“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) • Diagnosis: “Diabetic neuropathy” • CSF: Protein elevated at 124 ‒ Start metformin

• 2 days later, “increased numbness, • Diagnosis: Guillain-Barre Syndrome worse tingling, and with pain” ‒ IVIg treatment with full remission

• Examination with diminished reflexes ‒ Diagnosis: ?

Genetic causes Genetic causes • Charcot-Marie-Tooth disease • Suggested by a very long course ‒ Many forms, many genes • No treatable reason found despite repetitive evaluation • HNPP (PMP-22) • Loss of strength (motor nerves ‒ “Tool-belt” pressure causing pain damaged) without much reported and weakness sensory loss (usually) ‒ “Foot drop” • Pain < dysfunction • Porphyria • Family history • Amyloidosis

13 Rare genetic causes Hereditary Neuropathies

• Fabry’s disease (alpha-galactosidase)

• Metachromatic leukodystrophy (aryl sulfatase)

• Adrenoleukodystrophy

• Refsum’s disease (phytanic acid)

Neuropathic Gait Hereditary Neuropathies

Chronic sensory neuropathy CMT 1A High arches & Hammer toes PMP-22 CMT 1X CMT 2A2 Preserved gastrocnemius size duplication

Pictures from neuromuscular.wustl.edu, courtesy of Dr. Alan Pestronk

14 Case Vignettes Case Vignettes

Susan, 50 Gwenn, 32 John, 52 Sally, 42 Susan, 50 Gwenn, 32 John, 52 Sally, 42

DM – 12 yrs Hypothyroidism No PMH No PMH 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 B/N/T – 2 yrs N/T at night B/N/T – 6 days B/N/T – few months 3 months 3 months Hands, Hands, Arms Hands, Feet Hands, Hands, Arms Hands, Feet Feet Right hand Feet, Legs Burning Pain Feet Right hand Feet, Legs Burning Pain

Arms, Difficulty Pain Pain Arms, Difficulty Pain Pain Legs Opening jars Breathing Redness Legs Opening jars Breathing Redness

Imbalance Normal gait Imbalance Normal Strength Imbalance Normal gait Imbalance Normal Strength

Diabetic Neuropathy

Case Vignettes Case Vignettes

Susan, 50 Gwenn, 32 John, 52 Sally, 42 Susan, 50 Gwenn, 32 John, 52 Sally, 42

DM – 12 yrs Hypothyroidism No PMH No PMH 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 B/N/T – 2 yrs N/T at night B/N/T – 6 days B/N/T – few months 3 months 3 months Hands, Hands, Arms Hands, Feet Hands, Hands, Arms Hands, Feet Feet Right hand Feet, Legs Burning Pain Feet Right hand Feet, Legs Burning Pain

Arms, Difficulty Pain Pain Arms, Difficulty Pain Pain Legs Opening jars Breathing Redness Legs Opening jars Breathing Redness

Imbalance Normal gait Imbalance Normal Strength Imbalance Normal gait Imbalance Normal Strength

Diabetic Carpal Tunnel Diabetic Carpal Tunnel Guillain-Barre Neuropathy Syndrome Neuropathy Syndrome Syndrome

15 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 Hands, Hands, Arms Hands, Feet Feet Right hand Feet, Legs Burning Pain

Arms, Difficulty Pain Pain Legs Opening jars Breathing Redness

Imbalance Normal gait Imbalance Normal Strength

Diabetic Carpal Tunnel Guillain-Barre Small Fiber Neuropathy Syndrome Syndrome Neuropathy

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