a severe sleep disruption and a high prevalence of periodic limb movements, but no evidence of sleep disordered breathing or REM sleep behavior disorder.

High frequency extradural motor cortex stimulation transiently improves axial symptoms in a patient with Parkinson's disease

In a primate model of Parkinsons disease (PD), the benefit of extradural motor cortex stimulation (EMCS) was associated with high‐frequency stimulation (130 Hz), whereas no significant motor improvement was achieved at 10 Hz or intermediate frequencies of stimulation. We report the case of a 72‐year‐old female patient affected by severe PD who underwent bilateral EMCS. In baseline med‐off condition the patient was unable to arise from a chair and to stand without assistance. Stimulation at 3 and 60 Hz failed to provide any improvement of symptoms, whereas, when stimulating at 130 Hz, axial akinesia and walking improved consistently: the patient, in med‐off condition, was able to arise from chair and to walk without assistance. The patient underwent two brain 99mTc‐ Ethylcysteinate Dimer‐SPECT studies: semiquantitative and Statistical Parametric Mapping revealed that the regional cerebral perfusion was significantly increased in the supplementary motor area during stimulation at 130 Hz. After five months, the benefit of EMCS gradually disappeared.