Evaluation and validation of a patient-reported quality-of-life questionnaire for Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a chronic, progressive illness with a profound impact on the health-related quality of life (HRQoL). Disease-specific patient-reported HRQoL measures, such as PDQ-39 and its short version PDQ-8, are increasingly used in clinical practice to address the consequences of PD on everyday life. Due to limitations in the content, especially in non-motor symptoms and sleep disturbances of PDQ-8, PDQoL7, a 7-item, short-term, self-reported, PD-specific HRQoL questionnaire was developed. METHODS: A representative sample of 60 adults with idiopathic PD completed the PDQoL7 questionnaire and the existing validated PDQ-8 and EQ-5D-5L questionnaires (all in Greek). RESULTS: PDQoL7 summary index strongly correlated with PDQ-8 (rs = 0.833, P < 0.001) and EQ-5D-5L (rs = - 0.852, P < 0.001). The correlation between PDQoL7 and EQ-5D-5L was statistically significantly stronger compared to PDQ-8 and EQ-5D-5L (rs = - 0.852 vs rs = - 0.789 respectively, P < 0.001). The internal consistency of PDQoL7 was not affected by item deletion (positive item to total correlations: 0.29-0.63). No redundant items (with inter-item correlation coefficients greater than 0.80) were identified. Cronbach's α for PDQoL7 was comparable to PDQ-8 (0.804 versus 0.799 respectively). As PDQoL7 had three-dimensional structure, omega coefficient analysis confirmed its reliability (omega total: 0.88; omega hierarchical: 0.58). CONCLUSIONS: PDQoL7 is an acceptable, easy to use, valid and reliable tool for the determination of HRQoL in PD patients that is potentially more comprehensive than PDQ-8 based on the available evidence. PDQoL7 could allow for a more thorough evaluation of the impact of PD and contribute to guiding healthcare decisions. This will be confirmed in subsequent analysis on larger patient cohorts.

Screening for the C9ORF72 expansion in Greek Huntington Disease phenocopies and controls and meta-analysis of current data.

Background: Several European studies examined the role of C9orf72 repeat expansion in patients with Huntington-disease like phenotypes (HD-L). The scope of our study is to investigate the expansion frequency in a Greek HD-L cohort and the meta-analysis of all published cases. This will be of use in genetic counseling of these cases. Methods: A cohort of 74 patients with HD-L and 67 healthy controls were screened for the C9orf72 expansion status. Case-controls comparison was assessed with the Pearson's chi-square statistic for a 2 × 2 table.A systematic database search was conducted and seven studies, including the current study, were considered eligible for inclusion in a meta-analysis considering a total of 812 patients with HD phenocopies. Pooled mutation frequency was calculated using a Random Effects model or the Mantel-Haezsel fixed effects model, depending on the observed heterogeneity. Results: In our cohort, one patient was found to have a pathologic expansion of C9orf72, and none from the control group (chi-square: 0.91, p-value: 0.34). Pooled mutation frequency was found at 2% (CI: 1-3%) with low heterogeneity (I2:15%). Discussion: Based on this meta-analysis the recommendation for genetic testing for C9orf72 expansions is further solidified.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy revisited: Genotype-phenotype correlations of all published cases.

OBJECTIVE: The aim of this study was to evaluate the correlation between the various NOTCH3 mutations and their clinical and genetic profile, along with the presentation of a novel mutation in a patient. METHODS: Here, we describe the phenotype of a patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) harboring a novel mutation. We also performed an extensive literature research for NOTCH3 mutations published since the identification of the gene and performed a systematic review of all published cases with NOTCH3 mutations. We evaluated the mutation pathogenicity in a great number of patients with detailed clinical and genetic evaluation and investigated the possible phenotype-genotype correlations. RESULTS: Our patient harbored a novel mutation in the NOTCH3 gene, the c.3084 G > C, corresponding to the aminoacidic substitution p.Trp1028Cys, presenting with seizures as the first neurologic manifestation. We managed to find a correlation between the pathogenicity of mutations, severity of the phenotype, and age at onset of CADASIL. Significant differences were also identified between men and women regarding the phenotype severity. CONCLUSIONS: The collection and analysis of these scarce data published since the identification of NOTCH3 qualitatively by means of a systematic review and quantitatively regarding genetic profile and pathogenicity scores, highlight the significance of the ongoing trend of investigating phenotypic genotypic correlations.

A novel homozygous SACS mutation identified by whole exome sequencing-genotype phenotype correlations of all published cases.

ARSACS is an autosomal recessive disorder characterized by ataxia, spasticity, and polyneuropathy. A plethora of worldwide distributed mutations have been described so far. Here, we report two brothers, born to non-consanguineous parents, presenting with cerebellar ataxia and peripheral neuropathy. Whole-exome sequencing revealed the presence of a novel homozygous variant in the SACS gene. The variant was confirmed by Sanger sequencing and found at heterozygous state in both parents. This is the first reported mutation in this gene, in Greek population. This case report further highlights the growing trend of identifying genetic diseases previously restricted to single, ethnically isolated regions in many different ethnic groups worldwide. Additionally, we performed a systematic review of all published cases with SACs mutations. ARSACS seems to be an important cause of ataxia and many different types of mutations have been identified, mainly located in exon 10. We evaluated the mutation pathogenicity in all previously reported cases to investigate possible phenotype-genotype correlations. We managed to find a correlation between the pathogenicity of mutations, severity of the phenotype, and age of onset of ARSACS. Greater mutation numbers in different populations will be important and mutation-specific functional studies will be essential to identify the pathogenicity of the various ARSACS variants.

Effect of constant-current pallidal deep brain stimulation for primary dystonia on cognition, mood and quality of life: Results from a prospective pilot trial.

OBJECTIVE: Knowledge on the effects of DBS on cognitive functions is limited and no data exists on the effects of constant-current DBS (CC-GPi-DBS), which appears to prevail over constant-voltage stimulation. Our aim was to prospectively assess the effect of Constant-Current-GPi-DBS, using an 8-contact lead, on cognition, mood and quality of life. PATIENTS AND METHODS: Ten patients aged 27-49 underwent prospective neuropsychological assessment using dedicated tests. Various cognitive domains (intelligence, executive functions, memory, attention, visuo-spatial perception, verbal intelligence) as well as emotional state and quality of life were examined preoperatively and 1, 6 and 12 months after continuous constant-current DBS. RESULTS: Patients performed preoperatively below average on information processing speed, phonemic verbal fluency and working memory. At 6-months there was an improvement in phonemic verbal fluency (p < .05), which was retained at 12-months postoperatively (p = .05). Results also showed marginal improvement in the Trail Making-A test (p = .051) and the Stroop colour-word test (p < .05). Despite improvement in Quality of Life (Physical and Mental Component improved by 32.42% and 29.46% respectively), patients showed no discernible change in anxiety and depression status. CONCLUSIONS: CC-GPi-DBS for primary dystonia has no discernible negative impact on cognition and mood. If anything, we noted an improvement of certain cognitive functions.

Constant-Current Deep Brain Stimulation of the Globus Pallidus Internus in the Treatment of Primary Dystonia by a Novel 8-Contact (Octrode) Lead.

OBJECTIVE: To evaluate bilateral constant-current globus pallidus internus (GPi) deep brain stimulation using an 8-contact lead. METHODS: This prospective, open-label, single-center pilot study of 10 patients assessed the feasibility of delivering bilaterally constant-current GPi deep brain stimulation with a novel 8-channel lead to treat primary dystonia using standard scales as outcome measures. RESULTS: Patients included 4 men and 6 women with a mean age of 35.8 years ± 9.2 (range, 27-49 years). Mean age of onset was 18.5 years ± 9.1 (range, 8-35 years), and mean disease duration was 17.3 years (range, 7-27 years). All had primary dystonia (8 generalized dystonia, 1 segmental dystonia, 1 focal dystonia). The primary variable was determined as 50% reduction in dystonia symptoms from baseline to the 6-month follow-up, as defined by the Burke-Fahn-Marsden Dystonia Rating Scale. Six patients (60.0%) achieved >50% reduction in Burke-Fahn-Marsden Dystonia Rating Scale score and were classified as responders at the 6-month follow-up. Five of these 6 responders (83.3%) sustained that response through the assessment at the end of the first year. Constant-current stimulation was associated with significant improvement in pain and quality of life in all patients. Nearly 84% of the overall improvement occurred by the end of first month after stimulation onset, documenting an early response to treatment. Axial symptoms responded the best. CONCLUSIONS: Constant-current GPi deep brain stimulation proved safe and efficacious for treatment of primary dystonia. Motor scores improved by 54%, mostly within the first month. No phenotype-specific stimulation could be achieved, despite the capability of the new lead to stimulate specific loci within the GPi.

The Insertion of Electrodes in the Brain for Electrophysiological Recording or Chronic Stimulation Is Not Associated With Any Biochemically Detectable Neuronal Injury.

OBJECTIVE: The aim of this study was to evaluate the degree of brain tissue injury that could be potentially induced by the introduction of a) microrecording electrodes, b) macrostimulation electrodes, or c) chronic stimulation electrodes. We aimed to evaluate whether the use of five simultaneous microrecording tracks is associated with any brain injury not detectable by conventional imaging such as CT or MRI. MATERIALS AND METHODS: The study included 61 patients who underwent surgery for implantation of 121 DBS leads. In all cases, five simultaneous tracts were utilized for microelectrode recordings. All patients underwent measurements of serum S-100b at specific time points as follows: a) prior to the operation, and b) intraoperatively at specific stages of the procedure: 1) after opening the burr hole, 2) after the insertion of microrecording electrodes, 3) during macrostimulation, 4) at the end of the operation, and 5) on the first postoperative day. RESULTS: The levels of serum S-100B protein remained within the normal range during the entire period of investigation in all patients with the exception of two cases. In both patients, the procedure was complicated by intraparenchymal hemorrhage visible in neuro-imaging. The first patient developed a small intraparenchymal hemorrhage, visible on the postoperative MRI, with no neurological deficit. The second patient experienced a focal epileptic seizure after the insertion of the right DBS chronic lead and the postoperative CT scan revealed a right frontal lobe hemorrhage. CONCLUSION: These results strongly indicate that the insertion of either multiple recording electrodes or the implantation of chronic electrodes in DBS does not increase the risk of brain hemorrhage or of other intracranial complications, and furthermore it does not cause any biochemically detectable brain tissue damage.

Algorithmic design of a noise-resistant and efficient closed-loop deep brain stimulation system: A computational approach.

Advances in the field of closed-loop neuromodulation call for analysis and modeling approaches capable of confronting challenges related to the complex neuronal response to stimulation and the presence of strong internal and measurement noise in neural recordings. Here we elaborate on the algorithmic aspects of a noise-resistant closed-loop subthalamic nucleus deep brain stimulation system for advanced Parkinson's disease and treatment-refractory obsessive-compulsive disorder, ensuring remarkable performance in terms of both efficiency and selectivity of stimulation, as well as in terms of computational speed. First, we propose an efficient method drawn from dynamical systems theory, for the reliable assessment of significant nonlinear coupling between beta and high-frequency subthalamic neuronal activity, as a biomarker for feedback control. Further, we present a model-based strategy through which optimal parameters of stimulation for minimum energy desynchronizing control of neuronal activity are being identified. The strategy integrates stochastic modeling and derivative-free optimization of neural dynamics based on quadratic modeling. On the basis of numerical simulations, we demonstrate the potential of the presented modeling approach to identify, at a relatively low computational cost, stimulation settings potentially associated with a significantly higher degree of efficiency and selectivity compared with stimulation settings determined post-operatively. Our data reinforce the hypothesis that model-based control strategies are crucial for the design of novel stimulation protocols at the backstage of clinical applications.

ANCA-Negative Churg-Strauss Syndrome Presenting as Acute Multiple Cerebral Infarcts: A Case Report.

Eosinophilic granulomatosis with polyangiitis (EGPA, previously named Churg-Strauss syndrome) is a form of necrotizing vasculitis occurring in patients with asthma and eosinophilia. Ischemic stroke is a relatively rare complication of the disease. We report a case of a 63-year-old woman with multiple embolic infarcts, hypereosinophilia (for >7 years), and skin rash. Elevated cardiac enzymes and cardiac magnetic resonance imaging were consistent with endomyocarditis. The simultaneous presence of history of asthma, sinusitis, hypereosinophilia, and vasculitis led to the diagnosis of EGPA. This case contributes to the recent debate of the 2 possible presentations of the disease according to the ANCA (antineutrophil cytoplasmic antibodies) status. We furthermore underscore the need for careful differential diagnosis of the "ANCA negative" cases with persistent hypereosinophilia from the idiopathic hypereosinophilic syndrome.

Antithrombotic Treatment Management in Patients with Intracerebral Hemorrhage: Reversal and Restart.

BACKGROUND: Intracerebral hemorrhage is the pathological accumulation of blood within the brain. It is a type of stroke more likely to be lethal or to severely disable the patient and results from a wide variety of causes. On the other hand antithrombotic therapy is used for the prevention or/and the therapy of thromboembolic episodes. Antithrombotic drugs are very effective in reducing risk or mortality rate after a thromboembolic event, yet they are associated with significant hemorrhages. OBJECTIVE: The aim of this article is to review current literature for intracerebral hemorrhage and antithrombotic therapy and offer recommendations on the reversal, the discontinuation and the resumption of antithrombotic therapy. METHODS AND MATERIALS: Current literature has been reviewed for intracerebral hemorrhage associated with three major categories of patients, those with atrial fibrillation, those with prosthetic mechanical valves and those with venous thromboembolism. Antithrombotic therapy is categorized in antiplatelet agents and anticoagulants. The risk of intracerebral hemorrhage, of a thromboembolic event and of a rebleeding with or without antithrombotic therapy was also reported. CONCLUSION: Although no one can deny the usefulness of antithrombotic therapy a therapeutic strategy should be developed in order to optimize the clinical decision of stopping, reversing and restarting antithrombotic treatment. This review concludes in strong recommendations, yet a multidisciplinary panel by a stroke physician or neurologist, a cardiologist, a neuroradiologist and a neurosurgeon should evaluate the benefits and the risks for each patient and decide the best therapeutic strategy.

Classification and Prediction of Clinical Improvement in Deep Brain Stimulation From Intraoperative Microelectrode Recordings.

We present a random forest (RF) classification and regression technique to predict, intraoperatively, the unified Parkinson's disease rating scale (UPDRS) improvement after deep brain stimulation (DBS). We hypothesized that a data-informed combination of features extracted from intraoperative microelectrode recordings (MERs) can predict the motor improvement of Parkinson's disease patients undergoing DBS surgery. We modified the employed RFs to account for unbalanced datasets and multiple observations per patient, and showed, for the first time, that only five neurophysiologically interpretable MER signal features are sufficient for predicting UPDRS improvement. This finding suggests that subthalamic nucleus (STN) electrophysiological signal characteristics are strongly correlated to the extent of motor behavior improvement observed in STN-DBS.

Dominant efficiency of nonregular patterns of subthalamic nucleus deep brain stimulation for Parkinson's disease and obsessive-compulsive disorder in a data-driven computational model.

OBJECTIVE: Almost 30 years after the start of the modern era of deep brain stimulation (DBS), the subthalamic nucleus (STN) still constitutes a standard stimulation target for advanced Parkinson's disease (PD), but the use of STN-DBS is also now supported by level I clinical evidence for treatment-refractory obsessive-compulsive disorder (OCD). Disruption of neural synchronization in the STN has been suggested as one of the possible mechanisms of action of standard and alternative patterns of STN-DBS at a local level. Meanwhile, recent experimental and computational modeling evidence has signified the efficiency of alternative patterns of stimulation; however, no indications exist for treatment-refractory OCD. Here, we comparatively simulate the desynchronizing effect of standard (regular at 130 Hz) versus temporally alternative (in terms of frequency, temporal variability and the existence of bursts or pauses) patterns of STN-DBS for PD and OCD, by means of a stochastic dynamical model and two microelectrode recording (MER) datasets. APPROACH: The stochastic model is fitted to subthalamic MERs acquired during eight surgical interventions for PD and eight surgical interventions for OCD. For each dynamical system simulated, we comparatively assess the invariant density (steady-state phase distribution) as a measure inversely related to the desynchronizing effect yielded by the applied patterns of stimulation. MAIN RESULTS: We demonstrate that high (130 Hz)-and low (80 Hz)-frequency irregular patterns of stimulation, and low-frequency periodic stimulation interrupted by bursts of pulses, yield in both pathologic conditions a significantly stronger desynchronizing effect compared with standard STN-DBS, and distinct alternative patterns of stimulation. In PD, values of the invariant density measure are proven to be optimal at the dorsolateral oscillatory region of the STN including sites with the optimal therapeutic window. SIGNIFICANCE: In addition to providing novel insights into the efficiency of low-frequency nonregular patterns of STN-DBS for advanced PD and treatment-refractory OCD, this work points to a possible correlation of a model-based outcome measure with clinical effectiveness of stimulation and may have significant implications for an energy- and therapeutically-efficient configuration of a closed-loop neuromodulation system.

Dopamine agonists early monotherapy for the delay of development of levodopa-induced dyskinesias.

Dyskinesias are common, often disabling motor complications emerging in Parkinson's disease following chronic levodopa treatment. Common views associate the development of dyskinesias both with progressive loss of striatal dopamine nerve terminals and with intermittent delivery of the short half-life levodopa. Thus, according to continuous dopaminergic stimulation theory, dopamine agonists having half-lifes longer than levodopa would minimize the risk of the development of dyskinesias. The article highlights some interesting aspects of the clinical trials testing dopamine agonists monotherapy as a strategy that can reduce the risk of motor complications, and raises some concerns in terms of their early use in Parkinson's disease treatment to prevent or delay dyskinesia. Finally, we emphasize the need for reconsideration of arguments against use of levodopa as a starting therapy for Parkinson's disease.

Beta-band frequency peaks inside the subthalamic nucleus as a biomarker for motor improvement after deep brain stimulation in Parkinson's disease.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) remains an empirical, yet highly effective, surgical treatment for advanced Parkinson's disease (PD). DBS outcome depends on accurate stimulation of the STN sensorimotor area which is a trial-and-error procedure taking place during and after surgery. Pathologically enhanced beta-band (13-35 Hz) oscillatory activity across the cortico-basal ganglia pathways is a prominent neurophysiological phenomenon associated with PD. We hypothesized that weighing together beta-band frequency peaks from simultaneous microelectrode recordings in "off-state" PD patients could map the individual neuroanatomical variability and serve as a biomarker for the location of the STN sensorimotor neurons. We validated our hypothesis with 9 and 11 patients that, respectively, responded well and poorly to bilateral DBS, after at least two years of follow up. We categorized "good" and "poor" DBS responders based on their clinical assessment alongside a > 40% and <30% change, respectively, in "off" unified PD rating scale motor scores. Good (poor) DBS responders had, in average, 1 mm (3.5 mm) vertical distance between the maximum beta-peak weighted across the parallel microelectrodes and the center of the stimulation area. The distances were statistically different in the two groups ( p = 0.0025 ). Our biomarker could provide personalized intra- and postoperative support in stimulating the STN sensorimotor area associated with optimal long-term clinical benefits.

Supporting clinical decision making during deep brain stimulation surgery by means of a stochastic dynamical model.

OBJECTIVE: During deep brain stimulation (DBS) surgery for the treatment of advanced Parkinson's disease (PD), microelectrode recording (MER) in conjunction with functional stimulation techniques are commonly applied for accurate electrode implantation. However, the development of automatic methods for clinical decision making has to date been characterized by the absence of a robust single-biomarker approach. Moreover, it has only been restricted to the framework of MER without encompassing intraoperative macrostimulation. Here, we propose an integrated series of novel single-biomarker approaches applicable to the entire electrophysiological procedure by means of a stochastic dynamical model. APPROACH: The methods are applied to MER data pertinent to ten DBS procedures. Considering the presence of measurement noise, we initially employ a multivariate phase synchronization index for automatic delineation of the functional boundaries of the subthalamic nucleus (STN) and determination of the acceptable MER trajectories. By introducing the index into a nonlinear stochastic model, appropriately fitted to pre-selected MERs, we simulate the neuronal response to periodic stimuli (130 Hz), and examine the Lyapunov exponent as an indirect indicator of the clinical effectiveness yielded by stimulation at the corresponding sites. MAIN RESULTS: Compared with the gold-standard dataset of annotations made intraoperatively by clinical experts, the STN detection methodology demonstrates a false negative rate of 4.8% and a false positive rate of 0%, across all trajectories. Site eligibility for implantation of the DBS electrode, as implicitly determined through the Lyapunov exponent of the proposed stochastic model, displays a sensitivity of 71.43%. SIGNIFICANCE: The suggested comprehensive method exhibits remarkable performance in automatically determining both the acceptable MER trajectories and the optimal stimulation sites, thereby having the potential to accelerate precise target finalization during DBS surgery for PD.

Malignant neuroleptic syndrome following deep brain stimulation surgery: a case report.

BACKGROUND: The neuroleptic malignant syndrome is an uncommon but dangerous complication characterized by hyperthermia, autonomic dysfunction, altered mental state, hemodynamic dysregulation, elevated serum creatine kinase, and rigor. It is most often caused by an adverse reaction to anti-psychotic drugs or abrupt discontinuation of neuroleptic or anti-parkinsonian agents. To the best of our knowledge, it has never been reported following the common practice of discontinuation of anti-parkinsonian drugs during the pre-operative preparation for deep brain stimulation surgery for Parkinson's disease. CASE PRESENTATION: We present the first case of neuroleptic malignant syndrome associated with discontinuation of anti-parkinsonian medication prior to deep brain stimulation surgery in a 54-year-old Caucasian man. CONCLUSION: The characteristic neuroleptic malignant syndrome symptoms can be attributed to other, more common causes associated with deep brain stimulation treatment for Parkinson's disease, thus requiring a high index of clinical suspicion to timely establish the correct diagnosis. As more centers become eligible to perform deep brain stimulation, neurologists and neurosurgeons alike should be aware of this potentially fatal complication. Timely activation of the deep brain stimulation system may be important in accelerating the patient's recovery.

Infected internal pulse generator: Treatment without removal.

BACKGROUND: One of the rare but devastating complications of deep brain stimulation (DBS) is internal pulse generator (IPG) infection. In the majority of the cases, removal of the device is required, despite appropriate antibiotic therapy. We demonstrate that eradication of an IPG infection is feasible without removal of the IPG device. CASE DESCRIPTION: This article reports the authors' experience on two patients who underwent DBS for advanced Parkinson's disease (PD) and, subsequently, suffered from infection and skin breakdown over the IPG. The patients were treated with antibiotic therapy, surgical revision of the wound, intraoperative disinfection of the IPG and relocation of the subcutaneous pocket. In both cases, the infection was eradicated and DBS therapy was continued uninterrupted. CONCLUSION: Although not generally recommended, DBS IPG may be salvaged in selected cases of superficial device infection. Our experience suggests that it is possible to treat the infection without removing the device. Such an approach decreases the morbidity, duration of hospital stay and health care costs.

An observational trial to investigate the efficacy and tolerability of levetiracetam in trigeminal neuralgia.

OBJECTIVE: To explore the efficacy and tolerability of levetiracetam in medical treatment of trigeminal neuralgia. BACKGROUND: Antiepileptic drugs (AEDs) are considered as first-line treatment for trigeminal neuralgia, although their use is often limited due to incomplete efficacy and tolerability. Newer AEDs with improved safety profile may be useful in this disorder. METHODS: Patients suffering from trigeminal neuralgia (either primary or secondary) refractory to previous treatments were recruited to be treated with levetiracetam (3-4 g/day) for 16 weeks as add-on therapy, after a 2-week baseline period. Rescue medication was allowed in both the baseline and treatment phases. The primary efficacy measure was the number of attacks per day. The patients' efficacy evaluation, the patients' global evaluation for both safety and efficacy, changes in the Hamilton Depression Scale, the Hamilton Anxiety Scale, and the Quality of Life Measure Short Form-36 were secondary parameters. RESULTS: Twenty-three patients were included in the analysis. After treatment and compared to the baseline phase, the number of daily attacks decreased by 62.4%. All secondary parameters changed significantly with the exception of the Quality of Life Measure Short Form-36 score. Seven patients withdrew from the study. Five patients (21.7%) reported side effects and 2 withdrew. CONCLUSIONS: Levetiracetam may be effective and safe in trigeminal neuralgia treatment. Confirmation in a randomized controlled study is needed.