Clin Neuroradiol

https://doi.org/10.1007/s00062-018-0756-3

ORIGINAL ARTICLE

Varying Patterns of CNS Imaging in Influenza A

Encephalopathy in Childhood
Mete Dadak1 · Refik Pul2 · Heinrich Lanfermann1 · Hans Hartmann3 · Ute Hehr4 · Frank Donnerstag1 ·
Dirk Michels5 · Anita Blanka Tryc6

Received: 5 September 2018 / Accepted: 18 December 2018

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Abstract
Purpose The brain imaging findings in children with neurological complications associated with influenza A infections
are presented and analyzed and pathological imaging changes including atypical intracerebral hemorrhages in these
patients are discussed.
Methods Neuroimaging findings in six children with influenza encephalopathy following influenza A infection between
2012–2017 were retrospectively investigated. Of these five underwent magnetic resonance imaging (MRI) and one
computed tomography (CT). Gene analysis was performed in two cases with acute necrotizing encephalitis of childhood
(ANEC). Results The MRI findings of one child were concordant with mild encephalopathy with a reversible splenial
lesion (MERS); this patient recovered but remained aphasic. In two cases MRI showed typical bilateral thalamic
lesions as a feature of ANEC; genetic testing facilitated the diagnosis in one case. One of the patients died, the other
showed little improvement. The remaining three patients had multiple diffuse cerebral hemorrhages predominantly
affecting the supratentorial white matter after influenza A infection complicated by pneumonia, rhabdomyolysis and
sepsis requiring extracorporeal membrane oxygenation (ECMO).
Conclusion Neurological complications in children associated with influenza A infection may include MERS and ANEC.
Additionally, atypical disseminated intracerebral hemorrhages as a complication of influenza A infection is reported.

Keywords Acute necrotizing encephalitis of childhood · Mild encephalopathy with a reversible splenial lesion · Atypical
hemorrhage

Introduction

Influenza A infections have been associated with a wide

The authors M. Dadak and R. Pul contributed equally to the
manuscript.
 Mete Dadak dadak.mete@mh-
hannover.de
1
Department of Neuroradiology, Hannover Medical
School, Carl-Neuberg-Str-1, 30625 Hannover, Germany
2
Clinic for Neurology, University Hospital Essen,
Essen, Germany
3
Clinic for Pediatric Kidney, Liver and Metabolic
Disorders, Hannover Medical School, Hannover, Germany
4
Institute of Human Genetics, University of
Regensburg, Regensburg, Germany
5
Department of Radiology and Neuroradiology,
Klinikum Nordstadt, Hannover, Germany
6
Clinic for Neurology, Hannover Medical School,
Hannover, Germany
spectrum of neurological complications in children ranging
from seizures or focal neurological deficits to impaired
consciousness and coma [1]. Among the several described
types of influenza-associated encephalopathies there are
two forms with different clinical outcomes, namely acute
necrotizing encephalitis of childhood (ANEC) [2–4] and
the mild encephalopathy with reversible lesion in the
splenium (MERS) [5–7]. Both are characterized by their
specific magnetic resonance imaging (MRI) findings.
Although there are reports about patients with good
outcome follow- ing ANEC, Kim et al. noted that all
patients with severe neurologic sequelae had hemorrhagic
lesions diagnosed by MRI [8]. Typical neuroimaging
features of ANEC include bilateral thalamotegmental
lesions with often bithalamic petechial hemorrhages
without hemorrhages in the cere- bral hemispheric lesions
[2–4]. Typical MRI findings of MERS are reversible lesion
in the splenium of the corpus

K

callosum (SCC) and sometimes symmetrical lesions in the
parenchymal white matter showing T2 hyperintensity with
corresponding diffusion restriction and no hemorrhages.
These changes resolve nearly completely on follow up
imaging within days to weeks [5–7]; however, there are
many cases with different neuroradiological changes which
cannot be included into these categories [9]. This article
presents six children with neurological complications due
to typical and atypical changes after influenza A infection.
Materials and Methods
Patients
From January 2012 to December 2017 children with in-
fluenza A infections with neurological complication ad-
mitted to Hannover Medical School were retrospectively
included. Inclusion criteria were: patient under 18 years of
age, proven influenza A infection as well as central
nervous system (CNS) complications. From seven patients,
one with an epileptic seizure was excluded as the patient
only had a CT scan that was inconspicuous and the
patient was dis- charged the next day. All initially
presented with flu-like symptoms affecting the upper
respiratory or the gastroin- testinal tract. Of the patients
four developed neurological symptoms early during the
course of the disease. Another two went into acute
respiratory failure requiring mechan- ical ventilation and
extracorporeal membrane oxygenation (ECMO) treatment
and developed neurological symptoms during intensive
care treatment. All patients, four boys and two girls aged
between 10 months and 14 years had na- sopharyngeal
swabs positive for influenza A virus by RNA- RT PCR.
Genetic testing was performed in two cases with suspected
ANEC to detect a mutation in the causative gene
Fig. 1 A 14-year-old boy with mild encephalopathy with a reversible splenial lesion. Axial diffusion-weighted ( left sided images) and apparent
diffusion coefficient map images (right sided images) show restricted diffusion bilaterally in the white matter of the centrum semiovale (a) and
in the splenium (b) (arrows). The imaging changes disappeared without residual parenchymal lesion in the subsequent magnetic resonance
M. Dadak et al.
encoding the nuclear pore protein Ran Binding Protein 2
(RANBP2), which leads to increased susceptibility of de-
veloping ANEC [10]. Of the patients five had no previ-
ous history of seizures or neurological failures, usage of
antiepileptic drugs, or any type of vaccination during the
year before the acute illness. Of the patients one diagnosed
with MERS was previously diagnosed with Duchenne
mus- cular dystrophy (patient 1) and five of the six patients
un- derwent MRI and one underwent CT imaging.
MRI and CT Imaging
Of the patients four underwent MRI or CT imaging within
2 days after initial presentation. In two patients MRI was
per- formed 22 and 68 days after the onset of acute
symptoms, respectively. These images with protracted time
points were taken because of the long time spent on the
intensive care unit after early rapidly progressive severe
respiratory fail- ure and long-term ventilation. The MRI
examinations were performed with the patient under
intubation anesthesia with a field strength of 1.5 T or 3.0 T
(Magnetom Avanto, Aera or Verio, Siemens Medical
Systems, Erlangen, Ger- many). All MRI protocols
included axial fluid attenuated inversion recovery
(FLAIR), repetition time/echo time/ inversion time
(TR/TE/TI): 8800-9000/89-119/2500 ms, slice thickness
3.5–5.5 mm, slice spacing 4–6.5 mm, field of view (256–
320)× (173–224) mm; axial diffusion weighted imaging
(DWI, echo-planar imaging-spin echo), repeti- tion
time/echo time (TR/TE) 3200–10,600 ms, slice thick- ness:
4–6 mm, slice spacing 4–7.2 mm, b value= 0, 500 and
1000, field of view: (128–192)× (128–192) mm; ax- ial
turbo spin-echo (TSE) T2-weighted, repetition time/ echo
time (TR/TE) 2000–6000/80–133 ms, slice thick- ness 4–
5.5 mm, slice spacing 4–6.5 mm, field of view: (256–
320)× (173–320) mm and axial spin-echo (SE) T1-
Varying Patterns of CNS Imaging in Influenza A Encephalopathy in
Childhood
imaging (MRI) performed during the following days (patient 1), not shown
Table 1 Patient characteristics and neuroimaging findings
Patient Agea Sex Symptoms Neuroradiological Clinical Neuroradiological features Miscellaneous
diagnosis outcome
1 14 years m Somnolence, MERS Improved DWI: restriction bilaterally in the Duchenne
aphasia aphasia white matter of the centrum semiovale muscular
and in the splenium dystrophy
2 16 months m Coma ANEC Brain stem DWI: restriction bilaterally in the RANBP2
syndrome thalami positive
T2 images: swollen bilateral hyper-
intense thalami, extension in to the
lateral putamina, external and
extreme capsules, the dorsal pons and
the mid- brain
SWI: patchy bithalamic and tegmental
petechial hemorrhages, and hemor-
rhages in the inferior colliculi and
mammillary bodies
3 10 months m Epileptic Relapsing Death T2: symmetrical swollen bilateral RANBP2
seizures ANEC thalami negative
DWI: patchy restriction bilaterally in
the thalami
SWI: small spotty hemorrhages in the
right thalamus
second MRI:
SWI: progressive petechial
bithalamic hemorrhages and in the
red nuclei and inferior colliculi
4 3 years m Coma Hemorrhage Death CCT: multiple acute streaky intrac-
erebral hemorrhages
predominantly in the corpus
callosum and slight in
the posterior limb of the right
internal capsule
5 13 years f Coma, Hemorrhage Left-sided SWI: multiple diffuse large and pe- ECMO
left-sided hemipare- techial intracerebral hemorrhages in
hemiplegia, sis, im- the supratentorial brain predominantly
aphasia proved in the white matter, with splenial in-
aphasia volvement
6 26 months f Coma, Hemorrhage Somnolence SWI: small hemorrhages only in the ECMO
epileptic periventricular and peripheral white
seizures matter
m male, f female, MERS mild encephalopathy with a reversible splenial lesion, ANEC acute necrotizing encephalitis of childhood, ECMO extra-
corporeal membrane oxygenation, SWI susceptibility weighted imaging, CCT cranial computed tomography, DWI diffusion weighted imaging
a
At disease onset

weighted, repetition time/echo time (TR/TE) 232–541/

4.76–13 ms, slice thickness 4–5.5 mm, slice spacing 4–
6.5 mm, field of view: 256 × (154–218) mm images. Ad-
ditional MR sequences consisted of axial susceptibil- ity-
weighted imaging (SWI), repetition time/echo time
(TR/TE): 28–49/20–40 ms, slice thickness: 1.6–3 mm,
field- of-view: (256–320)× (186–221) mm images. One
somno- lent patient with dilated pupils underwent
sequential com- puted tomography using a 16-slice
Lightspeed CT scanner (General Electric Health Care,
Milwaukee, WI, USA).
Results
A total of six pediatric patients with influenza A presented
with neurological complications. Impaired consciousness
followed by epileptic seizures was the most common CNS
symptom, which occurred from the second day to second
week after onset of influenza. Of the patients two died, one
survived with severe brain stem syndrome and three
showed neurological improvements. Genetic testing for
RANBP2 gene mutation was positive in one of the two
cases of sus- pected ANEC. The clinical characteristics and
outcome of the patients are shown in Table 1.

K
Fig. 2 A 16-month-old boy
with acute necrotizing
encephalitis of childhood
(ANEC). Axial dif- fusion
weighted imaging (left sided
image) shows diffusion
restricted lesions with decreased
signal in apparent diffusion co-
efficient map (right sided
image) especially in the
rostromedial periphery of the
thalami (a) (ar- row below).
Axial T2-weighted 3T MRI
demonstrates swollen bilateral
thalami (arrow in b) with
symmetrical hyperintense
lesions continuing in the lat-
eral putamina, external and
extreme capsules (b, c) and in
the dorsal pons (d). The coronal
section delineates extension in
the midbrain (e). The suscepti-
bility weighted imaging 3T MRI
shows patchy petechial hemor-
rhages in the tegmentum (f), in
the inferior colliculi and mam-
millary bodies (g) and in the
thalami (h) and MRI reveals
extensive focal necrotic and
hemorrhagic change consistent
with ANEC (patient 2)

losum (Fig. 1b). These MRI signal alterations disappeared

Neuroimaging Findings

Out of the six patients, one patient was diagnosed with

MERS (patient 1), two patients with ANEC (patients 2
and 3), and three patients with intracerebral hemorrhages.
In the first patient (patient 1) presenting with symptoms
suggestive of encephalitis 2 days after clinical onset of
influenza, the MRI demonstrated restricted diffusion bilat-
erally symmetrically in the white matter of the centrum
semiovale (Fig. 1a) and in the splenium of the corpus cal-
without residual parenchymal lesions in the subsequent
MRI examinations performed in the following days (not
shown), consistent with MERS. In two cases the MRI
changes were consistent with a diagnosis of ANEC (pa-
tients 2 and 3). In one of these two cases (patient 2)
cerebral MRI showed swollen bilateral thalami with
symmetrical hyperintense T2 lesions continuing in the
lateral putamina, external and extreme capsules (Fig. 2b
and c) and in the dorsal pons (Fig. 2d). The coronal
section demonstrated extension to the midbrain (Fig. 2e).
Every lesion demon- strated restricted diffusion with
decreased signal intensity
Fig. 3 A 10-month-old boy
with acute necrotizing en-
cephalitis of childhood. T2
weighted 1.5T magnetic res-
onance imaging (MRI) shows
symmetrical swollen bilateral
hyperintense thalami (arrows
in a) accompanied by patchy
areas of restricted diffusion
with low apparent diffusion
coeffi- cient (ADC) values
(arrows in b, ADC map not
shown). The susceptibility
weighted imaging (SWI) 1.5T
MRI demonstrates spotty
hemorrhages in the right
thalamus (arrow in c). The SWI
detects patchy petechial hemor-
rhages in the central region of
the diffusion restricted bithala-
mic areas 3 months later
(arrows in d) and especially in
the red nuclei (arrow above)
and in the inferior colliculi
(arrow below)
(e) (patient 3)

in ADC maps, especially in the rostromedial periphery of the brainstem and hemorrhages were the main findings
the thalami (Fig. 2a). These changes indicated cytotoxic
edema in the first days after the onset of symptoms. Sus-
ceptibility weighted imaging (SWI) detected hemosiderin
deposition bithalamic and tegmental, especially in the infe-
rior colliculi and mammillary bodies, indicating petechial
hemorrhages (Fig. 2f to h). In the second case consistent
with ANEC (patient 3) the MRI showed bilaterally swollen
thalami with T2 hyperintensity without manifestation in
other brain regions (Fig. 3a). These MRI changes were
accompanied by patchy areas of restricted diffusion with
low ADC values (Fig. 3b, ADC map images not shown).
Time of flight venography ruled out deep cerebral vein
thrombosis. The SWI demonstrated spotty hemorrhages in
the right thalamus (Fig. 3c). After 3 months following the
acute illness, epileptic seizures relapsed with MRI deterio-
ration. The DWI now revealed diffuse diffusion restriction
in both thalami and in the white matter, indicating hypoxic-
ischemic injury (not shown). An SWI detected patchy
petechial hemorrhages in the central region of the diffu-
sion restricted bithalamic areas (Fig. 3d) and especially
in the red nuclei and in the inferior colliculi (Fig. 3e).
Symmetrical lesions in the swollen thalami extending to
indicating ANEC in concordance with previous studies
[11].
In the remaining three patients the common finding
was multiple intracerebral hemorrhages without thalamic
and pontotegmental involvement. The CT scan of the
head of one boy (patient 4) showed multiple acute streaky
intracere- bral hemorrhages predominantly in the corpus
callosum and in the posterior limb of the right internal
capsule (Fig. 4a and b). This patient died soon after the
CT scan. In two further cases (patients 5 and 6) SWI
detected multiple dif- fuse large and petechial
intracerebral hemorrhages predom- inantly affecting the
supratentorial white matter, with sple- nial involvement in
one case (Fig. 4c and d) (patient 5) and slighter
manifestations only in the periventricular and peripheral
white matter in another case (Fig. 4e and f) (pa- tient 6).
Both patients developed early coma and rapidly
progressive severe respiratory insufficiency requiring me-
chanical ventilation and ECMO treatment. The imaging
changes are summarized in Table 1.

Fig. 4 Patients with intracerebral hemorrhages. The CT shows multi-
ple acute streaky intracerebral hemorrhages predominantly in the cor-
pus callosum and slight in the posterior limb of the right internal cap-
sule (a, b) (patient 4). In two further cases SWI detected multiple dif-
fuse large and petechial intracerebral hemorrhages in the
supratentorial brain predominantly in the white matter, with splenial
involvement (pa- tient 5; c, d) and slighter manifestations only in the
periventricular and peripheral white matter (patient 6; e, f)
Discussion
In this retrospective study children with influenza A en-
cephalopathy were investigated. neuroimaging changes
including influenza-associated ANEC and MERS were
shown, both concordant with previous reports [2–7]. In
addition to typical imaging changes, three children with
confirmed influenza A infection accompanied by multior-
gan failure showed disseminated hemispheric hemorrhages
in the corpus callosum, and in the supratentorial periven-
tricular and peripheral white matter. The pathogenesis of
intracranial hemorrhage in these patients is more complex.
These bleedings are most likely multifactorial, as a result
of influenza-related vascular disturbance, an underlying
hem-
orrhagic diathesis, and potential adverse effect of ECMO
or anticoagulation required for ECMO discussed for adults
but have not been systematically studied in children [14].
In contrast to these atypical hemorrhages, neuroimaging
of the other cases with influenza-associated ANEC and
MERS showed typical MRI features. Cases of MERS re-
vealed typical transiently restricted diffusion bilaterally in
the white matter of the centrum semiovale (Fig. 1a) and in
the splenium (Fig. 1b) without bleeding. This phenomenon
has been repeatedly reported in many various clinical
conditions including ischemia, infections, posterior re-
versible encephalopathy syndrome (increased ADC value),
diffuse axonal injury, multiple sclerosis, Marchiafava-Big-
nami disease, status epilepticus, the use and withdrawal
of antiepileptic drugs and metabolic derangements such
as hypoglycemia and hypotonic hyponatremia [7, 16–18].
The reason for predilection of the splenium of the corpus
callosum remains unclear [7]. The main reason for the
transiently reduced diffusion with decreased ADC values
was postulated as development of intramyelinic edema
with separation of myelin sheath layers. Another possible
expla- nation for the reduced diffusion is a transient
inflammatory infiltrate with inflammatory cells and
macromolecules into the white matter as known in multiple
sclerosis [6, 15–17]. The thalamotegmental lesions with
often bithalamic pe- techial hemorrhages are one of the
typical MRI features of ANEC [2–4, 11, 12]. The
hemorrhages are described in the center of the thalami and
in the brainstem, the tegmentum as shown in Fig. 2f and
the thalami in Fig. 3c and d. The SWI technique detected
symmetric hemorrhages in the rostromedial thalamus
involving the medial and anterior nuclei and pulvinar
thalami (Fig. 2h) and the mammillary bodies (Fig. 2g).
Hemorrhages were detected in the inferior colliculi and red
nucleus, too (Fig. 2g and 3e). Additionally, hemispheric
lesions in the cerebral white matter have been described
but mostly without hemorrhages [4, 13].
This article reports varying patterns of CNS imaging in
influenza A encephalopathy in childhood. Atypical dissem-
inated intracerebral hemorrhages should be taken into con-
sideration as complications of influenza A infections.
Conflict of interest M. Dadak, R. Pul, H. Lanfermann, H.
Hartmann,
U. Hehr, F. Donnerstag, D. Michels and A.B. Tryc declare that they
have no competing interests
References
1. Ekstrand JJ, Herbener A, Rawlings J, Turney B, Ampofo K, Ko-
rgenski EK, Bonkowsky JL. Heightened neurologic complica-
tions in children with pandemic H1N1 influenza. Ann Neurol.
2010;68:762–6.
2. Mizuguchi M. Acute necrotizing encephalopathy of childhood:
a novel form of acute encephalopathy prevalent in Japan and Tai-
wan. Brain Dev. 1997;19:81–92.
 3. Porto L, Lanfermann H, Möller-Hartmann W, Jacobi G, Zanella
dall P, van der Knaap MS, Goglin KC, Tefft DL, Aubin C, de
F. Acute necrotising encephalopathy of childhood after exanthema
Jager P, Hafler D, Warman ML. Infection-triggered familial or
subitum outside Japan or Taiwan. Neuroradiology. 1999;41:732–4.
recurrent cases of acute necrotizing encephalopathy caused by
4. Wong AM, Simon EM, Zimmerman RA, Wang HS, Toh CH, Ng
mutations in a component of the nuclear pore, RANBP2. Am J
SH. Acute necrotizing encephalopathy of childhood: correlation
Hum Genet. 2009;84:44–51.
of MR findings and clinical outcome. AJNR Am J Neuroradiol.
11. Zeng H, Quinet S, Huang W, Gan Y, Han C, He Y, Wang Y.
2006;27:1919–23.
Clinical and MRI features of neurological complications after in-
5. Ishida Y, Kawashima H, Morichi S, Yamanaka G, Okumura A,
fluenza A (H1N1) infection in critically ill children. Pediatr
Nakagawa S, Morishima T. Brain magnetic resonance imaging in
Radiol. 2013;43:1182–9.
acute phase of pandemic influenza A (H1N1) 2009-associated en-
12. Xiujuan W, Wei W, Wei P, Limin W, Kangding L, Hong-Liang Z.
cephalopathy in children. Neuropediatrics. 2015;46:20–5.
Acute necrotizing encephalopathy: an underrecognized
6. Ka A, Britton P, Troedson C, Webster R, Procopis P, Ging J, Chua
clinicoradi- ologic disorder. Mediators Inflamm. 2015;
YW, Buckmaster A, Wood N, Jones C, Dale RC. Mild
https://doi.org/10.1155/ 2015/792578.
encephalopa- thy with reversible splenial lesion: an important
13. Albayram S, Bilgi Z, Selcuk H, Selcuk D, Cam H, Koçer N, Islak
differential of en- cephalitis. Eur J Paediatr Neurol. 2015;19:377–
C. Diffusion-weighted MR imaging findings of acute necrotizing
82.
encephalopathy. AJNR Am J Neuroradiol. 2004;25:792–7.
7. Bulakbasi N, Kocaoglu M, Tayfun C, Ucoz T. Transient sple-
14. Chow FC, Edlow BL, Frosch MP, Copen WA, Greer DM. Out-
nial lesion of the corpus callosum in clinically mild influenza-
come in patients with H1N1 influenza and cerebrovascular injury
associated encephalitis/encephalopathy. AJNR Am J Neuroradiol.
treated with extracorporeal membrane oxygenation. Neurocrit
2006;27:1983–6.
Care. 2011;15:156–60.
8. Kim JH, Kim IO, Lim MK, Park MS, Choi CG, Kim HW, Kim
15. Takanashi J, Barkovich AJ, Yamaguchi K, Kohno Y. Influenza-as-
JE, Choi SJ, Koh YH, Yang DM, Choo SW, Chung MJ, Yoon HK,
sociated encephalitis/encephalopathy with a reversible lesion in
Goo HW, Lee M. Acute necrotizing encephalopathy in Korean in-
the splenium of the corpus callosum: a case report and literature
fants and children: imaging findings and diverse clinical outcome.
review. AJNR Am J Neuroradiol. 2004;25:798–802.
Korean J Radiol. 2004;5:171–7.
16. Takanashi J. Two newly proposed infectious encephalitis/ence-
9. Yoshikawa H, Yamazaki S, Watanabe T, Abe T. Study of
phalopathy syndromes. Brain Dev. 2009;31:521–8.
influenza- associated encephalitis/encephalopathy in children
17. Takanashi J, Tada H, Maeda M, Suzuki M, Terada H, Barkovich
during the 1997 to 2001 influenza seasons. J Child Neurol.
AJ. Encephalopathy with a reversible splenial lesion is associated
2001;16:885–90.
with hyponatremia. Brain Dev. 2009;31:217–20.
10. Neilson DE, Adams MD, Orr CM, Schelling DK, Eiben RM, Kerr
18. Chen WX, Liu HS, Yang SD, Zeng SH, Gao YY, Du ZH, Li XJ,
DS, Anderson J, Bassuk AG, Bye AM, Childs AM, Clarke A,
Lin HS, Liang HC, Mai JN. Reversible splenial lesion syndrome
Crow YJ, Di Rocco M, Dohna-Schwake C, Dueckers G, Fasano
in children: retrospective study and summary of case series. Brain
AE, Gika AD, Gionnis D, Gorman MP, Grattan-Smith PJ,
Dev. 2016;38:915–27.
Hackenberg A, Kuster A, Lentschig MG, Lopez-Laso E, Marco
EJ, Mastroyianni S, Perrier J, Schmitt-Mechelke T, Servidei S,
Skardoutsou A, Ul-