Paul C. Van Ness

Two‐year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: Final results of the RNS System Pivotal trial

To demonstrate the safety and effectiveness of responsive stimulation at the seizure focus as an adjunctive therapy to reduce the frequency of seizures in adults with medically intractable partial onset seizures arising from one or two seizure foci.

Long-term treatment with responsive brain stimulation in adults with refractory partial seizures.

Objective: The long-term efficacy and safety of responsive direct neurostimulation was assessed in adults with medically refractory partial onset seizures. Methods: All participants were treated with a cranially implanted responsive neurostimulator that delivers stimulation to 1 or 2 seizure foci via chronically implanted electrodes when specific electrocorticographic patterns are detected (RNS System). Participants had completed a 2-year primarily open-label safety study (n = 65) or a 2-year randomized blinded controlled safety and efficacy study (n = 191); 230 participants transitioned into an ongoing 7-year study to assess safety and efficacy. Results: The average participant was 34 (±11.4) years old with epilepsy for 19.6 (±11.4) years. The median preimplant frequency of disabling partial or generalized tonic-clonic seizures was 10.2 seizures a month. The median percent seizure reduction in the randomized blinded controlled trial was 44% at 1 year and 53% at 2 years (p < 0.0001, generalized estimating equation) and ranged from 48% to 66% over postimplant years 3 through 6 in the long-term study. Improvements in quality of life were maintained (p < 0.05). The most common serious device-related adverse events over the mean 5.4 years of follow-up were implant site infection (9.0%) involving soft tissue and neurostimulator explantation (4.7%). Conclusions: The RNS System is the first direct brain responsive neurostimulator. Acute and sustained efficacy and safety were demonstrated in adults with medically refractory partial onset seizures arising from 1 or 2 foci over a mean follow-up of 5.4 years. This experience supports the RNS System as a treatment option for refractory partial seizures. Classification of evidence: This study provides Class IV evidence that for adults with medically refractory partial onset seizures, responsive direct cortical stimulation reduces seizures and improves quality of life over a mean follow-up of 5.4 years.

Chronic Intractable Epilepsy as the Only Symptom of Primary Brain Tumor

We identified 39 patients with chronic epilepsy (seizures ≥2 years) proven to have primary brain tumors. These cases represent ∼12% of the surgery cases for epilepsy in the same period. Mean age of seizure onset was 13.2 years: mean duration before operation was 10.5 years. Thirty‐eight of 39 had normal neurologic examination. Twenty‐six tumors were temporal, 7 were frontal, 4 were parietal, and 2 were occipital. Nine of 26 (34.6%) of the temporal group had contralateral interictal EEG spikes. Pathology was 15 ganglioglioma, 13 low‐grade astrocytoma, 4 oligodendroglioma, 2 low‐grade mixed glioma, 1 pleomorphic xanthoastrocytoma, 2 dysembryoplastic neuroepithelial tumor, and 1 ependymoma. Postoperative seizure frequency (minimum follow‐up 6 months) ranged from 15 to 16 seizure‐free or auras only in patients with temporal tumors and total gross tumor removal (mean follow‐up 28 months) to 0 of 6 seizure‐free in patients with extratemporal tumors who underwent subtotal resections or biopsy.

Endogenous inhibitor of GABA binding in mammalian brain

Abstract Binding of radioactive gamma-aminobutyric acid to homogenates of mammalian brain was detected by a centrifugation assay. The binding capacity of the tissue was maximal and stable with time only if the tissue was thoroughly washed to remove an endogenous inhibitor of binding. With such washed tissue, binding to total rat or cow brain appeared to involve two populations of sites in the absence of sodium ions, the major site having a dissociation constant of 150 nM and saturating at 80 pmol/g brain, and a minor site with a K D of 20 nM and saturating at 20 pmol/g wet tissue. This sodium-independent GABA binding as a whole was localized in the crude mitochondrial, microsomal, and synaptosomal membrane fractions.

Pentobarbital and EEG Burst Suppression in Treatment of Status Epilepticus Refractory to Benzodiazepines and Phenytoin

Summary: Seven patients with complex partial or secondarily generalized tonic‐clonic status epilepticus (SE) refractory to benzodiazepines (BZDs) and phenytoin (PHT) were treated with pentobarbital (PTB) coma with an EEG burst suppression (BSP) pattern. PTB administered by continuous intravenous (i.v.) infusion pump at a loading dose of 6–8 mg/kg in 40–60 min was usually sufficient to produce BSP activity and seizure control. PTB was continued 0–24 h at 1–4 mg/kg/h, adjusted to maintain blood pressure (BP) and BSP. Infusion rate was decreased if systolic BP (SBP) was <90 mm Hg. Normal saline fluid challenge was occasionally used to elevate BP, but in no case was it necessary to discontinue PTB infusion or use pressors. Other antiepileptic drugs (AEDs) were maintained at therapeutic levels for chronic seizure protection. Seizures were stopped in all cases. Four patients attained premorbid neurologic status, two patients briefly survived in vegetative states with recurring seizures after PTB withdrawal, and one patient died of asystole after receiving PTB for 7 h. Patients who had poor outcomes had prolonged seizures (16 h to 3 weeks) before insétéution of PTB anesthesia, and all had significant underlying central nervous system (CNS) pathology. PTB‐induced BSP appears to be safe and effective for refractory SE if it is started soon after failure of a BZD and PHT. Ultimate prognosis depends on SE etiology.

Prevalence of Human Immunodeficiency Virus Type 1 p24 Antigen in U.S. Blood Donors — An Assessment of the Efficacy of Testing in Donor Screening

Abstract Background. We performed a multicenter study in 1989 to determine whether screening whole-blood donors for human immunodeficiency virus type 1 (HIV-1) p24 antigen would improve transfusion safety by identifying carriers of the virus who are seronegative for HIV-1 antibody. Methods. More than 500,000 donations were tested at 13 U.S. blood centers with test kits from two manufacturers. Units found repeatedly reactive were retested in a central laboratory; if the results were positive, they were confirmed by a neutralization assay. A subgroup of units was also tested for HIV-1 by the polymerase chain reaction. Selected donors confirmed or not confirmed as having p24 antigen were contacted for follow-up interviews to identify risk factors and undergo retesting for HIV-1 markers. Results. Positive tests for p24 antigen were confirmed by neutralization in five donors (0.001 percent of all donations tested), all of whom were also positive for HIV-1 antibody and HIV-1 by polymerase chain reaction. Three ...

Mirror Focus: Function of Seizure Frequency and Influence on Outcome After Surgery

Summary: The concept of the mirror focus (MF) implies that an actively discharging epileptiform region may induce similar paroxysmal behavior in a homologous site. In a group of patients with complex partial seizures (CPS) we investigated whether occurrence of a MF was influenced by certain clinical factors and whether surgical out‐come was influenced by the presence of an MF. Factors studied included age at onset, duration, and total number of seizures. Patients had had CPS for >3 years and had pathologically proven temporal lobe neoplasms. Seizure frequency was estimated by the history‐taking physician. We estimated total seizure number by multiplying frequency by duration. Seven patients had MF, and 15 did not. Mean age at onset of seizures, duration of seizure disorder, and total seizure number did not vary statistically between the two groups of patients. All patients with an MF except 1 were seizure‐free at follow‐up. Ten of the 15 patients without MF were seizure‐free. Three patients who were not seizure‐free had had subtotal resection owing to tumor overlap with eloquent cortex. We conclude that an MF is not a contraindication to operation even when the preponderance of interictal spike activity is contralateral to the tumor or when seizures appear to arise from the MF on scalp EEG.

Evaluation of seizure-like episodes in survivors of moderate and severe traumatic brain injury.

Background:Transient paroxysmal alterations of consciousness or behavior are common sequelae of moderate and severe traumatic brain injury (TBI). Clinicians caring for patients with such episodes often diagnose them as epileptic seizures, a frequent and well-studied complication of TBI. As it is difficult to confirm this diagnosis, antiepileptic drugs are often used empirically. However, as such therapy is frequently ineffective, we studied the usefulness of prolonged video electroencephalogram (VEEG) monitoring in the clinical management of paroxysmal behaviors in TBI survivors. Methods:Records of patients referred evaluation in an epilepsy monitoring unit for management of medically intractable epilepsy were retrospectively reviewed. Patients with a documented history of moderate-to-severe brain injury preceding the onset of epilepsy were identified. These patients were studied by simultaneous videotape and scalp electroencephalographic recordings, and the majority also underwent magnetic resonance imaging and neuropsychologic studies. Results:Of the 1858 consecutive admissions over a 66-month period, 127 (7%) fulfilled enrollment criteria. VEEG monitoring was conducted for an average of 4.6 days. Monitoring was successful in establishing a diagnosis in 82% of the cases referred: 62% had focal seizures, 6% had generalized seizures, and 33% had psychogenic nonepileptic seizures. Of those with temporal lobe epilepsy, 53% had mesial temporal sclerosis, as shown by magnetic resonance imaging. Conclusions:VEEG is a useful procedure in the evaluation of TBI survivors with spells. The yield of diagnoses that may alter treatment is substantial. Additionally, mesial temporal sclerosis is associated with TBI. Given the variety of seizure types found in survivors of moderate-to-severe TBI, obtaining specific diagnosis of seizure type by VEEG monitoring impacts treatment options.

Posttraumatic epilepsy: the endophenotypes of a human model of epileptogenesis.

Posttraumatic epilepsy is a common complication of traumatic brain injury (TBI), occurring in up to 15–20% of patients with severe brain trauma. Trauma accounts for approximately 5% of chronic epilepsy in the community. Because it is a common condition, and because of the relatively short latency period between injury and onset of chronic seizures, posttraumatic epilepsy represents a good model to test antiepileptogenic therapies. However, several well‐conducted clinical trials have failed to demonstrate antiepileptogenic efficacy for several common anticonvulsants. Posttraumatic epilepsy can arise through a number of mechanisms, which often coexist within a single patient. Penetrating brain injury produces a cicatrix in the cortex and is associated with a risk of posttraumatic epilepsy of approximately 50%, whereas nonpenetrating head injury may produce focal contusions and intracranial hemorrhages, and is associated with a risk of posttraumatic epilepsy of up to 30%. Furthermore, closed head injury often produces diffuse concussive injury, with shearing of axons and selective damage to vulnerable brain regions, such as the hippocampus. The clinical, neurophysiologic, imaging, and neuropathologic features or epileptogenicity differ between these alternate mechanisms. It is likely that better understanding of the subtypes of epilepsy resulting from brain trauma will be required to successfully identify antiepileptogenic therapies.

Toward extended phenotype matching: a new operational paradigm for the transfusion service

BACKGROUND: Conventional pretransfusion testing uses hemagglutination to ensure donor‐recipient compatibility for ABO/D status and recipient alloantibodies. While screening large numbers of donor units for multiple antigens by hemagglutination is impractical, novel methods of DNA analysis permit the rapid determination of an extended human erythrocyte antigen (xHEA) phenotype. A prospective observational study was conducted at four hospital transfusion services to test an alternative paradigm of identifying xHEA‐typed units for patients in three cohorts by utilizing DNA analysis and a novel inventory management model.