Download Catastrophic Epilepsy of Infancy

Catastrophic Epilepsy of Infancy
Diagnostic Considerations in Progressive
Myoclonic Epilepsy
Motivation
• 12 month old with myoclonic seizures
Evaluation of a Paroxysmal Event
• Is the paroxysmal event a seizure?
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Syncope
Panic attack
Breath holding spell
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Benign sleep myoclonus
Behavioral
Non-epileptic seizure
• Classify the seizure using ILAE system
• Partial
• Generalized
• Identify any primary etiology
• Classify the epileptic syndrome
• Make an informed decision about treatment
Neonate
 Infancy
 Childhood
 Adolescence
 Adult
 Elderly
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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)
Incidence of Catastrophic Epilepsies
Infantile
Catastrophic
Spasms Epilepsy in Childhood
Lennox-Gastaut
Ion Channelopathies
Progressive Myoclonic
Epilepsy
Incidence of Catastrophic Epilepsies
Sialidosis
Infantile
Catastrophic
Spasms Epilepsy in Childhood
Lennox-Gastaut
Ion Channelopathies
Progressive MyoclonicLaFBD
UnverrichtNCL MERRF
Lundborg Epilepsy
Organization
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MERRF
NCL
Unverricht-Lundborg
Lafora body disease
Sialidosis
Dravet syndrome
Myoclonic Epilepsy with Ragged Red Fibers
MERRF
• Symptoms
• Canonical
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Myoclonus
Generalized epilepsy
Ataxia
(Ragged red fibers on
muscle biopsy)
• Common (over 50%)
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Sensorineural hearing loss
Peripheral neuropathy
Dementia
Short stature
Exercise intolerance
Optic atrophy
• Uncommon (<50%)
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Cardiomyopathy
Pigmentary retinopathy
Pyramidal signs
Ophthalmoparesis
Multiple lipomas
MERRF - Features
Sign/Symptom
Present/Evaluated
Myoclonus
Epilepsy
Normal early development
RRF (ragged red fibers)
Hearing loss
Lactic acidosis
Family history
Exercise intolerance
Dementia
Neuropathy
Short stature
Impaired sensation
Optic atrophy
Cardiomyopathy
W-P-W syndrome
Pigmentary retinopathy
Pyramidal signs
Ophthalmoparesis
Lipomatosis
Hirano & DiMauro 1996
62/62
62/62
17/17
47/51
41/45
24/29
34/42
8/10
39/52
17/27
4/7
9/18
14/36
2/6
2/9
4/26
8/60
3/28
2/60
Percentage
100
100
100
92
91
83
81
80
75
63
57
50
39
33
22
15
13
11
3
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
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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.
MERRF - Pathology
Muscle biopsy typically shows ragged-red fibers (RRF) with
the modified Gomori trichrome stain
Normal Muscle
Ragged Red Fibers
MERRF
• Muscle; biochemistry variable, with defects in
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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
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.
Neuronal Ceroid Lipofuscinosis
Etymology
• Ceroid
• L. [cera], wax, + G. [eidos], appearance
• Compare with “cerumen”
• Lipofuscinosis
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The product of peroxidation
of unsaturated fatty acids
and symptomatic, perhaps,
of membrane damage
rather than being
deleterious in its own right
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”
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
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 5th decade
INCL
• Juvenile
• Adult
• Northern epilepsy variant
LINCL
NCL
JNCL
ANCL
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
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”
NCL - Genetics and Pathophysiology
• Infantile type:
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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:
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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
Unverricht-Lundborg
Unverricht-Lundborg
• Neurodegenerative disorder
• onset from age six to 15 years
• stimulus-sensitive myoclonus, and tonic-clonic epileptic
seizures.
• Late symptoms
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ataxia
incoordination
intentional tremor
dysarthria
• May have normal lifespan
• Mentally alert but show emotional lability, depression,
and mild decline in intellectual performance over time.
Lafora Body Disease
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
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.
Sialidosis
Sialidosis
• Type I - “Cherry red spot myoclonus syndrome”
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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 AEDresponsive
Sialidosis
• Type II
• infantile and juvenile forms
• cherry red spots myoclonus plus somatic features
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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.
Sialidosis Pathophysiology
• Progressive lysosomal storage of sialidated
glycopeptides and oligosaccharides caused by a
deficiency of the enzyme neuraminidase
sialic acid (N-acetylneuraminic
acid, NANA)
• => 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.
Dravet Syndrome
Dravet syndrome
• Severe Myoclonic Epilepsy of Infancy (SMEI)
• Multiple mutations
• Allelic with “generalized epilepsy with febrile seizures
plus” (GEFS+)
Heterogeneity
Clinical Syndrome
FHM
Panayiou
topolous
Familial
Autism
GEFS+
SMEI
SCN1a
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SCN1b
SCN2a
GABRD
GABRG2
Gene
?
SCN1a
SCN1b
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
Diagnosis
• DNA testing
• Sequencing (70-90% of mutations)
• Deletion testing (10-30% of mutations)
• Sequencing cannot detect large heterozygous deletions
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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
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
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
Gene “normal”
Correct
conclusion
true negative
Wrong
conclusion
not detected
splice site?
large deletion?
upstream regulatory region?
previously reported
stop codon (nonsense)
unreported missense
intron?
known genetic
polymorphism
parent testing
Uncertain
Gene “abnormal”
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:
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2.5 x 10-8 mutations per nucleotide site per generation
0.0000025% per nucleotide
8100 nucleotides in SCN1a
Any individual has 1-(1-2.5x108)8100 chance of having a new
mutation
• => 0.02% (unlikely)
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
Treatment
• Avoid sodium channel medications
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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
Thank You