Ryu Kurokawa

Altered Blood Flow Distribution in the Rat Spinal Cord under Chronic Compression

Study Design. Sham-operation–controlled animal study to assess alterations in blood flow in the spinal cord in a chronic compression model. Laboratory investigation. Objective. Cervical myelopathy is a common cause of disability in elderly patients. Hypothesis was made that ischemia subsequent to the spinal cord compression plays an important role in the pathogenesis of the spinal cord dysfunction. This study was undertaken to assess alterations in the blood flow of the spinal cord under chronic compression in a rat model. Summary of Background Data. Histologic study of spinal cord from patients with spondylotic myelopathy showed ischemic tissue changes. Experimentally, spinal cord hypoperfusion in combination with chronic spinal cord compression induced myelopathy in dogs. We previously showed that chronic compression of the spinal cord in rats produces gradual deterioration of mobility of the animals accompanied by cord tissue degeneration compatible with ischemic changes. Methods. Chronic compression of the cervical spinal cord was implemented by implantation of a thin urethane polymer sheet under the C5–C6 laminae, which expands by absorbing tissue water over 48–72 hours. The control group underwent sham operation. Twelve weeks later, blood flow to the C3–C4 and C5–C6 spinal cord segments were measured by fluorescent microsphere methods. Results. In the control group, the blood flow in the C5–C6 segment was larger than C3–C4 segment. In the compression group, the blood flow in the C5–C6 was significantly reduced compared to the C3–C4 segment. Conclusion. Under chronic focal spinal cord compression, there was a decrease of the blood flow in the compressed segment in comparison to the rostral segment. Our data are compatible with the hypothesis that alteration in the spinal cord blood flow contributes to pathogenesis of myelopathy.

Cilostazol, a selective Type III phosphodiesterase inhibitor: prevention of cervical myelopathy in a rat chronic compression model

OBJECT Regional blood flow is decreased in experimental models of chronic spinal cord compression, and the alteration presumably contributes to the development of myelopathy. Cilostazol (Otsuka Pharmaceuticals Co.), a selective Type III phosphodiesterase inhibitor, has been shown to be neuroprotective in cerebral hypoperfusion animal models and clinically effective in preventing the recurrence of cerebral infarction. To investigate the neuroprotective effect of cilostazol on cervical spondylotic myelopathy, the preventive effect against progressive motor dysfunction and the loss of anterior horn motor neurons were assessed using a chronic cord compression model in rats. METHODS To produce chronic cervical cord compression in male Wistar rats, thin polyurethane sheets (3 × 5 × 0.7 mm) that gradually expand over 48-72 hours by absorbing water were implanted under the C5-6 laminae. In sham operations, the sheets were momentarily placed and then immediately removed. This model has been shown to reproduce characteristic features of clinical cervical myelopathy, with progressive motor disturbances after a latency period and insidious neuronal loss preceding the onset of symptoms. In the treatment group, cilostazol (30 mg/kg/day) was orally administered to the rats once a day, starting the day after surgery and continuing through the entire observation period of 25 weeks. In the control group, vehicle solution was administered under the same protocol. Changes in motor function were monitored by measuring bilateral forepaw grip strength and the duration of forced running on a treadmill. Twenty-five weeks after surgery, cervical spinal cords were examined histopathologically. RESULTS Cilostazol preserved both forepaw grip strength and forced running capability. The drug also preserved anterior horn motor neurons in the C5-6 spinal cord segment, which diminished in number in the untreated chronic compression group. The drug decreased the number of TUNEL-positive apoptotic cells. CONCLUSIONS These results indicate that cilostazol is neuroprotective in the chronically compressed cervical cord and is potentially useful in the treatment of cervical spondylotic myelopathy.

Limaprost Alfadex, a Prostaglandin E1 Derivative, Prevents Deterioration of Forced Exercise Capability in Rats with Chronic Compression of the Spinal Cord

Study Design. Basic animal research. Objective. Cervical spondylotic myelopathy is a common condition among elderly and often treated by surgery. To explore possibility of pharmacologic treatment, limaprost alfadex, a prostaglandin E1 derivative with vasodilatory and antiplatelet action, was tried in a rat chronic spinal cord compression model. Summary of Background Data. Limaprost increased the blood flow of cauda equina and improved motor functions in animal models of lumbar stenosis. The drug is clinically used to treat neurogenic intermittent claudication. Methods: Forty-two rats were allocated to four groups: (A) sham operation without permanent cord compression, given 5 mL/kg of distilled water twice a day (n = 6); (B) sham operation, receiving 300 &mgr;g/kg limaprost twice a day (n = 6); (C) cord compression, receiving the vehicle (n = 15); and (D) cord compression receiving the drug (n = 15). A thin polyurethane sheet that expands by absorbing water was implanted under the C5–C6 laminae to produce cord compression. For sham operation, the sheet was immediately removed. Exercise tests were repeated on a rotating treadmill until 26 weeks after surgery, and then the animals were killed and the spinal cord harvested for motor neurons counts. Results. Treadmill endurance (seconds, mean ± standard error of mean) 2 weeks after surgery was 497.7 ± 2.3, 434.5 ± 65.5, 423.1 ± 33.0, and 480.5 ± 19.5 in groups A, B, C, and D, respectively. At 26th week, the duration was 497.7 ± 2.3, 421.2 ± 78.8, 21.3 ± 11.7, and 441.3 ± 40.4 (P < 0.0001 for the decrease in C group, multivariate analysis of variance with correction for multiple measures.) The motor neuron counts were 38.3 ± 3.6, 38.2 ± 2.6, 32.6 ± 1.9, and 36.2 ± 2.3 in groups A, B, C, and D (P = 0.34), respectively. Conclusion. Limaprost alfadex prevented decline of forced locomotion capability in rats with chronic compression of the cervical cord.

Granulocyte Colony-Stimulating Factor Improves Motor Function in Rats Developing Compression Myelopathy.

Study Design. Basic animal research. Objective. The effects of granulocyte colony-stimulating factor (G-CSF) were assessed in a rat chronic spinal cord compression model to explore the potential of G-CSF as a pharmacological treatment for cervical spondylotic myelopathy. Summary of Background Data. G-CSF is a hematopoietic cytokine used clinically to treat neutropenia. Recently, neuroprotective effects of G-CSF have been reported in spinal cord disorders. Methods. To introduce the chronic cervical cord compression, thin polyurethane sheets were implanted under C5-C6 laminae of rats and gradually expanded by absorbing water. This model reproduces delayed compressive myelopathy of the cervical spine. In sham operations, the sheets were immediately removed. G-CSF (15 &mgr;g/kg) or normal saline (NS) was administered subcutaneously 5 days a week. Experimental groups were sham operation given NS; cord compression given NS; and cord compression given G-CSF. To assess motor functions, rotarod performance, and grip strength were measured. Twenty-six weeks after surgery, cervical spinal cords were examined histopathologically. In the prevention experiment, G-CSF or NS administration was started immediately after surgery. In the treatment experiment, their administration was started 8 weeks after surgery. In another experiment, in three groups in the prevention experiment, terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate–biotin nick end labeling staining was performed to assess apoptotic cell death at 8 weeks after surgery. Results. In the prevention experiment, administration of G-CSF preserved the motor functions and motor neurons throughout the 26 weeks, and significantly decreased the number of apoptotic cells at 8 weeks. In the treatment experiment, G-CSF administration from 8 weeks after surgery markedly restored the motor function temporarily to a level equal to the sham group. Conclusion. G-CSF prevents the decline in motor functions and preserves motor neurons in the rat chronic cord compression model. G-CSF also improves motor function in the progressive phase of compression myelopathy. Level of Evidence: N/A

False-Positive and False-Negative Results of Motor Evoked Potential Monitoring During Surgery for Intramedullary Spinal Cord Tumors

BACKGROUND Motor evoked potential (MEP) recording is used as a method to monitor integrity of the motor system during surgery for intramedullary tumors (IMTs). Reliable sensitivity of the monitoring in predicting functional deterioration has been reported. However, we observed false positives and false negatives in our experience of 250 surgeries of IMTs. OBJECTIVE To delineate specificity and sensitivity of MEP monitoring and to elucidate its limitations and usefulness. METHODS From 2008 to 2011, 58 patients underwent 62 surgeries for IMTs. MEP monitoring was performed in 59 operations using transcranial electrical stimulation. Correlation with changes in muscle strength and locomotion was analyzed. A group undergoing clipping for unruptured aneurysms was compared for elicitation of MEP. RESULTS Of 212 muscles monitored in the 59 operations, MEP was recorded in 150 (71%). Positive MEP warnings, defined as amplitude decrease below 20% of the initial level, occurred in 37 muscles, but 22 of these (59%) did not have postoperative weakness (false positive). Positive predictive value was limited to 0.41. Of 113 muscles with no MEP warnings, 8 muscles developed postoperative weakness (false negative, 7%). Negative predictive value was 0.93. MEP responses were not elicited in 58 muscles (27%). By contrast, during clipping for unruptured aneurysms, MEP was recorded in 216 of 222 muscles (96%). CONCLUSION MEP monitoring has a limitation in predicting postoperative weakness in surgery for IMTs. False-positive and false-negative indices were abundant, with sensitivity and specificity of 0.65 and 0.83 in predicting postoperative weakness.

Effect of Myoarchitectonic Spinolaminoplasty on Concurrent Hypertension in Patients With Cervical Spondylotic Myelopathy

Objective When treating patients with cervical spondylotic myelopathy (CSM), we often note amelioration in concomitant hypertension after surgery. To assess the effects of surgery and the mechanisms thereof, blood pressure (BP) and parasympathetic nervous activity were monitored prospectively in CSM patients undergoing surgery. Methods Sixty-eight consecutive CSM patients who underwent surgery with myoarchitectonic spinolaminoplasty were enrolled. BP and electrocardiography were recorded preoperatively and at 1, 3, and 6 months postoperatively. Forty-six patients completed the scheduled follow-ups and were analyzed. Preoperatively, 17 had a mean BP higher than 100 mmHg (the HT group) and 12 had hypertension despite taking medication (the HT-refractory group). To evaluate alterations in parasympathetic function, the coefficient of variation of the RR interval (CVRR) was evaluated. Results A significant BP reduction was observed in the HT group 6 months after surgery, but not in the normotensive group (n=29). The effect was more remarkable in the HT-refractory group. A transient BP increase at 1 and 3 months after surgery was observed in all groups. Comparisons were made between groups classified by age (over 65 years or younger than 60 years) and the presence or absence of an intramedullary hyperintense T2 signal on magnetic resonance imaging, but no significant differences were detected. Measurements of CVRR did not significantly differ between the groups over the course of follow-up. Conclusion Hypertension coexisting with CSM can be ameliorated after surgical treatment. The effect is likely to be mediated by moderation of sympathetic activity, rather than parasympathetic activation. We believe that a combination of adequate decompression of the spinal cord and relief from musculoskeletal stresses effectuate this moderation.

Multidetector Spinal CT Angiography with Intraarterial Contrast Injection As a Scout Survey for Spinal Vascular Lesions

Shinji Yamamoto, M. D., Ryu Kurokawa, M. D., Kazushige Itoki, M. D., Tetsuro Shingo, M. D., Toshiki Kawamoto, M. D., Phyo Kim, M. D. 獨協医科大学脳神経外科/〒321-0293 下都賀郡壬生町北小林 880[連絡先:山本慎司] Address reprint requests to:Shinji Yamamoto, M. D., Department of Neurosurgery, Dokkyo University School of Medicine, 880 Kitakobayashi, Mibu-machi, Shimotsuga-gun, Tochigi 321-0293, Japan 動注 MDCT angiography による脊髄血管病変の補助診断 Multidetector Spinal CT Angiography with Intraarterial Contrast Injection As a Scout Survey for Spinal Vascular