Tuesday, July 18, 2017

Complex febrile seizures-a systematic review

Whelan H, Harmelink M, Chou E, Sallowm D, Khan N, Patil R, Sannagowdara K, Kim JH, Chen WL, Khalil S, Bajic I, Keval A, Greydanus D. Complex febrile seizures-A systematic review. Dis Mon. 2017 Jan;63(1):5-23.

Inclusion criteria:  

Seizures associated with fever (T > 38°C)                   
Previously neurologically intact patient                      
Either: focal seizure characteristics OR lasts between 15 and 30 minutes OR multiple seizures within a 24 hour period                        
Child older than 6 months but younger than 6 years of age

Exclusion criteria:

Seizure lasting >30 minutes
History of epilepsy or afebrile seizures
Signs of central nervous system infection or inflammation
Metabolic abnormality capable of causing seizures
Clear neurologic abnormality to cause seizures (brain tumor, head trauma, or intracranial bleed etc.)

Question 1: What is the role of a lumbar puncture in the evaluation of complex febrile seizures?


There is no clear evidence to suggest for or against a lumbar puncture among patients with CFS. In general, the literature suggests that although the risk of acute bacterial meningitis with febrile seizures is low, the data are heterogeneous and may be biased toward SFS given the relative incidence of SFS to CFS. Given this, the clinician should consider a lumbar puncture in the context of each individual patient. However, bacterial meningitis should still be an important consideration in the areas without access to adequate immunization and in developing countries.  Future studies are needed to further clarify the need for a lumbar puncture.

Question 2: What is the role of brain imaging in the evaluation of complex febrile seizures?


Head CT scan is not routinely recommended in the evaluation or management of patients with complex febrile seizures. CT scans may have diagnostic use if there is a strong indication of an acute/subacute bleed or structural lesion based on patient’s exam and history.

Non-urgent, outpatient MRI brain is recommended for patient with focal complex febrile seizures, especially with postictal neurological deficit. Focal complex febrile seizures can be associated underlying structural brain abnormalities and can potentially cause hippocampal atrophy and sclerosis on follow up imaging. There is no evidence to support routine use of neuroimaging in children with CFS without interictal or postictal focality; however, in febrile status epilepticus there is evidence of hippocampal abnormalities found but this was in patients with febrile seizures greater than 30 minutes and thus not CFS. Urgent brain MRI in the emergency room is not recommended.

Question 3: What is the role, and what time frame is warranted, for use of electroencephalography in the evaluation of complex febrile seizures?


Routine EEG should be considered after a complex febrile seizure. If there is doubt that the event was a seizure, an EEG done on the day of, or shortly after, the seizure may be helpful to clarify.

Otherwise, in regards to timing as a prediction for future febrile and afebrile seizures, the evidence is conflicting thought there is the suggestion that obtaining the EEG within 7 days may increase the likelihood of finding abnormalities although the correlation to the timing of the detection of abnormalities and future prediction ability of epilepsy is unclear. There was also no clear evidence that particular EEG findings or abnormalities are able to predict the risk of development of epilepsy; rather the persistence of EEG abnormalities had more predictive value. However, future studies are needed to further clarify the issue.

Question 5: What is the risk of subsequent recurrence of febrile seizures after the initial complex febrile seizure?


Based on multiple studies discussed above, the risk factors for developing recurrent febrile seizures identified as follows:

(1) First degree relative family history of febrile seizures.
(2) Duration of fever less than 1 hour prior to seizure onset.
(3) Young age of onset of less than 18 months.
(4) Low temperature peak with initial febrile seizure.

The risk of developing recurrent febrile seizure at 2 years with no identifiable risk factor is about 15%. This risk increases to 20% if patient has one risk factor, 30% with two risk factors, more than 60% with three risk factors and to more than 70% with more than three risk factors. 
Interestingly, most of the reviewed studies found that complex febrile seizure does not increase the risk of having recurrent febrile seizures but showed increased risk of developing epilepsy.

Question 6: What is the role of use of anti-seizure medications in preventing the recurrence of complex febrile seizures?


Routine long-term daily prophylactic antiepileptic medications are not recommended to prevent recurrent complex febrile seizures as there is no clear data on use in CFS.

Intermittent use of phenobarbital and antipyretics, clobazam or rectal diazepam has some evidence supporting its use to prevent recurrence of CFS but the data does not effectively separate SFS from CFS and, thus, there may be a bias due to the relative incidence of the respective seizures (class III).
Based upon the class III study mentioned above, use of carbamazepine to prevent recurrent CFS is not recommended given other alternatives available such as phenobarbital.

A study comparing valproate, phenobarbital, and placebo seemed to show benefit from valproate with 4% of recurrence.  Again the study is devoid of detailed description of initial seizure and recurrent seizure types and thus clinical correlation should be considered.

An individualized risk-benefit approach is recommended for each patient at this time given the levels of evidence for use of prophylactic AED.

Further prospective studies of only CFS and CFS subtypes are needed to further elucidate any benefit.

Question 7: What is the risk of developing epilepsy after having a complex febrile seizure?


The estimate of long-term risk of epilepsy after initial febrile seizure is approximately 6–7%. In children with epilepsy, about 13% had previous febrile seizures. Additionally, there is evidence that some children (58%) have a second febrile seizure before they begin to afebrile seizures. The risk of epilepsy specifically after complex febrile seizure cannot be determined given that the majority of studies did not differentiate between SFS and CFS for the initial event. “Complex” features were found to increase the risk of epilepsy; however this finding was not consistent among all the studies.

There is a plethora of studies solely focused on long-term risk of epilepsy after febrile seizures. However, this literature suffers from lack of clarity in categorizing seizures as complex versus simple and not excluding children with neurodevelopmental disabilities, which could alter the results. In future studies, it is imperative to strictly follow the complex febrile seizures definition in selecting a cohort for follow-up, to generate meaningful and credible data. 

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