Childhood Onset Schizophrenia is a rare neuropsychiatric disorder significantly associated with 22q11.2 Deletion Syndrome. We describe a male patient, followed from childhood to adolescence, who exhibited premorbid impairments in language, learning and social abilities, along with comorbid anxiety disorders. Over time, he gradually developed Childhood Onset Schizophrenia, with neuroradiological findings of white matter hyperintensities, a dysmorphic corpus callosum and Hippocampal Malrotation. These findings were observed in the context of a genetic diagnosis of 22q11.2 Deletion Syndrome, despite the absence of the most common congenital malformations and clinical conditions typically associated with this syndrome. A remarkable aspect of this case report is the emphasis on the importance of suspecting 22q11.2 Deletion Syndrome even in cases where only the neuropsychiatric phenotype of Childhood-Onset Schizophrenia and structural brain alterations, is present. While abnormalities of white matter and corpus callosum are associated with schizophrenia in patients with 22q11.2 Deletion Syndrome, Hippocampal Malrotation is more frequently described in patients with epilepsy and prolonged febrile seizures. Recently, only 10 adult patients with 22q11.2 Deletion Syndrome have been reported to have Hippocampal Malrotation, six of whom were affected by schizophrenia, with or without epilepsy. Our case report aims to extend the neuroradiological findings associated with 22q11.2 Deletion Syndrome and Schizophrenia, including Hippocampal Malrotation. This is the first case report in which Hippocampal Malrotation has been described in Childhood Onset Schizophrenia and 22q11.2 Deletion Syndrome. We suggest that patients with Hippocampal Malrotation and Childhood Onset Schizophrenia, should have a chromosomal microarray performed to screen for 22q11.2 Deletion Syndrome.

OBJECTIVE: This study was undertaken to determine whether hippocampal T2 hyperintensity predicts sequelae of febrile status epilepticus, including hippocampal atrophy, sclerosis, and mesial temporal lobe epilepsy.
METHODS: Acute magnetic resonance imaging (MRI) was obtained within a mean of 4.4 (SD = 5.5, median = 2.0) days after febrile status on >200 infants with follow-up MRI at approximately 1, 5, and 10 years. Hippocampal size, morphology, and T2 signal intensity were scored visually by neuroradiologists blinded to clinical details. Hippocampal volumetry provided quantitative measurement. Upon the occurrence of two or more unprovoked seizures, subjects were reassessed for epilepsy. Hippocampal volumes were normalized using total brain volumes.
RESULTS: Fourteen of 22 subjects with acute hippocampal T2 hyperintensity returned for follow-up MRI, and 10 developed definite hippocampal sclerosis, which persisted through the 10-year follow-up. Hippocampi appearing normal initially remained normal on visual inspection. However, in subjects with normal-appearing hippocampi, volumetrics indicated that male, but not female, hippocampi were smaller than controls, but increasing hippocampal asymmetry was not seen following febrile status. Forty-four subjects developed epilepsy; six developed mesial temporal lobe epilepsy and, of the six, two had definite, two had equivocal, and two had no hippocampal sclerosis. Only one subject developed mesial temporal epilepsy without initial hyperintensity, and that subject had hippocampal malrotation. Ten-year cumulative incidence of all types of epilepsy, including mesial temporal epilepsy, was highest in subjects with initial T2 hyperintensity and lowest in those with normal signal and no other brain abnormalities.
CONCLUSIONS: Hippocampal T2 hyperintensity following febrile status epilepticus predicted hippocampal sclerosis and significant likelihood of mesial temporal lobe epilepsy. Normal hippocampal appearance in the acute postictal MRI was followed by maintained normal appearance, symmetric growth, and lower risk of epilepsy. Volumetric measurement detected mildly decreased hippocampal volume in males with febrile status.

A frequent complaint in medical settings is insomnia. Chronic insomnia is defined as the occurrence of sleep disturbance symptoms for a period of three months, three times per week, and in conjunction with at least one daytime symptom. In the case study, a young man with a documented seizure disorder underwent a thorough evaluation for chronic sleeplessness. Electroencephalograms, sleep investigations, and drug reviews were unsuccessful in determining the cause. Nonetheless, it was found that there was bilateral hippocampal malrotation. This link is distinct and hasn\'t been mentioned as a possible cause before.

OBJECTIVE: Elaborate a simple Magnetic Resonance Imaging (MRI)-based score to define Incomplete Hippocampal Inversion (IHI) in children (Phase 1), and evaluate the relation of IHI with (A) epilepsy, (B) seizure localization and (C) therapeutic response in a paediatric population (Phase 2).
METHODS: In Phase 1, incompletely inverted hippocampi were matched to completely inverted hippocampi. Multiple qualitative and quantitative hippocampal and extra-hippocampal features were evaluated in coronal-oblique T1-weighted (T1W) and coronal T2-weighted (T2W) images. Multivariate analysis was performed to elaborate the MRI-based score to define IHI. In Phase 2, epilepsy patients were matched to controls, and the T1W and T2W scores were applied. Multivariate analysis was performed to assess the relation of IHI and epilepsy, seizure localization and therapeutic response.
RESULTS: The hippocampal diameter ratio and parahippocampal angle in the coronal-oblique T1-weighted images, and the hippocampal diameter ratio and collateral sulcus depth in the coronal T2-weighted images predicted IHI in Phase 1. Simple and practical imaging-based scores were developed and are available on the website: https://ihiscore.netlify.app/. The Area Under the Receiver Operating Characteristic Curve of the T1W and T2W scores were, respectively, 0.965 and 0.983. In Phase 2, IHI independently predicted epilepsy (OR = 3.144, 95% CI = 1.981-4.991, p < 0.001), temporal lobe epilepsy (OR = 4.237, 95% CI = 1.586-11.318, p = 0.004), and drug resistant epilepsy (OR = 7.000, 95% CI = 2.800-17.500, p < 0.001).
CONCLUSIONS: The association between IHI and temporal lobe epilepsy (and the lack of association with extra-temporal epilepsy) favours the possibility of a relation between IHI and the pathophysiology of seizures in epileptic patients. Furthermore, IHI is a potential prognostic marker for therapeutic response in epilepsy.

OBJECTIVE: Debates over the relationship between hippocampal malrotation (HIMAL) and epilepsy continue without consensus. This study explores the role of HIMAL in a cohort of epilepsy caused by focal cortical dysplasia (FCD).
METHODS: In this study, 90 patients with epilepsy caused by FCD type I and type II and 48 healthy adults underwent a 3 Tesla MRI following a dedicated epilepsy protocol for the analysis of the prevalence and morphologic features of HIMAL. In addition, numerous clinical characteristics and hippocampal volumes were evaluated.
RESULTS: The cohort included a total of 90 patients (32 were HIMAL, 58 were non-HIMAL). Among these patients, 32 (35.6%) had HIMAL (22 left, four right, and six bilateral), which did not differ from the 48 controls, where 16 (33.3%) had HIMAL (12 left, two right, and two bilateral). Neither the quantitative features of HIMAL (diameter ratio, dominant inferior temporal sulcus height ratio, medial distance ratio, dominant inferior temporal sulcus angle, and parahippocampal angle), nor the accompanying characteristics of HIMAL (vertical dominant inferior temporal sulcus, enlarged temporal horn, and a low position of ipsilateral fornix) showed differences between patients with FCD and controls. No statistical difference in the clinical characteristics between FCD patients with HIMAL and those without was found. Neither the side nor the existence of HIMAL was correlated with the lateralization and location of FCD. As to the hippocampal volume, there was no difference between FCD patients with HIMAL and those without.
CONCLUSIONS: Hippocampal malrotation is a common morphologic variant in healthy controls as well as in patients with epilepsy caused by FCD type I and type II. Hippocampal malrotation could be less significant in epilepsy caused by FCD type I and type II.

Hippocampal malrotation (HIMAL) is an increasingly recognized neuroimaging feature but the clinical correlation and significance in epilepsies remain under debate. It is characterized by rounded hippocampal shape, deep collateral, or occipitotemporal sulcus, and medial localization of the hippocampus. In this review, we describe the embryonic development of the hippocampus and HIMAL, the qualitative and quantitative diagnosis issues, and the pathological findings of HIMAL. HIMAL can be bilateral or unilateral and more on the left side. Furthermore, the relevance of HIMAL diagnosis in clinical practice, including its role in epileptogenesis and the impact on the pre-surgical decision are reviewed. Finally, the relationship between HIMAL and hippocampal sclerosis (HS) and the possible role of genetics in the etiology of HIMAL are discussed. The evidence so far suggested that HIMAL does not have a significant role in epileptogenesis or surgical decision. HIMAL could be a genetic developmental imaging feature that represents a more diffuse but subtle structural error during brain development. Many questions remain to be explored, such as possible cognitive alteration associated with HIMAL and whether HIMAL predisposes to the development of HS. Further studies using high-quality MRI, unified consensus qualitative and quantitative diagnostic criteria, and comprehensive cognitive assessment are recommended.

Juvenile myoclonic epilepsy is the most common genetic generalized epilepsy syndrome, characterized by a complex polygenetic aetiology. Structural and functional MRI studies demonstrated mesial or lateral frontal cortical derangements and impaired fronto-cortico-subcortical connectivity in patients and their unaffected siblings. The presence of hippocampal abnormalities and associated memory deficits is controversial, and functional MRI studies in juvenile myoclonic epilepsy have not tested hippocampal activation. In this observational study, we implemented multi-modal MRI and neuropsychological data to investigate hippocampal structure and function in 37 patients with juvenile myoclonic epilepsy, 16 unaffected siblings and 20 healthy controls, comparable for age, gender, handedness and hemispheric dominance as assessed with language laterality indices. Automated hippocampal volumetry was complemented by validated qualitative and quantitative morphological criteria to detect hippocampal malrotation, assumed to represent a neurodevelopmental marker. Neuropsychological measures of verbal and visuo-spatial learning and an event-related verbal and visual memory functional MRI paradigm addressed mesiotemporal function. We detected a reduction of mean left hippocampal volume in patients and their siblings compared with controls (P < 0.01). Unilateral or bilateral hippocampal malrotation was identified in 51% of patients and 50% of siblings, against 15% of controls (P < 0.05). For bilateral hippocampi, quantitative markers of verticalization had significantly larger values in patients and siblings compared with controls (P < 0.05). In the patient subgroup, there was no relationship between structural measures and age at disease onset or degree of seizure control. No overt impairment of verbal and visual memory was identified with neuropsychological tests. Functional mapping highlighted atypical patterns of hippocampal activation, pointing to abnormal recruitment during verbal encoding in patients and their siblings [P < 0.05, familywise error (FWE)-corrected]. Subgroup analyses indicated distinct profiles of hypoactivation along the hippocampal long axis in juvenile myoclonic epilepsy patients with and without malrotation; patients with malrotation also exhibited reduced frontal recruitment for verbal memory, and more pronounced left posterior hippocampal involvement for visual memory. Linear models across the entire study cohort indicated significant associations between morphological markers of hippocampal positioning and hippocampal activation for verbal items (all P < 0.05, FWE-corrected). We demonstrate abnormalities of hippocampal volume, shape and positioning in patients with juvenile myoclonic epilepsy and their siblings, which are associated with reorganization of function and imply an underlying neurodevelopmental mechanism with expression during the prenatal stage. Co-segregation of abnormal hippocampal morphology in patients and their siblings is suggestive of a genetic imaging phenotype, independent of disease activity, and can be construed as a novel endophenotype of juvenile myoclonic epilepsy.

Early-onset epileptic encephalopathies, including West syndrome (WS), are a group of neurological disorders characterized by developmental impairments and intractable seizures from early infancy. We have now identified biallelic CNPY3 variants in three individuals with WS; these include compound-heterozygous missense and frameshift variants in a family with two affected siblings (individuals 1 and 2) and a homozygous splicing variant in a consanguineous family (individual 3). All three individuals showed hippocampal malrotation. In individuals 1 and 2, electroencephalography (EEG) revealed characteristic fast waves and diffuse sharp- and slow-wave complexes. The fast waves were clinically associated with seizures. CNPY3 encodes a co-chaperone in the endoplasmic reticulum and regulates the subcellular distribution and responses of multiple Toll-like receptors. The amount of CNPY3 in lymphoblastoid cells derived from individuals 1 and 2 was severely lower than that in control cells. Cnpy3-knockout mice exhibited spastic or dystonic features under resting conditions and hyperactivity and anxiolytic behavior during the open field test. Also, their resting EEG showed enhanced activity in the fast beta frequency band (20-35 Hz), which could mimic the fast waves in individuals 1 and 2. These data suggest that CNPY3 and Cnpy3 perform essential roles in brain function in addition to known Toll-like receptor-dependent immune responses.

OBJECTIVE Diagnostic criteria for hippocampal malrotation (HIMAL) on brain MRI typically include a rounded hippocampus, vertical collateral sulcus, and architectural blurring. Relationship to epileptogenesis remains speculative, and usefulness for surgical guidance is unknown. The study was performed to determine the prevalence of hippocampal rotational anomalies in a cohort of pediatric patients with intractable epilepsy undergoing evaluation for surgery and to determine the significance of this finding in the context of surgical planning. METHODS Forty-eight surgically treated children with intractable epilepsy were compared with matched healthy subjects; reviewers were blinded to surgical side. Each temporal lobe was evaluated for rounded hippocampus, blurring, vertical collateral sulcus, wide choroidal fissure, enlarged temporal horn, low fornix, hippocampal signal, and findings of hippocampal sclerosis. A mesial temporal lobe (MTL) score was calculated by summing the number of features, and the collateral sulcus angle (CSA) was measured in each temporal lobe. Surgical side, pathological diagnosis, and imaging findings elsewhere in the brain were tabulated. Presence of HIMAL, associated imaging features, and MTL score were compared between sides, between epilepsy and control groups, in relationship to side of surgery, and in relationship to postoperative outcome. RESULTS Only 3 epilepsy patients (6.2%) and no controls exhibited all 3 features of HIMAL (p = 0.12). Eight of 48 (16.7%) epilepsy versus 2 of 48 (4.6%) control subjects had both a rounded hippocampus and vertical collateral sulcus (suggesting HIMAL) (p = 0.045). In control and epilepsy subjects, most findings were more prevalent on the left, and the left CSA was more vertical (p < 0.0001). Epilepsy subjects had higher MTL scores (z = -2.95, p = 0.002) and more acute CSAs (p = 0.04) than controls. Only lateralizing raw MTL score had a significant association with surgical side (p = 0.03, OR 7.33); however, this was not significant when hippocampal sclerosis cases were excluded. HIMAL findings were more prevalent and MTL scores were higher in patients with resections involving the temporal lobes. On group analysis, HIMAL findings did not predict eventual surgical side and did not predict outcome, although the numbers are small. In 4 patients the abnormally rotated hippocampus was resected and showed hippocampal sclerosis and/or dysplastic changes on histopathology. All of these patients had a good outcome after surgery. CONCLUSIONS While increased in prevalence in children with intractable epilepsy, imaging findings of HIMAL did not have preoperative lateralizing utility in this group. Findings of HIMAL (including round hippocampus, architectural blurring, and vertical collateral sulcus) did not predict outcome after surgery, although the small number of patients with these findings limits evaluation. In the small number of patients in which the malrotated hippocampus was removed, outcome was good. Further research is needed to continue to define this association in children with intractable epilepsy, focusing on a temporal lobe cohort.

OBJECTIVE: Hippocampal malrotation is characterized by incomplete hippocampal inversion with a rounded shape and blurred internal architecture. There is still debate about whether hippocampal malrotation has pathologic significance. We present findings from the Consequences of Prolonged Febrile Seizures in Childhood (FEBSTAT) study on the frequency of and risk factors for hippocampal malrotation.
METHODS: FEBSTAT is a prospective multicenter study investigating the consequences of febrile status epilepticus in childhood. MRI studies of 226 patients with febrile status epilepticus were analyzed visually by two board-certified neuroradiologists blinded to clinical details and were compared with MRI studies of 96 subjects with first simple febrile seizure. Quantitative analysis of hippocampal volume was performed by two independent observers.
RESULTS: Hippocampal malrotation was present in 20 of 226 (8.8%) patients with febrile status epilepticus compared with two of 96 (2.1%) control subjects (odds ratio [OR], 4.56; 95% CI, 1.05-19.92). Hippocampal malrotation was exclusively left-sided in 18 of 22 (81.8%) patients and bilateral in the remaining four patients (18.2%). There was no case of exclusively right-sided hippocampal malrotation. Hippocampal malrotation was more common in boys than in girls (OR, 6.1; 95% CI, 1.7-21.5). On quantitative volumetric MRI analysis, the left hippocampal volume was smaller in patients with hippocampal malrotation than in control subjects with simple febrile seizure (p = 0.004), and the right-to-left hippocampal volume ratio was higher in the hippocampal malrotation group than in the simple febrile seizure group (p < 0.001).
CONCLUSIONS: Hippocampal malrotation is a developmental malformation that predominantly affects the left hippocampus in male patients and is more frequently found in children with prolonged febrile status epilepticus than in control subjects. These data provide further evidence that hippocampal malrotation represents a pathologic error in brain development rather than a normal variant.