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Tomikatsu Toyoda, Aij-Lie Kwan, Murad Bavbek, Neal F. Kassell, John E. Wanebo and Kevin S. Lee

Object. Monophosphoryl lipid A (MPL) and diphosphoryl lipid (DPL) are derivatives of the lipopolysaccharide (endotoxin) of Salmonella minnesota strain R595. Monophosphoryl lipid A is relatively nontoxic and can stimulate the natural defense or immune system. Diphosphoryl lipid is relatively toxic; however, at higher concentrations, it can also stimulate an immune response. The purpose of the present study was to determine the effects of these endotoxin analogs on cerebral vasospasm after the onset of subarachnoid hemorrhage (SAH) in rabbits.

Methods. Intrathecal administration of MPL or DPL (5 µg/kg) was performed immediately before and 24 hours after induction of SAH in New Zealand White rabbits. Forty-eight hours after induction of SAH, the animals were killed by perfusion fixation for morphometric analyses of vessels or perfused with saline and assayed for superoxide dismutase (SOD) activity. Additional rabbits were administered MPL or DPL and killed 24 hours later for assessment of SOD activity; no SAH was induced in these animals.

Experimental SAH elicited spasm of the basilar arteries in each group. Vasospasm was markedly attenuated in animals treated with MPL (p < 0.01 compared with vehicle-treated animals), but not in animals treated with DPL. A substantial reduction in SOD activity in the basilar artery accompanied the vasospasm; this loss of activity was significantly blocked by treatment with MPL, but not DPL. In animals that were not subjected to experimental SAH, MPL elicited a significant increase in SOD activity over basal levels, whereas DPL was ineffective.

Conclusions. These data provide evidence of a marked protective effect of the endotoxin analog MPL against vasospasm. Although the mechanism(s) responsible for the protective effect of MPL remains to be verified, an enhancement of basal antioxidant activity and an inhibition of SAH-induced loss of this activity are attractive candidates. An MPL-based therapy could represent a useful addition to current therapies for SAH-induced cerebral injury.

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Hakan H. Caner, Aij-Lie Kwan, Adam Arthur, Arco Y. Jeng, Rodney W. Lappe, Neal F. Kassell and Kevin S. Lee

✓ The potent vasoconstrictor peptide, endothelin-1 (ET-1), has been implicated in the pathophysiology of cerebral vasospasm that occurs after subarachnoid hemorrhage (SAH). This peptide is synthesized as a large prepropeptide that requires a series of modifying steps for its activation. The last of these steps involves the proteolytic conversion of a relatively inactive propeptide, Big ET-1, to its active, 21—amino acid peptide form. The enzyme responsible for converting Big ET-1 to ET-1 is a metalloprotease called endothelin-converting enzyme (ECE). In the present study the authors examined the effects of a newly developed inhibitor of ECE on responses to ET peptides in the normal basilar artery and on pathophysiological constriction in the spastic basilar artery after SAH.

In the first series of experiments the authors examined normal basilar arteries in the rabbit, which were exposed transclivally and measured on-line using videomicroscopy. Intravenous administration or topical application of an active inhibitor of ECE, CGS 26303, blocked vasoconstrictor responses to topically applied Big ET-1 but not to ET-1. In contrast, topical application of a structurally related compound that does not inhibit ECE, CGS 24592, was ineffective in blocking vasoconstriction that was elicited by a topical application of Big ET-1. These findings indicate that CGS 26303 when administered systemically is capable of blocking the conversion of Big ET-1 to ET-1 in the basilar artery without affecting the ability of the vessel to respond to ET-1. In the second series of experiments the authors examined the effects of the ECE inhibitor on cerebral vasospasm after experimental SAH. Intraperitoneal administration of CGS 26303 via osmotic minipumps significantly attenuated the delayed spastic response of the basilar artery to an intracisternal injection of autologous blood.

This study provides the first evidence that systemic administration of an inhibitor of ECE is capable of preventing cerebral vasospasm after SAH. The results reinforce a growing body of evidence that ETs play a critical role in the development of spastic constriction after SAH. Moreover, the findings indicate that blocking the conversion of Big ET-1 to its active ET-1 form using CGS 26303 may represent a feasible strategy for ameliorating cerebral vasospasm.

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Huei-Chuan Shih, Chih-Lung Lin, Shu-Chuan Wu, Aij-Lie Kwan, Yi-Ren Hong and Shen-Long Howng

Object

The authors previously demonstrated that 17β-estradiol benzoate (E2) treatment prevents subarachnoid hemorrhage (SAH)–induced cerebral vasospasm and preserves endothelial nitric oxide synthase (eNOS) in male rats. Changes in the expression of estrogen receptor (ER) subtypes ERα and -β and their roles in the E2-mediated preservation of eNOS in SAH remain unknown. In the present study the effects of SAH on the expression of ERα and -β in the cerebral arteries were clarified, and the receptor roles in the E2-mediated preservation of eNOS expression in SAH were differentiated.

Methods

A 2-hemorrhage SAH model was induced by 2 autologous blood injections into the cisterna magna of adult male rats. The effect of SAH on ERα and -β expression was evaluated. Other rats subcutaneously received implanted Silastic tubes containing corn oil with E2 and daily injections of various doses of an ERα- (methyl-piperidinopyrazole [MPP]) or ERβ-selective antagonist (R,R-tetrahydrochrysene) after the first hemorrhage. The protein levels of ERα, ERβ, eNOS, and inducible nitric oxide synthase (iNOS) from basilar arteries were examined using Western blot analysis, and their mRNAs were evaluated by reverse transcription–polymerase chain reaction.

Results

The ERα but not the ERβ was upregulated in the basilar artery after SAH. Treatment with MPP eliminated E2-mediated effects in SAH, relieved cerebral vasospasm, preserved eNOS expression, and suppressed iNOS expression.

Conclusions

Estrogen receptor α is upregulated in the basilar artery after SAH. Note that E2 exerts its protective effects through ERα-dependent pathways to relieve cerebral vasospasm and preserve eNOS expression. A selective ERα agonist may be the drug of choice for the treatment of patients with SAH.

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Yu-Hua Huang, Tao-Chen Lee, Tsung-Han Lee, Chen-Chieh Liao, Jason Sheehan and Aij-Lie Kwan

Object

Decompressive craniectomy is a life-saving measure for patients who have sustained traumatic brain injury (TBI), but patients undergoing this procedure may still die during an early phase of head injury. The aim of this study was to investigate the incidence, causes, and risk factors of 30-day mortality in traumatically brain-injured patients undergoing decompressive craniectomy.

Methods

The authors included 201 head-injured patients undergoing decompressive craniectomy in this 3-year retrospective study. The main outcome evaluated was 30-day mortality in patients who had undergone craniectomy after TBI. Demographic and clinical data, including information on death, were obtained for subsequent analysis. The authors identified differences between survivors and nonsurvivors in terms of clinical parameters; multivariate logistic regression was used to adjust for independent risk factors of short-term death.

Results

The 30-day mortality rate was 26.4% in traumatically brain-injured patients undergoing decompressive craniectomy. The majority of deaths following decompression resulted from uncontrollable brain swelling and extensive brain infarction, which accounted for 79.2% of mortality. In the multivariate logistic regression mode, the 2 independent risk factors for 30-day mortality were age (OR 1.035 [95% CI 1.006–1.064]; p = 0.018) and Glasgow Coma Scale (GCS) score before decompressive craniectomy (OR 0.769 [95% CI 0.597–0.990]; p = 0.041).

Conclusions

There is a high 30-day mortality rate in traumatically brain-injured patients undergoing decompressive craniectomy. Most of the deaths are attributed to ongoing brain damage, even after decompression. Risk factors of short-term death, including age and preoperative GCS score, are important in patient selection for decompressive craniectomy, and these factors should be considered together to ensure the highest chance of surviving TBI.

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Shang-Hang Shen, Aij-Lie Kwan, Bo-Liang Wang, Jian-Feng Guo, Guo-Wei Tan, Si-Fang Chen, Xi-Yao Liu, Feng Liu, Ming Cai and Zhan-Xiang Wang

Object

The occurrence of hydrocephalic macrocephaly is uncommon. When the condition does occur, it is usually seen in infants and young children. Patients with this disorder have an excessively enlarged head and weak physical conditions. Various surgical techniques of reduction cranioplasty for the treatment of these patients have been reported. In this study, a revised surgical procedure with the aid of simulated computer imaging for the treatment of hydrocephalic macrocephaly is presented.

Methods

Five cases of hydrocephalic macrocephaly in children ranging in age from 16 to 97 months were reviewed. These patients underwent surgical treatment at The First Affiliated Hospital of Xiamen University over a period of 4 years from January 2007 to January 2011. After physical examination, a 3D computer imaging system to simulate the patient's postoperative head appearance and bone reconstruction was established. Afterward, for each case an appropriate surgical plan was designed to select the best remodeling method and cranial shape. Then, prior to performing reduction remodeling surgery in the patient according to the computer-simulated procedures, the surgeon practiced the bone reconstruction technique on a plaster head model made in proportion to the patient's head. In addition, a sagittal bandeau was used to achieve stability and bilateral symmetry of the remodeled cranial vault. Each patient underwent follow-up for 6–32 months.

Results

Medium-pressure ventriculoperitoneal shunt surgery or shunt revision procedures were performed in each patient for treating hydrocephalus, and all patients underwent total cranial vault remodeling to reduce the cranial cavity space. Three of the 5 patients underwent a single-stage surgery, while the other 2 patients underwent total cranial vault remodeling in the first stage and the ventriculoperitoneal shunt operation 2 weeks later because of unrecovered hydrocephalus. All patients had good outcome with regard to hydrocephalus and macrocephaly.

Conclusions

There are still no standard surgical strategies for the treatment of hydrocephalic macrocephaly. Based on their experience, the authors suggest using a computer imaging system to simulate a patient's postoperative head appearance and bone reconstruction together with total cranial vault remodeling with shunt surgery in a single-stage or 2-stage procedure for the successful treatment of hydrocephalic macrocephaly.

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Aij-Lie Kwan, Murad Bavbek, Arco Y. Jeng, Wieslawa Maniara, Tomikatsu Toyoda, Rodney W. Lappe, Neal F. Kassell and Kevin S. Lee

✓ Delayed cerebral ischemia due to cerebral vasospasm is a major cause of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (SAH). Increasing evidence implicates the potent vasoconstrictor peptide endothelin (ET) in the pathophysiology of cerebral vasospasm. In the present study the authors examined the therapeutic value of blocking the production of ET-1 by inhibiting the conversion of its relatively inactive precursor, Big ET-1, to a physiologically active form. An inhibitor of ET-converting enzyme (ECE), CGS 26303, was injected intravenously after inducing SAH in New Zealand white rabbits. Injections of CGS 26303 were initiated either 1 hour after SAH (prevention protocol) or 24 hours after SAH (reversal protocol). One of three concentrations (3, 10, or 30 mg/kg) of CGS 26303 was injected twice daily, and all animals were killed by perfusion fixation 48 hours after SAH occurred. Basilar arteries were removed and sectioned, and their cross-sectional areas were measured in a blind manner by using computer-assisted videomicroscopy.

Treatment with CGS 26303 attenuated arterial narrowing after SAH in both the prevention and reversal protocols. The protective effect of CGS 26303 achieved statistical significance at all dosages in the prevention protocol and at 30 mg/kg in the reversal protocol. These findings demonstrate that inhibiting the conversion of Big ET-1 to ET-1 via intravenous administration of an ECE inhibitor can be an effective strategy for limiting angiographic vasospasm after SAH. Moreover, the results demonstrate that treatment with the ECE inhibitor is capable of reducing vasospasm even when initiated after the process of arterial narrowing has begun. Finally, the results provide further support for the role of ET in the establishment of cerebral vasospasm. The ECE inhibitor CGS 26303 thus represents a promising therapeutic agent for the treatment of cerebral vasospasm following aneurysmal SAH.

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Teng-yu Li, Jun-sheng Chu, Yu-lun Xu, Jun Yang, James Wang, Yu-Hua Huang, Aij-Lie Kwan and Gui-Huai Wang

Object

The aim of this study was to investigate the surgical strategies and outcomes for spinal ependymomas of different lengths.

Methods

The authors used data from 210 patients with spinal ependymomas (WHO Grades II and III) in this 10-year retrospective study (January 1999 to December 2008), dividing them into 3 different groups according to length (spinal ependymomas < 5 cm, 5–10 cm, and > 10 cm). All patients underwent tumor resection. The basic characteristics of the patients were reviewed and the functional status was assessed using the McCormick classification.

Results

There were 89, 81, and 40 patients, respectively, in the 3 groups (< 5 cm, 5–10 cm, and > 10 cm). Grosstotal resections (GTRs) were performed in 172 patients (81.9% overall, or 86.5%, 79.0%, and 77.5% in the 3 groups, respectively). Subtotal and partial resections were achieved in 38 patients (18.1%). Eight patients with medulla oblongata or upper cervical cord tumors received a tracheotomy postoperatively. The follow-up period ranged from 56 to 176 months. One hundred thirty-five patients (76.7%) experienced improvement, (88.2%, 83.8%, and 34.4% in the < 5 cm, 5–10 cm, and > 10 cm groups, respectively). Thirty-three patients (18.8%) maintained their pretreatment status, and 8 patients (4.5%) showed deterioration following tumor resection at 6 months. Tumor recurrence or progression was observed in 6 (2.9%) of the 210 patients. Among the 6 patients, recurrent tumors were located in the conus (n = 3), thoracic (n = 1), and medullocervical cord (n = 2).

Conclusions

Radical resection of spinal ependymomas could be performed in most patients, and the rate of GTR was significantly different in the different-length groups (< 10 cm vs > 10 cm, p = 0.032). Patients with longer tumors had worse surgical results compared with those with small tumors (p < 0.001), and more postoperative neuropathic pain and proprioceptive deficits could usually be observed in patients harboring larger tumors. Early diagnosis and timely operation are critical to achieving better neurological outcomes. For tumors with dense adhesions, complete removal should be performed cautiously because of the significant incidence of neurological deterioration.

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Barbara Cappelletto, Hakan H. Caner, Frank Schottler, Aij-Lie Kwan, David Eveleth, Patricia L. Foley, Neal F. Kassell and Kevin S. Lee

Calcium-activated proteolysis mediated by the protease inhibitor, calpain, has recently been implicated in the pathogenesis of cerebral vasospasm. The effect of one inhibitor of calcium-activated proteolysis, z-Leu-Phe-CONH-morpholene (zLF), on cerebrovascular constriction was examined in two experimental paradigms. In the first paradigm, the rabbit basilar artery (BA) was visualized via a transclival exposure, and its diameter was monitored using videomicroscopy. In the second experimental paradigm two intracisternal injections of autologous blood were administered to mimic a subarachnoid hemorrhage (SAH). The BA was visualized via the transclival exposure, and its luminal diameter was measured. Topical application of oxyhemoglobin (OxyHb), a known pathogenic agent in cerebral vasospasm, elicited vasoconstriction in normal animals, reducing arterial diameter to approximately 75% of resting levels. Pretreatment with zLF (100, 200, or 300 μM) attenuated vasoconstriction induced by OxyHb. In an experimental model of SAH, the diameter of the BA was reduced after the first injection of blood to approximately 67% of normal resting levels when measured 3 to 4 days later. This vasospastic response was reversed significantly by topical application of zLF (100 μM); vascular diameter was increased to approximately 84% of normal resting levels.

These findings demonstrate that both acute OxyHb-induced constriction and blood-induced vasospasm are sensitive to an inhibitor of the proteolytic enzyme, calpain. Together, these observations indicate an important role for calcium-activated proteolysis in the development and maintenance of vasospasm after SAH. In addition, it may be inferred from the data that inhibitors of calcium-activated proteolysis may be useful therapeutic agents for treating this form of cerebrovascular disease.

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Hung-Chen Wang, Tzu-Ming Yang, Wei-Che Lin, Yu-Jun Lin, Nai-Wen Tsai, Chia-Wei Liou, Aij-Lie Kwan and Cheng-Hsien Lu

Object

Increased plasma nuclear and mitochondrial DNA levels have been reported in critically ill patients, and extracellular DNA may originate from damaged tissues having undergone necrosis. This study tested the hypothesis that nuclear and mitochondrial DNA levels in CSF and plasma are substantially increased in patients with acute spontaneous aneurysmal subarachnoid hemorrhage (SAH) and decrease thereafter, such that nuclear and mitochondrial DNA levels may be predictive of treatment outcomes.

Methods

Serial nuclear and mitochondrial DNA levels in CSF and plasma from 21 adult patients with spontaneous aneurysmal SAH and 39 healthy volunteers who received myelography examinations during the study period were evaluated.

Results

Data showed that circulating plasma nuclear DNA concentrations and both nuclear and mitochondrial DNA levels in CSF significantly increased in patients with aneurysmal SAH on admission compared with the volunteers. In patients with poor outcome, the CSF nuclear and mitochondrial DNA levels were significantly higher on Days 1 and 4, and plasma nuclear DNA levels were significantly higher from Day 8 to Day 14. Higher CSF nuclear (> 85.1 ng/ml) and mitochondrial DNA levels (> 31.4 ng/ml) on presentation were associated with worse outcome in patients with aneurysmal SAH.

Conclusions

Higher CSF DNA levels on presentation, rather than plasma DNA levels, are associated with worse outcomes in patients with acute spontaneous aneurysmal SAH. More prospective multicenter investigations are needed to confirm the predictive value of CSF and plasma DNA levels on outcome.

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Chih-Lung Lin, Aaron S. Dumont, Ann-Shung Lieu, Chen-Po Yen, Shiuh-Lin Hwang, Aij-Lie Kwan, Neal F. Kassell and Shen-Long Howng

Object. The reported incidence, timing, and predictive factors of perioperative seizures and epilepsy after subarachnoid hemorrhage (SAH) have differed considerably because of a lack of uniform definitions and variable follow-up periods. In this study the authors evaluate the incidence, temporal course, and predictive factors of perioperative seizures and epilepsy during long-term follow up of patients with SAH who underwent surgical treatment.

Methods. Two hundred seventeen patients who survived more than 2 years after surgery for ruptured intracranial aneurysms were enrolled and retrospectively studied. Episodes were categorized into onset seizures (≤ 12 hours of initial hemorrhage), preoperative seizures, postoperative seizures, and late epilepsy, according to their timing.

The mean follow-up time was 78.7 months (range 24–157 months). Forty-six patients (21.2%) had at least one seizure post-SAH. Seventeen patients (7.8%) had onset seizures, five (2.3%) had preoperative seizures, four (1.8%) had postoperative seizures, 21 (9.7%) had at least one seizure episode after the 1st week postoperatively, and late epilepsy developed in 15 (6.9%). One (3.8%) of 26 patients with perioperative seizures (onset, preoperative, or postoperative seizure) had late epilepsy at follow up. The mean latency between the operation and the onset of late epilepsy was 8.3 months (range 0.3–19 months). Younger age (< 40 years old), loss of consciousness of more than 1 hour at ictus, and Fisher Grade 3 or greater on computerized tomography scans proved to be significantly related to onset seizures. Onset seizure was also a significant predictor of persistent neurological deficits (Glasgow Outcome Scale Scores 2–4) at follow up. Factors associated with the development of late epilepsy were loss of consciousness of more than 1 hour at ictus and persistent postoperative neurological deficit.

Conclusions. Although up to one fifth of patients experienced seizure(s) after SAH, more than half had seizure(s) during the perioperative period. The frequency of late epilepsy in patients with perioperative seizures (7.8%) was not significantly higher than those without such seizures (6.8%). Perioperative seizures did not recur frequently and were not a significant predictor for late epilepsy.