Neuroscience Clerkship

 

 

PERIPHERAL NEUROPATHY

 

Peripheral nerve disorders are among the most common neurologic problems seen, most in the out-patient setting. Many patients presenting themselves with complaints of numbness or weakness will eventually be shown to have a disorder of the peripheral nervous system. Although the differential diagnosis is large in these disorders, the combination of a directed neurologic history exam along with relatively simple ancillary testing will quickly narrow the differential diagnosis. As many of these disorders are treatable or curable, prompt recognition, especially early in the clinical course, is important.

Peripheral neuropathies (a.k.a., polyneuropathy, neuropathy) represent a more diffuse injury to the peripheral nervous system. Many disease processes may preferentially attack either the axon or the myelin sheath of the peripheral nerve. As a rule, axonal peripheral neuropathies affect the longest axons first. These are the so called "dying back" neuropathies. Transport of proteins and nutrients from the cell body is affected early, with subsequent breakdown and loss of the most distal peripheral nerve fibers. Patients develop numbness or weakness of the toes and feet initially which then slowly progresses up the leg. When the process reaches the upper calf, the finger tips become involved as well (i.e., the length from the spinal cord to upper calf is the same as that from spinal cord to finger tips). This results in the classic "stocking-glove" distribution of symptoms and signs.

Above: The typical distribution of most peripheral neuropathies are "length-dependent" (i.e., the longest nerves are affected the most). This leads to the stocking glove pattern (note - the legs are always affected more than the arms). In more severe cases, sensory loss may be found over the anterior chest and abdomen, reflecting degeneration of the distal thoracic intercostal nerves.
 

Symptoms and Signs

When nerve is diseased, it can react in a limited number of ways. Thus, many peripheral nerve disorders present with similar symptoms. Peripheral nerve may be viewed as supplying motor, sensory, as well as autonomic function. In addition, it is helpful to consider nerve on the basis of large and small fibers. All motor fibers are large fibers. All autonomic fibers are small fibers. However, sensory fibers are both of the large and small fiber type. Large sensory fibers mediate vibration, proprioception and touch, whereas small sensory fibers convey pain and temperature sensations. Pathology of these fiber types may create symptoms and signs by lack of function (negative symptoms and signs) or by extra or abnormal function (positive symptoms and signs). Everyone can relate to falling asleep on their arm which initially causes numbness or lack of feeling (negative symptom) followed by intense pins and needles paresthesias (positive symptom). Likewise, symptoms and signs in the different nerve fiber types can be divided into positive and negative (see table below).
 

Signs and Symptoms of Peripheral Nerve Disease
Nerve Type Negative Positive
 

Motor

 

Weakness

Atrophy

Clumsiness

Areflexia

Hypotonia

Deformities (pes cavus, kyphoscoliosis)

 

Fasciculations

Myokymia

Cramps

 

Sensory (Large Fiber)

 

 

Sensory loss to vibration and proprioception

Ataxia

Clumsiness

Areflexia

Hypotonia

 

 

"Tingling"

"Pins and needles"

 

 

 

Sensory (Small Fiber)

 

Sensory loss to pain and temperature

 

"Burning"

"Stabbing"

 

Autonomic

 

Postural hypotension

Anhidrosis

Impotence

Bowel or bladder disturbance

 

Hyperhidrosis

Gustatory sweating

 

Trophic

   

Foot ulceration

Charcot arthropathy

 

Thus, all of the above symptoms and signs are typically seen in the stocking-glove distribution. Most often, the ankle reflex is absent or diminished with the remaining reflexes normal, unless the neuropathy is severe. Likewise, muscle weakness and atrophy is most prominent distally, more in the feet than the hands.


Evaluation

There are well over 100 causes of peripheral neuropathy, including metabolic disorders, infections, vitamin deficiencies, toxic and drug-induced conditions, genetic abnormalities, inflammatory autoimmune conditions, dysproteinemias, and neoplasia.

To narrow the differential to a more reasonable number of conditions, one should first characterize the neuropathy for the following attributes:

Temporal course

acute, subacute or chronic

progressive, relapsing/remitting or step-wise progressive

Fiber types involved

motor

sensory large fiber

sensory small fiber

autonomic

Localization

symmetric/asymmetric

proximal/distal

Pathology

axonal

demyelinating

mixed

Family history

Occupational or exposure history

Possible associated medical conditions


Nearly all the information above can be obtained from the history and physical examination. Electromyography (EMG) and Nerve Conduction Studies (NCS) can help clarify the exact localization of the lesion and will often suggest the underlying type of pathology (axonal or demyelinating).

First in regards to the temporal course, most peripheral neuropathies are progressive and chronic. An relapsing/remitting course suggests an autoimmune etiology or an intermittent exposure. A step-wise progression course suggest a mononeuropathy multiplex pattern. Acute neuropathies are very uncommon and are associated with a limited diagnosis including:

Acute Peripheral Neuropathies

● GBS

● Porphyria

● Diphtheria

● Drugs (Dapsone, Nitrofurantoin, Vincristine)

● Toxins (Arsenic, Thallium, Triorthocresylphosphate)

● Tick Paralysis

Regarding fiber type involvement, most peripheral neuropathies are motor and sensory. For instance, pure motor or pure sensory neuropathies have a limited differential.

In analyzing polyneuropathies, one needs to concentrate on the overall pattern (i.e., the localization). Is there a distal/proximal gradient? Is there any asymmetry which might imply a mononeuritis multiplex pattern, or a superimposed radiculopathy or mononeuropathy? Most peripheral neuropathy have the typical stocking-glove pattern.

Next is the underlying pathology. Almost all peripheral neuropathies are associated with axonal loss. Very few have primary demyelinative pathology. Demyelination may be demonstrated either by pathological examination of nerve or more easily by EMG testing. On nerve conduction studies, demyelination is associated with markedly markedly slowed conduction velocities and conduction block between distal and proximal stimulation sites. Such a finding readily narrows the differential diagnosis.

Peripheral Neuropathies with Primary Demyelination

● Acute Inflammatory Demyelinating Polyradiculoneuropathy (Guillain Barré Syndrome)

● Charcot-Marie-Tooth Polyneuropathy

● Childhood Leukodystrophies

● Diphtheria

● Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP)

Idiopathic

Associated with HIV infection

Associated with MGUS (especially IgM)

Associated with anti-MAG antibodies

Associated with osteosclerotic myeloma

Associated with GM1 antibodies

Next family history is important. Over 25% of all peripheral neuropathies are inherited.

Clinical Clues to an Inherited Peripheral Neuropathies

● Several slow progression over years or decades

● Often the absence of "positive symptoms"

● Associated bony deformities, especially pes cavus

● History in the family of similar symptoms, or a family history of "polio", "rheumatism" (it is not unusual that inherited peripheral neuropathies were missed by past physicians)

 

 

 

Left: Pes cavus which is combination of a foreshortened foot; high arch and cocked-up toes. This skeletal deformity occurs when there is intrinsic foot muscle weakness present as a child during development. Pes cavus is highly associated with inherited peripheral neuropathies.

 

Of course, it is important to review any past medical history in a patient with a peripheral neuropathy. Several medical conditions are highly associated with peripheral neuropathy.

Common Medical Conditions Associated with Peripheral Neuropathies

● Diabetes (the most common cause of peripheral neuropathy in the US)

● Thyroid disease

● Cancer

● Renal Disease

● Liver Disease

● Lupus and other connective tissue disease

● HIV

Lastly, all patients should be questioned about toxic and occupational exposures. The most common toxin is alcohol. In addition, there are a large number of prescription medicines that may induce a peripheral neuropathy. Regarding occupational exposure, this is clearly much less frequent in the modern day due to rigorous OSHA standards. However, an occasional patient will be exposed to heavy metals or hexacarbons that result in their neuropathy.

Once all of the above information is known, the list of possible etiologies is often markedly reduced, so that more intelligent use of further laboratory testing can be employed to reach a diagnosis.


For instance, the differential diagnosis is markedly different among the following cases:

A 25 year-old woman with the onset acute of a motor > sensory peripheral neuropathy with demyelinating on the EMG

                                vs.

A 60 year-old man with slowly progressive motor neuropathy over 30 years and an exam showing pes cavus

                                vs.

A 45 year-old woman with Sjogren's syndrome and a pure sensory neuropathy

                                vs.

A 50 year-old alcoholic with a small fiber sensory neuropathy

In the cases above, the first is most likely GBS; the second an inherited neuropathy; the third an autoimmune sensory neuropathy associated with the patient's connective tissue disease, and the last patient is likely a small fiber neuropathy associated with alcohol abuse and poor nutrition. The subsequent evaluation and treatment would be markedly different among these four individuals.