Activated gliosis, accumulation of amyloid ß, and hyperphosphorylation of tau in aging canines with and without cognitive decline.

Canine cognitive dysfunction (CCD) syndrome is a well-recognized naturally occurring disease in aged dogs, with a remarkably similar disease course, both in its clinical presentation and neuropathological changes, as humans with Alzheimer's disease (AD). Similar to human AD patients this naturally occurring disease is found in the aging canine population however, there is little understanding of how the canine brain ages pathologically. It is well known that in neurodegenerative diseases, there is an increase in inflamed glial cells as well as an accumulation of hyperphosphorylation of tau (P-tau) and amyloid beta (Aß1-42). These pathologies increase neurotoxic signaling and eventual neuronal loss. We assessed these brain pathologies in aged canines and found an increase in the number of glial cells, both astrocytes and microglia, and the activation of astrocytes indicative of neuroinflammation. A rise in the aggregated protein Aß1-42 and hyperphosphorylated tau, at Threonine 181 and 217, in the cortical brain regions of aging canines. We then asked if any of these aged canines had CCD utilizing the only current diagnostic, owner questionnaires, verifying positive or severe CCD had pathologies of gliosis and accumulation of Aß1-42 like their aged, matched controls. However uniquely the CCD dogs had P-tau at T217. Therefore, this phosphorylation site of tau at threonine 217 may be a predictor for CCD.

Acute liver failure in a military recruit treated with valproic acid and harboring a previously unrecognized POLG-1 mutation.

Patients with mutations in the POLG-1 gene often are afflicted with drug-resistant seizures at an early age and have an increased risk of valproic acid-induced acute liver failure. Severe valproate hepatotoxicity most commonly arises in children within the first 3 months of treatment with an overall estimated incidence of 1 in 40,000 treated patients. Due to high mortality rates among transplanted children, many experts consider valproic acid-induced acute liver failure in patients with mitochondrial disorders to be a contraindication to liver transplant. We report the successful use of liver transplantation in a young man with valproic acid-associated acute liver failure harboring a previously unrecognized POLG-1 mutation.

Olfactory impairment and traumatic brain injury in blast-injured combat troops: a cohort study.

OBJECTIVE: To determine whether a structured and quantitative assessment of differential olfactory performance-recognized between a blast-injured traumatic brain injury (TBI) group and a demographically comparable blast-injured control group-can serve as a reliable antecedent marker for preclinical detection of intracranial neurotrauma. METHODS: We prospectively and consecutively enrolled 231 polytrauma inpatients, acutely injured from explosions during combat operations in either Afghanistan or Iraq and requiring immediate stateside evacuation and sequential admission to our tertiary care medical center over a 2½-year period. This study correlates olfactometric scores with both contemporaneous neuroimaging findings as well as the clinical diagnosis of TBI, tabulates population-specific incidence data, and investigates return of olfactory function. RESULTS: Olfactometric score predicted abnormal neuroimaging significantly better than chance alone (area under the curve = 0.78, 95% confidence interval [CI] 0.70-0.87). Normosmia was present in all troops with mild TBI (i.e., concussion) and all control subjects. Troops with radiographic evidence of frontal lobe injuries were 3 times more likely to have olfactory impairment than troops with injuries to other brain regions (relative risk 3.0, 95% CI 0.98-9.14). Normalization of scores occurred in all anosmic troops available for follow-up testing. CONCLUSION: Quantitative identification olfactometry has limited sensitivity but high specificity as a marker for detecting acute structural neuropathology from trauma. When considering whether to order advanced neuroimaging, a functional disturbance with central olfactory impairment should be regarded as an important tool to inform the decision process. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that central olfactory dysfunction identifies patients with TBI who have intracranial radiographic abnormalities with a sensitivity of 35% (95% CI 20.6%-51.7%) and specificity of 100% (95% CI 97.7%-100.0%).

Epidemiologic aspects of traumatic brain injury in acute combat casualties at a major military medical center: a cohort study.

OBJECTIVE: From the ongoing military conflicts in Iraq and Afghanistan, an understanding of the neuroepidemiology of traumatic brain injury (TBI) has emerged as requisite for further advancements in neurocombat casualty care. This study reports population-specific incidence data and investigates TBI identification and grading criteria with emphasis on the role of loss of consciousness (LOC) in the diagnostic rubric. METHODS: This is a cohort study of all consecutive troops acutely injured during combat operations-sustaining body-wide injuries sufficient to require immediate stateside evacuation-and admitted sequentially to our medical center during a 2-year period. A prospective exploration of the TBI identification and grading system was performed in a homogeneous population of blast-injured polytrauma inpatients. RESULTS: TBI incidence was 54.3%. Structural neuroimaging abnormalities were identified in 14.0%. Higher Injury Severity Score (ISS) was associated with abnormal neuroimaging, longer length of stay (LOS), and elevated TBI status-primarily based on autobiographical LOC. Mild TBI patients had normal neuroimaging, higher ISS, and comparable LOS to TBI-negative patients. Patients who reported LOC had a lower incidence of abnormal neuroimaging. INTERPRETATION: This study demonstrates that the methodology used to assign the diagnosis of a mild TBI in troops with complex combat-related injuries is crucial to an accurate accounting. The detection of incipient mild TBI, based on an identification system that utilizes LOC as the principal diagnostic criterion to discern among patients with outcomes of interest, misclassifies patients whose LOC may not reflect actual brain injury. Attempts to identify high-risk battlefield casualties within the current point-of-injury mild TBI case definition, which favors high sensitivity, will be at the expense of specificity.

Outcomes of 33 patients from the wars in Iraq and Afghanistan undergoing bilateral or bicompartmental craniectomy.

OBJECT: There are no published long-term data for patients with penetrating head injury treated with bilateral supratentorial craniectomy, or supra- and infratentorial craniectomy. The authors report their experience with 33 patients treated with bilateral or bicompartmental craniectomy from the ongoing conflicts in Iraq and Afghanistan. METHODS: An exploratory analysis of Glasgow Outcome Scale (GOS) scores at 6 months in 33 patients was performed. Follow-up lasting a median of more than 2 years was performed in 30 (91%) of these patients. The association of GOS score with categorical variables was explored using the Wilcoxon rank-sum test or Kruskal-Wallis analysis of variance. The Spearman correlation coefficient was used for ordinal/continuous data. To provide a clinically meaningful format to present GOS scores with categorical variables, patients with GOS scores of 1-3 were categorized as having a poor outcome and those with scores of 4 and 5 as having a good outcome. This analysis does not include the patients who died in theater or in Germany who underwent bilateral decompressive craniectomy because those figures have not been released due to security concerns. RESULTS: All patients were men with a median age of 24 years (range 19-46 years) and a median initial Glasgow Coma Scale (GCS) score of 5 (range 3-14). At 6 months, 9 characteristics were statistically significant: focus of the initial injury, systemic infection, initial GCS score, initial GCS score excluding patients with a GCS score of 3, GCS score on arrival to the US, GCS score on dismissal from the medical center, Injury Severity Score, and patients with cerebrovascular injury. Six factors were significant at long-term follow-up: focus of initial injury, systemic infection, initial GCS score excluding patients with a GCS score of 3, GCS score on arrival to the US, and GCS score on dismissal from the medical center. At long-term follow-up, 7 (23%) of 30 patients had died, 5 (17%) of 30 had a GOS score of 2 or 3, and 18 (60%) of 30 had a GOS score of 4 or 5. CONCLUSIONS: In this selected group of patients who underwent bilateral or bicompartmental craniectomy, 60% are independent at long-term follow-up. Patients with bifrontal injury fared best. Systemic infection and cerebrovascular injury corresponded with a worse outcome.

Early decompressive craniectomy for severe penetrating and closed head injury during wartime.

OBJECT: Decompressive craniectomy has defined this era of damage-control wartime neurosurgery. Injuries that in previous conflicts were treated in an expectant manner are now aggressively decompressed at the far-forward Combat Support Hospital and transferred to Walter Reed Army Medical Center (WRAMC) and National Naval Medical Center (NNMC) in Bethesda for definitive care. The purpose of this paper is to examine the baseline characteristics of those injured warriors who received decompressive craniectomies. The importance of this procedure will be emphasized and guidance provided to current and future neurosurgeons deployed in theater. METHODS: The authors retrospectively searched a database for all soldiers injured in Operations Iraqi Freedom and Enduring Freedom between April 2003 and October 2008 at WRAMC and NNMC. Criteria for inclusion in this study included either a closed or penetrating head injury suffered during combat operations in either Iraq or Afghanistan with subsequent neurosurgical evaluation at NNMC or WRAMC. Exclusion criteria included all cases in which primary demographic data could not be verified. Primary outcome data included the type and mechanism of injury, Glasgow Coma Scale (GCS) score and injury severity score (ISS) at admission, and Glasgow Outcome Scale (GOS) score at discharge, 6 months, and 1-2 years. RESULTS: Four hundred eight patients presented with head injury during the study period. In this population, a total of 188 decompressive craniectomies were performed (154 for penetrating head injury, 22 for closed head injury, and 12 for unknown injury mechanism). Patients who underwent decompressive craniectomies in the combat theater had significantly lower initial GCS scores (7.7 +/- 4.2 vs 10.8 +/- 4.0, p < 0.05) and higher ISSs (32.5 +/- 9.4 vs 26.8 +/- 11.8, p < 0.05) than those who did not. When comparing the GOS scores at hospital discharge, 6 months, and 1-2 years after discharge, those receiving decompressive craniectomies had significantly lower scores (3.0 +/- 0.9 vs 3.7 +/- 0.9, 3.5 +/- 1.2 vs 4.0 +/- 1.0, and 3.7 +/- 1.2 vs 4.4 +/- 0.9, respectively) than those who did not undergo decompressive craniectomies. That said, intragroup analysis indicated consistent improvement for those with craniectomy with time, allowing them, on average, to participate in and improve from rehabilitation (p < 0.05). Overall, 83% of those for whom follow-up data are available achieved a 1-year GOS score of greater than 3. CONCLUSIONS: This study of the provision of early decompressive craniectomy in a military population that sustained severe penetrating and closed head injuries represents one of the largest to date in both the civilian and military literature. The findings suggest that patients who undergo decompressive craniectomy had worse injuries than those receiving craniotomy and, while not achieving the same outcomes as those with a lesser injury, did improve with time. The authors recommend hemicraniectomy for damage control to protect patients from the effects of brain swelling during the long overseas transport to their definitive care, and it should be conducted with foresight concerning future complications and reconstructive surgical procedures.

Temporal lobectomy for refractory epilepsy in the U.S. military.

OBJECTIVES: To determine the characteristics, seizure outcomes, and quality-of-life outcomes for military beneficiaries undergoing partial temporal lobectomy for refractory epilepsy at the only U.S. military medical center with a comprehensive epilepsy surgery program. METHODS: The records of all 84 patients treated with partial temporal lobectomy between 1986 and 2000 at Walter Reed Army Medical Center were retrospectively reviewed. Outcome measures included seizure frequency according to the Engel classification system, driving, employment, anticonvulsant use, and military service. RESULTS: The study cohort consisted of 72 military dependents, 10 active duty military members, and 2 military retirees. Two years after surgery, 65 (92%) of 71 patients had seizure improvement (Engel classes I-III) and 46 (66%) of 71 had seizure remission (Engel class I). Driving and employment rates increased after surgery, whereas anticonvulsant use decreased. Five (50%) of 10 active duty patients achieved seizure remission postoperatively and continued to serve in the Armed Forces. Active duty patients had a later age of seizure onset, shorter duration of epilepsy, and greater proportion of lesional epilepsy, compared with nonactive duty patients. CONCLUSIONS: Epilepsy surgery outcomes in the U.S. military are similar to those reported from nonmilitary centers, with the majority of patients experiencing seizure remission and improvements in quality-of-life measures. Complete seizure remission after successful anterior temporal lobectomy enables some active duty military members to continue service in the U.S. Armed Forces.

Multiple subpial transection for intractable partial epilepsy: an international meta-analysis.

PURPOSE: Because the number and variety of patients at any single facility is not sufficient for clinical or statistical analysis, data from six major epilepsy centers that performed multiple subpial transections (MSTs) for medically intractable epilepsy were collected. METHODS: A meta-analysis was performed to elucidate the indications and outcome, and to assess the results of the procedure. Overall, 211 patients were represented with data regarding preoperative evaluation, procedures, seizure types and frequencies before and after surgery, postoperative deficits, and demographic information. Fifty-three patients underwent MST without resection. RESULTS: In patients with MST plus resection, excellent outcome (>95% reduction in seizure frequency) was obtained in 87% of patients for generalized seizures, 68% for complex partial seizures, and 68% for simple partial seizures. For the patients who underwent MST without resection, the rate of excellent outcome was only slightly lower, at 71% for generalized, 62% for complex partial, and 63% for simple partial seizures. EEG localization, age at epilepsy onset, duration of epilepsy, and location of MST were not significant predictors of outcome for any kinds of seizures after MST, with or without resection. New neurologic deficits were found in 47 patients overall, comparable in MST with resection (23%) or without (19%). CONCLUSIONS: These preliminary results suggest that MST has efficacy by itself, with minimal neurologic compromise, in cases in which resective surgery cannot be used to treat uncontrolled epilepsy. MST should be investigated as a stand-alone procedure to allow further development of criteria and predictive factors for outcome.