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.
1. 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-the-counter 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. This disorder manifests as weakness and sensory loss, usually beginning in the feet and then spreading into the legs and arms. The onset may follow a viral or other infectious-type illness by a week or 2, but can also develop spontaneously. The condition evolves and usually reaches maximum severity by 4 but not more than 8 weeks. The maximum impairment may be mild or progress to paralysis and need for ventilation. Weakness is usually the cause for the patient seeking medical attention. Loss of muscle stretch reflexes is an expected finding. Sensory deficits tend to be mild.
2. Laboratory findings of increased CSF protein concentration along with a normal or minimally elevated WBC count support the diagnosis. Nerve conduction studies that show slowing of velocity to <70% of normal or prolongation of distal latencies to >125% to 150% of normal support the diagnosis but this “demyelinating” pattern may not always be found. Screening for arsenic intoxication and acute intermittent porphyria should be performed because these disorders can produce a similar clinical picture. Tick bite paralysis also can mimic this condition.
3. Treatment. Patients with this working diagnosis should be admitted to a hospital. Mild cases may not need active intervention but should be observed closely for at least several days to ensure the deficits have stabilized. Weakness of a degree that impairs walking or use of the arms justifies active treatment. At least two-thirds of patients will have to follow a spontaneously improving course. Two treatments—plasmapheresis and intravenous gamma globulin infusion—have shown benefit of shortening the duration of the weakness. Better benefits tend to result if treatment is begun within the first week or two of onset.
a. Plasmapheresis, also called plasma exchange, is done by removing a portion of the plasma to eliminate components, as yet undefined, that are the mediators of the attack. The treatment usually consists of five exchanges done on every other day schedule. Vascular access through peripheral veins may be possible, but a central line is usually required. Treatments are generally well tolerated. Transient hypotension can occur, and therefore this mode may not be optimal for patients with labile cardiovascular systems.
b. Intravenous gamma globulin infusion is most commonly done on a 0.4 g/kg/day 5 days schedule. The total target dose of 2 g per kg can also be given on a more compressed schedule. This treatment has been shown to be equally effective to plasmapheresis and is often logistically easier. Headache and puritus are the more common side effects of the infusions. Major complications are infrequent but have included vascular occlusive incidents, which are presumed to be secondary to hyperviscosity due to the large protein infusion.
c. With either treatment, improvement may begin within as early as a few days but may not appear for weeks and then only manifest as a shortened overall duration of the illness. Lack of improvement over the first week or so of treatment is not a valid reason to switch from the initially chosen treatment method to another. About 10% of the patients whose condition improves with treatment may have a partial relapse within a few weeks. In such instances, another one or two plasma exchanges or gamma globulin infusions will usually reestablish the improvement. Major improvement occurs in a high percentage of patients, but even with these treatments, some patients still have a prolonged course necessitating weeks if not months of hospitalization. In more severe cases some degree of distal weakness, sensory loss, and paresthesia may persist.
Corticosteroids do not benefit patients with the acute form of inflammatory demyelinating neuropathy.
B. Chronic inflammatory demyelinating neuropathy.
1. Clinical features. The neuropathy is similar to the acute form described above but has a slower evolution that extends over at least 8 weeks and more commonly over many months. This condition does not often improve without active treatment. The laboratory and nerve conduction results are similar to those of the acute form. Monoclonal gammopathy of the IgM type can produce a very similar neuropathy, and evaluation should include a serum protein electrophoresis. If an IgM protein is found, a myelin-associated glycoprotein antibody test should also be performed because the presence of this antibody strongly supports the gammopathy being the cause of the neuropathy.
2. Treatment. The options are the same as for Guillain–Barré syndrome with the exception that corticosteroids can also be an effective intervention. Intravenous gamma globulin infusion or plasmapheresis are the more commonly chosen of the options. The schedules in II.A.3.a. for Guillain–Barré syndrome should be followed. If steroid treatment is chosen, prednisone at 1 mg per kg a day can be used. If the initial treatment is going to help, some signs of improvement should be evident within 1 month of initiation. Further improvement is then likely over the next few months. If steroids are chosen, a tapering schedule of 10 mg per month can be followed after the initial 4- to 6-week period of 1 mg per kg dosing. If worsening occurs after a dose decrease, an increase back to the previous effective dose should be made. After a dose decrease, some steroid-treated patients report symptoms of general aching, stiffness, and listlessness. These types of symptoms are not usually due to true exacerbation and are only nonspecific symptoms from the steroid dose decrease. These type symptoms improve 2 to 3 weeks after the dose decrease. If no true improvement has occurred within the 4 to 6 weeks of treatment, benefit is unlikely, and the medication should be tapered off completely over a few weeks. Treatment with steroids is much less expensive than plasmapheresis or gamma globulin infusion but long-term steroid side effects are factors in the decision about treatment type. Patients who show a good initial response to gamma globulin infusion or plasmapheresis may need recurring treatment. Re-exacerbation within 4 to 8 weeks of the initial treatment dictates retreatment. One to 2 days of pheresis or intravenous immune globulin should be repeated and the patient observed for the next month. The need for further treatment is then dictated by re-exacerbation versus sustained improvement. In some patients recurring treatment every 3 to 6 weeks may be required to maintain the improvement. If the patient has shown sustained improvement after several repeated treatment sessions, lengthening the interval between treatments, or not retreating unless definite worsening occurs, should be considered because remission is possible. The role of other immune suppressants like azathiorprine, mycophenolate, and rituximab have not been established in the longer term treatment of this condition.
C. Vasculitic neuropathy occurs due to inflammation of the vasa nervorum. The vasculitis is usually a component of a more generalized systemic disease but in rare cases may be limited to the peripheral nerves alone.
1. Clinical features. The presentation and evolution of this type of neuropathy tend to be unique. Progression occurs in a patchy manner such that a single nerve in a limb malfunctions and then a nerve in another location does the same. Individual deficits often appear rather suddenly, and then accumulate over days to weeks. This stepwise and cumulative pattern is termed mononeuritis multiplex. If left unchecked, the condition often evolves into generalized, symmetric polyneuropathy. Careful history taking identifies the stepwise pattern of progression.
Vasculitic neuropathy can be serious and usually continues to progress unless treated. The neuropathy may occur in association with polyarteritis nodosa, rheumatoid arthritis, systemic lupus erythematosus, or Wegener’s granulomatosis and may be a presenting feature of these conditions. It may also occur in isolation and is then termed non-systemic vasculitic neuropathy.
2. The diagnosis is supported by results of laboratory studies that identify any of the aforementioned systemic illnesses. Electromyography can help by showing a patchy “axonal” type pattern of involvement. Biopsy of a peripheral nerve in an area of clinical involvement, such as the sural or a superficial radial nerve, establishes the diagnosis if the results are positive.
3. Treatment requires immunosuppressive therapy. Prednisone at 1 mg per kg a day is the initial treatment, but an additional agent like cyclophosphamide will likely be required for sustained benefit. Cyclophosphamide should be given by physicians familiar with its use. It can be administered by means of daily oral dosage or monthly intravenous pulses. The initial response to treatment declares itself as a cessation of further worsening. Improvement requires axonal regeneration and occurs over months to several years. Severely affected areas may show persistent deficits despite overall improvement.
D. Brachial plexitis, also known as Parsonage–Turner syndrome or neuralgic amyotrophy, is easily diagnosable once it is fully manifest but can be difficult to differentiate from cervical nerve-root compression or intrinsic shoulder disease in its early stages. Brachial plexitis can be idiopathic or may appear a few weeks after an infection or immunization. Surgery, which can be on structures remote from the shoulder, can also provoke an attack. A dominantly inherited familial form is also known. The upper trunk of the brachial plexus tends to be most often involved.
1. Clinical features. Pain is the initial symptom. This begins in the neck, shoulder, or upper arm. It has a constant “deep in the bone” character and is usually unilateral. The pain intensifies over days to weeks and can become excruciating. Neck movement tends not to greatly worsen the pain, but arm or shoulder motion may. Several weeks after the onset of pain, symptoms of sensory loss and weakness appear. The sensory deficits tend to occur in the lateral arm and forearm and first two digits. Weakness most often occurs in the deltoid, biceps, supraspinatus, infraspinatus, and serratus anterior muscles. Significant atrophy can occur in the affected muscles. The pain usually lessens within 3 to 6 weeks. Sensory loss and weakness improve over months, but long-term deficits may persist. The acquired form tends not to recur but the familial form can.
Differentiation from a cervical nerve root compression syndrome requires cervical spine imaging. Imaging of the plexus may show signal enhancement or enlargement in the affected portions. Electrodiagnostic studies show acute denervation patterns on needle EMG in limb muscles but sparing of the parapinals. Conduction studies show low amplitude sensory nerve action potentials in amplitude in affected nerves, a finding that also helps distinguish plexopathy from radiculopathy.
2. Treatment. The lesion is presumably inflammatory in nature but treatment with oral or intravenous corticosteroids have shown no consistent benefit in small trials. The pain is often poorly responsive to even major analgesics but should be managed symptomatically as best as possible.
Metabolic Neuropathies
E. Alcoholic neuropathy is a sensorimotor polyneuropathy that primarily affects the distal legs but can also produce mononeuropathies.
1. Clinical features and diagnosis. The onset of the polyneuropathy is insidious, and progression takes place over months or longer. Sensory symptoms include numbness, paresthesia, and fiery pain. Motor abnormalities in the form of deficits of toe abduction or extension are present in many patients. Foot-drop can occur in more advanced cases. Electrodiagnostic studies show a pattern of axonal disease. Supporting laboratory findings include liver enzyme abnormalities and red cell macrocytosis.
2. Treatment consists of discontinuance of alcohol and establishment of an adequate diet plus supplementation of the diet with thiamine at 100 mg per day. Improvement takes place over months. Unstable walking resulting from concomitant alcoholic cerebellar disease recovers less well than the neuropathy and can limit overall improvement.
3. Mononeuropathy results from local compression of nerves during periods of alcoholic obtundation. Radial neuropathy at the humeral spiral groove causing wrist drop is the classic lesion. The deficit tends to recover over days to months as the pressure-injured internodal segments remyelinate. If deficits do not begin to improve within a month of onset, electrodiagnostic testing should be done to better define the degree of nerve injury and establish prognosis.
F. Diabetic neuropathy can appear in several different forms, which are not mutually exclusive. Other than optimal control of blood glucose levels there is still no specific therapy for biochemical abnormalities underlying the neuropathy. The principles of general symptom management outlined in Section I. should be followed.
1. Sensorimotor polyneuropathy causing bilateral foot numbness with or without a painful component is the most common type of diabetic neuropathy. Good control of blood glucose is the foundation of management, but neuropathic symptoms may develop despite this.
2. Lumbosacral plexopathy, also termed diabetic amyotrophy or radiculoplexopathy, is a distinctive syndrome (see Chapter 25, II.A.). The condition usually begins with spontaneous unilateral pain in the low back, hip, or proximal leg. The pain can become quite severe over the next week or so. Days or, more often, a few weeks after onset of the pain, paresthesia and sensory loss appear in the thigh and at times in the medial lower leg. Weakness most often affects the quadriceps and appears about the same time as the sensory loss. Notable muscle atrophy can occur in the affected muscles. The pain is often only partially responsive to even major analgesics but tends to begin improving within a month or 2 after onset. Considerable weight loss may occur with this condition. Occasionally, as the initially involved side is improving, the opposite side becomes involved. The long-term prognosis tends to be good, but recovery can extend over a year or more. Some patients have persisting motor deficits. Several small series in the literature suggest that a course of intravenous gamma globulin or corticosteroids by the oral or intravenous route may shorten the course of this syndrome. The dosing schemes outlined for the initial treatment of chronic inflammatory neuropathy can be utilized. Steroid dosing has not been standardized.
3. Thoracic radiculopathy is somewhat similar to lumbosacral plexopathy in terms of onset and time course. Unilateral band-like pain beginning spontaneously in the chest or upper lumbar region is the main symptom. The pain can be severe. Cutaneous hypersensitivity that makes the touch of clothing uncomfortable in the involved area also may be reported. Localized weakness of the lateral or anterior abdominal muscles may produce localized bulging of the abdominal wall, particularly when the patient is standing. Analgesics provide at best partial relief. Gabapentin and tricyclic antidepressants may partially improve the pain. Local anesthetic nerve blocks or topical lidocaine patches in the involved dermatome may help to some degree, as can use of a transcutaneous electrical nerve stimulation unit. The pain persists for some months but eventually resolves or greatly improves.
Medication Induced Neuropathies
G. Medication induced polyneuropathy can occur during treatment for neoplasms, autoimmune disorders, chronic infrections, and cardiac arrhythmia. Vincristine, paclitaxel and docetaxel, cis and carboplatinum, and bortezemab are the antineoplastic drugs most often associated with neuropathy. Colchicine, hydroxychloroquine, leflunomide, and thalidomine used for treatment of inflammatory and autoimmune disorders can cause neuropathy. The antibiotics dapsone, isoniazid, metronidazole, and nitrofurantoin have been reported to cause neuropathy. The antiarrythmic medication amiodarone can cause neuropathy.
1. Clinical features. All of these except platinum produce a sensorimotor neuropathy and the sensory deficits are usually the prominent features. The platinum compounds tend to affect only sensory neurons and can produce both sensory loss and ataxia. A significant painful component may develop with some of these agents. Motor deficits are usually mild, but if sensory deficits progress proximally to the mid-shin and fingertip levels, foot drop and weakness of the intrinsic hand muscles can occur. The occurrence and severity of neuropathy tend to be dose related and usually begin after several cycles of administration. The patients are actively aware of the deficits. Nerve conduction studies can help quantify the deficits.
2. Treatment. When repeated or prolonged use of the medication is required for treatment of the primary illness, lengthening of the interval between treatment or reduction of the dose at each treatment may allow the neuropathy to stabilize. Improvement is the expected course but the time interval may extend over months or longer. Some patients worsen for weeks to a few months after the dosing is reduced or stopped. The clinical pattern is termed “coasting.” Symptoms should be managed as described above in Section I.
Neuropathies Due to Infections
H. Lyme’s disease can produce several different types of peripheral neuropathy as well as other neurological manifestations such as meningitis and a delayed chronic encephalopathy. The bites of certain ticks of the Ixodes genus (e.g., I. dammini, most often) transmit the infectious agent Borrelia burgdorferi. Endemic areas include southern New England and the Mid-Atlantic states, the central regions of Wisconsin and neighboring states, and north coastal California plus Oregon.
1. Clinical features. The characteristic skin lesion erythema chronic migraines develops 3 to 20 days after the bite, as does a general flu-like syndrome of fever, malaise, and myalgia. The skin lesion occurs in approximately 80% of cases. Frank neurologic involvement occurs in approximately 15% of cases and tends to appear 1 to 3 months after the initial infection in the time frame termed the early disseminated phase of the illness. Less specific symptoms of headache occur in more than half of patients. A positive serologic result for antibodies against the infectious agent is helpful for establishing the cause, but test results may be negative for a month or so after the initial infection. An ELISA or immunofluorescence assay should be done first and if positive be followed up by an immunoblot test for IgM or IgG antibodies. The latter test helps to identify false-positive results.
2. Treatment. Antibiotic treatment appears to relieve all of the manifestations, either by shortening the duration of episodes or by alleviating more persistent symptoms such as polyneuropathy. Oral antibiotics can be used to manage the rash and flu-like phase of the initial stage of the infection. For adults, doxycycline 100 mg twice a day, amoxicillin 500 mg three times a day, or cefuroxime 500 mg twice a day for 2 to 3 weeks are recommended. Peripheral and central nervous system manifestations are best managed with intravenous penicillin G, 20 million U per day, or ceftriaxone, 2 g daily for the same 2 to 3 weeks.
3. Types of neuropathy of the early disseminated phase.
a. Facial nerve involvement produces typical Bell palsy, including pain in the ear region. Bilateral involvement occurs more frequently with Lyme’s disease than in the idiopathic form.
b. Radiculitis producing a syndrome similar to that described for diabetic thoracic radiculopathy (see II.E.3.) and consisting of dermatomal pain, which can reach a high level of intensity, sensory loss, and focal weakness. Limb as well as truncal spinal segments can be involved.
I. HIV infection can be associated with several types of peripheral neuropathy.
1. Typical acute inflammatory demyelinating neuropathy, Guillain–Barré syndrome, can occur early in the course of the infection. CSF pleocytosis with white cell counts of 10 or more is the only feature that distinguishes this form from the idiopathic variety. Therapy should be the same as for the idiopathic form of the disorder (see II.A.3.).
2. A distal symmetrical polyneuropathy with predominant painful symptoms can also occur in up to a third of patients and is more likely when viral load becomes greater than 10,000 copies per ml. Patients report painful paresthesia consisting of pressure-or burning-type sensations in the feet and distal legs. The hands can be involved to a lesser extent. Weakness is minimal. CSF tends to be normal to minimally abnormal. Nerve conduction studies show a pattern of axonal damage. Management of this type of neuropathy is symptomatic only, and the general guidelines for painful neuropathy presented in I.A. should be followed. A similar type neuropathy can occur in patients being actively treated with high activity antiretroviral therapy (HAART). This type neuropathy has symptoms and signs very similar to those produced by the HIV infection. A potential clue that the neuropathy is treatment-related is its appearance after HAART has been begun. Dosage reduction or substitution of potentially less neurotoxic medications should be considered if the status of the infection permits.
3. Polyradiculitis resulting from infection by cytomegalovirus is another distinctive form of neuropathy that affects patients with AIDS in the advanced stage of the illness. Patients report pain and weakness in the lower extremities and the back. The onset may be asymmetrical but becomes bilateral within days to weeks. Sensory loss develops in the limbs and perineal area. Bladder and bowel incontinence are also regular features. Progression to arm involvement is infrequent. CSF shows pleocytosis and elevated protein level. Pathologic specimens show inflammation of the nerve roots of the lumbar and sacral areas. Treatment with ganciclovir and foscarnet may stabilize the condition, but this lesion tends to be a poor prognostic indicator.
Other Neuropathies
J. Critical illness polyneuropathy occurs in patients who experience severe episodes of sepsis and multi-organ failure that require days to weeks of treatment in the intensive care unit.
1. Clinical features. The neuropathy typically becomes evident when respiratory support is withdrawn and the patient remains severely weak. Sensory loss may be found in patients with sensoriums clear enough for a detailed neurologic examination. Guillain–Barré syndrome is often considered in this setting. The CSF protein level tends to be normal in critical illness polyneuropathy in contrast to the latter. Nerve conduction studies show axonal rather than demyelinating patterns. Critical illness myopathy can also occur in this same setting. This condition is distinguished from the neuropathy by the finding of normal sensory examination and normal sensory nerve conduction studies. The myopathy patients have often received high-dose corticosteroids and nondepolarizing neuromuscular blocking agents as part of the ventilator support during the critical illness.
2. Treatment. Management is supportive. Recovery occurs over months. Aggressive management of hyperglycemia, which can occur in the acute phase of the critical illness, appears to lessen the occurrence of this neuropathy.
Recommended Readings
Amato AA, Russell JA. Neuromuscular Disorders. New York, NY: McGraw Hill Medical; 2008.
Bromberg MB, Smith AG, eds. Handbook of Peripheral Neuropathy. Boca Raton, FL: Informa Healthcare; 2005.
Dyck PJ, Thomas PK, eds. Peripheral Neuropathy. 4th ed. Philadelphia, PA: Saunders; 2005.
McKahnn GM. Guillain-Barré syndrome: clinical and therapeutic observations. Ann Neurol. 1990;27(suppl):S13–S16.
Van Doorn PA, Vermeulen M, Brand A, et al. Intravenous gamma globulin in treatment of patients with chronic inflammatory demyelinating polyneuropathy. Arch Neurol. 1991;48:217–220.