“Doc, DO I Have Neuropathy?” Case Vignettes Susan, 50 Gwenn, 32 John, 52 Sally, 42 DM – 12 yrs Hypothyroidism No PMH No PMH B/N/T – 2 yrs N/T at night B/N/T – 6 days B/N/T – few months 3 months Stanley Jones P. Iyadurai, MSc, PhD, MD Hands, Hands, Arms Hands, Feet Assistant Professor of Neurology Feet Right hand Feet, Legs Burning Pain Neuromuscular Division, Department of Neurology Arms, Difficulty Pain Pain The Ohio State University Wexner Medical Center Legs Opening jars Breathing Redness Imbalance Normal gait Imbalance Normal Strength “Neuropathy” - Definition Neuropathy - General Theme • Symmetric • “Neuron” and “Pathos” (Greek) • Insidious • More prominent distally and starts in • Disease of the Peripheral Nerve legs • Involves both motor and sensory • Dysfunction of the nerves outside of components the central nervous system • May cause pain • May cause loss of balance • Progressive, but not debilitating 1 Not all that tingles is Classification - Functional neuropathy ‘numbness and tingling’ • Motor – affects the motor nerves Weakness • not all numbness and tingling is • Sensory peripheral nerve ‒ Pain • RLS ‒ Small Fiber ‒ Large Fiber • edema ‒ Large and Small Fiber • deconditioning ‒ Neuronopathy (ganglionopathy) • central nervous system • Autonomic • Sweating Changes, Blood Pressure Changes • nerve root [‘sciatica’] Classification – Time-course Classification – Time-course • Acute Immune-mediated • Congenital/Hereditary • Infantile Weakness • Childhood-onset • Acquired • Relapsing ‒ Reversible? • Hereditary ‒ Demyelinating? · Motor-Sensory ‒ Immune-mediated? · Motor Syndromes ‒ Systemic diseases? · Sensory Syndromes 2 Neuropathy - Evaluation Examination • Vibration sense – the most sensitive test • Detailed History • Quantitative Tuning Fork (Rydel-Seiffer) • Family History • Pin scratch test (gradient) • Clinical Examination • Proprioception • Temperature sense – comparisons • Blood Work • Reflexes • Special Tests – EMG/NCS • Distal strength testing • Special Tests – Imaging ‒ “Bring your toes up” • Special Tests – Nerve/Muscle/Skin Biopsy ‒ “Curl your toes down” ‒ “Spread your toes” Work-up “Doc, DO I Have Neuropathy?” • CBC, CMP, LFTs • ESR, CRP, RF, ANA, ENA, ANCAs, ACE • Hgb A1c, fasting glucose, 2h glucose tolerance, TSH, T3, T4, B12, MMA, B6, B1, D • Lyme titer, RPR, HIV, Hepatitis panel, • Quantitative immunoglobulins, Special antibodies Amro Stino, MD • immunofixation electrophoresis Assistant Professor-Clinical • CSF Division of Neurology • EMG/NCS, consider MRI Brain/Spine, CT-C,A,P The Ohio State University Wexner Medical Center • Nerve/muscle biopsy, Skin biopsy*, Autonomic testing* *consider if EMG/NCS normal 3 ‘The Big 4’ – The Most Nerve Conduction Common Studies (NCS) • Diabetes AND impaired glucose tolerance ‒ A1c, 2h glucose tolerance test, fasting glucose • B12 deficiency ‒ B12 + MMA • Alcohol ‒ CAGE questionnaire • Plasma cell dyscrasias (paraproteinemias) – ‒ immunofixation electrophoresis Autonomic testing – sweat output Electromyography (EMG) as measure of small fiber neuropathy = QSART LENGTH DEPENDENT SWEAT LOSS – DISTAL IS < 1/3 PROXIMAL SWEAT VOLUME 4 Autonomic Testing - Autonomic Testing - Loss of Heart Rate Variation to Deep Breathing = Loss of Heart Rate Variation to Deep Breathing = Cardiac wall remodeling in diabetics = Poor Cardiac wall remodeling in diabetics = Poor Prognosis Prognosis Virtually no heart rate variation Courtesy of Brent Goodman, MD Courtesy of Brent Goodman, MD Why Do We Care About “Doc, DO I Have Neuropathy?” Details? • Not to Miss a Treatable Cause • Not to Miss an Immune-mediated Stanley Jones P. Iyadurai, MSc, PhD, MD Neuropathy – since it is often treatable Assistant Professor of Neurology Neuromuscular Division, Department of Neurology The Ohio State University Wexner Medical Center • Prevent Further Worsening of Neuropathy 5 Causes Metabolic • Metabolic • Vitamin deficiencies • Diabetes • Inflammatory conditions • Infections • Thyroid • Cancer • Drugs, Toxins • Uremic (usually on hemodialysis) • Nerve injury at specific locations • Immune Mediated Neuropathies • Genetic Vitamin Deficiencies Inflammatory conditions • Vitamin B12 • Vasculitides – often are very painful, multifocal, and require nerve and muscle biopsy. Treated with steroids and immunosuppressants • Vitamin B6 EVALUATE FOR SECONDARY CAUSES • Systemic Lupus Erythematosus • Vitamin B1 • Celiac Sprue-related Neuropathy • Vitamin E • Connective Tissue Disorders • Sarcoidosis 6 Infections Cancer • Due to any cancer in general • HIV • Lymphoma • Hepatitis • Multiple Myeloma • Lyme disease • Result of Cancer Treatments • Leprosy • Paraneoplastic – Specifically anti-Hu Paraproteinemias Drugs, Toxins • MGUS – often mimics CIDP • Chemotherapy drugs (demyelinating) • Amiodarone • Waldenstrom – more axonal • Dilantin • Amyloidosis – get significant autonomic • Disulfiram disturbance • Dapsone, Ethambutol • Multiple Myeloma – neuropathy usually • Leflunomide results more from chemotherapy • Alcohol (bortezomib) • “Huffing” • POEMS – Polyneuropathy, Organomegaly, • Agent Orange Endocrinopathy, M-protein Spike, Skin Changes. 7 Immune-Mediated Nerve Injuries Neuropathies • Carpal Tunnel • Evaluation based on specific antibodies in the serum • Common ones: anti-GM-1, anti-GQ1b, anti- • Ulnar Neuropathy tubulin and anti-Hu, anti-TS-HDS • Treatment is related to immune therapies and • Common Peroneal Neuropathy immunomodulation • IVIG, Plasmapheresis, Steroids, Rituximab Autoimmune Neuropathy “Doc, DO I Have Neuropathy?” Spectrum • Acquired, Immune Mediated Neuropathies ‒ GBS – reaches nadir in < 4 weeks ‒ CIDP – reaches nadir in > 8 weeks Amro Stino, MD Assistant Professor-Clinical Division of Neurology The Ohio State University Wexner Medical Center 8 Acquired Demyelinating Typical GBS (AIDP) Features • 90% + of GBS have AIDP presentation • Sensory phase of 3 - 10 days ‒ Numbness, tingling, tightness ‒ Pain in 75-90%: often in the lower back or proximal legs • Weakness spreads from legs to arms ‒ Facial involvement in about 50% of otherwise typical cases ‒ DTRs decreased to absent – • not always global • Autonomic involvement in ~ 70% (may be severe) ‒ Requires ICU stay • 25-40% require ventilator assistance (may be very rapid) ‒ 1/3 require intubation ‒ Predictors of impending respiratory failure may prompt PLEX instead of IVIG to allow for faster treatment Pictures from neuromuscular.wustl.edu, courtesy of Dr. Alan Pestronk response GBS Diagnostic Criteria GBS Overview Typical Necessary Criteria Supportive Criteria • Acute Inflammatory Demyelinating Polyradiculoneuropathy (AIDP) Symmetric weakness Sensory sx./signs Atypical Areflexia CN weakness (VII) • Acute Motor Axonal Neuropathy (AMAN) • Acute Motor Sensory Axonal Neuropathy Progression < 4 weeks ANS dysfunction (AMSAN) Both AMAN and AMSAN have association with GD1a High CSF protein and GM1 Demyelinating EPS • Miller Fisher Variant (MFS) – GQ1b • Pharyngeal Cervical Variant – GT1a 9 Chronic Inflammatory GBS Treatment Demyelinating • Responds to IVIG or Plasmapheresis Polyradiculoneuropathy • Chronic progressive, stepwise, or recurrent symmetric proximal and distal weakness and sensory dysfunction of all extremities, developing over at least 2 months and ‒Absent or reduced reflexes in all extremities CIDP Supportive Findings CIDP Treatment 1. Elevated CSF protein with leukocyte count < 10/mm (level A) • Responds to IVIG, Steroids, or 2. MRI showing GAD enhancement and/or hypertrophy Plasmapheresis of cauda, lumbosacral, or cervical nerve roots, or brachial or lumbosacral plexus (level C) 3. Abnormal sensory electrophysiology in at least one nerve (good practice point) 1. Normal sural with abnormal median (excluding CTS) or radial SNAP 2. CV < 80% of LLN (<70% if SNAP amplitude <80% of LLN) 3. Delayed SSEPs without CNS disease 10 Multifocal Motor Neuropathy Neuropathy – Treatment Principles • Associated with anti-GM1 IgM antibodies • Antibodies bind to node of Ranvier structures of • Address Reversible Causes of Neuropathy motor axons (GM1 enriched) and fix complement. ‒ B12 deficiency - 2000mcg daily by mouth or IM • Incidence: 0.6/100K ‒ B6 toxicity – reduce amount • Clinically: ‒ Alcohol abuse – abstinence, vitamin ‒ non-contiguous motor nerves affected replenishment ‒ weakness far in excess of atrophy noted (in • Pain Management – Try different classes +/- distinction to MND) Tramadol before going to Opiates ‒ asymmetric upper limb onset without sensory ‒ Tricyclics complaints ‒ SNRIs ‒ 20-30% can have brisk tendon reflexes ‒ Sodium Channel Blockers ‒ Combining galatocerbroside with GM1 ‒ Calcium Channel Blockers increases sensitivity to 75% ‒ Tramadol ‒ Opiates (long-acting) Treatment Treatment • Anticonvulsants • Antidepressants ‒ Gabapentin ‒ Amitriptyline (TCA) ‒ Pregabalin ‒ Nortriptyline (TCA) ‒ Topiramate ‒ Lamotrigine ‒ Desipramine (TCA) ‒ Carbamazepine ‒ Duloxetine (SNRI) ‒ Oxcarbazepine ‒ SSRIs 11 Treatment Common Mimics • Topical Anesthetics • RLS ‒ 5% Lidocaine patch ‒ Requip ‒ 0.075% Capsaicin patch ‒ Check Ferritin • Opioids • PLMS ‒ Tramadol ‒ Sleep study ‒ Oxycodone Case Presentation “Doc, DO I Have Neuropathy?” • 54-year old man presents to the ER with recent onset of numbness and tingling in bilateral hands and feet (“stocking-glove distribution”) Stanley Jones P. Iyadurai, MSc, PhD, MD Assistant Professor of Neurology • Examination – Reportedly Normal Neuromuscular Division, Department of Neurology The Ohio State University Wexner Medical Center • Blood sugar – 127 (Elevated) • Diagnosis? 12 Case presentation Case Follow-up (Cont’d)