twice per day for 1–2 years, usually preceded by parenteral administration of ceftriaxone (2 g daily) for 2 weeks. However, this regime is not always effective and recurrence has been documented. Additionally, trimethoprim has been proven ineffective against T. whipplei in in vitro studies.

Therefore, new evidence recommends the use of a different scheme: doxycycline (200 mg per day) and an alkalinizing agent, hydroxychloroquine (200 mg three times per day), which has been the only combination to prove bactericidal against T. whipplei.

In patients with neurologic involvement, the use of sulfamethoxazole or sulfasalazine has been recommended. Treatment duration is not standard, but at least 12–18 months of treatment is recommended. Follow-up should be performed with PCR as it quickly becomes negative if the regime is effective.

Avitaminosis A

Vitamin A is a fat-soluble vitamin that exists in three forms: retinoic acid, retinol, and retinaldehyde. It is not synthesized in the body, which is why it has to be obtained from different types of foods. It is essential for the formation of rhodopsin, the visual pigment of photoreceptors. Several conditions cause vitamin A deficiency: malabsorption, malnutrition, and conditions that impair vitamin A metabolism, such as alcoholism and liver diseases. Bariatric surgery is quickly becoming an important cause of vitamin A deficiency because of the alteration in nutrient absorption. Vitamin A deficiency has a prevalence of 52% in 1 year and 69% 4 years after bariatric surgery [35].

In the presence of early vitamin A deficiency, its demand can be met by the liver and blood, which contain significant amounts of the vitamin. With prolonged deficiency, the outer segments of photoreceptors start to shrink and are lost. At this point, there is a loss of visual sensitivity, and patients complain of night blindness (nyctalopia) as the first symptom [36]. Up to 2.8% of all patients who undergo bariatric surgery complain of nyctalopia. Other ocular symptoms include bilateral conjunctival and corneal xerosis, with

scarring and the presence of Bitot’s spots, which are the buildup of keratin debris located superficially in the conjunctiva and are oval, triangular, or irregular in shape [37].

The fundus examination of these patients will reveal multiple white or gray-white spots scattered in the peripheral retina that will resolve with supplementation. The diagnosis is made based on an electroretinogram (ERG) and dark adaptometry. Dark adaptometry will demonstrate elevated rod and cone thresholds, especially for rods. The ERG will reveal a reduced or undetectable rod ERG and a cone ERG with reduced amplitude and prolonged latency periods. S-cone function is also undetectable and is the last to recover [38].

Symptom improvement and changes in the ERG are generally seen within 1–3 days after supplementation. Peripheral rods and cones recover first, followed by macular photoreceptors, and S-cone function is the last to recover. Macular function may not recover until the 12th day and may remain abnormal for more than 6 months.

The reason why rods are more affected is not well known, but some authors suggest that because cones synthesize their pigment at a faster rate, they do so at the expense of the rods. Another theory states that there might be an alternative pathway for opsin photopigment regeneration involving Müller cells that could make cones less susceptible to vitamin A deficiency [38].

Other Deficiencies: Zinc and Copper

A case report described bilateral whitening of retinal layers simulating a cherry-red spot that returned to normal after supplementation of zinc and copper. Nyctalopia has also been reported in patients with chronic pancreatitis, alcoholic cirrhosis [39], and hemodialysis, which improved upon supplementation with zinc. This manifestation may be due to an alteration in the zincdependent enzyme alcohol dehydrogenase which catalyzes an important step in the rhodopsin pathway [40]. Patients with zinc deficiency also exhibit a depressed ERG, especially in scotopic conditions, suggesting rods may be more susceptible to zinc deficiency than cones.

Pancreatitis

In 1912, Othmar Purtscher described an entity consisting of multiple white retinal patches and peripapillary retinal hemorrhages in five patients with visual loss after head trauma. A similar picture has been observed as a rare complication of acute pancreatitis and has thus been referred to as “Purtscher-like retinopathy.” The incidence of the disease is unknown, but fewer than 60 cases have been published. It has been reported secondary to both acute alcoholic and nonalcoholic pancreatitis [41], systemic lupus erythematosus, thrombocytopenic purpura, renal failure, amniotic fluid or fat embolism. It usually presents as a sudden unilateral or bilateral decrease in vision, and a relative afferent pupil defect is often found. The episode is usually associated with symptoms such as epigastric pain, vomiting, fever, and elevated amylase and lipase levels. The retinopathy may precede the diagnosis of pancreatitis by as much as 6 months [42].

Fundus examination reveals numerous white retinal patches, superficial retinal hemorrhages, and cotton-wool spots around an apparently normal optic disk. Other findings include dilated and tortuous vessels, disk edema, and serous retinal detachment [7]. It usually spares the periphery. Fluorescein angiography can reveal focal areas of arteriolar obstruction, patchy capillary nonperfusion, disk edema, and dye leakage from retinal arterioles, capillaries, and venules [43].

The pathogenesis of this condition is unknown. Current evidence suggests that thrombi consisting of leukocytes form when proteolytic enzymes are released into the circulation as a result of pancreatic injury. This causes activation of the complement cascade and the formation of leukocyte, platelet, and fibrin aggregates. An experimental clinicopathologic study revealed occluded retinal arterioles and choroidal vessels with damage to the photoreceptors [44].

The severity of the retinopathy appears not to be related to the severity of the pancreatitis. Management consists in treatment of the underlying pathology. Clinically, the retinal lesions resolve over a period of weeks to a few months.

After resolution, the fundus may appear normal, but pigment migration and optic atrophy can occur. Although visual acuity may remain reduced, it will likely return to normal or near normal. Systemic steroids have been proposed for the treatment of traumatic Purtscher’s retinopathy, with positive results in one case report. The proposed mechanism of action is to block C5a-induced granulocyte aggregation and prevent the formation of thrombi, but the evidence is lacking to recommend this type of therapy.

Familial Adenomatous Polyposis

Familial adenomatous polyposis (FAP) is an autosomal dominant disease in which adenomatous polyps form in the colon and rectum. To make the diagnosis, more than 100 polyps have to be found. These usually appear in adolescence and almost invariably become malignant by age 50. It affects one in 7,500–10,000 people and accounts for approximately 1% of all colorectal cancers. The disease is due to an alteration in the adenomatous polyposis coli (APC) gene, a tumor suppressor gene on the long arm of chromosome 5 (5 q21-q22) [45].

FAP can manifest with extracolonic involvement (Gardner’s syndrome). The most frequent is congenital hypertrophy of the retinal pigment epithelium (CHRPE). Other manifestations include gastroduodenal polyps, osteomas, dental abnormalities, and intra-abdominal desmoid tumors.

Congenital hypertrophy of the RPE was first described by Blair and Trempe in 1980 [46]. The lesions are congenital and are variable in number: from 1 to 40 in both eyes, with an average of 6 in each eye. This type of congenital hypertrophy of the retinal pigment epithelium is better known as “bear tracks.” They are bilateral in 86% of cases [47]. Most lesions are round, small, and pigmented (Fig. 16.6), although they can present with a depigmented halo and have a variable size and variable degree of pigmentation. They can be present in normal individuals but are always less than 3 in number. They do not affect visual acuity but do create a scotoma in the area of the lesion as a result of photoreceptor atrophy. Histopathologic studies

have shown these lesions to correspond to benign hamartomatous malformations of the RPE.

CHRPE in familial adenomatous polyposis has been extensively studied because of the high degree of genotype-phenotype correlation that it exhibits. More than two-third of patients with FAP exhibit CHRPE, and the characteristics of the lesions are very similar within a family. Because they are congenital, they provide a useful tool for diagnosis and genetic counseling. For example, in fundus-posi- tive families, the finding of retinal lesions will have a positive predictive value of 100%, whereas no retinal lesions will mean that the gene has not been inherited. Additionally, depending on the characteristics of the lesions, each type is being traced to a different location on the APC gene and correlated with a specific severity/prognosis for the disease [48]. This means that in the future, a prediction of the presence and characteristics of the disease may be made based mainly on the characteristics of the fundus lesions.

Controversies and Perspectives

Gastrointestinal diseases with choroidal and retinal manifestations form a very diverse group of diseases, from autoimmune, to infectious, to related to malabsorption. Because they are relatively rare, their pathogenesis and treatment are not fully understood.

Inflammatory bowel disease still remains a mystery regarding its pathogenesis. Various theories have been proposed, including abnormal anti- gen-presenting cells, specific microorganisms, and genetic mutations. Various factors have also been implicated and include smoking or not smoking, HLA-B27 positivity, and stress. Until this is fully known, treatment will not be completely effective as it is not necessarily targeting the mechanism of disease. Actual treatments include sulfasalazine, systemic steroids, steroid-sparing immunomodulators, anti-TNF monoclonal antibodies, nutritional

modifications, and even some antibiotics and antihelminths. Despite the many treatments available, IBD patients often require extensive surgeries and many still die from the disease. Future research is directed towards a larger understanding of the pathogenesis and finding a more effective treatment.

Our knowledge of Whipple’s disease has increased greatly in the last decade, but despite treatment, recurrences are still frequent. Future directions are directed towards a more effective antibacterial treatment and more reliable tests for follow-up, such as PCR. Additionally, prospective lines of research include determining and understanding why some subjects are susceptible to the bacillus, and some never develop the disease.

Vitamin and mineral deficiencies are still quite prevalent in some developing countries, but bariatric surgery has created a whole new group of subjects with malabsorption syndromes, especially in developed countries. Future directions with this condition include better management of postoperative nutrition in these patients, and possibly the implementation of ophthalmic evaluation in these patients, as their risk of avitaminosis (specifically for vitamin A) is over 50%. Functional studies in these patients have also provided more information into the physiology of photoreceptors and their metabolic pathways.

Regarding familial adenomatous polyposis, the finding of congenital hypertrophy of the RPE is becoming very important for genetic counseling. Future research is directed towards linking specific lesion characteristics with specific mutations. In the future, a fundus exam could provide information not only regarding the diagnosis but also regarding the course and prognosis of the disease.

Research regarding immunologic susceptibilities will also be very useful in the diagnosis and treatment of these diseases. As stated in this chapter, patients with specific markers in human leukocyte antigens (HLA) such as HLA-B27 may have a worse prognosis or be more at risk for a specific manifestation. Therefore, more knowledge regarding the role of HLA in these diseases may help the physician give a more accurate diagnosis and prognosis, and in the future, a more

specific treatment may be indicated in subjects with these findings.

Focal Points

Choroidal and retinal manifestations of gastrointestinal diseases may precede other systemic symptoms and are usually very nonspecific. Most present as anterior or posterior uveitis. It is very important to determine the etiology as their treatments are very different (antibiotics, vitamin supplementation, steroids). Additionally, some of these diseases can be fatal (inflammatory bowel disease, pancreatitis, Whipple’s disease) and a more prompt diagnosis and treatment can lead to a better prognosis.

The most common ocular manifestation of inflammatory bowel disease is anterior nongranulomatous uveitis. In the posterior segment, it can present as vitritis, retinitis, papillitis, and posterior uveitis. Retinal vascular occlusion and vasculitis may also be present, among many other nonspecific findings. They may be present in as much as 10% of patients.

Whipple’s disease is caused by the bacillus Tropheryma whipplei and consists of gastrointestinal symptoms associated with seronegative polyarthralgias. Approximately 10% of patients with Whipple’s disease have ocular manifestations. These include keratitis, uveitis, vitritis, choroiditis, and retinitis.

Patients with avitaminosis A may present with corneal and conjunctival xerosis and nyctalopia. Multiple white spots may be seen in the fundus, and the ERG will show a decrease in rod and cone function. The condition is reversible with vitamin supplementation.

Pancreatitis may be accompanied by a Purtscherlike retinopathy, showing large areas of hemorrhages and ischemia, probably caused by vascular thrombosis by fibrin and leukocyte aggregates. The retinopathy may precede the gastrointestinal manifestations and could be important in providing either preventive or very early treatment.

Familial adenomatous polyposis is often associated with congenital hypertrophy of the RPE,