Approach

Management of underlying cause

Treatment of MNM varies depending on the underlying disorder causing the neuropathy; therefore, every attempt should be made to establish diagnosis of the underlying disorder. Treatment should be determined in association with a neuromuscular neurologist. In addition, a rheumatologist should be consulted if a connective tissue disease is present; infectious disease and hepatology consultations may also be necessary.

Treatment of the underlying vasculitic syndrome may be required in addition to treatment targeted at the MNM.[60]

Vasculitic neuropathy

Both primary and secondary systemic vasculitides are associated with significant morbidity and mortality, and treatment should begin quickly once they are diagnosed.[7][23]​​​​​

Treatment aims to control inflammation, with induction therapy to achieve remission followed by maintenance therapy for at least 24 months.​[6]​​​[7][61][62]​​

Patients with MNM caused by a vasculitic neuropathy, either in association with a generalised vasculitis or limited to the peripheral nerves, should be treated as follows:

  • Remove the inciting antigen if possible:

    • If the patient is exposed to a drug that can cause MNM, the drug should be stopped immediately.

    • Haemodialysis and immunosuppressive therapy may be needed if the clinical presentation is fulminant and the drug remains in the body.

    • If infection with hepatitis C, hepatitis B, or HIV is identified, the most important therapeutic strategy is to start antiviral therapy.

  • Consider immunosuppressive therapy and determine the best therapy to induce vasculitis remission:

    • Immunosuppressive therapy is usually used, although an inciting antigen cannot be identified in most MNM cases.

    • Initial therapy for most primary or secondary systemic vasculitides is a combination therapy of corticosteroids and cyclophosphamide, or corticosteroids alone for some disorders.[6][7][23][61][63]​​​​​​​​

  • If MNM is refractory to treatment, additional second-line therapies may be necessary:[7][23][61][63]​​​​​​​​

    • Patients may require more toxic medicines or strategies, although treatment choices should minimise therapeutic adverse effects; however, there is a lack of strong evidence to support these treatments.

    • Plasma exchange has the potential to remove circulating antibodies, immune complexes, and inflammatory mediators and is often used in combination with other therapies. It is not indicated as initial monotherapy in any vasculitic neuropathy.

    • Intravenous immunoglobulin (IVIG) is also an option for refractory MNM, and may be used first-line in fulminant cases of hepatitis C-associated cryoglobulinaemic vasculitic neuropathy. Multifocal motor neuropathy (MNM with motor deficit) generally responds to IVIG or subcutaneous immunoglobulin therapy, but is resistant to corticosteroid therapy and plasma exchange.[64]

    • Both a rheumatologist and a neuromuscular neurologist may need to be consulted.

  • Once remission occurs, therapy is modified to maintain remission and minimise adverse effects.[7][23][61][63]​​​​​​​​

Primary systemic vasculitic neuropathies

Primary systemic vasculitic neuropathies associated with MNM are: classic polyarteritis nodosa (PAN); eosinophilic granulomatosis with polyangiitis (EGPA; formerly known as Churg-Strauss syndrome); granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis); and microscopic polyarteritis.

Corticosteroid therapy

Corticosteroid treatment is always part of first-line therapy for MNM associated with these conditions.[6][65]

Treatment for MNM associated with classic PAN or EGPA begins with a risk assessment for an adverse prognosis. Indicators for poor prognosis are creatinine >1.58 mg/dL (>140 micromol/L); proteinuria >1 g/day; and central nervous system, gastrointestinal, or cardiac involvement.[1][66]​​​ MNM is not an indicator of a poor prognosis for these conditions.

For patients with mild classic PAN or EGPA without indicators of poor prognosis, prednisolone monotherapy alone may be sufficient.[1][60]​​​

For patients with classic PAN or EGPA and any factors indicating a poor prognosis, with granulomatosis with polyangiitis, or with microscopic polyarteritis (which are generally severe), standard corticosteroid therapy is intravenous methylprednisolone at diagnosis (for 3-5 days), followed by oral prednisolone until remission is achieved.[7]

Other therapies

Oral cyclophosphamide is part of standard therapy at diagnosis (in addition to corticosteroids) for patients with MNM associated with granulomatosis with polyangiitis or microscopic polyarteritis.[65]

For patients with classic PAN or EGPA, oral cyclophosphamide is part of standard therapy at diagnosis for patients with factors indicating a poor prognosis, and may be added for patients with an initially good prognosis if their vasculitic neuropathy is not controlled by prednisolone alone.[65]

Options for treating primary systemic vasculitic neuropathies with an insufficient response to first-line treatment include replacing oral cyclophosphamide with either intravenous pulse-dose cyclophosphamide, or methotrexate. Rituximab may be considered for treating primary systemic vasculitic neuropathies that are resistant to cyclophosphamide and methotrexate, or for patients who are intolerant of these treatments.[7][65]

Plasma exchange or IVIG may be given as adjunctive treatment for refractory vasculitis.[1][7][65]

See also Polyarteritis nodosa, Eosinophilic granulomatosis with polyangiitis, and Granulomatosis with polyangiitis.

Non-systemic vasculitic neuropathy

Therapy for non-systemic vasculitis presenting as MNM is similar to that for systemic vasculitides. Combination immunosuppression seems more effective at inducing remission and reducing disability than corticosteroids alone.[23]​ However, many neuromuscular neurologists begin therapy with corticosteroids alone and add cyclophosphamide only if the neuropathy is progressive despite corticosteroid therapy.[63]

First-line therapy for induction is intravenous methylprednisolone followed by oral prednisolone, with or without cyclophosphamide.[23] For patients with refractory neuropathy, replacement of oral cyclophosphamide with intravenous pulse-dose cyclophosphamide or methotrexate, and the periodic use of adjunctive IVIG or plasma exchange, may be considered.[23] Primary non-systemic vasculitic neuropathies usually respond well to these therapies, but rituximab is a further option for patients refractory to other treatments.[23]

Hepatitis B-associated polyarteritis nodosa (PAN)

A hepatologist, an infectious disease specialist, and a neuromuscular neurologist should all be involved in treatment decisions.

Immunosuppressive therapy alone can lead to activation of hepatitis B replication.[67] Therefore, patients with hepatitis B-associated PAN should have an initial course of therapy comprising prednisolone for immunosuppression and an antiviral agent for treating hepatitis B.[6]​ Adjunctive plasma exchange or IVIG may form part of first-line therapy for fulminant cases.[1]

For patients with vasculitic neuropathy with an insufficient response to first-line treatment, antiviral therapy should be amended and prednisolone continued. Plasma exchange or IVIG may be given as adjunctive treatment.[1][7]

​For current recommendations for antiviral therapy, see Hepatitis B.

See also Polyarteritis nodosa.​​

Hepatitis C-associated cryoglobulinaemic vasculitic neuropathy

A hepatologist, an infectious disease specialist, and a neuromuscular neurologist should all be involved in treatment decisions.

The goal of therapy is to achieve remission of the vasculitis without causing a sustained increase in the activity of the underlying hepatitis C. Corticosteroids may stimulate viral replication and increase viraemia, so antiviral therapy should be started once vasculitic neuropathy is under control.[1][68]​ 

In patients with MNM, initial immunosuppressive therapy with prednisolone plus cyclophosphamide is often used. Plasma exchange may form part of first-line therapy in fulminant cases.[1]

For vasculitic neuropathy with an insufficient response to first-line treatment, prednisolone is combined with an alternative immunosuppressant, such as intravenous pulse-dose cyclophosphamide or methotrexate. Rituximab may be considered for treating vasculitic neuropathy that is resistant to cyclophosphamide and methotrexate, or for patients who are intolerant of these treatments. Plasma exchange or IVIG may be used as adjunctive treatment. Antiviral therapy is continued.[1][7]

For current recommendations for direct-acting antiviral therapy, see Hepatitis C.

Antivirals and rituximab may be the initial treatment of choice for advanced hepatitis C-associated cryoglobulinaemic vasculitis and MNM.[7]

HIV-associated vasculitic neuropathy

Specialist consultation is recommended.

Patients positive for cytomegalovirus (CMV)

There are few reliable data on the treatment of CMV-associated vasculitis in HIV seropositive patients. These patients usually have advanced AIDS, with very high mortality if treatment is delayed. Both antiretroviral and antiviral therapies are required.[1]

For details of antiretroviral therapy, see HIV infection.

For details of antiviral therapy for CMV, see HIV-related opportunistic infections and Cytomegalovirus infection.

Patients negative for CMV

For patients who are negative for CMV, optimised antiretroviral therapy directed at HIV is the most important intervention. HIV-associated, CMV-negative vasculitic neuropathies often remit spontaneously.[69] A short course of oral prednisolone may be required to abrogate severe HIV-associated painful MNM.[40]

For details of antiretroviral therapy, see HIV infection.

Cancer-associated vasculitic neuropathy

Treatment of the underlying malignancy should be given priority. Following this, if neuropathy remains, immunosuppression with methylprednisolone followed by an oral prednisolone taper should be considered. Oral cyclophosphamide and/or IVIG are additional adjunctive treatment options. Management in combination with an oncologist and a neuromuscular neurologist is recommended.[1][7]

MNM from secondary vasculitis associated with connective tissue disease

MNM may result from a secondary vasculitis associated with a variety of connective tissue diseases: commonly rheumatoid arthritis and systemic lupus erythematosus, but vasculitic neuropathy may also present in Sjogren syndrome, mixed connective tissue disease, scleroderma, or relapsing polychondritis. The treatment of the underlying disorder varies among these conditions, but the goal of therapy is remission of the vasculitic process and MNM. Initial therapy is intravenous methylprednisolone followed by oral prednisolone.

A rheumatologist and a neuromuscular neurologist should be involved, as treatment will vary with the underlying connective tissue disease and involvement of other organ systems.

See also Rheumatoid arthritis, Systemic lupus erythematosus, Behcet syndrome, Sjogren syndrome, Overlap syndromes, and Systemic sclerosis (scleroderma).

Neurosarcoidosis

Neurosarcoidosis presenting with MNM is rare, and usually responds well to standard immunosuppressant therapy for sarcoidosis.[70]

See Sarcoidosis.

Maintenance treatment following remission

After remission is achieved, the goal is to maintain remission while minimising medication toxicities.

Due to high relapse rates when treatment is discontinued within 12 months, it is reasonable to maintain therapy for at least 24 months for a patient in remission.[1][23][61]

For patients whose MNM was controlled with prednisolone monotherapy that was gradually tapered over 6-12 months once remission was achieved, no additional treatments other than prednisolone are needed. [1]

For patients who required additional treatment to induce remission, maintenance therapy should also include one of the following in addition to prednisolone: continuing oral cyclophosphamide for 12 months, then tapering; or (for patients with cyclophosphamide intolerance or toxicity) switching from oral cyclophosphamide to oral or intravenous methotrexate or to oral azathioprine for 18-24 months.[1][23][61]

IVIG may be used as a maintenance treatment over 6-12 months for patients who did not respond to or were intolerant of other immunosuppressant treatments.[1]

For MNM due to secondary vasculitic neuropathies, treatment for the condition underlying the vasculitis may need to be continued.

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