Matti Puranen

Thymidine kinase gene therapy for human malignant glioma, using replication-deficient retroviruses or adenoviruses.

Herpes simplex virus thymidine kinase (HSV tk) gene therapy combined with ganciclovir (GCV) medication is a potential new method for the treatment of malignant glioma. We have used both retrovirus-packaging cells (PA317/tk) and adenoviruses (Adv/tk) for gene therapy for malignant glioma. Retrovirus-packaging cells were used for eight tumors in seven patients and adenoviruses were used for seven tumors in seven patients. As a control group, seven tumors in seven patients were transduced with lacZ marker gene 4-5 days before tumor resection. Safety and efficacy of the gene therapy were studied with clinical evaluation, blood and urine samples, MRI follow-up, and survival of the patients. Four patients with adenovirus injections had a significant increase in anti-adenovirus antibodies and two of them had a short-term fever reaction. Frequency of epileptic seizures increased in two patients. No other adverse events possibly related to gene therapy were detected. In the retrovirus group, all treated gliomas showed progression by MRI at the 3-month time point, whereas three of the seven patients treated with Adv/tk remained stable (p < 0.05). Mean survival times for retrovirus, adenovirus, and control groups were 7.4, 15.0, and 8. 3 months, respectively. The difference in the survival times between the adenovirus and retrovirus groups was significant (p < 0.012). It is concluded that HSV tk gene therapy is safe and well tolerated. On the basis of these results further trials are justified, especially with adenovirus vectors.

Familial intracranial aneurysms

BACKGROUND We set out to determine the prevalence of incidental intracranial aneurysms in first-degree relatives aged 30 years or more of people with intracranial aneurysms, and to see if polycystic kidney disease contributes to the aggregation of familial intracranial aneurysms. METHODS 91 families with two or more affected members had previously been identified from a 14 year series of 1150 intracranial aneurysm patients treated at the University Hospital of Kuopio, Finland. Magnetic resonance angiography was used as a preliminary screening method, followed by conventional four-vessel angiography to verify suspected aneurysms. Participants were also screened for polycystic kidneys by ultrasonography. FINDINGS Incidental aneurysms were detected in 40 individuals: 38 of 438 individuals from 85 families without polycystic kidney disease or other diagnosed heritable disorders, and two of 22 individuals from six families known to have polycystic kidney disease. The crude and age-adjusted prevalence of incidental intracranial aneurysms among screened first-degree relatives was 8.7 (SE 1.3)% (95% CI 6.2-11.7) and 9.1 (1.4)% (6.2-11.7), respectively, for the familial group and the crude prevalence for the polycystic kidney group was 9.1 (6.1)% (1.1-29.2). INTERPRETATION Our results demonstrate a high prevalence of incidental intracranial aneurysms among first-degree relatives aged 30 years or older of patients with the condition and indicate that the risk of having an aneurysm is about four times higher for a close relative than for someone from the general population. Also, polycystic kidney disease families are a small fraction of the familial intracranial aneurysm families.

Risk of Harboring an Unruptured Intracranial Aneurysm

BACKGROUND AND PURPOSE The purpose of the present study was to calculate the prevalence and relative risk of unruptured incidental intracranial aneurysms (IAs) among families with IA case(s) compared with the general population in one geographically defined area in East Finland and to identify the risk group that could benefit most from screening for IAs. We compared these results with our earlier study results of familial IA (FIA) cases, with two or more known IA cases in the same family. METHODS The study groups were collected from the catchment area of the University Hospital of Kuopio in East Finland. The inclusion criteria were age 30 to 70 years and unruptured incidental IAs > or =3 mm. Patients with previous subarachnoid hemorrhage or in whom a ruptured IA was found to be the cause of death were excluded from all study groups. During routine forensic autopsies the circle of Willis was studied for IAs to estimate the number of IAs in the general population. In the families with one known IA case and in FIA families, MR angiography was used as a preliminary screening method for IAs, followed by intra-arterial angiography to verify suspected IAs. Study populations were age and sex adjusted for the statistical calculations. RESULTS The relative risk for IAs among first-degree relatives in FIA families was 4.2 (95% confidence interval, 2.2 to 8.0) and among first-degree relatives in families with only one affected family member was 1.8 (95% confidence interval, 0.7 to 4.8) compared with the general population in East Finland. CONCLUSIONS First-degree relatives in FIA families constitute a high-risk group for incidental IAs, and this group would benefit from screening studies for IAs. Screening for IAs in families with only one affected member or in the general population is not recommended.

Multiple intracranial aneurysms in a defined population: prospective angiographic and clinical study.

Multiple intracranial aneurysms (MIA) have been detected in up to one-third of patients with cerebral aneurysms. Three main external factors influence these figures as follows: the quality of angiographies, the quantity of vessels studied, and referral policy. In a 1-year prospective study, we determined the incidence of MIA in a defined catchment area in East Finland by investigating all of the patients with intracranial aneurysms with panangiography. In 114 unselected patients, a total of 170 intracranial aneurysms were detected, and, of these, 39 (34%) harbored MIA. In contrast to most other reports, there was a male predominance in patients with MIA, and half of these men had hypertension. Intracavernous carotid and pericallosal aneurysms were more frequent in patients with MIA. The number of asymptomatic vertebrobasilar aneurysms was extremely low, and most of the nonruptured aneurysms were found in bilateral carotid angiograms. In spite of the active search, the proportion of vertebrobasilar aneurysms remained at 6%. Although our surgical policy was most active, one-third of the asymptomatic aneurysms remained untreated, mainly because of the poor condition of the patient.

One-year outcome in early aneurysm surgery: a 14 years experience

SummaryIn a consecutive series of 1150 patients with cerebral aneurysms diagnosed in our department by angiography or autopsy between the years 1977–1990, 1007 patients underwent definitive operative treatment of their aneurysms mainly by early surgery. More than half (55%) were operated on during the first three days after subarachnoid haemorrhage (SAH), and more than three quarters (77%) during the first week. The surgical mortality at 30 days was 9%; at one-yearfollow-up 13% had died. The total management mortality was 22%. The 618 patients presenting in Hunt and Hess Grades I–II had a 4% mortality, and 90% had an independent life at follow-up; 270 Grade III patients hat a 19% mortality and 68% were independent. There were 99 patients operated on in Grades IV–V with a 46% mortality and 30% were independent. Age of the patient and size of the aneurysm were strongly related to outcome; however, many of the giant aneurysms were operated on as an emergency because of large intracerebral haematomas. Best results were obtained in the anterior communicating artery (ACA) area; the lowest rate of useful recoveries was in the vertebro-basilar artery (VBA) area (71%). Early surgery did not prevent delayed ischaemic deficits.During the first 72 hours patients in Grades I–III can be operated on safely with good results. The results in Grades IV–V are poor, and we suggest that only cases with large haematomas or considerable hydrocephalus or those improving should be operated on in the first days after SAH, with limited hopes of functional recovery.

Shunt-dependent hydrocephalus after subarachnoid haemorrhage and aneurysm surgery : timing of surgery is not a risk factor

SummaryEarly hydrocephalus is a risk factor of shunt-dependent late hydrocephalus (SDHC). In the CT era 1980–1990 we had 835 consecutive patients operated on because of aneurysm and subarachnoid haemorrhage (SAH); 294 had an early hydrocephalus and 67 finally required a shunt. There were 14 patients with normal early CT and SDHC, in all 81 patients needed a shunt (10%). Patients with shunt did worse, they were older (53 vs 49) than the non-shunted group and there was a female preponderance.Pre-operative Grade correlated significantly with the need for a shunt operation; no one in Grade I developed SDHC, incidence in Grades III and IV was high (18% and 10%, respectively). Location was important; in vertebrobasilar area 28% and in anterior communicating area 14% but in middle cerebral area only 4% of the patients had SDHC.The amount of cisternal bleeding correlated significantly with SDHC; in 155 patients with non detectible or minimal cisternal blood only one developed SDHC, with severe cisternal bleeding the incidence was 16%. Ventricular bleeding increased the risk of SDHC, but intracerebral haematoma did not.Timing of surgery had no correlation with the risk of SDHC. Postoperative complications, haematomas and infections increased the risk of late SDHC. Delayed ischaemia correlated with the risk, but so did the treatment with nimodipine. Severe bleeding was the common predictor for the risk of SDHC. Location of the bleeding and postoperative problems are the other major causes. Outcome is, however, not so gloomy; 54% of patients with SDHC are independent one year later.

A ten percent prevalence of asymptomatic familial intracranial aneurysms: preliminary report on 110 magnetic resonance angiography studies in members of 21 Finnish familial intracranial aneurysm families.

The population in eastern Finland has been stable for generations, causing a high degree of genetic isolation and providing excellent possibilities for follow-up studies. Of 91 families with familial intracranial aneurysms, 21 were randomly selected for prospective magnetic resonance angiography studies for intracranial aneurysms. Sixteen intracranial aneurysms were detected in 11 asymptomatic family members of a total of 110 studied. The prevalence of intracranial aneurysms among these familial intracranial aneurysm families is 10%, approximately 10 times higher than in the average population. Our findings suggest that family members of familial intracranial aneurysm families should be examined for intracranial aneurysms. Familial intracranial aneurysm may be a genetic disorder.

A Ten Percent Prevalence of Asymptomatic Familial Intracranial Aneurysms

: The population in eastern Finland has been stable for generations, causing a high degree of genetic isolation and providing excellent possibilities for follow-up studies. Of 91 families with familial intracranial aneurysms, 21 were randomly selected for prospective magnetic resonance angiography studies for intracranial aneurysms. Sixteen intracranial aneurysms were detected in 11 asymptomatic family members of a total of 110 studied. The prevalence of intracranial aneurysms among these familial intracranial aneurysm families is 10%, approximately 10 times higher than in the average population. Our findings suggest that family members of familial intracranial aneurysm families should be examined for intracranial aneurysms. Familial intracranial aneurysm may be a genetic disorder.

3-D reconstructed magnetic resonance imaging in localization of subdural EEG electrodes: Case illustration

We report an illustrative case of presurgical evaluation for epilepsy surgery, where the three-dimensional reconstructed magnetic resonance imaging played a pivotal role in determining the exact location of the subdural strip electrodes in temporomesial area. The tip of one the frontal strip electrodes was actually recording the temporopolar ictal activity. This contributed conclusively to the decision for surgical treatment and to the excellent outcome.

The Fate of Patients with Incidental Intracavernous Carotid Artery Aneurysms (ICCAA)

Of 1150 patients with cerebral aneurysms, 35 had a total of 37 intracavernous carotid artery aneurysms (ICCAA); 27 were incidental findings. These aneurysms are associated with female sex, advanced age, hypertension and multiplicity — and their presence should prompt four vessel angiography. The mean aneurysm size of the 27 incidental aneurysms was 5.2 mm. In no case had clinical symptoms developed or was any growth of ICCAAs observed in angiographic controls during a mean follow-up time of 5.4 years (range 1-11 years). These asymptomatic aneurysms should be left alone, even with a very low risk therapeutic regimen.