Nobuo Kouyama

Role of Pituitary Radiosurgery for the Management of Intractable Pain and Potential Future Applications

Rationale: Two or three decades ago, cancer pain was treated by surgical/chemical hypophysectomy. In one report, the control of central pain (thalamic pain syndrome) was also approached with chemical hypophysectomy. Although in most of the patients these treatments resulted in a decrease in severe pain, concomitantly severe adverse effects (panhypopituitarism, diabetes insipidus and visual dysfunction) occurred in most patients. This historical evidence prompted us to perform Gamma Knife surgery (GKS) for this kind of intractable severe pain using a high irradiation dose to the pituitary stalk/gland. In the majority of patients, marked pain relief was achieved, surprisingly without any of the complications mentioned above. Materials and Methods: A prospective multicenter study was conducted to evaluate the efficacy and safety in patients treated in Prague, Hong Kong and Tokyo. Indications of this treatment were: (1) failure of other effective treatment approaches prior to GKS, (2) good general patient condition (Karnofsky performance status >40%), (3) response to morphine for pain control (cancer pain), and (4) no previous radiotherapy of brain metastases (GKS/conventional radiotherapy). Eight patients with severe cancer pain due to bone metastasis and 12 patients with post-stroke thalamic pain syndrome were treated with GKS. The target was the border between the pituitary stalk and gland. Maximum dose was 160 Gy for cancer pain and 140 Gy for central pain. Follow-up included 6 patients (>1 month) with cancer pain and 8 patients (> 6 months) with thalamic pain syndrome. Results: All patients (6/6) with cancer pain experienced significant pain reduction, and 87.5% (7/8) of the patients with thalamic pain had initially significant pain reduction. In some patients, pain reduction was delayed for several hours. Pain relief was noted within 7 days (median 2 days). No recurrence was observed in the patients with cancer pain. However, in 71.4% (5/7) of the patients with thalamic pain syndrome, disease recurred during the 6-month follow-up. Up to now, other complications have not been observed. Conclusion: Our clinical study protocol is only preliminary. Further clinical results on the management of thalamic pain are required to develop this treatment protocol. However, efficacy and safety have been shown in all our cases. In our opinion, this treatment has a potential to control severe pain, and GKS will play an important role in the management of intractable pain.

Localization of nerve fiber bundles by polarization-sensitive optical coherence tomography

Diagnostic modalities that can distinguish brain tumors from eloquent cortices or nerve fiber bundles are important for neurosurgery. For identifying nerve fiber bundles, various techniques such as diffusion tensor imaging and subcortical stimulation mapping have been used. In this article, we propose localization of nerve fiber bundles by polarization-sensitive optical coherence tomography (PS-OCT) for the first time. PS-OCT performs tomographic imaging by measuring the travel distance and the change in polarization of the backscattered light from the tissue at different traverse positions, enabling selective visualization of birefringent tissues such as nerve fiber bundles. We examined the imaging of nerve fiber bundles in blocks of fixed rat brains. Nerve fiber bundles in internal and external capsules of the rat brains appearing on the surfaces of the coronal, horizontal, and sagittal planes were identified as to their locations and orientations. The nerve fiber bundles were clearly visualized by PS-OCT. The image penetration depth of the PS-OCT images was about 1.0mm in gray matter and about 0.5mm in white matter, so the refractive indices of gray and white matters were assumed to be 1.4.

Gamma knife surgery of the pituitary: new treatment for thalamic pain syndrome

OBJECT Although reports in the literature indicate that thalamic pain syndrome can be controlled with chemical hypophysectomy, this procedure is associated with transient diabetes insipidus. It was considered reasonable to attempt gamma knife surgery (GKS) to the pituitary gland to control thalamic pain. METHODS Inclusion criteria in this study were poststroke thalamic pain, failure of all other treatments, intolerance to general anesthetic, and the main complaint of pain and not numbness. Seventeen patients met these criteria and were treated with GKS to the pituitary. The target was the pituitary gland together with the border between the pituitary stalk and the gland. The maximum dose was 140 to 180 Gy. All patients were followed for more than 3 months. CONCLUSIONS An initial significant pain reduction was observed in 13 (76.5%) of 17 patients. Some patients experienced pain reduction within 48 hours of treatment. Persistent pain relief for more than 1 year was observed in five (38.5%) of 13 patients. Rapid recurrence of pain in fewer than 3 months was observed in four (30.8%) of 13 patients. The only complication was transient diabetes insipidus in one patient. It would seem that GKS of the pituitary might have a role to play in thalamic pain arising after a stroke.

The effect of gamma knife irradiation on functions of striatum in rats

OBJECT An animal model has been developed to study the effect of gamma knife surgery(GKS) on cerebral function. METHODS A rat was fixed in a newly developed Régis-Valliccioni frame that enables the target region to be planned directly on the magnetic resonance images. The left striatum was irradiated with 150 Gy via a 4-mm collimator of the Leksell gamma knife. Apomorphine (dopamine agonist) was administered to elicit a circling behavior (apomorphine test) after the GKS so as to examine the time course of the changes in dopaminergic functions of irradiated striatum. After a series of behavioral analyses, irradiated brains were subjected to histological examination. Necrosis was observed in the irradiated area surrounded by hemorrhage and gliosis. The distance between the histologically estimated and planned centers of the irradiation areas was 1.0 ± 0.5 mm. The extent of the distance was due to errors along dorsoventral axis. The distribution of the irradiation areas influenced the activity and the circling behaviors in apomorphine test, which was suggestive of involvement of the nigrostriatal pathway. CONCLUSIONS Targeting by using the Régis-Valliccioni frame was very accurate compared with targeting with coordinates based on brain maps used hitherto. Although targeting improved the accuracy, further effort will still be necessary to reduce errors along dorsoventral axis. The apomorphine test indicated a reduced dopaminergic function of the irradiated area including striatum, which accompanied histological changes after a high dose of irradiation (150 Gy).

Transcriptomic analysis of rat brain tissue following gamma knife surgery: Early and distinct bilateral effects in the un-irradiated striatum

Gamma knife surgery (GKS) is used for the treatment of various human brain disorders. However, the biological effects of gamma ray irradiation on both the target area, and the surrounding tissues are not well studied. The effects of gamma ray exposure to both targeted and untargeted regions were therefore evaluated by monitoring gene expression changes in the unilateral irradiated (60 Gy) and contralateral un-irradiated striata in the rat. Striata of irradiated and control brains were dissected 16 hours post-irradiation for analysis using a whole genome 44K DNA oligo microarray approach. The results revealed 230 induced and 144 repressed genes in the irradiated striatum and 432 induced and 239 repressed genes in the un-irradiated striatum. Out of these altered genes 39 of the induced and 16 of the reduced genes were common to both irradiated and un-irradiated tissue. Results of semiquantitative, confirmatory RT-PCR and western blot analyses suggested that γ-irradiation caused cellular damage, including oxidative stress, in the striata of both hemispheres of the brains of treated animals.

Gamma Knife Radiosurgery Targeting Protocols for the Experiments with Small Animals

Background/Aims: Manipulation of brain functions via Gamma Knife (GK) irradiation would have numerous applications in clinical and experimental neurology. Methods: Alteration of brain functions in the unilaterally irradiated striatum was indexed through monitoring freely moving rat behaviors. Spontaneous activity and rotations on the apomorphine test, which can detect dopaminergic function imbalance, were indexed employing our behavior tracking system. The spatial distribution of necrotic lesions was explored using serial sections, and was assumed to represent the real foci of the GK target. Results: Distinct behavioral alterations corresponded to the precise locations of the lesions in various areas of the basal ganglia. Displacement of the irradiation sites in the anteromedial direction increased spontaneous activity, and posterolateral shift provoked circling behavior on the apomorphine test. Conclusion: Accurate positioning of the target is crucial for experimental GK irradiation locally focused on domains of a small brain such as that of the rat. Here, we propose a protocol for converting the ‘intended’ focus, based on brain map coordinates, to a ‘planned’ focus on the MR imaging coordinate system with the Régis-Valliccioni stereotactic frame.

Transcriptomics of unilateral irradiated and contralateral rat striata after gamma knife surgery

O1P-KØ8 Transcriptomics of unilateral irradiated and contralateral rat striata after gamma knife surgery Randeep Rakwal1, Junko Shibato1, Misato Hirano1, Nobuo Kouyama2, Yoko Katayama2, Motohiro Hayashi3, Hitoshi Iwahashi4, Yoshinori Masuo1 1 Human Stress Signal Research Center (HSS), AIST, Tsukuba, Japan; 2 Department of Physiology, School of Medicine, Tokyo Women’s Medical University, Tokyo, Japan; 3 Department of Neurosurgery, School of Medicine, Tokyo Women’s Medical University, Tokyo, Japan; 4 HSS, AIST, Ikeda, Japan