Pleural Fluid Eosinophilia With Combined Pharmacotherapy

Letters be modified to include the type of cross-diagnostic free-floating symptom profile of somatoform spectrum illness seen in this instance. Free-floating somatoform spectrum symptoms reflect the innate, plastic human ability to use, in varying degrees, nonverbal somatic communication and memory distortion to express underlying psychological distress. The distress that occurs in underlying attachment disturbances can be integrated with psychiatric illness and personality disorder and filtered through the expression of somatoform spectrum illness, as represented in this case. One hopes it can be better reflected in DSM’s future iterations, perhaps as suggested as a subcategory of somatoform disorders not otherwise specified. Ian Tofler, M.D., Drew University, Los Angeles, Calif. References

1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed, Text Revision. Washington, DC, APA, 2000, pp 507, 517 2. Lipowski ZJ: Somatization: the concept and its clinical application. Am J Psychiatry 1988; 145:1358–1368 3. Meadow R: Munchausen syndrome by proxy: the Hinterland of child abuse. Lancet 1977; 2:342–345 4. Schrier H, Libow J: Hurting for Love: Munchausen by Proxy Syndrome: The Perversion of Mother. New York, Guilford, 1993 5. Stuart S, Noyes R Jr: Attachment and interpersonal communication in somatization. Psychosomatics 1999; 40:34–43 6. Nemiah JC: Alexithymia: theoretical considerations. Psychother Psychosom 1977; 28:199–206 7. Sifneos PE: The prevalence of “alexithymic” characteristics in psychosomatic patients. Psychother Psychosom 1973; 22:225–262 8. Stoudemire A: Somatothymia. Psychosomatics 1991; 32:365–381 9. Elzinga BM, Beromnd B, Van Dyck R: The relationship between dissociative proneness and alexithymia. Psychother Psychosom 2002; 71:104–111 10. Kroenke K, Spitzer R, DeGruy F III, Hahn SR, Linzer M, Williams JB, Brody D,

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Davies M: Multisomatoform disorder: an alternative to undifferentiated somatoform disorder for the somatizing patient in primary care. Arch Gen Psychiatry 1997; 54:352–358

Pleural Fluid Eosinophilia With Combined Pharmacotherapy TO THE EDITOR: More than 100 medications can cause pulmonary symptoms, including pleural effusions.1 The risk for these side effects increases in patients taking a combination of medications because of the potentiation effect of the cytochrome P450 system or competitive protein binding. Symptoms of drug-induced pulmonary disease can mimic opportunistic infections, leading to misdiagnoses and fatalities. We report pleural fluid eosinophilia possibly induced by valproic acid and review the possible relationship of co-administered antipsychotic medications. Case Report Mr. A, a 34-year-old man with schizophrenia, was admitted to a local hospital for treatment of a psychotic episode. His treatment consisted of haloperidol, valproic acid, and diphenhydramine. Two weeks after admission, Mr. A developed a cough, fever (39.5⬚C), tachypnea, tachycardia, nausea, and vomiting and was transferred to the hospital’s medical floor. Antibiotics were administered because of suspected meningitis or encephalitis. Results of a diagnostic workup, including a lumbar puncture, a computerized tomography (CT) scan of the head, and tests for HIV and tuberculosis, were negative. An abdominal-pelvic CT scan revealed pericardial effusion, bilateral pleural effusions, and a left lower lobe infiltrate. Gatifloxacin was administered to treat suspected atypical

pneumonia. Mr. A’s WBC count peaked at 20 K/cm3, with eosinophilia greater than 5%. Results of virology studies were negative, as were legionella and strongyloides tests. Since Mr. A responded well to gatifloxacin, no efforts were made to tap his pleural effusions. His WBC count returned to normal, and his eosinophilia remitted, although he remained afebrile. After further recovery and psychiatric stabilization, Mr. A was discharged while taking 1500 mg/day of valproic acid, 15 mg/day of haloperidol, and 25 mg/ day of diphenhydramine. Only hours after discharge, Mr. A came to our hospital’s emergency department with tachycardia, tachypneia, a temperature of 39.1⬚C (102.4⬚F), and oxygen saturation of 94%. A chest examination revealed bibasilar decreased breathing sounds, with rhonchi at the base of the left lung. The results of laboratory tests at admission were within normal limits, except for an eosinophilia level of 15.4%. A chest radiograph showed bilateral effusions, with probable right middle lobe infiltrate and a right lower lobe cavity filled with fluid. An ECG revealed sinus tachycardia. Results of thoracocentesis showed 40% pleural fluid eosinophilia. Results of blood, urine, and sputum cultures were negative. Because of the previous negative workup for pleural effusion during Mr. A’s most recent hospitalization, a MEDLINE search was performed to look for medication-related causes of pulmonary eosinophilia. We found one report of eosinophilic pleural effusion induced by valproic acid.2 Therefore, valproic acid was discontinued to see whether Mr. A’s symptoms would improve. Over the next several days, his symptoms improved; he was afebrile, his serum eosinophil count returned to 4% within 3 days, and his chest X-rays showed significant diminution of exu-

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Letters dates. Since symptom improvement immediately followed discontinuation of valproic acid, we decided that that medication was the most likely cause of Mr. A’s eosinophilia. The antibiotic was discontinued, and Mr. A remained free of his symptoms. After stabilization of his psychiatric symptoms, Mr. A, was discharged. Discussion Valproic acid is frequently used for the treatment of bipolar disorder and impulsive and aggressive behavior. It is also used as an adjunct medication in patients with psychotic disorders such as schizophrenia.3 Common side effects are nausea, weight gain, somnolence, and tremor, and fatal hepatotoxicity has been reported in some cases. Serum eosinophilia is a possible but usually insignificant side effect. To our knowledge, only one previous case report of pleural effusion induced by valproic acid exists.2 Therein, valproic acid was thought to be the cause of the effusion. However, our patient was also concomitantly treated with antipsychotic medications: chlorpromazine and fluphenazine. Both older typical antipsychotics, such as chlorpromazine and fluphenazine, as well as newer atypical antipsychotics, such as clozapine, can infrequently cause eosinophilia. A case report exists regarding chlorpromazine-induced eosinophilic pleural effusions.4 Hence, the pleural eosinophilia in our patient, as well as in the earlier case, may have been caused by valproic acid or the concomitantly administered antipsychotic medication or by a potentiation effect. We know of no studies that exist to explain the mechanism by which these medications cause eosinophilia. A study in rats by Podolec et al.5 showed that central dopaminergic neurons have a regulatory function in eosinopenia, an

effect blocked by haloperidol. Therefore, it may be that higher doses of haloperidol cause an increase in eosinophils in the blood. Discontinuation of the antipsychotic medication instead of valproic acid might have led to symptom improvement in our patient or in the patient in the earlier case report. Since valproic acid and antipsychotics are frequently used in combination,3,6 medication side effects or interaction should be considered causative mechanism when patients are taking these medications alone or in combination and present with symptoms of pleural effusion. Catherine Chiles, M.D. Pieter Joost van Wattum, M.D., M.A. New Haven, Conn. References

1. Rosenow EC III: Drug-induced pulmonary disease. Dis Mon 1994; 40:253–310 2. Kaufman J, O’Shaughnessy IM: Eosinophilic pleural effusion associated with valproic acid administration. South Med J 1995; 88:881–882 3. Muller-Oelinghausen B, Retzow A, Henn FA, Giedke H, Walden J (European Valproate Study Group): Valproate as an adjunct to neuroleptic medication for the treatment of acute episodes of mania: a prospective, randomized, double-blind, placebo-controlled, multicenter study. J Clin Psychopharmacol 2000; 20:195–203 4. Shear MK: Chlorpromazine-induced PIE syndrome. Am J Psychiatry 1978; 135:492–493 5. Podolec Z, Vetulani J, Bednarczyk B, Szczeklik A: Central dopamine receptors regulate blood eosinophilia in the rat. Allergy 1979; 34:103–110 6. Wassef AA, Hafiz NG, Hampton D, Molloy M: Divalproex sodium augmentation of haloperidol in hospitalized patients with schizophrenia: clinical and economic implications. J Clin Psychopharmacol 2001; 21:21–26

Donepezil for Postoperative Delirium TO THE EDITOR: Delirium, a common problem in the general hospital, can re-

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sult in substantial morbidity and mortality. The definitive treatment of delirium is identification and correction of the underlying etiology; however, treatment of the associated psychiatric symptoms and cognitive impairment may be necessary. I report on the use of donepezil in the management of delirium after hip arthroplasty. Case History Ms. A, a 74-year-old white woman who was diagnosed with late-onset bipolar affective disorder at the age of 69, came to the hospital after sustaining a right hip fracture. In the emergency department, she was crying, alert, and fully oriented. She received 4 mg of intravenous morphine sulfate for pain. She slept well and answered questions appropriately the next morning but was drowsy. After hip arthroplasty, she was awake but verbally unresponsive. The next day, she continued to exhibit a blank expression, lethargy, and minimal verbal responses. A psychiatric consultation was obtained 2 days after her operation because of her verbal unresponsiveness. At the consultation, she displayed a fluctuating level of consciousness, was disoriented to place and time, had poor attention, uttered only a few words and short phrases, but was pleasant and no longer agitated. She did not report feeling depressed, manic, or anxious and was without auditory or visual hallucinations. Her score on the Mini Mental State Examination was 10 out of 30. Her performance on the clockdrawing task was poor and extremely delayed because of her fluctuating level of consciousness and preservation. Ms. A’s daughter reported similar episodes of withdrawal, mutism, anorexia, and irritability in the past whenever her medications were discontinued. Ms. A had no psychiatric history 437