neurological emergencies in cancer patients pete kang

Neurological Emergencies in Cancer Patients

Neurological Emergencies in Cancer Patients

Pete Kang

Neurologic Emergencies in Cancer PatientsNeurologic 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 PatientsNeurologic 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: epidemiologyBrain 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: mechanismBrain Tumors: mechanism

Direct tissue destruction Displacement of brain tissues

(tumor/edema) Compression of vasculature (ischemia) Compression of CSF pathways

(hydrocephalus)

Brain Tumors: clinical featuresBrain 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 featuresBrain 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: managementBrain 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)


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)


venous thromboembolism19-37% 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)


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


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: mechanismESCC: 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 featuresESCC: 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


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


Weakness

- present in 75% of pts who have ESCC

- usually symmetric Sensory complaints

- ascending numbness and paresthesias

ESCC: neuroimagingESCC: 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: neuroimagingESCC: 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 diagnosisESCC: 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: managementESCC: 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


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.


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


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 featuresLMM: 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/imagingLMM: 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: managementLMM: 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: epidemiologyStroke: 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 malignanciesStroke: 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 malignanciesStroke: 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 malignanciesStroke: 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 malignanciesStroke: 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: radiationComplications 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


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


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


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



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)



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


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)



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 SyndromesParaneoplastic 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 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 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


Necrotizing myelopathy

- rapidly ascending myelopathy

- flaccid paraplegia and death

- lymphoma, leukemia, lung cancer Peripheral nerve disorders

- Hodgkin’s disease & GBS and branchial neuritis


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

SourceSource

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

neurological emergencies in cancer patients pete kang

Documents

lung n

neuroblastoma n

n acute presentations

mechanism n hematogenous

epidemiology n definition

vertebral collapse n

majority n incidence

cauda equina n