1. A Practical Approach to Neuropathy
Robert W. Neel, MD
University of Cincinnati

2. Instructional Objectives
Upon completion of this course the participants should be able to:
1.  Describe basic patterns of neuropathy
2.  Evaluate a patient with neuropathy
3.  Construct a basic diagnostic approach to neuropathy
4.  Formulate a basic therapeutic plan for the treatment of neuropathy

3. What defines neuropathy?
Is it one entity?
How do we define it?
By symptoms? (neuropathy vs neuropathic)
By signs?
By electrodiagnostic testing?
By etiology?
Does the definition of neuropathy impact treatment?
We take for granted that we all know what we are talking about
Really should be a combination of symptoms and signs

4. Symptoms
Positive
Negative
Motor
Sensory
Autonomics

5. Symptoms Motor Sensory Positive Negative Cramps, spasms Weakness
burning, prickling paresthesias, dysesthesias, and allodynia
Numbness
Imbalance
Autonomics
Orthostatic
B/B, Sexual, Cardiac, GI

6. Peripheral Neuropathy
Mononeuropathy
Individual nerves (e.g. Radial, Ulnar)
Carpal tunnel (median neuropathy at the wrist)
Polyneuropathy
Distal symmetric polyneuropathy
Polyradiculoneuropathy
Prevalence: 2,400 per 100,000
Age > 55, prevalence is 8,000 per 100K
Definition of Distal Symmetric Polyneuropathy
We take for granted that we all know what we are talking about

7. Chronic Inflammatory Polyradiculoneuropathy (CIDP)
Autoimmune process similar to GBS
Progress beyond 8 weeks
Weakness (proximal=distal), sensory loss without significant pain, areflexia
Treatments include IVIG, plasmapheresis, steroids, and other immunosuppressive medications

8. Peripheral PolyNeuropathy
Primarily motor
Primarily sensory
Mixed
Large fiber vs. Small fiber
Autonomic involvement
Distal> proximal, distal=proximal, distal< proximal
Axonal vs demyelinating
Prevalence: 2,400 per 100,000
Age > 55, prevalence is 8,000 per 100K
Definition of Distal Symmetric Polyneuropathy
We take for granted that we all know what we are talking about

9. Distal Symmetric Polyneuropathy: Evidence Based Recommendations
1. Multiple neuropathic symptoms are more accurate than single symptoms
2. Signs are better predictors of polyneuropathy than symptoms
3. A single abnormality upon examination is less sensitive than multiple abnormalities
4. Relatively simple examinations are as accurate in diagnosing polyneuropathy as complex scoring systems
Symptoms: numbness, burning, prickling paresthesias, dysesthesias, and allodynia; motor weakness; sensory more likely to be asymmetric
Signs: acral, nondermatomal, non-single nerve distribution, centripetal.
Abnormal primary sensory modalities (pain, touch, hot, cold, vibration, and proprioception), motor system (weakness and atrophy), tendon reflexes (especially depressed or absent ankle jerks), or autonomic system
EDX: sural, peroneal; contralateral peroneal and sural and ipsilateral tibial if abnormal; median sensory, ulnar sensory, ulnar motor if abnormal.
5. There is too much inconsistency among the studies describing the accuracy of quantitative sensory testing (QST) to incorporate QST in the case definition. (Level U)
Diagnostic predictors studied varied
Single symptoms: foot numbness, foot pain, and complaints of sensory alteration.
complex composite symptom checklists
Single examination elements included absent ankle reflexes, decreased distal lower extremity strength, and decreased vibration or cold detection.
Composites ≥2 exam elements
England JD et al. Distal symmetric polyneuropathy: A definition for clinical research. Neurology 2005;64;

10. Evaluating a Patient for Neuropathy
Examination
Motor
Deep Tendon Reflexes
Reflex hammer (Tromner, Queens Square)
Sensory:
Safety pin, 128 C tuning fork
Electrodiagnostic (EDX)
EMG and Nerve conduction studies
Large fiber
Axonal
Demyelinating
What about small fiber?

11. Signs
Positive
Negative
Motor
Sensory
Autonomics

12. Signs Motor Sensory Positive Negative Distal to Proximal: Atrophy
Weakness
DTR loss (ankle)
Sensory
acral, nondermatomal, non-single nerve distribution, centripetal.
Loss of primary sensory modalities, acral and centripetal
(pin, temp, vibration, proprioception)
Autonomics

13. Neurophysiologic studies: EMG/NCS
Axonal vs Demyelinating?
Axonal (amplitudes)
NCV’s and distal latencies typically normal
CMAP/SNAP amplitudes low
Denervation changes on EMG (fibs)
Demyelinating (speeds)
NCV’s < 75 % lower limit of normal
Conduction block
Temporal dispersion of CMAP
Prolonged distal latencies, F-wave latencies

14. Diagnostic Approach to Neuropathy
Neuropathy is clinically diagnosed
Most diagnostic approaches focus on determining etiology
Etiology found 74-82%***
As low as 37%

15. Etiologies based on Neuropathy Type
Motor Neuropathies
Sensory Neuropathies
AIDP/CIDP
Acute motor axonal neuropathy
MMN
CMT
Lead intoxication
Porphyric neuropathy
Diabetes
Paraneoplastic
HIV/AIDS
B12 deficiency
Sjögren’s
Celiac sprue
Cisplatin, thalidomide, pyridoxine
Inherited sensory neuropathies
Paraproteinemic
Mixed
Most Peripheral Neuropathy is mixed variety w/ combo of motor/sensory/autonomic

16. Small-fiber neuropathies
Neuropathies w/ significant autonomic features
Idiopathic
DM/impaired glucose tolerance
Amyloid (early)
HIV
HSAN
Fabry’s
Tangier
Sjögren’s
Idiopathic
Diabetes
Amyloid
AIDP
Porphyria
HIV
HSAN
Toxic- ie, vincristine

17. Etiology? Nutritional/Metabolic Autoimmune Infectious Traumatic Toxic
Vitamin: Thiamine, B12, Vit D
Nutrients: Copper
Systemic disease: Thyroid, Diabetes, Renal Failure/Uremia, Porphyria
Autoimmune
Infectious
HIV, Syphilis, Lyme, Leprosy, HCV, HBV
Traumatic
Toxic
Lead, arsenic, organophosphates
Iatrogenic

18. Drugs Causing Peripheral Neuropathy
Allopurinol (prolonged)
Almitrine
Amiodarone
Chloroquine
Cisplatin
Colchicine
Dapsone
Didanosine
Disulfiram
Doxorubicin
Ethambutol
FK 506
Gold salts
Isoniazid
Levofloxacin
Metronidazole
Misonidazole
Nitrous oxide
Nitrofurantoin
Non-depolarizing Neuromuscular Blocking Agents
Paclitaxel (taxol)
Perhexiline
Phenytoin
Procainamide
Pyridoxine excess
Stavuldine
Suramin
Thalidomide
Vinca alkyloids (vinblastine, vincristine,
vindesine, vinorelbine)
Zalcitabine
Mendell, J 2001

19. Auto-immune Etiologies
Paraproteinemic neuropathy
Monoclonal Gammopathy (IgM)
Connective-tissue disease associated
Lupus, Rheumatoid, Sjogrens
Vasculitis (Polyarteritis)

20. Lab Testing Recommended for All Patients
Glucose Tolerance Testing
25-36% of neuropathy screens vs 15% controls
SPEP with Immunofixation
B12 and MMA
All Class III studies so only Level C recommendations
CSF analysis:
Low yield unless
demyelinating EDX
No mention of HgbA1C
17% of monoclonal gammopathies were detected with IFE rather than SPEP
Kahn SN and Bina M. Sensitivity of immunofixation electrophoresis for detecting IgM paraproteins ins erum. Clin Chem 1988; 34:
Lindenbaum, J et al. Diagnosis of Cobalamin deficiency: II: relative sensitivities of serum cobalamin, methylmalonic acid, and total homocysteine concentrations. Am J Hematology 1990;34: (Class II)
Savage DG and Lindenbaum, J et al. Sensitivity of serum methylmalonic acid and total homocysteine determinatiosn for diagnosing cobalamin deficiencies. A, J Med 1994;96: (Class III).

21. What is a reasonable approach?
Clinical History
Negative Symptoms
Positive Symptoms
Medication history!
Physical Exam Signs
Atrophy
DTRs
Motor Strength
Sensory: Vibration, Pin, Position Sense
Electrodiagnostic Studies (EMG/NCS)
Sweep the Side: 4 motor, 3-4 sensory
Lab Tests
B12, Homocysteine, MMA
Glucose, 2 hr GTT
SPEP, IFE
Others: ESR, TFTs
If demyelinating, may check SPEP/IFE, UPEP/Urine IFE, and CSF protein

22. Clinical Case A 45 year old man presents to a primary care doctor for his first adult physical in two decades for new symptoms over the last 4 months with numbness and tingling in his feet and toes. He has noted them just in the tips of the toes of both feet, but the symptoms have been slowly crawling up his toes to his feet. He takes no chronic medications and has no past medical history. His neurologic exam is normal except for increased pin sensation in the distal toes of both feet and mild decreased vibratory sense in the toes. The next best testing for diagnostic purposes is:
B12 and MMA
SPEP
Glucose testing
EMG
All of the above.

23. Treatment of Neuropathy
Therapeutic:
Demyelinating
Treat underlying etiology
Steroids, IVIG, Pheresis
Ie. Monoclonal gammopathy
Symptomatic:
Pharmacologic
Positive Symptoms
Negative Symptoms*
Non-Pharmacologic

24. Symptomatic Treatment of Neuropathy
Antiepileptic medications
Gabapentin (Neurontin) and Pregabilin (Lyrica)
Drowsiness largest side effect
Adjust for renal failure
Others are off label
Lamotrigine, Levetiracetam, Carbamazepine, TPM, Vimpat
Antidepressants
Cymbalta (Duloxetine) mg
Hyperhydrosis, GI, HTN
Amitryptiline/nortryptiline
Low doses (10-50 mg)
Anticholinergic
High doses
Prolonged QT

25. Other symptomatic treatments
Topical
Compounding topicals
Capsaicin
May burn
Lidocaine
Others
NSAIDs
Narcotics
Use cautiously
Avoid escalation
Mexilitene
Compounding topicals may include gabapentin, lidocaine, cyclobenzeprine, pregabilin, etc.

26. Special Neuropathies
A 56 year old male with type 2 diabetes presents with a one week course of severe pain in the left thigh and groin, followed by some weakness in the left leg and some new numbness in the left foot. He was diagnosed with type two diabetes 2 years ago but recently decided to get more serious about treatment and decided to go on a weight loss regimen. He has lost 25 lbs in the last 2 months and his blood sugar control is slowly getting better. His only medication is metformin.
His general examination reveals a heart rate of 84, blood pressure 140/85. His physical examination reveals an absent left quadriceps reflex, numbness on the back of the left calf and left lateral calf, and decreased left hip flexion and left knee extension. The right leg appears normal. Fasting blood glucose is 105 and hemoglobin A1c is 6.3.

27. Diabetic Amyotrophy
Diabetic amyotrophy (also called diabetic lumbosacral radioplexus neuropathy, or diabetic lumbosacral radiculoplexopathy) is an uncommon condition seen in type two diabetics, usually more common in men and patients with better glycemic control. It is often associated with a rapid weight change (weight loss or weight gain).
Patients generally present with excruciating pain in the lower back, hip, and proximal leg. Within days to weeks, weakness develops asymmetrically in the proximal thigh and leg. Although asymmetric motor symptoms and pain symptoms are most apparent, usually there is also sensory loss in the proximal and distal leg also.
The syndrome is monophasic and patients usually have good recovery, although usually not full recovery to pre-amyotrophy conditions.
Treatment is predominantly supportive (pain control and physical therapy) as immunotherapy has shown inconsistent results.