Toxoplasmosis and herpetic necrotizing retinitis

Ocular Toxoplasmosis

Ocular toxoplasmosis is caused by Toxoplasma gondii, an obligate intracellular apicomplexan protozoan parasite. It represents the single most frequent cause of infectious posterior uveitis worldwide, accounting for 30% to 50% of posterior uveitis cases in Europe.

Life Cycle and Transmission

• Definitive Hosts: Members of the cat family (Felidae), in which the sexual reproduction cycle occurs, shedding unsporulated oocysts in faeces.
• Intermediate Hosts: Humans, livestock, rodents, and birds, in which asexual replication occurs.
• Routes of Human Infection:
  1. Ingestion of tissue cysts in raw or undercooked meat (pork, lamb, beef);
  2. Ingestion of sporulated oocysts via contaminated water, unwashed soil-grown vegetables, or cat litter;
  3. Transplacental vertical transmission of tachyzoites during primary acute maternal infection during pregnancy.
• Historical vs. Modern Understanding: Historically believed to be almost entirely due to late reactivation of congenital infection, current epidemiological evidence confirms that a significant proportion of adult cases represent newly acquired, postnatal infections.

Clinical Presentation

• The Classic Lesion: A solitary, focal, elevated, fluffy yellowish-white patch of active necrotising retinochoroiditis with feathery, poorly demarcated borders. The primary infection resides within the neurosensory retina, with secondary granulomatous involvement of the underlying choroid.
• The "Satellite Lesion": In over 70% of reactivation cases, the active inflammatory focus arises immediately adjacent to the pigmented, atrophic margin of an old, healed chorioretinal scar.
• "Headlamp in the Fog": Intense focal inflammatory vitritis situated directly over the active retinochoroidal lesion creates the characteristic ophthalmoscopic appearance of a bright yellow headlight shining through dense fog.
• Associated Features:
  • Kyrieleis Arteriolitis: Segmental, glistening, bead-like, yellowish-white intra-arteriolar accumulations along retinal arterioles near or distant from the lesion. This represents an inflammatory endothelial response/immune-complex vasculitis rather than direct parasitic infiltration of the vessel wall, and resolves without leaving vascular occlusions.
  • Jensen Disease (Papillitis / Neuroretinitis): An active toxoplasmic lesion situated adjacent to or directly on the optic nerve head, producing profound visual loss, an afferent pupillary defect, marked disc swelling, and a secondary macular fan/star.
  • Anterior Spill-over: Granulomatous or non-granulomatous anterior uveitis accompanied by high intraocular pressure secondary to trabeculitis.

Evidence-Based Treatment Regimens for Ocular Toxoplasmosis

Not every toxoplasmosis lesion requires antimicrobial intervention. In immunocompetent hosts, small, peripheral lesions far from the macula and optic disc resolve spontaneously over 6 to 8 weeks. However, systemic antimicrobial therapy is strictly indicated for: lesions within 1 to 2 disc diameters of the fovea or optic disc, lesions threatening major retinal vascular arcades, large lesions ($>2\text{--}3\text{ disc diameters}$), severe vitritis ($>2+$ haze), or any lesion in an immunocompromised or monocular patient.

1. Classic Triple / Quadruple Therapy:
   • Pyrimethamine: $100\text{ mg}$ oral loading dose on day 1 (divided as two $50\text{ mg}$ doses), followed by $25\text{--}50\text{ mg once daily}$ orally for 4 to 6 weeks.
   • Sulfadiazine: $2.0\text{ g}$ oral loading dose, followed by $1.0\text{ g}$ orally four times daily ($4\text{ g/day}$) for 4 to 6 weeks.
   • Folinic Acid (Leucovorin): $10\text{--}25\text{ mg}$ orally three times weekly (co-administered to prevent pyrimethamine-induced dihydrofolate reductase inhibition, bone marrow suppression, and megaloblastic anaemia; folic acid must not be substituted).
   • Oral Prednisolone: $0.5\text{--}1.0\text{ mg/kg/day}$, introduced 24 to 48 hours AFTER starting antimicrobial coverage, and tapered off before discontinuing antiparasitic agents.
2. Alternative Standard Regimen (Co-Trimoxazole):
   • Trimethoprim/Sulfamethoxazole (Co-Trimoxazole $800/160\text{ mg}$): One double-strength tablet orally twice daily for 4 to 6 weeks, combined with adjunctive oral prednisolone. Co-trimoxazole is an alternative used in appropriate patients; regimen selection depends on allergy, pregnancy, immune status, lesion threat and monitoring requirements.
3. Local Intravitreal Therapy:
   • Intravitreal Clindamycin ($1.0\text{ mg}$) combined with Dexamethasone ($400\,\mu\text{g}$) in $0.1\text{ mL}$. Excellent option for pregnant patients (avoiding systemic teratogenicity), patients with severe sulfa allergy, or those non-compliant with oral therapy.

Herpetic Necrotising Retinopathies

Herpetic viral necrotising retinitis comprises two devastating clinical syndromes caused by members of the Herpesviridae family.

1. Acute Retinal Necrosis (ARN)

ARN occurs predominantly in immunocompetent individuals of either sex and any age, though it can also affect immunosuppressed hosts:

• Etiology: Varicella Zoster Virus (VZV) is the causative agent in the majority of cases ($~65\%$, typically in patients aged $>50\text{ years}$), followed by Herpes Simplex Virus type 1 (HSV-1) in older adults, and Herpes Simplex Virus type 2 (HSV-2) in young individuals ($<25\text{ years}$). Cytomegalovirus (CMV) is a rare cause.
• American Uveitis Society (AUS) Diagnostic Criteria: The diagnosis of ARN is entirely clinical and defined by four cardinal features:
  1. One or more discrete foci of full-thickness retinal necrosis with sharp, scalloped borders situated in the peripheral retina outside the major vascular arcades;
  2. Rapid, circumferential, progressive expansion of necrosis along the peripheral retina if untreated;
  3. Occlusive retinal vasculopathy with prominent arteriolar involvement (severe peri-arteritis, luminal thrombosis, and non-perfusion);
  4. Prominent intraocular inflammation: dense vitritis and granulomatous/non-granulomatous anterior uveitis.
• Bilateral Involvement: Without systemic antiviral therapy, contralateral eye involvement (Bilateral Acute Retinal Necrosis / BARN) develops in up to 30% to 50% of patients, typically within 2 to 12 weeks (and up to several years later).
• Complications: Rhegmatogenous Retinal Detachment (RRD) develops in 50% to 75% of eyes, typically occurring 4 to 12 weeks after the initial infection. Detachment results from vitreous traction acting upon paper-thin, atrophic necrotic retina, creating multiple, large, irregular, circumferential retinal breaks along the boundary between necrotic and healthy retina.
• Management Protocol:
  • Induction Antiviral: Intravenous Aciclovir ($10\text{ mg/kg}$ IV every 8 hours for 7 to 14 days) OR high-dose Oral Valaciclovir ($1.0\text{--}2.0\text{ g}$ orally three times daily).
  • Intravitreal Antiviral: Immediate co-administration of Intravitreal Foscarnet ($2.4\text{ mg in }0.1\text{ mL}$) or Ganciclovir ($2.0\text{ mg in }0.1\text{ mL}$) at presentation provides rapid local therapeutic drug levels while awaiting systemic saturation.
  • Maintenance Antiviral: Long-term oral valaciclovir ($1.0\text{ g}$ three times daily for 6 weeks, then $1.0\text{ g}$ daily for 3 to 12 months) to protect the fellow eye from BARN.
  • Systemic Corticosteroids: Oral prednisolone ($0.5\text{--}1.0\text{ mg/kg/day}$) introduced 24 to 48 hours AFTER starting antiviral coverage to clear vitritis and reduce tractional bands.
  • Selected prevention: Discuss laser or early vitrectomy individually; routine 360-degree laser for all ARN is not established.

2. Progressive Outer Retinal Necrosis (PORN)

PORN is a variant of herpetic retinitis occurring almost exclusively in severely immunocompromised individuals, classically patients with advanced HIV/AIDS exhibiting $\text{CD4}^+ < 50\text{ cells/}\mu\text{L}$:

• Etiology: Reactivation of Varicella Zoster Virus (VZV).
• characteristic Hallmarks:
  • Deep, multifocal, yellowish-white outer retinal opacification (involving the deep sensory retina and RPE);
  • Striking absence of intraocular inflammation: minimal or absent vitritis and anterior chamber reaction ("quiet eye") because the host lacks sufficient CD4+ T-lymphocytes to mount an inflammatory response;
  • Early and prominent involvement of the posterior pole and fovea;
  • Rapid coalescence of lesions producing a "cracked mud" fundus appearance;
  • Fulminant, relentlessly destructive course leading to total retinal detachment and no light perception within days to weeks. Requires aggressive dual IV antivirals (ganciclovir + foscarnet) combined with repeated intravitreal injections and immediate systemic antiretroviral therapy (ART).