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Show Journal of Neuro- Oplithalmology 19( 4): 263- 273, 1999. © 1999 Lippiiicott Williams & Wilkins, Inc., Philadelphia Annual Update of Systemic Disease- 1999: Emerging and Re- emerging Infections ( Part I) Larry Frohman, M. D., and Paul Lama, M. D. In Part I of this edition of the annual review of systemic diseases, we discuss Whipple's disease as an emerging infection and review new findings in an established infectious disease, Lyme disease, that can affect the visual system. Part II, which will appear in the March 2000 issue, will discuss the emerging infections babesiosis, ehrlichiosis, and Hantavirus and will review new findings that can affect the visual system from syphilis, an established infectious disease. WHIPPLE'S DISEASE Whipple's disease was first described in 1907 ( 1). The agent now known to cause WD, Tropheryma whippelii, is a periodic acid- Schiff ( PAS)- positive, rod- shaped bacterium, closely related genetically to the actinomycetes ( 2). The agent tends to accumulate within macrophages. The organism is endemic, and evidence points to it having an environmental source. As an example, in a German study, 25 of 38 ( 66%) waste- water samples from five sewage- treatment plants tested positive for T. whippelii DNA ( 3). Marth et al. ( 4) noted the predilection of the illness to strike HLA- B27- positive, middle- aged men, implying that host factors are involved in the susceptibility to what may be a ubiquitous pathogen. They commented that patients with WD have suppressed delayed- type hypersensitivity responses in vivo and decreased in vitro T- cell responses, as well as alterations in serum- suppressor factors and T- cell subpopulations. The organism seems to have a cytotoxic effect on immunoglobulin A ( IgA) plasma cells but is destroyed by macrophages. It is postulated that it is this toxic effect that allows it to elude local gut immune defenses ( 5). Marth et al. ( 4,6) reported that WD patients have reduced numbers of circulating cells expressing CDllb, a cell- adhesion and complement- receptor molecule on macrophages involved in the activation of intracellular killing of pathogens. Manuscript received July 21, 1999; accepted October 19, 1999. From the Department of Ophthalmology ( L. F., P. L.) and the Department of Neurosciences ( L. F.), UMD- New Jersey Medical School, Newark, New Jersey, U. S. A. Address correspondence and reprint requests to Larry Frohman, M. D., 90 Bergen Street, Sixth Floor, Newark, NJ 07103. This multisystem disorder typically features symptoms such as abdominal pain, fever, diarrhea, lymphade-nopathy, and polyarthralgia. Twenty percent of cases do not have gastrointestinal features, and neurologic involvement is seen in 10% of cases ( 7). Ocular involvement is said to occur in 2.7% of cases ( 8). The ophthalmic signs typically seen include uveitis, vitritis, and retinitis. Neuro- ophthalmic signs include nystagmus, optic neuritis, papilledema, gaze palsy, and ophthalmoparesis ( 9,10). Systemic Manifestations Whipple's disease does not have to present as a gastrointestinal disorder. Schilling et al. ( 11) reported a series of patients who presented with a seronegative, migrating, nondestructive polyarthralgia due to WD before any gastrointestinal symptoms developed. Whipple's disease can have a pulmonary presentation. Kelly et al. ( 12) reported a 31- year- old man without gastrointestinal illness whose chest radiograph demonstrated several pulmonary nodules that enlarged rapidly. The histology of the endobronchial lesions demonstrated WD. Riemer et al. ( 13) described a man with systemic WD with pericardial and pleural effusions and severe pulmonary hypertension. After 3 months of antibiotic treatment, there was a complete resolution, not only of the symptoms known to be associated with WD ( diarrhea, arthralgia, pericardial and pleural effusions), but also the pulmonary hypertension. Although cardiac involvement in WD has been noted, it is rare to be the main manifestation and rarely has required therapy beyond antibiotics. Schneider et al. ( 14) reported a case admitted because of dyspnea, fatigue, chest pain, and dizziness. Endoscopy was performed due to 6 months of diarrhea with an attendant 10- kg weight loss and revealed T. whippelii, confirmed by both the presence of typical PAS- positive material and by polymerase chain reaction ( PCR). The aortic valve was replaced after the diarrhea had resolved with antibiotic ( trimethoprim- sulfamethoxazole) therapy, and histologically demonstrated, PAS- positive, rod- shaped material was thought to be the cause of the aortic insufficiency. The authors pointed out that 58% of patients with WD have clinical cardiac findings, and 76% have cardiac lesions at autopsy. These cardiac manifestations may precede gastrointestinal involvement and may even be the sole manifestation of the illness. 263 264 L. FROHMAN AND P. LAMA Khairy and Graham ( 15) reported a 50- year- old man with WD and reviewed the literature on cardiac involvement. This man had severe tricuspid regurgitation and moderate aortic and mitral regurgitation. Both valvular and ventricular abnormalities were demonstrated. They reported that the cardiac manifestations of WD are myocarditis, constrictive pericarditis, valvular deformities, coronary arteritis, and congestive heart failure. WD may also be a cause of sudden cardiac death, as recently described by McGettigan et al. ( 16) and Mooney et al. ( 17). These patients died suddenly of an unrecognized myocarditis as part of WD. Marinella and Chey ( 18) showed that the syndrome of inappropriate secretion of antidiuretic hormone ( SIADH) may be seen in the course of WD, even when there is no gastrointestinal involvement, and that it may respond to antibiotic therapy. The series of Misbah et al. ( 19) reminds us that the diagnosis of WD can be made if one is suspicious, even if typical gastrointestinal signs are lacking. This series describes five patients, four with atypical features of WD ( immune thrombocytopenic purpura, juvenile chronic arthritis, isolated muscle weakness, and quadriparesis), as well as one case with fever of unknown origin, who had all been investigated elsewhere and had undergone normal jejunal biopsies with no evidence of PAS- positive macrophages. Yet, when PCR analysis for T. whippelii was also performed on various tissues ( including peripheral blood, lymph node, muscle, and synovium), it was positive in all patients in at least one tissue. Furthermore, PAS- positive material was seen in four of five cases in extragastrointestinal sites. This series serves to remind us that not only do patients not need to demonstrate typical gastrointestinal symptoms, but even if one has the acumen to suspect WD in such a case, that jejunal biopsy for histopathology is inadequate to rule out the disease. Mohm et al. ( 20) reported the fascinating case of a woman with 2 years of multiple abdominal lymphomas, polyserositis, and wasting. Whipple's disease was histologically confirmed in duodenal and lymph- node material. This patient, who also had seizures and coma, had PCR evidence of WD in both the biopsy materials and in the cerebrospinal fluid ( CSF). Antibiotic therapy ( trimethoprim- sulfamethoxazole) not only led to clinical improvement, but the lymphomas completely regressed. Ophthalmic Manifestations Many ocular manifestations of WD have been reported, including uveitis, vitritis, retinitis, myositis, papilledema, nystagmus ( oculopalatal myoclonus), and optic atrophy. These typically occur in the setting of an accompanying systemic illness. That WD can have its typical ocular manifestations in the absence of the characteristic gastrointestinal symptoms is evidenced by the case of Nishimura et al. ( 21). This patient, whose right eye ( OD) was phthisicle due to prior uveitis- induced neovascular glaucoma, presented with severe acute posterior uveitis in the left eye ( OS). There were no significant gastrointestinal signs; the systemic findings of fever, anemia, weight loss, rash, arthralgia, and myalgia were present. The evaluation of the anemia led to esophago-gastroduodenoscopy and jejunal biopsy. PAS- positive histiocytes were seen within the lamina propria, and PCR demonstrated T. whippelii rDNA. Worsening ocular inflammation OS responded to a subtenon injection of triamcinolone, whereas the systemic findings responded to trimethoprim- sulfamethoxazole therapy. The authors pointed out that WD should be considered in the differential diagnosis of recurrent uveitis. Williams et al. ( 22) reported the case of a man who presented with 5 months of bilateral granulomatous uveitis 7 months after uncomplicated bilateral cataract surgery. His medical history included a steroid- responsive arthritis and several months of fever of unknown origin. A biopsy of the remaining lens capsule was performed because of the refractory nature of what was thought to be phacoanaphylactic uveitis and yielded PAS- positive, diastase- resistant bacilli consistent with T. whippelii, confirmed by electron microscopy and PCR. Further confirmation was obtained via jejunal biopsy. Although the systemic component responded to trimethoprim-sulfamethoxazole, cefixime, rifampin, and doxycycline therapy, the resistant intraocular inflammation required intravenous ceftriaxone to control it. The authors noted the appearance of granular crystalline deposits on the iris margin and lens capsule and thought that these, along with similar deposits that may appear on the corneal endothelium, might be a useful diagnostic sign for WD. Sommer et al. ( 23) reported a case in which an isolated recurrence of WD occurred in the eye. This 63- year- old man had been treated for gastrointestinal WD 30 years before. When he presented with chronic bilateral vitritis, evaluation by jejunal biopsy was negative, but the PCR on the vitreous was positive in both eyes. Neurologic Manifestations The typical neurologic features include nonspecific findings such as drowsiness, behavioral changes, and loss of memory; cranial neuropathy, ataxia, and pseudobulbar palsy have also been reported ( 24,25). A recent case of cervical myelopathy from WD was reported by Clarke et al. ( 26). Neurologic features can also precede the systemic diagnosis of WD. Durand et al. ( 27) reported a French series of 52 WD patients. In eight cases ( 15%), gastrointestinal symptoms never were seen. In two ( 4%) of the cases, neurologic symptoms preceded the systemic diagnosis, whereas over their course, 11 patients ( 21%) had neurologic disease and five ( 10%) had ocular signs. Verhagen et al. ( 28) described a 65- year- old man with a 2- year history of WD ( including gastrointestinal disease) who developed manic psychosis, sensorineural hearing loss with semicircular canal paresis, hemiparesis, and internuclear ophthalmoplegia. He was treated with sulfamethoxazole- trimethoprim, which resulted in the reduction in size of a thalamic lesion as demonstrated on magnetic resonance imaging ( MRI), as well as a clinical improvement in his organic brain syndrome and ophthalmoplegia. Louis et al. ( 24) reported three new case of central J Neuro- Ophthalmol, Vol. 19, No. 4, 1999 ANNUAL UPDATE OF SYSTEMIC DISEASE: PART I 265 nervous system ( CNS) WD and reviewed the 84 cases they found in the literature. They pointed out that historically, many cases of CNS WD are not diagnosed until after death. They reported that 80% of cases had systemic signs. Cognitive and psychiatric changes were the most common neurologic manifestations, whereas the classic signs of oculomasticatory myorhythmia and ocu-lofacioskeletal myorhythmia were present in 20% of cases and were invariably accompanied by a supranuclear vertical gaze palsy. Tissue biopsy was a sensitive technique; 89% of those who had biopsies had positive results. They suggested that CNS WD should be considered in patients with unexplained systemic illness with neurologic signs, especially if supranuclear vertical gaze palsy, rhythmic myoclonus, dementia with psychiatric symptoms, or hypothalamic manifestations are seen. They recommended that patients with possible CNS WD undergo small- bowel biopsy. Unfortunately, Lynch et al. ( 29) showed that small- bowel biopsy, even when PCR is performed, may not detect all cases of CNS WD. They had six cases of CNS WD, four of which ( 67%) did not have PCR supporting the diagnosis of WD on jejunal biopsy. Similarly, De Coene et al. ( 30) reported a patient with a left parietal, ring- enhancing lesion on MRI, where the diagnosis of CNS WD required brain biopsy. In this case, there were no gastrointestinal symptoms, and the jejunal biopsy was negative on histopathology. Thus, even if the bowel biopsy is negative in a case of suspected CNS WD, brain biopsy should be considered. Peters et al. ( 31) described a variant of neuro- WD that resembles sarcoidosis. The authors described a 53- year-old man with " sarcoidlike" WD, which included granulomas, and pointed out that these two diagnoses must be differentiated, as treatment of WD with corticosteroids because of confusion with neurosarcoidosis can lead to progressive illness. Their patient was treated with procaine penicillin G and streptomycin followed by doxycycline. There was initial improvement, a later relapse responded to ceftriaxone and cefixime. Neuro- ophthalmic Manifestations Simpson et al. ( 32) reported a case of oculofacioskel-etal myorhythmia associated with cerebral WD. This case was unusual in that, although the patient's mental status improved after starting intravenous ceftriaxone, resolution of the convergent- divergent pendular nystagmus associated with a synchronous, rhythmic movement of the mouth, jaw, and extremities occurred only after treatment with valproate. The authors discussed the alternative therapies of intravenous trimethoprim-sulfamethoxazole for 2 weeks followed by oral trimethoprim- sulfamethoxazole twice daily for 1 year and the option of intravenous ceftriaxone followed by oral trimethoprim- sulfamethoxazole in combination with valproate in patients in whom the abnormal movements persist. Rajput and McHattie ( 33) reported a case of a progressive supranuclear ophthalmoplegia with leg myorhythmia. This patient had neither ocular nor facial myorhythmia. The neurologic symptoms developed 16 years after the onset of WD. The ocular symptoms ( but not the leg myorhythmia, which responded to valproate) were refractory to antibiotic therapy or therapy for parkinsonism or tremor. New Diagnostic Tools The original diagnosis of WD was based on the presence of rod- shaped organisms in silver stain sections of involved tissues. In 1961, these organisms were identified as a bacteria by electron microscopy. Diagnosis has traditionally relied on the demonstration of diastase-resistant, PAS- positive granules within the histiocytes of the lamina propria of the small intestine. Although the organism has not been cultured, new diagnostic tools emerged. In 1992, a 16S rRNA gene was detected and found to be specific for WD. Tasken et al. ( 35) pointed out that even when the diagnosis of WD was established by older methods, PCR may play a role. They described two cases in which therapy for WD had failed. In one, PCR demonstrated T. whippelii, and changing specific therapy was justified. In the other case, in which the diagnosis had been made by brain biopsy because the PCR was negative for WD, further diagnostic testing led to the correct diagnosis, monocyte- derived histiocytosis, being established. Mendel et al. ( 36) recently showed that stereotactic brain biopsy is an adequate method of obtaining tissue for the demonstration of neurologic involvement in WD. Their patient presented with nonfocal neurologic findings ( lethargy, behavioral changes) with hypogonadism and weight gain. An MRI scan revealed hyperintense lesions on T2- weighted sequences in the right fornix, putamen, and hypothalamus. The right putamen was biopsied and was consistent with WD. That PCR is more sensitive than traditional methods of detection is demonstrated by the case of Muller et al. ( 37), who demonstrated PCR reactivity for T. whippelii in segments of bowel that were histologically negative. They also showed that PCR was sometimes positive on peripheral blood lymphocytes but that a tissue biopsy was more reliable. Von Herbay et al. ( 38) performed the PCR assay on 37 bacterial control strains and intestinal biopsy samples from 16 patients without WD and 88 intestinal biopsy specimens from samples from 35 WD patients. In no case did a control test false- positive on PCR. In every pretherapy WD specimen that was formalin fixed, DNA of T. whippelii was detected, whereas those specimens fixed in Bouin's were negative. Treatment promulgated conversion of PCR to negative in 23 of 24 cases, typically within 1 year of therapy. However, despite negative intestinal PCR, symptomatic cerebral WD was found in their patients. Thus PCR from intestinal biopsy samples may be more helpful for diagnosis than for gauging disease eradication. As for the diagnosis of neurologic WD, von Herbay et al. ( 39) looked at CSF analysis in 24 patients with WD, with and without clinical neurologic disease, by cytology and PCR. Four of five patients ( 80%) with neurologic J Neuw- Ophlhalmol, Vol. 19, No. 4, 1999 266 L. FROHMAN AND P. LAMA illness tested positive for WD. Those without neurologic symptoms were grouped into those tested before or after antibiotic institution. Of the " virgin" samples, 70% without neurologic symptoms were positive; once therapy was instituted, the rate of detection dropped to 27%. Thus, even in WD patients without neurologic signs, CSF analysis may be a useful diagnostic tool for detecting subclinical neurologic infection. Singer ( 40) points out that despite the utility of PCR, diagnosis of WD still does not fulfill Koch's postulates, as it was not possible to culture the bacillus T. whippelii nor to infect other individuals with the pathogen. Delanty et al. ( 7) reported a case of WD with fever, dementia ( previously diagnosed as Alzheimer's), myoclonus, and arthritis. Frontal release signs " without abnormal eye findings" were described. Spinal fluid showed a pleocytosis ( 58% lymphocytes) with a protein level elevated to 426 mg/ dL. MR1 scan showed periventricular white matter changes and mild atrophy. DNA extraction from CSF failed, rendering PCR on the CSF impossible. Duodenal and brain biopsies were refused. Synovial fluid from the left knee showed 7,000 white blood cells/ mL and yielded a positive PCR for T. whippelii, thus the patient was treated for WD with intravenous ceftriaxone 2 g/ day for 2 weeks. Within 1 week, lethargy, fever, behavioral changes, and myoclonic jerks resolved. Two weeks into therapy, the CSF showed ten white cells, and protein had decreased to 92 mg/ dL. Thus, a search for joint symptoms in patients with suspected WD and also in patients with idiopathic dementia might yield diagnostic clues, as synovial fluid may be a fruitful source of readily accessible tissue to yield molecular evidence of WD in neurologically involved WD patients in whom the CSF testing has not been fruitful. Bodaghi et al. ( 41) reminded us that not only does the eye have limited ways to respond to inflammation, making several clinical syndromes look alike, but that these syndromes may even have histologic similarities. Fortunately, new diagnostic tools such as PCR may clarify specific infectious etiologies. In the case of Bodhaghi et al., a 60- year- old man had chronic and severe uveitis, seronegative febrile polyarthritis, meningitis, and lymph-adenopathy. His initial evaluation was for Behcet's disease and was noncontributory. Although 4 years earlier, he had a transient response to penicillin therapy, relapse had been seen 1 year before presentation, which featured flare of his systemic illness and posterior uveitis/ vitritis and papilledema. Prednisone therapy at 1 mg/ kg did not improve the clinical picture. An initial vitrectomy ruled out lymphoma; a second pars plana vitrectomy demonstrated PAS- positive, rod- like material, thought to be consistent with WD. Duodenal biopsy was normal. Although PCR was performed on vitreous and lymph node material and was negative for T. whippelii, he was treated as if he had WD with trimethoprim ( 300 mg/ day) sulfamethoxazole ( 1,600 mg/ day), and rifampin ( 600 mg/ day, with a favorable response. Subsequently, PCR on an inguinal node specimen showed 16S ribosomal RNA gene fragments diagnostic of a gram- positive bacterium phylogenetically related to T. whippelii, an Ar-throbacter species. Thus, Arthrobacter may present with a clinical syndrome resembling WD, may have PAS-positive material on biopsy, and may be differentiated from WD by molecular analysis. Thus, if PCR on ocular material does not yield an etiopathogenesis, a search should be made for other involved tissues to sample for PCR and histology. Besides using it as a diagnostic tool, Ramzan et al. ( 42) used PCR as a measure of therapeutic efficacy. He performed PCR for T. whippelii in 30 stored pre- and post- treatment biopsy specimens of patients with clinically suspected and histologically confirmed cases of WD, as well as in eight patients in whom WD had been considered in the differential diagnosis but could not be confirmed upon examination of biopsy specimen( s). PCR was positive in 29 of 30 ( 97%) of the patients with histologically confirmed WD and in seven of the eight ( 87%) of the patients in whom the disease was clinically suspected. They also had small- bowel biopsy specimens from 17 of the patients treated for WD. Twelve of these 17 ( 71%) patients had persistent positive results on PCR. Of these 12 patients, seven ( 58%) either never responded or had a clinical relapse. None of the five patients whose post- treatment biopsy specimens had negative results on PCR had a relapse. Their conclusion was that a positive post- therapy PCR may prognosticate relapse, and a negative post- therapy PCR was predictive of a good outcome. These data argue for routinely obtaining pre- and post-therapy biopsy specimens for PCR. Duprez et al. ( 43) reported the MRI findings in a pediatric case of neuro- WD. MRI demonstrated white matter lesions of very low signal intensity on Tl- weighted with hyperintensity on proton density and T2 sequences, with some peripheral enhancement on delayed contrast-enhanced Tl- weighted images. These lesions were seen to shrink with therapy. Therapy Petrides et al. ( 44) pointed out that clinical response to therapy may precede histologic remission. Their patient presented with weight loss, arthralgias, and diarrhea. Although the biopsy of the gastric mucosa was negative, duodenal biopsy revealed PAS- positive, foamy macrophages within the lamina propria, and bacilli typical of WD were found on electron microscopy. PCR confirmed the diagnosis, demonstrating the typical portion of the 16S ribosomal RNA gene sequence corresponding to the Whipple bacillus ( T. whippelii) in duodenum, stomach, and liver biopsies before therapy. Although the patient demonstrated clinical improvement and PCR did not show evidence of T. whippelii DNA within 3 months of starting antibiotics, histologic evidence of infection remained. The best regimen for the therapy of WD is not well- established, with different regimens touted by different authors. In the series of Durand et al. ( 27), of the 41 patients who completed initial successful therapy, seven ( 17%) relapsed. They noted that no patient relapsed after therapy by either trimethoprim- sulfamethoxazole, alone or after a combination of penicillin and J Neiiw- Ophlhulmol, Vol. 19. No. 4, 1999 ANNUAL UPDATE OF SYSTEMIC DISEASE: PART I 267 streptomycin, or after the combination of penicillin and streptomycin. They concluded that trimethoprim-sulfamethoxazole should be considered the antimicrobial agent of choice in the treatment of WD, minimizing the risk of cerebral involvement and relapses. Jo vie and Jovic ( 45), in reporting their series of WD cases with neurologic involvement, concluded that, even if subclinical, CNS involvement is invariable, although neurologic signs are seen in only 10% to 20% of patients, and that the CNS is the most common site of relapse. Although they recognize that the optimal antimicrobial regimen is not clear, they believe that all cases should undergo initial parenteral therapy with tetracycline, penicillin, streptomycin, chloramphenicol, or ampicillin, followed by long- term oral treatment with trimethoprim-sulfamethoxazole. They also note that once it occurs, CNS relapse is resistant to treatment. Alba et al. ( 46) also pointed out that despite therapy, neurologic relapses in patients with WD are common and that antibiotics that do not cross the blood- brain barrier are not adequate initial therapy. He they believe that patients with WD should be treated for 1 year with antibiotics that cross the blood- brain barrier such as parenteral penicillin with streptomycin, followed by oral trimethoprim- sulfamethoxazole and that CNS relapse is usually resistant to therapy. Singer et al. ( 40) echoed the view of Alba et al. that treatment should include antibiotics that penetrate the CSF, since there is a high incidence of unrecognized CNS involvement. He recommends daily parenteral administration of 1.2 million units of benzylpenicillin ( penicillin G) and streptomycin 1 g for 2 weeks, followed by treatment with cotrimoxazole ( trimethoprim 160 mg and sulfamethoxazole 800 mg) twice daily for 1 to 2 years. He also recommends PCR analysis of cerebrospinal fluid before and at the conclusion of therapy. Singer et al. ( 47) also reported a case of CNS WD that failed conventional therapy and responded to rifampin. Schnider et al. ( 48) reported their case and a review of all cerebral WD cases that were reported in a decade ( N = 15). They found that patients treated with penicillin alone had a worse prognosis than patients who also received streptomycin. Five of 12 ( 42%) of patients ( 40%) treated with trimethoprim/ sulfamethoxazole did not respond. They concluded that third- generation cephalosporins were beneficial and recommended an initial regimen of ceftriaxone combined with streptomycin for CNS WD. Williams et al. ( 22) reported their case of ocular inflammation in which therapy with the agent of choice, trimethoprim- sulfamethoxazole, was not possible due to drug intolerance. Cefixime, and later the combination of rifampin and doxycycline, did not eradicate the illness. In this patient, the addition of 2 g/ day of intravenous ceftriaxone sodium to rifampin and doxycycline caused a marked clinical improvement. Finally, Schneider et al. ( 49) reported a novel therapy for refractory WD using interferon gamma. This is based on the observation by Marth et al. ( 4,6) that patients with WD have reduced monocyte interleukin 12 production and decreased interferon gamma secretion by peripheral blood mononuclear cells in vitro. They postulate a genetic substrate for this defect. The patient of Schneider et al. ( 49) had a 10- year history of multiple antibiotic-resistant WD. Despite the absence of clinical neurologic disease, T. whippelli DNA was found in the CSF on PCR. The patient was started on a regimen of ceftriaxone/ chloramphenicol/ trimethoprim- sulfamethoxazole and interferon gamma. Over the next several months, clinical response was achieved, and PCR on CSF and duodenal tissue tested negative for T. whippelii. LYME DISEASE Introduction Lyme disease is the most common tick- borne infection in North America with more than 70,000 cases reported between 1982 ( since surveillance was begun) and 1994. The causative agent, a spirochete, Borrelia burgdorferi, is transmitted by the nymphal form of ixodid ticks that comprise the Ixodes ricinus complex. Specifically, /. scapularis ( formerly /. dammini) is the vector in the northeastern ( Massachusetts through Maryland) and midwestern ( Wisconsin and Minnesota) part of the United States, and /. pacificus is the vector in the west ( California and Oregon). Although Lyme disease has been reported in 43 states and the District of Columbia, more than 90% of cases occur in the above- mentioned endemic areas. Three genomic groups of B. burgdorferi have now been identified. B. burgdorferi sensu stricto is responsible for virtually all North American infections. The other two groups, B. garinii and B. afzelii, account for most strains found in Europe. Lyme disease usually begins in the summer since nymphal forms flourish during the months of May through July. Adults and larvae also feed on humans but are less likely to transmit the disease. There have been a number of focal epidemics occurring particularly in the northeast. A number of areas have been identified as highly endemic with attack rates between 1% and 3%. Two population- based studies of suburban communities of Westchester, NY, reported incidence rates between 2.6% and 3.0% and prevalences of 8.8% and 17% ( 50,51). Other areas of high endemicity include Great Island, MA, Fire Island, NY, and, of course, the region of Old Lyme, CT. The clinical features of Lyme disease begin with the development of a characteristic expanding annular rash, erythema chronicum migrans ( ECM), at the site of the tick bite, usually in the thigh, groin, or axilla. The central area turns blue and then clears. Secondary annular skin lesions also develop that may coalesce. The second stage occurs within days to weeks and may involve the CNS, heart, other skin sites, or joints. After months to years, the third stage of infection manifests. Stage 3 may occur after a long period of latency, making the diagnosis especially difficult. Ocular and neuro- ophthalmic manifestations are not common. They may include follicular conjunctivitis, nummular keratitis, uveitis including iritis ( anterior, intermediate, and posterior forms including J Neuro- Ophthalmol, Vol. 19, No. 4, 1999 268 L. FROHMAN AND P. LAMA panophthalmitis), choroiditis and exudative retinal detachment, meningitis with papilledema, and cranial neuropathy ( 52). Nonspecific episcleritis and conjunctivitis occur in early disseminated disease in approximately 10% to 11% of cases. All stages of the disorder are curable with antibiotic therapy, although relapses may occur. Diagnostic testing is largely comprised of various serologic tests and assays as well as culture. The Centers for Disease Control ( CDC) established a clinical definition of Lyme disease based on a combination of clinical signs and symptoms as well as results of laboratory test-ing ( 53). Diagnostic Modalities The classic clinical manifestation of an expanding rash after a tick bite occurring in a patient from a region of high endemicity for Lyme disease presents no diagnostic difficulty. Such a presentation carries a pretest probability of Lyme disease in the absence of any serologic testing of at least 80% as estimated by an expert panel ( 53). However, the clinician is not always fortunate enough to have a patient with such a presentation. Because Lyme disease is a systemic condition with protean manifestations and symptoms often occurring after a long period of latency without a history of an ECM- like rash or patient recollection of a tick bite, the diagnosis is considerably more difficult. This is especially true in those who present with late- stage presentations such as ocular or neuro- ophthalmic signs and symptoms. In these situations, the clinician will have to rely on the results of serologies to establish a diagnosis. Laboratory testing, however, often potentiates the confusion. The current laboratory modalities commonly available for diagnosis of Lyme disease include enzyme- linked immunosorbent assay ( ELISA) to detect the presence of antigen- specific IgM and IgG antibodies, indirect immunofluorescence assay ( IFA), antibody- capture immunoassay ( EIA), Western blotting, and, for confirmation, PCR, and culture. Unfortunately, there are significant limitations of serologic and laboratory testing. The pitfalls of such testing include a false positivity rate of as high as 7% in individuals with no known exposure, lack of interlabo-ratory standardization, and overall poor reliability and accuracy with as many as 21% of positive samples missed. Cross- reactivity with some syphilis serologic tests adds to the difficulty and confusion ( 54). In addition, there are between 5% and 10% of patients with positive serology as a result of previous infection who do not have active disease, meaning that their symptoms are a result of a condition other than Lyme disease. ELISA alone only has a sensitivity and specificity of 89% and 72%, respectively. The sensitivity is even less ( 50%) in the early stages of infection since it takes as long as 4 to 6 weeks after infection for seroconversion to occur. Additionally, because PCR can amplify DNA from dead or live spirochetes, it cannot distinguish active from inactive disease. Specimens for culture are of low yield unless a biopsy sample is obtained from the leading edge of suspected ECM lesions ( 55). The limitations of laboratory testing can unfortunately lead to both under- or overdiagnosis. The problem of overdiagnosis has been in part contributed by unwarranted enthusiasm on the part of the practitioner in assigning a Lyme disease diagnosis. This is partly related to the epidemic nature of the illness and high levels of patient awareness and anxiety regarding this condition. Thus, despite lack of firm clinical or laboratory evidence, many unnecessary treatment regimens have been administered. Reid et al. ( 56), at the Yale Lyme Disease Clinic, studied 209 patients with a presumptive diagnosis of Lyme disease assigned by their referring physicians and found that only 21% met their criteria for active Lyme disease. In these cases, 19% had previous infection but not active disease and 60% had no evidence of Lyme disease, active or past. Additionally, those classified as having previous disease or no evidence of disease had considerable use of health resources, had frequent minor adverse reactions, reported significant disability, and had high rates of depression and stress. It is quite apparent that specific guidelines are necessary to diminish unwarranted use of laboratory tests and inappropriate treatment. Recently the American College of Physicians established guidelines for laboratory evaluation of Lyme disease following the study of Tugwell and colleagues ( 57) on the use of laboratory testing in patients suspected of having this disease. They extracted clinical, epidemiological, and laboratory data by searching relevant articles in MEDLINE between 1982 and 1996. The data were used to calculate sensitivity, specificity, and likelihood ratios, and a random- effects model was used to combine the proportions from eligible studies. Three clinical scenarios were used as examples, and the predictive values of laboratory testing in each clinical situation were calculated. Guidelines were then formulated for laboratory testing of patients suspected of having Lyme disease based on the predictive values obtained. They concluded that those patients with a pretest probability of > 0.80 and < 0.20 should not undergo laboratory testing. In the former situation, a positive test confirms the diagnosis and a negative test only lowers the post- test probability to 0.63. Such patients should thus be treated empirically. In the latter situation, the pretest probability is so low that a positive test would more likely be a false positive rather than a true positive and a negative test would essentially rule out Lyme disease. This is true even if the patient is from a highly endemic area. Such patients should be evaluated for other diagnoses. Their analysis unfortunately did not include patients with more unusual manifestations such as neuro- ophthalmic or ocular manifestations; thus guidelines for this subset could not be established, but the authors did recommend two- step serologic testing as described previously while further studies are available. Diagnosis of neuroborreliosis requires a high index of clinical suspicion since the manifestations often occur long after clinical exposure and the symptoms may be nonspecific. Currently, the most sensitive diagnostic test is the demonstration of intrathecal antibody production. For patients with pretest probabilities between 0.20 and 0.80, sequential, serologic testing J Neum- Ophlhalmol, Vol. 19. No. 4, 1999 ANNUAL UPDATE OF SYSTEMIC DISEASE: PART I 269 with ELISA followed by Western blotting should be performed. This was supported by Porwancher ( 58) who analyzed IgM Western blot criteria by using bayesian analysis to compute the probability that the results of a patient's Western blot test represents true Lyme disease. He found that patients with low pretest probabilities of between 1% and 10% yielded post- test probabilities of 4% to 32%. Use of other assays such as T- cell proliferation responses need further validation. This assay in one study was not only positive in 11 of 12 patients with Lyme disease but also in eight of 12 normals ( 59). With respect to PCR assays, the published studies are insufficient to allow guidelines for their use. However, PCR assays of CSF and joint fluid may be promising. Thus it is essential that before initiating a serologic workup, a reasonable pretest probability should be determined based on the available clinical and epidemiological data. A cost- effective analysis of various treatment strategies would hence be useful in substantiating such guidelines. This was investigated by Nichol et al. ( 60), who performed a cost- effective analysis of four different test- treatment strategies in patients with suspected Lyme disease. These were ( i) no testing- no treatment, ( ii) testing with ELISA followed by antibiotic therapy in those patients with positive test results, ( iii) two- step testing with ELISA followed by Western blotting followed by antibiotic treatment in those patients with a positive result on either test, and ( iv) empirical antibiotic therapy. They concluded, as did Tugwell et al. ( 57), that the no testing- no treatment strategy should be applied to those with a low pretest probability of Lyme disease, empiric antibiotic therapy to those with a high pretest probability, and two- step testing to those with intermediate probability. It is hoped that adherence to these published guidelines would greatly reduce the cost of unnecessary testing and prevent treatment- related complications. Thus, it seems clear that reappraisal of existing diagnostic techniques and development of novel ones that may enhance a clinician's ability to assign or refute a diagnosis of Lyme Borreliosis is necessary. Currently Western blot analysis tests for a panel of antigens that are specific for Lyme infection. Engstrom et al. ( 61) established criteria for IgM blot positivity that require the presence of antibody for two of three of the following antigens: Osp C ( 24 kDa), BmpA ( 39 kDa), or FlaB ( flagellin, 41 kDa). An IgG Western blot is considered positive if five of ten bands are present. The greater the specificity of the separated antigens, the fewer the false-positive test results. There is accumulating evidence that a 37- kDa antigen may be important in the early IgM response. Gilmore and co- workers ( 62) recently isolated, cloned, and expressed this antigen and found that it was a flagellar outer sheath protein termed FlaA. A recombinant form was expressed, and sera from individuals with Lyme disease and negative controls were tested for reactivity against it. They found that 38% of Lyme disease patients tested positive, which increased to 57% when convalescent sera were assayed, but none of the controls tested positive ( 100% specificity). Therefore, inclusion of this putative flagellar outer sheath protein as part of a standardized panel of antigens for IgM immune antibody detection may significantly improve the specificity of Western immunoblot serodiagnostic testing. As mentioned previously, culturing B. burgdorferi usually gives a low yield except when obtained from the margin of an ECM rash via punch biopsy. Phillips et al. ( 63), however, prepared a culture medium that would allow growth of cell wall- deficient organisms or L-forms. Using their technique they were able to demonstrate growth of B. burgdorferi in 43 of 47 ( 91%) of patients with chronic Lyme disease, in many of whom serologic testing was inadequate to make a definitive diagnosis. Positive cultures were confirmed by fluorescent antibody immune- electron microscopy using monoclonal antibody against Osp A and Osp A PCR. The specificity was 100% when healthy controls were cultured. Since a standard for an infectious disease diagnosis is a positive culture, this new method of culturing Borrelia sp may be an excellent candidate for the gold standard for laboratory diagnosis of Lyme disease. We previously alluded that diagnosis of neuroborre-liosis is more challenging. To establish a diagnosis of CNS Lyme disease, several criteria need to be fulfilled while maintaining a high index of suspicion. Exposure to the appropriate ticks in an endemic area, a compatible neurologic deficit not explainable by any other condition, and at least one of the following: 1. documented ECM rash or biopsy proven B. burgdorferi lymphocytoma or acrodermatitis chronica atrophicans, 2. intrathecal antibody production ( current gold standard indicator of CNS Lyme infection), 3. other organ- system involvement with elevated serum titers of specific antibody, 4. fourfold rise in titers in paired serologic specimens, 5. histologic or PCR proof of the presence of B. burgdorferi are necessary to make the diagnosis. Since lumbar puncture is a necessary procedure in the workup of virtually any neurologic disorder, CSF testing for Lyme antibody is critical in those patients with a reasonable pretest probability for Lyme infection. A positive test usually indicates CNS infection. On the other hand, a normal CSF should not be used to exclude Lyme disease if the clinical suspicion is high. Although serum antibody levels are usually abnormal in those with documented intrathecal production of antibody, a positive CSF assay may occur in the absence of detectable serum levels if the patient has already received antibiotic therapy but at insufficient total dosage for eradication of CNS infection or the patient is in the early stages of infection. A false- positive result may occur but happens rather infrequently ( three of 77 [ 4%] in one study) ( 64,65). Ophthalmic Manifestations Most of the unusual Lyme manifestations reported in the literature in the past 2 years that involved the CNS J Neuro- Ophthalinol, Vol. 19, No. 4, 1999 270 L. FROHMAN AND P. LAMA did not involve the visual system or the globe and its structures. However, Miyashiro et al. ( 66) reported a case of nummular interstitial keratitis in a 57- year- old man who had contact with freshly killed deer and later developed foreign- body sensation in his right eye. He was found to have interstitial keratitis and was initially treated for herpes simplex stromal keratitis. Systemic workup only revealed a positive Lyme ELISA ( 178 U/ mL; normal, < 159 U/ mL). Although the background of this case, specifically the patient's contact with freshly killed deer, is highly suggestive of possible Lyme infection, several other factors are necessary to calculate the pretest probability of infection. Such factors include inactivity rate of the deer in the geographic location the animal inhabited, the patient's travel history to locations of high endemicity, and history of an EM- like rash or arthritis. If the demographics reveal low infectivity rate for the deer, low prevalence of Lyme borreliosis in the area, no travel to endemic regions, and no rash or other supporting systemic signs and symptoms, then the pretest probability for Lyme disease would be low. Thus, the likelihood that the positive ELISA test was actually a false- positive result would be high. Other important factors to consider in determining whether this was truly Lyme keratitis include the experience and reliability of the laboratory in assaying for Lyme antibody, results of Western blot analysis, as well as ocular and antibody titer response to antibiotic therapy. A specific diagnosis in a uveitis patient is often lacking. Results of a workup are often unrevealing and misleading. Lyme titers are usually ordered as a part of a battery of tests despite a lack of any specific history. To assess the utility of such testing, Mikkila and co- workers ( 67) evaluated 161 uveitis patients who reside in endemic areas for serum antibodies to B. burgdorferi. They found elevated levels in 26 patients ( 16.1%); however, only four ( 2%) patients had a history that would corroborate a Lyme diagnosis due to history of a tick bite, systemic symptoms, response to antibiotic therapy, or a positive PCR result. They concluded that such nonselective testing for Lyme disease was inappropriate even in patients coming from endemic areas. This is consistent with the previously mentioned recommendations. In a subsequent paper, however, Mikkila and colleagues ( 68) suggested that Lyme disease should be in the differential diagnosis in patients specifically manifesting intermediate or posterior uveitis. They reported seven cases over a 1- year period in 160 consecutive patients ( 4.3%). Four of the seven ( 57%) had positive ELISA from serum or CSF and two ( 29%) had positive PCR from serum or CSF. Six of the patients had a clinical history compatible with Lyme disease as a result of an ECM rash or other systemic symptoms compatible with those of Lyme disease or had a clinical response to antibiotics. Neurologic Manifestations The most common neurologic manifestations of Lyme disease include cranial neuropathy, lymphocytic meningitis, and encephalomyelitis. In patients with a more indolent course a disseminated mononeuropathy multiplex or a mild encephalopathy manifesting as nonfocal cognitive or memory deficits as well as neuropsychiatric abnormalities may occur. A post- Lyme syndrome may also occur, manifest with alterations in mood and cognition, in addition to symptoms of fatigue. Kan et al. ( 69) recently reported a case of pseudotumor cerebri in an 8- year- old child manifesting with acute onset headache, papilledema, and sixth nerve palsy. She was treated with ceftriaxone for 4 weeks and acetazol-amide with reduction in CSF opening pressure and resolution of papilledema and diplopia. A mild residual ab-ducens nerve palsy remained at 2 months after treatment. Twelve other cases were reviewed; however, 11 of 12 patients presented with systemic findings and signs of Lyme disease before the development of pseudotumor cerebri. Overall the authors report an excellent prognosis for Lyme- associated pseudotumor cerebri. Corticosteroids, serial lumbar punctures, shunt procedures, and other diuretics have not been used in this form of pseudotumor cerebri. Kobayashi et al. ( 70) described a case of an unusual form of encephalomyelitis in a 36- year- old Japanese woman, who had previously lived in the United States, who manifested with progressive cerebellar signs and mental deterioration. Clinically she had significant elevations in serum antibodies to the Lyme spirochete. She eventually died and at autopsy was found to have multifocal inflammatory changes in the cerebral cortex, thalamus, superior colliculus, dentate nucleus, inferior olivary nucleus, and spinal cord. Use of Warthin- Starry stain revealed organisms consistent with the appearance of B. burgdorferi. Occlusive vasculopathy as well as lymphocytic infiltration of the meninges were found. The pathology in many ways mimics that seen in CNS infection with Treponema pallidum. The syphilis spirochete is often associated with vasculitis, and obliterative endarteritis is typically seen in patients with meningovascular syphilis. The report by Oksi et al. ( 71) demonstrates the potential for B. burgdorferi generating cerebral vasculitis. Oksi et al. described three patients with known Lyme borreliosis who developed intracranial aneurysms. One of the three patients had a brain biopsy that demonstrated lymphocytic vasculitis and perivasculitis. This patient and one of the other two developed a subarachnoid hemorrhage. This is the first case report of cerebral artery aneurysm associated subarachnoid hemorrhage secondary to Lyme borreliosis; Lyme- associated coronary artery aneurysm was previously described in two patients with long- standing borreliosis. Although tissue was not available to establish a causal relationship in the other two patients, the propensity for this organism to invade vascular endothelial cells is known, and thus the association between Lyme disease and aneurysms merits serious causal consideration in clinical scenarios in which both conditions coexist. Treatment The treatment of Lyme borreliosis depends on the stage of the disease and presence or absence of CNS / Neuro- Ophthalmol, Vol. 19, No. 4, 1999 ANNUAL UPDATE OF SYSTEMIC DISEASE: PART I 271 infection. Oral doxycycline and amoxicillin are both effective, and a total of 10 days to 2 weeks of therapy is likely to be sufficient in patients with early manifestations such as an ECM rash. Amoxicillin is the preferred antibiotic in children and pregnant or lactating women. Cefuroxime axetil should be given to those in whom doxycycline is contraindicated or who are penicillin allergic. The macrolide antibiotics erythromycin or azithromycin can be substituted but have been found to be less effective ( 73- 75). In a large, randomized, double-blind trial in patients with erythema migrans, amoxicillin was found to be superior to azithromycin in establishing a cure with a lower rate of relapse 6 months after treatment was initiated. Longer courses are necessary for those with arthritic manifestations. Patients who have objective neurologic involvement, with the possible exception of facial palsy, are recommended to have parenteral antibiotics and a longer duration of therapy. Ceftriaxone 2 g/ day intravenously for approximately 4 weeks is a standard regimen. Patients with facial palsy and an abnormal CSF should also probably be treated intravenously. Thus, patients with Lyme facial palsy should undergo lumbar puncture to determine whether CSF antibody is present to determine route of administration. There is a recent report by Dotevall and Hagberg ( 76), however, that challenges the requirement for intravenous therapy in patients with neurologic manifestations. They treated 29 patients with Lyme infection and facial palsy and meningitis with oral doxycycline at a daily dose ranging between 200 and 400 mg for 9 to 17 days. Ninety percent of patients recovered without sequelae at 6 months. Post- treatment CSF evaluation disclosed a marked decrease in inflammatory cells and protein concentrations compared with pretreatment levels. This outcome compares favorably with published studies using intravenous antibiotics for Lyme- associated meningitis and facial palsy. Thus, it is conceivable that patients with milder CNS involvement may be adequately treated as outpatients with oral antibiotics. A prospective randomized trial would be helpful in deciding the most appropriate route of administration. At present there are no published guidelines for therapy of purely ocular manifestations. This is likely partly due to the low frequency in total number of cases of ocular involvement. However, the authors recommend intravenous therapy for 4 weeks for sight- threatening manifestations such as optic neuropathy and oral antibiotics for 2 weeks for anterior segment nonsight threatening conditions. Prophylaxis Prevention of Lyme infection can be approached in various ways including tick eradication, protection against tick exposure, antibiotic prophylaxis post- tick bite, or vaccination. Individuals who travel or go hiking in wooded tick- infested regions should wear long trousers tucked into socks with periodic checking for ticks. Post- tick bite antibiotic prophylaxis has not always been found to be useful for prevention of infection. The tick may not belong to the Ixodid genus, prolonged exposure is necessary for infection to occur, and not all Ixodid ticks harbor the spirochete. Even in areas of high Lyme disease prevalence, the percentage of ticks infected may only be one in three. A study in the Lyme, CT, area determined that the overall risk of Lyme disease in placebo- treated patients was only 1.2% ( 77). The sum of the results of published studies regarding antibiotic prophylaxis is equivocal. Patient anxiety about Lyme disease undoubtedly plays a role in compelling the physician to initiate antibiotic prophylaxis. Thus with the published uncertainty, the decision for such treatment will depend on multiple factors, some of which are unrelated to the pathogenesis of infection. Indeed, current physician practices support the lack of uniformity with respect to antibiotic prophylaxis. Since reinfection does not occur in patients with an expanded immune response against Borrelia antigens, a vaccine that can potentially confer long- term immunity against Lyme disease is possible. In particular, outer surface protein A ( OspA) antigens have been found to be highly immunogenic. A recombinant single protein OspA preparation was thus developed. This vaccine preparation was shown to confer protective immunity against B. burgdorferi in multiple animal trials involving mice and dogs. The mechanism of action is prevention of transfer of spirochete from tick to host via antibody-mediated killing of the spirochete in the tick midgut. Such success subsequently led to safety trials in humans and finally to a multicenter, double- blinded, placebo-controlled study initiated in 1994. This study compared a 30 fxg dose of the recombinant vaccine against a placebo vaccine. A total of 10,306 volunteers, ages 18 to 92 years, enrolled in this study involving 14 centers in the United States. The results indicate that the vaccine effectively confers protection up to 20 months after the first injection; however, a third dose is necessary to boost antibody levels and achieve a protection rate of greater than 80% ( 78,79). A trial investigating the efficacy in the pediatric population is underway. Although the vaccine appears to be efficacious, long- term immunity is unclear. Since antibody levels diminish fairly rapidly and protection is conferred by extent of antibody titers, it is logical that booster shots will be necessary periodically. Despite the early positive published results, a number of questions have yet to be answered. Cost- effectiveness is certainly a paramount issue. The facts are Lyme disease is not lethal, all stages of infection respond to antibiotics, and early disease such as erythema migrans can be effectively treated at a cost of $ 15 per patient. Moreover, the vaccine would make breakthrough infection or seroconversion difficult to determine, and Western blot analysis of other antigens would need to be performed. The false- positive rate will undoubtedly increase in this scenario. Finally, the full safety profile including the risk in pregnant women and those with immunologic disorders or higher risk HLA antigens was not evaluated and remains to be determined. For example, individuals who have the HLA- DR4 haplotype are at higher risk for development of chronic Lyme arthritis. This antigen preparation in an HLA- DR4 positive individual may in fact stimulate an antibody response that by molecular J Neuro- Ophthalmol, Vol. 19, No. 4, 1999 272 L. FROHMAN AND P. LAMA mimicry leads to a pathologic response in synovial tissue ( 80). 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