Involvement of Denervated Midbrain-Derived Factors in the Formation of Ectopic Cortico-Mesencephalic Projection after Hemispherectomy.

Neuronal remodeling after brain injury is essential for functional recovery. After unilateral cortical lesion, axons from the intact cortex ectopically project to the denervated midbrain, but the molecular mechanisms remain largely unknown. To address this issue, we examined gene expression profiles in denervated and intact mouse midbrains after hemispherectomy at early developmental stages using mice of either sex, when ectopic contralateral projection occurs robustly. The analysis showed that various axon growth-related genes were upregulated in the denervated midbrain, and most of these genes are reportedly expressed by glial cells. To identify the underlying molecules, the receptors for candidate upregulated molecules were knocked out in layer 5 projection neurons in the intact cortex, using the CRISPR/Cas9-mediated method, and axonal projection from the knocked-out cortical neurons was examined after hemispherectomy. We found that the ectopic projection was significantly reduced when integrin subunit ß three or neurotrophic receptor tyrosine kinase 2 (also known as TrkB) was knocked out. Overall, the present study suggests that denervated midbrain-derived glial factors contribute to lesion-induced remodeling of the cortico-mesencephalic projection via these receptors.SIGNIFICANCE STATEMENT After brain injury, compensatory neural circuits are established that contribute to functional recovery. However, little is known about the intrinsic mechanism that underlies the injury-induced remodeling. We found that after unilateral cortical ablation expression of axon-growth promoting factors is elevated in the denervated midbrain and is involved in the formation of ectopic axonal projection from the intact cortex. Evidence further demonstrated that these factors are expressed by astrocytes and microglia, which are activated in the denervated midbrain. Thus, our present study provides a new insight into the mechanism of lesion-induced axonal remodeling and further therapeutic strategies after brain injury.

The coexistence of psychogenic nonepileptic and epileptic seizures in the same patient is more frequent than expected: Is there any clinical feature for defining these patients?

OBJECTIVES: This study aimed to investigate the prevalence of psychogenic nonepileptic seizures (PNES) and PNES-epilepsy coexistence within all video-electroencephalography (EEG) monitoring unit (VEMU) referrals and to identify semiological and electrophysiological features to differentiate patients with PNES-epilepsy coexistence from PNES-only. METHODS: We retrospectively reviewed medical files, VEMU reports, and videos of 1983 adult patients. Demographical, historical, clinical, neuroimaging, and electrophysiological parameters of all patients were recorded. We classified patients into five groups as definite PNES-only, definite PNES-epilepsy coexistence, definite PNES-probable epilepsy coexistence, probable PNES-definite epilepsy coexistence, and probable PNES-only. We defined a "definite" group when we saw the ictal EEG and/or video recording of the seizure. The "probable" term is used when there is strong evidence from the history of a particular seizure type and suggestive interictal EEGs without video recordings. RESULTS: Two hundred and three of 1983 patients (10.23%) had PNES. Sixty-six of patients with PNES (32.51%) had definite PNES-epilepsy coexistence. When probable cases were included, the PNES-epilepsy coexistence ratio was 53.69% within all patients with PNES. The prevalence of PNES-epilepsy coexistence was 3.32% within all our VEMU referrals. Lower high school graduation rate, earlier age of disease onset, history of status epilepticus, febrile convulsion and brain surgery, use of three or more antiepileptic drugs, and abnormal magnetic resonance imaging (MRI) findings supported PNES-epilepsy coexistence (p < 0.05). On the contrary, seizure duration longer than 10 min was in favor of PNES-only (p < 0.05). CONCLUSIONS: The prevalence of PNES-epilepsy coexistence might be more frequent in VEMUs than expected. Some demographic and semiological features and electrophysiological findings might be useful in differentiating patients with PNES-epilepsy coexistence from patients with PNES-only.

Hemispherectomy in adults and adolescents: Seizure and functional outcomes in 47 patients.

OBJECTIVE: To examine longitudinal seizure and functional outcomes after hemispherectomy in adults and adolescents. METHODS: We reviewed 47 consecutive patients older than 16 years who underwent hemispherectomy between 1996 and 2016 at our center. Clinical, electroencephalographic (EEG), imaging, neuropsychological, surgical, and functional status data were analyzed. RESULTS: Thirty-six patients were 18 years or older at surgery; 11 were aged between 16 and 18 years. Brain injury leading to hemispheric epilepsy occurred before 10 years of age in 41 (87%) patients. At a mean follow-up of 5.3 postoperative years (median = 2.9 years), 36 (77%) had Engel class I outcome. Longitudinal outcome analysis showed 84% seizure freedom (Engel IA) at 6 months, 76% at 2 years, and 76% at 5 years and beyond, with stable longitudinal outcomes up to 12 years from surgery. Multivariate analysis demonstrated that acute postoperative seizures and contralateral interictal spikes at 6-month follow-up EEG were associated with seizure recurrence. Patients who could walk unaided preoperatively and had no cerebral peduncle atrophy on brain magnetic resonance imaging were more likely to experience worsening of motor function postoperatively. Otherwise, postoperative ambulatory status and hand function were unchanged. Of the 19 patients who completed neuropsychological testing, 17 demonstrated stable or improved postoperative outcomes. SIGNIFICANCE: Hemispherectomy in adults is a safe and effective procedure, with seizure freedom rates and functional outcome similar to those observed in children.

Differences in pediatric and adult epilepsy surgery: A comparison at one center from 1990 to 2014.

OBJECTIVE: Surgical volumes at large epilepsy centers are decreasing. Pediatric cohorts, however, show a trend toward more resections and superior outcome. Differences in pediatric and adult epilepsy surgery were investigated in our cohort. METHODS: The Bethel database between 1990 and 2014 was retrospectively analyzed. RESULTS: A total of 1916 adults and 1300 children underwent presurgical workup. The most common etiologies were medial temporal sclerosis (35.4%) in adults, and focal cortical dysplasias (21.1%) and diffuse hemispheric pathologies (14.7%) in children. Only 1.4% of the total cohort had normal histopathology. A total of 1357 adults (70.8%) and 751 children (57.8%) underwent resections. Surgery types for children were more diverse and showed a higher proportion of extratemporal resections (32.8%) and functional hemispherectomies (20.8%). Presurgical evaluations increased in both groups; surgical numbers remained stable for children, but decreased in the adult group from 2007 on. The patients' decision against surgery in the adult nonoperated cohort increased over time (total = 44.9%, 27.4% in 1995-1998 up to 53.2% in 2011-2014; for comparison, in children, total = 22.1%, stable over time). Postsurgical follow-up data were available for 1305 adults (96.2%) and 690 children (91.9%) 24 months after surgery. The seizure freedom rate was significantly higher in children than in adults (57.8% vs 47.5%, P < 0.001) and significantly improved over time (P = 0.016). SIGNIFICANCE: Pediatric epilepsy surgery has stable surgical volumes and renders more patients seizure-free than epilepsy surgery in adults. A relative decrease in hippocampal sclerosis, the traditional substrate of epilepsy surgery, changes the focus of epilepsy surgery toward other pathologies.

Long term neurocognitive improvement after "late" right hemispherectomy: case report and review of the literature.

OBJECTIVE: To study the long-term neurocognitive changes of a right-handed girl with intractable epilepsy after late right hemispherectomy and compare them with data in the literature. METHOD: The girl was affected by an epileptic encephalopathy associated with right fronto-temporo-parietal polymicrogyria; she was submitted to right hemispherectomy at the age of 5 and examined with cognitive and neuropsychological tests at the age of 17 years. The girl took advantage of neurocognitive rehabilitation for several years; she is currently seizure-free and off therapy. RESULTS: At the end of the follow-up, the full-scale IQ is stable and within the normal range (p = 88). As the discrepancy between verbal IQ (pp = 120) and performance IQ (pp = 71) is significantly high, the girl was subjected to neurocognitive evaluation with the following results: verbal problem solving, verbal short- and long-term memory, and executive functions are within normal range. The most fragile functional areas are visual and spatial reasoning, verbal working memory, short-term visuospatial memory, visual attention, and processing speed, all > 2 SD. The spatial tests, such as coding, matrix reasoning, picture concepts, and arithmetic reasoning (which are favored by other functions such as associative memory and learning ability), are less severely impaired. CONCLUSIONS: These findings show that good conceptual skills and verbal reasoning can compensate for some deficits in visual-perceptual and visuospatial functions.

Language plasticity after hemispherotomy of the dominant hemisphere in 3 patients: Implication of non-linguistic networks.

The neural networks involved in language recovery following hemispherotomy of the dominant hemisphere after language acquisition in children remain poorly known. Twelve hemispherotomized children (mean age at surgery: 11.3years) with comparable post-operative neuropsychological patterns underwent multi-task language functional MRI. Three of them had recovered from an initial postoperative aphasia i.e., hemispherotomy was performed on the language-dominant hemisphere. Our main results revealed (1) perisylvian activations in all patients after either left or right hemispherotomy; (2) no differences in activations between groups regarding the side of hemispherotomy; (3) additional activations in pre-frontal (3/3) and hippocampal/parahippocampal and occipito-parietal (2/3) areas, when comparing language activation in each of the three subjects with hemispherotomy of the language-dominant hemisphere to the group of 9 non-dominant hemispherotomized patients. These neural networks support the stronger engagement of learning and memory during language recovery in a hemisphere that was not initially actively subserving language.

Hemispherotomy in children with electrical status epilepticus of sleep.

OBJECTIVE Electrical status epilepticus of sleep (ESES) is a rare electrographic pattern associated with global regression, which is often poorly responsive to traditional epilepsy treatments and can have a devastating and permanent neurocognitive outcome. The authors analyzed clinical, electroencephalographic, and neuropsychological outcomes in 9 patients with refractory ESES treated with functional hemispherotomy to illustrate the wide clinical spectrum associated with the disease and explore the role of hemispherotomy in its treatment. METHODS During the period between 2003 and 2015, 80 patients underwent hemispherotomy at the authors' institution. Video electroencephalography (EEG) reports were reviewed for ESES or continuous spikes and waves during sleep (CSWS). Patients with preoperative ESES (> 85% slow-wave sleep occupied by spike waves), a unilateral structural lesion amenable to surgery, and more than 6 months of follow-up data were included in the analysis. Clinical data, EEG recordings, neuropsychological testing, and parental and clinician reports were retrospectively reviewed. RESULTS Nine patients were eligible for study inclusion. Age at seizure onset ranged from birth to 4.2 years (mean 1.9 years), age at ESES diagnosis ranged from 3.5 to 8.8 years (mean 6.0 years), and age at hemispherotomy ranged from 3.7 to 11.5 years (mean 6.8 years). All patients had drug-resistant epilepsy. The duration of epilepsy prior to hemispherotomy ranged from 2.7 to 8.9 years (mean ± SD, 5.0 ± 2.2 years). Engel Class I seizure outcome was observed in all 9 children, with a mean follow-up of 3.0 years (range 0.5-6.1 years). Hemispherotomy terminated ESES in 6 of 6 patients with available postoperative sleep EEG. All children had preoperative neuropsychological impairments. Developmental regression was halted postoperatively, but none of the children returned to their original pre-ESES baseline. Four children demonstrated academic gains, 2 of whom transitioned to mainstream classes. CONCLUSIONS Children with drug-resistant ESES and a unilateral structural lesion should be evaluated for hemispherotomy as they may experience the cessation of seizures, termination of ESES, and improvement in neuropsychological status.

Impact of intraoperative 3-T MRI with diffusion tensor imaging on hemispherectomy.

OBJECTIVE Hemispherectomy can produce remarkable seizure control of medically intractable hemispheric epilepsy in children, but some patients continue to have seizures after surgery. A frequent cause of treatment failure is incomplete surgical disconnection of the abnormal hemisphere. This study explores whether intraoperative 3-T MRI with diffusion tensor imaging (DTI) during hemispherectomy can identify areas of incomplete disconnection and allow complete disconnection during a single surgery. METHODS The charts of 32 patients with epilepsy who underwent hemispherectomy between January 2012 and July 2014 at the Florida Hospital for Children were reviewed. Patients were grouped as having had curative or palliative hemispherectomy. To assess the completeness of disconnection when the surgeon considered the operation completed, intraoperative 3-T MRI-DTI was performed. If incomplete disconnection was identified, additional surgery was performed until MRI-DTI sequences confirmed satisfactory disconnection. Seizure outcome data were collected via medical records at last follow-up. RESULTS Of 32 patients who underwent hemispherectomy, 23 had curative hemispherectomy and 9 had palliative hemispherectomy. In 11 of 32 surgeries, the first intraoperative MRI-DTI sequences suggested incomplete disconnection and additional surgery followed by repeat MRI-DTI was performed. Complete disconnection was accomplished in 30 of 32 patients (93.8%). Two of 32 disconnections (6.3%) were incomplete on postoperative imaging. Cross-sectional results showed that 21 of 23 patients (91.3%) who had curative hemispherectomy remained free of seizures (International League Against Epilepsy Class 1) at a median follow-up of 1.7 years (range 0.4-2.9 years). The longitudinal seizure freedom after curative hemispherectomy was 95.2% (SE 0.05) at 6 months, 90.5% (SE 0.06) at 1 year, and 90.5% (SE 0.05) at 2 years. CONCLUSIONS Intraoperative 3-T MRI-DTI sequences can identify incomplete disconnection during hemispherectomy and allow higher rates of complete disconnection in a single surgery. Higher rates of complete disconnection seem to achieve better seizure-free outcome following modified functional hemispherectomy.

National Trends and In-hospital Complication Rates in More Than 1600 Hemispherectomies From 1988 to 2010: A Nationwide Inpatient Sample Study.

BACKGROUND: Anatomic and functional hemispherectomies are relatively infrequent and technically challenging. The literature is limited by small samples and single institution data. OBJECTIVE: We used the Nationwide Inpatient Sample (NIS) database to report on a large population of hemispherectomy patients and their in-hospital complication rates over a 23-year period. METHODS: Between 1988 and 2010, we identified 304 pediatric hospitalizations in the NIS database where hemispherectomy was performed. Using the NIS weighting scheme, this inferred an estimated 1611 hospitalizations nationwide during this time period. Descriptive statistics were calculated on this inferred sample for patient and hospital characteristics and stratified by the presence of in-hospital complications. The adjusted odds of in-hospital complications and nonroutine discharge were estimated using multivariable models. RESULTS: The mean age of the patients was 5.9 years; 46% were female, and 54% were white. In the inferred series, 909 hospitalizations (56%) encountered at least 1 in-hospital complication; 42% were surgery related, and 25% were related to the hospitalization itself. For every 1-year increase in age, there was a corresponding 8% increase in the odds of a nonroutine discharge, adjusting for other potential confounders (95% confidence interval: 1.01-1.16). The most common in-hospital complication was the need for a blood transfusion (30%), followed by meningitis (10%), hydrocephalus (8%), postoperative hematoma/stroke (8%), and adverse pulmonary event (8%). Thirty-three mortalities (2%) were inferred from this series. CONCLUSION: This is the largest study to date examining hemispherectomy and associated in-hospital complication rates. This study supports early surgery in patients with medically intractable epilepsy and severe hemispheric disease.

Literacy after cerebral hemispherectomy: Can the isolated right hemisphere read?

OBJECTIVES: Cerebral hemispherectomy, a surgical procedure undergone to control intractable seizures, is becoming a standard procedure with more cases identified and treated early in life [33]. While the effect of the dominant hemisphere resection on spoken language has been extensively researched, little is known about reading abilities in individuals after left-sided resection. Left-lateralized phonological abilities are the key components of reading, i.e., grapheme-phoneme conversion skills [1]. These skills are critical for the acquisition of word-specific orthographic knowledge and have been shown to predict reading levels in average readers as well as in readers with mild cognitive disability [26]. Furthermore, impaired phonological processing has been implicated as the cognitive basis in struggling readers. Here, we explored the reading skills in participants who have undergone left cerebral hemispherectomy. METHODS: Seven individuals who have undergone left cerebral hemispherectomy to control intractable seizures associated with perinatal infarct have been recruited for this study. We examined if components of phonological processing that are shown to reliably separate average readers from struggling readers, i.e., phonological awareness, verbal memory, speed of retrieval, and size of vocabulary, show the same relationship to reading levels when they are mediated by the right hemisphere [2]. RESULTS: We found that about 60% of our group developed both word reading and paragraph reading in the average range. Phonological processing measured by both phonological awareness and nonword reading was unexpectedly spared in the majority of participants. Phonological awareness levels strongly correlated with word reading. Verbal memory, a component of phonological processing skills, together with receptive vocabulary size, positively correlated with reading levels similar to those reported in average readers. Receptive vocabulary, a bilateral function, was preserved to a certain degree similar to that of strongly left-lateralized phonological skills [3]. Later seizure onset was associated with better reading levels. CONCLUSIONS: When cerebral hemispherectomy is performed to control seizures associated with very early (in utero) insult, it has been found that the remaining right hemisphere is still able to support reading and phonological processing skills that are normally mediated by the left hemisphere. Our results also suggest the existence of variability in individuals after hemispherectomy, even within groups having the same etiology and similar timing of insult.

Etiology-specific differences in motor function after hemispherectomy.

Prediction of functional motor outcome after hemispherectomy is difficult due to the heterogeneity of motor outcomes observed. We hypothesize that this might be related to differences in plasticity during the onset of the underlying epileptogenic disorder or lesion and try to identify predictors of motor outcome after hemispherectomy. Thirty-five children with different etiologies (developmental, stable acquired or progressive) underwent functional hemispherectomy and motor function assessment before hemispherectomy and 24 months after hemispherectomy. Preoperatively, children with developmental etiologies performed better in terms of distal arm strength and hand function, but not on gross motor function tests. Postoperatively, the three etiology groups performed equally poor in muscle strength and hand function, but gross motor function improved in those with acquired and progressive etiologies. Loss of voluntary hand function and distal arm strength after surgery was associated with etiology, intact insular cortex and intact structural integrity of the ipsilesional corticospinal tract on presurgical MRI scans. In conclusion, postoperative motor function can be predicted more precisely based on etiology and on preoperative MRI. Children with developmental etiology more often lose distal arm strength and hand function and show less improvement in gross motor function, compared to those with acquired pathology.

Hemispherotomy and other disconnective techniques.

The surgical treatment of intractable epilepsy has evolved as new technical innovations have been made. Hemispherotomy techniques have been developed to replace hemispherectomy in order to reduce the complication rates while maintaining good seizure control. Disconnective procedures are based on the interruption of the epileptic network rather than the removal of the epileptogenic zone. They can be applied to hemispheric pathologies, leading to hemispherotomy, but they can also be applied to posterior quadrant epilepsies, or hypothalamic hamartomas. In this paper, the authors review the literature, present an overview of the historical background, and discuss the different techniques along with their outcomes and complications.

Hemispherectomy: a schematic review of the current techniques.

Anatomical hemispherectomy has been used for the treatment of seizures since 1938. However, it was almost abandoned in the 1960s after reports of postoperative fatalities caused by hydrocephalus, hemosiderosis, and trivial head traumas. Despite serious complications, the remarkable improvement of patients encouraged authors to carry out modifications on anatomical hemispherectomy in order to lessen its morbidity while preserving its efficacy. The effort to improve the technique generated several original procedures. This paper reviews current techniques of hemispherectomy and proposes a classification scheme based on their surgical characteristics. Techniques of hemispherectomy were sorted into two major groups: (1) those that remove completely the cortex from the hemisphere and (2) those that associate partial cortical removal and disconnection. Group 1 was subdivided into two subgroups based on the integrity of the ventricular cavity and group 2 was subdivided into three subgroups depending on the amount and location of the corticectomy. Grouping similar techniques may allow a better understanding of the distinctive features of each one and creates the possibility of comparing data from different authors.

The early years of hemispherectomy.

Today, hemispherectomy is a well-established procedure for the treatment of some sorts of catastrophic epilepsies. This, however, has not always been the case. The technique was developed to deal with brain tumors; however, the initial results were not remarkable. Moreover, when its morbidity became evident, it was almost abandoned. Had it not been for a shift in its use, with a huge increase in operations on patients with infantile hemiplegia, this surgery would certainly have disappeared. This paper focuses on the facts that surrounded these early years.

Emerging surgical and radiotherapeutic techniques for treating epilepsy.

PURPOSE OF REVIEW: Recent advances in epilepsy surgery have developed a resurgence of interest in the use of surgical techniques for the treatment of intractable epilepsy. RECENT FINDINGS: More invasive procedures such as hemispherectomy and multiple subpial transection have become more popular. Disconnective techniques such as multiple subpial transection have provided a surgical option for patients whose epileptogenic zone resides in the eloquent cortex. Alternatively, new minimally invasive neurostimulation therapies have been introduced to preserve maximal cerebral tissue. Radiosurgery has been recently utilized in the treatment of epilepsy with preliminary promising results. SUMMARY: In this analysis, the authors will attempt to review the more recent surgical approaches and their indications for the treatment of medically intractable epilepsy. For patients with the epileptogenic zone in the noneloquent cortex, seizure focus resection remains the most reasonable approach to therapy.