Necrotizing vasculitis may affect the central and peripheral nervous system. The vasculitides may become life threatening due to ischemic ulceration of the gut, kidney failure, and myocarditis; but it may also primarily involve the nervous system.
Although mild cases have been reported, a fulminant course is much more common. Therefore, its early recognition is paramount to secure a good outcome. Unfortunately, its perplexing initial presentation in many patients makes it very challenging to diagnose. This is also partly because this disorder may affect the central nervous system alone. Not uncommonly a major localizing deficit has occurred at the time of diagnosis. Angiitis of the central nervous system can be part of the systemic disorder which has to be uncovered before treatment is initiated. Three primary CNS vasculitides have been identified, many others are secondary to systemic vasculitis, connective tissue disease, malignancy, infections, and drugs. This section summarizes the most important clinical findings, the differential diagnosis, neuroimaging, and pathological characteristics. It also provides a recommendation for treatment.
Pathology and Classification
Vasculitis (or angiitis) on histologic analysis is characterized by inflammation involving layers of polymorphonuclear cells, mononuclear cells, and giant cells destroying the vessel wall resulting in fibrinoid necrosis, aneurysm formation, and possibly hemorrhage.
The pathological mechanisms that lead to vasculitis have not been elucidated. There is some evidence of cell-mediated immunity and when infiltrates are examined closely, they consist particularly of CD4 lymphocytes. Circulating immunocomplexes or a marked decrease in complement is not a typical feature in isolated CNS angiitis. When pathology is available either at autopsy or from a brain biopsy specimen, angiitis typically involves smaller blood vessels. The criteria for vasculitis have been outlined by Kolodny. These criteria include the following: a) intimal swelling and hyperplasia in arteries, b) adventitial lymphocytes infiltration in veins, c) subintimal and intimal fibrinoid change with adventitial accumulation of histiocytes, d) necrosis and fibrinoid change in media, e) fragmentation of internal elastic lamina, f) panmural infiltration of lymphocytes and histiocytes, g) and the presence of granulomas replacing all or part of the vessel wall.
These lesions involve a cluster of lymphocytes, large monocular cells, fibroblasts, multinucleated giant cells, and plasma cells. Inflammation of the small arteries and veins preferably involve the vessels of the leptomeninges and the branches that penetrate the cortex. (This characteristic is useful when performing a brain biopsy). Most notable is a panangiitis in a longitudinal and circumferential direction. In some patients, the abnormality involves the spinal cord arteries and arterioles, but this is an extremely uncommon cause of a myelopathy. Pathology involving the eye vasculature is uncommon and more widespread not only leading to retinal vasculitis but also uveitis or epiduritis.
The necrosis of the vessel wall results in occlusion and ischemia. A vessel wall rupture commonly leads to subarachnoid hemorrhage often involving the sulci and not the basal cisterns as in rupture from aneurysms located at the circle of Willis. Generally a brain biopsy is done at the time of diagnosis and should ideally involve the area that is abnormal on MRI scan. Although several series claim a sensitivity of 70%, a random brain biopsy has a much lower yield. If a brain biopsy is done, the specimen should include dura, leptomeninges, cortex, and white matter and fixated in 10% buffered formalin for light microscopy. Additional specimen can be frozen or stored with dry ice to be further examined by electron microscopy. Isolated angiitis of the central nervous system has been also termed granulomatous angiitis, but this connotation has been deleted because granulomatous changes are absent in 50% of the cases. When an underlying disorder is absent, central nervous system vasculitis is quite rare with only 300 cases or so reported. Related disorders are Eales disease, seen in India and the Middle East, with predominant retinal artery and vein involvement. Retinal hemorrhages and peripheral scotomas are common, but ischemic strokes have been reported.
Another disorder confined to the central nervous system is radiation angiitis due to carcinoma of the larynx, optic glioma, or pituitary tumor. A marked delay (often decades) is typical, but the effects can be devastating and the arteritis is not responsive to immunosuppression.
Isolated CNS angiitis is typically seen in younger (30-50 years) individuals with some predilection for females. It may present as an encephalopathy or dementia, multiple cranial neuropathies or recurrent transient ischemic attacks. Many reviews have noted the predominance of headache at presentation. Biller and Adam’s review claim that diffuse encephalopathy signs are present in up to 80% of the patients, but other reviews have predominantly highlighted the presence of behavioral changes. Obviously, a psychiatric presentation can make the diagnosis extremely challenging. This presentation may involve emotional lability but also at times histrionic behavior, confusional states mimicking dementia, suicidal depression, and acute psychotic exacerbations with visual hallucinations particularly when the occipital lobes have become infarcted. Localizing neurologic findings such as aphasia, apraxia, or hemiparesis often emerge. These neurologic signs and symptoms may be associated not only with infarction but also associated with lobar hemorrhages.
Because vasculitis of the central nervous system more likely can be seen in a setting of other disorders, a comprehensive medical examination is needed. For example, CNS angiitis can be seen in Behcet’s disease in which oral and genital ulcers and many other skin manifestations such as erythema nodosa and multiple pustules are present. Pustules may form 24 hours after a sterile needle prick (Pathergy) and may clinch the diagnosis. However when fever, weight loss and malaise, nondeforming arthritis, abdominal pain, as well as proteinuria and progressive renal failure occurs, polyarteritis nodosa or a more systemic necrotizing vasculitis should be considered. CNS vasculitis has been linked to drug abuse (e.g. amphetamine). However, histopathology available in the reported cases is scanty leading some investigators to conclude that the relationship between amphetamine and vasculitis is tentative at best. The proof of vasculitis due to cocaine is also weak. Many reported cases do show a vasculopathy, but inflammation is rarely impressive. We have noted a very severe occlusive vasculopathy (with a moyamoya pattern) but no evidence of vasculitis on biopsy. Other signs are absent peripheral pulses and difficulty recording blood pressure (Takayasu’s arteritis), uveitis (sarcoidosis), and recent asthma (Churg-Strauss).
The classification of the vasculitides is shown in Table 1.
Table 1 – Classification of angiitis
Isolated CNS vasculitis
Isolated angiitis (granulomatous)
CNS vasculitis due to secondary causes
Giant cell arteritis
Infections (herpes zoster, syphilis)
Moore’s clinical criteria for the diagnosis of CNS vasculitis are shown here in table 2 for reference. However it remains difficult to define a perfect set of criteria in this rare disorder (more experts than patients) and diagnostic tests, particularly interpretation of brain biopsy may not resolve uncertainties.
Table 2 – Moore’s clinical criteria for diagnosis of isolated angiitis of the CNS
Recent severe onset of headaches, confusion, or multifocal neurologic deficits that are recurrent of progressive
Typical angiographic findings
Exclusion of systemic disease or infection
Leptomeningeal or parenchymal biopsy findings confirming vascular inflammation with exclusion of infection, neoplasia, and non-inflammatory vascular disease
Central nervous system vasculitis is first suggested after routine neuroimaging. The CT scan may show cerebral infarcts in multiple territories but typically involving cortical structures. Although at times, a CT scan may be helpful in diagnosing Wegener’s granulomatosis in which bone thickening focal erosive changes of the natal septum and typical soft tissue mass in the sinuses are seen. The MRI scan more likely will document abnormalities in multiple and cortical structures but may also may be limited to scattered lesions in the white matter as well. Meningeal enhancement due to involvement of the meningeal vessels has been noted. Conversely, one may make an argument that a completely normal MRI scan including diffusion-weighted images would make the diagnosis of fulminant angiitis of the central nervous system highly unlikely. Obviously multiple cerebral infarcts on MRI are nonspecific findings and many disorders (although equally uncommon) may produce similar findings. They are listed in Table 3 and should be excluded before invasive tests (e.g. brain biopsy) are performed.
Table 3 – Differential diagnosis of multiple cerebral infarctions
Cardiac tumor (myxoma)
Antiphospholipid antibody syndrome
Cholesterol embolization syndrome
Thrombotic thrombocytopenia purpura
MR angiogram should be considered inferior to a conventional cerebral angiogram and current sequencing techniques may not visualized involvement of smaller arteries. Cerebral angiogram remains an important diagnostic test; but again, the findings are nonspecific and may be mimicked by many other disorders (Table 4).
Table 4 – Disorders with angiographic findings that can simulate vasculitis
Cerebral vasospasm following aneurysmal or traumatic subarachnoid hemorrhage
Multiple arterial dissections
Acute migraine (thunderclap) attack
However, many of the angiographic findings can be very suggestive of vasculitis particularly when there is alternating constrictions and obliterations ("cutoffs"), irregularities, and dilations in a beading pattern. These abnormalities are typically in the smaller blood vessels and careful viewing of the smaller branches is necessary to find these abnormalities.
The utility of cerebrospinal fluid in the diagnosis of central nervous system angiitis is very questionable. Cerebrospinal fluid examination may show entirely normal protein and cell count including at the time of flare-up. However, mildly increased protein can be seen, and some patients have only a mild pleocytosis with less than 20 lymphocytes per cubic mm. CSF is needed to exclude infectious causes of cerebral arteritis and might be found in cultures and serology. Fungi, tuberculosis, and syphilis may all cause a cerebral arteritis that has to be excluded by CSF and other diagnostic tests and is treated differently.
Blood and serology tests are necessary to exclude a connective tissue disorder. This should include antinuclear antibody, rheumatoid factor, antineutrophil cytoplasmic antibodies, sedimentation rate and serology against an immunodeficiency virus, herpes zoster virus, cytomegalovirus, syphilis, and toxoplasma. A drug screen is essential to exclude the recent use of cocaine or amphetamines. Ideally, the diagnosis is confirmed by a brain biopsy. Diagnostic evaluation are shown in Table 5.
Table 5 – Diagnostic tests in CNS vasculitis
· CBC with platelets
· C3/C4, CH-50
· ANA, ds DNA
· Rheumatoid factor
· Hepatitis serology
· Viral serology (HZV, HIV)
· Urine analysis for glomerular red cells
· Cerebrospinal fluid
· Neurophthalmologic evaluation
· MRI with gadolinium
· Cerebral angiogram
· Brain and meningeal biopsy
False negative brain biopsies remain a major problem in its diagnosis; and in some cases, the diagnosis remains probable on the basis of multiple infarction, cerebral angiographic findings, involvement of other arterial territories, and exclusion of an infectious trigger. Generally, temporal artery biopsy is negative in isolated CNS vasculitis.
The diagnostic evaluation of CNS vasculitis should take into account the presence of systemic signs. If present it may be more practical and safe to obtain a less invasive biopsy such as skin, muscle and kidney. It is useful to perform an MRA in a patient with multiple hyperintensity in cortical areas indicating vasculitis. The MRA may show in some instances fibromuscular dysplasia, atheromatous disease and intracranial stenosis or dissections. MRA should be followed by a cerebral angiogram and a meningeal or brain biopsy. In fulminant cases aggressive immuno-suppressive agents should be started before invasive diagnostic tests.
Many experts prefer a combination of corticosteroids and cyclophosphamide. There is good evidence that aggressive therapy with corticosteroids using 1–2 mg/kg per day in two divided doses and cyclophosphamide, 2 mg/kg per day orally may reverse isolated CNS vasculitis. Typically, corticosteroids are given for at least one month at a high dose and then start gradually tapering with alternate-day and morning dose. The side effects of corticosteroids are significant and involve cushingoid stigmata, delirium, paroxysmal myopathy, hypertension and rarely epidural lipomatosis with cord compression, hyperosmolar nonketotic hyperglycemia, and herpes zoster infections. Osteoporosis is uncommon with a comparatively short treatment, but supplemental calcium should be considered. Cyclophosphamide is probably needed in patients who have a fulminant form and there is some initial evidence that the corticosteroids alone may not reverse vasculitis. Cyclophosphamide is an alkylating agent and is used in an oral dose but has major toxicity including myelosuppression, increased risk of later malignancy particularly leukemia and lymphomas, and a risk of infertility. Egg and sperm harvesting should offered to young patients. The white blood cell count should be carefully monitored (>3000/mm3). Urinalysis may indicate the development of hemorrhagic cystitis. Cyclophosphamide can be tapered after one year. A follow-up cerebral angiogram may not be useful because scar tissue may result in persistent abnormal findings. MRI follow-up documenting absence of further infarction is probably a better monitoring tool. Recurrence is very uncommon.
VASCULITIS OF THE PERPHERAL NERVOUS SYSTEM
The peripheral nervous system may become involved in a variety of acute vasculitis syndromes but may occur isolated. It is present in up to 70 percent in vasculitic syndromes. It may be the first manifestation but features of a more generalized vasculitis become more obvious soon after presentation. Most commonly it is observed in polyarteritis nodosa, Churg-Strauss syndrome, and Wegener’s granulomatosis.
Commonly peripheral nerves are an innocent bystander and the ravaging organ involvement is apparent. Acute mode of onset is not very common (although expected when infarction is the presumed causation) and progression over weeks is typical.
In many connective tissue disorders it may take months to develop a functional disturbance. Transitory shooting pain and paresthesias, foot and wrist drop, and diminished sensation over large skin patches is typical. A "sock-glove" distal sensory-motor polyneuropathy is most common; however, cranial nerves may become involved as well (III, V,VI). Pain and a rapid crippling state are typical if untreated. An ascending paralysis resulting in a quadriparesis may occur, but the marked asymmetry makes a confusion with Guillain-Barré syndrome less likely. Cramping and burning sensation with inability to walk and constant sensation of "rock in a shoe" or "tight band in calves" are common complaints. Examination often shows some skin involvement (purpura, erythema multiforme). Radial, ulnar, and femoral nerves are commonly involved.
Nerve conduction studies will confirm nerve involvement. General observations in axonal damage are poor recruitement of motor units with voluntary effort, reduced amplitude of the motor response and mild slowing of the nerve conduction velocity. Over time reinnervation will produce long duration-high amplitude- motor unit potentials.
The diagnosis hinges on confirmation by sural nerve biopsy but biopsy may also include muscle (30% positive result), rectum (15% positive result), and liver (7% positive result).
The diagnosis of vasculitis is highly probable with transmural inflammatory cell infiltration but other features are very suggestive such as vascular thickening and sclerosis in combination with Wallerian degeneration, obliteration of vessel lumen, periadventitial hemosiderin and epineural capillary proliferation. A recent study found that biopsy of the superficial peroneal and peroneus brevis muscle resulted in a higher yield. Additional iron stains and immune staining for immunoglobulin could further increase the sensitivity.
Both cyclophosphamide (1–2 mg/kg orally) and prednisone (1 mg/kg/day) for 2 months followed by a tapering schedule can reduce damage and lead to improvement. Plasma exchange or azathioprine may be useful. Neuropathic pain can be treated with gabapentin, 900 to 3600 mg/day or low dose of prednisone, 10 mg/day after initial high-dose therapy of nortriptyline or amitriptyline. A recent report of a necrotizing vasculitis associated with cold agglutinins suggest improvement with plasma exchange.