Peripheral Neuropathy

John C. Kincaid

Peripheral neuropathy is the general term for diseases that affect the peripheral nervous system. The primary sites of pathology are the cell bodies, the axons, and the myelin sheath. Terms used to describe peripheral lesions, in a proximal to distal sequence, are as follows:

Neuronopathy: abnormality of the nerve cell body, usually producing motor, sensory, or autonomic dysfunction independently.

Radiculopathy: abnormality at the level of the nerve root, usually at a single spinal level and most often due to compression by a herniated disc or osteophyte.

Polyradiculopathy: abnormality involving the nerve roots at many spinal levels and most often caused by inflammation, infection, or infiltration by neoplastic cells.

Plexopathy and plexitis: abnormality affecting the brachial or lumbosacral plexus. Plexopathy is the more general term while plexitis implies an inflammatory etiology.

Polyradiculoneuropathy: abnormality at both the nerve roots and the peripheral nerve trunk level.

Polyneuropathy: abnormality of multiple peripheral nerve trunks, usually presenting in a length dependent symmetrical pattern.

Axonal neuropathy: neuropathy in which the primary site of pathology is the axons. Conduction studies show loss of response amplitudes and mild velocity slowing.

Demyelinating neuropathy: neuropathy in which the primary site of pathology is the myelin sheaths. The conduction study parameters listed are the standard electrophysiological definitions of demyleinating neuropathy.

Mononeuropathy: abnormality of an individual peripheral nerve trunk most often due to entrapment or local trauma.

Mononeuritis multiplex: abnormality of multiple, individual nerves trunks occurring in a serial fashion most often due to vasculitis affecting the vasa nervorum.

I. SYMPTOM BASED MANAGEMENT

Whether or not the specific cause of a neuropathy is known and a specific treatment is available, the patient often reports a group of symptoms that are relatively similar. Following a standard approach to management of these symptoms is useful. Neuropathic symptoms may include the following:

Pain

Paresthesias

Sensory loss

Weakness

Cramping

Unstable balance

A. Pain

is often the most bothersome symptom and may have several different characters. The paradigm described below is based on symptomatic treatment of painful diabetic neuropathy but should be applicable to other neuropathies.

1. Fiery, burning pain

(or cold, frostbite-like pain) is more felt in the toes, bottoms of the feet, and fingertips. If the symptom is bothersome enough for the patient to request treatment, an antiepileptic medication such as gabapentin should be tried first. An initial dose of 300 mg once or twice daily is reasonable. If a benefit is going to occur, some
improvement often begins within a day or two of starting the medication. The dosage may need to be increased to three times daily if symptoms are re-exacerbated before the next dose. The dose can be increased at weekly intervals to optimize the response but doses above 2,400 mg per day often provide no further benefit. Full relief of symptoms is often not achievable. Pregabalin may also provide symptomatic relief. This drug is only approved for use in symptomatic diabetic neuropathy and post-herpetic neuralgia but may help symptoms in other neuropathies. Approval for payment by insurance often limits the ability to use this medication. Mild analgesics such as aspirin or acetaminophen can help relieve low-level pain. Nonsteroidal anti-inflammatory drugs usually do not help this type of pain but can be tried.

Burning pain can often be improved by tricyclic antidepressants. Medications such as amitriptyline, nortriptyline, desipramine, and doxepin are the preferred agents. Antidepressants of the selective serotonin reuptake inhibitor class do not seem to provide much pain-modulating benefit but can be tried. When starting one of the tricyclic medications, inform the patient that side effects such as morning sedation, dry mouth, and blurred vision may occur. These effects usually lessen within a few days. Start these medications at a low dosage, such as 25 mg an hour before bedtime. Benefit may begin within a few days but may take several weeks to become evident. Increase the dosage by 10 to 25 mg every 1 to 2 weeks if there has been no benefit at the initial dosage, or if the pain intensity worsens after initial improvement. A dose of 35 to 75 mg is usually sufficient, but higher amounts can be used within the bounds of the particular drug. If a medication is beneficial, it should be continued for at least 6 months. At that point, a taper of 10 to 25 mg should be tried to determine whether the drug is still providing benefit. If symptoms worsen, the drug should be returned to the previous level. Long-term use may be needed. Newer antidepressant agents like duloxetine, which is approved for diabetic neuropathy, may help with this type of pain and have fewer side effects than the tricyclic drugs.

Pain not responsive to the agents above may require stronger analgesics such as tramadol, codeine, hydrocodone, or oxycodone in combination with acetaminophen. Longer-acting opioids such as sustained-release oxycodone, morphine, or methadone may provide smoother pain control for patients with severe discomfort. Methadone is the least expensive of these. Doses as low as 5 mg twice a day may help but up to 20 mg four times daily may be required for severe pain. It is important for the patient and physician to understand that even major analgesics will not usually provide complete pain relief. Achieving mild to moderate relief is a reasonable goal. Neuropathic pain is often worse when the patient retires for sleep, and, if possible, the stronger analgesics should be reserved for that time.

Topical capsaicin creams also may be helpful for this type of pain. Depletion of neurotransmitters in pain-sensing neurons is the proposed mechanism of action. These preparations are applied to the painful areas three or four times a day. Several weeks are required for benefit to appear, and a short-term increase in the pain may occur before the benefit begins. This medication is somewhat cumbersome to use. Topical lidocaine patches may be helpful if the pain is localized. Like the other interventions, they may lessen but will not eliminate the pain.

2. Short electric-like jabs of pain

are another form of neuropathic pain. These are often felt in the toes, feet, lower legs, or fingers. Each lasts a second or two, and tends to migrate from one site to another. The patient may yell or gasp due to the intensity of the pain. This type of pain often responds to gabapentin or pregabalin. Other anticonvulsant drugs such as phenytoin at 100 mg two or three times a day or carbamazepine at 100 mg twice a day up to 200 mg three times a day may help. Benefit from any of the medications often begins within a few days. The dosage may need to be increased if the initial benefit lessens. Monitoring of drug levels is probably not helpful in maximizing benefit. CBC should be monitored for patients undergoing maintenance therapy with carbamazepine.

3. Tight or band-like pressure pain

in the feet or lower parts of the legs is resistant to symptomatic treatment. Encourage patients not to rely on medication to provide relief from this type of pain.

4. Allodynia,

pain to non-noxious stimuli, often is an accompaniment to spontaneous pain. The patient perceives light touch in the involved area as exquisitely uncomfortable during and a few seconds after the touch. Wearing light cotton socks or gloves can lessen these sensations, as can tents in the foot end of the bed linens to keep the toes from being touched. The antidepressants discussed above may improve these sensations.

B. Paresthesia

is another form of sensory abnormality. This phenomenon takes the form of feelings of repetitive prickling, or “pins and needles” sensations. These sensations are felt in larger areas than the discrete sharp jabs of pain discussed in I.A.2. and may be felt in the toes, the feet, or the hands. They occur spontaneously or may be produced by touching of the body part. These sensations tend to improve with antiepileptic medications discussed above. Lessening of the intensity and frequency should be the goal of treatment rather than complete relief. Analgesics do not help these symptoms.

C. Sensory loss

can cause the affected areas to feel “dead, like blocks of wood or leathery.” Sensations such as these do not respond to symptomatic treatment. Because of the loss of sensation underlying these symptoms, it is important for the patient to visually inspect the bottoms of the feet at least twice daily for local trauma such as blisters or cuts. Unrecognized lesions may lead to more serious problems such as ulcers and infections. Properly fitting shoes are important.

D. Weakness

can occur focally in radiculopathy, plexopathy, mononeuropathy, or polyneuropathy. Bracing with an orthotic may partially compensate the deficit while recovery is awaited. Mobilization of the weak body part through a complete range of motion should be done at least daily to prevent contracture formation.

Patients with polyneuropathy tend to have distal, symmetric weakness. Weakness limited to the intrinsic foot muscles manifesting as difficulty abducting the toes is not clinically significant. Spread of the deficits to the toe extensors or flexors, or particularly the ankle musculature can impair balance. Ankle-foot orthotics may greatly improve standing and walking stability. Use of large-handled utensils may help compensate for finger and hand weakness. Physical and occupational therapy can help the patient maximize function.

2. Proximal, symmetric weakness

in the legs causing difficulty in getting up from chairs or with stairs, or of arm weakness causing lifting difficulty is relatively distinct and most often suggests inflammatory demyelinating neuropathy (Guillain-Barré syndrome or its chronic variants).

3. Unilateral proximal leg weakness

can occur in lumbar plexopathy, such as diabetic amyotrophy. Knee weakness can predispose patients to falling. Patients compensate by keeping the knee locked in extension. Minor dislodgment from that position, caused by a shift in body position or a slight bump from a passerby, exposes the weakness. Successful bracing of this joint is more difficult than at the ankle. A lift chair may help with getting up from a sitting position. Evaluation by a physical therapist and a physical medicine rehabilitation physician can be very helpful in optimally managing all of these situations.

E. Cramping

can be a bothersome component of peripheral neuropathy. Intrinsic foot and leg muscles like the gastrocnemius and hamstrings are the more common sites. Cramps may be provoked by movement or occur spontaneously. Successful treatment can be a challenge. Maintenance of proper hydration and serum potassium levels are important first steps. Use of quinine sulfate before bedtime has been the traditional mainstay of symptomatic treatment for prevention of nocturnal leg cramps. The 260 mg over-thecounter preparation was withdrawn by the U.S. Food and Drug Administration over concern for rare but potentially serious, unpredictable adverse hematological or other type events. Despite its long-time use and anecdotal support, no clinical study done to modern levels of design rigor is available to support quinine’s use. A 325 mg preparation is still available by prescription but is only approved for treatment of malaria. No other medication is currently approved for the treatment of this bothersome symptom. Traditional muscle relaxers do not help. Low doses of benzodiazepines like diazepam or clonazepam can be tried.

F. Unstable balance

can arise from sensory loss, cerebellar dysfunction, or weakness in the legs. Mild imbalance may require no active management other than caution on the
patient’s part. More pronounced deficits that put the patient at risk of falling require intervention. The intervention can be informal such as another person’s arm to hold, strategically placed furniture, or use of a shopping cart at the store. More formal aids include a cane, walker, wheelchair, or motorized scooter. Patients may have increased difficulty in darkness or in situations in which their eyes are temporarily closed, such as showering. A patient who has had several falls should be encouraged to use a wheelchair to avoid further injury. A physical medicine rehabilitation evaluation can help determine the best management.

II. DIAGNOSIS AND MANAGEMENT OF SPECIFIC CONDITIONS

Autoimmune Inflammatory Neuropathies

A. Acute inflammatory demyelinating neuropathy

(Guillain-Barré syndrome).

1. Clinical features.

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