History & Epidemiology

Vasculitis is a general term for a group of uncommon diseases that feature inflammation of the blood vessels. Central nervous system (CNS) vasculitis refers to vasculitis of the blood vessels in the brain and spinal cord. Because these blood vessels are so important to the function of the CNS, vasculitis can lead to a wide range of neurological symptoms.

Differentiating between primary angiitis of the CNS (PACNS), also known as primary CNS vasculitis, and CNS vasculitis due to secondary causes is important.1 Secondary CNS vasculitis etiology may be related to:2

  • Viral infections, including varicella zoster virus (VZV)
  • Bacterial triggers, including mycoplasma
  • Connective tissue disorders, including systemic lupus erythematosus (SLE)

Limited epidemiology data suggest that CNS vasculitis is rare with an annual incidence rate of 2.4 cases per 1 million persons a year.2 Classically, CNS vasculitis affects men more than women.1 CNS vasculitis has a median onset age of roughly 50 years.1 A systematic review revealed that the CNS vasculitis mortality rate is 8 to 23%.3

CNS Vasculitis Diagnosis & Presentation

The most common presenting symptom of CNS is headache.2 However, a history of “thunderclap” headache is not typically consistent with CNS vasculitis, and an alternate diagnosis should be investigated in these cases.1

Other CNS vasculitis symptoms include focal neurological defects, such as:2

  • Cognitive dysfunction
  • Stroke
  • Aphasia
  • Visual symptoms
  • Ataxia

The onset of CNS vasculitis is typically insidious, and its track usually progresses slowly.2 Diagnostic criteria for primary CNS vasculitis have been proposed and include1,2:

  • Unexplained acquired neurologic deficit after extensive evaluation of other causes
  • CNS vascular damage confirmed in angiography or histopathological examination, or both
  • No evidence of any other system vasculitis or any other disorders to which the angiographic or histopathologic features can be secondary

Diagnostic Workup

The CNS vasculitis diagnosis is typically difficult, and the CNS vasculitis workup requires clinical, laboratory, and radiologic approaches.2 All patients suspected of having CNS vasculitis should also undergo evaluation for stroke, which may include an electrocardiogram, echocardiography, lipid levels, and diabetes risk stratification.1

From the laboratory findings perspective, assessment of inflammatory markers can be helpful, such as:

  • Erythrocyte sedimentation rate
  • C-reactive protein
  • Rheumatoid factor
  • Anti-neutrophil cytoplasm antibody
  • Laboratory investigation of the cerebrospinal fluid (CSF)1

Inflammatory markers are typically normal in patients with primary CNS vasculitis. CSF analysis has a high negative predictive value for ruling out CNS vasculitis because most patients with CNS vasculitis have at least one abnormality in the CSF.1

From the radiologic findings perspective, conventional angiography is preferred to magnetic resonance angiography (MRA) because it is more sensitive. Abnormal conventional angiography findings may include alternating segments of stenosis and normal or dilated segments and arterial occlusions.2 A brain MRI may be performed; normal brain MRI in conjunction with normal CSF examination makes primary CNS vasculitis an unlikely diagnosis.1

Brain biopsy is considered the gold standard for diagnosis CNS vasculitis; however, primary and secondary vasculitis must still be differentiated if biopsy results are consistent with CNS vasculitis.1

Differential Diagnosis for CNS Vasculitis

The differential diagnosis for CNS vasculitis is broad and includes:

  • Infections, which can mimic CNS vasculitis
  • Neoplasms
  • Systemic inflammatory conditions
  • Genetic conditions1

Infectious CNS vasculitis may occur due to infectious etiologies, such as:

  • Human immunodeficiency virus (HIV)
  • Bacterial etiologies, such as spirochetes and subacute bacterial endocarditis
  • Fungal etiologies, such as aspergillosis.1

Intracranial atherosclerosis and embolic phenomenon are two important mimics of CNS vasculitis and should be carefully considered in the differential diagnosis.1 Additionally, reversible cerebral vasoconstriction syndromes (RCVS) — such as Call-Fleming syndrome, migrainous vasospasm, and postpartum angiopathy — are included in the differential diagnosis.2 Patients presenting with RCVS typically report typically have a history of “thunderclap” headache.1

Management of CNS Vasculitis

Pharmacotherapy

Pharmacologic treatment strategies for CNS vasculitis include the use of glucocorticoids or a mix of glucocorticoids with cyclophosphamide.2 The typical initial dose of prednisone is 1 mg/kg per day or 60 mg daily.1,2 This regimen is tapered over months.1

In patients who do not respond to monotherapy treatment with prednisone or in patients who have a severe initial presentation, cyclophosphamide therapy is added for at least three to six months, and often a 12- to 18-month duration is needed.1,2 Cyclophosphamide may be given intravenously or orally and must be monitored carefully.1 For patients who fail to improve with these treatments, diagnosis should be reevaluated.1

Treatment for CNS vasculitis due to a secondary cause should be directed at addressing that underlying cause.1

Nonpharmacotherapy

Nonpharmacological treatments can help with the symptoms. These include

  •  Physical therapy
  • Occupational therapy
  • Speech therapy
  • Cognitive exercises to boost brain and memory

Monitoring Management of CNS Vasculitis Side Effects

CNS vasculitis treatment response is monitored every three to six months via serial MRI and MRA.2 The two main medications, glucocorticoids and cyclophosphamide, carry many adverse effects that require careful monitoring.4

Glucocorticoids

Adverse effects include:

  • Osteoporosis, fractures, and osteonecrosis
  • Adrenal suppression
  • Cushingoid features
  • Diabetes and hyperglycemia
  • Myopathy
  • Glaucoma and cataracts
  • Psychiatric disturbance
  • Immunosuppression
  • Cardiovascular adverse effects
  • Gastrointestinal adverse effects
  • Dermatologic adverse effects
  • Growth suppression4

Contraindicated with:

  • Known hypersensitivity to glucocorticoids
  • Concurrent administration of live or live-attenuated vaccines
  • Systemic fungal infection
  • Osteoporosis
  • Uncontrolled hyperglycemia
  • Diabetes mellitus
  • Glaucoma
  • Joint infection
  • Uncontrolled hypertension
  • Herpes simplex keratitis
  • Varicella infection
  • Peptic ulcer disease
  • Congestive heart failure
  • Viral or bacterial infections not controlled by anti-infectives4

Advised baseline monitoring includes:

  • Patient’s height and weight
  • Blood pressure
  • Bone mass density
  • Ophthalmologic exam
  • Blood glucose
  • Lipid panel4

Significant drug-drug interactions exist and should be assessed carefully.4

Cyclophosphamide

Common adverse effects include:

  • Hemorrhagic cystitis
  • Amenorrhea
  • Myelosuppression
  • Alopecia
  • Nausea and vomiting5

To prevent hemorrhagic cystitis, patients should be advised regarding adequate intake of fluids.5

Contraindicated with patients who:

  • Have hypersensitivity to cyclophosphamide
  • Have a urinary flow obstructive condition
  • Are pregnant or breastfeeding5

Advised baseline monitoring includes:

  • Complete blood counts (necessary due to the possible adverse effect of myelosuppression)5
  • Urinalysis (recommended due to the possible adverse effect of hemorrhagic cystitis)5
  • Symptoms of cardiac or pulmonary toxicity

References

  1. Byram K, Hajj-Ali R, Calabrese L. CNS vasculitis: An approach to differential diagnosis and management. Curr Rheumatol Rep. 2018;20(37). doi:10.1007/s11926-018-0747-z.
  2. Godasi R, Pang G, Chauhan S, et al. Primary central nervous system vasculitis. In: StatPearls. NCBI Bookshelf version. StatPearls Publishing:2022. Accessed August 23, 2022.
  3. Beuker C, Strunk D, Rawal R, et al. Primary angiitis of the CNS: A systematic review and meta-analysis. Neurol Neuroimmunol Neuroinflamm. 2021;8(6):e1093.doi: 10.1212/NXI.0000000000001093.
  4. Hodgens A, Sharman T. Corticosteroids. In: StatPearls. NCBI Bookshelf version. StatPearls Publishing:2022. Accessed August 23, 2022.
  5. Ogino MH, Tadi P. Cyclophosphamide. In: StatPearls. NCBI Bookshelf version. StatPearls Publishing:2022. Accessed August 23, 2022.