Management of CNS Vasculitis and Takayasu’s Arteritis




CENTRAL NERVOUS SYSTEM VASCULITIS





A 34-year-old woman is admitted to the intensive care unit (ICU) following presentation to the emergency department with slurred speech, right-sided arm and leg weakness, severe headache, and mental status changes. Screening computed tomography (CT) scan in the emergency department showed several subacute ischemic infarctions in a widespread distribution. Initial laboratories were remarkable for an erythrocyte sedimentation rate (ESR) of 40 mm/h and a negative antinuclear antibody (ANA) test. You are asked by the ICU attending to evaluate the patient for possible central nervous system (CNS) vasculitis.


CASE STUDY 1


Introductory Comments


A request to “rule out CNS vasculitis” is often met with a feeling of anxiety. The consulting rheumatologist knows that this is a rare disease, and it is difficult to make the diagnosis with certainty. CNS vasculitis is probably the least commonly encountered form of vasculitis seen by a rheumatologist. The consultant is caught between the fear of missing a serious diagnosis and withholding needed therapy, and just as easily making the diagnosis inappropriately in the setting of a condition that mimics vasculitis and treating the patient too aggressively, with the potential to cause serious iatrogenic harm. There is no gold standard test to lead to the diagnosis, and clinical judgment and experience are of paramount importance. The rheumatologist should never feel alone in the evaluation of a patient with possible CNS vasculitis and should readily obtain the assistance and counsel from colleagues in neurology, vascular medicine, infectious diseases and imaging consultants, among others. To meet the challenge of offering the patient the optimum outcome in this difficult disease requires a team approach.


Several early points need to be covered before we try to address the question of whether our patient has CNS vasculitis. Importantly, CNS vasculitis is not one disease entity but a broad term that is imprecisely applied by too many physicians. Under the banner of CNS vasculitis are myriad vascular based abnormalities that may affect the CNS but do not reflect a true necrotizing vasculitis in etiology.


Our understanding of vasculitis of the CNS over the past decade has grown deeper. Described first almost 50 years ago, CNS vasculitis was considered a fatal disease. As recently as 1988, only 46 cases had been described. The advent of contrast angiography has probably contributed to the increase in diagnosis of CNS vasculitis since the 1970s, but making this diagnosis based solely on angiographic findings is tenuous. Newer imaging modalities have contributed to a far greater sensitivity in identifying CNS ischemia, but the modalities to identify true vascular inflammation as the etiology for that ischemia has not improved concurrently. Simply put, we are far better at identifying ischemia and damage to the brain than we are at identifying its exact etiology.


Our understanding of CNS vasculitis is fraught with many problems. There are no controlled trials that have addressed best practices for either the diagnosis or treatment of CNS vasculitis. There is a paucity of long-term follow-up data on patients diagnosed with CNS vasculitis. We lack an animal study model. Also, there is no classification criteria widely accepted within the rheumatology community for categorizing and reporting on CNS vasculitis. Regardless, a condition originally viewed as inexorably devastating without aggressive treatment is now viewed in a far more nuanced way with an appreciation that CNS vasculopathy has a spectrum of involvement and outcomes.


Definitions and Clinical Subsets


CNS vasculitis has been variously titled, over the past many years, as isolated angiitis of the CNS, primary CNS vasculitis, or primary vasculitis of the CNS ( Table 17-1 ). The currently accepted classification of CNS vasculitis, while still in evolution, can be broadly approached and divided along the following schema, which has helped bring some order to a heterogeneous set of terms and conditions:



Table 17-1

Definitions











Primary angiitis of the central nervous system (PACNS) is vasculitis limited to the CNS (brain, spinal cord, and meninges). Either contrast angiography or pathologic confirmation is employed to make this diagnosis. Should a biopsy be obtained, its results can then be used to further clarify PACNS as either “ Granulomatous Angiitis of the CNS (GACNS)” or “ Non-Granulomatous angiitis of the CNS (NGACNS).” 1
PACNS can be further classified based on the type of study used to make the diagnosis as either “Histologically Defined Angiitis of the CNS (HDACNS)” or “Angiographically Defined Angiopathy of the CNS (ADACNS).” 2
Secondary vasculitis of the central nervous system (SVCNS) is the nosology used to describe those patients with a systemic disease, often a systemic vasculitis or diffuse connective tissue disease, that has features referable to the CNS. SLE with CNS involvement would be a good example.
Reversible cerebral vasoconstriction syndromes (RCVS) is a vasospastic variant of CNS vascular disease. 3 This condition is defined by its reversible nature. This condition has at various times been called isolated benign cerebral vasculitis, benign acute cerebral angiopathy, CNS pseudovasculitis, migraine angiitis, and others. Most recently, it has been titled Benign Angiopathy of the central nervous system (BACNS), which emphasized its better prognosis. 4 RCVS is the current preferred name, reinforcing the concept of vascular process reversibility.

1 Younger DS, Calabrese LH, Hays AP. Granulomatous angiitis of the nervous system. Neurol Clin 1997;15:821.


2 Woolfenden AR, Tong DC, Marks MP, Ali AO, Albers GW. Angiographically defined primary angiitis of the CNS. Is it really benign? Neurology 1998;51:183-8.


3 Calabrese LH, Dodick DW, Schwedt TJ, Singhal AB. Narrative review: Reversible cerebral vasoconstriction syndromes. Ann Intern Med 2007;146:34–45.


4 Calabrese L, Gragg LA, Furlan AJ: Benign angiopathy: A distinct subset of angiographically defined primary angiitis of the central nervous system. J Rheumatol 1993;20:2046.



Primary angiitis of the central nervous system (PACNS) is, by definition, limited to the CNS (brain, spinal cord, and meninges). Either contrast angiography or pathologic confirmation is employed to make this diagnosis. Should a biopsy be obtained, its results can then be used to further clarify PACNS as either granulomatous angiitis of the CNS (GACNS) or non-granulomatous angiitis, sometimes referred to as atypical PACNS . One group has proposed a classification based on the type of study used to make the diagnosis with two subsets defined as “histologically defined angiitis of the CNS” (HDACNS) or “angiographically defined angiopathy of the CNS” (ADACNS). PACNS is a rare disease, with an incidence estimated at 2.4 cases per 1,000,000 person years.


Secondary vasculitis of the central nervous system (SVCNS) is the term applied in the nosology of CNS vasculitis to describe those patients with a systemic disease, often a systemic vasculitis or diffuse connective tissue disease, that has features referable to the CNS. Systemic lupus erythematosus (SLE) with CNS involvement would be a good example.


Reversible Cerebral Vasoconstriction Syndromes (RCVS) is another variant of the condition. This more recent addition to the nomenclature came from the realization that there are a subset of patients with a vasospastic variant of CNS vascular disease. The terminology in this condition has evolved as its reversible nature has become more central to our understanding of its course and prognosis. This condition has at various times been called isolated benign cerebral vasculitis, benign acute cerebral angiopathy, CNS pseudovasculitis, migraine angiitis, and others. Most recently, it was titled benign angiopathy of the central nervous system (BACNS), which emphasized its better prognosis. RCVS is the current preferred name, enforcing the concept of reversibility in the vascular anomaly.


The implication of an RCVS diagnosis is that the course of disease should be more benign by virtue of reversible vasospasm and that this reversibility portends a far better prognosis. The modifier ‘benign’ has been called into question though as some with this diagnosis do suffer significant and additive morbidity.


A difficulty at the time of presentation and initial diagnosis of CNS vasculitis lies in the dilemma that one cannot be certain that the clinical course is going to be one of vasospastic reversibility (RCVS) or progressive disease from necrotizing vasculitis (PACNS). The consulting rheumatologist must marshal all of his or her skills to evaluate and classify the patient quickly and correctly.


Differential Diagnosis


A large list of CNS vasculitis mimics, as well as consideration that CNS vasculitis might be a component of a larger, more systemic vasculitis, needs to be considered when evaluating a patient for CNS vasculitis ( Table 17-2 ). A thorough history and physical examination will go far in addressing each of the possible diagnoses.



Table 17-2

Differential Diagnosis of Central Nervous System Vasculopathy





















  • Secondary vasculitis of the CNS (SVCNS):




    • Polyarteritis nodosa



    • Allergic granulomatosis (Churg-Strauss syndrome)



    • Hypersensitivity vasculitis



    • Wegener’s granulomatosis



    • Takayasu’s arteritis



    • Behçet’s disease



    • Lymphomatoid granulomatosis



    • Cogan’s syndrome



    • Vasculitis from a diffuse connective tissue disease (SLE, MCTD)





  • Vasospastic disorders:




    • Postpartum angiopathy



    • Eclampsia



    • Pheochromocytoma



    • Subarachnoid hemorrhage



    • Migraine



    • Dissection



    • Hypertension associated



    • Exertional headaches





  • Infection:




    • Bacterial (endocarditis, meningitis, tuberculosis, spirochetal)



    • Viral (herpes, HIV, hepatitis C)



    • Fungal (aspergillus, histoplasmosis)





  • Other “mimics”:




    • Fibromuscular dysplasia



    • Amyloid



    • Moyamoya disease



    • Thrombotic thrombocytopenic purpura



    • Sickle cell anemia



    • Neurofibromatosis



    • Atherosclerosis



    • Myxoma embolism



    • Paraprotein



    • Cholesterol embolism



    • Pregnancy and post-partum vasculopathy



    • Demyelinating disease



    • Sarcoidosis



    • Embolic processes



    • Eale’s disease



    • Acute posterior placoid pigment epitheliopathy and cerebral vasculitis



    • Hypercoagulable states/antiphospholipid syndrome



    • Radicular vasculopathy



    • Traumatic dissection





  • Neoplasm:




    • Carcinomatous meningitis



    • Glioma



    • Malignant angioendotheliomatosis



    • Multiple myeloma



    • Angioimmunoproliferative disorders



    • CNS lymphoma





  • Drugs:




    • Amphetamine



    • Ephedrine



    • Cocaine



    • Ergotamine



    • Phenylpropanolamine



    • Heroin





  • Heritable Disorders:




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



CNS, central nervous system; HIV, human immunodeficiency virus; MCTD, mixed connective tissue disease; SLE, systemic lupus erythematosus.

From Calabrese LH, Duna GF. Vasculitis of the central nervous system. In: Weisman MH, Weinblatt ME, Louie JS, editors. Treatment of the Rheumatic Diseases. Philadelphia: W.B. Saunders; 2001; pp 345-52; and Calabrese LH, Furlan AJ, Gragg LA, Ropos TJ. Primary angiitis of the central nervous system: diagnostic criteria and clinical approach. Cleveland Clinic J Med 1992;59:293–306.


An immunocompromised state raises the risk for an opportunistic infectious process. Patients with underlying autoimmune diseases on aggressive immunosuppression regimens are especially problematic. The rheumatologist needs to consider the possibility that the underlying disease is the reason for new CNS manifestations (such as CNS lymphoma) as well as the possibility that the immunosuppression created with medications has allowed for an opportunistic infection.


Infectious angiitis can mimic PACNS and a high degree of suspicion for an infectious process should be maintained. Some of the infectious causes of angiitis include human immunodeficiency virus (HIV), hepatitis C, herpes zoster (HZV), histoplasmosis, Lyme disease, and syphilis. Fungal infections have a predilection for the base of the brain. Often these patients are immunosuppressed or ill from comorbid conditions. The need for consultation with an infectious disease specialist can’t be overemphasized.


Drug use can mimic CNS vasculitis and is often an inciting agent for RCVS, although the clinical picture can mimic PACNS. Careful history taking, often from family members, should concentrate on recent ingestion of cocaine, amphetamines, and ephedrine containing products (marketed for rapid weight loss). Urine toxicologic screening is recommended.


Attention should be paid to the age of the patient as drug abuse is more common in the younger age groups, whereas atherosclerosis, cerebral amyloid, and neoplasm are more common in the older population. Cerebral amyloid angiopathy should be in the differential diagnosis for an older patient with cerebral hemorrhages. The amyloid is usually found in the vessels in the leptomeninges and cortex with sparing of white matter.


A curious entity to consider in the setting of possible CNS vasculitis is after varicella zoster virus (VZV) contralateral hemiplegia. Approximately 1 to 4 weeks following a VZV infection as in herpes zoster ophthalmicus or trigeminal nerve involvement, a patient may develop a syndrome of contralateral hemiplegia. The current understanding of this curious clinical presentation is that a vasculitis involves the ipsilateral carotid artery or its middle cerebral artery branch. If in doubt, and a VZV-associated process is being considered, consultation with an infectious diseases expert and therapy for HZV should be considered.


Diagnostic Evaluation


Symptoms and Signs


The most common symptom of PACNS is headache, which becomes more chronic. Most patients diagnosed with CNS vasculitis have been ill for an extended period of time, often measured in months. Headache might then be followed by encephalopathy, and finally, multiple infarcts develop. Other neurologic features reported include stroke, seizure, hemorrhage, cranial neuropathies, cerebellar dysfunction, a mass lesion, spinal cord involvement, and cauda equina syndrome.


There is usually a delay in diagnosis from weeks to months as neurologic involvement increases. Although imaging may show multiple strokes, a key point is that the strokes are often of varying age, suggesting an ongoing process with repeated showering of infarcts. Generally, new neurologic events occur. Fever and weight loss are not requisite findings, nor do they preclude CNS vasculitis. Curiously, most cases of biopsy-proven PACNS occur in men.


A “thunderclap headache” characterized by an abrupt onset with evolution to maximal pain measured in minutes is more likely to herald the presentation of RCVS than of PACNS, which has a more indolent cephalgia presentation. There may be self-limited resolution and then recurrence of the headache before presentation and final diagnosis. This headache and clinical picture of RCVS is more common in women than men. The headache will then be followed by other neurologic signs and symptoms. RCVS may be spontaneous or secondary to ingested vasoactive substances, or as a finding in the postpartum period. Again, particular attention should be paid to the possibility of the patient using cannabis, decongestants, weight-loss supplements, and selective serotonin reuptake inhibitors (SSRIs) ( Table 17-3 ).



Table 17-3

Precipitating Factors and Conditions Associated with Reversible Cerebral Vasoconstriction Syndromes















Pregnancy and Puerperium



  • Early puerperium



  • Late pregnancy



  • Eclampsia



  • Preeclampsia



  • Delayed postpartum eclampsia

Catecholamine-Secreting Tumor



  • Pheochromocytoma



  • Bronchial carcinoid tumor

Exogenous Exposures



  • Drugs




    • Cannabis



    • Cocaine



    • “Ecstasy”



    • Amphetamine derivatives



    • Lysergic acid diethylamine




  • Medications




    • SSRIs



    • Ergotamine tartrate



    • Methergine



    • Bromocriptine



    • Lisuride



    • Sumatriptan



    • Isometheptine



    • Tacrolimus



    • Cyclophosphamide



    • Interferon alpha



    • Nasal decongestants



    • Phenylpropanolamine



    • Pseudoephedrine



    • Ephedrine




  • Red blood cell transfusion



  • IVIG



  • Alcohol



  • Miscellaneous




    • Hypercalcemia



    • Porphyria



    • Head trauma



    • Spinal subdural hematoma



    • Postcarotid endarterectomy



IVIG, intravenous immunoglobulin; SSRIs, selective serotonin reuptake inhibitors.

From Ducros A, Boubobza M, Porcher R, Sarov M, Valade D, Boussser MG. The clinical and radiological spectrum of reversible cerebral vasoconstriction syndrome. A prospective series of 67 patients. Brain 2007;130:3091-101; and Calabrese LH, Dodick DW, Schwedt TJ, Singhal AB. Narrative review: reversible cerebral vasoconstriction syndromes. Ann Intern Med 2007;146:34–44.


Laboratory Evaluation


Laboratory evaluation is, unfortunately, nonspecific in CNS vasculitis. There is no diagnostic serologic test for PACNS. Many patients are systemically ill, and this is reflected in an anemia of chronic disease, elevated acute phase reactants, and other nonspecific laboratory values reflecting an inflammatory condition. The laboratory is employed more to evaluate for the mimics of PACNS than to confirm the diagnosis of PACNS. A basic evaluation should include an evaluation for autoimmune disease, a hypercoaguable state (to include antiphospholipid antibodies), HIV, syphilis, blood cultures for bacteria, fungi, and mycobacteria.


Cerebrospinal fluid (CSF) analysis is usually abnormal in PACNS. The typical CSF fluid finding in PACNS is an elevated CSF protein with a CSF lymphocytosis.


The typical CSF fluid finding in RCVS is more bland, with a few cells but near normal, if not normal, protein. In approximately 50% of cases of RCVS, the CSF analysis is entirely normal. It usually resembles the analyses obtained in chronic meningitis.


Imaging Studies


Brain magnetic resonance imaging (MRI) study has supplanted brain CT as the imaging modality of choice for CNS vasculitis. It offers unparalleled sensitivity for detecting abnormalities. MRI is abnormal in more than 90% of cases. Specificity, however, is still wanting. The usual PACNS MRI findings include multiple, bilateral lesions that are usually infarcts or nonspecific signal change. Typical locations for lesions include the subcortical white matter, deep gray matter, deep white matter, and cortex. Although a normal brain MRI has a strong negative predictive value for PACNS, pathologic diagnosis has been made when the imaging study was unremarkable. Prominence of the meninges on gadolinium-enhanced MRI may be a finding in PACNS. MRI angiography (MRA) may well be abnormal but does not guarantee the level of clarity needed for the size blood vessel usually affected in PACNS, and so a transfemoral contrast angiogram is often required.


Most patients with CNS vasculitis are diagnosed now with contrast angiography. Traditional contrast angiography in CNS vasculitis would be expected to demonstrate classic “beading” of small vessels with alternating constrictions, ectasia, and dilatation. Microaneurysms are far less common than in polyarteritis nodosa. Commonly affected vessels include the small branches of the middle anterior arteries or the posterior cerebral arteries. Unless affected by atherosclerotic vascular disease, the more proximal and larger vessels are not affected by PACNS. The finding of atherosclerotic changes in the carotid siphon or other vessels should raise concern if the angiogram is then interpreted as showing vasculitis. It needs to be remembered that vasculitis is a dynamic, pathophysiologic process, and a contrast angiogram is no more than an imaging modality of intraluminal architecture and many processes other than vasculitis can result in a similar imaging result. It really cannot be stressed enough that even when an angiogram is “positive,” the careful clinician must maintain a healthy level of skepticism and consider alternative explanations to vasculitis for the angiographic findings. Many patients will still have another explanation for the luminal findings. Even a well-performed contrast angiogram lacks specificity for CNS vasculitis.


An abnormal angiogram then, while important to the diagnosis of CNS vasculitis, can be misleading because multiple conditions may lead to a similar picture. The radiologist’s report that an angiogram is “ consistent with vasculitis ” must be interpreted with caution and a circumspect approach taken by the treating rheumatologist. The angiographic findings in PACNS and RVCS may well be indistinguishable in the acute setting with no pathognomonic angiographic feature for necrotizing CNS vasculitis. A follow-up angiogram after several months of treatment is sometimes necessary to confirm that the initial findings represented a reversible process (RVCS) versus a necrotizing process (PACNS).


Just as a positive angiogram can lead to early diagnostic closure, a normal angiogram may not rule out vasculitis. GACNS, confirmed histologically, can sometimes result in a normal angiogram because the size of the affected vessels may be below the resolution of the imaging study. Most patients with a so-called positive angiogram have some condition other than GACNS.


Pathologic Evaluation


Biopsy of the leptomeninges/underlying cortex is the definitive method for confirming the diagnosis of PACNS. Some would argue that this procedure should be pursued before committing a patient to high-dose corticosteroids and cyclophosphamide with their attendant side effects. The procedure is subject to sampling bias with the possibility for a false-negative finding. It is recommended that the biopsy be taken from the nondominant temporal lobe. It should be appreciated that there is the potential for morbidity from the procedure itself although it is low (2% in one study). The risk of biopsy needs to be put into context when one considers the risk of empiric treatment with a cytotoxic agent or agents for a prolonged time period for a condition that does not have histologic confirmation. It is important to remember that angiography alone lacks specificity.


The pathology of PACNS is an inflammatory process centered about smaller veins and arterioles and is more prominent in the leptomeninges than in the deeper cortex. As noted previously, the infiltrate may be either granulomatous or nongranulomatous. A patchy distribution of involvement leads to sampling error.


Brain biopsy has a sensitivity for PACNS of approximately 80%.


In summary, a biopsy in conjunction with an angiogram is preferred in making the diagnosis of PACNS. The need for both studies is necessitated by the reality that an angiogram alone is too nonspecific. The added information obtained with biopsy supports a decision to give aggressive immunosuppression. Biopsy material should be submitted for staining for infectious etiologies in addition to routine histology.


In reality, obtaining a biopsy is not always feasible. In a clinical scenario that supports the diagnosis of RCVS, one could consider a delayed biopsy if treatment with corticosteroids and a calcium channel blocker for a predetermined time period does not result in clinical improvement.


Diagnostic Evaluation Summary


Making the definitive diagnosis of CNS vasculitis can clearly be challenging. A high index of suspicion must drive the evaluation because there is no single serologic test or imaging modality result that will confirm the diagnosis for the consulting rheumatologist with absolute certainty. The concept of benign disease (usually vasospasm) at one end of the spectrum and a truly inflammatory vasculitis at the opposite pole underpins our current understanding of CNS vasculitis. Finding the point on this spectrum that defines the individual patient is difficult and requires careful clinical judgment. A meticulous history and physical examination is of paramount importance. Interviewing family members is necessary to ascertain whether vasoactive drugs have been ingested. Over-the-counter supplements and illegal drug use must be addressed.


A variety of diagnostic tests are then employed in approaching the CNS vasculitis evaluation, and it is worth remembering that the majority of patients who are evaluated for CNS vasculitis are eventually diagnosed with another condition. An echocardiogram to evaluate for an embolic etiology to CNS findings is usually obtained. Electroencephalography, CT, and MRI imaging, and CSF analysis typically follow, both to evaluate for the mimics (see Differential Diagnosis) of vasculitis as well as to pursue the diagnoses of PACNS or RCVS. A totally normal MRI and CSF analysis strongly argues against PACNS, and when both studies are normal, they offer a high negative predictive value for vasculitis.


However, if these tests are abnormal and a high index of suspicion remains for vasculitis, then they should be followed by contrast angiography and then, finally, a leptomeningeal/cortical brain biopsy. It is natural to want to avoid an invasive procedure such as leptomeningeal biopsy and to depend on an angiogram report for diagnostic confirmation, but the predictive value of an angiogram is low and the consulting rheumatologist may well need to pursue tissue diagnosis. A diagnosis based solely on angiography is more tenuous than one based on histopathologic results. RCVS is a more likely diagnosis when only contrast angiography is used to make the diagnosis.


A follow-up contrast angiogram in 6 to 12 weeks is the confirmatory test for the diagnosis of RCVS. A failure to show angiographic resolution should raise the suspicion that something other than vasospasm is causing the patient’s clinical picture.


Diagnostic Criteria—Primary Angiitis of the Central Nervous System


The currently employed classification scheme originated with Calabrese and Mallek in their 1988 review and is a useful guide to diagnosis of PACNS.



  • 1.

    A history or clinical finding of an acquired neurologic deficit that remained unexplained after a thorough initial basic evaluation.


  • 2.

    Either classic (high-probability) angiographic evidence or histopathologic demonstration of angiitis within the CNS.


  • 3.

    No evidence of systemic vasculitis or any other condition to which the angiographic or pathologic features could be secondary.



Although no readily agreed-upon diagnostic criteria are accepted, a definite diagnosis of PACNS could be given with a compelling set of symptoms and signs including headache, additive neurologic deficits, a lack of an alternative explanation or diagnosis, supporting imaging studies, and a histologic sample demonstrating vasculitis.


Diagnostic Criteria—Reversible Cerebral Vasoconstriction Syndromes


RCVS or reversible cerebral vasoconstrictive syndrome is probably more common than is realized. Although this group of conditions does have a better prognosis than PACNS or SVCNS, it is easy for a patient to be misdiagnosed with PACNS with resultant unnecessarily aggressive treatment. Five elements have been proposed for the diagnosis of reversible cerebral vasoconstrictive syndrome :



  • 1.

    Presence of multifocal segmental cerebral artery vasoconstriction documented by direct or indirect angiography (transfemoral angiograpy, computerized tomographic angiography [CTA], magnetic resonance angiography [MRA])


  • 2.

    No evidence of aneursymal, subarachnoid hemorrhage (which is often observed after a stroke)


  • 3.

    CSF analysis shows normal or near-normal results (e.g., protein level < 80 mg/dL, leukocytes < 10 mm 3 , normal glucose level)


  • 4.

    Severe, acute headaches, with or without additional neurologic signs or symptoms


  • 5.

    Reversibility of angiographic abnormalities within 12 weeks after onset.



Treatment


There are no placebo-controlled, large scale, randomized trials performed that have defined the best approach to therapy for either PACNS or RCVS. This reflects the diagnostic uncertainty and low incidence of both PACNS and RCVS. Often, therapy is begun when one is not even certain which of these conditions is the correct diagnosis. Clinical judgment drives the treatment plan for all form of CNS vasculopathy. Continuous reevaluation of the diagnosis and assessment of response to therapy will allow for a measured change in treatment as time progresses.


Primary Angiitis of the Central Nervous System


Experience has shown that corticosteroids are first-line agents for PACNS, and most rheumatologists would favor 3 days of 1000 mg of methylprednisolone daily before transitioning to a regimen of 1 mg/kg/day of prednisone. The prednisone dose should be continued until clinical improvement is noted and inflammatory markers, if present, are improved. This is likely to take a month or more. A slow taper follows, if response is forthcoming, over the ensuing many months.


The addition of cyclophosphamide or other therapies should be considered on an individual basis for PACNS. Cyclophosphamide in combination with corticosteroids has a record of success dating back to the early 1980s, when a report on four patients with what was then called isolated angiitis of the central nervous system was published. Combination therapy was thus established as a standard of care, and it is generally accepted that true PACNS should be treated with more than corticosteroids alone. Aggressive therapy with the combination of corticosteroids and cyclophosphamide is generally advocated when the patient has a heavy disease burden along with a compelling diagnostic evaluation. If the patient can take oral medications, cyclophosphamide is dosed at 2 mg/kg/day starting along with corticosteroids. Some will delay, adding cyclophosphamide to see if monotherapy with corticosteroids results in prompt improvement, thereby trying to avoid cyclophosphamide. However, the threshold for adding cyclophosphamide for a firm diagnosis of PACNS is low. Prophylactic therapy for Pneumocystis jiroveci is recommended when cyclophosphamide is combined with corticosteroids. The duration of treatment and the tapering schedule for the corticosteroid/cyclophosphamide combination is empiric, but modeling the treatment on a Wegener’s granulomatosis regimen seems reasonable. Disease severity warranting the institution of cyclophosphamide may result in a treatment course extending to 2 years after clinical improvement.


Reversible Cerebral Vasoconstriction Syndromes


RCVS, especially if induced by a drug or other removable cause, does not necessarily require immunosuppression. In the setting of a firm diagnosis of RCVS, some advocate treatment with a calcium channel blocker either alone or combined with a faster tapering course of prednisone than would be used in PACNS. Frustratingly, the presentation of RCVS is often clouded by a less-than-clear diagnosis and so an initial course of corticosteroids is a prudent treatment. If response is forthcoming and the clinical picture becomes more consistent with a reversible angiopathy, then the initial corticosteroid dosing may be followed by a quick taper over approximately 3 months. Avoidance of all sympathomimetic drugs is mandatory. As a more developed understanding of RCVS has evolved, so has its treatment. A shorter during of corticosteroid therapy in combination with calcium channel blockers has become accepted. Calcium channel blockers are often continued long term.


A follow-up angiogram in 12 weeks would, if pursued, confirm the reversible nature of RCVS and offer significant prognostic data. Also, a lack of reversibility on angiogram would lend support to a diagnosis of PACNS and suggest the need for a longer and perhaps more intensive course of treatment.


At first presentation, when the rheumatologist is uncertain if the patient has PACNS or RCVS, clinical judgment should dictate just how aggressively to treat the patient. A fulminant presentation would warrant combined therapy with corticosteroids and cyclophosphamide, whereas a presentation consistent with RCVS (female, thunderclap headache, normal CSF) could be approached with corticosteroids and/or calcium channel blockers as the mainstay of therapy.


Prognosis


A retrospective study of a cohort of 101 patients with PACNS followed at Mayo Clinic was reported and indicated that four presentation manifestations were associated with an increased mortality rate. These features included focal neurologic deficits, cognitive impairment, cerebral infarction, and large vessel involvement. Treatment was continued for 12 to 18 months. Relapse occurred in 21 of the 101 patients, but those affected still had a similar outcome to those without relapse.


RCVS is not without potential morbidity. Cortical subarachnoid hemorrhage, intracerebral hemorrhage, seizure, and reversible posterior leukoencephalopathy have all been seen early in the course, usually in the first week of symptoms. In the second week, cerebral infarction and transient ischemic attack (TIA) may be seen. Still, the prognosis for RCVS is believed to be far better than that for PACNS. No relapse was seen in at least one study of 67 patients with RCVS, who were followed for a mean of 16 months. Sixteen patients with RCVS were followed for a mean of almost 3 years with excellent recovery, although one patient did have some form of relapse after therapy was tapered. No death occurred in this sample.


Summary


PACNS is a rare disease but one with an increased rate of mortality and morbidity if not recognized and treated early. Angiography and biopsy are key elements in the diagnostic approach and are complimentary. Early recognition and treatment are necessary to impact on its significant morbidity and mortality rates. High-dose corticosteroids, usually in combination with cyclophosphamide, are mainstays of treatment.


RCVS is characterized by its reversibility, usually over the course of several months. Headache is a heralding presentation. It has a number of exogenous triggers including drugs, pregnancy, or in the puerperium. CSF analysis is usually normal as are autoimmune serologies. A contrast angiogram usually shows segmental cerebral arterial vasoconstriction, which reverses by 12 weeks. Treatment is empirical but may include only observation with removal of an identified, inciting agent or some combination of calcium channel blockers and possible high-dose corticosteroids for a limited period of time. Most patients do well ( Table 17-4 ).


May 19, 2019 | Posted by in RHEUMATOLOGY | Comments Off on Management of CNS Vasculitis and Takayasu’s Arteritis
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