Ipsilateral simultaneous multiple hypertensive intracerebral hemorrhages: Analysis of hematoma formation and comparison with distribution of hypertensive mixed-type hematoma.

A 55-year-old Japanese woman with a history of hypertension and right putaminal hemorrhage developed simultaneous hemorrhages in the left thalamus and putamen and died 24 h later. There were no vascular anomalies in the brain. Synaptophysin immunostaining combined with eosin azure 50 (EA50) staining clearly identified the hematoma and the surrounding brain structures. In the right cerebral hemisphere, a cystic lesion as a sequela of the usual type of hypertensive putaminal hematoma was evident. In the left cerebral hemisphere, two fresh hematomas were evident. One was a thalamic hematoma, which had destroyed the dorsal and medial structures of the thalamus, and the other was an unusual putaminal hematoma, which had destroyed the entire putamen and crossed the internal capsule and caudate nucleus. α-Smooth muscle actin immunostaining combined with EA50 and Victoria bleu staining demonstrated three ruptured arteries associated with fibrin aggregates in the anterior thalamic nucleus and anterior putamen. Some circular structures composed of fibrin, suggesting the presence of ruptured arteries in the neighborhood, were evident in the thalamus and putamen. In the putamen, ruptured arteries and circular structures were present in the lateral to medial areas. Fibrin aggregates in the anterior thalamic nucleus were more numerous than those in the putamen. On the basis of these findings, we concluded that: (i) the artery with numerous fibrin aggregates in the anterior thalamic nucleus had ruptured first, followed by the arteries distributed in other parts of the thalamus and putamen; (ii) the unusual putaminal hematoma was attributable to rupture of the arteries around the center of the putamen, which are not responsible for the usual type of hypertensive putaminal hematoma; and (iii) it is suggested that even if hypertensive hemorrhage occurs simultaneously in the ipsilateral putamen and thalamus, the usual type of hypertensive mixed-type hematoma does not form.

Traumatic cervical vertebral artery dissection: A case with cerebral infarct due to newly formed thrombus in the cerebral arteries.

We report a 50-year-old man who developed fatal brainstem infarction five days after traumatic cervical vertebral artery dissection (CVAD). Autopsy revealed multiple fresh infarcts in the territory of the vertebrobasilar system. No thrombus was found in the infarct lesions. The cervical vertebral artery (CVA) showed severe atherosclerotic stenosis extending to the proximal half of the left side, similar stenosis at the origin on the right side, fresh thrombotic occlusion extending to the proximal half of the right side, and multiple dissections in the distal foraminal segments on both sides. In the distal half of the basilar artery (BA) and the origin of the right posterior cerebral artery (PCA), the lumen was extensively filled with fresh thrombus. Although an intricate mixture of white and red thrombi filled the lumen at the origin of the right PCA, the white thrombus gradually appeared at the periphery whereas the red thrombus occupied the central and more proximal part of the BA. We confirm that cerebral infarction associated with CVAD is due not only to emboli originating from the dislodged thrombus at sites of arterial dissection, as reported previously, but also to newly formed thrombus in the cerebral arteries caused by impaired blood flow, as was seen in the present case.

Immunohistochemical analysis of intrasulcal hematoma due to cerebral amyloid angiopathy in a brain-dead patient.

Neuropathological examinations of the brain in cases of brain death are usually insufficient because of autolysis. We examined a case of sporadic-type cerebral amyloid angiopathy-related hemorrhage (sCAA-H) in a 74-year-old Japanese woman who had been clinically established as brain dead 7 days before cardiac arrest. The brain was macerated, and a huge hematoma was evident in the right parieto-occipital region. Ordinary neuropathological examination was unable to clarify where the hematoma was located in the brain parenchyma or the subarachnoid space (SAS). Immunohistochemistry for amyloid-ß (Aß) and synaptophysin revealed that: (i) the hematoma affected the cerebral sulcus, cerebral cortex (CC) and subcortical white matter; (ii) the CC was destroyed at the depth of the cerebral sulcus; (iii) in three 6-µm-thick sections, ruptured Aß-positive vessels were seen only in the intrasulcal hematoma and not in the CC or intracerebral hematoma; and (iv) in the CC adjacent to the intrasulcal hematoma, a few macrophages were observed, indicating a fresh infarct of the CC. These findings indicate that sCAA-H occurred first in the cerebral sulcus due to rupture of multiple meningeal vessels, as had been documented in our previous reports. The present study shows that even in an autolytic dead brain, immunohistochemistry is more useful than ordinary staining methods. Other than double-barreled vessels, several vascular changes such as fibrinoid degeneration, segmental dilatation (so-called micro-aneurysmal dilatation), and hyalinous onion-like change of the intima were seen in the intrasulcal hematoma, SAS and CC. Interestingly these vascular changes were not observed in the ruptured Aß-positive vessels. More detailed studies will be needed to examine the correlation between these vascular changes and vessel rupture.

Cerebral amyloid angiopathy initially occurs in the meningeal vessels.

To clarify the frequency of CAA in the brain parenchyma and subarachnoid space (SAS), we counted sections of blood vessels showing positive staining for Aß in the SAS, cerebral cortex (CC) and cerebral white matter (WM) using paraffin-embedded sections of the frontal, temporal and occipital lobes. The specimens had been taken for routine neuropathological examination from the brains of 105 Japanese patients (aged 40-95 years) selected from among 200 consecutive patients autopsied between 1989 and 2015 at our hospital. We examined the anatomical ratios of blood-vessel sections in the SAS relative to the CC in three selected CAA cases, and those of Aß-positive blood-vessel sections in CAA cases. CAA was found in 53 of the 105 cases (50.5%), and the youngest patient affected was a 51-year-old man. The incidence of CAA increased with age. The anatomical ratio of blood vessel sections in the SAS relative to the CC was 1/3.70-1/4.37 (mean: 1/3.94). The ordinary CAA group, in which CAA was seen in both the SAS and CC, included 41 cases (77.4%). In 37 of these cases, the SAS/CC ratio of Aß-positive blood vessels was 1/0.05-1/0.66 (mean: 1/0.26), and in the other four cases the ratio was 1/1-1/1.5. In the ordinary CAA group, the SAS/CC ratio of Aß-positive blood vessels was smaller than the anatomical ratio. The meningeal CAA group, in which CAA was found only in the SAS, included 12 cases (22.6%). These patients ranged in age from their fifties to their nineties. There was no case in which CAA was limited only to the CC. We concluded that CAA initially develops in the meningeal blood vessels, and not in the cortical blood vessels. CAA in the WM was seen in 10 cases, not only in nine cases that were severe, but also in a mild case.

The clinical application of optimized AT(N) classification in Alzheimer's clinical syndrome (ACS) and non-ACS conditions.

We aimed to assess the utility of AT(N) classification in clinical practice. We measured the cerebrospinal fluid levels of amyloid-ß (Aß) 42, Aß40, phosphorylated tau, total tau, and neurofilament light chain (NfL) in samples from 230 patients with Alzheimer's clinical syndrome (ACS) and 328 patients with non-ACS. The concordance of two A-markers (i.e., Aß42 alone and the Aß42/Aß40 ratio) was not significantly different between the ACS (87.4%) and non-ACS (74.1%) groups. However, the frequency of discordant cases with AAß42-alone+/AAß-ratio- was significantly higher in the non-ACS (23.8%) than in the ACS group (7.4%). The concordance of two N-markers (i.e., total tau and NfL) was 40.4% in the ACS group and 24.4% in the non-ACS group. In the ACS samples, the frequency of biological Alzheimer's disease (i.e., A+T+) in Ntau+ cases was 95% while that in NNfL+ cases was 65%. Reflecting Aß deposition and neurodegeneration more accurately, we recommend the use of AT(N) classification defined by cerebrospinal fluid AAß-ratioTNNfL in clinical practice.

The hemorrhage caused by sporadic-type cerebral amyloid angiopathy occurs primarily in the cerebral sulci.

We examined a solitary hematoma in a patient with sporadic cerebral amyloid angiopathy (CAA). The hematoma affected the middle frontal sulcus, cerebral cortex (CC) and subcortical frontal white matter (sfWM). We embedded the hematoma in four paraffin blocks, each of which was cut serially into 6-µm-thick sections. The first section and every 18th section from each block were subjected to Elastica-Goldner (E-G) staining, and the distribution and diameter of the ruptured blood vessels (rBVs) were examined. The rBVs were then marked on diagrams representing each E-G-stained section. The present study yielded the following important findings: (i), early- and recently ruptured Aß-positive arteries were present mainly in the intrasulcal hematoma (ISH), rather than in the CC; (ii) many early-ruptured arteries in the ISH were larger in diameter than those in the CC; and (iii) ruptures of the cortical arteries, even near the cortical surface, did not occur so frequently and the ruptured vessels were small in size. We concluded that in patients with subcortical hematoma caused by sporadic-type CAA, successive rupturse of the meningeal vessels, mainly arteries, occur in the cerebral sulcus initially, followed by formation of an ISH and development of a fresh hemorrhagic or anemic infarct in the CC surrounding the ISH, the latter in most cases then extending into the brain parenchyma through the necrotic CC at the depth of the sulcus, finally creating a secondary hematoma in the subcortical white matter.

Complex arteriovenous fistulas at C1 causing hematomyelia through aneurysmal rupture of a feeder from the anterior spinal artery.

A 64-year-old woman presented with left occipital headache and right dissociated sensory loss due to hematomyelia on the left ventral side of C1 caused by rupture of an aneurysm on one of the feeders extending from the anterior spinal artery to complex epidural or dural and intradural arteriovenous fistulas (AVFs). Branches from the left occipital and ascending pharyngeal arteries and those from the left C2 radicular, left posterior spinal and anterior spinal arteries formed these multiple shunts, linking with a common venous drain flowing into the right petrosal vein. Surgical interception of all the shunts was achieved, making it unnecessary to directly treat the aneurysm in the spinal cord. The feeders, aneurysm and AVFs were not visualized on postoperative angiography, and the patient returned to a normal working life.

The impact of target positioning error and tumor size on radiobiological parameters in robotic stereotactic radiosurgery for metastatic brain tumors.

This study aimed to evaluate the effect of target positioning error (TPE) on radiobiological parameters, such as tumor control probability (TCP) and normal tissue complication probability (NTCP), in stereotactic radiosurgery (SRS) for metastatic brain tumors of different sizes using CyberKnife. The reference SRS plans were created using the circular cone of the CyberKnife for each spherical gross tumor volume (GTV) with diameters (φ) of 5, 7.5, 10, 15, and 20 mm, contoured on computed tomography images of the head phantom. Subsequently, plans involving TPE were created by shifting the beam center by 0.1-2.0 mm in three dimensions relative to the reference plans using the same beam arrangements. Conformity index (CI), generalized equivalent uniform dose (gEUD)-based TCP, and NTCP of estimated brain necrosis were evaluated for each plan. When the gEUD parameter "a" was set to - 10, the CI and TCP for the reference plan at the φ5-mm GTV were 0.90 and 80.8%, respectively. The corresponding values for plans involving TPE of 0.5-mm, 1.0-mm, and 2.0-mm were 0.62 and 77.4%, 0.40 and 62.9%, and 0.12 and 7.2%, respectively. In contrast, the NTCP for all GTVs were the same. The TCP for the plans involving a TPE of 2-mm was 7.2% and 68.8% at the φ5-mm and φ20-mm GTV, respectively. The TPEs corresponding to a TCP reduction rate of 3% at the φ5-mm and φ20-mm GTV were 0.41 and 0.99 mm, respectively. TPE had a significant effect on TCP in SRS for metastatic brain tumors using CyberKnife, particularly for small GTVs.

Radiobiological evaluation considering the treatment time with stereotactic radiosurgery for brain metastases.

Objective: We evaluated the radiobiological effect of the irradiation time with the interruption time of stereotactic radiosurgery (SRS) using CyberKnife® (CK) systemfor brain metastases. Methods: We used the DICOM data and irradiation log file of the 10 patients with brain metastases from non-small-cell lung cancer (NSCLC) who underwent brain SRS. We defined the treatment time as the sum of the dose-delivery time and the interruption time during irradiations, and we used a microdosimetric kinetic model (MKM) to evaluate the radiobiological effects of the treatment time. The biological parameters, i.e. α0, ß0, and the DNA repair constant rate (a + c), were acquired from NCI-H460 cell for the MKM. We calculated the radiobiological dose for the gross tumor volume (GTVbio) to evaluate the treatment time's effect compared with no treatment time as a reference. The D95 (%) and the Radiation Therapy Oncology Group conformity index (RCI) and Paddick conformity index (PCI) were calculated as dosimetric indices. We used several DNA repair constant rates (a + c) (0.46, 1.0, and 2.0) to assess the radiobiological effect by varying the DNA repair date (a + c) values. Results: The mean values of D95 (%), RCI, and PCI for GTVbio were 98.8%, 0.90, and 0.80, respectively, and decreased with increasing treatment time. The mean values of D95 (%), RCI, and PCI of GTVbio at 2.0 (a+c) value were 94.9%, 0.71, and 0.49, respectively. Conclusion: The radiobiological effect of the treatment time on tumors was accurately evaluated with brain SRS using CK. Advances in knowledge: There has been no published investigation of the radiobiological impact of the longer treatment time with multiple interruptions of SRS using a CK on the target dose distribution in a comparison with the use of a linac. Radiobiological dose assessment that takes into account treatment time in the physical dose in this study may allow more accurate dose assessment in SRS for metastatic brain tumors using CK.

Salvage therapy and late neurotoxicity in patients with recurrent primary CNS lymphoma treated with a modified ProMACE-MOPP hybrid regimen.

We report the efficacy of salvage therapy with a modified ProMACE-MOPP combined with radiation in patients with primary central nervous system lymphoma (PCNSL). Thirty-two immunocompetent patients were treated with a regimen of pirarubicin, cyclophosphamide, etoposide, vincristin, and methotrexate (MTX: 500 mg/m(2)) administered in 21-day cycles. Patients received 20 Gy of whole-brain radiotherapy after three cycles of chemotherapy. A single cycle of chemotherapy was repeated every four months for two years. Nine patients with CNS relapse were retreated with additional cycles of the ProMACE-MOPP hybrid regimen with a 90% objective response rate. Median complete response (CR) duration was 13.2 months and median survival time (MST) for the nine patients treated after initial relapse was 30 months. One of 17 patients (5.8%) who had less than 20 Gy of whole brain irradiation developed dementia. In contrast, six of seven (85.7%) patients who had more than 30 Gy of whole brain radiotherapy became demented. Maintaining a moderate dose of MTX, while adding chemotherapeutic agents and 20 Gy of whole brain radiation therapy, improved disease control and overall survival and lowered the incidence of delayed neurologic toxicity in patients with PCNSL. Additional treatment with a ProMACE-MOPP hybrid regimen is still effective for relapsed disease.

Clinicopathological study of diffuse type brainstem gliomas: analysis of 40 autopsy cases.

Diffuse type brainstem glioma is one of the most malignant types of brain tumors and the prognosis is extremely poor. The proliferative potential of these tumors is presumed to be very high, but there is little information about the cell kinetics of brainstem glioma because surgical resection is rarely performed. The histological grade, tumor spread, growth potential, and prognosis were evaluated in 40 autopsy cases of diffuse type brainstem glioma. To quantify the growth potentials of individual tumors, the proliferating cell indices of Ki-67 (MIB-1) and proliferating cell nuclear antigen (PCNA) monoclonal antibodies were measured. Mean MIB-1 and PCNA proliferating cell indices were 20.4% (24 cases) and 37.0% (28 cases), respectively, in 34 glioblastomas. The median survival time was 40 weeks in 22 treated patients. The mean PCNA proliferating cell index was 10.8% in four of five anaplastic astrocytomas and the median survival time in four treated patients was 91 weeks. The MIB-1 and PCNA proliferating cell indices of one astrocytoma were 2.9% and 20.3%, respectively, and the survival time was 56 weeks. The overall median survival time was 32 weeks. There was a significant difference in PCNA proliferating cell indices between glioblastomas and anaplastic astrocytomas (p < 0.05) and there was a significant difference in survival time between glioblastomas (40 weeks) and anaplastic astrocytomas plus astrocytoma (74 weeks) among the treated patients (p < 0.05). Supratentorial extension was more frequent in glioblastomas than in anaplastic astrocytomas (p < 0.05). Our results suggest that the majority of diffuse type brainstem gliomas are glioblastoma and the proliferative potential is probably as high as that of adult supratentorial glioblastoma. Supratentorial extension and dissemination are relatively frequent in the advanced stage. Anaplastic astrocytoma or astrocytoma is rarer and less infiltrative and proliferative, and carries a slightly better prognosis than glioblastoma.

Giant cell reparative granuloma of the temporal bone: neuroradiological and immunohistochemical findings.

A 38-year-old man presented with a giant cell reparative granuloma (GCRG) of the left temporal bone. Computed tomography showed a osteolytic middle cranial mass lesion. Magnetic resonance (MR) imaging showed the lesion as low intensity with heterogeneous enhancement by gadolinium on the T1-weighted images, and extremely low intensity on the T2-weighted images. Angiography showed the lesion as highly vascular and fed by branches of the left external carotid artery. After preoperative embolization, gross total removal of the tumor was performed. The postoperative course was uneventful and no evidence of recurrence has been found for more than 4 years. Histological examination revealed GCRG with multinucleated giant cells in the fibrous background, abundant collagen bundles, hemosiderin deposits, and trabeculae of reactive bone. Some of the mononuclear stromal cells and almost all of the giant cells were positive for CD68, suggesting histiocytic differentiation. These histological features reflect the marked decrease in signal intensity on T2-weighted MR images.

High cervical arteriovenous fistulas fed by dural and spinal arteries and draining into a single medullary vein: report of 3 cases.

OBJECT: The authors previously reported a case of complex arteriovenous fistula (AVF) at C-1 with multiple dural and spinal feeders that were linked with a common medullary venous channel. The purpose of the present study was to collect similar cases and analyze their angioarchitecture to gain a better understanding of this malformation. METHODS: Three such cases, affecting 2 males and 1 female in their 60s who had presented with hematomyelia (2) or progressive myelopathy (1), were treated surgically, and the operative findings from all 3 cases were compared using digital subtraction angiography (DSA) to determine the angioarchitecture. RESULTS: The C-1 and C-2 radicular arteries and anterior and posterior spinal arteries supplied feeders to a single medullary draining vein in various combinations and via various routes. The drainage veins ran along the affected ventral nerve roots and lay ventral to the spinal cord. The sites of shunting to the vein were multiple: dural, along the ventral nerve root in the subarachnoid space, and on the spinal cord, showing a vascular structure typical of dural AVF, that is, a direct arteriovenous shunt near the spinal root sleeve fed by one or more dural arteries and ending in a single draining vein, except for intradural shunts fed by feeders from the spinal arteries. In 2 cases with hemorrhagic onset the drainer flowed rostrally, and in 1 case associated with congestive myelopathy the drainer flowed both rostrally and caudally. Preoperative determination of the shunt sites and feeding arteries was difficult because of complex recruitment of the feeders and multiple shunt sites. The angioarchitecture in these cases was clarified postoperatively by meticulous comparison of the DSA images and operative video. Direct surgical intervention led to a favorable outcome in all 3 cases. CONCLUSIONS: A high cervical complex AVF has unique angioarchitectural characteristics different from those seen in the other spinal regions.

Usefulness of acceleration time for internal carotid artery origin stenosis.

Calcification of the internal carotid artery (ICA) hinders accurate evaluation of the stenosis by conventional ultrasonography due to acoustic shadow. We examined the relationship between acceleration time (AcT) and ICA origin stenosis. One hundred thrity seven samples (266 vessels) that enforced duplex ultrasonography in our hospital were targeted. The results have shown that there is a significant relationship between AcT and stenosis. AcT of more than 110 msec suggests that the stenosis is more than 60% by the North American Symptomatic Carotid Endarterectomy Trial (NASCET) method. AcT is thought to be useful for the diagnosis of ICA stenosis with calcification. (English Translation of J Jpn Coll Angiol 2011; 51: 365-371).

[Dissociated sensory loss caused by acupuncture injury to the cervical spinal cord].

A 31-year-old woman developed dissociated sensory loss below the right C-3 dermatome within an hour after acupuncture therapy for the left posterior neck pain. Moxa has been applied on the top of the acupuncture needle: Moxa needle. T2-weighted MR images on the following day showed a high-signal cord lesion at the C1/2 level on the left. After 10 days, the MRI lesion became clear; it involved the left lateral spinothalamic tract and the lateral corticospinal tract; however, her muscle strength and deep tendon reflexes were normal. The C1/2 focus reduced slightly 2 months after the accident, and the sensory impairment was localized below the Th7 dermatome. It was suggested that the cervical cord lesion was caused by the direct insertion of and thermal injury by the Moxa needle.

Modified ProMACE-MOPP hybrid regimen with moderate-dose methotrexate for patients with primary CNS lymphoma.

The object of this study was to assess the estimation of 2- and 5-year overall survival and tumor response and the frequency and severity of treatment morbidity with a modified ProMACE-MOPP hybrid protocol in patients with primary CNS lymphoma (PCNSL). Thirty-two immunocompetent patients were treated with a regimen of pirarubicin, cyclophosphamide, etoposide, vincristine, and methotrexate (500 mg/m(2)) administered in 21-day cycles. Intraventricular 10 mg of methotrexate was given for eight cycles once a week. Patients received 20 Gy of whole brain radiotherapy after three cycles of chemotherapy. A single cycle of chemotherapy was repeated every 4 months for 2 years. Older patients (aged >60) received a reduced dose of chemotherapeutic agents. Eighteen patients were followed up with neuroimaging and neuropsychological assessments for evidence of CNS toxicity. Sixteen patients completed the regimen as planned. The response rate was 87.5% after the initial chemoradiotherapy. The cumulative survival and progression-free survival rates at 5 years were 56 and 31%, respectively. The median survival time was 68 months. The median progression-free survival time was 39 months. Toxicity included grade 3 or 4 leukopenia in 33% of the cycles administered. There were eight grade 3 or 4 pulmonary toxicities. There were three deaths during chemotherapy: one as a result of sepsis and two of pneumonitis. Three patients (25%) experienced delayed neurologic toxicity while on the complete regimen. Maintaining the dose of methotrexate while adding chemotherapeutic agents improved disease control and overall survival in patients with PCNSL, but early toxicity and delayed neurotoxicity are still a risk of this approach.

Subcortical hematoma caused by cerebral amyloid angiopathy: does the first evidence of hemorrhage occur in the subarachnoid space?

Six autopsy cases of subcortical hematoma caused by CAA were examined to elucidate the primary site of hemorrhage. Immunohistochemistry for amyloid beta-protein (A beta) revealed extensive CAA in the intrasulcal meningeal vessels rather than in the cerebral cortical vessels. All of the examined cases had multiple hematomas in the subarachnoid space, mainly in the cerebral sulci, as well as intracerebral hematomas. Each intracerebral hematoma was connected to the subarachnoid hematomas at the depth of cerebral sulci or through the lateral side of the cortex. There was no debris of the cerebral cortical tissue in the subarachnoid hematomas. In case 2, another solitary subarachnoid hematoma, which was not connected to any intracerebral hematoma, was seen. In all of these subarachnoid hematomas, many ruptured A beta-immunopositive arteries were observed. These ruptured arteries did not accompany any debris of the brain tissue, some of them were large in diameter (250-300 microm), and several of them were far from the cerebral cortex. Therefore, it was considered that they were not cortical arteries but meningeal arteries. Within the cerebral cortex, there were only a few ruptured arteries associated with small hemorrhages. There were no ruptured vessels within the intracerebral hematomas. There was a strong suggestion that all of the subarachnoid hematomas, including the solitary one in case 2, originated from the rupture of the meningeal arteries. The present study indicates that in some cases of subcortical hematoma caused by CAA, the primary hemorrhage occurs in the subarachnoid space, in particular the cerebral sulci, because of rupture of multiple meningeal arteries. Infarction occurs subsequently in the cortex around the hematoma, the hematoma penetrates into the brain parenchyma, and finally, a subcortical hematoma is formed.