Transcript Brainstem disconnection

EP-125
Brainstem disconnection: two additional
patients and expansion of the phenotype
Andrea Poretti 1,2, Thierry A.G.M. Huisman 1,
Eugen Boltshauser 2
1Section
of Pediatric Neuroradiology, Division of Pediatric Radiology, Russell H Morgan
Department of Radiology and Radiological Science, The Johns Hopkins University School
of Medicine, Baltimore, MD
2Department of Pediatric Neurology, University Children’s Hospital of Zurich, Switzerland
ASNR 53rd Annual Meeting, Chicago, April 25-30, 2015
©AP
Disclosure
• We have nothing to disclose
• No relevant financial relations interfering with
our presentation
©AP
Brainstem disconnection (BD)
• Rare posterior fossa
congenital abnormality
• Only 12 children with BD
reported so far
• Diagnosis based on typical
neuroimaging findings:
– Nearly complete absence of a
brainstem segment with the
intact rostral and caudal
brainstem portions connected
only by a thin cord of tissue
Poretti A et al, Neuropediatrics, 2007
©AP
Brainstem disconnection
• Neuroimaging classification based on the location
of the disconnection: 1
2
3
1. Ponto-mesencephalic
2. Ponto-medullary
3. Ponto-cervical
• Outcome = poor
– The majority of children died within the first two
months of life
– No developmental milestones achieved
Bednarek N et al, Eur J Paediatr Neurol, 2005; McCann E et al, Pediatr Radiol, 2005; Okumura A et al, Am J Med Gen A, 2009
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Purpose
• To report on:
1.
2.
3.
4.
Clinical presentation + outcome
Imaging
Genetics
Neuropathology
in 2 children with a milder phenotype of BD to
extend the phenotypic spectrum of this very rare
congenital abnormality
©AP
Methods
1. Clinical findings & outcome: from clinical history
& follow-up examinations
2. Neuroimaging: qualitative evaluation of brain
MRI for infra-/supratentorial abnormalities
3. Genetic analysis
4. Neuropathology examination (n=1)
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1. Clinical findings
• Patient 1 (male):
– At birth: global hypotonia, reduced left facial movements,
feeding difficulties requiring a nasogastric tube
– Unstable body temperature (32.5-42.5°C), generalized
seizures, brief visual fixation, required a gastrostomy tube,
no auditory brainstem evoked responses
• Patient 2 (female):
– At birth: impaired mouth opening, unilateral preauricular
tag, long gap esophageal atresia (type Vogt IIIB)
– Epileptic seizures since the age of 2 weeks, unstable body
temperature (33.7-42.0°C), required a gastrostomy tube
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1. Outcome
• Patient 1:
– At 8 months of age: smiled, targeted reaction after a
tactile stimulus, moved all extremities spontaneously
and symmetrically, brought hands to the mouth
– Died at 8 months of age because of pneumonia
• Patient 2:
– At 14 months of age: development of hydrocephalus
 no VP-shunt because of palliative situation
– At 4.5 years of age (alive): no visual contact, no
spontaneous movements, generalized spasticity, no
developmental milestones have been reached
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2. Imaging: Patient 1
(A) Midsagittal and (B) coronal T2-weighted brain MR images at 3-weeks show a
markedly small pons with only a thin strand of tissue (arrow) anteriorly connecting
the spared upper portion of the pons and the medulla. The cerebellar vermis and
hemispheres are globally hypoplastic
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2. Imaging: Patient 2
(A) Midsagittal T2-weighted, (B) coronal FLAIR, (C) and (D) axial T2-weighted MR and
(E) time-of-flight MRA images at 3 weeks reveal absence of the middle and lower
pons with only two thin strands of tissue (arrows) anteriorly and posteriorly
connecting the upper pons and the medulla. The cerebellar vermis and hemispheres
are globally hypoplastic. The basilar artery is not visible.
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2. Imaging: Patient 2
A chest radiograph shows
partial fusion of the
posterior right 3/4/5 ribs
and butterfly shape/
hemivertebra of the
thoracic spine. Prominent
cardio-thymic silhouette.
©AP
3. Genetic findings
• Patient 1: Whole exome sequencing:
– Heterozygosity for a p.Thr30Ala (c.88-A>G) variant in
exon 3 in the BMP4 gene = inherited from the father
– Hemizygosity for a p.Arg293Gln (c.878-G>A) variant in
exon 7 in the SEPT6 gene on the X chromosome =
inherited from the mother and also found in the
oldest healthy brother
 Both variants are not causative for BD
• Patient 2: Array comparative genomic
hybridization (CGH):
– No copy number variants
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4. Neuropathology: Patient 1
• Brainstem: nearly-normal midbrain,
small superior cerebellar peduncles,
absent medial lemnisci, short and
small pons (mostly tegmentum, only
a thin rim of basis pontis), dysplastic
medulla
• Cerebellum: hypoplasia of the vermis,
otherwise normal
• Normal cerebral hemispheres
• Normal vertebral and basilar arteries,
no gliosis in the areas supplied by the
posterior circulation
Axial histologic section of upper pons and
cerebellum. Luxol Fast Blue/H&E combination
stain, 1x original magnification.
Courtesy of Dr. D.C. Miller, University of Missouri, Columbia, MO
©AP
Discussion: Phenotype
1. Survival:
 10 of 12 children reported: died < 2 months of age
 Our patients: survived longer (8 months and >4.5 years)
2. Last follow-up:
 Children who survived > 2 months: still hospitalized (5
months and 4 years of age), mechanical ventilation/
tracheostomy, gastrostomy, no development
 Our patients: no mechanical ventilation, patient 1 =
only BD patient who achieved developmental
milestones
 Our patients = milder phenotpye
©AP
BD patients reported so far
Age at death or
last follow-up
died at 6 weeks
(not ventilated)
Highest developmental
milestone(s) achieved
Anomalies outside the brain
no information
none
ponto-mesencephalic
died at 5 days
not applicable (too young)
none
male
ponto-mesencephalic
died at 7 weeks
(not ventilated)
no development
rib + vertebral anomalies, ectopic thyroid +
parathyroid, hydronephrosis, micrognathia
Bednarek
female
ponto-mesencephalic
died at 11 days
not applicable (too young)
none
McCann
male
ponto-medullary
died in first week
not applicable (too young)
none
Poretti
male
ponto-medullary
died at 21 days
not applicable (too young)
pulmonary atresia, transposition of the great
arteries, ventricular septal defect
Barth
male
ponto-medullary
died at 5 days
not applicable (too young)
none
Duffield
female
ponto-medullary
Okumura
female
ponto-medullary
Jurkiewicz
female
ponto-medullary
male
Reference
Gender
Disconnection
Mamourian
female
ponto-medullary
Sarnat case 1
male
Sarnat case 2
died at 8 weeks
(not ventilated)
alive at 4 years
(ventilated)
alive at 5 months
(tracheostomy)
no information
microophthalmia, hydronephrosis, bicornuate
uterus, vertebral anomalies
clumsy ocular tracking, limited
movements
cleft palate
no information
rib+vertebral anomalies, bilateral anothia,
micrognathia
ponto-medullary
died at 8 days
not applicable (too young)
none
female
ponto-medullary
died at 9 days
not applicable (too young)
inner ear anomalies
Our patient 1
male
ponto-medullary
Our patient 2
female
ponto-medullary
died at 8 months
(not ventilated)
alive at 4.5 years
(not ventilated)
brief fixation, smile, reach for
objects, limited head control
no visual contact,
no development
Agarwal/Yigazu
Carr
neurogenic bladder, hydronephrosis
esophageal atresia, tracheo-oesophageal
fistula, vertebral anomalies, ectopic pyelon
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Discussion: Pathomechanism
Malformation (pro)
Disruptive (vascular) lesion (pro)
1. A EN2 murine model: agenesis
of mesencephalon and
metencephalon; mutations in
EN2, however, not found in 2
children with BD
2. Presence of additional brain
malformations, dysmorphic
features, and extracerebral
involvement
1. Models with missing hindbrain
segments: remaining segments
always contiguous (≠ in BD)
2. Early vascular disruptions  tissue
liquefaction without gliotic scars
3. Association with syringomyelia 
progressively insufficient perfusion
due to hypoplastic basilar artery
and obstructed venous drainage
due to abnormal glial barrier
around the posterior brainstem
4. Negative genetic analysis (?)
Sarnat HB et al, Pediatr Dev Pathol, 2002; Barth PG et al, Neuropediatrics, 2008
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Conclusions
1. Although the long-term neurodevelopmental
outcome of BD remains unfavorable, the
expansion of the phenotypic spectrum may be
important in terms of family counseling
2. It remains unknown whether BD is genetically
driven (malformation) or is the outcome of a
prenatal (most likely vascular) disruptive insult
©AP
Acknowledgments
• Dr. Douglas C. Miller, Department of Pathology and
Anatomical Sciences, University of Missouri School
of Medicine, Columbia, Missouri, United States for
sharing neuropathology data of Patient 1
• The families of the affected children for supporting
this presentation
©AP