Primary angiitis of the CNS and ANCA-associated vasculitis: from pathology to treatment

The neurological findings can vary between the central and peripheral nervous systems. It is important to understand the scope of clinical and radiological involvement of AAV, since many clinical and radiological manifestations depend on the affected anatomical structure. The scope of the disease can affect the brain parenchyma, meninges, pituitary gland stalk, and spinal cord, in addition to non-CNS entities such as cranial nerves, orbits, and Sino-nasal structures [27]. Early signs of AAV of the CNS include ischemic infarction and intracranial hemorrhage that can either be restricted to the brain parenchyma or extend to the subarachnoid space and are often resistant to antiplatelet therapy [28]. Some papers reported relapsing cases of subarachnoid hemorrhage, and in a different case reported by Esfahani et al., intracranial hemorrhage appeared in a patient after administering tissue plasminogen activator (tPA) for acute ischemic stroke, which stresses the need of cautious diagnosis to exclude AAV [29, 30]. Cognitive impairment is another manifestation of brain parenchyma involvement and is characterized by a cognitive decline in abstract reasoning, memory, and attention [31]. Later outcomes of AAV of the CNS is posterior reversible encephalopathy syndrome (PRES) in the brain parenchyma, and it appears with symptoms like encephalopathy, headaches, and visual disturbances [27]. Hypertrophic pachymeningitis (HP), which can involve both the brain meninges and spinal cord, is also described among AAV patients. Studies have shown that AAV patients with HP present higher frequencies of headaches and cranial nerve palsy than those without HP [27, 32]. Moreover, the study by Shimojima et al. demonstrated that the prevalence of HP was lower in the early stages of AAV, which suggests that HP involvement is more common in the late stages of AAV and that CNS manifestation might prevail in the later stages of AAV [32]. Pituitary gland involvement is also a common presentation of AAV of the CNS that presents as either hypopituitarism, diabetes insipidus, or visual defects due to compression of the optic chiasm [33, 34].

Manuscripts on AAV manifestation in the central nervous system as well as the clinical assessment of AAV patients are presented in Table 3.

Headaches are thought to be the first and predominant manifestation of CNS vasculitis, especially in GPA patients, and this nonspecific presentation can delay the diagnosis [18]. Among the assessed research articles, a case study by Caramaschi et al. reported that CNS symptoms such as headaches, hearing loss, and olfactory deficiency were predominant [38]. Moreover, the most frequent clinical presentations among all forms of AAV patients were sensorimotor impairment and headaches, while other presentations of symptoms such as seizures, gait, and hearing loss were variable among research on different subsets [14, 35‐37]. Previous results can be explained by the different forms of AAV involved, which have a variation in the appearance of clinical symptoms. GPA mainly affects three important structures of the CNS: the meninges, pituitary gland, and cerebral vasculature, while EGPA and MPA lead mainly to cerebral infarctions and intracerebral hemorrhage [18, 25, 39]. The pituitary gland is estimated to be affected in 1.1–1.3% of GPA patients [18]. Hypophysis of the pituitary gland in those patients can cause abnormalities and dysfunction of both the posterior and anterior pituitary glands. Diabetes insipidus patients were reported in the finding of both Ma et al. and De Luna et al. The manifestation of diabetes insipidus is anatomically postulated to contribute to the pathogenesis and mechanism of AAV, especially in GPA, in which its granulomatous inflammation can invade Sino-nasal surrounding structures [39]. In addition to diabetes insipidus, inflammation can lead to secondary gonadism, secondary hypothyroidism, secondary adrenal insufficiency, and secondary growth hormone deficiency [40]. GPA subtype of AAV can also cause compression of the pituitary stalk, which can lead to hyperprolactinemia, galactorrhea, and visual disturbances [41]. Psychiatric disorders were also present among the assessed patients and manifested as depression, delirium, and cognitive impairment [28, 39]. The previous impairments are most likely linked to cerebral ischemic and hemorrhagic vasculitis damage, in addition to other presentations, such as transient ischemic attack (TIA), seizures, and cortical blindness [18]. The involvement of GPA in the meninges, especially granulomatous inflammatory thickening of the dura, has been proven to be linked to symptoms such as cerebellar ataxia, seizures, and cranial neuropathies. Chronic hypertrophic pachymeningitis is linked to ANCA serology and presented as an outcome for both GPA and MPA similarly [18]. Spinal cord involvement is more common among MPA patients than the other subtypes [27].

The clinical symptoms of PACNS are variable, and to help in recognizing the disease, three suggested clinical presentations were described [42]: (1) acute or subacute encephalopathy that can progress from confusion to drowsiness and coma; (2) multiple sclerosis presentation or mimicking presentation with atypical features, remitting and relapsing course such as optic neuropathy and brainstem episodes. In addition to symptoms such as seizures, persistent headaches, stroke-like episodes, and encephalopathy; and (3) intracranial mass lesions with headaches and focal signs [10, 43‐63]. To interpret these presentations, it is suggested that if large and medium vessels are involved, stroke is most likely the manifestation. If small vessels are involved, encephalopathy, cognitive dysfunction, and seizures are the main manifestations [13]. In a systematic review written by Sarti et al., 24 case series were grouped, and the clinical manifestation frequency was assessed. This case series had 585 patients diagnosed with PACNS, with 41% of the cases confirmed with a biopsy [11]. According to Sarti et al., headaches were present in 57.1% (320/560) of patients, making it the first and most common symptom among all PACNS cases [11]. However, thunderclap headaches should be excluded from this criterion, as it was shown that it is a manifestation of reversible cerebral vasoconstriction syndrome [13]. Cognitive impairment was reported in 42.7% (190/445) of patients, while stroke and TIA were present in 44.4% (340/564) of patients. Sundaram argues that the acute onset of focal neurological deficits is due to strokes and TIA [13]. Other presentations, such as seizures, impaired level of consciousness, and mood disorders, accounted for 26.9%, 30.6%, and 20.9%, respectively. In other reports, stroke-like symptoms, seizures, frontal lobe dementia, and ataxia were the first reported manifestations of PACNS rather than headaches [64‐66].

For patients suspected to have central nervous system vasculitis, it was recommended by the American College of Radiology Appropriateness Criteria (ACR) to use head magnetic resonance angiography (MRA) with or without contrast [67]. A summary of the most common MRI findings among AAV patients is as follows [19, 27, 35]:

Research has shown that cerebral ischemia is a predominant finding among AAV patients, as similarly confirmed in research conducted by Ma et al.; 24/29 patients showed cerebral ischemia on MRI [19]. Features of vascular alternating narrowing and dilation (VAND) were detected among GPA patients in the study performed by Lubas et al., suggesting that VAND can occur as a feature of vasogenic alteration in AAV [37]. In later stages of AAV of the CNS, vasogenic edema involving the bilateral parietal–occipital region might be found during screening and is consistent with PRES [27].

Radiological findings of PACNS are diverse and can be measured by several techniques depending on the size of vessels and the symptom manifestation. However, identifying features that are consistent with PACNS is challenging since many are common among the different subtypes of vasculitis. For example, in a study conducted by Arnet et al., luminal stenosis was a common finding among all types of vasculitis [68]. It is important to differentiate between radiological features that are consistent with other diseases while building a differential diagnosis. For example, changes and occlusions in the fusiform vessel wall are considered shared characteristics between PACNS and polyarteritis nodosa, giant cell arteritis, Sjogren syndrome, and infectious vasculitis [68].

The diagnosis of AAV of the CNS is composed of 3 clinical steps, laboratory, and radiological assessment. Starting with laboratory assessment, a very detailed workup should be ordered for patients who are suspected to have AAV. ANCA serology is a very important parameter to be assessed, although it is not a confirmatory or diagnostic parameter for AAV of the CNS. This is because a seronegative ANCA immunoassay is also a finding among many GPA and MPA patients and because ANCA can be positive in other vasculitis diseases, systemic disorders, infections, drugs, gastrointestinal diseases, and malignancies [27, 69]. A high-quality antigen immune assay for both anti-MPO and anti-PR3 is highly recommended, especially because it allows physicians to have more insight into the presentation of the disease and characteristics related to remission and relapses. Patients diagnosed with MPA have a lower relapse rate than patients diagnosed with GPA [14]. Inflammatory markers are very important for testing AAV, and its findings present as elevation of both erythrocyte sedimentation rates (ESR) and C-reactive protein (CRP), leukocytosis, and thrombocytosis [35, 70, 71]. Physicians suspecting AAV are also recommended to assess kidney function and autoimmune panels to assess mimics for differential diagnosis [27]. Since many cases of AAV present pituitary involvement, it is recommended to carry out an endocrine panel related to pituitary hormones, especially if an abnormal pituitary screening is obtained [33, 34]. Analysis of cerebrospinal fluid (CSF) is an important step in the diagnosis of AAV of the CNS, and physicians expect to find parameters of meningitis, such as protein > 0.40 g/l, WBC > 10/mm³, and glucose < 2.8 mmol/L [35]. Histopathology or biopsy of the CNS is the gold standard in the diagnosis of AAV, and several research works had limitations in their findings for not including CNS biopsy as a diagnostic tool [14]. Pathologists aim to find a necrotizing or granulomatous pattern, lympho-monocyte inflammatory infiltrate, multinucleated giant cells, and fibroblastic proliferation [5, 7, 72]. It is important to highlight that a negative biopsy result does not exclude the probability of AAV due to the segmental quality of the lesions present in the CNS [27]. MRI of the brain and spinal cord needs to be assessed for any abnormalities that were discussed in the previous section. Some scores are used to assess the degree of the disease manifestation, such as the Birmingham vasculitis activity score (BVAS), a clinical index of disease activity based on clinical evaluation of nine organ systems [73].

The investigation for PACNS is controversial, and until today, there are no clinical, laboratory, or radiological findings that are 100% confined to this condition. This imposes a challenge on physicians to make the correct diagnosis and exclude all the mimics and variants of the disease. The first diagnostic approach was proposed by Calabrese and Mallek in 1988 and included the following criteria [5, 74]:

In 2009, Birnbaum et al. proposed a modification to these criteria by highlighting the most likely mimics of PACNS [9]. They also proposed the level of certainty that is divided into definite, which is when tissue biopsy specimen results are consistent with the diagnosis of PACNS, and probable, if the result findings are highly probable of PACNS on angiogram, MRI, and CSF but without a confirmatory tissue biopsy [5, 9]. Therefore, after symptoms are suspected, the first step is to obtain an MRI, which in most cases of PACNS is pathological. Then, cerebral angiography or biopsy is indicated with other laboratory investigations to rule out secondary causes of CNS vasculitis and mimics of PACNS.

Laboratory parameters are needed, especially the laboratory workup focusing on inflammation and antibody-mediated disease. Assessment of CSF is also important in diagnosing PACNS and in excluding other possibilities of vasculitis, such as infections and neoplasms [13]. Pathological CSF findings that are consistent with PACNS were described as elevated cell count (pleocytosis) with or without an increase in protein levels, and the following was present in 43.5% of patients diagnosed with PACNS [75, 76]. Oligoclonal banding may also be found in the sample [77]. Neuroimaging is variable, and each technique has a different indication. CT scans are usually indicated for the detection of single or multiple infarcts and intracerebral hemorrhages. On the other hand, Magnetic resonance imaging (MRI) is indicated for the observation of parenchymal and meningeal lesions. Magnetic resonance angiography (MRA) helps detect large and medium-sized vessel involvement, while cerebral angiography (CA) or conventional 4-vessel digit subtraction angiography is considered a confirmatory imaging technique for PACNS. Biopsy is still the gold standard in confirming PACNS.

A suggested diagnostic criterion was proposed by Sarti et al. [11]. First, they calculated the median frequencies for both clinical and radiological features present in the case studies that they worked on. Accordingly, the median frequency for clinical features was 42.7% and that for radiological features was 46.6%. Second, they defined the major and minor clinical and radiological features based on whether they were greater than or less than the calculated frequencies. The major clinical features consisted of headaches, stroke, cognitive impairment, and focal neurological deficits, while the minor criteria consisted of seizures, altered levels of consciousness, and psychiatric disorders. For the neuroradiological findings, the major criteria consisted of multiple parenchymal lesions, parenchymal or meningeal contrast, enhancement vessel abnormalities, and vessel wall contrast enhancement. The minor features, on the other hand, consisted of parenchymal or subarachnoid hemorrhages and single parenchymal lesions.

Third, they developed 7 possible combinations of these features, but only the first two A and B combinations were consistent with the Calabrese and Mallek criteria and verified in all 32 case studies and, thus, can be taken into consideration in the future evaluation of patients. The first combination A consists of one clinical (major + minor) feature and one major neurological feature. On the other hand, combination B consists of two clinical features (at least one major feature with one of the major neurological features) [11]. However, this study has many limitations, and more research is needed to validate the implementation of such proposed criteria.

The management of AAV patients is based on the remission-induction phase, followed by a maintenance phase [78]. To differentiate between different research outcomes, Ma et al. defined 3 aspects of management findings with the Birmingham vasculitis activity score (BVAS) new/worse. This score defined complete remission as the absence of disease activity that needs stable maintenance immunosuppressive therapy, while partial remission was defined as a minimum reduction in the disease activity score by half without the appearance of new manifestations [14]. Relapse, however, was defined as the reoccurrence of new disease activity symptoms indicating inflammation, with the patient having achieved remission before [14]. Usually, the management regimen in remission induction consists of a combination of glucocorticoids with cyclophosphamide. Generally, the remission-induction phase is started using a highly potent immunosuppressant (e.g., cyclophosphamide) with glucocorticoids for a duration of up to three or four months, followed by the second phase, which is maintenance using an immunosuppressant (e.g., azathioprine) with a low-dose glucocorticoid for a duration of at least 1.5 to 2 years [79]. In a study performed by Suka et al., the use of cyclophosphamide and prednisone was assessed, and during the 18 months of follow-up, there was a notable improvement in health-related quality of life and significant improvement in BVAS score [80]. It is worth mentioning that among AAV patients in whom there is no threat of organ damage, methotrexate, which is an immunosuppressant with medium potency, can be used for the remission-induction phase [81]. New studies have introduced methotrexate as a good candidate for the maintenance phase [78].

Additionally, one newly emerged treatment option to be used in both the remission-induction and maintenance phases is rituximab (RTX) [21, 28, 82]. In the research work of Stone et al., 197 AAV patients with either GPA or MPA were included to compare the efficacy of the rituximab and cyclophosphamide regimens in the patient’s treatment [82]. The results of the study indicated that the rituximab regimen showed higher efficacy than the cyclophosphamide regimen with the same prevalence regarding the occurrence of adverse effects. For pregnant women, it is recommended to plan accordingly. Both male and female patients are prohibited from taking any teratogenic drugs, such as cyclophosphamide or methotrexate, 3–4 months before conception; however, current research has found that cyclophosphamide treatment during the 2nd and 3rd trimesters is relatively safe [83]. For spinal cord microscopic polyangiitis, Yang et al. reported a case where the resection of the intramedullary lesions proved to be effective in decreasing the neurological manifestation. The previous outcomes give hope in integrating surgical treatment into the management protocol of AAV with CNS involvement [84].

Similar to AAV patients, the therapeutic procedure of PACNS patients is based on two parts, remission induction and maintenance, with specific drugs used in each of the two phases. In one of the studies, 167 PACNS patients were included, and therapeutic options were compared. Although induction therapy consisting of the use of cyclophosphamide and glucocorticoids showed equal efficacy to therapy with glucocorticoids alone, the combined therapy was associated with a lower occurrence of relapses [43]. In another study, 52 patients with PACNS were included, and the results indicated that patients managed with combination therapy tend to show better treatment outcomes [85]. Usually, after four–six months into the remission-induction phase, the maintenance phase is conducted using several possible agents: azathioprine, mycophenolate mofetil, and methotrexate [7, 86]. Several new research studies have shown that biological agents (e.g., rituximab) can also be used in the remission-induction phase [87, 88]. In Table 4, agents used to treat PACNS patients with their dosage and route of administration will be demonstrated.