Human Brainstem and Cerebellum Atlas: Chemoarchitecture and Cytoarchitecture Paired to MRI.

Lesion localization is the basis for understanding neurologic disease, which is predicated on neuroanatomical knowledge carefully cataloged from histology and imaging atlases. However, it is often difficult to correlate clinical images of brainstem injury obtained by MRI scans with the details of human brainstem neuroanatomy represented in atlases, which are mostly based on cytoarchitecture using Nissl stain or a single histochemical stain, and usually do not include the cerebellum. Here, we report a high-resolution (200 µm) 7T MRI of a cadaveric male human brainstem and cerebellum paired with detailed, coregistered histology (at 2 µm single-cell resolution) of the immunohistochemically stained cholinergic, serotonergic, and catecholaminergic (dopaminergic, noradrenergic, and adrenergic) neurons, in relationship to each other and to the cerebellum. These immunohistochemical findings provide novel insights into the spatial relationships of brainstem cell types and nuclei, including subpopulations of melanin and TH+ neurons, and allows for more informed structural annotation of cell groups. Moreover, the coregistered MRI-paired histology helps validate imaging findings. This is useful for interpreting both scans and histology, and to understand the cell types affected by lesions. Our detailed chemoarchitecture and cytoarchitecture with corresponding high-resolution MRI builds on previous atlases of the human brainstem and cerebellum, and makes precise identification of brainstem and cerebellar cell groups involved in clinical lesions accessible for both laboratory scientists and clinicians alike.SIGNIFICANCE STATEMENT Clinicians and neuroscientists frequently use cross-sectional anatomy of the human brainstem from MRI scans for both clinical and laboratory investigations, but they must rely on brain atlases to neuroanatomical structures. Such atlases generally lack both detail of brainstem chemical cell types, and the cerebellum, which provides an important spatial reference. Our current atlas maps the distribution of key brainstem cell types (cholinergic, serotonergic, and catecholaminergic neurons) in relationship to each other and the cerebellum, and pairs this histology with 7T MR images from the identical brain. This atlas allows correlation of the chemoarchitecture with corresponding MRI, and makes the identification of cell groups that are often discussed, but rarely identifiable on MRI scan, accessible to clinicians and clinical researchers.

Database Review of 514 Patients with Os Odontoideum. Detailed Analysis of 258 Surgically Treated (1978-2019).

OBJECTIVE: Database review (1978-2019) is to identify the cause of os odontoideum, its presentation, associated abnormalities, and management recommendations. METHODS AND MATERIALS: Review of referral database of 514 patients and 258 surgically treated patients ages 4-64 years. Detailed history of early childhood trauma and initial encounter record retrieval were made. Patients had dynamic motion radiographs, dynamic motion MRI and also CT to identify pathology and reducibility of craniocervical instability. Preoperative crown halo traction was made before the year 2000 except in children. Intraoperative traction with O-arm/CT documentation was made since 2001. Reducible and partially reducible cases underwent halo traction under general anesthesia distraction, dorsal stabilization, and rib graft augmentation for fusion. Later semi-rigid instrumentation and subsequently rigid instrumentation was made. Irreducible compression of cervicomedullary junction was treated with ventral decompression. The follow up was 3-20 years. RESULTS: Database; acute worsening after trauma 262, insidious neurological deficit 252. Minimal/normal motion with neurological deficit was present in 18, previous C1-C2 fusion with worsening in 18. 28 patients of 64 without treatment worsened in 4 years. An intact odontoid process was seen in 52 children of 156 who had early craniovertebral junction trauma and later developed os odontoideum. SURGICAL EXPERIENCE: There were 174 patients with reducible lesions and partially reducible were 22. Irreducible lesions were 62. Of the reducible, 50 underwent transarticular C1-C2 fusion, 26 C1 lateral mass, and C2 pars screw fixation. 182 had occipitocervical fusion (19 had extension of previous C1-C2 fusion and 43 after transoral decompression). 62 with irreducible ventral compression of the cervicomedullary junction underwent transoral decompression; 43 had a trapped transverse ligament between the os and C2 body and 19 previous C1-C2 fusions. Compression was by the axis body, os odontoideum, and the posterior C2 arch. Syndromic and skeletal/connective tissue abnormalities were found in 86 (36%). COMPLICATIONS: 2 patients worsened, age 10 and 62, due to failure of semi-rigid construct. CONCLUSIONS: The etiology of os odontoideum is multifactorial considering the associated abnormalities, reports of congenital-familiar occurrence, and early childhood craniovertebral trauma which also plays a role in the etiology. Patients with reducible lesions require stabilization. Asymptomatic patients are at risk for later instability. Patients who underwent childhood C1-C2 fusion must be followed for later problems. The irreducibility was seen due to trapped transverse ligament, pannus, or previous dorsal C1-C2 fusion.

Endoscopic-assisted surgical approach for butterfly glioma surgery.

PURPOSE: Gliomas that spread along the white matter tracts of the corpus callosum to both hemispheres have traditionally been considered surgically challenging largely due to the relative complexity of safely achieving complete resections. We present a series of endoscopic-assisted resections of butterfly gliomas with post-operative radiological assessment of EOR and clinical outcome data. METHODS: Retrospective review of patients who underwent surgical resection of a butterfly glioma from 2007 to 2020. Butterfly gliomas were defined as gliomas, which appeared to arise from the corpus callosum with significant bilateral extension. All records were retrospectively reviewed with operative/clinical outcomes and complications recorded. RESULTS: 70 patients who underwent an endoscopic-assisted transcortical or interhemispheric approach for butterfly glioma resection met inclusion criteria. A unilateral transcortical approach was used in 86% of cases and an interhemispheric approach in 14%. The endoscope enhanced the visualization of the contralateral hemisphere and allowed for resection of tumor, not reached by standard microscopic visualization, in 100% of cases. 90% of resections resulted in greater than a 95% resection rate. Neurological deficits mostly consisted of motor (10%) and memory (6%) deficits and were most common with posterior tumors of the splenium. CONCLUSION: The endoscopic-assisted transcortical or interhemispheric approach for butterfly glioma resection is effective in achieving a greater than 95% resection with minimal complications. An angled approach allows careful maneuvering around complex anatomic structures and difficult corners, and should be examined further for its clinical benefits in a prospective manner.

Neurenteric cysts at foramen magnum in children: presentation, imaging characteristics, and surgical management-case series and literature review.

INTRODUCTION: Neurenteric cysts (NEC) are rare benign tumors of the central nervous system. Even more rare are the NEC at the ventral foramen magnum in children that are misdiagnosed. They cause distortion of the vertebrobasilar vascular system and cervicomedullary neural structures and are adherent to the latter. The inferior portion lies ventral to the upper most dentate ligament. This has implications in the surgical approach for complete excision. METHODS AND CASE SERIES: We reviewed our series of five children with ventral foramen magnum NEC in the MRI era and analyzed presentation, radiological findings and surgical management. A literature review is also presented. RESULTS: There were two females and five males. Headache and neurological deficit was present in all five; one child presented with recurrent meningitis. The NEC was present ventral to the cervicomedullary junction in all cases. The posterolateral transcondylar approach was used for complete excision with no recurrences. CONCLUSIONS: Neurenteric cysts at the ventral foramen magnum can be confused with other cystic lesions. Headaches are the most common presentation. The posterolateral transcondylar approach to the ventral cervicomedullary junction provides the most reliable avenue for entire resection.

Atlas assimilation: spectrum of associated radiographic abnormalities, clinical presentation, and management in children below 10 years.

OBJECTIVE: To analyze the varied presentation and management of atlas assimilation with associated radiographic abnormalities in children in the MRI era METHODS: Database analysis of 313 children (less than 10 years) RESULTS: Atlas assimilation (AA) was associated with atlantoaxial dislocation in 12, abnormal skull base and Chiari I abnormality in 42, C2-C3 segmentation failure and instability and Chiari I abnormality in 74, and condylar hypoplasia and basilar invagination in 74. Proatlas segmentation failures were 54, atlantoaxial rotary dislocation in 26 with Goldenhar's syndrome, abnormal C1 atlas posterior arch causing dynamic compression of cord in 31 children. Vascular compromise was documented in 26 children. The study encompassed ages 6 months to 10 years. Cranial nerves commonly affected were glossopharyngeal, vagal, and hypoglossal nerves. Children below 2 years presented with torticollis, failure to thrive, difficulty swallowing, and motor and sensory deficits. Craniovertebral junction instability associated with AA was treated with custom-built craniocervical orthosis below 5 years. Closed reduction of instability or basilar invagination was attempted with neuromuscular blockade under anesthesia and traction above age 5 years. Successful reduction was treated with dorsal foramen magnum and atlas decompression with occiput-C2 dorsal fusion using rib grafts below the age of 5 years and instrumentation after that. Follow-up was 2 to 32 years. Neurological recovery was seen in nearly all patients. CONCLUSIONS: Children with atlas assimilation and associated abnormalities may be symptomatic in early childhood. The treatment depends on the age and tailored to the abnormalities present. The long-term results have been successful.

Current management of juvenile idiopathic arthritis affecting the craniovertebral junction.

PURPOSE: Craniovertebral instability is a rare and serious problem. While previously treated surgically, better understanding of disease processes has permitted the field to move towards conservative management. Juvenile idiopathic arthritis (JIA) is one cause of pediatric craniovertebral instability. Early recognition and institution of appropriate medical therapy and bracing in a multidisciplinary fashion is critical to avoid long-term instability, joint abnormalities, or morbid surgical procedures. We seek to highlight cases of this rare problem and provide a principled approach to management decisions. METHODS: We review 6 cases that have presented over the last 6 years and highlight 3 cases in particular regarding craniovertebral instability as a presentation of JIA. We reviewed the clinical records and radiographic features with particular emphasis of the stability of the craniovertebral junction. RESULTS: Age range of the subjects was from 5 to 12. All patients presented with neck pain and abnormal head rotation. Four of the patients responded to medical management and/or cervical bracing with no long-term sequelae or instability. Two patients had refractory rotary subluxation, one that responded to manual reduction under pharmacological paralysis and bracing; the other had an incompetent transverse ligament requiring surgical reduction and fixation. CONCLUSIONS: Neck pain and abnormal head rotation in an older child is rare finding but should prompt suspicion as a manifestation of JIA to the general pediatrician or initial provider. Appropriate serologic studies and MRI studies with contrast at the craniovertebral junction is necessary for evaluation. Early institution of medical management and cervical bracing under a multidisciplinary team of pediatric rheumatology and neurosurgery is key to avoiding surgical intervention and long-term abnormalities at the craniovertebral junction.

Genome-wide DNA methylation investigation of glucocorticoid exposure within buccal samples.

AIM: Glucocorticoids play a major role in regulating the stress response, and an imbalance of glucocorticoids has been implicated in stress-related disorders. Within mouse models, CpGs across the genome have been shown to be differentially methylated in response to glucocorticoid treatment, and using the Infinium 27K array, it was shown that humans given synthetic glucocorticoids had DNA methylation (DNAm) changes in blood. However, further investigation of the extent to which glucocorticoids affect DNAm across a larger proportion of the genome is needed. METHODS: Buccal samples were collected before and after synthetic glucocorticoid treatment in the context of a dental procedure. This included 30 tooth extraction surgery patients who received 10 mg of dexamethasone. Genome-wide DNAm was assessed with the Infinium HumanMethylationEPIC array. RESULTS: Five CpGs showed genome-wide significant DNAm changes that were >10%. These differentially methylated CpGs were in or nearest the following genes: ZNF438, KLHDC10, miR-544 or CRABP1, DPH5, and WDFY2. Using previously published datasets of human blood gene expression changes following dexamethasone exposure, a significant proportion of genes with false-discovery-rate-adjusted significant CpGs were also differentially expressed. A pathway analysis of the genes with false-discovery-rate-adjusted significant CpGs revealed significant enrichment of olfactory transduction, pentose and glucuronate interconversions, ascorbate and aldarate metabolism, and steroid hormone biosynthesis pathways. CONCLUSION: High-dose synthetic glucocorticoid administration in the setting of a dental procedure was significantly associated with DNAm changes within buccal samples. These findings are consistent with prior findings of an influence of glucocorticoids on DNAm in humans.

Intracranial extradural arachnoid cyst in a child.

INTRODUCTION: Arachnoid cysts are benign developmental anomalies of arachnoid membrane origin that can occur anywhere along the neuro-axis. They are believed to develop from the splitting or duplication of the arachnoid membrane by CSF that is trapped by a ball-valve mechanism. Intracranial arachnoid cysts have only been described as intradural lesions while spinal arachnoid cysts can be both intradural or extradural. CASE REPORT: After an extensive literature review, we report the first case of an intracranial, extradural arachnoid cyst in a 5-yearold girl. The child presented with a 2-week history of suspected seizure-like activity and imaging revealed a large midline extradural CSF-containing arachnoid cyst causing severe compression of the superior sagittal sinus and underlying brain. Venous flow through the sagittal sinus was nearly obliterated. Osseous changes and bone growth adjacent to the cyst was also noted on imaging and intraoperatively. She underwent a bifrontal craniotomy and cyst excision with decompression of underlying brain and reestablishment of venous flow through the sagittal sinus.

Infantile cranial fasciitis: case-based review and operative technique.

BACKGROUND: Cranial fasciitis (CF) is an uncommon benign primary lesion of the skull that typically affects the pediatric age group. Due to the rarity of CF, no prospective studies exist. Earliest description of this condition dates to 1980. The limited scientific and clinical literature regarding CF is dominated by case reports. For these reasons, questions pertaining to the true incidence, genetic risk factors, prognosis, and long-term outcome remain unanswered. DISCUSSION: Clinically, CF presents as a firm, painless, growing scalp mass that is typically not considered in the differential diagnosis. Preoperative pathognomonic signs and symptoms are absent, and imaging features are often nonspecific. Treatment is typically through complete surgical resection, at which time histopathological examination confirms the diagnosis of CF. Reconstruction of the skull defect in the child is critical. Autograft techniques help maintain a rigid construct that integrates with the native skull while preserving its continued ability to grow. Generally, a good outcome is observed with complete resection. EXEMPLARY CASE: We report a case of CF in an infant with emphasis on operative nuances and early follow-up results. CONCLUSION: CF is a rare fibroproliferative disease that has a poorly defined incidence and long-term follow-up. Due to its locally invasive nature and nonspecific presentation, CF is often difficult to differentiate from malignancies and infections. Complete surgical resection is the best approach for diagnosis and cure. Its occult clinical presentation often allows it to achieve considerable growth, leaving a sizeable skull defect following resection. Since CF presents in the pediatric population, allograft reconstruction is preferred over titanium mesh or other synthetic materials to allow osseous integration and continued uninterrupted skull growth.

Breathing Inhibited When Seizures Spread to the Amygdala and upon Amygdala Stimulation.

Sudden unexpected death in epilepsy (SUDEP) is increasingly recognized as a common and devastating problem. Because impaired breathing is thought to play a critical role in these deaths, we sought to identify forebrain sites underlying seizure-evoked hypoventilation in humans. We took advantage of an extraordinary clinical opportunity to study a research participant with medically intractable epilepsy who had extensive bilateral frontotemporal electrode coverage while breathing was monitored during seizures recorded by intracranial electrodes and mapped by high-resolution brain imaging. We found that central apnea and O2 desaturation occurred when seizures spread to the amygdala. In the same patient, localized electrical stimulation of the amygdala reproduced the apnea and O2 desaturation. Similar effects of amygdala stimulation were observed in two additional subjects, including one without a seizure disorder. The participants were completely unaware of the apnea evoked by stimulation and expressed no dyspnea, despite being awake and vigilant. In contrast, voluntary breath holding of similar duration caused severe dyspnea. These findings suggest a functional connection between the amygdala and medullary respiratory network in humans. Moreover, they suggest that seizure spread to the amygdala may cause loss of spontaneous breathing of which patients are unaware, and thus has potential to contribute to SUDEP. SIGNIFICANCE STATEMENT: Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in patients with chronic refractory epilepsy. Impaired breathing during and after seizures is common and suspected to play a role in SUDEP. Understanding the cause of this peri-ictal hypoventilation may lead to preventative strategies. In epilepsy patients, we found that seizure invasion of the amygdala co-occurred with apnea and oxygen desaturation, and electrical stimulation of the amygdala reproduced these respiratory findings. Strikingly, the subjects were unaware of the apnea. These findings indicate a functional connection between the amygdala and brainstem respiratory network in humans and suggest that amygdala seizures may cause loss of spontaneous breathing of which patients are unaware-a combination that could be deadly.