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Mika Niemelä, Young Jin Lim, Michael Söderman, Juha Jääskeläinen, and Christer Lindquist

✓ One suprasellar, one mesencephalic, and nine cerebellar hemangioblastomas were treated with the gamma knife in 10 patients (median age 48 years) in Stockholm between 1978 and 1993. Four patients had von Hippel—Lindau disease, a dominant inherited trait predisposing to multiple hemangioblastomas. Six hemangioblastomas were treated with radiotherapy at a median margin dose of 25 Gy (20–35 Gy) before 1990 and the next five with a median of 10 Gy (5–19 Gy). Computerized tomography or magnetic resonance images were available for 10 of the 11 hemangioblastomas at a median follow-up time of 26 months (4–68 months) after radiosurgery. The solid part of six hemangioblastomas shrank in a median of 30 months, whereas four hemangioblastomas were unchanged at a median of 14 months. Five hemangioblastomas had an adjoining cyst and three of these cysts had to be evacuated after radiosurgery. One solitary hemangioblastoma later developed a de novo cyst that also needed evacuation. One patient with two cerebellar hemangioblastomas (margin dose 25 Gy each) developed edema at 6 months and required a shunt and prolonged corticosteroid treatment. The combined follow-up data of the 23 hemangioblastomas in 15 patients from previous literature and the present series indicate that, first, a solitary small- or medium-sized hemangioblastoma usually shrinks or stops growing after radiosurgery. The recommended margin dose is 10 to 15 Gy. Second, the adjoining cyst often does not respond to radiosurgery but requires later, sometimes repeated evacuation.

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Ronit Agid, Karel TerBrugge, Georges Rodesch, Tommy Andersson, and Michael Söderman

Object

Dural arteriovenous fistulas (DAVFs) of the anterior cranial fossa are rare lesions that can cause intracranial hemorrhage. Authors of previous reports mostly have described open surgical treatment for this fistula type. The authors' purpose in the present study was to describe their experience with anterior cranial fossa DAVFs, including their endovascular treatment.

Methods

All patients with anterior cranial fossa DAVFs diagnosed and treated in 3 separate institutions during the last 23 years were retrospectively identified. Clinical charts, imaging studies, and procedural notes were evaluated.

Results

Twenty-four patients (22 males and 2 females), ranging in age from 3 to 77 years, harbored 24 DAVFs in the anterior cranial fossa. Eleven patients were primarily treated with surgical disconnection and 2 with radiosurgery. Eleven patients were treated endovascularly; 7 of these patients (63.6%) were cured. In 4 cases of failed embolization, final disconnection was achieved through surgery. In fact, surgery was effective in disconnecting the fistula in 100% of cases. All endovascular procedures consisted of transarterial injections of diluted glue (N-butyl cyanoacrylate [NBCA]), and there were no complications. Brain edema developed around the venous pouch and confusion was apparent after venous disconnection in 1 surgically treated patient. No patient suffered a hemorrhage during the follow-up period.

Conclusions

Disconnection of an anterior cranial fossa DAVF by using transarterial catheterization through the ophthalmic artery and subsequent injection of NBCA is possible with a reasonable success rate and low risk for complications. In patients with good vascular access this procedure could be the treatment of choice, to be followed by open surgery in cases of embolization failure.

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Bengt Karlsson, Ingmar Lax, Masaaki Yamamoto, Michael Söderman, Hidefumi Jokura, Charles Rosen, and Julian Bailes

Object

The authors sought to assess the relationship between obliteration rate and different dose parameters following fractionated radiotherapy for arteriovenous malformations (AVMs). A comparison of the results of radiosurgery and radiotherapy for AVMs was made to calculate the best fit α/β value, which would then be used as a model for predicting the treatment outcome, independent of the number of fractions applied.

Methods

Data from 1453 patients were analyzed: 1154 treated with radiosurgery and 300 with fractionated radiotherapy. The relationships between dose and obliteration rate after 3 years were calculated, and the best fit curve to the empirical results was defined. The higher the dose per fraction, biologically effective dose, and the lower the total dose, the higher the obliteration rate. The isoeffective doses when comparing radiotherapy and radiosurgery independent of the α/β value could not be defined. The dose per fraction had the best predictive value, independent of the number of fractions.

Conclusions

Dose per fraction seems to be the decisive parameter for the treatment response following both radiotherapy and radiosurgery. A larger number of fractions did not increase the obliteration rate. The data indicate that higher doses per fraction should be used when irradiating AVMs.

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Bengt Karlsson, Patrick Hanssens, Robert Wolff, Michael Söderman, Christer Lindquist, and Guus Beute

Object

The aim of this study was to analyze factors influencing survival time and patterns of distant recurrences after Gamma Knife surgery (GKS) for metastases to the brain.

Methods

Information was available for 1855 of 1921 patients who underwent GKS for single or multiple cerebral metastases at 4 different institutions during different time periods between 1975 and 2007. The total number of Gamma Knife treatments administered was 2448, an average of 1.32 treatments per patient. The median survival time was analyzed, related to patient and treatment parameters, and compared with published data following conventional fractionated whole-brain irradiation.

Results

Twenty-five patients survived for longer than 10 years after GKS, and 23 are still alive. Age and primary tumor control were strongly related to survival time. Patients with single metastases had a longer survival than those with multiple metastases, but there was no difference in survival between patients with single and multiple metastases who had controlled primary disease. There were no significant differences in median survival time between patients with 2, 3–4, 5–8, or > 8 metastases. The 5-year survival rate was 6% for the whole patient population, and 9% for patients with controlled primary disease. New hematogenous spread was a more significant problem than micrometastases in patients with longer survival.

Conclusions

Patient age and primary tumor control are more important factors in predicting median survival time than number of metastases to the brain. Long-term survivors are more common than previously assumed.

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Bengt Karlsson, Hidefumi Jokura, Masaaki Yamamoto, Michael Söderman, and Ingmar Lax

Object

The results of a novel radiosurgical approach to treat large arteriovenous malformations (AVMs) with repeated radiosurgery are presented and discussed.

Methods

The outcome was studied following repeated Gamma Knife surgery (GKS) for large AVMs, defined as a nidus volume of 9 ml or more. The philosophy was to treat the whole AVM with a low dose of radiation (≥ 10 Gy), and to repeat the treatment if the AVM shrank but was not obliterated. The study included 133 patients with AVMs treated at one of three different institutions. Clinical information was available for all patients, and complete radiological follow-up was available in 89 patients after the first treatment, and in 19 after the second treatment.

Results

The estimated obliteration rate following repeated GKS was 62%. Four patients (3%) developed neurological deficits caused by the radiation, whereas five others (4%) developed cystic changes. The annual incidence of hemorrhage was high (7%), of which 35% occurred within the 1st year after the first treatment.

Conclusions

Repeated radiosurgery seems to be a viable option for some AVMs considered to be too large for conventional radiosurgical treatment. The incidence of posttreatment hemorrhages seems to be a larger clinical problem than radiation-induced complications.

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Michael Söderman, Göran Edner, Kaj Ericson, Bengt Karlsson, Tiit Rähn, Elfar Ulfarsson, and Tommy Andersson

Object

The aim of this study was to assess the clinical efficacy of gamma knife surgery (GKS) in the treatment of dural arteriovenous shunts (DAVSs).

Methods

From a database of more than 1600 patients with intracranial arteriovenous shunts that had been treated with GKS, the authors retrospectively and prospectively identified 53 patients with 58 DAVSs from the period between 1978 and 2003. Four patients were lost to follow-up evaluation and were excluded from the series. Thus, this study is based on the remaining 49 patients with 52 DAVSs. Thirty-six of the shunts drained into the cortical venous system, either directly or indirectly, and 22 of these were associated with intracranial hemorrhage on patient presentation. The mean prescription radiation dose was 22 Gy (range 10–28 Gy).

All patients underwent a clinical follow-up examination. In 41 cases of DAVS a follow-up angiography study was performed. At the 2-year follow-up visit, 28 cases (68%) had angiographically proven obliteration of the shunt and in another 10 cases (24%) there was significant flow regression. Three shunts remained unchanged.

There was one immediate minor complication related to the administration of radiation. Furthermore, one patient had a radiation-induced complication 10 years after treatment, although she recovered completely. There was one posterior fossa bleed 2 months after radiosurgery; a hematoma, as well as a lesion, was evacuated, and the patient recovered uneventfully. A second patient had an asymptomatic occipital hemorrhage approximately 6 months postradiosurgery.

The clinical outcome after GKS was significantly better than that in patients with naturally progressing shunts (p < 0.01, chi-square test); figures on the latter have been reported previously.

Conclusions

Gamma knife surgery is an effective treatment for DAVSs, with a low risk of complications. Major disadvantages of this therapy include the time elapsed before obliteration and the possibility that not all shunts will be obliterated. Cortical venous drainage from a DAVS, a risk factor for intracranial hemorrhage, is therefore a relative contraindication. Consequently, GKS can be used in the treatment of both benign DAVSs with subjectively intolerable bruit and aggressive DAVSs not responsive to endovascular treatment or surgery.

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Jason Sheehan

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Lars U. Wahlberg, Göran Lind, Per M. Almqvist, Philip Kusk, Jens Tornøe, Bengt Juliusson, Michael Söderman, Eva Selldén, Åke Seiger, Maria Eriksdotter-Jönhagen, and Bengt Linderoth

Object

The authors describe the first clinical trial with encapsulated cell biodelivery (ECB) implants that deliver nerve growth factor (NGF) to the cholinergic basal forebrain with the intention of halting the degeneration of cholinergic neurons and the associated cognitive decline in patients with Alzheimer disease (AD). The NsG0202 implant (NsGene A/S) consists of an NGF-producing, genetically engineered human cell line encapsulated behind a semipermeable hollow fiber membrane that allows the influx of nutrients and the efflux of NGF. The centimeter-long capsule is attached to an inert polymer tether that is used to guide the capsule to the target via stereotactic techniques and is anchored to the skull at the bur hole.

Methods

Six patients with mild to moderate AD were included in this Phase Ib open-label safety study and were divided into 2 dose cohorts. The first cohort of 3 patients received single implants targeting the basal nucleus of Meynert (Ch4 region) bilaterally (2 implants per patient), and after a safety evaluation, a second cohort of 3 patients received bilateral implants (a total of 4 implants per patient) targeting both the Ch4 region and the vertical limb of the diagonal band of Broca (Ch2 region). Stereotactic implantation of the devices was successfully accomplished in all patients. Despite extensive brain atrophy, all targets could be reached without traversing sulci, the insula, or lateral ventricles.

Results

Postoperative CT scans allowed visualization of the barium-impregnated tethers, and fusion of the scans with stereotactic MR images scan was used to verify the intended positions of the implants. Follow-up MRI at 3 and 12 months postimplantation showed no evidence of inflammation or device displacement. At 12 months, implants were successfully retrieved, and low but persistent NGF secretion was detected in half of the patients.

Conclusions

With refinement, the ECB technology is positioned to become an important therapeutic platform in restorative neurosurgery and, in combination with other therapeutic factors, may be relevant for the treatment of a variety of neurological disorders. Clinical trial registration no.: NCT01163825.

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Bengt Karlsson, Arne V. Johansson, Huai-Che Yang, Hidefumi Jokura, Masaaki Yamamoto, Roberto Martínez-Álvarez, Jun Kawagishi, Wan-Yuo Guo, Guus Beute, David H. C. Pan, Wen-Yuh Chung, Michael Söderman, Hitoshi Aiyama, and Tseng Tsai Yeo

OBJECTIVE

There is a strong clinical need to accurately determine the average annual hemorrhage risk in unruptured brain arteriovenous malformations (AVMs). This need motivated the present initiative to use data from a uniquely large patient population and design a novel methodology to achieve a risk determination with unprecedented accuracy. The authors also aimed to determine the impact of sex, pregnancy, AVM volume, and location on the risk for AVM rupture.

METHODS

The present study does not consider any specific management of the AVMs, but only uses the age distribution for the first hemorrhage, the shape of which becomes universal for a sufficiently large set of patients. For this purpose, the authors collected observations, including age at first hemorrhage and AVM size and location, in 3425 patients. The average annual risk for hemorrhage could then be determined from the simple relation that the number of patients with their first hemorrhage at a specific age equals the risk for hemorrhage times the number of patients at risk at that age. For a subset of the patients, the information regarding occurrence of AVM hemorrhage after treatment of the first hemorrhage was used for further analysis of the influence on risk from AVM location and pregnancy.

RESULTS

The age distribution for the first AVM hemorrhage was used to determine the average annual risk for hemorrhage in unruptured AVMs at adult ages (25–60 years). It was concluded to be 3.1% ± 0.2% and unrelated to AVM volume but influenced by its location, with the highest risk for centrally located AVMs. The hemorrhage risk was found to be significantly higher for females in their fertile years.

CONCLUSIONS

The present methodology allowed the authors to determine the average annual risk for the first AVM hemorrhage at 3.1% ± 0.2% without the need for individual patient follow-up. This methodology has potential also for other similar types of investigations. The conclusion that centrally located AVMs carry a higher risk was confirmed by follow-up information. Follow-up information was also used to conclude that pregnancy causes a substantially greater AVM hemorrhage risk. The age distribution for AVM hemorrhage is incompatible with AVMs present at birth having the same hemorrhage risk as AVMs in adults. Plausibly, they instead develop in the early years of life, possibly with a lower hemorrhage risk during that time period.