Received: 4 July 2023

| Accepted: 5 November 2023

DOI: 10.1002/epi4.12863

SHORT RESEARCH ARTICLE

A 5-­year-­old boy with super-­refractory status

epilepticus and RANBP2 variant warranting life-­saving
hemispherotomy

Barbora Straka1 | Miroslav Koblížek2 | Barbora Splítková1 |

Radka Valkovičová1 | Lenka Krsková2 | Markéta Kalinová2 | Markéta Vlčková3 |
Josef Zámečník2 | Petra Laššuthová1 | Lucie Sedláčková1 | David Staněk4 |
Alice Maulisová5 | Michal Tichý6 | Martin Kynčl7 | Pavel Kršek1
1
Department of Paediatric Neurology, Motol University Hospital and Second Faculty of Medicine, Charles University, Prague, Czech Republic
2
Department of Pathology and Molecular Medicine, Motol University Hospital and Second Faculty of Medicine, Charles University, Prague, Czech Republic
3
Department of Biology and Medical Genetics, Motol University Hospital and Second Faculty of Medicine, Charles University, Prague, Czech Republic
4
Second Faculty of Medicine, Charles University, Prague, Czech Republic
5
Department of Clinical Psychology, Motol University Hospital and Second Faculty of Medicine, Charles University, Prague, Czech Republic
6
Department of Neurosurgery, Motol University Hospital and Second Faculty of Medicine, Charles University, Prague, Czech Republic
7
Department of Radiology, Motol University Hospital and Second Faculty of Medicine, Charles University, Prague, Czech Republic

Correspondence
Barbora Straka, Department of Paediatric
Neurology, Motol University Hospital
and Second Faculty of Medicine, Charles
University, V Úvalu 84, Prague 15006,
Czech Republic.
Email: barbora.straka@fnmotol.cz
Present address
Markéta Kalinová, University Hospital
Královské Vinohrady, Šrobárova 1150/50,
Prague 10, 100 34, Czech Republic
David Staněk, DNAnexus Czech
Republic, Pernerova 697/35, Karlín,
Prague, 186 00, Czech Republic
Funding information
Grantová Agentura, Univerzita
Karlova, Grant/Award Number: 94121;
Ministerstvo Školství, Mládeže a
Tělovýchovy, Grant/Award Number:
LX22NPO5107; Ministerstvo Zdravotnictví
Ceské Republiky, Grant/Award Number:
00064203 and NV19-­04-­00369
Abstract
Focal cortical dysplasia (FCD) represents the most common cause of drug-­
resistant epilepsy in adult and pediatric surgical series. However, genetic fac-
tors contributing to severe phenotypes of FCD remain unknown. We present
a patient with an exceptionally rapid development of drug-­resistant epilepsy
evolving in super-­refractory status epilepticus. We performed multiple clini-
cal (serial EEG, MRI), biochemical (metabolic and immunological screening),
genetic (WES from blood-­and brain-­derived DNA), and histopathological in-
vestigations. The patient presented 1 month after an uncomplicated varicella
infection. MRI was negative, as well as other biochemical and immunological
examinations. Whole-­exome sequencing of blood-­derived DNA detected a het-
erozygous paternally inherited variant NM_006267.4(RANBP2):c.5233A>G
p.(Ile1745Val) (Chr2[GRCh37]:g.109382228A>G), a gene associated with a sus-
ceptibility to infection-­induced acute necrotizing encephalopathy. No combina-
tion of anti-­seizure medication led to a sustained seizure freedom and the patient
warranted induction of propofol anesthesia with high-­dose intravenous mida-
zolam and continuous respiratory support that however failed to abort seizure

Barbora Straka and Miroslav Koblížek contributed equally to the preparation of the manuscript.

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2023 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.

Epilepsia Open. 2023;00:1–8.  wileyonlinelibrary.com/journal/epi4 | 1

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2 STRAKA ET AL.

activity. Brain biopsy revealed FCD type IIa; this finding led to the indication of
an emergency right-­sided hemispherotomy that rendered the patient temporar-
ily seizure-­free. Postsurgically, he remains on antiseizure medication and experi-
ences rare nondisabling seizures. This report highlights a uniquely severe clinical
course of FCD putatively modified by the RANBP2 variant.
Plain Language Summary: We report a case summary of a patient who came to our
attention for epilepsy that could not be controlled with medication. His clinical course
progressed rapidly to life-threatening status epilepticus with other unusual neurologi-
cal findings. Therefore, we decided to surgically remove a piece of brain tissue in order
to clarify the diagnosis that showed features of a structural brain abnormality associ-
ated with severe epilepsy, the focal cortical dysplasia. Later, a genetic variant in a gene
associated with another condition, was found, and we hypothesize that this genetic
variant could have contributed to this severe clinical course of our patient.

KEYWORDS
epilepsy surgery, focal cortical dysplasia, hemispherotomy, RANBP2, refractory status
epilepticus

1 | I N T RO DU CT ION course of varicella infection. His family and past medi-

Malformations of cortical development (MCD), and spe-
cifically focal cortical dysplasia (FCD), represent the most
common etiology of focal drug-­resistant epilepsy in chil-
dren who undergo epilepsy surgery.1 Patients with FCD
tend to present early in childhood, with frequent daily
seizures, including episodes of status epilepticus, and
31%-­57% of them may show delayed developmental mile-
stones.2 However, super-­ refractory status epilepticus is
rare in patients with FCD, and itself poses great diagnostic
challenges. In recent years, multiple studies have shown
that genetic causes of FCD, MCD, and focal epilepsy may
influence patients' clinical presentation, the process of
presurgical investigation and postsurgical prognoses in
terms of postsurgical seizure freedom.3–6
We are presenting a case of uniquely rapid devel-
opment of drug-­ resistant epilepsy and super-­refractory
status epilepticus caused by focal cortical dysplasia, and
presenting the results of multiple molecular genetic in-
vestigations performed in order to elucidate the cause of
the patient's condition. Finally, we hypothesize that the
patient's unusually severe clinical course might have been
modified by previously undescribed genetic factors, in this
case a variant in RANBP2 gene.
2 | C L I N I C AL H ISTORY
A five-­year-­old patient was admitted to pediatric neurol-
ogy department with daily frequent unprovoked focal
aware tonic seizures, 1 month after an uncomplicated
cal history were unremarkable. The initial EEG showed
frequent interictal epileptiform discharges with a pre-
dominance over the right frontal, central, and parietal
regions with fast bilateral spread of the epileptiform
activity; brain MRI detected no distinct structural ab-
normalities (Figure 1). Biochemical, cytological, and
microbiological analyses (incl. PCR detection of vari-
cella zoster virus) of cerebrospinal fluid showed no
significant abnormalities. Metabolic screening of blood
and urine samples for inborn errors of metabolism,
mitochondrial disease, and lysosomal storage disor-
ders were negative. Blood samples showed no specific
alterations in the levels of amino acids, acylcarnitines,
uric acid, carnitine, homocysteine, very-­ long-­
chain
fatty acids, phytanic acid, pristanic acid, plasmalogens,
and biotinidase. Urine sample examination included
chemical analyses, screening for disorders of creatinine
biosynthesis and transport, of mucopolysaccharides, ol-
igosaccharides, ninhydrin, beta-­mannosidosis, organic
acids, amino acids, purines and pyrimidines, lactate,
polyols, and fructose. The activity of chitotriosidase in
blood leukocytes was within control levels. Enzyme ac-
tivity of tripeptidyl peptidase in blood leukocytes was
not consistent with the diagnosis of neuronal ceroid
lipofuscinosis type 2, and enzyme activity of beta-­
galactosidase was not consistent with the diagnosis of
GM1 gangliosidosis or Morquio B. disease. Genetic test-
ing consisting of whole-­exome sequencing (WES) was
initiated.
Frequent daily seizures with a left-­sided predominance
with a constant left-­sided postictal hemiparesis continued

STRAKA ET AL.
F I G U R E 1 T2w axial MRI images
at presentation and 3 months afterwards
(left and right panels, respectively). The
MRI at presentation (left panel) shows
no definite changes suggestive of focal
cortical dysplasia. The second MRI (right
panel) shows subtle signs of diffuse brain
atrophy evidenced by slightly enlarged
subarachnoid spaces.
despite a combination of multiple oral and intravenous
antiseizure medications (ASM) (e.g., midazolam, leveti-
racetam, lacosamide, and valproate), ketogenic diet, and
immunosuppressants (methylprednisolone and intrave-
nous immunoglobulins). Over the period of 4 months, the
patient developed severe muscle hypotonia, cognitive de-
cline, nonlateralized cerebellar, and extrapyramidal signs,
along with signs of progressive diffuse encephalopathy on
EEG. Initially, we associated these features with ongoing
drug-­resistant focal seizures and multiple administered
antiseizure medication (ASM). However, in later course
when the patient's clinical status did not improve but dete-
riorated, we started considering a possible neurodegener-
ative or neurometabolic condition that prompted further
investigations in this regard. Repeated MRI scans showed
unspecific bilateral changes related to ongoing status ep-
ilepticus but no etiology-­specific features and/or features
consistent with FCD (e.g., cortical thickening and blurring
of gray/white matter junction). Figure 2A depicts the evo-
lution of the patient's EEG findings. His condition deteri-
orated to a life-­threatening convulsive status epilepticus
with a left-­sided predominance that warranted induction
of propofol anesthesia with high-­dose intravenous mid-
azolam and continuous respiratory support that however
failed to abort seizure activity. Therefore, we performed
an open brain biopsy from the right frontal region, corre-
sponding to an area with maximum discharges on EEG.
Given that the risk/benefit ratio of multiple biopsies from
multiple brain lobes was considered excessively high, in
light of potential diagnostic benefit of multiple sampling,
we proceeded with a single biopsy from the most electro-
clinically active brain area.
Specimens from the diagnostic biopsy consisted of
cortex and white matter underneath. A major part of
the cortex showed architectural abnormalities with loss
of typical cortical lamination. Neurons formed irregular
clusters, and there was also radial lamination with vertical
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    3
neuronal columns. Numerous abnormally sized and atypi-
cally shaped neurons were scattered throughout the entire
thickness of the cortex. Initially, we termed them “giant
neurons,” as defined by Palmini et al.7 On the H&E stain-
ing, all of the giant neurons showed a near-­normal nuclear
and cytoplasmic morphology, and there was no evidence
of balloon cells. The border between gray and white mat-
ter was partially blurred and a lot of dystopic neurons oc-
curred in the adjacent white matter. We observed no signs
of inflammation, pathological accumulation, or any other
lesion (Figure 3A). All these features were consistent with
the diagnosis of focal cortical dysplasia (FCD). Gene panel
somatic resequencing of the brain tissue-­derived DNA
was initiated.
Based on these findings and an overall clinical status
of the patient, we proceeded to an emergency right-­sided
hemispherotomy. The patient was in an ongoing life-­
threatening status epilepticus warranting intubation and
mechanical ventilation, muscle relaxation, in addition to
constant severe postictal hemiparesis (observed during pe-
riods of diminished muscle relaxation). The patient's clini-
cal course is summarized in Figure 4.
Multiple samples were obtained in the course of sur-
gery. All samples of frontal and temporal cortex showed
parts of normal laminar cortex alternating with abnormal
cortical architecture, including all of the above-­described
features. Differential diagnosis included FCD type Ib (ac-
cording to Palmini classification7), FCD type Ia (accord-
ing to ILAE classification,8) and FCD type IIa. Additional
immunohistochemical studies (neurofilaments, NeuN,
and MAP2) elucidated architectural abnormalities and
dystopic neurons in white matter. The giant neurons
showed abnormal accumulation of neurofilaments and
were antiphosphoS6-­positive (Figure 3A). Therefore, we
reached the diagnostic conclusion of focal cortical dyspla-
sia type IIa, characterized by dysmorphic neurons, phos-
phoS6 positive, with abnormal neurofilament expression.
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STRAKA ET AL.
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STRAKA ET AL.     5

F I G U R E 2 A–C, Bipolar longitudinal (“double banana”) montage, green curves depicting right hemisphere, red curves left hemisphere,
blue curves midline. The first (scalp) interictal EEG after admission to the inpatient department. The arrows depict interictal spikes over
the right frontal-­central region (A). First (scalp) interictal EEG during the admission to the inpatient department due to clustering of focal
seizures. Arrows depict both spikes and pathological fast activity, both over the right F-­C region. B, Scalp EEG during focal status epilepticus
before the admission of the patient to the ICU. Note the overall slowing of the background activity and the fast bilateral spread of the
interictal spikes (C).

F I G U R E 3 A–F, Widespread foci of cortical dyslamination with clustering of neurons and formation of neuronal columns on H&E
stain (A, B), MAP2 (C) and NeuN (D). Dysmorphic neurons show accumulation of neurofilaments (E) and are phosphoS6 positive (F).

FIGURE 4 Timeline depicting key events in the patient's clinical course.

Shortly after the hemispherotomy, general anesthe-
sia was discontinued, the patient was weaned off re-
spiratory support, and his seizure frequency decreased.
Within days, the extrapyramidal signs and generalized
hypotonia subsided, and he started regaining motor
skills on left-­sided extremities, hemiplegic as a result
of the right-­sided hemispherotomy. Postoperative scalp
EEG showed, however, bilateral epileptiform discharges,
unexpectedly with the left-­ sided predominance, but
there was no EEG evidence of independent ictal focal
 |   
6 STRAKA ET AL.
contralateral onset. Right hemisphere was completely
disconnected, as evidenced by postsurgical MRI and dif-
fusion tensor imaging.
The patient was discharged 4 months after surgery on
a combination of four oral ASM with only sporadic sei-
zures, and the seizures disappeared completely 1 month
after discharge. Two and half years after the surgery,
the patient experienced rare nondisabling seizures from
sleep and displayed features of mild prefrontal syndrome,
severe attention-­deficit and hyperactivity, below-­average
verbal intellectual performance, right eye esotropy, left-­
sided hemiparesis, and central left facial nerve palsy.
3 | G E N ET IC FIN DIN G S
Exome sequencing of blood-­ derived DNA (Agilent
SureSelect v6) revealed a paternally inherited variant
NM_006267.4(RANBP2):c.5233A>G p.(Ile1745Val)
(Chr2[GRCh37]:g.109382228A>G) present in gnomAD9
with a population frequency of 0.0004%. Targeted rese-
quencing of coding regions of 43 genes associated with
malformations of cortical development (MCD) and ul-
tradeep exome sequencing of the FCD-­ derived DNA
obtained from brain biopsy (×2000 average raw cover-
age, Agilent SureSelectXT Custom 1-­499 kb and WES
v6) detected no putative causal variants, apart from the
germline variant in RANBP2 (variant allele frequency of
50%).
4 | D I S C U SSION
This report demonstrates an extremely atypical and dra-
matic life-­threatening course of focal epilepsy with cogni-
tive decline and signs of diffuse brain damage caused by
FCD type IIa that we have never observed before in a cohort
of our pediatric FCD patients during the entire duration of
pediatric epilepsy surgery program (2000-­ongoing).10
Despite a clear improvement in the patient's clinical sta-
tus after the hemispherotomy, multiple questions remain
to be answered. First, definite histopathological diagnosis
was only achieved after immunohistochemical confirma-
tion of neurofilament and phosphoS6 expression. In our
case, in H&E staining, “giant neurons,” originally de-
scribed by Palmini et al. as neurons of increased size with
that retain pyramidal morphology without overexpression
of neurofilaments,7 closely resembled dysmorphic neu-
rons; however, they were on the smaller end of the typical
size spectrum of dysmorphic neurons (16–43 μm).8
Second, it remains unclear why seizures reappeared
after a complete disconnection of the affected hemisphere.
Guerrini et al.11 recently reported three patients with
24709239, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/epi4.12863 by Cochrane Czech Republic, Wiley Online Library on [16/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
seizure relapse after hemispherotomy/hemispherectomy,
and they observed a gradient in variant allele frequency
between a more and a less affected hemisphere in a pa-
tient with Proteus syndrome. The authors stress that vari-
ant allele frequency of somatic pathogenic variants may
vary, and they suggest that a more widespread distribution
of the pathogenic variant, not limited to a single hemi-
sphere, might be the cause of unsatisfactory outcomes of
hemispherotomy/hemispherectomy. In our case, the deci-
sion to perform hemispherotomy in the first step, in con-
trast to a staged surgical procedure, was based on multiple
considerations. First, the patient was experiencing a life-­
threatening status epilepticus, refractory to multiple lines
of treatment, displayed a constant postictal hemiparesis,
and all of the available evidence pointed in the direction of
an extensive epileptogenic zone. The staged surgery there-
fore would most probably not have aborted the ongoing
status epilepticus and introduced inadequate risks, given
his life-­threatening condition.
Finally, the role of the RANBP2 variant, classified
as a variant of unknown significance, according to the
American College of Medical Genetics (ACMG) guide-
lines,12 remains enigmatic. RAN-­binding protein 2 con-
stitutes a nuclear pore protein; consequently, deficit in
nuclear transport in genetically predisposed individu-
als may result in cytokine storm, presence of cytokines
in central nervous system, disruption of brain–blood
barrier, and encephalopathy.13,14 Heterozygous patho-
genic variants in RANBP2, which may be incompletely
penetrant,15 predispose to an acute infection-­induced
necrotizing encephalopathy that manifests within days
from the onset of a febrile illness.13,16,17 Patients pres-
ent with a highly variable course that may result in a
complete recovery but also to a patient's death from
acute necrotizing encephalopathy. The clinical course
and neuroimaging features of our patient did not cor-
respond to those described in the literature, the pa-
tient did not present with necrotizing encephalopathy;
in fact, no publication to our knowledge reported no
MRI changes in patients with RANBP2-­related condi-
tions.13–16,18–21 We therefore do not assume that our pa-
tient suffered from a RANBP2-­related condition, but we
hypothesize that the missense variant could potentially
have contributed as a modifying factor to such atypi-
cally severe presentation of the patient's main diagnosis
of FCD, in temporal association with varicella infec-
tion. Interestingly, a patient with FCD and a pathogenic
variant in RANBP2 (NM_006267:c.C1754T: p.T585M)
and a history of coma due to presumed encephalitis
(no infectious cause had been identified) was recently
reported.22 Although genetic causes of FCD and focal
MCD in surgical series have been reported,4,6,23 we
still lack information on the role of predisposing and

STRAKA ET AL.
disease-­modifying factors that might influence clinical
course of patients with MCD.
Our report also highlights the importance of brain bi-
opsy in a nononcological clinical setting; the results of
brain biopsy directly influenced our decision to proceed
with hemispherotomy. The right frontal lobe as the larg-
est noneloquent brain area represents the most common
localization of brain biopsies. Moreover, electroclinical
features of the patient suggested the right frontal lobe as
the most likely localization of the epileptogenic zone, and
therefore, we regarded multiple biopsies from different
lobes too risky in light of potential added diagnostic value.
Our findings highlight the importance of a multitiered
approach to diagnostics of FCD24–26 that includes stan-
dard histopathological and immunohistochemical tools
and advanced genomics methods such as germline and
somatic WES.
AUTHOR CONTRIBUTIONS
Barbora Straka, Pavel Kršek, and Miroslav Koblížek were
involved in conceptualization, investigation, data cura-
tion, and writing. Radka Valkovičová, Barbora Splitkova,
Lenka Krsková, Markéta Kalinová, Markéta Vlčková,
Josef Zámečník, Petra Laššuthová, Lucie Sedláčková,
David Staněk, Alice Maulisová, Michal Tichý, and Martin
Kynčl were involved in investigation, data curation, and
writing.
ACKNOWLEDGMENTS
Supported by Ministry of Health of the Czech Republic,
grant no. NV19-­04-­00369, and by the Charles University,
project GA UK No 94121. Supported by Ministry of
Health, Czech Republic—conceptual development of re-
search organization, Motol University Hospital, Prague,
Czech Republic 00064203. Also Supported by project
nr. LX22NPO5107 (MEYS): Financed by EU—Next-­
Generation EU.
CONFLICT OF INTEREST STATEMENT
None of the authors has any conflict of interest to disclose.
We confirm that we have read the Epilepsia Open position
on issues involved in ethical publication and affirm that
this report is consistent with those guidelines.
DATA AVAILABILITY STATEMENT
Data that support the findings of this study are available
from the corresponding author upon reasonable request.
ETHICS STATE MENT
This work was approved by the Ethics Committee of the
Motol University Hospital, Prague, Czech Republic. The
patient's legal guardian provided an informed consent
with the study and with the publication of the results and
of this case report.
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    7
ORCID
Barbora Straka https://orcid.org/0000-0001-8448-2833
Petra Laššuthová https://orcid.
org/0000-0003-1726-5868
Lucie Sedláčková https://orcid.
org/0000-0003-2551-4764
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How to cite this article: Straka B, Koblížek M,
Splítková B, Valkovičová R, Krsková L, Kalinová M,
et al. A 5-­year-­old boy with super-­refractory status
epilepticus and RANBP2 variant warranting
life-­saving hemispherotomy. Epilepsia Open.
2023;00:1–8. https://doi.org/10.1002/epi4.12863