Does Impaired Glymphatic Drainage Cause Glymphedema? A Review Tailored to Neurocritical Care and Neurosurgery.

Research into the glymphatic system reached an inflection point with steep trajectory in 2012 when it was formally recognized and named, but the historical roots for it are solid and deep, dating back to pioneers such as Cushing, Weed, and Dandy. We provide an overview of key discoveries of the glymphatic system, which promotes bulk flow of fluid and solutes throughout the brain parenchyma. We also discuss the lymphatic drainage of the central nervous system. Evidence is building that failure of the glymphatic system causes glymphedema in patients commonly managed by neurocritical care and neurosurgery specialists. We review research supporting this for decompressive craniectomy, subarachnoid hemorrhage, and normal-pressure hydrocephalus. We argue that it is time for a paradigm shift from the traditional model of cerebrospinal fluid circulation to a revised model that incorporates the glymphatic pathway and lymphatic clearance. These recent breakthroughs will inspire new therapeutic approaches to recognize, reverse, and restore glymphatic dysfunction and to leverage this pathway to deliver brain-wide therapeutics.

The Frozen Brain State of Cryptococcus gattii: A Globe-Trotting, Tropical, Neurotropic Fungus.

Initially reported in tropical regions, Cryptococcus gattii infection is now diagnosed globally. Methods: case report; Literature review. Although initial reports described outbreaks of pulmonary and central nervous system (CNS) disease in tropical regions such as Australia and New Guinea, it is now clear that Cryptococcus gattii is a global, neurotropic pathogen. In contrast with C. neoformans, C. gattii patients are more likely to present with cryptococcomas in the brain and lungs and are often HIV negative. Imaging findings can mimick cancer leading to delays in diagnosis and definitive treatment. Some experts have speculated that the spread of C. gattii is due to climate change, newly recognized genotypes that cause disease in temperate zones (genotype VGII), international travel, and improved awareness among physicians and veterinarians. We emphasize neurocritical and neurosurgical management, because patients with CNS involvement often have high intracranial pressures (ICP). Cryptococcus gattii patients often have elevated ICP without 'red flag' radiographic signs of elevated ICP such as ventriculomegaly, cerebral edema, or effaced basal cisterns. Therefore, diagnosis of high ICP should be suspected based on clinical symptoms such as incapacitating headaches, progressive visual loss and associated papilledema, and then confirmed by measuring the opening pressure with lumbar puncture (LP). Cerebral intraparenchymal deposition of the large cryptococcal polysaccharide capsule and cryptococcal organisms causes poor brain compliance leading to a 'frozen brain state.' Mortality rates and clinical outcomes are significantly improved with early diagnosis, antifungal therapies, steroids, and aggressive management of elevated ICP including cerebrospinal fluid (CSF) diversion by serial LP's, external ventricular drains and CSF shunts. Following institution of antifungal therapy, about 10% of patients can worsen due to immune reconstitution inflammatory syndrome which responds to steroids. We recommend neurocritical and neurosurgical management of C. gattii patients with CNS involvement and elevated ICP. There is often poor correlation between elevated ICP and neuroimaging due to the frozen brain state.

Initial Conservative Management of Severe Hemispheric Stroke Reduces Decompressive Craniectomy Rates.

BACKGROUND: Pooled European trial results of early decompressive craniectomy (DC) for severe hemispheric stroke did not require radiographic mass effect as an inclusion criterion. Early surgery for supratentorial cerebral hemorrhage does not improve functional status or survival compared to initial conservative medical management. Early versus delayed DC for hemispheric stroke has not been investigated. METHODS AND RESULTS: A prospective inpatient neurosurgical database from October 2007 to March 2015 was queried for neurocritical care admissions for hemispheric ischemic stroke in patients aged 18-60 under IRB approval. A retrospective chart review was conducted using a structured questionnaire and the electronic medical record. We identified 30 patients who met the inclusion criteria for the pooled European early DC stroke trial. The mean age was 46, and the median NIH stroke score was 19. All hemispheric stroke patients were monitored in the neurocritical care unit with hourly neurochecks and daily CT scans for a minimum of 3 days. Eighteen patients (60 %) were managed with medical treatment only (MTO) with an average maximal septal shift of 5.2 mm and a pineal shift of 3.1 mm. Twelve patients (40 %) underwent DC with an average maximal septal shift of 6.8 mm and a pineal shift of 4.1 mm. Modified Rankin (MR) outcomes at 3 months for the overall group, MTO, and DC were as follows: MR 0-3 60 % versus 67 % versus 50 %; MR 4-5 27 % versus 17 % versus 42 %; and death 13 % versus 17 % versus 8 %, respectively. Four patients in the MTO group declined DC; 3 died and one survived with an MR of 4. No patients developed brainstem herniation prior to referral for DC. Surgical complications occurred in 4/12 (33 %) patients. CONCLUSIONS: Delayed DC for hemispheric stroke patients managed under protocol in the neurocritical care unit is a safe alternative to early, prophylactic DC for adults with severe hemispheric stroke. This strategy reduced DC rates by 60 % without an excess of death or survival with severe disabilities.

The sentinel rash and neurocutaneous presentation of atrial myxoma: Case report and literature review.

Introduction: Presenting symptoms of atrial myxoma are classically viewed as a triad of cardiac, embolic, and constitutional symptoms. Dermatologic manifestations are viewed as constitutional symptoms and have not received much attention. Methods: Illustrative case presentation and literature review. Results: I admitted a 28 y woman transferred to the comprehensive stroke center with an ischemic stroke treated with intravenous thrombolysis. She had a two year history of skin lesions in the hands/fingers and feet/toes/sole. Skin biopsies showed perivascular neutrophilic inflammatory dermatitis without skin vasculitis. Admission physical exam was notable for chronic skin changes on her hand and foot and an acute erythematous petechial rash over the right side of her face in the distribution of the right external carotid artery. MRI brain showed ischemia involving the right internal carotid artery territory. Transthoracic echocardiogram identified a 2.4 cm atrial myxoma with normal mitral valve function. She underwent uncomplicated cardiac surgery with confirmation of a villous myxoma. At her 8 week follow up visit, she had resolution of her neurologic deficits, and her skin rashes had cleared.Literature review identified 17 additional published cases of sentinel rashes preceding diagnosis of atrial myxoma. Skin changes were often reported in the hand and feet and may involve the digits, palm, and sole. In 8 cases, skin biopsy identified myxomatous emboli in dermal vessels. These cutaneous manifestations share similarities with Osler nodes and Janeway lesions first described in the 1890's, now understood to represent microemboli to the dermis. Seven of these 17 cases (41 %) developed strokes after the initial presentation of cutaneous changes. Our patient had an embolic event primarily affecting the right common carotid artery territory with facial cutaneous changes due to emboli to the external carotid artery territory and cerebral ischemia in the right internal carotid artery territory. Conclusion: I recommend reclassification of the cutaneous signs of atrial myxoma as embolic (to the dermis microvasculature) rather than a constitutional symptom. As the skin biopsy often fails to show myxomatous emboli, physicians should have a high suspicion for a proximal embolic source for patients with a migratory rash preferentially affecting distal extremities. Earlier diagnosis of atrial myxoma when the sentinel rash first appears provides a valuable window of opportunity for cardiac surgery before the patient experiences stroke or peripheral emboli.

The genesis of low pressure hydrocephalus.

BACKGROUND: Low pressure hydrocephalus (LPH) is an uncommon entity. Recognition of this treatable condition is important when clinicians are faced with the paradox of symptomatic hydrocephalus despite low intracranial pressures (ICP). Its etiology remains enigmatic. METHODS: We identified patients with LPH from the prospective, inpatient neuro-intensive care database over a 4-year period (2006-2010). RESULTS: Nine patients with LPH were identified over a 4-year period. The time from diagnosis of the initial neurosurgical condition to development of LPH varied from 7 days to 5 years. The sub-zero drainage method of Pang and Altschuler was successful in all cases. LPH was accompanied by transependymal edema in five patients despite low ICP. Four patients developed LPH during their initial admission for intracranial bleeding. As patients entered the LPH state, the ICP remained in a normal range yet daily CSF output from the external ventricular drain was reduced. When LPH patients were drained at sub-zero levels, daily CSF output exceeded baseline values for several days and then receded to baseline. Long-term management was achieved with low pressure shunt systems: six programmable shunts; one valveless ventriculoperitoneal shunt; two ventriculopleural shunts. Conditions most commonly associated with LPH are: subarachnoid hemorrhage, chronic hydrocephalus, brain tumors, and chronic CNS infections. CONCLUSIONS: Low pressure hydrocephalus is a challenging diagnosis. The genesis of LPH was associated with a drop in EVD output, symptomatic ventriculomegaly, and a remarkable absence of intracranial hypertension. When LPH was treated with the sub-zero method, a 'diuresis' of CSF ensued. These observations support a Darcy's flux of brain interstitial fluid due to altered brain poroelastance; in simpler terms, a boggy brain state.

Spinal cord oligodendroglioma with 1p and 19q deletions presenting with cerebral oligodendrogliomatosis.

Oligodendroglioma of the spinal cord is a rare tumor that most often presents with spinal cord symptoms. The authors present a case of spinal cord oligodendroglioma that was associated with cerebral rather than spinal cord symptoms. A 30-year-old woman developed nausea, vomiting, and severe headaches. Magnetic resonance imaging of the brain showed meningeal enhancement. The patient underwent a craniotomy with biopsies of the meninges and brain. The biopsy findings revealed an abnormal arachnoid thickening without tumor cells. The patient later developed hydrocephalus and underwent shunt placement. Cerebrospinal fluid cytological findings were negative for tumor cells or infection. She was found to have a cervical cord lesion at C3-4 that was initially nonenhancing but later enhanced after Gd administration. Biopsy of the cord lesion with partial resection showed a WHO Grade II oligodendroglioma with 1p and 19q deletions determined by fluorescence in situ hybridization. Neurooncological treatment with tumor radiation and temozolomide (Temodor) resulted in improvement in radiographic findings, symptoms, and long-term survival. This paper presents an extensive review of the literature, which revealed only 2 other reported cases of cerebral symptoms in adults that preceded spinal cord symptoms in a patient with oligodendroglioma of the spinal cord. It is also the first reported case of oligodendrogliomatosis due to a cervical spinal cord oligodendroglioma with 1p and 19q deletions.

Are Hygromas and Hydrocephalus After Decompressive Craniectomy Caused by Impaired Brain Pulsatility, Cerebrospinal Fluid Hydrodynamics, and Glymphatic Drainage? Literature Overview and Illustrative Cases.

BACKGROUND: Poorly understood cranial fluid accumulations are frequently observed after decompressive craniectomy and often termed "external hydrocephalus." These findings are difficult to explain using traditional models of hydrocephalus. METHODS: Representative cases, clinical management, and literature overview are presented. RESULTS: We present a hypothesis that abnormal cranial fluid accumulations develop after decompressive craniectomy in a vulnerable subset of patients as a result of 1) the large compliant cranial defect with durotomy causing reduced internal brain expansion, ventricular squeezing, and pulsatile cerebrospinal fluid (CSF) circulation; 2) impaired pulsatile CSF flow along major cerebral arteries and the adjoining perivascular spaces (Virchow-Robin spaces); 3) reduced clearance of interstitial fluid by the glymphatic system; and 4) redistribution of CSF from the subarachnoid space into the subdural and subgaleal compartments and the ventricles. CONCLUSION: Closure of the cranial defect with cranioplasty improves cerebral blood flow and CSF pulsatile circulation and is frequently sufficient to resolve the external hydrocephalus.

A 10-Year Analysis of 3693 Craniotomies during a Transition to Multidisciplinary Teams, Protocols, and Pathways.

INTRODUCTION: A Cochrane review of teams, protocols, and pathways demonstrated improved care efficiency and outcomes over a traditional model. Little is known about this approach for craniotomy. METHODS: This observational study involved sequential implementation of a multidisciplinary team, protocols, and a craniotomy pathway. Data on 3693 admissions were retrospectively reviewed at a tertiary care neurosurgery center from 2008 to 2017 for the top 6 diagnosis-related group codes. In June 2016, a searchable discharge summary template in the electronic medical record was implemented to capture data regarding quality, efficiency, and outcomes. RESULTS: Staffing transitioned to a team of neurosurgeons, neurointensivists, neurohospitalists, and midlevel practitioners. Order sets, protocols, and pathways were developed. Quality improvements were observed for craniotomy and cranioplasty surgical site infections, ventriculitis, coagulopathy reversal, and decompressive hemicraniectomy rates for stroke. Case volume increased 73%, yet craniotomy hospital days decreased from 2768 in 2008 to 2599 in 2017 because of reduced length of stay. We accommodated service line growth without hospital expansion or case backlogs. With an average California hospital day rate of $3341, the improved length of stay decreased costs by $14,666,990/y. We also present outcomes data, including craniotomy indications, operative timing, complications, functional outcomes, delays in discharge, and discharge destinations using the craniotomy discharge summary. CONCLUSION: Multidisciplinary teams, protocols, and pathways reduced craniotomy complication rates, improved hospital length of stay by 63%, reduced costs, and increased professional collegiality and satisfaction. A searchable craniotomy discharge summary is an important tool for continuous monitoring of quality and efficiency of care.

Diagnosis, Classification, and Management of Fourth Ventriculomegaly in Adults: Report of 9 Cases and Literature Review.

OBJECTIVE: An enlarged fourth ventricle, otherwise known as fourth ventriculomegaly (4th VM), has been reported previously in the pediatric population, yet literature on adults is scant. We report our experience with 4th VM in adults over an 11-year period and review the literature. MATERIALS AND METHODS: This was a retrospective chart review of adult patients with the diagnosis of 4th VM admitted to the intensive care unit in a tertiary care center. RESULTS: Nine patients were identified with 4th VM. Most presented with symptoms in the posterior fossa. Five cases were related to previous shunting and the underlying neurosurgical diseases, and average time interval to develop symptoms was 5.3 years. We divided our cases into primary, acquired, and degenerative based on the pathophysiology involved. Treatments included extended subzero cerebrospinal fluid diversion using a frontal external ventricular drain followed by low-pressure shunt revision, endoscopic third ventriculostomy, suboccipital decompression, and fourth ventricular catheter placement. Literature review identified additional published cases, and there were no reports of a formal classification scheme or treatment algorithm. CONCLUSIONS: This case series illustrates a narrow spectrum of etiologies associated with 4th VM in adults. We propose a simple classification scheme dividing 4th VM into 3 categories: primary, acquired, and degenerative. We recommend a stepwise treatment approach starting with extended subzero cerebrospinal fluid diversion followed by shunting for symptomatic primary and acquired 4th VM. Lower success rates and greater morbidity are associated with rescue procedures such as fourth ventricle drainage catheters, endoscopic third ventriculostomies, and skull base decompression.

Do Obese and Extremely Obese Patients Lose Weight After Lumbar Spine Fusions? Analysis of a Cohort of 7303 Patients from the Kaiser National Spine Registry.

MINI: The outcome of interest was ≥ 5% weight change 1 year postoperative from baseline. Seven thousand three hundred three lumbar fusions in the Kaiser Permanente Spine Registry between 2009 and 2013 were analyzed. Weight loss occurred in: body mass index < 30, 11.1%; obese, BMI 30 to 39, 16.6%, odds ratio = 1.42; extremely obese, body mass index ≥40, 21.1%, odds ratio = 1.73. STUDY DESIGN: A retrospective cohort study from the Kaiser Permanente Spine Registry. OBJECTIVE: The aim of this study was to determine whether obese and extremely obese patients with lumbar spine fusions lost a clinically significant amount of weight (≥5%) 1 year after their surgery. SUMMARY OF BACKGROUND DATA: Obesity in the United States has a prevalence of 35% and is a global health issue. Obesity is associated with lumbar spine disease. There is limited evidence regarding postsurgical weight loss after spine surgery. METHODS: Adult patients in the Kaiser Permanente Spine Registry with lumbar fusions performed between 2009 and 2013 were included in the study sample (n = 7303). The outcome of interest was ≥5% weight change 1 year postoperative from baseline. Three body mass index (BMI) groups were analyzed (BMI < 30; 30-39 obese; ≥40 extremely obese). Covariate analysis, multivariable logistic regression, odds ratios (ORs), and 95% confidence intervals (95% CIs) are provided. RESULTS: At the time of spine surgery, 4456 (61%) had a BMI < 30, 2519 (34.5%) had a BMI between 30 and 39, 232 (3.2%) had a BMI ≥40, and 96 (1.3%) were missing their intraoperative BMI. We observed the following weight loss pattern: BMI < 30, 11.1%; BMI 30 to 39, 16.6%; BMI ≥40, 21.1%. We observed the following weight gain pattern: BMI < 30, 15.6%; BMI 30 to 39, 12.7%; BMI ≥40, 9.5%. After risk-adjustment, obese and extremely obese patients were more likely to lose a clinically significant amount of weight 1 year after surgery (BMI 30-39: OR = 1.42, 95% CI 1.22-1.65; BMI ≥40: OR = 1.73, 95% CI 1.21-2.47) compared with nonobese patients. CONCLUSION: In this large cohort of patients with lumbar spinal fusions, we observed more significant weight loss in obese and extremely obese patients than nonobese patients. Additional research is needed to determine whether this weight loss is due to improvements in back pain and increased physical activity. LEVEL OF EVIDENCE: 3.

A retrospective cohort study from the Kaiser Permanente Spine Registry. The aim of this study was to determine whether obese and extremely obese patients with lumbar spine fusions lost a clinically significant amount of weight (≥5%) 1 year after their surgery. Obesity in the United States has a prevalence of 35% and is a global health issue. Obesity is associated with lumbar spine disease. There is limited evidence regarding postsurgical weight loss after spine surgery. Adult patients in the Kaiser Permanente Spine Registry with lumbar fusions performed between 2009 and 2013 were included in the study sample (n = 7303). The outcome of interest was ≥5% weight change 1 year postoperative from baseline. Three body mass index (BMI) groups were analyzed (BMI < 30; 30­39 obese; ≥40 extremely obese). Covariate analysis, multivariable logistic regression, odds ratios (ORs), and 95% confidence intervals (95% CIs) are provided. At the time of spine surgery, 4456 (61%) had a BMI < 30, 2519 (34.5%) had a BMI between 30 and 39, 232 (3.2%) had a BMI ≥40, and 96 (1.3%) were missing their intraoperative BMI. We observed the following weight loss pattern: BMI < 30, 11.1%; BMI 30 to 39, 16.6%; BMI ≥40, 21.1%. We observed the following weight gain pattern: BMI < 30, 15.6%; BMI 30 to 39, 12.7%; BMI ≥40, 9.5%. After risk-adjustment, obese and extremely obese patients were more likely to lose a clinically significant amount of weight 1 year after surgery (BMI 30­39: OR = 1.42, 95% CI 1.22­1.65; BMI ≥40: OR = 1.73, 95% CI 1.21­2.47) compared with nonobese patients. In this large cohort of patients with lumbar spinal fusions, we observed more significant weight loss in obese and extremely obese patients than nonobese patients. Additional research is needed to determine whether this weight loss is due to improvements in back pain and increased physical activity. Level of Evidence: 3.

Secondary stroke prevention with ximelagatran versus warfarin in patients with atrial fibrillation: pooled analysis of SPORTIF III and V clinical trials.

BACKGROUND AND PURPOSE: Patients with nonvalvular atrial fibrillation and prior stroke or transient ischemic attack (TIA) are at high risk for recurrent stroke. We investigated whether ximelagatran was noninferior to warfarin in patients with prior stroke or TIA. METHODS: We analyzed pooled data from the SPORTIF III and V trials in patients with prior stroke/TIA. The primary outcome was the composite annual rate of both ischemic and hemorrhagic strokes and systemic embolic events. Secondary analyses considered ischemic and hemorrhagic strokes separately, bleeding, and nonrandomized, concomitant therapy with aspirin < or =100 mg/d. RESULTS: Patients from SPORTIF III (n=3407) and SPORTIF V (n=3922) trials were categorized by prior stroke/TIA (21%) versus no prior stroke/TIA (79%) and by treatment group (ximelagatran vs warfarin). The primary event rate in patients with prior stroke/TIA was 2.83%/y with ximelagatran and 3.27%/y with warfarin (absolute difference, -0.44%; 95% CI, -1.88 to1.01; P=0.625). In those without prior stroke/TIA, the primary event rate was 1.31%/y with ximelagatran and 1.26%/y with warfarin (P=NS). Ischemic strokes outnumbered cerebral hemorrhages with both warfarin (31 of 36) and ximelagatran (30 of 32) treatment (difference between treatments was not significant). Combining aspirin with either anticoagulant was associated with higher rates of major bleeding (1.5%/y with warfarin and 4.95%/y with warfarin plus aspirin, P=0.004; 2.35%/y with ximelagatran and 5.09%/y with ximelagatran plus aspirin, P=0.046) but not lower rates of primary events. CONCLUSIONS: Ximelagatran was at least as effective as well-controlled warfarin for the secondary prevention of stroke. The nonrandomized, concomitant treatment with aspirin and anticoagulation was associated with increased bleeding without evidence of a reduction in primary outcome events.

Single-staged resections and 3D reconstructions of the nasion, glabella, medial orbital wall, and frontal sinus and bone: Long-term outcome and review of the literature.

BACKGROUND: Aesthetic facial appearance following neurosurgical ablation of frontal fossa tumors is a primary concern for patients and neurosurgeons alike. Craniofacial reconstruction procedures have drastically evolved since the development of three-dimensional computed tomography imaging and computer-assisted programming. Traditionally, two-stage approaches for resection and reconstruction were used; however, these two-stage approaches have many complications including cerebrospinal fluid leaks, necrosis, and pneumocephalus. CASE DESCRIPTION: We present two successful cases of single-stage osteoma resection and craniofacial reconstruction in a 26-year-old female and 65-year-old male. The biopolymer implants were preselected and contoured based on imaging prior to surgery. The ideal selection of appropriate flaps for reconstruction was imperative. The flaps were well vascularized and included a pedicle for easy translocation. Using a titanium mesh biopolymer implant for reconstruction in conjunction with a forehead flap proved advantageous, and the benefits of single-stage approaches were apparent. The patients recovered quickly after the surgery with complete resection of the osteoma and good aesthetic appearance. The flap adhered to the biopolymer implant, and the cosmetic appearance years after surgery remained decent. The gap between the bone and implant was less than 2 mm. The patients are highly satisfied with the symmetrical appearance of the reconstruction. CONCLUSIONS: Advances in technology are allowing neurosurgeons unprecedented opportunities to design complex yet feasible single-stage craniofacial reconstructions that improve a patient's quality of life by enhancing facial contours, aesthetics, and symmetry.

Risk Factors Associated With 30-day Readmissions After Instrumented Spine Surgery in 14,939 Patients: 30-day readmissions after instrumented spine surgery.

STUDY DESIGN: A retrospective review of instrumented spine registry from an integrated US healthcare system. OBJECTIVE: Investigate the 30-day readmission rate and risk factors after instrumented spine surgery. SUMMARY OF BACKGROUND DATA: Published readmission rates range from 2% to over 20%. We were interested in learning which patients were at greatest risk, when did readmissions occur, and why. METHOD: 30-day readmission rates were determined for 14,939 patients after an index spine procedure between 1/2009 and 3/2013. Data were analyzed with descriptive statistics, univariate, and multivariate logistic regression analysis. RESULT: The average age of the cohort was 59 (SD = 13.4) and 52% were female. The 30-day readmission rate was 5.5% (821/14,939). The temporal pattern for readmission was: 17% (140) at week 1, 48% (394) at week 2, 72% (591) at week 3, and 100% (821) at week 4. The leading causes were wound complications (infection, hematoma, dehiscence, seroma), sepsis, pain management, pneumonia, and pulmonary emboli/deep venous thrombosis. In a multivariate model, readmission risk factors were: malignancy (OR 2.99, 95% CI: 1.56, 5.73), operative time more than 400 minutes (OR 2.59, 95% CI: 1.66, 4.02), operative time 300-399 minutes (OR 2.33, 95% CI: 1.54-3.52), hospital stay 6-10 days (OR 2.03, 95% CI: 1.31-3.14), hospital stay more than 10 days (OR 1.85, 95% CI: 1.1, -3.08), surgical complications (OR 1.67, 95% CI: 1.18, 2.36), operative time 200-299 (OR 1.52, 95% CI: 1.04, 2.22), depression (OR 1.48, 95% CI: 1.14, 1.93), rheumatoid arthritis (OR 1.45, 95% CI: 1.05, 2.01), deficiency anemia (OR 1.30, 95% CI: 1.05, 1.61), and hypothyroidism (OR 1.29, 95% CI: 1.01, 1.64). CONCLUSION: Surgical complications (dural tear, deep infections, superficial infections, epidural hematoma), malignancy, lengthy operative times, and lengthy initial hospitalizations are all risk factors for 30-day readmission. These findings should be considered during preoperative assessment and surgical planning. LEVEL OF EVIDENCE: 3.

Glutamate AMPA receptor antagonist treatment for ischaemic stroke.

During cerebral ischaemia, glutamate is released in supraphysiological amounts and is toxic to brain tissue. This excitotoxicity is mediated by several glutamate receptor subtypes, including the ionotropic N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors. Clinical trials of drugs that block the NMDA receptor in acute ischaemic stroke have been disappointing. No improvement in clinical outcome of stroke has been seen with competitive NMDA antagonists (selfotel) and non-competitive NMDA antagonists (dextrorphan, GV150526, aptiganel and eliprodil). The AMPA receptor differs in important ways from the NMDA receptor. It is the principal mediator of fast excitatory neurotransmission. This ligand-gated cation channel is primarily permeable to sodium rather than calcium. It is found in grey and white matter. It is expressed by oligodendrocytes. This distribution may provide neuroprotection for both grey and white matter. In a variety of animal models, reduction in infarct volume with AMPA blockade has been demonstrated. AMPA antagonists also show benefit in spinal cord ischaemia and trauma. The clinical development of safe and effective AMPA blockers has been hampered by poor water solubility and associated renal toxicity. A novel, highly water-soluble, competitive AMPA receptor antagonist, YM872 ([2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl]acetic acid monohydrate; Yamanouchi), has been identified. Phase I clinical trial data indicate that this agent can be safely administered in young and elderly subjects. Sedation and other CNS associated adverse events determine the ceiling dose and become more problematic with infusion times exceeding 24 h. Phase II studies of YM872 in acute ischaemic stroke are ongoing.

Management and outcomes of malignant posterior reversible encephalopathy syndrome.

INTRODUCTION: Recognition of severe forms of posterior reversible encephalopathy syndrome (PRES) has improved. Management of these patients remains challenging, particularly in patients with the combination of edema and hemorrhage. METHODS: A prospective inpatient neuro-intensive care database was queried for patients with PRES. Malignant PRES was diagnosed by clinical assessments (GCS less than 8 and clinical decline despite standard medical management for elevated intracranial pressure) and radiographic criteria (edema with associated mass effect; brain hemorrhage exerting mass effect; effacement of basal cisterns, transtentorial, tonsillar, or uncal herniation). Malignant PRES was defined as: radiology studies consistent with PRES; GCS less than 8; and clinical decline despite standard elevated intracranial pressure management. RESULTS: Five cases were identified over a 4 year interval. The following contributing conditions were also present: chemotherapy (1), systemic lupus erythematosis (2), pregnancy (1), and methamphetamines (1). Neurocritical care interventions included: hyperosmolar therapy (5), anticonvulsants (5), management of coagulopathy (5), and ventilatory support (5). Neurosurgical interventions included: craniectomy (5), hematoma evacuation (3), and external ventricular drain (4). Brain biopsy was performed in 5 patients and was negative for vasculitis, demyelinating disease, tumor, or infection. Cyclophosphamide was administered to the two patients with SLE. With long-term follow up, all patients achieved good functional outcomes (modified Rankin score 1-2). CONCLUSION: In contrast to historical reports of high mortality rates (16-29%) for severe and hemorrhagic PRES variants, we had no fatalities and observed favorable functional outcomes with intracranial pressure monitoring and craniectomy for malignant PRES cases who fail medical ICP management.

Lower complication rates for cranioplasty with peri-operative bundle.

BACKGROUND: The overall benefits of craniectomy must include procedural risks from cranioplasty. Cranioplasty carries a high risk of surgical site infections (SSI) particularly with antibiotic resistant bacteria. The goal of this study was to measure the effect of a cranioplasty bundle on peri-operative complications. METHODS: The authors queried a prospective, inpatient neurosurgery database at Kaiser Sacramento Medical Center for craniectomy and cranioplasty over a 7 year period. 57 patients who underwent cranioplasties were identified. A retrospective chart review was completed for complications, including surgical complications such as SSI, wound dehiscence, and re-do cranioplasty. We measured cranioplasty complication rates before and after implementation of a peri-operative bundle, which consisted of peri-operative vancomycin (4 doses), a barrier dressing through post-operative day (POD) 3, and de-colonization of the surgical incision using topical chlorhexidine from POD 4 to 7. RESULTS: The rate of MRSA colonization in cranioplasty patients is three times higher than the average seen on ICU admission screening (19% vs. 6%). The cranioplasty surgical complication rate was 22.8% and SSI rate was 10.5%. The concurrent SSI rate for craniectomy was 1.9%. Organisms isolated were methicillin-resistant Staphylococcus aureus (4), methicillin-sensitive S. aureus (1), Propionibacterium acnes (1), and Escherichia coli (1). Factors associated with SSI were peri-operative vancomycin (68.6% vs. 16.7%, p=0.0217). Complication rates without (n=21) and with (n=36) the bundle were: SSI (23.8% vs. 2.8%, p=0.0217) and redo cranioplasty (19% vs. 0%, p=0.0152). Bundle use did not affect rates for superficial wound dehiscence, seizures, or hydrocephalus. CONCLUSIONS: The cranioplasty bundle was associated with reduced SSI rates and the need for re-do cranioplasties.

Rapid Warfarin reversal in the setting of intracranial hemorrhage: a comparison of plasma, recombinant activated factor VII, and prothrombin complex concentrate.

OBJECTIVE: To compare the safety and effectiveness of three methods of reversing coagulopathic effects of warfarin in patients with potentially life-threatening intracranial hemorrhage. METHODS: A retrospective electronic medical record review of 63 patients with warfarin-related intracranial hemorrhage between 2007 and 2010 in an integrated health care delivery system was conducted. The three methods of rapid warfarin reversal were fresh-frozen plasma (FFP), activated factor VII (FVIIa; NovoSevenRT [Novo Nordisk, Bagsværd, Denmark]), and prothrombin complex concentrate (PCC; BebulinVH [Baxter, Westlake Village, California, USA], ProfilnineSD [Grifols, North Carolina, USA]), each used adjunctively with vitamin K (Vit K, phytonadione). We determined times from reversal agent order to laboratory evidence of warfarin reversal (international normalized ratio [INR]) in the first 48 hours and compared INR rebound rates and complications in the first 48 hours. RESULTS: Reversal with FFP took more than twice as long compared with FVIIa or PCC. To reach an INR of 1.3, mean (±SD) reversal times were 1933 ± 905 minutes for FFP, 784 ± 926 minutes for FVIIa, and 980 ± 1021 minutes for PCC (P < 0.001; P < 0.01 between FFP and FVIIa, P < 0.05 between FFP and PCC). INR rebound occurred in 0 of 31 patients for FFP, 4 of 8 for FVIIa, and 0 of 7 for PCC (P = 0.001). Complications were uncommon. FVIIa was 15 and 3.5 times as expensive as FFP and PCC, respectively. CONCLUSION: As an adjunct to Vit K for rapid warfarin reversal, FVIIa and PCC appear more effective than FFP. Either FVIIa or PCC are reasonable options for reversal, but FVIIa is considerably more expensive and may have greater risk of INR rebound.