Atsushi Sasahara

Application of Nicardipine Prolonged-release Implants: Analysis of 97 Consecutive Patients with Acute Subarachnoid Hemorrhage

To the Editor: We read with great interest the article by Kasuya et al. (2) on the application of nicardipine prolonged-release implants for subarachnoid hemorrhage. They analyzed 97 consecutive patients and compared 69 treated patients with 28 untreated patients. The authors concluded that application of local nicardipine prolonged-release implants leads to a reduced incidence of a delayed ischemic neurological deficit. Although the rate of clinical vasospasm could be roughly reduced by 50%, we would have expected a more marked effect for a therapy with the potential of adding a new dimension to the current strategy of prevention and treatment of cerebral vasospasm. However, some shortcomings of the currently reported methodology and the study design still leave hope that local intrathecal therapy of cerebral vasospasm can become a significant step forward. This prospective nonrandomized Phase II-type study resulted in a comparison between two inhomogeneous patient groups concerning the known risk factors of cerebral vasospasm. The control group without local pharmacological treatment consisted of 16 Fisher Grade 2 patients, nine Fisher Grade 3 patients, and three Fisher Grade 4 patients. Therefore, the natural risk for vasospasm differed between the pharmacologically treated group with a great majority of Fisher Grade 3 patients and the control group with predominant Fisher Grades of 2 and 4 and, therefore, a lower risk of vasospasm (1, 4). Besides, it is important to emphasize, that an incidence of clinical vasospasm of 11% in the untreated group and 6% in the medical group seems unusually low for a patient group dominated by Fisher Grade 3 hemorrhages. The current report leaves some open questions with regard to pharmacokinetics and effectiveness of the clinical set-up. The patients received from 2 to 12 pellets, resulting in different dosages. There was no correlation done between the quantity of nicardipine and the incidence of vasospasm. Only a positive local effect as documented by angiography was available as control. There was no monitoring of cerebrospinal fluid (CSF) levels of nicardipine. It seems unlikely that the released nicardipine could be sequestrated within the local cistern by the surrounding blood clots. In an animal study done on dogs, Pradilla et al. (3) documented an excellent diffusion of Evans blue dye from controlledrelease polymers throughout the subarachnoid space after experimental hemorrhage. In summary, we believe in the potential benefit of local therapy as a major step ahead in the treatment of vasospasm. Nicardipine may not be the optimum agent, or the dosing must be optimized. Perhaps a cocktail of several agents achieves a superior effect.

Angles between A1 and A2 segments of the anterior cerebral artery visualized by three-dimensional computed tomographic angiography and association of anterior communicating artery aneurysms.

OBJECTIVE The angle of arteries at bifurcations, as well as the blood flow, are factors of hemodynamic stress on the apical region, where aneurysms often develop. Using images obtained with three-dimensional computed tomographic angiography, we sought to determine the angles between the A1 and A2 segments of the anterior cerebral artery of the anterior communicating artery (ACoA) complex associated with aneurysms. These angles cannot be detected by conventional cerebral angiography. METHODS The course of the anterior cerebral artery was studied using three-dimensional computed tomographic angiography in 42 consecutive patients with ACoA aneurysms. Twenty-one other subjects, randomly chosen from patients without aneurysms, served as controls. Bilateral A1-A2 angles of the contrast-opacified anterior cerebral artery were measured by three-dimensional computed tomographic angiography in patients with normoplastic A1 segments, and the relationship between the angle and the association of aneurysms was analyzed using cerebral angiography. RESULTS Of the 42 patients with ACoA aneurysms, 19 patients showed hypo- or aplastic A1 segments, as did only 2 of the 21 patients without ACoA aneurysms. The average A1-A2 angle was determined to be 116+/-24 degrees (mean+/-standard deviation) in 18 patients having ACoA complexes with normoplastic A1 segments with aneurysms; 17 patients without aneurysms had A1-A2 angles measuring 143+/-14 degrees (P < 0.0001). The A1-A2 angle associated with ACoA aneurysms was 103+/-20 degrees, which was much smaller than that of the non-aneurysm side in the former group (128+/-20 degrees) (P = 0.0036). CONCLUSION ACoA aneurysms are associated with the smaller A1-A2 angle junction of the ACoA complex, where higher hemodynamic stress may occur in patients with normoplastic A1 segments.

Role of p38 Mitogen-Activated Protein Kinase on Cerebral Vasospasm After Subarachnoid Hemorrhage

Background and Purpose— Inflammatory cytokines are involved in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH). This study was conducted to examine the role of p38 mitogen-activated protein kinase (MAPK) in the development of vasospasm and cytokine production. Methods— We measured the expression levels of genes and proteins related to inflammation in human vascular smooth muscle cells (hVSMCs) treated with hemolysate and FR167653 (FR) (1μmol/L), a selective p38MAPK inhibitor, for 48 hours by TaqMan real-time reverse transcription-polymerase chain reaction (RT-PCR) and ELISA. Twenty-one dogs were assigned to 3 groups of 7 animals: control, placebo, and FR-treated (1 mg/kg/d) groups in a double-hemorrhage model. The effects were assessed through the caliber of the basilar artery, and the changes in gene expressions and the activation of p38MAPK were assessed by Western blot analysis. Results— Treatment of hVSMCs with hemolysate induced significant upregulation of interleukin (IL)-1α, IL-1β, and IL-8 gene and protein expressions, which was suppressed significantly with FR. The mean vessel caliber on day 7, as a percentage of that of day 0, was 49% in the placebo, and 74% in the FR group (P = 0.0001). The gene expression levels of IL-1α, IL-1β, and IL-8 in the arterial wall were extremely elevated in the placebo, and significantly suppressed in the FR group (P = 0.0027, 0.0002, and 0.0073). p38MAPK phosphorylation was stimulated in the placebo and hemolysate in vitro, and suppressed in the FR group. Conclusions— These results suggest that p38MAPK is activated in the arterial wall after SAH, leading to the development of vasospasm, possibly through the upregulation of inflammatory cytokines.

Increased expression of ephrin A1 in brain arteriovenous malformation: DNA microarray analysis

A number of previous studies have revealed the abnormal expression of various angiogenesis-related genes or products in brain arteriovenous malformation (AVM). To understand the molecular process of this disease, we analyzed gene expression profiles in brain AVM. Using a DNA microarray consisting of 17,086 genes, we identified differentially expressed genes in 5 brain AVMs from their draining veins, vessels retaining basic venous architecture. Not many genes were differentially expressed between the AVM nidus and the draining vein. When we applied an absolute cut-off value for normalized log2 (cy5/cy3 ratio) of 0.4, 19 genes were selected. Genes such as SOX8, TRIM2, FENA1 (ephrin A1), and AQP4 were upregulated, and genes such as I_1000105, KRT18, IGFBP7, EMILIN-2, and KRT14 were downregulated. Genes relating to angiogenesis, such as vascular endothelial growth factor and angiopoietin and other members of the ephrin family, were not differentiated. Among differentially expressed genes detected in this analysis, we focused on ephrin A1, a gene related to embryogenesis and angiogenesis. The expression of ephrin A1 was two and three to nine times higher than that of the draining vein and normal brain, respectively, using real-time reverse transcription-polymerase chain reaction. For the first time, here we report the increased expression of ephrin A1 in brain AVM, which may play an important role in the pathogenesis of AVM.

Development of nicardipine prolonged-release implants for preventing vasospasm.

The intrathecally-implantable drug-delivery system was developed to maintain an effective concentration of vasodilatory drug in the target cistern for preventing cerebral vasospasm after subarachnoid hemorrhage (SAH), without systemic side effects nor the side effects associated with long-term intrathecal drug administration through indwelling catheters [2, 5]. Nicardipine was selected for the material of this drug delivery system because intrathecal administration of nicardipine has been reported to ameliorate or reverse vasospasm in animal SAH models [3] and has been used widely, effectively, and safely in patients with SAH, especially in Japan [4, 6]. The purpose of this study was to determine the efficacy of nicardipine prolonged-release implant for preventing vasospasm in dogs in a doseescalating placebo-controlled blind fashion.

Identification of Genes Differentially Expressed in Canine Vasospastic Cerebral Arteries after Subarachnoid Hemorrhage

To understand the molecular processes of continuous vasospasm of cerebral arteries after subarachnoid hemorrhage, mRNA differential display and screening of cDNA expression array were performed to identify genes that are differentially expressed in vasospastic arteries of canine two-hemorrhage models. The expression levels of 18 genes were found to be upregulated, and those of two genes to be downregulated. Of these, 12 represent known genes or homologues of genes characterized previously, and the other eight genes are not related to any sequences in the databases. The known genes include five upregulated inflammation-related genes encoding monocyte chemotactic protein-1, cystatin B, inter-alpha-trypsin inhibitor family heavy chain-related protein, serum amyloid A protein, and glycoprotein 130, suggesting that inflammatory reaction may be involved in the development of cerebral vasospasm. The upregulation of three known genes encoding stress-related proteins of vascular endothelial growth factor, BiP protein, and growth-arrest and DNA-damage-inducible protein may be involved in possible cell survival in the damaged arteries. A full-length cDNA for the unknown clone DVS 27, whose expression was most highly upregulated, was isolated from the cerebral artery cDNA library by hybridization. Characterization of these genes should help to clarify the molecular mechanism of continuous cerebral vasospasm after subarachnoid hemorrhage.

[Radiation-Induced Malignant Peripheral Nerve Sheath Tumor of the High Cervical Spine].

UNLABELLED CASE A 30-year-old woman presented with posterior cervical pain and left-sided omalgia. The patient had a history of non-Hodgkins lymphoma for which she had received prophylactic whole-brain irradiation(including at the upper cervical level)17 years previously. A magnetic resonance imaging(MRI)scan obtained 1 month previously showed an intradural extramedullary mass lesion at the left C1/2 level. We initially considered the tumor to be a benign schwannoma, but the patient subsequently developed left hemiparesis and was consequently admitted 2 days after her first visit. A second MRI scan showed that the tumor had progressed markedly. Hence, the patient underwent emergency surgical excision of the tumor. However, the tumor could only be partially removed because it had strongly adhered to the ventral aspect of the spinal cord. The tumor was pathologically diagnosed as a malignant peripheral nerve sheath tumor(MPNST). The residual tumor was subjected to local irradiation and surgery, but the treatment was unsuccessful, and the patient died on the 91st day of her illness. Conclusion:We report a case of radiation-induced high cervical MPNST arising from a benign schwannoma. All 9 previously reported cases of radiation-induced spinal MPNST were reviewed. Intraspinal MPNST of the high cervical region are extremely rare and are associated with a very poor prognosis. The 5-year survival rate of such tumors is markedly worse than that of other types of MPNST, and no standard treatment has been established for this condition.

[Trigeminal neuralgia caused by cerebellopontine angle lipoma:a case report and review of the literature].

A 59-year-old man presented with right trigeminal neuralgia of the second branch, which had been treated with carbamazepine. The pain could not be controlled adequately because of side effects. CT and MRI revealed a 2-cm lesion in the right cerebellopontine angle. Retrosigmoid lateral suboccipital craniectomy was performed, and a soft yellowish mass was found to be associated with the 5th, 7th, and 8th cranial nerves, anterior inferior cerebellar artery, and small vessels. The lipoma was partially resected from around the root entry zone(REZ)of the 5th nerve and small vessels were coagulated around the REZ. After surgery, there was no trigeminal neuralgia, but facial numbness and cerebellar signs were noted. Postoperative MRI showed decompression of the trigeminal nerve and venous infarction in the middle cerebellar peduncle. Reviewing similar cases, we found 19 lipoma patients presenting with trigeminal neuralgia. Symptoms of involvement of other cranial nerves were also present in 11 patients, and 14 were younger than 30 years old. Of 17 surgical cases, total resection was not attempted apart from one case. Although pain relief was achieved in all surgical cases, complications developed in 11. Surgery should be performed only in patients with disabling and uncontrolled symptoms.

Nonspastic hemifacial spasm confirmed by abnormal muscle responses

Background: Hemifacial spasm is usually diagnosed by inspection which mainly identifies involuntary movements of orbicularis oculi. Assessing abnormal muscle responses (AMR) is another diagnostic method. Case Description: We report a case of left hemifacial spasm without detectable involuntary facial movements. The patient was a 48-year-old man with a long history of subjective left facial twitching. On magnetic resonance imaging (MRI), the left VIIth cranial nerve was compressed by the left anterior inferior cerebellar artery (AICA), which was in turn compressed by the left vertebral artery. We initially treated him with botulinum toxin. We were able to record AMR, and hemifacial spasm occurred after AMR stimulation, although no spasm was detectable by inspection. Subsequently, we performed microvascular decompression with transposition of the AICA that compressed the VIIth cranial nerve. His hemifacial spasm resolved by 5 weeks after surgery and was not induced by AMR stimulation. Conclusion: Hemifacial spasm can sometimes be diagnosed by detecting AMR rather than by visual inspection. We propose that such hemifacial spasm should be termed nonspastic hemifacial spasm.

Clinical features of bilateral trigeminal neuralgia

Among 238 patients with bilateral trigeminal neuralgia(TN)who visited our hospital between April 2007 and June 2014, 5(2%)were surgically treated by microvascular decompression(MVD). The initial symptom was on the right side in four and on both sides in one patient. Intervals between the initial and second onset on the other side(left)were two months, and four, six, and eight years. None of the patients showed involvement of the first branch of the trigeminal nerve. The patients with bilateral TN were younger than the 154 patients with unilateral TN who were treated surgically by MVD in this period(45 vs. 65 years), and the bilateral TN patients predominantly were women(4/5 vs. 99/154). In the surgical field, the trigeminal nerve and root entry zone were compressed more by veins in the bi lateral TN patients than in the unilateral TN(4/5 vs. 60/154, respectively)patients. We could not identify any differences in MRI CISS before versus after the onset of left trigeminal neuralgia, suggesting that compression is not the sole cause of the symptom.