Yuguang Guan

Surgical Treatment of Patients with Rasmussen Encephalitis

Background: Rasmussen encephalitis (RE) is a rare progressive encephalitis that results in intractable seizures, cognitive decline and hemiparesis. Surgery seems to be the only effective way to control seizures in RE patients. Objective: To describe the clinical, electrophysiological, neuroradiological and histological findings of our patients with RE and to evaluate the outcome of their surgical treatment. Methods: A total of 20 patients were identified by the criteria of RE. Surgery was conducted in the left hemisphere in 6 patients and in the right hemisphere in 14. The surgical methods included anatomical hemispherectomy, functional hemispherectomy, hemispherotomy, lesion resection, multilobar resection, selective resection and bipolar electrocoagulation of functional cortexes. Results: The mean follow-up period was 5.45 years (range 3-8). After surgery, 16 patients (80%) were evaluated as being Engel class I. All of the patients had increases in cognitive abilities after surgery except 1 patient with bilateral RE. After surgery, most patients could walk independently, but the fine movement of the hands was lost. Postoperative hydrocephalus was observed in 1 patient after functional hemispherectomy, and there was no death in this series. Conclusion: Hemispherectomy and hemispherotomy were both confirmed as beneficial procedures in controlling seizures and improving quality of the life in RE cases.

Upregulation of adenosine kinase in Rasmussen encephalitis.

Abstract Rasmussen encephalitis (RE) is a rare neurologic disorder of childhood characterized by unihemispheric inflammation, progressive neurologic deficits, and intractable focal epilepsy. The pathogenesis of RE is still enigmatic. Adenosine is a key endogenous signaling molecule with anticonvulsive and anti-inflammatory effects, and our previous work demonstrated that dysfunction of the adenosine kinase (ADK)–adenosine system and astrogliosis are the hallmarks of epilepsy. We hypothesized that the epileptogenic mechanisms underlying RE are related to changes in ADK expression and that those changes might be associated with the development of epilepsy in RE patients. Immunohistochemistry was used to examine the expression of ADK and glial fibrillary acidic protein in surgically resected human epileptic cortical specimens from RE patients (n = 12) and compared with control cortical tissues (n = 6). Adenosine kinase expression using Western blot and enzymatic activity for ADK were assessed in RE versus control samples. Focal astrogliosis and marked expression of ADK were observed in the lesions of RE. Significantly greater ADK expression in RE versus controls was demonstrated by Western blot, and greater enzymatic activity for ADK was demonstrated using an enzyme-coupled bioluminescent assay. These results suggest that upregulation of ADK is a common pathologic hallmark of RE and that ADK might be a target in the treatment of epilepsy associated with RE.

Timing and type of hemispherectomy for Rasmussen’s encephalitis: Analysis of 45 patients

OBJECTIVE To describe the surgery outcomes of RE patients in one centerto identify the indication for surgical treatment that results in the most favorable outcome. METHOD Forty-five RE patients from a single center were retrospectively reviewed. Preoperative evaluations included assessments of clinical manifestations, cognitive status, a physical examination, MRI, positron emission tomography (PET), electroencephalography (EEG), and magnetoencephalography (MEG). The surgical outcomes included seizure outcome, neurological function, EEG, a cognitive evaluation, and antiepileptic drug withdrawal. RESULTS A total of 45 children (29 male) with RE were included in this study. The mean follow-up period from the first operation was 31.7months (range 6-96). The patients who underwent anatomical hemispherectomy or hemisphere disconnection had better seizure outcomes without greater perioperative complications compared with the patients who underwent functional hemispherectomy. Reoperative hemispherectomy was a safe and effective treatment for patients with postoperative epilepsy recurrence. After the last surgery, 34 patients (74.4%) were evaluated as Engel class I. Most of the patients had favorable neurological outcomes. Analysis revealed that the patientswith IQs greater 70 who underwent operations were more likely to suffer from IQ declines but were also more likely to have higher IQs in the future. SIGNIFICANCE Compared with functional hemispherectomy and hemisphere disconnection, anatomical hemispherectomy elicited better seizure outcomes with an acceptable level of complications. Early stage operations might lead to better cognitive status, but they are associated with a high risk of IQ decline.

Bilateral Rasmussen encephalitis.

Rasmussen encephalitis (RE) is a rare, chronic, inflammatory neurological disorder that usually affects one hemisphere of the brain. RE is characterized by frequent and severe seizures, progressive neurological dysfunction, and unilateral brain atrophy. This article documents a case of RE with bilateral involvement occurring at the age of 2. The patients seizures consisted of focal motor seizures (epilepsia partialis continua in the fingers on the right hand); tonic convulsions of the right arm and head turning to the right with impairment of consciousness; and secondarily generalized tonic-clonic seizures. Antiepileptic drugs did not effectively control the seizures. The pathology of the left frontoparietal lobe biopsy of the abnormal MRI signal showed typical neuronal loss, abundant lymphocytic infiltration into the perivascular space, and numerous microglial nodules. Bipolar electrocoagulation on functional cortexes, which failed to alter the course of the illness, was followed by high-dose prednisone (about 2 weeks worth), without improvement. Both functional hemispherectomies and anatomical hemispherectomies failed to halt the course of the illness, and contralateral seizures developed and became apparent after the operation, suggesting bilateral RE.

Preoperative Heart Rate Variability as Predictors of Vagus Nerve Stimulation Outcome in Patients with Drug-resistant Epilepsy

Vagus nerve stimulation (VNS) is an adjunctive treatment for drug-resistant epilepsy (DRE). However, it is still difficult to predict which patients will respond to VNS treatment and to what extent. We aim to explore the relationship between preoperative heart rate variability (HRV) and VNS outcome. 50 healthy control subjects and 63 DRE patients who had received VNS implants and had at least one year of follow up were included. The preoperative HRV were analyzed by traditional linear methods and heart rhythm complexity analyses with multiscale entropy (MSE). DRE patients had significantly lower complexity indices (CI) as well as traditional linear HRV measurements than healthy controls. We also found that non-responders0 had significantly lower preoperative CI including Area 1–5, Area 6–15 and Area 6–20 than those in the responders0 while those of the non-responders50 had significantly lower RMSSD, pNN50, VLF, LF, HF, TP and LF/HF than the responders50. In receiver operating characteristic (ROC) curve analysis, Area 6–20 and RMSSD had the greatest discriminatory power for the responders0 and non-responders0, responders50 and non-responders50, respectively. Our results suggest that preoperative assessment of HRV by linear and MSE analysis can help in predicting VNS outcomes in patients with DRE.

Upregulation of Neuronal Adenosine A1 Receptor in Human Rasmussen Encephalitis.

Rasmussen encephalitis (RE) is a rare neurological disorder characterized by unilateral inflammation of cerebral cortex and other structures, most notably the hippocampus, progressive cognitive deterioration, and pharmacoresistant focal epilepsy. The pathogenesis of RE with unilateral cortical atrophy and focal seizures is still enigmatic. Activation of adenosine A1 receptors (A1R) has been proven to prevent the spatial spread of seizures. We hypothesized that the epileptogenic mechanisms underlying RE are related to changes in neuronal A1R expression. Immunnohistochemistry was used to examine the expression of A1R and adenosine kinase (ADK) in cortical specimens from RE (n = 12), and compared with control cortical tissue. The quantification of A1R and ADK expression was evaluated by Western blot. A1R was predominantly localized in perinuclear of neurons and not in astrocytes or microglia. Upregulation of neuronal A1R was observed in the lesions of RE. Reactive astrocytes and subpopulation of remaining neurons demonstrated over-expression of the ADK within the lesions of RE. Significant increase of A1R and ADK expression in RE compared with controls was confirmed by Western blot. These results suggest that over-expression of ADK is a common pathologic hallmark of RE, and that upregulation of neuronal A1R in RE is crucial in preventing the spread of seizures.

Altered expression of neuropeptide Y receptors caused by focal cortical dysplasia in human intractable epilepsy

Focal cortical dysplasia (FCD) is a common cause of pharmacologically-intractable epilepsy, however, the precise mechanisms underlying the epileptogenicity of FCD remains to be determined. Neuropeptide Y (NPY), an endogenous anticonvulsant in the central nervous system, plays an important role in the regulation of neuronal excitability. Increased expression of NPY and its receptors has been identified in the hippocampus of patients with mesial temporal lobe epilepsy, presumed to act as an endogenous anticonvulsant mechanism. Therefore, we investigated whether expression changes in NPY receptors occurs in patients with FCD. We specifically investigated the expression of seizure-related NPY receptor subtypes Y1, Y2, and Y5 in patients with FCD versus autopsy controls. We found that Y1R and Y2R were up-regulated at the mRNA and protein levels in the temporal and frontal lobes in FCD lesions. By contrast, there was no significant change in either receptor detected in parietal lesions. Notably, overexpression of Y5R was consistently observed in all FCD lesions. Our results demonstrate the altered expression of Y1R, Y2R and Y5R occurs in FCD lesions within the temporal, frontal and parietal lobe. Abnormal NPY receptor subtype expression may be associated with the onset and progression of epileptic activity and may act as a therapeutic candidate for the treatment of refractory epilepsy caused by FCD.

Impairment of heart rhythm complexity in patients with drug-resistant epilepsy: An assessment with multiscale entropy analysis

OBJECTIVE Epilepsy and seizures can have dramatic effects on the cardiac function. The aim of this study was to investigate the heart rhythm complexity in patients with drug-resistant epilepsy (DRE). METHODS Ambulatory 24-h electrocardiograms (ECG) from 70 DRE patients and 50 healthy control subjects were analyzed using conventional heart rate variability (HRV) and multiscale entropy (MSE) methods The variation of complexity indices (CI), which was calculated from MSE profile, was determined. RESULTS DRE patients had significantly lower time domain (Mean RR, SDNN, RMSSD, pNN50) and frequency domain (VLF, LF, HF, TP) HRV measurements than healthy controls. Of the MSE analysis, MSE profile, CI including Slope 5, Area 1-5, Area 6-15 and Area 6-20 were significantly lower than those in the healthy control group. In receiver operating characteristic (ROC) curve analysis, VLF had the greatest discriminatory power for the two groups. In both net reclassification improvement (NRI) model and integrated discrimination improvement (IDI) models, CI derived from MSE profiles significantly improved the discriminatory power of Mean RR, SDNN, RMSSD, pNN50, VLF, LF, HF and TP. SIGNIFICANCE The heart rate complexity is impaired for DRE patients. CI are useful to discriminate DRE patients from subjects with normal cardiac complexity. These findings indicate that MSE method may serve as a complementary approach for characterizing and understanding abnormal heart rate dynamics in epilepsy. Furthermore, the CI may potentially be used as a biomarker in monitoring epilepsy.

Analysis of Altered Micro RNA Expression Profiles in Focal Cortical Dysplasia IIB.

Focal cortical dysplasia type IIB is a commonly encountered subtype of developmental malformation of the cerebral cortex and is often associated with pharmacoresistant epilepsy. In this study, to investigate the molecular etiology of focal cortical dysplasia type IIB, the authors performed micro ribonucleic acid (RNA) microarray on surgical specimens from 5 children (2 female and 3 male, mean age was 73.4 months, range 50-112 months) diagnosed of focal cortical dysplasia type IIB and matched normal tissue adjacent to the lesion. In all, 24 micro RNAs were differentially expressed in focal cortical dysplasia type IIB, and the microarray results were validated using quantitative real-time polymerase chain reaction (PCR). Then the putative target genes of the differentially expressed micro RNAs were identified by bioinformatics analysis. Moreover, biological significance of the target genes was evaluated by investigating the pathways in which the genes were enriched, and the Hippo signaling pathway was proposed to be highly related with the pathogenesis of focal cortical dysplasia type IIB.

Treatment of epilepsy with bipolar electro-coagulation: an analysis of cortical blood flow and histological change in temporal lobe.

Background: Bipolar electro-coagulation has a reported efficacy in treating epilepsy involving functional cortex by pure electro-coagulation or combination with resection. However, the mechanisms of bipolar electro-coagulation are not completely known. We studied the acute cortical blood flow and histological changes after bipolar electro-coagulation in 24 patients with intractable temporal lobe epilepsy. Methods: Twenty-four patients were consecutively enrolled, and divided into three groups according to the date of admission. The regional cortical blood flow (rCBF), electrocorticography, the depth of cortex damage, and acute histological changes (H and E staining, neuronal staining and neurofilament (NF) staining) were analyzed before and after the operation. The t-test analysis was used to compare the rCBF before and after the operation. Results: The rCBF after coagulation was significantly reduced (P < 0.05). The spikes were significantly reduced after electro-coagulation. For the temporal cortex, the depth of cortical damage with output power of 2–9 W after electro-coagulation was 0.34 ± 0.03, 0.48 ± 0.06, 0.69 ± 0.06, 0.84 ± 0.09, 0.98 ± 0.08, 1.10 ± 0.11, 1.11 ± 0.09, and 1.22 ± 0.11 mm, respectively. Coagulation with output power of 4–5 W completely damaged the neurons and NF protein in the molecular layer, external granular layer, and external pyramidal layer. Conclusions: The electro-coagulation not only destroyed the neurons and NF protein, but also reduced the rCBF. We concluded that the injuries caused by electro-coagulation would prevent horizontal synchronization and spread of epileptic discharges, and partially destroy the epileptic focus.