75 Quinine Retinopathy

Q , made from the bark of the cinchona tree, is an alkaloid with a long history of medicinal use and has been available in synthetic form since the 1940s. It is perhaps best known for the treatment of malaria (e.g., Mandel et al.8) but is also prescribed for night cramps,9 with a dosage of 200–300 mg. In the past, it was used as an abortifacient.4 Acute quinine toxicity, or cinchonism, may be characterized by blindness, tinnitus, nausea, vomiting, cardiac dysrrhythmias, coma, and even death. Symptoms of cinchonism are likely with doses above 4 g, and as little as 8 g may be fatal.10 There is marked interindividual variation in susceptibility to quinine that may give rise to so-called idiosyncratic toxic reactions.2,5,11 Serum quinine levels are a poor prognostic indicator.2 In addition, this author has experience of one patient (unpublished data) who had been taking therapeutic doses of quinine for night cramps but who was a covert alcoholic and developed a typical retinopathy presumed consequent upon impaired liver function.

Acute visual disturbances occur in approximately 40% of patients, but less than a third of those suffer permanent visual impairment.2 There is usually severe visual loss with gradual recovery over the subsequent days or weeks. These improvements in visual function, often dramatic, may incorrectly be ascribed to the effects of treatment. However, even though visual symptoms are common, patients usually present to physicians with a history of attempted suicide by quinine overdose, often in association with alcohol and/or other medication. This may delay referral to ophthalmologists and thence to electrophysiologists. Ocular quinine toxicity in humans has therefore been difficult to study in the acute phase.

In early presentation, fluorescein angiography shows attenuated retinal arteries with a return of normal choroidal fluorescence as the initial masking from acute retinal edema subsides. Histological examination may reveal collapse of retinal architecture, early gliosis, and vascular narrowing.3,6 The pathological process in the chronic phase is due to either delayed or secondary ischemia, although clinically, the onset of vascular attenuation often heralds the return of central visual function. The acute effects are less well characterized; one group has suggested the possibility of retinal toxicity, being unable to find histological evidence of acute ischemic changes in an experimental model.3

There does not appear to have been an electrophysiological study of quinine retinopathy since the introduction of the International Society for Clinical Electrophysiology of Vision (ISCEV) standard to electroretinography. However, early studies report an electronegative response to a single bright white flash under dark adaptation, similar to the maximal mixed rod-cone response in the current ISCEV standard. There is preservation of the photoreceptor derived a-wave but marked reduction in the postreceptoral b-wave.1,5,12 This appearance is superficially similar to that which occurs in association with ischemic damage to the inner nuclear layer consequent on central retinal artery occlusion. Typical findings appear in figure 75.1. In addition to the electronegative electroretinogram (ERG), note the marked delay and amplitude reduction in the 30-Hz flicker ERG. A further feature of note is the highly distinctive appearance when long-duration stimulation is used to assess ON and OFF pathway function. There is a profoundly electronegative ON response with virtually no b-wave, and an extended plateau to the OFF response d-wave, giving an overall waveform reminiscent of a sawtooth. This highly unusual waveform has been present in all cases of quinine retinopathy examined by the author in which ON and OFF response recording has been performed, but has not been recognized in other disorders and may be specific to quinine toxicity.

In the acute phase, there is marked generalized retinal abnormality involving all ERG waveforms but not accompanied by the electronegative waveform, which only becomes apparent some weeks later (unpublished data). It is postulated that the initial disturbance reflects the known effects of quinine on cell membranes (e.g., Malchow et al.7). The acute effects, in which there may be reduction of vision down to no light perception, can then be ascribed to generalized retinal dysfunction involving all retinal cell types, including the retinal ganglion cells. The visual evoked potential (VEP) at this stage may be undetectable. As the acute effects resolve, visual acuity may recover, and the a-wave of the ERG may show recovery. The characteristic negative ERG waveform is then a feature. The VEP may show recovery, presumably reflecting recovery of ganglion cell function, but tends not to be of normal latency. The VEP delay can be assumed to be secondary to continuing macular dysfunction, as the pattern ERG at this stage may be

F 75.1 ERGs and PERGs in two patients with quinine retinopathy following overdose. Data are shown from the right eye. Patient A is a 72-year-old female who took an overdose of quinine as an abortifacient some 40 years prior to investigation. Visual acuity was 6/18. Patient B is a 55-year-old male with an 11-month history and visual acuity of 6/6. Both patients show very similar

undetectable despite normal visual acuity (see figure 75.1). It is uncertain whether the negative ERG reflects inner retinal damage consequent upon vascular spasm and vessel attenuation or whether the vessel narrowing reflects loss of demand from inner retinal structures.

To conclude, the presence of a profoundly electronegative ERG in a patient with marked field constriction, pale disks, and attenuated retinal vasculature raises the question of quinine toxicity. Directed questioning of the patient may be necessary to reveal the relevant history, usually of an overdose. The nature of the ON and OFF response abnormality seems characteristic.

REFERENCES

1.Bacon P, Spalton DJ, Smith SE: Blindness from quinine toxicity. Br J Ophthalmol 1988; 72:219–224.

2.Boland ME, Brennand Roper SM, Henry JA: Complications of quinine poisoning. Lancet 1985; 1:384–385.

3.Buchanan TAS, Lyness RW, Collins AD, Gardiner TA, Archer DB: An experimental study of quinine blindness. Eye 1987; 1:522–524.

ERG findings. The rod-specific ERG is subnormal; there is an electronegative bright-flash ERG; cone flicker and single-flash ERGs are delayed and markedly subnormal; and ON-OFF response recording shows almost complete ON b-wave loss with an elevated and extended plateau to the d-wave. PERGs are undetectable despite the normal visual acuity in patient B.

4.Dannenberg A, Dorman SF, Johnson J: Use of quinine for self induced abortion. South Med J 1983; 76:846–849.

5.Gangitano JL, Keltner JL: Abnormalities of the pupil and VEP in quinine amblyopia. Am J Ophthalmol 1980; 89:425– 430.

6.Gass JDM: Stereoscopic Atlas of Macular Diseases: Diagnosis and Treatment, vol. 2, ed 3. St. Louis, CV Mosby, 1987.

7.Malchow RP, Qian H, Ripps H: A novel action of quinine and quinidine on the membrane conductance of neurons from the vertebrate retina. J Gen Physiol 1994; 104:1039– 1055.

8.Mandell GL, Douglas RG, Bennet JE (eds): Anti-infective Therapy. New York, Wiley, 1985.

9.Man-Son-Hing M, Wells G: Meta-analysis of efficacy of quinine for treatment of nocturnal leg cramps in elderly people. Br Med J 1995; 310:13–17.

10.Polson CJ, Tattersal RN: Clinical Toxicology. London, English Universities Press, 1959.

11.Wanwimolruk S, Chalcroft S, Coville PF, Campbell AJ: Pharmacokinetics of quinine in young and elderly subjects. Trans R Soc Trop Med Hyg 1991; 85:714–717.

12.Zahn JR, Brinton GF, Norton E: Ocular quinine toxicity followed by electroretinogram, electro-oculogram and pattern evoked potential. Am J Optometry Physiol Optics 1981; 58:492–498.

L ’ optic neuropathy (LHON) is a disease of optic atrophy first reported by Theodor Leber in 1871.9 This disease has an acute or subacute onset in both eyes, and it typically appears in young men in their teens and twenties. It causes a severe optic atrophy with severe visual loss within one year. The disease was considered to be hereditary because their patients showed a similar family history, in which male patients did not seem to transit the disease to their offspring, while children of female carriers always inherit the disease. Its hereditary type was unknown until in 1936. Imai and Moriwaki reported that it was a cytoplasmic inheritance.6 Nikoskelainen and his group proposed that mitochondrial DNA inheritance explained the hereditary patterns seen in LHON families.17,18

In 1988, Wallace et al. reported a new mutation of 11778 base pairs of mtDNA of patients with LHON.22 Since then, more than 20 primary or secondary mtDNA mutations have been associated with LHON. The 3460, 11778, and 14484 mtDNA mutations are considered to be the most important in the pathogenesis of this disease and are classified as primary mutations.1,4,5,8 Among the three mutations, the 11778 mutation is most frequently seen in patients with LHON. But the frequencies of the primary LHON mutations reportedly differ among ethnic groups.15,23

The characteristics of fundus are blurred disk margins, tortuous retinal vessels, irregular telangiectatic dilation of capillaries in peripapillary and prepapillary networks in the acute stage. In spite of such microangiopathy, fluorescein angiography shows no leakage around the optic nervehead. As the disease progresses, the microangiopathy disappears, and optic atrophy develops after at least two months. In the visual field, a relative centrocecal scotoma is detected in the acute stage, and then a large central scotoma is observed. In LHON, spontaneous recovery has been well known, but it does not occur often. Johns et al. have reported that patients with the 14484 mutation show a higher incidence of visual recovery than did patients with the 11778 or 3460 mutations and that visual loss may depend more on epigenetic factors in patients with the 14484 mutation than in patients with the other primary mutations.7 At the present time, no effective treatment is known for LHON.

In 1992, the authors reported the results of treatment with idebenone, a quinol compound that may contribute to stimulation of the formation of ATP, in a 10-year-old Japanese boy with LHON and homoplasmic 11778 mutation.10 The authors studied the effectiveness of idebenon combined with vitamin B2, vitamin C, and isopropyl unoprostone (Rescula) for recovery of the circulation of the optic nervehead for patients in the acute stage.13 In patients with visual acuity of 0.3 or more, there was no statistical difference between treated and untreated groups. But the recovery interval up to 0.3 was significantly shorter in the treated group than in the untreated group.

Electrophysiological study for LHON

Pathogenesis of LHON has been considered to be damage of the optic nerve. Smith et al.,21 and Nikoskeleinen et al. described the typical signs and appearance of fluorescein angiography.16 From their study, they assumed LHON to be caused by damage of retinal nerve fiber layer and proposed that this disease should be called Leber’s hereditary optic neuroretinopathy. In electrophysiological examination, electro-oculograms (EOGs), electroretinograms (ERGs), and visual evoked potentials (VEPs) are used in daily eye clinic. EOGs and ERGs have been reported to be normal in patients with LHON. In flash ERG, Riordan-Eva et al. reported the electrophysiological results of 34 patients with LHON; in three patients, the b-wave of the ERG was low in amplitude.19 They also showed the results of pattern ERGs for seven LHON patients. Pattern ERGs were normal in two patients, showed a low response in three patients, and in two others had normal P50 components but absent N95 components. Shibata et al. reported an ERG and VEP study for a 49-year-old male patient with LHON.20 The recordings of the VEPs and ERGs, four weeks after onset, showed attenuation of the pattern VEPs and P50 component and absence of N95 component in pattern ERGs bilaterally. However, the flash VEPs and flash ERGs were normal. Six months after the onset, the pattern ERGs and flash VEPs showed severe attenuation; however, the a- and b-waves in flash ERGs were normal. Mondelli et al. reported a VEP

study in 11 patients at the atrophic stage of LHON.14 Two patients showed no response bilaterally. Three patients showed no response of one eye and delayed latency and decreased amplitude of the other eye. In six patients, both latency and amplitude were abnormal. Dorfman et al. studied the pattern VEP in two brothers with early LHON.3 One month after onset, the latency of VEP was normal. Then the response developed prolonged latency and reduced amplitude, with the waveform developing a bifid positivity in a W configuration. The pattern size that was used in this study was a check of 1° 50¢ of arc.

Carroll and Mastaglia also found that pattern VEPs in patients with LHON were less delayed in P100 latency but showed a greater reduction in amplitude and were disorganized.2 The pattern size used was a check of 12¢ of arc. The authors reported the electrophysiological results of a 28-year-old male patient with LHON in the relatively acute stage.12 The single-flash ERG was normal in each eye. The pattern ERG showed normal latency of P50 in each eye, and the amplitude from the right eye decreased to 3.6 mV and that from the left eye to 2.5 mV. The flash VEP responses, though less delayed, were markedly reduced in amplitude in the relatively acute stage. The authors reported VEPs in a patient with the 11778 mutation who developed LHON at the age of 23 years.11 VEPs were recorded in the right eye at the presymptomatic and symptomatic stages. Pattern VEPs were not recorded in the left eye that had developed LHON 4 months earlier. In the presymptomatic stage (figure 76.1A) when the visual acuity of right eye was 1.0, N80 latency was the upper limit of normal, P100 was slightly delayed, and the amplitudes were in the normal range at three check sizes but not at the check size of 5¢. Three days after the onset of LHON (figure 76.1B), the patient’s visual

acuity was still 1.0. The amplitude was markedly reduced, but N80 and P100 were unchanged. Two weeks after onset (figure 76.1C), his visual acuity had decreased to 0.6. The amplitude showed a significant reduction, and N80 and P100 were further delayed. Pattern VEPs were not recordable one month after onset. During onset of LHON, there was a marked reduction in amplitude, followed by a delay in latency.

Figure 76.2 shows the waveforms of flash VEPs in the same patient as shown in figure 76.1. Flash VEPs were recorded at four different intensities of stimulus using red and ND filters. The visual stimulus was a xenon flash light of 0.3 joule ( J) and 2.0 J. The four stimulus intensities were 0.3 ¥ 10-2 J (-2.0 log unit), 0.3 ¥ 10-1 J (-1.0 log unit), 0.3 J (0 log unit), and 2.0 J (0.8 log unit). The intensity-latency curve and the intensity-amplitude curve served as critical variables. Three days and two weeks after onset, flash VEPs were slightly attenuated in the stimulus of low intensity compared in the presymptomatic stage. But N80 latency and P100 were not delayed, although pattern VEPs deteriorated rapidly. These results of VEPs by pattern and flash light stimuli suggested that in early LHON, the dissociation of damage to spatial and luminance channels existed.

To investigate the dissociation of damage between spatial luminance channels in early stage of LHON, patients with LHON were examined by use of pattern VEP and flash VEP, and the findings were compared with those in patients with optic neuritis (ON), including MS. Twenty-eight Japanese patients were investigated; 12 (18 eyes) with LHON and 16 (18 eyes) with ON, including eight patients of MS. Thirty normal volunteers (30 eyes) served as controls. In pattern VEP, the check size–amplitude curve and the check size–latency curve are shown in figure 76.3. Pattern VEPs

F 76.1 Waveforms of pattern VEPs from the right eye in a 23-year-old-patient with LHON. A, In the presymptomatic stage, visual acuity was 25/20. B, Three days after onset, visual acuity was

20/20. C, Two weeks after onset, visual acuity was 20/30. Numerals represent latency times of N80 and P100. (From Mashima Y, Imamura Y, Oguchi Y.11 Used by permission.)

F 76.2 Waveforms of flash VEPs from the right eye in the same patient as shown in figure 76.1. A, Presymptomatic stage. B, Three days after onset. C, Two weeks after onset. Numerals

F 76.3 Check size–amplitude curve in pattern VEPs. Open circles and bars represent the mean plus or minus standard deviation (S.D.) in normal subjects (30 eyes). Solid circles and bars represent the mean ± S.D. in patients with LHON, and open squares represent the mean ± S.D. in patients with optic neuritis (ON). N shows the number of eyes. Mean amplitude was significantly reduced in both LHON and ON patients compared with normal subjects in check sizes 10¢ and 20¢. There was no difference in amplitude between LHON and ON. (From Mashima Y, Imamura Y, Oguchi Y.11 Used by permission.)

represent latency times of N80 and P100. Stimulus delay was 20 ms after a trigger signal (vertical arrows). (From Mashima, Imamura Y, Oguchi Y.11 Used by permission.)

were recordable in 5 of the 12 patients with LHON and in 8 of the 16 patients with ON.

In normal subjects, the check size–amplitude curve represented a maximum response produced by check sizes of 10¢ to 20¢, which suggested a band-pass function. In patients with LHON and ON, however, the curve was linear. In LHON, as well as in ON, the mean amplitude was significantly reduced in comparison with normal subjects; except for a larger check size of 40¢ (see figure 76.3), there was no difference in amplitude between patients with LHON and ON (p > .05). The N80 latency in LHON as well as in ON was significantly delayed in comparison with normal subjects (figure 76.4). Moreover, the delay in the ON exceeded that in LHON. In flash VEP, the intensity-amplitude curve and the intensity-latency curve are shown in figures 76.5 and 76.6. Flash VEP were recordable in all patients with LHON and in all 16 patients with ON. Mean amplitude was significantly reduced in both patients with LHON and ON compared with normal subjects (see figure 76.5). There was no difference in amplitude between patients with LHON and ON (p > .05). Mean latency time was not delayed in LHON in comparison with normal subjects, but in ON the mean

From these results, it may be suggested that most of the nerve fibers in the luminance channels were less affected by LHON than nerve fibers in the spatial frequency channels. In an acute stage of LHON, luminance-related fibers may be less affected than the spatial frequency–related fibers are, whereas in patients with ON, all these types of fibers are damaged by inflammation or demyelination of the optic nerve.

F 76.4 Check size–latency curve in pattern VEPs. In patients with LHON, mean latency was delayed in comparison with normal subjects in two check sizes: 10¢ and 20¢. In patients with ON, mean latency was delayed in comparison with normal subjects in check sizes 10¢, 20¢, and 40¢ and patients with LHON in check sizes 20¢ and 40¢. (From Mashima Y, Imamura Y, Oguchi Y.11 Used by permission.)

F 76.5 Intensity-amplitude curve in flash VEPs. Open circles and bars represent the mean ± S.D. in normal subjects (30 eyes). Solid circles and bars represent the mean ± S.D. in patients with LHON, and open squares represent the mean ± S.D. in patients with ON. Mean amplitude was significantly reduced in both LHON and ON patients compared with normal subjects. There was no difference in amplitude between LHON and ON patients. (From Mashima Y, Imamura Y, Oguchi Y.11 Used by permission.)

F 76.6 Intensity-latency curve in flash VEPs. In patients with LHON, mean latency time was not delayed in comparison with normal subjects. In patients with ON, mean latency time was markedly delayed in comparison with normal subjects as well as with LHON patients. (From Mashima Y, Imamura Y, Oguchi Y.11 Used by permission.)

REFERENCES

1.Brown MD, Wallace DC: Spectrum of mitochondrial DNA mutations in Leber’s hereditary optic neuropathy. Clin Neurosci 1994; 2:138–145.

2.Carroll WM, Mastaglia FL: Leber’s optic neuropathy: A clinical and visual evoked potential study of affected and asymptomatic members of a six generation family. Brain 1979; 102:559–580.

3.Dorfman LJ, Nikoskeleinen E, Rosenthal AR, Sogg RL: Visual evoked potentials in Leber’s hereditary optic neuropathy. Ann Neurol 1977; 1:565–568.

4.Houponen K, Vikki J, Aula P, Nikoskeleinen EK, Savontaus ML: A new mtDNA mutation associated with Leber hereditary optic neuroretinopathy. Am J Hum Genet 1991; 48:1147–1153.

5.Howell N, Bindoff LA, McCullough DA, Kubacka I, Poulton J, Mackey D, et al: Leber hereditary optic neuropathy: Identification of the same mitochondrial ND1 mutation in six pedigrees. Am J Hum Genet 1991; 49:939–950.

6.Imai Y, Moriwaki D: A possible case of cytoplasmic inheritance in man: A critique of Leber’s disease. J Genet 1936; 33:163–167.

7.Johns DR, Heher KL, Miller NR, Smith KH: Leber’s hereditary optic neuropathy: Clinical manifestations of the 14484 mutation. Arch Ophthalmol 1993; 111:495–498.

8.Johns DR, Neufeld MJ, Park RD: An ND-6 mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Biochem Biophys Res Commun 1992; 187: 1551–1557.

9.Leber T: Uber hereditare und congenital-angelegte Sehnervenleiden. Graefes Arch Ophthalmol 1871; 17:249–291.

10.Mashima Y, Hiida Y, Oguchi Y: Remission of Leber’s optic neuropathy with idebenone. Lancet 1992; 340:368–369.

11.Mashima Y, Imamura Y, Oguchi Y: Dissociation of damage to spatial and luminance channels in early Leber’s hereditary optic neuropathy manifested by the visual evoked potential. Eye 1997; 11:707–712.

12.Mashima Y, Kigasawa K, Oguchi Y, Fujino T: Leber’s optic neuropathy—Electrophysiological studies. Folia Ophthalmol Jpn 1987; 38:1046–1053.

13.Mashima Y, Kigasawa K, Wakakura M, Oguchi Y: Do idebenone and vitamin therapy shorten the time to achieve visual recovery in Leber hereditary optic neuropathy? J Neuro-ophthalmol 2000; 20:166–170.

14.Mondelli M, Rossi A, Scarpini C, Dotti MT, Federico A: BAEP changes in Leber’s hereditary optic atrophy: Further confirmation of multisystem involvement. Acta Neurol Scand 1990; 81:349–353.

15.Newman NJ: Leber’s optic neuropathy: New genetic consideration. Arch Neurol 1993; 50:540–548.

16.Nikoskeleinen E, Hoyt WF, Nummelin K: Ophthalmoscopic findings in Leber’s hereditary optic neuropathy: I. Fundus findings in asymptomatic family members. Arch Ophthalmol 1982; 100:1597–1620.

17.Nikoskelainen E, Parjarvi E, Lang H, Kalimo H: Leber’s hereditary optic neuropathy: A mitochondrial disease? Proceedings of the 25th Scandiavian Congress. Neurology 1984; 69 (suppl 98):172–173.

18.Nikoskelainen E, Savontaus M-J, Wanne OP, Katila MJ, Nummelin KU: Leber’s hereditary optic neuroretinopathy a maternally inherited disease: A genealogic study in four pediagees. Arch Ophthalmol 1987; 105:665–671.

19.Riordan-Eva P, Sanders MD, Govan GG, Sweeney MG, Da Costa J, Harding AE: The clinical features of Leber’s hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation. Brain 1995; 118:319–337.

20.Shibata K, Shibagaki Y, Nagai C, Iwata M: Visual evoked potentials and electroretinograms in early stage of Leber’s hereditary optic neuropathy. J Neurol 1999; 246:847–849.

21.Smith LJ, Hoyt WF, Sausac JO: Ocular fundus in acute Leber optic neuropathy. Arch Ophthalmol 1973; 90:349–354.

22.Wallace DC, Singh G, Lott MT, Hodge JA, Schurr G, Lezza MS, Elsas LJ II, Nikoskelainen EK: Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science 1988; 242:1427–1430.

23.Yamada K, Oguchi Y, Hotta Y, Nakamura M, Isashiki Y, Mashima Y: Multicenter study on the frequency of three primary mutations of mitochondrial DNA in Japanese pedigees with Leber’s hereditary optic neuropathy: Comparison with American and British counterparts. J Neuro-ophthalmol 1999; 22:187–193.

P - glaucoma (POAG) is a chronic visual disorder characterized by elevated intraocular pressure (IOP) in the presence of an anatomically open anterior chamber angle, excavation and/or pallor of the optic disc along with the nerve fiber layer defects, and visual field loss. Visual loss in chronic glaucoma results from the destruction of the retinal ganglion cell axons that form the optic nerve. The optic nerve damage in POAG occurs over a protracted period of time (often months or years) and appears to be due to an increase in IOP to an intolerable level. Individuals with elevated IOP who do not exhibit optic disk, nerve fiber layer, or visual field defects (i.e., ocular hypertensives) are considered glaucoma suspects because they are at risk of developing the disease. However, the relationship between elevated IOP and the development of glaucoma remains unclear since many ocular hypertensives may not develop the disease while other individuals with apparently normal IOP develop the optic disk, nerve fiber layer, and visual field abnormalities that are characteristic of glaucoma (i.e., low-tension glaucoma). This suggests that there is considerable interindividual variability in the IOP level necessary to produce optic nerve damage.

The mechanism by which elevated IOP induces optic nerve damage is not known. The two primary hypotheses suggest that elevated IOP either interferes with blood flow at the optic nerve head (the vascular theory) or produces mechanical compression of the retinal ganglion cell axons in the region of the lamina cribrosa (mechanical theory). In either case, there is a slowly progressive loss of retinal ganglion cell axons that eventually results in the development of a characteristic visual field defect (figure 77.1), upon which the diagnosis of glaucoma is often made. However, the manifestation of a visual field defect may represent a relatively late stage in the progression of the disease, a time when retinal ganglion cell loss is virtually irreversible. Recent estimates suggest that 40% to 50% of the optic nerve axons can be lost prior to the development of a visual field defect that is detectable with manual perimetry.31 As a result there has

been considerable interest in developing more sensitive and more reliable methods for studying the pathogenesis and pathophysiology of retinal ganglion cell damage in glaucoma. The pattern electroretinogram (PERG) is one method that is being used in these studies.

The original suggestion by Maffei and Fiorentini24 that the PERG could be used to monitor the bioelectrical response of the retinal ganglion cells provided the impetus for a large number of studies on patients with glaucoma. In a general sense these investigations can be characterized as either (1) testing the hypothesis that the PERG has a ganglion cell origin by studying individuals with a disease that is known to directly affect these cells or (2) evaluating the possible clinical value of the PERG for detecting glaucoma. Taken together, these diverse studies have provided considerable insight concerning both the basic properties of the human PERG and the pathophysiology of retinal ganglion cell dysfunction in glaucoma.

Earlier electrophysiological studies of the pathogenesis and pathophysiology of visual dysfunction in glaucoma were hampered by the lack of an appropriate technique for directly evaluating the functional integrity of the neural elements in the proximal retina and, in particular, the retinal ganglion cells. Studies of the flash electroretinogram (ERG) in patients with glaucoma clearly illustrated that the more distal neural elements in the retina were unaffected,14,21 at least until relatively late in the disease process.3,12 The results of visual evoked potential (VEP) studies in glaucoma patients, on the other hand, indicated that the latency of the bioelectrical responses generated in the primary visual cortex was often increased.17,37 Therefore, the flash ERG and VEP results implied that there was a significant deficit within the primary visual pathway of glaucoma patients that was not the result of dysfunction in the neural elements of the distal retina. However, the mechanism whereby a loss in retinal ganglion cell axons would produce an increase in VEP latency remains unclear. Furthermore, the relationship between the VEP latency increase and the nature and extent

F 77.1 The diagnosis of chronic open-angle glaucoma is often based upon evidence of a visual field defect similar to the visual field loss apparent in this 65-year-old white male. This result was obtained by automated perimetry (Humphrey 30–2).

of the early damage to the optic nerve in glaucoma has not been established, perhaps because the VEP is an indirect reflection of retinal ganglion cell function that is dominated by the bioelectrical response of neural elements within the central 5 to 10 degrees of the visual field.36 Thus the availability of an electrophysiological technique to monitor a bioelectrical response that includes a component (or components) that originates in the proximal retina and possibly reflects the functional integrity of the retinal ganglion cells that themselves filled an obvious void.

There now have been numerous studies of the PERG in glaucoma patients, and the clear consensus of these studies is that PERG abnormalities frequently are evident in individuals with well-diagnosed POAG (table 77.1). Both PERG amplitude reductions and latency increases (or phase shifts) have been reported in various studies (figure 77.2), but because the latency increase is relatively small (about 5 to 8 ms) although statistically significant, the more robust amplitude reductions have drawn the most interest. The results of these investigations indicate that in glaucoma patients PERG amplitude reductions occur in the presence of normal flash and flicker ERGs. Some evidence also indicates that the PERG amplitude reductions become more profound when other signs of glaucoma (i.e., cupping and field loss) indicate an increase in the severity of the disease.19,45

Important confirmation of the conclusions drawn from studies of patients with glaucoma has come from studies of experimental glaucoma that is induced in primates by argon

F 77.2 Representative PERGs for low–temporal frequency (transient) and high–temporal frequency (steady-state) conditions are illustrated for an age-matched visual normal (control), two patients with diagnosed ocular hypertension and normal visual fields, and a patient with diagnosed POAG. Note that one ocular hypertensive produced good responses for both test conditions while in the other ocular hypertensive both responses were poor.

F 77.3 PERG amplitude is plotted as a function of temporal frequency. The data points have been replotted from Trick40 and represent values for 32 patients with chronic open-angle glaucoma and 32 age-matched controls average across check size.

further suggested that this represented a selective loss of the type A retinal ganglion cells that underlie the magnicellular stream of the primary visual pathway.22 Similarly, in the primate model of glaucoma the largest PERG deficits are

observed with high–temporal and low–spatial frequency stimuli, once again supporting the concept of a selective deficit in the magnicellular system.26,27 Possible variations in the extent of this selective damage associated with progression of the disease is a topic that requires further investigation.

More recently it has been suggested15 that the transient PERG includes two semi-independent processes that are evident as the N1-P1 and the P1-N2 components of the waveform (see figure 77.2). In diseases where damage is localized in the proximal retina and/or optic nerve only the P1-N2 component of the transient PERG is reduced. In diseases that affect the distal retina the N1-P1 component of the transient PERG is reduced (due to the direct influence of the disease on the retinal generators of this component), and the P1-N2 component is also reduced (since the input to the neural elements in the proximal retina/optic nerve is distorted by the effect on the distal retina). Based upon this observation the large-magnitude reduction Trick noted in the steady-state PERG also could be interpreted as resulting from the merging of the N1-P1 and N2-P2 components due to the high temporal frequency. In one study it was observed that the P1-N2 component of the transient PERG was more reduced than the N1-P1 component in glaucoma patients.48 Certainly, this relationship between the waveform components of both the transient and the steady-state PERG should be more completely evaluated.

Studies of the PERG in patients with ocular hypertension (see table 77.1) suggest that this retinal potential may provide a sensitive measure of retinal ganglion cell dysfunction that could be used to detect visual loss in ocular hypertensives prior to the development of glaucomatous visual field loss. PERG amplitude reductions are apparent in some, although not all ocular hypertensives (see figure 77.2). In different studies, however, the percentage of ocular hypertensives with abnormal PERGs has varied considerably. Porciatti et al.29 reported significant PERG amplitude reductions in 11 of 12 (91.6%) ocular hypertensives who had normal visual fields, while Wanger and Persson46 observed significant amplitude reduction in four of seven (57.1%) patients with unilateral ocular hypertension. Ambrosio et al.4 detected PERG amplitude reductions in 75% of the ocular hypertensives tested in their study but failed to indicate whether all of these were significant statistically. On the other hand, Trick et al.41 found significant PERG amplitude reductions in only 15 of 130 (11.5%) ocular hypertensives.

The high percentage of ocular hypertensives with PERG abnormalities that has been observed in some studies suggests that this retinal potential may be sensitive to early changes in visual processing that are associated with elevated IOP. However, this high figure also raises questions about the utility of the technique for predicting which patients will

develop glaucoma. Epidemiological evidence suggests that 0.5% to 2.0% of patients with mild to moderately elevated IOP (21 to 35 mm Hg) will develop visual loss each year.20 Long-term follow-up of ocular hypertensives suggests similar values.18,23 Thus the high percentages observed in some studies could also suggest that this technique has inadequate specificity (i.e., poorly discriminates the patients with impending glaucomatous visual field loss from other ocular hypertensives). The high percentage of abnormal responses observed in some studies may be partially the result of the small size of the samples tested and a loose definition of a significant deficit. In addition, it is likely that the sample selection criteria influenced the percentage of patients observed to have abnormal responses. Trick39 demonstrated that over 50% of ocular hypertensives who are considered to be at high risk of developing POAG (based upon a weighted combination of the following risk factors: age, IOP, family history of glaucoma, and cup-to-disk ratio) exhibit significant PERG amplitude reductions while less than 10% of low-risk ocular hypertensives exhibit these deficits. The larger group of ocular hypertensives later tested by Trick et al.41 were unselected for these risk factors and may have been composed of a large percentage of individuals who were at lower risk than the patients included in other investigations (e.g., Weinstein et al.48). Therefore, a prospective study will be necessary to eventually determine whether PERG amplitude reductions reliably precede the development of a glaucomatous visual field defect in these patients.

The exact relationship between IOP elevations and PERG amplitude reductions has not been determined. There is evidence that large, acute elevations in IOP (as might occur in angle-closure glaucoma or glaucoma secondary to ocular trauma) do produce reductions in PERG amplitude. However, in these cases the PERG amplitude reductions may not reflect only retinal ganglion cell dysfunction since the functional integrity of neural elements in the distal retina, the elements that provide input to the ganglion cells, is also disrupted by acute IOP elevations. It is uncertain whether smaller, chronic changes in IOP produce PERG alterations that are similar to the changes that occur as a result of acute IOP elevation. Among ocular hypertensives the correlation between IOP and PERG amplitude is weak (figure 77.4), while the association of other factors (such as age and blood pressure) with PERG amplitude may be as strong or stronger. This may simply reflect the variability in pressure tolerance of retinal ganglion cells between individuals, in which case evidence of intraindividual effects of elevated pressure may become obvious when prospective studies are completed. However, in an interesting study designed to separate the influence of IOP and retinal vascular perfusion on the PERG, Siliprandi et al.35 demonstrated that perfusion pressure rather than IOP plays the major role influencing the PERG. Perhaps, therefore, the

F 77.4 Among ocular hypertensives there is a weak, but statistically significant correlation between PERG amplitude and IOP (r = -0.16). The dashed line represents the best-fit linear regression (least squares) based upon the data for 153 patients.

PERG amplitude reductions associated with chronic glaucoma and ocular hypertension are more directly the result of retinal vascular changes and only indirectly result from elevated IOP.

Visual dysfunction in glaucoma and ocular hypertension has also been revealed in a variety of psychophysical studies. Color vision,1,42 contrast sensitivity,6 and temporal resolution43 deficits have all been observed in some ocular hypertensives as well as in glaucoma patients. The collective results of these studies suggest that the visual dysfunction associated with the development of glaucomatous damage is not constrained to the retinal areas where the characteristic visual field defects are observed; the damage often involves other retinal areas including the macula. Only color vision deficits have been demonstrated to precede visual field loss in prospective studies of patients developing glaucoma,10 but many glaucoma patients do not exhibit abnormal color vision,2,9 and the percentage of ocular hypertensive patients with color vision deficits exceeds the proportion expected to develop glaucoma.42 The relationship between these visual deficits and the visual dysfunction underlying the PERG abnormalities of glaucoma patients and ocular hypertensives has been explored incompletely. There is some evidence that the association between the color vision and the PERG deficits in ocular hypertensives is weak, a finding that could imply that different physiological mechanisms are involved in each deficit.

In a recent study Drance et al.9 examined the sensitivity and specificity of a variety of psychophysical, electrophysiological, and fundus imaging techniques in glaucoma patients, glaucoma suspects, and controls. The results indicated that both sensitivity and specificity were higher for the

PERG than for either color vision or contrast sensitivity. Several measures derived from optic disk imaging techniques, however, had higher sensitivity and specificity than did the PERG.

In conclusion, the PERG is a tool that has promise for investigating the pathophysiology of retinal ganglion cell dysfunction in glaucoma. Although it is doubtful that PERG will ever replace perimetry as the method of choice for detecting visual loss in glaucoma patients, it is clear that the technique can be a complement to the visual field in confirming a diagnosis of glaucoma. In addition, PERG studies should be considered in cases where it is difficult to obtain a reliable visual field. Nevertheless, it is important to remember that the precise sensitivity and specificity of the technique for detecting glaucomatous damage remains to be established. The clinical value of PERG for detecting retinal ganglion cell dysfunction in the ocular hypertensives who will develop glaucoma also remains an open question. However, prospective studies of the utility of the PERG in ocular hypertension are underway, so perhaps this issue will be resolved in the not too distant future.

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13.Fiorentini A, Maffei L, Pirchio M, et al: The ERG in response to alternating gratings in patients with diseases of the peripheral visual pathway. Invest Ophthalmol Vis Sci 1981; 21:490.

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15.Holder GE: Significance of abnormal pattern electroretinography in anterior visual pathway dysfunction. Br J Ophthalmol 1987; 71:166.

16.Howe JW, Mitchell KW: Simultaneous recording of pattern electroretinogram and visual evoked cortical potential in a group of patients with chronic glaucoma. Doc Ophthalmol Proc Ser 1984; 40:101–107.

17.Huber C: Pattern evoked cortical potentials and automated perimetry in chronic glaucoma. Doc Ophthalmol Proc Ser 1981; 27:87–94.

18.Jensen JE: Glaucoma screening: A 16-year follow-up of ocular normotensives. Acta Ophthalmol 1984; 62:203.

19.Korth M, Horn F, Storck B, Jonas J: Pattern electroretinograms in normal and glaucomatous eyes. Invest Ophthalmol Vis Sci 1987; 28 (suppl):129.

20.Leske MC: The epidemiology of open-angle glaucoma: A review. Am J Epidemiol 1983; 118:166.

21.Leydhecker G: The electroretinogram in glaucomatous eyes. Br J Ophthalmol 1950; 34:550–554.

22.Livingstone MS, Hubel DH: Segregation of form, color, movement and depth: Anatomy, physiology and perception. Science 1988; 240:740–749.

23.Lundberg L, Wettrell K, Linear E: Ocular hypertension: A prospective twenty-year follow-up study. Acta Ophthalmol 1987; 65:705.

24.Maffei L, Fiorentini A: Electroretinographic responses to alternating gratings before and after section of the optic nerve. Science 1981; 211:953–955.

25.Markoff JI, Breton ME, Shakin E, Franz J: Pattern reversal electroretinogram in glaucoma, glaucoma suspects and normals. Invest Ophthalmol Vis Sci 1983; 24 (suppl):102.

26.Marx MS, Podos SM, Bodis-Wollner I, et al: Flash and pattern electroretinograms in normal and laser-induced glaucomatous primate eyes. Invest Ophthalmol Vis Sci 1986; 27:378–386.

27.Marx MS, Podos SM, Bodis-Wollner I, et al: Signs of early damage in glaucomatous monkey eyes: Low spatial frequency losses in the pattern ERG and VEP. Exp Eye Res 1988; 46:173–184.

28.Papst N, Bopp M, Schnaudigel OE: Pattern electroretinogram and visually evoked cortical potentials in glaucoma. Graefes Arch Clin Exp Ophthalmol 1984; 222:29.

29.Porciatti V, Falsini B, Brunori S, et al: Pattern electroretinogram as a function of spatial frequency in ocular hypertension and early glaucoma. Doc Ophthalmol 1987; 65:349–355.

30.Quigley HA, Hohman RM: Laser energy levels for trabecular meshwork damage in the primate eye. Invest Ophthalmol Vis Sci 1983; 24:1305–1307.

31.Quigley HA, Hohman RM, Addicks EM, et al: Morphologic changes in the lamina cribrosa correlated with neural loss in open-angel glaucoma. Am J Ophthalmol 1983; 95:673–691.

32.Quigley HA, Sanchez RM, Dunkelberger GR, et al: Chronic glaucoma selectively damages large optic nerve fibers. Invest Ophthalmol Vis Sci 1987; 28:913–920.

33.Ringens PJ, Viifvinkel-Bruinenga S, van Lith GHM: The pattern elicited electroretinogram I. A tool in the early detection of glaucoma? Ophthalmologica 1986; 192:171–175.

34.Seiple W, Price MJ, Kupersmith M, Carr RE: The pattern electroretinogram in optic nerve disease. Ophthalmology 1983; 90:1127.

35.Siliprandi R, Bucci MG, Canella R, Cormignoto G: Flash and pattern electroretinograms during and after acute intraocular pressure elevation in cats. Invest Ophthalmol Vis Sci 1988; 29:558–565.

36.Sokol S: Visually evoked potentials: Theory, technique and clinical application. Surv Ophthalmol 1976; 21:18.

37.Towle VL, Moskowitz A, Sokol S, Schwartz B: The visual evoked potential in glaucoma and ocular hypertension: Effects of check size, field size, and stimulation rate. Invest Ophthalmol Vis Sci 1983; 24:175.

38.Trick GL: Anomalous PRRP spatial-temporal frequency tuning characteristics in glaucoma. Invest Ophthalmol Vis Sci 1983; 24 (suppl):102.

39.Trick GL: PRRP abnormalities in glaucoma and ocular hypertension. Invest Ophthalmol Vis Sci 1986; 27:749.

40.Trick GL: Retinal potentials in patients with primary open-angle glaucoma: Physiological evidence for temporal frequency tuning defects. Invest Ophthalmol Vis Sci 1985; 26:1750–1758.

41.Trick GL, Bickler-Bluth M, Cooper DG, et al: Pattern reversal electroretinogram (PRERG) abnormalities in ocular hypertension: Correlation with glaucoma risk factors. Curr Eye Res 1988; 7:201–206.

42.Trick GL, Nesher RN, Cooper D, et al: Dissociation of visual deficits in ocular hypertension. Invest Ophthalmol Vis Sci 1988; 29:1486–1491.

43.Tyler CW: Specific deficits of flicker sensitivity in glaucoma and ocular hypertension. Invest Ophthalmol Vis Sci 1981; 20:204.

44.van Lith GHM, Ringens P, de Heer LJ: Pattern electroretinogram and glaucoma. Dev Ophthalmol 1984; 9:133–139.

45.Wanger P, Persson HE: Pattern-reversal electroretinograms from normotensive, hypertensive and glaucomatous eyes. Ophthalmologica 1987; 195:205–208.

46.Wanger P, Persson HE: Pattern reversal electroretinograms in ocular hypertension. Doc Ophthalmol 1985; 61:27–31.

47.Wanger P, Persson HE: Pattern reversal electroretinograms in unilateral glaucoma. Invest Ophthalmol Vis Sci 1983; 24: 749.

48.Weinstein GW, Arden GB, Hitchings RA, et al: The pattern electroretinogram (PERG) in ocular hypertension and glaucoma. Arch Ophthalmol 1988; 106:923–928.

.

Chiasmal lesions

The principal cause of chiasmal dysfunction is pituitary tumor, the anatomical relationship between the optic chiasm and the pituitary gland making the chiasm susceptible to compression by lesions expanding from the pituitary fossa. The classic triad of neuro-ophthalmic signs in pituitary tumors of reduced visual acuity, visual field defects, and optic atrophy arises from suprasellar tumor extension with resulting compression of the chiasm. Other types of tumor, aneurysm, inflammation, demyelination, and trauma can also affect chiasmal function. A bitemporal hemianopia is the classic visual field defect due to a disturbance of the decussating fibers from the nasal retinae but occurs in less than 50% of patients with pituitary tumors and visual loss.42,78 Other types of visual field defect can result, including central scotoma. Approximately 13% of patients present with unilateral visual loss.25

The investigation of choice in patients with suspected chiasmal compression is neuroradiology, either magnetic resonance imaging (MRI) or high-resolution computed tomography (CT) scanning. There are probably two roles for electrophysiological testing. The first is in the initial assess-

result in severe irreversible visual loss, and it is therefore of critical importance that the correct diagnosis be reached promptly. Reports of misdiagnoses in the literature include (atypical) retrobulbar neuritis, glaucoma, cataract, hysteria, macular degeneration, refractive error, choroidal sclerosis, and vascular lesions.31,41,59,65 The second role for electrophysiology is in the follow-up and management of patients with radiologically confirmed lesions that might or might not show suprasellar extension and signs of visual pathway dysfunction and encompasses postoperative monitoring.

The likely involvement of the crossing fibers enables the use of hemifield stimulation in the visual evoked potential (VEP) assessment of chiasmal function, but adequate consideration of registration parameters is critical to VEP interpretation. A hemifield VEP abnormality may be the most sensitive electrophysiological index of early chiasmal

involvement, but some patients with reduced visual acuity have difficulty in maintaining accurate fixation, and it might not be possible to perform hemifield stimulation adequately in all patients. Full-field stimulation also gives accurate localization of chiasmal lesions but is slightly less sensitive.15,28 Multichannel recording is indicated; assessment of chiasmal function should not be attempted with a single midline channel.

An understanding of the results of hemifield pattern stimulation in normal individuals is important to accurate interpretation of the electrophysiological abnormalities in chiasmal dysfunction. Use of a large hemifield stimulus, for example, greater than a 12-degree radius, gives “paradoxical” lateralization of the normal P100 component of the pattern-reversal VEP ipsilateral to the stimulated hemifield.6 There is a contralateral N105/P135 complex. However, as the size of the stimulus field is progressively reduced, the P100 firstly becomes bilateral in distribution and then contralateral with a small hemifield stimulus (e.g., 2.5-degree radius36). Similar changes occur in patients with hemifield defects39 (see below). In general, when Fz is used as a reference, a small-field, small-check stimulus will show anatomical lateralization, whereas a large-check, large-field stimulus will show paradoxical lateralization. Bipolar recordings using ipsilateral hemisphere reference electrodes do not show paradoxical lateralization with any stimulus parameters, and the contribution to paradoxical lateralization of the signal recorded via the Fz “reference” is thus apparent.

Following the initial report by Muller52 that the flash VEP (FVEP) could be of abnormal latency in chiasmal dysfunction, other workers noted that the maximum FVEP abnormality was localized contralateral to the visual field defect.27,43,48,73 The first reports using contrast stimuli appeared in 1976. Van Lith’s group76 used both full-field and hemifield steady-state (8 Hz) stimulation in six patients with bitemporal hemianopia due to tumor, and found both phase and amplitude abnormalities contralateral to the stimulated eye.

The first detailed report of transient pattern VEP (PVEP) was that of Halliday’s group.34 Using a 16-degree radius, 50minute check stimulus, they found markedly asymmetrical

F 78.1 Crossed VEP asymmetry in a 48-year-old male with bitemporal hemianopia from a suprasellar mass (16-degree radius, 50-minute checks). A, With full-field stimulation, the normal P100 component is recorded over the right hemisphere when the left eye is stimulated and over the left hemisphere when the right eye is stimulated, that is, contralateral to the impaired temporal visual field and showing the phenomenon of paradoxical lateralization.

scalp distribution in ten patients with chiasmal dysfunction. In particular, they described the “crossed” asymmetry typical of chiasmal lesions in which the findings from one eye are more abnormal over one hemisphere but the distribution of abnormality changes such that findings from the fellow eye are more abnormal over the other hemisphere. Unexpectedly, the maximum abnormality was localized ipsilateral to the visual field defect, that is, the “paradoxical” lateralization referred to above (figure 78.1). PVEP abnormalities were present from some eyes with normal (kinetic) visual fields. The findings were contrasted to those in demyelination, in which preservation of waveform, a generally greater latency delay, and symmetry across the scalp were much more frequent. The use of hemifield stimulation was further elaborated in another publication by the same group.8

Holder38 confirmed this “crossed” asymmetry in ten patients, but when full-field stimulation (11-degree full-field, 26-minute checks, bipolar recording) was used, the maximal PVEP abnormality was always contralateral to the stimulated eye (figure 78.2). Although apparently contradictory, these findings are in fact consistent with those of Halliday’s group, the alternate abnormality lateralization reflecting the use of a smaller stimulating field/check size (see above). The abnormality lateralization was enhanced with a 4-degree radius, 13-minute check stimulus. It was confirmed that the

B, The use of hemifield recording demonstrates that the full-field responses reflect preservation of the responses to the preserved nasal fields. (From Halliday AM, Barrett G, Blumhardt LD, et al: The macular and paramacular subcomponents of the pattern evoked response. In Lehman D, Calloway E (eds): Human Evoked Potentials: Applications and Problems. New York, Plenum, 1975, pp 135–151. Used by permission.)

asymmetrical scalp distribution was atypical for demyelination and that abnormal VEPs could occur in eyes with full visual fields. Equally, normal PVEPs could occur in eyes with field defects. Latency delays were a frequent occurrence.

Those findings were extended in a study of 34 patients with histologically confirmed nonfunctioning chromophobe adenomas.41 The PVEP results were compared with clinical, radiological, and surgical findings. There were four eyes with normal PVEPs; one had a full visual field, one had a paracentral scotoma, and two had superior temporal quadrant defects. It is of interest that FVEPs in the latter two eyes were abnormal. Full fields but abnormal PVEPs occurred in two eyes. The PVEPs often indicated marked functional asymmetry when the neuroradiology (CT scan) suggested symmetrical midline suprasellar extension. The PVEPs were usually more sensitive than the conventional clinical tests of visual acuity and visual fields.

A number of other studies reported PVEP findings in chiasmal dysfunction, mostly (those using multichannel recording techniques) confirming the “crossed” PVEP asymmetry to be pathognomonic of chiasmal dysfunction but describing clinical and electrophysiological findings in varying degrees of detail.13–16,28,32,33,51,55,58,68,71 Gott and colleagues examined 83 patients with tomographically demonstrated pituitary tumors.32 Most were intrasellar and had normal fields and PVEPs. Suprasellar extension was radiologically

F 78.2 Crossed VEP asymmetry in a 48-year-old male with a nonfunctioning chromophobe adenoma showing crossed asymmetry of the VEPs. Use of a small field (11 degrees), small check stimulus (26 minutes), gives “anatomical” rather than “paradoxical” distribution of abnormality. The preoperative findings from the right eye show increased latency in the left hemisphere traces, in keeping with dysfunction of the decussating fibers from the right eye

demonstrated in 12 cases; all had abnormal PVEPs, but visual fields were normal in eight patients. The abnormality was usually an increased P100 latency, but asymmetrical scalp amplitude distribution was also observed (22-degree full field, abnormality ipsilateral to the field defect).

The ability of the PVEP to influence management was noted by Stark and Lenton,68 who cite one case with a radiologically confirmed pituitary tumor but unreliable clinical testing in which an abnormal PVEP prompted surgical intervention. Haimovic and Pedley33 found a delayed P100 (19 ¥ 13.5-degree hemifield, 31-minute checks, abnormality ipsilateral to the field defect) in one of 15 patients with hemifield stimulation but in four patients when full-field stimulation was used. This illustrates the difficulty in component identification with large-field stimuli, which can lead to spurious “delays.” Blumhardt7 forcefully argued this point. Others concluded that the VEP was not a suitable means of detecting subtle field defects following a study of eight patients51 with 5-degree hemifield, 50-minute checks: two patients who were normal, four with ipsilateral abnormality, and two with no lateralization. This failure to reveal abnormalities may relate to the choice of stimulus parameters and emphasizes the importance of this factor. The two patients with normal PVEPs were presumably postoperative because the visual field defects had “resolved.” There was, however, subjective desaturation to red. Flanagan and Harding28 carefully examined the effects of various stimulus parameters in nine patients with pituitary tumors; hemifield stimulation with a large-check, large-field stimulus was more sensitive than full-field stimulation in the early detec-

to the left hemisphere. Preoperative stimulation of the left eye shows an overall longer latency compared to the right eye, in keeping with a degree of optic nerve dysfunction; the right hemisphere traces are more abnormal than the left, in keeping with the chiasmal compression. Note the improvement after surgery such that the right eye findings no longer show any abnormality and the left eye findings now show no delay and less interhemispheric asymmetry.

tion of chiasmal dysfunction. This observation was later confirmed.13,15

Optimal use of medical therapy, such as bromocriptine, for pituitary lesions is aided by a sensitive, objective assessment of chiasmal function. Wass et al.74 first described PVEP improvement during bromocriptine therapy in patients with large pituitary tumors but did not supply full details. Pullan and colleagues examined hemifield PVEPs in five nonfunctioning and five functioning tumors (prolactinomata) before and after bromocriptine treatment.60 Suprasellar extension on CT scan was a criterion for patient selection. All patients with radiological evidence of tumor shrinkage showed PVEP improvement, as did one patient without evident radiological change. The author’s laboratory has also monitored patients with intrasellar lesions (unpublished data). Changes in the VEP may be the first indicator of functional involvement of the chiasm, preceding field loss, and thus precipitate a change from medical to surgical management. Serial postoperative VEP recording can also monitor the functional state of the optic nerves and chiasm in a patient following tumor excision (figure 78.3) and may help detect tumor recurrence prior to deterioration in visual fields or acuity. Similarly, some patients decline surgery when offered, and additional objective evidence of increasing visual pathway dysfunction may help them to reconsider.

VEP recording has also been used to monitor chiasmal function during surgery.2,17,20,26,54,61,77 There is no consensus in relation to the contribution of intraoperative recording to surgical outcome. There are inevitable limitations of the technique owing to the need for diffuse flash stimulation.

F 78.3 Serial VEPs in a patient with recurrence of a nonfunctioning chromophobe adenoma (11-degree full-field stimulus; 26-minute checks). The patient was aware of the recurrence but declined further surgical intervention. Initial findings from the right eye show a P100 component that is markedly delayed and is better seen in the ipsilateral hemisphere traces than the right in keeping with the lateralization expected with a small-field, small-check stimulus. The PVEP had become undetectable by March 1984 but without change in visual acuity. Right eye visual acuity dropped to 6/60 approximately one year later. The initial findings from the left eye show a well-formed PVEP in the ipsilateral hemisphere traces but marked abnormality in the right hemisphere traces in keeping with dysfunction of the decussating chiasmal fibers. The latency of the P10 component in the ipsilateral hemisphere traces increases by ~20 ms over a 4-year period with no deterioration in visual acuity. Note the continuing interhemispheric asymmetry. Visual fields were abnormal throughout but showed no significant deterioration. Neuroradiological investigation (CT scan) showed tumor expansion during the period of follow-up.

Chiasmal hypoplasia or aplasia can also be detected by using VEP techniques.4,70

The PERG has been suggested to be a useful prognostic indicator for visual outcome in the preoperative assessment of optic nerve compression in pituitary tumor.45,63 That has been confirmed in the author’s laboratories.57 An abnormal PERG correlates with a lack of postoperative recovery, presumably by demonstrating significant retrograde degeneration to the retinal ganglion cells.

The VEP is also of major importance in the demonstration of abnormal chiasmal routing in patients suspected of albinism.23 That issue is addressed elsewhere in this volume (see chapter 25).

Retrochiasmal lesions

U D The typical VEP appearance in unilateral retrochiasmal dysfunction is an “uncrossed” asymmetry in which there is an abnormal scalp distribution that is similar for each eye. The comments in the previous section regarding the influence of registration parameters on PVEP abnormality lateralization and component identification are equally applicable to retrochiasmal dysfunction and are of paramount importance to accurate interpretation of the findings. Although there are many reports of VEP changes, the development of improved neuroradiological techniques such as high-resolution CT scanning and MRI has greatly reduced any role that electrodiagnostic evaluation may have played in the diagnosis and management of these patients.

The PVEP is more sensitive than the FVEP in most conditions but needs a cooperative patient who is able and willing to fixate and concentrate. If this is not possible, the FVEP may give useful information. Equally, the two techniques can provide complementary information about the intracranial visual pathways (figure 78.4). A brief review of FVEP reports is therefore presented. There is consensus in the FVEP studies that any abnormality detected is lateralized to the side of the lesion (contralateral to the field defect) in unilateral hemisphere dysfunction, most differences relating to the incidence of abnormality in relation to the visual field defect. In summarizing the results of a number of studies with unilateral lesions, it seems that some 70–75% of patients with homonymous hemianopic defects have abnormal FVEPs, an abnormality being more likely to occur with complete homonymous hemianopia than with a quadrant- anopia.30,43–45,56,72,73 Some patients have FVEP abnormalities with lesions that do not produce a field defect.22,44,56 Abnormalities have also been reported to occur ipsilateral to the lesion with flashed pattern stimulation.64

The first report of contrast stimulation is that of Regan and Heron.62 By using a technique involving Fourier analysis, they found that the response to sine wave–modulated light was reduced, but that to pattern stimulation was normal, in a patient with a macular-sparing homonymous hemianopia. Wildberger et al.76 studied steady-state VEPs, both full-field and hemifield, in six patients with homonymous hemianopia and found abnormalities contralateral to the field defect but no difference between those with and without macular involvement.

Halliday’s group described the typical “uncrossed” asymmetry in homonymous hemianopia.8 When using full-field stimulation (50-minute checks, 16-degree radius), they found

F 78.4 Pattern (PVEP) and flash (FVEP) evoked potentials in a patient with a macular-sparing left homonymous hemianopia. PVEPs show no significant abnormality, but flash VEPs from both right and left eyes show an “uncrossed”

a markedly asymmetrical scalp distribution, the normal P100 component being recorded only over the damaged hemisphere, in keeping with the “paradoxical lateralization” originally described by the same group.6 Hemifield stimulation confirmed that the responses obtained with the full-field stimulus were due to preservation of the normal responses from the residual hemifield. Holder39 confirmed the “uncrossed” asymmetry in homonymous hemianopia but found the abnormality ipsilateral to the lesion when using small full-field stimulation (26or 13-minute checks, 5.5- or 4-degree radius) (figure 78.5). Although the cause of some controversy at the time, the apparently contradictory findings reflect the different registration parameters35,36 (see the previous section), in particular the size of the stimulating field and the avoidance of Fz as a “reference” electrode position. The lateralization of Halliday’s group was also demonstrated in a patient following unilateral occipital lobectomy for glioma by using similar techniques.39 Note that with an Fz “reference,” the abnormality lateralization is dependent on stimulus parameters, changing from paradoxical to anatomical with progressive reduction in stimulus field and check size (see figure 78.5).

Subsequent reports confirmed the “uncrossed” asym-

metry in retrochiasmal dysfunction.9,10,16,19,21,33,37,40,49–51,55,69

The main conclusions are that hemifield stimulation is more sensitive than full-field stimulation,19,33,49,55 that ear reference recording is unsatisfactory,37 and that, in general, the more severe the hemianopic defect, the more likely the PVEP to

asymmetry such that both eyes show relative latency delay in the traces from the affected right hemisphere. Note that the flash VEP is not subject to the phenomenon of paradoxical lateralization.

be abnormal. Normal PVEPs will often be found in quadrantic field defects.9,19,33,40 A dense, macular-splitting hemianopia can be expected to give an abnormal PVEP. The percentage of abnormal PVEPs in the presence of known field defects is in the region of 80–90%. Latency delay may be found, even with hemifield stimulation, in up to 25% of cases49 but does not approach the magnitude of that regularly seen in anterior visual pathway dysfunction. The problems of accurate component identification in the assessment of “delays” are again noted.

A particularly interesting report examined both P100 and the late P3 component in four patients with homonymous hemianopia, including one with clinical evidence of blindsight.66 The P3 was well formed to target stimuli in the preserved field for all four patients, but it was additionally present for target stimuli in the hemianopic field of the patient with “blindsight.” In contrast, the P100 component could only be recorded with stimulation of the preserved field in this patient. The authors suggested that cognitive processing could occur in the absence of subjective perception, presumably via a mechanism independent of the geniculostriate pathway.

B D C B Bilateral occipital lobe disease will result in bilateral homonymous hemianopic defects of variable severity; in its most severe form, there is complete cortical blindness. However, this may be denied by the patient (Anton’s syndrome). There

F 78.5 Pattern VEPs in a patient following left occipital lobectomy for glioma show the effects of variations in stimulus and recording parameters. The right occipital lobe is thus the main cortical origin of the potentials recorded. Channels 1 and 2 use occipital electrodes at O1 and O2 referred to an ipsilateral sylvian reference electrode. Channels 3 and 4 use the “Queen Square” montage (QS) with electrodes 5 cm anterior and lateral to the inion referred to Fz. Using a large stimulus field and check size, the QS montage shows “paradoxical” lateralization of the normal P100 component (arrowhead) such that it is recorded over the lobectomized left hemisphere. On reduction in field and check size, there

are few reports of PVEPs in patients with bilateral occipital infarction. Streletz et a1.69 describe the PVEPs in two cases as being of grossly abnormal waveform. Halliday’s group cite two cases, one with low-amplitude PVEPs of normal latency.9 Three personal cases39 all showed amplitude reductions, with latency changes seen in two of the three patients. Subsequent experience suggests that reduced amplitude responses are usually seen but that waveform abnormalities or mild latency changes can also occur depending on the degree of visual field preservation.

A later report describes PVEP findings in nine cases, some with bilateral occipital infarction.3 No response was seen in five cases, an increased latency in two, and normal findings in two. The findings correlated poorly with outcome. FVEPs were studied in ten patients, some with bilateral occipital infarction; these also showed poor correlation with outcome. There are even fewer reports of PVEPs in complete cortical blindness. Bodis-Wollner’s group11 report the case of a 6- year-old boy with normal PVEPs to high-contrast gratings and preservation of area 17 but destruction of areas 18 and 19 (partial in one hemisphere, complete in the other). Another single case is described with normal PVEPs yet bilateral destruction of area 17, with preservation of areas 18 (partial) and 19.18 They postulated that the PVEPs were mediated by extrageniculocalcarine pathways. A further patient had complete cortical blindness but normal latency PVEPs.3 Bodis-Wollner and Mylin12 studied the VEPs in two patients during recovery from cortical blindness with both monocular (gratings) and binocular (random dot correlo-

is a shorter latency response over the right hemisphere but no clearly identifiable component in the left hemisphere trace. Further reduction in field size results in the emergence of a normal P100 component in the right hemisphere trace and the appearance of a later positivity in the left hemisphere traces similar to that previously present in the right hemisphere traces with a large stimulus field. The exact stimulus parameters at which the transition from paradoxical to anatomical lateralization occurs can show marked interindividual variation. Note that the lateralization of the abnormality is constant using the sylvian reference montage, consistently showing the abnormality over the damaged hemisphere.

grams) simulation. The recovery of binocular vision occurred later than that of monocular vision. One further case is reported in which 1-degree 20-minute checks “sometimes” gave a response over one hemisphere 2–4 months following cortical blindness, but the exact nature of the stimulus is not defined and may be flashed pattern.56

Many more cases have been investigated using flash stimulation. Preserved FVEPs in cortical blindness have been described by some authors in adults,1,3,47,67 one group concluding that the FVEP was of prognostic value in basilar artery occlusion.1 Others examined childhood cortical blindness.5,24,29,52 In one series of 30 children, only one child with cortical blindness had extinguished FVEPs; some had abnormal FVEPs but appeared to have normal vision.29 The VEP was not thought a good method for diagnosing cortical blindness in children.

A recent study examined a group of children, some developmentally normal (DN; N = 14) and some developmentally delayed (DD; N = 16), who were “visually unresponsive.”75 The DN infants had normal visual function, with a small subset having normal VEPs and were considered to have visual inattention (VI). Sixteen infants had abnormal VEPs and abnormal neuroimaging studies (CT, MRI, or both) or microcephaly and thus were diagnosed as having cortical visual impairment. Visual acuity in these infants ranged from normal to no visual orienting to the low-vision Teller Acuity Cards. The inability to “fix and follow” in three further infants was attributed to oculomotor apraxia, and adjunctive oculomotor testing was recommended.

Electrophysiological examination is therefore of limited value in the clinical management of patients with retrochiasmal dysfunction, particularly with ever-improving neuroradiological techniques. However, the functional assessment provided by careful serial VEP recording can be valuable in the objective monitoring of disease progression or resolution and may add significantly to the clinician’s understanding of the underlying pathophysiological processes. Also, valuable information can be obtained by using electrophysiology as a research tool in the investigation of higher visual function.

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C measurements have a long history in the assessment of visual disorders caused by ocular pathology. Starting from the seminal studies of Halliday and his group of visual electrophysiological studies in multiple sclerosis (MS),90 other neurological disorders were investigated, using techniques of electroretinogram (ERG) and visual evoked potentials (VEPs) (figure 79.1). Surprisingly, visual studies not only in MS but also in Parkinson’s disease (PD) have allowed new insights into the pathophysiology of these neurological diseases and have revealed hitherto unknown aspects of visual system organization.

PD is generally known as a movement disorder, neuropharmacologically as a dopaminergic deficiency syndrome affecting the basal ganglia, and anatomically as loss of dopaminergic neurons of these structures. However, in the last two decades, anatomical, biochemical, neurophysiological, and clinical studies have demonstrated involvement of the central nervous system (CNS) beyond the basal ganglia. One of the affected areas is the visual system from the lowest level, from the retina up to the frontoparietal cognitive centers of the brain.

Because PD is predominantly a disease of the elderly, it is not surprising that many patients have visual complaints, such as tired eyes, blurred vision, and difficulty in reading. They may represent various etiologies and clinicians do not relate these nonspecific complaints to a disease known to be a “movement disorder.” Visual abnormalities specific to PD are usually hidden and not likely to be uncovered during a routine neurological examination or by ordinary highcontrast visual acuity (VA) testing. Contrast sensitivity (CS), a measure that can be affected independently from VA, provides a sensitive test for vision impairment in neurodegenerative diseases.26,28 Nonspecific visual complaints may, however, be related to impaired CS. Intact CS is very important for most visual functions,139 for example, for the normal perception and discrimination of depth.160 It is determined by the inverse of the minimal contrast necessary to distinguish objects of patterns presented at a given spatial fre-

quency (SF). CS is abnormal in PD.24,30,39,58,60,105,157 However, reduced CS in PD goes undocumented in the majority of patients, as many vision care specialists are not aware of testing for a potentially profound CS deficit in a patient with near normal VA. In CNS lesions, a VA score no worse than 20/40 may go along with a 20-fold reduction in CS to size of targets of considerable practical significance for everyday vision.26,28 The spatial and temporal selectivity of visual losses detected with CS in PD is consistent with the results of electrophysiological tests (electroretinogram [ERG] and visual evoked potentials [VEP]). Additionally, it has been shown that idiopathic PD patients, subjects with druginduced parkinsonism,109 and animals with experimentally induced parkinsonism81,82,84,110 exhibit similar visual impairments. The specificity of the common visual loss is likely to be due to dopaminergic deficiency. In all of these conditions, the visual impairment has been established with psychophysical and electrophysiological measures and supported by the results of neuropharmacological and histochemical studies.

MS commonly involves the visual pathways, as was noted as early as 1890 by Uhthoff.167 A spectrum of visual complaints exists, ranging from the manifestations of acute temporary demyelination of the optic nerve, resulting in sudden visual loss, to subtle clinical disturbance, which could be discovered only with neurophysiological or psychophysical testing. One of the breakthroughs in establishing the clinical value of VEP occurred when Halliday et al.90 first described that in carefully examined MS patients who have never suffered optic neuritis, commonly over 90% of subjects had abnormal, delayed VEPs. The original results, with slightly different percentages, were proven many times (see, for example, Logi et al.114). It is an established interpretation of visual deficits in MS that many patients may have suffered an asymptomatic involvement of the visual pathway.71,115 An understanding of this type of subclinical disease has been much aided by the availability of magnetic resonance imaging (MRI). Nearly all of the studies provide

F 79.1 Pattern visual evoked potentials, recorded from a midline occipital electrode from the left and right eyes of a healthy subject (A) and two patients who were recovering from acute attacks of optic neuritis in the right eye with onset four weeks (B) and three weeks (C) previously. (From Halliday AM, McDonald WI, Mushin J: Visual evoked response in diagnosis of multiple sclerosis. Br Med J 1973; 4:661–664; with permission of Lancet.)

evidence of more or less continuous disease activity,111,125,200 suggesting that even acute MS lesions do not give rise to symptoms or clinical signs. Recent data suggest that the damage caused by progressive subclinical lesions have a larger impact on the visual pathways than the damage caused by acute optic neuritis itself.115 Besides simple visual loss, MS patients are known to have heterogeneous neurocognitive disturbances, such as dysfunction of attention, visuospatial perception, memory, and executive mechanisms.141,153

In this chapter, electrophysiological studies of visual impairment in PD and MS are supplemented by psychophysical and imaging data when appropriate. We shall focus our discussion on the known physiology of neuronal receptive fields in the retina and cortex and on the relationship between the physiology of the visual pathways and the known or putative pathogenesis of PD and of MS. For each disease, we first discuss retinal, optic nerve, and primary visual cortical causes of visual impairment. Second, we discuss visual electrophysiological measurements that address cognitive aspects of visual processing, most likely involving extrastriate and nonoccipital cortices. We emphasize the clinical importance of new or newer versions of electrophysiological techniques that have emerged in the last decades as the result of physiological and pathophysiological studies of the visual system.

Electrophysiology and visual psychophysics of visual deficits caused by retinal and primary visual pathway involvement

P ’ D The deficiency of the neurotransmitter dopamine (DA) involves several CNS areas that sub-

serve vision. In the retina, DA is localized within amacrine and interplexiform cells.74 Dopaminergic neurons subserve a modulatory role in the retina and mediate center-surround interaction for establishing the receptive field structure of ganglion cells.33 Autopsy studies have shown decreased retinal DA concentration in PD93 but not in patients who received levodopa therapy shortly before their death. In the monkey retina, dopaminergic deficiency is achieved by systemic administration of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP), which causes a PD-like picture in nonhuman mammals.110 Furthermore, systemic MPTP and intraocular 6-hydroxydopamine, a known selective toxin of dopaminergic neurons, cause comparable retinal effects,82 as shown by neurohistochemistry and in vivo pattern ERG (PERG) recordings.

Spatial and temporal frequency contingent visual loss in PD: The importance of stimulus selection in clinical electrophysiology Following the original report of Bodis-Wollner and Yahr36 demonstrating delayed VEP in PD patients, there has been considerable controversy concerning visual changes in PD. However, in the ensuing decades, many electrophysiological and psychophysical studies have provided evidence for the validity of visual impairment in PD (for a review, see BodisWollner24). To demonstrate visual dysfunction, it is important to use visual stimuli that are optimal for foveal ganglion cells with strong center-surround organization, as dopamine appears to act as an essential neurotransmitter for receptive field organization.34 PERG records the activity of retinal ganglion cells (optic nerve cell body)116 and hence indirectly reflects the preganglionic retinal circuitry, which is essential for the center-surround organization of the mammalian retinal ganglion cells.34 Both PERG11 and VEP45 vary as a function of spatial and temporal parameters of the stimulation. Therefore, the visual electrophysiological abnormalities in PD remained controversial until studies critically evaluated electrophysiological responses to these parameters of stimulation.22,132,144,183 It became apparent that specific visual stimulus constraints are necessary for demonstrating dopaminergic deficits. These studies revealed that the VEP and PERG abnormality in PD is most evident for foveal stimuli of medium and high SFs—above 2 cycles per degree (cpd)—where normal observers are most sensitive for the visual stimuli,22 as shown by CS testing. Using stimuli of sinusoidal gratings of 50% contrast that were counterphase modulated at 7.5 Hz with a SF ranging from 0.5 to 6.9 cpd, Tagliati et al.181 have shown that aging and PD lead to different types of losses in the retina. In aged normal subjects, the PERG reflects a loss, compared to younger observers, at all the studied SFs, while PD patients showed a specific loss peaking at 5 cpd. Consequently, all PD patients had an attenuated PERG “tuning ratio,” calculated as the PERG amplitude of ratio of medium (5 cpd) to low (1 cpd) SF amplitudes

F 79.2 The PERG tuning function in PD: PERG spatial transfer function obtained in patients (squares) and age-matched subjects (diamonds). The functions are parallel at lower SF and very close at the higher SF tested (6.9 cpd). (From Tagliati M, BodisWollner I, Yahr MD: The pattern electroretinogram in Parkinson’s disease reveals lack of retinal spatial tuning. Electroencephalogr Clin Neurophysiol 1996; 100:1–11; with permission.)

(figure 79.2). The tuning ratio of the PERG covaried with the severity (Hoehn and Yahr scale) of PD. Because lack of tuning of the spatial CS in PD shows some similarity to the CS in normal subjects at reduced (scotopic) light levels, it has been suggested that DA is involved in the process of dark adaptation and the parkinsonian retina behaves as though inappropriately dark-adapted.201 However, PD patients do not show high SF losses when properly refracted, while the scotopic CS is not only low-pass, but also narrowed in spatial bandwidth. This is not the case in PD owing to the fact that DA deficiency has a specific and predictable effect on centersurround interaction of the receptive field and is responsible for the band-pass shape of spatial tuning in the retina at photopic levels. Indeed, light onset can increase the metabolism, or it can increase the DA release in the retina.51,65 Constant light exposure decreases the D2 receptor sites, which is associated with the decrease of sensitivity of presynaptic melatonin receptors.63 It is likely that enhanced DA release will augment the cell’s luminance contrast response by weakening the strength of the surround on the final retinal ganglion cell output, which is the difference of center and surround responses (as discussed below).

The role of DA in spatial processing in the retina The data above imply that the function of DA is rather complex. Indeed, animal and human physiological and pathophysiological studies have revealed a specific role of DA in neural signal processing.24,146,173 Pharmacological studies using D1 and D2 antagonists or a D1 agonist suggested that D1 and D2 recep-

F 79.3 The receptive field model representing signal summation over a retinal ganglion cell receptive field, as described by Enroth-Cugell and Robson.70 Upper diagram illustrates the concentric center and surround region. Signal from the center (C) and surround (S) have an antagonistic effect on the ganglion cell, expressed by the opposite sign of the C and S signals, either an on-center (+C) or an off-center (-C). Lower diagram shows the Gaussian profiles, assumed to describe the sensitivity of the center surround. (Adapted from Enroth-Cugell C, Robson JG: The contrast sensitivity of retinal ganglion cells of the cat. J Physiol (Lond) 1966; 187:517–552; with permission.)

tors synergistically optimize the spatial properties of retinal ganglion cells (for reviews, see Bodis-Wollner and Tagliati,33 Bodis-Wollner and Tzelepi34). The response of most retinal ganglion cells are based on center-surround antagonism of the receptive field, which was quantitatively described by the difference of two Gaussian functions70 (figure 79.3). Pharmacological studies have shown that D1 deficiency weakens the surround response and enhances low spatial frequencies, while D2 antagonists reduce the center response and suppress peak SF responses. The net result of D1 and D2 activation is therefore an enhanced center response to stimuli that have dimensions of the center diameter of the largest foveal ganglion cells (figure 79.4). On the basis of the results of human pharmaco-ERG studies, it has been also suggested that presynaptic D2 “autoreceptors” are involved in the surround D1 dopaminergic pathway.34 This interpretation is based on the fact that a high dose of -sulpiride (a D2 receptor blocker) allows greater DA effect on D1 receptors and enhances surround signals and therefore attenuates low SF responses.180 The results of experimental manipulations of DA on visual processing converge to an understanding of changed CS functions in dopaminergic deficiency, as has been described in PD.

In PD, foveal spatial vision is affected, as shown by impaired CS and electrophysiological measures to patterns with a SF above 2 cpd.30,175,181 On the basis of studies in PD and in the monkey model of PD, which show that the

F 79.4 The antagonistic effect of D1 and D2 receptor activation acting on different arms of the seesaw. As a consequence, the doubly opposite effects produce an overall synergistic action. The space underneath the curve represents the overall spatial frequency transfer function of the retina: Low-frequency decline occurs where D1 receptors are active. The peak of the curve is created by the seesaw pointing to the right. (Adapted from Bodis-Wollner I, Tzelepi A: Push-pull model of dopamine’s action in the retina. In Hung GK, Ciuffreda KC (eds): Models of the visual system. Kluwer Academic Publishers, 2002, pp 191–214; with permission.)

normal primate CS curve changes into a low pass function, the physiological spatial CS curve cannot represent a single type of ganglion cell in the primate retina. Nearly 40 years ago, Enroth-Cugell and Robson70 established the properties of cat retinal ganglion cells, describing their output as reflecting the linear interaction of center and surround organization for X cells and as a nonlinear process for Y cells. It was later shown by Hochstein and Shapley97 that Y cells have the same basic linear properties as X cells with the addition of nonlinearities originating from receptive field subunits. Another difference, originally pointed out by Enroth-Cugell and Robson,70 was a difference in the ratio of center versus surround receptive field diameter. It was also shown that center and surround mechanisms are cocentered; that is, the same very central photoreceptors contribute to both center and surround. Many later physiological studies, also in primates, have shown additional anatomical and functional differences in the properties of these two major classes of foveal ganglion cells. However, it remained uncontested that the retinal contribution to the normal foveal CS function relies on two types of retinal ganglion cells. For

understanding the role of DA in retinal processing, BodisWollner and Tzelepi34 reached back to the classical description of the retinal ganglion cell output as reflecting the linear interaction of two mechanisms, the center and surround, each of the two represented by a Gaussian profile of different size and height but cocentered and having different size ratios for the two classes of foveal ganglion cell (figure 79.5).

The results of vision studies in dopaminergic deficiency syndromes suggest that the two major foveal retinal ganglion cell classes are different concerning the predominant role of DA in their respective receptive field organization. This difference emanates from the role of D1 and D2 receptors, which have differential roles in the surround and center organization. On the basis of the role of dopaminergic mechanisms, it has been suggested that one class of ganglion cells has a dominant surround mechanism and strong D1 receptor–coupled dopaminergic mechanisms, mediating the response to low spatial frequencies. The receptive field of the second class of foveal neurons is dominated by the center organization, which is aided by strong D2 receptor activation by DA, which can amplify the response of the center through photoreceptor coupling. This type of neuron mediates the response to middle and high SF stimuli. D1 DA receptors themselves are at the front end of the retina, mediating horizontal cell coupling strength, important for the surround mechanism. Center photoreceptors themselves of course contribute to both. The signals of the receptors that feed into the center and into the surround organization remain most likely separate until they converge on their ganglion cells. Accordingly, Dacey et al.56 described two types of bipolar cells, which exhibit two types of center-surround organization. Smaller bipolars have stronger centers, while larger ones have stronger surrounds. It is possible that each type of ganglion cells receives input from similar bipolar input but is under the influence of neuropharmacologically different presynaptic organization.

Parallel pathways and vision in PD It should be emphasized that the pathophysiological evidence of separating foveal retinal ganglion cells into two classes, based on their dominant DA receptor and receptive field organization, is consistent with the notion of parallel pathways originating in the retina. However, there is no evidence that dopaminergic deficiency selectively affects one of these pathways. Rather, the opposite is true: Dopaminergic deficiency causes reduced activity of both classes of DA receptors. The reduction in the activity of both types of receptors, reducing the strength of the center and the subtractive surround, results in the lowpass retinal spatial transfer function in dopaminergic deficiency.

The effect of L-dopa on vision in PD CS loss does respond (at least acutely) to levodopa therapy in PD.40,99 Acute visual

F 79.5 Simplified schema of the D1–D2 interaction of the retina. The D1 DA pathway enhances the surround signal, while the D2 pathway enhances the center signal. Experimental results suggest that these two DA pathways are not independent of each other: D2 is involved in the D1 pathway participating in a negative

changes are especially striking in chronically treated patients who develop ON-OFF motor phenomena, having dyskinetic-akinetic motor fluctuations on a daily basis, according to the DA replaced or depleted state. In the OFF state, visual abnormalities are prominent, while they are less evident in the ON state.32 In ON-OFF patients, CS changes in tandem with motor fluctuations,30 revealing a normally tuned CS function in the ON state and a low-pass shape in the OFF state, suggesting that SF tuning is under dopaminergic modulation. A marked effect of levodopa therapy has been demonstrated on the PERG tuning ratio between patients treated and not treated with -dopa.181 PD patients receiving -dopa had higher PERG amplitude and improved SF tuning compared to untreated patients, although they have rarely achieved normal values (figure 79.6). These results suggest that L-Dopa therapy has a lasting effect on retinal processing.

Generally, both VEP and PERG impairments are sensitive to levodopa therapy,142,143 although there is an apparent

feedback loop, providing a greater D1 effect when D2 receptors are blocked. (Adapted from Bodis-Wollner I, Tzelepi A: Push-pull model of dopamine’s action in the retina. In Hung GK, Ciuffreda KC (eds): Models of the visual system. Kluwer Academic Publishers, 2002, pp 191–214; with permission.) (See also color plate 51.)

difference: Levodopa therapy improves PERG abnormalities to a higher degree than it does VEP deficits. One possible interpretation is that VEP changes in PD represent secondary, nondopaminergic and therefore more chronic alterations in visual processing. An essential proof of visual system involvement in PD and the relationship of visual and motor changes was recently provided by a longitudinal study of visual dysfunction in PD patients: CS is impaired in parallel with the worsening of motor score.60 These results therefore suggest that the visual system shares with the motor system progressive degeneration of dopaminergic neurons and/or progressive failure of the effect of -dopa therapy.

Visual losses in PD that may not be direct consequences of dopaminergic deficiency The foregoing discussion makes a case for the conclusion that visual dysfunction is an integral part of PD: The deficit fluctuates with motor symptoms in ON-OFF patients and worsens with the progression of motor symptoms. While the role of DA deficiency is strongly implied by

F 79.6 Effects of -dopa therapy on PERG amplitude. PERG amplitude obtained in age-matched subjects (triangles) and PD patients receiving (squares) and not receiving (diamonds) - dopa are plotted as a function of SF. PD patients receiving -dopa show higher values and better tuning compared to untreated patients, although they rarely achieve normal values. The dashed line represents the mean noise level during recordings. Error bars indicate standard error. (From Tagliati M, Bodis-Wollner I, Yahr MD: The pattern electroretinogram in Parkinson’s disease reveals lack of retinal spatial tuning. Electroencephalogr Clin Neurophysiol 1996; 100:1–11; with permission.)

all these studies, DA deficiency may not be exclusively responsible for visual changes in PD.

It has been noted that in dopaminergic deficiency, the spatial CS abnormality is even more profound when the grating is temporally modulated at 4–8 Hz,32,157 suggesting that a dopaminergic deficiency state also affects temporal processing.119 However, little is known of the relationship of the two types of retinal DA receptors to dynamic processing in the retina.

Compared to the clinically standardized pattern reversal stimulation, pattern onset/offset VEP is rarely used in patient studies, although it has been extensively studied physiologically.172,188,193 Onset versus offset VEP amplitude differs in healthy normals: The onset VEP amplitude is factors larger than the offset response. This is not so in PD, and the onset/offset amplitude ratio provides a simple measure to quantify one specific aspect of impaired vision.12 When horizontal sinusoidal gratings with 1 and 4 cpd were used, the evoked P1 offset amplitude was significantly larger in PD patients than in controls, particularly for 1 cpd, while onset P1 values and offset P1 latency did not show significant differences between patients and controls. It is known that onset versus offset retinal responses may be separated by using selective glutamate receptor blockers.166 The relevance of dopaminergic deficiency or other neurotransmitter alteration, such as the involvement of selective glutamate recep-

tor subtypes in the retina and beyond in generating the “supernormal” offset VEP in PD, has not yet been established. Although the findings appear robust and intriguing, no other studies have yet addressed the ramifications of these challenging results in PD.

There is a potential pathophysiological role of serotonin in the retina. Tremor is one of the cardinal symptoms of PD, but its treatment with dopaminergic agents is less than satisfactory. Recently, Doder et al.62 have shown that serotonergic dysfunction in PD, more precisely 5-HT1A receptor binding in the nucleus raphe, correlates with tremor severity. The original studies by Mangel and Brunken118 have revealed retinal dopaminergic amacrine cells with high affinity to 5-HTT. While it is not inconceivable that some visual dysfunction related to retinal serotonergic dysfunction, there have been no studies concerning this area.

Color vision deficits in PD Color vision abnormalities have frequently been reported in PD patients,18,41,42,60,94,95,129,147,152 most prominently in the blue-yellow axis (tritan). These short-wavelength sensitive cones are relatively scarce in number in the retina and therefore are more separated than middleand long-wavelength cones. Also, their behavior differs in many aspects from that of the other cones, providing input to the red-green pathway. Thus, the preservation of their receptive fields is mainly dependent on the interactions among dopaminergic interplexiform and amacrine cells, which are dysfunctional in PD.94,95 It is also possible that there is a loss of inhibitory inputs from dysfunctional dopaminergic interplexiform cells through D1 receptors to GABA-ergic horizontal cells. The diminished action of DA on D2 receptors also can diminish coupling and hence the overall sensitivity of cones. However, color test results should be handled very carefully because commercially available tests are often unlikely to be helpful in identifying the color deficiency in PD.18 For example, it was observed that general performance on some of these color tests is age related.18 Therefore, it is very important to use an age-matched control group for these experiments.

The abnormality of color vision (on both the blue-yellow and red-green axes) can be reversed by dopaminergic drugs.42 Impairment of color (red-green) VEP was more responsive to levodopa therapy than VEP evoked by luminance contrast stimuli.14 Although color vision abnormalities were not correlated with dopaminergic nigral degenerations as measured by single photon emission computer tomography (SPECT),128 the severity of parkinsonian symptoms and scores on the United Parkinson’s Disease Rating Scale (UPDRS), a generally accepted clinical measuring tool of motor impairment in PD, showed significant correlation with the error score of certain color vision tests.128

It has been thought that color vision impairment may be partially determined by motor deficiency in PD155 because

when the response does not require a motor action, then color vision impairments are not significant. However, the noted ERG and color VEP abnormalities are not consistent with this explanation.18,41,42,94,95,152 Furthermore, Diederich et al.59 found worse color discrimination in PD patients with visual hallucinations compared with patients without hallucinations. Further studies are necessary to clarify the relationship of color vision and motor abnormalities in PD.

Are there visual cortical deficits in PD? The evidence is that PERG changes in PD are linked to retinal dopaminergic deficiency. However, the retina may not be the only site of visual pathology in PD. The lateral geniculate nucleus2 and the visual cortex have dopaminergic innervation.154 Asymmetrically lateralized primary visual cortex glucose hypometabolism has been demonstrated in PD. The most severe abnormalities are contralateral to the most severe motoric dysfunction.37 It is therefore possible that occipital hypometabolism indirectly reflects basal ganglia dysfunction rather than being a consequence of disordered retinal input. Another possibility is that occipital hypometabolism reflects intrinsic cortical pathology.

Consistent with the notion of intrinsic cortical pathology is that CS losses in PD depend on pattern orientation. Orientation selectivity of visual neurons is first established in the primary visual cortex of primates and most mammals.19,202 The deficit in PD is more severe for horizontal patterns than for vertical patterns.38,157 This finding does not fit into the concept of retinal dopaminergic deficiency as the cause. One possible explanation may be visual cortical pathology in PD. The presence of intraocular differences in CS and VEP in PD is consistent with either retinal pathology58 or pathology affecting monocular columns in V1. However, it is difficult to explain the orientation-dependent CS abnormality in PD on the basis of retinal mechanisms. On the other hand, contrast adaptation, which has a cortical origin, is spared in PD.184 Studying the effect of dopaminergic therapy on orientation selective losses in PD may be valuable.

M S

The PERG in MS The PERG depends on the normal functioning of the intraretinal cell body of the optic nerve;116 therefore, one may expect an abnormal PERG in patients with optic nerve pathology. However, the intraretinal optic nerve fibers are myelinated in only 10% of humans; therefore, one would expect the PERG to be abnormal if there is primary axonal or preganglionic retinal pathology. From the known pathology of MS, the initial effect on the optic nerve is not at the cell body but at the myelinated optic nerve. Therefore, in MS or in any other demyelinating disease, PERG changes may perhaps occur only some months after acute optic neuritis as a secondary consequence of demyeli-

nation and retrograde degeneration of the retinal ganglion cells and axons. Indeed, it is a fact that normal PERG can be recorded during the acute stage of optic neuritis, and PERG abnormalities occur only after recovery from the symptoms of optic neuritis.163 In MS patients who were previously affected by optic neuritis, a correlation exists between PERG changes and the degree of optic nerve fiber loss (representing intraretinal axonal death). This result is consistent with the notion that a PERG abnormality in MS is secondary to demyelination.140

While several studies reported normal PERG amplitude and latency in the majority of MS patients with or without signs of optic neuritis,102,168 other investigators have shown decreased PERG amplitude in MS patients.71 PERG spatial tuning in MS was studied with sinusoidal grating stimuli with 8-Hz temporal modulation over a range (0.6–4.8 cpd) of spatial frequencies.71 MS patients with a previous history of optic neuritis or without optic neuritis showed general amplitude decreases that were worse at medium and high SFs. Thus, both groups had a low-pass shaped SF response curve; however, the PERG phase was delayed only in the optic neuritis group independently from the SF used. This is particularly important since several studies48,49,69 attempted to show that one of the two major classes of retinal ganglion cells, each sensitive to a slightly different range of spatial frequencies, are selectively vulnerable in MS.

All in all, PERG studies in MS are contradictory.71,102,140,168 It appears that the PERG has not yet proven itself in providing essential clinical information concerning the optic nerve in MS.

in PD or in any other disease with select involvement of certain types of neurones, appropriate pattern stimuli need to be selected for the best diagnostic yield. Pattern presentation (reversal versus on/off), stimulus details, such as element size or SF composition, orientation, and luminance do influence VEP diagnosis: Different stimuli may stimulate different and differentially vulnerable neuronal channels. Surprisingly, despite this physiological constraint, different stimulation parameters provide somewhat similar diagnostic yields of the VEP, suggesting that MS does not preferentially attack one or another stimulus-specific visual pathway. Employing more than one stimulus condition results in increased diagnostic yield.20,21,48,50 This increase in diagnostic yield can be understood as a simple result of increasing the probability of “hitting” different stimulus specific pathways that are unselective as far as the pathology of MS is concerned. These results are probably due to the fact that MS affects the nervous system haphazardly in a patchy manner.

Increasing the diagnostic yield by exploring the response to more than one type of stimulus was first shown by Camisa

F 79.7 Visual evoked potentials in two patients with definite

(A) and possible (B) MS. A, The latencies are normal for check stimulus and for oblique gratings. With the vertical grating there is a considerable delay in the left eye. B, The patient has normal and symmetrical latencies for all stimuli except vertical gratings, for which there is a 24to 30-ms interocular difference. (From Camisa J, Mylin LH, Bodis-Wollner I: The effect of stimulus orientation on the visual evoked potential in multiple sclerosis. Ann Neurol 1981; 10:532–539; with permission.)

et al.,41 who used pattern orientation as a variable (figure 79.7). Celesia et al.48 have obtained steady-state VEPs to sinusoidal gratings of several SFs and determined that applying more than one SFs can increase the diagnostic yield by 17%. Using checkerboard stimuli, different studies have found abnormal VEP latencies in 30–95% of patients with suspected MS, depending on the degree of clinical signs and symptoms.149 The main drawback in using conventional checkerboard VEP stimulation methods is that the results are less specific.31 Both false negatives and false positives are more likely with checkerboard pattern stimulation. Checkerboard pattern evoked responses are predictably more degraded by pure optical factors (undercorrection);20 hence, a poor checkerboard pattern evoked VEP might not be due to MS. Alternatively a false negative result may occur because the checkerboard pattern contains energy at many different spatial frequencies and orientations; hence, the response may be dominated by the responses of a healthy neuronal channel.27 In addition to spatial and temporal stimulus factors, pattern presentation (reversal versus on/off) and response component selection all influence the diagnosis. Ghilardi et al.83 have demonstrated that even the different

components of pattern VEP (N70 and P100) can be independently affected in patients with MS. Indirectly, this evidence suggests that the VEP latency is determined by intrinsic cortical processing and not only by optic nerve conduction.

VEP delay and cortical pathology in MS Consistent with earlier suggestions21,44,131 that VEP abnormalities in ON and MS have a postretinal origin, there is no correlation between VEP abnormalities and optic nerve fiber layer thickness in MS.140 The original theory, that VEP abnormalities in MS may represent intracortical pathology, emanated from findings concerning orientation selective visual losses.44,159 Orientation-specific effects in MS were originally demonstrated with psychophysical determination of CS as a function of grating orientation. These impairments were commonly observed at medium spatial frequencies.114,159,190 Camisa, Mylin and Bodis-Wollner44 reported that while the specific orientation (e.g., vertical versus horizontal) of a grating stimulus did not appreciably influence VEP latency of control observers, over half of MS patients exhibited orientationdependent delays of the VEP. This original finding was supported by several subsequent studies.43,54,103,104,114,190

Kupersmith and his colleagues estimated CS functions on the basis of VEP amplitude in MS patients.103,104 Four different orientations (0, 45, 90, and 135 degrees) and three spatial frequencies (low, medium, and high) were used. The study shows that more orientation-specific rather than SFspecific VEP abnormalities exist in MS. Moreover, orientation and SF abnormalities do not covary (they might be independently abnormal and different in MS patients). Logi et al.114 measured VEP and CS, comparing vertical and horizontal gratings using 1 and 4 cpd. They found that the use of vertical grating in clinical routine is more reliable for both VEP and CS measurements independently from the SF. However, Celesia et al.48 determined that using more SFs is equally important and can significantly increase the diagnostic yield in MS.

In summary, optic nerve pathology is not sufficient to explain orientation-dependent VEP latency changes in MS. Several electrophysiological studies have demonstrated that directional-selective circuitry exits in rat and rabbit mammalian retina (for the most recent, see Fried et al.76) and suggested that amacrine cells have a key role in the modulation of this circuit. However, pathology of amacrine cells of the retina in MS has never been demonstrated, and there is no evidence of directionally selective retinal circuits in the primate retina. In the cat,185 retinal ganglion cell receptive fields are not perfectly round; rather, they have an ovoid shape along the principal meridians. However, their aspect ratio is less than 1.3, while the human VEP latency orientational asymmetry can be well over 30%. Bodis-Wollner et al.29 suggested that orientation-dependent selective impair-

ment may occur if myelinated intracortical axonal branches, which “zip” together monocular orientation columns of neighboring visual field, suffer from patchy demyelinating processes. Thus, at present, the best explanation for orientation-dependent VEP losses in MS is demyelination of intracortical branching axons, connecting monocular orientation columns representing contiguous chunks of the visual field (figure 79.8).

The relationship of VEP and psychophysical measures of visual sensitivity in MS How close is the relationship between delayed VEP and visual acuity (VA)? An attack of optic neuritis starts with a sudden visual loss and decrease to a very low VA level (1/10), such as light perception. At this acute stage, the VEP is found to be nonrecordable.1 Delayed VEP is generally found in patients with VA remaining higher than 2/10. Delayed VEP recovers to normal with time in accordance with the recovery of VA; however, the recovery of subjective vision that time is still not perfect.9 Sanders et al.163 have reported that impairment in VEP amplitude is more related to decreased VA than VEP delay. However, a recent study has reported significantly decreased VEP amplitudes in MS patients with normal VA.61 In addition, a slight latency increase of VEP was also observed.

How close is the relationship between delayed VEP latency and reduced contrast sensitivity (CS)? CS and VEP are independently affected in MS29 (see figure 79.8). For one, CS is obtained at low contrast (threshold contrast), while the VEP is elicited with high-contrast patterns. It was suggested that CS is more sensitive than VEP because abnormal CS with normal VEP or less impaired VEP compared to the significantly reduced CS were observed.108,114 Additionally, CS measurements show a higher rate of abnormalities in MS and optic neuritis fellow eyes compared even to visual field testing,10,123,134,158,170 suggesting the diagnostic advantage of low-contrast patterns. Second, CS measurements test all “points” in the central 4–8 degrees of the retina, but deficits may lie outside the central 8 degrees.26,28,29,158,170

Advantages of visual field (VF) and CS testing were combined in a new test, called contrast perimetry (CP), to detect visual impairment in MS.3 With this method, as opposed to customary VF testing with punctuate stimuli, all “points” in the paracentral retina are tested with grating patterns covering several degrees of the visual field. In this study, the stimuli ranged in diameter from 1 to 8 degrees and were Gaussian apertured vertical sinusoidal gratings of 1 cpd, randomly presented in four paracentral VF quadrants. The independent variable was stimulus (grating patch) size, the independent variable being contrast. The largest CS decrease was found not with small but with large-sized stimuli (figure 79.9). This is different from CP changes in glaucomatous optic neuropathy (GOND). In GOND, the deficit is best seen with small stimuli.25 The explanation of this specific result in MS may

be that the mechanism of cortical interneuronal connections necessary for spatial summation suffers and is responsible for some visual deficits in MS, as was suggested by Bodis-Wollner et al.29 to explain orientation-dependent VEP changes in MS. Myelinated lateral cortical interconnections establish binding between neurons covering the same area of the VF but belonging in different functional groups. In the parafoveal area, optimal binding may occur over an area representing 2 to 4 degrees of visual space. Additionally, previous studies have established that myelinated axons of the visual cortex make like-with-like connections of monocular, orientationselective columns.121,189 Pattern VEP studies use extended visual stimuli as stimuli. When demyelinization affects intracortical like-with-like connections, then monocular deficits would be predicted to stimuli, which are oriented and extended patterns, as was shown by several VEP and CS

studies.44,83,103,104,158

Parallel pathways and MS There is little cellular-pathological evidence the affinity of MS to select visual pathways. However, there have been many attempts to evaluate whether MS functionally affects selective visual pathways.

Several studies57,73,120,126,145,150,156,195,196,203 have examined

the demyelination process of so-called parvocellular pathway and ventral stream projections and magnocellular pathway and dorsal stream connections, respectively. These parallel routes are segregated from both morphological and functional points of view. Magnocellular channels are responsible mainly for the analysis of motion and spatial location, whereas parvocellular channels are related to the processing of pattern and color. Physiological data from animals and humans demonstrated that certain experimental parameters allow a relatively predominant stimulation of the parallel pathways.112,169 It was inferred by some145,156,208 that magnocellular functions are more affected in MS and optic neuritis; others found that chromatic (parvocellular) function is more sensitive to MS.126,150,196 A third group of studies reported that luminance and chromatic responses are unselectively affected in MS.57,73,120,195

In a detailed study, steady-state (2–24 Hz) and transient chromatic and achromatic PERGs and VEPs were recorded by using high-contrast (90%) stimuli at low (0.3 cpd) SF.150 Chromatic CS was also measured at 5 Hz as a function of color ratio. Both transient and steady-state chromatic and achromatic VEPs and PERGs were delayed and decreased; however, chromatic PERGs displayed abnormalities to a higher degree. Chromatic VEP delays were remarkable also in the fellow, clinically normal eyes. CSs were reduced in the optic neuritis eyes for both luminance and chromatic gratings. On the basis of the results, it was suggested that the parvocellular stream probably is more impaired in optic neuropathy than the magnocellular stream. The observations of a recent MRI study support this hypothesis.46 Patients with

F 79.8 Contrast detection threshold measurements were taken for several gratings of different spatial frequencies. The patient’s contrast threshold was compared to the normal subject’s and charted as a visuogram. A, Normal VEP latency (122 ms) and normal visuogram OD, prolonged VEP latency (146 ms) and borderline visuogram OS, in a patient with probable MS. VAs were 20/20 OD and 20/25 OS. B, Normal visuogram in a 54-year-old woman with the spinal form of MS. VA was 20/20 OU. The VEPs had increased latencies (158 and 162 ms) in both eyes. C, Visuogram of a patient with definite MS who had cerebellar symptoms

and blurred vision in each eye separately and occurring episodically. The visuogram shows a high SF loss in the right eye only. VA was 20/20 OU. The evoked potential latency, on the other hand, is more prolonged in the left eye (144 ms as opposed to 134 ms in the right eye). (D) Bilaterally increased latency (140 ms OD, 150 ms OS) in a patient with probable MS. VA was 20/20 OU. The visuogram is abnormal in OD and borderline in OS. (From BodisWollner I, Hendley CD, Mylin LH, Thornton J: Visual evoked potentials and the visuogram in multiple sclerosis. Ann Neurol 1979; 5:40–47; with permission.)

F 79.9 Mean CSs as a function of the diameter (size) of the Gaussian limited patch of a grating pattern (so-called GABOR) in 26 normal observers, 23 definite MS patients, and eight probable MS patients. The increase of CS as a function of the size of a sinusoidal grating of a fixed spatial frequency (1 cpd) was explored in four quadrants of the VF field. The central 16 degrees of the VF were tested, and Gabor patches were localized to a point 4 degrees along the

secondary progressive MS were studied by using isoluminant red and green sinusoidal gratings of the same SFs combined out of phase for the stimulation of the parvocellular system and in phase for the stimulation of the magnocellular system. CS loss was highly correlated with lesion area seen on proton density MRI sequences of the postchiasmal pathway. Additionally, the parvocellular pathway was more affected than the magnocellular pathway.

Sartucci et al.164 compared the relative involvement of chromatic visual subsystems (parvocellular and koniocellular), recording VEPs to onset and offset of equiluminant sinusoidal gratings. According to VEP data, the red-green and yellow-blue axes appear to be equally involved.

A recent longitudinal study (for nine years) employed the visual testing technique, called high-pass resolution perimetry (HPRP). The study found that asymptomatic visual losses could be discovered already at the onset of relapsingremitting MS, and these losses progress only slowly during the course of MS.115 HPRP primarily tests high SF contrast sensitivity. Therefore, resolution perimetry losses in MS were attributed to the impairment of neurons selective for high spatial frequencies. High SF resolution is synonymous with good visual acuity. Therefore, if MS selectively affected high SF sensitive neurons, patients who have resolution perime-

diagonal from fixation without crossing the midline. Note that the CS decrease in patients was most pronounced at intermediate sizes of 2.5 and 3.7 degrees in both patient groups. The greatest number of eyes with abnormal CS was also found at these diameters. (From Antal A, Aita JF, Bodis-Wollner I: The paracentral visual field in multiple sclerosis: evidence for a deficit in interneuronal spatial summation? Vision Res 2001; 41:1735–1742; with permission.)

try losses should have lowered VA, correlating with the magnitude of the high SF loss. However, many MS patients have normal VA. There is little physiopathological evidence that demyelination affects the select class of parvocellular neurons. An explanation for high SF loss is not reconcilable with nonselective demyelination of the optic nerve, however, and it is unlikely to be caused by demyelination of the cortical like-with-like connections for the following reasons. Spatial summation area is inversely related to SF; that is, for normal detection of different SF gratings, the number of cycles is constant.80 A larger area is therefore needed for the detection of low SF gratings, and one would predict that pathology affecting intracortical connections would first affect the detectability of low, and not of high, SF gratings. To explain high SF losses in resolution perimetry by the process of demyelination, one would have to assume that the area necessary for the detection of gratings is actually larger for high rather than for low spatial frequencies. This is contrary to the psychophysical results, although no direct data exist on the spatial extent of intralaminar connections for different classes of SF selective neurons of the visual cortex.

The CP results,3 along with VEP results obtained with oriented pattern stimuli, suggest that the optic nerve demyelination affecting only one type of optic nerve fibers

could not be the sole source of visual defects in MS. MS pathology probably also causes scattered lesions of the network relying on myelinated lateral connections of the visual cortex, which may be detected with CP.

One possible resolution of the conflicting results and suggestions concerning MS selectivity for parallel pathways could come forth if visual studies critically selected patients on the basis of the duration and course of their disease. The summarized data provide some suggestion that MS imparts different vulnerability and damage to one of the two systems, depending on the chronicity of the disease. By using a spectrum of neuropsychological tests to quantify visuoperceptual dysfunctions in MS, it has been suggested that magnocellular pathway impairment occurs earlier in the course of MS,194 while apparently, a more profound parvocellular pathway deficit may exist in advanced MS; a short time course of MS may led to an opposite conclusion regarding the selective involvement of parallel pathways of vision. Taken together, these data do not suggest an easy pathophysiological explanation concerning selective neuronal involvement in the visual pathways in MS.

Higher visuocognitive abnormalities: Electrophysiology and psychophysics

P ’ D Many aspects of consciously controlled information processing, such as planning, problem solving, decision making, and response selection are associated with the functions of frontostriatal circuits.78,85,86,135–137 A dopaminergic dysregulation of this subcorticocortical system in PD leads to apparent higher-level cognitive dys- functions.53,78,122,136–138 Recent electrophysiological, neurophysiological, and functional imaging studies have attempted to link impaired and selective aspects of cognitive processing and related neuronal mechanism to the pathological anatomy and pathophysiology of PD. There is a considerable number of studies that have used visual stimuli to evaluate higher-order visuocognitive dysfunction in PD. Some of these studies controlled for the possibly contributing effect of lower-order (primary) visual dysfunction to cognitive defects. The most commonly used electrophysiological method to evaluate cognitive defects utilizes the power of event-related potentials (ERPs).

ERPs are thought to index the timing of stages of information processing such as stimulus evaluation, response selection, and context updating.107 ERPs are recorded in response to an external stimulus or event to which the subject is consciously paying attention. They are often elicited in the so-called oddball paradigm, in which subjects distinguish one rarely presented stimulus (target) from other stimuli (nontargets).176 The most extensively studied ERP component is the P300, appearing 300–400 ms after the onset of the target stimulus. P300 amplitude is maximal at

the midline electrodes (Cz and Pz) and is inversely related to the probability of the eliciting event.

Many visual ERP studies yielded a delayed P300 latency only in demented PD patients,87,174,175,179,187,198 although several studies reported a prolonged P300 latency in nondemented patients.8,161,177 This suggests that the slowness of visual information processing may be independent of or precede global dementia. However, it is uncertain why P300 latency is affected in some but not in all studies of nondemented PD patients. First, differences in visual paradigms should be taken into account. Wang et al.197 have observed that different interstimulus intervals (ISI) could differentiate PD patients from controls: Cognitive processes reflected by P300 latency to rare target stimuli were influenced by longer ISI in PD patients but not in control subjects. Second, P300 latency during the oddball paradigm in PD was also influenced by age at test, age at onset, and duration of

illness.8,161,197

Is a delayed visual P300 the passive consequence of primary visual delay? It is known that in the primary visual evoked potential (VEP), the P100 component, is delayed in PD.36 However, while P100 is delayed to patterns of spatial frequencies above 2.3 cpd in nondemented PD patients, the most evident P300 delay occurs to lower spatial frequencies.8 The possibility that a prolonged visual P300 latency is only a passive consequence of the P100 delay was ruled out by concurrently obtaining P100 and P300 measures in a visual ERP paradigm in PD.8,161 A prolongation of the normalized P300 latency (P300 - P100 latency difference, called central processing time) differentiated younger PD patients from controls.8 These data suggest that younger PD patients could be differentiated from other types of PD by using a concurrent VEP and visual P300 recording. These data were confirmed in non-Caucasian PD patients, who again conspicuously were the younger and not older patients.161 There is also neuropharmacological evidence that the visual P300 in PD is affected directly in PD. Amantidine shortened the latency of the visual P300 with little or no effect on the primary VEP component.13

Apparently, functional changes in visual cognition are reflected in separate electrophysiological mechanisms: Not only P100 and P300 are independently affected in PD; the analysis of earlier cognitive ERP components, such as N200, showed that its abnormality is uncorrelated with a change in P300.8 The visual N200 that follows P100 and precedes P300 is probably a visual form of the auditory mismatch negativity.182 This component is more negative for the infrequent deviant stimuli and is distributed over the extrastriate visual areas and the posterior-temporal cortex. N200 latency was delayed in nondemented PD patients, even when P300 was not prolonged using a simple visual paradigm.8 In a semantic discrimination task, the same result was found.177 These data further suggest that visual deficits and processes

indexed by various components of the visual ERP may reflect parallel processing.

patient is receiving should also be considered. Studies in MPTP-treated monkeys suggest that levodopa therapy alone does not affect the visual P300,84 although D2 receptor blockade could influence it.5 In patients, levodopa treatment has been found to shorten the latency of P300.171,174 However, some investigators have described a prolonged P300 latency in medicated patients.91,151 Accordingly, it has even been suggested that cognitive slowing in PD is related to abnormalities of nondopaminergic systems.148 A recent study is consistent but does not prove this hypothesis: P300 latency decreased in PD patients treated with amantidine, a low-affinity, uncompetitive NMDA receptor antagonist, even if they were on chronic levodopa therapy.13 However, amantidine’s effect might not be confined to glutamate receptors. It is thought that amantidine also acts as a dopaminomimetic substance, whether directly or indirectly, such as disinhibiting DA pathways. It is known that D1 receptor is involved in visual working memory in the prefrontal area (for a review, see Goldman-Rakic85). In the classical oddball paradigm, which is commonly used to elicit the P300 component, a target stimulus has to be stored in the working memory to be compared with subsequently presented stimuli for decision making. In addition, the prefrontal cortex was identified as one of the generators of P300.89 However, a recent study has found that the lateral occipital cortex also plays an important role in visual working memory,17 but there is no information about the neuropharmacological background of these processes.

Cholinergic agents are thought to enhance cognition and improve memory functions in healthy subjects and in several neurodegenerative disorders (for a recent review, see Freo et al.75). Therefore, it is not surprising that PD patients treated with anticholinergic drugs usually show poorer performance on different shortand long-term memory tests and have impaired cognitive shifting in card-sorting tests.64,113 It was determined by several studies (for a review, see Frodl-Bauch et al.77) that cholinergic substrates influence P300. However, there are no published studies of modifying the P300 in PD with anticholinergics.

Although numerous studies have analyzed P300 latency, only a few have examined P300 amplitude in PD. P300 amplitude increases when more attention is allocated, as in the case of unexpected or complex tasks. However, it is conceivable that raw P300 amplitude is misleading, since a nonspecific, age-related low voltage EEG recording could cause low P300 amplitude.8 Measuring the P300/P100 amplitude ratio could give a more reliable measure of the nature of amplitude alterations. Indeed, it was found that by this

measure, the individually normalized P300 amplitude provides a robust separation of younger nondemented PD patients from older patients and from age-matched control subjects8,161 (figure 79.10). It was observed that P300 amplitude changes parallel with the difficulty level the task, accordingly to the load on working memory;79 therefore, the detailed analysis of P300 amplitude gives also information about the impaired functioning of prefrontal areas.

Electrophysiological differential diagnosis of PD and related disorders

Most event-related potential (ERP) studies have used an active condition to evoke the P300 component (silent count or button press to the visual or auditory target stimuli). However, there is another positive wave, called P3a or passive P300, that is elicited by unexpected neutral stimuli under conditions of passive attention. This component is thought to reflect automatic cognitive processing. While P3a amplitude did not distinguish between demented PD patients and agematched controls, it separated the group of demented PD patients from Alzheimer’s disease patients.179 This result suggests that an abnormality of the passive P300 may depend on the specific underlying neuropathology of dementia.

Differentiating between multiple system atrophy (MSA) with striatonigral degeneration and idiopathic PD is often difficult, since autonomic failures or signs of pyramidal and cerebellar dysfunction may develop only late in the course of the disease. However, vision is usually less affected in MSA compared with PD, since the DA deficiency in the latter is generally recognized to be more pronounced. According to this evidence, visual tests may have significant values in the differential diagnosis of MSA and PD.

Although cognitive dysfunction was not considered a main feature of MSA, mild cognitive deficits are not uncommon. A recent study100 has found that the early negative components (N1 and N2) of the visual ERP were normal in the MSA group; however, the P3a component was frequently undetectable in the MSA group. Significant difference in P3b latency and P3b amplitude was found only in the MSA group, showing dominantly cerebellar features, not parkinsonian symptoms. In the MSA group, P3b latency significantly correlated with the size on MRI of the pons and the cerebellum.

In the future, a better differentiation of idiopathic PD and overlapping dementing illnesses such as diffuse Lewy body disease may be possible by using selective cognitive paradigms for visual electrophysiological studies.

Electrophysiological evidence of visual categorization impairment in PD

The vast majority of human mental activities are based on categorical processes. In everyday life, we classify the components of our environment into discrete categories as a cornerstone of adaptive and purposeful behavior.92 Electrophysiological evidence suggests that in the temporal

F 79.10 The P300/P100 (cognitive against primary ERP) amplitude ratio in normal subjects and in PD patients. A, Right eye. B, Left eye. C, Both eyes. To avoid confounding factors of absolute amplitude differences due to generally low-voltage recordings or poor primary visual responses, P300 amplitudes normalized to P100 amplitudes were evaluated. Individually normalized

domain, categorization processes can be divided into early and late phases. Basic visual feature encoding and initial stages of perceptual categorization take place in the first 200 ms poststimulus, whereas conceptual and semantic properties are represented in later stages of information processing.96,165 There is growing evidence that the motor symptoms first observed in PD are also accompanied by progressive neuropsychological deficits, including impairment of semantic memory and categorization processes. Thorpe and his associates found that nonanimal scenes elicited more negative responses than did images with animals even at 150 ms following stimulus onset (N1).186,192 In spite of relatively preserved basic-level visual functions, this difference was not observable in the PD group.6,7 Previous studies suggested that the striatofrontal system not only is necessary for higherlevel cognitive functions, including planning, attentional set-shifting, and problem solving,137 but also seems to be responsible for learning new categories and for generalization to novel exemplars of well-learned categories. The electrophysiological results above suggest that dopaminergic

P300/P100 ratios provided significant distinction of younger PD patients from age-matched controls. (From Antal A, Pfeiffer R, Bodis-Wollner I: Simultaneously evoked primary and cognitive visual evoked potentials distinguish younger and older patients with Parkinson’s disease. J Neural Transm 1996; 103:1053–1067; with permission.)

deficiency in the striatal and prefrontal areas may lead to the impairment of natural scene classification even when the mechanisms of visual analysis (occipito-temporal regions) are relatively spared. In this view, posterior visual areas do not distinguish between natural categories; a cooperation of the striatofrontal system is necessary for such functions.

Wang and his coworkers also measured the amplitude difference of N1 component using a delayed matching S1–S2 task.199 In this paradigm, first a simple geometric design is presented (S1), followed by another stimulus (S2), which can be the same or different as S1. ERP recorded only for S2 stimuli. Similarly to the above-mentioned studies, Wang et al.199 found a smaller amplitude difference in the patient group compared to normal subjects.

The N400 component of ERPs has been extensively investigated as an indicator of semantic relatedness: Pictures and words appearing in an incongruent semantic context elicit more negative N400.106 However, only a few studies investigated N400 in PD.124,178 Despite the methodological differences, reduced N400 amplitudes have been reported.

Electrophysiological evidence of impaired corticocortical interactions in PD The “binding” hypothesis of visual perception assumes that it is not feasible to provide specialized brain areas for each of the multitude of different tasks. Rather, different areas have to be “bound” together within very short time intervals to solve perceptual tasks.68 The binding mechanism is reflected in high-frequency, so-called gamma rhythms, representing neuronal synchrony. Gamma rhythms were originally revealed by intracerebral recordings and more recently in humans by advanced methods of analysis of the surface-recorded electroencephalogram (EEG).

Since the EEG represents nonstationary potentials, its frequency content changes as a function of time. Consequently, fast Fourier transform (FFT), which misses information about time, is not the ideal way to analyze short time bursts of electrophysiological rhythms. Techniques that are able to track frequency changes over time are necessary to analyze nonstationary potentials. The evaluation of visuocognitive dysfunction in PD was therefore extended, using wavelet analysis117 of the oscillatory brain activities, which occur at around 20–40 Hz and are known as gamma-band activity.35 This rhythm exists spontaneously and/or can be evoked, induced, or emitted in different structures of the CNS in response to olfactory, auditory, somatosensory, and visual stimuli or in connection with attentional/perceptual-cognitive processes. In normal observers, gamma range activity is enhanced during the N70 of the VEP and suppressed during the P300 time period.72,127,191 This cortical suppression is thought to reflect competitive hippocampal gamma activation associated with P300 target processing.191 In this case, hippocampal gamma activation may be due to short-term memory updating. Alternatively, according to the threshold regulation model by Elbert and Rockstroh,66 the P300 component of the ERP could represent an inhibition of the cortical pyramidal neurons responsible for gamma oscillation. In PD patients, the lack of “cognitive” gamma suppression may reflect visuocognitive processing deficits during the performance of the task. Gamma is known to be prevalent, for instance, in bistable conditions, such as ambiguous figures,101 which promote switching percepts. At this point, no such studies have been published on PD patients.

Levodopa therapy increases corticocortical coherence in PD patients.47 Using simple visual tracking, a task-related coherence increased after levodopa therapy, while without levodopa, coherence was reduced. It appears that ascending dopaminergic projections from the mesencephalon may modulate the pattern and extent of corticocortical coupling in visuomotor tasks.

M S

Electrophysiological correlates of visuocognitive deficits Visuocognitive deficits in MS are rarely selective. Complex impairments in attention, memory, and cognitive skills are frequently

noted, however, and they tend to vary from patient to patient (for a review, see Comi et al.52). In the early phases of the disease, the mental disturbances are usually absent or subtle, but they tend to progress with the disease, with phases of stability, which can last months or years. However, some patients can present severe cognitive dysfunctions at the beginning of the disease, and some have normal mental abilities even in the more advanced phases. Little is known about the natural history or characteristics of progression of these cognitive dysfunctions. Similar patterns in impairments of visuocognitive processes have been described in patients with lesions involving the white matter of the frontal lobes and also in patients with basal ganglia disorders.55 Recently, attempts have been made to identify the connections between lesion locations and visuocognitive deficits; however, the results have been contradictory owing to several factors: MS lesions are very heterogeneous and may have different functional consequences, such as that a neuropsychological test rarely addresses only the function of one area but draws on interconnections with other areas as well.

It has been suggested that auditory ERPs are more sensitive markers of cognitive dysfunctions in MS;88,141 however, several visual ERP studies found latency increase of late ERP components,67,130,133,141 amplitude reduction of the N2–P3 components,130 abnormal topography of P300,133 or even the absence of ERPs.133 Delayed ERPs are more common in patients with secondary progressive MS compared to other subgroups.67

There are too few studies that evaluate whether the ERP is predictive for the development of cognitive dysfunction during the course of the disease. A 31-year-old patient with ON only on the left eye was observed for five months.15 Auditory and visual ERPs were within normal limits 8 days after the onset of symptoms, at which time MRI showed several lesions of cerebral white matter. Twenty-eight days later, the number of MRI lesions had increased, and the auditory ERPs showed amplitude reductions; however, the visual ERPs remained well defined, with an N2-P3 amplitude increase parietally. Reaction times and performance were unchanged. Two week, later there were new lesions on MRI; however, some of the previous ones had disappeared or become smaller. While the auditory ERPs returned toward normal, there was no significant change in visual ERPs. Two weeks later, the patient developed optic neuropathy in the previously unaffected eye, and the MRI showed new cerebral lesions. Yet, the auditory ERPs were similar to the first (normal) recording; however, all of the visual ERP components showed significant delay. (Visual acuity was poor at that time, so it is possible that the delayed visual ERP delay was related to poor central vision.)

Correlation with imaging results There have been a number of studies designed to determine the connection between ERP

abnormalities and MRI lesion volumes.98,130,162 A high correlation was found between the MRI score and the incidence of abnormality on the ERP tests.130 MRI total lesion volume correlated with reduced N2 amplitude, which had mainly frontal distribution in this visual task.162 This study suggests that the total lesion volume probably is a more important factor in neurocognitive changes than the lesion location.

Conclusions

Neurophysiological, electrophysiological, and anatomical studies of the past decade provided new information of visual and visuocognitive changes in PD and MS. Until fairly recently, PD was traditionally characterized as a motor disorder resulting from a deficiency of the nigrostriatal dopaminergic system. Only in the last decades has its systematic classification been extended to incorporate visuospatial, visual perceptual, visuomotor, and visuocognitive impairments next to other sensory and vegetative dysfunctions. Abnormalities of electrophysiological and psychophysical tests, such as VEP, PERG, and CS, have provided evidence that the visual system is directly affected by dopaminergic deficiency. Animal models of PD have established a link between the visual abnormalities observed in PD and dopaminergic deficiency. In PD patients and in the monkey model of the disease, visual deficits improve acutely by -dopa therapy. As PD progresses, -dopa therapy seems to be less effective, and the clinical progression of the disease is paralleled by chronic progressive visual impairment, despite continued therapy. Although it is known that a dopaminergic dysregulation of the corticosubcortical system in PD patients may lead to higher-level visuocognitive dysfunctions,4 it is likely that underlying cognitive changes are codetermined by noradrenergic and cholinergic deficits and the appearance of cortical Lewy bodies.137

While one form of MS is characterized by intermittent appearance of clinical symptoms, compelling new evidence suggests continuous disease activity. Thus, despite the presence of new symptoms, it appears that many MS lesions are subclinical.111,125,200 While subclinical pathological changes are probably present earlier than clinical signs in MS, they can be detected with selective, sensitive visual tests, such as with contrast perimetry (CP), which combines the advantages of conventional contrast sensitivity and perimetry testing. It has in fact been shown that GOND, directly affecting the retinal ganglion cells, and demyelinating optic neuropathy, as in MS, have different CP signatures. The evidence is that GOND affects a type of ganglion cell with a broad spatial tuning profile, while MS affects overall (large scale) spatial summation. This result, suggesting the impairment of myelinated interconnections of neurons responding to adjacent visual spaces, is consistent with suggestions derived from VEP studies. It was shown that the VEP delay

in MS is pattern orientation dependent. VEP provides a near-selective and sensitive test for MS if it is elicited with at least two principal orientations of the visual stimulus grating patterns of medium (around 5 cpd) SF. This result is inconsistent with precortical pathology and suggests the involvement of the myelinated like-with-like horizontal interconnecting system of monocular columns of the visual cortex. These interconnections are likely candidates to supply ocular and orientation specific “zipping” of neuronal receptive fields to provide a unitary percept of the VF.

The relevance of primary (retinal) visual pathology to higher-level visuocognitive deficits in MS is not yet evident. There are so far few studies that have explored visuocognitive changes in reference to the notion that cortical interconnections are affected in this disease. Elucidating their relationship would be of pathophysiological and clinical interest. In both PD and MS, the role of other than dopaminergic processes involved in distributed parallel processing provides an area for future research, using modern techniques of clinical electrophysiology, such as wavelet transform of the EEG, transcranial magnetic stimulation, and event-related functional MRI.

In summary, in PD a specific retinopathy affecting center/surround interactions contributes to visual dysfunction. In MS the visual dysfunction is not entirely due to the demyelination of the optic nerve; rather, intracortical processing is also affected.

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R is an early consequence of the lysosomal storage diseases that are collectively referred to as the neuronal ceroid lipofuscinoses (NCLs) and the fatty acid oxidation disorder long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD) deficiency. This review summarizes recent developments that have been made in diagnosing and understanding the molecular bases of these disorders. The first symptoms of many of the NCLs often relate to visual loss from retinal degeneration. The resulting decrease in vision is typically evident at an early age, and the ophthalmologist may be the first specialist to examine the patient. Since the fundus of a young patient may be normal or not diagnostic of specific disease, the eventual diagnosis of the NCL often must come from additional testing. Since the retina is a readily accessible portion of the central nervous system, tests of retinal function have potential value not only for diagnosis, but also for future treatment trials in NCLs and LCHAD deficiency as rational interventions become available. This review will summarize ERG findings in young children with these metabolic disorders. Because the degeneration is often severe, even at an early age, specialized techniques developed for patients with retinitis pigmentosa are also necessary for analyzing the very small (submicrovolt) electroretinograms (ERGs).1,2

The neuronal ceroid lipofuscinoses (NCLs) are a group of progressive neurodegenerative disorders characterized by the accumulation of complex storage material within lysosomes. As a class, the NCLs are the most common neurodegenerative disorders affecting children. In a recent survey of the causes of intellectual and neurological deterioration in childhood, the NCLs represented the largest category with 16% of cases. All storage diseases combined accounted for 63% of cases. The worldwide incidence is

1:12,500 live births.14 The disease is characterized by severe psychomotor deterioration that progresses to a vegetative state, seizures, visual failure from retinal degeneration, and premature death.5,8,18 Four classical forms exist—three childhood-onset forms, which are all autosomal-recessive, and one adult-onset form, which may be autosomal-reces- sive or -dominant:

1.An infantile-onset form (INCL, CLN1), also called Haltia-Santavuori disease, Hagberg-Santavuori disease, or simply the Finnish form. This usually manifests at 8–24 months of age with severe psychomotor retardation, blindness, and microcephaly.

2.A late infantile-onset form (LINCL, CLN2), also called Jansky-Bielschowsky disease. This condition manifests at 2–4 years of age with ataxia, loss of speech, regression of developmental milestones, seizures, and later gradual loss of vision.

3.A juvenile-onset form ( JNCL, CLN3), also called Batten-Mayou syndrome, Spielmeyer-Vogt disease, or Spielmeyer-Sjögren syndrome, which manifests at 4–8 years of age with visual acuity loss that progresses to loss of virtually all useful vision over a year or two. Seizures, cognitive decline, and motor disturbances follow.

4.The adult-onset disorder (ANCL, CLN4 ),also called Kufs’ disease, usually manifests as a motor disturbance usually without visual symptoms or findings. Although Kufs’ disease is believed to be an autosomal-recessive trait, auto- somal-dominant inheritance has been described.

In addition, as many as 15 atypical forms have been described, some of which may be allelic to certain of the classical forms. One of the variant forms (vLINCL, CLN5) occurs essentially only in the Finnish population and shows

linkage to a site (13q22) distinct from the three classic forms of childhood NCL.16 In Europe, the term Batten’s disease is often used collectively for all forms of NCL.

All forms of NCL show accumulation of storage material that is autofluorescent, sudanophilic, and PAS-positive within lysosomes in neurons and other cells. Because of its osmophilic nature and appearance on light microscopy, the storage material resembles ceroid and lipofuscin but actually is a complex mixture of lipoproteins and other hydrophobic peptides. The lipoprotein deposits within cells on electron microscopy take on characteristic patterns that are used for diagnosis and classification. Granular inclusions are seen in INCL, Kufs’ disease, and some atypical forms of JNCL. Curvilinear inclusions predominate in classic LINCL. Variant forms of LINCL often show a mixture of curvilinear and fingerprint profiles. Fingerprint inclusions are seen in JNCL (with occasional to rare curvilinear inclusions). Historically, the diagnosis of this group of disorders has been established by looking for inclusion bodies in cells from brain biopsy or full-thickness rectal biopsy. More recently, skin or bulbar conjunctival biopsies have supplanted these more invasive surgical procedures. Buffy coat leukocytes can be used but may include a wider range of inclusions that may represent other storage disorders, such as the mucopolysaccharidoses. Muscle biopsy appears to be the only tissue suitable for diagnosis for ANCL or Kuf ’s disease.

The defective gene CLN1 for INCL encodes the enzyme palmitoyl-protein thioesterase-1 (PPT-1), an enzyme that removes long-chain fatty acids, mostly palmitate residues, from S-acylated proteins. As such, this enzyme is necessary for the reversible palmitoylation-depalmitoylation cycles used by signal transport proteins. Patients with INCL accumulate fatty acid esters of cysteine in their cells.7,18 The most common mutation is R122W, which accounts for 98% of disease chromosomes in Finland but is rare in other parts of the world. In the United States, R151X is the most common CLN1 mutation, accounting for about 40% of mutant alleles. The gene CLN2 for LINCL encodes a pepstatininsensitive lysosomal peptidase (TPP-1), which cleaves tripeptides from the N-terminus of small proteins before their degradation by other lysosomal proteases.6 The gene for the Finnish variant form of LINCL (CLN5) has been found to be a transmembrane protein that shows no homology to previous proteins and is distinct from the proteins defective in the other forms of NCL. The gene CLN3 for JNCL has been cloned and mutations have been defined, although the function of the gene is not known. The most frequent mutation for JNCL is a 1.02-kb deletion that is present in 90% of abnormal alleles in Finland and in 81–85% of abnormal alleles worldwide.18

Vision loss in the three classic childhood forms (INCL, LINCL, and JNCL) typically involves central vision initially and eventually results in profound visual loss, often with

complete blindness, within a few years after the onset of symptoms. The ERG becomes abnormal early in all forms of the disease and within a few years is usually totally abolished to standard single-flash recording techniques. Functional testing of patients with retinal degeneration involves both psychophysical and electrophysiological measures. Among psychophysical measures, visual acuity and visual fields quantify the degree of visual impairment from the disease and are important for determining the necessity of, and eligibility for, a variety of low-vision services. Determinations of legal blindness (20/200 or worse, or field diameter less than 20 degrees, in the better eye) also rely on these two measures. While acuity is typically measured with Snellen eye charts in the clinic, treatment trials for retinal disease often employ standardized measures of acuity based on the Bailey-Lovie eye charts.4 These charts have a number of advantages for clinical trials, such as a constant number of letters on each line and a logarithmic progression between lines. Similarly, while Goldmann perimetry has historically been used to quantify field loss, clinical trials are increasingly utilizing the additional quantification available with automated static perimetry. Among the earliest complaints in patients with retinal degeneration is night blindness. Devices such as the Goldmann-Weekers dark adaptometer (Haag Streit AG, Berne, Switzerland) have traditionally been used to measure the full time course of dark adaptation, but such measures are time consuming and laborious for both the patient and the examiner. An alternative is to measure the final dark-adapted threshold. Typically, this can be accomplished in less than 5 minutes after patching one eye of the patient for 45 minutes. Smaller and less expensive alternatives to the Goldmann-Weekers dark adaptometer, such as the SST-1 (LKC Technologies, Gaithersburg, MD), are now available for this purpose.13

The primary electrophysiological test for patients with retinal degeneration is the full-field ERG. The core of the full-field ERG protocol is a set of responses adhering to the International Society for the Clinical Electrophysiology of Vision (ISCEV) standards established in 1989.12 The standard specifies stimulus conditions and recording parameters to ensure that responses are comparable among test centers. Standardization has been a key development in ensuring that reports can be readily transferred and interpreted at centers around the country (or world) when a patient moves. It is also crucial for planning and implementing multicenter trials as rational therapeutic intervention becomes available.

The ISCEV standard specifies four responses of particular relevance to hereditary retinal degeneration (figure 80.1). The rod response is recorded following 45 minutes of dark adaptation, utilizing a flash (either blue or dim white) that is below the threshold for eliciting a cone ERG. Rods are affected at an early age in many forms of RP and allied retinal degenerations, so it is not unusual for the response to be non-

F 80.1 Computer-averaged ERGs to ISCEV standard protocol in patients with NCL. Top row, Rod responses to blue flash

detectable even in a young patient. To obtain a response that can be followed over time, the standard specifies a maximal response to a specified achromatic flash. The maximal response is a mix of rod-mediated and cone-mediated components; in a normal subject, approximately 70% of the amplitude is generated by rods. Two stimulus conditions are used to isolate the cones. An achromatic stimulus flickering at 30 Hz exceeds the flicker fusion frequency of rods; that is, only cones can respond. Similarly, an achromatic background of 34 cd/m2 (lower right panel) saturates the rods; cones alone mediate stable responses following 10 minutes of light adaptation. These four responses should be incorporated into any protocol designed to assess patients with hereditary retinal degeneration. When the patient is dark adapted ahead of time, either by patching the eye or by sitting in total darkness, the core protocol takes less than 20 minutes, allowing ample time for additional, more specialized testing.

The rate of progression of the retinal degeneration in patients with NCL is extremely rapid in comparison to typical forms of RP. As shown in figure 80.1, ERG responses may be significantly reduced in amplitude in patients as young as 2 years of age (#4702). This young girl was subsequently found

response to standard achromatic flash. Spikes are superimposed markers for stimulus onset. Bottom row, Light-adapted (1.5 log cd/m2 background) cone response to standard achromatic flash.

to have an active epileptic focus and diagnosed with juvenile NCL at age 4. The ERGs shown in the second column were obtained from a 5-year-old boy (#5370) with JNCL. Rod responses at this age are barely detectable, and the cone response to 31-Hz flicker is reduced by 80%. The patient tested at age 7 (#5099) had a nondetectable rod response and a cone response that was less than 1.0 mV in amplitude.

Specialized recording techniques, including the selective filtering of responses to periodic stimuli through narrowband amplification, can resolve ERG signals in the submicrovolt range.1 The need is particularly acute within the population of patients with RP and NCL. The requirements of following these patients and conducting clinical studies in RP and NCL have led to unique approaches to recording small signals. These techniques have evolved in conjunction with the availability of powerful but inexpensive computers to acquire and process the signals. Selective filtering of responses to periodic stimuli through narrowband amplification shares many advantages with Fourier analysis but is generally more commercially available. A key property of any system for acquiring submicrovolt signals is that the analysis be conducted on-line so that the quality of the

recording can be evaluated before the patient leaves. Another is the utilization of an artifact-reject window. Narrowband filtering removes the high-frequency components of blinks and the low-frequency components of movement. With this prefiltering, the artifact-reject window can be narrowed to two to three times the stimulus amplitude, further eliminating those components of noise at the stimulus frequency. With the techniques used here, signals greater than 0.05 mV can be reliably distinguished from noise.2

The ERGs in patients with INCL, LINCL, and JNCL (figures 80.2, 80.3, and 80.4) have been found to be abnormal early in the course of all three disease types.17 For a patient with INCL (figure 80.2), rod responses were severely subnormal; the ISCEV standard rod and bright-flash ERG showed a normal a-wave and a profoundly subnormal b-wave, indi-

cating that the earliest manifestations of this disease appear not to directly affect phototransduction. The electronegative ERG was interpreted as evidence for an effect on neurotransmission from proximal photoreceptors to ON bipolar cells. This appeared to occur at one of three possible sites: a disturbance of proximal photoreceptor function that interfered with presynaptic neurotransmission, a disturbance of the postsynaptic plate region, or some other effect on the bipolar cells, with subsequent reduction of the generation of the b-wave.

The ERGs of young patients with LINCL (figure 80.3) had mildy abnormal rod amplitudes, mildly prolonged rod implicit times, and severely subnormal, prolonged cone responses.17 Patients with more advanced stages of LINCL also had a greater loss of b-wave than a-wave, again consistent with loss of signal transmission from photoreceptor

F 80.2 Computer-averaged ERGs, using intravenous propofol sedation, to a modified ISCEV protocol in a patient with infantile NCL from the Arg151 stop mutation of the CLN1 gene that encodes PPT1. The tracings from the right and left eyes are shown in black; the red tracings show the average of both eyes from a normal subject age 1.6 years. The scotopic blue and red flash stimuli were matched in normal control subjects to produce equal

rod amplitudes. Note the sizable rod a-wave and profoundly subnormal rod b-wave for the blue flash, the electronegative configuration of the scotopic ERG to the bright white flash, and the subnormal, prolonged photopic cone response. (Reproduced with permission from Weleber RG: The dystrophic retina in multisystem disorders: The electroretinogram in neuronal ceroid lipofuscinosis. Eye 1998; 12:580–590.) (See also color plate 52.)

F 80.3 Computer-averaged ERGs to modified ISCEV protocol in three patients with late infantile NCL. The tracings from the right and left eyes are shown in black; the red tracings show the average of both eyes from an age-similar normal subject. Note the sizable but delayed rod responses, the prolongation of the scotopic

inner segments to bipolar cells. Unlike the ERG in either INCL or in JNCL, the rod responses in early LINCL were only mildly subnormal and prolonged but with much more preserved amplitude, even though cone responses were severely subnormal and delayed.

Patients with JNCL invariably showed severe ERG abnormalities when first tested (figure 80.4), with essentially no rod-mediated activity and marked loss of a-wave amplitudes.17 They showed even greater loss of b-wave amplitudes, creating electronegative configuration waveforms. Greater loss of b-wave than a-wave amplitude for patients with JNCL would be consistent with the inner retinal localization of the gene product for CLN3.16

Patients with inherited long-chain fatty acid oxidation disorders, such as long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, are deprived of an essential source of energy during fasting or metabolic stress when carbohydrate stores become depleted. The patients are typically treated with a modified diet consisting of medium-chain triglycerides or simply through restriction of dietary fat (low- fat/high-carbohydrate diet). These treatments dramatically reduce the progressive deterioration of cardiac, muscular,

oscillatory potentials, and the subnormal, prolonged cone responses. (Reproduced with permission from Weleber RG: The dystrophic retina in multisystem disorders: The electroretinogram in neuronal ceroid lipofuscinosis. Eye 1998; 12:580–590.) (See also color plate 53.)

hepatic, and neurologic function associated with this disorder. Without treatment, patients with LCHAD deficiency have severe disease that usually results in death during the first two years of life. Now that patients are living longer with dietary interventions, it has become apparent that retinal degeneration often is associated with LCHAD.

The LCHAD activity resides in the mitochondrial trifunctional protein (MTP). Enzyme activities of subunits of this protein are responsible for distinct steps within the b- oxidation cycle. Genes for both subunits of MTP have been localized to the p23 region of chromosome 2.10,19 The MTP deficiency can result from a mutation in either subunit, whereas LCHAD deficiency has only been reported with mutations in the a-subunit.3,9,11

The fundus appears to be normal in LCHAD deficiency at birth. Between the ages of 4 months and 5 years, some patients develop a granular appearance to the retinal pigment epithelium. This can occur with or without pigment clumping within the retina (figure 80.5).15 The patients subsequently show vessel attenuation and retinal atrophy (figure 80.6). ERGs in this subset of patients are characteristic of severe retinal degeneration (figure 80.7). Other patients with

F 80.4 Computer-averaged ERGs to a modified ISCEV protocol in three patients with juvenile NCL from mutation of the CLN3 gene. The tracings from the right and left eyes are shown in black; the red tracings show the average of both eyes from an age-similar normal subject. All responses were elicited using the same Ganzfeld stimulator, but because a different computer system was used for recording the responses for Case 6, a different normal is shown. Note

F 80.5 Fundus appearance in 4-year-old patient with LCHAD deficiency and early retinal degeneration. Note the characteristic dark brown spot in the fovea, the early thinning and atrophy of the retinal pigment epithelium (RPE), and the early pigment dispersion with fine clumping. The ERG was still normal at this stage. (See also color plate 55.)

the profoundly subnormal rod responses, the electronegative configuration of the scotopic ERG to the bright white flash for Cases 5 and 6, and the subnormal photopic responses, which were greater for the b-wave than the a-wave for Case 5. (Reproduced with permission from Weleber RG: The dystrophic retina in multisystem disorders: The electroretinogram in neuronal ceroid lipofuscinosis. Eye 1998; 12:580–590.) (See also color plate 54.)

F 80.6 Fundus appearance in a patient with later stage LCHAD deficiency and retinal degeneration. Note the more extensive atrophy of the RPE and choroid in the posterior pole. (See also color plate 56.)

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F 80.7 Computer-averaged ERGs to ISCEV standard protocol in a normal subject (first column) and a patient with LCHAD deficiency (second column). Rod

LCHAD deficiency do not seem to develop retinal degeneration and may retain entirely normal ERGs. Whether the presence or absence of retinal degeneration is related to the particular genetic mutation is currently under investigation.

Conclusion

Retinal degeneration is an early manifestation of the NCLs and is often seen in LCHAD deficiency. The techniques that have been developed for assessing and following the progression of retinal degeneration in RP should also be of considerable value in managing patients with these storage and metabolic disorders. Single-center treatment trials for these rare hereditary diseases are enormously difficult to conduct. However, the international acceptance of a standardized full-field ERG protocol should lead to an increase in multicenter clinical trials aimed at slowing the progression of retinal degeneration in both NCLs and LCHAD deficiency. The past decade has also seen dramatic advances in our understanding of the molecular biological bases of NCLs and LCHAD deficiency. With the identification of diseasecausing gene mutations comes the promise of gene therapy, which is the ultimate route to a cure. In the meantime,

responses are severely reduced in amplitude, while cone responses have delay characteristic of progressive retinal degeneration.

medical therapy with nutritional and environmental modifying factors has the potential for slowing the rate of disease progression in metabolic diseases that include hereditary retinal degeneration.

Supported by EY05235, the Foundation Fighting Blindness, and Research to Prevent Blindness.

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