Primary Central Nervous System Vasculitis

Article Author:
Raja Godasi
Article Editor:
Pradeep Bollu
Updated:
10/27/2018 12:31:49 PM
PubMed Link:
Primary Central Nervous System Vasculitis

Introduction

Primary angiitis of the central nervous system (PACNS) is a rare inflammatory disorder of the blood vessels of the brain and the spinal cord without any evidence of systemic vasculitis. PACNS was first described as a distinct clinical entity in 1959, and since, multiple different clinical presentations have been reported. Clinical manifestations of PACNS at the time of diagnosis are non-specific with various presenting symptoms. A headache has been the most common presenting symptom in the majority of the PACNS cases. Other symptoms include focal neurological deficits including hemiparesis, aphasia, numbness, visual symptoms, ataxia, among others.

Etiology

The exact etiology and pathogenesis of PACNS are unknown, but infectious agents such as varicella zoster virus (VZV) have been postulated as one of the triggers. Other proposed causes include the following:

  • Bacterial triggers including Mycoplasma, Rickettsia, Treponema
  • Viral infections including human immunodeficiency virus (HIV), hepatitis C virus, among others
  • Connective tissue disorders and systemic vasculitides including Systemic lupus erythematosus (SLE), Churg-Strauss syndrome, Behcet syndrome, Sjogren syndrome among others.

There is also a notable association between PACNS and cerebral amyloid angiopathy. The amyloid deposition has been identified as a possible trigger for PACNS in animal models.

Epidemiology

Studies which describe the exact epidemiology of this rare disorder have not been done, and the only available data shows an annual incidence rate of 2.4 cases per 1 million person-years. The disorder has also been found to have an equal distribution among both the sexes and the median age of diagnosis of about 50 years.

Pathophysiology

Specific activation of the immune system and more specifically, T cells by various triggers are thought to cause the inflammation of blood vessels in the central nervous system leading to PACNS. Immunohistochemical staining of biopsy samples in PACNS showed an extensive infiltration around the small cerebral arteries by CD45R0+ T cells. Matrix metalloproteinases such as MMP-9 have been described as one of the prime effector molecules in animal models of PACNS.

Histopathology

Histopathology in PACNS shows small and medium vessel vasculitis affecting parenchymal and leptomeningeal arteries. Three different types of vasculitic patterns have been described in PACNS. These include granulomatous type, necrotizing type, and lymphocytic type. The most common type, granulomatous, shows numerous granulomas with multinucleated cells. The necrotizing type presents with fibrinoid necrosis similar, and lymphocytic type shows extensive lymphocytic inflammation with plasma cells.

History and Physical

The onset of PACNS is usually insidious, and the course is slowly progressive. Acute presentations have also been reported but are, however, less common. Symptoms of PACNS are non-specific, and multiple symptoms are usually present at the initial presentation. A headache is the most common presenting symptom; other common presenting symptoms include cognitive dysfunction and stroke. Overall, the presenting symptoms and signs from the most common to the least common include:

  • A headache
  • Cognitive dysfunction
  • Stroke
  • Transient ischemic attack (TIA)
  • Aphasia
  • Visual symptoms including visual field deficits, blurred vision, and double vision
  • Seizures
  • Ataxia
  • Papilledema
  • Intracranial bleeding
  • Amnestic syndrome

A combination of symptoms is usually present in most patients. PACNS should always be considered as a possibility in cases of rapidly progressive cognitive decline and personality changes of unknown etiology.

Evaluation

Diagnosis of PACNS is difficult due to the absence of a biomarker in the setting of a variety of non-specific presentations. Laboratory investigations like erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor, anti-neutrophil cytoplasm antibody (ANCA) are neither sensitive nor specific for the diagnosis of PACNS. The only useful laboratory investigation is cerebrospinal fluid (CSF) examination which shows an abnormality in more than 90% of the cases. A mild increase in the leukocyte count or total protein or both is seen in a majority of cases. Radiographic findings are quite useful in cases of PACNS, an abnormal MRI is seen in more than 90% of a case of PACNS, with ischemia being the most common abnormality noted.

The diagnostic criteria for PACNS formulated by Calabrese and Mallek are used for diagnosis, and a diagnosis is made if all of 3 diagnostic criteria are met. These include the presence of an unexplained acquired neurologic deficit after extensive investigation for other causes, the presence of evidence of an inflammatory arteritic process within the CNS by either angiography or histopathological examination or both; and no evidence of any other system vasculitis or any other disorders to which the angiographic or histopathologic features can be secondary.

Henceforth, the principal tools in the diagnosis of PACNS are conventional angiography and central nervous system biopsy. Abnormal findings noted in angiography include alternating segments of stenosis and normal or dilated segments and arterial occlusions. Magnetic resonance angiography (MRA) may be used in the diagnosis instead of conventional angiography. However, it has a lesser sensitivity compared to a conventional angiogram. CNS biopsy can also be used in the diagnosis of PACNS, however, the sensitivity of biopsy is lower and the specificity higher.

A diagnostic approach which combines the clinical, laboratory and radiologic findings with angiography and, if a required biopsy is most prudent.

Treatment / Management

The treatment strategies for primary CNS vasculitis are primarily derived from case reports and cohort studies. In most patients use of glucocorticoids alone or in combination with cyclophosphamide was shown to improve symptoms. The response rates for both monotherapy and combination therapy were found to be similar, around 80%. The general recommendation is to start oral prednisone therapy promptly at the time of diagnosis at an initial dose of 1 mg/kg per day. In nonresponsive cases, cyclophosphamide should be started promptly. The sufficient duration of therapy is 12 to 18 months in most patients. In patients with more severe presentations, 1 gm methylprednisone per day for three days along with cyclophosphamide can be used. However, the evidence of intravenous (IV) steroids being superior to oral regimen has not been noted. Pulses of IV methylprednisone can be given as required for disease flares.

In cases of PACNS resistant to both glucocorticoids and immunosuppressants, tumor necrosis factor-alpha blockers (infliximab, etanercept) and mycophenolate mofetil can be used to treat the disease. These should be used as adjunctive therapy along with the standard therapy. Prophylactic therapy against Pneumocystis jirovecii and osteoporosis should be given to all patients along with the standard therapy.

Serial MRI and MRA every 4 to 6 weeks after initiation of the treatment and then every 3 to 4 months during the first year along with thorough neurological examinations are indicated for monitoring the course of the illness.

Differential Diagnosis

When considering the possibility of a diagnosis of PACNS, it is important to rule out other conditions which can mimic PACNS. These mimicking conditions can be grouped as below

The first group is termed as reversible cerebral vasoconstriction syndromes (RCVS) which include Call-Fleming syndrome, migrainous vasospasm, and post-partum angiopathy. These conditions bear the closest resemblance to primary CNS angiitis. They can be differentiated by their acute onset and normal CSF findings. On further testing, even though angiography may be abnormal in these cases, a biopsy will never show vasculitic changes.

The second group of disorders which can mimic PACNS are secondary CNS vasculitis. This is a broad grouping which encompasses numerous infectious, rheumatic, autoinflammatory disorders along with other disorders which can secondarily cause CNS vasculitis. The infectious causes of secondary CNS vasculitis include bacterial (tuberculosis, syphilis), viral (Epstein-Barr virus, VZV), and fungal (Candida, Aspergillus). The rheumatic and autoinflammatory causes include Churg-Strauss disease, SLE, Behcet syndrome, among others. Other disorders which can cause CNS vasculitis include Moyamoya disease, fibromuscular dysplasia, and radiation vasculopathy. A complete workup for these secondary CNS vasculitides should also be made before confirming a diagnosis of PACNS.

Prognosis

Prognostic indicators from randomized control trials lack cases of PACNS. However, data obtained from retrospective observational studies show favorable outcomes when patients are treated with either glucocorticoids or a combination of glucocorticoids and cyclophosphamide. Some degree of reduction in life expectancy is observed in PACNS cases when compared to general population. Poor outcomes are found to be associated with larger vessel involvement.


References

[1] Younger DS,Coyle PK, Central Nervous System Vasculitis due to Infection. Neurologic clinics. 2019 May;     [PubMed PMID: 30952418]
[2] Chen SH,Sur S,Sedighim S,Kassi A,Yavagal D,Peterson EC,Starke RM, Utility of diagnostic cerebral angiography in the management of suspected central nervous system vasculitis. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. 2019 Apr 2;     [PubMed PMID: 30952556]
[3] Younger DS, Central Nervous System Vasculitis Due to Substance Abuse. Neurologic clinics. 2019 May;     [PubMed PMID: 30952417]
[4] Younger DS, Treatment of Vasculitis of the Nervous System. Neurologic clinics. 2019 May;     [PubMed PMID: 30952416]
[5] Younger DS, Autoimmune Encephalitides. Neurologic clinics. 2019 May;     [PubMed PMID: 30952414]
[6] de Boysson H,Guillevin L, Polyarteritis Nodosa Neurologic Manifestations. Neurologic clinics. 2019 May;     [PubMed PMID: 30952413]
[7] Younger DS, Stroke due to Vasculitis in Children and Adults. Neurologic clinics. 2019 May;     [PubMed PMID: 30952410]
[8] Younger DS, Granulomatous Angiitis: Twenty Years Later. Neurologic clinics. 2019 May;     [PubMed PMID: 30952409]
[9] Younger DS, The Blood-Brain Barrier: Implications for Vasculitis. Neurologic clinics. 2019 May;     [PubMed PMID: 30952407]
[10] Caputi L,Erbetta A,Marucci G,Pareyson D,Eoli M,Servida M,Parati E,Salsano E, Biopsy-proven primary angiitis of the central nervous system mimicking leukodystrophy: A case report and review of the literature. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. 2019 Mar 22;     [PubMed PMID: 30910547]
[11] Sundaram S,Menon D,Khatri P,Sreedharan SE,Jayadevan ER,Sarma P,Pagnoux C,Sylaja PN, Primary angiitis of the central nervous system: Clinical profiles and outcomes of 45 patients. Neurology India. 2019 Jan-Feb;     [PubMed PMID: 30860105]
[12] Wojczal J,Kozera G,Luchowski P,Neubauer-Geryk J, Advantages in diagnosis of giant cell arteritis by ultrasound. Postepy dermatologii i alergologii. 2019 Feb;     [PubMed PMID: 30858775]
[13] Khatri GD,Krishnan V,Antil N,Saigal G, Magnetic resonance imaging spectrum of intracranial tubercular lesions: one disease, many faces. Polish journal of radiology. 2018;     [PubMed PMID: 30800191]
[14] Maggi P,Absinta M,Grammatico M,Vuolo L,Emmi G,Carlucci G,Spagni G,Barilaro A,Repice AM,Emmi L,Prisco D,Martinelli V,Scotti R,Sadeghi N,Perrotta G,Sati P,Dachy B,Reich DS,Filippi M,Massacesi L, Central vein sign differentiates Multiple Sclerosis from central nervous system inflammatory vasculopathies. Annals of neurology. 2018 Feb;     [PubMed PMID: 29328521]
[15] Baulier G,Issa N,Gabriel F,Accoceberry I,Camou F,Duffau P, Guidelines for prophylaxis of Pneumocystis pneumonia cannot rely solely on CD4-cell count in autoimmune and inflammatory diseases. Clinical and experimental rheumatology. 2018 May-Jun;     [PubMed PMID: 29533748]
[16] Barut K,Sahin S,Kasapcopur O, Pediatric vasculitis. Current opinion in rheumatology. 2016 Jan;     [PubMed PMID: 26555448]
[17] Kampylafka EI,Alexopoulos H,Dalakas MC,Tzioufas AG, Immunotherapies for Neurological Manifestations in the Context of Systemic Autoimmunity. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 2016 Jan;     [PubMed PMID: 26510559]
[18] Schuster S,Ozga AK,Stellmann JP,Deb-Chatterji M,Häußler V,Matschke J,Gerloff C,Thomalla G,Magnus T, Relapse rates and long-term outcome in primary angiitis of the central nervous system. Journal of neurology. 2019 Mar 23;     [PubMed PMID: 30904954]