Primary Angiitis of the CNS (PACNS)

  • Uncommon vasculitis with unknown etiology, restricted to the brain and spinal cord.
  • Incidence estimated between 2-4 cases per 1,000,000 person-years, equal in both sexes.
  • May occur at any age. Median age is 50 years, 50% of patients are 37-59 years old.
  • Unknown pathogenesis.
    • Infectious agents (VZV, others) have been proposed as triggers.
    • Matrix metalloproteinases (especially MMP-9), seem to be implicated in animal models of vasculitis.
    • A link exists between PACNS and cerebral amyloid angiopathy. The inflammatory reaction to amyloid β varies from no inflammation, to perivascular infiltrates, to granulomatous vasculitis (as seen in ABRA). APOE ε4/ε4 genotype is overrepresented in patients with cerebral amyloid angiopathy-related inflammation
  • Affects small and medium-sized vessels. Three histopathologic subtypes have been reported:
    1. Granulomatous (58%)
    2. Lymphocytic (28%)
    3. Necrotising (14%)
  • About 4% of patients present with a solitary tumor-like mass lesion. About 29% of those have amyloid angiopathy. The surgical excision of the lesion can be curative for some.
  • About 11-12% of patients present with intracranial hemorrhage (intracerebral or subarachnoid).
  • Spinal cord involvement may be seen in up to 5% of cases but is rarely isolated.
    • The thoracic cord is most frequently affected part
  • Angiographically-negative, biopsy-positive vasculitis has better prognosis.
    • Most patients with angiographically-negative PACNS will respond to corticosteroids +/- immunosuppressants.
    • Patients with large vessel involvement respond poorly to conventional immunosuppressive treatment and require treatment with cyclophosphamide.

Clinical manifestations

The clinical course may be acute, subacute, progressive, or relapsing-remitting.


In decreasing frequency:


  • Altered cognition
  • Headache
  • Hemiparesis
  • Stroke
  • Aphasia
  • TIA
  • Ataxia
  • Seizures
  • Visual symptoms (any kind)
  • Visual defect
  • Diplopia
  • Blurred vision
  • Amaurosis fugax or other monocular symptoms
  • Papilloedema
  • Intracranial hemorrhage
  • Amnestic syndrome
  • Paraparesis or quadriparesis
  • Parkinsonism or other extrapyramidal signs
  • Constitutional symptoms
  • Fever
  • Nausea or vomiting
  • Vertigo or dizziness
  • Dysarthria
  • Unilateral numbness

Diagnosis

  • Cerebral and meningeal biopsy is the gold standard for diagnosis of PACNS.
    • Carries a 1% risk of neurologic sequelae if done by an experienced neurosurgeon.
    • An optimum biopsy should contain dura, pia, cortex and white matter.
    • Arteries are affected segmentally. A negative biopsy does not exclude the diagnosis.
    • Reported sensitivity is between 53% and 63%. Radiologic targeting may increase its accuracy.
    • Deeper lesions can be biopsied stereotactically but this is rarely necessary.
  • Angiography has overall low sensitivity and specificity (both about 25-35%).
  • Diagnosis should never be made based on angiographic features alone.
  • Angiographic features suggestive of PACNS:
    • Alternating areas of narrowing and dilatation.
    • Arterial occlusions affecting many cerebral vessels in the absence of proximal vessel atherosclerosis or other abnormalities.
    • Microaneurysms (rare).
    • Delayed arterial emptying and anastomotic channels.
    • Multiple abnormalities in a single artery, or one type of abnormality in multiple arteries are less consistent with PACNS.
  • MRI sensitivity is 93-100%. PACNS is very unlikely if MRI is normal, however, rare cases with normal MRI have been reported.
  • MRI findings are nonspecific:
    • Cortical/subcortical infarcts are the most common lesion, are often multiple, bilateral
    • White matter T2/FLAIR hyperintensities
    • Micro/macrohemorrhages (parenchymal or subarachnoid)
    • Parenchymal and/or leptomeningeal enhancement
    • Tumor-like mass lesions (uncommon)
    • Vessel-wall imaging may reveal vessel wall thickening and intramural enhancement.
      • Vasculitic thickening and enhancement is typically concentric.
      • Atherosclerotic plaques may enhance, eccentrically.
  • CSF analysis is abnormal in 73-90% but the alterations are nonspecific:
    • Mild pleocytosis, often monocytic
    • Mildly (or rarely, greatly) raised protein

Angiographic mimics of PACNS

  • Reversible Cerebral Vasoconstriction Syndrome (RCVS)
  • Intracranial atherosclerosis
  • Multiple cerebral emboli
  • Subarachnoid haemorrhage
  • Drug-related vasospasm
  • CADASIL
  • Migraine
  • Intravascular lymphoma
  • Sickle cell disease
  • Antiphospholipid syndrome
  • Marfans’ syndrome, Ehlers-Danlos syndrome
  • Moyamoya
  • Radiation vasculopathy
  • Posterior Reversible Encephalopathy Syndrome (PRES)
  • Severe hypertension

Treatment

A treatment algorithm for PACNS (Salvarani et al. 2015) has been proposed. The algorithm differentiates between small-vessel (angiography-negative biopsy-positive) and large-vessel (angiography-positive) disease.


  • Small/distal vessel disease
    • Angiography negative and biopsy positive
    • Prominent leptomeningeal enhancement on MRI, in absence of cerebral infarcts
    • Aβ-related angitis (ABRA)
    1. Oral prednisone (1 mg/kg per day); for acute onset consider methylprednisolone bolus therapy (1000 mg per day for 3-5 days
    2. If response: progressive tapering of prednisone
    3. No response: add cyclophosphamide, or oral, or monthly pulse treatment
      • No/insufficient response: consider adding TNF-blocker or rituximab
  • Large/proximal vessel disease
    • Angiography positive (particulary with large/proximal vessel abnormalities)
    • Present with cerebral infarcts
    • Rapidly progressive disease course
      1. Induction therapy: Methylprednisolone bolus therapy (1000 mg per day for 3-5 days), oral prednisone (1 mg/kg per day), and cyclophosphamide (oral 2 mg/kg per day for 3-6 months, or IV 0.75 g/m2 per month for 6 months)
      2. If response: Maintenance therapy with low-dose prednisone with azathioprine (1-2 mg/kg per day), or mycophenolate mofetil (1-2 g per day)
      3. No/insufficient response: Consider adding TNF-blocker or rituximab



References

  • Adult Primary Central Nervous System Vasculitis. The Lancet 380, no. 9843 (August 2012): 767–77 doi: 10.1016/S0140-6736(12)60069-5
  • Management of Primary and Secondary Central Nervous System Vasculitis. Current Opinion in Rheumatology 28, no. 1 (January 2016): 21–28 doi: 10.1097/BOR.0000000000000229
  • An update of the Mayo Clinic cohort of patients with adult primary central nervous system vasculitis: description of 163 patients Medicine (Baltimore). 2015 May;94(21):e738. doi: 10.1097/MD.0000000000000738
  • Adult primary central nervous system vasculitis Lancet. 2012 Aug 25;380(9843):767-77. doi: 10.1016/S0140-6736(12)60069-5