Clinical manifestations

Presentation and course

By definition, these conditions involve progressive impairment of cognition. No evidence is available to suggest that the pattern of cognitive decline can distinguish between different vasculitides. Headache is very common in vasculitic dementia, much more so than in dementia from other causes, but it is not diagnostic. The headache is often of a throbbing migrainous kind and is especially common in the early stages of vasculitic dementia before frank cognitive loss develops. Cognitive loss proceeds more rapidly in vasculitic disease than it does in most other types of dementia, as most of the vasculitides evolve over weeks and months, rather than the years typical of most primary degenerative dementias. Depression may also be prominent early on, but this is not uncommon in many forms of dementia. Beyond these simple observations, it is the presence of other associated findings in the history, examination, and investigations that raises the possibility of a vasculitic cause for dementia. These findings may be subtle, and a high level of suspicion is often necessary to make the correct diagnosis. Establishment of the correct diagnosis is important, as many of these conditions are treatable. Table 1 lists the vasculitides and related conditions for which dementia or lesser degrees of cognitive impairment have been reported as the presenting clinical feature.

Table 1. Vasculitic Conditions with Dementia or Other Cognitive Impairment as the Presenting Feature

Primary angiitis of the CNS, an isolated granulomatous angiitis of the nervous system, though rare, is the archetypical vasculitic cause of dementia and the most difficult to diagnose because of its lack of associated extracranial abnormalities. About 30% of cases of primary angiitis of the CNS have cognitive impairment at first presentation and up to 70% will eventually develop cognitive impairment (57). "Primary angiitis of the central nervous system" is the preferred term, as granulomas are not always seen. It may affect adults of any age, and many cases have been reported in children. It typically evolves over days to months, with an average of 5 months from onset to diagnosis. Systemic features are usually absent. Spinal cord involvement occurs in 5% of cases. Papilledema occurs in 20% to 50%, there may also be an optic neuropathy, a low-grade aseptic meningitis may be present, and a CSF pleocytosis is present in two thirds of cases and helps distinguish primary angiitis from reversible vasoconstriction (Call-Fleming) syndrome (33). Headache is often prominent and is present in over two-thirds of patients (57). It may occasionally present with mass lesions that may be confused with tumors. Radiological, angiographic, and histological findings similar to those of primary angiitis of the CNS may be seen in association with Hodgkin disease, AIDS, lymphoma, varicella encephalitis, leukemia, sarcoidosis, dermatomyositis, and other conditions. Although some authors consider such cases to be primary angiitis of the CNS, this is not a useful practice, as the changes may be a nonspecific phenomenon. "Primary angiitis of the central nervous system" and its synonyms should be reserved for a condition occurring in isolation from systemic or other CNS disease. However, it should be noted that what otherwise appears to be primary angiitis of the central nervous system may coexist with lymphoma in 5.9% of patients (56). Historically, reversible cerebral vasoconstriction was often confused with primary angiitis of the central nervous system, but clues to the correct diagnosis come from a history of thunderclap headache, which strongly favors reversible cerebral vasoconstriction and imaging findings of small deep infarcts, extensive deep white matter lesions, tumor-like lesions, or multiple enhancing lesions, which are only seen in primary angiitis of the central nervous system (16).

Stroke occurs in 3% to 15% of cases of systemic lupus erythematosus. This is usually due to cardiac embolism, rather than vasculitis, as a true cerebral vasculitis is rare in systemic lupus erythematosus (21). Dementia may rarely occur in systemic lupus erythematosus; in such cases, dementia is invariably preceded by clinical and immunological manifestations of systemic lupus erythematosus, and in all but one reported case, a clear association with stroke is evident. Cognitive decline in systemic lupus erythematosus is much more common than frank dementia and affects a substantial minority of patients. It is typically of insidious onset and may have prominent effects on visuospatial and memory functions. It may resolve, and correlation with disease activity is poor. Much of the cognitive loss may be due to coexistent psychiatric illness. Antilymphocyte antibodies cross-reactive against neurons and anti-ribosomal antibodies may be part of the etiology.

Although not a vasculitis, dementia in association with the lupus anticoagulant or anticardiolipin antibodies alone has been reported (13; 14). The associated antibodies are of the IgG and not the IgM isotype. Most commonly, stroke is the first presentation, leading to a diagnosis of multi-infarct dementia in about 10% of cases in some series. The dementia can be progressive without clinical stroke, even early in the course (22). However, dementia of any kind is uncommon in this syndrome, and some series have not mentioned dementia as a complication at all.

Amyloid-beta related angiopathy (or cerebral amyloid angiopathy related inflammation) appears to be an immune response to amyloid-beta deposited in the walls of vessels as part of cerebral amyloid angiopathy leading to intramural inflammation. As such, it is seen in more elderly patients, often from the seventh decade of life, and it most commonly presents with subacute cognitive decline, focal neurologic deficits, and an encephalopathic picture; seizures and headache are both common (31; 68).

Sneddon syndrome features livedo reticularis (a blotchy purple discoloration of the skin) due to impaired superficial venous drainage; it is often seen in association with a number of collagen vascular diseases but may exist as an isolated entity. It is usually sporadic but may be seen in families when it has an autosomal dominant pattern. Sneddon syndrome is associated with antiphospholipid antibodies and, in some cases, verrucous endocarditis. In those without these antibodies, there may be an etiologic role for protein Z deficiency. Vasculitis seems rare, although one series reported a distal arteriopathy in 12 of 15 cases (37). Dementia is usually preceded by both livedo reticularis and repeated minor stroke. However, Sneddon syndrome may be associated with a greater degree of dementia than would be expected from known strokes (14). Cognitive impairment short of dementia is almost universal in these patients, the pattern being that of a subcortical dementia (36). Cerebral histopathology is sparse, but there is a vasculopathy affecting small and medium vessels characterized by intimal and medial proliferation with leukoencephalopathy and small cortical infarcts (27).

Susac syndrome, or retinocochleocerebral vasculopathy, usually affects women aged 20 to 40 years but may also affect men and women aged 9 to 69 years (66; 19). The syndrome, etiologically an autoimmune vasculopathy, possibly due to antiendothelial cell antibodies (38), comprises sensorineural hearing loss (in 40% fluctuating hearing loss, in 60% tinnitus, and in 50% bilateral), vertigo in over half, retinal arteriolar occlusions, and multiple small cerebral infarcts producing psychiatric, cognitive, and focal neurologic disturbances that may progress to dementia. The onset typically includes personality change and headache with or without hearing loss, but most patients become demented, by which time reflex changes, hearing loss, and retinal branch occlusions are universal. Progression is over a few weeks to 6 months. There are no systemic features.

A group of hereditary, autosomal dominant, cerebroretinal vasculopathies also exists; these are linked to chromosome 3p21 and include cerebroretinal vasculopathy, HERNS (hereditary endotheliopathy with retinopathy, nephropathy, and stroke), and hereditary vascular retinopathy. They are all rare and generally limited to a few families. All of these may produce some cognitive decline, sometimes to the point of dementia, and feature leukoaraiosis on MRI. HERNS and cerebroretinal vasculopathy may also produce lacunar infarcts and contrast-enhancing mass lesions. These generally present in midlife, although investigation may demonstrate abnormalities well before this. Migraine is a common accompaniment, and Raynaud phenomenon is common in hereditary vascular retinopathy. Diagnosis is facilitated by family history and careful ophthalmological evaluation.

Cerebral involvement in giant cell arteritis occurs in about 7% of cases (60), and when it occurs, it is usually encephalopathic or in association with infarcts.

Sjögren syndrome may involve the CNS, particularly when it is secondary, but in a retrospective series of 105 cases of primary and secondary Sjögren syndrome, no dementia was found and only eight cases had CNS involvement of any kind (09). Multiple sclerosis and stroke-like syndromes occur, and neuropsychiatric features, particularly depression, may be seen in two thirds of patients with CNS involvement; cognitive loss, not necessarily to the point of dementia, is seen in only about 10%.

Polyarteritis nodosa may rarely involve the CNS and cause multiple small infarcts and typical arteritic changes, sometimes with aneurysms that can be seen angiographically. However, headache, seizures, confusion, and psychoses are the common clinical features of CNS involvement in polyarteritis nodosa. Cognitive decline falling short of dementia is common in this as well as in Wegener granulomatosis and Churg-Strauss syndrome. The cognitive deficit is typically subcortical in nature, and some cognitive loss can be found in 20% to 30% of such patients if it is carefully sought, even when overall cognition appears intact. Cognition may also be affected in polyarteritis nodosa in the context of a diffuse encephalopathy.

Behçet disease may cause dementia in about 10% of those with neurologic involvement, but this invariably occurs in association with other neurologic deficits.

One instance of CNS vasculitis developing as a possible complication of daclizumab therapy has been reported (43), as has one instance arising in association with Hodgkin lymphoma and its treatment (35).

Clinical vignette

A 58-year-old Afro-Caribbean female was admitted to her local hospital with a 6-month history of depression, a 2-month history of apparent cognitive decline with irrelevant talk, and a 3-week history of refusing to go out, all of this accompanied by weight loss of 20 Kg.

On admission to the hospital, she was confused but alert. An initial CT brain scan was reported as normal. On later review, this was felt to be largely correct except for subtle hypodensities in the immediately subcortical frontal white matter bilaterally. A full blood count, erythrocyte sedimentation rate, urea, electrolytes, liver function tests, thyroid function, vitamin B12, and folate were all normal. C-reactive protein was less than 3 (normal, less than 10). During her first few days she was observed to be neither eating nor drinking, and there was fecal incontinence. She was felt to be depressed; a psychiatric opinion was sought and treatment started with citalopram. On her 10th hospital day, right partial seizures were noted and were treated initially with clonazepam and phenytoin. A further CT on day 13 showed a right thalamic infarct. The next day CSF examination revealed no cells, a protein of 0.65 g/L and a glucose of 3.9 mMol. On day 16 she developed right-sided weakness with initial rapid recovery. MRI at this stage revealed multiple lesions that did not enhance with gadolinium. She was transferred to the neurologic center.

On arrival she was drowsy but responded to verbal stimulation and obeyed 1-step commands. She was not oriented to place or day or year but knew the month. She was able to name her national prime minister and United States president and other simple objects. Other than diffusely increased tone, greater on the right than the left, there were no focal findings. There was evidence of a chest infection, CRP on arrival was 296, and diarrhea developed, subsequently found to be due to Clostridium difficile. Throughout her admission, changes in inflammatory markers were related to pneumonia and C difficile diarrhea and not to the cerebral condition. Additional blood work including ANCA, ANA, thrombophilia screen, and dsDNA was all normal.

On the 23rd day, pronounced right hemiparesis and hemisensory loss and increased tone on the left were also noted. Further MRI revealed new lesions that were nonenhancing.

A selective cerebral arteriogram carried out on day 24 was normal. Further CSF examination was once again entirely normal, and on day 26 a right frontal and dural brain biopsy was done, which again was normal. On this day a right homonymous hemianopia was also noted, and the next day there was some weakness of the left lower limb and increased right-sided weakness. On the basis of a working diagnosis of primary angiitis of the central nervous system, but with concern because of chest infections and C difficile diarrhea, treatment was started with 1g/day of methylprednisolone for three days. Subsequently, there was some improvement in alertness and cognition, formal assessment being hampered by an ICU admission for pneumonia. By day 38 she was alert, moving her left-sided limbs to command, and able to be sat out of bed. Three days later, further right focal motor seizures developed and persisted for three days despite intravenous lorazepam and phenytoin, only subsiding after treatment with levetiracetam, which was continued indefinitely thereafter.

On day 50 a psychosis developed, and on day 52 right frontal aversive seizures appeared. Further MRI on day 58 revealed new lesions, and prednisolone was resumed. On day 64 right focal status epilepticus with a fluctuating level of consciousness developed; EEG showed continuous left hemispheric PLEDs. The focal status settled in response to adjustment of her anticonvulsants although repeat EEG on day 67 was not improved, despite the clinical improvement. A second angiogram was done on day 69 in view of the lack of a confirmed diagnosis to date and concern that the first angiogram was suboptimal due to restlessness. This again was normal. She was stable for the next week, but on day 76 developed jargon aphasia intermixed with periods of no speech. MRI on day 79 revealed further new but nonenhancing lesions, and treatment was started with cyclophosphamide and prednisolone 40 mg per day in spite of the absence of a confirmed diagnosis. She remained stable thereafter. MRI on day 112 showed no further progression and possible improvement of the right parietal lesions.

Comment. This case illustrates a number of points. The first is the very nonspecific and prolonged onset with behavioral and cognitive decline without other neurologic features leading to an initial diagnosis of depression. The second is the initial response to high-dose methylprednisolone but with a long-term requirement for cyclophosphamide. And the third is the difficulty of making the diagnosis with normal CSF and angiography (both done twice) and brain biopsy, the diagnosis here being based on the clinical and imaging course, responsiveness to immunosuppressants, and lack of any other explanation.

Biological basis

Etiology and pathogenesis

Etiology varies according to the condition, although most of the vasculitides are idiopathic.

Primary angiitis of the CNS usually affects vessels in the 100 to 500 µm range, especially small leptomeningeal vessels and precapillary arterioles, although occasionally larger cerebral vessels may be involved. Venous involvement is usually minor, but it may be prominent. Lymphocytes, plasma cells, and other mononuclear cells, including some eosinophils, surround the affected vessels. Giant cells are variable but may be seen in the media, adventitia, or perivascular spaces. Complement may be involved (39).

Epidemiology

All of these conditions are rare. Primary angiitis of the central nervous system is estimated to occur in 5.1 cases per million person-years (44).

Differential diagnosis

Confusing conditions

A wide variety of conditions may cause a real or apparent subacute impairment of cognition:

Diagnostic workup

Initial investigation of subacute cognitive impairment should include EEG, complete blood count, erythrocyte sedimentation rate, syphilis serology, HIV serology, thyroxine or sensitive thyroid releasing hormone assay, blood urea nitrogen, electrolytes, and liver function tests. CT brain scan or MRI is also necessary. MRI is preferred where structural or vasculitic lesions are suspected because of its greater sensitivity for small and white matter lesions. Further specific investigation is directed by clinical suspicion and the results of the initial basic investigations. Chest x-ray, ECG, 24-hour Holter monitoring, carotid ultrasound, echocardiography, coagulation screen, lupus anticoagulant, antiphospholipid antibodies, antineutrophil cytoplasm antibodies, autoantibody screen, serology for infectious causes and mimics (S pneumoniae, Mycoplasma pneumoniae, tuberculosis, hepatitis B and C, JC virus, Bartonella, Epstein-Barr virus, cytomegalovirus, varicella zoster virus, human herpes viruses 6 and 7, adenoviruses, enteroviruses, measles virus, parvovirus B19, West Nile virus, HIV, syphilis, and fungi), and antinuclear factor may all be appropriate in the investigation of a suspected arteritis. CSF examination may provide a positive diagnosis in cases where the etiology is infective or malignant. However, in cases of arteritis, it may be normal or nonspecifically abnormal with a modestly raised protein, a mononuclear pleocytosis, and normal glucose.

In most cases where cognitive loss is due to vasculitis, these investigations will provide sufficient evidence to make a diagnosis and commence treatment. In some cases, particularly primary angiitis of the CNS, it may be necessary to obtain further proof, as the other investigations may be normal or nonspecifically abnormal.

In primary angiitis of the CNS, CT, MRI, and cerebral angiography may be normal or show only nonspecific changes, especially early in the disease (01; 12; 06). Angiography is considered to be the most sensitive and specific of the less invasive investigations, but may be falsely negative in up to two thirds of cases of primary angiitis of the CNS (42; 32; 01; 02; 53). A positive angiogram will demonstrate abnormalities in medium and small vessels such as alternating vessel narrowing and dilatations (often circumferential) and beading, but these findings may also be seen in other conditions, particularly reversible vasoconstriction syndrome but also fibromuscular dysplasia and atherosclerosis. Consequently, false-positive angiograms are not uncommon and may exceed true positive findings (48). Of the abnormal ones, nonspecific arterial narrowing is seen in 50%, and only 25% show "arteritic" changes (32). A normal MR scan makes a positive angiogram unlikely in the context of vasculitis in general, but this rule may be broken in primary angiitis of the CNS. There is increasing evidence that high-resolution contrast-enhanced MRI looking for vessel wall enhancement may be both specific and sensitive, even for intracranial disease (34; 52; 47; 06) and may facilitate distinguishing primary angiitis of the CNS from reversible cerebral vasoconstriction syndrome (40). However, other conditions including neurosarcoidosis may give rise to vessel wall enhancement (05).

The CT and MR appearances of primary angiitis of the CNS are typically those of bilateral supratentorial infarcts, which are more commonly seen in the white matter than in the grey and are not necessarily specific. Radiological misdiagnoses include multiple sclerosis, CADASIL, acute disseminated encephalomyelitis, and tumor (particularly low-grade glioma), and the disease can cause intracerebral hemorrhage. The appearance of enhancement in many of the lesions, of enlarged and enhancing Virchow-Robin perivascular spaces and of lesions in the spinal cord may be indicators in favor of primary angiitis (10).

The CSF findings in primary angiitis of the central nervous system are also variable. The CSF may occasionally be normal; more commonly, the CSF protein is mildly elevated with a modest lymphocytic pleocytosis of up to 150 cells/mm3 (15; 32; 28). However, the CSF is not always abnormal (06). Likewise, the EEG may be normal or slow with or without focal changes. Systemic investigations, such as the erythrocyte sedimentation rate, white count, antinuclear antibodies, rheumatoid factor, immune complexes, and cryoglobulins, are largely negative though the erythrocyte sedimentation rate and C-reactive protein may occasionally be elevated. Case series suggest that the erythrocyte sedimentation rate and C-reactive protein may be elevated more often in children than in adults.

The potential for both false positive and false negative angiograms and other nondiagnostic investigations means that a low threshold for brain and meningeal biopsy is necessary if the diagnosis is being seriously considered (64; 08; 51). In appropriately selected cases, up to three-quarters of patients biopsied will receive a positive diagnosis but, importantly, this is of an unsuspected alternative explanation in about half of the definite diagnoses (51; 65). Vasculitic changes in multiple medium and small arteries are typical, and occlusion of small vessels may be seen (42; 32; 12), but the condition may occasionally affect larger vessels, which may not be sampled on a peripheral biopsy (63). Granulomas are seen in about 60% of patients, with a lymphocytic infiltrate in most of the rest (41). However, biopsies may also be falsely negative. Larger open biopsies may help minimize this risk (69). In a series in which 24 patients had both positive angiograms and biopsies, the biopsies were negative in 18 (53). In another series, 24 patients with a clinical diagnosis of vasculitis, eight of whom had angiograms that were no more than suggestive of, rather than diagnostic of, vasculitis, had biopsies, none of which confirmed the clinical diagnosis (62). The most common finding was nonspecific inflammation. There is some evidence to suggest that patients with negative biopsies do not usually turn out to have primary angiitis of the central nervous system, at least not that which is responsive to immunosuppressants (03). It is becoming increasingly clear that many cases of angiogram-positive but biopsy-negative cases of primary angiitis of the CNS were in fact cases of reversible cerebral vasoconstriction syndrome (RCVS) (25), hence, the more benign course and lack of response to immunosuppression. Consequently, diagnosis of this condition requires an overall consideration of the history, imaging, angiography, biopsy, and other investigations (64).

A diagnosis of amyloid beta-related angiitis is supported by MRI findings of the underlying cerebral amyloid angiopathy including predominantly cortical microhemorrhages combined with changes related to inflammation including juxtacortical T2 hyperintensities and leptomeningeal enhancement. Angiography is normal as the affected vessels are too small to be seen on catheter angiography. Peripheral inflammatory markers are elevated only in a minority. The CSF shows a modestly elevated protein in 71% and mild pleocytosis in 45% (31; 11), but biopsy is generally necessary to confirm the diagnosis (64; 25; 51).

Neuropsychiatric systemic lupus erythematosus can be identified using a combination of CSF oligoclonal bands, elevated CSF antineuronal antibodies, and serum anti-ribosomal-P antibodies, though it remains to be established whether the immunological processes these abnormalities reflect are important in systemic lupus erythematosus presenting with cognitive loss.

Retinocochleocerebral vasculopathy may produce an elevated erythrocyte sedimentation rate and CSF protein with a slight lymphocytic pleocytosis. The EEG typically shows diffuse slowing. CT may be normal, but MRI shows multiple small areas of increased signal intensity reminiscent of multiple sclerosis. However, the pattern may be sufficiently distinctive to distinguish it from multiple sclerosis and other demyelinating conditions. In particular, the lesions are often very small (3 to 7 mm), tend to involve the central corpus callosum where they may appear rounded (snowballs) or linear (spokes), commonly affect deep grey structures, and may proceed to central cavitation, similar to lacunar infarcts. There may be leptomeningeal enhancement in about one third of cases (67; 66), and this may predict more aggressive disease with a higher relapse rate during treatment (17). Angiography is usually normal. Brain biopsy shows microinfarcts and medial and adventitial sclerosis around small arterioles (66) which may represent healed lesions; inflammatory changes have not been reported.

Where polyarteritis nodosa or a forme fruste is suspected, visceral or cerebral angiography or biopsy of an affected organ, subcutaneous nodule, or sural nerve may be diagnostic.

Angioendotheliomatosis, a condition in which a proliferation occurs of endothelial cells in many organs in the absence of signs of inflammation, may cause a subacute dementia developing over months, often associated with renal involvement and skin ulceration. Skin biopsy may be diagnostic.

Angiocentric, angiodestructive T-cell lymphoma (lymphomatoid granulomatosis) may rarely be limited to the CNS, where it may present with dementia and requires biopsy for diagnosis (30).

Management

Primary angiitis of the CNS initially should be treated with high-dose daily prednisolone (typically 80 mg) and cyclophosphamide, later reducing the prednisolone to alternate-day therapy but maintaining the cyclophosphamide (15). Although patients may respond to prednisolone alone, prednisolone monotherapy triples the risk of relapse (54) and may be insufficient (20). Cyclophosphamide may be given orally (about 2 mg/kg per day initially) or via a pulsed intravenous regime, although, extrapolating from ANCA-associated vasculitis, the pulsed regime may be associated with a higher relapse rate (18; 26). Azathioprine may not be sufficiently potent to be an alternative to cyclophosphamide, whereas mycophenolate and rituximab may be alternatives (28; 23; 24; 58; 59; 54). In children, similar considerations apply with maintenance with mycophenolate (07).

Amyloid-beta related angiitis can be treated with steroids, sometimes with additional immunosuppressive agents or intravenous immunoglobulin (31).

Wegener granulomatosis requires cyclophosphamide (20), often with steroids initially although it may be possible to switch to azathioprine after the induction of remission (29).

Retinocochleocerebral vasculopathy may be effectively treated with prednisolone 80 mg/day, but immunoglobulin and cyclophosphamide may be necessary, often in combination (61; 66). Reports suggest a similarity between Susac syndrome and dermatomyositis concerning etiology, natural history, and treatment (49).

Outcomes

This varies according to the condition. Untreated, primary angiitis of the CNS is usually fatal, whereas prolonged remission may be induced by treatment with cyclophosphamide and alternate-day steroids.

Susac syndrome may recur late after successful treatment even after decades (46), and early treatment may avoid permanent disability. Auditory loss tends not to recover (04).

Special considerations

Pregnancy

No information is available for most of these conditions. In Susac syndrome, four reported pregnancies resulted in two induced abortions, one normal pregnancy, and one postpartum exacerbation (04).