SEMINARS IN NEUROLOGY-VOI>UME 12, NO. 3 SEPTEMIIRR 1992
Neurologic Lyme Disease
Lylne disease (Lyrne borreliosis) is the most common arthropod-borne infection in the U~iitedStates.' It is a multistage and multisystem disorder produced by a tickborne spirochete bacterium, Borrelia burgdorferi.? Major organs involved include the skin (60 t; SO%),joints (60%),nervous system (10 to 40%), and heart (8 to 20%). Although there are earlier North American cases, the disease was first recognized in 1975 as the cause of epidemic arthritis in Lyme, Connecti~ut."~ T h e etiologic agent was identified in 1983.5.9.burgdorferi was probably imported from Europe to North America, where it has been present in Long Island ticks as far back as the early 1 9 4 0 ~ ~ B. burgdorferi is transmitted by the bite of an infected Ixodes tick.' North American vectors are I. dammini (deer tick) in the East, I. scapularis in the Southeast, and I. pacificus in the West. The Lone Star tick (Amblyomma americanum) and the Arnerican dog tick (Derniacentor variabilis) rnay be additional vectors;" whether flying insects ever transmit the disease is controversial."' Ixodes ticks have a three-stage life cycle (larva, nymph, adult) that lasts 2 to 3 years. Each stage involves one blood meal. B. burgdorferi is transmitted to the parasitized host by salivation o r regurgitation, but the tick must be attached fbr at least 24 to 48 hours." 'licks feed or1 dozens of' mammals, birds, and reptiles, which may serve as reservoirs to infect other ticks. Infected dogs, cats, horses, and cows may become clinically ill. However, larvae and riymphs prefer to feed on the whitefooted mouse (a key reservoir host), whereas adults prefer the white-tailed deer. Humans are accidental hosts. 1,yme disease shares characteristics of other human spirochetal diseases (syphilis, leptospirosis, relapsing fever)." After organisms are inoculated through the skin or mucous membrane, they disseminate to many organs, including the nervous system, where they may sequester to cause a chronic infection. Subsequent clinical disease occurs in stages, punctuated by silent periods. Lyme disease has been divided into early local (stage I), early disseminated (stage II), and late (stage 111) infection,? but these phases show considerable overlap. The clinical spectr;m of Lyme disease continues to expand as more cases are seen, and it has been referred to as the new
"great imitator."1JAlthough this term was criticized in a recent review," it seerns quite appropriate in light of the variety of neurologic syridrornes caused by the infectiorl. The Centers fhr Disease Control (CDC) have tracked 1,yme disease since 198'2. There has been an 18-fold increase in the disease between 1982 and 1989 (497 to 8803 cases)." Almost 8000 cases were reported in 1990, but this is likely an underestimate, since mandatory national reportirig has been in effect only sirice January 1991. Lyme disease has been reported from 46 states, but most cases occur in New ~ o r kNew , Jersey, (:onriecticut, Pennsylvania, and Wisconsin. T h e three niyjor North American foci are the coastal Northeast, the upper Miclwest (Wisconsin and Minnesota), and the Pacific coastal region. 'l'he increase in I.yme disease is not due solely to ireater awareness and testing. Recent epidemiologic studies find that the tick vector is spreading, and the percentage of infected ticks is increasing."' Most neurologists will need to be familiar with Lyme disease, if they have not already encountered it as a clinical problem.
NEUROLOGIC INVOLVEMENT Neurologic involveriient may complicate early or late disease; may cause acute, recurrent, or chronic symptoms; and may be maniftsted as isolated or combined central nervous system (CNS) and peripheral nervous system (PNS) syndromes (Table 1). Certain syndromes are associated with early infection (severe headache, meningitis, cranial nerve palsy, radiculoneuritis, mild encephalitis), whereas others are associated with late (more than 1 year) infection (encephalopathy, chronic polyneuropathy, encephalomyeliti~).~'~~' CENTRAL NERVOUS SYSTEM SYNDROMES
Headache with Meningismus During early infection, patients may develop severe headache and stiff neck, along with constitutional symptoms, with or without multifocal erythema migrans (EM)
Associate Professor of Neurology, Department of Neurology, Wealth Scienccs Center, Slate Univcr-sity of' New York at Stony Brook, Stony Brook, New York Reprint requests: Dr. Coyle, Department of' Neurology, IIealth Scienccs Center, SUNY at Stony Brook, Stony Brook, NY 11794-8121 Copyright 0 1992 by Thieme Medical Publishers, Inc, 381 Park Avenue South, New York, N Y 10016. All rights reserved.
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P. K. Coyle, M.D.
NEUROLOGIC LYME DISEASE-C~YLE
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CNS syndromes Headache with meningismus "Aseptic" meningitis Meningoencephalomyelitis Encephalitis Encephalomyelitis Meningoencephalitis Encephalopathy PNS syndromes Cranial nerve palsy Isolated (nerve VII most common; rarely nerves Il-VI, VIII-X)
Multiple (nerves Il-X) Radiculoneuropathy Radiculitis Mononeuritis Plexopathy Guillain-Barre-like syndrome Polyneuropathy Entrapment neuropathy Muscle disorders Myalgia Myositis Postinfectious syndromes Persistent fatigue Persistent encephalopathy Association not well established Benign intracranial hypertension Cerebrovascular disease Dementia Psychiatric disorders
Meningoencephalomyelitis Mild encephalitis (memory and coricerltration difficulties, mood changes, sleep disturbances) occurs in 20 to 50% of' meningitis patients. 'l'he electroencephalogram (EEG) may show slowing or poor regulation of background activity. More severe encephalitis is a rare complication of late CSF inflammatory changes are much less marked than in meningitis. Neuroimaging may be nonspecif'ically abnormal, with magnetic resonance imaging (MRI) evidence of small or punctate, scattered white matter lesions on T,-weighted images, and, rarely, larger lesions. In one patient brain biopsy showed increased numbers of microglial cells, occasional spirochetes, and little to no inflammation." Encephalomyelitis, with or without meningeal involvement, is a rare complication of late infection in North Arnerica,2:4 'L~I.:~IIClinical presentations of Lyme encephalomyelitis include transverse myelitis, hemiparesis, spastic paraparesis, movement disorders, and cerebellar syndromes. Since the course is gradually progressive, patients can be misdiagnosed as having multiple sclerosis (MS) or CNS neoplasm. CSF abnormalities in North American patients have not been striking. They iriclude rrlilcl mononuclear pleocytosis in 4076, elevated protein in 330/(,,and oligoclonal bands or intrathecal IgG production in less than a third. Only 40% show production of intrathecal anti-B. burgdorferi antibodies. CSF myelin basic protein and VDRI. are always negative.
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Table 1. Neurologic Syndromes Associated with Lyme Disease
Encephalopathy skin lesions. Cerebrospinal fluid (CSF) is normal, and most patients lack anti-B. burgdorferi antibodies because it is too early i11 the infection. 'l'his syndrome is probably a premeningitis stage, since experimental studies cletect spirochete corriponerits within the noninflammatory CSF.'""'
Meningitis Meningitis may develop when spirochetes disseminate and invade the CNS." T h e clinical picture and CSF findings suggest a viral or aseptic process, and symptoms may be mild. Meningitis may be acute, subacute, relapsing, or chronic. .I'tie rriost common syrnptorrl is fluctuatirig headache (90%')with mild stiff' neck (50% or more). Nausea, vomiting, low-grade fever, and photophobia are less common. Suggestive features include facial nerve palsy (50% or less), radicular symptoms (32%), and joint problems (24%). CSF shows mononuclear pleocytosis (generally less than 200 white blood cells [WBC]/mn13), with occasional plasma cells and atypical lymphocytes. Protein is elevated in 15 to 53%, but is generally less than 100 mgidl. Less than 50% of patients have oligoclonal bands, an increased immunoglobulin G (IgG) index, or intrathecal IgG production. A decreased CSF glucose concentration is unusual (less than 15%). Intrathecal anti-B. burgdorferi antibody production is present in 70 to 90~7~,2".~:~ Untreated meningitis will resolve over weeks to months, but may relapse. With appropriate anribiotics, there is a clinical and CSF response within days2'
Late infection is associated with a mild to moderate subacute encephalopathy characterized clinically by problems with memory arid cognition.lK~"~"Profound fatigue is a frequent accompaniment. Neuropsychologic testing will document objective deficits, but neuroirnaging and EEG are generally normal. CSF pleocytosis (less than 40 WBC/mm3) occurs in 4 to 5%, elevated protein (less than 100 mgldl) in 17 to 46%, and intrathecal antiB. burgdorferi antibody production in less than 50%. Oligoclonal bands and intrathecal IgG production are rare (less than 5%).
PERIPHERAL NERVOUS SYSTEM SYNDROMES Cranial Nerve Palsy Isolated cranial nerve palsy (occasionally multiple cranial nerves are involved) occurs in early infection when the initial serology may be negative. There may be occult meningitis, with inflammatory CSF changes, or normal CSF. Facial nerve palsy occurs in 11% of Lyme disease cases, accounts for 80 to 90% of Lynie-related cranial neuropathies, and is bilateral in 25 to 30%.17T h e natural course is similar to idiopathic Bell's palsy, with spontaneous resolution within 1 to 2 months. Convalescent titers done 6 to 8 weeks later are positive for antiB. burgdorferi antibodies (if no treatment is given to blunt the immune response). Optic nerve involvement by B. burgdorferi may present as disc edema, ischemic optic neuropathy, or optic neuritis. There may be other signs of CNS disease or an isolated optic nerve lesion. In a recent study from an endemic area, 20% of optic neu-
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SEMINARS IN NEUKOLOGY
Radiculoneuropathy Radiculoneuritis is much more common in Europe (Bannwarth's syndrome) than in North America. Following dissemination, there may be an asymmetrical, frequently painful radiculitis with dermatomal sensory and myotomal motor abnormalities. Variations include mononeuritis o r mononeuritis multiplex, brachial or lumbosacral plexopathy, and a Guillain-Barre-like syndrome.",""" There is mild CSF pleocytosis with elevated protein, and evidence on neurophysiologic testing of widespread nerve and root changes consistent with a multifocal axonal neuropathy. Radiculorleuropathy features may coincide with clinical meningitis and cranial neuropathy. A very mild chronic axonal polyneuropathy has been noted in about 36% of' svmptomatic late infer, ti on^.^^ T h e typical presentation is of intermittent tingling limb paresthesias with little objective sensory loss. There is subjective and objective (neurophysiologic) improvement with antibiotic therapy. In addition, 25% of' late infections have a mild median nerve entrapment (carpal tunnel) syndrome on neurophysiologic testing, which also improves with antibiotic treatment.'"
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Muscle Disorders Myalgias niay occur during spirochetal dissemination as part of the flulike syndronie. A few cases of myositis have been described in Lyme disease, but muscle involvement is much less common than other nervous system involvement." '" Patients have weakness arid niuscle pain, with occasional modest muscle enzyme (creatine kinase [CK]) elevation. Muscle biopsy shows interstitial and focal nodular myositis, with infiltrates of lymphocytes and occasional plasma cells. Spirochetes have been demonstrated in musclc, and patients respond to antibiotic treatment.
SEPTEMBER 1992
therapy. l'his is now less common in patients with early infection who receive prompt treatment with the newer antibiotic regimens. In a recent study only 8% of treated EM patients continued to have fatigue for u p to 6 ~ n o n t h s However, .~ 16% of treated patients with multiple EM o r constitutional symptotns had persistent fatigue. In late infections, therapy with penicillin has been associated with a higher rate of persistent fatigue than ceftriaxone t h e r a ~ y . ~ "
Persistent Encephalopathy Postinfcctious f'atigue is often accompanied by cognitive complaints (problems with memory and concentration). When patients undergo neuropsychologic testing, 60% have objective cognitive deficits.44 It is not known whether this syndrome reflects a persistent infection.
OTHER SYNDROMES Although the case reports in the literature are not sufficient to establish a causal relationship and to identify the full spectrum of involvement, Lyrne disease has been associated with benign intracranial hypertension, cerebrovascular disease, dementia, and psychiatric syndromes. A pseudotumor-like clinical syndrome has been described in children and adolescents infected with B. b~rgdorferi.~""CSF gerierally shows abnormalities in addition to increased pressure (mild pleocytosis, protein cleva~iori,elevated CSF Lyme antibody index). Cases of stroke and vasculopathy o r vasculitis have been reported, but most are from E u r ~ p e .These ~ ~ , ~stroke ~ patients have abriorrr~alCSF and may have a protracted and stepwise clinical course. Ilementia-like features may be seen in severe cases of' Lyme encephalomyelitis and encepl~alopathy."'~~" Finally, prominent psychiatric symptoms have occasionally occurred in neurologic Lyme patients.?"w,~n,uSevere anorexia, apathy, depression, emotional lability, euphoria, hallucinatior~s,arld personality changes have been reported. In most cases there were additional neurologic features, but in some cases a primary psychiatric condition was suspected.
POSTZNFECTZOUS SYNDROMES Postinfcctious Lyme syndromes refer to nonspecific symptoms that persist for months to a year o r more following treatment. These symptoms include fatigue and malaise, concentration and memory problems, headache, arid musculoskeletal complaints similar to fibromyalgia syndrome. Predisposing factors are late-stage infection, delayed treatment, severe systerriic features, and a Jarisch-Herxheimer reaction to antibiotic treatment.
PATHOGENESIS
Three merhanisrns might explain how B. burgdorferi causes neurologic disease. Disease could result from persistent neural infection, from a spirochete-triggered specific immune response directed against neural tissue, o r fro~rla spirochete-triggered nonspecific inflammatory process with indirect effects on neural tissue. There are data to support all three nieclianisnis, and it is likely that the various neurologic syndromes in Lyrne disease have different underlying etiologies. Persistent infection is likely when there is a sustained immune response with Persistent Fatigue the late appearance of antibodies against new antigens, Fatigue is one of the most common symptoms of' o r a late IgM response."l Spirochetes have also been Lyme disease and occurs in both early and late i n f e ~ - found in various bodily organs in late infection cases. tions. Whether severe fatigue alone, eithcr persistent or llowever, neurologic infections are not associated with episodic, can be a manifestation of late infection is con- much structural damage. T h e limited rleuropathologic troversial." However, in certain patients fatigue persists changes in Lyme disease indicate that spirochetes are for months following presumably adequate antibiotic quite sparse within infected CNS and muscle tissue and
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ritis cases had evidence of recent B. burgdorferi infection ."'
VOLUME 12, NUMBER 3
DIAGNOSIS NATIONAL SURVEILLANCE CASE DEFINITION I'he CDC case definition for Lyme disease requires a patient to have EM at least 5 cm in diameter, o r one o r morc latc disease features (neurologic, rheunratologic, cardiac) with laboratory confirniation.'%aboratory confirmation requires isolation of spirochete, detection of specific antibodies in serum or CSF, o r a rising antibody titer on acute and convalescent serum samples. In reality, these arc fairly stringent criteria that will not be fulfilled by a proportion of patients with true Lyme disease. T h e current practical diagnosis of Lyme disease is clinical, with suppordve laboratory data. Patients should have a consistent clinical picture, with probable cxposure to B. burgdorfcri. Exposure can be docurr~enteclby detection of specific antibodies, but occasional seronegative cases d o occur and the presence of antibodies is riot invariable."'.":' None of the tests routinely available can confirm active infection.
CLINICAL CRITERIA Four clinical fcatures support a diagnosis of Lyrne disease, and one establishes the diagnosis (Table 2). EM is a pathognomonic marker for Lyrrre disease. Unfortunately, this rash is seen in only SO to 80% of patients. T h e expanding erythematous skin lesion occurs at the tick bite site 8 to 9 (range, 2 to 28) days after the bite.h4Thc E M lesion is single; rrl~lltiplelesions indicate dissemination. Differential diagnosis includes erysipelas, fixed drug reaction, contact dermatitis, and insect bite. Although tick bite o r exposure preceding onset of neurologic disease is suggestive, less than 50% of Lyme disease patients give this history. When the tick strain is unknown, it is even less helprul. T h e Ixodes tick is quite small, often described as poppyseed-sized, compared with the much largcr and very common dog tick. Kesiderrce in, o r travel to, an errderrlic area increases the likelihood of Lyme disease. It is difficult to implicate B. burgdorferi in regions with little o r no endemic Lyme disease.
Table 2.
Diagnosis of Neurologic Lyme Disease
Clinical
Erythema migrans (EM) Tick bite or exposure Endemic area Extraneural involvement Suggestive neurologic syndrome
Laboratory
Current Specific antibody (ELISA) Nonspecific blood tests (sedimentation rate, IgM, liver function tests) CSF studies; including CSF Lyme antibody index Biopsy Research Antigen assays Cell-mediated immunity assays Immune complex assays Nucleic acid (PCR) assays
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cannot even be found in nerve. Inflammation is variable as is blood vessel involvement. This has raised the possibility that indirect factors are involved."'" Evidence for immune and inflammatory processes in neuroborreliosis includes: (1) detection of immune complexes and strong (2) autoantibodies to T-cell responses within CSF;54,55 neural components (including myelin, myelin basic protein, and n e u r o n ~ ) ; ~ ' . " ~cross-reactivity ~~3) of Lyme antibodies with neural tissue (including peripheral myelin, schwann cells, and ax on^);^^." (4) CSF T-cell lines reactive to myelin basic protein, peripheral myelin, galactocerebroside, and cardiolipin;"" and (5) detection of neopterin (an activated macrophage product) in CSF.6' Identification of the mcchanism of neural injury in Lyme disease would help guide therapy. Antibiotics may not be the only answer. In particular, encephalopathy and the postinfectious syndromes may involve processes that d o not directly relate to the spirochete and require a different approach.
Since Lyme disease is a systemic infection, extraneural involvement offers an important diagnostic clue. Neurologic disease that fbllows an acute flulike illness, associated with joint abnornralities (prominent arthralgias, episodic large joint swelling, oligoarticular arthritis, temporo~nandibularjoint pain), cardiac disease (atrioventricular conduction block, pericarditis, myocarditis), o r eye disease (conjunctivitis, uveitis) should suggest neuroborreliosis. Finally, although the full neurologic spectrum of North American Lymc disease has not yet been described, it is clear that certain syndromes are common. Lyme disease should be in the differential diagnosis of patients with unilateral o r bilateral Bell's palsy, aseptic rr~erringitis,atypical Guillain-Barri. syndrome, and mild
LABORATORY CRITERIA: CURRENT TESTS
Specific Antibody Specific antibody documents exposure to B. burgdorferi, but not active infection. In endemic areas a significant proportion of the population is antibody positive. Since half of infections are asymptomatic and never lead to disease, the fact that a patient is seropositive does not indicate that the concurrent neurologic problem is due to Lymc disease. Other eviclence (either clinical, or frorrr C:SP studies and an ancillary test) is needed to support a diagnosis of Lyme disease. Antibody is generally measured by enzyme-linked immunosorbent assay (ELISA). This test has superseded indirect immunofluorescence assays (IFA), which are labor-intensive and subjective, and require great expertise in interpretation. A number of conlniercial ELISA kits are available, but there are significant quality control ~woblenlsand interlaboratory diPferences."-" Tests are not standardized. They look at different isotypes and use diflerent antigen targets, different controls, and different mcthods to determine positive and negative results. In particular, samples with low levels of positive antibodies are most likely to be missed. Therefore it becomes important to use a reliable laboratory to assay for Lynie antibodies. Major causes for a false-negative serology are an insensitive assay, early stage infection (it takes several 203
VO1,UME 12, NUMBER 3
SEPTEMKh;K 1992
weeks to generate sufficient quantities of specific antiTable 3. CSF Studies in Suspected Lyme Disease body to be detectable) and early antibiotic treatment Routine Cell count, cytology, glucose, protein (which may abort the typical humlral response). lntrathecal production of antiSeveral major B. burgdorferi antigens are shared by B.burgdorferi antibodies (CSF Lyme other spirochetes and bacteria. For example, both Trepantibody index) onema pallidum, the causative organism of syphilis, and VDRL lntrathecal IgG production or IgG index B. burgdorferi may cause a positive fluorescent trepoOligoclonal bands nernal antibody absorption test (FTA-ABS). However, nontreponemal tests, such as the rapid plasma reagin Experimental B.burgdorferi antigens, culture, nucleic acids (PCR) and VDRL, are typically negative in Lyme d i ~ e a s e . ~ ' Autoantibodies, autoreactive T cells Syphilis arid other spirochetal diseases rriay give a falseSpecific and nonspecific immune compositive Lyme EI,ISA serology. Nonpathogenic oral spiplexes rochetes can also give false-positive Lyme serologies. This is particularly likely when a patient has known periodontal disease or has had recent dental manipulation. In such cases, however, the aritihody titer to the specific of proportional specific antibody in paired CSF and sespirochete will always be much higher than the antibody rum samples.y2-"'-" When the CSF 1,yme antibody index titer to B. burgdorferi. False-positive serologies have also is elevated, it confirms neurologic Lyme disease, but it is been noted with major bacterial infections (such as en- not invariably elevated. I t niay also persist for some time docarditis and sepsis), rickettsia1 infections, Epstein-Barr after appropriate treatment. With-current, reliable asantibodies are alr~lostnever detected in CSF , Lvme , viral infection (with polyclonal B-cell activation), hyper- says. when a patient is seronegative. Other suggestive CSF gammaglobulinemia, HIV- 1 infection, and autoimmune disorders with high autoantibody titers. In CSF, false- findings are mild mononuclear plcocytosis (particularly positive reactions have been reported with neurosyphilis, with plasma cells and atypical lymphocytes) and elevated tuberculous nieriingitis, and varicella-zoster meningo- protein. T h e exwerimental CSF studies listed in Table 3 are of great interest, but at the present tirne have limited encephalitis. availability. Western blot for Lvme antibodies is not currentlv standardized and involves extremely subjective interpretation. Unlike the situation in AIDS. it cannot be used as Ancillary Tests ari absolute confirmatory antibody test. It is probably most helpful to identify a fhlse-positive ELISA result."!' Helpful ancillary tests include nerve conduction In such cases, western blot shows that antibodies are restudies (to document multifocal axonal rieuropathy) and acting with nonspecific antigens, rather than B. burgneuroirnagirig. In patients with neuropathy, sural nerve dorferi-specific antigens. biopsy may show perivascular inflammatory infiltrate, especially within the epineurium, with axonal loss; spirochetes are not present. Evoked potential tests are genNonspecific Blood Tests erally normal, and EEG tends to be abnormal only in the encephalitis syndrome. Routine blood tests are rarely helpful. Almost 90% of patients with active disease have circulating immune complexes, but multiple assays must be used and the Culture findings are entirely nonspecific. I n early diseasc, patients nlay have elevated sedimentation rate (50%), inUnlike most infectious organisms, B. burgdorferi is creased IgM (33%), arid mild liver enzyme elevations (19%). Occasional patients have low levels of autoanti- virtually inrpossible to culture. T h e organism has a long dihodies (antinuclear antibodies, cryoglobulins, rheuma- viding time (q 12 hours), is fastidious, and requires special toid factor, and anticardiolipin antibodies). IgM anticar- media, prolonged incubation, and meticulous detail. The diolipin antibodies have been increased in some cases yield of culture attempts is generally less than 10%. with neurologic syndromes.
Biopsy Cerebrospinal Fluid Studies
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CSF is generally abnormal in CNS 1,yme syndromes (except for encephalopathy), and may be abnormal in certain PNS syndromes (those that involve the nerve root, o r in which occult meningitis is the cause of cranial neuropathy). However, normal CSF does not exclude neurologic Lyme disease. CSF studies for suspected Lyme disease are outlined in Table 3. Intrathecal production of specific antibodies (elevated CSF Lyme antibody index) is the most helpful CSF study for neuroborreliosis. It reflects a localized immune response caused by CNS spirochete invasion. There are several ways to d o this assay, but all irivolve a conlparison
Spirochetes have been shown in various tissues, including brain, meninges, muscle, retina, myocardium, bone, synoviurn, liver, arid spleen. However, routine biopsy is not helpful. Once past the early dissemination stage, spirochetes are sparsely distributed and limited in number within infected tissue. Since staining techniques are very susceptible to artifact, biopsies require expert. interpretation. T h e only high-yield biopsy site has been the edge of the expanding EM lesion.
LABORATORY CRITERIA: RESEARCH TESTS T h e research studies listed in Table 2 can aid the diagnosis of Lyme disease, but they are not standardized
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SEMINAKS IN NEUROLOGY
NEUKOLOGIC LY Mk: I)ISF,ASE-C~YLE
CONFOUNDING DIAGNOSES: MULTIPLE SCLEROSIS MS is mentioned frequently as an alternative diagnosis ro neurobon-eliosis. MS patients d o not have extraneural discasc features. MS patients have abnormal brain or spinal MKI (go%), abnormal evoked potentials (50%), CSF oligoclonal bands (YO to Y5%), intrathecal IgG production (70 to go%), and CSF myelin basic protein. Neuroborreliosis patients havc stereotyped syndromes, extraneural features, PNS involvement, more prominent CSF pleocytosis and protein elevation, arid an clcvatcd CSF Lyme antibody index. It is possible for a patient to have'both diagnoses. In endemic areas sorrle
MS patients will become infected and seroconvert. Since infections may trigger MS relapses, an MS patierit who is systemically infected could have a disease flarc-up that is not due to direct C:NS inf'ection. Patients with MS who have a true CNS irifectiorl should show an elevated (;SF Lyme antibody index with or without pleocytosis and increased protein. 'l'hey require antibiotics, but it will not change their primary diagnosis.
THERAPY AND PROGNOSIS T h e approach to therapy in Lyme disease should be aggressive treatrnent as early as possible. Parenteral antibiotics are given for neurologic Lyme disease associated with CSF abnorr~ialities."~ CNS 1,yme syndromes, regardless of hl, Frens OB. Pseudotumor cerebri syndrorne 70. associatccl with L y ~ n edisease. Am J Ophthalmol 1989; 107:81-2 1 7 . Brogan GX, Holnan CS, Viccellio P. T h e enlarging clinical spectruni of 1.yme disease: I.yme (:erebra1 vasculitis, a new disease entity. Ann Ernerg Med 1990;19:572-6 71. 48. M a y EF, Jabbari B. Stroke in neurohorreliosis. Stroke 1990;2 1 : 1232-5 49. lleik 1.. BUI-gdot-ferW, Donaldson JG. Neurologic abnor72. nlalities in 1.yme disease without erythema chronicurn tnig~.ans.Am J Med 1986;81:73-8 50. Carlsson M , Pvlalnivall R-E. Rorrelia infection as a cause of presenile dementia. Laricet 1987;2:798 73. 51. IN, Halperin J J , Dattwyler RJ. Lyrrre 111eni11goencephalitis: report of a severe, penicillin-resistant casc. Arthritis Rheum 1987;30:705-8 79. Edelrrian R. Perspective o n the development of vaccines against Lymc discasc. Vaccine 1991;9:531-2
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74. Dressler F, Yoshlnari N H , Steere AC. T h e T-cell proliferative assay in the diagnosis of' Lyme diseasc. Anri Intern Med 1991; 155:593-9 75. Kahn DW, Malawista SE. Lyme disease: I-ecommendations for diagnosis and treatment. Ann Intern Med 1991;114:472-81 76. Luft B.1, Gorevic PD, Halperin .]I, et al. A perspective on the treatment of L y ~ n eborreliosis. Rev Infect Dis 1989;l l:S1518-25
VOI,UME: 12, N U M B E R 3 SEPTI?'MBER 1992
Neurologic Lyme Disease
Lylne disease (Lyrne borreliosis) is the most common arthropod-borne infection in the U~iitedStates.' It is a multistage and multisystem disorder produced by a tickborne spirochete bacterium, Borrelia burgdorferi.? Major organs involved include the skin (60 t; SO%),joints (60%),nervous system (10 to 40%), and heart (8 to 20%). Although there are earlier North American cases, the disease was first recognized in 1975 as the cause of epidemic arthritis in Lyme, Connecti~ut."~ T h e etiologic agent was identified in 1983.5.9.burgdorferi was probably imported from Europe to North America, where it has been present in Long Island ticks as far back as the early 1 9 4 0 ~ ~ B. burgdorferi is transmitted by the bite of an infected Ixodes tick.' North American vectors are I. dammini (deer tick) in the East, I. scapularis in the Southeast, and I. pacificus in the West. The Lone Star tick (Amblyomma americanum) and the Arnerican dog tick (Derniacentor variabilis) rnay be additional vectors;" whether flying insects ever transmit the disease is controversial."' Ixodes ticks have a three-stage life cycle (larva, nymph, adult) that lasts 2 to 3 years. Each stage involves one blood meal. B. burgdorferi is transmitted to the parasitized host by salivation o r regurgitation, but the tick must be attached fbr at least 24 to 48 hours." 'licks feed or1 dozens of' mammals, birds, and reptiles, which may serve as reservoirs to infect other ticks. Infected dogs, cats, horses, and cows may become clinically ill. However, larvae and riymphs prefer to feed on the whitefooted mouse (a key reservoir host), whereas adults prefer the white-tailed deer. Humans are accidental hosts. 1,yme disease shares characteristics of other human spirochetal diseases (syphilis, leptospirosis, relapsing fever)." After organisms are inoculated through the skin or mucous membrane, they disseminate to many organs, including the nervous system, where they may sequester to cause a chronic infection. Subsequent clinical disease occurs in stages, punctuated by silent periods. Lyme disease has been divided into early local (stage I), early disseminated (stage II), and late (stage 111) infection,? but these phases show considerable overlap. The clinical spectr;m of Lyme disease continues to expand as more cases are seen, and it has been referred to as the new
"great imitator."1JAlthough this term was criticized in a recent review," it seerns quite appropriate in light of the variety of neurologic syridrornes caused by the infectiorl. The Centers fhr Disease Control (CDC) have tracked 1,yme disease since 198'2. There has been an 18-fold increase in the disease between 1982 and 1989 (497 to 8803 cases)." Almost 8000 cases were reported in 1990, but this is likely an underestimate, since mandatory national reportirig has been in effect only sirice January 1991. Lyme disease has been reported from 46 states, but most cases occur in New ~ o r kNew , Jersey, (:onriecticut, Pennsylvania, and Wisconsin. T h e three niyjor North American foci are the coastal Northeast, the upper Miclwest (Wisconsin and Minnesota), and the Pacific coastal region. 'l'he increase in I.yme disease is not due solely to ireater awareness and testing. Recent epidemiologic studies find that the tick vector is spreading, and the percentage of infected ticks is increasing."' Most neurologists will need to be familiar with Lyme disease, if they have not already encountered it as a clinical problem.
NEUROLOGIC INVOLVEMENT Neurologic involveriient may complicate early or late disease; may cause acute, recurrent, or chronic symptoms; and may be maniftsted as isolated or combined central nervous system (CNS) and peripheral nervous system (PNS) syndromes (Table 1). Certain syndromes are associated with early infection (severe headache, meningitis, cranial nerve palsy, radiculoneuritis, mild encephalitis), whereas others are associated with late (more than 1 year) infection (encephalopathy, chronic polyneuropathy, encephalomyeliti~).~'~~' CENTRAL NERVOUS SYSTEM SYNDROMES
Headache with Meningismus During early infection, patients may develop severe headache and stiff neck, along with constitutional symptoms, with or without multifocal erythema migrans (EM)
Associate Professor of Neurology, Department of Neurology, Wealth Scienccs Center, Slate Univcr-sity of' New York at Stony Brook, Stony Brook, New York Reprint requests: Dr. Coyle, Department of' Neurology, IIealth Scienccs Center, SUNY at Stony Brook, Stony Brook, NY 11794-8121 Copyright 0 1992 by Thieme Medical Publishers, Inc, 381 Park Avenue South, New York, N Y 10016. All rights reserved.
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P. K. Coyle, M.D.
NEUROLOGIC LYME DISEASE-C~YLE
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CNS syndromes Headache with meningismus "Aseptic" meningitis Meningoencephalomyelitis Encephalitis Encephalomyelitis Meningoencephalitis Encephalopathy PNS syndromes Cranial nerve palsy Isolated (nerve VII most common; rarely nerves Il-VI, VIII-X)
Multiple (nerves Il-X) Radiculoneuropathy Radiculitis Mononeuritis Plexopathy Guillain-Barre-like syndrome Polyneuropathy Entrapment neuropathy Muscle disorders Myalgia Myositis Postinfectious syndromes Persistent fatigue Persistent encephalopathy Association not well established Benign intracranial hypertension Cerebrovascular disease Dementia Psychiatric disorders
Meningoencephalomyelitis Mild encephalitis (memory and coricerltration difficulties, mood changes, sleep disturbances) occurs in 20 to 50% of' meningitis patients. 'l'he electroencephalogram (EEG) may show slowing or poor regulation of background activity. More severe encephalitis is a rare complication of late CSF inflammatory changes are much less marked than in meningitis. Neuroimaging may be nonspecif'ically abnormal, with magnetic resonance imaging (MRI) evidence of small or punctate, scattered white matter lesions on T,-weighted images, and, rarely, larger lesions. In one patient brain biopsy showed increased numbers of microglial cells, occasional spirochetes, and little to no inflammation." Encephalomyelitis, with or without meningeal involvement, is a rare complication of late infection in North Arnerica,2:4 'L~I.:~IIClinical presentations of Lyme encephalomyelitis include transverse myelitis, hemiparesis, spastic paraparesis, movement disorders, and cerebellar syndromes. Since the course is gradually progressive, patients can be misdiagnosed as having multiple sclerosis (MS) or CNS neoplasm. CSF abnormalities in North American patients have not been striking. They iriclude rrlilcl mononuclear pleocytosis in 4076, elevated protein in 330/(,,and oligoclonal bands or intrathecal IgG production in less than a third. Only 40% show production of intrathecal anti-B. burgdorferi antibodies. CSF myelin basic protein and VDRI. are always negative.
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Table 1. Neurologic Syndromes Associated with Lyme Disease
Encephalopathy skin lesions. Cerebrospinal fluid (CSF) is normal, and most patients lack anti-B. burgdorferi antibodies because it is too early i11 the infection. 'l'his syndrome is probably a premeningitis stage, since experimental studies cletect spirochete corriponerits within the noninflammatory CSF.'""'
Meningitis Meningitis may develop when spirochetes disseminate and invade the CNS." T h e clinical picture and CSF findings suggest a viral or aseptic process, and symptoms may be mild. Meningitis may be acute, subacute, relapsing, or chronic. .I'tie rriost common syrnptorrl is fluctuatirig headache (90%')with mild stiff' neck (50% or more). Nausea, vomiting, low-grade fever, and photophobia are less common. Suggestive features include facial nerve palsy (50% or less), radicular symptoms (32%), and joint problems (24%). CSF shows mononuclear pleocytosis (generally less than 200 white blood cells [WBC]/mn13), with occasional plasma cells and atypical lymphocytes. Protein is elevated in 15 to 53%, but is generally less than 100 mgidl. Less than 50% of patients have oligoclonal bands, an increased immunoglobulin G (IgG) index, or intrathecal IgG production. A decreased CSF glucose concentration is unusual (less than 15%). Intrathecal anti-B. burgdorferi antibody production is present in 70 to 90~7~,2".~:~ Untreated meningitis will resolve over weeks to months, but may relapse. With appropriate anribiotics, there is a clinical and CSF response within days2'
Late infection is associated with a mild to moderate subacute encephalopathy characterized clinically by problems with memory arid cognition.lK~"~"Profound fatigue is a frequent accompaniment. Neuropsychologic testing will document objective deficits, but neuroirnaging and EEG are generally normal. CSF pleocytosis (less than 40 WBC/mm3) occurs in 4 to 5%, elevated protein (less than 100 mgldl) in 17 to 46%, and intrathecal antiB. burgdorferi antibody production in less than 50%. Oligoclonal bands and intrathecal IgG production are rare (less than 5%).
PERIPHERAL NERVOUS SYSTEM SYNDROMES Cranial Nerve Palsy Isolated cranial nerve palsy (occasionally multiple cranial nerves are involved) occurs in early infection when the initial serology may be negative. There may be occult meningitis, with inflammatory CSF changes, or normal CSF. Facial nerve palsy occurs in 11% of Lyme disease cases, accounts for 80 to 90% of Lynie-related cranial neuropathies, and is bilateral in 25 to 30%.17T h e natural course is similar to idiopathic Bell's palsy, with spontaneous resolution within 1 to 2 months. Convalescent titers done 6 to 8 weeks later are positive for antiB. burgdorferi antibodies (if no treatment is given to blunt the immune response). Optic nerve involvement by B. burgdorferi may present as disc edema, ischemic optic neuropathy, or optic neuritis. There may be other signs of CNS disease or an isolated optic nerve lesion. In a recent study from an endemic area, 20% of optic neu-
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SEMINARS IN NEUKOLOGY
Radiculoneuropathy Radiculoneuritis is much more common in Europe (Bannwarth's syndrome) than in North America. Following dissemination, there may be an asymmetrical, frequently painful radiculitis with dermatomal sensory and myotomal motor abnormalities. Variations include mononeuritis o r mononeuritis multiplex, brachial or lumbosacral plexopathy, and a Guillain-Barre-like syndrome.",""" There is mild CSF pleocytosis with elevated protein, and evidence on neurophysiologic testing of widespread nerve and root changes consistent with a multifocal axonal neuropathy. Radiculorleuropathy features may coincide with clinical meningitis and cranial neuropathy. A very mild chronic axonal polyneuropathy has been noted in about 36% of' svmptomatic late infer, ti on^.^^ T h e typical presentation is of intermittent tingling limb paresthesias with little objective sensory loss. There is subjective and objective (neurophysiologic) improvement with antibiotic therapy. In addition, 25% of' late infections have a mild median nerve entrapment (carpal tunnel) syndrome on neurophysiologic testing, which also improves with antibiotic treatment.'"
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Muscle Disorders Myalgias niay occur during spirochetal dissemination as part of the flulike syndronie. A few cases of myositis have been described in Lyme disease, but muscle involvement is much less common than other nervous system involvement." '" Patients have weakness arid niuscle pain, with occasional modest muscle enzyme (creatine kinase [CK]) elevation. Muscle biopsy shows interstitial and focal nodular myositis, with infiltrates of lymphocytes and occasional plasma cells. Spirochetes have been demonstrated in musclc, and patients respond to antibiotic treatment.
SEPTEMBER 1992
therapy. l'his is now less common in patients with early infection who receive prompt treatment with the newer antibiotic regimens. In a recent study only 8% of treated EM patients continued to have fatigue for u p to 6 ~ n o n t h s However, .~ 16% of treated patients with multiple EM o r constitutional symptotns had persistent fatigue. In late infections, therapy with penicillin has been associated with a higher rate of persistent fatigue than ceftriaxone t h e r a ~ y . ~ "
Persistent Encephalopathy Postinfcctious f'atigue is often accompanied by cognitive complaints (problems with memory and concentration). When patients undergo neuropsychologic testing, 60% have objective cognitive deficits.44 It is not known whether this syndrome reflects a persistent infection.
OTHER SYNDROMES Although the case reports in the literature are not sufficient to establish a causal relationship and to identify the full spectrum of involvement, Lyrne disease has been associated with benign intracranial hypertension, cerebrovascular disease, dementia, and psychiatric syndromes. A pseudotumor-like clinical syndrome has been described in children and adolescents infected with B. b~rgdorferi.~""CSF gerierally shows abnormalities in addition to increased pressure (mild pleocytosis, protein cleva~iori,elevated CSF Lyme antibody index). Cases of stroke and vasculopathy o r vasculitis have been reported, but most are from E u r ~ p e .These ~ ~ , ~stroke ~ patients have abriorrr~alCSF and may have a protracted and stepwise clinical course. Ilementia-like features may be seen in severe cases of' Lyme encephalomyelitis and encepl~alopathy."'~~" Finally, prominent psychiatric symptoms have occasionally occurred in neurologic Lyme patients.?"w,~n,uSevere anorexia, apathy, depression, emotional lability, euphoria, hallucinatior~s,arld personality changes have been reported. In most cases there were additional neurologic features, but in some cases a primary psychiatric condition was suspected.
POSTZNFECTZOUS SYNDROMES Postinfcctious Lyme syndromes refer to nonspecific symptoms that persist for months to a year o r more following treatment. These symptoms include fatigue and malaise, concentration and memory problems, headache, arid musculoskeletal complaints similar to fibromyalgia syndrome. Predisposing factors are late-stage infection, delayed treatment, severe systerriic features, and a Jarisch-Herxheimer reaction to antibiotic treatment.
PATHOGENESIS
Three merhanisrns might explain how B. burgdorferi causes neurologic disease. Disease could result from persistent neural infection, from a spirochete-triggered specific immune response directed against neural tissue, o r fro~rla spirochete-triggered nonspecific inflammatory process with indirect effects on neural tissue. There are data to support all three nieclianisnis, and it is likely that the various neurologic syndromes in Lyrne disease have different underlying etiologies. Persistent infection is likely when there is a sustained immune response with Persistent Fatigue the late appearance of antibodies against new antigens, Fatigue is one of the most common symptoms of' o r a late IgM response."l Spirochetes have also been Lyme disease and occurs in both early and late i n f e ~ - found in various bodily organs in late infection cases. tions. Whether severe fatigue alone, eithcr persistent or llowever, neurologic infections are not associated with episodic, can be a manifestation of late infection is con- much structural damage. T h e limited rleuropathologic troversial." However, in certain patients fatigue persists changes in Lyme disease indicate that spirochetes are for months following presumably adequate antibiotic quite sparse within infected CNS and muscle tissue and
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ritis cases had evidence of recent B. burgdorferi infection ."'
VOLUME 12, NUMBER 3
DIAGNOSIS NATIONAL SURVEILLANCE CASE DEFINITION I'he CDC case definition for Lyme disease requires a patient to have EM at least 5 cm in diameter, o r one o r morc latc disease features (neurologic, rheunratologic, cardiac) with laboratory confirniation.'%aboratory confirmation requires isolation of spirochete, detection of specific antibodies in serum or CSF, o r a rising antibody titer on acute and convalescent serum samples. In reality, these arc fairly stringent criteria that will not be fulfilled by a proportion of patients with true Lyme disease. T h e current practical diagnosis of Lyme disease is clinical, with suppordve laboratory data. Patients should have a consistent clinical picture, with probable cxposure to B. burgdorfcri. Exposure can be docurr~enteclby detection of specific antibodies, but occasional seronegative cases d o occur and the presence of antibodies is riot invariable."'.":' None of the tests routinely available can confirm active infection.
CLINICAL CRITERIA Four clinical fcatures support a diagnosis of Lyrne disease, and one establishes the diagnosis (Table 2). EM is a pathognomonic marker for Lyrrre disease. Unfortunately, this rash is seen in only SO to 80% of patients. T h e expanding erythematous skin lesion occurs at the tick bite site 8 to 9 (range, 2 to 28) days after the bite.h4Thc E M lesion is single; rrl~lltiplelesions indicate dissemination. Differential diagnosis includes erysipelas, fixed drug reaction, contact dermatitis, and insect bite. Although tick bite o r exposure preceding onset of neurologic disease is suggestive, less than 50% of Lyme disease patients give this history. When the tick strain is unknown, it is even less helprul. T h e Ixodes tick is quite small, often described as poppyseed-sized, compared with the much largcr and very common dog tick. Kesiderrce in, o r travel to, an errderrlic area increases the likelihood of Lyme disease. It is difficult to implicate B. burgdorferi in regions with little o r no endemic Lyme disease.
Table 2.
Diagnosis of Neurologic Lyme Disease
Clinical
Erythema migrans (EM) Tick bite or exposure Endemic area Extraneural involvement Suggestive neurologic syndrome
Laboratory
Current Specific antibody (ELISA) Nonspecific blood tests (sedimentation rate, IgM, liver function tests) CSF studies; including CSF Lyme antibody index Biopsy Research Antigen assays Cell-mediated immunity assays Immune complex assays Nucleic acid (PCR) assays
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cannot even be found in nerve. Inflammation is variable as is blood vessel involvement. This has raised the possibility that indirect factors are involved."'" Evidence for immune and inflammatory processes in neuroborreliosis includes: (1) detection of immune complexes and strong (2) autoantibodies to T-cell responses within CSF;54,55 neural components (including myelin, myelin basic protein, and n e u r o n ~ ) ; ~ ' . " ~cross-reactivity ~~3) of Lyme antibodies with neural tissue (including peripheral myelin, schwann cells, and ax on^);^^." (4) CSF T-cell lines reactive to myelin basic protein, peripheral myelin, galactocerebroside, and cardiolipin;"" and (5) detection of neopterin (an activated macrophage product) in CSF.6' Identification of the mcchanism of neural injury in Lyme disease would help guide therapy. Antibiotics may not be the only answer. In particular, encephalopathy and the postinfectious syndromes may involve processes that d o not directly relate to the spirochete and require a different approach.
Since Lyme disease is a systemic infection, extraneural involvement offers an important diagnostic clue. Neurologic disease that fbllows an acute flulike illness, associated with joint abnornralities (prominent arthralgias, episodic large joint swelling, oligoarticular arthritis, temporo~nandibularjoint pain), cardiac disease (atrioventricular conduction block, pericarditis, myocarditis), o r eye disease (conjunctivitis, uveitis) should suggest neuroborreliosis. Finally, although the full neurologic spectrum of North American Lymc disease has not yet been described, it is clear that certain syndromes are common. Lyme disease should be in the differential diagnosis of patients with unilateral o r bilateral Bell's palsy, aseptic rr~erringitis,atypical Guillain-Barri. syndrome, and mild
LABORATORY CRITERIA: CURRENT TESTS
Specific Antibody Specific antibody documents exposure to B. burgdorferi, but not active infection. In endemic areas a significant proportion of the population is antibody positive. Since half of infections are asymptomatic and never lead to disease, the fact that a patient is seropositive does not indicate that the concurrent neurologic problem is due to Lymc disease. Other eviclence (either clinical, or frorrr C:SP studies and an ancillary test) is needed to support a diagnosis of Lyme disease. Antibody is generally measured by enzyme-linked immunosorbent assay (ELISA). This test has superseded indirect immunofluorescence assays (IFA), which are labor-intensive and subjective, and require great expertise in interpretation. A number of conlniercial ELISA kits are available, but there are significant quality control ~woblenlsand interlaboratory diPferences."-" Tests are not standardized. They look at different isotypes and use diflerent antigen targets, different controls, and different mcthods to determine positive and negative results. In particular, samples with low levels of positive antibodies are most likely to be missed. Therefore it becomes important to use a reliable laboratory to assay for Lynie antibodies. Major causes for a false-negative serology are an insensitive assay, early stage infection (it takes several 203
VO1,UME 12, NUMBER 3
SEPTEMKh;K 1992
weeks to generate sufficient quantities of specific antiTable 3. CSF Studies in Suspected Lyme Disease body to be detectable) and early antibiotic treatment Routine Cell count, cytology, glucose, protein (which may abort the typical humlral response). lntrathecal production of antiSeveral major B. burgdorferi antigens are shared by B.burgdorferi antibodies (CSF Lyme other spirochetes and bacteria. For example, both Trepantibody index) onema pallidum, the causative organism of syphilis, and VDRL lntrathecal IgG production or IgG index B. burgdorferi may cause a positive fluorescent trepoOligoclonal bands nernal antibody absorption test (FTA-ABS). However, nontreponemal tests, such as the rapid plasma reagin Experimental B.burgdorferi antigens, culture, nucleic acids (PCR) and VDRL, are typically negative in Lyme d i ~ e a s e . ~ ' Autoantibodies, autoreactive T cells Syphilis arid other spirochetal diseases rriay give a falseSpecific and nonspecific immune compositive Lyme EI,ISA serology. Nonpathogenic oral spiplexes rochetes can also give false-positive Lyme serologies. This is particularly likely when a patient has known periodontal disease or has had recent dental manipulation. In such cases, however, the aritihody titer to the specific of proportional specific antibody in paired CSF and sespirochete will always be much higher than the antibody rum samples.y2-"'-" When the CSF 1,yme antibody index titer to B. burgdorferi. False-positive serologies have also is elevated, it confirms neurologic Lyme disease, but it is been noted with major bacterial infections (such as en- not invariably elevated. I t niay also persist for some time docarditis and sepsis), rickettsia1 infections, Epstein-Barr after appropriate treatment. With-current, reliable asantibodies are alr~lostnever detected in CSF , Lvme , viral infection (with polyclonal B-cell activation), hyper- says. when a patient is seronegative. Other suggestive CSF gammaglobulinemia, HIV- 1 infection, and autoimmune disorders with high autoantibody titers. In CSF, false- findings are mild mononuclear plcocytosis (particularly positive reactions have been reported with neurosyphilis, with plasma cells and atypical lymphocytes) and elevated tuberculous nieriingitis, and varicella-zoster meningo- protein. T h e exwerimental CSF studies listed in Table 3 are of great interest, but at the present tirne have limited encephalitis. availability. Western blot for Lvme antibodies is not currentlv standardized and involves extremely subjective interpretation. Unlike the situation in AIDS. it cannot be used as Ancillary Tests ari absolute confirmatory antibody test. It is probably most helpful to identify a fhlse-positive ELISA result."!' Helpful ancillary tests include nerve conduction In such cases, western blot shows that antibodies are restudies (to document multifocal axonal rieuropathy) and acting with nonspecific antigens, rather than B. burgneuroirnagirig. In patients with neuropathy, sural nerve dorferi-specific antigens. biopsy may show perivascular inflammatory infiltrate, especially within the epineurium, with axonal loss; spirochetes are not present. Evoked potential tests are genNonspecific Blood Tests erally normal, and EEG tends to be abnormal only in the encephalitis syndrome. Routine blood tests are rarely helpful. Almost 90% of patients with active disease have circulating immune complexes, but multiple assays must be used and the Culture findings are entirely nonspecific. I n early diseasc, patients nlay have elevated sedimentation rate (50%), inUnlike most infectious organisms, B. burgdorferi is creased IgM (33%), arid mild liver enzyme elevations (19%). Occasional patients have low levels of autoanti- virtually inrpossible to culture. T h e organism has a long dihodies (antinuclear antibodies, cryoglobulins, rheuma- viding time (q 12 hours), is fastidious, and requires special toid factor, and anticardiolipin antibodies). IgM anticar- media, prolonged incubation, and meticulous detail. The diolipin antibodies have been increased in some cases yield of culture attempts is generally less than 10%. with neurologic syndromes.
Biopsy Cerebrospinal Fluid Studies
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CSF is generally abnormal in CNS 1,yme syndromes (except for encephalopathy), and may be abnormal in certain PNS syndromes (those that involve the nerve root, o r in which occult meningitis is the cause of cranial neuropathy). However, normal CSF does not exclude neurologic Lyme disease. CSF studies for suspected Lyme disease are outlined in Table 3. Intrathecal production of specific antibodies (elevated CSF Lyme antibody index) is the most helpful CSF study for neuroborreliosis. It reflects a localized immune response caused by CNS spirochete invasion. There are several ways to d o this assay, but all irivolve a conlparison
Spirochetes have been shown in various tissues, including brain, meninges, muscle, retina, myocardium, bone, synoviurn, liver, arid spleen. However, routine biopsy is not helpful. Once past the early dissemination stage, spirochetes are sparsely distributed and limited in number within infected tissue. Since staining techniques are very susceptible to artifact, biopsies require expert. interpretation. T h e only high-yield biopsy site has been the edge of the expanding EM lesion.
LABORATORY CRITERIA: RESEARCH TESTS T h e research studies listed in Table 2 can aid the diagnosis of Lyme disease, but they are not standardized
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SEMINAKS IN NEUROLOGY
NEUKOLOGIC LY Mk: I)ISF,ASE-C~YLE
CONFOUNDING DIAGNOSES: MULTIPLE SCLEROSIS MS is mentioned frequently as an alternative diagnosis ro neurobon-eliosis. MS patients d o not have extraneural discasc features. MS patients have abnormal brain or spinal MKI (go%), abnormal evoked potentials (50%), CSF oligoclonal bands (YO to Y5%), intrathecal IgG production (70 to go%), and CSF myelin basic protein. Neuroborreliosis patients havc stereotyped syndromes, extraneural features, PNS involvement, more prominent CSF pleocytosis and protein elevation, arid an clcvatcd CSF Lyme antibody index. It is possible for a patient to have'both diagnoses. In endemic areas sorrle
MS patients will become infected and seroconvert. Since infections may trigger MS relapses, an MS patierit who is systemically infected could have a disease flarc-up that is not due to direct C:NS inf'ection. Patients with MS who have a true CNS irifectiorl should show an elevated (;SF Lyme antibody index with or without pleocytosis and increased protein. 'l'hey require antibiotics, but it will not change their primary diagnosis.
THERAPY AND PROGNOSIS T h e approach to therapy in Lyme disease should be aggressive treatrnent as early as possible. Parenteral antibiotics are given for neurologic Lyme disease associated with CSF abnorr~ialities."~ CNS 1,yme syndromes, regardless of hl, Frens OB. Pseudotumor cerebri syndrorne 70. associatccl with L y ~ n edisease. Am J Ophthalmol 1989; 107:81-2 1 7 . Brogan GX, Holnan CS, Viccellio P. T h e enlarging clinical spectruni of 1.yme disease: I.yme (:erebra1 vasculitis, a new disease entity. Ann Ernerg Med 1990;19:572-6 71. 48. M a y EF, Jabbari B. Stroke in neurohorreliosis. Stroke 1990;2 1 : 1232-5 49. lleik 1.. BUI-gdot-ferW, Donaldson JG. Neurologic abnor72. nlalities in 1.yme disease without erythema chronicurn tnig~.ans.Am J Med 1986;81:73-8 50. Carlsson M , Pvlalnivall R-E. Rorrelia infection as a cause of presenile dementia. Laricet 1987;2:798 73. 51. IN, Halperin J J , Dattwyler RJ. Lyrrre 111eni11goencephalitis: report of a severe, penicillin-resistant casc. Arthritis Rheum 1987;30:705-8 79. Edelrrian R. Perspective o n the development of vaccines against Lymc discasc. Vaccine 1991;9:531-2
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74. Dressler F, Yoshlnari N H , Steere AC. T h e T-cell proliferative assay in the diagnosis of' Lyme diseasc. Anri Intern Med 1991; 155:593-9 75. Kahn DW, Malawista SE. Lyme disease: I-ecommendations for diagnosis and treatment. Ann Intern Med 1991;114:472-81 76. Luft B.1, Gorevic PD, Halperin .]I, et al. A perspective on the treatment of L y ~ n eborreliosis. Rev Infect Dis 1989;l l:S1518-25
VOI,UME: 12, N U M B E R 3 SEPTI?'MBER 1992
