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Brain & Development xxx (2015) xxx–xxx

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Original article

Misdiagnosis of gastroesophageal reflux disease as epileptic


seizures in children
Aysße Kaçar Bayram a, Mehmet Canpolat a, Neslihan Karacabey b, Hakan Gumus a,
Sefer Kumandas a, Selim Doğanay c, Duran Arslan b, Hüseyin Per a,⇑
a
Department of Pediatrics, Division of Pediatric Neurology, Erciyes University, Faculty of Medicine, Kayseri, Turkey
b
Department of Pediatrics, Division of Pediatric Gastroenterology, Erciyes University, Faculty of Medicine, Kayseri, Turkey
c
Department of Radiology, Division of Pediatric Radiology, Erciyes University, Faculty of Medicine, Kayseri, Turkey

Received 14 May 2015; received in revised form 15 August 2015; accepted 18 September 2015

Abstract

Background: Gastroesophageal reflux disease (GERD) can mimic epileptic seizure, and may be misdiagnosed as epilepsy. On the
other hand, GERD can be more commonly seen in children with neurological disorders such as cerebral palsy (CP); this co-
incidence may complicate the management of patients by mimicking refractory seizures.
Objective: The purpose of our study was to evaluate the clinical features, definite diagnoses and treatment approaches of the
patients with clinically suspected GERD who were referred to the division of pediatric neurology with a suspected diagnosis of
epileptic seizure. We also aimed to investigate the occurrence of GERD in children with epilepsy and/or CP.
Methods: Fifty-seven children who had a final diagnosis of GERD but were initially suspected of having epileptic seizures were
assessed prospectively.
Results: All patients were assigned to 3 groups according to definite diagnoses as follows: patients with only GERD who were
misdiagnosed as having epileptic seizure (group 1: n = 16; 28.1%), those with comorbidity of epilepsy and GERD (group 2: n = 21;
36.8%), and those with the coexistence of GERD with epilepsy and CP (group 3: n = 20; 35.1%). Five patients (8.8%) did not
respond to anti-reflux treatment and laparoscopic reflux surgery was performed. The positive effect of GERD therapy on paroxys-
mal nonepileptic events was observed in 51/57 (89.5%) patients.
Conclusions: GERD is one of the important causes of paroxysmal nonepileptic events. In addition, GERD must be kept in mind
at the initial diagnosis and also in the long-term management of patients with neurological disorders such as epilepsy and CP.
Ó 2015 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology.

Keywords: Children; Epileptic seizure; Gastroesophageal reflux disease; Misdiagnosis; Paroxysmal nonepileptic events

⇑ Corresponding author at: Erciyes University, Faculty of Medicine, 1. Introduction


Department of Pediatrics, Division of Pediatric Neurology, 38039,
Melikgazi, Kayseri, Turkey. Tel.: +90 (352) 2076666; fax: +90 (352) Paroxysmal nonepileptic events (PNEs) are charac-
4375825. terized by seizure like behaviors without concomitant
E-mail addresses: draysebayram@gmail.com (A.K. Bayram), ictal EEG changes. They may occur at all ages in child-
drmehmetcanpolat@gmail.com (M. Canpolat), dr.neslihan@yahoo.
com (N. Karacabey), hakgumus33@yahoo.com (H. Gumus),
hood. Clinical experience and a detailed history of the
skumandas@hotmail.com (S. Kumandas), selimdoganay@gmail.com patients usually lead to a correct diagnosis, and which
(S. Doğanay), duran@erciyes.edu.tr (D. Arslan), huseyinper@yahoo. is confirmed by diagnostic tests [1,2]. However, the accu-
com (H. Per).

http://dx.doi.org/10.1016/j.braindev.2015.09.009
0387-7604/Ó 2015 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology.

Please cite this article in press as: Bayram AK et al. Misdiagnosis of gastroesophageal reflux disease as epileptic seizures in children. Brain Dev
(2015), http://dx.doi.org/10.1016/j.braindev.2015.09.009
2 A.K. Bayram et al. / Brain & Development xxx (2015) xxx–xxx

rate diagnosis of PNEs in children is one of the most for GERD. GERD was diagnosed on the basis of clini-
common clinical problems faced by pediatricians. Misdi- cal history and symptoms; it was also confirmed by at
agnosis of epilepsy and unnecessary treatment with least one diagnostic test. The diagnostic tests for GERD
antiepileptic drugs are common in these patients. The included barium radiography, 24-h ambulatory esopha-
frequencies of PNEs in pediatric patients are reported geal manometry, gastroesophageal scintigraphy, and
to range from 3.5% to 39% at epilepsy referral centers upper gastrointestinal endoscopy. The diagnostic proce-
[2–4]. dures were evaluated by the pediatric gastroenterolo-
Gastroesophageal reflux disease (GERD) is a diges- gists. Acid reflux episode was defined as a pH < 4 in
tive disorder that can cause many different symptoms, the esophagus. Abnormal parameters of esophageal
and some symptoms of GERD may be associated with pH monitoring included the number of reflux episodes
PNEs. GERD can cause laryngospasm, bradycardia, lasting >5 min, and the percent total time when the
and apneic episodes in infants, which might be mistaken pH in the distal esophagus is <4.0. The test was consid-
as epileptic seizures [4–7]. The diagnosis of GERD is ered positive when the percent total time of the pH in
based on clinical history, symptoms and physical exam- the distal esophagus was greater than 6.3%, 1.2% and
ination. The application of further diagnostic tests 4.2% on upright position, recumbent position, and total
including barium contrast radiography, 24-h ambula- score, respectively. Gastroesophageal scintigraphy was
tory esophageal manometry, gastroesophageal scintigra- performed in patients with clinically or radiologically
phy, upper gastrointestinal endoscopy, and empiric trial suspected delayed gastric emptying.
of acid suppression are conducted to confirm the diag- Patients were assigned to one of the following three
nosis [8,9]. The purposes of GERD therapy in children groups according to definite diagnoses: patients with a
are relief of symptoms, the healing of tissue injuries final diagnosis of GERD who were initially referred with
and the prevention of growth retardation. The main a suspected diagnosis of epilepsy were categorized as
treatment options are lifestyle changes including postu- group I; children with comorbidity of epilepsy and
ral and nutritional suggestions, drug therapy such as GERD were defined as group II; and those with the
proton pump inhibitors and histamine H2-receptor coexistence of GERD, epilepsy, and cerebral palsy were
antagonists, and reflux surgery [7–10]. defined as group III.
In this study, we evaluated the clinical features, defi-
nite diagnoses and treatment approaches of the children 2.1. Statistical analysis
with clinically suspected GERD who were referred to
our division of pediatric neurology with a suspected All statistical analyses were performed by using SPSS
diagnosis of epileptic seizure. We also aimed to evaluate for Windows version 22.0 software (SPSS, Inc, Chicago,
the impact of GERD in children with epilepsy, whether IL, USA). Continuous variables were presented as mean
with or without cerebral palsy. ± standard deviation. Pearson’s chi-square test was used
to evaluate qualitative variables. Nonparametric statisti-
2. Methods cal data were assessed by using the Kruskal–Wallis test.
When a significant result was obtained, the Mann–
The study protocol was approved by Erciyes Univer- Whitney U test with Bonferroni’s correction was used
sity Local Ethics Committee (protocol # 96681246/195). for post hoc comparisons. A p value <0.05 was consid-
Informed consent was obtained before the study from ered as statistically significant.
the parents or legal guardians of the all patients. All
children with a final diagnosis of GERD who were ini- 3. Results
tially referred with a suspected diagnosis of epileptic sei-
zure were included to study. All enrolled children were The study population included 57 patients (27 boys
prospectively evaluated over a three-year period. and 30 girls). The mean age at diagnosis of GERD
Patients with typical GERD symptoms without was 40.9 ± 44.0 months (age range: 3 months–17 years).
nonepileptic events, those with previously diagnosed Average follow-up duration was 18.2 ± 7.7 months. The
GERD, and patients referred with a diagnosis of other distributions of patients according to definite diagnosis
neurological diseases except for a suspected diagnosis were as follows 16 patients (28.1%) in group I, 21
of epileptic seizure were excluded. All patients were patients (36.8%) in group II, and 20 patients (35.1%)
assessed by two experienced pediatric neurologists in in group III.
terms of detailed medical history, clinical symptoms, The medical history of the study population revealed
physical examination, neurologic evaluation, EEG, bio- premature birth in 9 patients (15.8%), hypoxic ischemic
chemical tests, and radiologic studies. Video-EEG mon- encephalopathy in 28 patients (49.1%), and febrile sei-
itoring and brain MRI were performed in patients if zures in 8 patients (14.0%). The clinical presentations
considered medically necessary. After the patients were of PNEs at admission were head and neck extension in
neurologically assessed, they underwent investigation 40 patients (70.2%), irritability in 30 patients (52.6%),

Please cite this article in press as: Bayram AK et al. Misdiagnosis of gastroesophageal reflux disease as epileptic seizures in children. Brain Dev
(2015), http://dx.doi.org/10.1016/j.braindev.2015.09.009
A.K. Bayram et al. / Brain & Development xxx (2015) xxx–xxx 3

head and eye deviation in 22 patients (38.6%), flexor (8.8%) did not respond to medical GERD therapy,
and/or extensor muscle contractions of upper limb in therefore laparoscopic reflux surgery was performed.
21 patients (36.8%), sleep disturbances including Oral Fe supplementation was given to all patients with
difficulty initiating sleep, frequent night awakenings iron deficiency anemia. PNEs were improved after
and restless sleep in 11 patients (19.3%), lip licking/ treatment for GERD in 51/57 patients (89.5%). Sandifer
swallowing in 8 patients (14.0%), weakness in 6 patients syndrome, flexor spasms, head drop, and myoclonus
(10.5%), Sandifer syndrome in 8 patients (14.0%), flexor were completely resolved after treatment for GERD.
spasms in 2 patients (3.5%), head drop in 2 patients The rates of improvement for other PNEs were as
(3.5%), myoclonus in 2 patients (3.5%), and torticollis follows: head and neck extension 33/40 patients
in 1 patients (1.8%) (Table 1). Among these patients, (82.5%), irritability 25/30 patients (83.3%), head and
flexor spasms were similar to infantile spasms (Video eye deviation 18/22 patients (81.8%), flexor and/or
1), head drop mimicked atonic seizure (Video 2), and extensor muscle contractions of upper limb 19/21
myoclonus resembled myoclonic seizure due to its patients (90.5%), sleep disturbances including difficulty
similar appearance. initiating sleep, frequent night awakenings and restless
PNEs were associated with eating in 9 patients sleep 8/11 patients (72.7%), lip licking/swallowing 6/8
(15.8%). Iron deficiency was observed in 20 patients patients (75.0%), weakness 5/6 patients (83.3%)
(35.1%). There was no statistically significant difference (Fig. 1). The average time for improvement of PNEs
in iron deficiency anemia among the all groups after treatment for GERD was 28.0 ± 2.5 days. There
(p = 0.124). Fifty patients (87.7%) were receiving was no significant difference among the groups in terms
antiepileptic drug therapy at admission. In these fifty of the average time of PNE improvement (p = 0.226).
patients, the number of receiving antiepileptic drugs In the overall study population, seven patients
for each patient ranged from 1 to 5 with a mean number (12.3%) were diagnosed with GERD without starting
of 2.0 ± 1.3 at admission. antiepileptic therapy; the antiepileptic drug therapy
The diagnosis of GERD was confirmed by using bar- was ceased in 9 patients (15.8%); the number of
ium radiography of the esophagus–stomach–duodenum, antiepileptic drugs was reduced in 5 patients (8.8%);
24-h esophageal pH monitoring, upper gastrointestinal and PNEs improved without additional antiepileptic
endoscopy, and multiple diagnostic tests in 34 (59.6%), therapy in 30 patients (52.6%) (Table 2).
13 (22.8%), 3 (5.3%), and 7 (12.3%) patients, respec- In group I, the diagnosis of GERD was made without
tively. Gastroesophageal scintigraphies were positive in starting antiepileptic drug therapy in 7/16 patients
7 patients (12.3%) who had chronic and refractory (43.7%), while antiepileptic drugs were ceased in 9/16
respiratory symptoms. patients (56.3%) after treatment for GERD. The
All patients were treated with proton pump inhibitors response rate to the GERD therapy was 100%.
or histamine-2 blockers, as well as postural and nutri- The mean age at diagnosis was 9.8 ± 5.8 months (age
tional suggestions, for at least 6 months. Five patients range: 3–20 months). The mean age at diagnosis was

Table 1
Main demographic features and distribution to the groups of different paroxysmal nonepileptic events in the patients with GERD.
n Group 1 Group 2 Group 3 Age (months) Gender p Valuea
(n = 16) (n = 21) (n = 20)
Head and neck extension 40 (70.2%) 10 15 15 41.8 ± 40.9 F:21, M:19 0.709b
Irritability 30 (52.6%) 10 7 13 42.6 ± 52.8 F:17, M:13 0.830b
Head and eye deviation 22 (38.6%) 5 7 10 41.3 ± 47.0 F:11, M:11 0.426b
Upper limb muscle 21 (36.8%) 9 7 5 33.5 ± 31.9 F:13, M:8 0.283b
contractions
Sleep disturbance 11 (19.3%) 1 2 8 33.5 ± 31.9 F:13, M:8 0.014b
Lip licking/swallowing 8 (14.0%) 3 4 1 28.5 ± 16.5 F:4, M:4 0.352b
Weakness 6 (10.5%) 4 2 0 28.2 ± 45.3 F:5, M:1 0.204b
Sandifer syndrome 8 (14.0%) 8 0 0 30.4 ± 16.2 F:5, M:3 <0.001b
Flexor spasms 2 (3.5%) 1 0 1 57.5 ± 71.4 F:1, M:1 0.667b
Head drop 2 (3.5%) 0 0 2 90.0 ± 42.4 F:0, M:2 0.147b
Myoclonus 2 (3.5%) 1 1 0 6.0 ± 2.8 F:1, M:1 0.554b
Torticollis 1 (1.8%) 0 1 0 11 F:1 0.418b
Abbreviations: n, number of patients; F, female; M, male.
Variables are expressed as mean ± standard deviation.
Values within parenthesis are presented as percentage.
a
Level of significance p < 0.05.
b
Pearson’s chi-square test.

Please cite this article in press as: Bayram AK et al. Misdiagnosis of gastroesophageal reflux disease as epileptic seizures in children. Brain Dev
(2015), http://dx.doi.org/10.1016/j.braindev.2015.09.009
4 A.K. Bayram et al. / Brain & Development xxx (2015) xxx–xxx

Fig. 1. Distribution of paroxysmal nonepileptic events, and results of GERD therapy.

Table 2
Effect of GERD therapy on antiepileptic drug therapy and paroxysmal nonepileptic events.
AEDs Group 1 Group 2 Group 3 Paroxysmal nonepileptic events
AEDs were not started 7/16 (43.7%) – – Improved
AEDs were ceased 9/16 (56.3%) – – Improved
AEDs were decreased – 3/21 (14.3%) 2/20 (10.0%) Improved
AEDs were not changed – 13/21 (61.9%) 17/20 (85.0%) Improved
AEDs were revised – 5/21 (23.8%) 1/20 (5.0%) Unaffected
Abbreviations: AEDs, antiepileptic drugs.

significantly lower when compared with the other 4. Discussion


groups (p < 0.001). The average follow-up duration
was 17.9 ± 9.7 months (range: 6–36 months). EEG was The mechanisms of involuntary reflex movements
performed during the follow-up period in all patients, related to GERD are unclear, although it is considered
and no epileptiform activity was seen on the follow-up that the abnormal movements during reflux are the result
EEGs. of a mechanism to protect the air passages from reflux
In group II, the number of antiepileptic drugs was material or to relieve the abdominal discomfort caused
reduced in 3/21 patients (14.3%). PNEs were improved by acid reflux [11]. The symptoms of GERD include
without additional antiepileptic drugs in 13/21 patients the following: recurrent regurgitation with/without vom-
(61.9%), while 5/21 patients (23.8%) did not respond iting, heartburn, abdominal pain or chest pain, persistent
to treatment for GERD. The response rate to the crying, dysphagia, stridor, wheezing, cough, hoarseness,
GERD therapy was observed as 76.2%, and it was sig- sleep disturbances, weight loss or poor weight gain, and
nificantly lower when compared with the other groups hematemesis [5,6,9,10]. However, many of the above-
(p = 0.005). mentioned symptoms of GERD are nonspecific in chil-
In group III, the number of antiepileptic drugs was dren, especially in infants. The neurobehavioral features
reduced in 2/20 patients (10.0%). PNEs were improved of GERD have been reported as irritability, crying,
without additional antiepileptic drugs in 17/20 patients head/eye version, contractions, torticollis, flexor and/or
(85.0%), while 1/20 patients (5.0%) did not respond to extensor spasm and dystonic movements [11–14]. We
treatment for GERD. The response rate to the GERD observed sleep disturbance, lip licking/swallowing,
therapy was observed as 95.0%. Sleep disturbances were weakness, flexor spasm, head drop, and myoclonus in
significantly higher when compared with the other our patients. Overall, PNEs improved in 51/57 patients
groups (p = 0.014), and they were improved in 6/8 (89.5%) after treatment for GERD. Moreover, the
patients (75.0%). condition of patients with flexor spasms, head drop,

Please cite this article in press as: Bayram AK et al. Misdiagnosis of gastroesophageal reflux disease as epileptic seizures in children. Brain Dev
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A.K. Bayram et al. / Brain & Development xxx (2015) xxx–xxx 5

and myoclonus improved without recurrence during the compared to the other groups (p < 0.001). At diagnosis
follow-up period. These findings support the view that of GERD, all patients were under 21 months and 11
PNEs may actually originate from GERD. Therefore, (67.8%) patients were infants. GERD is common in
we would like to emphasize that flexor spasm, head drop, infants but the symptoms of GERD are usually nonspeci-
and myoclonus must be considered as clues for the diag- fic, and also insufficient for diagnosis [11,12,18,19]. There-
nosis of GERD, especially in childhood. fore, pediatricians should be aware of the extraesophageal
Careful medical histories with a complete neurologi- manifestations of GERD. A detailed history and physical
cal assessment are usually sufficient to suspect PNEs. examination with attention to warning signals suggesting
Although the diagnosis of PNEs is usually not hard, other causes are important to establish a clinical diagnosis
its diagnosis can be difficult in patients with epilepsy. of GERD in infants and young children.
In the present study, the treatment response rate to In fact, GERD can be misdiagnosed as epileptic sei-
GERD therapy for PNEs was significantly lower in zures. In contrast, seizures can also be misdiagnosed
group II when compared with the other groups as GERD. Sweetman et al. [20] reported misdiagnosis
(p = 0.005). Although PNE symptoms suggested GERD of gelastic seizures as GERD in 6 patients with hypotha-
in these patients, they did not respond to treatment for lamic hamartoma. Auvin et al. [21] reported misdiagno-
GERD. Because the diagnosis remained uncertain in sis of West syndrome in 6 patients who were referred as
these patients and it was possible that they might have GERD. Parisi et al. [22] reported that 12 children with
been having epileptic seizures or coexistence of epileptic Panayiotopoulos syndrome, a benign epilepsy of child-
seizures and PNEs, the antiepileptic drug regimens were hood with occipital paroxysms, were misdiagnosed as
changed in addition to existing the GERD therapy. GERD. These rare but important conditions must also
Indeed, the symptoms of these patients improved after be taken into consideration by pediatricians in the differ-
modification of the antiepileptic drug regimens. ential diagnosis of GERD symptomatology.
Our study showed that sleep disturbances were signif- Children with neurological impairments are associ-
icantly higher in group III (p = 0.014). This result may be ated with increased risk of GERD [10,23]. On the other
associated with abnormalities in the neural control of the hand, GERD can play a role in PNEs in patients with
digestive system for the prevention of pulmonary aspira- epilepsy. The results of group II and group III are
tion in patients with cerebral palsy [15,16]. Primary peri- important in this respect.
stalsis and swallowing are depressed during sleep, as a The limitations of our study are failure to obtain 24-h
result of which the esophageal clearance of refluxed gas- ambulatory esophageal manometry and video-EEG
tric contents is delayed. Awakenings are thought to be an monitoring for all patients. Nevertheless, the typical
important protective mechanism against pulmonary characteristics of clinical history and symptoms, physi-
aspiration during sleep, and they are triggered by painful cal examination, and at least one diagnostic method
stimuli [16]. Del Giudice et al. [16] described the preva- were used to confirm the diagnosis of GERD; positive
lence and nature of gastrointestinal symptoms in 58 chil- responses to treatment for GERD supported the diag-
dren affected by cerebral palsy. The authors investigated nosis of GERD.
45 patients with symptoms suggesting GERD, and they In the literature, several pediatric studies reported
reported abnormal pH-monitoring and/or esophagitis that GERD had been misdiagnosed as epileptic seizure
in 41 of these patients. In another comparative study, [11–13]. This is the first clinical study in a large series
sleep interruptions were reported to be more frequent of patients to characterize children who were referred
in infants and young children with GERD [17]. We with a suspected diagnosis of epileptic seizure because
observed difficulties of initiating sleep, frequent night of clinical features, and were subsequently diagnosed
awakenings and restless sleep in this study, and all of with GERD; we also observed that GERD is commonly
these problems were improved after treatment for found in children with epilepsy, whether with or without
GERD in 72.7% of the overall study population and in cerebral palsy, which has a great impact on their clinical
75% of patients in group III. management and quality of life.
We would also like to emphasize that during this study In conclusion, GERD is one of the important causes
our awareness and clinical experience were increased. of PNEs. We would like to emphasize that children who
Therefore, in seven patients who were admitted in the last are admitted with a diagnosis of epileptic seizure should
year of the study and who were strongly suspected of be evaluated for GERD. Moreover the impact of
having GERD, and antiepileptic drug therapy was not GERD in children with epilepsy, whether with or with-
started. Antiepileptic drug therapy was ceased in 9 out cerebral palsy, must not to be ignored.
patients (15.8%) after treatment for GERD. Moreover,
16 patients (28.1%) were misdiagnosed with epileptic Author contributions
seizure. No epileptiform activity was seen on follow-up
EGGs in group I. In addition, the ages at diagnosis of HP conceived the study. HP, and AKB reviewed the
GERD were significantly lower in group I when literature, HP, AKB, DA, MC, HG and NK were

Please cite this article in press as: Bayram AK et al. Misdiagnosis of gastroesophageal reflux disease as epileptic seizures in children. Brain Dev
(2015), http://dx.doi.org/10.1016/j.braindev.2015.09.009
6 A.K. Bayram et al. / Brain & Development xxx (2015) xxx–xxx

involved in patient care, including the process of proce- conditions in pediatric patients, with comparison between his-
dure and routine clinical follow-up. HP, and AKB tamine-2 receptor antagonists and proton pump inhibitors. Curr
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(2015), http://dx.doi.org/10.1016/j.braindev.2015.09.009