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Catastrophic Epilepsy of Infancy Diagnostic Considerations in Progressive Myoclonic Epilepsy.

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Presentation on theme: "Catastrophic Epilepsy of Infancy Diagnostic Considerations in Progressive Myoclonic Epilepsy."— Presentation transcript:

1 Catastrophic Epilepsy of Infancy Diagnostic Considerations in Progressive Myoclonic Epilepsy

2 Motivation 12 month old with myoclonic seizures

3 Evaluation of a Paroxysmal Event Is the paroxysmal event a seizure? Classify the seizure using ILAE system Partial Generalized Identify any primary etiology Classify the epileptic syndrome Make an informed decision about treatment Syncope Panic attack Breath holding spell Benign sleep myoclonus Behavioral Non-epileptic seizure Neonate Infancy Childhood Adolescence Adult Elderly

4 Epilepsies in infancy Occur between 0-18 months of age Incidence at this time is ~80/100,000 Higher than childhood (up to 12y) Higher thatn adolescence (up to 18y) Developmental tasks Refinement of motor skills Development of complex intellectual skills Development of complex social skills Impact of epilepsy on these tasks can be divided Benign Intermediate Catastrophic (boundaries of this category are not clear cut)

5 Incidence of Catastrophic Epilepsies Catastrophic Epilepsy in ChildhoodInfantile Spasms Lennox-Gastaut Progressive Myoclonic Epilepsy Ion Channelopathies

6 Incidence of Catastrophic Epilepsies Catastrophic Epilepsy in ChildhoodInfantile Spasms Lennox-Gastaut Progressive Myoclonic Epilepsy Ion Channelopathies Sialidosis Unverricht- Lundborg NCLMERRF LaFBD

7 Infantile Spasms Characteristic flexor spasms, usually beginning in first year of life May be subtle, leading to delayed diagnosis Can be confused with benign epilepsies Benign infantile familial convulsions Benign infantile myoclonus Developmental progress is key discriminator Rate of infantile spasm is 1.6-5.0 per 10,000 live births EEG demonstrates hypsarrhythmia, modified hypsarrhythmia, or multifocal spike-wave discharges Most cases are symptomatic, with etiologic diagnosis in ~70%

8 Lennox-Gastaut Syndrome Accounts for 3-10% of all pediatric epilepsy cases Prevalence of LGS in Atlanta was reported as 0.26 per 1000 live births Defined by triad of Multiple types of generalized seizure Slow spike-wave on EEG Developmental delay Symptomatic or cryptogenic “Etiology is fundamentally similar to infantile spasms,” but present later in life Often evolves out of IS patients in first or second year (20% of LGS had prior IS with hypsarrhythmia) Seizures are difficult to control, and often persist into adulthood

9 Organization MERRF NCL Unverricht-Lundborg Lafora body disease Sialidosis Dravet syndrome

10 Myoclonic Epilepsy with Ragged Red Fibers

11 MERRF Symptoms Canonical Myoclonus Generalized epilepsy Ataxia (Ragged red fibers on muscle biopsy) Common (over 50%) Sensorineural hearing loss Peripheral neuropathy Dementia Short stature Exercise intolerance Optic atrophy Uncommon (<50%) Cardiomyopathy Pigmentary retinopathy Pyramidal signs Ophthalmoparesis Multiple lipomas

12 MERRF - Features

13 MERRF Onset is usually in childhood (may be younger) May be confused with Friedreich ataxia (abnormalities of proprioception and pes cavus) FH short stature Findings elevated serum lactate RRF on muscle biopsy Pathology Neuronal loss/gliosis of dentate nucleus and inferior olivary complex Dropout of Purkinje cells and neurons of the red nucleus Pallor of the posterior columns Degeneration of the gracile and cuneate nuclei Course: slowly progressive or rapidly downhill.

14 MERRF - Pathology Muscle biopsy typically shows ragged-red fibers (RRF) with the modified Gomori trichrome stain Normal MuscleRagged Red Fibers

15 MERRF Muscle; biochemistry variable, with defects in complex III complexes II and IV complexes I and IV or complex IV alone Maternally inherited More than 80% of cases are caused by a heteroplasmic G to A point mutation at nt 8344 of the tRNA(Lys) gene of mtDNA Additional patients have been reported with a T to C mutation at nt 8356 in the tRNA(Lys) gene



18 MERRF - Treatment The seizure disorder can be treated with conventional anticonvulsant therapy. No controlled studies have compared the efficacy of different anticonvulsants. No treatment for the genetic defect is currently available. Coenzyme Q10 (100 mg three times a day) L-carnitine (1000 mg 3 times a day) Are often used in hopes of improving mitochondrial function.

19 Neuronal Ceroid Lipofuscinosis

20 Etymology Ceroid L. [cera], wax, + G. [eidos], appearance Compare with “cerumen” Lipofuscinosis G. [lipos] “fat” L. [fuscare] “to make dark” Compare with “obfuscation” (~“brown”) L. [-osis] “abnormal condition” or “a state of disease” Ceroid and Lipofuscins are not the same “Ceroid is acid fast, fat insolvent, and probably a type of lipofuscin, although differing from true lipofuscins by failing to stain with Schmorl ferric-ferricyanide reduction stain” The product of peroxidation of unsaturated fatty acids and symptomatic, perhaps, of membrane damage rather than being deleterious in its own right

21 Neuronal ceroid lipofuscinosis Most common neurodegenerative disease in children (three autosomal recessive disorders) Characterized by Accumulation of autofluorescent substance within lysosomes of tissue (especially neurons) Epilepsy Progressive epileptic encephalopathy Vision loss Pathologic findings Light microscopy - ceroid EM - Granular osmophilic deposits, curvilinear profiles, fingerprint bodies Individual genes mutated in six forms have been identified


23 NCL Infantile type (Haltia-Santavuori) Begins end of the 1st year Death by ≈10 years Late infantile type (Jansky-Bielschowsky) most common type of NCL Presentation: myoclonic seizures beginning between 2 and 4 years in a previously normal child May live to 5 th decade Juvenile Adult Northern epilepsy variant NCL INCL LINCL JNCL ANCL

24 NCL - Signs and Symptoms Myoclonic seizures Intellectual deterioration Vision change Blindness Optic atrophy, brown discoloration of the macula are evident on retinal exam attenuation of vessels black pigmentary abnormalities (peripheral, “bone spicule”) Cerebellar ataxia is prominent Early onset may be associated with microcephaly

25 NCL - Lab findings Electroretinogram abnormal early in course deposition of storage substance within the rod and cone area Visual evoked potentials are characteristic markedly enlarged responses initially later absent Autofluorescent material accumulates in neurons fibroblasts secretory cells EM (skin or conjunctiva) curvilinear bodies “fingerprint profiles”

26 NCL - Genetics and Pathophysiology Infantile type: gene: palmitoyl protein thioesterase (PPT) a.k.a. PPT; CLN1; INCL; PPT1 chromosome 1p32 lysosomal enzyme palmitoyl-protein thioesterase-1 Failure of synaptic fusion and vesicle recycling Late infantile type: gene: TPP1 (sedolisin family of serine proteases) lysosomal cleavage of N-terminal tripeptides from substrates weaker endopeptidase activity Synthesized as inactive state, and activated by acidification Failure to degrade specific neuropeptides and a subunit of ATP synthase in the lysosome

27 Unverricht-Lundborg

28 Neurodegenerative disorder onset from age six to 15 years stimulus-sensitive myoclonus, and tonic-clonic epileptic seizures. Late symptoms ataxia incoordination intentional tremor dysarthria May have normal lifespan Mentally alert but show emotional lability, depression, and mild decline in intellectual performance over time.

29 Unverricht-Lundborg Defective function of cystatin B cysteine protease inhibitor Testing for the common dodecamer repeat expansion mutation and three other mutations is available on a clinical basis 99 % of Finnish disease is dodecamer ~90% of non-Finn populations Sequence analysis is available for others

30 Unverricht-Lundborg Treatment valproic acid is drug of first choice for myoclonus, GTCs clonazepam is an add-on therapy high-dose piracetam is used to treat myoclonus levetiracetam for both myoclonus and GTC Avoid Phenytoin sodium channel blockers (carbamazepine, oxcarbazepine, phenytoin) GABAergic drugs (tiagabine, vigabatrin) gabapentin and pregabalin In the past, mortality was 8-15yo, but now ~normal due to better supportive technology

31 Lafora Body Disease

32 Lafora body disease Presents between 10 and 18 years Epilepsy Generalized tonic-clonic seizures Myoclonic jerks appear later, but become more frequent and pronounced Mental deterioration is evident within 1 year of onset Other neurological signs cerebellar signs extrapyramidal signs EEG polyspike-wave discharges occipital predominance progressive slowing and disorganized background

33 Lafora body disease Treatment myoclonic jerks difficult to control combination of valproic acid and benzodiazepine (such as clonazepam) is effective in controlling the generalized seizures Autosomal recessive disorder EPM2A gene/laforin protein (58%) EPM2B gene/malin protein (35%) Causes aggregation of branched glycogen Diagnosis skin biopsy for inclusions (periodic acid-Schiff positive) Most prominent in the eccrine sweat gland duct cells

34 Lafora Body Disease - Brain Lafora bodies in the brain. Dense intraneuronal inclusions. H&E Stain Lafora bodies are present throughout the nervous system, particularly in the dentate nucleus, red nucleus, substantia nigra, and hippocampus.

35 Sialidosis

36 Type I - “Cherry red spot myoclonus syndrome” presents in 2nd decade complaints of visual deterioration fundoscopy shows a cherry red spot unlike Tay-Sachs, visual acuity declines slowly Extremity myoclonus Gradually progressive and debilitating Eventually renders patient nonambulatory Triggered by voluntary movement touch sound Not controlled with anticonvulsants Generalized convulsions occur in most patients which are more AED- responsive

37 Sialidosis Type II infantile and juvenile forms cherry red spots myoclonus plus somatic features coarse facial features corneal clouding (rare) dysostosis multiplex (seen as anterior beaking of the lumbar vertebrae) lymphocytes show vacuoles in the cytoplasm liver biopsy showes cytoplasmic vacuoles in Kupffer cells membrane-bound vacuoles are found in Schwann cell cytoplasm No distinctive neuroimaging findings or EEG abnormalities Patients with sialidosis have been reported to live beyond the 5th decade.

38 Sialidosis Pathophysiology Progressive lysosomal storage of sialidated glycopeptides and oligosaccharides caused by a deficiency of the enzyme neuraminidase => Accumulation and excretion of sialic acid (N-acetylneuraminic acid) covalently linked ('bound') to a variety of oligosaccharides and/or glycoproteins. Distinct from the sialurias where there is storage and excretion of “free” sialic acid Neuraminidase activity in sialuria is normal or elevated. sialic acid (N-acetylneuraminic acid, NANA)

39 Dravet Syndrome

40 Dravet syndrome Severe Myoclonic Epilepsy of Infancy (SMEI) Multiple mutations Allelic with “generalized epilepsy with febrile seizures plus” (GEFS+)

41 Heterogeneity SMEI SCN1a GEFS+ Familial Autism Panayiou topolous FHM ? SCN2a GABRD GABRG2 SCN1b? ? Clinical Syndrome Gene

42 SCN1a SCN1b

43 Red flags for SCN1a mutation Febrile seizures that Start before age 1 year Persist beyond 5-6 years Are prolonged; lasting >30 minutes Febrile seizures that evolve into epilepsy Seizures that are provoked by a hot bath or rapid temperature fluctuation Seizures following vaccination Family history of epilepsy, especially with heterogeneous seizure types

44 Diagnosis DNA testing Sequencing (70-90% of mutations) Deletion testing (10-30% of mutations) Sequencing cannot detect large heterozygous deletions Sequencing requires initiation with primers If the primers cannot bind, they produce nothing The normal allele creates a normal transcript It appears that everything is normal, because everything that was synthesized was normal! If testing shows sequence variability, parent testing is critical

45 Sequencing is positive True positive Pathogenic sequence alteration reported in the literature Sequence alteration predicted to be pathogenic but not reported in the literature Unknown sequence alteration of unpredictable clinical significance False positive - polymorphism Sequence alteration predicted to be benign but not reported in the literature Benign sequence alteration reported in the literature

46 Sequencing is negative True negative Patient does not have a mutation in the tested gene (e.g., etiology is not genetic, or is caused by a different gene) False positive Patient has a sequence alteration that cannot be detected by sequence analysis a large deletion splice site deletion Patient has a sequence alteration in a region of the gene (e.g., an intron or regulatory region) not covered by the laboratory's test

47 Gene “normal”Gene “abnormal” Correct conclusion Wrong conclusion Uncertain previously reported stop codon (nonsense) unreported missense intron? known genetic polymorphism true negative not detected splice site? large deletion? upstream regulatory region? parent testing

48 Parent testing If the child has a genetic change (polymorphism or deleterious mutation; doesn’t matter) there are only two possibilities Inherited from mom or dad New genetic change Generic rate of genetic change: 2.5 x 10-8 mutations per nucleotide site per generation 0.0000025% per nucleotide 8100 nucleotides in SCN1a Any individual has 1-(1-2.5x10 8 ) 8100 chance of having a new mutation => 0.02% (unlikely)

49 Parent testing Therefore, if you can prove a mutation is new it is very unlikely (< 0.02%) that it is a benign polymorphism that happened by chance in the single generation (less than, because some of those “chance” mutations will still be deleterious, and therefore should be subtracted from the total) If the clinical symptoms are compatible, such a result is accepted as sufficient evidence of causality (compare with p values of 0.05; we rarely get this definite in clinical medicine) If you can prove a mutation is “old” (inherited) It is not sufficient for disease, provided parents are unaffected

50 Treatment Avoid sodium channel medications carbamazepine phenytoin lamotrigine vigabatrin Preferred medications valproate - must think about risk of hepatic failure in the very young non FDA-approved clobazam stiripentol Referral to the MCBI Ion Channel Epilepsy Clinic

51 Thank You

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