DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY. 1962, 4, 170-179

Neil Gordon

The Investigation of Epilepsy

EPILEPSY is a symptom, and like any other symptom its significance may vary con- siderably from patient to patient. An occasional seizure in an otherwise healthy person may indicate no more than an increased predisposition to such attacks under a certain set of circumstances. The dramatic nature of this particular symp- tom, however, will demand a proportion- ately detailed examination of the patient, quite apart from the fact that the social implications of this diagnosis make it essential that the term is not used incorrectly.

There have been two recent trends in the study of epilepsy, the first is a realisation that whether the cause of fits can be elucidated or not their occurrence must be viewed against the background of a person’s liability towards them. The various factors, chemical or electrophysio- logical, that may account for this phen- omenon are as yet uncertain, but the aphorism that the commonest cause of focal epilepsy is idiopathic epilepsy is undoubtedly true. For instance, it is a common observation that among a group of patients who have had head injuries of roughly similar severity only a few will develop post-traumatic epilepsy. Secondly, it is becoming increasingly apparent that the diagnosis of idiopathic epilepsy is rarely an adequate one, even in the limited

extent of our present knowledge. Admit- tedly, it may seldom be possible to state exactly why a particular patient develops epilepsy, but the diagnosis of temporal lobe epilepsy as opposed to idiopathic epilepsy does reflect a certain increase of knowledge, with the additional prognostic and therapeutic implications of the former classification.

The Electroencephalogram If it is now accepted that the diagnosis

of ‘epilepsy’ is no longer sufficient, and that every attempt should be made to qualify this in some way or other, a fair amount of the credit for this must be given to workers in the field of electroence- phalography. For instance, Jackson and Beevor described the typical uncinate fit in 1890 and suggested that its origin was from within the uncal portion of the hippocampal gyrus, but the present under- standing of seizures arising from within the temporal lobe had to await the discoveries of Berger in 1933.

An EEG should be done in the majority of epileptic patients, since it may be of assistance in diagnosis, prognosis and treatment. Except in the classical form of petit ma1 precipitated by overbreathing, it is often difficult to be sure of the origin of the epileptic discharge, especially in children who cannot describe their symp-

Dr. Gordon is Consultant Neurologist to the Royal Manchester Children’s Hospital and Booth Hall Children’s Hospital.

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toms. Even when the patient suffers only from apparent lapses of consciousness doubt may be cast on the diagnosis of petit ma1 if, for instance, the attacks only occur infrequently. Then the electroence- phalogram may show not the expected outbursts of spike-and-wave activity but an epileptic discharge confined to the temporal lobe. Gastaut (1954) has stressed this difficulty in diagnosis by terming these seizures ‘temporal pseudo-lapses’.

The EEG may aid in the diagnosis between epilepsy and ‘attacks’ of psycho- genic origin when the episodes are of an unusual kind. The record may also show unexpected focal abnormalities, especially if the patient has only suffered from major convulsions. Conversely, clinical seizures suggesting a focal cortical origin for the epileptic activity may be found to be associated with generalised discharges arising from within the diencephalon. Howell (1955) has suggested that these attacks may be the result of a restricted spread by continuity of the epileptic discharge in the central areas of the brain, followed by projection to a restricted area of the cortex in one hemisphere. This would then lead to an attack mimicking a focal cortical seizure.

This test may therefore help in the ‘anatomical’ diagnosis of the epileptic discharge by revealing its site or origin, and there is no doubt that with the help of serial recordings and various activating techniques this can be established in the majority of cases. It may also aid in the ‘pathological’ diagnosis. The demonstra- tion of a well-marked cortical epileptogenic focus will strongly suggest the presence of a lesion in this area, although in a child it is likely to be of a non-progressive type, such as an area of gliosis resulting from ischaemia at birth (Earle et al. 1953). Sometimes the record shows generalised abnormalities which gradually become more marked and help to confirm that

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the patient is suffering from a progressive degenerative cerebral disease such as an inclusion-body encephalitis.

EEGS may be of use in prognosis as well as diagnosis. Harris and Tizard (1960) have shown that in the newborn there are two classes of fits. The first type is characterised by focal clonic movements and by focal electroencephalographic abnormalities. The clinical associations of this kind of seizure suggest that in many cases focal hemisphere damage may have resulted from previous anoxia. The second group include attacks of symmetrical tonic spasm, sometimes preceded or followed by clonic jerks and associated with a flattening of the record in the EEG. These fits accompany acute anoxia.

The significance of the EEG to the future prognosis of the infant who develops convulsions is uncertain, follow-up studies having concentrated more on the clinical aspects of the problem. Burke (1954) found that the incidence of neonatal convulsions was 0.2 per cent. Among the 46 infants studied, 18 died and 5 were severely retarded, 2 of these continuing to have fits. However, Tizard and Harris (1960) did consider that their findings suggested that the EEG in the newborn might be of prognostic value.

In the field of cerebral palsy there appears to be a poor correlation between the types of cerebral palsy, the incidence of epileptic seizures and the electroence- phalographic findings. Among 157 children referred to the electroencephalographic departments at the Royal Manchester Children’s Hospital and Booth Hall Children’s Hospital there were 66 suffering from hemiplegia, 41 from spastic tetra- plegia, 26 from spastic diplegia, 18 from athetosis and 6 from ataxic tetraplegia. Table I shows the electroencephalographic abnormalities in those with no history of epilepsy and Table I1 the abnormalities in those who had had seizures.

DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY. 1962, 4

0 Ataxic Tetraplegia . .

TABLE I-EEG ABNORMALITIES IN 109 CHILDREN WITH CEREBRAL PALSY AND NO HISTORY OF EPILEPSY

O I 0 1

General Focal

General Focal Normal Dysrhythmia Slow Waves

I Hemiplegia .. .. I 17 I 17 I 3 I 2 I 2 I

Focal Spikes Generalised and Epileptic

Sharp Waves Activity

I Athetosis . . . . I 12 I l I o I o I o I

Spastic Diplegia . . Athetosis . . . . Ataxic Tetraplegia . .

0 3 0 1 1

2 2 0 0 1

0 1 0 0 0

TABLE 11-EEG ABNORMALITIES IN 48 CHILDREN WITH CEREBRAL PALSY AND A HISTORY OF EPILEPSY

Hemiplegia .. .. I 2 1 6 1 7 1 6 I 4 I Spastic Tetraplegia . . I 3 I 4 I 3 I 0 I 2 I

Normal records and those showing only a generalised dysrhythmia may be less frequent in the patients who had had seizures but they still constitute nearly half the total. Epileptic activity also appears in a significant number of children giving no history of fits. The number of these children is too small to permit any conclusions to be drawn about the incidence of epilepsy and electroence- phalographic abnormalities in the different types of cerebral palsy, but the findings do show that in an individual patient the presence or absence of epileptic activity in a single EEG may be of no particular significance in relation to the occurrence of epilepsy.

Perlstein and his colleagues (1 947) found that the incidence of epilepsy among patients with cerebral palsy was 86 per cent

in the spastic group and 12 per cent in the athetoid group. The comparable figures given by Aird and Cohen were 66 and 34 per cent. Crothers and Paine (1959) found that 73 out of 97 children with natal and prenatal hemiplegia had abnormal EEGS, though only 55 per cent of the group ever had epileptic fits. Of the children with postnatal hemiplegia, 72 per cent suffered from epilepsy and roughly the same percentage had abnormal EEGS. Epilepsy was much less frequent among those with normal or borderline EEGS. Ab- normal tracings were found in 31 of the 54 patients with spastic cerebral palsy and 42 of the 86 with extrapyramidal and mixed types. These authors also correlated the type of electroencephalographic abnor- mality with the patient's clinical state. The only definite finding appeared to be the

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NEIL GORDON

~ dJ~Jp&“~ I i I

Fig. 1 . EEG from a mentally backward boy, aged 12 years, having numerous major and minor fits unresponsive to treatment of any kind.

poor prognostic significance of widespread 2-2+ per second spike-and-wave complexes or ‘petit ma1 variant’ (Fig. 1). This finding was likely to be associated with severe brain damage and mental retardation, although the patient might cease to suffer from epilepsy with increasing age.

Lundervold (1960) has emphasised that single records from cerebral palsied child- ren are of very limited value. He found, however, that serial examinations, espec- ially when compared with clinical and radiological findings, gave useful infor- mation and helped to differentiate between stationary and progressive lesions. In fact, there is no doubt that unless a single EEG

gives exactly the information sought from it, repeated records may be essential if full use is to be made of this ancillary method. This is particularly true of prognosis, as was stressed by Chao and others (1958). A normal EEG in a child having convulsions is a good prognostic sign, and the associ-

ation of typical petit ma1 seizures with the classical 3-per-second spike-and-wave activity in the EEG almost always means that there is no associated cerebral disease. It has already been said that in children the demonstration of slow spike-and-wave activity or ‘petit ma1 variant’ is a poor prognostic sign, and the more violently disorganised pattern termed ‘hypsarhyth- mia’ (Fig. 2) is even more likely to denote severe mental and physical disability. This pattern may also be an indication for urgent treatment with steroids (Bower and Jeavons 1961). The demonstration of a generalised dysrhythmia will rarely add any useful information to the patient’s assessment, unless it shows significant changes in serial records. Well-marked generalised abnormalities, however, even in the absence of epileptic activity, are likely to mean that the epilepsy is symp- tomatic rather than ‘ideopathic’. Also, in the case of so-called febrile convulsions,

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DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY. 1962, 4

RC-RL

-uo

L --.-.. .... - Fig. 2. EEG from a boy of 9 months suffering from ‘massive spasms’. The epilepsy and the hypsarhy-

thmia disappeared within a few days of starting treatment with ACTH.

the finding of an abnormal EEG should lead to a more guarded prognosis so far as the occurrence of further fits unasso- ciated with fever is concerned.

In discussing diagnosis, it has been shown that the EEG may help in the differentiation between different types of epilepsy, particularly between true petit ma1 and other forms of minor epilepsy, and this may well be helpful in planning treatment. The dione group of drugs, which are so helpful in the treatment of true petit mal, may well aggravate focal cortical seizures. Apart from sometimes indicating the type of treatment most likely to benefit the patient, the usefulness of the EEG in controlling therapy is limited. There may be a poor correlation between the occurrence of epileptic activity in the record and the clinical incidence of seizures, but it is probably true that if such activity persists to any severe degree it would be unwise to discontinue treat-

ment even if the clinical response is satisfactory. Serial EEGS are particularly necessary if the patient’s fits do not respond to appropriate drugs. This will probably form part of further investigations to try and establish the cause of the epilepsy, since ‘symptomatic’ epilepsy is certainly more difficult to treat than ‘idiopathic’. Even when no lesion can be demonstrated radiologically, clear-cut focal abnormalities on the EEG may indicate a damaged area of the cortex. If adequate and protracted medical treatment has failed to control the patient’s fits, and if the focus is in an area of the brain which can be removed without serious disability resulting, surgical treatment may be considered. Histological examination of the excised portion may reveal an area of gliosis, possibly the result of previous ischaemia (Earle et al. 1953), but some- times neoplastic changes are found un- expectedly.

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NEIL GORDON

Other Routine Investigations Radiological examination of the skull

is probably the investigation most often done in epileptics, but the films rarely demonstrate any significant abnormalities. Intracranial calcification suggesting cysti- cercosis, toxoplasmosis or even an intra- cranial tumour is a very uncommon finding, and radiological evidence of raised intracranial pressure is not usually seen when there are no obvious clinical signs. Other routine tests, such as the Wassermann reaction and blood-counts, are also unlikely to help except in excep- tional cases. Examination of the cerebro- spinal fluid is an unrewarding investigation unless there is a definite suggestion that the epilepsy is symptomatic of an intra- cranial lesion. In fact, apart from the EEG, the results of such routine tests are usually within the limits of normal and the question of carrying out more elaborate investigations arises. Abnormalities found on clinical examination may indicate the lines that these should take, whether the findings are neurological or indicate some disorder of another system, as in the patient recorded by Litchfield et al. (1958), who had been having attacks of uncon- sciousness for 20 years, which were eventually found to be a result of heart block.

Biochemical Investigations In the absence of any abnormal physical

signs indicating an intracranial lesion, the next group of tests to be considered are those designed to reveal metabolic dis- orders. The electrolyte estimations most likely to show significant abnormalities are the serum-levels ofcalcium and phosphorus. The occurrence of epileptic seizures as a symptom of tetany is well known, but it is not so often recognised that tetany can lead to epilepsy in its more chronic forms. Cantor (1961) reported the case of a man of 73 who had been subject to generalised

convulsions ever since an operation on the thyroid gland 25 years before. The man’s serum-calcium was found to be 4.4 mg. per 100 ml., and after treatment with thyroid extract and calciferol the patient’s condition greatly improved and the fits stopped. Hyperparathyroidism may also lead to cerebral damage, and although this is most likely to cause dementia, convul- sions may also occur (Tizard 1960). Pyridoxine dependency or deficiency as a cause of fits in infants should be tested for by giving pyridoxine, which abolishes the convulsions if this is the cause.

Another condition which may present as epilepsy, even with focal fits, is hypo- glycaemia. When the cause is a hyperplasia or adenoma of the islet cells of the pancreas the diagnosis may prove difficult (Williams 1959). The timing of the seizures may suggest this diagnosis if they tend to occur after a period of fasting, and the description of the attacks may be sufficiently unusual at least to establish that the epilepsy is of a symptomatic type. In childhood the blood-sugar may fall to significantly low levels after the ingestion of amino-acids, including leucine, without any associated abnormality of the pancreas (Cochrane et al. 1956). The hypoglycaemia of hepatorenal glycogen storage (von Gierke’s) disease may cause twitching or convulsions, as may also the hypogly- caemia of hypopituitarism.

The difficulty in diagnosing hypogly- caemia as a cause of epilepsy is increased by the fact that the glucose-tolerance test may well be normal between the attacks and the blood-sugar level may quickly return to normal during them, especially if convulsions occur. One of the unusual ways in which hypoglycaemia may remain undisclosed for a long time is illustrated by the case-report published by Dormandy and Porter (1961). Their patient had suffered from epilepsy for 38 years and had often been admitted to hospital in a

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confused state. The results of repeated glucose-tolerance tests and estimations of fasting blood-sugar levels were within normal limits but urine chromatograms for sugars gave large fructose spots. Further investigations confirmed that the patient was suffering from fructose intol- erance and that after the ingestion of fructose, which could not be correctly metabolised, the blood glucose fell although the total blood sugar remained within normal limits.

In problems of this kind a urine chromatogram for sugars may certainly be a useful screening test. A urine chromatogram for amino-acids may also show significant abnormalities, especially in children. Phenylketonuria may present with frequent epileptic seizures, sometimes in the form of infantile spasms (Kirman 1961). A number of metabolic disorders leading to brain damage have now been described, such as ‘maple sugar urine disease’ and ‘Hartnup’s disease’.

Allan and colleagues (1958) described a family of which two members were mentally defective. One of these had convulsions and was originally thought to be suffering from idiopathic epilepsy. Further investigations showed that the urine amino-acid chromatogram was grossly abnormal, and it has now been shown that the abnormal substance ex- creted in the urine was argininosuccinic acid (Westall 1959). In the hope of discovering other defects of protein meta- bolism, Miss V. K. Wilson at the Royal Manchester Children’s Hospital, has examined the urines from over 200 patients with mental deficiency and epilepsy. This work will be published shortly, but so far only an excess of the sulphur-containing amino-acids has been found. There does not seem to be a direct relationship between the abnormal amino-aciduria and the occurrence of convulsions, as has been suggested by Choremis et al. (1959).

Neurosurgical Investigations It is a common experience to investigate

a patient suffering from frequent epileptic seizures with all the tests that have been discussed and to find no significant abnormalities, except perhaps an abnormal EEG. If the patient responds satisfactorily to medical treatment, a period of further observation to ensure that progress con- tinues to be satisfactory may be all that is required. However, if the fits continue in spite of intensive and varied anticonvulsant therapy, and especially if the patient finds it impossible to lead a normal life, one must decide whether any further steps can be taken that might lead to improvement. These will usually take the form of more detailed electro-encephalographic studies, air encephalography, or carotid arterio- graphy, in the hope of demonstrating a focal cerebral lesion or at least evidence of a cortical epileptogenic focus that might be amenable to surgery.

When there is no evidence of a progres- sive cerebral lesion, the decision to carry out such tests will largely depend on the failure of medical treatment. If there are signs of cerebral damage, such as infantile hemiplegia, an operation to remove the damaged section of brain may be con- sidered, but most of these patients will show no clinical abnormalities. Then, the next step may be to try and demonstrate focal abnormalities in the EEG, if necessary with the use of special techniques such as sphenoidal electrodes or activating drugs like bemegride. In the case of temporal lobe epilepsy it will almost always be possible to confirm the evidence of the patient’s history suggesting that the fits are arising from this area (Falconer and Cavanagh 1959). However, the absence of focal activity in the EEG by no means excludes the possibility of a cortical lesion. This was shown in a case reported by Bates et al. (1956). A child of 12 years had suffered from convulsions and out-

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bursts of temper. All investigations, in- cluding air-encephalography and carotid arteriography, were normal, and the EEGS showed outbursts ‘of bilateral sharp and slow wave complexes in the frontal regions. When these complexes were studied on a number of occasions, it was noted that they showed slight but con- sistent differences on the two sides. As the child was quite unmanageable, it was decided on the electroencephalographic evidence alone to turn a frontal flap. A large angiomatous malformation with evidence of previous haemorrhage and thrombosis was found, and after this had been removed improvement was sufficient for the patient to return to an ordinary school.

In patients who do nor respond to medical treatment it will have to be decided sooner or later whether special radiological investigations are going to be carried out. Even though there may be no abnormalities on examination to indicate cerebral damage the description of the fits may strongly suggest the diagnosis of focal epilepsy, and the electroencephalo- graphic findings may also favour the presence of a focal cortical lesion. If this is in an area which can be removed without serious disability resulting, further investigations are particularly indicated. The epileptogenic lesion may be only a small area of cortical scarring, in which case all the radiological tests may be negative, but surgical removal can still be considered on the basis of the electro- encephalographic results alone, especially if these include electrocorticography (Earle et al. 1953). However, the accessibility of the lesion should not be the deciding factor, since even a long history of epilepsy does not entirely exclude the possibility of a progressive lesion, usually a benign type of glioma.

The other lesions most likely to lead to chronic epilepsy are vascular anomalies.

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These may be small and difficult to demonstrate, as in the case recorded by Bates et al. (1956). Occasionally an angioma may be filled by vertebral but not by carotid angiography, which empha- sises that if it is decided to carry out tests of this kind it seems only logical to complete the radiological investigations by every available means before presuming that they cannot demonstrate any intra- cranial lesion. Bleeding from a small angioma, perhaps early in life, may lead to spontaneous cure of the vascular lesion but leave a benign cyst within the brain to act as an epileptogenic focus. A lesion of this type may be associated with diffuse epileptic activity in the EEG and this is sometimes found to be less marked on the side of the lesion, presumably owing to an interference with electrical con- duction (Fig. 3).

Conclusions In epileptics whose history and clinical

examination reveal nothing to indicate a progressive lesion, certain investigations, such as X-rays of the skull, an EEG, and biochemical tests, should if possible be done as a routine.

Tetany is recognised by finding a low level of total or ionised calcium. Hypo- glycaemia may not be present between the attacks. In hyperinsulinism (idiopathic or due to hypertrophy or neoplasm of the islets of Langerhans) hypoglycaemia occurs on fasting but loading tests are necessary to reveal the leucine-reactive or carbohydrate (fructose, glucose)-reactive forms. Urine chromatography for amino- acids reveals phenylketonuria, Hartnup’s disease, maple syrup urine disease, and argininosuccinic aciduria ( Allan’s syn- dr ome) .

The main indication for doing more elaborate investigations, such as air-ence- phalography and carotid arteriography, is the patient’s response to medical treatment.

DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY. 1962, 4

Fig. 3. EEG from a patient with a large cyst occupying the medial and posterior part of the left frontal lobe, showing the preponderance of abnormal activity from over the right central regions.

This will necessitate a period of obser- also seems essential to complete such tests vation, which should be adequate for an before coming to a decision that may assessment of the patient’s progress but affect the patient’s future life, such as not too long, especially in children. It admission to an epileptic colony.

REFERENCES Aird, R. B., Cohen, P. (1950) ‘Electroencephalography in cerebral palsy.’ J. Pediut., 37,448354. Allan, J. D., Unsworth, D. C., Dent, C. E., Wilson, V.K. (1958) ‘A disease probably hereditary, charac-

terised by severe mental deficiency and a constant gross abnormality of amino-acid metabolism.’ Lancet, i, 182-187.

Bates, J. A. V., Cobb, W., Williams, D. J. (1956) ‘A verified case of secondary bilateral synchrony.’ Electroenceph. din. Neurophysiol., 8, 161.

Bower, B. D., Jeavons, P. M. (1961) ‘The effect of corticotrophin and prednisolone on infantile spasms with mental retardation.’ Arch. Dis. Childh., 36, 23-33.

Burke, J. B. (1954) ‘The prognostic significance of neonatal convulsions.’ Zbid, 29, 342-345. Cantor, A. M. (1961) ‘A case of unrecognised tetany.’ Brit. J. clin. Pruct., 15, 609. Chao, D. H., Druckman, R., Kellaway, P. (1958) Convulsive Disorders of Children. Philadelphia and

Choremis, C., Kyriakides, V., Karpouzas, J. (1959) ‘Aminoaciduria in epilepsy.’ J. Pediut., 55, 593-601. Cochrane, W. A., Payne, W. W., Simkiss, M. J., Woolf, L. I. (1956) ‘Familial hypoglycemia precipitated

Crothers, ,B., Pain, R. S. (1959) ‘The natural history of cerebral palsy.’ Cambridge, Mass.: Harvard

Dormandy, T. L., Porter, R. J. (1961) ‘Familial fructose and galactose intolerance.’ Lancet, i, 1189-1194. Earle, K. M., Baldwin, M., Penfield, W. (1953) ‘Incisural sclerosis and temporal lobe seizures produced

Falconer, M. A., Cavanagh, J. B. (1959) ‘Clinico-pathological considerations of temporal lobe epilepsy

Gastaut, H. (1954) The Epilepsies, Electro-clinical Correlations. (Amer. Lecture Series, No. 204). Spring-

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by amino-acids.’ J. din. Invest., 35, 41 1422.

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by hippocampal herniation at birth.’ Arch. Neurol. Psychiut. (Chicago), 69, 2742.

due to small focal lesions. A study of cases submitted to operation.’ Bruin, 82,483-504.

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NEIL GORDON

Harris, R., Tizard, J. P. M. (1960) ‘The electroencephalogram in neonatal convulsions.’ J. Pediar., 57,

Howell, D. A. (1955) ‘Unusual centrencephalic seizure patterns.’ Brain, 78, 199-208. Jackson, J. H., Beevor, C. E. (1890) ‘Case of tumour of the right tempero-sphenoidal lobe bearing on the

localisation of the sense of smell and on the interpretation of a particular variety of epilepsy.’ Ibid, 12, 346349.

Kirman, B. H. (1961) ‘Phenylketonuria: clinical aspects.’ Cer. Palsy Bull., 3, 244-248. Litchfield, J. W., Manley, K. A., Polak, A. (1958) ‘Stokes-Adams attacks treated with corticotrophin.’

Lancet, i, 935-937. Lundervoold, A. (1960) ‘EEG in cerebral palsy.’ Cer. Palsy Bull., 2, 82-88. Perlstein, M. A., Gibbs, E. L., Gibbs, F. A. (1947) ‘The electroencephalogram in infantile cerebral palsy.’

In ‘Epilepsy’. Ass. Res. nerv. Dis. Proc., 26, 377-384. Tizard, J. P. M. (1960) In Paediatrics for the Practitioner. Suppl. 1960. Ed. Gaisford, W. F. and Lightwood,

R. C. London: Butterworth. - Harris, R. (1960) ‘The electroencephalogram : neonatal fits.’ Electroenceph. clin. Neurophysiol., 12, 543. Westall, R. G. (1960) ‘Argininosuccinic aciduria: identification and reactions of the abnormal metabolite

in a newly described form of mental disease, with some preliminary metabolic studies.’ Biochem. J., 77, 135-144.

Williams, D. (1959) In Biochemical Aspects of Neurological Disorders. Ed. Cummings, J. N. and Kremer, M. Blackwell: Oxford.

501-520.

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