Case Series

This is a case series of three patients with Bipolar Affective Disorder (BPAD) who developed Valproate Induced Hyperammonaemic Delirium (VIHD) in the psychiatry department of a tertiary care hospital. All the patients were on irregular treatment with sodium valproate for several years before occurrence of the adverse drug reaction (ADR). Before restarting valproate for the current episode of mania the baseline Liver Function Tests (LFT) were done to rule out any evidence of hepatic impairment and impending danger of hepatotoxicity.

Case 1

A 46-year-old male developed features of BPAD following an accident 20 years back. He was on irregular therapy with valproate. He developed decreased sleep and excessive talk following which he was admitted to the Psychiatry department and started on Sodium valproate 500 mg twice daily along with Lorazepam 2mg once daily. Eighteen days later the patient developed confusion and lack of orientation in place and time. The drug was continued for six more days following which the patient’s condition progressively deteriorated. The arterial ammonia was investigated and found to be 81 micromoles/L (Normal-11-32 micromoles/L). His random blood sugar, renal function tests and LFT were normal. Valproate was stopped following which there was drastic improvement in the clinical condition of the patient. The arterial ammonia level fell to 46micromoles/L three days after stopping the drug. The patient was started on Lithium 600mg thrice daily.

Case 2

A 53-year-old male with BPAD was admitted to the psychiatry ward. He was on valproate therapy since 12 years but often defaulted. For his current episode of mania he was re-started on valproate 500 mg orally twice daily along with Olanzapine 10 mg twice daily and Lorazepam 2 mg at night. Two days later the patient developed confusion, lack of orientation to time, place, or person; his memory was impaired and he had decreased concentration and attention. His arterial ammonia was estimated four days later and was found to be 130micromoles/L and Spacing error hence the drug was stopped on the next day. LFT was repeated and found to be normal during the period. The patient showed good clinical improvement in the symptoms after stopping valproate. The arterial ammonia was found to be falling and was 50micromoles/L three days after stopping the drug. The patient was started on Lithium 600mg thrice daily.

Case 3

A 36-year-old female with BPAD since the age of 17 years had episodic attacks of mania and was using sodium valproate for the last two years. Default of the medications resulted in reappearance of maniac attacks and she was admitted in psychiatric ward and started on sodium valproate 200 mg thrice daily orally along with Lithium 600 mg thrice daily and Lorazepam 2 mg at night. Two days later the patient was found to be drowsy and later fell unconscious. The arterial ammonia estimated was 68micromoles/L and valproate was stopped on the same day and dose of Lithium was escalated. As in the previous case LFT were normal in this patient also. Three days later the patient had clinically improved from the symptoms and the arterial ammonia was 34 micromoles/L.

Discussion

Sodium valproate is an antiepileptic drug used as a mood stabilizer in acute mania and BPAD. The occurrence of VIHD in persons with normal LFT is not a common ADR. The first case of hyperammonaemic encephalopathy due to valproate was published in the 1990s [1]. A prospective study screening for hyperammonaemia in patients receiving valproate in psychiatry setting found that a positive correlation exists between the serum concentration of valproate and ammonia levels [2].

Hyperammonaemia can be either asymptomatic or symptomatic. It may occur with both therapeutic and supratherapeutic concentrations of valproic acid, indicating influence of other factors. Patients who have been on valproate for several years without developing any complications can suddenly develop symptoms of encephalopathy [3].

Delirium or acute confusional state is a serious neuropsychiatric syndrome frequently seen in the elderly. Rapid and fluctuating in course it presents with inattention, global changes in cognition and generalized severe disorganization of behaviour [4].

Patients monitored in our hospital were middle aged and had symptoms suggestive of delirium. All the three patients were on sodium valproate for several years and often defaulted. In the current episode of mania they received the drug in therapeutic concentration. The causality assessment with Naranjo Score was 5 indicating a Probable causality for the ADR. World Health Organisation scale also showed it was a probable ADR. Re-challenge was not done in any of the patients. Since the ADR increased the length of stay it was of moderate severity.

Despite the co-administration of other drugs, the temporal relation of termination of valproate and symptomatic improvement of patients suggest that the offending drug is valproate. The elevation of ammonia levels in the absence of deranged LFT supports the occurrence of VIHD. The positive correlation between stoppage of the valproate and quick reversal of clinical symptoms with fall in arterial ammonia levels in all the three patients is also suggestive of VIHD. [Table/Fig-1] compares the present case series with those published in the literature.

[Table/Fig-1]:

Comparison of present case series with similar reports in literature.

Patient details		Diseasefor whichvalproateinitiated	AgeandSex	TotalValproatedose(mg/day)	Duration ofvalproateuse	Concomitantdrugs	Serumammonialevels		Rechallenge	Management	Naranjo’sCausalityAssessment
Patient details		Diseasefor whichvalproateinitiated	AgeandSex	TotalValproatedose(mg/day)	Duration ofvalproateuse	Concomitantdrugs	1^st*	2^nd**	Rechallenge	Management	Naranjo’sCausalityAssessment
Present case series	Case 1VIHD	BPAD	46 M	1000	Several years with default.Valproate restarted for mania	Lorazepam	81	46	Not done	Valproatestopped	5-Probable
	Case 2VIHD	BPAD	53 M	1000		OlanzepineLorazepam	130	50
	Case 3VIHD	BPAD	36 F	600		LithiumLorazepam	68	34
Pradeep et al., [5]	Case 1VIHD	BPAD	53 M	1000	Dose increased 2 days before VIHD	Nil	95	25	Done	Valproate stopped	Not available
	Case 2VIHD	BPAD	60 M	1000	1 month		150	80	Not done
	Case 3VIHD	Seizure	20 M	750	3 years		366	-	Not done
Wadzinski et al., [6]	Case 1VIHE	PTSD	51 F	1000	7 days	Topiramate, Quetiapine	232	56	Not done	Valproate stoppedCarnitine	Not available
Wadzinski et al., [6]	Case 2VIHE	BPADOCD	29 F	1500	5 months	FluvoxamineClonazepam	182	41	Not done	Valproate stopped	Not available
Dixit et al., [7]	Case 1VIHD	Mania	31 M	1000 escalated to 1500	15 days	TopiramateOlanzepine	98	30	Not done	Valproate stopped	9-Definite

*Ammonia level checked first after suspecting hyperammonaemia **2 or 3 days after stopping valproate

VIHD-Valproate Induced Hyperammonaemic delirium; VIHE- Valproate Induced Hyperammonaemic Encephalopathy

BPAD-Bipolar Affective Disorder, PTSD-post traumatic stress disorder; OCD-Obsessive Compulsive Disorder

Valproate induced hyperammonaemia is a transient phenomenon but can become chronic and complicated and lead to VIHD if undetected. It could manifest as drowsiness, disorientation, and reversible cognitive deficits, which may progress to marked sedation, coma, and even death. Rashkind et al., states that valproate induced delirium occurs more commonly in the paediatric population [8].

Risk Factors for development of hyperammonaemia are high initial dose, long term valproate therapy, concomitant medicines such as antipsychotics or anticonvulsants added to valproate [9]. A well-established risk factor for hyperammonaemia in the neurological literature is the combination of valproic acid with other antiepileptic medications like phenobarbitone, phenytoin and topiramate [10].

The causes of valproate induced hyperammonaemia are many. As proposed by Panda et al., a reduction in hepatic N-Acetyl glutamate, an obligatory activator of Carbamoyl phosphate synthetase I (CPS I) by valproate metabolite propionate is one among them. Decline in CPS I activity disrupts the urea cycle thus resulting in defective ammonia utilization and accumulation [11].

Another mechanism proposed is reduction in hepatic carnitine levels by valproate. This results in decreased beta oxidation of fatty acids, which decreases Acetyl CoA leading to disruption of the urea cycle, resulting in hyperammonaemia [12]. Other mechanisms like induction of mitochondrial glutamine transport by valproate causing increased glutamate uptake by kidney and release of ammonia; inhibition of glutamate uptake by astrocytes, leading to neuronal injury and cerebral edema have also been proposed [13,14]. Deficiency of Ornithine transcarbamylase enzyme is the most common inherited cause of hyperammonaemia and valproate therapy can worsen the pre-existing hyperammonaemia [15].

Several drugs cause hyperammonaemia by disrupting the urea cycle. Glycine which is used in transurethral resection of prostate stimulates ammonia production [16]. Salicylates can reduce mitochondrial function in the liver as suggested by the Reye syndrome [17]. Although the mechanisms are unclear there have been a few reported case of hyperammonaemia due to carbamazepine, ribavirin and Sulfadoxine/Pyrimethamine [18–20]. Discontinuation of valproate helps in dramatic clinical improvement. The role of carnitine (2-4g/day) for prevention and treatment of VIHD has been established [10].

Conclusion

Hyperammonaemic delirium can be missed because of its close similarity with symptoms suggestive of worsening of psychosis. Hence it could be suggested that plasma ammonia levels should be monitored promptly in all patient developing altered mental status after receiving valproate therapy. There is also need of systematic evaluation of safety and efficacy for longer term use of valproate.

*Ammonia level checked first after suspecting hyperammonaemia **2 or 3 days after stopping valproateVIHD-Valproate Induced Hyperammonaemic delirium; VIHE- Valproate Induced Hyperammonaemic EncephalopathyBPAD-Bipolar Affective Disorder, PTSD-post traumatic stress disorder; OCD-Obsessive Compulsive Disorder

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