Unmasking Anxiety: Unusual Presentation of Phenytoin Toxicity

INTRODUCTION

Phenytoin toxicity can manifest in a spectrum of clinical presentations, often involving the central nervous system. Classic neurological signs such as nystagmus, ataxia, and altered mental status are well-documented, but the drug’s adverse effects can also include a range of neuropsychiatric disturbances. These disturbances can significantly affect a patient’s quality of life and may sometimes be the predominant or even the initial presentation of toxicity, potentially complicating diagnosis. The neuropsychiatric manifestations of phenytoin toxicity is diverse and can include alterations in mood, behavior, and cognition. Patients may experience symptoms such as irritability, depression, anxiousness, confusion, and memory impairment, although presentation with predominantly anxiety symptoms as a neuropsychiatric manifestation is rare and not well documented.¹ In some instances, more severe psychiatric symptoms like psychosis, including delusions and hallucinations, can occur.² These effects, though less common, highlight the importance of considering phenytoin toxicity in patients presenting with unexplained psychiatric symptoms, even in the absence of classic neurological signs. Factors such as individual patient variability, drug interactions, and alterations in physiology can contribute to the development of these neuropsychiatric complications. Literature does not provide specific information on the prevalence of anxiety disorder and panic disorder in cases of phenytoin toxicity. There are papers that primarily focus on broader neuropsychiatric manifestations like psychosis, mood changes, and cognitive impairment, along with the more classic neurological symptoms of phenytoin toxicity.

Treatment with the most commonly used antiepileptic drugs is associated with reduced serum levels of folate or vitamin B12.^3,4 Vitamin B12 deficiency, in turn, may manifest as various psychiatric disorders, including depression, bipolar disorder, panic disorder, psychosis, phobias, and dementia.^5–7 Phenytoin is one of the most widely prescribed antiepileptic drugs in developing countries because of its low cost and wide availability. In the 1980s, phenytoin was promoted as an antidepressant, and while it is now rarely used as a psychotropic agent, a controlled study did demonstrate its efficacy in treating mania.^8,9

Phenytoin toxicity is influenced by the route of administration, duration of exposure, and dosage. Phenytoin metabolism is dose-dependent, transitioning from first-order kinetics (a constant percentage of drug is metabolized per unit of time) at low drug concentrations to zero-order kinetics (a constant amount of drug is metabolized per unit of time) at higher concentrations. This shift reflects the saturation of metabolic pathways, meaning that small increases in dosage can lead to disproportionately large increases in serum drug levels and subsequent adverse effects. The earliest signs of phenytoin toxicity typically include horizontal nystagmus and unsteady gait. With increasing toxicity, symptoms progress to include slurred speech, lethargy, confusion, psychomotor slowing, mild cognitive impairment, and depression. Additional side effects of phenytoin can include gingival hyperplasia, hirsutism, hypocalcemia, osteomalacia, drug rash, and cardiovascular effects such as bradycardia and hypotension. In severe cases, phenytoin toxicity may manifest as acute encephalopathy and, paradoxically, seizures (when blood phenytoin levels exceed 40 μg/ml). Clinical toxicity was observed in 15% of patients and biochemical toxicity in 36%, with a significant association between the two (P < 0.01), phenytoin toxicity in traumatic brain injury (TBI).^10,11

CASE REPORT

A 38-year-old male presented to the Psychiatry Outpatient Department of Government Medical College of Eastern India with complaints of anxiousness, palpitation, and dizziness associated with two episodes of loss of consciousness in the last 3 weeks. His wife also reported an increased frequency of aggression and forgetfulness for the last 2 weeks. On probing further, he gave a history of a family dispute over land-related issues 1 month ago, following which he started experiencing difficulty falling asleep at night, fatigue, dizziness, and palpitations. There was a history of traumatic brain injury following a road traffic accident one and a half months ago, for which he was treated successfully conservatively by the Department of Neurosurgery and was started on tablet phenytoin 100 mg thrice daily dosing. He had no other comorbidities or chronic drug intake, fever, or seizure. He was admitted to the Psychiatry Inpatient Department of Government Medical College of Eastern India for treatment, observation, and further investigations. He was started on tablet Escitalopram 10 mg and tablet Clonazepam 0.5 mg on a once-daily basis following standard prescribing guidelines. Due to increasing distress and autonomic symptoms like sweating and palpitation, a tremor tablet, Propranolol 20, was added twice daily after checking blood pressure (146/94 mmHg) and pulse rate (110 bpm). His Hamilton Anxiety Rating Scale score was 22 (moderate) on the day of admission. Weekly follow-up of the Hamilton Anxiety Rating Scale (HAM-A) score was done, with no significant improvement.

Clinical examination revealed gait disturbance and a positive Romberg’s sign. A neuromedicine consultation was taken, and accordingly, a non-contrast computed tomography (CT) scan of the brain followed by a contrast-enhanced magnetic resonance imaging (MRI) of the brain was done, which showed old multiple constitutional microbleeds in both cerebral hemisphere, and he was started on tablet Cinnarizine 20 mg in a tapering dose and intravenous Ondansetron 8 mg for worsening of vertigo and new-onset vomiting. Contrast-enhanced MRI of the cervical spine was done, but no abnormality was detected. Otorhinolaryngology (ENT) and ophthalmology consultations were taken, but no abnormality was detected. His complete hemogram, thyroid profile, blood sugar, HbA1c, liver function test, renal function test, creatine phosphokinase (CPK), uric acid, C-reactive protein (CRP), and Electrocardiogram (ECG) showed no significant abnormality, but his lipid profile was deranged (total cholesterol-253, triglyceride-286). Serum phenytoin reporting was done, suspecting phenytoin toxicity, which was >40.0 H (biological reference interval 10.00–20.00 μg/ml), followed by serum vitamin B12 (436 pg/ml) and serum folate (3.8 ng/ml) levels. The final diagnosis and treatment plan were revised after consultation with the Department of Neuromedicine, followed by folic acid and methylcobalamin supplementation with discontinuation of the phenytoin tablet. After 3 days, he started showing gradual clinical improvement and a resultant fall in serum phenytoin level. The tablet Escitalopram was gradually tapered down and stopped over 2 weeks, but he continued to show clinical improvement [Figure 1]. After 33 days of inpatient management, he was discharged in hemodynamically stable condition with a tapering dose of tablet clonazepam with eventual discontinuation and referral to the neuromedicine department for further follow-up and assessment of the need for antiepileptic medication, if necessary.

Close

Figure 1:

Vertical timeline chart depicting chronological order of events. TBI: Traumatic brain injury, ENT: Otorhinolaryngology.

Export to PPT

DISCUSSION

The cause of anxiety symptoms and aggression is debatable, with a previous history of psychiatric illness and treatment. Background of conflict amongst family members prior to the onset of symptoms might have acted as a precipitating factor, but gradual resolution of symptoms following tapering off phenytoin and methylcobalamine and folic acid supplementation instead of an adequate trial of escitalopram directs more towards a causal relationship with phenytoin toxicity.

The World Health Organization 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 for the modification of physiological function.” A “serious adverse reaction” is one that is fatal, incapacitating, or can result in or prolong hospitalization. Anxiety disorder caused by phenytoin toxicity is a rare or under-recognized occurrence. However, it can be debilitating for the patient and may require extended hospitalization. Therefore, when patients present with anxiety symptoms, the possibility of phenytoin toxicity should be considered and evaluated when the patient has a history of phenytoin intake.

CONCLUSION

This case illustrates the potential for phenytoin toxicity to manifest as neuropsychiatric disorders, including anxiety disorders. While the patient presented with a complex clinical picture, including a history of traumatic brain injury and recent family conflict, the temporal relationship between phenytoin administration, elevated serum phenytoin levels, and the subsequent improvement following drug discontinuation strongly suggests a causal link between phenytoin toxicity and his symptoms.

Furthermore, the improvement observed with methylcobalamin and folic acid supplementation suggests a possible contribution of phenytoin-related vitamin B12 and folate deficiency to the patient’s symptoms. This is consistent with the established association between phenytoin treatment and reduced levels of these vitamins and the role of vitamin B12 deficiency in the development of various psychiatric disorders, including anxiety disorders. Thus, suggesting that physicians must keep in mind regarding the adverse effects of medications and the potential of phenytoin to cause neuropsychiatric symptoms at an elevated dose. A patient presenting with neuropsychiatric symptoms such as anxiety, dizziness, and palpitations must be assessed clinically with appropriate neurological examination techniques and tools to rule out any organic pathology and possible adverse effects related to any medication.

In conclusion, this case emphasizes the importance of considering phenytoin toxicity as a differential diagnosis of patients presenting with new-onset anxiety symptoms, even in the absence of classic neurological signs, particularly when there is a history of phenytoin use. Monitoring serum phenytoin levels and considering potential vitamin deficiencies are crucial in the management of such patients.