WEST SYNDROMEPrepared by:

D.MOAWEYAH QASIM (R3)SUPERVISED BY:

DR.ABEER MATAR(PEDIATRIC NEUROLOGIST)

• - Introduction

• - Classification.

• -clinical manifstation

• -Treatment

• - updated guidelines from 2004 till 2012 from american academy of neurology .

introduction

• West syndrome is a severe epilepsy syndrome composed of the triad of infantile spasms, an interictal electroencephalogram (EEG) pattern termed hypsarrhythmia, and mental retardation, although the diagnosis can be made even if 1 of the 3 elements is missing (according to international classification)

• The syndrome's namesake, Dr W J West, gave the first detailed description of infantile spasms, which occurred in his own child.In a letter to the editor of The Lancet in 1841, West described the events as "bobbings" that "cause a complete heaving of the head forward towards his knees, and then immediately relaxing into the upright position.These bowings and relaxings would be repeated alternately at intervals of a few seconds, and repeated from 10 to 20 or more times at each attack, which would not continue more than 2 or 3 minutes; he sometimes has 2, 3 or more attacks in the day."

• Infantile spasms constitute a unique, age-specific epilepsy syndrome of early infancy characterized by epileptic spasms often accompanied by neurodevelopmental regression and an EEG finding of hypsarrhythmia.

– When all 3 components are present, the eponym “West syndrome” is commonly used.

• The incidence is 2–3 per 10,000 live births , the lifetime prevalence rate is 1.5–2 per 10,000 children.

• Infantile spasms are slightly more common in males, and a family history exists in 3%–6% of cases.

• The spontaneous remission rate of infantile spasms described in limited natural history studies is 30%.

• A 2004 AAN/Child Neurology Society parameter on the medical treatment of infantile spasms concluded:

– Adrenocorticotropic hormone (ACTH) is probably an effective agent for short-term treatment of infantile spasms (Level B)

– Vigabatrin (VGB) is possibly effective for short-term treatment of infantile spasms (Level C) and for treatment of children with tuberous sclerosis (Level C)

• In children with infantile spasms and tuberous sclerosis, 2 Class III studies from the 2004 practice parameter showed spasms cessation at 2–3 weeks in 16 of 28 (57%) patients treated with VGB, with overall response rate of 100% in both studies. Therefore, VGB is possibly effective for short-term treatment of infantile spasms in the majority of children with tuberous sclerosis (Level C).

• Data were insufficient at that time to recommend other antiepileptic drugs (AEDs), the ketogenicdiet, pyridoxine, or IV immunoglobulin (IVIg) for short-term treatment of infantile spasms or to assess the impact of treatment on long-term outcomes.

• Since 2004, only one study provided evidence higher than Class IV, a single large Class III randomized controlled trial (RCT) comparing low-dose and high-dose VGB for treatment of infantile spasms.

– This study showed more patients in the high-dose group achieved spasms cessation within 14 days relative to those in the low-dose VGB group.

– In the symptomatic tuberous sclerosis complex (TSC) subgroup, the spasm-free rate was higher in those allocated high-dose VGB.

– A post analysis video-EEG performed at any subsequent visit showed hypsarrhythmia resolution in 30.8% of patients on high-dose VGB vs 13.2% on low-dose VGB.

Classification based on etiology:

• Symptomatic:Patients are diagnosed with symptomatic infantile spasms if an identifiable factor is responsible for the syndrome. Virtually any disorder that can produce brain damage can be associated with infantile spasms.

– Hydrocephalus

– Microcephaly

– Sturge weber syndrome

– Tuberous sclerosis

–HIE

–Congenital infections

–Meningitis

– Encephalitis

–Pyridoxine deficiency

–Maple syrup urine disease

–Phenylketonuria

–Biotinidase deficiency

– Trauma

• Cryptogenic:Patients have cryptogenic infantile spasms if no cause is identified but a cause is suspected and the epilepsy is presumed to be symptomatic.

• Idiopathic:Patients may be considered to have idiopathic infantile spasms if normal psychomotor development occurs prior to the onset of symptoms, no underlying disorders or presumptive causes are present, and no neurologic or neuroradiologic abnormalities exist. Some investigators use the terms idiopathic and cryptogenic interchangeably.

Treatment:

• Compared with other forms of epilepsy, West syndrome is difficult to treat. To raise the chance of successful treatment and keep down the risk of longer-lasting effects, it is very important that the condition is diagnosed as early as possible and that treatment begins straight away.

•

Commonly used first-line treatments for infants with West syndrome include the following:

ACTHVigabatrinPrednisonePyridoxine (vitamin B-6)

Second-line treatments include the following: BenzodiazepinesValproic acid LamotrigineTopiramateZonisamideLevetiracetam

Treatment options

Prednisone• A 2004 American Academy of Neurology and Child

Neurology Society practice parameter concluded that "there is insufficient evidence that oral corticosteroids are effective in the treatment of infantile spasms”

• One study found that after approximately 2 weeks, hormonal therapy provided better relief from spasm than did vigabatrin. The 2004 multicenter, randomized, controlled trial compared hormonal therapy (either oral prednisolone or IM tetracosactide depot) with vigabatrin in 107 infants with infantile spasms. More infants assigned hormonal treatments (73%) had no spasms on days 13 and 14 than did infants assigned vigabatrin (54%).

Pyridoxine• Two distinct treatment situations exist in which

pyridoxine is used in patients with West syndrome.

• First is intravenous (IV) administration during diagnostic EEG to assess whether the patient's seizures and EEG abnormalities are related to pyridoxine deficiency. In this approach, administer 50-100 mg IV during a diagnostic EEG; if dramatic improvement is noted in the EEG, the patient is believed to have pyridoxine-dependent seizures.

• Second is long-term oral administration. The effectiveness of long-term, oral, high-dose pyridoxine in West syndrome has been investigated in multiple open-label studies, with promising results. Most patients who respond to long-term, oral, high-dose pyridoxine do so within 1-2 weeks of initiation.

Valproic acid

• Valproic acid is considered an effective second-line AED therapy against spasms associated with West syndrome.

• Dose-10-15 mg/kg/day PO/IV divided q6-8h

• Monitor: LFTs

ACTH

• A 2004 American Academy of Neurology and Child Neurology Society practice parameter concluded that "ACTH is probably effective for the short-term treatment of infantile spasms and in resolution of hypsarrhythmia” and "here is insufficient evidence to recommend the optimum dosage and duration of treatment with ACTH for the treatment of infantile spasms."

• Corticotropin is associated with serious, potentially life-threatening adverse effects. It must be administered intramuscularly, and such injections are painful for the infant to receive and are unpleasant for the parent to perform.

• A prospective, single-blind study demonstrated no difference in effectiveness between high-dose, long-duration corticotropin (150 U/m2/day for 3 wk, tapering over 9 wk) and low-dose, short-duration corticotropin (20-30 U/day for 2-6 wk, tapering over 1 wk with respect to spasm cessation and improvement in the patient's EEG. Hypertension was more common with larger doses

Vigabatrin• Vigabatrin is indicated as monotherapy for

children aged 1 month to 2 year with infantile spasms. Its precise mechanism of action is unknown. The drug is a selective, irreversible inhibitor of gamma-aminobutyric acid transaminase (GABA-T). GABA-T metabolizes GABA, an inhibitory neurotransmitter, thereby increasing CNS GABA levels. Vigabatrin use must be weighed against the risk of permanent vision loss.Vigabatrin was approved by the US Food and Drug Administration (FDA) in August 2009. It is available only from a restricted access program.

Topiramate• Topiramate is a sulfamate-substituted

monosaccharide with a broad spectrum of antiepileptic activity that may have state-dependent sodium channel blocking action, may potentiate the inhibitory activity of the neurotransmitter GABA, and may block glutamate activity.

• A 2004 American Academy of Neurology and Child Neurology Society practice parameter concluded that "there is insufficient evidence to recommend topiramate for the treatment of infantile spasms."

Levetiracetam

• Levetiracetam's mechanism of action is the inhibition of N-type calcium channels, the modulation of GABA and glycine receptors, and binding to SVA2 protein.

• An open-label trial of 5 infants with new-onset, cryptogenic infantile spasms showed levetiracetam to be clinically effective. Two children became seizure free, while 2 others showed a minimum of 50% reduction in seizures. The dose ranged from 30-60 mg/kg/day.

clonazepam

• Clonazepam is considered a second-line AED therapy against spasms associated with West syndrome. However, adverse effects and the development of tolerance limit the drug's usefulness over time. Nitrazepam and clobazam are not approved by the FDA but are available in many countries worldwide.

Prognosis • It is not possible to make a generalised

prognosis for development due to the variability of causes, the differing types of symptoms and etiology. Each case must be considered individually.

• The prognosis for children with idiopathic West syndrome are mostly more positive than for those with the cryptogenic or symptomatic forms.

• A large proportion (up to 90%) of children suffer severe physical and cognitive impairments, even when treatment for the attacks is successful. This is not usually because of the epileptic fits, but rather because of the causes behind them (cerebral anomalies or their location or degree of severity).

• Permanent damage often associated with West syndrome in the literature include cognitive disabilities, learning difficulties and behavioural problems, cerebral palsy (up to 5 out of 10 children), psychological disorders and often autism (in around 3 out of 10 children). Once more, the etiology of each individual case of West syndrome must be considered when debating cause and effect.

• Statistically, 5 out of every 100 children with West syndrome do not survive beyond five years of age, in some cases due to the cause of the syndrome, in others for reasons related to their medication. Only less than half of all children can become entirely free from attacks with the help of medication. Statistics show that treatment produces a satisfactory result in around three out of ten cases, with only one in every 25 children's cognitive and motoric development developing more or less normally.

• Sometimes West syndrome turns into a focal or other generalised epilepsy. Around half of all children develop Lennox-Gastaut syndrome.

• Are other forms of corticosteroids as effective as ACTH for treatment of infantile spasms?

• Are low-dose ACTH regimens effective for short-term treatment of infantile spasms?

• Is ACTH more effective than VGB for short-term treatment of infantile spasms?

• What other agents are as effective as ACTH for treatment of infantile spasms?

• Does successful early treatment of infantile spasms lead to long-term improvement of neurodevelopmental outcomes or decreased incidence of epilepsy?

AAN Classification of Evidence

• All studies rated Class I, II, III, or IV

• Five different classification systems

– Therapeutic

• Randomization, control, blinding

– Diagnostic

• Comparison with gold standard

– Prognostic

– Screening

– Causation

AAN Level of Recommendations

• A = Established as effective, ineffective or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population

• B = Probably effective, ineffective or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population

• C = Possibly effective, ineffective or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population

• U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven

– Note that recommendations can be positive or negative

Translating Class to Recommendations

• A = Requires at least two consistent Class I studies*

• B = Requires at least one Class I study or two consistent Class II studies

• C = Requires at least one Class II study or two consistent Class III studies

• U = Studies not meeting criteria for Class I through Class III

Methods

• MEDLINE and EMBASE were searched (2002–August 2011) using OVID interface– Relevant, fully published, peer-reviewed articles– See appendix e-3 of the published guideline for the complete

search strategy

• At least two authors reviewed each article for inclusion, with a third author arbitrating differences

• Risk of bias was determined using the classification of evidence scheme for therapeutic articles

• Strength of recommendations was linked directly to levels of evidence

• Conflicts of interest were disclosed

AAN Classification of Evidencefor Therapeutic Interventions

• Class I: Class I: A randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences. The following are also required:– Concealed allocation

– Primary outcome(s) clearly defined

– Exclusion/inclusion criteria clearly defined

AAN Classification of Evidencefor Therapeutic Interventions, cont.– Adequate accounting for dropouts (with at least 80% of enrolled

subjects completing the study) and crossovers with numbers sufficiently low to have minimal potential for bias.

– For noninferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also required*:• The authors explicitly state the clinically meaningful difference to

be excluded by defining the threshold for equivalence or noninferiority.

• The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard treatment (e.g., for a drug, the mode of administration, dose and dosage adjustments are similar to those previously shown to be effective).

• The inclusion and exclusion criteria for patient selection and the outcomes of patients on the standard treatment are comparable to those of previous studies establishing efficacy of the standard treatment.

• The interpretation of the results of the study is based upon a per protocol analysis that takes into account dropouts or crossovers.

AAN Classification of Evidencefor Therapeutic Interventions, cont.

• Class II: A randomized controlled clinical trial of the intervention of interest in a representative population with masked or objective outcome assessment that lacks one criteria a–e above or a prospective matched cohort study with masked or objective outcome assessment in a representative population that meets b–e above. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

AAN Classification of Evidencefor Therapeutic Interventions, cont.

• Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement.**

• Class IV: Studies not meeting Class I, II, or III criteria including consensus or expert opinion.

*Note that numbers 13 in Class I, item 5 are required for Class II in equivalence trials. If any one of the three is missing, the class is automatically downgraded to Class III.

**Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer’s (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).

Clinical Question 1

• Are other forms of corticosteroids as effective as ACTH for treatment of infantile spasms?

• Only one Class III study showed similar efficacy between ACTH and oral prednisolone.

• Data are insufficient regarding the equivalence of other corticosteroids to ACTH (Class III and IV evidence).

• The evidence is insufficient to recommend the use of prednisolone, dexamethasone, and methylprednisolone as being as effective as ACTH for short-term treatment of infantile spasms (Level U).

Clinical Question 2

• Are low-dose ACTH regimens effective for short-term treatment of infantile spasms?

• A Class I study showed similar efficacy between low-dose (20–30 IU) and high-dose (150 IU/m2) natural ACTH, and a Class II study using the same low-dose natural ACTH showed clinical and EEG response rates of 40%. The evidence suggests that low-dose ACTH is probably as effective as high-dose ACTH for short-term treatment of infantile spasms (Class I and II evidence).

• Low-dose ACTH should be considered as an alternative to high-dose ACTH for treatment of infantile spasms (Level B).

Clinical Question 3

• Is ACTH more effective than vigabatrin for short-term treatment of infantile spasms?

• Two Class III studies (1 from the 2004 parameter and a later study) demonstrated that ACTH is more effective than VGB for short-term treatment of children with infantile spasms (excluding those with TSC). A small Class III study and a Class IV study found no difference in short-term outcome between ACTH and VGB.

• Previous practice parameter recommendation remained unchanged: ACTH (Level B) or VGB (Level C) may be offered for short-term treatment of infantile spasms. Evidence suggests that ACTH may be offered over VGB (Level C).

Clinical Question 4

• What other agents are as effective as ACTH for treatment of infantile spasms?

• Data from previously reviewed and updated evidence are insufficient to determine whether valproic acid (VPA), vitamin B6, nitrazepam (NZP), levetiracetam(LEV), zonisamide (ZNS), topiramate (TPM), the ketogenic diet, sulthiame, or other novel therapies (e.g., IV immunoglobulin, thyrotropin-releasing hormone) are effective in the treatment of infantile spasms (Class III and IV evidence). A single Class III study showed better outcome for combination therapy with ACTH and magnesium sulfate.

• The evidence is insufficient to recommend other therapies (VPA, vitamin B6, NZP, LEV, ZNS, TPM, the ketogenic diet, or novel/combination therapies) for treatment of infantile spasms (Level U).

Clinical Question 5

• Does successful early treatment of infantile spasms lead to long-term improvement of neurodevelopmental outcomes or decreased incidence of epilepsy?

• A Class II study showed that hormonal therapy (ACTH or prednisolone) relative to VGB therapy leads to better neurodevelopmental outcome in children with cryptogenic spasms.

• One previous Class III study and 1 newer Class II study showed that shorter lag time to treatment improves long-term cognitive outcomes.

• Hormonal therapy (ACTH or prednisolone) may be considered for use in preference to VGB in infants with cryptogenic infantile spasms, to possibly improve developmental outcome (Level C).

• A shorter lag time to treatment of infantile spasms with either hormonal therapy or VGB may be considered to improve long-term cognitive outcomes (Level C).

Clinical Context

• This update focuses on questions for which data were insufficient to answer in the 2004 practice parameter.

• There was a marked paucity of randomized treatment trials carefully designed to provide a definitive answer to any of the questions proposed initially.

• The United Kingdom Infantile Spasms Study (UKISS) showed higher responder rates for infants treated with high-dose ACTH and prednisolone than with VGB (Class III).

• However, the evidence is still insufficient to conclude that prednisolone is as effective as ACTH, because UKISS was underpowered to answer this question.

• The current literature suggests that the underlying etiology of infantile spasms is an important outcome determinant. Analysis of children with cryptogenic spasms may provide more insight into a treatment’s efficacy by removing the confounding effect of etiology.

• Class II data from UKISS suggest that hormonal agents (e.g., ACTH, prednisolone) are associated with better developmental outcome than VGB. Questions remain, however, regarding optimal ACTH formulation, dose, and treatment duration.

• To date, the evidence is insufficient to support the use of agents other than ACTH and VGB.

Future Research Recommendations

• Multicenter RCTs of infantile spasms with multiple treatment arms (ACTH vs VGB vs. prednisolone, or combination hormonal therapy and VGB) are needed to determine the most effective therapy for infantile spasms and should include EEG, clinical seizure occurrence, and standardized developmental outcome measures.

• The International Collaborative Infantile Spasms Study a multicenter RCT comparing hormonal therapy & VGB with hormonal therapy alone, is currently underway.

• It is hoped that this study, and the recently concluded Canadian randomized, double-blind trial of add-on flunarizine to prevent cognitive deterioration associated with infantile spasms will provide further evidence regarding the use of combination therapy.

• In addition, further studies are needed to determine the optimal duration of VGB therapy, to minimize the retinal toxicity AE in patients with infantile spasms.

References

1. Riikonen R. Epidemiological data of West syndrome in Finland. Brain Dev2001;23:539 –541.

2. Ludvigsson P, O´ lafsson E, Sigurardóttir S, Hauser WA. Epidemiologic features of infantile spasms in Iceland. Epilepsia 1994;35:802– 805.

3. Trevathan E, Murphy CC, Yeargin-Allsopp M. The descriptive epidemiology of infantile spasms among Atlanta children. Epilepsia 1999;40:748 –751.

4. Hattori H. Spontaneous remission of spasms in West syndrome: implications of viral infection. Brain Dev 2001;23: 705–707.

5. Hrachovy RA, Glaze DG, Frost JD Jr. A retrospective study of spontaneous remission and long-term outcome in patients with infantile spasms. Epilepsia1991;32:212–214.

6. Mackay MT, Weiss SK, Adams-Webber T, et al. Practice parameter: medical treatment of infantile spasms: report of the American Academy of Neurology and the Child Neurology Society. Neurology 2004;62:1668–1681.

7. Elterman RD, Shields WD, Mansfield KA, Nakagawa J. Randomized trial of vigabatrin in patients with infantile spasms. Neurology 2001;57:1416 –1421.

8. Vigevano F, Cilio MR. Vigabatrin versus ACTH as first-line treatment for infantile spasms: a randomized, prospective study. Epilepsia 1997;38:1270 –1274.

9. Elterman RD, Shields WD, Bittman RM, Torri SA, Sagar SM, Collins SD. Vigabatrinfor the treatment of infantile spasms: final report of a randomized trial. J Child Neurol 2010;25:1340 –1347.

10. Lux AL, Edwards SW, Hancock E, et al. The United Kingdom Infantile Spasms Studycomparing vigabatrin with prednisolone or tetracosactide at 14 days: amulticentre, randomised controlled trial. Lancet 2004;364:1773–1778 .

11. Darke K, Edwards SW, Hancock E, et al. Developmental and epilepsy outcomes atage 4 years in the UKISS trial comparing hormonal treatments to vigabatrin forinfantile spasms: a multi-centre randomized trial. Arch Dis Child 2010;95:382–386.

12. Willmore LJ, Abelson MB, Ben-Menachem E, Pellock JM, Shields WD. Vigabatrin:2008 update. Epilepsia 2009;50:163–173.

13. Hardus P, Verduin WM, Engelsman M, et al. Visual field loss associated withvigabatrin: quantification and relation to dose. Epilepsia 2001;42:262–267.

14. Snead OC, Benton JW, Myers GJ. ACTH and prednisone in childhood seizuredisorders. Neurology 1983;33:966–970.

15. Durbin S, Mirabella G, Buncic JR, Westall CA. Reduced grating acuityassociated with retinal toxicity in children with infantile spasms on vigabatrintherapy. Investigative Ophthalmology and Visual Science 2009;50:4011–4016.

16. Westall CA, Nobile R, Morong S, Buncic JR, Logan WJ, Panton CM. Changes in theelectroretinogram resulting from discontinuation of vigabatrin in children. DocOphthalmol 2003;107:299–309.

17. Mirabella G, Morong S, Buncic JR, et al. Contrast sensitivity is reduced in childrenwith infantile spasms. Invest Ophthalmol Vis Sci 2007;48:3610–3615.

18. McCoy B, Wright T, Weiss S, Go C, Westall CA. Electroretinogram changes in apediatric population with epilepsy: Is vigabatrin acting alone? Journal of ChildNeurology 2011;26:729–733.

19. Wheless JW, Carmant L, Bebin M, et al. Magnetic resonance imaging abnormalities

associated with vigabatrin in patients with epilepsy. Epilepsia 2009;50:195–205.20. Simao GN, Zarei Mahmoodabadi S, Snead OC, Go C, Widjaja E. Abnormal axial

diffusivity in the deep gray nuclei and dorsal brain stem in infantile spasm treated

with vigabatrin. AJNR Am J Neuroradiol 2011;32:199–203. 21. Westall CA, Morong SE, Buncie JR, Logan W. Importance of baseline for

electrophysiology assessment of drug induced changes in children with seizures.Journal of Vision 2002;2:92a.

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