Hospital Medicine

Primary angiitis of the central nervous system

Primary angiitis of the central nervous system

I. Problem/Condition.

Cerebral vasculitis is a rare and enigmatic disorder defined by inflammation of the blood vessels of the leptomeninges, brain and/or spinal cord. Inflammation of the cerebral vessels leads to narrowing, occlusion and thrombosis which can then result in ischemia and necrosis. This inflammatory process is typically categorized as primary or secondary.

Primary angiitis of the central nervous system (PACNS) is predominantly confined to the central nervous system (CNS) without affecting other organs, whereas secondary cerebral vasculitis is due to an underlying systemic process, such as infection, malignancy or connective tissue disease, which results in CNS as well as other organ involvement. For the remainder of this review, the focus will be on PACNS.

Epidemiology

PACNS is a rare disorder. The incidence has been estimated at 2.4 per 1,000,000 person-years. Most biopsy proven cases in the literature demonstrate a slight male predominance. Patients of all ages, from children to the elderly, may potentially be affected, but most case series report a median age of onset in the 4th decade.

Clinical presentation

Initial symptoms are often indolent and non-specific, adding to the challenge of diagnosing PACNS. Typically patients develop low-grade progressive headaches and insidious cognitive impairment or altered cognition. Although not necessarily common at symptom onset, most patients will experience focal neurologic symptoms (weakness, sensory loss, vision loss) or transient ischemic attacks (TIAs) or strokes at some point in their course.

Recurrent TIAs or strokes may be a clue suggesting the diagnosis. Patients may also experience seizures, ataxia or a myelopathy if the disease involves the spinal cord.

II. Diagnostic Approach

A. What is the differential diagnosis for this problem?

PACNS has a broad differential.

Major categories to consider include:

  • Reversible cerebral vasoconstriction syndrome (RCVS)

  • Secondary vasculitis or vasculitis mimics due to an underlying systemic process

    • Infectious diseases

      • Bacterial (including Treponema pallidum, Borrelia burgdorferi, Bartonella, Mycobacterium tuberculosis)

      • Viral (including, herpes simplex virus, varicella-zoster virus, hepatitis B, hepatitis C, human immunodeficiency virus (HIV))

      • Fungal (including Aspergillus, Coccidioides, Histoplasma)

      • Parasitic (including cysticercosis)

    • Systemic vasculitis: which can often be further categorized by the vessel size predominantly affected.

      • Small vessel: Churg-Strauss syndrome, giant cell arteritis (Wegener's granulomatosis), microscopic polyarteritis, Henoch-Schonlein purpura, essential cryoglobulinemia

      • Medium vessel: Polyarteritis nodosa, Kawasaki

      • Large vessel: Giant cell, Takayasu's arteritis

      • Other: Behcet's disease (vasculitis that can affect vessels of all sizes)

    • Connective tissue diseases: (Note the underlying pathology is not always due to inflammatory changes. Systemic lupus erythematosus, for example, rarely causes CNS vasculitis, but more typically causes a vasculopathy with small vessel thickening, hyalinization and thrombosis.)

      • Systemic lupus erythematosus

      • Sjogren's syndrome

      • Rheumatoid arthritis

      • Scleroderma

      • Mixed connective tissue disease

    • Malignancy

      • Intravascular lymphoma

      • Primary CNS lymphoma

      • Hodgkin's and non-Hodgkin's lymphoma

      • Multifocal glioma

      • Paraneoplastic syndromes

    • Other

      • Sarcoidosis

      • Antiphospholipid antibody syndrome

      • Cardiac myxoma

      • Cholesterol atheroembolism

      • Radiation vasculopathy

      • Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

      • Mitochondrial encephalopathy, lactic acidosis and stroke syndrome (MELAS)

B. Describe a diagnostic approach/method to the patient with this problem

Two key questions should be addressed when confronted with a suspected case of PACNS:

  1. Is this reversible cerebral vasoconstriction syndrome?

  2. Is this secondary to an underlying systemic process?

Consider PACNS a diagnosis of exclusion, as secondary causes of CNS vasculitis are much more common.

1. Historical information important in the diagnosis of this problem.

During the history, establish the patient's constellation of signs and symptoms and focus on eliciting information that could suggest an underlying systemic process (infectious, systemic vasculitis, connective tissue disease, etc.). The tempo and course of symptoms can be helpful as well.

In RCVS, patients often present with a sudden onset or "thunderclap" headache and tend to have a monophasic course as opposed to PACNS, where patients tend to have slowly progressive headaches and a chronic course.

Specific questions which may be helpful, include the following:

  • Do you have headaches? If so, describe the quality, severity, progression, and any accompanying symptoms. Did the headaches begin suddenly or would you describe a more gradual, progressive course?

  • Have you ever had any focal neurologic symptoms such as weakness, sensory loss, difficulty with speech, loss of vision, difficulty with balance, or coordination?

  • Have you or your family members noted any personality, behavioral or cognitive changes?

  • Is there any history of seizures or unexplained loss of time or loss of consciousness events?

  • Have there been any preceding infectious symptoms? Fever, chills, sweats, weight loss? Any notable travel history? Any risk for immunosuppression?

  • Has there been any use of illicit drugs (especially stimulants) or vasoactive medications (including triptans, selective serotonin reuptake inhibitors)?

  • Do you have any arthralgias or rashes?

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

While there are no specific physical examination maneuvers to diagnose PACNS, a thorough general exam is imperative, particularly searching for the suggestion of any underlying systemic process.

A careful skin exam may reveal signs of systemic vasculitis such as palpable purpura (seen in various systemic vasculitic syndromes and collagen vascular disease), livedo reticularis (seen in multiple vasculitis mimics including systemic lupus erythematosus and antiphospholipid antibody syndrome) or genital or mucosal ulcers (seen in Behcet's).

Fundoscopic exam should be done to look for evidence of infection, sarcoidosis or suggestion of retinal vasculitis.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

The diagnostic tools in PACNS are limited by their lack of sensitivity and specificity and there is no one laboratory result or imaging finding that can make the diagnosis. Brain biopsy is the gold standard for establishing the diagnosis, but as noted below, this too is an imperfect diagnostic tool.

Rather, the constellations of results should suggest the diagnosis, in part by ruling out evidence of other systemic mimics. Should suspicion of PACNS persist after initial laboratory studies, cerebrospinal fluid (CSF) and neuroimaging, further evaluation with a cerebral catheter angiogram and/or brain biopsy should be considered.

Laboratory evaluation

Again, laboratory studies will not establish the diagnosis, but may prove useful by excluding other potential diagnoses such as systemic vasculitis, connective tissue disease or infection. In PACNS, typically, all of the tests listed below will be normal/unremarkable. Of note, serologic testing for systemic vasculitides is rarely useful unless the history or exam have suggested the diagnosis.

However, if there are underlying laboratory abnormalities, suspicion would increase for an alternative diagnosis (e.g. an elevated erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP] might suggest a systemic infectious or inflammatory process).

Studies to consider, include the following:

  • Complete blood count with differential

  • Basic metabolic panel and liver function tests

  • Urinalysis and urine toxicology screen

  • ESR, CRP

  • Anti-nuclear antibody, anti-Ro/SSA, anti-La/SSB, rheumatoid factor

  • Antineutrophil cytoplasmic antibodies (ANCAs)

  • Hypercoagulable states including: antiphospholipid antibodies, anti-beta 2 glycoprotein

  • HIV, hepatitis, syphilis serologies, blood cultures

Should the clinical context be suggestive, further serologies looking for specific infectious agents may also be indicated (e.g. if the patient spent time in prison or has an exposure history, further assessment for mycobacterium tuberculosis might be warranted with placement of a purified protein derivative, PPD, and/or serologic testing with quantiFERON).

Cerebrospinal fluid

Analysis of CSF is an essential component of the evaluation. Results of lumbar puncture are abnormal in 80-90% of patients with biopsy confirmed PACNS. Classically there is a mild lymphocytic pleocytosis (median leukocyte count 17-55cells/ml) and elevated protein (median total protein 98-100 mg/dl).

As with laboratory studies, CSF analysis also aids in excluding vasculitis mimics such as infectious diseases and malignancy.

CSF should be sent for the following:

  • Cell count and differential, protein, glucose

  • Bacterial, fungal, mycobacterial cultures

  • Venereal Disease Research Laboratory (VDRL) test (evaluating for syphilis)

  • Flow cytometry and cytology (evaluating for malignancy)

  • Herpes simplex virus polymerase chain reaction (PCR), varicella-zoster virus (VZV) PCR (and consider VZV serum/CSF ratio of immunoglobulin (IgG) if high clinical suspicion) and other infectious agents suggested by the clinical history

Neuroimaging

While fraught with a lack of specificity, brain imaging remains a key element of the diagnosis of PACNS. Magnetic resonance imaging (MRI) offers better sensitivity than computed tomography (CT), and MRI should be performed with contrast. MRI findings typically include multiple, often bilateral, infarcts within the gray and white matter, with or without contrast enhancement and sometimes with meningeal enhancement.

In a case series of 90 patients with PACNS diagnosed by biopsy or cerebral angiography, MRI abnormalities were found in 97% of patients. The most common MRI abnormality was cortical or subcortical infarcts in 53% of patients, and of those with infarcts, 85% had multiple infarctions. Intracranial hemorrhage was much less common, seen in only 8%. Rarely, PACNS can also present with a tumor-like mass lesion.

While MRI alone cannot make the diagnosis, it is important to note that a normal MRI, combined with normal CSF results, has a high negative predictive value, and will essentially exclude the diagnosis of PACNS.

If suspicion for PACNS remains high after initial evaluation with laboratory studies, CSF and contrast-enhanced MRI, cerebral catheter angiography should be performed. Angiography is considered the gold-standard imaging modality to detect vessel abnormalities associated with vasculitis. The classic findings are multi-focal areas of vessel irregularity with areas of stenosis alternating with dilatation, often referred to as "beading".

With PACNS, the vessel abnormalities are typically seen in small to medium caliber vessels, and less commonly in large vessels. While angiography is better at picking up abnormalities in small and medium-sized vessels when compared to MRI, the diagnostic utility of angiography should not be overestimated, as it too may miss the diagnosis and be normal in 50% of biopsy-proven cases, likely because even angiography lacks the spatial resolution to pick up some small vessel changes.

Caution is further advised with angiography because of poor specificity. One study of 38 patients who underwent both angiography and biopsy found that of the 14 patients with typical angiographic findings of vasculitis, none of them had PACNS at brain biopsy. The poor specificity of angiogram is due to the myriad of entities that can mimic the appearance of vasculitis, such as cerebral vasospasm, intracranial atherosclerosis and CNS infection.

A potential emerging imaging technique for patients with suspected PACNS is high-resolution intracranial arterial wall contrast-enhanced MRI, commonly known as "black-blood" sequences. As opposed to traditional angiography that only visualizes the vessel lumen, this nascent imaging technique offers the ability to visualize the part of the brain affected by PACNS: the vessel wall.

While more studies are needed to determine the sensitivity and specificity of arterial wall imaging for diagnosing PACNS, preliminary evidence suggests that vasculitis can be distinguished from intracranial atherosclerosis by the pattern of wall thickening and contrast enhancement. Vasculitis results in smooth circumferential concentric wall thickening and enhancement of the intracranial vessel wall versus the eccentric irregular wall thickening and enhancement seen with intracranial atherosclerotic plaque. Small case series also suggest that high resolution MRI vessel wall imaging may distinguish PACNS from RCVS.

Brain biopsy

Ultimately the diagnosis of PACNS depends upon histopathology that demonstrates inflammation of the blood vessels within the leptomeninges, brain and/or spinal cord without evidence of a secondary etiology such as infection, malignancy or systemic vasculitis. There are several pathological patterns that have been described: granulomatous, lymphocytic and acute necrotizing.

Granulomatous vasculitis is characterized by mononuclear infiltration within the vessel wall with well-formed granulomas and multinucleated giant cells. Lymphocytic has a predominantly lymphocytic inflammation throughout the vessel wall and acute necrotizing, the least commonly seen, is characterized by transmural fibrinoid necrosis.

PACNS associated with cerebral amyloid angiopathy (CAA) has also been described. In these cases there is an inflammatory response to vascular amyloid. The degree of inflammatory response ranges from perivascular inflammation to a true vasculitis with inflammation involving the vessel wall.

The utility of brain biopsy in PACNS is both in potentially offering a definitive diagnosis, but also, perhaps more importantly, in excluding other conditions that would require different treatment, such as infection, malignancy or neurodegenerative disease.

Biopsy should be considered whenever a patient continues to clinically decline despite initial treatment with prednisone or whenever escalating therapy to longer-term "steroid-sparing" immunosuppression is considered, as immunosuppression has significant morbidity associated with it and could potentially worsen underlying conditions such as infection.

Important questions to consider prior to pursuing biopsy, include the following:

  • Will biopsy be diagnostic?

Unfortunately because PACNS tends to be a focal and segmental disease, there is a considerable likelihood of sampling error with biopsy, and false negatives can be as high as 25%. Biopsy may be diagnostic for alternative etiologies in 30-40% of patients. In one series of 61 patients who underwent biopsy for suspected PACNS, 28% had definite PACNS, 8% had probable PACNS, 39% had alternative diagnoses (infection, primary CNS lymphoma, non-lymphomatous tumors, Creutzfeldt-Jakob disease, multiple sclerosis, non-infectious encephalitis, sarcoidosis, sterile infarct, and arteriovenous malformation), and 25% were non-diagnostic.

  • What is the morbidity associated with biopsy?

Morbidity is estimated at 2-4% for major events such as hemorrhage or new focal deficit post-biopsy.

  • Where to biopsy?

To obtain the highest yield from biopsy most sources recommend targeting a lesion identified on imaging and including leptomeninges. If there are no imaging lesions amenable to biopsy, the traditional biopsy target is the non-dominant temporal lobe tip including the surrounding leptomeninges.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

Diagnostic criteria for PACNS were initially proposed by Calabrese & Mallek in 1987:

  • Presence of an unexplained neurologic deficit after thorough evaluation

  • Cerebral angiogram and/or histopathology consistent with CNS angiitis

  • No evidence of an alternative explanation, such as systemic vasculitis, for the angiogram or biopsy findings

As emphasized in the last of these criteria, the diagnosis can only made after other processes have been excluded. It is important to keep in mind that PACNS is rare and other systemic disorders remain more prevalent.

One of the key entities to consider in the differential is RCVS. RCVS can be distinguished from PACNS by a number of characteristics. See Table I.

Table I.

Distinguishing reversible cerebral vasoconstriction syndrome from primary angiitis of the central nervous system
Reversible cerebral vasoconstriction syndrome Primary angiitis of the central nervous system
Demographic 2:1 female Male predominance
Clinical onset Acute Subacute to chronic
Headache Severe, "thunderclap" Insidious, progressive, dull ache
Cerebrospinal fluid Typically normal (assuming no subarachnoid hemorrhage) Abnormal in 80-90% with lymphocytosis and elevated protein
Precipitants Drug or vasoactive substance exposure, postpartum, catecholamine secreting tumors, etc. Unknown
Angiogram By definition angiogram is always initially abnormal with segmental narrowing and dilatation affecting small and/or large vessels and angiographic abnormalities should reverse within 4-12 weeks May be normal or may demonstrate beading or other vessel irregularities, typically affecting small vessels
Clinical course Monophasic without new symptoms more than 1 month after clinical onset Typically chronic, in some cases progressive and fatal

After evaluating for possible RCVS, the next step is to evaluate for a systemic process only secondarily affecting the brain. With most systemic disorders, there will be clues from the history, physical exam, laboratory, or imaging work-up to further guide additional investigation.

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

Because PACNS is a diagnosis of exclusion, the majority of diagnostic tests sent are low yield. For example, while it is important to send laboratory studies for connective tissue and systemic vasculitides, without any suggestive clinical history, or physical exam findings, these tests are unlikely to result in a diagnosis.

Overall, making the diagnosis of PACNS requires caution and keen clinical suspicion as there are a number of more common disease mimics and even the tests considered gold standards for the diagnosis of PACNS (catheter angiography and biopsy) suffer from low sensitivity and specificity.

III. Management while the Diagnostic Process is Proceeding

A. Management of primary angiitis of the central nervous system.

It is important to ensure an accurate diagnosis, as alternative systemic processes, such as infection or malignancy, typically require different treatments. It is also imperative to rule-out RCVS, as this diagnosis does not require immunosuppression.

There are no randomized controlled trials comparing therapies for PACNS; treatment protocols are derived from the treatment of systemic vasculitides. Immunosuppressive therapy is considered the mainstay of treatment.

  • If the patient is acutely ill, therapy with intravenous methylprednisolone 1g/day should be initiated for 3 days followed by prednisone 1 mg/kg/day for 1 month with a slow taper over 12 months. Of note, some experts avoid intravenous corticosteroids as they may lead to steroid-induced mental status changes, and prefer to start with prednisone 1 mg/kg/day.

  • If the patient has biopsy confirmed PACNS, treatment with cyclophosphamide should be started with corticosteroids. Cyclophosphamide can be given as a daily oral dose 1.5-2 mg/kg/day or as an intravenous monthly infusion of 600-750 mg/m2. Note, dosing does need to be adjusted for patients with significant renal insufficiency.

Cyclophosphamide should be continued for 3-6 months, depending on the patient's clinical response, and then possibly switched to a less toxic regimen for an additional 6-12 months, such as azathioprine, mycophenolate mofetil or methotrexate.

  • For patients without a clear diagnosis, i.e., those without a biopsy or with inconclusive biopsy results, starting with corticosteroids alone is recommended and then proceeding to brain biopsy and consideration of escalating immunosuppressive therapy with cyclophosphamide if the patient has continued clinical or radiographic progression.

Throughout treatment, patients need to be monitored closely both for adverse effects of therapy (see next section) as well as for progression of disease. Features concerning for possible progression would be continuing or worsening headaches, worsening cognition or new focal deficits (vision change, weakness, sensory loss). Serial screening MRI scans 1 month or so after initiation of therapy and then every few months or until the patient seems to have clinically stabilized should also be performed.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem

Unfortunately, treatments for PACNS are not benign, as immunosuppressive regimens have associated morbidity. This again emphasizes the need for strong clinical suspicion, ideally confirmed by radiographic evidence and biopsy histopathology, prior to starting treatment.

All patients treated with high dose glucocorticoids are at risk for osteoporosis. To help decrease the risk of glucocorticoid-induced osteoporosis all patients should be on calcium 1200 mg/day and vitamin D 800 IU/day, and higher risk populations may also require treatment with bisphosphonates.

Glucocorticoids and cyclophosphamide also increase the risk for opportunistic infections. In particular, patients should receive prophylaxis for Pneumocystis jirovecii.

Cyclophosphamide additionally has a number of other potential risks, including the following:

  • Myelosuppression and leukopenia: a complete blood count should be checked every 2 weeks in patients on oral cyclophosphamide and 7-14 days after each monthly pulsed dose if on intravenous dosing.

  • Gonadal toxicity and teratogenicity.

  • Increased risk of malignancy including hematologic malignancy, skin cancer and bladder cancer.

  • Hemorrhagic cystitis, which is likely related to duration of cyclophosphamide use and is less common with use less than 3-6 months and less common with intravenous pulsed dosing. Mesna administration with cyclophosphamide may help prevent cystitis.

IV. What's the evidence?

Birnbaum, J, Hellmann, DB. "Primary angiitis of the central nervous system". Arch Neurol. vol. 66. Jun 2009. pp. 4607-9.

Calabrese, LH, Dodick, DW, Schwedt, TJ, Singhal, AB. "Narrative review: reversible cerebral vasoconstriction syndromes". Ann Intern Med. vol. 146. Jan 2007. pp. 34-44.

Ducros, A, Bousser, MG. "Reversible cerebral vasoconstriction syndrome". Pract Neurol. vol. 9. Oct 2009. pp. 256-67.

Hajj-Ali, RA. "Primary angiitis of the central nervous system: differential diagnosis and treatment". Best Pract Res Clin Rheumatol. vol. 24. Jun 2010. pp. 413-26.

Hajj-Ali, RA, Calabrese, LH. "Central nervous system vasculitis". Curr Opin Rheumatol. vol. 21. Jan 2009. pp. 10-8.

Salvarani, C, Brown, RD, Calamia, KT, Christianson, TJ, Huston, J, Meschia, JF. "Rapidly progressive primary central nervous system vasculitis". Rheumatology (Oxford). vol. 50. Feb 2011. pp. 349-58.

Salvarani, C, Brown, RD, Calamia, KT, Christianson, TJ, Weigand, SD, Miller, DV. "Primary central nervous system vasculitis: analysis of 101 patients". Ann Neurol. vol. 62. Nov 2007. pp. 442-51.

Scolding, NJ. "Central nervous system vasculitis". Semin Immunopathol. vol. 31. Nov 2009. pp. 527-36.

Obusez, EC, Hui, F, Hajj-Ali, RA, Calabrese, LH, Hammad, T, Jones, SE. "High-resolution MRI vessel imaging: spatial and temporal patterns of reversible cerebral vasoconstriction syndrome and central nervous system vasculitis". AJNR AM J Neuroradiol. vol. 35. Aug 2014. pp. 1527-32.

Salvarani, C, Brown Jr, RD, Calamia, KT, Christianson, TJH, Huston III, J, Meschia, JF. "Primary central nervous system vasculitis: comparison of patients with and without cerebral amyloid angiopathy". Rheumatology. vol. 47. Aug 2008. pp. 1671-77.

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