Peripheral Neuropathy Practical Points and Update

Devon I. Rubin, M.D.

Professor of Neurology

Mayo Clinic

Jacksonville, Florida

No Relevant Financial

Relationships

Learning Objectives After completion of this talk you should be able to:

• Perform a practical, cost-effective evaluation

• Identify “atypical” neuropathies

• Understand treatment options for various neuropathies

66 yo man with 2 years of

foot numbness/ burning.

Exam: Decreased

sensation (to mid shins),

absent Achilles reflexes

6 months ago diagnosed

with type 2 DM

DEFINE:

Differential diagnosis?

Tests?

Treatments?

Signs &

Symptoms

(M, S, Auto)

Anatomic

Distribution Temporal

Profile

Perform a careful neuromuscular examination !

Distal

Symmetric Proximal & Distal

Symmetric or Asymmetric (polyradiculopathy)

Focal

Multifocal

Asymmetric (mononeuropathy,

mononeuritis multiplex)

Distal Sensorimotor Peripheral Neuropathy

• “Length-dependent” (Legs before arms)

• Symmetric

Sensory loss (“glove-stocking”) Joint position/Vibration

Pin/Temperature

Weakness Toes > Ankles > Interossei / Hand muscles

Hypo-Reflexia

Achilles > Quads > UEs

Atypical Features (HAMP-er’s Dx)

Feature Consider

Hands > Feet Mononeuropathy (median, ulnar)

Polyradiculopathy (CIDP)

Cervical cord

Asymmetric Mononeuropathy (peroneal, ulnar)

Radiculopathy (L5, S1)

Polyradiculopathy

ALS

Motor without sensory Motor neuron disease/motor neuropathy

Distal myopathy

Proximal (with distal) weakness Polyradiculopathy

Myopathy (IBM) +/- neuropathy

NMJ disorder

What workup is needed?

Labs EMG

Nerve biopsy Genetic testing

Goals of EMG 1) Confirm “peripheral neuropathy”

2) Determines pathophysiology (axonal vs demyelinating)

3) Identify / exclude “mimicking” disorders

Uniform Demyelination

Inherited etiologies

CMT 1a

Segmental Demyelination

Acquired etiologies

AIDP (GBS)

CIDP

MGUS (esp IgM), anti-MAG neuropathy, Osteosclerotic myeloma

Hereditary neuropathy with pressure palsy

CV 17 m/s

Laboratory Testing How Extensive?

OGTT 61%

Hgb A1C 26%

F.glucose 11%

ANA 3%

SPEP 3%

Vit B12 2%

TSH 0%

ESR 0%

(n=138 Smith AG 2004)

AAN Practice Parameter Neurology 2009;72:185-192

The yield of screening laboratory tests is 37% - 58%.

Conclusion:

“Screening laboratory tests are possibly useful in determining the cause . . .”

Tests with the highest yield of abnormality are: glucose, B12, SPEP/IEP.

My Approach . . .

CBC Anemia, myeloproliferative

AST, ALT, creatinine Hepatic or renal disease

Fasting glucose, Hgb A1C

OGTT

Diabetes

Impaired glucose tolerance

B12, Methylmalonic acid

(Vitamin E, copper)

Vitamin deficiencies

SPEP

Monoclonal protein study

Metastatic bone survey

Fat aspirate

Paraproteinemia

Osteosclerotic myeloma

Amyloidosis

TSH Hypo-, Hyperthyroidism

ESR, ANA, ENA, ds-DNA Vasculitis, connective tissue disease

Other Tests if:

HIV, Hepatitis serologies,RPR Risk factors

Urine heavy metal screen Risk factors

(wrist drop, GI symptoms, hair loss, abdominal pain, etc.)

Antibody testing

GM1 Motor only neuropathy

MAG If monoclonal protein (IgM) and demyelination

SGPG, anti-sulfatide Rapid or subacute onset, severe sensory loss/ataxia

CSF Polyradiculopathy

Hereditary Clues

• “Always clumsy”, childhood onset

• Foot deformities (high arches/hammertoes), foot pain, gait difficulties, podiatrist consultations

• Examine accompanying family members

CMT 1a

When to Consider Genetic Testing $ $

AAN Practice Parameter

Useful for patients who exhibit a classic hereditary

neuropathy phenotype.

(+ Family History, Early onset, Demyelinating)

Insufficient evidence in cryptogenic PN without

hereditary phenotype.

Nerve Biopsy

Diagnosable disorders

Vasculitis

Amyloid

Sarcoid

Leprosy

CMT 1, 3

Micrometastases

Neurogenic tumors

When to order? Subacute

Severe

Rapidly progressive

*AAN Practice Parameter 2009

Skin Biopsy Intraepidermal Nerve Fiber Quantification

• Validated, reproducible marker of small fiber sensory pathology

• AAN Practice Parameter: “Possibly useful”

• Abnormal in 88% of pts with small fiber PN and normal NCS

*Hlubocky A, et al. Neurologist 2010

But . . . not a perfect test.

66 yo man with 2 years of

foot numbness/ burning.

Exam: Decreased

sensation (to mid shins),

absent Achilles reflexes

6 months ago diagnosed

with type 2 DM

Types of Neuropathy Associated with Diabetes

Diabetes and Neuropathy

** Vincent AM et al. J Periph Nerve Sys 2009

***Kassardjian et al. J Neurol Sci 2015

PN may precede DM dx

(no definite increase in small fiber PN in prediabetes)***

Tight glycemic control may delay PN

?? Optimal treatment and outcome

75 yo woman with 6

months of foot and hand

numbness and

imbalance.

EMG: Demyelinating PN

IgM lambda monoclonal

gammopathy.

• Present in ~10% of PN • 50% - IgM (often MAG antibody)

• Assess/follow for systemic amyloidosis or hematologic malignancy (lymphoma, osteosclerotic myeloma)

• Treatment: Rituximab, IVIg

• Cochrane Review (IgA and IgG PN) (2015) • 1 RCT trial (n=18) of PLEX: modest improvement in weakness of NDS

score (no difference in overall score) • Observational studies: Limited support for cyclophosphamide +

prednisone, IVIG, corticosteroids

• Autologous stem cell transplant improved POEMS PN (n=60), Class IV evidence (Neurology 2015)

Monoclonal Gammopathy

• 65 yo woman

• 3 months - numbness in hands and face

• 1 month – numb feet and leg weakness

• Exam:

• Symmetric, proximal and distal weakness

• Areflexia

• Distal sensory loss in hands/feet

Hands 1st, Subacute, Proximal weakness

Thoughts?

STOPSwitch:

1Stimulator: 0.5 HzRate: Level: 0.1 msDur: Single 0.0 mASTOPSwitch:

1Stimulator: 0.5 HzRate: Level: 0.1 msDur: Single 0.0 mA5 ms

Average: Off

12.0

81.5mA

2 mV

54.9mA

2 mV

97.2mA

2 mV

56.4mA

2 mV

Recording Site: Abductor pollicis brevis

Lat1ms

Durms

AmpmV

AreamVms

TempoCStimulus Site

Distmm

Diffms

CVm/sSegment

Recording Site: Abductor pollicis brevis

A1: ElbowA2: WristA3: Elbow (U)A4: Wrist (U)A4: Wrist (U)

Elbow-WristWrist-Abductor pollicis brevisWrist (U)-Abductor pollicis brevisElbow (U)-Wrist (U)

22.4 13.6 2.3 17.4 37.7 7.6 8.9 6.7 33.3 35.3NR NR NR NR 38.7 0.4 38.8

14.8 16 240 7.6 70 0.4

STOPSwitch:

1Stimulator: 0.5 HzRate: Level: 0.1 msDur: Single 0.0 mA

Recording Site: Abductor pollicis brevis

Lat1ms

Durms

AmpmV

AreamVms

TempoCStimulus Site

A4: Wrist (U)A3: Elbow (U)A2: WristA1: Elbow

A1A1

A2A2

A3A3

A4A4A4A4

STOPSwitch:

1Stimulator: 0.5 HzRate: Level: 0.1 msDur: Single 0.0 mA5 ms

Amp 1: 2-10kHz

4

2 mV

2 mV

2 mV

2 mV

New Nerve Other Side MNCMNC F-Waves SNC Rep Stim MUNE CMAPscan

A4A4A4A4

A4: Wrist (U)A4: Wrist (U)

A3A3

A3: Elbow (U)

A2A2

A2: Wrist

A1A1A1: Elbow

Sig. Enhancer: Off

Amp 1: 2-10kHz

Step: 4

APB, Stim: Wrist, Elbow

Left Median MNC

Record

# 5

10:41:45

Chronic Inflammatory Demyelinating Polyradiculopathy (CIDP)

Classic Features

• Progressive or relapsing motor and sensory symptoms (>2 months)

• Symmetric

• Distal and proximal weakness

• Motor > sensory

• EMG: (true) demyelinating features

• CSF: elevated protein

• Burning feet only

• Normal reflexes

• Normal strength

• Normal CSF protein

• No demyelination

CIDP - Atypical Forms DADS (Distal Acquired Demyelinating Symmetric)

Distal weakness

Distal sensory loss

MADSAM (Multifocal acquired demyelinating sensory and motor; Lewis-Sumner )

Motor or motor and sensory

Asymmetric

Multifocal

CISP (chronic immune sensory polyradiculopathy)

Sensory only

Focal CIDP

Treatment of CIDP

• IVIg* (Lancet Neurol 2008 Feb;7:136-144)

• 0.4 g/kg x 5 days, then weekly x 1 month, then every other week

• Corticosteroids* • 60 mg daily, slow taper (over months)

• Plasmapheresis

• Other immunosuppressants • Azathioprine • Cyclophosphamide • Cyclosporine • Rituximab • Methotrexate† • Interferon β †

*Positive response in up to 87%. Viala et al, 2010

† No statistically significant benefit

Peripheral neuropathy news 1 TWEET

@RubinPNCMETalk 0 FOLLOWING

brief key updates in PN You FOLLOWERS

Boca Raton, FL

Tweets

Folate-deficiency Neuropathy @FolatePN

Distal, symmetric, sensory>motor, axonal neuropathy. Slow

progression (mos – yrs). +/- anemia, macrocytosis; folate <

3.0 ng/mL. 5/18 improved with replacement.

Celiac Disease Neuropathy @GlutenPN

68 pts (44 CD; 24 + gliadin abs); 11 with PN (2º to other

deficiencies – Vit E, Cu, Folate – or other autoimmune). Other

causes in majority. 6 with PN without cause. (McKeon,

Neurology 2014)

Statin Neuropathy @StatinPN?

2002 Neurology. Case control study: 1 case per 2200 (880 –

7300) person-years of statin use.

Systematic review (2006) Meta-analysis 4 cohort studies:

OR 1.8 (1.1 – 3.4); Incidence 12/100,000 person-years

Tweets

Recent

@phillipsawesomecourse

director

@MayoClinic

Treatment

1. Treat the medical disorder (DM, nutritional

deficiency, etc.)

2. Remove offending agent (EtOH, medications, etc.)

3. If immune-mediated (CIDP, MMN, vasculitis): immune

modulating Rx (IVIg, prednisone, immunosuppressants)

4. Symptomatic treatment

Neuropathic pain

Numbness

Weakness (AFO, PT/OT)

Symptomatic Treatment Neuropathic Pain

Anticonvulsants Antidepressants Topical Agents Other

Tricyclics SSRI

Pregabalin*

(Level A)

Gabapentin*

(Level B)

Valproic acid

(Level B)

Oxcarbazepine

Lamotrigine

Lacosamide

Phenytoin

Carbamazepine

Topiramate

Amitriptyline

(Level B)

Nortriptyline

Duloxetine*

(Level B)

Venlaflaxine

(Level B)

Fluoxetine

Desipramine

Imipramine

Capsaicin

(Level B)

Lidocaine

1% amitriptyline / 0.5% ketamine gel

Tramadol

(Level B)

Dextromethorphan (Level B)

Morphine

(Level B)

Oxycodone

(Level B)

Mexiletine

NSAIDS

Alpha-lipoic acid

*FDA approved

Treat with maximal (tolerated) dose

Adequate length of treatment (4-6 weeks)

Bril V. Muscle Nerve 2011

Symptomatic Medications Medication Maximum Dose

Gabapentin 900-3600 mg/day

Pregabalin 300 – 600 mg/day

Amitriptyline, nortriptyline 25-100 mg/day

Venlafaxine 75-225 mg/day

Duloxetine 60-120 mg daily

Phenytoin 100 mg daily

Carbamazepine 400 mg TID

Dextromethorphan 400 mg/day

Tramadol 200 mg/day

Lidocaine (5%) patch 3 patches to skin, 12 hrs on/12 hrs off

1% amitriptyline + 0.5% ketamine Apply up to 5 times daily

Alpha lipoic acid 600 mg/day

Take Home Points

• Define anatomic distribution and fiber type involvement

• EMG to determine axonal vs demyelinating

• Red flags (“HAMP”er) • Hands, Asymmetric, Motor, Proximal

• Adequate dose and 4-6 week trial of neuropathic pain medications

References

• Bright R, et al. Therapeutic options for chronic inflammatory demyelinating polyradiculoneuropathy: a systematic review. BMC Neurology

• Bril, et al. Evidence-Based guideline: treatment of painful diabetic neuropathy. Muscle Nerve June 2011.

• Stork AC, et al.. Treatment for IgG and IgA paraproteinaemic neuropathy. Cochrane Database Syst Rev. 2015 Mar 24

• England JD, et al. Practice parameter: Evaluation of distal symmetric polyneuropathy: role of laboratory and genetic testing (an evidence based review). Neurology 2009; 72:185-192

• England JD, et al. Practice parameter: Evaluation of distal symmetric polyneuropathy: role of autonomic testing, nerve biopsy, and skin biopsy (an evidence based review). Neurology 2009; 72:177-184

• Karam C, et al. Polyneuropathy improvement following autologous stem cell transplantation for POEMS syndrome. Neurology 2015; 84: 1981-1987.

• Koike H. et al. Clinicopathologic featuers of folate-deficiency neuropathy. Neurology 2015; 84:1026-1033.

• Law M, Rudnicka AR. Statin safety: a systematic review. Am J Cardiol 2006; 97[suppl]: 52C-60C.

• Pascuzzi RM. Peripheral Neuropathy. Med Clin N Am 2009; 93: 317-342

• Stieglbauer K, et al. Beneficial effect of rituximab monotherapy in multifocal motor neuropathy. Neuromuscular Disorders 2009;19:473-475.

• Vincent AM, Hinder, LM, Pop-Busui R, Feldman EL. Hyperlipidemia: a new therapeutic target for diabetic neuropathy. J Periph Nerv Sys 2009; 14:257-267.

• Viala K. et al. A current view of the diagnostic, clinical variants, response to treatment and prognosis of chronic inflammatory demyelinating polyradiculoneuropathy. J Periph Nerv Sys 2010; 15:50-56.

Differential Diagnosis Distal Sensorimotor Neuropathy

More common

• Diabetes

• Paraproteinemia

• Hereditary (CMT type 2)

• Systemic medical illnesses

•Hypothyroidism

•Renal failure

•Hepatic failure

• B12 deficiency

Less common

• Toxins - thallium, mercury, gold, arsenic, hexacarbons

• Medications •colchicine, phenytoin, ethambutol, metronidazole, nitrofurantoin, chloroquine, disulfiram, lithium, amiodorone

• Infectious •HIV, syphilis, Lyme

• Alcohol

• Systemic vasculitis - RA, PAN, SLE, scleroderma

• Sarcoidosis

• Amyloidosis

• Critical illness neuropathy

Sensory Neuropathy Small fiber (autonomic)

• Idiopathic

• Amyloidosis

• Diabetes

• EtOH (thiamine def)

• Vasculitis

• Fabry’s disease

• Tangier’s disease

• Hereditary sensory neuropathy

Severe Sensory Neuropathy / Ganglionopathy

• Severe sensory loss

• Poor proprioception

• Sensory ataxia

• Pseudoathetosis

• Sjogren’s

• Lyme

• Syphilis

• Sarcoid

• HIV, HTLVI

• Paraneoplastic (Small cell lung)

• B6 toxicity

• B12 deficiency

• Vitamin E deficiency

• Cisplatinum, thalidomide

• Spinocerebellar ataxia

• Friedreich’s ataxia

Demyelinating Neuropathies

Uniform

• Charcot Marie Tooth type 1

• Adrenomyeloneuropathy

• Metachromatic leukodystrophy

• Krabbe’s disease

• Cerebrotendinous xanthomatosis

Segmental

• CIDP (AIDP)

• MGUS (esp IgM)

• Anti-MAG neuropathy

• Osteosclerotic myeloma

• Toxic (amiodarone, perhexiline, arsenic, hexane)

• Hereditary neuropathy with pressure palsy (HNPP)

Mononeuritis Multiplex Etiologies

• Vasculitis

• Hepatitis C (Cryoglobulinemia)

• Diabetes

• Sarcoidosis

• Amyloidosis

• Hereditary neuropathy with liability to pressure palsies (chrom 17 del)

• Leprosy (sensory only)

• Multifocal motor neuropathy with conduction block (motor only)

Motor Predominant “Neuropathies”

Motor Neuron Diseases

• ALS (hyperreflexia) (*asymmetric)

• Spinal muscular atrophy

• Kennedy’s disease

Distal Myopathies

• Inclusion body myositis

• Distal muscular dystrophies

NMJ disorders

• Lambert Eaton myasthenic syndrome

• Neuropathy / Polyradiculopathy

• CIDP / Guillain-Barre syndrome

• Multifocal motor neuropathy with conduction block (*asymmetric)

• GM1-antibody associated motor neuropathy

• Porphyria

• Lead intoxication

• Diphtheria

• Dapsone, Vincristine

• Hereditary (CMT)

Subacute Polyradiculopathy

• Inflammatory (GBS, CIDP)

• Vasculitis

• Diabetes

• Infectious (HIV, CMV, Lyme)

• Sarcoid

• Paraproteinemia

• Infiltrative (amyloid, neoplastic)

• Vascular malformation (dural AVF)

Motor Predominant “Neuropathies”

Motor Neuron Diseases

• ALS (hyperreflexia) (*asymmetric)

• Spinal muscular atrophy

• Kennedy’s disease

Distal Myopathies

• Inclusion body myositis

• Distal muscular dystrophies

NMJ disorders

• Lambert Eaton myasthenic syndrome

Neuropathy / Polyradiculopathy

• CIDP / Guillain-Barre syndrome

• Multifocal motor neuropathy with conduction block (*asymmetric)

• GM1-antibody associated motor neuropathy

• Porphyria

• Lead intoxication

• Diphtheria

• Dapsone, Vincristine

• Hereditary (CMT)

“Mononeuritis Multiplex” Etiologies

• Vasculitis, Vasculitis, Vasculitis

• Hepatitis C (Cryoglobulinemia)

• Diabetes

• Sarcoidosis

• Amyloidosis

• Hereditary neuropathy with liability to pressure palsies (chrom 17 deletion)

• Leprosy (sensory only)

• Multifocal motor neuropathy with conduction block (motor only)

Medications that Cause Neuropathy

• Sensorimotor

• Amiodarone

• Colchicine (+myopathy)

• Disulfiram

• Isoniazid

• Nitrofurantoin

• Phenytoin

• Tacrolimus

• Taxanes (paclitaxel, docetaxel)

• Thalidomide

• Vinca alkaloids

• Sensory

• Cisplatin

• Ethambutol

• Metronidazole

• Nitrous oxide

• Nucleoside analogues (ddC, ddI)

• Pyridoxine

• Motor

• Chloroquine (+myopathy)

• Dapsone

• Vincristine

• 50 yo man

• 3 months of painless, progressive right wrist drop

• 6 months later - left wrist drop

• No sensory loss

Hands only, Subacute, Motor only

Multifocal Motor Neuropathy with Conduction Block (MMN)

Clinical:

Single or multiple nerves

Not at common sites of

compression

Radial nerve predilection

GM1 antibodies + (~ 50%)

Treatment:

IVIg

Cyclophosphamide

Rituximab (3 pts)*

* Stieglbauer et al. Neuromuscular Disorders 2009