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DisPONnect
A Case of Pontine Glioma
The Medical City | Department of Pediatrics
ASMPH Interns – Group 2
Outline
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Patient Information and Data
Approach to Diagnosis
Course in the Wards
Diagnostics
Therapeutics
Prognosis and Complications
Biopsychosocial Aspect: Palliative
Care
Patient History
DisPONnect
A Case of Pontine Glioma
Identifying Information
Patient Name: SA
Age: 8 years old
Nationality: Filipino
Religion: Roman Catholic
Handedness: Right
Admitted: November 15, 2013
Information: EC and RA, patient’s
parents
Good Reliability
Chief Complaint
Inarticulation
(Nabubulol at Nagba-babytalk)
Patient History
• Asymmetrical changes in smile
• Lopsided, with almost no movement on the
right
• Mild-moderate throbbing frontal headache
once a week
3 Weeks PTA
• Not aggravated by movement or light exposure
• Alleviated by liniment application (Vicks
Vaporub)
• No dizziness, changes in vision, dysphagia,
imbalance, behavioral changes, motor or
sensory deficits
• No consult done
Patient History
• Sudden changes in articulation
• “Baby talk”
• Slurring of speech
9 Days PTA
• No other associated symptoms
• No consult done
Patient History
• Persistence of symptoms
• Sudden episodes of drooling
• Dysphagia
• Difficulty swallowing food with choking
episodes
6 Days PTA
• No other associated symptoms
• No changes in sensorium
• No consult done
Patient History
• Weakness of the left lower extremity
• Difficulty wearing left slipper
• Dragging of left foot
• Drunken gait
4 Days PTA
Admission
• Inability to articulate
• No other symptoms
• Persistence of symptoms led to consult with AP
• Advised admission
Review of Systems
General
• (+) Recent weight gain. No fever, fatigue.
HEENT
• No eye discharge or blurring of vision. No hearing loss or
tinnitus. No colds. No dry mouth or gum bleeding. No
hoarseness.
Respiratory
Cardiovascular
Gastrointestinal
• No cough, hemoptysis, sputum production, difficulty
breathing.
• No chest pain, palpitations, orthopnea, cyanosis, pallor and
easy fatiguability.
• No abdominal pain, vomiting and loose stools.
Genitourinary
• No dysuria, frequency, hematuria, nocturia.
Skin
• No pruritus, rashes, dryness, color changes.
Musculoskeletal
Neurologic
• No muscle or joint pain.
• See HPI
Past Medical History
• Past Illnesses
– No previous history of cancer, stroke, seizures, eye
correction, pneumonia, PTB, cardiac disease, hypertension,
diabetes, asthma, kidney or thyroid disease
• Hospitalizations
– Previously admitted for Dengue Fever in 2012
• Surgeries
– No previous surgical procedures
• Trauma
– No history of trauma
• Allergies
– No allergies to food or medications
• Medication
– No current medication use
Family History
• Patient is of Filipino descent
from Maybunga, Pasig City
• Bronchial Asthma in the
maternal aunt
• No family history of cancer,
stroke, seizures, diabetes,
hypertension, heart disease,
allergies
• Household Members:
–
–
–
–
Patient
Patient’s Siblings
Patient’s Parents
Patient’s maternal Aunt
History of Birth and Infancy
Birth History
• Born full term via normal
spontaneous delivery to a
37-year old G3P3 (3003)
• Birth Weight: 3.08kg
• Good Activity, Good Cry
• Attended by: OB-GYN
• No perinatal or neonatal
complications
Nutritional History
• Not breastfed
– Due to low maternal milk
production
• Formula Milk: NAN HA,
Gain, Lactum
• Weaned at 6mo of age
• Current Diet: meats,
vegetables and fruits
• Preferences: sour foods
(e.g. sinigang isda)
24-Hour Food Recall
Regular Days
Days Immediately Prior to Illness
Breakfast
1c rice, 1 egg, 1pc hotdog
Lunch
1c rice, ½c chicken adobo
Snack
1 cheese sandwich
Beginning 6 days prior to illness,
patient was only able to consume
fluids as solids would cause her to
choke (e.g. ½c clear broth)
Dinner
1c rice, 1 pork chop
Immunization History
Vaccine
Complete
BCG
Unknown
X
X
Hepatitis B (1-2-3)
X
MMR (1-2)
X
Measles (1)
X
Varicella (1)
Influenza
None
X
DPT/Polio (1-2-3 booster
1-2)
Hemophilus influenza B
(HIB) (1-2-3 booster)
Pneumococcal
booster)
Incomplete
X
(1-2-3
X
X
Rotavirus (1-2)
X
Hepatitis A (1-2)
X
Typhoid
X
History of Childhood
Developmental History
Personal and Social History
• Gross Motor
• Grade 3 Student
– Able to do backward heel to
toe walk
• Fine Motor
– Able to draw a complete
person
– Can write fairly well
• Language
– Can add and subtract
– Can distinguish between left
and right
• Personal/Social
– Can dress self completely
– Above average performance
(6th honor)
• Favorite Subject: Science
and English
• Hobbies: Spend time with
friends, singing and dancing
• Has shown interest in the
opposite sex, but has no
crushes
Environmental History
• Residence: 1-story cement structure
– Maybunga, Pasig City
•
•
•
•
Electricity: Meralco
Water: Manila Water Company, Inc.
Near to major roads, but not near any factory
No exposure to tobacco, toxins or environmental
hazards
• Waste: Daily, not segregated
Stakeholder Analysis
Stakeholder
Role
Stand on the
Issue
Intensity of Stand
Degree of
Influence
Insight
Mother
Primary Caregiver
Ally
Father
Primary
Breadwinner
Ally
High
Mother and Father
both regularly check
up on the health
status of the patient
Brothers and Sisters
Secondary
Breadwinners,
Social Support
Ally
Moderate
High Father regularly
checks up on the
health status of the
patient
High
Decision making
regarding patient’s
health concerns is
largely decided by
the parents and the
maternal aunt
High
Decision making
regarding patient’s
health concerns is
largely decided by
the parents
Maternal Aunt
Secondary Caregiver,
Decision-Maker
Ally
High
High
Mid
Mother and Father
are worried about ,
but not fully aware
of the possible
severity of the
patient’s condition
Mid
Siblings are worried
about, but not fully
aware of the
possible severity of
the patient’s
condition
Mid
The aunt was one of
the companions of
the patient when
she was brought in
at the ER
At the ER, the
mother would often
let the aunt decide
on what to do with
the patient
Aunt is worried
about, but not fully
aware of the
possible severity of
the patient’s
condition
Physical Examination
DisPONnect
A Case of Pontine Glioma
Physical Examination
Anthropometrics
Weight: 34.5kg
Z-score (0,2)
Height: 138cm
Z-score (0,2)
BMI: 18.11kg/m2
General Survey
Awake, Alert
Not in CardioRespiratory
Distress
GCS 15
Vital Signs
BP: 118/76mmHg
HR: 82bpm
RR: 20cpm
Temperature: 36.5C
Pain: 0/10
Physical Examination
• Eyes:
– Anicteric sclerae, pink palpebral conjunctivae, no
cataracts or discharge
• Skin:
– Fair color, no rashes, good skin turgor, hair evenly
distributed, nails with no clubbing
• Ears:
– No visible mass or lesion, no discharge, no auricular
tenderness, patent canal, intact tympanic membrane
with cone of light
Physical Examination
• Nose
– No deformities, no nasal discharge, no nasal
congestion
• Throat
– Lips moist and pink, no cleft lip or palate, no
tonsillopharyngeal congestion
• Neck
– Flat neck veins, no cervical lymphadenopathy
Physical Examination
• Chest/Lungs
– Symmetric chest expansion, no retractions, clear
breath sounds, no rales, no wheezes
• Cardiovascular
– Adynamic precordium, normal rate, regular rhythm,
good S1/S2, no murmurs, heaves or thrills
• Abdomen
– Flat, no previous surgical scars, normoactive bowel
sounds, no masses palpated, no organomegaly, no
tenderness
Physical Examination
• Genitalia
– Grossly female genitalia, no discharge
• Extremities
– Full and equal pulses, no edema, no cyanosis, CRT
<2 seconds
Neurologic Examination
Cranial Nerves
I
Intact Smell
II
Visual acuity: intact
Confrontation fields: no visual field cuts
Fundoscopy: (+) RO Reflex
Disc: Sharp margins, yellowish, round, cup to disc ratio < 0.5
Vessels: AV ratio 2:3. No indentations. No arterial light reflex.
Macula: 2.5 disc distance temporal to disc. No vessels noted
around the macula.
II and III
III, IV, and VI
Pupils equally reactive to light and accomodation
Intact EOM movement along all cardinal positions of gaze
Neurologic Examination
Cranial Nerves
V
Touch/ pin-prick intact along V1, V2, and V3
Intact Masseter and Temporalis tone
VII
Forehead Crease: No asymmetry
Palpebral fissures, lid closure: No asymmetry
Shallow nasolabial fold, right
VIII
Intact gross hearing
IX and X
Midline uvula, (-)
gag reflex
XI
Shrugs shoulder, can turn head from side to side against
resistance
XII
No tongue deviation
Neurologic Examination
Extremity
Strength
Sensation
Right Upper
Extremity
5/5
100%
Left Upper
Extremity
4/5
100%
Right Lower
Extremity
5/5
100%
Left Lower
Extremity
4/5
100%
Neurologic Examination
No Flaccidity or Rigidity
No Atrophy or Hypertrophy
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Neurologic Examination
• Cerebellar
– Dragging gait on the left
– Dysdiadochokinesia: Left
– Dysmetria: Left
• Babinski: Bilateral
• Meningeal signs
– Negative Kernig’s and Brudzinski’s sign
– No neck rigidity
Salient Features
SUBJECTIVE
• 8-year old female
• No history of neurologic
disease
• 3 week history of rightsided facial weakness
• 6 day history of drooling,
dysphagia and slurred
speech
• Left-sided weakness
• Unstable gait
OBJECTIVE
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Stable VS, GCS 15
Shallow nasolabial fold, right
Dysarthria
Absent gag reflex
Left-sided motor weakness
(4/5)
• (+) Dysdiadochokinesia,
dysmetria, left
• (+) Dragging gait
• (+) Babinski, bilateral
Approach to
Diagnosis
DisPONnect
A Case of Pontine Glioma
Neurologic Diagnosis
Is there a lesion?
Where is the lesion?
What is the lesion?
Autoimmune
Metabolic
Trauma/
Toxins
Idiopathic
Infectious/
Neoplastic
Inflammatory
Vascular
What is
the
Lesion?
Developmental/
Congenital
What is the Lesion?
Stroke in the Young
Vascular
Acute hemiplegia,
unilateral weakness,
sensory disturbance,
dysarthria, dysphagia
Acute onset  progressive
symptoms that may evolve
over several hours
Arterial Thrombosis,
Venous Thrombosis,
Intracranial Hemorrhage
Causes of stroke in childhood:
Congenital/Acquired Cardiac
disease, Hematologic
Abnormalities, Metabolic
disease, Inflammatory
disorders, Trauma
Infectious
Neoplastic
What is the Lesion?
Arteriovenous Malformation
Vascular
• Abnormal shunting of blood  expansion of vessels
and a space-occupying effect or rupture of a vein and
intracerebral bleeding
• May remain asymptomatic throughout life but can
rupture and bleed any time
Infectious
Neoplastic
• History of ipsilateral seizures and migraine-like
headaches
• Ruptured AV malformation: severe headache, vomiting,
nuchal rigidity, progressive hemiparesis, and seizure
What is the Lesion?
Aneurysm
• Usually asymptomatic
Vascular
• Located at the carotid bifurcation or on the anterior
and posterior cerebral arteries rather than the circle of
Willis.
• Results from a congenital weakness of the vessel
Infectious
Neoplastic
• Ruptured aneurysms: intense headache, nuchal rigidity,
coma, intracerebral hemorrhage and progressive
hemiparesis
What is the Lesion?
Meningitis
• Acute infection of the central nervous system (CNS)
Vascular
Infectious
• May present acutely, subacutely and chronically
(>1week)
• Often preceded by fever, respiratory or gastrointestinal
symptoms, followed by nonspecific signs of CNS
infection such as increasing lethargy and irritability
• Systemic infection + meningeal symptoms, seizures and
altered mental status
Neoplastic
What is the Lesion?
Brain Lesion
• Most common in children 4 -8 years old
Vascular
Infectious
Neoplastic
• Causes: emboli, meningitis, chronic otitis media and
mastoiditis, sinusitis, soft tissue infection of the face or scalp,
orbital cellulitis, dental infections, penetrating head injuries,
immunodeficiency states, and infection of ventriculoperitoneal
shunts
• 80% of abscesses are found in the frontal, parietal and
temporal lobes
• Clinical presentation: low grade fever, headache and lethargy
 vomiting, severe headache, seizures, papilledema, focal
neurologic signs (hemiparesis), coma
• Cerebellar abscess: nystagmus, ipsilateral ataxia and
dysmetria, vomiting, and headache
What is the Lesion?
Primary CNS Lesion
Vascular
• 2nd most frequent malignancy in childhood
• Higher incidence in children >7 years
• Progressive Symptoms
• Brainstem tumor effects: motor weakness, cranial
nerve deficits, cerebellar deficits, and/or signs of
increased intracranial pressure
Infectious
Neoplastic
Metastatic Lesion
• Uncommon
• Primary neoplasia: ALL, lymphoma, neuroblastoma,
rhabdomyosarcoma, Ewing sarcoma, osteosarcoma,
and clear cell sarcoma of the kidney
Is There a Lesion?
• Yes!
Baby Talk and Slurring of Speech  Dysarthria
• Dysarthria: disorders in articulating speech sounds
– Vs. Dysphonia
– Vs. Dysprosody
– Vs. Dysphasia
• Motor paralysis of organs of articulation
Dysarthria
Dysarthria
Cause of Dysarthria
• Drooling + Dysphagia
– Swallowing Problem
• Absent Gag Reflex
CRANIAL NERVE IX and X Palsy
Dysarthria: http://trialx.com/curetalk/wp-content/blogs.dir/7/files/2011/05/diseases/Dysarthria-1.jpg
• Dysarthria, drooling,
dysphagia
• Absent Gag Reflex
• Right-sided weak
smile
• Shallow nasolabial
fold, right
• Weak left side:
dragging left foot
• Motor: 4/5, Left
Cranial
Nerve IX
and X Palsy
Left-sided
Motor
Weakness
Central
Facial
Palsy, Right
Cerebellar
Signs
• “Drunken” gait
• Dysmetria,
Dysdiadochokinesia,
left
Central Facial Nerve Palsy, Right
• Possible Location of Lesion:
– Left Corticobulbar Tract
– Above the Facial Nucleus
(located at the Pons)
Left-Sided Weakness
• Corticospinal Tract
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–
–
–
–
Cerebral Cortex
Mesencephalon
Pons
Medulla
Spinal Cord
• Contralateral lesion above
decussation
Cerebellar Signs
• Unsteady gait
• Dysmetria, Left
• Dysdiadochokinesia, Left
• Possible Locations:
–
–
–
–
–
Cerebrum
Cerebellum
Midbrain
Pons
Midbrain
http://www.asn.org/neurographics/3/2/1/2.shtml
Cranial Nerves and the Brainstem
• CN involvement
– Above Nucleus: Contralateral
– At Nucleus and Below:
Ipsilateral Manifestations
• Corticospinal Tract
– Contralateral weakness
Pontine Lesions
• Cranial Nerve Nuclei
– Abducens nerve (CN VI)
– Trigeminal nerve (CN V)
– Cochlear and the lateral and
superior vestibular (CN VIII)
– The superior and inferior
salivatory nuclei and the
lacrimal nucleus (cranial nerves
VII and IX)
• Fiber Tracts
– Corticospinal, corticobulbar,
and corticopontine,
spinocerebellar, spinothalamic,
lateral tectospinal, rubrospinal,
and corticopontocerebellar
tracts
Localization
Brainstem Lesion, Possibly Pontine
Course in the Wards:
Diagnostic
DisPONnect
A Case of Pontine Glioma
Course in the Wards: Diagnostic
•
•
•
•
Patient was admitted in her 3rd week of illness
S/O > Weakness of the left upper extremity (4/5), slurring of speech, drooling
and shallow nasolabial fold, right
A> Vascular Insults probably right MCA, space-occupying lesions vs. Stroke in
the Young
P> Referral to Pediatric Neurology; Neurovital signs to be monitored every 4
hours with strict aspiration precaution
Diagnostics
Laboratories: CBC with PC, serum electrolytes (Na, K, Cl,
iCa), creatinine, ESR, PT and aPTT
Imaging: Cranial MRI plain and with IV contrast
Patient’s Diagnostics
DisPONnect
A Case of Pontine Glioma
Diagnostics: Rationale
DIAGNOSTIC
RATIONALE FOR USE IN OUR PATIENT
Laboratory
Complete Blood Count To check for infection, or provide clues for possible causes of
stroke in the young (polycythemia, thrombocytosis or
thrombocytopenia)
Estimated
Sedimentation Rate
To check for signs of inflammation
Serum Electrolytes
To rule out electrolyte imbalances which can present with
weakness or mimic stroke in the young
Creatinine
To establish baseline before undergoing cranial MRI with
contrast
Imaging
Cranial MRI
To evaluate cranial anatomy and identify signs of infection,
swelling or mass lesions
Diagnostics: Rationale
• Erythrocyte Sedimentation Rate
– Rate at which RBC sediment in a period of 1 hour
– Non-specific test used to detect conditions associated with acute and
chronic inflammation (infection, cancers, autoimmune diseases)
– A young stroke patient will often have signs of inflammation in the
blood
Adams et al., 2003; European Stroke Initiative Executive Committee and the EUSI writing committee, 2003
Diagnostics: Rationale
• Coagulation Tests (PT, aPTT)
– Measure how quickly the blood clots
– Abnormal results may either point to excessive bleeding or excessive
clotting which present as risk factors to stroke (ischemic or
hemorrhagic)
Adams et al., 2003; European Stroke Initiative Executive Committee and the EUSI writing committee, 2003
Diagnostics: CBC
November 15, 2013
Result
Reference Range
Hemoglobin
134g/L
115-155
Hematocrit
0.41
0.35-0.45
Red Blood Cell
5.06 x 10^12/L
4.00-5.20
White Blood Cell
11.30 x 10^9/L
4.50-10.00
Mean Corpuscular Hgb
26pg
25-33
Mean Corpuscular Hgb Conc.
0.32
0.31-0.37
Mean Cell Volume
83fl
77-95
RDW
12.5
11.5-16.0
238 x 10^9/L
140-440
Neutrophil
0.82
0.56-0.66
Lymphocyte
0.14
0.22-0.40
Monocyte
0.04
0.04-0.06
Eosinophil
0.00
0.01-0.04
Basophil
0.00
0.00-0.01
Thrombocyte (Platelet)
Differential Count
Erythrocyte Morphology
Normocytic, Normochromic
Diagnostics: Clotting Factors, ESR
| November 15, 2013
Result
Reference Range
Prothrombin Time
Control
13.0 seconds
Patient
12.2 seconds
12.0-14.0
Percent (%) Activity
1.15
0.70-1.30
INR
0.92
Activated Partial Thromboplastin Time
Control
30.8 seconds
Patient
27.5 seconds
28.0-37.0
Result
Reference Range
10mm/hr
6-20
ESR
Diagnostics: Blood Chemistry
November 15, 2013
Result
Reference Range
Creatinine (Blood)
0.80mg/dL
0.41-0.58
Ionized Calcium
4.72mg/dL
4.48-5.26
135.00mmol/L
136.00-145.00
3.00mmol/L
3.50-5.10
105.00mmol/L
98.00-107.00
Sodium
Potassium
Chloride
Literature:
Biopsy on Brain Glioma
Biopsy is seldom performed outside
specialized biomedical research
protocols for DIPG, unless the
diagnosis of this tumor is in
doubt. Biopsy may be indicated
for brain stem tumors that are
focal or atypical, especially when
the tumor is progressive or when
surgical excision may be possible.
Childhood Brain Tumor Foundation
April 2010
If imaging findings are typical,
biopsy is not usually
necessary to confirm the
diagnosis and should only be
performed in the context of a
formal clinical trial
Diffuse Pontine Glioma, UpToDate
Nov 2013
Literature:
Biopsy on Brain Glioma
Biopsy in children with MR
findings of a diffuse intrinsic
tumor is controversial and is
not recommended
unless there is suspicion of
another diagnosis, such as
infection, demyelination,
vascular malformation,
multiple sclerosis, or
metastatic tumors.
Nelson’s Textbook of Pediatrics
19th Ed.
Stereotactic biopsy done for
clarifying a diagnostic imaging
in brainstem tumors is
important in obtaining a
definitive diagnosis with a
low rate of complications.
Perez, et al. “Stereotactic biopsy for
brainstem tumors in pediatric patients”,
Jan 2010
Literature:
Radiologic Imaging
• MRI is the neuroimaging standard for primary
brain tumors
– Both diagnostic and prognostic
– Help distinguishes between diffusely infiltrating and focal nodular
tumors
Ropper and Brown. 2005. Adam and Victor’s Principles of Neurology. 8th ed. New York: McGraw-Hill
Literature:
Magnetic Resonance Imaging
• Diffuse Type
– More common
– Mass effect with hypointense signal
on T1 and heterogenously
increased signal on T2
– Asymmetric enlargement of the
pons
Ropper and Brown. 2005. Adam and Victor’s Principles of Neurology. 8th ed. New York: McGraw-Hill
Adjunctive Diagnostics
• Tumors in the pituitary/suprasellar region,
optic path, and infratentorium
– Better delineation with MRI than with CT
• Tumors of the midline and the
pituitary/suprasellar/optic chiasmal region
– Evaluation for neuroendocrine dysfunction
• Tumors affecting the optic path
– Formal ophthalmologic examination: oculomotor function, visual
acuity, fields of vision
Kumar et. al. Nelson’s Textbook of Pediatrics, 19th Ed. New York: McGraw-Hill
Adjunctive
AdjunctiveDiagnostics
Diagnostics
• Suprasellar and pineal regions
– Preferential sites for germ cell tumors
– Serum and CSF B-HCG and AFP
• Tumors that spread to the leptomeninges
– Medulloblastoma/PNET, ependymoma, and germ
cell tumors
– Lumbar puncture and cytologic analysis of the CSF
Kumar et. al. Nelson’s Textbook of Pediatrics, 19th Ed. New York: McGraw-Hill
Patient’s MRI
• Impression:
– Brainstem mass lesion with
surrounding vasogenic edema.
Consider a glioma.
– No evidence of hydrocephalus or
herniation noted at this time.
Brainstem Glioma
Epidemiology, Etiology, Classification and
Pathogenesis
DisPONnect
A Case of Pontine Glioma
Epidemiology
• Brainstem Gliomas
– 10-20% of all CNS tumors in children
– More common in children than adults
• Diffuse Intrinsic Pontine Glioma (DIPG)
– Leading cause of brain tumor–related death in children
– 15% of all childhood brain tumors
– 58-75% of all brainstem tumors
Khatua, et al. 2011. Diffuse intrinsic pontine glioma – current status and future strategies. Child Nervous
System Journal. 27: 1391-97. Springer-Verlag.
Jallo, G. 2005. Brainstem gliomas. Child Nervous System Journal. 22: 1-2. November 2005.
Epidemiology
• Mean age at diagnosis is at 7 to 9 years
• Males and females equally affected
• USA: 200-300 children per year with this
diagnosis of which 60-75% are DIPG
• Incidence is greater in whites (18.52 per
100,000 person-years) than in blacks
• Philippines and India – low incidence countries
Khatua, et al. 2011. Diffuse intrinsic pontine glioma – current status and future strategies. Child Nervous
System Journal. 27: 1391-97. Springer-Verlag.
Jallo, G. 2005. Brainstem gliomas. Child Nervous System Journal. 22: 1-2. November 2005.
Brainstem Anatomy
Classification
• Localization
• Diffuse
– Diffuse Intrinsic
Pontine
• Non-Diffuse
– Focal (e.g. Tectal)
– Cervicomedullary
– Dorsal Exophytic
WHO GRADING SYSTEM FOR ASTROCYTOMA
Grade
Name
Histologic Features
I
Pilocytic
Astrocytoma
No pleiomorphic cells, low proliferative
potential
II
Low-Grade
Astrocytoma
Low cellularity, minimal atypia
III
Anaplastic
Astrocytoma
Anaplasia, Mitotic activity
IV
GBM
Microvascular proliferation
Pons
• Pontine tegmentum
• Cranial nerves V, VI, VII VIII
Diffuse Intrinsic Pontine Gliomas
•
•
•
•
80% of gliomas
Acute onset, high-grade
Rapid deterioration in 1-2 months
TRIAD:
– Multiple cranial nerve deficits (CN VI, CN VII
most common)
– Long tract signs
– Ataxia
• Late stage: invasion of adjacent levels of
brainstem and cerebellar peduncles
Midbrain
Focal Gliomas
•
•
•
•
•
5% of Gliomas
Can be located anywhere in brainstem
Most common: tectum of midbrain
Well-defined margins
Indolent course
Tectal gliomas: OBSTRUCTIVE hydrocephalus
Dorsal Exophytic Gliomas
• 10-15% of gliomas
• Arise from subependymal glial tissue in
floor of 4th ventricle
• Over 90%: Pilocytic Astrocytomas
• Grow along path of least resistance (4th
ventricle)
• Long history of nonspecific headache
and vomiting
• Long tract signs usually not present
Cervicomedullary Lesions
Medulla
• CN IX, X, XI, XII
Cervicomedullary Gliomas
•
5-10% of brainstem gliomas
•
Arise from the lower medulla or the
upper cervical spinal cord
•
Slow-growing, low-grade
•
Medulla: dysphagia, sleep apnea,
dysarthria, recurrent URTI
•
Cervical cord: chronic neck pain,
spasticity, weakness
•
Hydrocephalus: unusual in
cervicomedullary gliomas.
Molecular Genetics of Brainstem
Gliomas
• Platelet-derived growth factor
(PDGF) and its receptor (PDGFR):
major driving forces of
tumorigenesis
• Gain Poly (ADP-ribose)
polymerase (PARP-1)
• Epidermal growth factor receptor
(EGFR)
– Expression indicates high grade
tumor
• p53 mutations
Clinical Presentation
• Varied symptoms depending on the
location of the lesion
• Usually present with a short duration
of symptoms (<3 months)
• Common: abnormal or limited eye
movements, diplopia, asymmetric
smile, clumsiness, difficulty walking,
loss of balance, weakness
Clinical Presentation
• Classical Triad
1.
2.
3.
Multiple cranial neuropathies (77%)
Long tract signs (53%)
Cerebellar signs (87%)
• Cranial nerve palsies, long tract signs
(e.g. hemiparesis) and ataxia
– Over 50% of patients
• Hydrocephalus with elevated ICP
– Less than 10% of patients
• Intratumoral hemorrhage
– 6% of patients
Donaldson, et al. 2008. Advances toward an understanding of brainstem gliomas. Journal of Clinical
Oncology. 24 (8): 1266-72. American Society of Clinical Oncology.
Course in the Wards:
Therapeutics
DisPONnect
A Case of Pontine Glioma
Hospital Day 01
• Subjective/Objective
– Afebrile and with stable vital signs
– Awake and comfortable with no symptoms of headache,
vomiting, dizziness
– Still presented with a shallow nasolabial fold, right and
left-sided extremity weakness (4/5) with no deterioration
• Assessment
– Supratentorial Mass, r/o Malignancy
• Plan
– Monitored every 4 hours and maintained on strict
aspiration precautions
Hospital Day 02: AM
• Subjective/ Objective
– Afebrile with stable vital signs
– Awake and comfortable
– Previously mentioned symptoms of right shallow nasolabial fold and
extremity weakness were noted to have progressed, from a 4/5 to 1/5;
intact extraocular muscles, (-) gag reflex
– MRI results revealed brainstem mass lesion, possibly glioma
• Assessment
– t/c Brainstem Glioma
• Plan
–
–
–
–
–
Referral to Oncology service
IVF D5NL (based on maintenance)
Dexamethasone 40mg/IV every eight hours
Additional monitoring through pulse oximetry
Stand-by intubation was ordered and a request for a family conference
was initiated
Hospital Day 02: PM
• Subjective/Objective
– Patient had throbbing frontal headache, spontaneously
resolving, with 2 episodes of vomiting, non-bilious, nonprojectile
– Patient was noted to have 94% oxygen saturation at room air
• Assessment
– t/c Brainstem Glioma
• Plan
– Oxygen support via nasal cannula at 2lpm
– Mannitol 20% (50ml) was started every 8 hours and monitoring
was changed to every 2 hours
– Neurosurgery was called upon for further evaluation but was
eventually deferred
Hospital Day 03
• Subjective/Objective
– Improvement in the severity of the headache, no
recurrence of vomiting
– Afebrile with stable vital signs
– No progression of neurologic symptoms
• Assessment
– Diffuse Pontine Glioma
• Plan
– Family Conference
Family Conference
• Attendees: Attending Physician, Pediatric Oncologist,
Pediatric Resident, Patient’s Parents, Sister and two
Aunts
• Diagnosis and prognosis were disclosed to the family
members and pertinent points discussed included the
different options for the patient including surgery,
radiation, chemotherapy and palliative care.
• After discussion, patient’s family arrived at a
consensus and opted to give the patient a good
quality of life and asked for a referral to palliative care
and subsequent home care.
Hospital Day 04
• Subjective/Objective
– Patient more comfortable
– Able to tolerate feedings of soft, pureed foods with no
difficulty in breathing
– Still with left-sided extremity weakness, without
progression
• Assessment
– Pontine Glioma
• Plan
– Further discussion and action with palliative care
– Patient was deemed fit for discharge
Therapeutic Options
DisPONnect
A Case of Pontine Glioma
Surgical Resection
CONCLUSION:
Surgery is advocated for patients with well delineated, posteriorly,
posterolaterally and ventrolaterally located tumors having slow
progression and relative preservation of motor power
Chemotherapy
FINDINGS:
• 43 patients with a defined clinico-radiological diagnosis of DIPG
treated with radiotherapy + Temozolomide (75mg/m2), after
which up to 12 courses of 21 days of adjuvant Temozolomide
(75-100mg/m2) were given 4x weekly
Chemotherapy
FINDINGS:
• Overall survival: 56%
• Median survival: 9.5months
• 2 year survivors: 5 (median age of 13.6years at diagnosis)
• No survival benefit of the addition of dose dense temozolomide, to
standard radiotherapy in children with classical DIPG.
• Further exploration: Prolonged survival in adolescents
Chemotherapy
FINDINGS:
• Time to tumor progression and survival times are longer than
those previously reported in other DPG series
• Arguments for therapeutic benefits:
– Stable disease
– Partial responses in DPG on MR imaging
– Enhanced delivery of chemotherapy afforded by osmotic
BBBD supports the further examination of this treatment
modality for patients with DPG.
Immunology
FINDINGS:
• VAE can be used as a novel virus-gene therapy strategy
for glioma since it significantly inhabits GSC activity
– Expression of exogenous Endo-Angio fusion gene can inhibit
HBMEC proliferation.
Immunology
FINDINGS:
• Amplification of the D-type cyclins and CDK4/6
• Loss of Ink4a-ARF leading to aberrant cell proliferation
• Targeting: cyclin-CDK-Retinoblastoma pathway in a genetically
engineered PDGF-B-driven brainstem glioma mouse model
Immunology
FINDINGS:
• 7-day treatment course with PD significantly prolonged survival
by 12% in the PDGF-B; Ink4a-ARF deficient BSG model.
• Furthermore, a single dose of 10 Gy radiation therapy followed
by 7 days of treatment with PD increased the survival by 19% in
comparison to RT alone.
Radiation Therapy
• External Radiation Therapy
– Uses a machine outside the body to send radiation toward the cancer
• Internal Radiation Therapy
– Uses a radioactive substance sealed in needles, seeds, wires, or
catheters that are placed directly into or near the cancer
Methods of Radiation
• Conformal Radiation
Therapy
– Creates a 3D picture of the
tumor and customizes
radiation beams to fit the
tumor, allowing precise and
high dose radiation to reach
its target
Methods of Radiation
• Hyperfractionated Radiation Therapy
– Total dose of radiation is divided into small doses
and given more than once in a day.
Other Treatment Options
CONCLUSION:
We conclude that r beta IF plus hyperfractionated therapy
can be tolerated by children with newly diagnosed brain
stem gliomas, although there is occasional dose-limiting
hepatic, blood, and central nervous system toxicity. This
therapy did not result in a higher rate of disease control.
Other Treatment Options
CONCLUSION:
The major conclusion from this trial is that the hyperfractionated
method of Rx 2 did not improve event-free survival (p = 0.96)
nor did it improve survival (p = 0.65) over that of the
conventional fractionation regimen of Rx 1, and that both
treatments are associated with a poor disease-free and survival
outcome.
Future Management
CONCLUSION:
IFN-beta gene therapy following tumor cell lysate-pulsed dendritic cells
immunotherapy resulted in a significant prolongation in survival of the mice.
Moreover, when this combination was performed twice, 50% of treated mice
survived longer than 100 days. Considering these results, this combination
therapy may be one promising candidate for glioma therapy in the near
future.
Brainstem Glioma
Complications, Prognosis, Prevention
DisPONnect
A Case of Pontine Glioma
Complications
Cognitive Dysfunction
• J Neurooncol. 2013 Sep;114(3):339-44. Epub 2013 Jun 29. Clinicoradiologic characteristics of long-term survivors of diffuse intrinsic
pontine glioma. Jackson S, Patay Z, Howarth R, Pai Panandiker AS, OnarThomas A, Gajjar A, Broniscer A
• Three of four patients who underwent a detailed evaluation showed
cognitive function in the borderline or mental retardation range.
Complications
Behavioral Change
• J Neurooncol. 2006 May;77(3):267-71. Epub 2005 Nov 29. Pathological
laughter and behavioural change in childhood pontine glioma. Hargrave
DR, Mabbott DJ, Bouffet E.
• A report on nine children who either at the time of presentation or
progression demonstrated marked behavioural changes manifesting as
either "pathological laughter" or separation anxiety in the form of school
refusal.
Complications
Locked-In Syndrome
• Childs Nerv Syst. 1993 Aug;9(5):256-9. Pontine gliomas causing locked-in
syndrome. Masuzawa H, Sato J, Kamitani H, Kamikura T, Aoki N.
• A review of 8 children who died of pontine gliomas
• All children became mute and quadriplegic with cranial nerve palsies with
the oldest child, (17yo), unquestionably showing classical locked-in
syndrome for the last 4 months.
• Six of the remaining 7 (average 5 yo), while labeled as semi-comatose,
responded to calling by blinking and/or vertical eyeball movement.
Complications
Radiation Necrosis
Hypopituitarism/Hypothyroidism
Bone Marrow Suppression
Prognosis
• Survival period is shorter in children who
presented with cranial nerve palsies (more
likely to have malignant tumors)
• Children with histologically malignant tumors
had poorer outcomes
– Best Survival Time: presence of Rosenthal fibers
and calcification
– Poor Survival Time: presence of mitoses
• Decreased survival associated with two CTScan features:
– Hypodense tumor prior to contrast
– Tumor involving the entire brainstem
Albright et al. Prognostic factors in pediatric brainstem gliomas. Journal of Neurosurgery. 1986. 65 (5):
751-755
Prognosis
• Median Survival Duration: 9-12
months even with treatment
Time
Survival Rate
1 Year
37%
2 Year
20%
3 Year
13%
Brainstem Glioma
Biopsychosocial Impact: Palliative Care
DisPONnect
A Case of Pontine Glioma
Factors that Place Families at
High-Risk
• Single parents or two parent families functioning at a single
parent family
• Preexisting chronic health or mental health problems
• Economic problems: rural or urban poor: overextended
middle-class families (debts): Job loss and minimal or no
health insurance
• Seperation, divorce
• Chronic Unresolved Conflicts
• Language difference: immigrant, foreign national,
significantly different subculture
• Families away from their cultural support network because
of the child’s need for medical treatment
Initial Diagnostic Period:
A Time of Crisis
• Family’s Reaction to Diagnosis
– Shock, disbelief, guilt, anger, and fear
– As the diagnosis is accepted, anger and guilt
become significant emotions
Initial Diagnostic Period:
A Time of Crisis
• Family’s Reaction to Diagnosis
– An important task is to decide about telling the
child about his or her diagnosis
Child’s Reaction to Diagnosis and
Treatment
• School-Age Children
– Immediate concerns revolve around
hospitalizaton, separation from parents, and fear
of medical procedures
– Constant reassurance is needed
– Behavioral interventions may be necessary to gain
cooperation
Child’s Reaction to Diagnosis and
Treatment
• School-Age Children
– May have delayed or immediate reactions
•
•
•
•
•
Psychosomatic complaints
Nightmares
Labile emotions
Regressions
Stoic, adult-like acceptance
Child’s Reaction to Diagnosis and
Treatment
• School-Age Children
– More likely to be verbal about their illness
– Developmental period of vigorous inquiry
Child’s Reaction to Diagnosis and
Treatment
• School-Age Children
– A special physician-child education session may be
necessary
• Can enhance compliance with procedures and
treatment
– Major activity outside the home is school, may
help towards having some “normalcy”
Treatment and Adaptation
Period
• Normalcy is emphasized
• “Burden of Normalcy” is created
– The family has to reorganize itself but seem
“normal”
Talking to the Dying Child
• Two modes of Communicaton
– Protective Approach
– Open Approach
Talking to the Dying Child
• “Understanding, acceptance, and convetance
of permission to discuss any aspect of the
illness decreases feelings of isolation and
alienation from parents and other meaningful
adults and gives the child the sense that his or
her illness is not too terrible to discuss.”
Talking to the Dying Child
• Common questions
– “Am I going to die”
• If yes, then
–
–
–
–
“When?”
“What will death be like?”
“What will happen to me after I die?”
“Will the “bad things” I have done or thought case
me to be punished?”
– “Will my parents be all right?”
– “When can I be with my family again”
– “Will it hurt when I die?”
End of Life Challenges: On Active
and Passive Euthanasia
• “Helping a child on his way” and “Ending a
child’s suffering”
– Open discussion does not yet warranted to
chidren
• Active euthanasia: Implies unwarranted
assumption of infallibility on the part of the
physician
• Children should not be allowed to die in agony
Bereavement in the Family
• “... More intense grief reactions of somatic
types, greater deression, anger and guilt with
accompanying feelings of despair”
Bereavement in the Family
• Parents suffer from both the loss of the child
and the loss of what the child represented to
them.
Bereavement in the Family
• Better adjustement if:
– With Viable and ongoing “significant other”
– Open and responsive communication with child
during illness
– Those with consistend life philosophies
Bereavement in the Family
• Siblings should also be informed
– Tailored to developmental ages
• Follow-up counseling should be offered
Update on AS
DisPONnect
A Case of Pontine Glioma
Thank You.
“Life is not measured by the breaths we take,
but the moments that take our breath away.”
Hillary Cooper
DisPONnect
A Case of Pontine Glioma