628
NEUROLOGY, NEUROPSYCHOLOGY, NEUROPHYSIOLOGY
Zdrav Vestn | November – December 2021 | Volume 90 | https://doi.org/10.6016/ZdravVestn.3092
Copyright (c) 2021 Slovenian Medical Journal. This work is licensed under a
Creative Commons Attribution-NonCommercial 4.0 International License.
A practical approach to the diagnosis and management 
of primary angiitis of the central nervous system
Praktični pristop k obravnavi bolnika s primarnim vaskulitisom osrednjega živčevja
Nik Krajnc, Gregor Brecl Jakob
Abstract
Vasculitides present a rare and heterogeneous group of diseases that affect small, middle-sized and/or large arteries. Most 
of them are systemic diseases, however, they can also present as an isolated (primary) angiitis of the central nervous 
system. Among the most common presenting symptoms are: headache, cognitive deficits, and encephalopathy, but they 
frequently present with ischaemic and/or haemorrhagic stroke, and transitory ischaemic attack too. In the cerebrospinal 
fluid, lymphocytic pleocytosis and/or elevated proteins can be seen, with acute phase proteins and other laboratory find-
ings (rheumatology and microbiological tests, cytology) being commonly negative. The findings on magnetic resonance 
imaging of the brain are non-specific in 90%. With negative magnetic resonance imaging and cerebrospinal fluid findings, 
the diagnosis of primary angiitis of the central nervous system is highly implausible. On angiography, in approximately 
40% of patients the vascular beading, a non-specific finding of dilated areas alternating with narrowing of the blood ves-
sels can be seen. Biopsy rpesents the golden standard, although it is false negative in 25% of cases due to its segmental 
distribution. Most studies suggest corticosteroids and cyclophosphamide as an induction therapy, folowed by a mainte-
nance therapy (azathioprine or mycophenolate mofetil) in 6–12 months. Primary angiitis of the central nervous system still 
presents a diagnostic challenge with early therapeutic intervention being crucial for a better outcome.
Izvleček
Vaskulitisi so redka in raznolika skupina bolezni, ki prizadenejo male, srednje velike in/ali velike žile. Večinoma gre za 
sistemske bolezni, vendar lahko v redkih primerih prizadenejo samo žilje v osrednjem živčevju; tedaj jih imenujemo pri-
marni vaskulitisi osrednjega živčevja. Najpogosteje se kažejo z glavobolom, s kognitivnim upadom in z encefalopatijo, 
neredko pa tudi s sindromom ishemične ali hemoragične možganske kapi ali s prehodno pretočno motnjo. Pri diagnostici-
ranju se poslužujemo odvzema likvorja, v katerem ugotavljamo limfocitno pleocitozo s povišanimi vrednostmi beljakovin. 
Vnetni parametri in ostali laboratorijski izvidi krvi (revmatološki, mikrobiološki, citološki izvidi) so praviloma normalni. 
Department of Neurology, University Medical Centre Ljubljana, Ljubljana, Slovenia
Correspondence / Korespondenca: Nik Krajnc, e: krajnc.nik@gmail.com
Key words: vasculitis; angiitis; central nervous system; headache; ischemic stroke; angiography; biopsy; cyclophosphamide
Ključne besede: vaskulitis; angiitis; osrednje živčevje; glavobol; ishemična možganska kap; angiografija; biopsija; ciklofosfamid
Received / Prispelo: 20. 5. 2020 | Accepted / Sprejeto: 5. 5. 2021
Cite as / Citirajte kot: Krajnc N, Brecl Jakob G. A practical approach to the diagnosis and management of primary angiitis of the central 
nervous system. Zdrav Vestn. 2021;90(11–12):628–36. DOI: https://doi.org/10.6016/ZdravVestn.3092
eng slo element
en article-lang
10.6016/ZdravVestn.3092 doi
20.5.2020 date-received
5.5.2021 date-accepted
Neurology, neuropsychology, neurophysiology Nevrologija, nevropsihologija, nevrofiziologija discipline
Professional article Strokovni članek article-type
A practical approach to the diagnosis and 
management of primary angiitis of the central 
nervous system
Praktični pristop k obravnavi bolnika s primarnim 
vaskulitisom osrednjega živčevja article-title
A practical approach to the diagnosis and 
management of primary angiitis of the central 
nervous system
Praktični pristop k obravnavi bolnika s primarnim 
vaskulitisom osrednjega živčevja alt-title
vasculitis, angiitis, central nervous system, 
headache, ischemic stroke, angiography, biop-
sy, cyclophosphamide
vaskulitis, angiitis, osrednje živčevje, glavobol, 
ishemična možganska kap, angiografija, biopsija, 
ciklofosfamid
kwd-group
The authors declare that there are no conflicts 
of interest present.
Avtorji so izjavili, da ne obstajajo nobeni 
konkurenčni interesi. conflict
year volume first month last month first page last page
2021 90 11 12 628 636
name surname aff email
Nik Krajnc 1 krajnc.nik@gmail.com
name surname aff
Gregor Brecl Jakob 1
eng slo aff-id
Department of Neurology, 
University Medical Centre 
Ljubljana, Ljubljana, Slovenia
Klinični oddelek za bolezni 
živčevja, Nevrološka klinika, 
Univerzitetni klinični center 
Ljubljana, Ljubljana, Slovenija
1
Slovenian Medical Journallovenian Medical Journal
629
PROFESSIONAL ARTICLE
A practical approach to the diagnosis and management of primary angiitis of the central nervous system
1 Introduction
Vasculitides are a rare and heterogenous group of 
diseases whose main characteristics are inflammation 
and necrosis of small, medium-sized and large artery 
walls (1,2). Any organ can be affected, including the 
central and peripheral nervous systems, which are nor-
mally secondarily affected (1). They then present with 
a variety of neurological symptoms that depend on the 
size and location of the affected vessels, making the di-
agnosis of central nervous system (CNS) vasculitis all 
the more difficult (3,4).
Rarely, vasculitis is predominantly confined to the 
CNS, in which case it is termed primary angiitis of the 
central nervous system (PACNS). It was first described 
by Harbitz in 1922 as an unknown form of angiitis, and 
then later in 1959 by Cravioto and Feigin as an inde-
pendent clinical entity which they named non-infec-
tious granulomatous angiitis (5). Our article is a review 
of the key characteristics of PACNS and, as part of a 
differential diagnosis, of secondary CNS vasculitides, 
to significantly facilitate the diagnosis of such diseas-
es. At the end of the article, we also briefly present the 
treatment of patients with PACNS at the Department of 
Neurology at the University Medical Centre Ljubljana.
2 Epidemiology
PACNS is an extremely rare disease affecting most-
ly small and medium-sized leptomeningeal and/
or parenchymal arteries (3). The yearly incidence is 
2.4/1,000,000 (6). It generally affects middle-aged men 
with a median age of 50 years, but it can also affect 
children (2,7). Approximately 3–5% of cerebrovascular 
events in those under 50 years of age are due to PACNS 
(8). Its course is slow and progressive (9).
Magnetnoresonančno slikanje (MRI) glave nam v 90 % pokaže nespecifične spremembe. V primeru negativnega slikovnega 
izvida in normalnega likvorskega izvida je diagnoza primarnega vaskulitisa osrednjega živčevja praktično izključena. Na 
angiografiji pri približno 40 % bolnikov ugotavljamo izmenjujoče se stenoze in ektazije, ki so nespecifične najdbe, saj jih 
lahko opažamo tudi pri drugih boleznih. Zlati standard za postavitev diagnoze je biopsija, ki je zaradi segmentne prizade-
tosti žilja lažno negativna v 25 %. Zdravljenje pričnemo z indukcijskimi imunosupresivi, izmed katerih največkrat uporab-
ljamo metilprednizolon in ciklofosfamid, v nadaljevanju (po 6–12 mesecih) pa preidemo na vzdrževalno imunouspresivno 
zdravljenje, največkrat z azatioprinom ali mikofenolat mofetilom. Bolniki s primarnim vaskulitisom osrednjega živčevja so 
zaradi omejitev pri diagnostičnih preiskavah še vedno velik diagnostični izziv. Ob vsem tem je zgodnja diagnoza ključna za 
ugoden izid bolezni.
3 Etiopathogenesis
The aetiology and pathogenesis of PACNS are still 
unexplored. Several factors are thought to be respon-
sible for PACNS and among them, infections with the 
varicella-zoster virus, West Nile virus, Mycoplasma gal-
lisepticum and human immunodeficiency virus (HIV) 
have most often been mentioned, although a clear 
pathogenetic link is not known (10-13). Previous in-
fection is thought to be responsible for the loss of in-
tegrity of the blood-brain barrier due to the breakdown 
of tight junctions, leading to increased permeability for 
leukocytes (1). Leukocyte entry into the CNS causes as-
trocyte dysfunction with vasogenic oedema, the accu-
mulation of toxic substances in the interstitium and ox-
idative stress, all contributing to impaired angiogenesis 
(5,14). These changes lead to the breakdown of vascular 
walls, which manifests as alternating areas of thicken-
ing and stenosis, impairing perfusion in areas of the 
CNS (15). The weakening of vascular walls can cause 
them to tear, leading to intracranial haemorrhage (8).
4 Clinical presentation
The clinical presentation is extremely diverse. The 
course is normally subacute or chronic, but it can al-
so be acute with periods of exacerbations and remis-
sions. Progressive headache is the most common 
symptom (50–60%) along with qualitative disorders of 
consciousness (50–70%), followed by focal neurologic 
deficits (e.g. hemiparesis, ataxia, aphasia, dysarthria, 
visual disturbances), epileptic seizures and/or psychiat-
ric symptoms (8,9,16,17). Focal neurologic deficits are 
absent in 25–30% (16,18). Recurrent ischaemic stroke 
and transitory ischaemic attack (TIA) are present in 
30–50% of patients (7).
630
NEUROLOGY, NEUROPSYCHOLOGY, NEUROPHYSIOLOGY
Zdrav Vestn | November – December 2021 | Volume 90 | https://doi.org/10.6016/ZdravVestn.3092
5 Diagnosis
Diagnostic criteria for PACNS have been established 
by Calabrese and Mallek in 1988 (2). For confirmation 
of the diagnosis, patients must have all three of the fol-
lowing criteria (1,19,20):
• acquired and unexplained neurological or psychiat-
ric symptoms or signs,
• classic angiographic or pathohistological character-
istics of vasculitis, and
• the absence of signs of systemic vasculitis or other 
conditions mimicking the angiographic or patho-
histological characteristics of vasculitis.
In 2009, Birnbaum and Hellmann divided the cri-
teria according to the degree of certainty into definite 
and probable PANCS (5). Certain criteria include bi-
opsy-proven vasculitis, while probable criteria include 
those without histological confirmation but with a 
pathological angiogram, brain MRI and/or cerebrospi-
nal fluid (CSF) (19).
5.1 Laboratory findings
CSF examination with a lumbar puncture is the 
most important laboratory test for diagnosing PACNS 
(21). A pathologic CSF result is present in 74.4% of 
PACNS patients, similar to that which we find in asep-
tic meningitis with increased protein, mild lymphocyt-
ic pleocytosis and normal glucose (16,22,23). Oligoclo-
nal bands and an increased IgG index are rarer findings 
(up to 23.5%) (22,24). These findings are non-specific, 
but the diagnosis of PACNS is less likely with a normal 
CSF (16).
Ruling out secondary causes of CNS vasculitis is 
crucial (7). When diagnosing systemic vasculitides, the 
following investigations are normally performed: in-
flammatory parameters (estimated sedimentation rate, 
C-reactive protein), antinuclear antibodies (ANA), 
antineutrophil cytoplasmic antibodies (ANCA), anti-
phospholipid antibodies, rheumatoid factor, cryoglob-
ulin, C3, C4 and hepatitis B and C serologies (4,16). Es-
timated sedimentation rate (ESR) is usually increased 
in secondary vasculitides and normal in 90% of PACNS 
cases (16).
5.2 Imaging findings
A head CT can reveal abnormalities, but it is a poor-
ly sensitive method for visualising changes of PACNS 
(18). For initial assessment, a brain MRI is significantly 
more sensitive, showing pathologic changes in 93.3%, 
most commonly those of ischaemic stroke (43.3%), fol-
lowed by hyperintense lesions in the cortex, subcortical 
white matter and deep grey matter in T2- and FLAIR 
sequences (37.5%), tumour-mimicking mass effect le-
sions or post-contrast meningeal signal enhancement 
(16,23,25). The latter is present in 10–15% of patients 
and is a good prognostic indicator (21). In the acute 
stage of infarction, diffusion weighted imaging (DWI) 
helps us decide whether the lesion is acute or chronic, 
while susceptibility weighted imaging (SWI) is used to 
exclude microhaemorrhages (26). Due to its high neg-
ative predictive value, PACNS can be practically ruled 
out in the case of a normal MRI (7). The spinal cord is 
affected in less than 5%, while only a few cases of brain-
stem involvement have been described in the literature 
(22,27).
In diagnostic criteria, Calabrese and Mallek es-
tablished alternating stenoses and ectasias (string of 
beads, beading) visible on angiography as a condition 
for diagnosis (28). This finding is non-specific, being 
characteristic of vasculopathy and not vasculitis (16). 
Other angiographic findings include the narrowing of 
arteries in individual areas, collateral circulation and 
regionally extended circulation time (21). Multiple mi-
croaneurysms, often found in abdominal or renal an-
giograms in systemic vasculitides, are rarely found in 
the CNS (29). On the other hand, a normal angiogram 
does not exclude vasculitis; only 59.5% of patients have 
angiographically visible changes. Angiography has a 
limited sensitivity (20–90%) and specificity (20–60%), 
particularly due to limited resolution for arteries less 
than 500 µm, which PACNS affects the most (5,16). A 
retrospective study of 38 patients was performed at the 
Department of Neuroradiology in Washington, D.C., 
of whom 14 had angiographic changes characteristic 
of vasculitis. All patients also underwent biopsy, none 
of which confirmed the diagnosis of vasculitis (30). 
Vasculitic changes are normally found in both hemi-
spheres (26,31).
When the imaging examination reveals the associ-
ated findings, they direct us to the secondary causes of 
vasculitis. Venous sinus thrombosis is most commonly 
found in patients with Behçet’s disease, post-contrast 
leptomeningeal enhancement in tuberculous meningi-
tis and post-contrast pachymeningeal enhancement in 
rheumatoid arthritis-associated vasculitis. Paranasal si-
nus and orbital granulomas are found in granulomato-
sis with polyangiitis and enlarged lacrimal and salivary 
glands in Sjögren’s disease (26).
631
PROFESSIONAL ARTICLE
A practical approach to the diagnosis and management of primary angiitis of the central nervous system
5.3 Pathohistological diagnosis
When tests are inconclusive and the diagnosis is 
unclear, a brain biopsy is performed, which is, despite 
its low sensitivity (53–74%), the gold standard for di-
agnosing PACNS (16). A 1999 study of 61 patients with 
suspected PACNS was published at the University of 
Michigan. The study included patients with multifocal 
neurological deficits and brain MRI and/or CT who 
underwent a brain and meningeal biopsy. After the bi-
opsy, only 28% of patients had a confirmed diagnosis 
of PACNS, 8% probable PACNS, and the remaining 
patients either had a confirmed alternative diagnosis 
(39%) or remained undiagnosed after the biopsy (25%) 
(32). Alternative diagnoses confirmed by biopsy most 
often represent hypertensive changes, followed by am-
yloid angiopathy, infarctions, vascular malformations, 
infections and others (16). Pathological biopsy results 
with classical angiographic results are found only in 
11.2% (23).
Vascular involvement is usually segmental, leading 
to a high proportion of false-negative biopsies. The bi-
opsy sensitivity can be increased by sampling the area 
with a pathological angiographic result, namely both 
the cortex and leptomeninges (16,22). In case of inac-
cessibility of the angiographically pathological area, 
a biopsy of the non-dominant temporal lobe is per-
formed (22). The risk of complications after biopsy is 
not negligible. In a study by the Neurology Department 
of New York University, complications occurred in 13 
patients (16%). Among the most common, intracere-
bral haemorrhage, transiently altered mental state, and 
epileptic seizure were observed. One patient suffered a 
stroke (33). The procedural mortality is, however, low 
(0.03–2%) (34). Despite the lack of PACNS treatment 
guidelines, a biopsy is recommended as it helps with 
identifying alternative diagnoses, especially those that 
may initially respond to immunosuppressive therapy 
(e.g. primary CNS lymphoma) (16,32,34).
In PACNS, transmural inflammation with vascu-
lar wall damage is observed. The most common sub-
type is the granulomatous pattern (58%), followed by 
the lymphocyte pattern (28%) and acute necrotizing 
vasculitis (14%) (16,31). The granulomatous form is 
in some cases associated with β amyloid deposits. In 
this case, it is called amyloid β-related angiitis (ABRA) 
(16). The latter is a unique form of CNS vasculitis as it 
occurs in elderly patients and often appears on a brain 
MRI with contrast as a mass effect lesion with men-
ingeal enhancement (22). Necrotizing vasculitis is sta-
tistically significantly more common in patients with 
intracranial haemorrhage. Granulomatous and/or nec-
rotizing patterns are found in patients with a rapidly 
progressing clinical presentation, poorer response to 
treatment and often fatal outcome, while lymphocytic 
vasculitis is more benign and more common in chil-
dren (31).
6 Differential diagnosis
As part of the differential diagnosis of PACNS, caus-
es of secondary vasculitis, occurring as part of various 
diseases, e.g. systemic vasculitis, autoimmune disease 
or infection, need to be ruled out first (35). Some mi-
croorganisms are angioinvasive, and the rest trigger a 
defensive inflammatory response that causes second-
ary tissue damage (29). The most common causes are 
presented in Table 1.
An important differential diagnostic option is al-
so reversible cerebral vasoconstriction syndrome 
(RCVS), which is more common in women and usual-
ly manifests as an acute, sudden headache (“worst ever 
headache”) (6,7). It can occur spontaneously, but it can 
be secondary to postpartum angiopathy or in connec-
tion with the use of vasoactive substances (cannabis, 
selective serotonin reuptake inhibitors, nasal decon-
gestants) (22,26). The key to diagnosis is the revers-
ibility of angiographic findings, normally occurring 
spontaneously within one to three months (36). The 
main complications of RCVS include cerebral oedema 
(38%), subarachnoid haemorrhage (22%), posterior 
reversible encephalopathy syndrome (PRES) (9–14%), 
and less commonly stroke or intracranial haemorrhage 
(26,37). The distinction between PACNS and RCVS is 
crucial and the demarcation is usually relatively clear 
with a thorough history and appropriate diagnostic 
tests. The main differences between them are present-
ed in Table 2.
Angiographic mimics also include atherosclerosis, 
fibromuscular dysplasia, Moyamoya disease, radia-
tion-related vasculopathy, and intravascular lymph-
oproliferative diseases (19,38-40). Stroke in different 
areas of circulation also occurs in coagulopathies, e.g. 
antiphospholipid syndrome, or in left atrial myxoma. 
Atherosclerotic and thromboembolic infarctions are 
rarely accompanied by inflammatory CSF changes 
(41).
In case of reasonable suspicion, genetic diseases, 
e.g. cerebral autosomal dominant or recessive arteri-
opathy with subcortical infarcts and leukoencephalop-
athy (CADASIL, CARASIL), retinal vasculopathy with 
cerebral leukodystrophy (RVCL), and mitochondrial 
632
NEUROLOGY, NEUROPSYCHOLOGY, NEUROPHYSIOLOGY
Zdrav Vestn | November – December 2021 | Volume 90 | https://doi.org/10.6016/ZdravVestn.3092
oesophageal encephalopathy and mitochondrial en-
cephalitis, lactic acidosis, and stroke-like episodes 
(MELAS), should be excluded (42-45).
One of the differential diagnostic options is also Su-
sac syndrome, an autoimmune endotheliopathy affect-
ing the CNS, inner ear and retinal microvasculature 
Types of disease Examples
Systemic vasculitides
Gigantocellular arteritis, Takayasu's arteritis, polyarteritis nodosa, Kawasaki disease, eosinophilic 
granulomatosis with polyangiitis (Churg-Strauss syndrome), granulomatosis with polyangiitis 
(Wegener's granulomatosis), microscopic polyangiitis, cryoglobulinemia, Bürger's disease, Cogano's 
syndrome, Behcet's disease, Henoch-Schönlein purpura, Goodpasture's syndrome
Other systemic diseases
Systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, dermatomyositis, 
polymyositis, antiphospholipid syndrome, sarcoidosis, systemic scleroderma, chronic inflammatory 
bowel disease (Crohn's disease, ulcerative colitis), mixed connective tissue
Infections Syphilis, tuberculosis, meningococcal meningitis, rickettsiosis, Lyme borreliosis, bartonelosis, brucellosis, endocarditis, leptospirosis, Whipple's disease
HIV, varicella-zoster virus, herpes simplex virus, cytomegalovirus, hepatitis B and C virus, parvovirus 
B19
Echinococcosis, cryptococcosis, cysticercosis, schistosomiasis, trichinosis, toxocariasis, candidiasis, 
mucormycosis, invasive aspergillosis, histoplasmosis, coccidioidomycosis
Haematological diseases 
and tumours
Hodgkin's and non-Hodgkin's lymphoma, myelodysplastic syndrome, hairy cell leukemia, 
paraneoplastic vasculitis, malignant angioendotheliomatosis
Toxic vasculitis/
vasculopathy Amphetamines and derivatives, cocaine, sympathomimetics, marijuana, contraceptives, ecstasy
Other Histiocytosis, familial hemophagocytic histiocytosis, graft-versus-host disease, Eales disease, C4 complement deficiency
Table 1: Causes of secondary vasculitis (3,5,47,48).
PACNS RCVS
Sex and median age at onset More frequent in men (50 years) Women (42 years)
Disease onset Chronic Acute
Disease course Chronic, response to immunosuppresive treatment Self-limiting
Trigger Unknown Identified in 50%
CSF Elevated leukocytes and protein Normal
MRI Hyperintense vascular walls Minimally higher signal intensity
Haemorrhagic infarction Rare Frequent
Biopsy Vasculitis No signs of vasculitis
Treatment Glucocorticoids, cytotoxic treatment Calcium channel blockers, avoiding triggers
Table 2: Main characteristics and differences between primary vasculitis of the central nervous system and reversible 
cerebral vasoconstriction syndrome (7,22).
Legend: CSF – cerebrospinal fluid , PACNS – primary angiitis of the central nervous system), RCVS – reversible cerebral 
vasoconstriction syndrome.
and is manifested by the classic triad: encephalopathy, 
sensorineural hearing loss and visual disturbances. Su-
sac syndrome brain MRI is characterized by changes in 
the corpus callosum (snowball lesions), which help us 
to distinguish this diagnosis from PACNS (46).
633
PROFESSIONAL ARTICLE
A practical approach to the diagnosis and management of primary angiitis of the central nervous system
7 Treatment
PACNS treatment focuses on the control of intramu-
ral inflammation, the prevention of secondary ischaemic 
events, and the management of neurological symptoms 
such as epileptic seizures and psychiatric symptoms (6). 
Treatment of secondary vasculitis depends on the cause 
(infection, cancer, systemic inflammatory or autoim-
mune disease), but sometimes we still decide on short-
term glucocorticoid treatment (49).
The proposed algorithm for PACNS treatment dis-
tinguishes between small-vessel vasculitis, where glu-
cocorticoid treatment is indicated and, in case of poor 
response, cyclophosphamide (CYC) combination ther-
apy, and large-vessel vasculitis, in which combination 
therapy is advised regardless of the success of glucocor-
ticoid treatment (34). Combination therapy is generally 
used, although examples of induction therapy with glu-
cocorticoids without CYC have been reported in the lit-
erature (50). The first-line treatment are glucocorticoids 
with high initial doses (7.5–15 mg/kg or 1 g of methyl-
prednisolone per day for three days, then 1 mg/kg or 64 
mg of methylprednisolone per day). As the second-line 
treatment, we use pulsed CYC at a dose of 15 mg/kg or 1 
g per day once a month. The dose should be adjusted ac-
cording to the patient’s age and renal function (51). After 
approximately six months, when a satisfactory response 
is achieved, it is recommended to change CYC for less 
toxic maintenance treatment with azathioprine (AZA) 
(1–2 mg/kg/day), methotrexate (20–25 mg/week) or 
mycophenolate mofetil (MMF) (1–2 g/day) for a fur-
ther 1–2 years (25,51,52). According to some studies, a 
relapse is expected in 33% of patients, making mainte-
nance treatment crucial with a recommended duration 
of 12–18 months (25,53). Mortality is still high (6–15%) 
despite treatment. Poorer prognostic factors are high-
er age at diagnosis, involvement of larger vessels, focal 
neurological deficits in the clinical presentation, and, in 
general, greater burden of disease at onset. Rituximab 
and infliximab have also been shown to be effective in 
relapsed patients, but a higher risk of lymphoma has 
been observed in the latter, which is why it is not recom-
mended in combination with high doses of glucocorti-
coids and CYC (17,25).
After 4–6 weeks of treatment, a repeat MRI is rec-
ommended, followed by repeat MRIs every 3–4 months. 
In follow-ups, the absence of new changes, signifying 
disease activity, is crucial; the old changes persist, as a 
rule (4). In some patients we can rely only on symptom 
improvement to judge the treatment response.
7.1 Prophylactic treatment
Long-term treatment with glucocorticoids is associ-
ated with a number of side effects such as osteoporosis, 
myopathy, dyslipidaemia, glucose intolerance, gastritis, 
peptic ulcers and gastrointestinal bleeding, so a pro-
phylactic administration of proton pump inhibitors, 
bisphosphonates, calcium and vitamin D are required 
(4,34). With a combination of high-dose glucocorticoids 
and another immunosuppressive drug, prophylaxis 
against Pneumocystis jirovecii pneumonia is crucial. The 
European League Against Rheumatism (EULAR) advis-
es prophylaxis with trimethoprim/sulfamethoxazole at a 
dose of 800/160 mg every other day or 400/80 mg daily 
during CYC treatment (54). According to some guide-
lines, patients receiving CYC require controls of blood 
count every 14 days, but in any case, blood count should 
be monitored before each CYC application (55).
As part of the secondary prevention of vascular 
events, antithrombotic protection with acetylsalicylic ac-
id is advised, but it does not affect the outcome of treat-
ment with effective immunosuppression (56). Depend-
ing on concomitant symptoms, we also use symptomatic 
treatment (antiepileptic drugs, antipsychotics, antide-
pressants) and drugs for the management of cardiovas-
cular risk factors (statins, antihypertensive treatment).
8 Management of patients with PACNS 
at the Department of Neurology at the 
Medical Centre Ljubljana
Between 2014 and 2019, nine patients with PACNS 
were treated at the Department of Neurology at the 
University Medical Centre Ljubljana: seven women and 
two men. As we manage about half of neurological pa-
tients in Slovenia, we estimate the incidence of PACNS 
at 1.62/1,000,000. The mean age of patients at the onset 
of symptoms was 50.6 (36–59) years.
The majority of patients (7; 77.8%) complained of 
headache with associated symptoms of stroke in the 
anterior and/or posterior circulation; only two patients 
(22.2%) had isolated headache at the onset of symptoms. 
Concomitant epileptic seizures were observed in only 
one patient.
In five (55.6%) patients, mild lymphocytic pleocyto-
sis with elevated protein was detected in the CSF; oligo-
clonal bands in the CSF and at the same time not in the 
serum were present in only two patients. In blood work, 
slightly elevated inflammatory parameters were observed 
in four (C-reactive protein) or five (ESR) patients, the 
634
NEUROLOGY, NEUROPSYCHOLOGY, NEUROPHYSIOLOGY
Zdrav Vestn | November – December 2021 | Volume 90 | https://doi.org/10.6016/ZdravVestn.3092
References
1. Salvarani C, Brown RD, Hunder GG. Adult primary central nervous 
system vasculitis. Lancet. 2012;380(9843):767-77. DOI: 10.1016/S0140-
6736(12)60069-5 PMID: 22575778 
2. Hajj-Ali RA. Primary angiitis of the central nervous system: differential 
diagnosis and treatment. Best Pract Res Clin Rheumatol. 2010;24(3):413-
26. DOI: 10.1016/j.berh.2009.12.003 PMID: 20534374 
3. Salvarani C, Pipitone N, Hunder GG. Management of primary and 
secondary central nervous system vasculitis. Curr Opin Rheumatol. 
2016;28(1):21-8. DOI: 10.1097/BOR.0000000000000229 PMID: 26599380 
4. Vera-Lastra O, Sepúlveda-Delgado J, Cruz-Domínguez MP, Medina G, 
Casarrubias-Ramírez M, Molina-Carrión LE, et al. Primary and secondary 
central nervous system vasculitis: clinical manifestations, laboratory 
findings, neuroimaging, and treatment analysis. Clin Rheumatol. 
2015;34(4):729-38. DOI: 10.1007/s10067-014-2831-8 PMID: 25425493 
5. Younger DS. Headaches and vasculitis. Neurol Clin. 2014;32(2):321-62. 
DOI: 10.1016/j.ncl.2013.11.004 PMID: 24703534 
6. Twilt M, Benseler SM. Central nervous system vasculitis in adults and 
children. Handb Clin Neurol. 2016;133:283-300. DOI: 10.1016/B978-0-
444-63432-0.00016-5 PMID: 27112683 
7. Giang DW. Central nervous system vasculitis secondary to infections, 
toxins, and neoplasms. Semin Neurol. 1994;14(4):313-9. DOI: 10.1055/s-
2008-1041091 PMID: 7709082 
8. Beuker C, Schmidt A, Strunk D, Sporns PB, Wiendl H, Meuth SG, et 
al. Primary angiitis of the central nervous system: diagnosis and 
treatment. Ther Adv Neurol Disord. 2018;11:1756286418785071. DOI: 
10.1177/1756286418785071 PMID: 30034536 
9. Wan C, Su H. A Closer Look at Angiitis of the central nervous 
system. Neurosciences (Riyadh). 2017;22(4):247-54. DOI: 10.17712/
nsj.2017.4.20170052 PMID: 29057849 
10. Bhat G, Mathur DS, Saxena GN, Jain S, Singh AP, Bhaduria D. 
Granulomatous angiitis of the central nervous system associated with 
herpes zoster. J Assoc Physicians India. 2002;50:977-8. PMID: 12126361 
11. Alexander JJ, Lasky AS, Graf WD. Stroke associated with central 
nervous system vasculitis after West Nile virus infection. J Child Neurol. 
2006;21(7):623-5. DOI: 10.1177/08830738060210071301 PMID: 16970859 
12. Thomas L, Davidson M, McCluskey RT. Studies of PPLO infection. I. 
The production of cerebral polyarteritis by Mycoplasma gallisepticum 
in turkeys; the neurotoxic property of the Mycoplasma. J Exp Med. 
1966;123(5):897-912. DOI: 10.1084/jem.123.5.897 PMID: 5938817 
13. Nogueras C, Sala M, Sasal M, Viñas J, Garcia N, Bella MR, et al. Recurrent 
stroke as a manifestation of primary angiitis of the central nervous system 
in a patient infected with human immunodeficiency virus. Arch Neurol. 
2002;59(3):468-73. DOI: 10.1001/archneur.59.3.468 PMID: 11890855 
14. Benarroch EE. Blood-brain barrier: recent developments and 
clinical correlations. Neurology. 2012;78(16):1268-76. DOI: 10.1212/
WNL.0b013e318250d8bc PMID: 22508848 
15. Giannini C, Salvarani C, Hunder G, Brown RD. Primary central nervous 
system vasculitis: pathology and mechanisms. Acta Neuropathol. 
2012;123(6):759-72. DOI: 10.1007/s00401-012-0973-9 PMID: 22421812 
remaining laboratory results to exclude secondary vas-
culitis were negative. The brain MRI showed significant 
changes in the areas of the anterior and/or posterior cir-
culation in all patients, whilst only six (66.7%) patients 
had a positive angiography. Based on the clear clinical 
presentation and potential procedural complications, we 
did not decide to perform a biopsy in any patient. All pa-
tients received recommended treatment with glucocor-
ticoids and CYC. The latter was introduced on average 
within 19.9 (7–29) days after hospital admission. CYC 
treatment lasted an average of 13.2 (11–16) months, af-
ter which 66.7% of patients were transitioned to MMF 
and 33.3% to AZA. Maintenance treatment was discon-
tinued in one patient after 37 months, with treatment of 
remaining patients still ongoing. Glucocorticoid thera-
py was gradually reduced to complete discontinuation 
after 31.8 (11–63) months. No patient suffered relapse 
or died, the median NIHSS (National Institute of Health 
Stroke Scale) ratings at discharge and after six months 
were 3 (0–10) and 1 (0–11). Acetylsalicylic acid treat-
ment was also initiated in all patients as part of second-
ary prevention, except for one patient who was treated 
with clopidogrel.
Based on our clinical experience, switching from CYC 
to MMF/AZA after 12 months is safe with a low risk of 
relapse, while data are unfortunately insufficient to esti-
mate the duration of MMF/AZA maintenance treatment.
9 Conclusion
The diagnosis of PACNS is difficult due to the diverse 
clinical presentation and the lack of specific laboratory 
and imaging tests. Secondary causes of vasculitis should 
be ruled out. The gold standard for diagnosis is a biopsy 
of the leptomeninges and brain parenchyma, which al-
so helps us rule out alternative diagnoses. An important 
mimic of PACNS is RCVS, which can also manifest with-
out a characteristic acute headache. Treatment includes 
glucocorticoids, CYC, and appropriate symptomatic 
treatment, with MMF/AZA most commonly used for 
maintenance treatment. In the future, we expect new di-
agnostic markers, as well as guidelines that would facili-
tate the diagnosis and treatment of patients with PACNS.
Conflict of interest
None declared.
635
PROFESSIONAL ARTICLE
A practical approach to the diagnosis and management of primary angiitis of the central nervous system
16. Patel S, Ross L, Oon S, Nikpour M. Rituximab treatment in primary angiitis 
of the central nervous system. Intern Med J. 2018;48(6):724-7. DOI: 
10.1111/imj.13814 PMID: 29898271 
17. Bougea A, Anagnostou E, Spandideas N, Triantafyllou N, Kararizou E. An 
update of neurological manifestations of vasculitides and connective 
tissue diseases: a literature review. Einstein (Sao Paulo). 2015;13(4):627-
35. DOI: 10.1590/S1679-45082015RW3308 PMID: 26313435 
18. Bhattacharyya S, Berkowitz AL. Primary angiitis of the central nervous 
system: avoiding misdiagnosis and missed diagnosis of a rare disease. 
Pract Neurol. 2016;16(3):195-200. DOI: 10.1136/practneurol-2015-001332 
PMID: 26837371 
19. John S, Hajj-Ali RA. CNS vasculitis. Semin Neurol. 2014;34(4):405-12. DOI: 
10.1055/s-0034-1390389 PMID: 25369436 
20. Gowdie P, Twilt M, Benseler SM. Primary and secondary central 
nervous system vasculitis. J Child Neurol. 2012;27(11):1448-59. DOI: 
10.1177/0883073812459352 PMID: 23006496 
21. Dutra LA, de Souza AW, Grinberg-Dias G, Barsottini OG, Appenzeller S. 
Central nervous system vasculitis in adults: an update. Autoimmun Rev. 
2017;16(2):123-31. DOI: 10.1016/j.autrev.2016.12.001 PMID: 28087351 
22. Gan C, Maingard J, Giles L, Phal PM, Tan KM. Primary angiitis of the 
central nervous system presenting as a mass lesion. J Clin Neurosci. 
2015;22(9):1528-31. DOI: 10.1016/j.jocn.2015.03.030 PMID: 26119979 
23. McVerry F, McCluskey G, McCarron P, Muir KW, McCarron MO. 
Diagnostic test results in primary CNS vasculitis: A systematic review 
of published cases. Neurol Clin Pract. 2017;7(3):256-65. DOI: 10.1212/
CPJ.0000000000000359 PMID: 30107009 
24. Kraemer M, Berlit P. Primary central nervous system vasculitis: clinical 
experiences with 21 new European cases. Rheumatol Int. 2011;31(4):463-
72. DOI: 10.1007/s00296-009-1312-x PMID: 20024553 
25. Abdel Razek AA, Alvarez H, Bagg S, Refaat S, Castillo M. Imaging spectrum 
of CNS vasculitis. Radiographics. 2014;34(4):873-94. DOI: 10.1148/
rg.344135028 PMID: 25019429 
26. Broussalis E, Trinka E, Kraus J, McCoy M, Killer M. Treatment strategies for 
vasculitis that affects the nervous system. Drug Discov Today. 2013;18(17-
18):818-35. DOI: 10.1016/j.drudis.2013.05.009 PMID: 23707219 
27. Polencic Aljosa PM. Vodusek David Bozidar. Primarni vaskulitis osrednjega 
živčevja, omejen na možgansko deblo. Zdrav Vestn. 2005;74(7/8):435-8. 
28. Calabrese LH, Mallek JA. Primary angiitis of the central nervous system. 
Report of 8 new cases, review of the literature, and proposal for diagnostic 
criteria. Medicine (Baltimore). 1988;67(1):20-39. DOI: 10.1097/00005792-
198801000-00002 PMID: 3275856 
29. Carolei A, Sacco S. Central nervous system vasculitis. Neurol Sci. 
2003;24(0):S8-10. DOI: 10.1007/s100720300026 PMID: 12774201 
30. Kadkhodayan Y, Alreshaid A, Moran CJ, Cross DT, Powers WJ, Derdeyn 
CP. Primary angiitis of the central nervous system at conventional 
angiography. Radiology. 2004;233(3):878-82. DOI: 10.1148/
radiol.2333031621 PMID: 15498898 
31. Salvarani C, Brown RD, Christianson T, Miller DV, Giannini C, Huston J, et 
al. An update of the Mayo Clinic cohort of patients with adult primary 
central nervous system vasculitis: description of 163 patients. Medicine 
(Baltimore). 2015;94(21):e738. DOI: 10.1097/MD.0000000000000738 
PMID: 26020379 
32. Alrawi A, Trobe JD, Blaivas M, Musch DC. Brain biopsy in primary angiitis 
of the central nervous system. Neurology. 1999;53(4):858-60. DOI: 
10.1212/WNL.53.4.858 PMID: 10489055 
33. Torres J, Loomis C, Cucchiara B, Smith M, Messé S. Diagnostic Yield and 
Safety of Brain Biopsy for Suspected Primary Central Nervous System 
Angiitis. Stroke. 2016;47(8):2127-9. DOI: 10.1161/STROKEAHA.116.013874 
PMID: 27354225 
34. Limaye K, Samaniego EA, Adams HP. Diagnosis and Treatment of 
Primary Central Nervous System Angiitis. Curr Treat Options Neurol. 
2018;20(9):38. DOI: 10.1007/s11940-018-0522-5 PMID: 30076478 
35. Suri V, Kakkar A, Sharma MC, Padma MV, Garg A, Sarkar C. Primary angiitis 
of the central nervous system: a study of histopathological patterns 
and review of the literature. Folia Neuropathol. 2014;52(2):187-96. DOI: 
10.5114/fn.2014.43790 PMID: 25118904 
36. Lopez JI, Holdridge A, Chalela J. Headache and vasculitis. Curr Pain 
Headache Rep. 2013;17(3):320. DOI: 10.1007/s11916-012-0320-9 PMID: 
23338772 
37. Singhal AB, Topcuoglu MA, Fok JW, Kursun O, Nogueira RG, Frosch MP, et 
al. Reversible cerebral vasoconstriction syndromes and primary angiitis 
of the central nervous system: clinical, imaging, and angiographic 
comparison. Ann Neurol. 2016;79(6):882-94. DOI: 10.1002/ana.24652 
PMID: 27043703 
38. Becker J, Horn PA, Keyvani K, Metz I, Wegner C, Brück W, et al. Primary 
central nervous system vasculitis and its mimicking diseases - clinical 
features, outcome, comorbidities and diagnostic results - A case 
control study. Clin Neurol Neurosurg. 2017;156:48-54. DOI: 10.1016/j.
clineuro.2017.03.006 PMID: 28324788 
39. Kraemer M, Berlit P. Primary central nervous system vasculitis 
and moyamoya disease: similarities and differences. J Neurol. 
2010;257(5):816-9. DOI: 10.1007/s00415-009-5425-7 PMID: 20037765 
40. Ghazaleh D, Beran A, Berry B, Ghannam M. Occlusive radiation cerebral 
vasculopathy implies medical complexity: a case report. J Med Case 
Reports. 2019;13(1):170. DOI: 10.1186/s13256-019-2104-x PMID: 31159883 
41. Byram K, Hajj-Ali RA, Calabrese L. CNS Vasculitis: an Approach 
to Differential Diagnosis and Management. Curr Rheumatol Rep. 
2018;20(7):37. DOI: 10.1007/s11926-018-0747-z PMID: 29846828 
42. Wang MM. Cadasil. Handb Clin Neurol. 2018;148:733-43. DOI: 10.1016/
B978-0-444-64076-5.00047-8 PMID: 29478611 
43. Devaraddi N, Jayalakshmi G, Mutalik NR. CARASIL, a rare genetic cause 
of stroke in the young. Neurol India. 2018;66(1):232-4. DOI: 10.4103/0028-
3886.222859 PMID: 29322992 
44. Stam AH, Kothari PH, Shaikh A, Gschwendter A, Jen JC, Hodgkinson 
S, et al. Retinal vasculopathy with cerebral leukoencephalopathy and 
systemic manifestations. Brain. 2016;139(11):2909-22. DOI: 10.1093/
brain/aww217 PMID: 27604306 
45. Carroll MB. MELAS masquerading as a systemic vasculitis. J Clin 
Rheumatol. 2007;13(6):334-7. DOI: 10.1097/RHU.0b013e31815c2516 
PMID: 18176143 
46. Marrodan M, Acosta JN, Alessandro L, Fernandez VC, Carnero Contentti 
E, Arakaki N, et al. Clinical and imaging features distinguishing Susac 
syndrome from primary angiitis of the central nervous system. J Neurol 
Sci. 2018;395:29-34. DOI: 10.1016/j.jns.2018.09.029 PMID: 30273791 
47. Younger DS. Central Nervous System Vasculitis Due to Substance Abuse. 
Neurol Clin. 2019;37(2):425-40. DOI: 10.1016/j.ncl.2019.01.012 PMID: 
30952417 
48. Younger DS, Coyle PK. Central Nervous System Vasculitis due to 
Infection. Neurol Clin. 2019;37(2):441-63. DOI: 10.1016/j.ncl.2019.01.002 
PMID: 30952418 
49. Pagnoux C, Hajj-Ali RA. Pharmacological approaches to CNS vasculitis: 
where are we at now? Expert Rev Clin Pharmacol. 2016;9(1):109-16. DOI: 
10.1586/17512433.2016.1112265 PMID: 26559201 
50. de Boysson H, Arquizan C, Touzé E, Zuber M, Boulouis G, Naggara 
O, et al. Treatment and Long-Term Outcomes of Primary Central 
Nervous System Vasculitis. Stroke. 2018;49(8):1946-52. DOI: 10.1161/
STROKEAHA.118.021878 PMID: 29986936 
51. Daikeler T, Tyndall A. Primary angiitis of the central nervous 
system-a territory about to be discovered. Rheumatology (Oxford). 
2017;56(12):2258. DOI: 10.1093/rheumatology/kex408 PMID: 29040748 
52. Hajj-Ali RA, Calabrese LH. Primary angiitis of the central nervous system. 
Autoimmun Rev. 2013;12(4):463-6. DOI: 10.1016/j.autrev.2012.08.004 
PMID: 22971519 
636
NEUROLOGY, NEUROPSYCHOLOGY, NEUROPHYSIOLOGY
Zdrav Vestn | November – December 2021 | Volume 90 | https://doi.org/10.6016/ZdravVestn.3092
53. Hammad TA, Hajj-Ali RA. Primary angiitis of the central nervous system 
and reversible cerebral vasoconstriction syndrome. Curr Atheroscler Rep. 
2013;15(8):346. DOI: 10.1007/s11883-013-0346-4 PMID: 23793732 
54. Beelen J, Benseler SM, Dropol A, Ghali B, Twilt M. Strategies for 
treatment of childhood primary angiitis of the central nervous system. 
Neurol Neuroimmunol Neuroinflamm. 2019;6(4):e567. DOI: 10.1212/
NXI.0000000000000567 PMID: 31355303 
55. Mukhtyar C, Guillevin L, Cid MC, Dasgupta B, de Groot K, Gross W, et 
al.; European Vasculitis Study Group. EULAR recommendations for the 
management of primary small and medium vessel vasculitis. Ann Rheum 
Dis. 2009;68(3):310-7. DOI: 10.1136/ard.2008.088096 PMID: 18413444 
56. de Boysson H, Parienti JJ, Arquizan C, Boulouis G, Gaillard N, Régent 
A, et al. Maintenance therapy is associated with better long-term 
outcomes in adult patients with primary angiitis of the central nervous 
system. Rheumatology (Oxford). 2017;56(10):1684-93. DOI: 10.1093/
rheumatology/kex047 PMID: 28340158