Autoimmune Peripheral Nervous System Disorders

Autoimmune peripheral nervous system disorders include the neuropathies caused by connective tissue diseases, systemic vasculitis, and autoimmune disorders of peripheral myelin. Neuropathic pain may precede the diagnosis of systemic or focal vasculitis or occur during the course of established disease. When neuropathy precedes the diagnosis of vasculitis, the absence of more severe systemic symptoms may delay the diagnosis. Inflammation leading to ischemia of focal peripheral nerves may result in the clinical syndrome of mononeuropathy multiplex. This syndrome is characterized by pain, numbness, and weakness in the distribution of multiple peripheral nerves. The peripheral nerves most commonly affected include the ulnar, median, and peroneal nerves. Dysfunction in the territories of these nerves will typically occur at sites of peripheral nerve entrapment and at sites distal from locations usually associated with peripheral entrapment. Distal symmetrical polyneuropathy (DSP) may also occur in the setting of vasculitis and connective tissue disease. DSP is characterized by numbness, tingling, and pain in a characteristic symmetrical stocking-glove distribution. Symptoms typically begin in the feet and consist of burning, aching, and dysesthesias. Not uncommonly, asymmetry of progression of DSP leads to a consideration of autoimmune vasculitis and may assist in the clinical diagnosis.

Acute inflammatory demyelinating polyneuropathy, known as Guillain-Barré syndrome, occurs at an annual incidence of approximately 1.11 per 100,000 person-years, with a 20% increase every decade after the first decade of life. Paresthesias or dysesthesias typically precede the development of weakness, which proceeds in an ascending pattern. Contemporary treatment strategies have limited the disability associated with the disorder, but a small proportion of patients may have resulting disability and chronic pain. During the acute phase of the illness, pain is often a prominent symptom. A review of pain in patients with Guillain-Barré syndrome has highlighted the importance of recognizing the primary components of pain and secondary pain syndromes. Deep aching, throbbing pain in the low back region associated with radiation into the lower extremities is typically the most excruciating and disabling pain during the acute episode. A positive straight-leg raise test may accompany the acute pain. Accompanying the low back and radicular pain, myofascial pain may coincide with the development of muscle spasm, cramping, and muscular tenderness. Stabbing, shocklike, or electric pain may be present in the extremities and face. Ectopic impulses caused by acute nerve root inflammation may be the pathologic mechanism associated with the acute neuropathic pain component in Guillain-Barré syndrome. Chronic neuropathic pain may actually persist beyond treatment of and recovery from the paralytic disorder in a small proportion of patients. The autonomic nervous system dysfunction present in Guillain-Barré syndrome may lead to the development of headaches, cardiovascular instability, and visceral pain secondary to ileus and urinary retention.

Treatment of primary neuropathic pain in Guillain-Barré syndrome includes the use of antineuropathic agents in addition to immune-based therapy for the primary disease. Antineuropathic agents commonly used include tricyclic antidepressants, anticonvulsants, and opioids (oral and parenteral, when necessary). In severe cases, epidurally administered local anesthetics or opioids may be of benefit in the acute stage. Treatments beneficial for secondary pain syndromes include muscle relaxants (e.g., baclofen, tizanidine) for acute myofascial pain and supportive measures for the acute dysautonomia (e.g., intravenous fluid administration, stool softeners, urinary drainage).

Human Immunodeficiency Virus–Related Neuropathies

Nervous system complications of human immunodeficiency virus (HIV) type 1 infection have been reviewed by Price. Peripheral neuropathic pain is recognized as a common accompaniment of HIV infection. Neuropathic pain may complicate any stage of the infection and result in disordered sleep and ambulation, disability, and psychosocial distress. It is estimated that 35% of patients infected with HIV experience symptomatic DSP whereas as many as 67% of patients infected with HIV may experience asymptomatic DSP when evaluated neurologically. The peripheral neuropathic pain syndromes characteristic of HIV infection are summarized in Table 25.3 .

During the acute course of seroconversion, acute inflammatory demyelinating polyneuropathy may develop and cause numbness, weakness, and peripheral neuropathic pain. The disorder may be the initial manifestation of HIV seroconversion. Its course may be similar to that of Guillain-Barré syndrome, though with a higher incidence of more severe weakness, atrophy, and profound sensory loss. Treatment of moderate to severe cases uses the standard strategies for the treatment of Guillain-Barré syndrome (e.g., immunotherapy, antineuropathic agents, epidural infusions). The acute polyneuropathy associated with seroconversion typically resolves with mild, if any, residual sequelae of neuropathic pain. The chronic form of the disorder, chronic inflammatory polyneuropathy, appears in the intermediate to late stages of the disease. It is manifested as neuropathic pain associated with more severe sensory loss, weakness, and gait disturbance.

With the advent of successful antiretroviral therapy, long-term survival rates for those with HIV infection have increased, and as a result, there has been an associated increase in the incidence of chronic neuropathic pain attributable to the treated disease, as well as the treatments. In addition to the neuropathies associated with primary HIV infection, antiretroviral agents may be neurotoxic. In particular, the dideoxynucleoside family of nucleoside analogue reverse transcriptase inhibitors has been shown to have specific peripheral neurotoxic effects. Antiretroviral-induced neuropathies are manifested by distal dysesthesias, burning, tingling, and shooting pains. This antiretroviral-induced polyneuropathy can be distinguished from HIV polyneuropathy in that it occurs more abruptly with more rapid progression and is often more painful. Antiretroviral polyneuropathy occurs in 26% to 66% of patients, but the symptoms often improve with drug cessation or reduction. Allodynia may be experienced during ambulation and can be debilitating. Difficulty with sleep is a common accompaniment secondary to allodynia and spontaneous dysesthesias.

A distal symmetrical HIV-induced sensory axonal polyneuropathy may occur in the intermediate or late stages of infection. The polyneuropathy is manifested as burning pain, numbness, and evoked dysesthesias beginning in the lower extremities, with variable progression to upper extremity involvement. Similar to the antiretroviral neuropathies, allodynia may impair sleep and ambulation. Another intermediate-stage phenomenon, vasculitic mononeuropathy multiplex, may coexist with other peripheral nervous system symptoms of HIV infection. Symptoms of vasculitic neuropathy are similar to those that characterize the connective tissue disorders. Pain, numbness, dysesthesias, and motor symptoms are multifocal and asymmetrical. They often persist despite treatment of the primary disease.

During the course of the illness, especially if untreated or refractory to treatment, opportunistic infections may contribute to the neurologic symptoms. Cytomegalovirus infection may give rise to progressive polyradiculopathy or mononeuropathy multiplex, or both. The polyradiculopathy is characterized by the development of pelvic and lower extremity radicular pain and urinary retention and may progress to cauda equina syndrome. Rapid progression with ascending paralysis, central nervous system involvement, and death occurs in untreated cases. Reactivation of other latent nervous system infections such as neurosyphilis, herpes simplex virus, and toxoplasmosis has been well characterized in advanced HIV and may lead to neuropathic peripheral or central pain syndromes.

Treatment of HIV-related peripheral neuropathy and neuropathic pain follows the usual course of management of neuropathic pain syndromes in general. However, in contrast to other neuropathic syndromes, such as post-herpetic neuralgia and diabetic peripheral neuropathy, the neuropathic pain associated with HIV and HIV-related neuropathies has proved difficult to treat. In particular, the antiepileptic drug lamotrigine has been shown to be of benefit in refractory cases.

Idiopathic Sensory Polyneuropathy

A significant number of patients will exhibit symptoms of peripheral neuropathic pain in a characteristic stocking-glove distribution without a definable causative agent. The disorder is estimated to occur in approximately 25% of those 65 years and older and in as many as 50% of those 85 and older. In many cases the disorder is characterized by loss of peripheral pain and temperature sensation. However, in a significant proportion of cases, complaints of burning, tingling, and symptoms of restless legs syndrome may predominate. This syndrome may be associated with difficulty ambulating, falls, and a reduction in quality of life. It is hypothesized that age-related changes in the peripheral nervous system may contribute to the development of age-related idiopathic sensory neuropathy. As is true for other sensory neuropathies, the symptoms are typically worse at night. This may lead to disrupted sleep and failed attempts at restoring sleep with therapy aimed toward minimizing insomnia. In most cases, physical examination reveals evidence of loss of pain and temperature sensation distally in the lower extremities. In more severe cases there may be loss of large-fiber sensation, with deficits in vibration and joint position sense. It is imperative to exclude vitamin deficiencies, insulin resistance, and incipient diabetes mellitus in the evaluation of these patients. Therapy is aimed toward achieving restorative sleep and minimizing awakenings secondary to pain. An antineuropathic agent, such as a tricyclic antidepressant or anticonvulsant given at bedtime, represents common first-line therapy. An open-label study using topical 5% lidocaine has demonstrated improvement in symptoms over baseline without significant adverse effects.

Subacute Sensory Neuronopathy

Sensory neuronopathy is a rare disorder characterized as an autoimmune response to antigens found on cells in the dorsal root ganglia. The disorder may also result from the effects of drugs or neurotoxins (cisplatin or pyridoxine). It is characterized by ataxia and sensory loss, frequently with painful dysesthesias beginning in the lower extremities and rarely in the upper extremities, trunk, or facial region. This disorder is slowly progressive and may not improve following immunotherapy aimed at removal of paraneoplastic or autoimmune antibodies. Sensory neuronopathy has most commonly been associated with small cell cancer of the lung, Sjögren’s syndrome, and the presence of anti-Hu antibodies. In addition to immunotherapy aimed at treatment of the primary disorder or tumor resection (if relevant), the goal of symptomatic therapy is reduction of the neuropathic pain components and prevention of a secondary pain syndrome through limb protection and ambulatory assistive devices. When the disorder is associated with toxin or drug exposure, treatment is typically limited to supportive measures and treatment of any neuropathic pain components.

Tabes Dorsalis

Perhaps once the most commonly encountered chronic neuropathic pain condition, neurosyphilitic involvement of the dorsal root entry zone represents a classic neurologic pain disorder. The disorder is characterized by “lightning pain” involving the lower extremities. Similar pain may occur in the trunk, thorax, and abdomen. Tabetic pain may occur for brief periods (seconds or minutes) or last for several days. Occasionally, visceral involvement predominates, known as “visceral crises.” These crises are characterized by attacks of epigastric or pelvic pain accompanied by nausea and vomiting. Physical examination is remarkable for loss of sensory modalities distally in the lower extremities. There may also be significant ataxia, hypotonia, and dysautonomia. The neuropathologic hallmark of tabes dorsalis is inflammatory infiltrates along the dorsal roots with degeneration of the posterior columns. Therapy involves standard antibiotic therapy to eradicate the Treponema pallidum organism . Antineuropathic agents such as anticonvulsants and tricyclic antidepressants are used for symptomatic therapy. Argyll Robertson pupils (miotic pupils that are unresponsive to light but react with accommodation) are usually present. Though characteristic of the disorder, the classic finding of Charcot’s joints is the result of deep anesthesia caused by the disorder. Even though it is an important secondary complication of the neurologic syndrome, once the disorder has reached the stage of profound joint hypoalgesia, the protective mechanism of pain (and therefore the need for aggressive therapy) has been severely attenuated.