Neurological manifestations in ANCA-associated vasculitis - assessment and treatment

KEYWORDS:

• ANCA-associated vasculitis
• peripheral neuropathy
• central nervous system vasculitis
• vasculitis treatment
• immunosuppressants

Antineutrophil cytoplasmic antibodies associated vasculitis (AAV) is an entity that encompasses three systemic autoimmune diseases: granulomatosis with polyangitis (GPA; formerly Wegener’s granulomatosis), microscopic polyangitis (MPA) and eosinophilic granulomatosis with polyangitis (EGPA; formerly Churg–Strauss syndrome) [1]. Their main common features are necrotizing inflammation of medium to small vessels and association with antineutrophil cytoplasmic antibodies (ANCA) production. AAV is rare with incidence ranging from 15 to 25/1 million in the general population [2]. It has a systemic course which means, the disease can affect virtually any organ. Although, the involvement of respiratory tract and kidneys remain hallmarks of the disease, the neurological manifestations are not rare, and if present, they may help in establishing the diagnosis and impose changes to the treatment regimen.

Peripheral nervous system manifestation

Peripheral nervous system (PNS) involvement can be among many other symptoms [3] or be the first sign of the disease [4]. It is observed in all AAV – most frequently in EGPA patients (60–70%; especially in those ANCA positive) and in about half of the patients with MPA (20–50%) and GPA (15–50%) [3,5–7]. Pathophysiologically, it is explained as an inflammation of vasa nervorum leading to ischemia with axonal degeneration and presents as a mononeuritis multiplex. Frequently affected nerves include peroneals, tibial, ulnar, and median nerves. Another typical manifestation is symmetrical polyneuropathy, with progressive course when untreated. Patients experience sudden onset of pain, burning sensation, numbness, limb weakness, foot or wrist drop and other sensory and/or motor deficits.

Diagnosis is based on clinical evaluation and can be confirmed by electrodiagnostic studies, which show multifocal axonal loss of fibers [6]. Nerve or muscle-nerve biopsy can be useful in diagnostically difficult cases.

PNS involvement has a burden of significant long-term damage and life quality impairment [8]. Most research did not found direct association with higher mortality [3,9], although there are recent data suggesting higher mortality in MPA patients with PNS involvement [10].

Central nervous system manifestation

Contrary to PNS, central nervous system (CNS) involvement in AAV is rare (5–15% patients), with no significant predisposition to any particular type of vasculitides [6], and is considered as an alarming manifestation. It is caused by brain or spinal cord vasculitis, or granulomas (spreading from extracranial locations or forming in CNS tissues) [11]. Because of inflammatory process single or diffused ischemic, hemorrhagic or granulomatous lesions can occur [9]. Pituitary gland involvement is also described as CNS manifestations [12]. Clinical presentation depends of lesion type, and varies from headaches through neuropsychiatric (cognitive impairment, memory deficits) to neurological symptoms (seizures, paresis, impaired consciousness) which can be transient or permanent. Diagnosis is based on neurological examination and imaging studies – mainly contrast-enhanced MRI, where most commonly white matter lesions can be observed. However, these changes are highly non-specific, and should be analyzed by experienced clinicists aware of other vasculitis complications such as infections and of cardiovascular origin. In differential diagnosis CSF analysis can be useful and in diagnostically challenging cases brain biopsy should be taken under consideration.

Hypertrophic pachymeningitis in both: intracranial (more common) and spinal forms, was brought recently as a possible AAV manifestation [13].

Data considering CNS involvement and mortality suggest no direct correlation [9], but influence of CNS involvement on chronic organ damage is undoubtful [8].

Cranial nerves involvement

Cranial nerves are rarely involved in MPA and EGPA (<5% of patients), however more frequently in GPA (up to 15% of patients) [6,7]. Optic and olfactory nerves are affected by spreading granulomas and peripheral cranial nerves (III–XII) can be involved because of pachymeningitis or other inflammatory process [14]. Clinical presentation involves visual impairment, olfactory impairment, facial nerve palsy, dysphagia and sensory disorders. Diagnosis is made upon neurological investigation and imaging studies (MRI).

Treatment

Neurological involvement is in majority of cases a part of generalized systemic disease, and as such should be treated. There is no specific treatment directed solely toward the neurological symptoms. The key issue is initiating AAV treatment as early in the disease course as it is possible [15]. Thus establishing proper diagnosis remains crucial and acknowledging the neurological symptoms as a possible AAV manifestation can be helpful. Treatment based on immunosuppressive agents consists of two phases: induction of remission, which takes 3–6 months, and maintenance continued for at least 18–24 months. Standard initial therapy starts with high-dose corticosteroids (prednisone 1 mg/1 kg for approximately 1 month, then tapering) accompanied by additional immunosuppressive agent such as cyclophosphamide (CYC, 15 mg/kg adjusted to age and renal function, preferably intravenous pulses every 2–3 weeks). Maintenance therapy is based on low-dose corticosteroids, azathioprine (AZA) or methotrexate (MTX) [16]. In severe cases of life endangering systemic AAV steroid pulses are used (3–5 days of 500–1000 mg methylprednisolone). Additional plasmapheresis has also potential benefits in these cases; however there is limited research on its effect on neurological involvement [17]. In low activity disease induction can be achieved by corticosteroids, MTX or mycophenolate mofetil (MMF). Leflunomide, used in low activity GPA, should be avoided in cases with neurological manifestation because of neurotoxic side effects [18]. Recent studies proved efficacy of rituximab (RTX, monoclonal anti-CD20 antibody) in induction as well as maintenance therapy and according to the latest British AAV treatment guidelines it can be used interchangeably with CYC [19]. There is no sufficient data supporting RTX improving neurological manifestations, however some case report based studies seem to be promising [20,21].

Other monoclonal antibodies have lower efficacy (infliximab, etanercept) or are under investigation (belimumab, mepolizumab). Still, because of financial issues and lack of long-term observations, RTX treatment is not used routinely in every center as a first choice treatment, but should be strongly considered in cases of refractory disease [20,21]. There are also encouraging reports about beneficial effects of intravenous immunoglobulins, especially for EGPA patients with residual neurological manifestations [22].

Neurological manifestations play significant role in AAV clinical image and are considered as a disease activity major indicator. Patients’ evaluation should include assessment for the neurological disorders, not only at the diagnosis, but also during follow-up period. On the other hand, unexplained neuropathies, as an initial manifestation, can lead to AAV diagnosis. Therefore interdisciplinary approach is essential throughout whole patient care process and requires cooperation of the internists and neurologists. As there is no definite treatment for AAV, and the best thing we can achieve is remission, early treatment initiation or escalation in case of a relapse, can prevent from long-term, chronic organ damage, including neurological deficits.

Although it is clear there are different phenotypes of the AAV, treatment regimens are now universal. Considering increasing research on systemic vasculitides, future will bring more therapeutic options for particular manifestations. Hopefully we will also be able to reduce complications of corticosteroids and highly potent immunosuppressant treatment.

Declaration of interest

A Wludarczyk has been funded a research grant from the Polish National Science Centre – NCN No. 2013/11/N/NZ5/00022. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.