Hemiconvulsion–hemiplegia–epilepsy syndrome: Current understandings

e u r o p e a n j o u rn a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 2 ) 1e9

Official Journal of the European Paediatric Neurology Society

Review article

Hemiconvulsionehemiplegiaeepilepsy syndrome: Currentunderstandings

Stephane Auvin a,b,c,*, Vanina Bellavoine c, Dana Merdariu c, Catherine Delanoe d,Monique Elmaleh-Berges e, Pierre Gressens a,b,c, Odile Boespflug-Tanguy b,c

a Inserm, U676, Paris, FrancebUniversite Paris 7, Faculte de Medecine Denis Diderot, Paris, FrancecAPHP, Hopital Robert Debre, Service de Neurologie Pediatrique, Paris, FrancedNeurophysiology Department, Robert Debre Children Hospital, APHP, Paris, FranceeRadiology Department, Robert Debre Children Hospital, APHP, Paris, France

a r t i c l e i n f o

Article history:

Received 10 August 2011

Received in revised form

3 January 2012

Accepted 7 January 2012

Keywords:

Hemiconvulsion

Hemiplegia

Febrile seizure

Status epilepticus

Edema

CACNA1A

Epileptogenesis

* Corresponding author. Service de NeuroloSerurier, 75935 Paris Cedex 19, France. Tel.:

E-mail address: [email protected] (S. Auv

Please cite this article in press as: AuvinEuropean Journal of Paediatric Neurology

1090-3798/$ e see front matter ª 2012 Europdoi:10.1016/j.ejpn.2012.01.007

a b s t r a c t

HemiconvulsioneHemiplegia (HH) syndrome is an uncommon consequence of prolonged

focal febrile convulsive seizures in infancy and early childhood. It is characterized by the

occurrence of prolonged clonic seizures with unilateral predominance occurring in a child

and followed by the development of hemiplegia. Neuroradiological studies showed

unilateral edematous swelling of the epileptic hemisphere at the time of initial status

epilepticus (SE). This acute phase is followed by characteristic cerebral hemiatrophy with

subsequent appearance of epilepsy, so called HemiconvulsioneHemiplegiaeEpilepsy

(HHE) syndrome. The etiologies and the underlying mechanisms remain to be under-

stood. Using a review of the literature, we summarized the data of the last 20 years. It

appears that idiopathic HH/HHE syndrome is the most common reported form. The basic

science data suggest that immature brain is relatively resistant to SE-induced cell injury.

Several factors might contribute to the pathogenesis of HH/HHE syndrome: 1. prolonged

febrile seizure in which inflammation may worsen the level of cell injury; 2. inflammation

and prolonged ictal activity that act on bloodebrain-barrier permeability; 3. predisposing

factors facilitating prolonged seizure such as genetic factors or focal epileptogenic lesion.

However, these factors cannot explain the elective involvement of an entire hemisphere.

We draw new hypothesis that may explain the involvement of one hemisphere such as

maturation of brain structure such as corpus callosum or genetic factors (CACNA1A

gene) that are specifically discussed. An early diagnosis and a better understanding

of the underlying mechanisms of HHE are needed to improve the outcome of this

condition.

ª 2012 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights

reserved.

gie Pediatrique et des Maladies Metaboliques, CHU Hopital Robert Debre, 48, boulevardþ33 1 40 03 53 91; fax: þ33 1 40 03 47 74.in).

S, et al., Hemiconvulsionehemiplegiaeepilepsy syndrome: Current understandings,(2012), doi:10.1016/j.ejpn.2012.01.007

ean Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

mailto:[email protected]

http://dx.doi.org/10.1016/j.ejpn.2012.01.007



e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 2 ) 1e92

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003. Neuro-imaging data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004. EEG findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 005. Neuropathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 006. Etiologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 007. Pathophysiological hypothesis (Fig. 2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

7.1. Occurrence of cytotoxic edema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 007.2. Edema restricted to one hemisphere . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

1. Introduction 2. Diagnosis

HemiconvulsioneHemiplegia (HH) syndrome is an

uncommon consequence of prolonged focal febrile convulsive

seizures in infancy and early childhood. It was first described

by Gastaut et al.1 It is characterized by the occurrence of

prolonged clonic seizures with unilateral predominance

occurring in the course of a febrile illness in a child usually

younger than 4 years, and followed by the development of

hemiplegia. Neuroradiological studies showed unilateral

edematous swelling of the epileptic hemisphere at the time of

initial SE. This acute phase is followed by characteristic global

atrophy of one hemisphere independent of any vascular

territory with subsequent appearance of epilepsy, so called

HemiconvulsioneHemiplegiaeEpilepsy (HHE) syndrome.2,3 In

the latter, seizures of temporal lobe origin aremost frequently

observed. The incidence of these syndromes has declined

dramatically in the industrialized countries over the past 30

years.4 It seems that mostly idiopathic HHE syndrome is now

observed. Moreover, the accurate management of status epi-

lepticus (especially the introduction of intravenous or rectal

diazepam in the early 1960s) may play a role in this decline.

However, few cases are recurrently reported.

The mechanisms underlying the HH/HHE syndrome are

unclear. Until recently, the proposed pathogenic mechanism

was a neuronal injury induced by venous thrombosis and/or

excitotoxicity.5 Previous abnormalities of the brain were also

suggested as underlying mechanism. We have recently re-

ported the neuropathological data of a patient with acute HH

syndrome showing cytotoxic edema without any evidence of

malformation, inflammatory response or infectious disease.

We found axonal damages in the thalamus of the epileptic

hemisphere6 illustrating the involvement of the whole hemi-

sphere in this condition.

Here,wehavereviewedtheavailabledataof the last20years

using a Pubmed search from January 1st 1990 to August 1st,

2011 (using two keywords: “hemiconvulsion” and “hemi-

plegia”). We briefly summarize the electroclinical data and

theneuro-imagingfindingsof theHH/HHEsyndrome.Wefocus

our analysis on the possible causes of the acute phase of HH/

HHEsyndrome suggestingnewpathophysiological hypothesis.

Please cite this article in press as: Auvin S, et al., HemiconvulsioEuropean Journal of Paediatric Neurology (2012), doi:10.1016/j.ejp

The diagnosis of HH syndrome should be discussed each time

that a persistent flaccid hemiplegia is observed after a pro-

longed febrile seizure in a child. The early seizure is most

often a prolonged clonic convulsion, usually with marked

unilateral predominance. In addition to the hemiplegia, other

post-ictal neurologic deficits can be observed such as motor

aphasia.7e9 It is not uncommon that the prolonged convul-

sions were unnoticed by the caregivers due to nighttime or

sleep time of the child leading to a prolonged duration of

status epilepticus (SE).10e12

During the acute period, edema of the affected hemisphere

can be severe resulting in life-threatening such as temporal

lobe herniation.10,13 Imaging should be performed as early as

possible to confirm the diagnosis. As described below, MRI

study with the clinical evaluation permits to diagnose HH

syndrome.

After a free interval of variable duration, spontaneous

recurrent seizures appear. 85% of the patients that have

epilepsy startedwithin 3 years of the initial HH phase (average

interval of 1e2 years).14 The seizures are often complex partial

seizures originating from the temporal lobe. In a study of 37

patients, it has been shown using stereo-EEG recordings in

adults that most of the patients exhibit several types of

seizures from different area.5 Interictal-EEG recordings

showed more frequently multifocal spikes and sharp-waves.5

Long-term cognitive outcome following HHE syndrome has

been poorly studied. Most of the patients have severe intel-

lectual disability.9,15 Surgical treatment can be discussed with

an improvement more than half of the patients.5,16 Exclusive

temporal lobe involvement seems to be a very good predictor

of seizure freedom after surgery.16

3. Neuro-imaging data

There are now several reports of patients with

longitudinal MRI investigations.11,17 Patients observed in our

institution showed similar findings. Early MRI demonstrates

diffuse signal anomalies confined to one hemisphere (Fig. 1):

nehemiplegiaeepilepsy syndrome: Current understandings,n.2012.01.007



e u r o p e a n j o u rn a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 2 ) 1e9 3

hypersignal on T2 sequence and diffusion imaging (DWI)

involving the whole pathologic hemisphere, within some

cases, mass effect on contralateral hemisphere. As a result of

mass effect also, ipsilateral temporal lobe herniation has been

reported in few patients.10,13

Hypersignal on diffusion imaging (DWI) is also noted on

early MRI reflecting a restricted diffusion due to cytotoxic

edema; consequently, ADC (apparent diffusion coefficient) is

decreased, resulting in hypointensity on ADC map (Fig. 1D).

This reduced ADC involved the entire affected hemisphere

with predominance in the subcortical white matter. All these

anomalies affect only one hemisphere. It is not uncommon to

observe a diaschisis with contralateral cerebellar hemisphere

atrophy as a sequellae.9

There is currently no patient that has been reported to

have abnormal angio-MRI study (Table 1).

On day 8e15, cytotoxic edema decrease, with pseudo-

normalization of the ADC maps, but hypersignal due at this

stage, to gliosis, with ongoing loss of volume is visible on T2

images. One month after the HH syndrome, the evolution is

Fig. 1 e Imaging studies at acute phase ofHH syndrome in a 18-m

of the left hemisphere sparing the thalamus and left basal gangl

admission (B) T1-Weighted, (C) T2-weighted, (D)ADCmapof thed

throughout the left hemisphere involving both gray and white m

whitematter onT1; hypersignal of thewhole hemisphere onT2. A

sparing only the thalamus and basal ganglia, with subcortical w


characterized by a cerebral atrophy of the initially involved

hemisphere.

Initially, proton Magnetic Resonance Spectroscopy

(1H-MRS) shows a reduction in the concentration of the

neuronalmarker N-acetyl aspartate [NAA] and amild increase

of lactate.17 Evolution in the first two weeks shows stability or

a slight increase of NAA level,11,17 that remain stable one

month after the event.17

If the temporal modifications of the MRI in HHE patients

seem now well known, these data do not provide any

convincing explanation about the mechanisms which deter-

mine the early and diffuse involvement of the white matter

and the unilaterality of the damage observed in HH/HHE

syndrome.

4. EEG findings

An EEG recording is important at the acute phase of HH

syndrome to exclude an ongoing subtitle status epilepticus.

onth-old boy. A: CT-ScanDay1 after admission: hypodensity

ia, without mass effect. BeD: MRI study on day 3 after

iffusion-weightedsequence. BrainMRI showsabnormalities

atter: loss of differentiation between gray and subcortical

DCmapdemonstrates hypointensity of the left hemisphere

hite matter predominance, due to cytotoxic edema.




Table 1 e Summary of the data of published HH/HHE patients (the last 20-years).

CSF Coagulation Metabolicinvestigations

MRI angiographyat diagnosis

Etiology

Franzoni, 2010 N N N N Idiopathic

Sakakibara, 2009 NA NA N NA SCN1A

Sankhyan, 2008 N N NA NA Idiopathic

Auvin, 2007 N N N N Idiopathic

Berhouma, 2007 N NA NA N Idiopathic

Toldo, 2007 N NA N N Idiopathic

Mondal, 2006 NA Protein S

deficiency

NA NA

Kawada, 2004 N NA NA N

Freeman, 2002 (3 patients) 1: N 1: NA 1: N 1: NA Idiopathic

2: N 2: NA 2: N 2: NA Idiopathic

3: N 3: NA 3: N 3: NA Idiopathic

Kimura, 2002 N NA N NA Idiopathic

Scantlebury, 2002 (2 patients) 1: NA 1: V 1: NA 1:N

2: N 2: V and MTHFR 2: NA 2:N

Wakamoto, 2002 N NA NA N

V: Factor V Leiden Mutation; CSF: cerebrospinal fluid; MTHFR: methyl tetra hydro folate reductase mutation; N: Normal; NA: not available;

SCN1A: de novo mutation of SCN1A gene.


However, the diagnosis of HHE does not require EEG to be

confirmed. At the late stage of HHE syndrome, EEG recoding

would permit to identify epileptogenic area of the atrophic

hemisphere that may need surgical management in case of

pharmacoresistance.5

At the acute stage of HH syndrome, the ictal discharge is

characterized by rhythmic (2e3/s) slowwaves that are usually

bilateral with higher amplitude on the affected hemisphere

associated with spikes, sharp-waves and episodic fast activity

(10/s). It is very common that the discharge may change in

shape and frequency.17 The use of polygraphic recording

(EMGeEEG) does not permit to correlate clinical symptoms to

EEG abnormalities.5

After the prolonged seizure, slow waves and spikes are

followed by delta slowing with higher amplitude on the

affected hemisphere.6,8,13 Short period of suppression activity

may be observed.6 These abnormalities contrast with the

recordingof theunaffectedhemisphere that usually showslow

waves associated with reappearing physiological rythms.5

5. Neuropathology

Few pathologic data are available. Two papers by Mori et al.

are the first studies reporting the pathological findings of HHE

syndrome.18,19 The post-mortem specimens reported by Mori

showed diffuse cortical scarring in the laminae. Only one

patient had malformation (polymicrogyria in the left sylvian

fissure). He reported the studies of two brains from infants

who died several days after hemiconvulsions and/or gener-

alized status epilepticus. In these two patients, CSF was

normal and the histological examination did not reveal any

inflammatory process or vascular lesions. Diffuse laminar

necrosis and edema in cortical layers 3 and 5 extending

throughout the hemisphere and including hippocampus were

the main histological features.18,19

We recently reported the neuropathological study of an

acute HH syndrome.6 We did not find any underlying


conditions. Moreover, we did not observe any cell death as

a result of prolonged SE. Anti-neurofilament immunostaining

was very useful to determine the existence of axonal damage

in the thalamus of the epileptic hemisphere in our patient.6

The last available data are from a surgical biopsy of the

right temporal cortex of a patient that had decompressive

craniectomy. The examination showed some granular cells

within a diffuse spongiosis and edemawithout cell necrosis.10

Both pathological and angio-MRI studies did not provide

any evidence of the involvement of thrombosis or vascular

abnormalities. Themost recent data did not report a high level

of cell injury. These studies did not find any evidence for an

underlying condition of the epileptic hemisphere such as

pathological findings suggesting encephalitis or cortical and/

or hippocampal dysplasia.

6. Etiologies

The HH/HHE syndromes have been described to result of

multiple etiologies but in many patients no cause is obvious.

Hyperthermia is most often present during the acute phase of

initial SE, suggesting that HH/HHE syndrome may be a severe

variant of complicated febrile convulsions.20 Most of the

recent available data report idiopathic HH/HHE syndrome. In

the last 20 years, more than 50 patients have been re-

ported5,8,15,16 in Table 1. Salih et al. reported the initial

presentation and the long-term outcome of 6 HHE patients.

Their data suggest that all of them were idiopathic.8 More

recently, a retrospective case series reported 8 patients.

However, most of the patient (n ¼ 6/8) was diagnosed at the

late HHE stage excluding any investigation regarding the

etiology.9 One of the two patients that have been observed

since the HH phase experienced measles at time of initial SE

onset and MRI studies revealed a temporal lobe tuberculoma

that might have lowered the seizure threshold.9 The details of

the etiology and standard investigations of the other patients

are reported in the Table 1. Fourteen of 15 have had typical





idiopathic HH/HHE syndrome. Looking at the available data, it

is obvious that the seizure threshold in some patients may

have been lowered by a preexisting condition but we did not

find any direct etiology such as homolateral epileptogenic

brain abnormalities or thrombosis (Table 1). A patient has been

reported to have HHE syndrome as a presenting feature of L-2-

hydroxy-glutaric aciduria. The authors reported a full recovery

of the left hemiplegia within the first 24 h and the MRI study

did not reveal edema restricted to one hemisphere.21 The

diagnosis of HH syndrome in this patient seems unlikely.

Until recently, the proposed etiologies were venous

thrombosis, metabolic disease, focal brain abnormalities

leading to a prolonged focal status epilepticus inducing the

hemispheric cytotoxic edema.5 The recent data don’t support

that these etiologies are frequent in HH/HHE syndrome

(see Table 1).

In the last years, typical idiopathic HH/HHE syndrome has

been mostly reported (Table 1). In one third of the reported

cases, precipitating factors have been reported such as

contralateral cortical dysplasia (n ¼ 1), coagulation disorders

without proved thrombosis (n ¼ 2), viral infection (n ¼ 1) and

SCN1Agenemutation (n¼ 1). Themost frequent findings in the

recent years have been the identifications of coagulation

disorders (3/20): protein S deficiency (n ¼ 1),22 factor V Leiden

mutation (n¼ 1) andhomozygous for theMTHFRC677Tmutant

gene (n ¼ 1).7 These findings increase the likelihood of throm-

bosis as the cause and allows for consideration of anti-

coagulation to prevent recurrence or progression. However,

only one of the three patients exhibited abnormal MRI-

angiography showing a paucity of distal vessels in left middle

cerebral artery on late MRI study showing hemispheric brain

atrophy.22 In our previous report,6 we did not find any throm-

bosis as well as in our most recent patients (unshown data).

Venous thrombosis should be always discussed appropriately.

Finally, it has been suggested that HH syndrome may

represent a variant of the dual pathology that may be

observed in prolonged febrile seizure followed by hippo-

campal sclerosis. In case of mesial temporal sclerosis, cortical

lesions such as neuronal migration disorders, low-grade

tumors, or gliotic lesions have been frequently observed.

These lesions may represent a common pathogenic mecha-

nism, which could explain the predisposition to prolonged

febrile seizures and the development of mesial temporal

sclerosis due to a dual pathology (combination of develop-

mental abnormalities and prolonged febrile seizure).23 In the

recent years, only one patient has been reported to have

a contralateral focal cortical dysplasia.12 We cannot exclude

that such epileptogenic lesion can be undetected by the MRI.24

However, none of neuropathological data have demonstrated

such abnormalities.6,18,19 The collection of neuropathological

data are needed to investigate the presence of cortical or

hippocampal dysplasia.

Several studies have suggested that human herpes virus

(HHV)-6may be a commonetiologic agent in febrile seizures. If

it is true that HHV-6B and HHV-7 primary infection coincides

with the peak incidence of FS, the available data did not permit

to determine the role of these viruses in FS occurrence.25 It

may be related to the fever induced by the primoinfection or

HHV-6 CNS invasion.26 In case of HH syndrome, only one

patient has been reported with HHV-7 primoinfection.27 In


this patient a PCR analysis was positive in the plasma while it

was negative in CSF. The patient had a seroconversion for

HHV-7 shown by a raise of anti-HHV-7 antibodies in plasma.

Kawada et al. excluded a CNS invasion but they suggest

a possible endothelial involvement leading to vascular

disorder explaining the hemispheric involvement.27

Regarding the available data (Table 1), it is difficult to

conclude on the involvement of HHV-6 and/or HHV-7 in HH/

HHE syndrome pathogenesis. CSF analyses are frequently re-

ported as normal. However, negative PCR result in CSF cannot

exclude meningitis or menigoencephalitis. In a large series of

662 patients, mostly immunocompetent, detection of HHV-6

and EBV by CSF PCR did not correlate clinically in several

individuals with the presence of a CNS infection.28 Further

investigations such as PCR from brain tissue as well as path-

ological investigations (immunostaining and electronic

microscopy) are needed to investigate adequately this

hypothesis.

7. Pathophysiological hypothesis (Fig. 2)

The pathophysiological mechanisms of HH/HHE syndrome

remain unclear. Several factors might contribute to the

pathogenesis of HH/HHE syndrome:

(1) Seizure of long duration that may pass unnoticed leading

to impairment of neuronal energy metabolism and exci-

totoxic cell injury.

(2) Prolonged febrile seizure in whom inflammation may

worsen the level of cell injury

(3) Inflammation and prolonged ictal activity that act on

bloodebrain-barrier permeability

(4) Predisposing factors facilitating prolonged seizure such as

genetic factors and/or focal epileptogenic lesion.

The most surprising findings in HH syndrome is the elec-

tive involvement of one hemisphere. Here, we discuss the

pathophysiological hypothesis of 1. the occurrence of cyto-

toxic edema, 2. restricted to one hemisphere. We suggest new

hypothesis based on the current knowledge.

7.1. Occurrence of cytotoxic edema

First of all, it may be suggested that the hemispheric edema is

a direct result of the focal febrile seizures. The question

remains why we see so many children with prolonged and/or

focal febrile convulsions who do not suffer similar

consequences.

The occurrence of edema is frequent in venous throm-

bosis. However, the hypothesis of venous thrombosis appears

unlikely. Despite coagulation disorders have been observed in

several patients, there is no evidence for an involvement of

thrombosis in both MRI angiography and neuropathological

studies (see above).

In experimental studies, it has been shown that SE in

immature brain result in moderate cell injury level.29,30 The

immaturity of the brain structure cannot be taken into an

account to explain a particular sensibility to brain injury. If

long lasting SE in immature brain cannot explain such a level




Fig. 2 e Current understanding of the pathophysiological mechanisms involved in HH/HHE syndrome.


of injury, it has been described that inflammation and

hyperthermia may worsen acute consequence of SE.31e33

These factors may contribute to cell injury but it can explain

the pathophysiology of HH syndrome. Moreover, hyper-

thermia and inflammation are also observed in prolonged FS.

It is now well established that prolonged SE act on

BloodeBrain-Barrier (BBB). It is likely that the combination of

inflammation and SE increase the leakage of the barrier. But it

has not yet been proved in human. In experimental studies, it

has been shown that prolonged SE induced by lith-

iumepilocarpinemodelwas responsible of BBB leakage. These

phenomena were observed in all adult animal, in 2/3 of P21

rats and none of P9 rats.34,35

As described here, there are several hypotheses explaining

a high level of cerebral injury leading to edema (Fig. 2). But

none of them can explain why the edema is restricted to one

hemisphere.

7.2. Edema restricted to one hemisphere

There is currently no explanation of the unilateral involve-

ment of acute edema in HH syndrome. This acute phase is the

start of definitive consequences observed in this disease such

as hemiplegia and brain atrophy with epilepsy. There is

currently no way to reverse these phenomena. A better

understanding is necessary to improve our management of

the patients. Here, we discuss new hypotheses.

� Regional maturation of brain structures across the

development


A focal lesion or a restriction of the diffusion of the

epileptic discharge to one hemisphere can be suggested. Bahi-

Buisson et al. have suggested that the kinetics of regional

cortical maturation could be involved.12 The major commis-

sure connecting the cerebral hemispheres is the corpus cal-

losum (CC). Its implicationmay be suggested. The CC changes

structurally throughout life, but most dramatically during

childhood and adolescence. During the first 10 years of life, the

connections between the two cerebral hemispheres mature

gradually. This coincides with improvement in interhemi-

spheric integration during childhood, as has been shown

behaviorally in many transfer tasks. It is possible that this

developmental profile of CC play a role in bilateral synchro-

nization of seizure discharge. Data are needed to confirm this

hypothesis.

� Focal CNS infection by neurotrophic virus

The existence of a preexisting cerebral lesion modifying

the cortical excitability has been suggested a long time ago. In

HH syndrome, Gastaut has originally described ipsilateral

structural abnormalities such as neonatal hypoxiceischemic

lesions and neuronal migration disorders.1 In the recent year,

it appears that reported the HH syndromes are mostly idio-

pathic. This modification may be explained by the dramatic

decrease of incidence of this condition. However, CNS viral

infectionmay act as a focal trigger. As discussed above, HHV-6

and HHV-7 are neurotrophic virus. Moreover, several reports

suggest that HHV-6 and HHV-7 infection may be associated

with prolonged febrile seizures and status epilepticus.36,37 It is





still unclear if these virus by inducing fever act as a precipi-

tating factor or if they cause both fever and focal invasion of

the brain inducing in some case focal brain lesion leading to

the occurrence of unilateral edema.

� CACNA1A gene hypothesis

Recently, a patient with HHE syndrome occurring during

a B19 parvovirus infection has been reported with a hetero-

zygous S218L mutation in CACNA1A gene. The genetic study

of CACNA1A gene has been performed in this patient because

of history of cerebellar ataxia and episodic unconsciousness

with vomiting.38

The CACNA1A gene encodes the main subunit (1A) of the

neuronal P/Q type voltage-gated calcium-ion channel.39 In

humans, mutations in CACNA1A have been described in

familial hemiplegic migraine (OMIM #141499) but also in epi-

lepsy.40e43 In case of hemiplegic migraine, some reports may

give us an insight of the occurrence of localized brain edema.

Chabriat et al. first described a young womanwith hemiplegic

migraine (HM) due to CACNA1A gene mutation that had

reversible reduction of water diffusion in the brain during

a prolonged attack of hemiplegic migraine.44 The diffusion

changes were observed in the contralateral hemisphere 3 and

5 weeks after the onset of hemiplegia. These results suggest

the occurrence of hemispheric cytotoxic edema during severe

attacks of hemiplegic aura. The reduction of water mobility

measured in the abnormal region strongly suggests the

shrinkage of the extracellular space and the accumulation of

intracellular water.45

One particular type of CACNA1A mutation, the S218L

mutation, was found in patients who suffered from particu-

larly severe attacks of HMwhichwere triggered by trivial head

trauma and were associated with often fatal excessive

cerebral edema. Stam et al. found a de novo mutation in

two patients with early seizures and cerebral edema

after trivial head trauma.46 In these two patients, the edema

was restricted to one hemisphere. Malpas T et al. reported a

5-year-old girl with severe HM induced byminor head trauma.

She has a de novo mutation in CACNA1A (p. Arg1349Gln). She

had a right-sided focal seizure on day 8, and on day 10

following the injury MRI demonstrated marked enlargement

of the left cerebral hemisphere with generalized sulcal

effacement and significant mass effect.47

Moreover, the role of other genes polymorphisms may be

discussed. The ideal gene candidates should be genes that

regulated both inflammation and edema. Bradykinin path-

ways should be investigated because bradykinin receptors are

over-expressed in epileptic tissue48 Moreover, it has been

shown in a model of focal brain injury that the inhibition of

bradykinin receptor leads to a lower level of BBB leakage and

a lower level of injury.49

The Fig. 2 summarizes the different pathway that may be

involved in hemispheric brain edema. The pathogenesis

seems related to interplay among consequences of prolonged

seizure activity, inflammation and hyperthermia. The

involvement of genetic predisposition and viral infection are

strongly suggested. But it remains to be proved in larger series.

The hemispheric brain atrophy is the result of the cytotoxic

edema. The early decrease of NAA in MRI spectroscopy


suggests the occurrence of an early neuronal involvement.

Both hyperthermia and inflammation probably worsen the

level of cell injury. Neuropathological data and MRI data have

shown that the brain injury is not restricted to cortical and

subcortical area. We found axonal damage in thalamus of the

epileptic hemisphere.6 All these process lead to hemispheric

atrophy.

8. Conclusion

IN the HH/HHE syndrome, early edema of the entire epileptic

hemisphere is the initiation of a cascade that is not totally

understood. The previous hypothesis of undiagnosed

thrombosis seems to be currently excluded even if it is

important to rule out this hypothesis in clinical practice.

Moreover, experimental data do not suggest a particular

vulnerability to cell injury during brain development. Pro-

longed seizure activity, hyperthermia, inflammation and

blood brain barrier damage probably contribute to the path-

ogenesis of HH/HHE syndrome. Since these factors are also

combined in prolonged febrile seizures, we think that addi-

tional factor(s) lead to HH/HHE pathogenesis. Regarding to the

current knowledge, we suggest that genetic factors, progres-

sive maturation of the corpus callosum or focal epileptogenic

lesionmay play a role in the HH/HHE syndrome pathogenesis.

Data are needed to improve our understanding of this

condition that is responsible of definitive motor impairment

and refractory focal epilepsy. Prospective collaborative

studies are needed.

Acknowledgment

Stephane Auvin is partially support by INSERM Grant (Contrat

Interface INSERM 2010); Pierre Gressens is partially support by

AP-HP Grant.

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Hemiconvulsion–hemiplegia–epilepsy syndrome: Current understandings

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