Reversible AlteredConsciousness With
Brain Atrophy
Caused by ValproicAcidHideo Yamanouchi, MD*,Takako Ota, MD†, George Imataka, MD†,
Eiji Nakagawa, MD*, andMitsuoki Eguchi, MD*
A 5-year-old female developed alteration of consciousness during 3 days of long-term treatment with valproic acid for localization-related epilepsy. Computed
tomography revealed cerebral atrophy, and electroencephalography presented slow background activity.
Consciousness cleared only 12 hours after valproic acidwas discontinued, and normal electroencephalography
results were evident 1 week later. Cerebral atrophy
was nonexistent 2 months later. This rapidly developing but reversible alteration of consciousness in parallel with brain atrophy is recognized as a rare idiosyncratic adverse effect of valproic acid. © 2003 by
Elsevier Inc. All rights reserved.
Yamanouchi H, Oka T, Imataka G, Nakagawa E, Eguchi
M. Reversible altered consciousness with brain atrophycaused by valproic acid. Pediatr Neurol 2003;28:382-384.

Introduction
Stupor or coma induced by valproic acid may be
associated with hyperammonemia with or without hepatic
dysfunction [1,2]. Different from this category, reversible
cognitive and behavioral deterioration associated with aradiologic finding of brain atrophy has been reported as arare adverse effect of valproic acid and is characterized bya subacute or chronic course without hyperammonemia[3-5]. Recovery occurs throughout weeks or months after
discontinuation of valproic acid therapy. Reported here isvalproic acid–related alteration of consciousness associated with brain atrophy that progressed throughout only 3days and resolved within 12 hours after discontinuation ofvalproic acid.

Case Report
This 5-year-old female was the product of a 39-week gestation and anormal delivery. She manifested normal developmental milestones. She
remained healthy until aged 2 years, when she presented with drop
episodes followed by unconsciousness for several minutes. Electroencephalogram (EEG) demonstrated normal background activity during thewakeful state and bilateral intermittent focal spikes throughout anterior
temporal and central regions during sleep recording. She was diagnosed
with localization-related epilepsy. Valproic acid was introduced at 10mg/kg/day and maintained at 15 mg/kg/day. Blood-screening tests,
including liver function tests, blood cell counts, and serum amylase
assays, performed at 2 weeks and 2 months after valproic acid introduction, revealed normal findings. No seizures were observed at the above
dose of valproic acid until the patient was 5 years of age, when a brief
generalized clonic seizure occurred. Computed tomography (CT) disclosed normal findings (Fig 1A, B). Because the recurrent seizure wasassociated with a low serum concentration of valproic acid (25.7 ␮g/mL),the valproic acid dose was increased to 20 mg/kg/day, with a resulting
steady-state serum concentration of 76.4 ␮g/mL.
After 3 months, she was admitted to the hospital because of alterationof consciousness, which developed throughout 3 days. Before this
disturbance, mental and motor development had been normal, even after
seizure onset. She could maintain arousal and was reactive to painful ortactile stimuli but had difficulty stating her name. She demonstrated little
interest in her surroundings and hardly talked with her mother. She was
not incontinent, agitated, or irritable. Physical and neurologic examination results were normal. Routine complete blood cell count was normal,
as were levels of serum electrolytes, glucose, calcium, phosphate, urea
nitrogen, creatinine, ammonia, lactate, and pyruvate; liver-function test
results were normal, and carnitine, amino acid, and organic acid analysis
yielded normal results. The serum valproic acid concentration was 107
␮g/mL. CT indicated mild enlargement of cerebral sulci and pericerebral
spaces; ventricular size was normal and no cerebellar or brainstem
atrophy was observed (Fig 1C, D). EEG during wakefulness revealed
diffuse slowing of background activity (Fig 2); a sleep recording depicted
normal background activity.
Valproic acid treatment was discontinued on admission because ofprevious case reports linking it to reversible mental deterioration associated with brain atrophy [3-5]. The next morning, approximately 12hours after admission, her consciousness level became completely
normal. EEG repeated 1 week after valproic acid discontinuation manifested normal background activity during wakefulness, and no paroxysmal discharge was observed (Fig 3). Administration of phenobarbital wasbegun 10 days after the discontinuation of valproic acid. Serial CT

From the *Department of Pediatrics, Dokkyo University School ofMedicine; and the †Department of Pediatrics, Shimotsuga General
Hospital, Tochigi, Japan.

Communications should be addressed to:
Dr. Yamanouchi; Department of Pediatrics, Dokkyo University Schoolof Medicine; 880 Kitakobayashi; Mibu, Shimotsuga;
Tochigi 321-0293, Japan.
Received July 25, 2002; accepted December 10, 2002.

382© 2003 by Elsevier Inc. All rights reserved.
doi:10.1016/S0887-8994(03)00005-5 ● 0887-8994/03/$—see front matter

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Figure 1. Serial brain CT. (A, B) Two years before
alteration in consciousness. (C, D) On admission. (E, F)
Two months after discontinuation of valproic acid. Observenormal findings in A and B, as well as E and F, contrastingwith mild atrophic changes in the cerebrum in C and D.

demonstrated improvement in the atrophic change of the cerebrum 1
month later, followed by a complete return to normal after 2 months (Fig1E, F). Subsequent magnetic resonance imaging revealed no significant
change in the brain. On follow-up in the outpatient department 5 months
after discontinuation of valproic acid, she manifested no abnormalities,
and her parents described her behavior and mental function as entirely
normal.

Discussion
Rapidly developing alteration of consciousness associated with brain atrophy and its dramatic resolution after
discontinuation of valproic acid treatment characterizes
the clinical feature in this patient. EEG in the wakeful state
revealed slowing background activity when the patientmanifested altered consciousness, and EEG activity returned to normal when she recovered consciousness.
Rapid depression of consciousness raises suspicion ofvalproic acid–related encephalopathy with hyperammonemia, which may occur in isolation [2] or in association
with such underlying disorders as urea cycle enzyme

deficiency [1]. Mitochondrial disorders such as MELAS(mitochondrial myopathy, encephalopathy, lactic acidosis,
and strokelike episodes) [6] and cytochrome c deficiency
with hepatic failure [7] can be triggered by valproic acid.
Carnitine deficiency may predispose patients to encephalopathy upon initiation of valproic acid therapy [8].
Finally, paradoxic epileptogenic effects of valproic acid,particularly induction of nonepileptic-status epilepticus,
also are part of the differential diagnosis [9].
This patient’s clinical features and course were similar
to those in previously reported pediatric cases [3-5] inwhich valproic acid was associated with reversible cognitive or behavioral deterioration and brain atrophy. Suchstates often persist for months, with reduction or disappearance of mental deterioration requiring weeks ([3];patient 1 in [4]; [5]) or even months (patient 2 in [4]).
Compared with those described in these reports, thispatient appears to be unique in that clinical manifestations
developed throughout only 3 days and disappeared only 12

Figure 2. Waking electroencephalography on admission,
revealing diffuse slowing of background activity. Calibration marks: 1 second, 100 ␮V.

Yamanouchi et al: Brain Atrophy by Valproic Acid 383

Figure 3. Waking electroencephalography 1 week after
discontinuation of valproic acid, revealing normal background activity. Calibration marks: 1 second, 100 ␮V.

hours after valproic acid discontinuation. The abnormalities observed were not mental deterioration, as in previous
reports [3-5], but instead appeared to be a rapidly progressive alteration in state of consciousness. Had valproic acidtreatment been continued, this patient might have appeared
to manifest mental deterioration or dementia, possibly
raising suspicion of a neurodegenerative disorder with asubacute or chronic course.
An important feature in this patient is the correlation
between clinical manifestations and EEG findings ofslowing during wakefulness. Most previously reported
pediatric cases of reversible brain atrophy and mental
deterioration associated with valproic acid therapy demonstrated normal background EEG activity [4,5]. However, McLachlan’s study [3] indicated that the waking
EEG during a mentally abnormal state of a patient receiving valproic acid treatment presented slowing of background activity (8-Hz slow alpha rhythm) dominated in
the bilateral occipital area in a patient 13 years of age.
Valproic acid–induced mental changes and brain atrophy may be associated with parkinsonism in adults [10].
Armon et al. reported that 11 of 16 patients manifesting
parkinsonism during valproic acid therapy demonstrated
progression of cerebral atrophy [10]. CT was obtained in
two patients whose signs were reversible after discontinuation of valproic acid. In pediatric cases, mental change
and brain atrophy can occur either in isolation ([5] andpresent case) or in association with neurologic signs suchas tremor, ataxia, and nystagmus [3,4]. Thus, this syndrome is variable: mental state may deteriorate rapidly,
subacutely, or chronically, and with or without otherneurologic signs, such as tremor. Rate of recovery also isvariable.
The pathogenesis of these reversible phenomena isunknown, although interference with the pituitary-adrenal
axis and changes in blood-brain barrier permeability have

384

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been hypothesized [3]. Irrespective of mechanisms, a drug
effect should be considered whenever brain atrophy andrapid change of consciousness occur in a patient receiving
valproic acid. Even if other indications of valproic acidtoxicity are lacking, valproic acid treatment should bediscontinued without delay as further evaluation proceeds.

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