Validation of a non-motor fluctuations questionnaire in Parkinson's disease.

INTRODUCTION: Non-motor fluctuations (NMF) in Parkinson's disease (PD) remain poorly recognized but have a high impact on patients' quality of life. The lack of assessment tools limits our understanding of NMF, compromising appropriate management. Our objective was to validate a hetero-questionnaire for NMF in PD patients at different stages of the disease: without treatment, without motor fluctuations, with motor fluctuations. METHODS: We included patients in 15 centers in France. Our questionnaire, NMF-Park, resulted from previous studies, allowing us to identify the more pertinent NMF for evaluation. Patients reported the presence (yes or no) of 22 selected NMF, and their link with dopaminergic medications. The assessment was repeated at one and two years to study the progression of NMF. We performed a metrological validation of our questionnaire. RESULTS: We included 255 patients (42 without treatment, 88 without motor fluctuations and 125 with motor fluctuations). After metrological validation, three dimensions of NMF were found: dysautonomic; cognitive; psychiatric. The sensory/pain dimension described in the literature was not statistically confirmed by our study. DISCUSSION: Our questionnaire was validated according to clinimetric standards, for different stages of PD. It was clinically coherent with three homogeneous dimensions. It highlighted a link between fatigue, visual accommodation disorder, and cognitive fluctuations; and the integration of sensory/pain fluctuations as part of dysautonomic fluctuations. It focused exclusively on NMF, which is interesting considering the described differences between non-motor and motor fluctuations. CONCLUSION: Our study validated a hetero-questionnaire of diagnosis for NMF for different stages of PD.

Prevalence and characterisation of vocal fold motion impairment (VFMI) in patients with Multiple system atrophy compared with Parkinson's disease.

INTRODUCTION: Multiple system atrophy (MSA) is a neurodegenerative disorder in which vocal fold mobility can be affected, sometimes leading to life-threatening situations. Our aim was to know if laryngeal examination could help differentiate MSA from Parkinson's disease (PD). MATERIALS AND METHODS: Between 2004 to 2014, all consecutive patients diagnosed with probable MSA were included in this retrospective, monocentric study. Flexible laryngoscopy was obtained in 51 MSA patients and compared with 27 patients with Parkinson's disease (PD). Laryngeal muscles EMG was available in 6 MSA patients. RESULTS: Vocal fold motion impairments (VFMI) was found in 35 (68.6%) MSA patients: 15 (29.4%) had uni- or bilateral vocal fold abnormal movement (VFAM), 13 (25.5%) had uni- or bilateral vocal fold abductor paresis (VFABP), 4 (7.8%) had uni- or bilateral vocal fold adductor paresis (VFADP), 10 (19.6%) had bilateral vocal fold paralysis (BVFP). VFMI was found in 13 PD patients (48.1%) all of whom had VFADP. Presence of BVFP was found associated with stridor (P<0.001) and dysphagia (P=0.002). In all muscles examined in 6 MSA patients, the EMG showed neuropathic patterns. CONCLUSIONS: Our data support that VFMI may be encountered in two-thirds of MSA with a variable degree of gravity. Laryngological examination should be considered as a supplementary tool for the diagnosis and prognosis of MSA. VFMI in particular VFAM, VFABD and BVFP should be discussed as an additional possible red flag even at an early stage of MSA and could help discriminate MSA from PD.

Parkinson's disease associated with 22q11.2 deletion: Clinical characteristics and response to treatment.

BACKGROUND: While it is known that 22q11.2 microdeletions (22q11.2-del) increase the risk of Parkinson's disease (PD), the characteristics of PD associated with 22q11.2-del have not been specifically explored. OBJECTIVE: This report aimed to assess the clinical characteristics and treatment responses of PD patients with 22q11.2-del, and to describe any features that might lead neurologists to investigate the comorbidity. METHODS: Nine PD patients (eight men, one woman) with 22q11.2-del were followed at seven centers of the French PD Expert Network (Ns-Park). RESULTS: PD diagnosis was made before 22q11.2-del diagnosis in seven cases; their main characteristics were early onset (32-48 years) and good initial levodopa sensitivity, but with a course characterized by severe and early-onset levodopa-induced motor complications and psychiatric manifestations. Three patients received deep brain stimulation (DBS) that was effective. CONCLUSION: Searching for 22q11.2-del in PD patients presenting with suggestive features is relevant as the clinical presentation is similar to idiopathic PD, but with other associated characteristics, including a severe evolution. Results with DBS are similar to those reported for idiopathic PD.

A combined pharmacokinetic/pharmacodynamic model of levodopa motor response and dyskinesia in Parkinson's disease patients.

PURPOSE: Levodopa is the reference treatment for Parkinson's disease. However, after several years of treatment, dyskinesia may occur and strategies to overcome this side effect still need to be explored. We identified a unique population pharmacokinetic/pharmacodynamic model in Parkinson's disease to investigate the relationship and dissociability of motor response and dyskinesia. METHODS: Thirty parkinsonian patients (Hoehn and Yahr stages 3-4), treated with levodopa and suffering from peak-dose dyskinesia, were included in a prospective open-label study. They received a single dose of levodopa equal to 150 % of their usual daily dose. Blood samples, motor evaluations (UPDRS III scale) and peak-dose dyskinesia (Goetz scale) were examined after administration. A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed using NONMEM software. RESULTS: Pharmacokinetic analysis identified a one-compartment model with the following parameter values [bootstrap 95 % CI]: absorption rate constant (KA) 1.86 1/h [1.08-3.25], clearance 36.6 L/h [31.3-42.8], and volume of distribution 42.9 L [34.3-52.3]. Between-subject variability was 122 % [71-183] and 38 % [26-47] for KA and clearance, respectively. Residual variability was 1120 µg/L [886-1290]. UPDRS III and dyskinesia were best described with an effect compartment and similar KE0 values of 1.37 1/h [1.01-1.77]. For UPDRS III, the E0, EC50, Emax, and Hill coefficient were 31.4 [28.4-35.3], 1410 µg/L [1200-1700], 0.72 [0.71-0.75], and 4.26 [3.20-5.58], respectively. For dyskinesia, the EC50 and Emax were 6280 µg/L [3420-37,900] and 17.9 [12.3-80.8], respectively. Residual variability was 3.15 [2.75-3.53] for UPDRS III and 2.66 [1.94-3.51] for dyskinesia. No covariates influenced the parameters. CONCLUSIONS: In patients treated with levodopa and suffering from dyskinesia, the motor response and dyskinesia have close onsets and duration effects. Maximal motor response tends to be inevitably associated with dyskinesia.

Progressive supranuclear palsy and corticobasal degeneration: Diagnostic challenges and clinicopathological considerations.

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are two atypical parkinsonian syndromes first described half a century ago. The spectrum of these conditions as well as, more generally, the concept of tauopathy have dramatically changed over the past decade and especially in recent years. In particular, clinicopathological correlations have led to the description of several subtypes of these diseases and the features they share with other neurodegenerative diseases. The present paper is a review of how the concepts of PSP and CBD have evolved over time. In particular, it focuses on the different presentations of the disease and the overlapping syndromes that can complicate the differential diagnoses. Also discussed are some of the tools that may prove useful in making a diagnosis. Indeed, differential diagnosis issues are of particular importance in light of the likely emergence of pathology-specific disease-modifying therapies in the near future.

Essential tremor: Update of therapeutic strategies (medical treatment and gamma knife thalamotomy).

Tremor is a highly prevalent movement disorder that markedly reduces quality of life. The management of severe tremor is particularly challenging. Pharmacological treatment is available, but no real breakthrough has emerged recently. Propranolol and primidone are still the two most recommended agents, followed by topiramate. However, surgical treatments for medically refractory tremors are expanding. Gamma knife (GK) thalamotomy is an option particularly suitable for patients who are not candidates for deep brain stimulation. Owing to the fact that it is a non-invasive procedure without craniotomy, GK radiosurgery has almost no contraindications. Since the late 1990s, more than 250 case reports and patient series have been published. Most of these studies show that unilateral GK thalamotomy is well tolerated and reduces tremor disability. A recent study with prospective blinded assessment has confirmed its safety, together with significant improvements in tremor scores and activities of daily living.

News and controversies regarding essential tremor.

Essential tremor is the most common movement disorder in adults. It is characterized by a postural and kinetic tremor affecting the arms, but it can also affect other body parts. It evolves gradually and can be responsible for a functional impairment in activities of daily living. Its pathophysiology remains poorly understood and effective therapeutic options are limited. There are significant semiological variations between patients, and the term "essential tremor" seems to encompass a wide range of heterogeneous clinical phenotypes. The diagnostic criteria presented in 1998 are now challenged. Furthermore, there is a current debate concerning the etiology of this affection, as to whether essential tremor is a complex degenerative disorder or a functional reversible disorder of neuronal oscillation. In this review, we summarize some aspects of clinical, etiologic and therapeutic news, to better address the questioning on unravelling the clinical presentation and examine the current pathophysiological controversy in this disorder.

Controlled general anaesthesia for subthalamic nucleus stimulation in Parkinson's disease.

OBJECTIVE: To report the short-term (1 year) and long-term (5 years) outcome of patients with Parkinson's disease (PD) with subthalamic nucleus (STN) stimulation operated upon under controlled general anaesthesia (GA). METHODS: 213 consecutive patients with PD were included between January 2000 and March 2009 and operated upon under a particular type of GA with close control of the level of sedation allowing intraoperative recordings. 188 patients were assessed 1 year postoperatively. 65 patients also completed the long-term observation period and were evaluated 5 years postoperatively. RESULTS: The Unified PD Rating Scale III score in the 'Off drug--On stim' condition was improved at 1 year and 5 years by 61% and 37%, respectively, (p<0.001). Motor complications decreased at short-term and long-term by 68% and 65%, respectively, for dyskinesia and by 52% and 48%, respectively, for fluctuations, (p<0.001). Dopaminergic treatment could also be reduced at short-term and long-term by 46% and 49%, respectively (p<0.001). There was no significant modification of mood and cognition assessments (Mattis scale and Beck depression inventory) at 1 year and 5 years. Concerning the main adverse events related to the surgery, we report four haematomas (1.9%) with two deaths (0.9%), eight cases of transient confusion (3.7%) and no epileptic seizure. CONCLUSIONS: Our results confirm that STN stimulation performed under controlled GA is efficient and has similar short-term and long-term motor effects than intervention under local anaesthesia. Furthermore, this specific procedure is not associated with more adverse events. The success of such an intervention requires strict anaesthetic monitoring and accurate STN identification.

Update of cartilaginous tumours according to the WHO classification 2020.

Cartilaginous tumours are a large and heterogeneous group of neoplasms characterised by the presence of a chondroid matrix, with lobular growth and arcuate, ring-like or popcorn-like calcification patterns. MRI shows hyperintensity in T2-weighted sequences and a lobulated or septal relief in postcontrast images. In the WHO 2020 classification, chondral tumours are classified as benign, intermediate or malignant. Despite technological advances, they continue to pose a challenge for both the radiologist and the pathologist, being the main difficulty the differentiation between benign and malignant tumours, which is why they require a multidisciplinary approach. This paper describes the main changes introduced in the 2020 update, describes the imaging characteristics of the main cartilaginous tumours and provides the radiological keys to differentiate between benign and malignant tumours.

Addictive behaviors and Parkinson's disease.

INTRODUCTION: In Parkinson's disease, the degeneration of the dopaminergic system and the longstanding exposure to dopamine replacement therapy (DRT) may cause, in a group of vulnerable patients, dysregulation of the brain reward system. STATE OF THE ARTS: These patients develop DRT-related compulsions, which include addiction to levodopa or dopamine dysregulation syndrome (DDS), punding, and impulse control disorders (ICDs). ICDs or behavioral addiction reported in Parkinson's disease include pathological gambling, hypersexuality, compulsive buying and binge eating. Although the underlying pathophysiology is still poorly understood, these behaviors are linked by their reward-based and repetitive nature. Such behaviors may result in devastating psychosocial impairment for the patients and are often hidden. PERSPECTIVE AND CONCLUSIONS: The recognition of these behaviors is important and allows a better clinical management. Although the limited data do not permit particular therapeutic strategies, some approaches are worth considering: DRT reduction, trials of non-dopaminergic medications and subthalamic chronic stimulation.

Deep brain stimulation can suppress pathological synchronisation in parkinsonian patients.

BACKGROUND: Although deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a highly effective therapeutic intervention in severe Parkinson's disease, its mechanism of action remains unclear. One possibility is that DBS suppresses local pathologically synchronised oscillatory activity. METHODS: To explore this, the authors recorded from DBS electrodes implanted in the STN of 16 patients with Parkinson's disease during simultaneous stimulation (pulse width 60 µs; frequency 130 Hz) of the same target using a specially designed amplifier. The authors analysed data from 25 sides. RESULTS: The authors found that DBS progressively suppressed peaks in local field potential activity at frequencies between 11 and 30 Hz as voltage was increased beyond a stimulation threshold of 1.5 V. Median peak power had fallen to 54% of baseline values by a stimulation intensity of 3.0 V. CONCLUSION: The findings suggest that DBS can suppress pathological 11-30 Hz activity in the vicinity of stimulation in patients with Parkinson's disease. This suppression occurs at stimulation voltages that are clinically effective.

Subthalamic Deep Brain Stimulation Modulates Proprioceptive Integration in Parkinson's Disease During a Postural Task.

Defective proprioceptive integration may play a role in the pathophysiology of motor symptoms in Parkinson's disease (PD). Dysfunction related to proprioceptively-evoked postural reactions in PD patients is still a controversial issue, with only a limited number of studies to date and mostly discordant results. The aims of the present study were (1) to determine whether or not the proprioceptive defect in PD underlies postural impairment and (2) whether or not deep brain stimulation of the subthalamic nucleus (STN-DBS) affects proprioceptive integration. We examined proprioceptive integration during a postural task in 13 PD patients and 12 age-matched control subjects, using a muscle-tendon vibration paradigm. Analysis of the center of pressure displacement and kinematic data indicates a greater degree of postural destabilization and a reduced ability to maintain a vertical orientation in PD. We found a significant positive effect of STN-DBS on these postural features. Our findings indicate that Parkinson patients, even in the absence of any clinical evidence of instability, falls, or freezing, use proprioceptive information for postural control less efficiently than healthy subjects. Furthermore, STN-DBS was found to improve proprioceptive integration, with positive impacts on postural orientation and balance.

Suppression of beta oscillations in the subthalamic nucleus following cortical stimulation in humans.

It is unclear how subthalamic nucleus activity is modulated by the cerebral cortex. Here we investigate the effect of transcranial magnetic stimulation (TMS) of the cortex on oscillatory subthalamic local field potential activity in the 8-35 Hz (alpha/beta) band, as exaggerated synchronization in this band is implicated in the pathophysiology of parkinsonism. We studied nine patients with Parkinson's disease (PD) to test whether cortical stimulation can modulate synchronized oscillations in the human subthalamic nucleus. With patients at rest, single-pulse TMS was delivered every 5 s over each primary motor area and supplementary motor area at intensities of 85-115% resting motor threshold. Subthalamic local field potentials were recorded from deep brain stimulation electrodes implanted into this nucleus for the treatment of PD. Motor cortical stimulation suppressed beta activity in the subthalamic nucleus from approximately 0.2 to 0.6 s after TMS (repeated measures anova; main effect of time, P < 0.01; main effect of side, P = 0.03), regardless of intensity. TMS over the supplementary motor area also reduced subthalamic beta activity at 95% (P = 0.05) and 115% resting motor threshold (P = 0.01). The oscillatory activity decreased to 80 +/- 26% of baseline (averaged across sites and stimulation intensities). Suppression with subthreshold stimuli confirmed that these changes were centrally driven and not due to peripheral afference. The results may have implications for mechanisms underlying the reported therapeutic benefits of cortical stimulation.

Assessment of cortico-spinal tract impairment in multiple system atrophy using transcranial magnetic stimulation.

OBJECTIVE: Among Parkinsonian syndromes, pyramidal signs suggesting cortico-spinal impairment are a hallmark of multiple system atrophy (MSA). Although it is crucial to diagnose correctly this disease to choose the appropriate treatment, the available diagnostic criteria lack sensitivity. Cortical excitability patterns assessed by transcranial magnetic stimulation (TMS) do not differentiate Parkinsonian disorders. TMS using triple stimulation technique (TST) accurately detects cortico-spinal impairment. We hypothesized that this technique could detect such impairment in MSA patients. METHODS: The TST was applied along with single and paired-pulse TMS to 31 patients fulfilling the diagnostic criteria for MSA-P (n=10), MSA-C (n=4), progressive supranuclear palsy (PSP; n=6) and Idiopathic Parkinson's disease (IPD; n=11) and 11 control subjects. RESULTS: Single and paired-pulse TMS patterns did not differ between any patient group. The TST pattern was abnormal in five MSA-P, one MSA-C and one PSP patients but not in IPD patients or controls. The mean TST ratio for MSA-P (86.6%) was significantly different from IPD (99.1%; p<0.05) whereas ratios for MSA-C (92.1%) and PSP (93.3%) were not different from IPD or controls (99.5%). CONCLUSIONS: These results suggest that TST is effective to assess cortico-spinal impairment in MSA. SIGNIFICANCE: TST might be useful for the diagnosis of atypical Parkinsonism.

Treatment efficiency and economic feasibility of biological oxidation, membrane filtration and separation processes, and advanced oxidation for the purification and valorization of olive mill wastewater.

Olive mill wastewater (OMW) is a major waste stream resulting from numerous operations that occur during the production stages of olive oil. The resulting effluent contains various organic and inorganic contaminants and its environmental impact can be notable. The present work aims at investigating the efficiency of (i) jet-loop reactor with ultrafiltration (UF) membrane system (Jacto.MBR), (ii) solar photo-Fenton oxidation after coagulation/flocculation pre-treatment and (iii) integrated membrane filtration processes (i.e. UF/nanofiltration (NF)) used for the treatment of OMW. According to the results, the efficiency of the biological treatment was high, equal to 90% COD and 80% total phenolic compounds (TPh) removal. A COD removal higher than 94% was achieved by applying the solar photo-Fenton oxidation process as post-treatment of coagulation/flocculation of OMW, while the phenolic fraction was completely eliminated. The combined UF/NF process resulted in very high conductivity and COD removal, up to 90% and 95%, respectively, while TPh were concentrated in the NF concentrate stream (i.e. 93% concentration). Quite important is the fact that the NF concentrate, a valuable and polyphenol rich stream, can be further valorized in various industries (e.g. food, pharmaceutical, etc.). The above treatment processes were found also to be able to reduce the initial OMW phytotoxicity at greenhouse experiments; with the effluent stream of solar photo-Fenton process to be the least phytotoxic compared to the other treated effluents. A SWOT (Strength, Weakness, Opportunities, Threats) analysis was performed, in order to determine both the strengths of each technology, as well as the possible obstacles that need to overcome for achieving the desired levels of treatment. Finally, an economic evaluation of the tested technologies was performed in an effort to measure the applicability and viability of these systems at real scale; highlighting that the cost cannot be regarded as a 'cut off criterion', since the most cost-effective option in not always the optimum one.

Microflora evaluation of two agro-industrial effluents treated by the JACTO jet-loop type reactor system.

Jet-loop type reactors developed in our group have been successfully used for biological treatment of winery and olive oil wastewaters. The objective of the present work was to study the influence of the reactor hydrodynamics, causing high shear stress applied on the nozzle and its influence on the composition of the microbial population. Winery and olive oil industry effluents were treated and analysed. Microbial consortia were enriched and selected under different bio-treatment conditions of the effluents. In the case of the winery wastewaters, the isolates identified belong to the genera of Pseudomonas and Bacillus. Saccharomyces cerevisiae was also present in the consortia but no filamentous fungi were detected. In the case of the olive oil wastewaters, Bacillus megaterium 2 was the predominant microorganism. It was not detected any type of fungi.

Oxalate uptake in fetal rat myoblasts.

Oxalate uptake was studied in fetal rat myoblasts to attempt to define the characteristics of oxalate transport in myocardial cells. Oxalate uptake was found to be time, temperature and pH dependent and was inhibited by metabolic inhibitors (Dinitrophenol and iodoacetamide). Inhibition of oxalate uptake by 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) suggested transport by an anion exchange mechanism. Both chloride and sulfate inhibited oxalate uptake suggesting competition by both ions for a combined transporter. Although medium calcium concentration and calcium ionophores had no effect on oxalate uptake, the calcium channel blocker, nifedipine, significantly decreased oxalate uptake. Diacylglycerol (DAG) stimulated oxalate uptake, while forskolin had no effect. These studies suggest that myocardial cells transport oxalate by a mechanism similar to that described in renal epithelial cells. The uptake of oxalate by myocardial cells raises questions about the physiologic role of oxalate in myocardial cells and the mechanism of cardiac problems in primary hyperoxaluria.

Port-access cardiac surgery: clinical experience with first 50 cases.

BACKGROUND: Minimally invasive cardiac surgery constitutes an expanding field for the treatment of many cardiac diseases. We analyze our experience with the first 50 patients operated upon using the port-access system. METHODS: From October 1999 to October 2000, 50 patients underwent cardiac operations with the port-access technique, for the correction of mitral and tricuspid disease, atrial septal defect closure, and removal of cardiac tumors. The mean age was 56.5 years. In 23 patients the mitral valve was repaired, in 14 cases a prosthetic replacement was performed, in 2 patients a paravalvular leak was resutured, 1 patient had a cardiac myxoma removed, and 1 patient had a correction of tricuspid regurgitation. In 9 cases an atrial septal defect closure was performed. RESULTS: One redo patient, with severe tricuspid regurgitation, needed conversion to sternotomy; in all the other cases the results of surgery were good and there were no surgical limitations. The mean cross-clamping time and bypass time were 53 +/- 19 and 77 +/- 27 min respectively. The mean in-hospital stay was 6 days. Re-exploration for bleeding was required in 7 patients (14%). Three patients (6%) presented with a postoperative neurological lesion; 2 recovered completely within 48 hours whereas 1 patient had permanent hemiplegia at discharge. There was one hospital death (an 81-year-old patient died of multiorgan failure on the thirteenth postoperative day). CONCLUSIONS: Minimally invasive port-access surgery is a reliable alternative to conventional surgery for the treatment of mitral and tricuspid disease, the removal of cardiac tumors, and the correction of atrial septal defects. It reduces trauma to the patient, provides a better cosmetic result and also allows for a faster recovery. Careful patient selection is important to avoid complications. Redo patients can be successfully treated and the risks of re-sternotomy avoided.

[Acute heart failure in a patient treated by mitoxantrone for multiple sclerosis]. / Insuffisance cardiaque aiguë chez une patiente traitée par mitoxantrone pour sclérose en plaques.

Mitoxantrone is an immunosuppressive drug usually delivered in severe relapsing remitting multiple sclerosis. It can also be used in secondary progressive and progressive relapsing remitting multiple sclerosis. Left ventricular ejection fraction has to be monitored because of the cardiotoxicity risk of mitoxantrone. Acute cardiac side effects in multiple sclerosis have not yet been described. We report the single case of an acute heart failure occurring in a cohort of more than 800 patients treated with mitoxantrone. We discuss about interruption criteria as maximal cumulative dose allowed and left ventricular ejection fraction cut off value.

[Primary leiomyosarcoma of the cavernous sinus associated with Epstein-Barr virus in a kidney graft]. / Leiomyosarcome primitif du sinus caverneux associé au virus Epstein-Barr chez un greffé rénal.

Immunodeficient patients have an increased incidence of neoplasms, whether the immunodeficiency is due to genetic disorder, the acquired immunodeficiency syndrome (AIDS), or immunosuppressive therapy. Leiomyosarcoma (LMS) is a rare neoplasm, even if its incidence has increased because of AIDS. Less than fifteen cases were described after organ transplantation. An intracranial localization is exceptional (five cases in the literature) and was never described after organ transplantation, to our knowledge. Our present report focuses on a 45-year-old immunocompromised patient, who received immunosuppressive therapy for renal transplantation. He suffered from atypical peri-orbital headaches six months after transplantation and a mass involving the cavernous sinus was identified. Surgical biopsy was performed. Histologic examination revealed a LMS. Epstein-Barr virus was identified by quantitative polymerase chain reaction in the LMS. Immunosuppression was reduced, the patient received adriamycin and protontherapy was realized. He died two years after the transplantation because of tumor progression and kidney failure.