Neuroimaging Rates for Closed Head Trauma in a Community Hospital.

OBJECTIVES: We aimed to characterize the utility of neuroimaging for head trauma in a suburban community hospital and determine whether imaging practices conform to most recent pediatric guidelines. METHODS: The electronic medical record was surveyed for computed tomographic and magnetic resonance imaging head scans on patients aged 1 to 18 years who were evaluated for trauma. The query included the following: date, sex, type of scan (computed tomography or magnetic resonance imaging), age, patient location, reason for scan, Glasgow Coma Scale (GCS) score (if entered), result, and text from physician's notes. RESULTS: A total of 2679 patients were identified. Within this cohort was a maximum of 29 surgical patients, of whom 8 required a surgical procedure but not neurosurgery among the 592 patients who had a GCS score of 14-15 entered, 2 were confirmed/possible neurosurgical patients, giving a neurosurgical rate of 0.34%. When the GCS 3-13 patient group was analyzed, the relative risk of requiring neurosurgery climbed to 52. Using an established algorithm for pediatric head trauma imaging would have reduced the number of scanned patients to 533. The individual cost of identifying the 29 surgical patients in our population exceeded $31,000. CONCLUSIONS: Our rate of serious lesions in GCS 14-15 patients was identical to a larger prospective study in urban teaching hospitals. Using their previously described algorithm might have reduced the number of patients scanned by more than 70% and saved close to $750,000 for the study period.

Brivaracetam augments short-term depression and slows vesicle recycling.

OBJECTIVE: Brivaracetam (BRV) decreases seizure activity in a number of epilepsy models and binds to the synaptic vesicle glycoprotein 2A (SV2A) with a higher affinity than the antiepileptic drug levetiracetam (LEV). Experiments were performed to determine if BRV acted similarly to LEV to induce or augment short-term depression (STD) under high-frequency neuronal stimulation and slow synaptic vesicle recycling. METHODS: Electrophysiologic field excitatory postsynaptic potential (fEPSP) recordings were made from CA1 synapses in rat hippocampal slices loaded with BRV or LEV during intrinsic activity or with BRV actively loaded during hypertonic stimulation. STD was examined in response to 5 or 40 Hz stimulus trains. Presynaptic release of FM1-43 was visualized using two-photon microscopy to assess drug effects upon synaptic vesicle mobilization. RESULTS: When hippocampal slices were incubated in 0.1-30 µm BRV or 30 µm-1 mm LEV for 3 h, the relative CA1 field EPSPs decreased over the course of a high-frequency train of stimuli more than for control slices. This STD was frequency- and concentration-dependent, with BRV being 100-fold more potent than LEV. The extent of STD depended on the length of the incubation time for both drugs. Pretreatment with LEV occluded the effects of BRV. Repeated hypertonic sucrose treatments and train stimulation successfully unloaded BRV from recycling vesicles and reversed BRVs effects on STD, as previously reported for LEV. At their maximal concentrations, BRV slowed FM1-43 release to a greater extent than in slices loaded with LEV during prolonged stimulation. SIGNIFICANCE: BRV, similar to LEV, entered into recycling synaptic vesicles and produced a frequency-dependent decrement of synaptic transmission at 100-fold lower concentrations than LEV. In addition, BRV slowed synaptic vesicle mobilization more effectively than LEV, suggesting that these drugs may modify multiple functions of the synaptic vesicle protein SV2A to curb synaptic transmission and limit epileptic activity.

Seletracetam enhances short term depression in vitro.

Seletracetam (SEL), an analog of the antiepileptic drug levetiracetam (LEV), decreases seizure activity in a number of epilepsy models and binds to the synaptic vesicle protein SV2A with a higher affinity than LEV. Experiments were performed to determine if SEL, like LEV, reduces the later EPSPs in long trains of stimuli in a manner dependent upon access to the interior of synaptic vesicles and SV2A binding. When hippocampal slices were incubated in 3-30µM SEL for 3h, but not 30 min, the relative amplitude of the CA1 field excitatory synaptic potentials decreased over the course of a train of high frequency stimuli more than for control slices. This short term depression was frequency and dose dependent and largely disappeared when the spontaneous activity during the loading period was removed by cutting the Schaffer collaterals. The SEL effect was also observed in slices loaded during prolonged stimulation at 1Hz, but not 10Hz. Hippocampal slices loaded with both SEL and FM1-43 to visualize synaptic boutons released the FM1-43 in response to prolonged stimulation much more slowly than control slices during prolonged stimulation. Like LEV, SEL produced a frequency-dependent decrement of synaptic transmission that was dependent upon the drug entering recycling synaptic vesicles and compatible with SV2A binding. Previous observations of SV2A binding affinity correlated with the current effect of SEL and the previously reported effect of LEV on synaptic transmission validate SV2A as an extremely attractive target for future antiepileptic drug development.

Temperatures achieved in human and canine neocortex during intraoperative passive or active focal cooling.

Focal cortical cooling inhibits seizures and prevents acquired epileptogenesis in rodents. To investigate the potential clinical utility of this treatment modality, we examined the thermal characteristics of canine and human brain undergoing active and passive surface cooling in intraoperative settings. Four patients with intractable epilepsy were treated in a standard manner. Before the resection of a neocortical epileptogenic focus, multiple intraoperative studies of active (custom-made cooled irrigation-perfused grid) and passive (stainless steel probe) cooling were performed. We also actively cooled the neocortices of two dogs with perfused grids implanted for 2 hours. Focal surface cooling of the human brain causes predictable depth-dependent cooling of the underlying brain tissue. Cooling of 0.6-2°C was achieved both actively and passively to a depth of 10-15 mm from the cortical surface. The perfused grid permitted comparable and persistent cooling of canine neocortex when the craniotomy was closed. Thus, the human cortex can easily be cooled with the use of simple devices such as a cooling grid or a small passive probe. These techniques provide pilot data for the design of a permanently implantable device to control intractable epilepsy.

Mild passive focal cooling prevents epileptic seizures after head injury in rats.

OBJECTIVE: Post-traumatic epilepsy is prevalent, often difficult to manage, and currently cannot be prevented. Although cooling is broadly neuroprotective, cooling-induced prevention of chronic spontaneous recurrent seizures has never been demonstrated. We examined the effect of mild passive focal cooling of the perilesional neocortex on the development of neocortical epileptic seizures after head injury in the rat. METHODS: Rostral parasagittal fluid percussion injury in rats reliably induces a perilesional, neocortical epileptic focus within weeks after injury. Epileptic seizures were assessed by 5-electrode video-electrocorticography (ECoG) 2 to 16 weeks postinjury. Focal cooling was induced with ECoG headsets engineered for calibrated passive heat dissipation. Pathophysiology was assessed by glial fibrillary acidic protein immunostaining, cortical sclerosis, gene expression of inflammatory cytokines interleukin (IL)-1α and IL-1ß, and ECoG spectral analysis. All animals were formally randomized to treatment groups, and data were analyzed blind. RESULTS: Cooling by 0.5 to 2°C inhibited the onset of epileptic seizures in a dose-dependent fashion. The treatment induced no additional pathology or inflammation, and normalized the power spectrum of stage N2 sleep. Cooling by 2°C for 5.5 weeks beginning 3 days after injury virtually abolished ictal activity. This effect persisted through the end of the study, >10 weeks after cessation of cooling. Rare remaining seizures were shorter than in controls. INTERPRETATION: These findings demonstrate potent and persistent prevention and modification of epileptic seizures after head injury with a cooling protocol that is neuroprotective, compatible with the care of head injury patients, and conveniently implemented. The required cooling can be delivered passively without Peltier cells or electrical power.

Impact of epilepsy surgery on seizure control and quality of life: a 26-year follow-up study.

PURPOSE: The short-term efficacy and safety of epilepsy surgery relative to medical therapy has been established, but it remains underutilized. There is a lack of data regarding the long-term seizure-control rates and quality of life outcomes after epilepsy surgery. This study represents the longest follow-up study to date, with a mean follow-up duration of 26 years. METHODS: We studied the seizure and health-related quality of life outcomes of patients who underwent epilepsy surgery by Dr. Sidney Goldring from 1967 to 1990. Retrospective clinical chart reviews gathered perioperative data and surveys obtained follow-up data. Seizure outcome was evaluated using the Engel classification system. KEY FINDINGS: Of 361 patients, 117 (32.4%) completed follow-up interviews. Fifty-six patients (48%) were Engel class I. Mean overall Quality of Life in Epilepsy (QOLIE-31) questionnaire score for the cohort was 68.2 ± 16. Eighty percent of patients reported their overall quality of life now as being better than before surgery. Seizure freedom was associated with better quality of life. We did not observe a statistically significant association between postoperative complications and long-term outcome. Patients who underwent temporal lobe resection achieved better seizure outcomes than those who underwent other types of procedures. Astatic seizures and bilateral surgery were associated with a worse Engel class outcome. SIGNIFICANCE: Our study demonstrates that the beneficial effects of epilepsy surgery are sustained over decades, and that these beneficial effects are correlated with an improved quality of life. The confirmation of its durability makes us optimistic that the outcomes from modern epilepsy surgery will be even better and that our present enthusiasm for this treatment modality is not misplaced.

Levetiracetam has an activity-dependent effect on inhibitory transmission.

PURPOSE: Previous work has shown that levetiracetam (LEV) binds the vesicular protein SV2A and reduces excitatory neurotransmitter release during trains of high-frequency activity, most likely by accessing its binding site through vesicular endocytosis into excitatory synaptic terminals. Because there are differences in excitatory and inhibitory transmitter release mechanisms, and there are suggestions that neurons differ in their SV2A expression, we were curious whether LEV also reduces inhibitory transmission. METHODS: We used patch-clamp recording from CA1 neurons in rat brain slices to quantify the effects of LEV on inhibitory postsynaptic currents (IPSCs). We were able to elicit pure IPSCs by stimulating inhibitory terminals close to neuronal soma and blocking excitatory postsynaptic currents with specific antagonists. KEY FINDINGS: We found that LEV reduces inhibitory currents in a frequency-dependent manner, with the largest relative effect on the later IPSCs in the highest frequency trains. However, in contrast to excitatory postsynaptic currents (EPSCs), LEV reduced IPSC trains after a briefer, 30 min incubation. When spontaneous activity during incubation was blocked with antagonists of excitatory transmission, LEV no longer reduced IPSCs. If slices were returned to LEV-free artificial cerebrospinal fluid (ACSF) after LEV incubation, but prior to recording, the IPSC reduction failed to appear. However, if synaptic activity was limited by treating with excitatory transmitter antagonists, after the initial LEV exposure, LEV still diminished trains of IPSC. The concentration required to diminish IPSC trains was lower than for EPSCs. SIGNIFICANCE: LEV exerts a qualitatively similar, frequency-dependent effect on both IPSCs and EPSCs. The much shorter latency for IPSC reduction is consistent with the greater levels of spontaneous inhibition in brain slices, supporting the hypothesis that vesicular uptake is necessary for the entry of LEVs into terminals. The vesicular entry of LEV resembles the cell entry pathways for tetanus and botulinum neurotoxins, but is unique for small, neuroactive drugs. Although the reduction of IPSC trains by LEV initially seems counterintuitive for an antiepileptic drug, there are multiple reasons that disruption of γ-aminobutyric acid (GABA) release could ultimately attenuate pathologic discharges.

Optical control of focal epilepsy in vivo with caged γ-aminobutyric acid.

OBJECTIVE: There is enormous clinical potential in exploiting the spatial and temporal resolution of optical techniques to modulate pathophysiological neuronal activity, especially intractable focal epilepsy. We have recently utilized a new ruthenium-based caged compound, ruthenium-bipyridine-triphenylphosphine-γ-aminobutyric acid (RuBi-GABA), which releases GABA when exposed to blue light, to rapidly terminate paroxysmal activity in vitro and in vivo. METHODS: The convulsant 4-aminopyridine was used to induce interictal activity and seizures in rat neocortical slices and anesthetized rats. We examined the effect of blue light, generated by a small, light-emitting diode (LED), on the frequency and duration of ictal activity in the presence and absence of RuBi-GABA. RESULTS: Neither blue light alone, nor low concentrations of RuBi-GABA, affected interictal activity or baseline electrical activity in neocortical slices. However, brief, blue illumination of RuBi-GABA, using our LED, dramatically reduced extracellular spikes and bursts. More impressively, illumination of locally applied RuBi-GABA rapidly terminated in vivo seizures induced by topical application of 4-aminopyridine. The RuBi-GABA effect was blocked by the GABA(A) antagonist picrotoxin, but not duplicated by direct application of GABA. INTERPRETATION: This is the first example of optical control of in vivo epilepsy, proving that there is sufficient cortical light penetration from an LED and diffusion of caged GABA to quickly terminate intense focal seizures. We are aware that many obstacles need to be overcome before this technique can be translated to patients, but at the moment, this represents a feasible method for harnessing optical techniques to fabricate an implantable device for the therapy of neocortical epilepsy.

Chitotriosidase as a biomarker of cerebral adrenoleukodystrophy.

BACKGROUND: Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder characterized by the abnormal beta-oxidation of very long chain fatty acids (VLCFA). In 35-40% of children with ALD, an acute inflammatory process occurs in the central nervous system (CNS) leading to demyelination that is rapidly progressive, debilitating and ultimately fatal. Allogeneic hematopoietic stem cell transplantation (HSCT) can halt disease progression in cerebral ALD (C-ALD) if performed early. In contrast, for advanced patients the risk of morbidity and mortality is increased with transplantation. To date there is no means of quantitating neuroinflammation in C-ALD, nor is there an accepted measure to determine prognosis for more advanced patients. METHODS: As cellular infiltration has been observed in C-ALD, including activation of monocytes and macrophages, we evaluated the activity of chitotriosidase in the plasma and spinal fluid of boys with active C-ALD. Due to genotypic variations in the chitotriosidase gene, these were also evaluated. RESULTS: We document elevations in chitotriosidase activity in the plasma of patients with C-ALD (n = 38; median activity 1,576 ng/mL/hr) vs. controls (n = 16, median 765 ng/mL/hr, p = 0.0004), and in the CSF of C-ALD patients (n = 38; median activity 4,330 ng/mL/hr) vs. controls (n = 16, median 0 ng/mL/hr, p < 0.0001). In addition, activity levels of plasma and CSF chitotriosidase prior to transplant correlated with progression as determined by the Moser/Raymond functional score 1 year following transplantation (p = 0.002 and < 0.0001, respectively). CONCLUSIONS: These findings confirm elevation of chitotriosidase activity in patients with active C-ALD, and suggest that these levels predict prognosis of patients with C-ALD undergoing transplantation.

Focal cooling devices for the surgical treatment of epilepsy.

Focal cooling may provide a safe, nondestructive alternative to resective and disconnective strategies that have been proposed or used to control refractory epilepsy. Observations of the effects of direct application of iced saline on the cortical surface during cortical mapping surgery and induced seizures have led to interest in developing implantable cooling therapy devices for refractory localizable epilepsies. In this article, the authors provide an overview of the historical background, physiology, and animal and human data leading to the development of implantable cooling devices for the treatment of medically refractory epilepsy.

A new mechanism for antiepileptic drug action: vesicular entry may mediate the effects of levetiracetam.

Levetiracetam (LEV) is one of the most commonly prescribed antiepileptic drugs, but its mechanism of action is uncertain. Based on prior information that LEV binds to the vesicular protein synaptic vesicle protein 2A and reduces presynaptic neurotransmitter release, we wanted to more rigorously characterize its effect on transmitter release and explain the requirement for a prolonged incubation period for its full effect to manifest. During whole cell patch recordings from rat hippocampal pyramidal neurons in vitro, we found that LEV decreased synaptic currents in a frequency-dependent manner and reduced the readily releasable pool of vesicles. When we manipulated spontaneous activity and stimulation paradigms, we found that synaptic activity during LEV incubation alters the time at which LEV's effect appears, as well as its magnitude. We believe that synaptic activity and concomitant vesicular release allow LEV to enter recycling vesicles to reach its binding site, synaptic vesicle protein 2A. In support of this hypothesis, a vesicular "load-unload" protocol using hypertonic sucrose in the presence of LEV quickly induced LEV's effect. The effect rapidly disappeared after unloading in the absence of LEV. These findings are compatible with LEV acting at an intravesicular binding site to modulate the release of transmitter and with its most marked effect on rapidly discharging neurons. Our results identify a unique neurobiological explanation for LEV's highly selective antiepileptic effect and suggest that synaptic vesicle proteins might be appropriate targets for the development of other neuroactive drugs.

Outcomes after allogeneic hematopoietic cell transplantation for childhood cerebral adrenoleukodystrophy: the largest single-institution cohort report.

Cerebral adrenoleukodystrophy (cALD) remains a devastating neurodegenerative disease; only allogeneic hematopoietic cell transplantation (HCT) has been shown to provide long-term disease stabilization and survival. Sixty boys undergoing HCT for cALD from 2000 to 2009 were analyzed. The median age at HCT was 8.7 years; conditioning regimens and allograft sources varied. At HCT, 50% demonstrated a Loes radiographic severity score ≥ 10, and 62% showed clinical evidence of neurologic dysfunction. A total of 78% (n = 47) are alive at a median 3.7 years after HCT. The estimate of 5-year survival for boys with Loes score < 10 at HCT was 89%, whereas that for boys with Loes score ≥ 10 was 60% (P = .03). The 5-year survival estimate for boys absent of clinical cerebral disease at HCT was 91%, whereas that for boys with neurologic dysfunction was 66% (P = .08). The cumulative incidence of transplantation-related mortality at day 100 was 8%. Post-transplantation progression of neurologic dysfunction depended significantly on the pre-HCT Loes score and clinical neurologic status. We describe the largest single-institution analysis of survival and neurologic function outcomes after HCT in cALD. These trials were registered at www.clinicaltrials.gov as #NCT00176904, #NCT00668564, and #NCT00383448.

Epilepsy: an anticipatory presentation of pediatric Wegener's granulomatosis.

Wegener's granulomatosis is a necrotizing, granulomatous vasculitis that primarily affects the respiratory tract and kidneys. It is rare in children. Few pediatric and adult case reports described seizures and central nervous system involvement at initial presentation, and none described central nervous system involvement in the absence of respiratory or renal disease. We describe a 17-year-old girl with secondarily generalized seizures and granulomatous lesions in her brain. Although a systemic inflammatory disorder was suspected, she lacked evidence of pulmonary or renal involvement, so her signs were initially labeled as postinfectious encephalitis or variant acute disseminated encephalomyelitis. After 1 year of immunosuppressive therapy, she developed additional signs, leading to histologic confirmation on lung biopsy of Wegener's granulomatosis. This case emphasizes the need for close follow-up to monitor the asynchronous development of diagnostic clues when a systemic vasculitis is suspected but cannot be confirmed.

Optical suppression of experimental seizures in rat brain slices.

PURPOSE: To determine if a small ultraviolet emitting diode (UV LED) could release sufficient gamma-aminobutyric acid (GABA) from a caged precursor to suppress paroxysmal activity in rat brain slices. METHODS: Electrophysiologic recordings were obtained from rat brain slices bathed with caged GABA: 4-[[(2H-benzopyran-2-one-7-amino-4-methoxy)carbonyl]amino]butanoic acid (BC204), at concentrations between 3 and 30 microm. Seizure-like activity was induced by perfusing slices with extracellular medium lacking magnesium and containing 4-aminopyridine (4-AP; 100 microm). A small, high-power UV LED was used to uncage BC204 and determine whether an increase in ambient GABA could alter normal or paroxysmal activity in the slice. RESULTS: UV LED illumination, in the absence of BC204, had no effect on CA1 population spikes or seizure-like activity. The light did induce a small temperature elevation (<0.15 degrees C) over the current intensities and exposure durations used in these experiments. In the presence of BC204, UV light decreased the CA1 population spike and seizure-like activity. The BC204 effect can be best accounted for by release of GABA: The reduction of population spikes and seizure-like activity was blocked by the GABA antagonist picrotoxin, and BC204 illumination produced a membrane polarization that reversed at the expected potential for GABA(A) receptors. DISCUSSION: These experiments establish that illumination of a low concentration of caged GABA with a tiny UV LED can release sufficient GABA to attenuate seizure-like activity in brain slices. Because our seizure model is very severe, it is probable that this technique would have a robust effect in human focal epilepsy.

Levetiracetam has a time- and stimulation-dependent effect on synaptic transmission.

We recently reported that rodent hippocampal slices incubated with levetiracetam for 3h had altered responses to repetitive stimulation and reduced neurotransmitter release. However, our experiments failed to determine the actual time course of diminished transmission in individual slices followed over time. We have now been able to record from the same slices for up to 3h to determine the latency of the levetiracetam effect after the onset of exposure. Within 30 min of levetiracetam exposure, the later field potentials of a burst were reduced. Between 60 and 180 min the relative size of later field potentials remained stable. Similar time-dependent reductions were not seen in control slices or in slices exposed to the inactive levetiracetam isomer UCB L060. These new results establish a clear time dependence of the levetiracetam effect, even in vitro, and are best explained by levetiracetam acting within neurons to alter synaptic vesicle release.

The therapeutic potential of focal cooling for neocortical epilepsy.

The therapy of the focal cortical epilepsies remains unsatisfactory. Close to a third of patients fail to gain adequate control with antiepileptic drugs and a portion of those who do, experience unacceptable side effects. Morever, the favorable response rate after surgical resection, approximately 60%, is not nearly as high as the response rate of complex partial seizures caused by mesial temporal sclerosis. The suppressive effect of cooling on neuronal activity has been recognized for over a century. Therefore, we have begun to explore the possible application of cooling as a therapy for focal cortical seizures. In initial brain slice experiments, we found that cooling to 20 degrees C could rapidly terminate paroxysmal activity. Then we developed an in vivo model of focal seizures using a local injection of the convulsant 4-aminopyridine and found that cooling the injected area to less than 24 degrees C with a thermoelectric Peltier device aborted seizures within a few seconds. Other laboratories have independently confirmed our initial observations. More recent experiments from our laboratory have shown that cooling, per se, is not associated with significant cortical damage, even at surface temperatures as low as 5 degrees C. Advances in the fabrication of extremely thin thermoelectric devices, less than a few hundred microns thick, has raised the possibility of incorporating an implantable cooling unit into a closed loop seizure detection and treatment system.

Leptin inhibits 4-aminopyridine- and pentylenetetrazole-induced seizures and AMPAR-mediated synaptic transmission in rodents.

Leptin is a hormone that reduces excitability in some hypothalamic neurons via leptin receptor activation of the JAK2 and PI3K intracellular signaling pathways. We hypothesized that leptin receptor activation in other neuronal subtypes would have anticonvulsant activity and that intranasal leptin delivery would be an effective route of administration. We tested leptin's anticonvulsant action in 2 rodent seizure models by directly injecting it into the cortex or by administering it intranasally. Focal seizures in rats were induced by neocortical injections of 4-aminopyridine, an inhibitor of voltage-gated K+ channels. These seizures were briefer and less frequent upon coinjection of 4-aminopyridine and leptin. In mice, intranasal administration of leptin produced elevated brain and serum leptin levels and delayed the onset of chemical convulsant pentylenetetrazole-induced generalized convulsive seizures. Leptin also reduced neuronal spiking in an in vitro seizure model. Leptin inhibited alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptor-mediated synaptic transmission in mouse hippocampal slices but failed to inhibit synaptic responses in slices from leptin receptor-deficient db/db mice. JAK2 and PI3K antagonists prevented leptin inhibition of AMPAergic synaptic transmission. We conclude that leptin receptor activation and JAK2/PI3K signaling may be novel targets for anticonvulsant treatments. Intranasal leptin administration may have potential as an acute abortive treatment for convulsive seizures in emergency situations.