Emmanuelle Schmitt

Subthalamic stimulation in Parkinson’s disease: restoring the balance of motivated behaviours

Addictions to dopaminergic drugs or to pleasant behaviours are frequent and potentially devastating neuropsychiatric disorders observed in Parkinsons disease. They encompass impulse control disorders, punding and dopamine dysregulation syndrome. A relationship with dopaminergic treatment is strongly suggested. Subthalamic stimulation improves motor complications and allows for drastic reductions in medication. This treatment might, therefore, be considered for patients with behavioural addictions, when attempts to reduce dopaminergic medication have failed. However, conflicting data have reported suppression, alleviation, worsening or new onset of behavioural addictions after subthalamic stimulation. Non-motor fluctuations are also a disabling feature of the disease. We prospectively investigated behaviour in a cohort of 63 patients with Parkinsons disease, before and 1 year after subthalamic stimulation using the Ardouin scale, with systematic evaluation of functioning in overall appetitive or apathetic modes, non-motor fluctuations, dopaminergic dysregulation syndrome, as well as behavioural addictions (including impulse control disorders and punding) and compulsive use of dopaminergic medication. Defined drug management included immediate postoperative discontinuation of dopamine agonists and reduction in levodopa. Motor and cognitive statuses were controlled (Unified Parkinsons Disease Rating Scale, Mattis Dementia Rating Scale, frontal score). After surgery, the OFF medication motor score improved (-45.2%), allowing for a 73% reduction in dopaminergic treatment, while overall cognitive evaluation was unchanged. Preoperative dopamine dysregulation syndrome had disappeared in 4/4, behavioural addictions in 17/17 and compulsive dopaminergic medication use in 9/9 patients. New onset of levodopa abuse occurred in one patient with surgical failure. Non-motor fluctuations were significantly reduced with improvements in off-dysphoria (P ≤ 0.001) and reduction in on-euphoria (P ≤ 0.001). There was an inversion in the number of patients functioning in an overall appetitive mode (29 before versus 2 after surgery, P ≤ 0.0001) to an overall apathetic mode (3 before versus 13 after surgery, P < 0.05). Two patients attempted suicide. Improvement in motor fluctuations is linked to the direct effect of stimulation on the sensory-motor subthalamic territory, while improvement in dyskinesias is mainly explained by an indirect effect related to the decrease in dopaminergic drugs. Our data suggest that non-motor fluctuations could similarly be directly alleviated through stimulation of the non-motor subthalamic territories, and hyperdopaminergic side effects might improve mainly due to the decrease in dopaminergic medication. We show an overall improvement in neuropsychiatric symptomatology and propose that disabling non-motor fluctuations, dopaminergic treatment abuse and drug-induced behavioural addictions in Parkinsons disease may be considered as new indications for subthalamic stimulation.

Parkinsonian apathy responds to dopaminergic stimulation of D2/D3 receptors with piribedil

Apathy is one of the most common symptoms encountered in Parkinsons disease, and is defined as a lack of motivation accompanied by reduced goal-directed cognition, behaviour and emotional involvement. In a previous study we have described a delayed withdrawal syndrome after successful motor improvement related to subthalamic stimulation allowing for a major decrease in dopaminergic treatment. This withdrawal syndrome correlated with a diffuse mesolimbic dopaminergic denervation. To confirm our hypothesis of parkinsonian apathy being related to mesolimbic dopaminergic denervation, we performed a randomized controlled study using piribedil, a relatively selective D2/D3 dopamine agonist to treat parkinsonian apathy, using the model of postoperative apathy. A 12-week prospective, placebo-controlled, randomized, double-blinded trial was conducted in 37 patients with Parkinsons disease presenting with apathy (Starkstein Apathy Scale score > 14) following subthalamic nucleus stimulation. Patients received either piribedil up to 300 mg per day (n = 19) or placebo (n = 18) for 12 weeks. The primary end point was the improvement of apathy under treatment, as assessed by the reduction of the Starkstein Apathy Scale score in both treatment groups. Secondary end points included alleviation in depression (Beck Depression Inventory), anxiety (Beck Anxiety Inventory), improvement of quality of life (PDQ39) and anhedonia (Snaith-Hamilton Pleasure Scale). Exploratory endpoints consisted in changes of the Robert Inventory score and Hamilton depression scales. An intention to treat analysis of covariance analysis was performed to compare treatment effects (P < 0.05). The number of premature study dropouts was seven in the placebo and five in the piribedil groups, mostly related to intolerance to hypodopaminergic symptoms. At follow-up evaluation, the apathy score was reduced by 34.6% on piribedil versus 3.2% on placebo (P = 0.015). With piribedil, modifications in the Beck depression and anxiety scores were -19.8% and -22.8%, respectively versus +1.4% and -8.3% with placebo, without reaching significance level. Piribedil led to a trend towards improvement in quality of life (-16.2% versus +6.7% on placebo; P = 0.08) and anhedonia (-49% versus -5.6% on the placebo; P = 0.08). Apathy, assessed by the Robert Inventory score, improved by 46.6% on piribedil and worsened by 2.3% on placebo (P = 0.005). Depression, measured by the Hamilton score, improved in the piribedil group (P = 0.05). No significant side effects were observed. The present study provides a class II evidence of the efficacy of the dopamine agonist piribedil in the treatment of apathy in Parkinsons disease.

Assessment of White Matter Injury and Outcome in Severe Brain Trauma: A Prospective Multicenter Cohort

Background:Existing methods to predict recovery after severe traumatic brain injury lack accuracy. The aim of this study is to determine the prognostic value of quantitative diffusion tensor imaging (DTI). Methods:In a multicenter study, the authors prospectively enrolled 105 patients who remained comatose at least 7 days after traumatic brain injury. Patients underwent brain magnetic resonance imaging, including DTI in 20 preselected white matter tracts. Patients were evaluated at 1 yr with a modified Glasgow Outcome Scale. A composite DTI score was constructed for outcome prognostication on this training database and then validated on an independent database (n = 38). DTI score was compared with the International Mission for Prognosis and Analysis of Clinical Trials Score. Results:Using the DTI score for prediction of unfavorable outcome on the training database, the area under the receiver operating characteristic curve was 0.84 (95% CI: 0.75–0.91). The DTI score had a sensitivity of 64% and a specificity of 95% for the prediction of unfavorable outcome. On the validation-independent database, the area under the receiver operating characteristic curve was 0.80 (95% CI: 0.54–0.94). On the training database, reclassification methods showed significant improvement of classification accuracy (P < 0.05) compared with the International Mission for Prognosis and Analysis of Clinical Trials score. Similar results were observed on the validation database. Conclusions:White matter assessment with quantitative DTI increases the accuracy of long-term outcome prediction compared with the available clinical/radiographic prognostic score.

The prominent role of serotonergic degeneration in apathy, anxiety and depression in de novo Parkinson’s disease

SEE SCHRAG AND POLITIS DOI101093/AWW190 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Apathy, which can occur separately or in combination with depression and anxiety, is one of the most frequently encountered neuropsychiatric symptoms in Parkinsons disease. Pathophysiological evidence suggests that parkinsonian apathy is primarily due to a mesolimbic dopaminergic denervation, but the role of the serotonergic alteration has never been examined, despite its well-known involvement in the pathogenesis of depression and anxiety. To fill this gap, we address here the pure model of de novo Parkinsons disease, without the confounding effects of antiparkinsonian treatment. Fifteen apathetic (Lille Apathy Rating Scale scores ≥ -21) and 15 non-apathetic (-36 ≤ Lille Apathy Rating Scale scores ≤ -22) drug-naïve de novo parkinsonian patients were enrolled in the present study and underwent detailed clinical assessment and positron emission tomography imaging, using both dopaminergic [(11)C-N-(3-iodoprop-2E-enyl)-2-beta-carbomethoxy-3-beta-(4-methylphenyl)-nortropane (PE2I)] (n = 29) and serotonergic [(11)C-N,N-dimethyl-2-(-2-amino-4-cyanophenylthio)-benzylamine (DASB)] (n = 27) presynaptic transporter radioligands. Apathetic parkinsonian patients presented higher depression (P = 0.0004) and anxiety (P = 0.004) scores - as assessed using the Beck Depression Inventory and the part B of the State-Trait Anxiety Inventory, respectively - compared to the non-apathetic ones - who were not different from the age-matched healthy subjects (n = 15). Relative to the controls, the non-apathetic parkinsonian patients mainly showed dopaminergic denervation (n = 14) within the right caudate nucleus, bilateral putamen, thalamus and pallidum, while serotonergic innervation (n = 15) was fairly preserved. Apathetic parkinsonian patients exhibited, compared to controls, combined and widespread dopaminergic (n = 15) and serotonergic (n = 12) degeneration within the bilateral caudate nuclei, putamen, ventral striatum, pallidum and thalamus, but also a specific bilateral dopaminergic disruption within the substantia nigra-ventral tegmental area complex, as well as a specific serotonergic alteration within the insula, the orbitofrontal and the subgenual anterior cingulate cortices. When comparing the two parkinsonian groups, the apathetic patients mainly displayed greater serotonergic alteration in the ventral striatum, the dorsal and the subgenual parts of the anterior cingulate cortices, bilaterally, as well as in the right-sided caudate nucleus and the right-sided orbitofrontal cortex. Regression analyses also revealed that the severity of apathy was moreover mainly related to specific serotonergic lesions within the right-sided anterior caudate nucleus and the orbitofrontal cortex, while the degree of both depression and anxiety was primarily linked to serotonergic disruption within the bilateral subgenual parts and/or the right dorsal part of the anterior cingulate cortex, without prominent role of the dopaminergic degeneration in the pathogenesis of these three non-motor signs. Altogether, these findings highlight a prominent role of the serotonergic degeneration in the expression of the neuropsychiatric symptoms occurring at the onset of Parkinsons disease.

The hidden sister of motor fluctuations in Parkinson's disease: A review on nonmotor fluctuations

Only a few years after the introduction of levodopa, the first descriptions of motor fluctuations and dyskinesia related to dopaminergic therapy appeared. In PD, attention turned to their management, that had dampened the euphoria of the “levodopa miracle.” It soon became clear that neuropsychiatric, autonomic, and sensory features also tend to develop fluctuations after chronic exposure to l‐dopa. The diversity of fluctuating nonmotor symptoms, their largely subjective nature, coupled with a frequent lack of insight led to difficulties in identification and quantification. This may explain why, despite the high impact of nonmotor symptoms on patient autonomy and quality of life, evaluation of nonmotor fluctuations is not part of clinical routine. In view of the lack of specific validated assessment tools, detailed anamnesis should ideally be coupled with an evaluation in both ON and OFF drug conditions. The mechanisms of nonmotor fluctuations are not well understood. It is thought that they share dopaminergic presynaptic pharmacokinetic and postsynaptic pharmacodynamic mechanisms with the classical motor complications, but involve different neural pathways. Although symptoms fluctuate with dopaminergic treatment, serotonine and norepinephrine denervation, as well as interactions between neurotransmitter systems, probably contribute to their diversity. The lack of validated tools for assessment of these phenomena explains the almost complete absence of treatment studies. Management, largely resulting from expert opinion, includes psychiatric follow‐up, nondopaminergic drugs, and advanced dopaminergic treatment, including drug delivery pumps and DBS. This review aims to provide a starting point for the understanding, diagnosis, and management of nonmotor fluctuations.

Postoperative apathy can neutralise benefits in quality of life after subthalamic stimulation for Parkinson's disease

Background Subthalamic nucleus deep brain stimulation (STN-DBS) improves motor symptoms of Parkinsons disease, leading to improvement in health-related quality of life (HRQoL). However, an excessive decrease in dopaminergic medication can lead to a withdrawal syndrome with apathy as the predominant feature. The present study aims to assess the impact of postoperative apathy on HRQoL. Methods A cohort of 88 patients who underwent STN-DBS was divided into two groups, those who were apathetic at 1 year and those who were not, as measured by the Starkstein scale. HRQoL was assessed using the Parkinsons disease questionnaire 39 (PDQ-39) and was compared between the two groups. We also compared activities of daily living, motor improvement and motor complications (Unified Parkinsons Disease Rating Scale, UPDRS), depression and anxiety, as well as cognition and drug dosages. Baseline characteristics and postoperative complications were recorded. Results One year after surgery, 27.1% of patients suffered from apathy. While motor improvement was significant and equivalent in both the apathy (−40.4% of UPDRS motor score) and non-apathy groups (−48.6%), the PDQ-39 score did not improve in the apathy group (−5.5%; p=0.464), whereas it improved significantly (−36.7%; p≤0.001) in the non-apathy group. Change in apathy scores correlated significantly with change in HRQoL scores (r=0.278, p=0.009). Depression and anxiety scores remained unchanged from baseline in the apathy group (p=0.409, p=0.075), while they improved significantly in patients without apathy (p=0.006, p≤0.001). A significant correlation was found between changes in apathy and depression (r=0.594, p≤0.001). Conclusions The development of apathy after STN-DBS can cancel out the benefits of motor improvement in terms of HRQoL. Systematic evaluation and management of apathy occurring after subthalamic stimulation appears mandatory.

Psychostimulant effect of levodopa: reversing sensitisation is possible

Background Levodopa therapy in Parkinsons disease (PD) is associated with non-motor complications resulting from sensitisation of the ventral striatum system. Recent studies showed an improvement in non-motor complications in PD patients with subthalamic stimulation. We hypothesised that ventral striatum desensitisation might contribute to this improvement. Methods Psychostimulant effects of levodopa were prospectively assessed in 36 PD patients with an acute levodopa challenge, before and 1 year after chronic subthalamic stimulation, using the Addiction Research Centre Inventory euphoria subscale. Postoperative evaluation was performed with the same dose of levodopa used in the preoperative assessment and after switching off stimulation. Preoperative and postoperative non-motor fluctuations in everyday life were investigated with the Ardouin Scale. Furthermore, in order to artificially reproduce non-motor fluctuations, a levodopa challenge keeping subthalamic stimulation on was performed to assess depression, anxiety and motivation before and after surgery under the different medication conditions. Results After 1 year of chronic subthalamic stimulation with 60.3% reduction in dopaminergic medication, the acute psychostimulant effects of levodopa were significantly reduced compared with preoperatively, as measured by the euphoria subscale (7.22±4.75 vs 4.75±5.68; p=0.0110). On chronic subthalamic stimulation and with markedly reduced dopaminergic medication, non-motor fluctuations were significantly improved. While off medication/on stimulation scores of depression and anxiety were improved, in the on medication/on stimulation condition the motivation score worsened. Conclusions Acute psychostimulant effects of levodopa (off stimulation) were significantly reduced 1 year after surgery. These findings are likely due to desensitisation of the ventral striatum, allowed by the reduction of dopaminergic treatment, and the replacement of pulsatile treatment with continuous subthalamic stimulation.

Disentangling the role of cortico-basal ganglia loops in top-down and bottom-up visual attention: An investigation of attention deficits in parkinson disease

It is solidly established that top–down (goal-driven) and bottom–up (stimulus-driven) attention mechanisms depend on distributed cortical networks, including prefrontal and frontoparietal regions. On the other hand, it is less clear whether the BG also contribute to one or the other of these mechanisms, or to both. The current study was principally undertaken to clarify this issue. Parkinson disease (PD), a neurodegenerative disorder primarily affecting the BG, has proven to be an effective model for investigating the contribution of the BG to different brain functions; therefore, we set out to investigate deficits of top–down and bottom–up attention in a selected cohort of PD patients. With this objective in mind, we compared the performance on three computerized tasks of two groups of 12 parkinsonian patients (assessed without any treatment), one otherwise pharmacologically treated and the other also surgically treated, with that of a group of controls. The main behavioral tool for our study was an attentional capture task, which enabled us to tap the competition between top–down and bottom–up mechanisms of visual attention. This task was suitably combined with a choice RT and a simple RT task to isolate any specific deficit of attention from deficits in motor response selection and initiation. In the two groups of patients, we found an equivalent increase of attentional capture but also comparable delays in target selection in the absence of any salient distractor (reflecting impaired top–down mechanisms) and movement initiation compared with controls. In contrast, motor response selection processes appeared to be prolonged only in the operated patients. Our results confirm that the BG are involved in both motor and cognitive domains. Specifically, damage to the BG, as it occurs in PD, leads to a distinct deficit of top–down control of visual attention, and this can account, albeit indirectly, for the enhancement of attentional capture, reflecting weakened ability of top–down mechanisms to antagonize bottom–up control.

Atypical clinical presentation of intracranial hypotension: coma.

Sirs: Intracranial hypotension syndrome usually presents as postural cephalgia. It occurs after cerebrospinal fluid (CSF) leakage, either spontaneously following the rupture of a spinal arachnoïd cyst or secondary to lumbar puncture. Recently several cases of intracranial hypotension have been reported in literature with more severe clinical presentations, in particular encephalopathy [1–4]. We report a case of intracranial hypotension presenting with coma, which led to the death of the patient. The patient, a 64-year-old man, was followed for a malignant non Hodgkin lymphoma involving the velum and the left amygdala (Ann Arbor stage 2). He benefited from a first treatment of ACVBP intravenously chemotherapy (Rituximab 375 mg/m2 day 1, doxorubicine 75 mg/m2 day 1, cyclophosphamide 1200 mg/m2 day 2, vindesine 2 mg/m2 day 1 and day 5, bléomycine 10 mg day 1 and day 5) and intrathecally (methotrexate 15 mg, Hydrocortisone 25 mg day 1) according to LNH 2001/05 study, without any complications. During the second treatment, 11 days after the intrathecal administration, the patient presented with decreased consciousness, a left hemiparesis and a right non-reactive mydriasis requiring that he be transferred to an intensive care unit with intubation and artificial respiration. MRI (Figure) showed findings characteristic of intracranial hypotension (bilateral subdural collections with dural enhancement, diencephalon displacement, effacement of basilar cisterns and low lying cerebellar tonsils) associated with a bilateral temporal herniation, and hyper T2 of the posterior part of the trunk and right mesio temporal region, possibly secondary to compression. The sequel was partially favorable, the clinical examination revealing only psychomotor impairment. Two cerebral MRIs were carried out 7 and 14 days after the clinical episode. The first MRI showed a regression of bitemporal herniation, some restoration of CSF in the basilar cisterns, the persistence of bilateral subdural collections and of the T2 hypersignal of the cerebral trunk and right mesio temporal region. The second MRI showed a partial disappearance of the T2 hypersignal of the cerebral trunk and right mesio temporal region. Spinal MRI did not find any nerve root abnormality. The patient presented with a second episode of disorders of consciousness 12 days after the beginning of the third treatment of chemotherapy, although he did not benefit from intrathecal administration. CT showed findings of stability of intracranial hypotension. A lumbar blood patch was placed, but the patient’s condition declined. The patient was treated in the neurological unit with major deterioration of general and neurological status with spastic paraparesis, swallowing disturbance and drowsiness in relation to brainstem and mesiotemporal involvement. Death occurred from a lung infection in this precarious situation. The diagnosis of intracranial hypotension was made on radiological findings, not on clinical presentation (the patient never complained of severe postural cephalgia). The MRIs showed bilateral subdural collections with dural enhancement, diencephalon displacement, effacement of basilar cisterns and low lying cerebellar tonsils, signs usually described in the intracranial hypotension syndromes [5]. Severe intracranial hypotension might have caused cerebral abnormalities which were associated with bilateral temporal herniation and T2 hypersignal of the cerebral trunk and right mesio temporal regions. These involvements were probably responsible for the severity of the clinical presentation through the compression of vascular structures by temporal herniation (posterior cerebral artery) and of diencephalic compression [4]. Following the first episode, the neurological state of the patient improved without returning to normal, and MRI showed the persistence of parenchymatous lesions resulting in T2 hypersignal of the cerebral trunk and right mesio temporal region partially regressive. The site of the CSF leak was not identified in this observation. The patient had previously benefited from repeated lumbar punctures, but again he showed obtundation without having benefited from a repeated intrathecal chemotherapy administration. The site of the CSF leak must be located, either by carrying out an isotopic cisternography exploring the whole neuraxis, or by searching for a morphological spinal nerve root abnormality by MRI. The discovery of a structural abnormality can lead to a LETTER TO THE EDITORS

Nontraumatic Subarachnoid Hemorrhage Management: Evaluation with Reduced Iodine Volume at CT Angiography

PURPOSE To evaluate the technical quality and the diagnostic performance of a protocol with use of low volumes of contrast medium (25 mL) at 64-detector spiral computed tomography (CT) in the diagnosis and management of adult, nontraumatic subarachnoid hemorrhage (SAH). MATERIALS AND METHODS This study was performed outside the United States and was approved by the institutional review board. Intracranial CT angiography was performed in 73 consecutive patients with nontraumatic SAH diagnosed at nonenhanced CT. Image quality was evaluated by two observers using two criteria: degree of arterial enhancement and venous contamination. The two independent readers evaluated diagnostic performance (lesion detection and correct therapeutic decision-making process) by using rotational angiographic findings as the standard of reference. Sensitivity, specificity, and positive and negative predictive values were calculated for patients who underwent CT angiography and three-dimensional rotational angiography. The intraclass correlation coefficient was calculated to assess interobserver concordance concerning aneurysm measurements and therapeutic management. RESULTS All aneurysms were detected, either ruptured or unruptured. Arterial opacification was excellent in 62 cases (85%), and venous contamination was absent or minor in 61 cases (84%). In 95% of cases, CT angiographic findings allowed optimal therapeutic management. The intraclass correlation coefficient ranged between 0.93 and 0.95, indicating excellent interobserver agreement. CONCLUSION With only 25 mL of iodinated contrast medium focused on the arterial phase, 64-detector CT angiography allowed satisfactory diagnostic and therapeutic management of nontraumatic SAH.