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Abdominal Migraine and Treatment With Intravenous Valproic Acid

Received May 19, 2005; revised October 5, 2005; accepted October 17, 2005. From the Dept. of Psychiatry and Behavioral Sciences and the Dept. of Pediatrics, Stanford Univ. School of Medicine; Lucile Packard Children’s Hospital, Palo Alto, CA. Address correspondence and reprint requests to Dr. Shaw, Dept. of Psychiatry and Behavioral Sciences, Stanford Univ. School of Medicine, 401 Quarry Rd., Palo Alto, CA 94305-5719. e-mail: rjshaw{at}stanford.edu

INTRODUCTION

TOP INTRODUCTION Case Reports Discussion REFERENCES

 
Abdominal migraine is a syndrome characterized by episodes of recurrent severe abdominal pain, nausea, and/or vomiting, that interferes with normal daily activities but with periods of wellness between episodes.¹ Although there is widespread acceptance of the syndrome among practitioners, there is limited information regarding its treatment.² Valproic acid (VPA), which is used for migraine prophylaxis has, on occasion, been used with apparent success in cases of abdominal migraine.^2,3 This case report describes two patients with suspected acute abdominal migraine whose symptoms resolved with administration of intravenous (IV) valproic acid.

Case Reports

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Case 1
"A" is a 12-year-old Caucasian girl with a 6-year history of episodic abdominal pain and intermittent headaches who was self-inducing vomiting for pain relief. Her cyclic vomiting episodes were associated with confusion, aggressive behavior including biting and scratching, and self-mutilation. Her behavioral issues were present only in the context of pain, emesis, and dehydration. Extensive medical work-up, including tests to screen for porphyria and serum amino acids, failed to identify a cause for A’s emesis and abdominal pain. Intestinal biopsies did reveal mild inflammation in the antrum of the stomach and the terminal ileum, which was treated with famotidine. Relevant psychosocial background included a history of sexual molestation by an elderly neighbor, the separation of her mother and stepfather, a recent change of school, and the medical illness of her grandmother.

A was unsuccessfully tried on multiple medications, including Reglan®, Zofran®, and Phenergan® for her nausea and emesis during a series of 10 inpatient admissions. Imitrex® and IV dihydroergotamine resulted in mild but temporary relief of her abdominal pain, supporting the hypothesis that her pain episodes were due to abdominal migraines. During periods of intense agitation, A had trials of risperidone, haloperidol, chlorpromazine, lorazepam, and diphenhydramine, with greater benefits from treatment with the antipsychotic agents.

During A’s three admissions for abdominal pain and emesis, she received IV valproic acid (500 mg tid), which was rapidly titrated to achieve a serum valproic acid level between 100 µg/dl and 120 µg/dl. On each occasion, IV valproic acid led to a rapid resolution of her symptoms of abdominal pain and vomiting, with a concurrent reduction in her symptoms of agitation. In the absence of any clear medical findings, A was given a presumptive diagnosis of abdominal migraine, and recommendations were made to continue her valproic acid orally on an outpatient basis. "A" experienced side effects of weight gain that led to the addition of topiramate in an effort to regulate her appetite. This was only partially successful, and her mother elected to discontinue A’s valproic acid. However, a successful treatment plan was developed that included the use of Imitrex® nasal spray for mild episodes of abdominal pain, and inpatient admission for IV valproic acid for more severe episodes of pain that were accompanied by agitation and behavioral dyscontrol.

Case 2
"B" is a 17-year-old African American young woman who presented with a chief complaint of mid-epigastric abdominal pain and vomiting. On admission, B was found curled up in a fetal position and would only nod or shake her head in response to questions. B refused all oral intake, with the exception of pain medication, and received intravenous (IV) fluids for dehydration. Records indicated that she had had five similar episodes in the past, beginning at age 10, with subsequent attacks at ages 15, 16, and 17. The patient had had a recent 5-day stay for similar symptoms of emesis and abdominal pain but continued to experience vomiting on hospital discharge. Four days of retching, non-bloody, non-bilious emesis followed, until her most recent hospital admission. An extensive medical work-up was conducted, with negative findings, with the exception of an endoscopy showing esophageal erosions at the lower esophageal sphincter, an EEG revealing diffuse slowing and a moderate degree of encephalopathy, and an upper gastrointestinal series demonstrating delayed gastric motility.

One week into her admission, B began to demonstrate signs of delirium with agitation, which included striking out at nurses, biting, and self-induced vomiting, as well as auditory hallucinations. Efforts were made to manage her aggression with trials of olanzapine, haloperidol, and lorazepam. Because of the episodic nature of B’s pain, the suspicion of abdominal migraine was raised. B was started on treatment with IV valproic acid, and, as therapeutic serum levels were achieved, her pain symptoms began to improve. She became more vocally responsive, and her aggression and auditory hallucinations also resolved. B’s appetite gradually improved, and she was able to eat regularly without associated nausea or vomiting. B was remarkably engaged in subsequent interviews, in extreme contrast to her previous behavior. She reported multiple stressors that included the onset of domestic violence at age 10 years, immediately preceding her first episode of pain, two unplanned pregnancies and abortions at ages 15 and 17 years, the shooting death of her boyfriend at age 16 years, and concern regarding her grandmother’s health during her most recent hospitalization. Upon discharge, B reported complete resolution of her symptoms.

Discussion

TOP INTRODUCTION Case Reports Discussion REFERENCES

 
Abdominal migraine is a subtype of recurrent abdominal pain that is characterized by discrete episodes of pain with clear-cut symptom-free intervals.^2,4 The condition is more commonly seen in children, with a peak prevalence at age 10 years.² The term "abdominal migraine" was first used in 1921 to describe attacks of abdominal pain in the absence of headache.² Criteria proposed by Dignan et al.⁵ include dull, poorly localized abdominal pain lasting at least 1 hour, severe enough to interfere with normal daily activities and with associated symptoms of nausea, vomiting, anorexia, and/or pallor (Table 1). Such descriptions highlight features exhibited by both our patients. Furthermore, in both patients, the onset and resolution of symptoms were sudden, a feature commonly found in patients with this syndrome.

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TABLE 1. Criteria for Diagnosis of Abdominal Migraine2,5

In contrast to acute and chronic abdominal pain, an explanation for recurrent abdominal pain is seldom found.² It is estimated that only 5%–10% of children with recurrent abdominal pain have an underlying organic process that contributes to their pain.⁴ Over the years, there has been increasing support for the view that otherwise unexplained recurrent abdominal pain is psychological in origin. It is known that both the gut and the nervous system are derived from the same embryologic tissues and that the enteric nervous system and CNS have direct effects on each other.⁴ One proposed mechanism is that stress first contributes to increased arousal in the CNS, releasing neuropeptides and neurotransmitters, which, in turn, leads to dysregulation of the gastrointestinal system.⁴ Although many individuals may experience some type of abdominal distress under stressful situations, those with recurrent abdominal pain may react to the stress differently or may have maladaptive coping mechanisms.⁶ In both our cases, family stressors were significant, and B, in particular, noted that each of her episodes was preceded by a significantly stressful life event.

Perhaps the most intriguing comparison between our two patients is the accompanying aggressive behavior and mental status changes. One explanation may lie in the link between abdominal migraine and migraine headaches, which are commonly associated with impaired consciousness.⁷ Gascon and Barlow (cited in Pietrini et al.) first noted the association of an acute confusional state during migraine attacks, later termed acute confusional migraine, which is commonly associated with agitation.⁷ Acute confusional migraine has been characterized by transient episodes of amnesia.⁸ The pathogenic process underlying acute confusional migraine is still under discussion, but one study attributes such findings to generalized reversible brain dysfunction, especially involving the temporal lobes and deep midline structures.⁷ This correlates with electrophysiological hypotheses for abdominal migraine, which describe electrical discharge from the hypothalamus. EEG changes have also been noted in abdominal migraine and were present in one of our patients. This may provide one hypothesis for the findings of amnesia noted in both our patients, since lesions of the amygdala and hippocampus have been associated with memory deficits.⁸

There is little information on drug management for abdominal migraine, but anti-migraine drugs have been found to be effective prophylactic agents. Migraine headache sufferers have abnormal concentrations of vasoactive amines, such as noradrenaline and serotonin, and anti-migraine drugs act by interfering with the biochemical pathways so as to prevent these attacks. Although there have been no studies looking into similar biochemical imbalances in children with abdominal migraine, drugs that are effective in classic migraine headaches have been proven to work well in the related condition of abdominal migraine.

To our knowledge, this is the first published report demonstrating the successful use of IV valproic acid for the treatment of abdominal migraine. In both these cases, symptoms of abdominal pain and nausea, as well as associated mental status changes responded quickly to IV valproic acid once therapeutic levels were reached. Valproic acid’s mechanism of action in treating migraine headaches is not completely understood, but it may be related to its effect on brain gamma aminobutyric acid (GABA), the main inhibitory neurotransmitter.⁹ Valproic acid is known to increase brain GABA levels through a variety of mechanisms, including blocking GABA reuptake, inhibiting the enzymes that break down GABA, and increasing GABA release from nerve terminals.¹⁰ In migraine, there is increased activity of excitatory amino acids used to synthesize GABA. Hence, the increased GABA effect from treatment with valproic acid may inhibit these excitatory amino acids and, consequently, inhibit migraine. GABA concentrations have been shown to be decreased in patients with behavioral dyscontrol, which may explain valproic acid’s role in treating behavioral disturbances in migraine patients by enhancing GABA levels.¹⁰

These cases demonstrate the potential for IV valproic acid to resolve both pain and mental status changes associated with abdominal migraine. Further exploration into valproic acid’s mechanism of action, clinical trials confirming its therapeutic advantage, and determination of the duration required for treatment will be necessary to help develop specific treatment protocols.

REFERENCES

TOP INTRODUCTION Case Reports Discussion REFERENCES

 

1. Worawattanakul M, Rhoads JM, Lichtman SN, et al: Abdominal migraine: prophylactic treatment and follow-up. J Pediatr Gastroeneterol Nutr 1999; 28:37–40[CrossRef][Medline]
2. Russell G, Abu-Arefeh I, Symon DN: Abdominal migraine: evidence for existence and treatment options. Paediatr Drugs 2002; 4:1–8[Medline]
3. Corbo J: The role of anticonvulsants in preventive migraine therapy. Curr Pain Headache Rep 2003; 7:63–66[Medline]
4. Weydert JA, Ball TM, Davis MF: Systematic review of treatments for recurrent abdominal pain. Pediatrics 2003; 111:e1-e11
5. Dignan F, Abu-Arafeh I, Russell G: The prognosis of childhood abdominal migraine. Arch Dis Child 2001; 84:415–418[Abstract/Free Full Text]
6. Compas BE, Thomsen AH: Coping and responses to stress among children with recurrent abdominal pain. Dev Behav Pediatrics 1999; 20:323–324
7. Pietrini V, Terzano MG, D’Andrea G, et al: Acute confusional migraine: clinical and electroencephalographic aspects. Cephalagia 1987; 7:29–37[CrossRef][Medline]
8. Sheth RD, Riggs JE, Bodensteiner JB: Acute confusional migraine: variant of transient global amnesia. Pediatr Neurol 1995; 12:129–131[CrossRef][Medline]
9. Serdaroglu G, Erhan E, Tekgul H, et al: Sodium valproate prophylaxis in childhood migraine. Headache 2002; 42:819–822[CrossRef][Medline]
10. Davis LL, Ryan W, Adinoff B, et al: Comprehensive review of the psychiatric uses of valproate. J Clin Psychopharmacol 2000; 20:1S-17S[CrossRef]

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