Neuro-onkologi di Rumah Sakit PGI Cikini Jakarta 2008

NEURO ONCOLOGY AND

METABOLIC COMPLICATION
Dr.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-Oncologi
Departemen Neurologi FKUI-RSCM
Jakarta

Global Concept on Health

1980 1990
Decade of the Gastrointestinal (Enteric Brain)???

1990 2000
Decade of the Brain

2000 2010
Bone & Joint Decade

2010 2020
Decade of the Proteomic ????

Early detection for Oncologic Prone Person with/ without Clinical Events
Early diagnostic is the best
Good QoL

HUMAN EVOLUTION:
SOCIO-HEALTH-PHARMACO ECONOMIC
NATIONAL HEALTH SYSTEM

Neuro-oncology
Recently 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, Neuro
imaging, CT-Scan, MRI, MRA, EEG)
MRI nobel prize 2003

Neuro-oncology

A 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 tumor
Primary brain tumors rarely spread to other areas of the body, but
they can spread to other parts of the brain and to the spinal axis
The 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 socioeconomic, health system and cultural of Indonesia.

Brain Tumor
Primary
Secondary

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Neuro-oncology
PRIMARY BRAIN TUMOR (BT I)
Prognosis of patient with primary brain tumor are
determinated by :

Histological type
Grade
Post-operative size
Extend of the tumor
Patient age
Performance status of patient
Duration of symptoms

Neuro-oncology
SECONDARY BRAIN TUMOR (BT II)

Secondary brain tumor > primary brain tumor

Metastases to brain :
Lung cancer, breast cancer, melanoma and kidney

Secondary 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.

Effects of brain tumor

Direct:
Suppression of neural tissue
Suppression of vascular tissue

Indirect:
Immunity changes
Hematologic abnormality
Hormonal imbalance
Electrolyte imbalance

Brain edema

Neurologic deficits

ICP

Seizure
Systemic changes

Monro-Kellie-Burrow doctrine
Physiologic state with normal intracranial pressure
(ICP)
Major intracranial components:
Brain (80%)
Arterial & venous blood (10%)
CSF (10%)

Cranium: a rigid container, intracranial volume:

constant
Intracranial volume: are shown with ICP (N 10 - 15
mmHg)

ICP = Pressure sagital venous + CSF

a. Physiologic state w/ normal ICP

b. Moderate 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)
c. Large Intracranial mass w/ decompensation (ICP), beyond the
pressure-buffering capacity of venous blood & CSF

Pressure-volume curve

Initial phase:
no ICP (compensatory venous blood & CSF)
The compliance is high (elastance low)

Further expansion: compliance is low (elastance high)

Terminal stage:
Compensatory: exhausted
Steep rise in pressure (no compliance, highest elastance)

Seizures
30 -90% of intracranial tumor pts
High incidence:
Low grade
Location: supratentorial, cortical, frontal lobe
Age: 45 - 64 y.o.

Originate not from the mass itself, but from

the brain adjacent to the tumor nidus

Effects of seizures
Hypoxia & hypercapnia
Respiratory acidoses
Hypoglycemia
Hypocalcemia

Seizures

Metabolic changes

Vascular changes
Neurotransmitter alteration:
GABA & somatostatin
Deafferentiation & trans
synaptic degeneration
Local neuronal injury
Electrolyte imbalance

Immunity changes
Most of the CNS is immunologically privilaged.
Lymphocytic infiltration: << systemic tumors
CNS tumor

Structure of BBB

secreting immunosupp
factors: TGF-2, PG E2, & IL-10

Brain lymph (-)

suppression of
Ag-presenting cells

inactivate lymphocyte

humoral & cell-mediated

responses

Lacking certain antigens

Loss of MHC expression
Down-regulation of
Ag-processing mechanism
escape immune surveillance

Diminished immune response

Hematologic Abnormality
Cancer: thrombosis, bleeding, susceptibility to
infection
Thromboembolic complication:
Risk of any intracranial procedure: length of operative
procedure or duration of pt immobility
Type: DVTs in 72% of meningioma, 60% of gliblastoma,
20% of brain metastases
Solid tumor: thromboembolism, metastatic: DIC
Location: pt w/ suprasellar tumor suffer PE 5x than tumor
situated elsewhere
Grading: platelet adhesiveness more prominent among
malignant tumors than benign ones

Hematologic Abnormality
Hematologic abNs: >90% of oncologic pts
Polycythemia
Cytopenia
Coagulopathy
Thrombosis
DIC (spec. brain metastases)

Autopsy from brain tumor pts:

Pulmonary embolism (PE) 3%
DVT 27,5%

Attached to vessel walls

localised clotting
activation & thrombus
formation
Activate platelets by:
- Platelet adhesion to
tumor cell surface
-Malignant cell relase
of proaggregatory mol
Activate the monocyte
macrophage syst, &
induce their expression
of tissue factor

Multiple procoagulant
substances:
-tissue factor
-Cancer procoagulant
-Factor V receptor

Tumor cells

Major protein on
the surface that regulate
the fibrinolytic pathway:
-tissue-type
plasminogen activator
-plasminogen activator inh 1 & 2
Released proinflammatory
cytokines that impair normal
anticoagulant activity of
vasc endothel: TNF & IL-1

-coagulation factors: V, VIII, IX, & XI

-markers of coagulation activation:
D-dimer, FDP, thrombin-antithrombin
complex

Nutritional changes
Normal physiological conditions:
Brain energy from aerobic oxidation of
glucose
A gradually circulating glucose ketone
utilization for energy >>

Cancer cells:
Unable to transition from glucose ketone
Energy from glucose & lactate

Hormonal Changes
Especially: sellar region tumors, pituitary
adenoma hypo/hyper: cortisol, GH,
prolactin, TSH, FSH, LH
Steroid hormone receptors: meningiomas
& astrocytomas
Meningiomas:
progesterone receptors
growths: menstrual cycle & pregnancy

Electrolyte changes

Hyper/hyponatremia
Hyper/hypocalcemia
Hyper/hypophosphatemia
Hyper/hypokalemia
Hyper/hypouricemia
Hyper/hypoglicemia
corticosteroids
Brain edema

hypernatremia
Secondary to diabetes
insipidus or iatrogenic
causes

hyponatremia
ADH
Drugs: carbamazepine
Hyperosmolar state (mannitol th/)
SIADH secondary to
intracranial hypertension,
hypoxia, stress, pain, morphine,
Barbiturates

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

Neuro-oncology
New Cases Brain Tumor

Clinical Symptom
& Sign of Brain
Tumor
Headache
Seizure
Hemiparise
etc

Neurological
Examination :
General
Neurology
Neurooptamology

Radiology &
Neuro-imaging
Skull X-Ray
Basis
Selatursica
CT-Scan
axial &
coroner
MRI, MRA,
DWI
Nuclear
Machine

Laboratories
Blood
analysis
Lever
Function
Kidney
Function
Coagulation
system
etc

Neuro-oncology & Systemic Complication

Direct complications of neuro oncology
Indirect complications of neuro oncology
Neurologic complications of chemotherapy
and Biologic Therapies.
Neurlogic complications of Radiotion
Therapy

Direct effects of cancer

Side effects of chemotherapy

Surgery
Radiation
Infection
Coagulopathies
Cachexia

Neurologic Complications

The most complicated

of the Indirect NeuroComplication of
Cancer in neurooncology.................

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

Pathogenesis
Onconeuronal immunity
Antibodies ( onconeuronal antibodies)
against the cancer-expressed neuronalproteins (onconeuronal antigen).

Other immunologic mechanisms

Abnormal production of immunoglobulin
/immunoglobulin fragments by neoplastic
cells.

Diagnosis of PNS
Usually 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 & cerebellum

Initial 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 encephalomyelitis; 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 &

nerve

Paraneoplastic 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 muscle
Peripheral 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 junction

Lambert-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 cranioneuropathies ( transient ptosis and diplopia).
LEMS is associated with Ca 50% to 70%(SCLC, LM
and other Ca)

PNS of the
neuromuscular..cont
Myathenia 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..cont

Dermatomyositis 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 C5C9 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 Prognosis

PNCD : 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..cont

Paraneoplastic OpsoclonusMyoclonus(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..cont

Peripheral nervous system : subacute sensory
neuropathy, sensorimotor neuropathy,
sensorimotor neuropathy associated with Mproteins,etc.
Neuromuscular Junction and muscle :
LEMs, treatment(tailored) of the tumor + PE,IVIg,
immonosuppressive+ cholinesterase inhibitors
MG relies on cholinesterase inhibitor +immunotherapy comprises thymectomy, immunosuppressive, PE and IVIg.
S.Shamsili, P.S Smitt, 2005

Conclusion
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.

THANK

YOU
Neuro-oncology : HUT 110 Rumah Sakit Universitas Kristen Indonesia,Jkt 26.01.08