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Neurological Emergencies in Cancer Patients. Pete Kang. Neurologic Emergencies in Cancer Patients. Neurologic sx’s present in 38% of oncology-related ED visits Most common neurologic dx’s among cancer patients @ Memorial Sloan-Kettering Cancer Center: Brain mets 16%

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neurologic emergencies in cancer patients
Neurologic Emergencies in Cancer Patients
  • Neurologic sx’s present in 38% of oncology-related ED visits
  • Most common neurologic dx’s among cancer patients @ Memorial Sloan-Kettering Cancer Center:

Brain mets 16%

Metabolic encephalopathy 10%

Bone mets 10%

Epidural tumor 8%

neurologic emergencies in cancer patients1
Neurologic Emergencies in Cancer Patients
  • Brain tumors
  • Epidural spinal cord compression (ESCC)
  • Leptomeningeal metastasis (LMM)
  • Stroke
  • Acute neurologic complications of cancer treatment
  • Paraneoplastic syndromes
brain tumors epidemiology
Brain Tumors: epidemiology
  • Each year:

17,500 dx’d with primary brain tumors

66,000 dx’d with symptomatic brain metastases

lung, breast, skin, GU, GI account for majority

  • Incidence is increasing:

- improved diagnostic methodology

- better access to health care among the elderly

- improved survival among cancer patients

brain tumors mechanism
Brain Tumors: mechanism
  • Direct tissue destruction
  • Displacement of brain tissues (tumor/edema)
  • Compression of vasculature (ischemia)
  • Compression of CSF pathways (hydrocephalus)
brain tumors clinical features
Brain Tumors: clinical features
  • Headache

- presenting sx in 35% of patients

- 70% of patients will have a headache at some point

- “classic”: mild @ onset, worse in morning, improves after rising

- usually: dull, non-throbbing headache, gradually increases, chronic

- accompanied by impaired MS, nausea/vomiting

  • Focal deficits
  • Cognitive disturbances

- presenting sx in 30% of patients

brain tumors clinical features1
Brain Tumors: clinical features
  • Seizure

- presenting sx in 33% of pts with gliomas

- presenting sx in 15-20% of pts with brain mets

- postictal deficits or Todd’s paralysis

  • Papilledema

- older studies: present in 70%

- now: 8%

  • Acute presentations: hydrocephalus, intratumoral hemorrhage, seizures
brain tumors management
Brain tumors: management

Symptomatic Treatments

  • cerebral edema

- emergency management

1. hyperventilation (w/in 30sec, for 15-20min)

2. hyperosmolar agents (mannitol 20-25% @ 0.5-2.0g/kg over 15-20min; w/in minutes, for several hours)

3. diuretics (with mannitol)

4. IV dexamethasone, 40-100mg bolus + same/day

5. barbiturates/hypothermia

- non-emergency management

dexamethasone (10mg po q6hrs)

brain tumors management1
Brain tumors: management
  • seizures

symptomatic treatment: anticonvulsants

prophylactic treatment: controversial

- two randomized prospective studies (>170 pts with both primary and metastatic brain tumors) showed no significant benefit with prophylactic treatment

- possible exceptions: melanoma brain mets, pts w/ both brain mets and leptomeningeal mets (both groups 50-60% risk of seizures)

brain tumors management2
Brain tumors: management
  • venous thromboembolism

19-37% of brain tumor pts will develop VT

IVC filters vs. anticoagulation

- several retrospective studies showed lower risk of complications with anticoagulation compared to IVC filters

- possible exceptions include:

post-operative patients

pts with choriocarcinomas or melanomas

other contraindications to anticoagulation (e.g. GI bleeds)

brain tumors management3
Brain tumors: management

Definitive Treatments

  • Curative surgical resections

e.g., meningiomas, vestibular schwannomas, pituitary adenomas, certain glial tumors

  • Palliative surgical resections: malignant tumors

relieve neurologic symptoms

allow safer delivery of radiation treatments

  • External beam irradiation

post-op focal EBI: single brain lesion

whole brain EBI: best for multiple mets & pts with single brain mets & widespread systemic spread

brain tumors management4
Brain tumors: management
  • Brachytherapy
  • Stereotactic surgery
  • New modalities:

implantation of chemotherapy-filled biodegradable polymers

immunotherapy

gene therapy

epidural spinal cord compression escc epidemiology
Epidural Spinal Cord Compression (ESCC): epidemiology
  • Definition: compression of the thecal sac by tumor in the epidural space, either at the level of the spinal cord or the cauda equina
  • Occurs in approximately 5% of cancer patients
  • R/O cord compression is the most common reason for neuro-oncologic consultation at Memorial Sloan-Kettering
  • Treatability when dx’d early & poor outcome once neurologic function deteriorates
escc mechanism
ESCC: mechanism
  • Hematogenous spread of tumor cells to bone marrow of vertebral bodies
  • Compresses thecal sac by:

1) Direct growth posteriorly

2) Produce vertebral collapse

  • 15-20% of pts: spread of paraspinal tumors through the neuroforamen to compress the thecal sac

Common in: lymphomas, renal cell carcinoma, Pancoast tumor of the lung

  • Enlarging epidural tumor compresses epidural venous plexus, causing vasogenic edema, with eventual spinal cord infarction
  • Slowly progressive lesions much more likely to be reversible than rapidly progressive lesions
escc clinical features
ESCC: clinical features
  • Underlying malignancies:

~20% prostate

~20% lung

~20% breast

~10% non-Hodgkin’s lymphoma

~10% multiple myeloma

~10% renal cell carcinoma

~10% virtually every other primary tumor

  • Pediatric: sarcomas, neuroblastoma
  • 20% of ESCC cases occur as initial presentations of the underlying malignancies
  • Location: 60% in thoracic, 30% in lumbar, 10% cervical
escc clinical features1
ESCC: clinical features
  • Pain

- 95% of ESCC patients as initial symptom

- precedes other symptoms of ESCC by 1-2 mos

- worsens with recumbency (vs. pain of disc prolapse or OA, which improves when pt lies down)

- thoracic localization

- percussion tenderness

- acute worsening may be sign of pathologic fx

- radicular pain almost always bilateral

escc clinical features2
ESCC: clinical features
  • Weakness

- present in 75% of pts who have ESCC

- usually symmetric

  • Sensory complaints

- ascending numbness and paresthesias

escc neuroimaging
ESCC: neuroimaging
  • Plain spinal radiographs

- False-negatives in 10-17% (paraspinal invasion)

- 30-35% of bone must be destroyed before radiography turns positive

- In cancer pts w/ back pain alone, major vertebral body collapse associated with >75% chance of ESCC

- If both plain films and bone scans are negative for pt w/ back pain alone, the risk of ESCC may be as low as 2%

  • Modality of choice: MRI and CT myelography

- CT myelography allows for simultaneous CSF collection

escc neuroimaging1
ESCC: neuroimaging
  • 37-year-old patient with breast cancer who presented with acute low back pain. T1-weighted sagittal MR image of the lumbar spine showing metastases in the body of L3 with extension into the posterior elements.
escc differential diagnosis
ESCC: differential diagnosis
  • Must consider benign conditions such as:

- disc herniation

- suppurative bacterial infections

- TB

- hemorrhage

- chordoma

- vertebral hemangioma

  • Other malignant conditions:

- vertebral metastases w/o epidural extension

- leptomenigeal diseases (co-exist in 25%)

- intramedullary spinal metastases (lung cancer)

- chronic progressive radiation myelopathy

escc management
ESCC: management
  • Pain

- corticosteroids (alleviate vasogenic edema)

- appropriate analgesics (e.g., opiates)

  • DVT prophylaxis for paraparetic pts
  • Corticosteroids

- randomized trial showed significantly higher percentage of pts receiving DXM remained ambulatory over time

  • Laminectomy

- small randomized trial showed no difference in outcome between laminectomy & radiotherapy vs. radiotherapy alone

- poor access to anterior tumor & further destabilization of spine

escc management1
ESCC: management
  • Fractionated external beam radiotherapy

2500-4000 cGy in 10-20 fractions over 2-4 weeks

Importance of early detection:

- 80-100% of pts who were ambulatory at start of treatment remain ambulatory.

- 33% of pts who were non-ambulatory will regain their ability to walk.

- 2-6% of paraplegic pts will regain their ability to walk.

Medial survival following onset of ESCC is ~6 months.

50% of the patients who are still alive at 1 year will be ambulatory.

escc management2
ESCC: management
  • Vertebrectomy

gross total tumor resection followed by spinal reconstruction with bone grafting

Recent series:

- 82% of pts post-op improved

- 67% of non-ambulatory pts were able to walk post-op

Strongly considered in:

- pts w/ spinal instability or bone w/in spinal canal

- local recurrence post-RT

- known radioresistant tumor

Mortality: 6-10%

Complication rate: 48%

wound breakdown (rel. to steroids), stabilization failure, infection, hemorrhage

escc management3
ESCC: management
  • Chemotherapy

For chemo-sensitive tumors:

Hodgkin’s disease, NHL, neuroblastoma, germ-cell tumors, breast cancer

  • Bisphosphonates

Reduce the incidence of pathologic fx’s & bone pain in pts with multiple myeloma or breast cancer

  • Recurrence

10% of all irradiated pts will experience local recurrence

Chemotherapy and surgery (vertebrectomy) should be considered

leptomeningeal metastases lmm epidemiology
Leptomeningeal Metastases (LMM): Epidemiology
  • Definition: Tumor cells seeding the meninges along the CSF pathways
  • 0.8-8.0% of all cases of cancer
  • LMM is especially likely with:

- leukemia

- NHL

- breast cancer

- small-cell lung cancer (SCLC)

lmm clinical features
LMM: clinical features
  • Spinal signs

- involvement of tumor cells with the nerve roots

- asymmetric weakness, sensory loss, parasthesias, depressed reflexes

- >70% of pts

- common in the lumbrosacral region

- pain and sphincter dysfunction are less common

  • Cranial nerve involvement

- 30-50% of pts will have cranial nerve symptoms/signs

- oculomotor nerves (III, IV, VI) are most commonly involved

lmm diagnostic tests imaging
LMM: diagnostic tests/imaging
  • Lumbar puncture/CSF

- elevated opening pressure (>50%), elevated WBC (>70%), elevated protein (>75%), reduced glucose (25-30%)

- positive cytology after 1 LP: 50%; after 3 LPs: 90%

- future use of biochemical markers

  • Brain MRI

- meningeal enhancement (50%)

- hydrocephalus (<40%)

  • Spine MRI

- meningeal enhancement (>50%)

  • Myelogram

- subarachnoid masses (<25%)

lmm management
LMM: management
  • Intrathecal chemotherapy

- via dural puncture or indwelling ventricular reservoir

- multiple drug therapy does not confer advantage over a single-agent therapy with methotrexate

- leucovorin po bid X 4d reduces systemic toxicity from methotrexate

- alternatives: cytosine arabinoside, thiotepa

  • Localized cranial or spinal irradiation

- for pts with focal symptoms or CSF block only

  • Median survival: 3-6 months with treatment
  • 15-25% of pts survive more than one year
stroke epidemiology
Stroke: epidemiology
  • 7% of cancer patients experience symptomatic stroke during their lifetime
  • Cause equally divided between cerebral infarctions and hemorrhages
  • Hematologic vs. Non-hematologic malignancies
stroke in hematologic malignancies
Stroke: in hematologic malignancies

Leukemias

  • Mostly hemorrhagic strokes
  • At autopsy: 18% of AML and 8% of ALL had hemorrhagic strokes
  • Risk factors for hemorrhagic strokes:

1) Thrombocytopenia (< 20,000/mul)

2) DIC (found in APML)

3) Hyperleukocytosis

- 10% of AML pts w/ WBC > 100,000/mul will die w/in 10 days of starting therapy due to intracerebral or pulmonary hemorrhage

- less often in ALL (inc. risk w/ >400,000/mul

stroke in hematologic malignancies1
Stroke: in hematologic malignancies
  • Cerebral infarction occurs less frequently (septic emboli or DIC)
  • Cerebral venous thrombosis in L-asparaginase-treated ALL pts (presents with headaches & seizures)

Lymphomas

  • Substantially less common
  • Cerebral infarction ocurs more commonly (septic emboli, nonbacterial thrombotic endocarditis, DIC)
  • Intracerebral hemorrhage occurs less commonly

Waldenstrom’s macroglobulinemia & multiple myeloma

  • Hyperviscosity: headache, visual complaints, lethargy --> seizures, focal deficits, coma
stroke in non hematologic malignancies
Stroke: in non-hematologic malignancies
  • Intracranial hemorrhages

- ~50% of strokes in pts w/ non-hematologic tumors

- mechanism: bleeding into the intracerebral mets

- common underlying cancers: melanoma, germ-cell tumors, non-SCLC

- 67% presents w/ stroke-like symptoms, while remaining will have more gradual deterioration

- management: corticosteroids, surgical evacuation, surgery/radiation

stroke in non hematologic malignancies1
Stroke: in non-hematologic malignancies
  • Ischemic infarcts

- majority of ischemic infarcts are due to atherosclerotic disease unrelated to the malignancy

- hypercoagulability of cancer may contribute

- non-bacterial thrombotic endocarditis fairly common

- management:

evaluate cardiovascular causes

treat underlying malignancy

heparin?

  • Rare causes:

- tumor embolization

- direct compression of superior sagittal sinus causing venous infarction

complications of treatments radiation
Complications of Treatments: radiation
  • Mechanism:

- direct injury to neural structures

- damaging blood vessels that supply neural structures

- damaging endocrine organs

- producing tumors

  • Acute reaction

- relatively uncommon

- occur w/ large doses (> 300 cGy) given to pts w/ cerebral edema and increased ICP

- increased edema w/in neural structures

complications of treatments radiation1
Complications of Treatments: radiation
  • Early delayed reaction

- weeks to months post-RT

- mechanism: transient demyelination

- most recover spontaneously w/in 6-8 weeks

  • Late delayed reaction

- early as 3 months, usually 1-2 years post-RT

- mechanism: radiation necrosis

- often progressive and irreversible

- risk much higher in pts post-brachytherapy or stereotactic radiosurgery

- steroids & surgery

  • Cerebral atrophy & leukoencephalopathy

- cognitive problems

complications of treatments radiation2
Complications of Treatments: radiation
  • Cranial neuropathy

- optic neuropathy

occurs months to years post-RT

pain-less, progressive visual loss w/ optic atrophy

- radiation-induced otitis media & conductive hearing loss

  • Lhermitte’s sign: electric sensation produced by neck flexion

- resolves spontaneously (transient demyelination of posterior columns)

complications of treatments chemotherapy
Complications of Treatments: chemotherapy
  • Intrathecal methotrexate: aseptic meningitis

- 10-40% of pts

- 2-4 hours after injection, last for 12-72 hours

- CSF shows granulocytic pleocytosis, elevated protein

- self-limited; no treatment required

  • Cytosine arabinoside: cerebellar syndrome

- high doses (3 g/m2/12 hours), 25% of pts

- somnolence, confusion to ataxia in 2-5 days post-CT

- some resolve spontaneously, some permanent

  • Corticosteroids

- acute: psychosis, hallucinations, blurred vision, tremor, seizures, myelopathy

- chronic: myopathy, cerebral atrophy

complications of treatments chemotherapy1
Complications of Treatments: chemotherapy
  • 5-Fluorouracil

- acute: cerebellar syndrome, encephalopathy

- chronic: cerebellar syndrome, Parkinsonian syndrome

  • Taxol/taxotere

- acute: arthralgias, myalgis (common)

- chronic: neuropathy (common)

  • Vincristine

- acute: encephalopathy, seizures, cortical blindness, extrapyramidal syndrome

- chronic: neuropathy (common)

complications of treatments chemotherapy2
Complications of Treatments: chemotherapy
  • Carboplatin

- acute: strokes, retinopathy

  • Cisplatin

- acute: vestibulopathy, Lhermitte’s sign, encephalopathy, seizures, focal deficits, strokes

- neuropathy (common), ototoxicity (common)

complications of treatments bone marrow transplantation
Complications of Treatments: bone marrow transplantation
  • Allogeneic BMT pts: 50-70%, smaller proportions in autologous BMT pts
  • Toxic-metabolic encephalopathy (37% of pts)
  • Seizures (12-16% of pts)
  • CNS infections (7-14% of pts)
  • GBS following BMT unrelated to GVHD (case reports)
  • Cerebrovascular complications (4-13% of pts)
complications of treatments bone marrow transplantation1
Complications of Treatments: bone marrow transplantation
  • Acute GVHD not associated with neurologic complications
  • Chronic GVHD

- occurs in 40% of HLA-matched, 75% of HLA-mismatched transplants

- “auto”-immune disorders of PNS (DDx of “weakness”):

myasthenia gravis

polymyositis

chronic inflammatory demyelinating polyneuropathy

paraneoplastic syndromes
Paraneoplastic Syndromes
  • Very rare
  • Autoimmune etiology
  • Account for a high-percentage of patients who have these particular syndromes

e.g., 50% of pts w/ subacute cerebellar degeneration have an underlying neoplasm

  • Frequently develop before the diagnosis of tumor
  • Run a course independent of underlying tumor
paraneoplastic syndromes1
Paraneoplastic Syndromes
  • Paraneoplastic cerebellar degeneration

- most common

- progresses over weeks to months

- severe truncal and appendicular ataxia and dysarthria

- small-cell lung cancer, gynecologic cancers, breast cancer, Hodgkin’s disease

- CSF: elevated protein, mild pleocytosis, oligoclonal bands

- MRI: early shows normal scan; later may show cerebellar atrophy

- anti-Yo IgG (anti-Purkinje cell cytoplasmic antibody type I)

- generally do not improve after antineoplastic or immunosuppressive therapy

paraneoplastic syndromes2
Paraneoplastic Syndromes
  • Paraneoplastic Opsoclonus-Myoclonus

- involuntary, multidirectional, high-amplitude, conjugate, chaotic saccades

- neuroblastoma in children, small-cell lung cancer, breast cancer

- anti-Ri (antineuronal nuclear antibody type II)

- prognosis better than PCD; remissions occur spontaneously post-cancer treatment

  • Paraneoplastic Encephalomyelitis/Sensory neuronopathy

- one or more of: dementia, brain-stem encephalitis, cerebellar degeneration, myelopathy, autonomic neuropathy, subacute sensory neuronopathy

- most pts have SCLC

paraneoplastic syndromes3
Paraneoplastic Syndromes
  • Necrotizing myelopathy

- rapidly ascending myelopathy

- flaccid paraplegia and death

- lymphoma, leukemia, lung cancer

  • Peripheral nerve disorders

- Hodgkin’s disease & GBS and branchial neuritis

paraneoplastic syndromes4
Paraneoplastic Syndromes
  • Lambert-Eaton Myasthenic Syndrome

- autoimmune IgG to voltage-gated Ca++ channels on presynaptic nerve terminals

- weakness, fatigability, pain, esp. of proximal muscles, with reduced or absent reflexes

- may be improvement in strength w/ repeated muscle contractions

- 75% of male and 25% of female pts have underlying neoplasm, usually SCLC

- NCS: low amp muscle action potentials that increase significantly after exercising for 10-15 sec

- autoantibodies that bind solubilized Ca++ channel w-conotoxin complexes

source
Source
  • Schiff D, Batchelor T, Wen PY. Neurologic Emergencies in Cancer Patients. Neurologic Clinics, 16:449, 1998
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