Primary Angiitis of the Central Nervous System. Dr Laura Ross Rheumatology Registrar St Vincent s Hospital

Transcription

1 Primary Angiitis of the Central Nervous System Dr Laura Ross Rheumatology Registrar St Vincent s Hospital

2 CASE PRESENTATION

3 Case presentation Mr RH 47 year old man PMHx: Hypertension Diagnosed age 44 years Umbilical hernia 3 failed surgical repairs Ex-smoker 25 pack year history Quit 14/12/14 Minimal alcohol

4 Case presentation Mr RH SHx: Works as a chef Runs cooking school Six months France / six months rural Victoria Interest in whole animal cooking nose to tail Has inflated pig lungs during cooking process Very supportive wife Wife has MEPOA

5 Case presentation Mr RH FHx: Mother: seropositive rheumatoid arthritis Aunt: polymyalgia rheumatica

6 Case presentation Mr RH Initial presentation Fatigue since October 2014 December 2014 Sudden onset drenching night sweats Mild increase in inflammatory markers noted Presented mid-december to ED Facial droop, slurred speech & confusion 1 week profound lethargy & myalgias preceding presentation

7 Case presentation Mr RH CRP 148 ESR 56 MRI Brain Right pontine infarct MRA Preserved vessels No meningeal enhancement LP Protein 0.38, glucose 3.2 RCC 1 WCC 32 No growth TB PCR negative Cryptococcal antigen negative

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9 Case presentation Mr RH Treatment Broad spectrum antibiotics Incl cover for brucellosis, listeria, TB, bartonella Prednisolone 50mg daily

10 Case presentation Mr RH Progress Improved with introduction of steroids Steroids weaned to 12.5mg daily Discharged 5/1/15

11 Case presentation Mr RH 9/1/15 Represented to ED New left arm & leg weakness & sensory symptoms Cognitive impairment

12 Case presentation Mr RH Further investigations MRI Brain / MRA Strokes pons, bilateral frontal lobes, thalamus No vessel abnormality on angiography No meningeal enhancement LP (9/1/15) Protein 0.54 glucose 3.1 RCC 1 WCC 44 Culture negative Repeat LP (19/1/15) Protein 0.54 glucose 4.2 RCC 1 WCC 16 Culture negative

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14 Case presentation Mr RH Ferritin 1097 ACE 14 TSH 1.10 Thyroid Ab negative ANA negative ENA negative dsdna negative ANCA negative RhF & ACCP negative Complement levels normal Antineuronal Ab negative Antiphospholipid Ab negative Urine microscopy & PCR negative Alpha virus negative Bartonella negative Brucella negative Leptospirosis negative Rickettsial serology negative Lyme serology negative CMV negative Rotavirus PCR negative Toxoplasma IgM negative Q fever negative Quantiferon gold negative TOE December 14 & January 15 NAD

15 Case presentation Mr RH MRIB 19/12/14 R pontine infarct MRIB 11/1/15 L thalamic infarct R cortical frontal lobe infarct DSA 11/1/15 Narrowing of bilateral P1 segment MRI B 13/2/15 R frontal lobe PET 16/1/15 NAD

16 Case presentation Mr RH Progress Continued on antibiotics to cover CNS TB Continued doxycycline Prednisolone increased back to 50mg daily Patient discharged to neurorehabilitation unit

17 Case presentation Mr RH Progress Referred to RVEEH 4/3/15 Developed uveitis Retinal vasculitis on ophthalmic assessment Had received 2 months TB treatment with isoniazid, rifampicin, pyridone & doxycycline Impression: Likely cerebral vasculitis Continue prednisolone 50mg Commenced azathioprine

18 Case presentation Mr RH Progress Progressive cognitive impairment Repeat imaging New multi-territory infarcts Admitted to St Vincent s Hospital August 2015

19 Case presentation Mr RH MRI B 19/3/15 Multiple acute and sub acute infarcts No bleeding or vascular irregularity MRI B 28/7/15 3 new infarcts R superior frontal gyrus, R parietal subcortical white matter, L temporal lobe

20 Case presentation Mr RH Further investigations Serum EPG & FLC negative BMAT no lymphoma no TB Temporal artery biopsy negative Hepatitis A,B,C negative HIV negative Skin biopsy non diagnostic HbA1c 7.6%

21 Case presentation Mr RH Treatment Pulse IV methylprednisolone oral prednisolone Oral cyclophosphamide started 17/8/15 Progress Feb 2016 Weaning course prednisolone & ongoing cyclophosphamide Ongoing fatigue Persistent cognitive impairment & mood disturbance Follow up MRI Feb 2016 Stable appearance

22 PRIMARY ANGIITIS OF CNS (PACNS)

23 PACNS First described by Cravioto & Feigin 1959 Only 46 cases reported in literature until 1986 Development of diagnostic criteria provoked greater academic interest in condition Hajj-Ali Lancet Neurol

24 PACNS Primary angiitis of CNS Inflammation & destruction of CNS vessels without evidence of vasculitis outside CNS Rare condition Annual incidence rate 2.4 cases per 1,000,000 person years Hajj-Ali et al Lancet Neurol Salvarani et al Ann Neurol

25 Epidemiology Roughly even gender distribution Median age at diagnosis 47 years 50% patients years at diagnosis 75% diagnoses made within 6 months of first neurological symptom Reduced long term survival Salvarani et al Ann Neurol

26 Diagnosis Common disease presentations Chronic aseptic meningitis Recurrent focal neurological deficits Spread over time & space Unexplained focal & diffuse neurological dysfunction Multi-territory infarcts & altered cognition

27 CLINICAL FEATURES AT PRESENTATION

28 Salvarani et al Medicine (21)

29 Salvarani et al Medicine (21)

30 Salvarani et al Medicine (21)

31 Diagnostic criteria

32 Diagnostic criteria Birnbaum & Hellmann criteria Definite PACNS Biopsy proven Probable PACNS No histology High probability angiogram Abnormal MRI CSF consistent with vasculitis

33 DIAGNOSTIC ASSESSMENT

34 Lumbar puncture Essential!!! To exclude infection & malignancy High negative predictive value Diagnosis excluded by normal MRI & normal LP Low specificity Typical findings Elevated protein Lymphocytic pleocytosis

35 Conditions that must be excluded Infection VZV HCV HIV Mycobacteria Fungi Syphilis Malignancy CNS lymphoma Intravascular lymphoma Leptomeningeal metastases

36 Magnetic Resonance Imaging Mainstay of imaging Sensitivity % Looking for changes of: Multiple strokes Haemorrhagic / thrombotic White matter lesions no respect for grey / white matter border Leptomeningeal enhancement Mass lesions in 5% patients MR Angiography Hajj-Ali Lancet Neurol

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38 Angiography No specific findings Fails to rule out competing diagnosis Sensitivity 40-90% Specificity 25-50% Changes most likely to be bilateral & in multiple vessel beds Salvarani et al Lancet Salvarani et al Ann Neurol

39 Angiography More common causes of abnormal cerebral angiogram Atherosclerosis Reversible cerebral vasoconstriction syndrome Fibromuscular dysplasia Moyamoya disease

40 PACNS MIMICS

41 Disease mimics Reversible cerebral vasoconstriction syndromes Systemic inflammatory condition ie secondary cerebral vasculitis Infection Coagulopathy PRES Genetic conditions eg MELAS

42 Reversible cerebral vasoconstriction syndrome Post partum migraine Call-Fleming syndrome Migraine angiitis Thunderclap-headache associated vasoconstriction Cerebral vasospasm Cocaine Amphetamines Sumatriptan Serotonergic & sympathomimetic drugs Tumours Calabrese et al Ann Intern Med

43 Reversible cerebral vasoconstriction syndrome Common presentation Headache Often recurrent headache Focal neurological deficits Can have strokes on imaging

44 Diagnostic features Calabrese et al Ann Intern Med : 34-44

45 PACNS vs RCVS Salvarani et al Lancet

46 PACNS vs RCVS Salvarani et al Lancet

47 Treatment - RCVS Observation Calcium channel blockers Possible role for high dose steroids Most patients fully recover Strokes seen in up to 54% patients Calabrese et al Ann Intern Med

48 When should we consider PACNS? Multi-territory cerebral infarcts distribution over time and space associated with inflammatory changes in CSF Subacute or chronic headache with cognitive impairment or aseptic meningitis Chronic meningitis after infection or neoplastic disorders have been excluded

49 BRAIN BIOPSY

50 Brain biopsy Gold standard diagnostic test 35-60% have biopsy proven vasculitis Low specificity False negative rate up to 25% Yield increased by open wedge resection including overlying leptomeninges Hajj-Ali et al Lancet Neurol Salvarani et al Lancet Salvarani et al Medicine ( 21) De Boysson et al Arthritis & Rheum (5)

51 Brain biopsy Complications 1% risk of permanent neurological deficit COVAC cohort (France) 13% post-procedure complication Fever / inflammatory syndrome PACNS-related transient neurological deterioration Biospy site abscess formation Salvarani et al Lancet de Boysson et al Arthritis & Rheumatol (5)

52 HISTOPATHOLOGICAL SUBTYPES

53 Subtypes Granulomatous angiitis 25% associated with β-amyloid deposition (ABRA) Lymphocytic angiitis Necrotising angiitis Angiographically defined PACNS Mass-like lesion Cerebral amyloid angiopathy associated Hajj-Ali et al Lancet Neurol

54 Granulomatous angiitis Most common histopathological subtype 25% - 50% patients have associated β4 amyloid deposition Amyloid-Beta Related Angiitis of CNS (ABRA) Granulomatous angiitis with amyloid deposition Likely to be older at diagnosis Present with cognitive dysfunction Leptomeningeal enhancement Favourable response to steroid therapy Often require prolonged therapy Hajj Ali Lancet Neurol Salvarani et al Lancet

55 Lymphocytic angiitis 28% cases? More benign clinic course Hajj Ali Lancet Neurol Salvarani et al Lancet

56 Necrotising angiitis 17% cases Can be associated with granulomatous angiitis More commonly associated with intra-cranial haemorrhage Similar appearance to PAN Hajj Ali Lancet Neurol Salvarani et al Lancet

57 Cerebral amyloid associated angiitis (CAA) Variable inflammatory response to cerebral amyloid deposition Immunosuppression treats angiitis Amyloid deposition unchanged Clinical outcome often poor Hajj Ali Lancet Neurol

58 ABRA vs CAA Histological diagnosis ABRA granulomatous angiitis, transmural, destructive CAA perivascular infiltrate, non-destructive? Spectrum of same disease Hajj Ali et al Lancet Neurol

59 TREATMENT

60 Treatment No prospective studies No randomised controlled trials Treatment based on ANCA associated vasculitis protocols High dose prednisolone Cyclophosphamide Case reports of biologic treatment Rituximab TNFα inhibitors Hajj-Ali et al Lancet Neurol Salvarani et al Lancet De Boysson et al Arthritis & Rheum (5)

61 Glucocorticoids Mainstay of treatment Mayo cohort 75 / 159 patients received glucocorticoid monotherapy > 80% favourable response No variation between histological pattern or biopsy vs angiogram proven vasculitis Median length oral prednisolone treatment 9 months CORVAC cohort (France) 7/52 patients received glucocorticoid monotherapy Median duration of steroid use 23 months Salvarani et al Medicine (21) Salvarani et al Arthritis & Rheum (6) De Boysson et al Arthritis & Rheum (5)

62 Cyclophosphamide More likely to receive cyclophosphamide if High disability score at diagnosis Infarcts seen on MRI Larger vessel involvement Mayo Cohort 72/82 patients received cyclophosphamide 49/72 patients received oral cyclophosphamide Favourable response in ~ 80% patients Median length treatment 7 months CORVAC Cohort 85% patients received first line cyclophosphamide 1 patient received oral cyclophosphamide Salvarani et al Medicine (21) Salvarani et al Arthritis & Rheum (6) De Boysson et al Arthritis & Rheum (5) Oon et al Int Med J

63 Treatment Biologics Case reports only Rituximab TNFα inhibitors Salvarani et al Medicine (21) Salvarani et al Arthritis & Rheum (6) De Boysson et al Arthritis & Rheum (5)

64 Maintenance therapy Real benefit yet to be determined Mayo / CORVAC cohorts Approx 50% patient receive maintenance therapy Azathioprine > Mycophenolate > Methotrexate De Boysson et al Arthritis & Rheum (5) Salvarani et al Medicine (21)

65 Salvarani et al Medicine (21)

66 Disease monitoring Rarely serological markers to follow Clinical symptoms difficult to follow Serial imaging

67 Disease relapse Relapse rate ~25% Predictors of relapse Prednisolone monotherapy 39% vs 18% Leptomeningeal enhancement Seizures at presentation de Boysson Arthritis & Rheum 2014: Salvarani et al Medicine (21)

68 Treatment for relapsed disease? More steroid More cyclophosphamide TNFα inhibitors / rituximab MMF Chlorambucil Plasma exchange Salvarani et al Medicine (21) Salvarani et al Arthritis & Rheum (6)

69 PROGNOSIS

70 Disability at follow up Salvarani et al Arthritis & Rheumatol (6)

71 Disability at follow up Salvarani et al Arthritis & Rheumatol (6)

72 Disability at follow up Salvarani et al Arthritis & Rheumatol (6)

73 Disability at follow up Salvarani et al Arthritis & Rheumatol (6)

74 Mortality Salvarani et al Medcine (21)

75 Mortality Mortality reported between 6-15% in large cohort studies Poor prognostic indicators Increased age at diagnosis Presentation with focal neurological deficits Cognitive impairment Infarction Large vessel involvement Good prognostic indicators Prominent gadolinium enhancement (lesions / leptomeninges) Evidence of β-amyloid deposition ABRA Salvarani et al Ann Neurol Salvarani et al Medicine 94 (21) De Boysson et al Arthritis & Rheum

76 Conclusion PACNS is rare When PACNS is suspected, the correct diagnosis is usually something else. All patients must have LP Normal MRI & LP excludes cerebral vasculitis Angiographic changes without imaging or LP changes is not cerebral vasculitis Failure to respond to treatment should prompt re-assessment