ISCHEMIC STROKE / CLASSIFICATION AND ETIOPATOGENESIS

Primary angiitis of the central nervous system (PACNS)

Created 24/05/2023, last revision 30/06/2023

  • Primary angiitis of the central nervous system (PACNS), also known as primary central nervous system vasculitis, is a rare autoimmune disease that affects the blood vessels exclusively in the brain and spinal cord
  • it is characterized by inflammation of medium to small blood vessels
  • vasculitis results in infarcts, sometimes in combination with hemorrhages (~10%)  [Calabrese, 1997]
  • duration and course of the disease can vary from relatively benign to fulminant forms with high mortality; some individuals may experience relapses or periods of disease activity, while others may achieve long-term remission with appropriate treatment
    • benign forms have been termed BACNS (Benign angiopathy of CNS)
  • interdisciplinary approach to diagnosis and therapy is required (rheumatologist, internist, endocrinologist, neurologist, radiologist, and pathologist)
Primary angiitis of CNS (DSA and CTA)

Etiopathogenesis

  • the exact cause is unclear; cell-mediated autoimmunity is assumed
  • inflammatory involvement of the vascular wall leads to narrowing or occlusion of the arteries (in combination with thrombosis)
  • it is not associated with any known infections or systemic autoimmune disorders

Epidemiology

  • occurs most often in the 4-6th decade (but cases at 7 months or 78 years of age have also been described)
  • males: females ratio 7:3
  • PACNS as a cause of stroke is very rare (< 0.2% of all strokes)

Clinical presentation

PACNS has a variable course in terms of the spectrum of symptoms, severity and rate of progression

  • course
    • usually progressive with an accumulation of CNS lesions and worsening deficits
    • less common is a remitting (15%) or oligosymptomatic course (benign PACNS)
  • symptoms
    • headache (~60%), usually chronic, progressive
      • thunderclap-headache is more likely to be indicative of RCVS
    • encephalopathy
      • altered level of consciousness (~50%)
      • cognitive impairment, behavioral changes
      • epileptic seizures (~15%)
    • infarcts with focal symptoms
      • paresis, aphasia, ataxia, sensory disturbances, etc.
      • visual disturbances (from nonspecific to hemianopsia)
      • spinal symptoms (~5-14%)    [Calabrese, 1997]
  • PACNS has no clinical signs of involvement of other systems; when they are found, consider other vasculitis
    • rash, purpura, arthritis (polyarteritis nodosa or Churg-Strauss)
    • sinusitis, pulmonary involvement (PGA)
    • oral and genital ulcerations, uveitis (Behcet’s disease)
    • lymphadenopathy and arthritis (sarcoidosis)

Diagnostic evaluation

In general, PACNS is very rare and extremely difficult to diagnose. It occurs predominantly in younger patients without traditional vascular risk factors and the manifestation of systemic disease. A thorough evaluation is required, including a detailed medical history, physical examination, blood tests, brain imaging, and a cerebrospinal fluid analysis. To confirm the diagnosis, a brain biopsy should be performed.

Diagnostic criteria [Calabrese, 1988]
  • a neurologic deficit that cannot be explained by another more probable disease
  • the presence of vasculitic changes on vascular imaging (including vessel wall imaging) and/or histology
  • absence of systemic vasculitis
  • absence of other disorders explaining the abnormal vascular imaging

Laboratory tests

  • ESR, CRP – mild elevation or normal
    • may be normal in PACNS; significant elevation should lead to suspicion of secondary vasculitis
  • CSF
    • initially normal findings; in the later course, hyperproteinorachia and mild lymphocytic pleocytosis (in 80-90%), reflecting aseptic meningitis  [Hajj-Ali, 2015]
      • in contrast to PACNS, patients with RCVS  have negative CSF findings
    • sometimes positive oligoclonal bands
    • no tumor cells, no signs of bacterial or viral inflammation
  • blood tests to exclude other vasculitides

Neuroimaging

Vascular imaging

Angiography (CTA/MRA/DSA) and neurosonology

  • CTA
    • performed as the baseline imaging (from the aortic arc)
    • segmental stenoses/occlusions + potential aneurysmal enlargement of small and medium-sized vessels without accompanying calcifications (rule out the combination of vasculitis and atherosclerotic involvement)
      • DDX  of premature atherosclerosis – atherosclerotic involvement in typical localization (bifurcation, siphon, M1 segment of MCA) + calcifications
    • may be negative in case of small-sized vessels involvement
  •  DSA
    • nonspecific findings similar to CTA
    • more sensitive in case of smaller vessels involvement;   negative DSA should lead to the indication of biopsy in case of clinical suspicion of PACNS (in many cases, mainly the penetrating vessels are affected, where AG findings are negative)
  • MRA – not sensitive enough to detect lesions of small and medium-sized arteries
  • neurosonography
    • detection of intracranial stenoses on Doppler (nonspecific finding)
    • ultrasound may be used to diagnose and monitor stenosis dynamics (or to differentiate spasm and RCVS)

Vessel wall imaging

  • post-contrast high-resolution dark (black) blood MRI sequences
  • wall imaging must be assessed with caution
    • enhancement does not always reflect an underlying vasculopathy or vasculitic origin (Kang, 2021)
    • false-positive findings can occur:
      • due to poststenotic low flow
      • after mechanical recanalization
      • due to leptomeningeal enhancement or enhancement of organized thrombus
PACNS

Primary angiitis of the central nervous system (PACNS)

Brain imaging
  • brain CT
    • nonspecific findings – infarcts and/or leukoaraiosis, possibly hemorrhage
  • brain MRI
    • nonspecific findings –  infarcts localized cortically, in basal ganglia or periventricular white matter (usually multiple and bilateral) – hyperintense on T2 and FLAIR  Periventricular lesions in PACNS
    • sometimes postcontrast enhancement of lesions and leptomeningeal enhancement can be seen (area ideal for biopsy)
    • repeated examinations allow monitoring of disease dynamics (including DWI sequences)
PET or PET/CT

Biopsy

  • a positive biopsy is the only confirmation of a “definitive” diagnosis of PACNS (in the absence of biopsy or negative findings, we can talk about “possible” CNS vasculitis)
    • inconsistency between AG findings and biopsy findings is quite common; a false negative biopsy is common – due to segmental involvement, a healthy artery segment may be captured [McVerry, 2017]
    • a positive biopsy is described in approximately 9-36% of cases
    • even with a “positive” biopsy, infection or malignancy must be excluded
    • the biopsy is also of differential diagnostic importance as it allows to exclude diseases with similar clinical and radiological manifestations
      • in one study, 36% of the patients had vasculitis, 25% had negative findings, and 39% had other etiologies (lymphoma, SM, infection) [Alrawi, 1999]
      • according to another paper, PACNS was found in only 11% of suspected patients, and in 30%, other etiologies were found (encephalitis, lymphoma, CAA)   [Torres, 2016]
  • If possible, take the biopsy from a lesion seen on MRI (ideally in the area of confluent leptomeninges), otherwise from the F or T lobe pole of the non-dominant hemisphere
    • open biopsy is more productive compared to stereotactically guided punch biopsy [Torres, 2016]
  • biopsy should include a sample of dura and leptomeninges (higher detection of changes in blood vessels), cortex, and white matter
  • histological findings:
    • lymphocytic infiltrates with histiocytes and plasma cells, mainly in the intima and media
    • detection of large cells (giant cells) is frequent but not essential for diagnosis
    • the adventitia is thickened and contains inflammatory cells expanding into the subarachnoid space
  • serious complications < 4%  [Torres, 2016]

Differential diagnosis

Management

  • treatment for PACNS aims to reduce inflammation, control symptoms, and prevent long-term complications.
  • a quick decision on the initiation of immunosuppressive therapy in progressive forms without a definitive diagnosis of PACNS is especially challenging
  • the course of the disease or treatment cannot be reliably monitored by laboratory markers
  • it is problematic to distinguish permanent residual CNS damage from an ongoing inflammatory process (this may result in an erroneous escalation of immunosuppression with side effects)
  • there are no randomized trials for treatment; we rely on expert consensus opinion
  • glucocorticoids (GC) and immunosuppressive drugs are the mainstay of therapy
    • immunosuppression puts the patient at risk of numerous complications (always carefully weigh early tapering and the true necessity of escalation)
  • experience grows with additional biological therapy (rituximab, tocilizumab) in severe progressive conditions or if the first-line therapy is not tolerated

Immnusosupresive therapy

I.Remission induction
(duration 2-6 months, until clinical and radiological remission is achieved)

PREDNISONE  – 1 mg/kg/day PO or IV bolus 1g/d of SOLUMEDROL  (3-5 days)
CYCLOPHOSPHAMIDE (CYC)  – 2 mg/kg/day (max 200mg/d) nebo monthly pulses of 750 mg/m2  (for 3-6 months)

Biological therapy (can be used in case of intolerance or resistance to conventional treatment, or in combination with CYC in the severe course)

  • tumor necrosis factor–α blockers
    • infliximab (INFLECTRA) – a single infusion of 5 mg/kg
    • etanercept (ENBREL) – 25 mg twice a week for 20 months, then 25 mg/kg once a week for 8 months
  • rituximab (MABTHERA) – antibody against CD20 B-lymphocyte antigen [Patel, 2018]
  • tocilizumab (ROACTEMRA)  – IL-6 receptor antibody
  • fewer relapses and perhaps better outcome have been described with the combination of GC+CYC   [Salvarani, 2015]
  • in patients with a more severe course, prefer combination therapy from the start + initial IV bolus of GC  [Beuker, 2018]
  • concomitant gastric protection and monitoring of adverse events are necessary
  • induction of remission should last 2-4 months  [Beuker, 2018]

Standard secondary stroke prevention

  • same as with other types of stroke
  • antiplatelet therapy
    • ASA or CLP
    • no hard data on the use of DAPT
  • aggressive management of vascular risk factors (statin, ACE-I, etc.)
  • adequate hydration (risk of hypoperfusion, e.g., after diarrhea, febrile episodes, etc.)
  • physical and occupational therapy

Interventional procedures

  • little experience; most of the angioplasty studies had cerebral vasculitis as a contraindication
  • angioplasty may be considered in a malignant course to treat the most severe symptomatic stenosis
    • isolated case reports  [Latacz, 2019]
    • worse results compared to atherosclerotic lesions (McKenzie, 1996)

Monitoring

Monitoring of disease activity

  • difficult in general, as there is no specific laboratory marker of disease activity
  • monitor neurostatus (new focal deficit?)
  • MRI follow-up
    • to exclude new, clinically silent ischemias during glucocorticosteroid tapering
    • follow-up MRI no later than week 4 after initiation of therapy (within a week for more severe conditions), then 3-4 months after that
    • repeat contrast-enhanced high-resolution MRI – to monitor the resolution of wall inflammation ( only possible in larger arteries – ICA and arteries of the circle of Willis)
  • large and medium-sized arteries can be monitored with TCCD/MRA/CTA (stenosis grade, new-onset stenosis, etc.)

Monitoring of immunosupressive therapy

  • monitoring, prevention, and treatment of side effects of medication
    • CYC – frequent CBC monitoring
    • steroids
      • diabetes screening and management
      • gastric ulcer prophylaxis
      • prevention of osteoporosis
  • change the dosing carefully (risk of premature taper or unnecessary escalation)
  • advice patients to take pneumocystis pneumonia prevention if they are on long-term steroid therapy

Prognosis

  • a favorable outcome can be expected when patients are treated early with a combination of glucocorticoids and cyclophosphamide
  • poor outcome is associated with extensive vascular involvement and multiple strokes
  • rare fulminant variants are associated with high mortality
  • relapses may result in the worsening of neurologic deficit
  • prolonged use of steroids and immunosuppressants is associated with a significant risk of adverse events (hypertension, type 2 DM, osteoporosis, an increased risk of opportunistic infections, etc.)

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Primary angiitis of the CNS (PACNS)
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