The Personalized Parkinson Project: examining disease progression through broad biomarkers in early Parkinson's disease.

BACKGROUND: Our understanding of the etiology, pathophysiology, phenotypic diversity, and progression of Parkinson's disease has stagnated. Consequently, patients do not receive the best care, leading to unnecessary disability, and to mounting costs for society. The Personalized Parkinson Project (PPP) proposes an unbiased approach to biomarker development with multiple biomarkers measured longitudinally. Our main aims are: (a) to perform a set of hypothesis-driven analyses on the comprehensive dataset, correlating established and novel biomarkers to the rate of disease progression and to treatment response; and (b) to create a widely accessible dataset for discovery of novel biomarkers and new targets for therapeutic interventions in Parkinson's disease. METHODS/DESIGN: This is a prospective, longitudinal, single-center cohort study. The cohort will comprise 650 persons with Parkinson's disease. The inclusion criteria are purposely broad: age ≥ 18 years; and disease duration ≤5 years. Participants are followed for 2 years, with three annual assessments at the study center. Outcomes include a clinical assessment (including motor and neuro-psychological tests), collection of biospecimens (stool, whole blood, and cerebrospinal fluid), magnetic resonance imaging (both structural and functional), and ECG recordings (both 12-lead and Holter). Additionally, collection of physiological and environmental data in daily life over 2 years will be enabled through the Verily Study Watch. All data are stored with polymorphic encryptions and pseudonyms, to guarantee the participants' privacy on the one hand, and to enable data sharing on the other. The data and biospecimens will become available for scientists to address Parkinson's disease-related research questions. DISCUSSION: The PPP has several distinguishing elements: all assessments are done in a single center; inclusion of "real life" subjects; deep and repeated multi-dimensional phenotyping; and continuous monitoring with a wearable device for 2 years. Also, the PPP is powered by privacy and security by design, allowing for data sharing with scientists worldwide respecting participants' privacy. The data are expected to open the way for important new insights, including identification of biomarkers to predict differences in prognosis and treatment response between patients. Our long-term aim is to improve existing treatments, develop new therapeutic approaches, and offer Parkinson's disease patients a more personalized disease management approach. TRIAL REGISTRATION: Clinical Trials NCT03364894 . Registered December 6, 2017 (retrospectively registered).

Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society.

OBJECTIVE: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs (AEDs) (gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, and zonisamide-reviewed in the order in which these agents received approval by the US Food and Drug Administration) in the treatment of children and adults with newly diagnosed partial and generalized epilepsies. METHODS: A 23-member committee, including general neurologists, pediatric neurologists, epileptologists, and doctors in pharmacy, evaluated the available evidence based on a structured literature review including MEDLINE, Current Contents, and Cochrane library for relevant articles from 1987 until September 2002, with selected manual searches up until 2003. RESULTS: There is evidence either from comparative or dose-controlled trials that gabapentin, lamotrigine, topiramate, and oxcarbazepine have efficacy as monotherapy in newly diagnosed adolescents and adults with either partial or mixed seizure disorders. There is also evidence that lamotrigine is effective for newly diagnosed absence seizures in children. Evidence for effectiveness of the new AEDs in newly diagnosed patients with other generalized epilepsy syndromes is lacking. CONCLUSIONS: The results of this evidence-based assessment provide guidelines for the prescription of AEDs for patients with newly diagnosed epilepsy and identify those seizure types and syndromes where more evidence is necessary.

Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society.

OBJECTIVE: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs (AEDs) (gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, and zonisamide) in the treatment of children and adults with refractory partial and generalized epilepsies. METHODS: A 23-member committee including general neurologists, pediatric neurologists, epileptologists, and doctors in pharmacy evaluated the available evidence based on a structured literature review including MEDLINE, Current Contents, and Cochrane library for relevant articles from 1987 until March 2003. RESULTS: All of the new AEDs were found to be appropriate for adjunctive treatment of refractory partial seizures in adults. Gabapentin can be effective for the treatment of mixed seizure disorders, and gabapentin, lamotrigine, oxcarbazepine, and topiramate for the treatment of refractory partial seizures in children. Limited evidence suggests that lamotrigine and topiramate are also effective for adjunctive treatment of idiopathic generalized epilepsy in adults and children, as well as treatment of the Lennox Gastaut syndrome. CONCLUSIONS: The choice of AED depends upon seizure and/or syndrome type, patient age, concomitant medications, AED tolerability, safety, and efficacy. The results of this evidence-based assessment provide guidelines for the prescription of AEDs for patients with refractory epilepsy and identify those seizure types and syndromes where more evidence is necessary.

False lateralization by subdural electrodes in two patients with temporal lobe epilepsy.

The authors present two patients with medically refractory partial seizures who had invasive recordings with stereotactic depth EEG (SEEG) and subdural electrodes (SDE) as part of their presurgical workup. SDE recordings were falsely lateralizing in both of these patients with pathologically proven mesial temporal sclerosis. In temporal lobe epilepsy, SEEG electrodes should be considered when presurgical studies are discordant.

Vagus nerve stimulation for the treatment of bilateral independent temporal lobe epilepsy.

PURPOSE: We studied the effect of vagus nerve stimulation (VNS) on seizure reduction in patients with intractable epilepsy with bilateral independent temporal lobe foci. METHODS: Ten patients who met the criterion of the presence of two distinctive clinical and ictal EEG seizure patterns were identified and followed up for 1 year. RESULTS: Six patients had >50% reduction in their seizure frequency that persisted up to > or =1 year of follow-up, whereas four patients reported small or no reduction in their partial seizures. CONCLUSIONS: VNS is often effective and well tolerated in this select group of intractable epilepsy patients.

Surgical treatment of Parkinson's disease: ablation, stimulation and transplantation.

Clinicians now have an extensive and effective pharmacopeia to treat the symptoms of Parkinson's disease - especially in the early and moderate stages of the disorder. Ultimately, a significant number of patients with the disorder find that, as their disease progresses, pharmacotherapy fails to control symptoms or produces unacceptable adverse effects as higher medication doses are used. For patients with Parkinson's disease whose symptoms are insufficiently controlled by medical therapy, surgical treatments can reduce symptoms, enhance functional capacity and sometimes reduce medication requirements. This article reviews the current state-of-the-art in surgical interventions for Parkinson's disease, with an emphasis on deep brain stimulation therapy, an evolving treatment that accomplishes symptom control in a reversible, adjustable and nondestructive manner.

Deep brain stimulation for advanced Parkinson's disease.

Deep brain stimulation (DBS) is a new and promising technique for the treatment of movement disorders. Medically intractable Parkinson's disease (PD) is one of the most common indications for DBS. There are three possible subcortical targets for PD, depending on the symptomatology (i.e., the motor subdivision of the thalamus, the globus pallidus internus, the subthalamic nucleus [STN]). Thalamic stimulation has been well established as a safe and effective treatment for essential tremor and the tremor associated with PD. Globus pallidus internus and STN DBS are being investigated for the treatment of all the cardinal signs of PD. This article describes the pathophysiology of PD, the surgical treatment history of PD, surgical techniques used for DBS implants, and the role the perioperative nurse has in the care of the patients undergoing these procedures.

Order effects in response times of parkinsonian patients and normal controls.

Response latencies were measured in 6 parkinsonian patients and 6 normal subjects in a choice reaction task requiring the discrimination of two different tones with different probabilities of occurrence (frequent and rare). Response latency was measured from stimulus onset to onset of electromyographic activity in the responding muscle. Rare-tone responses were separated on the basis of the number of frequent tones intervening between the rare tone of interest and the immediately preceding rare tone (defined as rare-tone position). Frequent-tone responses were separated by the number of consecutive frequent tones occurring either before or after a rare tone (defined as frequent-tone position). Rare- and frequent-tone position had a significant impact on response latency. Both patients and controls had the shortest response latencies to rare tones when four frequent tones (the median interval for these experiments) intervened. Similarly, the response latency to frequent tones increased at approximately this same median interval after a rare event for both patients and controls. These findings suggest that normal controls utilize probability information about both global probabilities and their immediate past experience in order to modify upcoming responses. Our findings also indicate that patients with Parkinson's disease do not differ from normal subjects in this regard, and thus that even subtle attributes of preprogramming are not affected in Parkinson's disease, despite suggestions by others to the contrary.

Simple and choice reaction time in Parkinson's disease.

Reaction-times were evaluated in 6 parkinsonian patients and 6 normal control subjects using a simple reaction task and 3 choice reaction tasks of differing complexity. Reaction-times were measured as the time from stimulus onset to the onset of electromyographic activity in the responding muscle. Reaction-time was significantly delayed in patients compared to controls in all tasks, but to a greater extent in the more difficult tasks. The relative magnitude of the change, however, was only 4% in the simple reaction task and 8% in the more difficult choice tasks. These results suggest that the deficit in Parkinson's disease is unlikely to represent a defect in preprogramming as suggested by some investigators. Instead, our results indicate a disturbance in the cerebral processing of the auditory stimuli after their occurrence and prior to the initiation of motor activity.

Cerebral accompaniments to simple and choice reaction tasks in Parkinson's disease.

In order to clarify the nature and basis of the delayed reaction time that occurs in Parkinson's disease, we measured reaction times and cerebral responses in six parkinsonian patients and six normal age-matched control subjects. Each participated in one simple reaction task and three choice reaction tasks of different complexity. The reaction times were delayed in the parkinsonian patients in all conditions but especially in the more difficult choice tasks. In addition, the cerebral responses showed delayed latencies of the N1, N2, and P3 components of the event-related cerebral potential. These findings are similar to the changes that we observed previously in patients with both Parkinson's disease and dementia, and suggest that bradyphrenia may account, in part, for the slowing of response time in Parkinson's disease.

Semiology of temporal lobe seizures: value in lateralizing the seizure focus.

PURPOSE: To determine the lateralizing value of the clinical manifestations of seizures in patients with temporal lobe epilepsy (TLE), we made a retrospective videotape analysis of complex partial seizures (CPS) in 55 patients who underwent temporal lobectomy and were seizure-free postoperatively for >2 years. METHODS: Blinded to clinical details, we reviewed videotapes from video-EEG telemetry monitoring with attention paid to seizure semiology. RESULTS: Useful lateralizing features included unilateral clonic activity (with the seizure focus contralateral in all patients), unilateral dystonic or tonic posturing (with the seizure focus contralateral in 90 and 86%, respectively), unilateral automatisms (with the seizure focus ipsilateral in 80%), and ictal speech preservation (with the seizure focus contralateral to the language-dominant hemisphere in 80%). Versive head rotation occurring < or = 10 s before seizures secondarily generalized consistently predicted a contralateral focus. Seizure manifestations less predictive but suggestive of lateralization included ictal speech arrest and postictal speech status, with predictive values of 67%. Seizure manifestations not providing reliable lateralizing information included eye deviation, type of aura, and versive head movements occurring at times other than immediately before seizures secondarily generalized. CONCLUSIONS: In TLE, several clinical seizure manifestations are useful in lateralizing the seizure focus, although some provide no reliable information. Therefore, ictal semiology can assist in the evaluation of patients for seizure surgery, providing additional information in the lateralization of TLE.

Management of seizures and epilepsy.

While the evaluation and treatment of patients with seizures or epilepsy is often challenging, modern therapy provides many patients with complete seizure control. After a first seizure, evaluation should focus on excluding an underlying neurologic or medical condition, assessing the relative risk of seizure recurrence and determining whether treatment is indicated. Successful management of patients with recurrent seizures begins with the establishment of an accurate diagnosis of epilepsy syndrome followed by treatment using an appropriate medication in a manner that optimizes efficacy. The goal of therapy is to completely control seizures without producing unacceptable medication side effects. Patients who do not achieve complete seizure control should be referred to an epilepsy specialist, since new medications and surgical treatments offer patients unprecedented options in seizure control.

The effect of ABO blood group on the diagnosis of von Willebrand disease.

In order to firmly establish a normal range for von Willebrand factor antigen (vWF:Ag), we determined plasma vWF:Ag concentrations in 1,117 volunteer blood donors by quantitative immunoelectrophoresis. The presence of the ABO blood group has a significant influence on vWF:Ag values; individuals with blood group O had the lowest mean vWF:Ag level (74.8 U/dL), followed by group A (105.9 U/dL), then group B (116.9 U/dL), and finally group AB (123.3 U/dL). Multiple regression analysis revealed that age significantly correlated with vWF:Ag levels in each blood group. We then performed reverse ABO typing on stored plasma from 142 patients with the diagnosis of von Willebrand disease (vWd). Of 114 patients with type I vWd, blood group O was found in 88 (77%), group A in 21 (18%), group B in 5 (4%), and group AB in none (0%), whereas the frequency of these blood groups in the normal population is significantly different (45%, 45%, 7% and 3%, respectively) (P less than .001). Patients with type II or III vWd had ABO blood group frequencies that were not different from the expected distribution. There may be a subset of symptomatic vWd patients with decreased concentrations of structurally normal vWf (vWd, type I) on the basis of blood group O. Some individuals of blood group AB with a genetic defect of vWF may have the diagnosis overlooked because vWF levels are elevated due to blood type.