Brain & Development xxx (2015) xxx–xxx

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Original article

Misdiagnosis of gastroesophageal reflux disease as epileptic

seizures in children
Ays e Kaç
Kac¸ar
ar Bay ram a, Mehmet Canpolat a,  Neslihan Karaca
Bayram Karacabey b, Hakan Gumus a,
Kumandas a, Selim Doğ
Sefer Kumandas anay c, Duran Arslan b, Hü
Dog˘anay Hu¨ seyin 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.
  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

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

http://dx.doi.org/10.1016/j.b
http://dx.doi.org/10.1016/j.braindev.201
raindev.2015.09.009
5.09.009
0387-7604/    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
2 A.K. Bayram et al./ Brain & Development xxx (2015) xxx–xxx
rate diagnosis of PNEs in children is one of the most
common clinical problems faced by pediatricians. Misdi-
agnosis of epilepsy and unnecessary treatment with
antiepileptic drugs are common in these patients. The
frequencies of PNEs in pediatric patients are reported
to range from 3.5% to 39% at epilepsy referral centers
[2–4].
Gastroesophageal reflux disease (GERD) is a diges-
tive disorder that can cause many different symptoms,
and some symptoms of GERD may be associated with
PNEs. GERD can cause laryngospasm, bradycardia,
and apneic episodes in infants, which might be mistaken
as epileptic seizures   [4–7]. The diagnosis of GERD is
based on clinical history, symptoms and physical exam-
ination. The application of further diagnostic tests
including barium contrast radiography, 24-h ambula-
tory esophageal manometry, gastroesophageal scintigra-
phy, upper gastrointestinal endoscopy, and empiric trial
of acid suppression are conducted to confirm the diag-
nosis [8,9]. The purposes of GERD therapy in children
are relief of symptoms, the healing of tissue injuries
and the prevention of growth retardation. The main
treatment options are lifestyle changes including postu-
ral and nutritional suggestions, drug therapy such as
proton pump inhibitors and histamine H2-receptor
antagonists, and reflux surgery [7–10].
In this study, we evaluated the clinical features, defi-
nite diagnoses and treatment approaches of the children  
with clinically suspected GERD who were referred to
our division of pediatric neurology with a suspected
diagnosis of epileptic seizure. We also aimed to evaluate
the impact of GERD in children with epilepsy, whether
with or without cerebral palsy.
2. Methods
The study protocol was approved by Erciyes Univer-
sity Local Ethics Committee (protocol # 96681246/195).
Informed consent was obtained before the study from
the parents or legal guardians of the all patients. All
children with a final diagnosis of GERD who were ini-
tially referred with a suspected diagnosis of epileptic sei-
zure were included to study. All enrolled children were
prospectively evaluated over a three-year period.
Patients with typical GERD symptoms without
nonepileptic events, those with previously diagnosed
GERD, and patients referred with a diagnosis of other
neurological diseases except for a suspected diagnosis
of epileptic seizure were excluded. All patients were
assessed by two experienced pediatric neurologists in
terms of detailed medical history, clinical symptoms,
physical examination, neurologic evaluation, EEG, bio-
chemical tests, and radiologic studies. Video-EEG mon-
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
neurologically assessed, they underwent investigation
Please cite this article in press as: Bayram AK et al. Misdiagnosis of gastroesophageal reflux disease as epileptic seizures in children. Brain Dev
for GERD. GERD was diagnosed on the basis of clini-
cal history and symptoms; it was also confirmed by at
least one diagnostic test. The diagnostic tests for GERD
included barium radiography, 24-h ambulatory esopha-
geal manometry, gastroesophageal scintigraphy, and
upper gastrointestinal endoscopy. The diagnostic proce-
dures were evaluated by the pediatric gastroenterolo-
gists. Acid reflux episode was defined as a pH < 4 in
the esophagus. Abnormal parameters of esophageal
pH monitoring included the number of reflux episodes
lasting >5 min, and the percent total time when the
pH in the distal esophagus is <4.0. The test was consid-
ered positive when the percent total time of the pH in
the distal esophagus was greater than 6.3%, 1.2% and
4.2% on upright position, recumbent position, and total
score, respectively. Gastroesophageal scintigraphy was
performed in patients with clinically or radiologically
suspected delayed gastric emptying.
Patients were assigned to one of the following three
groups according to definite diagnoses: patients with a
final diagnosis of GERD who were initially referred with
a suspected diagnosis of epilepsy were categorized as
group I; children with comorbidity of epilepsy and
GERD were defined as group II; and those with the
coexistence of GERD, epilepsy, and cerebral palsy were
defined as group III.
2.1. Statistical analysis
All statistical analyses were performed by using SPSS
for Windows version 22.0 software (SPSS, Inc, Chicago,
IL, USA). Continuous variables were presented as mean
± standard deviation. Pearson’s chi-square test was used
to evaluate qualitative variables. Nonparametric statisti-
cal data were assessed by using the Kruskal–Wallis test.
When a significant result was obtained, the Mann– 
Whitney U   test with Bonferroni’s correction was used
for post hoc comparisons. A p  value <0.05 was consid-
ered as statistically significant.
3. Results
The study population included 57 patients (27 boys
and 30 girls). The mean age at diagnosis of GERD
was 40.9 ± 44.0 months (age range: 3 months–17 years).
Average follow-up duration was 18.2 ± 7.7 months. The
distributions of patients according to definite diagnosis
were as follows 16 patients (28.1%) in group I, 21
patients (36.8%) in group II, and 20 patients (35.1%)
in group III.
The medical history of the study population revealed
premature birth in 9 patients (15.8%), hypoxic ischemic
encephalopathy in 28 patients (49.1%), and febrile sei-
of PNEs at admission were head and neck extension in
40 patients (70.2%), irritability in 30 patients (52.6%),
 A.K. Bayram et al. / Brain & Development xxx (2015) xxx–xxx 3

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

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6 A.K. Bayram et al./ Brain & Development xxx (2015) xxx–xxx
involved in patient care, including the process of proce-
dure and routine clinical follow-up. HP, and AKB
performed the literature review and wrote the manu-
script. AKB also made statistical analysis. DA, HG
and SK also made helpful suggestions to improve the
manuscript.
Funding
The authors received no financial support for the
research, authorship, and/or publication of this article.
Ethical approval
Informed consent was obtained from all the parents
or legal guardians of the children included. This study
was approved by the Local Ethics Committee of Erciyes
University (protocol # 96681246/195).
Acknowledgement
We would like to thank all patients and families for
their participation in this study.
Appendix A. Supplementary data
Supplementary data associated with this article can
be found, in the online version, at http://dx.doi.org/10.
1016/j.braindev.2015.09.009.
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