Vasculitis of the central nervous system
Last edited on : 23/09/2024
The vasculitides of the central nervous system constitute a heterogeneous group of conditions characterized by inflammatory lesions of the vessel walls in the central nervous system. Their etiologies are diverse, their clinico-radiological presentation is polymorphic, and their diagnosis, requiring (semi)-invasive examinations, is challenging.
The most difficult differential diagnosis is that of acute reversible cerebral angiopathy ("spastic angiitis"), especially for primary central nervous system vasculitides (absence of extra-neurological signs).
Generalities
Clinical and diagnostic orientation
Polymorphic clinic: focal deficits, partial or generalized epileptic seizures, cranial nerve involvement, ataxia, visual disturbances, signs of diffuse encephalopathy and altered vigilance, headaches, meningeal signs,...
Less commonly: isolated medullary signs (10-15% of cases), cauda equina syndrome or simple radicular pain (dural sac inflammation), ischemic or hemorrhagic strokes,…
Onset can be (sub)acute or chronic, and the evolution is equally variable…
However, some presentations are particularly suggestive:
- Stroke in a young subject with inflammatory CSF
- Multiple focal deficits with headaches
- Recurrent strokes at short intervals without an embolic etiology
- Rapidly progressive focal deficits without explanation after standard workup
- Chronic fluctuating myelopathy without explanation after standard workup
The diagnostic suggestion is therefore particularly difficult for primary CNS vasculitides (absence of extra-neurological signs except for possible fever, arthralgia, or asthenia).
Secondary vasculitides generally pose fewer diagnostic problems: history of medication use or drug abuse, late onset of neurological signs in the course of an infection or systemic disease,... Some infectious vasculitides (e.g., post-zoster, tuberculosis) can, however, develop very late outside of any febrile context with or without extra-neurological manifestations.
The presence of systemic symptomatology or a history of systemic disease in the absence of iatrogenic causes and infectious context should always suggest a systemic disease with CNS involvement.
Some presentations are very suggestive:
- Neurological signs + unexplained headaches in a patient over 60 years → Horton disease?
- Chorea or psychotic episode in a young woman → SLE?
- Rhombencephalitis → Behçet?
Complementary examinations
Biology
No interest for primary CNS vasculitides (ESR moderately elevated in 1-2/3 of cases). Can provide elements in favor of systemic or infectious diseases (hemato-CRP, ESR, ANA, ANCA, RF, serologies for HIV/Borrelia/Syphilis,...).
Lumbar puncture
Possible variable abnormalities: elevated protein in CSF ++, low glucose in CSF, lymphocytic meningitis ++, SAH, increased gammaglobulins with or without oligoclonal bands, increased intracranial pressure,… sometimes strictly normal (10 to 20% of cases). Systematic performance of serologies and PCR that should return negative.
Brain imaging
CT brain scan generally shows hypodensities of varying size suggesting ischemic lesions, rarely hyperdensities indicating hemorrhages or even brain atrophy.
Brain MRI may show similar types of abnormalities, hyperintensities in the white matter (common in those > 60 years, potentially suggestive of MS in younger patients). The association with cortical abnormalities (suggesting or not infarcts) is more indicative. Sometimes there are pseudo-tumor-like lesions or miliary appearances (multiple punctiform parenchymal lesions). Angio-MRI has poor sensitivity for small-caliber intracerebral vessels.
Cerebral angiography is the gold standard: segmental arterial stenosis +- separated by fusiform dilatations (string of beads appearance) = suggestive appearance but poorly specific (DD: arterial spasms in the context of spastic angiitis, SAH, or severe hypertension), irregularities in the vessel walls, stenoses, vascular occlusions, aneurysms… and sometimes strictly normal (→ repeat angiography later in case of strong clinical suspicion)… and may sometimes overestimate the lesions.
Brain and leptomeningeal biopsy = definitive diagnosis
Invasive but necessary for positive diagnosis → to be discussed on a case-by-case basis.
Diagnosis and differential diagnoses
Positive diagnosis requires a biopsy of a CNS lesion. A CSF analysis and angiography (for some authors, an angio-MRI is sufficient) that are strictly normal reasonably exclude the diagnosis.
The main clinico-radiological differential diagnoses are: stroke, epilepsy, intracranial tumors, MS and other demyelinating conditions, reversible cerebral angiopathy. The abnormalities observed at angiography are usually indistinguishable from reversible cerebral angiopathy (whose management and treatment are radically different).
Primary central nervous system vasculitides
= vascular involvement limited to the CNS, etiology unknown, rare. Histology characterized by a mononuclear infiltrate (+- granulomas with lymphocytes/macrophages/Langhans cells/epithelioid cells +- fibrinoid necrosis), predominant in vessels < 500 micrometers. 2 males > 1 female, ++ > 40 years.
Spontaneous prognosis very poor: progressive deterioration/stepwise in a few weeks/months, rapid death is the rule. Possible transient remissions.
No EBM, consensus for histologically confirmed cases, no consensus otherwise. Initial treatment: corticosteroids (1g/day IV bolus for 3-5 days then 1mg/kg/day to be reduced by 10mg/day each week until a maintenance dose of 10mg/day) +- cyclophosphamide 2mg/kg/day (azathioprine = second choice) for 2-6 months depending on clinical-radiological evolution. Maintenance therapy: Medrol 10-20mg/day every other day + azathioprine 2mg/kg/day (or methotrexate or cyclophosphamide infusions once a month) – for 6-12 months after remission.
In case of diagnostic doubt with reversible cerebral angiopathy, there is no consensus. Example of management: treatment with nimodipine → repeat angiographies up to 3 months → in case of deterioration/persistence for > 3 months clinically/radiologically: consider biopsy.
Primary systemic vasculitides - systemic diseases with vascular involvement of the central nervous system
CNS involvement in 10 to 20% of PAN (up to 50% if considering headaches, ocular signs, and cranial nerve involvement). Possible forms with predominant cutaneous expression (hypersensitivity vasculitides). CNS involvement is only exceptionally revealing and not correlated with prognosis.
A differential diagnosis to consider in the atheromatous patient is that of multiple cholesterol emboli (→ TIA, livedo, renal, digestive, muscular involvement). Detection of cholesterol crystals in the biopsy of a target organ.
Related conditions: Churg-Strauss (constant asthma, hypereosinophilia), Cogan's syndrome (vestibular involvement, bilateral deafness, interstitial keratitis).
Horton
Typical clinic: > 50 years, headaches (++ temporal-occipital and constant), DEG, very high ESR. The occurrence of visual disturbance (sometimes inaugural!) or oculomotor paralysis constitutes a therapeutic emergency in this context. Confirmation of diagnosis by ultrasound and/or biopsy of the temporal artery. CNS involvement in 25 to 50% of cases. Stroke in 2.5 to 25%.
Takayasu
++ 20 to 40 years, ++ women, ++ Asian/Caribbean/North African. 85% survival at 10 years. Rare severe forms in children. As in Horton, the occurrence of visual disturbances requires urgent initiation of treatment (long-term corticosteroids… cyclophosphamide if refractory).
Wegener and lymphomatoid granulomatosis
Pulmonary and renal involvement generally predominant. CNS involvement is exceptional in Wegener (! cranial nerve involvement is frequent) but nearly 20% in lymphomatoid granulomatosis.
Exceptional primary systemic vasculitides
Buerger's disease (++ male smokers, ++ distal limb involvement).
Susac syndrome (= retino-cochlear encephalopathy): ++ young women, bilateral deafness, visual disturbances, diffuse encephalopathies,… angiography often normal.
Acute plaque epithelialopathy: ++ severe visual disturbances often spontaneously resolving. Rare cerebral involvement (sometimes several years after visual involvement).
Kohlmeier-Degos disease (= malignant atrophying papulosis): characteristic skin lesions, gastrointestinal and neurological involvement. Rapid death!
Systemic-associated vasculitides
CNS involvement occurs in 20% of Behçet's… but usually it involves venous thrombosis… arteritis (++ subacute rhombencephalitis) is exceptional.
CNS involvement in 25 to 75% of SLE (inaugural in 15%, 2nd cause of mortality after lupus nephropathy, poor prognostic factor: drop in 10-year survival from 80% to 50%). However, arteritis seems rare (frequent neurological complications from venous thrombosis, hypertension, endocarditis, coagulation disorders, iatrogenic causes). All clinical presentations are possible (very suggestive: young woman with psychotic episodes). Forms with possible remissions (DD = MS). In case of isolated CNS involvement, diagnosis can be very difficult (MRI poorly specific, biology can still be cold). Poorly defined treatment (corticosteroids +- immunosuppressants).
CNS involvement in Sjögren's disease is associated with peripheral nervous system involvement in 50% of cases. Psychiatric signs in 60%. Focal deficits in 25%. Poorly defined treatment (corticosteroids? plasmapheresis?).
Exceptional CNS involvement: scleroderma, mixed connective tissue disease, celiac disease, ulcerative colitis, dermatomyositis, rheumatoid arthritis, sarcoidosis.
Secondary vasculitides
Infectious vasculitides of the central nervous system
They are more frequent and potentially underdiagnosed. Generally occur late in the course of an infection. Varied origins:
- Bacteria: bacterial meningitis, bacterial endocarditis, Lyme, tuberculosis, syphilis, Bartonella, rickettsioses, chlamydia, mycoplasma,…
- Viruses: HSV, VZV, CMV, HIV,…
- Parasites: toxoplasmosis, cysticercosis, protozooses,…
- Fungi: aspergillosis, candidiasis, cryptococcosis, coccidioidomycosis, histoplasmosis, mucormycosis,…
Toxic and iatrogenic vasculitides
Ischemic or hemorrhagic strokes can, rarely, occur due to drug use: cocaine, crack, heroin, amphetamines, carbamazepine, sympathomimetics (nasal sprays containing ephedrine,…).
True histologically documented vasculitides are described although the lesion mechanism is usually vasospasm in the context of hypertensive episodes. Other causes: immunosuppression, transplant rejection, radiotherapy.
Vasculitides due to cerebral amyloid angiopathy
See the article on cerebral amyloid angiopathies. Initiate corticosteroid treatment in case of doubt and rapid progression.
Paraneoplastic vasculitides
Paraneoplastic vasculitides (++ systemic) are rare and mainly found in hematologic diseases and carcinomatous meningitis. Strokes in a cancer patient usually result from other mechanisms: DIC and other coagulation disorders, non-bacterial endocarditis, venous thrombosis, tumor emboli, ruptured oncotic aneurysms,…
Bibliography
EMC, traité de neurologie, Elsevier, 2018
Jameson JL et al., Harrison's Principles of Internal Medicine, 20th edition, McGraw Hill Higher Education, 2018