from a neurovascular perspective , the brain is one of the most delicate and complex surgical fields . the postoperative course can vary , and transient or permanent mental deterioration or neurological deficits can occur . these may be due to many factors , such as postoperative vasospasm , delayed hemorrhage , acute infarction , brain swelling , seizure , hypoglycemia , or electrolyte imbalance , and accurate differential diagnosis at this stage is essential . we present an unusual case of postoperative mental deterioration due to hyperammonemia without signs of hepatic failure . our case provides evidence that life - threatening hyperammonemic encephalopathy can occur within days of initiation of valproic acid therapy after neurovascular surgery . a 57-year - old female patient was referred to the neurosurgery department by a hospital neurologist , after radiologic imaging for chronic headache revealed a paraclinoid aneurysm . the patient 's chronic headache had been managed with conservative treatment ( including medication ) for several months , and her medical history was otherwise unremarkable . the patient had no other complaints , her vital signs were stable , and her complete blood count ( cbc ) , routine biochemistry tests , urinalysis , liver function , thyroid function , lipid profile , and creatine kinase levels were normal , as were her erythrocyte sedimentation rate ( esr ) and c - reactive protein ( crp ) levels . the patient was hepatitis b antibody - positive with a history of hepatitis b vaccination . a neurological examination failed to reveal any deficits ; however a 65 mm aneurysm was observed on computed tomographic ( ct ) angiography . there was a postero - medial outpouching at the ophthalmic level with a daughter sac ( fig . after careful dissection , the neck of the aneurysm was exposed , and two fenestrated clips were applied . the patient was transferred to a recovery unit , where she recovered fully from anesthesia . subsequently , she was transferred to a general ward , where she received standard postoperative care . routine laboratory tests showed that her cbc , serum electrolytes , blood sugar , serum osmolality , liver enzymes , blood urea nitrogen , and creatinine were normal . on postoperative day 1 , the patient was administered analgesic and anticonvulsant medication , including 300 mg valproic acid three times a day with a soft diet . on postoperative day 4 , she was transferred to the intensive care unit , where emergency diffusion mri and ct angiography of the brain were performed . although the imaging showed evidence of minimal scattered acute infarctions , it failed to identify a definite abnormality that could explain her mental state . a simple chest x - ray and arterial blood gas analysis ( abga ) failed to reveal any respiratory or metabolic problems such as hypoxia , hypercapnia or acidosis . except for mildly elevated esr and crp , a neurologic examination also failed to identify any abnormalities such as abnormal pupil reflex or hemiparesis , except for the decreased mental status . moreover , the patient did not perform any seizure - like movements or tremors . even though the radiologic findings , such as mild narrowing of the internal cerebral artery ( fig . 2 ) and a minimal acute infarct in the cortex and subcortical white matter of the left frontal and temporal lobes , could not conclusively explain the patient 's mental deterioration , she was thought to be suffering from transient cerebral ischemia due to postoperative vasospasm . 3-h therapy ( hypervolemia , hemodilution , hypertension ) was initiated . oral diet and medications were withdrawn , and an intravenous vasodilator was started with sufficient hydration to maintain a strictly positive balance . the patient began to regain consciousness one day after starting treatment , and after two more days she was almost fully conscious , with only some confusion remaining . as before , laboratory tests and physical examination failed to reveal any cause of the deterioration . however , on this occasion we measured the blood levels of valproic acid , which turned out to be toxic ( 149.40 mg / l ; therapeutic range , 50 - 100 we then checked blood ammonia level , which were also markedly elevated ( 553 mmol / l ; normal range , 9 - 33 mmol / l ) . at the same time , liver enzymes and other markers of hepatic function , such as g - glutamyl transferase , aspartate transaminase , alanine transaminase , and alkaline phosphatase , as well as abga , were all within the normal ranges . valproic acid was discontinued , and the patient received oxygen , thiamine and a lactulose enema . she regained full consciousness within 24 hours , and the ammonia levels returned to normal within 48 hours . our diagnosis was hyperammonemic encephalopathy induced by valproic acid , following neurovascular surgery for an unruptured aneurysm . valproic acid is a broad - spectrum anti - epileptic drug ( aed ) with several neurological indications2 ) . in particular , it is used as a first - line drug in brain surgery or brain trauma patients in our department , to prevent postoperative or post - traumatic seizures . its initial loading dose is 20 - 30 mg / kg administered at 6 - 10 mg / kg / min2 ) , followed by a maintenance dose of 900 - 1200 mg / day . valproate has a number of recognized side effects , including hepatotoxicity , renal toxicity , thrombocytopenia , blood dyscrasia , coagulopathy and teratogenicity35 ) . therefore , it is important to monitor blood chemistry and the drug 's blood concentration . although several explanations have been proposed , the key mechanism seems to be valproate - induced inhibition of hepatic carbamoylphosphate synthetase i , the first enzyme of the urea cycle 78 ) . mildly elevated blood ammonia levels have been observed in 16 - 52% of patients receiving valproic acid 59 ) , with a reported incidence of 20% for asymptomatic and 5% for symptomatic cases5 ) . the experience with our patient shows that even a short treatment ( in this case three days ) with a standard dose can increase serum valproate to toxic levels . the relationship between valproate - induced hyperammonemia and hyperammonemia - induced encephalopathy is not fully understood , and there have been conflicting reports258 ) . dewolfe et al.2 ) found that the hyperammonemia was transient and not associated with changes in consciousness , while others have suggested that hyperammonemia can cause encephalopathy12 ) . elevated serum ammonia can inhibit glutamate uptake by astrocytes and exacerbate extracellular glutamate accumulation , leading to excitotoxic neuronal injury16 ) . another hypothesis suggests that elevated serum ammonia is conjugated in the brain with alpha - ketoglutarate to produce glutamate . this could lead to alpha - ketoglutarate depletion and a subsequent block in the krebs cycle , which could precipitate cell damage and neuronal death14 ) . elevated serum ammonia has also been reported to increase the risk of seizure due to excessive activation of n - methyl - d - aspartic acid - type glutamate receptors8 ) . known risk factors for vhe include congenital enzymatic defects of the urea cycle , underlying liver disease , long - term valproic acid treatment , concomitant anti - epileptic therapy , and strict vegetarianism15 ) . to these , tsia and chen8 ) added three major risk factors : initiation of valproate treatment , high initial dose , and catabolic state . at therapeutic concentrations , 90 - 95% of serum valproic acid consequently , a decrease in protein binding capacity caused by conditions such as metabolic acidosis , low albumin level , and older age could lead to unusually high serum valproic acid concentrations8 ) . postoperatively , patients may present with metabolic acidosis and low albumin levels , which , following tsia and chen8 ) , which may have exposed our patient to two risk factors at the same time : initiation of treatment and catabolic state . because there is a high probability that aed therapy with valproic acid will be initiated in most neurosurgical and brain trauma patients , we may suppose that such patients may have a higher risk of valproate - induced hyperammonemic encephalopathy ( vhe ) . hydration , sodium phenylacetate , lactulose , and l - carnitine may also be of benefit8 ) . when ammonia levels are in excess of 680 g / dl ( 400 mol / l ) hemodialysis could be an additional therapeutic option18 ) . in the case of our patient , the hemodilutional effect of the 3-h therapy and discontinuation of oral valproic acid after the first episode of mental deterioration were sufficient to allow her to regain full consciousness . the occurrence of neurological deficits following brain surgery should prompt the physician to make an accurate differential diagnosis . serum ammonia levels should be part of the basic work - up in all patients presenting with mental deterioration after brain surgery or trauma , even when their liver function is normal and valproic acid has been administered at normal doses and for a short period of time .
neurological deficits after brain surgery are not uncommon , and correct and prompt differential diagnosis is essential to initiate appropriate treatment . 
 we describe a patient suffering from loss of consciousness due to hyperammonemia , following valproic acid treatment after surgery for an unruptured cerebral aneurysm . 
 a 57-year - old female patient underwent successful aneurysmal neck clipping to correct an unruptured aneurysm . 
 her postoperative course was good , and she received anti - epileptic therapy ( valproic acid ) and a soft diet . within a few days the patient experienced mental deterioration . 
 her serum valproic acid reached toxic levels ( 149.40 mg / l ) , and serum ammonia was fifteen times the upper normal limit ( 553 mmol / l ; normal range , 9 - 33 mmol / l ) . 
 after discontinuation of valproic acid and with conservative treatment , the patient recovered without any complications . 
 valproate - induced hyperammonemic encephalopathy is an unusual but serious neurosurgical complication , and should not be disregarded as a possible cause of neurological deficits after neurovascular surgery . 
 early diagnosis is crucial , as discontinuation of valproic acid therapy can prevent serious complications , including death .