Vera van Velthoven

The impact of molecular genetic analysis of the VHL gene in patients with haemangioblastomas of the central nervous system

OBJECTIVES Haemangioblastoma of the CNS occurs as a sporadic entity and as a manifestation of the autosomal dominant von Hippel-Lindau disease with the major additional components retinal angioma, renal cancer, and pheochromocytoma. Genetic testing for germline mutations predisposing to von Hippel-Lindau disease has been available since identification of the VHL tumour suppressor gene. The impact of this testing was evaluated in patients with haemangioblastomas seen in this centre. METHODS A register and database of patients with symptomatic haemangioblastomas for the last 15 years was evaluated. The VHL gene was analysed by the SSCP method for all exons and Southern blotting for mutations and deletions of the gene. RESULTS 141 patients with haemangioblastoma of the CNS were registered. In 81 patients (57%) there was a disease predisposing germline mutation including eight novel mutations. Population related calculation of patients from the administrative district of Freiburg disclosedVHL germline mutations in 22% of the patients with haemangioblastoma. Analysis of mutation carriers for clinical information suggestive of the syndrome showed (1) a positive family history of a brain tumour in 50%, (2) a history for the patient of extracranial manifestations in 36% (retinal angioma 30%, pheochromocytoma 6%), and (3) 19% presenting with multiple brain tumours when first admitted. By genetic testing of haemangioblastoma patients without any indications of von Hippel-Lindau disease mutation carriers were identified in 14%. Sensitivity of VHL germline testing was 86%. CONCLUSIONS DNA analysis for VHL germline mutations is clearly superior to clinical information in the diagnosis of von Hippel-Lindau disease. Although the percentage of von Hippel-Lindau disease associated haemangioblastoma decreases after the fourth decade of life and is infrequent in patients without other symptomatic lesions and a negative family history, it is recommended that every patient with CNS haemangioblastoma should be screened for von Hippel-Lindau disease germline mutations. This provides the key information and enables screening for extraneurological tumours of the patients and investigations of the patient′s family to ameliorate management of von Hippel-Lindau disease.

The Brain Tumor Board: Lessons to Be Learned from an Interdisciplinary Conference

Background: The aim of this study is to analyze the work of the interdisciplinary Brain Tumor Board (BTB) which was established at Freiburg University Hospital in 1998. Patients and Methods: From January 1998 to December 2003, a total of 1,516 patients were discussed in 259 meetings of the BTB. The protocols of the BTB were analyzed retrospectively. Results: In 79% of the patients, the diagnosis was based on histological findings or a typical radiological appearance of a lesion, or both. This group was composed of 4 subgroups: 28% benign skull base tumors (19% meningiomas, 4% pituitary adenomas, 3% acoustic schwannomas, 2% others), 24% primary brain tumors of glial origin (8% glioblastomas, 12% gliomas other than glioblastomas, 5% oligoastrocytomas or oligodendrogliomas), 19% brain metastases, and 8% other brain or skull base tumors. In 13% of the cases, the exact diagnosis was still unknown when the patient was presented. 8% of the presentations were motivated by nontumorous interdisciplinary problems (e.g. arterio-venous malformations). The recommendations given by the BTB included: 23% further diagnostic procedures (11% non-invasive examinations, 12% stereotactic biopsies), 57% active antitumoral therapy (22% resection, 17% fractionated radiotherapy, 13% radiosurgery, 5% chemotherapy, <1% embolization), 20% no treatment (14% watchful waiting, 6% supportive care). 91% of the BTB recommendations were realized within 3 months. Conclusion: Interdisciplinary care seems to be particularly necessary in patients with benign skull base tumors, gliomas and brain metastases. Decisions made in a small interdisciplinary group of experts have a high potential of subsequently being realized.

Seizure and cognitive outcomes of epilepsy surgery in infancy and early childhood

AIMS To investigate seizure and developmental outcomes following epilepsy surgery in very young children and determine their predictive factors. METHODS We retrospectively reviewed the clinical data, surgical variables, and outcomes of 30 children under 3 years of age that underwent resection for refractory focal epilepsy in our institution in 2001-2011. RESULTS Seizure onset was in the first year of life in 27 (90%) cases and mean age at surgery was 20 months (range 5-33.6). Pathology consisted of cortical malformations in 24 (80%) cases, glioneuronal tumour and infarction with or without cortical dysplasia in three (10%) cases each. Morbidity was comparable with older paediatric cohorts. At 1-11.6 year follow-up (mean 4.1) 21 of 30 (70%) children achieved seizure freedom (Engel I), six (20%) demonstrated worthwhile improvement (Engel II/III) and three (10%) did not benefit from surgery (Engel IV). Intralobar lesionectomy more often resulted in seizure freedom than multilobar or hemispheric surgery. The abundance of non-regional interictal and ictal EEG findings did not preclude seizure freedom. Presurgical developmental impairment was established in 25 of 28 (89%) children; its severity correlated with longer epilepsy duration and determined postoperative developmental outcome. Developmental progress was established in 26 out of 28 (93%) children following surgery, showing stabilized trajectories rather than catch-up. CONCLUSIONS Resective surgery in very young children is safe and effective in terms of seizure control and developmental progress. Our findings underline the importance of early intervention in order to timely stop seizures and their deleterious effects on the developing brain.

Epilepsy surgery for glioneuronal tumors in childhood: avoid loss of time.

BACKGROUND In contrast to the abundance of seizure outcome reports in epilepsy surgery for glioneuronal tumors in childhood and adolescence, there is a dearth of information regarding cognitive outcomes. OBJECTIVE To investigate the seizure and cognitive outcome of children and adolescents that underwent resective surgery for glioneuronal tumor-associated refractory epilepsy and determine their predictive factors. METHODS We retrospectively analyzed the presurgical findings, resection types, and outcomes over 1.3 to 12.3 years (mean, 7.3) of 29 consecutive patients, who underwent resection in 2000 to 2011. The mean age at epilepsy onset was 7.9 years (range, 0-15.4), the mean age at surgery was 11.7 years (range, 2.6-17.3), and the mean epilepsy duration to surgery was 3.8 years (range, 0.3-15.3). Etiology comprised 13 dysembryoplastic neuroepithelial tumors and 16 gangliogliomas, with additional focal cortical dysplasia in 5 cases. RESULTS Eighty-six percent of children were seizure free 12 months after surgery; at final follow-up, 76% remained seizure free and 62% had discontinued antiepileptic drugs. Gross total resection was related to significantly higher rates of seizure freedom. Higher presurgical cognitive functioning (full-scale IQ, verbal IQ) was related to shorter epilepsy duration to surgery independent of age at epilepsy onset, thus determining postsurgical functioning. Improvements in verbal IQ, performance IQ, and visual memory as well as a trend toward improvement in full-scale IQ were established after surgery. Despite individual losses in full-scale IQ, verbal or visual memory, no deterioration was noted in any cognitive variable on a group level. CONCLUSION Completeness of resection predisposes to favorable outcomes regarding seizure alleviation. Whereas cognitive functioning deteriorates with time in glioneuronal tumor-related refractory epilepsy, surgery is linked to improvement rather than to deterioration on a group level.

Seizure control and developmental trajectories after hemispherotomy for refractory epilepsy in childhood and adolescence

To evaluate the seizure control and developmental outcomes after hemispherotomy for refractory epilepsy in childhood and to identify their predictive factors.

VHL c.505 T>C mutation confers a high age related penetrance but no increased overall mortality

BACKGROUND Germline mutations of the VHL gene cause von Hippel-Lindau syndrome (VHL). In southern Germany, a specific mutation in this gene, c.505 T>C, is one of the most frequent alterations owing to a founder effect. METHODS This study was conducted to evaluate morbidity, specific clinical risk profile, and mortality among a series of VHL c.505 T/C mutation carriers. A total of 125 eligible subjects carryingVHL c.505 T/C underwent ophthalmoscopy and gadolinium enhanced magnetic resonance imaging of the brain, the spinal cord, and the abdomen. Age related penetrance, morbidity, and mortality were assessed. RESULTS Frequently observed lesions were phaeochromocytoma (47%), retinal angiomas (36%), haemangioblastoma of the spine (36%), and haemangioblastoma of the brain (16%). Four patients developed renal cell carcinoma. VHL was symptomatic in 47% of subjects; 30% were asymptomatic despite the presence of at least one VHL related tumour and 23% of the carriers had no detectable VHL lesion. Of the 19 patients who had died (15%), 10 died of symptomatic VHL lesions. Overall penetrance by cumulative incidence functions is estimated at 48% by 35 years and 88% by 70 years. In contrast to the only existing published report based on patients with presumably unselected VHLgermline mutations, the mortality rate for c.505 T/C mutation carriers is comparable to that of the general population of Germany. CONCLUSIONS Our results are an important example that a specific genotype, at least in the case ofVHL c.505 T/C, can favourably impact on mortality despite a high age related penetrance. Our study also indirectly provides objective data which might be useful to the life and health insurance industry; it would appear that c.505 T>C mutation positive subjects have similar disease specific mortality to that of the general population owing to a combination of phenotype and timely detection of mutation carrier status followed by aggressive clinical screening and, if necessary, treatment.

Reoperation for refractory epilepsy in childhood: a second chance for selected patients.

BACKGROUND Reoperations account for >10% in pediatric epilepsy surgery cohorts, and they are especially relevant in young children with catastrophic epilepsy. OBJECTIVE To determine surgical outcomes and their predictive factors in reoperations for refractory epilepsy in childhood. METHODS We retrospectively analyzed presurgical findings, resections, and outcomes of 23 consecutive children who underwent reoperations from 2000 to 2011. RESULTS Etiology included cortical dysplasia with/without glioneuronal tumor in 19 patients (83%), sole glioneuronal tumor in 2, and tuberous sclerosis and Rasmussen encephalitis in 1 each. The reasons for the failure of the initial surgery were functional considerations in 8 (35%), incorrect delineation of the epileptogenic zone in 8 (35%), and resection not performed as initially planned in 7 (30%) cases. Final procedures included 8 (35%) intralobar, 8 (35%) multilobar resections, and 7 (30%) hemispherotomies. Following reoperations, 14 (61%) patients were seizure free, 6 (26%) showed significant or worthwhile improvement, and 3 (13%) did not respond to surgery. Six of 8 patients who underwent the first resection before the age of 3 years, 6 of 8 whose first resection was limited by functional considerations, and all 7 with hemispherotomy as the final resection achieved seizure freedom after reoperation. CONCLUSION Reoperation is particularly beneficial for selected children with refractory epilepsy associated with cortical dysplasia that did not respond to an initial limited and/or early resection but achieved seizure freedom after extensive procedures. When indicated, reoperation should be performed at the youngest possible age to profit from higher functional plasticity in compensating for neurological deficit.

Characterization of hemangioblastomas of spinal nerves

OBJECTIVE:Hemangioblastoma is classified as a benign tumor of the central nervous system. Peripheral nervous system hemangioblastomas to date have been described only in a few case reports. Experience in treating patients with these rare lesions, which harbor diagnostic and therapeutic pitfalls, is limited. METHODS:To characterize these lesions better, we reviewed our hemangioblastoma database for patients who underwent surgery for extradural hemangioblastoma of the spinal nerve. RESULTS:Between 1983 and 2003, six patients underwent surgery for spinal nerve hemangioblastomas at our institution. These tumors occurred in 2% of all patients with hemangioblastomas of the central nervous system, or 6% of all patients with spinal hemangioblastomas. The occurrence did not differ in von Hippel-Lindau disease cases versus sporadic cases. Radiographically, the tumors easily could be mistaken for schwannomas or metastases; however, they did have some typical features. If a hemangioblastoma was not suspected primarily, profuse bleeding could complicate surgery. Most of the tumors arose from the dorsal sensory fascicles. The vascular supply was from extradural circulation. In general, the surgical outcome of these lesions was good, and permanent neurological deficit was rare. However, local recurrence was observed in three of six patients. CONCLUSION:These tumors harbor diagnostic and therapeutic pitfalls. In general, the tumors are surgically more challenging, and clinically significant bleeding as well as local tumor recurrence is more common than in intradural hemangioblastomas, mostly because of the frequency of incorrect initial radiographic diagnosis. We suggest that because of the surgical consequences, hemangioblastoma should always be considered to be an important radiological differential diagnosis for nerve sheath tumors. Angiography can bring clarification to ambiguous cases.

Early identification of individuals at high risk for cerebral infarction after aneurysmal subarachnoid hemorrhage: the BEHAVIOR score

Cerebral infarction (CI) is a crucial complication of aneurysmal subarachnoid hemorrhage (SAH) associated with poor clinical outcome. We aimed at developing an early risk score for CI based on clinical characteristics available at the onset of SAH. Out of a database containing 632 consecutive patients with SAH admitted to our institution from January 2005 to December 2012, computed tomography (CT) scans up to day 42 after ictus were evaluated for CIs. Different parameters from admission up to aneurysm treatment were collected with subsequent construction of a risk score. Seven clinical characteristics were independently associated with CI and included in the Risk score (BEHAVIOR Score, 0 to 11 points): Blood on CT scan according to Fisher grade ≥ 3 (1 point), Elderly patients (age ≥ 55 years, 1 point), Hunt&Hess grade ≥ 4 (1 point), Acute hydrocephalus requiring external liquor drainage (1 point), Vasospasm on initial angiogram (3 points), Intracranial pressure elevation > 20 mm Hg (3 points), and treatment of multiple aneurysms (‘Overtreatment’, 1 point). The BEHAVIOR score showed high diagnostic accuracy with respect to the absolute risk for CI (area under curve = 0.806, P < 0.0001) and prediction of poor clinical outcome at discharge (P < 0.0001) and after 6 months (P = 0.0002). Further validation in other SAH cohorts is recommended.

Rupture of a spinal artery aneurysm attributable to exacerbated Sjögren syndrome: case report.

OBJECTIVEPresentation of a patient with acute subarachnoid hemorrhage from a ruptured spinal artery aneurysm attributable to exacerbated Sjögren syndrome. CLINICAL PRESENTATIONA 46-year-old woman with symptoms of exacerbated Sjögren syndrome experienced the acute onset of extreme headache accompanied by nuchal rigidity. INTERVENTIONA computed tomographic scan revealed subarachnoid hemorrhage. Angiography showed an isolated aneurysm of a branch of the right vertebral artery that was a feeding artery of the anterior spinal artery. Neither operative clipping nor endovascular coiling of the aneurysm was reasonable, owing to the high risk of occluding the anterior spinal artery during the intervention. Further diagnostic measures confirmed Sjögren syndrome and revealed cryoglobulinemic vasculitis, membranoproliferative glomerulonephritis with acute renal failure, Hashimoto thyroiditis, and acute hydrocephalus. In the course of conservative treatment, the patient recovered completely from the subarachnoid hemorrhage. One year after treatment with glucocorticoids and immunosuppressive agents, both the aneurysm and the vasculitis could no longer be detected on conventional angiography. CONCLUSIONGenerally, spinal artery aneurysms are exceptionally rare, and few cases of rupture with subsequent subarachnoid hemorrhage have been published. We report on a ruptured spinal aneurysm attributable to Sjögren syndrome–associated cryoglobulinemic vasculitis. Conservative treatment with glucocorticoids and immunosuppressive agents led to resolution of the vasculitic spinal aneurysm.