Delivery of Adeno-Associated Virus Vectors to the Central Nervous System for Correction of Single Gene Disorders.

Genetic disorders of the central nervous system (CNS) comprise a significant portion of disability in both children and adults. Several preclinical animal models have shown effective adeno-associated virus (AAV) mediated gene transfer for either treatment or prevention of autosomal recessive genetic disorders. Owing to the intricacy of the human CNS and the blood-brain barrier, it is difficult to deliver genes, particularly since the expression of any given gene may be required in a particular CNS structure or cell type at a specific time during development. In this review, we analyzed delivery methods for AAV-mediated gene therapy in past and current clinical trials. The delivery routes analyzed were direct intraparenchymal (IP), intracerebroventricular (ICV), intra-cisterna magna (CM), lumbar intrathecal (IT), and intravenous (IV). The results demonstrated that the dose used in these routes varies dramatically. The average total doses used were calculated and were 1.03 × 1013 for IP, 5.00 × 1013 for ICV, 1.26 × 1014 for CM, and 3.14 × 1014 for IT delivery. The dose for IV delivery varies by patient weight and is 1.13 × 1015 IV for a 10 kg infant. Ultimately, the choice of intervention must weigh the risk of an invasive surgical procedure to the toxicity and immune response associated with a high dose vector.

Diffusely invasive supratentorial rosette-forming glioneuronal tumor: illustrative case.

BACKGROUND: Rosette-forming glioneuronal tumors (RGNTs) are rare tumors composed of mixed glial and neurocytic components. Most lesions are confined to the posterior fossa, especially in the region of the fourth ventricle, in young adults. In few instances, diffuse involvement of the supratentorial region is identified, thereby creating significant challenges in diagnosis, surgical intervention, and prognostication. OBSERVATIONS: The authors present a 23-year-old female with chronic headaches, papilledema, and hydrocephalus who underwent radiographic evaluation revealing obstructive hydrocephalus and diffuse supratentorial enhancing and nonenhancing cystic and nodular lesions. The patient underwent a right frontal craniotomy and septostomy. An exophytic nonenhancing right frontal horn lesion was resected, and an enhancing third-ventricular lesion was biopsied. Final pathology of both of the lesions sampled was consistent with RGNT. Next-generation sequencing demonstrated tumor alterations in the FGFR-1 and PIK3CA genes. Targeted therapy with the FGFR inhibitor erdafitinib demonstrated a partial remission. LESSONS: Diffuse supratentorial spread of RGNT is an extremely rare presentation of an already uncommon pathology. In some cases, gross-total resection may not be feasible. Goals of surgery include acquiring tissue for diagnosis, maximizing safe resection, and treating any associated hydrocephalus. FGFR inhibitors may be of benefit in cases of disease progression.

Spontaneous Propionibacterium Acnes abscess with intraventricular rupture in an immunocompetent adult without prior neurosurgical intervention.

Previously viewed as a culture contaminant, Propionibacterium Acnes can cause infection following neurosurgical intervention. Its role in brain abscess in the immunocompetent, surgically naïve population has been infrequently reported. Herein, we describe an immunocompetent 55-year-old man with no risk factors found to have a thalamic abscess with intraventricular rupture.

Utilization of anterior lumbar interbody fusion for severe kyphotic deformity secondary to Pott's disease: illustrative case.

BACKGROUND: Spinal tuberculosis may result in severe kyphotic deformity. Effective restoration of lordosis and correction of sagittal balance often requires invasive osteotomies associated with significant morbidity. The advantages of focusing on symptomatic management and staging in the initial treatment of these deformities have not been well reported to date. OBSERVATIONS: The authors reported the case of a 64-year-old Vietnamese woman with a history of spinal tuberculosis who underwent anterior lumbar interbody fusion (ALIF) for symptomatic treatment of L5-S1 radiculopathy resulting from fixed kyphotic deformity. Postoperatively, the patient experienced near immediate symptom improvement, and radiographic evidence at 1-year follow-up showed continued lordotic correction of 30° as well as stable sagittal balance. LESSONS: In this case, an L5-S1 ALIF was sufficient to treat the patient's acute symptoms and provided satisfactory correction of a tuberculosis-associated fixed kyphotic deformity while effectively delaying more invasive measures, such as a vertebral column resection. Patients with adult spinal deformity may benefit from less invasive staging procedures before treating these deformities with larger surgeries.

Evidence for increased intraabdominal pressure as a cause of recurrent migration of the distal catheter of a ventriculoperitoneal shunt: illustrative case.

BACKGROUND: Placement of a ventriculoperitoneal (VP) shunt is an effective treatment for several disorders of cerebrospinal fluid flow. A rare complication involves postoperative migration of the distal catheter out of the intraperitoneal compartment and into the subcutaneous space. Several theories attempt to explain this phenomenon, but the mechanism remains unclear. OBSERVATIONS: The authors report the case of a 37-year-old nonobese woman who underwent placement of a VP shunt for idiopathic intracranial hypertension. Postoperatively, the distal catheter of the VP shunt migrated into the subcutaneous space on three occasions despite the use of multiple surgical techniques, including open and laparoscopic methods of abdominal catheter placement. Notably, the patient repeatedly displayed radiographic evidence of chronic bowel distention consistent with increased intraperitoneal pressure. LESSONS: In this case, the mechanism of catheter migration into the subcutaneous space did not appear to be caused by pulling of the catheter from above but rather by expulsion of the catheter from the peritoneum. Space in the subcutaneous tissues caused by open surgical placement of the catheter was permissive for this process. Patients with chronic increased intraabdominal pressure, such as that caused by bowel distention, obesity, or Valsalva maneuvers, may be at increased risk for distal catheter migration.

Would you use novel oral anticoagulants (NOACs) for thromboprophylaxis in patients with an underlying hypercoagulable state? A literature review through a case report.

Antiphospholipid syndrome (APLS) is an autoimmune condition that predisposes to venous and arterial thrombosis. Warfarin is the agent of choice for anticoagulation. However, a need for routine international normalised ratio (INR) checks and multiple drug interactions are some of the difficulties with warfarin. Currently, there is mixed evidence for and against the use of novel oral anticoagulants (NOACs) for thromboprophylaxis. We present a case report of a patient with APLS on a NOAC for secondary thromboprophylaxis who developed a stroke and discuss current evidence regarding the use of NOACs in patients with APLS. The patient was switched to warfarin for secondary thromboprophylaxis with an INR goal of 2-3. Literature review revealed mixed case reports for and against NOACs for secondary prevention of thrombotic events in patients with APLS. There needs to be further randomised controlled trials to evaluate the efficacy of NOACs for thromboprophylaxis in patients with APLS.

Association of Patterns of Mild Traumatic Brain Injury with Neurologic Deterioration: Experience at a Level I Trauma Center.

INTRODUCTION: There are about 2.5 million emergency room visits for traumatic brain injury (TBI) every year and 75%-95% of all TBI patients have mild TBI. Previous studies have suggested that a large proportion of mild TBI patients can be treated in a non-aggressive manner, but they have not differentiated mild TBI as per radiological patterns to help in the selection of these patients. Our study aimed to identify different patterns of mild TBI to determine if certain injuries make patients more prone to neurologic worsening than others, and thus require more intensive monitoring. We also studied the factors associated with neurologic deterioration. METHODS: We conducted a retrospective study using an institutional trauma database to identify TBI patients between the years of 2015 and 2016 with admission Glasgow Coma Score (GCS) of 13 to 15, through chart review by the investigators. Radiological and neurological worsening was determined through computed tomography (CT) scan results, GCS scores, and the requirement for neurosurgical intervention. We identified the prevalence of demographic characteristics, radiological patterns, and risk factors. We studied neurologic deterioration (decline in GCS to less than 13 at 48 hours or earlier after admission) and surgical intervention among patients with different radiological patterns of TBI. We further studied the cohort of isolated subdural hematoma (SDH) patients requiring surgery to evaluate the associated risk factors. RESULTS: Out of 374 patients with mild TBI (mean age was 63 years), 59% were male, 77% were Caucasian, the median GCS was 15, majority of patients had isolated SDH (45%), and mixed pattern of hemorrhage (39%); the use of antiplatelet (33%) was the most commonly identified risk factors. Overall 7% of patients were found to have neurologic deterioration (GCS to less than 13) and 9% required surgical intervention at 48 hours or earlier after admission. The most common pattern of TBI requiring surgical intervention was isolated SDH (85%). Among the cohort of patients with isolated SDH, 17% required surgical intervention and 69% of those isolated SDH patients requiring surgery had neurologic deterioration. The most common risk factor in isolated SDH patients requiring surgery was antiplatelet use (34%), anticoagulant use (20%), alcohol abuse (17%), severe renal failure (17%), and thrombocytopenia (7%). Mean size of SDH in patients requiring surgery was 1.6 cm with 0.8 cm of midline shift. CONCLUSION: This study identified the pattern of mild TBI associated with neurological worsening at our Level I Trauma Center. Among patients with mild TBI, SDH patients seem to be at highest risk for deterioration and requirement for surgery. If these results can be externally validated through a multi-center study, these patients could be selectively identified for aggressive monitoring in the intensive care unit (ICU) and repeat CT scans.