11/12/2013 WEBINAR: “Understanding and Living Well with Small Fiber Neuropathy” ” Saturday, November 16th, 2013 2 - 3:15 pm ET 1 - 2:15 pm CT 12 - 1:15 pm MT 11 am - 12:15 pm PT Presented by: Shanna K. Patterson, MD St. Luke’s - Roosevelt Hospital Center Corey W. Hunter, MD Ainsworth Institute of Pain Management Brought to you by The Neuropathy Association and Transgenomic, Inc. 1 11/12/2013 Presentation Objectives WHAT PARTICIPANTS CAN TAKE AWAY FROM THE WEBINAR: Understand the relationship between small fiber neuropathy(SFN) and peripheral neuropathy; Recognize the symptoms and signs of small fiber neuropathy; Understand the importance of getting an evaluation and accurate diagnosis of small fiber neuropathy; Appreciate the role of current and emerging (clinical research trials) approaches for diagnosing and treating small fiber neuropathy; and, Review the spectrum of pain management strategies. SFN: Introduction Two general categories of peripheral nerve fibers: Large diameter Myelinated Sensory and motor function Small diameter Unmyelinated or thinly myelinated Sensory function only Located in the superficial layer of skin, known as the epidermis, as well as in sweat glands in the skin Also involved in innervation of the cardiovascular, genitourinary and gastrointestinal systems 2 11/12/2013 SFN: Introduction Small fiber neuropathy is a type of neuropathy where only small diameter nerve fibers are affected. A recent study showed that the prevalence of small fiber neuropathy in the Southern Netherlands was approximately 53 cases per 100,000. The incidence was higher in men than women, and in older individuals. (Neurology 2013) SFN: Sensory Symptoms Symptoms are usually sensory in nature and include pain, numbness or other uncomfortable sensations, such as tingling. “Length dependent”: begins in the distal limbs, such as the feet “Non-length dependent”: involves different locations on the body, may occur in a multifocal, patchy distribution. Symptoms of pain or tingling, or other uncomfortable sensations are often more common than numbness in SFN. (Muscle Nerve 1992) Because small diameter nerve fibers do not connect to muscles, weakness will not be a symptom in this type of neuropathy. Small fiber neuropathy may be a cause of muscle cramps. In an evaluation of 12 consecutive patients with cramps but without neuropathic complaints (pain, tingling, etc.) 60% had small fiber neuropathy, as diagnosed with skin biopsy. (Muscle Nerve 2013) 3 11/12/2013 SFN: Autonomic Symptoms Some (but not all) SFN patients may also develop symptoms of autonomic neuropathy. • Peripheral autonomic nerves control several vital body functions -- which we do not consciously think about -- including blood pressure, heart rate, digestion, dilation and constriction of the pupils of the eye, sexual function, and bowel and bladder emptying. - Gastrointestinal symptoms: constipation, diarrhea, early feelings of satiety. - Cardiovascular symptoms: blood pressure changes with position causing dizziness when standing. - Genitourinary symptoms: difficulty beginning to urinate, feeling of incomplete bladder emptying, urinary incontinence, and sexual dysfunction. - Other symptoms: abnormal sweating and increased sensitivity to warm and cold temperatures. SFN: Signs Clinical signs on physical examination of a person with SFN can include Reduced temperature or pain (pin prick) sensation Reduced light touch sensation Increased sensitivity (hyperesthesia) to touch Painful sensation to touch (allodynia) However, in many cases the sensory examination may also be normal. 4 11/12/2013 SFN: Testing Neuropathy involving large diameter nerves is detectable with nerve conduction studies (NCS), but isolated small diameter nerve involvement is not detectable using this test. Testing for SFN is important: It can lead to psychological validation for patients who previously did not know the reason for their symptoms. Objective diagnosis facilitates search for cause, as well as treatment. SFN: Testing Quantitative sensory testing: An automated, standardized system that quantifies thresholds across several sensory modalities. This allows for a more precise and sensitive means of detecting abnormalities in sensation. Skin punch biopsies: The density of small diameter nerve fibers in a small (3mm) sample of epidermal tissue (most superficial layer of skin) is measured. In SFN there is a reduced number of nerve fibers (reduced epidermal nerve fiber density). 5 11/12/2013 SFN: Causes Many causes of SFN are similar to those of large fiber neuropathy. Small fiber sensory neuropathy is a major manifestation in type 1 diabetes…and more prevalent than large fiber neuropathy. (Diabetes Care) If the cause of neuropathy is found, this can improve the chances of treating the neuropathy. In approximately half of cases no cause for SFN is found. Ongoing research continues to search for additional causes. SFN: Causes Causes of SFN include: • • • • • • • • • • Metabolic conditions: diabetes, borderline diabetes Toxic effects: alcohol abuse, heavy metals, certain medications Deficiency or excess of vitamins Infections: hepatitis C, Lyme disease, HIV, Leprosy Auto-immune conditions: vasculitis, paraneoplastic conditions (autoimmune response to malignancy), Sjögren’s syndrome, Celiac disease Hematologic conditions: malignancies, abnormal protein production Hereditary neuropathies Fabry disease: alpha-galactosidase A enzyme deficiency Familial amyloidosis: transthyretin gene mutation Voltage gated sodium channel mutations 6 11/12/2013 SFN: Relationship to sodium channel mutations In one study, 30% of patients with idiopathic SFN were found to have SCN9A-gene mutations. (Clinical Genetics 2012) This mutation produces abnormal increased function in nerve sodium channels. This type of sodium channel is more specific to small diameter peripheral nerves. (This genetic cause may not be able to account for an equally high percentage of idiopathic large diameter neuropathy cases). Treatment of pain symptoms for these patients may be best achieved by using neuropathic pain medications that decrease sodium channel activity, such as gabapentin or carbamazepine. SFN: Evaluating for Causes History Detailed history to evaluate for possible exposures to certain medications, toxins, etc. Family history of certain conditions Risk factors for certain conditions Detailed medical history Looking for certain physical examination features suggestive of other potentially contributory causes. Laboratory evaluation May include genetic testing 7 11/12/2013 SFN: Treatment If a reversible or treatable underlying cause is identified, this should be addressed. If blood sugar control is achieved and maintained, or a vitamin deficiency is corrected, for example, over time the neuropathy may improve. It is difficult to precisely predict, as each patient’s clinical situation and course is different. In certain autoimmune-related types of SFN treatment with IVIG (intravenous immunoglobulin) may be effective. More information to come regarding symptomatic management of pain with Dr. Corey Hunter… SFN: Possible Relationship to Fibromyalgia Several recent studies have shown that a significant proportion of patients with fibromyalgia have reduced epidermal nerve fiber density on punch skin biopsies. (Brain 2013, Pain 2013) Additional research is ongoing, but the cause of other painful conditions or syndromes may in the end be related to small fiber neuropathy. 8 11/12/2013 Managing SFN: Overview Small fiber neuropathy is frequently associated with neuropathic pain. - A variety of medications for treatment of pain exist, and there are a number of consensus guidelines that help clinicians in selecting appropriate treatment(s). - Limited evidence for specific medications in the treatment of pain from small fiber neuropathies. How do clinicians partner with patients to select pain treatments? - evidence of safety - efficacy in other neuropathic conditions - tolerability - cost - co-morbid conditions - drug interactions Partnering with a multi-disciplinary team of health care professionals is important. - neurologist specializing in neuromuscular diseases - physical therapist - pain medicine specialist - immunologist Managing SFN: Treating Underlying Cause Is Key • Treat the underlying cause of SFN (when possible) and the pain Careful screening for reversible causes of small fiber neuropathy is critical. • 50% of SFN patients are given an “idiopathic” (or unknown cause) diagnosis Many patients with small fiber neuropathy are given an “idiopathic” diagnosis even after comprehensive evaluation -- for these patients, pain management is critical. • Evaluate and treat the autonomic symptoms e.g., excessive sweating, gastroparesis, orthostatic hypotension • Evaluate and treat the co-morbid symptoms e.g., anxiety, depression, sleep disturbances 9 11/12/2013 Managing SFN: Pharmacological Treatments First-line treatments: - Gabapentin (FDA-indicated for PHN) - Gabapentin once-daily dose (FDA-indicated for PHN) - Pregabalin (FDA-indicated for painful DPN, fibromyalgia, and PHN) - Topical capsaicin (FDA-indicated for PHN) - Topical lidocaine (FDA-indicated for PHN) Second-line treatments: - Duloxetine (FDA-indicated for painful DPN, fibromyalgia, chronic back pain) - Tapentadol extended-release(FDA-indicated for painful DPN) - Topical capsaicin (FDA-indicated for PHN) - Topical lidocaine (FDA-indicated for PHN) - Amytriptyline - Nortriptyline - Tramadol - Venlafaxine Third-line treatments: - Tapentadol extended-release (FDA-indicated for painful DPN) - Tramadol Managing SFN: Non-Pharmacological Treatments According to the National Center for Complementary and Alternative Medicine (NCCAM), nearly 40% of Americans use health care approaches developed outside of mainstream Western -- or conventional -- medicine for specific conditions or overall well-being. - Dietary supplements For more information about - Mind and body practices Complementary and Alternative e.g., acupuncture, biofeedback, yoga, Medicine, visit meditation, tai chi, hypnotherapy http://nccam.nih.gov/health/pain. - Physical therapy - Cool or warm soaks, soft socks, foot tents It is critical that you inform your doctor(s) about any alternative / complementary medicines you might be considering. 10 11/12/2013 Managing SFN: Interventional Treatments Infusion Therapy Ketamine (requires in-patient hospital admission) Lidocaine Regional Nerve Blocks under Ultrasound Sympathetic Blocks Stellate Ganglion for the Upper Extremities Lumbar Sympathetic Chain for the Lower Extremities Spinal Cord Stimulators Intrathecal Pumps SFN Clinical Research Studies A placebo-controlled, randomized, double blind trial of milnacipran for the treatment of idiopathic neuropathy pain Safety and tolerability of lacosamide in patients with gain-of-function Nav1.7 mutations-related small fiber neuropathy Metanx effects on nerve fiber density in neuropathic diabetics (SLHN2011-18) Safety and efficacy of gabapentin for neuropathic pain in Fabry disease For a more comprehensive list of neuropathy clinical trials and to locate clinical trials in your vicinity, visit www.clinicaltrials.gov and search using the words “neuropathy” and the “name of the city” you live in (e.g., neuropathy, NYC). 11 11/12/2013 Q and A Provided by: For more information about Transgenomic, Inc. and SCN9A testing, visit www.transgenomic.com/labs/neurology. For more information about peripheral neuropathy, small fiber neuropathy, and The Neuropathy Association, visit www.neuropathy.org. 12 11/12/2013 Testing for SCN9A Pain-related Disorders The SCN9A gene encodes the sodium channel protein Nav1.7 that is located in peripheral neurons. SCN9A mutations may cause a loss- or gain-of-function of Nav1.7 whose primary function is mediating pain sensations. Gain-of-function mutations result in hyper-excitability of pain signaling neurons causing extreme sensitivity to pain, while loss-of-function mutations have the opposite effect on pain sensation.¹ Learn more about SCN9A testing and Transgenomic Labs: www.transgenomic.com/labs/neurology (P) 1.877.274.9432 / (F) 1.855.263.8668 / [email protected] 1. Drenth, JP, et al. Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders. J. Clinical Investigation, 2017;117;3603-9. 2. Klein CJ, et al. Infrequent SCN9A mutations in congenital insensitivity to pain and erythromelalgia. J Neurol Neurosurg Psychiatry, November 2012. 3. Faber CG, et al. Gain of Function Nav1.7 Mutation in Idiopathic Small Fiber Neuropathy. Ann Neurol. 2012; 71:26-39. 4. Fertleman CR, et al. SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes.Neuron. 2006;52:767-74. 13