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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