British Journal ofOphthalmology, 1990,74,739-742

Is thioridazine retinopathy progressive? Relationshipof pigmentary changes to visual function

Michael F Marmor

AbstractThioridazine toxicity has been described as a

'progressive chorioretinopathy', but thisdesignation can be misleading. During the firstyear after thioridazine exposure retinalpigmentation evolves from a granular to apatchy or nummular appearance. However,visual function and the electroretinogramtypically improve during this period. Somecases may show chorioretinal atrophy andfunctional loss many years later, but thereis little evidence for ongoing drug-relatedprogression. Late atrophy may representdegeneration of cells that were injured sub-clinically at the time of initial drug exposure.Although thioridazine toxicity produces an

evolving pigmentary disturbance, functionalchanges must be monitored independently offundus appearance.

but recent articles have attached new significanceto the findings: the late appearance has beentermed a 'nummular retinopathy',6 and theevolution of pigmentation called 'progressivechorioretinopathy'.7The latter terminology implies that thiorida-

zine toxicity progresses after the drug has beenstopped, as has been reported occasionally withchloroquine toxicity.8-" However, clinicalexperience with thioridazine is not altogetherconsistent with this description. For example,functional recovery within the first severalmonths after stopping the drug has been notedrepeatedly.4 121 3 It is critical to make distinctionsbetween short and long term changes, betweenthe evolution of pigmentation and the evolutionof functional loss, and between pharmacologicaltoxicity (from retained toxin) and the timerelated decompensation of subclinically injuredtissue.

Department ofOphthalmology, StanfordUniversity School ofMedicine, Stanford,CA 94305, USAM F MarmorCorrespondence to:Michael F Marmor, MD.Accepted for publication5 July 1990

Toxicity from thioridazine has been recognisedsince 1960.1 Ingestion of high doses (typicallyexceeding 800 mg/day) for just a few weeks maybe sufficient to cause symptoms of reducedacuity and poor dark adaptation.` If retino-pathy is recognised at this early stage, the funduscharacteristically shows coarse granular pig-mentation involving the macula and sometimesmid periphery as well. However, these granularchanges evolve over time into large, patchy areasof hypo- or hyperpigmentation.2 3 This change inappearance has been recognised for a long time,

Material and methodsWe have seen seven cases of thioridazine toxicityfor whom broad retinal functional parameters(electroretinogram, dark adaptation or visualfields) were measured sequentially. In four cases

the examinations included the first year aftertoxic exposure; in six cases the examinationsextended to between 51/2 and 28 years afterexposure. Table 1 summarises the drug history,fundus changes and visual function studies ofthese patients.

Table I Case histories and clinicalfindings

Extent ofLength of

Dark adaptation Scotopic ERG*Dose Exposure (at Time after Visual acuity Visualfield (log units threshold (% ofnormal

Case Sex (mg/day) high dose) exposure Age Fundus appearance (best eye) (perimetry) elevation) min. amplitude)

I M 2400 5Weeks 0 38 - 20/70 - -3 Weeks 38 Granular 20/30 3°2 Months 38 20/30 4-3 Months 38 - 20/25 30 -

S Months 38 Pigm. coalesced 20/25 220 -

13 Months 39 Clumps, nummular 20/25 200 2 52 F 1800 4-6 Weeks 2 Months 25 Granular 20/100 200 4 0*

1 Year 26 Nummular 20/25 Scotomas 0-75 Normal2 Years 27 Nummular 20/30 Scotomas -

51/2 Years 31 Nummular 20/30 Normal - Normal3 F 900-1200 2-3 Years 0 29 Granular 20/60 30 - 0*

7 Years 36 Nummular 20/25 10° 2 5-1011 Years 40 Nummular 20/50 10° -

15½ Years 45 Nummular 20/30 5° -

4 M 1600 2 Months 1 Month 27 Granular 20/25 - 0 3 Normal15 Years 41 Mild nummular 20/20 Scotomas Normal Normal

5 M 1200 >5 Weeks 16 Years 48 Nummular 20/25 Scotomas 2 50(3-4 Years 17 Years 49 Nummular [20/80] [5°] 2 50on drugs) 18/2 Years 51 Nummular 20/25 Scotomas 2 50

6 F ? I Year 4 Years 35 Nummular 20/20 -

14 Years 45 Nummular 20/20 Scotomas 1 5020 Years 52 Nummular 20/25 Scotomas 2 45

7 M 2400 Few months 0 28 - Reduced -

2 Months 28 - 20/30 - -

13 Years 41 Nummular 20/40 15° 2 5 2528 Years 56 Atrophic 20/25 20 3-5 0

*Hand held flash recordings; all others made with full field stimulus.

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Figure I Fundusappearance ofcase 3. (A)Soon after stoppingthioridazine: granularretinopathy. (B) Seven yearslater: patchy nummularretinopathy. (C) Elevenyears after thioridazine:there has been enlargement ofsome ofthe demarcatedatrophic zones (arrows) thatlie within larger areas ofRPE damage.

Fig IA Fig lB

ResultsFigs 1-2 illustrate the typical progression offundus changes. Soon after stopping thiorida-zine the fundus had a coarse granular appear-ance, most striking in the posterior pole (FigLA). Over the first year after cessation ofthe drugthe pigment coalesced to produce larger pigmentclumps and areas of geographic atrophy ornummular retinopathy (Fig IB). Over the ensu-ing years the atrophic zones tended to enlargevery slowly, though the basic pattern of atrophywas remarkably constant over long periods oftime (Fig IC). Occasionally the nummularretinopathy progressed to diffuse end-stageatrophy (Figs 2A, B).The functional changes associated with the

early evolution (granular to nummular) and lateevolution (nummular expansion) of thioridazineretinopathy are quite different. During the firstyear after exposure to the drug visual functiontypically improved despite the evolution of pig-mentary changes in the fundus. Fig 3 illustratesthe early functional status ofcases 1-4 by the bestavailable sequential data - electroretinogram(ERG), dark adaptation, or visual field. Visualfunction was often depressed during the first fewmonths of the toxic exposure, but showed adegree of recovery thereafter. Once the fundusappearance had stabilised (roughly one year afterdrug exposure), visual function either remainedstable (Fig 4) or showed a rate of deteriorationthat was extremely slow and was measurable only

Fig IC

over a period of several years. Fig 5 illustrates thelate functional status of cases 2-7.

Case 5 seemed for a while to contradict thisdescription, insofar as he complained of a rapidloss of visual acuity and visual field that began 16years after stopping thioridazine. During thecourse of one year he progressed from goodperipheral vision with isolated scotomas tosevere tunnel vision with only a tiny 50 centralisland, and he sought training in the use of a longcane. However, his nummular fundus lesionschanged only minimally during this period, andhis ERG remained stable. Confronted with theinconsistencies, he miraculously 'recovered'.

DiscussionThe fundus appearance in thioridazine retino-pathy evolves within the first year from thecoarse granular retinopathy of acute toxicity tothe patchy or nummular retinopathy of latethioridazine damage (Fig 1). However, all ourcases showed significant visual improvement (orat worst, stability), during the first year aftertoxic levels of thioridazine were stopped, despitean increasingly atrophic fundus appearance.For example, patient 2, who initially had a verylow ERG (extinguished to a hand held flash)recovered to show almost normal responses.These observations are consistent with reports ofvisual recovery when the drug is stopped beforeretinal damage is too pervasive.4 1213 Thus itappears that thioridazine retinopathy does notprogress functionally during the change fromgranular to nummular retinopathy.Improvement during the first year after

thioridazine does not rule out the possibility thatthe drug might continue to exert a toxic effectover the long term if drug depots remain in thetissues. Thioridazine (like other phenothiazines)is bound to melanin and may well persist in theeye for a long time.'4 '5 Our data show that thereis a risk of very slow or very late functionaldecompensation, and cases of late functional losshave also been reported by others,37 includingtwo that were decumented with ERGs.6 At thesame time the relative stability of findings insome ofmy patients suggests that late functionalloss may not be inevitable.

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Is thioridazine retinopathy progressive? Relationship ofpigmentary changes to visualfunction

Figure 2 Fundusappearance ofcase 7. (A)Thirteen years after stoppingthioridazine: patchy anddiffuse RPE atrophy. (B)Twenty eightyears afterthioridazine: end-stagechorioretinal atrophy.

Fig 2A

It seems clear from our experience and pub-lished reports67 that the geographic areas ofchorioretinal atrophy in thioridazine toxicitymay expand very slowly. But do these latedegenerative changes represent a direct pharma-cological effect of thioridazine in the tissues? Ifind it difficult to believe that enough drug wouldpersist to cause severe and progressive damagemany years after exposure (at least 15 years forcases 3 and 4), especially when the toxic effectswere diminishing or stable during earlier years.An expansion of atrophic lesions over time can

occur in diseases unrelated to drugs, such as agerelated maculopathy and the 'creep' of retinalpigment epithelial (RPE) atrophy'7 18 that occursmonths to years after macular photocoagulation.It is possible that in late thioridazine toxicity weare seeing the non-specific expansion of scars,equivalent to the' late exposure of areas ofsubclinical drug induced RPE damage thatoccurred at the time of original drug usage.Thioridazine probably injures cells over largerareas ofRPE than are visible initially by ophthal-moscopy or angiography. These areas ofmarginalinjury may decompensate or degenerate yearslater when time and age related pathology taketheir toll. At least one author has asked whethersimilar arguments may apply to chloroquineretinopathy.'9 In thioridazine cases withrelatively mild initial damage (such as cases 2 and

Short Term Changes

Figure 3 Diagram offunctional status (short-term)during the firstyear afterthioridazine exposure forcases 1-4. The 'functionalindex' represents a compositeofavailable ERG darkadaptation and visualfielddata normalised betweenabsent (0%) and normal(100%)function. This indexis only a schematic device todemonstrate trends ofimprovement or regression(the actual datafor each caseare given in Table 1).

100m

" 800c

3 600

- 40C

0

* 20

00 2 4 6 8 10 12+Months

Fig 2B

4), the prognosis over the long term is probablyfairly good; in patients in whom there is morewidespread damage in the early years (such ascases 1, 3, and 7) the prognosis will be muchmore guarded, since decompensation of thecompromised RPE could eventually lead todiffuse atrophy.

Until the late pigmentary and functionalchanges in thioridazine can be clearly shown tobe a result ofcontinued drug action I suggest thatthioridazine toxicity not be referred to as aprogressive chorioretinopathy. That term carriesan implication of monotonic functional declinefrom a primary disease process. There is noquestion that many cases of thioridazine retino-pathy show late deterioration; however, theexamples in this paper show that the early funduschanges from granular to nummular retinopathydo not correlate with a 'progression' of visual loss(indeed, vision typically improves), and the lateatrophic fundus changes are variable in onset andmay represent a secondary decompensation.There is unquestionably a risk of late atrophicdegeneration, but the cause of this retinopathy iscomplex, and it may not always progress.These conclusions have important clinical

implications. First, in thioridazine toxicity (andindeed retinal disease in general) pigmentaryscarring is not necessarily equivalent to func-tional damage. Patients with thioridazine toxicitymust be followed up with functional tests such asvisual field and the ERG, in addition to observa-tion of the fundus, if progression and toxicity isto be assessed accurately. Secondly, the fact thatsevere late loss of function does occur in occa-sional individuals indicates that patients withthioridazine toxicity need to be followed up in-definitely todocument the stability or progressionof disease. Thirdly, the hypothesis that subclini-cal damage may exist at the time of initial toxicexposure suggests a possible therapeutic strategy.Ischaemic damage to the retina can be minimisedby treatment with dextromethorphan,2" whichblocks the secondary death of marginally injuredcells by the release of excitatory amino acids. Ifagents can eventually be found that reduce theamount of secondary RPE decompensation afterthioridazine exposure, the long term visual riskswould be greatly reduced.

Case 5 reminds us of an additional caveat:functional tests may be influenced by non-organic factors. Many patients using thioridazinehave psychiatric disease, and their subjective

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Manor

CONE(photopic)

MAXIMAL(scotople)

HAND-HELD FLASH ERG

Extinguished Extinguished

FULL-FIELD ERG

1 year

been made. Psychophysical tests may be suffi-cient for routine follow-up when there is noprogression ofvisual symptoms, but it is import-ant to have a baseline ofobjective data at the timeof initial diagnosis to allow for later comparisonsthat may be needed.

This work was supported in part by NIH-NEI Research GrantEY01678, and an unrestricted grant from Research to PreventBlindness, Inc.

5.5 year

Figure 4 I

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recovery after retinal ischemia. Arch Ophthalmol 1989; 107:mg story for progressive retinopathy might have 40911l.

TIME AFTERTHIORIDAZINE

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