British Journal of Neurosurgery (1992) 6, 177-185

ORIGINAL ARTICLE

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Untoward clinical effects after stereotactic radiosurgery for intracranial arteriovenous malformations J. C. SUTCLIFFE, D. M. C. FORSTER, L. WALTON, P. S. DIAS & A. A. KEMENY Radiosurgical Service, Royal Hallamshire Hospital, Glossop Road, Shefield SlO 2JF, UK

Abstract Stereotactic radiosurgery has become one of the most acceptable means of treating deep-seated intracranial arteriovenous malformations, as well as being a useful adjunct in a number of other pathologies. One hundred and sixty patients are discussed, having follow-up of at least 2 years. Radionecrosis occurred in six patients and haemorrhage in the latent period prior to thrombo-obliteration in a further six. Successful thrombo-obliteration was ultimately achieved in 76% of patients. As a bonus, epilepsy was improved in 29 of 48 patients presenting with seizures and worsened transiently in only three of these.

Key words: Stereotactic radiosurgery, arteriovenous malfonnawn, radionecrosis, haemorrhage, epilepsy.

Introduction Surgery for an intracranial arteriovenous malformation (AVM) has always carried a significant risk’J of morbidity and mortality and whilst these risks have, with the advent of modern anaesthetic and surgical techniques, substantially reduced:-5 such operations may still pose a significant surgical challenge. Leksell introduced his stereotactic frame in 19486 and first suggested radiosurgery in the early 1950s, trying first photons from a 300 kV X-ray tube, then protons from the Uppsala 185 MeV synchrocyclotron, before turning to gamma-rays from cobalt-60 in his unit in 1968.’ Since these early days the system has been refined and developed to yield a technique which carries with it a low risk and yet does not sacrifice the goal of treatment, namely the obliteration of the nidus of the malformation. In Sheffield, between September 1985 and December 1990, stereotactic radiosurgery

(STRS) has been used to treat a total of 507 patients with AVMs. Amongst these patients there were three main groups of ‘untoward events’ occurring after radiosurgery: radionecrosis, haemorrhage and epilepsy. This study presents the incidence of these events in those patients who had been followed up for at least 2 years.

Materials and methods

Among the patients who have been treated with STRS for intracranial AVMs, 160 have a follow-up of at least 2 years. Their ages range from 11 months to 76 years (Fig. l), the sex distribution being equal. These patients were referred primarily from other units within the UK, but also from other countries. The gamma unit (Elekta Instruments Inc, Tucker, Georgia, USA) delivers high precision, narrow beams of ionizing radiation from

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J. C. Sutclife et al.

FIG. 1. Age of patients. MyPatients treated; $, radionecrosis.

201 cobalt-60 sources in the form of gammarays (of energy 1.17 and 1.33 MeV) in a single dose, although one or more adjacent or overlapping fields can be used. The irradiation is given using a combination of fields can be used. The irradiation is given using a combination of fields with up to four different collimator sets, with sizes from 4 to 18 mm. Treatment is planned so that the periphery of the lesion lies as closely as possible to the steepest gradient of the isodose contour and receives 2500 cGy, with the peak dose at the centre of the nidus not exceeding 5000 cGy. This is the standard dose used in most cases, but some reduction was made, usually of the order of 10-15%, in children under 10 years, patients with unusually large AVMs and in a few cases where the dose to a vital structure such as an optic nerve would have exceeded lo00 cGy. Localization of the AVM is performed with angiography, using the Leksell stereotactic system (Forth Medical Ltd, 28 Kingfisher Court, Newbury, Berkshire, UK). The referring unit was requested to perform C T scans at 6-monthly intervals following treatment and to repeat angiography at an interval of 2 years. The films were sent to this department and critically appraised by the senior author and neuroradiologist, at which stage the degree of thrombo-obliteration was graded on a scale from 0 to 4 (Table I).

TABLE I. Angiographic grading Grade

Angiographic findings Nochange

0 1 2

Minimal reduction in size

Significant reduction in size Absence of fast-flowcomponents No trace of any remaining abnormal vessels

3 4

Single 99

(62%)

Two vessels 40 (30%)

nG.2.

Number of feeding vessels.

Results

Radionecrosis is not always a well-defined term. For the purpose of this study radionecrosis is used to describe a clinico-radiological phenomenon, namely the development of neu-

Stereotactic radiosurgery

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TABLE 11. Patients suffering radionecrosis

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Time post Age Patient (years) Sex treatment 1 2 3 4 5 6

M.S. P.C. J.B. A.R. S.C. M.A.

13 16 19 21 30 39

F

10 9 9 13 15 17

M

F M

F F

Site

Size No. of Volume (cm) feeders (mm’

Pons Pons Leftsylvian Lefttrigone Leftrolandic Right thalamus

2 1 2 2 2 2

4

2.5 4 3 4 2.5

5183 6371 7917 5833 12,335 5278

TABLE 111. Presenting features of radionecrosis Presentation Patient

Age (years) Sex

1 M.S.

13

2 P.C.

3 4 5 6

J.B. A.R. S.C. M.A.

Initially

Radionecrosis

Outcome

F

Haemorrhage

Persistent

16

M

Haemorrhage

19 21 30 39

F

Seizures Haemorrhage Seizures Haemorrhage

Ataxia/dysuthria VI/VIIn palsies Bilat VIIn palsies internuclear ophthalmoplegia Right hemiparesis Headache Left hemiparesis Left hemiparesis

M

F F

+

+

Persistent

Improved Improved Improved Persistent

TABUIV. Patients suffering deterioration in epilepsy

Patient

Age (years) Sex

Presentation seizures

1 J.R.

26

M

Major +focal

2 J.B.

38

M

Minor

3 R.M.

14

M

Minor

rological sequelae following brain irradiation, associated with an area of tissue swelling within the intensely irradiated volume, in the absence of haemorrhage or other known aetiology. Sometimes the term radionecrosis is applied, by other authorities, only on the basis of the C T appearances (low attenuation surrounded by a ring of contrast enhancement). A total of six (3.7%) patients suffered what is thought to have been radiation-induced brain damage as a result of their treatment, this occurring between 9 and 17 months after STRS (Table 11). Of these six patients, five had malformations supplied by two main

Complication

Change in medication

Recurred after None STRS (3 y) Increased in Nil to severity carbamazepine Major (4 months) Increased valproate

feeding vessels and one had only a single feeder. In this series, 99 (62%) AVMs were fed by a single feeder, 48 (30%) by two and 12 (7.5%) by three vessels (Fig. 2), with only one having over three feeding vessels. The clinical features of radiation-induced brain damage reflected the anatomical site of the AVM (Table 111). The two youngest patients to develop such features had pontine lesions and developed cranial nerve palsies, associated with ataxia in one and with an internuclear ophthalmoplegia in the other. In both cases the symptoms have persisted. Three further patients developed increasing hemiparesis, two

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FIG.3. (a) Contrast enhanced CT

scan showing a left sylvian AVM before STRS (top left) and at 6 (top right), 12 (bottom left) and 18 months (bottom right) after. (b) Same patient as in (a) 2 years following STRS. (c) Axial MRI scan before STRS showing signal voids from the AVM. (d) Parasagittal view at the same stage. The abnormal vessels are well demonstrated. (e) The same patient one year following STRS, axial view. Reactive changes are seen on this T2-weighted image. (f) Parasagittal view at the same stage as (c). T1-weighted image shows fewer flow voids. (9) Two years following STRS the flow voids have disappeared. (h) Parasagittal view at the same stage as (e).

of which improved with steroids, but the third did not. Only one patient presented with headache and symptoms of raised intracranial pressure; these symptoms subsequently im-

proved. All the patients are relatively young (the eldest being 39 years), four female and two male, fitting into the modal distribution groups of the total (Fig. 1).

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Stereotactic radiosurgery

Haemorrhage, as an untoward event, is defined in this context as an intracranial haemorrhage occurring during the latent period following STRS prior to complete radiation-induced thrombo-obliteration proven by angiography, assuming that these are spontaneous bleeds and not associated with trauma. A total of six of these 160 patients (3.75%) suffered a haemorrhage after treatment but

before thrombo-obliteration had been achieved. These included one fatal case where there had been no previous haemorrhage. Three (1.9%) patients suffered a bleed in the first year after STRS, two (1.3%) during the second year and a further patient (0.6%) suffered a late haemorrhage in the third year, having only achieved partial thrombo-obliteration at that stage. The overall success rate of

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STRS, as judged by complete or virtually complete thrombo-obliteration of the AVM, on the first 50 patients treated was 50 and 72% at one years and 72 and 76%, respectively, at 2 years.g Epilepsy was, in this series, the sole presenting feature in 18% of patients and a further 12% had fits associated with a haemorrhage. Of the 48 patients out of the 160 with 2-year follow-up presenting with epilepsy, 38% have had no further seizures at all after STRS and a further 22% have improved seizure control. Thus there was an overall improvement in 60%. Control of seizures deteriorated in three of these 48 patients (6%), either because of recurrence of seizures as a late event, or because of increased drug requirements. One patient, who was not previously on medication, required treatment for prolonged partial seizures which became worse during the morning following STRS (Table IV). A few other untoward effects were encountered. Complications related to angiography occurred in two patients. In one a transient hepatitis developed, in the other a transient hemiballismus, which did not require treatment. A transient superficial cellulitis at one of the skull fixation sites has been noted on one or two occasions. Nausea and occasional vomiting has occurred in some patients with posterior fossa lesions, early in the series. This has not delayed discharge and has not been a problem since the introduction of antiemetics and dexamethasone, starting the day before STRS and finishing 24 h after treatment, for such patients.

high dose field will become occluded by intimal and medial degeneration and basal lamina thickening, together with an inflammatory response, leading to ischaemic changes in larger vessels with platelet adhesion and ultimately obliteration. If any functionally important vessels, lacking a collateral circulation, are included in this process further ischaemic brain damage will occur. This may give rise to clinical signs if an eloquent area is affected. Hence the location of the AVM is of importance in the development of clinically significant radionecrosis. These changes can be followed on CT, MRI (Fig. 3) or, perhaps better still, PET if available. The angiographic changes (Fig. 4) follow a similar time course to these, correlating with the time of fibrinoid necrosis of the vessels. By 2 years the active changes are almost over. Some degree of necrosis, i.e. death of tissue, as a result of the irradiation is likely if normal tissues are present within the malformation and, therefore, within the high dose radiation field. In the treatment of cerebral AVM thrombo-obliteration is what the radiosurgeon plans and hopes to achieve. Indeed this has been known to be a side-effect of conventional, fractionated radiotherapy for many years.1°-12 However, in the context of an ‘untoward effect’, radionecrosis may be an exaggerated and, possibly, idiosyncratic response, which fortunately occurs in only a few cases. If this were the case it might be best referred to as ‘hyper-reactive radionecrosis’, but this is not a generally accepted term. Stereotactic radiation could have similar effects on any vessel, normal or pathological. Fortunately, however, the pathological vessels Discussion at the nidus of an AVM seem to be particularly Irradiation of biological tissues is thought to sensitive to radiation in the doses delivered in cause an immediate effect at an intracellular this way and preservation of normal vessels in level in the form of ionic flux, hydroxyl release the territory of AVMs successfully treated by and changes in membrane permeability, al- STRS is usually found. Dose rate itself, in this series, does not though there are usually no discernible clinical effects for several months. However, in due appear to explain why some patients develop course some astrocytic or glial cells will die and neurological deterioration whereas others if radiation has depleted the stem cell popula- treated in a similar manner do not. All our tion replacement cells will not appear. In patients received standardized treatment, the addition, capillaries and small arterioles in the dose rates in the patients who had no ill effects

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FIG. 4. Left carotid angiogram of the same patient as in Fig. 3 showing the sylvian A V M before (top) and 2 years after (bottom) STRS.

being similar to those in whom neurological deterioration appeared. Nevertheless, these dose rates are high in comparison to those used in conventional, fractionated radiotherapy. The size of the AVM does, theoretically, influence the development of neurological deterioration, as the larger the nidus the greater the chance of including functional tissue in the field of high dose irradiation and the larger the rim of normal tissue receiving just less than the prescribed dose. Steiner pointed out in 1979 that patients with AVMs exceeding 3 cm in maximum diameter are more likely to experience neurological deteriora-

tion.13 (Of our total of 355 patients treated hitherto, 22% had AVMs larger than 3 cm in diameter.) Four of our six patients with neurological deterioration had AVMs exceeding or equalling 3 cm. The total volume of the lesion is taken into account in patient selection and the choice of dose (Table 11). Volume itself is not a limiting factor for the Leksell system, if one bears in mind the reduced rate of thrombo-obliteration and the progressively increasing risk of radiation-induced side-effects. The manner of initial presentation of the AVM, either haemorrhage, steal phenomenon

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or epilepsy, does not seem to relate to the development of neurological deterioration. One is, however, forming the impression that a persisting neurological deficit prior to radiation, perhaps an indication of limited cellular reserve, may be associated with a higher than usual risk of sequelae. The risk of haemorrhage from an untreated AVM is 2-3% per year14-16 in patients who have not bled recently. Following a haemorrhage the rebleed rate rises to 6% in the first year and then falls again to 2-3%.5J7 Our patients coniirm further this pattern prior to radiosurgery; 76% of all our patients presented initially with a haemorrhage. The risk of haemorrhage from an AVM decreases, as might be expected, following STRS, as the thrombo-obliteration progresses. It is already lower than the expected rate at the end of the first year. Epilepsy is often a feature of AVMs and the effects of STRS on epilepsy have not so far been described. Epilepsy is considerably improved in the majority of patients treated in this series. The reason for this has not been proven. These patients with high flow vascular malformations are clearly not candidates for depth electrode recording. However, it would seem likely that the epileptogenic focus may lie in the functional tissue immediately adjacent to the malformation and, therefore, might be included in the high dose field. Irradiation of this region may thereby eliminate the focus. T o our knowledge no patient has yet developed epilepsy following STRS when this was not present in some form beforehand, although clearly this could happen whilst the high flow malformation persists unobliterated.

Leksell units in S t o c k h ~ l m CharlottesvillelE ,~~ and Pitt~burgh.'~It remains open to debate what incidence of radiation-induced sideeffects is acceptable, bearing in mind the risk of haemorrhage in the untreated, the rate of successful obliteration, and the prospects of improvement in epileptic status. The time scale of the development of radionecrosis demands follow-up for at least 2 years. In this series there does not appear to be a relationship with age or sex (although there does seem to be a trend for young people to respond quicker and better to this form of treatmentE). The only clear risk factors, apart from dose, for the development of radionecrosis are the size of the malformation and its location in an eloquent area. In addition, there is the possibility that patients who have suffered a severe or persisting neurological deficit before radiation may be more prone to untoward effects.

Acknowledgements This work could not have been carried out without the enthusiastic and skilled support of the nurses, secretaries, radiographers, medical technicians, physicists, anaesthetists, radiotherapists and radiologists, as well as the neurosurgical junior medical staff at the Royal Hallamshire and Weston Park Hospitals in Sheffield.

Address for correspondence: D. M. C. Forster, Neurosurgical Unit, Royal Hallamshire Hospital, Sheffield S10 2JF, UK. References

Conclusions Whilst treating an AVM in an eloquent area with STRS is, perhaps not surprisingly, hazardous because of the risk of involving normal end arteries, these risks compare favourably with those of open surgery. The overall incidence of radionecrosis in this series, 3.7%, appears to be similar to the experience of other

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Untoward clinical effects after stereotactic radiosurgery for intracranial arteriovenous malformations.

Stereotactic radiosurgery has become one of the most acceptable means of treating deep-seated intracranial arteriovenous malformations, as well as bei...
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