~
~~
Case Report
Diazepam and its effects on visual fields M J Elder, FRACO, FRACS
0.5 and an intraocular pressure varying between 10 mmHg and 12 mmHg on a tension series. The ocular media were clear, the macula and peripheral retinae were normal and the patient was emmetropic. Humphrey automated visual fields were performed using the ‘30-2 stimulus 111, full from prior date’ strategy and a 70 mm full field + 3.0 dioptre correction lens. The results are shown in Figures 1 and 2. There was considerable visual field loss in each eye and the results seemed reliable. For example, in the right eye there was only 1/33 fixation losses, 0/15 false positive errors, 1/7 false negative errors, 662 questions asked, total test time of 20.5 minutes and a fluctuation of 2.63Db. No treatment was instituted and she was reviewed six months later. She was aware of a significant improvement in her visual field and this corresponded to a reduction in the dose of diazepam to 2.5 mg mane and 10 mg nocte. The examination findings were unchanged and the visual fields were markedly improved. The patient was reviewed one year later. She had ceased taking diazepam. The eyes remained normal to examination and the fields are presented in Figures 3 and 4. The field analyser and testing conditions were constant over the period of testing.
Abstract A patient who experienced severe visual field loss whilst taking 100 mg of diazepam that reverted to normal on cessation of the drug is described. Diazepam affects GABA inhibitory neurones and the physiology of this in the retina and visual cortex is reviewed.
Key words: Benzodiazepine, diazepam, GABA, visual fields. Diazepam is commonly prescribed for anxiety, hypnosis, muscle spasms and epilepsy. The majority of the therapeutic action is due to modulation of gamma-aminobutyric acid (GABA)induced changes in chloride conduction of neurones by binding to GABA receptors.’ A lesser effect is via other peripheral receptors. A patient is described with visual field loss possibly due to diazepam. The author hypothesises that this loss is due to GABA modulation either in the retina or the visual cortex. Case Report A 71-year-old Caucasian woman presented for a routine check because her sister had recently been diagnosed as having chronic open-angle glaucoma. She had no ocular symptoms, was otherwise well but was taking 25 mg diazepam four times daily for anxiety. On examination both eyes were similar with uncorrected visual acuity of 6/9, cup-disc ratio of
Discussion GABA and the retina GABA is found in the retinas of all vertebrate^^.^ in similar concentrations to the brain.4 In nonmammals GABA is released synaptically from amacrine and horizontal cells but in mammals, only amacrine cells release GABA. GABA receptors are stimulated by GABA and muscimol and inhibited by benzodiazepines, bicuculline and picrotoxin.
University of Otago, Dunedin, New Zealand. -
Reprint requests: Dr M J Elder, Department of Ophthalmology, University of Otago, PO Box 913, Dunedin, New Zealand. Diazepam and its effects on visual fields
267
Figure 1 Humphrey automated visual field of left eye whilst the patient was taking diazepam 25 mg four times daily.
Figure 3 Visual field of left eye 18 months after Figure 1 and with the patient on no medication.
Many studiess-" have shown a single population of high-affinity receptors for benzodiazepines and that these receptors localise to the inner plexiform layer in rats and birds.12.13 In all species, the release of GABA by amacrine cells causes cellular hyperpolarisation and therefore inhibition of their distal neurones, the ganglion cells. GABA applied to the retina iontophoretically supresses spontaneous activity and light evoked discharge of all retinal ganglion cells.4 Robbins14 has shown that in laboratory rats, the ERG is unaffected by intravenous midazolam or chronic intraperitoneal injections of flurazepam for up to 56 days. Neither photopic nor scotopic ERGS were affected, nor were the oscillatory potentials. The a- and b- waves reflect light-evoked activity of
the photoreceptors and inner nuclear neurones respectively whilst the oscillatory potentials probably reflect feedback from amacrine cells to bipolar cells.15 Therefore it can be concluded that benzodiazepines alter retinal function solely by affecting the amacrine-ganglion cell interaction and that a GABA-modulating drug such as diazepam has the potential to alter visual field sensitivity purely due to its retinal effects.
GABA and the visual cortex The main inhibitory transmitter in the visual cortex is GABAi6 and its effects are blocked by bicuc~lline.~~~ Simple cells show major changes in their recep-
Figure 2 Visual field of right eye whilst the patient was raking diazepam 25 mg four times daily.
Figure 4 Visual field of the right eye 18 months after Figure 2 and with the patient on no medication.
268
Australian and New Zealand Journal of Ophthalmology 1992; ZO(3)
tive fields after application of bicuculline. There is a large increase in response magnitude, a loss of the discrete ‘on and off subregions in the field, a loss of directional selectivity and a loss of orientation selectivity.18-20When the level of GABA block is adequate there is absolute loss of directional sensitivity and this is due to an inhibitor input during stimulus movement in the non-preferred direction.*’ Complex cells also show significant receptive field changes with bicuculline. It increases response magnitude, reduces or eliminates orientation selectivity and reduces or eliminates directional s e l e c t i ~ i t y .Approximately ~~,~~ half of the complex cells have orientation selectivity due to a selective GABAergic process.” Benzodiopines and indices of visual function Benzodiazepines are known to affect critical flicker fusion thresholds (CFFT), ocular readaptation time and visual masking. Besser and Duncan24showed that an oral dose of 10 mg of diazepam induced a significant depression in the CFFT which was apparent at 30 minutes, maximal at two hours and had returned to pre-drug baselines by six hours. A review of 96 drug-dose combinations showed that in general the CFFT was decreased by most neuroleptics, anxiolytics and hypnotics and increased with s t i m u l a n t ~CFFT .~~ is therefore a relatively non-specific index of visual performance. BergmaP has shown that an oral dose of 20 mg of oxazepam alters light adaptation. He exposed patients to a bright flash of light then measured the time for an optokinetic pattern to elicit nystagmus. The readaptation time was increased from 12 seconds to 18 seconds with oxazepam and the peak effect corresponded to the plasma levels. The optokinetic reflex is a complex arc involving retina, visual cortex and the oculomotor system. Unfortunately, by using a motor response as an end point (nystagmus) we can only conclude that oxazepam affects at least one component of the optokinetic reflex. Visual masking is the reduction of visibility of a stimulus (usually a letter) by the addition of a second stimulus (usually random dots or a pattern) either just preceding or just following the first stimulus. Emre et aL2’ showed that 12 mg of midazolam orally significantly enhances the masking effect and that this effect correlates with the known pharmacokinetics of the drug. They conclude that the enhanced inhibition slows down processing of visual information so that integration occurs over a longer Diazepam and its effects on visual fields
time interval. However, localisation to either retina or cerebral cortex is not possible. It is clear that in the retina the lateral inhibition of ganglion cells by amacrine cells is a powerful influence on their receptive fields. At least some of this inhibition is due to the neurotransmitter GABA being released by amacrine cells. This GABAergic system influences only the inner retinal layer and does not seem to be involved in transmission between photoreceptors, bipolar cells and ganglion cells. This system is altered by benzodiazepines and therefore it is possible that an oral dose of benzodiazepine could affect retinal hnction. The visual cortex is profoundly influenced by the inhibitory GABA system. This is apparent in both simple and complex cell receptive field changes after application of bicuculline which is similar in action to benzodiazepines. Whilst no similar studies have been done on the effects of benzodiazepines it seems reasonable that it too should cause receptive field changes. A search of the literature has revealed no reported cases of visual field changes with benzodiazepines. The case presented here is not a controlled study, but the automated perimetry gives high levels of confidence in the data and the patient herself was adamant that her subjective improvement in visual function corresponded to the reduction in the dose of diazepam from 100 mg to 10 mg per day. In conclusion, it is probable that oral doses of benzodiazepines can cause reversible visual field loss due to inhibition of the GABAergic system in either the retina, the visual cortex or both. This has widespread social importance.
References 1. Wilson JD. Harrison’s principles of internal medicine, 12th ed. New York: McGraw Hill, 1991;71. 2. Neal MJ. Minireview: Amino acid transmitter substances in the vertebrate retina. Gen Pharmacol 1976;7:321-2. 3. Kuriyama K. Kisken B, Haber B, Roberts E. The gammaaminobutyric acid system in rabbit retina. Brain Res 1968;9: 165-8. 4. Bolz J, Frumkes T, Voight T, Wassle H. Action and localization of gamma-aminoburyric acid in the cat retina. J Fhysiol (London) 1985:362:369-93. 5. Howells RD, Hiller JM, Simon EJ. Benzodiazepine binding sites are present in retina. Life Sci 1979;25:2131-6. 6. Howeiis RD, Simon EJ. Benzodia~epinebinding in chicken retina and its interaction with gamma aminobutyric acid. Eur J Pharmacol 1980;67:133-7. 7. Borbe HO, Miller WE, Wollert U, The identification of benzodiazepine receptors with brain-like specificity in bovine retina. Brain Res 1980;182:466-9. 269
8. Paul S, Zatz M, Skolnick P. Demonstration of “brain specific” benzodiazepine receptors in rat retina. Brain Res 1980,187:243-6. 9. Osborne NN. Benzodiazepine binding to bovine retina. Neurosci Lett 1980;16:167-70. 10. Regan JW, Roeske WR, Yamamura HI. 3H-Flunitrazepam binding to bovine retina and the effect of GABA thereon. Neuropharmacology 1980;19:413-15. 11. Seighart W, Drexler G, Supavilai P, Karobath M. Properries of benzodiazepine receptors in rat retina. Expl Eye Res 1982;34:961-8. 12. Skolnick P, Paul S, Zatz M, Eskay R. “Brain-specific” benzodiazepine receptors are localized in the inner plexiform layer of rat retina. Eur J Pharmacol 1980;66:133-6. 13. Alstein M, Dudai Y, Vogel 2. Benzodiazepine receptors in chick retina: development and cellular localization. Brain Res 1981;206:198-202. 14. Robbins J. Ikeda H. Benzodiazepines and the mammalian retina. I. Autographic localisation of receptor sites and the lack of effect on the electroretinogram. Brain Res 1989;479:313-22. 15. Ikeda H. Retinal mechanisms and the clinical electroretinogram. In: Halliday AM, Butler SR, Paul R, eds. A text book of clinical neurophysiology. New York: Wiley, 1987;569-94. 16. Iversen LL, Michell JF, Srinivasan V. The release of yamino-butyric acid during inhibition in the cat visual cortex. J Physiol (London) 1971;212:510-34. 17. Sillito AM. The effectiveness of bicuculline as an antagonist of GABA and visually evoked inhibition in the cat’s striate cortex. J Physiol (London) 1975;250:287-304. 18. Sillito AM. Modification of the receptive field properties
270
of neurons in the visual cortex of bicuculline, a GABA antagonist. J Physiol (London) 1974;239:36-7P. 19. Sillito AM. Functional considerations of the operation of GABAergic inhibitory processes in the visual cortex. Cerebral Cortex. New York: Plenum Press, 1984;2:91-117. 20. Tsumoto T, Eckart W, Creutzfeldt 0. Modification of orientation sensitivity of cat visual cortex neurones by removal of GABA mediated inhibition. Exp Brain Res 1979;34:351-63. 2 1. Innocenti GM, Fiore I. Postsynaptic inhibitory components of the response to moving stimuli in area 17. Brain Res 1974;80:229-89. 22. Sillito AM. The contribution of inhibitory mechanisms to the receptive field properties of neurones in the striate cortex of the cat. J Physiol (London) 1975;250:305-29. 23. Sillito AM. Inhibitory processes underlying the directional specificity of simple, complex and hypercomplex cells in the cat’s visual cortex. J Physiol (London) 1977;271:699-720. 24. Besser GM, Duncan C. The time course of action of single doses of diazepam, chlorpromazine and some barbiturates as measured by auditory flutter fusion and visual flicker fusion thresholds in man. Br J Pharmac Chemother 1967;30:341-8. 25. Smith JM, Misiak H. Critical flicker frequency and psychotropic drugs in normal human subjects - A review. Psychopharmacology 1976;47: 175-82. 26. Bergman H, Borg S, Hogman B, Larsson H, Linde JC, Tengrath B. The effect of oxazepam on ocular readaptation time. Acta Ophthalmologica 1979;57:145-50. 27. Emre M, Groner M, Hofer D, Groner R, Fisch D. Effects of benezodiazepinesin forward and backward visual masking. Clin Vision Sci 1989;4:257-63.
Australian and New Zealand Journal of Ophthalmology 1992; 20(3)
~~
Case Report
Diazepam and its effects on visual fields M J Elder, FRACO, FRACS
0.5 and an intraocular pressure varying between 10 mmHg and 12 mmHg on a tension series. The ocular media were clear, the macula and peripheral retinae were normal and the patient was emmetropic. Humphrey automated visual fields were performed using the ‘30-2 stimulus 111, full from prior date’ strategy and a 70 mm full field + 3.0 dioptre correction lens. The results are shown in Figures 1 and 2. There was considerable visual field loss in each eye and the results seemed reliable. For example, in the right eye there was only 1/33 fixation losses, 0/15 false positive errors, 1/7 false negative errors, 662 questions asked, total test time of 20.5 minutes and a fluctuation of 2.63Db. No treatment was instituted and she was reviewed six months later. She was aware of a significant improvement in her visual field and this corresponded to a reduction in the dose of diazepam to 2.5 mg mane and 10 mg nocte. The examination findings were unchanged and the visual fields were markedly improved. The patient was reviewed one year later. She had ceased taking diazepam. The eyes remained normal to examination and the fields are presented in Figures 3 and 4. The field analyser and testing conditions were constant over the period of testing.
Abstract A patient who experienced severe visual field loss whilst taking 100 mg of diazepam that reverted to normal on cessation of the drug is described. Diazepam affects GABA inhibitory neurones and the physiology of this in the retina and visual cortex is reviewed.
Key words: Benzodiazepine, diazepam, GABA, visual fields. Diazepam is commonly prescribed for anxiety, hypnosis, muscle spasms and epilepsy. The majority of the therapeutic action is due to modulation of gamma-aminobutyric acid (GABA)induced changes in chloride conduction of neurones by binding to GABA receptors.’ A lesser effect is via other peripheral receptors. A patient is described with visual field loss possibly due to diazepam. The author hypothesises that this loss is due to GABA modulation either in the retina or the visual cortex. Case Report A 71-year-old Caucasian woman presented for a routine check because her sister had recently been diagnosed as having chronic open-angle glaucoma. She had no ocular symptoms, was otherwise well but was taking 25 mg diazepam four times daily for anxiety. On examination both eyes were similar with uncorrected visual acuity of 6/9, cup-disc ratio of
Discussion GABA and the retina GABA is found in the retinas of all vertebrate^^.^ in similar concentrations to the brain.4 In nonmammals GABA is released synaptically from amacrine and horizontal cells but in mammals, only amacrine cells release GABA. GABA receptors are stimulated by GABA and muscimol and inhibited by benzodiazepines, bicuculline and picrotoxin.
University of Otago, Dunedin, New Zealand. -
Reprint requests: Dr M J Elder, Department of Ophthalmology, University of Otago, PO Box 913, Dunedin, New Zealand. Diazepam and its effects on visual fields
267
Figure 1 Humphrey automated visual field of left eye whilst the patient was taking diazepam 25 mg four times daily.
Figure 3 Visual field of left eye 18 months after Figure 1 and with the patient on no medication.
Many studiess-" have shown a single population of high-affinity receptors for benzodiazepines and that these receptors localise to the inner plexiform layer in rats and birds.12.13 In all species, the release of GABA by amacrine cells causes cellular hyperpolarisation and therefore inhibition of their distal neurones, the ganglion cells. GABA applied to the retina iontophoretically supresses spontaneous activity and light evoked discharge of all retinal ganglion cells.4 Robbins14 has shown that in laboratory rats, the ERG is unaffected by intravenous midazolam or chronic intraperitoneal injections of flurazepam for up to 56 days. Neither photopic nor scotopic ERGS were affected, nor were the oscillatory potentials. The a- and b- waves reflect light-evoked activity of
the photoreceptors and inner nuclear neurones respectively whilst the oscillatory potentials probably reflect feedback from amacrine cells to bipolar cells.15 Therefore it can be concluded that benzodiazepines alter retinal function solely by affecting the amacrine-ganglion cell interaction and that a GABA-modulating drug such as diazepam has the potential to alter visual field sensitivity purely due to its retinal effects.
GABA and the visual cortex The main inhibitory transmitter in the visual cortex is GABAi6 and its effects are blocked by bicuc~lline.~~~ Simple cells show major changes in their recep-
Figure 2 Visual field of right eye whilst the patient was raking diazepam 25 mg four times daily.
Figure 4 Visual field of the right eye 18 months after Figure 2 and with the patient on no medication.
268
Australian and New Zealand Journal of Ophthalmology 1992; ZO(3)
tive fields after application of bicuculline. There is a large increase in response magnitude, a loss of the discrete ‘on and off subregions in the field, a loss of directional selectivity and a loss of orientation selectivity.18-20When the level of GABA block is adequate there is absolute loss of directional sensitivity and this is due to an inhibitor input during stimulus movement in the non-preferred direction.*’ Complex cells also show significant receptive field changes with bicuculline. It increases response magnitude, reduces or eliminates orientation selectivity and reduces or eliminates directional s e l e c t i ~ i t y .Approximately ~~,~~ half of the complex cells have orientation selectivity due to a selective GABAergic process.” Benzodiopines and indices of visual function Benzodiazepines are known to affect critical flicker fusion thresholds (CFFT), ocular readaptation time and visual masking. Besser and Duncan24showed that an oral dose of 10 mg of diazepam induced a significant depression in the CFFT which was apparent at 30 minutes, maximal at two hours and had returned to pre-drug baselines by six hours. A review of 96 drug-dose combinations showed that in general the CFFT was decreased by most neuroleptics, anxiolytics and hypnotics and increased with s t i m u l a n t ~CFFT .~~ is therefore a relatively non-specific index of visual performance. BergmaP has shown that an oral dose of 20 mg of oxazepam alters light adaptation. He exposed patients to a bright flash of light then measured the time for an optokinetic pattern to elicit nystagmus. The readaptation time was increased from 12 seconds to 18 seconds with oxazepam and the peak effect corresponded to the plasma levels. The optokinetic reflex is a complex arc involving retina, visual cortex and the oculomotor system. Unfortunately, by using a motor response as an end point (nystagmus) we can only conclude that oxazepam affects at least one component of the optokinetic reflex. Visual masking is the reduction of visibility of a stimulus (usually a letter) by the addition of a second stimulus (usually random dots or a pattern) either just preceding or just following the first stimulus. Emre et aL2’ showed that 12 mg of midazolam orally significantly enhances the masking effect and that this effect correlates with the known pharmacokinetics of the drug. They conclude that the enhanced inhibition slows down processing of visual information so that integration occurs over a longer Diazepam and its effects on visual fields
time interval. However, localisation to either retina or cerebral cortex is not possible. It is clear that in the retina the lateral inhibition of ganglion cells by amacrine cells is a powerful influence on their receptive fields. At least some of this inhibition is due to the neurotransmitter GABA being released by amacrine cells. This GABAergic system influences only the inner retinal layer and does not seem to be involved in transmission between photoreceptors, bipolar cells and ganglion cells. This system is altered by benzodiazepines and therefore it is possible that an oral dose of benzodiazepine could affect retinal hnction. The visual cortex is profoundly influenced by the inhibitory GABA system. This is apparent in both simple and complex cell receptive field changes after application of bicuculline which is similar in action to benzodiazepines. Whilst no similar studies have been done on the effects of benzodiazepines it seems reasonable that it too should cause receptive field changes. A search of the literature has revealed no reported cases of visual field changes with benzodiazepines. The case presented here is not a controlled study, but the automated perimetry gives high levels of confidence in the data and the patient herself was adamant that her subjective improvement in visual function corresponded to the reduction in the dose of diazepam from 100 mg to 10 mg per day. In conclusion, it is probable that oral doses of benzodiazepines can cause reversible visual field loss due to inhibition of the GABAergic system in either the retina, the visual cortex or both. This has widespread social importance.
References 1. Wilson JD. Harrison’s principles of internal medicine, 12th ed. New York: McGraw Hill, 1991;71. 2. Neal MJ. Minireview: Amino acid transmitter substances in the vertebrate retina. Gen Pharmacol 1976;7:321-2. 3. Kuriyama K. Kisken B, Haber B, Roberts E. The gammaaminobutyric acid system in rabbit retina. Brain Res 1968;9: 165-8. 4. Bolz J, Frumkes T, Voight T, Wassle H. Action and localization of gamma-aminoburyric acid in the cat retina. J Fhysiol (London) 1985:362:369-93. 5. Howells RD, Hiller JM, Simon EJ. Benzodiazepine binding sites are present in retina. Life Sci 1979;25:2131-6. 6. Howeiis RD, Simon EJ. Benzodia~epinebinding in chicken retina and its interaction with gamma aminobutyric acid. Eur J Pharmacol 1980;67:133-7. 7. Borbe HO, Miller WE, Wollert U, The identification of benzodiazepine receptors with brain-like specificity in bovine retina. Brain Res 1980;182:466-9. 269
8. Paul S, Zatz M, Skolnick P. Demonstration of “brain specific” benzodiazepine receptors in rat retina. Brain Res 1980,187:243-6. 9. Osborne NN. Benzodiazepine binding to bovine retina. Neurosci Lett 1980;16:167-70. 10. Regan JW, Roeske WR, Yamamura HI. 3H-Flunitrazepam binding to bovine retina and the effect of GABA thereon. Neuropharmacology 1980;19:413-15. 11. Seighart W, Drexler G, Supavilai P, Karobath M. Properries of benzodiazepine receptors in rat retina. Expl Eye Res 1982;34:961-8. 12. Skolnick P, Paul S, Zatz M, Eskay R. “Brain-specific” benzodiazepine receptors are localized in the inner plexiform layer of rat retina. Eur J Pharmacol 1980;66:133-6. 13. Alstein M, Dudai Y, Vogel 2. Benzodiazepine receptors in chick retina: development and cellular localization. Brain Res 1981;206:198-202. 14. Robbins J. Ikeda H. Benzodiazepines and the mammalian retina. I. Autographic localisation of receptor sites and the lack of effect on the electroretinogram. Brain Res 1989;479:313-22. 15. Ikeda H. Retinal mechanisms and the clinical electroretinogram. In: Halliday AM, Butler SR, Paul R, eds. A text book of clinical neurophysiology. New York: Wiley, 1987;569-94. 16. Iversen LL, Michell JF, Srinivasan V. The release of yamino-butyric acid during inhibition in the cat visual cortex. J Physiol (London) 1971;212:510-34. 17. Sillito AM. The effectiveness of bicuculline as an antagonist of GABA and visually evoked inhibition in the cat’s striate cortex. J Physiol (London) 1975;250:287-304. 18. Sillito AM. Modification of the receptive field properties
270
of neurons in the visual cortex of bicuculline, a GABA antagonist. J Physiol (London) 1974;239:36-7P. 19. Sillito AM. Functional considerations of the operation of GABAergic inhibitory processes in the visual cortex. Cerebral Cortex. New York: Plenum Press, 1984;2:91-117. 20. Tsumoto T, Eckart W, Creutzfeldt 0. Modification of orientation sensitivity of cat visual cortex neurones by removal of GABA mediated inhibition. Exp Brain Res 1979;34:351-63. 2 1. Innocenti GM, Fiore I. Postsynaptic inhibitory components of the response to moving stimuli in area 17. Brain Res 1974;80:229-89. 22. Sillito AM. The contribution of inhibitory mechanisms to the receptive field properties of neurones in the striate cortex of the cat. J Physiol (London) 1975;250:305-29. 23. Sillito AM. Inhibitory processes underlying the directional specificity of simple, complex and hypercomplex cells in the cat’s visual cortex. J Physiol (London) 1977;271:699-720. 24. Besser GM, Duncan C. The time course of action of single doses of diazepam, chlorpromazine and some barbiturates as measured by auditory flutter fusion and visual flicker fusion thresholds in man. Br J Pharmac Chemother 1967;30:341-8. 25. Smith JM, Misiak H. Critical flicker frequency and psychotropic drugs in normal human subjects - A review. Psychopharmacology 1976;47: 175-82. 26. Bergman H, Borg S, Hogman B, Larsson H, Linde JC, Tengrath B. The effect of oxazepam on ocular readaptation time. Acta Ophthalmologica 1979;57:145-50. 27. Emre M, Groner M, Hofer D, Groner R, Fisch D. Effects of benezodiazepinesin forward and backward visual masking. Clin Vision Sci 1989;4:257-63.
Australian and New Zealand Journal of Ophthalmology 1992; 20(3)
