1. Department of Pediatrics
Febrile Seizures
Randy Williamson
UTRGV
Department of Pediatrics
October 2017

2. Goals of lecture History of Febrile seizures Definition Mechanism
Simple versus Complex
Testing needed
Treatment
Prognosis
Febrile Status and FEBSTAT study
Febrile Seizure Variants
Conclusion

3. History
Seizures associated with fever have been described in the literature since the 1800’s and identified well before this
William Lennox was one of the first clinicians to focus on the background and risk factors for FS and the risk of progression to epilepsy (BCH, ILAE)
Historical early paper and presentation in 1952 in Louisville, KY

6. Definition of Febrile Seizures
Defined as a seizure in association with febrile illness in the absence of a central nervous system infection, acute electrolyte imbalance in children, or head trauma
Occur in 2-5 % of children and are the most common form of childhood seizures
Age typically mentioned is 6 months to 5 years (varies) without previous afebrile seizures

8. Fever may not be detected before the seizure, but it must be present at least in the immediate post acute period
Clinically should be further separated into simple and complex febrile seizures
Although neurologically abnormal children are more likely to experience complex febrile seizures and have a higher risk for subsequent afebrile seizures, the child’s prior neurologic condition is not used to classify the seizure as simple or complex febrile seizures

9. Defined by International League Against Epilepsy
1) Seizure after one month of age with fever present a. illness is not related to a CNS infection b. child does not have an acute electrolyte imbalance c. no history of prior afebrile seizures
2) Body temperature of more than F (38.4 C) although the increased temperature may not occur until after the seizure
3) Child may be neurologically normal or abnormal

10. Mechanism Not completely understood
Related to fever induced change to GABA ?
Inflammation related to fever infection?
Genetic in nature ?

11. Genetics of Febrile Seizures
FS are 2-3 times more common in family members of affected children than general population
Higher rates in monozygotic twins
Occurrence of febrile seizures in 1st degree relatives is a risk factor for recurrence

12. Nakayama, 2009
Extensive genetic studies have shown multiple loci exists for susceptibility to FS
Six susceptibility FS loci have been identified on chromosomes 8q13-q21 (FEB1), 19p (FEB2), 2q23-q24 (FEB3), 5q14-q15 (FEB4), 6q22-q24 (FEB5), and 18p11 (FEB6)
Furthermore, mutations in the voltage-gated sodium channel subunit genes (SCN1A, SCN2A and SCN1B) and the GABA(A) receptor subunit genes (GABRG2 and GABRD) have been identified in Dravet Syndrome & GEFS+

13. Nakayama concluded that causative genes have not been identified in patients with FS
FS are likely genetically complex disorders believed to be influenced by variations in several susceptibility genes

14. Risk Factors
A history of febrile seizures in a first-or second-degree relative
A neonatal nursery stay of more than 30 days
Neuro-Developmental delay
Attendance at day care
Children with two of these factors had a 28% chance of experiencing at least one febrile seizure

15. There is the thought that a rapid rise in temperature is responsible is a risk factor for febrile seizures; yet there are no clinical data to support this hypothesis
There is thought that height of temperature may play a role in febrile seizures
There is thought that the type of illness causing the fever may play a role in febrile seizures

17. Type of Febrile Seizure
It’s important to characterize the type of febrile seizure into simple or complex
Helps to determine testing needed, treatment, and prognosis

18. Simple Febrile Seizures
Defined as febrile seizure that is characterized by one of the below:
Lasting less than 15 minutes
Seizure clinically is generalized (whole body involved)
Only one episode in 24 hours
Child usually returns to normal baseline quickly

19. Most common type of childhood seizure disorder
70-80% of all febrile seizures
2-5% of all children
Age onset is typically from 6 months to 5 years
Peak incidence at 6-36 months

21. Evaluation for Simple Febrile Seizures
Should be aimed at the underlying infection
Careful H & P
Labs considered (CMP, Blood, Urine; Trauma survey or UDS if suspicious)
Strongly consider CSF if < 12 months and or concerned about meningitis
Do not need EEG, imaging, or admission if child returns to normal baseline quickly

22. Risk of recurrence FS first recurrence ranges from 23%–42%
90% of recurrence occurs during the first two years
30% have a 2nd seizure
15% have a 3rd seizure
This % increases when first febrile seizure is < 12 months

23. No difference in learning or intelligence
No deaths have been reported as a direct result from a single simple febrile seizure

24. Risk of developing epilepsy
1% at 7 years of age
Increases to 2-3% at 25 years with multiple seizures and + family history
This is slightly higher than the general population

25. Treatment recommendations
Diastat or nasal midazolam for abortive therapy
No EEG or imaging needed
Appropriate emotional support and education is vital to reduce parental anxiety
Neither continuous or intermittent antipyretics indicated, except for comfort for the child and as fever reducer
Neurology follow up considered or encouraged(schools need papers filled out)

26. AAP Guidelines
Evaluation after a simple febrile seizure should direct attention toward identifying the cause of the fever
Meningitis considered in the differential diagnosis, and LP should be performed if the child is ill-appearing or if clinical signs of concern
Or who is deficient in Hib and S pneumoniae immunizations or for whom immunization status is unknown
Or been pretreated with antibiotics

27. AAP
In general, a simple febrile seizure does not usually require further evaluation, specifically EEGs, blood studies, or neuroimaging

28. Complex Febrile Seizures
Defined as febrile seizure that is characterized by one or more of the below:
Duration > 15 minutes
More than one episode in 24 hours
Clinically, a focal seizure
Represent 20% to 30% of all febrile seizures

29. In the National Collaborative Perinatal Project, 1706 children with febrile seizures were identified and followed
Initial febrile seizure was defined as complex in approximately 28%
Recurrent episodes within 24 hours in 16%
Prolonged duration (>15 minutes) in 8%
Focal features were present in 4%

30. May require a more extensive evaluation than simple febrile seizures
Initial studies to consider similar to simple febrile seizures (CSF, blood, urine)
Consider admission or observation to hospital
EEG considered
Reasonable to image all patients
If focal, imaging and EEG should likely be obtained

31. Imaging MRI More sensitive and clinically useful
Sedation usually needed
Delay in getting the procedure

32. CT
Ease of accessibility
May not need sedation
Consider long term risks of radiation exposure
If one suspects trauma or any acute event

33. EEG
If needed, can be obtained as outpatient if child stable
EEG can be limited by post seizure slow waves
Can assist in classifying seizure type, epilepsy syndrome, and risk of recurrence

34. Recurrence
Berg and Shinnar reported on 136 children who had recurrent febrile seizures
41.2% had 1 or more complex features
Strong association between focal seizures and prolonged seizures
Experiencing a complex feature during the first febrile seizure was an important predictor of subsequent epilepsy

35. Predictors for the development of epilepsy in this study were an: (1) abnormal neurological and developmental status, (2) history of afebrile seizures in a parent or older sibling, or (3) complex features
10% of children with 2 or more of the previously mentioned risk factors (including complex features) developed epilepsy

36. Prospective studies have found that having more than 1 complex feature of a febrile seizure (prolonged and focal) further increased the risk of developing subsequent unprovoked seizures (Epilepsy)

37. Suggested Protocol for Febrile Seizures (Patel & Vidaurre)

38. Treatment for Febrile Seizures
Care during a seizure
Abortive medications
Preventive medications

39. Steps when managing febrile seizures at home
During a seizure, place the child on his or her side on a protected surface and observe carefully
Stay calm, don’t panic
Loosen clothing if needed
Monitor airway but don’t put anything in mouth
Keep track of time, and if the seizure lasts longer than 5 minutes can give abortive treatment or call 911

40. Abortive Treatment Diastat or nasal midazolam for abortive therapy
Both demonstrated to be effective
Candidates include children at high risk for prolonged or multiple seizures or live far from medical care
Main risk factor is that the first seizure lasted more than 10 minutes; therefore, not all children with a febrile seizure need to have abortive therapy available at home

41. Benzodiazepines Can be used in 2 ways
Abortive therapy when a child has a seizure (rectal/nasal)
Works within minutes
Dose based on weight
Can limit prolonged seizures
Limits ED visits, hospitalizations, testing
Call the clinic the following day for refills !

42. Preventative oral daily dosing of Benzodiazepine during the time of a febrile illness
Reduces the risk of recurrent febrile seizures
Dosed for few days during fever
30-50% of patients developed side effects (ataxia, lethargy, and irritability)
Risk of lethargy masking a severe underlying infection is a concern(meningitis)
Not typically used by Peds Neurologists or AAP

43. One study found that over 70% of children with prolonged FS >15 minutes end up with febrile status epilepticus (FSE) defined as >30 min even with treatment
Oral, nasal, or rectal Benzodiazepine can be effective for preventing prolonged febrile seizures/status
Can Diazepam/Midazolam prevent epilepsy if prolonged seizure leads to mesial temporal sclerosis(MTS) ?

44. Prevention of Febrile seizures
Should daily continuous seizure meds be started ?
Is dependent on the below factors:
Studies obtained(imaging, EEG, Labs)
Age at onset
Neurodevelopmental abnormalities
Complexities of the seizure (focal, status)
Family History
Recurrence

45. Phenobarbital and Valproate have both been proven to be effective for the prevention of recurrent febrile seizures
Reduces the risks of recurrence
Valproate not usually dosed as increased risks of hepatotoxicity in children < 2 years
Behavior disturbances/sedation are associated with daily dosing of Phenobarbital

46. Both Diazepam and Phenobarbital have significant side effects that have to be weighed individually
Most studies suggest that the benefit does not outweigh the risk of treating
Newer AEDs like Levetiracetam could be considered and would likely have less side effects

47. Antipyretics Do they prevent febrile seizures ?
Commonly recommended to parents for the period of fever/infection
Alternate ibuprofen with acetaminophen
Studies indicate that acetaminophen given every 4-6 hours is effective in reducing the fever
No definitive proof of preventing febrile seizures

48. Febrile Status Epilepticus
Presenting in febrile status epilepticus is not uncommon
Febrile status represents ~25% of all cases of childhood status epilepticus

49. Studies suggest that prolonged febrile seizures are a causative factor in mesial temporal sclerosis (MTS) and partial epilepsy in adulthood
Approximately two-thirds of adults with TLE have had a febrile seizure
Nearly 75% of these febrile seizures were considered to be either prolonged or have complex features

50. Coronal T2 Brain – 20 months old with focal FSE

51. FEBSTAT Study
Prospective study seeking to determine the acute and long-term consequences of febrile status epilepticus (FSE) in childhood
199 children age 1 month to 5 years presenting with FSE (30 minutes) were enrolled in FEBSTAT
All MRIs were reviewed by 2 neuro-radiologists blinded to clinical details
A group of 96 children with first time simple FS who were imaged using a similar protocol served as controls

52. Results:
A total of 22 (11.5%) children had definitely abnormal (n 17) or equivocal increased T2 signal in the hippocampus following FSE compared with none in the control group
Extrahippocampal imaging abnormalities were present in 15.7% of the FSE group and 15.6% of the controls
However, extrahippocampal imaging abnormalities of the temporal lobe were more common in the FSE group (7.9%) than in controls (1.0%)

53. Conclusions:
This prospective study demonstrates that children with FSE are at risk for acute hippocampal injury and that a substantial number also have abnormalities in hippocampal development
This may be related to temporal lobe seizures in adults

54. 11-month-old child with focal FSE lasting 120 minutes

55. Febrile Seizure Variants

56. SMEI Also known as Dravet syndrome 1st described in 1982
Seizures usually 1st begin in first few months to one year of life as febrile but then afebrile seizures occur
Can present with febrile status

57. Seizures can be generalized, clonic or hemiclonic
Abnormalities in the SCN1A gene have been identified
Not specific for Dravet as other epilepsies have been linked like GEFS+ to this abnormality
Can progress to epileptic encephalopathy
Severe cognitive and motor decline in most but not all

58. One study with 37 patients demonstrated 31 with mental retardation or cognitive decline but seizures were less in adulthood than infancy/childhood
Mortality can be as high as 10-20%
Treatments include Keppra, Depakote, Topiramate, Zonegran, KGD, Clobazam, Stiripental
Meds that can worsen Pheyntoin, carbamazepine(Na+ channel modifiers)

59. Genetic epilepsy with febrile seizures plus (GEFS+)
Described in 1997, febrile seizures with later development of differing epilepsy syndromes within the same family
Wide range of mild to severe phenotypes
Although Dravet syndrome falls within this spectrum, only 10% of GEFS+ families have SCN1A mutations (Scheffer et al., 2009)
Other mutations include SCN1B, SCN2A, and GABRG2

60. Most common phenotypes are febrile seizures (FS) often with afebrile generalized tonic-clonic seizures
In about one third, additional seizure types occur, such as absences, myoclonic, or atonic seizures
Developmental outcome is guarded

61. Febrile-infection related Epilepsy syndrome (FIRES)
Syndrome occurs between early childhood and the second decade
Previously healthy child, a few days after a nonspecific febrile infection
Develops focal seizures that rapidly evolve to status epilepticus that can last days
Febrile illness precedes the episode in 96% of patients
Testing is usually negative or nonspecific

62. MRI may show abnormal mesial temporal structures
One study describes a previously healthy 5-year-old child who developed hippocampal atrophy onset of MTS abnormalities in the setting of suspected FIRES

63. Day 5 of illness

64. Day 15 of illness

65. Day 37 of illness

66. EEG between seizures shows generalized slowing
Status epilepticus or frequent seizures usually persists despite many antiepileptic drug (AED) trials (Mikaeloff et al., 2006; Kramer et al., 2011)
May be placed in burst suppression
Immunosuppressive treatment does not help
Ketogenic diet helped almost half of the patients in one series (Nabbout et al., 2010)

67. After several weeks or months, the seizures finally decrease and stop, with progressive recovery of consciousness, but patients are left with major cognitive deterioration and intractable epilepsy
Prognosis is poor, with most children experiencing resultant refractory epilepsy and profound neurocognitive deficits
Proximity to the febrile illness suggests an underlying immune process, although antibody testing to date remains negative in most, and response to immunosuppression disappointing

68. Gastroenteritis-related seizures
This recognized entity where afebrile seizures occur in the context of mild gastroenteritis
One paper discusses 114 cases included seizures accompanying an episode of gastroenteritis without clinical signs of dehydration, electrolyte imbalance or fever
Age at onset ranged from 8–52 months, with an average interval of 2.3 days between the onset of the gastroenteritis and seizures
No patient subsequently developed epilepsy

69. Conclusion Better understand definition of febrile seizures
Be able to separate into simple and complex
Appropriate testing for febrile seizures
Appropriate treatment for febrile seizures
Progressing to epilepsy is in general low risk
Standardized prehospital treatment protocol for febrile status for EMT
Standardized treatment/testing in ED & hospital
Education for families and follow up if needed

70. Hamati-Haddad A, Abou-Khalil B
Hamati-Haddad A, Abou-Khalil B. Epilepsy diagnosis and localization in patients with antecedent childhood febrile convulsions; Neurology.
Annegers JF, Hauser WA, Shirts SB, Kurland LT. Factors prognostic of unprovoked seizures after febrile convulsions. NEJM
Abou-Khalil B, Andermann E, Andermann F, Olivier A, Quesney; Temporal lobe epilepsy after prolonged febrile convulsions: excellent outcome after surgical treatment. Epilepsia.

71. Verity CM, Butler NR, Golding J
Verity CM, Butler NR, Golding J. Febrile convulsions in a national cohort followed up from birth, I: prevalence and recurrence in the first five years of life. Br Med J (Clin Res Ed).
Camfield P, Camfield C, Gordon K, Dooley J. What types of epilepsy are preceded by febrile seizures? A population-based study
Complex Febrile Seizures : A Practical Guide to Evaluation and Treatment; Anup D. Patel and Jorge Vidaurre; J Child Neurol

72. Autoimmune and inflammatory epilepsies; Rima Nabbout; epilesia
Rapid Onset of Hippocampal Atrophy in Febrile-Infection Related Epilepsy Syndrome (FIRES); Byler; J Child Neurol
Febrile Seizures: Evaluation and Treatment; Anup D. Patel, MD, and M. Scott Perry, MD
Epilepsia: Recommendations for the management of “febrile seizures” Ad hoc Task Force of LICE Guidelines Commission; ILAE webite

73. Brain Dev May;31(5):359-65; Progress in searching for the febrile seizure susceptibility genes; Nakayama, J
Epilepsia; 2016 Jul; Risk factors for subsequent febrile seizures in the FEBSTAT study
AAP: Guidelines on Febrile Seizures
ILAE: Definition of Febrile Seizures
Epilepsia; 2016 Jul Risk factors for subsequent febrile seizures in the FEBSTAT study