Walsh and Hoyt's Clinical Neuro-Ophthalmology

Spirochetal Diseases

"Spirochetes are widely distributed in nature and often are found in aquatic environments, but they colonize humans. All spirochetal infections are characterized by skin or mucous membrane penetration followed by a spirochetemia that produces damage during several clinical stages (2)."

CHAPTER 56 Spirochetal Diseases Robert L. Lesser BORRELIA SPECIES Other Diseases Caused by Treponema Species Lyme Disease LEPTOSPIRA AND LEPTOSPIROSIS Relapsing Fever Clinical Manifestations TREPONEMA SPECIES Diagnosis Syphilis Treatment Syphilis, Human Immunodeficiency Virus Infection, and the Acquired Immune Deficiency Syndrome (AIDS) Spirochetes are motile, slender, Gram-negative bacteria that are 0.1-3.0 m long, coiled in a helical shape (1), with one or more complete turns in the helix (Fig. 56.1). Wound around the helical protoplasmic cylinder and encased in an outer sheath are numerous periplasmic flagella, also called axial fibrils, axial filaments, or endoflagella that are thought to be responsible for locomotion of the organisms. Spirochetes belong to the order Spirochetales. This order contains two families: Spirochaetaceae and Leptospiraceae. Of the four genera in the family Spirochaetaceae, Treponema and Borrelia contain species that cause significant human disease. The family Leptospiraceae contains a single genus, BORRELIA SPECIES Like all spirochetes, Borrelia species are Gram-negative helical organisms that are 0.2-0.5 m wide and 3-20 m long, with a protoplasmic cylinder surrounded by a cyto-plasmic membrane, then by periplasm and, finally, by an outer membrane. Borrelia are longer and more loosely coiled thanother spirochetes (1). There are 19 species of Borrelia. B. burgdorferi is responsible for all cases of Lyme disease inthe United States, whereas B. afzelii and B. garinii are responsible for the disease in Europe and Asia (2). Other Borrelia species cause relapsing fever. LYME DISEASE Lyme disease is a tick-borne spirochetal infection that is the most commonvector-born e disease inthe United States (2). It was first described in1977 after 39 children and 12 adults developed a unique, remitting-relapsing, oligoarticu-lar arthritis that at first was thought to be a form of juvenile 3077 Leptospira, and one major species in it, L. interrogans, is pathogenic for humans (1). Spirochetes are widely distributed in nature and often are found in aquatic environments, but they colonize humans. All spirochetal infections are characterized by skin or mu-cous membrane penetration followed by a spirochetemia that produces damage during several clinical stages (2). Many of the diseases they produce-Lyme disease, relapsing fever, leptospirosis, and syphilis (Table 56.1)-have unique ocular and neuro-ophthalmologic findings. Others, such as bejel, yaws, and pinta, are of less importance and will not be dis-cussed inan y detail inthis text. rheumatoid arthritis. The condition initially was called Lyme arthritis because the first cases were clustered inthree adjoin-ing communities of Lyme, Old Lyme, and East Haddam, Connecticut, and because the main feature of the disease was the arthritis (3). It was renamed Lyme ‘‘disease'' in recognition of its multi-system involvement, including the skin, heart, joints, and both the peripheral and central ner-vous systems. A tick vector from the Ixodes ricinus complex was identified shortly thereafter (4,5), and within a few years, a previously unidentified spirochete, Borrelia burg-dorferi, was recognized as the causative agent (6,7). In retro-spect, certain features of the disease, including the classic initial skin lesion-erythema migrans (discussed lat-er)- and the peripheral nervous system findings had been described years earlier (3,8) but the disease itself had not. Lyme disease occurs throughout the world but is most prevalent in the United States and Western Europe (9). About 15,000 cases of Lyme disease are reported annually 3078 CLINICAL NEURO-OPHTHALMOLOGY Figure 56.1. Morphology of spirochetes. A, Dark-field microscopy of Borrelia burgdorferi. 600. B, Electron micrograph showing the longitudinal appearance of Trepo-nema pallidum. (A, From Preac-Mursic V, Pfister HW, Spiegel H, et al. First isolationof Borrelia burgdorferi from aniris biopsy. J ClinNeuroophthalmol 1993; 13 155-161. B, From Paris-HamelinA. Syphilis serology in1991. J ClinNeuroophthalmol 1991;11 144-151.) inthe United States. Most cases occur inthe Northeast from Maine to Maryland, but many cases also occur in the Mid-west in Wisconsin and Minnesota and in the West in northern California and Oregon (10) (Fig. 56.2A). The incidence of Lyme disease inthe United States has almost doubled in the last decade (Fig. 56.2B), due inpart to better recognitionof its clinical manifestations and improved diagnostic tests and inpart to the increase inthe number of deer, the preferred Table 56.1 Spirochetes and the Human Diseases They Produce Organism Disease Borrelia burgdorferi Lyme disease Borrelia species Relapsing fever Louse-borne Tick-borne Treponema pallidum pallidum Syphilis Treponema pallidum pertenue Yaws Treponema pallidum endemicum Bejel (endemic syphilis) Treponema carateum Pinta Leptospira interrogans Leptospirosis Anicteric Icteric host of the tick that transmits the disease in the Northeast United States. In 2002, for example, 23,763 cases were re-ported in the United States (11). In Europe, a similar increase incases has beenn oted, particularly inwooded areas of Germany, Austria, Slovenia, and Sweden (12). As noted previously, Lyme disease is transmitted by ticks belonging to the Ixodes ricinus complex (2,9). Inthe North-east and in the Midwest regions of the United States, the disease is transmitted by the Ixodes scapularis (also called I. dammini) tick, first in the immature larval and nymphal stage to white-footed mice and theninthe adult stage to deer (Fig. 56.3). Ticks need a blood meal from their host at each stage of development. Although humans may be bitten at any of these three stages, the disease occurs most fre-quently in late spring or summer when feeding by nymphs is most common (Fig 56.4). Many persons are bitten by infected ticks, but tick attachment for at least 24 hours after feeding is required for transmission of the spirochete (13). Thus, the number of persons who develop Lyme disease after the bite of anin fected tick is relatively small. Neverthe-less, for the reasons mentioned above, the number of cases reported in the Northeast United States continues to rise each year. Despite the rise incases inthe Northeast United States, the incidence of Lyme disease in Northern California and Oregonremain s low because the mainhost tick, I. neotomae, SPIROCHETAL DISEASES 3079 A B Figure 56.2. Epidemiology of Lyme disease inthe United States. A, Number of cases by county in the United States in 2000. Total number of cases from counties shown in black represented 90% of all cases that year. B, Number of cases of Lyme disease in the United States by year, from 1982 through 2000. (From Centers for Disease Control and Prevention. Lyme disease-United States 2000. MMWR 2002;51 29-31.) 3080 CLINICAL NEURO-OPHTHALMOLOGY A B C D Figure 56.3. The mainvector of Lyme disease, the hard-bodied deer tick, Ixodes scapularis (previously called Ixodes dammini). A, (left to right), Larva, nymph, adult male, and adult female forms of Ixodes scapularis. Note marked differences in size among forms. B, Nymph form of I. scapularis ona blade of grass. C, Adult female form of I. scapularis ona blade of grass (arrowhead). The much larger dog tick, Dermacentor variabilis, is below the deer tick for comparison. D, Adult form of I. scapularis during feeding. The tick's head is completely below the animal's skin. (A, From Reik L Jr. Lyme disease. InScheld WM, Whitley RJ, Durack DT, eds. Infections of the Central Nervous System. New York, Raven Press, 1991 657-692. B-D, From Matuschka FR, SpielmanA. The vector of Lyme disease spirochete. N Engl J Med 1992;327 542.) does not bite humans. Thus, only the I. pacificus ticks that feed on infected wood rats in the larval stage transmit the disease to humans in this part of the country (2). In Europe, the principal vector is I. ricinus and, in Asia, I. persulcatus (14). Clinical Manifestations Lyme disease consists of three main stages. Stage 1 is the stage of early infection. Stage 2 is the stage of early dissemination. Stage 3 is the stage of chronic dissemination. Stage 1 (Early Infection) Inabout 80% of cases, Lyme disease begins with a skin lesioncalled erythema migrans (3,9,15,16). The lesionoc-curs at the site of the tick bite beginning as an erythematous macule or papule, expanding circumferentially, often in-creasing to several dozen centimeters. The rash develops within a few days of the bite and, as it expands, there often is central clearing giving the appearance of a bull's eye. The rash usually is asymptomatic, occurring most frequently in the thigh, groin, or axilla in adults, and more commonly on the scalp, neck, and face in children (Fig. 56.5). Frequently, affected individuals initially have a flulike illness with fever, chills, headache, arthralgias, myalgias, malaise, and regional lymphadenopathy. There usually are no upper respiratory or gastrointestinal symptoms with the flulike illness, although some affected individuals also have lethargy, neck stiffness, and even mild confusion. Conjunctivitis occurs in about 10% of cases. Most of these early findings clear within about 3 to 4 weeks. Stage 2 (Early Dissemination) Within a few weeks to months after early infection, pa-tients may develop early disseminated Lyme disease charac-terized primarily by joint, cardiac and/or neurologic involve-ment (3,9,16,17). SPIROCHETAL DISEASES 3081 Figure 56.4. Life cycle of the deer tick, Ixodes scapu-laris (Ixodes dammini). (From ZaidmanGW. The ocular manifestations of Lyme disease. Int Ophthalmol Clin 1993; 33 9-22.) NEUROLOGIC About 15-20% of patients develop neurologic findings including lymphocytic meningitis, facial nerve palsy and a painful radiculitis (17). Lymphocytic meningitis is the most common neurologic disturbance. It is characterized by mild headache, neck stiffness, photophobia, and nausea and vom-iting. Pleocytosis, with elevated protein, often is seen. Some patients have a low-grade encephalopathy, whereas others, particularly children, develop elevated intracranial pressure, oftenassociated with papilledema (17). Insuch cases, B. burgdorferi oftencanbe cultured from the spinal fluid. Facial nerve palsy, both unilateral and bilateral, fre-quently occurs in patients with second-stage Lyme disease (17). It may be associated with signs and symptoms of men-ingitis, or it may occur in isolation. It occasionally is pre-ceded by swelling, erythema, and paresthesias of the face, particularly inbilateral cases (18,19). Isolated bilateral si-multaneous or sequential facial nerve palsy is a rare neuro-logic manifestation except in patients with Lyme disease and, to a lesser extent, in patients with sarcoidosis (see Chap-ter 59). Thus, all patients with bilateral simultaneous or se-quential facial nerve palsies should be screened for Lyme disease (19) (Fig. 56.6). Cranial neuropathies other than facial nerve palsy can occur in patients with second-stage Lyme disease. These include ocular motor nerve pareses, singly or in combination, and hearing loss (17,19-21). Patients who develop cranial neuropathies in this setting often show enhancement of the affected nerves on magnetic resonance (MR) imaging (Fig. 56.7). A small percentage of patients with second-stage Lyme disease develop severe central nervous system (CNS) manifestations, including cerebellar ataxia, cerebral vasculi-tis, transverse myelitis, encephalitis, and brainstem damage (17). Some patients even develop a steroid-sensitive intracra-nial mass that may be mistaken for primary lymphoma (22). In addition to CNS manifestations, a substantial percent-age of patients with second-stage Lyme disease develop a radiculitis, or peripheral neuropathy (17,21). The most com-mon features include severe radicular pain, intermittent or constant limb paresthesias, and hypesthesias on the trunk or proximal limbs. Electrophysiologic testing in such cases reveals evidence of axonal sensorimotor polyradiculoneur-opathy or polyradiculopathy (21). CARDIAC About 5% of patients with second-stage Lyme disease develop cardiac involvement (23,24). The most common manifestations are atrioventricular block, myocarditis, and left-ventricular dysfunction. Less commonly, pancarditis de-velops. The cardiac disease that occurs inLyme disease ap- 3082 CLINICAL NEURO-OPHTHALMOLOGY A C Figure 56.5. Skinlesion s of acute Lyme disease. A, Classic erythema migrans lesion(9 cm indiameter) near the axilla. The lesionhas partial central clearing, a bright red outer border, and a target center. B, Abdomi-nal erythema migrans rash with central clearing. C, Multiple erythema migrans rashes on back. (A, From Steere AC. Lyme disease. N Engl J Med 2001;345 115-125. B, Courtesy of Dr. David Leffell. C, Courtesy B of Dr. David Leffell.) parently develops from direct infection of the myocardium, as B. burgdorferi oftencan be cultured from this tissue (25,26). JOINTS A substantial percentage of patients with second-stage Lyme disease develop intermittent arthralgias, associated with joint swelling and pain in large joints, especially the knee (27). In about 10% of treated patients, the arthritis per-sists even though live spirochetes cannot be cultured, sug-gesting that this is caused either by vasculitis or an autoim-mune response and not by direct effects of the organism (3,27). OTHER MANIFESTATIONS Patients who develop second-stage Lyme disease may have manifestations other than neurologic, cardiac, or joint disease. Some of these nonspecific manifestations include lymphocytoma of the skin, hematuria, orchitis, lymphade-nopathy, severe malaise and fatigue, nonproductive cough, and mild or recurrent hepatitis (28). Stage 3 (Chronic Dissemination) Months to years after the initial tick bite, about 60% of untreated patients with Lyme disease develop manifestations caused by chronic dissemination of B. burgdorferi (3,9,29). SPIROCHETAL DISEASES 3083 Figure 56.6. Facial nerve paresis in Lyme disease. The patient was a 17-year-old girl who developed the suddenon set of right facial weakness about 3 months after going on a camping trip, during which she was bitten by a tick. A, There is weakness of the entire right side of the face. Note mild right facial erythema and fullness. B, The patient cannot close the right eyelids tightly during attempted eyelid closure. Results of serologic testing and lumbar puncture were consistent with a diagnosis of neuroborrel-iosis. The patient recovered completely after medical treatment. Figure 56.7. Neuroimaging appearance in a patient with stage 2 (early disseminated) Lyme disease (neuroborreliosis) compli-cated by multiple cranial neuropathies. The patient was a 64-year-old woman with diplopia, occipital headaches, and right periorbital swelling that occurred 6 weeks after she went hunting for mushrooms in a wooded area in Western Illinois and 4 weeks after she developed a ‘‘bull's eye'' rash onher thigh that was thought to be a cellulitis. Anexamin ation revealed minimal stiffness of the neck, mild right periorbital swelling, a right abducens nerve paresis, and swelling of the right optic disc. She subsequently developed right facial paralysis. A CT scan revealed a slightly enlarged right optic nerve, and a lumbar puncture showed a normal opening pressure, a mild lymphocytic pleocytosis, and an increased protein concentration of 71 mg/dl. A, T1-weighted axial MR image after intravenous injection of paramagnetic contrast material shows abnormal enhancement of the subarachnoid portions of both oculomotor nerves (between arrows). B, T1-weighted coronal MR image after intravenous injection of paramagnetic contrast material shows an enlarged and enhancing right trigeminal nerve (curved white arrow) as compared to the normal left trigeminal nerve (straight black arrow). The results of serologic studies were consistent with infection with Borrelia burgdorferi, and the patient improved after appropriate therapy. (From Nelson JA, Wolf MD, Yuh WTC, et al. Cranial nerve involvement with Lyme borreliosis demonstrated by magnetic resonance imaging. Neurology 1992; 42 671-673.) 3084 CLINICAL NEURO-OPHTHALMOLOGY These include involvement of joints, skin, and nervous system. JOINTS As noted above, Lyme arthritis usually develops in the second-stage of the disease as a mono- or oligoarticular in-flammatory arthritis. Inmost cases, the arthritis lasts only a few months; however, about 10% of patients develop a chronic disease that eventually causes erosion of cartilage and bone (27). Chronic Lyme arthritis appears to have an immunogenetic basis because it occurs more frequently in patients with HLA-DR4 than in the general population. The arthritis also occurs more frequently in the United States thanEurope (3,27). SKIN Whereas erythema migrans occurs as the first sign of Lyme disease, another skinlesionis characteristic of the third-stage of the disease. Acrodermatitis chronica atro-phicans is the characteristic skinlesionof third-stage Lyme disease (3,30). The skindevelops a bluish-red discoloration with doughy swelling first seen in the distal extremities. Eventually, the underlying subcutaneous tissue atrophies and the skin develops a parchment-like appearance. Unlike ery-thema migrans, which is a self-limited lesion, acrodermatitis chronica atrophicans persists throughout life. NERVOUS SYSTEM Neurologic manifestations develop in about 5% of un-treated patients with Lyme disease (3,31). Chronic encepha-litis is the most common neurological finding, particularly inEurope (Fig. 56.8). Patients who develop this complica- Figure 56.8. Neuroimaging in organic brain syndrome caused by late (chronic disseminated) Lyme disease. T2-weighted MR image in a 32-year-old man with fatigue, decreased memory, and poor concentration caused by late Lyme disease shows three punctate areas of increased signal intensity adjacent to the posterior horns of the lateral ventricles. (From Reik L Jr. Lyme disease. In Scheld WM, Whitley RJ, Durack DT, eds. Infections of the Central Nervous System. New York, Raven Press, 1991 657-692.) tion may have difficulty with gait, bladder dysfunction, hear-ing loss, poor memory, severe cognitive problems, and, rarely, dementia. Symptoms usually are gradual in onset. Some patients, particularly those in the United States, de-velop an encephalopathy consisting primarily of subtle cog-nitive disturbances (31). Others develop spastic paraparesis or transverse myelitis with bladder dysfunction, stroke, or evidence of cerebellar dysfunction. More commonthanCNS dysfunctioninthe third-stage of Lyme disease is the occurrence of a peripheral neuropathy, characterized by intermittent paresthesias or radicular pain and consistent with mononeuritis multiplex or diffuse poly-neuropathy (31,32). Electrophysiologic testing in these pa-tients demonstrates evidence of an axonal neuropathy (32). Ocular Manifestations of Lyme Disease Ocular findings in Lyme disease are not common (33,34). A nonspecific, self-limited follicular conjunctivitis occurs in about 10% of stage-one Lyme disease. Periorbital edema, photophobia, ocular and facial pain, and subconjunctival hemorrhages also have beendescribed during this stage. Most other manifestations of Lyme disease occur in the sec-ond and third stages (35). Unilateral or bilateral granuloma-tous iridocyclitis, vitritis with a characteristic ‘‘spiderweb'' appearance, choroiditis, chorioretinitis, and pars planitis all are sufficiently common in patients with both clinical and laboratory findings consistent with Lyme disease to suggest a causal relationship (36,37). Occasionally, vitritis is the pre-senting sign of Lyme disease as in the case reported by Schu-bert et al. inwhich a vitreous tap revealed B. burgdorferi (36). In another case of recurrent iridocyclitis, B. burgdorferi was isolated inaniris biopsy (38). The severity of intraocular inflammation caused by Lyme disease ranges from mild to severe. Macular edema, multiple cream colored choroidal infiltrates, pigmentary retinopathy, cystoid macular edema, and a birdshot-like retinopathy have beendescribed. Retinal vasculitis, acute posterior multifocal placoid pigment epitheliopathy, and vitreous hemorrhage at-tributable to Lyme disease also have beenreported (39-41). In addition, a number of authors have described cases of Lyme disease that were complicated by endophthalmitis (42-44). Insome of these cases, B. burgdorferi has been isolated from a vitrectomy specimen. Although nongranulo-matous anterior uveitis can be a manifestation of Lyme dis-ease, it generally is symptomatic, being associated with pain and redness of the affected eye, and, in severe cases, with decreased vision. This presentation is different from that of juvenile rheumatoid arthritis, inwhich affected childrenmay have asymptomatic uveitis. Thus, childrenwith Lyme arthri-tis do not have to undergo periodic screening for intraocular inflammation if they are asymptomatic (45). Corneal complications of Lyme disease are extremely rare. Some patients with second-stage Lyme disease develop subepithelial nummular corneal infiltrates that interfere with visionwheninthe visual axis. These infiltrates usually are bilateral and located within the stroma (Fig. 56.9). Other patients develop interstitial keratitis or peripheral ulcerative keratitis during the third stage of the disease (46,47). Be- SPIROCHETAL DISEASES 3085 Figure 56.9. Stromal keratitis in late (chronic disseminated) Lyme dis-ease. Slit-lamp photograph ina 25-year-old manshows multiple subepithe-lial infiltrates (arrowheads). (From Reim H, Reim M. Augenbefunde bei Infektion mit Borrelia burgdorferi. Klin Monatsbl Augenheilkd 1992; 201 83-91.) cause the infiltrates can be treated with topical steroids, the keratitis probably is immune-mediated rather than caused by active infection (48,49). In addition, patients with second-stage Lyme disease who develop facial nerve palsy may develop exposure keratopathy. Figure 56.10. Orbital myositis in Lyme disease. Contrast-enhanced, fat-suppressed T1-weighted MR images obtained through the orbits show diffuse homogeneous thickening of the medial, lateral, and inferior rectus muscles of the right orbit. Minimal thickening of the superior muscle group can be seen. The tendinous insertions are not involved. Scattered inflammatory changes in the ethmoid sinuses and the left maxillary sinus can be seen. A, Axial view. B, Coronal view. (From Fatterpekar GM, Gottesman RI, Sacher M, et al. Orbital Lyme disease: MR imaging before and after treatment: Case report. AJNR Am J Neuroradiol 2002;23 657-659.) Other rare complications of Lyme disease, usually seen in the second or third stages of the disease include posterior scleritis (50) and orbital myositis (51,52,52a) (Fig. 56.10). Neuro-Ophthalmologic Manifestations of Lyme Disease Like the ocular manifestations of Lyme disease, the neuro-ophthalmologic manifestations occur primarily in the second and third stages of the disease (20,53). As noted above, facial nerve palsies, both unilateral or bilateral, are the most com-moncran ial neuropathies seeninLyme disease, occurring in up to 50% of cases of Lyme meningitis in one series (21). About one-third of the cases are bilateral. Some patients develop unilateral or bilateral sixth nerve pareses either from direct infection or associated with elevated intracranial pres-sure (20,53). Involvement of the oculomotor, trochlear, and trigeminal nerves also has been described. The pathophysiol-ogy of these cranial neuropathies is multifactorial. Mecha-nisms include direct infection, increased intracranial pres-sure, inflammation, immune-mediated, and ischemic. The most common neuro-ophthalmic presentation is either meningitis or meningoencephalitis associated with papilledema with or without sixth nerve palsy (53). This has incorrectly been called pseudotumor cerebri by some authors; however, it actually is an aseptic meningitis because the cerebrospinal fluid (CSF) contains inflammatory cells, an increased protein concentration, and, in some cases, evi-dence of B. burgdorferi (54). Patients usually respond to appropriate treatment with systemic antibiotics and, in some cases, corticosteroids (20,53,54); however, if left untreated, patients with increased intracranial pressure associated with Lyme disease candevelop post-papilledema optic atrophy. 3086 CLINICAL NEURO-OPHTHALMOLOGY Figure 56.11. Neuroretinitis in stage 2 (early disseminated) Lyme disease. The patient was a 32-year-old actress who was performing in an outdoor play in Connecticut when she developed decreased vision in the right eye. She was found to have a right anterior optic neuropathy and was told she had multiple sclerosis. On examination, the patient had visual acuity of 20/50 OD and 20/15 OS. There is moderate swelling and hyperemia of the right optic disc associated with a star figure of hard exudate inthe macula. The results of serologic testing were consistent with infection with Borrelia burg-dorferi, and the patient was treated with systemic antibiotics. The patient was told that she did not have multiple sclerosis. She eventually made a full recovery. Figure 56.12. Unilateral anterior optic neuritis in stage 1 (early disseminated) Lyme disease. The patient was a 39-year-old woman with Lyme disease and evidence of aseptic meningitis who devel-oped acute loss of visionin the right eye. Anexamin ation performed 8 days after visual loss began revealed that the patient had only light perception visioninthe right eye. Left eye vision was normal. The right pupil was amaurotic. A, The right optic disc is swollen. A flame-shaped intraretinal hemorrhage (arrowhead) is present su-perior to the disc, and the retinal veins are mildly dilated and tor-tuous. B, The left optic disc is normal. The patient was treated with a subtenon injection of Kenalog, having recently been treated with both intravenous and oral antibiotics. Visual acuity eventually im-proved to 20/50 inthe right eye, the optic disc swelling resolved, and optic atrophy developed. C, Five weeks after the onset of visual symptoms, the right optic disc is pale, and there is generalized loss of the retinal nerve fiber layer. (From Farris BK, Webb RM. Lyme disease and optic neuritis. J Clin Neuroophthalmol 1988;8:73-78.) SPIROCHETAL DISEASES 3087 The differentiation of meningitis caused by Lyme disease and viral aseptic meningitis may be difficult in the absence of systemic manifestations of Lyme disease; however, the presence of papilledema, lower temperature, longer duration of symptoms, and milder pleocytosis favored the diagnosis of Lyme disease inon e study (55). Although rare, both neuroretinitis (Fig. 56.11) and optic neuritis (Fig. 56.12) have been reported in patients with sec-ond- and third-stage Lyme disease (53,56-59). In one series of pediatric cases, two children had optic neuritis, one unilat-eral and one bilateral (60). One other child in this series developed optic atrophy from elevated intracranial pressure, perhaps in association with optic neuritis. At least one case of chiasmal neuritis also has beenreported inthe setting of Lyme disease (61) (Fig. 56.13). The occurrence of optic neuritis and neuroretinitis in pa-tients with Lyme disease is sufficiently rare that patients who develop either condition and who have a negative history for tick bite, rash, or a recent flulike syndrome, do not require routine testing for Lyme disease. Even in patients with optic neuritis and positive Lyme titers, the two conditions may not be related. For example, Jacobson and colleagues screened patients with isolated optic neuritis who lived in an endemic area and found that four patients (20%) had positive titers for B. burgdorferi (62). Although these authors initially sug-gested that Lyme disease may have beenrespon sible for the optic neuritis in these cases, one of the authors subsequently reviewed his series and concluded that none of the four pa-tients with positive laboratory findings, but no systemic find-ings, had Lyme disease (63). Similarly, although rare in-stances of anterior ischemic optic neuropathy have been reported in patients with laboratory (but not clinical) evi-dence of B. burgdorferi infection, anassociationis unlikely and we do not recommend testing for Lyme disease in pa-tients with otherwise typical anterior ischemic optic neurop-athy unless there is a suggestive history or signs. Neverthe-less, in one series, three patients with optic neuritis all had A B Figure 56.13. Chiasmal optic neuritis in early-disseminated Lyme disease. The patient was a 10-year-old girl with progressive loss of vision in the right eye associated with fatigue as well as ankle, wrist, and temple pain. Visual acuity was light perception OD and 20/20 OS. There was a right RAPD, and the right optic disc was pale. A, Coronal T1-weighted MR scan after intravenous injection of gadolinium shows enlargement and enhancement of the prechiasmal portion of the right optic nerve (arrowhead). The patient was found to have serologic evidence of Lyme disease and was treated with systemic antibiotics. B, T1-weighted, enhanced, coronal MR image after treatment with antibiotics shows that the right prechiasmal portion of the optic nerve is no longer enlarged and does not enhance. (From Scott IU, Silva-Lepe A, Siatkowski RM. Chiasmal optic neuritis in Lyme disease. Am J Ophthalmol 1997;123 136-138.) classic findings of Lyme disease to justify a true association and other convincing cases reported in the literature. Uncom-mon neuro-ophthalmologic findings in patients with other-wise typical Lyme disease include Horner syndrome and Argyll Robertson-like pupils (20,33,53) (Fig. 56.14). Chronic Lyme Disease Some patients develop pain, fatigue, and cognitive diffi-culties after well-documented infection by B. burgdorferi. Symptoms may include fatigue, sleeping difficulties, prob-lems with memory, and difficulty with concentration. These patients do not have any response to additional treatment beyond the standard short-term therapy (see below). In one study of patients given prolonged treatment, there was no difference in treatment response between the group treated with antibiotics and the group given placebo (64). The Infec-tious Disease Society of America has concluded that ‘‘chronic'' Lyme disease should not be considered as a sepa-rate entity because there is not enough evidence to distin-guish it from either fibromyalgia or chronic fatigue syn-drome (65). Unfortunately, many patients with nonspecific findings such as pain and fatigue but with no clinical or serological evidence have been incorrectly diagnosed with and treated for ‘‘chronic Lyme disease'' (66,67). DIAGNOSIS A clinical diagnosis is appropriate when a patient with a history of a tick bite or who has beeninan endemic area develops classical erythema migrans. Rapid expansion of the rash helps distinguish it from other types of rashes (68). In the absence of such a lesion, the diagnosis is made by recognition of other clinical findings combined with the re-sults of serologic testing using both an enzyme-linked immunoabsorbent assay (ELISA) and a Western blot test for confirmation(9,69 -71) (Table 56.2). Westernblot is consid-ered positive inacute disease if two of three IgM bands are 3088 CLINICAL NEURO-OPHTHALMOLOGY Figure 56.14. Transient preganglionic Horner syndrome in Lyme disease. The patient was a 30-year-old man with a history of a tick bite, following which he developed headache, a low-grade fever, chills, myalgias, malaise, and a stiff neck. He then developed an erythematous target-shaped rash on the left calf and experienced an episode of lightheadedness while urinating. He went to a local hospital, where a diagnosis of Lyme disease was made, and treatment with oral tetracycline was begun. About 2 days later, he noted drooping of the left upper eyelid and an inequality in the size of his pupils. A, Left Horner syndrome. Note mild left ptosis and anisocoria with left pupil smaller than right. The results of pharmacologic testing were consistent with a preganglionic left Horner syndrome. The patient was treated with a 10- day course of intravenous antibiotics and noted gradual improvement in both ptosis and anisocoria. B, After 10 days of antibiotic therapy, the Horner syndrome has generally resolved. (From Glauser TA, Brennan PJ, Galetta SL. Reversible Horner's syndrome and Lyme disease. J Clin Neuroophthal-mol 1989;9:225-228.) positive. After about 6 weeks, if 5 of 10 specific IgG bands are present, the diagnosis is considered confirmed. Unfortu-nately, these tests often are negative within the first few weeks of infection, with about 20-30% of infected patients having a positive IgM response. By 4 weeks, however, 95-99% of patients have a positive IgG response. In patients who have beenill for more thana month, a positive IgM by itself is not diagnostic of Lyme disease (71). In patients with Lyme meningitis, a positive ELISA demonstrating intrathe-cal productionof IgM, IgG, and IgA in the CSF is the rule (21). Use of the polymerase chainreaction (PCR) to diagnose Lyme disease is of some value (72), but the results may remainpositive evenafter all the organisms have beenkilled. There also is a risk of false-positive results whenthe test is performed in a commercial laboratory (73). Antigen-based tests of blood and urine are experimental and not considered reliable enough to be used clinically (73). Patients who receive appropriate treatment for proven Lyme disease (see below) may continue to show positive IgG and IgM antibody titers against B. burgdorferi. Inaddi-tion, some patients with positive antibody titers but who have no clinical evidence of Lyme disease may have had asymptomatic infection. In vaccine trials, about 10% of pa- Table 56.2 Lyme Disease National Surveillance Case Definition A case of Lyme disease is defined as follows: I. A person with erythema migrans, clinically noted by a physician. This skin lesion expands slowly over days to weeks to form a large round lesion, often with central clearing. To be counted for surveillance purposes, a solitary lesion must be at least 5 cm. II. A person with at least one later manifestation plus laboratory evidence of infection. A. Manifestation: Nervous system: Lymphocytic meningitis, cranial neuritis, radi-culoneuropathy, or rarely, encephalomyelitis, alone or in combination. For encephalomyelitis to be counted for surveillance purposes, there must be evidence of intrathecal antibody production against Borrelia burgdorferi in cerebrospinal fluid. Cardiovascular system: Acute-onset, high-grade (second- or third-degree) atrioventricular conduction defects that resolve in days to weeks and are sometimes associated with myocarditis. Musculoskeletal system: Recurrent, brief attacks (weeks to months) of objective joint swelling in one or a few joints sometimes followed by chronic arthritis in one or a few joints. B. Laboratory evidence: Isolation of B. burgdorferi from tissue or body fluid or detection of diagnostic levels of antibody to the spirochete by the two-test approach of enzyme-linked immunosorbent assay and Western blot, interpreted according to the Centers for Disease Control and Prevention/Association of State and Territorial Public Health Laboratory Directors' criteria. In a person with acute disease of less than 1 month's duration, IgM and IgG antibody responses should be measured in acute and convalescent serum samples. An IgM Western blot is considered positive if at least two of the following three bands are present: 23, 39, or 41 kd. An IgG blot is considered positive if at least five of the following 10 bands are present: 18, 23, 28, 30, 39, 41, 45, 58, 66, or 93 kd. Only the IgG response should be used to support the diagnosis after the first month of infection. After that time, an IgM response alone is likely to be a false-positive result. (From Steere AC. A 58-year-old man with a diagnosis of chronic Lyme disease. JAMA 2002;288:1002-1009.) tients had IgG conversion despite having no evidence of active clinical disease (74) Because of these observations, it is important not to attribute atypical clinical findings from another illness to Lyme disease based on laboratory testing alone. In the meantime, newer tests using recombinant spiro-chetal peptides are being tested (75,76) and may be useful for diagnosing Lyme disease in the future; however, false-positive results occur in patients with syphilis, Rocky Moun-tain Spotted Fever, and various autoimmune diseases. These usually can be distinguished from Lyme disease clinically or with other serologic tests. Occasionally, patients who have been incompletely treated withinthe first few weeks of infectiondevelop joint or neurologic symptoms but remain seronegative because they did not develop a humoral response to the spirochete. When treated, these patients respond to an appropriate course of therapy. Some of these patients are said to have ‘‘seronegative Lyme disease,'' but this designation is incor-rect because they never actually fulfilled the clinical criteria from the Centers for Disease Prevention and Control (CDC) for the diagnosis of Lyme disease. It also is important to SPIROCHETAL DISEASES 3089 remember that the same ticks that transmit B. burgdorferi also cancause other diseases, such as ehrlichiosis and babe-siosis (see Chapters 54 and 55) (77). For example, in one study, almost one-third of patients had evidence of both Lyme disease and babesiosis (78). TREATMENT The current treatment recommended for patients with stage 1 or stage 2 Lyme disease is doxycycline (79). The antibiotic is given for 14-21 days and also is effective against human granulocytic ehrlichiosis, which can be trans-mitted by the same tick. Amoxicillinis the second-choice agent for patients who are allergic to doxycycline and for both pregnant women and children under 8 years of age. Patients who have neurologic manifestations other than iso-lated facial nerve paresis usually are treated for 2-4 weeks with intravenous ceftriaxone (79,80) (Table 56.3). Intrave-nous ceftriaxone also is the preferred treatment for patients with Lyme disease who have neuro-ophthalmologic (as well as ocular) manifestations (81). Transient worsening of symp-toms after treatment secondary to a Jarisch-Herxheimer reac-tionhas beendescribed (81), however, and some authors recommend concomitant treatment with steroids. There is no advantage to intravenous ceftriaxone over oral doxycy-cline for localized or early disease that is unassociated with neurologic manifestations (82). Treatment of all forms of Lyme disease is highly success-ful (9). In one study, long-term results of a group of patients with culture-confirmed Lyme disease revealed that over 90% were asymptomatic (83). However, among patients with fre-quent recurrent tick bites, about 15% developed a second episode of erythema migrans. There is no evidence that extended treatment of patients with Lyme disease for more than 1 month is beneficial (84). In addition, patients given prolonged treatment may develop various drug-related complications, such as biliary dysfunc-tion( 84), and evendeath (85). Unfortunately, as noted previously, misdiagnosis of Lyme disease is common because of frequent serological testing in patients with vague and nonspecific findings. Improper diagnosis is the most common cause of ‘‘treatment failure.'' The prognosis for most persons with true Lyme disease is excellent. PROPHYLAXIS AND PREVENTION Because ticks must be attached at least 24 hours for trans-missionof the spirochete to occur, prophylactic therapy is not necessary if the tick is removed quickly after the bite. The frequency of Lyme disease after a tick bite is 1% (86). Should one wish to treat a patient who has had tick attach-ment for more than24 hours but less than72 hours, a single dose of 200 mg of doxycycline is effective in preventing Lyme disease (87). Protective clothing, avoidance of tick-infested areas, tick checks, and aracides are all helpful in decreasing the risk of contracting the disease (3). An effective vaccine was devel-oped (88) but is not commercially available (89). Table 56.3 Antibiotic Treatment Regimens for Lyme Disease Stage 1 (Early Infection) and Stage 2 (Early Dissemination) Adults Doxycycline, 100 mg orally twice daily for 14-21 days Amoxicillin, 500 mg orally 3 times daily for 14-21 days Alternatives in case of doxycycline or amoxicillin allergy Cefuroxime axetil, 500 mg orally twice daily for 14-21 days Erythromycin, 250 mg orally 4 times a day for 14-21 days Children (8 years or younger) Amoxicillin, 250 mg orally 3 times a day or 50 mg/kg per day in 3 divided doses for 14-21 days Alternatives in case of amoxicillin allergy Cefuroxime axetil, 125 mg orally twice daily or 30 mg/kg per day in 2 divided doses for 14-21 days Erythromycin, 250 mg orally 3 times a day or 30 mg/kg per day in 3 divided doses for 14-21 days Stage 2 (Early Disseminated with Neurologic Abnormalities) or Stage 3 (Chronic Dissemination) Adults Ceftriaxone, 2 g intravenously once a day for 14-28 days Cefotaxime, 2 g intravenously every 8 hours for 14-28 days Penicillin G sodium, 20 million U intravenously in 6 divided doses every 4 hours for 14-28 days Alternative in case of ceftriaxone or penicillin allergy Doxycycline, 100 mg orally 3 times a day for 30 days, but this regimen may be ineffective for late neuroborreliosis Facial palsy alone: Oral regimens may be adequate Children (8 years or younger) Ceftriaxone, 75 to 100 mg/kg/day (maximum, 2 g) intravenously once a day for 14-28 days Cefotaxime, 150 mg/kg/day in 3 or 4 divided doses (maximum, 6 g) for 14-28 days Penicillin G sodium, 200,000 to 400,000 U/kg/day in 6 divided doses for 14-28 days Arthritis (Intermittent or Chronic) Oral regimens listed above for 30-60 days or intravenous regimens listed above for 14-28 days Cardiac Abnormalities First-degree atrioventricular block: oral regimens, as for early infection High-degree atrioventricular block (PR interval more than 0.3 seconds): intravenous regimens and cardiac monitoring Once the patient has stabilized, the course may be completed with oral therapy Pregnant Women Standard therapy for manifestation of the illness; avoid doxycycline (Adapted from Steere AC. A 58-year-old man with a diagnosis of chronic Lyme disease. JAMA 2002;288:1002-1009.) RELAPSING FEVER Relapsing fever is characterized by two or more episodes of high fever and constitutional symptoms, interrupted by periods in which patients are asymptomatic. During the fe-brile periods, numerous spirochetes circulate in the blood causing fever, headache, tachycardia, myalgia, and abdomi-nal pain. There is no skin rash in this disease, as there is in Lyme disease (Table 56.4), and between fevers, spiroche-temia is not observed. Fevers recur because during spiroche-temia, there is antigenic variation in the bacteria. 3090 CLINICAL NEURO-OPHTHALMOLOGY Table 56.4 Comparison of Tick Borne Replasing Fever (TBRF), Louse-Borne Replasing Fever (LBRF), and Lyme Disease Characteristic TBRF LBRF Lyme disease Agent Several species B. recurrentis B. burgdorferi sensu lato* Vector Ornithodoros species (soft ticks) Pediculus humanus (human body louse) lxodes species (hard ticks) Usual reservoir Rodents† Humans Rodents Epidemiology Endemic Epidemic Endemic Distribution Tropical and temperate regions East Africa‡ North America, Eurasia In vitro cultivation Yes No§ Yes Fever (temperature of 39 C) CommonCommon Rare Fever relapses Multiple Few None Neurological involvement Common¶ Rare Common Local skin rash No No Common (ECM||) Arthritis No No Common Spirochetes on blood smear Yes Yes No Serological assay specificity Fair to poor Fair to poor Good to excellent Antibiotic therapy Several doses Single or few doses Several doses Jarisch-Herxheimer reactionModerate Moderate to severe Mild * Included are B. burgdorferi sensu stricto, B. afzelii, and B. garinii. † The reservoir for B. duttoni in some locations may be humans. ‡ LBRF has a potential worldwide distribution because of association with the human body louse. § In vitro cultivation of B. recurrentis has been reported but not confirmed [24]. ¶ Common in 10% of patients with disseminated disease. || Erythema chronicum migrans. (From Cadavid D, Barbour AG. Neuroborreliosis during relapsing fever: Review of the clinical manifestations, pathology, and treatment of infections in humans and experimental animals. Clin Infect Dis 1998;26:151-164.) Relapsing fever was recognized as a distinct disease by physicians in ancient Greece, but it was not until the 19th century that the etiology was determined (1,2). There are two forms of the disease. The epidemic form of relapsing fever is caused by Bor-relia recurrentis and is transmitted by the human body louse, Pediculus humanus corporis and by the human head louse, Pediculus humanus capitis (2,90). Most examples of this form of relapsing fever occur in settings of overcrowding in which there is poor general hygiene. The endemic form of relapsing fever is transmitted by soft-body ticks (1,2,90). Most cases of endemic relapsing fever occur in the Westernan d Southwesternstates of Washington, California, New Mexico, Colorado, Kansas, Oklahoma, and Texas. Endemic relapsing fever also occurs with regularity in Mexico, Central and South America, the Mediterranean, Central Asia, and most of Africa (Table 56.4). The incubation period for both epidemic and endemic re-lapsing fever is 6-8 days, with a range of 2-14 days (91). The onset is sudden and characterized by the combination of fever, headache, tachycardia, and muscle pain that may suggest malaria. Other nonspecific manifestations that also may occur include abdominal pain, headache, diarrhea, dry TREPONEMA SPECIES The family Spirochaetaceae, which includes organisms that belong to the genus Borrelia, also includes organisms that belong to a second genus, Treponema. Treponemes are slender, tightly coiled, unicellular, helical cells that are 5-15 m long and 0.09-0.18 m wide (1) (Fig. 56.15). The ends cough, and neck pain. After the initial febrile episode of 3-7 days, the patient improves and is asymptomatic, only to develop subsequent, numerous relapses. Neurologic complications occur in 10-30% of patients with relapsing fever (92). Involvement of the facial nerve is most common, but trigeminal nerve paresis, abducens nerve paresis, and sensorineural hearing loss have been reported. Ocular complications occur in some patients with relaps-ing fever, but only in the endemic (tick-borne) form. The most common are conjunctival injection, photophobia, and eye pain(90,91); however, unilateral or bilateral eyelid edema, keratitis, iritis, cyclitis, retinitis, choroiditis, and optic neuritis, have been described. These manifestations do not occur initially but may become evident during the third or fourth febrile episode. Visionoftendecreases rapidly once the eye is involved. The diagnosis of relapsing fever usually is suspected on clinical and epidemiologic grounds and can be confirmed indirectly by serologic tests such as an ELISA test or West-ernblot or directly by observationof the organisms inaf-fected body fluids or tissues, culture of the organisms from the fluids or tissue, or identification of Borrelia nucleic acid by PCR. The optimum treatment for most patients is penicil-lin. Most patients experience complete recovery. of the organism are tapered, and three axial fibrils are present at each end. Treponemes move with a drifting rotary motion, characterized in part by a distinctive undulating movement intheir center. Two species of Treponema can infect humans. T. pallidum SPIROCHETAL DISEASES 3091 Figure 56.15. Morphology of Treponema species. Note tightly coiled, unicellular organism that is tapered at both ends. Also note axial filaments, some of which are disrupted. 34,000. (From Clinical Symposia No. 23-3. Syphilis. Summit, NJ, CIBA Pharmaceutical Company, 1969.) causes several different disorders, depending on the particu-lar subspecies that is responsible. T. pallidum pallidum causes syphilis, a complex systemic illness of major neuro-logic and neuro-ophthalmologic significance. T. pallidum pertenue causes yaws, a destructive cutaneous disease of childhood that is characterized by papillomatous skinlesion s and that occurs almost exclusively among primitive rural populations in warm tropical areas of Africa, South America, and Southeast Asia (2). T. pallidum endemicum produces bejel, anextremely rare systemic disorder that also is called nonvenereal endemic syphilis. Finally, T. carateum causes pinta, a cutaneous disease of childhood that is characterized by papillosquamous skin lesions. It occurs only in remote, rural regions of southern Mexico, Central America, and Co-lombia (2). SYPHILIS Syphilis is the most important disease caused by the Treponema species, whether considered from a medical, neurologic, visual, economic, or social standpoint. Syphilis, occasionally called ‘‘lues'' from the Latin phrase, lues vene-reum, meaning ‘‘disease,'' ‘‘sickness,'' or ‘‘pestilence,'' was first recognized in the late 1400s. It is unclear if it was imported into Europe from the New World by Christopher Columbus or was a primary Europeandisease that spread among people living in crowded conditions. A pandemic known as the Great Pox spread through Europe and Asia at the time of the returnof Columbus from America. Although it is not clear if T. pallidum was the cause, it seems likely. The name syphilis is derived from the poem ‘‘The Sinister Shepherd'' by Fracastorius. He described a shepherd named Syphilus who cursed both the sunan d the gods that had caused the drought leading to the loss of his sheep. The sun took great offense and produced a plague-like disease (93). Mercury was the only treatment available for syphilis until the early 20th century, when Ehrlich introduced the arsenic derivative, arsphenamine (Salvarsan). Bismuth, fever ther-apy, malaria injections, and heat therapies were other treat-ments that were tried. In 1927, Dr. Julius Wagner von Jauregg was given the Nobel Prize for using malaria injec-tions to treat neurosyphilis. In 1903, Metchinkoff and Roux transferred the disease to chimpanzees. The organism was described in the primary lesion and lymph nodes 2 years later. Wasserman subsequently described a complement fix-ation test for the diagnosis of syphilis using fetal calf liver and, later, extracts of uninfected beef liver and heart (94). This test was the basis of the Venereal Disease Research Laboratories, or VDRL, test that still is used today. Epidemiology Congenital syphilis is transmitted from the mother to the fetus either by infectioninutero or, less frequently, as the fetus passes through the birth canal. Acquired syphilis is transmitted primarily by sexual activity, either through inter-course, sexual contact, touching a person who has active lesions, or by oral transmission. Transmission through blood transfusion is rare. It occasionally occurs with a needle stick or handling infected material without proper protection. In 1937, it was estimated that 10% of Americans would be infected with syphilis during their lives (95). The incidence of syphilis was greatest from 1940 to 1945, whenit was spread by servicemen returning from Europe at the end of World War II. More recently, rates have declined dramati-cally because of both public health measures and treatment with penicillin. In 1990 the annual incidence of primary and secondary syphilis in the United States was 20.3 cases per 100,000, whereas in2001 it was 2.12 cases per 100,000 (11). Although this represents a decrease of 90% over the decade, the annual incidence actually increased by 2% in 2001 (11) and appears to continue to be increasing. The increase is occurring in homosexual and bisexual males who appear to be abandoning safe-sex practices (96-98) (Fig. 56.16). For example, during the year 2000 there was a 55% increase of cases inNew York City compared with the previous year, and in California, cases increased by 68% during the same time period (99). During 2001, there againwas anin crease inthe number of cases inmales, with anin crease of almost 21% incities with populations greater than 200,000 (99). A 3092 CLINICAL NEURO-OPHTHALMOLOGY Figure 56.16. Number of acquired cases of syphilis by gender in the United States from 1980 through 2002, per 100,000 population. Note increase in cases in men (primarily homosexual and bisexual) compared with women from 2000 through 2002. (From Centers for Disease Control and Prevention. Primary and secondary syphilis-United States, 2002. MMWR 2003; 52 1117-1120.) Figure 56.17. The chancre of primary syphilis. A, Single chancre of the penis. The lesion has raised borders and a smooth base. B, Single chancre of the fourchette. Again, note the raised borders and smooth base. C, Multiple chancres of the labia minora. (From Clinical Symposia No. 23-3. Syphi-lis. Summit, NJ, CIBA Pharmaceutical Company, 1969.) SPIROCHETAL DISEASES 3093 vivid example of the personal impact of the disease was published in2003 (100). Pathogenesis Within hours to days after penetrating the intact mucous membrane or gaining access to the body through abraded skin, T. pallidum enters the lymphatics and bloodstream, following which the organisms disseminate throughout the body. Nearly every organ inthe body canbe involved, in-cluding the eye and the brain (101). The organisms divide every 30-33 hours. The infectious dose varies from patient to patient, but clinical lesions usually develop when there is a concentration of about 107 organisms per gram of tissue; the incubation period is directly proportional to the size of the inoculum (102). Clinical Manifestations Syphilis usually is divided into three main stages-pri-mary, secondary, and tertiary (94,103)-although there is considerable overlap among stages. There may be a latent period between the secondary and tertiary stages, which we will not discuss in this chapter as it has no neuro-ophthalmo-logic significance. Primary Stage The chancre of primary syphilis begins at the site of inoc-ulation (Fig. 56.17). It is a single, painless papule that quickly erodes and becomes indurated. It usually appears about 21 days after infection but may develop as early as 3 days or as late as 90 days after inoculation (94). In some cases it may not be noticed, whereas in others it may never develop. Multiple chancres candevelop inpatien ts, particu-larly those infected with the human immunodeficiency virus (HIV) Type 1 (104). These lesions, which contain spiro-chetes, usually heal spontaneously in 2-8 weeks, but they canlast longer inimmun ocompromised hosts. Because the chancre is located wherever inoculation oc-curred, common sites include external genitalia, mouth, peri-anal area and anal canal. Rarely, chancres develop on the eyelids at the lateral or medial canthi, where they may be mistaken for a chalazion (Fig. 56.18). Chancres involving Figure 56.18. Chancre of primary syphilis affecting the right lower eyelid (arrowhead) in a 47-year-old man. Note smooth base and slightly raised border. the eyelid are usually associated with lymphadenopathy. Re-gardless of the location of the inoculation, within hours to days after it occurs, the organisms multiply and disseminate hematogenously and to local lymphatics. The CNS can be invaded at this time. Secondary Stage Secondary syphilis develops 2-8 weeks after the appear-ance of the chancre, and this stage lasts until an immune response develops. Clinical manifestations of secondary syphilis are widespread and protean; they include cutaneous, systemic, neurologic and visual signs and symptoms (2,94,103,105) (Table 56.5). Cutaneous lesions are common in patients with secondary syphilis, occurring in 90% of patients (Fig. 56.19). They may be macular, maculopapular, papular, pustular, or a com-binationof these forms. They usually beginonthe trunk and proximal extremities. Involvement of the palms and soles is particularly suggestive of the disease (2,94). Lesions are discrete, painless, 3-10 mm in diameter, and persist for a few days to 8 weeks (96). Papules that occur inwarm, moist intertriginous areas may enlarge, coalesce, and erode to pro-duce moist, gray-white-to-erythematous, highly infectious plaques called condylomata lata. Other highly infectious lesions develop on mucous membranes. These mucous patches appear as painless, silver, superficial erosions sur-rounded by a red periphery (Fig. 56.20). These lesions may develop on the bulbar or tarsal conjunctiva (94). Episcleritis and scleritis are rare, but can occur during this stage. Low-grade fever, malaise, sore throat, laryngitis, an-orexia, weight loss, and arthralgias are the most common constitutional symptoms reported in patients with secondary syphilis, and generalized lymphadenopathy is a common finding (105). As the spirochetes disseminate, various organs inthe body canbe affected, leading to immune-complex glomerulonephritis, acute nephrotic syndrome, hepatitis, and proctitis. Synovitis, osteitis, and periosteitis also can occur in secondary syphilis. Patients complain of nocturnal pain over the affected area (94). The painis increased by heat. Table 56.5 Clinical Manifestations of Secondary Syphilis Manifestation Percentage of Cases Skin lesions 90 Mouth and throat lesions 35 Genital lesions 20 Constitutional symptoms 70 Central nervous system 8-40 Renal Rare Gastrointestinal Rare Hepatic Rare Arthritis, osteitis, and periostitis Rare (Adapted from Tramont EC. Treponema pallidum [syphilis]. In Mandell GL, Bennet JE, Dolin R, eds. Principles and Practice of Infectious Diseases. Ed 5. New York, Churchill Livingstone, 2000:2474-2489.) 3094 CLINICAL NEURO-OPHTHALMOLOGY Figure 56.19. Cutaneous lesions of secondary syphilis. A, Extensive papulosquamous rash on the trunk and arms. B, Lesions on the chin. Note raised borders and hyperpigmented base. C, Papulosquamous syphilids on the fingers, palms, and wrists. D, Maculopapular lesions on the sole. (A-C, From Clinical Symposia No. 23-3. Syphilis. Summit, NJ, CIBA Pharmaceutical Company, 1969. D, From Friberg TR. Syphilitic chorioretinitis. Arch Ophthalmol 1989;107 1676-1677.) Syphilitic periosteitis occasionally affects the bones sur-rounding the orbit, particularly the upper rim. The CNS is affected in up to 40% of patients with second-ary syphilis, with about 1-2% developing neurologic symp-toms and signs (101). The most common presentation is aseptic meningitis that primarily affects the basal meninges. Affected patients have severe headache, nausea, and vomit-ing. Meningismus and fever occur in about 50% of patients. Multiple cranial neuropathies are not uncommon. Some pa-tients develop papilledema and may be thought to have ‘‘pseudotumor cerebri'' until the CSF is examined (Fig. 56.21). Patients in whom syphilitic basilar meningitis is par-ticularly severe may develop communicating hydrocephalus, subarachnoid hemorrhage, subdural hematoma, superior sagittal sinus thrombosis, nystagmus, or a combination of these findings (94,101). Rare patients with secondary syphi-lis develop meningomyelitis that may be characterized by spastic paraparesis, root pain with and without sensory loss, or Brown-Sequard syndrome. Lymphocytic pleocytosis and increased protein concentra-tioninCSF is present whenthere is CNS involvement in secondary syphilis. Spirochetes may be cultured from the CSF inthis setting, evenwhenthe CSF is otherwise com-pletely normal (106). About 5% of patients with secondary syphilis have ocular manifestations of the disease (107). Inflammation may affect the anterior or posterior segment of the eye and may consist of uveitis, chorioretinitis, retinal vasculitis, or a combination of these. These ocular findings may be the initial or the major manifestations of the underlying disease. Unilateral or bilateral iritis is the most common ocular finding (107,108) (Fig. 56.22); although it occurs in4 -10% of pa-tients, it represents almost 70% of the ocular manifestations. The iritis may be associated with reddish spots onthe iris called roseolae, or it may be more severe and fibrinous with a significant anterior chamber reaction and development of keratitic precipitates, anterior and posterior synechiae, and secondary glaucoma. Although the inflammatory response SPIROCHETAL DISEASES 3095 Figure 56.20. Mucous patches from secondary syphilis. The lesions are superficial erosions with a red border. A, A small patch onthe surface of the tongue (arrowhead). B, A large patch on the undersurface of the tongue. (A, From Tramont EC. Treponema pallidum [syphilis]. In Mandell GL, Douglas RG Jr, Bennett JE, eds. Principles and Practice of Infectious Diseases. Ed 3. New York, Churchill Livingstone, 1990 1794-1808. B, From Clinical Symposia No. 23-3. Syphilis. Summit, NJ, CIBA Pharmaceutical Company, 1969.) Figure 56.21. Papilledema in a patient with aseptic syphilitic meningitis. The patient was a 40-year-old woman who developed a mild fever, headache, a stiff neck, and transient obscurations of vision. Visual acuity was 20/20 OU. Visual fields showed enlargement of the blind spots. A, The right ocular fundus shows fully developed papilledema with numerous peripapillary and posterior pole hemorrhages and exudates. B, The left ocular fundus also shows numerous peripapillary hemorrhages and exudates. A lumbar puncture revealed a lymphocytic pleocytosis with an increased concentration of protein. The results of immunologic testing were consistent with secondary syphilis and syphilitic meningitis. 3096 CLINICAL NEURO-OPHTHALMOLOGY Figure 56.22. Severe uveitis with iris papules (roseolae) insecon dary syphilis. Note extensive anterior synechiae and irregularity of the pupil. (From Margo CE, Hamed LM. Ocular syphilis. Surv Ophthalmol 1992; 37 203-220.) A C Figure 56.23. Central chorioretinitis in secondary syphilis. The patient was a 31-year-old manwith an8-day history of blurred visioninboth eyes. Visual acuity was 9/200 OD and 20/50 OS. A, Maculopapular rash over neck and back. B, Patchy alopecia of scalp. C, Right ocular fundus shows a single large area of chorioretinitis with overlying serous retinal detachment (arrows). A diagnosis of secondary syphilis was made on the basis of the clinical findings and the results of serologic testing. (From Gass JDM, Braunstein RA, Chenoweth RG. Acute syphilitic posterior placoid chorioretinitis. Ophthalmology 1990; B 97 1288-1297.) SPIROCHETAL DISEASES 3097 may be stronger anteriorly, it is present in all parts of the eye and thus constitutes a true panuveitis (109-111). Both uveitis and vitritis can be the first signs of syphilis. Chorioretinitis occurs both in congenital and acquired syphilis (112). It is the most commonophthalmologic find-ing in patients with posterior uveitis (113). The chorioretini-tis tends to be posterior. It may be diffuse, multifocal, dis-seminated, areolar, or localized (113) (Figs. 56.23 and 56.24). Diffuse or multifocal chorioretinitis occurs most ofteninthe late secondary stage of syphilis. It oftenis bilat-eral, but it may be asymmetric. It is characterized by circum-scribed areas of gray-yellow appearance located primarily, but not exclusively, in the peripapillary area and often sur-rounds the optic disc. This form of chorioretinitis is called syphilitic posterior placoid chorioretinitis (114,115). Ste-roids can increase the risk of developing this complication (116) (Fig. 56.25). A macular pseudohypopyonan d uveal effusioncanbe seeninsome cases (117,118) (Fig. 56.26). Figure 56.24. Central chorioretinitis in secondary syphilis. The patient was a 42-year-old man with pain and decreased vision. Visual acuity was 8/200 OD and 20/30 OS. There was significant uveitis in both eyes. A, Maculopapular rash onthe palm of the left hand. B, The right ocular fundus shows a single large central lesion of chorioretinitis with an overlying detachment of the sensory retina (arrows). C, Fluorescein angiogram, arteriovenous phase, shows diffuse hypofluorescence centrally and small spots of hypofluorescence within an area of hyperfluorescence (leopard-spot hypofluorescence) superiorly. D, Fluorescein angiogram, late venous phase, shows persistent intense staining inferiorly and temporal to the macula. (From Gass JDM, Braunstein RA, Chenoweth RG. Acute syphilitic posterior placoid chorioretinitis. Ophthalmology 1990;97 1288-1297.) In disseminated choroiditis, there oftenis a salt-and-pepper appearance of the fundus, similar to that seen in congenital syphilis, except that the granular deposition of pigment oc-curs mainly inthe posterior pole rather thanthe periphery. Areolar choroiditis is infrequent. It is characterized by mul-tiple lesions that begininthe posterior pole and thenbecome evident in the periphery. The lesions initially are black but subsequently become white as they increase in size. Local-izedsyphilitic chorioretinitis is primarily located inthe posterior pole. Some patients with secondary syphilis develop a retinal vasculitis without associated choroiditis (119). Such patients may develop peripheral focal retinal necrosis, periphlebitis, or a combination of these complications (119,120) (Fig. 56.27). Patients with secondary syphilis may develop a variety of neuro-ophthalmologic manifestations. Because most of these findings are nonspecific, they do not serve to differen- 3098 CLINICAL NEURO-OPHTHALMOLOGY Figure 56.25. Worsening of syphilitic chorioretinitis from steroids . A, Funduscopic appearance of the posterior pole in the right eye at presentation. B, Late fluorescein angiogram demonstrating macular edema in the right eye. C, Clinical appearance 3 weeks after starting prednisone. Note substantial worsening characterized by the appearance of multiple yellow, placoid macular lesions (arrows). D, Fluorescein angiogram demonstrating areas of blocked fluorescence corresponding to the placoid macular lesions clinically. E, Fundus photography 5 days after discontinuation of prednisone but before antimicrobial therapy. F, Fluorescein angiogram demonstrating resolution of areas of blocked fluorescence 5 days after discontinuation of prednisone. (From Zamani M, Garfinkel RA. Corticosteroid-induced modulation of acute syphilitic posterior placoid chorioretinitis. Am J Ophthalmol 2003;135 891-894.) SPIROCHETAL DISEASES 3099 A B Figure 56.26. Macular pseudohypopyon from secondary syphilis. The patient was a 48-year-old man with progressive loss of visionin the right eye. Visual acuity was 2/200 OD and 20/40 OS. A, Fundus photograph of left eye shows elevation and whitening of entire macular region. Note that the lesion appears to have a fluid meniscus, resulting in the white area being thicker inferiorly than superiorly. B, Fluoresceinan giogram, late phase, shows perivascular leakage of fluoresceindye and hyperfluorescence in the area corresponding to the fluid meniscus. (From Ouano DP, Brucker AJ, Saran BR. Macular pseudohy-popyonfrom secondary syphilis. Am J Ophthalmol 1995;119 372-374.) Figure 56.27. Retinal vasculitis in secondary syphilis. The patient was a 41-year-old man with recurrent secondary syphilis who experienced decreased vision in the right eye. A, Right ocular fundus shows extensive retinal vascular sheathing with intraretinal hemorrhages. B, In another patient with secondary syphilis, the right ocular fundus shows hyperemia and swelling of the right optic disc associated with intraretinal hemorrhages and exudates and areas of venous sheathing. C, The inferior fundus in the same eye shows an area of intense vascular sheathing. D, Fluorescein angiogram, arteriovenous phase, shows extensive and diffuse staining of both large and small retinal veins. Note leakage of dye from optic disc. (A, From Levy JH, Liss RA, Maguire AM. Neurosyphilis and ocular syphilis in patients with concurrent human immunodeficiency virus infection. Retina 1989;9:175-180. B-D, From Halperin LS, Berger AS, Grand MG. Syphilitic disc edema and periphlebitis. Retina 1990;10 223-225.) 3100 CLINICAL NEURO-OPHTHALMOLOGY tiate syphilis from other neurologic diseases. For example, anterior and retrobulbar optic neuritis, neuroretinitis, periop-tic neuritis (optic perineuritis), and papilledema all can be caused by syphilis. Papillitis and retrobulbar optic neuritis occur inthe late secondary stage of syphilis. They may be unilateral or bilateral, and they may occur in isolation or in association with syphilitic meningitis. As in typical optic neuritis, the visual loss caused by syphilitic optic neuritis is rapid, severe, and associated with a variety of visual field defects (121-125). Neuroretinitis frequently occurs in patients with second-ary syphilis, sometimes in association with meningitis (126,127) (Fig 56.28). If the patient is seen after the disc swelling has resolved and only the exudates are present, the process may be thought to be a retinal abnormality. Perioptic neuritis is an inflammation of the meningeal sheaths of the optic nerve that often produces mild swelling of the optic disc without causing a loss of visual acuity or color vision(128,129) (Fig. 56.29). The visual field insuch cases usually is normal; however, if the disc swelling is severe, there may be an enlarged blind spot, and some pa-tients develop generalized constriction of the field. Although perioptic neuritis usually is bilateral, it can be unilateral. Normal visual acuity and color visionina patient who ap-pears to have papilledema, but in whom the intracranial pres-sure is normal and CSF contains some inflammatory cells and increased protein content should suggest a diagnosis of optic perineuritis. Papilledema is seen in patients with syphilitic meningitis. It is indistinguishable from the papilledema associated with increased intracranial pressure from other causes. It cannot Figure 56.28. Neuroretinitis in syphilis. A, Right optic disc swelling and a ‘‘hemi-star'' of hard exudate in the macula of a 31-year-old woman with visual acuity of 9/200 OD and 20/20 OS and cells in the vitreous of both eyes. B, Spirochetes morphologically consistent with Treponema pallidum are present in the aqueous humor from the patient's right eye using dark-field microscopy. (From Smith JL. Spirochetes inlate seronegative syphilis despite penicillintherapy. InSmith JL, ed. Neuroophthalmology Symposium of the University of Miami and the Bascom Palmer Eye Institute.Vol 4. St Louis, CV Mosby, 1968 1-14.) be differentiated from optic perineuritis without a lumbar puncture. Chiasmal dysfunction occurs in rare patients with second-ary syphilis who have basilar meningitis (130). It usually is associated with decreased visual acuity and color vision deficits caused by simultaneous damage to the intracranial optic nerves. Patients with secondary syphilis may develop homony-mous visual field defects from involvement of the postchias-mal visual pathway. Such defects occur more frequently from syphilitic arteritis rather than from meningitis. Patients who have an homonymous hemianopia and papilledema may have an unrelated intracranial tumor, an intracranial gumma (see below), or basilar meningitis. In rare patients, an infarc-tioninthe parietal or occipital lobe produces sufficient is-chemic swelling to cause increased intracranial pressure and papilledema. Patients with secondary syphilis who lose all or part of their vision may develop visual hallucinations that may be formed or unformed (Charles Bonnet syndrome). As noted above, the cranial nerves are commonly affected in patients with syphilitic basilar meningitis. Any of the ocu-lar motor nerves may be damaged. The oculomotor nerve is affected more frequently than either the trochlear or the abducens nerves. In some cases, there are multiple ocular motor neuropathies suggesting cavernous sinus involve-ment. In other cases, unilateral or bilateral ophthalmoparesis is associated with evidence of an optic neuropathy, suggest-ing involvement of the orbital apex (131). Cranial nerves other than the ocular motor nerves not in-frequently are damaged in patients with secondary syphilis. The facial nerve is commonly involved, as is the vestibulo- SPIROCHETAL DISEASES 3101 Figure 56.29. Optic perineuritis in secondary syphilis. The patient was a 41-year-old man with leg pain, bilateral hearing loss, and black spots inthe field of visionof both eyes. He had a maculopapular rash onthe scrotum and penis. Visual acuity was 20/20 OU, and visual fields were full. There were cells in the anterior chambers and vitreous of both eyes. A, The right optic disc is swollenan d hyperemic. A few cottonwool spots are present inthe peripapillary region. B, The left optic disc is swollenan d hyperemic. Several cottonwool spots and at least one hemorrhage are seeninthe peripapillary region. Lumbar puncture revealed a normal opening pressure; however, there was a mild pleocytosis, and the protein concentration in the CSF was increased (82 mg/dl). The results of testing of the serum and CSF were consistent with a diagnosis of secondary syphilis. Both the uveitis and the optic disc swelling resolved after treatment with penicillin. (From Kline LB, Jackson WB. Syphilitic optic perineuritis and uveitis. In Smith JL, ed. Neuroophthalmology Focus 1980. New York, Masson, 1979 77-83.) Figure 56.30. Cardiovascular syphilis. A, Patient with a large syphilitic aneurysm that has eroded through the sternum and is projecting beneath the skin (arrowhead). B, Thoracic aortogram, posteroanterior view, shows large aneurysm of the ascending aorta. (From Spencer FC. Diseases of great vessels. In Schwartz SI, ed. Principles of Surgery. New York, McGraw-Hill, 1969 691-719.) 3102 CLINICAL NEURO-OPHTHALMOLOGY cochlear nerve. When a patient with evidence of syphilis has acute sensorineural hearing loss associated with an ipsi-lateral sixth nerve paresis, syphilitic meningitis is likely (132). Tertiary Stage Tertiary syphilis is a slowly progressive inflammatory dis-ease that can affect any organ, but primarily involves the cardiovascular and central nervous systems. The underlying pathologic lesion of cardiovascular syphi-lis is endarteritis obliterans, affecting the vasa vasorum of the aorta. This causes medial necrosis with destruction of elastic tissue and subsequent aortitis with formation of a saccular or fusiform aneurysm (133) (Fig. 56.30). Symptom-atic aortitis occurs in about 10% of patients with untreated syphilis; however, pathologic lesions can be demonstrated onpostmortem examinationinup to 83% of untreated pa-tients. The neurologic involvement in tertiary syphilis is called neurosyphilis. Neurosyphilis canbe either asymptomatic or symptomatic (Table 56.6). Asymptomatic neurosyphilis occurs in 8-40% of untreated patients (134). In these pa- Table 56.6 Clinical Manifestations of Neurosyphilis Meningovascular Hemiplegia or hemiparesis Seizures Generalized Focal Aphasia Parenchymatous Tabes dorsalis Shooting or lightning pains Ataxia Pupillary disturbances (Argyll Robertson, tonic) Impotence Bladder disturbances Fecal incontinence Peripheral neuropathy Romberg sign Cranial nerve involvement (II-VII) General paresis Changes in personality, affect, sensorium, intellect, insight, and judgment Hyperactive reflexes Speech disturbances (slurring) Pupillary disturbances (Argyll Robertson) Optic atrophy Tremors (face, tongue, hands, legs) Meningoencephalitis Depends on site and extent of process Gummatous Depends on location and size of lesion (Adapted from Tramont EC. Treponema pallidum [syphilis]. In Mandell GL, Bennet JE, Dolin R, eds. Principles and Practice of Infectious Diseases. Ed 5. New York, Churchill Livingstone, 2000:2474-2489.) tients, the CSF shows pleocytosis, elevated protein, de-creased glucose, and a positive VDRL (135,136). Symptom-atic neurosyphilis most often presents as meningovascular or parenchymatous neurosyphilis, but rare patients develop meningoencephalitis and others develop single or multiple gummas (Fig. 56.31). Meningovascular syphilis develops in10 -12% of pa-tients, months to years after the initial infection. The peak incidence occurs at about 7 years. The condition causes a wide spectrum of neurologic symptoms and signs, all of which result from progressive ischemia caused by small-vessel endarteritis with secondary occlusion (94). Affected patients present with symptoms and signs of diffuse menin-geal inflammation combined with deficits attributable to focal damage to the cerebral blood supply (137,138). These patients tend to have episodic prodromal signs and symp-toms weeks to months before they develop irreversible neu-rologic deficits. These episodic phenomena include head-ache, vertigo, memory impairment, insomnia, seizures, changes in behavior, and personality changes. Left untreated, patients develop hemiparesis, aphasia, and other focal neuro-logic deficits caused by progressive arterial insufficiency. Visual field defects, particularly homonymous hemianopia, may develop, and cranial neuropathies, including ocular motor nerve paresis, are not uncommon. Some patients have papilledema, and Horner syndrome has been reported. Patients with meningovascular syphilis may develop optic nerve damage. Some patients experience sudden visual loss associated with an optic neuropathy that clinically resembles acute idiopathic or deymyelinating optic neuritis, but unlike idiopathic demyelinating optic neuritis, it does not improve spontaneously or with steroid therapy. Other patients have painless visual loss associated with an altitudinal field defect and a swollen optic disc with peripapillary hemorrhages sug-gesting an acute anterior ischemic optic neuropathy. Still other patients experience slowly progressive unilateral or bilateral visual loss with evidence of optic nerve dysfunction (138). The optic neuropathy in all of these settings is caused by progressive ischemia of intracranial portions of the optic nerves. Neither CT scanning nor MR imaging is particularly help-ful in patients with meningovascular syphilis because such patients usually have multiple small infarcts involving the gray and white matter. Angiography in such patients usually demonstrates multifocal areas of arterial narrowing (139). Although the middle cerebral artery is one of the more com-mon areas affected, any of the intracranial or spinal cord arteries may be involved by the process (140). Parenchymatous neurosyphilis takes two mainforms: tabes dorsalis and general paresis. Both types have signifi-cant neuro-ophthalmologic manifestations. In addition, some patients have clinical features of both disorders and are said to have taboparesis. Patients with tabes dorsalis have signs and symptoms of damage to the spinal cord, primarily the posterior columns, dorsal roots, and dorsal root ganglia. In the early stages of the disease, affected patients have attacks of ‘‘lightning pains'' most ofteninthe lower extremities, occurring episod-ically for minutes to hours. Some patients experience pares- SPIROCHETAL DISEASES 3103 Figure 56.31. Schematic representation of natural history of untreated syphilis in immunocompetent persons. (From Golden MR, Marra CM, Holmes KK. Update onsyphilis: Resurgence of anold problem. JAMA 2003;290 1510-1514.) thesias rather than lightning pains, and 10-20% have attacks of abdominal pain called ‘‘visceral crises'' (94,141). As tabes dorsalis progresses, patients experience progressive loss of sensation with patchy anesthesia, decreased proprio-ception with loss of vibratory sensation, loss of pain sensa-tion, and loss of deep-tendon reflexes in ankles and knees. The loss of proprioception and decreased sensation leads to repeated inadvertent injury of affected limbs, resulting in late manifestations such as Charcot joints. Patients also may develop bowel and bladder incontinence and a broad-based slapping ataxic gait (94,141). One of the major neuro-ophthalmologic features of tabes dorsalis are Argyll Robertsonpupils (142). These are small, irregular pupils with no reaction to light stimulation, but a normal or near normal reaction to near (Fig. 56.32). Argyll Robertsonpupils are caused by damage to the most dorsal pupillomotor fibers in the mesencephalon, but they generally are unassociated with the disorders of vertical gaze that char-acterize dorsal midbrain (Parinaud) syndrome. Argyll Rob-ertsonpupils are discussed indetail inChapter 16 of this text. Many patients with tabes dorsalis who do not have typical Argyll Robertsonpupils nevertheless have pupils that are abnormally reactive and anisocoric. In some cases, the pupils react to neither light nor near stimulation. In others, there is unilateral or bilateral light-near pupillary dissociation as is seeninpatien ts with Argyll Robertsonpupils but with a light reactionthat is more obvious thanin the true Argyll Robertson pupil, a near response that is unusually slow and tonic, and a tonic redilation after constriction. The appear-ance thus is that of a tonic pupil and probably is caused by damage to the ciliary ganglion or the short posterior ciliary nerves. When tonic pupils occur in patients with tabes dor-salis, they usually are bilateral (143,144). Tonic pupils also are described indetail inChapter 16 of this text. Some patients with tabes dorsalis have ‘‘alternating my-driasis.'' This phenomenon occurs most often during the visceral crises described above. Pupils may have anabn or- 3104 CLINICAL NEURO-OPHTHALMOLOGY Figure 56.32. Argyll Robertsonpupils intabes dorsalis. The patient had no visual complaints. A, The pupils are slightly irregular and nonreactive to direct light stimulation. B, Both pupils react briskly to anaccommodative stimulus. mal shape caused by iris atrophy. This atrophy may be seg-mental and associated with loss of the pupillary light reflex in that region. The cause of alternating mydriasis in patients with tabes dorsalis is unknown but may be related to oculo-sympathetic stimulation or hypofunction. Patients with tabes dorsalis may have ptosis and, in rare cases, lid retraction. Most patients who have eyelid retraction also have paresis of upgaze. Such patients presumably have a more widespread lesioninthe dorsal midbrainthando patients with Argyll Robertson pupils. Blepharospasm has beenreported inpatien ts with tabes dorsalis and may be related to inflammatory or ischemic irritation of the facial nerve nuclei in the brainstem. Optic atrophy is a common but nonspecific finding in patients with tabes dorsalis. It appears to develop about 10-20 years after the initial infection. Visual field defects are variable and include concentric constriction, localized defects, cecocentral scotomas, central scotomas, altitudinal and arcuate defects. The pathogenesis of tabetic optic atro-phy is unclear but seems to be a primary neuronal degenera-tionrather thaninin flammatory or ischemic process. Tabetic optic atrophy usually results insevere visual loss or complete blindness. Cranial neuropathies occur in some patients with tabes dorsalis. The ocular motor nerves may be affected, in which case the oculomotor nerve is affected more oftenthaneither the trochlear or abducens nerves. Cranial neuropathies may be single or multiple and unilateral or bilateral. General paresis develops 15-20 years after the initial infection (145). Patients with this form of parenchymal syph-ilis have a progressive disturbance of personality, affect, mentation, and intellect. Ocular and neuro-ophthalmologic manifestations of general paresis are similar to those seen in tabes dorsalis but much less common. They include Argyll Robertson pupils, optic atrophy, visual hallucinations, cra-nial neuropathies, and pigmentary retinopathy. The manifestations of general paresis can be remembered using the mnemonic PARESIS: personality (emotional lability, paranoia); affect (carelessness in appearance); reflexes (hyperactive); eye (Argyll Robertsonpupils); sensorium (illusions, delusions, especially megalomania, hallucinations); intellect (decreased recent memory, judg-ment, insight); and speech (slurred) (94). Many patients who develop general paresis also have HIV infection (94). In such patients, it may be difficult to distin-guish the manifestations caused by syphilis and that caused by the virus; however, the presence of Argyll Robertson pupils suggests that at least some of the manifestations are related to syphilis. Although meningovascular syphilis and parenchymatous neurosyphilis are the most common forms of neurosyphilis, two other forms may occur: meningoencephalitis and gum-matous syphilis. Syphilitic meningoencephalitis is a rare complicationof tertiary syphilis. The clinical manifestations are those of a diffuse process involving both cerebral hemispheres, and the pathology is that of a necrotizing encephalitis (132). A gumma is a nonspecific granulomatous lesion that oc-curs in patients with both acquired and congenital tertiary syphilis. It most oftendevelops inthe skeletal system, skin, and mucocutaneous tissues, but it can arise in any organ, including the eye, orbit, brain, and spinal cord. Gummas may be single or multiple. They vary in size from micro-scopic lesions to large masses that produce local destruction as well as mass effect. Clinical findings are dependent upon location. Gummas can develop in almost any part of the eye and adnexa, including the eyelid, conjunctiva, sclera, cornea, ciliary body, choroid, retina, and orbit (146,147). Gummas affecting the optic nerve and chiasm have been reported in patients with tertiary syphilis (148), as have gummas in the cerebral hemispheres, brainstem, and cerebellum (149-152). Some gummas appear to be intra-axial, whereas others, par-ticularly those inthe posterior fossa, are extra-axial. Gummas have an increased signal on T2-weighted MR images. They may or may not enhance on T1-weighted im-ages after intravenous injection of paramagnetic contrast ma-terial; however, there almost always is enhancement of the meninges adjacent to the lesion (151,153). SPIROCHETAL DISEASES 3105 Avariety of nongummatous ocular and orbital lesions may develop in patients with tertiary syphilis. Interstitial keratitis can occur that is similar in appearance to the interstitial kera-titis of congenital syphilis (153a) (Fig. 56.33); however, it is unilateral whereas congenital syphilitic interstitial keratitis almost always is bilateral. Some patients develop a condition called keratitis punctata profunda characterized by small gray nodules in the deep and middle layers of the corneal stroma associated with iridocyclitis. Keratitis with hypopyon and marginal corneal ulcers, as well as syphilitic tarsitis, may develop in some patients, and linear opacities located deep in the corneal stroma and extending from the limbus of one quadrant of the cornea to the limbus of the opposite quadrant, can be seen in others. Scleritis, fibrinous iritis, and gummatous iritis may also develop inpatien ts with tertiary syphilis (154). Finally, some patients with tertiary syphilis develop panuveitis and others develop nonspecific chorioret-inal scarring. Congenital Syphilis Although congenital syphilis occurs most frequently in the early stages of untreated maternal infection, it can be transmitted to the fetus at almost any stage of the disease. It can produce spontaneous abortion, neonatal death, or latent infection that does not become manifest until years later in life (155,156). Rhinitis (snuffles), followed by the develop-ment of a diffuse maculopapular desquamative rash with extensive sloughing of the epithelium, particularly on the palms and soles and around the mouth and anus, are the most significant abnormalities in the perinatal period (157). A generalized osteochondritis and perichondritis may affect the architecture of all bones of the skeletal system, most prominently the nose (saddle-nose deformity) and metaphy-ses of the lower extremities (‘‘saber shin'') (158). A B Figure 56.33. Acute interstitial keratitis in tertiary syphilis. A 43-year-old womanhad suddenvisual loss inher left eye. Syphilis had been diagnosed serologically 4 years earlier, but she did not complete a course of medical treatment. Examination revealed markedly diminished visual acuity in the left eye. A, Left cornea shows marked edema and folds of Descemet's membrane. The right cornea is clear. Funduscopy revealed no abnormalities. A VDRL test was negative, but an FTA-ABS test was positive ( ), as was a test for Treponema pallidum hemagglutination antibodies (TPHA) ( ; titer, 1 640). There were no skin lesions. Treatment was begun with topical fluorometholone, intramuscular penicillin G, benzathine (2.4 million U once a week for 3 weeks), and oral doxycycline (100 mg twice daily for 2 weeks). Six months later, visual acuity inthe left eye was normal. B, Left cornea is now clear with no evidence of lesions or scars. (From Dinis de Gama R, Cidade M. Interstitial keratitis as the initial expression of syphilitic reactivation. N Engl J Med 2002;346:1799.) A child with untreated congenital syphilis who survives the first 6-12 months of life usually enters a latent period. Subsequently, other findings may develop. The combination of interstitial keratitis (see below), notched incisors, and deafness is known as Hutchinson's triad and is diagnostic of congenital syphilis (159). About two-thirds of all children with congenital syphilis have ocular findings (107). One of the most common ocular manifestations is interstitial keratitis (160), which eventually occurs inalmost 40% of patients, 80% of whom develop it between the ages of 5 and 20. The remainder of patients with congenital syphilis who develop interstitial keratitis either have it at birth or develop it later inlife. As noted previously, congenital syphilitic interstitial keratitis almost always is bilateral. Another common ocular abnormality in patients with con-genital syphilis is chorioretinitis. As is the case with the chorioretinitis of acquired syphilis, the chorioretinitis that occurs in patients with congenital syphilis can take several forms, including a salt-and-pepper fundus, circumscribed chorioretinitis, retinal scarring with atresia of blood vessels and optic atrophy, and a pigmentary retinopathy mimicking retinitis pigmentosa (113) (Fig. 57.34). Neuro-ophthalmologic findings in patients with congeni-tal syphilis are similar to those that occur inpatien ts with acquired syphilis, including pupillary abnormalities, optic neuropathy, homonymous and bitemporal visual field de-fects, ocular motor dysfunction, and other cranial neuropa-thies (92,161). Pathology The primary pathologic abnormality of both congenital and acquired syphilis, found in all stages of the disease, is an obliterative endarteritis that consists of concentric endo- 3106 CLINICAL NEURO-OPHTHALMOLOGY Figure 56.34. Chorioretinitis in congenital syphilis. Note extensive chorioretinal scarring with areas of both hypopigmentation and hyperpig-mentation. (From Ho AC, Guyer DR, Yannuzzi LA, et al. Ocular syphilis: Classic manifestations and recent observations. Semin Ophthalmol 1993; 8:53-60.) thelial and fibroblastic proliferative thickening (162). The primary chancre is characterized pathologically by an in-tense infiltration of plasma cells and scattered histiocytes, progressive concentric endothelial and fibroblastic prolifera-tive thickening of small blood vessels and, eventually, an obliterative endarteritis. Spirochetes can be identified in the lesion by a variety of methods, including silver staining, immunofluorescent staining, and other specific antibody staining techniques. Hyperkeratitis is the primary feature of the skin lesions of secondary syphilis and is especially prom-inent in condylomata. Acute syphilitic meningitis generally affects the structures at the base of the brain, including the meningeal sheaths of the optic nerves, the optic chiasm, and the cranial nerves. Involvement of the optic nerve is characterized by infiltra-tion of the perioptic meninges and pial septae of the nerve by mononuclear cells (163). The principal histopathologic finding in meningovascular neurosyphilis is an obliterative endarteritis that affects pri-marily the vasa vasorum and the small- and medium-sized intracranial arteries. Without treatment, progressive inflam-mationof vessels ultimately produces proliferationof suben-dothelial fibrous material and irreversible occlusion (164). Patients with tabes dorsalis show gross pathologic changes in the spinal cord, including atrophy of the posterior columns and of the posterior nerve roots as they enter the spinal canal, particularly at the lower thoracic and lumbo-sacral levels (165). Posterior columndegen erationinlon g-standing tabes is so marked that it produces an excavated dorsal surface that is the origin of the name of the condition (tabes is the Latinword for ‘‘a wasting away''). The pathologic changes seen in patients with general pa-resis reflect the degenerative nature of the disease. Macro-scopic examination of the brains from affected patients re-veals diffuse cortical atrophy, dilation of the ventricles, and granular ependymitis (166). The gumma is a granulomatous lesion with a necrotic coagulated center that contains small vessels affected by the endarteritis (166). Spirochetes almost never are seen in gum-mas because these lesions are caused by a hyperimmune response to T. pallidum pallidum antigen and not by the organism itself. SYPHILIS, HUMAN IMMUNODEFICIENCY VIRUS INFECTION, AND THE ACQUIRED IMMUNE DEFICIENCY SYNDROME (AIDS) Because they share a commonmode of transmissionan d because a chancre may facilitate entry of HIV-1 into the body, syphilis and HIV-1 infection or AIDS often are present in the same patient (167). The coinfection of a patient with syphilis with HIV may alter the natural history by several mechanisms: (a) increasing the tendency of such patients to develop neurosyphilis, (b) decreasing the latent period be-fore neurosyphilis develops, (c) increasing the severity of the manifestations, and (d) reducing the response to otherwise appropriate therapy (168-170). The ocular and neuro-ophthalmologic manifestations of secondary and tertiary syphilis may be more extensive and severe when associated with concurrent HIV-1 infection. Diagnosis The laboratory diagnosis of syphilis can be made directly by light, phase-contrast, or dark-field microscopy. T. pal-lidum has a corkscrew appearance and moves in a spiraling motion with a characteristic undulation at its midpoint. Un-less there are a large number of organisms, however, certain artifacts may be mistakenly identified as treponemes. The diagnosis of syphilis also can be made by direct examination of a biopsy specimen using a silver stain, immunofluorescent or immunoperoxidase staining, PCR, or a combination of these techniques. Inadditionto the direct diagnosis of syphilis, a number of tests can be used to diagnose syphilis indirectly. Serologic tests are the most common indirect methods used to diagnose both congenital and acquired syphilis (93,94,171). Most of these tests measure one of two different types of antibodies: nonspecific nontreponemal reaginic antibody and specific antitreponemal antibody (Table 56.7). Tests that detect nonspecific nontreponemal reaginic anti-body are inexpensive, rapid, and convenient for screening large numbers of patients. They also are helpful in determin-ing disease activity. Tests that measure specific antitrepone-mal antibodies are more sensitive and specific for past infec-tion. The original nontreponemal tests for syphilis detected nonspecific IgG and IgM antibodies, also called ‘‘reagins,'' directed against a lipoidal antigen that results from the inter-actionof host tissues with T. pallidum or from T. pallidum alone (94,141). Extracts of normal tissue, such as beef heart or liver, originally were used as similar antigens. A more standardized preparation containing cardiolipin, lecithin, and cholesterol is now used as the antigen for these tests SPIROCHETAL DISEASES 3107 Table 56.7 Percentage of Untreated Patients with Positive Responses to Commonly Used Serologic Tests Early (Primary Late (Late Latent Type of Testa and Secondary) and Tertiary) Nonspecific nontreponemal tests 70-100 60-98 (VDRL, RPR, ART) Specific treponemal tests 50-85 97-100 (FTA-ABS, TPHA, MHA-TP, TPI) aThe nonspecific nontreponemal tests should revert to negative (nonreactive) when appropriate treatment is given except in unusual circumstances (see text). Specific treponemal tests may also revert to negative if effective treatment is given early. (Adapted from Tramont EC. Treponema pallidum [syphilis]. In Mandell GL, Bennet JE, Dolin R, eds. Principles and Practice of Infectious Diseases. Ed 5. New York, Churchill Livingstone, 2000:2474-2489.) (172). This preparationproduces fewer false-positive reac-tions than occur with extracts from beef heart or liver. The standard nontreponemal antigen test for syphilis is the VDRL test, inwhich heated serum is tested for its ability to flocculate a suspension of antigen. This test may be modi-fied inon e of two ways: as a rapid plasma reagin (RPR) card test or as anautomated reagin test (ART). Nonspecific reaginic tests become reactive in primary syphilis within 4-7 days after a chancre appears, and all of these tests usually give positive results in untreated primary, secondary, and tertiary syphilis. The tests should give negative results (e.g., become nonreactive) 1 year after treatment in primary syphi-lis and 2 years after therapy in secondary syphilis (172). Nonspecific nontreponemal tests often are negative in con-genital syphilis (173,174). Unfortunately, none of the nonspecific nontreponemal tests for syphilis is 100% sensitive for the disease. Indeed, at the time of early presentation, about 30% of patients with primary syphilis have a nonreactive VDRL (172). In addi-tion, although once positive, the VDRL, RPR, and ART are quite useful in determining the success or failure of previous treatment of syphilis, a negative test does not eliminate the possibility that a patient has either congenital or acquired syphilis. The principal specific antitreponemal antibody tests for syphilis are the fluorescent treponemal antibody absorption test for syphilis (FTA-ABS), the Treponema pallidum hem-agglutination (TPHA) test, the microhemagglutination test for Treponema pallidum (MHA TP test), and the Treponema pallidum immobilization(TPI) test. The FTA-ABS is a stan-dard indirect immunofluorescent antibody test that uses T. pallidum harvested from rabbit testes as the antigen. The patient's serum is first absorbed with nonpathogenic trepo-nemal antigen to remove any cross-reacting antibody that may have developed against saprophytic treponemes in the oral cavity or genital tract. The serum then is incubated with specific antigen. Once positive, the FTA-ABS remains posi-tive for life (176). It is not, however, 100% sensitive in patients ultimately diagnosed as having either congenital or acquired syphilis (173). Nevertheless, it is extremely useful and is the major specific antitreponemal test that is used to diagnose syphilis. The TPI test is the most sensitive and specific antitreponemal test for syphilis. It determines the ability of antibody plus complement to immobilize live T. pallidum visualized under a dark-field microscope. It is ex-pensive, time-consuming, and difficult to perform. Thus, it is not used as a routine screening test for syphilis. Neverthe-less, in a patient who may have multiple spirochetal infec-tions, a positive TPI test is 100% specific for syphilis. Acute or transient false-positive non-treponemal reaginic test reactions occur when there is a strong immunologic stimulus, such as anacute bacterial or viral infection or after a vaccination (Table 56.8). Positive reactions persist for months in patients with autoimmune or connective tissue disease, particularly systemic lupus erythematosus. Biologic false-positives also occur among HIV-infected patients. A false-positive nontreponemal reaginic test usually can be verified and syphilis can be excluded when a specific anti-treponemal antibody test is negative. Unfortunately, many of the same disorders that produce a false-positive nontreponemal reaginic test also produce a false-positive specific treponemal test reaction (Table 56.8). In addition, the FTA-ABS, TPHA, and MHA-TP tests may Table 56.8 Causes of False-Positive Serologic Test Reactions for Syphilis Aging Blood transfusions (multiple) Chancroid Chickenpox Connective tissue (collagen vascular) disease Drug addiction Hepatitis HIV infection (early) Infectious mononucleosis Leprosy Leptospirosis Liver disease (chronic) Lyme diseasea Lymphogranuloma venereum Malaria Measles Mycoplasma pneumonia Pneumonococcal pneumonia Pregnancy Ratbite fever (Spirillum minor) Relapsing fever Rheumatic heart disease Rickettsial disease Scarlet fever Subacute bacterial endocarditis Trypanosomiasis Tuberculosis Vaccinia (vaccination) aVDRL (RPR)-negative. (Adapted from Tramont EC. Treponema pallidum [syphilis]. In Mandell GL, Bennet JE, Dolin R, eds. Principles and Practice of Infectious Diseases. Ed 5. New York, Churchill Livingstone, 2000:2474-2489.) 3108 CLINICAL NEURO-OPHTHALMOLOGY be positive when the VDRL and RPR are negative, as in Lyme disease and HIV infection. Thus, the only definitive way to distinguish between a false-positive and a true-positive test result for syphilis is with the TPI test. In summary, the nonspecific nontreponemal reaginic anti-body tests are used for screening large numbers of patients for syphilis, whereas the specific treponemal antibody tests are used for confirming the diagnosis, particularly in com-plex cases. Although most cases of acquired syphilis canbe easily diagnosed using direct or indirect tests for syphilis, a diagno-sis of congenital syphilis may be difficult, particularly when an infant born to a mother with syphilis has no characteristic clinical findings. The most reliable means to diagnose con-genital syphilis is to test the mother at the time of birth. Because the CNS is invaded during the spirochetemia of acquired syphilis in at least 40% of patients (101) and be-cause spirochetemia occurs withinhours to days after infec-tion, all patients with syphilis should be assumed to have CNS invasion until proven otherwise (136). The finding of a mononuclear pleocytosis, an increased protein content, a positive VDRL or RPR test, evidence of local CNS anti-treponemal antibody, using a modified FTA-ABS or TPHA test, or a combination of these, establishes the diagnosis of neurosyphilis, whether or not the patient has neurologic symptoms or signs (171) (Fig. 56.35). A negative CSF VDRL does not eliminate the diagnosis of neurosyphilis (154). Thus, in patients suspected of neurosyphilis, with or without eye or neuro-ophthalmic involvement, specific treponemal antibody tests are necessary to make the diag-nosis. Treatment T. pallidum is sensitive to a variety of antibiotics, particu-larly penicillin and its derivatives. The effectiveness of rec- Figure 56.35. Guidelines for diagnosis of central nervous system syphilis. ommended therapies for latent syphilis and neurosyphilis is supported more by clinical experience rather than controlled trials. As a general rule, patients with primary, secondary, or congenital syphilis without evidence of CNS disease can be treated with less medication, using an intramuscular, in-travenous, or oral route, than can patients with evidence of CNS disease regardless of the stage. Patients who are HIV- 1 positive and patients with tertiary syphilis usually require a higher dose of antibiotics delivered through an intramuscu-lar or intravenous route for a longer period of time to main-tain appropriate concentrations of the drug in the blood and CSF (136). Inparticular, neurosyphilis usually is treated with aqueous crystal penicillin G given intravenously in a dose of 12-24 millionun its for 10-14 days (2-4 millionun its every 4 hours), followed by intramuscular injections of ben-zathine penicillin given once a week in a dose of 2.4 million units for 3 consecutive weeks after completion of IV therapy (103,171). The intramuscular injections of benzathine peni-cillin are used to treat organisms that may be dividing slowly and thus not be killed by the intravenous penicillin G. Ceftri-axone and azithromycin have been used to treat neurosyphi-lis and to treat syphilis in patients who also have HIV infec-tionor AIDS, but their long-term efficacy requires further evaluation (177,178). Although no prospective, controlled clinical trials have established the optimum dose or duration of therapy for any of the stages of syphilis or its complica-tions, the CDC has established guidelines for treatment of syphilis (103) (Table 56.9). In our opinion, the treatment of a patient with syphilis, regardless of the stage, should be determined with the aid of anexpert inin fectious disease. Steroids may be used in patients with neuro-ophthalmo-logic findings with penicillin to avoid the Jarisch-Herxhei-mer reaction(179). This reaction, which can also occur in patients with Lyme disease, is a systemic response that oc- SPIROCHETAL DISEASES 3109 Table 56.9 CDC Recommended Treatments for Syphilis Primary, Secondary, or Early Latent Syphilisa Recommended: Benzathine penicillin G, 2.4 million units in a single dose, intramuscularly For penicillin allergy: Doxycycline, 100 mg by mouth twice daily for 14 days Late Latent Syphilis, Syphilis of Unknown Duration, Tertiary Syphilis Recommended: Benzathine penicillin G, 2.4 million units weekly for 3 weeks, intramuscularly For penicillin allergy: Doxycycline, 100 mg by mouth twice daily for 28 days Neurosyphilis, Syphilitic Eye Disease, Syphilitic Auditory Disease Recommended: Aqueous crystalline penicillin G, 18-24 million units per day administered as 3-4 million units intravenously every 4 hours or continuous infusion for 10-14 days Alternative: Procaine penicillin 2.4 million units intramuscularly once daily plus probenecid 500 mg by mouth 4 times a day, both for 10-14 days Precautions 1. Pregnant women should not be treated with doxycycline. 2. Patients with non-life-threatening allergies to penicillin should ideally be desensitized. 3. Patients with serious allergies to sulfonamides should not be treated with probenecid-containing regimens. aLatent syphilis is defined as seroreactivity without other evidence of disease. Early latent syphilis is diagnosed in patients infected within the preceding year as defined by 1 of the following: (a) a documented seroconversion; (b) unequivocal symptoms of primary or secondary syphilis; or (c) a sex partner documented to have primary, secondary, or early latent syphilis. (Adapted from Golden MR, Marra CM, Holmes KK. Update on syphilis: resurgence of an old problem. JAMA 2003;290:1510-1514.) curs about 1-2 hours after the initial treatment of a spiro-chetal infection with penicillin (180). It lasts for 12-24 hours and is characterized by fever, chills, myalgia, headache, tachycardia, hyperventilation, vasodilation with flushing, and mild hypotension. It is caused by release of a heat-stable pyrogenfrom the killed spirochetes (181). All patients with early syphilis and congenital syphilis need clinical serologic follow-up 6 and 12 months after treat- LEPTOSPIRA AND LEPTOSPIROSIS The family Leptospiraceae contains only one genus, Lep-tospira (from the Greek words lepto, meaning ‘‘thin'' or ‘‘fine,'' and spira, meaning ‘‘coil''). As their name implies, Leptospira are finely coiled, motile spirochetes that are 6-20 m long and 0.1 m wide (1) (Fig. 56.36). Although there are more than200 serotypes of pathogenic leptospires, all of the serotypes pathogenic to humans belong to a single species, L. interrogans. Infection with this spirochete causes a disease called leptospirosis (2,183). Leptospirosis occurs around the world and primarily af-fects wild and domestic animals; humans are an accidental host. The most important sources of human infection in the United States are dogs, livestock, and rodents, but rats are the most important source worldwide. Most cases occur in late summer or early fall inyoun g, adult menwho live in rural areas (183,184). About 100 cases occur inthe United ment, whereas patients with syphilis of more than 1 year's duration should have repeat nonspecific nontreponemal anti-body testing 24 months after treatment. All patients with neurosyphilis should be monitored with both serologic and CSF examination for at least 5 years. Retreatment should be considered whenever either symptoms or clinical or labora-tory signs of syphilis persist. Patients treated for syphilis should be tested for HIV and other sexually transmitted dis-eases at regular intervals. Prognosis Syphilis is a curable disease. Patients who are treated ade-quately during the primary, secondary, or latent stage of the disease usually have complete resolution of signs and symptoms with little or no residua. Syphilitic optic neuritis, optic perineuritis, and neuroretinitis all have a good prog-nosis with early treatment (182). Patients with permanent neurologic deficits or aortitis may have permanent neuro-logic and psychiatric deficits. Argyll Robertson pupils do not recover their normal function. Prevention The CDC has recently launched the National Syphilis Elimination Plan (99). Prevention efforts are continuing among populations who are at higher risk for syphilis, partic-ularly homosexual and bisexual men. The CDC is working with state and local public health organizations to develop and implement effective strategies for education, screening, risk reduction, and community organization. OTHER DISEASES CAUSED BY TREPONEMA SPECIES As noted above, infection by Treponema species other than Treponema pallidum pallidum causes the spirochetal infections known as yaws, bejel, and pinta (3). None of these disorders is of sufficient neuro-ophthalmologic interest to warrant their inclusion in this chapter. The reader interested in these conditions should consult the previous edition of this text. Figure 56.36. Morphology of Leptospira interrogans. Electronmi-crograph shows major features of the spirochete, which has regular tight coils and hooked ends. Note relationship of outer sheath (OS) and axial fibrils (AF). (From GutmanLT. The spirochetes. In Joklik WK, Willett HP, Amos DB, et al, eds. Zinsser Microbiology. Ed 20. Norwalk, Conneticut, Appleton& Lange, 1992 657-675.) 3110 CLINICAL NEURO-OPHTHALMOLOGY States annually, of which 25% occur in Hawaii (184). Al-though the number of cases related to occupational exposure is declining, there has been an increase from recreational exposure (2). Leptospirosis may occur in persons who travel to endemic areas, particularly those who have contact with natural water that is contaminated with rat urine (185,186). Outbreaks have occurred in Nicaragua, Costa Rica, India, and among participants in an EcoChallenge competition in Borneo (185-187). The largest outbreak inthe United States oc-curred in Springfield, Illinois, among athletes and commu-nity residents after a triathlon (188). Swallowing of contami-nated lake water soon after a heavy rainstorm was the main contributing risk factor. Leptospires enter the body by penetrating intact mucous membranes or abraded skin. They enter the bloodstream and are rapidly transported to all parts of the body, including the CNS and the eye. Some people habitually exposed to in-fected animals or material contaminated with their urine may remainasymptomatic but still develop serologic evidence of infection. CLINICAL MANIFESTATIONS Symptomatic infection may either be the mild anicteric form that accounts for 90% of cases or the more severe Figure 56.37. Schematic diagram showing biphasic nature of leptospirosis and relevant investigations at different stages of disease. Specimens 1 and 2 for serology are acute-phase specimens, 3 is a convalescent-phase sample that may facilitate detection of a delayed immune response, and 4 and 5 are follow-up samples that can provide epidemiological information, such as the presumptive infecting serogroup. (From Levett PN. Leptospirosis. Clin Microbiol Rev 2001;14 296-326.) icteric form. Both types have a septicemic phase lasting 4-7 days followed by defervescence for 1-2 days. Subsequently, animmun e phase develops that may last from 4-30 days. Inthe septicemic phase, there is widespread dissemination of the leptospires, whereas in the immune phase, circulating antibodies against Leptospires cause organ damage (Fig. 56.37). Anicteric Leptospirosis In the septicemic phase, patients experience sudden fever, chills, severe myalgia, malaise, abdominal pain, nausea and vomiting, and eye and neck pain. They then improve for about 1-2 days. Although not all patients develop the im-mune phase, those that do develop a headache that becomes increasingly severe, accompanied by severe myalgias, par-ticularly of the paraspinal region, calf, neck, and abdomen. Other manifestations that occur during the immune phase include muscle tenderness, dyspnea, and lymphadenopathy (189). Ocular manifestations of leptospirosis include eye pain, conjunctival hyperemia and chemosis, and photophobia (190,191) (Fig 56.38, Fig 56.39). Other commonocular find-ings include uveitis, vitritis, papillitis, chorioretinitis, and cotton-wool spots (192-195). In one study from New Cale-donia, where there is a high incidence of leptospirosis, eye SPIROCHETAL DISEASES 3111 Figure 56.38. Bilateral conjunctival chemosis and subconjunctival hem-orrhage in a patient with anicteric leptospirosis. (Courtesy of Drs. Arnold Kaufmanan d George Schmid.) findings included uveitis (diffuse or anterior), optic neuritis, interstitial keratitis, pars planitis, and third nerve palsy (196). Almost half of the patients had systemic findings, usually neurologic, at the time of diagnosis. The uveitis that occurs in anicteric leptospirosis frequently is acute, but it may be chronic or recurrent. It may be unilat-eral or bilateral. Nongranulomatous uveitis is more common than granulomatous uveitis. The onset of the uveitis may be so mild that it goes unnoticed, or it may be extremely severe and associated with loss of vision. Hypopyon occurs in about 12% of patients with severe uveitis. About 50% of patients develop aseptic meningitis that A B Figure 56.39. Neuroretinitis and retinitis in anicteric leptospirosis. The patient was a 14-year-old girl who had blurred vision inthe left eye. Visual acuity was 20/30 OS. A, The left optic disc is markedly swollen, and there are several hard exudates in the macula. B, Several areas of retinitis, one of which is centered over a blood vessel and is associated with a focal periphlebitis (arrowhead), are seeninthe midperipheral fundus of the left eye. (Courtesy of Drs. JohnO. Susac and J. LawtonSmith.) lasts a few days to weeks, and about 7% of patients develop encephalitis, myelitis, peripheral neuritis, or a combination of these manifestations (197). Icteric Leptospirosis (Weil Disease) Icteric leptospirosis, also called Weil disease, is a more severe form of leptospirosis than nonicteric leptospirosis. It is characterized by impaired renal and hepatic function, pulmonary involvement, systemic hemorrhage with evi-dence of widespread vasculitis, vascular collapse, and severe alterations of consciousness (198). Hepatosplenomegaly oc-curs in about 25-50% of cases, and 5-10% of patients die, usually from liver failure. Ocular findings are both common and important in icteric leptospirosis. In the appropriate setting, conjunctival chemo-sis and scleral icterus are almost pathognomonic of the dis-ease. Other ocular manifestations include uveitis, cotton-wool spots, retinal vasculitis and optic disc swelling (194). DIAGNOSIS The diagnosis of leptospirosis should be suspected from the clinical setting. In patients with the icteric form, the ocu-lar manifestations are typical. In addition, the serum creati-nine phosphokinase is elevated with minor elevations of serum aspartate aminotransferase and alanine aminotransfer-ase. 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