Widespread correction of brain pathology in feline alpha-mannosidosis by dose escalation of intracisternal AAV vector injection.

Alpha-mannosidosis is caused by a genetic deficiency of lysosomal alpha-mannosidase, leading to the widespread presence of storage lesions in the brain and other tissues. Enzyme replacement therapy is available but is not approved for treating the CNS, since the enzyme does not penetrate the blood-brain barrier. However, intellectual disability is a major manifestation of the disease; thus, a complimentary treatment is needed. While enzyme replacement therapy into the brain is technically feasible, it requires ports and frequent administration over time that are difficult to manage medically. Infusion of adeno-associated viral vectors into the cerebrospinal fluid is an attractive route for broadly targeting brain cells. We demonstrate here the widespread post-symptomatic correction of the globally distributed storage lesions by infusion of a high dose of AAV1-feline alpha-mannosidase (fMANB) into the CSF via the cisterna magna in the gyrencephalic alpha-mannosidosis cat brain. Significant improvements in clinical parameters occurred, and widespread global correction was documented pre-mortem by non-invasive magnetic resonance imaging. Postmortem analysis demonstrated high levels of MANB activity and reversal of lysosomal storage lesions throughout the brain. Thus, CSF treatment by adeno-associated viral vector gene therapy appears to be a suitable complement to systemic enzyme replacement therapy to potentially treat the whole patient.

External ventricular drain migration into the cisterna magna: A case report.

Background: External ventricular drain (EVD) insertion is a common neurosurgical procedure used to treat acute hydrocephalus. In this report, we present a rare case of an EVD that was initially correctly placed within the frontal horn but subsequently migrated to the cisterna magna, the first to be reported in the literature. Case Description: A 46-year-old man with postoperative meningitis and hydrocephalus underwent EVD insertion using an improvised EVD system. The EVD was also used as a route for the administration of intraventricular antibiotics. The patient was restless and agitated during his treatment, causing him to move his head frequently. Serial computed tomography scans showed that the EVD was initially correctly placed within the frontal horn and then migrated to the cisterna magna. Conclusion: Inward catheter migration is a rare complication of EVD insertion and is an important concern since it may cause neurologic deficits and potentially harmful sequelae. We have also highlighted measures that can be taken to prevent a similar event in the future.

Validation of a simplified model for subarachnoid hemorrhage in mice.

BACKGROUND: Subarachnoid hemorrhage (SAH) represents a severe injury to the brain and is associated with a high mortality (40%). Several experimental SAH models are described in the literature requiring specialized equipment and a high degree of surgical expertise. Our goal was to validate a simplified, cost-effective model to permit future studies of SAH. METHODS: SAH was induced by injection of homologous blood into the cisterna magna. Perfusion-fixation then perfusion of gelatinous India ink was performed. Brains and brainstems were collected and imaged for analysis of cerebral vasospasm. Triphenyl tetrazolium chloride (TTC) staining was used to analyze brain tissue cell death 24 hours following stroke. A composite neuroscore was utilized to assess SAH-related neurologic deficits. RESULTS: Anterior cerebral artery and basilary artery diameters were significantly reduced at 24 hours post SAH induction. Middle cerebral artery diameter was also reduced; however, the results were not significant. TTC staining showed no infarcted tissue. Neuroscores were significantly lower in the SAH mice, indicating the presence of functional deficits. CONCLUSIONS: This simplified model of SAH elicits pathological changes consistent with those described for more complex models in the literature. Therefore, it can be used in future preclinical studies examining the pathophysiology of SAH and novel treatment options.

Tic-Related Obsessive-Compulsive and Eating Disorders in Dandy-Walker Variant: A Case Report and Systematic Reappraisal of Psychiatric Profiles.

Dandy-Walker complex (DWC) consists of a continuum of brain malformations involving the posterior fossa, often leading to psychiatric manifestations during adulthood. We discussed the case of a young woman with Dandy-Walker variant (DWV) and a comorbid complex neuropsychiatric presentation, who was diagnosed with an eating disorder, obsessive-compulsive disorder, and a tic disorder. Afterwards, we conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020-compliant systematic review reappraising all evidence of psychiatric outcomes in adults with DWC. Overall, 34 studies were eligible for data extraction, comprising 36 patients. Psychiatric profiles were more common among young adult males, with DWC lesions, especially DWV subtype, being often discovered incidentally after admission to mental health inpatient facilities. Most patients were diagnosed with psychosis and bipolar disorder, often comorbid with cognitive impairment. Psychotropic polypharmacy was frequently prescribed, generally leading to complete recovery. Evidence from our case report and systematic review indicates the importance of monitoring long-term psychiatric sequelae among adult patients with DWC malformations.

Cerebrospinal Fluid Diversion from the Cisterna Magna in Patients with Idiopathic Intracranial Hypertension and Slit Ventricles: Long-Term Effectiveness, Revision Rates, and Clinical Outcomes.

OBJECTIVE: Idiopathic intracranial hypertension (IIH) is a cerebrospinal fluid (CSF) disorder defect that is frequently treated with CSF shunts. Shunts utilizing the cisterna magna as a proximal reservoir have been described in literature; however, long-term outcomes are unknown. The present study aims to describe the long-term effectiveness, revision rates, and clinical outcomes of this shunt in 14 patients with IIH and slit ventricles. METHODS: A single-center retrospective review of 14 IIH patients treated by cisterna magna shunts was performed. Shunt histories, including revision rate and time until first shunt failure for ventricular, lumbar, and cisterna magna shunts were recorded. "Revision rate" was calculated as the total number of shunt revisions over years of total shunt placement. The average follow-up time was 12.08 years. RESULTS: The mean age at first cisterna magna shunt placement was 18.1 years (6.6-43.3 years) and all patients had radiological evidence of slit ventricles. Cisterna magna shunts improved or resolved clinical symptoms for all 14 patients and had a lower rate of revisions (0.42 revision/year) compared to ventricular (0.72 revision/year) and lumbar (1.30 revision/year) shunts. Of the 11 patients still requiring CSF diversion at the end of the study, eight had functioning shunts that utilized the cisterna magna. CONCLUSIONS: The cisterna magna shunt may be a suitable option for patients with IIH and slit ventricles. Further study is needed to understand the clinical utility of this shunt for the population in which it is indicated.

A technique for repeated blood and cerebrospinal fluid sampling from individual rats over time without the need for repeated anesthesia.

Ethical animal use follows the 3R's: Replacement, Reduction and Refinement. Here, we present the use of simultaneous jugular vein and cisterna magna catheterization via a port system in rats for repeated fluid sampling for 14 consecutive days without loss of catheter patency. This technique allows repeated intra-animal sampling without anesthesia and, if used with pooling samples from a cohort of animals, replaces the need for terminal collections for sufficient sample volumes.

Simple procedure for assessing diffuse subarachnoid hemorrhage successfully created using filament perforation method in mice.

The murine model of subarachnoid hemorrhage (SAH) is a valuable experimental tool for investigating molecular and cellular mechanisms, and the endovascular filament perforation technique can be used to simulate prominent pathophysiological features observed after human SAH; however, current validation methods for assessing an appropriate SAH model are limited. Here, we introduce a simple procedure for selecting a mouse model of diffuse SAH. SAH was induced in 24 mice using a standard filament perforation method. After confirming survival at 24 h, SAH was scored 0-1 based on T2*-weighted images on whole-brain magnetic resonance imaging (MRI) and visual surveillance of the cisterna magna (CM) through the dura mater. The CM-based SAH grading correlated well with a reference parameter defined by extracted brain (r2 = 0.53, p < 0.0001). The receiver operating characteristic curve revealed a sensitivity of 85% and a specificity of 91% for detecting diffuse SAH, with a similar area under the curve (0.89 ± 0.06 [standard error of the mean]) as the MRI-based grading (0.72 ± 0.10, p = 0.12). Our data suggest that confirming an SAH clot in the CM is a valuable way to select a clinically relevant diffuse SAH model that can be used in future experimental studies.

Benzodiazepines for Treatment-Resistant Major Depressive Disorder and Obsessive-Compulsive Disorder With Comorbid Mega Cisterna Magna.

This article discusses the case of an adult woman with comorbid major depressive disorder (MDD) and obsessive-compulsive disorder (OCD). Due to her poor response to initial treatment regimens, a brain computed tomography (CT) was performed, revealing mega cisterna magna (MCM). Subsequently, she responded well to the addition of lorazepam, a benzodiazepine, along with fluvoxamine and quetiapine XR. The clinical significance of MCM and MDD-OCD remains partially understood. Thus, this case report aims to contribute to the literature and review the treatment of benzodiazepines in relation to MCM, MDD, and OCD comorbidities.

Animal Welfare Aspects in Planning and Conducting Experiments on Rodent Models of Subarachnoid Hemorrhage.

Subarachnoid hemorrhage is an acute life-threatening cerebrovascular disease with high socio-economic impact. The most frequent cause, the rupture of an intracerebral aneurysm, is accompanied by abrupt changes in intracerebral pressure, cerebral perfusion pressure and, consequently, cerebral blood flow. As aneurysms rupture spontaneously, monitoring of these parameters in patients is only possible with a time delay, upon hospitalization. To study alterations in cerebral perfusion immediately upon ictus, animal models are mandatory. This article addresses the points necessarily to be included in an animal project proposal according to EU directive 2010/63/EU for the protection of animals used for scientific purposes and herewith offers an insight into animal welfare aspects of using rodent models for the investigation of cerebral perfusion after subarachnoid hemorrhage. It compares surgeries, model characteristics, advantages, and drawbacks of the most-frequently used rodent models-the endovascular perforation model and the prechiasmatic and single or double cisterna magna injection model. The topics of discussing anesthesia, advice on peri- and postanesthetic handling of animals, assessing the severity of suffering the animals undergo during the procedure according to EU directive 2010/63/EU and weighing the use of these in vivo models for experimental research ethically are also presented. In conclusion, rodent models of subarachnoid hemorrhage display pathophysiological characteristics, including changes of cerebral perfusion similar to the clinical situation, rendering the models suited to study the sequelae of the bleeding. A current problem is low standardization of the models, wherefore reporting according to the ARRIVE guidelines is highly recommended. Animal welfare aspects of rodent models of subarachnoid hemorrhage. Rodent models for investigation of cerebral perfusion after subarachnoid hemorrhage are compared regarding surgeries and model characteristics, and 3R measures are suggested. Anesthesia is discussed, and advice given on peri- and postanesthetic handling. Severity of suffering according to 2010/63/EU is assessed and use of these in vivo models weighed ethically.

Pre-clinical delivery of gene therapy products to the cerebrospinal fluid: challenges and considerations for clinical translation.

While the majority of gene therapy studies in neurological indications have focused on direct gene transfer to the central nervous system (CNS), there is growing interest in the delivery of therapeutics using the cerebrospinal fluid (CSF) as a conduit. Historically, direct CNS routes-of-administration (RoAs) have relied on tissue dynamics, displacement of interstitial fluid, and regional specificity to achieve focal delivery into regions of interest, such as the brain. While intraparenchymal delivery minimizes peripheral organ exposure, one perceived drawback is the relative invasiveness of this approach to drug delivery. In this mini review, we examine the CSF as an alternative RoA to target CNS tissue and discuss considerations associated with the safety of performing such procedures, biodistribution of therapeutics following single administration, and translation of findings given differences between small and large animals. These factors will help delineate key considerations for translating data obtained from animal studies into clinical settings that may be useful in the treatment of neurological conditions.

Simple methods for cerebrospinal fluid collection in fetal, neonatal, and adult rat.

BACKGROUND: Cerebrospinal fluid (CSF) collection and its analysis are common medical practices useful in the diagnosis, therapy, and prevention of central nervous system (CNS) disorders. In recent years, several types of research have improved our insight into CSF and its role in health and disease. Yet, many characteristics of this fluid remain to be fully understood. NEW METHODS: Here, we describe how to collect CSF from embryonic, postnatal, and adult stages of the rat. In adults, CSF can be collected through simple stereotaxic surgery to expose the membrane overlying the cisterna magna (CM) of an anesthetized rat and collection of CSF through micropipette puncture through the membrane. In embryos and pups, CSF is aspirated, using a fire-polished micro-capillary pipette, from the CM of animals. RESULTS: Application of these methods provides the maximum volume of pure, uncontaminated CSF (embryonic day 19: 10-15 microliter, postnatal day 5: 20-30 microliter, adults: 100-200 microliter) with a success rate of approximately 95% in every age. COMPARISON WITH EXISTING METHODS: Compared to the existing protocols, these methods obtain considerable volumes of CSF, which may accelerate the measurement of biological markers in this fluid. Also, these techniques do not require surgical skills and according to the practical points mentioned during sampling, the procedures can be performed in rapid fashion. CONCLUSION: We describe simple methods for collecting CSF in live rats. These protocols provide clean, uncontaminated CSF for experiments to understand the exact role of this fluid in the development and maintenance of the CNS health.

16p11.2 Microduplication Syndrome with Increased Fluid in the Cisterna: Coincidence or Phenotype Extension?

We report the first case of a child with 16p11.2 microduplication syndrome with increased fluid in the cisterna magna seen on magnetic resonance imaging (MRI). This finding may correspond to a Blake's Pouch Cyst (BPC) or a Mega Cisterna Magna (MCM), being impossible to differentiate through image examination. The molecular duplication was diagnosed using chromosomal microarray analysis with single nucleotide polymorphism (SNP). We review the clinical and neuroimaging features in published case reports in order to observe the findings described in the literature so far and present a skull three-dimensional model to contribute to a better understanding. Despite the variable expressivity of the syndrome being well known, there is no case described in the available literature that mentions the association of 16p11.2 microduplication and the presence of BPC or MCM seen in neuroimaging exams. This finding may represent an extension of the phenotype not yet reported or may present itself as a coincidence in a child with various malformations.

Anatomical Implications of Chiari I and Basilar Invagination (Type B) in the IV Ventricle and Cisterna Magna.

OBJECTIVE: To analyze the anatomical changes of the IV ventricle and cisterna magna in the Chiari malformation I (CMI) and basilar invagination (type B). METHODS: This is a controlled study with 161 exams of magnetic resonance imaging (MRI) of adults grouped into control (n = 37), basilar invagination (BI; n = 31), Chiari malformation I (CMI; n = 37), and CMI+BI (n = 56). The MRIs were analyzed using the visualization software Osirix (Pixmeo, Bernex, Geneva, version 3.8.2). The morphometric variables were: distance from the obex to the McRae line; length of the IV ventricle floor; and the area and volume of the cisterna magna. The univariate ANOVA followed by Tukey's post-hoc test was applied to evaluate the difference between the groups. The difference between sexes was evaluated by the t test for each group. RESULTS: Alterations in the cisterna magna and IV ventricle were more evident only in the CMI and CMI+BI groups. For both sexes, the CMI and CMI+BI groups showed: a reduction in the CSF space (P < 0.001), cisterna magna with volume reduction (P < 0.001), low position of the obex (P < 0.001), and IV ventricle more elongated (male P = 0.007 and female P < 0.001). The BI group had no significant change in the analysis by sex. CONCLUSIONS: The CMI (isolated and associated with BI) showed a low obex position and elongation of the IV ventricle due to traction towards the spinal canal. The reduction of cisterna magna volume added to the occupation of the cerebellar tonsils can impact in the cerebrospinal fluid dynamics. The BI when isolated was not related to alterations in the parameters of cerebrospinal fluid spaces studied.

A novel method for repeated cerebrospinal fluid sampling and long-term monitoring of intracranial pressure in rats.

Cannulation implantation into the cisterna magna is an important procedure in cerebrospinal fluid (CSF) sampling and intracranial pressure (ICP) monitoring. The disadvantages of existing techniques include the risk of brain damage, compromised muscle mobility, and the complexity of the procedures. In the present study, the authors describe a modified, simple, and reliable procedure for long-term cannulation implantation into the cisterna magna in rats. The device consists of four parts: the puncture segment, the connection segment, the fixing segment, and the external segment. Intraoperative ICP monitoring and post-operative computed tomography (CT) scans were performed, which confirmed the accuracy and safety of this method. There were no limitations on the daily activities of the rats when long-term drainage was carried out for 1 week. This new technique offers an improved method of cannulation and will be a potentially useful method for CSF sampling and ICP monitoring in neuroscience research.

Reappraisal of intradural findings in Chiari malformation type I.

OBJECTIVE: Management of Chiari malformation type I (CM-I) requires the functional restoration of an obstructed cisterna magna. In posterior fossa decompression with duraplasty (PFDD), various intradural pathologies are suggested to alter CSF flow at the craniocervical junction and require surgical correction. However, reports of the spectrum of intraoperative intradural findings and their nuances are scarce, especially those characterizing rarer findings pertaining to the vascular structures and vascular compression. METHODS: The authors conducted a retrospective cohort analysis of adults and children who underwent first-time PFDD for CM-I (2011-2021), with and without syringomyelia. The surgical reports and intraoperative videos were reviewed, and the frequency and nature of the intradural observations in regard to the tonsils, arachnoid, and vasculature were analyzed along with the clinical findings and surgical outcomes. RESULTS: All 180 patients (age range 1-72 years; median [interquartile range] 24 (14-38) years; 37% of patients were children < 21 years of age) exhibited multiple intradural findings, with a median of 7 distinct concurrent observations in each patient. Novel findings not previously reported included posterior inferior communicating artery (PICA) branches compressing the neural elements at the cervicomedullary junction (26.7%). Other common findings included arachnoid adhesions (92.8%), thickening (90.6%), webs at the obex (52.2%), tonsillar gliosis (57.2%), tonsillar hypertrophy (18.3%), adhesions obstructing the foramen of Magendie (FoM) (62.2%), PICA obstruction of the FoM (17.2%), and dural scarring (87.8%). Tonsillar gliosis and intertonsillar adhesions obstructing the FoM were more common in children than adults. Tonsillar gliosis and arachnoid webs were more common among syringomyelia patients. After multivariable adjustment, none of the observed findings were independently associated with syringomyelia, preoperative symptoms, or postoperative improvement. The vast majority of patients improved postoperatively. The complication rate was low: 1.2% of patients required revision PFDD at > 3 years postoperatively, 3.6% experienced other operative complications, and 0% had CSF leaks. CONCLUSIONS: The diversity of intradural findings and observations revealed in this study suggests that obstructive and compressive structural anomalies may be more common than previously reported among CM-I patients, both those patients with and those without syringomyelia and especially those with obstructive and compressive PICA branches. Although the authors cannot conclude that all these findings are necessarily pathological, further study may determine how they contribute to CM-I pathology and symptomatology in the setting of a compromised cisterna magna.

Biodistribution of Adeno-Associated Virus Gene Therapy Following Cerebrospinal Fluid-Directed Administration.

Adeno-associated virus (AAV)-based gene therapies, exemplified by the approved therapy for spinal muscular atrophy, have the potential to deliver disease-course-altering treatments for central nervous system (CNS) indications. However, several clinical trials have reported severe adverse events, including patient deaths following high-dose systemic administration for muscle-directed gene transfer, highlighting the need to explore approaches utilizing lower doses when targeting the CNS. Animal models of disease provide insight into the response to new AAV therapies. However, translation from small to larger animals and eventually to humans is hampered by anatomical and biological differences across the species and their impact on AAV delivery. We performed a literature review of preclinical studies of AAV gene therapy biodistribution following cerebrospinal fluid (CSF) delivery (intracerebroventricular, intra-cisterna magna, and intrathecal lumbar). The reviewed literature varies greatly in the reported biodistribution of AAV following administration into the CSF. Differences between studies, including animal model, vector serotype used, method used to assess biodistribution, and route of administration, among other variables, contribute to differing outcomes and difficulties in translating these preclinical results. For example, only half of the published AAV-based gene therapy studies report vector copy number, the most direct readout following administration of a vector; none of these studies reported details such as the empty:full capsid ratio and quality of encapsidated genome. Analysis of the last decade's literature focusing on AAV-based gene therapies targeting the CNS underscores limitations of the body of knowledge and room for continued research. In particular, there is a need to understand the biodistribution achieved by different CSF-directed routes of administration and determining if specific cell types/structures of interest will be transduced. Our findings point to a clear need for a more systematic approach across the field to align the assessments and elements reported in preclinical research to enable more reliable translation across animal models and into human studies.

Reference ranges of fetal cisterna magna volume measurements by three-dimensional ultrasonography in the late second trimester considering sonographic experience.

BACKGROUND: Volume measurements of fetal cisterna magna (CM) by three-dimensional (3D) ultrasonography may have a role in the diagnosis of various posterior fossa abnormalities. PURPOSE: To evaluate reference intervals and reliability of fetal CM volume values by virtual organ computer-aided analysis (VOCAL) in structurally normal fetuses, considering experience of evaluators. MATERIAL AND METHODS: Three operators with different 3D sonography experience levels measured CM volumes of 100 structurally normal fetuses at 18-27 weeks of gestation. Reference intervals for CM volumes were generated. Intraclass correlation coefficients (ICC) were calculated. RESULTS: Mean fetal CM volume measurements by the three operators did not significantly (P = 0.49, P = 0.22, and P = 0.17, respectively) change through 20-23 weeks of gestation. Moderate degrees of inter-observer reliability were found with an ICC of 0.69 between novice and intermediate-level, ICC of 0.74 between experienced and intermediate-level, and ICC of 0.78 between experienced and novice observer, respectively. The novice sonographer generally overestimated CM measurements. Intra-observer reliability was good (ICC=0.85). CONCLUSION: A reference chart for fetal CM volume by VOCAL was formed, revealing uniform mean values of 20-23 weeks of gestation. The inter-observer reliability is moderate, and biases seem relatively common for all experience categories.

Early distribution of18 F-labeled AAV9 vectors in the cerebrospinal fluid after intracerebroventricular or intracisternal magna infusion in non-human primates.

BACKGROUND: The delivery of adeno-associated virus (AAV) vectors via the cerebrospinal fluid (CSF) has emerged as a valuable method for widespread transduction in the central nervous system. Although infusion into the cerebral ventricles is a common protocol in preclinical studies of small animals, the cisterna magna has been recognized as an alternative target for clinical studies because it can be reached in a less invasive manner using an intrathecal catheter via the subarachnoid space from a lumbar puncture. METHODS: We evaluated the early distribution of fluorine-18-labeled AAV9 vectors infused into the lateral ventricle or cisterna magna of four non-human primates using positron emission tomography. The expression of the green fluorescent protein was immunohistochemically determined. RESULTS: In both approaches, the labeled vectors diffused into the broad arachnoid space around the brain stem and cervical spinal cord within 30 min. Both infusion routes efficiently transduced neurons in the cervical spinal cord. CONCLUSIONS: For gene therapy that primarily targets the cervical spinal cord and brainstem, such as amyotrophic lateral sclerosis, cisterna magna infusion would be a feasible and effective administration method.

Relative prevalence and outcome of fetal posterior fossa abnormality.

AIM: To find out the relative incidence and outcome of posterior fossa abnormality (PFA) in terms of survival at birth until 2 years of age. METHODS: We conducted a prospective study; all fetuses diagnosed with posterior fossa abnormality were followed-up. The outcome was observed with respect to survival, the presence of associated anomalies, the existence of developmental delay after a telephonic interview. RESULTS: Out of 2703 children with congenital anomalies, 921 (34.1%) had a central nervous system defect; 76 cases of PFA were fully followed. Dandy-Walker malformation (DWM) was present in 50% (38/76), mega cisterna magna 18.4% (14/76), Blake pouch cyst 13.2% (10/76), vermian hypoplasia (VH) 13.2% (10/76) and arachnoid cyst 5.2% (4/76). The diagnosis was possible before 20 weeks in only 12 (15.8%) cases. The mean gestational age at delivery was 34.7 ± 6.7 weeks. Associated anomalies were seen in 35/76 (46.1%) cases. A total of 35/76 (46.1%) survived after 2 years; there was developmental delay in 9.2% of cases. CONCLUSION: There is a large variation in the outcome of PFA depending upon the type of anomaly. Associated anomalies are common in VH and DWM, making their prognosis worse.

Compromised Cranio-Spinal Suspension in Chiari Malformation Type 1: A Potential Role as Secondary Pathophysiology.

In Chiari Malformation Type I (CM1), low-lying tonsils obstruct the cisterna magna at the foramen magnum, thereby compromising the essential juncture between the cranial and spinal compartments. The anatomical obstruction of the cisterna magna inhibits bi-directional CSF flow as well as CSF pulse pressure equilibration between the intracranial compartment and the intraspinal compartment in response to instances of increased intracranial pressure. Less understood, however, are the roles of the spinal cord suspension structures at the craniocervical junction which lend viscoelastic support to the spinal cord and tonsils, as well as maintain the anatomical integrity of the cisterna magna and the dura. These include extradural ligaments including the myodural bridges (MDBs), as well as intradural dentate ligaments and the arachnoid framework. We propose that when these elements are disrupted by the cisterna magna obstruction, tonsillar pathology, and altered CSF dynamics, there may arise a secondary pathophysiology of compromised and dysfunctional cranio-spinal suspension in CM1. We present intraoperative images and videos captured during surgical exposure of the craniocervical junction in CM1 to illustrate this proposal.