Identifying and treating VHE
Asymptomatic elevations in ammonia without evidence of hepatic injury are common, might be related to valproic serum levels, and may occur in up to one-half of psychiatric patients receiving VPA.2-4 In contrast, VHE is a rare and potentially lethal idiosyncratic event unrelated to duration of VPA treatment, dosage, or valproic serum level.2-4 In addition, prior safe use might not protect against future VHE.3,4
VHE presents as delirium with characteristic acute changes in mental status, including alterations in cognition or level of consciousness ranging from lethargy to coma, along with possible focal neurological findings or vomiting.1,3,4 Although more common among patients with a seizure disorder, VHE also might be associated with new seizure activity in patients who do not have a seizure disorder.5
Although symptomatically acute in onset, emergence is unpredictable and can occur within days or up to years of use with therapeutic VPA dosing and valproic serum levels.2,4 Complicating identification, laboratory transaminase or ammonia elevations may or may not be present2-4; however, VHE typically occurs in the setting of hyperammonemia and normal transaminase levels.2 Reversible EEG findings are nonspecific2 and could show generalized slowing with occasional bursts of frontal intermittent rhythmic delta activity and triphasic waves.2,4
Pathophysiological descriptions of emergent VHE have been hypothesized,2-4 but the definitive causal mechanism remains unclear.6 Published VHE risk factors2-6 include:
- polypharmacy (especially anti-convulsants)
- inherited or dietary-based carnitine deficiency
- urea cycle disorders
- mental retardation.
How would you treat VHE?
a) cholinesterase inhibitors
b) antipsychotic therapy
c) supportive care
d) ammonia-reducing agents such as lactulose, carnitine, and neomycin
e) discontinue valproate
Outcome Normalized ammonia
Four days after discontinuing divalproex and starting lactulose, Mr. D’s fluctuating level of arousal, orientation, attention, and perceptual disturbances resolve along with restoration of environmental relatedness in setting of normalized ammonia level to 39 µg/dL. He is euthymic, non-psychotic, and without cognitive impairment at time of discharge. An “allergy” to divalproex is entered in his electronic medical record in an effort to discourage future retrial.
The authors’ observations
Once identified, management of VHE invariably includes consideration for discontinuation of valproate1,2,4,19; other adjunctive, expediting, ammonia-reducing strategies, including lactulose and carnitine, have also been described.2,4,5,20 Although lactulose is more commonly used, carnitine supplementation might be associated with a preferable dosing schedule and drug interaction and side-effect profile.20 Rapidly deteriorating clinical status could indicate hemodialysis.4
Of critical importance, these management strategies rely on awareness of and prompt identification of the condition, which includes an ability to distinguish emergent VHE from the mental illness VPA is used to treat.
Stopping the offending agent generally results in complete recovery in VHE patients with psychiatric illness.4 Most (>90%, n = 31) psychiatric patients in our and prior5 case series reviews recovered within 2 weeks of intervention.5 Cautious resumption of divalproex could be considered if there is a compelling clinical indication and you suspect that a putative polypharmacy agent such as topiramate has been removed; otherwise future retrial of VPA should be avoided.14
Mr. D’s case was consistent with a valproate-related hyperammonemic delirious event. He had preadmission acute onset, intra-daily fluctuating confusion, and visual perceptual disturbances with nausea, asterixis, gait disturbance, elevated ammonia, and a supportive EEG months after starting divalproex. Similar to our case, some challenging aspects of identifying emergent VHE include:
- earlier safe use of divalproex over extended periods
- lack of elevated VPA serum level
- lack of transaminase elevation
- lack of apparent risk factors
- presence of background serious mental illness, which can distract from VHE detection via misattribution to uncontrolled primary mental illness.