Review article
Hemiconvulsion–hemiplegia–epilepsy syndrome: Current understandings

https://doi.org/10.1016/j.ejpn.2012.01.007Get rights and content

Abstract

Hemiconvulsion–Hemiplegia (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 Hemiconvulsion–Hemiplegia–Epilepsy (HHE) syndrome. The etiologies and the underlying mechanisms remain to be understood. 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 blood–brain-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.

Introduction

Hemiconvulsion–Hemiplegia (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 Hemiconvulsion–Hemiplegia–Epilepsy (HHE) syndrome.2, 3 In the latter, seizures of temporal lobe origin are most 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 epilepticus (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 reported 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 hemisphere in this condition.

Here, we have reviewed the available data of the last 20 years using a Pubmed search from January 1st 1990 to August 1st, 2011 (using two keywords: “hemiconvulsion” and “hemiplegia”). We briefly summarize the electroclinical data and the neuro-imaging findings of the HH/HHE syndrome. We focus our analysis on the possible causes of the acute phase of HH/HHE syndrome suggesting new pathophysiological hypothesis.

Section snippets

Diagnosis

The diagnosis of HH syndrome should be discussed each time that a persistent flaccid hemiplegia is observed after a prolonged 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.7, 8, 9 It is not uncommon that the prolonged convulsions were unnoticed by the caregivers due to nighttime or sleep time of the

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): 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,

EEG findings

An EEG recording is important at the acute phase of HH syndrome to exclude an ongoing subtitle status epilepticus. 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 (2–3/s) slow waves that are usually bilateral

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 generalized status epilepticus. In these two patients, CSF was normal and the

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 reported5, 8, 15, 16 in Table 1. Salih et al. reported the initial presentation and the

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 excitotoxic 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 blood–brain-barrier permeability

  • (4)

    Predisposing factors facilitating prolonged seizure such as

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. Prolonged seizure activity, hyperthermia, inflammation and blood brain barrier damage probably

Acknowledgment

Stéphane Auvin is partially support by INSERM Grant (Contrat Interface INSERM 2010); Pierre Gressens is partially support by AP-HP Grant.

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