332 SAMT VOL 75 1 APR 1989
Phenytoin auto-induction?
Case reports
R. MILLER, P. L. A. BILL, J. DU TOIT
Summary
Auto-induction of phenytoin metabolism is considered by
many to be insignificant. Two cases, in which elimination of
phenytoin apparently increased with continuous use, are
presented. The first patient showed an increase in elimination
capacity (Vmax) from 511 mg/d to 613 mg/d over a perid of 5
months. The second patient showed an increase in Vmax from
512 mg/d to 570 mg/d over a perid of 1 year. In neither case
was compliance in question. The recognition that therapeutic
failure may be due to enzyme induction could obviate ex-
pensive diagnostic procedures as well as narrow down the
therapeutic alternatives.
S Air Med J 1989; 75: 332-333.
It has been reported that there is no evidence for auto-
induction of phenytoin metabolism I and also that if it occurs it
appears to be insignificant. 2
Two cases in which elimination of phenytoin apparently
increased with continuous use are presented.
Case reports
Case 1
An 18-year-old man, weighing 80 kg, with no previous or
family history of any neurological disorder experienced his
first tonic/clonic seizure while exercising. Clinical examination
and computed tomography of the brain revealed no abnorma-
lity. A second generalised seizure occurred 2 months later.
Phenytoin 300 mg daily was started on 20 May 1986. After 12
further seizures the dose was increased to phenytoin 400 mg
daily in 2 divided doses.
Two weeks after the change in dose a midday phenytoin
plasma concentration of 60 J.LmoVI was measured. This concen-
tration-dose pair is consistent with an elimination capacity
(Vmu) of 511 mg/d (Bayesian approach 3). The phenytoin dose
was increased to 425 mg/d, which was expected to give an
average phenytoin plasma concentration at the upper end of
the therapeutic range. After two further seizures over a period
of 2 months a midday phenytoin plasma concentration of 50
J.LmoVI was obtained, which is consistent with a V mu of 554
mg/d. After a further seizure the dose was increased .to
phenytoin 450 mg daily in 2 divided doses. A midday pheny-
toin plasma concentration of 35 J.LmoVI was obtained after 4
weeks on this dose. The patient experienced a seizure 3 weeks
later and a phenytoin plasma concentration of 37,6 J.Lmol/l was
measured. The last 2 concentration-dose pairs were consistent
with a V max of 613 mg/d.
Department of Pharmacology, University of Durban-
Westville, Durban
R. MILLER, D.Se.
J. DU TOIT, DIP. PHARM.
Department of Neurology, University of Natal, Durban
P. L. A. BILL, ER.CP.
Accepted 20 Apr 1988.
The dose of phenytoin was increased to 200 mg in the
morning and 300 mg at night. During the 6 months the
patient was taking phenytoin 500 mg daily, midday plasma
concentrations at 67,2, 76,8, 64,0 and 61,2 J.Lmol/1 were
measured at least I month apart. These 4 concentration-dose
pairs are consistent with a Vmu of 606 mg/d, which' is similar
to the previous value. The patient's Vmax therefore increased
from 511 mg/d after 3 ｷ･ｾｳＧ phenytoin treatment to 613
mg/d after 5 months phenytoin treatment after which it
appeared to remain stable for the next 7 months.
Case 2
A 21-year-old man, weighing 81 kg, presented to hospital
with a history of tonic/clonic seizures from childhood. He was
referred to the Clinical Pharmacokinetic Laboratory at the
University of Durban-Westville for assessment on 2 March
1981.
Over the years he had received a number of different drug
treatment regimens. However, for the preceding 9 months he
had been taking a constant dose of phenytoin lOO mg 3 times
daily and sodium valproate 200 mg twice daily. He was
experiencing an average of I tonic/clonic seizure a month. The
measured phenytoin plasma concentration of 12 J.LmoVI was
lower than expected for a dose of phenytoin 300 mg/d.
However, the concurrent use of sodium valproate has been
shown to reduce phenytoin plasma concentrations. 4
Sodium valproate was discontinued and the phenytoin dose
was increased to 200 mg 12-hourly. Three weeks after dosage
adjustment the phenytoin plasma concentration measured 8,5
hours after the morning dose was 60,4 J.Lmol/1. This concentra-
tion-dose pair is consistent with a Vmax of 512 mg/d (Bayesian
. approach 3). During this period the patient experienced 4
auras. Four months later the phenytoin plasma concentration
measured 96 J.LmoVI with the same dosing regimen. The fact
that the sample was taken 4 hours after ingestion may partially
explain the increase from the preceding level. The patient
experienced no seizures or side-effects and was advised to
maintain the dose of phenytoin at 400 mg daily. .
The patient returned I year later on 13 September 1982
after having experienced a tonic/clonic seizure for the first
time since the dosage adjustment. A phenytoin plasma concen-
tration of 33,6 J.Lmol/1 was measured 8 hours after the morning
dose. This concentration-dose pair is consistent with a V mu of
570 mg/d. The phenytoin doSe was increased to 200 mg in the
morning and 250 mg at night. After 4 weeks' continuous
dosing, phenytoin plasma concentration measured 8 hours
after the morning dose was 48 J.LmoVI, which is expected with
a V mu of 570 mg/d.
Discussion
Contrary to many published reports it appears that auto-
induction of phenytoin can cause clinically significant enhance-
ment of phenytoin elimination. Both patients were highly
motivated and compliance was not in question. This pheno-
menon may have gone unnoticed in many cases because initial
baseline phenytoin plasma concentrations were not measured.

Many clinicians regard such baseline levels as unnecessary if
the patient's seizures are well controlled. We feel, however,
that in certain siruations a deterioration in seizure control after
some time could mistakenly be anributed to worsening of the
clinical condition of the patient or tolerance. The recognition
that therapeutic failure may be due to enzyme induction could
obviate expensive diagnostic procedures as well as narrow
down the therapeutic alternatives.
•
Neuroblastoma ID adults
A report of 3 cases
A. BEHR, R. R. J. UIJS, J. I. PHILLlPS
Summary
Well documented as one of the more frequent tumours of
childhood, neuroblastomas in adults are rare. Correct diag-
nosis, and distinction from other small-cell neoplasms, is thus
often delayed. Three further cases'are described in 2 women
and 1 man between the ages of 26 years and 47 years.
Metastatic disease existed at the time of initial presentation in
1 patient, while another·had experienced multiple recurrences
at the primary site before correct diagnosis. All, however, had
a favourable response to chemotherapy, 'albeit in the short
term. Primary diagnosis was made by fine-needle aspiration
cytology, together with electron microscopic evaluation
of aspirated cells in 1 case. The histological, cytological and
electron microscopic characteristics of neuroblastomas are
presented and illustrated, and their differentiation from other
small cell tumours in adults discussed.
S Air Med J 1989; 75: 333-335.
Neuroblastoma is the third most common solid rumour found
in children, superseded only by lymphomas and brain rumours. I
In adults, however, it is an uncommon Ｎｭ｡ｬｩｧｮｾ ｣ｹＮ ｔｨ｜ｾｰ｡ ･ｲ
describes 3 cases to be added to the 47 III the hterarure.-
Materials and methods
The rumours were diagnosed by conventional pathological
techniques. Immunoperoxidase stains were used on wax sec-
tions treated with 3% hydrogen peroxide in methanol and
Department of Anatomical Pathology, School of Pathology,
South African Institute for Medical Research and Uni-
versity of the Witwatersrand, Johannesburg
A. BEHR, M.B. B.CH., F.F. PATH. (SA)
J. I. PHILLIPS, PH.D.
Department of Radiotherapy, Hillbrow Hospital and Uni-
versity of the Witwatersrand, Johannesburg
R. R. J. UIJS, M.B. CH B., F.F.RAD. (T.)(S.A.)
Reprint requests [0: Dr A. Behr, Depr of Anatomical Pathology, SAIMR, PO Box 1038,
Johannesburg, 2000 RSA.'
Accepted 16 Sept 1988
SAMJ VOL 75 1 APR 1989 333
REFERENCES
1. Porter RJ, Pirlick WHo Antiepileptic drugs. In: Kauung BG, ed. Basic and
Clinical Pharmacology. Los Altos, Calif.: Lange Medical Publications, 1984:
269.
2. Petruch F, Schiippel RV A, Steinhilber G. Effect of diphenylhydantoin on
hepatic drug hydroxylation. EUT] Clin Pharmacol1974; 7: 281-285.
3. Vozeh S, Muir KT, Sheiner LB, Follath F. Predicting individual phenytoin
dosage.] Pharmacokinel Biapharm 1981; 9: 131-146.
4. Gugler R, von Unruh GE. Clinical pharmacokinetics of valproic acid. Clin
Pharmacokinel 1980; 5: 67-83.
horse serum. The sections were incubated with primary anti-
body (NSE S 100 protein, cytokeratin, EMA) at 25°C for 1
hour. Thereafter incubation with secondary biotinylated anti-
body and Vecta stain ABC kit was performed followed by
treatment with 3,3'-diaminobenzidine tetrahydrochloride
(DAB). The specimens were processed for transmission electron
microscopy according to a standard method. 7
Fine-needle aspiration (FNA) of the retroperitoneal mass
was performed under ultrasonographic guidance to ensure
sampling from a non-necrotic area. The procedure utilised a
22-gauge needle anached to a 20 ml syringe. Only 1 trans-
abdominal needle pass was required to obtain sufficient material
for light and electron microscopy. After aspiration, the material
was expelled directly onto plain glass slides, fixed in 95%
alcohol for 1 minute, and stained immediately using a 2-
minute rapid Papanicolaou stain. The syringe and needle were
rinsed in glutaraldehyde for electron microscopy.
Case reports
Case 1
A 47-year-old white woman presented to hospital in
September 1985 with an 1I-month history of a recurrent mass
below the right scapula. The lesion was originally noted in
October 1984 and excised. A noncommittal diagnosis of an
undifferentiated tumour was made. No further therapy was
instiruted.
In May 1985 a recurrent 10 x 5 cm mass at the original site
was subjected to repeat excision. At the same time, a thyroid-
ectomy was performed for a clinically palpable nodule, sus-
pected to be the primary site. A peripheral neuroblastoma was
diagnosed on histological examination of a specimen from the
back lesion, while the thyroid mass proved to be benign. Two
further local recurrences were resected in July 1985.
On examination no residual tumour was palpable. Urinary
catecholamine assay, computed tomography (CT) and bone
and liver scans were negative. Chest radiography was normal.
Vincristine, adriamycin and cyclophosphamide chemotherapy
was instituted, followed by VP 16 and Velbe. In addition,
5 500 cGy of radiotherapy was administered to the rumour
area. At present the patient is well and free of disease.