TABLE 1. Retinitis Pigmentosa and Some Allied Retinal Diseases

1. Autosomal dominant forms of retinitis pigmentosa
   
2. Autosomal recessive forms of retinitis pigmentosa
   
3. Sex-linked (X-chromosome-linked) forms of retinitis pigmentosa
   
4. Isolate (simplex) forms of retinitis pigmentosa
   
5. Progressive cone-rod degeneration
   
6. Atypical retinitis pigmentosa including sector, unilateral, and paravenous forms
   
7. Some syndromes or diseases of which retinitis pigmentosa is a part:
   1. Bassen-Kornzweig syndrome (abetalipoproteinemia)
      
   2. Refsum disease
      
   3. Friedreich-like ataxia with retinitis pigmentosa
      
   4. Usher syndrome: types I, II, and III
      
   5. Laurence-Moon-Bardet-Biedl syndrome
      
   6. Kearns-Sayre syndrome
      
   7. Hereditary cerebroretinal degenerations including Batten disease
      
   8. Olivopontocerebellar atrophy
      
   9. Alström disease
      
   10. Cockayne syndrome
       
   
   
8. Congenital amaurosis of Leber
   
9. Choroideremia
   
10. Gyrate atrophy of the choroid and retina
    
11. Retinitis punctata albescens
    
12. Stationary forms of night blindness
    

Most patients have no associated systemic disease and, therefore, are considered cases of nonsyndromic retinitis pigmentosa. A few cases have associated nonocular disease (i.e., syndromic retinitis pigmentosa). The most common syndromic form is Usher syndrome. About 15% of all cases of retinitis pigmentosa have an associated partial hearing loss (Usher syndrome, type II) and another 2% to 6% have associated profound congenital deafness and vestibular ataxia (Usher syndrome, type I).

Patients with retinitis pigmentosa characteristically report difficulty with adaptation and night blindness in adolescence. They lose midperipheral and then far peripheral visual field in adulthood. As their condition progresses, they develop tunnel vision and a tendency to blue blindness. Most have reductions in central vision between ages 50 and 80. Signs on ophthalmoscopic examination include attenuated retinal arterioles, waxy pallor of the optic discs, and intraretinal bone spicule pigment around the midperiphery^8–20 (Fig. 1). The bone spicule pigment is typically distributed 20 degrees to 40 degrees eccentric to the foveola in the zone where rods are normally in maximum concentration. Most show vitreous cells and a posterior vitreous detachment.¹⁴ Most patients develop posterior subcapsular cataracts in adulthood.²¹ An estimated 10% develop cystoid macular edema.^22,23 Refractive errors such as astigmatism and myopia are common.^24,25 Histologic studies of autopsy eyes have shown that loss of vision is due to degeneration of both rod and cone photoreceptor cells.^26–34

ELECTRORETINOGRAMS

In 1945 Karpe³⁵ reported that patients with advanced retinitis pigmentosa have very small or nondetectable (less than 10 μV) electroretinograms (ERGs). Subsequently it has been shown that patients with early retinitis pigmentosa can have reduced but easily detectable ERG responses.^36–39 Responses are not only reduced in size but are also delayed with respect to the time interval between stimulus flash onset and corresponding response peaks (i.e., b-wave implicit time).^38–42 These ERG changes can be detected in some instances many years before diagnostic abnormalities are visible on fundus examination.⁴¹

Figure 2 illustrates representative full-field ERGs from a normal subject and four children with early retinitis pigmentosa. Rod responses to single 0.5-Hz flashes of blue light (left column) are reduced and, when detectable, are delayed in b-wave implicit times. Cone responses to 30-Hz white flickering light (right column) are normal or reduced in amplitude and normal or delayed in b-wave implicit times. In most cases, cone b-wave implicit times are so delayed that a phase shift occurs between the stimulus flash onset (designated by the vertical lines) and the corresponding response peaks; each stimulus flash elicits the next-plus-one response in contrast to the normal. In mixed cone-rod responses to single 0.5-Hz flashes of white light (middle column), the cornea-negative a-wave generated by the photoreceptors is reduced in amplitude in all genetic types; this reflects the early involvement of the photoreceptors in this group of diseases.⁴¹

The reduced and delayed ERGs recorded from patients with widespread progressive forms of retinitis pigmentosa contrast with the reduced ERGs with normal b-wave implicit times observed in patients with self-limited sector retinitis pigmentosa. Figure 3 shows full-field ERGs from a father and son with dominantly inherited sector retinitis pigmentosa separated in age by almost 30 years; they have comparably reduced ERGs with normal b-wave implicit times. Patients with sector retinitis pigmentosa usually have patches of intraretinal pigment that are confined to one or two quadrants of the periphery of each fundus, with loss of peripheral rods and cones and consequent reductions in both rod and cone full-field ERG amplitudes. ERGs recorded from patients with sector retinitis pigmentosa are comparable to those recorded from patients who have large chorioretinal scars in the periphery.⁴¹

Full-field ERG testing can be used not only to identify which patients have widespread progressive forms of retinitis pigmentosa but also to determine which relatives are normal. Relatives of patients with retinitis pigmentosa, age 6 or older, with normal rod and cone ERG amplitudes and implicit times have not been observed to develop widespread progressive forms of retinitis pigmentosa at a later time.^41–43

CARRIERS OF X-LINKED RETINITIS PIGMENTOSA

Females with the carrier state of X-linked retinitis pigmentosa can present with an area of bone spicule pigmentation in the periphery or an abnormal tapetal reflex in the macula. Less than 50% of carriers of child-bearing age show diagnostic findings on ophthalmoscopic examination, whereas more than 90% have abnormal ERGs.⁴⁴ Abnormal ERGs in obligate carriers are either reduced in amplitude or delayed in cone b-wave implicit time, or both, in one or both eyes^44,45 (Fig. 4). Daughters of obligate carriers can have either normal ERGs or abnormal ERGs similar to those recorded from obligate carriers.⁴⁴

Female carriers of X-linked retinitis pigmentosa can have a slowly progressive retinal degeneration, although the natural course remains to be defined. Some female carriers have had considerable loss of visual field and substantial reductions in ERG amplitudes by age 70.⁴⁴

The abnormal ERGs of female carriers of X-linked retinitis pigmentosa contrast with the normal full-field ERG amplitudes and normal fundi observed in obligate female carriers of autosomal recessive disease.⁴⁴ Carriers of X-linked retinitis pigmentosa have a 50% chance of having an affected son and a 50% chance of having a carrier daughter with each childbirth.

NATURAL COURSE

The ERG provides a quantitative measure of remaining retinal function in patients with retinitis pigmentosa. Figure 5 illustrates ERGs from affected patients followed over a 10-year period; responses become smaller as the condition progresses. Responses less than 10 μV are nondetectable with conventional recording techniques (i.e., without signal averaging). Patients with nondetectable conventional ERGs can still retain considerable visual function because most are not legally blind until ERG amplitudes decline to 0.05 μV or less.

Signal averaging with a bipolar artifact reject buffer and narrow-bandpass filtering have extended the range of detectability of responses from affected patients 100-fold or more so that responses can be quantitated throughout almost the entire course of the disease. ERGs can now be recorded that are as low as 1 μV to 0.5-Hz flashes of white light (normal 350 μV) with signal averaging alone and, with bandpass filtering and signal averaging, as low as 0.05 μV to 30-Hz white flicker (normal equal to or greater than 50 μV). Full-field ERG function could be detected with at least one test criterion in 90% of an outpatient population with retinitis pigmentosa and a visual field diameter greater than 8 degrees. In an adult male with X-linked retinitis pigmentosa (whose ERGs could not be quantitated without signal averaging) computer-averaged ERGs show changes in ERG function over a 2-year period^46,47 (Fig. 6).

Among 94 patients, ages 6 to 49 years, with the common forms of retinitis pigmentosa, full-field ERGs declined significantly over a 3-year interval in 66 of 86 patients (77%), with detectable responses at baseline. Patients lost on average 16% of remaining full-field ERG amplitude per year to single flashes of white light (95% confidence limits, 13.1% to 18.6%) and 18.5% of remaining amplitude per year to 30-Hz white flicker (95% confidence limits, 15.1% to 21.5%). Patients lost on average 5.2% of remaining foveal cone ERG amplitude per year, indicating that loss of retinal function was primarily extrafoveal in these patients. They lost on average 4.6% of remaining visual field area per year in the Goldmann perimeter with a V-4_e white test light, whereas visual acuity and dark-adaptation thresholds remained relatively stable. Bone spicule pigment increased in 54% for whom comparisons could be make over a 3-year interval, suggesting that observation of increased pigmentation as a means of following this condition is not as sensitive as full-field ERG testing.⁴⁶

Caution must be exercised in applying these population ERG results to predict longitudinal patterns in individual patients, because standard deviations derived from standard errors have revealed considerable variation around the mean for these patients.⁴⁶ However, these results, describing the natural course on a quantitative basis, provide a frame of reference for planning interventions in similar populations to stabilize or slow the course of retinitis pigmentosa, particularly if monitored with full-field ERG testing.

MOLECULAR GENETIC STUDIES

Substantial genetic heterogeneity exists among patients with retinitis pigmentosa with abnormalities in over 25 genes identified as of 2001; an updated list is maintained on the RetNet site (http://www.sph.uth.tmc.edu/Retnet/sum-dis.htm). Genes so far identified as causes of nonsyndromic retinitis pigmentosa, as well as Usher syndrome, are given in Table 2.^48–87 Molecular genetic analyses have revealed defects in genes encoding proteins involved in the phototransduction cascade (Fig. 7), the retinoid cycle (Fig. 8), and structural components of photoreceptors, as well as in photoreceptor and retinal pigment epithelial proteins with unknown functions.

TABLE 2. Estimated Proportions of Cases of Retinitis Pigmentosa (RP) Caused by Identified Genes

Of the more than 25 genes so far found to be causes of retinitis pigmentosa, some are known to play a role in the phototransduction cascade in rod photoreceptors (e.g., rhodopsin, the α- and β-subunits of rod cyclic guanosine monophosphate-phosphodiesterase (cGMP-PDE), the α-subunit of the rod cGMP gated channel, and arrestin). Other genes are thought to encode structural proteins in the outer segments (peripherin/RDS and ROM1). Others are involved in the recycling of vitamin A (CRALBP, RPE65, LRAT, and ABCA4). Some genes encode transcription factors (NRL and NR2E3) or proteins involved in the escort of opsin from the inner to the outer segment (RPGR and TULP1). The more than 25 genes (see Table 2) account for about 50% to 60% of cases of retinitis pigmentosa in the United States.

It should be noted that defects in the same gene can result in different phenotypes; for example, most rhodopsin mutations lead to retinitis pigmentosa, but some cause stationary night blindness. Defects in the ABCA4 gene can result in juvenile macular degeneration or a generalized cone-rod degeneration. Some mutations in the USH2A gene lead to retinitis pigmentosa with partial hearing loss, whereas another mutation in the same gene results in only retinitis pigmentosa. Variable clinical expression can exist among patients with the same gene defect, suggesting that factors other than the gene defect itself (e.g., diet, environment, modifier genes) affect the course of the disease with possible implications for therapy.

TREATMENT TRIALS

Many treatments have been attempted for the common forms of retinitis pigmentosa including various vitamins and minerals, vasodilators, tissue therapy with placental extract, cortisone, cervical sympathectomy, injections of a hydrolysate of yeast ribonucleic acid (RNA), ultrasound, transfer factor, dimethyl sulfoxide (DMSO), ozone, muscle transplants, and subretinal injections of fetal retinal cells.^88–95 None of these has been shown to have proven therapeutic benefit. A study of patients evaluated before and after receiving electric stimulation, autotransfused ozonated blood, and ocular surgery in Cuba showed that this intervention provided no benefit and raised the possibility that this intervention was aggravating the course of the disease.⁹⁵ None of these attempts at treatment was conducted with a randomized, controlled, double-masked protocol, which is necessary to avoid possible patient or examiner biases. Most of these studies were performed without electroretinographic data as an end point for evaluating efficacy, so that the amount of remaining retinal function could not be quantitated in an objective manner.

Claims of success with one or another treatment for patients with retinitis pigmentosa that are based solely on subjective reporting of improved visual function are to be interpreted with caution. Spontaneous fluctuations in visual acuity and visual field are well known in this condition. Given the slow course of retinitis pigmentosa without treatment, it will usually require several years to assess whether or not any proposed treatment has an effect on stabilizing or slowing the course of the disease. The problem of assessing treatments may be further complicated by the genetic heterogeneity of this condition and the stage of disease at which treatment is initiated.

The common forms of retinitis pigmentosa have now yielded to treatment. In a randomized, controlled, double-masked trial among 601 patients ages 18 to 49, the course of retinal degeneration as monitored by the ERG was slower on average among patients taking a daily supplement of vitamin A palmitate, 15,000 IU/day, than among those not on this dose. Furthermore, the course appeared to be faster on average among patients taking a daily supplement of 400 IU/day of vitamin E than those not on this dose.⁹⁶ Among a subset of 125 patients who could perform visual field testing with great precision, those on vitamin A showed a slower rate of decline of visual field than those in the control group.⁹⁷ The optimal total intake of vitamin A palmitate in this study population appeared to be approximately 18,000 IU/day (i.e., 3000 IU of vitamin A in a regular diet and 15,000 IU/day of vitamin A as a supplement); higher intake did not provide greater benefit (Fig. 9). These findings have led to the recommendation that most adult patients with the common forms of retinitis pigmentosa should take a daily supplement of 15,000 IU of vitamin A in the palmitate form under the supervision of their ophthalmologist and avoid high-dose supplementation with vitamin E. For the average patient in the trial, it has been estimated that treatment with vitamin A could add 7 additional years of useful vision⁹⁶; that is, the average patient with 1.3 μV of cone function who starts vitamin A at age 32 would retain useful vision until age 70 rather than age 63 if left untreated. For some patients with larger pretreatment ERGs, vitamin A supplementation could make the difference whereby these patients retain some vision for their entire lives.

Vitamin A may provide its benefit through the rescue of remaining cones, thereby, explaining how one supplement can help patients with many different rod-specific gene defects. The daily intake of a vitamin A supplement may provide protection against possible transient decreases in serum retinol concentrations that may adversely affect photoreceptor function. With respect to vitamin E, it has been hypothesized that a daily dose of 400 IU may adversely affect the course of retinitis pigmentosa at least in part by inhibiting the absorption or transport of vitamin A, because it was observed that the patients receiving vitamin E had slight but significant decreases in serum retinol concentration compared with those not receiving vitamin E.⁹⁶

Because doses greater than 25,000 IU/day of preformed vitamin A can be associated with liver disease when taken over the long term, patients should have a fasting serum vitamin A and liver function profile before starting this treatment and annually thereafter while on this treatment. Beta-carotene is not predictably converted to preformed vitamin A and, therefore, should not be considered as a substitute for treatment with vitamin A palmitate. Because of the risk of birth defects associated with high-dose vitamin A supplementation, women who are pregnant or planning to become pregnant should not take this supplement. Because patients younger than age 18 were not included in this study, no formal recommendation can be made for patients with retinitis pigmentosa younger than this age.^96,97 No toxic side effects have been observed in adults with retinitis pigmentosa in good general health on this dose of vitamin A who have been followed for up to 12 years.⁹⁸

RETINITIS PIGMENTOSA ASSOCIATED WITH HEREDITARY ABETALIPOPROTEINEMIA

In 1950 Bassen and Kornzweig described an 18-year-old girl, born of first cousins, who had a malabsorption syndrome, a generalized retinal degeneration, a diffuse neuromuscular disease similar to Friedreich's ataxia, and a peculiar crenation of the red blood cells, now called acanthocytosis.^99–101 In 1958 low serum cholesterol (less than 50 mg per dl) was observed.¹⁰² Soon thereafter, an absence of low-density plasma lipoproteins or so-called β-lipoproteins was found, and the term abetalipoproteinemia was assigned to this recessively inherited disorder.^103–105 Other classes of lipoproteins have also been found to be abnormal.¹⁰⁶

Patients with hereditary abetalipoproteinemia can assimilate fat into the intestinal mucosa, but a defect exists in its removal from this site because of the lack of chylomicra. Intestinal biopsies have revealed normal-sized villi filled with lipid droplets that are essentially triglycerides. Mutations in the gene encoding a microsomal triglyceride transfer protein have been found in patients with this condition.¹⁰⁷ It appears that the liver and then the retina become depleted of vitamin A. Abnormal ERGs have been reported in a 15-month-old child¹⁰⁸ and a 6-year-old patient¹⁰⁹ in whom the fundi were still normal. The original case described by Bassen and Kornzweig showed multiple white dots in the early stages, but by age 31, the patient developed multiple areas of pigment epithelial cell atrophy. In other cases, the typical intraretinal pigment associated with retinitis pigmentosa has been noted in the retinal periphery.

Patients with this condition are treated with a low-fat diet and supplements of the fat-soluble vitamins A, E, and K. Vitamin A supplementation has been shown to restore elevated dark-adaptation thresholds and reduced ERG responses to normal in patients with the early stages^110,111 (Fig. 10). More advanced cases have not responded, but in one such case in which the retina was examined after the death of the patient, widespread loss of photoreceptor cells was observed.¹¹² Vitamin A therapy may not maintain retinal function over the long term, because patients have been reported in whom vitamin A levels have been restored to normal and yet the retinal degeneration has appeared to progress.^113,114 Because these patients have low serum vitamin E levels, supplementation with vitamin E in addition to vitamin A has been advocated with reported stabilization of retinal function.^115-19

RETINITIS PIGMENTOSA ASSOCIATED WITH REFSUM DISEASE

Refsum disease is a recessively inherited condition in which the patient accumulates exogenous phytanic acid.^120,121 Findings include a peripheral neuropathy, ataxia, an increase in cerebrospinal fluid protein with a normal cell count, and retinitis pigmentosa. All have elevated serum phytanic acid. Some cases have anosmia, neurogenic impairment of hearing, electrocardiogram (EKG) abnormalities, and skin changes resembling ichthyosis. Patients show a granular fundus with areas of depigmentation around the periphery and have a subnormal ERG in the early stages or show more typical retinitis pigmentosa with a nondetectable ERG in more advances stages.¹²²

A defect exists in the conversion of phytanic acid to alpha-hydroxy phytanic acid, specifically in the introduction of a hydroxyl group on the alpha carbon of phytanic acid¹²³ (Fig. 11). The pathogenesis appears to involve accumulation of phytanic acid in a variety of tissues including the retinal pigment epithelium (RPE).¹²⁴

Treatment consists of restricting not only animal fats and milk products (i.e., foods that contain phytanic acid) but also green leafy vegetables containing phytol.¹²⁵ Success of treatment depends on the patient maintaining his or her body weight; if body weight becomes reduced, phytanic acid is released from tissue stores, resulting in an increase of phytanic acid in serum and exacerbation of symptoms. Refsum¹²⁶ has reported two patients whose serum phytanic acid levels were lowered to normal and who showed improvement in motor nerve conduction velocity, some relief of ataxia, and return of the cerebrospinal fluid protein to normal. Moreover, the retinitis pigmentosa and hearing impairment did not progress; one of these patients was followed for 10 years and the other for many years. One young adult with a mild form of this disorder has been followed on a low-phytol, low-phytanic acid diet for 4 years; full-field ERGs, reduced about 75% below normal before commencement of this diet, have remained about the same over this period⁴² (Fig. 12). Long-term effects of this diet on retinal function continue to be studied.

FREIDREICH-LIKE ATAXIA WITH RETINITIS PIGMENTOSA

Another rare recessively inherited form of ataxia associated with retinitis pigmentosa has recently been described. These patients present in adulthood with Friedreich-like ataxia, dysarthria, hyporeflexia, and decreased proprioceptive and vibratory sensation, as well as markedly decreased serum vitamin E levels. In later stages, patients can develop the fundus changes of retinitis pigmentosa and abnormal ERGs. Molecular genetic analysis has revealed a mutation in the α-tocopherol-transfer protein (α-TTP) gene. Oral administration of vitamin E restored serum vitamin E levels to normal and appeared to halt or slow the progression of the neurologic abnormalities and retinitis pigmentosa in three patients followed for 1, 4, and 10 years, respectively.^127,128

USHER SYNDROME

About 15% to 20% of affected individuals with retinitis pigmentosa have associated hearing loss, sometimes referred to as Usher syndrome in recognition of the British ophthalmologist, C.H. Usher, who emphasized that this condition was recessively inherited.^129,130 Patients with Usher syndrome type I typically have night blindness in the first or second decade, profound congenital deafness (i.e., greater than 70 dB loss of all frequencies) with unintelligible speech, and vestibular ataxia, whereas those with Usher syndrome type II usually report night blindness in the second to fourth decade, have a partial early onset hearing loss with intelligible speech, and do not show ataxia.¹³¹ Patients with Usher syndrome type II have been shown to have abnormalities in the cilia of sperm and abnormalities in the connecting cilia in many remaining photoreceptors in autopsy eyes.^132,133 Patients with Usher syndrome type III have onset of hearing loss in midadulthood that can progress to profound deafness; some have vestibular ataxia.^84,134

Molecular genetic analyses have revealed gene loci for Usher syndrome type I (further subdivided as types A-F), for Usher syndrome type II (further subdivided as types A-C), and for Usher syndrome type III. Patients with Usher syndrome type IB have mutations in a long-tailed, unconventional myosin designated as myosin VIIA.¹³⁵ It has been estimated that mutations in the MYO7A gene on chromosome 11q account for approximately 75% of cases of Usher syndrome type I.¹³⁶ Patients with Usher syndrome type IIA have been found to have mutations in the USH2A gene on chromosome 1q.¹³⁷ This gene normally encodes a protein called usherin that has several laminin epidermal growth factor-like and fibronectin type III motifs; it is possibly involved in cell adhesion to Bruch's membrane. It has been estimated that mutations in the USH2A gene account for about 85% of cases of Usher syndrome type II.¹³⁷ Some patients have been identified with autosomal recessive retinitis pigmentosa without hearing loss who have a mutation in the USH2A gene, Cys759Phe.¹³⁸ Mutations in the USH3 gene on chromosome 3q have been identified in a population from Finland and Italy.⁸⁴ The frequency of Usher syndrome type III in the United States is unknown.

About 2% to 6% of congenitally deaf children will develop Usher syndrome type I. If a child presents with profound deafness and a balance disorder manifested by late onset of walking usually after 15 months of age, the possibility of Usher syndrome type I should be considered.¹³⁹ The diagnosis of retinitis pigmentosa as part of Usher syndrome can be made in early life with ERG testing. No tests of retinal function are yet available to identify carriers of Usher syndrome.

Patients with Usher syndrome appear to have a slowly progressive retinal degeneration. Rates of progression on a year-to-year basis remain to be defined. Patients with Usher syndrome type II may reasonably be treated with vitamin A palmitate 15,000 IU per day because these patients were included among those with autosomal recessive retinitis pigmentosa in a clinical trial of vitamin A for retinitis pigmentosa.⁹⁶

LAURENCE-MOON-BARDET-BIEDL SYNDROME

The Laurence-Moon-Bardet-Biedl syndrome includes retinitis pigmentosa, mental retardation, polydactylism, truncal obesity, and hypogonadism as the most frequent features.^140–147 Some authors have subdivided this syndrome into two disorders: polydactylism is found primarily in patients with the Bardet-Biedl form, whereas neurologic findings are found primarily in patients with the Laurence-Moon form.^148,149 However, some patients have been described with both polydactylism and neurologic abnormalities and, therefore, would seem to qualify for inclusion in both syndromes.^150,151 Variability of clinical expression is well known, and some patients may have this condition without mental retardation or polydactylism.^152–156 Genetic heterogeneity exists as the condition has been linked to six distinct loci. Renal disease can be a part of this syndrome,¹⁵⁷ and, therefore, patients should have their blood pressure and urine checked periodically, with appropriate treatment instituted for their hypertension and renal disease if detected.

Retinal degeneration is the most common feature of the Laurence-Moon-Bardet-Biedl syndrome, occurring in about 90% of cases.¹⁵⁷ The macula is often involved early in this condition. The fundus in early life may be granular without pigment formation, so that the diagnosis is only established after electroretinographic testing.¹⁵⁸ A child born with polydactylism to normal parents should be a suspect for this syndrome. Once this syndrome is identified in one individual, parents would know that they have a 25% chance with each succeeding childbirth of having another child with this condition. In some, presumably rare, instances a second abnormal gene locus is required and the chance of having a second affected child may be less than 25%.¹⁵⁹ No treatment is known for the retinal degeneration that occurs as part of this syndrome.

CONGENITAL AMAUROSIS OF LEBER

Congenital amaurosis of Leber is usually an autosomal recessive disorder associated with severe reduction in vision near birth and very reduced ERGs.^160–165 Patients characteristically have hyperopia and nystagmus, and fundus examination reveals granularity, white flecks, or intraretinal bone spicule pigment or some combination. When recessively inherited, parents would know that they have a 25% chance with each succeeding childbirth of having a child with this condition. Retardation of mental development has been reported in some patients, possibly secondary to visual impairment.¹⁶⁴ Leber congenital amaurosis can occur in patients with a de novo mutation not present in the affected patient's parents; in this dominant form, the chance of having an affected child is 50%, possibly lower if the affected patient is a mosaic.¹⁶⁶ Leber congenital amaurosis involving the retina and pigment epithelium should not be confused with Leber optic atrophy, a maternally inherited condition involving the optic nerve associated in some families with an abnormality in mitochondrial deoxyribonucleic acid (DNA).^167,168

In 8 of 15 families with one form of this condition studied, mutations in the guanylate cyclase gene on chromosome 17p have been identified, suggesting that cGMP production in photoreceptors is abolished in this form. Consequently, photoreceptor excitation would be expected to be impaired due to closure of cGMP-gated cation channels with hyperpolarization of the plasma membrane. It has been proposed that the cGMP concentration in photoreceptor cells cannot be restored to the dark level, leading to a situation equivalent to constant light exposure during photoreceptor development.¹⁶⁹ A model for this disease exists in the rd/rd chicken, which is functionally blind at hatching with an extinguished ERG, absent guanylate cyclase activity, and a mutation in the guanylate cyclase gene.^170,171 Mutations in another gene, designated as RPE65, which is involved in the vitamin A cycle via the isomerase in the RPE, account for about 16% of cases of Leber congenital amaurosis in the United States;^172,173 mutations in this gene are also a cause of about 2% of cases of autosomal recessive retinitis pigmentosa.¹⁷³ Other genes found to be abnormal in Leber congenital amaurosis are cone-rod homeobox-containing gene (CRX), aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1), tubby-like protein 1 (TULP1), homologous to crumbs protein in Drosophila (CRB1), and retinitis pigmentosa GTPase regulator interacting protein 1 (RPGRIP1). TULP1 encodes a protein thought to play a role in the escort of proteins in the inner segment. RPGRIP1 encodes a protein normally found in the photoreceptor connecting cilium; defects in this protein may interfere with transport of proteins from the inner to the outer segment. The functions of the proteins encoded by the other abnormal genes are not as well understood.

OTHER FORMS OF RETINITIS PIGMENTOSA

Mutations in the CRB1 gene⁷⁷ have been observed in an unusual recessively inherited form of retinitis pigmentosa called preserved para-arteriolar retinal pigment epithelium (PPRPE). Like patients with typical Leber congenital amaurosis, these patients are highly hypermetropic. The condition is named for the relative preservation of the RPE adjacent to and underlying retinal arterioles in earlier stages; in later stages the RPE previously spared is lost. The degeneration associated with this condition appears to be rapidly progressive.¹⁷⁴

Retinitis punctata albescens can be associated with some signs and symptoms characteristic of retinitis pigmentosa.¹⁷⁵ Patients usually present with profound adaptational problems and gradual loss of peripheral vision. Examination with a direct ophthalmoscope reveals multiple punctate white deposits in the macula and around the midperiphery at the level of the pigment epithelium for which this condition was named. Patients have retinal arteriolar attenuation and some develop round areas of atrophy of the RPE in the midperiphery, as well as intraretinal bone spicule pigment in the midperiphery. This raises the possibility that this condition is a variant of retinitis pigmentosa.^176,177 This form of retinal degeneration may affect the eyes of a patient asymmetrically; often these patients receive a neurologic evaluation in search of an intracranial abnormality before it is realized that the visual loss is due to a widespread retinal degeneration. Full-field ERGs of such patients are invariably abnormal with reductions in amplitude and delays in implicit times. The condition is usually slowly progressive, although the course appears to vary from one individual to another. This condition has been thought to be inherited by an autosomal recessive mode, but a dominant mode of transmission can occur; therefore, ERG testing of relatives of affected patients is recommended to help establish the mode of transmission. A null mutation in the peripherin/RDS gene has been reported in one family with this condition with a dominant mode of transmission;¹⁷⁸ other families with an autosomal recessive mode of transmission have shown mutations in the cellular retinaldehyde binding protein (CRALBP) gene.¹⁷⁹

Another atypical form of retinitis pigmentosa is designated as progressive cone-rod degeneration.^156,180 Patients with this form typically present with reduced visual acuity, photophobia, color deficiency, and night deficiency and show signs of macular degeneration, retinal arteriolar attenuation, and, in some cases, intraretinal bone spicule pigment in the peripheral fundus. Dark-adaptation testing shows elevated final dark-adaptation thresholds across the fundus, whereas full-field ERGs show a profound loss of cone function and some reduction in rod function across the retina. Patients with the earlier stages of cone-rod degeneration typically have rod ERGs that are more than 30 times larger than cone ERGs. The condition is usually inherited by an autosomal recessive mode but can also be inherited by an autosomal dominant mode. Mutations have been found in the retina-specific ATP-binding cassette transporter (ABCA4) gene,¹⁸¹ the same gene that has been found to be abnormal in patients with juvenile macular degeneration (Stargardt) disease. No treatment is know for patients with cone-rod degeneration.

Other unusual forms of retinitis pigmentosa include those designated as paravenous or unilateral. The paravenous form is usually characterized by slightly reduced full-field ERGs with normal implicit times and intraretinal pigment and atrophy of the pigment epithelium confined to the distribution of the retinal veins in each eye. Unilateral retinitis pigmentosa is characterized by fundus changes of retinitis pigmentosa in one eye with no evidence of retinal degeneration in the other eye. Full-field ERGs are substantially reduced in the affected eye and normal in the fellow eye. Patients with unilateral retinitis pigmentosa do not develop retinitis pigmentosa in the fellow eye at a later time. In my experience, patients with either paravenous or unilateral disease have presented with a negative family history for retinal degeneration, suggesting that these forms of retinitis pigmentosa are not inherited.

Female carriers of this disease^186,187 may demonstrate fundus changes that include patchy depigmentation of the RPE and coarse pigment granularity or even pigment clumps in the periphery. However, carriers typically retain normal visual acuities and normal final dark-adapted rod thresholds.^187,188 Generally carriers have been thought to have a nonprogressive course,¹⁸⁹ but carriers with severe disease have been described.^190,191 In contrast to the carrier state of X-linked retinitis pigmentosa, ERGs of carriers of choroideremia usually are normal,^184,185,190 although reduced amplitudes have been reported in some cases.^183,185,192

The gene responsible for this condition, RAB escort protein 1 (REP-I), was identified in 1990.¹⁹³ Many mutations in this gene have been described subsequently.^194,195 It has been proposed that loss of the REP protein results in defects in RAB protein prenylation; the lack of prenylation in turn is thought to affect protein trafficking inside the RPE or choroidal cells triggering the degenerative process in this condition.^196–198

Interfamilial and intrafamilial variability of clinical expression is known to exist in this disease. The natural course of choroideremia on a year-to-year basis remains to be defined. Correlations, if any, between specific gene defects and clinical expression of the disease remain to be found. No treatment is known.

Patients have plasma ornithine concentrations elevated ten- to twenty-fold^207,208 because of a deficiency of ornithine-ketoacid-amino-transferase (OAT) activity (Fig. 16).^209–211 Affected individuals cannot convert ornithine to pyrroline-5-carboxylic acid (PCA); this deficiency can be detected in extracts of cultured skin fibroblasts. Patients have virtually no OAT activity, and carrier parents have a partial deficiency. Plasma lysine²¹² and glutamate and glutamine,²¹³ as well as serum and urine creatine,²¹⁴ have also been found to be reduced. More than 60 mutations have been discovered in the OAT gene on chromosome 10 in affected patients.^215–218

Because arginine is a precursor of ornithine and because arginine, but not ornithine, is a constituent of food protein, it has been suggested that dietary restriction of protein and arginine will reduce plasma ornithine levels in these patients.²¹⁹ OAT-deficient mice produced by gene targeting develop a retinal degeneration over several months that is amenable to treatment postweaning with an arginine-restricted diet.^220,221

The hyperornithinemia associated with human disease has been lowered toward normal with a low-protein, low-arginine diet in all cases so far studied^{219,222–225} and with vitamin B₆ (300 to 500 mg/day) in some cases.^205,226,227 However, extreme protein restriction (10 to 15 g/day) under supervision in the hospital has been difficult to achieve at home and therefore many patients have followed modified (20 to 35 g/day) protein restriction resulting in a slight decrease in their plasma ornithine levels. Some investigators have reported improvements in visual acuity, visual fields, dark-adaptation thresholds, and/or ERGs in patients with gyrate atrophy after onset of either the diet or vitamin B₆,^{223,225,228–230} whereas others have not documented any significant improvement in visual function despite substantial reductions in plasma ornithine concentrations.^224,231 Improvement in muscle morphology following creatine supplementation has been observed in several patients.²³²

Kaiser-Kupfer and coworkers²³³ have reported results of severe arginine restriction of two pairs of siblings younger than 10 years who were followed for 5 to 7 years. The plasma ornithine levels were reduced to approximately the normal range (106 and 121 μmol/L) in one pair of siblings and were twice the upper limit of normal (251 and 313 μmol/L) in the other pair. These younger siblings had significantly less atrophy than their elder siblings when they reached or approached the same age at which their elders began the diet. Thus, there is evidence that a low-protein, low-arginine diet can slow progression of the chorioretinal degeneration, but only a small number of patients have so far been studied.

The goal of treatment is to maintain plasma ornithine levels as close to normal as possible. Because some patients may respond to supplementation with pyridoxine (vitamin B₆), all patients are initially given a trial of this vitamin to determine to what extent, if any, it will lower plasma ornithine levels. Both pyridoxine-responsive and nonresponsive patients are then placed on a low-protein, low-arginine diet. Biochemical control has been classified as good to excellent (less than 200 μmol/L), fair (200 to 400 μmol/L), and poor (greater than 400 μmol/L). In the management of children, expertise is required to be certain that growth and development remain normal while lowering ornithine levels with a low-protein diet. An arginine-free essential amino acid mixture [for example, Cyclinex™—1 or Cyclinex™—2 (Ross Laboratories), depending on the patient's age] is used to provide sufficient nitrogen and meet essential amino acid requirements. In adults, a low-protein diet is also likely to result in amino acid deficiency. Thus, adults should also be placed on an arginine-free essential amino acid mixture. Lysine supplementation may be necessary, depending on plasma levels. As a precaution, all patients are placed on a multivitamin preparation with minerals. In addition to a regular ocular examination, all patients on this treatment regimen should have their serum amino acid and protein levels monitored periodically.²³⁴

Patients who present with a widespread loss of photoreceptor function with abnormal ERGs and symptoms of cerebral deterioration may have a cerebroretinal degeneration, grouped under the overall heading of neuronal-ceroid lipofuscinosis, or Batten disease. These diseases, which are recessively inherited, are characterized by accumulation of lipopigments (lipofuscin and ceroid) in neurons and other cell types. Batten disease can be subdivided into an infantile form (psychomotor deterioration by age 2, ataxia, microcephaly, granular inclusions on conjunctival biopsy), a late-infantile form (seizures, rapid mental deterioration in early childhood, curvilinear inclusions on conjunctival biopsy), a juvenile form (mental deterioration beginning around age 6, bull's eye maculopathy, fingerprint inclusions on conjunctival biopsy), and an adult-onset form (seizures, slow dementia, abnormal inclusions best seen on muscle biopsy).

Molecular genetic studies have revealed that the juvenile onset form of Batten disease results from defects in the CLN3 gene on chromosome 16p; most patients have a 1.2 kb deletion in this gene on at least one chromosome.²³⁹ The gene encodes a novel protein of unknown function. The mechanism of apoptosis appears to be involved in the demise of both cerebral neurons and photoreceptors.²⁴⁰ No treatment exists for the retinal degeneration associated with this condition.

Patients with olivopontocerebellar atrophy (more recently designated as SCA7, a form of spinocerebellar ataxia) can present with a history of tremors, ataxia, and dysarthria and show findings of oculomotor impairment and retinal degeneration. This condition is inherited by a dominant mode with variable penetrance. Some patients have retinal arteriolar attenuation, a diffuse disturbance of the RPE, and very reduced ERGs. Some patients may show only neurologic findings and have normal fundi and normal retinal function, whereas others have had abnormal ERGs with no diagnostic findings on fundus examination and no history of neurologic disease.^241,242 Patients with this condition have been found to have expansions of CAG trinucleotide repeats on DNA analysis.²⁴³

Other rare syndromes associated with retinal degeneration include Alström disease and Cockayne syndrome. Patients with Alström disease have retinitis pigmentosa with profound loss of vision in the first decade and very reduced ERGs. Systemic findings include diabetes mellitus, obesity, deafness, renal failure, baldness, and hypogenitalism.^244,245 Patients with Cockayne syndrome show extensive loss of vision by the second decade and have retinitis pigmentosa, dwarfism, deafness, mental deterioration, and premature aging.²⁴⁶ No treatments are known for these conditions.

The previous classification of these diseases was based on the family of origin (e.g., Nougaret type), by the original description of the ERG waveforms associated with the condition (e.g., Riggs type or Schubert-Bornschein), or by the ophthalmologist who first described the disease (e.g., Oguchi disease). These diseases are now being reclassified by molecular genetic analysis.²⁴⁷

Missense mutations in three different genes encoding members of the rod phototransduction cascade have been reported to cause dominantly inherited stationary night blindness. Specifically, the mutations are the Ala292Glu and Gly90Asp mutations in rhodopsin,^248,249 the His258Asp mutation in the β-subunit of rod phosphodiesterase,²⁵⁰ and the Gly38Asp mutation in the α-subunit of rod transducin.²⁵¹ The latter mutation has only been seen in the descendants of Jean Nougaret. Although the Ala292Gly rhodopsin mutation apparently causes a complete loss of rod function (i.e., Riggs type),²⁴⁸ the other mutations cause an incomplete loss of rod function.^251,252

Some evidence exists from psychophysical and ERG testing that the rods are constitutively active in the dark in some forms of stationary night blindness. This has been suggested for patients with the rhodopsin, Gly90Asp mutation.²⁴⁹ The ERG abnormalities in patients with the Gly38Asp mutation in the α-subunit of rod transducin can be simulated by light adapting the normal retina, compatible with the idea that these patients have mutant rod transducin that is constitutively active in the dark.²⁵² Further evidence that these patients have rod photoreceptors despite their night blindness is provided by fundus reflectometry studies that have shown normal levels of rhodopsin and normal rhodopsin kinetics.²⁵³

Oguchi disease is a recessively inherited form of stationary night blindness. Following 1 hour of dark adaptation, patients with Oguchi disease have no rod b-wave in response to dim blue light flashes, a cornea-negative response to white light, and a normal cone response to 30-Hz white flicker. Following complete dark adaptation after 12 hours, some patients have a normal rod b-wave amplitude and normal rod b-wave implicit time but only in response to one or two flashes of light.²⁵⁴ Apparently the test flash used to elicit the ERG, although relatively dim, can be intense enough to light adapt the rod system. Molecular genetic analyses have shown a null mutation, Asn309(1-bp del), in the gene encoding arrestin in some patients of Japanese descent.²⁵⁵ Several null mutations have also been described in the gene encoding rhodopsin kinase in some patients of Eastern European descent.²⁵⁶ Both arrestin and rhodopsin kinase participate in the deactivation of photoactivated rhodopsin. The lack of either arrestin or rhodopsin kinase would be expected to have the same physiologic effect, namely the prolongation of photoactivated rhodopsin with a consequent abnormality in rod sensitivity.

Fundus albipunctatus is another form of recessively inherited stationary night blindness.^257,258 Patients with fundus albipunctatus have a delay in rod visual pigment and foveal cone pigment regeneration, as monitored with fundus reflectometry.²⁵⁷ Changes in visual pigment levels parallel the prolonged cone and rod limbs of the dark-adaptation curve. Full-field ERGs have been found to be normal with respect to both cone and rod amplitudes and b-wave implicit times after full dark adaptation.²⁵⁸ The findings in fundus albipunctatus suggest an abnormality in visual pigment regeneration secondary to some abnormality in the relationship between the photoreceptors and the pigment epithelium. The composition of the yellow-white lesions and their relationship to the abnormality in visual pigment regeneration are not known. Patients with this condition have been observed to have defects in the gene encoding 11-cis retinol dehydrogenase.²⁵⁹

A form of stationary night blindness for which the precise gene defect remains unknown is congenital nyctalopia with myopia. This condition (i.e., Schubert-Bornschein type) is inherited by either an X-linked or autosomal recessive mode.^260–262 The extent of the myopia is characteristically -3.5 to -14.5 diopters (D). Patients cannot attain normal dark-adapted rod thresholds and have fundus findings of myopia. Their rod ERG b-wave responses to dim blue light are nondetectable, and the patients have a characteristic cornea-negative response to white light in the dark-adapted state and normal or nearly normal cone responses to 30-Hz white flicker. The preservation of the a-wave from the rod photoreceptors with loss of the b-wave from neurons proximal to the photoreceptors suggests some abnormality in intraretinal transmission of the response from the rod photoreceptors to proximal retinal cells. ERG amplitudes are reduced in congenital nyctalopia with myopia compared with those from normal emmetropes; this probably occurs because of the known reductions of ERG amplitude seen in patients with moderate axial myopia as the only finding.²⁶³

The ERG abnormality in congenital nyctalopia with myopia has been reported as an acquired defect in patients with cutaneous malignant melanoma, who have an acute onset of night blindness with selective reduction in the rod b-wave response²⁶⁴ (Fig. 18). Development of an antibody to the melanoma that also reacts to retinal cells with an interruption in rod signal transmission has been considered as a probable mechanism to account for the sudden onset of night blindness in patients with this paraneoplastic retinopathy.

Patients with congenital nyctalopia have been further subdivided into two groups designated as the complete or incomplete form of the condition based on dark-adaptation measures and ERG amplitudes. In the complete form, the rod a-wave is normal, whereas the rod b-wave is absent and responses are mediated by the cone system. In the incomplete form, rod ERG responses, although reduced in amplitude, are still measurable to dim blue light, and the cone ERG is also subnormal. Although patients with the complete form have moderate or high myopia, those with the incomplete form are thought to have mild myopia or slight hyperopia.²⁶⁵ Whereas the gene for the complete form remains unknown, a gene that encodes for a subunit of an L-type voltage-gated calcium channel has been found to be mutated in the incomplete form.²⁶⁶ The long-term course of patients with the incomplete form remains to be established.

It is of interest that stationary forms of night blindness, with impairment of rod photoreceptor function but no evidence of rod photoreceptor cell death, are not associated with pigment migration or attenuation of the retinal vessels, whereas these latter findings are characteristically seen in patients with rod photoreceptor cell degeneration and retinitis pigmentosa.²⁶⁷ Although stationary forms of night blindness are rare, it is important to identify these conditions when patients present with night blindness on a retinal basis, because the long-term prognosis in these patients is good, in contrast to the progressive disease seen in patients with night blindness associated with retinitis pigmentosa.

The medical history should include information on operations and illnesses, as well as current medications and nutritional supplements. Intestinal resection, pancreatic disease, or liver disease may have affected absorption and/or metabolism of vitamin A. Chronic intake of some medications (e.g., hydroxychloroquine, phenothiazines, etc.) may have compromised retinal function. A history should also include questions regarding hearing capability, because about 15% of patients with retinitis pigmentosa have a high-tone partial hearing loss, and about 5% have profound congenital deafness. A history of polydactylism, mental retardation, or renal disease raises the possibility of an associated retinal degeneration. A detailed family history is helpful to determine if other family members are affected with retinal degeneration and whether consanguinity exists in the parents, because this raises the likelihood of a hereditary disease.

The ocular examination should include a refraction because approximately 50% of patients with retinitis pigmentosa have 1 or more diopters of astigmatism in the less astigmatic eye.²⁵ Uncorrected myopia can result in night blindness; therefore, it is important to confirm whether the patient has the correct prescription. Reading vision should be tested and lenses prescribed as needed so that the patient can read at least 8-point print. A visual field should then be performed with either the Goldmann perimeter or the Humphrey Field Analyzer. We recommend testing with both a small (e.g., I-4-e or II-4-e) and large (e.g., IV-4-e or V-4-e) white test light if the Goldmann perimeter is used, because many patients will not have sufficient function to detect the small light over years of follow-up; in this case, the large test light will be the basis for future comparisons. If the Humphrey Field Analyzer is used, we advise use of the size III or size V target using both the 30-2 and 60-2 programs to assess the central and the midperipheral visual fields; again, use of the larger test light insures that data is available for long-term comparisons. Tests of color vision should then be performed, preferably without dilation and under standard lighting conditions. In our experience, the Farnsworth panel D15 and the Ishihara plates are useful for initial screening for red and green color deficiencies; a tritan axis of confusion (i.e., acquired blue blindness) can occur in patients with retinitis pigmentosa as the condition becomes more advanced. Following these tests, applanation pressures are measured; elevated pressures (greater than 35 mm Hg) can result in diminished ERG amplitudes and must be borne in mind when interpreting the ERG as a measure of remaining retinal function.

Pupils are then maximally dilated with phenylephrine hydrochloride and cyclopentolate hydrochloride and the patient patched. After 30 to 45 minutes of dark adaptation, final dark-adaptation thresholds are measured, usually with an 11-degree white test light in the Goldmann-Weekers dark adaptometer, to determine whether the patient has impaired final rod thresholds. Several regions should be assessed to determine whether elevated rod thresholds, if present, are generalized or confined to a portion of the retina (as in sector retinitis pigmentosa). After dark-adaptation testing, full-field ERG testing can be performed. If ERG responses are detected without computer averaging, the test can be accomplished within 10 to 15 minutes per eye; if computer averaging is required, the test may take 20 to 30 minutes per eye. This sequence of evaluations helps to insure that the patients have their dark-adaptation and ERG testing before more extensive light exposure associated with ophthalmoscopy that might light adapt the patient and, thereby, affect the dark-adaptation and ERG measurements.

After dark-adaptation and ERG testing, patients are examined with pupils fully dilated, at which time the refractive error can be confirmed by retinoscopy and glasses modified as required. Slit lamp examination and direct and indirect ophthalmoscopy are performed; fine retinal deposits (e.g., those seen in retinitis punctata albescens) and slight retinal arteriolar attenuation may be appreciated with direct but not indirect ophthalmoscopy. If cataracts are present, a retinal acuity can be obtained using a retinal potential acuity meter or equivalent instrument to compare retinal acuity with distance acuity.

When X-linked disease is suspected, the patient's mother or other female relatives should be evaluated, if possible, with both a fundus examination and ERG testing to determine whether these relatives show signs of the carrier state and, if affected, how much retinal function is retained. Carriers of X-linked retinitis pigmentosa have abnormal full-field ERGs in one or both eyes in more than 90% of cases, whereas carriers of autosomal recessive disease have normal fundi and normal ERG amplitudes. A diagnosis of X-linked disease is an aid in determining visual prognoses in male patients with retinitis pigmentosa, because untreated males with X-linked disease characteristically become virtually blind by age 30 to 45, whereas untreated males with autosomal recessive disease usually become virtually blind by age 45 to 60.

Adult patients with the common form of retinitis pigmentosa should be advised that their condition is treatable with vitamin A palmitate.^96,270,271 Before treatment is initiated, eligible patients should have a fasting serum vitamin A level and serum liver function profile. Information regarding available sources of the correct dose of vitamin A palmitate (i.e., 15,000 IU/day for adults) should be provided because this dose is often not available in pharmacies or nutritional outlets. Patients should be advised that higher doses provide no additional benefit and that doses equal to or greater than 25,000 IU/day are potentially toxic over the long term. Women should be advised not to take this dose of vitamin A if they are pregnant or planning to become pregnant because of the risk of birth defects associated with high-dose vitamin A supplementation. All patients with the common forms of retinitis pigmentosa should be advised of the possible adverse effect of high-dose (i.e., equal to or greater than 400 IU/day) vitamin E supplementation. Patients should be encouraged to eat a regular diet without selecting foods high in vitamin A and to have annual checks of their fasting serum vitamin A level and serum liver function profile by their internist while on this dose of vitamin A.

As part of the initial evaluation, every effort should be made not only to establish the diagnosis and explain the genetic implications, if any, but also to offer referral to psychologic, social, and community resources where appropriate. Follow-up examinations are usually recommended every 2 years to help determine the course of the disease as monitored by visual acuity, visual fields, and ERGs; to adjust glasses and provide low vision aids as required; and to determine whether cataract surgery is indicated. In the case of retinitis pigmentosa, cataract surgery is usually deferred until a patient cannot read with either eye. A trial of dilating drops taken at dusk (e.g., homatropine 2%) may be made in an effort to determine whether the patient can meet his or her visual needs without surgery. Cataract extraction has the greatest potential for improving vision among those patients who have cataracts that are large enough to impair ophthalmoscopic visualization of the fundus, full-field ERGs that are detectable with computer averaging (as a measure of remaining foveal and extrafoveal retinal function), and a retinal acuity that is better than distance acuity.

Acetazolamide has been reported to be useful for patients with retinitis pigmentosa with cystoid macular edema; some patients on this drug have shown an improvement in visual acuity, whereas others have claimed subjective improvement in the absence of measurable changes in visual acuity. The value of this treatment remains to be established.^272–274

If Bassen-Kornzweig syndrome or Refsum disease is suspected in a patient with autosomal recessive retinitis pigmentosa younger than age 40, serum lipoprotein electrophoresis or serum phytanic acid should be assessed after fasting for 12 hours. If nutritional deficiency or intestinal malabsorption is suspected, a fasting serum vitamin A level should be obtained. A serologic test for syphilis should be performed if this diagnosis is suspected, because retinitis pigmentosa has been associated with this disease. A fasting serum vitamin E level should be considered in patients with the signs of retinitis pigmentosa who also report the onset of ataxia in adulthood in search of low serum vitamin E levels because some success has been reported with vitamin E supplementation for this rare disorder.^127,128

Every effort should be made to answer the patient's questions faithfully and to provide a clear description of not only what abnormalities exist but also how much function remains. Discussion of results of the ocular examination with the patient, and with the patient's family if indicated, must be individualized for each case. The measurement of any remaining ERG function is of advantage in this regard, because the patient can be shown in positive terms what function he or she possesses, and computer averaging and narrow bandpass filtering is particularly important, because most patients with remaining vision have detectable cone ERGs with use of this specialized technology (which can detect responses as low as 0.05 μV) but will show nondetectable responses with conventional full-field ERG systems (which can detect responses only as low as 10 μV). It is important to impress on the patient that these conditions in general progress at a very slow rate. Remarks such as “Your vision may last for 2 years or 30 years” should be avoided; the patient usually hears only the more severe prognosis and does not understand that in most instances he or she may retain vision for 20 to 40 years or more after the initial evaluation, particularly in the case of retinitis pigmentosa or choroideremia. It is also helpful to learn what the patient believes he or she was told previously so that any misconceptions can be addressed. For example, some patients believe that retinal dystrophy and degeneration are “different diseases” and erroneously conclude that there is no agreement regarding the diagnosis.

It is very important to provide literature to the patient at the time of the initial visit, because most patients cannot assimilate all the information given to them verbally. Printed information describing their condition, patterns of inheritance, reasons why they should be followed over time by their ophthalmologist, the significance of molecular genetic studies, and so forth should be available for distribution in the office. Patients may wish to receive a copy of the results of their ocular examination and a copy of their ERG waveforms because part of this report can be useful in showing the patient how much retinal function remains.

When a child is diagnosed with retinitis pigmentosa or an allied retinal degeneration, the parents usually request a full written report. With the parents' agreement, the patient should be provided with sufficient verbal information at the time of the examination to allow the child to understand his or her own visual symptoms. For example, if the child is night deficient, then the child should be told to be careful engaging in activities under conditions of dim illumination. If the child has decreased peripheral vision, then the child should be advised that it may be difficult if not unsafe to play certain sports (e.g., baseball or hockey). A child may well be legally blind because of loss of acuity and yet still be able to read with magnifying lenses; if this child has sufficient visual field, he or she may well be able to perform in a regular school. Both the child and the parents benefit by knowing how much visual function remains rather than how much has been lost; conclusions about long-term visual prognosis should be deferred until the child has been examined several times over 2-year intervals. In the case of children aged 6 to 18 with the common forms of retinitis pigmentosa, reduced doses of vitamin A palmitate adjusted for age and weight may be considered on a trial basis with the agreement of the parents and follow-up by the ophthalmologist and pediatrician.

Fig. 19 illustrates a schematic model of a hand-held monocular pocketscope that is about 4 in. long. The instrument provides a patient with a 40-degree field of view and gives the patient his or her best daylight vision at night in one eye; it has a green display. This monocular device can be head mounted. Monocular devices are most useful in patients with a best corrected vision of better than 20/200 and a visual field diameter of greater than 20 degrees in at least one eye. Candidates considering a monocular device should also have good mobility in daylight with one eye patched. Patients who depend heavily on a far temporal crescent for mobility are not good candidates; nor are patients who, because of a central scotoma, cannot view the output screen in these devices. The patient should be advised to assess the value of the device for routine activities before making a decision as to whether or not to obtain it.

A new generation night-vision device is presently being field tested. This binocular electro-optical device (about 1.25 in. thick) is worn like a pair of glasses. This instrument uses digital amplification and has a black and white display. It is connected to a powerpack that can be carried in the patient's pocket or attached to a belt. This instrument has a 40-degree field of view. It remains to be determined whether this binocular night vision aid will be more helpful than a handheld monocular device for patients with retinitis pigmentosa and other night blinding retinal disorders.

In families with a single affected male, retinitis pigmentosa may be inherited by an autosomal recessive or X-linked mode; ERG testing and fundus examination of the mother can help to determine whether or not she is a carrier of X-linked disease. A careful family history and examination of relatives of an affected patient with ERG testing can aid in establishing this mode of transmission. It is important to recognize that retinitis pigmentosa may skip generations and nonetheless be transmitted by a dominant mode; the dominant mode with variable penetrance should be suspected in patients who have large cone ERGs with substantial delays in implicit time under age 20.

A digenic mode of inheritance should be considered if a pedigree with multiple affected members is inconclusive as to whether the disease is transmitted by an autosomal recessive or autosomal dominant mode. In digenic transmission, two unlinked mutations, neither of which results in retinitis pigmentosa by itself, cause this disease in patients who have both mutations. Patients affected with digenic retinitis pigmentosa can have asymptomatic parents but have a 25% chance of having an affected child with each birth. The discovery of this mode of transmission provides one explanation on a molecular genetic basis for the pattern of inheritance described clinically as dominant retinitis pigmentosa with reduced or incomplete penetrance.⁷

Some young people may have retinitis pigmentosa and yet be asymptomatic and show no diagnostic findings on a routine ocular examination. By age 30, more than 90% of patients can be diagnosed with the ophthalmoscope, but younger than age 30, ERG testing is indicated if the patient wants to be certain whether or not he or she is affected. The ERG identifies those who are affected and those who are normal; in families with retinitis pigmentosa, patients age 6 and older with normal ERGs would not be expected to develop this condition at a later time.

Recent advances with molecular genetic techniques undoubtedly will facilitate genetic counseling; for example, about 25% of patients with autosomal dominant retinitis pigmentosa in the United States have rhodopsin gene mutations detectable through analysis of leukocyte DNA; patients identified through analysis of DNA would have an ocular examination including ERG testing to confirm the diagnosis and to determine the amount of remaining retinal function, because variable clinical expression at a given age is known to exist among patients with the same rhodopsin gene mutation. It is important to establish the correct genetic type in families with retinitis pigmentosa, not only for the sake of providing accurate genetic counseling but also as a guideline in establishing long-term visual prognoses of affected patients, because patients with dominantly inherited disease generally retain vision longer than those with autosomal recessive or X-linked disease.

Mutant human gene constructs have now been injected into mouse eggs to create transgenic models of human retinal degenerations; genes of interest have also been “knocked-out” to produce animal models of retinal degeneration. These models are being used to define pathogenesis as well as to search for treatments. Gene therapy with an RPE65 gene construct has been used successfully to restore retinal function in an RPE65 canine model of retinal degeneration.²⁷⁹ Mutant genes can also be synthesized in the laboratory and their expression studied in a variety of in vitro systems.^280–283 Antibodies produced to abnormal gene products may be applied to autopsy eyes of animal models, as well as to autopsy eyes of patients with retinal degenerations, to reveal the amount and distribution of the mutant gene product in remaining photoreceptor cells and thereby help to clarify pathogenesis.

Disease progression in most patients with retinitis pigmentosa and allied diseases can be followed objectively throughout almost the entire course with ERG testing using computer averaging and narrow bandpass filtering. The variability of clinical severity at a given age seen among patients with the same gene defects suggests that some other factor(s) other than the gene defects alone (e.g., light, diet, environment, or modifier genes) may be involved in the clinical expression of some of these diseases.²⁸⁴ Possible therapies may be discovered through risk factor analyses of subgroups of patients with known gene defects followed over a period of years. Wherever possible, randomized, controlled, double- masked trials should be conducted to assess the clinical value of proposed therapies.

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