Fluorescence image-guided neurosurgery.

Surgery plays an important role in the management of high-grade gliomas (HGG) and imparts significant tumor-free and overall survival advantages. However HGG margins are often invisible, making their gross total resection (GTR) a difficult task. Hence intraoperative technology such as intraoperative fluorescence was a revolutionary discovery. A critical literature review revealed fluorescence improved the GTR of HGG from 36% using standard surgery to 74.5 and 84.4% using aminolevulinic acid (ALA) or fluorescein (FLCN), respectively. The differences between ALA-fluorescence image-guided neurosurgery (FIGS) and FLCN-FIGS in HGG were not statistically significant. However, the cost per quality added life years was US$16,218 and US$3181 for ALA-FIGS and FLCN-FIGS, respectively. Therefore, FIGS provided a reliable intraoperative tumor marker. Both ALA- and FLCN-FIGS significantly improved GTR and were cost-effective.

Immunohistochemical evaluation of O6 -methylguanine DNA methyltransferase (MGMT) expression in 117 cases of glioblastoma.

Temozolomide (TMZ) is an oral alkylating agent which is widely used in the treatment of glioblastoma (GBM) and is composed of astrocytic and/or oligodendroglial tumors, and the evaluation of O(6) -methylguanine DNA methyltransferase (MGMT) expression is important to predict the response to TMZ therapy. In this study, we conducted immunohistochemical analysis of 117 cases of Japanese GBM including 19 cases of GBM with oligodendroglioma component (GBMO), using a scoring system for quantitative evaluation of staining intensity and proportion of MGMT, and performed survival analysis of these patients. Immunohistochemically, 55 cases (47%) were positive for MGMT with various intensities and proportions (total score (TS) ≥ 2), while 62 cases (53%) were negative (TS = 0). The distribution of MGMT expression pattern was not affected by any clinicopathological parameters such as the histological subtype (GBM vs. GBMO), age and gender. The survival analysis of these patients revealed that the minimal expression of MGMT (TS ≥ 2) was a significant unfavorable prognostic factor (P < 0.001) as well as resectability (P = 0.004). Moreover, multivariate analysis showed that minimal MGMT expression in GBM was the most potent independent predictor for progression free survival (P < 0.001) and also overall patient survival (P < 0.001). This is the first report employing the scoring system for both staining intensity and proportion to evaluate immunohistochemical MGMT expression in GBM. In addition, our results emphases the clinicopathological values of the immunohistochemical approach for MGMT expression in glioma patients as a routine laboratory examination.

New criteria for the sonographic diagnosis of a plaque ulcer in the extracranial carotid artery.

OBJECTIVE: The diagnostic power of carotid sonography in detecting plaque ulcers may be inadequate when using the conventional criteria. We aimed to evaluate the usefulness of new criteria that we devised through a preliminary analysis of 50 endarterectomy cases before the present series. SUBJECTS AND METHODS: Thirty carotid arteries of 30 consecutive patients who underwent endarterectomy (28 men; age range, 46-83 years) were studied. In the long- and short-axis B-mode images of carotid arteries, the concavity of the plaque surface and the surface echo intensity were carefully investigated. The conventional criteria stipulate a concavity larger than 2 × 2 mm with a well-defined back wall and flow reversal within the recess. Our new criteria specify a concavity in the plaque with the basal border echo weaker than that of the adjacent plaque surface, regardless of size. The final diagnosis was based on surgical and histologic findings. RESULTS: Among the 30 carotid arteries, 14 arteries had 14 ulcers at surgery. Seventeen concavities were detected by sonography, and 12 of them, including six smaller than 2 × 2 mm, were truly ulcers. Two concavities with an echo intensity of the basal border equal to or greater than that of the adjacent surface were not true ulcers. Only two of 14 ulcers were not detected by sonography. The sensitivity and specificity of the conventional criteria were 35.7% and 75.0%, respectively, and those of our new criteria were 85.7% and 81.3%, respectively. CONCLUSION: Our new criteria for the sonographic diagnosis of plaque ulcer are more useful than the conventional ones.

Photodynamic Therapy of Malignant Gliomas.

Recently, the clinical applications of photodynamic therapy (PDT) in the management of malignant brain tumors have attracted significant attention. Meta-analysis of the observational studies on this treatment in high-grade gliomas (Eljamel, 2010) included more than 1,000 patients and reported median survival in cases of newly diagnosed and recurrent glioblastoma multiforme (GBM) of 16.1 and 10.3 months, respectively. In some series, increase in the long-term survival rates was also observed. Few controlled trials demonstrated statistically significant impact of PDT on prolongation of survival in patients with GBM in comparison to conventional management. The main treatment-related adverse event is short-lasting excessive photosensitivity of the skin and retina after photosensitizer administration, but its negative consequences can be easily avoided with appropriate protective measures. Overall, PDT may be considered to be a safe and effective adjuvant therapeutic option for patients with newly diagnosed and recurrent malignant gliomas. Aggressive tumor resection seems to be an important prerequisite to maximize treatment efficacy.

O6-methylguanine-DNA methyltransferase is downregulated in transformed astrocyte cells: implications for anti-glioma therapies.

BACKGROUND: A novel alkylating agent, temozolomide, has proven efficacious in the treatment of malignant gliomas. However, expression of O6-methylguanine-DNA methyltransferase (MGMT) renders glioma cells resistant to the treatment, indicating that identification of mechanisms underlying the gene regulation of MGMT is highly required. Although glioma-derived cell lines have been widely employed to understand such mechanisms, those models harbor numerous unidentified genetic lesions specific for individual cell lines, which complicates the study of specific molecules and pathways. RESULTS: We established glioma models by transforming normal human astrocyte cells via retroviral-mediated gene transfer of defined genetic elements and found that MGMT was downregulated in the transformed cells. Interestingly, inhibitors of DNA methylation and histone deacetylation failed to increase MGMT protein levels in the transformed astrocyte cells as well as cultured glioblastoma cell lines, whereas the treatment partially restored mRNA levels. These observations suggest that downregulation of MGMT may depend largely on cellular factors other than promoter-hypermethylation of MGMT genes, which is being used in the clinic to nominate patients for temozolomide treatment. Furthermore, we discovered that Valproic acid, one of histone deacetylase inhibitors, suppressed growth of the transformed astrocyte cells without increasing MGMT protein, suggesting that such epigenetic compounds may be used to some types of gliomas in combination with alkylating agents. CONCLUSION: Normal human astrocyte cells allow us to generate experimental models of human gliomas by direct manipulation with defined genetic elements, in contrast to tumor-derived cell lines which harbor numerous unknown genetic abnormalities. Thus, we propose that the study using the transformed astrocyte cells would be useful for identifying the mechanisms underlying MGMT regulation in tumor and for the development of rational drug combination in glioma therapies.

Stepwise revascularization for prevention of postoperative hyperperfusion.

Abrupt normalization of cerebral blood flow (CBF) after surgical procedures to improve excessive cerebral hypoperfusion can cause irreversible brain parenchymal damage. Such hyperperfusion, which is caused by inflow at normal blood pressure into maximally dilated fine vessels, is an important complication following carotid endarterectomy (CEA). Strict control of blood pressure in the perioperative period can prevent this complication except in a few patients, who have severe cerebral hypoperfusion and poor cerebrovascular reserve due to extremely severe stenosis of the ipsilateral or the bilateral carotid arteries, for which CEA is indicated. The requirement for improved CBF and the risk of postoperative hyperperfusion conflict in the pathogenesis of these patients. We tried to prevent abrupt improvement in perfusion by attempting gradual restoration of CBF. Superficial temporal artery-middle cerebral artery anastomosis was first performed to improve the poor cerebrovascular reserve by allowing insufficient blood flow. A few weeks later, CEA was performed to completely restore CBF. This surgical approach obtained good results without postoperative problems in four patients. The indications of this surgical management and efficacy of stepwise restoration of CBF to prevent postoperative hyperperfusion depend on careful preoperative evaluation of perfusion studies.

Fluorescence-Guided Resection of Malignant Glioma with 5-ALA.

Malignant gliomas are extremely difficult to treat with no specific curative treatment. On the other hand, photodynamic medicine represents a promising technique for neurosurgeons in the treatment of malignant glioma. The resection rate of malignant glioma has increased from 40% to 80% owing to 5-aminolevulinic acid-photodynamic diagnosis (ALA-PDD). Furthermore, ALA is very useful because it has no serious complications. Based on previous research, it is apparent that protoporphyrin IX (PpIX) accumulates abundantly in malignant glioma tissues after ALA administration. Moreover, it is evident that the mechanism underlying PpIX accumulation in malignant glioma tissues involves an abnormality in porphyrin-heme metabolism, specifically decreased ferrochelatase enzyme activity. During resection surgery, the macroscopic fluorescence of PpIX to the naked eye is more sensitive than magnetic resonance imaging, and the alert real time spectrum of PpIX is the most sensitive method. In the future, chemotherapy with new anticancer agents, immunotherapy, and new methods of radiotherapy and gene therapy will be developed; however, ALA will play a key role in malignant glioma treatment before the development of these new treatments. In this paper, we provide an overview and present the results of our clinical research on ALA-PDD.

Sonographic Detection of Abnormal Plaque Motion of the Carotid Artery: Its Usefulness in Diagnosing High-Risk Lesions Ranging from Plaque Rupture to Ulcer Formation.

We investigated the feasibility of using sonography of abnormal plaque motion to diagnose high-risk carotid lesions ranging from plaque rupture to ulcer formation. Fifty consecutive carotid arteries of 49 patients (71 ± 7 y, 37 males) who underwent carotid endarterectomy were investigated by carotid sonography to find a plaque concavity (sonographic ulcer [SU]), fine trembling motion inside the plaque (FTMI) and systolic retractive motion of the plaque surface (SRMS). Plaque rupture or ulcer, necrotic core and intra-plaque hemorrhage were determined at carotid endarterectomy. Twenty-two SUs, 41 cases of FTMI and 20 cases of SRMS were detected by carotid sonography. The sensitivity and specificity of SU in diagnosing plaque rupture or ulcer at carotid endarterectomy were 48% and 90%, and those of FTMI were 93% and 60%. Plaques with SRMS more frequently had both a necrotic core and intra-plaque hemorrhage than those without SRMS (80% vs. 30%, p = 0.0005). Abnormal plaque motion detected by carotid sonography is useful in detecting a ruptured or ulcerated plaque with a necrotic core and/or hemorrhage.

Evaluation of carotid distal pressure for prevention of hyperperfusion after carotid endarterectomy.

BACKGROUND: Sometimes preoperative cerebral misery perfusion induces an occurrence of hyperperfusion after carotid endarterectomy (CEA). We intraoperatively measured carotid proximal and distal pressures and evaluated their role in predicting hyperperfusion. METHODS: Twenty-one sites with an indication of CEA were preoperatively assessed based on the bilateral perfusional state of the cerebral blood flow (CBF) and delta CBF by single photon emission computed tomography (SPECT). Postoperative SPECT was performed immediately and on the fifth day after surgery. The distal and proximal pressures were intraoperatively measured through an internal shunt tube, and the evaluated relationship against hyperperfusion was shown on postoperative SPECT. RESULTS: Despite strict control of blood pressure, 7 patients postoperatively showed hyperperfusion on SPECT and 2 of them had transient neurological symptoms. The distal pressure was significantly different between the postoperative hyperperfusion group and the normal one; however, proximal pressure and the difference between proximal and distal pressures were not significantly different. In the hyperperfusion group, delta pressure was apparently higher, and delta CBF and distal pressure were significantly lower than those of the normal group. CONCLUSION: Intraoperative measurement of distal pressure as well as preoperative estimation of the cerebrovascular perfusion and the reserve is of importance in predicting postoperative hyperperfusion.

Diagnostic impact of baseline cerebral blood flow in patients with acute ischemic stroke prior to intravenous recombinant tissue plasminogen activator therapy.

OBJECTIVE: To determine whether severe cerebral perfusion defects measured by SPECT prior to rt-PA therapy attribute to severe intracerebral hemorrhage (SICH). METHODS: We measured baseline cerebral blood flow (CBF) using technetium-99m-labeled hexamethylpropyleneamine oxime (99mTc-HMPAO) SPECT qualitatively prior to rt-PA therapy, in 52 consecutive patients (range 38-93 years). The degree and extent of the asymmetry of local CBF were analyzed semi-quantitatively. We did not administrate rt-PA in patients with severe perfusion defects. Clinical outcome and the incidence of SICH were studied. RESULTS: Three (5.8%) patients had severe perfusion defects that were undetected by CT and/or DWI. The other 49 (94.2%) patients had mild perfusion defects. The asymmetry of local CBF was 0.08±0.08 (n=3) and 0.3±0.15 (n=49) in the two groups, respectively. The percentages of the ipsilateral hemisphere in which perfusion was impaired severely were 17.5±9.5% (n=3) and 0.43±0.87% (n=49). Two patients were found petechial hemorrhage, but there was no patient who developed SICH in the former group following conventional antithrombotic therapy. In the latter group, SICH occurred in 1/49 (2.0%) patient following rt-PA therapy. CONCLUSION: These results suggest that rt-PA therapy for patients with severe cerebral perfusion defects may cause SICH and baseline CBF may contribute to identify patients at high risk for SICH after intravenous rt-PA therapy.

Phase II clinical study on intraoperative photodynamic therapy with talaporfin sodium and semiconductor laser in patients with malignant brain tumors.

OBJECT: The objective of the present study was to perform a prospective evaluation of the potential efficacy and safety of intraoperative photodynamic therapy (PDT) using talaporfin sodium and irradiation using a 664-nm semiconductor laser in patients with primary malignant parenchymal brain tumors. METHODS: In 27 patients with suspected newly diagnosed or recurrent primary malignant parenchymal brain tumors, a single intravenous injection of talaporfin sodium (40 mg/m(2)) was administered 1 day before resection of the neoplasm. The next day after completion of the tumor removal, the residual lesion and/or resection cavity were irradiated using a 664-nm semiconductor laser with a radiation power density of 150 mW/cm(2) and a radiation energy density of 27 J/cm(2). The procedure was performed 22-27 hours after drug administration. The study cohort included 22 patients with a histopathologically confirmed diagnosis of primary malignant parenchymal brain tumor. Thirteen of these neoplasms (59.1%) were newly diagnosed glioblastomas multiforme (GBM). RESULTS: Among all 22 patients included in the study cohort, the 12-month overall survival (OS), 6-month progression-free survival (PFS), and 6-month local PFS rates after surgery and PDT were 95.5%, 91%, and 91%, respectively. Among patients with newly diagnosed GBMs, all these parameters were 100%. Side effects on the skin, which could be attributable to the administration of talaporfin sodium, were noted in 7.4% of patients and included rash (2 cases), blister (1 case), and erythema (1 case). Skin photosensitivity test results were relatively mild and fully disappeared within 15 days after administration of photosensitizer in all patients. CONCLUSIONS: Intraoperative PDT using talaporfin sodium and a semiconductor laser may be considered as a potentially effective and sufficiently safe option for adjuvant management of primary malignant parenchymal brain tumors. The inclusion of intraoperative PDT in a combined treatment strategy may have a positive impact on OS and local tumor control, particularly in patients with newly diagnosed GBMs. Clinical trial registration no.: JMA-IIA00026 (https://dbcentre3.jmacct.med.or.jp/jmactr/App/JMACTRS06/JMACTRS06.aspx?seqno=862).

Identification of high-risk carotid artery stenosis: motion of intraplaque contents detected using B-mode ultrasonography.

OBJECT: Identification of the risk of rupture and vulnerability of arterial plaque is not yet clearly understood. The aim of this study was to assess the clinical features of the motion of intraplaque contents (MIC) detected by B-mode ultrasonography. The MIC is characterized by the peculiar movement of the intraplaque contents that is not synchronized with the heartbeat; however, the movement of the carotid artery (CA) wall depends on the heartbeat. METHODS: From January 2008 to November 2010, 1798 consecutive patients with transient ischemic attacks (TIAs) or acute ischemic stroke underwent CA ultrasonography for the examination of the MIC. Patients with CA stenosis greater than 50% were followed up until they underwent carotid endarterectomy or CA angioplasty and stent placement. If neither of these procedures were used, the patients were followed up at 90 days. Chi-square and Mann-Whitney tests were performed to compare the categorical and continuous demographic data and risk factors. The effect of the MIC on the rate of recurrent cerebral ischemia was examined using Kaplan-Meier and univariate Cox regression analyses. RESULTS: One hundred and fifteen patients had CA stenosis greater than 50%. Among these 115 patients, 58 with a total of 59 CA stenoses had MIC. Twenty-four recurrent ischemic events were associated with MIC, whereas only 6 such events occurred in the absence of MIC. The MIC decreased event-free survival (log-rank test = 15.8, p < 0.001); univariate Cox analysis confirmed that MIC increased the risk of a recurrent ischemic event (HR 5.12, 95% CI 2.08-12.58; p < 0.001). CONCLUSIONS: The MIC is one of the findings of vulnerable plaques. The MIC is more useful in predicting the recurrence of TIAs or ischemic events in patients with symptomatic CA stenosis.

Spontaneous echo contrast and thrombus formation at the carotid bifurcation after carotid endarterectomy.

Spontaneous echo contrast (SEC) consists of numerous microechoes swirling in the cardiovascular lumen and is usually seen during blood stasis in dysfunctional left atrium. However, SEC and consecutive local thrombus formation at the carotid artery early after carotid endarterectomy (CEA) have not been reported. This study retrospectively investigated the clinical importance and therapeutic strategy of postoperative SEC and thrombus formation in 113 consecutive patients who underwent CEA between 2001 and 2009. Ultrasonography was routinely performed preoperatively, intraoperatively, and 1 day and 1 week after the operation. If SEC and/or thrombus was detected at any time after the operation, follow-up ultrasonography was performed at short intervals, once a week for inpatients and once every 1-2 months for outpatients. Eight of the 113 patients (7%) had SEC after the operation from Day 1 to 12 (mean 7.2 days), and 6 of these 8 patients developed local de novo thrombus formation at the site of SEC from Day 6 to 33 (mean 14.7 days). The maximum luminal narrowing by the thrombi were 26-62% (mean 37%). After administering anticoagulant therapy, all thrombi disappeared from Day 13 to 190 (mean 57 days) from CEA. SEC seen after CEA is highly associated with consecutive local thrombus formation. Postoperative geometric blood stasis with the absence of intima may be the causative factor for its development.

Cilostazol may suppress restenosis and new contralateral carotid artery stenosis after carotid endarterectomy.

Carotid artery restenosis is a serious complication following carotid endarterectomy (CEA), so preventative management of the risk factors is important. The present study investigated the potential of cilostazol, a mediator of vascular stabilization as well as inhibitor of platelet aggregation, to suppress restenosis on the ipsilateral carotid artery and new plaque development on the contralateral carotid artery. Eighty-two patients treated by CEA were divided into two groups according to the postoperative antiplatelet aggregation drugs into the cilostazol and other groups. Patients were periodically examined for recurrence of the plaque on the ipsilateral side, development of plaque on the contralateral side, and the bilateral intermedia thicknesses measured by ultrasonographic examination for up to 6 years. Restenosis and development of the contralateral plaque were not detected in any patients in the cilostazol group, whereas such changes were found in seven patients in the other group. Cilostazol might be effective to inhibit the growth mechanism of plaque.

Cilostazol may prevent cerebral vasospasm following subarachnoid hemorrhage.

Cilostazol is an antiplatelet aggregation inhibitor drug associated with increased cerebral blood flow and inflammation suppression. This study evaluated administration of cilostazol to prevent cerebral vasospasm following subarachnoid hemorrhage (SAH) in 50 patients treated surgically from December 2004 to November 2006. All patients, excluding those with Hunt and Kosnik grade 5 or who had undergone late surgery, were classified into two groups: 26 patients who received 200 mg/day cilostazol from postoperative day 1 to day 14 and 24 control patients. The frequency and the degree of cerebral vasospasm, occurrence of ischemic lesion, and clinical symptoms due to vasospasm were compared between the two groups. The appearance of severe vasospasm on angiography, persistent symptomatic spasm, and new cerebral infarction due to vasospasm demonstrated by neuroimaging were apparently lower in the cilostazol group than in the control group, suggesting that cilostazol may significantly suppress cerebral vasospasm following SAH.

Careful exclusion of non-neoplastic brain components is required for an appropriate evaluation of O6-methylguanine-DNA methyltransferase status in glioma: relationship between immunohistochemistry and methylation analysis.

Evaluation of O6-methylguanine-DNA methyltransferase (MGMT) expression is important for antiglioma therapy as many clinical trials have demonstrated that promoter hypermethylation and low level expression of MGMT are associated with an enhanced response to alkylating agents. However, here we report that the current strategies used to evaluate MGMT status in gliomas are unreliable. We observed discordance in the MGMT expression status when immunohistochemical evaluation and polymerase chain reaction-based methylation assessments were used: 73% of gliomas with methylated MGMT promoter had substantial numbers of MGMT-immunopositive tumor cells. Furthermore, when MGMT expression was tested in tumor homogenates using reverse transcription-polymerase chain reaction, 43% of tumors were found positive, in comparison to only 24%, when histologic samples were assayed immunohistochemically. To explain these inconsistencies we undertook a detailed immunohistochemical evaluation of tumor samples and found that some gliomas demonstrated remarkably high expression of MGMT in the entire tumor whereas others contained only a small immunopositive area. Additionally, we found that gliomas contained various types of non-neoplastic cells expressing MGMT, including lymphocytes, vascular endothelial cells, and macrophages/microglias, which contribute to overall MGMT expression detected in tumor homogenates, and thus result in overestimation of tumor MGMT expression. Therefore, to correctly establish MGMT expression in the tumor, which could be informative of glioma sensitivity to alkylating agents, exclusion of non-neoplastic brain components from analysis is required.

Signaling adaptor protein Crk is indispensable for malignant feature of glioblastoma cell line KMG4.

Signaling adaptor protein Crk has been shown to be involved in pathogenesis of human cancers including brain tumor where Crk was reported to be overexpressed. In this study, we addressed whether Crk is indispensable for malignant phenotype of brain tumor. In 20 surgical specimens of glioma, mRNA of both CrkI and CrkII was found to be elevated in malignant tumor. To define a precise role of Crk, we have established Crk-knockdown cell lines of glioblastoma KMG4 by siRNA, and early phase of cell adhesion to laminin was found to be suppressed. Wound healing assay revealed the decreased cell motility in Crk knockdown cells, and suppression of both anchorage-dependent and -independent growth were demonstrated in these cells. Furthermore, in vivo tumor forming potential was also markedly suppressed. These results suggest that Crk is required for early attachment to laminin, cell motility, and growth of glioblastoma cell line KMG4.

Prevalence and clinical importance of spontaneous echo contrast within the carotid artery in patients with ischemic cerebrovascular disease.

OBJECTIVE: Spontaneous echo contrast (SEC) is composed of numerous microechoes swirling in the cardiovascular lumen, usually appearing during blood stasis. This study aimed to clarify the clinical importance of SEC in the carotid artery (CA) in patients with ischemic cerebrovascular disease (ICVD). METHODS: In 264 CAs of 132 consecutive patients with ICVD and in 40 CAs of 20 healthy control subjects, SEC was classified as none, faint, or dense, and CA abnormalities, including plaque, plaque ulcer, mural thrombus, and internal CA stenosis, were assessed with 10-MHz sonography. RESULTS: The overall prevalence of SEC was greater in CAs of patients with ICVD (164/264 [62%]) than in CAs of control subjects (6/40 [15%]; P < .0001). Dense SEC was more specifically detected in CAs of ICVD with the prevalence of 81 (31%) of 264, which was greater than that of controls (1/40 [3%]; P = .0002). Dense SEC was more frequently detected in CAs with plaque (38/98 [39%]) than in those without (43/166 [26%]; P = .0285), in CA plaque with ulcerative lesions (7/10 [70%]) than in those without (31/88 [35%]; P = .0325), in CA plaque with a thrombus (11/12 [92%]) than in those without (27/86 [31%]; P < .0001), and in CAs with severe stenosis (11/13 [85%]) than in those with mild stenosis (25/75 [33%]; P = .0005) and in those without stenosis (45/176 [26%]; P < .0001). CONCLUSIONS: Dense SEC was frequently observed in CAs of patients with ICVD, especially in those with local atheromatous lesions, although the influence of systemic factors could not be excluded. Dense SEC within a CA may be a marker of ICVD.

[Effects of low-dose pergolide therapy on cardiac valves in patients with Parkinson's disease].

BACKGROUND: Pergolide mesilate is widely used to treat Parkinson's disease in both the USA and Japan, but the maintenance dose is distinctly different between the USA (usually more than 1.5 mg/day) and Japan (usually less than 1.5 mg/day). Although several reports from the USA have suggested that mitral, aortic, and tricuspid valvular lesions were caused by pergolide, it is unclear whether low-dose pergolide therapy causes such valvular lesions. OBJECTIVES: The effects of low-dose pergolide therapy on cardiac valves were studied in Japanese patients with Parkinson's disease. METHODS: One hundred and five consecutive patients with Parkinson's disease approved for our protocol were enrolled in this study. Forty patients were treated with low-dose pergolide (0.05-1.5 mg/day for 2-115 months), and were included in the pergolide group (mean age 71 +/- 6 years). The other 44 patients received no ergot-derived dopamine receptor agonists, and 32 patients acted as age-matched controls (mean age 71 +/- 7 years). Both groups of patients underwent echocardiographic examination to detect organic lesions in cardiac valves such as thickening of the leaflet, annular calcification, restriction of valve motion and valvular tenting, and valvular regurgitation greater than 2 + on the 4-point scale. RESULTS: No significant difference was observed in the incidence of aortic, mitral and pulmonic valve lesions between the pergolide group and the control group. Although no organic lesions were detected in the tricuspid valve, the incidence of tricuspid regurgitation was significantly higher in the pergolide group than in the control group (p < 0.05). CONCLUSIONS: Although low-dose pergolide of less than 1.5 mg/day does not cause serious damage in the left-sided valves, it may induce tricuspid regurgitation.