Journal of

Clinical Medicine

Article
Pediatric Miller Fisher Syndrome; Characteristic
Presentation and Comparison with Adult Miller
Fisher Syndrome
Yeonji Jang 1 , Jae-Hwan Choi 2 , Jong Hee Chae 3 , Byung Chan Lim 3 , Seong-Joon Kim 1 and
Jae Ho Jung 1, *
1 Department of Ophthalmology, Seoul National University Children’s Hospital,
Seoul National University College of Medicine, 101 Daehak-ro Jongno-gu, Seoul 03080, Korea;
ibeyj3721@naver.com (Y.J.); ophjun@snu.ac.kr (S.-J.K.)
2 Department of Neurology, Pusan National Yangsan Hospital, Yangsan 50612, Korea;
rachelbolan@hanmail.net
3 Department of Pediatrics, Pediatric Clinical Neuroscience Center, Seoul National University Children’s
Hospital, Seoul National University College of Medicine, Seoul 03080, Korea; chaeped1@snu.ac.kr (J.H.C.);
prabbit7@snu.ac.kr (B.C.L.)
* Correspondence: jaeho.jung@snu.ac.kr; Tel.: +82-2-2072-1765; Fax: +82-2-747-5130




Received: 5 October 2020; Accepted: 2 December 2020; Published: 3 December 2020


Abstract: Background: We aimed to investigate the characteristic presentation of Miller Fisher

syndrome (MFS) in pediatrics and compare it with that in adults. Methods: We performed
a retrospective review of medical records, laboratory findings, and disease course of pediatric MFS.
The data were compared with those of adult MFS, and literature review was done. Unpaired and
paired comparisons between groups were made using Wilcoxon rank-sum and signed-rank tests,
respectively. Results: Median age for pediatric MFS was 9.8 ± 6.5 years. There were 5 (45.5%) male
and 6 (54.5%) female patients. All patients had preceding infection. Two patients (22.2%) had tested
positive for anti-GQ1b antibody. Ten patients (90.1%) were treated with intravenous immunoglobulin,
and 2 (18.2%) also received intravenous methylprednisolone. Within one month, 8 (72.7%) patients
showed recovery, and all 11 (100%) recovered fully within 3 months. Further, the pediatric group had
higher frequency of unilateral involvement of ophthalmoplegia, ataxia, and autonomic symptoms
but lower antiganglioside antibody positivity and manifestations of areflexia than the adult group.
Conclusions: Neuro-ophthalmic manifestations and disease course of pediatric MFS were similar to
those of adult MFS as stated in the literature. However, the presence of autonomic symptoms was
higher and anti-GQ1b antibody positivity was lower in pediatric MFS than in adult MFS.

Keywords: Miller Fisher syndrome; acute inflammatory demyelinating polyneuropathy; ophthalmoplegia;

antiganglioside antibodies

1. Introduction
Miller Fisher syndrome (MFS) is an acute self-limiting disorder characterized by a clinical
triad of ophthalmoplegia, ataxia, and areflexia [1,2]. MFS has been considered a variant of
Guillain-Barré syndrome (GBS) and can overlap with the pharyngeal-cervical-brachial (PCB) variants
of GBS, or Bickerstaff brainstem encephalitis (BBE) in the clinical course [3]. Many atypical clinical
manifestations, beyond the classic triad, are considered for the differential diagnosis between posterior
fossa tumor, Wernicke syndrome, botulism, or meningitides [4].

J. Clin. Med. 2020, 9, 3930; doi:10.3390/jcm9123930 www.mdpi.com/journal/jcm

J. Clin. Med. 2020, 9, 3930 2 of 11

Because anti-GQ1b ganglioside antibodies have been detected in the sera of patients during the
acute phase of MFS, BBE, and GBS with ophthalmoparesis, they seem to have a close relationship with
MFS [5]. Therefore, anti-GQ1b antibodies have been considered as a crucial biomarker for MFS.
However, these clinical findings and laboratory results were based on the adult patient group
because the prevalence of MFS in pediatric patients is significantly lower than that in adults [6,7].
There are only limited case reports or case series about MFS in pediatric patients. The paucity of
information may lead to difficulties in the diagnosis of MFS in the pediatric patient group.
The aim of this study was to describe the distinct clinical characteristics and disease course of
MFS in pediatric patients and compare them with those in adult patients.

2. Materials and Methods

This retrospective, case–control comparative study included patients diagnosed with MFS at Seoul
National University Children’s Hospital (SNUCH) and Pusan National University Yangsan Hospital
(PNUYH). The study protocol was reviewed and approved by the Institutional Review Boards of Seoul
National University Hospital and Pusan National University Yangsan Hospital. The study procedures
were conducted in accordance with the tenets of the Declaration of Helsinki. The requirement for
informed consent was waived because of the retrospective nature of the study.

2.1. Subjects and Materials

We retrospectively reviewed the medical records of the patients with MFS between January 2001
and December 2019. Pediatric patients were classified as being under 18 years of age at the time of
diagnosis. Pediatric MFS patients from SNUCH were included, and adult MFS patients from PNUYH
were also included for comparison.
The diagnoses of MFS and subtyping were categorized as follows [2]: (1) classic MFS;
ophthalmoplegia and ataxia; (2) incomplete MFS; acute ophthalmoparesis, ataxic neuropathy,
ptosis, or mydriasis; (3) Bickerstaff brainstem encephalitis (BBE); ophthalmoplegia, ataxia,
and hypersomnolence; (4) overlapping MFS; overlap with Guillain-Barre syndrome (GBS) variants.
Furthermore, overlapping MFS was divided into classic GBS, pharyngeal-cervical-brachial weakness
(PCB), paraparetic GBS, and bifacial weakness with paranesthesia.
The data in the records revealed that all patients underwent neuro-ophthalmologic examinations
including best-corrected visual acuities, presence of ptosis, ocular motility test, presence of internal
ophthalmoplegia (pupil palsy), presence of ataxia, and tendon reflex. Further, we collected the
data of preceding infection history, presence of anti-GQ1b antibodies, nerve conduction study,
cerebrospinal fluid (CSF) analysis, and atypical symptoms or signs beyond the classic MFS symptom
triad. We excluded patients who had a previous neurological illness or less than 6 months of follow-up.

2.2. Analysis
We investigated clinical features of pediatric MFS and determined its distinct characteristics
by a comparison between the pediatric group and the adult group. We compared the clinical
manifestations, laboratory findings, and disease course between the pediatric patient group and
the adult patient group. The Fisher’s exact test and independent T-test were used to compare the
results, while Mann–Whitney’s U-test was used in the circumstance that needed a nonparametric test.
Statistical analysis was performed using the SPSS program (ver. 20.0; SPSS, Inc., Chicago, IL, USA).

2.3. Literature Review

We performed a literature search of the PubMed (Medline) databases for articles published up to
March 2020 including the search terms “pediatric”, “children”, and “childhood” in combination with
“Miller Fisher syndrome”, “Miller-Fisher syndrome”, and “MFS”. Case reports or series about pediatric
MFS were included. Studies written in non-English language or having the full text unavailable were
J. Clin. Med. 2020, 9, 3930 3 of 11

excluded for accuracy. Each article obtained from the search was investigated to determine its potential
inclusion in the review.

3. Results

3.1. Pediatric Miller Fisher Syndrome Characteristics

A total of 11 patients with pediatric MFS were included. The demographic and clinical
characteristics of the patients are listed in Table 1. The mean age of MFS onset in the pediatric
group was 9.8 ± 6.5 years.
First, all the patients had preceding infection: 5 (45.5%) had gastrointestinal symptoms, 6 (54.5%)
had upper respiratory symptoms, and 1 (9.1%) had fever with ear pain. Second, regarding the initial
symptoms presented, 7 (63.6%) patients had diplopia, and 4 (36.4%) patients, 1 in each, complained of
lower leg weakness, gait disturbance, facial palsy, and voice change. The initial symptoms appeared
on average 7.9 ± 4.8 days after the preceding infection.
Third, regarding the clinical diagnosis of the patients, 6 (54.5%) had classic MFS, 4 (36.4%) had
overlapping MFS, and 1 (9.1%) had acute ophthalmoparesis. Nine (81.8%) showed atypical clinical
manifestations; among them, 3 (27.3%) had autonomic dysfunction (night sweating, hypertension,
and tachycardia), 1 (9.1%) complained about urticaria, and 1 (9.1%) had tinnitus.
Fourth, in terms of laboratory test at initial visit, 2 (22.2%) of 9 patients had tested positive for
anti-GQ1b antibodies. We excluded 1 patient who was examined for antiganglioside antibody 12 years
after the onset. Seven patients (63.6%) had albumin-cytologic dissociation in the cerebrospinal fluid
study. In addition, nerve conduction studies demonstrated that 6 (60%) of 10 patients who had available
examination results had prolonged terminal latency and decreased nerve conduction velocity.
Last, 10 (90.9%) pediatric patients had been treated with intravenous immunoglobulin,
and 2 (18.2%) had also received intravenous dexamethasone injection. One (9.1%) patient received
supportive care without medical treatment.
Nine (81.8%) patients had recovered completely within one month, and the remaining 2 (18.2%)
recovered within three months.

3.2. Comparison between Pediatric Miller Fisher Syndrome and Adult Miller Fisher Syndrome
Table 2 shows the clinical features, laboratory findings, and disease course in the pediatric and the
adult MFS. The two groups showed similar clinical features, but pediatric MFS cases tended to have
more unilateral involvement of external ophthalmoplegia (p = 0.01), ataxia (p = 0.01), and autonomic
symptoms (p = 0.04) than adult MFS cases. Areflexia was a less dominant feature in pediatric MFS than
in adult MFS (p = 0.04). Regarding laboratory findings, pediatric patients showed lower positivity in
anti-GQ1b antibody testing (p = 0.02) and higher albumin-cytologic dissociation (p < 0.01) than adult
patients. The number of pediatric patients who showed complete improvement within a month was
higher than that in adult patients (p = 0.04).
J. Clin. Med. 2020, 9, 3930 4 of 11

Table 1. Demographic and clinical characteristics of pediatric Miller Fisher syndrome (MFS).

Age Ophthalmoplegia Hyporeflexia Additional Ganglioside Timing of CSF/NCS Time to Complete

Diagnosis Range/ Ataxia Treatment Improvement
EO IO Ptosis or Areflexia Manifestations Antibodies Ab Test Abnormalities
Sex
V(R), Dysesthesia, dizziness,
cMFS 16/M R R (+) (−) GQ1b 0 (+)/(−) IVIG 1 month
H(R) night sweat, urticaria
V(R),
cMFS 17/M (−) R (+) (+) Dysesthesia (−) 0 (−)/(+) IVIG 1 month
H(R)
V(B),
cMFS 12/F B (−) (+) (-) Dysesthesia, ocular pain (−) 2 (+)/(+) IVIG 1 month
H(B)
No study IVIG, IV
cMFS 1/M H(L,ab) (−) (−) (+) (+) (−) - (−)/(−) 3 months
result steroid
V(B),
cMFS 2/M (−) B (+) (−) (−) (−) 5 (−)/(−) IVIG 1 month
H(B)
V(L), Facial palsy, dysesthesia, IVIG, IV
cMFS 13/F L (−) (+) (+) GQ1b 0 (+)/(+) 1 month, recur
H(R) fever, tachycardia steroid
Facial palsy, limb
oMFS No study
2/F (−) (−) B (+) (+) weakness, dysphagia, - (+)/(+) IVIG 3 months
(MFS/GBS/PCB) result
dysarthria
oMFS voice change, tongue
7/F (−) (−) (−) (+) (+) (−) 3 (+)/(+) IVIG 1 month
(AAN/GBS/PCB) deviation, limb weakness
Limb weakness,
oMFS
1/F (−) (−) (−) (+) (+) dysphagia, hoarseness, (−) 8 (+)/(+) IVIG 1 month
(AAN/GBS/PCB)
hypertension
Tinnitus, uvula
oMFS (−)/no study Supportive
15/F H(B,ab) (−) (−) (+) (−) deviation, absent gag (−) 18 1 month
(MFS/PCB) result care
reflex
V(L),
AO 17/M (−) L (−) (−) Lower limb pain (−) 1 (+)/(−) IVIG 3 months
H(L)
cMFS = classic MFS; oMFS = overlapping MFS; GBS = Guillain-Barre syndrome; PCB = pharyngeal-cervical-brachial weakness; AAN = acute ataxic neuropathy; AO = acute
ophthalmoparesis; EO = external ophthalmoplegia; IO = internal ophthalmoplegia; Ab = antibodies; CSF = cerebrospinal fluid; NCS = nerve conduction study; B = bilateral; R = right eye;
L = left eye; ab = abduction limitation only; IVIG = intravenous immunoglobulin.
J. Clin. Med. 2020, 9, 3930 5 of 11

Table 2. Comparison between pediatric and adult Miller Fisher syndrome.

Pediatric (n = 11) Adult (n = 36) p-Value

Age of onset 9.8 ± 6.5 46.4 ± 16.9
Male:Female 5:6 22:14 0.4895
Preceding infection 11/11 (100%) 31/36 (86.1%) 0.3216
External ophthalmoplegia 9/11 (81.8%) 35/36 (97.2%) 0.1323
Internal ophthalmoplegia 3/11 (27.3%) 13/36 (36.1%) 0.7252
Unilateral:Bilateral 4:5 2:34 0.0103 *
Ataxia 10/11 (90.9%) 17/36 (47.2%) 0.0141 *
Areflexia 6/11 (54.5%) 31/36 (86.1%) 0.0394 *
Dysesthesia 5/11 (45.5%) 12/36 (33.3%) 0.4933
Multiple cranial nerve 3/11 (27.3%) 13/36 (36.1%) 0.7252
Limb weakness 3/11 (27.3%) 4/36 (11.1%) 0.3296
Autonomic symptoms 3/11 (27.3%) 1/36 (2.8%) 0.0352 *
Antiganglioside Antibody
2/9 a (22.2%) 25/35 a (71.4%) 0.0172 *
positivity
Albumin-cytologic dissociation in
7/11 (63.6%) 4/32 a (12.5%) 0.0022 *
CSF study
NCS abnormality 6/10 a (60.0%) 6/18 a (33.3%) 0.2425
Treatment
Supportive care 1/11 (9.1%) 8/36 (22.2%) 0.6631
IVIG only 8/11 (72.7%) 26/36 (72.2%) 1
IVIG + PP or systemic
2/11 (18.2%) b 2/36 (5.6%) c 0.2294
corticosteroid
Response to treatment
Within 1 month 8/11 (72.7%) 13/36 (36.1%) 0.0433 *
Within 3 months 11/11 (100%) 29/36 (80.6%) 0.1751
a.Statistics using the number of patients who were available for each test. b Two patients received IVIG + steroid.
c One patient received IVIG + steroid, and one patient received IVIG + plasmapheresis * p < 0.05, CSF = cerebrospinal
fluid; NCS = nerve conduction study; IVIG = intravenous immunoglobulin; PP = plasmapheresis.

3.3. Literature Review

No case–control or cohort studies on pediatric MFS are available in the literature.
Recently, Yoon et al. conducted a retrospective review of anti-GQ1b antibody syndrome in children,
but it relied on serologic diagnosis [8]. Otherwise, 53 pediatric cases of 41 case reports were found,
and the clinical characteristics of the reviewed cases are demonstrated in Table 3 [9–49]. Details of
individual cases were also available as supplement.

Table 3. Demographics of pediatric Miller Fisher syndrome in the literature, and its comparison with
pediatric MFS in our study.

Published Data (n = 53) Present Study (n = 11)

Age of onset 6.9 ± 4.2 9.8 ± 6.5
Male:Female 28:22 5:6
Preceding infection 45/53 (84.9%) 11/11 (100%)
External ophthalmoplegia 52/53 (98.1%) 9/11 (81.8%)
Internal ophthalmoplegia 21/53 (39.6%) 3/11 (27.3%)
Unilateral:Bilateral 9 a :44 4:5
Ataxia 39/53 (73.6%) 10/11 (90.9%)
Areflexia 41/53 (77.4%) 6/11 (54.5%)
Autonomic symptoms 7/53 (13.2%) 3/11 (27.3%)
Anti-GQ1b Antibody positivity 25/38 b (65.8%) 2/9 b (22.2%)
Antiganglioside Antibody
8/38 b (21.1%) 0/9 b (0%)
positivity rather than GQ1b c
J. Clin. Med. 2020, 9, 3930 6 of 11

Table 3. Cont.

Published Data (n = 53) Present Study (n = 11)

Albumin-cytologic dissociation in
18/49 b (36.7%) 7/11 (63.6%)
CSF study
NCS abnormality 13/31 b (41.9%) 6/10 b (60.0%)
Treatment
Supportive care 12/53 (22.6%) 1/11 (9.1%)
IVIG only 30/53 (56.6%) 8/11 (72.7%)
IVIG + PP or systemic
7/53 (13.2%) 2/11 (18.2%)
corticosteroid
Other treatments d 4/53 (7.5%) 0/11 (0%)
Response to treatment
Within 1 month 12/34 b (35.3%) 8/11 (72.7%)
Within 3 months 26/34 b (76.5%) 11/11 (100%)
a. Unilateral involvement at disease onset. b Statistics using the number of patients who were available for each test.
c GM, GD, GT antibody. d Only corticosteroid treatment (intravenous or oral).

4. Discussion
This retrospective comparative study showed that neuro-ophthalmic manifestations and disease
course of pediatric MFS were similar to those of adult MFS. Pediatric MFS patients had a good
prognosis; furthermore, pediatric MFS patients tended to recover faster than adult MFS patients.
However, there was a lower incidence of bilateral ocular manifestation at initial presentation among
pediatric MFS patients than among adult MFS patients. The presence of autonomic symptoms, such as
hypertension, tachycardia, and night sweating, was higher, and anti-GQ1b antibody positivity at the
time of diagnosis was lower in pediatric MFS than in adult MFS.
Preceding infection is an important clue for differential diagnosis in MFS. Koga et al. showed in
their case–control study that Campylobacter jejuni and Haemophilus influenzae infections were evident in
21% and 8% of MFS patients, respectively [50]. Berlit and Rakicky reported that 71.8% of MFS patients
had a preceding viral infection [51]. Yoon et al. demonstrated that in Korean pediatric MFS cases,
72.7% had a preceding infection, and the majority of them had gastrointestinal symptoms [8]. In the
literature review, 84.9% of patients had preceding illness, and upper respiratory infection was the
most common infection in pediatric patients (46.7%). Our study showed that 10 (90.9%) patients had
preceding gastrointestinal or upper respiratory symptoms. One patient developed MFS after an event of
ear pain with fever in this study. Similarly, unusual infections such as acute pyelonephritis, acute otitis
media, acute arthritis with viral infection, measles, and mumps were reported [15,27,36,37,40].
Interestingly, in this study, more pediatric MFS patients presented autonomic symptoms than did
adult patients. Previously, Malhotra et al. reported that three pediatric patients with MFS showed
hypertension [9]. They suggested a possible association between autonomic instability and MFS in
pediatrics. The literature review also revealed similar results: seven cases demonstrated autonomic
manifestations, primarily hypertension and tachycardia (13.2%, Table 3) [9,23,26,27]. Mori et al.
reported that 16% of adult MFS patients showed autonomic symptoms, but they were due to all
micturition disturbances [52]. Acute ophthalmoplegia combined with autonomic symptoms, such as
hypertension or tachycardia, could be helpful diagnostic clues for pediatric MFS.
In the clinical features of ophthalmoplegia, the prevalence of bilateral involvement at the initial
visit in pediatric patients was lower than that in adults. MFS has a progressive pattern in the early
phase; the pattern of ophthalmoplegia may therefore differ depending on the timing of diagnosis.
For instance, studies have shown six cases starting with unilateral external ophthalmoparesis and
then spreading bilaterally as the disease progressed [13,14,16,18,30,41]. The incidence of bilateral
involvement in MFS was expected to be part of the disease progression. We therefore infer that the
laterality may not be a distinctive feature of pediatric MFS. However, we would like to highlight that
J. Clin. Med. 2020, 9, 3930 7 of 11

progressive ophthalmoplegia after preceding infection could be a helpful feature for MFS diagnosis
in children.
Pediatric MFS patients had more ataxia than did adult MFS patients. There was no subtype
difference between pediatric and adult cases in our study, although most pediatric MFS patients had
the classic MFS. In general, pediatric patients have limitations in expressing their symptoms compared
to adult patients. Therefore, we suggest that it might be helpful to closely observe the obvious sign
ataxia in MFS diagnosis in pediatrics.
Serological, immunological, and pathological evidence showed the inconclusive role of anti-GQ1b
antibodies in MFS [53–56]. The positivity rate for anti-GQ1b antibodies has been reported as more
than 80% in MFS. Therefore, testing for antibodies has been considered as a shred of supportive
evidence for the diagnosis of MFS, especially in adult patients [52]. However, only 22.2% tested
positive for anti-GQ1b antibodies in our study. The literature review for pediatric MFS case reports
revealed that 25 out of 38 cases (65.8%) tested positive for anti-GQ1b antibodies (Table 3). From our
investigation and literature review, we postulated that the presence of anti-GQ1b antibodies is
lower among pediatrics than among adults. This discrepancy may be explained in the following
manner. First, the host-mimicking immune response to ganglioside epitopes may be different in
the pediatric group, especially in the early infantile group. In the literature review, only one case
presented ganglioside antibody among six patients aged under two years old who tested positive for
anti-GQ1b antibodies [9,12,18,19,31,49]. Second, the timing of antibody testing may yield different
results; anti-GQ1b IgG antibody titers peak at the onset of the disease, then decay rapidly during
the course of clinical recovery [57], eventually becoming undetectable as early as one month after
onset [58]. The timing of the testing can determine the sensitivity or specificity of the test results. In our
study, six (54.5%) patients had tested for anti-GQ1b antibody within three days of onset, but others
had delayed testing. We therefore suggest that anti-GQ1b antibody testing should be performed
immediately when MFS is suspected. On the other hand, anti-GQ1b testing may have a limited role in
the diagnosis of MFS in pediatrics compared to that in adults.
In this study, seven (63.6%) pediatric patients showed albumin-cytologic dissociation, and it was
much higher than that of adult patients. However, we supposed this finding had less meaning than
others because several studies reported albumin-cytologic dissociation in MFS, but the dissociation
ranged widely from 37% to 76% [55,59–62]. Furthermore, because normal cerebrospinal fluid protein
values decline over the first year of life, albumino-cytologic dissociation of pediatric group might be
overestimated [63–65].
MFS is generally regarded as a self-limiting, benign condition, and the limited epidemiological
evidence available supports this view. The median period between neurologic onset and the
disappearance of ataxia and ophthalmoplegia was one and three months, respectively [51,52].
However, this epidemiological evidence is based on data from adult patients. From the current
study, pediatric patients also had a good prognosis and similar outcome to adult patients group.
In addition, pediatric patients showed a higher percentage of complete recovery within one month
than did adult patients (p = 0.04).
Our study had some limitations. First, because of the retrospective nature of the study, we had
a relatively small number of subjects included as well as variable investigations, descriptions,
and follow-up. Second, ganglioside antibody was expressed in different forms, which can be of
diagnostic value in atypical MFS. Koga et al. demonstrated the possibility of other ganglioside
antibodies rather than GQ1b antibody in seronegative MFS patients [53]; however, we could not test
other antiganglioside antibody forms in all patients. Third, it has been reported that the intensity
of anti-GQ1b antibody correlated with disease activity [5]. Therefore, further studies for serial
antibody testing and other antiganglioside antibody testing can expand our understanding of this
unusual disease.
J. Clin. Med. 2020, 9, 3930 8 of 11

In summary, we observed that pediatric MFS shared many clinical characteristics with adult MFS
and had a good prognosis. However, pediatric MFS had several distinct features, accompanied by
autonomic symptoms such as hypertension and low positivity of anti-GQ1b antibody.

Supplementary Materials: The following are available online at http://www.mdpi.com/2077-0383/9/12/3930/s1,

Table S1: Published cases of pediatric Miller-Fisher syndrome.
Author Contributions: Conceptualization: J.H.J. Methodology: J.H.J., Y.J. Validation: Y.J., J.H.J., J.-H.C.
Formal analysis: Y.J., J.H.J. Investigation: Y.J., J.H.J., S.-J.K. Resources: J.H.J., S.-J.K., J.H.C., B.C.L. Data curation:
Y.J., J.-H.C. Writing—original draft preparation: Y.J., J.H.J. Writing—review & editing: J.H.J., S.-J.K., J.-H.C., J.H.C.,
B.C.L. Supervision: J.H.J., S.-J.K. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Acknowledgments: This research did not receive any specific grant from funding agencies in the public,
commercial, or not-for-profit sectors.
Conflicts of Interest: The authors declare no conflict of interest.

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