Continuous Electroencephalogram (cEEG) Findings and Neurodevelopmental Outcomes in Neonates with Congenital Heart Disease (CHD) at 12-24 Months of Age.

OBJECTIVE: This study aims to assess the role of continuous EEG (cEEG) background patterns and duration of cross-clamp time and cardiopulmonary bypass (CPB) in children with congenital heart disease (CHD) undergoing cardiac surgery and its correlation with abnormal neurodevelopmental outcomes at 12-24 months on Bayley Scales of Infant and Toddler Development (BSID-III). METHODS: This retrospective cohort study included infants with CHD and cEEG monitoring, who underwent surgery by 44 weeks gestational age. RESULTS: 34 patients were included, who were operated at median age - 7 days. Longer duration of cross- camp time was associated with poor language composite scores (LCS) (p value = 0.036). A significant association existed between severity of encephalopathy in 24-hour post-operative period and poor LCS (p value = 0.026). CONCLUSION: Majority of neonates with CHD have below average cognitive, language and motor composite scores on BSID-III. Longer duration of cross-clamp time and severity of encephalopathy during 24-hour post-operative EEG monitoring are associated with poor LCS.

Continuous electroencephalography (cEEG) in infants with congenital heart disease (CHD).

BACKGROUND: Neonates with congenital heart disease (CHD) undergoing cardiopulmonary bypass (CPB) surgery have increased risk of impaired neurodevelopmental outcomes secondary to brain injury. This study aims to characterize pre- and post-operative continuous EEG (cEEG) patterns to detect abnormal cerebral activity in infants with CHD and investigate whether an association exists between the degree of encephalopathy in pre- and post-operative cEEG. METHODS: This retrospective cohort study conducted between 2010 and 2018 at a tertiary hospital in Cleveland, OH included infants with CHD with cEEG monitoring, who underwent CPB surgery within first 6 months of life. RESULTS: Study included 77 patients, of which 61% were males who were operated at median age 6 days. Pre-operatively, 69% and 87% had normal cEEG and sleep-wake cycles, respectively. Post-operatively, 80% had abnormal cEEG. Longer circulatory arrest time and CPB were associated with lack of continuity (p 0.011), excessive discontinuity (p 0.007) and prolonged inter-burst interval (IBI) duration (p value < 0.001). A significant association existed between severity of encephalopathy in immediate and 24-h post-operative period (p value < 0.001). CONCLUSIONS: More than 80% of neonates with CHD have abnormal post-operative EEG. Longer circulatory arrest time and CPB were associated with lack of continuity, excessive discontinuity, and prolonged IBI duration on post-operative EEG. IMPACT: This study shows that majority of neonates with congenital heart disease (CHD) have normal pre-operative EEG with a continuous background and normal sleep-wake cycles. Also, 80% of neonates had abnormal post-operative EEG. Longer duration of arrest time and bypass time was associated with lack of continuity, excessive discontinuity, and prolonged IBI duration during post-operative EEG monitoring. These findings will help clinicians when counseling parents in the intensive care unit, risk stratification, and long-term neurodevelopmental monitoring in these high-risk patients.

Response to lacosamide monotherapy in a patient with medically refractory Jeavons syndrome: a case report and review of the literature.

Jeavons syndrome is a childhood genetic generalized epilepsy characterized by eyelid myoclonia with or without absences, eyelid closure-induced epileptiform discharges and/or seizures and photoparoxysmal response. This syndrome accounts for up to 12.9% of generalized epilepsies, however, it is frequently under-reported. The utility of lacosamide in genetic generalized epilepsy and Jeavons syndrome is unclear. We present a case of a 15-year-old female with medically refractory Jeavons syndrome with seizure resolution in response to lacosamide monotherapy at standard daily doses. She had failed treatment with adequate trials of ethosuximide, valproic acid, lamotrigine, topiramate and the ketogenic diet, either as monotherapy or in combination. The frequency of seizures was confirmed in the epilepsy monitoring unit. She was treated with a loading dose of 200 mg of intravenous lacosamide and started at a maintenance dose of 100 mg, twice daily. The EEG showed a dramatic response with resolution of seizures and dramatic improvement in interictal discharges. She remained seizure-free for 11 months on lacosamide monotherapy after which seizures recurred in the setting of medication non-compliance. This highlights the potential role of lacosamide as an option in this syndrome if other drugs are ineffective or not tolerated.

Frequency-dependent effects of contralateral repetitive transcranial magnetic stimulation on penicillin-induced seizures.

Transcranial magnetic stimulation (TMS) has been shown to modulate multiple brain functions, warranting further exploration in clinical applications. TMS treatment for epilepsy is particularly promising because of its anti-convulsive capabilities. However, TMS has been found to both inhibit and facilitate various experimental and clinical seizures, depending on the TMS parameters used. Repetitive TMS (rTMS) pulse frequency is recognized as one of the most influential parameters and thus was investigated in this study at 1, 5 and 10 Hz for its effects on a rat model of penicillin-induced seizures. High-dose penicillin-induced seizures were characterized by a combination of myoclonic and tonic-clonic (GTC) seizures. rTMS effects were analyzed with intracranial electroencephalographic (iEEG) data and video-captured behaviors. Animals treated with 1 and 5 Hz consistently showed evidence of anti-convulsive properties in their iEEG-based seizure profiles when compared to sham rTMS treatment. In contrast, data from 10 Hz rTMS suggested facilitative characteristics. Our results showed that 5 Hz rTMS consistently outperformed 1 Hz rTMS in seizure suppression. This re-emphasizes the importance in accurately characterizing TMS effects on seizure suppression due to the heterogeneous nature of seizures. Thus, finely tuned TMS treatment has great potential to become a powerful asset in combating epilepsy.

Multimodal investigations of trans-endothelial cell trafficking under condition of disrupted blood-brain barrier integrity.

BACKGROUND: Stem cells or immune cells targeting the central nervous system (CNS) bear significant promises for patients affected by CNS disorders. Brain or spinal cord delivery of therapeutic cells is limited by the blood-brain barrier (BBB) which remains one of the recognized rate-limiting steps. Osmotic BBB disruption (BBBD) has been shown to improve small molecule chemotherapy for brain tumors, but successful delivery of cells in conjunction with BBBD has never been reported.We have used a clinically relevant model (pig) of BBBD to attempt brain delivery of TALL-104, a human leukemic T cell line. TALL-104 cells are potent tumor killers and have demonstrated potential for systemic tumor therapy. The pig model used is analogous to the clinical BBBD procedure. Cells were injected in the carotid artery after labeling with the MRI T1 contrast agent GdHPDO3A. Contrast CT scans were used to quantify BBBD and MRI was used to detect Gd++-loaded cells in the brain. Transcranial Doppler was used to monitor cerebral blood flow. EEG recordings were used to detect seizures. Immunocytochemical detection (Cresyl Violet, anti-human CD8 for TALL-104, Evans Blue for BBB damage, GFAP and NEUN) was performed. RESULTS: At the concentration used TALL-104 cells were tolerated. Incomplete BBBD did not allow cell entry into the brain. MRI scans at 24 and 48 hours post-injection allowed visualization of topographically segregated cells in the hemisphere that underwent successful BBBD. Perivascular location of TALL-104 was confirmed in the BBBD hemisphere by Cresyl violet and CD8 immunocytochemistry. No significant alteration in CBF or EEG activity was recorded during cell injections. CONCLUSIONS: Our data show that targeted CNS cell therapy requires blood-brain barrier disruption. MRI-detectable cytotoxic anti-neoplastic cells can be forced to transverse the BBB and accumulate in the perivascular space. The virtual absence of toxicity, the high anti-tumor activity of TALL-104, and the clinical feasibility of human osmotic BBBD suggest that this approach may be adopted to treat brain or spinal cord tumors. In addition, BBBD may favor CNS entry of other cells that normally lack CNS tropism.

Seizure-promoting effect of blood-brain barrier disruption.

PURPOSE: It is generally accepted that blood-brain barrier (BBB) failure occurs as a result of CNS diseases, including epilepsy. However, evidences also suggest that BBB failure may be an etiological factor contributing to the development of seizures. METHODS: We monitored the onset of seizures in patients undergoing osmotic disruption of BBB (BBBD) followed by intraarterial chemotherapy (IAC) to treat primary brain lymphomas. Procedures were performed under barbiturate anesthesia. The effect of osmotic BBBD was also evaluated in naive pigs. RESULTS: Focal motor seizures occurred immediately after BBBD in 25% of procedures and originated contralateral to the hemisphere of BBBD. No seizures were observed when BBB was not breached and only IAC was administered. The only predictors of seizures were positive indices of BBBD, namely elevation of serum S100beta levels and computed tomography (CT) scans. In a porcine model of BBBD, identical procedures generated an identical result, and sudden behavioral and electrographic (EEG) seizures correlated with successful BBB disruption. The contribution of tumor or chemotherapy to acute seizures was therefore excluded. CONCLUSION: This is the first study to correlate extent of acute BBB openings and development of seizures in humans and in a large animal model of BBB opening. Acute vascular failure is sufficient to cause seizures in the absence of CNS pathologies or chemotherapy.

Sonic hedgehog-induced neural precursor proliferation after adult rodent spinal cord injury.

OBJECT: The glycoprotein molecule sonic hedgehog (Shh) has been shown to play a critical role in neuraxial development. To assess its role in the repair of demyelination following spinal cord injury (SCI), escalating doses of Shh were injected into demyelinated lesions in adult rat spinal cords. METHODS: Twenty-seven adult rats underwent thoracic laminectomy and chemical demyelination of the spinal cord dorsal columns without neurological deficit A subset of 20 rats was treated after 3 days by direct injection of Shh at two different doses. Rats were killed at 7 or 21 days after SCI, and tissue samples underwent immediate fixation or were placed into cell culture. Diffuse cellular proliferative responses throughout the gray and white matter were observed in up to 70% of Shh-treated rats. Proliferation around the central canal, believed to be derived from the ventricular ependyma consistent with neuronal stem cell induction, was demonstrated in up to 60% of the treated rats. No significant proliferation in these areas was detected in control rats. Dorsal areas of nestin-positive cells were also observed in 70% of rats treated with high doses of Shh, and these observations were reproduced in cell culture as well as in cultures of dorsal spinal cord explants. Cell counts revealed significant increases in the percentage of oligodendrocyte precursors and neurons in treated compared with control rats. CONCLUSIONS: Exogenous Shh administration promotes nestin-positive cell proliferation after SCI in adult rodents. These cells are believed to be derived from neural precursor cells. The populations of oligodendrocyte precursors and neurons were likewise increased in Shh-treated rats, suggesting that these cells may be derived from neural stem cells.