INCREASED ICP -PG DISCUSSION

 

• 3 ys old on treatment for neuroblastoma stage 3 develops  irritability,  vomiting,weakness of left leg and arm. Bp 120/74mm hg pr 70/mt He is drowsy irritable,pupil  irregular, gaze palsy +, tone increased on left side, plantar up going disc margins are blurred . pt was put on ,head elevation dexamethasone  and other symptomatic measures
• The signs and symptoms of increased intracranial pressure (ICP) are often a signal of a serious intracranial process that may require surgicalor intensive care intervention depending on the underlying cause.
• Brain tumors are the most common solid neoplasms in children and frequently lead to increased ICP by direct mass effect or blockage of cerebrospinal fluid (CSF) flow
• Children with increased ICP may present with a history of recurrent vomiting, lethargy, and new headaches of increasing frequency or severity (crescendo headaches) or that awaken them from sleep

Increased Intracranial Pressure

• Loss of appetite, nausea, vomiting, headache, or lethargy
• Inattention, decreased ability to arouse
• Papilledema, upward gaze paresis
• Increased tone, positive Babinski reflex
• Focal signs and history compatible with an intracranial mass
• Mass lesion, cerebral edema, or enlarged ventricles in an imaging study
• Elevated cerebrospinal fluid pressure measured manometrically in the intrathecal or intracranial space

 

• Physical findings may include elevated optic disk, failure of upward gaze, hypertonicity of the extremities, and depressed alertness or inattention. Localized findings on neurologic examination may point to a lesion indicative of a space-occupying intracranial mass, which could contribute to increased ICP 

 

What is the Pathophysiology?

• The problem of increased ICP can be understood in terms of theMonro-Kellie doctrine, which applies to he rigid cranial compartment and pressure-volume relationships of the contents. This doctrineis conceptually useful even though not lways quantitatively predictive because of the variable compliance of the child’s skull and dural membranes, particularly in the first 2 years of life before mos tof the cranial sutures are fused. The skull and dura mater form a relatively rigid compartment; any increase in 1 of the 3 intracranial volume  components—brain parenchyma, CSF, and blood—must occura t the expense of one or both of the other 2. Decreased volume leads to increased pressure in an inverse relationship; however, the rise becomes much steeper when initial compliance factors are over whelmed.Irreversible damage to brain tissue occurs primarily as a result of ressure of the other components overtaking the arterial blood pressure and not allowing adequate tissue perfusion.
• In younger children, non-fused sutures allow ore compliance if volume increases are relatively slow, but this factor is not as true for acute volume increases. In addition, pressure gradients exist across compartments or sites of CSF flow obstruction, or even around lesions within brain parenchyma, and this leads to focal findings in addition to those caused by global ICP or perfusion changes.
• Changes in any of the 3 components making up the intracranial lvolume may result in increased ICP in several ways. First, the brain parenchyma component ay be directly increased by mass lesions such as neoplasms, abscesses, or hemorrhages. Vasogenic edema may increase the brain parenchyma olume because of vascular leakage due to cytokines. Brain edema may also result from cytotoxic damage, cell death, and necrosis, producing increased interstitialoncotic pressure from released proteins and ions, and cellular inflammatory and repair processes. The immediate cause may be mediated by cellular insults including hypoxemia; intermediary metabolic toxins, including neuronal excitotoxins; and depletion of energy substrates which are consequential to major vessel thrombosis, contusional trauma or diffuse axonal injury, anoxia from cardiac arrest, hypertensive encephalopathy, encephalitic infection, or external metabolic poisoning. Edema with head trauma is worse in children than in adults and may be a combination of vasogenic and cytotoxic edema and related to neurogenic inflammatory release of substance P and calcitonin gene–related peptide at the molecular level.
• Second, the pressure of the CSF volume component (ventricles or subarachnoid spaces) may increase in hydrocephalus. Hydrocephalus can result in 2 ways: from a discrepancy in the rate of formation of CSF relative to absorption and from an obstruction between the point of formation in the lateral ventricles and the sites of absorption at the arachnoid granulations. An obstruction can occur with a congenital malformation; a parenchymal or intraventricular mass such as a cyst or neoplasm; CSF inflammatory cells from meningitis, ventriculitis, or hemorrhage; subarachnoid protein or debris; displaced brain parenchyma from mass effect; or even overgrowth of dural tissue. The small passageways connecting the ventricular system, the foramen of Monro and the aqueduct of Sylvius; the exits of the ventricular system, the foramen of Magendie and foramen of Luschka; and the cisterns surrounding the brain stem are particularly vulnerable points of obstruction. Another type of brain edema, interstitial edema, is characterized by periventricular transudation of CSF into the adjacent white matter and is generally seen in patients with acute or subacute hydrocephalus.
• Third, ICP may rise because the intravascular volume component may increase. One process that leads to this increase is venous outflow obstruction, such as with a dural sinus thrombosis. Many cases of idiopathic intracranial hypertension are associated with transverse sinus stenosis or thrombosis. Other processes that raise jugularvenous pressure may also increase ICP. In addition, the intracranial arterial vascular volume is affected by carbon dioxidepartial pressure. It not only increases with hypercapnia but alsodecreases with hypocapnia, which occurs with compensatory central neurogenic hyperventilation or iatrogenic lowering of ICP bymechanical hyperventilation.
• Because the physiology is dynamic, it has proven useful to quantitate ICP for management purposes. Intracranial pressureis oftenmeasured as cm H2O while blood pressure is noted as mm Hg; both types of units are noted here. Normal ICP levels are somewhat lower in the neonatal and infantile period at about 6 cm H2O (5 mm Hg),but in adolescents, pressures above 25 cm H2O (18 mm Hg) are abnormal and may produce symptoms. Although it is possible tohave normal cognitive function at an ICP of 52 cm H2O (40 mm Hg),this assumes an adequate perfusion pressure.
• The ICP becomes clinically significant when the perfusion pressure is compromised, whichmay occur when the ICP is 78 cm H2O (60 mm Hg) below the mean arterial pressure, and it can become dangerous when the ICP is only52 cm H2O (40 mm Hg) below the mean arterial pressure. Decreasedperfusion produces swollen, damaged tissue, which increases thebrain parenchymal compartment volume and further exacerbates the pressure-volume problem in a snowballing fashion.As ICP increases, brain perfusion pressure may be maintained transiently by a spontaneous increase in mean arterial pressure, a response referred to as the Cushing response (hypertension along with bradycardia and bradypnea). Although the relationship may not be universally reliable, when it is present with other suggestive clinical circumstances, the rise in systemic pressure can be a useful clinical sign of increased ICP. Normally, changes in arterial cerebrovascular resistance meet changes in perfusion pressure to maintain constant cerebral blood flow, a process called autoregulation. However, this process is frequently compromised after head trauma or asphyxia.
• Acute or subacute changes in pressure within an intracranial compartment may produce a pressure gradient across compartments that may precipitate brain herniation syndrome (Figure 68-1). An ominous heralding sign of transtentorial herniation of the uncus of the temporal lobe is loss of the pupillary light reflex caused by entrapment of the third cranial nerve. This herniation often leads to irreversible brain stem damage as well as infarcts and additional secondary edema, which can end with brain death. Focally increased posterior fossa pressure may result in a pressure cone downward through the foramen magnum–compressing medullary centers, also leading to apnea and brain death. A marginally compensated system could be decompensated by an ill-advised lumbar puncture when the spinal compartment pressure is acutely lowered, increasing the pressure gradient across the foramen magnum and producing herniation.

 

What are the Differential Diagnosis?

• Complicated migraine, seizures, and metabolic derangements are common problems that sometimes have a clinical presentation similar to increased ICP. A characteristic prodrome or the “pounding” nature of the pain may help separate migraine from increased ICP. At the initial headache presentation or when only a short headache history is present, the complicated migraine diagnosis may be oneof exclusion. If children display focal neurologic signs with some ofthe general symptoms of increased ICP, an imaging study to rule outa space-occupying lesion and confirm the safety of a lumbar puncture,and a subsequent measurement of normal pressure by lumbarpuncture manometry, may need to be performed as support for the diagnosis of migraine.
• In children who are only partially responsive, the task of distinguishinga seizing or postictal state from a ondition that may be producing increased ICP is sometimes difficult. Findings that suggesta seizure include rhythmic, clonic movements or sudden myoclonicjerks; rapid or variable changes of tone or posturing that aredifferent from the decerebrate posturing that may accompany a process producing increased ICP; abrupt, fluctuating changes of autonomicfunction (eg, heart rate, blood pressure, pupillary size); salivaproduction without swallowing; and a history of prior seizures.
• Sometimes, however, only direct electroencephalogram (EEG) monitoringwith ICP monitoring are able to distinguish ongoing electrographic“subclinical” seizure activity from increased ICP as the causeof the change in level of responsiveness.In some cases, diffuse brain dysfunction from a toxic or metabolicetiology mimics increased ICP. Such toxic/metabolic causes include medication toxicity, electrolyte or blood chemistry imbalances,and systemic infections. With toxic/metabolic disorders, inattentionis often accompanied by a confusional state with disorientation, incoherence, and sometimes agitation. In contrast,with subacutely increased ICP, inattention is frequently accompaniedby slowness of thought, perseveration, decreased mental activity, and impaired gait.

 Which all Laboratory Tests are relevant?

• If mental status changes suggest a toxic or metabolic aberration,appropriate laboratory screens should be performed, which may include electrolytes, toxicologic screen, liver function tests, and kidney function tests. If signs of meningeal irritation or infection are present without lateralized signs of altered tone or strength, evidencing an inter-compartmental pressure gradient, a CSF examination should be done. Otherwise the possibility of herniation after lumbarpuncture might be clarified by a preceding imaging study. If thereis lumbar tap danger, CSF analysis and pressure measurements can also be made from a ventriculostomy. If there are clinical signs ofincreased ICP and no focal clinical or maging signs of a mass, a lumbar puncture can also be diagnostic and therapeutic for idiopathic intracranial hypertension.

 

 

 

What is the role of Imaging Studies

• A computed tomography (CT) scan should be performed wheneverchildren’s signs or symptoms indicate the possibility of increasedICP. Severe head trauma patients frequently have a particularly dynamic pathophysiology, and an additional early CT scan may beindicated for increasing hemorrhage, mass effect, or ventricular sizealong with ICP monitoring. Intravenous (IV) contrast should be given if a source of disruption in the blood-brain barrier (eg, infection,inflammation, neoplasia) is suspected. A magnetic resonancevenogram can be obtained if there is a possibility of a venous sinus thrombosis. Computed tomography angiography or traditional intraluminalangiography with the option of intervention to preventrebleeding may be the best studies in the case of an intracranial hemorrhage of unknown source.

What is the Management Interventions in Increased Intracranial Pressure?

• Keep head of bed elevated to 30 degrees.
• Maintain normal or elevated systemic blood pressure

.• Control hyperventilation to Paco2 at 32–38 mm Hg and provide supplementalO2 and PEEP as needed to keep Pao2 .90 mm Hg

• If ICP progressively rises, pressure waves .20 mm Hg last longer than 5 minutes, or any pressure in first 24 hours is .30 mm Hg, give mannitol, 250–1,000 mg/kg IV. This may be repeated to maintain serum osmols at 300–320 mOsm.
• If mannitol needs repeating in ,6 hours or osmolality is .320 mOsm —Give pentobarbital, 5 mg/kg IV, then 2 mg/kg/h IV monitoring to blood level of 25–35 mg/mL, burst-suppression pattern with 10 s between bursts on EEG, and cardiac index .2.7 L/min/m2.
• or Give midazolam by titrating the dose upward starting at 0.1 mg/kg/h IV to the same EEG criteria and limited by the same cardiac index criteria. Particularly in trauma cases in which the cerebral lesion is primarily uni-hemispheric and pressure is rapidly Increasing, hemicraniectomy should be considered.

 

 

 

What is the Management?

If idiopathic intracranial hypertension is diagnosed, the pressure can be monitored until stable with lumbar punctures. Increased ICP may respond to diuretics such as acetazolamide at high dose (20 mg/kg/d)or furosemide, as well as the removal of CSF during the lumbar puncture.

The primary danger in this condition is an expanding blindspot and eventual blindness due to pressure at the optic nerve head.Visual fields should be monitored, and if medical therapy is not successful,lumbar or ventricular peritoneal shunt placement can bedone surgically.

 

• Encephalopathic children whose ICP is markedly elevated or likely to rise rapidly require treatment in an intensive care unit. When diagnosticimaging studies reveal an etiology for the increased ICP, suchas a rapidly enlarging epidural hematoma, immediate neurosurgical jcraniotomy may be necessary. Other focal space-occupyinglesions seen on scans may not require immediate craniotomy, dependingon size and position of the lesion as well as the distortion of normalbrain tissue and potential for imminent loss of perfusion;neoplastic lesions may require diagnostic biopsy or excisional biopsywithin a few days if surgically accessible. Mineralocorticoids (dexamethasone0.25–0.5 mg/kg every 6 hours) are useful in situationsin which the pressure is produced by a component of vasogenicedema, such as that surrounding neoplasms. Measures should alsobe used to help prevent a stress ulcer. Hypotonic IV fluids should beavoided, and the patient should be monitored for the syndrome ofinappropriate secretion of antidiuretic hormone with serum and urineosmolalities. Hypoglycemia and hyperglycemia should also be avoided. If acute danger of herniation due to a pressure gradient produced by CSF flow blockage is present, a temporary ventriculostomy may be indicated to relieve the CSF pressure. If an infectious process, including focal lesions, abscess, cerebritis, or encephalitis, is suspected, antibiotics or antiviral agents are indicated. Following directed specific treatment of the underlying lesion, the increased ICP may resolve spontaneously.
• If hydrocephalus due to CSF flow obstruction is still present after initial therapy is completed, ventriculoperitoneal (VP) shunting of CSF may be necessary. Endoscopic third ventriculotomy avoids long-term VP shunt hardware complications of obstruction and infection but is less often successful in relieving the pressure in younger children than older ones.
• If there is no mass or other space-occupying lesion to be surgically removed, interventional therapies are directed toward maintaining perfusion of recovering brain tissue.
•  In patients with head injury, a GCS score of 8 or less can be used as a guideline for ICP monitoring. Intracranial pressure can be monitored on an ongoing basis with commonly used neurosurgically placed devices, including the fiber-optic micro-transducer and intraventricular catheter or ventriculostomy. The former device can measure pressure in brain parenchyma as well as in fluid-filled spaces. A distinct advantage of the latter device is in allowing for therapeutic CSF drainage to relieve pressure, although it may be difficult to place if the ventricles are small or shifted and it carries a slight risk of hemorrhage or infection (increasing to a plateau at day 4 of 1%–2% per day).
• Intracranial hypertension frequently peaks at 1 to 4 days after severe trauma. Intracranial pressure monitoring with devices and therapy based on the measurements, however, have not been helpful in mostcases of severe ischemic damage, infection, or poisoning. This finding may be due to the widespread nature of the insult and braininvolvement so that little normally responding tissue remains inwhich perfusion could be maintained.
• Children with a decreased or fluctuating level of responsiveness may require EEG monitoring of cerebral lectrical activity. Seizuresmay occur even in the presence of increased ICP. Anticonvulsant therapy is indicated if evidence of clinical or electrographic seizuresis present. In addition, the EEG may be used to monitor barbiturateorbenzodiazepine-induced coma, used for severely increased ICP.
• Respiratory physiology and ventilation are important in childrenwith increased ICP because hypoxia and ypercapnia can contribute to vasodilation and increased pressure. Rapid sequence intubationand avoiding ketamine and uccinylcholine help minimize elevations of ICP. Transmission of elevated intrathoracic pressure to intracranialvessels can be avoided by sedation and decreasing the inspiratory phase of the ventilator and avoiding high positive pressure and endexpiratory pressure. If acute lowering of pressure is necessary, hyperventilation to reduce the intracranial arterial blood volume is veryeffective, but on a chronic basis, carbon dioxide partial pressure should be kept at 32 to 38 mm Hg to avoid decreasing brain cell perfusion.Indomethacin is also a cerebral vasoconstrictor and carriesthe same risk to adequate perfusion. Elevating the head of the bed toabout 30 degrees and avoiding flexion or turning of the neck to prevent jugular kinking are effective in reducing ICP. Pain, fever, shivering,and seizures must be treated ggressively. Because the goal is toensure perfusion while lowering ICP, maintaining and even elevating systemic mean arterial pressure by appropriate use of fluid therapyand pressor agents are key therapeutic measures.
• Diuretic agents such as mannitol (osmotherapy) (0.25–1 g/kg bolus) may also be useful through reducing brain volume by removing water, changing the rheologic characteristics of blood, and producingreflex vasoconstriction, but caution is advised. Mannitol, as a chronic infusion, can eventually cross the blood-brain barrier anddraw more fluid into the brain. It is most effective where the bloodbrainbarrier is intact.
• Hypertonic saline (3%) (2–6 mL/kg bolus,then 0.1–1.0 mL/kg/h as a continuous infusion) may be an effectivealternative. Serum osmolarity greater than 320 mOsm/kg can leadto renal failure. By giving diuretic agents at intervals as a bolus and titrating up to the ICP-lowering dose, such effects can generally beavoided. Sometimes these agents are used to counter ICP plateauwaves or increased pressure with endotracheal suctioning or other procedures.
• In children with severe refractory increased ICP, especially if secondary to an acute focal process, barbiturates such as pentobarbital or the benzodiazepine midazolam can be given as a continuous IV infusion with appropriate monitoring of brain electrical activity, serum levels, and systemic and brain perfusion pressures (Box 68-1). These agents may serve to reduce brain metabolism without impairing vascular autoregulation significantly. Their risk is in reducing cardiac output and inducing associated infections, particularly pneumonia. Xenon CT measures multiple areas of local blood flow and may be a useful bedside technique to help specify targeted therapies.
• Decompressive craniotomy or craniectomy in early severe trauma in small series of patients has been associated with up to 50% goodoutcomes. Hypothermia to 93.2°F (34°C) for cardiac arrest and numerous “neuroprotective” agents continue to be studied as means to slow metabolism and the resulting excitotoxic glutamatergic damageand thereby reduce cytotoxic edema and spread of the volume of irreversibly damaged brain tissue into the surrounding penumbra of damaged but not dead brain.

 

NEUROBLASTOMA

Definition

Malignant embryonal tumor of precursor cells of sympathetic ganglia and adrenal medulla

Entity characterized by:

• Occasional spontaneous regression and differentiation to benign tumor especially in infants less than 12 months of age
•  Usually extremely malignant course in children in the advanced stage

Incidence

• Eight percent of all neoplasia in childhood
•  Annually new diagnosis in 11 in 1 million children less than 16 years of age
•  Most frequent malignant neoplasia in infants
•  Mean age at diagnosis 2.5 years

What is the Cumulative age distribution?

• <1 year of age 35%
•  <2 years of age 50%
•  <4 years of age 75%
•  <10 years of age 90%
• Rarely observed in adolescents and adults
•  Boy-girl ratio of 1.1:1.0

What is the Etiology and Pathogenesis?

• Etiology and Pathogenesis
•  Etiology unknown
•  Incidence of neuroblastic precursor cells in autopsies of infants less than 3 months
• old who have died from other causes is 40 times higher than expected
•  When discussing etiology factors such as alcohol and other drugs during pregnancy,parental occupation and viral infection should be considered
•  Familial occurrence as well as sibling and twin disease with different stages of neuroblastoma within the same family are rarely described
•  Association with neurofibromatosis, Hirschsprung disease, heterochromia iridis
•  Tumor cell chromosomal changes and various karyotypic abnormalities in the majority of patients are detectable (see below

what is the Molecular Cytogenetics?

• MYCN amplification and expression of neurotropic receptors (TRK1, –2, –3), neuropeptides (vasoactive intestinal polypeptide, VIP, somatostatin, SS), DNA index, and chromosomal changes (deletion 1p suppressor gene on chromosome 11, deletion 14, etc.) are prognostic factors which are summarized in the following

• <12 months(AGE)  MYCN  USUALLY NORMAL, dna -hyperploid, TRK 1- HIGH  STAGE  1,2,4s survival 95%

   

• >12 months mycn – normal   dna diploid          TRK- 1  LOW    STAGE 3,4, 50% SURVIVAL
• 1—5 years     mycn-      commonly  amplified      dna  Diploid            TRK1     Low    STAGE        3, 4                  25%

 

 

 

 

 

 

 

 

 

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what is the Pathology?

Macroscopic Features

• Pale gray, soft tumors with necrosis and calcification; in large tumors the demarcations are unclear; and the tumors are highly invasive into surrounding structures

Microscopic Features

• High variability with various differentiation stages of sympathetic nervous tissue ranging from undifferentiated neuroblastoma to ganglioneuroblastoma, to differentiated ganglioneuroma

– Differentiation with:

• Electron microscopy: for cytoplasmic structures as neurofilaments, neural tubules,neurosecretory granules
•  Immunohistochemistry: immunoperoxidase, neuron-specific enolase (NSE)
•  Fluorescence testing for intracellular catecholamines
•  Histologically small round-cell sarcoma which has to be differentiated from:– Primitive neuroectodermal tumor (PNET) , Embryonal undifferentiated rhabdomyosarcoma, Retinoblastoma, Ewing sarcoma, Lymphoma

Well-differentiated form: islets with polymorphic nucleus separated by fibrillary material; sometimes cells are characteristically arranged as rosettes

what are the Clinical Manifestations?

• Occurrence in any area with sympathetic nervous tissue

Primary locations in order of frequency

• Abdomen 65%
•  Adrenal medulla or sympathetic ganglia 46%
•  Posterior mediastinum 15%
•  Pelvic 4%
•  Head and neck 3%
•  Others 8%
•  Rarely: primary tumor undetectable

Common Symptoms

• Weight loss
•  Fever
•  Abdominal disturbances
•  Irritability
•  Pain of bones and joints
•  Child will not stand up, will not walk
•  Pallor
•  Lassitude

What are the Symptoms Associated with Catecholamine Production?

• Paroxysmal attacks of sweating, flushing, pallor
•  Headache
•  Hypertension
•  Palpitations

What are the Paraneoplastic Syndromes?

• VIP syndrome: untreatable diarrhea and low level of potassium caused by VIP in 5–10% of children
•  Opsoclonus: occurring mostly in well-differentiated neuroblastoma
•  Occasionally anemia in children with bone marrow infiltration (associated with thrombocytopenia and leukocytopenia) or in children with massive intratumoral hemorrhage

What are the Local Symptoms and Classic Signs?

Eyes

• Periorbital edema, swelling and yellow-brown ecchymoses
•  Proptosis and exophthalmos, strabismus, opsoclonus
•  Papillary edema, bleeding of the retina, atrophy of the optic nerve

Neck

• Cervical lymphadenopathy
•  Supraclavicular tumor
•  Horner syndrome: enophthalmos, miosis, ptosis, anhydrosis

Chest, Posterior Mediastinum and Vertebrae

• Compression of trachea: coughing, dyspnea
•  Infiltration in intervertebral foramina: dumbbell tumor
•  Compression of nerves: disturbances of gait, muscle weakness, paresthesia, bladder dysfunction, constipation (the latter symptoms indicate that emergency decompression is necessary)

Abdomen

• Retroperitoneal: intra-abdominal tumor, often firm on palpation; irregular mass often crossing the midline
•  Paravertebral and presacral: tendency to grow into the intravertebral foramina causing neurological dysfunction
•  Occasionally abdominal distension

Liver

• In infants marked hepatomegaly histologically known as “pepper type”

Skin

• Subcutaneous nodules of blue color which become reddish and then white owing to vasoconstriction from release of catecholamines after palpation
•  Nodules are mainly observed in neonates or infants with disseminated neuroblastoma

Bone

• Bone pain, sometimes as one of the first signs
•  Involvement mainly in the skull and long bones
•  On X-rays seen as lytic defects with irregular margins and periosteal reactions

Bone marrow

• Infiltration in more than 50% of patients
•  Peripheral thrombocytosis may indicate early stage of bone marrow infiltration
•  Peripheral thrombocytopenia and/or anemia indicate advanced stage of bone marrow infiltration

Where does Metastatic Spread occur?

• Lymphatic and/or hematogenous spread
•  Often initially present in:
•  40–50% of children less than 1 year of age
•  70% of children more than 1 year of age
•  In children with local neuroblastoma 35% have involvement of lymph nodes
•  Metastatic spread mostly in bone marrow, bone, liver and/or skin, rarely in brain,spinal cord, heart, lung

What are the Laboratory Findings?

Urinary catecholamine metabolites (tyrosine metabolism)

• High levels of vanillylmandelic acid (VMA) in 95%, homovanillic acid (HVA) in 90% and 3-methoxy-4-hydroxyphenylglycol (MHPG) in 97% of patients
•  Other metabolites of catecholamine metabolism for differentiation of pheochromocytoma, olfactory neuroblastoma, and melanoma
•  Spot tests with some false-positive and false-negative results
•  Urinary catecholamine metabolite analyses useful: follow-up tumor marker

Bone marrow

• Aspiration and biopsy at two or more locations for detection of bone marrow involvement

Diagnostic Imaging

Conventional X-ray

• Thoracic X-ray for mediastinal tumor
•  Abdominal X-ray: often calcifications visible in the tumor
•  Skeletal survey for cortical bone metastases (differential diagnosis: bone tumor,Langerhans histiocytosis, infectious disease of bone, battered-child syndrome, metastatic spread of other neoplasia

Methylisobenzyl guanidinium (MIBG) scintigraphy

• Radiolabeled specific and sensitive method for evaluation of the primary tumor and focal metastatic disease

Ultrasound, computed tomography and/or magnetic resonance imaging

• Provision of detailed information on tumor size, extension, metastases of abdominal, hepatic, skeletal, pulmonary, mediastinal and central nervous system involvement

Myelography

• In patients presenting with symptoms of neural compression (paraparesis)

What are the Differential Diagnosis?

Besides other tumors (see above Pathology):

• Osteomyelitis
•  Rheumatoid arthritis
•  Signs of VIP syndrome: infectious or autoimmune intestinal disorders
•  In opsoclonus or ataxia: neurological disorders
•  In infants with hepatomegaly: storage diseases

What is the staging?

International neuroblastoma staging system

Stage Description

• I Localized tumor with complete gross excision, with or without microscopic residual disease; representative ipsilateral lymph nodes negative for tumor microscopically (nodes attached to and removed with the primary tumor may be positive)
• IIA Localized tumor with incomplete gross excision; representative, ipsilateral nonadherent lymph nodes negative for tumor microscopically
• IIB Localized tumor with or without complete gross excision, with ipsilateral nonadherent lymph nodes positive for tumor. Enlarged contralateral lymph nodes must be negative microscopically
• III Unresectable unilateral tumor infiltrating across the midline, with or without regional lymph node involvement; or localized unilateral tumor with contralateral regional lymph node involvement; or midline tumor with bilateral extension by infiltration (unresectable) or by lymph node involvement
• IV Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin or other organs (except as defined for stage 4S)
• IVS Localized primary tumor (as defined for stages I, IIA, or IIB) with dissemination limited to skin, liver or bone marrow (limited to infants aged less than 1 year)

Therapy

• Therapy depends on age, stage, localization of neuroblastoma and molecular features at diagnosis

Surgical procedure

• Initial surgery for staging and eventually tumor excision without injury to vital structures;

and for biopsy

• Often radical resection becomes possible after chemotherapy and/or radiotherapy
•  Up to 25% of children with neuroblastoma initially have local lymph node involvement

Complications of surgery:

• Hemorrhage
•  In adherent tumors to the kidney, nephrectomy
•  Horner syndrome

Chemotherapy

• Combinations of chemotherapy: cyclophosphamide/ifosfamide, cisplatin, doxorubicin and epipodophyllotoxin according to international protocols
•  The course of therapy is divided into an induction phase and a consolidation phase

Radiotherapy

• Neuroblastoma is radiosensitive

Irradiation is limited by:

•  Age of the patient
•  Long-term sequelae
•  Combination with chemotherapy

When is Irradiation is indicated:?

• For shrinking of large tumor masses
•  For decompression of intraspinal tumor masses
•  For palliative treatment

What is the Risk-Adapted Management?

Low risk

• Stages I, IIA, IIB, IVS (DNA index more than 1)
•  No MYCN amplification
•  Favorable histology
•  Radical tumor resection eventually after chemotherapy and/or radiotherapy
•  Stage IVS (infants less than 12 months of age): high cure rate of 85–92% after staging and eventually tumor resection without chemotherapy and/or radiotherapy; infants with MYCN amplification are high-risk patients
•  In rapid progressive hepatomegaly with dyspnea initial chemotherapy and eventually low-dose irradiation of the liver (1.5–6 Gy) may be helpful  In children with intraspinal compression chemotherapy alone and/or neurosurgical intervention with laminectomy

Intermediate- and high-risk group

• Stage II: 1–21 years of age, MYCN amplification; unfavorable histology
•  Stages III, IV, IVS: 0–21 years of age, MYCN amplification; or: 1–21 years of age, unfavorable histology (without MYCN amplification)
•  Mostly good response to induction chemotherapy (see above)
•  Persistent bone and/or bone marrow involvement is prognostically unfavorable
•  Induction phase: chemotherapy followed by eventual residual tumor resection, followed by maintenance chemotherapy and/or radiotherapy

Persistent neuroblastoma:

•  High-dose chemotherapy with autologous stem cell support
•  Allogeneic stem cell transplantation with the objective of graft-versus-tumor effect is still experimental

Treatment of minimal residual disease (MRD) provided by MIBG imaging [see Methylisobenzyl guanidinium (MIBG) scintigraphy above]; retinoids for induction of neuroblast differentiation; specific monoclonal antibody against neuroblastoma cell antigen (3F8, GD2a)

Therapy in Relapse

• For curative or palliative goals: topotecan, paclitaxel (Taxol), irinotecan or etoposide
•  Radiolabeled MIBG therapy as experimental option

What is the Prognosis?

• Dependent on age (favorable if less than 18 months of age at diagnosis), stage (see Staging above) and localization:
•  Favorable prognosis in primary neuroblastoma of thorax, presacral and cervical location
• – Involvement of lymph nodes correlates with poor prognosis

 Low-risk groups (see Risk-Adapted Management above) -more than 90% long-term survival

 Intermediate and high-risk groups:

• Response to initial treatment: 60–78% of children with complete or partial remission

•  After consolidation therapy including double high-dose chemotherapy with autologous stem cell support event-free survival after 3 years is 40–60%