4/20/18. Kelly G. Gwathmey, MD University of Virginia April 23, 2018
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1 Kelly G. Gwathmey, MD University of Virginia April 23, 2018 Outline Vasculitic Neuropathies Autoimmune Small Fiber Neuropathies Sensory Neuronopathies (Dorsal Root Ganglionopathies) Other Autoimmune Large Fiber Neuropathies Trigeminal Neuropathies 1
2 Vasculitic Neuropathy Definition Damage to the peripheral nerves as a consequence of vasculitis Classic Presentation: Mononeuritis Multiplex Inflammation of several separate nerves in unrelated portions of the body Case #1: 62 Year-old with Numbness, Pain and Weakness 62 year-old woman developed ankle edema, streaking of her skin, and malaise Developed the following symptoms: right foot paresthesias and numbness spread to the left foot, then right hand, then left hand severe neuropathic pain diffuse weakness and ataxia 10 lb weight loss 2
3 62 Year-old with Numbness, Pain and Weakness On exam: Normal cranial nerves Motor exam: Normal bulk/tone Bilateral hip flexion 4-/5 Left finger extension/abduction/flexion 4/5 Decreased pinprick to the wrist and ankle bilaterally Impaired proprioception at the toes and right fingers Deep tendon reflexes were normal 62 Year-old with Numbness, Pain and Weakness 3
4 62 Year-old with Numbness, Pain and Weakness 62 Year-old with Numbness, Pain and Weakness Multiple mononeuropathies (mononeuritis multiplex) Admit from EMG lab 4
5 62 Year-old with Numbness, Pain and Weakness TSH 5.8, T4 1.4 ESR 54 (0-20) CRP 5.7 (<0.5) HIV nonreactive Hep B Ab NEG Hep C Ab NEG ENA panel NEG Myeloperoxidase >8 (nml <1) Proteinase 3 NEG PPD test negative. 62 Year-old with Numbness, Pain and Weakness SEVERE NECROTIZING VASCULITIC NEUROPATHY DUE TO MICROSCOPIC POLYANGIITIS Lancet Neurol 2014 Jan;13(1):
6 62 Year-old with Numbness, Pain and Weakness Started on 60 mg of prednisone Started rituximab induction 375 mg/m 2 x 4 weeks Gabapentin Azathioprine Classification Schemes International Chapel Hill Consensus Conference 2. Peripheral Nerve Society Task Force classification Primary Systemic Vasculitides Secondary Systemic Vasculitides Non-systemic/localized Vasculitides 3. Based on size of involved vessel Nerve Large Arteriole Microvasculitis 6
7 Specific Forms of Vasculitic Neuropathies Primary systemic vasculitic neuropathy Anti-neutrophil cytoplasmic antibody (ANCA)- associated vasculitis Microscopic polyangiitis (MPA) Eosinophilic granulomatous polyangiitis (EGPA, previously Churg-Strauss) Granulomatosis with polyangiitis (GPA, previously Wegener s granulomatosis) Polyarteritis nodosa (PAN) When Would You Think About Systemic Vasculitis? The key is involvement of other organ systems. Lungs Kidneys Joints GI tract Skin Eosinophilia Constitutional symptoms ANCAs Perinuclear ANCA react to myeloperoxidase (MPO) Cytoplasmic ANCA react to proteinase-3 (PR3) 7
8 Polyarteritis Nodosa Medium vessel vasculitis No ANCA (differentiates from small vessel vasculitis) May be associated with hepatitis B Affects kidneys, skin, joints, GI tract, nerves Spares the lungs (differentiates from small vessel vasculitis) Microscopic Polyangiitis and Granulomatous Polyangiitis Small vessel vasculitis Associated with ANCAs (GPA with PR3, MPA with MPO) No granulomas in MPA (unlike GPA, EGPA) Affects the ear, nose, throat (less in MPA) Tracheal/pulmonary involvement Renal involvement Skin- most common leukocytoclastic angiitis Eye involvement 8
9 Eosinophilic Granulomatosis with Polyangiitis Vasculitis of small and medium vessels Associated with MPO antibodies Phases of the disease Prodromal Eosinophilic Vasculitic Ear and nose Respiratory involvement Skin- subcutaneous nodules Cardiovascular Renal (to a lesser extent than MPA and GPA) GI tract By Nephron - Own work, CC BY-SA 3.0, Specific Forms of Vasculitic Neuropathies Secondary systemic vasculitic neuropathy Rheumatoid arthritis Sjögren s syndrome Systemic lupus erythematosus Sarcoidosis 9
10 Specific Forms of Vasculitic Neuropathies Non-systemic vasculitic neuropathy No multiorgan involvement Weight loss and fever may be present Mean age 59, women affected more often Progressive asymmetric multifocal neurological deficits 66-96% have pain Collins MP and Periquet MI. Non-systemic vasculitic neuropathy. Curr Opin Neurol. 2004; 17(5): Specific Forms of Vasculitic Neuropathies Specific forms of localized microvasculitis Diabetic and non-diabetic lumbosacral radiculoplexus neuropathy (DLRPN and LRPN) Middle aged to older aged individuals with Type II DM Frequent concomitant weight loss Asymmetric, acute onset, hip/thigh>>foot/leg Eventually bilateral Pain weakness Autonomic symptoms Upper extremity symptoms Dyck PJ and Windebank AJ. Diabetic and nondiabetic lumbosacral radiculoplexus neuropathies: new insights into the pathophysiology and treatment. Muscle Nerve. 2002; 25(4):
11 Dividing Vasculitic Neuropathies by Histopathology Nerve Large Arteriole Small arteries, large arterioles, smaller vessels Pathologic changes are seen in epineural and perineural vessels ( microns in diameter) Microvasculitis Affects the smallest arterioles(<40 microns), microvessels, and venules Dividing Vasculitic Neuropathies by Histopathology Nerve Large Arteriole Primary systemic vasculitis Rheumatoid arthritis Hepatitis C Cryoglobulinemia HIV Paraneoplastic Microvasculitis Sjögren s NSVN DLRPN/LRPN 11
12 Clinical Features of Vasculitic Neuropathy Acute/subacute Painful sensory or sensorimotor deficits Mononeuropathy multiplex or asymmetric polyneuropathy Constitutional symptoms Myalgias Arthralgias Weight loss Abdominal pain Night sweats Evaluation of Vasculitic Neuropathies Labs EMG ANCAs CBC (eosinophils), CMP, urine, ESR, CRP, ANA, RF, ENA, complement, hepatitis B surface antigen, hepatitis C antibodies Asymmetrical or non-length dependent axonal neuropathy Occasional pseudo-conduction block Identify a nerve for biopsy 12
13 Biopsy in Vasculitic Neuropathies When is it indicated? Nerve large arteriole vasculitis Epineurial and perineurial vessels Fibrinoid necrosis of the tunica media/intima Microvasculitis Smaller arterioles without internal elastic lamina, microvessels, and venules Inflammation of the vessel wall with fragmentation and necrosis of the tunica media Treatment of Systemic and Non-systemic Vasculitic Neuropathy Induction therapy High dose corticosteroids Cyclophosphamide Methotrexate (milder disease) Refractory Disease Rituximab IVIG PLEX Maintenance therapy Cyclophosphamide Azathioprine Methotrexate 13
14 Outline Vasculitic Neuropathies Autoimmune Small Fiber Neuropathies Sensory Neuronopathies (Dorsal Root Ganglionopathies) Other Autoimmune Large Fiber Neuropathies Trigeminal Neuropathies Autoimmune Small Fiber Neuropathy Definition Autoimmune sensory and autonomic neuropathy affecting the small unmyelinated and thinly myelinated nerves Classic Presentation Length-dependent, non length-dependent, or generalized loss of thermal/pain sensation with associated neuropathic pain and autonomic dysfunction 14
15 Case #2: 57 Year-old Man with Diffuse Paresthesia 57 year old with no remarkable past medical history Acute onset paresthesia in feet Spread to hands, then lips, tongue, nose within weeks Refractory neuropathic pain No weakness Dry eyes and dry mouth 57 Year-old Man with Diffuse Paresthesia Evaluation included: Normal nerve conduction studies and EMG Normal laboratory studies: paraneoplastic, SPEP, ANA, ANCA, ESR, CRP, A1c, anti-ssa/ssb, angiotensin converting enzyme, hepatitis B and C, B6 and B12 15
16 Skin Biopsy Normal Abnormal Lip Biopsy 16
17 57 Year-old Man with Diffuse Paresthesia Treatment 20 mg per day of prednisone for seronegative Sjögren s syndrome Differential Diagnosis of Small Fiber Neuropathy Autoimmune Metabolic Toxic Infectious Inherited Other Sarcoidosis Sjögren s Paraneoplastic Celiac disease Glucose dysmetabolism Hypertriglyceridemia Drugs ETOH Hepatitis C Cryoglobulinemia HIV Fabry Familial amyloidosis Hereditary sensory and autonomic neuropathy Sodium channel mutations Amyloid Fibromyalgia Monoclonal gammopathy 17
18 Clinical Features of Autoimmune Small Fiber Neuropathy Sarcoidosis Reported in up to 2/3 of sarcoidosis patients Length-dependent and generalized presentations Sjögren s Syndrome Acute or slowly progressive Length-dependent, generalized, or multifocal Trigeminal nerve involvement semanagement/pulmonary/sarcoidosis/ Clinical Features of Autoimmune Small Fiber Neuropathy Other Dysimmune acute onset generalized pain syndromes childhood or adult onset 89% had evidence of disordered autoimmunity on labs Celiac disease Paraneoplastic disease Oaklander AL Immunotherapy prospects for painful smallfiber sensory neuropathies and ganglionopathies. Neurotherapeutics 2016 Jan; 13(1):
19 Evaluation of Small Fiber Neuropathy Skin Biopsy (Pathologic Gold Standard) Punch biopsy of the lateral distal leg (foot, distal thigh, proximal thigh) Stained with pan-axonal marker protein gene product 9.5 (PGP 9.5) Count intraepidermal nerve fiber density, sudomotor fibers, pilomotor fibers Autonomic Testing Quantitative sudomotor axon reflex test (QSART) Helpful for distal small fiber neuropathy Thermoregulatory sweat testing Treatment in Autoimmune Small Fiber Neuropathy Immunotherapy (corticosteroids, IVIg, other immunosuppressants) Symptomatic management 19
20 Outline Vasculitic Neuropathies Autoimmune Small Fiber Neuropathies Sensory Neuronopathies (Dorsal Root Ganglionopathies) Other Autoimmune Large Fiber Neuropathies Trigeminal Neuropathies Sensory Neuronopathy Definition Neuropathy caused by damage to the dorsal root ganglia Classic Presentation Early-onset ataxia Multifocal, asymmetric sensory deficits 20
21 Case #3: 76 Year-old with Progressive Ataxia Patient has a 1 year history of Sjögren s syndrome (sicca symptoms, anti-ssa antibodies) Went from working 9 hour shifts to wheelchair-bound within 2 weeks. He denied weakness but could not walk because his legs were numb. He was diagnosed with Guillain-Barré syndrome and given IVIg. Received 4 more months of IVIg. Numbness then progressed. 76 Year-old with Progressive Ataxia Labs unremarkable: ESR, CRP, ANA, SPEP, ANCA, paraneoplastic, hepatitis B, C. MRI neural axis normal CSF remarkable for a protein of 89 mg/dl. 21
22 76 Year-old with Progressive Ataxia Exam: Normal muscle bulk, tone, strength Decreased pinprick to the level of the waist Impaired proprioception to the level of the hips and to the level of the wrists Reflexes were absent in the legs, normal in the arms Severe gait ataxia, could not ambulate despite maximum assistance 76 Year-old with Progressive Ataxia 22
23 76 Year-old with Progressive Ataxia All of the following were attempted: Mycophenolate mofetil High dose corticosteroids Hydroxychloroquine IVIg Anatomy of the Dorsal Root Ganglion 23
24 Differential Diagnosis of the Acquired Sensory Neuronopathies Onset Disease Association Paraneoplastic Subacute-Chronic Small cell lung cancer, bronchial carcinoma, breast cancer, ovarian cancer, lymphoma, neuroendocrine tumours, sarcoma Inflammatory Subacute-Chronic Sjögren s syndrome, rheumatoid arthritis, systemic lupus erythematosus, autoimmune hepatitis Infection related Subacute HIV (also EBV, VZV, measles, HTLV-1) Medication Subacute-Chronic Platinum based chemotherapy (cisplatin, oxaliplatin, carboplatin), antibiotic toxicity has been suggested Vitamin associated Subacute-Chronic Vitamin B6 Idiopathic Chronic Not Known Clinical Features of Sensory Neuronopathies Upper limbs may be involved first/early Sensory loss involves the trunk, face, scalp, and eventually there is global loss of all sensory modalities Sensory ataxia Pseudoathetosis Autonomic dysfunction If overlap with other systems (brainstem, spinal cord, cerebellumthink paraneoplastic) 24
25 Evaluation of Sensory Neuronopathies Labs Anti-Hu and anti-cv2/crmp-5 antibodies (paraneoplastic) ANA, anti-ssa/ssb, ESR, CRP (autoimmune, Sjögren s) CSF EMG Severe, generalized, non-length-dependent sensory neuropathy Blink reflexes Imaging Studies looking for malignancy MRI demonstrates increased T2-weighted signal in the posterior columns Treatment of Sensory Neuronopathies Tumor treatment (paraneoplastic) Immunotherapy Symptomatic management 25
26 Outline Vasculitic Neuropathies Autoimmune Small Fiber Neuropathies Sensory Neuronopathies (Dorsal Root Ganglionopathies) Other Autoimmune Large Fiber Neuropathies Trigeminal Neuropathies Rheumatoid Arthritis-associated Polyneuropathy Nearly 60% of patients will have electrodiagnostic evidence of a neuropathy. 20% will be symptomatic. 2 primary groups of polyneuropathy included vasculitic and distal symmetric neuropathy. Distal symmetric neuropathy is likely partially due to vasculitis. Symptoms include pain, paresthesia, loss of sensation, and distal motor weakness. Demyelinating polyneuropathies are associated with anti-tnf alpha drugs Agarwal V, Singh R, et al. A clinical, electrophysiological, and pathological study of neuropathy in rheumatoid arthritis. Clin Rheumatol Jul; 27(7): Reda H, Chin RL. Peripheral neuropathies of rheumatologic disease and gluten-related disorders. Semin Neurol Sep; 34(4): Joaquim AF, Appenzeller S. Neuropsychiatric manifestations in rheumatoid arthritis. Autoimmun Rev Dec; 14(12): Battacharyya S, Helfgott SM. Neurologic complications of systemic lupus erythematosus, sjögren syndrome, and rheumatoid arthritis. Semin Neurol Sep; 34(4):
27 SLE-associated Polyneuropathy Polyneuropathy occurs in SLE 1-13% of the time. Distal sensory predominant polyneuropathy occurs most commonly (55% of the time) Corticosteroids, IVIG, rituximab, PLEX all used. Battacharyya S, Helfgott SM. Neurologic complications of systemic lupus erythematosus, sjögren syndrome, and rheumatoid arthritis. Semin Neurol Sep; 34(4): Florica B, Aghdassi E, et al. Peripheral neuropathy in patients with systemic lupus erythematosus. Semin Arthritis Rheum Oct; 41(2): Reda H, Chin RL. Peripheral neuropathies of rheumatologic disease and gluten-related disorders. Semin Neurol Sep; 34(4): Unterman A, Nolte JE, et al. Neuropsychiatric syndromes in systemic lupus erythematosus: a meta-analysis. Semin Arthritis Rheum.2011 Aug; 41(1): Sjögren s Syndrome-associated Polyneuropathy Up to 22% of patients will have clinically evident polyneuropathy A pure sensory polyneuropathy constitutes 25-60% of all cases of polyneuropathy in Sjogren s syndrome (small fiber, large fiber, or neuronopathy) Sensorimotor polyneuropathy may be associated with severe extraglandular disease Other forms of polyneuropathy Demyelinating Autonomic Vasculitic Polyradiculopathies Treatments include corticosteroids, IVIg, infliximab, rituximab, and TPE Battacharyya S, Helfgott SM. Neurologic complications of systemic lupus erythematosus, sjögren syndrome, and rheumatoid arthritis. Semin Neurol Sep; 34(4): Mori K, Iijima M, Koike H, Hattori N, et al. The wide spectrum of clinical manifestations in Sjögren s syndrome-associated neuropathy. Brain 2005; 128, Reda H, Chin RL. Peripheral neuropathies of rheumatologic disease and gluten-related disorders. Semin Neurol Sep; 34(4):
28 Outline Vasculitic Neuropathies Autoimmune Small Fiber Neuropathies Sensory Neuronopathies (Dorsal Root Ganglionopathies) Other Autoimmune Large Fiber Neuropathies Trigeminal Neuropathies Trigeminal Neuropathy Definition An isolated neuropathy of the trigeminal nerve Classic Presentation Numbness in the skin or mucosal membranes in the distribution of the trigeminal nerves and neuropathic weakness of the muscles of mastication 28
29 Anatomy of the Trigeminal Nerve Trigeminal Neuropathy versus Trigeminal Neuralgia Trigeminal Neuropathy Trigeminal Neuralgia Numbness of the skin and mucosa Weakness of muscles of mastication Brief attacks of lancinating pain No sensory impairment No motor impairment 29
30 Differential Diagnosis of Trigeminal Neuropathy Autoimmune Neoplastic Vascular Infectious Trauma Other Idiopathic Mixed connective tissue disease Sjögren s syndrome Progressive systemic scleroderma Sarcoidosis Multiple sclerosis Carcinomatous meningitis Intra or extracranial compression Perineural spread Metastasis Pontine ischemia or hemorrhage Vascular malformation Leprosy Viruses Lyme Syphilis Fungi Surgical Dental Radiation Amyloid Pseudotumor cerebri Specific Forms of Trigeminal Neuropathy Undifferentiated and mixed connective tissue disease - most common Scleroderma- may be an isolated, early feature Sjögren s syndrome Sarcoid- granulomatous disease of the trigeminal nerve 30
31 Clinical Features of Trigeminal Neuropathy Partial or complete sensory loss Occasional allodynia and hyperalgesia Corneal reflex affected Motor involvement is almost never a feature Neuropathic pain may be present Evaluation of Trigeminal Neuropathies Laboratory studies CBC, ESR, extractable nuclear antigen testing including SSA and SSB antibodies (salivary gland biopsy if necessary) RNP antibodies Imaging MRI with and without contrast with attention to the skull base Electrophysiological studies blink reflexes 31
32 Treatment of Trigeminal Neuropathies Not an indication for immunosuppression Symptomatic improvement with prednisone is rare Focus on symptomatic management of neuropathic pain Neurotrophic keratitis Smith, J.H., Cutrer, F.M., Numbness matters: a clinical review of trigeminal neuropathy. Cephalalgia 31, Outline Vasculitic Neuropathies Autoimmune Small Fiber Neuropathies Sensory Neuronopathies (Dorsal Root Ganglionopathies) Other Autoimmune Large Fiber Neuropathies Trigeminal Neuropathies 32
33 References Agarwal V, Singh R, et al. A clinical, electrophysiological, and pathological study of neuropathy in rheumatoid arthritis. Clin Rheumatol Jul; 27(7): Alshekhlee A, Basiri K, Miles JD, Ahmad SA, Katirji B. Chronic inflammatory demyelinating polyneuropathy association with tumor necrosis factor-alpha antagonists. Muscle Nerve 2010; 41 (5): Battacharyya S, Helfgott SM. Neurologic complications of systemic lupus erythematosus, sjögren syndrome, and rheumatoid arthritis. Semin Neurol Sep; 34(4): Collins MP, Dyck PJB, Gronseth GS. Peripheral Nerve Society Guideline on the classification, diagnosis, investigation and immunosuppressive therapy of non-systemic vasculitic neuropathy: executive summary. J Periph Nerv Syst 2010;15: Collins MP and Periquet MI. Non-systemic vasculitic neuropathy. Curr Opin Neurol. 2004; 17(5): Dyck PJ and Windebank AJ. Diabetic and nondiabetic lumbosacral radiculoplexus neuropathies: new insights into the pathophysiology and treatment. Muscle Nerve. 2002; 25(4): Florica B, Aghdassi E, et al. Peripheral neuropathy in patients with systemic lupus erythematosus. Semin Arthritis Rheum Oct; 41(2): Joaquim AF, Appenzeller S. Neuropsychiatric manifestations in rheumatoid arthritis. Autoimmun Rev Dec; 14(12): Gwathmey KG. Sensory neuronopathies. Muscle Nerve 2016; 53, Gwathmey KG, Burns TM, Collins MP, Dyck PJB. Vasculitic neuropathies. Lancet. Neurol. 2014; 13, Ibitoye RT, Wilkins A, Scolding NJ. Neurosarcoidosis: a clinical approach to diagnosis and management. J Neurol 2017; May; 264(5): Jeanette JC, Falk RJ, Bacon A, Baus N, et al revised International Chapel Hill Consensus Conference nomenclature of vasculitides. Arthritis Rheum. 2013; 65(1):1-11 References #2 Mori K, Iijima M, Koike H, Hattori N, et al. The wide spectrum of clinical manifestations in Sjögren s syndrome-associated neuropathy. Brain 2005; 128, Morozumi S, Kawagashira Y, Iijima M, et al. Intravenous immunoglobulin treatment for painful sensory neuropathy associated with Sjögren s syndrome. J Neurol Sci 2009; 279 (1-2): Oaklander AL Immunotherapy prospects for painful small-fiber sensory neuropathies and ganglionopathies. Neurotherapeutics 2016;13(1): Pavlakis PP, Alexopoulos H, Kosmidis ML, et al. Peripheral neuropathies in Sjögren s syndrome: a critical update on clinical features and pathogenetic mechanisms. J Autoimmun 2012; 39 (1-2): Reda H, Chin RL. Peripheral neuropathies of rheumatologic disease and gluten-related disorders. Semin Neurol Sep; 34(4): Smith JH, Cutrer FM. Numbness matters: a clinical review of trigeminal neuropathy. Cephalalgia 2011; 31, Tavee, JO, Stern, BJ, Neurosarcoidosis. Contin. Lifelong Learn. Neurol. 2014; 20, Unterman A, Nolte JE, et al. Neuropsychiatric syndromes in systemic lupus erythematosus: a meta-analysis. Semin Arthritis Rheum.2011 Aug; 41(1): Wakasugi D, Kato T, Gono T, et al. Extreme efficacy of intravenous immunoglobulin therapy for severe burning pain in a patient with small fiber neuropathy associated with primary Sjögren s syndrome. Mod Rheumatol 2009; 19(4): Yee, AMF. Sarcoidosis: Rheumatology perspective. Best Pract. Res. Clin. Rheumatol. 2016; 30,
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