Neurologic Granulomatosis with Polyangiitis (formerly called Wegener's)

Neurologic manifestations of granulomatosis with polyangiitis (GPA; formerly called Wegener's) are primarily cranial neuropathies and peripheral neuropathies. ^{[1, 2]} Other neurologic manifestations include seizures, cerebritis, stroke syndromes, and granulomas extending from the sinuses, which may affect the pituitary gland, resulting in diabetes insipidus.

The reported incidence of neurologic involvement during the course of GPA varies in different studies ^[3] . The few large patient series that are available indicate that prior to the advent of cyclophosphamide treatment, about 50% of patients with GPA had neurologic involvement; ^{[4, 5]}  in a more recent study, only 25% of GPA patients had neurologic involvement.

Nishino et al presented the definitive work on neurologic involvement of GPA. ^[6] This large series remains authoritative due to its size and scope. Of 324 patients reviewed, one third experienced central or peripheral nervous system involvement. Most had peripheral neuropathy or cranial neuropathies. A pattern of symmetrical polyneuropathy was seen in some patients, but peripheral neuropathy most often manifested as acute mononeuritis multiplex.

Cranial nerves II, VI, and VII are affected most commonly, either by direct vasculitic injury, compression, extension of granulomatous disease from adjacent sinuses, or cavernous sinus thrombosis. Cranial nerves IX, X, and XII are less commonly affected. As with cerebral parenchymal lesions, injury can occur because of direct effects of inflammation, tissue ischemia due to thrombosis of inflamed blood vessels, or compression due granulomatous tissue formation and edema.

The following is a tally of nervous system involvement in the series reported by Nishino et al:

• Peripheral neuropathy - 53 patients

• Mononeuritis multiplex - 42 patients

• Cranial neuropathies - 21 patients

• External ophthalmoplegia - 16 patients

• Seizures - 10 patients

• Cerebritis - 5 patients

• Stroke syndrome - 13 patients

Cerebral parenchyma may be affected by either cerebritis or stroke syndromes. The most common peripheral nerve injury encountered was peroneal neuropathy, followed by tibial, sural, median, and ulnar neuropathies. Rarely reported neurologic disorders include myopathy, aseptic meningitis, and diabetes insipidus. GPA rarely presents as a neurologic illness: only 9 (3%) of the 324 cases presented as ophthalmoplegia in this series.

A few patients presenting with signs of meningeal inflammation have been reported in whom diffuse dural enhancement was seen on magnetic resonance imaging. Similar findings have been reported in cases of neurosarcoidosis. Presentation as cerebritis with edematous masslike lesions and invasive-appearing mass lesions around the paranasal sinuses have also reported.

For further information on this topic, see the Medscape Reference article Granulomatosis with Polyangiitis, as well as Otolaryngologic Manifestations of Granulomatosis with Polyangiitis, and Dermatologic Manifestations of Granulomatosis With Polyangiitis.

Presentations of neurologic granulomatosis with polyangiitis (GPA) are extremely varied, with manifestations in the CNS such as seizures, altered cognition (ie, cerebritis), focal motor and sensory complaints, and stroke syndromes.

Presentations may involve chronic, acute, or stepwise deterioration referable to parenchymal or meningeal inflammation and scarring, and this variable tempo of onset also may be seen in the associated peripheral nerve syndromes and cranial neuropathies. A history of headaches and other symptoms related to inflammation of meningeal or parenchymal structures should be sought initially and on follow-up visits.

Ocular manifestations of GPA include the following:

• Proptosis

• Episcleritis

• Cavernous sinus thrombosis

• Corneoscleral ulcers

• Dacryocystitis

• Uveitis

• Conjunctivitis

• Retinal occlusion/cherry-red spot

• Scleritis

• Afferent pupillary defect, decreased acuity (optic neuritis)

• Ophthalmoplegias (nuclear or supranuclear)

Other neurologic signs and syndromes include the following:

• Delirium (cerebritis)

• Hemiparesis (stroke, cerebritis)

• Other cranial neuropathy (potentially any cranial nerve)

• Seizure (mass lesion)

• Spasticity, hyperreflexia, Babinski sign (ie, upper motor neuron signs)

• Weakness, numbness (neuropathy)

Disorders to be considered in the differential diagnosis of granulomatosis with polyangiitis (GPA) with neurologic manifestations include the following:

• Acute Inflammatory Demyelinating Polyradiculoneuropathy

• Amyotrophic Lateral Sclerosis

• Aseptic Meningitis

• Brainstem Gliomas

• Cavernous Sinus Syndromes

• Cerebral Aneurysms

• Frontal Lobe Epilepsy

• Leptomeningeal Carcinomatosis

• Multiple Sclerosis

• Sarcoidosis and Neuropathy

• Lymphoma and other multifocal (metastatic) neoplasms

• Lymphomatoid granulomatosis (lung and cerebral involvement)

• Other disorders causing inflammation or infection of various organs, including sarcoidosis

• Carotid disease and stroke

• Rosai-Dorfman Disease

c-ANCA

Laboratory diagnosis of granulomatosis with polyangiitis (GPA) has been assisted greatly by the emergence of testing for c-antineutrophil cytoplasmic antibody (ANCA) levels ^{[7, 8]} , which, if elevated, are 97% specific for WG. ^{[9, 10]}

Testing for c-ANCA is 90% sensitive for the diagnosis when the presentation is classic, involving both upper and lower respiratory system and kidneys; sensitivity drops to 40% in limited granulomatosis with polyangiitis (GPA) (ie, limited to only kidneys or respiratory system).

Along with other markers of inflammation such as C-reactive protein and erythrocyte sedimentation rate, c-ANCA levels can be used to monitor disease and response to therapy. However, they cannot reliably predict potential for disease relapse. ^[11]

Other laboratory abnormalities include the following:

• Anemia

• Thrombocytosis

• Hypergammaglobulinemia

• Rheumatoid factor

• Cryoglobulins or circulating immune complexes (rare)

• Creatine kinase elevation (in cases with myopathy)

The primary investigations used to localize the lesions in granulomatosis with polyangiitis (GPA) with neurologic involvement are as follows:

• Electromyography (EMG)

• Nerve conduction studies

• Cerebrospinal fluid (CSF) analysis

• Magnetic resonance imaging (MRI)

Electromyography and nerve conduction studies

EMG and nerve conduction studies may reveal acute and/or chronic denervation in involved muscles, slowed nerve conductions, decreased amplitude of action potentials, and myopathy. A typical picture would involve few to several nerves in an asymmetrical pattern (ie, mononeuritis multiplex).

Neuroimaging studies

Neuroimaging studies produce nonspecific findings. On both magnetic resonance imaging (MRI) and computed tomography (CT) scans, areas of cerebritis may appear as supratentorial, irregularly enhancing, edematous lesions of any size. Meningeal involvement, seen as enhancement, is less common but is reported. Ischemic or hemorrhagic infarcts also may be suggested by neuroimaging.

CSF analysis

CSF analysis commonly reveals nonspecific inflammatory CSF abnormalities such as the following:

• Mild to moderate pleocytosis, mostly lymphocytes

• Elevated protein level

• Elevated immunoglobulin G level

Other studies

Biopsy of the sural nerve may demonstrate vasculitis with noncaseating granulomas, affecting small arteries. Lesions may contain acute and chronic inflammatory features of vasculitis with focal areas of demyelination.

Autopsy studies in neurologic granulomatosis with polyangiitis (GPA) are sparse, and although cerebral vasculitis sometimes has been assumed clinically in patients with infarctions (and seizures), tissues usually appear bland. Similarly, angiography may miss small-vessel vasculitis.

Treatment measures for patients with neurologic manifestations of granulomatosis with polyangiitis (GPA) are the same as those for the disease in general. As with many rare autoimmune illnesses, evidence for treatment efficacy remains class III (retrospective case studies). ^{[12, 13]} Newer agents such as rituximab are touted as possible therapies for disease refractory to more traditional immune suppressants, such as cyclophosphamide. ^[14] These patients require close follow-up for response to therapy, potential relapse, and medication toxicity (eg, serial chest radiographs, renal function tests, liver function tests, CBC count, urinalysis), as well as specific neurologic tests such as neuroimaging. For example, in patients with active CNS inflammation clinically or by MRI, repeat MRI with contrast every 1-3 months would be reasonable.