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Primary cns vasculitis
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- 2. • Primary angiitisof the central nervous system (PACNS) is a rare inflammatory disorder of the blood vessels affects the blood vessels supplying the brain parenchyma, spinal cord and leptomeninges, and less frequently veins and venules, occurring in the absence of any evidence of systemic vasculitis. • Clinical manifestations are non-specific with various presenting symptoms. • Headache is the most common presenting symptom in the majority of the PACNS cases. • The exact etiology and pathogenesis of PACNS are unknown, but infectious agents have been postulated as one of the triggers (VZV, HIV, HCV, Bacterial). • There is also a notable association between PACNS and cerebral amyloid angiopathy. The amyloid deposition has been identified as a possible trigger for PACNS in animal models.
- 3. The exact epidemiologyof this rare disorder have not been done (some data shows an annual incidence rate of 2.4 cases per 1 million person-years). Equal distribution among both sexes and the median age of diagnosis of about 50 years. Epidemiology PACNS mainly affects younger stroke patients lacking CVS risk factors. Approximately 3-5% of CVS in patients <50 years are caused by PACNS.
- 4. Pathological findingscan affect both small and large vessels of the CNS. Specific activation of the immune system (especially T-cells) by various cause inflammation of blood vessels in the CNS. Immunohistochemical staining of biopsy samples in PACNS showed an extensive infiltration around the small cerebral arteries by CD45R0+ T cells. Infiltration of immune cells within vessels wall destruction of the vessels walls Thickening of vessels walls with alternating segments of stenosis Poor blood circulation Pathophysiology On the other hand, weak vessels walls can rupture leading to hemorrhage.
- 5. Affection ofparenchymal and leptomeningeal arteries. Three different types of vasculitis patterns have been described in PACNS (granulomatous type, necrotizing type, and lymphocytic type). The most common type, granulomatous, shows numerous granulomas with multinucleated cells. The necrotizing type presents with fibrinoid necrosis, and lymphocytic type shows extensive lymphocytic inflammation with plasma cells. Granulomatous Necrotizing Lymphocytic Histopathology
- 6. The onset ofPACNS is usually insidious, and the course is slowly progressive. Acute presentations have also been reported but are, however, less common. Clinical presentation Non-specific Multiple symptoms Headache is the most common presenting symptom •Cognitive dysfunction •Stroke •Transient ischemic attack (TIA) •Aphasia •Visual symptoms including visual field deficits, blurred vision, and double vision •Seizures •Ataxia •Papilledema •Intracranial bleeding •Amnestic syndrome The presenting symptoms and signs from the most common to the least common include:
- 7. Headache 60% Cognitive impairment 50% Focalneurological deficits Marked constitutional symptoms such as fever, weight loss and night sweats are less frequent and can be indicative of systemic vasculitides. In about 5% of patients primary CNS vasculitis can affect the spinal cord and isolated vasculitic myelopathies have also been reported.
- 8. A combination ofsymptoms is usually present in most patients. PACNS should always be considered as a possibility in cases of rapidly progressive cognitive decline and personality changes of unknown etiology.
- 9. Diagnostic criteria 1- A historyof clinical findings of an acquired otherwise unexplained neurologic deficit. 2- Presence of classic angiographic or histopathologic features of angiitis within the CNS. 3- No evidence of systemic vasculitis or of any other disorder that could cause or mimic the angiographic or pathologic features.
- 10. Definite • Confirmedby tissue biopsy. Probable • High probability finding on an angiogram with abnormal findings on MRI and a CSF profile consistent with PACNS (in the absence of tissue confirmation). Diagnostic certainty
- 11. Subtypes of PACNS Smallvessels Large/medium vessels According to the size of affected vessel In contrast, LV-PACNS is more likely to present with focal deficits and acute ischemia on MRI. Isolated SV-PACNS is associated with: -A more severe encephalopathic presentation with cognitive impairment and seizures. -A more abnormal CSF analysis and more diffuse gad enhanced lesions on MRI. -More relapses.
- 12. CAROLIN BEUKE. (N.D.).PRIMARY ANGIITIS OF THE CENTRAL NERVOUS SYSTEM: DIAGNOSIS AND TREATMENT. THER ADV NEUROL DISORD. HTTPS://DOI.ORG/ 10.1177/1756286418785071
- 13. Evaluation Laboratory • Detection ofANA, RF, ANCA, antiphospholipid Ab, bacterial or viral Ag is usually suggestive of systemic vasculitis or auto-immune disease. • Elevated ESR and CRP neither sensitive nor specific. • Serological tests are needed to exclude infection including varicella, mycobacteria, syphilis, human HIV, and fungi. • No specific marker for PACNS.
- 14. CSF The only usefullaboratory investigation is CSF examination which shows an abnormality in more than 90% of the cases. Should be performed in all patients. Inflammatory findings: lymphocytic pleocytosis, elevated protein.
- 15. Normal CSF (cellcount <5 cells /μl or total protein concentration <45 mg/dl) >> search for DD. OCB and IgG are only found occasionally. Increased interleukin (IL)17-producing CD41 cells in CSF can differentiate PACNS from ischemic stroke. Values more than 250 cells/μl are indicative for infection. Malignant vasculitis can be detected with CSF cytology and flow cytometry. CSF
- 16. The cornerstone forestablishing the diagnosis of PACNS. Imaging Cerebral angiography MRI, MRA CT,CTA vessel beading Intracranial vessels Narrowing and dilatation Fusiform arterial dilation Delayed contrast enhancement Development of collateral circulation Multilocular occlusions
- 17. Vessel beading isnot a specific feature for PACNS It is also seen in: • Noninflammatory vasculopathies. • Non-vasculitis conditions such as atherosclerosis. • After radiation. • Neurofibromatosis. • Atrial myxomas. • Infections. • Vasospasm.
- 18. DSA is thegold standard imaging. It’s not 100% specific. Possibly due to the waxing and waning pattern of stenosis. VALERIE L JEWELLS. (N.D.). CNS VASCULITIS; AN OVERVIEW OF THIS M ULTIPLE SCLEROSIS MIMIC; CLINICAL AND MRI IMPLICATIONS. SEMINARS IN ULTRASOUND CT AND MRI. HTTPS://DOI.ORG /HTTPS://DOI.ORG/10.1053/J.SULT.2020.02.004
- 19. MRI ofthe brain is abnormal in more than 90% of patients, but the pattern of abnormal findings is not specific. MRI should include T1, T2, FLAIR, DWI, ADC, GRE, with and without gadolinium administration. Multifocal bilateral T2, FLAIR lesions in cortical, subcortical, DWM and gray matter. New and old coexisting ischemic lesions. Lesions can be accompanied by subarachnoid and ICH. Mass lesions that can mimic a tumors or abscess. Gd enhancement of parenchymal lesions and the leptomeninges. Imaging Cerebral angiography MRI, MRA CT,CTA
- 20. MRI/MRA is thefirst diagnostic test of choice. VALERIE L JEWELLS. (N.D.). CNS VASCULITIS; AN OVERVIEW OF THIS M ULTIPLE SCLEROSIS MIMIC; CLINICAL AND MRI IMPLICATIONS. SEMINARS IN ULTRASOUND CT AND MRI. HTTPS://DOI.ORG /HTTPS://DOI.ORG/10.1053/J.SULT.2020.02.004 MRA is a less invasive imaging modality and therefore can be used to monitor the disease course, however, in comparison with DSA, MRA is less sensitive in the detection of both lesions localized in the posterior circulation and in distal arteries.
- 21. Occipital Temporal Parietal Frontal WM lesions distribution 2/3rd ofCNSV cases have WM involvement. MCA>PCA>ACA MRI protocol Standard protocol is 3D T1, T2, FLAIR, and post contrast imaging with MRA, perfusion and SWI (for depicting hemosiderin from intraparenchymal hemorrhages and hemosiderosis). Recently, vessel wall imaging can be used as a part of the protocol to detect vessel wall inflammation, preferentially performed at 3T via black blood sequences using T2 TSE or T2* weighted-GRE sequences with FLAIR and TOF MRI as well as fat sat T1 images. VALERIE L JEWELLS. (N.D.). CNS VASCULITIS; AN OVERVIEW OF THIS M ULTIPLE SCLEROSIS MIMIC; CLINICAL AND MRI IMPLICATIONS. SEMINARS IN ULTRASOUND CT AND MRI. HTTPS://DOI.ORG /HTTPS://DOI.ORG/10.1053/J.SULT.2020.02.004
- 22. Vessel wallimaging uses different techniques to suppress the signal of intraluminal blood (“black blood imaging”), thus allowing evaluation of the vessel wall and possibly the detection of inflammatory changes within the vessel wall. Vessel wall contrast enhancement has been reported as a potential sign of CNS vasculitis In particular, differentiating between inflammation, intracranial atherosclerotic plaques, and other wall abnormalities based on the typical enhancement patterns was reported. High resolution contrast-enhanced MRI (HR-MRI) “Black Blood MRI” PATZIG, M., FORBRIG, R., KÜPPER, C. ET AL. DIAGNOSIS AND FOLLOW-UP EVALUATION OF CENTRAL NERVOUS SYSTEM VASCULITIS: AN EVALUATION OF VESSEL-WALL MRI FINDINGS. J NEUROL 269, 982–996 (2022). HTTPS://DOI.ORG/10.1007/S00415- 021-10683-7
- 23. CT /CTAmay demonstrate occlusion, stenosis, and wall thickening of large vessels. It’s limitations are insensitivity for WM assessment, leptomeningeal enhancement or depiction of small vessels. Imaging Cerebral angiography MRI, MRA CT,CTA
- 24. PRIMARY ANGIITIS OFTHE CENTRAL NERVOUS SYSTEM MAGNETIC RESONANC E IMAGING SPECTRUM OF PARENCHYMAL, MENINGEAL, AND VASCULAR LESIONS AT BASE LINE. (N.D.). STROKE. DOI:10.1161/STROKEAHA.116.016194 Multiple ischemic lesions (A-B), post- contrast leptomeningeal enhancement (C), multiple focal stenosis of bilateral MCA on TOF MRI (D).
- 25. PRIMARY ANGIITIS OFTHE CENTRAL NERVOUS SYSTEM MAGNETIC RESONANC E IMAGING SPECTRUM OF PARENCHYMAL, MENINGEAL, AND VASCULAR LESIONS AT BASE LINE. (N.D.). STROKE. DOI:10.1161/STROKEAHA.116.016194 Right frontal acute intraparenchymal hemorrhage (A), 3 months later on (B-C) showing post contrast enhancement.
- 26. PRIMARY ANGIITIS OFTHE CENTRAL NERVOUS SYSTEM MAGNETIC RESONANC E IMAGING SPECTRUM OF PARENCHYMAL, MENINGEAL, AND VASCULAR LESIONS AT BASE LINE. (N.D.). STROKE. DOI:10.1161/STROKEAHA.116.016194 Patterns of contrast enhancement in PACNS, punctate (A), incomplete sub centimetric (B), leptomeningeal (C), parenchymal enhancement (D).
- 27. PRIMARY ANGIITIS OFTHE CENTRAL NERVOUS SYSTEM MAGNETIC RESONANC E IMAGING SPECTRUM OF PARENCHYMAL, MENINGEAL, AND VASCULAR LESIONS AT BASE LINE. (N.D.). STROKE. DOI:10.1161/STROKEAHA.116.016194 Post circulation CVS with bilateral PCA stenosis. Chronic infarct and proximal stenosis of left MCA.
- 28. Multifocal segmental narrowing (A), multipleDWI lesions in different vascular territories(B), concentric enhancement of the M1-segment of the left middle cerebral artery on black blood MRI(C), vessel beading on MRI- TOF-angiography(D), bilateral infarctions of variable size (E), and intracerebral hemorrhage (F). CAROLIN BEUKE. (N.D.). PRIMARY ANGIITIS OF THE CENTRAL NERVOUS SYSTEM: DIAGNOSIS AND TREATMENT. THER ADV NEUROL DISORD. HTTPS://DOI.ORG/ 10.1177/1756286418785071
- 29. -Vessel wall contrastenhancement of the right distal M1 segment is seen at initial presentation on vessel wall imaging (A), which remains unchanged at two-months follow-up (B) despite immunosuppressive therapy. -Correlating TOF-MRA findings (C, D), showing unchanged high-grade stenosis of the affected segment. PATZIG, M., FORBRIG, R., KÜPPER, C. ET AL. DIAGNOSIS AND FOLLOW-UP EVALUATION OF CENTRAL NERVOUS SYSTEM VASCULITIS: AN EVALUATION OF VESSEL-WALL MRI FINDINGS. J NEUROL 269, 982–996 (2022). HTTPS://DOI.ORG/10.1007/S00415- 021-10683-7
- 30. -At initial presentation(A, C), there is marked vessel wall contrast enhancement of the posterior circulation, including the basilar artery (arrow) and left PCOM (arrowhead). -Follow-up vessel wall imaging after ten years (B, D) shows complete resolution of vessel wall contrast enhancement of the PCOM and regressive but still persistent vessel wall contrast enhancement of the basilar artery. -Correlating TOF-MRA images (E, F) demonstrate resolution of a high-grade stenosis of the left PCOM. PATZIG, M., FORBRIG, R., KÜPPER, C. ET AL. DIAGNOSIS AND FOLLOW-UP EVALUATION OF CENTRAL NERVOUS SYSTEM VASCULITIS: AN EVALUATION OF VESSEL-WALL MRI FINDINGS. J NEUROL 269, 982–996 (2022). HTTPS://DOI.ORG/10.1007/S00415- 021-10683-7
- 31. Angio Positive • In large/proximal vessel affection. Angio Normal • In small vessel (<500 μm in diameter) affection. In case of negative angiographic findings >> brain biopsy should be considered as an important step towards diagnosing PACNS.
- 32. Biopsy • Due tothe focal and segmental distribution of the disease, the sensitivity of brain biopsy is as a result of sampling errors between 53–74%. • The diagnostic yield can be increased by 80% by targeting areas of imaging abnormalities. • If affected lesions are not accessible for surgery, a biopsy from the right (nondominant) frontal lobe with its overlying leptomeninges tissue is recommended. • Negative biopsy cannot rule out the diagnosis of cerebral vasculitis, but histopathological examination often results in alternative diagnoses (special attention is paid to PACNS mimics like infections, neoplasms especially lymphoma, and degenerative disease. Biopsy is safe! Brain biopsies are associated with rather low morbidity and mortality rates; therefore, a biopsy should be obtained, if the diagnosis is uncertain.
- 33. CAROLIN BEUKE. (N.D.).PRIMARY ANGIITIS OF THE CENTRAL NERVOUS SYSTEM: DIAGNOSIS AND TREATMENT. THER ADV NEUROL DISORD. HTTPS://DOI.ORG/ 10.1177/1756286418785071
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- 35. RCVS Formerly RCVS was describedas a subtype of PACNS, called benign angiopathy of the CNS. Typical clinical features are sudden and recurrent attacks of severe (usually thunderclap) HEADACHE with or without focal neurological deficits or seizures. More in Females. Mean age of onset 42 yrs. The most important non- inflammatory DD to PACNS. Headache RCVS is more often detected in patients with exposure to vasoactive drugs, migraine, hypertension, eclampsia or in the postpartum period.
- 37. RCVS Neuro imaging may showinfarctions (located in the superficial border zone or watershed regions), cortical SAH, and lobar ICH. Angiogram shows multifocal segmental cerebral artery vasoconstriction; dissection and unruptured aneurysms occur significantly more frequently than in cerebral vasculitis. Angiographic follow up 12 weeks after clinical onset usually shows complete or substantial resolution of abnormalities in RCVS. Intra-arterial nimodipine use during convential angiography showed reverse of vessel narrowing in RCVS in contrast with PACNS.
- 38. A-CT scan showinga small cSAH, B-MRI (FLAIR) showing a small cSAH, C- CT scan showing an occipital intracerebral haemorrhage, D-MRI showing sequelae of bilateral occipital infarcts and left frontal-parietal infarct, E-MRI (FLAIR) showing hypersignals consistent with a RPLS, F-Control MRI in the same patient after 28 days showing resolution of the RPLS.
- 39. Diffuse intracerebral vasoconstrictionon initial angiogram, after 2 wk of headache then right hemiparesis and encephalopathy. B, Resolution of vasoconstriction after 4 mo.
- 40. Systemic vasculiti s CNS involvement most oftenarises in patients with: Bechet's disease. Wegener’s granulomatosis. Churg–Strauss syndrome.
- 41. Bechet’s = Variable vessel size vasculitis Large vessel vasculitis Involves >2mm size vessels, including the ICA, M1 segment of the MCA, A1 segment of the ACA, and P1 segment of the PCA. Takayasu’s arteritis (<50 yo), Giant cell arteritis and temporal arteritis (>50 yo) are common large vessel causes. Medium size vessel vasculitis Most commonly Kawasaki’s disease and polyarteritis nodosa involve the M2, A2, and P2 segments. Small vessel vasculitis SLE, granulomatosis with polyangiitis +/- eosinophils, IgA vasculitis, and microscopic polyangiitis
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- 43. Moyamoya angiopathy. Divry-van Bogaert syndrome. fibromuscular dysplasia. Fabry disease. Sneddon’s syndrome. Non- inflammatory vascular diseases
- 44. Malignancy In singlecases, the occurrence of PACNS in association with Hodgkin’s lymphoma, non- Hodgkin’s lymphoma and angio-immuno-lympho-proliferative lesions has been reported. Furthermore, intravascular lymphoma (IVL), a subtype of extra-nodal diffuse large B-cell lymphoma, is an important differential diagnosis of primary CNS vasculitis characterized by intravascular proliferation of lymphoma cells with a predilection for the CNS and skin.
- 45. Infection VZV vasculopathy: Aninfectious arteritis that causes ischemic infarction of the brain and spinal cord, and cerebral hemorrhage, as well as aneurysm and carotid dissection. Diagnosis of VZV infection can be made by detection of anti-VZV IgG antibody in the CSF. PACNS should be distinguished from other infectious agents that can affect the CNS including: Hepatitis C virus, HIV, Streptococcus pneumoniae, Neisseria meningitidis, Bartonella spp ,Mycobacterium tuberculosis, Borrelia burgdorferi, and Treponema pallidum.
- 46. Other mimics CADASIL • An ADarteriopathy with manifestation in early adulthood. • Clinical symptoms include: migraine, recurrent transient ischemic attacks or strokes, psychiatric disorders, cognitive impairment, and epilepsy. • Brian MRI typically shows large or small white matter abnormalities. • The most typical findings are white matter hyperintensities in the anterior temporal lobe (temporal pole) seen on T2 sequence. Susac syndrome • Autoimmune-mediated endotheliopathy characterized by the clinical triad of: Branch retinal artery occlusions. Encephalopathy. Neurosensorial hearing loss. • It causes microangiopathic occlusion of precapillary arterioles in the brain, retina, and inner ear. Anti-phospholipid syndrome • Present by diverse neurologic manifestations including: stroke, TIA, seizures, movement disorders, neuropsychiatric manifestations, and cognitive decline. • Angiography shows intracranial abnormalities suggestive of vasculitis.
- 47. ALIAGA FREDERIK BARKHOF,E. S. (N.D.). CHAPTER 13 - MRI MIMICS OF MULTIPLE SCLEROSIS. IN HANDBOOK OF CLINICAL NEUROLOGY (PP. 291–316). ELSEVIER.
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- 49. ALIAGA FREDERIK BARKHOF,E. S. (N.D.). CHAPTER 13 - MRI MIMICS OF MULTIPLE SCLEROSIS. IN HANDBOOK OF CLINICAL NEUROLOGY (PP. 291–316). ELSEVIER.
- 50. ALIAGA FREDERIK BARKHOF,E. S. (N.D.). CHAPTER 13 - MRI MIMICS OF MULTIPLE SCLEROSIS. IN HANDBOOK OF CLINICAL NEUROLOGY (PP. 291–316). ELSEVIER.
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- 52. Induction therapy Combination therapy Steroids Cyclophosphamide High-dose ofIV CST (1000 mg daily for 3–5 days), or oral prednisone (1 mg/kg per day) are currently the most frequently used therapies. IV is not more effective than oral! Given either as an oral dose (2 mg/kg/day) for 3–6 months, or as IV pulse (750 mg/m2/ month) for 6 months. Monitor: Leukocyte nadir and disease course. Side effects (infection, especially bladder, cancer and infertility). It is contraindicated during pregnancy.
- 53. In patients whoare intolerant to conventional immunosuppressive therapeutic regimens .. or in patients failing to respond to cyclophosphamide therapy .. Biological agents Rituximab TNF-α blockers (infliximab and etanercept)
- 54. Maintenance therapy Goal: Limiting the risk ofrelapses and preventing long-term disabilities. Started 4–6 months after initiation of the induction therapy. Corticosteroid-sparing low- risk immunosuppressive agents Azathioprine Methotrexate Mycophenolate mofetil 1-2 mg/kg/day 1-2 g/day 20-25 mg/week
- 55. CAROLIN BEUKE. (N.D.).PRIMARY ANGIITIS OF THE CENTRAL NERVOUS SYSTEM: DIAGNOSIS AND TREATMENT. THER ADV NEUROL DISORD. HTTPS://DOI.ORG/ 10.1177/1756286418785071
- 56. Duration of treatment • Validateddata are lacking. In principle, induction therapy should be administered for 6–12 months based on individual response to treatment. • Decisions on de-escalation of induction therapy should depend on the achievement of clinical stability.
- 57. Prognosis • Older patientsand those with infarctions on the MRI scan had an increased mortality rate. • Meningeal gadolinium enhancements on MRI and seizures were associated with an increased risk of relapse. • Involvement of larger or rather proximal cerebral vessels seems to be associated with a higher mortality rate and poorer prognosis, requiring a more aggressive treatment.
- 58. Disease monitoring • Combinationof repeated neurological examinations and periodic neuroradiological imaging (e.g. MRI and MRA) during therapy and afterwards is recommended for assessing disease activity. • MRI should be performed 4–6 weeks after the initiation of therapy and afterwards every 3–4 months in the first year of treatment. • CSF examinations can additionally be helpful in the follow up to document improvement in the inflammatory response. • In patients with severe clinical course and worsening neurological symptoms, serial conventional angiography might be necessary. • Color duplex sonography might be useful for follow-up examinations in patients with cerebral artery stenoses
Editor's Notes
- #25 33-year-old male presenting with seizures rapidly progressive cognitive impairment. A. DWI..multiple acute deep and superficial ischemic lesions (black arrowheads). B. Corresponding multiple hyperintensity signal on FLAIR. C. Post-contrast leptomeningeal enhancement (left focus, arrows) and punctuate foci of parenchymal enhancement (right focus, arrows). D. Three-dimensional TOF MRA..multiple focal stenoses (white arrowheads) of bilateral middle cerebral artery branches. PACNS diagnosis was confirmed on biopsy.
- #26 48-year-old male with persistent headaches and recent onset of seizures presenting altered vigilance. A.Right anterior frontal lobar acute intraparenchymal hemorrhage (black arrowhead). B and C.Three months after first episode, patients present a parietal ischemic-hemorrhagic lesion (black arrowhead) with important surrounding edema (white arrowheads). Pre- and post-gadolinium T1 sequences (C) demonstrate 2 hemorrhagic foci (white arrowheads) and major peripheral gadolinium uptake (white arrows). MR angiography was normal.
- #27 –D, Axial sections demonstrating various patterns of contrast enhancement in PACNS. A.Multiple punctate foci of parenchymal enhancement in the periventricular and deep white matter (arrowheads). B.Incomplete subcentimetric rims of gadolinium contrast enhancement in the left centrum semiovale (arrowheads). C.Leptomeningeal (arrow) and subcortical (arrowheads) gadolinium uptake. D.Subacute ischemic gadolinium uptake from blood–brain barrier disruption in a patient with multiple PACNS-related ischemic lesions.
- #28 A 24-y-old man with ischemic stroke in the posterior circulation (axial section of diffusion-weighted imaging sequence, arrow) and recent history of worsening headaches. TOF demonstrates bilateral proximal posterior cerebral artery stenoses. B, A 65-y-old woman, with recent history of left middle cerebral artery infarct, presents with worsening of symptoms in a context of persisting headaches. MRI demonstrates a chronic infarct (axial section of fluid-attenuated inversion recovery sequence, hyperintense lesion, arrow) and left proximal middle artery stenoses