Delayed presentation of traumatic supra- and infratentorial extradural hematoma: illustrative case.

BACKGROUND: Supra- and infratentorial epidural hematomas (SIEDHs) are a rare subtype of epidural hematoma (EDH), showing expanding bleeding on both sides of the tentorium, and account for <2% of EDHs (Aji, Apriawan, and Bajamal, 2018). These lesions can typically expand and decompensate quickly, making immediate diagnosis and surgical intervention crucial. OBSERVATIONS: The authors' patient presented >48 hours from a blunt trauma to the right side of the head with progressive vomiting and bruising behind the right ear. He had a Glasgow Coma Scale score of 15 on arrival. Head computed tomography showed an SIEDH measuring approximately 3 cm, and, given the hematoma's size and mass effect, the patient was taken emergently to the operating room for decompression, where the source of bleeding was noted to be an emissary vein from the transverse sinus. The linear parietooccipital fracture was mended with mesh cranioplasty. Patient imaging and follow-up showed an excellent recovery. LESSONS: Although SIEDH is rare, patients can present in a delayed fashion and be neurologically intact. The threshold to obtain imaging to rule out delayed hemorrhage should be low in any patient with a history of trauma in the region of a dural venous sinus.

Discontinuation of Levetiracetam and Valproic Acid Due to Adverse Effects in Early Post-traumatic Seizure Prophylaxis.

INTRODUCTION: Levetiracetam (LEV) and valproic acid (VPA) are two anti-epileptic drugs (AEDs) routinely used for post-traumatic seizure (PTS) prophylaxis at our institution. In our practice, VPA is used for its beneficial effects on behavioral agitation and headaches, but it is also associated with abnormal liver function tests (LFTs). Both medications may be associated with thrombocytopenia. There is less literature comparing the adverse effect profiles and discontinuation rates of LEV and VPA in the context of PTS prophylaxis. We conducted a quality improvement (QI) analysis to determine the safety of LEV and VPA for traumatic brain injury (TBI) patients at our institution. In particular, our QI analysis involved calculating the rates of discontinuation or change of drug regimen due to the adverse effects. METHODS: Our QI analysis focused on patients treated for TBI at our institution during a six-year period. We recorded the AED used and if the AED was discontinued or switched due to thrombocytopenia, behavioral agitation, headaches, or elevated LFTs (including elevated aspartate aminotransferase or alanine aminotransferase values). We also recorded the incidence of early PTS, defined as seizures within seven days of the TBI. RESULTS: Our QI analysis included patients with a mean age of approximately 49 years with nearly 75% males. The mean Glasgow Coma Scale (GCS) score was 12.88, with 73.11% of patients having a mild GCS. The three leading injury mechanisms were fall, assault, and motor vehicle collision. The three leading types of TBI were traumatic subarachnoid hemorrhage, subdural hematoma, and cerebral contusion. Among patients with no prior history of seizures, we found an early PTS incidence of 7.28%. For patients administered LEV and VPA, 0.11% (1/898) and 3.85% (4/104) had the medication discontinued or changed because of thrombocytopenia (p < 0.001), respectively. For patients on LEV, 4.01% (36/898) and 1.78% (16/898) had the medication discontinued or changed because of behavioral agitation and headaches, respectively. For patients on VPA, 2.88% (3/104) had the medication discontinued or changed because of hepatotoxicity. In total, 5.90% versus 6.73% (p > 0.5) of patients on LEV and VPA, respectively, had their medication regimens changed due to the adverse effects. CONCLUSIONS: The incidence of early PTS in our patients is within the range of what has been reported in the literature. The rate of discontinuation of LEV and VPA on account of adverse events is low in the context of PTS prophylaxis. Both medications had similar overall rates of discontinuation. VPA was discontinued more frequently than LEV due to thrombocytopenia, but discontinuation was not common in either case. LEV is associated with behavioral agitation and headaches, which makes VPA a desirable alternative for patients suffering from these symptoms.

Delayed Traumatic Intracerebral Hematoma: A Pathophysiological Classification and Literature Review.

Delayed traumatic intracerebral hematoma (DTICH) is a relatively common occurrence after a traumatic brain injury (TBI). Several case series have been performed to study DTICH, many of which offer different definitions of DTICH. Some definitions involve a delayed progression of an existing hemorrhage, and others involve a de novo intracerebral hematoma that was not evident on the initial trauma evaluation. We propose a classification system for DTICH that accounts for the subtleties in the clinical manifestation and pathophysiology of the different types of DTICH, with the ultimate goal of providing strategies to prevent and manage DTICH. Based on the senior author's clinical experience, we generated a classification system for DTICH, and each type of DTICH was illustrated with a case. We defined type 1A (case 1A), the classic presentation of DTICH as predominantly characterized in the literature, as an intracerebral hematoma unseen on initial computed tomography imaging that typically develops five days to one week following blunt or penetrating head trauma. We defined type 1B (case 1B) as a hematoma that forms after at least one week following trauma in areas of the brain initially hemorrhage-free. We defined type 2 (case 2) as a hematoma that develops rapidly following a surgical evacuation of a different hematoma. We defined type 3 (case 3) as a hematoma that develops after a traumatic head injury in areas of non-hemorrhagic contusion, usually frontal or temporal. A literature review was performed using select terms on PubMed to find articles related to DTICH, excluding articles describing DTICH from an underlying vascular injury. After performing the literature review and screening articles by title and/or abstract, a total of 79 articles were found to meet the inclusion and exclusion criteria. We recorded which type of DTICH from our classification system best correlated with the articles in our literature review. Taken together with results from the literature, the proposed classification system is based on the senior author's clinical experience. Overall, DTICH is a relatively common occurrence after head trauma, and our pathophysiologic classification has the potential to help outline future studies to recognize and prevent the development of DTICH.

Predicting nonlinear relationships between external and internal concentrations with physiologically based pharmacokinetic modeling.

Although external concentrations are more readily quantified and often used as the metric for regulating and mitigating exposures to environmental chemicals, the toxicological response to an environmental chemical is more directly related to its internal concentrations than the external concentration. The processes of absorption, distribution, metabolism, and excretion (ADME) determine the quantitative relationship between the external and internal concentrations, and these processes are often susceptible to saturation at high concentrations, which can lead to nonlinear changes in internal concentrations that deviate from proportionality. Using generic physiologically-based pharmacokinetic (PBPK) models, we explored how saturable absorption or clearance influence the shape of the internal to external concentration (IEC) relationship. We used the models for hypothetical chemicals to show how differences in kinetic parameters can impact the shape of an IEC relationship; and models for styrene and caffeine to explore how exposure route, frequency, and duration impact the IEC relationships in rat and human exposures. We also analyzed available plasma concentration data for 2,4-dichlorophenoxyacetic acid to demonstrate how a PBPK modeling approach can be an alternative to common statistical methods for analyzing dose proportionality. A PBPK modeling approach can be a valuable tool used in the early stages of a chemical safety assessment program to optimize the design of longer-term animal toxicity studies or to interpret study results.

Opportunities and challenges related to saturation of toxicokinetic processes: Implications for risk assessment.

Top dose selection for repeated dose animal studies has generally focused on identification of apical endpoints, use of the limit dose, or determination of a maximum tolerated dose (MTD). The intent is to optimize the ability of toxicity tests performed in a small number of animals to detect effects for hazard identification. An alternative approach, the kinetically derived maximum dose (KMD), has been proposed as a mechanism to integrate toxicokinetic (TK) data into the dose selection process. The approach refers to the dose above which the systemic exposures depart from being proportional to external doses. This non-linear external-internal dose relationship arises from saturation or limitation of TK process(es), such as absorption or metabolism. The importance of TK information is widely acknowledged when assessing human health risks arising from exposures to environmental chemicals, as TK determines the amount of chemical at potential sites of toxicological responses. However, there have been differing opinions and interpretations within the scientific and regulatory communities related to the validity and application of the KMD concept. A multi-stakeholder working group, led by the Health and Environmental Sciences Institute (HESI), was formed to provide an opportunity for impacted stakeholders to address commonly raised scientific and technical issues related to this topic and, more specifically, a weight of evidence approach is recommended to inform design and dose selection for repeated dose animal studies. Commonly raised challenges related to the use of TK data for dose selection are discussed, recommendations are provided, and illustrative case examples are provided to address these challenges or refute misconceptions.