Soledad Navarro

Stimulation of the subthalamic nucleus in Parkinson’s disease: a 5 year follow up

Background: The short term benefits of bilateral stimulation of the subthalamic nucleus (STN) in patients with advanced levodopa responsive Parkinson’s disease (PD) are well documented, but long term benefits are still uncertain. Objectives: This study provides a 5 year follow up of PD patients treated with stimulation of the STN. Methods: Thirty seven consecutive patients with PD treated with bilateral STN stimulation were assessed prospectively 6, 24, and 60 months after neurosurgery. Parkinsonian motor disability was evaluated with and without levodopa treatment, with and without bilateral STN stimulation. Neuropsychological and mood assessments included the Mattis Dementia Rating Scale, the frontal score, and the Montgomery-Asberg Depression Rating Scale (MADRS). Results: No severe peri- or immediate postoperative side effects were observed. Six patients died and one was lost to follow up. Five years after neurosurgery: (i) activity of daily living (Unified Parkinson Disease Rating Scale (UPDRS) II) was improved by stimulation of the STN by 40% (“off” drug) and 60% (“on” drug); (ii) parkinsonian motor disability (UPDRS III) was improved by 54% (“off” drug) and 73% (“on” drug); (iii) the severity of levodopa related motor complications was decreased by 67% and the levodopa daily doses were reduced by 58%. The MADRS was unchanged, but cognitive performance declined significantly. Persisting adverse effects included eyelid opening apraxia, weight gain, addiction to levodopa treatment, hypomania and disinhibition, depression, dysarthria, dyskinesias, and apathy. Conclusions: Despite moderate motor and cognitive decline, probably due to disease progression, the marked improvement in motor function observed postoperatively was sustained 5 years after neurosurgery.

Tourette’s syndrome and deep brain stimulation

In this prospective double blind randomised “N of 1” study, a patient with a severe form of Tourette’s syndrome was treated with bilateral high frequency stimulation of the centromedian-parafascicular complex (Ce-Pf) of the thalamus, the internal part of the globus pallidus (GPi), or both. Stimulation of either target improved tic severity by 70%, markedly ameliorated coprolalia, and eliminated self injuries. Severe forms of Tourette’s syndrome may benefit from stimulation of neuronal circuits within the basal ganglia, thus confirming the role of the dysfunction of limbic striato-pallido-thalamo-cortical systems in this disorder.

Bilateral, pallidal, deep-brain stimulation in primary generalised dystonia: a prospective 3 year follow-up study

BACKGROUND We have previously reported the efficacy and safety of bilateral pallidal stimulation for primary generalised dystonia in a prospective, controlled, multicentre study with 1 year of follow-up. Although long-term results have been reported by other groups, no controlled assessment of motor and non-motor results is available. In this prospective multicentre 3 year follow-up study, involving the same patients as those enrolled in the 1 year follow-up study, we assessed the effect of bilateral pallidal stimulation on motor impairment, disability, quality of life, cognitive performance, and mood. METHODS We studied 22 patients with primary generalised dystonia after 3 years of bilateral pallidal stimulation. We compared outcome at 3 years with their status preoperatively and after 1 year of treatment. Standardised video recordings were scored by an independent expert. Data were analysed on an intention-to-treat basis. FINDINGS Motor improvement observed at 1 year (51%) was maintained at 3 years (58%). The improvement in quality of life (SF-36 questionnaire) was similar to that observed at 1 year. Relative to baseline and to the 1 year assessment, cognition and mood were unchanged 3 years after surgery, but slight improvements were noted in concept formation, reasoning, and executive functions. Pallidal stimulation was stopped bilaterally in three patients because of lack of improvement, technical dysfunction, and infection, and unilaterally in two patients because of electrode breakage and stimulation-induced contracture. No permanent adverse effects were observed. INTERPRETATION Bilateral pallidal stimulation provides sustained motor benefit after 3 years. Mild long-term improvements in quality of life and attention were also observed.

Bilateral pallidal deep brain stimulation for the treatment of patients with dystonia-choreoathetosis cerebral palsy: a prospective pilot study

BACKGROUND Cerebral palsy (CP) with dystonia-choreoathetosis is a common cause of disability in children and in adults, and responds poorly to medical treatment. Bilateral pallidal deep brain stimulation (BP-DBS) of the globus pallidus internus (GPi) is an effective treatment for primary dystonia, but the effect of this reversible surgical procedure on dystonia-choreoathetosis CP, which is a subtype of secondary dystonia, is unknown. Our aim was to test the effectiveness of BP-DBS in adults with dystonia-choreoathetosis CP. METHODS We did a multicentre prospective pilot study of BP-DBS in 13 adults with dystonia-choreoathetosis CP who had no cognitive impairment, little spasticity, and only slight abnormalities of the basal ganglia on MRI. The primary endpoint was change in the severity of dystonia-choreoathetosis after 1 year of neurostimulation, as assessed with the Burke-Fahn-Marsden dystonia rating scale. The accuracy of surgical targeting to the GPi was assessed masked to the results of neurostimulation. Analysis was by intention to treat. FINDINGS The mean Burke-Fahn-Marsden dystonia rating scale movement score improved from 44.2 (SD 21.1) before surgery to 34.7 (21.9) at 1 year post-operatively (p=0.009; mean improvement 24.4 [21.1]%, 95% CI 11.6-37.1). Functional disability, pain, and mental health-related quality of life were significantly improved. There was no worsening of cognition or mood. Adverse events were related to stimulation (arrest of the stimulator in one patient, and an adjustment to the current intensity in four patients). The optimum therapeutic target was the posterolateroventral region of the GPi. Little improvement was seen when the neurostimulation diffused to adjacent structures (mainly to the globus pallidus externus [GPe]). INTERPRETATION Bilateral pallidal neurostimulation could be an effective treatment option for patients with dystonia-choreoathetosis CP. However, given the heterogeneity of motor outcomes and the small sample size, results should be interpreted with caution. The optimum placement of the leads seemed to be a crucial, but not exclusive, factor that could affect a good outcome. FUNDING National PHRC; Cerebral Palsy Foundation: Fondation Motrice/APETREIMC; French INSERM Dystonia National Network; Medtronic.

Neurosurgery at an earlier stage of Parkinson disease: a randomized, controlled trial.

Background: Stimulation of the subthalamic nucleus is an effective treatment for advanced Parkinson disease (PD) and is currently performed after a mean disease duration of 14 years, when severe motor complications have resulted in marked loss of quality of life. We examined whether surgery at an early stage would maintain quality of life as well as improve motor function. Methods: Twenty patients with PD of short duration (time elapsed since first symptom ± SD: 6.8 ± 1.0 years) with mild to moderate motor signs (Unified Parkinsons Disease Rating Scale III “off” medication: 29 ± 12) who responded well to levodopa treatment were included in pairs, matched for age, duration and severity of disease, and impairment in socioprofessional functioning. Patients were prospectively randomized to undergo bilateral subthalamic nucleus stimulation (n = 10) or receive optimized medical treatment (n = 10). Parkinsonian motor scores, quality of life, cognition, and psychiatric morbidity were assessed at inclusion and at 6, 12, and 18 months after randomization. Results: Quality of life was improved by 24% in surgical and 0% in nonsurgical patients (p < 0.05). After 18 months, the severity of parkinsonian motor signs “off” medication, levodopa-induced motor complications, and daily levodopa dose were reduced by 69%, 83%, and 57% in operated patients and increased by 29%, 15%, and 12% in the group with medical treatment only (p < 0.001). Adverse events were mild or transient, and overall psychiatric morbidity and anxiety improved in the surgical group. Conclusions: Subthalamic nucleus stimulation should be considered a therapeutic option early in the course of Parkinson disease.

Internal Pallidal and Thalamic Stimulation in Patients With Tourette Syndrome

BACKGROUND Tourette syndrome (TS) is thought to result from dysfunction of the associative-limbic territories of the basal ganglia, and patients with severe symptoms of TS respond poorly to medication. High-frequency stimulation has recently been applied to patients with TS in open studies using the centromedian-parafascicular complex (CM-Pf) of the thalamus, the internal globus pallidus (GPi), or the anterior limb of the internal capsule as the principal target. OBJECTIVE To report the effect of high-frequency stimulation of the CM-Pf and/or the GPi, 2 associative-limbic relays of the basal ganglia, in patients with TS. DESIGN Controlled, double-blind, randomized crossover study. SETTING Medical research. PATIENTS Three patients with severe and medically refractory TS. INTERVENTION Bilateral placement of stimulating electrodes in the CM-Pf (associative-limbic part of the thalamus) and the GPi (ventromedial part). MAIN OUTCOME MEASURES Effects of thalamic, pallidal, simultaneous thalamic and pallidal, and sham stimulation on neurologic, neuropsychological, and psychiatric symptoms. RESULTS A dramatic improvement on the Yale Global Tic Severity Scale was obtained with bilateral stimulation of the GPi (reduction in tic severity of 65%, 96%, and 74% in patients 1, 2, and 3, respectively). Bilateral stimulation of the CM-Pf produced a 64%, 30%, and 40% reduction in tic severity, respectively. The association of thalamic and pallidal stimulation showed no further reduction in tic severity (60%, 43%, and 76%), whereas motor symptoms recurred during the sham condition. No neuropsychological, psychiatric, or other long-term adverse effect was observed. CONCLUSIONS High-frequency stimulation of the associative-limbic relay within the basal ganglia circuitry may be an effective treatment of patients with TS, thus heightening the hypothesis of a dysfunction in these structures in the pathophysiologic mechanism of the disorder.

Bilateral Deep Brain Stimulation of the Pallidum for Myoclonus-Dystonia Due to ε-Sarcoglycan Mutations: A Pilot Study

OBJECTIVE To assess the efficacy of bilateral deep brain stimulation of the internal pallidum in patients with myoclonus-dystonia due to genetically proved ε-sarcoglycan (SGCE-M-D) deficiency. DESIGN Patients with documented SGCE-M-D undergoing bilateral deep brain stimulation of the internal pallidum were recruited. Standardized assessments of M-D were videorecorded before surgery and 6 to 9 months and 15 to 18 months after surgery, using the movement and disability subscales of the Burke-Fahn-Marsden Dystonia Rating Scale and the Unified Myoclonus Rating Scale. The analysis was based on blinded evaluation of the recordings. SETTING Movement disorder unit in a university hospital in Paris. PATIENTS Five consecutive patients with documented SGCE-M-D. MAIN OUTCOME MEASURES Myoclonus and dystonia scores at follow-up. RESULTS The median myoclonus score decreased from 76 before surgery (range, 38-116) to 10 at 6 to 9 months after surgery (range, 6-31). The median dystonia score decreased from 30.0 before surgery (range, 18.5-53.0) to 4.5 after surgery (range, 3.5-16.0). Disability was also improved and symptoms remained stable between the postoperative evaluations. No adverse effects occurred. CONCLUSIONS Bilateral deep brain stimulation of the internal pallidum is safe and highly effective in this homogeneous population of patients with SGCE-M-D. This therapeutic option should therefore be considered for patients with severe, drug-resistant forms of the disorder.

Optimal target localization for subthalamic stimulation in patients with Parkinson disease

Objective: To further determine the causes of variable outcome from deep brain stimulation of the subthalamic nucleus (DBS-STN) in patients with Parkinson disease (PD). Methods: Data were obtained from our cohort of 309 patients with PD who underwent DBS-STN between 1996 and 2009. We examined the relationship between the 1-year motor, cognitive, and psychiatric outcomes and (1) preoperative PD clinical features, (2) MRI measures, (3) surgical procedure, and (4) locations of therapeutic contacts. Results: Pre- and postoperative results were obtained in 262 patients with PD. The best motor outcome was obtained when stimulating contacts were located within the STN as compared with the zona incerta (64% vs 49% improvement). Eighteen percent of the patients presented a postoperative cognitive decline, which was found to be principally related to the surgical procedure. Other factors predictive of poor cognitive outcome were perioperative confusion and psychosis. Nineteen patients showed a stimulation-induced hypomania, which was related to both the form of the disease (younger age, shorter disease duration, higher levodopa responsiveness) and the ventral contact location. Postoperative depression was more frequent in patients already showing preoperative depressive and/or residual axial motor symptoms. Conclusion: In this homogeneous cohort of patients with PD, we showed that (1) the STN is the best target to improve motor symptoms, (2) postoperative cognitive deficit is mainly related to the surgery itself, and (3) stimulation-induced hypomania is related to a combination of both the disease characteristics and a more ventral STN location.

α-Internexin expression identifies 1p19q codeleted gliomas

Background: α-Internexin (INA) is a proneural gene encoding a neurofilament interacting protein that is upregulated in some gliomas, particularly oligodendrogliomas. Methods: INA expression was evaluated by immunohistochemistry in a series of 122 gliomas, and correlated to the 1p19q codeletion, a favorable prognostic marker of oligodendroglial tumors. Results: INA expression was strong (>10% positive cells) in 22 cases (22 oligodendroglial tumors and 0 astrocytic tumors), weak (<10% cells) in 14 cases (12 oligodendroglial tumors, 2 glioblastoma with an oligodendroglial component, and 0 astrocytic tumors), and negative in 86 cases (49 oligodendroglial tumors, 9 glioblastoma with an oligodendroglial component, and 28 astrocytic tumors). Among the 27 tumors exhibiting the 1p19q codeletion (all with an oligodendroglial phenotype), INA was detected in 96% (26/27, 18 strong, 8 weak) as compared to 11% (10/95, 4 strong, 6 weak) in the tumors without 1p19q codeletion (with an oligodendroglial or an astrocytic phenotype) (p < 0.001). In oligodendroglial tumors, INA expression specificity for 1p19q codeletion was 86%, sensitivity 96%, positive predictive value 76%, and negative predictive value was 98%. The prognostic impact of INA expression could be evaluated in grade III oligodendroglial tumors. Similar to 1p19q deletion, positive INA expression was correlated with better progression-free survival (52.6 vs 8.7 months [p = 0.001]) and overall survival (121.1 vs 31.4 months [p = 0.0001]). Conclusion: α-Internexin (INA) expression appears to be a simple, reliable prognostic marker and a surrogate marker of 1p19q codeletion.

Lenalidomide monotherapy as salvage treatment for recurrent primary CNS lymphoma

The prognosis of patients with primary CNS lymphoma (PCNSL) who fail high-dose methotrexate (HD-MTX)–based chemotherapy remains poor, particularly in older individuals, and improvements in salvage chemotherapy are needed. The few cytotoxic agents available for this condition demonstrate limited efficacy.1 Lenalidomide is an immunomodulatory agent, derived from thalidomide, with antiproliferative activities that might act by modifying the tumor microenvironment and activating cytotoxic T and natural killer cells.2 Its efficacy has been established in multiple myeloma and more recently as a single agent or in combination with rituximab in several types of non-Hodgkin lymphomas. In refractory or relapsed systemic diffuse large B-cell (DLBC) lymphomas, lenalidomide exhibited a 28%–35% response rate with a good safety profile.3,4 Interestingly, pomalidomide, a lenalidomide analog, showed activity against CNS lymphoma in murine models and is currently investigated in a phase I study (NCT 01722305). Although little is known about the capacity of lenalidomide to cross the blood–brain barrier,5 this drug appears to be potentially active in PCNSL. The objective of this retrospective case series was to determine the response rate to a standard dose of lenalidomide.