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Neurological Emergencies in Cancer Patients

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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  1. Neurological Emergencies in Cancer Patients Pete Kang

  2. 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%

  3. Neurologic Emergencies in Cancer Patients • Brain tumors • Epidural spinal cord compression (ESCC) • Leptomeningeal metastasis (LMM) • Stroke • Acute neurologic complications of cancer treatment • Paraneoplastic syndromes

  4. 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

  5. Brain Tumors: mechanism • Direct tissue destruction • Displacement of brain tissues (tumor/edema) • Compression of vasculature (ischemia) • Compression of CSF pathways (hydrocephalus)

  6. 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

  7. 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

  8. 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)

  9. 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)

  10. 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)

  11. 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

  12. Brain tumors: management • Brachytherapy • Stereotactic surgery • New modalities: implantation of chemotherapy-filled biodegradable polymers immunotherapy gene therapy

  13. 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

  14. 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

  15. 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

  16. 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

  17. ESCC: clinical features • Weakness - present in 75% of pts who have ESCC - usually symmetric • Sensory complaints - ascending numbness and paresthesias

  18. 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

  19. 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.

  20. 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

  21. 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

  22. 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.

  23. 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

  24. 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

  25. 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)

  26. 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

  27. 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%)

  28. 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

  29. 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

  30. 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

  31. 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

  32. 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

  33. 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

  34. 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

  35. 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

  36. 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)

  37. 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

  38. 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)

  39. Complications of Treatments: chemotherapy • Carboplatin - acute: strokes, retinopathy • Cisplatin - acute: vestibulopathy, Lhermitte’s sign, encephalopathy, seizures, focal deficits, strokes - neuropathy (common), ototoxicity (common)

  40. 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)

  41. 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

  42. 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

  43. 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

  44. 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

  45. 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

  46. 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

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

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