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Year : 1985  |  Volume : 33  |  Issue : 1  |  Page : 27-31

Ocular changes associated with long term phenothiazine usage

Department of Ophthalmology, Christian Medical College Vellore, India

Correspondence Address:
T A Alexander
Department of Ophthalmology Christian Medical College, Vellore
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Source of Support: None, Conflict of Interest: None

PMID: 2867036

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How to cite this article:
Alexander T A, John JK, Thomas A, Verghese A. Ocular changes associated with long term phenothiazine usage. Indian J Ophthalmol 1985;33:27-31

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Alexander T A, John JK, Thomas A, Verghese A. Ocular changes associated with long term phenothiazine usage. Indian J Ophthalmol [serial online] 1985 [cited 2021 Mar 7];33:27-31. Available from: https://www.ijo.in/text.asp?1985/33/1/27/27327

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Phenothiazines produce numerous com­plications affecting almost all systems of the body. Ocular changes with long term therapy was first reported by Greiner and Berry[1] in the form of dense, dark brown lenticular opacities. Since then various authors have demonstrated ocular changes like conjunctival pigmentation, tear film depression, corneal deposits, stellate cataracts and pigmentary retinopathy.

The commonest phenothiazine to be used as an antipsychotic agent is chlorpromazine (CPZ). Lenticular changes seem to be the commonest ocular change associated with long term usage of chlorpromazine. The incidence varies from 25% to 78%[4],[5] Barsa et al[4], having reviewed the highest number of patients (658 cases) on various phenothia­zines, reported lenticular changes in 27% of the cases and combined lenticular and corneal changes in 5%. Siddall[5], in his series of 50 patients on only chlorpromazine reported lenticular involvement in 78% of cases. The changes in the lens, reported by him, were pigment deposition (78%) with a stellate pattern in 32%, and anterior cataract in 10% of the cases.

The corneal changes commonly seen are deposition of dark brown pigments, mainly in the endothelial layer and in the stromal layers in severe cases, small white masses in the epithelium, superficial punctate kerati­tis and increased visibility of corneal nerves. All cases showing corneal changes had lenti­cular changes also and the incidence varied from 5% to 78%[4],[5]

Pigmentary changes in the fundus are usually seen with phenothiazines of the piperi­dine group, like Thioridazine. The changes reported are diffuse granularity of the fundus, deposition of irregular, sharply defined, dark brown pigments mainly in the macular region and an acute pigmentary degenera­tion. However, with chlorpromazine the retinal changes are not so common.

Many authors have tried to determine the toxic level of chlorpromazine. Siddall[6] found that a dosage of more than 800 mg./ day for 20 months is oculotoxic, while in all cases reported by Wetterholm[3] the total dose had exceeded 1000 gm. Bock and Swain[7] were unable to show ocular changes in cases who received a total dose upto 114 gm. Satonove[8] in his study reported a threshold value of 800 mg. CPZ per day, while Rasmussen et al[9] demonstrated ocular changes in patients whose mean daily dosage of CPZ was 325 mg. (range 100-800 mg. per day).

According to Crane et al[10] the minimum cumulative quantity of CPZ sufficient to produce eye opacities varies from 200 to 630 gm. Buffalo and associates[11] placed the critical value of CPZ at 1 kg.

We undertook a retrospective study of patients on long term phenothiazines to determine the incidence of ocular lesions and to see if a relationship existed between the dose of phenothiazine and the duration of therapy to the severity and incidence of ocular lesions.

  Material and method Top

60 patients who had been on phenothiazines for a period of at least one year con­tinuously were examined for symptoms and signs of ocular change. The dose and dura­tion of the medication the patient had received was not known to the ophthal­mologist when the patient was being examined. A detailed ocular examination, bio-microscopy, colour vision testing, tono­metry, photostress test and fluorescein angiography were done. The duration and total dose of medication the patient had been on continuously, was calculated. A drug-free control group of 30 normal individuals were examined on the same lines.

  Observations Top

The patient group did not differ statistically from the control group with regard to age and sex. Of the 60 patients 44 were males and 16 were females. Their ages ranged from 16 to 50 years [Table - 1].

A large majority of the patients (67%) had no ocular symptoms. Of the others the commonest symptoms were blurring of vision (20%), lacrimation (13 3%) and night blind­ness (5%). These symptoms did not corres­pond to the presence of any of the ocular findings The conjunctivae showed an increased pigmentation around the limbus and palpebral region in 8.3% of the cases of the patient group and 6.7% of the control group. This was not statistically signi­ficant.

7 patients (6%) had a yellowish pig­ment deposition on the endothelial surface and deeper layers of the stroma in the cornea. These deposits were scattered all over the endothelial surface with increased density in the palpebral region. In two of these patients there was an increased visibility of corneal nerves. All patients with corneal changes had associated lesions in the lens also.

Lenticular changes were seen in 28 patients (46.7%) as compared to 6 (20) in the control group. All 28 patients had pigment deposits and of them 28.3% had cataracts. The cataracts were all anterior subcapsular in location and stellate in shape. They were granular, whitish and projecting into the anterior cortical layer of the lens. The pigment deposition varied from fine and discrete to a definite 3 to 7 pointed star shaped pattern. Fine black pigments were seen around the macula in 5 cases (8.3%).

Tonometry, colour vision testing and fluore­scein angiograms were within normal limits.

The control group did not reveal any change either in the cornea or in the retina.

All the patients were predominantly on chlorpromazine, the total dose ranging from 44.7 gm. to 957 gms. over a duration of 12 months to 178 months. All these patients were also concomitantly on trihexyphenidyl 0.24 gm. to 20.52 gm. 31 of these patients had received other antipsychotic medication (56.3% in the group with lesions and 46.4% in the group without lesions). The maximum total individual doses were trifluoperazine 33.4 gm., thioridazine 38 g.m.. fluphenazine 1.16 gm. and haloperidol 16.2 gm. These were insignificantly dispersed between the groups with and without ocular changes.

The ocular changes found among the patient group were compared to the findings in the controls. The incidence of pigment deposits and cataracts were found to be significantly higher than in the control group. The corneal findings just failed to reach statistical significance [Table - 2].

Within the patient group. those patients with ocular lesions were compared to those without lesions with regard to the total dose of CPZ taken and the duration of treatment.

The differences were significant-the former being more so [Table - 3]. Patients with a formed cataract were compared to those without lesions on the same variables and the differences were again found to be statistically significant [Table - 4].

  Discussion Top

As reported by other workers in the past[2],[3],[4],[5], we find that in our series the com­monest changes in the eye are lenticular changes.

The conjunctiva showed no specific change and the macular pigmentation seen in 5 of our patients was not statistically significant. Other workers[12] have described macular pigmentation mostly with the piperidine group of phenothiazines in high doses. Since our patients were mostly on CPZ this finding would be easily explained.

Corneal changes, though just failing to reach statistical significance, were all associ­ated with severe changes in the lens, either formed cataracts, or severe pigmentation. White epithelial masses and superficial punctate keratitis as described by Siddall[5] was not seen in our series. There were yellowish pigment deposits on the endothelial surface on the deeper layers of the stroma, more dense in the palpebral region. The increased visibility of corneal nerves could be due to the contrast imparted by the pigment deposits in the cornea. No thicken­ing or beading of corneal nerves was seen.

The commonest and most significant changes seen in the eye were the lenticular changes (46.6%). The changes in the lens have been graded into stages by earlier workers[4],[5]. However, in our series, differen­tiation into the groups specified by Barsa[4] or by Siddall[5] was not easily done. It seems that the process from pigmentation to cata­ract formation passes through at least 3 stages

Stage 1 - Stage of pigment dispersion

Characterised by punctate, discrete, brownish­ yellow pigmentary deposits in the anterior pole of the lens, unassociated with catarac­tous changes. The pigments vary from a few to large numbers tending towards formation of a stellate pattern.

Stage 2 - Stage of transition : The pig­ment deposition is more marked and a definite stellate pattern is present. The star may be 3 to 7 pointed, and fine subcapsular cataractous changes may be present in the central region.

Stage 3 - Stage of cataract formation

The pigment deposition is very dense with a whitish, granular, anterior subcapsular stellate cataract. The cataractous change may project into the anterior stromal layer of the lens. The changes were restricted to only the anterior pole in the pupillary area. The periphery and posterior region did not show any change.

In the analysis of the dosage and duration of medication to ocular changes, a few problems were encountered. All patients were concomitantly on antiparkinsonian agents. 31 of the patients had been sporadi­cally on other antipsychotics also along with CPZ. However, the sample group consisted of those who had been predominantly on CPZ. The total dose of other drugs was relatively lower, and insignificantly dispersed between the groups with and without lesions. The study being retrospective in nature, the possible effects of the other drugs, though statistically negated, cannot be neglected, particularly as the therapeutic efficacy in dosage with relation CPZ shows a wide variation.

A definite statistical significance was seen between lesions in the eye and the dose and duration of continuous medication. The total dose of CPZ seemed more significant than the duration of drug use. It was also clear that all cases who progressed into stage 3 of lenticular change-i.e. cataract forma­tion, had received a total dose of 200 gm. of CPZ or more. The converse however, was not necessarily true, as 3 of the 28 patients with no lesions had been prescribed 216.6 to 229.5 gm. and 9 of the 17 patients with pigmentary changes only (stages 1 and 2) had imbibed 200 to 347.5 gm. of CPZ.

The relationship of lenticular changes to the dosage of CPZ varies with different studies. Reviewing the literature, Bond and Yee[13] noted that when the cumulative dose of CPZ exceeded I kg. Visible deposits occurred in the lens. No deposits were found in patients with a total dose of 500 gm. or less. Prien et a1[14] showed pigmentary changes on high doses compared to a low dose of CPZ over a period of six months. Our study is in keeping with the observation of Crane et al[10]. that the minimum cumula­tive dose of CPZ sufficient to produce eye opacities is 200 to 600 gm.

The dosage and duration of drug intake are individually significant. All patients tend to get a similar dose of medication and hence it seems logical to assume that those patients getting a higher total dose would have been on medication for a longer duration.

It is not known why these pigmentary changes occur. Whether it is a deposition of melanin or related compounds[15]. or a CPZ derivative released by ultraviolet light[16] is conjectural, particularly as the distribution of pigment is in the exposed areas and reported to be more in the summer months. If this is so. the duration of sensitisation may be a critical factor.

Needless to say, further work is required before such details can be conclusively demonstrated, particularly controlling the number of drugs taken and deriving longi­tudinally the sequence in which ocular changes occur. We have started a prospec­tive study of patients which may yield some information on this aspect. In the meantime, this study indicates that lenticular changes are the most significant ophthalmologic sequel to long term chlorpromazine usage and the changes seem dependent on the total dosage and the duration of drug intake. A patient who has received 200 gm. of CPZ has a high risk of developing cataractous changes in the lens.

  References Top

Greiner, A.C., and Berry, K., 1964, Can Med. Assoc. J. 90 : 663.  Back to cited text no. 1
Margalis, L.H., and Goble, J.L., 1965, JAMA, 193 :7.  Back to cited text no. 2
Wetterholm, D.H., Snow, H.L and Winter, F.C. 1965., Arch. Ophthalmol, 74: 55.  Back to cited text no. 3
Barsa, J.A.. Newton, J.C and Saunders, J.C. 1965, JAMA 193: 10.  Back to cited text no. 4
Siddall, J.R., 1965, Arch. Ophthalmol 75: 460.  Back to cited text no. 5
Siddall, J.R., 1966, Can. J. Ophthalmol 1 : 190.  Back to cited text no. 6
Bock, R. and Swain, J. Amer. J_ Ophthalmoi 1963, 56: 808.  Back to cited text no. 7
Satonove, A., 1965, JAMA 191 : 263.  Back to cited text no. 8
Rasmussen, K., Kirk, L. and Faurbye, A. 1976, Acta Psychiatr Scand 53 : 16.  Back to cited text no. 9
Crane, G.E., Jhonson, A.W. and Buffaloe, W.J., 1971, Amer J. Psychiatry 127 : 1045.  Back to cited text no. 10
Buffaloe, W,J., Johnson, A.W. and Sandiffer, M G., 1Q67, Amer J Psychiatry 124: 250.  Back to cited text no. 11
Kinross-Wright, V. Clinical trial of a new phenothiazine compound : NP-207. Psychiatric Research Report, American Psychiatric Association. 1956, 4 : 89.  Back to cited text no. 12
Bond, W.S., and Yee G.C. 1980; Amer J.. Hosp Pharm. 37:74,  Back to cited text no. 13
Prien, R.F., Delong, S.L., Cole, J.O , Levine, J. and Chase, C., 1970; Arch Gen Psychiatry 23 : 464.  Back to cited text no. 14
Greiner, A C. and Nicholson, G.A., 1964; Can. Med. Assoc. J. 91 : 627.  Back to cited text no. 15
Perry, T.L., Culling, C.F., Berry, K. and Hansen. S.. 1964, Science 146: 81.  Back to cited text no. 16


  [Table - 1], [Table - 2], [Table - 3], [Table - 4]


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