Epidemiology and Risk Factors. The Swedish dermatologist, Afzelius, first described an expanding ringlike skin lesion following a tick bite in 1910. He called this lesion erythema chronicum migrans.y , y The first case report of erythema migrans in the United States involved a physician in Wisconsin who was bitten by a tick while hunting. This was reported in 1970. y In the mid-1970s a number of children and adults from Lyme, Old Lyme, and Haddam, Connecticut, presented with recurrent attacks of asymmetric large joint pain and swelling that was often preceded by an erythematous expanding plaque-like skin lesion with central clearing. y This disease was termed Lyme arthritis. Lyme arthritis was later renamed Lyme disease. In 1979, Andrew Spielman, while searching for the tick vector of human babesiosis, named one tick suspect, Ixodes dammini, in honor of the distinguished Harvard pathologist Gustave Dammin. y , y This tick would later be identified as the vector of Lyme disease.y In 1981, Willi Burgdorfer isolated the Lyme spirochete from ticks collected on Shelter Island. y By 1983, two separate groups headed by Steere and Benach yj cultured Borrelia burgdorferi from patients with Lyme disease, conclusively establishing this organism as the infectious agent. y , y
In Canada, Lyme disease occurs in Ontario and Manitoba; in the United States the highest incidence of Lyme disease has been reported in Connecticut, Delaware, Maryland, New Jersey, New York, Pennsylvania, Rhode Island, and Wisconsin. The tick vector in the Northeast and Midwest is the black-legged tick, I. scapularis, which has a northern (I. dammini) and southern form.y The usual vector of Lyme disease on the West Coast is I. pacificus; the frequency of Lyme disease is much lower on the West Coast than in the Northeast.
Pathogenesis and Pathophysiology. Lyme disease is caused by invasion of the CNS by the spirochete, B. burgdorferi. The pathophysiology of Lyme disease bears several similarities to the pathophysiology of syphilis. The organism initially invades the body through intradermal inoculation.
This occurs through a tick bite. B. burgdorferi is transmitted through the mouth parts of the tick. The tick bite is painless. Transmission of infection occurs only after prolonged attachment and feeding over 24 hours. Humans are most likely to be bitten in the late spring and early summer. y Similar to syphilis, inoculation is followed by a spirochetemia with wide dissemination, and like syphilis, invasion of the CNS initially presents as a meningitis. The various neurological syndromes are felt to result not only from infection of the CNS by B. burgdorferi, but also from the reaction of the immune system to the spirochete and the associated inflammatory response. The spirochetes activate T-cell subsets and induce cytokine production (including interleukins 1 and 6, and tumor necrosis factor alpha). In addition, they cause production of autoantibodies to axonal proteins, gangliosides, neurons, myelin components, and cardiolipin. y
Clinical Features. The neurological manifestations of Lyme disease are classically divided into early syndromes and late syndromes. The early syndromes include meningitis, facial nerve and other cranial nerve palsies, and radiculoneuritis. Delayed syndromes include sensorimotor polyradiculoneuropathy, encephalopathy, and encephalomyelitis.^ , y] , W
Signs and symptoms of meningitis may develop while the characteristic skin lesion, erythema migrans, is still present and typically occurs within 12 weeks of infection. Most patients complain of headache and fatigue and some may have severe pain between the scapule, severe fatigue, myalgias, and arthralgias. The diagnosis of Lyme disease is made by the examination of the CSF that demonstrates a lymphocytic pleocytosis with a normal glucose concentration and a mildly to moderately elevated protein concentration. Paired samples of serum and CSF should be sent to detect the intrathecal production of B. burgdorferi antibody (usually IgG or IgA). Intrathecal anti-Borrelia burgdorferi antibody production can be detected in 50 to 90 percent of cases. CSF PCR can be used to amplify B. burgdorferi DNA and is positive in 30 to 40 percent of patients with Lyme meningitis. y , y] Culture of the organism from CSF is rarely positive.
The most frequent neurological abnormality in patients with Lyme disease is facial nerve palsy that is unilateral or bilateral and most often occurs within 4 weeks of the appearance of erythema migrans. Patients may also complain of headache and fatigue. Other cranial nerves may also be involved in Lyme disease, including II,
III, IV, V, VI, VIII, and IX to XII, although involvement of these cranial nerves is rare. y The most useful diagnostic tests for patients with a facial nerve palsy are a serum Lyme enzyme-linked immunosorbent assay (ELISA), Western blot, and a CSF examination. The CSF may demonstrate a lymphocytic pleocytosis and intrathecal antibody production of anti- Borrelia burgdorferi antibodies, although the latter is found in less than 10 percent. y In patients with a facial nerve palsy and a normal CSF examination, oral doxycycline (100 mg orally, twice daily for 2 weeks) can be used, however, patients with a facial nerve palsy and a CSF pleocytosis should be treated with intravenous ceftriaxone. y]
Early in the course of spirochetemia, patients may complain of severe sharp, jabbing, or deep and boring pain in a radicular nerve distribution. Often, the limb that was the site of the tick bite is the site of the pain. W Within days to weeks there may be sensory loss, weakness, or hyporeflexia in the limb. There may be clinical signs of an associated myelitis characterized by sphincter dysfunction or Babinski's sign. Patients may also have a facial nerve palsy. The diagnosis is made by the examination of CSF and through electromyography (EMG). The majority of patients have a CSF lymphocytic pleocytosis, an increased CSF protein concentration, and evidence of intrathecal production of anti- Borrelia burgdorferi antibody.yi The majority of patients also have a positive Lyme serology and Western blot. [ioi] The abnormalities on EMG are consistent with a polyradiculopathy with a predominantly axonal process. y Some patients may have a clinical presentation suggestive of the Guillain-Barre syndrome with areflexia and a predominantly motor involvement. EMG findings of a primarily axonal process and CSF evidence of a lymphocytic pleocytosis, however, are not consistent with a diagnosis of Guillain-Barre. Guillain-Barre syndrome may occur as a postinfectious complication of Lyme disease. In these patients, the EMG does show changes typical of a demyelinating process, and examination of the CSF demonstrates the characteristic cytoalbuminological dissociation.y
Encephalopathy was initially described in patients with systemic manifestations of Lyme disease and in particular, arthritis. The patients have a mild confusional state characterized by difficulty with memory and cognitive slowing often accompanied by fatigue and malaise. Neuropsychological testing is abnormal, but CSF abnormalities may or may not be present. Pleocytosis is reported in 5 percent of patients, and intrathecal anti- Borrelia burgdorferi antibody production is present in less than 50 percent of patients.y , W Active neurological involvement that is suggested by CSF abnormalities, the psychological consequences of chronic illness, and possibly residual neurological deficits of a past infection with Lyme disease may affect a patient's perception of cognitive dysfunction. In addition, evidence from quantitative analysis of SPECT scans suggests that Lyme encephalopathy patients with measurable memory deficits have reduced perfusion affecting primarily subcortical frontotemporal white matter and basal ganglia. 
Patients with chronic Lyme radiculoneuropathy present with sensory symptoms, particularly distal paresthesias in a
stocking and glove or a stocking distribution. A less common presentation is pain in the distribution of the cervical, thoracic, or lumbosacral dermatomes. This syndrome is distinct from the painful symptoms of radiculoneuritis that occurs within a few weeks of infection with B. burgdorferi. Although patients with a chronic radiculopathy complain of pain, it is much less severe than in the acute radiculoneuritis form. Electrophysiological studies demonstrate a mild sensorimotor radiculoneuropathy with axonal loss, minor decreases in the distal compound action potential amplitudes (sensory greater than motor), little or no slowing of nerve conduction velocities, and mild to moderate distal and paraspinal muscle denervation. y.1 In patients who complain of paresthesias, mildly prolonged distal motor or sensory latencies and mild slowing of distal motor conduction velocities is present. y These patients do not typically have a facial nerve palsy, and examination of the CSF is usually normal.y
A very rare, late neurological syndrome in North American Lyme disease affects both the brain and spinal cord white matter. Examination of the CSF demonstrates a lymphocytic pleocytosis, a mildly elevated protein concentration and the intrathecal production of anti- Borrelia burgdorferi antibodies.W
Evaluation. The diagnosis of CNS Lyme disease begins with asking the patient about a history of a tick bite, whether there was travel to an endemic area, and if the skin lesion was characteristic of erythema migrans. This lesion begins as a painless macule, which continues to expand until it becomes an annular erythematous plaque. It occurs at the site of a tick bite an average of 8 to 9 days after infection. As the lesion expands, the center may become clear, vesicular, or edematous forming a bull's-eye lesion.y Serum should be sent for ELISA and Western blot testing. A positive serology is indicative of exposure to the organism and should not be considered proof of active infection. Interpretation of the serological test is further confounded by the evidence that seronegative Lyme cases exist. CNS infection is most readily confirmed if the paired serum and CSF anti-Borrelia burgdorferi antibody titer demonstrates the intrathecal production of these antibodies. Other CSF abnormalities suggestive of Lyme disease are a mononuclear or lymphocytic pleocytosis, an elevated protein concentration, and a normal glucose concentration. As described in the specific clinical features of each neurological syndrome, the CSF is almost always abnormal in Lyme meningitis and early radiculoneuritis. The CSF is at times abnormal with an isolated facial nerve palsy or with encephalomyelitis and can be normal or abnormal when encephalopathy is present. The CSF is typically normal in chronic Lyme disease sensorimotor polyradiculoneuropathy. y
Management. Facial nerve palsy without CSF abnormalities may be treated with oral doxycycline 100 mg twice a day for 2 weeks. Intravenous ceftriaxone is the drug of choice for all other neurological syndromes of Lyme disease. The adult dose is 2 g/d, and the pediatric dose is 75 to 100 mg/kg/d. Treatment with ceftriaxone should be continued for at least 2 weeks, and many physicians prefer 4 weeks of therapy. y¡i
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