FIRES and IHHE: Delineation of the syndromes

Authors

  • Rima Nabbout

    Corresponding author
    1. Inserm, U663, Paris, France
    2. University Paris Descartes; CEA, Gif sur Y vete, France
    • Department of Pediatric Neurology, Referral Center for Rare Epilepsies, Necker Infants Maladies Hospital, APHP, Paris, France
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Address correspondence to Rima Nabbout, Department of Neuropediatrics, Centre de référence épilepsies rares, Hôpital Necker Enfants malades, 149 rue de Sèvres, 75015 Paris, France. E-mail: rimanabbout@yahoo.com, rima.nabbout@nck.aphp.fr

Summary

Idiopathic hemiconvulsion hemiplegia and epilepsy syndrome (IHHE) and febrile infection–related epilepsy syndrome (FIRES) are rare epileptic syndromes characterized by the occurrence of status epilepticus in a previously healthy child during or closely after a febrile episode. In both syndromes, there is no evidence of central nervous system infection (encephalitis) and the etiology remains unclear. Treatment is disappointing, particularly in FIRES, except for a response to ketogenic diet (KD) in half of patients. In IHHS, children develop hemispheric brain atrophy with contralateral hemiplegia, epilepsy, and a variable degree of cognitive deficit. Patients with FIRES develop refractory epilepsy with severe cognitive deficit affecting the temporal and frontal lobe functions. The role of inflammation is hypothesized with a vicious circle involving inflammation and seizure activity facilitated by brain maturation putting them under the concept of “acute encephalopathy with inflammation-mediated status epilepticus.”

Idiopathic hemiconvulsion hemiplegia and epilepsy syndrome (IHHE) and febrile infection–related epilepsy syndrome (FIRES) are rare childhood epileptic syndromes. They are characterized by the occurrence of refractory status epilepticus during or after fever without evidence of central nervous system infection. Their incidence could be underestimated in the literature, since there are no epidemiologic studies considering these two entities. However, they are recognized worldwide and were both included in the last proposition for classification of the International League Against Epilepsy (ILAE) (Berg et al., 2010).

Idiopathic Hemiconvulsion Hemiplegia and Epilepsy Syndrome (IHHE)

Hemiconvulsion-hemiplegia epilepsy syndrome (HHE) is characterized by the combination of unilateral convulsive status epilepticus (SE), mainly clonic, followed by transient or permanent ipsilateral hemiplegia. It occurs in infants during the course of a nonspecific febrile illness, mainly in the first 2 years of life and in any case before the age of 4 years (Gastaut et al., 1960). SE is usually long and might persist for hours if not treated. In order to differentiate this condition from the more common unilateral deficit after a “complex” febrile seizure, a minimum duration of hemiplegia of 1 week is required (Chauvel & Dravet, 2005) . In opposition to the sequence of stroke where seizure occurs several hours after onset of the motor deficit, in HHS, the seizure(s) itself generates brain edema cell death with motor defect and often later epilepsy as additional sequel. Several months following the status pharmacoresistant partial epileptic seizures recur (Gastaut et al., 1960). This sequence is stereotyped and HHS with or without epilepsy (HHS ± E) has been introduced as an epileptic syndrome in the first ILAE classification of epilepsies (1989) and was included among epilepsy syndromes and epilepsies in the recent report of the ILAE Taskforce on Classification and Terminology (Berg et al., 2010).

Hemiconvulsion-hemiplegia epilepsy syndrome was reported as “symptomatic” in many instances, since it complicates the course of preexisting brain disorder, that is, Sturge-Weber disease, agenesis of the corpus callosum or tuberous sclerosis. However, many cases are idiopathic (IHHS) and occur in apparently healthy infants who exhibit neither clinical nor imaging evidence of preexisting brain lesion. In addition to the role of fever, specific viruses have been advocated but are not found in the cerebrospinal fluid (CSF). Moreover, CSF comprises neither pleocytosis nor oligoclonal profile excluding an infection of the central nervous system (CNS). Three fourths of patients remain with epilepsy (Roger et al., 1982). IHHS was hypothesized to represent the end of the spectrum of febrile status epilepticus and that its incidence has decreased with the use of benzodiazepines as rescue therapy in long-lasting febrile seizures. However, modern radiologic series of febrile status might not support this hypothesis (Shinnar et al., 2012). Seizures start with rhythmic unilateral. They predominate on one side and last several hours, up to 24 h. Ictal electroencephalography (EEG) shows high amplitude 2–3 Hz rhythmic slow-wave activity with low-amplitude fast activity and rhythmic spikes contralateral to the predominating jerks (Chauvel & Dravet, 2005). Magnetic resonance imaging (MRI) shows increased diffusion on one side, mainly in the perisylvian and parietooccipital areas (Fig. 1A), followed by atrophy (Fig. 1B).

Figure 1.

(A) Diffusion-weighted axial images showed a diffuse swelling and hyperintensity of the whole left cerebral hemisphere at day 2. (B) FLAIR axial sequence showed a hemispheric left atrophy 2 months after the status.

Febrile Infection–Related Epilepsy Syndrome (FIRES)

Previously described as DESC (devastating epilepsy in school age children) (Mikaeloff et al., 2006), FIRES is characterized by the development of seizures in healthy children during or a few days following nonspecific febrile infection (Van Baalen et al., 2009). Seizures rapidly aggravate and turn to status epilepticus followed by pharmacoresistant epilepsy and cognitive function deficit (Mikaeloff et al., 2006; Van Baalen et al., 2009).

In almost half of patients, fever has disappeared when the first seizures occur. Seizure semiology points to a focal onset with lateral deviation of the head, chewing movements, and some autonomous features, suggesting a mesial temporal lobe involvement. Clonic jerks of the mouth extending to the limbs indicate the extension to the opercular. Several seizures, up to 100, may occur each day rising from both hemispheres. The EEG between seizures shows slow waves over the whole brain that neurophysiologists tend to qualify as an “encephalitis” pattern (Mikaeloff et al., 2006; Van Baalen et al., 2010).

Investigations to search for some viral or autoimmunity contributions remain negative: There are a few cells in the CSF, polymerase chain reaction is negative, and electrophoresis of CSF proteins shows no oligoclonal bands. Antibodies against voltage-gated potassium channels, N-methyl-d-aspartate receptor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, and gamma-aminobutyric acid B receptors antibodies are negative and although some “neuronal antibodies are reported in a few case reports, the cause or consequence role of these antibodies is not clear and this syndrome is considered as an encephalopathy rather than an encephalitis (Van Baalen et al., 2010; Nabbout et al., 2011).

Early MRI might be disappointing since it shows at most bulging of the mesial temporal structures during the first weeks of the disease, with T2 hypersignal (Fig. 1A).

Status epilepticus persists usually whatever the conventional antiepileptic schedule, and the use of general anesthesia is not only disappointing but might be a negative cognitive prognosis factor (Kramer et al., 2011). Only ketogenic diet showed an efficacy in almost one half of patients when tried even late in the course of the disease (Nabbout et al., 2010; Kramer et al., 2011). In the most refractory cases, death may occur after 4-8 months of ongoing seizures, and postmortem examination performed in a few patients only revealed cell loss but no lymphocyte infiltration, adding to the concept of encephalopathy rather than encephalitis.

After several weeks or months, seizures finally decrease, with progressive recovery of consciousness, but patients are left with major cognitive deterioration and intractable. At that chronic stage, seizures tend to occur in clusters every 2–4 weeks and ictal EEG shows that they involve the same regions as during the status epilepticus. Cognitive functions are affected with a severe episodic memory, speech, and frontal lobe functions deficit (Mikaeloff et al., 2006).

MRI ≥6 months show bilateral mesial temporal atrophy (Fig. 2B) and T2 hypersignal in almost half of cases; however, in all, positron emission tomography scan identified a very large area of hypometabolism involving bilaterally orbitofrontal and temporoparietal regions, with a good correspondence to the specific cognitive troubles that each child exhibited (Mazzuca et al., 2011). Genes involved in epilepsy with fever sensitivity (SCN1A, PCDH19) or in refractory status epilepticus often initiated in the setting of febrile illness as in Alpers disease (POLG), did not show any mutation or rare copy number variations (Appenzeller et al., 2012).

Figure 2.

(A) T2 coronal sections showing the mesial temporal structures bulging in a patient with febrile infection–related epilepsy syndrome (FIRES) at day 5. (B) T2 coronal sections of the same patient at M3 of his disease and 2 months after the status.

Refractory status epilepticus following a common febrile infection in the absence of identified infectious agent is reported in a few small series and case reports in the literature and we suggested with others (Nabbout et al., 2011; Kramer et al., 2011) that these entities with different names might share a common pathophysiology based on a vicious circle with inflammation inducing seizures evolving to status and status enhancing and keeping active the inflammatory pathways (Nabbout et al., 2011). We proposed to group these entities under the concept of acute “encephalopathy with inflammation-mediated status epilepticus” (Nabbout et al., 2011). This hypothesis questions the place of specific antiinflammatory and immunomodulatory therapies in these devastating syndromes (Nabbout, 2012).

Disclosure

None of the authors has any conflict of interest to disclose.

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