Download Presentation - Neuropathology

Neuropathology and Epilepsy
Neuronal migration defects
Hippocampal sclerosis
April 18, 2015
Overview
• Neuronal migration defects
– Pachygyria/Lissencephaly
– Polymicrogyria
– Neuronal heterotopia
– Cortical dysplasia
• Hippocampal sclerosis
Neuronal migration defects
• Diverse causes and
risk factors
– Inherited/sporadic
– Environmental risk
factors
•
•
•
•
EtOH
Retinoic acid
Heavy metals
Irradiation
– Viral infections
– Ischemia
Vocabulary
• Match the defect to the definition
Pachygyria
Small disorganized convolutions
Polymicrogyria
Disorganization of neurons with
cytologic abnormalities
Neuronal heterotopia
Cleft that extends from pial
surface to ventricle lined with
cortex
Misplaced collections of normal
appearing neurons
Cortical dysplasia
Schizencephaly
Widened gyri
Trivia Question
During normal development, when do gyri and
sulci begin to appear in the fetal brain?
a. 10-12 weeks
b. 18-20 weeks
c. 25-28 weeks
d. 32-34 weeks
Clinical Case
7 month old boy is brought to the epileptologist for
intractable seizures. On examination, he has a short small
chin, thin upper lip, and low set ears. He has spastic
quadriparesis and requires a feeding tube because of
recurrent aspirations. MRI brain shows essentially smooth
frontal, parietal, occipital lobes with a thick cortex and
without sulci or gyri. What is the most likely diagnosis?
a. Miller-Dieker syndrome
b. Lissencephaly type II
c. Subcortical band heterotopia
d. Cobblestone lissencephaly
e. Polymicrogyria
Miller Dieker Syndrome
• Microcephaly and characteristic facies: bitemporal
hollowing, short nose with broad nasal bridge and
upturned nares, thin upper lip, small chin, low-set
posteriorly rotated ears
• Neonatal period with hypotonia which progresses to
spastic quadriparesis
• Seizures that are difficult to control
• Global developmental delay with life expectancy
~1year
• Microdeletions chromosome 17 (LIS1 gene)
• Associated with LISSENCEPHALY TYPE 1
• Can have isolated lissencephaly without the
syndrome…
Lissencephaly Type I
• Impaired formation of
gyri resulting in reduced
number of enlarged gyri
(pachygyria)
• Most severe form: agyria
or “smooth brain”
• Imaging: smooth, cerebral
cortex thickened with
variable preservation of
white matter
• Pathology: Thick cortex
with 4 layers instead of 6
Lissencephaly
• Other types
– Lissencephaly X linked
• mutations in DCX gene on X chromosome (males)
• usually lethal
– Lissencephaly Type II
• “cobblestone” lissencephaly
– irregular and less smooth in appearance
• associated with other disorders such as WalkerWalburg syndrome, Fukuyama muscular dystrophy,
muscle-eye-brain disease of Santavuori
Pathology: Lissencephaly/Pachygyria
• H&E
Clinical Case
A five month old baby is being evaluated for
seizures. He has multiple dysmorphic features
and severe hypotonia, and MRI of the brain
shows pachygyria. Skeletal radiographs show
calcific stippling of the patella. Very long-chain
fatty acid levels are elevated in plasma. Which
of the following is incorrect regarding this
condition?
a.
b.
c.
d.
e.
This is a peroxismal disorder
Liver cirrhosis occurs in these patients
Kidney cysts can be seen in these patients
White matter is not involved
Polymicrogyria may be seen in these
patients
Zellweger Syndrome
“Cerebrohepatorenal Syndrome”
• Peroxisomal disorder with white matter changes
and abnormalities in neuronal migration
• Dysmorphic features
• Chonodroplasia puncata (stippling of patella)
• Eye issues, hypotonia, cirrhosis, PCKD
• Caused by mutations in PEX genes
• Short life expectancy
• Associated with pachygyria and/or
polymicrogyria
Polymicrogyria
• Disorganized confluence of
small gyri that appear to be
partially fused
• May be unilateral or bilateral
• Perisylvian is MOST common
• Thought to occur later in
development at 17-26 weeks
• Can occur with
schizencephaly
• Often as feature of various
syndromes
• Associated with seizures and
intellectual disability
Pathology: Polymicrogyria
• H&E
• NeuN
Heterotopias
Which of the following is incorrect regarding
periventricular nodular heterotopia?
a.
b.
c.
d.
e.
It is a disorder of neuronal migration
It is more common in females
It is most commonly X-linked
Seizures are a common clinical manifestation
Heterotopias are clusters of defective neurons in
an area of otherwise normal cortex
Heterotopia
• Abnormally located normal neurons
• Theory: neurons never began migration and stayed in
subventricular area where the cortical neurons originate
• Diverse
– Sporadic vs inherited
– Independent vs part of syndrome
– Asymptomatic vs associated with seizures and developmental delays
• Periventricular nodular heterotopias (also called subependymal)
– Least severe, most common
• Majority of cases result from mutations in FLNa gene on X
chromosome
– Males do not survive embyronic period
– Women develop seizures and/or intellectual disability
Periventricular nodular heterotopia
Heterotopia: Pathology
• Subependymal heterotopia
– H&E
– NeuN
Cortical Dysplasia
• Local expansion of the
cortical gyri with blurring
of the border between
the cerebral cortex and
underlying white matter
• Disorganization of
neurons with cytologic
abnormalities
•
Binucleated cells, reactive glial
cells, balloon cells
• Areas may be surgically
resected in cases of
medically intractable
epilepsy
Cortical dysplasia: Pathology
• H&E
• GFAP
• NeuN
Clinical Case
21 year old man comes to the clinic because he has been having spells in
which he suddenly stops what he was previously doing and stares for about a
minute, sometimes picking at his nose and his shirt. He cannot recall what
happens during the spell itself. He says, however, that he knows when a spell
is going to happen because he experiences a warm sensation in his epigastric
region, followed by a sensation of fear and rapid recollection of episodes of
past life experiences along with palpitations. He may have post-ictal
confusion. His EEG shows focal spikes. Which of the following best describes
the type of seizure this patient has?
a. Temporal lobe seizures
(focal seizure with secondary generalization and alteration of awareness)
a. Frontal lobe seizures
b. Absence seizures
c. Occipital lobe seizures
d. Parietal lobe seizures
Hippocampal Sclerosis
• AKA Mesial temporal
sclerosis
• Gliosis and neuronal
loss in the
hippocampus in
association with long
standing seizure
disorder
• Imaging: atrophy of
hippocampus with
dilation of temporal
horn of lateral
ventricle, usually
unilateral
Hippocampal sclerosis
• Unclear whether sclerosis is the cause or the
consequence of seizures
• Possible link between prolonged infantile
febrile convulsions and later development of
temporal lobe epilepsy/ hippocampal sclerosis
• Cases of successful treatment of medically
intractable epilepsy with surgical resection
points to sclerosis as cause of epilepsy
Hippocampal sclerosis: Pathology
• Developmental
– H&E
– GFAP
– NeuN
• Epilepsy
– H&E
Summary
• Neuronal migration defects and hippocampal sclerosis
are pathological changes associated with epilepsy
• Pachygyria/lissencephaly and polymicrogyria describe
size of gyrus and are associated with various
syndromes
• Neuronal heterotopia are normal neurons in the
wrong places
• Cortical dysplasia are abnormal neurons in setting of
disorganized cortical architecture
• Hippocampal sclerosis may the cause or consequence
of epilepsy
References
1. Neuropathology (Prayson). Chapter 4: Congenital Malformations, Perinatal
Diseases, and Phacomatoses by Folkerth and Lidov.
2. Comprehensive Board Review in Neurology by Borsody
3. Comprehensive Review in Clinical Neurology (multiple choice question
book) by Chen-Ching et al