Phenytoin-induced Ogilvie syndrome: A rare case report

Abstract

Phenytoin is a widely prescribed antiepileptic drug that is associated with various adverse effects, but gastrointestinal manifestations are rare. Therapeutic drug monitoring is essential for ensuring safe and effective dosing by measuring the drug levels in the blood. We present the case of a 65-year-old individual with a history of seizure disorder, hypertension, and stable chronic kidney disease, who presented with acute abdominal distension and constipation. Imaging studies revealed acute colonic pseudo-obstruction, while serum phenytoin levels were elevated at 25.6 μg/mL (therapeutic range: 10–20 µg/mL). The patient’s symptoms resolved following gradual tapering of phenytoin and initiation of levetiracetam over 2 weeks. This case highlights a rare presentation of phenytoin toxicity manifesting as Ogilvie syndrome and underscores the importance of therapeutic drug monitoring and early recognition of gastrointestinal symptoms in patients on phenytoin therapy.

Introduction

Phenytoin is a widely used antiepileptic drug (AED) known for its efficacy in managing seizures. The drug is thoroughly studied clinically and scientifically for its therapeutic effects and adverse reactions. Phenytoin, even within therapeutic concentrations, can cause adverse effects, with toxicity becoming evident at higher doses. Gum hypertrophy, hirsutism, osteomalacia, anemia, among others, can be seen at therapeutic levels. Cardiac, central nervous, and gastrointestinal manifestations can be seen in toxicity.^1–3 Here, we detail a case of phenytoin-induced acute colonic pseudo-obstruction (Ogilvie syndrome).

Case report

A 65-year-old individual, a known case of seizure disorder, hypertension, and stable chronic kidney disease (CKD; ~45.58 mL/min/1.73 m²), came to the hospital with complaints of abdominal distension for 3 days and constipation for 1 day. The patient had vague abdominal pain with neither vomiting nor a fever history. He has been taking the tablet amlodipine (5 mg once daily) for hypertension and tablet phenytoin (300 mg once daily) for seizure disorder for 15 years. On examination, he was conscious, oriented, and hemodynamically stable. General examination was normal. Systemic examination revealed a distended abdomen with sluggish bowel sounds. Per rectal examination showed an empty rectum. Baseline blood analyses were in the usual range. An X-ray of the abdomen showed a grossly dilated gas-filled colon with the normal caliber of rectosigmoid, pointing to acute colonic pseudo-obstruction. Computed Tomography imaging showed dilated colonic loops without evidence of mechanical obstruction (Figures 1 and 2). Surgical consultation was sought, and colonic decompression was recommended via rectal tube insertion. Following colonic decompression, symptoms improved within a week.

Figure 1.

CT abdomen showing features of Ogilvie syndrome (acute colonic pseudo-obstruction): coronal view demonstrates markedly dilated loops of the colon, particularly the cecum and ascending colon, without evidence of a mechanical obstruction.

Figure 2.

Axial CT image of the abdomen in a patient with Ogilvie syndrome (acute colonic pseudo-obstruction): the scan reveals significantly dilated colonic loops with thin bowel walls, suggestive of a functional obstruction in the absence of a mechanical cause. There is no evidence of a transition point, volvulus, or obstructing mass, which supports the diagnosis of pseudo-obstruction.

Following are the laboratory results: hemoglobin: 13.3 g/dL, total WBC count: 10,000 cells/mm³, platelets: 235,000/µL, urea: 46 mg/dL, creatinine: 1.57 mg/dL, bilirubin: 0.6 mg/dL, total protein: 7.3 g/dL, sodium: 137 mmol/L, potassium: 3.6 mmol/L, magnesium: 1.9 mg/dL, calcium: 7.9 mg/dL. Serum phenytoin levels were significantly elevated (25.6 μg/mL), confirming toxicity as the underlying cause. Hence, phenytoin was gradually tapered over 2 weeks. Levetiracetam was started and continued as a maintenance anticonvulsant. Based on the clinical profile, history, and investigations, a diagnosis of acute colonic pseudo-obstruction due to high phenytoin levels was made. The patient’s abdominal symptoms resolved within a few weeks after tapering the drug and transitioning to levetiracetam. The prompt recognition of drug-induced acute colonic pseudo-obstruction and timely intervention helped to prevent any further complications.

Diagnostic challenges

The clinical overlap between paralytic ileus, mechanical obstruction, and acute colonic pseudo-obstruction made diagnosis challenging. Common causes such as electrolyte imbalances, infections, or medications affecting motility were ruled out. The elevated serum phenytoin level (25.6 μg/mL) combined with clinical presentation and imaging ultimately pointed toward drug-induced Ogilvie syndrome.

Discussion

Antiepileptic activity of phenytoin was explicitly tried out in 1938 in the recently evolved electroconvulsive dummy, and thenceforth, it has been a primary AED. It is a voltage-gated sodium channel inhibitor, which steadies the sodium channel’s inactive state and then lengthens the refractory period of neurons. ⁴ It has a limited therapeutic range of 10–20 µg/mL. Hydroxylation involving CYP2C9 and CYP2C19, and glucuronide conjugation within the liver, is responsible for its metabolism. There occurs a shift from first order to zero order above the therapeutic span. Generally, central nervous system manifestations, such as ataxia, nystagmus, and slurred speech, are seen. CKD is often considered a risk factor for drug toxicity; however, in this case, CKD may not have been a predisposing factor in the development of phenytoin toxicity. This is because the majority of phenytoin is excreted as inactive metabolites in the bile, with only 1%–5% of the drug eliminated unchanged in the urine. ⁵ The patient’s mildly elevated serum creatinine levels may reflect baseline renal dysfunction rather than a significant contributor to phenytoin toxicity. The primary mechanism by which phenytoin could affect the normal functioning of the gut is by blocking voltage-dependent L-type calcium channels in the smooth muscle cells, which are crucial for the initiation of smooth muscle contractions. ⁶ Gastrointestinal manifestations are unusual in phenytoin toxicity. Notably, a case report by Kayyali et al. describes a similar presentation of phenytoin-induced Ogilvie syndrome in a middle-aged patient, highlighting the clinical relevance of this association. ⁷ In our patient, the phenytoin level was 25.6 µg/mL (high). The complex pharmacokinetics and dynamics of the drug on intestinal motility and smooth muscles can explain the gastrointestinal manifestation of acute colonic pseudo-obstruction in our patient. ⁸ Given phenytoin’s narrow therapeutic index, regular therapeutic drug monitoring (TDM) is critical in preventing toxicity, particularly in long-term therapy. In this circumstance, the early detection of the atypical symptoms led to appropriate management, highlighting the need for doctors to consider drug toxicity in unexplained gastrointestinal cases. Literature also suggests that psychotropic and AEDs can disrupt colonic motility and defecation reflexes.^9–12 In addition, a recent report from Jordan highlights the risk of severe complications, including caecal perforation, in Ogilvie syndrome cases following cesarean section, emphasizing the clinical urgency in prompt diagnosis and intervention. ¹³ Causality assessment using the Naranjo Scale ¹⁴ (score: 9) confirmed a “definite” association with phenytoin toxicity. Similarly, the World Health Organization- Uppsala Monitoring Centre (WHO-UMC) scale of probability ¹⁵ was found to be “probable,” hypothesizing a causal relationship to the drug. The severity assessment of adverse drug reaction (ADR) by the modified Hartwig and Siegel scale categorized the reaction as moderate (level 4b: the ADR is the reason for admission). ¹⁶ Applying the predictability assessment using the Schumock and Thornton scale categorized the ADR into the “not preventable” category. ¹⁷ Although a dechallenge with the offending drug was done, no rechallenge was considered because of the seriousness of the ADR. Based on the evidence from the above different ADR assessments and causality scales, we can attribute this reaction to phenytoin.

Follow-up and outcomes

After the gradual tapering of phenytoin, the transition from phenytoin to levetiracetam has contributed to a significant improvement in the patient’s condition. During follow-up, 2 weeks later, he reported no recurrence of abdominal distension or pain since the change in medication. The patient’s overall well-being has remained stable, with seizure control effectively maintained on levetiracetam. This highlights the favorable prognosis when phenytoin toxicity is promptly recognized and managed through therapeutic adjustment.

Learning outcomes

1. Ogilvie syndrome should be considered in patients on chronic AED therapy presenting with unexpected colonic dilation.

2. TDM is essential in chronic phenytoin therapy as regular monitoring can help in preventing toxicity, especially in cases where long-term use and nonlinear pharmacokinetics can lead to an unexpected dose-dependent toxicity.

3. Clinicians should remain vigilant for rare adverse effects of commonly used drugs, as even well-established medications such as phenytoin, in this case, can cause uncommon but serious reactions, highlighting the importance of clinical vigilance in unexplained cases.

Conclusion

Phenytoin toxicity can manifest in various ways, with acute colonic pseudo-obstruction being a rare presentation. This case highlights the critical role of early recognition of atypical symptoms and the importance of serum drug level monitoring in preventing such serious complications. Physicians should consider the possibility of phenytoin toxicity in patients presenting with undiagnosed gastrointestinal conditions with a history of chronic phenytoin use. TDM plays a crucial role in the prevention of such ADRs by guiding safe and effective dosing as well as the introduction of an apt dosing regimen, especially in long-term therapy. This report highlights the importance of recognizing rare gastrointestinal manifestations of commonly prescribed anticonvulsants.