Cerebral cavernous malformations (CCM) are hamartomatous vascular malformations characterized by abnormally enlarged capillary cavities without intervening brain parenchyma. They cause seizures and focal neurological deficits due to cerebral hemorrhages. CCM loci have already been assigned to chromosomes 7q (CCM1), 7p (CCM2), and 3q (CCM3) and have been identified in 40%, 20%, and 40%, respectively, of families with CCM. Loss-of-function mutations have been identified in CCM1/KRIT1, the sole CCM gene identified to date. We report here the identification of MGC4607 as the CCM2 gene. We first reduced the size of the CCM2 interval from 22 cM to 7.5 cM by genetic linkage analysis. We then hypothesized that large deletions might be involved in the disorder, as already reported in other hamartomatous conditions, such as tuberous sclerosis or neurofibromatosis. We performed a high-density microsatellite genotyping of this 7.5-cM interval to search for putative null alleles in 30 unrelated families, and we identified, in 2 unrelated families, null alleles that were the result of deletions within a 350-kb interval flanked by markers D7S478 and D7S621. Additional microsatellite and single-nucleotide polymorphism genotyping showed that these two distinct deletions overlapped and that both of the two deleted the first exon of MGC4607, a known gene of unknown function. In both families, one of the two MGC4607 transcripts was not detected. We then identified eight additional point mutations within MGC4607 in eight of the remaining families. One of them led to the alteration of the initiation codon and five of them to a premature termination codon, including one nonsense, one frameshift, and three splice-site mutations. All these mutations cosegregated with the disease in the families and were not observed in 192 control chromosomes. MGC4607 is so far unrelated to any known gene family. Its implication in CCMs strongly suggests that it is a new player in vascular morphogenesis.

Of the cerebral vascular lesions that can be treated with intravascular detachable balloon techniques, carotid-cavernous sinus fistulas and vertebro-vertebral fistulas have the best results. The great advantage of this technique is that the cerebral blood flow can usually be preserved after the occlusion of the fistula. The authors report 17 postraumatic carotid-cavernous sinus fistulas successfully treated with preservation of the carotid blood flow in 12 cases. None of the patients died, and the morbidity was limited to one case of third nerve palsy. The treatment of aneurysms by this method is, however, much more difficult and dangerous. Of 14 cases treated, seven good results were obtained. Two patients died and two had a poor outcome. The embolization of certain brain angiomas with calibrated-leak balloons using bucrylate promises to be important in the future.

SUMMARY Twelve patients, eleven with a carotid obstruction and one with an occlusion of the middle cerebral artery, were studied before and after a successful unilateral extra-intracranial arterial by-pass, (EIAB) using PET and the 15-0 steady-state technique to measure regional cerebral blood flow (CBF), oxygen extraction fraction and oxygen metabolic rate (CMRO 2 ). In the whole group of patients, both CBF and CMRO, increased significantly on both cerebral hemispheres after EIAB, returning toward control levels defined in age-matched subjects. Mean oxygen extraction fraction, on the other hand, was not affected. Individually, three different effects of EIAB emerged: 1) Alleviation of a state of long standing unilateral "misery-perfusion", as reported earlier; 2) parallel increase of CBF and CMRO2 bilaterally, which appeared due to improvement of a hemodynamic depression of metabolism, the precise mechanism of which remains obscure; 3) Complex, unexpected changes in the CBF-CMRO 2 couple again resulting in increases in CMRO 2 . This metabolic improvement afforded by EIAB in our patients has not been reported before; it suggests that long-standing hemodynamic failure may induce a metabolic depression that is still potentially reversible by surgical revascularization. Stroke Vol 16, No 4, 1985 THE CONTINUOUS OXYGEN 15 INHALATION METHOD provides a regional measurement of the cerebral blood flow (CBF) and oxygen metabolic rate (CMRO,). Earlier semi-quantitative studies carried out by this method 1 -2 showed the disappearance, after an extra-intracranial by-pass operation (EIAB), of two different patterns of focal functional anomaly. The first one, termed misery-perfusion, consists of a lowered CBF and an increased oxygen extraction fraction (OEF) downstream from a carotid occlusion. This pattern reflects the relative maintenance of the CMRO, and was interpreted as evidence of a drop in the cerebral perfusion pressure to a point beyond the lower threshold of CBF auto-regulation. For the second type, involving a reduced CBF with no rise in the OEF, no satisfactory pathophysiological interpretation was put forward. 2However in these semi-quantitative studies it was possible neither to measure the CMRO, nor to detect bilateral effects of the EIAB, both of which objectives form the centre of present work. Patients and MethodsThe study involved 12 consecutive patients in whom the permeability of the EIAB was verified. One preoperative study was an isolated CBF measurement (case No. 3). Eleven of these patients suffered from internal carotid artery (ICA) obstruction and the last a middle cerebral artery (MCA) occlusion. Mean age was 56 ± 9.3 years.Individual clinical, angiographic and CT Scan data Received July 16, 1984; revision #1 accepted December 7, 1984. are summed up in table 1. The advisability of EIAB was judged on the basis of clinical and angiographic criteria, independently of pre-operative PET results. Clinical signs of "hemodynamic" ischemia was the deciding factor in 5 cases (patients No. 5,6,9,11,12) ...

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