Acta Ophthalmologica 2017

Ophthalmological findings in children with

encephalitis

Fowler,3 Agneta Rydberg1,2 and Ronny Wickstr€
Kerstin Hellgren,1,2 Asa om1,3
1
Department of Neuropediatrics, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden
2
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
3
Neuropediatric Unit, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden

ABSTRACT.
also seen. However, the aetiology often
Purpose: To evaluate ophthalmological abnormalities in children with acute
remains unknown in up to 50% of the
encephalitis.
cases. The symptoms of acute
Methods: Thirty-six children included in a hospital-based prospectively and encephalitis are similar in children
consecutively collected cohort of children with acute encephalitis were investi- and adults with most cases presenting
gated for ophthalmological abnormalities. The investigation included clinical with fever, headache and altered sen-
ophthalmological examination, fundus photography, neuro-ophthalmological sorium. Focal neurological symptoms
examinations as well as visual and stereo acuity. Results on laboratory or seizures may also be present. The
examinations, clinical findings, neuroimaging and electroencephalography reg- long-term outcome after encephalitis in
istrations were recorded for all children. childhood varies from death or severe
Results: The median age was 4.0 years (Interquartile Range 1.9–9.8). The sequelae to full recovery. Predicting the
aetiology was identified in 74% of cases. Three of 36 patients were found to have prognosis after encephalitis in child-
abnormal ophthalmological findings related to the encephalitis. Transient sixth hood is difficult due to an often weak
nerve palsy was seen in a 15-year-old child and transient visual impairment was relationship between the clinical pic-
seen in a 3.5-year-old child. Bilateral miosis and ptosis, i.e. autonomic nerve ture in the acute phase and the preva-
system symptoms, were seen in an 11-month-old child, with herpes simplex 1 and lence of remaining sequelae (Fowler
et al. 2010; DuBray et al. 2013;
N-methyl-D-aspartate receptor antibody encephalitis. All three children recov-
Michaeli et al. 2014). Some correlation
ered and improved their ophthalmological function with time.
is seen with a worse outcome in agents
Conclusion: Only 3 of 36 children were found to have ophthalmological that cause necrosis or vasculitis, e.g.
abnormalities due to encephalitis and they all improved with time. Thus, HSV-1, but the individual variation in
ophthalmological consultation does not seem to fit in a screening programme for a given aetiology is large.
childhood encephalitis but should be considered in selected cases. Ophthalmological complications
have been reported in association with
Key words: central nervous system – infection – neurological – ophthalmological out- CNS infections and often seem to be
come – paediatric agent specific. Known ocular com-
plications in, for instance, herpetic
Acta Ophthalmol. 2017: 95: 66–73 viral infections include conjunctivitis,
ª 2016 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd dacryoadenitis, episcleritis, keratitis,
iritis and optic neuritis (Matoba 1990;
doi: 10.1111/aos.13305
Chong et al. 2004). Ophthalmoplegia
estimated to be 2–18/100.000 child- and cranial nerve palsies have also
Introduction years (Koskiniemi et al. 1997; Clarke been documented in association with
Infections in the central nervous system et al. 2006; Thompson et al. 2012). encephalitis in a limited amount of
(CNS) are relatively uncommon but Encephalitis is often caused by studies, and mostly in small case series
potentially devastating. viruses such as herpes simplex virus (Correll et al. 2015; Malcles et al.
The true incidence of encephalitis is (HSV), enterovirus, varicella zoster 2015). Ptosis and sixth nerve palsy
difficult to estimate due to differences virus (VZV), influenza virus or arthro- were reported in two cases with diag-
in reporting systems, but the highest pod-borne viruses, e.g. tick-borne nosed encephalitis due to influenza type
incidence is seen in young children and encephalitis (TBE) virus or West Nile A (Migita et al. 2001). In a case series
in the elderly. In the western world the virus, but cases due to bacteria, fungi of 24 patients with HSV caused brain-
incidence of childhood encephalitis is or autoimmune-mediated disease are stem encephalitis 81% had neuro-

66

ophthalmological symptoms such as
abnormal ocular movements, nystag-
mus, anisocoria, ptosis, spasmodic
movements and oscillopsia (Livorsi
et al. 2010). Acute retinal necrosis is a
well-known and feared sight-threaten-
ing condition, which has been strongly
associated with HSV and in some cases
also to Epstein–Barr virus (EBV)
caused neuroinflammation (Kim et al.
2011; Papageorgiou et al. 2014). How-
ever, few, if any, studies have described
ophthalmological findings in a paedi-
atric population with clinical
encephalitis of unselected origins.
The purpose of this study was to
evaluate ophthalmological findings at
illness onset in a hospital-based con-
secutively recruited population of chil-
dren with encephalitis of various and
unselected aetiological origin.
Materials and Methods
Children aged 28 days to 16 years with
acute encephalitis and meningoen-
cephalitis 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 encephali-
tis was based on the following criteria:
(1) signs of cerebral dysfunction either
as (i) encephalopathy defined as altered
consciousness, personality or beha-
vioural changes lasting for more than
24 hr, or (ii) abnormal electroen-
cephalography (EEG) findings compat-
ible with encephalitis, plus at least one
of the following: abnormal results of
neuroimaging compatible with
encephalitis, positive focal neurologi-
cal findings or seizures. Cases with
abnormal EEG findings compatible
with encephalitis but not showing
abnormalities on neuroimaging, focal
neurological findings, seizures or
encephalopathy were classified as
meningoencephalitis. (2) Signs of
inflammation, defined either as pleocy-
tosis (≥6 white blood cells/ll), fever
(>38°C) or elevated infectious parame-
ters, C-reactive protein (CRP) and
white blood cells (WBC). Catarrhalia
was considered not to be sufficient.
Children with another verified 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
sufficient neurology for inclusion.
Demographic characteristics, clinical
signs and symptoms were recorded for
all children.
Blood and cerebrospinal fluid
(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 admis-
sion 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 produc-
tion. 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 anti-
gens, such as N-methyl-D-aspartate
receptor (NMDAR) antibodies, were
not routinely done. However, in chil-
dren 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 pre-
sent. Faeces were analysed with PCR
for enterovirus and if gastrointestinal
symptoms were present most children
were also tested for norovirus, sapo-
virus 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 defined as con-
firmed aetiologies, whereas other
agents found in blood, faeces or
nasopharynx were labelled as proba-
ble aetiologies.
In children who underwent neu-
roimaging, pathological changes com-
patible with encephalitis were recorded.
A computer tomography (CT) was
performed in 22/36 patients, whereas
Acta Ophthalmologica 2017
magnetic resonance imaging (MRI)
was performed in 15/36.
All children included in the study
underwent an EEG examination within
the first 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 com-
patible 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 Cardiff 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 beha-
viour was assessed using coloured
sugar strands. For the preschool chil-
dren, the HVOT or LH symbols were
used for evaluation of recognition acu-
ity 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 defined
as present if at least one item was
identified, and absent if none was.
A thorough clinical examination of
the eyes was performed using slit
lamp and funduscopy. Fundus photog-
raphy was taken when possible.
Neuro-ophthalmological examinations
included pupils, ocular motility, nys-
tagmus 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 fulfilled the inclusion criteria under-
went ophthalmological examinations on
at least one occasion at the time of onset.
Median age at first examination was
4.0 years (interquartile range 1.9–9.8,
distribution in years and gender is
shown in Fig. 1).
67
Acta Ophthalmologica 2017
5 and abnormal movements on the right
4
3 Neuroimaging was performed in 23
2
1 All children had an EEG recording
0
<1 1 2 3 4 5 6 7
Fig. 1. Gender distribution and age in years at first ophthalmological examination. y-axis
represents number of children, x-axis represents age in years.
Clinical characteristics
Thirty-one children fulfilled the criteria
of encephalitis and five children were
classified as meningoencephalitis.
Encephalopathy lasting for more
than 24 hr in the acute phase was seen
in 20 children, in five children a
changed sensorium was noted but it
was not considered to be severe enough
to be defined as encephalopathy or not
lasting for more than 24 hr, and they
were thus classified as meningoen-
cephalitis. 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 five
children a polynuclear dominance was
seen [enterovirus (1), TBE (2), influ-
enza 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 8–830).
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 pres-
sure was measured during the LP and it
was noted to be increased in three,
ranging from 30–55 cm H20 (<20 cm
H2O).
68
Female
Male
8 9 10 11 12 13 14 15 16 17
Aetiology
In 25/36 patients a plausible aetiolog-
ical agent was found. In nine of these
cases the aetiology was considered as
confirmed [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 Kawasaki’s dis-
ease. In the remaining 15 cases the
aetiology was found outside the CSF
and regarded as a possible causes:
rotavirus in faeces (6), influenza 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 man-
ifestation during Hashimotos disease.
Neurological findings
Seizures during the acute phase were
seen in 19/36 (53%) children, with five
presenting with status epilepticus.
Focal neurological findings were seen
in 13 children with balance distur-
bances being the most frequent symp-
tom 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
side progressing into oral and trunchal
choreoathetosis together with beha-
vioural changes.
Neuroimaging and EEG
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 pic-
ture compatible with encephalitis.
performed during the acute phase, 30
of which showed abnormalities com-
patible with encephalopathy. In two
cases the EEG recording was consid-
ered inconclusive due to sedation or
being performed during a postictal
phase thus making interpretation diffi-
cult. Four children had a normal EEG
recording.
Ophthalmological findings
In 28 of the 36 (78%) subjects VA was
obtained at first 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 measure-
ments, i.e. picking sugar strands, one
of which at first 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 sub-
normal 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 first visit and showed
decreased VA on first 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 pre-
sented as Case 2 below), was found to
have previously undetected signifi-
cant refractive errors (hypermetropia)
unrelated to the encephalitis. She also
had esotropia and deficient stereo acu-
ity. The third case, a 12-year-old girl,
was wearing contact lenses and had
known aniso-myopia and amblyopia in
 Acta Ophthalmologica 2017

right and left eye, respectively, and

binocular VA was 0.25 with LH sym-
1.25 1.25
bols. Stereo acuity was absent. The
ophthalmological examination was
1.00 1.00 otherwise normal, see fundus pho-
tographs of right and left eyes in Fig. 3.
0.75 0.75 On follow-up visit 4 months later,
binocular VA was 0.5 and on 1 year
0.50 0.50
follow-up had improved to 1.0 (monoc-
ular VA 0.9 on both eyes). Stereo
acuity normalized. There was no other
0.25 0.25
abnormal ophthalmological finding
0 5 10 15 20 0 5 10 15 20 during the course.
Examination age in years at onset Examination age in years at discharge
Case 2
Fig. 2. Visual acuity (decimal values) in the study group (n = 36) related to age at onset (left A 3.9-year-old girl had a sudden onset
graph; n = 27) and at discharge (right graph; n = 32). y-axis represents best visual acuity in
of seizures and unconsciousness after a
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,
short fever episode. Acute CT brain
presented as Case 1. Black triangle is indicating a 3.9-year-old girl with influenza b encephalitis scan was normal. EEG showed abnor-
and undiagnosed refractive errors with secondary previously undiagnosed esotropia, presented as mal, generally slow activity compatible
Case 2. Three toddlers did not provide numerical values and are not included in the graphs. In one with encephalitis. Tracheal specimen
subject visual acuity was never assessed. revealed influenza B. At first ophthal-
mological visit she was found to be
highly hyperopic in both eyes (+6.75
her right eye. Compared to previous (see Case 4 below) with impaired spherical equivalent) and had an
examinations, before the encephalitis, consciousness had initially bilateral accommodative right convergent
her VA was unchanged, in both eyes. miosis and subsequently, on second squint. Visual acuity (VA) of right
Twenty-five subjects (67%) had normal exam, bilateral ptosis, symptoms and left eye was 0.25 and 0.4, respec-
or near-normal VA according to age on which are in accordance with brain- tively. She had no ocular palsy or other
first visit. In eight patients initial exam- stem encephalitis. She suffered from neuro-ophthalmological pathology.
ination of VA was impossible because encephalitis caused by HSV-1 and She had a history of intermittent
of impaired consciousness or health later developed an anti-NMDAR untreated esotropia. On 2 months’ fol-
status. Seven of them had normal or encephalitis which has been described low-up, wearing the prescribed glasses,
near-normal VA on second visit, of previously (Wickstr€ om et al. 2014). her distance VA had improved to 0.4
which two toddlers did not co-operate No patient had signs of ocular and 0.65 on her right and left eye,
enough to produce numerical VA but inflammation such as keratitis, con- respectively, and to 0,8 binocularly at
showed age normal visual behaviour. junctivitis, uveitis or retinitis. No one near. There was no strabismus with
As stated above, one subject was never had papillary oedema. correction, although stereo acuity was
assessed for VA, but had otherwise still only partially positive.
normal neuro-ophthalmological find-
Case presentations
ings on examination. This was a boy Case 3
of 15 years who had too severe head- Case 1 A 15-year-old, previously healthy boy,
ache at onset to perform a VA test, and A 3.5-year-old boy, previously healthy, was referred to the hospital from the
never returned to planned controls, but arrived at the hospital with a history of general practitioner with suspected
reported full VA on telephone. gastroenteritis symptoms, i.e. vomiting, meningoencephalitis. He had a 2 weeks
Stereo acuity was present in 24 diarrhoea and fever for 3 days. His history of reoccurring fever, nausea,
subjects, absent in two subjects and behaviour was altered and he was vomiting and headache. Two days
not evaluated, due to lack of co- easily agitated and at bad ease. On before arrival to the hospital he had
operation, in 10 subjects. Clinical data the way to the hospital, there was a developed double vision, which per-
of all 36 subjects are presented in sudden onset of seizures and decreased sisted. He was otherwise unaffected.
Table 1. consciousness. At the hospital addi- CSF analysis revealed 86 monocytes/ll
Ocular motility was found to be tional symptoms were noticed includ- and albumin 353 mg/l. Opening
abnormal in three cases. One 15-year- ing unsynchronized and asymmetrical intracranial pressure during LP was
old boy, (see Case 3 below), with movements of extremities. Acute CT increased to 42 cm H2O. MRI and CT
encephalitis of unknown aetiological brain scan showed slight general brain scans were normal. EEG was
agent, had a transient, isolated sixth oedema and EEG showed a pattern pathological and encephalitis suspect.
nerve palsy, which resolved com- compatible with encephalitis. No virus The ophthalmological examination
pletely. One almost 4-year-old girl was found in CSF but faeces were showed a convergent squint and a right
(see Case 2 below) had a previously positive for rota- and sapovirus. At sixth nerve palsy, but otherwise a
undiagnosed intermittent esotropia, first ophthalmological visit he was normal ophthalmological examination
most likely due to severe bilateral restless and overactive and co-operated with normal VA 1.0 in both eyes with
hypermetropia. One girl of 11 months moderately. VA was 0.16 and 0.2 in his his own glasses. He was slightly

69
Acta Ophthalmologica 2017

Table 1. Clinical data of the study group.

Age at
onset
Years:
Case Agents Gender months VA RE VA LE VA Binoc Method Stereo Neurological signs CT/MRI

1 Rota- and M 03:07 0.16 0.2 0.25 LH linear Neg Visual impair, seizures, N
Sapovirus balance problems,
hallucinations
2 Influenza B F 03:11 0.25 0.4 LH linear Neg Seizures, esotropia N
3 Unknown M 15:10 1 1 KM 550″ Sixth nerve palsy N
4 HSV and F 00:11 Ptosis, miosis, seizures Abn
NMDAR ab
5 Enterovirus F 06:05 1 1 KM 60″
6 Unknown M 06:05 1 1 HVOT 60″ Seizures N
7 Unknown F 02:03 0.63 0.63 Cardiff Ataxia N
8 Mykoplasma F 02:05 0.4 LH single 200″ Seizures N
9 Unknown M 11:06 1 1 KM 30″ Seizures Abn
10 EBV F 16:00 15″ Seizures N
11 Unknown F 16:11 1 1 KM 550″ N
12 NMDAR ab F 07:11 60″ Seizures, dysphasia N
13 Rotavirus F 01:11 0.5 LH at near 200″ Seizures, balance
problems
14 Rotavirus M 02:11 0.65 LH single 550″ Balance problems N
15 Enterovirus F 01:09 16 c/d (appr 0.5) TAC 550″ Seizures, balance N
problems
16 TBE F 07:08 1 1 KM Pos N
17 Unknown F 09:03 27c/d (appr 0.9) TAC Seizures Abn
(Hashimoto)
18 Rotavirus F 03:00 0.63 0.63 LH linear 550″ Seizures N
19 Influenza B F 02:03 0,63 Cardiff 550″ Seizures, balance N
problems
20 TBE+Borrelia F 03:11 0.63 0.63 LH linear 200″
21 Rotavirus M 00:10 Truncal instability
22 Unknown F 12:03 0.3 0.8 KM
23 Norovirus F 01:09
24 Unknown F 15:11 1 1 KM 550″ Seizures, weakness N
left side
25 Rotavirus F 04:04 0.8 0.8 LH linear 200″
26 TBE F 06:09 1 1 KM 550″
27 Unknown M 03:09 0.63 LH linear 550″
(Kawasaki)
28 Unknown M 15:03 N
29 Sapovirus F 01:06 0.63 (6c/d) Cardiff (TAC) 550″ Seizures, balance N
problems
30 TBE M 06:04 0.4 0.4 0.8 LH linear Balance problems
31 Enterovirus F 00:05 600″ Seizures
32 Rotavirus F 00:11 550″ Seizures N
33 Enterovirus M 04:00 0.63 0.5 LH linear 550″ Seizures N
34 Unknown F 01:08 Seizures, balance N
problems
35 TBE F 12:04 1 1 KM 550″
36 EBV F 12:09 1.3 1.3 KM Seizures Abn

HSV = herpes simplex virus, NMDAR = N-methyl-D-aspartate receptor, ab = antibodies, EBV = Epstein–Barr virus, TBE = tick-borne encephali-
tis, 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 findings.

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 remain-
ing strabismus and a positive stereo
acuity. The aetiology to the encephali-
tis remained unknown.
Case 4
A previously healthy girl of 11 months
was admitted to the hospital because of
generalized seizures preceded by gas-
troenteritis 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 first
ophthalmological examination on day 2
revealed bilateral miosis and a sluggish
pupillary reaction to light. No nystag-
mus, palsy or other ocular motor dys-
function was noted and fundus
examination was normal. Due to motor
anxiety and lowered consciousness she

70

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 4–5 she showed increasing irri-
tability. CSF 1 week later was still
pleocytic but HSV negative. There
was a slight clinical improvement dur-
ing the following days. However,
2 weeks later the symptoms progressed
with fever, aggressive behaviour in
combination with oral and truncal
choreoathetosis and dystonia. Oph-
thalmological 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 analy-
sis of serum and CSF confirmed a con-
version into positive titres of NMDAR
antibodies most likely triggered by the
viral infection. She was put under
corticosteroid treatment. Ophthalmo-
logic 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 findings have been
described previously (Wickstr€
om et al.
2014).
Discussion
In this hospital-based study of a con-
secutively recruited paediatric cohort
with clinical encephalitis symptoms
we found few ophthalmological abnor-
malities at presentation. Of 36 patients,
there were three cases who displayed
different neuro-ophthalmological symp-
toms, related to the encephalitis.
The symptoms of encephalitis are
similar in adults and children. How-
ever, the initial symptoms may be
vague and young children often have
more subtle symptoms and CNS affec-
tion is not always readily noticed.
Encephalitis may, therefore, be over-
looked early in the disease. Indeed, a
prompt start of antibacterial and
antiviral treatment, which may affect
outcome, is complicated by the often
Acta Ophthalmologica 2017
unspecific and very common nature of
symptoms such as fever, headache,
nausea and lethargy (Fowler et al.
2008; Thompson et al. 2012). The out-
come 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 findings at presentation
(Fowler et al. 2008). However, oph-
thalmological 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 virus–caused
encephalitis, displayed a transient mild
visual impairment, which recovered
within a short time span. There was
no sign of ocular inflammation, optic
disc abnormality or retinal necrosis.
His co-operation during the examina-
tion improved with his clinical recov-
ery, which probably had a significant
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 findings.
In previous studies, optic nerve
inflammation 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
71
Acta Ophthalmologica 2017
resolved quickly thereafter. This sug-
gests that the cause was the increased
intracranial pressure and not necessar-
ily the encephalitis per se. In one other
case, an accommodative esotropia was
found accidently and without any ocu-
lar 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 post-
vaccination against, e.g. influenza and
haemophilus influenza 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 conver-
sion 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 pre-
dominate (Goldberg et al. 2014). How-
ever, reports of ophthalmological
symptoms are rare. Outteryck and co-
workers have described a case of a
65-year-old woman, with anti-
NMDAR 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 (visual-
evoked potentials) showed signs of
asymptomatic optic neuritis.
72
In our study of an unselected Swed-
ish paediatric cohort with encephalitis,
a wide distribution of different aetio-
logical agents was seen. There are,
however, few studies with a similar
design and comparisons are, therefore,
difficult to make. In this study TBE was
the most frequently confirmed aetio-
logical agent and in none of these cases
ophthalmological abnormalities were
found.
Epstein–Barr 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 encephali-
tis, 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 aetio-
logical agent group. Another limitation
is not having included neurophysiolog-
ical 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 effect on the oph-
thalmological outcome. Hence, oph-
thalmological consultation does not
seem to fit 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:
Kerstin Hellgren
Department of Neuropediatrics
Astrid Lindgren Children’s Hospital
Karolinska University Hospital, Solna
S-171 76 Stockholm
Sweden
Tel: +468-517 77752
Fax: +468-672 3330
Email: kerstin.hellgren@ki.se
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 finding
eligible patients, and Lena Jacobson, Ulrika Liden
and Lena Falkman for help in examining the
patients.
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