The Modifying of Functional Connectivity Induced by Peripheral Nerve Field Stimulation using Electroacupuncture for Migraine: A Prospective Clinical Study.

OBJECTIVE: We examined the functional connectivity (FC) in patients with migraine compared with healthy subjects before and after C2 peripheral nerve field stimulation with electroacupuncture (EA-C2-PNfS) to evaluate the effect of EA-C2-PNfS and elucidate the mechanism of migraine. METHODS: Twenty-six patients with migraine and 24 healthy controls were recruited. All patients underwent resting state functional magnetic resonance imaging before and after 3 months of EA-C2-PNfS. We evaluated a numerical rating scale, the Headache Impact Test, and the Self-Rating Depression Scale, which assesses depression. Healthy controls underwent magnetic resonance imaging twice at a 3-month interval without acupuncture. An analysis of FC in the region of interest in the pain matrix was performed. RESULTS: Twenty patients with migraine and 23 healthy controls (mean ± standard deviation: 44.9 ± 12.9 years of age) were included. Three patients had migraine with aura (55.0 ± 18.0 years of age), 11 patients had migraine without aura (MWoA) (45.6 ± 14.6 years of age), and six patients had chronic migraine (40.8 ± 13.9 years of age). The clinical assessments significantly improved after EA-C2-PNfS in the MWoA group only. In FC analysis, the MWoA group showed a significant decrease after EA-C2-PNfS in FC between the right hypothalamus and left insula. Right hypothalamus-related FC was lower before acupuncture in the chronic migraine group than in the MWoA group. CONCLUSION: After EA-C2-PNfS for MWoA, significant changes in FC were observed at the hypothalamus and insula. Our results indicate that EA-C2-PNfS could improve migraine headache by modifying pain-related FC.

Clinical Effect of C2 Peripheral Nerve Field Stimulation Using Electroacupuncture for Primary Headache.

OBJECTIVE: We applied C2 peripheral nerve field stimulation using electroacupuncture (EA-C2-PNfS) for primary headache, and investigated its clinical effectiveness. MATERIALS AND METHODS: Fifty-four primary headache patients (10 men, 44 women) with a mean age of 48.6 ± 15.0 years underwent EA-C2-PNfS for three months. We used questionnaires to assess outcomes; pain intensity (11-point numerical rating scale [NRS]), quality of daily life (Headache Impact Test [HIT-6]), depression (Self-Rating Depression Scale [SDS]). Monthly headache days and acute headache medication days were obtained from diaries. RESULTS: The headache intensity significantly declined after the EA-C2-PNfS with reduction of NRS pain scale; 7.4 ± 1.9 at baseline, 4.9 ± 2.9 at three month (p < 0.001). Both HIT-6 and SDS showed significant improvement (p < 0.001). Some patients showed moderate depression in SDS before treatment, that was alleviated in patients with tension-type headache after the EA-C2-PNfS. Monthly headache days significantly decreased from 18.0 ± 9.0 at one month to 14.0 ± 10.2 at three months (p < 0.001), accompanied with reduction of the monthly acute headache medication days from 8.0 ± 6.7 to 6.4 ± 6.5 (p = 0.003). CONCLUSIONS: EA-C2-PNfS was successfully used for reducing severity and disability in primary headache patients. We conclude that EA-C2-PNfS is a favorable option for medically intractable primary headache as less-invasive neuromodulation.

Clostridium difficile infection induced by pregabalin-associated agranulocytosis.

A 33-year-old man who had recently undergone surgery for cervical spondylotic myelopathy was prescribed pregabalin for neuralgia, and the dose was increased to 600 mg/day during hospitalization. However, the patient was diagnosed with a Clostridium difficile infection on day 34 after admission. A complete blood count showed agranulocytosis (neutrophil count: 105/µL). We did not observe any changes in vital signs, a relative increase in band cells, or intestinal edema. The patient's agranulocytosis resolved after withdrawing pregabalin. This is the first reported case of agranulocytosis associated with pregabalin. Periodic monitoring of the white blood cell count is therefore considered to be useful in patients receiving high-dose pregabalin therapy.

Valproic acid inhibits angiogenesis in vitro and glioma angiogenesis in vivo in the brain.

Antiangiogenic strategy is promising for malignant glioma. Histone deacetylase inhibitors (HDACIs) are unique anticancer agents that exhibit antiangiogenic effects. The in vitro and in vivo antiangiogenic effects of HDACIs, valproic acid (VPA), were investigated in malignant glioma in the brain. In vitro, VPA preferentially inhibited endothelial cell proliferation compared to glioma cell proliferation at the optimum concentration in a dose-dependent manner. VPA reduced vascular endothelial growth factor (VEGF) secretion of glioma cells in a dose-dependent manner under both normoxic and hypoxic conditions. VPA was also found to inhibit tube formation in the angiogenesis assay. In vivo, treatment with VPA combined with irinotecan reduced the number of vessels expressing factor VIII in the brain tumor model. VPA inhibits glioma angiogenesis by direct (inhibition of endothelial cell proliferation and tube formation) and indirect (decreased secretion of VEGF by glioma cells) mechanisms. These data suggest a potential role for VPA as an adjuvant therapy for patients with malignant glioma.

[Intracerebral xanthogranuloma with specific MRI features: a case report].

We report a case of a 47-year-old male who had a left frontal lobe mass with specific magnetic resonance imaging (MRI). Four years previous to his admission to our hospital, he developed acute myelocytic leukemia and he was implanted with peripheral blood stem cell transplantation. One month before his admission, he was unable to walk due to right leg motor weakness. MRI revealed a round mass lesion at the left frontal lobe. Initial diagnosis was a brain abscess, so he was administered some antibacterial drug. However, his neurological symptoms kept getting worse with increase of mass size on MRI. T1-weighted MR images showed the mass as a low intensity lesion with incomplete ring-like Gd-enhancement. T2-weighted images showed the mass as a high intensity lesion with many linear shadows inside the mass. Diffusion weighted images showed the mass as a low intensity lesion. MR spectroscopy revealed an elevation of choline and lactate peak. Differential diagnosis was glioma or demyelinating disease. At the operation, the mass was light yellow and seen to be rich with vessels. The pathological diagnosis was xanthogranuloma in the brain. Postoperative course was uneventful. The frontal residual mass lesion decreased in size and Gd-enhancement.

Transarterial embolization with use of lipiodol and gelatin sponge for active nasal bleeding from hepatocellular carcinoma metastasis in the pituitary gland.

A 58-year-old man presented with a very rare case of pituitary metastasis from hepatocellular carcinoma with active nasal bleeding which was treated by transarterial embolization using ethiodized oil (Lipiodol) and gelatin sponge. After treatment, nasal bleeding ceased and tumor size decreased. The prognosis for patients with pituitary metastases is very poor, so aggressive treatment is recommended to alleviate symptoms. This minimally invasive approach may be a reasonable therapeutic option for pituitary metastases.

[Usefulness of quantitative H-MR spectroscopy for the differentiation between radiation necrosis and recurrence of anaplastic oligodendroglioma].

We report a case, in which quantitative 1H-MR spectroscopy (MRS) was useful for the differentiation between radiation necrosis and a recurrent tumor. The present case is a 44-year-old man who underwent the subtotal removal of a mass lesion in the left frontal lobe. The histological diagnosis was anaplastic oligodendroglioma (WHO grade III). Postoperatively, a fractionated radiotherapy (total 64Gy) and chemotherapy were performed. MRI after the radiotherapy showed no contrast enhancing lesion. MRI, 5 years after the radiotherapy, showed a growing enhancing lesion and a T1 hypointensity lesion without enhancement, both of which indicated a recurrent tumor. MR spectroscopy was performed for the differential diagnosis of these lesions. The spectrum was acquired by the point resolved spectroscopy (PRESS) method by TR/TE=2,000 ms/68 ms, 136 ms, and 272 ms and evaluated with peak pattern and quantification value of metabolite. MRS of the enhancing lesion demonstrated a decrease of the Choline-containing compounds (Cho) concentration, disappearance of N-acetylaspartate (NAA), decrease of Creatine/ Phosphocreatine (t-Cr) and presence of Lipids (Lip) and Lactate (Lac), all of which are characteristic finding of a radiation necrosis. The histological diagnosis of this lesion showed evidence also of radiation necrosis. On the other hand, MRS of the T1 hypointensity lesion without enhancement showed, a marked high peak of the Cho concentration, which is characteristic for a recurrent tumor. The histological findings of this lesion showed a diffuse proliferation of recurrent tumor cells. Quantitative 1H-MRS is a useful tool for the differentiation between radiation necrosis and recurrent tumors.

Efficacy of keishibukuryogan, a traditional Japanese herbal medicine, in treating cold sensation and numbness after stroke: clinical improvement and skin temperature normalization in 22 stroke patients.

Cold sensation and numbness have been reported as post-stroke sensory sequelae attributable to distal axonopathy, which is caused by chronic ischemia of diseased limbs resulting from dysfunction of vasomotor regulatory systems. Keishibukuryogan is a traditional herbal medicine used to treat symptoms of peripheral ischemia such as cold extremities. This study investigated clinical improvement and skin temperature in peripheral ischemia patients to determine the efficacy of keishibukuryogan in alleviating post-stroke cold sensation and numbness. Twenty-two stroke patients with cold sensation and/or numbness were enrolled in this study. Subjective cold sensation and numbness, evaluated using the visual analogue scale, were found in 21 and 31 limbs, respectively. The skin temperature of diseased and healthy limbs was recorded. We observed all patients for 4 weeks and 17 patients for 8 weeks after administration of keishibukuryogan. The skin temperature of diseased limbs was significantly higher than baseline at 4 weeks and 8 weeks, whereas that of healthy limbs did not change significantly. Cold sensation and numbness were significantly improved at 4 weeks and 8 weeks compared to baseline. Keishibukuryogan administration resulted in warming of diseased limbs and improved cold sensation and numbness, probably by increasing peripheral blood flow.

Current practices and future directions of therapeutic strategy in glioblastoma: survival benefit and indication of BNCT.

Since 1998, we are performing clinical studies on treatment of GBM using conventional fractionated photon radiation therapy (CRT), proton beam therapy (PBT) or boron neutron capture therapy (BNCT). We investigated whether these radiation modalities improves the survival of patients with GBM. Sixty-eight cases of newly diagnosed GBM have been treated in our institution. After surgery, radiation therapy was performed using CRT with a dose of 60.0-61.2 Gy (n=36), hyperfractionated PBT concomitant with fractionated photon irradiation with a total dose of 96.6 Gy (n=17), or a single fraction of BNCT (n=15). In PBT, the surrounding volume of 2 cm from main tumor mass and the volume of perifocal edema were irradiated at dose of 75.6 and 60 Gy, respectively. The median OS time of the case series of BNCT for GBM has been reported as 13-20.7 M. In this study, the median OS and median time to MR change (TTM) for all patients were 25.7 and 11.9 M, respectively. The 1- and 2-year survival rates were 85.7% and 45.5%, respectively. On the other hand, in the patients who underwent CRT and ACNU-based chemotherapy, OS and 2-year survival rate were 14.2M and 17.9%, respectively. In the patients who underwent high-dose PBT, OS and 2-year survival rate were 21.3M and 38.5%, respectively. The present small case series of selected patients showed survival benefit after BNCT. The comparison using previously reported prognostic factor-based classifications suggest that outcome of BNCT in terms of survival appeared to have non-inferiority compared to the standard therapy. With respect to the case series as a high-dose radiation trial, the outcome (OS: 9.5-25 M) of previously reported may still be comparable to that of BNCT. Randomized trials of comparably selected patients are required to demonstrate conclusively that prolonged survival is a result of this tumor-selective radiotherapy.

Acquired hemophilia first manifesting as life-threatening intracranial hemorrhage: case report.

A 74-year-old man presented with life-threatening intracranial hemorrhage and prolonged activated partial thromboplastin time (APTT). The massive subdural hematoma was removed, but multiple intracranial hemorrhages occurred despite the administration of factor VIII and factor IX concentrates. Subdural hematoma, intracerebral hemorrhage in the left temporal lobe, and thalamic hemorrhage subsequently occurred with further prolongation of APTT. He died of enlargement of the thalamic hemorrhage. Acquired hemophilia was diagnosed caused by factor VIII inhibitor. Acquired hemophilia may cause life-threatening hemorrhage, and should be considered in patients with intracranial hemorrhages associated with unexplained prolongation of APTT.

[Case report of germinoma with synchronous lesions in the thalamus and para lateral ventricle].

A 25-year-old man presented with headache and consciousness disturbance. MRI revealed well enhanced mass lesions using gadolinium at bilateral thalamus and right para lateral ventricle with mild perifocal edema. Obstructive hydrocephalus was observed. On neuroendoscopic observation, the tumor was not appeared on the surface of the ventricle, therefore biopsy of the lesion was not sufficient to make a definitive pathological diagnosis. Third ventriculostomy was successful and the patient's consciousness improved. One week later, a stereotactic biopsy for right para lateral ventricle lesion made possible the histological diagnosis of typical germinoma. Post operative course was uneventful. Chemotherapy (CDDP and etoposide) following 30 Gy whole ventricle irradiation resulted in the complete response of the lesion. Four years later, he has no neurological deficit except for mild disturbance in his eye movement. Our experience suggests that a synchronous lesion at thalamus and para lateral ventricle seems to be due to subependymal infiltration other than CSF dissemination.

Combined use of sodium borocaptate and buthionine sulfoximine in boron neutron capture therapy enhanced tissue boron uptake and delayed tumor growth in a rat subcutaneous tumor model.

We have previously reported that buthionine sulfoximine (BSO) enhances sodium borocaptate (BSH) uptake by down regulating glutathione (GSH) synthesis in cultured cells. This study investigated the influence of BSO on tissue BSH uptake in vivo and the efficacy of BSH-BSO-mediated boron neutron capture therapy (BNCT) on tumor growth using a Fisher-344 rat subcutaneous tumor model. With BSO supplementation, boron uptake in subcutaneous tumor, blood, skin, muscle, liver, and kidney was significantly enhanced and maintained for 12h. Tumor growth was significantly delayed by using BSO. With further improvement in experimental conditions, radiation exposure time, together with radiation damage to normal tissues, could be reduced.

Anti-angiogenic and immunomodulatory effect of the herbal medicine "Juzen-taiho-to" on malignant glioma.

Juzen-taiho-to (JTT) is known as a Japanese herbal medicine that increases the immune function via the enhancement of phagocytosis, cytokine induction, and antibody production. Anti-neoplastic effects on malignant gliomas have been reported by means of the enhancement of the immune function in both animals and humans. We evaluated whether JTT has anti-angiogenic effects on malignant glioma growth in vitro and in vivo. In vitro, the anti-proliferative effect of JTT on malignant glioma cells and endothelial cells was assessed by cell proliferation assay. In vivo, a subcutaneous model of malignant glioma with different-aged mice (old, 43 weeks; young, 8 weeks) was used. After oral administration of JTT to mice, their immunological function and angiogenic status of tumor tissues were assessed by flow cytometry and immunohistochemistry, respectively. JTT inhibited human endothelial cell, but not glioma cell, proliferation in vitro. In vivo, the NK (natural killer) cell ratio within PBMC (peripheral blood mononuclear cells) and NK activity of fresh splenocytes obtained from JTT-treated old mice were significantly increased compared to the ratio and activity in control mice. In old mice, the vessel area of tumor tissues in JTT treatment groups was significantly decreased. These enhancements of immunological function and the inhibition of angiogenic activity were not observed in young mice. JTT not only increased host immunological function but also exerted anti-angiogenic effects on malignant glioma growth. JTT would be useful as an adjuvant medicine for malignant gliomas through its enhancement of systemic immunological function and its anti-angiogenic action.

Effect of J coupling and T2 Relaxation in Assessing of Methyl Lactate Signal using PRESS Sequence MR Spectroscopy.

PURPOSE: This work was aimed at quantification of lactate concentration using proton MR spectroscopy (MRS). We carried out a basic study to clarify the characteristics of signal change and T2 relaxation time of lactate that occur by J coupling in point resolved spectroscopy (PRESS) sequence. MATERIALS AND METHODS: Proton MRS was done for a water phantom containing 10 mmol/L creatine and lactate on a clinical 1.5 T MR system by using an asymmetric PRESS sequence. The coupling constant J was 7.35 Hz. In acquisitions, TE was varied from 68 ms up to 544 ms, with an increment of 68 ms (1/2J) and TR was fixed to 10000 ms. RESULTS: The shape and signal intensity of the lactate signal vary depending on its phase. The lactate signal intensity at TE 272 ms was higher than at TE 136 ms despite the longer TE. T2 relaxation times of lactate in the negative in-phase (TE 136 ms, TE 408 ms) and positive in-phase (TE 272 ms, TE 544 ms) were 1033 ms and 1042 ms, respectively (no significant differences), so that when the same phase was used, regardless of the phase condition, T2 relaxation behavior was not different. We considered that our results included over expression and loss of lactate signal depending on the phase. CONCLUSIONS: For evaluation of the lactate peak, we recommend the use of the positive in-phase signal because it is larger than the negative in-phase signal. The influence of the asymmetric PRESS sequence, which may cause loss and over expression of lactate signal, should be considered in the calculation of the quantification. The T2 relaxation time should be also considered in the calculation of the lactate value since it affects the value considerably.

MicroPET detection of enhanced 18F-FDG utilization by PKA inhibitor in awake rat brain.

To obtain PET imaging of glucose metabolism in the brains of conscious rats, a method of rat head fixation was developed. PET measurement with microPET was performed for 60 min after 18F-FDG injection. Significant enhancement of glucose utilization in the right striatum was observed with infusion of Rp-adenosine-3,5-cyclic phosphorothioate triethylamine (Rp-cAMPS). FDG uptake increments were also seen in the ipsilateral frontal cortex and thalamus. As initial FDG uptake in the brain was not significantly altered by Rp-cAMPS, increased glucose metabolism might be due to an increase in the phosphorylation rate by hexokinase rather than the delivery process from plasma to the brain. In contrast to awake rats, the effect of Rp-cAMPS was abolished by anesthesia using chloral hydrate, indicating that neuronal activity has an important role in short term regulation of hexokinase activity through the cAMP/PKA system in the brain. These results strongly demonstrated the value of measuring glucose utilization in the brains of conscious rats.