Five-year symptomatic hemorrhage risk of untreated brainstem cavernous malformations in a prospective cohort.

Hemorrhage of brainstem cavernous malformation (CM) would cause various symptoms and severe disability. The study aimed to elaborate on the 5-year actuarial cumulative hazard of symptomatic hemorrhage. Patients diagnosed in our institute between 2009 and 2013 were prospectively registered. All clinical data were obtained, follow-up was performed, and risk factors were evaluated. Four hundred sixty-eight patients (217 female, 46.4%) were included in the study with a median follow-up duration of 79.0 months. A total of 137 prospective hemorrhages occurred in 107 patients (22.9%) during 1854.0 patient-years. Multivariate Cox analysis found age ≥ 55 years (hazard ratio (HR) 2.166, p = 0.002), DVA (HR 1.576, p = 0.026), superficial-seated location (HR 1.530, p = 0.047), and hemorrhage on admission (HR 2.419, p = 0.026) as independent risk factors for hemorrhage. The 5-year cumulative hazard of hemorrhage was 30.8% for the overall cohort, 47.8% for 60 patients with age ≥ 55 years, 43.7% for 146 patients with DVA, 37.9% for 272 patients with superficial-seated lesions, and 37.2% for 341 patients with hemorrhage on admission. As a stratified analysis, within subcohort of 341 patients with a hemorrhagic presentation, age ≥ 55 years (HR 3.005, p < 0.001), DVA (HR 1.801, p = 0.010), and superficial-seated location (HR 2.276, p = 0.001) remained independently significant. The 5-year cumulative hazard of hemorrhage was 52.0% for 119 patients with both DVA and hemorrhagic presentation. The 5-year cumulative hemorrhagic risk was 30.8% and was higher in subgroups if harboring risk factors that helped to predict potential hemorrhagic candidates and were useful for treatment decision-making.Clinical Trial Registration-URL: http://www.chictr.org.cn Unique identifier: ChiCTR-POC-17011575.

A rare mutant of OFD1 gene responsible for Joubert syndrome with significant phenotype variation.

Joubert syndrome (JBTS), a rare genetic disorder resulted from primary cilium defects or basal-body dysfunction, is characterized by agenesis of cerebellar vermis and abnormal brain stem. Both genotypes and phenotypes of JBTS are highly heterogeneous. The identification of pathogenic gene variation is essential for making a definite diagnosis on JBTS. Here, we found that hypoplasia of cerebellar vermis occurred in three male members in a Chinese family. Then, we performed whole exome sequencing to identify a novel missense mutation c.599T > C (p. L200P) in the OFD1 gene which is the candidate gene of X-linked JBTS (JBST10). The following analysis showed that the variant was absent in the 1000 Genomes, ExAC and the 200 female controls; the position 200 Leucine residue was highly conserved across species; the missense variant was predicted to be deleterious using PolyPhen-2, PROVEAN, SIFT and Mutation Taster. The OFD1 expression was heavily lower in the proband and an induced male fetus compared with a healthy male with a wild-type OFD1 gene. The in vitro expression analysis of transiently transfecting c.599T or c.599C plasmids into HEK-293T cells confirmed that the missense mutation caused OFD1 reduction at the protein level. And further the mutated OFD1 decreased the level of Gli1 protein, a read-out of Sonic hedgehog (SHH) signaling essential for development of central neural system. A known pathogenic variant c.515T > C (p. L172P) showed the similar results. All of these observations suggested that the missense mutation causes the loss function of OFD1, resulting in SHH signaling impairs and brain development abnormality. In addition, the three patients have Dandy-Walker malformation, macrogyria and tetralogy of Fallot, respectively, the latter two of which are firstly found in JBTS10 patients. In conclusion, our findings expand the context of genotype and phenotype in the JBTS10 patients.

Two different prenatal imaging cerebral patterns of tubulinopathy.

To illustrate the prenatal cerebral imaging features associated with tubulinopathy, we report on five affected fetuses from unrelated families, with a de-novo heterozygous variant in a tubulin gene (TUBA1A, TUBB2B or TUBB3). We identified two distinct prenatal imaging patterns related to tubulinopathy: a severe form, characterized by enlarged germinal matrices, microlissencephaly and a kinked brainstem; and a mild form which has not been reported previously in the prenatal literature. The latter form is associated with non-specific features, including an asymmetric brainstem, corpus callosal dysgenesis, a lack of Sylvian fissure operculization and distortion of the anterior part of the interhemispheric fissure with subsequent impacted medial borders of the frontal lobes, the combination of which, in the absence of additional extracerebral anomalies, is highly suggestive of tubulinopathy. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Biometric assessments of the posterior fossa by fetal MRI: A systematic review.

BACKGROUND: Posterior fossa abnormalities (PFAs) are commonly identified within routine screening and are a frequent indication for fetal magnetic resonance imaging (MRI). Although biometric measurements of the posterior fossa (PF) are established on fetal ultrasound and MRI, qualitative visual assessments are predominantly used to differentiate PFAs. OBJECTIVES: This systematic review aimed to assess 2-dimensional (2D) biometric measurements currently in use for assessing the PF on fetal MRI to delineate different PFAs. METHODS: The protocol was registered (PROSPERO ID CRD42019142162). Eligible studies included T2-weighted MRI PF measurements in fetuses with and without PFAs, including measurements of the PF, or other brain areas relevant to PFAs. RESULTS: 59 studies were included - 6859 fetuses had 62 2D PF and related measurements. These included linear, area and angular measurements, representing measures of PF size, cerebellum/vermis, brainstem, and supratentorial measurements. 11 measurements were used in 10 or more studies and at least 1200 fetuses. These dimensions were used to characterise normal for gestational age, diagnose a range of pathologies, and predict outcome. CONCLUSION: A selection of validated 2D biometric measurements of the PF on fetal MRI may be useful for identification of PFA in different clinical settings. Consistent use of these measures, both clinically and for research, is recommended.

Surgical managements and patient outcomes after severe hemorrhagic events from brainstem cavernous malformations.

To evaluate the surgical outcomes and predictors and the impact of surgical timing of patients who suffered a severe hemorrhagic event from brainstem cavernous malformations (CMs). The clinical data of all patients who underwent surgical treatment after a severe bleeding ictus from brainstem CMs between 2011 and 2017 were retrospectively reviewed. The study population consisted of 61 surgical patients (40, 65.6% female). Surgical times of < 3 weeks, ≥ 3-8 weeks, and > 8 weeks since the last bleeding ictus were observed in 23 (37.7%), 24 (39.3%), and 14 (23.0%) patients, respectively. The mean modified Rankin scale (mRS) score evaluated on admission was 4.2. With a mean follow-up of 39.8 months, 39 patients (63.9%) had a favorable outcome (mRS ≤ 2), and the mean mRS score was 2.3. The logistic regression analysis identified age, having disrupted consciousness and/or respiration, and time to surgery from last hemorrhage as significant predictors of long-term outcome. In particular, patients with surgery performed during the acute period (< 3 weeks, P = 0.06) or chronic period (> 8 weeks, P = 0.01) tended to have poor outcomes when compared with those with surgery during the subacute period (≥ 3-8 weeks). Favorable neurological outcomes can be achieved in patients who were surgically treated after a severe hemorrhagic ictus from brainstem CMs, and operation during subacute hemorrhage (≥ 3-8 weeks) could benefit these patients.

Bosley-Salih-Alorainy syndrome in patients from India.

Bi-allelic HOXA1 pathogenic variants clinically manifest as two distinct syndromes, Bosley-Salih-Alorainy syndrome (BSAS) and Athabascan brainstem dysgenesis syndrome, mainly reported in two different populations from Saudi Arabia and southwest North America, respectively. Here we report two siblings of Indian origin with BSAS phenotype caused by a novel homozygous exon 2 HOXA1 pathogenic variants.

Loss of Protocadherin-12 Leads to Diencephalic-Mesencephalic Junction Dysplasia Syndrome.

OBJECTIVE: To identify causes of the autosomal-recessive malformation, diencephalic-mesencephalic junction dysplasia (DMJD) syndrome. METHODS: Eight families with DMJD were studied by whole-exome or targeted sequencing, with detailed clinical and radiological characterization. Patient-derived induced pluripotent stem cells were derived into neural precursor and endothelial cells to study gene expression. RESULTS: All patients showed biallelic mutations in the nonclustered protocadherin-12 (PCDH12) gene. The characteristic clinical presentation included progressive microcephaly, craniofacial dysmorphism, psychomotor disability, epilepsy, and axial hypotonia with variable appendicular spasticity. Brain imaging showed brainstem malformations and with frequent thinned corpus callosum with punctate brain calcifications, reflecting expression of PCDH12 in neural and endothelial cells. These cells showed lack of PCDH12 expression and impaired neurite outgrowth. INTERPRETATION: DMJD patients have biallelic mutations in PCDH12 and lack of protein expression. These patients present with characteristic microcephaly and abnormalities of white matter tracts. Such pathogenic variants predict a poor outcome as a result of brainstem malformation and evidence of white matter tract defects, and should be added to the phenotypic spectrum associated with PCDH12-related conditions. Ann Neurol 2018;84:646-655.

The spectrum of brainstem malformations associated to mutations of the tubulin genes family: MRI and DTI analysis.

OBJECTIVES: To describe the spectrum of brainstem malformations associated to mutations in the tubulin genes taking advantage of magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). METHODS: Fifteen patients (six males; median age, 1.25 years; range, 1 month to 31 years) with mutations in the tubulin genes (TUBA1A = 8, TUBB2B = 4, TUBB3 = 3) studied with MRI and DTI were included in the study. Brain MR exams were reviewed to describe the malformative aspects of the brainstem. Malformations of the supratentorial brain and cerebellum were also recorded. Tractography was performed in seven selected cases. RESULTS: Fourteen patients (93%) showed complex malformations of the brainstem. Most common findings, apparent on anatomical MR sequences, were brainstem asymmetry (12 cases, 5 of which with a crossed pattern characterised by a hypertrophic right medulla oblongata and hypertrophic left pons), short and small pons on midline (10 cases) and anterior brainstem clefting (6 cases). DTI revealed abnormal transverse pontine fibres (13 cases), fusion of corticospinal tracts and medial lemnisci (9 cases) and a small decussation of the superior cerebellar peduncles (7 cases). CONCLUSIONS: Conventional/anatomical MRI and DTI reveal a complex pattern of brainstem malformations associated with tubulin genes mutations. KEY POINTS: • Brainstem malformations affect 93% patients with mutated tubulin genes • MRI shows homolateral and crossed brainstem asymmetries, clefts and pons hypoplasia • DTI demonstrates irregular representation of transverse pontine fibres and fusion of corticospinal tracts.

Well-formed cerebellum and brainstem-like structures in a mature ovarian teratoma: Neuropathological observations.

In the surgical case of a mature cystic teratoma of the ovary that arose in a 16-year-old girl, a large amount of well-differentiated and highly organized cerebellar tissue was found. Three layers of the cerebellar cortex were well formed, and synaptophysin-positive "glomeruli" were found in the granule cell layer. Some Purkinje cells exhibited focal expansion and a dysmorphic appearance of the dendrites. Adjacent to the cerebellar tissue, a large space lined by the ependymal layer and a club-shaped CNS tissue mass resembling the brainstem were found, and structures reminiscent of the midbrain tectum and pontine nuclei were distinguished within this mass. The CNS tissue was surrounded by the leptomeninges and a skull-like, bony shell. Structures consistent with the supra-tentorial CNS tissue were not found. This case represents an example of infra-tentorial CNS tissue that was well-differentiated and organized to an exceptionally high degree in an ovarian mature teratoma. Various degenerative changes have been documented in CNS tissue in ovarian teratomas, but the dendritic abnormalities of Purkinje cells seen in the present case are novel findings.

Mutation of Npr2 leads to blurred tonotopic organization of central auditory circuits in mice.

Tonotopy is a fundamental organizational feature of the auditory system. Sounds are encoded by the spatial and temporal patterns of electrical activity in spiral ganglion neurons (SGNs) and are transmitted via tonotopically ordered processes from the cochlea through the eighth nerve to the cochlear nuclei. Upon reaching the brainstem, SGN axons bifurcate in a stereotyped pattern, innervating target neurons in the anteroventral cochlear nucleus (aVCN) with one branch and in the posteroventral and dorsal cochlear nuclei (pVCN and DCN) with the other. Each branch is tonotopically organized, thereby distributing acoustic information systematically along multiple parallel pathways for processing in the brainstem. In mice with a mutation in the receptor guanylyl cyclase Npr2, this spatial organization is disrupted. Peripheral SGN processes appear normal, but central SGN processes fail to bifurcate and are disorganized as they exit the auditory nerve. Within the cochlear nuclei, the tonotopic organization of the SGN terminal arbors is blurred and the aVCN is underinnervated with a reduced convergence of SGN inputs onto target neurons. The tonotopy of circuitry within the cochlear nuclei is also degraded, as revealed by changes in the topographic mapping of tuberculoventral cell projections from DCN to VCN. Nonetheless, Npr2 mutant SGN axons are able to transmit acoustic information with normal sensitivity and timing, as revealed by auditory brainstem responses and electrophysiological recordings from VCN neurons. Although most features of signal transmission are normal, intermittent failures were observed in responses to trains of shocks, likely due to a failure in action potential conduction at branch points in Npr2 mutant afferent fibers. Our results show that Npr2 is necessary for the precise spatial organization typical of central auditory circuits, but that signals are still transmitted with normal timing, and that mutant mice can hear even with these deficits.

Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum.

CASK is a multi-domain scaffolding protein that interacts with the transcription factor TBR1 and regulates expression of genes involved in cortical development such as RELN. Here we describe a previously unreported X-linked brain malformation syndrome caused by mutations of CASK. All five affected individuals with CASK mutations had congenital or postnatal microcephaly, disproportionate brainstem and cerebellar hypoplasia, and severe mental retardation.

Surgical treatment of hemorrhagic brainstem cavernous malformations.

CONTEXT: Microsurgery is considered to be the optimal treatment for brainstem cavernous malformations (BCMs); however, the high surgery-related morbidity requires further assessment of therapeutic protocols. AIMS: The surgical experience and the optimal surgical strategy for the management of brainstem cavernous malformations is discussed. MATERIALS AND METHODS: From September 2007 to August 2014, a total of 120 patients with BCMs underwent surgical treatment in our hospital. The clinical features and neurological outcome of these patients were retrospectively analysed, and our institutional surgical strategy was discussed. RESULTS: The preoperative annual hemorrhage and rehemorrhage rates were 4.2% and 42.9%, respectively. Gross total resection was achieved in 116 patients (96.7%) and subtotal resection in 4 (3.3%). After a mean follow-up of 50.7 ± 26.5 months (range: 18-90 months), the neurological status showed improvement in 71 patients (67.0%) and remained stable in 24 (22.6%). The postoperative new-onset or worsened symptoms occurred in 53 cases. During the follow-up period, 58.5% of these symptoms improved and 32.1% remained stable. The mean modified Rankin score (mRS) score was 2.51 ± 0.90 preoperatively, 2.73 ± 0.83 postoperatively, and 1.71 ± 0.98 at the recent follow-up. The surgery-related mortality was 1.7% (n = 2), and two patients suffered from recurrence during the follow-up period. The preoperative mRS was considered to be an independent predictive factor of the neurological outcome (P = 0.003). CONCLUSIONS: Safe resection and a favourable outcome can be achieved via a standardized surgical strategy based on appropriate surgical indications, optimal selection of safe trajectories, and application of advanced supplementary techniques in the surgical treatment of BCMs.

Brainstem disconnection: two additional patients and expansion of the phenotype.

Brainstem disconnection (BD) is a rare posterior fossa abnormality defined by the nearly complete absence of a brainstem segment with the rostral and caudal brainstem portions connected only by a thin cord of tissue. The outcome is poor and the majority of children die within the first 2 months of life without achieving developmental milestones. We report on the cases of two children with BD and a prolonged spontaneous survival. Neither patient required intubation or mechanical ventilation and each survived longer than 2 months (one child died at the age of 8 months, the other is alive at the age of 4.5 years). In addition, patient 1 is the only child with BD reported so far who achieved some developmental milestones. Although the long-term neurodevelopmental outcome of BD remains unfavorable, the expansion of the phenotypic spectrum may be important in terms of counseling.

Abnormal sonographic appearance of posterior brain at 11-14 weeks and fetal outcome.

OBJECTIVE: The aim of this retrospective study was to describe the sonographic appearance of the posterior brain anatomy in normal fetuses at 11 to 14 weeks of pregnancy and to determine the fetal outcome when one of the posterior brain anatomical space is not recognized. METHODS: Two groups of patients were included in the study: a control group of consecutive 311 healthy fetuses with a normal sonogram and a study group of 21 fetuses with absence of one of the three posterior brain spaces. In each fetus, images of the mid-sagittal view of the fetal face and brain at 11 to 14 weeks of gestation were obtained. RESULTS: In all fetuses with absence of one of the three posterior brain spaces, a severe anomaly, including open spina bifida, cephalocele, Dandy-Walker complex, and chromosomal aberrations, was associated. CONCLUSION: Our study indicates that the sonographic finding characterized by the absence of one of the three posterior brain spaces seems to facilitate not only the detection of open spina bifida, as previously reported, but also of other neural tube defects, such as cephalocele, and is an important risk factor for cystic posterior brain anomalies, and/or chromosomal abnormalities. Thus it seems a poor prognostic finding for major fetal abnormalities.

Neurochemical abnormalities in the brainstem of the Sudden Infant Death Syndrome (SIDS).

The brainstem has been a focus in Sudden Infant Death Syndrome (SIDS) research for 30 years. Physiological and animal model data show that cardiorespiratory, sleep, and arousal mechanisms are abnormal after exposure to SIDS risk factors or in infants who subsequently die from SIDS. As the brainstem houses the regulatory centres for these functions, it is the most likely site to find abnormalities. True to this hypothesis, data derived over the last 30 years shows that the brainstem of infants who died from SIDS exhibits abnormalities in a number of major neurotransmitter and receptor systems including: catecholamines, neuropeptides, acetylcholinergic, indole amines (predominantly serotonin and its receptors), amino acids (predominantly glutamate), brain derived neurotrophic growth factor (BDNF), and some cytokines. A pattern is emerging of particular brainstem nuclei being consistently affected including the dorsal motor nucleus of the vagus (DMNV), nucleus of the solitary tract (NTS), arcuate nucleus (AN) and raphe. We discuss the implications of these findings and directions that this may lead in future research.

Radiological features of horizontal gaze palsy with progressive scoliosis. An 'Aunt Minnie' diagnosis?

Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare autosomal recessive disorder characterized by congenital absence of normal horizontal eye movements and progressive scoliosis through childhood and adolescence. The characteristic radiological features in HGPPS are butterfly configuration of the medulla, split pons sign, selective volume loss of dorsomedial brainstem, relatively spared cerebellum, relatively prominent inferior olivary nucleus and absent posterior prominence of the facial colliculi and gracilis and cuneate nuclei. These radiological features are reflective of ROBO3 gene mutation required for hindbrain axon midline crossing. Awareness of this diagnosis is important as the radiological features are characteristic enough to be considered as a rare 'Aunt Minnie' and a radiologist may be the first one to raise the possibility of this diagnosis as in this case.

A case of cerebral hypomyelination with spondylo-epi-metaphyseal dysplasia.

We reported on a male patient with rare leukoencephalopathy and skeletal abnormalities. The condition was first noticed as a developmental delay, nystagmus and ataxia at 1 year of age. At 4 years of age, he was diagnosed as hypomyelination with skeletal abnormalities from clinical features, brain magnetic resonance imaging (MRI) and skeletal X-rays. His brain MRI revealed diffuse hypomyelination. These findings suggested the classical type of Pelizaeus-Merzbacher disease (PMD) caused by proteolipid protein (PLP)-1 gene or Pelizaeus-Merzbacher-like disease (PMLD). However, we found neither mutation nor duplication of PLP-1. The patient had severe growth retardation and general skeletal dysplasia compatible with spondylo-epi-metaphyseal dysplasia; however the mutation of discoidin domain receptor (DDR) 2 gene was absent. The co-morbidity of hypomyelination with skeletal abnormalities is rare. We performed array CGH and no causal copy number variation was recognized. Alternatively, this condition may have been caused by a mutation of the gene encoding a molecule that functions in both cerebral myelination and skeletal development.

Severe second-trimester obstructive ventriculomegaly related to disorders of diencephalic, mesencephalic and rhombencephalic differentiation.

By review of a series of cases, we set out to identify sonographic features suggestive of an obstructive mechanism in second-trimester fetuses with ventriculomegaly and describe developmental disorders related to pathological differentiation of the diencephalon, mesencephalon and rhombencephalon that lead to obstruction of cerebrospinal fluid flow. We studied retrospectively 11 fetuses referred for severe second-trimester ventriculomegaly of undetermined origin. Neurosonography was performed with detailed analysis of the third ventricle, thalami, cerebral aqueduct and cerebellum. The cerebral imaging data were compared with neuropathological data in eight patients, with a focus on the level and etiology of the obstruction. Parenchymal thinning and reduction of the pericerebral spaces were highly suggestive of ventriculomegaly due to an obstructive mechanism. The ventriculomegaly was related to diencephalosynapsis (thalamic fusion and third ventricle atresia) in five cases and partial/complete aqueduct stenosis in six; it was associated with cerebellar hypoplasia in six cases, including rhombencephalosynapsis in two cases. In nine patients, disorders of the diencephalon, mesencephalon and rhombencephalon were present. In cases of severe isolated ventriculomegaly in which sonographic features are suggestive of an obstructive mechanism, close examination of the third ventricle, thalami, aqueduct of Sylvius and cerebellum may reveal pathological differentiation of the diencephalon, mesencephalon or rhombencephalon, often in combination.

Neurological features of epilepsy, ataxia, sensorineural deafness, tubulopathy syndrome.

AIM: Recently, we reported a previously unrecognized symptom constellation comprising epilepsy, ataxia, sensorineural deafness, and tubulopathy (EAST syndrome) associated with recessive mutations in the KCNJ10 gene. Here, we provide a detailed characterization of the clinical features of the syndrome to aid patient management with respect to diagnosis, prognostic counselling, and identification of best treatment modalities. METHOD: We conducted a retrospective review of the detailed neurological and neuroradiological features of nine children (four females, five males; age range at last examination 6-20y) with genetically proven EAST syndrome. RESULTS: All children presented with tonic-clonic seizures in infancy. Later, non-progressive, cerebellar ataxia and hearing loss were noted. Whilst seizures mostly responded well to treatment, ataxia proved to be the most debilitating feature, with three patients non-ambulant. All available magnetic resonance imaging (MRI) revealed subtle symmetrical signal changes in the cerebellar dentate nuclei. Moreover, four patients had a small corpus callosum and brainstem hypoplasia, and three had a small spinal cord. Regional quantitative volumetric analysis of the images confirmed the corpus callosum and brainstem hypoplasia and showed further patterns of variation from the norm. INTERPRETATION: The neurological features of EAST syndrome appear to be non-progressive, which is important for prognostic counselling. The spectrum of EAST syndrome includes consistent abnormalities on brain MRI, which may aid diagnosis. Further longitudinal documentation is required to determine the true natural history of the disorder.