Category Archives: Neurotrauma

Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition

The scope and purpose of the Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition. is 2-fold: to synthesize the available evidence and to translate it into recommendations. This document provides recommendations only when there is evidence to support them. As such, they do not constitute a complete protocol for clinical use.

The intention is that these recommendations be used by others to develop treatment protocols, which necessarily need to incorporate consensus and clinical judgment in areas where current evidence is lacking or insufficient.

Carney et al. think it is important to have evidence-based recommendations to clarify what aspects of practice currently can and cannot be supported by evidence, to encourage use of evidence-based treatments that exist, and to encourage creativity in treatment and research in areas where evidence does not exist. The communities of neurosurgery and neurointensive care have been early pioneers and supporters of evidence based medicine and plan to continue in this endeavor. The complete guideline document, which summarizes and evaluates the literature for each topic, and supplemental appendices (A-I) are available online at https://www.braintrauma.org/coma/guidelines 1).

4th edition

Free article of Neurosurgery


1) Carney N, Totten AM, OʼReilly C, Ullman JS, Hawryluk GW, Bell MJ, Bratton SL, Chesnut R, Harris OA, Kissoon N, Rubiano AM, Shutter L, Tasker RC, Vavilala MS, Wilberger J, Wright DW, Ghajar J. Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition. Neurosurgery. 2016 Sep 20. [Epub ahead of print] PubMed PMID: 27654000.

Book: Neurotrauma Management for the Severely Injured Polytrauma Patient

Neurotrauma Management for the Severely Injured Polytrauma Patient

Neurotrauma Management for the Severely Injured Polytrauma Patient

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This text addresses many of the questions which occur when medical professionals of various disciplines interact and have different plans and interventions, each with its own valid scientific and/or experience-based rationale:  Questions involving tourniquet placement, ideal fluids and volumes for resuscitation, VTE prophylaxis and many other management considerations. Straightforward decisions in the patient with a single diagnosis often conflict when applied to the neurologically injured polytrauma patients.

 Neurotrauma Management for the Severely Injured Polytrauma Patient answers as many of these questions as possible based on the current literature, vast experience with severe neurotrauma in the current conflicts in Afghanistan and Iraq, and the experience of trauma experts across the globe as well as proposes areas for future study where answers are currently less clear.

Product Details

  • Published on: 2017-01-13
  • Original language: English
  • Number of items: 1
  • Dimensions: 10.00″ h x .0″ w x 7.00″ l, .0 pounds
  • Binding: Hardcover
  • 340 pages

James M. Ecklund, M.D., F.A.C.S. serves as Chairman of the Inova Neuroscience Institute. Prior to joining Inova Medical Group, he served as Professor and Chairman of the Neurosurgery Program of the National Capital Consortium, which includes Walter Reed Army Medical Center, National Naval Medical Center and the Uniformed Services University. He is a retired colonel in the U.S Army and was deployed as a Neurosurgeon to both Afghanistan and Iraq. His program received the vast majority of American neurotrauma casualties.

Dr. Ecklund’s primary clinical and research interests include complex spine, cerebrovascular disease and neurotrauma with an emphasis on blast and penetrating injury. He directs a neurotrauma laboratory at the Uniformed Services University, has over 100 publications and abstracts, and has lectured throughout the world. He also has served on multiple oversight and advisory boards for the Veterans Administration, Department of Defense, National Institutes of Health, NATO, Neurotrauma Foundation, and Brain Trauma Foundation.

Leon E. Moores, MD, MS, FACS is the CEO of Pediatric Specialists of Virginia and the Associate Chair for Pediatric Programs at the Inova Neuroscience Institute. He retired as a Colonel from the US Army where he led as an Infantry Platoon Leader, Chief of Neurosurgery at Walter Reed, Chairman of the Department of Surgery at Walter Reed, Deputy Commander of the National Naval Medical Center, and Commander of the Fort Meade Medical System. Dr Moores also served two tours of duty in Afghanistan and Iraq.
Dr Moores’ clinical and research interests center on brain and spinal tumors in children, CNS infections in combat soldiers, and complex craniofacial reconstruction in severe head and facial trauma. He is a Professor of Surgery and Pediatrics at the Uniformed Services University, and a Professor of Neurosurgery at Virginia Commonwealth University.

Update: Vernet’s syndrome


In contrast to the majority of classic brainstem syndromes, the interpretation of Schmidt’s syndrome (ipsilateral palsy of the IX, X, XI, and XII cranial nerves with contralateral hemiparesis) and Vernet’s syndrome (ipsilateral palsy of the IX, X, and XI nerves with contralateral hemiparesis) is controversial. They are sometimes addressed as crossed brainstem syndromes but also as syndromes due to multiple cranial nerve lesions without contralateral hemiparesis. In this study, the historic descriptions and recent publications about Schmidt’s and Vernet’s syndromes were reviewed and critically analysed. We conclude that historic descriptions and later publications describe exclusively patients with extracerebral lesions of multiple cranial nerves. “Central” syndromes of Schmidt and Vernet caused by brainstem lesion appear not to exist. An extremely extensive lesion explaining these hypothetical unilateral brainstem syndromes is theoretically possible but, however, was apparently never observed in any of the known unilateral brainstem diseases 1).

Symptoms

Symptoms of this syndrome are consequences of this paresis. As such, in an affected patient, you may find:

dysphonia/hoarseness

soft palate dropping

deviation of the uvula towards the normal side

dysphagia

loss of sensory function from the posterior 1/3 of the tongue

decrease in the parotid gland secretion

loss of gag reflex

sternocleidomastoid and trapezius muscles paresis.

Etiology

A variety of neoplasms, vascular insults, infections, and trauma have been reported to cause JFS 2).


The causes of Vernet syndrome are primary tumors such as Glomus jugulare tumors (most frequently), meningioma, vestibular schwannoma, cerebellopontine angle metastases, inflammation such as meningitis and malignant otitis externa, and sarcoidosis, Guillain-Barre syndrome 3).

Trauma 4) 5).

Cholesteatoma (very rare) 6).

Obstruction of the jugular foramen due to bone diseases 7).

Varicella-zoster virus 8).

Giant cell arteritis 9) 10).

Internal jugular vein thrombosis 11).

After carotid endarterectomy 12).

Large mycotic aneurysm of the extracranial internal carotid artery after acute otitis media 13).

Systemic erythematous lupus 14).


1) Krasnianski M, Neudecker S, Zierz S. [The Schmidt and Vernet classical syndrome. Alternating brain stem syndromes that do not exist?]. Nervenarzt. 2003 Dec;74(12):1150-4. Review. German. PubMed PMID: 14647918.
2) Robbins KT, Fenton RS. Jugular foramen syndrome. J Otolaryngol. 1980 Dec;9(6):505-16. PubMed PMID: 7206037.
3) Ha SW, Kim JK, Kang SJ, Kim MJ, Yoo BG, Kim KS, et al. A case of Vernet’s syndrome caused by non-specific focal inflammation of the neck. J Korean Soc Clin Neurophysiol. 2007;9:81–84.
4) , 5) Kim HS, Ko K. Penetrating trauma of the posterior fossa resulting in Vernet’s syndrome and internuclear ophthalmoplegia. J Trauma. 1996 Apr;40(4):647-9. PubMed PMID: 8614050.
6) Erol FS, Kaplan M, Kavakli A, Ozveren MF. Jugular foramen syndrome caused by choleastatoma. Clin Neurol Neurosurg. 2005 Jun;107(4):342-6. PubMed PMID: 15885397.
7) Erol FS, Kaplan M, Kavakli A, Ozveren MF.Jugular foramen syndrome caused by choleastatoma. Clin Neurol Neurosurg. 2005 Jun;107(4):342-6.
8) Jo YR, Chung CW, Lee JS, Park HJ. Vernet syndrome by varicella-zoster virus. Ann Rehabil Med. 2013 Jun;37(3):449-52. doi: 10.5535/arm.2013.37.3.449. PubMed PMID: 23869347; PubMed Central PMCID: PMC3713306.
9) Jeret JS. Giant cell arteritis and Vernet’s syndrome. Neurology. 1999 Feb;52(3):677. PubMed PMID: 10025824.
10) Cherin P, De Gennes C, Bletry O, Lamas A, Launay M, Dubs A, Godeau P. Ischemic Vernet’s syndrome in giant cell arteritis: first two cases. Am J Med. 1992 Sep;93(3):349-52. PubMed PMID: 1524092.
11) Shima K, Iwasa K, Yoshita M, Yamada M. Vernet’s syndrome induced by internal jugular vein thrombosis. J Neurol Neurosurg Psychiatry. 2016 Nov;87(11):1252-1253. doi: 10.1136/jnnp-2015-311665. PubMed PMID: 26354943.
12) Tamaki T, Node Y, Saitoum N, Saigusa H, Yamazaki M, Morita A. Vernet’s syndrome after carotid endarterectomy. Perspect Vasc Surg Endovasc Ther. 2013 Dec;25(3-4):65-8. doi: 10.1177/1531003514525476. PubMed PMID: 24625858.
13) Amano M, Ishikawa E, Kujiraoka Y, Watanabe S, Ashizawa K, Oguni E, Saito A, Nakai Y, Ikeda H, Abe T, Uekusa Y, Matsumura A. Vernet’s syndrome caused by large mycotic aneurysm of the extracranial internal carotid artery after acute otitis media–case report. Neurol Med Chir (Tokyo). 2010 Jan;50(1):45-8. PubMed PMID: 20098025.
14) Leache Pueyo JJ, Campos del Alamo MA, Gil Paraíso P, Ortiz García A. [Vernet’s syndrome as an early manifestation of systemic erythematous lupus]. An Otorrinolaringol Ibero Am. 1997;24(2):135-41. Spanish. PubMed PMID: 9199109.

Selective brain cooling

Systemic hypothermia, the method used in almost all major clinical trials, is limited by the time to target temperature, the depth of hypothermia, and complications, problems that may be solved by selective brain cooling.

see Prophylactic Hypothermia for severe traumatic brain injury.


Selective brain cooling (SBC) can occur in hyperthermic humans despite the fact that humans have no carotid rete, a vascular structure that facilitates countercurrent heat exchange located at the base of the skull in some mammals.


Emissary and angular veins, upper respiratory tract, tympanic cavity and cerebrospinal fluid are major components of SBC system in humans. The efficiency of SBC is increased by evaporation of sweat on the head and by ventilation through the nose, but it is surprising to find out that mammals do not display SBC during exercise hyperthermia. What is the explanation then for the SBC at high body temperatures?

The hypothesis of Irmak et al., is that selective brain cooling protects the brain from thermal damage in a long-standing manner by allowing adaptive mechanisms to change the craniofacial morphology appropriate for different environmental conditions. Since the brain can only be as big that can cool, it is not surprising to find a lower (below 1300 cm(3)) cranial volume in Australian Aborigines with respect to the one (over 1450 cm(3)) in Eskimos. In addition to lower brain volume, other craniofacial features such as thick everted lips, broader nasal cavity and bigger paranasal sinuses that provide more evaporating surfaces seem to be anatomical variations developed in time for an effective SBC in hot climates. It was reported previously that these biological adaptations result from the tissues of neural crest origin. Among the crest derivatives, leptomeninges, skeletal and connective tissues of the face and much of the skull seem to be structures upon which environment operates to produce more convenient craniofacial morphology for an effective SBC.

Selective brain cooling seems to be a mechanism leading to adaptive craniofacial diversity observed in different geographical regions. Thus, SBC is necessary for long-term biological adaptation, not for protecting the brain from acute thermal damage 1).


In experimental models of neuronal damage, therapeutic hypothermia proved to be a powerful neuroprotective method.

In clinical studies of traumatic brain injury (TBI), this very distinct effect was not reproducible. Several metaanalysis draw different conclusions about whether therapeutic hypothermia can improve outcome after TBI. Adverse side effects of systemic hypothermia, such as severe pneumonia, have been held responsible by some authors to counteract the neuroprotective effect. Selective brain cooling (SBC) attempts to take advantage of the protective effects of therapeutic hypothermia without the adverse side effects of systemic hypothermia.

Case series

2006

Qiu et al., present the results of a study in which noninvasive selective brain cooling (SBC) was achieved using a head cap and neckband. Ninety patients with severe TBI were divided into a normothermia control group (n=45) and a SBC group (n=45), whose brain temperature was maintained at 33-35 degrees C for 3 days using a combination of head and neck cooling. At 24, 48 and 72h after injury, the mean intracranial pressure (ICP) values of the patients who underwent SBC were lower than those of the normothermia controls (19.14+/-2.33, 19.72+/-1.73 and 17.29+/-2.07 mmHg, versus 23.41+/-2.51, 20.97+/-1.86, and 20.13+/-1.87 mmHg, respectively, P<0.01). There was a significant difference in the neurological recovery of the two groups at the 6-month follow-up after TBI. Good neurological outcome (Glasgow Outcome Scale score of 4 to 5) rates 6 months after injury were 68.9% for the SBC group, and 46.7% for the control group (P<0.05). There were no complications resulting in severe sequelae. In conclusion, the noninvasive SBC described here is a safe method of administering therapeutic hypothermia, which can reduce ICP and improve prognosis without severe complications in patients with severe TBI 2).


Sixty-six in-patients were randomized into three groups. In one group, brain temperature was maintained at 33 – 35 degrees C by cooling the head and neck (SBC); in a second group, mild systemic hypothermia (MSH; rectal temperature 33 – 35 degrees C) was produced with a cooling blanket; and a control group was not exposed to hypothermia. Natural rewarming began after 3 days. Mean intracranial pressure 24, 48 or 72 h after injury was significantly lower in the SBC group than in the control group. Mean serum superoxide dismutase levels on Days 3 and 7 after injury in the SBC and MSH groups were significantly higher than in the control group. The percentage of patients with a good neurological outcome 2 years after injury was 72.7%, 57.1% and 34.8% in the SBC, MSH and control groups, respectively. Complications were managed without severe sequelae. Non-invasive SBC was safe and effective 3).

Case reports

2016

Three different methods of SBC were applied in a patient who had severe traumatic brain injury TBI with recurrent increases of intracranial hypertension refractory to conventional forms of treatment:

(1) external cooling of the scalp and neck using ice packs prior to hemicraniectomy

(2) external cooling of the craniectomy defect using ice packs after hemicraniectomy

(3) cooling by epidural irrigation with cold Ringer solution after hemicraniectomy.

External scalp cooling before hemicraniectomy, external cooling of the craniectomy defect, and epidural irrigation with cold fluid resulted in temperature differences (brain temperature to body temperature) of - 0.2°, - 0.7°, and - 3.6°C, respectively. ICP declined with decreasing brain temperature.

Previous external cooling attempts for SBC faced the problem that brain temperature could not be lowered without a simultaneous decrease of systemic temperature. After hemicraniectomy, epidural irrigation with cold fluid may be a simple and effective way to lower ICP and apply one of the most powerful methods of cerebroprotection after severe TBI 4).

Animal studies

2015

Adult male Sprague-Dawley rats (mean weight = 300 g; n = 25) were subjected to brain injury using a modified Marmarou method. Immediately after the onset of TBI, rats were randomized into three groups. Selective brain cooling was applied around the head using ice packages. Intracranial Temperature (ICT) and ICP were continuously measured at 0, 30, 60, 120, and 180 minutes and recorded for all groups. Group 1 (n = 5) was normothermia and was assigned as the control group. Group 2 (n = 10) received moderate hypothermia with a target ICT of between 32°C – 33°C and Group 3 (n = 10) was given a deeper hypothermia with a target ICT of below 32°C.

All subjects reached the target ICT by the 30th minute of hypothermia induction. The ICT was significantly different in Group 2 compared to Group 1 only at the 120th minute (P = 0.017), while ICP was significantly lower starting from the 30th minute (P = 0.015). The ICT was significantly lower in Group 3 compared to Groups 1 and 2 starting from the 30th minute (P = 0.001 and P = 0.003, respectively). The ICP was significantly lower in Group 3 compared to Group 1 starting from 30th minute (P = 0.001); however, a significant difference in ICP between Group 3 and Group 2 was observed only at the 180th minute (P = 0.047).

Results of this study indicate that selective brain cooling is an effective method of decreasing ICP in rats; however, the deeper hypothermia caused a greater decrease in ICP three hours after hypothermia induction 5).

2013

Anesthetized male Sprague-Dawley rats were divided into two major treatment groups. Immediately after the onset of fluid percussion TBI, a craniectomy window of 6 × 8 mm was made at the right parietal, and a cold water bag (0°C-1°C or 5°C-6°C) was applied locally for 30 min. Additional groups of rats were used as craniectomy and craniectomy + FPI controls. Physiological parameters, such as brain and colonic temperature, mean arterial pressure, and heart rate, were monitored during FPI. Functional motor outcomes were evaluated using the inclined plane test (maximal grasp angle). Cellular infarction volume was calculated using triphenyltetrazolium chloride staining. Apoptosis and neuronal marker-positive cells in the cortex were measured by immunofluorescence staining. All functional and morphologic parameters were assessed 72 h after injury.

Compared with the craniectomy + FPI control groups, the groups treated with 5°C-6°C local cold water therapy showed significant attenuation of the FPI-induced motor deficits, weight loss, and cerebral infarction but no effect on colonic temperature. The FPI-induced apoptosis and neuronal loss were also significantly reduced by local cooling.

The results suggest that local cooling with 5°C-6°C cold water therapy may ameliorate TBI in rats by reducing infarction volume, neuronal cell loss, and apoptosis, resulting in improved functional outcome. They propose that the use of local cooling at the craniectomy site after FPI might have clinical benefits in the future 6).


1) Irmak MK, Korkmaz A, Erogul O. Selective brain cooling seems to be a mechanism leading to human craniofacial diversity observed in different geographical regions. Med Hypotheses. 2004;63(6):974-9. PubMed PMID: 15504564.
2) Qiu W, Shen H, Zhang Y, Wang W, Liu W, Jiang Q, Luo M, Manou M. Noninvasive selective brain cooling by head and neck cooling is protective in severe traumatic brain injury. J Clin Neurosci. 2006 Dec;13(10):995-1000. PubMed PMID: 17113984.
3) Liu WG, Qiu WS, Zhang Y, Wang WM, Lu F, Yang XF. Effects of selective brain cooling in patients with severe traumatic brain injury: a preliminary study. J Int Med Res. 2006 Jan-Feb;34(1):58-64. PubMed PMID: 16604824.
4) Westermaier T, Nickl R, Koehler S, Fricke P, Stetter C, Rueckriegel SM, Ernestus RI. Selective Brain Cooling after Traumatic Brain Injury: Effects of Three Different Cooling MethodsCase Report. J Neurol Surg A Cent Eur Neurosurg. 2016 Dec 30. doi: 10.1055/s-0036-1596057. [Epub ahead of print] PubMed PMID: 28038481.
5) Girisgin AS, Kalkan E, Ergin M, Keskin F, Dundar ZD, Kebapcioglu S, Kocak S, Cander B. An experimental study: does the neuroprotective effect increase when hypothermia deepens after traumatic brain injury? Iran Red Crescent Med J. 2015 Apr 25;17(4):e21233. doi: 10.5812/ircmj.17(4)2015.21233. PubMed PMID: 26023335; PubMed Central PMCID: PMC4443303.
6) Wang CC, Chen YS, Lin BS, Chio CC, Hu CY, Kuo JR. The neuronal protective effects of local brain cooling at the craniectomy site after lateral fluid percussion injury in a rat model. J Surg Res. 2013 Dec;185(2):753-62. doi: 10.1016/j.jss.2013.07.002. PubMed PMID: 23938315.

Progesterone for acute traumatic brain injury

Systematic reviews

2016

Ma et al., updated the searches of the following databases: the Cochrane Injuries Group’s Specialised Register (30 September 2016), the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 9, 2016), MEDLINE (Ovid; 1950 to 30 September 2016), Embase (Ovid; 1980 to 30 September 2016), Web of Science Core Collection: Conference Proceedings Citation Index-Science (CPCI-S; 1990 to 30 September 2016); and trials registries: Clinicaltrials.gov (30 September 2016) and the World Health Organization (WHO) International Clinical Trials Registry Platform (30 September 2016).

They included randomised controlled trials (RCTs) of progesterone versus no progesterone (or placebo) for the treatment of people with acute TBI.

Two review authors screened search results independently to identify potentially relevant studies for inclusion. Independently, two review authors selected trials that met the inclusion criteria from the results of the screened searches, with no disagreement.

They included five RCTs in the review, with a total of 2392 participants. We assessed one trial to be at low risk of bias; two at unclear risk of bias (in one multicentred trial the possibility of centre effects was unclear, whilst the other trial was stopped early), and two at high risk of bias, due to issues with blinding and selective reporting of outcome data.All included studies reported the effects of progesterone on mortality and disability. Low quality evidence revealed no evidence of a difference in overall mortality between the progesterone group and placebo group (RR 0.91, 95% CI 0.65 to 1.28, I² = 62%; 5 studies, 2392 participants, 2376 pooled for analysis). Using the GRADE criteria, we assessed the quality of the evidence as low, due to the substantial inconsistency across studies.There was also no evidence of a difference in disability (unfavourable outcomes as assessed by the Glasgow Outcome Score) between the progesterone group and placebo group (RR 0.98, 95% CI 0.89 to 1.06, I² = 37%; 4 studies; 2336 participants, 2260 pooled for analysis). We assessed the quality of this evidence to be moderate, due to inconsistency across studies.Data were not available for meta-analysis for the outcomes of mean intracranial pressure, blood pressure, body temperature or adverse events. However, data from three studies showed no difference in mean intracranial pressure between the groups. Data from another study showed no evidence of a difference in blood pressure or body temperature between the progesterone and placebo groups, although there was evidence that intravenous progesterone infusion increased the frequency of phlebitis (882 participants). There was no evidence of a difference in the rate of other adverse events between progesterone treatment and placebo in the other three studies that reported on adverse events.

This updated review did not find evidence that progesterone could reduce mortality or disability in patients with TBI. However, concerns regarding inconsistency (heterogeneity among participants and the intervention used) across included studies reduce our confidence in these results.There is no evidence from the available data that progesterone therapy results in more adverse events than placebo, aside from evidence from a single study of an increase in phlebitis (in the case of intravascular progesterone).There were not enough data on the effects of progesterone therapy for our other outcomes of interest (intracranial pressure, blood pressure, body temperature) for us to be able to draw firm conclusions.Future trials would benefit from a more precise classification of TBI and attempts to optimise progesterone dosage and scheduling 1).

2012

Ma et al., searched: the Cochrane Injuries Group’s Specialised Register (13 July 2012), Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 7, 2012), MEDLINE (Ovid) (1950 to August week 1, 2012), EMBASE (Ovid) (1980 to week 32 2012), LILACS (12 August 2012), Zetoc (13 July 2012), Clinicaltrials.gov (12 August 2012), Controlled-trials.com (12 August 2012). SELECTION CRITERIA: We included published and unpublished randomised controlled trials (RCTs) of progesterone versus no progesterone (or placebo) for the treatment of people with acute TBI. DATA COLLECTION AND ANALYSIS: Two review authors independently screened search results to identify the full texts of potentially relevant studies for inclusion. From the results of the screened searches two review authors independently selected trials meeting the inclusion criteria, with no disagreement. MAIN RESULTS: Three studies were included with a total of 315 people. Two included studies were of high methodological quality, with low risk of bias in allocation concealment, blinding and incomplete outcome data. One study did not use blinding and had unclear risk of bias in allocation concealment and incomplete outcome data. All three studies reported the effects of progesterone on mortality. The pooled risk ratio (RR) for mortality at end of follow-up was 0.61, 95% confidence interval (CI) 0.40 to 0.93. Three studies measured disability and found the RR of death or severe disability in patients treated with progesterone to be 0.77, 95% CI 0.62 to 0.96. Data from two studies showed no difference in mean intracranial pressure or the rate of adverse and serious adverse events among people in either group. One study presented blood pressure and temperature data, and there were no differences between the people in the progesterone or control groups. There was no substantial evidence for the presence of heterogeneity.

Current clinical evidence from three small RCTs indicates progesterone may improve the neurologic outcome of patients suffering TBI. This evidence is still insufficient and further multicentre randomised controlled trials are required 2).

2011

Junpeng et al., searched: the Cochrane Injuries Group’s Specialised Register (to April 2010), Cochrane Central Register of Controlled Trials 2010, Issue 1 (The Cochrane Library), MEDLINE (Ovid) (1950 to April week 1 2010), EMBASE (Ovid) (1980 to week 14 2010), LILACS (to 17 April 2010 ), Zetoc (to 21 April 2010), Clinicaltrials.gov (17 April 2010 ), Controlled-trials.com (17 April 2010).

They included published and unpublished randomised controlled trials (RCTs) of progesterone versus no progesterone (or placebo) for the treatment of acute TBI.

Two authors independently screened search results to identify the full texts of potentially relevant studies for inclusion. From the results of the screened searches two authors independently selected trials meeting the inclusion criteria, with no disagreement.

Three studies were included with 315 patients. All three studies reported the effects of progesterone on mortality. The pooled relative risk (RR) for mortality at end of follow-up is 0.61, 95% confidence interval (CI) 0.40 to 0.93. Three studies measured disability and found the RR of death or severe disability in patients treated with progesterone was 0.77, 95% confidence interval (CI) 0.62 to 0.96. Two studies presented data on intracranial pressure and adverse events. One study presented blood pressure and temperature data. There was no substantial evidence for the presence of heterogeneity.

Current clinical evidence from three small RCTs indicates progesterone may improve the neurologic outcome of patients suffering TBI. This evidence is still insufficient and further multicentre randomised controlled trials are required 3).


Progesterone has been associated with robust positive effects in animal models of traumatic brain injury (TBI) and with clinical benefits in two phase 2 randomized controlled trials. Skolnick et al, investigated the efficacy and safety of progesterone in a large, prospective, phase 3 randomized controlled trial.

A multinational placebo controlled study, in which 1195 patients, 16 to 70 years of age, with severe traumatic brain injury TBI (Glasgow Coma Scale score, ≤8 (on a scale of 3 to 15, with lower scores indicating a reduced level of consciousness and at least one reactive pupil) were randomly assigned to receive progesterone or placebo. Dosing began within 8 hours after injury and continued for 120 hours. The primary efficacy end point was the Glasgow Outcome Scale score at 6 months after the injury.

Proportional-odds analysis with covariate adjustment showed no treatment effect of progesterone as compared with placebo (odds ratio, 0.96; confidence interval, 0.77 to 1.18). The proportion of patients with a favorable outcome on the Glasgow Outcome Scale (good recovery or moderate disability) was 50.4% with progesterone, as compared with 50.5% with placebo. Mortality was similar in the two groups. No relevant safety differences were noted between progesterone and placebo.

Primary and secondary efficacy analyses showed no clinical benefit of progesterone in patients with severe TBI. These data stand in contrast to the robust preclinical data and results of early single-center trials that provided the impetus to initiate phase 3 trials. (Funded by BHR Pharma; SYNAPSE ClinicalTrials.gov number, NCT01143064 .) 4).

There was no significant difference between the progesterone group and the placebo group in the proportion of patients with a favorable outcome (relative benefit of progesterone, 0.95; 95% confidence interval [CI], 0.85 to 1.06; P=0.35). Phlebitis or thrombophlebitis was more frequent in the progesterone group than in the placebo group (relative risk, 3.03; CI, 1.96 to 4.66). There were no significant differences in the other prespecified safety outcomes. Conclusions This clinical trial did not show a benefit of progesterone over placebo in the improvement of outcomes in patients with acute TBI. (Funded by the National Institute of Neurological Disorders and Stroke and others; PROTECT III ClinicalTrials.gov number, NCT00822900 .) 5).


There is significant theoretical evidence for the potential role of estrogen and progesterone use in altering the pathogenesis of SAH. Nevertheless, this has received mixed reviews in both case controlled studies and cohort analysis within the literature 6)


1) Ma J, Huang S, Qin S, You C, Zeng Y. Progesterone for acute traumatic brain injury. Cochrane Database Syst Rev. 2016 Dec 22;12:CD008409. doi: 10.1002/14651858.CD008409.pub4. [Epub ahead of print] Review. PubMed PMID: 28005271.
2) Ma J, Huang S, Qin S, You C. Progesterone for acute traumatic brain injury. Cochrane Database Syst Rev. 2012 Oct 17;10:CD008409. doi: 10.1002/14651858.CD008409.pub3. Review. PubMed PMID: 23076947.
3) Junpeng M, Huang S, Qin S. Progesterone for acute traumatic brain injury. Cochrane Database Syst Rev. 2011 Jan 19;(1):CD008409. doi: 10.1002/14651858.CD008409.pub2. Review. Update in: Cochrane Database Syst Rev. 2012;10:CD008409. PubMed PMID: 21249708.
4) Skolnick BE, Maas AI, Narayan RK, van der Hoop RG, MacAllister T, Ward JD, Nelson NR, Stocchetti N; the SYNAPSE Trial Investigators. A Clinical Trial of Progesterone for Severe Traumatic Brain Injury. N Engl J Med. 2014 Dec 10. [Epub ahead of print] PubMed PMID: 25493978.
5) Wright DW, Yeatts SD, Silbergleit R, Palesch YY, Hertzberg VS, Frankel M, Goldstein FC, Caveney AF, Howlett-Smith H, Bengelink EM, Manley GT, Merck LH, Janis LS, Barsan WG; the NETT Investigators. Very Early Administration of Progesterone for Acute Traumatic Brain Injury. N Engl J Med. 2014 Dec 10. [Epub ahead of print] PubMed PMID: 25493974.
6) Young AM, Karri SK, Ogilvy CS. Exploring the use of estrogen & progesterone replacement therapy in subarachnoid hemorrhage. Curr Drug Saf. 2012 Jul;7(3):202-6. Review. PubMed PMID: 22950381.

Update: Syndrome of the trephined

Syndrome of the trephined is a rare, important complication of a craniectomy characterized by neurological dysfunction that improves with cranioplasty. Its varied symptoms include motor, cognitive, and language deficits. Its exact characterization appears suboptimal, with differing approaches of evaluation.

The “Motor Trephine Syndrome (MTS)” also known as the “Sunken brain and Scalp Flap Syndrome” or the “Sinking Skin Flap Syndrome (SSFS)” or the “Syndrome of the trephined” is an unusual syndrome in which neurological deterioration occurs following removal of a large skull bone flap.

In 1977 Yamura and Makino coined the term “syndrome of the sunken skin flap” to describe the neurological symptoms due to a craniectomy defect 1).

Certain patients are particularly susceptible to the presence of a large skull defect. The term “Neurological Susceptibility to a Skull Defect” (NSSD) is therefore suggested as a blanket term to describe any neurological change attributable to the absence of cranial coverage 2).

Epidemiology

Despite the early recognition of neurological symptoms directly linked to craniectomy, the description of this syndrome has often relied on a small series or single clinical case reports. It may be more common than had been previously appreciated 3).

Pathophysiology

Various factors like stretching of the dura and underlying cortex due to the atmospheric pressure, cicatrical changes occurring between the cortex, dura and the skin exerting pressure on the skull contents, and impairment of the venous return due to the atmospheric pressure acting on the region of skull defect with a resultant increase in the local external pressure have been implicated in the pathophysiology of the “syndrome of the trephined” 4) 5) 6).

Clinical features

Skull defect can result in various symptoms of the” syndrome of the trephined “like headache, dizziness, undue fatigability, vague discomfort at the site of defect, feeling of apprehension and insecurity, mental depression and intolerance to vibration as described by Grant and Norcross 7).

Also severe dysautonomia and worsening the patient condition is described 8).

In a systematic review, symptoms most commonly include motor, cognitive, and language deficits (57%, 41%, 28%, respectively), with improvement after cranioplasty within 3.8 ± 3.9 days. 9).

2015

The neurological deterioration can be exacerbated or precipitated by CSF diversion procedures like a ventriculoperitoneal shunt.

If one considers Fodstad et al.’s remarks about the effects of atmospheric pressure in patients with skull defects, it is also conceivable that in patients with craniectomies too close to the midline, the sagittal sinus is more prone to collapse by atmospheric pressure. In this situation the normal CSF to sagittal sinus pressure gradient would be lost, leading to poor CSF absorption and thus an increase in extraaxial fluid collections and ventriculomegaly; cranioplasty would reverse this effect 10).


A case report of syndrome of the trephined revealed by vertical diplopia 11).

An extreme syndrome of the trephined after decompressive craniectomy is reported by Bijlenga et al. The most extensive clinical syndrome observed was established over 4 weeks and consisted of bradypsychia, dysartria, and limb rigidity with equine varus feet predominating on the right. The syndrome was aggravated when the patient was sitting with the sequential appearance over minutes of a typical parkinsonian levodopa-resistant tremor starting on the right side, extending to all four limbs, followed by diplopia resulting from a left abducens nerve palsy followed by a left-sided mydriasis. All signs recovered within 1-2 h after horizontalisation. It was correlated with an orthostatic progressive sinking of the skin flap, MRI and CT scan mesodiencephalic distortion without evidence of parenchymal lesion. Brain stem auditory evoked potential wave III latency increases were observed on the right side on verticalisation of the patient. EEG exploration excluded any epileptic activity. Symptoms were fully recovered within 2 days after cranioplasty was performed. The cranioplasty had to be removed twice due to infection. Bradypsychia, speech fluency, limb rigidity and tremor reappeared within a week after removal of the prosthesis. While waiting for sterilisation of the operative site, the symptoms were successfully prevented by a custom-made transparent suction-cup helmet before completion of cranioplasty 12).

Treatment

The therapeutic value of cranioplasty has been proved by various experiments. Increase in cerebrospinal fluid (CSF) and superior sagittal sinus pressure, cerebral expansion, increase in CSF motion after cranioplasty due to an increase in cerebral arterial pulsations and improvement in cerebral blood flow, cerebral metabolism and cerebral vascular reserve capacity have been demonstrated after cranioplasty 13) 14) 15) 16).

Reviews

2016

Electronic searches of PubMed, MEDLINE, Web of Knowledge, and PsycINFO databases used the key words “syndrome of the trephined” and “sinking skin flap.” Non-English-language and duplicate articles were eliminated. Title and abstract reviews were selected for relevance. Full-text reviews were selected for articles providing individual characteristics of SoT patients.

A review identified that SoT most often occurs in male patients (60%) at 5.1 ± 10.8 months after craniectomy for neurotrauma (38%). The average reported craniectomy is 88.3 ± 34.4 cm and usually exists with a “sunken skin flap” (93%). Symptoms most commonly include motor, cognitive, and language deficits (57%, 41%, 28%, respectively), with improvement after cranioplasty within 3.8 ± 3.9 days. Functional independence with activities of daily living is achieved by 54.9% of patients after 2.9 ± 3.4 months of rehabilitation. However, evaluation of SoT is inconsistent, with only 53% of reports documenting objective studies.

SoT is a variable phenomenon associated with a prolonged time to cranioplasty. Due to current weaknesses in objectivity, Ashayeri et al., hypothesize that SoT is often underdiagnosed and recommend a multifaceted approach for consistent evaluation.

SoT is a serious complication that lacks exact characterization and deserves future investigation. Improved understanding and recognition have important implications for early intervention and patient outcomes 17).

2015

Annan et al., selected the references for this review by searching PubMed, focusing on articles published prior to June 2013 and using references from relevant articles.

They used the following search terms: ‘trephined syndrome’, ‘syndrome of the trephined’, ‘Sinking skin flap’, and ‘sinking skin flap syndrome’. There were no language restrictions. The final reference list was generated on the basis of its relevance to the topics covered in this review.

Clinicians need to be aware of sinking skin flap syndrome and to look for abnormal neurological developments in patients with craniectomy in order to avoid unnecessary testing and to prevent its occurrence. Accordingly, cranioplasty can be undertaken as soon as necessary 18).

Case series

1984

Forty patients with cranial bone defects after craniectomy underwent extensive cerebrospinal fluid (CSF) hydrodynamic investigations by means of a CSF infusion test before and after cranioplasty. The results of these investigations were related to the clinical signs of the patients before and after cranioplasty and to the size and location of the skull bone defect. Twenty-two patients were considered to have “the syndrome of the trephined” (ST). The remaining patients were either free of symptoms or had symptoms not related to ST. CSF hydrodynamic variables that were changed before and normalized after cranioplasty include the following: Resting pressure, sagittal sinus pressure, buffer volume, elastance at resting pressure and pulse variations at resting pressure. The changes were statistically significant mainly in ST patients who were also relieved of their symptoms after cranioplasty 19).

Case reports

2015

A 52 year old male suffered severe head injury in a road traffic accident and underwent a craniectomy and contusectomy of the left Fronto-Temporo-Parietal (FTP) region for treatment of Acute Subdural hematoma (SDH) as well as hemorrhagic and non-hemorrhagic contusions of the brain with severe mass effect. On recovery from this acute event he was bed bound, on tracheostomy, his GCS was E4VTrM4 with residual right sided hemiparesis. Three months later, he developed Hydrocephalus for which a Right Ventriculo-Peritoneal (V-P) shunt was performed. Following this procedure, severe depression of the skin/scalp flap occurred and the neurological recovery was not as expected. He was diagnosed as a case of “Syndrome of the trephined”. An immediate Cranioplasty was performed, on the third month following the craniectomy procedure, in an attempt to resolve the rapidly deteriorating neurological status of the patient.

In the case presented, following the early Cranioplasty which was performed within three months of the initial craniectomy, the patient’s neurological condition and cognitive functions showed a remarkable, immediate and dramatic improvement. The early Cranioplastic repair led to a remarkable clinical recovery of the patient, with improvement in the cognitive behavior and motor deficit with a rapid reversal of the sensorimotor paresis, reflecting an improvement in brain perfusion 20).

2012

Kwon et al., report a case of a patient with sinking skin flap syndrome who suffered from reperfusion injury after cranioplasty 21).

2009

A 77-year-old male patient with an acute subdural hematoma was treated using a hemicraniectomy and evacuation of the hematoma. On the 9th postoperative day there was deterioration in sensorium associated with a sunken scalp flap and worsening midline shift on CT. A significant improvement in sensorium and a filling up of the scalp flap occurred after maintaining the patient’s head in a dependent position. The patient subsequently made an excellent recovery following replacement of the bone flap 22).

2004

A 45-year-old lady underwent right fronto-parietal craniotomy and subtotal excision of a parasagittal meningioma. Bone flap was not replaced as it was infiltrated by the tumor. In the postoperative period she developed episodes of altered sensorium associated with worsening of left hemiparesis and a sunken scalp at the site of bone defect. Computed tomography (CT) of brain showed sunken scalp flap in the right fronto-parietal region with compression of the underlying brain. A diagnosis of syndrome of the trephined was considered and her symptoms improved with cranioplasty 23).


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Posttraumatic Stress Disorder: Perspectives for the Use of Deep Brain Stimulation

Posttraumatic stress disorder (PTSD) may develop after a person is exposed to one or more traumatic events, such as sexual assault, warfare, serious injury, or threats of imminent death.

The diagnosis may be given when a group of symptoms, such as disturbing recurring flashbacks, avoidance or numbing of memories of the event, and hyperarousal, continue for more than a month after the occurrence of a traumatic event.

Most people having experienced a traumatizing event will not develop PTSD. People who experience assault-based trauma are more likely to develop PTSD, as opposed to people who experience non-assault based trauma such as witnessing trauma, accidents, and fire events.

Children are less likely to experience PTSD after trauma than adults, especially if they are under ten years of age.

War veterans are commonly at risk for PTSD.


Mild traumatic brain injury (mTBI) contributes to development of affective disorders, including post-traumatic stress disorder (PTSD).

Psychiatric symptoms typically emerge in a tardive fashion post-TBI, with negative effects on recovery. Patients with PTSD, as well as rodent models of PTSD, demonstrate structural and functional changes in brain regions mediating fear learning, including prefrontal cortex (PFC), amygdala (AMYG), and hippocampus (HC). These changes may reflect loss of top-down control by which PFC normally exhibits inhibitory influence over AMYG reactivity to fearful stimuli, with HC contribution. Considering the susceptibility of these regions to injury, Schneider et al., examined fear conditioning (FC) in the delayed post-injury period, using a mouse model of mTBI. Mice with mTBI displayed enhanced acquisition and delayed extinction of FC. Using Proton magnetic resonance spectroscopic imaging ex vivo, they examined PFC, AMYG, and HC levels of gamma-aminobutyric acid (GABA) and glutamate as surrogate measures of inhibitory and excitatory neurotransmission, respectively. Eight days post-injury, GABA was increased in PFC, with no significant changes in AMYG. In animals receiving FC and mTBI, glutamate trended toward an increase and the GABA/glutamate ratio decreased in ventral HC at 25 days post-injury, whereas GABA decreased and GABA/glutamate decreased in dorsal HC. These neurochemical changes are consistent with early TBI-induced PFC hypoactivation facilitating the fear learning circuit and exacerbating behavioral fear responses. The latent emergence of overall increased excitatory tone in the HC, despite distinct plasticity in dorsal and ventral HC fields, may be associated with disordered memory function, manifested as incomplete extinction and enhanced FC recall 1).

Treatment

Although most patients often improve with medications and/or psychotherapy, approximately 20-30% are considered to be refractory to conventional treatments. In other psychiatric disorders, DBS has been investigated in treatment-refractory patients. To date, preclinical work suggests that stimulation at high frequency delivered at particular timeframes to different targets, including the amygdala, ventral striatum, hippocampus, and prefrontal cortex may improve fear extinction and anxiety-like behavior in rodents. In the only clinical report published so far, a patient implanted with electrodes in the amygdala has shown striking improvements in PTSD symptoms.

Neuroimaging, preclinical, and preliminary clinical data suggest that the use of DBS for the treatment of PTSD may be practical but the field requires further investigation 2).

1) Schneider BL, Ghoddoussi F, Charlton JL, Kohler RJ, Galloway MP, Perrine SA, Conti AC. Increased Cortical Gamma-Aminobutyric Acid Precedes Incomplete Extinction of Conditioned Fear and Increased Hippocampal Excitatory Tone in a Mouse Model of Mild Traumatic Brain Injury. J Neurotrauma. 2016 Sep 1;33(17):1614-24. doi: 10.1089/neu.2015.4190. Epub 2016 Mar 18. PubMed PMID: 26529240.
2) Reznikov R, Hamani C. Posttraumatic Stress Disorder: Perspectives for the Use of Deep Brain Stimulation. Neuromodulation. 2016 Dec 19. doi: 10.1111/ner.12551. [Epub ahead of print] Review. PubMed PMID: 27992092.