NEURO ONCOLOGY AND METABOLIC COMPLICATIONDr.Teguh A.S Ranakusuma SpS(K)*; Dr.Tiara A Wicaksono SpS**Guru Besar Tetap Neurologi FKUI & Kepala Divisi Neuro-onkologi*Staf Pengajar Neuro-Onkologi Neurologi**Divisi Neuro-OncologiDepartemen Neurologi FKUI-RSCMJakarta Neuro-onkologi di Rumah Sakit PGI Cikini Jakarta 2008

Global Concept on Health1980 1990Decade of the Gastrointestinal (Enteric Brain)???1990 2000Decade of the Brain2000 2010 Bone & Joint Decade2010 2020Decade of the Proteomic ????

HUMAN EVOLUTION: SOCIO-HEALTH-PHARMACO ECONOMICNATIONAL HEALTH SYSTEMEarly detection for Oncologic Prone Person with/ without Clinical EventsEarly diagnostic is the bestGood QoL

Neuro-oncologyRecently in Indonesia :An increased incidence of primary & secondary brain tumor.General symptoms are due to mass effect (increased intracranial pressure).Destruction of adjacent brain tissue.The focal symptoms depends on the location tumor.

Diagnosis procedure are better (Radiology, Neuroimaging, CT-Scan, MRI, MRA, EEG)MRI nobel prize 2003

Neuro-oncologyA lesion in the brain should not be assumed to be a metastases just because a patient had a previous cancer; such assumption could result in overlooking appropriate treatment of curable tumorPrimary brain tumors rarely spread to other areas of the body, but they can spread to other parts of the brain and to the spinal axisThe suggested guideline for work-up, management, and follow-up in order how to solve neuro-oncologic problems in Indonesia are showed in following tables with consideration of the special socio-economic, health system and cultural of Indonesia.

Brain TumorPrimarySecondary

Neuro-oncologyPRIMARY BRAIN TUMOR (BT I)Prognosis of patient with primary brain tumor are determinated by : Histological typeGradePost-operative sizeExtend of the tumorPatient agePerformance status of patientDuration of symptoms

Neuro-oncologySECONDARY BRAIN TUMOR (BT II)Secondary brain tumor > primary brain tumorMetastases to brain :Lung cancer, breast cancer, melanoma and kidneySecondary brain tumor :Usually multiple, solitary metastases may also occur Brain involvement can occur with cancer on the nasopharyngeal region by direct extension along the cranial nerves or through the foramina at the base of skull.Metastases meningeal involvement can also occur especially with leukemia, lymphoma, small cell lung cancer, breast cancer and primary CNS tumors such as medulloblastoma & ependymal gliomas.

New Case of Brain Tumor

GP; Neurologist; Non Neurologist

- Ro, CT Scan, MRI, MRA, MRS, PET- SPECT Laboratory ECG, Doppler, Evoked Potensial

Positive Brain Tumor: VP Shunt BiopsyStereo tacticOpenResectionResidual tumor

Primary Brain Tumor IICP PA Total Removal To Reduce Tumor Size

Secondary Brain Tumor IICP Soliter

Histologic Finding (PA)

Radiosurgery

Radiotherapy

Chemotherapy

Out come

Quality of life & life expectancy

3 cm

Definitive Radio Tx

3 Modalities Treatment

?

Palliative

Depend on Primary Cancer

Clinical-Neurologic Examination

Medical anticipation

Non Brain Tumor

Stop ???

No Budget

Neuro Emergency

Effects of brain tumorDirect:Suppression of neural tissueSuppression of vascular tissue

Indirect:

ICP Immunity changesHematologic abnormalityHormonal imbalanceElectrolyte imbalanceNeurologic deficits

Seizure

Systemic changesBrain edema

Monro-Kellie-Burrow doctrinePhysiologic state with normal intracranial pressure (ICP)Major intracranial components:Brain (80%)Arterial & venous blood (10%)CSF (10%)Cranium: a rigid container, intracranial volume: constantIntracranial volume: are shown with ICP (N 10 - 15 mmHg) ICP = Pressure sagital venous + CSF

Physiologic state w/ normal ICPModerate Intracranial mass w/ compensation (normal ICP) intracranial content (egress of venous blood into the jugular veins & egress of CSF through the for. magnum spinal canal)Large Intracranial mass w/ decompensation (ICP), beyond the pressure-buffering capacity of venous blood & CSF

Pressure-volume curveInitial phase: no ICP (compensatory venous blood & CSF)The compliance is high (elastance low)Further expansion: compliance is low (elastance high)Terminal stage: Compensatory: exhaustedSteep rise in pressure (no compliance, highest elastance)

Seizures 30 -90% of intracranial tumor ptsHigh incidence:Low gradeLocation: supratentorial, cortical, frontal lobeAge: 45 - 64 y.o.Originate not from the mass itself, but from the brain adjacent to the tumor nidus

Effects of seizuresHypoxia & hypercapniaRespiratory acidoses HypoglycemiaHypocalcemiaMetabolic changesVascular changesNeurotransmitter alteration: GABA & somatostatinDeafferentiation & trans synaptic degenerationLocal neuronal injuryElectrolyte imbalanceSeizures

Immunity changesDiminished immune responseStructure of BBBinactivate lymphocytesuppression of Ag-presenting cellsMost of the CNS is immunologically privilaged.Lymphocytic infiltration:

Hematologic AbnormalityCancer: thrombosis, bleeding, susceptibility to infectionThromboembolic complication:Risk of any intracranial procedure: length of operative procedure or duration of pt immobilityType: DVTs in 72% of meningioma, 60% of gliblastoma, 20% of brain metastasesSolid tumor: thromboembolism, metastatic: DIC Location: pt w/ suprasellar tumor suffer PE 5x than tumor situated elsewhereGrading: platelet adhesiveness more prominent among malignant tumors than benign ones

Hematologic AbnormalityHematologic abNs: >90% of oncologic ptsPolycythemiaCytopeniaCoagulopathyThrombosisDIC (spec. brain metastases)Autopsy from brain tumor pts:Pulmonary embolism (PE) 3%DVT 27,5%

Tumor cellsMultiple procoagulant substances:tissue factorCancer procoagulantFactor V receptorMajor protein on the surface that regulate the fibrinolytic pathway:tissue-type plasminogen activatorplasminogen activator inh 1 & 2Released proinflammatory cytokines that impair normal anticoagulant activity of vasc endothel: TNF & IL-1Attached to vessel walls localised clotting activation & thrombus formationActivate platelets by:- Platelet adhesion to tumor cell surfaceMalignant cell relaseof proaggregatory molActivate the monocyte macrophage syst, & induce their expression of tissue factor-coagulation factors: V, VIII, IX, & XI-markers of coagulation activation: D-dimer, FDP, thrombin-antithrombin complex

Nutritional changesNormal physiological conditions: Brain energy from aerobic oxidation of glucoseA gradually circulating glucose ketone utilization for energy >>Cancer cells: Unable to transition from glucose ketone Energy from glucose & lactate

Hormonal ChangesEspecially: sellar region tumors, pituitary adenoma hypo/hyper: cortisol, GH, prolactin, TSH, FSH, LHSteroid hormone receptors: meningiomas & astrocytomasMeningiomas: progesterone receptorsgrowths: menstrual cycle & pregnancy

Electrolyte changesHyper/hyponatremia Hyper/hypocalcemia Hyper/hypophosphatemia Hyper/hypokalemia Hyper/hypouricemia Hyper/hypoglicemiaADHDrugs: carbamazepineHyperosmolar state (mannitol th/)SIADH secondary to intracranial hypertension, hypoxia, stress, pain, morphine, BarbiturateshyponatremiaSecondary to diabetes insipidus or iatrogenic causeshypernatremiacorticosteroidsBrain edema

Neuro-oncologyTreatment :Some brain tumor are curable by surgery alone, and some are curable by surgery & radiation therapyThe reminder require surgery, radiation therapy and chemotherapy.Tumor that requires all modalities are infrequently curable.

Neuro-oncologyClinical Symptom & Sign of Brain TumorHeadacheSeizureHemiparise etc

Neurological Examination :GeneralNeurologyNeuro-optamology

Radiology & Neuro-imagingSkull X-RayBasisSelatursicaCT-Scan axial & coronerMRI, MRA, DWINuclear MachineLaboratoriesBlood analysisLever FunctionKidney FunctionCoagulation systemetcNew Cases Brain Tumor

Neuro-oncology & Systemic ComplicationDirect complications of neuro oncology

Indirect complications of neuro oncology

Neurologic complications of chemotherapy and Biologic Therapies.

Neurlogic complications of Radiotion Therapy

Direct effects of cancerSide effects of chemotherapySurgeryRadiationInfectionCoagulopathiesCachexia

Neurologic ComplicationsThe most complicated of the Indirect Neuro- Complication of Cancer in neuro-oncology.................

Neurologic complications Two pathological processes: 1. Paraneoplastic syndrome: a response paraneoplastic antineureal autoantibodies

2. As the complications of cancer therapy: caused by neurotoxicities prosses of radiation and chemotherapy or combination L Bataller, J Dalmau.,2003.; W.T Cornblath, 2004

Paraneoplastic syndrome(PNS) Can affect virtually any part of the nervous system : from muscle, neuromuscular junction, peripheral nerve, dorsal root ganglion, spinal cord, brainstem, brain cortex to the optic nerve and retina

PathogenesisOnconeuronal immunity Antibodies ( onconeuronal antibodies) against the cancer-expressed neuronal- proteins (onconeuronal antigen).

Other immunologic mechanisms Abnormal production of immunoglobulin /immunoglobulin fragments by neoplastic cells.

Diagnosis of PNSUsually established by : Clinical phenomena: specific-clinical neurologic history presence of accompanying symptoms. Clinical electro-physiologic phenomena: peripheral neurpathies ( motoric, sensoric and autonomic) Neuro-imaging Phenomena :Ctscan, MRI, PET, SPECT etc Cerebrospinal Fluid studies

PNS of the brain & cerebellumInitial symptoms , Focal to multifocal or multifocal from the onset. Cortical encephalitis : epilepsia partialis continua Limbic encephalitis : short-term memory problems, confuseion, irritability, depression & seizure Brainstem encephalitis : cranioneuropathies, dysarthria, dysphagia, autonomic centers disorder, oculor movement disorder : nystagmus, supranuclear/nuclear pareses

PNS of the brain.. cont Cerebellitis resulting in cerebellar ataxia and do not associate with encephalomyelitis in several cases of paraneoplastic cerebellar degeneration(PNCD). Myelitis causing motor weakness as a result of upper/lower motor neuron dysfunction, segmental rigidity, myoclonus & muscle spasms.

PNS of the brain..cont Paraneoplastic cerebellar degeneration : Initial symptoms dizziness, nausea & vomiting, patients develop gait and limb ataxia, blurry vision, or diplopia, dysarthria, and dysphagia. Paraneoplastic opsoclonus-myoclonus syndrome: ocular motility characterized by involuntary chaotic saccades that occur in all direction of gaze and frequently assoiciates with myoclonus & ataxia. ( Lung&Breast Ca in adult; neuroblastoma in children) (L.Battaller, J.Dalmau., 2003)

PNS of the spinal cord The most common PNS of the spinal cord : Stiff-man syndrome; myelitis and ence- phalomyelitis; subacute motor neuropathies ( Hodgkins lymphoma ); acute/subacute necrotizing myelopathy ( viral infection ); progressive multifocal leukoencephalopathy (papavavirus infection); primary lateral sclerosis-like syndrome (breast cancer ).

PNS of the dorsal root ganglia & nerveParaneoplastic sensory neuronopathy : associated with symmetric or asymmetric deficits of all modalities of sensation, painful dysesthesias, radicular pain and decreased or absent reflexes,due to process of inflamatory infiltrates, neuronal degeneration, proliferation of satellite cells, and secondary Wallerian degeneration of the spinal cord & often associated with paraneoplastic encephalomyelitis.

PNS of the dorsal..cont Paraneoplastic peripheral neuropathies 5 groups :subacute axonal/demyelinating peripheral neuropathies.Vasculitis of the nerve and musclePeripheral neuropathies associated with monoclonal gammopathies(multiple myeloma, osteosclerotic myeloma, POEMS syndrome/ polyneuropathy, organomegaly, endocrinopathy, M component and skin changes, Waldenstrms macroglobulinemia and Castlemans disease/angiofollicular lymph node hyperplasia).Gullian-Barre and plexitis.Neuromyotonia ( Isaacs syndrome )

PNS of the neuromuscular junctionLambert-Eaton myasthenic syndrome(LEMS) : proximal muscle weakness in lower& upper extremities (fatique, leg weakness, muscle ache & vague parasthesias), autonomic dysfunction ( dry mouth, erectile dysfunction, constipation, altered sweating & orthostatic hypotension), mild cranio-neuropathies ( transient ptosis and diplopia). LEMS is associated with Ca 50% to 70%(SCLC, LM and other Ca)

PNS of the neuromuscular..contMyathenia gravis (MG) : fatigue, diplopia, ptosis, dysarthria, neuromuscular respiratory failure and weakness of the extremities.

Paraneoplastic clinical manifestation of thymoma or thymic hyperplasia, total thymectomi can develop MG up 6 years after surgery, breast Ca is the most common cause of extrathymic malignancies.

PNS of the muscle The muscle : Polymyositis/dermatomyositis Acute necrotizing myopathy Cachectic myopathy Carcinoid myopathy Myotonia

PNS of the muscle..cont...Polymyositis & dermatomyositis are different immune-mediated inflammatory disorders of the muscle, with similar neurologic symptoms : myalgias, muscle tenderness & proximal muscle weakness frequently accompanied by dyphagia and involvement of neck flexor-extensor muscles, respiratory muscles failure. Inflammatory infiltrates predominantly of CD8+T-cells are main cause of muscle injury & fiber necrosis in polymyositis.

PNS of the muscle..contDermatomyositis is associated with skin changes characterized by purplish discoloration of the eyelids( heliotrope rash) with edema and erythematous, scaly lesions over the knuckles. Associated with an immune-mediated intramuscular angiopathy thought to be antibody-mediated, which leads muscle ischemic, necrosis and charateristic perifascicular atrophy ( CD4+T cells, B-cells and macrophages/inflam.infil.; and C3, C9 & membrane attack complex/ImmunoGl&compl.)

PNS of the muscle..cont.. Acute necrotizing myopathy: this syndrome develop subacute myalgias & rapidly progressive weakness of the extremities, with frequent involvement of pharyngeal & respiratory muscles. Ca most frequently involved are SCLC, Ca of GIT, Breast, kidney & prostate, deposits of C5-C9 in intramuscular vessels & muscle fibers. DD/ rhabdomyolysis induced by CTh & cytokines (IL-2, interferon- ).

Treatment There is extensive evidence that many PNS are mediated by immunologic responses against onco-neuronal antigens. A practical implication is that these immunologic disorders frequently are associated with antibodies that are excellent diagnostic markers of PNS & Ca, and the second implication is that prompt detection & treatment of the tumor is the most efficacious therapeutic approach, at times leading to stabilization of the PNS. S. Shamsili, P.S Smitt, 2005

Treatment and PrognosisPNCD : tumor excision, plasma-exchange, steroids, IVIg or cyclophosphamide, the outcome is generally poor & no recommended treatment exists.Limbic encephalitis : treat the DIC, antitumor th/, spontaneous complete recopvery has been described.Encephalomyelitis : tumor treatment offers the best chance of stabilizing the patients neurologic status. S Shamsili, P.S Smitt 2005

Treatment & prog..contParaneoplastic Opsoclonus-Myoclonus(POM) may remit either spontaneously, following treatment of the tumor, or in associatein with clonazepam or thiamine treatment.Stiff-man syndrome, response to treatment with baclofen, diazepam, valproate, vigabatrin, and carbamazepin, steroid, PE and IVIg.

Treatment and prog..contPeripheral nervous system : subacute sensory neuropathy, sensorimotor neuropathy, sensorimotor neuropathy associated with M-proteins,etc.Neuromuscular Junction and muscle : LEMs, treatment(tailored) of the tumor + PE,IVIg, immonosuppressive+ cholinesterase inhibitors MG relies on cholinesterase inhibitor +immuno- therapy comprises thymectomy, immuno- suppressive, PE and IVIg.

S.Shamsili, P.S Smitt, 2005

C o n c l u s i o n Although PNSNS are not common, their recognition is important.In Indonesia the medical facilities is insufficient.However, the diagnosis of a PNSNS can lead to the diagnosis of an underlying tumor or avoid the continued search for metastasis in a patient who has known cancer. An appropriate diagnosis leads to providing appropriate treatment and prognostic information with unfortunate consequence of high cost.

T H A N KY O U Neuro-oncology : HUT 110 Rumah Sakit Universitas Kristen Indonesia,Jkt 26.01.08