Journal of Neuro-Ophthalmology, December 1987, Volume 7, Issue 4

Lyme disease. A neuro-ophthalmologic view.

Lyme borreliosis is a spirochetal infection with a potential to produce a clinical disease in the human host with protean manifestations as diverse as the spectrum of disease caused by Treponema pallidum. Neuro-ophthalmologic manifestations of Lyme borreliosis are emphasized in this short review. A brief historical chronicle of Lyme disease is offered. Potential pitfalls in the diagnosis of Lyme disease with an emphasis on false negative serology and currently available diagnostic modalities are presented. Therapeutic options for Lyme borreliosis are briefly reviewed.

TouTl/a/ of Clllumi NfU'O-ophllwlmoloxy 7141: 185-190. 1987 Lyme Disease A Neuro-ophthalmologic View Alan B. MacDonald, M.D. Lyme borreliosis is a spirochetal infection with a poten­tial to produce a clinical disease in the human host with protean manifestations as diverse as the spectrum of disease caused by Trepollt?mn pnllidlllll. Neuro-ophthal­mologic manifestations of Lyme borreliosis are empha­sized in this short review. A brief historical chronicle of Lyme disease is offered. Potential pitfalls in the diag­nosis of Lyme disease with an emphasis on false nega­tive serology and currently available diagnostic modali­ties are presented. Therapeutic options for Lyme borre­Iiosis are briefly reviewed. Key Words: Lyme-Borrelin. human-Spirochete infec­tion - Borreliosis, history- Borreliosis, diagnosis. From the Department of Pathology, Southampton Hospital. Southampton, New York. Address corre pondence and reprint requests to Dr. A. B. MacDonald at Department of Pathology, Southampton Hospital. 240 Meeting House Lane, Southampton, Y 11968, U.s.A. 185 ( 1987 Raven Pre s, Ltd .. New York Lyme disease, a spirochetal infection due to Bor­relia /ll/rgdorferi, is increasingly being appreciated as presenting with neuro-ophthalmological mani­festations. Recognized in the United States (26 states to date) as well as in Europe, Australia, China, and the Soviet Union, this infection has emerged as a worldwide public health problem (1). This review will address historical perspec­tives, general signs of the disease, neurologic and ophthalmologic manifestations, serologic at­tributes, and treatment strategies. HISTORICAL SYNOPSIS OF l YME DISEASE In 1977 a new disease was described in Connect­icut, named Lyme arthritis for the community where a cluster of patients had an illness resem­bling juvenile rheumatoid arthritis (2). A Euro­pean dermatologist enrolled in a fellowship pro­gram at the Yale School of Medicine solved a piece of the puzzle by recognizing that the skin lesion that many of the patients with Lyme arthritis de­scribed as a sentinel sign of the disease was iden­tical to erythema chronicum migrans, first de­scribed in 1909 by a Swedish dermatologist. Arvid Afzelius (3). This observation was enormously im­portant because it called attention to the very ex­tensive experience in the European medical litera­ture that linked the erythema chronicum migrans lesion with several clinical observations. The first was the association of the skin lesion with an arthropod bite, specifically the hard tick Ixodes ri­filll/ S. Second, many patients with this specific skin lesion developed neurologic illnesses (but very few patients in Europe had arthritis). Third, antibiotic therapy seemed to hasten clinical re­covery from the dermatologic condition and its neurologic sequelae, and this suggested that the /86 A. B. MacDONALD illness might be due to a bacterium. In rapid suc­cession the Yale group described examples of the Lyme malady with extraarticular manifestations (cardiac, hepatic, testicular) and identified cases of neurologic illness in Lyme patients (4). Lyme ar­thritis was renamed Lyme disease. Field studies resulted in the discovery of a hitherto unknown species of hard tick that was named Ixodes dam­mini. The distribution of the new tick species was especially high in the epidemic area in Lyme, Con­necticut. Clinical trials at Yale showed that, as Eu­ropean physicians had observed, antibiotics were preferable to corticosteroids in treating the illness (5). The infectious agent continued to elude investi­gators at Yale and in Europe. Serum banks were established. Convalescent Lyme sera were tested with >200 viruses, bacteria, spirochetes, and rick­ettsial species, all without success. For a time, in­vestigators in France and Germany were con­vinced that a rickettsial infection was responsible for the disease, but serologic studies failed to sup­port this hypothesis. Six years passed and the pathogenesis of Lyme disease remained obscure (6). The discovery of the infectious agent that causes Lyme disease and its European equivalents was made by one man working alone in his laboratory in Hamilton, Montana. Dr. Willy Burgdorfer was attempting to demonstrate a tick reservoir for the agent of Rocky Mountain spotted fever in a coastal New York region that had several fatal cases of this rickettsial infection in 1981. Dissections of the tick vector of Rocky Mountain spotted fever, Der­macentor variabilis, collected from Shelter Island, New York, yielded no evidence of the rickettsial pathogen. This prompted Burgdorfer and his col­leagues, Dr. Jorge Benach and Dr. Edward Bosler, to test the hypothesis that ixodid ticks from the same ecosystem might be a reservoir for patho­genic rickettsiae. Hundreds of ixodid ticks were dissected and not one harbored rickettsiae. Two of the dissections revealed a large microfilarial proto­zoan by Giemsa stain that Burgdorfer recognized as a species that was pathogenic for deer. As he carefully scrutinized these specimens, he saw a faintly staining randomly coiled filamentous form that other observers would have overlooked. Burgdorfer recognized that these were spiro­chetes, and, in an instantaneous moment of vi­sion, he recalled all the previous observations by European workers linking the ixodid tick to the er­ythema chronicunt migrans il.lhess and the parallel studies of Lyme disease. In addition, he knew that one paper published in 1948 had described spiro-chetes in skin biopsy specimens from patients with the erythema chronicum migrans lesion. It appeared that he had discovered the long sought elusive infectious agent (7). Confirmation would require satisfaction of Koch's postulates. Dr. Alan Barbour was responsible for the suc­cessful in vitro cultivation of the spirochete from Burgdorfer's tick dissections (8). Primary isolation and pure culture of the spirochete were triumphs that accrued from Barbour's extensive experience with the cultivation of the agent of relapsing fever Borrelia hermsii. Establishment of a stable labora­tory strain of the Lyme disease spirochete was a third major milestone. With the spirochete in pure form, animal inoculation studies confirmed that it caused a similar disease and could be recovered from laboratory animals. Convalescent sera from Lyme disease patients bound avidly to the spiro­chete in immunofluorescence assays. Deoxyribo­nucleic acid homology studies established that the spirochete was sufficiently similar to other Borrelia spirochetes to be grouped with them, but suffi­ciently unique to be assigned a new species name, B. burgdorferi (9). In short order, a similar spiro­chete was recovered from the European ixodid tick, Benach et al. (10) and the Yale group (11) re­covered the spirochete from the blood and spinal fluid of Lyme disease patients, and Berger et ai. reported spirochetes in skin biopsies from patients with erythema chronicum migrans and Lyme dis­ease (12). DIAGNOSIS OF LYME DISEASE Clinical and Laboratory Evidence According to the criteria of the Centers for Dis­ease Control, Lyme disease is diagnosed on either clinical, serological, or microbiological evidence (13). Definite clinical cases of Lyme disease are those in which the oval or annular expanding cu­taneous lesion erythema chronicum migrans is manifest (Figs. 1 and 2). Additional evidence is not required if this pathognomonic skin sign is recog­nized. Between 40 and 60% of patients with ery­thema chronicum migrans do not develop a diag­nostic serologic titer (14). Serology alone is consid­ered diagnostic if the patient's blood has a high antibody titer against the spirochete B. burgdorferi by either immunofluorescence or enzyme linked immunoassay (ELISA) methods (15) (Fig. 3). Cross-reactivity with Treponema pallidum may be manifest as a low titer FTA-ABS reactive result in Lyme disease. Therefore, it is not surprising that some syphilitic sera will produce low titer reac­tions in Lyme serology methods (16). Lympho- LYME DISEASE AND THE VISUAL SYSTEM 187 FIG. 1. Erythema chronicum migrans of the homoge­neous oval type. Pretibial skin in an 81-year-old man. There was no cutaneous pain or pruritis, no constitu­tional symptoms were noted. cytes from Lyme disease patients will undergo a proliferative response in vitro when they are incu­bated with B. burgdorferi, and this demonstrates the cellular immune response to the spirochete (17). Primary isolation of the spirochete from tissue or body fluids is a research procedure, which although tedious and extremely expensive, will yield uneqUivocal evidence of active Lyme FIG. 2. Erythema chronlcum migrans of the annular type "bull's eye." Skin of thigh in a 24-year-old vroman. There were concurrent "aseptic" meningitis and second degree heart block. RG. 3. Borrelia burgdorleri. (A) 831 reference stain­ATCC #35211 demonstrates indirect immunofluores­cence image (x 1,000). Pooled reactive human Lyme sera and goat anti-human IgG-fluorescein. (8) Primary isolate from skin-1986 (erythema chronicum migrans) lesion. Dark-field microscope image (x 1,000). disease in culture positive cases that are either clinically or serologically negative or equivocal (18,19). Finally, identification of B. burdgorferi in biopsy tissue specimens by histologic methods (silver impregnation or immunohistochemistry) is an additional method for documenting infection (20). General clinical manifestations of Lyme disease are shown in Table 1. A carefully taken patient history with a focused series of questions directed at the known presentations of Lyme disease is ex­tremely useful. Physicians should pursue the pos­sibility of Lyme disease when the patient's history reveals such paired symptoms as palpitations and arthritis, meningitis accompanied by "eczema," Bell's palsy in a patient with a cardiac pacemaker, or multiple sclerosis in a patient with rheumatoid arthritis. These and other combinations of signs and symptoms occurring either synchronously or metachronously should arouse suspicion. OPHTHALMOLOGIC MANIFESTATIONS Probably the first ophthalmic manifestations of Lyme disease were conjunctivitis, episcleritis, or photophobia in patients who showed the ery­thema chronicum migrans lesion. Recognition of Jeli,. NtIlro-ophlNdmol. Vol. 7. No.4. 1987 /88 A. B. MacDONALD TABLE 1. General clinical manifestations of Lyme disease Erythema chronicum migrans, single lesion Homogeneous oval type (pink. red. or purple) Annular type (single ring. bull's eye, target) Transient evanescent type Erythema chronicum migrans. multiple lesions Erythematous types, adults Urticarial types. children Transient evanescent type Myalgia Arthralgia Joint effusions Periostitis Synovitis Tendonitis Profound fatigue Pharyngitis lymphadenitis Fever Chills Palpitations Syncope Orchitis Cough Hoarseness Hepatitis nervous system involvement (Table 2) brought various cranial nerve palsies into the Lyme disease spectrum (Table 3) (21). Unilateral or bilateral fa­cial nerve palsies were and remain the most fre­quent cranial neuropathies (22-25). Untreated VII nerve palsies may be followed by exposure kera­titis or corneal abrasion. Involvement of nerves VI, IV, III, or Uin some cases is the only expression of the infection (22,23,26-29). Papilledema, usually bilateral (22,30), is recognized in isolated cases of Lyme disease and may occur as a delayed mani­festation of the infection (31). Optic neuritis may occur with dissemination of neurologic symptoms TABLE 2. Neurological signs and symptoms of Lyme disease Headache Impaired concentration Short-term memory problems Personality changes Psychosis Sensory neuritis Motor neuropathy Autonomic neuropathy Paralysis (transverse myelitis) Carpal tunnel syndrome (often bilateral) Dementia Multiple sclerosis-like illness Cranial neuropathies Vertigo Hearing impairment Stiff neck Chorea S~illlreo; TABLE 3. Ophthalmologic signs and symptoms of Lyme disease Diplopia Optic neuritis Papilledema Exposure keratitis Conjunctivitis Panophthalmitis Cortical blindness Symptoms of eye pressure Photophobia Blurred vision in time and space leading to a multiple sclerosis­like illness in some patients with Lyme disease (32). Panophthalmitis leading to loss of one .eye has been described in one case where a patIent showed the diagnostic skin lesion, diagnostic se­rology, and apparently developed a Herxheimer reaction with a possible ophthalmic component while receiving antibiotic therapy. Spirochetes consistent with B. burgdorferi were found in the vitreous by histologic methods (33). Lyme disease in pregnancy may be transmitted from mother to fetus (34). Untreated infections have the potential for stillbirth and other adverse outcomes including malformations of the cardio­vascular system (35). One case of cortical blind­ness has been listed in an infant born to a woman who had Lyme disease during her pregnancy (36). An additional infant showed reactive Borrelia se­rology, conjunctivitis, blepharitis, strabismus, mental retardation, cranial enlargement, chronic meningitis, recurrent arthritis, and persistent maculopapular rash since birth (37). Experimental inoculation of hamsters with B. bllrgdol'feri has shown that the spirochetes are ca­pable of invading the eye. One study identified B. l1/./l'gdOlferi in the eyes of 9 of 20 hamsters following intraperitoneal inoculation (38). A second study of similar design found spirochetes in eye cultures of 4 of 7 hamsters (39). SEROLOGIC ATTRIBUTES Problem of False-negative Results Serologic methods for the confirmation of a clin­ical diagnosis of Lyme disease are helpful when a high titer result from a reliable laboratory is ob­tained. A negative result in any clinical situation under no circumstances excludes the diagnosis, and this caveat cannot be overstated. Quality con­trol is essential in serology methods. Some of the potential pitfalls of B. burgdorferi serology tech­niques are summarized in Table 4. No Lyme test exists that has the sensitivity of the FfA-ABS test in syphilis. (But it is useful to recall that the FTA- LYME DISEASE AND THE VISUAL SYSTEM /89 TABLE 4. Pitfalls in the serodiagnosis of Lyme disease, 1987 TABLE 6. Minimal bacteriocidal concentrations­Borrelia burgdorferj' REFERENCES • Data from Johnson et al. (44). D CDso • curative dose 50% for experimentally infected hamsters with Borrelia burgdorferi. 1. Schmid GP. The global distribution oi Lvme disease. Rl'l' II/It'r! Di,: 1985;7:-11-50. . 2. Steere AC, Malawista SE, Snydman DR. Lyme ilrthritis: an epidemic of oligoarticular arthntis in children and adults in three Connecticut communities. Arthritis Rht'ulII 1977;20:7­17. 3. AfzeJius A. Erythema chronicum migran . Ada Dalll V('//­eml (St,'t'kll) 1921;2:120-5. -I. ~teere AC, Bart~nhagen NH. Craft jE, et al. The arly clin­Ical manifestatIOns of Lyme disease. All/I 1"fl'rIl Med 1983;99:76-82. system syphilis. A Herxheimer reaction should be anticipated in patients with ocular or central nervous system borreliosis, and appropriate corti­costeroid coverage should be planned to deal with this possibility. Various reports (44-46) of in vitro antibiotic susceptibility of B. bllrgdorferi have been abstracted in Tables 5 and 6 and appropriate com­parisons with neurosyphilis are included. Cef­triaxone sodium (Rocephin, Roche Labs, utley, NJ) is currently the antibiotic with the lowest min­imal inhibitory concentration against B. bllrgdor­feri, the best penetration of the blood-brain bar­rier, and the widest clinical margin between achievable tissue drug levels and antibiotic con­centration required to kill B. /llIrgdorferi. 1.975 240 287 2.352 CDsoD (mg/kg) 6.5 ILglml 0.04 ILg/ml 0.80 ILg/ml 0.05 ILgtml Antibiotic Concentration Penicillin G Ceftriaxone Tetracycline Erythromycin HINDSIGHT, FORESIGHT, AND INSIGHT The spectrum of ophthalmologic disease in Lyme disease remains to be defined by ophthal­mologists, for it should be stressed that much of the current domain ha been explored by physi­cians in nonophthalmologic specialties. Argyll Robertson's elegant clinical observation of a pupil­lary abnormality in 1869 served many generations of patients and physicians. We have yet to define the neuropathologic substrate for this paradigm of physical examination. The gap between the limbus and the cortex ha been bridged by physicians who shared their observations of disease pro­cesses. It is hoped that this brief review has set the stage for further discovery. TREATMENT STRATEGIES FOR LYME DISEASE-1987 Therapeutic options have been reviewed by others (40-43) and will be revised as new antibi­otics are approved for use. It is the author's opinion that patients with neuro-ophthalmological manifestations of Lyme disease should be treated with parenteral antibiotics in doses comparable with those required in treating central nervous TABLE 5. Logistical considerations-therapy of neuroborreliosis Lack of antibody production Immunosuppressive effect of Lyme disease infection Antibody production aborted or curtailed by early antibiotic therapy Instability and nonhomogeneity of laboratory spirochetes Loss of antigen epitopes in serial subculture of spirochetes Use of a variety of spirochete strains by different laboratories in reagent production Lack of interlaboratory standardization Lack of a national standard serum bank for Lyme control sera Lack of Western blot to test problem sera for specificity of reaction against specific spirochetal protein epitopes and glycoprotein epitopes ABS test was the culmination of years of research and stepwise progress through an "alphabet soup" of serologic methods.) Antibiotic selection Ability to penetrate eye and brain Antibiotic half·life versus kinetics of spirochete cell division Bacteriocidal versus bacteriostatic mechanism of action Special considerations: antibiotic allergy. pregnancy. encephalitis. impending vision loss Parenteral versus oral therapy Oral therapy for early disease manifestations Parenteral therapy for meningitis. established parenchymal infections involving nervous system and eye Parenteral therapy for patients who relapse. reactivate. or become reinfected Results of therapy-no ideal direct monitor Antibody titers post-therapy-not helpful (antibodies are serological "scars") Cultures (post-treatment) are a research procedure with unpredictable yield Clinical symptomatic improvement-subjective Herxheimer-like reactions indicate spirochete cell lysis Potential for use of colloidal gold curve on cerebrospinal fluid as the most objective parameter to follow activity of neuroborreliosis Research procedures-aqueous humor and cerebrospinal fluid: Dark-field exam, antibody detection. 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The histopathology of experimen­tally infected hamsters with the Lyme disease spirochete, Borrelia 11IIrgrlorferi. Proe Soc Ex,' Bioi Med 1986;181:263-9. 40. Steere AC, Pachner AR. Malawista SE. Neurological abnor­malities of Lyme disease: successful treatment with high dose intravenous penicillin. All/I Illtem Med 1983;99:767­72. 41. Diringer MN, Halperin lJ, Dattwyler RJ. Lyme meningoen­cephalitis- report of a severe penicillin re istant case. Ar­IIrrilis RlleulII (in press). 42. Dattwyler RJ, Halperin lJ. Failure of telTacydine therapy in early Lyme disease. Arthritis Rileum 1987;30:448-50. 43. Dattwyler R). Halperin J), Pass H, Luft BJ. CeflTiaxone as effective therapy in refractory Lyme disease. I Infect Di;; 1987;155:1322 -5. 44. Johnson RC, Kodner C Russell M. In vitro and in vivo 5U ­ceptibility of the Lyme disea e spirochete Borrelia bllrgd'lT­feT! to four antimicrobial agents. Alltimicrob Agents Clle­muther 1987;31:164-7. 45. Preac-Mursic V, Wilske B, Schierz G. European Borrelia bllrgrl,Jr(eri isolated from humans and ticks: culture condi­tions and antibiotic susceptibility. lel/tralbl Bakteriol Micro­bioi Hyg A 1986;263:112-8. 46. Berger BW, Kaplan MH, Rothenberg IR, Barbour AG. Iso­lation and characterization of Lyme disease spirochetes from kin of patients with erythema chronicum migrans. I Am Acad Dermalt,l 1985;13:444-9.