Rare and de novo coding variants in chromodomain genes in Chiari I malformation.

Chiari I malformation (CM1), the displacement of the cerebellum through the foramen magnum into the spinal canal, is one of the most common pediatric neurological conditions. Individuals with CM1 can present with neurological symptoms, including severe headaches and sensory or motor deficits, often as a consequence of brainstem compression or syringomyelia (SM). We conducted whole-exome sequencing (WES) on 668 CM1 probands and 232 family members and performed gene-burden and de novo enrichment analyses. A significant enrichment of rare and de novo non-synonymous variants in chromodomain (CHD) genes was observed among individuals with CM1 (combined p = 2.4 × 10-10), including 3 de novo loss-of-function variants in CHD8 (LOF enrichment p = 1.9 × 10-10) and a significant burden of rare transmitted variants in CHD3 (p = 1.8 × 10-6). Overall, individuals with CM1 were found to have significantly increased head circumference (p = 2.6 × 10-9), with many harboring CHD rare variants having macrocephaly. Finally, haploinsufficiency for chd8 in zebrafish led to macrocephaly and posterior hindbrain displacement reminiscent of CM1. These results implicate chromodomain genes and excessive brain growth in CM1 pathogenesis.

Onset of Chiari type 1 malformation: insights from a small series of intrauterine MR imaging cases.

PURPOSE: Morphometric studies on idiopathic Chiari malformation type 1 (CM1) pathogenesis have been mainly based on post-natal neuroimaging. Prenatal clues related to CM1 development are lacking. We present pre- and post-natal imaging time course in idiopathic CM1 and assess fetal skull and brain biometry to establish if clues about CM1 development are present at fetal age. METHODS: Multicenter databases were screened to retrieve intrauterine magnetic resonance (iuMR) of children presenting CM1 features at post-natal scan. Syndromes interfering with skull-brain growth were excluded. Twenty-two morphometric parameters were measured at fetal (average 24.4 weeks; range 21 to 32) and post-natal (average 15.4 months; range 1 to 45) age; matched controls were included. RESULTS: Among 7000 iuMR cases, post-natal scans were available for 925, with postnatal CM1 features reported in seven. None of the fetuses presented CM1 features. Tonsillar descent was clear at a later post-natal scan in all seven cases. Six fetal parameters resulted to be statistically different between CM1 and controls: basal angle (p = 0.006), clivo-supraoccipital angle (p = 0.044), clivus' length (p = 0.043), posterior cranial fossa (PCF) width (p = 0.009), PCF height (p = 0.045), and PCFw/BPDb (p = 0.013). Postnatally, only the clivus' length was significant between CM1 cases and controls. CONCLUSION: Pre- and post-natal CM1 cases did not share striking common features, making qualitative prenatal assessment not predictive; however, our preliminary results support the view that some of the pathogenetic basis of CM1 may be embedded to some extent already in intrauterine life.

Posterior fossa volume in idiopathic intracranial hypertension: a magnetic resonance imaging-based study.

BACKGROUND: The etiology of idiopathic intracranial hypertension (IIH) is uncertain. Studies suggest the fundamental cause of the Chiari 1 malformation, a congenitally hypoplastic posterior fossa, may explain the genesis of IIH in some patients. PURPOSE: To assess the hypothesis that linear and volumetric measurements of the posterior fossa (PF) can be used as predictors of IIH. MATERIAL AND METHODS: A retrospective analysis of magnetic resonance imaging (MRI) studies on 27 patients with IIH and 14 matched controls was performed. A volumetric sagittal magnetization prepared rapid acquisition gradient echo sequence was used to derive 10 linear cephalometric measurements. Total intracranial and bony posterior fossa volumes (PFVs) were derived by manual segmentation. The ratio of PFV to total intracranial volume was calculated. RESULTS: In total, 41 participants were included, all women. Participants with IIH had higher median body mass index (BMI). No significant differences in linear cephalometric measurements, total intracranial volumes, and PFVs between the groups were identified. Linear measurements were not predictive of volumetric measurements. However, on multivariate logistic regression analysis, the likelihood of IIH decreased significantly per unit increase in relative PFV (odds ratio [OR]=3.66 × 10-50; 95% confidence interval [CI]=1.39 × 10-108 to 1.22 × 10-5; P = 0.04). Conversely, the likelihood of IIH increased per unit BMI increase (OR=1.19; 95% CI=1.04-1.47; P = 0.02). CONCLUSION: MRI-based volumetric measurements imply that PF alterations may be partly responsible for the development of IIH and Chiari 1 malformations. Symptoms of IIH may arise due to an interplay between these and metabolic, hormonal, or other factors.

The Relationship Between Imbalance Symptom and Cardiac Pulsation Induced Mechanical Strain in the Brainstem and Cerebellum for Chiari Malformation Type I.

Chiari malformation Type I (CMI) is known to have an altered biomechanical environment for the brainstem and cerebellum; however, it is unclear whether these altered biomechanics play a role in the development of CMI symptoms. We hypothesized that CMI subjects have a higher cardiac-induced strain in specific neurological tracts pertaining to balance, and postural control. We measured displacement over the cardiac cycle using displacement encoding with stimulated echoes magnetic resonance imaging in the cerebellum, brainstem, and spinal cord in 37 CMI subjects and 25 controls. Based on these measurements, we computed strain, translation, and rotation in tracts related to balance. The global strain on all tracts was small (<1%) for CMI subject and controls. Strain was found to be nearly doubled in three tracts for CMI subjects compared to controls (p < 0.03). The maximum translation and rotation were ∼150 µm and ∼1 deg, respectively and 1.5-2 times greater in CMI compared to controls in four tracts (p < 0.005). There was no significant difference between strain, translation, and rotation on the analyzed tracts in CMI subjects with imbalance compared to those without imbalance. A moderate correlation was found between cerebellar tonsillar position and strain on three tracts. The lack of statistically significant difference between strain in CMI subjects with and without imbalance could imply that the magnitude of the observed cardiac-induced strain was too small to cause substantial damage to the tissue (<1%). Activities such as coughing, or Valsalva may produce a greater strain.

Feasibility of rapid spine magnetic resonance evaluation for spinal cord syrinx in the pediatric population.

PURPOSE: This study investigates the feasibility of ultrafast fluid sensitive techniques for evaluation of pediatric spinal cord syrinx. Rapid imaging could obviate the need for sedation, which is often required for children undergoing lengthier standard spine imaging. METHODS: Children undergoing standard spine imaging for Chiari malformation, suspected Chiari malformation, or syrinx were included. Patients who provided informed consent were imaged with rapid acquisition sagittal and axial T2 HASTE spine sequences in addition to standard spine imaging. Standard and rapid spine imaging were then reviewed separately by a pediatric neuroradiologist. The presence or absence of syrinx, syrinx diameter, and length were assessed. The degree of cerebellar tonsillar ectopia, conus position, and evaluation of the filum were also recorded. RESULTS: Seventy-six patients aged 1 month to 18 years (mean 7 years) met the inclusion criteria. The sensitivity and specificity of rapid spine imaging for syrinx was 87.8% and 94.7% respectively. All syrinxes > 2.3 mm in diameter were identified with the rapid spine sequences. There was no statistically significant difference between rapid and standard spine imaging in assessment of syrinx diameter or length. Compared with standard spine imaging, rapid spine sequences demonstrated a 100% sensitivity for low-lying conus and a 98.2% sensitivity for cerebellar tonsillar ectopia. The filum was identified on only 31.6% of the rapid spine studies. CONCLUSION: Rapid T2 imaging demonstrated a high sensitivity for the presence and extent of spinal cord syrinx and may provide an alternative to traditional, lengthier standard spine imaging in selected patients.

Morphometric and volumetric analysis of the posterior cranial fossa in adult Chiari malformation type I with and without group B basilar invagination.

BACKGROUND: The frequent association of basilar invagination (BI) makes the understanding of the pathogenesis of Chiari malformation type I (CMI) difficult. The influence of group B type of BI (the BI without obvious atlantoaxial instability) on the skeletal morphology has not been thoroughly studied. The objective of this study is to evaluate the skeletal alterations in the posterior cranial fossa (PCF) of adult CMI cases with and without group B BI. METHODS: Fifty-four adult CMI without BI cases (CMI-only group) and 30 adult CMI with group B BI cases (CMI-BI group) were retrospectively studied. Fifty-six adult patients with unruptured intracranial aneurysms were included as the controls. Several linear and angular variables, and the bony volume of the PCF were analyzed based on thin-slice computed tomography data. RESULTS: Morphological analysis revealed a significant difference in several variables from controls compared to CMI-only, and CMI-BI patients. The clivus and occipital bone, shortened and elevated in CMI-only patients, were further flattened in BI-associated CMI patients. Furthermore, although out of the scope for the diagnostic threshold of BI, the CMI-only cases also had a tendency to form BI. The association of BI modified several variables, without further reducing the bony PCF volume. CONCLUSIONS: These findings indicate that the variables associated with group B BI tend to be a continuum of the same pathological abnormalities that originate from the same pathological alterations in CMI patients.

Histological and intraoperative evaluations of the arachnoid in patients with Chiari I malformation.

BACKGROUND: Arachnoid dissection for decompression of Chiari I malformation is controversial. Whether arachnoid changes have an impact on the clinical course is not established. This paper documents the histological spectrum of arachnoid changes and evaluates correlations with preoperative, intraoperative, and postoperative data. METHOD: Arachnoid samples of 162 consecutive foramen magnum decompressions from 2006 to 2016 were studied. Arachnoid thickness and degrees of fibrosis and cellularity were determined with the examiner blinded for clinical data. Based on 145 first time decompressions, a histological classification for arachnoid features was developed. RESULTS: The arachnoid was thicker in secondary compared with primary decompressions (176.1 ± 158.2 µm vs. 35.9 ± 43.5 µm; p = 0.0026) and in adults compared to children (37.3 ± 45.3 µm vs. 21.8 ± 7.7 µm; p = 0.0007). In primary decompressions, arachnoid thickness, degrees of fibrosis, and cellularity followed a normal distribution with all features shifted significantly to higher grades in secondary decompressions. The histological classification correlated with the preoperative severity of gait ataxia, motor weakness, and sensory deficits, whereas it had no predictive power for postoperative short- or long-term results. By comparison, the intraoperative evaluation of arachnoid changes accounting for relationships between arachnoid and surrounding tissues showed higher correlations with preoperative symptoms and had significant predictive power for postoperative short- and long-term results. CONCLUSIONS: Histological changes of the arachnoid correlate with preoperative symptoms. Relationships between arachnoid and surrounding tissues show even higher correlations with predictive power for short- and long-term outcomes. These findings suggest a pathophysiological role for the arachnoid in Chiari I malformation.

Severe and progressive neuronal loss in myelomeningocele begins before 16 weeks of pregnancy.

BACKGROUND: Despite undisputable benefits, midtrimester prenatal surgery is not a cure for myelomeningocele (MMC): residual intracranial and motor deficits leading to lifelong handicap question the timing of prenatal surgery. Indeed, the timing and intensity of intrauterine spinal cord injury remains ill defined. OBJECTIVE: We aimed to describe the natural history of neuronal loss in MMC in utero based on postmortem pathology. STUDY DESIGN: Pathology findings were analyzed in 186 cases of myelomeningocele with lesion level between S1 and T1. Using a case-control, cross-sectional design, we investigated the timewise progression and topographic extension of neuronal loss between 13 and 39 weeks. Motor neurons were counted on histology at several spinal levels in 54 isolated MMC meeting quality criteria for cell counting. These were expressed as observed-to-expected ratios, after matching for gestational age and spinal level with 41 controls. RESULTS: Chiari II malformation increased from 30.7% to 91.6% after 16 weeks. The exposed spinal cord displayed early, severe, and progressive neuronal loss: the observed-to-expected count dropped from 17% to ≤2% after 16 weeks. Neuronal loss extended beyond the lesion to the upper levels: in cases <16 weeks, the observed-to-expected motor neuron count was 60% in the adjacent spinal cord, decreasing at a rate of 16% per week. Progressive loss was also found in the upper thoracic cord, but in much smaller proportions. The observed-over-expected ratio of motor neurons was not correlated with the level of myelomeningocele. CONCLUSIONS: Significant neuronal loss is present ≤16 weeks in the exposed cord and progressively extends cranially. Earlier prenatal repair (<16 weeks) could prevent Chiari II malformation in 69.3% of cases, rescue the 17% remaining motor neurons in the exposed cord, and prevent the extension to the upper spinal cord.

Chiari malformation type I and basilar invagination originating from atlantoaxial instability: a literature review and critical analysis.

INTRODUCTION: Recently, a novel hypothesis has been proposed concerning the origin of craniovertebral junction (CVJ) abnormalities. Commonly found in patients with these entities, atlantoaxial instability has been suspected to cause both Chiari malformation type I and basilar invagination, which renders the tried and tested surgical decompression strategy ineffective. In turn, C1-2 fusion is proposed as a single solution for all CVJ abnormalities, and a revised definition of atlantoaxial instability sees patients both with and without radiographic evidence of instability undergo fusion, instead relying on the intraoperative assessment of the atlantoaxial joints to confirm instability. METHODS: The authors conducted a comprehensive narrative review of literature and evidence covering this recently emerged hypothesis. The proposed pathomechanisms are discussed and contextualized with published literature. CONCLUSION: The existing evidence is evaluated for supporting or opposing sole posterior C1-2 fusion in patients with CVJ abnormalities and compared with reported outcomes for conventional surgical strategies such as posterior fossa decompression, occipitocervical fusion, and anterior decompression. At present, there is insufficient evidence supporting the hypothesis of atlantoaxial instability being the common progenitor for CVJ abnormalities. Abolishing tried and tested surgical procedures in favor of a single universal approach would thus be unwarranted.

Chiari type 1-a malformation or a syndrome? A critical review.

OBJECTIVE: As the understanding of pathophysiology behind Chiari malformation still is limited, the treatment of Chiari malformation type 1 remains rather empirical. This may result in suboptimal treatment strategy and outcome in many cases. In this review, we critically address whether the condition known today as Chiari malformation type I should rather be denoted Chiari syndrome. METHODS: The current knowledge of Chiari malformation type 1 is summarized from the historical, etymological, genetic, clinical, and in particular pathophysiological perspectives. RESULTS: There are several lines of evidence that Chiari malformation type 1 represents a condition significantly different from types 2 to 4. Unlike the other types, the type 1 should rather be considered a syndrome, thus supporting the reasons to reappraise the traditional classification of Chiari malformations. CONCLUSION: We propose that Chiari malformation type 1 should rather be denoted Chiari syndrome, while the notation malformation is maintained for types 2-4.

Is there a relationship between the extent of tonsillar ectopia and the severity of the clinical Chiari syndrome?

BACKGROUND: Chiari 1 malformation is diagnosed if the cerebellar tonsils extend at least 5 mm below the opisthion-basion line. OBJECTIVE: To examine the correlation of the extent of tonsillar ectopia with the prevalence and severity of the symptoms associated with the Chiari malformation. METHODS: Patients (N = 428) were grouped according to the extent of tonsillar ectopia on the mid-sagittal MRI image (group 1, 0-< 3 mm; group 2, 3-5 mm; group 3, > 5 mm). Groups were compared regarding demographics, symptoms, neurological signs, pain score, and response to HADS and sf-36 questionnaires. Results were analyzed using one-way ANOVA, chi-square, and two sample Z test, and Student's t test for pairwise comparison, (statistical significance p < 0.05). A logistic regression analysis was performed to determine the relationship between tonsillar ectopia and the probability of a patient reporting any particular symptom. RESULTS: There were 97,148 and 183 patients in groups 1, 2, and 3 respectively. Groups did not differ with regard to antecedent trauma or female preponderance. Patients in group 1 were more symptomatic than those in groups 2 and 3 with regard to some symptoms, (p = 0.04-p = 0.000). Regression analysis confirmed an inverse relationship between the extent of tonsillar ectopia and the likelihood of many symptoms. The pain score was greatest in group 1, (p = 0.006). Prevalence of objective signs of myelopathy did not differ between groups except for Hoffmann sign which was more prevalent in group 1, (p = 0.034). HADS and sf-36 scores did not differ between groups. CONCLUSION: The severity of the symptoms associated with the Chiari malformation does not correlate directly with the extent of tonsillar ectopia. The extent of tonsillar ectopia should be re-evaluated as the threshold for diagnosis of Chiari 1 malformation.

Operative findings and surgical outcomes in patients undergoing Chiari 1 malformation decompression: relationship to the extent of tonsillar ectopia.

BACKGROUND: The diagnosis of Chiari 1 malformation is based on the extent of tonsillar ectopia. OBJECTIVE: To examine the relationship between the extent of tonsillar ectopia and the intra-operative findings and clinical outcome following Chiari decompression surgery. METHODS: Patients were divided into four groups depending on the position of the cerebellar tonsil (T): group 1: 0 < T < 3; group 2: 3 ≤ T ≤ 5; group 3: 5 < T ≤ 10; and group 4: T > 10. Intra-operative observations were recorded with regard to compression of the brain stem by posterior inferior cerebellar artery (pica), neuroma formation along the first cervical (C1), and accessory spinal nerves (XI), and pallor of the cerebellar tonsils. Brain stem auditory evoked potentials, (BAEP), were monitored in each case. One hundred sixty-eight patients accrued between 2009 and 2013 agreed to participate in an outcome study to determine the effectiveness of foramen magnum decompression. Findings across the four groups were compared using one-way ANOVA. Observed differences were further subjected to paired analysis. Intra-group comparisons were made using the paired t test. A P value less than 0.05 was considered statistically significant. RESULTS: There were 98 patients in group 1, 147 patients in group 2, 180 patients in group 3, and 63 patients in group 4. The mean extent of tonsillar ectopia was 0.4, 4.0, 7.1, and 14.3 mm in the four groups respectively. The prevalence of tonsillar pallor was greatest in group 4. Otherwise, there was no difference observed in the operative findings. A reduction of > 0.1 msec in the wave III-wave V latency of the BAEP was noted in all four groups with equal frequency. One hundred ten patients complied with at least 6 months follow-up. There was no difference in the prevalence of symptoms between the four groups at the time of initial evaluation and at 6 weeks and 6 months following surgery. There was a statistically significant reduction in the intensity of individual symptoms 6 months following surgery regardless of the extent of tonsil ectopia. CONCLUSION: Other than the finding of tonsillar pallor, there was no relationship between the extent of tonsillar ectopia and the intraoperative anatomical and physiological observations, nor was there any relationship to the likelihood of symptomatic improvement following surgery. These observations call into question the focus on the extent of tonsillar of ectopia in assessing the patient who presents with symptoms of the Chiari malformation.

Acute deterioration of adults with Chiari I malformation associated with extensive syrinx.

Background: Chiari I malformation (CMI) is usually a chronic disorder, although it may also present as a life-threatening condition with need for urgent decompression. Studies of acute deterioration of CMI are scarce. The identification of preoperative radiological factors that predict acute deterioration in adult patients with CMI facilitates planning of early decompression and decreases CMI-related morbidity.Patients and methods: This is a retrospective study of all adult patients with CMI who were referred to Sahlgrenska University Hospital, Sweden and underwent occipitocervical decompression in the period 2006-2016. In total, 65 consecutive patients were included and data regarding the preoperative degree of tonsillar herniation and syrinx (size, length and degree of rostral extension) were registered. Acute deterioration and the need for urgent surgical decompression within 24 h of hospitalisation were noted.Results: Three patients presented with acute deterioration of symptoms (4.6%) and showed an increased length and size of syrinx and more rostral extension of syrinx as compared to non-acute patients with CMI.Conclusion: Our study highlights the incidence of acute deterioration of CMI and shows the importance of assessing preoperative size, length and rostral extension of CMI-associated syrinx as indicators of acute deterioration so that CMI patients can be assigned to early surgical decompression.

Comparison of high-field MRI and multidetector CT for grading Chiari-like malformation and syringomyelia in Cavalier King Charles Spaniels.

Chiari-like malformation (CM) and syringomyelia (SM) are common illnesses that can cause debilitating neuropathic pain in Cavalier King Charles spaniels (CKCS). The current imaging modality to screen CKCS for CM/SM is MRI of the brain and cervical spine. Magnetic resonance imaging provides good soft tissue detail and contrast of the cerebellum and cervical spinal cord. Computed tomography (CT) is another cross-sectional imaging technique that facilitates brain and neck evaluation; however, soft tissue resolution does not match that of MRI. Computed tomography benefits include identification of concurrent craniocervical junction anomalies (atlantooccipital overlap) and shorter imaging/anesthesia times with the ability to use only sedation. The aim of this retrospective, method comparison study is to assess the utility of multidetector CT for screening CM and SM in CKCS as compared to high-field MRI. Three groups of observers with different levels of experience graded CM and SM based on the British Veterinary Association/Kennel Club CM/SM classification criteria. Thirty CKCS underwent multidetector CT and 3 Tesla MRI studies. Computed tomography and MRI studies were reviewed at different timepoints to minimize bias. Computed tomography has lower Cohen's Kappa agreement for each observer group compared to MRI. The intraclass correlation coefficient averaging CM and SM for all groups was excellent using MRI, while CT was poor for SM and moderate for cerebellar herniation. Greater observer experience resulted in a higher agreement for CT and MRI. Magnetic resonance imaging should remain the standard for screening of CM and SM as CT can result in misclassification and greater disagreement.

Association between craniovertebral junction abnormalities and syringomyelia in patients with chiari malformation type-1.

OBJECTIVE: To assess the correlation between craniovertebral junction (CVJ) abnormalities and syringomyelia in patients with Chiari malformation type-1 (CM1). METHODS: This was a retrospective study including patients with CM1. Identification of cases was done by searching a radiology database at a university hospital from 2012 to 2017. Patients were divided into 2 groups based on whether CVJ abnormalities were present (CVJ+) or absent (CVJ-). The patients` demographic and clinical data were reviewed. All magnetic resonance imaging studies were examined by a certified neuroradiologist. RESULTS: Sixty-four consecutive patients with CM1 were included. The mean age was 24+/-17 years; 59% were females. The CVJ+ group had more female patients (p=0.012). The most frequent CVJ abnormality was platybasia (71%), followed by short clivus (44%) and cervical kyphosis (33%). The CVJ abnormalities were more in Syringomyelia cases (p=0.045). However, the results were not significant when hydrocephalus cases were excluded. CONCLUSION: Among CM1 patients, CVJ abnormalities were found more in patients with syringomyelia. Future studies with larger sample size are required to further study the correlation between CVJ abnormalities and both syringomyelia and hydrocephalus in CM1 patients.

Dynamic cerebellar herniation in Chiari patients during the cardiac cycle evaluated by dynamic magnetic resonance imaging.

PURPOSE: Cerebellar herniation in Chiari patients can be dynamic, following the cerebrospinal fluid pulsatility during the cardiac cycle. We present a voxel intensity distribution method (VIDM) to automatically extract the pulsatility-dependent herniation in time-resolved MRI (CINE MRI) and compare it to the simple linear measurements. The degree of herniation is furthermore compared on CINE and static sequences, and the cerebellar movement is correlated to the presence of hydrocephalus and syringomyelia. METHODS: The cerebellar movement in 27 Chiari patients is analyzed with VIDM and the results were compared to linear measurements on an image viewer (visual inspection, VI) using a paired t test. Second, an ANOVA test is applied to compare the degree of herniation on static 3D MRI and CINE. Finally, the Pearson's correlation coefficient is calculated for the correlation between cerebellar movement and the presence of hydrocephalus and syringomyelia. RESULTS: VIDM showed significant movement in 85% of our patients. Assuming that movement < 1 mm cannot be detected reliably on an image viewer, VI identified movement in 29.6% of the patients (p = 0.002). The herniation was greater on static sequences than on CINE in most cases, but this was not statistically significant. The cerebellar movement was not correlated with hydrocephalus or syringomyelia (Pearson's coefficient < 0.3). CONCLUSIONS: VIDM is a sensitive method to detect tissue movement on CINE MRI and could be used for Chiari patients, but also for the evaluation of cyst membranes, ventriculostomies, etc. The cerebellar movement appears not to correlate with hydrocephalus and syringomyelia in Chiari patients.

Quantification of changes in brain morphology following posterior fossa decompression surgery in women treated for Chiari malformation type 1.

PURPOSE: While 84% of patients surgically treated for Chiari malformation type 1 (CM1) demonstrate improved quality of life after posterior fossa decompression surgery, there are many risks associated with this surgery. Surgical planning to identify candidates likely to improve postoperatively may benefit from an improved understanding of morphological changes after decompression surgery. To evaluate these changes, we quantified 59 morphological parameters on 42 CM1 adult female patients before and after CM1 decompression surgery. METHODS: Fifty-nine morphological parameters in the posterior cranial fossa, cranio-cervical, and intracranial regions in the midsagittal plane were evaluated using 42 T1-weighted magnetic resonance images of female CM1 patients before and after surgery, and 42 healthy female controls. Morphological differences before and after surgery were compared through the development of a technique to establish the opisthion location, a key reference point not present after surgery. RESULTS: In addition to the expected reduction of the cranio-caudal dimension of the cerebellum, objective analyses showed a significant increase in the area of the cerebrospinal fluid spaces, posterior (6×) and inferior (2.6×) to the cerebellum (+ 112 ± 102 and + 140 ± 127 mm2, respectively). This increased area was primarily impacted by an average reduction in the occipital bone length of 24.5 ± 7.3 mm following surgery. Based on multiple angles, results demonstrated a 2°-4° anterior rotation of the cerebellum after surgery. CONCLUSION: Our results show that decompression surgery results in significant changes in the cerebellum and cerebrospinal fluid spaces. Further investigation should determine how these morphological changes impact clinical outcomes.

T2 prolongation in the cerebellar vermis on prenatal MRI of fetuses with Chiari 2 malformations.

AIM: To describe a new finding in fetuses with Chiari 2 malformations recognised at in utero (iu) magnetic resonance imaging (MRI), specifically T2 prolongation (high signal) in the cerebellar vermis. MATERIALS AND METHODS: This was a prospective observational study of iuMRI studies performed at two time points on 20 fetuses with Chiari 2 malformations and 10 control fetuses at the same time points. High T2 signal in the cerebellar vermis was noted and correlated with posterior fossa dimensions was assessed. RESULTS: High T2 signal in the cerebellar vermis was found in over half of the fetuses with a Chiari 2 malformation, but was not correlated with the degree of reduction in size of the bony posterior fossa. CONCLUSION: The present findings suggest that abnormal high T2 signal in the cerebellum is common in fetuses with Chiari 2 malformations and although the cause of the signal change is not known at present it may represent vasogenic oedema as a result of restricted venous drainage.

Chiari Malformation Type 1 in EPAS1-Associated Syndrome.

A syndrome of multiple paragangliomas/pheochromocytomas, somatostatinoma, and polycythemia due to somatic mosaic gain-of-function mutation of EPAS1, encoding HIF-2α, was previously described. HIF-2α has been implicated in endochondral and intramembranous ossification. Abnormal bone growth of the skull base may lead to Chiari malformation type I. We report two cases of EPAS1 gain-of-function mutation syndrome with Chiari malformation and developmental skull base anomalies. Patients were referred to the Section on Medical Endocrinology, Eunice Kennedy Shriver NICHD, NIH for evaluation of recurrent and metastatic paragangliomas or pheochromocytoma. The syndrome was confirmed genetically by identification of the functional EPAS1 gain-of-function mutation in the resected tumors and circulating leukocytes. Both patients were confirmed for characteristics of EPAS1 gain-of-function mutation syndrome by complete blood count (CBC), plasma biochemistry, and computed tomography (CT) of the abdomen and pelvis. Chiari malformation type I and abnormal bony development of the posterior fossa was found on MRI and CT of the head. The present study implicates EPAS1 mutations in abnormal posterior fossa development resulting in Chiari malformation type I.

The newer classifications of the chiari malformations with clarifications: An anatomical review.

In 1891, Hans Chiari described a group of congenital hindbrain anomalies, which were eventually named after him. He classified these malformations into three types (Chiari malformations I, II, and III), and four years later added the Chiari IV malformation. However, numerous reports across the literature do not seem to fit Chiari's original descriptions of these malformations, so researchers have been encouraged to propose new classifications to encompass these variants (e.g., Chiari 0, Chiari1.5, and Chiari 3.5 malformations). Moreover, there is a continued misunderstanding and misuse of the term "Chiari IV malformation." Therefore, the current review intended to describe anatomical, pathophysiological, and clinical aspects of the newer classifications with clarifications of the Chiari malformations. We reviewed available literature about Chiari malformations and their variants using "PubMed" and "Google Scholar." We also looked into the term Chiari IV, clarifying its original description and citing examples where the term has been used erroneously. References in the reviewed articles were searched manually. Variants of the originally described Chiari malformations are termed Chiari 0, Chiari 1.5, and Chiari 3.5. Each has distinct anatomical characteristics and some of these are extremely rare and incompatible with life (e.g. Chiari 3.5). Chiari IV malformation has been further clarified. Some physicians might be unfamiliar with the newer classifications of Chiari malformations because these conditions are rare or even unique. Furthermore, care is needed in using the term "Chiari IV malformation", which must be consistent with Chiari's original description, i.e. an occipital encephalocele containing supratentorial contents. Clin. Anat. 31:314-322, 2018. © 2018 Wiley Periodicals, Inc.