- Email: [email protected]
The recognition and treatment of lyme disease
ADDITIONAL
ARTICLES
THE RECOGNITION AND TREATMENT OF LYME DISEASE Bertrand Agus, MD
ELSEVIER
Lyme disease is the most-common tick-borne disease in the United States, and its incidence is increasing, especially after the damp winter of 1993-94 in the Northeast. In 1982, investigators discovered that Lyme disease was caused by the spirochete, Borrelia burgdorferi. Since then, several strains of that organism have been described, possibly explaining differing clinicalpresentationsin Europe and the United States. It is crucial to diagnose Lyme disease in its earliest phases, as treatment with antibiotics usually results in a complete cure. Failure to make an early diagnosis and certain genetic factors contribute to a pattern of chronic disease in some patients. Diagnosis is made di$icult by lack of a history orfinding of a tick bite and by the fact that the pathognomonic finding, the rash of erythema chronicum migrans, is seen in only a minority of cases. Serologic diagnosis depends on the enzyme-linked immunosorbent assay, which is neither specific nor reliable, and the Western blot, which is notyet standardized. Particularly vexing is the confusion of Lyme disease with fibromyalgia, a common rheumatic disease of uncertain etiology with many overlapping symptoms. This confusion often leads to prolonged, unnecessary, and expensive treatments with dubious results. In general, Lyme disease responds well to a variety of oral and parenteral antibiotics. SpeFrom the New York University New York, New York.
200
School
of Medicine,
0 1995
Elsevier
cial problems arise in the treatment of Lyme disease in pregnancy and in the choice of antibiotics in growing children. A vaccine for Lyme prophylaxis is expectedforhigh-riskindividuals. (Prim Care Update Ob/Gyns 1995; 2:200-203)
The term “Lyme arthritis” was coined by a team of scientists from Yale University headed by Dr. Alan Steere in 1976. His investigation centered about a mysterious outbreak of polyarthritis, mainly in children, who were bitten by ticks along the banks of the Connecticut River, near the towns of Lyme, Old Lyme, and East Haddam. Further observations showed that the disease was not confined to children and that arthritis was just one manifestation of a larger condition called “Lyme disease,” which could affect the skin, nervous system, and heart. In 1982, the spirochete Borreh burgdorferi was identified as the putative causative agent. Subsequently, it was discovered that the organism was transmitted by the tick species complex Zxodes persulcatus. The common name of “deer tick” referred to a subspecies of Zxodes that previously was called dammini but that now is referred to as Zxodes scapularis, the most common tick in the Northeast and Midwest. Zxodes pacificus is the most common tick vector in the West.l Recent polymerase chain reaction analyses have identified several strains of B burgdorferi that may account for Science
Inc.
1068-607X/95/$9.50
* SSDI
different clinical spectra various countries.2
seen in
Epidemiology and Pathogenesis The majority of cases of Lyme disease occur in the Northeast, Midwest (especially Wisconsin), Georand Northern California. gia, Factors that influence spread of the disease include the presence of deer and the deer tick, landscape features such as woods and uncut grass, and the exposure of domestic pets, especially dogs, to wooded areas. Infected ticks have also been found in residential landscapes and inner-city parks. In addition, infected ticks have been spread by birds to islands off the East Coast, such as Nantucket and Martha’s Vineyard. Members of the family Zxodidae, which include hard-bodied ticks, are known to have four developmental stages: egg, larva, nymph, and adult. Each stage molts into the succeeding stage after a blood meal, and almost any vertebrate is a potential host. In the adult stage, or sexual stage, only a female tick will feed on blood and, only after mating with a male, will produce eggs for the next generation of ticks. The most prevalent stage of tick is the nymph stage, and approximately 25% of all nymphs are infected with Borrelia. Even though 90% of adult deer ticks are infected, these sexually mature ticks are much less abundant. This is because adults seek vertebrate hosts from about October to April, but many cannot
1068-607X(95)00041-G
Prim
Care
Update
ObiGyns
LYME
survive the cold temperatures of winter. Warm winters, such as the one in 1994-1995, should increase the incidence of Lyme disease transmitted by adult forms. The sudden appearance in the spring of the plentiful, infected nymphs accounts for the seasonal peak of Lyme disease cases in the spring and continued presentation of new cases through the summer months.
Diagnosis Borrelia burgdo@eri spirochetes can be seen rarely on electron microscopy of synovia of biopsied joints but are extremely difficult to grow in culture. Using special media, the organism may take as long as 10 months to grow out, making this an impractical technique for diagnosis and management. Patients develop serological responses to the infecting organism: typically, IgM antibodies can be detected by enzymelinked immunosorbent assay (ELISA) about 2 weeks after infection and are followed by a rise in IgG antibodies. Although reasonably sensitive, ELISAs can be falsely negative in disease less than 2 weeks in duration, and in patients treated early with antibiotics. Falsepositive ELISAs can be seen in the presence of other spirochetal infection such as syphilis, leptospirosis, and relapsing fever. The test may also be positive in rheumatoid arthritis, systemic lupus erythematosus, mononucleosis, and EpsteinBarr virus syndrome. The gold standard for specificity is the Western blot analysis, although there is lack of uniformity in the interpretation of results. Dressler et al3 recommend that at least two common IgM bands be present to confirm diagnosis in early disease, in addition to at least five IgG bands. Other laboratories require only four bands including a specific band, such as 41.
Studies Volume
in mice
2, Number
6. 1995
show that the
organisms are capable of changing antigenicity in prolonged cases, thereby activating differing host immune mechanisms and leading to a picture of autoimmune disease. Human patients with chronic Lyme disease have also been found to have increases in tissue types HLADR2 and HLA-DR4, which are seen in many cases of chronic rheumatoid arthritis. This observation has led to speculation that chronic Lyme arthritis is a kind of reactive arthritis analogous to the association of Reiter’s disease and the other spondyloarthropathies with HLAB27. The implication of this thesis is that therapy for chronic Lyme disease should involve immunemodulating agents, rather than prolonged ~tibiotics.
DISEASE
10-14 days of the tick bite. The most common joint involved is the knee, which can have large eifusions. Arthrocentesis shows a rather bland effusion with few inflammatory cells, but a chronic proliferative synovitis identical to rheumatoid arthritis can be seen in some cases. Assuming the host is not continually infected, the natural history of the arthritis is characterized by chronic relapses and partial remissions, with gradual defervescence. Rarely, the arthritis can progress to joint destruction similar to rheumatoid arthritis. Such patients have been found to have increases in HLA-DRZ, HLA-DR4, and HLA-DW3, but the latter two associations have been disputed.*
NEUROLOGICAL FEATLJRES
Clinical Manifestations DERMATOLOGICAL FEATURES The only pathognomonic sign of Lyme disease is the rash of erythema chronicum migrans, seen in 60-80% of early cases. Typically, the rash begins about 24-48 hours after exposure at the site of the tick bite, usually in the warmer areas of the body such as the axillae and groin. The skin lesion initially looks like a red macule. It expands over hours and days, in an annular fashion, with partial central clearing resembling a smoke ring. These lesions can achieve gigantic proportions, involving almost half the body’s skin surface. Biopsy usually reveals only a mild in~ammatory infiltrate. In about 10% of cases in Europe, a chronic lesion called acrodermatitis chronica atrophicans was reported. Rarer skin lesions include borrelia lymphocytoma and a scleroderma-like lesion.
RHEUMATOLOGICAL FEATURES Patients with untreated Lyme disease usually develop myalgias, arthralgias, and frank arthritis within
Lyme disease can affect both the central and peripheral nervous systems. In early disease, an acute meningoradiculitis is seen, often with evidence of lymphocytosis of the spinal fluid. Cranial nerves, as well as peripheral nerves, can be involved, causing pain and paresis. The most notable ne~ropa~y is Bell’s palsy, which is a common presentation for Lyme disease. Bilateral Bell’s palsy, which is usually seen only in Lyme disease, can occur. Antibodies may be detected in spinal fluid even if they are not present in the sera. Some patients develop a chronic encephalomyelitis, causing fatigue, headaches, memory impairment, di~culty in concentration, irritability, and emotional lability. There can be considerable difficulty in differentiating such symptoms from endogenous depression and/or the fibromyalgia syndrome. In fact, many patients with the latter two conditions are treated for neuroborreliosis even without serological confirmation. Although brain MRI and neurometric EEG studies are usually normal or nondiagnostic in Lyme neuroborreliosis, certain 201
AGUS
studies suggest that st~d~d neuropsychiatric testing is of value in di~erentiati~g this condition from other diseases,5*6 Similar to chronic Lyme arthritis, it is unknown whether chronic neuroborreliosis is due to persistent infection or to autoimmun~ty. Data suggest that molecular mimicry may be operating, in that patients with chronic ~~euroborreli~sis have an antibody response to ~agellin which cross-reacts with neural tissue in a ne~roblastoma cell lines7 A sensitive way to detect minute amounts of bacterial protein is the polymerase chain reaction. This technique has been applied to synovial and ~~rebrospinal fluid but occasionally gives false positive results.’ These findings have been disputed by Keller et al,’ who not only found no evidence of false positives, but observed that the overwhelming number of active cases of neuroborreliosis and active Lyme disease had positive PCR reactions. Until this controversy can be resolved, spinal fluid tests for borreliosis must be interpreted with caution.
CARDIACFEATURES Cardiac involvement with Lyme disease occurs in about 10% of cases, usually presenting with a variable degree of heart block and premature ventricular contractions. Lyme disease should be considered in cases of myocarditis of unclear etiology.” Some patients develop pericarditis and congestive heart failure, Although some patients require a temporary cardiac pacemaker, the ~?~~e~~heIrning majority respond to antibiotic therapy alone within 6 weeks.
Di~erentia~ Diagnosis Lyme disease has protean manifestations, and thus, the differential diagnosis includes many diverse
co~lditions. In general, the presence of the classic eruption of erythema ~h~o~iGurn migrans confirms the diagnosis. In the absence of this finding, connective tissue diseases such as systemic lupus erythematosus, juvenile rheumatoid arthritis, and postviral arthritis have to be excluded by appropriate blood tests. Testing is necessary for rheumatoid factor, ANA, and specific antiviral titers, such as hepatitis B, coxsac&e, influenza, and parvovirus 33.9. Other tick-borne infections, such as Rocky Mountain spotted fever and Q fever, also should be excluded by appropriate serological tests. Brain CT, MRI, and lumbar puncture may be necessary to exclude neurological diseases such as encephalitis, meningitis, and multiple sclerosis, Rheumatic fever can be excluded by history of sore throat and/or ASLO titers, A major entity to exclude is fibromyalgia, a common disorder seen mainly in women between the ages of 30 and 60. Known by many names, such as myofascial pain syndrome, chronic fatigue syndrome, fibrositis, neurasthenia, and temporomandibular joint syndrome, it is far more common than Lyme disease. Symptoms of ~bromyal~ia include fatigue, myalgias, muscle stiEness, sleep disturbance, and cognitive difficulties, all of which have been described in Lyme disease. Depression underlies many of the ~l~nifestat~ons of fibromyalgia, although some patients may have a coexistent connective tissue or metabolic disease, such as rheumatoid arthritis, lupus, or hypothyroidism. Some depressed patients with fibromyalgia are reluctant to acknowledge the ps~~~hia~iG component of their condition and latch on to Lyme disease as a physical basis to explain their illness and disability. Some ~bromyalgia patients respond to mild antidepressants, muscle relaxants, physical therapy, and injection of tender points. Such a response would not be expected to
occur in Lyme disease patients. Some patients with fibromyalgia who happen to have positive Lyme serologies, either because of past infection or by living in, or frequenting, endemic areas, can erroneously incur long, expensive, and often unsuccessful treatments with both oral and parenteral antibiotics. Physicians increasingly may find that their role as a patient advocate pits them against insurance campanies who balk at costly intravenous treatments for such patients. In such cases, primary care physicians should obtain objective consultation from a rheumatologist or infectious disease specialist.
Lyme Disease and Pregnancy Most authorities believe that untreated Lyme infection in pregnancy places the fetus at risk. Abramowsky and colleagues recently described four aborted female fetuses at 1?-23 weeks’ gestation that showed evidence of a nonsypllilitic spiro~hetal infection, possibly Lyme disease, suggesting an ascending infection origi~ati~ in the maternal intestinal tract.” Another study showed that BorreIia burgdorferi can attach to, and pass through, endothelial surfaces, including the amniotic membrane.~’ Nevertheless, in a study of Z&30(1 Lyme disease cases from the endemic area of Westchester County, New York, Strobino et alI3 could End no association between exposure of mothers to Lyme disease prior to conception or during pregnancy with any increased risk of fetal death, prematurity, or excessive fetal malformations. Until the issue can be resolved, all pregnant women with suspected or confirmed Lyme disease should be treated.
Treatment of Lyme Disease Fortunately, Lyme disease is sensitive to most antibiotics, and there is no evidence that resistant strains of Borrelia burgdorferi are emerging. Most regimens consist of a s-week course of oral antibiotics. Doxycycline is the drug of choice, and should be administered in a dose of 100 mg twice daily. However, tetracycline and doxycycline should be avoided in pregnancy and in growing children because they can injure growing bone and teeth. Caution must be used with tetracyclines in sunny climates because of photosensitivity, and patients receiving these drugs should apply sun screens with a high sun protective factor. Oral penicillin or ampicillin is effective in a dose of 500 mg four times a day, especially if augmented with probenecid, but allergy can limit this combination. Alternative treatment with erythromycin 500 mg orally four times a day or clarithromycin 500 mg twice daily is effective, but the latter drug is con~aindi~ated in pregnancy because it can lead to birth defects. For patients with central nervous system involvement, or who fail at least two courses of oral antibiotics, the treatment of choice is intravenous ceftriaxonc in single doses of 1.5-2 g daily. This drug can be administered in the home setting with the aid of a home infusion service, so that patients can carry on a normal lifestyle during the treatment period. The efficacy of prolonged treatment beyond 3 weeks, or repeated intravenous courses, is not proven. The same regimens work as well in cases of cardiac
Volume
2. Number
6, 19%
involvement, which might also include antiarrhythmia drugs, temporary cardiac pacing, and treatment for congestive heart failure. Because autoimmune mechanisms may be responsible for chronic symptoms, particularly musculoskeletal disease, it is rational to treat selected patients with nonsteroidal antiin~ammatory drugs and occasiona joint injection with corticosteroids. An exception must be made for pregnancy, in which case the nonsteroidal drugs are contraindicated. In such cases, supportive measures such as local heat and liniments are useful. Selective joint injection with methylprednisolone is possible in pregnancy, as this drug is inactivated by the placenta. A good second-line drug for nonpregnant patients is hydrcrxychloroquine in doses of 200 mg twice daily for several months, if necessary. If the above guidelines are followed, more than 90% of patients with Lyme disease should make a complete recovery. The remaining patients, particularly those with neuroborreliosis and/or chronic arthritis, face an uncertain prognosis, although permanent disability and death are very rare.
References Sonenshine DE. Biology of ticks, vol. 1. New York: Oxford University Press, 199151-6. Rosa PA, Hogan D, Schwan TG. Polymerase reaction analysesidentify two distinct classesof Barrelia ~urg~or~e~j.J Clin Microbial 1991; 29:524-32. Dressier F, Whalen JA, Rei~hardt BN, et al, Western blotting in the serodiagnosis of Lyme disease, J Infect Dis 1993;167-32. Pfluger KH, ReimersCO, Neubert U,
et al. Lyme borreliosis and possible associationwith HLA antigens. Tissue Antigens 1989;33:375-81. 5. Krupp LB, Mawr D, Schwartz J. et al. Cognitive functioning in late Lyme borreliosis. Arch Neurol 1992;48:1125-9.
6. Kaplan RF, Meadows ME, Vincent LC, Logigian EL, Steere AC. Memory impairment and depression in patients with Lyme en(~ephelopathy. Neurology 1992;42:1263-7. Fikrig E, Berland R, Chen M, William S, Sigal LW, Flavell RA. Serologic responseto the Borrelia burgdorferi flagellin demonstrates an epitope common to a neuroblastoma cell line. Proc Nat1 Acad Sci U S A 1993;90:183-7. Malawista SE, Schoen RT, Moore TL, Dodge DE, White TJ, Persing DH. Failure of multitarget detection of Borrelia burgdorferi-associated DNA sequencesin svnovial fluids of patients with j~~~e~ilerheumatoid arthritis. Arthritis Rheum 1992:3!?: 246-7. 9. Keller TL, Hnlprin JJ, Whitman M. PCR detection of Borrelia burgdorf&i DNA in cerebrospinal fluid of Lyme neuroborreliosis. Neurology 1992;42:32-42.
10. Klein J, Stanek C, I3ittner R, Horvat R, Holzinger C, Clogar D. Lyme borreliosis asa causeof myocarditis and heart muscle disease.Eur Heart J 199l;lZ(Suppl D):73-5. 11. Abramo~~7skyC, deter-Patterson P, Cortinas E. Non-s~~~h~l~ticspirochetosisin secondtrimester fetuses. Pediatr Path01 1991;11:827-38. 12. Szczepanski A, Fune MB, Benach JL. Lane BP, Fleit HB. Interaction between Borreliu hurgdorferi and endothelium in vitro. J Clin Invest 1990;85:1637-47.
13. Strobino BA, Williams CL. Abid S, Chalson R. Spierling P. Lyme diseaseand pregnancy outcome, a prospective study in two thousand patients. Am J Obstet Gynecol 2993; 369~367-74. Address correspondence and reprint requests to Bertrand Agus, MD. 2.51 E. 33rd St.. New York, NY 10016.
203
ARTICLES
THE RECOGNITION AND TREATMENT OF LYME DISEASE Bertrand Agus, MD
ELSEVIER
Lyme disease is the most-common tick-borne disease in the United States, and its incidence is increasing, especially after the damp winter of 1993-94 in the Northeast. In 1982, investigators discovered that Lyme disease was caused by the spirochete, Borrelia burgdorferi. Since then, several strains of that organism have been described, possibly explaining differing clinicalpresentationsin Europe and the United States. It is crucial to diagnose Lyme disease in its earliest phases, as treatment with antibiotics usually results in a complete cure. Failure to make an early diagnosis and certain genetic factors contribute to a pattern of chronic disease in some patients. Diagnosis is made di$icult by lack of a history orfinding of a tick bite and by the fact that the pathognomonic finding, the rash of erythema chronicum migrans, is seen in only a minority of cases. Serologic diagnosis depends on the enzyme-linked immunosorbent assay, which is neither specific nor reliable, and the Western blot, which is notyet standardized. Particularly vexing is the confusion of Lyme disease with fibromyalgia, a common rheumatic disease of uncertain etiology with many overlapping symptoms. This confusion often leads to prolonged, unnecessary, and expensive treatments with dubious results. In general, Lyme disease responds well to a variety of oral and parenteral antibiotics. SpeFrom the New York University New York, New York.
200
School
of Medicine,
0 1995
Elsevier
cial problems arise in the treatment of Lyme disease in pregnancy and in the choice of antibiotics in growing children. A vaccine for Lyme prophylaxis is expectedforhigh-riskindividuals. (Prim Care Update Ob/Gyns 1995; 2:200-203)
The term “Lyme arthritis” was coined by a team of scientists from Yale University headed by Dr. Alan Steere in 1976. His investigation centered about a mysterious outbreak of polyarthritis, mainly in children, who were bitten by ticks along the banks of the Connecticut River, near the towns of Lyme, Old Lyme, and East Haddam. Further observations showed that the disease was not confined to children and that arthritis was just one manifestation of a larger condition called “Lyme disease,” which could affect the skin, nervous system, and heart. In 1982, the spirochete Borreh burgdorferi was identified as the putative causative agent. Subsequently, it was discovered that the organism was transmitted by the tick species complex Zxodes persulcatus. The common name of “deer tick” referred to a subspecies of Zxodes that previously was called dammini but that now is referred to as Zxodes scapularis, the most common tick in the Northeast and Midwest. Zxodes pacificus is the most common tick vector in the West.l Recent polymerase chain reaction analyses have identified several strains of B burgdorferi that may account for Science
Inc.
1068-607X/95/$9.50
* SSDI
different clinical spectra various countries.2
seen in
Epidemiology and Pathogenesis The majority of cases of Lyme disease occur in the Northeast, Midwest (especially Wisconsin), Georand Northern California. gia, Factors that influence spread of the disease include the presence of deer and the deer tick, landscape features such as woods and uncut grass, and the exposure of domestic pets, especially dogs, to wooded areas. Infected ticks have also been found in residential landscapes and inner-city parks. In addition, infected ticks have been spread by birds to islands off the East Coast, such as Nantucket and Martha’s Vineyard. Members of the family Zxodidae, which include hard-bodied ticks, are known to have four developmental stages: egg, larva, nymph, and adult. Each stage molts into the succeeding stage after a blood meal, and almost any vertebrate is a potential host. In the adult stage, or sexual stage, only a female tick will feed on blood and, only after mating with a male, will produce eggs for the next generation of ticks. The most prevalent stage of tick is the nymph stage, and approximately 25% of all nymphs are infected with Borrelia. Even though 90% of adult deer ticks are infected, these sexually mature ticks are much less abundant. This is because adults seek vertebrate hosts from about October to April, but many cannot
1068-607X(95)00041-G
Prim
Care
Update
ObiGyns
LYME
survive the cold temperatures of winter. Warm winters, such as the one in 1994-1995, should increase the incidence of Lyme disease transmitted by adult forms. The sudden appearance in the spring of the plentiful, infected nymphs accounts for the seasonal peak of Lyme disease cases in the spring and continued presentation of new cases through the summer months.
Diagnosis Borrelia burgdo@eri spirochetes can be seen rarely on electron microscopy of synovia of biopsied joints but are extremely difficult to grow in culture. Using special media, the organism may take as long as 10 months to grow out, making this an impractical technique for diagnosis and management. Patients develop serological responses to the infecting organism: typically, IgM antibodies can be detected by enzymelinked immunosorbent assay (ELISA) about 2 weeks after infection and are followed by a rise in IgG antibodies. Although reasonably sensitive, ELISAs can be falsely negative in disease less than 2 weeks in duration, and in patients treated early with antibiotics. Falsepositive ELISAs can be seen in the presence of other spirochetal infection such as syphilis, leptospirosis, and relapsing fever. The test may also be positive in rheumatoid arthritis, systemic lupus erythematosus, mononucleosis, and EpsteinBarr virus syndrome. The gold standard for specificity is the Western blot analysis, although there is lack of uniformity in the interpretation of results. Dressler et al3 recommend that at least two common IgM bands be present to confirm diagnosis in early disease, in addition to at least five IgG bands. Other laboratories require only four bands including a specific band, such as 41.
Studies Volume
in mice
2, Number
6. 1995
show that the
organisms are capable of changing antigenicity in prolonged cases, thereby activating differing host immune mechanisms and leading to a picture of autoimmune disease. Human patients with chronic Lyme disease have also been found to have increases in tissue types HLADR2 and HLA-DR4, which are seen in many cases of chronic rheumatoid arthritis. This observation has led to speculation that chronic Lyme arthritis is a kind of reactive arthritis analogous to the association of Reiter’s disease and the other spondyloarthropathies with HLAB27. The implication of this thesis is that therapy for chronic Lyme disease should involve immunemodulating agents, rather than prolonged ~tibiotics.
DISEASE
10-14 days of the tick bite. The most common joint involved is the knee, which can have large eifusions. Arthrocentesis shows a rather bland effusion with few inflammatory cells, but a chronic proliferative synovitis identical to rheumatoid arthritis can be seen in some cases. Assuming the host is not continually infected, the natural history of the arthritis is characterized by chronic relapses and partial remissions, with gradual defervescence. Rarely, the arthritis can progress to joint destruction similar to rheumatoid arthritis. Such patients have been found to have increases in HLA-DRZ, HLA-DR4, and HLA-DW3, but the latter two associations have been disputed.*
NEUROLOGICAL FEATLJRES
Clinical Manifestations DERMATOLOGICAL FEATURES The only pathognomonic sign of Lyme disease is the rash of erythema chronicum migrans, seen in 60-80% of early cases. Typically, the rash begins about 24-48 hours after exposure at the site of the tick bite, usually in the warmer areas of the body such as the axillae and groin. The skin lesion initially looks like a red macule. It expands over hours and days, in an annular fashion, with partial central clearing resembling a smoke ring. These lesions can achieve gigantic proportions, involving almost half the body’s skin surface. Biopsy usually reveals only a mild in~ammatory infiltrate. In about 10% of cases in Europe, a chronic lesion called acrodermatitis chronica atrophicans was reported. Rarer skin lesions include borrelia lymphocytoma and a scleroderma-like lesion.
RHEUMATOLOGICAL FEATURES Patients with untreated Lyme disease usually develop myalgias, arthralgias, and frank arthritis within
Lyme disease can affect both the central and peripheral nervous systems. In early disease, an acute meningoradiculitis is seen, often with evidence of lymphocytosis of the spinal fluid. Cranial nerves, as well as peripheral nerves, can be involved, causing pain and paresis. The most notable ne~ropa~y is Bell’s palsy, which is a common presentation for Lyme disease. Bilateral Bell’s palsy, which is usually seen only in Lyme disease, can occur. Antibodies may be detected in spinal fluid even if they are not present in the sera. Some patients develop a chronic encephalomyelitis, causing fatigue, headaches, memory impairment, di~culty in concentration, irritability, and emotional lability. There can be considerable difficulty in differentiating such symptoms from endogenous depression and/or the fibromyalgia syndrome. In fact, many patients with the latter two conditions are treated for neuroborreliosis even without serological confirmation. Although brain MRI and neurometric EEG studies are usually normal or nondiagnostic in Lyme neuroborreliosis, certain 201
AGUS
studies suggest that st~d~d neuropsychiatric testing is of value in di~erentiati~g this condition from other diseases,5*6 Similar to chronic Lyme arthritis, it is unknown whether chronic neuroborreliosis is due to persistent infection or to autoimmun~ty. Data suggest that molecular mimicry may be operating, in that patients with chronic ~~euroborreli~sis have an antibody response to ~agellin which cross-reacts with neural tissue in a ne~roblastoma cell lines7 A sensitive way to detect minute amounts of bacterial protein is the polymerase chain reaction. This technique has been applied to synovial and ~~rebrospinal fluid but occasionally gives false positive results.’ These findings have been disputed by Keller et al,’ who not only found no evidence of false positives, but observed that the overwhelming number of active cases of neuroborreliosis and active Lyme disease had positive PCR reactions. Until this controversy can be resolved, spinal fluid tests for borreliosis must be interpreted with caution.
CARDIACFEATURES Cardiac involvement with Lyme disease occurs in about 10% of cases, usually presenting with a variable degree of heart block and premature ventricular contractions. Lyme disease should be considered in cases of myocarditis of unclear etiology.” Some patients develop pericarditis and congestive heart failure, Although some patients require a temporary cardiac pacemaker, the ~?~~e~~heIrning majority respond to antibiotic therapy alone within 6 weeks.
Di~erentia~ Diagnosis Lyme disease has protean manifestations, and thus, the differential diagnosis includes many diverse
co~lditions. In general, the presence of the classic eruption of erythema ~h~o~iGurn migrans confirms the diagnosis. In the absence of this finding, connective tissue diseases such as systemic lupus erythematosus, juvenile rheumatoid arthritis, and postviral arthritis have to be excluded by appropriate blood tests. Testing is necessary for rheumatoid factor, ANA, and specific antiviral titers, such as hepatitis B, coxsac&e, influenza, and parvovirus 33.9. Other tick-borne infections, such as Rocky Mountain spotted fever and Q fever, also should be excluded by appropriate serological tests. Brain CT, MRI, and lumbar puncture may be necessary to exclude neurological diseases such as encephalitis, meningitis, and multiple sclerosis, Rheumatic fever can be excluded by history of sore throat and/or ASLO titers, A major entity to exclude is fibromyalgia, a common disorder seen mainly in women between the ages of 30 and 60. Known by many names, such as myofascial pain syndrome, chronic fatigue syndrome, fibrositis, neurasthenia, and temporomandibular joint syndrome, it is far more common than Lyme disease. Symptoms of ~bromyal~ia include fatigue, myalgias, muscle stiEness, sleep disturbance, and cognitive difficulties, all of which have been described in Lyme disease. Depression underlies many of the ~l~nifestat~ons of fibromyalgia, although some patients may have a coexistent connective tissue or metabolic disease, such as rheumatoid arthritis, lupus, or hypothyroidism. Some depressed patients with fibromyalgia are reluctant to acknowledge the ps~~~hia~iG component of their condition and latch on to Lyme disease as a physical basis to explain their illness and disability. Some ~bromyalgia patients respond to mild antidepressants, muscle relaxants, physical therapy, and injection of tender points. Such a response would not be expected to
occur in Lyme disease patients. Some patients with fibromyalgia who happen to have positive Lyme serologies, either because of past infection or by living in, or frequenting, endemic areas, can erroneously incur long, expensive, and often unsuccessful treatments with both oral and parenteral antibiotics. Physicians increasingly may find that their role as a patient advocate pits them against insurance campanies who balk at costly intravenous treatments for such patients. In such cases, primary care physicians should obtain objective consultation from a rheumatologist or infectious disease specialist.
Lyme Disease and Pregnancy Most authorities believe that untreated Lyme infection in pregnancy places the fetus at risk. Abramowsky and colleagues recently described four aborted female fetuses at 1?-23 weeks’ gestation that showed evidence of a nonsypllilitic spiro~hetal infection, possibly Lyme disease, suggesting an ascending infection origi~ati~ in the maternal intestinal tract.” Another study showed that BorreIia burgdorferi can attach to, and pass through, endothelial surfaces, including the amniotic membrane.~’ Nevertheless, in a study of Z&30(1 Lyme disease cases from the endemic area of Westchester County, New York, Strobino et alI3 could End no association between exposure of mothers to Lyme disease prior to conception or during pregnancy with any increased risk of fetal death, prematurity, or excessive fetal malformations. Until the issue can be resolved, all pregnant women with suspected or confirmed Lyme disease should be treated.
Treatment of Lyme Disease Fortunately, Lyme disease is sensitive to most antibiotics, and there is no evidence that resistant strains of Borrelia burgdorferi are emerging. Most regimens consist of a s-week course of oral antibiotics. Doxycycline is the drug of choice, and should be administered in a dose of 100 mg twice daily. However, tetracycline and doxycycline should be avoided in pregnancy and in growing children because they can injure growing bone and teeth. Caution must be used with tetracyclines in sunny climates because of photosensitivity, and patients receiving these drugs should apply sun screens with a high sun protective factor. Oral penicillin or ampicillin is effective in a dose of 500 mg four times a day, especially if augmented with probenecid, but allergy can limit this combination. Alternative treatment with erythromycin 500 mg orally four times a day or clarithromycin 500 mg twice daily is effective, but the latter drug is con~aindi~ated in pregnancy because it can lead to birth defects. For patients with central nervous system involvement, or who fail at least two courses of oral antibiotics, the treatment of choice is intravenous ceftriaxonc in single doses of 1.5-2 g daily. This drug can be administered in the home setting with the aid of a home infusion service, so that patients can carry on a normal lifestyle during the treatment period. The efficacy of prolonged treatment beyond 3 weeks, or repeated intravenous courses, is not proven. The same regimens work as well in cases of cardiac
Volume
2. Number
6, 19%
involvement, which might also include antiarrhythmia drugs, temporary cardiac pacing, and treatment for congestive heart failure. Because autoimmune mechanisms may be responsible for chronic symptoms, particularly musculoskeletal disease, it is rational to treat selected patients with nonsteroidal antiin~ammatory drugs and occasiona joint injection with corticosteroids. An exception must be made for pregnancy, in which case the nonsteroidal drugs are contraindicated. In such cases, supportive measures such as local heat and liniments are useful. Selective joint injection with methylprednisolone is possible in pregnancy, as this drug is inactivated by the placenta. A good second-line drug for nonpregnant patients is hydrcrxychloroquine in doses of 200 mg twice daily for several months, if necessary. If the above guidelines are followed, more than 90% of patients with Lyme disease should make a complete recovery. The remaining patients, particularly those with neuroborreliosis and/or chronic arthritis, face an uncertain prognosis, although permanent disability and death are very rare.
References Sonenshine DE. Biology of ticks, vol. 1. New York: Oxford University Press, 199151-6. Rosa PA, Hogan D, Schwan TG. Polymerase reaction analysesidentify two distinct classesof Barrelia ~urg~or~e~j.J Clin Microbial 1991; 29:524-32. Dressier F, Whalen JA, Rei~hardt BN, et al, Western blotting in the serodiagnosis of Lyme disease, J Infect Dis 1993;167-32. Pfluger KH, ReimersCO, Neubert U,
et al. Lyme borreliosis and possible associationwith HLA antigens. Tissue Antigens 1989;33:375-81. 5. Krupp LB, Mawr D, Schwartz J. et al. Cognitive functioning in late Lyme borreliosis. Arch Neurol 1992;48:1125-9.
6. Kaplan RF, Meadows ME, Vincent LC, Logigian EL, Steere AC. Memory impairment and depression in patients with Lyme en(~ephelopathy. Neurology 1992;42:1263-7. Fikrig E, Berland R, Chen M, William S, Sigal LW, Flavell RA. Serologic responseto the Borrelia burgdorferi flagellin demonstrates an epitope common to a neuroblastoma cell line. Proc Nat1 Acad Sci U S A 1993;90:183-7. Malawista SE, Schoen RT, Moore TL, Dodge DE, White TJ, Persing DH. Failure of multitarget detection of Borrelia burgdorferi-associated DNA sequencesin svnovial fluids of patients with j~~~e~ilerheumatoid arthritis. Arthritis Rheum 1992:3!?: 246-7. 9. Keller TL, Hnlprin JJ, Whitman M. PCR detection of Borrelia burgdorf&i DNA in cerebrospinal fluid of Lyme neuroborreliosis. Neurology 1992;42:32-42.
10. Klein J, Stanek C, I3ittner R, Horvat R, Holzinger C, Clogar D. Lyme borreliosis asa causeof myocarditis and heart muscle disease.Eur Heart J 199l;lZ(Suppl D):73-5. 11. Abramo~~7skyC, deter-Patterson P, Cortinas E. Non-s~~~h~l~ticspirochetosisin secondtrimester fetuses. Pediatr Path01 1991;11:827-38. 12. Szczepanski A, Fune MB, Benach JL. Lane BP, Fleit HB. Interaction between Borreliu hurgdorferi and endothelium in vitro. J Clin Invest 1990;85:1637-47.
13. Strobino BA, Williams CL. Abid S, Chalson R. Spierling P. Lyme diseaseand pregnancy outcome, a prospective study in two thousand patients. Am J Obstet Gynecol 2993; 369~367-74. Address correspondence and reprint requests to Bertrand Agus, MD. 2.51 E. 33rd St.. New York, NY 10016.
203