Yanaga et al. Journal of Medical Case Reports
https://doi.org/10.1186/s13256-023-03964-4(2023) 17:221

Journal ofMedical Case Reports

Open Access

CASE REPORT

Acute pancreatitis during valproic acidadministration in a patient with vasculardementia, epileptic seizures, and psychiatric
symptoms: a case report
Mako Yanaga1, Naomichi Okamoto1* , Reia Hashimoto1, Ryohei Igata1, Yuki Konishi1, Atsuko Ikenouchi1,2,Naoki Isomoto3, Takahiro Shinkai1, Masaru Harada3 and Reiji Yoshimura1

Abstract
Background Valproic acid (VPA) is a relatively safe drug widely used for the treatment of epileptic seizures and mania
in bipolar disorder, as well as the prevention of migraine headaches. Here, we present a case of VPA-induced pancreatitis in a patient with vascular dementia, epileptic seizures, and psychiatric symptoms. He had no distinctive abdominal symptoms.
Case presentation A 66-year-old Japanese man was treated with VPA for agitation and violent behavior due to vascular dementia, epileptic seizures, and psychiatric symptoms. During admission, he experienced a sudden decreasein consciousness and blood pressure. Abdominal findings were unremarkable; however, blood tests showed aninflammatory response and elevated amylase levels. Contrast-enhanced abdominal computed tomography showed
diffuse pancreatic enlargement and inflammation extending to the subrenal pole. VPA-induced acute pancreatitis wasdiagnosed, VPA was discontinued, and high-dose infusions were administered. Acute pancreatitis resolved after treatment initiation.
Conclusions Clinicians should be aware of this relatively rare side effect of VPA. Diagnosis may be challenging inelderly people and patients with dementia as they may present with non-specific symptoms. Clinicians shouldconsider the risk of acute pancreatitis when using VPA in patients who cannot report spontaneous symptoms. Bloodamylase and other parameters should be measured accordingly.
Keywords Valproic acid, Acute pancreatitis, Vascular dementia, Symptomatic epilepsy, Psychiatric symptoms*Correspondence:
Naomichi Okamoto
nokamoto@med.uoeh-u.ac.jp
1
Department of Psychiatry, University of Occupational
and Environmental Health, Fukuoka 8078555, Japan
2
Medical Center for Dementia, Hospital of the University of Occupational
and Environmental Health, Fukuoka 8078555, Japan3
Third Department of Internal Medicine, University of Occupationaland Environmental Health, Fukuoka 8078555, Japan

Background
Valproic acid (VPA) is a widely used drug for the treatment of epileptic seizures and mania in bipolar disorder, as well as for the prevention of migraine headaches[1]. VPA is a relatively safe drug [2]; however, a rare side
effect is acute pancreatitis, with a frequency of approximately 0.003–0.7% [3]. VPA-induced pancreatitis is morecommon in young patients than in elderly patients [4].
While one report showed that the prognosis was worse
in half of the cases [5], another reported a relatively good

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Yanaga et al. Journal of Medical Case Reports(2023) 17:221

prognosis [4]; therefore, the outcome may vary from caseto case.
Here, we present a case of VPA-induced pancreatitis ina patient with vascular dementia, epileptic seizures, andpsychiatric symptoms. In this case, a sudden loss of consciousness and hypotension occurred without abdominalsymptoms, including pain.

Case presentation
We report the case of a 66-year-old Japanese man. He
developed a subarachnoid hemorrhage at the age of 56(10 years ago). After the subarachnoid hemorrhage, heexperienced cognitive decline and generalized epilepticseizures. He received levetiracetam 1000 mg/day, carbamazepine 400 mg/day, and VPA 400 mg/day to control
generalized epileptic seizures. Prior to referral to thehospital, the patient was wheelchair-bound and required
assistance with bathing and toileting; however, he could
communicate briefly. He had no history of alcohol use orsmoking.
On April 19, he was referred to our hospital for medication adjustment due to the sudden onset of agitationand violent behavior. On admission, his vital signs werenormal (temperature 36.5 °C, heart rate pulse 60 bpm,
blood pressure 138/95 mmHg). In addition to the abovedrugs, he was periodically taking antihypertensive drugs(telmisartan 60 mg/day, enalapril 5 mg/day, cilnidipine 10 mg/day), and psychotropic drugs (quetiapine125 mg/day, tiapride 100 mg/day, ramelteon 8 mg/day),which have been added 6 months prior to our referral.
The patient’s psychiatric symptoms included intermittent episodes of irritability and agitation. He experienced
sudden somnolence, but there were no abnormal neurological findings such as involuntary movements or seizure. Levetiracetam had been administered at the doseof 1000 mg/day for a long time before the onset of agitation and violent behavior; therefore, we denied increased
irritability as a drug side effect. Although there were noepileptic waves evident on the electroencephalogram,
we suspected epileptic seizure with interictal psychiatric symptoms and increased the dose of VPA from 400
to 800 mg/day on May 7 to control irritability and agitation. There were no changes in the other prescribedmedications. After the dose was increased, there wasstill no improvement in the patient’s irritability and violent behavior; therefore, the dose of VPA was increased
further to 1200 mg/day on May 14. As liver enzyme elevations (aspartate aminotransferase: 47 U/I, alanine aminotransferase: 108 U/I) were observed with an increased
dose, the dose of VPA was reduced to 800 mg on May
21, and his liver enzyme levels improved (aspartateaminotransferase: 28 U/I; alanine aminotransferase: 66U/I). He presented with complaints of nausea and mildPage 2 of 6

headache on May 22. The patient had no complaints of
spontaneous and objective abdominal symptoms. Simple
abdominal radiography showed gas and stool retention in
the intestinal tract; however, intestinal obstruction wasnegative (Fig. 1). A brain computed tomography (CT)scan showed no evidence of cerebral hemorrhage orother new lesions.
The patient had a sudden decrease in level of consciousness and blood pressure (temperature 36.1 °C,
heart rate pulse 79 bpm, blood pressure 54/38 mmHg) on
May 23, with poor physical findings, including abdominal findings and normal head CT, electrocardiogram, andechocardiogram findings. Blood tests showed an inflammatory reaction (white blood cell: 6.3 × ­103/µL, neutrophil: 91.6%, C-reactive protein: 4.97 mg/dL) and elevatedamylase (1926 U/I). Contrast-enhanced abdominal CT
showed diffuse pancreatic enlargement (arrow on axial
plane in Fig. 2) and inflammation extending beyond thesubrenal pole (arrow on coronal plane in Fig. 2). There
was no contrast failure zone, suggesting contrast CT
grade 2 acute pancreatitis.
The patient had undergone cholecystectomy for cholecystitis at the age of 61 (5 years ago) and was not hyperlipidemic. We discontinued VPA and initiated treatment
with a high-volume infusion since we suspected druginduced acute pancreatitis. The inflammatory response
and elevated amylase enzyme levels improved, and theacute pancreatitis resolved after the treatment. We diagnosed VPA as the suspected drug based on three itemsof the World Health Organization–Uppsala Monitoring Centre Causality Rating Scale (e.g., event or laboratory test abnormality, with reasonable time relationshipto drug intake and unlikely to be attributed to disease orFig. 1 Simple abdominal radiography. Simple abdominal
radiography shows gas and stool retention in the intestinal tract;
however, intestinal obstruction is negativeYanaga et al. Journal of Medical Case Reports(2023) 17:221

Page 3 of 6Fig. 2 Contrast-enhanced abdominal computed tomography scan. Contrast-enhanced abdominal computed tomography scan shows diffuse
pancreatic enlargement (arrow on axial plane) and inflammation extending beyond the sub-renal pole and beyond (arrow on coronal plane). Thereis no contrast failure zone, suggesting contrast computed tomography grade 2 acute pancreatitis

Fig. 3 An electroencephalogram. An electroencephalogram shows right frontal rhythmic delta waves (arrow), with findings suggestive of epileptic
seizuresYanaga et al. Journal of Medical Case Reports(2023) 17:221

Page 4 of 6other drugs, response to withdrawal clinically reasonable) [6]. He had somnolence after discontinuation of
VPA on May 31. An electroencephalogram showed rightfrontal rhythmic delta waves with findings suggestive ofepileptic seizures (arrow in Fig. 3). Therefore, we madea definitive diagnosis of epileptic seizures with psychiatric symptoms. We increased the dose of carbamazepinefrom 400 to 800 mg for epileptic seizure control. After
increasing the dose of carbamazepine, his agitation andviolent behavior decreased, and he was discharged fromour hospital on August 18, and admitted to a facility(blood data and disease course summary are shown in
Table 1 and Fig. 4). At the 6-month follow-up, psychiatric symptoms were stable and there was no recurrence ofpancreatitis.

Discussion
Here, we presented a case of VPA-induced severe acutepancreatitis with vascular dementia, epileptic seizures,and psychiatric symptoms. This report is clinically significant because (1) clinicians should be aware of thisrelatively rare adverse effect, and (2) VPA-induced

Table 1 Patient’s blood data change
April 19(hospitalized)

May 19

May 23 (acutepancreatitis)

May 25June 1

August 3(discharge fromhospital)

WBC, cells/μL

3200

3400

6300

7200

5500

3100

RBC, × ­106 cells/μL

3.87

3.65

3.80

3.30

3.04

3.87

PLT, × ­103 cells/μL

16219611092370

183

AST, IU/L

4247

19142225

ALT, IU/L55

10846303353Amylase, IU/L

––

1926

662

127–

BUN, mg/dL

12143211512Creatinine, mL/min

0.89

0.85

1.85

0.82

0.65

0.81

CRP, mg/L

0.30

–

4.97

9.83

10.1

0.16

Blood level of VPA, μg/mL–

87.5––––

Blood level of carbamazepine, μg/mL

–––

7.8

9.7–

ALT alanine aminotransferase, AST aspartate aminotransferase, BUN blood urea nitrogen, CRP C-reactive protein, PLT platelet, RBC red blood cell, VPA valproic acid, WBC
white blood cellFig. 4 Disease course summary. We show patient’s disease course summaryYanaga et al. Journal of Medical Case Reports(2023) 17:221

acute pancreatitis is predominant in younger patientsand is rarely reported in elderly patients, and diagnosis can be difficult as there are fewer complaints in theelderly and patients with dementia.
Acute pancreatitis, an extremely rare side effect ofVPA, was first noted in two case reports in 1979 [7, 8],
and its frequency is approximately 0.003–0.7% [3]. The
pathophysiology of VPA-induced pancreatitis is still
not well known [4]; however, it is thought to be due topancreatic duct contraction, cytotoxic and metaboliceffects, accumulation of toxic metabolites or intermediates, and hypersensitivity reactions [9]. It is speculated
that glutathione peroxidase and selenium are reducedin cases of VPA-induced acute pancreatitis, and that
free radicals injure pancreatic cell membranes due toreduced antioxidant activity [10]. In this case, VPAinduced acute pancreatitis occurred after VPA wasincreased from 400 to 1200 mg/day (which was subsequently reduced to 800 mg/day due to liver damage);
however, there was no relationship between the occurrence of VPA-induced acute pancreatitis and blood
VPA concentration, and it could occur at any time after
the onset of therapy [11, 12].
Presentations of pancreatitis include epigastric or diffuse abdominal pain (80–95%), nausea and vomiting(40–80%), abdominal distension, fever, breathlessness,
impaired consciousness, with pyrexia, low oxygen saturation, tachypnoea, tachycardia, hypotension, abdominalguarding, ileus and/or oliguria [13]. A diagnosis of acutepancreatitis requires two out of three criteria: (1) abdominal pain consistent with pancreatitis, (2) serum amylase or lipase levels three or more times higher than theupper limit of normal, and (3) findings consistent withpancreatitis on cross-sectional abdominal imaging [13].
Diagnosing drug-induced pancreatitis requires ruling out
more common etiologies such as gallstone pancreatitis
and ethanol-induced acute pancreatitis [14]. If the pancreatitis resolves after discontinuation of a drug with thepotential to cause pancreatitis, suspicion of drug-induced
pancreatitis is increased [14]. Diagnosis of VPA-induced
acute pancreatitis can be difficult because there are lesscomplaints in elderly people and patients with dementia. VPA-induced acute pancreatitis is predominant inyounger patients with a mean age of 12.7 years [4] andis rarely reported in elderly patients over 60 years, as inthis case. The current patient presented with symptomsof shock due to a decrease in blood pressure, which led
to early detection and therapeutic intervention. Oxygen, intravenous fluid resuscitation, analgesia and nutrition are fundamentals of initial treatment [13]. The
subsequent prognosis in this case was good; however,the patient did not exhibit early abdominal pain symptoms, which are commonly reported. Clinicians should

Page 5 of 6

consider the risk of acute pancreatitis when VPA is usedin patients who cannot complain of spontaneous symptoms, such as patients with dementia, and should measure blood amylase and other parameters as necessary.

Conclusions
In conclusion, VPA-induced acute pancreatitis may occur
in elderly individuals and patients with dementia. Furthermore, clinicians should be mindful of delayed diagnosis because of the lack of subjective symptoms. Bloodamylase and other parameters should be measured asnecessary.
Acknowledgements
The authors would like to thank the patient and his family for their willingness
to consent to this case report presentation.
Author contributions
All authors made a significant contribution to the work reported, whether thatis in the conception, study design, execution, acquisition of data, analysis, andinterpretation, or in all these areas, took part in drafting, revising, or criticallyreviewing the article; gave final approval of the version to be published; haveagreed on the journal to which the article has been submitted; and agree tobe accountable for all aspects of the work. All authors read and approved thefinal manuscript.
Funding
The authors received no specific funding for this work.
Availability of data and materials
The datasets used and/or analyzed during the current case report are available
from the corresponding author upon reasonable request.

Declarations
Ethics approval and consent to participate
This study was conducted in accordance with ethical guidelines. Since thiswas a case report, the ethics committee of the University of Occupational andEnvironmental Health waived the need for review.
Consent for publication
Written informed consent was obtained from the patient for publication ofthis case report and any accompanying images. A copy of the written consent
is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare no competing interests.
Received: 18 August 2022 Accepted: 1 May 2023

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