Parinaud's Oculoglandular Syndrome
Elmer Y. Tu
Table Of Contents
SKIN TEST (HANGER-ROSE TEST)
RARE CAUSES OF PARINAUD'S OCULOGLANDULAR SYNDROME
|Parinaud's oculoglandular conjunctivitis is a form of follicular, granulomatous
conjunctivitis (with or without ulceration), often
associated with a visible swollen preauricular and/or submandibular
lymph node on the same side1 (Fig. 1). The conjunctival granuloma may occur in bulbar or palpebral conjunctiva, upper
or lower. Fever and other systemic signs may or may not
be present. The conjunctival granulomas and the regional lymph node
swelling usually diminish in 4 to 5 weeks, although in some cases the
enlarged lymph nodes may progress to suppuration.|
Parinaud's oculoglandular syndrome (POS) consists of the characteristic granulomatous conjunctival inflammation, usually unilateral, with extension to or involvement of local, ipsilateral lymph nodes. Although cat-scratch disease (CSD) is by far the most common etiology, as a syndrome it does not constitute a disease with a specific origin or pathology but is a common endpoint for multiple infectious and noninfectious processes. The clinical findings in CSD are most representative of the originally described Parinaud's conjunctivitis. Other known causative agents are listed in Table 1. Although cat-scratch disease is usually a benign, self-limiting disease, laboratory examinations should be obtained to determine the exact causal agent and to rule out other more serious infections. Diagnostic considerations for Parinaud's oculoglandular conjunctivitis are listed in Table 2.
*May cause conjunctival ulcers
|Cat-scratch disease is caused by Bartonella henselae (formerly Rochalimaea) and rarely by Afipia felis.2,3 Eye involvement (benign inoculation lymphoreticulosis)4,5 develops in those persons who have close contact with cats, especially
children younger than 10 years of age. Over 90% of patients report
a history of being scratched by a healthy cat (see Fig. 2), often a kitten.6 Kittens are the most susceptible to infection with B. henselae and may manifest an asymptomatic bacteremia for several weeks, whereas
some adult cats have been shown to be chronic carriers. Transmission
from cat to cat is mediated by the cat flea, whereas cat-to-human
transmission may occur from trauma (scratch), inhaling
materials infected by cats, being licked by infected animals, or
rubbing one's eye after contact. Human-to-human transmission
has not been reported, and patient isolation is, therefore, not
required. It is also not considered necessary to remove the cat from
the home because of the low overall rate of human transmission.7 However, multiple infections within the same family have been reported.8 A primary inoculation lesion in the conjunctiva, skin, or mucous membrane
occurs in about 76% of patients.5|
The annual incidence of CSD is approximately 24,000, with children or adolescents making up 80% of cases.6,9 Parinaud's is classified as an atypical manifestation of CSD and occurs in approximately 3% to 7% of all infections.4,10 Seven to 14 days after exposure, redness, irritation, watery conjunctival discharge, and the sensation of a foreign body develop in the eye. The typical lesion consists of a unilateral granulomatous nodule located in the upper or the lower palpebral conjunctiva, surrounded by follicles (Fig. 3), intense chemosis, and injection. The fornices and bulbar conjunctiva may be involved (Fig. 4). The granuloma may be single, large, and flat, or there may be multiple elevated vegetations (Fig. 5). Corneal involvement usually consists of superficial punctate keratitis, but rarely may cause significant keratitis.11
Finding the inoculation site is often helpful in the diagnosis of cat-scratch disease. If the skin is involved first, a primary, nonpruritic papule or pustule appears 3 to 7 days after the animal scratch or bite. The skin papules persist for 7 to 21 days and disappear without a scar. A variety of other skin lesions including erythema nodosum, erythema multiforme, and nonspecific morbilliform rashes may occur.
Regional granulomatous lymphadenopathy is present in all patients with cat-scratch disease and may involve the head, neck, and axilla (Fig. 6). One to 3 weeks after inoculation, preauricular, cervical, and submaxillary nodes are visible on the affected side. The nodes are firm, are usually nontender, and may be enlarged to the size of a golf ball. Approximately 10% of these lymph nodes progress to suppuration. Systemic symptoms and signs are common but are usually mild. Low-grade fever, chills, headaches, anorexia, and general malaise may also be present. Without treatment, the course is benign, and complete recovery within 2 to 3 months is the rule.
Immunocompromised hosts are more likely to develop the disseminated form of the disease as bacillary angiomatosis, a reactive vascular skin tumor mimicking Kaposi's sarcoma, or bacterial peliosis, an infiltration of systemic organs.12,13 B. henselae is an emerging human pathogen and was noted in 10% of a group of HIV patients in South Africa screened by PCR.14,15 Although immunocompetent individuals are not advised to avoid infected cats, studies in immunocompromised patients have produced conflicting recommendations.16
|Cat-scratch disease has been recognized as a clinical entity for
more than 50 years. B. henselae is a small, pleomorphic, gram-negative bacillus that has been identified
in conjunctival granuloma, skin, and lymph node specimens. The
organism is best demonstrated using the Warthin-Starry silver
impregnation stain. With a modified Brown-Hopp tissue Gram stain, the
organism can be detected as a pleomorphic, gram-negative, nonacid-fast
bacterium measuring 0.3 to 1 μm by 0.6 to 3 μm. The
bacteria are found in the vessel walls of capillaries and
in macrophages in the germinal centers, appearing as a single organism
or in chains. Focal areas of necrosis are noted with activated histiocytes
and polymorphonuclear in the surrounding cells, forming a granuloma.|
B. henselae is very difficult to isolate using standard laboratory techniques. First described in 1990 by Relman et al., polymerase chain reaction (PCR) amplifying the 16S rRNA of B. henselae is both a highly sensitive and specific method for identifying the organism.17 Its successful use has been described on conjunctival specimens as well as lymph node biopsies and aspirates.18–21 There is no cross reactivity with other Bartonella species.
|Two serologic tests are available for the confirmation of B. henselae exposure—an indirect immunofluorescence test (IFA) produced by the CDC and various enzyme-linked immunoassays (ELISA). These tests have varying sensitivities and specificities, but CDC-processed tests yield above 90% for both.22 Predictability at other centers may be different depending on the laboratory. Because these tests rely on the robust host immune response seen in CSD, accuracy in immunocompromised patients is significantly less.9 Studies of various ELISAs show a greater predictability with IgM titers than IgG, but to achieve high specificity and sensitivity, the results need to be combined with the following diagnostic criteria. Cross reactivity with other Bartonella species is possible resulting in false positives.23–25|
|SKIN TEST (HANGER-ROSE TEST)|
|A skin test for cat-scratch disease was one of the original diagnostic criteria for CSD. The antigen was obtained from a suppurative lymph node and used as a skin-test antigen. A dose of 0.1 ml of the antigen is inoculated intradermally with a positive reaction creating a central papule or erythema measuring 0.5 to 1 cm in diameter after 48 to 72 hours. The size of the skin reaction did not correlate with the severity of the illness. With the advent of other serology and PCR, the risk of using foreign human lymphoid tissue outweighs its benefits.|
|Diagnosis of cat-scratch disease includes the following criteria.|
Clinical characteristics combined with either serologic or pathologic confirmation make the diagnosis of CSD-related Parinaud's oculoglandular syndrome. Other, more serious, infections should also be considered at the time of presentation because of the morbidity related to those diseases. In addition, noninfectious causes, primarily malignancies such as lymphoma or metastatic disease, should be considered and a biopsy taken if tests for infectious agents are inconclusive.
|The prognosis of cat-scratch disease is excellent, with few reports
of permanent ocular damage. Even without treatment, CSD will resolve
in 2 to 4 months in the majority of cases. Complications in immunocompetent
individuals are rare, although encephalopathy, thrombocytopenic
purpura, osteomyelitis, lymph node enlargement simulating malignant
lymphoma, and parotid gland tumor have been reported.26 Because of the affinity of B. henselae for vascular endothelium, immunocompromised individuals may develop disseminated
vasoproliferative disease, such as bacillary angiomatosis and
Topical antibiotics are of questionable benefit because a cure is achieved primarily through systemic medication. Supportive management may include analgesics and antipyretic agents. For systemic and posterior ocular manifestations, oral corticosteroids have been effective in reduction of inflammation and improvement in function, but its need and utility in isolated POS has not been established.27,28
Aspiration of the lymph node, if suppuration occurs, can be done to relieve painful adenopathy and to provide material for serologic testing and histopathology. A 16-gauge needle and a 20-ml syringe may be used after anesthetizing and prepping the skin. Incision and drainage is, however, not recommended because a fistulous tract may develop, and discharge may persist for several months resulting in permanent scarring.
The self-limited nature of CSD both makes the need for systemic antibiotics unclear and antibiotic efficacy difficult to evaluate. Success has been reported with erythromycin and doxycycline. Prior to the identification of B. henselae as the causative agent in CSD, Margileth reviewed available studies on antibiotic treatment of CSD and concluded that four agents had the most reasonable probability of efficacy based on a varied set of outcome criteria: Rifampin, Ciprofloxacin, Gentamicin, and Trimethoprim/Sulfamethoxazole. Rifampin 10–20 mg/kg/day q 12–24 hours being the most effective in the group.5 In the only prospective, randomized study of therapy of CSD, Bass et al. found that a single 500-mg dose of azithromycin followed by four daily doses of 250 mg resulted in more rapid resolution of lymphadenopathy than placebo at 1 month.29 CSD in immunocompromised individuals predisposes to more disseminated disease, and therefore, the threshold for systemic antibiotics use is lower. Azithromycin (as in dosage listed earlier) or doxycycline (100 mg b.i.d) has been shown to be efficacious in these individuals.9,30 Antibiotic treatment and observation should continue for several months because of the possibility of recurrence.
|Tularemia is caused by Francisella tularensis (formerly Pasteurella tularensis). It is primarily an infectious disease of small wild animals such
as rabbits, hares, ground squirrels, rats, mice, and foxes. The infection
usually occurs from direct contact with infected animals, especially
rabbits, and is typically seen in hunters or meat cutters (Fig. 7). The disease can also be transmitted indirectly by insect vectors, including
deerflies, mosquitoes, lice, and especially ticks. Incubation
time is 2 to 10 days.31|
Oculoglandular tularemia is an acute infectious conjunctivitis characterized by unilateral, necrotizing, granulomatous conjunctival inflammation with subsequent ulceration.32–34 The granulomas may occur in the upper or lower tarsal or bulbar conjunctiva. The ocular findings are associated with tender regional lymphadenitis on the same side and severe systemic manifestations, including fever, malaise, headaches, chills, vomiting, and occasionally pneumonia and severe prostration. Corneal ulcers with perforation, panophthalmitis, optic neuritis, and dacryocystitis may also occur but are rare.35,36
Conjunctival tularemia should be suspected when a patient has killed, skinned, or cleaned rabbits or has been bitten by ticks. Findings include multiple yellow tarsal conjunctival nodules with necrotic, shallow ulcers; tender regional lymphadenopathy; and moderate to severe systemic signs with an acute onset. These features distinguish this entity from other more benign causes of Parinaud's conjunctivitis. Smears or cultures showing pleomorphic gram-negative coccobacilli can confirm the disease. Serology titers of 1:160 or higher within 2 to 3 weeks after onset of clinical disease are considered diagnostic of the disease.35 Because of its highly contagious nature, F. tularensis is a potential bioterrorism organism, and clinical samples should be handled carefully.
Administration of the drug of choice, streptomycin, 7.5–10 mg/kg intramuscularly b.i.d. for 7 days, results in rapid recovery and prevents relapse. Gentamicin at 1.7 mg/kg IM or IV every 8 hours is an acceptable alternative.31 In addition, for the conjunctivitis, topical antibiotics such as gentamicin ophthalmic drops should be instilled every 2 hours for 1 week, then five times daily until resolution. Anecdotal reports of success with systemic fluoroquinolones have also been noted. Subconjunctival antibiotics may be used for corneal or uveal complications. Corticosteroids should be avoided. It is best to manage these patients with the help of an internist, because patients with systemic complications, such as septicemia or endocarditis, and immunologically compromised persons need close medical supervision. Mortality is noted to be between 8% and 30%.35
|Ocular sporotrichosis is a chronic infection caused by Sporothrix schenckii, a fungus found in soil and vegetative material.37 Sporotrichosis may be localized to the conjunctiva as a primary infection
or may be secondary to involvement of the lid and face. The first
evidence of infection in the skin of the eyelid is the appearance of a
hard, spherical, elastic movable, nontender nodule that may later become
attached to the skin. The nodule is initially pink, then purple, and
finally black and necrotic, described as a sporotrichotic chancre. Subcutaneous
nodules appear along the course of the lymphatics draining
extending from the area.38 Numerous soft, yellow, granulomatous nodules, which may ulcerate, develop
in the palpebral or bulbar conjunctiva (Fig. 8) of the involved eye. The conjunctival ulcers usually discharge a
small amount of purulent material. The preauricular and submandibular
lymph nodes are grossly enlarged and may suppurate. The patient does
not usually appear systemically ill.|
The organism grows in 3 to 5 days on Sabouraud agar. Biopsy of the nodules may reveal the cigar-shaped organism on PAS or Gomori's methenamine silver (GMS) staining. Direct fluorescent antibody staining is also available for rapid diagnosis. The infection responds well to systemic itraconazole 200 mg daily. Ketoconazole is not effective.39 Topical fluconazole therapy may be added for conjunctival disease.37 Sporotrichosis may also respond to orally administered iodides (SSKI), which increase the host immune response to the organism. Therapy begins with a saturated solution of potassium iodide, 1 ml in a glass of water three times daily. The dose is increased by 0.5 to 1 ml/day until a daily dose of 9 to 12 ml is reached. To avoid recurrence, iodides should be continued for 4 to 6 weeks after clinical resolution.39 With all treatments, therapy should be continued past the appearance of clinical resolution.
|The acid-fast bacillus Mycobacterium tuberculosis causes conjunctival tuberculosis. The incidence in the United States is low, but continues to be important
internationally. Other mycobacteria are less-common causes. Eye
involvement may occur with ocular trauma, direct inoculation, or extension
from contiguous tuberculous sites, such as the skin lesions in
cutaneous tuberculosis (lupus vulgaris).40,41 The conjunctival infection consists of a small, unilateral, painless, and
indolent ulcer on the tarsal conjunctiva and fornix; this is surrounded
by a small nodule. Rarely, there are larger nodules and hypertrophic
lesions. The regional lymph nodes are often enlarged.|
A chest roentgenogram and a tuberculin skin test should be performed. Scrapings from the conjunctival lesion usually show acid-fast bacilli. Histologically, the conjunctiva nodules consist of typical tubercles with epithelioid cells, Langhans' giant cells, and caseous necrosis. Although smears and biopsy findings suggest the diagnosis, it should be confirmed by culture because many diseases may mimic tuberculosis.
Systemic therapy with two effective antituberculous medications, usually isoniazid plus ethambutol, rifampin, or streptomycin, is required.42
|Conjunctival syphilis is caused by Treponema pallidum and may occur during the primary, secondary, or tertiary stages of the disease.43 In primary syphilis the conjunctival lesion is an indolent ulcer with an indurated margin and a gray base. The lid may be involved and is markedly swollen. A dense scar follows healing of the ulcer. Secondary syphilis of the conjunctiva is characterized by multiple granulomatous nodules or a diffuse, rose red, jelly-like thickening of the tarsal conjunctiva. An acute granulomatous iridocyclitis is usually present in the early secondary stage of dissemination accompanied by other secondary manifestations in the skin and mucous membranes. In tertiary syphilis (gumma), the conjunctiva may be involved as a result of syphilitic tarsitis. Regional lymph nodes are often enlarged in all three stages of syphilis. Complications such as uveitis, pannus, perforation, and panophthalmitis may occur. Diagnosis is confirmed by dark-field examination of scrapings or exudates and serologic tests (VDRL, fluorescent treponemal antibody-absorption testing [FTA-ABS], and microhemagglutination [MHA-TP]). Treatment is the systemic administration of penicillin; the dose depends on the stage of the disease. Local ocular disease may be treated with supportive care.|
|Some pathogenic fungi that are responsible for facial and lid skin infections
may secondarily invade the conjunctiva with an associated regional
lymphadenopathy. These include Coccidioides immitis (coccidioidomycosis)44,45 and Blastomyces dermatitidis (blastomycosis).46 C. immitis is endemic in the southwestern United States, parts of Mexico, and Central
and South America and is the etiologic agent for coccidioidomycosis.47|
Ocular involvement may occur with primary pulmonary infection and is often associated with erythema nodosum. Palpebral conjunctival granulomas are often a manifestation of the disseminated disease. Phlyctenular conjunctivitis, episcleritis, scleritis, keratoconjunctivitis, or iridocyclitis may be present. These are considered hypersensitivity responses to the coccidioidal antigen and usually subside with time. In the posterior eye, manifestations may range from an asymptomatic focal chorioretinitis to a fulminating granulomatous process involving the entire eye. C. immitis is a dimorphic fungi that produces characteristic barrel-shaped arthroconidia, but will exhibit multinucleated spherules in pathologic specimens.48 The diagnosis of coccidioidomycosis is confirmed by culture and serologic tests. The treatment of choice for extrapulmonary disease is the triazole antifungals 400 mg/day (ketoconazole, fluconazole) or itraconazole 200 mg b.i.d.39 Amphotericin B is reserved for worsening or severe disease. All these mycoses produce a regional nonspecific lymphadenopathy.
|RARE CAUSES OF PARINAUD'S OCULOGLANDULAR SYNDROME|
|Parinaud's oculoglandular syndrome is an uncommon disorder with the
vast majority of cases due to the agents noted previously. Other infectious
etiologies, listed following, rarely occur, but should be considered
when the history or evaluation for more common diseases is negative. Certain
noninfectious disorders resulting in conjunctival granulomas
and regional lymphadenopathy can normally be elucidated by a careful
history. Finally, lymphoma and metastatic disease may mimic the findings
The actinomycete Actinomyces israelii, a higher order anaerobic bacterium, is often introduced by trauma with a high incidence among farmers, laborers, and horticulturists. Initially the skin of the face and eyelids is involved, and then the infection extends to the conjunctiva. Large fungating verrucous plaques and ulcerating granulomas appear, and the active borders show numerous minute abscesses.
Infectious mononucleosis is an acute self-limited lymphoproliferative disease caused by the Epstein-Barr virus and characterized by fever, pharyngitis, and cervical lymphadenopathy.49,50 A unilateral tarsal conjunctival granuloma may occur. The presence of atypical lymphocytes and heterophil antibodies (Monospot test) in the blood establishes the diagnosis. Tests for antibodies to the Epstein-Barr virus are also available, which can help determine stage of infection.
Mumps is an airborne viral infection that causes localized swelling of the parotid glands. Ocular involvement may occur in the form of granulomatous conjunctivitis, with dacryoadenitis, optic neuritis, tenonitis, scleritis, and extraocular muscle palsies. Mumps may be accompanied by complications such as orchitis, pancreatitis, and meningoencephalitis.
Several organisms found primarily in animals may cause Parinaud's conjunctivitis in humans. These organisms include Pasteurella multocida,51 a gram-negative bacterium found in the oral cavity of cats and dogs; Yersinia pseudotuberculosis; Yersinia enterocolitica;52 Burkholderia mallei (glanders),53 an organism studied for bioterrorism purposes; Listeria monocytogenes, a common food contaminant; and Rickettsia conorii, an organism conveyed by ticks from dogs and responsible for Mediterranean spotted fever. Humans acquire these infections from animal sources, and airborne infection may occur in laboratory workers.
Granulomatous conjunctivitis caused by Haemophilus ducreyi (chancroid)54 or lymphogranuloma venereum is rare and is usually due to direct primary inoculation by venereal contact through the fingers or by accidental contamination of the eye in laboratory workers.55 Corneal ulcers with perforation have been reported.
Caterpillar hairs (ophthalmia nodosa)56 accidentally lodged in the palpebral conjunctiva may also cause a granulomatous conjunctivitis and regional lymphadenopathy. Tarantula hairs are barbed in similar fashion to encourage progressive penetration and have been reported to cause granulomatous inflammation in every layer of the eye including the cornea (Fig. 9) and conjunctiva.57–59 Implantation of synthetic fibers may result in a “Teddy Bear Granuloma” of the palpebral conjunctiva.60 Simple removal is curative without need for other medications.61
The author and editors wish to express the appreciation to George N. Chin, MD, author of this chapter in the previous edition. Some of that material has been used in this revision.
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29. Bass JW, Freitas BC, Freitas AD, Sisler CL, Chan DS, Vincent JM, et al: Prospective randomized double blind placebo-controlled evaluation of azithromycin for treatment of cat-scratch disease [comment]. Pediatric Infectious Disease Journal 17:447–52, 1998