Febrile seizures

Olivier Dulac

Hôpital Necker-Enfants Malades,

Université Paris V, INSERM U663

olivier.dulac@nck.aphp.fr

Definition

• Seizures precipitated by fever that is not

due to an intracranial infection or other

definable CNS cause

• They result from

– Fever

– Immature brain

– Genetic predisposition

Incidence

• The most common type of seizures in the

pediatric age group

• They affect 2 to 5% of children aging three

months to five years

• 2 to 10% develop subsequent unprovoked

seizures

• About one-third of all children with a first

febrile seizure will experience recurrent

Clinical manifestations

• Febrile seizures are

– Tonic / clonic

– Hypotonic (syncope?)

– Uni- or bilateral

• Not as myoclonus, spasms, or non convulsive

• Distinguish:

– Simple Febrile : generalized, <15 minutes, single

– Complex seizures: partial, >15 minutes, repeated

Risk

• Unilateral seizures may be followed by a Todd hemiplegia lasting a few hours, rarely several days

• The incidence of Todd hemiplegia is probably in the range of 0.4% of all cases of FS

• If lasting hours, seizure may be first stage of HH (hemiconvulsion – hemiplegic) syndrome

MRI in HH syndrome

3.2.93 29.9.93

Diffusion vs T1and FLAIRHH syndrome

Hippocampal Atrophy :

A mild form of HHE syndrome?

A possible mechanism for

HH syndrome?

Epileptic

activityCytokines?

Cell

Death

+

Network

reorganization

Viral

infection

triggering

factor

Callosal maturation permits bilateral involvement

Pathways between mesial temporal

and neocortical structures

1) infant 2) adolescent

Neocortical dysplasia Hippocampal atrophy

Temporal lobe epilepsy :

A model to distinguish

semantic and episodic memories

0 5 10 20years

Semantic

abilities

learning

Episodic

memory

ChildAdolescent

Investigations in FS

• Lumbar punction for children under 12 months with first seizure, to exclude:

– Bacterial meinigitis

– Herpetic encephalitis• Seizures affect one side of the face

• On 2nd/3rd day of fever

• CSF, MRI not reliable� begin with Aciclovir ®

• Blood glucose (hypoglycaemia), calcium

• + Viral investigations

Infectious aetiology• Viruses are responsible for precipitating illness in 90% of cases– Herpes virus 6 (Roseola Infantum) and 7 may be responsible for triggering febrile seizures

– Rotavirus infection have been also associated with encephalopathic manifestations

• Bacterial infections less commonly cause FS

• The incidence of febrile seizures with shigellosis is about 19.7%

• Fever resulting from immunization can provoke febrile seizures.– Prognosis seems favorable in most cases.

– Mainly with pertussis (wdpt not dtap) and measles vaccines.

Risk of recurrence

• Early age at onset (< 12 months)

• Family history of febrile seizures or epilepsy

• Epilepsy or febrile seizures in a first degree

relative

• Short duration between 2 fits < 3 months

• Relatively low fever at time of first seizure

• Brief duration between fever onset and initial

seizure

+ (possible)+Attendance at day care

+Duration of illness before

seizure

+Level of temperature at first

seizure

+Age of onset <18 months

-+Developmental delay or

neurological problems.

++Family history febrile seizures

in a first degree relative

Predicting

recurrence after a

first febrile seizure

Predicting a first

febrile seizure

Genetic factors

• FS occur with increase frequency among family members of patients with FS

• Most studies suggest a dominant mode of inheritance with reduced penetrance and variable expression

• Six loci of FS susceptibility :

– 8q 13-q21 (FEB1),

– 19 q (FEB2),

– 2q23-q24 (FEB3),

– 5q14-q15 (FEB4),

– 6q22-q24,

– 18q11

Risk of epilepsy following FS

• Non febrile seizures following febrile convulsions occur in 2% - 7% of patients

• Risk for generalized epilepsy is increased by:– Positive family history of non febrile seizures

– Large number of brief generalized febrile seizures

• Risk for partial epilepsy:– Prolonged lateralized febrile seizures.

– Early age at onset of febrile seizures and persisting neurologic dysfunction

– MRI studies have shown frequent evidence of hippocampal atrophy and mesial temporal sclerosis in patients with intractable temporal lobe epilepsy and history of prolonged febrile seizures

Epilepsy syndromes following

febrile seizures

• Absence epilepsy in 15% -25% of children with history of FS

• The incidence of FS in patients with Benign Rolandic epilepsy ranges from 9% to 20% which clearly is in excess of its incidence in the general population.

• Myoclonic absences

• Juvenile myoclonic epilepsy

Have been observed to follow FCs

Febrile seizures +

• FS usually with multiple recurrences, that recur

after the age of 6 years, and often associated

with non febrile generalized seizures (Scheffer

and Berkovic 1997).

• Dominant transmission termed as GEFS+ to.

• Missense mutations in the pore-forming subunit

– sodium channel subunit (SCN1B, SCN1A, and

SCN2A)

– defect in the gamma 2 subunit of GABA receptor

Dravet syndrome

• At the severe end of the GEFS+ spectrum is

Severe Myoclonic Epilepsy of infancy (SMEI,

Dravet syndrome):

– Onset in the 1st year of life

– Unilateral (alternating sides) and generalized

– Clonic

– With mild fever

– Myoclonus and SW occurring after age 3 years

• Families in which both Dravet syndrome and

GEFS+ presented in different individuals have

been reported

Treatment of FS

Three main issues are especially important

for the treatment:

– febrile seizures are extremely upsetting

for the parents

– the recurrence rate is 30-40%

– the febrile status occurs unpredictably

and is potentially damaging to the CNS

Acute management

• Control of the ongoing seizure

• Treatment of the fever preferably with

external cooling and paracetamol

• Treatment of the underlying illness

Management of continuing seizure

• Placement in the recovery semi-prone lateral position

• Adequate airway should be maintained

• Benzodiazepines, usually diazepam is the first choice:

– rectally in solution at seizure onset 0.5mg/kg/dose

– or intravenously 0.3 mg/kg/dose

– or midazolam buccally

• Seizures are controlled more quickly with intravenous

diazepam than with intranasal midazolam, although

midazolam is as safe as diazepam

Prophylaxis of recurrence

• Two types of prophylactic treatment :

– Intermittent prophylaxis given at the first sign

of a febrile illness (0.3 mg/kg/dose

Diazepam t.d.s)

– Continuous prophylaxis by administering

daily anticonvulsant drugs

Continuous prophylaxis

• Children with high risk for recurrence are good candidates

(complex FS or onset before 1 year of life)

• Usually maintained for 1 year :

– a vast majority of recurrences take place within 1 year of the first seizure

– severe seizures occur mainly in younger infants

• Phenobarbitone (3 mg/kg/d) � blood level of around 15 µg

• Sodium valproate reduces recurrences by about two-thirds

Side effects of

continuous prophylaxis

• Acute poisoning in the child or siblings

• Abrupt discontinuation provoking seizures

• The interactions with other medications

• The interference with calcium-phosphorus

metabolism

• Phenobarbital side effect on behavior and I.Q

Conclusions

• Differencial diagnosis: bacterial meningitis, viral encephalitis

• Distinguish simple/complicated FS

• Risk factors: HH syndrome, Dravet syndrome, mesial temporal lobe epilepsy

• Treatment restricted to complicated/earlyonset FS

– Intermittent (benzodiazepine)

– And/or continuous (valproate)

Stiripentol in Dravet syndromeDouble blind, multicentric

• % Responders

• Seizure frequency

• Seizure cessation

Placebo Stiripentol p

5% 71% <2.10-5

14/mths 6.5/mths <0.05

0 9

20

21

Placebo

Stiripentol

Treatment of Dravet syndrome

• Avoid carbamazepine, phenobarbital, phenytoin, vigabatrin and lamotrigine

• Valproate after the first seizure (complex, first year of life)

• Preventive treatment of seizures in case of fever, with diazepam

• Clobazam and Stiripentol are added afterthe first prolonged seizure or repeatseizures