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Febrile Seizures A Journey of Knowledge

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1 Febrile Seizures A Journey of Knowledge
Dr Abdulhafeez Mohamed Khair MBBS.CABP.MHPE.MRCPCH Pediatric Neurology Clinical Fellow CME activity,

2 Presentation headlines
Overview & background. Simple febrile seizures. Complex/complicated febrile seizures. Febrile epilepsy syndromes. Febrile status epilepticus. Illness-related seizures. Milestones of medical evidence.

3 Case scenario, 1980s 2 yr old boy, healthy, Em C/s, developmentally: N. Had URI symptoms for 3 days then spiked ↑fever. Episode of GTC sz for 2 minutes, aborted. Pediatrician consulted, referred immediately to ER. Hospitalized for 7 days, CSF done, received IV Abx, discharged on continuous adol & PO Abx for 1wk. Offered valproate, family refused, had further 4 episodes, all are short, same description, no sp Rx.

4 Prof. Mustafa Salih Emeritus Professor of Pediatrics and Consultant Pediatric Neurologist at the College of Medicine, King Saud University, Riyadh, Saudi Arabia.   165 publications, 5 textbooks. Current editor in 7 peer-reviewed journals. 6 international awards,3 named diseases, 2 named diagnostic procedures.

5 Overview

6 Historical milestones
Recognized as distinct from other seizures in the mid-19th century. Thermometer at the end of the 1800s. Early 20th century, FS considered severe & fatal. 1940s Lennox investigated risk factors for recurrence and later epilepsy. 1970s 1st FS considered top emergency. Late 1990 first AAP quality guidelines. 2000: First complete  ILAE task force on classification and terminology of FS.

7 Hippocrates (460–370 BC) “Children are likely to have fits if the fever is high”. “These may be generalized or partial”. “This most commonly happens under the age of seven A positive family history is important”. “The brain is the seat of this disease” Those suffering from brain fever (meningitis) have convulsions and some of these die rapidly”. “Many come through safely but with minor damage.

8 Definition/s The NIH (1980)an abnormal, sudden, excessive electrical discharge of neurons (gray matter) that propagates down the neuronal processes (white matter) to affect an end organ in a clinically measurable fashion, occurring in infancy or childhood, usually between 3 months and 5 years of age, associated with fever, but without evidence of intracranial infection or defined cause. The ILAE (1993)a seizure occurring in childhood after age 1 month, associated with a febrile illness not caused by infection of the CNS, without previous neonatal seizures or a previous unprovoked seizure, and not meeting the criteria of other acute symptomatic seizures. AAP (2008)a seizure occurring in febrile children between the ages of 6 and 60 months who do not have an intracranial infection, metabolic disturbance, or history of afebrile seizure The AAP definition does not exclude children with pre-existing neurological disease.

9 Epidemiology Affects 2-5 % of children.
Incidence 460/100,000 in age group 0-4 yrs. Peak age group for first FS is months. 60% males. GTC80%, tonic13%, atonic3%., focal4%. FH +ve in 1st degree relative in % of cases. Patterson JL, Pediatric Annals, 2013

10 Causes of FS Menkes textbook of child neurology, 5th edition, 1997

11 Risk of development of 1st FS
Height of temperature. Hx of FS in a first- or in a higher degree relative. Developmental delay. Day care attendance. Neonatal nursery stay > 28 days. Vaccination !!. Viral infections (HHV6). Iron & zink deficiencies ?? . Hapers LC, Emerg Med Clin North Am. 2011 In the first 2 wks following vaccination. Viral infe

12 FS, Patho-physiology Sanjay Sisodiva, Nature Genetics, 2014

13 Simple Febrile Seizures

14 Simple febrile seizures
The setting is fever in a child aged 6 months to 5 yrs. The single seizure is generalized and lasts <15 minutes. The child is otherwise neurologically healthy &without neurologic abnormality by examination or by developmental history. Fever (and seizure) is not caused by meningitis, encephalitis, or any other illness affecting the brain. The seizure is described as either a generalized clonic or a generalized tonic-clonic seizure Graves RC et al, American family physician J, 2012

15 Evaluation Hx & PE for fever focus. U & E for possible derangement.
?? Neuro-imaging if there is Hx of trauma or concerning focal neurological signs. CSF for <18 months/ 1st episode. ?? None.

16 50% non-compliant, 40% side effects.
The first febrile seizure: antipyretic instruction plus either phenobarbital or placebo to prevent recurrence. Camfield PR, Camfield CS, Shapiro SH, Cummings C Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada DB-RCT, 102 pts. Pts started on Phenobarbitone Vs placebo after their first febrile seizure. Results: daily therapy with PHP reduced rate of subsequent febrile seizures from 25 per 100 subjects per year to 5 per 100 subjects per year. 50% non-compliant, 40% side effects. J Pediatr.1980 Low PHP blood level correlates with seizure recurrence.

17 Continuous sodium valproate or phenobarbitone in the prevention of “simple” febrile convulsions Ngwane E, Bower B. University Department of Paediatrics, John Radcliffe Hospital, Oxford In RCT, pts allocated into valproate, phenobarbital & placebo groups after first febrile seizure. Results : only 4% of children taking valproic acid, as opposed to 35% of control subjects, had a subsequent febrile seizure. Conclusion: valproate is as effective in preventing recurrent simple febrile seizures as phenobarbital and significantly more effective than placebo. Arch Dis Child.1980 No case of fatal hepatotoxicity is reported.

18 A controlled trial of diazepam administered during febrile illnesses to prevent recurrence of febrile seizures Rosman NP1, Colton T, Labazzo J, Gilbert PL, Gardella NB, Kaye EM, Van Bennekom C, Winter MR Department of Pediatrics, Tufts University School of Medicine, Boston, MA DB-RCT, 406 children (mean age, 24 months) who had at least one febrile seizure. Diazepam (0.33 mg/kg) or placebo was administered PO Q8hr during all febrile illnesses. Results: Reduction in the risk of febrile seizures with diazepam (relative risk = 0.18; 95 percent confidence interval, 0.09 to 0.37; P < 0.001). Number to treat to prevent one FS was 14. N Engl J Med. 1993 July Side effects encountered in 40% of trial group. Risk reduced from 31% to 23% high no to treat

19 Antipyretic effectiveness of acetaminophen in febrile seizures: ongoing prophylaxis versus sporadic usage Schnaiderman D, Lahat E, Sheefer T, Aladjem M Paediatric Division, Assaf Harofeh Medical Centre, Sackler School of Medicine, Tel Aviv University, Israel RCT, 104 pts ( previously healthy ) . 3 groups, regular acetaminophen, PRN acetaminophen & placebo during fever>39.9. Results: The incidence of febrile seizures did not differ significantly between the 3 groups, nor did the early recurrence of febrile seizures. Eur J Pediatr.1994

20 Buccal midazolam as rescue therapy for acute seizures Rod C Scott Neurosciences Unit, Institute of Child Health, University College London, London, UK Cohort: pts with prolonged seizures>5 min due to any cause in the ER. RCT, pts assigned to PR diazepam Vs buccal midazolam. Results: midazolam aborted 56% of seizures, while diazepam 27% (P<0.05). The Lancet Neurology, October 2005 Age group 1-5 yrs. No infants in this study.

21 Candidacy for rescue Bndz:
Are febrile seizures an indication for rescue benzodiazepine treatment, and if so, in which cases? A meta-analysis study Carol Camfield Department of Pediatrics, Dalhousie University and the IWK Health Centre, Halifax, Nova Scotia, Canada Candidacy for rescue Bndz: Pts with hx of prolonged FS>10 min( risk of 2nd prolonged FSE is 20% Vs 6.8% if 1st FS<10 min). Pts with difficulty accessing acute health services. Anxious parents ?? (consensus, no studies). Epileptic disorders, October 2014

22 Complex febrile seizures

23 Complex Febrile Seizures
FS + atypical feature  Age <6 m, > 60 m. Focal onset. Occurs more than once during a febrile illness or in 24 hr period. lasts more than minutes. Slow recovery time. ? Lower temperature.

24 Late febrile convulsions: a clinical follow-up Pavone L1, Cavazzuti GB, Incorpora G, Galli V, Parano E, Benatti A, Rizzo R, Ciccarone V Pediatric Department, University of Catania, Catania, Italy 222 pts with FS after 6 yrs of age. 94 pts out of 222 (42.3%) had subsequent fits, both febrile & afebrile. Risk of subsequent FS was 36%. Risk of subsequent afebrile seizures in late febrile seizure was 15.8%. Brain & development, 1989

25 Complex febrile seizures Berg AT, Shinnar S School of Allied Health Professions, Northern Illinois University, DeKalb, IL, USA Prospective, 686 pts with complex FS. low fever at the time of the seizure was marginally associated with prolonged duration (P:0.05) There were strong correlations between focality and prolonged duration (R:0.92). Longer seizures tend to recur as long. No link to future epilepsy. Epilepsia, 1996

26 Risk or progression to epilepsy
Risk might be increased with(4 folds) Family history of epilepsy. Complex features Early neuro-developmental disorders. No increased risk with: The number of recurrences of F.S. FH of febrile convulsions. Age of onset or gender. long-term prophylactic use of AED. Tsai ML, J Formos Med Assoc. 1999 Overall risk of epilepsy in this study is 12% regardless of the febrile seizure type.

27 Mesial Temporal Sclerosis
Strong correlation exist between MTS & hx of childhood febrile seizures. Egg & chicken debate. FS(CFS)MTSTLE. MTS CFSTLE. Both CFS & MTS may have shared genetic background. Cendes F, Curr Opin Neurol. 2004  Nathali T, Epilepsy Research and Treatment, 2012 Relation is now thought to be of correlation nature rather than causal relationship.

28 Clinical and EEG risk factors for subsequent epilepsy in patients with complex febrile seizures Kim H1, Byun SH, Kim JS, Lim BC, Chae JH, Choi J, Kim KJ, Hwang YS, Hwang H. Department of Pediatrics, Seoul National University Bundang Hospital, Gyeonggi-do, Republic of Korea 1091 pt with FS, recruited from Single-center, retrospective cohort. Results: Among 183 pts with CFS, 22 pts (12.0%) developed subsequent epilepsy. Epileptiform discharges (focal in all cases) were significantly more frequent in pts with subsequent epilepsy (50% vs. 13%, p=0.002), OR of 5.15 (95% confidence interval, ). Epilepsy Research, 2013

29 Complex febrile seizures: study of the associated pathology and practical use of complementary tests Berzosa López R1, Ramos Fernández JM2, Martínez Antón J3, Espinosa Fernández MG1, Urda Cardona A1 Hospital Materno Infantil Carlos Haya, Málaga, Spain Retrospective review, , pts 6 m-6 yrs with CFS excluding pts with previous neurological disease. NeuroimagingN in all pts. EEG could not be linked to risk of future epilepsy. Conclusion: The incidence of complications in complex febrile seizure in this series did not justify the systematic admission or the systematic study with complementary tests when the neurological examination was normal. Analis de pediatria, 2015 3000 children in this study

30 Generalized Epilepsy with Febrile Seizures Plus

31 GEFS + Heterogeneous, familial syndrome with pts displaying FS often after 6 yrs of age &/or varieties of afebrile seizure types. AD with several genetic make-up theories. Variable seizure difficulty. Neuroimaging is usually normal. Some pts are intellectually disabled (?? Epileptic encephalopathy). Isabelle Gourfenkil-An, Orphanet, 2002

32 GEFS+ neuro-genetics GEFS+ type 1 GEFS+ type 2 GEFS+ type 3
Mutations in SCN1B, a gene encoding a Na-channel β subunit GEFS+ type 2 Mutations in SCN1A, a gene encoding a sodium channel α subunit GEFS+ type 3 Mutations in the GABRG2 gene, which encodes the GABA γ2 subunit Polizzi A, Child`s Nervous System.  2012

33 SCN1A-beta subunit(2q24.3) Generalized epilepsy with febrile seizure plus type 2. Early infantile epileptic encephalopathy (EIEE). Severe myoclonic epilepsy in infancy ( Dravet syndrome). Intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC). Myoclonic- astatic epilepsy (Doose syndrome). Malignant migrating partial seizures of infancy. Familial febrile seizures type 3A. Familial hemiplegic migraine type 3. Guala A, Am J Med Genet A. 2014

34 Dravet syndrome 1st FS at age of 6-9 m, usually status.
High recurrence with febrile illnesses. Photosensitivity, photic stimulation and exercise may also provoke seizures. Development arrest evident by 2 yrs. Seizures then tend to occur with minimal or no temp. 80% have SCN1A-beta subunit mutation. Special EEG changes. Stiripentol  & keto-diet are effective therapies. Ingo Helbig, Orphanet, 2014 EEGspikes or poly spike-waves with a slowing of background activity are noted as well as multifocal discharges.

35 F.I.R.E.S

36 F.I.R.E.S Febrile Infection-Related Epilepsy Syndrome.
Affects 1:100,000 children, usually 3-15 yrs old. Seizures happens solely during febrile illnesses. Seizures are explosive, prolonged & lifelong. Learning & motor disabilities, behavioral disorders, memory issues & sensory changes over time. May be fatal. Kramer U et al, Epilepsia, 2011

37 F.I.R.E.S, cont Unknown etiology, assumed genetic immunological ,inflammatory or mitochondrial factors. Mostly focal Sz, can progress to be generalized. EEG: generalized slow background, ictal epileptic activity (temporal, frontal). MRI initially normal, then slowly shows brain atrophy +/- temporal hyper-intensities. Roberto H et al, Seizure, 2013 Boys are affected more than girls. Though the disease thought to be familial, it has not been reported twice in the same family.

38 F.I.R.E.S, management AED, often ineffective.
High dose Bndz or barbiturates. Burst suppression may be needed. VNS ??. Immunotherapy. RCT by Sakuma in Japan, has found 85% of steroid group responded well, but none in IVIG group, making conclusive immunotherapy difficult. Plasma exchange is under current trial.

39 Small case series, 7 pts with FIRES.
Efficacy of ketogenic diet in severe refractory status epilepticus initiating fever induced refractory epileptic encephalopathy in school children (FIRES) Nabbout R1, Mazzuca M, Hubert P, Peudennier S, Allaire C, Flurin V, Aberastury M, Silva W, Dulac O Department of Neuropediatrics, Hôpital Necker-Enfants Malades, Paris, France Small case series, 7 pts with FIRES. KD↓seizure frequency by 50% in 4-7 days. One pts stopped KD relapse died. No long term follow up. Epilepsia (Special report), 2010

40 Febrile Status Epilepticus

41 Febrile status epilepticus
Prolonged FS > 30 min. Incidence is 4/100,000 per yr. Peak age 1-2 yrs, rare beyond 5 yrs. Maximal prevalence in Asian descents. 65% generalized, 35% focal initially. Caution for mild convulsion-related fever. Hesdorffer DC et al, J Pediatr. 2013 Previously healthy children with no previous neurological impairment.

42 Febrile status epilepticus, cont
Patho-physiology: not exactly known. MRI shows hippocampus swelling in50% of pts, can be seen from 72 hr post seizure?TLE. Anti-pyretics do not shorten seizure duration. Priority is to rule out CNS infection. Routine seizure management advised. No conclusive evidence regarding future epilepsy. Seinfeld S et al, Epilepsia. 2014

43 Demographics and outcomes of patients with pediatric febrile convulsive status epilepticus Nishiyama M1, Nagase H2, Tanaka T2, Fujita K2, Maruyama A2, Toyoshima D3, Nakagawa T3, Taniguchi-Ikeda M3, Morioka I3, Morisada N3, Takada S3,Iijima K3 Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan Poor outcome factors(253 pts):- Male sex. Body temp above 40°C on admission(OR:3.39). Seizure duration >120 minutes. Impaired consciousness at 12 hrs after sz(OR:41.8) Presence of nonconvulsive status epilepticus. Pediatric Neurology, May 2015 Descriptive, 5 yrs study. Cases of neurological worsening were categorized as poor outcome using the pediatric cerebral performance category scale.

44 Afebrile febrile seizures

45 Afebrile febrile seizures
Distinct epilepsy syndrome. Children with provoked seizures were afebrile at the time of seizure but manifested definite symptoms or signs of minor infection. Mostly cough, coryza, vomiting or diarrhea. Special association with rota virus GE. Occurs in the first 3 days of illness. Risk of subsequent epilepsy is 5.7%. Lee WL, Pediatric neurology, 2004 Care should be thoroughly taken for elaborating on history of minor infections in any child with seizure even if afebrile.

46 A comparison of provoked seizures and febrile seizures associated with minor infections Eun-Ju Lee (Lee EJ), Won Seop Kim (Kim WS) Department of Pediatrics, College of Medicine and Medical Research Institute, Chungbuk National University, Korea 120 pts, 5 yrs retrospective descriptive study. Sz provoked by minor extra-cranial infections, contrasting them with febrile and Afebrile provoked sz. 50% had GE, 28% had URIs in provoked group. No difference of epilepsy risk in both groups(P:0.09) risk of future epilepsy is low with/without fever. Korean Journal of Pediatrics, 2007

47 AS-GI: no↑risk of epilepsy(P:0-001), good prognosis.
Are afebrile seizures associated with minor infections a single seizure category?hospital-based prospective cohort study on outcomes of 1st afebrile seizure in early childhood Zhang T1, Ma J, Gan X, Xiao N Department of Rehabilitation, Children's Hospital of Chongqing Medical University, Chongqing, China 3 groups:1st afebrile sz ass/w GI infection (AS-GI), 1st afebrile sz ass/w non-GI infection (AS-nGI), & 1st unprovoked sz (US). AS-GI: no↑risk of epilepsy(P:0-001), good prognosis. AS-nGI had no difference from US for sz recurrence (P:0.451), worse overall neurological prognosis. Epilepsia, 2014

48 Vaccination-induced FS
Very Rare, with or without presence of fever. Linkage to vaccine is possible if within 72hr. ↑risk with LAV (MMR) or WCV(DPT). Concomitant vaccination administration ↑risk. No higher risk for subsequent seizures or future neuro-developmental disability. None of the standard vaccinations is currently contraindicated for children with FS. Controversy regarding routine rescue diazepam with vaccination in high risk group. Principi N, Expert Rev Vaccines Aug measles disease itself results in 1 in 1000 infected children developing encephalitis, and 1 in 50 and 1 in 250 children with pertussis disease experience convulsions and encephalopathy. live attenuated vaccines for which events may be delayed until 7-14 days after.

49 Future/ongoing researches
Using a rat model to evaluate neuronal injury from FS, and looking at future development of epilepsy following FS University of California, CA, USA. T he North London Status Epileptics in Childhood Surveillance Study (NLSTEPSS) in the United Kingdom is evaluating incidence, morbidity &treatment children with SE, including FSEGOS (NIH), UK. The FEBSTAT study is evaluating the long-term consequences of FSE using MRI, EEG, developmental/neuropsychological testing, virology, genetics, psychiatric interview and parental interviews  Columbia University, Ny, USA. The genetics of FS, the sub-types and sub-syndromes are also being studied using twin pairs University of Melbourne, Austalia.

50 Case scenario No 2, 2015 20 months old girl, previously healthy.
Hx of low grade fever, given adol, followed by GTC Sz with eye uprolling for 2 min. Seen in PEC post-ictal, normal PE. Observed for 6 hrs. No blood tests, no CSF, no Abx, no anti-pyretics, no imaging, no EEG, discharged on no Rx. Follow up offered with Gen.peds.

51 Summary points Febrile seizures are generally benign, but most families with consider them very frightening. Prolonged or atypical FS may do have long term neurological consequences. Extensive work-up(?LP) for FS is not often needed. Think of FS related epilepsy syndromes. More studies are needed for better understanding of pathological & clinical aspects of FS.

52 References Sugai K. Current management of febrile seizures in Japan: an overview. Brain Dev. 2010;32:64–70. [3. Baumann RJ, Duffner PK. Treatment of children with simple febrile seizures: the AAP practice parameter. American Academy of Pediatrics. Pediatr Neurol 4. National Institute of Health. Febrile seizures: long-term management of children with fever-associated seizures. Pediatrics 5. Guidelines for epidemiologic studies on epilepsy. Commission on Epidemiology and Prognosis, International League Against Epilepsy. Epilepsia 6. Germano IM, Zhang YF, Sperber EF, Moshe SL. Neuronal migration disorders increase susceptibility to hyperthermia-induced seizures in developing rats. Epilepsia 7. Takano T, Sakaue Y, Sokoda T, Sawai C, Akabori S, Maruo Y, et al. Seizure susceptibility due to antihistamines in febrile seizures. Pediatr Neurol 8. Vestergaard M, Christensen J. Register-based studies on febrile seizures in Denmark. Brain Dev 9. Livingston S, Pauli LL, Pruce I, Kramer II. Febrile convulsions: diagnosis, treatment, and prognosis. Pediatr Ann 10. Knudsen FU. Febrile seizures: treatment and outcome. Brain Dev 11. Berg AT, Shinnar S. Complex febrile seizures. Epilepsia 12. Shinnar S, Glauser TA. Febrile seizures. J Child Neurol. 2002;17(Suppl 1). 13. Paul SP, Blaikley S, Chinthapalli R. Clinical update: febrile convulsion in childhood. Community Pract 14. Stafstrom CE. The incidence and prevalence of febrile seizures. In: Baram TZ, Shinnar S, editors. Febrile seizures. San Diego: Academic Press; pp. 1–25. 15. Sadleir LG, Scheffer IE. Febrile seizures. BMJ Bassan H, Barzilay M, Shinnar S, Shorer Z, Matoth I, Gross-Tsur V. Prolonged febrile seizures, clinical characteristics, and acute management. Epilepsia. 2013. Principi N, Esposito S. Vaccines and febrile seizures. Expert Rev Vaccines. 2013. Brown NJ, Berkovic SF, Scheffer IE. Vaccination, seizures and vaccine damage. Curr Opin Neurol.2007.




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