Moyamoya Syndrome: Differential Diagnosis in Patients With Central Nervous System Symptoms and Hyperthyroidism.

Moyamoya syndrome, known as secondary moyamoya disease, is associated with various primary illnesses, such as brain tumor, meningitis, autoimmune disease, and thyrotoxicosis, and their relations are not clear. We report a rare case of moyamoya syndrome in a patient with Graves' disease. An 18-year-old woman was admitted to our hospital due to convulsions. She had symptoms of palpitations and fatiguability for half a year and transient numbness in her left upper extremity and dysarthria for a month. In physical findings, tachycardia and diffuse thyroid swelling were noted. A blood test revealed thyrotoxicosis and antithyroid antibody, and a diagnosis of Graves' disease was obtained. Brain magnetic resonance imaging (MRI) showed bilateral internal carotid artery occlusion. We finally diagnosed the patient with moyamoya syndrome caused by Graves' disease. Moyamoya disease or syndrome can cause symptoms like a stroke, sometimes requiring neurosurgical treatment. In our case, the therapy for Graves' disease resolved the symptoms. When diagnosing moyamoya disease, it is necessary to confirm whether there are any background diseases, such as Graves' disease.

Significance of upper cervical epidural venous engorgement on head computed tomography in the initial diagnosis of spontaneous intracranial hypotension: patient series.

BACKGROUND: Spontaneous intracranial hypotension (SIH) is a rare condition characterized by positional headache, for which contrast-enhanced magnetic resonance imaging (MRI) is the preferred diagnostic method. Although MRI reveals characteristic findings, head computed tomography (CT) is usually the first diagnostic step, but identifying features of SIH on CT is often difficult. This study was specifically designed to evaluate the utility of head CT in detecting upper cervical epidural venous engorgement as a sign of SIH. OBSERVATIONS: Of 24 patients with SIH diagnosed between March 2011 and May 2023, 10 did not undergo upper cervical CT. In the remaining 14 patients, engorgement of the upper cervical epidural venous plexus was observed. CT detection rates were consistent with MRI for spinal fluid accumulation or dural thickening. After treatment, in 92.9% of patients, the thickness of the epidural venous plexus decreased statistically significantly from 4.8 ± 1.3 mm to 3.6 ± 1.2 mm. LESSONS: This study suggests that upper cervical spine CT focused on epidural venous engorgement may be helpful in the initial diagnosis of SIH and may complement conventional MRI evaluation. Extending CT imaging to the upper cervical spine will improve the diagnostic accuracy of patients with positional headaches suspected to be SIH.

Spontaneous resorption of a convexity arachnoid cyst associated with intracystic hemorrhage and subdural hematoma: A case report.

Background: Intracranial arachnoid cysts (ACs) are developmental anomalies usually filled with cerebrospinal fluid (CSF), rarely resolving throughout life. Here, we present a case of an AC with intracystic hemorrhage and subdural hematoma (SDH) that developed after a minor head injury before gradually disappearing. Neuroimaging demonstrated specific changes from hematoma formation to AC disappearance over time. The mechanisms of this condition are discussed based on imaging data. Case Description: An 18-year-old man was admitted to our hospital with a head injury caused by a traffic accident. On arrival, he was conscious with a mild headache. Computed tomography (CT) revealed no intracranial hemorrhages or skull fractures but an AC was seen in the left convexity. One month later, follow-up CT scans showed an intracystic hemorrhage. Subsequently, an SDH appeared then both the intracystic hemorrhage and SDH gradually shrank, with the AC disappearing spontaneously. The AC was considered to have disappeared, along with the spontaneous SDH resorption. Conclusion: We present a rare case where neuroimaging demonstrated spontaneous resorption of an AC combined with intracystic hemorrhage and SDH over time, which may provide new insights into the nature of adult ACs.

De novo formation of twig-like middle cerebral artery: An illustrative case.

Background: Twig-like middle cerebral artery (T-MCA) is a rare vascular abnormality characterized by the replacement of the M1 segment of the middle cerebral artery (MCA) with a plexiform arterial network of small vessels. T-MCA is generally regarded as an embryological persistence. Conversely, T-MCA may also be a secondary sequela but no reports of cases of de novo formation exist. Here, we report the first case describing possible de novo T-MCA formation. Case Description: A 41-year-old woman was referred to our hospital from a nearby clinic because of transient left hemiparesis. Magnetic resonance (MR) imaging revealed mild stenosis of the bilateral MCAs. The patient then underwent MR imaging follow-ups once a year. MR imaging at the age of 53 showed a right M1 occlusion. Cerebral angiography revealed a right M1 occlusion and formation of a plexiform network consistent with the occlusion site, leading to the diagnosis of de novo T-MCA. Conclusion: This is the first case report describing possible de novo T-MCA formation. Although a detailed laboratory examination did not confirm the etiology, autoimmune disease was suspected to have precipitated this vascular lesion.

Nonaneurysmal subarachnoid hemorrhage associated with COVID-19 infection: A case report.

Background: Most coronavirus disease 2019 (COVID-19)-related cerebrovascular disorders are ischemic while hemorrhagic disorders are rarely reported. Among these, subarachnoid hemorrhage (SAH) is very rarely reported and nonaneurysmal SAH has been reported in only about a dozen cases. Here, we report a case of nonaneurysmal SAH as the only clinical manifestation of COVID-19 infection. In addition, we reviewed and analyzed the literature data on cases of nonaneurysmal SAH caused by COVID-19 infection. Case Description: A 50-year-old woman presented to an emergency department with a sudden headache, right hemiparesis, and consciousness disturbance. At that time, no fever or respiratory failure was observed. Laboratory data were within normal values but the rapid antigen test for COVID-19 on admission was positive, resulting in a diagnosis of COVID-19 infection. Computed tomograms (CTs) showed bilateral convexal SAH with a hematoma but three-dimensional CT angiograms showed no obvious sources, such as a cerebral aneurysm. Therefore, the patient was diagnosed with nonaneurysmal SAH associated with COVID-19 infection. With conservative treatment, consciousness level and hemiparesis both improved gradually until transfer for continued rehabilitation. Approximately 12 weeks after onset, the patient was discharged with only mild cognitive impairment. During the entire course of the disease, the headache, hemiparesis, and mild cognitive impairment due to nonaneurysmal SAH with small hematoma were the only abnormalities experienced. Conclusion: Since COVID-19 infection can cause nonaneurysmal hemorrhaging, it should be considered (even in the absence of characteristic infectious or respiratory symptoms of COVID-19) when atypical hemorrhage distribution is seen as in our case.

Impact of breast cancer subtype on clinical outcomes after Gamma Knife radiosurgery for brain metastases from breast cancer: a multi-institutional retrospective study (JLGK1702).

INTRODUCTION: Brain metastasis (BM) is one of the most important issues in the management of breast cancer (BC), since BMs are associated with neurological deficits. However, the importance of BC subtypes remains unclear for BM treated with Gamma Knife radiosurgery (GKS). Thus, we conducted a multicenter retrospective study to compare clinical outcomes based on BC subtypes, with the aim of developing an optimal treatment strategy. METHODS: We studied 439 patients with breast cancer and 1-10 BM from 16 GKS facilities in Japan. Overall survival (OS) was analyzed by the Kaplan-Meier method, and cumulative incidences of systemic death (SD), neurologic death (ND), and tumor progression were estimated by competing risk analysis. RESULTS: OS differed among subtypes. The median OS time (months) after GKS was 10.4 in triple-negative (TN), 13.7 in Luminal, 31.4 in HER2, and 35.8 in Luminal-HER2 subtype BC (p < 0.0001). On multivariate analysis, poor control of the primary disease (hazard ratio [HR] = 1.84, p < 0.0001), active extracranial disease (HR = 2.76, p < 0.0001), neurological symptoms (HR 1.44, p = 0.01), and HER2 negativity (HR = 2.66, p < 0.0001) were significantly associated with worse OS. HER2 positivity was an independent risk factor for local recurrence (p = 0.03) but associated with lower rates of ND (p = 0.03). TN histology was associated with higher rates of distant brain failure (p = 0.03). CONCLUSIONS: HER2 positivity is related to the longer OS after SRS; however, we should pay attention to preventing recurrence in Luminal-HER2 patients. Also, TN patients require meticulous follow-up observation to detect distant metastases and/or LMD.

Evaluation of First-line Radiosurgery vs Whole-Brain Radiotherapy for Small Cell Lung Cancer Brain Metastases: The FIRE-SCLC Cohort Study.

Importance: Although stereotactic radiosurgery (SRS) is preferred for limited brain metastases from most histologies, whole-brain radiotherapy (WBRT) has remained the standard of care for patients with small cell lung cancer. Data on SRS are limited. Objective: To characterize and compare first-line SRS outcomes (without prior WBRT or prophylactic cranial irradiation) with those of first-line WBRT. Design, Setting, and Participants: FIRE-SCLC (First-line Radiosurgery for Small-Cell Lung Cancer) was a multicenter cohort study that analyzed SRS outcomes from 28 centers and a single-arm trial and compared these data with outcomes from a first-line WBRT cohort. Data were collected from October 26, 2017, to August 15, 2019, and analyzed from August 16, 2019, to November 6, 2019. Interventions: SRS and WBRT for small cell lung cancer brain metastases. Main Outcomes and Measures: Overall survival, time to central nervous system progression (TTCP), and central nervous system (CNS) progression-free survival (PFS) after SRS were evaluated and compared with WBRT outcomes, with adjustment for performance status, number of brain metastases, synchronicity, age, sex, and treatment year in multivariable and propensity score-matched analyses. Results: In total, 710 patients (median [interquartile range] age, 68.5 [62-74] years; 531 men [74.8%]) who received SRS between 1994 and 2018 were analyzed. The median overall survival was 8.5 months, the median TTCP was 8.1 months, and the median CNS PFS was 5.0 months. When stratified by the number of brain metastases treated, the median overall survival was 11.0 months (95% CI, 8.9-13.4) for 1 lesion, 8.7 months (95% CI, 7.7-10.4) for 2 to 4 lesions, 8.0 months (95% CI, 6.4-9.6) for 5 to 10 lesions, and 5.5 months (95% CI, 4.3-7.6) for 11 or more lesions. Competing risk estimates were 7.0% (95% CI, 4.9%-9.2%) for local failures at 12 months and 41.6% (95% CI, 37.6%-45.7%) for distant CNS failures at 12 months. Leptomeningeal progression (46 of 425 patients [10.8%] with available data) and neurological mortality (80 of 647 patients [12.4%] with available data) were uncommon. On propensity score-matched analyses comparing SRS with WBRT, WBRT was associated with improved TTCP (hazard ratio, 0.38; 95% CI, 0.26-0.55; P < .001), without an improvement in overall survival (median, 6.5 months [95% CI, 5.5-8.0] for SRS vs 5.2 months [95% CI, 4.4-6.7] for WBRT; P = .003) or CNS PFS (median, 4.0 months for SRS vs 3.8 months for WBRT; P = .79). Multivariable analyses comparing SRS and WBRT, including subset analyses controlling for extracranial metastases and extracranial disease control status, demonstrated similar results. Conclusions and Relevance: Results of this study suggest that the primary trade-offs associated with SRS without WBRT, including a shorter TTCP without a decrease in overall survival, are similar to those observed in settings in which SRS is already established.

Salvage gamma knife radiosurgery for active brain metastases from small-cell lung cancer after whole-brain radiation therapy: a retrospective multi-institutional study (JLGK1701).

PURPOSE: To evaluate the efficacy of gamma knife radiosurgery (GKS) for brain metastases (BMs) from small-cell lung cancer after whole-brain radiotherapy (WBRT). METHODS: We retrospectively analyzed the usefulness and safety of GKS in 163 patients from 15 institutions with 1-10 active BMs after WBRT. The usefulness and safety of GKS were evaluated using statistical methods. RESULTS: The median age was 66 years, and 79.1% of patients were men. The median number and largest diameter of BM were 2.0 and 1.4 cm, respectively. WBRT was administered prophylactically in 46.6% of patients. The median overall survival (OS) was 9.3 months, and the neurologic mortality was 20.0%. Crude incidences of local control failure and new lesion appearance were 36.6% and 64.9%, respectively. A BM diameter ≥ 1.0 cm was a significant risk factor for local progression (hazard ratio [HR] 2.556, P = 0.039) and neurologic death (HR 4.940, P = 0.031). Leukoencephalopathy at the final follow-up was more prevalent in the therapeutic WBRT group than in the prophylactic group (P = 0.019). The symptom improvement rate was 61.3%, and neurological function was preserved for a median of 7.6 months. Therapeutic WBRT was not a significant risk factor for OS, neurological death, local control, or functional deterioration (P = 0.273, 0.490, 0.779, and 0.560, respectively). Symptomatic radiation-related adverse effects occurred in 7.4% of patients. CONCLUSIONS: GKS can safely preserve neurological function and prevent neurologic death in patients with 1-10 small, active BMs after prophylactic and therapeutic WBRT.

Treatment Outcomes of Burr-Hole Surgery for Chronic Subdural Hematoma in the Elderly Living Beyond Life Expectancy: A Study Comparing Cure, Recurrence, and Complications in Patients Aged ≥80 Years versus ≤79 Years.

BACKGROUND: Few reports have focused on chronic subdural hematoma (CSDH) in the very elderly, who have lived beyond average life expectancy. Our aim is to appraise treatment outcomes of burr-hole craniotomy for CSDH in the elderly, focusing on cure, recurrence, and complications. METHODS: Fifty patients ≤79 years of age (group A) and 73 patients ≥80 years of age (group B) were studied. Recurrence was defined as requiring reoperation for hematoma regrowth or symptomatic failure. A cure was regarded as having been achieved in the absence of hematoma on postoperative computed tomography. Complications were defined as any harmful event related to the treatment procedure for CSDH. RESULTS: Cure was documented in 31 patients in group A (63%) and 24 patients in group B (33%) (P = 0.0017). Median intervals to cure were 2.76 and 3.73 months, respectively (P = 0.06). Cumulative cure rates were 51%/76% and 36%/59%, respectively, at the sixth/twelfth postoperative months. Recurrence was documented in 2 patients (4%) and 11 patients (15%), respectively (P = 0.07). Median intervals to recurrence were 0.81 and 1.25 months, respectively (P = 0.049). Cumulative recurrence-free rates were 96%/92% and 87%/75%, respectively, at the third/sixth postoperative months. Complications were observed in 2 patients (4%) and 4 patients (5%), respectively (P = 1.00). CONCLUSIONS: With advancing age, CSDH might show a greater tendency to recur and a longer time is required to achieve a cure. However, complications developed only in high-risk patients. Thus, surgical treatment for CSDH in elderly patients, even those who have lived beyond life expectancy, might provide acceptably effective results.

Long-term follow-up results of stereotactic radiosurgery for vestibular schwannomas larger than 8 cc.

BACKGROUND: Accumulated stereotactic radiosurgery (SRS) experience for large vestibular schwannomas (VSs) based on over 5 years of follow-up are as yet insufficient, and chronological volume changes have not been documented. METHOD: Among 402 patients treated between 1990 and 2015, tumor volumes exceeded 8 cc in 30 patients. We studied 19 patients with follow-up for more than 36 post-SRS months or until an event. Median tumor volume was 11.5 cc (range; 8.0 to 30.6). The target volume was basically covered with 12.0 Gy. RESULTS: The median magnetic resonance imaging and clinical follow-up periods were both 98 months (range 49 to 204). Tumor shrinkage was documented in 13 patients (72%), no change in 2 (11%), and growth in the other 3 (17%). Therefore, the crude growth control rate was 83%. All three patients with tumor enlargement needed salvage treatment. Thus, the crude clinical control rate was 84%. Actuarial further procedure-free rates were 91%, 83% and 76%, at the 60th, 120th, and 180th post-SRS month. Among six patients followed chronologically, transient tumor expansion was observed in three (43%) and two cystic VSs showed rapid tumor growth. Transient trigeminal neuropathy occurred in two patients (11%). No patients experienced facial nerve palsy. None of the six patients with useful hearing pre-SRS maintained serviceable hearing. Ventricular-peritoneal shunt placement was required in three patients. CONCLUSIONS: Long-term tumor control with SRS was moderately acceptable in large VSs. In terms of functional outcome, trigeminal neuropathies and facial palsies were rare. However, hearing preservation remains a challenge. In the long term, chronological tumor volumes were generally decreased after SRS. However, caution is required regarding rapid increases in tumor size, especially for cystic type VSs. Further studies are needed to optimize clinical positioning of SRS for large VSs.

Applicability and limitations of a recently-proposed prognostic grading metric, initial brain metastasis velocity, for brain metastasis patients undergoing stereotactic radiosurgery.

PURPOSE: This study, based on our brain metastasis (BM) patients undergoing stereotactic radiosurgery (SRS) procedures, aimed to validate whether the recently-proposed prognostic grading system, initial brain metastasis velocity (iBMV, scoring the cumulative number of BMs at the time of SRS divided by time [years] since the initial primary cancer diagnosis), is generally applicable. METHODS: This was an institutional review board-approved, retrospective cohort study using our prospectively accumulated database including 3498 patients who underwent SRS for BMs during the 19.5-year-period between July, 1998 and December, 2017. We excluded four lost to follow-up, 24 for whom the day of primary cancer diagnosis was not available, 665 with synchronous presentation and 651 with pre-SRS radiotherapy and/or surgery, ultimately studying 2150 patients. Patients were categorized into two classes by iBMV scores, i.e., < 2.00 and ≥ 2.00. RESULTS: In a multivariable model, iBMV was directly associated with a higher risk of death (p < 0.0001). The median survival time of patients with iBMV scores < 2.00, 10.0 (95% CI; 9.2-10.9) months, was longer than that of patients with iBMV scores ≥ 2.00, 6.3 (5.6-6.7) months, showing a significant difference between the two groups (HR 1.599, 95% CI 1.458-1.753, p < 0.0001). The same results were obtained in patients with non-small cell lung, breast, kidney or other cancers. Among 608 patients who underwent repeat SRS for newly-developed BMs, iBMV score categories correlated well with brain metastasis velocity risk groups (p < 0.0001). CONCLUSIONS: Our present results support the validity of iBMV for predicting survival after SRS.

The NASSAU (New ASSessment of cerebral Arteriovenous Malformations yet Unruptured) Analysis: Are the Results From The ARUBA Trial Also Applicable to Unruptured Arteriovenous Malformations Deemed Suitable for Gamma Knife Surgery?

BACKGROUND: The optimal management of unruptured brain arteriovenous malformations (AVMs) is controversial after the ARUBA trial. OBJECTIVE: To confirm or repudiate the ARUBA conclusion that "medical management only is superior to medical management with interventional therapy for unruptured brain arteriovenous malformations." METHODS: Data were collected from 1351 patients treated with Gamma Knife Surgery (GKS; Elekta AB, Stockholm, Sweden) for unruptured and untreated AVMs The follow-up was 8817 yr (median 5.0 and mean 6.5). The results of the analyses were compared to that found in patients randomized to medical management only in the ARUBA trial and extrapolated to a 10-yr time period. Our data were also compared to the natural course in a virtual AVM population for a 25-yr time period. RESULTS: The incidence of stroke was similar among ARUBA and our patients for the first 5 yr. Thereafter, the longer the follow-up, the relatively better outcome following treatment. Both the mortality rate and the incidence of permanent deficits in patients with small AVMs were the same as in untreated patients for the first 2 to 3 yr after GKS, after which GKS patients did better. Patients with large AVMs had a higher incidence of neurological deficits in the first 3 yr following GKS. The difference decreased thereafter, but the time until break even depended on the analysis method used and the assumed risk for hemorrhage in patent AVMs. CONCLUSION: The ARUBA trial conclusion that medical management is superior to medical management with interventional therapy for all unruptured AVMs could be repudiated.

Prognostic Importance of Cumulative Intracranial Tumor Volume in Patients with Gastrointestinal Brain Metastasis Treated with Stereotactic Radiosurgery.

BACKGROUND: The disease-specific Graded Prognostic Assessment (ds-GPA) for patients with gastrointestinal (GI) tract cancer brain metastases (BM) suggests Karnofsky Performance Status (KPS) as the only pertinent prognostic factor. We evaluated the prognostic importance of cumulative intracranial tumor volume (CITV). METHODS: KPS, CITV, and overall survival were collected from consecutive patients with stereotactic radiosurgery-treated GI BM. Patients were grouped into 2 independent cohorts for development and validation of the model (termed "exploratory" and "validation" cohorts). Analyses were performed using logistic regression, Cox proportional hazards models, Net Reclassification Index (NRI >0), integrated discrimination improvement (IDI >0), and Akaike information criterion. RESULTS: In univariable logistic regression models, both CITV and KPS were independently associated with patient survival. The association between CITV and overall survival remained robust after controlling for KPS (P < 0.001) in a multivariable Cox proportional hazards model. Based on NRI analysis of the exploratory cohort, we found that a CITV cutoff of 12 cm3 best augments the prognostic accuracy of GI-ds-GPA. In this analysis, incorporation of CITV (as < or ≥12 cm3) improved prognostication of the GI-specific GPA model by NRI >0 of 0.397 (95% confidence interval [CI], 0.165-0.630; P < 0.001) and IDI of 0.019 (95% CI, 0.004-0.033; P = 0.013). We confirmed the prognostic usefulness of the CITV-incorporated GI-ds-GPA in an independent validation cohort, in which CITV incorporation improved prognostic usefulness with an NRI >0 of 0.478 (95% CI, 0.257-0.699; P < 0.001) and IDI of 0.028 (95% CI, 0.014-0.043; P < 0.001). CONCLUSIONS: CITV is an important prognostic variable in patients with stereotactic radiosurgery-treated GI BM and augments the prognostic accuracy of the GI-ds-GPA index.

Postsurgical Salvage Radiosurgery for Nonfunctioning Pituitary Adenomas Touching/Compressing the Optic Chiasm: Median 13-Year Postirradiation Imaging Follow-up Results.

BACKGROUND: There is little information on long-term outcomes after salvage treatment by either surgery or stereotactic radiosurgery (SRS) for patients with recurrent/residual nonfunctioning pituitary adenomas (NFPAs). OBJECTIVE: To reappraise the efficacy and safety of SRS for patients with NFPAs touching/compressing the optic apparatus (OA). METHODS: We studied 27 patients (14 females, 13 males; mean age: 61 [range, 19-85] yr) who underwent SRS between 1998 and 2008 for NFPAs with such condition. The median tumor volume was 4.9 (range, 1.8-50.8) cc. To avoid excess irradiation to the OA, the lower part of the tumor was covered with a 50% or a 60% isodose gradient, ie 49% to 98% (mean, 84%; median, 88%) of the entire tumor received the selected doses. Median doses at the tumor periphery/OA were 7.6/11.0 (interquartile range [IQR], 5.8-9.1/10.1-11.8) Gy. RESULTS: Seven patients (26%) were confirmed to be deceased due to unrelated diseases at a median post-SRS period of 149 (IQR, 83-158) mo. Follow-up magnetic resonance imaging (MRI) showed tumor growth in 2 patients (7%) at the 11th and 134th post-SRS month; the former underwent surgery and the other SRS. Excluding these 2 patients, the latest follow-up MRI examinations, performed 13 to 238 (median: 168, IQR: 120-180) mo after SRS, showed no size changes in 5 (19%) and shrinkage in 20 (74%) patients. Cumulative incidences of tumor growth control were 96.3% and 91.8% at the 120th and 180th post-SRS month. None of our patients developed subjective symptoms suggesting SRS-induced optic neuropathy or endocrinological impairment. CONCLUSION: In patients with NFPAs touching/compressing the OA, SRS achieves good long-term results.

Validity of a Recently Proposed Prognostic Grading Index, Brain Metastasis Velocity, for Patients With Brain Metastasis Undergoing Multiple Radiosurgical Procedures.

PURPOSE: This study of our patients with brain metastasis who underwent multiple stereotactic radiosurgery (SRS) procedures aimed to validate whether the recently proposed prognostic grading system, brain metastasis velocity (BMV), is generally applicable. The BMV scores the cumulative number of new brain metastases that developed after the first SRS divided by time (years) since the initial SRS. Patients were categorized into 3 classes by their BMV scores (ie, ≤3, 4-13, and ≥14). METHODS AND MATERIALS: This retrospective cohort study was approved by the Tokyo Women's Medical University Institutional Review Board (number 1981). We used our prospectively accumulated database, which included 833 patients who underwent a second SRS procedure for newly detected lesions, using a gamma knife, for brain metastases. Patients who had whole-brain radiation therapy were excluded. The procedures took place during the 19-year period between July 1998 and June 2017. Furthermore, among the 833 patients, 250 underwent a third SRS procedure, and 88 had a fourth SRS procedure. RESULTS: The median survival times (MSTs) after the second SRS were 12.9 months (95% confidence interval [CI], 10.2-17.1) for the BMV group with a score of ≤3; 7.5 months (CI, 6.5-9.0) for the group scoring 4 to 13, and 5.1 months (CI, 4.0-5.6) for the group scoring ≥14 (P = .0001). The corresponding MSTs after the third SRS were 13.2 months (95% CI, 9.1-21.6), 8.0 months (CI, 6.2-11.2), and 5.7 months (CI, 4.8-7.8; P = .0001). Respective MSTs after the fourth SRS were 13.2 months (95% CI, 9.1-21.6), 8.0 months (CI, 6.2-11.2), and 5.7 months (CI, 4.8-7.8; P < .0001). The mean BMV score of patients with small cell lung cancer, 24.8, was significantly higher than that of patients with non-small cell lung cancer, 17.7 (P = .032). CONCLUSIONS: Our present results support the validity of BMV for predicting survival not only after the second SRS but also after the third and fourth SRS.

Three-stage Gamma Knife treatment for metastatic brain tumors larger than 10 cm3: a 2-institute study including re-analyses of earlier results using competing risk analysis.

OBJECTIVEThe results of 3-stage Gamma Knife treatment (3-st-GK-Tx) for relatively large brain metastases have previously been reported for a series of patients in Chiba, Japan (referred to in this study as the C-series). In the current study, the authors reappraised, using a competing risk analysis, the efficacy and safety of 3-st-GK-Tx by comparing their experience with that of the C-series.METHODSThis was a retrospective cohort study. Among 1767 patients undergoing GK radiosurgery for brain metastases at Mito Gamma House during the 2005-2015 period, 78 (34 female, 44 male; mean age 65 years, range 35-86 years) whose largest tumor was > 10 cm3, treated with 3-st-GK-Tx, were studied (referred to in this study as the M-series). The target volumes were covered with a 50% isodose gradient and irradiated with a peripheral dose of 10 Gy at each procedure. The interval between procedures was 2 weeks. Because competing risk analysis had not been employed in the published C-series, the authors reanalyzed the previously published data using this method.RESULTSThe overall median survival time after 3-st-GK-Tx was 8.3 months (95% CI 5.6-12.0 months) in the M-series and 8.6 months (95% CI 5.5-10.6 months) in the C-series (p = 0.41). Actuarial survival rates at the 6th and 12th post-3-st-GK-Tx months were, respectively, 55.1% and 35.2% in the M-series and 62.5% and 26.4% in the C-series (HR 1.175, 95% CI 0.790-1.728, p = 0.42). Cumulative incidences at the 12th post-3-st-GK-Tx, determined by competing risk analyses, of neurological deterioration (14.2% in C-series vs 12.8% in M-series), neurological death (7.2% vs 7.7%), local recurrence (4.8% vs 6.2%), repeat SRS (25.9% vs 18.0%), and SRS-related complications (2.3% vs 5.1%) did not differ significantly between the 2 series.CONCLUSIONSThere were no significant differences in post-3-st-GK-Tx results between the 2 series in terms of overall survival times, neurological death, maintained neurological status, local control, repeat SRS, and SRS-related complications. The previously published results (C-series) are considered to be validated by the M-series results.

Prognostic grading system specifically for elderly patients with brain metastases after stereotactic radiosurgery: a 2-institution study.

OBJECTIVEWith the aging of the population, increasing numbers of elderly patients with brain metastasis (BM) are undergoing stereotactic radiosurgery (SRS). Among recently reported prognostic grading indexes, only the basic score for brain metastases (BSBM) is applicable to patients 65 years or older. However, the major weakness of this system is that no BM-related factors are graded. This prompted the authors to develop a new grading system, the elderly-specific (ES)-BSBM.METHODSFor this IRB-approved, retrospective cohort study, the authors used their prospectively accumulated database comprising 3267 consecutive patients undergoing Gamma Knife SRS for BMs during the 1998-2016 period at the Mito GammaHouse. Among these 3267 patients, 1789 patients ≥ 65 years of age were studied (Yamamoto series [Y-series]). Another series of 1785 patients ≥ 65 years of age in whom Serizawa and colleagues performed Gamma Knife SRS during the same period (Serizawa series [S-series]) was used for validity testing of the ES-BSBM.RESULTSTwo factors were identified as strongly impacting longer survival after SRS by means of multivariable analysis using the Cox proportional hazard model with a stepwise selection procedure. These factors are the number of tumors (solitary vs multiple: HR 1.450, 95% CI 1.299-1.621; p < 0.0001) and cumulative tumor volume (≤ 15 cm3 vs > 15 cm3: HR 1.311, 95% CI 1.078-1.593; p = 0.0067). The new index is the addition of scores 0 and 1 for these 2 factors to the BSBM. The ES-BSBM system is based on categorization into 3 classes by adding these 2 scores to those of the original BSBM. Each ES-BSBM category has 2 possible scores. For the category ES-BSBM 4-5, the score is either 4 or 5; for ES-BSBM 2-3, the score is either 2 or 3; and for ES-BSBM 0-1, the score is either 0 or 1. In the Y-series, the median survival times (MSTs, months) after SRS were 17.5 (95% CI 15.4-19.3) in ES-BSBM 4-5, 6.9 (95% CI 6.4-7.4) in ES-BSBM 2-3, and 2.8 (95% CI 2.5-3.6) in ES-BSBM 0-1 (p < 0.0001). Also, in the S-series, MSTs were, respectively, 20.4 (95% CI 17.2-23.4), 7.9 (95% CI 7.4-8.5), and 3.2 (95% CI 2.8-3.6) (p < 0.0001). The ES-BSBM system was shown to be applicable to patients with all primary tumor types as well as to those 80 years or older.CONCLUSIONSThe authors found that the addition of the number of tumors and cumulative tumor volume as scoring factors to the BSBM system significantly improved the prognostic value of this index. The present study is strengthened by testing the ES-BSBM in a different patient group.

A novel method to determine the natural course of unruptured brain arteriovenous malformations without the need for follow-up information.

OBJECTIVEThere is a strong clinical need to accurately determine the average annual hemorrhage risk in unruptured brain arteriovenous malformations (AVMs). This need motivated the present initiative to use data from a uniquely large patient population and design a novel methodology to achieve a risk determination with unprecedented accuracy. The authors also aimed to determine the impact of sex, pregnancy, AVM volume, and location on the risk for AVM rupture.METHODSThe present study does not consider any specific management of the AVMs, but only uses the age distribution for the first hemorrhage, the shape of which becomes universal for a sufficiently large set of patients. For this purpose, the authors collected observations, including age at first hemorrhage and AVM size and location, in 3425 patients. The average annual risk for hemorrhage could then be determined from the simple relation that the number of patients with their first hemorrhage at a specific age equals the risk for hemorrhage times the number of patients at risk at that age. For a subset of the patients, the information regarding occurrence of AVM hemorrhage after treatment of the first hemorrhage was used for further analysis of the influence on risk from AVM location and pregnancy.RESULTSThe age distribution for the first AVM hemorrhage was used to determine the average annual risk for hemorrhage in unruptured AVMs at adult ages (25-60 years). It was concluded to be 3.1% ± 0.2% and unrelated to AVM volume but influenced by its location, with the highest risk for centrally located AVMs. The hemorrhage risk was found to be significantly higher for females in their fertile years.CONCLUSIONSThe present methodology allowed the authors to determine the average annual risk for the first AVM hemorrhage at 3.1% ± 0.2% without the need for individual patient follow-up. This methodology has potential also for other similar types of investigations. The conclusion that centrally located AVMs carry a higher risk was confirmed by follow-up information. Follow-up information was also used to conclude that pregnancy causes a substantially greater AVM hemorrhage risk. The age distribution for AVM hemorrhage is incompatible with AVMs present at birth having the same hemorrhage risk as AVMs in adults. Plausibly, they instead develop in the early years of life, possibly with a lower hemorrhage risk during that time period.

Clinical significance of conformity index and gradient index in patients undergoing stereotactic radiosurgery for a single metastatic tumor.

OBJECTIVEAlthough the conformity index (CI) and the gradient index (GI), which were proposed by Paddick and colleagues, are both logically considered to correlate with good posttreatment results after stereotactic radiosurgery (SRS), this hypothesis has not been confirmed clinically. The authors' aim was to reappraise whether high CI values correlate with reduced tumor progression rates, and whether low GI values correlate with reduced complication incidences.METHODSThis was an institutional review board-approved, retrospective cohort study conducted using a prospectively accumulated database including 3271 patients who underwent Gamma Knife SRS for brain metastases (BMs) during the 1998-2016 period. Among the 3271 patients, 925 with a single BM at the time of SRS (335 women and 590 men, mean age 66 [range 24-93] years) were studied. The mean/median CIs were 0.62/0.66 (interquartile range [IQR] 0.53-0.74, range 0.08-0.88) and the mean/median GIs were 3.20/3.09 (IQR 2.83-3.39, range 2.27-11.4).RESULTSSRS-related complications occurred in 38 patients (4.1%), with a median post-SRS interval of 11.5 (IQR 6.0-25.8, maximum 118.0) months. Cumulative incidences of post-SRS complications determined by a competing risk analysis were 2.2%, 3.2%, 3.6%, 3.8%, and 3.9% at the 12th, 24th, 36th, 48th, and 60th post-SRS month, respectively. Multivariable analyses showed that only two clinical factors (i.e., peripheral doses and brain volume receiving ≥ 12 Gy) correlated with complication rates. However, neither CIs nor GIs impacted the incidences of complications. Among the 925 patients, post-SRS MRI was performed at least once in 716 of them, who were thus eligible for local progression evaluation. Among these 716 patients, local progression was confirmed in 96 (13.4%), with a median post-SRS interval of 10.8 (IQR 6.7-19.5, maximum 59.8) months. Cumulative incidences of local progression determined by a competing risk analysis were 7.7%, 12.6%, 14.2%, 14.8%, and 15.3% at the 12th, 24th, 36th, 48th, and 60th post-SRS month, respectively. Multivariable analyses showed neurological symptoms, extracerebral metastases, repeat SRS, and CIs to correlate with incidences of local progression, whereas GIs had no impact on local tumor progression. Particularly, cumulative incidences of local progression were significantly lower in patients with CIs < 0.65 than in those with CIs ≥ 0.65 (adjusted hazard ratio 1.870, 95% confidence interval 1.299-2.843; p = 0.0034).CONCLUSIONSTo the authors' knowledge, this is the first analysis to focus on the clinical significance of CI and GI based on a large series of patients with BM. Contrary to the majority opinion that dose planning with higher CI and lower GI results in good post-SRS outcomes (i.e., low local progression rates and minimal complications), this study clearly showed that the lower the CIs were, the lower the local progression rates were, and that the GI did not impact complication rates.

Complications after stereotactic radiosurgery for brain metastases: Incidences, correlating factors, treatments and outcomes.

BACKGROUND AND PURPOSE: Complications after stereotactic radiosurgery (SRS) for brain metastases (BMs) were analyzed in detail using our database including nearly 3000 BM patients. MATERIALS AND METHODS: This was an institutional review board-approved, retrospective cohort study using our prospectively accumulated database including 3271 consecutive patients who underwent gamma knife SRS for BMs during the 1998-2016 period. Excluding four patients lost to follow-up, 112 with three-staged treatment and 189 with post-operative irradiation, 2966 who underwent a single-session of SRS only as radical irradiation were studied. RESULTS: The overall median survival time after SRS was 7.8 (95% CI; 7.4-8.1) months. Post-SRS complications occurred in 86 patients (2.9%) 1.9-211.4 (median; 24.0, IQR; 12.0-64.6) months after treatment. RTOG neurotoxicity grades were 2, 3 and 4 in 58, 25 and 3 patients, respectively. Cumulative incidences determined with a competing risk analysis were 1.4%, 2.2%, 2.4%, 2.6% and 2.9% at the 12th, 24th, 36th, 48th and 60th post-SRS month, respectively. Among various pre-SRS clinical factors and radiosurgical parameters, multivariable analyses demonstrated solitary tumor (Adjusted HR; 0.584, 95% CI; 0.381-0.894, p = 0.0133), controlled primary cancer (Adjusted HR; 2.595, 95% CI; 1.646-4.091, p < 0.0001), no extra-cerebral metastases (Adjusted HR; 1.608, 95% CI; 1.028-2.514, p = 0.0374), KPS ≥80% (Adjusted HR; 2.715, 95% CI; 1.245-5.924, p = 0.0121) and largest tumor volume ≥3.3 cc (Adjusted HR; 0.516, 95% CI; 0.318-0.836, p = 0.0072) to be independently significant predictors of a higher incidence of complications. CONCLUSION: The post-SRS complication incidence is acceptably low (2.9%). Meticulous long-term follow-up after SRS is crucial for all patients.