Jonathan Jagid

Induction of Eph B3 after spinal cord injury.

Spinal cord injury (SCI) in adult rats initiates a cascade of events producing a nonpermissive environment for axonal regeneration. This nonfavorable environment could be due to the expression of repulsive factors. The Eph receptor protein tyrosine kinases and their respective ligands (ephrins) are families of molecules that play a major role in axonal pathfinding and target recognition during central nervous system (CNS) development. Their mechanism of action is mediated by repellent forces between receptor and ligand. The possible role that these molecules play after CNS trauma is unknown. We hypothesized that an increase in the expression of Eph proteins and/or ephrins may be one of the molecular cues that restrict axonal regeneration after SCI. Rats received a contusive SCI at T10 and in situ hybridization studies 7 days posttrauma demonstrated: (i) a marked up-regulation of Eph B3 mRNA in cells located in the white matter at the lesion epicenter, but not rostral or caudal to the injury site, and (ii) an increase in Eph B3 mRNA in neurons in the ventral horn and intermediate zone of the gray matter, rostral and caudal to the lesion. Immunohistochemical analyses localizing Eph B3 protein were consistent with the mRNA results. Colocalization studies performed in injured animals demonstrated increased Eph B3 expression in white matter astrocytes and motor neurons of the gray matter. These results suggest that Eph B3 may contribute to the unfavorable environment for axonal regeneration after SCI.

Clinical Outcomes Using Modest Intravascular Hypothermia After Acute Cervical Spinal Cord Injury

BACKGROUNDAlthough a number of neuroprotective strategies have been tested after spinal cord injury (SCI), no treatments have been established as a standard of care. OBJECTIVEWe report the clinical outcomes at 1-year median follow-up, using endovascular hypothermia after SCI and a detailed analysis of the complications. METHODSWe performed a retrospective analysis of American Spinal Injury Association and International Medical Society of Paraplegia Impairment Scale (AIS) scores and complications in 14 patients with SCI presenting with a complete cervical SCI (AIS A). All patients were treated with 48 hours of modest (33°C) intravascular hypothermia. The comparison group was composed of 14 age- and injury-matched subjects treated at the same institution. RESULTSSix of the 14 cooled patients (42.8%) were incomplete at final follow-up (50.2 [9.7] weeks). Three patients improved to AIS B, 2 patients improved to AIS C, and 1 patient improved to AIS D. Complications were predominantly respiratory and infectious in nature. However, in the control group, a similar number of complications was observed. Adverse events such as coagulopathy, deep venous thrombosis, and pulmonary embolism were not seen in the patients undergoing hypothermia. CONCLUSIONThis study is the first phase 1 clinical trial on the safety and outcome with the use of endovascular hypothermia in the treatment of acute cervical SCI. In this small cohort of patients with SCI, complication rates were similar to those of normothermic patients with an associated AIS A conversion rate of 42.8%.

Clinical application of modest hypothermia after spinal cord injury.

There is widespread interest in the use of hypothermia in the treatment of CNS injury. While there is considerable experience in the use of cooling for a variety of brain pathologies, limited data exist after spinal cord injury. In the past few years, technological advances in the induction and maintenance of cooling have been achieved and can potentially allow for a more accurate evaluation of this form of treatment. We report a series of 14 patients with an average age of 39.4 years (range, 16-62 years) with acute, complete (AIS A) cervical spinal cord injuries who underwent a protocol using an intravascular cooling catheter to achieve modest (33 degrees C) systemic hypothermia. There was an excellent correlation between intravascular and intrathecal cerebrospinal fluid temperature. The average time between injury and induction of hypothermia was 9.17 +/- 2.24 h (mean +/- SEM); the time to target temperature was 2.72 +/- 0.42 h; the duration of cooling at target temperature was 47.6 +/- 3.1 h; the average total length of time of cooling was 93.6 +/- 4 h. There was a positive correlation between temperature and heart rate. Most documented adverse events were respiratory in nature. We were able to effectively deliver systemic cooling using the cooling catheters with minimal variation in body temperature. The study represents the largest, modern series of hypothermia treatment of acute spinal cord injury with intravascular cooling techniques and provides needed baseline data for outcome studies to include larger multi-center, randomized trials.

Whole-Brain Proton MR Spectroscopic Imaging of Mild-to-Moderate Traumatic Brain Injury and Correlation with Neuropsychological Deficits

Changes in the distribution of the magnetic resonance (MR)-observable brain metabolites N-acetyl aspartate (NAA), total choline (Cho), and total creatine (Cre), following mild-to-moderate closed-head traumatic brain injury (mTBI) were evaluated using volumetric proton MR spectroscopic imaging (MRSI). Studies were carried out during the subacute time period following injury, and associations of metabolite indices with neuropsychological test (NPT) results were evaluated. Twenty-nine subjects with mTBI and Glasgow Coma Scale (GCS) scores of 10-15 were included. Differences in individual metabolite and metabolite ratio distributions relative to those of age-matched control subjects were evaluated, as well as analyses by hemispheric lobes and tissue types. Primary findings included a widespread decrease of NAA and NAA/Cre, and increases of Cho and Cho/NAA, within all lobes of the TBI subject group, and with the largest differences seen in white matter. Examination of the association between all of the metabolite measures and the NPT scores found the strongest negative correlations to occur in the frontal lobe and for Cho/NAA. No significant correlations were found between any of the MRSI or NPT measures and the GCS. These results demonstrate that significant and widespread alterations of brain metabolites occur as a result of mild-to-moderate TBI, and that these measures correlate with measures of cognitive performance.

Detrimental effects of systemic hyperthermia on locomotor function and histopathological outcome after traumatic spinal cord injury in the rat

OBJECTIVEPosttraumatic hyperthermia has been demonstrated to worsen neurological outcome in models of brain injury. The purpose of this study was to examine the effects of systemic hyperthermia on locomotor and morphological outcome measures after traumatic spinal cord injury (SCI) in the rat. METHODSAfter a T10 laminectomy, spinal cord contusions were produced from a height of 12.5 mm onto exposed cords (NYU Impactor; New York University Neurosurgery Laboratory, New York, NY) in adult rats that were divided into three groups. Group 1 (n = 9) underwent whole body hyperthermia (rectal temperature, 39.5°C) 30 minutes postinjury for 4 hours, Group 2 (n = 8) underwent normothermia (rectal temperature, 37°C) 30 minutes postinjury for 4 hours, and Group 3 (n = 10) underwent traumatic SCI with no postinjury thermal treatment. Twice-weekly assessments of locomotor function were made during a 6-week survival period using the Basso-Beattie-Breshnahan locomotor rating scale. Forty-four days after injury, animals were perfused, and their spinal cords serially sectioned. Sections were stained with hematoxylin, eosin, and Luxol fast blue for histopathological analysis. The percentage of tissue damage was quantitatively determined by using computer-aided image analysis. RESULTSThe results showed that 4 hours of postinjury hyperthermia significantly worsened locomotor outcome (final Basso-Beattie-Breshnahan scores were 9.7 ± 0.3 [Group 1] versus 10.8 ± 0.4 [Group 2] versus 11.3 ± 0.3 [Group 3]) and led to an increase in the percentage of tissue damage (32.9 ± 3.2% [Group 1] versus 22.3 ± 2.8% [Group 3]). CONCLUSIONThese data suggest that complications of SCI (e.g., fever, infection) leading to an elevation of systemic temperature may add to the severity of secondary injury associated with traumatic SCI and significantly affect neurological outcome.

Objective monitoring of tremor and bradykinesia during DBS surgery for Parkinson disease

Objective: High-frequency subthalamic nucleus deep brain stimulation (STN-DBS) is an established treatment for patients with advanced Parkinson disease (PD). To date, intraoperative monitoring of parkinsonian symptoms, such as tremor and bradykinesia, is largely based on subjective strategies. We conducted a pilot study to evaluate short-term intraoperative outcomes of unilateral macrostimulation of the STN-DBS in PD patients using a neuromotor symptom registration device (CATSYS 2000 System). Methods: We studied 12 consecutive PD patients who received staged unilateral STN-DBS implants and 10 male control subjects free of neurologic deficits using a simple portable system with two sensors: a tremor pen and a touch recording plate. Results revealed excellent test–retest reliability for postural tremor in control subjects. PD patients were evaluated preoperatively during “off” state and intraoperatively for rest, postural tremor intensity, and frequency of finger tapping. Comparisons between premacrostimulation and postmacrostimulation were made using analysis of variance for repeated measures. Results: Electronic rest tremor registration revealed a mean improvement of ×12.5 in tremor intensity measurements in the stimulated/contralateral side (p = 0.002). An overall ×3.8 improvement was registered on the nonstimulated/ipsilateral side. Significant improvements after STN-DBS were also recorded for postural tremor and frequency of finger tapping. Conclusion: Using a noninvasive, simple, and sensitive electronic recording method of intraoperative motor symptom registration, we were able to supplement short-term clinical observation by objectively quantifying the characteristics of tremor and finger tapping in response to subthalamic nucleus deep brain macrostimulation.

Laser thermal ablation for mesiotemporal epilepsy: Analysis of ablation volumes and trajectories

To identify features of ablations and trajectories that correlate with optimal seizure control and minimize the risk of neurocognitive deficits in patients undergoing laser interstitial thermal therapy (LiTT) for mesiotemporal epilepsy (mTLE).

Laser Interstitial Thermal Therapy for Mesial Temporal Lobe Epilepsy

Approximately one-third of patients with epilepsy do not achieve adequate seizure control through medical management alone. Mesial temporal lobe epilepsy (MTLE) is one of the most common forms of medically refractory epilepsy referred for surgical management. Stereotactic laser amygdalohippocampotomy using magnetic resonance-guided laser interstitial thermal therapy (MRg-LITT) is an important emerging therapy for MTLE. Initial published reports support MRg-LITT as a less invasive surgical option with a shorter hospital stay and fewer neurocognitive side effects compared with craniotomy for anterior temporal lobectomy with amygdalohippocampectomy and selective amygdalohippocampectomy. We provide a historical overview of laser interstitial thermal therapy development and the technological advancements that led to the currently available commercial systems. Current applications of MRg-LITT for MTLE, reported outcomes, and technical issues of the surgical procedure are reviewed. Although initial reports indicate that stereotactic laser amygdalohippocampotomy may be a safe and effective therapy for medically refractory MTLE, further research is required to establish its long-term effectiveness and its cost/benefit profile. ABBREVIATIONS ATLAH, anterior temporal lobectomy with amygdalohippocampectomyLITT, laser interstitial thermal therapyMRg-LITT, magnetic resonance-guided laser interstitial thermal therapyMTLE, mesial temporal lobe epilepsySAH, selective amygdalohippocampectomySLAH, stereotactic laser amygdalohippocampotomy.

Objective tremor registration during DBS surgery for Essential Tremor

Essential Tremor (ET) is characterized by a 4-12-Hz postural and kinetic tremor, most commonly affecting the upper limbs. Deep brain stimulation (DBS) of the thalamus (Vim) has been found to be highly effective in severe/refractory forms of ET. Intra-operative assessment of tremor is performed using clinical methods based on patient and physician perception of tremor intensity. We present for the first time the case of a patient whose tremor was objectively monitored/quantified pre- and intra-operatively using device-based tremor registration to supplement clinical measures. We present the case of a 76-year-old right-handed woman that received unilateral (left-sided) DBS of the ventrointermediate (Vim) nucleus of thalamus (Vim) for medically refractory ET. Tremor was monitored with an accelerometer-based Tremor Pen, which is part of a simple portable device (CATSYS 2000 System, Danish Product Development Ltd., DK, www.catsys.dk). The patient was asked to perform tasks for tremor evaluation before and during thalamic DBS. Tremor quantification revealed a significant improvement (34.7-fold) in the contralateral (right) limb following macro-stimulation. No significant improvement was registered in the ipsilateral (non-operated) side. Simple electronic tremor registration methods during DBS of the Vim nucleus of the thalamus may supplement the existing methodology that is solely based on subjective measures derived from clinical observations.

Laser Interstitial Thermal Therapy: Lighting the Way to a New Treatment Option in Neurosurgery.

ABBREVIATIONS LITT, laser interstitial therapyNd:YAG, neodymium-doped yttrium aluminum.