less sensitive for adult inclusion conjunctivitis. The DFAs and EIAs are widely available and equally sensitive. The DNA amplification tests are highly sensitive and specific for identifying C. trachomatis infection in the conjunctiva and genital tracts of both adults and neonates. Cell culture is the definitive technique but is less available and is less sensitive than DNA amplification procedures.
The presence of serum IgM antibodies against Chlamydiae in newborns suggests a systemic infection, particularly pneumonia, but serologic tests have little use in diagnosing other C. trachomatis infections.
Most tests for C. trachomatis do not detect C. psittaci or C. pneumonia, but tests based on the detection of chlamydial genus-specific antigen detect C. psittaci and C. pneumoniae (e.g. DFA test [LPS, Ortho] that identifies all three species).
PROPHYLAXIS
The recommended prophylaxis for neonates to prevent both gonococcal neonatal ophthalmia and chlamydial ophthalmia is one application of tetracycline or erythromycin ointment within 1 hour after delivery. Credé prophylaxis with 1% silver nitrate is equally effective in preventing chlamydial eye infection of the newborn.
TREATMENT
Systemic
Because C. trachomatis infection is not limited to the eye in either neonatal infants or adults, it is necessary to use systemic antimicrobial treatment. Moreover, the sexual consorts of adults and the parents of infants must also receive a full course of therapy. Simultaneous treatment of all sexual partners is important to prevent reinfection. It also is prudent to examine all sexual partners for other venereal diseases, such as gonorrhea, syphilis, and HIV.
For infants, effective therapy is provided by erythromycin suspension 50 mg/kg/day PO in four equal doses for 2 weeks.
Children older than 4 months can be treated with azithromycin pediatric suspension 200 mg/5 ml in a single dose of 20 mg/kg body weight.
For adults with chlamydial eye infections one 1-g dose of oral azithromycin for genital C. trachomatis infections; a repeat dose at 1 week may be considered for those with eye infection.
Alternative treatment regimens for adults include one of the following:
●Doxycycline 100 mg b.i.d. for 2 weeks;
●Erythromycin base 500 mg PO four times a day for 7 days; or
●Ofloxacin 300 mg twice a day for 7 days (not for use in patients under 18 years or in pregnant or lactating women); or
●Amoxicillin 500 mg PO three times a day for 7 days.
C. psittaci and C. pneumoniae eye infections are treated with the same drugs and dosages for 4 to 6 weeks.
Ocular
Because chlamydial infections are systemic, local therapy alone should be discouraged; it has been shown that topical treatment alone is extremely slow and only partially effective in treating adult or neonatal inclusion conjunctivitis and that relapses are
frequent. Local antimicrobial treatment with tetracycline or erythromycin ointment to the eye is not necessary for patients on full oral therapeutic doses of antibiotic. Topical sulfonamide alone is even less effective than topical tetracyclines or erythromycin; topical rifampin ointment has been used in the treatment of ocular chlamydial infections but, as with other topical antimicrobial agents, is of limited use.
For the occasional adult patient who develops an anterior iritis with inclusion conjunctivitis, the use of topical corticosteroids carries no more risk than to any other patient as long as the patient is under systemic treatment with antimicrobial agents or has received a full course of systemic antimicrobial treatment. When used without systemic antichlamydials, topical corticosteroids are definitely contraindicated for the treatment of chlamydial conjunctivitis or keratitis because the medications prolong the disease.
PRECAUTIONS
The use of erythromycin estolate or ethylsuccinate is known to carry a high risk of toxic hepatitis, and erythromycin is also generally less well tolerated than oral tetracyclines. Although sulfonamides have been given in the past, they carry a high risk of systemic toxicity, which precludes their use for chlamydial infection.
Nongranulomatous anterior uveitis may develop as a response to chlamydial infection in patients who are positive for HLA B27. The uveitis does not respond to antimicrobial treatment alone but can be suppressed with adequate doses of topical corticosteroids. Recurrent episodes of uveitis occur with this syndrome but are unrelated to further chlamydial infection.
REFERENCES
Bersudsky V, Rehany U, Tendler Y, et al: Diagnosis of chlamydial infection by direct enzyme-linked immunoassay and polymerase chain reaction in patients with acute follicular conjunctivitis. Graefes Arch Clin Exp Ophthalmol 237(8):617–620, 1999.
Carta F, Zanetti S, Pinna A, et al: The treatment and follow up of adult chlamydial ophthalmia. Br J Ophthalmol 78(3):206–208, 1994.
Dean D, Shama A, Schachter J, Dawson CR: Identification of an avian strain of Chlamydia psittaci causing severe keratoconjunctivitis in a bird fancier. Clin Infect Dis 20:1179–1185, 1995.
Grossman M, Schachter J, Sweet R, et al: Prospective studies in chlamydia in newborns. In: Mardh P-A, Holmes KK, Oriel JD, et al, eds: Chlamydial infections. Amsterdam, Elsevier Biomedical, 1982:213–216.
Lietman T, Dawson CR, Schachter J, Dean D: Chronic follicular conjunctivitis associated with Chlamydia pneumoniae and Chlamydia psittaci.
Clin Infect Dis 26:1335–1340, 1998.
MMWR: 1998 guidelines for treatment of sexually transmitted diseases. MMWR 47:53–59, 1998.
20 INFECTIOUS MONONUCLEOSIS
075
(Epstein–Barr Virus)
Matilda Frances Chan, MD, PhD
Rochester, New York
Steven S. T. Ching, MD
Rochester, New York
Infectious mononucleosis (IM) is a clinical syndrome that is characterized by the triad of fever, tonsillar pharyngitis and
Mononucleosis Infectious • 20 CHAPTER
39
1DiseasesSECTIONInfectious •
lymphadenopathy. Epstein–Barr virus (EBV), the primary agent of infectious mononucleosis, is a widely disseminated herpesvirus that is spread by intimate contact between susceptible persons and asymptomatic EBV shedders. Contact of EBV with oropharyngeal epithelial cells followed by viral replication and infection of neighboring lymphoid B cells leads to dissemination of infection throughout the lymphoreticular system of which the lacrimal gland and conjunctiva are components. Other acute infections known to cause mononucleosis syndromes include cytomegalovirus, Toxoplasma spp., human immunodeficiency virus, human herpesvirus type 6, hepatitis virus and possibly human herpesvirus type 7.
●Sclera: episcleritis, scleritis.
●Uvea: iritis, vitritis, multifocal choroiditis, retinitis (punctuate, hemorrhagic), intraocular posttransplant lymphoproliferative disorder.
●Neuro-ophthalmologic: accommodation paresis, convergence deficiency, hemianopsia, nystagmus, ophthalmoplegia, optic neuritis, papilledema.
Laboratory findings
Hematologic
Peripheral blood smear characterized by atypical lymphocytes (more than 10%) and lymphocytosis (60–70%).
ETIOLOGY/INCIDENCE
EBV infection occurs worldwide. Approximately 90 to 95% of adults are EBV-seropositive. The rate of EBV exposure and development of antibodies by the age of four is close to 100% in developing countries and between 25 to 50% in sociologically underprivileged communities in the United States. The majority of primary EBV infections throughout the world are subclinical and the risk of development of clinical symptoms depends on the age of exposure. In children younger than 6 years, EBV infection may be asymptomatic or present as an upper respiratory infection. EBV infection is the etiologic agent in 75% of children and adolescents manifesting the IM syndrome. The vast majority of adults are not susceptible to infection because of immunity due to prior exposure.
Serologic
●Heterophile antibodies — Paul–Bunnell and Monospot tests are sensitive and specific for IM and antibodies appear within one week of clinical symptoms and remain positive for up to one year.
●Specific EBV antibodies — levels of IgM and IgG antibodies against viral capsid antigens (VCA) and nuclear antigen (EBNA) are used for heterophil-negative mononucleosis.
The current recommendation is that patients with clinical suspicion for IM should have a white blood cell count with differential and a heterophile test. If the heterophile test is negative but there is still a strong clinical suspicion, EBV antibody levels should be measured.
The direct detection of EBV genome fragments in ocular tissues can be achieved using polymerase chain reaction (PCR).
DIAGNOSIS
Clinical signs and symptoms
Systemic
The clinical course of the systemic illness is characterized by the following classic signs:
●Two to five days of prodrome of malaise, headache and low grade fever;
●Subsequent development of moderate to high fever, tonsillitis and/or pharyngitis and lymphadenopathy;
●Acute symptoms resolve in one to two weeks, but fatigue often persists for months.
Other systemic manifestations associated with infectious mononucleosis include the following:
●Severe fatigue;
●Splenomegaly (50 to 60%);
●Skin rash (associated with antibiotic use);
●Neurologic syndromes (Guillain–Barré syndrome, cranial nerve palsies, meningoencephalitis, aseptic meningitis, transverse myelitis, peripheral neuritis);
●Hematologic abnormalities.
TREATMENT
Systemic
●Rest, fluids and acetaminophen are recommended. Aspirin should not be given to children or teenagers because of the risk for the development of Reye’s syndrome.
●Avoid strenuous activity and contact sports to decrease the risk of splenic rupture.
●The use of systemic steroids is unproven, but they can be used for special circumstances such as airway restriction, hematologic or neurologic complications and uveitis.
●Aciclovir and immunomodulating drugs such as interleu- kin-2 and interferon alpha have not been proven to alter clinical course.
Ocular
●Topical steroids have been used to treat stromal keratitis and uveitis.
●The therapeutic benefits of topical aciclovir or topical trifluridine have not been well studied.
Ocular
●Conjunctiva: follicular, granulomatous, or membranous conjunctivitis; subconjunctival hemorrhage, hyperemia.
●Cornea: punctuate epithelial keratitis, dendritic keratitis, stromal keratitis (subepithelial infiltrates, nummular opacities, ring-shaped granular opacities, multilevel stromal infiltrates), intrastromal neovascularization, keratoconjunctivitis sicca, linear endotheliitis.
●Lacrimal system: dacryoadenitis, dacryocystitis, Sjögren’s syndrome, aqueous tear deficiency.
COMMENTS
Dendritic and stromal keratitis have only rarely been reported for this disease. However, the lesions may be indistinguishable from some manifestations of herpes simplex keratitis; therefore, caution is advised in the use of steroids.
As demonstrated by reports on stromal infiltration and neovascularization, this entity should be considered in the differential diagnosis of interstitial keratitis. A case report describing a patient with acute EBV infection and with corneal findings
40
of stromal edema with a distinct line of endothelial keratic precipitates suggests that EBV infection should be considered in the differential diagnosis of linear endotheliitis (BJ Shin, SS Ching, ARVO abstract, 2002).
SUMMARY
IM is a disease of children and young adults caused by EBV infection. Fortunately, ocular involvement is usually mild and requires no intervention. However, because the virus can affect the ocular system in multiple areas, the possibility of this entity should be kept in mind when the practitioner encounters puzzling ocular inflammation.
REFERENCES
Al-Attar L, Berrocal A, Warman R, et al: Diagnosis by polymerase chain reaction of ocular posttransplant lymphoproliferative disorder after pediatric renal transplantation. Am J Ophthalmol 137:569–571, 2004.
Aronson MD: Infectious mononucleosis in adults and adolescents. Online. Available at: UptoDate online version 12.3. http://www.uptodate.com. Accessed December 13, 2004.
Chodosh J, Gan Y, Sixbey JW: Detection of Epstein–Barr virus genome in ocular tissues. Ophthalmology 103:687–690, 1996.
Kaye SB, Baker K, Bonshek R, et al: Human herpesviruses in the cornea. Br J Ophthalmol 84:563–571, 2000.
Matoba AY: Ocular disease associated with Epstein–Barr virus infection. Surv Ophthalmol 35:145–150, 1990.
Matoba AY, Wilhelmus KR, Jones DB: Epstein–Barr viral stromal keratitis. Ophthalmology 93:746–751, 1986.
Palay DA, Litoff D, Krachmer JH: Stromal keratitis associated with Epstein– Barr virus infection in a young child. Arch Ophthalmol 111:1323–1324, 1993.
Pflugfelder SC, Crouse CA, Atherton SS: Ophthalmic manifestations of Epstein–Barr virus infection. Int Ophthalmol Clin 33:95–101, 1993.
21 INFLUENZA 487.1
Daniel H. Spitzberg, MD, FACS
Indianapolis, Indiana
ETIOLOGY/INCIDENCE
Influenza is an acute respiratory infection of specific viral etiology. There are three distinct antigenic types of influenza virus, designated A, B, and C; although type C usually produces only a minor illness, antigenic types A and B can cause major epidemics. The disease often occurs sporadically or in localized outbreaks, particularly in schools or military camps, and usually in fall or winter.
DIAGNOSIS
Clinical signs and symptoms
Systemic
The characteristics of influenza include the sudden onset of:
●Headache;
●Fever, which gradually subsides over 2 to 3 days;
●Malaise;
●Muscular aching;
●Substernal soreness;
●Nasal stuffiness, coryza;
●Mild pharyngeal infection, sore throat;
●Nonproductive cough;
●Nausea.
Influenza may cause necrosis of the respiratory epithelium, predisposing the body to secondary bacterial infections. Contracted early in pregnancy, influenza has been implicated in multiple congenital deformities of the fetus, including anencephaly and congenital cataract.
Ocular
Complications of influenza in the eye include:
●Conjunctival redness, subconjunctival hemorrhages;
●Acute catarrhal conjunctivitis;
●Superficial punctate or interstitial keratitis;
●Dendritic ulcer due to opportunistic herpes simplex;
●Palpebral edema;
●Dacryoadenitis, dacryocystitis;
●Secondary bacterial infections of the cornea, conjunctiva, or both;
●Bilateral, self-limited nongranulomatous anterior uveitis;
●Retinal angiospasm, edema, exudates, hemorrhages, stellate retinopathy;
●Venous thrombosis;
●Extraocular muscle myalgias, paralysis of third or fourth cranial nerve, tendonitis;
●Accommodative spasm, episcleritis, mydriasis, myopia;
●Cellulitis, panophthalmitis;
●Cataract (congenital);
●Optic neuritis (associated with encephalitis);
●Bilateral simultaneous corneal graft rejection after influenza vaccination;
●Optic neuritis after influenza vaccination;
●Bilateral optic neuropathy associated with influenza vaccination.
Uveitis associated with influenza can become chronic, with exacerbations and remissions.
TREATMENT
Systemic
Prophylactically, amantadine protects 50% to 70% of recipients exposed to influenza A viruses and is indicated for patients older than 1 year during influenza A outbreaks, especially individuals for whom influenza would pose a grave risk, such as the elderly. It may be most effective in individuals who already have antibodies against influenza A virus strains; therefore, previous vaccination does not interfere with and may augment its effect. Amantadine also may have therapeutic value if given promptly after the first symptoms of infection appear. The administration of amantadine 100 mg twice daily should be continued for at least 10 days.
Ocular
In cases of mild uveitis homatropine 5% solution should be applied topically four times daily to control pain.
Influenzal uveitis can become chronic, with exacerbations and remissions; patients with this type of uveitis respond well to topical ocular corticosteroid therapy for short time periods.
Influenza • 21 CHAPTER
41
1DiseasesSECTIONInfectious •
Prednisolone topical 0.12% ophthalmic solution can be applied two or three times daily for 1 week to control low-grade uveitis.
Catarrhal marginal ulcers are an immunologic response to the viral infection and should be treated with 0.12% prednisolone solution four times daily.
Supportive
Bedrest and gradual return to full activity are advisable to reduce complications; the patient’s cough reflex can be depressed with codeine (adult dose 15 to 60 mg PO).
Codeine is more effective than salicylates for the treatment of influenzal headache and myalgia; salicylates often increase discomfort by causing sweats and chills. Antibiotics should be reserved for treating bacterial complications.
PROPHYLAXIS
Routine yearly immunization with polyvalent influenza virus vaccine is strongly recommended for high-risk groups, including pregnant women and persons older than 65 years regardless of their health status. Persons of all ages who have chronic rheumatic heart disease, other cardiovascular disease, chronic bronchopulmonary disease, diabetes mellitus, or Addison’s disease should be considered for prophylactic treatment.
PRECAUTIONS
If the fever persists for longer than 4 days, if the cough becomes productive, or if the white cell count rises above 12,000/mm3, secondary bacterial infection should be ruled out or verified and treated.
Although the duration of uncomplicated influenza is 1 to 7 days and complete recovery is the rule, preexisting respiratory disease or secondary bacterial pneumonia can lead to a fatal outcome. Most fatalities are due to bacterial pneumonia; pneumococcal pneumonia is most common, but staphylococcal pneumonia is most serious.
In general, serious ocular complications of influenza are rare; however, secondary bacterial infections must be watched closely. The cornea is the usual site of most serious ocular complications; this area and the anterior chamber are in the areas in which the main follow-up examinations should be focused.
REFERENCES
Giraldi C, Paterni F, Cecchini S, et al: Paralysis of the parasympathetic ocular nerve after influenza syndrome. Rev Neurol 61:180–182, 1991.
Grossman M, Jawetz E: Infectious diseases: viral and rickettsial. In: Krupp MA, Chatton MJ, eds: Current medical diagnosis and treatment. Los Altos, CA, Lange, 1982:821–822.
Hull TP, et al: Optic neuritis after influenza vaccination. Am J Ophthalmol 124(5):703–704, 1997. PMID: 9372734; UI: 98040003.
Knight V: Influenza. In: Isselbacher KJ, Adams RD, Braunwald E, et al, eds: Harrison’s principles of internal medicine. 9th edn. New York, McGrawHill, 1980:785–789.
Majde JA, Brown RK, Jones MW, et al: Detection of toxic viral-associated double-stranded RNA (ds RNA) in influenza-infected lung. Microb Pathol 10:105–115, 1991.
Rabon RJ, Louis GJ, Zegarra H, Gutman FA: Acute bilateral posterior angiopathy with influenza A viral infection. Am J Ophthalmol 103:289–293, 1987.
Ray CL, et al: Bilateral optic neuropathy associated with influenza vaccination. J Neuroophthalmol 16(3):182–184, 1996. PMID: 8865010; UI: 97018394.
Schlaegel TF, Jr: Uveitis associated with viral infections. In: Duane TD, ed: Clinical ophthalmology. Hagerstown, MD, Harper & Row, 1982: 4(46):1–13.
Solomon A, et al: Bilateral simultaneous corneal graft rejection after influenza vaccination. Am J Ophthalmol 121(6):708–709, 1996. PMID: 8644815; UI: 96243666.
22 KOCH–WEEKS BACILLUS 372.03
Alan Sugar, MD
Ann Arbor, Michigan
Roni Mintz, MD
Ann Arbor, Michigan
ETIOLOGY/INCIDENCE
Koch–Weeks bacillus is also known as Hemophilus influenzae biogroup aegyptius. It is a small, gram-negative, slender rod or coccobacillus. This organism was originally isolated as a cause of secondary infection in eyes with trachoma and as a cause of epidemic ‘pink eye.’ Despite some early confusion with classification, Koch–Weeks bacillus is considered to be a subspecies of H. influenzae.
Acute H. aegyptius conjunctivitis affects children during hot weather, especially in the tropical and subtropical climates of the Middle East and North Africa. Transmission is by flies and contact with ocular secretions. There is a 24-hour incubation period. Severe conjunctivitis develops rapidly with injection, chemosis, subconjunctival hemorrhage, and purulent discharge. Infection may follow or coincide with acute trachoma, although the relationship between these infections is not fully understood.
Although most patients do not develop systemic illness, a fulminant bacteremia may follow the resolution of conjunctivitis in patients infected with a distinct H. aegyptius strain known as the Brazilian purpuric fever (BPF) clone. This infection is associated with hemorrhagic skin lesions and often is rapidly fatal.
COURSE/PROGNOSIS
●There is rapid onset of injection, chemosis, and subconjunctival hemorrhage.
●Severe mucopurulent discharge occurs for about 3 days.
●Lid edema and preauricular node tenderness occur.
●Pseudomembrane may develop, especially in infants.
●Resolution usually occurs in 10 to 14 days without treatment.
●There may be relapse or chronic papillary conjunctivitis.
●Inferior limbal corneal ulcers may occur in the first few days.
●Phlyctenular conjunctivitis and conjunctival scarring may follow.
●Central corneal ulceration and perforation are rare.
●BPF follows resolution of conjunctivitis and is characterized by fever, vomiting, skin hemorrhage, hypotensive shock, and death if untreated.
42
DIAGNOSIS
Laboratory findings
●Thin, poorly staining gram-negative bacilli or coccobacilli on scrapings.
●Culture on chocolate agar or blood agar in high-CO2 environment.
●Enhanced growth in presence of another organism.
23 LEPROSY 023
(Hansen’s Disease)
Timothy J. Ffytche, LVO, FRCS, FRCOphth
London, England
TREATMENT
Local
●Hourly antibiotic eyedrops during the day and ointment at bedtime usually lead to resolution in 3 days.
Agents used include:
●Fluoroquinolones;
●Chloramphenicol;
●Sulfacetamide;
●Polymyxin B;
●Gentamicin;
●Tobramycin;
●Tetracycline;
Adequate treatment is helpful in preventing chronic conjunctivitis.
Systemic
Intravenous treatment for BPF with:
●Amoxicillin;
●Ampicillin;
●Azithromycin;
●Third-generation cephalosporins;
●Imipenem;
●Meropenem.
The use of oral rifampin in children with conjunctivitis in endemic areas for BPF may prevent onset of systemic illness.
COMPLICATIONS
●Chronic papillary conjunctivitis.
●Conjunctival scarring, especially when superimposed on trachoma.
●Periorbital or orbital cellulitis.
●BPF (as discussed).
ETIOLOGY/INCIDENCE
Leprosy is a chronic granulomatous infection caused by the acid-fast bacillus Mycobacterium leprae. It is communicable and probably transmitted via droplets, although other methods of spread may occur.
The organisms have an affinity for neural tissue in parts of the body where the temperature is relatively low; thus, the skin, peripheral nerves, mucous membranes, testes and eyes are primarily involved. The disease leads to disfigurement and loss of mobility and in a significant number of patients, the deformities may be accompanied by visual impairment. In many countries, leprosy still carries a social stigma due to ignorance that has persisted for centuries.
DIAGNOSIS
Clinical signs and symptoms
The clinical picture of the disease is influenced by the immunity of the host, which is highest in the paucibacillary form (PB) and lowest in the multibacillary form (MB). Ocular involvement may occur through five main pathways:
●Directly in MB disease through invasion of the anterior part of the globe, which is susceptible because of its relatively low temperature;
●Indirectly in both types of leprosy through the effects of damage to the superficial branches of the fifth and seventh cranial nerves;
●During the two forms of acute inflammatory reaction that occur when there is a sudden alteration in the disease immunity; these are known as reversal reactions and erythema nodosum leprosum (ENL) and may develop spontaneously or as a result of changes in therapy, an intercurrent infection, or stress;
●Through damage to the adnexa;
●Through secondary infection.
REFERENCES
Brenner DJ, Mayer LW, Carlone GM, et al: Biochemical, genetic, and epidemiologic characterization of Haemophilus influenzae biogroup aegyptius (Haemophilus aegyptius) strains associated with Brazilian purpuric fever. J Clin Microbiol 26:1524–1534, 1988.
Dawson CF: Epidemic Koch–Weeks conjunctivitis and trachoma in the Coachilla Valley of California. Am J Ophthalmol 49:801–808, 1960.
Morrissey I, Burnett R, Viljoen L, et al: Surveillance of the susceptibility of ocular bacterial pathogens to the fluoroquinolone gatifloxacin and other antimicrobials in Europe during 2001/2002. J Infect 49:109–114, 2004.
Perkins BA, Tondella ML, Bortolotto IM, et al: Comparative efficacy of oral rifampin and topical chloramphenicol in eradicating conjunctival carriage of Haemophilus influenzae biogroup aegyptius: Brazilian Purpuric Fever Study Group. Pediatr Infect Dis J 11:717–721, 1992.
Ocular and periocular
●Cornea: corneal hypesthesia, corneal ulcer, exposure keratopathy, leproma, pannus, superficial stromal keratitis, thickened corneal nerves.
●Episclera and sclera: episcleritis, scleritis, staphyloma.
●Eyebrows: madarosis; nodules, thickening of the skin.
●Eyelids: dermatochalasis, distichiasis, ectropion, entropion, lagophthalmos, madarosis, nodules, trichiasis.
●Iris: iridocyclitis (acute or chronic), iris atrophy, iris pearls, nodular leproma, synechiae (Figure 23.1).
●Lacrimal system: dacryocystitis, (acute or chronic), epiphora, nasolacrimal duct obstruction.
●Pupil: anisocoria, corectopia, diminished or absent response to light, miosis, occlusio pupillae, polycoria, seclusio pupillae.
Leprosy • 23 CHAPTER
43
1DiseasesSECTIONInfectious •
FIGURE 23.1 Anterior synechiae and adjacent iris nodule in patient with leprosy.
●Others: decreased intraocular pressure, paralysis of seventh nerve, phthisis bulbi, secondary cataract, secondary glaucoma.
TREATMENT
Systemic
The development of resistant organisms to standard antileprosy drugs, together with noncompliance, has led to a radical reappraisal of the therapy for the disease over the past two decades with the universal introduction of multidrug therapy (MDT).
Paucibacillary disease
The regimen recommended by the World Health Organization (WHO) consists of dapsone 100 mg/day as self-medication and rifampicin 600 mg once a month under surveillance, with treatment continued for at least 6 months.
Multibacillary disease
The WHO recommends dapsone 100 mg/day and clofazimine 50 mg/day as self-medication and once-monthly supervised doses of rifampicin 600 mg and clofazimine 300 mg. Treatment in MB cases should be continued for at least 1 year and preferably until negative skin smears are obtained. Doses are reduced proportionately for children. Patients who cannot take clofazamine can be treated with combinations of ofloxacin and minocycline.
Acute reactions
In leprosy, acute reactions require prompt and energetic therapy to avoid permanent neural and ocular damage; treatment includes the use of systemic corticosteroid preparations, doses starting at 40 mg of prednisone daily and analgesic agents. In addition, control of the reaction can be facilitated by the use of clofazimine and thalidomide (if available).
MDT has now become standard leprosy treatment everywhere, although a few of the more traditional therapies, such as chaulmoogra oil and herbal remedies, still persist in some parts of the world. Prophylactic vaccination with the bacillus Calmette–Guérin has been found to provide some protection in several areas where the disease is endemic.
Ocular
The ocular manifestations of leprosy are influenced by many factors and may vary according to ethnic groups. There are four main causes of blindness that can occur singly or in combination:
●Lagophthalmos, leading to exposure keratopathy;
●Corneal hypesthesia, predisposing to corneal ulceration;
●Acute or chronic iridocyclitis;
●Secondary cataract.
Medical and surgical treatments have an important role in preventing sight-threatening complications and in treating ocular and adnexal disease.
Medical
Exposure keratopathy may result from facial nerve involvement, especially if combined with corneal hypesthesia. It can occur after an acute neuritis in a reversal reaction or as part of chronic paralysis. To protect the cornea, it should be treated energetically with lubricating eyedrops and broad-spectrum antibiotic drops and ointment and the neuritis may respond to systemic steroid therapy. Lid surgery may be necessary in the later stages.
Acute iridocyclitis that occurs in ENL responds to conventional anti-inflammatory treatment with local mydriatic and steroid drops. During an attack, 1% atropine t.i.d. should be used with dexamethasone every hour; the dosage can be reduced as the inflammation subsides. In severe cases, subconjunctival injections of steroids and mydriatic agents may be necessary. If secondary glaucoma develops, oral hypotensive agents, such as acetazolamide 250 mg q.i.d., should be added to this regimen.
Chronic iridocyclitis occurs in MB disease, resulting in iris atrophy; a profound miosis may develop and cause considerable visual loss. This condition does not respond to local mydriatic or steroid therapy in the late stage, but attempts can be made to dilate the pupils with daily instillations of 5% phenylephrine or 1% atropine before the atrophy becomes too advanced.
Surgical
Lid surgery is designed to prevent corneal damage from exposure caused by facial nerve paralysis; procedures range from simple lateral tarsorrhaphy to more elaborate operations, such as temporalis transfer. Malpositions of the lids also require surgical correction to avoid secondary corneal disease and an infected lacrimal sac, which can provide a reservoir of infection, should be removed.
Intraocular surgery is tolerated reasonably well by the leprous eye as long as there is no active inflammation and such procedures as optical iridectomy, cataract surgery and corneal grafts may be performed safely. There is no contraindication to intraocular lens implantation in PB cases, but it should be avoided in MB disease when chronic iridocyclitis is present.
PRECAUTIONS
The institution of multidrug therapy has been the most significant factor in the control of eye complications and supervised administration in order to encourage compliance with treatment is very important for its success.
●Dapsone toxicity includes anorexia, nausea and vomiting, neuropathy, anemia and agranulocytosis and the drug should not be given to patients with glucose-6-phosphate dehydrogenase deficiency.
44
●Clofazimine can provoke diarrhea and causes red discolorprimary systemic infection and/or following a latent period ation of the skin, conjunctiva and urine, which may be diswith associated secondary uveitis. Leptospira interrogans, the
turbing to the patient. |
causative agent of leptospirosis, is a gram-negative, microaero- |
● Rifampicin may give rise to gastrointestinal and respiratory |
philic bacterium that belongs to the family Spirochaetaceae. |
symptoms, acute renal failure, thrombocytopenic purpura, Leptospira are very thin, spiral-shaped, motile, and best visualhepatic reactions and skin rashes. ized by dark field microscopy. The antigenic specificity of the
●Steroids given either topically or systemically should be Leptospira allows classification into different serovars. Anti-
monitored carefully to avoid steroid-induced glaucoma and secondary cataract.
COMMENTS
Visual impairment in leprosy is caused mainly by damage to the cornea through paralysis of the facial and trigeminal nerves, by cataract and by the complications of acute and chronic iridocyclitis. Patients are often unaware of ocular involvement and therefore it may go undetected at a stage when preventive measures would be most effective. The education of leprosy workers to screen for eye disease and of patients on self-care and drug compliance therefore becomes fundamentally important.
The aim of therapy should be the prevention of ocular changes through attention to eye protection and hygiene and to the early diagnosis of intraocular disease. Once the eye is affected, continuous supervision should be the goal, even after the patient has completed multidrug therapy and is classified as ‘cured.’ Whenever late complications develop, attempts should be made to preserve useful vision by medical and surgical measures. This may often mean that long-standing prejudices and the stigma of the disease must be overcome to avoid blindness, which is especially tragic in these individuals who are already disabled and disadvantaged.
REFERENCES
Brand MB: The care of the eye in Hansen’s disease. 3rd edn. Carville, LA, Gillis W. Long Hansen’s Disease Centre, 1993.
Courtright P, Johnson GJ: Prevention of blindness in leprosy. Rev edn. London, International Centre for Eye Health, 1991.
ffytche TJ: The prevalence of disabling ocular complications of leprosy: a global study. Ind J Lepr 70:49–59, 1998.
Hogeweg M: Ocular leprosy. Int J Lepr 69:30–35, 2001.
Joffrion VC: Ocular leprosy. In: Hastings leprosy. 2nd edn. Edinburgh, Churchill Livingstone, 353–364, 1994.
WHO Expert Committee on Leprosy, Seventh Report. Geneva, World Health Organization, 1998 (Technical Report Series No. 874).
24 LEPTOSPIROSIS 100.9
S. R. Rathinam, MNAMS
Madurai, Tamal Nadu, India
Emmett T. Cunningham, Jr., MD, PhD, MPH
San Francisco, California
ETIOLOGY
Leptospirosis, borreliosis, and syphilis are three important spirocheatal diseases, each of which can manifest both as a
genically related serovars are grouped as serogroups whose members cross agglutinate with each other, but they do not cross agglutinate with members of other serogroups. There are nearly 270 serovars grouped into 23 serogroups. Rats are the most common reservoir. However, many other mammals have been identified as reservoirs, including cattle, dogs, pigs, raccoons, skunks and opossums. Urine of infected animals is the most common vehicle of transmission. Unlike Trepanema, Leptospira have the ability to survive outside the body in diverse environments and can live freely in alkaline soil and water for up to months. When the host is exposed to a contaminated source, the Leptospira enter the body through breaks in the skin and mucous membranes. After an average incubation period of 2 to 7 days, hematogenous dissemination and multiplication of Leptospira occur in various organs producing a diverse array of clinical manifestations.
DIAGNOSIS
Clinical findings
Systemic leptospirosis is a multi-system disorder, but the severity and disease course varies considerably, from mild to lethal. The clinical picture depends, to a large extent, on the organ systems involved. Anicteric systemic illness occurs in 85% to 90% of case. A minority develop icteric, septecemic leptospirosis, or Weil’s syndrome. The most notable feature of severe leptospirosis is the progressive impairment of hepatic and renal function, and renal failure is the most common cause of death. Damage to the endothelial lining of the capillaries and subsequent interference with blood flow appear to be responsible for the lesions associated with leptospirosis. Common systemic clinical findings include any of the following:
●Abrupt onset of fever and rigor;
●Intense headache, myalgia and prostration;
●Muscle tenderness — particularly involving the calves and lumbar area;
●Scleral icteris with or without conjunctival injection;
●Meningeal irritation;
●Delirium/psychosis;
●Anuria or oliguria;
●Jaundice;
●Multi-organ hemorrhages;
●Cardiac arrhythmia or failure.
Physicians may easily miss the diagnosis, as symptoms are extremely variable, and can mimic other infectious diseases. The differential diagnoses of systemic leptospirosis includes:
●Dengue fever;
●Influenza;
●Hanta virus infection;
●Viral hepatitis;
●Hemorrhagic yellow fever;
●Malaria;
●Typhoid;
●Relapsing fever;
●Meningitis;
Leptospirosis • 24 CHAPTER
45
1DiseasesSECTIONInfectious •
●Encephalitis;
●Rickettsial disease.
Systemic findings usually last for about a week, when development of immunoglobulins in the plasma coincides with rapid immune clearance of the organisms. However, even after clearance from the blood, Leptospira can remain in immunologically privileged sites, including the renal tubules, brain, and anterior chamber of the eye, for weeks to months. Uveitis is, therefore, an important late complication of leptospirosis. The precise incidence of uveitis in patients with systemic leptospirosis is not known, but has been estimated to be as low as 3% and as high as 92%. Intraocular inflammation may manifest as quickly as 2 days after infection, or may be delayed for up to 4 years. Most cases of leptospiral uveitis occur around six months following the onset of systemic disease. The onset and severity of leptospiral uveitis is quite variable and the severity does not appear to correlate with the severity of systemic disease. Uveitis may occur as single or recurrent episodes. The primary anatomical location of inflammation in patients with uveitis tends to be either anterior or diffuse. Anterior uveitis is usually insidious and mild in contrast to the severe, acute, and relapsing course characteristic of diffuse inflammation.
Ocular manifestation
The spectrum of ocular manifestation leptospirosis includes:
●Septecemic phase:
●Conjunctival chemosis;
●Scleral icteris.
●Immune phase:
●Interstitial keratitis;
●Iritis;
●Hypopyon;
●Vitreous cells;
●Membranous vitreous opacities;
●Papillitis;
●Retinal vasculitis;
●Cataract;
●Cranial nerve palsies;
●Neuroretinitis.
LEPTOSPIRAL UVEITIS
Leptospiral uveitis is one of the most common causes of hypopyon uveitis in leptospiral endemic areas. Early onset and a rapid progression of cataract, while relatively uncommon, is a unique feature in this entity. While dense vitreous inflammation with the formation of veil like membranous vitreous opacities are commonplace and may persist for several months, most patients regain excellent vision. Disc hyperemia and edema are more common than cranial nerve paresis, which can involve the third, fourth, sixth, and seventh cranial nerves. Retinal vasculitis with perivascular sheathing of the vein is frequently seen leptospiral uveitis, however occlusion and neovascularization are not common. Although leptospiral uveitis is one of the most frequent entities, it remains under diagnosed mainly because of its varying clinical manifestations.
Differential diagnoses of leptospiral uveitis includes
●HLA-B27-associated anterior uveitis.
●Behçets disease.
●Sarcoidosis.
●Syphilis.
●Tuberculosis.
●Lyme disease.
●Toxoplasmosis.
●Endogenous endophthalmitis.
●Acute retinal necrosis.
PROGNOSIS
Leptospiral uveitis carries a good prognosis. When the inflammation is transient, complete resolution with restoration of good vision is the rule. Cataract and occasionally corticosteroid induced ocular hypertension can complicate the course. Intraocular pressure lowering therapy and/or cataract extraction followed by intra-ocular lens implantation usually carry an excellent prognosis.
Laboratory work up
Routine laboratory findings in leptospirosis are often non-diagnostic.
CBC may reveal:
●Neutrophilia;
●Elevated ESR;
●Thrombocytopenia;
●Azotemia; and
●Anemia.
Urine examination may reveal:
●Microscopic hematuria;
●Proteinuria;
●Pyuria; and
●Granular casts.
In cases of systemic leptospirosis, isolation of the organisms from body fluids such as blood, urine, or cerebrospinal fluid can confirm the diagnosis. Isolation is possible within one week of infection, but is successful only in 50% of cases, even at this early stage. Unlike Treponema pallidum, Leptospira can be grown only in special media such as Ellinghausen McCullough Johnson Harris (EMJH) medium. Urine cultures become positive during the second week of illness and remain positive for up to 30 days. Beyond ten days of systemic infection, the Microscopic Agglutination Test (MAT) is the prefered assay. The MAT involves mixing motile bacteria in liquid medium with titrated amounts of patients serum. When the serum contains antibodies, agglutination is seen under dark field microscopy. Seroconversion or a fourfold or greater rise in paired serum samples or a titer above 1 : 400 dilution in the presence of a compatible clinical illness is considered diagnostic for systemic leptospirosis. In the chronic stage of leptospirosis, a titer of 1 : 100 dilutions is usually taken as significant. Other serological tests that are available, including ELISA, macroscopic agglutination, indirect hemagglutination, lepto dipstick, microcapsule agglutination tests, and lateral flow assays.
TREATMENT OF SYSTEMIC LEPTOSPIROSIS
There remains some controversy concerning the use of antimicrobial treatment of leptospirosis. However, several case series have reported a shortened duration of illness when antibiotic therapy was administered within 2–4 days. Leptospires are sensitive in vitro to most antimicrobial agents, including peni-
46
cillin, amoxicillin, doxycycline and ceftriaxone. In practice, severe systemic leptospirosis is treated with intravenous penicillin G administered as 1.5 million units every 6 hours for one week. Ceftriaxone can also be used and has the benefit of reduced frequency of administration. For mild to moderate cases, doxycycline may be given in doses of 100 mg twice daily for one week.
In addition to antimicrobial agents, supportive therapy is mandatory in cases of severe infection. Depending upon the organ system involved, the following measures may need to be considered:
●Dialysis in patients with renal failure;
●Mechanical ventilation and airway protection in patients with respiratory compromise;
●Continuous cardiac monitoring;
●Management of electrolytes loss in patients with dehydration, hypotension and hemorrhage; and
●Administration of vitamin K in patients with hypoprothrombinemia.
Chemoprophylaxis may be impractical to administer in highly endemic areas, but is likely to be useful for travelers and military personnel who visit endemic areas, or following accidental laboratory infection. Doxycycline (200 mg/week) may have a significant protective effect in reducing morbidity and mortality.
TREATMENT OF LEPTOSPIRAL UVEITIS
Corticoteroids are the mainstay of treatment for leptospiral uveitis. The preferred mode of delivery depends upon the severity, laterality and anatomical location of the inflammation. Options include:
●Hourly topical application of a corticosteroid such as prednisolone acetate, 1%, together with a cycloplegic/mydriatic agent in severe anterior uveitis;
●A posterior sub-tenon depot-corticosteroids injection, such as triamcinolone acetonide, 40 mg, in diffuse uveitis; and
●Oral corticosteroids (0.5–1.5 mg/kg body weight/day) in bilateral diffuse uveitis.
It is not known whether the systemic antibiotic treatment during the systemic phase of illness has any protective role on long term complications such as uveitis.
PREVENTION
Leptospirosis is a re-emerging waterborne, zoonotic, spirochetal disease recognized throughout the world, especially in tropical
— countries with heavy rainfall. The clinical presentation of leptospirosis varies and is not sufficiently characteristic, making the diagnosis of both systemic leptospirosis and leptospiral uveitis difficult. Currently recognized risk factor for contracting leptospirosis include:
Prevention is best accomplished by effective control and avoidance of known contaminated sources.
REFERENCES
Bharti AR, Nally JE, Ricaldi JN, et al: Leptospirosis: a zoonotic disease of global importance. Lancet Infect Dis 3:757–771, 2003. Review.
Duke-Elder S, ed: Diseases of the uveal tract system of ophthalmology. London, Hendry Kimpton, 1966:II:322–325.
Faine S, Alder B, Bolin C, et al: Leptospira and leptospirosis. 2nd edn. Melbourne, Australia, Medisci, 1999.
Heath CW, Alexander AD, Galton MM: Leptospirosis in the United States: 1949–1961. New Engl J Med 273:857–864, 915–922, 1965.
Levett PN: Leptospirosis. Clin Meicobiol Rev 14:296–326, 2001.
Martins MG, Matos KTF, da Silva MV, de Abreu MT: Ocular manifestations in the acute phase of leptospirosis. Ocular Immunol Inflam 6:75–79, 1998.
Panaphut T, Domrongkitchaiporn S, Vibhagool A, et al: Ceftriaxone compared with sodium penicillin g for treatment of severe leptospirosis. Clin Infect Dis 36:1507–1513, 2003.
Rathinam SR, Namperumalsamy P, Cunningham ET, Jr: Spontaneous cataract absorption in patients with leptospiral uveitis. Br J Ophthalmol 84:1135–1141, 2000.
Rathinam SR, Rathnam S, Selvaraj S, et al: Uveitis associated with an epidemic outbreak of leptospirosis. Am J Ophthalmol 124:71–79, 1997.
Sturman RM, Laval J, Weil VJ: Leptospiral uveitis. Arch Ophthalmol 61:633– 639, 1959.
Woods AC, ed: Endogenous uveitis. Baltimore, Williams & Wilkins, 1960: 76–78.
25 LYME DISEASE 104.8
Gerald W. Zaidman, MD, FAAO, FACS
Valhalla, New York
Lyme disease is the most common arthropod-related disease in the United States, Europe and portions of Japan. Currently more than 15,000 cases occur each year.
ETIOLOGY/INCIDENCE
Lyme disease is transmitted by the bite of an Ixodes tick infected with Borrelia burgdorferi. Ehrlichiosis and babesiosis are also transmitted by the Ixodes tick. The disease is a multisystem spirochetal disorder that can mimic many other diseases. As in syphilis, another spirochetal illness, Lyme disease occurs in three stages.
The Ixodes tick life cycle consists of three stages – larval, nymphal and adult. Mice and deer are most commonly involved in this life cycle, but any mammal can serve as the tick’s host. The nymphal stage is the most aggressive; ticks in this stage feed in mid to late spring. Because of their extremely small size,
●Occupational exposure — rice field workers, mining ranch- Ixodes ticks may not be noticed on the skin and their bite may
ers, abattoir workers, veterinarians, sewer workers and military personnel;
●Recreational activities — fresh water swimming, canoeing, kayaking, and trail biking;
●Household exposure — infestation by infected rodents and exposure to infected pet dogs and domesticated live stock.
not be remembered by the victim.
Seventy-five percent of cases occur during the summer months. There is a bimodal distribution of age groups with 2 peaks, one in children between 5 and 14, the other in adults between 30 and 59.
Clusters of Lyme disease occur in three geographic areas of the United States:
Disease Lyme • 25 CHAPTER
47
1DiseasesSECTIONInfectious •
1.The northeast, especially southern Connecticut and Westchester County and Long Island in the state of New York.
2.The upper midwest in Minnesota and Wisconsin.
3.The northwest, in Washington, Oregon and northern California.
DIAGNOSIS
Clinical signs and symptoms
Systemic
The clinical manifestations of untreated Lyme disease occur in three stages.
Stage 1
●Localized bull’s eye skin rash, or erythema chronicum migrans.
●Pathognomonic skin rash begins 3 to 30 days after tick bite (as many as 18% of patients can present without the skin rash).
Stage 2
Optic nerve disease may be unilateral, bilateral, solitary, or associated with other neurologic or neuro-ophthalmologic manifestations. There is some evidence that children are more predisposed to optic nerve disease than adults.
Late Stage 2 or Stage 3
Most of the severe ocular signs of the disease are seen, including:
●Episcleritis;
●Symblepharon;
●Keratitis;
●Iritis;
●Posterior or intermediate uveitis;
●Pars planitis;
●Vitreitis;
●Chorioretinitis;
●Exudative retinal detachment;
●Retinal pigment epithelial detachment;
●Cystoid macular edema;
●Branch retinal artery occlusion;
●Retinal vasculitis;
●Cranial nerve palsies.
●Follows weeks to months later.
●Neurologic (15% of patients), cardiac (5%), or arthritic maniOf this group, keratitis, vitreitis and pars planitis are the most
festations (60%); neurologic signs can include.
●Cranial neuropathy (especially Bell’s palsy).
●Meningitis.
●Headache.
●Neuritis.
Stage 3
●Follows weeks to months later.
●Chronic Lyme arthritis most common manifestation.
●Chronic neurologic syndromes include.
●Neuropsychiatric disease.
●Peripheral neuropathy.
Ocular
Ocular manifestations of Lyme disease may involve any portion of the eye and will vary depending on the stage of the disease.
Stage 1
●Conjunctivitis.
●Photophobia.
common. The keratitis usually is a bilateral, patchy, nummular stromal keratitis. Posterior segment inflammatory disease generally presents as a bilateral pars planitis associated with granulomatous iritis and vitreitis. Many of these patients also will have granulomatous keratic precipitates and posterior synechiae.
PATHOGENESIS
The pathogenesis of the disease is not well understood but the symptoms are believed to be due to direct infection and a delayed hypersensitivity mechanism. A very controversial aspect of the disease is the form of the disease known as ‘late’ or ‘chronic’ Lyme disease. Some patients may develop chronic or relapsing inflammation (including uveitis). It is unknown if these patients truly have Lyme disease and if they represent treatment failures, persistence of organism, infection with another tick borne pathogen or an autoimmune phenomenon.
These symptoms are mild and transient and ophthalmologists are not usually consulted.
Stage 2
Significant ophthalmic complications first appear; the most common are various neuro-ophthalmologic signs. Typically, the patient may first present with a seventh cranial nerve palsy (Bell’s palsy); some individuals may display the triad of Lyme neuroborreliosis:
●Cranial nerve palsy;
●Meningitis;
●Radiculopathy.
Blurred vision also can be noted during this stage, secondary to:
●Papilledema;
●Optic atrophy;
●Optic or retrobulbar neuritis;
●Pseudotumor cerebri.
Laboratory findings
Because many patients with suspected Lyme disease do not recall the causative tick bite or the skin rash, laboratory tests are important in establishing the diagnosis; however, much confusion can occur in interpreting the tests used for Lyme disease. The organism and its DNA have been detected in CSF, urine and sera but only early in the disease. PCR is superior to cultures but it is not standardized and not widely available.
The two most frequently used tests are the immunofluorescent assay (IFA) and the enzyme-linked immunosorbent assay (ELISA); the principal limitation of these serologic tests has been the high frequency of both false-negative and false-positive results. False-negative results occur during the acute phase of Lyme disease, before patients have developed a sufficient antibody response to give a positive serologic test. False-positive readings are due to serologic cross-reactivity among Lyme disease, syphilis, Rocky Mountain spotted fever and other disorders.
To improve diagnostic accuracy, some laboratories use the immunoblot (Western blot) test; this test is more specific, sensi-
48