Neurological Emergencies in Cancer Patients

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Neurological Emergencies in Cancer Patients

• Pete Kang

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Neurologic Emergencies in Cancer Patients

• Neurologic sxs present in 38 of
  oncology-related ED visits
• Most common neurologic dxs among cancer patients
  _at_ Memorial Sloan-Kettering Cancer Center
• Brain mets 16
• Metabolic encephalopathy 10
• Bone mets 10
• Epidural tumor 8

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Neurologic Emergencies in Cancer Patients

• Brain tumors
• Epidural spinal cord compression (ESCC)
• Leptomeningeal metastasis (LMM)
• Stroke
• Acute neurologic complications of cancer
  treatment
• Paraneoplastic syndromes

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Brain Tumors epidemiology

• Each year
• 17,500 dxd with primary brain tumors
• 66,000 dxd 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

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Brain Tumors mechanism

• Direct tissue destruction
• Displacement of brain tissues (tumor/edema)
• Compression of vasculature (ischemia)
• Compression of CSF pathways (hydrocephalus)

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Brain Tumors clinical features

• Headache
• - presenting sx in 35 of patients
• - 70 of patients will have a headache at some
  point
• - classic mild _at_ 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

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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 Todds paralysis
• Papilledema
• - older studies present in 70
• - now 8
• Acute presentations hydrocephalus, intratumoral
  hemorrhage, seizures

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Brain tumors management

• Symptomatic Treatments
• cerebral edema
• - emergency management
• 1. hyperventilation (w/in 30sec, for 15-20min)
• 2. hyperosmolar agents (mannitol 20-25 _at_
  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)

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Brain tumors management

• seizures
• symptomatic treatment anticonvulsants
• prophylactic treatment controversial
• - two randomized prospective studies (gt170 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)

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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)

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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

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Brain tumors management

• Brachytherapy
• Stereotactic surgery
• New modalities
• implantation of chemotherapy-filled
  biodegradable polymers
• immunotherapy
• gene therapy

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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 dxd early poor outcome once
  neurologic function deteriorates

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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

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ESCC clinical features

• Underlying malignancies
• 20 prostate
• 20 lung
• 20 breast
• 10 non-Hodgkins 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

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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

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ESCC clinical features

• Weakness
• - present in 75 of pts who have ESCC
• - usually symmetric
• Sensory complaints
• - ascending numbness and paresthesias

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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 gt75
  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

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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.

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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

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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

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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.

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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

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ESCC management

• Chemotherapy
• For chemo-sensitive tumors
• Hodgkins disease, NHL, neuroblastoma,
  germ-cell tumors, breast cancer
• Bisphosphonates
• Reduce the incidence of pathologic fxs 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

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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)

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LMM clinical features

• Spinal signs
• - involvement of tumor cells with the nerve
  roots
• - asymmetric weakness, sensory loss,
  parasthesias, depressed reflexes
• - gt70 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

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LMM diagnostic tests/imaging

• Lumbar puncture/CSF
• - elevated opening pressure (gt50), elevated WBC
  (gt70), elevated protein (gt75), 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 (lt40)
• Spine MRI
• - meningeal enhancement (gt50)
• Myelogram
• - subarachnoid masses (lt25)

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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

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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

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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 (lt 20,000/mul)
• 2) DIC (found in APML)
• 3) Hyperleukocytosis
• - 10 of AML pts w/ WBC gt 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/ gt400,000/mul

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Stroke in hematologic malignancies

• Cerebral infarction occurs less frequently
  (septic emboli or DIC)
• Cerebral venous thrombosis in L-asparaginase-treat
  ed 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
• Waldenstroms macroglobulinemia multiple
  myeloma
• Hyperviscosity headache, visual complaints,
  lethargy --gt seizures, focal deficits, coma

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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

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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

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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 (gt 300 cGy) given to pts
  w/ cerebral edema and increased ICP
• - increased edema w/in neural structures

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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

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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
• Lhermittes sign electric sensation produced by
  neck flexion
• - resolves spontaneously (transient
  demyelination of posterior columns)

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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

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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)

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Complications of Treatments chemotherapy

• Carboplatin
• - acute strokes, retinopathy
• Cisplatin
• - acute vestibulopathy, Lhermittes sign,
  encephalopathy, seizures, focal deficits, strokes
• - neuropathy (common), ototoxicity (common)

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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)

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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

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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

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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, Hodgkins 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

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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

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Paraneoplastic Syndromes

• Necrotizing myelopathy
• - rapidly ascending myelopathy
• - flaccid paraplegia and death
• - lymphoma, leukemia, lung cancer
• Peripheral nerve disorders
• - Hodgkins disease GBS and branchial neuritis

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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

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Source

• Schiff D, Batchelor T, Wen PY. Neurologic
  Emergencies in Cancer Patients. Neurologic
  Clinics, 16449, 1998