Wegener Granulomatosis Neuropathy
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Neurologic manifestations of Wegener granulomatosis (WG) 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 WG 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 WG had neurologic involvement [4, 5] ; in a more recent study, only 25% of WG patients had neurologic involvement.
Nishino et al presented the definitive work on neurologic involvement of Wegener’s granulomatosis. [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. WG 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 Wegener Granulomatosis, as well as Otolaryngologic Manifestations of Wegener Granulomatosis and Dermatologic Manifestations of Wegener Granulomatosis.
Presentations of neurologic Wegener granulomatosis (WG) 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 Wegener granulomatosis 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 Wegener granulomatosis with neurologic manifestations include the following:
Acute Inflammatory Demyelinating Polyradiculoneuropathy
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
Laboratory diagnosis of Wegener granulomatosis (WG) 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 Wegener’s granulomatosis (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 WG with neurologic involvement are as follows:
Electromyography (EMG)
Nerve conduction studies
Cerebrospinal fluid (CSF) analysis
Magnetic resonance imaging (MRI)
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 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 commonly reveals nonspecific inflammatory CSF abnormalities such as the following:
Mild to moderate pleocytosis, mostly lymphocytes
Elevated protein level
Elevated immunoglobulin G level
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 Wegener granulomatosis 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 Wegener granulomatosis 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.
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Huang YH, Ro LS, Lyu RK, Chang HS, Wu YR, et al. Wegener’s granulomatosis with nervous system involvement: a hospital-based study. Eur Neurol. 2015. 73 (3-4):197-204. [Medline].
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Tervaert JW, Huitema MG, Hené RJ, Sluiter WJ, The TH, van der Hem GK, et al. Prevention of relapses in Wegener’s granulomatosis by treatment based on antineutrophil cytoplasmic antibody titre. Lancet. 1990 Sep 22. 336(8717):709-11. [Medline].
Spranger M, Schwab S, Meinck HM, Tischendorf M, Sis J, Breitbart A, et al. Meningeal involvement in Wegener’s granulomatosis confirmed and monitored by positive circulating antineutrophil cytoplasm in cerebrospinal fluid. Neurology. 1997 Jan. 48(1):263-5. [Medline].
Miloslavsky EM, Lu N, Unizony S, Choi HK, Merkel PA, Seo P, et al. Myeloperoxidase-Antineutrophil Cytoplasmic Antibody (ANCA)-Positive and ANCA-Negative Patients With Granulomatosis With Polyangiitis (Wegener’s): Distinct Patient Subsets. Arthritis Rheumatol. 2016 Dec. 68 (12):2945-2952. [Medline]. [Full Text].
Schirmer JH, Wright MN, Herrmann K, Laudien M, Nölle B, Reinhold-Keller E, et al. Myeloperoxidase-Antineutrophil Cytoplasmic Antibody (ANCA)-Positive Granulomatosis With Polyangiitis (Wegener’s) Is a Clinically Distinct Subset of ANCA-Associated Vasculitis: A Retrospective Analysis of 315 Patients From a German Vasculitis Referral Center. Arthritis Rheumatol. 2016 Dec. 68 (12):2953-2963. [Medline].
Kerr GS, Fleisher TA, Hallahan CW, Leavitt RY, Fauci AS, Hoffman GS. Limited prognostic value of changes in antineutrophil cytoplasmic antibody titer in patients with Wegener’s granulomatosis. Arthritis Rheum. 1993 Mar. 36(3):365-71. [Medline].
Sharma A, Kumar S, Wanchu A, Lal V, Singh R, Gupta V. Successful treatment of hypertrophic pachymeningitis in refractory Wegener’s granulomatosis with rituximab. Clin Rheumatol. 2010 Jan. 29(1):107-10. [Medline].
Bachmeyer C, Cadranel JF, Demontis R. Rituximab is an alternative in a case of contra-indication of cyclophosphamide in Wegener’s granulomatosis. Nephrol Dial Transplant. 2005 Jun. 20(6):1274. [Medline].
Shah S, Geetha D. Place in therapy of rituximab in the treatment of granulomatosis with polyangiitis and microscopic polyangiitis. Immunotargets Ther. 2015. 4:173-83. [Medline]. [Full Text].
Thomas F Scott, MD Professor, Program Director, Department of Neurology, Drexel University College of Medicine; Director, Allegheny MS Treatment Center
Thomas F Scott, MD is a member of the following medical societies: American Academy of Neurology, American Neurological Association, Consortium of Multiple Sclerosis Centers, National Multiple Sclerosis Society Advisory Board, Allegheny Chapter
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Florian P Thomas, MD, PhD, MA, MS Chair, Neuroscience Institute and Department of Neurology, Director, Multiple Sclerosis Center and Hereditary Neuropathy Centers, Hackensack University Medical Center; Founding Chair and Professor, Department of Neurology, Hackensack Meridian School of Medicine at Seton Hall University; Professor Emeritus, Department of Neurology, St Louis University School of Medicine; Editor-in-Chief, Journal of Spinal Cord Medicine
Florian P Thomas, MD, PhD, MA, MS is a member of the following medical societies: Academy of Spinal Cord Injury Professionals, American Academy of Neurology, American Neurological Association, Consortium of Multiple Sclerosis Centers, National Multiple Sclerosis Society, Sigma Xi
Disclosure: Nothing to disclose.
Niranjan N Singh, MBBS, MD, DM, FAHS, FAANEM Adjunct Associate Professor of Neurology, University of Missouri-Columbia School of Medicine; Medical Director of St Mary’s Stroke Program, SSM Neurosciences Institute, SSM Health
Niranjan N Singh, MBBS, MD, DM, FAHS, FAANEM is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Headache Society
Disclosure: Nothing to disclose.
Carmel Armon, MD, MSc, MHS Chair, Department of Neurology, Assaf Harofeh Medical Center, Tel Aviv University Sackler Faculty of Medicine, Israel
Carmel Armon, MD, MSc, MHS is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, American College of Physicians, American Epilepsy Society, American Medical Association, American Neurological Association, American Stroke Association, Massachusetts Medical Society, Sigma Xi
Disclosure: Received research grant from: Neuronix Ltd, Yoqnea’m, Israel<br/>Received income in an amount equal to or greater than $250 from: JNS – Associate Editor. UpToDate – Author Royalties.
Wegener Granulomatosis Neuropathy
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