Ординатура / Офтальмология / Английские материалы / Electrophysiology of Vision_Lam_2005

Bardet–Biedl syndrome and Alstro¨m syndrome share similar clinical features such as obesity, pigmentary retinopathy, and diabetes mellitus. However, Alstro¨m syndrome is not associated with mental retardation and polydactyly, and in contrast to BBS, Alstro¨m syndrome is associated with nystagmus, early loss of central vision, and generalized cone–rod rather than rod–cone dysfunction.

REFSUM SYNDROME

Refsum disease, described by Refsum in the mid 1900s, is a rare autosomal recessive disorder associated with abnormal metabolism resulting in the accumulation of phytanic acid, a branched-chain fatty acid (111,112). Refsum disease is due to dysfunction of the peroxisome, an organelle found in cells of most tissues, and is genetically heterogeneous (113). Infantile form of Refsum disease is due to defective assembly or biogenesis of peroxisome. Clinical features of infantile Refsum disease include mental retardation, failure to thrive, pigmentary retinopathy, sensorineural hearing loss, minor facial dysmorphism, hepatomegaly, neuromuscular hypotony, and peripheral neuropathy. Infantile Refsum disease can be caused by mutations of the PEX1 and PEX2 genes. Examples of other peroxisomal biogenesis disorders include neonatal adrenoleukodystrophy and Zellweger syndrome, both of which have overlapping features with infantile Refsum disease. In contrast, classic form of Refsum disease is associated with point mutations and deletions of the PAHX gene which encodes phytanonyl-CoA hydroxylase, an enzyme which activates phytanic acid to phytanoyl-CoA before it is oxidized. Clinical features of classic Refsum disease include pigmentary retinopathy, polyneuropathy, and cerebellar dysfunction.

Early diagnosis of Refsum disease is critical because the condition is treatable with dietary restriction of phytanic acid and plasma exchange. Serum phytanic acid is typically consistently elevated. Visual symptoms such as night visual impairment and decreased vision may be the only

early presenting symptoms. Progressive pigmentary retinal degeneration with vascular attenuation and macular atrophy is the primary ocular finding. Nystagmus may be present. Full-field ERG is usually markedly impaired early in the disease and is a helpful diagnostic tool especially in infantile Refsum disease (7). Both rod and cone responses are reduced and prolonged, and the b-wave may be more affected than the a-wave suggesting greater inner retinal dysfunction; a negative pattern of the scotopic combined rod–cone response with a b-wave to a-wave amplitude of less than 1 may occur (114–116). With treatment, neurologic symptoms improve and visual function stabilizes (114). Rarely, older adults with pigmentary retinopathy, mildly impaired ERG, and elevated serum phytanic acid are found and are considered as having a variant of Refsum disease (117).

ABETALIPOPROTEINEMIA (BASSEN–KORNZWEIG SYNDROME)

In 1950, Bassen and Kornzweig reported an 18-year-old girl with generalized retinal degeneration, Friedreich ataxia, and abnormal red blood cells, and in 1960, an absence of apolipoprotein B in plasma was found to be associated with this rare autosomal recessive disorder which was subsequently called abetalipoproteinemia (118,119). Apolipoprotein B is the only apoprotein of low density lipoprotein (LDL) and accounts for about 35% of apoprotein composition of very low density lipoprotein (VLDL). Apolipoprotein B is also a component of chylomicrons, and patients with abetalipoproteinemia have reduced absorption of fat as well as fat-soluble vitamins such as A and E. Serum levels of cholesterol and triglycerides in abetalipoproteinemia are extremely low. Abetalipoproteinemia is caused by point mutations of the gene encoding microsomal triglyceride transfer protein (MTP) which catalyzes the transport of triglyceride, cholesteryl ester, and phospholipid from phospholipid surfaces (120,121). Clinical features of abetalipoproteinemia start in childhood and include celiac syndrome with steatorrhea, progressive ataxic

neuropathy, abnormal red blood cells (acanthocytosis), and pigmentary retinal degeneration. Treatment of abetalipoproteinemia consists of low-fat diet and oral supplementation of vitamins A and E.

Ocular manifestations include pigmentary retinopathy, ophthalmoplegia, ptosis, nystagmus, and angioid streaks. The pigmentary retinopathy occurs in all patients with abetalipoproteinemia and is similar to RP (rod–cone dystrophy) with progressive diffuse retinal atrophy accompanied by vascular attenuation and pigmentary clumping (bone spicules) (122). Visual acuity and macular function are usually relatively spared in early disease. Full-field ERG responses in abetalipoproteinemia are similar to those found in RP with greater impairment of rod response than cone response in early disease although b-wave implicit times tend to be less delayed in abetalipoproteinemia (7). The EOG and VEP responses are correspondingly reduced (123–125). As the disease progresses, full-field ERG responses become non-detect- able. With initiation of large doses of oral vitamin A or vitamin A and E in previously untreated patients, partial recovery of visual function and full-field ERG responses may occur in less advance cases even if the ERG responses are non-detectable (126–128). Further, chronic combined vitamin A and E therapy initiated prior to the age of 2 years can markedly lessen but not prevent the development of pigmentary retinopathy and impaired ERG responses (123,129–131). Taken together, investigators have concluded that full-field ERG is useful in monitoring visual function in response to therapy in abetalipoproteinemia. Of interest, patients with hypobetalipoproteinemia, which is associated with mutations in the apolipoprotein B gene, also have reduced apolipoprotein B and demonstrate clinical features and ERG findings similar to abetalipoproteinemia (129).

NEURONAL CEROID LIPOFUSCINOSIS

Neuronal ceroid lipofuscinosis is a group of genetic heterogeneous autosomal recessive disorders with numerous

phenotypic variations, characterized by the accumulation of lipopigments in lysosomes (132,133). Primary clinical features include progressive pigmentary retinopathy, regression of intellect, and seizures. The infantile form of the disease [also known as infantile neuronal ceroid lipofuscinosis (INCL), ceroid lipofuscinosis 1 (CLN1), Haltia-Santavuori disease, or Finnish form] with onset before age two is caused by mutations of the gene encoding palmitoyl-protein thioesterase on chromosome 1p32. Patients with CLN1 have blindness and severe psychomotor retardation. The late infantile form (LINCL, CLN2, or Jansky–Bielchoesky disease) with onset between age 2.5 and 4.0 is associated with mutations of the CLN2 gene on chromosome 11p15. Patients with CLN2 have regression of developmental milestones, seizures, and later loss of vision. The late infantile form is also associated with several other genetic loci including 13p22 (CLN5) and 15q22 (CLN6). The juvenile form (JNCL, CLN3, Batten disease, or Vogt–Spielmeyer disease) with onset between age 4.5 and 8.0 is due to mutations of the CLN3 gene on chromosome 16. Patients with CLN3 have rapid progressive loss of vision with slower intellectual regression. The juvenile form is also associated with other genetic loci such as 8p23 (CLN8). The adult form (ANCL, CLN4, or Kufs disease) is associated with psychomotor regression and mild visual symptoms or findings. Of interest, one of the early descriptions of the disorder was by Batten, and the term ‘‘Batten disease’’ has been used occasionally to encompass all neuronal ceroid lipofuscinoses (134).

Visual impairment from progressive pigmentary retinal degeneration with vascular attenuation and macular atrophy is often the presenting symptom especially in patients with the juvenile form of the disease (Fig. 8.5). The diagnosis is confirmed by electron microscopic identification of lipopigments in peripheral blood lymphocytes. Full-field ERG is a helpful ancillary test to detect retinal dysfunction and is severely impaired in the early stages of the disease even when visible retinal changes are still mild (135). With progression, the ERG responses become non-detectable. In INCL, Weleber (136) reported that the earliest full-field ERG manifestation

Figure 8.5 Retinal atrophy and pigment clumping in a 9-year-old girl with neuronal ceroid lipofuscinosis, juvenile form (Batten disease). Visual acuity was 20=100 in each eye, and full-field ERG responses were moderately reduced. The patient had insidious progressive visual loss and night vision impairment. She also exhibited periods of inattention, inappropriate behavior, and verbal confusion. The diagnosis was confirmed by electron microscopic identification of cytoplasmic granules in peripheral blood lymphocytes. (Refer to the color insert.)

is a marked loss of the scotopic and photopic b-wave with relative preservation of the a-wave (negative pattern, b-wave to a-wave amplitude ratio <1) suggesting a greater dysfunction of the inner retina. For late infantile form of the disorder, the same author noted severely reduced and prolonged cone responses with impaired but less affected rod response, and in the juvenile form, the rod response was non-detectable with severely reduced, negative pattern photopic cone and bright-flash scotopic responses. Likewise, Horiguchi and Miyake noted similar ERG findings in patients with juvenile neuronal ceroid lipofuscinosis, and Eksandh et al. found nondetectable rod responses and marked diminished cone responses in patients with CLN3 mutations (137,138). In the adult form of the disease, Dawson et al. (139) found severely diminished photopic cone responses. Heterozygous carriers of neuronal ceroid lipofuscinosis generally have mild impairment of rod full-field ERG, pattern ERG, and EOG compared to normals but carriers cannot be accurately determined on an individual basis based on these findings (140).

KEARNS–SAYRE SYNDROME:

MITOCHONDRIAL RETINOPATHY

Kearns–Sayre syndrome, Pearson syndrome, and chronic progressive external ophthalmoplegia (CPEO) are associated with identical deletions of the mitochondrial DNA. The variability in clinical manifestations among these disorders is related to the difference in tissue distributions of the mutant mitochondrial DNA. In Kearns–Sayre syndrome, mutant DNAs are more localized to muscles and central nervous system while in Pearson syndrome, mutant DNAs are found in high levels in all tissues. In contrast, in CPEO mutant DNA are likely to be very localized to involve mostly muscles. Initially described in 1958, the clinical features of Kearns–Sayre syndrome include progressive external ophthalmoplegia with ptosis, pigmentary retinopathy, cardiomyopathy, heart block, muscle weakness, cerebellar dysfunction, deafness, short stature, and electroencephalographic changes (141). Aside from mitochondrial DNA analysis, the diagnosis may be supported by the finding of ragged red fibers on muscle biopsy.

When present, the pigmentary retinopathy in Kearns– Sayer syndrome is variable in severity and frequently asymptomatic. Full-field ERG responses are generally mildly to moderately impaired in patients with mild retinopathy but may be markedly diminished in severe cases. EOG impairment also occurs but EOG cannot be obtained in patients with ophthalmoplegia that is severe enough to prevent adequate eye movements for EOG testing. In a study of 61 patients with mitochondrial myopathy, Mullie et al. (142) found 22 (36%) with pigmentary retinopathy. Of these 22 patients, 18 had ‘‘salt and pepper’’ retinal appearance consisting of diffuse stippled areas of hypopigmentation and hyperpigmentation and visual acuity of mostly 20=40 or better. Of the remaining 4 patients, two had RP-like changes with hand-movement and light perception vision, but unlike classic RP, pigment clumping was present at the maculas. The other two patients had severe generalized atrophy of the retinal pigment epithelium and choriocapillaris with severe visual loss. Ten of the 18 patients with ‘‘salt and pepper’’ retinopathy were studied with

EOG and full-field ERG; both the rod and cone ERG responses as well as the EOG light-peak to dark-trough amplitude ratios demonstrated mild to moderate reductions with diminished cone flicker response being the most consistent finding. However, other studies have shown that normal EOG and ERG may occur in Kearns–Sayre retinopathy, and conversely, in some cases the ERG is diminished before the retinal pigmentary changes are visible (143–145). In addition, reduced scotopic with normal photopic ERG responses in a patient with Kearns–Sayre syndrome has also been reported (146), and abnormal scotopic ERG responses are common in children with mitochondrial disorders (147).

Impaired VEP in Kearns–Sayre syndrome is common (148–150). This is likely due in part to retinal dysfunction from the retinopathy as well as from the electroencephalographic alterations associated with central nervous system involvement.

RUBELLA RETINOPATHY

Pigmentary retinopathy may be a manifestation of the postrubella syndrome. The retinopathy is usually bilateral but may be asymmetric. Although post-rubella retinopathy may mimic RP in appearance, retinal vascular attenuation is generally not present. Electroretinogram is a key diagnostic test in distinguishing the two conditions. Full-field ERG is normal in almost all cases of post-rubella retinopathy but may occasionally be mildly below the normal range (151,152). Of interest, in patients with asymmetric retinal pigmentary changes, ERG amplitudes may be relatively more reduced in the more affected eye (153).

SYPHILITIC RETINOPATHY

Chorioretinitis and pigmentary retinopathy may be a feature of syphilitic or post-syphilitic syndrome. Not surprisingly, impaired ERG responses and impaired EOG are found patients with syphilitic chorioretinitis (154). However, in

contrast to RP, the full-field ERG response is generally only mildly or moderately impaired and is more likely to have reduced amplitude than prolonged implicit time (155).

ENHANCED S-CONE SYNDROME

In 1990, Marmor et al. (156) reported eight patients with night blindness, maculopathy, and unusual but characteristic full-field ERG responses which represent increased responses of blue or short-wavelength sensitive cones (S cones), and this rare but distinct autosomal recessive retinal degeneration was named ‘‘enhanced S-cone syndrome.’’

Symptoms of night blindness, reduced visual acuity, and visual field disturbance usually occur within the first two decades of life, but symptoms and signs of this disorder show variable expressivity even within the same family (157). Visual acuity ranges from 20=20 to 20=200, and visual field ranges from full to central and mid-pheripheral ring scotomas. Retinal findings include cystoid maculopathy, yellow fleck-like lesions peripherally or near the vascular arcades, and gray or pigmentary degeneration (Fig. 8.6). Despite the early onset of this disorder, progression is usually slow (156,157).

Full-field ERG is a key test for diagnosing enhanced S-cone syndrome. The dark-adapted ERG shows no response to low-intensity stimuli that normally activate rods. With high-intensity stimuli that normally activate both rods and cones, the dark-adapted ERG demonstrates large, slow responses. The light-adapted ERG flash cone response also shows similar large, slow waveforms that are nearly identical to those elicited by scotopic high-intensity stimuli (Figs. 8.6 and 8.7). Under standardized clinical ERG conditions, the specific findings include: (1) a severely reduced or non-detect- able rod response to the scotopic dim flash, (2) a subnormal slow a-wave and a much reduced slow b-wave for both the scotopic bright-flash response and for the photopic flash cone response, (3) reduced oscillatory potentials, and (4) reduced photopic flicker responses. The ERG pattern of

Figure 8.7 Similar standard full-field ERG morphology of the scotopic combined rod–cone response and the photopic cone response in three patients with enhanced S cone syndrome demonstrating inter-individual variation.

increased S-cone sensitivity is not unique to enhanced S-cone syndrome but is also found in Goldmann–Favre syndrome (158). In the enhanced S-cone syndrome, EOG light-peak-to- dark-trough amplitude ratios are reduced (156).

The number of S-cone photoreceptors is increased in patients with enhanced S-cone syndrome. Hood et al. (159) using high intensity flashes and a cone photorecptor activation model (see Chapter 6) found large a-waves in response to blue and white flashes, which were driven almost entirely by photoreceptors containing S-cone pigment. These findings

Figure 8.6 (Facing page) Full-field ERG responses and retinal appearance in a 32-year-old woman with enhanced S-cone syndrome. Note the non-detectable rod response and the similar morphology of the tracings of the scotopic combined rod–cone response and the photopic cone response. Gray retinal atrophy with rare pigment clumping is evident particularly near the vascular arcades and in the mid-peripheral region. (Refer to the color insert.)