Valproic acid is one of the most common antiepileptic drugs used for the treatment of several seizure disorders. A 20-year-old man presented with a sudden decline of consciousness. He had a neurosurgery operation for intracranial and intraventricular hemorrhage. Following surgery, antiepileptic medication was administered to the patient in order to control his seizure events. On valproic acid treatment, he began to complain of fever and dyspnea. His symptoms persisted despite receiving empirical antibiotic treatment. All diagnostic tests for infectious causes were negative. A high-resolution computed tomography scan of the chest revealed predominantly dependent consolidation and ground-glass opacities in both lower lobes. The primary differential was drug associated with interstitial lung disease. Therefore, we discontinued valproic acid treatment and began methylprednisolone treatment. His symptoms and radiologic findings had significantly improved after receiving steroid therapy. We propose that clinicians should be made aware of the potential for valproic acid to induce lung injury.
Valproic acid is one of the most common antiepileptic drugs used for the treatment of several seizure disorders. It is approved by the Food and Drug Administration for use in the treatment of manic episodes associated with bipolar disorder, as an adjunctive therapy in multiple types of seizures, and for the prophylaxis of migraine headaches.
Valproic acid is known to induce several adverse effects involving the hepatobiliary, renal, neurologic, hematologic, cardiovascular, gastrointestinal, and metabolic systems
A 20-year-old man presented with a sudden decline of consciousness. He had no significant past medical history, and had never smoked.
On admission, the patient's vital signs were as follows: blood pressure, 130/80 mm Hg; pulse rate, 88 beats per minute; respiratory rate, 16 breaths per minute; and body temperature, 36.7℃. A clear breathing sound without fine crackles and no wheezing was heard following chest auscultation of both lower lung fields. The patient's laboratory test results were as follows: hemoglobin, 11.8 g/dL; white blood cell count, 8,330 cells/µL (neutrophils 77.2%, lymphocytes 8.8%, monocytes 9.1%, eosinophils 4.8%, and basophils 0.1%); and platelet count, 172,000 cells/µL. The patient's serum biochemistry test results revealed aspartate aminotransferase 23 IU/L, alanine aminotransferase 15 IU/L, total bilirubin 0.4 mg/dL, alkaline phosphatase 51 IU/L, total protein 6.7 g/dL, albumin 3.9 g/dL, blood urea nitrogen 13.8 mg/dL, creatinine 0.7 mg/dL, total cholesterol 125 mg/dL, procalcitonin 0.61 ng/mL, and C-reactive protein 0.83 mg/dL. Arterial blood gas analysis of the fraction of inspired oxygen (FiO2) was 0.28, and revealed the following: pH, 7.481; partial pressure of oxygen (PaO2), 165.0 mm Hg; partial pressure of carbon dioxide (PaCO2), 26.1 mm Hg; bicarbonate (HCO3-), 19.2 mEq/L; and saturation level of oxygen (SaO2), 99.5%. Chest radiography showed no active parenchymal lesion (
Following surgery, the patient was administered anti-hypertensive medication (nicardipine, 2 mg/hr, intravenous) and antibiotics (ceftriaxone, 2 g every 24 hours), as well as intravenous vitamin K (10 mg, every 8 hours) and tranexamic acid (500 mg, every 8 hours) to control bleeding. On day six following hospitalization, antiepileptic medication was administered to the patient to control his seizure events (sodium valproate, 400 mg, every 8 hours). On day fourteen following hospitalization, the patient's neurologic symptoms were improved. However, he began complaining of fever and dyspnea. The patient's vital signs were as follows: blood pressure, 140/80 mm Hg; pulse rate, 118 beats per minute; respiratory rate, 28 breaths per minute; and body temperature, 39.1℃. A coarse breathing sound with fine crackles and no wheezing was heard following chest auscultation of both lower lung fields. The patient's laboratory test results were as follows: hemoglobin, 12.2 g/dL; white blood cell count, 19,480 cells/µL (neutrophils 91.6%, lymphocytes 3.0%, monocytes 4.6%, eosinophils 0.6%, and basophils 0.2%); and platelet count, 282,000 cells/µL. The patient's serum biochemistry test results revealed aspartate aminotransferase 38 IU/L, alanine aminotransferase 25 IU/L, total bilirubin 0.5 mg/dL, alkaline phosphatase 43 IU/L, total protein 6.6 g/dL, albumin 3.8 g/dL, BUN 20.1 mg/dL, creatinine 0.7 mg/dL, total cholesterol 142 mg/dL, procalcitonin 0.61 ng/mL, and C-reactive protein 12.62 mg/dL. Arterial blood gas analysis of the fraction of inspired oxygen (FiO2) was 0.28, and revealed the following: pH, 7.506; partial pressure of oxygen (PaO2), 55.0 mm Hg; partial pressure of carbon dioxide (PaCO2), 28.6 mm Hg; bicarbonate (HCO3-), 22.4 mEq/L; and saturation level of oxygen (SaO2), 89.0%. Chest radiography revealed consolidation in both lower lung fields (
The patient required mechanical ventilation support due to the rapid and progressive aggravation of clinical symptoms. Hence, administration of empirical antibiotic therapy for hospital-acquired pneumonia was commenced (meropenem, 1 g every 8 hours, and levofloxacin, 750 mg every 24 hours). Despite two days of antibiotic therapy, the patient's radiologic and clinical findings persisted. Consequently, bronchoscopy with bronchoalveolar lavage was performed at the superior segment of the right lower lobe. Bronchoalveolar lavage fluid differential cell counts were as follows: white blood cell, 1,780 cells/µL (neutrophils 83%, lymphocytes 15%, macrophage 1%, eosinophils 1%, and basophils 0%); and red blood cell, 11,350 cells/µL. The bronchoscopic washing specimens were negative for
Valproic acid is one of the most common antiepileptic drugs used for the treatment of several seizure disorders. However, valproic acid is known to induce several adverse effects involving the hepatobiliary, renal, neurologic, hematologic, cardiovascular, gastrointestinal, and metabolic systems. Adverse pulmonary effects associated with valproic acid, such as diffuse alveolar hemorrhage or eosinophilic effusion, have rarely been reported. Additionally, we found no reports in the literature of any association between valproic acid administration and interstitial lung disease
Several types of drugs can cause DILD. However, the associated incidence of DILD varies for each individual drug. DILD may be mild to progressive, and in its more severe manifestation, DILD may result in respiratory failure and acute respiratory distress syndrome. Further, DILD may develop within the first few days of treatment, or may not manifest until several years after treatment.
Diagnosis of DILD generally depends on a definite temporal association between exposure to the causative agent, and the development of respiratory signs and symptoms. Specific markers, histological findings, and diagnostic clinical features are generally unremarkable in DILD
A pathological examination was not performed on the patient in the current case report. However, infectious pathogens were excluded as the cause of interstitial pneumonia, as a microbial culture was negative for infectious bacteria. In addition, the patient's symptoms and infiltrations on chest radiography occurred soon after initiating treatment with valproic acid. After discontinuing valproic acid and initiating steroid therapy, the patient's symptoms and radiological findings had improved. Therefore, the patient was diagnosed with interstitial lung disease caused by valproic acid administration.
Accordingly, we propose that clinicians should be made aware of the potential for valproic acid to induce lung injury. In addition, the administration of valproic acid for the treatment of seizure disorders may require special attention.
No potential conflict of interest relevant to this article was reported.
Chest radiography showed no active parenchymal lesion on admission.
At day 5 after the initiation of valproic acid, chest radiography revealed bilateral consolidation in both lower lung fields (A). A high-resolution computed tomography scan of the chest revealed predominantly dependent consolidation with air bronchogram and ground-glass opacities in both lower lobes (B).
After the discontinuation of quetiapine therapy and 14 days of steroid therapy, a high-resolution computed tomography scan of the chest revealed a decreased extent of consolidation in both lung fields.