CHALLENGING CASE: CHRONIC DISEASE—DEVELOPMENTAL AND BEHAVIORAL IMPLICATIONS

Cyclic *

CASE behavioral entity. An earlier report in the Journal’s Denise is a 10-year-old girl who was admitted to Challenging Case series—a child with severe school the hospital for treatment of dehydration secondary refusal and emotional lability subsequently found to to severe vomiting for 2 days. She was unable to have a brain tumor—illustrates this phenomenon.2 retain any liquids. This was her 62nd admission for These are the cases that challenge the clinical skills of similar symptoms. These began when she was 5 pediatricians, psychologists, and psychiatrists. They years old. There was no family history of relatives are especially challenging to medical doctors trained with similar symptoms, but a paternal grandmother to diagnose disorders manifested by symptoms that had severe episodes for much of her life. express interrelationships between mind and body. Denise’s parents were unable to determine what trig- I asked three physicians trained as pediatricians to gered Denise’s vomiting episodes. At various times, comment on this case. They represent subspecialties they had restricted certain foods, focused on more that bring different points of view to the evaluation regular sleep times for her, and assessed possible process. Richard M. Katz, M.D., is Assistant Profes- stressors in school, but the episodes seemed to occur sor of Pediatrics at The Johns Hopkins University at random times. The family lived on a farm, and School of Medicine. He is a pediatric gastroenterol- their primary product was hogs. Denise was the ogist with an active clinical, teaching, and research second of four children. She was doing well in the program who directs a program for the evaluation fifth grade and was active in 4-H and in Sunday and treatment of children with feeding disorders. school. There were four living grandparents nearby, Michael S. Jellinek, M.D., is Professor of Pediatrics as well as many aunts, uncles, and cousins. There and Psychiatry at Harvard Medical School. His were frequent family get-togethers. At physical ex- scholarly writing effectively bridges the language amination, Denise was irritable, spoke in monosylla- and clinical perspectives of pediatrics and psychia- bles, and preferred to remain curled in a fetal posi- try. Recently, Dr. Jellinek was instrumental in the tion with her eyes closed. Her temperature was development of a practical office-based screening 98.8°F; her pulse was 120 beats per minute; her re- test for behavioral problems seen by pediatricians in spiratory rate was 20; and her blood pressure was primary care practice. Karen Olness, M.D., is Pro- 85/60 mm Hg. Her eyes were slightly sunken. Her fessor of Pediatrics at Case Western Reserve Univer- mouth was dry, and her skin appeared dry. Intrave- sity School of Medicine. She has contributed signifi- nous fluids were begun. After 24 hours, Denise was cantly to our understanding and use of various forms able to retain popsicles and sips of water. After 48 of hypnotherapy and other methods of behavior hours, she was ravenously hungry and was eating modification in pediatric practice. Dr. Olness contrib- solids without difficulty. Her personality had uted this challenging case. changed dramatically. She was talkative, she laughed frequently, and she was discharged to Martin T. Stein, MD Professor of Pediatrics home. Division of Primary Care Pediatrics and Adolescent Medicine Index terms: child, cyclic vomiting syndrome. School of Medicine University of California, San Diego Dr. Martin T. Stein San Diego, California Children and adolescents with recurrent episodes REFERENCES of vomiting without an apparent etiology are not seen frequently by general pediatricians. Hospital- 1. Abu-Arafeh I, Russell G: Cyclic vomiting syndrome in children: A population-based study. J Pediatr Gastroenterol Nutr 1995:21:454–456 based behavioral pediatricians might have more ex- 2. Stein MT, Duffner P, Werry J, Trauner D: School refusal. J Dev Behav perience with this entity. A recent epidemiologic Pediatr 17:187–190, 1996 study in Scotland suggests a higher than expected prevalence of chronic cyclic vomiting syndrome Dr. Richard M. Katz 1 (CVS)–1.9%. I selected this case because it represents The first description of fitful or cyclic vomiting is a situation that straddles the boundary between now more than 100 years old, but our understanding clearly defined organic disease and a psychosocial- and interpretation of the signs and symptoms of this debilitating, complex, and confusing disease entity

* Originally published in J Dev Behav Pediatr. 1997;18(4) have not greatly advanced. CVS was first described PEDIATRICS (ISSN 0031 4005). Copyright © 2001 by the American Acad- by in England in 1882, and his original emy of Pediatrics and Lippincott Williams & Wilkins. description is just as apt today as it was then: “These

940 PEDIATRICS Vol.Downloaded 107 No. 4from April www.aappublications.org/news 2001 by guest on September 27, 2021 cases seem to be all of the same kind, there being fits the function of the brain and spinal cord. Intracranial of vomiting which recur after intervals of uncertain mass lesions causing increased intracranial pressure or length. The intervals themselves are free from signs direct invasion of the emetic control centers of the brain of disease. The vomit continues for a few hours or are often insidious, and it is not unusual for gastroen- days. When it has been severe, the patients are left terologists to make the diagnosis on the basis of history, much exhausted.”1 examination, and imaging studies. Frequently, seizure CVS is defined by current convention as having disorders are the first suspects when recurrent vomit- “essential and supportive” criteria.2 Essential criteria ing is the primary complaint. It is also well established include recurrent, severe, discrete episodes of vom- that migraine is one of the disorders presenting as CVS. iting, with varying intervals of normal health be- The absence of a defined etiology for CVS natu- tween episodes. The duration of vomiting episodes rally hinders definitive therapy for individuals, and ranges from hours to days, and no apparent cause of no clinical trials of pharmacologic agents for relief of vomiting can be found. Supportive criteria require a and vomiting in CVS have yet been pub- stereotypical pattern of vomiting, with each episode lished. The overall goals of treatment must be to similar within individuals as to time of onset, inten- ameliorate or interrupt symptoms when they occur, sity, duration, frequency, and associated signs and to abort episodes before they occur, and to prevent symptoms. These episodes are self-limited and are future episodes. Therapeutic approaches to patients associated with symptoms of nausea, , mo- afflicted with the intense nausea and vomiting of tion sickness, abdominal pain, and . CVS should be aggressive and intensive to provide Also associated with CVS are fever, , , relief as rapidly as possible. The initial treatment dehydration, excess salivation, and social with- must ensure that the patient is stable from a cardio- drawal. respiratory perspective. Hydration must be main- CVS, which seems to be the cause of Denise’s tained throughout the episode, and, often, intrave- recurrent hospitalizations, is clearly a disease process nous therapy should be instituted early in the course that can be established only after exclusion of iden- of the event. Oral feedings should be discontinued to tifiable causes of vomiting. Vomiting is a nonspecific minimize vomiting, but case reports indicate that sign that can result from a disorder of any major some patients prefer to consume large volumes of organ system. Assessment of any individual with liquids during an event (the precise mechanism is recurrent vomiting requires specific diagnostic test- unknown, but presumably vomiting might tempo- ing to ensure that underlying, identifiable causes of rarily decrease nausea).3 Metabolic disturbances cyclic patterns of vomiting can be diagnosed. Many such as acidosis, hypoglycemia, or electrolyte abnor- conditions that are difficult to distinguish from CVS malities should be corrected rapidly; they might re- can be life threatening if diagnosis is delayed or quire infusions of 10% dextrose solutions at 1.25 ϫ to missed. Therefore, the differential diagnosis of vom- 2.00 ϫ the maintenance level, especially if a meta- iting must be carefully evaluated in each patient bolic abnormality is suspected. presenting with recurrent, prolonged, or chronic vomiting to rule out identifiable causes before a di- Pharmacologic therapy should include agnosis of CVS can be entertained. agents. Commonly used agents have included chlor- Gastrointestinal obstruction is the most immedi- promazine, butyrophenones (droperidol), and benz- ately dangerous condition associated with emesis amides such as metoclopramide and trimethobenz- and should always be evaluated as a possible cause amide. Serotonin (5HT3)-receptor antagonists such of recurring vomiting. Vomiting, either bilious in as have gained considerable favor as nature or not, is associated with malrotations, inter- for CVS. Often, these agents are used in nal , webs, atresias, and intussusception. Su- combination with anxiolytics such as . A perior mesenteric artery syndrome, peptic ulcer dis- recent article reported the use of parenteral ketorolac ease, , , and upper gastrointestinal as an effective agent in limiting severity and aborting tract motility disorders can present with recurring eme- an event of CVS. This suggests a new category of sis. Parasitic disease, such as those caused by Giardia, possible etiologies of CVS, i.e., disorders of prosta- must also be considered in the differential diagnosis of glandin release.4 Therapeutic goals must also include chronic vomiting. Inflammatory bowel disease, pancre- prophylaxis for future events. Additional classes of atic disease, and celiac disease might also have frequent pharmacologic agents have been tried for both the vomiting as a sign of presentation. Inborn errors of acute phase of illness and to prevent recurrences. metabolism present with vomiting as a primary mani- Agents such as , propranolol, atenolol, festation of enzymatic defect. Emesis, which might be and anticonvulsants including phenytoins and bar- recurrent, is often the first clue of urea cycle defects, biturates have been used for years to treat presumed such as ornithine transcarbamylase deficiency; of or- CVS and/or psychiatric causes of CVS. Most re- ganic acidemias, including methylmalonic acidemia; of cently, trials (uncontrolled) of a motilin agonist fatty acid oxidation defects, including medium-chain (erythromycin5) attempted to abort CVS attacks; acyl-CoA dehydrogenase deficiencies; of disorders of erythromycin showed some promise in preventing gluconeogenesis (pyruvate carboxylase deficiency), as recurrence in some patients. Finally, some families well as such entities as hereditary fructose intolerance with CVS patients use homeopathic medications and and porphyria. Central nervous system involvement in megavitamins, but no scientific data are available to the differential diagnosis of CVS includes all aspects of support claims of effectiveness.

Downloaded from www.aappublications.org/news by guest on September 27, 2021 SUPPLEMENT 941 Richard M. Katz, MD tress.4 Although Denise’s family did not observe any Assistant Professor of Pediatrics pattern to her illness, one could suggest that both Division of Pediatric and Nutrition Denise and her parents keep diaries of the anteced- School of Medicine ents, symptoms, and consequences of her episodes. The Johns Hopkins University These might reveal subtle precipitants, maladaptive Medical Director responses, and minor symptoms that had gone un- Feeding Disorders Program Kennedy Krieger Institute noticed. A psychogenic etiology, even if quite plau- Baltimore, Maryland sible, should not preclude ongoing attention to or- ganic etiologies that might be synergistic and not REFERENCES evident early in the course, e.g., inflammatory bowel disease.5 If the assessment of triggers indicates a 1. Gee S: On fitful or recurrent vomiting. St. Batholomew’s Hosp Rep 18:1–6, 1882 tendency toward anxiety, one could attempt relax- 2. Consensus criteria from the International Symposium on Cyclical Vom- ation training, perhaps augmented with biofeedback, iting Syndrome, St Bartholomew’s Hospital, London, England, 1994. on the premise that raising the child’s threshold for J Pediatr Gastroenterol Nutr 21:Svi, 1995 physiologic arousal could reduce the frequency or 3. Fleisher DR: Management of cyclic vomiting syndrome. J Pediatr Gas- severity of episodes. If a specific trigger can be iden- troenterol Nutr 21:S52–S56, 1995 4. Pasricha PJ, Schuster MM, Saudek CD, Wand G, Ravich WJ: Cyclic tified, a desensitization paradigm might be useful, by vomiting: Association with multiple homeostatic abnormalities and analogy with behavioral treatment of specific pho- response to ketorolac. Am J Gastroenterol 91:2228–2232, 1996 bias. 5. Vanderhoof JA, Young R, Kaufman SS, Ernst L: Treatment of cyclic Although not described in this case history, vomiting in childhood with erythromycin. J Pediatr Gastroenterol Nutr 21:S60–S62, 1995 chronic or severe CVS can bring a host of secondary risks: major restructuring of family life in response to the perceived needs of the ill child, an immature or Dr. Michael S. Jellinek too intense parent-child relationship, and “special Dr. Linden Cassidy status” for the child whom the parents might view as CVS can cause much suffering for children and vulnerable and in need of protection. In Denise’s their families. Although CVS was first described case, if this syndrome continues as she enters pu- more than a century ago, its pathogenesis and treat- berty, the secondary consequences of her illness ment remain elusive.1 Because the diagnosis requires might limit peer relationships, lower self-esteem, and exclusion of other disorders (such as a central ner- complicate her ability to separate and individuate vous system tumor or metabolic, endocrine, or spe- from her parents as an adolescent. If CVS begins to cific gastrointestinal structural or inflammatory le- impair Denise’s development, family and/or indi- sions), the child with CVS typically has endured vidual psychotherapy might be helpful. numerous laboratory and radiographic studies, all with negative findings.2 During episodes, the child Michael S. Jellinek, MD often becomes acutely dehydrated and frighteningly Professor of Psychiatry and Pediatrics ill. Denise and her family, long before the 62nd epi- Harvard Medical School Chief, Child Psychiatry Services sode described above, have no doubt been stressed, Massachusetts General Hospital disappointed, and possibly angry about the pediatri- Boston, Massachucetts cian’s inability to cure her illness.3 The pediatrician not only faces personal frustra- REFERENCES tion but must also help the family and child cope 1. Fleisher DR: The cyclic vomiting syndrome described. J Pediatr Gastro- with their own helplessness and, at times, despair, enterol Nutr 21:S1–S5, 1995 while still maintaining a strong alliance with them. 2. Li BUK: Cyclic vomiting: The pattern and syndrome paradigm. J Pediatr Without this sense of trust, the family is likely to Gastroenterol Nutr 21:S6–S10, 1995 “doctor shop” and thus expose Denise to unneces- 3. Magagna J: Psychophysiologic treatment of cyclic vomiting. J Pediatr Gastroenterol Nutr 21:S31–S36, 1995 sary procedures, such as repeated endoscopies or 4. Fleisher DR: The cyclic vomiting syndrome: A report of 71 cases and even laparotomy. Families are often greatly relieved literature review. J Pediatr Gastroenterol Nutr 17:361–369, 1993 when the pediatrician identifies this well-accepted 5. Gonzalez-Heydrich J, Kerner JA Jr, Steiner H: Testing the psychogenic disorder and reassures them that their child has no vomiting diagnosis. Am J Dis Child 145:913–916, 1991 life-threatening or progressive disease. The pediatri- cian might draw an analogy to other episodic condi- Dr. Karen Olness tions, such as headache, for which no clear organic CVS consists of discrete episodes of nausea and cause can be identified but which are not alarming. vomiting lasting many hours or several days, sepa- The pediatrician can then help the family to design a rated by symptom-free intervals of similar or varying collaborative strategy for responding to future epi- lengths.1 A biologic cause is often not apparent. Be- sodes that will minimize delay and expedite anti- cause it occurs rarely in the practice of any individ- emetic and rehydration treatment.4 ual physician or psychologist, most practitioners are Given the morbidity and cost associated with CVS, unfamiliar with it. Families often experience frustra- a psychiatric assessment for emotional triggers for tion and anxiety when long, complex diagnostic ef- CVS, such as depression, anxiety, or trauma, and the forts do not explain the symptoms. The life of the child’s interepisode functioning might well be war- affected child and family is disrupted by the epi- ranted. In many cases, there is an identifiable trigger sodes and also by the uncertainty related to making for the episodes, often emotional excitement or dis- plans that might be canceled because of CVS.

942 SUPPLEMENT Downloaded from www.aappublications.org/news by guest on September 27, 2021 Children and adolescents with CVS describe the pressed with ranitidine. Some patients have premon- nausea as unbearable. Because repeated vomiting itory symptoms of CVS, such as slight abdominal might lead to peptic esophagitis, they often drink pain or a feeling of severe . They should at- large amounts of water during episodes to dilute the tempt to abort episodes with pharmacologic or psy- acid and bile and make vomiting episodes less pain- chologic methods. Several clinical reports on the use ful. Often, children with CVS describe abdominal of prophylactic drugs indicate mixed or unpredict- pain, diarrhea, , chills, and fever. They able results. Both children and families need psycho- often have low-grade fever, hypertension, and flush- logic support. At the present time, the CVSA provides ing during episodes. Most children demonstrate a great deal of such support, as well as education for marked personality and behavioral changes during both families and the medical profession. episodes, with regressive behavior, many demands, and moaning with discomfort. Only sleep seems to Karen Olness, MD Professor of Pediatrics bring relief, but these children will awaken from Division of General Academic Pediatrics 2 sleep with more vomiting. School of Medicine The differential diagnosis of CVS is extensive, al- Case Western University though many diagnoses can be ruled out by history Cleveland, Ohio or laboratory findings. Life-threatening conditions, such as , intermittent as- REFERENCES sociated with malrotation, internal hernias, and in- 1. Li BUK: Cyclic vomiting syndrome. J Pediatr Gastroenterol Nutr 21: testinal lymphangiomas, can present with cyclic S1–S62, 1995 vomiting episodes. might also begin 2. Fleisher DR: The cyclic vomiting syndrome: A report of 71 cases and literature review. J Pediatr Gastroenterol Nutr 17:361–369, 1993 with CVS-like symptoms, although they usually do 3. Abell TL, Kim CH, Malagelada JR: Idiopathic cyclic nausea and not relent. Chronic intestinal pseudo-obstruction can vomiting: A disorder of gastrointestinal motility? Mayo Clin Proc 63: cause intermittent vomiting,3 as can obstructive uro- 1169–1175, 1988 logic disease. It is important to check the urinary tract in the evaluation of CVS. Increased intracranial Dr. Martin T. Stein pressure and/or focal central nervous system lesions and family dysautonomia also frequently present CVS exemplifies the need for precise clinical acu- men in both diagnosis and treatment. Specific disor- with intermittent vomiting. ders of gastrointestinal, neurological, urological and Several inborn errors of metabolism are mani- metabolic function might not be apparent during an fested by vomiting. These include organic acidurias, initial evaluation. The diagnostic challenge is height- fatty acid oxidation defects, disorders of carbohy- ened by the frequent development of psychological drate metabolism, and more frequently, disorders of symptoms and family disruption often seen in chil- amino acid metabolism. The patient described in this dren with recurrent episodes of painful emesis. The case had a urea cycle defect, ornithine transcarbamy- case of Denise reminds us that the diagnostic evalu- lase deficiency. This was relatively easily controlled ation is not complete until established medical by a low-protein diet; vomiting recurred only if she causes of CVS have been investigated. That Denise breached the diet. I have had referred to me 17 seemed to be well adjusted in school and at home children with years of CVS history who turned out to despite her episodes of recurrent vomiting might have a urea cycle defect. Several had experienced have been the clue to her underlying metabolic de- prolonged hospitalizations on child psychiatric units. fect. An affective disorder or significant family con- I have also seen children and adolescents with CVS flict did not appear to be associated with her symp- for whom there was no biologic explanation after years toms. of diagnosis. Among such children, there is often a Dr. Olness noted that our inability to find a cause strong family history of migraine, seizures, or allergies. for CVS reflects an inadequacy in medical diagnosis I think that a failure to identify a precise cause for CVS rather than a psychological diagnosis. (Could this symptoms reflects our inadequacy in diagnostics rather point of view be influenced, in part, by our current than a psychologic diagnosis. Most families with CVS knowledge that is often caused or any other chronic illness will have secondary psy- by an infectious agent, Helicobacter pylori?) The dis- chologic issues. Often, they perceive themselves as mis- covery of anatomic neurological diseases, urologic judged and powerless. Individual or group psycho- disorders, and many gastrointestinal disorders therapy might be helpful. Fortunately for families with should not be difficult. However, inborn errors in CVS, there is now an active national organization that metabolism1 and some disorders of gastrointestinal is on the Internet (http://ezinfo.ucs.indiana.edu/ motility might be more difficult to investigate and ϳjdbickel/cvs.html). The mailing address is Cyclic diagnose. The case of Denise makes it clear that the Vomiting Syndrome Association (CVSA), 13180 Caro- skills of selected specialists can be helpful in arriving line Court, Elm Grove, WI 53122. The e-mail address is at a treatable cause. [email protected]. A fascinating hypothesis links CVS with abdomi- Management of CVS episodes includes early initi- nal migraine.2 A family history for migraine head- ation of antiemetic agents, usually beginning with aches is frequent in children with CVS. The cyclic intravenous ondansetron, rehydration if necessary, pattern of illness with a state of well-being between and facilitation of sleep. If esophageal pain and episodes is similar in the two entities. Quantitative bleeding occur, gastric acid secretion should be sup- electroencephalographic changes in CVS are consis-

Downloaded from www.aappublications.org/news by guest on September 27, 2021 SUPPLEMENT 943 tent with patterns recorded in patients with mi- secondary sources of behavioral symptoms and fam- graine.3 Intravenous ondansetron, a 5-hydroxytryp- ily conflicts, diagnostic precision is strengthened. tamine-3 antagonist, is used for children with CVS, as noted by Dr. Katz. A preliminary observation REFERENCES suggests that sumatriptan, a 5-hydroxytryptamine-1 1. Korson M: Metabolic etiologies of cyclic or recurrent vomiting. J Pediatr agonist, might be effective when used at the first sign Gastroenterol Nutr 21:S15–S19, 1995 4 2. Symon DNK, Russell G: The relationship between cyclic vomiting syn- of a CVS episode. drome and abdominal migraine. J Pediatr Gastroenterol Nutr 21: Recurrent vomiting is a dramatic example of many S42–S43, 1995 clinical situations in children and adolescents in 3. Jernigan SA, Ware LM: Reversible quantitative EEG changes in cases of which the evaluation process must incorporate med- cyclic vomiting: Evidence for migraine equivalent. Dev Med Child Neurol 33:80–85, 1991 ical and psychosocial data collection simultaneously. 4. Huang S, Lavine J: Efficacy of sumatriptan in aborting attacks of cyclic When the clinician is sensitive to the primary and vomiting. Gastroenterology 112:A751, 1997

944 SUPPLEMENT Downloaded from www.aappublications.org/news by guest on September 27, 2021 Cyclic Vomiting Martin T. Stein, Richard M. Katz, Michael S. Jellinek, Linden Cassidy and Karen Olness Pediatrics 2001;107;940

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/107/Supplement_1/940.c itation Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Gastroenterology http://www.aappublications.org/cgi/collection/gastroenterology_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 27, 2021 Cyclic Vomiting Martin T. Stein, Richard M. Katz, Michael S. Jellinek, Linden Cassidy and Karen Olness Pediatrics 2001;107;940

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/107/Supplement_1/940.citation

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2001 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

Downloaded from www.aappublications.org/news by guest on September 27, 2021