1/30/2019. Disclosures. Learning Objectives. An Approach to Small Fiber Neuropathies

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1 An Approach to Small Fiber Neuropathies Disclosures A. Gordon Smith, MD C. Kenneth and Dianne Wright Distinguished Chair in Clinical and Translational Research (Neurology) Professor and Chair of Neurology Virginia Commonwealth University Consulting Alexion Disarm Therapeutics Regenesis Clinical Laboratory Utah Cutaneous Nerve Lab Research Funding NIH (NIDDK, NINDS) ADA ADA 7-11-AEC23, R01DK064814, DP3DK104394, U10NS077305, U10NS Learning Objectives 1. Identify symptoms and signs suggestive of small fiber neuropathy 2. Review investigations in patients with suspected SFN 3. Discuss causes and treatment of small fiber neuropathy Hanewinckel, R., et al. (2016). "Prevalence of polyneuropathy in the general middle-aged and elderly population." Neurology 87(18):

2 SFN Symptoms Burning Tingling Aching Electrical Itching Allodynia (bed sheets) Terkelsen, A. J., Karlsson, P., Lauria, G., Freeman, R., Finnerup, N. B., & Jensen, T. S. (2017). The diagnostic challenge of small fibre neuropathy: clinical presentations, evaluations, and causes. Lancet Neurol, 16(11), SFN Diagnosis SFN Defined as 2/3: 1. Clinical signs of small fiber dysfunction 2. Skin Biopsy 3. QST Large fiber sensory signs or abnormal NCS excluded SFN Devigili, G., Tugnoli, V., Penza, P., Camozzi, F., Lombardi, R., Melli, G., et al. (2008). The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain, 131(Pt 7), Terkelsen, A. J., Karlsson, P., Lauria, G., Freeman, R., Finnerup, N. B., & Jensen, T. S. (2017). The diagnostic challenge of small fibre neuropathy: clinical presentations, evaluations, and causes. Lancet Neurol, 16(11),

3 Pain characteristics in SFN Devigili, G., Tugnoli, V., Penza, P., Camozzi, F., Lombardi, R., Melli, G., et al. (2008). The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain, 131(Pt 7), Devigili, G., Tugnoli, V., Penza, P., Camozzi, F., Lombardi, R., Melli, G., et al. (2008). The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain, 131(Pt 7), Large Myelinated Fibers Motor - weakness Touch sensation numbness (pain) Proprioception/vibration- unsteadiness Small Myelinated Fibers Pain sensation painful paresthesias Temperature thermal sensory loss <5% isolated SFN Small Un-myelinated Fibers Pain sensation- painful paresthesias Autonomic dizziness, syncope, GI etc. 3

4 Griffin JW, Thompson WJ. Glia. 2008;56:1518 Small unmyelinated axons in the skin are the foot soldiers of the peripheral nervous system Jack Griffin

5 Early (Developing) DPN is Characterized by Progressive Small Fiber (but not large fiber) Loss The IGTN Study: Diet and Exercise are associated with reinnervation and improved pain in IGTN Smith, A. G., Russell, J., Feldman, E. L., Goldstein, J., Peltier, A., Smith, S., et al. (2006). Lifestyle intervention for pre-diabetic neuropathy. Diabetes Care, 29(6), doi: /dc Capsaicin Axotomy with Reinnervation Baseline 48 Hours Polydefkis M, Hauer P, Sheth S, Sirdofsky M, Griffin JW, McArthur JC. The time course of epidermal nerve fibre regeneration: studies in normal controls and in people with diabetes, with and without neuropathy. Brain Jul;127(Pt 7):

6 Exercise improves nerve regenerative capacity Singleton, J. R., Marcus, R. L., Lessard, M. K., Jackson, J. E., & Smith, A. G. (2014). Supervised exercise improves cutaneous reinnervation capacity in metabolic syndrome patients. Ann Neurol, n/a n/a. doi: /ana Lauria, G., Bakkers, M., Schmitz, C., Lombardi, R., Penza, P., Devigili, G., et al. (2010). Intraepidermal nerve fiber density at the distal leg: a worldwide normative reference study. Journal of the Peripheral Nervous System : JPNS, 15(3), Diagnostic performance IENFD and QST among painful neuropathy patients compared to normal controls NCS abnormal in approximately 70% of neuropathy patients. Frequently normal in those with burning feet/small fiber neuropathy (~40%). Specificity data are lacking Sensitivity and specificity reported to be 70-80%. Concerns regarding specificity in specific populations (diabetes). Smith, A. G. (2014). Do all neuropathy patients need an EMG at least once? Continuum (Minneapolis, Minn.), 20(5 Peripheral Nervous System Disorders), doi: /01.con c7 Devigili, G., Tugnoli, V., Penza, P., Camozzi, F., Lombardi, R., Melli, G., et al. (2008). The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain, 131(Pt 7),

7 Diagnostic Performance of NCS and IENFD for DPN IENFD and NCS 366 diabetic patients recruited from a large community care network, age 18-70, underwent NCS, IENFD (distal leg) and validated examination and symptom scores. Neuropathy was defined based on two gold standards 1. Signs (UENS>4) and symptoms (MNSI>2) of neuropathy 2. Signs and symptoms with one confirmatory test other than that being evaluated (QST, QSART, IENFD, NCS) or signs or symptoms + 2 confirmatory tests. Signs/Symptoms + Confirmatory Test Signs and Symptoms Modality Sensitivity Specificity PPV NPV Sural Amplitude Sural Sensory + Peroneal Motor (amplitude or CV) IENFD Limitations to Skin Biopsy Not specific in patients with diabetes. A negative skin biopsy does not fully exclude neuropathy. Technically demanding. Black Box Population prevalence of DPN 18% 7

8 Smith AG, Kim G, Porzio M, et al. Corneal confocal microscopy is efficient, well-tolerated, and reproducible. Journal of the Peripheral nervous system : JPNS Mar(1):54 8. Smith AG, Kim G, Porzio M, et al. Corneal confocal microscopy is efficient, well-tolerated, and reproducible. Journal of the Peripheral nervous system : JPNS Mar(1):

9 Tavakoli, M., Ferdousi, M., Petropoulos, I. N., Morris, J., Pritchard, N., Zhivov, A., et al. (2015). Normative values for corneal nerve morphology assessed using corneal confocal microscopy: a multinational normative data set. Diabetes Care, 38(5), Chen, X., Graham, J., Dabbah, M. A., Petropoulos, I. N., Ponirakis, G., Asghar, O., et al. (2015). Small nerve fiber quantification in the diagnosis of diabetic sensorimotor polyneuropathy: comparing corneal confocal microscopy with intraepidermal nerve fiber density. Diabetes Care, 38(6), CCM as a Diagnostic and Screening Tool for Diabetic Neuropathy (DP3DK104394) 1. Prospectively screen patients being seen for annual retinopathy screening for DPN using CCM, IENFD, NCS and clinical scales (200). 2. Determine responsiveness to change for each DPN measure (100). 3. Assess clinical meaning of baseline measures and their change over time. 9

10 Laboratory Testing for SFN In all patients: Thorough history and examination Diabetes/Prediabetes A1c Dyslipidemia B12 SPEP/IFIX England, J. D., Gronseth, G. S., Franklin, G., Carter, G. T., Kinsella, L. J., Cohen, J. A., et al. (2009). Practice Parameter: evaluation of distal symmetric polyneuropathy: role of laboratory and genetic testing (an evidence-based review). Report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation. Neurology, 72(2), Terkelsen, A. J., Karlsson, P., Lauria, G., Freeman, R., Finnerup, N. B., & Jensen, T. S. (2017). The diagnostic challenge of small fibre neuropathy: clinical presentations, evaluations, and causes. Lancet Neurol, 16(11),

11 Hereditary Causes for SFN Ulcerated hands/feet in a patient with HSAN1 secondary to a SPTLC1 mutation. Treatable Disorders HSAN 1 Fabry TTR Amyoidois Sodium Channel Mutations Mary M Reilly Pract Neurol 2007;7: Courtesy Vera Fridman, MD Fabry Disease: α Galctosidase Deficiency (Xlinked) Painful neuropathy, often in childhood. Hypohidrosis Stroke Renal failure Hearing loss Angiokeratoma Corneal verticillata Screening for Fabry Disease Has a Very Low Diagnostic Yield de Greef, B. T. A., Hoeijmakers, J. G. J., Wolters, E. E., Smeets, H. J. M., van den Wijngaard, A., Merkies, I. S. J., et al. (2016). No Fabry Disease in Patients Presenting with Isolated Small Fiber Neuropathy. PLoS One, 11(2), e

12 Transthyretin Familial Amyloid Polyneuropathy Early SFN with painful neuropathy (not uniform) Autonomic neuropathy Early carpal tunnel syndrome Multisystem involvement (cardiomyopathy) Large fiber and motor involvement with progression. Routine screening for TTR mutations in idiopathic SFN has a very low diagnostic yield. Among 172 patients with idiopathic small fiber neuropathy, no pathogenic mutations were found in the TTR gene, and one variant in GLA gene with normal α galactosidase level. Adams, D., Gonzalez-Duarte, A., O'Riordan, W. D., Yang, C.-C., Ueda, M., Kristen, A. V., et al. (2018). Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. The New England Journal of Medicine, 379(1), Samuelsson, K., Radovic, A., Press, R., Auranen, M., Ylikallio, E., Tyynismaa, H., et al. (2018). Screening for Fabry disease and Hereditary ATTR amyloidosis in idiopathic small-fiber and mixed neuropathy. Muscle & Nerve, 84(suppl 1),

13 8/28 patients with confirmed idiopathic small fiber neuropathy had Nav 1.7 mutations Faber, C. G., Hoeijmakers, J. G., Ahn, H. S., Cheng, X., Han, C., Choi, J. S., et al. (2011). Gain of function Na(V) 1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol, 71(1), doi: /ana Huang, J., Han, C., Estacion, M., Vasylyev, D., Hoeijmakers, J. G. J., Gerrits, M. M., et al. (2014). Gain-of-function mutations in sodium channel Na(v)1.9 in painful neuropathy. Brain, 137(Pt 6), doi: /brain/awu079 Blesneac, I., Themistocleous, A. C., Fratter, C., Conrad, L. J., Ramirez, J. D., Cox, J. J., et al. (2018). Rare NaV1.7 variants associated with painful diabetic peripheral neuropathy. Pain, 159(3), Peripheral Neuropathy Research Registry (PNRR) 457 patients with axonal neuropathy 278 Idiopathic (67% painful) 179 DPN (77% painful) SCN9A (Na v 1.7), SCN10A (Na v 1.8), SCN11A (Na v 1.9) sequenced. Haplotype analysis. 36 SN9A, 31 SCN10A and 15 SCN11A nonsynonymous missense variants. 47.7% of patients had a low frequency missense variant in at least one gene. Incidence of previously reported gain of function mutations was <3%, and these were unrelated to pain. Not significantly different from EVS-EA reference population. Wadhawan, S., Pant, S., Golhar, R., Kirov, S., Thompson, J., Jacobsen, L., et al. (2017). NaV channel variants in patients with painful and nonpainful peripheral neuropathy. Neurology Genetics, 3(6), e

14 Wadhawan, S., Pant, S., Golhar, R., Kirov, S., Thompson, J., Jacobsen, L., et al. (2017). NaV channel variants in patients with painful and nonpainful peripheral neuropathy. Neurology Genetics, 3(6), e Peltier, A., Goutman, S. A., & Callaghan, B. C. (2014). Painful diabetic neuropathy. Bmj, 348(may06 1), g1799 g DPN is Associated with Increased Risk of Depression and Anxiety 50% relative increase in risk of depression in those with neuropathy (DPN and CSPN) compared to controls (23% vs. 15%, p<0.001). 50% with painful DPN have depression or anxiety and 26% have both. Pain and gait instability are most potent predictors of depression. Callaghan, B., et al. (2015). "Longitudinal patient-oriented outcomes in neuropathy: Importance of early detection and falls." Neurology 85(1): Selvarajah, D., et al. (2014). "The contributors of emotional distress in painful diabetic neuropathy." Diabetes & vascular disease research 11(4): Bai, J. W., et al. (2017). "Neuropathy and presence of emotional distress and depression in longstanding diabetes: Results from the Canadian study of longevity in type 1 diabetes." J Diabetes Complications 31(8):

15 5 Take Home Points 1. Peripheral neuropathy is very common, but isolated SFN is uncommon. Many (most?) patients with SFN evolve to mixed large and small fiber neuropathy. 2. Diagnostic evaluation can be limited unless warning signs (young age, progressive, systemic features, specific findings). 3. Choose your skin biopsy laboratory carefully 4. Routine genetic screening is not recommended. 5. Pharmacological treatment is of modest benefit. Exercise and attention to comorbid depression/anxiety are important. Treatment Induced Neuropathy of Diabetes (TIND). TIND is Common and Underappreciated 11% of 954 patients evaluated for peripheral neuropathy in a large tertiary care neuropathy clinic. TIND occurred in 104/168 (62%) of patients with a decline in A1c of >2% over 3 months Decrease of A1c of 2-3% over 3 months there was a 20% risk. A decrease of >4% was associated with an 80% risk. Gibbons, C. H., & Freeman, R. (2010). Treatment-induced diabetic neuropathy: a reversible painful autonomic neuropathy. Ann Neurol, 67(4), Gibbons, C. H., & Freeman, R. (2015). Treatment-induced neuropathy of diabetes: an acute, iatrogenic complication of diabetes. Brain, 138(Pt 1),

16 Treatment Induced Neuropathy of Diabetes (TIND) 26 T1D patients with TIND 19/26 with stable glycemic control had improvement in neuropathy severity. 7/26 with unstable glycemic control had worsening severity Additional studies of TIND are required to understand potential outcomes in an era of medical metrics where physician reimbursement may be tied to achievement of excessively rapid glycemic control. Gibbons, C. H., & Freeman, R. (2015). Treatment-induced neuropathy of diabetes: an acute, iatrogenic complication of diabetes. Brain, 138(Pt 1), Gibbons, C. H. (2017). Treatment induced neuropathy of diabetes-long term implications in type 1 diabetes. J Diabetes Complications, 31(4),