Journal of Pediatric Gastroenterology & Nutrition:
Abdominal Migraine in Children With Neurofibromatosis Type 1: A Case Series and Review of Gastrointestinal Involvement in NF1
Heuschkel, Robert*; Kim, Sarah*; Korf, Bruce†; Schneider, Gretchen†; Bousvaros, Athos*
*Division of Gastroenterology, Children's Hospital, †Partners Center for Human Genetics, Boston, Massachusetts, U.S.A.
Accepted March 15, 2001.
Supported by the National Institutes of Health (Training Grant in Pediatric Gastroenterology and Nutrition No. T32-DK07477-16; RH), Bethesda, Maryland, U.S.A.
Address correspondence and reprint requests to Dr. Athos Bousvaros, Division of Gastroenterology, Hunnewell Building, Ground Floor, Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, U.S.A. (e-mail: firstname.lastname@example.org).
Background: Symptomatic involvement of the gastrointestinal tract in children with neurofibromatosis type 1 (NF1) is rare. Most reported complications in adults are caused by the presence of neurofibromas in the stomach, small bowel, or mesentery. In contrast, abdominal pain in children with NF1 may be the result of nonanatomic causes, such as migraine. There are no previous reports of an association between abdominal migraine and NF1.
Methods: Children with abdominal migraine were identified from a group of children with NF1, all of whom had been followed up for a minimum of 3 years. Medical records of cases were reviewed independently by two authors. MEDLINE was searched via PubMed for all reports of children with NF1 and any associated gastrointestinal involvement.
Results: Six children with NF1 and intermittent, episodic, severe abdominal pain are reported. Investigations for obstructive or inflammatory causes of abdominal pain were negative. All patients had previously been diagnosed with migraine headaches by a neurologist. In five of the six patients, propranolol (10–15 mg three times daily) resulted in relief of their abdominal pain within days of starting therapy. Our review identified 24 children in the medical literature with gastrointestinal complications of NF1, mostly secondary to visceral neurofibromas. In almost all of these cases, clinical examination and simple radiologic investigations led to the definitive diagnosis. There were no reports of abdominal migraine complicating NF1.
Conclusions: Abdominal pain secondary to migraine is an unrecognized cause of abdominal pain in children with NF1 and may be more common than anatomic causes of abdominal pain in children with NF1. In children with NF1 and severe recurrent abdominal pain in whom an evaluation for anatomic lesions is negative, a trial of migraine therapy may be indicated.
Gastrointestinal involvement has been reported in children and adults with neurofibromatosis type 1 (NF1). In his first description of the condition, von Recklinghausen (1) reported a patient with malignant transformation of neurofibromas in the stomach and duodenum. Intraabdominal complications of neurofibromatosis are varied and include neuropathic constipation, intestinal ischemia and infarction, intestinal duplications, bowel obstruction, and small bowel adenocarcinoma (2–5). However, most NF1 patients have no intestinal symptoms, and gastrointestinal complications of NF1 in children remain quite rare (6).
Abdominal migraine is thought to occur in 2% to 4% of schoolchildren (7,8). It occurs in less than 10% of children with classical migraine headache (8). Because abdominal migraine often presents without headache, it may be difficult to diagnose (9). With the availability of effective prophylaxis, an early diagnosis of abdominal migraine can improve substantially a child's quality of life (8,10).
In this article, we describe six children with NF1, migraine headache, and features of abdominal migraine. Gastrointestinal evaluation demonstrated no other identifiable pathologic characteristics, and in five of the six patients, the administration of propranolol either improved or abolished the abdominal pain. We propose that abdominal migraine is an underrecognized cause of abdominal pain in children with NF1. In the absence of other identifiable pathologic features, a therapeutic trial of treatment for abdominal migraine should be considered.
We describe six children with NF1, chronic abdominal pain, and migraine headaches. These children sought treatment at the Neurofibromatosis Clinic at Children's Hospital, where a prospective database of more than 500 children with neurofibromatosis is maintained. Our cases were selected from the subgroup of 126 children who had been followed up for a minimum of 3 years since referral to the program; 93 of these children were between 3 and 11 years of age. Medical records were reviewed independently by two investigators (SK, AB). A summary of their stigmata of neurofibromatosis, gastrointestinal findings, and diagnostic evaluations is given in Table 1. Case reports summarizing the clinical course of the six patients are given below.
For review of the current literature, a combination of hand-searching and computer-based techniques was used. Original articles were identified from the MEDLINE database (1966–September 1999) via PubMed for all reports of children with NF1 associated with gastrointestinal involvement. A combination of the MeSH terms neurofibromatosis, child, gastrointestinal system and disease, gastrointestinal, migraine, and abdominal pain was used in the search. References of all articles published after 1966 were reviewed, and relevant earlier references were obtained in full.
A 7-year-old female diagnosed with NF1 at the age of 4 years had headache and abdominal pains. The headache was vascular in nature, primarily frontal, lasting approximately 2 hours at a time. The abdominal pain was poorly localized, occurred daily, and lasted as long as 2 hours, but without any temporal association. Physical examination, laboratory studies, and upper gastrointestinal series were nonrevealing (Table 1). The patient was begun on propranolol (10 mg, three times daily) with prompt relief of both headache and abdominal symptoms. Discontinuation of propranolol several months later resulted in recurrence of the abdominal symptoms within 1 week, and propranolol was restarted, once again with a rapid clinical response. The pain occurred only intermittently over the next few years and finally resolved by age 18 years.
A 6-year-old female, diagnosed with NF1 at the age of 3 years, had headache and abdominal pain. A frontal, throbbing headache occurred once or twice weekly. The headaches occurred together with abdominal pains. Nausea sometimes accompanied these headaches. Physical examination, gastroenterologic consultation, laboratory studies, a head magnetic resonance imaging scan and a computed tomography scan of the abdomen failed to identify a cause of the pain (Table 1). At age 7 years, during a particularly severe episode of acute abdominal pain, the patient underwent an emergency appendectomy. The appendix was reported as histologically normal. Propranolol (10 mg, three times daily) was prescribed for abdominal pain at age 15 years, with rapid clinical improvement. The symptoms completely resolved by age 16 years, and medication was discontinued 1 year later.
A 5-year-old female, diagnosed with NF1 at the age of 2 years, had headache and abdominal pain. The headaches occurred almost daily, lasted up to 2 hours, and were characterized by a frontally located, throbbing pain. At times, the headaches were accompanied by vomiting. The abdominal pain also lasted approximately 2 hours, occurred in the lower abdomen, and periodically was accompanied by vomiting and sometimes nausea. There was no associated diarrhea, constipation, or nausea. Physical examination, laboratory tests, and cranial and spinal magnetic resonance imaging scans did not identify a cause of the pain. A spinal magnetic resonance imaging scan showed no lumbosacral neurofibromas. The headaches and abdominal pain persisted despite a trial of Esgic (butalbital 50 mg, acetaminophen 325 mg, and caffeine 60 mg; Forest Pharmaceuticals, St. Louis, MO). On starting propranolol (10 mg, three times daily) at age 7 years, the patient's headaches and abdominal pain resolved within a few days. The propranolol was discontinued at age 10 years without recurrence of symptoms.
A 9-year-old female, diagnosed with NF1 at the age of 7 years, had headache and abdominal pain. The headache was a constant pain located in her frontal region. The abdominal pains did not correlate temporally with her headaches. The pains were either diffuse or localized to the lower left quadrant of the abdomen and often were accompanied by vomiting. At the age of 9 years, the patient was again evaluated for severe, acute abdominal pain. Physical examination was unremarkable except for the stigmata of neurofibromatosis. Abdominal examination, abdominal plain film, laboratory testing, and barium swallow/upper gastrointestinal series were normal. Propranolol (10 mg, three times daily) and psyllium (Metamucil; Proctor & Gamble, Cincinnati, OH) were prescribed with resolution of symptoms within a few days. A relapse of symptoms while taking the medication required an increase in propranolol dose (15 mg, three times daily), which again achieved a decrease in both the frequency and intensity of the headaches and abdominal pain within 1 week.
A 9-year-old female diagnosed with NF1 at the age of 6 months had headache and abdominal pain. The headaches were frontal and occasionally so severe that the patient missed school and experienced vomiting and nosebleeds. They were relieved partially by acetaminophen. The abdominal pain occurred one to three times weekly and was located in the periumbilical region. The pain would sometimes be accompanied by nausea, vomiting, and fever. Physical examination, laboratory evaluation, brain magnetic resonance imaging scan and upper gastrointestinal series with small bowel follow-through were all unremarkable. Cyproheptadine (2 mg, three times daily) was prescribed at the onset of these symptoms and the patient experienced only a temporary improvement. Subsequently, sertraline was prescribed with partial improvement in the headache and abdominal pain. Propranolol (10 mg, three times daily) was prescribed at the age of 9 years. The symptoms resolved within a few weeks and all medications were finally discontinued at age 14 years.
A male diagnosed with NF1 at age 7 years had headache and abdominal pain within 1 year of diagnosis. The headaches were bitemporal and accompanied by vomiting and occasionally abdominal pain. A head computed tomography and magnetic resonance imaging scan were both reported as normal. The abdominal pain was initially in the epigastric region, but then migrated to the left side of the abdomen. This pain occurred once or twice weekly, was occasionally accompanied by fever and vomiting, and sometimes required hospitalization. Physical examination was unremarkable except for the stigmata of neurofibromatosis. Laboratory studies, lactose hydrogen breath test, and upper gastrointestinal series with small bowel follow-through were all normal. A trial of antacid therapy at bedtime brought about no improvement. A trial of propranolol was proposed after 3 months of painful episodes, some of which had been severe enough to warrant hospitalization. However, symptoms then resolved spontaneously before the initiation of propranolol therapy. The patient had no further episodes of abdominal pain during several years of follow-up.
Neurofibromatosis 1 is an autosomal dominant genetic disorder of variable phenotypic expression with an incidence of about 1:3000 (11). The defect has been mapped to chromosome 17q11.2 (12). Seven clinical features are used to establish the diagnosis of NF1 (13). These include: café-au-lait macules, neurofibromas, axillary or inguinal freckling, optic glioma, Lisch nodules, osseous lesions (sphenoid dysplasia, pseudoarthrosis), and a first-degree relative with NF1. Other nongastrointestinal complications of NF1 include developmental delay, precocious puberty, scoliosis, renovascular hypertension, pheochromocytomas, carcinoid tumors, somatostatinomas, leukemias, and central nervous system neoplasms (13,14).
Severe gastrointestinal complications of NF1 are rare in childhood, because neurofibromas generally develop after puberty. Hochberg et al. (5) reviewed 39 cases of NF1 with gastrointestinal involvement and identified only two children. After a thorough search of the literature, we identified a total of 24 children with NF1 and reported gastrointestinal complications (Table 2). Presenting features of gastrointestinal involvement in NF1 include: dyspepsia, abdominal pain, abdominal distension, constipation, bowel obstruction, and gastrointestinal bleeding (2–5,15–24). Most reported complications are caused by the presence of mass lesions in the stomach, small bowel, or mesentery. Histologically, these lesions may be divided into three different forms: neuronal hyperplasia and mucosal ganglioneuromatosis; stromal tumors; and periampullary carcinoid tumors of the duodenum (25). In some cases, identifying these specific pathologic lesions may allow the clinician to make a retrospective diagnosis of NF1.
Gastrointestinal complications of NF1 caused by mass lesions usually can be diagnosed easily with standard clinical and radiologic investigations. Of the 24 reported cases of gastrointestinal lesions in children with NF1, all were diagnosed by clinical examination in conjunction with contrast radiography, abdominal ultrasound, or computed tomography and magnetic resonance imaging. Fifteen of the 24 children had a palpable abdominal mass or abdominal distension at presentation. Although we cannot exclude completely the presence of abdominal neurofibromas in the children presented in our series, the incidence of clinically significant abdominal neurofibromas in children is likely to be very low. In a series of 62 asymptomatic adults with NF1 undergoing routine ultrasound screening, abdominal neurofibromas were identified in only four patients (26). Pheochromocytomas causing hypertension are known to complicate NF1 in adults and not children (27). None of the children in this series were known to be hypertensive.
In the six children described in our report, the results of physical examination, laboratory tests, and imaging studies were normal; in no case were specific mass lesions identified. Therefore, a subset of children with NF1 may have paroxysmal, severe, and sometimes incapacitating abdominal pain at presentation, with an unrevealing diagnostic evaluation. We propose that these children may have abdominal migraine based on our observations. Although there is no specific diagnostic test for migraine, an objective diagnosis can be made based on standardized diagnostic criteria. (28) These criteria include: poorly localized, dull, or colicky pain severe enough to interfere with normal daily activities; at least two other symptoms (i.e., anorexia, vomiting, nausea, or pallor); attacks lasting at least 1 hour; and long symptom-free periods between attacks. Only 50% of patients with abdominal migraine have any other associated symptom, for example, headache (8). The children in our series had typical clinical symptoms as described above, a history of migraine headaches, and responded well to two of the standard drugs used for migraine (propranolol and cyproheptadine) (29). However, even without therapy, symptoms of abdominal migraine may resolve spontaneously by later childhood or adolescence, and therapy usually lasts from 6 months to 3 years (29). The resolution of abdominal pain episodes with age as our series of children grew older also supports the diagnosis of migraine.
Although we report a possible association between NF1 and migraine, our study was not a prospective survey, but a retrospective review of a large patient population of children with NF1. Therefore, we cannot state whether there is an increased incidence of abdominal migraine in children with NF1. However, we suspect this migraine-type syndrome is probably more common in children with NF1 than an anatomic lesion causing abdominal pain. In our database of more than 500 children with NF1 evaluated by this program, no patients had a history of a bowel obstruction or hemorrhage from a neurofibroma. If the patient's symptoms are suggestive of a mass lesion, investigations such as those in Table 2 should readily identify the problem (30–46).
In conclusion, abdominal migraine may be a significant cause of undiagnosed abdominal pain in children with NF1. The migraine episodes may be so severe that they mimic an acute abdomen and lead to unnecessary surgery (patient 2). Because these children are relatively healthy between attacks, they may go untreated for long periods of time. If investigations identify no mass lesions as a cause of acute abdominal pain in patients with neurofibromatosis, the clinician should consider abdominal migraine as a cause. In these children, the institution of pharmacologic therapy for migraine may result in rapid symptomatic improvement.
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