Transcript Diapositive 1

eEdE#: eEdE196
Neonatal and early infantile epilepsy due to
Inherited metabolic disorders:
Clinical and neuroimaging correlation
1Prince
K TLILI-GRAIESS1,2, N MAMA.2, M GAHA2, M Al ENEZI1,
N Al Khuraish1, B TABARKI3
Sultan Military Medical City (PSMMC)- Neuroradiology Section
Riyadh,Saudia Arabia, 2Sousse Medical School, Sousse, Tunisia, 3Prince Sultan
Military Medical City (PSMMC)- Pediatric Neurology, Riyadh, Saudia Arabia
Presentation eEdE#: eEdE196
Presented by: Kalthoum TLILI-GRAIESS
ASNR, Washington, May 21-26, 2016
Disclosures
• We have no financial disclosures
or conflicts of interest to declare.
Purpose
We aim to:
1. Familiarize the radiologist with the clinical/EEG presentation of
early onset epilepsy due to inherited metabolic disorders (IMD).
2. Recognize MRI features of the main IMD causing early onset
seizures, particularly the treatable IMD.
3. Discuss the role of both conventional and advanced MRI
techniques, Diffusion Weighted Imaging and MR Spectroscopy
(DWI and MRS), in the diagnostic imaging work-up of IMD
associated with epilepsy.
Background
 IMD are common cause of early onset epilepsy/epileptic encephalopathy.
However, seizures rarely dominate and are frequently associated with other
neurological symptoms, such as hypotonia and/or cognitive disturbances.
 Occasionally, specific clinical signs and distinctive electroencephalographic (EEG)
patterns may suggest a specific metabolic disease or certain epileptic syndromes.
West's syndrome, early myoclonic encephalopathy are known to accompany
particular metabolic disorder (eg. branched-chain organic acidurias, nonketotic
hyperglycinemia),
 However seizure types are rarely specific for a particular metabolic disorder, nor
are EEG findings.
Neuroimaging pattern can be highly suggestive in some IMD and
therefore limit the biochemical and genetics work-up and may even
suggest treatable conditions .
Background
• The differential diagnosis of seizure disorders is
extremely wide and includes:
Ion channel disorders (e.g. SCN1A mutations),
Malformations of cortical development,
Neurocutaneous syndromes,
Chromosomal disorders,
Hypoxic–ischaemic encephalopathy,
Congenital infection, sepsis, and tumours.
Inherited metabolic disorders
Background
• IMD may have clinical presentation mimicking in neonates
hypoxo-ischemic encephalopathy (HIE): lethargy, poor
feeding, vomiting, muscular hypotonia, irritability, apnea,
and/or seizures.
• However, clinical history is usually different:
1. No perinatal event suggesting ischemia and/or hypoxia
2. Familial history of neonatal/early infantile death.
3. Familial history of epilepsy.
4. Refractory seizures
5. Metabolic acidosis / Hyperammonia
Clinical clues: When is an inherited metabolic disorder
probable?
• Epilepsy
• Neonatal seizures
• Early onset (neonatal period,
infancy)
• More than 1 type of seizure:
myoclonic/PME, IS, multifocal
• Intractable, resistant to AED
• Epileptic encephalopathy
• Seizures occurring after fasting,
•
protein-rich meal,
• Unexplained status epilepticus
• Epilepsy and clear regression
-That are not easily controlled
with a first-line anticonvulsant
- and no obvious infectious,
structural, traumatic or
cerebrovascular cause is not
established.
Interictal EEG is characterized by:
- Slowing of background activity.
- and progressive appearance of
epileptiform abnormalities: focal and
then multifocal and diffuse, forming a
picture of epileptic encephalopathy.
- Burst suppression
Pathogenesis of epileptic seizures associated
with inherited neurometabolic disorders
•
IMD classified by mechanism:
1. Energy production disorders
2. Intoxication disorders
3. Neurotransmitter defects
4. Disorders of the biosynthesis +
breakdown
of complex molecules
5. Associated brain malformations
Relation type of Epilepsy and specific IMD?
 Often non specific as well as the electroencephalographic
(EEG) findings.
 Refractory Epilepsy with or without mental deficiency
(mitochondrial disorders, Storage diseases…).
 Early Myoclonic Epilepsy, West Syndrome (organic Acidurias,
NonKetotic Hyperglycinemia)
 Epilepsy with dysmorphy (Zellweger Syndrome ), Abnormal
movement (Creatine deficiency).
 Epilepsia partialis continua or status epilepticus may reveal
mitochondrial disorders.
Is there any correlation
Between age of onset and type of IMD ?
 Neonate and infants mainly involved
 IMD Present with multiple seizure types, global
neurodevelopmental impairment.
 Many are antiepileptic drug (AED) treatment resistant.
N.I. Wolf. Epileptic Disord 2005
Approach/Methods
We reviewed the cases of neurometabolic diseases
associated with neonatal and early infantile epilepsy
collected in our institutions and analyzed for clinical and
EEG presentation as well as imaging features. Selected
cases will be presented in a case- review format
Overview
CASES
Neonatal Epileptic Encephalopathy
•
•
•
•
•
•
•
ISOD/Mb cofactor deficiency
Glycine Encephalopathy
Urea Cycle disorders
Mitochondrial Disease
Organic acidemias
Zellweger Syndrome
Pyridoxine-dependent epilepsy
Although the large range of metabolic etiologies, only cases of the
most frequent IMD related Neonatal Epileptic encephalopathy and
L. Papetti et al. / Brain & Development 2013
with MRI slightly suggestive
pattern will be presented.
Some IMD mimic HIE
•
•
•
•
Mitochondrial Disease
Isolated Sulfite Oxidase Deficiency
Molybdenum CoFactor Deficiency
Some organic acidopathies
# Case 1
Sibling 1, Full term girl neonate. Day 1: Jerkiness, twitching, myoclonic
reactions and poor sucking. Seizures refractory to different AED.
•Extensive WM swelling and T2
hyperintensity
•Edematous T2 pattern of the basal
ganglia;
•Widespread WM and basal ganglia
diffusion restriction.
• Relatif sparing of thalami.
Sibling 2, 2 year-old with severe development delay and frequent seizures.
Extensive brain damage with:
•Significant loss of WM
with cystic changes.
•Ex vacuo dilatation of
ventricles.
•Mushrom shaped gyri.
•Atrophy og basal ganglia
•Hyperintensity in midbrain and
pontine tegmentum
Molybdenum Cofactor deficiency MOCS 2
• 14 months-old male child.
• 12 months-old male child.
• West Syndrome with microcephaly. • Developmental delay and epilepsy.
Molybdenum Cofactor deficiency
Sequella of Hypoxo-ischemic
Encephalopathy
Differentiation from severe HHI is made by
predominant thalamic involvement in HII relatively
absent in MCoD
Molybdenum cofactor deficiency (MoCD)
• Autosomal recessive disorder, mimic ischaemic encephalopathy
• Molybdenum cofactor: essential for the function of 3 enzymes:
 Sulfite oxydase , catalyses the oxydation of sulfite into sulfate; deficiency results in
elevated levels of sulfite, extremely neurotoxic.
 Xanthine oxydase results in low uric acid levels and elevated xanthine levels.
 Aldehydedehydrogenase, catalyses the formation of xanthine from hypoxanthine.
• Severe neurologic symptoms in the first days of life, the leading
symptom is drug-resistant epilepsy.
• The disorder should be considered in all cases of intractable seizures
in the newborn period and infants with clinical and radiological
features of ischemic encephalopathy.
Molybdenum cofactor deficiency
• MRI pattern:
 In the acute phase: hyperintensity on T2WI of the white matter and
caudate nuclei suggestive of edema. Widespread diffusion restriction
with elevated lactate and decreased NAA on MRS.
 In the subacute phase, the basal ganglia may show T1 and T2
shortening, similar to that of neonatal asphyxia sparing thalami.
 In the more chronic phase , marked volume loss of caudate and
lentiform nuclei and white matter with T1 and T2 prolongation and
frank cystic changes. Sparing of thalami is against HII.
# Case 2
SEIZURES since birth; presented at 3 months for hypotonia, poor
feed, development delay.
 Thinning of the cortex with zone of
Presentation similar to that of
MCoD.
mushroom- like gyral pattern.
 Atrophy of the basal ganglia and
cystic degeneration of WM.
Ex-vacuo ventricular dilatation
Sparing of the thalami
Isolated sulfite oxydase Deficiency SUOX gene
Isolated Sulfite oxidase deficiency
 Rare autosomal recessive disorder of the
newborn that can be mistaken for
neonatal asphyxia
 Gene SUOX mapped to Chr 12q13.2-13.3.
Imaging:
Early in the disease: edema in cerebral
cortex, WM and BG with restricted
diffusion in BG.
Hippocampi relatively spared
 The presentation is similar to that of
molybnenum cofactor deficiency. The
latter is more common.
T1 shortening at cortical – WM junction
and in BG .
 Lens ectopia is common.
MRS: decrease in NAA/ Cr ratio and a
rise in the Cho/Cr.
 Sulfite is extremely neurotoxic Energy
production disorder

Biology: ↑sulfite level in urine
Rapide development of BG atrophy and
cystic degeneration of WM within the first
month: cystic leucomalacia.
# Case 3
Term neonate. Hypotonia followed by continuous seizures and
deep coma. Familial history of neonatal death
MRI Day 5
Ala-Lac
Glx
Glx
Carbamyl phosphate synthase Deficiency
Glu
Glu
ADC map
ADC

Swelling/edema of white matter with ↑T2 signal of basal ganglia

ADC map: Reduced diffusion cortical and subcortical white matter and striatum.Ala-Lac

1H-MRS
(short & longTE) Increased glutamine with Alanine-lactate triplet.
Urea cycle disorders
• 5 types: Citrullinemia, Ornithine carbamyl transferase deficiency,
Carbamyl phosphate synthetase deficiency, Arginase deficiency and
Argininosuccinate lyase deficiency.
• All causing hyperammonemia and high Glutamine: Toxic to the brain.
• Acute hyperammonemia rapidly leads to encephalopathy, cerebral
edema, and, if untreated, death
• Cerebral edema result from accumulation of glutamine in astrocytes
 selectively affects WM: Astrocytic swelling related To osmolar
effect of intracellular Glutamine?
• Neuroimaging pattern:
– Reduced diffusion: cortex and subcortical WM, basal ganglia and thalami.
– ↑T2 signal: globi pallidi, putamina, caudate nuclei
– 1H-MRS typically: ↑glutamine/ glutamate + lactate >>> Diagnostic.
– Rapid development of atrophy with severe cystic encephalomalacia
Neonate admitted at 1 month of life. Since Day 2 hypotonia, poor feeding.
3 died in the family. Increased Ammonia level
Glu Glu
Glu
Carbamyl Phosphate Synthase Deficiency CPS1
Glu
1 month later
# Case 4
Term neonate with hypotonia, refractory seizures , respiratory failure and high lactic acid.
Early death. 3 siblings neonatal death and same clinical presentation.
Day 15
Extensive swelling and T2 hyperintensity of the WM, deep GM, midbrain and brainstem.
Diffusion restriction at pallidi, corpus callosum and pericentral subcortical WM.
Complex 1
MRS at frontal WM shows predominent lactate peak.
Deficiency
Isolated complex I deficiency
The most common enzymatic defect of the oxidative phosphorylation disorders.
It may cause a wide range of clinical disorders, ranging from lethal
neonatal disease to adult-onset neurodegenerative disorders.
Neonatal symptoms include severe respiratory distress, apnea, muscular
hypotonia, weakness, seizures, cardiac hypertrophy, and/or hepatomegaly.
Marked lactic acidosis with elevated blood lactate and pyruvate levels.
Neuroimaging: Neonatal presentation includes
 WM abnormalities , involvement of the posterior columns in the lower
brainstem, pontine corticospinal tracts and subcortical white matter, with an
HIE-like involvement of the cortex and thalami in the absence of history of birth
asphyxia
 Variable sites of diffusion restriction indicating acute insult.
 MRS: predominent Lactate peak on MRS which should lead to more
extensive investigation of oxidative phosphorylation disorders.
# Case 5
Term neonate, day 2 respiratory distress, continuous myoclonies followed by
deep coma. MRI and EEG performed at Day 15
TE 144
Mi
Gly
Gly
TE 35
T2 symmetrical high-signal in the
tegmentum of the pons. Apart from
the absence of normal hyposignal of
the myelinted PLIC, supratentorial
Grey and WM signal intensity within
normal limits.
TE 144
Mi
Gly
Gly
high-signal lesions
TE 35
DWI:
in tegmentum
of the pons, the pyramidal tracts, the
middle cerebellar
pedicles
PLIC
Burst-Suppression
Pattern
highlyand
suggestif,
May be noted in:
• Pyridoxino-Dependant Epilepsy (PDE)
• Isolated Sulfite Oxidase Deficiency (ISOD)
Important Myoinositol/Glycine peak at 3.56 ppm (35ms)
• Glycine
NonKetotic
Only
(Gly) Hyperglycinemia
persists at long echo time (144ms)
• Mitochondrial disorders
NonKetotic Hyperglycinemia (NKH)
• NKH: autosomal recessive IMD due to a defect in the glycine cleavage
system.
• The disorder leads to the accumulation of glycine in body fluids and
in the central nervous system with its subsequent neurotoxicity.
• The sites of abnormal signal intensity in NKH are confined to the WM tracts
that are myelinated at birth.
• DWI findings reflect the histopathologic changes of the disease which
consist of spongiosis of the myelinated brain tissue due to myelin
vacuolation.
• Microcystic changes are mostly found in the ascending tracts in the brain
stem, posterior limbs of the internal capsules, the cerebellar peduncles,
optic tracts and optic chiasma
• MRS provide biochemical evidence of elevated cerebral glycine levels by
demonstration of Glycine peaks at 3.56 ppm with a long echo time.
# Case 6
3-day-old baby girl full term with refractory seizures mainly clonic and myoclonic.
DAY 3
hemorrhage noted affecting the left parietal lobe and the left parasagittal region
DAY 24
Bilateral and symmetrical abnomal T2 high signal In pons and midbrain
along the cortico-spinal tract with mild brain atrophic changes
At 3months refractory status epilepticus with burst Suppression on EEG.
3 months
PDE should always be included in the
differential diagnosis of neonatal seizures
that are refractory to treatment with
antiepileptic drugs: PDE is a treatable
neurometabolic disorder.
No specific imaging features.
Pyridoxine Dependent Epilepsy (PDE)
Reported associated abnormalities:
17 Months Mutation in LDH7A1gene
Corpus callosum hypoplasia
Subependymal cysts
Ventriculomegaly
Gray matter heterotopia
White matter abnormalities including
hemorrhage
Gray and white matter atrophy
Mega cisterna magna.
Paucity of the cerebral WM with
Mild diffuse brain atrophy
Pyridoxine-dependent epilepsy (PDE).
PDE, rare autosomal disorder caused by ALDH7A1 gene mutations.
PDE described in 1954, in 1995 Folinic acid responsive seizures (FARS)
described, in 2006 genetic defect identified and in 2009 FARS shown to
be identical
PDE is characterized by early intractable seizures not controlled with AED
but responding both clinically and EEG to pyridoxine (vitamin B6) with
“normal” neurodevelopmental outcome.
Refractory seizures in the first week of life, mainly clonic and myoclonic.
EEG: variable,
Late onset seizure>1 month possible with even status epilepticus.
Pyridoxine-dependent epilepsy (PDE).
MRI: Non secific
Neonatal period:
•Ventricles normal in size and myelin pattern
appropriate for age with increased incidence of
mega cisterna magna.
•Thinning of the posterior third of the corpus
callosum
•Brain hemorrhage
Later and if non treated:
Ventriculomegaly with atrophy of the cortex and
subcortical white matter .
Friedman SD et al. Dev Med Child Neurol. 2014
# Case 7
Full-term neonate, dysmorphic with seizures and
history history of two death with Zellweger syndrome
Small geminolytic cyst with hemorrhagic component (yellow arrow) in the left caudothalamic
groove, Polymicrogyria mainly in perisylvian region (red arrow) and thin corpus callosum.
Zellweger syndrome
Zellweger syndrome, Peroxisomal disorder causing
abnormal catabolism of very long chain fatty acids
Clinical features :
Neonatal hypotonia, feeding problems, hearing
loss, vision loss, and seizures.
Dysmorphy: flattened face, broad nasal bridge,
and high forehead
Life-threatening problems in other organs and
tissues, such as the liver, heart, and kidneys.
Possible skeletal abnormalities, including large
fontanels and characteristic chondrodysplasia
punctata.
Imaging Key features:
Unmyelinated PLIC ,
Frontal or opercular
polymicrogyria
Geminolytic cyst
MRS: Low NAA and
prominent lipids peaks at
0.9 and 1.3ppm
Infantile metabolic epilepsy
L. Papetti et al. / Brain & Development 2013
# Case 8
7 months, Developmental delay and epilepsy. Admitted for sepsis and
metabolic acidosis
Brain atrophic changes with abnormal signal intensity at frontal subcortical white matter
and bilateral striatum.
Reduced diffusion in some of the affected areas indicating metabolic crisis causing
the current clinical setting.
Ethylmalonic Acidemia
# Case 9
2 year-old , known cas of propionic acidemia, admitted with
fever and generalized tonico-clonic seizures.
Hypodensity at bilateral basal ganglia and frontal subcortical WM.
Mild brain volume loss, delayed myelination with T2 high signal of bilateral
striatum and subcortical WM. No restricted diffusion.
Propionic Acidemia
Propionic and Ethylmalonic Acidemias
Epilepsy is relatively rare. Usually seizures noted with
metabolic decompensation.
Lesions of the striatum with usually WM involvement.
Volume loss, and delay in myelination are typically identified
during later episodes of decompensation.
MRS may demonstrated decreased NAA, and increased
lactate during encephalopathic episodes when compared
with MRS during metabolically stable periods.
# Case 10
•16 months-old girl with one week respiratory distress
•At the age of 9 months, seizures and progressive loss of developmental
and motor acquisitions with sudden alopecia and global hypotonia.
Hypodensity and T2
hyperintensity of frontal WM,
genu of the corpus callosum
and caudate nuclei.
cho
NAA
DWI: Hypersignal
demonstrating zones of
restricted diffusion related to
cytotoxic and myelin edema.
Note the U fibers involvement
and the peripheral high signal of
the genu contrasting with the
Acquired alopecia indicate possible Biotin
more central low signal (arrow).
responsive encephalopathy Likely related to
lactate
SRM 144 : decreased NAA
biotinidase deficiency
& presence of lactate
5 month MRI follow-up
Pharmacologic doses of biotin
Normal pattern of the spectrum
Progression of myelination with resolution of WM and GM abnormalities
except for the genu of the corpus callosum: high signal T2, low signal T1 and
high ADC level, stigmate of cystic degeneration.
Biotinidase deficiency
Biotinidase deficiency is an inborn error of metabolism with
autosomal recessive inheritance that usually presents in infancy with
developmental delay, seizures, alopecia, and dermatitis.
Episodes of acute deterioration separated with periods of apparent
normality.
The main imaging findings reported:
White matter abnormalities, including delayed myelination and
Enlargement of the ventricular system and/or the extracerebral
spaces.
DWI may demonstrate new lesions and
MRS demonstrates the lactate peak, related to anaerobic metabolism
# Case 11
12 year-old boy, progressive epileptic encephalopathy
since first year of life.
NA
A
NAA
Cho
Cho
NGC
SB Pariéto-occipitale
Creatine deficiency due to guanidinoacetate methyltransferase deficiency
Creatine deficiency syndromes
Creatine deficiency syndromes include disorders due to:
 Defects in synthesis (GAMT deficiency and arginineglycine amidinotransferase (AGAT) deficiency) and
 Defects in the transport of creatine across the blood–
brain barrier (X-linked creatine transporter defect).
In GAMT deficiency :often have abnormal hyperintensity of the globi
pallidi on FLAIR and T2 WI.
AGAT deficiency and creatine transporter defects can only be
detected by low or absent creatine peak on proton MRS of the brain.
MRS is therefore the most important technique in diagnosis.
MRS is also important in assessing response to therapy.
# Case 12
2 year-old female child with regression milstones and
myoclonic seizures since 9 months of age.
• Appropriate myelination milstone for 2 Y
• Prominent cerebellar atrophy
• Mild hyperintensities in the deep WM
Neuronal ceroid lipofuscinose
Gene CLN3
•Decreased NAA peak
Differential diagnosis,
Cerebellar atrophy
• Neurodegenerative disorders :
 Neuronal Ceroid Lipofuscinosis NCL
 Late-onset GM2 Gangliosidosis: in late disease stages
with cerebral and cerebellar atrophy.
• Mitochondrial disorders :
 Complex I, II, IV and combined complex I + III and II + III
deficiencies
 Cenzyme Q10 Deficiency.
 Myoclonus epilepsy with ragged red fibers (MERRF)
• Hypomyelination 4H Syndrome, POL R 3B: Cerebellar and
vermis atrophy with milder hypomyelination.
Neuronal ceroid lipofuscinosis.
 Lysomal neurodegenerative disorder caused by accumulation of
lipopigments (such as lipofuscin and ceroid) in lysosomes of neurones and
other tissues. Seizures and regression
 Possibly the most common group of neurodegenerative disorders in children.
 4 types: Infantile, Late infantile, juvenile and adult.
NCL should be considered in a patient with progressive epileptic
encephalopathy when MRI shows such features:
 Cerebral atrophy, thin cortex, one of the cardinal findings regardeless of
the type in both infantile and late infantile NCL.
 Cerebellar atrophy is a more prominent feature and shows rapid
progression in late infantile NCL than in other form.
 Mild hyperintensities in the deep WM due to gliosis or loss of myelin as
demonstrated in pathological studies/ secondary involvement.
Neuronal Ceroid Lipofuscinosis
 MRS Progressive changes with decreased NAA and increased mI and
Glx. In long standing disease, mI the most prominent and lactate absent.
 Reduced NAA, prominent mI and no detectable lactate seem to be more
consistent with late infantile NCL: Therefore MRS help to differentiate
NCL from other neurometabolic disorders such as mitochondrial or
peroxisomal encephalopathies.
 Diagnosis of NCL has to be considered in children with cerebellar
atrophy, hypointense thalami, Periventricular T2 hyperintensities with
decreased NAA and increased mI and no Lactate.
SUMMARY/CONCLUSION
 Recognition of typical neuroimaging features of some IMD causing
epilepsy in neonates and infants participate in the earlier recognition
and management of these disorders.
DWI allows detection and characterization of regions of different
diffusitivity indicating cytotoxic/myeline edema and disease activity.
MRS may demonstrate specific pattern and therefore guide metabolic
investigations.
 A specific diagnosis of metabolic disorders in epileptic patients may
indicate the possibility of specific treatment that can improve seizures
and allows genetic counseling.
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[email protected]
Professor of Radiology, Medical School of Sousse. Tunisia
Consultant Pediatric Neuroradiology, PSMMC Riyadh . Saudi Arabia