Primary Angiitis of the CNS

Vasculitis is inflammation of blood vessel walls leading to disruption of the normal structural and physiologic characteristics of the affected vessels, which in turn results in vascular occlusion and/or formation of aneurysms with consequent ischemia and hemorrhage.

Numerous forms of vasculitis can affect the central nervous system (CNS). This review focuses on primary angiitis of the central nervous system (PACNS), a rare form of vasculitis restricted to the brain and spinal cord. Only biopsy-proved case series are referenced in this report.

The etiology and pathogenesis of primary angiitis of the central nervous system (PACNS) are unknown. The fundamental mechanism of all vasculitides is immunologic; Crowe discussed 4 different mechanisms of tissue injury that might apply to the pathogenesis of vasculitis: immune complexes, direct antibody-mediated damage, delayed hypersensitivity, and cytotoxic T lymphocytes.[1] With the limited knowledge we have about PACNS, no strong evidence supports any of these mechanisms in the pathogenesis of this disease, although the granulomatous nature of inflammation suggests a role of cell-mediated immunity.[2]

As in other autoimmune disorders, T cells that become sensitized in the course of systemic illness or viral infection probably later contribute to a cellular immune response directed against cross-reacting epitopes in CNS vessels.[3] Other authors propose that, in the setting of altered host defense mechanisms, a virus or other pathogen may lead directly or indirectly to diffuse cerebral vasculitis.[4]

The latter hypothesis is supported by the rare condition in which vasculitis involving mainly the ipsilateral anterior circulation with consequent infarcts occurs days to weeks following varicella-zoster infection of the first division of the trigeminal nerve. The mechanism seems to be retrograde spread of the virus from Gasserian ganglion to the arteries of the anterior circle of Willis.[5]

Pathologically confirmed cases of PACNS have been reported in patients with Hodgkin disease, amyloid angiopathy, and graft-versus-host disease. However, available information in these cases does not allow any conclusion about the causal relation between these diseases and PACNS.[2]

Regardless of the etiology of PACNS, the main mechanism of neurologic damage in these patients is ischemic. This results from 3 consequences of inflammation in the vascular wall: obstruction of the vessel lumen, increased local coagulation from the effects of proinflammatory cytokines on the endothelial surface, and alteration in vasomotor tone.[6]

Frequency

The rarity of primary angiitis of the central nervous system (PACNS) and the lack of consensus on diagnostic criteria make incidence and prevalence of the disease difficult to estimate.

PACNS is reported more frequently in North America, Europe, Australia, and New Zealand. Whether the disease has a higher incidence in these regions or it has just been more successfully diagnosed and reported there is unclear.

Mortality/Morbidity

Mortality and morbidity of PACNS are hard to determine due to the variability in diagnosis means and treatment among published series. However, treatment with steroids and immunosuppressants has improved the outcomes of the disease, which used to be fatal. In a recent report, 14% of 29 patients with biopsy-proven PACNS died or had severe morbidity (Modified Rankin Scale of 5) at follow-up of 1.14 years.[7]

Sex

Men are more commonly affected by PACNS than women; the male-to-female ratio is about 7:3.[4]

Age

In most reported cases, patients were in the fourth to sixth decades of life at time of diagnosis. However, patients aged 7 months to 78 years have been described.[8, 9, 10]

Prognosis of primary angiitis of the central nervous system (PACNS) is usually guarded, even with appropriate therapy. Prognosis is good in benign angiopathy of the CNS and postpartum CNS angiopathy, but these diagnoses are usually confirmed only in retrospect.

Primary angiitis of the central nervous system (PACNS) patients should be educated about the chronic nature of the disease, and about the potential toxic side effects of steroids and immunosuppressants.

Patients should also be educated about the importance of controlling other cerebrovascular risk factors, such as hypertension, diabetes, hyperlipidemia, and smoking.

Mode of onset, presenting symptoms, and the course of primary angiitis of the CNS (PACNS) are widely varied, with almost all neurologic signs and symptoms having been reported.[2]

• In a review of 68 patients with a pathological diagnosis from different series, the most common symptoms on presentation were nonfocal, such as headache (58%) and altered mental status (47%). Localizing symptoms frequently seen on presentation were lateralized weakness (32%), aphasia (14%), ataxia (14%) and nonspecific visual complaints (17%). Seizures were among the presenting symptoms in about 15% of patients.[2]

• Although tissue injury from vasculitis is ischemic, PACNS is extremely rare among unselected patients with ischemic stroke. In a retrospective review of more than 4000 cases of stroke in one center over a period of 19 years, only 6 cases (0.15%) of first ischemic stroke were caused by PACNS.[11]

• When stroke occurs in the course of PACNS, preceding or concomitant evidence usually points to widespread CNS disease.[2]

• Hemorrhagic stroke is reported in approximately 11% of patients, with intracerebral bleed most common[4] , usually in the absence of precipitating factors (hypertension, trauma, or coagulopathy). Subarachnoid hemorrhage and spinal subdural hematoma have also been reported.

• Spinal cord involvement causing weakness in lower extremities and bladder dysfunction is reported in 5-14% of patients, sometimes before or without any evidence of cerebral dysfunction.[4, 12]

• In the review of 68 patients with pathological diagnosis, the diagnosis was made more than 6 months after the onset of symptoms in 54% of cases.[2]

• The course is usually progressive, producing a clinical picture of multifocal neurologic dysfunction; however, about 15% of patients have fluctuating and relapsing-remitting symptoms early in the course of the disease.

• Seizures, including intractable status epilepticus, headache, and cognitive decline are common presenting features in children with negative-angiogram small-vessel primary angiitis of the CNS.[13]

Constitutional symptoms commonly seen in systemic vasculitides like fever, fatigue, and weight loss are not usually prominent in PACNS. Only 13% of 31 patients in a recent report had constitutional symptoms.[14]

Possible findings on neurologic examination are broad, depending on the affected areas in the CNS. Common findings are hemiparesis, impaired cognition or decreased level of consciousness, aphasia, ataxia, and paraparesis.[2]

Despite the diversity of signs and symptoms, Scolding and colleagues recognized 3 broad categories of clinical patterns:[15]

1. Acute or subacute encephalopathy that may progress to coma if not treated.

2. A picture of relapsing remitting neurologic deficits similar to multiple sclerosis, but with other symptoms uncommon in multiple sclerosis such as severe persistent headache and seizures.

3. A picture suggestive of rapidly progressive space-occupying lesion with headache and focal neurologic deficits.

Careful general physical examination is important to detect signs of diseases that may cause a secondary CNS angiitis. Skin rash, purpura, and arthritis are seen in many systemic vasculitides like polyarteritis nodosa and Churg Strauss disease. Wheezing is particularly common in Churg Strauss disease, while sinusitis is common in Wegener granulomatosis. Painful genital and mouth ulcers or uveitis are seen in Behcet disease. Lymphadenopathy and arthritis might be seen in sarcoidosis.

Complications of primary angiitis of the central nervous system (PACNS) are nonspecific. Patients who are immobile due to neurologic deficits are at higher risk for pneumonia, decubitus ulcers, and deep venous thrombosis (DVT).

Patients in whom CNS angiitis is suspected should undergo a thorough workup to exclude systemic vasculitis and other diseases that can mimic primary angiitis of the central nervous system (PACNS).

CSF examination

Although it is nonspecific, CSF is abnormal in most patients with PACNS. Mild-to-moderate CSF pleocytosis, predominantly lymphocytes, is found in approximately 70-90% of cases.[2, 14] The vast majority of patients have elevated CSF protein, with a median protein concentration of 98 mg/dL (range 44-1034 mg/dL) in a recent report.[14] In some patients, oligoclonal bands can be detected in the CSF, reflecting an inflammatory process in the CNS. The glucose is usually normal. Cultures and cytology studies are important to exclude CNS infection and malignancies. In some patients, initial CSF examination results might be normal, but subsequent lumbar punctures show abnormalities as the disease evolves.

Other general lab studies

CBC, antinuclear antibodies (ANA), RF, SSA/SSB, p-ANCA, c-ANCA, cryoglobulin, complement levels, other tests for rheumatic diseases, and syphilis serology usually produce normal results but are helpful to rule out other conditions that can mimic PACNS.

ESR is usually normal or mildly elevated.

Head CT

Head CT in patients with primary angiitis of the central nervous system (PACNS) shows various combinations of nonspecific findings, including cerebral infarcts or hemorrhages with mass effect, hydrocephalus, or white matter hypodensity. CT may also be normal.

MRI of the brain

MRI of the brain is essential in the evaluation of patients with possible PACNS; it helps to exclude other diagnoses such as CNS tumors, demyelinating diseases, multiple small infarcts, and hydrocephalus.

MRI has also other benefits; it raises the suspicion of PACNS earlier by providing the clinician with evidence of a more extensive process than suspected on clinical grounds. It may also document the progression of the disease or response to therapy. MRI may also help in selecting a site for brain biopsy.

In PACNS, lesions on MRI are hyperintense on T2-weighted images and FLAIR sequences, and isointense or hypointense in T1-weighted images. Acute infarcts are represented by restricted diffusion on diffusion-weighted images (DWI).[18]

The MRI usually shows multiple lesions, predominantly in subcortical and deep white matter areas, with homogenous or patchy contrast enhancement.[19] MRIs showed prominent leptomeningeal enhancement in 8 of 49 patients with biopsy-proven PACNS in a recent series[9] , half of those 8 patients had vascular beta-amyloid deposits associated with granulomatous vascular inflammation.

The conventional resolution of magnetic resonance angiography (MRA) is insufficient to show the medium-sized and small vessels usually affected in PACNS.

Some of the publications that reported low sensitivity of MRI in PACNS described patients without pathological diagnosis who could have had benign angiopathy of the CNS or other diseases.

Patients in most of the recent reports of PACNS have had an abnormal brain MRI.

Cerebral angiogram

When PACNS is suspected after routine laboratory studies, CSF exam, and MRI of the brain, a cerebral catheter angiogram should be performed. Classic findings are segmental changes of the contour and caliber beading of the contrast column, reflecting areas of narrowing and dilatation in the vessels. However, the angiography is neither sensitive nor specific for PACNS. Typical findings on angiography should not be relied on to make a diagnosis of PACNS or to justify the long-term steroid and immunosuppressant therapy. On the other hand, a negative angiography should be followed by a brain biopsy when clinical suspicion is high and long-term therapy is being considered.[20]

In 48 angiographies on 43 patients from different series, only 12 showed changes highly suggestive of vasculitis.[2]

In another recent retrospective study of 38 patients who underwent cerebral angiogram followed by brain biopsy for possible PACNS, typical angiographic findings of vasculitis were noted in 14 patients. On biopsy, none of these patients had PACNS and 6 of them had another specific pathological diagnosis, including infarctions, Alzheimer disease, and CADASIL. In the same study, 2 patients were diagnosed with PACNS on biopsy; neither of them had an angiogram read as typical for vasculitis.[21]

Many other conditions can give a similar angiographic picture of vasculitis, including atherosclerosis, benign angiopathy, reversible cerebral vasoconstriction syndromes, vasospasm after subarachnoid hemorrhage, hypertension, migraine, trauma, chronic meningitis, and oral contraceptives and sumatriptan use.

Brain biopsy

Brain biopsy is the only method able to establish a diagnosis of primary angiitis of the central nervous system (PACNS) and to rule out other diseases. Because vessels in leptomeninges are involved in most cases, the leptomeninges should always be sampled.

Lesions seen on MRI should be biopsied if accessible; otherwise, the nondominant frontal or temporal lobe can be sampled. Both open and stereotactic biopsies have been used with similar outcomes.

In a retrospective review, 61 patients underwent brain biopsy for suspected PACNS; 22 patients (36%) of them had pathological diagnosis of PACNS, 15 patients (25%) had no pathological diagnosis, and 24 patients (39%) had alternative diagnoses, including infections, primary CNS lymphoma, metastatic tumors, sarcoidosis, MS, and arteriovenous malformation.[22] This study, along with other reports, suggests a moderate sensitivity of less than 70% of brain biopsy in PACNS. False negative results have been reported, which is expected given the patchy distribution of the disease. However, specificity of brain biopsy in PACNS is considered to be high.

In a study of 79 patients, PACNS was confirmed in 11% of patients, and an alternative diagnosis was indentified in 30%. Cerebral amyloid angiopathy, encephalitis, demyelination, and CNS lymphoma were the most common alternative diagnoses. Post-surgical complications occured in 16% of patients, a quarter of which were serious.[23]

Small-vessel PACNS in children is a recently recognized subset in which cerebral angiogram is normal by definition. In a report of 11 cases, nonlesional biopsy was as good as lesional biopsy in confirming the diagnosis. Pathology showed intraluminal lymphocytic infiltrates without granulomatosis.[13]

Primary angiitis of the central nervous system (PACNS) affects arterioles and venules less than 300 microns in diameter with vessels of the leptomeninges almost always involved.[2] Concomitant involvement of larger vessels such as the arteries of the circle of Willis and its branches has been reported.

Typical histopathological features are chronic granulomatous inflammation and giant cells.[24] Detection of giant cells is not required to make the diagnosis.[2] Nongranulomatous inflammation and fibrinoid necrosis of vessel walls have been described.

Inflamed walls of the affected vessels are infiltrated with different subpopulations of leukocytes; including lymphocytes, monocytes, histiocytes, and plasma cells. In the few cases when immunophenotyping of leukocytes was done, the infiltrating cells were mainly CD4 T lymphocytes.[2]

Three histopathological patterns of vasculitis were observed in the Mayo Clinic review.[7] Granulomatous inflammation was the most common (58%) with nearly half of the cases associated with deposition of beta-A4 amyloid in the vessel wall. Pure lymphocytic infiltration was seen in 28% of cases, and necrotizing inflammation was seen in 14% of cases.

Several reports have described PACNS in association with beta-A amyloid deposition, usually in patients younger than expected for the more common sporadic cerebral amyloid angiopathy. This association is usually seen with granulomatous PACNS, and its etiology is unknown. It has been suggested that PACNS associated with amyloid is part of a spectrum of inflammatory responses evoked by these substances.[7, 25, 26]

Microscopic examination also reveals necrotic ischemic lesions, hemorrhages, and tract degeneration.

Kolodny and colleagues proposed the following sequence for the development of vasculitic lesions:[24]

1. Intimal swelling and hyperplasia in arteries and adventitial lymphocyte infiltration in veins

2. Subintimal fibrinoid change and adventitial accumulation of histiocytes

3. Necrosis and fibrinoid change in media, fragmentation of internal elastic lamina, panmural infiltration of lymphocytes and histiocytes

4. Typical lesions: A granulomatous mass replaces all or part of vessel wall (lymphocytes, large mononuclear cells, fibroblasts, multinucleated giant cells, and variable numbers of plasma cells)

5. Possibly representing a late-stage, abundant fibrosis and relatively sparse lymphocytic infiltration, accompanied by large mononuclear and giant cells

When initially abnormal, brain MRI and CSF examination can be used with clinical findings to evaluate patient response to treatment.

Patients taking cyclophosphamide should be evaluated periodically for signs of drug toxicity. CBC should be performed every 2 weeks. The dose should be reduced or the drug should be temporarily held in case of leucopenia (WBC < 4000) or absolute neutropenia (neutrophils < 2000).

Patients, especially elderly patients, taking steroids should be given vitamin D and calcium supplements for bone mineral loss, and H2 blockers or proton-pump inhibitors for peptic ulcer disease. Blood glucose should also be monitored closely to detect iatrogenic diabetes.

Combined immunosuppressive therapy is the treatment of choice for primary angiitis of the central nervous system (PACNS). This therapy was initially proposed after its success in patients with systemic vasculitis such as Wegner granulomatosis and polyarteritis nodosa but is not supported by evidence from controlled trials in PACNS.

Current recommendation is oral prednisone, 1 mg/kg/d, and cyclophosphamide, 2 mg/kg/d. Treatment consists of 2 phases: Induction of remission and maintenance of remission. Duration of each phase is debatable, but most centers use prednisone and cyclophosphamide for 4-6 months to induce clinical remission, and then taper prednisone off to continue cyclophosphamide for 1 year.

Joseph and Scolding suggest a the following relatively different plan:[6]

• An induction regimen for 9-12 weeks: Cyclophosphamide 2.5 mg/kg/d coupled with intravenous methylprednisolone, 1 g/d for 3 days, then oral prednisolone, 60 mg/d, to be decreased by 10 mg at weekly intervals to reach a dose of 10 mg/d, if possible.

• A maintenance regimen for further 10 months: Alternate day steroids (10-20 mg prednisolone) along with azathioprine, 2 mg/kg/d, substituted for cyclophosphamide.

Methotrexate, 10–25 mg weekly, might be used in case of cyclophosphamide or azathioprine toxicity. Although no prospective controlled studies have been performed on this treatment, retrospective reviews showed good outcomes of prednisone with cyclophosphamide therapy in PACNS and provide support for the use of this regimen in pathologically confirmed cases.

Intravenous immunoglobulin (IVIG), plasmapheresis, and monoclonal antibodies have not been used extensively in PACNS. Their use in systemic vasculitis has produced variable results.[6]

Rituximab has recently been used in combination with steroids in two patients, with reported neurologic improvement.[27]

Benign angiopathy of CNS (BACNS) is probably not a true vasculitis, but rather reversible vasoconstriction, and should be treated differently. Several case series showed good outcomes of prednisone, 1 mg/kg/d, for a short course (< 6 mo), along with calcium channel blockers such as verapamil, amlodipine, or nimodipine.[17] However, many authors now recommend only nimodipine, 60 mg every 4-8 hours for 4-12 weeks, without steroids.[24] Some patients have resolved on no treatment.

In patients with presumed BACNS, a brain biopsy should be obtained in cases of questionable diagnosis, failure of medical management, and persistence of symptoms.

Insertion of external ventricular drain might be indicated as usual in cases of primary angiitis of the central nervous system (PACNS) with intraparenchymal or intraventricular hemorrhage and associated hydrocephalus.

Rheumatology, infectious diseases, or other medical specialties should be consulted as indicated in individual cases of primary angiitis of the central nervous system (PACNS). Neurologists not familiar with the use of cyclophosphamide should seek the aid of a rheumatologist or oncologist.

A calorie-controlled and sodium-controlled diet should be advised for patients with primary angiitis of the central nervous system (PACNS) who take steroids. These patients should also be taking adequate vitamin D and calcium supplements.

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Class Summary

These agents have antiinflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Prednisone (Sterapred)

Used as an immunosuppressant in the treatment of vasculitis and autoimmune disorders. It decreases inflammation by suppression of migration of polymorphonuclear leukocytes and reversal of increased capillary permeability, suppresses the immune system by reducing activity and volume of the lymphatic system, and suppresses adrenal function at high doses.

Class Summary

These agents interfere with processes that promote immune reactions resulting from diverse stimuli.

Cyclophosphamide (Cytoxan, Neosar)

Alkylating agent. Activated in the liver to its active metabolite, 4-hydroxycyclophosphamide, which alkylates the target sites in susceptible cells. The mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

When used in autoimmune diseases, mechanism of action is thought to involve immunosuppression due to destruction of immune cells via DNA cross-linking.

In high doses, affects B cells by inhibiting clonal expansion and suppression of production of immunoglobulins. With long-term, low-dose therapy, affects T cell functions.

Azathioprine (Imuran)

Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. Mechanism whereby azathioprine affects autoimmune diseases unknown. Works primarily on T cells. Suppresses hypersensitivities of cell-mediated type and causes variable alterations in antibody production. Immunosuppressive, delayed hypersensitivity, and cellular cytotoxicity tests are suppressed to a greater degree than antibody responses. Works very slowly; may require 6-12 mo of trial prior to effect. Up to 10% of patients may have idiosyncratic reaction disallowing use. Do not allow WBC count to drop below 3000/mL or lymphocyte count to drop below 1000/mL.

Class Summary

Inhibits calcium ions from entering slow channels or select voltage-sensitive areas of vascular smooth muscle.

Nifedipine (Adalat, Procardia)

Inhibits calcium ion from entering the slow channels or select voltage-sensitive areas of vascular smooth muscle producing vasodilation.

Nimodipine (Nimotop)

For improvement of neurologic impairments resulting from cerebrovascular spasms.

Nimodipine shares the pharmacology of other calcium channel blockers; animal studies indicate that nimodipine has a greater effect on cerebral arteries than other arteries; this increased specificity may be due to the drug's increased lipophilicity.

Verapamil (Calan, Calan SR, Covera-HS, Verelan)

Inhibits calcium ion from entering the slow channels or select voltage-sensitive areas of vascular smooth muscle during depolarization; produces relaxation of vascular smooth muscle and vasodilation; slows automaticity and conduction of AV node.