AN APPROACH TO PERIPHERAL NEUROPATHY
Peter-Brian Andersson MBChB, DPhil.
Goals:
1. Learn how basic science anatomy and physiology applies to understanding neuropathy.
2. Learn the patterns of disease by which peripheral neuropathy presents clinically.
3. Learn a simple approach to diagnose peripheral neuropathy at the bedside.
Reading:
Cecil Essentials of Medicine, 7th Ed. 2007 p1146-51
Further reading for reference:
Hughes, RAC 2008 Prac Neurol 8: 396-405
Hughes, RAC 2002 BMJ 324:466-9
Poncelet, AN 1998 Am Fam Phys 57:755-764
Donofrio, PD & Albers, JW.1990 Muscle & Nerve 13:889-903
Lecture Notes: The Key Points.
A useful approach to neurology clinical problem solving is to ask and answer the
following questions in sequence:
1) Where is the lesion?
2) What is the cause of the lesion?
3) What is the treatment of the lesion?
The approach is used in the seminar. Peripheral neuropathy is a common condition and
encountered in a whole host of medical subspecialities, not just the neurology service,
and the reason is because it has so many causes.
Bedside Question 1. Where is the lesion?
The answer hinges on knowing the anatomy of peripheral nervous system and how injury
causes symptoms and signs. The peripheral nervous system consists of root, plexus and
peripheral nerve. Each of these potential localizations causes a signature clinical pattern
which can be deduced at the bedside. Root injury (radiculopathy) produces motor and
sensory deficits in a segmental distribution, plexus injury (plexopathy) in the distribution
of its organizational anatomy and peripheral nerve injury in a particular nerve
distribution. Setting radiculopathy and plexopathy aside, disease can either affect the
nerve cell body, also called neuronopathy (which in the case of motor neurons is called
motor neuron disease and for sensory neurons is called sensory ganglionopathy), or the
peripheral process (which is by convention referred to as peripheral neuropathy).
Peripheral nerve injury (peripheral neuropathy) results when nerves are diseased either:
1) focally (called mononeuropathy) like carpal tunnel syndrome, as may be seen in
pregnancy with fluid retention, or
2) focally but multiply (called mononeuritis multiplex) for example in vasculitis,
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or 3) diffusely (called polyneuropathy) for example chronic ethanol toxicity.
Recognizing these different patterns at the bedside is important because their causes and
treatments are different. What determines the clinical presentation of neuropathy?
The clinical effects of a peripheral neuropathy depend on:
#1) whether the injury affects the axon or the myelin,
#2) what modalities are affected (motor, sensory or autonomic) and
#3) what nerve fibers are affected (large fibers or small fibers).
#1) Axonal neuropathy or Demyelinating neuropathy?
Peripheral neuropathies can be divided histopathologically, electrodiagnostically and
clinically depending on whether the injury is axonal or demyelinating. Wallerian
degeneration is the name of a characteristic pathology after acute focal injury to
peripheral nerve (eg. infarction or transection). Axonal degeneration goes hand in hand
with reinnervation attempts by the regenerating nerve. Both have characteristic
histopathologic (denervation atrophy, axon dropout for the former and regenerating
sprouts for the latter), electrodiagnostic (reduced compound muscle action potential
amplitude with reduced recruitment of muscle fibers on EMG for the former and large
motor unit potentials on EMG for the latter) and clinical signs (weakness with atrophy)
that permit diagnosis of this pattern of neuropathy.
On the other hand the pattern of typical demyelinating neuropathies is characterized
histopathologically by loss of myelin and onion bulb formation, electrodiagnostically by
slowed conduction velocities (uniform in hereditary causes with rare exception and nonuniform in acquired), little or no signs of reinnervation on EMG, and clinically by
weakness without wasting, a tendency for predominant motor over sensory deficits and
generalized arreflexia. Peripheral nerves (e.g. the greater auricular) may even be palpably
hypertrophic on examination.
#2) What modalities are affected?
For convenience motor, sensory and autonomic nerve injury can be considered to
produce “positive” and “negative” effects as follows:
Motor nerves
Sensory
Large Fiber
Sensory
Small Fiber
Loss of function “Negative”
Wasting
Hyopotonia
Weakness
Hyporeflexia
Orthopedic deformity
↓ Vibration
↓ Proprioception
Hyporeflexia
Sensory ataxia
↓ Pain
↓ Temperature
Altered function “Positive”
Fasciculations
Cramps
Paresthesias
Dysesthesias
Allodynia
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Autonomic
nerves
↓ Sweating
Hypotension
Urinary retension
Impotence
Vascular color changes
↑ Sweating
Hypertension
#3 Which fibers (large or small) are affected?
All motor fibers are large and myelinated, autonomic fibers are all small mostly
unmyelinated and sensory fibers may be either large (proprioception and vibration and
touch) or small (pain and temperature0.
Bedside Question 2: What is the cause of the lesion?
There are a whole host of causes of peripheral neuropathy! A strategy to sort them out is
essential to the clinician. Understanding the syndrome of peripheral neuropathy is a
metaphor for much of the art of clinical medicine – learning how to organize volumes of
medical data and isolate and apply that which is pertinent. The need here is to have an
approach at the bedside to sort through the many potential etiologies by a familiarity of
pathophysiology, the patterns of disease presentation, and a knowledge of short lists of
differential diagnoses for those patterns rather than tedious (and costly) “shot gunning”.
Finding the etiology is also to answer the third question of clinical neurology, namely
“What is the treatment of the lesion?” because in this syndrome the treatment is of the
underlying cause and the symptoms (e.g. pain, orthstasis, ataxia and foot deformities).
Here is a clinical approach to make an etiologic diagnosis: Use the 7 D’s:
1. What is the duration?
2. What is the distribution of the deficits?
3. What are the deficits (which fibers are involved)?
4. What is the disease pathology (axonal or demyelinating)?
5. Is there an inherited (developmental) neuropathy?
6. Is there drug/toxin exposure?
Appended are some lists of differential diagnoses based on the above principles for
questions 1, 2 and 4.
THIS TABLE IS PROVIDED TO YOU FOR REFERENCE ONLY!
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1. DURATION OF NEUROPATHY?
• Most polyneuropathies are chronic i.e. months and years
• For acute polyneuropathies think
Guillain Barre syndrome
Vasculitis
Toxins and Drugs
Tick paralysis
Diphtheria
Porphyria
• If relapses and remissions think
Intermittent toxin exposure
Chronic Inflammatory Demyelinating Polyneuropathy
2. DISTRIBUTION OF NEUROPATHY DEFICITS?
• If predominant motor fibers think:
Motor neuron disease (motor neuronopathy) – exclusively motor
Multifocal motor neuropathy – exclusively motor
Acute Inflammatory Demyelinating Polyneuropathy (Guillain-Barre)
Chronic Inflammatory Demyelinating Polyneuropathy
Lead intoxication
Acute porphyria
Charcot-Marie-Tooth disease (HMSN)
• If pure sensory/ severe proprioceptive deficit, think sensory neuronopathy:
Carcinoma (paraneoplastic)
Sjogrens syndrome
Drugs like Cisplatinum, styrene, B6 toxicity
HIV
Friedrich’s ataxia
• If autonomic nerves involved (small fiber) think:
Diabetes
Amyloid
Drugs like Vincristine, ddI, ddC
HIV
Hereditary Sensory Autonomic Neuropathy (HSAN)
Guillain-Barre
Acute porphyria
4. DISEASE PATHOLOGY?
• If demyelination and uniform, cause is hereditary. Think of:
Charcot-Marie-Tooth disease (HMSN)
Hereditary Neuropathy with Liability to Pressure Palsy
Rarer myelin disorders like adreno- and metachromatic leukodystrophy
Friedrich’s ataxia
• If demyelination is non uniform the cause is acquired. Think of:
Acute Inflammatory Demyelinating Polyneuropathy
Chronic Inflammatory Demyelinating Polyneuropathy
Monoclonal gammopathy
Acute arsenic poisoning
Friedrich’s ataxia
Axonal polyneuropathies are by far more common than demyelinating forms. If otherwise
unremarkable however length dependent, chronic, sensory more than motor axonal
polyneuropathy without associated toxin, drug or disease consider cryptogenic sensory axonal
polyneuropathy. Exclude treatable diseases with the following five laboratory tests (no need for
antibody panels!): TSH (for hypothyroidism), HBA1c (for diabetes), B12 and methylmalonic acid
(for B12 deficiency), serum protein electrophoresis with immunofixation (for monoclonal
gammopathy) and creatinine (for uremia).
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