 you guys want to get started okay so hopefully we won't have any computer malfunctions everything's plugged in I anyhow this is going to be on pediatric ubi it is it's like you know ubi it is but not just for small people so there there's a lot of material in here and I won't cover everything but I try to hit some high points and some things I think that will be useful clinically so pediatric ubi is a subject that really deserves special consideration because of their unique diagnostic management issues and therapeutic dilemmas and inheritance population a history review of systems and complete examination can be difficult to obtain in a preverbal or uncooperative child and then differential diagnosis varies with age with an over-representation of infectious etiologies the specific pediatric masquerade syndromes such as juvenile and sanctilogranium loma or retinoplastoma and you can dogenous syndromes like house hockey's disease or a juvenile idiopathic arthritis and then atypical presentations of diseases that are familiar in adults like starkardosis which present differently in kids and then the choice and interpretation of laboratory tests has to be tailored to the child the onset of non-infectious disease is sometimes is usually insidious chronic bilateral and sometimes asymptomatic with the frequent development of complications structural complications we know that the presentation of patients with acute complications is itself a risk factor for poor visual prognosis in jay especially and is a risk for the development of further complications and I think is a graphic testimony to diagnostic delay and maybe screen failure in this population and of course there's the unique risk of amblyopia in kids so just in terms to give you an idea of the epidemiology I pediatric uveitis about four times less frequent than it is in adults and represents about 13% of the patients that you might see in a tertiary care setting with a slight female predominance and represents about 20,000 children in the United States in it in the tertiary care setting in the last 10 years there have been some shifts in terms of the distribution the anatomic distribution of uveitis with increased the numbers of patients with pen uveitis and intermediate uveitis in a decreased number of patients with posterior uveitis probably due to better recognition and treatment of toxoplasmosis and a toxic crisis toxoplasmosis being the most common posterior manifestation population-based studies just as in adults show anterior predominance anterior uveitis predominance and then of course there is referral bias and geographic biases especially true in kids so for example in a survey that was done in the United States a couple of years ago the most common diagnoses were idiopathic followed by JAA associated disease parthenitis and toxoplasmosis and this is represented in this slide here in the top slide by Smith shows the distribution of those those diagnoses but the next study showed is a compilation of 19 studies internationally and you can see that there is a much higher percentage of infectious etiologies in this and this is borne out by two other studies in India and one in Colombia in which fully 58% of the posterior uveitis are infectious and most of those being toxoplasmosis so where in the world you are actually matters in terms of the distribution of the uveitis that you see the complications such as catastrophic complications like cataract macrodemic glaucoma vitreous opacity and your scar and coronary vascularization are related to the uveitis duration the anatomic location of the uveitis and timely referral so visual impairment you know is to you know visual impairment is common in 15% in large series with visual loss varying anywhere from 15 to 69% at five years with blindness unilateral blindness occurring a third of the patients in that last study from Colombia that I showed you. Again it's useful to think of things in broad diagnostic categories infectious non infectious and masquerade syndromes they are a little bit different than they are in adults infectious you know you'd be most common again anterior uveitis would be herpedic but you also have post infectious autoimmune syndromes which we'll talk about posterior uveitis again the most common diagnosis toxoplasmosis but toxic crisis more often seen in children Bartonella nematode infectious disease Lyme these are all diseases that seem to have child age specific peaks in childhood and then of course you have the torch syndromes in kids non infectious we'll go through this a little bit more detail but you know JAA is the most common systemic association intermediate give you eyes and parts planets is has a little bit different character in children and I comprised about 11 to 20% of the patients that we see and then of course non infectious posterior uveitis does occur in children a unique childhood type of sarcoidosis and then less often the kind of multifolk accordities although they do occur and then of course the masquerade syndromes that are unique to children such as retinoblastoma and leukemia juvenile xanthogranuloma and an over representation of trauma probably in kids this was actually an interesting study from the Netherlands which you showed there aren't that many states of just infectious uveitis in tertiary care setting in their study they found it's infectious disease was about 17% of the kids they saw they were diagnosed clinically with imaging labs and serology and aqueous humor analysis and show that a specific IgG was determined in a very high percentage of patients 70% of the patients and was accurate in 98% of them and aqueous humor analysis was also very important establishing the diagnoses so overall again no surprises that occupy your toxoplasmosis was most common diagnosis that was made then viral including you know anterior viral disease and arm was about 30% one of the take-homes of this was that child that unilateral disease it's fear is more often infectious and safe bilateral disease and their recommendation was in a child that presents with you know the site threatening of the I said have low threshold to perform aqueous humor tap so they perform aqueous humor tasks with impunity and perform you know I wouldn't go when Whitmer coefficients there which we don't do here but I think the message is clear that you want to make the diagnosis early a child with whom you think you have an infectious theology so another way to think about the differential diagnosis rather than you know lists so it always has a cut it's always useful to think of things in a number of different ways would be the age of presentation okay so infants might present with a congenital infectious syndrome such as toxoplasmosis rubella as you see here some congenital syndrome whereas a child the age between the ages of two and ten years old may be more likely to have an acquired either infection or a systemic autoimmune disease such as JIA adolescents again I may have toxoplasmosis but you might see you know entities like intermediate UVS a little bit more often and then you do see some children with multifocal disease leukemia and then post-infectious autoimmune type of UVA disease then of course you know any childhood age always have your antennae up for you know unusual things this is a serious retinal detachment to in a four-year-old kid with VHH pretty unusual okay but it can happen depending upon where you are again in the world so the first you know disease that I think of when I think of juvenile when I think of pediatric uvitis is JIA associated disease so it's the most common systemic disease that presents with anterior uvitis it encompasses a spectrum of childhood authorities and is the most common form of childhood arthritis it is about 20 to 33 percent of the anterior uvitis in tertiary care setting there are depending upon the classification system that you use there are several subtypes of JIA oligoarticular disease for fewer joints is the most common that is associated with inflammation in the eye can be persisted or extended but you also have to remember that there are rheumatoid factor negative and positive polyarthritis that do present with arthritis psoriatic arthritis that presents with that estimate as the Midas related arthritis which is more like kind of B-27 presentation with acute presentation so they may not be as frequent but we see them and they're there for sure for the purposes of board you know examinations systemic disease stills disease does not present with arthritis other so you have a subtype oligo articular disease more commonly than the other risks for the development of uvitis are a and a positivity younger age of onset of arthritis and then female sex so female sex is more often a risk for the development of uvitis but we'll see that male sex is more of a risk for poor visual prognosis so the children usually present asymptomatically with a white quite eye with bilateral non-grinding loans uvitis usually between six months and four years of age in the vast majority of these kids the arthritis precedes the uvitis better than about 10% patient the uvitis may precede the arthritis delaying significantly the entry of the child's health care system and children presenting with complications at presentation which as we will see is very very common the other thing to note is that the systemic and the accurate activity are not necessarily synchronous they can be independent of one another and you know parents need to know that so the eye disease may be active when the joy disease is not and vice versa or they may be simultaneously active at presentation depending upon the study you look no matter how you cut it there are is a very high percentage of accurate complications at at presentation so Hopkins 45% of them in Germany 67% in a tertiary care setting and then in the site study which was a good recently conducted study in the United States among five large University practices 60% of patients presented with at least one complication unfortunately the proportion of severe disease is really unchanged with the current screening guidelines that are in place for GA makes one think that maybe they should be changed so as you probably know these are the screening guidelines and it's not as complicated as it looks but I'm basically children with oligoarticular disease or polyarticular disease that are any positive need to be screened every three to four months whereas children are screened who are less than seven years of age and then onset greater than seven years of age it's extended to six months I think that that's a general guideline we examine patients sometimes a lot more frequently than that particularly kids that are active particularly kids that have complications in their other eye particularly kids that are wished for losing vision so complications the sites that there are a lot of studies about occupations the site study showed that the most frequent complications are banned characterately postures sneakier and although it didn't exactly address cataract cataract is probably the third okay so you also have you know a hypertension macrodema if you're retinal membrane as I just showed you 60% of eyes presented with at least one and the incidence of new complications per years about 15% prior years that's for the development of new complications so present with a complication you're at risk of developing more complications the converse is that if children don't have complications of presentation their risk for complications much less which is interesting so the predictor of a poor visual prognosis with vision between 2015 and 2200 active inflammation number one okay number two the presence of a structural complication particularly postures and prior surgery those were found by the site study okay other studies that are important risk factors for poor visual prognosis include ubi is before we're concurrent with the onset of arthritis if I mentioned you before so those kids are not you know don't get in to be seen a shorter interval from the onset of arthritis to ubi is prolonged referral to a specialist as we've seen lots of times in our client and male sex visual outcomes you know are really not great it depends on you know what what's kind of study that you're doing but these are all from tertiary care centers and there's an undoubtedly ascertainment bias from a tertiary care center but you know 30% frequency of visual impairment 24% of legal blindness is high at presentation okay and in the site study as I mentioned to you before 40% of patients with visual impairment you know 20 25% 2200 and you know with a not insignificant rate of the progression of visual loss in these studies so we'll get into you know treatment and the modification that shortly so JAA is something that really needs attention needs treatment sarcoidosis is often mentioned as a cause of you guys and children but it's actually pretty rare okay it's you know more common there are two to three cases per million in Denmark and 80% of the cases in the United States are usually in the southeast and among African Americans as we mentioned before in an adult lecture sarcoidosis seem not infrequently here due to this kind of pocket of sarcoidosis in the skin and even population they're kind of two forms of sarcoidosis in children there's early onset sarcoidosis less than five years of age and that presents differently than although adult onset sarcoidosis more often with skin lesions with botanist papules arthritis and an ocular inflammation in any anatomic region of the eye and much less often with pulmonary manifestations it's thought that a lot of these kids are actually have a mutation in the card not to mutation although there are sporadic cases of just idiopathic juvenile sarcoidosis the later onset of sarcoidosis in children from eight to the 15 years of age are is much more like the multi systemic disease you see in adults with a higher instance of pulmonary involvement the ocular manifestations are similar to that in adults but are frequently fairly severe with chronic bilateral rhinoluminescubitis intermediate post-cubitis the assessment lysis I'm is preferred to aces the to some converting enzyme physiologically elevated in children again chest x-rays good screening for older children and then biopsy is required for you know definitive exclusively diagnosis and try to look at places that are you know not they're more accessible like the skin of the lymph nodes with conectiva so the differential diagnosis sarcoidosis produces you know inflammation and arthritis you think about things that produce the inflammation arthritis such as JAA and then there's a another uncommon disease that is a autosomal dominant entity called familial juvenile systemic granulomatosis or blouse syndrome or jab syndrome depending upon you know who's writing paper that is phenotypically almost identical to sarcoidosis okay J I just put this slide up to look at the so that you can see the differences between JAA and sarcoidosis non-granulomatous versus granulomatous anterior involvement in JAA versus any involved any anatomic region in sarcoid oligarricular arthritis versus polyarticular arthritis in sarcoid and the infrequent would no pulmonary involvement in JAA and possible pulmonary involvement yes yes I do get asked that and there's no value to a blind conjectiva biopsy the yield is extremely low that however it's worth examining the conjectiva because if there are nodules then I think that if the nodules present then the nodule could be actually produce diagnostic yield so what is blouse syndrome it is a triad of granulomatous dermatitis polyarthritis and uveitis in the absence of pulmonary disease in young children okay between the ages of one and four it's autosomal dominant it has a 100% phenotypic correlation with the card 15 no to not to mutation phenotypically this produces a panneuviatus the multiple chorditis in young kids and frequent development of ocular complications can also produce some nasty posterior segment vascular vascular apathy such as an urban type of syndrome and it's differential is that of early onset sarcoid because it's probably the same disease and JAA this is kind of an interesting study so sometimes it's you know useful to think about well how does the kid present well we know that you know JAA most often insidious type of bilateral non-granulomatous uveitis what about bilateral acute non-granulomatous uveitis how often is that percent well Andrea Bermbeam did a study in Chicago that among their uveitis population showed it was pretty uncommon about 1% of all of their patients those patients were younger than a similar cohort uveitis patients but about a quarter of them were less than 17 years of age most the cases had a limited duration but recurrences were very very common and the etiologies were either post-infectious or drug induced or idiopathic there are were some other diagnosis such as tubular interstitial lefritis carousal disease in B27 and their recommendation was to evaluate these children with serum ISO tighter and anti-structilizing oh tighter B27 you know right baby to my blog so bilateral simultaneous acute non-granulose the entry of the it is you know think about something post-infectious or drug induced just have that in the back of your mind because you can make the diagnosis and it's important to do that because it could potentially have significant morbidity issues you will see in a second so post-strepid cockle uveitis syndrome is a bilateral non-granulose immunity a sequela to group a strap I can occur in isolation or with a systemic presentation usually there's a lag between the onset of the uveitis and the systemic condition and anti-struct elicin oh tires are elevated in the vast majority of the patients there's a evidence of either concurrent or previous systemic illness in a 87% of the patients and most the kids and there's a higher representation pediatric patients in this okay the other thing it's not just an anterior uveitis you can have significant posterior uveitis including the tritis infocal retinitis disswelling and multiple corditis it's important to make this diagnosis for obvious reasons it requires multi-disciplinary management with the identification of the strap so that you limit the potential sequela of this disease including you know the melanin or fridus or cardiac disease just a couple of clinical caviar stored cultures probably not very valuable patients that have a streptococcal cutaneous infection again would have low yield so obtaining serum ASO tide is important someone raised the value of tonsillectomy in this and apparently this is of no value the other kind of bilateral non-grainel injury current enter uveitis that you have to think about in this group although uncommon is tubular interstitial lymphitis and uveitis syndrome continue it is characterized by this triad the nephritis usually precedes the uveitis but not necessarily okay so 20% of the time you can have uveitis first 50% of the time it can be concurrent again just like the you know the drug-induced type it can be recurrent in about 50% of the time with posterior uveitis involvement which it which can be significant with structural complications in about you know a fifth of the kids so the mean onset this seems to be this kind of bimodal distribution yet young kids teenagers and then people in their 30s so think about that when you have bilateral simultaneous inflammation there's a female predominance and then overall it's uncommon but about 1 to 2% seen in tertiary care setting it's thought to have an auto inflammatory pathogenesis there are HLA associations with it and it's thought to be due to some type of drug or microbial trigger the diagnosis is definitively made by renal biopsy it's often you often miss the opportunity to make that diagnosis because the patient will present with uveitis first but there are other presumptive clinical diagnoses and criteria that have been elaborated by Mandeville that include abnormal serum creatinine clearance and abnormal urinary analysis one test that's extremely useful as a screening test is the beta urinary beta 2 mycoclobulin which is elevated in a very high percentage of patients and then obtaining a good history we've had you know a kid that we were seeing from China you know they've had there's a Caucasian child that was parents were in the Foreign Service and been seen by multiple doctors with recurrent anterior uveitis and you know with lots of steroids and all this and you know we got a good history on that on the child is having multiple recurrent fevers weight loss and anorexia and turns out to have TINU so rather than treating him with continuous topical steroids and giving him cataracts and hypertension which is what he came in with we're able to make a diagnosis and then you know he's on immunomidotorotherapy for his kidney so it's important the treatment is usually with topical corticosteroids but not always it seems that the patients that we've had here have required more extended therapy because they've had multiple exacerbations and managed them in conjunction with pediatric nephrology they like to put them on immunomodulator such as cell set and tachyrolimus okay so pediatric intermediate uveitis intermediate uveitis is always an interesting disease whether or not it's in children or in adults it seems to represent a much higher percentage of children that we see we see quite a few kids with intermediate uveitis and in my clinical experience and I think that any other people it seems to be a more severe disease in children than it is in adults it usually presents unilaterally and asymmetrically but is usually bilateral the findings as opposed to adults you can have actually significant anterior segment inflammation and children that present intermediate uveitis in particular as you know the sneak one on intermediate uveitis is vitritis right okay and I snowball snow banks and cyclical membranes vitrious opacity but you have to have vitrious inflammation and I have found I think that some you see vitrious inflammation with big clumps of vitrious opacity particularly in the anterior vitrious of children it just seems to you know be right behind the lens probably has to do with the fact that the peripheral retina and the ciliary body are the active sites along with the peripheral retinal vasculature so retinal vasculitis is seen usually a phlebitis periflebitis in about a third of the patients and magardema is a very common reason for decreased visual acuity so the differential diagnosis as we as in adults I you talk about intermediate uveitis that is associated with systemic condition or not okay and if it is not associated with systemic condition it is termed parcellinus parcellinus is the idiopathic variety of intermediate uveitis okay just a couple of words you know you have to think about infectious diseases more often in kids right so presenting as intermediate uveitis particularly kids are from endemic areas for Lyme disease cat scratch toxic riasis can have a peripheral granuloma that may simulate intermediate uveitis sarcoid and blau and then a couple of entities that you might not think about in terms of intermediate uveitis that may produce kind of an anterior intermediate uveitis like fuchs heterochromic aerocyclitis frequently those patients will have significant vitreous opacity it may even require a tractomy there are children with JAA that have significant anterior uveitis a significant anterior vitriol inflammation and then of course mass grade syndromes complications so children are more apt to present with certain complications than adults that have intermediate uveitis so kids are more more frequently will present with cataract, ocular hypertension at least in the series that we conducted here band care atop these kind of hallmark for chronic disease in childhood and dyskidema and vitreous hemorrhage so there they seem to be more frequent in kids macular edema is a frequent cause of visual loss patients can also develop peripheral retinal detachment and bolus vernoschisis that may be due to a coats like vascular response secondary to chronic inflammation so you can have exudative retinal detachment in the periphery there can be traction due to the fact that the vitreous becomes abnormal peripherally and will produce traction on the peripheral retina and unfortunately sometimes you can also have a combined traction or regulatory component which can be which would require surgery to be difficult to fix it's also very important to think about when you're putting ports into an eye if you're doing retractomy or putting in a register or something like that to know where that traction is to know where the snow banks are because you can induce an nitrogenic problem quickly so the prognosis again it's problematic when you're kind of there's this kind of disconnect at least in my opinion when you reduce the literature and then when you look at the patient in front of you sometimes you know so the literature is you know suggests that the vast majority of patients with um pediatric intermediate you guys do well okay and they do basically okay 86 percent of them with you know 2040 vision but we you do see you know about 20 percent of patients doing really poorly so you have to kind of individualize your therapy and not have be complacent and say oh it's just to me you guys you know it's it'll get better it'll be okay um but really follow patients particularly younger children that present with more severe disease these are the kids that have the higher risk of complications more prolonged course and a worse visual outcome okay so um you know in adults that have a couple floaters no macadamia um so for well just well subscribe certain scribe snowballs and I probably wouldn't treat that patient in a child you know that has significant anterior vitreous capacities macadamia you know you're going to treat them you might even treat them without macadamia if they're symptomatic it really depends if they have a significant vasculitis and papillitis um those may be indications to treat the patient there was a study by again in Netherlands where they have this axis this great database of kids which show showed earlier onset less than seven years versus later onset had a significantly poor visual prognosis so that early and aggressive treatment would be uh recommended for patients with a younger age of onset who particularly those that present with structural complications or significant vitreous haze um so it's similar in JAA okay I you know you would be much more aggressive in the treatment of patients with JAA that presented with an awkward complication you wouldn't just continue topical steroids you might really consider advancing their therapy so we use a modified step ladder approach as we discussed previously using topical and periocular steroids for anterior segment inflammation periocular steroids can be very useful in patients with unilateral or asymmetric qc's but the problem is that some of the kids are really young and that that requires trip to the OR that may be done in conjunction with examination under anesthesia which is fun um but then again I at least in our experience it seems that periocular injections and intervitational injections in children seem to produce ocular hypertension more often than they do in adults I don't hesitate to use systemic corticosteroids in this situation for a defined period of time but we all know that systemic corticosteroids are not advisable for chronic use in anybody particularly in children due to the you know growth retardation in the side effects of the medication another modality that is probably underutilized is rentocryopexy indirect laser certainly in the presence of peripheral neovascularization but recent studies seem to indicate that even in the absence of that it modifies the course of the UVIs the inflammation and the salutary in terms of the treatment of macrodema and then there's the question of do you immunomodulate the patient or do you perform a detracting on the patient with intermediate UVIs that question is open but there have been some interesting studies so we looked at a group of 39 patients 77 eyes of intermediate UVIs and we found that as I mentioned before ocular complications that were at least new were you know ocular hypertension then cataract to macrodema as we've known before but we managed these patients with a kind of a step ladder algorithm that involved immunomodulation first surgery second for the presence of a ocular complication that required us to get into the back of the eyes of just a cataract or epiretinal membrane and we found that we were really we were able to get patients completely off of steroids most patients of all but one of them and that at three quarters these patients were would respond extremely well with the inactive disease so I think that it is a really reasonable approach on the other hand I do the Gildiari I think it was in Steve Foster's group published this it was an uncontrolled study about five years ago of 28 eyes of 20 patients with intermediate UVIs that were on systemic therapy that still had active disease so they pulse them with some steroids and for the track to me on these patients and 96% of them you know had inflammatory control at the last follow-up I mean it was impressive but no controlled data and you know I think that looking at the interval of the information is important but still I think it is a reasonable is a treatment option that really needs to be explored because you have on the one hand patients on immunomodulatory therapy for long periods of time versus the chance of possibly putting a child into remission by a surgical procedure again surgery can be very complex and difficult in a patient and a young kid in whom the posterior highlights completely attached which you want to get off so the chances of inducing complications it's higher than it is so a subject for further investigation so you guys all know about the torch infections right toxo others rubella cytomegalovirus and herpes what you may not I appear toxoplasmosis we talked about last time okay so I'm not going to dwell on that but you know it's congenital infection but the current thinking for your board purposes is that probably two-thirds of these are are postnatally acquired diseases so the most of the toxo we see are probably not congenital infections and that there is a you know triad for congenital toxoplasmosis that you need to know for your tests corioretinitis hydrocephalus intracranial calcifications and that the thing that is important about that is that a very high percentage of kids with congenital toxoplasmosis will have active disease and will stay active for a long time so they if they're diagnosed with congenital toxo they need to be treated can you be treated for a year that's current with antiparasitic therapy what you may not know is the lymphocytic coriomeningitis virus which is probably should be in the other of the congenital toxa of the congenital infections that we see it's a single-stranded RNA virus that produces a symptomatic maternal illness in about two-thirds of the cases it's vertically transmitted during a maternal viremia and it can be diagnosed serologically by testing the mother and the child it produces systemic findings that are very similar to that use the congenital toxoplasmosis so the differential is really toxo okay it can produce macrosephaly hydrocephalus and intracranial calcifications coriorental scars as you can see here optic atrophy nystagmus and the differential diagnosis really serologically and then the pattern of the intracranial calcifications which is more periventricular in lcmv whereas it's more diffused in toxoplasmosis acute toxicoriasis is a uniquely kid disease so kids with a history of contact with puppies you know and pica i may present with i may they can be infected with the second stage larva you know atoxicara kinase or catech and it produces a unilateral painless decreased vision and it's in the differential diagnosis of leukocorea and strabismus there are basically three presentations okay so this is a posterior granuloma presentation which is probably the most common and then there are peripheral granulomas with with a tractional band that connects usually to the disc and then in an older age and usually around 10 patients can present with an endophthalmatis it's a diagnosis that one suspects clinically and it confirms serologically by aliza one would want to perform an ultrasound on the child to present with this so that you exclude the presence of calcium and you can also perform intraocular fluid analysis for aliza and pcr so the obvious big important differential is sporadic unilateral retinoblastoma endophthalmatis toxoplasmosis and then of course you have to think about retinobaster disease that that can present children that may produce something like this dragon from a peripheral granuloma such as our up here fever there's really no good satisfactory treatment for this unfortunately usually treatment is centered on you know treating the inflammation with periocular and systemic steroids many people will use albendazol to treat this but it's not been shown to be to eradicate it and then vitroretinal surgery is not uncommonly needed I'm just going to mention dusin in the differential diagnosis diffuse subacute unilateral neurotonitis the etiology are two you know ascreted worms that I present usually in the midwest or the southeastern United States I think there's some worm that lives up in Idaho too because we've seen patients that seem to have a dusin type of picture they're all from Idaho I don't know why but anyway it's said they present with unilateral disease unilateral retinal wipeout is where it used to be called okay recurrent multifocal diffuse inflammation of the of the retinal pigment epithelium and it starts out like a white dot syndrome okay and it progresses to involve the entire retina usually with tracks in the back of the eye vaso occlusion of occlusion and the end stage of the disease kind of looks more like a late rp or post-traumatic immaculopathy more toxic chorea retinopathy and really the the treatments that have been recommended the definitive treatment is to burn the worm if you can identify it so identify the worm and laser it some people have used albendazol to kind of stun the worm okay so that it doesn't move around so much it seems to and then and then kill it and there is no post inflammatory reaction after lasering the worm so far has been reported you have to consider endogenous bacterial and fungal infections I particularly in the immunologically immature immature neonates and hospitalized children and those that are immunosuppressed you know important I don't need to tell you guys who are over always over there doing these consults but important pathogens include pseudomonas staff group B strep hemophilus and candida usually there is an extra-ocular focus right usually there's some type of underlying systemic condition that tips you off of this is an infectious process always have the differential diagnosis of retinoblastoma in the back of your mind right so retinoblastoma you know with no apparent infection is important so an eye that doesn't have a post your snikia right no signs of inflection you better be thinking about retinoblastoma neuro retinitis okay neuro retinitis is infection of the optic nerve followed by the retina usually inflection of the optic inflammation optic nerve followed by exudative neurosensory detachment then precipitation of precipitate incident macula producing a macular star and you can think of it you know it can be infectious idiopathic or idiopathic recurrent attacks but it can also be associated with other inflammatory disorders such as ermine syndrome or non-effects as opposed to you get is such as sarcoidosis inflammatory bowel disease for the purposes of this discussion the thing that you need to think about in terms of neuro retinitis in children is Bartonella eye or cascatch disease Bartonella Hensalea and Quintana and Bacilliformis a three most common pathogens it has a very high age specific instance in children okay it is important to think about this disease when you see a swollen optic nerve or certainly a macular star in a child and ask them about extra-ocular manifestations because usually a weak preceding that patients will have had a flu like illness with regional adenopathy and arithmenus populate the site of the scratch of the cat scratch and then they can have disseminated infection with fever myalgia and the most the worst possible thing would be encephalitis and ocular disease caused by a Bartonella Hensalea includes Parnas ocular glandular syndrome and then neuro retinitis okay but it can also produce a multifocal retinitis multifocal corditis and peripapillary angiomas and dys optic disc gremulomas the other thing that it can produce is retinal vascular occlusive disease so those are unusual manifestations they're important to keep in mind when you have a unilateral process like this in a child with a branch artery inclusion pretty unusual right it's a clinical diagnosis with confirmatory serology with immunofluorescence assays in western blot there is a duplex PCR that is extremely highly sensitive that can differentiate they can speciate the infection the the differential diagnosis is broad you have to think about other infections syphilis Lyme disease for sure I do some in this part of the world Rocky Mountain spotted fever herpes mumps and then as I mentioned to you before non-infectious causes like sarcoidosis and then vascular catholic causes hypertension diabetic papillopathy naii and pseudoterminal kemia there are no definitive treatment guidelines the natural history for cat scratch disease infectious cat scratch disease is it's for the majority of patients to recover vision in 24 vast majority and then like 80 percent 87 percent better than 2025 but most people the recommendation really is to treat the patients with antibiotics for about two weeks two weeks to a month and the infectious disease guys here do that as well and in adults you can use doxycycline, ciprofloxidon with or without rifampin when I obviously avoid doxycycline in child less than seven years of age so zithros good for everybody right and rifampin just to let you know that you know in terms of the idiopathic infectious and idiopathic recurrent varieties the the ancillary testing is the same but there is no association between neuro retinitis and multiple sclerosis I think that's important to know and the other thing is that recurrent disease seems to involve a neuro retinitis involves a recurrent inflammation of the optic dysvasculature and these patients the visual prognosis is worse the and the MRI finally shows enhancement of the retro bulb optic nerve only um Lyme disease we don't see a whole lot of Lyme disease here we're asked to consult about Lyme disease not frequently and people from the east coast and from endemic areas do come here so and kids and their kids get it okay because they're out playing in the tick grass um only 25 percent of kids what we call a bite so it's important to take good history if you see that rash in a patient from endemic area um you've made the diagnosis what is the name of that rash erythema and migraines right so that's actually diagnostic okay if you have the right history that ration of Bell's palsy um systemic it's it's a spirochetal disease so you know it has same stages as or similar stages as syphilis um early with erythema migraines a flu-like illness disseminated with fever meningitis Bell's palsy arrhythmia is an arthritis and then persistent phase with arthritis and neurologic symptoms the ocular manifestations vary with the disease so that the in the early stage of the disease you see a follicular conjunctivitis subcontractable hemorrhage but the the uveitis occurs usually in the disseminated and persistent phase and the most common anatomic presentation is that of um intermediate uveitis although you can also see posterior uveitis and neuro adenitis so neuro adenitis is important in the differential diagnosis and then the keratitis the corneal complications are usually late again it is a clinical diagnosis with supportive serology the CDC represents a two-step process in diagnosis including enzyme immuno assay if it's positive then a second step for western blotting which requires at least five IgG bands to make the diagnosis it is treated with IV antibiotics neurological dose is similar to syphilis okay so it's considered CNS disease masquerade syndromes okay the most important masquerade syndromes in children retinoblastoma but also acute leukemias okay can present with a pseudo-hypopeon as you see here that is often tinged with blood so if you see a pseudo-hypopeon that doesn't layer out lumpy bumpy type of thing this is not a b-27 associated uveitis you have to take good history get a cbc that is an important diagnosis to make an anterior paris chamber paracetesis make the diagnosis or a good history again retinoblastoma don't want to do it anterior chamber paracetesis in that particular case and then children that and then children that might present with for example iris nodules hyphaemen elevated intraocular pressure you might think about jxg so the other things on here intraocular foreign bodies always something to think about you know which we often don't think about the kids get them kids kids get trauma okay so the diagnostic approach you know you want to do a comprehensive medical history review of systems complete augury examination sometimes you have to take kids to the operating room do an e-way that may also facilitate treatment after you've gotten a laboratory workup and then directed laboratory and slamming investigations as guided by your clinical suspicion and your examination and differential diagnosis so there are therapeutic dilemmas right and treatment of kids so you have people you know corticosteroids can produce cataract and ocular complications ocular hypertension growth retardation if used for a long period of time and then there's therapeutic timidity with respect to the use of non-steroidal immunomodulation right and then kids have our greater surgical risks too they you know the zubarin inflammatory responses and then there are inherent complications of the diseases as we've talked about so JAA is loaded with them okay so they and intermediate you guys should present with with complications so the approach as in adults you want to eliminate the inflammation treating infection with the appropriate antibiotic therapy okay and then follow a kind of a step ladder algorithm using steroids as your first line treatment by any route that is necessary to treat the infection okay topical periocular or systemic depending upon the laterality and severity and then a brief you know well-defined period of systemic corticosteroids particularly if you're contemplating bridging the patient to immunomodulatory therapy okay and then serious bearing immunomodulation and of course this kind of dilemma as to whether or not what the real place of therapeutic retraction is and we've gone over some of these lectures we've gone over some of these topics in the therapeutic lecture but just to to remind you or to refresh your memory you have conventional immunomodulatory therapy consisting of the anti metabolites to just methotrexate cells out t-cell transduction or calcineurine inhibitors like cyclosporin, tycholimus, and the outglading agents like thorium cell and cyclophosphide which are used a lot less frequently carrying a lot higher risk of treatment related complications and now that we have other agents available to research the biologics. The word about methotrexate it's as you know it's the first line immunomodulatory agent in both the probably adults and in kids and it produces inflammatory control in about three quarters of patients which also means that 24 percent 25 percent don't respond. It's steroid sparing and it works in a lot of patients as monotherapy. How long do you keep a kid on you know methotrexate? Well you know there's actually been some studies about that and it seems that the longer the period of disease inactivity and longer you're on methotrexate the better your or the lesser chance for disease reactivation and three years is actually what this Dutch studies are recommending which kind of confirms what we've been doing clinically for a while. So for people that don't respond to methotrexate one strategy is to switch agents in the same class so some folks that respond to met they don't respond to methotrexate will respond to cell septin vice versa. Cyclosporin add-on can be beneficial in kids. Yeah so usually it takes about three months for methotrexate to actually even become active so I would wait three months after that so six months if they don't have a response after six months then I would consider switching agents and then I would switch the agent to give them three and a half four months after that on that agent before advancing them. In JAA I'm you know I I think that rather than switching agents I might advance them to biologic that would be my paradigm. Cyclosporin can be added on you know it's of a equivocal benefit but it seems to be better tolerated in children and then you have the biological response modifiers and here they are okay they're a whole bunch of them and they target you know different specific either membrane bound or soluble receptors, TNF, CD20, interleukin-1 and interleukin-6. It's not important to go through all of these other than to mention that the most common agents that we use in children are the anti-TNF inhibitors infliximab and adalimumab. We've gone over some of these medications already infliximab and adalimumab in a at least a opinion expert paper have been recommended as first line agents in the treatment of Bechet's disease as opposed to your segment manifestation so as soon as you see it they're on it okay and as second line agents in JAA associated uroocyclitis and as potential second line agents as steered sparing medications for a variety of recalcitrant postures post your inflammatory diseases. As you know we you have infliximab it's a chimeric mouse human antibody it is administered IV there is a little bit more flexibility with respect to dosing and frequency of dosing so we can dose from five to 20 milligrams per kilogram it's steered sparing it allows tapering of immunomodulation is differentially more effective than the tanner sept which really has no use in uveitis we usually maintain patients with low doses of an anti metabolite because to prevent anti chimeric antibodies but it's non-remitting there is no real good head-to-head data to show between the efficacy of infliximab or adalimumab although in some of the rheumatologic literature it seems that adalimumab actually may have you know better efficacy adalimumab certainly is easier to administer you know it's subcutaneous administration it's every two weeks but the dose is fixed right so it's a 40 milligram dose every two weeks or 20 milligrams if you're 20 milligrams if it's a younger child um you can increase the frequency to every week if you have to do it the advantages are obvious and we don't really know if it's more effective than infliximab I think again we will see that you know you have some choices as far as switching agents I want you to be aware of the sycamore trial okay that was recently published in the New England Journal of Medicine which was a randomized controlled clinical trial the efficacy and safety and cost effectiveness of combination therapy of adalimumab plus methotrexate versus methotrexate alone in refractory JAA so kids that were on stable doses of methotrexate were randomized to either receiving adalimumab or placebo okay and this study basically concluded that the combination of the two medications significantly delayed the time to treatment failure versus methotrexate alone that's important so that there were many more treatment failures in the placebo group and in the combination group and in a post hoc analysis it seemed that the combination of adalimumab and methotrexate showed significant differences in the time to treatment response that makes sense right it takes three months for methotrexate to work adalimumab has usually has onset in about two two weeks as expected or as as one should have their antennae you know up the frequency of adverse events and serious adverse events were much higher much higher in the adalimum okay so the concerns we have you know are increased infections all all kids get screened for tb there is an increased risk of lymphoma although that signal varies in the population that you're looking at it seems that patients that it's where certain autoimmune disease may themselves be predisposed to developing cancer and it may not be a direct drug effect and then of course the increased risk of demyelination in a patient that has demyelined disease so you don't want to put them on these on these medications so what happens if you know I mean not everybody responds to tnf right so and there is a waning response their treatment related side effects people can't you will not be able to tolerate it so one thing you can do is you can change anti-tnf agents so there are different medications that you can use so say you put someone on adalimumab and they don't seem to be doing okay you can flip maybe change them to infliximab because you might have a little bit more flexibility in terms of dosing okay you can dose people at with higher doses than medication there are other anti-tnf medications also golemumab and simsia that there are just case reports but seem to be effective as alternative agents and then there are third line biologics that target different receptors such as rituximab, orensia, abatosept, tosylizimab which is a humanized anti-IL-6 receptor antibody phase two results recently published which were encouraging that and we have had several children using this medication that seem to respond pretty well to that who have failed other anti-tnf medications anakinara which is IL-1 receptor and declysmab which is making comeback because it's been approved for the use of MS and so maybe we'll be able to use it again in UVIS showed advocacy in UVIS but the company didn't think that it was profitable enough to actually bring it to market so final slide does this all work I think it does okay I think that immunomodulatory therapies is essential in preventing acute complications and preserving vision in children with the UVitis the JIA literature certainly seems to suggest that series at Hopkins showed you know seven of 75 children a significant reduction in the risk of acute complications that are associated with with decreased vision and blindness in the better scene in another center single center study with 23 patients which 86 percent of patients were approved for stable vision okay but in that group it was the early institution of immunomodulatory therapy that was critical in obtaining that so kids make sense obviously that have complications that are doing worse that get treated later may not have better visual outcome and then the site data shows a significant reduction 60 percent risk of visual loss particularly in the visual impairment group for children or a manager of IMT so that's what I got for pediatric UVitis modifying the prognosis you know suppress the inflammation early introduction of steward sphering immunomodulation I think that things in the future that are important will be to really identify well clinically you have you can identify surrogate mark markers of severe disease right so children to come in with posterior sneakier you know with cataract uh accurate hypertension you know they're at risk but there are other non-invasive modalities such as laser flare photometry that may actually be useful in and have positive predictive value I think reassessing the screening guidelines for JAA is probably necessary then vigilant post-marketing surveillance of the medications thanks