Transcript Clinical Conundrum: A toddler presenting with emesis and

Amit Salkar, MD
Nicole Bernard, MD
Bhairav Patel, MD
Robert Mignacca, MD
Dell Children’s Medical Center of Central Texas
7th Annual Pediatric Conference
Saturday, April 12, 2014
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Discuss what was learned from each step in
obtaining this child's diagnosis
Identify areas of improvement in patient care
Explain areas of group learning from the case
presentation
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22-month-old, previously healthy male
presents to an outside hospital with 2 days of
emesis
He is appropriately fluid resuscitated for mildto-moderate dehydration
CBC reveals a Hgb of 4.7, MCV of 45.6, RDW
of 26.6, and platelets of 525
Transferred to DCMC for further evaluation
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Review of systems is negative
Child is otherwise healthy
His mother states that he is a “picky eater”
and consumes ~ ½ gallon of cow’s milk per
day for the last several months
Family history is unremarkable
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Vital signs are significant for tachycardia
Physical exam reveals a pale, fussy but
consolable toddler
Otherwise, his physical exam is normal
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Child continues to have emesis and low urine
output
Additional fluid resuscitation is given
His mother seems worried, stating that he
has been “very sleepy” and “not himself”
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Acute emesis and altered mental status, and
severe anemia raised suspicion for an
intracranial process
CT Head without contrast was ordered STAT,
which led to the diagnosis
Vein of Trolard (lateral)
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Deep cerebral venous thrombosis
Associated bilateral deep white matter and
right caudate nucleus venous infarctions
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Hypercoagubility work-up was initiated
Transfused with 5 ml/kg of pRBCs
Post-transfusion Hgb 4.3 (lower than initial
value)
Started on iron supplementation and
Lovenox therapy
Transfused again with pRBCs
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Although lethargy improved, patient
continued to have some bouts of emesis and
began complaining of headache
Repeat imaging showed stable findings
Symptoms were attributed to increase
intracranial pressure from cerebral sinus
venous thrombosis (CSVT)
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Symptoms of increased ICP gradually
improved
Discharged home 8 days after admission
Instructed to follow-up with Hematology for
ongoing management of Lovenox therapy
and iron deficiency anemia (IDA)
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Hypercoagulability work-up initiated while
inpatient reveals heterozygous mutation of
the PT20210A allele
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Review CSVT in children, including definition,
epidemiology, clinical manifestations,
imaging, and risk factors
Discuss the relationship between the
PT20210A prothrombin gene mutation and
CSVT
Explore the association between IDA and
CSVT
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Ischemic stroke consists of
 Arterial ischemic stroke (AIS)
 Cerebral sinus venous thrombosis (CSVT) [1]
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Childhood stroke
 Cerebrovascular event in patients 30 days to 18
years of age [2]
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Defined as thrombotic occlusion of cerebral
veins or sinuses
 Associated with venous infarction in ~ 50% of
cases
 Proportion of AIS to CSVT is ~ 3:1
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Venous congestion leads to focal cerebral
edema progressing to venous infarction and
hemorrhage [1]
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Reported incidence of 0.67 per 100,000
children per year
CSVT was more common in neonates [3]
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Decreased level of consciousness
Headache
Focal neurological signs such as hemiparesis
Cranial nerve palsies [3]
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Drains majority of deep gray nuclear structures
Located in the ventricles and deep basal cisterns
Choroidal, septal, and thalamostriate veins
converge to form the paired internal cerebral
veins
Internal cerebral veins and basal veins of
Rosenthal join to form the great vein of Galen,
which joins the inferior sagittal sinus to form the
straight sinus
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Straight sinus drains to the torcular and
subsequently to the transverse sinuses 
sigmoid sinuses  internal jugular veins
Variations of drainage are extremely
common, which in part determines variable
brain injury to thrombosis
Figure 5
The spectrum of presentations of venous infarction
caused by deep cerebral vein thrombosis.
van den Bergh, Walter; van der Schaaf, Irene; van Gijn,
Jan
Neurology. 65(2):192-196, July 26, 2005.
Figure 5 Anatomy of the deep cerebral venous system.
(A, B) Axial and sagittal view of deep venous system and
basal ganglia: 1. caudate nucleus; 2. thalamus; 3. basal
veins (veins of Rosenthal); 4. internal cerebral veins; 5.
great cerebral vein (vein of Galen). (C, D) Axial and
sagittal maximum intensity projection (MIP) images of
the deep venous system. (E-F) Axial and sagittal MIP
images; the deep venous system is demarcated in red.
©2005 American Academy of Neurology. Published by LWW_American Academy of Neurology.
2
Superior sagittal sinus
Inferior sagittal sinus
Superior sagittal sinus
Straight sinus
Internal cerebral veins
Torcular
Sigmoid sinus
Transverse sinus
Basal vein of Rosenthal
Torcular
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Catheter angiography - gold standard
 Invasive (complications of stroke, groin
hematoma, femoral artery injury)
 Highest radiation exposure
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CT angiography
 Excellent sensitivity
 Requires administration of iodinated contrast
 Radiation exposure
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MR venography
 Excellent sensitivity
 Can be done without contrast (although not as
good as contrast enhanced MRV and not great for
partial thrombosis)
 Typically contrast is given
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Ultrasound - acceptable for dural sinuses in
neonate
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Head and neck disorders 38% (of which 61%
were infections)
 Otitis media, mastoiditis, and sinusitis (preschool
children)
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Acute systemic diseases 31%
 Dehydration, sepsis [3]
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Chronic systemic diseases 54%
 Connective-tissue disorders
 Hematologic disorders
 Malignancy
 Cardiac disease
 Disorders requiring indwelling catheter [3]
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Coagulation disorders 32%
 Deficiencies in protein C, protein S, and
antithrombin III,
 Factor V Leiden and PT20210A prothrombin gene
mutations
 Presence of anticardiolipin antibody and Lupus
anticoagulant [3]
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Iron-deficiency anemia
 2005 review of 42 cases of children with CSVT by
Sebire et al. published in Brain
▪ 50% had probable IDA [4]
 Increasing number of case reports and reviews
describing IDA as a risk factor for CSVT [5-9]
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Common
Low risk for pathology unless homocysteine
is elevated
If homocysteine is elevated, improvement
can be seen with folic acid.
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Obesity
Inactivity
Pregnancy hormones
Anesthesia/surgery
Crush injury
Tobacco
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Clinically, the balance between bleeding and
clotting requires a significant change (or
multiple less significant ones) to result in
pathology
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Prothrombin (Factor II) functional point
mutation on Cr 11 of non-coding region of
prothrombin
Increased protein expression [16-19]
Increased protein stability [20]
G20210a mutation 1-3% of general population
Prevalence rates of G20210a in pediatric patients
with thrombosis have shown to be 4-10%
 Population
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 Caucasians, with few Middle Eastern, and Hispanic
incidence
 Rare in Asian and African American [20-22]
Zadro R, Herak DC. Inherited prothrombitc risk factors in children with first ischemic stroke. Biochem Med (Zagreb). 2012;22 (3):298-310. [23]
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CSVT is associated with inherited
prothrombotic risk
Laugesaar et al. showed 3 fold increase risk of
CSVT in children with PT G20210A, showing
significant risk both on
 Meta-analysis (OR 11.9; 95%CI) and
 Case-control (OR 3.3; 95% CI) studies [24]
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Retrospective review (Young et al.) of 374
thrombotic events in 26 hospital centers,
10% (38 children) had G20210A mutation [25]
92% of VT had an acquired risk factor
54% had an additional inherited risk factor
Majority of VTE were older children (96% > 2
years)
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Excluding neonates the mean age was 10.6
years
Only 25% with FH thrombotic event
CSVT manifested in 6 of 34 thrombotic
events
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2007 case-controlled study published in
Pediatrics by Maguire JL, et. al.
 Studied children aged 12 to 38 months who were
previously healthy with no identifiable risk factors
for stroke
 Case patients had lower median hemoglobin
levels and MCV and higher platelet counts [7]
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2007 case-controlled study published in
Pediatrics by Maguire JL, et. al.
 Children with IDA accounted for more than half of
all stroke cases
 Children with stroke were 10 times more likely to
have IDA than controls [7]
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2014 case-controlled study published in
Annals of Hematology
 Very similar to study by Maguire, except for
having a higher number of case patients
 57.1% of stroke cases had IDA and no other
identified cause, compared to 26% of controls [9]
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2014 case-controlled study published in
Annals of Hematology
 Previous healthy children who developed stroke
were 3.8 times more likely to have IDA than
healthy children who did not develop stroke
 Significant interaction between IDA and
thrombocytosis among studied cases [9]
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Hypercoaguable state directly related to irondeficiency and/or anemia
 IDA causes microcytosis and reduced RBC
deformability
 Turbulence replaces laminar blood flow, allowing
platelets to come in contact with endothelium,
initiating coagulation cascade and development
of thrombus [6]
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Thrombocytosis secondary to IDA
 Iron inhibits platelet production, which explains
thrombocytosis in IDA
 Iron also required for synthesis of essential
platelet components and therefore needed for
maximum platelet production above steady-state
levels
 Bump in platelets observed when iron is initially
replaced [6]
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Anemic hypoxia
 Mismatch between oxygen supply and end-artery
oxygen demand leads to ischemia and infarction
[2]
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Patient continues to follow-up with
Hematology for ongoing management of
anticoagulation (6 months duration) and IDA
Repeat MRV Brain with contrast ~ 1 month
after discharge showed resolution of
thrombosis
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No evidence of neurologically sequelae
Due for repeat imaging around the time of
discontinuation of Lovenox
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Include intracranial process on differential for
children presenting with emesis
Recognize risk factors for CSVT
Consider IDA as potential risk factor for
CSVT, although the literature is still evolving
Prevention of IDA can be simple as taking a
good diet history and educating parents
about proper nutrition
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