Key-words:
Acute psychosis - phenytoin toxicity - rare side effect
Introduction
Patients with epilepsy have increased vulnerability to psychiatric comorbidity including
psychotic disorders.[[1]] Antiepileptic drug (AED)-induced psychotic disorder (AIPD) represents an iatrogenic,
adverse drug reaction. The prevalence of AIPD has been reported to range from 1.0%
to 8.4% in clinical trials of AEDs.[[2]] Various AEDs have been associated with either a positive or a negative effect as
pertaining to psychiatric manifestations such as topiramate, vigabatrin, levetiracetam,
tiagabine, and zonisamide have been associated primarily with adverse psychotropic
effects, while gabapentin, pregabalin, lacosamide, and lamotrigine demonstrated a
more beneficial psychotropic profile, especially with regard to affective symptoms.[[2]] Phenytoin has rarely been shown to be a causative agent of acute psychosis in patients.
We present such a rare case of phenytoin toxicity leading to acute psychosis and complete
recovery following phenytoin withdrawal.
Case Report
A 26-year-old male presented to our institute with a complaint of a headache with
diminution of vision for the past 3 months. He had no comorbidities and no history
of any behavioral abnormalities or any chronic drug intake. On examination, his visual
acuity in the right eye was 6/18 and in the left eye was 6/60 as per Snellen chart.
On confrontation method, he had right temporal and left inferior and nasal field cuts.
Imaging revealed an intra-axial left parieto-occipital region space occupying lesion,
with heterogeneous enhancement and with perilesional edema with mass effect. He was
started on phenytoin 300 mg in HS dosing and was scheduled for surgery. Subsequently,
he underwent left occipital craniotomy and gross total tumor excision. He received
one dose of steroids (Injection Dexamethasone 4 mg) intraoperatively, with no steroids
being given postoperatively. The postoperative period was uneventful, and he was discharged
in a stable condition. Biopsy revealed Glioblastoma Multiforme. Ten days later, the
patient again presented to our emergency department in an agitated state with a history
of unwarranted aggression toward his relatives. He had delusions of persecution with
irrelevant, excessive talking and no insight into his behavior. He had severe gait
ataxia. Physical examination revealed he had horizontal nystagmus. Investigations
including complete blood count, liver function tests, renal function tests, fasting
blood sugar, serum electrolytes, serum Vitamin B12, and folic acid, X-ray chest and
computed tomography were all normal. His cerebrospinal fluid examination revealed
red blood cell-170, white blood cell-5 (100% polymorphs), sugar-51 (blood sugar-121),
and protein-71. The patient was initially suspected to have partially treated meningitis
and was started on anti-meningitis treatment. However, his symptoms did not improve.
On a suspicion of phenytoin toxicity, his serum levels were checked which revealed
excessively high levels of >40 μg/ml. Phenytoin was stopped, following which the patient
improved and he was discharged. At 2-week follow-up, the patient was normal, with
no further episode of similar behavior. Repeat phenytoin values at follow-up were
within the normal range.
Discussion
Phenytoin is one of the most widely prescribed antiepileptic in developing countries
because of being cheap and widely available. In the 1980s, phenytoin was promoted
as an anti-depressant.[[3]] Although phenytoin is now rarely used as a psychotropic agent, a controlled study
did show efficacy for mania.[[4]]
Phenytoin toxicity depends on the route of administration, duration, exposure, and
dosage. Phenytoin metabolism is dose-dependent. Elimination follows first-order kinetics
(fixed percentage of drug metabolized during a per unit time) at the low drug concentrations
and zero-order kinetics (fixed amount of drug metabolized per unit time) at higher
drug concentrations. This change in kinetics reflects the saturation of metabolic
pathways. Thus, very small increments in dosage may result in adverse effects. The
earliest signs of phenytoin toxicity are typically horizontal nystagmus and unsteady
gait. More severe toxicity results in slurred speech, along with a gradually worsening
mental status typified by lethargy, confusion, sedation, psychomotor slowing, mild
cognitive impairment, and depression. Other side effects from phenytoin include gingival
hyperplasia, hirsutism, hypocalcemia, osteomalacia, drug rash, cardiovascular effects
such as bradycardia and hypotension. An acute encephalopathy and paradoxically seizures
may develop with toxicity (blood phenytoin (PHT) levels, >40 μg/mL).[[5]],[[6]]
Adverse effects with phenytoin use manifesting in various psychiatric disorders or
behavioral symptoms have been reported earlier. Acute psychosis as caused by phenytoin
toxicity has been rarely reported. McDanal and Bolman[[7]] reported a case of chronic epileptic patient on long term phenytoin use, who presented
with psychotic behavior, with no other symptoms of phenytoin toxicity, with below
normal phenytoin levels (<5 μg/ml), although the patient did improve following phenytoin
withdrawal. Gatzonis et al.[[8]] reported the case of acute psychosis developing in a case of trigeminal neuralgia,
which improved after stopping phenytoin, although serum levels were again normal.
Borasi et al.[[9]] are the only ones who report a chronic epileptic with a history of 15 years of
phenytoin intake, presenting with acute psychosis and raised serum levels of the same,
who improved after stopping phenytoin. Our case is the only one where a short history
of the recommended dosage of phenytoin intake is associated with acute psychosis.
Treatment with most of the commonly used AEDs is associated with reduced folate or
vitamin B12 serum levels.[[10]],[[11]] Psychiatric disorders that may be diagnosed in patients having vitamin B12 deficiency
include depression, bipolar disorder, panic disorder, psychosis, phobias, and dementia.[[12]],[[13]],[[14]] Our patient, though, had normal Vitamin B12 and folate levels, ruling this out
as a cause of his psychosis.
Chen et al.[[15]] in their study on psychotic disorders caused by AEDs found that four factors are
associated with AED-AIPD: Female gender, temporal lobe involvement and use of levetiracetam,
and a negative association with carbamazepine. Disorganized behavior and thinking
were predominant in AED-AIPD. Patients with AED-AIPD differed from non-AED-AIPDs in
having better outcome along with a shorter duration of psychotic episodes. None of
their AIPD patients demonstrated a chronic course of psychosis. Nadkarni and Devinsky
hypothesized that epileptiform discharges may mimic electroconvulsive therapy in a
focal area, and discharge suppression by AEDs may lead to psychopathology.[[16]] Trimble suggested that there is a disturbance of monoamine metabolism in these
patients, and speculated that an increase in central dopamine activity caused by AED
medication may increase their risk of developing psychoses.[[17]] However, no absolute mechanism of action has been found till date.
Conclusion
The WHO defines an adverse drug reaction as “A response to a drug which is noxious
and unintended, and which occurs at doses normally used in man for the prophylaxis,
diagnosis, or therapy of disease, or the modifications of physiological function.”
A “serious adverse reaction means an adverse reaction which is fatal, life-threatening,
disabling, incapacitating, or which results in or prolongs hospitalization.” Acute
psychosis caused by phenytoin has been previously unknown or incompletely documented.
There is a possible causal relationship between the adverse event and the drug, and
such an adverse event is debilitating for the patient and prolongs the hospital stay.
Thus, acute psychosis as a manifestation of phenytoin toxicity should be kept in mind
and be evaluated for in patients presenting with such symptoms.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms.
In the form the patient(s) has/have given his/her/their consent for his/her/their
images and other clinical information to be reported in the journal. The patients
understand that their names and initials will not be published and due efforts will
be made to conceal their identity, but anonymity cannot be guaranteed.
