REVlEW ARTICLE

HEMISPHERECTOMV AND ITS ALTERNATIVES IN THE TREATMENT OF INTRACTABLE EPILEPSY IN PATIENTS WITH INFANTILE H E M I PLEGlA Robert Goodman

This article traces the rise and fall of the standard hemispherectomy operation, and reviews the current neurosurgical options for patients with infantile hemiplegia and medically intractable seizures.

The rise of hemispherectomy Hemispherectomy, or more accurately cerebral hemidecortication, consists of the removal of the cortex of one cerebral hemisphere, along with a variable portion of the ipsilateral basal ganglia. In the standard operation the ablation leaves a large cavity which is in continuity with the ventricular system.

The operation was independently described by Dandy (1928) and L’hermitte (1928) as a radical treatment for malignant gliomas of the non-dominant cerebral hemisphere. It soon became apparent, however, that the operation was not curative and was no better at improving the length or quality of life than more conservative treatments.

McKenzie (1938) carried out the first hemispherectomy for the treatment of intractable seizures in a patient with infantile hemiplegia. The report generated little interest, however, and the popularity of the operation dates from the publication

in 1950 of Krynauw’s series of 12 hemispherectomies, all performed on patients with infantile hemiplegia who had seizures and behavioural disorders. His short-term results were impressive: in- tractable seizures were abolished and severe behavioural disorders were dra- matically improved, without deterioration of motor or cognitive function. However, his follow-up was limited, ranging from two weeks to five years, with a mean of less than 18 months.

The operation was enthusiastically adopted in many parts of the world for the treatment of cases of infantile hemiplegia with intractable epilepsy or severe behavioural disorders, or both. Since 1950 many published series have confirmed that the short-term results of hemispherectomy are excellent, provided the pre-existent damage is largely or entirely confined to one cerebral hemisphere (White 1961, Griffith 1967, Ignelzi and Bucy 1968, Wilson 1970, Rasmussen 1983). For example in the Wilson ( 1 970) series of 50 cases aged between 1% and 31 years at the time of operation, seizures were completely or substantially relieved in 41 cases. Preoperatively, 34 of the 50 patients had severe behavioural problems (principally

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B involving aggressiveness, impulsiveness E and hyperactivity), and these disorders

were abolished or greatly improved in 3 1 of -2 the 34. 3

4 ki Hemispherectomy rarely resulted in B intellectual deterioration or loss of 2 linguistic abilities (Wilson 1970). Indeed, - .- 5? in some instances hemispherectomy 3 appeared to enhance intellectual function, z perhaps by allowing the withdrawal of I 0 sedative anticonvulsants, or perhaps by * E protecting the intact hemisphere from I I. bombardment by seizure discharges 2 originating in the damaged hemisphere 2 (Krynauw 1950, White 1961, Griffith 1967,

Smith and Sugar 1975). Candidates for * G hemispherectomy typically had a marked a hemiparesis before surgery, and this was .- c) not worsened by the operation (Wilson ‘CI 1970). On the contrary, several authors

have reported a postoperative reduction in 9

CI s spasticity, accompanied by an improve- 2 ment in motor function (Krynauw 1950, 2 White 1961, Ignelzi and Bucy 1968). After 3 hemispherectomy, all patients had a

homonymous hemianopia (Wilson 1970). X Enthusiasm for hemispherectomy may have reached its zenith in 1968, with the publication of a review of 420 hemi- spherectomy cases from the world literature (Ignelzi and Bucy 1968). Although the mean duration of reported follow-up was only 18 months, the authors felt justified in reaching the following conclusion: ‘There are few major neurosurgical procedures which are attended with such persisting and gratifying results for all concerned. It is obvious that practically all children suffering from this condition [infantile cerebral hemiatrophy] should have a cerebral hemidecortication’. By the time this statement appeared, however, other more disquieting conclusions were already in print.

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The fall of hemispherectomy Even in the early days of hemispherectomy it was clear that the operation was not without risk. One of Krynauw’s 12 original patients died suddenly and inexplicably immediately after surgery (Krynauw 1950). Early complications have included haemorrhage, infection, fatal brain-stem displacement, and hydrocephalus of the cavitv and remaining hemimhere fDandv 252

1928, Gardner 1954, McKissock 1954, Cabieses et al. 1957). In White’s (1961) review of 269 hemispherectomy cases, postoperative mortality was 6 . 6 per cent, with a mean duration of follow-up of 16 months, but many clinicians were prepared to accept this level of risk for an operation that characteristically transformed the lives of severely handicapped individuals.

Serious late complications of hemi- spherectomy were first reported by Laine et al. (1964). Since then, several long-term follow-up studies have made it increasingly apparent that the long-term risk of hemispherectomy had been grossly underestimated (Griffith 1967, Falconer and Wilson 1969, Wilson 1970, Rasmussen 1983). In these studies the incidence of severe late complications varied from 17 to 35 per cent, with a high mortality rate. In Wilson’s series, for example, 20 per cent of hemispherectomized patients died from late complications, in addition to the 12 per cent who died from early complications (Wilson 1970). The mortality rate has been smaller in other series, and Falconer and Wilson (1969) stressed that some late deaths may be avoidable if active neurosurgical management of compli- cations is instituted soon enough. Nevertheless, as the long-term risks of hemispherectomy became apparent, the operation was largely abandoned.

The principal delayed complications of hemispherectomy are haemorrhage, hydro- cephalus and haemosiderosis, occurring as soon as one year or as late as 20 years after surgery, as described by Oppenheimer and Griffith (1966), Falconer and Wilson (1969), Wilson (1970) and Rasmussen (1983). These studies have shed some light on the pathogenesis of the delayed complications. In those patients who have come to surgery or necropsy the hemispherectomy cavity has been lined with a subdural membrane, so that the entire cavity can be thought of as a huge subdural collection which is in continuity with the third ventricle through the widely patent foramen of Monro. It seems likely that the subdural lining tends to bleed into the cavity, possibly as a result of shearing stresses associated with juddering of the remaining hemisphere when the head is jolted. Fresh and altered blood from the hemisDherectomv cavitv can pass through

the foramen of Monro into the circulating CSF, leading to chronic iron deposition both in the ependymal lining of the ventricular system and in the pial covering of the brain’s surface (Oppenheimer and Griffith 1966, Hughes and Oppenheimer 1969). The ependymal deposition may account for the proliferative ependymitis which can obstruct either the aqueduct or the exit foramina of the fourth ventricle, thereby producing hydrocephalus. The pial deposition seems to result in a superficial haemosiderosis which is particularly damaging to the cerebellum, brain-stem and eighth cranial nerves. These pathogenic mechanisms are of more than theoretical interest, since they provide a rationale for modifying the hemispherectomy technique in a way that may reduce or eliminate the late complications (Adams 1983).

The search for a safe alternative The demise of the standafd hemi- spherectomy operation inevitably prompted the question of whether any other operation could provide the benefits of a standard hemispherectomy without court- ing the same risks. Operations that have seemed fairly promising in this respect include modified hemispherectomies, com- missurotomies (split-brain operations) and stereotactic amygdalotomies. These three groups of operations will be discussed in turn. In addition, it should not be forgotten that focal excisions can be beneficial for selected hemiplegic patients. Thus, if the clinical and neuro- physiological findings suggest that a particular patient’s seizures all start in the anterior temporal lobe on the damaged side, an anterior temporal lobectomy may be therapeutic.

Modified hemispherectomy

A subtotal hemispherectomy consists of the removal of between two-thirds and four-fifths of the damaged hemisphere, leaving some functional cortex intact. For example in a hemiplegic patient who has good bilateral peripheral vision, a subtotal hemispherectomy could spare the posterior third of the hemisphere (including the posterior part of the temporal lobe), thereby preserving the visual fields. Leaving an intact portion of the damaged

SUBTOTAL HEMISPHERECTOMY

hemisphere seems to protect the patient from late complications, perhaps by splinting the normal hemisphere and thereby reducing the chance that minor head-trauma will lead to shearing stresses on the subdural membrane.

In Rasmussen’s series of @patients who had received a subtotal hemispherectomy between four and 26 years previously (median 10 years), only two patients (5 per cent) developed late complications; this compares with a late complication rate of 33 per cent for patients who had undergone a standard hemispherectomy at the same centre (Rasmussen 1983). The success rate for subtotal hemispherectomy, as judged by seizure control, is slightly lower than the success rate for a standard hemispherectomy. Rasmussen’s results again provide a useful comparison: subtotal hemispherectomy resulted in complete or nearly complete reduction of seizures in 68 per cent ofpatients; standard hemispherectomy produced a similar improvement in 85 per cent of patients (Rasmussen 198 3).

MONTREAL-TYPE HEMISPHERECTOMY In order to combine the therapeutic effectiveness of a standard hemi- spherectomy with the relative long-term safety of a subtotal hemispherectomy, the Montreal group devised an ingenious hybrid operation (Rasmussen 1983). Most of the damaged hemisphere is removed, leaving part of the frontal lobe anteriorly and part of the parieto-occipital region posteriorly. These remaining portions are then disconnected from the rest of the brain by sectioning the white-matter connections to the brain-stem and the intact hemisphere. Anatomically the result is a subtotal hemispherectomy; func- tionally the result is a complete hemispherectomy. In theory the vascular- ised but disconnected frontal and parieto- occipital poles should protect the patient from late complications without increasing the seizures.

It is still too early to be sure that this theory holds up in practice, but the preliminary results are very promising. Rasmussen (1983) reported on eight patients who had received a Montreal-type hemispherectomy: in seven cases the operation resulted in complete or nearly

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complete cessation of seizures, and the eighth patient's seizures were markedly reduced in frequency and severity. No late complications had occurred, but the duration of follow-up was still relatively brief (between two and six years).

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OXFORD-TYPE HEMISPHERECTOMY Adams (1983), in Oxford, has pioneered an alternative modification of the standard hemispherectomy. After performing a complete hemispherectomy, special pre- cautions are taken to avoid long-term complications (Fig. 1). The convexity dura on the operated side is mobilised and then sutured down to the falx, tentorium and floor of the anterior and middle cerebral fossae. As a result the hemispherectomy cavity is filled principally by an extradural collection rather than by a subdural collection. In addition, the residual subdural collection is isolated from the ventricular system by obstructing the ipsilateral foramen of Monro with a plug of muscle. If the delayed complications of standard hemispherectomy are indeed the result of having a large subdural collection in direct continuity with the ventricular system, then Adams' technique should be able to prevent late complications. Though

Fig. 1. Diagram illustrating modification of hemispherectomy by creating large exiradural space. Boxed arrow empasises importance of preserving septum pellucidum; double arrow shows foramen of Monro obstructed. (From A d a m 1983; reproduced by permission.)

plausible, this theory is still unproven. Adams reported on four patients who had undergone an Oxford-type hemispher- ectomy: seizures had ceased and behaviour had improved in all cases and no late complications had occurred, but follow-up was less than three years.

Commissurotomy Commissurotomy (the split-brain oper- ation) has been in use for over 40 years as a treatment for intractable seizures. Blume (1984) recently reviewed the clinical and experimental justification for commis- surotomy. To summarize, the forebrain commissures, particularly the corpus callosum, appear to play a major r61e in the spread of seizure discharges from one hemisphere to the other. By blocking this spread, division of the commissures can prevent focal seizure-discharges from evolving into generalized seizures or complex partial seizures. Somewhat more surprisingly, commissurotomy sometimes also reduces the frequency or severity of simple partial seizures.

Since commissurotomy does not destroy cerebral cortex, the operation causes relatively little functional impairment. Although division of the commissures can

be shown by neuropsychological testing to induce a variety of cognitive deficits (Campbell et al. 1981), generally these do not interfere with a patient’s everyday life. Operative mortality is low. Early operative complications include sepsis, hydro- cephalus, aseptic ventriculitis and a transient ‘acute disconnection syndrome’, involving left-sided apraxia, mutism, confusion, regressed behaviour and alternating focal seizures. No delayed complications of commissurotomy have been reported in over 40 years experience of the operation, apart from a few cases of delayed worsening of focal seizures (Spencer et al. 1984).

Luessenhop (1970) reported two patients with infantile hemiplegia and intractable generalized seizures who had been submitted to ‘complete commis- surotomies’ (i.e. division of the entire corpus callosum, the anterior commissure, one fornix and the hippocampal commissure) at three years of age. One patient had only two generalized seizures in the 22 months following surgery, and the other had only occasional focal motor seizures in the nine months following surgery.

Avila et al. (1980) described two patients with congenital hemiplegia whose in- tractable seizures and behavioural disorders were considerably improved following anterior callosotomies (i. e. division of only the anterior half or two-thirds of the corpus callosum) at 18 years of age. Unfortunately the duration of follow-up was not reported.

More recently, Goodman et al. (1985) described five patients with congenital hemiplegia and intractable seizures who had undergone either a complete commissurotomy or a complete callos- otomy between two and 12 years previously (mean five years). The patients were aged between nine and 39 years at the time of operation. The response was excellent in four cases: incapacitating seizures had ceased, though some relatively innocuous seizures had persisted, e.g. episodes of malar numbness or rare nocturnal episodes of stiffening of the hemiparetic arm. The fifth patient’s disabling seizures had persisted, though their frequency had decreased by 75 per cent. There were no relapses or late

complications. If the visual fields were intact preoperatively, commissurotomy did not produce hemianopia. If the hemiparesis was submaximal preoper- atively, commissurotomy did not worsen the hemiparesis. In order to obtain satisfactory seizure control with as small an operation as possible, Goodman and colleagues recommend an anterior cal- losotomy as the initial operation, to be followed, if incapacitating seizures persist, by completion of the callosotomy a few months later. Performing the callosotomy in two stages has the additional advantage of reducing the severity and duration of the acute disconnection syndrome (Harbaugh et al. 1983).

Stereotactic amygdalotomy Stereotactic destruction of the amygdala has been used in the treatment of convulsive and behavioural disorders (Heimburger et al. 1966). Balasubramaniam and Kanaka (1975) carried out stereotactic amygdalotomies on 10 patients with infantile hemiplegia aged between 11 and 20 years, all of whom had severe behavioural disorders, and eight of whom had intractable seizures. In each case the amygdalotomy was unilateral, being carried out on the hemisphere contralateral to the hemiparesis. At follow-up there had been cessation o r near-cessation of seizures in all eight epileptic patients. As far as postoperative behaviour was concerned, seven patients were ‘very much docile and given to occasional outbursts only’, while the other three were ‘manageable when given drugs, though not leading a useful life’. There were no deaths attributable to the operation, and no postoperative complications are mentioned.

Although the results of amygdalotomy seem impressive, the study has an important methodological limitation. Before surgery all the epileptic patients received a combination of phenytoin, phenobarbitone and primidone in ‘max- imal tolerable dose’. After operation they were maintained on a lower dose of phenytoin and phenobarbitone alone. Since anticonvulsant blood-levels were not available, it is impossible to be sure that the preoperative seizures and behavioural disturbances were not aggravated by the anticonvulsant regime, with postoperative

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TABLE I

Advantages Disadvantages

Modified hemispherectomy High probability Serious late that all seizures complications may will cease* occur

Functioning cortex is sacrificed*

Commissurotomy High probability Some seizures that incapacitating persist, though seizures will be usually relieved relatively minor Functioning cortex not sacrificed No serious late complications reported to date Can be converted subsequently into a hemispherectomy if necessary

*Less so with subtotal hemispherectomy than with Montreal-type or Oxford-type hemispherectomy.

improvement being due principally or entirely to the reduction in drug therapy. The benefits of amygdalotomy have yet to be confirmed in a study without these limitations.

Discussion Various neurosurgical operations are available for the treatment of intractable seizures, with or without behavioural disorders, in patients with infantile hemiplegia. Preliminary results suggest that some of these operations are both effective and relatively safe. However, they should only be considered if incapacitating seizures persist despite adequate trials of suitable anticonvulsants, used singly and in combination, and adjusting dosage where appropriate according to blood levels.

Which is the most suitable operation? There is no simple answer, partly because pertinent long-term comparative studies have yet to be carried out, and partly because different operations may suit different patients. For a few patients the clinical and neurophysiological findings may suggest that a limited excision (e.g. anterior temporal lobectomy) should be the operation of first choice. For most patients, however, the choice will be between a modified hemispherectomy and

a commissurotomy. Since the benefits of stereotactic amygdalotomy are still unconfirmed, this option will not be discussed further.

Both hemispherectomies and commis- surotomies can be performed on children or adults. At one extreme, hemi- spherectomy has been performed on a 1 %- year-old with hemiplegia, and commis- surotomy on a three-year-old. At the other extreme, both operations have been performed on patients with infantile hemiplegia in their 30s.

The pros and cons of modified hemispherectomy and commissurotomy are compared in Table I. The two sets of operations differ in four main areas: safety, efficacy, preservation of function and convertibility.

Safety Commissurotomy has the best long-term safety record. It has been performed for over 40 years and no life-threatening late complications have been described (though conceivably this could reflect inadequate follow-up or too-small sample sizes). Modified hemispherectomies do not have as good a safety record: Rasmussen (1983) reported fatal late complications in 5 per cent of the patients who had undergone a subtotal hemispherectomy. The long-term risk for a Montreal-type hemispherectomy is likely to be similar; that for an Oxford-type hemispherectomy is unknown.

Efficacy Modified hemispherectomies, particularly the Montreal and Oxford types, are highly effective procedures, abolishing seizures completely or nearly completely in most patients. Commissurotomies are also effective but ‘complete cures’ are unlikely: in the largest available series they did relieve incapacitating seizures in four of five patients with congenital hemiplegia, but all the beneficiaries continued to have rare or relatively minor seizures (Goodman et al. 1985).

Preservation of function Whereas a Montreal-type or an Oxford- type hemispherectomy automatically re- sults in the loss of any functioning cortex on the damaged side, a subtotal

hemispherectomy can spare some func- tioning cortex and a commissurotomy preserves all cortex (whether functioning or not). The clinical importance of these differences varies from case to case. If a patient already has a dense hemiplegia and a homonymous hemianopia, neither a commissurotomy nor a modified hemi- spherectomy is likely to produce additional neurological impairment. By contrast, if a patient has a submaximal hemiparesis and intact visual fields, different operations will induce different degrees of impairment. For example a Montreal-type hemispherectomy will ag- gravate the hemiparesis and produce hemianopia, while a commissurotomy will have neither of these adverse effects.

Convertibility If necessary, a commissurotomy can later be converted into a modified hemi- spherectomy. For example if patients continue to have incapacitating seizures despite a complete callosotomy, they can still undergo a Montreal-type hemi- spherectomy. The converse does not hold.

Even when all these considerations are taken into account, it is still difficult to decide which operative strategy to employ for any given patient. At present it is not possible to predict which patients will respond well to a commissurotomy, and which will only respond to a modified hemispherectomy. In this state of ignorance a choice has to be made between a ‘definitive’ and an ‘escalating’ approach.

The definitive approach is designed to produce maximum benefit from a single operation, with all patients undergoing either a Montreal-type or an Oxford-type hemispherectomy. Seizures and be- havioural disorders are likely to be cured in most cases. However, this undoubted benefit is purchased at a price. First, all patients will need a careful life-long follow- up because of the small risk of potentially fatal late complications. Second, the operation impairs the neurological functioning of some patients, e.g. those with normal visual fields. The main drawback to the definitive approach is that had all the patients undergone a

commissurotomy, many of them would have received comparable benefits at a lower price.

The escalating approach initially employs as conservative an operation as possible, only resorting to radical operations when more conservative ones have failed. One possible escalating strategy would involve a three-stage plan: (1) first an anterior callosotomy; (2) if that fails to produce adequate seizure control, then a complete callosotomy; and (3) if that also fails, then either a Montreal-type of an Oxford-type hemispherectomy. By following this strategy most patients would be rid of incapacitating seizures without having to undergo a modified hemispherectomy, with its attendant risks and impairments. The main drawback to this escalating approach is that the most resistant cases still end up with a hemispherectomy, but they have had to go through three operations instead of only one.

The escalating approach has particular advantages for the patient with a submaximal hemiparesis and intact visual fields, since a commissurotomy will produce much less impairment than a modified hemispherectomy. For patients who already have dense hemiparesis and a hemianopia, however, the advantages of the two approaches are more balanced. The choice is likely to depend partly on local experience and partly on the views of individual clinicians, patients and parents.

The need for a multi-centre study Although commissurotomies and modified hemispherectomies both seem promising, more information is needed about their relative safety and efficacy. This information could be obtained most easily by pooling the results of different centres, using standardized evaluations both before surgery and during follow-up. This collaboration would increase the sample size and would allow a direct comparison between similar patients who had undergone different operations.

Accepted for publication 8th July 1985.

Author’s Appointment Registrar, Epilepsy Unit, The Maudsley Hospital, Denmark Hill, London SE5 8AZ.

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