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Original Article
Severe Refractory Status Epilepticus Owing to Presumed Eucephalitis Uri Kramer, MD; Zamir Shorer, MD; Bruria Ben-Zeev, MD; Tally Lerman-Sagie, MD; Hadassa Goldberg-Stem, MD; Eli Lahat, MD
ABSTRACT The severe refractory type of status epilepticus is very rare in the pediatric population. Eight children vi^ith the severe refractory type of status epilepticus owing to presumed encephalitis are described. The age at the onset of status epilepticus of the eight study children ranged between 2.5 and 15 years. Seven of the eight children presented with fever several days prior to the onset of seizures. A comprehensive clinical and laboratory investigation failed to delineate a cause for their seizures. Burst suppression coma was induced by pentothal, midazolam, propofol, or ketamine in all of the children. The mean duration of anesthesia was 28 days (range 4-62 days), but the seizures persisted in spite of repeated burst suppression cycles in all of them. Two children died. Four of the surviving children continued to suffer from seizures, and cognitive sequelae were present throughout follow-up in four children. In summary, the severe refractory type of status epilepticus of the acute symptomatic type owing to relatively mild encephalitis carries a high mortality rate and poor morbidity in terms of seizures and cognition at follow-up. (J Child Neurol 2005;20:184-187).
Severe Refractory Status Epilepticus / Kra.mer et, al
Refractory status epilepticus is defmed as the persistence of seizure activity despite appropriate medical and antiepileptic therapy.' The relative incidence of refractory status epilepticus is estimated as being 9% of all status epilepticus in adults,^ whereas it is unknown in children. Severe refractory status epilepticus is defined as the reappearance of seizures following treatment with coma-inducing drugs, and its relative incidence is not known for any age group. Several studies reported on the duration of episodes of status epilepticus in children^^: it was longer than 1 hour in 26% to 45%,^'' longer than 2 hours in 17% to 25%,'*'^ and longer than 4 hours in 10%,'* with the longer duration of a status epilepticus occurring significantly more often in the acute symptomatic group.^ The etiology of status epilepticus has been classified into idiopathic, remote symptomatic, febrile, acute symptomatic, and a type associated with a progressive encephalopathy.^ There is a small subgroup of pediatric patients with severe refractory status epilepticus that belongs to an acute symptomatic group: these children undergo normal neurodevelopment and present with the symptomatology of a mild infection prior to the status epilepticus. This small group comprises 36% of all children with severe refractory status epilepticus" and carries a significantly higher mortality rate than that predicted in children with status epilepticus.^" Severe refractory status epilepticus is very rare among children, and we found only one published series of eight such patients in our search of the literature.^ We describe the clinical symptomatology, treatment, and outcome of eight more pediatric patients with severe refractory status epilepticus. PATIENTS From January 1998 to March 2003, eight children with severe refractory status epilepticus of unknown etiology were hospitalized in five hospitals in Israel. During this period, an additional three children were treated in these hospitals for severe refractory status epilepticus owing to known etiologies (metabolic diseases in two, meningitis in one). Three of them had an apparently normal medical and neurologic status prior to the onset of seizures, one had mild cognitive delay, one had rare photosensitive seizures, one had two episodes of febrile convulsions, and two were diagnosed as having familial Mediterranean fever with no prior history of seizures. Seven of the study children had a febrile disease during the 2 to 10 days prior to the presentation of severe refractory status epilepticus. Notably, fever was present < 5 days before seizure onset in six of them. One child also presented with a concomitant erythematous rash. Severe refractory status epilepticus developed within a few hours to 4 days from the first seizure episode and within 24 hours in five of them. All eight of our patients presented with partial seizures, including simple partial seizures, partial seizures secondarily generalized, and complex partial seizures.
Received Jan 27, 2004. Received revised April 13, 2004. Accepted for publication April 15, 2004. From the Child Development Center and Pediatric Neurology Unit (Dr Kramer), Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Pediatric Neurology Units, Departments of Pediatrics, at: Soroka Medical Center (Dr Shorer), BeerSeva; Sheba Medical Center (Dr. Ben-Zeev), Ramat-Gan; Wolfson Medical Center (Dr Lerman-Sagie), Holon; Schneider Medical Center (Dr GoldbergStem), Petah-Tiqva; and Assaf Harofe Medical Center (Dr Lahat), Tzrifin, Israel. Address correspondence to Dr Uri Kramer, Child Development Center and Pediatric Neurology Unit, Beit Habriut Strauss, 14 Balfour St, Tel Aviv 65211, Israel. Tel: 972-3-5402639; fax: 972-3-6973992; e-mail:
[email protected].
185
Investigation All eight patients underwent a thorough investigation during their hospitalization, including serologic tests for viruses including cytomegalovirus, Epstein-Barr virus, enteroviruses, and polymerase chain reaction in the cerebrospinal fiuid for herpes simplex. In addition, most children also underwent serologic tests for Barlonella heiiselae (the agent for cat scratch disease) (7), Mycoplasmapneumoniae (6), and Rickettsia sp (3). Tliey underwent a full metabolic workup (5), as well as routine tests to rule out collagen vascular diseases (6). All test results were negative. Cerebrospinal fluid studies showed mild pleocytosis (> 5 white blood cells but < 100) infivepatients: the white blood cell count in the cerebrospinal fiuid was 18 to 27 WBC/mm' in four patients. There was a predominance of nionocytes (60-100%) in all cases. The glucose level in the cerebrospinal fiuid ranged from 60 to 93 mg/dL, and protein levels were 20 to 60 mg/dL. The first magnetic resonance imaging (MRI) performed during the acute phase was normal, whereas the second MRI performed several weeks after disease onset revealed mild atrophy infivepatients. These five included two who were not treated with corticosteroids. One patient had bilateral hippocampal hyperintensity in T^ suggestive of focal edema, one had ependymal enhancement on MRI suggestive of encephalitis, and one had normal results. A follow-up MRI after discharge from the hospital was performed in three of the five survivors who originally had abnoniial findings, and their results were normal. Electroencephalography (EEG) performed continuously or intermil;tently during the hospitalization revealed one {n = 4) or two (n = 4) epileptic foci in all patients during the non-burst suppression periods. TVeatment All patients were treated part of the time with pentothal (pentobarbital is not available in Israel), mostly during the burst suppression trial, and part of the time with midazolam drips (n, = 7), which seemed to enable a lower level of sedation while still controlling the seizures. In addition, the children were treated with propofol (n = 3), high-dose phenobarbital (?). = 2), diazepam drip (ri = 2), and ketamine {n = 1). Burst suppression coma was induced in all patients. A single burst suppression period lasted 18 to 96 hours (burst suppression cycle continued for 48 hours or more in all but two children). The total period of mechanical ventilation was 4 to 62 days (mean 27.75 days, SD 19.4 days). The child with only 4 days of burst suppression anesthesia continued with a midsizolain drip with no need for further mechanical ventilation. Concomitantly with anesthetic agents, the children were treated with different combinations of antiepileptic drugs: 5 to 10 antiepileptic drugs for each patient, intravenous imniunoglobulin (n = 7), and corticosteroids (ra = 5). Corticosteroids were given as a pulse of either dexaniethasone (4-8 mg/d) or methylprednisolone (20-30 mg/kg/d) for a period of several days. The seizures gradually disappeared in all patients, with no clear correlation with either the repetitive trials of induced burst suppression coma or treatment with multiple antiepileptic drugs. Follow-up Two children died (25%). The first was an 8-year-old boy who died owing to sepsis and liver failure after 41 days of anesthesia, and the second was a 15-year-old boy who died owing to a tear in the esophagus and bleeding into the lungs following 28 days of anesthesia. All six survivors needed rehabilitation following the cessation of the status epilepticus. The period from cessation of mechanical ventilation until steady state lasted between 1 and 6 months and was correlated to (;lie duration of anesthesia. During that period, the children manifested cortical blindness (ra = 2), autistic behavior (ra = 2), loss of speech (n =1), and ataxia and choreoathetosis (ra = 1).
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Table 1. Description of the Study Patients Agents
Patient
(yr)
WBCs in CSF
1 2 3 4 5 6 7 8
8 15 4 3.5 5.5 8 2.5 9
— 21 27 — 20 100 2 18
Age
MRI
AEDS In)
Atrophy Bilateral hippocampal edema Atrophy Atrophy Atrophy Ependymal enhancement Atrophy Normal
8 7 8 5 10 6 8 5
Anesthesia Period Anesthesia (minj for
T, M T, M, P, Pb, K T, M T, M, Pb T, M T, M, P T, M, P T, M
41 28 4 42 62 21 15 7
Seizures at Follow-up
Cognition at Follow-up
Died Died Refractory CPS Mild delay Few, PSGEN Normal Rare Still in rehabilitation Refractory CPS ADHD, LD None Mild delay (unchanged) None Still inrehabilitation
ADHD = attention-deficit and hyperactivity disorder; AEDs = antiepileptic drugs; CPS = complex partial seizures; CSF = cerebrospinal fluid; K = Ketalar; LD = learning disabilities; M = midazolam; MRI = magnetic resonance imaging; P = propofol; Pb = phenobarbital; PSGEN = partial seizures secondarily generalized; T = thiopental; WBCs = white blood cells.
At follow-up, four of the six surviving children had seizures, whereas two had refractory complex partial seizures. One child has moderate mental retardation. Three children have severe attention-deficit hyperactivity disorder and learning disabilities. One child has normal development, and one has mild global delay. This child had mild developmental delay prior to hospitalization, and there is no clear evidence of cognitive deterioration.
DISCUSSION The severe refractory type of status epilepticus is very rare in the pediatric population, and the available information on this condition is sparse. Our search of the literature turned up one article by Sahin et a], who retrospectively reviewed 22 cases of severe refractory status epilepticus treated at Children's Hospital, Boston, between 1992 and 2000, of whom eight apparently had severe refractory status epilepticus with a presumed encephalitic etiology." We report the clinical presentation, investigation, and outcome of eight additional patients whose presumed etiology for severe refractory status epilepticus was encephalitis and in whom burst suppression coma was induced. Seven of the eight patients had febrile illness prior to or concomitant with seizure onset. All had negative bacterial and viral cultures, as well as a negative polymerase chain reaction for herpes simplex. We therefore postulated that the etiology for the acute disease might be encephalitis of an unidentified agent. Five of the children presented with mild pleocytosis in their cerebrospinal fluid. This finding, however, does not confirm the presence of encephalitis because pleocytosis was noted in a substantial number of patients with status epilepticus without encephalitis.' All of our patients had either continuous EEG monitoring or repeated EEG recordings. The recording showed that four patients had two seizure foci. The existence of more than one epileptic focus owing to encephalitis is not surprising and probably plays a part in the severity of the epileptic process. The strategy of treating refractory status epilepticus involves the acquisition of burst suppression by means of agents such as pentobarbital, pentothal, midazolam, and propofol. Many studies had been designed to evaluate the relative efficacy of these different agents,^" as well as of the use of isoflurane'^ or ketamine.'" The depth and duration of burst suppression" can also play a role in detemiining the efficacy of the treatment. No conclusions regarding the efficacy of therapeutic strategies can be made from the present series owing to the small number of patients. In spite of several periods of burst suppression with different durations
for each patient, this technique did not achieve persistent freedom fro.m seizures in any of them. Our observation is, therefore, that there was no clear correlation between cessation of seizures and any of the agents we used. This observation is supported by data from animal studies. Refractory status epilepticus or selfsustaining status epilepticus occurs when seizures continue in a self-sustaining manner for many hours after the initial cause has been eliminated. This phenomenon demonstrates that status epilepticus differs from single seizures, which are terminated by powerful inhibitory feedback and are followed by postictal changes that make the brain refractory to further seizure activity. A model for self-sustaining status epilepticus was recently developed by intermittent electrical stimulation of the perforant path in free-running rats. This model demonstrated that resistance to standard anticonvulsants develops progressively during the course of self-sustaining status epilepticus: although diazepam and phenytoin were highly effective when given before or at the onset of self-sustaining status epilepticus, both lost their effectiveness when their administration was delayed beyond 70 minutes after the onset of stimulation. A number of physiologic and biochemical changes have been described that can account for the refractoriness of the seizures, among them the failure of inhibitory mechanisms or the enhancement of excitatory mechanisms. Failure of inhibition can be associated with changes in 7-aminobutyric acid (GABA)^ receptor function, thus explaining the failure of GABAergic drugs, such as diazepam, when given late in the course of self-sustaining status epilepticus. At the same time, however, diazepani-resistant selfsustaining status epilepticus can be interrupted by neuromodulators, which presynapticcilly modulate glutamate release or postsynaptically block A'-methyl-D-aspartate (NMDA) receptors. Experiments in rats have shown that the maintenance phase of selfsustaining status epilepticus depends on activation of NDMA receptors and that NMDA receptor blockers (ie, MK-801 and ketamine) can abolish the status epilepticus.'^ These observations might suggest novel approaches to the treatment of refractory status epilepticus. Specifically, optimal pharmacotherapeutic strategies for status epilepticus might need to be matched to the molecular state of the seizing networks, either by the development of new agents with affinity for NMDA receptors, such as felbamate, or by the use of anesthesia involving the currently available NMDA channel blocker ketamine in refractory cases.'" Owing to its rarity, there are no large-scale studies on the mortality or neurologic sequelae following severe refractory status
Severe Refractory Status Epilepticus / Kramsr el, al.
187
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