Acta Ophthalmologica 2016

Ophthalmological findings in children with

encephalitis

3 Rydberg Agneta1,2 and Wickstr
Hellgren Kerstin,1,2 Fowler Asa,
om Ronny1,3
1

Department of Neuropediatrics, Astrid Lindgren Childrens Hospital, Karolinska University Hospital, Stockholm, Sweden
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
3
Neuropediatric Unit, Department of Womens and Childrens Health, Karolinska Institutet, Stockholm, Sweden
2

ABSTRACT.
Purpose: To evaluate ophthalmological abnormalities in children with acute
encephalitis.
Methods: Thirty-six children included in a hospital-based prospectively and
consecutively collected cohort of children with acute encephalitis were investigated for ophthalmological abnormalities. The investigation included clinical
ophthalmological examination, fundus photography, neuro-ophthalmological
examinations as well as visual and stereo acuity. Results on laboratory
examinations, clinical findings, neuroimaging and electroencephalography registrations were recorded for all children.
Results: The median age was 4.0 years (Interquartile Range 1.99.8). The
aetiology was identified in 74% of cases. Three of 36 patients were found to have
abnormal ophthalmological findings related to the encephalitis. Transient sixth
nerve palsy was seen in a 15-year-old child and transient visual impairment was
seen in a 3.5-year-old child. Bilateral miosis and ptosis, i.e. autonomic nerve
system symptoms, were seen in an 11-month-old child, with herpes simplex 1 and
N-methyl-D-aspartate receptor antibody encephalitis. All three children recovered and improved their ophthalmological function with time.
Conclusion: Only 3 of 36 children were found to have ophthalmological
abnormalities due to encephalitis and they all improved with time. Thus,
ophthalmological consultation does not seem to fit in a screening programme for
childhood encephalitis but should be considered in selected cases.
Key words: central
come paediatric

nervous

system infection neurological ophthalmological

out-

Acta Ophthalmol.
2016 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd

doi: 10.1111/aos.13305

Introduction
Infections in the central nervous system
(CNS) are relatively uncommon but
potentially devastating.
The true incidence of encephalitis is
dicult to estimate due to dierences
in reporting systems, but the highest
incidence is seen in young children and
in the elderly. In the western world the
incidence of childhood encephalitis is

estimated to be 218/100.000 childyears (Koskiniemi et al. 1997; Clarke

et al. 2006; Thompson et al. 2012).
Encephalitis is often caused by
viruses such as herpes simplex virus
(HSV), enterovirus, varicella zoster
virus (VZV), inuenza virus or arthropod-borne viruses, e.g. tick-borne
encephalitis (TBE) virus or West Nile
virus, but cases due to bacteria, fungi
or autoimmune-mediated disease are

also seen. However, the aetiology often

remains unknown in up to 50% of the
cases. The symptoms of acute
encephalitis are similar in children
and adults with most cases presenting
with fever, headache and altered sensorium. Focal neurological symptoms
or seizures may also be present. The
long-term outcome after encephalitis in
childhood varies from death or severe
sequelae to full recovery. Predicting the
prognosis after encephalitis in childhood is dicult due to an often weak
relationship between the clinical picture in the acute phase and the prevalence of remaining sequelae (Fowler
et al. 2010; DuBray et al. 2013;
Michaeli et al. 2014). Some correlation
is seen with a worse outcome in agents
that cause necrosis or vasculitis, e.g.
HSV-1, but the individual variation in
a given aetiology is large.
Ophthalmological
complications
have been reported in association with
CNS infections and often seem to be
agent specic. Known ocular complications in, for instance, herpetic
viral infections include conjunctivitis,
dacryoadenitis, episcleritis, keratitis,
iritis and optic neuritis (Matoba 1990;
Chong et al. 2004). Ophthalmoplegia
and cranial nerve palsies have also
been documented in association with
encephalitis in a limited amount of
studies, and mostly in small case series
(Correll et al. 2015; Malcles et al.
2015). Ptosis and sixth nerve palsy
were reported in two cases with diagnosed encephalitis due to inuenza type
A (Migita et al. 2001). In a case series
of 24 patients with HSV caused brainstem encephalitis 81% had neuro-

Acta Ophthalmologica 2016

ophthalmological symptoms such as

abnormal ocular movements, nystagmus, anisocoria, ptosis, spasmodic
movements and oscillopsia (Livorsi
et al. 2010). Acute retinal necrosis is a
well-known and feared sight-threatening condition, which has been strongly
associated with HSV and in some cases
also to EpsteinBarr virus (EBV)
caused neuroinammation (Kim et al.
2011; Papageorgiou et al. 2014). However, few, if any, studies have described
ophthalmological ndings in a paediatric
population
with
clinical
encephalitis of unselected origins.
The purpose of this study was to
evaluate ophthalmological ndings at
illness onset in a hospital-based consecutively recruited population of children with encephalitis of various and
unselected aetiological origin.

Materials and Methods

Children aged 28 days to 16 years with
acute encephalitis and meningoencephalitis who were admitted to our
primary and tertiary care hospital in
northern Stockholm, between May
2011 and May 2013, were enrolled in
this study. The diagnosis of encephalitis was based on the following criteria:
(1) signs of cerebral dysfunction either
as (i) encephalopathy dened as altered
consciousness, personality or behavioural changes lasting for more than
24 hr, or (ii) abnormal electroencephalography (EEG) ndings compatible with encephalitis, plus at least one
of the following: abnormal results of
neuroimaging
compatible
with
encephalitis, positive focal neurological ndings or seizures. Cases with
abnormal EEG ndings compatible
with encephalitis but not showing
abnormalities on neuroimaging, focal
neurological ndings, seizures or
encephalopathy were classied as
meningoencephalitis. (2) Signs of
inammation, dened either as pleocytosis (6 white blood cells/ll), fever
(>38C) or elevated infectious parameters, C-reactive protein (CRP) and
white blood cells (WBC). Catarrhalia
was considered not to be sucient.
Children with another veried cause of
symptoms such as bacterial meningitis
or other underlying neurological or
metabolic disease that per se could
explain the symptoms were excluded.
Pure ataxia was not considered
sucient neurology for inclusion.

Demographic characteristics, clinical

signs and symptoms were recorded for
all children.
Blood and cerebrospinal uid
(CSF) were prospectively sampled
according to the study protocol as
well as when clinically motivated. All
children underwent routine laboratory
tests of serum at the time of admission including serology, CRP and
WBC. Antibody titres in blood were
analysed for Borrelia Burgdorferi and
TBE virus in all, and depending on
clinical symptoms some cases were
tested for enterovirus, adenovirus,
mycoplasma pneumoniae, HSV1 and
HSV2. Lumbar puncture (LP) was
performed during the acute phase
with routine analysis of the CSF,
including WBC, levels of protein,
glucose, lactate and microbiological
analyses. Microbiological analysis of
the CSF included bacterial culture
and virological tests for HSV1,
HSV2, VZV and enterovirus with
polymerase chain reaction (PCR)
and/or intrathecal antibody production. Depending on season and the
clinical picture, the CSF was also
tested for other aetiologies, such as
Borrelia Burgdorferi, human herpes
virus 6, parechovirus, cytomegalovirus
and EBV in some cases. Tests for
antibodies directed at neuronal antigens, such as N-methyl-D-aspartate
receptor (NMDAR) antibodies, were
not routinely done. However, in children where the initial aetiological
screening was negative and in whom
no clinical improvement was seen,
tests for neuronal antibodies were
considered. Nasopharyngeal aspirate
was tested for respiratory viruses
when respiratory symptoms were present. Faeces were analysed with PCR
for enterovirus and if gastrointestinal
symptoms were present most children
were also tested for norovirus, sapovirus and rotavirus. The detection of
a viral agent in the CSF or intrathecal
production of antibodies and the
presence of antibodies against TBE
virus in serum was dened as conrmed aetiologies, whereas other
agents found in blood, faeces or
nasopharynx were labelled as probable aetiologies.
In children who underwent neuroimaging, pathological changes compatible with encephalitis were recorded.
A computer tomography (CT) was
performed in 22/36 patients, whereas

magnetic resonance imaging (MRI)

was performed in 15/36.
All children included in the study
underwent an EEG examination within
the rst days of admission. Episodic or
continuous, focal or generalized, slow
activity (delta and/or theta) with or
without epileptiform discharges were
considered as EEG abnormalities compatible with encephalitis.
Visual acuity (VA) was evaluated
with age appropriate methods and
according to general health condition.
Monocular VA was measured when
possible. The youngest children were
assessed with the Teller Acuity Cards
(Teller 1979) and the Cardi Acuity
Test (Adoh & Woodhouse 1994;
Sharma et al. 2003). When these tests
were not possible to use, due to lack of
co-operation, the child0 s visual behaviour was assessed using coloured
sugar strands. For the preschool children, the HVOT or LH symbols were
used for evaluation of recognition acuity and, for school children, the KM
letter chart was used (Hedin et al.
1980; Hyvarinen et al. 1980; Moutakis
et al. 2004). All numerical values of VA
were transferred to decimal values,
according to the literature, to facilitate
comparisons (Rydberg et al. 1999;
Leone et al. 2014; Larsson et al. 2015).
Stereo acuity was assessed with the
Lang (I or II) or the TNO stereo test
(Ancona et al. 2014) and was dened
as present if at least one item was
identied, and absent if none was.
A thorough clinical examination of
the eyes was performed using slit
lamp and funduscopy. Fundus photography was taken when possible.
Neuro-ophthalmological examinations
included pupils, ocular motility, nystagmus and ocular alignment.
Ethical approval

This study was approved by the

local ethics committee (Dnr 2010/
1206-31/1).

Results
Thirty-six patients (26 girls and 10 boys)
who fullled the inclusion criteria underwent ophthalmological examinations on
at least one occasion at the time of onset.
Median age at rst examination was
4.0 years (interquartile range 1.99.8,
distribution in years and gender is
shown in Fig. 1).

Acta Ophthalmologica 2016

5
Female
Male
4

and abnormal movements on the right

side progressing into oral and trunchal
choreoathetosis together with behavioural changes.
Neuroimaging and EEG

0
<1 1

10 11 12 13 14 15 16 17

Fig. 1. Gender distribution and age in years at rst ophthalmological examination. y-axis
represents number of children, x-axis represents age in years.

Clinical characteristics

Aetiology

Thirty-one children fullled the criteria

of encephalitis and ve children were
classied as meningoencephalitis.
Encephalopathy lasting for more
than 24 hr in the acute phase was seen
in 20 children, in ve children a
changed sensorium was noted but it
was not considered to be severe enough
to be dened as encephalopathy or not
lasting for more than 24 hr, and they
were thus classied as meningoencephalitis. Twenty-four children had a
history of, or presented with, fever.
Headache was present in 16 children
old enough to verbalize this symptom.
Nausea, vomiting or diarrhoea was
seen in 19 children.
Pleocytosis in CSF was seen in 22/36
children. In most cases there was a
mononuclear predominance, but in ve
children a polynuclear dominance was
seen [enterovirus (1), TBE (2), inuenza B (1) and unknown (1)]. Five
children underwent a second LP during
the acute phase and, in four of them,
the number of cells in the CSF had
increased. The average number of cells
in CSF was 95 WBC/ll (range 8830).
The albumin level in CSF was
increased in 11 children ranging from
256 to 960 mg/l (<220 mg/l).
In a few children the opening pressure was measured during the LP and it
was noted to be increased in three,
ranging from 3055 cm H20 (<20 cm
H2O).

In 25/36 patients a plausible aetiological agent was found. In nine of these

cases the aetiology was considered as
conrmed [enterovirus by PCR in CSF
(1), TBE ab in serum (5), EBV by PCR
in CSF (1) and NMDAR antibodies
(2)]. In one case the encephalitis was a
manifestation during Kawasakis disease. In the remaining 15 cases the
aetiology was found outside the CSF
and regarded as a possible causes:
rotavirus in faeces (6), inuenza B virus
in NPH (2), enterovirus in faeces (3),
norovirus in faeces (1), sapovirus in
faeces (1), HSV1 in serum with PCR
with a switch from IgM to IgG ab0 s in
convalescent sera (1) and mykoplasma
pneumonia antibodies in serum (1). In
one child the encephalitis was a manifestation during Hashimotos disease.
Neurological findings

Seizures during the acute phase were

seen in 19/36 (53%) children, with ve
presenting with status epilepticus.
Focal neurological ndings were seen
in 13 children with balance disturbances being the most frequent symptom found in eight cases. Ataxia,
dysphasia, unilateral sixth nerve palsy,
transient weakness of left side and
hallucinations were other symptoms
present in one child each. Furthermore,
one child, described more in detail below,
showed abnormal tongue movements

Neuroimaging was performed in 23

children with abnormal results in four
children. An abnormal CT scan was
seen in two children, and both also had
a pathological MRI scan. In total, four
children had a pathological MRI picture compatible with encephalitis.
All children had an EEG recording
performed during the acute phase, 30
of which showed abnormalities compatible with encephalopathy. In two
cases the EEG recording was considered inconclusive due to sedation or
being performed during a postictal
phase thus making interpretation dicult. Four children had a normal EEG
recording.
Ophthalmological findings

In 28 of the 36 (78%) subjects VA was

obtained at rst visit. Of those, 20
provided monocular VA of both eyes
and eight were evaluated binocularly.
In seven subjects VA was obtained
later during the clinical course or at
discharge. In one subject, no VA was
evaluated. Three toddlers were only
evaluated with qualitative measurements, i.e. picking sugar strands, one
of which at rst visit and monocularly
and the other two at discharge and
binocularly. Best VA in association
with age at onset and at discharge is
shown in Fig. 2. VA was found subnormal in three cases. One of these
three cases, a 3.5-year-old boy,
(marked as a black diamond in Fig. 2
and presented as Case 1, see below),
infected with rota virus, had impaired
consciousness at rst visit and showed
decreased VA on rst examination,
without any other ocular pathology.
His VA was improving and found
normal on last follow-up. The second
case, a 3.9-year-old girl (marked as
a black triangle in Fig. 2 and presented as Case 2 below), was found to
have previously undetected signicant refractive errors (hypermetropia)
unrelated to the encephalitis. She also
had esotropia and decient stereo acuity. The third case, a 12-year-old girl,
was wearing contact lenses and had
known aniso-myopia and amblyopia in

Acta Ophthalmologica 2016

1.25

1.25

1.00

1.00

0.75

0.75

0.50

0.50

0.25

0.25
0

5
10
15
Examination age in years at onset

20

5
10
15
Examination age in years at discharge

20

Fig. 2. Visual acuity (decimal values) in the study group (n = 36) related to age at onset (left
graph; n = 27) and at discharge (right graph; n = 32). y-axis represents best visual acuity in
decimal values and x-axis represents age in years. Black diamond is indicating a 3.5-year-old boy
with rota-positive encephalitis and impaired visual acuity at onset but improving with time,
presented as Case 1. Black triangle is indicating a 3.9-year-old girl with inuenza b encephalitis
and undiagnosed refractive errors with secondary previously undiagnosed esotropia, presented as
Case 2. Three toddlers did not provide numerical values and are not included in the graphs. In one
subject visual acuity was never assessed.

her right eye. Compared to previous

examinations, before the encephalitis,
her VA was unchanged, in both eyes.
Twenty-ve subjects (67%) had normal
or near-normal VA according to age on
rst visit. In eight patients initial examination of VA was impossible because
of impaired consciousness or health
status. Seven of them had normal or
near-normal VA on second visit, of
which two toddlers did not co-operate
enough to produce numerical VA but
showed age normal visual behaviour.
As stated above, one subject was never
assessed for VA, but had otherwise
normal neuro-ophthalmological ndings on examination. This was a boy
of 15 years who had too severe headache at onset to perform a VA test, and
never returned to planned controls, but
reported full VA on telephone.
Stereo acuity was present in 24
subjects, absent in two subjects and
not evaluated, due to lack of cooperation, in 10 subjects. Clinical data
of all 36 subjects are presented in
Table 1.
Ocular motility was found to be
abnormal in three cases. One 15-yearold boy, (see Case 3 below), with
encephalitis of unknown aetiological
agent, had a transient, isolated sixth
nerve palsy, which resolved completely. One almost 4-year-old girl
(see Case 2 below) had a previously
undiagnosed intermittent esotropia,
most likely due to severe bilateral
hypermetropia. One girl of 11 months

(see Case 4 below) with impaired

consciousness had initially bilateral
miosis and subsequently, on second
exam, bilateral ptosis, symptoms
which are in accordance with brainstem encephalitis. She suered from
encephalitis caused by HSV-1 and
later developed an anti-NMDAR
encephalitis which has been described
previously (Wickstr
om et al. 2014).
No patient had signs of ocular
inammation such as keratitis, conjunctivitis, uveitis or retinitis. No one
had papillary oedema.
Case presentations
Case 1

A 3.5-year-old boy, previously healthy,

arrived at the hospital with a history of
gastroenteritis symptoms, i.e. vomiting,
diarrhoea and fever for 3 days. His
behaviour was altered and he was
easily agitated and at bad ease. On
the way to the hospital, there was a
sudden onset of seizures and decreased
consciousness. At the hospital additional symptoms were noticed including unsynchronized and asymmetrical
movements of extremities. Acute CT
brain scan showed slight general
oedema and EEG showed a pattern
compatible with encephalitis. No virus
was found in CSF but faeces were
positive for rota- and sapovirus. At
rst ophthalmological visit he was
restless and overactive and co-operated
moderately. VA was 0.16 and 0.2 in his

right and left eye, respectively, and

binocular VA was 0.25 with LH symbols. Stereo acuity was absent. The
ophthalmological examination was
otherwise normal, see fundus photographs of right and left eyes in Fig. 3.
On follow-up visit 4 months later,
binocular VA was 0.5 and on 1 year
follow-up had improved to 1.0 (monocular VA 0.9 on both eyes). Stereo
acuity normalized. There was no other
abnormal ophthalmological nding
during the course.
Case 2

A 3.9-year-old girl had a sudden onset

of seizures and unconsciousness after a
short fever episode. Acute CT brain
scan was normal. EEG showed abnormal, generally slow activity compatible
with encephalitis. Tracheal specimen
revealed inuenza B. At rst ophthalmological visit she was found to be
highly hyperopic in both eyes (+6.75
spherical equivalent) and had an
accommodative
right
convergent
squint. Visual acuity (VA) of right
and left eye was 0.25 and 0.4, respectively. She had no ocular palsy or other
neuro-ophthalmological
pathology.
She had a history of intermittent
untreated esotropia. On 2 months follow-up, wearing the prescribed glasses,
her distance VA had improved to 0.4
and 0.65 on her right and left eye,
respectively, and to 0,8 binocularly at
near. There was no strabismus with
correction, although stereo acuity was
still only partially positive.
Case 3

A 15-year-old, previously healthy boy,

was referred to the hospital from the
general practitioner with suspected
meningoencephalitis. He had a 2 weeks
history of reoccurring fever, nausea,
vomiting and headache. Two days
before arrival to the hospital he had
developed double vision, which persisted. He was otherwise unaected.
CSF analysis revealed 86 monocytes/ll
and albumin 353 mg/l. Opening
intracranial pressure during LP was
increased to 42 cm H2O. MRI and CT
brain scans were normal. EEG was
pathological and encephalitis suspect.
The ophthalmological examination
showed a convergent squint and a right
sixth nerve palsy, but otherwise a
normal ophthalmological examination
with normal VA 1.0 in both eyes with
his own glasses. He was slightly

Acta Ophthalmologica 2016

Table 1. Clinical data of the study group.

Case

Agents

Gender

Age at
onset
Years:
months

Rota- and
Sapovirus

03:07

0.16

0.2

2
3
4

F
M
F

03:11
15:10
00:11

0.25
1

5
6
7
8
9
10
11
12
13

Inuenza B
Unknown
HSV and
NMDAR ab
Enterovirus
Unknown
Unknown
Mykoplasma
Unknown
EBV
Unknown
NMDAR ab
Rotavirus

F
M
F
F
M
F
F
F
F

06:05
06:05
02:03
02:05
11:06
16:00
16:11
07:11
01:11

14
15

Rotavirus
Enterovirus

M
F

02:11
01:09

16
17

F
F

07:08
09:03

18
19

TBE
Unknown
(Hashimoto)
Rotavirus
Inuenza B

F
F

03:00
02:03

0.63

20
21
22
23
24

TBE+Borrelia
Rotavirus
Unknown
Norovirus
Unknown

F
M
F
F
F

03:11
00:10
12:03
01:09
15:11

0.63

25
26
27

F
F
M

04:04
06:09
03:09

28
29

Rotavirus
TBE
Unknown
(Kawasaki)
Unknown
Sapovirus

M
F

15:03
01:06

30
31
32
33
34

TBE
Enterovirus
Rotavirus
Enterovirus
Unknown

M
F
F
M
F

06:04
00:05
00:11
04:00
01:08

0.4

0.63

0.5

LH linear

35
36

TBE
EBV

F
F

12:04
12:09

1
1.3

1
1.3

KM
KM

VA RE

VA LE

VA Binoc

Method

Stereo

Neurological signs

CT/MRI

LH linear

Neg

0.4
1

LH linear
KM

Neg
550

Visual impair, seizures,

balance problems,
hallucinations
Seizures, esotropia
Sixth nerve palsy
Ptosis, miosis, seizures

1
1
0.63

1
1
0.63

60
60

KM
HVOT
Cardi
LH single
KM

Seizures
Ataxia
Seizures
Seizures
Seizures

KM

N
N
N
Abn
N
N
N

0.25

0.4

LH at near

200
30
15
550
60
200

0.65
16 c/d (appr 0.5)

LH single
TAC

550
550

KM
TAC

Pos

27c/d (appr 0.9)

0,63

LH linear
Cardi

550
550

0.63

LH linear

200

0.3

0.8

KM

KM

550

0.8
1

0.8
1

LH linear
KM
LH linear

200
550
550

Cardi (TAC)

550

0.5

0.63

Seizures, dysphasia
Seizures, balance
problems
Balance problems
Seizures, balance
problems
Seizures
Seizures
Seizures, balance
problems

N
N
Abn

N
N
N
Abn
N
N

Truncal instability

0.63

0.63 (6c/d)
0.4

0.8

LH linear
600
550
550

Seizures, weakness
left side

Seizures, balance
problems
Balance problems
Seizures
Seizures
Seizures
Seizures, balance
problems

N
N

N
N
N

550
Seizures

Abn

HSV = herpes simplex virus, NMDAR = N-methyl-D-aspartate receptor, ab = antibodies, EBV = EpsteinBarr virus, TBE = tick-borne encephalitis, m = male, f = female, VA = Visual acuity, RE = right eye, LE = left eye, Binoc = binocular, c/d = cycles per degree, TAC = Teller acuity cards,
neg = negative, pos = positive, visual impair = visual impairment, CT = Computer tomography of the brain, MRI = Magnetic resonance imaging of
the brain, N = normal, Abn = abnormal ndings.

myopic. Fundus photographs are

shown in Fig. 4. He received oral
carbanhydrase-inhibitor
(Diamox)
treatment and recovered fast. The sixth
nerve palsy had regressed completely
on 1 month follow-up, with no remaining strabismus and a positive stereo
acuity. The aetiology to the encephalitis remained unknown.

Case 4

A previously healthy girl of 11 months

was admitted to the hospital because of
generalized seizures preceded by gastroenteritis symptoms and high fever.
Initial CT brain scan was normal. EEG
showed left-sided slow activity with
spikes and sharp waves. CSF analysis
revealed a monocytic pleocytosis (24

monocytes/ll). Results from PCR of the

CSF were positive for HSV1. The rst
ophthalmological examination on day 2
revealed bilateral miosis and a sluggish
pupillary reaction to light. No nystagmus, palsy or other ocular motor dysfunction was noted and fundus
examination was normal. Due to motor
anxiety and lowered consciousness she

Acta Ophthalmologica 2016

Fig. 3. Fundus photographs of right eye (left picture) and left eye (right picture) of Case 1.
Considered normal.

Fig. 4. Fundus photographs of right eye (left) and left eye (right) of CASE 3. Considered normal.

could not participate in VA testing. On

days 45 she showed increasing irritability. CSF 1 week later was still
pleocytic but HSV negative. There
was a slight clinical improvement during the following days. However,
2 weeks later the symptoms progressed
with fever, aggressive behaviour in
combination with oral and truncal
choreoathetosis and dystonia. Ophthalmological examination showed
bilateral complete ptosis. With manual
holding of eyelids she followed a torch
light with both eyes and there was still
miosis. No abnormal eye movements
or nystagmus was seen and the eyes
were parallel. VA testing was not
possible to assess but there was no
fundus pathology. A CT scan showed
changes consistent with necrosis due to
herpes encephalitis. Subsequent analysis of serum and CSF conrmed a conversion into positive titres of NMDAR
antibodies most likely triggered by the
viral infection. She was put under
corticosteroid treatment. Ophthalmologic examination 3 months later
showed age-normal VA (7.9 cycles/

degree), no ocular motor dysfunction

or abnormality and still normal fundi.
The clinical characteristics without
ophthalmological ndings have been
described previously (Wickstr
om et al.
2014).

Discussion
In this hospital-based study of a consecutively recruited paediatric cohort
with clinical encephalitis symptoms
we found few ophthalmological abnormalities at presentation. Of 36 patients,
there were three cases who displayed
dierent neuro-ophthalmological symptoms, related to the encephalitis.
The symptoms of encephalitis are
similar in adults and children. However, the initial symptoms may be
vague and young children often have
more subtle symptoms and CNS aection is not always readily noticed.
Encephalitis may, therefore, be overlooked early in the disease. Indeed, a
prompt start of antibacterial and
antiviral treatment, which may aect
outcome, is complicated by the often

unspecic and very common nature of

symptoms such as fever, headache,
nausea and lethargy (Fowler et al.
2008; Thompson et al. 2012). The outcome after encephalitis in children
varies from full recovery to death or
severe sequelae. As previously shown in
adults, neuropsychological sequelae are
also often observed following CNS
infections in children.
In a previous retrospective study of a
paediatric population with clinically
diagnosed encephalitis, it was shown
that the children displayed persisting
sequels at discharge for which the
strongest predictive factor was focal
neurological ndings at presentation
(Fowler et al. 2008). However, ophthalmological symptoms were not
investigated.
The ophthalmological examinations
in this study were obviously dependent
on the health status and consciousness
of the patients. VA was possible to
evaluate at an early time point in 78%
(28/36) of the patients and visual
impairment at onset was rare. One
boy, with plausible rota viruscaused
encephalitis, displayed a transient mild
visual impairment, which recovered
within a short time span. There was
no sign of ocular inammation, optic
disc abnormality or retinal necrosis.
His co-operation during the examination improved with his clinical recovery, which probably had a signicant
impact on the VA test performance. In
two cases refractive errors were the far
most likely reason to the subnormal
VA, which hence was to be regarded as
incidental ndings.
In previous studies, optic nerve
inammation has been described as a
cause of visual deterioration in
encephalitis (Gore et al. 2007; Bae
et al. 2011). Acute retinal necrosis is a
rare and devastating condition, causing
permanent visual loss that has been
associated with herpetic encephalitis
and, also, in rare cases with EBV
infections (Vandercam et al. 2008;
Kim et al. 2011). In our cohort there
were two cases with possible herpetic
aetiology and none of them had retinal
involvement.
Ocular motor involvement has been
frequently described in patients with
encephalitis. In this study there was
only one case, with isolated transient
sixth nerve palsy. In that particular
case, the intracranial pressure was
increased and treated, and the palsy

Acta Ophthalmologica 2016

resolved quickly thereafter. This suggests that the cause was the increased
intracranial pressure and not necessarily the encephalitis per se. In one other
case, an accommodative esotropia was
found accidently and without any ocular palsy.
Isolated sixth nerve palsy is the most
common form of cranial nerve palsies
encountered in young patients at
neuro-ophthalmology clinics (Menon
et al. 1984). In most cases its origin
remains unknown and the prognosis
benign, although recurrence is common
(Menon et al. 1984; Jukes 2014).
Known causes to isolated sixth nerve
palsy include Lyme neuroborreliosis,
idiopathic intracranial hypertension,
vasculitis, post-head trauma, CNS
tumours, myasthenia gravis and postvaccination against, e.g. inuenza and
haemophilus inuenza among others
(Kosker et al. 2014; Sharma et al.
2014; Woo et al. 2014; Correll et al.
2015; Paley et al. 2015). Nandi and
Biswas described one 7-year-old boy
with bilateral isolated sixth nerve palsy
and EBV mononucleosis without any
sign of encephalitis (Nandi & Biswas
2014).
In our study one 11-month-old girl
displayed a two-phase clinical course,
which was shown to be caused by HSV
encephalitis and a subsequent conversion into anti-NMDAR encephalitis
(Wickstr
om et al. 2014). Initially there
was bilateral miosis associated with
decreased consciousness and later on
development of bilateral ptosis and
general irritability. There was no other
ocular motor involvement. Bilateral
miosis, regarded as a sign of autonomic
nerve system involvement, might have
been preceding the clinical symptoms
of brainstem encephalitis in her case.
In children with anti-NMDAR
encephalitis, symptoms of abnormal
behaviour, speech disturbance, seizures
and movement disorder seem to predominate (Goldberg et al. 2014). However, reports of ophthalmological
symptoms are rare. Outteryck and coworkers have described a case of a
65-year-old
woman,
with
antiNMDAR encephalitis (Outteryck et al.
2013). She had no subjective visual
disturbances but optical coherence
tomography imaging of the optic nerve
head, as well as neurophysiological
examination of visual function (visualevoked potentials) showed signs of
asymptomatic optic neuritis.

In our study of an unselected Swedish paediatric cohort with encephalitis,

a wide distribution of dierent aetiological agents was seen. There are,
however, few studies with a similar
design and comparisons are, therefore,
dicult to make. In this study TBE was
the most frequently conrmed aetiological agent and in none of these cases
ophthalmological abnormalities were
found.
EpsteinBarr virus (EBV) infections
are known to cause ocular complications
including conjunctivitis, dacryoadenitis,
episcleritis, keratitis, iritis and optic
neuritis. Ophthalmoplegia and cranial
nerve palsies have also been reported
(Kim et al. 2011). In this study there was
one case with EBV-associated encephalitis, which had no ophthalmological
symptoms.
One advantage with this study is the
epidemiological, multidisciplinary and
prospective design. The results are
also representing a population-based
cohort, rather than describing patients
in a referral centre with the obvious
risk of a biased selection. However, one
limitation is the relatively small cohort,
which yields few cases in each aetiological agent group. Another limitation
is not having included neurophysiological evaluations of visual function,
which possibly could have revealed
more subtle functional abnormalities.

Conclusion
Ophthalmological abnormalities at
clinical presentation were few and
encephalitis did not seem to have any
permanent negative eect on the ophthalmological outcome. Hence, ophthalmological consultation does not
seem to t in a screening programme
of children with encephalitis, but
should be considered in selected cases.

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Received on March 24th, 2016.

Accepted on September 25th, 2016.
Correspondence:
Hellgren Kerstin
Department of Neuropediatrics
Astrid Lindgren Childrens Hospital
Karolinska University Hospital, Solna
S-171 76 Stockholm
Sweden
Tel: +468-517 77752
Fax: +468-672 3330
Email: [email protected]
Financial support without any role in the design
and conduct of this study was obtained from
Stockholm County Council, IKEA Foundation,
The Jerring Foundation, Linnea & Josef Carlsson0 s
Foundation and Sigvard & Marianne Bernadotte
Research Foundation for Children Eye Care.
The authors thank Jessica Widegren for nding
eligible patients, and Lena Jacobson, Ulrika Liden
and Lena Falkman for help in examining the
patients.