Are we slowly erasing "idiopathic" from our ophthalmic vocabulary?

“Idiopathic” refers to a disease of unknown cause. It reminds one of the word idiot, which is a middle English term (1250-1300 AD) referring to a person who lacks skill or expertise (Latin idiōta, Greek idiṓtoēs).1 Both McCulley and Al-Mujaini present aspects of reactive lymphoid hyperplasia (RLH) in this issue of the Journal. The one reports on the management of RLH with rituximab and the other elaborates on RLH in the pediatric population. RLH is a condition which is often resistant to treatment and a challenge for the clinician. Histologically, lymphoproliferative disorders of the ocular region lie on a continuum with idiopathic orbital inflammatory disease (previously known as orbital pseudotumor) representing the most benign form of the disorder. The disease can progress via RLH and atypical lymphoid hyperplasia to eventually present as malignant lymphocytic lymphoma. Each histological stage is still etiologically tainted today by the term “idiopathic.”

In lymphoproliferative disorders, the body's immune system in the form of lymphocytes, plasma cells, eosinophils, etc., is involved. The logical conclusion, when one considers a possible etiology, is that there has to be an antigen of unknown origin that the immune system is responding to. Currently, our best clinical approach is to suppress the “army” of lymphocytes, plasma cells, and eosinophils with immunosuppressive agents and because as “idiots” we do not know what the antigen (“enemy”) is, we cannot yet adequately address the initiator of the tissue response.

But some progress has been made in the identification of possible antigens in lymphoproliferative disorders. Helicobacter pylori has been well documented as associated with mucosa-associated lymphoid tissue lymphomas. Targeting the organism with antibiotic therapy successfully treats the B-cell lymphomas in many cases.2 Recently, Chlamydia psittaci has been identified in ocular adnexal MALT lymphomas. The frequency varies depending on the geographic area where the reports emanate from, suggesting a non-homogenous global distribution of this antigen.3 This knowledge allows several targeted therapeutic approaches (including simple antibiotics in the form of doxycycline with which every ophthalmologist is familiar) to be considered in this disease. Although conflicting results have been reported, some very convincing case series have alerted the ophthalmic community to C. psittaci as a possible antigen in ocular adnexal MALT lymphomas.

Even conditions that require extensive management, such as idiopathic intracranial hypertension (IIH) the “idiopathic” seems to be slowly fading. Kesler et al.4 compared anthropological parameters especially waist-to-hip ratios of 44 consecutive IIH patients to 184 cases from their obesity clinic and 199 cases from the national obesity study. They found that IIH patients have fat accumulation in the lower body, whereas metabolic syndrome patients have upper body adiposity – the “pear” versus the “apple” adiposity distribution. Jugular valve insufficiency is known to be more frequent in IIH patients than controls (70% vs. 30%). This fact supports the pressure transmission from raised intra-abdominal obesity into the intracranial venous system as etiological mechanism. Will we perhaps in the future speak of “obesity induced” rather than “idiopathic” intracranial hypertension and remove another “idiopathic” from our vocabulary?

When considering the issue of idiopathic uveitis, Fuch's heterochromic uveitis (FHU) comes to mind. FHU, once an “idiopathic” condition, is now linked to Rubella virus infection.5 Universal population-based immunization programs against Rubella in the developed world have been accredited with the significant lower rates of FHU seen in these countries today. Not too long ago, many uveitis cases were still regarded as “idiopathic” and the only treatment we could offer was suppression of the immune response primarily with steroids, nonsteroidal anti-inflammatory drugs, and immune modulating pharmacological agents. Polymerase chain reaction technology (PCR), a molecular technique for the diagnosis of ocular infectious disease together with in vitro Goldman-Witmer coefficient testing, has assisted in accumulating evidence that up to half of the previously labeled “idiopathic” uveitis cases are now recognized due to infective antigens such as herpes simplex virus, herpes zoster virus, cytomegalovirus,6 Epstein-Barr virus, human herpes virus 6 (HHV-6), human immunodeficiency virus (HIV), tuberculosis, syphilis, and toxoplasmosis slowly removing “idiopathic” from the uveitis literature as well.

For many ophthalmologists, facial rosacea and its resultant chronic blepharitis has proven to be a real clinical challenge, mainly because we do not yet know the exact cause – another “idiopathic” condition. Systemic tetracyclines, topical steroids, and topical metronidazole cream all relieve symptoms in a temporary fashion, but not permanently. Recently, Li et al.7 correlated ocular Demodex folliculorum infestation of the eye lashes and serum immunoreactivity to Bacillus proteins in patients with facial rosacea. They demonstrated a significant correlation between serum immunoreactivity and facial rosacea (P = 0.009), lid margin inflammation (P = 0.040), and ocular Demodex infestation (P = 0.048). They furthermore demonstrated that lid scrubs with tea tree oil shampoo, but not baby shampoo, successfully killed and eradicated Demodex mites. Demodex folliculorum is the most common ectoparasite in humans. In skin, D. folliculorum is found in hair follicles, whereas Demodex brevis lives in sebaceous glands. In the eyelid, D. folliculorum can be found in the lash follicle, whereas D. brevis burrows deep into lash sebaceous glands and meibomian glands. Could these findings perhaps point to a treatable culprit and end the “idiopathic” nature of the ever so common chronic blepharitis of the human eyelids as well?

We as researchers should continue searching for and identifying the “enemies” (causes) of current idiopathic conditions. Although this process is ongoing, we should also attempt to increase the efficacy of the “army and the ammunition” (therapies) while reducing the “fire and the smoke” (side effects) by competent and skillful use of inter alia immunosuppressive agents.