Bipolar Disorder and Valproate-Induced Hyperammonemic Encephalopathy in an Adolescent with Diabetes

Chief Complaint and Presenting Problem

F. is a 15 year-old Dominican-Russian male, with a recent diagnosis of bipolar disorder, who presented to the emergency department (ED) with grandiose delusions, labile affect, agitation and aggressive behavior, disorganized thought process, racing thoughts, pressured speech, and an increase in goal-directed activity. He had presented with similar symptoms and was hospitalized twice in the six weeks prior to this presentation.

History of Present Illness

F.'s mother reported that F. had been in his usual state of health until six weeks prior to his current presentation, when he was first admitted to an inpatient psychiatric unit for aggressive behavior and delusional thinking. He was started on lithium, discharged after three days, and then subsequently readmitted to a second hospital with similar symptoms. A head computed tomography (CT) scan was reportedly negative. F. was discharged after two weeks from his second hospitalization. F. was subsequently reported to be non-adherent to his treatment regimen following discharge; F.'s mother reportedly did not fill discharge prescriptions in a timely manner. Thus, F. was re-hospitalized with the current presentation approximately three weeks later.

Further history was significant for many stressors at home and school. In one incident, F.'s mother had been involved in many arguments with F.'s teachers over reading “The Da Vinci Code,” as she felt the content was too mature for him. He reported feeling very “stressed and angry” about this. In a second incident, F. had been accused of trying to “convert” a girl he tutored to his mother's religion. F.'s mother reportedly reacted by threatening the girl's parents, and F. reportedly accused the girl of cheating on tests, which alienated him from his peers at school. F. also reportedly developed a reduced need for sleep and paranoid delusions. He reported seeing “evil” in a Picasso painting and was reportedly preoccupied with Socialists and referential delusions about the number “3,” feeling that it had something to do with Socialism. He was reported to be hyper-religious, stating that he was “talking with Jesus.”

On the day of the current presentation, F. reportedly encountered emergency medical services (EMS) on a local movie set. He was agitated and disorganized, yelling that he was a movie stuntman. Upon arrival at the ED, F. was reported to be very agitated, disorganized, and threatening. He reportedly asserted that he had been invited by the movie director to be a stuntman in a new movie. He eventually required chlorpromazine 50 mg intramuscularly (IM) and diphenhydramine 50 mg IM to treat his agitation and delusions. His speech was pressured, and he was reported to be engaging in increased goal-oriented activities such as drawing and asking other patients to take his pulse. F.'s mood was reported to be labile, and he talked illogically about “love, peace, and happiness.” He also reportedly endorsed racing thoughts, grandiose delusions that he knew how to fly and could solve the financial crisis by talking to the President, and paranoid ideation that Socialists were after him. He was admitted to the adolescent psychiatric unit.

There was no past history of significant mood symptoms, other than an episode of suicidal ideation when F. was 11 years old, during which he was reportedly feeling very depressed and held a knife to his chest, although he never harmed himself. F. had broken a glass window with his fist and punched a staff member in the ED upon his initial presentation and on the inpatient adolescent unit during his first admission. There was no other history of disruptive behavior, mood or anxiety symptoms, substance abuse, or history of learning problems.

Past Psychiatric History

F. was hospitalized three times in the past 6 weeks. During his first and second hospitalizations, F. was treated with quetiapine and lithium, though the doses are unknown. F. denied past substance use, which his mother corroborated. Previous urine toxicology results were negative.

Developmental History

Mother denied that F. had been exposed to any toxins or medications in utero, but reported that she had experienced significant psychological stress during the pregnancy as a result of F.'s father leaving the country. She denied any medical problems or complications during the pregnancy. F. was born full term at 7 lbs., 5 oz., with no complications during delivery.

Mother reported that he was exclusively breast-fed. She described him as a “happy” and “quiet baby” who met all of his developmental milestones either on time or early. He was reported to have had no developmental, learning or behavior problems in his infancy, preschool, or grade school years. F. was reported to have had an easy temperament, was well-related to his mother and peers, and was able to attend school without difficulty. Similarly, in his preadolescent and early adolescent years, he was reported to exhibit no developmental difficulties.

Educational History

F. started at a Montessori school in a major city at the age of 3 years, and then attended public school for 3 months starting at the age of 5 years. As a result of experiencing dissatisfaction with the school, F.'s mother was reported to home-school him for 6 months. The family subsequently moved, and F. attended first and second grades at another Montessori school while his mother reportedly started Montessori teacher training herself. The family moved again, and F. attended third through seventh grade at a Montessori school in a different major city. He was again home-schooled for eighth grade as a result of mother's reported inability to pay debts incurred at the Montessori school. F. subsequently entered public high school for ninth and tenth grades and reportedly did very well there, receiving As in English and math.

Social History

F.'s mother moved to the United States in the 1990s from Europe. His father and mother met at that time, and were together for 5 months, during which F. was conceived. F.'s father then moved to Europe where he currently lives with his family; F. has had very little contact with him. F. traveled to Europe to visit his father once at the age of 10 years but had little communication, except through email, with his father due to a language barrier.

F. has a 32-year-old half-sister, with whom he was raised, who now lives outside the United States. His only other known relative is an aunt who lives nearby. His mother works a number of jobs and currently has financial difficulties.

F. and his mother belong to a church that incorporates elements of Buddhism, Christianity, the paranormal, alchemy, and spirits of nature, who are reportedly fearful of an invasion by Socialists. F.'s mother is also reported to have a long history of distrust of Western medicine and practices and has refused vaccinations and medications for her son.

F. has no known history of physical or sexual abuse or exposure to domestic violence. He has exhibited poor peer interactions recently as a result of his inappropriate behavior but prior to that had been reported to have age-appropriate friendships.

Family History

There is no known family history of diagnosed psychiatric illness. There is no family history of diabetes.

Medical History

In the ED, a random blood glucose level was found to be elevated at 301. A pediatric endocrinology consult was obtained, and F. was diagnosed with maturity onset diabetes of the young (MODY), which had been previously undetected. He was started on both standing and sliding scale insulin regimens after failure to respond to oral medications.

Medication History

F. was not taking psychiatric medications on admission, although there is some question as to whether or not his mother had been giving him herbal remedies. A lithium prescription, written for him upon discharge from his second hospitalization three weeks prior, had been filled the day before his current presentation.

Mental Status Examination on Admission

F. was a well-nourished young man who appeared his stated age. Psychomotor agitation was noted as he paced around the ED and engaged in inappropriate behaviors, such as asking other patients to take his pulse. He appeared somewhat anxious, and his affect was labile. His speech was pressured, and he reported racing thoughts. His thought process was disorganized and perseverative, at times tangential. He displayed delusional thinking, trying to convince other patients and staff that he was a stuntman who was hired to appear in a new movie. F. denied suicidal and homicidal ideation. His judgment and insight were poor. His impulse control was severely impaired. Attempts to perform a mini-mental status examination failed, due to his disorganized thinking, but he remained alert throughout his stay in the ED without any evidence of fluctuating consciousness.

Hospital Course

A urine toxicology screen in the ED was negative. Physical examination revealed no abnormal findings other than the mental status examination. In addition to the elevated blood glucose 301 mg/dL (normal (nl) = 70–99), hemoglobin A1c was high at 7% (nl = 4.5–6.3%). Other abnormal labs in the ED include: Na +which was slightly low at 135 mmol/L (n l = 137–147), BUN was slightly elevated at 24 mg/dL (nl = 6–22), GGT was < 8 IU/L (nl = 15–85), AST 65 U/L was elevated (nl = 11–39), thyroid-stimulating hormone (TSH) was slightly elevated at 4.943 uIU/mL (nl- = 0.35–4.8), lithium was low at 0.17 mmol/L, and urine ketones 5mg/dL (trace) and urine protein 30 mg/Dl (1+) were present. Other laboratory values were reported to be within normal limits.

Once admitted to the inpatient unit, F. was restarted on lithium 300 mg PO three times a day (TID). He continued to display severe agitation and aggressive behavior, and chlorpromazine 100 mg twice a day (BID) and clonazepam 1mg BID were added. He required frequent as-needed medications, including chlorpromazine 50 mg IM and diphenhydramine 50 mg IM, and occasional wrist and ankle restraints to treat his aggressive behavior. Clonazepam was increased to 2 mg BID. At that time, the lithium level was sub-therapeutic, but TSH was noted to be rising. As a result, four days into his hospitalization, lithium was cross-titrated to valproate 500 mg PO TID, and F.'s chlorpromazine dose was increased to 100 mg PO BID and 200 mg PO at bedtime. Some clinical improvement was seen, and eventually F.'s valproate level reached therapeutic range on total 1750 mg daily.

When F.'s QTc was found to be increased on repeated EKGs, chlorpromazine was tapered, and haloperidol 2 mg PO BID started. Further clinical improvements were noted, but F. began to experience excessive daytime sleepiness. This was at the same time his mother had given him an unknown white powder (an herbal “antiseptic”) to sniff while visiting one day. Consultation was requested by pediatrics, pediatric endocrinology, and pediatric neurology to investigate potential medical etiology of his increasing sedation. All labs were within normal limits, including CBC, basic metabolic panel including liver function tests, hepatitis screen, ESR, ceruloplasmin, serum copper, ANA, B12, folate, urine organic acids, and serum amino acids.

F.'s serum ammonia level was elevated to 96 umol/L (nl 11–35). His valproate level was therapeutic at 100 ug/mL, liver function tests were within normal limits, and there was no evidence of lactic acidosis. He was diagnosed with valproate-induced hyperammonemic encephalopathy, and treatment with levocarnitine was recommended. After levocarnitine 500 mg PO BID liquid was initiated, a carnitine level showed normal total carnitine, free carnitine, and carnitine esters. At the same time, one dose each of haloperidol and valproate were held, and F. appeared significantly less sedated.

F. subsequently experienced an oculogyric crisis, most likely a withdrawal dyskinesia, which necessitated treatment with IM and then standing PO benztropine. Valproate was continued at the current dose, and with levocarnitine, consecutive ammonia levels trended downwards. F. exhibited further clinical improvement without excessive sedation. Metformin 1500 mg PO daily was also replaced with glargine, titrated up to 14 units every morning, while his insulin sliding scale was continued, during the same period.

Despite frequent attempts at psychoeducation regarding bipolar disorder and diabetes, F.'s mother continued to bring herbal remedies and juices high in sugar. The Administration for Children's Services was consulted, and F. was placed in foster care. He was discharged from the unit after six weeks and referred for treatment at the adolescent day hospital. Discharge medications included valproate 500 mg once in the morning, 1250 mg at bedtime, levocarnitine 500 mg PO BID, clonazepam 1 mg PO at bedtime, haloperidol 1 mg PO in the morning, and 3 mg at bedtime, benztropine 2 mg PO BID, docusate 100 mg PO TID, one multivitamin tablet PO daily, novolog sliding scale before meals, and glargine 14 units every morning.

In the day hospital, F. showed continued symptomatic improvement; however, he developed leukopenia, and haloperidol was discontinued, to good effect. He was eventually transferred to the outpatient clinic on a regimen of valproate 500 mg once in the am and 1250 mg at bedtime and levocarnitine 500 mg PO BID. After his first visits to the outpatient clinic, F. began to exhibit mild sedation again, finding it difficult to wake up for school and other appointments, and his ammonia level was again found to be elevated. His levocarnitine dose was increased further to 750 mg BID, but follow-up labs showed persistent hyperammonemia. He was cross-titrated back to lithium, eventually up to 600 mg PO BID, to good effect. He displayed no increase in manic symptoms, and his TSH remained within normal limits. His ammonia level reduced to normal, where it remains.

Throughout his treatment in the outpatient clinic (10 months), F. has remained stable, aside from a period of a few days during which he stopped taking his medication stating that he simply “forgot” to take them. At that time, his foster mother and case manager noted a slight increase in irritable mood when he became agitated over a foster care agency policy of enforced psychological evaluation and treatment for his biological mother. The irritability decreased upon restarting lithium. Throughout, he has managed to produce honors-level work in the eleventh grade at his high school.

Diagnostic Impression And Case Formulation

F. is a 15-year-old male with a history of severe manic and psychotic symptoms, in the setting of undiagnosed diabetes and multiple psychosocial stressors, consistent with bipolar disorder. Notable in his course of illness were three hospitalizations as a result of severity of his symptoms and non-adherence to treatment. Comprehensive medical, endocrinological and neurological work ups revealed elevated blood sugars consistent with maturity onset diabetes of the young.

From a biological perspective, F. may be predisposed toward mental illness, given his mother's presentation. Although not formally diagnosed, F.'s biological mother presents as a parent with unusual beliefs, questionable reality testing, and a past history of compromised judgment, which may represent manifestations of an underlying psychiatric disorder. Potential medical etiologies of bipolar symptoms, such as substance abuse or endocrinopathies, were essentially ruled out; however, given untreated diabetic illness at presentation, it is possible that hyperglycemia and its complications may be contributing. Finally, F. developed an unusual complication of valproate in the form of hyperammonemic encephalopathy, which required treatment with carnitine.

From a psychosocial perspective, F. has experienced many major stressors within his family, including financial problems, abandonment by his father, frequent relocation, inadequate medical and psychiatric follow-up, and lack of social support. Although intelligent, motivated, hardworking and reliable, he appears to have immature coping skills and relies very heavily on his mother's care.

Multi-Axial Diagnoses

Discussion

This case of a mid-adolescent with bipolar disorder and diabetes represents an interesting intersection of medical, psychological, and sociocultural issues. Although it is not known how long F. had experienced hyperglycemia, it is possible that the elevated blood sugar contributed to the acuity of the presenting clinical picture. Observational studies in mid-twentieth century reported that the prevalence of type 2 diabetes in patients with schizophrenia was higher than that of the general population (Lebovitz 2003). It is not known whether adolescents with bipolar disorder would have a similar risk, but there has been recent evidence that there may be a common genetic vulnerability between schizophrenia and bipolar disorder (Braman & Sham 2001).

Maturity onset diabetes of the young (MODY) is a heterogeneous group of disorders characterized by onset before age 25, autosomal dominant inheritance, and nonketotic diabetes mellitus. The primary defect in the function of pancreatic beta cells is a result of one of several genetic mutations. The most frequent clinical presentation is of mild, asymptomatic hyperglycemia in non-obese youth. MODY can be differentiated from type 2 diabetes by significant family history of diabetes, young age at onset, and lack of obesity (Fajans et al. 2001). Although there is no reported family history of diabetes, reliability of mother as informant may be questionable.

In addition, although F. was not apparently abusing illicit substances, which may often be a precipitating or perpetuating factor in adolescent mania, F. had ingested several unknown substances given by his mother, described as herbal remedies. Although there is no way to ascertain exactly the contents of these substances, herbal remedies may have central nervous system activity and/or interact with, and mimic or exacerbate effects of drugs (Fugh-Berman 2000). For example, a patient with unipolar depression on phenelzine was reported to develop mania in the context of ginseng and bee pollen (Jones & Runikis 1987). Ephedrine alkaloids can result in sympathomimetic toxicity (Tovar et al. 2009); valerian can produce drowsiness and sedation (Elvin-Lewis 2001). St. John's Wort, a potent inhibitor of cytochrome P450 isoenymes, can produce lethargy and mild serotonin syndrome in interaction with selective serotonin reuptake inhibitors (Fugh-Berman 2000). Thus, it is possible that components of the herbal remedies may have interacted with F.'s medication, or had unique psychoactivity.

Another very interesting aspect of the case was F.'s development of valproate-induced hyperammonemic encephalopathy (VHE). This is an unusual but serious adverse effect characterized by lethargy, cognitive slowing, vomiting and focal neurological deficits. Untreated, the syndrome can lead to seizures and coma. Fortunately, this complication of valproate (VPA) was picked up quickly in the evaluation of F.'s excessive daytime somnolence, and treatment was initiated. Although VHE is not well understood, the clinical syndrome is thought to result from elevated ammonia levels in the blood. Hyperammonemia leads to an increase in central nervous system glutamine, which leads to astrocyte swelling and cerebral edema (Segura-Bruna et al. 2006).

Several mechanisms may be involved. One putative mechanism is that VPA induces a carnitine deficiency, which results in non-specific signs and symptoms of hepatoxicity and elevated blood ammonia levels. VPA-associated hepatoxicity is idiosyncratic in onset, and often occurs within the first few months of treatment. Risk factors for VPA-induced heptatoxicity include neurological conditions, multiple anticonvulsant therapy, age less than 24 months, and use of ketogenic diet (Raskind et al. 2000). Given available history and findings on examination, none of these risk factors was apparent.

Carnitine, an important nutrient found in meat and dairy products, is an essential amino acid necessary in oxidation of fatty acids and energy production in mitochondria and is necessary for metabolism of VPA. Carnitine stores can be depleted by long-term treatment with VPA. A second putative mechanism associated with hyperammonemia and VPA involves no hepatic injury. It is associated with inhibition of carbamoylphosphate synthetase-I, and ornithine transcarbamylase, enzymes in the urea cycle (Elgudin et al. 2003).

Signs and symptoms of encephalopathy may not be directly related to VPA dosage or serum levels, and serum ammonia levels may run high in patients receiving VPA with or without clinical symptoms. Dietary protein intake, even modest amounts, may increase serum ammonia levels but there is little systematic data (Gidal et al. 1997). VHE seems to be more frequent in patients with carnitine deficiency or congenital enzymatic defects of the urea cycle. Elevated ammonia levels have been observed in patients receiving therapeutic levels of VPA (Verrotti et al. 2002). Other anticonvulsants such as phenytoin and carbamazepine may exacerbate VHE. Although there has been a case report describing VHE in a 35-year-old adult bipolar patient who presented to the ED with coma, it does not appear that this has been reported before in an adolescent patient (Elgudin et al. 2003).

VHE generally resolves quickly after dosage reduction or discontinuation, so early recognition is extremely important. In this case, although the VHE was most likely idiosyncratic in onset, it is possible that there was a dietary interaction, given the use of supplements, or perhaps an unrecognized enzymatic deficiency. It was fortunate that the clinical team made the diagnosis quickly so that treatment could be initiated. Carnitine supplementation may facilitate fatty acid B-oxidation and increase mitochondrial levels of acetyl-CoA which may prevent some consequences of VPA treatment. In addition, post prandial hyperammonemia may be reduced if VPA is not administered with high protein meals (Verrotti et al. 2002).

It is possible that F.‘s complex clinical picture of bipolar disorder, MODY and VHE may all reflect a “perfect storm” of intersecting underlying medical and psychiatric genetic vulnerabilities, which remain speculative but intriguing.