A Case of Pontine Glioma

A Case of Pontine Glioma
DisPONnect A Case of Pontine Glioma The Medical City | Department of Pediatrics ASMPH Interns – Group 2

Outline 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

Inarticulation (Nabubulol at Nagba-babytalk)
Chief Complaint Inarticulation (Nabubulol at Nagba-babytalk)

Patient History 3 Weeks PTA Asymmetrical changes in smile
Lopsided, with almost no movement on the right Mild-moderate throbbing frontal headache once a week 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 9 Days PTA Sudden changes in articulation
“Baby talk” Slurring of speech No other associated symptoms No consult done

Patient History 6 Days PTA Persistence of symptoms
Sudden episodes of drooling Dysphagia Difficulty swallowing food with choking episodes No other associated symptoms No changes in sensorium No consult done

Patient History 4 Days PTA Weakness of the left lower extremity
Difficulty wearing left slipper Dragging of left foot Drunken gait Inability to articulate No other symptoms Admission Persistence of symptoms led to consult with AP Advised admission

Review of Systems General HEENT Respiratory Cardiovascular
(+) 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 No cough, hemoptysis, sputum production, difficulty breathing. Cardiovascular No chest pain, palpitations, orthopnea, cyanosis, pallor and easy fatiguability. Gastrointestinal No abdominal pain, vomiting and loose stools. Genitourinary No dysuria, frequency, hematuria, nocturia. Skin No pruritus, rashes, dryness, color changes. Musculoskeletal No muscle or joint pain. Neurologic See HPI

Past Medical History Past Illnesses Hospitalizations Surgeries Trauma
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 Nutritional 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 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)

Days Immediately Prior to Illness
24-Hour Food Recall Regular Days Days Immediately Prior to Illness Breakfast 1c rice, 1 egg, 1pc hotdog 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) Lunch 1c rice, ½c chicken adobo Snack 1 cheese sandwich Dinner 1c rice, 1 pork chop

Immunization History Vaccine Complete Incomplete None Unknown BCG X
DPT/Polio (1-2-3 booster 1-2) Hemophilus influenza B (HIB) (1-2-3 booster) Hepatitis B (1-2-3) MMR (1-2) Measles (1) Varicella (1) Pneumococcal (1-2-3 booster) Influenza Rotavirus (1-2) Hepatitis A (1-2) Typhoid

History of Childhood Developmental History Grade 3 Student
Personal and Social History Gross Motor 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 Grade 3 Student 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 High Mother and Father both regularly check up on the health status of the patient Decision making regarding patient’s health concerns is largely decided by the parents and the maternal aunt Mid Mother and Father are worried about , but not fully aware of the possible severity of the patient’s condition Father Primary Breadwinner Brothers and Sisters Secondary Breadwinners, Social Support Moderate High Father regularly checks up on the health status of the patient Decision making regarding patient’s health concerns is largely decided by the parents Siblings are worried about, but not fully aware of the possible severity of the patient’s condition Maternal Aunt Secondary Caregiver, Decision-Maker 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 Vital Signs General Survey
Weight: 34.5kg Z-score (0,2) Height: 138cm BMI: 18.11kg/m2 Vital Signs BP: 118/76mmHg HR: 82bpm RR: 20cpm Temperature: 36.5C Pain: 0/10 General Survey Awake, Alert Not in CardioRespiratory Distress GCS 15

Physical Examination Eyes: Skin: Ears:
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 Throat Neck
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 Cardiovascular Abdomen
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 Extremities
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 Pupils equally reactive to light and accomodation III, IV, and VI Intact EOM movement along all cardinal positions of gaze

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

Extremity Strength Sensation Right Upper Extremity 5/5 100% Left Upper Extremity 4/5 Right Lower Extremity Left Lower Extremity

++ ++ ++ ++ ++ ++ No Flaccidity or Rigidity No Atrophy or Hypertrophy ++ ++

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 OBJECTIVE 8-year old female
No history of neurologic disease 3 week history of right-sided facial weakness 6 day history of drooling, dysphagia and slurred speech Left-sided weakness Unstable gait 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 Rizzy’s part Is there a lesion?
Where is the lesion? What is the lesion? Rizzy’s part

Developmental/ Congenital
What is the Lesion? Vascular Infectious/ Inflammatory Trauma/ Toxins Autoimmune Metabolic Idiopathic Neoplastic Developmental/ Congenital

What is the Lesion? Stroke in the Young Vascular Infectious Neoplastic
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 Vascular Infectious Neoplastic

Arteriovenous Malformation
What is the Lesion? Arteriovenous Malformation 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 History of ipsilateral seizures and migraine-like headaches Ruptured AV malformation: severe headache, vomiting, nuchal rigidity, progressive hemiparesis, and seizure Vascular Infectious Neoplastic Result from failure of normal capillary bed development between arteries and veins during embryogenesis

What is the Lesion? Aneurysm Vascular Infectious Neoplastic
Usually asymptomatic 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 Ruptured aneurysms: intense headache, nuchal rigidity, coma, intracerebral hemorrhage and progressive hemiparesis Vascular Infectious Neoplastic

What is the Lesion? Meningitis Vascular Infectious Neoplastic
Acute infection of the central nervous system (CNS) 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 Vascular Infectious Neoplastic Italicized – present in the patient Acutely - (symptoms evolving rapidly over 1-24 hours) Subacutely - (over 1-7days) Chronic - (>1week)

What is the Lesion? Brain Lesion Vascular Infectious Neoplastic
Most common in children 4 -8 years old 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 Vascular Infectious Neoplastic Italicized – present in the patient

What is the Lesion? Primary CNS Lesion Metastatic 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 Vascular Infectious Neoplastic Metastatic Lesion Italicized – present in the patient 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:

Cranial Nerve IX and X Palsy Dysarthria, drooling, dysphagia
Absent Gag Reflex Left-sided Motor Weakness Weak left side: dragging left foot Motor: 4/5, Left Cerebellar Signs “Drunken” gait Dysmetria, Dysdiadochokinesia, left Central Facial Palsy, Right Right-sided weak smile Shallow nasolabial fold, right

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
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

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 Fiber Tracts
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

Brainstem Lesion, Possibly Pontine
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
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

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 ESR is said to be nonspecific because increased results do not tell the doctor exactly where the inflammation is in the body or what is causing it, and also because it can be affected by other conditions besides inflammation. For this reason, the ESR is typically used in conjunction with other tests. Adams et al., 2003; European Stroke Initiative Executive Committee and the EUSI writing committee, 2003

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 Hematocrit 0.41 Red Blood Cell 5.06 x 10^12/L White Blood Cell 11.30 x 10^9/L Mean Corpuscular Hgb 26pg 25-33 Mean Corpuscular Hgb Conc. 0.32 Mean Cell Volume 83fl 77-95 RDW 12.5 Thrombocyte (Platelet) 238 x 10^9/L Differential Count Neutrophil 0.82 Lymphocyte 0.14 Monocyte 0.04 Eosinophil 0.00 Basophil Erythrocyte Morphology Normocytic, Normochromic

Diagnostics: Clotting Factors, ESR | November 15, 2013
Result Reference Range Prothrombin Time Control 13.0 seconds Patient 12.2 seconds Percent (%) Activity 1.15 INR 0.92 Activated Partial Thromboplastin Time 30.8 seconds 27.5 seconds Result Reference Range ESR 10mm/hr 6-20

Diagnostics: Blood Chemistry November 15, 2013
Result Reference Range Creatinine (Blood) 0.80mg/dL Ionized Calcium 4.72mg/dL Sodium 135.00mmol/L Potassium 3.00mmol/L Chloride 105.00mmol/L

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 No consensus on the Use and value of biopsy *DIFFUSE INTRINSIC PONTINE GLIOMA Unless the clinical or imaging picture is atypical, surgery is usually not recommended in children with a clinical diagnosis of diffuse brainstem glioma outside of formal clinical trials [37]. The morbidity associated with surgery in this eloquent region of the brain and the sampling error associated with biopsies preclude routine biopsy to identify patients with lesions that are not high-grade astrocytomas [10,38,39]. Pontine biopsy should only be performed by surgeons with expertise in this procedure and in the context of a clinical trial where the analysis will influence therapy [34].

Literature: Biopsy on Brain Glioma
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 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.

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 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 which reflects edema and tumor infiltration. Ropper and Brown 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 however, lumbar puncture is contraindicated in individuals with newly diagnosed hydrocephalus secondary to CSF flow obstruction or in individuals with infratentorial tumors. Lumbar puncture in these individuals may lead to brain herniation, resulting in neurologic compromise and death. Kumar et. al. Nelson’s Textbook of Pediatrics, 19th Ed. New York: McGraw-Hill

Adjunctive 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 however, lumbar puncture is contraindicated in individuals with newly diagnosed hydrocephalus secondary to CSF flow obstruction or in individuals with infratentorial tumors. Lumbar puncture in these individuals may lead to brain herniation, resulting in neurologic compromise and death. Kumar et. al. Nelson’s Textbook of Pediatrics, 19th Ed. New York: McGraw-Hill

Patient’s Reading Multiplanar examination of the brain showed an enlarged brainstem with a fairly to well-defined isointense to hypointense T1W and heterogenously hyperintense T2W mass in the pon with surrounding edema extending into the cerebellar peduncles, medulla, and lower midbrain. It measures 3.3 x 3.3 X 2.7 CM (CC X W X AP). A portion of the mass in its right anteroinferior aspect exhibit thick rim enhancement with minimal central area of necrosis or hemorrhage measuring 1.2 x 1.4 x 3.4 cm. The rest of the mass exhibit no significant contrast enhancement. The anterior fourth ventricle is slightly indented.ß

Patient’s MRI Impression:
Brainstem mass lesion with surrounding vasogenic edema. Consider a glioma. No evidence of hydrocephalus or herniation noted at this time. Multiplanar examination of the brain showed an enlarged brainstem with a fairly to well-defined isointense to hypointense T1W and heterogenously hyperintense T2W mass in the pon with surrounding edema extending into the cerebellar peduncles, medulla, and lower midbrain. It measures 3.3 x 3.3 X 2.7 CM (CC X W X AP). A portion of the mass in its right anteroinferior aspect exhibit thick rim enhancement with minimal central area of necrosis or hemorrhage measuring 1.2 x 1.4 x 3.4 cm. The rest of the mass exhibit no significant contrast enhancement. The anterior fourth ventricle is slightly indented.ß

Brainstem Glioma Epidemiology, Etiology, Classification and Pathogenesis DisPONnect A Case of Pontine Glioma

Epidemiology Brainstem Gliomas Diffuse Intrinsic Pontine Glioma (DIPG)
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 References: Brainstem gliomas in adults: prognostic factors and classification. Guillamo JS, Monjour A, Taillandier L, Devaux B, Varlet P, Haie-Meder C, Defer GL, Maison P, Mazeron JJ, Cornu P, Delattre JY, Association des Neuro-Oncologues d'Expression Française (ANOCEF). Brain. 2001;124(Pt 12):2528. Pubmed. Journal of Child Neurology Nov;24(11): doi: / Epub 2009 Jul 28. Pediatric high-grade gliomas and diffuse intrinsic pontine gliomas. Fangusaro, J. Joint Meeting of the Pediatric and Oncologic Drugs Advisory Committee. FDA. April 27, An Overview of Pediatric High-Grade Gliomas and Diffuse Intrinsic Pontine Gliomas. Rishi R. Lulla and Jason Fangusaro. Khatua, et al Diffuse intrinsic pontine glioma – current status and future strategies. Child Nervous System Journal. 27: Springer-Verlag. Jallo, G 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: 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 References: Brainstem gliomas in adults: prognostic factors and classification. Guillamo JS, Monjour A, Taillandier L, Devaux B, Varlet P, Haie-Meder C, Defer GL, Maison P, Mazeron JJ, Cornu P, Delattre JY, Association des Neuro-Oncologues d'Expression Française (ANOCEF). Brain. 2001;124(Pt 12):2528. Pubmed. Journal of Child Neurology Nov;24(11): doi: / Epub 2009 Jul 28. Pediatric high-grade gliomas and diffuse intrinsic pontine gliomas. Fangusaro, J. Joint Meeting of the Pediatric and Oncologic Drugs Advisory Committee. FDA. April 27, An Overview of Pediatric High-Grade Gliomas and Diffuse Intrinsic Pontine Gliomas. Rishi R. Lulla and Jason Fangusaro. Khatua, et al Diffuse intrinsic pontine glioma – current status and future strategies. Child Nervous System Journal. 27: Springer-Verlag. Jallo, G Brainstem gliomas. Child Nervous System Journal. 22: 1-2. November 2005.

Brainstem Anatomy Three connected parts: midbrain, pons and medulla
-serve as conduit through which axonal tracts pass to the spinal cord, cerebrum or exit as cranial nerves Neurologic deficits resulting from brainstem tumors result from mass effect or invasion of white matter tracts or nuclei

WHO GRADING SYSTEM FOR ASTROCYTOMA
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 Gliomas can also be Ganglioma (WHO Grade I) Focal, dorsal exophytic and cervicomedullary gliomas are usually pilocytic astrocytoma (WHO grade I) and fibrillary astrocytoma (WHO grade II). Brainstem gliomas are typically astrocytomas. Other low-grade gliomas with indolent growth such as ganglioglioma are also seen. DIPGs are typically anaplastic astrocytoma (WHO grade III) and glioblastoma multiforme (WHO grade IV). Growth of low-grade gliomas typically respect fiber tracts and pial borders. In contrast, high-grade gliomas grow and expand without respecting anatomic boundaries of these surrounding tissues.

Pons Pontine tegmentum Cranial nerves V, VI, VII VIII
Gray matter structures in pontine tegmentum: trigeminal (V), abducens (VI), facial (VII) and vestibulocochlear (VIII) CN nuclei Nuclei of trigeminal nerve: large (motor nuclei in pons and sensory nuclei extending fr midbrain to upper cervical spinal cord) Three divisions of trigeminal nerve exit the lateral pons superior to middle cerebellar peduncle Motor nucleus controls muscles of mastication while larger sensory components distribute to face, mouth, nasal cavity, orbit, anterior half of scalp, and dura matter Cranial nerves VI, VII, VIII exit the brainstem anteriorly near pontomedullary junctions Abducens nerve prone to injury because it has the longest intracranial course passing between 2 layers of dura on floor of posterior fossa to cavernous sinus, and innervates the LR muscle after passing through the superior orbital fissure Injury to abducens nerve: horizontal diplopia Injury to facial nerve: ipsilateral facial weakness and loss of corneal reflex when lesion is peripheral Seventh nerve injury proximal or in cerebellopontine angle, ipsilateral hyperacusis, absent taste sensation in anterior tongue and disturbed secretion of tears and saliva are present Because of anatomic location: difficult to obtain tissue for histopathologic confirmation of tumor type and grade

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 Multiple cranial nerve deficits Bilateral and multiple cranial nerve involvement is frequent in DIPG. Abducens (CN VI) palsy is the most frequent cranial neuropathy at presentation Facial palsy is also frequently seen at initial presentation. Involvement of CN VIII causes deafness and contributes to ataxia. Lower cranial nerve involvement causes aspiration, and difficulty in speech, swallowing and maintaining normal head positions. Long tract signs often present with severe limb weakness and hyperreflexia, resulting in their difficulty to walk and sometimes even to sit. Long tract involvement also causes loss of tactile, nociceptive and proprioceptive sensations, causing numbness and contributing to ataxia. Ataxia CN VIII involvement and loss of proprioceptive sensation contribute to ataxia. Invasion of cerebellar peduncles is also common in DIPG, which is another factor contributing to ataxia. At least two of the triad need to be present along with MRI evidence to establish the diagnosis of DIPG Other symptoms DIPG patients, both DIPG patients may also have other symptoms including headache, nausea and vomiting etc. indicating increased intracranial pressure from edema or hydrocephalus. Approximately 10% of DIPG patients have hydrocephalus at initial presentation grow unhindered along the medullary axis both rostrally and caudally, without involving the fourth ventricle (Epstein and Farmer 1993). The expansion of a high-grade tumor is not contained or controlled by the surrounding tissue matrix. At autopsy, the vast majority of DIPGs are high-grade and more than 50% have disseminated within the neuraxis Fibrillary, presence of nuclear atypia, scant cytoplasm and microcysts

Midbrain periaqueductal gray circumferential around aqueduct of Sylvius and reticular formation in the tegmentum Oculomotor (III) and trochlear nuclei (IV) reside in the midbrain (third nerve exits ventrally from the medial spects of the crus cerebri in the interpeduncular fossa) Lesions of oculomotor nerve result in external strabismus, ptosis, and dilation of the pupil from loss of parasympathetic innervation of the radial muscles of the iris Fourth cranial nerve: exits the posterior brainstem near the lower margin of inferior colliculus (failure of downwardgaze when eye turned to the nose), may complain of vertical or skew (diagonal) diplopia Tectum of midbrain: dorsal to the aqueduct of Sylvius and contains nuclei within the superior and inferior colliculi, which participate in visual and auditory processing

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 Obstructive hydrocephalus: due to compression of cerebral aqueduct (signs of increased ICP: nausea, vomiting, diplopia, papilledema) Less frequently, patients with tectal lesions will have frank extraocular movement dysfunction including Parinaud syndrome (paralysis of upgaze, lid retraction, convergence nystagmus, and pupils that react better to accommodation than to light). medullary glioma or midbrain tegmental glioma: usually larger, present with CN dysfunction, ataxia, long tract signs

Reticular Formation Reticular formation: extends the length of dorsal brainstem: controls vital functions such as BP and respiration, regulates general level of alertness

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 increased ICP including headache, nausea and/or vomiting, lethargy, downward gaze preference, changes in vision and cranial nerve palsies (including abducens palsy). infants: failure to thrive grows posteriorly, filling the fourth ventricle, only about 10% of tumor mass growth occurs in brainstem, which is spared for a long time and results in very gradual progression of symptoms

Cervicomedullary Lesions
Because of rostral and caudal anatomic barriers, the tumor grows toward the avenue of least resistance, which in this region is the floor of the fourth ventricle, thus becoming dorsally exophytic (Fig. 3.1 ) (Epstein and Farmer 1993) . Cervicomedullary tumors originate within the upper cervical cord below the cervicomedullary barrier. Caudal growth is limited by the circumferential pia of the upper cord and follows a cylindrical shape, similar to spinal cord tumors. Rostral growth is limited by the crossing fibers of the low medulla, and thus directs the growth toward the least resistant area, the obex, which is the midline point of the dorsal medulla that marks the caudal angle of the fourth ventricle (Fig. 3.2 ) (Epstein and Farmer 1993) . From there the tumor may rupture through the obex into the fourth ventricle and cause obstructive hydrocephalus.

Medulla CN IX, X, XI, XII involve lower cranial nerves and can cause respiratory difficulties (including apnea), recurrent URTIs or s wallowing difficulties and aspiration of food and saliva dorsal sensory nuclei and nucleus ambiguous, in the anterolateral part of the reticular formation Motor fibersfrom this nucleus leave the medulla as fibers of the glossopharyngeal nerve (IX), vagus (X) and bulbar accesory (XI)nerves Lesions of these nerves affect swallowing and vocalization and exit the medulla in the dorsolateral medullary groove Hypoglossal nucleus (XII) located medially in the inferior medulla and innervates ipsilateral striated muscle of the tongue after exiting from the ventrolateral medullary groove. Dorsal motor nucleusof the vagus nerve: located lateral to hypoglossal nucleus and important part of the parasympathetic ervous system Inferior vestibular nuclei (VIII) positioned dorsolateral in the medullar near anterior fourth ventricle

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. Medulla: failure to thrive secondary to nausea, vomiting or dysphagia, also with sleep apnea, dysarthria and recurrent upper respiratory tract infections. Cervical cord: chronic neck pain and/or progressive myelopathy with spasticity and weakness Tumors with epicenters in the upper cervical cord grow dorsally into the cisterna magna. Those with epicenters in the lower medulla grow centrifugally as focal nodules. Failure to thrive is commonly encountered in infants with tumors of the cervicomedullary junction due to lower cranial nerve dysfunction resulting in swallowing difficulties.

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 Expression of EGFR was reported in the majority of high grade and less than 20% of low grade DIPG by immunohistochemistry staining [27]. The same study also reported that 25% of grade III and 50% of grade IV tumors had EGFR gene amplification. Recent data show that strong EGFR immunohistochemistry staining was seen in about 27% cases [23], lower than in the earlier report, and that amplification rate of the EGFR gene is also much lower (about 7-9%) [23, 25]. Approximately 50% of DIPG had p53 mutation [29,30] and three groups reported loss of a region of 17p containing the p53 gene in 31%, 57% and 64% cases, respectively [23, 28, 31]. In approximately 50% of DIPG patients, allelic loss of a region of 10q where PTEN is located was observed [31-33]. While the etiology and exact pathophysiology of DIPG remain to be determined, critical pathways and potential treatment targets have been identified, and critical conclusions can be drawn: (1) pediatric DIPGs differ from adult high-grade gliomas, (2) pediatric DIPGs differ from pediatric supratentorial high-grade gliomas, (3) genomic studies of DIPG demonstrate aberrations in druggable targets, (4) significant interpatient and intrapatient variability exists, and (5) the tumor microenvironment appears to play a key role in DIPG tumorigenesis. An intriguing characteristic of DIPG is the predominant age group affected, with a peak incidence in middle childhood, suggesting an etiology associated with development. In efforts to define a potential cell of origin, Monje et al. (2011) examined the spatial and temporal distribution of neural precursor cells in the human brainstem. They described a distinct cell population in the ventral pons that is Nestin and Vimentin immunopositive (both markers of primitive neuroectodermal cell types in the developing and post-natal CNS); approximately half of these cells are also positive for the basic helix-loop-helix transcription factor Olig2 (classically associated with oligodendroglial lineage precursor cells). They demonstrated that the density of this Nestin+ Vimentin+ Olig2+ cell type normally changes during childhood. It is present in all ventral brainstem structures during infancy, decreases by 2 years of age, and then increases again during middle childhood. What regulates the changing density of this cell population in humans is unknown. However, using a mouse model, Monje et al. (2011)determined that Hedgehog signaling drives proliferation of Olig2+ cells in the ventral pons of mice. In addition, Hedgehog activity and Hedgehog-responsive cells increased in the ventral pons of the mouse during the time period corresponding to middle childhood in humans. These studies suggest that the nature of neural precursor cells in the ventral pons and the microenvironment within the developing brain may influence the disease process. Puget et al. (2012) also implicated the Sonic Hedgehog pathway in a trial in which they performed genomic studies on a large number (n = 61) of newly diagnosed children with DIPG. In this study, DIPG was distinguished from high-grade gliomas by several genes involved in the Sonic Hedgehog pathway. The authors suggest that the gene expression signatures of DIPG were associated with “differential reprogramming of embryonic signaling organizers.” They demonstrated involvement of two distinct oncogenic pathways that resulted in two biological DIPG subgroups, including one group with an oligodendroglial phenotype that was associated with PDGFRA gain or amplification, and another group referred to as the mesenchymal and pro-angiogenic phenotype that was associated with higher expression of STAT3. Both the Monje and Puget studies implicate altered gene expression during development as potentially key steps in DIPG pathogenesis. Histones play an important role in gene regulation, influencing chromatin structure and accessibility, and post-translational modifications of the histone tail play a role in epigenetic regulation of gene expression. Notably, two recent studies demonstrated somatic mutations in histone H3.3 associated with DIPG (Khuong-Quang et al., 2012; Wu et al., 2012). Wu et al. (2012) performed whole genome sequencing on DNA of seven patients with DIPG and showed that four of these seven had a mutation in H3F3A (the gene that encodes the H3.3 protein) or HIST1H3B (gene which encodes H3.1) that resulted in a K27M substitution (lysine replaced by methionine at amino acid 27). They expanded this study in 43 additional DIPG patients and found that 78% of DIPG patients demonstrated K27M substitutions in H3F3A or HIST1H3Bcompared to only 22% of non-brainstem glioma patients. Similarly,Khuong-Quang et al. (2012) demonstrated that 71% of 42 DIPG patients had the K27M mutation compared to 14% of supratentorial glioblastomas. They also noted that patients with wild type H3.3 had better overall survival. Interestingly, H3.3 is located on Chromosome 1q, an area commonly gained in DIPG (Barrow et al., 2011; Warren et al., 2011c). However, in the study by Wu et al. (2012), there was no significant correlation between the presence of H3F3A mutations and gain of chromosome 1q. Lysine 27 of the histone H3 tail is also a key residue for epigenetic regulation of neural precursor cell differentiation (Liu and Casaccia, 2010). Several genomic studies have identified a number of chromosomal aberrations and targets in DIPG, including PDGFRA, MDM4, MYCN, EGFR, MET, KRAS, CDK4, amongst others (Paugh et al., 2010, 2011;Zarghooni et al., 2010; Barrow et al., 2011; Warren et al., 2011c; Grill et al., 2012; Li et al., 2012). Not surprisingly, many of the identified aberrations involve genes that regulate cell growth, cell death, and repair pathways. Rather than describe each of these in detail, it is important to realize that, although these studies significantly contribute to our knowledge and understanding of the biology of DIPG, the number of samples is relatively small. The glaring fact is that no one target is identified in all tumor cells of all patients with DIPG. Treating a single target will therefore unlikely result in a significantly improved outcome for these patients. Indeed, clinical trials evaluating individual molecularly targeted agents have been performed in children with DIPG without success. Precise reasons for the lack of efficacy are unknown, but in most, if not all, studies, it is unknown if the target was expressed, was insufficiently expressed, or whether drug exposure at the target site was adequate. Presumably, combinations of several targeted agents will be necessary to observe an effect given the multiple chromosomal alterations found in individual patient samples.

Slurring of speech and inarticulation (CN IX, X) Drooling Dysphagia
Facial asymmetry (cranial nerve VII)- — Shallow nasolabial fold right- Facial nucleus or fibers —Ipsilateral paralysis of facial muscles Slurring of speech and inarticulation (CN IX, X) Drooling Dysphagia (-) gag reflex Left upper and lower extremity (4/5)- —Corticospinal fibers —Contralateral hemiplegia Dragging gait on left, dysdiadochokinesia, left Bilateral babinski Corticospinal tract Ataxia- CN VIII, proprioception Types of ataxia and their characteristics Ataxia can result from damage to several different motor or sensory regions of the central nervous system, as well as peripheral nerve pathology (Bastian 1997). In general, problems in the proprioceptive system, visual system and vestibular system, the cerebellum and/or any problem in the interconnections of these systems, can lead to ataxia. According to some researchers, ataxia has two categories: sensory and cerebellar ataxia (Bastian 1997, Mariotti et al. 2005), to others, e.g. Morgan, ataxia has three types: sensory, cerebellar and vestibular ataxia (Morgan 1980). Still other researchers consider frontal ataxia as a 4th type (Erasmus 2004 ). In some cases, the symptoms of two or three ataxia types can be observed, which is referred to as mixed ataxia (Edwards 1996). Sensory ataxia The term sensory ataxia is used to indicate ataxia due to loss of proprioception (sensitivity to joint and body part position), which generally depends on dysfunction of the dorsal columns of the spinal cord, since they carry proprioceptive information up to the brain. In some cases, the cause may be dysfunction of the various brain parts which receive that information, including the thalamus, and parietal lobes. Sensory ataxia shows itself with an unsteady "stomping" gait with heavy heel strikes and postural instability that is characteristically worsened when the lack of proprioceptive input cannot be compensated by visual input, such as in poorly lit environments (en.wikipedia.org). The patient stands with his / her feet together and eyes shut, which will cause the patient's instability to worsen, producing wide oscillations and possibly a fall (en.wikipedia.org). This is an indicator that the Romberg's test is positive, which is the most significant finding that differentiates sensory ataxia from other types of ataxia (Bannister 1992). Losses of vibration sense in the extremities and deep tendon reflexes are important characteristics of sensory ataxia. Worsening of the finger-pointing test with the eyes closed is another feature of sensory ataxia (en.wikipedia.org). Sensory ataxia can be observed in types of hereditary ataxia such as Friedreich's ataxia and spinocerebellar ataxia. Sensory ataxia may also be observed in diseases such as diabetic or alcoholic neuropathy, vitamin B12 inadequacy neuropathy, tabes dorsalis, tumoral conditions found in the posterior cord of the medulla spinalis, and in multiple sclerosis (Edwards 1996). Vestibular ataxia Vestibular ataxia develops as a result of peripheral or central diseases which directly affects the vestibular nuclei and/or the afferent and efferent connections of the vestibular nuclei. A patient with vestibular ataxia has disturbances of balance in standing and sitting. The patient tends to stagger when walking, has a broad base support and may lean backwards or towards the side of the lesion. Head and trunk motion and subsequently arm motion are often decreased (Borello-France et al. 1994). The patient is limited particularly when crossing the street and shopping at the market since his/her balance is disrupted when performing a head or eye movement. Vestibular ataxia may be accompanied by vertigo, nausea, vomiting, blurred vision and nystagmus due to the vestibular system's role in sensing and perceiving self-motion and stabilizing gaze via the vestibulo-ocular reflex (Horak&Shupert 1994). Extremity ataxia is by no means observed in vestibular ataxia. Deep tendon reflexes are considered normal. Vestibular ataxia can develop due to central factors such as medullar stroke and multiple sclerosis, and peripheral vestibular diseases such as Menier's, hydrops, benign paroxysmal vertigo, or vestibular neuronitis. Cerebellar ataxia Cerebellar ataxia develops as a result of lesions to the cerebellum, and/or the afferent and efferent connections of the cerebellum. Vestibulo-cerebellar dysfunction is related to the flocculonodular lobe (flocculus and nodulus) and involves problems regulating balance and controlling eye movements. This shows itself with postural instability, in which the person tends to separate the feet on standing to gain a wider base, and avoid oscillations (especially posterior-anterior ones); instability is therefore worsened when standing with the feet together (irrespective of whether the eyes are open or closed: this is a negative Romberg's test) (en.wikipedia.org, Liao et al. 2008, Morton&Bastian 2004). Spino-cerebellar dysfunction corresponds to the vermis and paravermis and patients will present with a wide-based gait, characterized by uncertain start and stop, lateral deviations, and unequal steps and abnormal inter-joint coordination patterns. When this part of the cerebellum is damaged, gait ataxia or walking in-coordination occurs (en.wikipedia.org, Ilg et al. 2008, Timmann et al. 2008, Ilg et al. 2007, Morton&Bastian 2007). Cerebro-cerebellar dysfunction indicates a lesion of the deep pontine nuclei connections with the cerebellum. The cerebrocereebellum contributes to planning and monitoring of movements and damage here results in disturbances in performing voluntary, planned movements (en.wikipedia.org, Schmahmann 2004). Symptoms associated with cerebellar ataxia include: Dysmetria: This refers to inaccuracy in achieving a final end position (hypermetria equals overshoot; hypometria equals undershoot). This clearly is demonstrated by the patient attempting the finger-nose test. Tremor: Kinetic tremor, which is oscillation that occurs during the course of the movement Intention tremor, which is the increase in tremor towards the end of the movement Postural tremor, which occurs when holding a limb in a given position Titubation, which is tremor affecting the head and upper trunk typically after lesion of the vermis Postural truncal tremor, which affects the legs and lower trunk, is seen in anterior cerebellar lobe lesions Dyssynergia: is distinct particularly during multi-joint movements. This may have several reasons: agonist-antagonist and synergistic muscles may not be able to contract in correct order during voluntary movement; or antagonist muscle may be failing to control eccentric contraction during the concentric contraction of agonist muscle. With the combination of these two factors, the extremity undergoes a sudden velocity resulting in inappropriate and uncontrolled motor movement. Dysdiadockokinesia: This is the inability to perform rapidly alternating movements such as alternately tapping with palm up and palm down. The rhythm is poor and force of each tap is variable. Hypotonia: This occurs in acute cerebellar lesions, but it is rarely seen in chronic lesions. Hypotonia is distinct particularly in proximal and antigravity muscles. Weakness and fatigue: This describes a generalized non-specific weakness as a feature of cerebellar dysfunction. This occurs more often with extensive and deep lesions and is most apparent in the proximal musculature. Fatigue has also been noted as a common feature of cerebellar dysfunction. Dysarthria: This occurs due to in-coordination between tongue and lip muscles. The patient speaks like he is drunk. Nystagmus: abnormal eye movements that develop in horizontal and vertical directions mostly as nystagmus at the end point (Edwards 1996). Deep tendon reflexes are maintained in cerebellar lesions, and gain a pendular characteristic. Cerebellar ataxia can be observed in diseases such as spino-cerebellar ataxia among hereditary ataxias, Friedreich's ataxia, chronic alcoholism, paraneoplastic cerebellar degeneration, pontocerebellar angle tumors and multiple sclerosis. Frontal ataxia Frontal ataxia (also known as gait apraxia) is observed when tumors, abscesses, cerebro vascular accidents and normal pressure hydrocephalus effect the frontal area. It has the below listed features: Patient has difficulties standing erect Even with use of support, patient tends to lean towards hyperextension Patient's legs are in scissors-cross position during walking and there is incoordination between the legs and trunk Ataxia is accompanied by frontal dementia, urinary incontinence, frontal release signs and perseveration (jeffmann.net/NeuroGuidemaps/gait). Mixed ataxia Mixed ataxia refers to the type of ataxia when symptoms of two or more types of ataxia are observed together, such as occurance of sensory and cerebellar ataxia symptoms. In some diseases, mixed ataxia may be observed frequently. For instance, in Multiple Sclerosis, cerebellar, vestibular and sensory ataxia may be observed together; whereas in cases of spino-cerebellar ataxias, cerebellar and sensory ataxia may be seen. Features of basic types of ataxia are briefed in Table 1 below:

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 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 Cranial nerve palsies – symptoms related to the nerves that supply the muscles of the eye and face, and muscles involved in swallowing. Usually the sixth or the seventh nerve. This include double vision, inability to close the eyelids completely, dropping one side of the face, and difficulty chewing and swallowing. CN VI and VII are most commonly affected but III, IV, IX, and X may also be involved Long tract signs – hyperreflexia, clonus, increased tone, presence of Babinski reflex. Results in weakness of the arms or legs and difficulty with speech and walking. Cerebellar involvement – ataxia, incoordination, dysmetria, dysarthria Other symptoms may occur including behavioral changes, night terrors and school difficulties. References: Donaldson, et al Advances toward an understanding of brainstem gliomas. Journal of Clinical Oncology. 24 (8): American Society of Clinical Oncology.

Course in the Wards: Therapeutics DisPONnect A Case of Pontine Glioma

Hospital Day 01 Subjective/Objective Assessment Plan
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 Assessment Plan
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 Assessment Plan
Patient had throbbing frontal headache, spontaneously resolving, with 2 episodes of vomiting, non-bilious, non-projectile 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

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.

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 Abstract Malignant gliomas are the most common and deadly brain tumors. Nevertheless, survival for patients with glioblastoma, the most aggressive glioma, although individually variable, has improved from an average of 10 months to 14 months after diagnosis in the last 5 years due to improvements in the standard of care. Radiotherapy has been of key importance to the treatment of these lesions for decades, and the ability to focus the beam and tailor it to the irregular contours of brain tumors and minimize the dose to nearby critical structures with intensity-modulated or image-guided techniques has improved greatly. Temozolomide, an alkylating agent with simple oral administration and a favorable toxicity profile, is used in conjunction with and after radiotherapy. Newer surgical techniques, such as fluorescence-guided resection and neuroendoscopic approaches, have become important in the management of malignant gliomas. Furthermore, new discoveries are being made in basic and translational research, which are likely to improve this situation further in the next 10 years. These include agents that block 1 or more of the disordered tumor proliferation signaling pathways, and that overcome resistance to already existing treatments. Targeted therapies such as antiangiogenic therapy with antivascular endothelial growth factor antibodies (bevacizumab) are finding their way into clinical practice. Large-scale research efforts are ongoing to provide a comprehensive understanding of all the genetic alterations and gene expression changes underlying glioma formation. These have already refined the classification of glioblastoma into 4 distinct molecular entities that may lead to different treatment regimens. The role of cancer stem-like cells is another area of active investigation. There is definite hope that by 2020, new cocktails of drugs will be available to target the key molecular pathways involved in gliomas and reduce their mortality and morbidity, a positive development for patients, their families, and medical professionals alike.

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 Abstract Diffuse intrinsic pontine glioma (DIPG) has a dismal prognosis with no chemotherapy regimen so far resulting in any significant improvement over standard radiotherapy. In this trial, a prolonged regimen (21/28d) of temozolomide was studied with the aim of overcoming O(6)-methylguanine methyltransferase (MGMT) mediated resistance. Forty-three patients with a defined clinico-radiological diagnosis of DIPG received radiotherapy and concomitant temozolomide (75mg/m(2)) after which up to 12 courses of 21d of adjuvant temozolomide (75-100mg/m(2)) were given 4 weekly. The trial used a 2-stage design and passed interim analysis. At diagnosis median age was 8years (2-20years), 81% had cranial nerve abnormalities, 76% ataxia and 57% long tract signs. Median Karnofsky/Lansky score was 80 (10-100). Patients received a median of three courses of adjuvant temozolomide, five received all 12 courses and seven did not start adjuvant treatment. Three patients were withdrawn from study treatment due to haematological toxicity and 10 had a dose reduction. No other significant toxicity related to temozolomide was noted. Overall survival (OS) (95% confidence interval (CI)) was 56% (40%, 69%) at 9months, 35% (21%, 49%) at 1year and 17% (7%, 30%) at 2years. Median survival was 9.5months (range months). There were five 2- year survivors with a median age of 13.6years at diagnosis. This trial demonstrated no survival benefit of the addition of dose dense temozolomide, to standard radiotherapy in children with classical DIPG. However, a subgroup of adolescent DIPG patients did have a prolonged survival, which needs further exploration.

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 Abstract Diffuse intrinsic pontine glioma (DIPG) has a dismal prognosis with no chemotherapy regimen so far resulting in any significant improvement over standard radiotherapy. In this trial, a prolonged regimen (21/28d) of temozolomide was studied with the aim of overcoming O(6)-methylguanine methyltransferase (MGMT) mediated resistance. Forty-three patients with a defined clinico-radiological diagnosis of DIPG received radiotherapy and concomitant temozolomide (75mg/m(2)) after which up to 12 courses of 21d of adjuvant temozolomide (75-100mg/m(2)) were given 4 weekly. The trial used a 2-stage design and passed interim analysis. At diagnosis median age was 8years (2-20years), 81% had cranial nerve abnormalities, 76% ataxia and 57% long tract signs. Median Karnofsky/Lansky score was 80 (10-100). Patients received a median of three courses of adjuvant temozolomide, five received all 12 courses and seven did not start adjuvant treatment. Three patients were withdrawn from study treatment due to haematological toxicity and 10 had a dose reduction. No other significant toxicity related to temozolomide was noted. Overall survival (OS) (95% confidence interval (CI)) was 56% (40%, 69%) at 9months, 35% (21%, 49%) at 1year and 17% (7%, 30%) at 2years. Median survival was 9.5months (range months). There were five 2- year survivors with a median age of 13.6years at diagnosis. This trial demonstrated no survival benefit of the addition of dose dense temozolomide, to standard radiotherapy in children with classical DIPG. However, a subgroup of adolescent DIPG patients did have a prolonged survival, which needs further exploration.

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. Abstract The prognosis for patients with diffuse pontine gliomas (DPG) remains poor. New aggressive innovative treatments are necessary to treat this disease. From 1984 to 1998, eight patients (4M/4F), median age 11 years, with DPG were treated with monthly osmotic blood-brain barrier disruption (BBBD)chemotherapy using intraarterial carboplatin or methotrexate and intravenous cytoxan and etoposide. Patients presented for a median duration of 6 weeks with increased intracranial pressure, long tract signs, diplopia, ataxia, and nausea/vomiting. DPG was demonstrated on magnetic resonance (MR) imaging in seven patients and on CT in one. Two patients had biopsies that showed an astrocytoma and an anaplastic astrocytoma. Three tumors enhanced on MR imaging after contrast administration. Three patients had radiation therapy before BBBD chemotherapy and four afterwards. Two patients had chemotherapy (tamoxifen, topotecan) before BBBD chemotherapy and two afterwards. In general, patients were evaluated with MR imaging every 3 months to monitor for a response to treatment. The median number of chemotherapy cycles that were administered by BBBD was 10, mean 10. Three patients also received one, two, or three cycles of intraarterial chemotherapy without BBBD. One patient that was started on carboplatin was converted to methotrexate, and five that were started on the methotrexate protocol were later converted over to carboplatin. One patient received monthly methotrexate followed by 14 days of procarbazine and one patient started on methotrexate was switched to navelbine. MR imaging demonstrated two partial responses, five patients with stable disease, and one with disease progression. The median time to tumor progression was 15 months with the range from <1 to 40 months. The median survival from the time of diagnosis was 27 months, ranging from 7 to 80 months. The median survival time from the first BBBD or intraarterial treatment was 16.5 months, ranging from 5 to 69 months. One patient was lost to follow-up with an unknown date of death. Although the sample size is small, the TTP and survival times are longer than those previously reported in other DPG series. In addition, the ability to demonstrate stable disease or partial responses in DPG on MR imaging argues for the therapeutic benefit of BBBD chemotherapy. The 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. Abstract The development of the cancer stem cell (CSCs) niche theory has provided a new target for the treatment of gliomas. Gene therapy using oncolytic viral vectors has shown great potential for the therapeutic targeting of CSCs. To explore whether a viral vector carrying an exogenous Endo-Angio fusion gene (VAE) can infect and kill glioma stem cells (GSCs), as well as inhibit their vascular niche in vitro, we have collected surgical specimens of human high-grade glioma (world health organization, WHO Classes III-VI) from which we isolated and cultured GSCs under conditions originally designed for the selective expansion of neural stem cells. Our results demonstrate the following: (1) Four lines of GSCs (isolated from 20 surgicalspecimens) could grow in suspension, were multipotent, had the ability to self-renew and expressed the neural stem cell markers, CD133 and nestin. (2) VAE could infect GSCs and significantly inhibit their viability. (3) The Endo-Angio fusion gene was expressed in GSCs 48 h after VAE infection and could inhibit the proliferation of human brain microvascular endothelial cells (HBMEC). (4) Residual viable cells lose the ability of self-renewal and adherent differentiation. In conclusion, VAE can significantly inhibit the activity of GSCs in vitro and the expression of exogenous Endo-Angio fusion gene can inhibit HBMEC proliferation. VAE can be used as a novel virus-gene therapy strategy for glioma.

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 Abstract Diffuse intrinsic pontine glioma (DIPG) is an incurable tumor that arises in the brainstem of children. To date there is not a single approved drug to effectively treat these tumors and thus novel therapies are desperately needed. Recent studies suggest that a significant fraction of these tumors contain alterations in cell cycle regulatory genes including amplification of the D-type cyclins and CDK4/6, and less commonly, loss of Ink4a-ARF leading to aberrant cell proliferation. In this study, we evaluated the therapeutic approach of targeting the cyclin-CDK-Retinoblastoma (Rb) pathway in a genetically engineered PDGF-B-driven brainstem glioma (BSG) mouse model. We found that PD (PD), a CDK4/6 inhibitor, induces cell-cycle arrest in our PDGF-B; Ink4a-ARF deficient model both in vitro and in vivo. By contrast, the PDGF-B; p53 deficient model was mostly resistant totreatment with PD. We noted that a 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 (RT) followed by 7 days of treatment with PD increased the survival by 19% in comparison to RT alone. These findings provide the rationale for evaluating PD in children with Ink4a-ARF deficient gliomas.

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. Abstract Diffuse intrinsic pontine glioma (DIPG) is an incurable tumor that arises in the brainstem of children. To date there is not a single approved drug to effectively treat these tumors and thus novel therapies are desperately needed. Recent studies suggest that a significant fraction of these tumors contain alterations in cell cycle regulatory genes including amplification of the D-type cyclins and CDK4/6, and less commonly, loss of Ink4a-ARF leading to aberrant cell proliferation. In this study, we evaluated the therapeutic approach of targeting the cyclin-CDK-Retinoblastoma (Rb) pathway in a genetically engineered PDGF-B-driven brainstem glioma (BSG) mouse model. We found that PD (PD), a CDK4/6 inhibitor, induces cell-cycle arrest in our PDGF-B; Ink4a-ARF deficient model both in vitro and in vivo. By contrast, the PDGF-B; p53 deficient model was mostly resistant totreatment with PD. We noted that a 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 (RT) followed by 7 days of treatment with PD increased the survival by 19% in comparison to RT alone. These findings provide the rationale for evaluating PD in children with Ink4a-ARF deficient gliomas.

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.

CONCLUSION: Future Management
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

Cognitive Dysfunction
Complications Cognitive Dysfunction J Neurooncol Sep;114(3): Epub 2013 Jun 29. Clinico-radiologic characteristics of long-term survivors of diffuse intrinsic pontine glioma. Jackson S, Patay Z, Howarth R, Pai Panandiker AS, Onar-Thomas A, Gajjar A, Broniscer A Three of four patients who underwent a detailed evaluation showed cognitive function in the borderline or mental retardation range. COGNITIVE DYSFUNCTION Clinico-radiologic characteristics of long-term survivors of diffuse intrinsic pontine glioma. Jackson S, Patay Z, Howarth R, Pai Panandiker AS, Onar-Thomas A, Gajjar A, Broniscer A J Neurooncol Sep;114(3): Epub 2013 Jun 29. Department of Oncology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mailstop 260, Memphis, TN, 38105, USA. Diffuse intrinsic pontine glioma (DIPG) is the deadliest central nervous system tumor in children. The survival of affected children has remained poor despite treatment with radiation therapy (RT) with or without chemotherapy. We reviewed the medical records of all surviving patients with DIPG treated at our institution between October 1, 1992 and May 31, Blinded central radiologic review of the magnetic resonance imaging at diagnosis of all surviving patients and 15 controls with DIPG was performed. All surviving patients underwent neurocognitive assessment during follow-up. Five (2.6 %) of 191 patients treated during the study period were surviving at a median of 9.3 years from their diagnosis (range years). Two patients were younger than 3 years, one lacked signs of pontine cranial nerve involvement, and three had longer duration of symptoms at diagnosis. One patient had a radiologically atypical tumor and one had a tumor originating in the medulla. All five patients received RT. Chemotherapy was variable among these patients. Neurocognitive assessments were obtained after a median interval of 7.1 years. Three of four patients who underwent a detailed evaluation showed cognitive function in the borderline or mental retardation range. Two patients experienced diseaseprogression at 8.8 and 13 years after diagnosis. A minority of children with DIPG experienced long-term survival with currently available therapies. These patients remained at high risk for tumor progression even after long follow-ups. Four of our long-term survivors had clinical and radiologic characteristics at diagnosis associated with improved outcome. J Neurooncol May;77(3): Epub 2005 Nov 29. Pathological laughter and behavioural change in childhood pontine glioma. Hargrave DR, Mabbott DJ, Bouffet E. Source Paediatric Oncology Unit, Royal Marsden Hospital, Downs Road, SM2 5PT, Sutton, Surrey, UK. Abstract Children with pontine glioma usually present classically with ataxia, motor deficits and cranial nerve palsies. The pons has generally not been regarded as a structure that mediates complex affective behaviour. However, we report 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. A mechanism of how pontine lesions can cause such complex affective and cognitive behaviour has been suggested to consist of the disruption of a network of cerebro-ponto-cerebellar pathways and the evidence for this mechanism is discussed. Locked-in syndrome is a rare neuropsychological disorder. Its primary features are quadriplegia and paralysis of the cranial nerves except for those responsible for vertical eye movements. Childs Nerv Syst Aug;9(5):256-9. Pontine gliomas causing locked-in syndrome. Masuzawa H, Sato J, Kamitani H, Kamikura T, Aoki N. Department of Neurosurgery, Kanto Teishin Hospital, Toyko, Japan. The terminal phase of pontine glioma is reportedly characterized by disturbance of consciousness. The authors retrospectively reviewed 8 children who died of pontine gliomas in their hospitals. The hospital records were analyzed specifically in regard to neurological status and terminal case. All children became mute and quadriplegic with cranial nerve palsies. The oldest child, 17 years in age, unquestionably showed the classical locked-in syndrome for the last 4 months. Six of the remaining 7 (average 5 years of age), while labeled as semicomatose, responded to calling by blinking and/or vertical eyeball movement. The authors consider that they were indeed awake in the locked-in state until very near death. This would raise a serious ethical problem of whether or not they should be intubated and kept ventilator-dependent at the time of respiratory failure, which often occurs.

Behavioral Change Complications
J Neurooncol May;77(3): 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. J Neurooncol May;77(3): Epub 2005 Nov 29. Pathological laughter and behavioural change in childhood pontine glioma. Hargrave DR, Mabbott DJ, Bouffet E. Source Paediatric Oncology Unit, Royal Marsden Hospital, Downs Road, SM2 5PT, Sutton, Surrey, UK. Abstract Children with pontine glioma usually present classically with ataxia, motor deficits and cranial nerve palsies. The pons has generally not been regarded as a structure that mediates complex affective behaviour. However, we report 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. A mechanism of how pontine lesions can cause such complex affective and cognitive behaviour has been suggested to consist of the disruption of a network of cerebro-ponto-cerebellar pathways and the evidence for this mechanism is discussed. Locked-in syndrome is a rare neuropsychological disorder. Its primary features are quadriplegia and paralysis of the cranial nerves except for those responsible for vertical eye movements. Childs Nerv Syst Aug;9(5):256-9. Pontine gliomas causing locked-in syndrome. Masuzawa H, Sato J, Kamitani H, Kamikura T, Aoki N. Department of Neurosurgery, Kanto Teishin Hospital, Toyko, Japan. The terminal phase of pontine glioma is reportedly characterized by disturbance of consciousness. The authors retrospectively reviewed 8 children who died of pontine gliomas in their hospitals. The hospital records were analyzed specifically in regard to neurological status and terminal case. All children became mute and quadriplegic with cranial nerve palsies. The oldest child, 17 years in age, unquestionably showed the classical locked-in syndrome for the last 4 months. Six of the remaining 7 (average 5 years of age), while labeled as semicomatose, responded to calling by blinking and/or vertical eyeball movement. The authors consider that they were indeed awake in the locked-in state until very near death. This would raise a serious ethical problem of whether or not they should be intubated and kept ventilator-dependent at the time of respiratory failure, which often occurs.

Complications Locked-In Syndrome Childs Nerv Syst Aug;9(5): 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. Locked-in syndrome is a rare neuropsychological disorder. Its primary features are quadriplegia and paralysis of the cranial nerves except for those responsible for vertical eye movements. Childs Nerv Syst Aug;9(5):256-9. Pontine gliomas causing locked-in syndrome. Masuzawa H, Sato J, Kamitani H, Kamikura T, Aoki N. Source Department of Neurosurgery, Kanto Teishin Hospital, Toyko, Japan. Abstract The terminal phase of pontine glioma is reportedly characterized by disturbance of consciousness. The authors retrospectively reviewed 8 children who died of pontine gliomas in their hospitals. The hospital records were analyzed specifically in regard to neurological status and terminal case. All children became mute and quadriplegic with cranial nerve palsies. The oldest child, 17 years in age, unquestionably showed the classical locked-in syndrome for the last 4 months. Six of the remaining 7 (average 5 years of age), while labeled as semicomatose, responded to calling by blinking and/or vertical eyeball movement. The authors consider that they were indeed awake in the locked-in state until very near death. This would raise a serious ethical problem of whether or not they should be intubated and kept ventilator-dependent at the time of respiratory failure, which often occurs.

Bone Marrow Suppression
Complications Radiation Necrosis Hypopituitarism/Hypothyroidism Bone Marrow Suppression Complications Secondary to Treatment Modalities RADIATION NECROSIS Bevacizumab as therapy for radiation necrosis in four children with pontine gliomas. Liu AK, Macy ME, Foreman NK Int J Radiat Oncol Biol Phys. 2009;75(4):1148. Diffuse pontine gliomas are a pediatric brain tumor that is fatal in nearly all patients. Given the poor prognosis for patients with this tumor, their quality of life is very important. Radiation therapy provides some palliation, but can result in radiation necrosis and associated neurologic decline. The typical treatment for this necrosis is steroid therapy. Although the steroids are effective, they have numerous side effects that can often significantly compromise quality of life. Four children with pontine gliomas treated at the Children's Hospital in Denver and the University of Colorado Denver developed evidence of radiation necrosis both clinically and on imaging. Those 4 children then received bevacizumab as a treatment for the radiation necrosis. After bevacizumab therapy, 3 children had significant clinical improvement and were able to discontinue steroid use. One child continued to decline, and, in retrospect, had disease progression, not radiation necrosis. In all cases, bevacizumab was well tolerated. HYPOTHALAMIC HYPOPITUITARISM FOLLOWING EXTERNAL RADIOTHERAPY FOR TUMOURS DISTANT FROM THE ADENOHYPOPHYSIS D. A. PERRY-KEENE, J. F. CONNELLY, R. A. YOUNG, H. N. B. WETTENHALL, F. I. R. MARTIN* Clinical Endocrinology Volume 5, Issue 4, pages 373–380, July 1976

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 CT-Scan features: Hypodense tumor prior to contrast Tumor involving the entire brainstem Albright et al. Prognostic factors in pediatric brainstem gliomas. Journal of Neurosurgery (5):

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 The diagnosis of cancer has a powerful and lasting impact not just on the child, but also on his or her family and immediate community. Familes must endure the transition from feeling in control of heir lives to living with constant uncertainty. The need to depend on the medical system for answers and cure requires enormous adjustment by the parents. No family mamber – whether it be grandparent, sibling, or other relative – is unaffected. Marriages, careers, and relationships with others are significantly affected. Some familes become more cohesive, devloping increased strengths and a positive redefinition of values. Other, often thse with preexisting vulnerabilites, suffer various degrees of dysequilibrium. As doctors, it is our job to indentify the different factors that place families at high risk for dysequilibrium.

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 As the diagnosis is accepted, guilt and anger become significant emotions. They may be directed in many ways. Anger, in particular, may be directed at physicians, other staff members, or the hospital at large. Those who were involved in the initial presentation of the diagnosis (a presentation that radically alters the family's life) may, for a short time, be the focus of significant negative feelings. Guilt is expressed in ruminations as parents seek reasons that cancer has occurred in their child. Many parents pass through a period of self-blame during which they focus on transgressions they may have committed and for which they feel they are now being punished. They may begin searching for evidence that they failed to pay sufficient attention to early signs of less than optimal health in their child. Some parents may berate themselves for not taking complaints seriously enough, for having children when “cancer runs in the family,” for smoking during pregnancy, or for living in polluted urban or industrial areas. Careful listening and supportive attention by the oncology staff are important to these families. These families need reassurance that they are not responsible for causing the disease. Such interventions free parental energies for the extensive emotional support needed by their sick child or adolescent and the child's siblings. Parents often launch themselves into intense activity. They rapidly absorb information about the disease and its treatments while protecting the child patient and mobilizing their own support systems.

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 An important task for parents is deciding when, how, and what to tell their child about the diagnosis. Children, as well as parents, later recall vividly what took place when the diagnosis was revealed. Ideally, the parents should be the ones to share this information with their child. Parents need much guidance in this task. They often use euphemisms and attempt to protect their child (and themselves) from the harsh realities of the diagnosis and the illness itself. They need help in understanding why such information must be presented both honestly and calmly, how (including the timing issue of “when”) to communicate information about the nature of the illness as well as the impending changes in activities, appearance, and energy. Many parents find it difficult to believe that thoughtfully open communication promotes understanding and trust. They need repeated explanation that honest discussion, when properly timed and tailored to the age and developmental level of the child, works best. Such communication avoids the distortions of secrets held, promises not kept, and misinformation given. 14 Family stress can be better managed once the child understands and accepts the diagnosis. This paves the way for more open communication within the family. 15,16 and 17

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 The young child's immediate concerns revolve around hospitalization, separation from parents, and fear of medical procedures. Toddlers and preschoolers are particularly sensitive to separations and changes in familiar routines. These young patients may view hospitalization and disruption of usual daily life as punishment. This perception is further reinforced by the experience of painful and invasive medical procedures. Hospitalized young children need constant reassurance from their parents that they will not be abandoned and that hospitalization and medical interventions are not a form of punishment. The young child's concerns about body boundaries along with fears of mutilation require special attention in relation to all medical procedures, from temperature taking to lumbar punctures. Before any medical procedure, children should receive a brief, honest description about that procedure. They should be told what the procedure is for, how it will be done, and the intensity and duration of any associated pain. 18 This description should be combined with behavioral interventions that reduce the child's anxiety and distress surrounding medical procedures. 18,19 and 20 Behavioral interventions include a system of positive incentives in combination with strategies of attentional distraction designed to help the child control fear before and during tests or treatments. The presentation of a valued reward may elicit the extra motivation to cooperate (e.g., to try to remain still). Expectations for the child's behavior must be realistic and must allow the child to succeed. Children often want to be brave and not fight medical procedures. They welcome the physician's help in controlling their fears, especially when it is presented in concert with the child's primary care nurse and parent. Such help may take the form of attentional distraction, emotive imagery, or hypnosis. During painful procedures, children can be engaged and distracted through storytelling, fantasy play, drawing, cognitive puzzles, and video games. Parents should be helped to develop these skills for use with their children. A more structured desensitization or emotive imagery procedure is most useful when the child's fears are not directly linked to aversive procedures. This technique is first introduced away from the treatment area. The aim is to teach the child mastery of the feared situation through repeated fantasy—for example, imagining how a favorite storybook hero would cope. The fantasy is designed to elicit motivation to master the pain rather than to avoid it. Finally, clinical hypnosis can be used to train the child to refocus attention on images or thoughts that are unrelated to the source of distress. Hypnosis is not appropriate for all children and adolescents. Appropriate evaluation of the child is needed. Those successfully trained in this technique of focusing attention while “letting go” of hypervigilance can gain a sense of improved comfort and control. 21,22 All these techniques succeed by diverting the child's attention away from the feared procedure and toward more positive activity. When surgery is planned, the child needs special preparation. Visits to the operating and recovery rooms and familiarization with the surgical personnel and surgical garb (i.e., masks and gowns) help to ease the child's fear and to lessen the shock of the strange environment. The child also needs to be prepared for the consequences of surgery. Discussions about amputation or other resulting disabilities or deformities must begin early. This kind of trauma is best handled when children have several days to assimilate the information, to voice their fears, and to adjust expectations in the light of further explanations. Other amputees can help to contain some of the child's anxiety. Finally, as with all intensive and painful procedures, physical comforting (appropriate touch, holding, and massage) is essential. The stress of illness and hospitalization can cause psychologic regression in all patients. For the young child, regression may take the form of loss of newly acquired skills (e.g., toilet training, speech, self-feeding). Previously discarded behaviors, such as thumb sucking or clinging, may reemerge. Disturbing dreams or night fears may occur. Parents should be helped to understand this regression as part of the child's efforts to cope. The best approach is to avoid either scolding or ignoring these behaviors. Adaptive regressive behaviors generally subside after the acute phase of illness. At times, regressive patterns may become more entrenched and can become serious problems. For example, although increased dependency between parent and child is inevitable, this can lead to more extreme symbiotic regression, a maladaptive behavior pattern that is often difficult to change given the anxieties as well as misperceptions of both parent and child.

School-Age Children May have delayed or immediate reactions Psychosomatic complaints Nightmares Labile emotions Regressions Stoic, adult-like acceptance The young child's immediate concerns revolve around hospitalization, separation from parents, and fear of medical procedures. Toddlers and preschoolers are particularly sensitive to separations and changes in familiar routines. These young patients may view hospitalization and disruption of usual daily life as punishment. This perception is further reinforced by the experience of painful and invasive medical procedures. Hospitalized young children need constant reassurance from their parents that they will not be abandoned and that hospitalization and medical interventions are not a form of punishment. The young child's concerns about body boundaries along with fears of mutilation require special attention in relation to all medical procedures, from temperature taking to lumbar punctures. Before any medical procedure, children should receive a brief, honest description about that procedure. They should be told what the procedure is for, how it will be done, and the intensity and duration of any associated pain. 18 This description should be combined with behavioral interventions that reduce the child's anxiety and distress surrounding medical procedures. 18,19 and 20 Behavioral interventions include a system of positive incentives in combination with strategies of attentional distraction designed to help the child control fear before and during tests or treatments. The presentation of a valued reward may elicit the extra motivation to cooperate (e.g., to try to remain still). Expectations for the child's behavior must be realistic and must allow the child to succeed. Children often want to be brave and not fight medical procedures. They welcome the physician's help in controlling their fears, especially when it is presented in concert with the child's primary care nurse and parent. Such help may take the form of attentional distraction, emotive imagery, or hypnosis. During painful procedures, children can be engaged and distracted through storytelling, fantasy play, drawing, cognitive puzzles, and video games. Parents should be helped to develop these skills for use with their children. A more structured desensitization or emotive imagery procedure is most useful when the child's fears are not directly linked to aversive procedures. This technique is first introduced away from the treatment area. The aim is to teach the child mastery of the feared situation through repeated fantasy—for example, imagining how a favorite storybook hero would cope. The fantasy is designed to elicit motivation to master the pain rather than to avoid it. Finally, clinical hypnosis can be used to train the child to refocus attention on images or thoughts that are unrelated to the source of distress. Hypnosis is not appropriate for all children and adolescents. Appropriate evaluation of the child is needed. Those successfully trained in this technique of focusing attention while “letting go” of hypervigilance can gain a sense of improved comfort and control. 21,22 All these techniques succeed by diverting the child's attention away from the feared procedure and toward more positive activity. When surgery is planned, the child needs special preparation. Visits to the operating and recovery rooms and familiarization with the surgical personnel and surgical garb (i.e., masks and gowns) help to ease the child's fear and to lessen the shock of the strange environment. The child also needs to be prepared for the consequences of surgery. Discussions about amputation or other resulting disabilities or deformities must begin early. This kind of trauma is best handled when children have several days to assimilate the information, to voice their fears, and to adjust expectations in the light of further explanations. Other amputees can help to contain some of the child's anxiety. Finally, as with all intensive and painful procedures, physical comforting (appropriate touch, holding, and massage) is essential. The stress of illness and hospitalization can cause psychologic regression in all patients. For the young child, regression may take the form of loss of newly acquired skills (e.g., toilet training, speech, self-feeding). Previously discarded behaviors, such as thumb sucking or clinging, may reemerge. Disturbing dreams or night fears may occur. Parents should be helped to understand this regression as part of the child's efforts to cope. The best approach is to avoid either scolding or ignoring these behaviors. Adaptive regressive behaviors generally subside after the acute phase of illness. At times, regressive patterns may become more entrenched and can become serious problems. For example, although increased dependency between parent and child is inevitable, this can lead to more extreme symbiotic regression, a maladaptive behavior pattern that is often difficult to change given the anxieties as well as misperceptions of both parent and child.

School-Age Children More likely to be verbal about their illness Developmental period of vigorous inquiry School-age children are likely to be verbal about their illness and to request information about all aspects of the disease and treatment. They often pose difficult questions about the reasons for and causes of their illness. Children at this age also experience pride of mastery from the learning associated with their illness. They enjoy learning the proper labels for their disease, treatments, and medications. They can use this information effectively when they return to school. This is a developmental period of vigorous inquiry. The diagnosis of a severe illness, with all the associated anxiety, prompts a barrage of questions. From the outset, these questions should be answered in a simple, straightforward approach. A sample exchange might be Q: Why are we going to the hospital? A: Because Dr. Jones thinks you may have a serious illness. Q: What kind of serious illness? A: It may be a blood disease called leukemia. Q: Does that mean I am going to die? A: We are going to the children's hospital because they have special treatments for leukemia that have cured many children. Parents often need to engage in specific scripting because they are not used to conveying stressful information to their children. Helping this process should begin at the intake meeting. If the family's usual practice is to avoid issues, the child will learn that asking questions produces discomfort in the parents. Parental discomfort increases the child's personal distress. Behavioral interventions to enhance management of stress should focus on developing self-regulatory skills, acquired through biofeedback, hypnosis, or imagery training. Here again, parents often are willing participants. Their participation augments both successful learning by the child patient and parental stress management skills. Once the physician has formed a working relationship with the child, a special education session between physician and child, without the parent, provides an opportunity to correct any misconceptions or to offer more detailed information to the child. Obviously, the amount of detail presented depends on the age, comfort level, and sophistication of the child. This approach may lead to a warm bond between physician and child that can enhance compliance (adherence) with procedures and treatment. Although some parents may feel threatened by this exclusion, most are grateful that the physician is sharing the educational task with them. The major activity of children outside of the home is school. School begins the processes of working toward independence from parents, establishing peer relationships, and acquiring academic skills. The physical and emotional concomitants of life-threatening illness disrupt school attendance and performance.

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” Parents often need to engage in specific scripting because they are not used to conveying stressful information to their children. Helping this process should begin at the intake meeting. If the family's usual practice is to avoid issues, the child will learn that asking questions produces discomfort in the parents. Parental discomfort increases the child's personal distress. Behavioral interventions to enhance management of stress should focus on developing self-regulatory skills, acquired through biofeedback, hypnosis, or imagery training. Here again, parents often are willing participants. Their participation augments both successful learning by the child patient and parental stress management skills. Once the physician has formed a working relationship with the child, a special education session between physician and child, without the parent, provides an opportunity to correct any misconceptions or to offer more detailed information to the child. Obviously, the amount of detail presented depends on the age, comfort level, and sophistication of the child. This approach may lead to a warm bond between physician and child that can enhance compliance (adherence) with procedures and treatment. Although some parents may feel threatened by this exclusion, most are grateful that the physician is sharing the educational task with them. The major activity of children outside of the home is school. School begins the processes of working toward independence from parents, establishing peer relationships, and acquiring academic skills. The physical and emotional concomitants of life-threatening illness disrupt school attendance and performance.

Treatment and Adaptation Period
Normalcy is emphasized “Burden of Normalcy” is created The family has to reorganize itself but seem “normal” Given the improved survival rate in childhood cancer, health care professionals emphasize normality throughout the treatment and adaptation period. This approach creates a “burden of normalcy”8 as the family is faced with the task of reorganizing itself, changing previous priorities and expectations, and reassigning roles. Optimally, both parents are physically and emotionally available to share the responsibility of the child's care. Unfortunately, this is often not the case. The increased burden of care falls more heavily on one parent. 40 Families who live in communities without a major cancer treatment center face additional problems: the need to travel long distances for treatment; separation from home and most supports during a stressful and frightening time; and the strain on finances resulting from transportation, child care, and accommodations, all combined with rising medical costs.

Talking to the Dying Child
Two modes of Communicaton Protective Approach Open Approach Struggling with their own anticipations and fears of separation and death, the family needs assistance in refocusing on their child's thoughts and concerns. Many parents are unable to discuss the imminence of death with their child. 131 Parents often believe that the child is unaware of the prognosis and approaching death. Two opposing modes of communication at this time are described in the literature. 132 These are labeled “ the protective approach in which the ill child is shielded from knowledge of the disease diagnosis and prognosis; and, the open approach, which encourages providing an environment in which the child feels free to express concerns and ask questions about his or her condition.” 133 In the past, it was frequently assumed that children did not understand death and that creating an atmosphere of cheerful normality would protect the child from the seriousness of the illness as well as from the awareness of death as a possibility. Nonetheless, research has shown that children who exhibited a higher level of adaptation to the illness were members of families in which open discussion was allowed and maintained. Waechter 134 conducted a study of hospitalized and fatally ill children and stated that giving a child the opportunity to discuss issues related to death does not heighten anxiety. These findings support the prediction that “understanding, acceptance, and conveyance 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.” 134 In published accounts, parents themselves have documented with great feeling the self-awareness of their dying children. Well-known examples include books by John Gunther, Doris Lund, Mickie Sherman, and Nancy Roach. 135,136,137 and 138 What do we say to the dying child? How do you help? Children generally have two main questions. The first is, Am I going to die? When the answer is understood to be yes, the second questions is, When? It is helpful to point out to the child what can and cannot be done regarding the illness. Telling the child that cure is no longer a possibility is the most difficult but also the most important message to convey. It is easy for caregivers to camouflage difficult messages in professional jargon. One must give the child this particular message in an open, straightforward manner without going to the extreme of appearing uncaring. The child needs at this time a feeling of security and trust maintained through honest communication. In telling dying children that a cure is no longer possible, one must also leave room for hope. Hope is redirected from cure to comfort. Comfort includes having people around they love, being free of further diagnostic or treatment procedures, and having pain controlled. Although adolescents may need some time alone, one of the greatest fears of young patients is being abandoned by or separated from family and friends. If these children are in the hospital, a nonrestrictive visiting policy for family should be provided, and interaction with friends and other patients should be encouraged. Even children cared for at home need repeated reassurances that they will not be left alone. Providing comfort also involves acknowledgment and acceptance of the range of feelings that come and go. Children should be told that it is all right to feel confused, sad, or angry—and to talk about these feelings, or, at times, to remain silent. To the extent possible, children should be encouraged to participate in normal daily routines. Continued attendance at school (even if part-time) and involvement in family functions counteract boredom and boost quality of life. Each day can be organized so even children confined to bed feel they are important contributors to their world. Preserving familiar behaviors and schedules also serves to minimize feelings of being a burden. When given the opportunity, children frequently ask many questions. These often ask (a) what will death be like; (b) what will happen to them after they die; (c) if the “bad things” they have done or thought will cause them to be punished; (d) whether their parents will be all right after their death; (e) when they will again be with those closest to them; and (f) whether they will experience much pain while dying. Parents benefit from being informed of these thoughts. Parents also benefit from exploring their own spirituality. Such explorations, with or without the help of clergy, provide strength to parents as they provide support for both their dying and their healthy children. Depending on the child's religious upbringing, other spiritual concerns and questions may arise. For example, children experiencing considerable guilt and conflict or feelings of isolation may become frightened and preoccupied about whether “the devil is in their heart” or whether “God will stop watching over them.” Consultation with a chaplain specializing in work with terminally ill children can allay the child's fears and bring the child and family a renewed sense of comfort and peace. Parents often need help understanding their child's questions and providing answers at a level consistent with the child's developmental stage and knowledge of the disease.139 Some children keep most of their thoughts about death to themselves. This may be due to fear of emotional abandonment by family members and significant others or that their awareness adds an unbearable emotional burden to parents and siblings. 140 Through play, art, drama, and therapeutic conversation, mental help professionals can ascertain the child's private perceptions and concerns and can correct distortions, dispel fantasies, and promote self-esteem through mastery of fears.141 Parents should be encouraged to participate in such processes. As death approaches, it is important to help families to believe that they have done all they could for their child. Parents trying to hold on to any semblance of control may seem less cooperative or easily frustrated and annoyed. Such responses are appropriate given the sequence of experiences leading to the terminal phase of illness. Living with dying is a significant additional stress for families. 142 One needs to respect each family's readiness, delicately balancing life issues with those related to palliative care, death, and loss. The medical team's participation and investment in caring for the dying child is extremely important to and greatly appreciated by all families, even those who appear to be coping well on their own. The terminal phase of illness is an especially crucial time to involve all significant family members. As separation anxiety is heightened, feelings of helplessness and despair may prevail. Family members often find it helpful to participate in the child's physical and emotional care. This care can take place in the hospital or at home. It can include everything from having a sibling help the child eat to having a parent administer medications and oxygen. Family members vividly recollect these terminal events. They can either be plagued by them or find solace in their remembrance. 132 Parents, siblings, and others close to the child benefit greatly from having someone available with whom to share their thoughts, fears, and concerns, whether rational or irrational. Sensitive assistance should be given to the family with difficult decisions and preparations. Parents need repeated reassurance about the importance of their vigil with the child and how this vigil reduces their child's feelings of isolation and abandonment through the moment of death. Home hospice staff usually can provide assistance and guidance to parents and other family members.

“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.” Struggling with their own anticipations and fears of separation and death, the family needs assistance in refocusing on their child's thoughts and concerns. Many parents are unable to discuss the imminence of death with their child. 131 Parents often believe that the child is unaware of the prognosis and approaching death. Two opposing modes of communication at this time are described in the literature. 132 These are labeled “ the protective approach in which the ill child is shielded from knowledge of the disease diagnosis and prognosis; and, the open approach, which encourages providing an environment in which the child feels free to express concerns and ask questions about his or her condition.” 133 In the past, it was frequently assumed that children did not understand death and that creating an atmosphere of cheerful normality would protect the child from the seriousness of the illness as well as from the awareness of death as a possibility. Nonetheless, research has shown that children who exhibited a higher level of adaptation to the illness were members of families in which open discussion was allowed and maintained. Waechter 134 conducted a study of hospitalized and fatally ill children and stated that giving a child the opportunity to discuss issues related to death does not heighten anxiety. These findings support the prediction that “understanding, acceptance, and conveyance 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.” 134 In published accounts, parents themselves have documented with great feeling the self-awareness of their dying children. Well-known examples include books by John Gunther, Doris Lund, Mickie Sherman, and Nancy Roach. 135,136,137 and 138 What do we say to the dying child? How do you help? Children generally have two main questions. The first is, Am I going to die? When the answer is understood to be yes, the second questions is, When? It is helpful to point out to the child what can and cannot be done regarding the illness. Telling the child that cure is no longer a possibility is the most difficult but also the most important message to convey. It is easy for caregivers to camouflage difficult messages in professional jargon. One must give the child this particular message in an open, straightforward manner without going to the extreme of appearing uncaring. The child needs at this time a feeling of security and trust maintained through honest communication. In telling dying children that a cure is no longer possible, one must also leave room for hope. Hope is redirected from cure to comfort. Comfort includes having people around they love, being free of further diagnostic or treatment procedures, and having pain controlled. Although adolescents may need some time alone, one of the greatest fears of young patients is being abandoned by or separated from family and friends. If these children are in the hospital, a nonrestrictive visiting policy for family should be provided, and interaction with friends and other patients should be encouraged. Even children cared for at home need repeated reassurances that they will not be left alone. Providing comfort also involves acknowledgment and acceptance of the range of feelings that come and go. Children should be told that it is all right to feel confused, sad, or angry—and to talk about these feelings, or, at times, to remain silent. To the extent possible, children should be encouraged to participate in normal daily routines. Continued attendance at school (even if part-time) and involvement in family functions counteract boredom and boost quality of life. Each day can be organized so even children confined to bed feel they are important contributors to their world. Preserving familiar behaviors and schedules also serves to minimize feelings of being a burden. When given the opportunity, children frequently ask many questions. These often ask (a) what will death be like; (b) what will happen to them after they die; (c) if the “bad things” they have done or thought will cause them to be punished; (d) whether their parents will be all right after their death; (e) when they will again be with those closest to them; and (f) whether they will experience much pain while dying. Parents benefit from being informed of these thoughts. Parents also benefit from exploring their own spirituality. Such explorations, with or without the help of clergy, provide strength to parents as they provide support for both their dying and their healthy children. Depending on the child's religious upbringing, other spiritual concerns and questions may arise. For example, children experiencing considerable guilt and conflict or feelings of isolation may become frightened and preoccupied about whether “the devil is in their heart” or whether “God will stop watching over them.” Consultation with a chaplain specializing in work with terminally ill children can allay the child's fears and bring the child and family a renewed sense of comfort and peace. Parents often need help understanding their child's questions and providing answers at a level consistent with the child's developmental stage and knowledge of the disease.139 Some children keep most of their thoughts about death to themselves. This may be due to fear of emotional abandonment by family members and significant others or that their awareness adds an unbearable emotional burden to parents and siblings. 140 Through play, art, drama, and therapeutic conversation, mental help professionals can ascertain the child's private perceptions and concerns and can correct distortions, dispel fantasies, and promote self-esteem through mastery of fears.141 Parents should be encouraged to participate in such processes. As death approaches, it is important to help families to believe that they have done all they could for their child. Parents trying to hold on to any semblance of control may seem less cooperative or easily frustrated and annoyed. Such responses are appropriate given the sequence of experiences leading to the terminal phase of illness. Living with dying is a significant additional stress for families. 142 One needs to respect each family's readiness, delicately balancing life issues with those related to palliative care, death, and loss. The medical team's participation and investment in caring for the dying child is extremely important to and greatly appreciated by all families, even those who appear to be coping well on their own. The terminal phase of illness is an especially crucial time to involve all significant family members. As separation anxiety is heightened, feelings of helplessness and despair may prevail. Family members often find it helpful to participate in the child's physical and emotional care. This care can take place in the hospital or at home. It can include everything from having a sibling help the child eat to having a parent administer medications and oxygen. Family members vividly recollect these terminal events. They can either be plagued by them or find solace in their remembrance. 132 Parents, siblings, and others close to the child benefit greatly from having someone available with whom to share their thoughts, fears, and concerns, whether rational or irrational. Sensitive assistance should be given to the family with difficult decisions and preparations. Parents need repeated reassurance about the importance of their vigil with the child and how this vigil reduces their child's feelings of isolation and abandonment through the moment of death. Home hospice staff usually can provide assistance and guidance to parents and other family members.

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?” Struggling with their own anticipations and fears of separation and death, the family needs assistance in refocusing on their child's thoughts and concerns. Many parents are unable to discuss the imminence of death with their child. 131 Parents often believe that the child is unaware of the prognosis and approaching death. Two opposing modes of communication at this time are described in the literature. 132 These are labeled “ the protective approach in which the ill child is shielded from knowledge of the disease diagnosis and prognosis; and, the open approach, which encourages providing an environment in which the child feels free to express concerns and ask questions about his or her condition.” 133 In the past, it was frequently assumed that children did not understand death and that creating an atmosphere of cheerful normality would protect the child from the seriousness of the illness as well as from the awareness of death as a possibility. Nonetheless, research has shown that children who exhibited a higher level of adaptation to the illness were members of families in which open discussion was allowed and maintained. Waechter 134 conducted a study of hospitalized and fatally ill children and stated that giving a child the opportunity to discuss issues related to death does not heighten anxiety. These findings support the prediction that “understanding, acceptance, and conveyance 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.” 134 In published accounts, parents themselves have documented with great feeling the self-awareness of their dying children. Well-known examples include books by John Gunther, Doris Lund, Mickie Sherman, and Nancy Roach. 135,136,137 and 138 What do we say to the dying child? How do you help? Children generally have two main questions. The first is, Am I going to die? When the answer is understood to be yes, the second questions is, When? It is helpful to point out to the child what can and cannot be done regarding the illness. Telling the child that cure is no longer a possibility is the most difficult but also the most important message to convey. It is easy for caregivers to camouflage difficult messages in professional jargon. One must give the child this particular message in an open, straightforward manner without going to the extreme of appearing uncaring. The child needs at this time a feeling of security and trust maintained through honest communication. In telling dying children that a cure is no longer possible, one must also leave room for hope. Hope is redirected from cure to comfort. Comfort includes having people around they love, being free of further diagnostic or treatment procedures, and having pain controlled. Although adolescents may need some time alone, one of the greatest fears of young patients is being abandoned by or separated from family and friends. If these children are in the hospital, a nonrestrictive visiting policy for family should be provided, and interaction with friends and other patients should be encouraged. Even children cared for at home need repeated reassurances that they will not be left alone. Providing comfort also involves acknowledgment and acceptance of the range of feelings that come and go. Children should be told that it is all right to feel confused, sad, or angry—and to talk about these feelings, or, at times, to remain silent. To the extent possible, children should be encouraged to participate in normal daily routines. Continued attendance at school (even if part-time) and involvement in family functions counteract boredom and boost quality of life. Each day can be organized so even children confined to bed feel they are important contributors to their world. Preserving familiar behaviors and schedules also serves to minimize feelings of being a burden. When given the opportunity, children frequently ask many questions. These often ask (a) what will death be like; (b) what will happen to them after they die; (c) if the “bad things” they have done or thought will cause them to be punished; (d) whether their parents will be all right after their death; (e) when they will again be with those closest to them; and (f) whether they will experience much pain while dying. Parents benefit from being informed of these thoughts. Parents also benefit from exploring their own spirituality. Such explorations, with or without the help of clergy, provide strength to parents as they provide support for both their dying and their healthy children. Depending on the child's religious upbringing, other spiritual concerns and questions may arise. For example, children experiencing considerable guilt and conflict or feelings of isolation may become frightened and preoccupied about whether “the devil is in their heart” or whether “God will stop watching over them.” Consultation with a chaplain specializing in work with terminally ill children can allay the child's fears and bring the child and family a renewed sense of comfort and peace. Parents often need help understanding their child's questions and providing answers at a level consistent with the child's developmental stage and knowledge of the disease.139 Some children keep most of their thoughts about death to themselves. This may be due to fear of emotional abandonment by family members and significant others or that their awareness adds an unbearable emotional burden to parents and siblings. 140 Through play, art, drama, and therapeutic conversation, mental help professionals can ascertain the child's private perceptions and concerns and can correct distortions, dispel fantasies, and promote self-esteem through mastery of fears.141 Parents should be encouraged to participate in such processes. As death approaches, it is important to help families to believe that they have done all they could for their child. Parents trying to hold on to any semblance of control may seem less cooperative or easily frustrated and annoyed. Such responses are appropriate given the sequence of experiences leading to the terminal phase of illness. Living with dying is a significant additional stress for families. 142 One needs to respect each family's readiness, delicately balancing life issues with those related to palliative care, death, and loss. The medical team's participation and investment in caring for the dying child is extremely important to and greatly appreciated by all families, even those who appear to be coping well on their own. The terminal phase of illness is an especially crucial time to involve all significant family members. As separation anxiety is heightened, feelings of helplessness and despair may prevail. Family members often find it helpful to participate in the child's physical and emotional care. This care can take place in the hospital or at home. It can include everything from having a sibling help the child eat to having a parent administer medications and oxygen. Family members vividly recollect these terminal events. They can either be plagued by them or find solace in their remembrance. 132 Parents, siblings, and others close to the child benefit greatly from having someone available with whom to share their thoughts, fears, and concerns, whether rational or irrational. Sensitive assistance should be given to the family with difficult decisions and preparations. Parents need repeated reassurance about the importance of their vigil with the child and how this vigil reduces their child's feelings of isolation and abandonment through the moment of death. Home hospice staff usually can provide assistance and guidance to parents and other family members.

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 “Helping a child on his way” and “ending the child's suffering” are sometimes whispered or unspoken issues during the terminal stage of illness. More open and frank appraisal of these issues by health professionals with respect to adults with terminal illness is finally occurring. This more open discussion does not yet apply to children. An influential pediatric psychiatrist at a major university medical center once said, “I consider active euthanasia unthinkable. It implies an unwarranted assumption of infallibility on the part of the physician (spontaneous remissions have occurred in the sickest patients).” 32 Yet, in referring to heroic measure to save a comatose terminally ill child, he also stated, “Passive euthanasia (negative euthanasia) is a different matter.” 32 Physicians of terminally ill adult cancer patients may offer them the option of shortening their suffering. This may be accomplished through instructions not to treat new infections, not to use resuscitation, to withdraw steroids in patients with CNS tumors, to decrease or remove supplementary oxygen, or to use very-high-dose narcotics to remove the patient from suffering from pain. Similar approaches are known to be used at times by those treating pediatric oncology patients. These realities are rarely openly discussed. Although many health care professionals agree that children should not be allowed to die in agony, children do die that way. 128,147 A physician and the health care team ideally should be open to parents who wish to inquire about helping their child die in comfort. The physician can serve as a special listener, selectively interpreting and responding to the parent's concerns about suffering. When a parent wishes to ease the pain of dying through more aggressive use of pain medications or through the removal of those treatments that slow the pace of the dying, the physician must examine parental wishes in the context of physician's knowledge of the child's clinical status. If the physician finds his or her perceptions concordant with those of the parent, we believe it appropriate to stand by that parent, to be an advocate for the needs of the dying child while adhering to local laws and medical ethics. Parents obviously have more control in these situations when their terminally ill child is at home or in a residential hospice. After the child's death, the involved professional needs to be available to the parents. It takes time for them to absorb the reality of a passive euthanasia decision into their lives and values. Coming fully to terms with their decision may, like the mourning process, extend over several years. Actions of passive euthanasia are taken out of love and perhaps a feeling in some that they do not have the “infinite strength” to stand vigil over the terminal suffering of their child. Be aware that the echoes and emotional doubts over these actions linger for extended periods of time. As health professionals, we should be available to listen to the parents quietly and acceptingly.

Bereavement in the Family
“... More intense grief reactions of somatic types, greater deression, anger and guilt with accompanying feelings of despair” The death of a child is one of life's great tragedies. It disrupts a family system in multiple ways. In our society, the bereavement process may have even greater consequences than in earlier times because of the absence of general familiarity with death and its rituals. Death in children accounts for less than 5% of mortality in the United States.151 Cancer deaths account for 18% of that pediatric mortality. 151 This means that families who lose a child to cancer are an isolated minority, with relatively few social supports for their grief. The child's death marks the major milestone in a bereavement process initiated when the cancer diagnosis was first heard. Varying degrees of family disruption consequent to such a death have been identified. 142,152,153,154 and 155 Included are rates of marital separation and divorce ranging from 23% to 60%. 156,157 One study comparing bereavement in parents with bereavement over the death of a parent or spouse found “more intense grief reactions of somatic types, greater depression . . . anger and guilt with accompanying feelings of despair.” 158 Lewis and Lewis159 identify “sudden” (guiltand mourning), “acute” (anger, overidealizing, fantasy), and “chronic” (remorse, relief, and guilt) reactions. The bereavement process continues in undulating waves, perhaps for as long as 3 to 5 years after a child's death. 160,161 and 162 No parents ever “get over” the death of their child. The parents suffer from both the loss of the child and the loss of what the child represented to them. In our culture, children represent continuity of their parents' lives into the future, beyond death.163 Children also are vessels into which parents tend to pour hopes and dreams not only for the child but also for themselves through the child's growth. Mothers and fathers differ from one another in their responses based on their own personalities, life experiences, and beliefs. The impact of the loss varies with the age of the child: A “different kind of pain” is associated with the death of younger and older children. 163 The older the child, the more experience the family has had with him or her. The more formed his or her personality, the greater the effects on the family system and its members, and the more extensive the memories. A child's death may precipitate guilt in parents in reaction to feelings they perceive as negative toward the child. These usually involve wishes that “it would all finally end.”159 When this kind of guilt is left unresolved, unexposed, and unexamined, it is a significant psychologic risk factor for the parent. Other special vulnerabilities involve the deceased child's role in the family. For example, the more emotionally dependent the family was on the child and the more the child was viewed by one or both parents as an emotional extension of self (in a need fulfillment or symbiotic sense), the more disruptive the child's death is to the family system. 142,164 The same is true for a child who served as the essential bond between parents or one who was the “communicator” for spouses in conflict. Spinetta and colleagues2 found that certain family coping efforts during the course of the illness can make a difference in their adaptation after the death. Better adjustment was seen in (a) parents who had a viable and ongoing “significant other” to turn to for help during the course of the illness; (b) those who had an open and responsive communication with the child during the illness and who gave their child the information and emotional support he or she needed; and (c) those who had a consistent philosophy of life that helped the family to accept the diagnosis and cope with its consequences. Participation in the care of the child during his or her life is associated with healthier bereavement responses. Similarly, attendance to the child during the dying process through home care or hospice care makes a significant difference, attenuating guilt feelings and anger. Siblings should be informed by the parents of their dying sibling's status and of the child's death (if siblings are not present). This should be done in a way that is tailored to siblings' developmental stages. Siblings, like the parents, have immediate and long-term reactions. These reactions vary, based on factors that include the quality of their relationship with the deceased, whether they were same or different gender, whether there was a twin relationship, and whether the deceased was an older or younger child. Children of the same gender as the deceased sibling and twins are always at higher risk for failure in working through the loss. In the absence of guidance, and depending on family dynamics, they may feel it necessary to take on the identity of the deceased. Families generally do not seek professional help to deal with the upheaval and sadness of bereavement. If they were involved in a hospice, follow-up counseling is supposed to be offered. Parents, siblings, and grandparents benefit from the opportunity to reflect on and review the illness-dying-death experience until acceptance occurs.17 When the atmosphere of the treatment site is accepting, families may return over a period of many years for spontaneous visits to the oncology service where their child was treated. Ongoing availability and interest in the health of these families should not stop at the point of the child's death.

Parents suffer from both the loss of the child and the loss of what the child represented to them. The death of a child is one of life's great tragedies. It disrupts a family system in multiple ways. In our society, the bereavement process may have even greater consequences than in earlier times because of the absence of general familiarity with death and its rituals. Death in children accounts for less than 5% of mortality in the United States.151 Cancer deaths account for 18% of that pediatric mortality. 151 This means that families who lose a child to cancer are an isolated minority, with relatively few social supports for their grief. The child's death marks the major milestone in a bereavement process initiated when the cancer diagnosis was first heard. Varying degrees of family disruption consequent to such a death have been identified. 142,152,153,154 and 155 Included are rates of marital separation and divorce ranging from 23% to 60%. 156,157 One study comparing bereavement in parents with bereavement over the death of a parent or spouse found “more intense grief reactions of somatic types, greater depression . . . anger and guilt with accompanying feelings of despair.” 158 Lewis and Lewis159 identify “sudden” (guiltand mourning), “acute” (anger, overidealizing, fantasy), and “chronic” (remorse, relief, and guilt) reactions. The bereavement process continues in undulating waves, perhaps for as long as 3 to 5 years after a child's death. 160,161 and 162 No parents ever “get over” the death of their child. The parents suffer from both the loss of the child and the loss of what the child represented to them. In our culture, children represent continuity of their parents' lives into the future, beyond death.163 Children also are vessels into which parents tend to pour hopes and dreams not only for the child but also for themselves through the child's growth. Mothers and fathers differ from one another in their responses based on their own personalities, life experiences, and beliefs. The impact of the loss varies with the age of the child: A “different kind of pain” is associated with the death of younger and older children. 163 The older the child, the more experience the family has had with him or her. The more formed his or her personality, the greater the effects on the family system and its members, and the more extensive the memories. A child's death may precipitate guilt in parents in reaction to feelings they perceive as negative toward the child. These usually involve wishes that “it would all finally end.”159 When this kind of guilt is left unresolved, unexposed, and unexamined, it is a significant psychologic risk factor for the parent. Other special vulnerabilities involve the deceased child's role in the family. For example, the more emotionally dependent the family was on the child and the more the child was viewed by one or both parents as an emotional extension of self (in a need fulfillment or symbiotic sense), the more disruptive the child's death is to the family system. 142,164 The same is true for a child who served as the essential bond between parents or one who was the “communicator” for spouses in conflict. Spinetta and colleagues2 found that certain family coping efforts during the course of the illness can make a difference in their adaptation after the death. Better adjustment was seen in (a) parents who had a viable and ongoing “significant other” to turn to for help during the course of the illness; (b) those who had an open and responsive communication with the child during the illness and who gave their child the information and emotional support he or she needed; and (c) those who had a consistent philosophy of life that helped the family to accept the diagnosis and cope with its consequences. Participation in the care of the child during his or her life is associated with healthier bereavement responses. Similarly, attendance to the child during the dying process through home care or hospice care makes a significant difference, attenuating guilt feelings and anger. Siblings should be informed by the parents of their dying sibling's status and of the child's death (if siblings are not present). This should be done in a way that is tailored to siblings' developmental stages. Siblings, like the parents, have immediate and long-term reactions. These reactions vary, based on factors that include the quality of their relationship with the deceased, whether they were same or different gender, whether there was a twin relationship, and whether the deceased was an older or younger child. Children of the same gender as the deceased sibling and twins are always at higher risk for failure in working through the loss. In the absence of guidance, and depending on family dynamics, they may feel it necessary to take on the identity of the deceased. Families generally do not seek professional help to deal with the upheaval and sadness of bereavement. If they were involved in a hospice, follow-up counseling is supposed to be offered. Parents, siblings, and grandparents benefit from the opportunity to reflect on and review the illness-dying-death experience until acceptance occurs.17 When the atmosphere of the treatment site is accepting, families may return over a period of many years for spontaneous visits to the oncology service where their child was treated. Ongoing availability and interest in the health of these families should not stop at the point of the child's death.

Better adjustement if: With Viable and ongoing “significant other” Open and responsive communication with child during illness Those with consistend life philosophies The death of a child is one of life's great tragedies. It disrupts a family system in multiple ways. In our society, the bereavement process may have even greater consequences than in earlier times because of the absence of general familiarity with death and its rituals. Death in children accounts for less than 5% of mortality in the United States.151 Cancer deaths account for 18% of that pediatric mortality. 151 This means that families who lose a child to cancer are an isolated minority, with relatively few social supports for their grief. The child's death marks the major milestone in a bereavement process initiated when the cancer diagnosis was first heard. Varying degrees of family disruption consequent to such a death have been identified. 142,152,153,154 and 155 Included are rates of marital separation and divorce ranging from 23% to 60%. 156,157 One study comparing bereavement in parents with bereavement over the death of a parent or spouse found “more intense grief reactions of somatic types, greater depression . . . anger and guilt with accompanying feelings of despair.” 158 Lewis and Lewis159 identify “sudden” (guiltand mourning), “acute” (anger, overidealizing, fantasy), and “chronic” (remorse, relief, and guilt) reactions. The bereavement process continues in undulating waves, perhaps for as long as 3 to 5 years after a child's death. 160,161 and 162 No parents ever “get over” the death of their child. The parents suffer from both the loss of the child and the loss of what the child represented to them. In our culture, children represent continuity of their parents' lives into the future, beyond death.163 Children also are vessels into which parents tend to pour hopes and dreams not only for the child but also for themselves through the child's growth. Mothers and fathers differ from one another in their responses based on their own personalities, life experiences, and beliefs. The impact of the loss varies with the age of the child: A “different kind of pain” is associated with the death of younger and older children. 163 The older the child, the more experience the family has had with him or her. The more formed his or her personality, the greater the effects on the family system and its members, and the more extensive the memories. A child's death may precipitate guilt in parents in reaction to feelings they perceive as negative toward the child. These usually involve wishes that “it would all finally end.”159 When this kind of guilt is left unresolved, unexposed, and unexamined, it is a significant psychologic risk factor for the parent. Other special vulnerabilities involve the deceased child's role in the family. For example, the more emotionally dependent the family was on the child and the more the child was viewed by one or both parents as an emotional extension of self (in a need fulfillment or symbiotic sense), the more disruptive the child's death is to the family system. 142,164 The same is true for a child who served as the essential bond between parents or one who was the “communicator” for spouses in conflict. Spinetta and colleagues2 found that certain family coping efforts during the course of the illness can make a difference in their adaptation after the death. Better adjustment was seen in (a) parents who had a viable and ongoing “significant other” to turn to for help during the course of the illness; (b) those who had an open and responsive communication with the child during the illness and who gave their child the information and emotional support he or she needed; and (c) those who had a consistent philosophy of life that helped the family to accept the diagnosis and cope with its consequences. Participation in the care of the child during his or her life is associated with healthier bereavement responses. Similarly, attendance to the child during the dying process through home care or hospice care makes a significant difference, attenuating guilt feelings and anger. Siblings should be informed by the parents of their dying sibling's status and of the child's death (if siblings are not present). This should be done in a way that is tailored to siblings' developmental stages. Siblings, like the parents, have immediate and long-term reactions. These reactions vary, based on factors that include the quality of their relationship with the deceased, whether they were same or different gender, whether there was a twin relationship, and whether the deceased was an older or younger child. Children of the same gender as the deceased sibling and twins are always at higher risk for failure in working through the loss. In the absence of guidance, and depending on family dynamics, they may feel it necessary to take on the identity of the deceased. Families generally do not seek professional help to deal with the upheaval and sadness of bereavement. If they were involved in a hospice, follow-up counseling is supposed to be offered. Parents, siblings, and grandparents benefit from the opportunity to reflect on and review the illness-dying-death experience until acceptance occurs.17 When the atmosphere of the treatment site is accepting, families may return over a period of many years for spontaneous visits to the oncology service where their child was treated. Ongoing availability and interest in the health of these families should not stop at the point of the child's death.

Siblings should also be informed Tailored to developmental ages Follow-up counseling should be offered The death of a child is one of life's great tragedies. It disrupts a family system in multiple ways. In our society, the bereavement process may have even greater consequences than in earlier times because of the absence of general familiarity with death and its rituals. Death in children accounts for less than 5% of mortality in the United States.151 Cancer deaths account for 18% of that pediatric mortality. 151 This means that families who lose a child to cancer are an isolated minority, with relatively few social supports for their grief. The child's death marks the major milestone in a bereavement process initiated when the cancer diagnosis was first heard. Varying degrees of family disruption consequent to such a death have been identified. 142,152,153,154 and 155 Included are rates of marital separation and divorce ranging from 23% to 60%. 156,157 One study comparing bereavement in parents with bereavement over the death of a parent or spouse found “more intense grief reactions of somatic types, greater depression . . . anger and guilt with accompanying feelings of despair.” 158 Lewis and Lewis159 identify “sudden” (guiltand mourning), “acute” (anger, overidealizing, fantasy), and “chronic” (remorse, relief, and guilt) reactions. The bereavement process continues in undulating waves, perhaps for as long as 3 to 5 years after a child's death. 160,161 and 162 No parents ever “get over” the death of their child. The parents suffer from both the loss of the child and the loss of what the child represented to them. In our culture, children represent continuity of their parents' lives into the future, beyond death.163 Children also are vessels into which parents tend to pour hopes and dreams not only for the child but also for themselves through the child's growth. Mothers and fathers differ from one another in their responses based on their own personalities, life experiences, and beliefs. The impact of the loss varies with the age of the child: A “different kind of pain” is associated with the death of younger and older children. 163 The older the child, the more experience the family has had with him or her. The more formed his or her personality, the greater the effects on the family system and its members, and the more extensive the memories. A child's death may precipitate guilt in parents in reaction to feelings they perceive as negative toward the child. These usually involve wishes that “it would all finally end.”159 When this kind of guilt is left unresolved, unexposed, and unexamined, it is a significant psychologic risk factor for the parent. Other special vulnerabilities involve the deceased child's role in the family. For example, the more emotionally dependent the family was on the child and the more the child was viewed by one or both parents as an emotional extension of self (in a need fulfillment or symbiotic sense), the more disruptive the child's death is to the family system. 142,164 The same is true for a child who served as the essential bond between parents or one who was the “communicator” for spouses in conflict. Spinetta and colleagues2 found that certain family coping efforts during the course of the illness can make a difference in their adaptation after the death. Better adjustment was seen in (a) parents who had a viable and ongoing “significant other” to turn to for help during the course of the illness; (b) those who had an open and responsive communication with the child during the illness and who gave their child the information and emotional support he or she needed; and (c) those who had a consistent philosophy of life that helped the family to accept the diagnosis and cope with its consequences. Participation in the care of the child during his or her life is associated with healthier bereavement responses. Similarly, attendance to the child during the dying process through home care or hospice care makes a significant difference, attenuating guilt feelings and anger. Siblings should be informed by the parents of their dying sibling's status and of the child's death (if siblings are not present). This should be done in a way that is tailored to siblings' developmental stages. Siblings, like the parents, have immediate and long-term reactions. These reactions vary, based on factors that include the quality of their relationship with the deceased, whether they were same or different gender, whether there was a twin relationship, and whether the deceased was an older or younger child. Children of the same gender as the deceased sibling and twins are always at higher risk for failure in working through the loss. In the absence of guidance, and depending on family dynamics, they may feel it necessary to take on the identity of the deceased. Families generally do not seek professional help to deal with the upheaval and sadness of bereavement. If they were involved in a hospice, follow-up counseling is supposed to be offered. Parents, siblings, and grandparents benefit from the opportunity to reflect on and review the illness-dying-death experience until acceptance occurs.17 When the atmosphere of the treatment site is accepting, families may return over a period of many years for spontaneous visits to the oncology service where their child was treated. Ongoing availability and interest in the health of these families should not stop at the point of the child's death.

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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

A Case of Pontine Glioma

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