J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.38.3.225 on 1 March 1975. Downloaded from Journal of Neurology, Neurosurgery, and Psychiatry, 1975, 38, 225-231

Involuntary movements caused by phenytoin intoxication in epileptic patients

S. AHMAD, JOHN LAIDLAW, G. W. HOUGHTON, AND A. RICHENS From the National Hospitals-Chalfont Centre for Epilepsy, Chalfont St Peter, Bucks. and the Department of Clinical Pharmacology, St Bartholomew's Hospital, London

SYNOPSIS The case histories of four patients who developed choreoathetoid movements during intoxication with phenytoin are presented. Drug intoxication was confirmed in each case by measur- ing the serum phenytoin concentration. Drug interactions were, in part, responsible for the occur- rence of intoxication in three of them. Phenytoin intoxication is not always easy to recognize, par- ticularly when nystagmus is minimal or absent, as in these four patients. The estimation of the serum phenytoin concentration is invaluable in this situation.

The classical signs of phenytoin intoxication are signs. A left carotid arteriogram showed a shift to the Protected by copyright. coarse nystagmus, ataxia, and dysarthria, which right of the anterior cerebral artery, and a pneumo- are signs of cerebellar dysfunction. Less com- encephalogram (AEG) showed displacement of the monly, other neurological disturbances may be ventricles to the right without significant alteration caused by phenytoin intoxication (Glaser, 1972). of ventricular size or shape. A gross unilateral abnormality over the left hemisphere posteriorly was Although choreoathetosis has been described seen on EEG. The pathological significance of these (Peters, 1962; Logan and Freeman, 1969; findings was uncertain. His fits were bizarre in Kooiker and Sumi, 1974; McLellan and Swash, pattern and were asymmetrical, being more marked 1974), only a few cases have been documented on the right, and being accompanied by transient adequately. During the last two years we have aphasia. A three day course of corticotrophin seen involuntary movements in four patients, (ACTH) was without effect, but when pheneturide two of whom presented with severe choreo- 400 mg daily was started the fits appeared to de- athetosis. These patients are described in the crease in frequency and severity. However, four days following case reports. after starting this drug, he developed marked choreo- athetoid movements involving head, neck, and upper CASE 1 limbs. Although it was felt at the time that this was due to the same process as that causing the fits, the http://jnnp.bmj.com/ Patient R.C. was a 19 year old man who developed movements disappeared when pheneturide was with- epilepsy at 7 years of age. Investigations at this time drawn. revealed no focal lesion, although the generalized abnormalities seen on the electroencephalogram The following year four admissions were required (EEG) were more marked in the right frontoparietal to attempt to achieve better control of his fits. On region. Four days after he was started on phenytoin two occasions he was noticed to have minimal signs 150 mg and phenobarbitone 120 mg daily, he be- of a transient left hemiplegia. came drowsy and developed coarse nystagmus and In May 1973, he was admitted to a mental hospital on October 1, 2021 by guest. an extensor plantar response. Withdrawal of drug and during his stay there his anticonvulsant therapy therapy was followed by a disappearance of the was altered in order to control his frequent fits. neurological signs. Sulthiame 300 mg and diazepam 30 mg daily were When 10 years old, he was admitted to hospital added, and the primidone which he had been receiv- with frequent major fits, occurring once or twice ing for several years was discontinued. Phenytoin hourly on the day of admission. He was semi- 300 mg daily was continued unchanged. His fits conscious and irritable, but there were no localizing appeared to come under better control on this new (Accepted 5 September 1974.) drug regime, but when interviewed in June 1973 for 225 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.38.3.225 on 1 March 1975. Downloaded from 226 S. Ahmad, John Laidlaw, G. W. Houghton, and A. Richens possible admission to the National Hospitals- 200 Chalfont Centre for Epilepsy, he was noted to be -J00- fidgety, almost to the extent of making choreiform movements. Admission was arranged for the follow- -50- ing month but he failed to arrive. Almost two o months later an urgent request for his transfer to the 0 Chalfont Centre was made by another hospital to w I O- which he had been admitted three weeks earlier with u an episode of vomiting and repeated major fits. to During his stay in this hospital, his drug therapy had been increased to 600 mg phenytoin, 300 mg I. sulthiame, 180 mg phenobarbitone, and 1 500 mg of E beclamide daily. 4D When admitted to the Chalfont Centre on 10 September 1973, he was unable to stand and showed bizarre dystonic posturing. The upper limbs were 0 2 3 4 5 b 7 abducted and internally rotated at the shoulder, Days semiflexed at the elbow, markedly flexed at the wrist FIG. 1 Case 1. Decay in serum phenytoin concen- and metacarpophalangeal joints, and extended at the tration after discontinuing all drug therapy. The interphalangeal joints. This posture was con- horizontal dotted line indicates the limit of accurate tinuously disturbed by choreoathetoid movements detection of the method. Note: 4 FiM= 1 Fgfml. involving the face, trunk, and all four limbs. Slow extension and flexion movements of the wrists and fingers were seen and adduction and abduction, re- Protected by copyright. traction, and internal rotation movements of the with increasing frequency and he was therefore shoulders. The feet were plantar-flexed and the big started on 150 mg phenytoin and 150 mg pheno- toe dorsiflexed. There were continuous slow flexion barbitone daily. Two weeks later the dose of pheny- and extension movements of the hips and knee toin was increased to 250 mg daily, but without an joints. He was unable to hold his tongue protruded, exacerbation of the choreoathetoid movements. At and grimacing movements of the face were occurring this time, examination of his nervous system re- frequently. Slight nystagmus was seen on lateral vealed only slight fine tremor of his hands and mild gaze. The limb and trunk movements so disturbed impairment of coordination, in addition to the odd his posture that he twice fell out of bed, and had movements mentioned above, which occurred eventually to be managed for the first 24 hours in a mainly when he was talking. No nystagmus was side ward with no furniture and with mattresses seen. A serum phenytoin level measured when he had lining the floor and walls. A serum phenytoin level been stabilized on 250 mg of the drug was 23 F±M measured on admission was 203 ,uM (51 Vg/ml) (6 F±g/ml). He was eventually discharged four months which is well into the toxic range (100 ,uM, 25 pLg/ml after his admission. is regarded as the upper limit of the therapeutic range

in our laboratory). CASE 2 http://jnnp.bmj.com/ All drug therapy was withheld for seven days and the decay of the serum phenytoin concentration was Patient M.H., a 34 year old woman, developed epi- followed (Figure). The decay was at first very slow, lepsy of unknown aetiology at 8 years of age. Her but by the fifth day the concentration was only a major and minor fits had proved difficult to control. little above the limit of detection (see Discussion She had received 500 mg phenytoin and 250 mg section for comment on these observations). An phenobarbitone daily (as five Epanutin and pheno- EEG recorded 24 hours after admission showed a barbitone capsules) for 10 years before her admis-

moderately severe generalized abnormality, with a sion to the Chalfont Centre, although her parents on October 1, 2021 by guest. dominant frequency of 4-6 Hz. A week after admis- reduced the dose to three capsules daily whenever sion the dominant had increased to a frequency of she developed diplopia. 6-7 Hz. On admission on 9 November 1972, no neuro- At this time his abnormal movements had largely logical abnormalities were found. An EEG showed a ceased, although he continued to have odd, un- mild diffuse abnormality, with a dominant rhythm restrained movements for the rest of his four months of 7-9 Hz. On 16 November her drug dosage was stay at the Chalfont Centre. After seven days without reduced to 300 mg phenytoin and 180 mg pheno- anticonvulsant therapy his minor fits were occurring barbitone daily because she was becoming ataxic. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.38.3.225 on 1 March 1975. Downloaded from Involuntary movements caused by phenytoin intoxication in epileptic patients 227

Phenytoin intoxication was later confirmed when the Three days later she was beginning to show signs of a result of a serum phenytoin level was available on a return of her previous ataxia, dysarthria, involuntary specimen taken at the time of drug reduction. The movements, and sleepiness. On 15 February she was level was 180 tiM (45 t±g/ml). unable to stand unaided, and therefore phenytoin On 25 November she developed a febrile illness was again withdrawn. A serum sample taken just which was treated with ampicillin 250 mg six hourly. before stopping the drug showed a phenytoin level Her temperature rose to 39.50C but settled again of less than 5 ,uM (1 ,ug/ml). within two days. Ten days later, on 5 December, she Her fits were again difficult to control, requiring an was noticed again to be ataxic and dysarthric, and intravenous drip of diazepam on one occasion. showed incoordination on heel-to-shin testing. She Eventually satisfactory control was achieved with did not have nystagmus. An EEG at this time 180 mg phenobarbitone, 750 mg primidone, and 600 showed rather more slow activity, with runs of mg carbamazepine daily. The involuntary move- rhythmic waves at 4-5 Hz anteriorly. The following ments gradually disappeared during the next month day a relief doctor diagnosed status epilepticus and and, although her ataxia has improved, her gait re- transferred her to a local hospital, where her drug mains a little unsteady at the time of writing a year dosage was increased to the original level. Her 'fits', later. however, did not improve and it became obvious that the diagnosis was incorrect. She was returned to CASE 3 the Chalfont Centre and drug therapy was immedi- ately withdrawn. Twenty-four hours later her serum Patient W.C., a 28 year old woman, had her first phenytoin level was 170 ,uM (42.5 ,ug/ml). She was epileptic fit when 18 years of age. Investigations at dysarthric, grossly ataxic, and she showed con- the National Hospital, Queen Square, when she was tinuous movements of her limbs. She was transferred 20 years old revealed no cause for her epilepsy, but to the National Hospital, Queen Square, for investiga- her father had been epileptic since early childhood. Protected by copyright. tion. On admission to the Chalfont Centre in 1969 she was On arrival she was found to be fully conscious and receiving 250 mg phenytoin, 750 mg primidone, 300 followed events around her, but cooperation was mg sulthiame, and 10 mg dexamphetamine daily. extremely limited. She was perpetually grimacing, Larger doses of sulthiame had caused ataxia. Soon frowning, raising her eyebrows, pursing her lips, after admission she was noted to be ataxic, and had smiling, and showing bizarre movements of mouth slight nystagmus on lateral gaze. Withdrawal of and tongue. She was unable to stand, even with sulthiame led to a disappearance of these signs. In help, and exhibited restless movements of trunk and May 1970, 200 mg pheneturide daily was started limbs which were considered to resemble athetosis because of frequent major fits. She remained on this more than chorea. The only reflexes which could be treatment for the following three years. Several EEG elicited were the biceps and triceps bilaterally and recordings during her first four years at the Chalfont these were diminished. The plantar responses were Centre had shown runs of bilateral, high amplitude flexor. Muscle power, coordination, and sensation slow waves, spikes, and polyspikes. were untestable. After withdrawal of her phenytoin In February 1972 she developed athetoid move- therapy, the involuntary movements slowly im- ments of her right arm, and uncontrollable twitching proved, but she remained generally incoordinated of her mouth, but these symptoms appeared to http://jnnp.bmj.com/ and ataxic. Her fits were adequately controlled on respond to 10 mg diazepam given intravenously. 750 mg primidone and 180 mg phenobarbitone On 13 June 1973 she was started on chlorphenir- daily. Investigation at this time showed an erythro- amine 12-16 mg daily for hay fever, which she had cyte sedimentation rate (ESR) of 51 mm in the first had annually since childhood, and this drug was hour, but this gradually fell to normal. Cerebro- continued until the end of the month. On 25 June spinal fluid, chest and skull radiographs, and an she was noticed to be fidgeting her hands and toes. AEG were normal. EEGs on this and previous She had slight grimacing movements of her face, occasions showed only a diffusely abnormal record. and, although she could protrude her tongue and on October 1, 2021 by guest. On her return to the Chalfont Centre on 3 Jan- hold it steady, involuntary movements of her lower uary 1973, she remained ataxic and her fits became jaw caused her to bite the protruded tongue. Her inadequately controlled. It was noted that after fits speech was slightly explosive, but not slurred. She she showed involuntary movements resembling was not ataxic and she did not hayve nystagmus. A those which occurred during phenytoin intoxication. serum phenytoin level estirnated on 28 June was In order to achieve better control of her fits she was 120 XuM (30 Fg/ml). By the time this result was started on 150 mg phenytoin daily on 9 February. available four weeks later, the abnormal movements J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.38.3.225 on 1 March 1975. Downloaded from 228 S. Ahmad, John Laidlaw, G. W. Houghton, and A. Richens had settled spontaneously, and a repeat serum DISCUSSION phenytoin estimation without a change of anti- convulsant therapy was 63 ± 4.4 liM (mean ± SD of Although phenytoin is one of the most valuable seven specimens estimated over four days). Subse- drugs in current use for the management of quently the single tablet of pheneturide which she major epilepsy, it produces a wide range of had been receiving was withdrawn without change in adverse effects (Glaser, 1972). The commonest the frequency of her fits, and the serum phenytoin adverse effect on the central nervous system is level fell further, to 39 ± 4.1 FiM. the well-recognized syndrome of phenytoin intoxication. This syndrome is an expression of CASE 4 a functional disturbance of the cerebellum, pro- ducing coarse nystagmus on lateral gaze, ataxia, Patient L.A., a 61 year old woman, had been ad- and mitted to the Chalfont Centre in 1967. She had had slurred speech. The syndrome is reversible in fits since the age of 45 years, and these were con- its early stages, although prolonged intoxication sidered to be temporal lobe in origin. Several EEG can lead to permanent ataxia. Whether phenytoin recordings had demonstrated frequent sharp wave toxicity is responsible for the Purkinje cell loss in and spike discharges of greatest amplitude and the cerebellum is disputed (Dam, 1972). showing phase reversal over the right temporal lobe, Less commonly, a syndrome which has been accentuated by overbreathing. Intellectual deteriora- called 'phenytoin encephalopathy' occurs. Rose- tion had caused her admission to a mental hospital man (1961) coined the term 'Dilantin inebriety' in 1966. On admission to the Chalfont Centre, she to describe the association ofcerebellar signs and was receiving 300 mg phenytoin, 600 mg sulthiame, 1000 mg phensuximide, and 150 mg promazine daily. behavioural abnormalities, changes in mood, Soon after admission, diazepam was substituted for and a slowing of the dominant rhythm in theProtected by copyright. promazine. In 1968 it was noticed that she had a EEG, with the appearance of high voltage delta tremor of her right hand with possibly a slight in- waves, sometimes occurring in paroxysms. crease in the tone of the right arm, accompanied by Subsequently, Levy and Fenichel (1965) de- occasional twitching movements. These were thought scribed an increase of fit frequency and a change to be signs of Parkinsonism and she was started on in pattern occurring with phenytoin intoxication. 150 mg orphenadrine daily. The fits changed from typical t onic-clonic In November 1972, an attempt was made to with- convulsions to ones in which opisthotonic draw sulthiame therapy, but frequent minor fits posturing was evident, resembling those de- occurring a few days later made it necessary to scribed in animals by Gruber et al. (1940). Two start the drug again. A serum phenytoin level of their patients had unilateral motor and measured earlier in the year was 80 ,uM (20 ,ug/ml), sensory signs, including hemianaesthesia, hemi- but just before withdrawal of sulthiame a lower paresis, and homonymous hemianopia, and value was recorded, 60 FM (15 ,ug/ml). these signs receded on withdrawal of phenytoin. A year later, in November 1973, she became Transient hemiplegia had also been described by ataxic and had marked tremor of both hands. Morris et al. (1956), although the two patients http://jnnp.bmj.com/ Shortly afterwards, she became confused and de- these authors were veloped involuntary jerkings of the upper limbs, presented by receiving only shrugging of the shoulders, bizarre movements of 200 mg phenytoin daily. Confusion with a post- the mouth and facial muscles, and fidgeting of her ictal Todd's paralysis must, of course, be borne fingers. She had coarse finger tremor, mild nystag- in mind. mus on lateral gaze, and incoordination of upper and One of the patients studied by Levy and lower limbs. A serum phenytoin level at this time Fenichel (1965) developed lip smacking which was 105 ,uM (26.5 tug/ml). Sulthiame, phensuximide, occurred during fits provoked by phenytoin on October 1, 2021 by guest. and diazepam were withdrawn and she was started intoxication. More obvious involuntary move- on 750 mg primidone. The dose of phenytoin re- ments associated with intoxication had been mained unchanged at 300 mg/day. Within seven days the involuntary movements had disappeared, al- mentioned by Peters (1962). Several adult though she remains unsteady on her feet at the time patients manifested bizarre extrapyramidal symp- of writing four months later. Two weeks after the toms, including head nod, fish mouthing, and change of drug her serum phenytoin level had fallen athetoid movements. Logan and Freeman (1969) to 30 [uM (7.5 Ftg/ml). also describe a patient (case 4) in whom choreic J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.38.3.225 on 1 March 1975. Downloaded from Involuntary movements caused by phenytoin intoxication in epileptic patients 229 and athetoid movements of face and all extremi- phenytoin intoxication can occur in the absence ties, with dystonic posturing of the arms, occur- of nystagmus. In our patients nystagmus was red. In this and three other patients, a diagnosis either minimal or absent, despite the presence of of a childhood degenerative disease was enter- gross ataxia and involuntary movements. We tained, and the authors stress that phenytoin would agree with Perlo and Schwab (1969) and intoxication should always be considered when Logan and Freeman (1969) that the diagnosis of mental and neurological deterioration occurs in a phenytoin intoxication is not always an easy one patient receiving the drug. to make, and emphasize that it should be con- Kooiker and Sumi (1974) have reported two sidered when any unusual neurological or patients with severe involuntary movement dis- behavioural disturbance occurs in a patient orders characterized by facial grimacing and receiving the drug. The estimation of serum mouthing movements, flailing movements of the phenytoin concentration is invaluable in this arms, dystonic posturing of the trunk, and situation. ataxia. Both patients were dysarthric but nystag- mus was seen only transiently in one. Serum PRACTICAL IMPLICATION IN MANAGEMENT A few phenytoin levels were well into the toxic range. important points in the management of epilepsy McLellan and Swash (1974) have also described are illustrated by these cases. Case 1 highlights two patients with prominent choreoathetoid the danger of introducing sulthiame in a patient movements and dystonia associated with toxic who is already receiving phenytoin. Judging by serum phenytoin levels. It was noted that the serum phenytoin level subsequently obtained voluntary movement accentuated the choreo- when he was taking 250 mg daily, the level on athetosis. Although cerebellar signs were seen, in 300 mg daily in this patient would probably be Protected by copyright. neither case were these a prominent feature. One within the therapeutic range of 40-100 ,uM patient was noted to have asterixis, a sign de- (10-25 ,ug/ml). Sulthiame is a potent inhibitor of scribed also by Engel et al. (1971). Both patients phenytoin metabolism, and has been shown to lost their involuntary movements when the dose produce an average increase in the serum level of phenytoin was lowered. of approximately 7500 (Houghton and Richens, Although the movement disorders shown by 1974a, b). Of the 194 patients newly admitted to our patients were, in general, similar to those of The National Hospitals-Chalfont Centre for previously reported cases, a few points of neuro- Epilepsy during the last two years 33 (170%) had logical interest arise. The occurrence at an toxic serum phenytoin concentrations, and of earlier age of choreoathetoid movements and these 10 (300O) were receiving sulthiame in other neurological signs in case 1, and, albeit less addition to phenytoin. Phenytoin intoxication clear cut, in cases 3 and 4, supports the sugges- would explain his odd, athetoid movements tion by Logan and Freeman (1969) that drug when he was interviewed before admission. The toxicity seems to interact with underlying presence of these movements, or perhaps an cerebral disease. Our patients' rate of recovery actual increase in fit frequency, provoked by http://jnnp.bmj.com/ from intoxication was variable, but was slow- intoxication, accounts for the increase in the est in the two (cases 1 and 2) who were most dose of his drugs before admission to the severely intoxicated. In our experience, the Chalfont Centre, although doubling the dose of neurological manifestations of phenytoin in- phenytoin to 600 mg daily was inappropriate, toxication may long outlast the presence of the particularly with the simultaneous administra- drug in the serum, sometimes by many months. tion of sulthiame.

The subsequent sensitivity of case 2 to small Withdrawal of all therapy led to a slow fall in on October 1, 2021 by guest. amounts of phenytoin was notable. A dose of serum phenytoin concentration (Figure). If the 150 mg daily, leading to a serum concentration rate of metabolism were proportional to the of only 5 ,uM (1 ,ug/ml), provoked marked signs serum concentration of the drug, as occurs with of intoxication within a few days. Levy and first order kinetics, a log-linear fall in serum Fenichel (1965) had the same experience with concentration against time would have been one of their patients. predicted (Arnold and Gerber, 1970). This was Perlo and Schwab (1969) pointed out that obviously not so, and the deviation from first J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.38.3.225 on 1 March 1975. Downloaded from 230 S. Ahmad, John Laidlaw, G. W. Houghton, and A. Richens order kinetics in this patient has two explana- Richens, 1974a, b), pheneturide (Huisman et al., tions. At high serum concentrations phenytoin 1970), isoniazid (Kutt et al., 1966), and various metabolism becomes saturated, resulting in others (Kutt, 1972). It is notable that two of our kinetics more closely resembling zero order than patients (cases 1 and 4) were receiving sulthiame, first order-that is, a linear, rather than log- and one (case 3) was receiving pheneturide in linear, fall in serum concentration (Arnold and addition to phenytoin. It is also worthy of com- Gerber, 1970; Gerber and Wagner, 1972; ment that a factor responsible for inhibition of Atkinson and Shaw, 1973; Houghton and phenytoin metabolism was mentioned in three of Richens, 1974c; Richens, 1974). Furthermore, the published case reports of choreoathetosis in the simultaneous withdrawal of sulthiame in this epileptic patients. Administration of anaesthetic patient would have resulted in a progressive agents preceded the onset of involuntary move- restoration of the activity of the hydroxylase ments in two of the patients studied by Logan enzyme metabolizing phenytoin, and this exag- and Freeman (1969); the case reported by Engel gerated the change in rate of metabolism during et al. (1971) was receiving isoniazid for tubercu- the first few days after drug withdrawal. lin conversion; and one of the patients described Case 2 illustrates one of the problems which by McLellan and Swash (1974) had been re- arises with the management of epilepsy in a ceiving sulthiame. neurological outpatients clinic. Unreliable drug Although multiple drug therapy is sometimes taking occurs frequently, and admission to necessary in severe epilepsy, it is unfortunately hospital results in a substantial increase of serum true that toxic combinations of drugs are most drug concentrations (Gibberd et al., 1970). In often encountered in the patient whose epilepsy our experience, titration of drug dosage by the is essentially drug resistant. He sometimes suffers Protected by copyright. patient or his parents is also frequently en- not only his fits, but iatrogenic disease in addi- countered. While this may lead to effective tion. In our experience often the most valuable control, it presents a hazard when the patient is contribution to the welfare of such a patient is to admitted to hospital and given the prescribed withdraw all or most of his drug therapy. dose regularly. Although this patient had been Sometimes, dramatic improvement in both prescribed 500 mg phenytoin daily, her average mental and physical state results. intake was probably substantially below this. It is known that quite small increments in drug The authors would like to thank Dr T. C. Nicol (Lingfield can to a increase in the Hospital School), Dr M. Swash (The London Hospital), dosage lead considerable and Dr R. Kocen (The National Hospital, Maida Vale) serum level once the therapeutic range of serum for their help in compiling these case histories. Financial concentration has been reached, for the relation- assistance was provided by the British Epilepsy Associa- ship between the two is non-linear, becoming tion and Chalfont Research Fund. progressively steeper as the dose increases (Bochner et al., 1972; Atkinson and Shaw, 1973; REFERENCES Mawer et al., 1974; Richens, 1974). The control Arnold, K., and Gerber, N. (1970). The rate of decline of http://jnnp.bmj.com/ of many patients with therapeutic serum pheny- diphenylhydantoin in human plasma. Clinical Pharmacol- toin levels is on a knife edge, so that intoxication ogy and Therapeutics, 11, 121-134. be a number of environ- Atkinson, A. J., Jr, and Shaw, J. M. (1973). Pharmacokinetic can precipitated by study of a patient with diphenylhydantoin toxicity. mental changes which cause only a relatively Clinical Pharmacology and Therapeutics, 14, 521-528. slight reduction in hydroxylating enzyme activ- Bochner, F., Hooper, W. D., Tyrer, J. H., and Eadie, M. J. ity. It is possible that a febrile illness in case 2 (1972). Effect of dosage increments on blood phenytoin was an additional precipitating factor. The concentrations. Journal of Neurology, Neurosurgery, and Psychiatry, 35, 873-876. on October 1, 2021 by guest. timing of the antihistamine therapy in case 3 Dam, M. (1972). Diphenylhydantoin. Neurologic aspects of that inhibit toxicity. In Antiepileptic Drugs, pp. 227-235. Edited by suggests chlorpheniramine might D. M. Woodbury, J. K. Penry, and R. P. Schmidt. Raven phenytoin metabolism, although we know of no Press: New York. reports indicating such an interaction. It is Engel, J., Cruz, M. E., and Shapiro, B. (1971). Phenytoin recognized, however, that a number of drugs encephalopathy? Lancet, 2, 824-825. Gerber, N., and Wagner, J. G. (1972). Explanation of dose- may inhibit phenytoin metabolism-for example, dependent decline of diphenylhydantoin plasma levels by sulthiame (Hansen et al., 1968; Houghton and fitting to the integrated form of the Michaelis-Menten J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.38.3.225 on 1 March 1975. Downloaded from Involuntary movements caused by phenytoin intoxication in epileptic patients 231

equation. Research Communications in Chemical Pathology Kutt, H., Winters, W., and McDowell, F. H. (1966). Depres- and Pharmacology, 3, 455-466. sion of parahydroxylation of diphenylhydantoin by anti- Gibberd, F. B., Dunne, J. F., Handley, A. J., and Hazleman, tuberculosis chemotherapy. Neurology (Minneap.), 16, B. L. (1970). Supervision ofepileptic patients taking pheny- 594-602. toin. British Medical Journal, 1, 147-149. Kutt, H. (1972). Diphenylhydantoin. Interactions with other Glaser, G. H. (1972). Diphenylhydantoin. Toxicity. In drugs in man. In Antiepileptic Drugs, pp. 169-180. Edited Antiepileptic Drugs, pp. 219-226. Edited by D. M. Wood- by D. M. Woodbury, J. K. Penry, and R. P. Schmidt. bury, J. K. Penry, and R. P. Schmidt. Raven Press: New Raven Press: New York. York. Levy, L. L., and Fenichel, G. M. (1965). Diphenylhydantoin Gruber, C. M., Haury, V. G., and Drake, M. E. (1940). 3. activated seizures. Neurology (Minneap.), 15, 716-722. The toxic actions of sodium diphenyl hydantoinate (Dilan- tin) when injected intraperitoneally and intravenously in Logan, W. J., and Freeman, J. M. (1969). Pseudodegenera- experimental animals. Journal of Pharmacology and tive disease due to diphenylhydantoin intoxication. Experimental Therapeutics, 68, 433-436. Archives of Neurology, 21, 631-637. Hansen, J. M., Kristensen, M., and Skovsted, L. (1968). McLellan, D. L., and Swash, M. (1974). Choreo-athetosis and Sulthiame (Ospolot) as inhibitor of diphenylhydantoin encephalopathy induced by phenytoin. British Medical metabolism. Epilepsia, 9, 17-22. Journal, 2, 204-205. Houghton, G. W., and Richens, A. (1974a). Phenytoin Mawer, G. E., Mullen, P. W., Rodgers, M., Robins, A. J., intoxication induced by sulthiame in epileptic patients. and Lucas, S. B. (1974). Phenytoin dose adjustment in Journal of Neurology, Neurosurgery, and Psychiatry, 37, epileptic patients. British Journal of Clinical Pharmacology, 275-281. 1, 163-168. Houghton, G. W., and Richens, A. (1974b). Inhibition of Morris, J. V., Fischer, E., and Bergin, J. T. (1956). Rare phenytoin metabolism by sulthiame in epileptic patients. complication of phenytoin sodium treatment. British British Journal of Clinical Pharmacology, 1, 59-66. Medical Journal, 2, 1529. Houghton, G. W., and Richens, A. (1974c). Rate of elimina- Perlo, V. P., and Schwab, R. S. (1969). Unrecognized tion of tracer doses of phenytoin at different steady-state dilantin intoxication. In Modern Neurology, pp. 589-597. serum phenytoin concentrations in epileptic patients. Edited by S. Locke. Little, Brown: Boston. British Journal of Clinical Pharmacology, 1, 155-161. Peters, H. A. (1962). Anticonvulsant drug intolerance.

Huisman, J. W., Heycop Ten Ham, M. W. van, and Zijl, Neurology (Minneap.), 12, 299. Protected by copyright. C. H. W. van (1970). Influence of ethylphenacemide on Richens, A. (1974). Drug estimation in the treatment of serum levels of other anti-epileptic drugs. Epilepsia, 11, epilepsy. Proceedings of the Royal Society of Medicine, 207-215. 67, 1227-1229. Kooiker, J. C., and Sumi, S. M. (1974). Movement disorder Roseman, E. (1961). Dilantin toxicity. A clinical and electro- as a manifestation of diphenylhydantoin intoxication. encephalographic study. Neurology (Minneap.), 11, 912- Neurology (Minneap.), 24, 68-71. 921. http://jnnp.bmj.com/ on October 1, 2021 by guest.