Category Archives: Neurotrauma

Neurocritical Care for the Advanced Practice Clinician

Neurocritical Care for the Advanced Practice Clinician

Neurocritical Care for the Advanced Practice Clinician

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Product Details

  • Published on: 2017-08-21
  • Original language: English
  • Number of items: 1
  • Dimensions: 7.75″ h x 5.25″ w x 1.00″ l,
  • Binding: Hardcover
  • 470 pages

Editorial Reviews

From the Back Cover

By utilizing a review of case-based studies and providing concise management recommendations from leaders in the field, this book provides essential knowledge for those practicing in a dynamic specialty. In the rapidly developing field of Neurocritical Care, Advanced Practice Clinicians have become an integral component of the multi-disciplinary team. This essential volume provides a frame of reference for advanced practice nurses, physician assistants, physicians, and students on a wide range of common Neuro ICU diagnoses and management strategies.

About the Author

Jessica White is a physician assistant in the Neuroscience ICU at Yale New Haven Hospital.  She has served as part-time faculty at Yale University and Quinnipiac University physician assistant programs, teaching topics of neurology and neurocritical care. Her research interests include family satisfaction and the role of the physician assistant in the multi-disciplinary team. Her training was completed at Midwestern University with a Master of Medical Science from the Physician Assistant program.

 

Dr. Sheth graduated from Johns Hopkins University and the University of Pennsylvania School of Medicine. He was recruited to Yale as the founding chief of the Division of Neurocritical Care and Emergency Neurology and Chief of Clinical Research. His interests are in the advancement of therapies and care of patients with devastating acute neurological syndromes. He is a recognized clinical, a translational scientist, has directed multicenter studies testing potential therapies against brain swelling, stroke, and hemorrhage. He is the winner of the Robert Siekert Award from the American Heart Association, and his research has been funded by the NIH, American Academy of Neurology, American Heart Association(AHA). He has written over 100 publications in critical care neurology and stroke. His collaborative work is dedicated to the improved understanding of neurological disease in the critically ill.

 

Update: Decompressive craniectomy for traumatic brain injury

Decompressive craniectomy for traumatic brain injury

Intracranial hypertension is the largest cause of death in young patients with severe traumatic brain injury 1).

The management of traumatic brain injury progressed significantly in the 1980s and 1990s due to advances in neuroimaging (widespread introduction of CT scanning), prehospital management, neurointensive care (widespread adoption of ICP monitoring and tiered therapeutic protocols) and rehabilitation. This led to a renaissance of interest in decompressive craniectomy (DC) with many uncontrolled studies reporting a survival benefit with DC 2) 3).

Since that time, DC has been increasingly studied in the setting of different conditions, including subarachnoid hemorrhage, and malignant middle cerebral artery infarction.

Furthermore, dural opening, usually followed by insertion of a dural graft (duraplasty), has meanwhile become an integral part of the decompressive surgery technique 4).

The 21st century, so far, has seen consistent efforts to improve the evidence base for DC following TBI with the conduct of randomized clinical trials5).

In severely head injured children, a study has shown that decompressive craniectomy resulted in good recovery in all children in the study, suggesting the procedure has an advantage over non-surgical treatment in children.

In one of the largest studies on pediatric patients, Jagannathan et al. found a net 65% favorable outcomes rate in pediatric patients for accidental trauma after craniectomy when followed for more than five years. Only three patients were dependent on caregivers.

This is the only prospective randomised controlled study to date to support the potential benefit of decompressive craniectomy following traumatic brain injury.

Outcome

Early decompressive craniectomy (DC) has been used as the first stage treatment to prevent secondary injuries in cases of severe traumatic brain injury (TBI). Postoperative management is the major factor that influences outcome.

Intracranial pressure monitoring in conjunction with postoperative treatment, after early DC, is associated with a significantly reduced risk of death6).

Patients surviving from DC need a second operation to repair the bone defect.

In the 2010s the use of decompressive craniectomy (DC) in everyday neurosurgical practice has largely increased, even though the effectiveness of this procedure is still uncertain 7).

Complications

The conversion of the cranium from a “closed box” to an “open box” alters the barometric pressure, cerebrospinal fluid (CSF), and cerebral blood flow (CBF) and may or may not lead to syndrome of the trephined (sinking skin flap syndrome) 8).

Trials

The claim that decompressive craniectomy increases unfavourable outcome is overstated and not supported by the data presented in DECRA trial.

Sahuquillo et al. believe it premature to change clinical practice. Given the dismal outcome in these patients, it is reasonable to include this technique as a last resort in any type of protocol-driven management when conventional therapeutic measures have failed to control ICP, the presence of operable masses has been ruled out and the patient may still have a chance of a functional outcome. The main lesson to be learned from this study is that an upper threshold for ICP must be used as a cut-off for selecting decompressive craniectomy candidates 9).

see RescueICP Study.

Systematic review and meta-analysis

Although many studies have been conducted in this topic, there is still much uncertainty about the effectiveness of surgical treatment in TBI 10).

Zhang et al. aimed to perform a systematic review and metaanalysis to examine the prognostic value of decompressive craniectomy (DC) in patients with traumatic intracranial hypertension. PubMed, EMBASE, Cochrane Controlled Trials Register, Web of Science, http://clinicaltrials.gov/ were searched for eligible studies. Ten studies were included in the systematic review, with four randomized controlled trials involved in the meta-analysis, where compared with medical therapies, DC could significantly reduce mortality rate [risk ratio (RR), 0.59; 95% confidence interval (CI), 0.47-0.74, P < 0.001], lower intracranial pressure (ICP) [mean difference (MD), -2.12 mmHg; 95% CI, -2.81 to -1.43, P < 0.001], decrease the length of ICU stay (MD, -4.63 days; 95% CI, -6.62 to -2.65, P < 0.001) and hospital stay (MD, -14.39 days; 95% CI, -26.00 to -2.78, P = 0.02), but increase complications rate (RR, 1.94; 95% CI, 1.31-2.87, P < 0.001). No significant difference was detected for Glasgow Outcome Scale at six months (RR, 0.85; 95% CI, 0.61-1.18, P = 0.33), while in subgroup analysis, early DC would possibly result in improved prognosis (P = 0.04). Results from observational studies supported pooled results except prolonged length of ICU and hospital stay. Conclusively, DC seemed to effectively lower ICP, reduce mortality rate but increase complications rate, while its benefit on functional outcomes was not statistically significant 11).

Case series

2016

31 patients aged 16-72 of either sex who sustained a severe, non-penetrating TBI and underwent a unilateral DC for evacuation of parenchymal or extra-axial hematoma or for failure of medical therapy to control intracranial pressure (ICP).

Review of the electronic medical record of patients undergoing DC for severe TBI and assessment of extended Glasgow Outcome Score (e-GOS) at 6-months following DC.

The mean age was 39.3y ± 14.5. The initial GCS was 5.8 ± 3.2, and the ISS was 29.7 ± 6.3. Twenty-two patients underwent DC within the first 24 h, two within the next 24 h and seven between the 3rd and 7th day post injury. The pre-DC ICP was 30.7 ± 10.3 and the ICP was 12.1 ± 6.2 post-DC. Cranioplasty was performed in all surviving patients 1-4 months post-DC. Of the 29 survivors following DC, the e-GOS was 8 in seven patients, and 7 in ten patients. The e-GOS was 5-6 in 6 others. Of the 6 survivors with poor outcomes (e-GOS = 2-4), five were the initial patients in the series.

In patients with intractable cerebral hypertension following TBI, unilateral DC in concert with practice guideline directed brain resuscitation is associated with good functional outcome and acceptable-mortality 12).

2009

A case control study comparing a group of patients (n: 16) operated for severe TBI between January 2002 and July 2004 according to an institutional management protocol characterized by an early decompressive craniectomy (DC) approach versus a historical control group (n: 20) managed before the implementation of such protocol. Mortality and Glasgow Outcome Score (GOS) at 6 months were used as the main outcome variables.

An early DC protocol implemented within 12 hours from injury in 16 patients with severe isolated TBI and a Marshall score between III or IV was associated with a lesser mortality than the conventional approach with ventriculostomy and Intensive Care Unit (ICU) management alone. The GOS was significantly better in the DC group (p=0.0002) than in the control group.

The use of an early DC protocol for severe TBI patients (Glasgow Coma Scale <9) had a significantly improved outcome compared with the conventional approach with ventriculostomy and ICU management in Simòn Bolivar Hospital in Bogotá, Colombia 13).

1)

Alvis-Miranda H, Castellar-Leones SM, Moscote-Salazar LR. Decompressive Craniectomy and Traumatic Brain Injury: A Review. Bull Emerg Trauma. 2013 Apr;1(2):60-8. Review. PubMed PMID: 27162826; PubMed Central PMCID: PMC4771225.
2)

Polin RS, Shaffrey ME, Bogaev CA. et al.Decompressive bifrontal craniectomy in the treatment of severe refractory posttraumatic cerebral edema. Neurosurgery 19974184–92.92
3)

Whitfield PC, Patel H, Hutchinson PJ. et al.Bifrontal decompressive craniectomy in the management of posttraumatic intracranial hypertension. Br J Neurosurg 200115500–7.7
4)

Hutchinson P, Timofeev I, Kirkpatrick P. Surgery for brain edema. Neurosurg Focus.2007;22:E14
5)

Kolias AG, Adams H, Timofeev I, Czosnyka M, Corteen EA, Pickard JD, Turner C, Gregson BA, Kirkpatrick PJ, Murray GD, Menon DK, Hutchinson PJ. Decompressive craniectomy following traumatic brain injury: developing the evidence base. Br J Neurosurg. 2016 Apr;30(2):246-50. doi: 10.3109/02688697.2016.1159655. Epub 2016 Mar 14. PubMed PMID: 26972805; PubMed Central PMCID: PMC4841020.
6)

Kim DR, Yang SH, Sung JH, Lee SW, Son BC. Significance of intracranial pressure monitoring after early decompressive craniectomy in patients with severe traumatic brain injury. J Korean Neurosurg Soc. 2014 Jan;55(1):26-31. doi:10.3340/jkns.2014.55.1.26. Epub 2014 Jan 31. PubMed PMID: 24570814.
7)

Aarabi B, Hesdoffer DC, Ahn ES, Aresco C, Scalea TM, Eisenbergh HM: Outcome following decompres- sive craniectomy for malignant swelling due to se- vere head injury. J Neurosurg 104: 469–479, 2006
8)

Gadde J, Dross P, Spina M. Syndrome of the trephined (sinking skin flap syndrome) with and without paradoxical herniation: a series of case reports and review. Del Med J. 2012 Jul;84(7):213-8. PubMed PMID: 23252092.
9)

Sahuquillo J, Martínez-Ricarte F, Poca MA. Decompressive craniectomy in traumatic brain injury after the DECRA trial. Where do we stand? Curr Opin Crit Care. 2013 Apr;19(2):101-6. doi: 10.1097/MCC.0b013e32835eba1a. Review. PubMed PMID: 23422159.
10)

Moon JW, Hyun DK. Decompressive Craniectomy in Traumatic Brain Injury: A Review Article. Korean J Neurotrauma. 2017 Apr;13(1):1-8. doi: 10.13004/kjnt.2017.13.1.1. Epub 2017 Apr 30. Review. PubMed PMID: 28512611; PubMed Central PMCID: PMC5432443.
11)

Zhang D, Xue Q, Chen J, Dong Y, Hou L, Jiang Y, Wang J. Decompressive craniectomy in the management of intracranial hypertension after traumatic brain injury: a systematic review and meta-analysis. Sci Rep. 2017 Aug 18;7(1):8800. doi: 10.1038/s41598-017-08959-y. PubMed PMID: 28821777.
12)

Grindlinger GA, Skavdahl DH, Ecker RD, Sanborn MR. Decompressive craniectomy for severe traumatic brain injury: clinical study, literature review and meta-analysis. Springerplus. 2016 Sep 20;5(1):1605. doi: 10.1186/s40064-016-3251-9. eCollection 2016. PubMed PMID: 27652178; PubMed Central PMCID: PMC5028365.
13)

Rubiano AM, Villarreal W, Hakim EJ, Aristizabal J, Hakim F, Dìez JC, Peña G, Puyana JC. Early decompressive craniectomy for neurotrauma: an institutional experience. Ulus Travma Acil Cerrahi Derg. 2009 Jan;15(1):28-38. PubMed PMID: 19130336; PubMed Central PMCID: PMC3413286.

Update: Chronic traumatic encephalopathy in American football players

There is tremendous media attention regarding chronic traumatic encephalopathy (CTE), primarily because of the deaths of high profile American football players who were found to have CTE upon neuropathology 1).

Physicians in clinical practice are likely to face an increasing number of retired football players seeking evaluation for chronic neurobehavioral symptoms. Guidelines for the evaluation and treatment of these patients are sparse. Clinical criteria for a diagnosis of CTE are under development. The contribution of CTE vs other neuropathologies to neurobehavioral symptoms in these players remains unclear.

Gardner et al. describe the experience in evaluating and treating a series of 14 self-referred symptomatic players. The aim is to raise awareness in the neurology community regarding the different clinical phenotypes, idiosyncratic but potentially treatable symptoms, and the spectrum of underlying neuropathologies in these players 2).

Altered Corpus Callosum White Matter Microstructure

Forty retired National Football League (NFL) players, ages 40-65, were matched by age and divided into two groups based on their age of first exposure (AFE) to tackle football: before age 12 or at age 12 or older. Participants underwent DTI on a 3 Tesla Siemens (TIM-Verio) magnet. The whole CC and five subregions were defined and seeded using deterministic tractography. Dependent measures were fractional anisotropy (FA), trace, axial diffusivity and radial diffusivity. Results showed that former NFL players in the AFE <12 group had significantly lower FA in anterior three CC regions and higher radial diffusivity in the most anterior CC region than those in the AFE ≥12 group. 3).

Prevention

Findings suggest that regulation of practice equipment could be a fair and effective way to substantially reduce subconcussive head impact in thousands of collegiate football players 4).

Case series

2017

Case series of 202 football players whose brains were donated for research. Neuropathological evaluations and retrospective telephone clinical assessments (including head trauma history) with informants were performed blinded. Online questionnaires ascertained athletic and military history.

Neuropathological diagnoses of neurodegenerative diseases, including CTE, based on defined diagnostic criteria; CTE neuropathological severity (stages I to IV or dichotomized into mild [stages I and II] and severe [stages III and IV]); informant-reported athletic history and, for players who died in 2014 or later, clinical presentation, including behavior, mood, and cognitive symptoms and dementia.

Among 202 deceased former football players (median age at death, 66 years [interquartile range, 47-76 years]), CTE was neuropathologically diagnosed in 177 players (87%; median age at death, 67 years [interquartile range, 52-77 years]; mean years of football participation, 15.1 [SD, 5.2]), including 0 of 2 pre-high school, 3 of 14 high school (21%), 48 of 53 college (91%), 9 of 14 semiprofessional (64%), 7 of 8 Canadian Football League (88%), and 110 of 111 National Football League (99%) players. Neuropathological severity of CTE was distributed across the highest level of play, with all 3 former high school players having mild pathology and the majority of former college (27 [56%]), semiprofessional (5 [56%]), and professional (101 [86%]) players having severe pathology. Among 27 participants with mild CTE pathology, 26 (96%) had behavioral or mood symptoms or both, 23 (85%) had cognitive symptoms, and 9 (33%) had signs of dementia. Among 84 participants with severe CTE pathology, 75 (89%) had behavioral or mood symptoms or both, 80 (95%) had cognitive symptoms, and 71 (85%) had signs of dementia.

In a convenience sample of deceased football players who donated their brains for research, a high proportion had neuropathological evidence of CTE, suggesting that CTE may be related to prior participation in football 5).

1)

Riley DO, Robbins CA, Cantu RC, Stern RA. Chronic traumatic encephalopathy: Contributions from the Boston University Center for the Study of Traumatic Encephalopathy. Brain Inj. 2015;29(2):154-63. doi: 10.3109/02699052.2014.965215. PubMed PMID: 25587744.
2)

Gardner RC, Possin KL, Hess CP, Huang EJ, Grinberg LT, Nolan AL, Cohn-Sheehy BI, Ghosh PM, Lanata S, Merrilees J, Kramer JH, Berger MS, Miller BL, Yaffe K, Rabinovici GD. Evaluating and treating neurobehavioral symptoms in professional American football players: Lessons from a case series. Neurol Clin Pract. 2015 Aug;5(4):285-295. PubMed PMID: 26336629.
3)

Stamm JM, Koerte IK, Muehlmann M, Pasternak O, Bourlas AP, Baugh CM, Giwerc MY, Zhu A, Coleman MJ, Fritts NG, Martin B, Chaisson C, McClean MD, Lin AP, Cantu RC, Tripodis Y, Stern R, Shenton ME. Age at First Exposure to Football is Associated with Altered Corpus Callosum White Matter Microstructure in Former Professional Football Players. J Neurotrauma. 2015 Jul 22. [Epub ahead of print] PubMed PMID: 26200068.
4)

Reynolds BB, Patrie J, Henry EJ, Goodkin HP, Broshek DK, Wintermark M, Druzgal TJ. Practice type effects on head impact in collegiate football. J Neurosurg. 2015 Aug 4:1-10. [Epub ahead of print] PubMed PMID: 26238972.
5)

Mez J, Daneshvar DH, Kiernan PT, Abdolmohammadi B, Alvarez VE, Huber BR, Alosco ML, Solomon TM, Nowinski CJ, McHale L, Cormier KA, Kubilus CA, Martin BM, Murphy L, Baugh CM, Montenigro PH, Chaisson CE, Tripodis Y, Kowall NW, Weuve J, McClean MD, Cantu RC, Goldstein LE, Katz DI, Stern RA, Stein TD, McKee AC. Clinicopathological Evaluation of Chronic Traumatic Encephalopathy in Players of American Football. JAMA. 2017 Jul 25;318(4):360-370. doi: 10.1001/jama.2017.8334. PubMed PMID: 28742910.

Update: Tirilazad

Tirilazad

U74006F (U-74006F) is a member of steroid drugs called 21 aminosteroids, which are potent inhibitors of lipid peroxidation with little or no glucocorticoid or mineralocorticoid activity 1).


Alotaibi et al. performed a post-hoc analysis of 3567 patients who underwent clipping of ruptured intracranial aneurysms in the randomized trials of tirilazad mesylate from 1990 to 1997. These trials included 162 centers and 156 surgeons from 21 countries. Primary and secondary outcomes were: Glasgow outcome scale score and mortality, respectively. Total publications, H-index, and graduate degrees were used as academic indicators for each surgeon. The association between outcomes and academic factors were assessed using a hierarchical logistic regression analysis, adjusting for patient covariates.

Academic profiles were available for 147 surgeons, treating a total of 3307 patients. Most surgeons were from the USA (62, 42%), Canada (18, 12%), and Germany (15, 10%). On univariate analysis, the H-index correlated with better functional outcomes and lower mortality rates. In the multivariate model, patients under the care of surgeons with higher H-indices demonstrated improved neurological outcomes (p = 0.01) compared to surgeons with lower H-indices, without any significant difference in mortality. None of the other academic indicators were significantly associated with outcomes.

Although prognostication following surgery for ruptured intracranial aneurysms primarily depends on clinical and radiological factors, the academic impact of the operating neurosurgeon may explain some heterogeneity in surgical outcomes 2).


The multicenter Tirilazad database (3551 patients) was used to create this clinical outcome prediction model in order to elucidate significant brain-body associations. Traditional binary logistic regression models were used.

Binary logistic regression main effects model included four statistically significant single prognostic variables, namely, neurological grade, age, stroke, and time to surgery. Logistic regression models demonstrated the significance of hypertension and liver disease in development of brain swelling, as well as the negative consequences of seizures in patients with a history of myocardial infarction and post-admission fever worsening neurological outcome.

Using the aforementioned results generated from binary logistic regression models, we can identify potential patients who are in the high risk group of neurological deterioration. Specific therapies can be tailored to prevent these detriments, including treatment of hypertension, seizures, early detection and treatment of myocardial infarction, and prevention of hepatic encephalopathy 3).


Data were extracted from two concurrently conducted randomized clinical trials of the drug tirilazad; the designs of these studies were similar. The studies included 1701 patients with severe and 476 patients with moderate TBI. Differences were primarily investigated between studies performed in Europe and North America, but also among European regions and between Canada and the United States. Associations among regions and outcomes (6-month mortality rate and Glasgow Outcome Scale scores) were studied using multivariable logistic regression analysis. Comparisons between continents and among regions within Europe showed differences in the distribution of patient ages, causes of injury, and several clinical characteristics (motor score, pupillary reactivity, hypoxia, hypotension, intracranial pressure [ICP]). and findings on computerized tomography scans. Secondary referrals occurred 2.5 times more frequently in Europe. Within Europe secondary referral was mainly associated with an increased proportion of patients with mass lesions (46% in the European Study compared with 40% in the North American Study). Therapy for lowering ICP was more frequently applied in North America. After adjustments for case mix and management, mortality and unfavorable outcomes were significantly higher in Europe (odds ratios = 1.58 and 1.46, respectively). Significant differences in outcome between regions within Europe or within North America were not observed.

Despite the use of a strict study protocol, considerable differences in patient characteristics and case management exist between continents and among countries, reflecting variations in social, cultural, and organizational aspects. Outcomes of TBI may be worse in Europe compared with North America, but this finding requires further study 4).


Striking problems with imbalance concerning basic prognostic variables were observed in spite of the large population studied. These imbalances concerned pretreatment hypotension, pretreatment hypoxia, and the incidence of epidural hematomas. In future trials of pharmacological therapy for severe head injury, serious consideration must be given to alternative randomization strategies. Given the heterogeneous nature of head injury and the identification of populations that do relatively well with standard therapy, target populations with a higher risk for mortality and morbidity may be more suitable for clinical trials of such agents 5).


The efficacy of U74006F in reducing cerebral infarct size was investigated in a rabbit model of thromboembolic stroke. Each animal received either U74006F (3.0 mg/kg immediately before and 2 hr after embolization, n = 8) or vehicle control (n = 10). Hematocrit, mean arterial pressure, PCO2, PO2, and pH were measured and controlled both before and after the administration of an autologous clot into one internal carotid artery. Regional cerebral blood flow (in ml/100 g/min, mean +/- SEM) measured by hydrogen clearance was similar in both groups, being reduced from 68.2 +/- 9.6 to 5.2 +/- 1.9 in the control group immediately after clot embolization and from 73.3 +/- 14.9 to 7.0 +/- 1.7 in the U74006F group. Four hours after embolization the brain was harvested and cerebral infarct size was determined using the triphenyl-tetrazolium chloride technique (% hemisphere, mean +/- SEM). In the U74006F-treated group, the infarct size was significantly reduced (P < 0.05) to 14.8 +/- 6.4 from a control value of 36.0 +/- 6.4. Additionally, cerebral blood flow values after embolization were consistently higher in the U74006F group, although the differences were not statistically significant. This data suggests that the 21-aminosteroid U74006F may have a protective effect in cerebral ischemia 6).


The ability of a non-glucocorticoid 21 aminosteroid U74006F to inhibit lipid peroxidation of central nervous system tissue in vitro and to enhance the early neurological recovery and survival of mice after a severe concussive head injury is described. In the in vitro studies, U74006F was found to be an extremely potent inhibitor of lipid peroxidation in an assay system where the glucocorticoid steroid methylprednisolone and the non-glucocortoid steroids U72099E and U75718A were almost completely ineffective. In the head-injury studies, unanesthetized male CF-1 mice were subjected to a 900 gm-cm closed head injury produced by a 50-gm weight being dropped 18 cm. This concussive injury resulted in immediate unconsciousness (loss of righting reflex) in all animals and death in approximately 30%. Survivors received a tail vein injection of either vehicle or U74006F (0.001 to 30 mg/kg) within 5 minutes postinjury. Their neurological status was evaluated 1 hour later using a grip test. The grip-test score indicated that intravenous administration of a single dose of U74006F resulted in a significant improvement by as much as 168.6% in the neurological status 1 hour postinjury over a broad dose range (0.003 to 30 mg/kg). A 1-mg/kg dose given intravenously within 5 minutes and again at 1 1/2 hours after a severe injury, in addition to improving early recovery, also increased the 1-week survival rate to 78.6% compared to 27.3% in vehicle-treated mice (p less than 0.02). The compound was also effective in enhancing early recovery after a more moderate injury. This study demonstrates that early treatment after severe concussive head injury with a potent inhibitor of iron-dependent lipid peroxidation can significantly benefit the injured brain in mice and promote both early neurological recovery and long-term survival 7).


In a study it was tested for effects on brain edema and metabolites after impact injury to the closed skull. Anesthetized cats were blindly treated with U-74006F or vehicle at 30 min (1 mg/kg) and 2.5 hr (0.5 mg/kg) after head or sham injury. They were sacrificed 4 hr after injury by in situ fixation of the brain. Head-injured cats were selected for unilateral (left) cerebral contusion. Metabolites (enzyme fluorometry) and edema (specific gravity) were measured in the cerebral cortex and white matter bilaterally. Cerebral hemisphere, contusion, and vasogenic edema volumes were morphometrically measured. Magnitude of edema and metabolites in tissue with vasogenic edema was similar in vehicle- and drug-treated cats. By contrast, the cortex and nonedematous white matter neighboring contusion in drug-treated cats had lactate, glucose, and glycogen levels that suggested an improved metabolic state over vehicle treatment. Most metabolites were not affected by trauma or treatment in the uncontused hemisphere. These results suggest that postinjury treatment with the nonglucocorticoid steroid U-74006F may benefit the metabolism of nonedematous tissue adjacent to contusion 8).


The present study evaluated the effect on the development of regional cerebral edema after lateral fluid-percussion (FP) brain injury. Male Sprague-Dawley rats (n = 40) were anesthetized and subjected to FP brain injury of moderate severity centered over the left parietal cortex (2.5-2.6 atms). Fifteen minutes after brain injury, animals randomly received an i.v. bolus of either U74006F (3 mg/kg, n = 21) followed by a second bolus (3 mg/kg) at 3 hr or buffered sodium citrate vehicle (equal volume, n = 15). An additional group of 12 surgically prepared but uninjured animals served as preinjury controls. At 48 hr after injury, animals were sacrificed and brain tissue assayed for water content and regional cation concentrations. With the use of specific gravimetric techniques, no significant differences were observed in posttraumatic cerebral edema between drug- and control-treated animals. However, using wet weight/dry weight methodology, we found that administration of U74006F significantly reduced water content in the right hippocampus (contralateral to the site of injury) compared to saline-treated animals (p less than 0.05). U74006F also significantly prevented the postinjury increase in sodium concentrations in the ipsilateral hippocampus (p less than 0.05) and thalamus (p less than 0.03). Regional concentrations of potassium were unaltered after drug treatment. Administration of U74006F significantly reduced postinjury mortality, from 28% in control animals to zero in treated animals (p = 0.01). These results suggest that lipid peroxidation may be involved in the pathophysiological sequelae of brain injury and that 21-aminosteroids may be beneficial in the treatment of brain injury 9).


The effects of 5 days of pretreatment with the 21-aminosteroid anti-oxidant U74006F have been examined on the rate of functional degeneration of cat soleus motor nerve terminals after axon section. Female cats were dosed for 5 days with either 7.7, 13.0 or 30.0 mg/kg (average doses) of U74006F p.o. twice daily followed by unilateral sciatic nerve section at the hip level on day 5. On day 7, the bilateral in vivo soleus nerve muscle prep. was set up to assess the neuromuscular functional status of the 48 h degenerating soleus nerve terminals in comparison to the contralateral non-sectioned preparation. In untreated cats, the ratio of the nerve-evoked (0.4 Hz) contractile tension of the 48 h nerve-sectioned to that of the contralateral non-sectioned was only 52 +/- 8%. U74006F pretreatment produced a dose-related improvement with the 13.0 mg/kg dose having the best effect; the ratio was 86 +/- 5% (P less than 0.01 vs untreated). The maintenance of tetanic tension during a 10 s period of 100 Hz nerve stimulation was also improved by the 13.0 mg/kg dose from only 54.0 +/- 5.2% in untreated animals to 72.2 +/- 5.7 (P less than 0.02). These results show a preservation of motor nerve function during early degeneration by the anti-oxidant U74006F thus providing further evidence for a free radical-mediated process in anterograde degeneration 10).


Vollmer et al. performed a work to establish whether the nonglucocorticoid, 21-aminosteroid, U74006F, could prevent the development of delayed cerebral vasospasm after experimental subarachnoid hemorrhage. The subarachnoid hemorrhage was produced by percutaneous injection of 4.5 mL of nonheparinized autologous blood into the cisterna magna of rabbits. U74006F (1 mg/kg) or placebo was injected intraperitoneally every 12 hours starting 12 hours prior to induction of hemorrhage for a total of six doses. The animals were sacrificed by perfusion fixation. The basilar artery was removed on day 2 and processed for morphometric analysis. Control/placebo and subarachnoid hemorrhage/placebo basilar artery diameters were 651.2 +/- 25.4 and 366.3 +/- 34.2 mu, respectively. Control/U74006F basilar artery diameters (669.8 +/- 21.8 mu) were not significantly different from that of the control/placebo group. U74006F treatment greatly minimized subarachnoid hemorrhage-induced reduction in mean luminal diameter (563.7 +/- 48.2 mu) (p less than 0.001). These results demonstrate considerable therapeutic promise for U74006F in the prevention of cerebral vasospasm 11).


Young et al. investigated the effects of U74006F on the early ionic edema produced by middle cerebral artery occlusion in rats. Intravenous doses of 3 mg/kg U74006F were given 10 minutes and 3 hours after occlusion. Tissue concentrations of Na+, K+, and water at and around the infarct site were measured by atomic absorption spectroscopy and by wet-dry weight measurements 24 hours after occlusion. Compared with vehicle treatment, U74006F treatment reduced brain water entry, Na+ accumulation, K+ loss, and net ion shift by 25-50% in most brain areas sampled in the frontal and parietal cortex. However, reductions of ionic edema were most prominent and reached significance (p less than 0.005, unpaired two-tailed t test) mostly in the frontoparietal and parietal cortex areas adjacent to the infarct site. Our findings suggest that a steroid drug without glucocorticoid or mineralocorticoid activity can reduce edema in cerebral ischemia but that the effects are largely limited to tissues in which collateral blood flow may be present 12).

Studies in experimental models of ischemic stroke had suggested that tirilazad had neuroprotective properties. As a result, clinical studies were undertaken to assess the safety and efficacy of tirilazad in the treatment of acute ischemic stroke.


Marshall et al., prospectively studied the efficacy of tirilazad mesylate, a novel aminosteroid, in humans with head injuries.

A cohort of 1120 head-injured patients received at least one dose of study medication (tirilazad or placebo). Eighty-five percent (957) of the patients had suffered a severe head injury (Glasgow Coma Scale [GCS] score 4-8) and 15% (163) had sustained a moderate head injury (GCS score 9-12). Six-month outcomes for the tirilazad- and placebo-treated groups for the Glasgow Outcome Scale categories of both good recovery and death showed no significant difference (good recovery in the tirilazad-treated group was 39% compared with the placebo group in which it was 42% [p=0.461]; death in the tirilazad-treated group occurred in 26% of patients compared with the placebo group, in which it occurred in 25% [p=0.750]). Subgroup analysis suggested that tirilazad mesylate may be effective in reducing mortality rates in males suffering from severe head injury with accompanying traumatic subarachnoid hemorrhage (death in the tirilazad-treated group occurred in 34% of patients; in the placebo group it occurred in 43% [p=0.026]). No significant differences in frequency or types of serious adverse events were shown between the treatment and placebo groups.

Striking problems with imbalance concerning basic prognostic variables were observed in spite of the large population studied. These imbalances concerned pretreatment hypotension, pretreatment hypoxia, and the incidence of epidural hematomas. In future trials of pharmacological therapy for severe head injury, serious consideration must be given to alternative randomization strategies. Given the heterogeneous nature of head injury and the identification of populations that do relatively well with standard therapy, target populations with a higher risk for mortality and morbidity may be more suitable for clinical trials of such agents 13).

Trials

Trials of tirilazad were identified from searches of the Cochrane Library and communication with the Pharmacia & Upjohn company, the manufacturer of tirilazad. Data relating to early and end-of-trial case fatality, disability (Barthel Index and Glasgow Outcome Scale), phlebitis, and corrected QT interval were extracted by treatment group from published data and company reports and analyzed by using the Cochrane Collaboration meta-analysis software REVMAN.

Six trials (4 published, 2 unpublished) assessing tirilazad in 1757 patients with presumed acute ischemic stroke were identified; all were double-blind and placebo controlled in design. Tirilazad did not alter early case fatality (odds ratio [OR] 1.11, 95% confidence interval [CI] 0.79 to 1.56) or end-of-trial case fatality (OR 1.12, 95% CI 0.88 to 1.44). A just-significant increase in death and disability, assessed as either the expanded Barthel Index (OR 1.23, 95% CI 1.01 to 1.51) or Glasgow Outcome Scale (OR 1. 23, 95% CI 1.01 to 1.50) was observed. Tirilazad significantly increased the rate of infusion site phlebitis (OR 2.81, 95% CI 2.14 to 3.69). Functional outcome (expanded Barthel Index) was significantly worse in prespecified subgroups of patients: females (OR 1.46, 95% CI 1.08 to 1.98) and subjects receiving low-dose tirilazad (OR 1.31, 95% CI 1.03 to 1.67); a nonsignificant worse outcome was also seen in patients with mild to moderate stroke (OR 1. 40, 95% CI 0.99 to 1.98).

Tirilazad mesylate increases death and disability by about one fifth when given to patients with acute ischemic stroke. Although further trials of tirilazad are now unwarranted, analysis of individual patient data from the trials may help elucidate why tirilazad appears to worsen outcome in acute ischemic stroke 14).

1) , 6)

Wilson JT, Bednar MM, McAuliffe TL, Raymond S, Gross CE. The effect of the 21-aminosteroid U74006F in a rabbit model of thromboembolic stroke. Neurosurgery. 1992 Nov;31(5):929-33; discussion 933-4. PubMed PMID: 1436419.
2)

Alotaibi NM, Ibrahim GM, Wang J, Guha D, Mamdani M, Schweizer TA, Macdonald RL. Neurosurgeon academic impact is associated with clinical outcomes after clipping of ruptured intracranial aneurysms. PLoS One. 2017 Jul 20;12(7):e0181521. doi: 10.1371/journal.pone.0181521. eCollection 2017. PubMed PMID: 28727832; PubMed Central PMCID: PMC5519166.
3)

Lo BW, Fukuda H, Angle M, Teitelbaum J, Macdonald RL, Farrokhyar F, Thabane L, Levine MA. Clinical outcome prediction in aneurysmal subarachnoid hemorrhage – Alterations in brain-body interface. Surg Neurol Int. 2016 Aug 1;7(Suppl 18):S527-37. doi: 10.4103/2152-7806.187496. eCollection 2016. PubMed PMID: 27583179; PubMed Central PMCID: PMC4982352.
4)

Hukkelhoven CW, Steyerberg EW, Farace E, Habbema JD, Marshall LF, Maas AI. Regional differences in patient characteristics, case management, and outcomes in traumatic brain injury: experience from the tirilazad trials. J Neurosurg. 2002 Sep;97(3):549-57. PubMed PMID: 12296638.
5) , 13)

Marshall LF, Maas AI, Marshall SB, Bricolo A, Fearnside M, Iannotti F, Klauber MR, Lagarrigue J, Lobato R, Persson L, Pickard JD, Piek J, Servadei F, Wellis GN, Morris GF, Means ED, Musch B. A multicenter trial on the efficacy of using tirilazad mesylate in cases of head injury. J Neurosurg. 1998 Oct;89(4):519-25. PubMed PMID: 9761043.
7)

Hall ED, Yonkers PA, McCall JM, Braughler JM. Effects of the 21-aminosteroid U74006F on experimental head injury in mice. J Neurosurg. 1988 Mar;68(3):456-61. PubMed PMID: 3343616.
8)

Dimlich RV, Tornheim PA, Kindel RM, Hall ED, Braughler JM, McCall JM. Effects of a 21-aminosteroid (U-74006F) on cerebral metabolites and edema after severe experimental head trauma. Adv Neurol. 1990;52:365-75. PubMed PMID: 2396533.
9)

McIntosh TK, Thomas M, Smith D, Banbury M. The novel 21-aminosteroid U74006F attenuates cerebral edema and improves survival after brain injury in the rat. J Neurotrauma. 1992 Spring;9(1):33-46. PubMed PMID: 1619674.
10)

Hall ED, Yonkers PA. Preservation of motor nerve function during early degeneration by the 21-aminosteroid anti-oxidant U74006F. Brain Res. 1990 Apr 16;513(2):244-7. PubMed PMID: 2350694.
11)

Vollmer DG, Kassell NF, Hongo K, Ogawa H, Tsukahara T. Effect of the nonglucocorticoid 21-aminosteroid U74006F experimental cerebral vasospasm. Surg Neurol. 1989 Mar;31(3):190-4. PubMed PMID: 2922661.
12)

Young W, Wojak JC, DeCrescito V. 21-Aminosteroid reduces ion shifts and edema in the rat middle cerebral artery occlusion model of regional ischemia. Stroke. 1988 Aug;19(8):1013-9. PubMed PMID: 3400099.
14)

Tirilazad mesylate in acute ischemic stroke: A systematic review. Tirilazad International Steering Committee. Stroke. 2000 Sep;31(9):2257-65. Erratum in: Stroke 2001 Jan;32(1):279. PubMed PMID: 10978061.

Update: Posttraumatic epilepsy

Traumatic brain injury (TBI) is one of the most common causes of acquired epilepsy, and posttraumatic epilepsy (PTE) results in significant somatic and psychosocial morbidity.

The incidence of early post-traumatic seizures after civilian traumatic brain injury ranges 4-25%.

The true incidence of PTE in children is still uncertain, because most research has been based primarily on adults.

PTE in a pediatric population with mild traumatic brain injury (MTBI), was found to confer increased risk for the development of PTE and intractable PTE, of 4.5 and 8 times higher, respectively. As has been established in adults, these findings confirm that MTBI increases the risk for PTE in the pediatric population 1).

Risk

The risk of developing PTE relates directly to TBI severity, but the latency to first seizure can be decades after the inciting trauma. Given this “silent period,” much work has focused on identification of molecular and radiographic biomarkers for risk stratification and on development of therapies to prevent epileptogenesis.

Research suggests that there are reciprocal relationships between mental health (MH) disorders and epilepsy risk.

Data suggest that PTE is associated with mental health (MH) outcomes 2years after TBI, findings whose significance may reflect reciprocal, biological, psychological, and/or experiential factors contributing to and resulting from both PTE and MH status post-TBI. Future work should consider temporal and reciprocal relationships between PTE and MH as well as if/how treatment of each condition influences biosusceptibility to the other condition 2).

Treatment

The control of early post-traumatic seizure is mandatory because these acute insults may add secondary damage to the already damaged brain with poor outcome. Prophylactic use of antiepileptic drugs have been found to be have variable efficacy against early post-traumatic seizures.

Based on current studies, however, anticonvulsants have been shown to reduce early PTE occurring within the first 7 days, but little to no benefits have been shown in late PTS occurring after 7 days 3).

Clinical management requires vigilant neurologic surveillance and recognition of the heterogeneous endophenotypes associated with PTE.

Appropriate treatment of patients who have or are at risk for seizures varies as a function of time after TBI, and the clinician’s armamentarium includes an ever-expanding diversity of pharmacological and surgical options.


The lack of evidence on which antiepileptic drug to use in PTE is surprising given the number of patients prescribed an antiepileptic drug therapy for TBI. On the basis of currently available Level III evidence, patients treated with either levetiracetam or phenytoin have similar incidences of early seizures after TBI 4).

There is no statistically significant difference in the efficacy of Phenytoin and Levetiracetam in prophylaxis of early posttraumatic seizures in cases of moderate to severe traumatic brain injury 5).


Most recently, neuromodulation with implantable devices has emerged as a promising therapeutic strategy for some patients with refractory PTE 6).

Systematic review

During June and July 2015, a systematic literature search was performed that identified 6097 articles. Of these, 7 met inclusion criteria. A random-effects meta-analysis was performed. A total of 1186 patients were included. The rate of seizure was 35 of 654 (5.4%) in the levetiracetam cohort and 18 of 532 (3.4%) in the phenytoin cohort. The meta-analysis revealed no change in the rate of early PTS with levetiracetam compared with phenytoin (relative risk, 1.02; 95% confidence interval, 0.53-1.95; P = .96).

The lack of evidence on which antiepileptic drug to use in PTS is surprising given the number of patients prescribed an antiepileptic drug therapy for TBI. On the basis of currently available Level III evidence, patients treated with either levetiracetam or phenytoin have similar incidences of early seizures after TBI 7)

Case series

2016

In a retrospective multicenter cohort study including 5 regional pediatric trauma centers affiliated with academic medical centers, the authors examined data from 236 children (age < 18 years) with severe traumatic brain injury (TBI) (admission Glasgow Coma Scale score ≤ 8, ICD-9 diagnosis codes of 800.0-801.9, 803.0-804.9, 850.0-854.1, 959.01, 950.1-950.3, 995.55, maximum head Abbreviated Injury Scale score ≥ 3) who received tracheal intubation for ≥ 48 hours in the ICU between 2007 and 2011.

Of 236 patients, 187 (79%) received seizure prophylaxis. In 2 of the 5 centers, 100% of the patients received seizure prophylaxis medication. Use of seizure prophylaxis was associated with younger patient age (p < 0.001), inflicted TBI (p < 0.001), subdural hematoma (p = 0.02), cerebral infarction (p < 0.001), and use of electroencephalography (p = 0.023), but not higher Injury Severity Score. In 63% cases in which seizure prophylaxis was used, the patients were given the first medication within 24 hours of injury, and 50% of the patients received the first dose in the prehospital or emergency department setting. Initial seizure prophylaxis was most commonly with fosphenytoin (47%), followed by phenytoin (40%).

While fosphenytoin was the most commonly used medication for seizure prophylaxis, there was large variation within and between trauma centers with respect to timing and choice of seizure prophylaxis in severe pediatric TBI. The heterogeneity in seizure prophylaxis use may explain the previously observed lack of relationship between seizure prophylaxis and outcomes 8).

1)

Keret A, Bennett-Back O, Rosenthal G, Gilboa T, Shweiki M, Shoshan Y, Benifla M. Posttraumatic epilepsy: long-term follow-up of children with mild traumatic brain injury. J Neurosurg Pediatr. 2017 Jul;20(1):64-70. doi: 10.3171/2017.2.PEDS16585. Epub 2017 May 5. PubMed PMID: 28474982.

2)

Juengst SB, Wagner AK, Ritter AC, Szaflarski JP, Walker WC, Zafonte RD, Brown AW, Hammond FM, Pugh MJ, Shea T, Krellman JW, Bushnik T, Arenth PM. Post-traumatic epilepsy associations with mental health outcomes in the first two years after moderate to severe TBI: A TBI Model Systems analysis. Epilepsy Behav. 2017 Jun 25;73:240-246. doi: 10.1016/j.yebeh.2017.06.001. [Epub ahead of print] PubMed PMID: 28658654.

3)

Kirmani BF, Robinson DM, Fonkem E, Graf K, Huang JH. Role of Anticonvulsants in the Management of Posttraumatic Epilepsy. Front Neurol. 2016 Mar 22;7:32. eCollection 2016. Review. PubMed PMID: 27047441.

4)

Khan NR, VanLandingham MA, Fierst TM, Hymel C, Hoes K, Evans LT, Mayer R, Barker F, Klimo P Jr. Should Levetiracetam or Phenytoin Be Used for Posttraumatic Seizure Prophylaxis? A Systematic Review of the Literature and Meta-analysis. Neurosurgery. 2016 Sep 30. PubMed PMID: 27749510.

5)

Khan SA, Bhatti SN, Khan AA, Khan Afridi EA, Muhammad G, Gul N, Zadran KK, Alam S, Aurangzeb A. Comparison Of Efficacy Of Phenytoin And Levetiracetam For Prevention Of Early Post Traumatic Seizures. J Ayub Med Coll Abbottabad. 2016 Jul-Sep;28(3):455-460. PubMed PMID: 28712212.

6)

Rao VR, Parko KL. Clinical Approach to Posttraumatic Epilepsy. Semin Neurol. 2015 Feb;35(1):57-63. Epub 2015 Feb 25. PubMed PMID: 25714868.

7)

Khan NR, VanLandingham MA, Fierst TM, Hymel C, Hoes K, Evans LT, Mayer R, Barker F, Klimo P Jr. Should Levetiracetam or Phenytoin Be Used for Posttraumatic Seizure Prophylaxis? A Systematic Review of the Literature and Meta-analysis. Neurosurgery. 2016 Dec;79(6):775-782. PubMed PMID: 27749510.

8)

Ostahowski PJ, Kannan N, Wainwright MS, Qiu Q, Mink RB, Groner JI, Bell MJ, Giza CC, Zatzick DF, Ellenbogen RG, Boyle LN, Mitchell PH, Vavilala MS; PEGASUS (Pediatric Guideline Adherence and Outcomes) Study.. Variation in seizure prophylaxis in severe pediatric traumatic brain injury. J Neurosurg Pediatr. 2016 Oct;18(4):499-506. PubMed PMID: 27258588.