1. An Approach to Peripheral Neuropathy
Peter-Brian Andersson
MBChB,BSc(Med)(Hons),DPhil
3 goals
1. See how a working knowledge of the anatomy and physiology is applied to evaluate a patient with peripheral neuropathy.
2. Learn the patterns of disease by which peripheral neuropathy presents clinically.
3. From these and putting it all together, learn a simple approach at the bedside to diagnose peripheral neuropathy.
Among the most common – 2.4% population. Rises with age – 8%
You will come into contact!

2. The 3 questions of clinical neurology…
#1. Where is the lesion?
#2. What is the etiology?
#3. What is the treatment?
The 3 questions of clinical neurology…
Peripheral neuropathy no different from any of the other syndromes of neurology…
Localization and determination of etiology (questions 1 and 3) key, as treatment of peripheral neuropathy is the treatment of the underlying condition. This will be the focus of the lecture therefore.
Roots, plexus, nerves. Peripheral nerves can be diseased singly or multiply. The distinction important as the pathophysiology and etiologies different – focal, multifocal or diffuse. This is a determination that can be made at the bedside… Know your anatomy and mononeuropathies and plexopathies straightforward.
Which leaves the polyneuropathies…
ama/pub/category/7172.html

3. The patterns of peripheral neuropathy…
Mononeuropathy?
Polyneuropathy?
multiple nerves
contiguous
typically length dependent (“stocking-glove”)
Polyneuropathy is common! 2.4%
(8% over 55 yr)
Focal, multifocal or diffuse
Nervous system CNS, PNS,
PNS roots plexus and nerve
What do we mean – disease of the peripheral nerve
Two broad pathologic divisions 1) – disease of the cell body or neuronopathy.
If motor neuronopathy, this is motor neuron disease – i.e.
Acquired – ALS,
Inherited – Familial ALS, SMA, X-linked bulbospinal muscular atrophy
If sensory neuronopathy, this is sensory ganglionopathy,
2) - disease of the peripheral process or peripheral neuropathy.
Mononeuropathy
MM – C Multiple entrapments, I Infection (leprosy, Lyme), I NI:Vasculitis,, Inflammatory demyelinating polyneuropathy, Parsonage Turner, Infiltrations – leukemia, lymphoma, sarcoid, M Diabetes
Polyneuropathy – typically mean length dependent – glove and stocking when both motor and sensory involved. Much more difficult to diagnose because number of etiologies higher which produce this pattern.
ama/pub/category/7172.html

4. Overview of the Lecture –Mastering polyneuropathy
#1. Where is the injury?
The syndrome depends on:
what modalities are injured,
what fibers are injured,
whether axon or myelin (or both) injured.
#2. What is the etiology?
Tricky – hence an approach necessary at the bedside.
#3. What is the treatment?
Depends on reversing the underlying cause.
Three common examples

5. Fiber types, Myelin, Shwann cells. Layers. Suggests the pathology…
Review the anatomy.
Fiber types, Myelin, Shwann cells. Layers.
Suggests the pathology…
What modality
What fibers - Large fibers (thickly myelinated m/s motor and proprioception)
and small fibers (thinly myelinated 5-15m/s and unmyelinated 0.2-2m/s) conducting pain, touch and autonomic fibers
3. Axonal or demyelinating

6. The clinical effect of a polyneuropathy depends on ) what modalities involved ) what fibers are effected ) whether the injury is axonal or demyelinating.
Effects of the polyneuropathy producing disease depend on
1. what modality,- will return to this later when consider the signs and symptoms
2. what fibers are affected (large or small), what does this mean, and
3. whether the injury is axonal or demyelinating.
Need to consider the anatomy and electrophysiology which will explain the clinical findings and strategies to approach diagnosis.
Adapted from

7. The clinical response to motor nerve injury
Loss of function
“- symptoms”
Disturbed function
“+ symptoms”
Motor nerves
Wasting
Hypotonia
Weakness
Hyporeflexia
Orthopedic deformity
Fasiculations
Cramps

8. Axonal or demyelinating
What modalities
What fibers
Axonal or demyelinating

9. The clinical response to sensory nerve injury
Loss of function
“- symptoms”
Disordered function
“+ symptoms”
Sensory
“Large Fiber”
↓ Vibration
↓ Proprioception
Hyporeflexia
Sensory ataxia
Paresthesias
“Small Fiber”
↓ Pain
↓ Temperature
Dysesthesias
Allodynia
Paresthesia – tingling
Dysesthesia - condition in which an unpleasant sensation is produced by ordinary stimuli
Allodynia - Pain that results from a non-injurious stimulus to the skin.

10. The clinical response to autonomic nerve injury
Loss of function
“- symptoms”
Disturbed function
“+ symptoms”
Autonomic nerves
↓ Sweating
Hypotension
Urinary retention
Impotence
Vascular color changes
↑ Sweating Hypertension

12. The two types of peripheral neuropathies:
axonopathies and myelinopathies
Can be divided histopathologically, electrodiagnostically and clinically
How nerve conduction is prevented
Features of Wallerian degeneration

13. EMG reduced interference pattern as a result of denervation
Two motor neurons red and green. Two motor units. Motor unit a few fibers to a few thousand.
Axonal degeneration of green neuron. Denervation atrophy – ie. angular atrophic myocytes. CMAP is reduced.
Reinnervation of green motor unit territory by red – larger motor unit action potential duration and amplitude
EMG reduced interference pattern as a result of denervation
EMG high amplitude and duration as result of reinnervation, reduced interference, high frequency
Segmental demyelination. Conduction block produces weakness. Motor units remain histologically the same. EMG reduced recruitment but motor units normal size and amplitude.
From Kumar: Robbins and Cotran: Pathologic Basis of Disease, 7th ed.

14. Using nerve conduction studies in polyneuropathy
= Low!
= Slow!
Demyelination reduces conduction velocity. There is temporal dispersion as some axons conduct slower than before – causing widening of the CMAP duration, as well as complete conduction block where charge is dissipated, in more severe cases.
Axonal degeneration reduces CMAP, SNAP amplitudes
= Slow!
Copyright ©2002 BMJ Publishing Group Ltd.
Hughes, R. A C BMJ 2002;324:

15. Normal Nerve Axonal degeneration

16. Wallerian Degeneration
3 classic patterns of nerve degeneration
Axonal 1. axonal degeneration, 2. wallerian degeneration, 3. segmental demyelination
Difference in pace
Wallerian degen – the nerve distal to the injury typically transection. Described by Waller in 19th century. Digestion chambers with degenerated myelin in the center called myelin ovoids
Macrophage invasion
Similar age
Proximal stump sends out up to 25 regenerative sprouts or regenerting cluster

17. Axonopathies
By far the majority of the toxic, metabolic and endocrine causes
NCVs: CMAPs ↓ 80% lower limit of normal w/o or min velocity or distal motor latency change.
Legs>> arms.
EMG: Signs of denervation (acute, chronic) and reinnervation

18. Segmental Demyelination
Normal
Demyelination
Normal
Demyelination

19. Myelinopathies global arreflexia
Unusual by comparison with axonopathies
Clues: hypertrophic nerves on exam
global arreflexia
weakness without wasting
motor >> sensory deficits
NCS can discriminate inherited from acquired
NCS: Distal motor latency prolonged (>125% ULN)
Conduction velocities slowed (<80% LLN)
May have conduction block
EMG: Reduced recruitment w/o much denervation

20. Question #2. What is the etiology?
Only a limited number of ways a peripheral nerve can react to injury, thus a multitude of different etiologies can cause similar effects…
Exhaustive
Expensive

21. Problem: The multitude causes of peripheral neuropathy!!!
Inherited: e.g. Charcot-Marie-Tooth disease (HMSN)
Infectious: e.g. Leprosy
Inflammatory: e.g. Guillain Barre syndrome (AIDP)
Neoplastic: e.g. Monoclonal gammopathy
Metabolic: e.g. Diabetes
Drug: e.g. Vincristine
Toxic: e.g. Ethanol

22. How then are we to sort through the causes to make an etiologic diagnosis?... Use the 6 D’s….
What is the distribution of the deficits?
What is the duration?
What are the deficits (which fibers are involved)?
What is the disease pathology (axonal or demyelinating or mixed)
Is there an inherited (developmental) neuropathy?
Is there drug/toxin exposure?

23. 1. What is the distribution of the deficits?
Asymmetry
1. Mononeuropathy
2. Mononeuritis multiplex – e.g. vasculitis
Symmetric (glove/stocking) = polyneuropathy

24. 2. What is the duration? Ask: Acute or Chronic?
Most polyneuropathies are chronic – ++months-yrs
Acute polyneuropathies
e.g. Guillain Barre syndrome
Vasculitis
Relapses and remissions
e.g. Intermittent toxin exposure
Acute 4wks
Subacute 8 weeks
Chronic more than 8 weeks

25. 3. What are the deficits (which fibers affected)?
If predominant motor fibers think of:
Guillain Barre syndrome
Lead toxicity
Charcot-Marie-Tooth disease
If pure sensory/ severe proprioceptive deficit, think of sensory neuronopathy:
Carcinoma (paraneoplastic)
Vitamin B6 toxicity
If autonomic nerves involved (small fiber) think of:
Diabetes
Amyloid
Drugs like vincristine, ddI, ddC

26. 4. What is the disease pathology?
The vast majority are axonal.
Demyelination a key finding because its causes are relatively few.
If demyelination uniform the cause is hereditary.
e.g. Charcot-Marie Tooth type I (HMSN)
If otherwise unremarkable chronic sensorimotor axonal polyneuropathy… exclude
alchohol, diabetes, hypothyroidism, uremia, B12 deficiency & monoclonal gammopathy

27. 5. Is there an inherited (developmental) neuropathy?
Among the most common!
Clues – orthopedic deformities (feet, spine)
– long duration
– indolent progression
– few “positive” symptoms
– examine/question the family members!

28. 6. Drug or toxin exposure? Demyelinating Axonal e.g. Glue sniffing
Arsenic
e.g.
Cancer drugs like vincristine and paclitaxel
Antibiotics like chloroquine, ethambutol, isoniazid and metronidazole
Cardiac medications like amiodarone

29. Polyneuropathy Example #1
58 year old movie industry executive
2 yrs toe numbness, paresthesias and pain
Stocking numbness of toes with absent ankle jerks
No medical history or family history or medications
Multiple consultations & lab testing without etiologic diagnosis

30. (A common axonal polyneuropathy) Ethanol Neuropathy
Among the most common neuropathies worldwide
Chronic
Numbness, paresthesias, pain in stocking distribution
Sensory >>> Motor
Loss of ankle reflexes
History!
Ethanol toxicity and nutritional deficiency
Vitamin B1 (thiamine)

31. Polyneuropathy Example #2
23 yr old professional baseball player with no past medical or family history & no medications.
Severe pain in back and flank followed by weakness over hours to inability to walk.
Severe weakness legs, milder weakness arms
Arreflexia
Numbness of feet
Diarrheal illness 2 weeks ago

32. (A common demyelinating polyneuropathy) Guillain-Barre Syndrome
Rapid, severe, typically ascending paralysis
Post infectious in 60%
Paresthesias, pain, numbness
Autonomic nerves
Reflexes lost
Cytoalbuminologic dissociation in the CSF

33. Polyneuropathy Example #3
55 year old obese woman
Family history positive for diabetes
4-5 years of nocturia and 1-2 years of polyuria
Dry skin over the feet
Stocking numbness in all modalities to the ankles
Absent ankle reflexes

34. (A common mixed axonal & demyelinating polyneuropathy) Diabetic Polyneuropathy
Multiple forms of neuropathy in diabetes
Sensory >>> motor polyneuropathy
Autonomic involvement common
CSF protein frequently elevated
Glucose control!
Foot care

35. Peripheral Neuropathy in summary…
1. Patterns: mononeuropathy, mononeuropathy multiplex or polyneuropathy – focal, multifocal or diffuse
2. “Signature” manifestations of a polyneuropathy depend on what modalities affected (motor, sensory, autonomic) and whether it is axonal or demyelinating.
3. Examination, NCS/EMG & biopsy can discriminate axonopathy from myelinopathy
4. The multiple potential etiologies of polyneuropathy are manageable recognizing patterns of disease by the 6 Ds

37. Plan of the Nervous System
UMN c. v v th v v m. v
drg
T1-L2 ^
cord
<
DorC ^
> Sy ^
Spth
r.g.n.
III,VII,IX,X
S2-4
LMN ^
PSy ^
Motor
Sensory
Autonomic ^
<

38. The Motor Unit
Peripheral neuropathy no different from any of the other syndromes of neurology…
Localization and determination of etiology (questions 1 and 3) key, as treatment of peripheral neuropathy is the treatment of the underlying condition. This will be the focus of the lecture therefore.
Roots, plexus, nerves. Peripheral nerves can be diseased singly or multiply. The distinction important as the pathophysiology and etiologies different – focal, multifocal or diffuse. This is a determination that can be made at the bedside…
From Dumitru, D. Electrodiagnostic Medicine, Hanley & Belfus. Philadelphia. 1995