Fundoplication and gastrostomy in familial dysautonomia

Fundoplication and gastrostomy in familial dysautonomia Felicia B. Axelrod, MD, Thomas H. G o u g e , MD, Howard B. Ginsburg, MD, Babu S. Bangaru, MD, a n d Charles Hazzi, MD From the Departments of Pediatrics and Surgery, New York University Medical Center, New York Fundoplication with gastrostomy has become a frequent treatment for patients with familial dysautonomia, so we evaluated the use of both procedures in 65 patients. Although patients differed widely in presenting signs and age, from 5 weeks to 40 years, gastroesophageal reflux was documented in 95% of patients by cineradiography or pH monitoring. Panendoscopy was a useful adjunct. Preoperative symptoms of gastroesophageal reflux included vomiting, respiratory infections, and exaggerated autonomic dysfunction. Severe oropharyngeal incoordination frequently coexisted and resulted in misdirected swallows with aspiration, d e p e n d e n c e on g a v a g e feedings, or poor weight gain and dehydration. Follow-up after surgical correction ranged from 3 months to 11 years; 55 patients (85%) were available f o r a l-year postoperative assessment. We had no instances of surgical death. The long-term mortality rate was 14%, primarily related to severe preexisting respiratory disease. Beyond the first postoperative year, 30 patients had pneumonia attributed to continued aspiration, exacerbation of preexisting lung disease, or recurrence of gastroesophageal reflux. Of 11 patients who vomited postoperatively, six had recurrence of reflux. Recurrence of gastroesophageal reflux was documented in eight patients (12%), and we revised the fundoplication in three patients. The number of patients with cyclic crises was reduced from 18 to 7; retching replaced overt vomiting in all but two of these seven patients, neither of whom had recurrence of reflux. Because oropharyngeal incoordination was prominent, concomitant use of gastrostomy and an antireflux procedure was especially effective in the treatment of younger patients with familial dysautonomia, before the development of severe respiratory disease. Despite the development of severe morning nausea in 15 patients, the combination procedure resulted in significantly improved nutritional status, decreased vomiting, and decreased respiratory problems. Appropriate use of gastrostomy feedings also contributed to success of the operation. The generally g o o d outcome of fundoplication with gastrostomy confirms the benefit of this procedure in familial dysautonomia. (J PEDIATR1991;118:388-94)

Familial dysautonomia is an autosomal recessive disorder associated with gastrointestinal dysfunction. 1 Oropharyngeal incoordination, abnormal esophageal motility, decreased lower esophageal sphincter pressure, prolonged gastric emptying time, and gastroesophageal reflux have all Submitted for publication April 16, 1990; accepted Oct. 1, 1990. Reprint requests: Feticia B. Axelrod, MD, New York University Medical Center, 530 First Ave., New York, NY 10016. 9/20/25774

388

been reported. 250ropharyngeal incoordination can result in misdirected swallows and cause aspiration pneumonia, a, 6 I

BUN FD GER

Bloodurea nitrogen Familial dysautonomia Gastroesophageal reflux

[

Gastroesophageal reflux is another cause of aspiration pneumonia 4, 6-8 as well as episodic wheezing, 7, 8 apnea,9 and chronic esophagitis 1~with anemia. Reflux is not always as-

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sociated with overt emesis. 7-9 Dysphagia caused by oropharyngeal incoordination results in insufficient caloric and fluid intake, failure to thrive, and dehydration. As a consequence of the infierent neurologic abnormalities in FD 11 and the slowly progressive nature of the disorder, 12 gastrointestinal abnormalities do not resolve with time. Disease expression varies considerably, and symptoms are not consistent. As in other neuromuscular disorders,13, 14 medical management with thickened feedings, positioning, and drugs has had limited success. 5, 15 An early favorable experience with fundoplication and gastrostomy in the treatment of FD has been reported. 5 Although cyclic episodes of retching and autonomic instability were not eliminated, overt emesis and its associated risks were decreased. In general, surgical intervention is advocated for prolonged intractable symPtoms or lifethreatening complications. 1619 In our experience the symptoms of GER can be unusual because of coexisting autonomic dysfunction. Dysphagia is so common that gastrostomy should be performed at the same time, and not closed unless strict criteria are met. This review was undertaken to determine whether use of both fundoplication and gastrostomy would benefit FD patients who had intractable gastrointestinal dysfunction and who frequently had both dysphagia and GER. METHODS Patient selection. Of 371 patients registered with the New York University Medical Center Dysautonomia Treatment and Evaluation Center, 65 patients with FD underwent fundoplication from November 1978 through December 1989. Patients ranged in age from 5 weeks to 40 years (mean age 9.4 +_ 8.9 years). Twenty-seven patients (42%) were <5 years and 17 patients (26%) <2 years of age; seven patients (11%) were >20 years of age. Thirty-three patients were male. The diagnosis of FD was confirmed by established criteria. 1 Evaluation for surgery Was based on severity and type of clinical symptoms and on failure of response to medical management. Severe dysphagia, recurrent pneumonia, or progressive radiographic pulmonary changes, recurrent vomiting, and apnea were considered indications for surgery. Mffny patients had more than one of these indications. Preoperative clinical features are summarized in Table I. Overt vomiting was present in 42 patients (65%), but the pattern varied. Nine patients had postprandial vomiting or nocturnal emesis, 15 patients had vomiting when stressed with a superimposed infection or obstipation, and 18 patients had the cyclical type of vomiting considered characteristic of FD. 1 Prokinetic agents and H2 blockers were tried in approx-

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389

T a b l e I. Clinical features: Preoperatively and 1 year postoperatively

Clinical symptoms

preoperative Postoperative patients (n = 65) patients (n = 55)

Gastrointestinal Vomiting Hematemesis Blood in stool Chest pain Respiratory Pneumonia Wheezing Apnea Laryngitis Nutritional status (weight-for-height) <5th percentile ~50th percentile

No.

%

No.

%

42 24 5 23

65 37 8 35

11 0 0 5

20

52 2i 24 6

80 32 37 9

20 9 1 1

36 16 2 2

16 21

25 32

3 35

5 64

9

imately half our patients before surgery: However, clinical response, as judged by cessation of the prominent symptoms, was not satisfactory. Drug therapy was attempted more often in the older patients. The mean age of 33 patients given a trial of ranifidine was 14.8 + 8.3 years; the mean age of the remaining 32 patients was 4.2 ___ 5.9 years (p = 0.0001). Metoclopramide was tried in 29 patients whose mean age was 15.1 -+ 8.3 years; the mean age of the other 36 patients was 4.9 _ 6.5 years (t9 = 0.0001). Clinical and laboratory assessment. Height and weight, hemoglobin and blood urea nitrogen measurements, and chest radiographs were obtained preoperatively and during follow-up. Cyclic vomiting was defined as vomiting without intercurrent infections, more than three times a year, and associated with signs of autonomic dysfunction such as profuse sweating, hypertension, tachycardia, and irritability. Occasionally, GER caused autonomic problems, such as bradycardia, hypotension, and syncope, in the absence of vomiting, 2~ Documented episodes of pneumonia were recorded for estimation of frequency p e r patient. Sequelae were assessed by evaluating chest radiograph s . Because short stature occurs frequently in FD, nutritional status was assessed with standardized weight-forheight percentiles from the National Center for Health Statistics. On the basis of these percentiles, patients who were at less than the 5th percentile were considered malnourished. Patients at the 50th percentile or greater were considered well nourished. The BUN level was used to assess hydration. Diagnostic studies. Evaluation of gastrointestinal function began with standardized cineradiography. 21 Distal esophageal pH monitoring for 18 to 24 hours was performed

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Axelrod et al.

The Journal of Pediatrics March 1991

Table III. Documentation of gastroesophageal reflux by preoperative diagnostic studies (n = 61)

Table II. Causes of death Interval since surgery

Age (yr) at death

Cause of death

Gastrostomy present

3 mo 10 mo 13 mo 1.5 yr 1.5 yr 3.3 yr 3.5 yr 4.8 yr 5.5 yr

2.0 30.0 2.3 18.5 12.0 6.5 7.0 12.8 8.5

Pneumonia/sepsis Renat failure Sleep death Seizure Head injury Pneumonia Unknown Sleep death Pneumonia

Yes Yes Yes Yes Yes Yes Yes No No

with a flexible indwelling micro pH probe with an outer diameter of 1.2 mm and an external reference electrode (Synectics Medical Inc., Irving, Tex.). The intraesophageal electrode was placed at 87% of the distance from the nares to the lower esophageal sphincter22; placement was confirmed radiographieally. On the basis of pH recordings every 4 seconds, data were analyzed by a computer with reference to the number of reflux episodes (pH <4), the number of episodes lasting >5 minutes, and total acid exposure time as a percentage of recorded time in postprandial and interprandial periods. The results were interpreted as outlined by Jolley et al. 23 for children and by DeMeester et al. 24 in adults. Panendoscopy was performed in 22 patients (34%), including 19 of the 24 patients who had hematemesis. Panendoscopy, because it is an invasive procedure, was reserved for patients with unusual symptoms such as syncope or when ulcer disease was suspected. Mild to moderate esophagitis was defined as erythema sufficient to obscure the fine-vessel pattern of the mucosa, friability, and a granular appearance. Severe esophagitis included ulcerations, linear erosions, and leukoplakia. Biopsies were performed routinely. Of the 65 patients, 61 had diagnostic studies of gastrointestinal function. Four patients were not examined because of severe dysphagia or parental refusal. Three of these four patients were dependent on gavage feedings; the fourth patient was malnourished, with the weight-for-height percentile markedly below the 5th percentile and a BUN level of 35 mg/dl (12.5 mmol/L). Surgical procedure. A complete fundoplication was performed with a loose wrap of the Nissen type and hiatal repair. For adult patients the bougie size was 40 or 42F; correspondingly smaller sizes were used in younger patients. Metal clips were placed at the site of fundoplication. All patients bad a gastrostomy because of the frequent association of oropharyngeal incoordination and anticipated problems with gas bloat. Of the 65 patients, seven (11%) had gastrostomy before fundoplieation surgery.

Patients with positive findings/procedures performed

Cineradiography Extended pH monitoring Cineradiography and extended pH monitoring Both studies positive Only pH monitoring positive Only cineradiography positive Panendoscopy Mild-to-moderate esophagitis Severe esophagitis Hiatal hernia Patulous hiatus

No.

%

43 / 58 28/30

74 93

15/27 10/27 1/27

56 36 4

14/22 5/22 5/22 4/22

64 23 23 18

Our criteria for gastrostomy closure included a postoperative cineradiograph that documented normal swallowing of liquid and demonstration of the patient's ability to consume sufficient fluids to maintain normal BUN values. Fifteen gastrostomies (23%) were closed; four patients had gastrostomy removal against advice. Two patients had pyloroplasty because of delayed gastric emptying as noted on cineradiography. Analysis of data. Details of clinical features, investigations, and outcome were recorded for each patient. Data were analyzed with a computer-aided statistical package~ror the Macintosh II computer (StatView II, Abacus Concepts, Somerville, N.J.). RESULTS We performed postoperative examinations at 3 months and 1 year, and then annually; 55 patients (85%) were available for the 1-year postoperative assessment. Followup ranged from 3 months to 11 years. Two of the nine patient deaths, from causes unrelated to surgery, occurred within 1 year (Table II).

Diagnostic confirmation of gastrointestinal dysfunction Gastroesophageal reflux. Gastroesophageal reflux was confirmed in 58 (95%) of 61 examined patients by at least one of three types of diagnostic study. In the three patients without confirmation of reflux, only cineradiography was performed, but clinical histories were highly suspect on the basis of recurrent pneumonias in the year before surgery and radiographic evidence of increasing lung disease. Two of these three patients had cyclic vomiting with hematemesis; one of these two patients had apnea and the other had frequent wheezing. Of the 27 patients who had both cineradiography and

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Fundoplication and gastrostomy in FD

391

Table IV. Characteristics of eight patients with documented recurrence of gastroesophageal reflux Patient Operative age (yr) Sex Postoperative clinical problems No. of pneumonia cases Wheezing Overt emesis Diagnostic studies (positive for GER) Cineradiography Esophageal pH monitoring Endoscopy Postoperative treatment Metoclopramide Ranitidine Surgical revision

0.6 M

0.9 F

1.5 M

2.6 F

3.7 M

7 F

9 M

15 F

10 + +

0 +

3 + +

2 + +

5 + +

1 +

15 + -

3 + -

+ ND +

+ ND ND

+ +

+

+ + +

+ +

ND +

ND +

+ + -

+

+ +

+ + -

+ + +

+ -

+ + -

+ -

ND, Not done.

extended pH monitoring, at least one study showed the presence of G E R in 26 (96%) (Table III). Esophageal pH monitoring was the most sensitive indicator of GER. No significant difference was detected with age; patients <5 years of age had essentially the same percentage yield for G E R as that for the total population. Of these 27 patients, 10 had panendoscopy; esophagitis was found in nine patients. Most often, direct visualization revealed abnormalities compatible with mild to moderate esophagitis (64%). Biopsies allowed discrimination between acute and chronic esophagitis but were not as helpful in classifying severity. Four patients had a very patulous lower esophagus. Eight patients had hiatal hernias detected by cineradiography or by panendoscopy. Patients with hiatal hernia were significantly older (22.0 +_ 10.8 years, p -- 0.006). Of the eight patients with confirmed recurrence of GER, only one had evidence of migration of the fundoplication wrap into the chest as indicated by movement of surgically placed metal clips. When symptoms strongly suggested recurrence of G E R and diagnostic tests did not confirm the clinical impression, the diagnostic evaluation was repeated. In Contrast to the preoperative experience, extended pH monitoring was not more sensitive than cinesophagrams and panendoscopy yielded positive results more frequently than other studies. In three cases visual inspection by panendoscopy yielded the only positive test result (Table IV). Oropharyngeal incoordination. Other than history, cineradiography was the only means used to document oropharyngeal incoordination. Misdirected swallows with aspiration into the trachea were noted on 30 of 58 cineradiographs (52%), but seven other children had such severe dysphagia that cineradiography could not be performed. Gastrointestinal symptoms. Preoperatively, vomiting was

the most common gastrointestinal symptom (65% of patients). One year postoperatively the overall number of patients with vomiting was reduced from 42 to 11 (Table I), and the pattern of vomiting was altered. Postprandial and nocturnal emesis was eliminated. Of the original 18 patients with cyclic vomiting, seven patients continued a cyclic crisis pattern, but retching replaced vomiting in all but two of these seven patients. The cyclic crisis pattern appeared in three additional patients postoperatively; all three had vomiting. Of the remaining six patients with postoperative vomiting, regurgitation was precipitated by choking on respiratory secretions. Thus the n u m b e r of patients who vomited in association with the stress of illness was decreased from 15 to 5. The eleventh patient with postoperative vomiting was a child whose postprandial retching recurred 2 weeks after operation and escalated into episodic vomiting 6 months later. Of the 11 patients manifesting postoperative vomiting, recurrence of G E R was confirmed in six. Surgical revision of t h e fundoplication was performed in three patients, including the one in whom postprandial retching escalated to episodic vomiting. Surgical revision eliminated the vomiting. Although hematemesis was common preoperatively, it was eliminated by surgery. Reports of chest pain also decreased, but five patients had intermittent substernal chest pain consistent with esophageal spasm or obstruction. In four of the five patients, diazepam and bethanechol were helpful and symptoms resolved within 1 year. In one patient, pain and progressive dysphagia persisted despite medical therapy and esophageal dilation. The most difficult postoperative problem was the development of attacks of severe nausea in 15 (27%) of the 55 patients. The onset of the nausea occurred from sev-

392

A x e l r o d et al.

eral weeks to almost a year after surgery. Typically the nausea was present on arousal from sleep and caused loud, repeated retching. Excessive salivation and spitting of secretions were also common. This type of nausea was unrelated to use of the gastrostomy for nighttime feedings. It was unresponsive to venting and modification of diet. Use of prokinetics was helpful in some cases. Diazepam was usually the most effective agent in affording relief. Respiratory symptoms, Preoperatively, respiratory symptoms were prominent. Only nine patients (14%) had clear chest radiographs. Severe lung disease with increased markings bilaterally or atelectasis was present in 55%. Patients who aspirated were more likely to have extensive radiographic findings. Bilateral interstitial fibrosis and segmental atelectasis were present in 23 (77%) of the 30 patients with confirmed aspiration, in contrast to 11 (38%) of the 29 patients Who had only GER (p = 0.01). Three patients with severe lung disease had preexisting tracheostomies. Fifty-two patients (80%) had a total of 115 episodes of pneumonia in the year before surgery (mean 1.8 + 1.4). Wheezing episodes occurred in 32% and episodic laryngitis in 9% (Table I). Daytime apnea or syncopal episodes had occurred in 24 patients (37%). In the first postoperative year, 20 (36%) of 55 patients had at least one episode of pneumonia and a total of 28 episodes (mean 0.5 ___0.9, a significant improvement in frequency compared with the year before surgery; p = 0.0001). Of these 20 patients, 4 had no further episodes of pneumonia. Although a total of 30 patients had pneumonia beyond the first postoperative year, 12 of the 30 patients had only a single episode. Of the 18 patients with repeated pneumonia, seven had recurrence of GER but only four had overt emesis. Two of three patients, who did not have confirmation of GER before surgery, were among those patients who continued to have pneumonia beyond the first postoperative year, but the frequency of pneumonia was much reduced. Occasional aspiration caused by misdirected swallowing of food, or even of saliva, was the presumed cause of Continued or recurrent pneumonia in many of the 30 patients, including the 13 (87%) of 15 whose cineradiographs were positive for aspiration postoperatively. Despite radiographic evidence of continued swallowing problems, five patients had gastrostomy tubes removed against advice; one died of aspiration pneumonia 2 years after gastrostomy closure. Nineteen of the patients who continued to have pneumonia had radiographic evidence of extensive lung disease preoperatively. One had a tracheostomy before surgery; progressive respiratory compromise necessitated tracheostomy in three other patients postoperatively. Wheezing decreased significantly (p < 0.05) (Table I).

The Journal o f Pediatrics March 1991

Six of the nine patients with wheezing postoperatively had recurrence of GER. The other three patients with persistent wheezing had severe preexisting lung disease. Daytime apnea resolved in the 15 patients who had this symptom preoperatively but appeared in another patient postoperatively before she died of renal failure. Nutritional status. Preoperatively, severe dysphagia caused malnutrition. Twenty-five percent of patients had weight-for-height at <5th percentile for age, and only 32% were appropriately nourished with weight-for-height at >__50th percentile (Table I). With gastrostomies for supplementing oral feedings, nutritional status and hydration improved significantly. Preoperative and postoperative weight-for-height percentiles were subjected to analysis of variance. The seven patients with preexisting gastrostomies were included in the general analysis. A positive postoperative shift was confirmed, with the largest group of patients being at the 50th percentile or greater (p = 0.0001). Surgery also effected an increase in mean hemoglobin level from 11.5 to 12.1 mg/dl (p = 0.01). The change in the mean serum BUN level was from 22.3 to 19.5 mg/dl, (8.0 to 7.0 mmot/L) (p = 0.07). Mortality rate. The overall mortality rate was 14%. Patients with the most severe preexisting respiratory disease, according to radiographs, had the highest rate. There was one death (3%) among those 29 patients whose preoperative radiographs revealed only unilateral disease, but 8 deaths (22%) among those 36 patients with bilateral disease or atelectasis (p <0.05). None of the deaths was considered a complication of surgery, because no death occurred within a 3-month postoperative period (Table II). DISCUSSION A recent study of survival 2s confirmed that the prognosis for patients with FD had improved significantly since Brunt and McKusick's review 26 in 1970. Early recognition of the disorder and aggressive treatment are thought to contribute to better survival, but the effects of particular treatments have not been analyzed. We consider fundoplication with gastrostomy to be one of the most important treatments. Of a total registered patient population of 371, 136 patients (37%) have had fundoplication with gastrostomy since November 1978. Sixty-five patients (48%) underwent the procedure at New York University Medical Center, where the involvement of a limited number of physicians provided consistency in care and observation, facilitating accurate data retrieval. Lack of recognition or improper treatment of gastrointestinal dysfunction in FD can lead to serious respiratory and nutritional problems. Both GER and oropharyngeal incoordination are common. The respiratory complications are life threatening and directly affect prognosis. Not all

Volume 118 Number 3

pulmonary symptoms are caused by inhalation of refluxed gastric contents; aspiration of oral contents or even reflex bronchospasm must be considered as possible causes. 27, 28 Gastrointestinal dysfunction continues even into adulthood. The intractable course is attributed to lack of neuronal maturation in this population. Our patients responded poorly to conservative treatment measures, including trials of prokinetic agents. In addition, it is difficult to commit patients, already neurologically unstable, to lifelong use of drugs with central nervous system effects. The most valuable clue to the presence of GER was an accurate history. Preoperatively, cineradiography and extended pH monitoring correlated well with the clinical impression of GER. Recurrence of GER, however, was not easily confirmed despite strong clinical signs. In one patient, symptoms developed 3 years postoperatively, and another patient had clinical symptoms 2 years after surgery. Results of initial studies of both patients were negative, and it took more than a year before G E R could be documented in each case. Compared with the results in other reviews, Is' 19 our incidence of recurrent G E R was high and may have been caused by the repeated episodic retching in some patients. Vomiting and its associated risks of aspiration and esophagitis decrease with fundoplication, but surgery does not eliminate the dysautonomic crisis. In many patients, systemic signs of autonomic dysfunction, such as tachycardia, hypertension, diaphoresis, irritability, and abdominal discomfort, persisted in a cyclic pattern, but retching replaced vomiting. These modified crises continued to be responsive to diazepam therapy. 29 In addition, the gastrostomy facilitated gastric decompression and administration of medications and fluids and this made management at home easier. The cause of the postoperative daily morning nausea is not understood. In contrast to t h e postoperative dysautonomic crisis, the nausea did not respond consistently to administration of diazepam. The nausea was occasionally helped by prokinetic drugs but was unaffected by gastric decompression or modification of gastrostomy feedings. Fundoplication with gastrostomy improves nutritional status by decreasing subsequent acute respiratory illnesses and by allowing provision of supplemental calories and fluid. The most significant improvement in nutritional status occurred in younger patients with fewer respiratory problems whose primary problem was dysphagia. Longterm effects of improved nutrition on other features of the disease, such as height and spinal curvature, will eventually be assessed. Removal of the gastrostomy is justified if patients can demonstrate normal swallowing by cineradiography and drink sufficient amounts of fluid to prevent dehydration. We conclude that oropharyngeal incoordination and

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393

G E R are prominent features of FD. Neither appears to resolve with time. Fundoplication with gastrostomy is a safe and effective treatment. We believe that gastrostomy should always accompany fundoplication in patients with dysautonomia and should be closed only in a patient who has normal swallowing on cineradiography and can consistently maintain adequate nutrition and hydration with oral intake. Surgery significantly reduces vomiting, improves nutritional status, and decreases respiratory problems. Some patients, especially those with cyclic vomiting, may have troublesome morning nausea postoperatively. Younger patients with minimal lung disease have the best prognosis. Early evaluation and treatment of gastrointestinal dysfunction with fundoplication and gastrostomy should reduce many of the life-threatening and debilitating features of FD. REFERENCES

1. Axelrod FB, Nachtigall R, Dancis J. Familial dysautonomia: diagnosis, pathogenesis and management. In: Schulman [, ed. Advances in pediatrics; vol 21. Chicago: Year Book Medical Publishers, 1974:75-96. 2. Brunt PW, Margulies SI, Coburn WM, Donner MW, Hendrix TR. The esophagus in dysautonomia: a manometric and cincfluorographic study. Gut 1967;8:636-7. 3. Gypes TM, Linde ML. Familial dysautonomia: the mechanism of aspiration. Radiology 1968;91:471-5. 4. Linde LM, Westover JL. Esophageal and gastric abnormalities in dysautonomia. Pediatrics 1962;29:303-6. 5. Axelrod FB, Schneider KM, Ament ME, Kutin ND, Fonkalsrud EW. Gastroesophageal fundoplication and gastrostomy in familial dysautonomia. Ann Surg 1982;195:253-8. 6. Axelrod FB, Dancis J. Familial dysautonomia. In: Kendig E, Chernick V, eds. Disorders of the respiratory tract in children. 4th ed. Philadelphia: WB Saunders, 1983:872-6. 7. Berquist WE, Rachelefsky GS, Kadden M, et al. Gastroesophageal reflux-associated recurrent pneumonia and chronic asthma in children. Pediatrics 1981;68:29-35. 8. Euler AR, Byrne W J, Ament ME, et al. Recurrent pulmonary disease in children: a complication of gastroesophageal reflux. Pediatrics 1979;63:47-51. 9. Spitzer AR, Boyle JT, Tuchman DN, Fox WW. Awake apnea associated with gastroesophageal reflux: a specific clinical syndrome. J PEDIATR1984;104:200-5. 10. Shub MD, Ulshen MH, Hargrove CB, et al. Esophagitis: a frequent consequence of gastroesophageal reflux in infancy. J PEDIATR 1985;107:881-4. 11. Pearson J. Familial dysautonomia (a brief review). J Auton Nerv Syst 1979;1:119-26. 12. Axelrod FB, Iyer K, Fish I, et al. Progressive sensory loss in familial dysautonomia. Pediatrics 1981;67:517-22. 13. Bray PF, Herbst J J, Johnson DG, et al. Childhood gastroesophageal reflux: neurological and psychiatric syndromes mimicked. JAMA 11977;237:1342-5. 14. Berezin S, Newman LJ, Schwarz SM, Spiro AJ. Gastroesophageal reflux associated with nemaline myopathy of infancy. Pediatrics 1988;81:111-5. 15. Axelrod FB, Branon N, Becker M, Nachtigall R, Dancis J.

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Treatment of familial dysautonomia with bethanechol (Urecholine). J PED~ATR1972;81:573-8. Herbst JJ. Gastroesophageal reflux. J PEDIATR 1981;98: 859-70. Foglia RP, Fonkalsrud EW, Ament ME, et al. Gastroesophageal fundoplication for the management of chronic pulmonary disease in children. Am J Surg 1980;140:72-9. Leape LL, Ramenofsky ML. Surgical treatment of gastroesophageal reflux in children: results of Nissen's fundoplication in 100 children. Am J Dis Child 1980;134: 935-8. Tunell WP, Smith El, Carson JA. Gastroesophageal reflux in childhood: the dilemma of surgical success. Ann Surg 1983; 197:560-5. Axelrod FB, Maayan C, Hazzi C, Bangaru BS, Shannon DC. Bradycardia associated with hiatal hernia and gastroesophageal reflux relieved by surgery. Am J Gastroenterol 1987;82:159-61. McCauley RGK, Darling DB, Leonidas JC, Schwartz AM. Gastroesophageal reflux in infants and children: a useful classification and reliable physiologic technique for its demonstration. Am J Radiol 1978;130:47-50.

22. Sondheimer JM. Gastroesophageal reflux: update on pathogenesis and diagnosis. Pediatr Clin North Am 1988 ;35:103-16. 23. Jolley SG, Johnson DG, Herbst J J, Pena A, Gainer R. An assessment of gastroesophageal reflux in children by extended pH monitoring of the distal esophagus. Surgery 1978;84:16-24. 24. DeMeester TR, Johnson LF, Joseph G J, Toscano MS, Hall AW, Skinner DB. Patterns of gastroesophageal reflux in health and disease. Ann Surg 1976;184:459-70. 25. Axelrod FB, Abularrage JJ. Familial dysautonomia: a prospective study of survival J PEDIATR 1982;101:234-6. 26. Brunt PW, McKusick VA. Familial dysautonomia: a report of genetic and clinical studies with a review of the literature. Medicine 1970;48:343-74. 27. Orenstein SR, Orenstein DM. Gastroesophageal reflux and respiratory disease in children. J PEDIATR 1988;112:847-58. 28. Jolley SG, Smith EI, Tunell WP. Protective antireflux Operation with feeding gastrostomy. Ann Surg 1985;201:736-40. 29. Axelrod FB. Familial dysautonomia. In: Gellis SC, Kagan BM, eds. Current pediatric therapy. 12th ed. Philadelphia: WB Saunders, 1986:92-4.

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