blood flow

Normal vs Restricted Blood Flow in the Brain

Cells of the immune system attack the brain blood vessel walls, which leads to swelling and irritation of the wall, restricting the space inside, and reducing blood flow.

Patients with CNS vasculitis can present with:

  • Seizures and intractable seizure status
  • Headaches
  • Stroke or other severe focal neurological deficits including impaired vision, speech deficits or movement abnormalities
  • Severe diffuse deficits such as memory difficulties, cognitive dysfunction or behaviour problems
  • Psychiatric symptoms such as hallucinations
  • Fluctuating level of consciousness 

CNS vasculitis often affects previously healthy children. If the inflammation solely targets the blood vessels of the brain and/or spinal cord in these children, the disease is then referred to as primary CNS vasculitis or childhood Primary Angiitis of the CNS (cPACNS). 

All children require a careful assessment for an associated systemic illness such as an infection, rheumatic disease or malignancy. Children who develop CNS vasculitis in the context of an underlying illness are considered to have Secondary CNS Vasculitis.  

Primary Angiitis of the CNS Secondary Vasculitis of the CNS

Diagnosing CNS Vasculitis: Calabrese criteria

The diagnosis of primary CNS vasculitis / childhood Primary Angiitis of the CNS (cPACNS) requires:

  • A newly acquired focal or diffuse neurological deficit and/or psychiatric symptom in a child > 1 month and <19 years of age plus 
  • Angiographic and/or brain biopsy evidence of CNS vasculitis in the absence of an underlying systemic condition known to cause or mimic the findings 

cPACNS subtypes

CNS vasculitis is subdivided based on the modality that confirms the diagnosis. Children with evidence of vasculitis on angiography are considered to have angiography-positive, large-medium vessel CNS vasculitis. Those who have a negative angiography and evidence of vasculitis solely on brain biopsy are commonly classified as angiography-negative, small vessel CNS vasculitis. Children with evidence of inflammation and suspected CNS vasculitis who have not had a confirmatory test should be classified as "inflammatory brain disease, suspected CNS vasculitis". 

Angiography-positive, large vessel cPACNS

  • Inflammation is targeting the large and medium cerebral vessels.
  • Diagnosis is confirmed by angiography, which may show evidence of cerebral vessel stenosis, beading, tortuosity, and/or occlusion (see References Aviv, 2006; Aviv 2007; Eleftheriou, 2010).
  • Two subtypes of angiography-positive cPACNS are recognized based on disease course: 
    • Non-Progressive cPACNS is a monophasic inflammatory vessel wall disease affecting unilaterally the proximal vessel segments of the anterior and/or middle cerebral artery and/or the distal internal carotid artery. This monophasic inflammatory disease is also known as Transient Cerebral Arteriopathy (TCA), Focal Cerebral Arteriopathy (FCA), and Post-Varicella Angiopathy (PVA).
    • Progressive cPACNS is an ongoing inflammatory disease of the CNS vessels frequently affecting both proximal and distal vessel segments. It may present as a unilateral or bilateral vessel disease. Diagnosis is confirmed on angiography when children either have both proximal and distal vessel stenoses in ≥ 1 vascular territory on initial angiography or have new vessel segments affected on repeat vascular imaging at three months of illness. The latter commonly occurs despite corticosteroid therapy. Fortunately, children with progressive cPACNS on corticosteroid therapy commonly do not acquire new neurological deficits. 
  • Children with angiography-positive CNS vasculitis do not require a brain biopsy; in fact biopsies commonly demonstrate tissue damage due to ischemia.

Angiography-negative, small vessel cPACNS

  • Inflammation is solely targeting the small cerebral vessels. 
  • Diagnosis is confirmed by brain biopsy, which typically demonstrates evidence of intramural and perivascular inflammation. The characteristic inflammatory phenotype is a lymphocytic infiltrate of primarily T-cells, some additional B-cells, macrophages and eosinophils may be found . Fibrinoid necrosis or granulomas are not commonly seen (see References Elbers, 2010; Twilt 2011).
  • By definition, children with small vessel CNS vasculitis have a normal angiography.
  • Different subtypes of small vessel vasculitis may exist. This needs to be further studied.
  • To date, no specific MRI pattern was found to be associated with SV-cPACNS. However, leptomeningeal enhancement appears to be specific for SV-cPACNS, in particular considering demyelinating diseases as a differential diagnoses. Of note: Spinal cord inflammation and optic nerve inflammation are commonly seen in children with SV-cPACNS.  

Diagnosis Criteria for Secondary CNS Vasculitis

Children ≤18 years of age are diagnosed with secondary CNS vasculitis if they have evidence of 

  • Any newly acquired focal and/or diffuse neurological and/or psychiatric deficit plus 
  • Angiography and/or brain biopsy evidence of CNS vasculitis
  • In the presence of an underlying systemic condition such as an infection, rheumatic disease or other

Secondary CNS vasculitis can be caused by  a large number of underlying conditions. Infection is the most common cause for secondary CNS vasculitis.  A thorough evaluation for an underlying systemic condition is required when a child presents with newly acquired neurological and/or psychiatric deficit. 

Causes of Secondary CNS Vasculitis

Infectious/post-infectious

  • Bacterial
    • Mycobacterium tuberculosis
    • Streptococcus pneumoniae
    • Salmonella species
    • Mycoplasma pneumoniae
    • Treponema pallidum
    • Other
  • Spiorochete
    • Borrelia burgdorferi
  • Viral
    • Varicella zoster virus
    • HIV
    • Hepatitis C virus
    • Cytomegalovirus
    • Epstein-Barr virus
    • Parvovirus B19
    • Enterovirus
    • West Nile virus
    • Other
  • Fungal
    • Actinomycosis
    • Candida albicans
    • Aspergillus
    • Other

Systemic rheumatic diseases

  • Systemic lupus erythematosus
  • Systemic vasculitis
    • Anti-neutrophil cytoplasmatic antibodies (ANCA) associated vasculitis
      • Granulomatosis with Polyangiitis (GPA, formerly known as Wegener's granulomatosis)
      • Microscopic polyangiitis (MPA)
      • Eosinophilic Granulomatosis with Polyangiitis (EGPA, formerly known as Churg–Strauss syndrome)
    • Polyarteritis nodosa (PAN)
    • Kawasaki disease
    • Takayasu's arteritis
    • Henoch-Schoenlein purpura (HSP)
  • Behçet's syndrome 
  • Sjögren's syndrome
  • Juvenile Dermatomyositis
  • Scleroderma

Systemic inflammatory diseases 

  • Inflammatory bowel disease
  • Hemophagocytic lymphohistiocytosis (HLH)

Other systemic diseases or exposures

  • Graft-versus-host diseases
  • Radiation
  • Drug-induced CNS vasculitis
  • Haemoglobinopathies
  • Malignancies
  • Other

Differential diagnosis and mimics of Angiography-Positive CNS Vasculitis in Children

  •  Noninflammatory CNS vasculopathies:
    • Dissection
    • Thrombembolic disease
    • Hemoglobin disorders
    • Antiphospholipid antibody (aPL) syndrome
    • Fibromuscular dyplasia
    • Genetic collagen vascular disorders (Marfan Syndrome, Ehlers-Danlos Syndrome, others)
    • Moyamoya disease (idiopathic)
  • Conditions associated with cerebral vasospasms:
    • Channelopathies including familiar hemiplegic migraine and calcium channelopathy
    • Reversible vasoconstrictive syndrome (RVS)
    • Idiopathic vasospasms
  • Genetic syndromes with associated vasculopathy:
    • Neurofibromatosis type 1 (NF1)
    • Down's syndrome
    • Posterior fossa malformations–hemangiomas–arterial anomalies–cardiac defects–eye abnormalities–sternal cleft and supraumbilical raphe syndrome (PHACES)
    • Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)
    • Fabry disease
    • Homocysteinuria
  • Other syndromes with associated cerebral vasculopathy
    • Cogan syndrome (vasculopathy plus inflammatory eye disease [interstitial keratitis] and vestibularauditory dysfunction)
    • Susac syndrome (noninflammatory vasculopathy resulting in retinopathy, hearing loss and encephalopathy)

Differential diagnosis and mimics of Angiography-Negative CNS Vasculitis in Children

  • Nonvasculitic inflammatory brain diseases:
    • Demyelinating diseases (acute demyelinating encephalomyelitis, multiple sclerosis, idiopathic or demyelinating optic neuritis)
    • Antibody-mediated inflammatory brain diseases (anti-NMDAR encephalitis, antibody-mediated limbic encephalitis, neuromyelitis optica, Hashimoto encephalitis, post-mycoplasma encephalitis, celiac-disease-associated encephalitis, Paediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections or PANDAS)
    • T-cell mediated inflammatory brain diseases (Rasmussen's encephalitis)
    • Granulomatous inflammatory brain diseases (Neurosarcoidosis)
  • Infections
    • Tuberculosis
    • JC virus
  • Metabolic diseases with associated inflammatory or ischemic brain lesions:
    • Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)
    • Rolandic mitochondrial encephalomyopathy (ROME)
    • Polymerase gamma deficiency (POL-γ)
  • Malignancies

Angiocentric lymphoma

The above list is modified from M. Twilt ., The spectrum of CNS vasculitis in children and adults. Nat Rev Rheumatol. 2011 Dec 20;8(2):97-107.