Insights on cognitive reorganization after hemispherectomy in Rasmussen’s encephalitis. A narrative review

International audienceAbstract Rasmussen’s encephalitis is a rare neurological pathology affecting one cerebral hemisphere, therefore, posing unique challenges. Patients may undergo hemispherectomy, a surgical procedure after which cognitive development occurs in the isolated contralateral hemisphere. This rare situation provides an excellent opportunity to evaluate brain plasticity and cognitive recovery at a hemispheric level. This literature review synthesizes the existing body of research on cognitive recovery following hemispherectomy in Rasmussen patients, considering cognitive domains and modulatory factors that influence cognitive outcomes. While language function has traditionally been the focus of postoperative assessments, there is a growing acknowledgment of the need to broaden the scope of language investigation in interaction with other cognitive domains and to consider cognitive scaffolding in development and recovery. By synthesizing findings reported in the literature, we delineate how language functions may find support from the right hemisphere after left hemispherectomy, but also how, beyond language, global cognitive functioning is affected. We highlight the critical influence of several factors on postoperative cognitive outcomes, including the timing of hemispherectomy and the baseline preoperative cognitive status, pointing to early surgical intervention as predictive of better cognitive outcomes. However, further specific studies are needed to confirm this correlation. This review aims to emphasize a better understanding of mechanisms underlying hemispheric specialization and plasticity in humans, which are particularly important for both clinical and research advancements. This narrative review underscores the need for an integrative approach based on cognitive scaffolding to provide a comprehensive understanding of mechanisms underlying the reorganization in Rasmussen patients after hemispherectomy

The Development of Pragmatic Skills in Children after Hemispherotomy: Contribution from Left and Right Hemispheres

PURPOSE: Hemispherotomy (H) is the standard treatment used to cure hemispheric epileptic syndromes in childhood. The postoperative linguistic profile involves hemispheric specialization processes and developmental cognitive plasticity. This research concerns pragmatic aspects of language as a tool for communication which involves both linguistic and extralinguistic communication in context. Our aim was to analyze whether any correlation exists with age at surgery and side of surgery on pragmatic skills following H. METHOD: Forty children who underwent H (23 females, 16 right H) were evaluated at a mean age of 12.8 years (±2.6) with two receptive tasks (oral comprehension and syntactic judgment), the Children's Communication Checklist (CCC) rating scale, and the Behavioral Rating Inventory of Executive Function (BRIEF) questionnaire in order to evaluate the role of executive functions on pragmatic skills. Children operated on before the age of 18 months were considered the "early" group (5 right H and 9 left H), while those operated on later were called the "late" group (11 right H and 15 left H). KEY FINDINGS: The whole group had significant deficits in all three measures. We demonstrated a statistically significant crossed interaction between the side of H and the age at H with pragmatic language impairments (F(1,36)=17.48; p=.0002) and disorders in executive function (F(1,36)=5.80; p=.021) in left early H and in right late H patients. These findings are consistent with the previous studies of pragmatic language impairments concerning adolescents and adults with right hemisphere damage and emphasize the contribution of structural language in the early stage of verbal communication. SIGNIFICANCE: These results emphasize for the first time that hemispherotomized children have pragmatic language impairments that are independent of receptive language. Our findings are congruent with the recent theory on pragmatic language development in childhood with evidence of a participation of the left hemisphere at the early age followed by right hemispheric specialization and involvement of executive functions, independently of receptive language

Cognitive outcome after left functional hemispherectomy on dominant hemisphere in patients with Rasmussen encephalitis: beyond the myth of aphasia. Patient series

International audienceBACKGROUND Rasmussen encephalitis is a rare chronic neurological pathology frequently treated with functional hemispherectomy (or hemispherotomy). This surgical procedure frees patients of their severe epilepsy associated with the disease but may induce cognitive disorders and notably language alterations after disconnection of the left hemisphere. OBSERVATIONS The authors describe longitudinally 3 cases of female patients with Rasmussen encephalitis who underwent left hemispherotomy in childhood and benefited from a favorable cognitive outcome. In the first patient, the hemispherotomy occurred at a young age, and the recovery of language and cognitive abilities was rapid and efficient. The second patient benefited from the surgery later in childhood. In addition, she presented a reorganization of language and memory functions that seem to have been at the expense of nonverbal ones. The third patient was a teenager during surgery. She benefited from a more partial cognitive recovery with persistent disorders several years after the surgery. LESSONS Recovery of cognitive functions, including language, occurs after left hemispherotomy, even when performed late in childhood. Therefore, the surgery should be considered as early as possible to promote intercognitive reorganization

Cognitive outcome after left functional hemispherectomy on dominant hemisphere in patients with Rasmussen encephalitis: beyond the myth of aphasia. Patient series

International audienceBACKGROUND Rasmussen encephalitis is a rare chronic neurological pathology frequently treated with functional hemispherectomy (or hemispherotomy). This surgical procedure frees patients of their severe epilepsy associated with the disease but may induce cognitive disorders and notably language alterations after disconnection of the left hemisphere. OBSERVATIONS The authors describe longitudinally 3 cases of female patients with Rasmussen encephalitis who underwent left hemispherotomy in childhood and benefited from a favorable cognitive outcome. In the first patient, the hemispherotomy occurred at a young age, and the recovery of language and cognitive abilities was rapid and efficient. The second patient benefited from the surgery later in childhood. In addition, she presented a reorganization of language and memory functions that seem to have been at the expense of nonverbal ones. The third patient was a teenager during surgery. She benefited from a more partial cognitive recovery with persistent disorders several years after the surgery. LESSONS Recovery of cognitive functions, including language, occurs after left hemispherotomy, even when performed late in childhood. Therefore, the surgery should be considered as early as possible to promote intercognitive reorganization

Preservation of frontal white matter tracts in ventricular surgery: favoring an anterior interhemispheric transcallosal approach vs a transcortical transfrontal transventricular approach

Abstract   Secondary to the creation of a surgical corridor and retraction, white matter tracts degenerate, causing long-term scarring with potential neurological consequences. Third and lateral ventricle tumors require surgery that may lead to cognitive impairment. Our objective is to compare the long-term consequences of a transcortical transfrontal approach and an interhemispheric transcallosal approach on corpus callosum and frontal white matter tracts degeneration. Surgical patients with ventricular tumor accessible through both approaches were included and clinico-radiological data were retrospectively analyzed. The primary endpoint was the callosotomy length at 3-month post-operative T1 MRI, corrected by the extension of the tumor and the use of neuronavigation. Secondary outcomes included perioperative criteria such as bleeding, use of retractors and duration, FLAIR hypersignal on 3-month MRI, and re-do surgeries. To assess white matter tract interruption, 3-month FLAIR hypersignal was superposed to a tractography atlas. Seventy patients were included, 57 (81%) in the transfrontal group and 13 (19%) in the interhemispheric group. There was no difference in the mean callosotomy length on 3-month MRI (12.3 mm ± 5.60 transfrontal vs 11.7 mm ± 3.92 interhemispheric, p = 0.79) on univariate and multivariate analyses. The callosotomy length was inferior by − 3.13 mm for tumors located exclusively in the third ventricle (p = 0.016), independent of the approach. Retractors were used more often in transfrontal approaches (60% vs 33%, p < 0.001). The extent of frontal FLAIR hypersignal was higher after transfrontal approach (14.1 mm vs 0.525 mm, p < 0.001), correlated to the use of retractors (p < 0.05). After the interhemispheric approach, no tract other than corpus callosum was interrupted, whereas, after the transfrontal approach, frontal arcuate fibers and projections from the thalamus were interrupted in all patients, the cingulum in 19 (33%), the superior fronto-occipital fasciculus in 15 (26%), and the superior longitudinal fasciculus in 2 (3%). Transfrontal and interhemispheric approaches to the third and lateral ventricles both lead to the same long-term damage to the corpus callosum, but the transfrontal approach interrupts several white matter tracts essential to cognitive tasks such as attention and planning, even in the non-dominant hemisphere. These results encourage all neurosurgeons to be familiar with both approaches and favor the interhemispheric approach when both can give access to the tumor with a comparable risk. Neuropsychological studies are necessary to correlate these anatomical findings to cognitive outcomes

Dissecting the genetic basis of focal cortical dysplasia: a large cohort study

International audienceGenetic malformations of cortical development (MCDs), such as mild MCDs (mMCD), focal cortical dysplasia (FCD), and hemimegalencephaly (HME), are major causes of severe pediatric refractory epilepsies subjected to neurosurgery. FCD2 are characterized by neuropathological hallmarks that include enlarged dysmorphic neurons (DNs) and balloon cells (BCs). Here, we provide a comprehensive assessment of the contribution of germline and somatic variants in a large cohort of surgical MCD cases. We enrolled in a monocentric study 80 children with drug-resistant epilepsy and a postsurgical neuropathological diagnosis of mMCD, FCD1, FCD2, or HME. We performed targeted gene sequencing ( ≥ 2000X read depth) on matched blood-brain samples to search for low-allele frequency variants in mTOR pathway and FCD genes. We were able to elucidate 29% of mMCD/FCD1 patients and 63% of FCD2/HME patients. Somatic loss-of-function variants in the N-glycosylation pathway-associated SLC35A2 gene were found in mMCD/FCD1 cases. Somatic gain-of-function variants in MTOR and its activators (AKT3, PIK3CA, RHEB), as well as germline, somatic and two-hit loss-of-function variants in its repressors (DEPDC5, TSC1, TSC2) were found exclusively in FCD2/HME cases. We show that panel-negative FCD2 cases display strong pS6-immunostaining, stressing that all FCD2 are mTORopathies. Analysis of microdissected cells demonstrated that DNs and BCs carry the pathogenic variants. We further observed a correlation between the density of pathological cells and the variant-detection likelihood. Single-cell microdissection followed by sequencing of enriched pools of DNs unveiled a somatic second-hit loss-of-heterozygosity in a DEPDC5 germline case. In conclusion, this study indicates that mMCD/FCD1 and FCD2/HME are two distinct genetic entities: while all FCD2/HME are mosaic mTORopathies, mMCD/FCD1 are not caused by mTOR-pathway-hyperactivating variants, and ~ 30% of the cases are related to glycosylation defects. We provide a framework for efficient genetic testing in FCD/HME, linking neuropathology to genetic findings and emphasizing the usefulness of molecular evaluation in the pediatric epileptic neurosurgical population

Focal polymicrogyria in children: Contribution of invasive explorations and epileptogenicity mapping in the surgical decision

International audienceObjective: Report of the contribution of invasive EEG (iEEG) and epileptogenicity mappings (EM) in a pediatric cohort of patients with epilepsy associated with focal polymicrogyria (PMG) and candidates for resective surgery.Method: Retrospective pediatric case series of patients presenting focal PMG-related refractory epilepsy undergoing an invasive exploration (iEEG) at Fondation Rothschild Hospital. We reviewed clinical data, structural MRI, and visual analysis of iEEG recordings. Moreover, time-frequency analysis of SEEG signals with a neuroimaging approach (epileptogenicity maps) was used to support visual analysis.Results: Between 2012 and 2019, eight patients were selected. Five patients were explored with stereoelectroencephalography (SEEG) only, one patient with subdural exploration (SDE) only and two patients first underwent SEEG and then SDE. The mean age at seizure onset was 40.3 months (range 3-120), and the mean age for the iEEG 10.8 years (range 7-15). The epileptogenic zone (EZ) appeared concordant to the PMG lesion in only one case, was larger in three cases, smaller in two cases and different in one case. Four cases were selected for tailored resective surgery and one for total callosotomy. Two patients remained seizure-free at their last follow-up (mean 32.6 months, range 7-98). Epileptogenicity mapping (EM) refined the qualitative analysis, showing in four patients an EZ larger than visually defined.Conclusion: This study is the first pediatric study to analyze the value of iEEG and EM as well as operability in focal PMG-related refractory epilepsy. The results illustrate the complexity of this pathology with variable concordance between the EZ and the lesion and mixed response to surgery

Epileptogenic mosaic brain malformations: a single-cell and spatial transcriptomic landscape

Brain somatic mutations in mTOR pathway genes are the primary etiology of focal cortical dysplasia type II (FCDII), a brain malformation characterized by cortical dyslamination and the presence of mTOR-hyperactive dysmorphic neurons and balloon cells. FCDII is a significant cause of drug-resistant epilepsy in children who undergo epilepsy surgery to control seizures. The neurodevelopmental effects of mTOR pathway somatic mutations and the affected cell types remain unclear. We investigated ten surgical FCDII tissues with somatic mTOR-activating mutations using histological, genetic, single-cell, and spatial transcriptomic approaches. Histopathology measures revealed that dysmorphic neurons and balloon cells, although enriched for the mutations, only represent a minor fraction (<10%) of mutated cells in the dysplastic tissues. Transcriptomic analysis of laser-captured pools of dysmorphic neurons showed their immature principal neurons signature, while balloon cells correlated with the astrocytic cell lineage and displayed transcriptomic signatures usually observed in neuroglial progenitor cells. By combining single-nuclei profiling and long-read sequencing, we showed that FCDII somatic mutations affect multiple brain cell lineages, thus suggesting they occurred at early developmental stages. Moreover, we observed that mTOR-activating mutations in different cell types lead to cell-specific transcriptomic alterations. Finally, using spatial transcriptomics, we correlated histological and gene expression alterations, thus allowing unprecedented insights into FCDII pathology. Our results highlight an unforeseen diversity of FCDII cell types affected by mTOR pathway mutations and represent a significant resource for better understanding FCDII-related epilepsy and identifying biomarkers for targeted therapeutics