Neurological emergencies in cancer patients
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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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Neurological Emergencies in Cancer Patients

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Neurological emergencies in cancer patients

Neurological Emergencies in Cancer Patients

Pete Kang


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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