1. ESO Course Leukaemia and Lymphoma 12-14 June 2011 Ascona, Switzerland Neurological problems in patients with haematological neoplasms C W Hess, Bern

3. Neuroradiologist

4. Neurosurgeon

8. 75% brain supratentorial, 20% brain posterior fossa, 12 % leptomeninges

9. solitary in 75 % , multiple in 25 %

10. the deep structures (around ventricles) or lobar

11. Rx CT/MRI contrast enhancement in almost 100% (except following steroids!), enhancement may be homogenous – heterogeneous DD: malignant gliomas, metastases, sarcoidosis, and inflammatory disease (ADEM) Dg: • CSF: pleocytosis in 36%, cytology with lymphoma cells in 20% (Fischer L, 2006) • stereotactic biopsy if possible • histology: diffuse large B celllymphoma • looking for extra-cns involvement (staging): complete blood count CT thorax & abdomen, bone marrow biopsy; Eye slit lamp exam, LDH, HIV.

13. 75% brain supratentorial, 20% brain posterior fossa, 12 % leptomeninges

14. solitary in 75 % , multiple in 25 %

15. the deep structures (around ventricles) or lobar

16. Rx CT/MRI contrast enhancement in almost 100% (except following steroids!), enhancement may be homogenous – heterogeneous DD: malignant gliomas, metastases, sarcoidosis, and inflammatory disease (ADEM) • responsive to steroids (melts away in >40%) BUT: steroids may obscure histology (-> aim at histological diagnosis before starting a “steroid trial”) • relapses are usually no longer steroid responsive Th: • Problem: BB-Barrier renders chemotherapy difficult • high dose(≥3 g/m2)MTX, WB Rx (<60 yrs), Autolog. Stem-Cell Transpl., intrathRituximab? …

18. short term memory ↓

19. long term memory ↓Histo-pathological Dg: diffuse large B cell NHL

21. short term memory ↓

22. long term memory ↓Histo-pathological Dg: diffuse large B cell NHL

24. short term memory ↓

25. long term memory ↓Histo-pathological Dg: diffuse large B cell NHL

27. short term memory ↓

28. long term memory ↓Histo-pathological Dg: diffuse large B cell NHL

30. short term memory ↓

31. long term memory ↓Histo-pathological Dg: diffuse large B cell NHL

33. short term memory ↓

34. long term memory ↓Histo-pathological Dg: diffuse large B cell NHL

35. Primary central nervous system lymphoma (PCNSL) Male, 79 y. gait difficulty, falls, and memory problems MRI: T1 without Gd Contrast T1 with Gd Contrast Histo-pathological Dg: diffuse large B cell NHL

36. Primary central nervous system lymphoma (PCNSL) Male, 79 y. gait difficulty, falls, and memory problems MRI: T2 T1 with Gd Contrast Histo-pathological Dg: diffuse large B cell NHL

37. Multifocal central nervous system lymphoma MRI T1 with Gd Contrast Female, 51 y. Headache, episodic fever, night sweat, nausea vomitus, fatigue Episodes of R sided weakness & dysarthria sometimes confusion lasting mins to 1h Clinical S & S: - alertness ↓ - fatigue - no focal deficits Histo-pathological Dg: diffuse large B cell NHL

38. Multifocal central nervous system lymphoma MRI T1 with Gd Contrast Female, 51 y. Headache, episodic fever, night sweat, nausea vomitus, fatigue Episodes of R sided weakness & dysarthria sometimes confusion lasting mmin to 1h Clinical S & S: - alertness ↓ - fatigue - no focal deficits Histo-pathological Dg: diffuse large B cell NHL Histo-pathological Dg: diffuse large B cell NHL

39. Direct neoplastic manifestation in the nervous system of haematological neoplasms: 2. Secondary (metastatic) nervous system involvement Most frequent direct neurologic complications of hematologic malignancies (Leptomeningeal M.) , (Leptomeningeal M.) , (Leptomeningeal M.) , (Leptomeningeal M.) , (Leptomeningeal M.) J.E.C. Bromberg, AAN April 2011

40. Direct neoplastic manifestation in the nervous system of haematological neoplasms: 2. Secondary (metastatic) nervous system involvement Frequency of Various Tumours of Origin Among Patients with Leptomeningeal Metastasis “CSF”(Meningeosisneoplastica) J Grewal, J P Duic, M Almaliah, S Kesari, E J Dropcho. Neurology MedLINK, updated 19. July 2010

41. A. Direct neoplastic manifestation in the nervous system of haematological neoplasms Secondary (metastatic) nervous system involvement 2.a. Leptomeningeal metastasis, “CSF” (meningeosislymphomatosa = lymphomatousmeningitis) Leukaemia (particularly ALL•)or NHL , rarely HD or plasma cell tumours - Clinical S & S: nausea, vomitus, headache (not obligatory), cranial nerve involv., cognitive problems, or radiating pain due to nerve root involvement - MRI often negative & usually without contrast enhancement! (>< carcinomas), (sometimes subarachnoid nodules, intradural nerve contrast enhancement) - CSF pressure often↑, lymphocytic pleocytosis, and/or increased protein (in 80%), and/or hypoglycorrhachia; cytology (+ immunophenotypingbyflowcytometry) (! perform lumbar puncture after MRI: -> i.c. hypotension -> dural enhancement! ) • ALL: often as CNS recurrence when adequate CNS prophylaxis was not given (standard prophylactic treatment: intrathecal MTX and/or Cytarabine) Problem: BB-Barrier renders chemotherapy difficult

42. Flow cytometric dot plots of cerebrospinal fluid specimens demonstrating lymphoma populations (immunophenotyping) Surface immunoglobulin-negative B-cell lymphoma Monoclonal B-cell population CD20– B-cell T-lymphoma Small population of monoclonal B cells with low cellularity Hedge U et al. Blood 2005;105:496-502 relative fluorescent intensity

43. Leptomeningeal metastasis(meningeosislymphomatosa) 3 yrsagotreatedforT-cell NHL incl. autologousstemcell transplantation MRI T1 with Gd Contrast VII & VIII New: Gait ataxia, memory problems, bilateral Abducens nerve paresis, right lid drooping, dysphagia

44. Leptomeningeal metastasis(meningeosislymphomatosa) 3 yrsagotreatedforT-cell NHL incl. autologousstemcell transplantation MRI T1 with Gd Contrast VI New: Gait ataxia, memory problems, bilateral Abducens nerve paresis, right lid drooping I,, dysphagia

45. A. Direct neoplastic manifestation in the nervous system of haematological neoplasms Secondary (metastatic) nervous system involvement 2.b. Systemic NHL infiltrating the CNS parenchyma (brain or spinal cord) Burkitt lymphoma and diffuse large B-cell lymphoma (HL: exceedingly rare) 3-24% of pts with systemic NHL develop a CNS localization, e.g. as CNS recurrence. In 20-25% of these CNS localization is present at beginning of disease (brain << CSF)

46. A. Direct neoplastic manifestation in the nervous system of haematological neoplasms Secondary (metastatic) nervous system involvement 2.c. Peripheral Nerve and Nerve Root Involvement „Neurolymphomatosis“ - NHL infiltrating cranial nerves, peripheral nerves, or nerve roots. - Clinical S & S: sensory loss, and/or focal weakness • asymmetric polyneuropathy or mononeuropathy or cranial neuropathy • severe pain (rarely painless) • sensory loss, and/or weakness • rapid evolution - CSF: Pleocytosis and/or protein↑ in 40-60%; malignant cells in 40% of pts. - Imaging: Gd-MRI (may be negative), PET-CT in 90% positive - Nerve biopsy may be necessary Problem: Blood-Nerve-Barrier (BNB) renders chemotherapy difficult

47. Peripheral Nerve and Nerve Root Involvement „Neurolymphomatosis“ R S1 nerve root Baehring JM et al. Neuro-Oncology 2003;5:104–115

48. Peripheral Nerve and Nerve Root Involvement „Neurolymphomatosis“ MRI T1 with Gd Contrast R Facial Nerve Baehring JM et al. Neuro-Oncology 2003;5:104–115

49. A. Direct neoplastic manifestation in the nervous system of haematological neoplasms secondary (metastatic) nervous system involvement 2.d. Epidural spinal cord (or caudaequina) compression - direct invasion of the spinal canal from a vertebral body or via the intervertebral foramina from paraspinal regions (extra-axial non-CNS location). - Multiple Myeloma (approximately 20% of cases) >> HL, NHL: caused by vertebral body collapse and impingement of bone on the spinal cord - 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

50. A. Direct neoplastic manifestation in the nervous system of haematological neoplasms secondary (metastatic) nervous system involvement 2.d. Epidural spinal cord compression by Multiple Myeloma, HL, or NHL Outside of BB-Barrier: easily amenable to systemic treatment and chemosensitive & radiosensitive CAVE: Epidural NHL may co-exist with a leptomeningeal localization of lymphoma, which may be clinically silent.

51. A. Direct neoplastic manifestation in the nervous system of haematological neoplasms secondary (metastatic) nervous system involvement 2.d. Epidural spinal cord compression: Multiple Myeloma

52. A. Direct neoplastic manifestation in the nervous system of haematological neoplasms secondary (metastatic) nervous system involvement 2.d. Epidural spinal cord compression: Multiple Myeloma High power fieldshowingtypicalplasmacells T1 Low power viewshowing multiple plasmacells Infiltrativemass at level of T1 dorsal processvertebrae. F. Aziz, S. Doddi & S. Ghimire. The Internet Journal of Neurology2010;13

53. B. Indirect manifestation affecting the NS Paraneoplasticcerebellar degeneration (PCD) from HL HL is 3rd cause of PCD after lung Ca (anti-Hu AB) and ovarian Ca (anti-Yo AB) In HL it usually occurs after diagnosis or during long periods of remission (>< Ca) Pg: if HL not treated -> irreversible loss of Purkinje cells and atrophy of cerebellum Treatment aims at HL, otherwise no efficient treatment known (immunosuppression?) - Clinical S & S: Subacutedysarthria, nystagmus, truncal ataxia, and limb dysmetria 1.a. anti-Tr AB associated paraneoplastic cerebellar degeneration (PCD) Least severe form of PCD, may remit with treatment 1.b. anti-mGluR1 AB associated paraneoplastic cerebellar degeneration (PCD) Hodgkin Lymphoma Reed-Sternberg Cell

54. Paraffin sections of rat cerebellum (A) and Hodgkin lymphoma (B): incubated with biotinylated immunoglobulin G from an anti-Tr-positive serum and counterstained with haematoxylin. Reed-Sternberg cells Purkinijecell 20 µm 6 µm Bernal F et al. Neurology 2003;60;230-234

56. Anti-NMDAR limbic encephalitis: coronal MRI FLAIR T1 with Gd Contrast Pellkofer HL et al. J NeurolNeurosurgPsychiatry 2010;81:1407-1408

57. Paraneoplastic limbic encephalitis MRI coronal SPECT mediastinal node enlargement arrow shows a Hodgkin’s-Reed-Stemberg cell with positive staining for CD30, magn. x600 Olmos D et al. Journal of Clinical Oncology2007;25:1802-1806

58. B. Indirect manifestation affecting the NS 2. Paraneoplasticlimbic encephalitis from HL: the “Ophelia syndrome” John William Waterhouse: Ophelia (1894) Carr I: Lancet 1982; 1:844-845

59. 2. Paraneoplasticlimbic encephalitis from HL: the “Ophelia syndrome” Tumors associated with paraneoplastic limbic encephalitis (all types): Ophelia Gultekin SH et al. Brain 2000;123:1481-494

60. B. Indirect manifestation affecting the NS 3. Paraneoplastic neuropathies from Lymphomas 3.a. Demyelinating polyneuritis: GBS (motor >> sensory) or CIDP from HL >> NHL 3.b. Chronic polyneuropathies: motor, sensory, autonomic from NHL >> HL 3.c. Autonomic dysfunction in NHL >> HL 3.d. Vasculitic neuropathy in HL & NHL: Axonal mononeuritis multiplex GBS = Guillain-Barré Syndrome: • acute inflammatory demyelinating polyneuritis (AIDP) • acute motor [sensory] axonal neuropathy (AMSAN / AMAN) Chronic variants of GBS: • chronic inflammatory demyelinating polyneuritis (CIDP) • mulitfocal motor neuropathy (MMN) • paraproteinaemic neuropathies: IgM(- anti-MAG, - CANOMAD: chronic ataxic neuropathy with ophthalmoplegia, M-protein, agglutination and disialosyl antibodies) IgG, IgA

61. Clinical presentations of neuropathies: Distribution distal symmetrical polyneuropathy usually predominantly sensory maybe painful proximal symmetrical polyneuropathy usually predominantly motor mononeuritis multiplex asymmetrical, multifocal mostly acute, often painful motor and/or sensory length dependent examples: proximal diabetic mono-n. plexus neuritis vasculitic neuropathies multifocal motor n. chronic inflammatory demyelinatingp. (CIDP) acute GBS diabetic, alcoholic, uraemic, toxic drug-induced, etc.

62. Axonal versus demyelinatingpolyneuropathy (ENMG) M normal Aetiology rule of thumb: Ae: toxic(dose-dependent) metabolic vasculitic „degenerative“ Ae: immune mediated inflammatory (GBS, CIDP) some genetic Ae: pressure palsy immune mediated inflammatory (MMN, …..) axonal demyelinating focal demyelinisation conduction block possible

63. Clinical presentations of neuropathies: Type of fibres involved Functions conveyed (signs) tendon reflexes position sense vibration sense autonomic peripheral ns - perspiration anhidrosis - postural hypotension - pain and warmth perception pain and cold perception diameter NCV Mechanorec. Sharp pain Slow pain (skin) Cold Warmth Mechanorec. Sharp pain Slow pain (skin) Cold Warmth

64. B. Indirect manifestation affecting the NS 4. Plasma cell disorders (dyscrasias) with dysimmune neuropathies 4.a. Benign monoclonal gammopathy MGUS: IgM-Gammopathy: demyelinating large fibre PNP (CIDP) - subtype with anti-MAG AB, slow progression, but relatively resistant to th. IgG-Gammopathy: axonal small (and medium) fibre PNP IgA-Gammopathy: rare 4.b. Primary systemic amyloidosis: axonal small fibre PNP with prominent autonomic features (other organs affected such as heart etc.) 4.c. Myeloma producing amyloid: Small fibre polyneuropathy PNP (axonal) Patients do not generally respond to treatment of the myeloma, but may respond to rituximab or stem cell transplantation. Pg: invasion of peripheral nerves by amyloid.

65. B. Indirect manifestation affecting the NS 4. Plasma cell disorders (dyscrasias) with dysimmune neuropathies 4.d. Osteolytic myeloma without amyloidosis: slowly progressive peripheral sensorimotor PNP, usually as late finding 4.e. Osteosclerotic myeloma: • Chronic sensorimotor inflammatory demyelinatingpolyneuropathyCIDP in 75% of patients. CSF protein↑ Pg: mostly IgG or IgM protein, usually with lambda light chains. PNP improves with treatment of the myeloma! special subtype: • POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Edema, M-protein, and Skin abnormalities). Pg role of vascularendothelial growth factor (VEGF)! - Waldenströmmacroglobulinaemia: demyelinating peripheral senorimotorpolyneuropathy CIDP in 10% of pts

66. D. Complications of treatment affecting the nervous system 1. Neurologic Complications of Radiotherapy (RT) 1.a. Post-radiation Dropped Head Syndrome (postactinicptosiscapitis) Weakness of neck extensor muscles causing an inability to extend the neck, from high-dose “mantle field” radiotherapy for HL. Typically no sensory deficit! Symptoms begin many years (> 20 years) after RT. Pg: combination of primary muscle damage and anterior horn/nerve root lesions? 1.b. Post-radiation Brachial Plexopathy Clinical S. & S.: Delayed progressive dysfunction (>1 year - up to 15 years): Paraesthesia (100%), hypaesthesia (75%), weakness (50%), pain (50%, delayed) Typical are fasciculations and myokymia (clinically and EMG) [>< tumour invasion] Pg: Hyalinization and obliteration of blood vessels causes ischaemia of nerve fibres EMG needle recording: myokymic discharge

67. D. Complications of treatment affecting the nervous system 1. Neurologic Complications of Radiotherapy (RT) 1.a. Post-radiation Dropped Head Syndrome (postactinicptosiscapitis) Weakness of neck extensor muscles causing an inability to extend the neck, from high-dose “mantle field” radiotherapy for HL. Typically no sensory deficit! Symptoms begin many years (> 20 years) after RT. Pg: combination of primary muscle damage and anterior horn/nerve root lesions? 1.b. Post-radiation Brachial Plexopathy Clinical S. & S.: Delayed progressive dysfunction (>1 year - up to 15 years): Paraesthesia (100%), hypaesthesia (75%), weakness (50%), pain (50%, delayed) Typical are fasciculations and myokymia (clinically and ENMG) [>< tumour invasion] Pg: Hyalinization and obliteration of blood vessels causes ischaemia of nerve fibres 1.c. Post-radiation carotid artery atherosclerosis (➔ stenosis, relatively frequent) with cerebrovascular complications (ischaemia)

68. D. Complications of treatment affecting the nervous system 2. Neurologic Complications of Chemotherapy 2.a. Drug induced Polyneuropathy (PNP) from Systemic Application - Vincristine: as most neurotoxicvinca alkaloid causes a large fibre sensori-motor (and later also -> small fibre) axonal PNP in most patients. Also: mononeuritis! - Clinical S. & S.: few weeks following initiation of therapy and progress for several weeks after drug discontinuance (coasting phenomenon) before reversible Early paraesthesias of fingertips -> toes, fine finger movements↓ -> glove and stocking sensory deficit, weakness of extensor muscles of feet Early loss of Achilles reflexes -> all deep tendon reflexes disappear eventually - Vinblastinemay cause a predominantly length-dependent small fiber sensory peripheral PNP - Cisplatincausis a length-dependent large fiber sensory peripheral PNP or ganglionopathy with a coasting phenomenon and only partial (if any) reversibility - 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 - Cytarabine: sensory PNP - Bortezomid: “axonal, dose-dependentneuropathy“ ? [Filosto M et al 2007]

70. Distal symmetrical sensory or sensorimotor PNP = length dependent • distal proximal* • legs > arms • sensory > motor plus symptoms: paraesthesias /dysaesthesias pain minus symptoms: numb feeling * toxic & metabolic PNP: involvement of the longest neurites earlier and more pronounced distal-symmetrical (= length dependent) PNP

71. • often also autonomic involvement • palmo-plantar anhidrosis • palmo-plantar hyperaemia (vasoparalysis due to damage to the peripheral sympathicus) Distal symmetrical sensory or sensorimotor PNP = length dependent • distal proximal • legs > arms • sensory > motor

72. distal muscleatrophy distal paresis Distal symmetrical sensory / sensori-motor PNP, large fibre areflexia pall- anaesthesia distal hypaesthesia

73. D. Complications of treatment affecting the nervous system 2. Neurologic Complications of Chemotherapy 2.b. Drug induced Encephalitis or Encephalopathy / Myelopathy - Rituximab: JC-virus induced progressive multifocal leukoencephalopathy (PML) - Methotrexate (high dose): Reversible Encephalopathy in children - Cytarabine: Cerebellar Encephalopathy / Myelopathy 2.c. Cardiomyopathy producing cardiac emboli - Doxorubicin causes a cumulative, dose-dependent cardiomyopathy - Clinical S. & S.: transient ischemic attacks (TIA) or cerebral infarction 2.c. Intrathecal chemotherapy with methotrexate, cytarabine • CNS prophylaxis in the setting of NHL and leukaemia (ALL) • Therapy for meningeal metastasis (lymphomatous meningitis) - Chemical meningitis (methotrexate ≈ 10% risk; cytarabine ≈ 40% risk). Liposomal cytarabine is currently approved only for use in lymphomatous meningitis. - Transverse myelopathy - Delayed progressive leukoencephalopathy

74. Progressive multifokale Leukencephalopathy(PML) MRI T2

75. The two prototypical Types of Peripheral Neuropathy: Large fibre polyneuropathy Acralparaesthesias of feet (fingertips) & hands (toes) Deficits in sensory discrimination and proprioception (vibration sense & position sense↓) -> Afferent dysmetria, ataxia Pinprick and temperature sensation spared Deep tendon reflexes diminished -> lost rather early Weakness, muscle wasting in sensori-motor PNP Small fibre polyneuropathy: Numbness in the feet and hands, burning and aching pains, burning feet Pinprick and temperature sensation are lost out of proportion to proprioception Deep tendon reflexes often relatively spared (abolished rather late during the course) Autonomic dysfunction: anhidrosis, palmo-plantar hyperaemia in advanced cases -> postural hypotension, diarrhea, impotence, and bladder dysfunction Later during the course of the disease -> Combination of the two!

76. Distal symmetrical sensorimotorpolyneuropathy, large fibre many toxic & drug-induced PNP: Alcohol, vincristine, diphenylhydantoin, isoniazid • paraesthesia • pallhypaesthesia • dysmetria / ataxia • motor weakness • muscle atrophy • vasoparalysis • anhidrosis diameter NCV Mechanorec. Sharp pain Slow pain (skin) Cold Warmth

77. Autonomic polyneuropathy + thinly myelinated sensory f. (= small fibre neuropathy) • anhidrosis • pain • analgesia • trophic skin lesions • mydriasis • orthostatic hypotonia • impotence • paraesthesias diameter NCV

78. Distal symmetrical autonomic polyneuropathy: evolution • palmaranhidrosis • palmarerythema • pain during rest • plantar anhidrosis • hyperaemia (vasoparalysis) • burning feet • possibly restless legs • orthostatic hypotonia • impotence • bladder dysfunction

79. trophic ulcers hyperaemia anhidrosis allodynia + burning feet e.g.:diabetic polyneuropathy thalidomide polyneuropathy

80. Ommaya-Reservoir Wikipedia

81. Cerebral Symptoms Present Initially in 140 Patients with Leptomeningeal Metastasis (Meningeosisneoplastica) from Solid Tumors after: Posner JB. Neurologiccomplications of cancer. FA Davis, Philadelphia, 1995, p 102.

83. 75% brain supratentorial, 20% brain posterior fossa, 12 % leptomeninges

84. solitary in 75 % , multiple in 25 %

85. the deep structures (around ventricles) or lobar

86. Rx CT/MRI contrast enhancement in 100% (except following steroids!), enhancement homogenous – heterogeneous DD: malignant gliomas, metastases, sarcoidosis, and inflammatory disease (ADEM) 1.a. patients with immuno-suppression (typically patients with AIDS; Azathioprin) Pg: highly associated with Epstein-Barr virus (EBV) infection 1.b. immuno-competent patients (with increasing frequency for unkown reasons) 1.c. rare cases with poorly characterized low-grade lymphomas, Burkitt lymphomas, and T-cell lymphomas

87. A. Direct neoplastic manifestation in the nervous system of haematological neoplasms Secondary (metastatic) nervous system involvement 2.e. Angiotropic large cell lymphoma affecting the CNS - diffuse large cell lymphoma -> aggregates inside vascular lumina - Ischemic strokes -> progressive focal neurologic deficits, myelopathy, progressive polyradiculopathy, peripheral mononeuropathy, or myopathy. 2.f. Bing-Neel syndrome (from Waldenström’smacroglobulinaemia) - CNS infiltration of malignant lymphoplasmatic cells - Clinical S & S: diffuse encephalopathy, focal neurologic deficits and/or seizures

88. 1. Paraneoplasticcerebellar degeneration from HL: DD Darnell RB et al. SeminOncol 2006;33:270-298

89. 4. Plasma cell disorders (dyscrasias) with dysimmune neuropathies Darnell RB et al. SeminOncol 2006;33:270-298

90. Aspergillosis in multiple myeloma Lortholary O. et al. ClinInfect Dis2000;30:41-46

91. D. Complications of treatment affecting the nervous system 1. Neurologic Complications of Radiotherapy (RT) 1.d. Acute Brachial Plexitis (≈ Parsonage Turner Syndrome = Neuralgic amyotrophia) in HL 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!) Pg: immune mediated, RT merely as “trigger” 1.e. Episodic Neurologic Dysfunction (TIAs?) [Feldmann 1986] Usually in HL following radiotherapy - Clinical S & S: Visual disturbances, language dysfunction, segmental motor, or segmental sensory defects. Pg: poorly understood Feldmann E, Posner JB. “Episodicneurologicdysfunction in patientswithHodgkin’sdisease,” ArchNeurology 1986;43:1227–1233

92. A.temporal development? speed of development context with possible trigger t B.distribution? distal - proximal symmetrical - asymmetrical legs – arms - head C.type of nerve fibres involved? sensory - motor – autonomic temperature-pain or position sense Clinical presentations of neuropathies t D.accompanying symptoms? pain, ataxia, cns symptoms

93. 2. Paraneoplasticlimbic encephalitis Diagnostic tests in paraneoplastic limbic encephalitis (all types): Gultekin SH et al. Brain 2000;123:1481-494

94. POEMS syndrome (= Crow-Fukase syndrome) Patient with solitarymyeloma with monoclonal gammopathy of IgG / λ type POE(E)MS = polyneuropathy, organomegaly, edema, endocrinopathy, M-protein, skin changes NORMAL control PATIENT dark, dusky violaceous skin (vasoparalysis)

95. POEMS syndrome (= Crow-Fukase syndrome) Patient with solitary myeloma with monoclonal gammopathy of IgG / λ type Sural nerve biopsy showing a severe axonal polyneuropathy -> arrows indicate Wallerian degeneration NORMAL control PATIENT 10 µm Methylene blue stain

96. B. Indirect manifestation affecting the NS 5. Primary Angiitis of the Central Nervous System (PACNS) in HL Granulomatousangiitis that affects small arteries of the leptomeninges, and parenchyma of the brain and spinal cord in the absence of systemic vasculitis - Clinical S & S: headache, encephalopathy, seizure, haemorrhage, and multifocal infarcts 6. Cerebrovascular Complications from Polycythaemiavera & Leukaemias (AML >> ALL) 6. a. Ischaemic complications - Diffuse encephalopathy with headaches, blurred vision, and confusion - Ischaemic events (TIA, stroke), deep venous thrombosis Pg: blood hyperviscosity↑ (sludge), leucostasis in severe leucocytoses 6.b. Intracerebral or subdural haemorrhage as a result of secondary thrombocytopenia Leucocyte counts > 100 x 109/l may cause sludging or leucostasis -> haemorrhage or cortical infarction Clinically this may present with focal deficits or diffuse encephalopathy.

97. C. CNS Infections due to neoplasm-induced immunosuppression Bacterial meningitis often occurs in the setting of myelo-suppression or neoplasm-related immunoglobulin deficiency Opportunistic infections particularly in T-cell–depleted patients, following stemcelltransplantation cryptococcal meningitis, aspergillosis, nocardia, toxoplasmosis Viral encephalitis in bortezomibtreatment(proteasomeinhibitor) herpes simplex virus, varicella-zoster virus, JC-virus (leading to progressive multifocal leukoencephalopathyPML)