Child NeurologyHemiconvulsion-hemiplegia-epilepsy syndrome

Jeffrey R Tenney MDPhD

Mark B Schapiro MD

ABSTRACT

Hemiconvulsion-hemiplegia-epilepsy (HHE) syndrome is an uncommon outcome of prolonged fo-cal status epilepticus in childhood The prolonged focal motor seizure usually occurs during thecourse of a febrile illness and is followed by hemiplegia ipsilateral to the side of convulsions Thisis accompanied by radiologic evidence of acute cytotoxic edema in the affected hemisphere fol-lowed by chronic atrophy Intractable epilepsy may develop at a time remote from the initial pre-sentation The clinical features of HHE syndrome were first described more than 5 decades agobut its pathophysiology remains poorly understood and the long-term cognitive outcomes areunclear Early recognition of the syndrome may help provide patients and families with an accu-rate prognosis regarding the subsequent development of epilepsy Neurologyreg 201279e1ndashe4

GLOSSARYFIRES fever-induced refractory epileptic encephalopathy in school-aged children HH hemiconvulsion-hemiplegiaHHE hemiconvulsion-hemiplegia-epilepsy HHS hemiconvulsion-hemiplegia syndrome MR magnetic resonanceNORSE new-onset refractory status epilepticus

CLINICAL CASE PART I A 21-month-old boy former 25-week premature infant with a history of bilateralgrade IIIIV intraventricular hemorrhages and hydrocephalus with ventriculo-peritoneal shunt presentedwith a likely prolonged period of right-sided jerking There was no prior history of seizures and his motor andlanguage development was age-appropriate His parents stated that he was in his usual state of health andacting normally on the day prior to presentation but he did have a tactile fever He was last seen normal atmidnight when he was checked on by his parents His mother found him 6 hours later with right face armand leg jerking but he had no impaired consciousness or eye deviation During transport he had continuousright-sided jerking but was conscious and moving the left side normally He was febrile upon arrival to theemergency room and he initially received IV lorazepam and IV valproic acid with no effect At that point hedeveloped gaze deviation to the right and mental status deterioration He received IV fosphenytoin wasintubated and was admitted to the intensive care unit The right-sided face arm and leg jerking continued soa pentobarbital infusion was started The total duration of the seizure was approximately 10 hours The patientremained in a pentobarbital coma for 48 hours before it was weaned and levetiracetam was started as a maintenanceantiepileptic medication On hospital day 5 his mental status improved but he was noted to have a right facialdroop right visual field deficit right hemiparesis right hyperreflexia and no spontaneous speech

Differential diagnosis Acute focal weakness following a seizure in a child has many serious etiologies that must beinvestigated (table) The evaluation is focused on excluding serious or treatable causes Evaluation should begin withMRI and magnetic resonance (MR) angiography to exclude structural lesions such as neoplasms intracerebralabscesses acute disseminated encephalomyelitis developmental brain malformations or signs of trauma and vascu-lar disorders such as ischemic or hemorrhagic infarctions In the case presented it was also important to evaluate forventriculo-peritoneal shunt malfunction causing increased intracranial pressure with funduscopic examinationMRI and shunt externalization if needed Other testing should include EEG serum glucose and CSF analysis

CLINICAL CASE PART II Following resolution of burst suppression the EEG became severely suppressedover the entire left hemisphere MRI brain done on hospital day 5 showed restricted diffusion with apparentdiffusion coefficient correlation throughout the left hemisphere (figure A) This progressed over the next

Correspondence amp reprintrequests to Dr Tenneyjeffreytenneycchmcorg

From the Department of Neurology Cincinnati Childrens Hospital Medical Center Cincinnati OH

Go to Neurologyorg for full disclosures Disclosures deemed relevant by the authors if any are provided at the end of this article

RESIDENTamp FELLOWSECTION

Section EditorMitchell SV ElkindMD MS

Copyright copy 2012 by AAN Enterprises Inc e1

month to more pervasive signal abnormalities andvolume loss of the entire left hemisphere that werelikely consistent with diffuse cortical necrosis (figureB) Routine electrolytes and CSF analysis at the timeof presentation were within normal limits

At the last follow-up (16 months posthospital-ization) the patient remained seizure- free on leve-tiracetam The presenting symptoms hospitalcourse and imaging were most consistent withhemiconvulsion-hemiplegia (HH) syndrome sincehe has not developed subsequent epilepsy His motorfunctioning improved with weekly physical therapyoccupational therapy and he was taking some stepsindependently He continued to have limited use ofthe right upper extremity especially with fine motormovements of the hand Speech progressed well and

he was speaking in sentences counting and identify-ing some letters

DISCUSSION Epidemiology HHE syndrome wasfirst reported by Gastaut and colleagues1 approxi-mately 50 years ago The specific incidence is un-known but it has been reported that it is declining indeveloped countries23 This could be due to im-proved and more rapid treatment of status epilepti-cus as well as the wider availability of rectal and IVbenzodiazepines A decrease in the incidence of fe-brile status epilepticus due to increased rates of child-hood immunizations is another possible explanation

Clinical characteristics The first report in the Englishliterature of HHE syndrome (1960) described theclinical electrographic radiologic and pathologicfeatures of 150 children identified with the syn-drome1 Children are usually less than 4 years of ageat the time of presentation and a concurrent febrileillness should be present The initial stage is referredto as HH syndrome (HHS) since epilepsy has not yetdeveloped HHS is characterized by prolonged(hours) unilateral and clonic convulsions that areoften initially unrecognized and many times thechild is found having the convulsions in his or herbed4 The hemiconvulsion has the following charac-teristics that have been described by Chauvel andDravet4 1) duration of hours and at times more than24 hours 2) variable location of the jerking with apossibility of contralateral seizures if it is prolonged3) inconstancy of impairment of consciousness 4)variable onset with possible headeye deviation uni-lateral jerking or bilateral jerks evolving to unilateraljerks and 5) the possibility of severe autonomicsymptoms such as hypersalivation respiratory disor-ders and cyanosis HHE syndrome can be dividedinto 2 groups based on known etiologies IdiopathicHHE syndrome is only associated with fever and pre-

Figure MRI brain

MRI brain done on hospital day 5 shows fluid-attenuated inversion recovery (FLAIR) (left) diffusion-weighted imaging (middle) and apparent diffusioncoefficient (right) signal abnormalities throughout the left hemisphere (A) These abnormalities are not consistent with any vascular territories This pro-gressed over the next month to more pervasive signal abnormalities and volume loss of the entire left hemisphere that were likely consistent with diffusecortical necrosis as seen on the T2-weighted (left) and FLAIR axial (middle) and coronal (right) images (B)

Table Differential diagnosis of postictal focalweakness in childhood

Seizure with postictal paralysis

Stroke

Ischemic

Hemorrhagic

Neoplasm

Infectious

Encephalitis

Meningitis

Intracranial abscess

Acute disseminated encephalomyelitis

Metabolic

Hypoglycemia

Mitochondrial disorder (mitochondrial myopathyencephalopathy lactic acidosis and strokelike episodes)

Developmental brain malformation

Trauma

Psychogenic

e2 Neurology 79 July 3 2012

sumed extracranial infection while the symptomatictype is associated with fever as well as some identi-fied predisposing factor (head trauma intracranialinfection or cerebral vascular disease)

Unilateral hemispheric swelling occurs during thetime of convulsive status epilepticus The earliestchanges seen are edema of the subcortical white mat-ter in the affected hemisphere5 This is followed bythe development of global cerebral hemiatrophy overweeks to months6 An important distinguishing fea-ture from stroke is that these abnormalities are inde-pendent of any vascular territory In addition inHHE syndrome the MRI often shows prominentdiffusion restriction within the internal capsule basalganglia and portions of the thalamus initially as itdid in this case MR angiography in this case wasnormal and is consistent with data from larger caseseries of HHE syndrome that have shown normalvascular imaging7 The radiologic abnormalities cor-respond with clinical changes such as hemiplegia vi-sual field deficit or aphasia

Pathogenesis The etiology of HHE syndrome re-mains unclear but it is likely the result of multiplefactors Radiologic findings indicate that there is arelationship between a sequence of events includingearly repetitive seizures brain edema cortical andsubcortical atrophy and chronic epilepsy in many ofthe cases4 It is clear from pathologic examinationsthat the hemispheric swelling is related to cytotoxicedema8 Other reported pathologic features are spon-giosis and disruption of the normal cellular architec-ture It has been proposed that these changes couldbe related to the primary presumed viral infectionwith resultant inflammatory cytokine damage2 Therehas also been speculation that the syndrome is directlyrelated to the prolonged ictal activity The young ageseen at the time of onset is possibly related to the pro-pensity of the immature brain to develop unilateral ictaldischarges This prolonged unilateral ictal activitycould cause excessive neuronal excitation via N-methyl-D-aspartic acid (NMDA) glutamate receptors Thiscould lead to a cascade of increased intracellular cal-cium causing cytotoxic edema and eventual necrosisand apoptosis Most likely is that there is a synergisticrelationship between inflammation and seizures thatpotentiates status epilepticus and cellular damage It hasbeen proposed that HHE syndrome along with fever-induced refractory epileptic encephalopathy in school-aged children (FIRES) and new-onset refractory statusepilepticus (NORSE) may be part of the same spec-trum of inflammatory mediated encephalopathy andstatus epilepticus syndromes with the difference in clin-ical expression related to the stage of brain maturation9

There are no known underlying genetic factors associ-ated in children with HHE syndrome however a re-

cent report has linked it with CACNA1A mutation andpossible cerebral vasospasm10

Much of the data related to the pathogenesis ofHHE syndrome support the existence of a ldquofebrileidiopathic HHE syndromerdquo that shares some com-monalities with simple febrile seizures However therelative rarity of HHE syndrome has caused someauthors to question this connection and raise thepossibility that children who develop HHE syn-drome may have a preexisting cerebral lesion whichtransforms what would have been a simple febrileseizure into focal status epilepticus4

Treatment and prognosis Treatment for HHE syn-drome during the early acute phase of the illness ismainly supportive and in the short term most chil-dren do well once the initial status epilepticus is con-trolled However it has been proposed based onradiologic and pathologic findings that the use ofanti-edema agents and NMDA-type glutamate re-ceptor antagonists during the acute period could helpto stop neuronal injury2

After some variable period (months to years) ofseizure freedom approximately two-thirds of patientswill develop epilepsy that is in many cases intractable11

Making a distinction between idiopathic and symptom-atic types of HHE is important because the 2 typesdiffer in long-term prognosis12 Patients with the idio-pathic type tend to develop temporal lobe epilepsywhereas those in the symptomatic group have an earlieronset of epilepsy and it is a symptomatic generalizedtype No guidelines exist as to whether children withHHE syndrome should be on chronic anticonvulsantmedication to prevent the remote seizures There is evi-dence that surgical treatment of delayed intractable epi-lepsy in HHE syndrome is beneficial12

The motor deficits associated with HHE syn-drome have a variable course with some patients hav-ing persistent hemiplegia and others with completeresolution1 Physical and occupational therapy can beuseful in the acute and chronic periods of the syn-drome in order to maximize motor function Long-term cognitive and language outcomes associatedwith HHE syndrome are poorly understood Chau-vel and Dravet have reported mental retardation as afeature in one-third of the patients with intractableepilepsy referred for epilepsy surgery but a more re-cent study demonstrated that outcome can vary de-pending on which hemisphere is affected and mentalretardation is not universal413 Patients with retainedlanguage in the affected hemisphere tended to have abetter cognitive outcome

Based on this literature the prognosis for our pa-tient can be made His focal status epilepticus seemedto be related to a prolonged febrile seizure as in manyof the idiopathic cases However he had preexisting

Neurology 79 July 3 2012 e3

neuronal injury which places him in the symptomaticHH category making early symptomatic generalizedepilepsy more likely Long-term language outcome maybe dependent upon whether the functional cortex wasreorganized following cerebral injury Future fMRI forlanguage function could help to establish the prognosisin this regard more accurately

FUTURE PERSPECTIVES HHE syndrome is arare but serious disorder in the pediatric populationIt can greatly impact the quality of life for patientsand their families Health care dollars spent on pa-tients with this disorder could be substantial giventhe remote development of medically intractable ep-ilepsy and possibly lifelong hemiplegia

HHE syndrome should be preventable by contin-ued advances related to the rapid resolution of sei-zures The severe impairments associated with HHEsyndrome makes it imperative that continued re-search into the pathophysiology and treatment of thedisorder is performed It would be reasonable to pur-sue research related to preventing cytotoxic damageacutely with the use of NMDA antagonists or aggres-sive early treatment of cerebral edema

AUTHOR CONTRIBUTIONSJ Tenney qualifies as an author based on the following contributions

draftingrevising the manuscript for content and analysisinterpretation of

diagnostic testing M Schapiro qualifies as an author based on the follow-

ing contributions draftingrevising the manuscript for content and analy-

sisinterpretation of diagnostic testing

DISCLOSUREThe authors report no disclosures relevant to the manuscript Go to

Neurologyorg for full disclosures

REFERENCES1 Gastaut H Poirier F Payan H et al HHE syndrome

hemiconvulsions hemiplegia epilepsy Epilepsia 19601418ndash447

2 Auvin S Devisme L Maurage C et al Neuropathologicaland MRI findings in an acute presentation of hemiconvul-sion-hemiplegia a report with pathophysiological implica-tions Seizure 200716371ndash376

3 Salih M Kabiraj M Al-Jarallah A et al Hemiconvulsion-hemiplegia-epilepsy syndrome a clinical electroencepha-lographic and neuroradiological study Childs Nerv Syst199713257ndash263

4 Chauvel P Dravet C The HHE syndrome In Roger JBureau M Dravet C et al eds Epileptic Syndromes inInfancy Childhood and Adolescence Montrouge JohnLibbey Eurotext 2005277ndash293

5 Toldo I Calderone M Boniver C et al Hemiconvulsion-hemiplegia-epilepsy syndrome Early magnetic resonanceimaging studies and neuroradiological follow-up BrainDev 200729109ndash111

6 Sankhyan N Sharma S Kamate M et al Hemiconvulsion-hemiplegia-epilepsy syndrome sequential MRI follow-upNeurology 20089e28

7 Aicardi J Amsli J Chevrie J Acute hemiplegia in in-fancy and childhood Dev Med Child Neurol 196911162ndash173

8 Freeman J Coleman L Smith L et al Hemiconvulsion-hemiplegia-epilepsy syndrome characteristic early mag-netic resonance imaging findings J Child Neurol 20021710 ndash16

9 Nabbout R Vezzani A Dulac O et al Acute encephalop-athy with inflammation-mediated status epilepticus Lan-cet Neurol 20111099ndash108

10 Yamazaki S Ikeno K Abe T et al Hemiconvulsion-hemiplegia-epilepsy syndrome associated with CACNA1AS218L mutation Pediatric Neurol 201145193ndash196

11 Aicardi J Amsli J Chevrie J Acute hemiplegia in in-fancy and childhood Dev Med Child Neurol 196911162ndash173

12 Kim D Kim K Chu K et al Surgical treatment of delayedepilepsy in hemiconvulsion-hemiplegia-epilepsy syndromeNeurology 2008702116ndash2122

13 Mirsattari S Wilde N Pigott S Long-term cognitive out-come of hemiconvulsion-hemiplegia-epilepsy syndromeaffecting the left cerebral hemisphere Epilepsy Behav200813678ndash680

e4 Neurology 79 July 3 2012

DOI 101212WNL0b013e31825dce5f201279e1-e4 Neurology

Jeffrey R Tenney and Mark B SchapiroChild Neurology Hemiconvulsion-hemiplegia-epilepsy syndrome

This information is current as of July 2 2012

ServicesUpdated Information amp

httpnneurologyorgcontent791e1fullhtmlincluding high resolution figures can be found at

References httpnneurologyorgcontent791e1fullhtmlref-list-1

This article cites 12 articles 1 of which you can access for free at

Citations httpnneurologyorgcontent791e1fullhtmlotherarticles

This article has been cited by 1 HighWire-hosted articles

Subspecialty Collections

httpnneurologyorgcgicollectionviral_infectionsViral infections

httpnneurologyorgcgicollectionstatus_epilepticusStatus epilepticus

httpnneurologyorgcgicollectiondevelopmental_disordersDevelopmental disordersfollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

rights reserved Print ISSN 0028-3878 Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright Copyright copy 2012 by AAN Enterprises Inc All

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology

month to more pervasive signal abnormalities andvolume loss of the entire left hemisphere that werelikely consistent with diffuse cortical necrosis (figureB) Routine electrolytes and CSF analysis at the timeof presentation were within normal limits

At the last follow-up (16 months posthospital-ization) the patient remained seizure- free on leve-tiracetam The presenting symptoms hospitalcourse and imaging were most consistent withhemiconvulsion-hemiplegia (HH) syndrome sincehe has not developed subsequent epilepsy His motorfunctioning improved with weekly physical therapyoccupational therapy and he was taking some stepsindependently He continued to have limited use ofthe right upper extremity especially with fine motormovements of the hand Speech progressed well and

he was speaking in sentences counting and identify-ing some letters

DISCUSSION Epidemiology HHE syndrome wasfirst reported by Gastaut and colleagues1 approxi-mately 50 years ago The specific incidence is un-known but it has been reported that it is declining indeveloped countries23 This could be due to im-proved and more rapid treatment of status epilepti-cus as well as the wider availability of rectal and IVbenzodiazepines A decrease in the incidence of fe-brile status epilepticus due to increased rates of child-hood immunizations is another possible explanation

Clinical characteristics The first report in the Englishliterature of HHE syndrome (1960) described theclinical electrographic radiologic and pathologicfeatures of 150 children identified with the syn-drome1 Children are usually less than 4 years of ageat the time of presentation and a concurrent febrileillness should be present The initial stage is referredto as HH syndrome (HHS) since epilepsy has not yetdeveloped HHS is characterized by prolonged(hours) unilateral and clonic convulsions that areoften initially unrecognized and many times thechild is found having the convulsions in his or herbed4 The hemiconvulsion has the following charac-teristics that have been described by Chauvel andDravet4 1) duration of hours and at times more than24 hours 2) variable location of the jerking with apossibility of contralateral seizures if it is prolonged3) inconstancy of impairment of consciousness 4)variable onset with possible headeye deviation uni-lateral jerking or bilateral jerks evolving to unilateraljerks and 5) the possibility of severe autonomicsymptoms such as hypersalivation respiratory disor-ders and cyanosis HHE syndrome can be dividedinto 2 groups based on known etiologies IdiopathicHHE syndrome is only associated with fever and pre-

Figure MRI brain

MRI brain done on hospital day 5 shows fluid-attenuated inversion recovery (FLAIR) (left) diffusion-weighted imaging (middle) and apparent diffusioncoefficient (right) signal abnormalities throughout the left hemisphere (A) These abnormalities are not consistent with any vascular territories This pro-gressed over the next month to more pervasive signal abnormalities and volume loss of the entire left hemisphere that were likely consistent with diffusecortical necrosis as seen on the T2-weighted (left) and FLAIR axial (middle) and coronal (right) images (B)

Table Differential diagnosis of postictal focalweakness in childhood

Seizure with postictal paralysis

Stroke

Ischemic

Hemorrhagic

Neoplasm

Infectious

Encephalitis

Meningitis

Intracranial abscess

Acute disseminated encephalomyelitis

Metabolic

Hypoglycemia

Mitochondrial disorder (mitochondrial myopathyencephalopathy lactic acidosis and strokelike episodes)

Developmental brain malformation

Trauma

Psychogenic

e2 Neurology 79 July 3 2012

sumed extracranial infection while the symptomatictype is associated with fever as well as some identi-fied predisposing factor (head trauma intracranialinfection or cerebral vascular disease)

Unilateral hemispheric swelling occurs during thetime of convulsive status epilepticus The earliestchanges seen are edema of the subcortical white mat-ter in the affected hemisphere5 This is followed bythe development of global cerebral hemiatrophy overweeks to months6 An important distinguishing fea-ture from stroke is that these abnormalities are inde-pendent of any vascular territory In addition inHHE syndrome the MRI often shows prominentdiffusion restriction within the internal capsule basalganglia and portions of the thalamus initially as itdid in this case MR angiography in this case wasnormal and is consistent with data from larger caseseries of HHE syndrome that have shown normalvascular imaging7 The radiologic abnormalities cor-respond with clinical changes such as hemiplegia vi-sual field deficit or aphasia

Pathogenesis The etiology of HHE syndrome re-mains unclear but it is likely the result of multiplefactors Radiologic findings indicate that there is arelationship between a sequence of events includingearly repetitive seizures brain edema cortical andsubcortical atrophy and chronic epilepsy in many ofthe cases4 It is clear from pathologic examinationsthat the hemispheric swelling is related to cytotoxicedema8 Other reported pathologic features are spon-giosis and disruption of the normal cellular architec-ture It has been proposed that these changes couldbe related to the primary presumed viral infectionwith resultant inflammatory cytokine damage2 Therehas also been speculation that the syndrome is directlyrelated to the prolonged ictal activity The young ageseen at the time of onset is possibly related to the pro-pensity of the immature brain to develop unilateral ictaldischarges This prolonged unilateral ictal activitycould cause excessive neuronal excitation via N-methyl-D-aspartic acid (NMDA) glutamate receptors Thiscould lead to a cascade of increased intracellular cal-cium causing cytotoxic edema and eventual necrosisand apoptosis Most likely is that there is a synergisticrelationship between inflammation and seizures thatpotentiates status epilepticus and cellular damage It hasbeen proposed that HHE syndrome along with fever-induced refractory epileptic encephalopathy in school-aged children (FIRES) and new-onset refractory statusepilepticus (NORSE) may be part of the same spec-trum of inflammatory mediated encephalopathy andstatus epilepticus syndromes with the difference in clin-ical expression related to the stage of brain maturation9

There are no known underlying genetic factors associ-ated in children with HHE syndrome however a re-

cent report has linked it with CACNA1A mutation andpossible cerebral vasospasm10

Much of the data related to the pathogenesis ofHHE syndrome support the existence of a ldquofebrileidiopathic HHE syndromerdquo that shares some com-monalities with simple febrile seizures However therelative rarity of HHE syndrome has caused someauthors to question this connection and raise thepossibility that children who develop HHE syn-drome may have a preexisting cerebral lesion whichtransforms what would have been a simple febrileseizure into focal status epilepticus4

Treatment and prognosis Treatment for HHE syn-drome during the early acute phase of the illness ismainly supportive and in the short term most chil-dren do well once the initial status epilepticus is con-trolled However it has been proposed based onradiologic and pathologic findings that the use ofanti-edema agents and NMDA-type glutamate re-ceptor antagonists during the acute period could helpto stop neuronal injury2

After some variable period (months to years) ofseizure freedom approximately two-thirds of patientswill develop epilepsy that is in many cases intractable11

Making a distinction between idiopathic and symptom-atic types of HHE is important because the 2 typesdiffer in long-term prognosis12 Patients with the idio-pathic type tend to develop temporal lobe epilepsywhereas those in the symptomatic group have an earlieronset of epilepsy and it is a symptomatic generalizedtype No guidelines exist as to whether children withHHE syndrome should be on chronic anticonvulsantmedication to prevent the remote seizures There is evi-dence that surgical treatment of delayed intractable epi-lepsy in HHE syndrome is beneficial12

The motor deficits associated with HHE syn-drome have a variable course with some patients hav-ing persistent hemiplegia and others with completeresolution1 Physical and occupational therapy can beuseful in the acute and chronic periods of the syn-drome in order to maximize motor function Long-term cognitive and language outcomes associatedwith HHE syndrome are poorly understood Chau-vel and Dravet have reported mental retardation as afeature in one-third of the patients with intractableepilepsy referred for epilepsy surgery but a more re-cent study demonstrated that outcome can vary de-pending on which hemisphere is affected and mentalretardation is not universal413 Patients with retainedlanguage in the affected hemisphere tended to have abetter cognitive outcome

Based on this literature the prognosis for our pa-tient can be made His focal status epilepticus seemedto be related to a prolonged febrile seizure as in manyof the idiopathic cases However he had preexisting

Neurology 79 July 3 2012 e3

neuronal injury which places him in the symptomaticHH category making early symptomatic generalizedepilepsy more likely Long-term language outcome maybe dependent upon whether the functional cortex wasreorganized following cerebral injury Future fMRI forlanguage function could help to establish the prognosisin this regard more accurately

FUTURE PERSPECTIVES HHE syndrome is arare but serious disorder in the pediatric populationIt can greatly impact the quality of life for patientsand their families Health care dollars spent on pa-tients with this disorder could be substantial giventhe remote development of medically intractable ep-ilepsy and possibly lifelong hemiplegia

HHE syndrome should be preventable by contin-ued advances related to the rapid resolution of sei-zures The severe impairments associated with HHEsyndrome makes it imperative that continued re-search into the pathophysiology and treatment of thedisorder is performed It would be reasonable to pur-sue research related to preventing cytotoxic damageacutely with the use of NMDA antagonists or aggres-sive early treatment of cerebral edema

AUTHOR CONTRIBUTIONSJ Tenney qualifies as an author based on the following contributions

draftingrevising the manuscript for content and analysisinterpretation of

diagnostic testing M Schapiro qualifies as an author based on the follow-

ing contributions draftingrevising the manuscript for content and analy-

sisinterpretation of diagnostic testing

DISCLOSUREThe authors report no disclosures relevant to the manuscript Go to

Neurologyorg for full disclosures

REFERENCES1 Gastaut H Poirier F Payan H et al HHE syndrome

hemiconvulsions hemiplegia epilepsy Epilepsia 19601418ndash447

2 Auvin S Devisme L Maurage C et al Neuropathologicaland MRI findings in an acute presentation of hemiconvul-sion-hemiplegia a report with pathophysiological implica-tions Seizure 200716371ndash376

3 Salih M Kabiraj M Al-Jarallah A et al Hemiconvulsion-hemiplegia-epilepsy syndrome a clinical electroencepha-lographic and neuroradiological study Childs Nerv Syst199713257ndash263

4 Chauvel P Dravet C The HHE syndrome In Roger JBureau M Dravet C et al eds Epileptic Syndromes inInfancy Childhood and Adolescence Montrouge JohnLibbey Eurotext 2005277ndash293

5 Toldo I Calderone M Boniver C et al Hemiconvulsion-hemiplegia-epilepsy syndrome Early magnetic resonanceimaging studies and neuroradiological follow-up BrainDev 200729109ndash111

6 Sankhyan N Sharma S Kamate M et al Hemiconvulsion-hemiplegia-epilepsy syndrome sequential MRI follow-upNeurology 20089e28

7 Aicardi J Amsli J Chevrie J Acute hemiplegia in in-fancy and childhood Dev Med Child Neurol 196911162ndash173

8 Freeman J Coleman L Smith L et al Hemiconvulsion-hemiplegia-epilepsy syndrome characteristic early mag-netic resonance imaging findings J Child Neurol 20021710 ndash16

9 Nabbout R Vezzani A Dulac O et al Acute encephalop-athy with inflammation-mediated status epilepticus Lan-cet Neurol 20111099ndash108

10 Yamazaki S Ikeno K Abe T et al Hemiconvulsion-hemiplegia-epilepsy syndrome associated with CACNA1AS218L mutation Pediatric Neurol 201145193ndash196

11 Aicardi J Amsli J Chevrie J Acute hemiplegia in in-fancy and childhood Dev Med Child Neurol 196911162ndash173

12 Kim D Kim K Chu K et al Surgical treatment of delayedepilepsy in hemiconvulsion-hemiplegia-epilepsy syndromeNeurology 2008702116ndash2122

13 Mirsattari S Wilde N Pigott S Long-term cognitive out-come of hemiconvulsion-hemiplegia-epilepsy syndromeaffecting the left cerebral hemisphere Epilepsy Behav200813678ndash680

e4 Neurology 79 July 3 2012

DOI 101212WNL0b013e31825dce5f201279e1-e4 Neurology

Jeffrey R Tenney and Mark B SchapiroChild Neurology Hemiconvulsion-hemiplegia-epilepsy syndrome

This information is current as of July 2 2012

ServicesUpdated Information amp

httpnneurologyorgcontent791e1fullhtmlincluding high resolution figures can be found at

References httpnneurologyorgcontent791e1fullhtmlref-list-1

This article cites 12 articles 1 of which you can access for free at

Citations httpnneurologyorgcontent791e1fullhtmlotherarticles

This article has been cited by 1 HighWire-hosted articles

Subspecialty Collections

httpnneurologyorgcgicollectionviral_infectionsViral infections

httpnneurologyorgcgicollectionstatus_epilepticusStatus epilepticus

httpnneurologyorgcgicollectiondevelopmental_disordersDevelopmental disordersfollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

rights reserved Print ISSN 0028-3878 Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright Copyright copy 2012 by AAN Enterprises Inc All

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology

sumed extracranial infection while the symptomatictype is associated with fever as well as some identi-fied predisposing factor (head trauma intracranialinfection or cerebral vascular disease)

Unilateral hemispheric swelling occurs during thetime of convulsive status epilepticus The earliestchanges seen are edema of the subcortical white mat-ter in the affected hemisphere5 This is followed bythe development of global cerebral hemiatrophy overweeks to months6 An important distinguishing fea-ture from stroke is that these abnormalities are inde-pendent of any vascular territory In addition inHHE syndrome the MRI often shows prominentdiffusion restriction within the internal capsule basalganglia and portions of the thalamus initially as itdid in this case MR angiography in this case wasnormal and is consistent with data from larger caseseries of HHE syndrome that have shown normalvascular imaging7 The radiologic abnormalities cor-respond with clinical changes such as hemiplegia vi-sual field deficit or aphasia

Pathogenesis The etiology of HHE syndrome re-mains unclear but it is likely the result of multiplefactors Radiologic findings indicate that there is arelationship between a sequence of events includingearly repetitive seizures brain edema cortical andsubcortical atrophy and chronic epilepsy in many ofthe cases4 It is clear from pathologic examinationsthat the hemispheric swelling is related to cytotoxicedema8 Other reported pathologic features are spon-giosis and disruption of the normal cellular architec-ture It has been proposed that these changes couldbe related to the primary presumed viral infectionwith resultant inflammatory cytokine damage2 Therehas also been speculation that the syndrome is directlyrelated to the prolonged ictal activity The young ageseen at the time of onset is possibly related to the pro-pensity of the immature brain to develop unilateral ictaldischarges This prolonged unilateral ictal activitycould cause excessive neuronal excitation via N-methyl-D-aspartic acid (NMDA) glutamate receptors Thiscould lead to a cascade of increased intracellular cal-cium causing cytotoxic edema and eventual necrosisand apoptosis Most likely is that there is a synergisticrelationship between inflammation and seizures thatpotentiates status epilepticus and cellular damage It hasbeen proposed that HHE syndrome along with fever-induced refractory epileptic encephalopathy in school-aged children (FIRES) and new-onset refractory statusepilepticus (NORSE) may be part of the same spec-trum of inflammatory mediated encephalopathy andstatus epilepticus syndromes with the difference in clin-ical expression related to the stage of brain maturation9

There are no known underlying genetic factors associ-ated in children with HHE syndrome however a re-

cent report has linked it with CACNA1A mutation andpossible cerebral vasospasm10

Much of the data related to the pathogenesis ofHHE syndrome support the existence of a ldquofebrileidiopathic HHE syndromerdquo that shares some com-monalities with simple febrile seizures However therelative rarity of HHE syndrome has caused someauthors to question this connection and raise thepossibility that children who develop HHE syn-drome may have a preexisting cerebral lesion whichtransforms what would have been a simple febrileseizure into focal status epilepticus4

Treatment and prognosis Treatment for HHE syn-drome during the early acute phase of the illness ismainly supportive and in the short term most chil-dren do well once the initial status epilepticus is con-trolled However it has been proposed based onradiologic and pathologic findings that the use ofanti-edema agents and NMDA-type glutamate re-ceptor antagonists during the acute period could helpto stop neuronal injury2

After some variable period (months to years) ofseizure freedom approximately two-thirds of patientswill develop epilepsy that is in many cases intractable11

Making a distinction between idiopathic and symptom-atic types of HHE is important because the 2 typesdiffer in long-term prognosis12 Patients with the idio-pathic type tend to develop temporal lobe epilepsywhereas those in the symptomatic group have an earlieronset of epilepsy and it is a symptomatic generalizedtype No guidelines exist as to whether children withHHE syndrome should be on chronic anticonvulsantmedication to prevent the remote seizures There is evi-dence that surgical treatment of delayed intractable epi-lepsy in HHE syndrome is beneficial12

The motor deficits associated with HHE syn-drome have a variable course with some patients hav-ing persistent hemiplegia and others with completeresolution1 Physical and occupational therapy can beuseful in the acute and chronic periods of the syn-drome in order to maximize motor function Long-term cognitive and language outcomes associatedwith HHE syndrome are poorly understood Chau-vel and Dravet have reported mental retardation as afeature in one-third of the patients with intractableepilepsy referred for epilepsy surgery but a more re-cent study demonstrated that outcome can vary de-pending on which hemisphere is affected and mentalretardation is not universal413 Patients with retainedlanguage in the affected hemisphere tended to have abetter cognitive outcome

Based on this literature the prognosis for our pa-tient can be made His focal status epilepticus seemedto be related to a prolonged febrile seizure as in manyof the idiopathic cases However he had preexisting

Neurology 79 July 3 2012 e3

neuronal injury which places him in the symptomaticHH category making early symptomatic generalizedepilepsy more likely Long-term language outcome maybe dependent upon whether the functional cortex wasreorganized following cerebral injury Future fMRI forlanguage function could help to establish the prognosisin this regard more accurately

FUTURE PERSPECTIVES HHE syndrome is arare but serious disorder in the pediatric populationIt can greatly impact the quality of life for patientsand their families Health care dollars spent on pa-tients with this disorder could be substantial giventhe remote development of medically intractable ep-ilepsy and possibly lifelong hemiplegia

HHE syndrome should be preventable by contin-ued advances related to the rapid resolution of sei-zures The severe impairments associated with HHEsyndrome makes it imperative that continued re-search into the pathophysiology and treatment of thedisorder is performed It would be reasonable to pur-sue research related to preventing cytotoxic damageacutely with the use of NMDA antagonists or aggres-sive early treatment of cerebral edema

AUTHOR CONTRIBUTIONSJ Tenney qualifies as an author based on the following contributions

draftingrevising the manuscript for content and analysisinterpretation of

diagnostic testing M Schapiro qualifies as an author based on the follow-

ing contributions draftingrevising the manuscript for content and analy-

sisinterpretation of diagnostic testing

DISCLOSUREThe authors report no disclosures relevant to the manuscript Go to

Neurologyorg for full disclosures

REFERENCES1 Gastaut H Poirier F Payan H et al HHE syndrome

hemiconvulsions hemiplegia epilepsy Epilepsia 19601418ndash447

2 Auvin S Devisme L Maurage C et al Neuropathologicaland MRI findings in an acute presentation of hemiconvul-sion-hemiplegia a report with pathophysiological implica-tions Seizure 200716371ndash376

3 Salih M Kabiraj M Al-Jarallah A et al Hemiconvulsion-hemiplegia-epilepsy syndrome a clinical electroencepha-lographic and neuroradiological study Childs Nerv Syst199713257ndash263

4 Chauvel P Dravet C The HHE syndrome In Roger JBureau M Dravet C et al eds Epileptic Syndromes inInfancy Childhood and Adolescence Montrouge JohnLibbey Eurotext 2005277ndash293

5 Toldo I Calderone M Boniver C et al Hemiconvulsion-hemiplegia-epilepsy syndrome Early magnetic resonanceimaging studies and neuroradiological follow-up BrainDev 200729109ndash111

6 Sankhyan N Sharma S Kamate M et al Hemiconvulsion-hemiplegia-epilepsy syndrome sequential MRI follow-upNeurology 20089e28

7 Aicardi J Amsli J Chevrie J Acute hemiplegia in in-fancy and childhood Dev Med Child Neurol 196911162ndash173

8 Freeman J Coleman L Smith L et al Hemiconvulsion-hemiplegia-epilepsy syndrome characteristic early mag-netic resonance imaging findings J Child Neurol 20021710 ndash16

9 Nabbout R Vezzani A Dulac O et al Acute encephalop-athy with inflammation-mediated status epilepticus Lan-cet Neurol 20111099ndash108

10 Yamazaki S Ikeno K Abe T et al Hemiconvulsion-hemiplegia-epilepsy syndrome associated with CACNA1AS218L mutation Pediatric Neurol 201145193ndash196

11 Aicardi J Amsli J Chevrie J Acute hemiplegia in in-fancy and childhood Dev Med Child Neurol 196911162ndash173

12 Kim D Kim K Chu K et al Surgical treatment of delayedepilepsy in hemiconvulsion-hemiplegia-epilepsy syndromeNeurology 2008702116ndash2122

13 Mirsattari S Wilde N Pigott S Long-term cognitive out-come of hemiconvulsion-hemiplegia-epilepsy syndromeaffecting the left cerebral hemisphere Epilepsy Behav200813678ndash680

e4 Neurology 79 July 3 2012

DOI 101212WNL0b013e31825dce5f201279e1-e4 Neurology

Jeffrey R Tenney and Mark B SchapiroChild Neurology Hemiconvulsion-hemiplegia-epilepsy syndrome

This information is current as of July 2 2012

ServicesUpdated Information amp

httpnneurologyorgcontent791e1fullhtmlincluding high resolution figures can be found at

References httpnneurologyorgcontent791e1fullhtmlref-list-1

This article cites 12 articles 1 of which you can access for free at

Citations httpnneurologyorgcontent791e1fullhtmlotherarticles

This article has been cited by 1 HighWire-hosted articles

Subspecialty Collections

httpnneurologyorgcgicollectionviral_infectionsViral infections

httpnneurologyorgcgicollectionstatus_epilepticusStatus epilepticus

httpnneurologyorgcgicollectiondevelopmental_disordersDevelopmental disordersfollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

rights reserved Print ISSN 0028-3878 Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright Copyright copy 2012 by AAN Enterprises Inc All

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology

neuronal injury which places him in the symptomaticHH category making early symptomatic generalizedepilepsy more likely Long-term language outcome maybe dependent upon whether the functional cortex wasreorganized following cerebral injury Future fMRI forlanguage function could help to establish the prognosisin this regard more accurately

FUTURE PERSPECTIVES HHE syndrome is arare but serious disorder in the pediatric populationIt can greatly impact the quality of life for patientsand their families Health care dollars spent on pa-tients with this disorder could be substantial giventhe remote development of medically intractable ep-ilepsy and possibly lifelong hemiplegia

HHE syndrome should be preventable by contin-ued advances related to the rapid resolution of sei-zures The severe impairments associated with HHEsyndrome makes it imperative that continued re-search into the pathophysiology and treatment of thedisorder is performed It would be reasonable to pur-sue research related to preventing cytotoxic damageacutely with the use of NMDA antagonists or aggres-sive early treatment of cerebral edema

AUTHOR CONTRIBUTIONSJ Tenney qualifies as an author based on the following contributions

draftingrevising the manuscript for content and analysisinterpretation of

diagnostic testing M Schapiro qualifies as an author based on the follow-

ing contributions draftingrevising the manuscript for content and analy-

sisinterpretation of diagnostic testing

DISCLOSUREThe authors report no disclosures relevant to the manuscript Go to

Neurologyorg for full disclosures

REFERENCES1 Gastaut H Poirier F Payan H et al HHE syndrome

hemiconvulsions hemiplegia epilepsy Epilepsia 19601418ndash447

2 Auvin S Devisme L Maurage C et al Neuropathologicaland MRI findings in an acute presentation of hemiconvul-sion-hemiplegia a report with pathophysiological implica-tions Seizure 200716371ndash376

3 Salih M Kabiraj M Al-Jarallah A et al Hemiconvulsion-hemiplegia-epilepsy syndrome a clinical electroencepha-lographic and neuroradiological study Childs Nerv Syst199713257ndash263

4 Chauvel P Dravet C The HHE syndrome In Roger JBureau M Dravet C et al eds Epileptic Syndromes inInfancy Childhood and Adolescence Montrouge JohnLibbey Eurotext 2005277ndash293

5 Toldo I Calderone M Boniver C et al Hemiconvulsion-hemiplegia-epilepsy syndrome Early magnetic resonanceimaging studies and neuroradiological follow-up BrainDev 200729109ndash111

6 Sankhyan N Sharma S Kamate M et al Hemiconvulsion-hemiplegia-epilepsy syndrome sequential MRI follow-upNeurology 20089e28

7 Aicardi J Amsli J Chevrie J Acute hemiplegia in in-fancy and childhood Dev Med Child Neurol 196911162ndash173

8 Freeman J Coleman L Smith L et al Hemiconvulsion-hemiplegia-epilepsy syndrome characteristic early mag-netic resonance imaging findings J Child Neurol 20021710 ndash16

9 Nabbout R Vezzani A Dulac O et al Acute encephalop-athy with inflammation-mediated status epilepticus Lan-cet Neurol 20111099ndash108

10 Yamazaki S Ikeno K Abe T et al Hemiconvulsion-hemiplegia-epilepsy syndrome associated with CACNA1AS218L mutation Pediatric Neurol 201145193ndash196

11 Aicardi J Amsli J Chevrie J Acute hemiplegia in in-fancy and childhood Dev Med Child Neurol 196911162ndash173

12 Kim D Kim K Chu K et al Surgical treatment of delayedepilepsy in hemiconvulsion-hemiplegia-epilepsy syndromeNeurology 2008702116ndash2122

13 Mirsattari S Wilde N Pigott S Long-term cognitive out-come of hemiconvulsion-hemiplegia-epilepsy syndromeaffecting the left cerebral hemisphere Epilepsy Behav200813678ndash680

e4 Neurology 79 July 3 2012

DOI 101212WNL0b013e31825dce5f201279e1-e4 Neurology

Jeffrey R Tenney and Mark B SchapiroChild Neurology Hemiconvulsion-hemiplegia-epilepsy syndrome

This information is current as of July 2 2012

ServicesUpdated Information amp

httpnneurologyorgcontent791e1fullhtmlincluding high resolution figures can be found at

References httpnneurologyorgcontent791e1fullhtmlref-list-1

This article cites 12 articles 1 of which you can access for free at

Citations httpnneurologyorgcontent791e1fullhtmlotherarticles

This article has been cited by 1 HighWire-hosted articles

Subspecialty Collections

httpnneurologyorgcgicollectionviral_infectionsViral infections

httpnneurologyorgcgicollectionstatus_epilepticusStatus epilepticus

httpnneurologyorgcgicollectiondevelopmental_disordersDevelopmental disordersfollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

rights reserved Print ISSN 0028-3878 Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright Copyright copy 2012 by AAN Enterprises Inc All

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology

DOI 101212WNL0b013e31825dce5f201279e1-e4 Neurology

Jeffrey R Tenney and Mark B SchapiroChild Neurology Hemiconvulsion-hemiplegia-epilepsy syndrome

This information is current as of July 2 2012

ServicesUpdated Information amp

httpnneurologyorgcontent791e1fullhtmlincluding high resolution figures can be found at

References httpnneurologyorgcontent791e1fullhtmlref-list-1

This article cites 12 articles 1 of which you can access for free at

Citations httpnneurologyorgcontent791e1fullhtmlotherarticles

This article has been cited by 1 HighWire-hosted articles

Subspecialty Collections

httpnneurologyorgcgicollectionviral_infectionsViral infections

httpnneurologyorgcgicollectionstatus_epilepticusStatus epilepticus

httpnneurologyorgcgicollectiondevelopmental_disordersDevelopmental disordersfollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

rights reserved Print ISSN 0028-3878 Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright Copyright copy 2012 by AAN Enterprises Inc All

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology