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“Mrs. G,” a 35-year-old married mother of three healthy children, including a newborn, was referred to the inpatient obstetric unit for management of an acute onset of fever. She had been diagnosed as having postpartum psychosis and had been hospitalized on the psychiatric unit for the past 16 days after a postpartum psychotic episode.
Mrs. G previously worked as a journalist but had been unemployed for several years. Her medical history was marked by two similar episodes of agitation, confusion, and mystic delusions starting on day 3 after each delivery, which required her immediate transfer to a psychiatric hospital and treatment with antipsychotic medication. The outcome of each episode was favorable, with a weaning from antipsychotics within 4 to 6 weeks postpartum and no psychiatric symptoms between episodes. Mrs. G reported no medical family history and denied use of alcohol, tobacco, or other drugs. The current episode began suddenly on postpartum day 3. Although midwives initially reported only an anticipatory anxiety focused on the possible recurrence of postpartum psychosis, by midday they noticed an increased level of anxiety and a mild obnubilation (mental clouding). Within hours, Mrs. G became confused, agitated, and violent, and verbal contact with her quickly became impossible as she aimlessly shouted her husband's name while trying to leave her room. After placement of physical restraints and an intramuscular injection of loxapine (100 mg), the patient was immediately transferred to a psychiatric hospital. Initial medical reports indicated normal results on physical examination and laboratory tests (complete electrolyte panel, CBC, liver function tests, and ECG).
On postpartum day 16, Mrs. G presented with fever (40°C [104°F]) and leukorrhea. Endometritis was suspected. On readmission to the obstetric ward, her treatment included risperidone (2 mg/day), alprazolam (1.5 mg/day), the phenothiazine antipsychotic cyamemazine (62.5 mg/day), and the anticholinergic tropatepine (10 mg/day). Antibiotic treatment was started to treat a possible infection.
Unlike in her previous postpartum episodes, Mrs. G's mental status responded only partially to antipsychotic treatment. A liaison psychiatry consultation was requested. The liaison psychiatrist found a mildly agitated and disoriented young woman who had wet herself and was circling around her bed. The patient was logorrheic, and her speech, which was mostly incoherent, revealed memory impairment. Strikingly, this mild state of confusion fluctuated during the interview, confirming midwives' reports of hourly changes in the patient's behavior. Mrs. G anxiously expressed feelings of guilt toward her newborn and the belief that her diagnosis of postpartum psychosis made her less able to take care of her children. She displayed no anger toward her children and no ideas of persecution, infanticide, or suicide. She also expressed the belief that “God talks to humankind through premonitory dreams or providential meetings,” a claim that had previously been interpreted as a mystic delusion. However, it appeared that this view was part of her cultural and religious background, as was later confirmed by her husband, who reported that she had held this belief for a long time and that it was shared by her relatives.
Overall, Mrs. G was more confused and less delusional than one would have expected in a typical postpartum psychosis. Puzzled by this clinical picture, the psychiatrist reconsidered the diagnosis of postpartum psychosis and extended his examination to assess the differential diagnosis. He found that Mrs. G had chronic headaches and a habitual reluctance to consume meat. His clinical examination revealed little; the patient had a well-tolerated fever, stable blood pressure and pulse, and no signs of severe sepsis. A neurological examination was unremarkable. The psychiatrist ordered immediate blood tests, including ammonia levels.
Within an hour, hyperammonemia was confirmed (224 μmol/liter, controls <50 μmol/liter), along with a respiratory alkalosis and a marked inflammatory syndrome. Results of liver function tests, as well as all the other blood tests, were normal. The psychiatrist contacted the internal medicine fellow, who confirmed the need for an immediate multidisciplinary management of a probable late-onset urea cycle disorder. He decided to transfer the patient to the intensive care unit (ICU), despite the reluctance of the obstetrical team, who felt that the patient should instead be in a secure psychiatric facility. In the ICU, an etiologic treatment of urea cycle disorder-induced hyperammonemia was immediately started under the guidance of a metabolic physician. It combined intravenous sodium benzoate, sodium phenylbutyrate (each at a loading dose of 10 g, then 2 g five times per day), citrulline (2 g five times per day), and protein-free hypercaloric nutrition delivered through a nasogastric tube. Antibiotic treatment was continued with co-amoxiclav (amoxicillin trihydrate and potassium clavulanate), and the differential diagnosis workup was completed. CT imaging of the brain was unremarkable. Blood and CSF cultures were sterile. During the night, the patient's neuropsychiatric status improved in conjunction with a drop in her ammonia level (her ammonia level fell to 64 μmol/liter the day after initiation of treatment and to 19 μmol/liter the following day). The diagnosis of urea cycle disorder was substantiated by plasma amino acid chromatography showing high glutamine-glutamate and low citrulline concentrations.
Within 5 days, this treatment yielded a complete and stable normalization of both Mrs. G's neuropsychiatric status and her ammonia plasma level. Weaned from antipsychotics and asymptomatic, she was discharged 13 days after the diagnosis of urea cycle disorder was made, with instructions for a protein-restricted diet and prescriptions for oral sodium benzoate, sodium phenylbutyrate, and citrulline. The diagnosis of urea cycle disorder was secondarily confirmed by molecular analysis. Ornithine transcarbamylase and N-acetyl glutamate synthase deficiency were ruled out. Carbamyl phosphate synthase (CPS) gene analysis found two mutations (p.P87S and p.R803C), confirming CPS1 deficiency.
Six months after discharge, Mrs. G remained free of psychiatric symptoms on a regimen of sodium benzoate, sodium phenylbutyrate, and citrulline (each at 2 g three times per day). Her cerebral MRI was unremarkable. However, neuropsychological tests revealed an IQ in the lower normal range (verbal IQ=77, performance IQ=84), restricted working memory, and mild attention deficit, which contrasted with the fact that she had worked as a journalist several years ago. Further investigations of Mrs. G's family history revealed that her mother had 11 pregnancies with six miscarriages. One boy died unexpectedly at 2 days of life and one girl died at age 4 after measles. Mrs. G's sister also had a postpartum acute confusion, and her brother, who is also reluctant to eat meat, had several episodes of acute ataxia associated with strange behaviors.
Case Study Reference: Viguera AC, Emmerich AD, Cohen LS. Case records of the Massachusetts General Hospital. Case 24-2008. A 35-year-old woman with postpartum confusion, agitation, and delusions. N Engl J Med. 2008 Jul 31;359(5):509-15. doi: 10.1056/NEJMcpc0804290. PMID: 18669430.