Management of Intracranial Pressure in Traumatic Brain Injury

Traumatic brain injury (TBI) is the result of an external force acting upon the head, causing damage to the brain. The severity of injury, mechanism by which the injury occurs, and the frequency of the high-force impact all play a role in the determination of a TBI. TBI describes a wide range of traumatic pathologies which is comprised of damage done to a multitude of cranial central nervous system components. TBI patients typically present with a series of symptoms are correlated with the presence of an intracranial injury, such as physical/cognitive difficulties. A major concern associated with intracranial injuries is the management of intracranial pressure (ICP), a resulting factor of a TBI which facilitates into intracranial hematoma and/or cerebral edema. These conditions have adverse effects on one’s brain, and the immediate management and relief of intracranial pressure are crucial in avoiding hydrocephalus and brain herniation, conditions which lead to sensory loss and even death. In this chapter, we will begin by thoroughly understanding what a TBI is, its clinical presentation, and the first-tier examination to determine severity. Then, we will progress into the anatomy of the brain, followed by a thorough investigation into intracranial pressure management strategies and prognosis

Diffuse Axonal Injury: A Devastating Pathology

Traumatic brain injury (TBI) also known as intracranial injury is the result of a lesion within the brain due to an external force. Common forms of TBI result from falls, violence, and/or vehicle crashes; the classification of this pathology is dependent on the severity of the lesion as well as the mechanism of trauma to the head. One of the most common onsets of traumatic brain injuries result from mild to severe lesions to the white matter tracts of the brain called diffuse axonal injury (DAI); however, additional forms of TBI’s can present in non-penetrating forms. Penetrating forms of TBI’s such as trauma to the head via a foreign object do also contribute to the many millions of TBI cases per year, but we will not discuss these traumatic injuries as in depth within this chapter. The onset of diffuse axonal injury will vary on a per-patient basis from mild to severe, based on a standardized neurological examination rated on the Glasgow Coma Scale (GCS), which indicates the severity of brain damage present. While there is a spectrum of severity for DAI patients, a concussion is typically observed within a larger majority of patients in addition to other overwhelming trauma

Management Strategies and Outcomes for VHL-related Craniospinal Hemangioblastomas

Hemangioblastomas are rare and benign tumors accounting for less than 2% of all central nervous system (CNS) tumors. The vast majority of hemangioblastomas occur sporadically, whereas a small number of cases, especially in younger patients, are associated with Von Hippel–Lindau (VHL) syndrome. It is thought that loss of tumor suppressor function of the VHL gene results in stabilization of hypoxia-inducible factor alpha with downstream activation of cellular proliferative and angiogenic genes that promote tumorigenesis. VHL-related hemangioblastomas predominantly occur in the cerebellum and spine. Lesions are often diagnosed on contrast-enhanced craniospinal MRIs, and the diagnosis of VHL occurs through assessment for germline VHL mutations. Surgical resection remains the primary treatment modality for symptomatic or worrisome lesions, with excellent local control rates and neurological outcomes. Stereotactic radiotherapy can be employed in patients who are deemed high risk for surgery, have multiple lesions, or have non-resectable lesions. Given the tendency for development of either new or multiple lesions, close radiographic surveillance is often recommended for asymptomatic lesions

Management Strategies and Outcomes for VHL-related Craniospinal Hemangioblastomas

<p>Hemangioblastomas are rare and benign tumors accounting for less than 2% of all central nervous system (CNS) tumors. The vast majority of hemangioblastomas occur sporadically, whereas a small number of cases, especially in younger patients, are associated with Von Hippel–Lindau (VHL) syndrome. It is thought that loss of tumor suppressor function of the VHL gene results in stabilization of hypoxia-inducible factor alpha with downstream activation of cellular proliferative and angiogenic genes that promote tumorigenesis. VHL-related hemangioblastomas predominantly occur in the cerebellum and spine. Lesions are often diagnosed on contrast-enhanced craniospinal MRIs, and the diagnosis of VHL occurs through assessment for germline VHL mutations. Surgical resection remains the primary treatment modality for symptomatic or worrisome lesions, with excellent local control rates and neurological outcomes. Stereotactic radiotherapy can be employed in patients who are deemed high risk for surgery, have multiple lesions, or have non-resectable lesions. Given the tendency for development of either new or multiple lesions, close radiographic surveillance is often recommended for asymptomatic lesions.</p

The JAK inhibitor tofacitinib rescues intestinal barrier defects caused by disrupted epithelial-macrophage interactions

BACKGROUND AND AIMS Loss-of-function variants in protein tyrosine phosphatase non-receptor type-2 (PTPN2) promote susceptibility to inflammatory bowel diseases (IBD). PTPN2 regulates Janus-kinase (JAK) and signal transducer and activator of transcription (STAT) signaling, while protecting the intestinal epithelium from inflammation-induced barrier disruption. The pan-JAK inhibitor, tofacitinib, is approved to treat ulcerative colitis but its effects on intestinal epithelial cell-macrophage interactions and on barrier properties are unknown. We aimed to determine if tofacitinib can rescue disrupted epithelial-macrophage interaction and barrier function upon loss of PTPN2. METHODS Human Caco-2BBe intestinal epithelial cells (IECs) and THP-1 macrophages expressing control or PTPN2-specific shRNA were co-cultured with tofacitinib or vehicle. Transepithelial electrical resistance and 4 kDa fluorescein-dextran flux were measured to assess barrier function. Ptpn2fl/fl and Ptpn2-LysMCre mice, which lack Ptpn2 in myeloid cells, were treated orally with tofacitinib citrate twice daily to assess the in vivo effect on the intestinal epithelial barrier. Colitis was induced via administration of 1.5% DSS in drinking water. RESULTS Tofacitinib corrected compromised barrier function upon PTPN2 loss in macrophages and/or IECs via normalization of (i) tight junction protein expression, (ii) excessive STAT3 signaling, and (iii) IL-6 and IL-22 secretion. In Ptpn2-LysMCre mice, tofacitinib reduced colonic pro-inflammatory macrophages, corrected underlying permeability, and prevented the increased susceptibility to DSS colitis. CONCLUSIONS PTPN2 loss in IECs or macrophages compromises IEC-macrophage interactions and reduces epithelial barrier integrity. Both of these events were corrected by tofacitinib in vitro and in vivo. Tofacitinib may have greater therapeutic efficacy in IBD patients harboring PTPN2 loss-of-function mutations