Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas.

Cavernous angiomas are vascular malformations mostly located in the central nervous system and characterized by enlarged capillary cavities without intervening brain parenchyma. Clinical symptoms include seizures, haemorrhage and focal neurological deficits. Cavernous angiomas prevalence is close to 0.5% in the general population. They may be inherited as an autosomal dominant condition in as much as 50% of cases. Cerebral cavernous malformations (CCM) loci were previously identified on 7q, 7p and 3q (refs 4,5). A strong founder effect was observed in the Hispano-American population, all families being linked to CCM1 on 7q (refs 4,7). CCM1 locus assignment was refined to a 4-cM interval bracketed by D7S2410 and D7S689 (ref. 8). Here we report a physical and transcriptional map of this interval and that CCM1, a gene whose protein product, KRIT1, interacts with RAP1A (also known as KREV1; ref. 9), a member of the RAS family of GTPases, is mutated in CCM1 families. Our data suggest the involvement of the RAP1A signal transduction pathway in vasculogenesis or angiogenesis.

[Cavernomas of the central nervous system. Historical data and changing ideas]. / Les cavernomes du système nerveux central. Historique et évolution des idées.

Since the advent of modern neuroimaging (MRI) cerebral cavernomas are usually diagnosed "in vivo". In this paper we describe the data which improved our knowledge of the disease: 1) nosologically, cerebral cavernomas belong to the group of cerebral vascular hamartomas which can be associated between themselves ("mixed" lesions); 2) hemodynamically, the annual risk of hemorrhage increases after a first bleeding and in deep located lesions (brainstem); 3) association between cavernomas and developmental venous anomalies may be observed; the later on must be left in place at operation; 4) immunocytochemical studies (PCNA) show that cavernomas should be considered more as a benign vascular tumor than as a malformation; 5) familial forms (20%) are characterized by multiple locations and "de novo" lesions; 6) better understanding of the natural history of cavernomas, which is a dynamic lesion, leads to broader surgical indications (no alternative treatment).

Prospective follow-up of 33 asymptomatic patients with familial cerebral cavernous malformations.

BACKGROUND: Cerebral cavernous malformation (CCM) is one of the most common vascular malformations of the CNS. Familial CCM are increasingly diagnosed, but little is known about their natural history, especially in asymptomatic patients. OBJECTIVE: To determine the degree of spontaneous evolution of familial CCM in a population of 33 symptom-free patients. METHODS: During a previous national survey, the authors analyzed the clinical and MRI features of 173 patients from 57 unrelated French families, including 73 asymptomatic subjects. Of these 73 subjects, 33 prospectively underwent two serial clinical and MRI examinations. Cerebral MRI systematically included spin echo and gradient echo sequences. Occurrence of clinical symptoms and MRI changes of CCM, namely, hemorrhage, change in signal intensity, change in size, and appearance of new lesions, were recorded by means of comparison of the first and last MRI examinations. RESULTS: The 33 patients (234 CCM, mean 7.1 lesions/subject, range 1 to 85 lesions/subject) were followed during a mean period of 2.1 years (range 0.5 to 4.5 years). Two patients became symptomatic: One presented with brainstem hemorrhage and one with partial seizure. Comparison of the two serial MR images found changes in 15 patients (46%): 1) Bleeding occurred in three type II lesions (1.3%) in three patients (9.1%); 2) 30 new lesions appeared in 10 patients (30.3%); 3) change in signal intensity was observed in one lesion (0.4%) in one patient (3%); and 4) increase in size was observed in four lesions (1.7%) in three patients (9.1%). CONCLUSIONS: This prospective study confirms the dynamic nature of CCM. The appearance of new lesions in 30% of patients has to be retained as a hallmark of the familial condition.

The in vivo metabolic pattern of low-grade brain gliomas: a positron emission tomographic study using 18F-fluorodeoxyglucose and 11C-L-methylmethionine.

OBJECTIVE: The object of the present study was to identify metabolic differences between low-grade astrocytomas and oligodendrogliomas and to improve their diagnosis and noninvasive assessment, because both types of tumors look very similar from the point of view of clinical and radiological data (as assessed by computed tomography and magnetic resonance imaging). METHODS: Before any aggressive treatment, 22 patients with primary low-grade gliomas (astrocytomas in 12 patients and oligodendrogliomas in 10) were investigated with positron emission tomography for both glucose metabolism (18F-fluorodeoxyglucose) and amino acid uptake (11C-L-methylmethionine). An original software that allows a full metabolic analysis of the tumor region of interest (defined from the T1-weighted magnetic resonance image) and compares tumor tissue uptake tracer concentrations with average healthy tissue values has been implemented for data processing. Heterogeneity of each individual tumor has been taken into account and was expressed in histograms, which provided data about the mean and also extreme and intermediate values of tracer concentrations and the way these values are distributed among the full tumor mass. RESULTS: It has been shown that both tumor types exhibit a glucose hypometabolism (slightly more pronounced with astrocytomas), whereas they strongly differ in methionine uptake, which is high in all oligodendrogliomas and either decreased, normal, or moderately increased in astrocytomas. This latter metabolic difference between both tumor populations may be partially explained by their different cell densities. CONCLUSION: This study suggests that despite similar radiological and clinical presentations, these two kinds of low-grade gliomas are metabolically different and could therefore have specific responses to different therapies. Moreover, their in vivo metabolic follow-up with positron emission tomography should rely on different parameters, depending on their histological type; methionine uptake may be more relevant than glucose metabolism in the follow-up of oligodendrogliomas.

Pediatric cerebral aneurysms.

OBJECT: The exceptional pediatric aneurysm can be distinguished from its adult counterpart by its location and size; however, patient outcomes remain difficult to evaluate based on the published literature. METHODS: Twenty-two children, all consecutively treated in three neurosurgery departments, were included in this study. Each patient's preoperative status was determined according to the Hunt and Hess classification. Routine computerized tomography scanning and angiography were performed in all children on the 10th postoperative day. Each patient's clinical status was evaluated 2 to 10 years postoperatively by applying the Glasgow Outcome Scale (GOS). Twenty-one children presented with a subarachnoid hemorrhage (SAH) and one child harbored an asymptomatic giant aneurysm. Thirteen patients were in good preoperative grade (Hunt and Hess Grades I to III) and eight in poor preoperative grade (Hunt and Hess Grade IV or V). The symptomatic aneurysms were located on the internal carotid artery bifurcation (36.4%); middle cerebral artery (36.4%), half of which were found on the distal portion; anterior communicating artery (18.2%); and within the vertebrobasilar system (9.1%). A giant aneurysm was observed in 14% of patients. Overall outcome was favorable (GOS Score 5) in 14 children (63.6%) and death occurred in five (22.7%). Causes of unfavorable outcome included the initial SAH in four children, a complication in procedure in three children, and edema in one child. CONCLUSIONS: Pediatric aneurysms have a specific distribution unlike that of aneurysms in the adult population. The incidence of giant aneurysms and outcomes were similar to those in the adult population. The major cause of poor outcome was the initial SAH, in particular, the high proportion of rebleeding possibly due to a delay in diagnosis.

An uncommon electrocardiographic change in subarachnoid hemorrhage: increase in the Sokolow's Index.

In this paper we are reporting a case of electrical left ventricular hypertrophy with increased Sokolow's index following subarachnoid hemorrhage. Two-dimensional echocardiography ruled out anatomical left ventricular hypertrophy, and the Sokolow's index eventually reverted to normal. This electrocardiographic abnormality has rarely been associated with subarachnoid hemorrhage and does not appear to be related to the neurologic grade of the patient because he presented with headaches only and was conscious throughout (Hunt and Hess grade I). The possibility that such electrocardiographic changes should reflect anatomical changes in the heart should always be ruled out by proper investigations (i.e., echocardiography and coronarography), as the presence of cardiac disorders would greatly influence medical and surgical management. In terms of electrocardiography, this observation suggests that the Sokolow's index is a poor indicator of left ventricular hypertrophy, and tends to reflect a more comprehensive catecholaminergic process.

Brain cavernoma: a dynamic lesion.

BACKGROUND: Although the prevalence of brain cavernomas is high (0.50%), for unknown reasons, only a few of them display aggressive clinical behavior. METHODS: From a personal series of 65 operated and histopathologically verified cavernomas, we have conducted a long-term study, both retrospectively and prospectively, of the main features that cause some cavernomas to be dynamic lesions. RESULTS: Hemorrhage is the most common phenomenon. Extralesional bleeding due to the rupture of peripheral caverns is most often observed. These are never as immediately devastating as hemorrhages originating from a high-flow, high-pressure AVM. Extralesional hemorrhages tend toward spontaneous resorption, but the risk of recurrence exists and may lead to permanent disability or death (especially when the lesion is located in the brain stem). Intralesional bleeding caused by rupture of contiguous caverns is less frequently observed. This may lead to the formation of large cysts. Calcifications are mostly observed in patients presenting with chronic epilepsy. The bleeding risk of calcified cavernomas is low, but it can exist and should be taken into account in the surgical decision making. The growth of the cavernomatous matrix was obvious in three large cavernomas (two with calcification). No bleeding was found inside the lesions, suggesting a pure "intrinsic" growth. The role of pathologic angiogenic factors is highly probable in these cases. "De novo" appearing lesions were observed in five cases (four belonging to familial forms) on the magnetic resonance imaging survey of operated patients. Perilesional atrophy was observed in three cases (two operated) in patients with a long-lasting evolution. It suggests that the brain metabolism can be disturbed by slow, chronic effusion of blood around the cavernoma. CONCLUSIONS: The dynamism of cavernomas is determined by extrinsic factors, mainly hemorrhage (with its own consequences); and by intrinsic factors: the pseudotumoral growth of the cavernous matrix. Therefore, when they are symptomatic, cavernomas should be totally removed.

Proliferating cell nuclear antigen (PCNA) in cerebral cavernomas: an immunocytochemical study of 42 cases.

BACKGROUND: The natural history and growth mechanisms of cerebral cavernous angiomas are unclear, which makes them difficult to manage. We attempted to evaluate the evolutive potential of cavernomas by studying the proliferative capacity of cells. METHODS: We studied 42 histologically verified cavernomas with monoclonal antibody to proliferating cell nuclear antigen (PCNA), an accessory protein of the cell cycle, the rate of which is increased in proliferative cells. The PCNA Labeling Index (PCNA LI) was calculated in each case, and the results were compared with histologic findings (lacy areas, thick walls, thrombi, hemosiderin) and clinical features (epilepsy, hematomas, pseudotumorous signs). RESULTS: Thirty-six of 42 cases (85.7%) revealed stained cells. PCNA LI ranged from 1 to 48% (mean: 23.39%). Statistical analyses showed a positive correlation between PCNA LI and the extent of lacy areas (p < 0.05). On the contrary, collagenous-walled and thrombotic areas rarely showed positively stained cells. We found no relationship between PCNA LI and clinical features. CONCLUSIONS: A proliferative capacity of endothelial cells does exist in some areas of cavernomas and may explain, besides thromboses and hemhorrages, the growth and even de novo appearance of these lesions. Occurrence of fragile blood cavities, thickening of others, and changes in blood flow may influence the evolution of lesions. Our results suggest that in cavernomas, some areas may undergo specific changes, which makes them more dynamic lesions than previously thought.

[Intracranial cavernous angioma]. / Cavernomes intracrâniens.

Cavernous angiomas are vascular malformations that belong to the group of hamartomas. Evidence to support the hypothesis that some intracranial cavernous angiomas are benign vascular tumors is lacking. As they are angiographically occult, cavernous angiomas were largely overlooked and were considered rare before CT scan and MRI became available. Both of these techniques provide a quick and accurate diagnosis in cases of epilepsy, brain hemorrhage or intracranial hypertension. Most of the hemispheric cavernous angiomas are situated subcortically, in the neighborhood of the rolandic fissure. In the brain stem, they can be found mostly in the pons. Cerebellum and spinal cord are seldom involved. Cavernous angiomas may occur in children, as well as in familial forms, or in association with other visceral locations. It is important to know that some cavernous angiomas are able to grow, owing to a variety of mechanisms, which may result in rupture and cerebral hemorrhage. The improvement of both imaging and surgical techniques have reduced the risks of death or heavy sequelae. Some deeply located cavernous angiomas, however, are still inaccessible to surgery.

[Isolated exertion headache and Chiari's malformation]. / Céphalée d'effort isolée et malformation de Chiari.

A 47 year-old woman had been suffering from exertional headache for 2 1/2 years. Neurological examination was normal. X-rays of the skull and cranio-cervical junction and CT were normal. MRI sagittal sections disclosed a Chiari type I malformation. The headache disappeared after occipital craniectomy and atlas laminectomy.

[Associated vertebral angioma and epidural cavernoma (author's transl)]. / Angiome vertébral associé à un cavernome épidural.

A 27 year old man developed a pyramidal syndrome with hypoesthesia up to the level of D8, over a period of two months. Radiographic examination revealed the presence of an angioma of D8. Selective angiography demonstrated that there was epidural invasion as well as an angioma of the vertebral body, and enabled embolization of the 2 pedicles of the lesion to be performed. This produced only a partial, temporary improvement, and a posterior epidural tumor was found and removed by operation. The histological appearance of the tumor was that of a cavernoma, and rapid and permanent recovery of normal neurological function was obtained after the operation. The authors discuss the pathogenicity of the neurological disorders associated with single bone angiomas, and the problems raised by their treatment.

[Granular cell pituicytoma (choristoma) of the pituitary stalk]. / Pituicytome à cellules granulaires (choristome) de la tige pituitaire

A case of granular cell tumour in the pituitary stalk is described marked by the sudden loss of visual acuity in the left eye, followed by the right years later. A comparison with 17 cases previously published and with cases of asymptomatic granular cell nodules leads the authors to suggest the term granular cell pituicytoma. They discuss the place of this neoformation among other systemic granular cell tumours (granular cell myoblastoma). Fifteen patients were operated on, complete excision being carried out in only three (including the case published). Whether complementary cobalt therapy is useful remains problematical since very few cases have been published because of the slow development of the neoplasm.

[Hemodynamic study of obstructive lesions of the internal carotid artery: value of coupled measurement of regional cerebral blood flow and volume]. / Etude hémodynamique des lésions obstructives de l'artère carotide interne: intérêt de la mesure couplée du débit et du volume sanguins cérébraux régionaux.

A study of 130 patients having presented either a transient ischemic attack or a completed stroke, or admitted for an asymptomatic carotid stenosis, allowed the following investigations: CT-scan, doppler, angiography, measurement of the regional cerebral blood flow (rCBF) by the study of 133Xe clearance (Novocerebrograph (R)), and measurement of the regional cerebral blood volume (rCBV) made by gamma emission tomography after autotransfusion of 99m Tc-labeled erythrocytes with an Elscint Apex 415 ECT (R) camera. Our aim was to look in which case a rCBF and/or a rCBV interhemispheric asymmetry was observed, by comparing the previous hemodynamic parameters with clinical, CT-scan and angiographic data. Although a rCBF and/or a rCBV asymmetry appeared more often among patients presenting with infarction than among those of the asymptomatic category, this does not seem specific for any clinical grade. The same statement applies to the comparison between hemodynamic parameters and CT data. The arterial lesions were classified in 4 groups: no stenosis (12 cases), uni or bilateral moderate carotid stenosis (40 cases), unilateral severe carotid stenosis or occlusion (65 cases), bilateral carotid severe stenosis or occlusion (13 cases). We observed a rCBF asymmetry among some patients in the 4 groups, although this was more frequent among the two latter groups. Nevertheless no case of a rCBV asymmetry was observed in the 2 first groups. Such an asymmetry was present in 31 percent of the patients belonging to the two latter groups. In patients of the third group the asymmetry was always due to a relative increase of rCBV beyond the carotid lesion.(ABSTRACT TRUNCATED AT 250 WORDS)

[Extramedullary hematopoiesis of thoracic and vertebral intraductal localization. Apropos of a case. Review of the literature]. / Hématopoïèse extra-médullaire de localisation thoracique et intra-canalaire vertébrale. A propos d'un cas. Revue de la littérature.

The authors report a case of extramedullary haematopoiesis, presenting in the form of several tumor masses in the posterior mediastinum and in the vertebral canal. The patient presented with oedema in his lower limbs due to compression of the inferior vena cava by the mediastinal masses. The asymptomatic mass in the vertebral canal was detected by magnetic resonance imaging. The patient was first operated on to avoid spinal cord compression by the tumor and subsequently to relieve compression of the inferior vena cava. The masses removed from the vertebral canal and the mediastinum were found on histologic examination to be extramedullary haematopoiesis. The cause of the disease was unknown in this case. Such disease is often disclosed in the course of hemolytic anaemias or other medullar deficiency diseases as a compensatory phenomenon when the bone marrow fails. An other explanation is that it is a manifestation of a myeloproliferative disorder in which heterotopic pluripotential cells are transformed into haematopoietic cells. The authors review 88 cases reported in the world literature.

[Anterior ethmoidal dural fistulae. 3 new cases]. / Fistules durales ethmoïdales antérieures. Trois nouvelles observations.

The authors report three new cases of anterior ethmoidal dural fistulae: a pure pial and two dural and pial fistulae which presented in the form of rupture. The emphasise the computed tomographic features, revealing a unilateral frontopolar haematoma and the need for angiographic assessment including study of the internal and external carotid arteries. Carotid angiography of the fistula defines the therapeutic modalities which are generally surgical.

[Cerebellar, pulmonary and cutaneous localizations of juvenile xanthogranuloma]. / Localisations cérébelleuse, pulmonaires et cutanées d'un xanthogranulome juvénile.

BACKGROUND: Juvenile xanthogranuloma is one of the most common non-langerhan cell histiocytoses in children. Usually cutaneous, there are disseminated forms. However, neurological localizations remain exceptional. CASE REPORT: We report the case of a cerebellar localization, associated with cutaneous and pulmonary lesions in a 13-month old child. Surgical treatment of the cerebellar lesion was associated with vinblastin chemotherapy, that led to total regression of the cutaneous and pulmonary lesions, neurological stabilization, without recurrence on the control IRM, after a period of 7 years. DISCUSSION: This is the second reported case of histologically documented cerebellar juvenile xanthogranuloma. In the event of cutaneous juvenile xanthogranuloma, the neurological examination must be attentive and supplemented, in case of any suspicion, by medical imaging. We believe that surgical treatment of neurological juvenile xanthogranuloma is necessary, in the event of symptomatic lesions and accessible to surgery. No consensus has been reached on subsequent treatments (radiotherapy, chemotherapy) and must be discussed according to the clinical profile and data in the literature.

[Surgical findings and results after failure of lumbar chemonucleolysis. 72 cases]. / Constations opératoires et résultats après échec de la chimionucléolyse lombaire. 72 cas.

Seventy two patients undergoing lumbar chemonucleolysis (LCN) involving one (49 cases) or two (23 cases) discs underwent surgery after failure of the procedure. In 5 cases the disc prolapse responsible for the recurrence of pain was at a different site from that of the LCN. Analysis of true failures in the light of operative findings showed that the presence of a migrated disc sequestrum at a distance from the space injected was rare (7% of cases). By contrast, the discovery of a true sub-ligamentous disc prolapse was common (32%). In 1/3 of cases these prolapses contained actual intra-discal sequestra within a scanty amount of basic substance, as if the enzyme had destroyed the latter but had no action upon the former. Simple disc protrusions were discovered in 36% of cases, combined in one case out of five with stenosis of a lateral recess. Finally, in 25% of cases the disc explored was flat, combined in 1 case out of 3 with a considerable inflammatory reaction. The percentage of good and very good operative results was 60.7% overall, rising to 70% taking into consideration only those patients undergoing LCN at one level only. The authors feel that no longer than a month should be allowed to pass before deciding to operate after failure of LCN.

[The ventrolateral position]. / La position ventro-latérale.

AIM: To propose an alternative to the sitting position and the other horizontal positions while maintaining the advantages of the sitting position and assuring maximum safety for the patient particularly with respect to the risk of air embolism. POSITION: The patient is positioned as for the sitting position with the median axis of the posterior cranial fossa prolonging the spinal axis. The head is maintained by a Mayfield head holder and is inclined without force. The patient rests laterally on the apron, the thorax and the lower limbs resting on cushions. The upper limbs rest on the arm rests interdependent with the table facilitating surgical access and rolling movements. DATA: Since 1993, this position was used for 556 patients. For 81.3% of the patients lesions were located in the posterior cranial fossa and for 12.75% in the supratentorial region. Access to the cervical area was achieved for 4.7% of the patients. RESULTS: This position gave us access to the lesions without specific difficulties, irrespective of the patient's morphology. There were no air embolism events and no capnographic anomaly was reported. CONCLUSION: Since discontinuing use of the sitting position in our institution, we have found that the ventrolateral position can replace the sitting position advantageously. It allowed us to approach lesions located in a large area, from the cervical spine to the supratentorial area located behind external auditory meatus, and was compatible with anesthetic and surgical requirements.

[Intracerebellar schwannoma. Apropos of a case. Review of the literature]. / Schwannome intra-cérébelleux. A propos d'un cas. Revue de la littérature.

Intracranial schwannoma represents 8% of all primary brain tumors. It usually develops from the Schwann cells of a cranial nerve. Hemispheric intraparenchymal localisations are quite rare; 15 cases have been reported (3, 5, 12, 10, 14, 15, 18, 19, 23, 26, 28, 29) including one intraventricular localization (8). Intracerebellar localization is even by more exceptional. In 1977, one case was reported by Komminoth (16). Since then only one other case has been published in 1987 by Sarkar (25). In this paper, we report a third case.

[Unilateral endonasal approach to hypophyseal adenomas]. / Abord endonasal unilatéral des adénomes hypophysaires.

The endonasal approach for transsphenoidal hypophysectomy is a simple technique for exposing the floor of the sella turcica. In our institution we have operated 162 patients (64 microadenomas and 98 macroadenomas), over a ten-year period, by using that approach. The floor of the sella turcica is exposed through an incision performed posteriorly to the nostril at the junction of cartilaginous and bony septum. Postoperative rhinological complications are less frequently observed after unilateral endonasal approach than after sublabial one, and it is more comfortable for the patient. The morbidity of unilateral endonasal transsphenoidal approach is comparable to that of other series.