Primary cns vasculitis

PACNS

1. Primary CNS Vasculitis (PACNS) By/ Lobna Ahmed

2. Primary angiitis of 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 epidemiology of 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 findings can 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. Pathophysiology On the other hand, weak vessels walls can rupture leading to hemorrhage.

5. Affection of parenchymal 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. Histopathology

6. The onset of PACNS 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. 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 i solated vasculitic myelopathies have also been reported.

8. A combination of symptoms 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

10. Diagnostic certainty

11. 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

14. CSF The only useful laboratory 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. CSF

16. The cornerstone for establishing the diagnosis of PACNS. vessel beading

17. Vessel beading is not 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. Valerie L Jewells. (n.d.). CNS Vasculitis; An Overview of this Multiple 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 of the 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.

20. Valerie L Jewells. (n.d.). CNS Vasculitis; An Overview of this Multiple 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. WM lesions distribution 2/3rd of CNSV 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 Multiple 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 wall imaging 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 /CTA may demonstrate occlusion, stenosis, and wall thickening of large vessels. It’s limitations are insensitivity for WM assessment, leptomeningeal enhancement or depiction of small vessels.

24. Primary Angiitis of the Central Nervous System Magnetic Resonance Imaging Spectrum of Parenchymal, Meningeal, and Vascular Lesions at Baseline. (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 of the Central Nervous System Magnetic Resonance Imaging Spectrum of Parenchymal, Meningeal, and Vascular Lesions at Baseline. (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 of the Central Nervous System Magnetic Resonance Imaging Spectrum of Parenchymal, Meningeal, and Vascular Lesions at Baseline. (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 of the Central Nervous System Magnetic Resonance Imaging Spectrum of Parenchymal, Meningeal, and Vascular Lesions at Baseline. (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), multiple DWI 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 contrast enhancement 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. In case of negative angiographic findings >> brain biopsy should be considered as an important step towards diagnosing PACNS.

32. Biopsy Due to the 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

34. Differential diagnosis

35. RCVS Formerly RCVS was described as 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.

36. RCVS Neuro imaging may show infarctions (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.

37. A-CT scan showing a 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.

38. Diffuse intracerebral vasoconstriction on initial angiogram, after 2 wk of headache then right hemiparesis and encephalopathy. B, Resolution of vasoconstriction after 4 mo.

39. Systemic vasculitis CNS involvement most often arises in patients with: Bechet's disease. Wegener’s granulomatosis. Churg–Strauss syndrome.

40. 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

41. Vasculitis 2 nd to CT diseases

42. Moyamoya angiopathy. Divry -van Bogaert syndrome. fibromuscular dysplasia. Fabry disease. Sneddon’s syndrome. Non-inflammatory vascular diseases

43. Malignancy In single cases, 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.

44. Infection VZV vasculopathy: An infectious 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.

45. Other mimics

46. Aliaga Frederik Barkhof , E. S. (n.d.). Chapter 13 - MRI mimics of multiple sclerosis. In Handbook of Clinical Neurology (pp. 291–316). ELSEVIER.

47. Other mimics

48. Aliaga Frederik Barkhof , E. S. (n.d.). Chapter 13 - MRI mimics of multiple sclerosis. In Handbook of Clinical Neurology (pp. 291–316). ELSEVIER.

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. Treatment Induction therapy Maintenance therapy Corticosteroids Immunosuppressants Biologics

51. Induction therapy High-dose of IV 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.

52. In patients who are intolerant to conventional immunosuppressive therapeutic regimens .. or in patients failing to respond to cyclophosphamide therapy .. Biological agents Rituximab TNF-α blockers (infliximab and etanercept)

53. Maintenance therapy Goal: Limiting the risk of relapses 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

54. Carolin Beuke. (n.d.). Primary angiitis of the central nervous system: diagnosis and treatment. Ther Adv Neurol Disord . https://doi.org/ 10.1177/1756286418785071