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 disclosed VHL 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 role of tumor resection in the treatment of glioblastoma multiforme in adults.

BACKGROUND: The therapeutic impact of tumor resection is poorly defined. Therefore the current study was conducted. METHODS: A retrospective, 2-institutional study was conducted (1991-1994) to compare the treatment results of stereotactic biopsy plus radiation therapy (99 patients; tumor dose: 60 gray [Gy]) with those of surgical resection plus radiation therapy (126 patients; tumor dose: 60 Gy). Only adult patients with supratentorial, lobar located, de novo glioblastoma were included. Survival time was analyzed with the Kaplan-Meier method. Prognostic factors were obtained from the multivariate Cox proportional hazards model. RESULTS: Patients were categorized in the Radiation Therapy Oncology Group (RTOG) Classes IV (46 patients), V (157 patients), and VI (22 patients). The resection group and the biopsy group did not differ in terms of age, pretreatment Karnofsky performance status KPS), gender, duration of symptoms, presenting symptoms, tumor location, tumor size, and the frequency of midline shift. Patients in the biopsy group more often were found to have left-sided tumors (P < 0.001). Transient perioperative morbidity and mortality rates were 1% and 1%, respectively, in the biopsy group and 5% and 1.6%, respectively, in the resection group (P > 0.05). The median survival time was 37 weeks for the resection group and 33 weeks for the biopsy group. The difference was not statistically significant (P = 0.09). The most favorable pretreatment prognostic factor was patient age < 60 years (P < 0.01). Tumor resection was highly effective in patients with midline shift (P < 0.01). In patients without midline shift radiation therapy alone was found to be as effective as tumor resection plus radiation therapy (P = 0.5). Patients with midline shift were more likely to have a worse KPS during the course of primary radiation therapy (P < 0.05). CONCLUSIONS: For RTOG Classes IV-VI patients with moderate mass effect of the tumor, radiation therapy alone is a rational treatment strategy. Tumor resection should be performed in patients with pretreatment midline shift whenever possible.

Chronic subdural haematoma--a comparison of two different treatment modalities.

Burr-hole craniotomy (BHC) and closed-system drainage undoubtedly is currently the most accepted treatment offered in chronic subdural haematoma (CSDH). Although twist-drill trephination (TDT) techniques have been available for years, now a special subdural catheter kit has been launched for treatment of CSDH. In a prospective study, 33 patients with 36 CSDH were treated with a 5-mm TDT regimen and insertion of a CORDIS subdural catheter (CORDIS Corp., Miami, USA). The results are compared with a consecutive series of 33 patients treated previously with an 11-mm BHC and closed-system drainage for 40 CSDH: Recurrence and persistence rate of CSDH treated with TDT necessitating a second intervention was 18.1%, no further surgical intervention was necessary. In BHC treated patients, 33.3% of haematomas had to be reoperated on, another 6.0% had to be re-operated on a third time. Infection rate in BHC treated patients was 18.1% as compared with a 0% infection rate in patients treated with the TDT technique. Mortality rate for the BHC method was 9.0% as compared with 6.0% in the TDT treatment regimen. Significantly better clinical results are achieved using the TDT technique with insertion of a special subdural catheter, making this procedure superior to the BHC regimen.

Aspartate, glutamate, glutamine, glycine and gamma-aminobutyric acid in human bioptic neocortical areas: comparison to autoptic tissue.

Amino acid concentrations were determined by high performance liquid chromatography in distinct areas of human neocortex of autoptic and bioptic origin. The concentrations in autoptic tissue were similar in all cortical areas which may be explained by postmortem proteolysis, abolishing regional differences seen in bioptic tissue. Aspartate, glutamate, glycine and gamma-aminobutyric acid concentrations were lower, but glutamine levels were higher, in biopsied than in autopsied tissue. Glycine and gamma-aminobutyric acid concentrations increased with the age of biopsied patients. The differences seen suggest that only amino acid concentrations determined in bioptic tissue may yield a reliable data base for the interpretation of pathological alterations in neocortical biopsies of patients with brain diseases.

Sympathetic nervous system and pain: a clinical reappraisal.

The target article discusses various aspects of the relationship between the sympathetic system and pain. To this end, the patients under study are divided into three groups. In the first group, called "reflex sympathetic dystrophy" (RSD), the syndrome can be characterized by a triad of autonomic, motor, and sensory symptoms, which occur in a distally generalized distribution. The pain is typically felt deeply and diffusely, has an orthostatic component, and is suppressed by the ischemia test. Under those circumstances, the pain is likely to respond to sympatholytic interventions. In a second group, called "sympathetically maintained pain" (SMP) syndrome, the principal symptoms are spontaneous pain, which is felt superficially and has no orthostatic component, and allodynia. These symptoms, typically confined to the zone of a lesioned nerve, may also be relieved by sympathetic blocks. Since the characteristics of the pain differ between RSD and SMP, the underlying kind of sympathetic-sensory coupling may also vary between these cases. A very small third group of patients exhibits symptoms of both RSD and SMP. The dependence or independence of pain on sympathetic function reported in most published studies seems to be questionable because the degree of technical success of the block remains uncertain. Therefore, pain should not be reported as sympathetic function independent until the criteria for a complete sympathetic block have been established and satisfied.

Opioid receptor-mediated control of acetylcholine release in human neocortex tissue.

The effects of various opioid receptor agonists and antagonists on evoked acetylcholine release were studied in slices of human neocortex prelabelled with [3H]-choline, superfused and depolarized electrically (2 min, 3 Hz, 2 ms, 24 mA) or by K+ (20 mM). The delta-opioid receptor agonist DPDPE and the kappa-opioid receptor agonist U50488 reduced the evoked [3H]-overflow (acetylcholine release) in a concentration-dependent fashion; the delta-opioid receptor antagonist naltrindole and the kappa-opioid receptor antagonist norbinaltorphimine, respectively, antagonized these effects. Application of the mu-opioid receptor agonist DAGO also resulted in an inhibition of acetylcholine release; however, both delta- and kappa-opioid receptor antagonists were able to block this effect. The mu-opioid receptor agonists morphine and (+)-nortilidine had no effect. These results indicate that acetylcholine release in human neocortex is inhibited through delta- and kappa-opioid receptors, but not through mu-opioid receptors. Acetylcholine release was significantly increased by the delta-opioid receptor antagonist naltrindole in the presence of a mixture of peptidase inhibitors providing evidence for a delta-opioid receptor-mediated inhibition of acetylcholine release by endogenous enkephalin. K(+)-evoked acetylcholine release in the presence of TTX was inhibited by U50488, but not by DPDPE, suggesting the presence of kappa-opioid receptors on cholinergic terminals and the localization of delta-receptors on cortical interneurons. Therefore, the potent effect of DPDPE on acetylcholine release is likely to be indirect, by modulation of intrinsic cortical neurons. These interneurons probably do not use GABA as neurotransmitter since both GABAA and GABAB receptor agonists (muscimol and baclofen, respectively) were without effect on acetylcholine release.

Deafness due to bilateral endolymphatic sac tumours in a case of von Hippel-Lindau syndrome.

A case of bilateral endolymphatic sac tumours is reported. In a patient with von Hippel-Lindau syndrome, tumour growth in the right cerebellopontine angle caused deafness. The tumour was removed and classified as a metastasis from a thyroid carcinoma. However, on thyroidectomy no primary neoplasm could be found. Eight years later a similar tumour was operated on in the left petrosal bone. Histological appearance, immunocytochemical findings, and the clinical context gave evidence that the tumours had to be reclassified as endolymphatic sac tumours--extremely rare entities. The report supports the hypothesis, suggested by the few earlier case reports, that endolymphatic sac tumours could be one of the inherent tumour manifestations in von Hippel-Lindau syndrome.

Spontaneous otogenic pneumocephalus.

A very rare case of otogenic pneumocephalus in a healthy 24-year-old man with a widely pneumatized right mastoid, precipitated by forceful Valsalva's maneuver, is reported. When a pneumocephalus is suspected, computed tomography scans are mandatory. The pertinent literature is discussed and the potential mechanisms causing spontaneous pneumocephalus are described. To the best of our knowledge, only two other similar cases have been reported up to now.

[Mucoid pseudocyst of the common peroneal nerve. Value of MRI (report of a case)]. / Pseudo-kyste mucoïde du sciatique poplité externe. Intérêt de l'IRM (rapport d'un cas).

The authors report a new case of ganglion cyst of the peroneal nerve. The rarity of this entity induced the authors to report this new case, emphasizing the value of MRI which constitutes a reliable non-invasive examination for the visualization of this lesion.

[Trigeminal neuralgia-how patients experience their condition disease.]. / Trigeminusneuralgie-wie erleben die Patienten ihre Krankheit : Eine Betrachtung Betroffener.

INTRODUCTION: Effective treatment of patients with trigeminal neuralgia is often a long and complicated procedure. The symptoms of trigeminal neuralgia are clearly defined in most cases. Sudden and brief episodes of severe and stabbing pain (tic douloureux) occur, with pain usually starting from a trigger point. Recent reports suggest 80-90% suppression of pain with various treatment regimens, which seems to indicate that the diagnosis and successful treatment of the disorder are no longer a major problem. In fact, however, the intense suffering of patients and isolated reports in the literature suggest that there are still considerable diagnostic difficulties. Patients are referred from one specialist to another, in most cases without the necessary interdisciplinary cooperation, and countless interventions and attempts at therapy not only remain unsuccessful, but may cause serious adverse effects. METHODS: The records of 120 trigeminal neuralgia patients in two different areas of Germany were analysed retrospectively. In addition, the course of the disorder from the initial symptoms up to the institution of effective therapy was documented by means of information obtained from the general practitioner or other physicians. The patients themselves were also interviewed about their history. RESULTS: After a so-called pain career of 51/2 years, each patient had taken an average of 4,000 pills or capsules, 2,500-3,000 of which were carbamazine, lost 1-2 healthy teeth in attempts to treat the painful condition, undergone three or four maxillofacial or ENT operations, or been subjected to exeresis. The result is prolongation and exacerbation of suffering and an apparently hopeless situation. The financial burden on the patients and the health insurance companies is enormous. DISCUSSION: Apparently there is a considerable need for more information about the clinical symptoms, cause, diagnosis and therapy of trigeminal neuralgia, especially as the symptoms are often no longer typical because they have become chronic or are the result of previous treatment. This is needed by all specialists involved, including dentists and general practitioners. In patients in whom clinical criteria suggest the diagnosis of trigeminal neuralgia, drug treatment should be initiated immediately in consultation with the neurologist or neurosurgeon. For cases in which drug treatment fails or resistance to the drug develops surgical treatments are available, such as non-destructive microvascular decompression or thermocoagulation of the gasserian ganglion.

The relation of intracranial pressure B-waves to different sleep stages in patients with suspected normal pressure hydrocephalus.

The interpretation of data from continuous monitoring of intracranial pressure (ICP) in patients with suspected normal pressure hydrocephalus (NPH) is the subject of controversy. Despite the fact that overnight ICP monitoring is widely used for the diagnosis of NPH, normative criteria are poorly defined. The present study demonstrates that there is a relationship between the relative frequency, the absolute amplitude, the wavelength and the morphology of B-waves and different sleep stages. Intraventricular intracranial pressure was recorded continuously overnight in 16 patients with suspected normal pressure hydrocephalus. Simultaneous polysomnography was performed to investigate the relation of spontaneous ICP oscillations to different sleep stages. A correlative analysis was done with the data of 13 patients. Three patients were excluded, one who was awake throughout the night and two in whom polysomnography was incomplete due to technical reasons. The mean resting cerebrospinal fluid (CSF) pressure was 12.87 cm CSF. B-waves were observed in the ICP recordings of all patients. They were present for a mean of 72% of the total recording time. The relative frequency of B-waves was higher during REM sleep and sleep stage 2 as compared to wakefulness (87.8% and 83.2% vs. 56. p < 0.05). The absolute amplitude was higher during REM sleep than in wakefulness (9.56 vs. 3.44 cm CSF, p < 0.05). Wavelengths were longer in REM sleep than in wakefulness and stages 1 and 2 (62.4 vs. 42, 40.7 and 44.8 sec, p < 0.05). The morphology of B-waves was also related to different sleep stages. Ramp-type B-waves were associated with REM sleep in six patients, however, were also present in sleep stage 2 in three of them. Knowledge of the relation of spontaneous ICP oscillations to different sleep stages may help to establish physiological foundations and alterations. Furthermore, polysomnography may be useful to avoid erroneous interpretation of ICP recordings due to sleep stage related variability.

Facial myokymia due to acoustic neurinoma.

The case of a 62-year-old female patient who presented with facial myokymia is reported. The patient had a 13-year history of progressive left-sided hearing loss. In further course, involuntary, wormlike, rippling movements of the left facial muscles developed. Computed tomography revealed a tumor located in the left cerebellopontine angle. Electrophysiologic examinations confirmed the diagnosis of facial myokymia. The tumor, which evolved from the eighth cranial nerve, was totally removed microsurgically. The tumor was histologically verified to be an acoustic neurinoma. Postoperatively, the patient had a facial nerve paralysis, and the facial myokymia was no longer present. The present case provides further evidence that facial myokymia may be triggered by alterations at one of various sites along the course of the motor axons of the facial nerve.

Rapid dedifferentiating meningioma with repeated multifocal recurrences and pulmonary metastases.

A 62-year-old woman presented with a convexity meningioma which, after primary surgery, was histopathologically graded as grade II. There followed three more operations due to repeated rapid local recurrences. After each of these three operations histology revealed dedifferentiated grade III tumors. At third recurrence moreover, other multiple tumor masses in the vicinity of the primary tumor site and in the lung were found. These had the same histological appearance as the local recurrences. The patient died 30 months after primary surgery from respiratory failure due to the multiple lung metastases.

Primary leiomyosarcoma of the spinal leptomeninges.

A case of leiomyosarcoma of the spinal leptomeninges is presented, with clinical, radiological, light microscopic and immunohistochemical data. The probable origin of the tumor from a pluripotent mesenchymal cell is discussed.

Facial myokymia and spastic paretic facial contracture as the result of anaplastic pontocerebellar glioma.

The case of a 36-year-old man who sought treatment of right facial myokymia and spastic paretic facial contracture is reported. Computed tomography and magnetic resonance imaging revealed a tumor located in the right cerebellar peduncle and the right dorsal pons bulging into the fourth ventricle. After microsurgical partial resection of the mass, which was verified histologically as an anaplastic glioma, facial myokymia initially ceased. The vermicular rippling movements were less intense upon recurrence and could be controlled by low-dose dexamethasone in the further course, when magnetic resonance imaging showed an interstitial pontine edema after percutaneous radiation therapy. It is assumed that facial myokymia and spastic paretic facial contracture were generated by ectopic activity due to alterations in the microenvironment at the intrapontine portion of the axons of the seventh nerve caused by the compressive effect of the tumor and later by edema.

Surgical resection and radiation therapy versus biopsy and radiation therapy in the treatment of glioblastoma multiforme.

There has been considerable controversy over the concept of treating glioblastoma multiforme with cytoreductive surgery. Therefore, a retrospective study of cases treated between 1986 and 1991 was conducted to analyze and compare the results of stereotactic biopsy followed by radiation therapy performed in 58 patients with those of surgical resection plus radiation therapy in 57 patients. In both groups, conventionally fractionated radiation (1.7 to 2.0 Gy/day) was delivered, with a total dose of 50 to 60 Gy. Biopsy was performed only in patients with tumors judged to be inoperable. These patients carried a higher surgical risk and were in worse neurological condition than the patients in the resection group. The median survival time for the resection group was 39.5 weeks, as compared with 32 weeks for the biopsy group. This difference was not significant. The most important prognostic factor was the patient's age. The treatment variable biopsy versus resection did not reach prognostic relevance. In patients with midline shift who underwent biopsy, the Karnofsky Performance Scale score decreased in more patients during radiation therapy. The clinical status 6 weeks after surgery, however, showed no significant differences between the two groups. The comparable survival times for the two groups place doubt on the concept of treating glioblastoma multiforme with cytoreductive surgery. Presently, radiation therapy is the most effective treatment for patients with glioblastoma. There is no question that decompressive surgery followed by radiation therapy should be performed whenever necessary for sever space-occupying lesions and when it will not cause new neurological deficits.

Central nervous system lesions in von Hippel-Lindau syndrome.

CNS manifestations were studied in 97 gene carriers of von Hippel-Lindau syndrome (HLS). Haemangioblastomas of the CNS were found in 43 patients (44%), 23 females and 20 males. The mean age at diagnosis was 39 years (12-73 years). A total of 93 haemangioblastomas were detected of which 74% were intracranial and 26% were located in the spinal cord; 75% were predominantly cystic and 25% presented as solid lesions. Multiple lesions were found in 42% of HLS-associated haemangioblastomas, but in none of 51 patients with CNS haemangioblastoma without HLS. Haemangioblastoma was the cause of death in 82% of patients with HLS. Although microsurgery has considerably improved post-operative results, multifocal tumour development and recurrence remain a serious problem in the clinical management of HLS gene carriers.

Indications for surgery and prognosis in patients with cerebral cavernous angiomas.

Seventy-three cerebral cavernous angiomas were removed microsurgically from a series of 71 patients between August, 1983 and December, 1989. This retrospective investigation assessed the current indications for surgery and determined the prognosis for patients with cerebral cavernous angioma. There were 38 males and 33 females with a mean age of 37 years. Analysis included clinical presentation and history, neuroradiological findings, indications for surgery, and postoperative course. After an average follow-up period of 15 months, 35 patients were symptom-free, 16 had improved preoperative complaints, six were unchanged, and eight had deteriorated. Microsurgical extirpation of the malformation is indicated in all symptomatic patients where neuroimaging demonstrates the presence of a readily accessible cerebral cavernoma. Surgery is recommended in cases with deep-seated lesions causing massive hemorrhage, repetitive minor bleeding, or significant long-standing and progressive neurological disabilities. Clinically silent cavernomas located in eloquent regions of the brain contraindicate surgery, but should be closely monitored. Patients presenting with convulsions or neurological deficits caused by easily accessible cavernomas of the hemispheres have the best prognosis and a negligible risk for surgical complications. Those with deep-seated lesions of eloquent regions of the brain that have bled or caused sustained neurological disorders face the highest risk for morbidity owing to the surgical intervention, requiring careful preoperative evaluation.