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O C U L O S Y S T E M I C D I S E A S E

Signs and SymptomsInflammatory bowel disease (IBD)is a difficult to diagnose and debilitat-ing condition.'"'' Although the exactcause and mechanisms of IBD haveyet to be completely understood, itis widely accepted that both are theresult of an inappropriate immuneresponse that occurs in geneticallysusceptible individuals as the resultof a complex interaction among envi-ronmental factors, microbial factorsand the intestinal immune system.^The two major subclassifications ofIBD include ulcerative colitis (UC)and Crohn's disease.'"^ Overlappingsymptoms of UC and Crohn's diseaseoften delay diagnosis, despite avail-ability of endoscopie and radiologieinspective procedures along with his-tological samplings.'

The Vienna Classification, whicharose from the 1998 World Congressof Gastroenterology Working Party,has been used to prospectively designa simple and objective Crohn's diseasephenotypic classification. Th e modelincludes the components of age atonset, anatomic location and diseasebehavior.^ Today, many refer to arevised Crohn's disease classificationthat combines genotype with pheno-type.^ Severe endoscopie lesions inCrohn's disease are defined by deepand extensive ulcrations on at leastone part ofthe colon.'

Pediatric-onset IBD, consisting ofCrohn's disease and ulcerative coli-tis, has significant medical morbidityand in many young persons is alsoassociated with psychological and psy-chosocial challenges.^ Depression andanxiety are particularly prevalent, add-ing to the multifaceted complicationsof the disease. Unique biochemicalcytokines from the disease itself aswell as the emotional Stressors pro-duce system-wide pathologies as do

the vast array of medications whichare used to treat it.^Crohn's ileitis may cause an ini-tial proliferation of adipocytes result-ing in fat hyperplasia. This leads toan inflammatory process potentiallycausing mesenteric and retroperito-neal fibrosis.'"

One-third of the patients withCrohn's disease will develop inflam-matory ileitis, colitis or ileocolitis bythe time of diagnosis.^ While thediseased location remains generallystable over time, up to one-thirdof the patients develop a strictur-ing (stenosis or narrowing) anomalyor a penetrating intestinal complica-tion.-''^ Half of all patients experiencean intestinal complication within 20years after diagnosis.^''^ The annualincidence of hospitalizations is 20%.-'Half of all patients require surgerywithin 10 years after diagnosis.-' Therisk of postoperative recurrence rangesbetween 44 %-55% over 10 years.^'''

Ocular symptoms can result fromthe disease itself or may result fromtoxicities to the immunosuppressantmedications used to treat the diseasessymptoms and proce sses." Localsigns and symptoms are consistentwith uveitis and include pain upon eyemovement, conjunctival hyperemia,photophobia and lacrimation. Anti-tumor necrosis factor alpha (TNFalpha) agents are increasingly beingused to treat patients with Crohn'sdisease among other inflammatorysystemic diseases and persistent uve-i t is ." One report describes a 68-year-old m an with Crohn's esophagitis whodeveloped a bilateral toxic anterioroptic neuropathy during infliximabinfusion." Three additional cases ofpossible infliximab-associated anterioroptic neuropathy have been reportedin the literature." Cataractogenesismay also be stimulated by system-ic anti-inflammatory medications.Common ocular findings include

acute anterior uveitis, conjunctivitis,peripheral corneal infiltrates, and reti-nal periphlebitisPathophysiology

The current models of Crohn's dis-ease relate disturbances of the epithe-lial interface between the gut mucosaand intestinal microbiota.-' This para-digm suggests that mucosal damageby luminal bacteria is an early, ini-tiating factor in the pathogenesis ofdisease.'*''^ A number of susceptibil-ity genes have been detected by largegenome wide screening-approaches.'^The incidence and development ofCrohn's disease in the individual islargely dependent upon genetic andmicrobial factors as well as childhoodhygiene, socioeconomic status andfactors determined by living condi-tions and environm ent.'^

Some features of Crohn's diseaseargue against a primary mucosal pro-cess."* Phenotypic studies point toa macrophage defect while geneticstudies suggest an impaired innateimmunity to intracellular bacte-ria.-' Intracellular pathogens, such asListeria, Salmonella, and Mycobacteria,invade via the gastrointestinal tractwith minimal or no acute mucosalpathology.'* These organisms theninfect and persist in lymphatic tissuesbefore inducing pathology, in the gutor elsewhere, as a secondary process.''Crohn's disease results from impairedmacrophage responses to intracellu-lar pathogens causing digestive sys-tem mucosal damage.'' Subepithelialpathology precedes ulcration.''

Abnormal immune responses foundin IBD have led to the use of serumbiomarkers such as anti-Saccharomy-ces cerevisiae antibody [ASCA], penuclear antineutrophil cytoplasmicantibody [pANCA] and antibodiesto flagellin [anti-CBirl]) to improvediagnostic confidence regarding posi-tive IBD identification.' These bio-

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markers are used to stratify patientswith UC arid CD according to diseasephenotype and risk of complications.^Further, the IBD biomarkers can beused to identify the relative risk ofprogression for early disease states tocomplicated disease behaviors, per-mitting the development of long-termstrategy regarding therapeutic deci-

ManagementPresent therapeutic guidelines for

IBD and Crohn's disease follow asequential approach that focuses ontreating the acute disease and induc-ing clinical remission.^'' Subsequentaims are to maintain an effective clini-cal response. In general, pharmaco-logie approaches are geared towardpromoting mucosal healing.^'' Earlyuse of biologic therapy, in combina-tion with immunomodulators, seemto produce the best results with theleast complications and lowest risksfor relapse. This method decreasesthe need for treatment with cortico-steroids while protecting against stric-turing coniplications, hospitalizationsand surgeries."

Crohn's ' disease induces physicalsigns and symptoms w hich are primar-ily secondary to delays which take placein completing the appropriate diagnos-tic testing.^ This leads to an extendedperiod where appropriate treatment isomitted.1 T he disease process is chron -ic and incurable, requiring life-longtherapeutic^ approaches to initiate andmaintain symptom control, improvequality of life, avoid hospitalizations,avoid surgery, minimize short andlong-term toxicity and minimize com-plications such as stricturing, fistulae,osteoporosis, associated bony fracturesand linear grovrth failure in pdiatrie

used to provide a direct evaluationof the alimentary tube and is capableof uncovering the mucosal lesionsthat are pathognomonic of the dis-ease. Endoscopie examination per-mits detailed description of lesions,the ir surface exten t and severity. ^Endoscopie reassessment can be usedto reevaluate tissues, evaluate the sue-eess of treatment and serve as a pre-dictor for the risk of clinical relapseand need for surgery.^" Achievementof mucosal healing, which can beobtained by administration of severaltypes of drugs, is assoeiated with abetter outcome, less surgery and hos-

Patients with gastrointestinalsymptoms ' must be evaluated by agastroenterologist. Endoscopy is

Magnetic resonance enterographyis a clinically useful technique forthe evaluation of both intraluminaland extraluminal small bowel disease.It is particularly useful in youngerpatients with Crohn's disease.i"* MRenterography offers the advantagesof multiplanar capability and lack ofionizing radiation.^'' It allows evalu-ation of bowel wall with contrastenhancement with the ability to dis-tinguish wall thickening and edema(Croh n's disease activity).i'' It can alsodepict other pathologic findings suchas lymphadeno pathy, fistula and sinusformation, abscesses and abnormalfold patterns."

The most important pharmacologieprogress with respect to managementfor Crohn's disease has been in theclass of TN F blockers. ^ These agentshave been shown to be effective forcontrolling com plicated disease cours-es.^^ Despite the fact that anti-TNFalpha antibodies are well-toleratedand highly effective in Crohn's dis-ease, 25% to 40% of patients w ho ini-tially benefit from treatment developintolerable adverse events (lymphoma,infection) or lose their responsivenessduring maintenance therapy. ^^'^^

Probiotics (live microorganismsingested by the host in appropriate

quantities for benefit) have becomea popular supportive and alternativetreatment for conditions of the GItract, including chronic disorderssuch as IB D and Croh n's disease. ^Unfortunately, the evidence suggeststhere is only minimal benefit by anyprobiotic for Crohn's disease, thoughthey have been found effective as anadjunctive therapy in inducing andmaintaining remission for UC.^''

The hygiene hypothesis has ledresearchers to the administration ofhelminths (deliberate infestation withthe ova of a helminth: parasitic wormssuch as hookworms and whipworms)for the purpose of regaining moreefficient modulation of the intesti-nal immune system.^^ Another newapproach has been to improve thesystem-wide mucosal barrier functionknown to be impaired in Crohn's dis-ease patients.^^

Treatments produce variableresponses with only approximately10% of the patients having the ben-efit of prolonged clinical remission.'''^Systemic steroid dependency has beenrecorded in up to one-third of thepatients, with surgery being requiredin up to one-third of patients follow-ing the initiation of steroid therapy.-'

Management of uveitic and asso-ciated oculo-inflammatory complica-tions is accomplished with topicalcycloplegia and steroids with dosingdictated by severity. An appropri-ate topical steroid taper is recom-mended for cases requiring longercourses of treatment. Complicationsinduced by systemic medicinal toxic-ity will require adjustments by thesystemic medical team. Frequent oph-thalmic follow up is recommendedfor the purposes of reassessment.Communication between the ocularteam and systemic medical team willensure that the systemic strategy iseffective and not resulting in addi-tional co-morbidities.

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clinical Pearls Crohn's disease is a disablingcondition over time. The impact ofchanging treatment paradigms withincreased use of immunosuppressantsand biological agents on its naturalhistory remains poorly understood. A coordinated approach betweenthe systemic care team and the eyecare team is critical. Written or tele-phone correspondence charting prog-ress and future strategy should bemade by all health care providers.

1 . Arai R. Serologie markers; impact on eariy diag-nosis and disease stratification in inflammatory bovi/eldisease. Postgrad Med . 2010 Nov; 122(4); 177-85.2. Szigethy E, McLafferty L, Goyai A. infiammatorybo\Ne\ disease. Chiid Adoiesc Psychiatr Clin N Am.2010Apr ;19 (2 ) ;301 -18 .3. Peyrin-Birouiet L, Loftus EV Jr, Coiombei JF,Sandbo rn WJ . The naturai history of aduit Crohn's dis-ease in popuiation-based cohorts. Am J Gastroenterol.2010Feb;105(2);289-97.4. Behr MA. The path to Crohn's disease; is mucosaipathology a secondary event? Infiamm Bowei Dis.2010May;16 (5 ) ;896 -902 .5. Stefaneiii T, Maiesci A, Repici A, et ai. New insightsinto infiammatory bowei disease pathophysioiogy;paving the way for novei therapeutic targets. CurrDrug Targets. 2008 May;9(5);413-8.6. Fedorak RN. is it t ime to re-ciassify Crohn's dis-ease? Best Pract Res Ciin Gastroenteroi. 2004;18Suppi;99-106.7. Louis E, Coiiard A, Oger AF, et al. Behaviour ofCrohn's disease according to the Vienna ciassifica-t ion; changing pattern over the course of the disease.Gut. 2001 Dec;49(6);777-82.8. Lichtenstein GR. Emerging prognostic markersto determine Crohn's disease naturai history andimprove m anagement strategies; a review of recent iit-erature. Gastroenteroi iHepatoi. 2010 F eb;6(2);99-107.9. Aiiez M, Lmann M. Roie of endoscopy in predict-ing the disease course in infiammatory bowel disease.Worid J Gastroentero i. 201 0 Jun;16(21 );2626-32.1 0. Jacobs E, Cosyns JP, Fiasse R. Retroperitoneai,mesenteric and muitifocai fibrosis; review of theiraetiopathogenesis. A possihie role of adipocytes asin Crohn's disease? Acta Gastroenteroi Beig. 2010Apr-Jun;73(2);252-60.1 1 . Chan JW, Casteiianos A. infliximab and ante-rior optic neuropathy; case report and review of theiiterature. Graefes Arch Ciin Exp Ophthaimoi. 2010Feb;248(2);283-7.1 2. Vavricka SR, Rogler G. Recent advances in. theetioiogy and treatment of Crohn's disease. MineryaGastroentero i Dieto i. 201 0 Jun;56(2);203-11.1 3. Lin MV, Bionski W, Lichtenstein GR. What isthe optimai therapy for Crohn's disease; step-up ortop-down? Expert Rey Gastroenteroi iHepatoi. 2010Apr;4(2); 167-80.1 4. Tolan DJ, Greenhaigh R, Zeaiiey lA, et al. MRenterographic manifestations of smaii bowei Crohndisease. Radiographies. 2010 Mar;30(2);367-84.1 5. Reinisch W. iHow to manage ioss of response to

anti-TNF in Crohn's disease? Curr Drug Targets. 2010Feb;11(2);152-5.1 6. Fidder HH, Hommes DW. Anti-TNF and Crohn'sdisease; when shouid we start? Curr Drug Targets.2010 Feb;11(2);143-7.1 7. Guandaiini S, Update on the roie of probiotics inthe therapy of pdiatrie infiammatory bowei disease.Expert Rev Ciin Immunoi. 2010 Jan;6(1);47-54.

Signs and SymptomsIt was the further analysis of a caseof homocystinuria from 1933 thatled to the discovery that homocyste-

ine causes vascular disease by havinga direct effect on arterial cells andtissues.^ The significance of homo-cysteine in human disease remainedunclear until 1962, when cases ofhomocystinuria were associated withadvancing vascular disease.'"^ Thebroader biomdical significance ofhomocysteine was discovered whenchildren with mental retardation,accelerated growth, dislocated ocularlenses and frequent vascular thrombo-sis (systemic and ocular) were foundto excrete homocysteine in the urine(homocystinuria).-^'-^ Methylmalonicaciduria and homocystinuria are themost frequent inherited errors of vita-min Bj2 metabolism, caused by aninability of the cell to convert thevitamin to both of its active forms.^Although considered a disease ofinfancy, some patients develop symp-toms in childhood, adolescence, oradulthood.^ There are four subtypesof homocystinuria with type I mani-festing metal retardation.'' In homo-cystinurias type II, III and IV, thereis accumulation of homocysteine buta decrease of methionine, thus, thereis no mental retardation.'^ In the casesinvolving the eye, in most instancesthe subtypes are II, III and IV.^

Homocysteine contributes to thegenesis of arteriosclerosis which is oneof the underlying causes of vasculardisease.^"^ This occurs when bloodhomocysteine concentrations become

elevated as a result of dietary, genetic,metabolic, hormonal or toxic fac-tors. '-^ Numerous clinical and epide-mioiogic studies have established ele-vated blood homocysteine as a potentindependent risk factor for vasculardisease in the general population.-'

Bone disease and cardiovasculardisease is often detected in patientswith homocystinuria.-''^ The majorocular complication of homocystin-uria is ectopia lentis, where zonulardisease induces alterations of thesefibers.-''^ Changes in zonular chem-istry weakens the connection of thesupportive fibers to the lens lead-ing to progressive lens dislocation.^'^Ectopia lentis occurs in up to 70% ofpatients with homocystinuria by ageeight and in up to 95% of individualswith the disorder by age 40.'' Ectopialentis is also associated with othersystemic diseases which alter collagenstructure and function such as Marfansyndrome and Weill-Marchesani syn-drome.'' Untreated patients developmental retardation, skeletal disordersand thromboembolic episodes whichcan lead to death by 20 years of age.-'Hyperhomocysteinemia has been sug-gested and documented as a specificrisk factor for retinal vein occlusion.^PathophysiologyHomocysteine is an amino acidin the blood formed by the removalof the terminal methyl group fromniethionine.^'-''^ Homocysteine is acompound which is "corrosive" tolong-living collagen (elastin), life-long proteins (fibrillin) and proteo-glycans.' Homocysteine can be recy-cled into methionine or convertedinto cysteine which is necessary forprotein synthesis, via the B-vitamins[(pyridoxine (B^), or cyanocobalamin(Bj2)]-^ This "sulfur metabolic path-way" plays a central role in cell m etab-olism and includes the sulfur aminoacids methionine and cysteine. These

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