Clinical Practice Guideline for Stroke Rehabilitation in Korea 2016

“Clinical Practice Guideline for Stroke Rehabilitation in Korea 2016” is the 3rd edition of clinical practice guideline (CPG) for stroke rehabilitation in Korea, which updates the 2nd edition published in 2014. Forty-two specialists in stroke rehabilitation from 21 universities and 4 rehabilitation hospitals and 4 consultants participated in this update. The purpose of this CPG is to provide optimum practical guidelines for stroke rehabilitation teams to make a decision when they manage stroke patients and ultimately, to help stroke patients obtain maximal functional recovery and return to the society. The recent two CPGs from Canada (2015) and USA (2016) and articles that were published following the 2nd edition were used to develop this 3rd edition of CPG for stroke rehabilitation in Korea. The chosen articles' level of evidence and grade of recommendation were decided by the criteria of Scotland (2010) and the formal consensus was derived by the nominal group technique. The levels of evidence range from 1++ to 4 and the grades of recommendation range from A to D. Good Practice Point was recommended as best practice based on the clinical experience of the guideline developmental group. The draft of the developed CPG was reviewed by the experts group in the public hearings and then revised. “Clinical Practice Guideline for Stroke Rehabilitation in Korea 2016” consists of ‘Chapter 1; Introduction of Stroke Rehabilitation’, ‘Chapter 2; Rehabilitation for Stroke Syndrome, ‘Chapter 3; Rehabilitation for Returning to the Society’, and ‘Chapter 4; Advanced Technique for Stroke Rehabilitation’. “Clinical Practice Guideline for Stroke Rehabilitation in Korea 2016” will provide direction and standardization for acute, subacute and chronic stroke rehabilitation in Korea.

Clinical Analysis of Intracranial Hemangiopericytoma

OBJECTIVE: Intracranial hemangiopericytomas (HPCs) are rare tumors with aggressive behavior, including local recurrence and distant metastasis. We conducted this retrospective study to evaluate the efficacy of grossly total resection and adjuvant radiotherapy (RT) for these tumors. METHODS: A total of 13 patients treated for intracranial HPC from January 1995 through May 2013 were included in this retrospective study. We analyzed the clinical presentations, radiologic appearances, treatment results, and follow-up outcomes, as well as reviewed other studies. RESULTS: The ages of the patients at the time of diagnosis ranged from 26 to 73 years (mean : 48 years). The majority of the patients were male (92.3%), and the majority of the tumors were located in the parasagittal and falx. The ratio of intracranial HPCs to meningiomas was 13 : 598 in same period, or 2.2%. Seven patients (53.8%) had anaplastic HPCs. Nine patients (69.2%) underwent gross total tumor resection in the first operation without mortality. Eleven patients (84.6%) underwent postoperative adjuvant RT. Follow-up period ranged from 13 to 185 months (mean : 54.3 months). The local recurrence rate was 46.2% (6/13), and there were no distant metastases. The 10-year survival rate after initial surgery was 83.9%. The initial mean Karnofsky performance scale (KPS) was 70.8 and the final mean KPS was 64.6. CONCLUSION: Gross total tumor resection upon initial surgery is very important. We believe that adjuvant RT is helpful even with maximal tumor resection. Molecular biologic analyses and chemotherapy studies are required to achieve better outcomes in recurrent intracranial HPCs.

De Novo Aneurysm after Treatment of Glioblastoma

A rare case of spontaneous subarachnoid hemorrhage from newly developed cerebral aneurysm in glioblastoma patient is presented. A 57-year-old man was presented with headache and memory impairment. On the magnetic resonance image and the magnetic resonance angiography, a large enhancing mass was found at right frontal subcortex and intracranial aneurysm was not found. The mass was removed subtotally and revealed as glioblastoma. He took concurrent PCV chemotherapy and radiation therapy, but the mass recurred one month later after radiotherapy. He was then treated with temozolomide for 7 cycles. Three months after the completion of temozolomide therapy, he suffered from a subarachnoid hemorrhage due to a rupture of a small de novo aneurysm at distal anterior cerebral artery. He underwent an aneurysm clipping and discharged without neurologic complication.

Imaging of Distal Dural Ring Plane and Paraclinoid Internal Carotid Artery Aneurysms with 3D Rotational Angiography / 신경중재치료의학

PURPOSE: The distal dural ring (DDR) plane separates the intradural from extradural paraclinoid internal carotid artery (ICA) aneurysm. The purpose of this study was to evaluate the feasibility of the localization of the DDR plane drawn by the bony landmarks in patients with paraclinoid ICA aneurysms at 3D rotational angiography (3DRA). MATERIALS AND METHODS: 13 consecutive patients who underwent a 3DRA for the evaluation of 16 paraclinoid ICA aneurysms were reviewed retrospectively. On a dedicated workstation, multiplanar reconstruction (MPR) image along the virtual plane of DDR was reconstructed from the mask run image of 3DRA. Three bony landmarks were used to locate virtual plane of DDR: tuberculum sellae, inferior root of anterior clinoid process (ACP) and supero-medial aspect of optic strut. The MPR image was fused with 3D volume-rendered reconstruction image. Medial and posterior inclination angle of virtual plane of DDR was measured. The location of the paraclinoid ICA aneurysm was categorized into indradural, transdural, and extradural. RESULTS: In all cases, the DDR plane was identified and the relationship between the DDR plane and the paraclinoid ICA aneurysm was successfully determined on fusion image of 3DRA mask and contrast runs by dual volume visualization. The aneurysm locations determined with 3DRA were 8 intradural, 6 transdural and 2 extradural. The medial and posterior inclination angles of DDR plane ranged at 8 to 43degrees(mean 17.4degrees), and -2 to 20degrees(mean 6.4degrees), respectively. CONCLUSION: Localization of the paraclinoid ICA aneurysm in relation to the virtual plane of DDR is feasible with 3DRA and dual volume visualization.

In vivo Tracking of Transplanted Bone Marrow-Derived Mesenchymal Stem Cells in a Murine Model of Stroke by Bioluminescence Imaging

OBJECTIVE: This study was designed to validate the cell trafficking efficiency of the in vivo bioluminescence image (BLI) study in the setting of transplantation of the luciferase expressing bone marrow-derived mesenchymal stem cells (BMSC), which were delivered at each different time after transient middle cerebral artery occlusion (MCAO) in a mouse model. METHODS: Transplanting donor BMSC were prepared by primary cell culture from transgenic mouse expressing luciferase (LUC). Transient focal infarcts were induced in 4-6-week-old male nude mice. The experiment mice were divided into five groups by the time of MSC transplantation : 1) sham-operation group, 2) 2-h group, 3) 1-day group, 4) 3-day group, and 5) 1- week group. BLI for detection of spatial distribution of transplanted MSC was performed by detecting emitted photons. Migration of the transplanted cells to the infarcted area was confirmed by histological examinations. Differences between groups were evaluated by paired t-test. RESULTS: A focal spot of bioluminescence was observed at the injection site on the next day after transplantation by signal intensity of bioluminescence. After 4 weeks, the mean signal intensities of 2-h, 1-day, 3-day, and 1-week group were 2.6x10(7) +/- 7.4x10(6), 6.1x10(6) +/- 1.2x10(6), 1.7x10(6) +/- 4.4x10(5), and 8.9x10(6) +/- 9.5x10(5), respectively. The 2-h group showed significantly higher signal intensity (p < 0.01). The engrafted BMSC showed around the infarct border zones on immunohistochemical examination. The counts of LUC-positive cells revealed the highest number in the 2-h group, in agreement with the results of BLI experiments (p < 0.01). CONCLUSION: In this study, the results suggested that the transplanted BMSC migrated to the infarct border zone in BLI study and the higher signal intensity of LUC-positive cells seen in 2 hrs after MSC transplantation in MCAO mouse model. In addition, noninvasive imaging in real time is an ideal method for tracking stem cell transplantation. This method can be widely applied to various research fields of cell transplantation therapy.

Contrast-Enhanced Magnetic Resonance Angiography for Evaluation of the Steno-occlusive Disease of the Supraaortic Arteries: Comparison with Computed Tomography Angiography and Digital Subtraction Angiography

PURPOSE: To intra-individually compare diagnostic accuracy of high-resolution contrast-enhanced magnetic resonance angiography (CE-MRA) with computed tomography angiography (CTA) and digital subtraction angiography (DSA) for the assessment of supraaortic steno-occlusive disease. MATERIALS AND METHODS: Twenty-eight patients (20 men, 8 women, 53-79 years of age) underwent supraaortic CE-MRA, CTA and DSA. CE-MRA was performed on two 1.5T MR scanners (voxel dimension: 0.66x0.66x1.1 or 1.2 mm3), and CTA on 64-slice CT scanners (voxel dimension: 0.42x0.42x0.63 mm3). All the three examinations were completed within 40 days (median 19 days; range 1-40 days). Retrospective evaluation and measurement of diameter of 6 extracranial and 9 intracranial arterial segments was done by 2 experienced radiologists. RESULTS: A total of 420 arterial segments were examined by CE-MRA, CTA and DSA. On DSA, 34 stenoocclusive lesions were noted at extracranial (n=19) and intracranial (n=15) vessels. For extracranial stenosis greater than 70%, sensitivity, specificity, positive predictive value (PPV) and negative predictive values (NPV) were 94.7%, 98.7%, 90.0% and 99.3% on CE-MRA, and 94.7%, 99.3%, 94.7% and 99.3% on CTA. For intracranial stenosis greater than 50%, sensitivity, specificity, PPV and NPV were 93.3%, 98.3%, 77.8%and 99.6% on CE-MRA, and 86.7%, 97.9%, 72.2% and 99.1% on CTA, with DSA as the standard of reference. CONCLUSION: Supraaortic CE-MRA is as reliable as CTA in depicting the arterial stenosis, and is effective in screening of significant stenosis of both extracranial and intracranial arterial stenosis.

Pituitary Apoplexy Producing Internal Carotid Artery Compression: A Case Report

We report a case of pituitary apoplexy resulting in right internal carotid artery occlusion accompanied by hemiplegia and lethargy. A 43-yr-old man presented with a sudden onset of severe headache, visual disturbance and left hemiplegia. Investigations revealed a nodular mass, located in the sella and suprasellar portion and accompanied by compression of the optic chiasm. The mass compressed the bilateral cavernous sinuses, resulting in the obliteration of the cavernous portion of the right internal carotid artery. A border zone infarct in the right fronto-parietal region was found. Transsphenoidal tumor decompression following conservative therapy with fluid replacement and steroids was performed. Pathological examination revealed an almost completely infarcted pituitary adenoma. The patient's vision improved immediately after the decompression, and the motor weakness improved to grade IV+ within six months after the operation. Pituitary apoplexy resulting in internal carotid artery occlusion is rare. However, clinicians should be aware of the possibility and the appropriate management of such an occurrence.

Seizures in Patients with Brain Tumors

OBJECTIVES: To determine the presentation, incidence, and risk factors of seizures in patients treated for brain tumors. METHODS: One hundred patients who consecutively underwent a craniotomy for the treatment of supratentorial brain tumors were assessed. The pathologies of the patients enrolled in the study included glioma (n=56), meningioma (n=31), metastatic brain tumor (n=7), primary central nervous system lymphoma (n=4), and central neurocytoma (n=2). Anti-epileptic drugs (AEDs) were administered to all patients for up to six months after the surgery. Pre-defined variables for outcome analysis included tumor grade and location, extent of tumor resection, number of seizures, age at tumor diagnosis, adjuvant therapy, medication and radiological abnormalities. RESULTS: Thirty patients (30%) presented at least a single episode of seizure at the time of admission. Five of these patients (16.7%) developed the seizure during the follow-up period. Newly developed seizure was noticed in six out of seventy patients (8.6%) without prior seizure. Histopathology was malignant gliomas in 10 and supratentorial meningioma in one. Early seizure developed only in two patients. CONCLUSION: Compared with patients without seizure, patients with seizure at the time of admission showed younger age (p=0.003), a higher portion of low-grade glioma (p=0.001), tumor location in the frontal and temporal lobes (p=0.003) and cortical involvement (p=0.017). Our study suggestes that tumor progression is considered a significant risk factor for seizure development in glioma patients.

Tethered Cord Syndrome ; Surgical Indication, Technique and Outcome

OBJECTIVE: The authors tried to reveal some unique features of lipomeningomyelocele (LMMC), including clinical presentation, factors precipitating onset of symptoms, pathologic entities of LMMC associated with tethered cord syndrome, and surgical outcome in LMMC patients. METHODS: Seventy-five patients with LMMC were enrolled in this study. Neuro-imaging and intraoperative findings allowed classification of LMMC into three Types. The patients were divided into two groups by age : A (51 patients), from birth to 3 years, and B (24 patients), from 3 to 24 years. For prevention of retethering of the cord, a mega-dural sac rebuilding procedure was performed in 15 patients. RESULTS: During a mean postoperative follow-up period of 4 years, the surgical outcome was satisfactory in terms of improved pain and motor weakness, but disappointing with reference to the resolution of bowel and bladder dysfunction. Among these 75 patients with LMMC, preoperative deficits were improved after surgery in 29 (39%), remained stable in 28 (37%), changed slightly in 13 (17%), and worsened in 5 (7%). Patients in group A achieved better outcomes than those in group B. Depending on the type of lesion, patients with types I and II LMMC have better outcomes than those with type III LMMC. Finally, retethering of the cord with neurological deterioration occurred in 4 (5.3%) of the 75 patients, but no retethering was found in the 15 patients who were recently treated with a mega-dural sac rebuilding procedure. CONCLUSION: Our data continue to support the opinion that early diagnosis and optimal surgery are still essential for the treatment of patients with LMMC, since there is a high likelihood of residual neurological functions that can be preserved. Based on our surgical experience of untethering and decompression of lipomas, a mega-dural sac repair is useful to prevent retethering of the cord.

Temozolomide Chemotherapy in Patients with Recurrent Malignant Gliomas

Numerous studies have demonstrated the clinical activity of temozolomide, a second-generation alkylating agent, against malignant brain tumors, however, its activity has not been reported in an Asian population. This study analyzed the efficacy and toxicity of temozolomide in 25 adult patients with recurrent or progressive malignant gliomas after surgery and standard radiation therapy with or without chemotherapy, enrolled in our institution since July 2000. Sixteen patients had glioblastoma multiforme (GBM), six with anaplastic astrocytoma, and three with anaplastic oligodendroglioma. Of the 25 patients, 3 (12%) achieved a complete response (CR), 8 (32%) achieved a partial response (PR), 6 (24%) had stable disease (SD), and 8 (32%) had progressive disease (PD). Two patients achieved a CR, 4 patients achieved a PR, 3 patients had SD and 7 patients had PD in GBM, and 1 patient achieved a CR, 4 patients achieved a PR, 3 patients had SD, 1 patient had PD in the non-GBM patients. Median progression free survival was 8 weeks in GBM and 22 weeks in the non-GBM patients. The median overall survival of each group was 17 weeks and 28 weeks. Temozolomide demonstrated moderate activity in recurrent and progressive malignant gliomas without serious toxicity.

Unusual Clinical Course of Giant Vertebral Artery Aneurysm after Proximal Artery Embolization: Case Report / 대한뇌혈관외과학회지

The authors present the case of a patient who suffered from cerebellar dysfunction, radiographically documented brainstem compression, and neurological deterioration after proximal artery occlusion in a giant vertebral artery aneurysm. Symptom resolution was achieved after complete embolization of remained lumen of aneurysm. The cause of neurological deterioration is brainstem compression due to mass effect of the aneurysm. In order to avoid this fatal complication, it is necessary to determine appropriate therapy for the vertebral artery giant aneurysm by evaluating cerebral blood flow and other factors about growth of aneurysm.

Traumatic Carotid-cavernous Fistula with Contralateral Proptosis: Case Report

Traumatic carotid-cavernous fistula frequently results in proptosis on the side of the fistula by retrograde drainage from the cavernous sinus to the superior ophthalmic vein. The involvement of the opposite orbit is due to the presence of connections between the cavernous sinuses on both sides, but exclusive contralateral orbit involvement is rare. We report a case in which the CCF with a contralateral proptosis developed in a 63 year-old man after a motor vehicle accident. MR angiography depicted the markedly dilated left cavernous sinus and left superior ophthalmic vein, sparing the right side. However, angiography showed a direct fistula between the right internal carotid artery and cavernous sinus with exclusive contralateral venous drainage via the intercavernous sinus. A detachable balloon was used to occlude the fistula, and the contralateral orbital symptom regressed.

Surgical Treatment of Middle Cranial Fossa Arachnoid Cyst by Wide Excision and Fenestration

OBJECTIVE: The results of the excision of both outer and inner membranes with fenestration to the basal and parasellar cisterns for symptomatic primary middle cranial fossa arachnoid cysts are presented. METHODS: Twenty-three symptomatic cases of middle cranial fossa arachnoid cyst treated by excision with fenestration from 1993 to 2001 at our hospital were analyzed retrospectively. RESULTS: There was no significant morbidity and mortality after surgery and no recurrence of cyst during the follow-up period(mean 40.8 months). We observed reduction of the cyst with expansion of the surrounding brain and clinical improvement in most of the patients. All cases of type III by Galassi classification, 83% of type II cases and half of type I cases were belonged to the excellent group(reduction of the cyst size over 50% during follow-up period). Seventeen cases(74%) were belonged to the excellent group and 6 cases(26%) were the good group(reduction of the cyst size under 50% during follow-up period). CONCLUSION: The results of this study suggest that the excision and fenestration procedure may be considered as the primary shunt-independent procedure in patients with symptomatic middle cranial fossa arachnoid cyst.

Botulinum Toxin A for Spasmodic Torticollis, Hemifacial Spasm and Facial Synkinesis

Botulinum toxin type A(BTA) is well known treatment agent in the treatment of paralytic strabismus in ophthalmological field for more than 15 years. Its therapeutic potential as temporary paralyzing agent was adopted to treat several neurologic, movement disorders. In recent years, BTA is considered as initial medical treatment option in such as blepharospasm, hemifacial spasm, spasmodic torticollis, spasmodic dysphonia. Authors applied BTA injection in cases with spasmosmodic torticollis, hemifacial spasm, facial synkinesis and experienced staisfactory result. So authors present our experience of BTA injection therapy and discuss techniques, advantages and disavantages.

Clinical Analysis of Spontaneous Intracranial Hypotension

OBJECTIVE: Spontaneous intracranial hypotension(SIH) is a rare condition presented with cardinal postural headache and low CSF pressure. The authors describe the characteristic clinical features, imaging findings, and treatment methods in the patients with spontaneous intracranial hypotension. METHODS: Between May 1994 and Aug. 2001, eight patients were diagnosed with spontaneous intracranial hypotension based on characteristic radiologic and clinical findings in our department. All cases were shown diffuse meningeal enhancement(DME) on magnetic resonance(MR) image. Two cases had subdural hematoma. RESULTS: The most characteristic feature on Brain MR image is DME with/without subdural fluid collection. Radionuclide image reveals direct leaking point and rapid appearance of urinary bladder activity. Direct leaking points were detected in all four cases who performed radioisotope study. Autologous epidural blood patches were applied to four cases, and all of them were improved without complication. Among four patients treated with conservative method, three were improved, but one patient was died of spontaneous chronic subdural hematoma. CONCLUSION: We suggest that 1) meticulous studies need to be performed aggressively if SIH is diagnosed clinically and radiologically, 2) the most effective study may be radioisotope study, and 3) if leaking point is found, aggressive management such as autologous epidural blood patches is recommended.

Percutaneous Vertebroplasty with Polymethymethacrylate in the Treatment of Osteoporotic Vertebral Body Compression Fractures: Preliminary Report

No abstract available.

Potentials and limitations of adenovirus-p53 gene therapy for brain tumors

We investigated the antineoplastic potentials of recombinant adenovirus containing wild-type p53 cDNA (Ad5CMV-p53) for malignant gliomas. In four human glioma cell lines (U-251 and LG expressing endogenous mutant p53, and U-87 and EFC-2 expressing wild-type p53) and two rat glioma cell lines (9L and C6, each expressing mutant and wild-type p53), gene transfer efficiency determined by X-gal staining and Western blotting was varied (10-99% at 10-500 multiplicity of infection, MOI). Growth inhibitory effect was drastic (>90% at 100 MOI) in U-251 cells and only moderate or minimal in other cell lines harboring wild-type p53 or low gene transfer efficiency. Ex vivo transduction of U-251 cells with Ad5CMV-p53 suppressed the in vivo tumorigenicity of the cells. Histopathologic examination for Ad5CMV-p53 toxicity to rat brains showed inflammatory reactions in half of the tested brains at 10(8) MOI. U-251 cells were inoculated intracerebrally in nude mice and injected Ad5CMV-p53 into the tumor, in which neither the tumor suppression nor the survival benefit was observed. In conclusion, heterogeneity of the cellular subpopulations of malignant glioma in p53 status, variable and insufficient gene delivery to tumor, and adenoviral toxicity to brain at higher doses may be limiting factors to be solved in developing adenovirus-p53 gene therapy for malignant gliomas.

Potentials and limitations of adenovirus-p53 gene therapy for brain tumors

We investigated the antineoplastic potentials of recombinant adenovirus containing wild-type p53 cDNA (Ad5CMV-p53) for malignant gliomas. In four human glioma cell lines (U-251 and LG expressing endogenous mutant p53, and U-87 and EFC-2 expressing wild-type p53) and two rat glioma cell lines (9L and C6, each expressing mutant and wild-type p53), gene transfer efficiency determined by X-gal staining and Western blotting was varied (10-99% at 10-500 multiplicity of infection, MOI). Growth inhibitory effect was drastic (>90% at 100 MOI) in U-251 cells and only moderate or minimal in other cell lines harboring wild-type p53 or low gene transfer efficiency. Ex vivo transduction of U-251 cells with Ad5CMV-p53 suppressed the in vivo tumorigenicity of the cells. Histopathologic examination for Ad5CMV-p53 toxicity to rat brains showed inflammatory reactions in half of the tested brains at 10(8) MOI. U-251 cells were inoculated intracerebrally in nude mice and injected Ad5CMV-p53 into the tumor, in which neither the tumor suppression nor the survival benefit was observed. In conclusion, heterogeneity of the cellular subpopulations of malignant glioma in p53 status, variable and insufficient gene delivery to tumor, and adenoviral toxicity to brain at higher doses may be limiting factors to be solved in developing adenovirus-p53 gene therapy for malignant gliomas.

Stereotactic Craniotomy and Trans-Sulcal Approach for Small Subcortical Lesions

OBJECTIVE: It is difficult to localize accurately the small mass lesions seen in CT, MRI images in the operating field, espacially in the subcortical location. To minimize possible neurologic deficit for intraprenchymal exploration, the stereotactic technique is essential. Authors evaluated the stereotactic craniotomy and transsulcal approach in localizing various small subcortical mass lesions. METHOD: For last 3 years, stereotactic craniotomy was done in 7 patients in our institute. They were 1 cysticercosis, 1 cavernous hemangioma, 1 inflammatory sclerosis, 3 tuberculous granulomas, 1 metastatic tumor. They were all subcortical location and associated with mass effect. According to locations, four of them were located in the somatosensory cortex, 1 in supplementary frontal cortex, 1 in temporal cortex, 1 in parietal cortex. After application of stereotactic frame, the patients were transferred to CT/MR unit for target localization. Multiple target points were obtained from images and the patient were taken to the operating room. Scalp incisions and bone flaps were designed with physical placement method with stereotactic probe. After dural opening, the subcortical mass was traced with stereotactic probe. Transgyral approaches were used in 4 patients and transculcal approach in 3 patients under the stereotactic guidance. RESULTS: Small craniotomy with accurate localization was possible without difficulty in all cases. Furthermore there was no need for intraparenchymal exploration to localize the subcortical mass. There was no operative mortality, 1 patient developed transient hemiparesis lasting 3 weeks. No other patient showed neurologic deficit. CONCLUSION: Stereotactic craniotomy and localization seems to be helpful for removal of small subcortical masses. small craniotomy with accurate localization was possible. In the eloquent areas, transsulcal approach seems to be particularly useful to prevent possible neurologic sequele.

Two Cases of Multiple Hemangioblastomas in a Von Hippel-Lindau Family

Hemangioblastoma is uncommon, accounting for 1 to 2.5% of all primary neoplasms of the central nervous system. Ten to 20% of hemangioblastomas occur as part of Von Hippel-Lindau disease(VHL). Multiple hemangioblastomas are seen only with VHL and these are seen in up to half of VHL-associated hemangioblastomas. We have treated two cases of multiple hemangioblastomas associated with VHL disease in a family, sister(case I, 48/female) and her brother(case II, 41/male). Both patients had renal and pancreatic cysts in addition to CNS hemangioblastomas. Their hemangioblastomas were removed totally, and then their neurological symptoms had Improved. With a review of the literature, the authors present a family of VHL-associated multiple hemangioblastomas.