Should continuous dopaminergic stimulation be a standard of care in advanced Parkinson's disease?

The standard of care is a term that refers to the level of care, skill, and treatment that a healthcare provider should offer to a patient based on the current scientific evidence and the level of medical knowledge available in the field. For Parkinson's disease (PD), the standard care is mostly considered to be oral treatment with dopaminergic drugs, particularly levodopa which remains the 'gold standard'. However, effective management with levodopa during the later stages of the disease becomes increasingly challenging due to the ongoing neurodegenerative process, the consequences of its pulsatile dopaminergic stimulation, and the gastrointestinal barriers to effective drug absorption. As a result, the concept of applying continuous dopaminergic stimulation has emerged with infusion therapies (continuous subcutaneous apomorphine, levodopa-carbidopa intestinal gel, and levodopa-entacapone-carbidopa intestinal gel infusion). These therapies seek to provide continuous stimulation of striatal dopamine receptors that is efficient not only in alleviating clinical symptoms, but also in delaying, reducing, and possibly preventing the onset of levodopa-related motor (fluctuations, dyskinesia) and non-motor complications; and they are also associated with clinically relevant side effects. Clinical studies and real-life experience support the notion that infusion therapies should be accepted as part of the standard of care for patients with advanced PD who have refractory, severe, and disabling motor complications that affect their quality of life. However, they should be considered based on the needs of individualized patients and the access to these advanced therapies needs to be made more accessible to the general PD population.

Adopting the Rumsfeld approach to understanding the action of levodopa and apomorphine in Parkinson's disease.

Dopaminergic therapies dominate the treatment of the motor and non-motor symptoms of Parkinson's disease (PD) but there have been no major advances in therapy in many decades. Two of the oldest drugs used appear more effective than others-levodopa and apomorphine-but the reasons for this are seldom discussed and this may be one cause for a lack of progress. This short review questions current thinking on drug action and looks at whether adopting the philosophy of ex-US Secretary of State Donald Rumsfeld reveals 'unknown' aspects of the actions of levodopa and apomorphine that provide clues for a way forward. It appears that both levodopa and apomorphine have a more complex pharmacology than classical views would suggest. In addition, there are unexpected facets to the mechanisms through which levodopa acts that are either forgotten as 'known unknowns' or ignored as 'unknown unknowns'. The conclusion reached is that we may not know as much as we think about drug action in PD and there is a case for looking beyond the obvious.

Apathy in depression: An arterial spin labeling perfusion MRI study.

INTRODUCTION: Apathy, as defined as a deficit in goal-directed behaviors, is a critical clinical dimension in depression associated with chronic impairment. Little is known about its cerebral perfusion specificities in depression. To explore neurovascular mechanisms underpinning apathy in depression by pseudo-continuous arterial spin labeling (pCASL) magnetic resonance imaging (MRI). METHODS: Perfusion imaging analysis was performed on 90 depressed patients included in a prospective study between November 2014 and February 2017. Imaging data included anatomical 3D T1-weighted and perfusion pCASL sequences. A multiple regression analysis relating the quantified cerebral blood flow (CBF) in different regions of interest defined from the FreeSurfer atlas, to the Apathy Evaluation Scale (AES) total score was conducted. RESULTS: After confound adjustment (demographics, disease and clinical characteristics) and correction for multiple comparisons, we observed a strong negative relationship between the CBF in the left anterior cingulate cortex (ACC) and the AES score (standardized beta = -0.74, corrected p value = 0.0008). CONCLUSION: Our results emphasized the left ACC as a key region involved in apathy severity in a population of depressed participants. Perfusion correlates of apathy in depression evidenced in this study may contribute to characterize different phenotypes of depression.

Postural instability and gait disorders after subthalamic nucleus deep brain stimulation in Parkinson's disease: a PET study.

INTRODUCTION: Patients with Parkinson's disease sometimes report postural instability and gait disorders (PIGD) after subthalamic nucleus deep brain stimulation (STN-DBS). Whether this is the direct consequence of DBS or the result of natural disease progression is still subject to debate. OBJECTIVE: To compare changes in brain metabolism during STN-DBS between patients with and without PIGD after surgery. METHODS: We extracted consecutive patients from a database where all Rennes Hospital patients undergoing STN-DBS are registered, with regular prospective updates of their clinical data. Patients were divided into two groups (PIGD and No PIGD) according to changes after surgery, as measured with a composite score based on the selected Unified Parkinson's Disease Rating Scale items. All patients underwent positron emission tomography with 18[F]-fluorodeoxyglucose 3 months before and after surgery. We ran an ANOVA with two factors (group: PIGD vs. No PIGD; and phase: preoperative vs. postoperative) on SPM8 to compare changes in brain metabolism between the two groups. RESULTS: Participants were 56 patients, including 10 in the PIGD group. The two groups had similar baseline (i.e., before surgery) characteristics. We found two clusters of increased metabolism in the PIGD group relative to the No PIGD group: dorsal midbrain/pons, including locomotor mesencephalic region and reticular pontine formation, and right motor cerebellum. CONCLUSION: We found different metabolic changes during DBS-STN among patients with PIGD, concerning brain regions that are already known to be involved in gait disorders in Parkinson's disease, suggesting that DBS is responsible for the appearance of PIGD.

Subthalamic deep brain stimulation influences complex emotional musical experience in Parkinson's disease.

Subthalamic deep brain stimulation (STN DBS) is an effective treatment for reducing the motor symptoms of patients with Parkinson's disease (PD), but several side effects have been reported, concerning the processing of emotions. Music has been shown to evoke powerful emotional experiences - not only basic emotions, but also complex, so-called aesthetic experiences. The goal of the present study was therefore to investigate how STN DBS influences the experience of both basic and more complex musical emotions in patients with PD. In a three-group between-participants design, we compared healthy controls (HC), patients receiving STN DBS (PD-DBS), and patients who were candidates for STN DBS and receiving medication only (PD-MO) on their assessments of subjectively experienced musical emotions. Results showed that in general, the experience of musical emotions differed only marginally between the PD-MO, PD-DBS, and HC groups. Nonetheless, we were able to discern subtle but distinct effects of PD and STN DBS in the emotional responses. Happy music, for instance, seemed to induce a heightened experience of negative emotions (tension) in PD-MO patients. STN DBS appeared to normalize this particular effect, but increased nostalgic feelings - a rather complex affective experience - in response to the same emotional stimuli. This should not be taken as indicating a bias for nostalgia in the PD-DBS subgroup, as these patients found music inducing melancholy to be less nostalgic and more joyful than HC did. In conclusion, our study showed that music elicits slightly altered emotional experiences in patients with and without STN DBS. In particular, STN DBS seems to induce less distinct emotional responses, blurring the boundaries between complex musical emotions.

Repetitive transcranial magnetic stimulation over the orbitofrontal cortex for obsessive-compulsive disorder: a double-blind, crossover study.

This pilot study was designed to assess the efficacy of low-frequency repetitive transcranial magnetic stimulation (rTMS) over the right orbitofrontal cortex (OFC) by means of a double-cone coil in patients suffering from obsessive-compulsive disorder. We hypothesized that low-frequency stimulation of the OFC would lead to a reduction in clinical symptoms, as measured on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). A randomized, double-blind, crossover design was implemented with two 1-week treatment periods (active stimulation versus sham stimulation) separated by a 1-month washout period. Concomitantly, a subgroup of patients underwent a positron emission tomography (PET) scan after each stimulation sequence. Statistical analyses compared the Y-BOCS scores at the end of each period. At day 7, we observed a significant decrease from baseline in the Y-BOCS scores, after both active (P<0.01) and sham stimulation (P=0.02). This decrease tended to be larger after active stimulation than after sham stimulation: -6 (-29, 0) points versus -2 (-20, 4) points (P=0.07). Active versus sham PET scan contrasts showed that stimulation was related to a bilateral decrease in the metabolism of the OFC. The OFC should definitely be regarded as a key neuroanatomical target for rTMS, as it is easier to reach than either the striatum or the subthalamic nucleus, structures favored in neurosurgical approaches.

Semantic dementia: aspects of the early diagnosis.

Semantic dementia is a lobar atrophy syndrome, related to a degeneration of anterior temporal regions, and characterized by a very predominant impairment of semantic memory. Whereas the diagnosis is relatively easy to establish in the typical form and if the patient is seen early, the emergence of possible additional cognitive or psycho-behavioural disorders can lead to a misdiagnosis in favour of a frontotemporal dementia syndrome or even probable Alzheimer's disease.

[Bacterial meningitis: factors related to the delay before appropriate antibiotic administration in the emergency department]. / Méningites bactériennes : facteurs associés au délai d'instauration d'une antibiothérapie adaptée aux urgences.

OBJECTIVES: We had for aim to check the appropriateness of our practices according to French guidelines (17th consensus conference, SPILF 2008) and to identify variables associated with the delay before appropriate measures were implemented. METHODS: Our retrospective observational study (2009-2011) focused on acute bacterial meningitis (ABM) in adults. Data was collected on a standardized questionnaire from medical charts and nurse reports. RESULTS: We included 31 adults presenting with ABM; 29 (93.5%) received ceftriaxone or cefotaxime in the emergency department. Indications for corticosteroids and brain imaging complied with guidelines in respectively 71.0% and 83.9% of cases. The median delays (IQR) were: admission/lumbar puncture (LP), 2h43 [1h09-5h57]; admission/antimicrobials, 3h21 [1h34-5h11]. The indication of suspected ABM in the admission letter was associated with earlier LP (P=0.01), and was almost significantly associated also with faster initiation of adequate antibiotic therapy (P=0.05). CONCLUSIONS: Suspicion of ABM mentioned in the admission letter was associated to a better management in the emergency department.

[Apathy neural bases in neurodegenerative disorders]. / Bases neurales de l'apathie dans les maladies dégénératives.

Apathy is widely recognized as a lack of motivation, which expresses through the cognitive, behavioral and emotional dimensions of living. It is described within several neuropsychiatric syndromes such as degenerative disorder and is associated with poorer outcomes. In order to better understand the underpinnings of apathy and to develop specific treatment strategies, much research has been conducted to define its neural bases. In the present review, perfusion, metabolic, pathologic and functional results of apathy neural bases in Alzheimer's and Parkinson's diseases are displayed. Methods and strategies to control for confounding factors such as depression, cognitive impairments and other behavioral disorders are described. Results are not strictly identical between disorders and even within disorders. Variation of methods employed on assessment tools and control for confounding factors such as cognitive disorders, depression, other behavioral disorders and medical treatment is thought to be the main reason for this discrepancy. However, it seems that the inferior prefrontal cortex, especially the orbitofrontal cortex, the lateral prefrontal cortex and the anterior cingulate are of particular interest. The second part of the review discusses the literature in these three areas in conditional learning essentially via the reward characteristic encoding, auto-initiated and perseverance behaviors and emotional experience and its regulation.

[Psychogenic movement disorders]. / Les mouvements anormaux psychogènes.

Psychogenic Movement Disorders (PMDs) are a subtype of conversion disorder, classified under somatoform disorders in the DSM. Diagnosis and treatment of PMDs are challenging for both neurologists and psychiatrists. Typical clinical characteristics of these disorders are acute onset, fast progression, movement patterns incongruent with organic movement disorders, distractibility, variability and simultaneous occurrence of various abnormal movements and dysfunctions. The diagnosis of PMDs should not be regarded as a diagnosis of exclusion and electrophysiology is not always helpful. The cause of PMDs is unknown and the underlying brain mechanisms remain uncertain. However, recent functional magnetic resonance imaging studies have demonstrated altered blood flow in conversion disorders that may reflect changes in synaptic activity. Involvement of allied health professionals and psychotherapy continue to be the mainstay of treatment.

Subthalamic nucleus stimulation in Parkinson disease induces apathy: a PET study.

OBJECTIVE: Apathy may be induced by subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson disease (PD). We therefore wished to test the hypothesis that apathy induced by STN-DBS correlates with changes in glucose metabolism, using (18)FDG-PET. METHODS: Twelve patients with PD were assessed 3 months before (M-3) and 3 months after (M+3) STN-DBS with (18)FDG-PET and the Apathy Evaluation Scale. RESULTS: Apathy had significantly worsened at M+3 after STN-DBS. Positive correlations were observed between this variation in apathy scores and changes in glucose metabolism, especially in the right frontal middle gyrus (Brodmann area [BA] 10) and right inferior frontal gyrus (BA 46 and BA 47). Negative correlations between the two were observed in the right posterior cingulate gyrus (BA 31) and left medial frontal lobe (BA 9). CONCLUSION: These preliminary results confirm the role of the subthalamic nucleus in associative and limbic circuitry in humans and suggest that it is a key basal ganglia structure in motivation circuitry.

[Gaucher's disease in Rennes University hospital: a 10-year retrospective study]. / Etude rétrospective sur dix ans des patients atteints de maladie de Gaucher au CHU de Rennes.

INTRODUCTION: Gaucher's disease (GD) remains rare and cohort studies are essential to improve our knowledge of this disease. METHODS: We performed a 10-year retrospective study of patients with GD followed-up in the Rennes University teaching hospital. RESULTS: Among a population of 1,500,000 inhabitants, 12 patients with GD were identified. Eight were men, and four were women. Mean age at diagnosis was 32.3 years and the first symptoms appeared around 31 years old. Main symptoms were: splenomegaly (82%), hepatomegaly (64%), thrombocytopenia (73%), anemia (64%), deterioration of general status (45%), bone pain (27%). Parkinsonism was noted in two patients, polyclonal gammopathy in two others, and monoclonal gammopathy was evidenced in four patients, with chronic lymphocytic lymphoma in one of them. Enzymatic activity dosage confirmed the diagnosis of GD for eight patients. For the remaining four patients, diagnosis was obtained by identification of Gaucher's cells on tissue examination. Substitutive enzymotherapy (SE) was performed for seven patients, with great improvement of initial symptoms. For two of these seven patients, SE is changed for miglustat with persistent improvement of clinical status. CONCLUSION: Association between GD and Parkinsonism or between GD and gammopathy was confirmed in our study. Other cohort studies are needed to improve the knowledge of GD.

Emotion recognition impairment and apathy after subthalamic nucleus stimulation in Parkinson's disease have separate neural substrates.

OBJECTIVE: To test the hypothesis that emotion recognition and apathy share the same functional circuit involving the subthalamic nucleus (STN). METHODS: A consecutive series of 17 patients with advanced Parkinson's disease (PD) was assessed 3 months before (M-3) and 3 months (M+3) after STN deep brain stimulation (DBS). Mean (+/-S.D.) age at surgery was 56.9 (8.7) years. Mean disease duration at surgery was 11.8 (2.6) years. Apathy was measured using the Apathy Evaluation Scale (AES) at both M-3 and M3. Patients were also assessed using a computerised paradigm of facial emotion recognition [Ekman, P., & Friesen, W. V. (1976). Pictures of facial affect. Palo Alto: Consulting Psychologist Press] before and after STN DBS. Prior to this, the Benton Facial Recognition Test was used to check that the ability to perceive faces was intact. RESULTS: Apathy had significantly worsened at M3 (42.5+/-8.9, p=0.006) after STN-DBS, in relation to the preoperative assessment (37.2+/-5.5). There was also a significant reduction in recognition percentages for facial expressions of fear (43.1%+/-22.9 vs. 61.6%+/-21.4, p=0.022) and sadness (52.7%+/-19.1 vs. 67.6%+/-22.8, p=0.031) after STN DBS. However, the postoperative worsening of apathy and emotion recognition impairment were not correlated. CONCLUSIONS: Our results confirm that the STN is involved in both the apathy and emotion recognition networks. However, the absence of any correlation between apathy and emotion recognition impairment suggests that the worsening of apathy following surgery could not be explained by a lack of facial emotion recognition and that its behavioural and cognitive components should therefore also be taken into consideration.

Subthalamic nucleus stimulation affects orbitofrontal cortex in facial emotion recognition: a PET study.

Deep brain stimulation (DBS) of the bilateral subthalamic nucleus (STN) in Parkinson's disease is thought to produce adverse events such as emotional disorders, and in a recent study, we found fear recognition to be impaired as a result. These changes have been attributed to disturbance of the STN's limbic territory and would appear to confirm that the negative emotion recognition network passes through the STN. In addition, it is now widely acknowledged that damage to the orbitofrontal cortex (OFC), especially the right side, can result in impaired recognition of facial emotions (RFE). In this context, we hypothesized that this reduced recognition of fear is correlated with modifications in the cerebral glucose metabolism of the right OFC. The objective of the present study was first, to reinforce our previous results by demonstrating reduced fear recognition in our Parkinson's disease patient group following STN DBS and, second, to correlate these emotional performances with glucose metabolism using (18)FDG-PET. The (18)FDG-PET and RFE tasks were both performed by a cohort of 13 Parkinson's disease patients 3 months before and 3 months after surgery for STN DBS. As predicted, we observed a significant reduction in fear recognition following surgery and obtained a positive correlation between these neuropsychological results and changes in glucose metabolism, especially in the right OFC. These results confirm the role of the STN as a key basal ganglia structure in limbic circuits.

[Continuous subcutaneous infusion of apomorphine for the treatment of Parkinson's disease]. / L'apomorphine en perfusion sous-cutanée continue dans le traitement de la maladie de Parkinson.

Apomorphine administered by subcutaneous infusion has been used efficiently in parkinsonian patients to treat severe motor fluctuations and levodopa-induced dyskinesias. Despite increasing evidence of its efficacy and its relative safety, apomorphine infusion therapy is still underused. This article reviews pharmacokinetic properties, efficacy, tolerability and indications of apomorphine infusion in Parkinson's disease.

Does subthalamic nucleus stimulation induce apathy in Parkinson's disease?

BACKGROUND: Subthalamic Nucleus Deep Brain Stimulation (STN-DBS) has been shown to significantly improve motor symptoms in advanced Parkinson's disease (PD). Only few studies, however, have focused on the non-motor effects of DBS. METHODS: A consecutive series of 15 patients was assessed three months before (M-3), then three months (M3) and six months (M6) after surgery. Mean (+/- SD) age at surgery was 59.7 (7.6). Mean disease duration at surgery was 12.2 (2.8) years. The Mini International Neuropsychiatric Inventory was used to assess psychiatric disorders three months before surgery. Depression was evaluated using Montgomery and Asberg Rating Scale (MADRS). Anxiety was evaluated using the AMDP system (Association for Methodology and Documentation in Psychiatry). Apathy was particularly evaluated using the Apathy Evaluation Scale (AES) and the Starkstein Scale. All these scales were performed at every evaluation. RESULTS: Apathy worsened at M3 and M6 after STN-DBS in comparison with the preoperative evaluation: the AES mean score was significantly impaired between the preoperative (38.4+/-7.1) and both the postoperative M3 (44.6+/-9.5, p = 0.003) and M6 scores (46.0+/-10.9, p = 0.013). Significant worsening of apathy was confirmed using the Starkstein scale. There was no evidence of depression: the mean MADRS score did not differ before surgery (9.1+/-7.4) and at both M3 (8.6+/-8.2) and M6 (9.9+/-7.7) after STN-DBS. The anxiety level did not change between preoperative (9.4+/-9.2) and both M3 (5.5+/-4.5) and M6 (6.6+/-4.6) postoperative states. CONCLUSION: Although STN-DBS constitutes a therapeutic advance for severely disabled patients with Parkinson's disease, we should keep in mind that this surgical procedure may contribute to the inducing of apathy. Our observation raises the issue of the direct influence of STN- DBS on the limbic system by diffusion of stimulus to the medial limbic compartment of STN.