METASTATIC DISEASES OF NERVOUS SYSTEM

1. DR. SUMIT S. KAMBLE
SR NEUROLOGY
GMC, KOTA

2. BRAIN METASTASIS
 Most common intracranial tumors in adults.
 Accounting for more than one-half of brain tumors.
 Incidence of brain metastases increasing, due to both
improved detection of small metastases by MRI and
better control of extracerebral disease resulting from
improved systemic therapy

3.  Common causes of brain metastases in adults with their
approximate frequency are:
 Lung — 50 percent
Breast — 15 to 20 percent
Unknown primary - 10 percent
Melanoma — 10 percent
Colon and rectum - 5 percent
 Distribution of metastases roughly follows the relative
weight of and blood flow to each area.
 Cerebral hemispheres — 80 percent
Cerebellum — 15 percent
Brain stem — 5 percent

4. SYMPTOMS OF BRAIN METASTASES
Symptom Patients %
 Headache 42
 Focal weakness 27
 Cognitive dysfunction 31
 Seizure 20
 Gait ataxia 17
 Sensory disturbance 6
 Speech problems 10

5. Imaging Studies
 Contrast-enhanced MRI is preferred imaging study
 Radiographic features that can help differentiate brain
metastases from other CNS lesions include:
I. Presence of multiple lesions
II. Localization at the junction of the grey and white matter
III. Circumscribed margins
IV. Large amounts of vasogenic edema compared to the size
of the lesion

6.  MRI
 T1
 typically iso to hypointense
 if haemorrhagic may have intrinsic high signal
 non-haemorrhagic melanoma metastases can also have
intrinsic high signal due to the paramagnetic properties of
melanin
 T1C+
 enhancement pattern can be uniform, punctate, or ring-
enhancing, but it is usually intense
 delayed sequences may show additional lesions, therefore
contrast-enhanced MR is the current standard for small
metastases detection
 T2
 typically hyperintense
 FLAIR: typically hyperintense with hyperintense peri-
tumoural oedema

7.  MR spectroscopy
 intratumoural choline peak with no choline elevation in the
peritumoural oedema
 any tumour necrosis results in a lipid peak
 NAA depleted
 DWI: oedema is out of proportion with tumour size and
appears dark on trace-weighted DWI
Nuclear medicine
 FDG PET
 Considered the best imaging tool for metastases.
 Only detect mets up to 1.5 cm in size, therefore contrast
MRI remains the gold standard to rule out small mets.

8. Radiographic Features of Brain Metastases

9. Overveiw of Management
 Specific treatments directed against the brain
metastases
 Management or prevention of complications (eg,
seizures, cerebral edema, prevention of deep venous
thrombosis)
 Treatment of systemic malignancy if appropriate

10. Prognostic Classification
Recursive Partitioning Analysis (RPA)
 Parameters that determine survival are:
i. Performance status
ii. The extent of extracranial disease
iii. Age
iv. Primary diagnosis

11. Recursive Partitioning Analysis
(RPA)
Recursive Partitioning Analysis
Class I Class II Class III
• Karnofsky
performance score 70
or higher
• Age < 65
• Controlled primary
tumor
• Without extracranial
metastases
Median survival was 7.1
months. These patients
are considered to have a
favorable prognosis.
• Karnofsky
performance score 70
or higher
• Age > 65
• Uncontrolled primary
tumor
• Other extracranial
metastases
Median survival in this
group was 4.2 months.
• Karnofsky
performance score
less than 70
Median survival of 2.3
months. This group is
considered to have a
poor prognosis.

13. Management of Brain mets based on RPA
 Patients having a favorable prognosis - treatment
focuses on the eradication or control of the brain
metastases. Includes surgical resection and various
forms of radiation therapy (eg, whole brain,
stereotactic radiosurgery).
 Patients having a poor prognosis- treatment focuses
on control of symptoms caused by the brain
metastases, as well as maintenance of neurologic
function to as great an extent as possible.

14. • Various modalities :
1.WBRT
2.SRS(STEREOTACTIC RADIOSURGERY)
3.SURGERY
4. SUPPORTIVE CARE WITH DEXAMETHASONE

18. Symptom Management
 Control of peritumoral edema and increased
intracranial pressure with corticosteroids
 Treatment and prevention of seizures
 Management and prevention of venous
thromboembolic disease

19. Control of Vasogenic Edema
 Dexamethasone is the standard agent:
 relative lack of mineralocorticoid activity reduces the
potential for fluid retention.
 dexamethasone associated with a lower risk of
infection and cognitive impairment compared to other
glucocorticoids
 Dose and schedule —
 Dexamethasone regimen consists of a 10 mg loading
dose, followed by 4 mg four times per day or 8 mg
twice daily.

20. Treatment and Prevention of
Seizures
 Patients who have one or more seizures associated
with a primary or metastatic brain tumor, initial
treatment with a single agent antiepileptic drug (AED)
(Grade 1A)
 Patients without a history of seizures and who have
not undergone a neurosurgical procedure, recommend
NOT using prophylactic AEDs (Grade 1B)

21. Management and Prevention of Venous
Thromboembolic Disease
Treatment of venous thromboembolism
 Anticoagulation in all patients with brain tumors and
venous thromboembolism (VTE) except those that have a
high rate of intracranial hemorrhage (ie, metastases from
melanoma, choriocarcinoma, thyroid carcinoma, and renal
cell carcinoma)
 VTE in low-grade glioma and benign tumors should be
treated for three to six months.
 Long-term anticoagulation is recommended for malignant
gliomas.

22.  LMW heparin rather than warfarin for anticoagulation
Prophylaxis of VTE
 Patients undergoing surgery, use pneumatic compression
stockings combined with postoperative LMW heparin or
unfractionated heparin beginning 12 to 24 hours after
surgery and continuing until ambulation is resumed.

23. SPINAL METASTASIS
 Spine most common site for skeletal metastases
a. Metastatic lesions are most common tumors of the
spine (95-98%)
b. 5-10% of the patients with cancer develop spine
metastases*
c. All age groups with highest age incidence in between 40
and 65 years
d. Male:Female – 3:2
 Vertebral body affected first
 Approximately 70% of patients who die of cancer have
evidence of vertebral metastases on autopsy

24. Pathophysiology
 Hematogenous Spread:
 Batson’s plexus
 Arterial embolization
 Direct invasion

25. Primary Sites
 Breast (30.2%)
 Lung (20.3%)
 Blood (10.2%)
 Prostate (9.6%)
 Urinary tract (4%)
 Skin (3.1%)
 Unknown 1° (2.9%)
 Colon (1.6%)
 Other (18.1%)

26. Level of Metastases
 Thoracic 70%
 Lumbar 20%
 Cervical 10%
Basis of anatomic location
 Intradural - 5%
◦ Intramedullary
◦ Extramedullary
 Extradural - 95%
◦ Pure epidural – rare
◦ Arising from the vertebrae - most frequent

27. Clinical Presentation
 Pain (85%)
 Biologic: local release of cytokines, periosteal irritation, stimulation
of intraosseous nerves, increased pressure or mass effect from tumor
tissue in the bone
 Mechanical: nerve compression, pathologic fractures, instability
 Weakness (34%)
 Spinal cord compression in 20%
 Early: edema, venous congestion, and demyelination
 Late: secondary vascular injury and spinal infarction
 Mass (13%)
 Constitutional Symptoms

28. Evaluation
 History
 Physical Exam
 Laboratory:
 CBC, ESR, CRP, LFT, BUN, Creatinine
 Ca, PO4, Alk Phosphatase
 Urinalysis: routine, Bence-Jones Proteins
 Special: PSA, thyroid Function test, serum and urine
protein electrophoresis, liver function tests, stool guaiac,
CEA

29. Imaging
 Plain x-ray
- Bone mets can be purely lytic, blastic ,mixed
i. Lytic - lung, kidney, breast, GIT, melanoma
ii Blastic – prostate , bronch.carcinoids, bladder,
stomach
iii. Mixed – breast ,lung, GIT

30.  X-ray of spine: AP, lateral, oblique
 “winking owl” sign: pedicle destruction
 Vertebral body destruction is not visible until 30-50%
of trabeculae are involved
 Negative x-ray does not rule out tumor
 Bone scan
 Superior sensitivity
 Extent of dissemination
 Define the most accessible lesion
to biopsy in cases of unknown
primary

32.  MAGNETIC RESONANCE IMAGING
◦ Superior sensitivity and specificity
◦ Method of choice to evaluate spine
◦ Define the intramedullary, intradural
and extramedullary lesions
◦ Extent of the lesion
◦ Differentiation from other pathologies
such as infection and osteoporotic
◦ Fat suppression and Gadolinium
enhancement to improve the delineation
◦ Hypointense T1 , hyperintense in T2 and
gadolinium enhanced T1

33. Biopsy
 Indicated if diagnosis is unclear after workup
 Options:
 CT-guided: most accessible lesion, minimal morbidity,
tattoo tract for later excision
 Accuracy: 93% for lytic lesions, 76% for sclerotic lesions
 Open: cost, delay, definitive for benign tumors

34.  PER CUTANEOUS APPROACHES FOR BIOPSY
Posterior cervical C 1 – 3= Transoral
Sub axial cervical Anterior or posterior to sternocleidomastoid
Thoracic and
Lumbar
Transpedicular or Postero lateral
Sacral Posterolateral

35. Management
 General Mx
 Medical Mx / Radiotherapy Mx
 Surgical Mx
 Pain Mx
 General Mx
- Anemia
- Steroids
- Nutritional Status
- Hydrational status
- Supplements

36.  Medical Mx
i.Chemotherapy
ii.Hormonal
iii Biphosphonate
 Chemotherapy
Given as therapeutic and palliative treatment
especially in Breast , lung , Renal cell ca.

37.  Hormonal
- Breast , prostate and endometrial ca.
- Endocrine dependant organs.
 Biphosphonate
- Inhibit osteoclast-mediated resorption
- Induce osteoclast apoptosis
- Standard treatment in hypercalcemia in malignancy
- Reduces metastatic bone pain esp. clodronate and pamidronate
- Recalcification

38.  Radiotherapy
- Pain relief – mode of action not really understood –
reduces tumour bulk, reduces pain mediator
(PG)releasing cells
- Post fixation irradiation
- Prevention of spinal cord compression-recent vertebral
collapse
- Pts with contraindication for surgery

39. External Beam Radiotherapy (EBRT)
 Radiosensitivity
 Myeloma & Lymphoma: most radiosensitive
 Prostate, Breast, Lung and Colon: moderately
 Thyroid, Kidney, Melanoma: not radiosensitive
 Dose
 5,000 cGy in 25 fractions over 5 weeks (C & L-spine)
 4,500 cGy over 4½ -5 weeks in T-spine

40. Surgical Mx
 Mostly Palliative
Indications
1. Spinal instability
2. Spinal compression secondary to retropulsed bones or spinal
deformity
3. Radiation-resistant tumors (sarcoma, non-small cell lung
cancer, colon, renal cell, melanoma)
4. Failure of radiation (progression during treatment or
recurrence)
5. Intractable pain unresponsive to medical treatment
6. Unknown primary tumor (histological diagnosis)
7. Rapid progression of neurological deficits

41.  Goals of Surgery
i. Correct and prevent deformity by stabilizing
deformity
ii. Decompressing neural structures
iii. Open biopsy if primary unknown

42.  Pre-operative prognostic values/scoring
Score = < 5 dies within 3 months
> 9 survives average 12 mths
Surgery = <5, non surgical , > 9 surgical

43. Category iii – grey area , either medical or surgical .
- if there is severe epidural cord compression
non radiosensistive , needs surgery

44. Score
2-3 – wide / marginal for long term survival
4-5 – marginal/intralesional
6-7 – palliative surgery for short term palliation
8-10 – non operative supportive care

45. Surgical approach
 Anterior approach
- modern era
- Predominant area of metastasis
- Does not disturb posterior stability in presence of the
kyphosis
- Pain relief in 80 – 95% of pts
- Neurologic improvement in 75% of pts
 Post decompressive laminectomy
- old era
- limited value in regaining neurologic function

46. LEPTOMENINGIAL METASTASIS
 Invasion of leptomeninges or CSF by cancer is called
leptomeningeal metastasis (LM) or neoplastic meningitis.

47.  Clinically diagnosed LM affect ~ 5% of pt with
metastatic cancer
 Autopsy studies → the frequency of LM averages 19%
of pts with cancer pts.
 LM is diagnosed in
1. 4-15% of pt with solid tumors
2. 5-15% of pt with leukemia and lymphoma
3. 1-2% of pt with primary brain tumor

48.  Modes of spread:
 Hematogenous: most common
 Endoneural/perineural: paravertebral tumors
 Direct
 Choroid plexus
 Iatrogenic
 Mortality/Morbidity
 Median survival-7 months for LM from Breast cancers
- 4 months for LM from Small cell lung
- 3.6 months for LM from Melanomas
 Without therapy, survive 4-6 weeks
 With therapy, most pts die from the systemic complication
of their cancer

49. Signs and symptoms
LM classically presents with pleomorphic clinical
manisfestations encompassing symptoms and signs in
3 domains
 Cerebral hemispheres
 Posterior fossa/Cranial nerves
 Spinal cord and roots

53. DIAGNOSIS
 Patients may be diagnosed with LM when one of the
following criteria is met:
 1. Positive CSF cytology
 2. Positive LM biopsy
 3. Positive MRI in a pateint with a clinical syndrome
compatible with the diagnosis
 4. Abnormal CSF biochemical markers consistent with
LM

54. MRI
 Highly sensitive for diagnosis of LM from solid tumors
(76-100%)
 Less sensitive for hematopoieric tumors
 Solid tumor → MRI positive for LM 88%
 Hematopoietic tumor → MRI positive for LM 48%

55. Typical MRI findings
 Leptomeningeal enhancement in LM can be linear
but often has irrigularity or nodularity
 Often visible in the subarachnoid space, cerebellar
folia, or cortical surface, and tumor masses, especially
at the base of the brain, with or without hydrocephalus
 Occasionally, frank LM are not seen on MRI, but bulky
subependymal disease or multiple small sulcal
metastases suggest the diagnosis.

56. Figure 2. Post-gadolinium T1-weighted sagittal (A) and coronal (B) images demonstrate
diffuse nodular subependymal and leptomeningeal metastases from the patient’s primary
glioblastoma multiforme.
Martin Begemann et al. Neurology 2004;63:E8
©2004 by Lippincott Williams & Wilkins

57. MRI SPINE
 MRI can show linear enhancement of the entire cord
and linear or nodular enhancement of the cauda
equina.
 Occasionally, clumping of nerve roots at the cauda
equina suggests the diagnosis if contrast enhancement
is not seen.13
 A spinal tumor may obstruct CSF flow, resulting in
hydrocephalus.

58. Multiple enhancing nodules are scattered along the cauda equina (blue arrows) with
extensive leptomeningeal enhancement of the conus (yellow arrows).

59. CSF ANALYSIS
 CSF analysis is the gold standard.
 Presence of malignant cells in the CSF is diagnostic of
LM. (sensitivite 71% → 86% → 93% →…)
Abnormalities include
 1. increased opening pressure (200 mm of H2O)
 2. Increased leukocytes (4/mm3)
 3. elevated protein (50 mg/dL)
 4. decreased glucose (60 mg/dL)
 5. positive cytology

60. CSF CYTOLOGY

61. TUMOUR MARKERS
 Tumor markers (eg, CEA, PSA, CA-15-3, CA-125, and
MART-1 and MAGE-3 in melanoma) may provide
evidence for CSF dissemination of disease, even when
serial cytological evaluations are negative.
 Level of tumor markers are compared between CSF
and Serum if CSF level greater than 1% of that in the
serum is virtually diagnostic of LM.
 CSF-IMMUNOHISTOCHEMISTRY
 CSF- CYTOGENETICS
 BIOPSY

63. TREATMENT

64. POOR RISK PATIENTS
Palliative regimen -
 RT can be useful for relief of symptoms .
 Analgesics are given for persistent pain.
 Anticonvulsants should be reserved for patients with
seizures (10 to 20 percent of cases) and should not be
administered prophylactically.
 Serotonin reuptake inhibitors or stimulant
medications (eg, modafinil, methylphenidate) for
depression or fatigue.

65. GOOD RISK PATIENTS
 Surgery-
1. Intraventricular catheter and subgaleal reservoir
2. Ventriculoperitoneal shunt
 Chemothery
1. Regional
2. Systemic
 Radiotherapy

66. NEOPLASTIC PLEXOPATHY
 1% of patients who have cancer develop plexus
involvement.
 Brachial plexopathy due to neoplastic infiltration in
breast or lung cancer;
 lumbosacral plexopathy in patients with gynecologic
cancer, prostate cancer, sarcomas, lymphomas, or
colorectal cancer;
 should be distinguished from radiationinduced
plexopathy.
 Treatment for neoplastic plexopathy includes
radiation and pain control.

68. References
 Nervous System Metastases From Systemic Cancer
journals.lww.com/continuum/toc/2015
 Radiotherapeutic and surgical management for newly
diagnosed brain metastasis/es: An American Society
for Radiation Oncology evidence-based guideline
(2012)
 Leptomeningeal metastases, Cancer treatment and
research, Springer 2005
 UPTODATE.COM