Epilepsia, 51(10):2033–2037, 2010 doi: 10.1111/j.1528-1167.2010.02703.x
FULL-LENGTH ORIGINAL RESEARCH
Efficacy of ketogenic diet in severe refractory status epilepticus initiating fever induced refractory epileptic encephalopathy in school age children (FIRES) *yRima Nabbout, *Michel Mazzuca, zPhilippe Hubert, xSylviane Peudennier, {Catherine Allaire, **Vincent Flurin, yyMarina Aberastury, zzWalter Silva, and *yOlivier Dulac *Department of Neuropediatrics, Centre de Re´fe´rence E´pilepsies Rares, Hoˆpital Necker-Enfants Malades, Paris, France; yInserm U663, University Paris Descartes, Hoˆpital Necker-Enfants Malades, Paris, France; zPediatric Intensive Care Unit, Hoˆpital Necker-Enfants Malades, Paris, France; xDepartment of Pediatrics, Hoˆpital Morvan, CHU Brest, France; {Department of Pediatrics, Hoˆpital Morvan, CHU Brest, France; **Department of Pediatrics, Hoˆpital Anne de Bretagne, CHU Rennes, France; yyDepartment of Pediatrics, Hoˆpital Le Mans, France; and zzDepartment of Child Neurology, Hospital Italiano de Buenos Aires, Argentine
SUMMARY Purpose: Fever induced refractory epileptic encephalopathy in school age children (FIRES) is a devastating condition initiated by prolonged perisylvian refractory status epilepticus (SE) triggered by fever of unknown cause. SE may last more than 1 month, and this condition may evolve into pharmacoresistant epilepsy associated with severe cognitive impairment. We aimed to report the effect of ketogenic diet (KD) in this condition. Methods: Over the last 12 years we collected data of nine patients with FIRES who received a 4:1 ratio of fat to combined protein and carbohydrate KD. They presented with SE refractory to conventional antiepileptic treatment.
Pharmacoresistant status epilepticus (SE) is both a diagnostic and a therapeutic challenge. In some previously healthy children aged from 4–11years whose intractable SE follows fever, all attempts to identify intracranial infection may fail (Mikaeloff et al., 2006), including postmortem neuropathology (Baxter et al., 2003). SE may last more than 1 month, and this condition may either end in death (Baxter et al., 2003) or evolve into pharmacoresistant epilepsy associated with severe cognitive impairment (Mikaeloff et al., 2006). This condition was first called ‘‘Devastating epileptic encephalopathy in school age children’’ (DESC) (Mikaeloff et al., 2006), and later the more appropriate term of ‘‘Fever induced refractory epileptic encephalopathy in
Accepted July 9, 2010; Early View publication August 31, 2010. Address correspondence to Rima Nabbout, Department of neuropediatrics, Centre de reference epilepsies rares, Hpital Necker Enfants malades, 149 rue de Svres, 75015 Paris, France. E-mail:
[email protected] and
[email protected] Wiley Periodicals, Inc. ª 2010 International League Against Epilepsy
Results: In seven patients, KD was efficacious within 2–4 days (mean 2 days) following the onset of ketonuria and 4–6 days (mean 4.8 days) following the onset of the diet. In one responder, early disruption of the diet was followed by relapse of intractable SE, and the patient died. Epilepsy affected the other six responders within a few months. Discussion: KD may be an alternative therapy for refractory SE in FIRES and might be proposed in other types of refractory SE in childhood. KEY WORDS: Status epilepticus, Ketogenic diet, Encephalitis, Fever induced refractory epileptic encephalopathy in school age children, Devastating epileptic encephalopathy in school age children.
school age children’’ (FIRES) (Van Baalen et al., 2009, 2010). Patients with recent worsening of seizure frequency with impact on brain function were shown to be excellent candidates for the ketogenic diet (KD) (Villeneuve et al., 2009). This series comprised two patients with FIRES who responded promptly to KD. We, therefore, applied this treatment to seven additional patients with FIRES for whom conventional intravenous SE therapy had failed.
Patients We gathered patients who received KD for pharmacoresistant SE as an innovating means of treatment each time we were faced to or asked for advice for a new patient exhibiting the features of FIRES. Nine patients were followed over a period of 12 years in five centers. All patients previously had normal health and psychomotor development. Characteristics of the patients are given in Table 1. The age of patients ranged from 54–98 months (mean 74 months, or 6 years). They had no personal or familial
2033
Epilepsia, 51(10):2033–2037, 2010 doi: 10.1111/j.1528-1167.2010.02703.x
4 1
6 3
+/Flu
+/Pharyngitis
+/Gastroenteritis
)/Pharyngitis
+/Mumps vaccination
+/Unknown, myalgias
)/Pharyngitis
3/M/81
4/M/77b
5/M/54
6/F/86
7/F/62
8/F/95b
9/M/72b 25
8
4
50
6
17
15
55
30
Lag from SE onset to KD (days) Ictal semiology
Generalized, left hemiface clonia Generalized, flush, mouth clonia Eye staring, R arm automatisms, R facial clonia Generalized, eyes deviation L/R, alternating hemibody clonia Alternating hemiclonia (L and R) palpebral clonia Abdominal pain then clonic generalized
Generalized, L eyelid and mouth clonia Hypertonia, eyes deviation
Peribuccal clonia
Ictal EEG
Bitemporal and R rolandic spikes Migrating focus/mainly bitemporal
R frontal and temporal polyspikes Disorganized background continuous sd activity Migrating focus
R temporal and rolandic polyspikes Frontal and temporal polyspikes Alternating migrating spikes
Bitemporal spike waves
CZP, PHT, PB, CBZ, LVT/ Transitory/NAc CZP, PHT, PB, CBZ/No/ NAc
2/4
2/6
3/5
3/4
3/5
VPA, CBZ, CZP/NAc/NAc VPA, TPM, PHT, PB/No/No effect CZP, PHT, PB, VGB, CBZ/ No/No effect
4/6
3/No
2/4
No KU/Noa
Lag to ketonuria/to efficacy days
CZP, PHT, PB/No/ NAc
VPA, CZP, PB, PTHVGB,CBZ/Partial clinical/No effect CZP, PHT, PB, VPAVGB, LTG/No/Transient effect CZP, VPA, VGB/NAc/NAc
AEDs/steroids/pentothal before KD
6
3
1
6
4
d
NS
4
NS
Lag to new seizures months
SE, Status epilepticus; P, patient; F, Female; M, Male; L, left; R, right; AED, antiepileptic drug; VPA, sodium valroate; CZP, clonazepam; PB, phenobarbital; PHT, phenytoin; VGB, vigabatrin; CBZ, carbamazepine; LTG, lamotrigine; TPM, topiramate; LVT, levetiracetam. a Ketosis was not reached. b Use of ketocal. c NA: Not applicable; patients did not receive this medication. d Died 4 days after KD interruption.
5
5
4
3
+/Pharyngitis
2/F/98b
4
)/Small pox vaccination
Fever/etiology
Lag from fever to SE (days)
1/F/62
Patient/gender/ age onset SE (months)
Table 1. Clinical and EEG characteristics of the series with response to AEDs and to the ketogenic diet
2034 R. Nabbout et al.
2035 Ketogenic Diet in FIRES antecedents. A nonspecific febrile illness had preceded the first seizures by 1–6 days (mean 4 days). At the onset of neurologic symptoms, six patients still had fever. Patients mainly exhibited partial seizures involving perisylvian areas, and within
