Ординатура / Офтальмология / Английские материалы / Essentials in Ophthalmology Pediatric Ophthalmology Neuro-Ophthalmology Genetics_Lorenz, Borruat_2008

12.2.3.3.3Neurologic Manifestations

Neurologic manifestations of the disease are mostly seen in Stage 3. This stage can produce lymphocytic meningitis and can be responsible for episodic headache, mild neck stiffness, and subtle encephalitis. Neurologic manifestations of the disease occur in 10%–15% of cases of Lyme disease. Cranial neuropathy (such as unilateral or bilateral facial palsy), motor or sensory radiculoneuritis, mononeuritis multiplex, cerebellar ataxia or myelitis can be present.

The disease can produce axonal polyneuropathy which manifests primarily as spinal radicular pain or distal paresthesia. The most common syndrome is chronic progressive encephalomyelitis [28]. The major symptoms are difficulties with gait and bladder dysfunction. A large variety of symptoms may occur during the advanced stage of disease. The

cerebrospinal fluid (CSF) presents increased concentration of IgG and, occasionally, both IgM and IgA. Oligoclonal bands are commonly present and myelin basic protein may be present [29]. The late stage of the disease remains difficult to treat: immune-mediated disease can be responsible for symptoms.

12.2.3.3.4Diagnosis

of Lyme Disease

Direct isolation of B. burgdorferi remains difficult. The spirochete has been isolated from skin lesions, CSF, blood and affected tissues. A silver staining technique appears suitable for direct demonstration of spirochetes within tissue biopsy samples.

In most cases of Lyme disease the diagnosis is suspected on indirect detection of B. burgdorferi antibodies by ELISA tests. The ELISA test can

be confirmed by a Western blot test. In endemic areas a high prevalence of positive ELISA test is seen in the absence of Lyme disease.

12.2.3.3.5Treatment and Prevention

of Lyme Disease

Treatment recommendations for Lyme disease in Stage 1 consist of doxycycline in patients older than 8 years of age, except in pregnant women

[62]. A single dose of 200 mg doxycycline given within 72 h after I. scapularis tick bite was shown to prevent the development of Lyme disease [40]. During the second or third stage of the disease ceftriaxone is considered the therapy of choice [26]. Amoxicillin is the alternative therapy in young children or in pregnant women. The eye structure offers poor permeability to doxycycline or to amoxicillin. Risk of tick transmission remains low: less than 3.2% of patients bitten by ticks in endemic areas develop Lyme disease. The risk increases when ticks feed for 72 h or longer [49].

Summary for Clinicians

■Lyme disease is produced by infection with the spirochete Borrelia burgdorferi.

■Neuroophthalmic manifestations of Lyme disease correspond mainly to the development of uveitis, facial palsy, optic disc edema, although many other manifestations can be observed.

12.2.4 Cat Scratch Disease

12.2.4.1 Introduction

Fig. 12.5.  Parinaud’s syndrome due to cat scratch disease in a 7-year-old girl

Cat scratch disease was first described in 1889 by Henri Parinaud: he reported three patients with chronic fever, regional lymphadenopathy and follicular conjunctivitis. The disease was later described as Parinaud oculoglandular syndrome. The etiologic agent of the disease was isolated much later: a Gram-negative rod. Serological

12 studies have proven the association between Rochalimaea henselae infection and cat scratch disease. Recently the genera Bartonella and Rochalimaea were united according to 16S rRNA similarities [3]. The disease is transmitted by the bite or scratch of an infected animal. Animal fleas (Ctenocephalides felis) are also suspected to transmit the disease. An erythematous papule or pustule develops at the site of infection and is associated with local lymphadenopathy, fever, malaise and fatigue. Systemic complications such as splenomegaly, splenic abscess, encephalopathy, granulomatous hepatitis, pneumonia, and osteomyelitis occur only rarely.

12.2.4.2Ocular

and Neuroophthalmologic Manifestations

Ocular manifestation occurs several weeks after a cat scratch in about 10% of patients and is characterized by local lymphadenopathy and follicular conjunctivitis which was described as Parinaud’s oculoglandular syndrome (Fig. 12.5). Other later manifestations include anterior uveitis, papillitis, neuroretinitis and serous retinal manifestations.

In a recent series of 24 patients with the presumptive diagnosis of cat scratch disease, 27 (83%) of 35 eyes had posterior segment findings [52]. Retinal or choroidal white lesions were found in 83% of cases, disc edema and macular star were found in 46% of eyes, and serous elevation of the neurosensory retina and vitreous inflammation were found in 20% of eyes. Vasoocclusive disease was found in 4 eyes. Severe papillitis can be seen in 9% of patients.

Stellate maculopathy was originally used by Leber to describe an idiopathic disease; later the term macular star was used. It corresponds to a leakage of lipid-rich exudates within the outer plexiform layer. Even though a macular star is frequently associated with cat scratch disease, it is not specific as it can be associated with many infectious diseases such as syphilis, salmonella, herpes simplex, mumps, leptospirosis, toxocariasis, toxoplasmosis and non-infectious conditions such as increased intracranial pressure, hypertensive retinopathy, and anterior ischemic optic neuropathy.

Bartonella henselae has been also associated with obliterative vasculitis. Bacterial invasion of the vascular endothelium is known to be the origin of the thrombotic mechanism. Optic nerve swelling may also contribute to vascular occlusion. Vascular occlusion can be associated with a local vasoproliferative response, which induces neovascularization [11].

Fluorescein angiography will often reveal late staining of the submacular region and optic disc leakage that is associated with perivenous staining surrounding the disc.

12.2.4.3 Neurologic Manifestations

Approximately 2% of patients will develop systemic complications including involvement of CNS, liver, spleen, lung, bone, and skin. Neurologic manifestation usually begin about 1–6 weeks after the onset of lymphadenopathy, and consists mostly of meningitis, encephalitis, radiculitis and myelitis [31, 32].

inoculation. The incubation period is 2–6 weeks. The chancre heals in the absence of therapy in 3–6 weeks. The primary infection is usually followed by a secondary infection 4–10 weeks later. A latent infection can be present between the secondary and the tertiary stage. Patients with early syphilis (stage I or stage II) are contagious and can sexually transmit the disease. Patients with late syphilis (stage III) are not sexually contagious.

12.2.4.4 Therapy

Many antibiotic therapies, including doxycycline and rifampicin, have been proposed to treat Bartonella henselae infection. More recently, azithromycin has been proposed as an alternative therapeutic agent [10]. However, the efficacy of specific therapies remains to be demonstrated.

Summary for Clinicians

■Cat scratch disease results from an infection by Bartonella henselae.

■Parinaud’s oculoglandular syndrome is the commonest ocular manifestation of cat scratch disease and represents a primary infection in the vicinity of the eye.

■Secondary ocular manifestations include uveitis, papillitis, macular edema, and neuroretinitis.

■About 2% of systemic complications can be observed.

12.3 Sexually Transmitted Diseases

12.3.1 Syphilis

12.3.1.1 Introduction

Acquired syphilis is a sexually transmitted disease caused by the spirochete Treponema pallidum. The clinical course of infection consists of three stages: primary, secondary and tertiary stage or late syphilis [22]. The chancre is the first manifestation of the disease; it consists of a painless indurated ulcer that develops at the site of

12.3.1.2Ocular

and Neuroophthalmologic Manifestations

Protean clinical manifestations of the disease can be observed according to its stage of development. During the primary stage a chancre is rarely observed on the eyelid or on the conjunctiva. Ocular manifestations are mainly seen during the secondary and tertiary stages. During the secondary stage, it can be responsible for vitritis, diffuse or localized choroiditis, neuroretinitis, papillitis, optic neuropathy, exudative retinal detachment associated with choroidal effusion [25], retinal vasculitis and occlusive retinal vasculopathy [55]. Anterior optic neuritis is a frequent complication of neurosyphilis; it occurs mostly during stages II and III of the disease. When hard macular exudates are present, the term of neuroretinitis is used. The Argyll Robertson pupil is a rare but typical sign of mesencephalic involvement in neurosyphilis. Pupils are small, irregular, and react poorly to light but constrict normally during convergence.

During initiation of antibiotic therapy a severe ocular inflammation can be observed (Ja- risch–Herxheimer reaction) that can be associated with bilateral retinal detachment and giant retinal tears [45]. Ocular syphilis is a rare cause of uveitis occurring in fewer than 2% of cases.

The retinopathy of syphilis is usually described as salt and pepper retinopathy. Fluorescein angiography will reveal hypofluorescent zones associated with hyperfluorescent zones (leopard spots). Indocyanine green angiography reveals two type of lesions in patients with syphilitic posterior uveitis: late-phase scattered hyperfluorescent spots and persistent staining of the retinal vessels (Figs. 12.6, 12.7, 12.8) [39].

12.3.1.3 Diagnostic Tests

The Venereal Disease Laboratory Test (VDRL) reflects the activity of the disease: the VDRL test progressively decreases by about one dilution every month after adequate therapy. The VDRL tests can be negative during very early stages of the disease or during late syphilis (about 25% of untreated patients have a VDRL test that becomes non-reactive). The clinical diagnosis of syphilis is confirmed by the presence of specific laboratory tests such as the FTA-ABS test and TPHA, which remain positive throughout life.

12.3.1.4 Therapy

Standard therapy of a patient with ocular syphilis consists of 18–24 million units of intravenous aqueous penicillin G given daily for 10–14 days, which is divided into six doses [34]. An alternative therapy to intravenous penicillin is ceftriaxone [35].

12

Summary for Clinicians

■Ocular complications of syphilis occur mostly in the advanced stage of the disease and are protean.

■VDRLtive. is often negative and TPHA posi-

12.3.2Human Immunodeficiency Virus (HIV)

and Ocular Infection

12.3.2.1 Introduction

In the family of retroviridae, the Lentiviruses, are subdivided into two groups: human immunodeficiency virus type 1 and 2 (HIV) and the human T cell leukemia/lymphoma virus type I and type II (HTLV-I and HTLV-II). Early HIV infection is often asymptomatic.

HIV viruses are responsible for acquired immunodeficiency syndrome (AIDS) in the late stage of HIV infection. In the absence of therapy, the progression of HIV infection towards immunodeficiency depends on the progressive loss of CD4+ T lymphocytes (about 65×106/l per year). Ocular and neurological manifestations of HIV infection are mostly seen when the CD4+ cell count falls below 50×106/l.

Many neurologic complications can be observed during HIV disease. Primary neurologic complications consist mostly of neurocognitive disorders, meningitis and meningo-encephalitis, headaches, vascular myelopathy, neuropathies, and myopathies. Secondary neurologic complications occur only in advanced stages of the disease and consist of opportunistic infections (toxoplasmosis, Cryptococcus neoformans, CMV, JC virus and other opportunistic infections). In AIDS patients, opportunistic infection occurs when the CD4+ cells are not able to control the infection.

The development of highly active antiretroviral therapy (HAART) has changed the evolution of AIDS, drastically decreasing the incidence of opportunistic infections. However, opportunistic infection such as CMV retinitis can be the inaugural manifestation of AIDS in patients unaware of their infection. Ocular manifestations of infectious diseases can be frequently observed in AIDS patients. This chapter focuses mainly on ocular manifestation of CMV retinitis, which remains the major ocular manifestation in AIDS patients in the absence of the introduction of an effective anti-retroviral therapy.

12.3.2.2 HIV Retinopathy

HIV retinopathy is observed in any stage of HIV infection and fundus lesions include peripheral hemorrhages and cotton wools spots. It can be seen at any stage of the disease. HIV retinopathy corresponds to an ischaemic microan-

giopathy. Optical coherence tomography (OCT) images demonstrate the presence of progressive and subtle thinning of the retinal nerve fiber layer.

12.3.2.3 CMV Retinitis

The immune status of the host will play a major role in the development of ocular disease. When sufficient CD4+ cells are present, no opportunistic infection will develop in HIV-positive patients. CMV infection is frequent: more than 50% of the general healthy population has a positive serologic test for CMV. CMV retinitis usually occurs at the end stage of the disease or in advanced HIV infection, when the CD4+ cell count is below 50×106/l.

Cytomegalovirus infection can be asymptomatic or can manifest as visual loss. Cytomega-

lovirus retinitis has a typical “crumble cheese and ketchup” aspect corresponding to white granulomatous lesions and hemorrhages (Fig. 12.9). Cytomegalovirus infection can be the inaugural symptom of AIDS and HIV infection must always be ruled out in the presence of such lesions.

Therapy of CMV retinitis was a major problem for AIDS patients before the advent of HAART therapy. Ocular lesions are associated with systemic CMV infection. Virus can be excreted in the urine. Systemic CMV infections are treated with intravenous antiviral drug therapy: ganciclovir, foscavir or cidofovir (HPMPC). Systemic therapy with antiviral drugs is associated with many side-effects: leukocyte toxicity (ganciclovir); renal insufficiency (foscavir) and ocular hypotony (cidofovir). An induction therapy of 3 weeks or more is used to obtain a cicatrisation of the lesions. This induction therapy is followed

by a maintenance therapy. Relapse of the disease may occur upon cessation of therapy. The incidence of CMV retinitis has decreased considerably with the use of HAART. Nowadays, CMV retinitis occurs only in HIV-positive patients that are not under HAART therapy or in HIVnegative patients who are treated with systemic immunosuppressive drugs after kidney or bone marrow transplantation.

Local therapies have been developed in a compassionate use to avoid the systemic toxicity of drugs. Intraocular ganciclovir injections are successful in controlling the disease. An intraocular drug delivery system was recently developed to produce constant intraocular release of ganciclovir and to allow better control of ocular disease. At the same time, oral drugs, such as oral ganciclovir, were developed but the drug has poor bioavailability and frequent relapses of CMV retinitis are seen.

The development of HAART has changed the evolution of AIDS. Before the HAART era, patient death was seen after a mean time of 18 months after the onset of CMV retinitis. For the first time HAART produced an increase in CD4+ cell count. The restoration of immunity is responsible for the onset of an immune recovery vitritis, hypopyon or frosted angiitis

syndrome. The increase in CD4+ cell count over a value of about 180×106/l allows the cessation of anti-CMV therapy without presenting a risk of relapse.

The development of an oral prodrug of ganciclovir, valganciclovir, has changed the

CMV retinitis, oral valganciclovir is given at a therapeutic dosage of 900 mg twice a day until cicatrisation of the lesions. Maintenance therapy is given until the CD4+ cell count reaches a value over 180×106/l. With the increase in CD4+ cell count, an immune recovery vitritis can be observed and cystoid macular edema may develop. The onset of macular edema parallels a marked decrease in visual acuity. Local therapies with posterior subtenon’s steroid injections (40 mg triamcinolone acetonide) have been proposed to control inflammation and to restore good visual acuity. The injection is performed in the supero-temporal quadrant of the eye. The needle is inserted under the conjunctiva and the subtenon’s capsule.

Despite aggressive therapy in AIDS patients with CMV retinitis, long-term follow-up of patients reveals a poor visual outcome in some. Retinal detachment is a classical complication

alitis).

■Secondary infectious complications are seen when the CD4+ cell count falls below 200×106/l.

■CMV retinitis occurs when the CD4+ cell count is <50×106/l.

12.4 Encephalopathies Due to Viral and Non-Conventional Agents

Lymphocytic choriomeningitis virus (LCMV) belongs to the Arenaviridae family. Virus carriers are chronically infected rodents such as mice and hamsters. The virus is excreted during active infection by saliva, nasal secretions, milk, semen, urine and feces. Contamination occurs either by inhalation of aerosols or by contact with the virus. One-third of the patients remain asymptomatic despite viral infection. Half of the patients develop asymptomatic meningitis or meningoencephalitis. LCMV infection appear biphasic with the following initial symptoms: fever, malaise, myalgia, headache, photophobia, nausea, vomiting, soar throat, cough, and adenopathy. Eye manifestations occur usually in the presence of neurologic symptoms but chorioretinal lesions may be the only manifestation of infection [4]. The following findings are observed in patients with choriomeningitis virus infection: chorioretinitis 71%, chorioretinal scar 36%, optic atrophy 21%, nystagmus 10%, esotropia 4%, microphthalmia 4%, and cataract 4% [2]. Classical neurologic manifestations include unexplained hydrocephalus, microor macroencephaly, in-

was later used to characterize these diseases. Human TSEs are divided by etiology into infectious (5%), sporadic (80%), and inherited diseases (15%). Sporadic CJD occurs at a rate of 0.5 to 1 per million populations per year. Inherited TSEs occur after a mutation of the prion gene, located on chromosome 20p. They include Gerstmann- Straussler-Scheinker syndrome (GSS) and fatal familial insomnia (FFI).

Less than 5% of TSE is secondary to iatrogenic or dietary exposure (infectious TSEs).

Variant Creutzfeldt–Jacob (vCJD) disease was first described in 1996 as a new TSE in human beings. This disease has now been causally linked to bovine spongiform encephalopathy (BSE) [8].

The infectious agent involved in the sporadic form of Creutzfeldt–Jacob is a prion protein (PrpSc). This agent has been identified by Western blot in neuronal tissue, in neuronal retina, optic nerve, and in retinal pigment epithelium [58]. The abnormal PrpSc molecule will induce the normal molecule Prpc to undergo a change of conformation into PrpSc. Diagnosis of the sporadic form of Creutzfeldt–Jacob disease (CJD) relies on an appropriate clinical profile supported by the results of EEG (periodic sharp wave complex) and CSF (14-3-3 protein) [27]. Between 1992 and 2002, 2,451 patients were reported with sporadic form of CJD: 136 cases from Australia, 68 from Austria, 146 from Canada, 491 from France, 450 from Germany, 342 from Italy, 100 from the Netherlands, 438 from UK, 18 from Slovakia, 183 from Spain, and 79 from Switzerland. The median age at death was 68 years (range: 20–92). EEG abnormalities, i.e., typical sustained periodic sharp wave complexes (PSWCs), were present in 58.4% of cases. EEG anomalies were higher in the presence of codon 129 genotype. CSF 14-3-3 protein was present in 62.1% of sporadic CJD [9].

Presumed iatrogenic Creutzfeldt–Jacob has a very low incidence. In 2000, only 267 cases were reported worldwide: 3 cases were related to corneal grafting (1 confirmed, 1 probable, 1 possible), 114 were related to dura mater grafts, 139 were related to human growth hormone treatment, 4 to human pituitary gonadotrophin therapy and 7 to neurosurgical or stereotactic EEG electrodes [6].

Diagnostic criteria for probable vCJD are summarized by the National CJD Surveillance Unit [60]. Definitive diagnosis can be performed after neuropathological confirmation of brain biopsy samples. Spongiform change and gliosis on histology are still used in diagnosis. Immunohistochemistry became possible with the development of Prp-specific antibodies. More recently a highly sensitive Western blot analysis was developed by Wadsworth et al. [58]. For diagnosis of vCJD, Prp-specific antibodies or Western blot analysis of lymphoid tissue is now available (lymphotropism of the disease). Tonsil biopsy samples associated with MRI can also be helpful. The Heidenhain variant of CJD is of particular concern for the ophthalmologist, as these patients present with visual loss when their cognitive functions are still intact. Visual symptoms result from posterior involvement of the optic radiations, and a rapidly progressive often bilateral homonymous hemianopia is the rule.

CJD or vCJD must be suspected in the presence of patients presenting with an unexplained visual loss or in the presence of a homonymous hemianopia in the absence of a proliferative cerebral lesion or ischemic lesion (on brain MRI or CT). In the classical form of CJD a large percentage of patients had visual symptoms. The presence of neurological or psychiatric symptoms in patients of less than 50 years old .

When CJD is suspected, disinfection of ophthalmic instruments is critical to prevent transmission of the disease. Each country has recommendations for prevention of the disease. The Swiss CJD Task Force has proposed three alternatives in the population at risk of transmission of CJD: (1) the use of disposable instruments, (2) the use of contact lenses that can be sterilized at 134°C for 18 min and (3)

the disinfection with 2.5% Na hypochlorite, but the corrosive nature of this agent limits its clinical use.

Summary for Clinicians

■Transmissible spongiform encephalopathies represent a wide group of diseases.

■According to the mode of transmission they can be subdivided into a sporadic form (80%), inherited disease (15%) or infectious (5%).

■The infectious agent involved in the sporadic form of Creutzfeldt–Jacob is a prion protein (PrpSc).

12.4.3JC Virus

and Progressive Multifocal Leukoencephalopathy

JC virus (JCV) is a human polyomavirus. The virus is very common, affecting 70%–90% of the general population [42]. The pathogenesis of the infection remains unclear. Primary infection occurs in childhood. JC virus has been detected in the urinary tract of immunosuppressed individuals and pregnant women. In normal individuals the disease remains asymptomatic. In the presence of severe immunodeficiency unrestricted viral replication can lead to tissue destruction in the urogenital tract, CNS, and lung. Before the AIDS pandemic, progressive multifocal leukoencephalopathy (PML) only occurred as an extremely rare complication of malignant diseases such as lymphoma or leukemia or in association with granulomatous disorders such as tuberculosis and sarcoidosis. The number of PML cases has increased dramatically since the onset of AIDS. For decades the definitive diagnosis of PML was based on a positive brain biopsy, and detection of JCV DNA or viral antigens. More recently polymerase chain reaction (PCR) analysis of CSF has shown high sensitivity for viral detection in 80%–90% of bi- opsy-confirmed PML patients [37, 59].

JC virus has been detected in 32% of paraf- fin-embedded eyes of HIV patients whereas