ESO Course <br />Leukaemia and Lymphoma 12-14 June 2011 <br />Ascona, Switzerland<br />Neurological problems in patients w...
Neurological problems in patients with haematological neoplasms<br />Diagnosis<br /><ul><li> Neurologist
Neuroradiologist
 Neurosurgeon
Neuropathologist</li></ul>Treatment<br />interdisciplinary affair:<br />- Oncologist<br />- Radio-Oncologist<br />- Neurol...
 Neurosurgeon</li></li></ul><li>Neurological problems in patients with haematological neoplasms<br />A. Direct neoplastic ...
A. Direct neoplastic manifestation in the nervous system of 	haematological neoplasms<br />Primary central nervous system ...
75% brain supratentorial, 20% brain posterior fossa, 12 % leptomeninges
solitary in 75 % , multiple in 25 %
the deep structures (around ventricles) or lobar
Rx CT/MRI contrast enhancement in almost 100% (except following steroids!), </li></ul>enhancement may be homogenous – hete...
A. Direct neoplastic manifestation in the nervous system of 	haematological neoplasms<br />Primary central nervous system ...
75% brain supratentorial, 20% brain posterior fossa, 12 % leptomeninges
solitary in 75 % , multiple in 25 %
the deep structures (around ventricles) or lobar
Rx CT/MRI contrast enhancement in almost 100% (except following steroids!), </li></ul>enhancement may be homogenous – hete...
Primary central nervous system lymphoma (PCNSL)<br />Male, 66 y.<br />Increasing mental slowing,<br />apathy, and memory p...
short term memory ↓
long term memory ↓</li></ul>Histo-pathological Dg:<br />diffuse large B cell NHL<br />
Primary central nervous system lymphoma (PCNSL)<br />Male, 66 y.<br />Increasing mental slowing,<br />apathy, and memory p...
short term memory ↓
long term memory ↓</li></ul>Histo-pathological Dg:<br />diffuse large B cell NHL<br />
Primary central nervous system lymphoma (PCNSL)<br />Male, 66 y.<br />Increasing mental slowing,<br />apathy, and memory p...
short term memory ↓
long term memory ↓</li></ul>Histo-pathological Dg:<br />diffuse large B cell NHL<br />
Primary central nervous system lymphoma (PCNSL)<br />Male, 66 y.<br />Increasing mental slowing,<br />apathy, and memory p...
short term memory ↓
long term memory ↓</li></ul>Histo-pathological Dg:<br />diffuse large B cell NHL<br />
Primary central nervous system lymphoma (PCNSL)<br />Male, 66 y.<br />Increasing mental slowing,<br />apathy, and memory p...
short term memory ↓
long term memory ↓</li></ul>Histo-pathological Dg:<br />diffuse large B cell NHL<br />
Primary central nervous system lymphoma (PCNSL)<br />Male, 66 y.<br />Increasing mental slowing,<br />apathy, and memory p...
short term memory ↓
long term memory ↓</li></ul>Histo-pathological Dg:<br />diffuse large B cell NHL<br />
Primary central nervous system lymphoma (PCNSL)<br />Male, 79 y.<br />gait difficulty, falls, and <br />memory problems<br...
Primary central nervous system lymphoma (PCNSL)<br />Male, 79 y.<br />gait difficulty, falls, and <br />memory problems<br...
Multifocal central nervous system lymphoma<br />MRI T1 <br />with Gd Contrast<br />Female, 51 y.<br />Headache, episodic f...
Multifocal central nervous system lymphoma<br />MRI T1 <br />with Gd Contrast<br />Female, 51 y.<br />Headache, episodic f...
Direct neoplastic manifestation in the nervous system of haematological neoplasms:<br />2.   Secondary (metastatic) nervou...
Direct neoplastic manifestation in the nervous system of haematological neoplasms:<br />2.   Secondary (metastatic) nervou...
A. 	Direct neoplastic manifestation in the nervous system of 	haematological neoplasms<br />Secondary (metastatic) nervous...
Flow cytometric dot plots of cerebrospinal fluid specimens <br />demonstrating lymphoma populations (immunophenotyping)<br...
Leptomeningeal metastasis(meningeosislymphomatosa) <br />3 yrsagotreatedforT-cell NHL<br />incl. autologousstemcell<br />t...
Leptomeningeal metastasis(meningeosislymphomatosa) <br />3 yrsagotreatedforT-cell NHL<br />incl. autologousstemcell<br />t...
A. Direct neoplastic manifestation in the nervous system of 	haematological neoplasms<br />Secondary (metastatic) nervous ...
A. Direct neoplastic manifestation in the nervous system of haematological neoplasms<br />Secondary (metastatic) nervous s...
Peripheral Nerve and Nerve Root Involvement „Neurolymphomatosis“<br />R<br />S1 nerve root<br />Baehring JM et al. Neuro-O...
Peripheral Nerve and Nerve Root Involvement „Neurolymphomatosis“<br />MRI T1 <br />with Gd Contrast<br />R<br />Facial Ner...
A. Direct neoplastic manifestation in the nervous system of haematological neoplasms<br />secondary (metastatic) nervous s...
A. Direct neoplastic manifestation in the nervous system of haematological neoplasms<br />secondary (metastatic) nervous s...
A. Direct neoplastic manifestation in the nervous system of haematological neoplasms<br />secondary (metastatic) nervous s...
A. Direct neoplastic manifestation in the nervous system of haematological neoplasms<br />secondary (metastatic) nervous s...
B. Indirect manifestation affecting the NS<br />Paraneoplasticcerebellar degeneration (PCD) from HL<br />HL is  3rd cause ...
Paraffin sections of rat cerebellum (A) and Hodgkin lymphoma (B):<br />incubated with biotinylated immunoglobulin G from a...
B. Indirect manifestation affecting the NS<br />2. Paraneoplastic limbic encephalitis from HL<br />2.a. Anti-NMDA (N-methy...
Anti-NMDAR limbic encephalitis: coronal MRI<br />FLAIR<br />T1 with Gd Contrast<br />Pellkofer HL et al. J NeurolNeurosurg...
Paraneoplastic limbic encephalitis <br />MRI coronal<br />SPECT<br />mediastinal node<br />enlargement<br />arrow shows a ...
B. Indirect manifestation affecting the NS<br />2. Paraneoplasticlimbic encephalitis from HL: the “Ophelia syndrome”<br />...
2. Paraneoplasticlimbic encephalitis from HL: the “Ophelia syndrome”<br />Tumors associated with paraneoplastic limbic enc...
B. Indirect manifestation affecting the NS<br />3. Paraneoplastic neuropathies from Lymphomas<br />3.a.	Demyelinating poly...
Clinical presentations of neuropathies: Distribution<br />distal symmetrical<br />polyneuropathy<br />usually predominantl...
Axonal versus demyelinatingpolyneuropathy (ENMG)<br />M<br />normal<br />Aetiology<br />rule of thumb:<br />Ae: toxic(dose...
Clinical presentations of neuropathies: Type of fibres involved<br />Functions conveyed (signs)<br />tendon reflexes<br />...
B. Indirect manifestation affecting the NS<br />4. Plasma cell disorders (dyscrasias) with dysimmune neuropathies<br />4.a...
B. Indirect manifestation affecting the NS<br />4. Plasma cell disorders (dyscrasias) with dysimmune neuropathies<br />4.d...
D. Complications of treatment affecting the nervous system<br />1. Neurologic Complications of Radiotherapy (RT)<br />1.a....
D. Complications of treatment affecting the nervous system<br />1. Neurologic Complications of Radiotherapy (RT)<br />1.a....
D. Complications of treatment affecting the nervous system<br />2. Neurologic Complications of Chemotherapy<br />2.a. Drug...
Drug-Induced Polyneuropathy: symmetrical, length dependent<br />mostimportantexamples<br />axonal:<br />- Vincristine [Onc...
Distal symmetrical sensory or sensorimotor PNP<br />= length dependent<br />• distal  proximal*<br />• legs > arms<br />•...
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LLA 2011 - C. Hess - Neurological problems in patients with haematological neoplasms

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LLA 2011 - C. Hess - Neurological problems in patients with haematological neoplasms

  1. 1. ESO Course <br />Leukaemia and Lymphoma 12-14 June 2011 <br />Ascona, Switzerland<br />Neurological problems in patients with haematological neoplasms<br />C W Hess, Bern<br />
  2. 2. Neurological problems in patients with haematological neoplasms<br />Diagnosis<br /><ul><li> Neurologist
  3. 3. Neuroradiologist
  4. 4. Neurosurgeon
  5. 5. Neuropathologist</li></ul>Treatment<br />interdisciplinary affair:<br />- Oncologist<br />- Radio-Oncologist<br />- Neurologist<br /><ul><li>Neuroradiologist
  6. 6. Neurosurgeon</li></li></ul><li>Neurological problems in patients with haematological neoplasms<br />A. Direct neoplastic manifestation in the nervous system<br />B. Indirect manifestation affecting the nervous system<br />C. CNS Infections due to neoplasm-induced immunosuppression<br />D. Complications of treatment affecting the nervous system<br />
  7. 7. A. Direct neoplastic manifestation in the nervous system of haematological neoplasms<br />Primary central nervous system lymphoma (PCNSL)<br />= NHL involving the brain, spinal cord, meninges, or eyes <br /> usually without previous or concurrent involvement of other organs; <br />ca. 6 % of intracranial neoplasms and ca. 1 % of all lymphomas<br /><ul><li>remain confined to the CNS
  8. 8. 75% brain supratentorial, 20% brain posterior fossa, 12 % leptomeninges
  9. 9. solitary in 75 % , multiple in 25 %
  10. 10. the deep structures (around ventricles) or lobar
  11. 11. Rx CT/MRI contrast enhancement in almost 100% (except following steroids!), </li></ul>enhancement may be homogenous – heterogeneous<br />DD: malignant gliomas, metastases, sarcoidosis, and inflammatory disease (ADEM)<br />Dg: • CSF: pleocytosis in 36%, cytology with lymphoma cells in 20% (Fischer L, 2006)<br /> • stereotactic biopsy if possible<br />• histology: diffuse large B celllymphoma<br />• looking for extra-cns involvement (staging): complete blood count<br /> CT thorax & abdomen, bone marrow biopsy; Eye slit lamp exam, LDH, HIV.<br />
  12. 12. A. Direct neoplastic manifestation in the nervous system of haematological neoplasms<br />Primary central nervous system lymphoma (PCNSL)<br />= NHL involving the brain, spinal cord, meninges, or eyes <br /> usually without previous or concurrent involvement of other organs; <br />ca. 6 % of intracranial neoplasms and ca. 1 % of all lymphomas<br /><ul><li>remain confined to the CNS
  13. 13. 75% brain supratentorial, 20% brain posterior fossa, 12 % leptomeninges
  14. 14. solitary in 75 % , multiple in 25 %
  15. 15. the deep structures (around ventricles) or lobar
  16. 16. Rx CT/MRI contrast enhancement in almost 100% (except following steroids!), </li></ul>enhancement may be homogenous – heterogeneous<br />DD: malignant gliomas, metastases, sarcoidosis, and inflammatory disease (ADEM)<br />• responsive to steroids (melts away in >40%)<br /> BUT: steroids may obscure histology <br />(-> aim at histological diagnosis before starting a “steroid trial”)<br />• relapses are usually no longer steroid responsive<br />Th: • Problem: BB-Barrier renders chemotherapy difficult<br /> • high dose(≥3 g/m2)MTX, WB Rx (<60 yrs), Autolog. Stem-Cell Transpl., intrathRituximab? …<br />
  17. 17. Primary central nervous system lymphoma (PCNSL)<br />Male, 66 y.<br />Increasing mental slowing,<br />apathy, and memory problems over months<br />MRI: T1 with Gd Contrast<br />Clinical S & S:<br />- not fully orientated<br /> to time and place<br /><ul><li>alertness greatly ↓
  18. 18. short term memory ↓
  19. 19. long term memory ↓</li></ul>Histo-pathological Dg:<br />diffuse large B cell NHL<br />
  20. 20. Primary central nervous system lymphoma (PCNSL)<br />Male, 66 y.<br />Increasing mental slowing,<br />apathy, and memory problems over months<br />MRI: T1 with Gd Contrast<br />Clinical S & S:<br />- not fully orientated<br /> to time and place<br /><ul><li>alertness greatly ↓
  21. 21. short term memory ↓
  22. 22. long term memory ↓</li></ul>Histo-pathological Dg:<br />diffuse large B cell NHL<br />
  23. 23. Primary central nervous system lymphoma (PCNSL)<br />Male, 66 y.<br />Increasing mental slowing,<br />apathy, and memory problems over months<br />MRI: T1 with Gd Contrast<br />Clinical S & S:<br />- not fully orientated<br /> to time and place<br /><ul><li>alertness greatly ↓
  24. 24. short term memory ↓
  25. 25. long term memory ↓</li></ul>Histo-pathological Dg:<br />diffuse large B cell NHL<br />
  26. 26. Primary central nervous system lymphoma (PCNSL)<br />Male, 66 y.<br />Increasing mental slowing,<br />apathy, and memory problems over months<br />MRI: T1 with Gd Contrast<br />Clinical S & S:<br />- not fully orientated<br /> to time and place<br /><ul><li>alertness greatly ↓
  27. 27. short term memory ↓
  28. 28. long term memory ↓</li></ul>Histo-pathological Dg:<br />diffuse large B cell NHL<br />
  29. 29. Primary central nervous system lymphoma (PCNSL)<br />Male, 66 y.<br />Increasing mental slowing,<br />apathy, and memory problems over months<br />MRI: T1 with Gd Contrast<br />Clinical S & S:<br />- not fully orientated<br /> to time and place<br /><ul><li>alertness greatly ↓
  30. 30. short term memory ↓
  31. 31. long term memory ↓</li></ul>Histo-pathological Dg:<br />diffuse large B cell NHL<br />
  32. 32. Primary central nervous system lymphoma (PCNSL)<br />Male, 66 y.<br />Increasing mental slowing,<br />apathy, and memory problems over months<br />MRI: T1 with Gd Contrast<br />Clinical S & S:<br />- not fully orientated<br /> to time and place<br /><ul><li>alertness greatly ↓
  33. 33. short term memory ↓
  34. 34. long term memory ↓</li></ul>Histo-pathological Dg:<br />diffuse large B cell NHL<br />
  35. 35. Primary central nervous system lymphoma (PCNSL)<br />Male, 79 y.<br />gait difficulty, falls, and <br />memory problems<br />MRI: T1 without Gd Contrast T1 with Gd Contrast<br />Histo-pathological Dg:<br />diffuse large B cell NHL<br />
  36. 36. Primary central nervous system lymphoma (PCNSL)<br />Male, 79 y.<br />gait difficulty, falls, and <br />memory problems<br />MRI: T2 T1 with Gd Contrast<br />Histo-pathological Dg:<br />diffuse large B cell NHL<br />
  37. 37. Multifocal central nervous system lymphoma<br />MRI T1 <br />with Gd Contrast<br />Female, 51 y.<br />Headache, episodic fever, <br />night sweat, nausea<br />vomitus, fatigue<br />Episodes of R sided<br />weakness & dysarthria<br />sometimes confusion<br />lasting mins to 1h<br />Clinical S & S:<br />- alertness ↓<br />- fatigue<br />- no focal deficits<br />Histo-pathological Dg:<br />diffuse large B cell NHL<br />
  38. 38. Multifocal central nervous system lymphoma<br />MRI T1 <br />with Gd Contrast<br />Female, 51 y.<br />Headache, episodic fever, <br />night sweat, nausea<br />vomitus, fatigue<br />Episodes of R sided<br />weakness & dysarthria<br />sometimes confusion<br />lasting mmin to 1h<br />Clinical S & S:<br />- alertness ↓<br />- fatigue<br />- no focal deficits<br />Histo-pathological Dg:<br />diffuse large B cell NHL<br />Histo-pathological Dg:<br />diffuse large B cell NHL<br />
  39. 39. Direct neoplastic manifestation in the nervous system of haematological neoplasms:<br />2. Secondary (metastatic) nervous system involvement<br />Most frequent direct neurologic complications of hematologic malignancies<br />(Leptomeningeal M.)<br />, (Leptomeningeal M.)<br />, (Leptomeningeal M.)<br />, (Leptomeningeal M.)<br />, (Leptomeningeal M.)<br />J.E.C. Bromberg, AAN April 2011<br />
  40. 40. Direct neoplastic manifestation in the nervous system of haematological neoplasms:<br />2. Secondary (metastatic) nervous system involvement<br />Frequency of Various Tumours of Origin Among Patients with Leptomeningeal Metastasis “CSF”(Meningeosisneoplastica)<br />J Grewal, J P Duic, M Almaliah, S Kesari, E J Dropcho. Neurology MedLINK, updated 19. July 2010<br />
  41. 41. A. Direct neoplastic manifestation in the nervous system of haematological neoplasms<br />Secondary (metastatic) nervous system involvement<br />2.a. Leptomeningeal metastasis, “CSF”<br />(meningeosislymphomatosa = lymphomatousmeningitis) <br />Leukaemia (particularly ALL•)or NHL , rarely HD or plasma cell tumours<br /> - Clinical S & S: nausea, vomitus, headache (not obligatory), cranial nerve involv., <br /> cognitive problems, or radiating pain due to nerve root involvement <br /> - MRI often negative & usually without contrast enhancement! (>< carcinomas), <br /> (sometimes subarachnoid nodules, intradural nerve contrast enhancement)<br /> - CSF pressure often↑, lymphocytic pleocytosis, and/or increased protein (in 80%), and/or hypoglycorrhachia; cytology (+ immunophenotypingbyflowcytometry)<br />(! perform lumbar puncture after MRI: -> i.c. hypotension -> dural enhancement! )<br />• ALL: often as CNS recurrence when adequate CNS prophylaxis was not given<br />(standard prophylactic treatment: intrathecal MTX and/or Cytarabine)<br />Problem: BB-Barrier renders chemotherapy difficult<br />
  42. 42. Flow cytometric dot plots of cerebrospinal fluid specimens <br />demonstrating lymphoma populations (immunophenotyping)<br />Surface immunoglobulin-negative B-cell lymphoma<br />Monoclonal B-cell population<br />CD20– B-cell T-lymphoma<br />Small population of monoclonal B cells with low cellularity<br />Hedge U et al. Blood 2005;105:496-502 <br />relative fluorescent intensity<br />
  43. 43. Leptomeningeal metastasis(meningeosislymphomatosa) <br />3 yrsagotreatedforT-cell NHL<br />incl. autologousstemcell<br />transplantation<br />MRI T1 <br />with Gd Contrast<br />VII & VIII<br />New:<br />Gait ataxia, memory problems, bilateral Abducens nerve paresis, right lid drooping, dysphagia<br />
  44. 44. Leptomeningeal metastasis(meningeosislymphomatosa) <br />3 yrsagotreatedforT-cell NHL<br />incl. autologousstemcell<br />transplantation<br />MRI T1 <br />with Gd Contrast<br />VI<br />New:<br />Gait ataxia, memory problems, bilateral Abducens nerve paresis, right lid drooping I,, dysphagia<br />
  45. 45. A. Direct neoplastic manifestation in the nervous system of haematological neoplasms<br />Secondary (metastatic) nervous system involvement<br />2.b. Systemic NHL infiltrating the CNS parenchyma (brain or spinal cord)<br />Burkitt lymphoma and diffuse large B-cell lymphoma (HL: exceedingly rare)<br /> 3-24% of pts with systemic NHL develop a CNS localization, e.g. as CNS recurrence.<br /> In 20-25% of these CNS localization is present at beginning of disease<br /> (brain << CSF)<br />
  46. 46. A. Direct neoplastic manifestation in the nervous system of haematological neoplasms<br />Secondary (metastatic) nervous system involvement<br />2.c. Peripheral Nerve and Nerve Root Involvement „Neurolymphomatosis“<br /> - NHL infiltrating cranial nerves, peripheral nerves, or nerve roots. <br /> - Clinical S & S: sensory loss, and/or focal weakness<br /> • asymmetric polyneuropathy or mononeuropathy or cranial neuropathy <br /> • severe pain (rarely painless)<br /> • sensory loss, and/or weakness<br /> • rapid evolution<br /> - CSF: Pleocytosis and/or protein↑ in 40-60%; malignant cells in 40% of pts. <br /> - Imaging: Gd-MRI (may be negative), PET-CT in 90% positive<br /> - Nerve biopsy may be necessary<br />Problem: Blood-Nerve-Barrier (BNB) renders chemotherapy difficult<br />
  47. 47. Peripheral Nerve and Nerve Root Involvement „Neurolymphomatosis“<br />R<br />S1 nerve root<br />Baehring JM et al. Neuro-Oncology 2003;5:104–115 <br />
  48. 48. Peripheral Nerve and Nerve Root Involvement „Neurolymphomatosis“<br />MRI T1 <br />with Gd Contrast<br />R<br />Facial Nerve<br />Baehring JM et al. Neuro-Oncology 2003;5:104–115 <br />
  49. 49. A. Direct neoplastic manifestation in the nervous system of haematological neoplasms<br />secondary (metastatic) nervous system involvement<br />2.d. Epidural spinal cord (or caudaequina) compression <br /> - direct invasion of the spinal canal from a vertebral body or via the intervertebral foramina from paraspinal regions (extra-axial non-CNS location). <br /> - Multiple Myeloma (approximately 20% of cases) >> HL, NHL: caused by vertebral body collapse and impingement of bone on the spinal cord<br /> - Clinical S & S: back pain (progressive, worse when lying flat, and improved with walking), weakness, sensory loss, autonomic dysfunction (painless urinary retention, faecal incontinence, and impotence), and ataxia<br />
  50. 50. A. Direct neoplastic manifestation in the nervous system of haematological neoplasms<br />secondary (metastatic) nervous system involvement<br />2.d. Epidural spinal cord compression <br /> by Multiple Myeloma, HL, or NHL<br />Outside of BB-Barrier:<br />easily amenable to systemic treatment<br />and chemosensitive & radiosensitive<br />CAVE: Epidural NHL may co-exist with a leptomeningeal localization of lymphoma, which may be clinically silent.<br />
  51. 51. A. Direct neoplastic manifestation in the nervous system of haematological neoplasms<br />secondary (metastatic) nervous system involvement<br />2.d. Epidural spinal cord compression: <br /> Multiple Myeloma<br />
  52. 52. A. Direct neoplastic manifestation in the nervous system of haematological neoplasms<br />secondary (metastatic) nervous system involvement<br />2.d. Epidural spinal cord compression: Multiple Myeloma<br />High power fieldshowingtypicalplasmacells<br />T1<br />Low power viewshowing multiple plasmacells<br />Infiltrativemass at level of T1 <br />dorsal processvertebrae. <br />F. Aziz, S. Doddi & S. Ghimire. The Internet Journal of Neurology2010;13<br />
  53. 53. B. Indirect manifestation affecting the NS<br />Paraneoplasticcerebellar degeneration (PCD) from HL<br />HL is 3rd cause of PCD after lung Ca (anti-Hu AB) and ovarian Ca (anti-Yo AB)<br />In HL it usually occurs after diagnosis or during long periods of remission (>< Ca)<br />Pg: if HL not treated -> irreversible loss of Purkinje cells and atrophy of cerebellum<br />Treatment aims at HL, otherwise no efficient treatment known (immunosuppression?)<br />- Clinical S & S: Subacutedysarthria, nystagmus, truncal ataxia, and limb dysmetria<br />1.a. anti-Tr AB associated paraneoplastic cerebellar degeneration (PCD)<br />Least severe form of PCD, may remit with treatment<br />1.b. anti-mGluR1 AB associated paraneoplastic cerebellar degeneration (PCD)<br />Hodgkin<br />Lymphoma<br />Reed-Sternberg Cell<br />
  54. 54. Paraffin sections of rat cerebellum (A) and Hodgkin lymphoma (B):<br />incubated with biotinylated immunoglobulin G from an anti-Tr-positive serum <br />and counterstained with haematoxylin. <br />Reed-Sternberg cells<br />Purkinijecell<br />20 µm<br />6 µm<br />Bernal F et al. Neurology 2003;60;230-234<br />
  55. 55. B. Indirect manifestation affecting the NS<br />2. Paraneoplastic limbic encephalitis from HL<br />2.a. Anti-NMDA (N-methyl-D-aspartate) receptor encephalitis<br />Anti-NMDA type, commonly associated with ovarian teratomas in young females<br />Maybe lethal without treatment<br />Clinical picture of Anti-NMDA type may resemble catatonia / paranoid psychosis!<br />Often, but not invariably improving after successfully treating the underlying neoplasm<br /><ul><li>Clinical S. & S.: memory loss, confusion, seizures, and psychiatric abnormalities, rhythmic movement disorder, hypoventilation requiring ventilation, and autonomic instability</li></ul>2.b. other, not yet identified antibodies<br />
  56. 56. Anti-NMDAR limbic encephalitis: coronal MRI<br />FLAIR<br />T1 with Gd Contrast<br />Pellkofer HL et al. J NeurolNeurosurgPsychiatry 2010;81:1407-1408<br />
  57. 57. Paraneoplastic limbic encephalitis <br />MRI coronal<br />SPECT<br />mediastinal node<br />enlargement<br />arrow shows a Hodgkin’s-Reed-Stemberg cell <br />with positive staining for CD30, magn. x600<br />Olmos D et al. Journal of Clinical Oncology2007;25:1802-1806<br />
  58. 58. B. Indirect manifestation affecting the NS<br />2. Paraneoplasticlimbic encephalitis from HL: the “Ophelia syndrome”<br />John William Waterhouse: <br />Ophelia (1894)<br />Carr I: Lancet 1982; 1:844-845<br />
  59. 59. 2. Paraneoplasticlimbic encephalitis from HL: the “Ophelia syndrome”<br />Tumors associated with paraneoplastic limbic encephalitis (all types):<br />Ophelia<br />Gultekin SH et al. Brain 2000;123:1481-494<br />
  60. 60. B. Indirect manifestation affecting the NS<br />3. Paraneoplastic neuropathies from Lymphomas<br />3.a. Demyelinating polyneuritis: GBS (motor >> sensory) or CIDP from HL >> NHL<br />3.b. Chronic polyneuropathies: motor, sensory, autonomic from NHL >> HL<br />3.c. Autonomic dysfunction in NHL >> HL<br />3.d. Vasculitic neuropathy in HL & NHL: Axonal mononeuritis multiplex <br />GBS = Guillain-Barré Syndrome: <br />• acute inflammatory demyelinating polyneuritis (AIDP)<br />• acute motor [sensory] axonal neuropathy (AMSAN / AMAN)<br />Chronic variants of GBS:<br /> • chronic inflammatory demyelinating polyneuritis (CIDP)<br />• mulitfocal motor neuropathy (MMN)<br />• paraproteinaemic neuropathies: IgM(- anti-MAG, - CANOMAD: chronic ataxic neuropathy with ophthalmoplegia, M-protein, agglutination and disialosyl antibodies)<br />IgG, IgA<br />
  61. 61. Clinical presentations of neuropathies: Distribution<br />distal symmetrical<br />polyneuropathy<br />usually predominantly sensory<br />maybe painful<br />proximal symmetrical<br />polyneuropathy<br />usually predominantly motor<br />mononeuritis multiplex<br />asymmetrical, multifocal<br />mostly acute, often painful<br />motor and/or sensory<br />length<br />dependent<br />examples:<br />proximal diabetic mono-n.<br />plexus neuritis<br />vasculitic neuropathies<br />multifocal motor n.<br />chronic inflammatory<br />demyelinatingp. (CIDP)<br />acute GBS<br />diabetic, alcoholic,<br />uraemic, toxic<br />drug-induced, etc. <br />
  62. 62. Axonal versus demyelinatingpolyneuropathy (ENMG)<br />M<br />normal<br />Aetiology<br />rule of thumb:<br />Ae: toxic(dose-dependent) <br /> metabolic<br />vasculitic<br /> „degenerative“<br />Ae: immune mediated<br />inflammatory<br /> (GBS, CIDP)<br /> some genetic<br />Ae: pressure palsy<br />immune mediated<br />inflammatory<br /> (MMN, …..)<br />axonal<br />demyelinating<br />focal demyelinisation<br />conduction block possible<br />
  63. 63. Clinical presentations of neuropathies: Type of fibres involved<br />Functions conveyed (signs)<br />tendon reflexes<br />position sense<br />vibration sense<br />autonomic peripheral ns<br />- perspiration anhidrosis<br />- postural hypotension<br />- pain and warmth<br /> perception<br />pain and cold<br /> perception<br />diameter<br />NCV<br />Mechanorec. Sharp pain Slow pain<br /> (skin) Cold Warmth<br />Mechanorec. Sharp pain Slow pain<br /> (skin) Cold Warmth<br />
  64. 64. B. Indirect manifestation affecting the NS<br />4. Plasma cell disorders (dyscrasias) with dysimmune neuropathies<br />4.a. Benign monoclonal gammopathy MGUS: <br />IgM-Gammopathy: demyelinating large fibre PNP (CIDP)<br /> - subtype with anti-MAG AB, slow progression, but relatively resistant to th.<br />IgG-Gammopathy: axonal small (and medium) fibre PNP<br />IgA-Gammopathy: rare<br />4.b. Primary systemic amyloidosis: axonal small fibre PNP with prominent autonomic features (other organs affected such as heart etc.)<br />4.c. Myeloma producing amyloid: Small fibre polyneuropathy PNP (axonal)<br />Patients do not generally respond to treatment of the myeloma, but may respond to rituximab or stem cell transplantation.<br />Pg: invasion of peripheral nerves by amyloid. <br />
  65. 65. B. Indirect manifestation affecting the NS<br />4. Plasma cell disorders (dyscrasias) with dysimmune neuropathies<br />4.d. Osteolytic myeloma without amyloidosis: slowly progressive peripheral sensorimotor PNP, usually as late finding<br />4.e. Osteosclerotic myeloma: <br /> • Chronic sensorimotor inflammatory demyelinatingpolyneuropathyCIDP <br />in 75% of patients. <br /> CSF protein↑ <br />Pg: mostly IgG or IgM protein, usually with lambda light chains. <br />PNP improves with treatment of the myeloma!<br />special subtype:<br /> • POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Edema, M-protein, and Skin abnormalities). Pg role of vascularendothelial growth factor (VEGF)!<br />- Waldenströmmacroglobulinaemia: demyelinating peripheral senorimotorpolyneuropathy CIDP in 10% of pts<br />
  66. 66. D. Complications of treatment affecting the nervous system<br />1. Neurologic Complications of Radiotherapy (RT)<br />1.a. Post-radiation Dropped Head Syndrome (postactinicptosiscapitis)<br />Weakness of neck extensor muscles causing an inability to extend the neck, <br />from high-dose “mantle field” radiotherapy for HL. Typically no sensory deficit!<br />Symptoms begin many years (> 20 years) after RT.<br />Pg: combination of primary muscle damage and anterior horn/nerve root lesions?<br />1.b. Post-radiation Brachial Plexopathy<br />Clinical S. & S.: Delayed progressive dysfunction (>1 year - up to 15 years): <br />Paraesthesia (100%), hypaesthesia (75%), weakness (50%), pain (50%, delayed)<br />Typical are fasciculations and myokymia (clinically and EMG) [>< tumour invasion]<br />Pg: Hyalinization and obliteration of blood vessels causes ischaemia of nerve fibres<br />EMG needle recording:<br />myokymic<br />discharge<br />
  67. 67. D. Complications of treatment affecting the nervous system<br />1. Neurologic Complications of Radiotherapy (RT)<br />1.a. Post-radiation Dropped Head Syndrome (postactinicptosiscapitis)<br />Weakness of neck extensor muscles causing an inability to extend the neck, <br />from high-dose “mantle field” radiotherapy for HL. Typically no sensory deficit!<br />Symptoms begin many years (> 20 years) after RT.<br />Pg: combination of primary muscle damage and anterior horn/nerve root lesions?<br />1.b. Post-radiation Brachial Plexopathy<br />Clinical S. & S.: Delayed progressive dysfunction (>1 year - up to 15 years): <br />Paraesthesia (100%), hypaesthesia (75%), weakness (50%), pain (50%, delayed)<br />Typical are fasciculations and myokymia (clinically and ENMG) [>< tumour invasion]<br />Pg: Hyalinization and obliteration of blood vessels causes ischaemia of nerve fibres<br />1.c. Post-radiation carotid artery atherosclerosis (➔ stenosis, relatively frequent) <br />with cerebrovascular complications (ischaemia) <br />
  68. 68. D. Complications of treatment affecting the nervous system<br />2. Neurologic Complications of Chemotherapy<br />2.a. Drug induced Polyneuropathy (PNP) from Systemic Application<br /> - Vincristine: as most neurotoxicvinca alkaloid causes a large fibre sensori-motor <br /> (and later also -> small fibre) axonal PNP in most patients. Also: mononeuritis!<br /> - Clinical S. & S.: few weeks following initiation of therapy and progress for <br /> several weeks after drug discontinuance (coasting phenomenon) before reversible<br /> Early paraesthesias of fingertips -> toes, fine finger movements↓ <br /> -> glove and stocking sensory deficit, weakness of extensor muscles of feet Early loss of Achilles reflexes -> all deep tendon reflexes disappear eventually<br /> - Vinblastinemay cause a predominantly length-dependent small fiber sensory <br /> peripheral PNP<br /> - Cisplatincausis a length-dependent large fiber sensory peripheral PNP or <br />ganglionopathy with a coasting phenomenon and only partial (if any) reversibility<br /> - Thalidomid causes a sensori-motor peripheral PNP, sometimes with a coasting phenomenon, and reversibility of weakness but only partial or often lacking reversibility of sensory deficits after cessation. For the development of PNP, the duration of exposure is more important than total cumulative dose<br /> - Cytarabine: sensory PNP<br /> - Bortezomid: “axonal, dose-dependentneuropathy“ ? [Filosto M et al 2007]<br />
  69. 69. Drug-Induced Polyneuropathy: symmetrical, length dependent<br />mostimportantexamples<br />axonal:<br />- Vincristine [Oncovin®], - Vinblastine [Velbe®], - Bortezomid[Argyriou, AA et al. 2008]<br />- Suramin°, - Carboplatin°, - Cisplatin [Platinol®]° (coasting phenomenon!)<br /><ul><li>Cholchicine ‡, - Sulfonamides‡, - Nitrofurantoine ‡†</li></ul>- Isoniazid (INH), - Gentamicin, - Sulfasalazine [Salazopyrin® Azulfidine® etc.]<br />Phenytoine[Dilantin®], -Statines<br />- Paclitaxel [Taxol®] †, - Metronidazole[Flagyl® etc.] †, - Thalidomid†<br />- AIDS drugs: nucleoside analogues,nucleosidereversetranscriptaseinhibitors(NRTI)<br />Zalcitabine [Hivid®], Stavudine [Zerit®] †<br />- Gold salts *- Disulfiram [Antabuse®]<br />- Bortezomid (vasculitic? idiosyncratic?) [Saifee T A et al. 2010]<br />demyelinating:<br />- Amiodaron [Cordarone®, Pacerone®], Bortezomid? *<br />- Tacrolimus [Prograf®] ‡<br />*maybe subacute, GBS-like†painful ‡ predominantly motor °sensory sensory-motor <br />
  70. 70. Distal symmetrical sensory or sensorimotor PNP<br />= length dependent<br />• distal proximal*<br />• legs > arms<br />• sensory > motor<br />plus symptoms:<br />paraesthesias /dysaesthesias<br /> pain<br />minus symptoms:<br />numb feeling<br />* toxic & metabolic PNP: involvement of the<br /> longest neurites earlier and more pronounced<br />distal-symmetrical (= length dependent) PNP<br />
  71. 71. • often also autonomic involvement<br />• palmo-plantar anhidrosis<br />• palmo-plantar hyperaemia<br /> (vasoparalysis due to<br /> damage to the<br /> peripheral sympathicus)<br />Distal symmetrical sensory or sensorimotor PNP<br />= length dependent<br />• distal proximal<br />• legs > arms<br />• sensory > motor<br />
  72. 72. distal<br />muscleatrophy<br />distal<br />paresis<br />Distal symmetrical sensory / sensori-motor PNP, large fibre<br />areflexia<br />pall-<br />anaesthesia<br />distal<br />hypaesthesia<br />
  73. 73. D. Complications of treatment affecting the nervous system<br />2. Neurologic Complications of Chemotherapy<br />2.b. Drug induced Encephalitis or Encephalopathy / Myelopathy<br /> - Rituximab: JC-virus induced progressive multifocal leukoencephalopathy (PML)<br />- Methotrexate (high dose): Reversible Encephalopathy in children<br /> - Cytarabine: Cerebellar Encephalopathy / Myelopathy<br />2.c. Cardiomyopathy producing cardiac emboli<br /> - Doxorubicin causes a cumulative, dose-dependent cardiomyopathy<br /> - Clinical S. & S.: transient ischemic attacks (TIA) or cerebral infarction<br />2.c. Intrathecal chemotherapy with methotrexate, cytarabine<br />• CNS prophylaxis in the setting of NHL and leukaemia (ALL)<br />• Therapy for meningeal metastasis (lymphomatous meningitis)<br /> - Chemical meningitis (methotrexate ≈ 10% risk; cytarabine ≈ 40% risk). Liposomal cytarabine is currently approved only for use in lymphomatous meningitis.<br /> - Transverse myelopathy<br /> - Delayed progressive leukoencephalopathy<br />
  74. 74. Progressive multifokale Leukencephalopathy(PML)<br />MRI T2<br />
  75. 75. The two prototypical Types of Peripheral Neuropathy:<br />Large fibre polyneuropathy<br />Acralparaesthesias of feet (fingertips) & hands (toes)<br />Deficits in sensory discrimination and proprioception (vibration sense & position sense↓) <br />-> Afferent dysmetria, ataxia<br />Pinprick and temperature sensation spared<br />Deep tendon reflexes diminished -> lost rather early<br />Weakness, muscle wasting in sensori-motor PNP<br />Small fibre polyneuropathy:<br />Numbness in the feet and hands, burning and aching pains, burning feet<br />Pinprick and temperature sensation are lost out of proportion to proprioception<br />Deep tendon reflexes often relatively spared (abolished rather late during the course)<br />Autonomic dysfunction: anhidrosis, palmo-plantar hyperaemia<br />in advanced cases -> postural hypotension, diarrhea, impotence, and bladder dysfunction<br />Later during the course of the disease -> Combination of the two!<br />
  76. 76. Distal symmetrical sensorimotorpolyneuropathy, large fibre<br />many toxic & drug-induced PNP: Alcohol, vincristine, diphenylhydantoin, isoniazid<br />• paraesthesia<br />• pallhypaesthesia<br />• dysmetria / ataxia<br />• motor weakness<br />• muscle atrophy<br />• vasoparalysis<br />• anhidrosis<br />diameter<br />NCV<br />Mechanorec. Sharp pain Slow pain<br /> (skin) Cold Warmth<br />
  77. 77. Autonomic polyneuropathy + thinly myelinated sensory f.<br />(= small fibre neuropathy)<br />• anhidrosis<br />• pain<br />• analgesia<br />• trophic<br /> skin lesions<br />• mydriasis<br />• orthostatic<br />hypotonia<br />• impotence <br />• paraesthesias<br />diameter<br />NCV<br />
  78. 78. Distal symmetrical autonomic polyneuropathy: evolution<br />• palmaranhidrosis<br />• palmarerythema<br />• pain during rest<br />• plantar anhidrosis<br />• hyperaemia<br /> (vasoparalysis)<br />• burning feet<br />• possibly restless legs<br />• orthostatic hypotonia<br />• impotence<br />• bladder dysfunction<br />
  79. 79. trophic<br />ulcers<br />hyperaemia<br />anhidrosis<br />allodynia +<br />burning feet<br />e.g.:diabetic polyneuropathy<br />thalidomide polyneuropathy<br />
  80. 80. Ommaya-Reservoir<br />Wikipedia<br />
  81. 81. Cerebral Symptoms Present Initially in 140 Patients with Leptomeningeal Metastasis (Meningeosisneoplastica) from Solid Tumors<br />after: Posner JB. Neurologiccomplications of cancer. FA Davis, Philadelphia, 1995, p 102.<br />
  82. 82. A. Direct neoplastic manifestation in the nervous system of haematological neoplasms<br />Primary central nervous system lymphoma (PCNSL)<br />= NHL involving the brain, spinal cord, meninges, or eyes <br /> usually without previous or concurrent involvement of other organs; <br />ca. 6 % of intracranial neoplasms and ca. 1 % of all lymphomas<br /><ul><li>remain confined to the CNS
  83. 83. 75% brain supratentorial, 20% brain posterior fossa, 12 % leptomeninges
  84. 84. solitary in 75 % , multiple in 25 %
  85. 85. the deep structures (around ventricles) or lobar
  86. 86. Rx CT/MRI contrast enhancement in 100% (except following steroids!), </li></ul>enhancement homogenous – heterogeneous<br />DD: malignant gliomas, metastases, sarcoidosis, and inflammatory disease (ADEM)<br />1.a. patients with immuno-suppression (typically patients with AIDS; Azathioprin)<br /> Pg: highly associated with Epstein-Barr virus (EBV) infection<br />1.b. immuno-competent patients (with increasing frequency for unkown reasons)<br />1.c. rare cases with poorly characterized low-grade lymphomas, Burkitt lymphomas, and T-cell lymphomas<br />
  87. 87. A. Direct neoplastic manifestation in the nervous system of haematological neoplasms<br />Secondary (metastatic) nervous system involvement<br />2.e. Angiotropic large cell lymphoma affecting the CNS<br /> - diffuse large cell lymphoma -> aggregates inside vascular lumina<br /> - Ischemic strokes -> progressive focal neurologic deficits, myelopathy, progressive polyradiculopathy, peripheral mononeuropathy, or myopathy.<br />2.f. Bing-Neel syndrome (from Waldenström’smacroglobulinaemia) <br /> - CNS infiltration of malignant lymphoplasmatic cells<br /> - Clinical S & S: diffuse encephalopathy, focal neurologic deficits and/or seizures<br />
  88. 88. 1. Paraneoplasticcerebellar degeneration from HL: DD<br />Darnell RB et al. SeminOncol 2006;33:270-298<br />
  89. 89. 4. Plasma cell disorders (dyscrasias) with dysimmune neuropathies<br />Darnell RB et al. SeminOncol 2006;33:270-298<br />
  90. 90. Aspergillosis in multiple myeloma<br />Lortholary O. et al. ClinInfect Dis2000;30:41-46<br />
  91. 91. D. Complications of treatment affecting the nervous system<br />1. Neurologic Complications of Radiotherapy (RT)<br />1.d. Acute Brachial Plexitis (≈ Parsonage Turner Syndrome = Neuralgic amyotrophia) in HL<br />Acute shoulder and arm pain followed by arm/hand sensory loss and weakness within days to weeks of starting RT; improvement occurs despite continued RT (may also occur without any RT in HD!)<br />Pg: immune mediated, RT merely as “trigger”<br />1.e. Episodic Neurologic Dysfunction (TIAs?) [Feldmann 1986]<br />Usually in HL following radiotherapy<br /> - Clinical S & S: Visual disturbances, language dysfunction, segmental motor, or segmental sensory defects.<br />Pg: poorly understood<br />Feldmann E, Posner JB. “Episodicneurologicdysfunction in patientswithHodgkin’sdisease,” ArchNeurology 1986;43:1227–1233<br />
  92. 92. A.temporal development?<br />speed of development<br /> context with possible trigger<br />t<br />B.distribution?<br />distal - proximal <br /> symmetrical - asymmetrical<br /> legs – arms - head<br />C.type of nerve fibres involved?<br />sensory - motor – autonomic<br />temperature-pain or position sense<br />Clinical presentations of neuropathies<br />t<br />D.accompanying symptoms?<br />pain, ataxia, cns symptoms<br />
  93. 93. 2. Paraneoplasticlimbic encephalitis<br />Diagnostic tests in paraneoplastic limbic encephalitis (all types):<br />Gultekin SH et al. Brain 2000;123:1481-494<br />
  94. 94. POEMS syndrome (= Crow-Fukase syndrome)<br />Patient with solitarymyeloma with monoclonal gammopathy of IgG / λ type<br />POE(E)MS = polyneuropathy, organomegaly, edema, endocrinopathy, M-protein, skin changes <br />NORMAL<br />control<br />PATIENT<br />dark, dusky violaceous skin<br />(vasoparalysis)<br />
  95. 95. POEMS syndrome (= Crow-Fukase syndrome)<br />Patient with solitary myeloma with monoclonal gammopathy of IgG / λ type<br />Sural nerve biopsy showing a severe axonal polyneuropathy<br />-> arrows indicate Wallerian degeneration<br />NORMAL<br />control<br />PATIENT<br />10 µm<br />Methylene blue stain<br />
  96. 96. B. Indirect manifestation affecting the NS<br />5. Primary Angiitis of the Central Nervous System (PACNS) in HL<br />Granulomatousangiitis that affects small arteries of the leptomeninges, and parenchyma of the brain and spinal cord in the absence of systemic vasculitis<br /> - Clinical S & S: headache, encephalopathy, seizure, haemorrhage, <br /> and multifocal infarcts<br />6. Cerebrovascular Complications from Polycythaemiavera & Leukaemias (AML >> ALL)<br />6. a. Ischaemic complications<br /> - Diffuse encephalopathy with headaches, blurred vision, and confusion<br /> - Ischaemic events (TIA, stroke), deep venous thrombosis<br /> Pg: blood hyperviscosity↑ (sludge), leucostasis in severe leucocytoses<br />6.b. Intracerebral or subdural haemorrhage as a result of secondary thrombocytopenia<br />Leucocyte counts > 100 x 109/l may cause sludging or leucostasis -><br />haemorrhage or cortical infarction <br />Clinically this may present with focal deficits or diffuse encephalopathy.<br />
  97. 97. C. CNS Infections due to neoplasm-induced immunosuppression<br />Bacterial meningitis <br /> often occurs in the setting of myelo-suppression or neoplasm-related immunoglobulin deficiency <br />Opportunistic infections <br /> particularly in T-cell–depleted patients, following stemcelltransplantation<br />cryptococcal meningitis, aspergillosis, nocardia, toxoplasmosis <br />Viral encephalitis<br />in bortezomibtreatment(proteasomeinhibitor)<br /> herpes simplex virus, varicella-zoster virus, <br /> JC-virus (leading to progressive multifocal leukoencephalopathyPML) <br />

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