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Keywords:

  • Ocular blood flow;
  • Retinal perfusion;
  • Scanning laser Doppler flowmetry

Abstract

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Summary:  Purpose: Reduced cerebral blood flow and decreased cerebral glucose metabolism have been identified in patients with epilepsy treated with antiepileptic drug (AED) therapy. The purpose of this study was to determine whether ocular haemodynamics are similarly reduced in patients with epilepsy treated with AEDs.

Methods: Scanning laser Doppler flowmetry was used to measure retinal capillary microvascular flow, volume, and velocity in the temporal neuroretinal rim of 14 patients diagnosed with epilepsy (mean age, 42.0 ± 0.9 years). These values were compared with those of an age- and gender-matched normal subject group (n = 14; mean age, 41.7 ± 0.3 years). Student's unpaired two-tailed t tests were used to compare ocular blood-flow parameters between the epilepsy and normal subject groups (p < 0.05; Bonferroni corrected).

Results: A significant reduction in retinal blood volume (p = 0.001), flow (p = 0.003), and velocity (p = 0.001) was observed in the epilepsy group (13.52 ± 3.75 AU, 219.14 ± 76.61 AU, and 0.77 ± 0.269 AU, respectively) compared with the normal subject group (19.02 ± 5.11 AU, 344.03 ± 93.03 AU, and 1.17 ± 0.301 AU, respectively). Overall, the percentage mean difference between the epilepsy and normal groups was 36.31% for flow, 28.92% for volume, and 34.19% for velocity.

Conclusions: Patients with epilepsy exhibit reduced neuroretinal capillary blood flow, volume, and velocity compared with normal subjects. A reduction in ocular perfusion may have implications for visual function in people with epilepsy.

Local alterations in cerebral blood flow and glucose metabolism have been identified in patients undergoing epileptic seizures. Some investigators have reported an increase in cerebral blood flow local to the point of focus (1,2). In other studies, an initial increase in cerebral flow followed by hypoperfusion has been described (3,4), the nature of which appears to be dependent on the form of epilepsy and seizure. In addition to the seizure activity, antiepileptic drug (AED) therapy has been reported to alter the haemodynamics of the brain. A number of AEDs have been investigated including carbamazepine (CBZ), phenytoin (PHT), phenobarbital (PB), sodium valproate (VPA), and vigabatrin (VGB), all of which have been reported to result in decreased cerebral metabolic rate for glucose and/or cerebral blood flow (5–7).

Although blood flow has been extensively investigated in the brains of patients with epilepsy, this area of investigation has not been extended to the eye, which is surprising, given that the eye and brain are a haemodynamic continuum, united by the sympathetic nervous system and the carotid arterial network. Studies investigating the effect of systemic drugs or vasoactive stimuli on cerebral and ocular blood flow in normal subjects have identified parallel changes in the brain and eye (8–11). It is therefore possible that a reduction in cerebral blood flow, previously reported in patients receiving AED therapy, may be replicated in the ocular circulation.

Visual disruption has been reported in up to 30% of patients diagnosed with epilepsy (12). Specific visual problems associated with AED therapy include diplopia, blurred vision, reductions in contrast sensitivity and visual acuity, colour-perception deficits, and visual field loss (13–21). Some of these visual disturbances may be attributable to AED therapy, whereas others may be related to the disease process itself. If, as we suspect, the compromised cerebral perfusion in epilepsy patients is extended to the eye, then patients in whom visual disturbances are evident may have a reduction in ocular perfusion that exacerbates or contributes to the problem.

The purpose of this study was to investigate whether epilepsy patients receiving AED therapy have altered ocular haemodynamics when compared with an age- and gender-matched normal subject group.

METHODS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Subjects

The study cohort comprised two age- and gender-matched subject samples: 14 patients diagnosed with epilepsy and receiving AED therapy and 14 normal healthy volunteers. Table 1 outlines the subject sample characteristics.

Table 1.  Subject sample characteristics showing the age, gender, and eye distribution for the normal and epilepsy groups
 age (yr)Gender (n)Eye (n)
GroupMeanSDMFRL
Normal41.70.37777
Epilepsy42.00.97777

Epilepsy patients were recruited from the epilepsy clinics of Birmingham University (Queen Elizabeth Psychiatric Hospital, Birmingham, U.K.) and the City Hospital NHS Trust, Birmingham, U.K. Patients were excluded if they had a history of ischaemic heart disease, hypertension, hypotension, diabetes mellitus, or multiple sclerosis. Patient underwent a full ophthalmic examinations and were excluded if they had glaucoma, intraocular pressure >22 mm Hg (Goldmann applanation tonometry), significant cataract, or any other sight-threatening disease.

Normal control subjects had no history of ocular or neurologic disease or surgery. Intraocular pressures were <22 mm Hg, and Humphrey visual fields were normal. Normal subjects and epilepsy patients were required to have best-corrected visual acuities of ≥6/9 in both eyes and a mean refractive error of <6 dioptres with astigmatism <2 dioptres cylinder in the test eye. Each normal subject underwent a comprehensive ophthalmic examination to rule out abnormalities of the optic nerve head, macular region, anterior segment, and posterior pole. The ocular exclusion criteria for the normal and epilepsy groups were similar; however, epilepsy patients were not excluded for abnormal fundus appearance or visual field abnormality thought to arise from VGB drug toxicity.

Ethical committee approval was obtained for all experimental procedures, and written informed consent was acquired from each participant before study enrolment.

Experimental procedures

Only epilepsy patients who had been seizure free for at least 24 h were included in the study. The possibility of subclinical seizure activity during testing could be ruled out only by synchronized EEG recording, which was not possible during this study. Ocular blood-flow measurements were carried out at approximately the same time of day for each subject to avoid diurnal fluctuations known to occur in blood flow (22). On the morning of the test, subjects were requested to avoid caffeine-containing products, alcohol, nicotine (in any form), and strenuous exercise. Subjects were requested to relax for 15 min before blood-flow measurements commenced.

Scanning laser Doppler flowmetry

Scanning laser Doppler flowmetry (SLDF) provides a reproducible technique for the determination of retinal blood flow, volume, and velocity at the capillary level. The principle of the technique has been described previously (23,24). In brief, SLDF combines laser Doppler flowmetry with laser scanning ophthalmoscopy to produce a two-dimensional map of the vascular perfusion of the retinal capillary network.

SLDF was performed at a single session using the Heidelberg Retina Flowmeter (HRF; Heidelberg Engineering, Heidelberg, Germany). The test eye of each subject was dilated with Tropicamide, 1%. With a 10 × 2.5-degree field, three mapped images were acquired across the superior section of the optic nerve head and peripapillary retina. Images were focused on the neuroretinal microvasculature and the focus setting kept constant for subsequent images. Perfusion maps were generated by using fast Fourier transformation (software version 1.02) and assessed for clarity and eye movement by a single observer. Only good-quality perfusion maps with minimal eye movement were retained for subsequent analysis. To ensure this, perfusion maps were scored on a scale of 0–20 for image clarity and eye movement, and only images with a combined score of ≥15 were accepted for analysis.

A 10 × 10-pixel frame was used to obtain mean arbitrary values for blood flow, volume, and velocity. A previous study by our group (25) established a search strategy for manipulating the 10 × 10-pixel frame in a given area of 15 × 15 pixels to find the highest mean values of flow, volume, and velocity. This strategy accounts for local variations in flow attributable to vascular pulsations and was used for subsequent analysis. Efforts were made to optimize the reproducibility of the capillary blood-flow measurements acquired by ensuring a constant direct current (DC) level of between 110 and 150 AU (26) and avoiding areas interrupted by saccades.

Statistical analysis

Student's unpaired two-tailed t tests were used to identify differences in blood volume, flow, and velocity between the different subject groups. Significance was taken at p ≤ 0.05 (Bonferroni corrected).

RESULTS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Of the epilepsy patients included, two had complex partial seizures only, three had simple and complex partial seizures, six had complex seizures that secondarily generalised, and three had simple partial seizures that became complex partial with secondary generalisation. The mean duration of the epilepsy for the group was 26.5 ± 12.3 years. Patients had received a range of AED therapy including one or more of the following: VGB, CBZ, lamotrigine (LTG), VPA, PHT, PB, clobazam (CLB), and gabapentin (GBP). Of the epilepsy patients, four had abnormal Humphrey program 30-2 standard (white-on-white) visual fields (mean defect, –5.35 ± 2.15 dB).

No significant difference was apparent between the two groups for age, systolic blood pressure, and diastolic blood pressure (p > 0.05). Table 2 shows the mean values for the SLDF parameters together with the percentage mean difference and t test results. A significant reduction in ocular blood flow (p = 0.001), volume (p = 0.003), and velocity (p = 0.001) was observed in the epilepsy group when compared with the normal group, and of those, the greatest reduction in ocular perfusion was observed for blood flow.

Table 2.  Descriptive statistics and t-test results for SLDF parameters measured in the epilepsy and normal subject groups
 Volume (AU)Flow (AU)Velocity (AU)
Control (mean ± SD)19.02 ± 5.11344.03 ± 93.651.17 ± 0.30
Epilepsy (mean ± SD)13.52 ± 3.75219.14 ± 76.610.77 ± 0.27
Mean difference5.51124.890.40
Percentage difference28.92%36.31%34.19%
t-Test p value0.003  0.0010.001

DISCUSSION

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Overall, patients diagnosed with epilepsy exhibit reduced blood flow, volume, and velocity measured at the temporal neuroretinal rim compared with age- and gender-matched normal volunteers. This is the first time that retinal perfusion has been investigated in epilepsy patients.

A decreased cerebral metabolic rate for glucose and decreased cerebral blood flow has been previously identified in epilepsy patients treated with AEDs (5–7). This phenomenon is most likely the result of depressed metabolism and reduced metabolic requirement (5). Our results suggest that this reduction in cerebral blood flow extends to the eye, either as a direct result of the disease process or as a secondary consequence of AED therapy. All of the patients included in this investigation were receiving AED therapy; a trial involving an untreated epileptic groups would be required to establish whether the reduction in ocular blood flow is due to the disease, to AED therapy, or to a combination of the two.

Reduced ocular blood flow in the retina has direct implications for the viability and functioning of retinal cells, and consequently, visual function. This relation has been demonstrated in ocular disease. In some subgroups of glaucoma, for example, altered ocular perfusion and compromised autoregulation in the retina have been linked to the onset of visual loss (27–29). Retinal ganglion cell death and subsequent axonal degeneration in glaucoma is reported to occur by apoptosis (30), and ischaemia has been identified as a possible mechanism. Compromised perfusion, secondary to increased intraocular pressure, may impede axonal transport of neurotrophins in retinal ganglion cells through the depletion of energy resources (31). Alternatively, altered neurotransmitter levels, a primary response to ischaemia, may result in an increased potential for neurotoxicity within the retina, with subsequent visual loss (32). Because both the epilepsy disease process and the AED therapy manipulate neurotransmitter levels, the potential for damage is likely to be exacerbated by ischaemia.

Some AEDs, such as CBZ and VGB, are known to result in visual disturbances (18,21). Of the epilepsy patients recruited for this investigation, four had clinically abnormal visual fields; all of the patients had received VGB. The epilepsy patients included in this study were diagnosed with varying seizure types including simple, complex partial, and secondarily generalised seizures. The patients were receiving a range of AEDs including CBZ, VPA, PHT, and VGB. The drug dosages and duration of treatment varied between patients, and the limited subject numbers precluded a statistical comparison among the different treatment regimens and seizure histories. A review of the adverse side effects associated with the AED therapy that the epilepsy patients were receiving revealed few potential systemic-perfusion interactions. PHT and PB have sometimes been associated with anaemia, and an uncommon side effect of CBZ administration includes oliguria with hypertension and left ventricular failure (33). In this study, all of the epilepsy patients exhibited normal blood pressure results.

The absolute values obtained with SLDF for blood flow, volume, and velocity are dependent on a number of factors including cardiac cycle (34), zero-offset (35), and sampling depth. Cardiac synchronisation was unavailable at the time of this study; however, to account for variability due to cardiac cycle, the mean value from three mapped images obtained for each subject was used for analysis. The penetration of infrared light into the retina by the HRF is between 300 and 400 μm. Such a sampling depth will allow the visualisation of retinal microvascular flow, but not choroidal flow, because of the high absorption properties of the pigment epithelium (23). The HRF uses a zero-offset to account for noise occurring because of back-scattered light (35). Although the zero-offset is likely to vary between individuals with varying amounts of media opacities and thus back-scattered light, the fact that the subjects included in this study were relatively young and free of media opacities should minimise the differences between the groups.

In this investigation, SLDF measurements were localised to the temporal neuroretinal rim. This area of the neuroretinal rim has been previously reported to exhibit the least variability with SLDF (36). It is possible that other components of the ocular circulation may be depressed in patients with epilepsy, including other areas of the retina, the choroid, and retrobulbar arteries. Further investigation of other ocular vascular beds is required to determine whether the reduction in retinal blood flow, volume, and velocity is paralleled in other areas of the ocular circulation in epilepsy patients. A study designed to investigate both cerebral and ocular blood flow would provide insight into whether compromised haemodynamics of the brain are, as we suspect, directly correlated with decreased ocular perfusion.

In conclusion, blood flow, volume and velocity measured with SLDF are reduced in the temporal neuroretinal rim of epilepsy patients when compared with those in age-matched normal subjects. Compromised ocular blood flow may exacerbate or contribute to visual disturbances in epilepsy patients. Future investigations are required to determine whether this haemodynamic alteration is drug or disease dependent.

Acknowledgment: This work was funded in part by Aventis. We are grateful to Ms. Sally Embleton for her kind assistance with data collection.

REFERENCES

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  • 1
    Kahane P, Mauguiere F. Ictal cerebral blood flow (CBF) changes studied by positron emission tomography (PET) and simultaneous stereoelectroencephalographic recordings (SEEG). Rev Neurol 1999;155: 4726.
  • 2
    Hill RA, Chiappa KH, HuangHellinger F, et al. Hemodynamic and metabolic aspects of photosensitive epilepsy revealed by functional magnetic resonance imaging and magnetic resonance spectroscopy. Epilepsia 1999;40: 91220.
  • 3
    Rabinowicz AL, Salas E, Besberra F, et al. Changes in regional cerebral blood flow beyond the temporal lobe in unilateral temporal lobe epilepsy. Epilepsia 1997;38: 10114.
  • 4
    DeSimone R, Silvestrini R, Marciani MG, et al. Changes in cerebral blood flow velocities during childhood absence seizures. Pediatr Neurol 1998;18: 1325.
  • 5
    Theodore WH. Antiepileptic drugs and cerebral glucose metabolism. Epilepsia 1988;29(suppl 2):S4855.
  • 6
    Matsuda H, Fukuchi T, Onuma T, et al. Interictal cerebral and cerebellar blood flow in temporal lobe epilepsy as measured by a non-invasive technique using Tc-99m HMPAO. Clin Nucl Med 1996;21: 86772.
  • 7
    Spanaki MV, Siegel H, Kopylev L, et al. The effect of vigabatrin (γ-vinyl GABA) on cerebral blood flow and metabolism. Neurology 1999;53: 151822.
  • 8
    Harris A, Arend O, Kopecky K, et al. Physiological perturbation of ocular and cerebral blood flow as measured by scanning laser ophthalmoscopy and color Doppler imaging. Surv Ophthalmol 1994;38: S816.
  • 9
    Harris A, Tippke S, Sievers C, et al. Acetazolamide and CO2: acute effects on cerebral and retrobulbar hemodynamics. J Glaucoma 1996;5: 3945.
  • 10
    Schmetterer L, Findl O, Strenn K, et al. Role of NO in the O2 and CO2 responsiveness of cerebral and ocular circulation in humans. Am J Physiol 1997;273: R200512.
  • 11
    Kiss B, Dallinger S, Findl O, et al. Acetazolamide-induced cerebral and ocular vasodilation in humans is independent of nitric oxide. Am Physiol J 1999;276: R16617.
  • 12
    Ludwig BL, Marsan CA. Clinical ictal patterns in epileptic patients with occipital electroencephalographic foci. Neurology 1975;25: 46371.
  • 13
    Bayer A, Thiel HJ, Zrenner E, et al. Colour vision deficiencies and enhanced sensitivity to glare in epileptic patients treated with carbamazepine and phenytoin: ocular side-effects of anti-epileptic drugs. Nervenarzt 1995;66: 8996.
  • 14
    Steinhoff BJ, Freudenthaler N, Paulus W. The influence of established and new antiepileptic drugs on visual perception, II: a controlled study in patients with epilepsy under long-term antiepileptic medication. Epilepsy Res 1997;29: 4958.
  • 15
    Eke T, Talbot JF, Lawden MC. Severe persistent visual field constriction associated with vigabatrin. Br Med J 1997;314: 1801.
  • 16
    Krauss GL, Johnson MA, Miller NR. Vigabatrin-associated retinal cone system dysfunction. Neurology 1998;50: 6148.
  • 17
    Krauss G, Miller NR. Vigabatrin: an effective antiepilepsy drug: balancing the risk of visual dysfunction. Ann Pharmacother 1999;33: 13678.
  • 18
    Nousiainen I, Kalviainen R, Mantyjarvi M. Color vision in epilepsy patients treated with vigabatrin or carbamazepine monotherapy. Ophthalmology 2000;107: 8848.
  • 19
    Nousiainen I, Kalviainen R, Mantyjarvi M. Contrast and glare sensitivity in epilepsy patients treated with vigabatrin or carbamazepine monotherapy compared with healthy volunteers. Br J Ophthalmol 2000;84: 6225.
  • 20
    Manuchehri K, Goodman S, Siviter L, et al. A controlled study of vigabatrin and visual abnormalities. Br J Ophthalmol 2000;84: 499505.
  • 21
    Hilton EJR, Cubbidge RP, Hosking SL, Betts T, Comaish IF. Patients treated with vigabatrin exhibit central visual function loss. Epilepsia 2002;43: 13519.
  • 22
    Claridge KG, Smith SE. Diurnal variation in pulsatile ocular blood flow in normal and glaucomatous eyes. Surv Ophthalmol 1994;38: S198205.
  • 23
    Michelson G, Schmauss B. Two dimensional mapping of the perfusion of the retina and optic nerve head. Br J Ophthalmol 1995;79: 112632.
  • 24
    Michelson G, Schmauss B, Langhans MJ, et al. Principle, validity, and reliability of scanning laser Doppler flowmetry. J Glaucoma 1996;5: 99105.
  • 25
    Hosking SL, Embleton SJ, Cunliffe IA. Application of a local search strategy demonstrates preferential loss of high-velocity blood flow in the neuroretinal rim of glaucoma patients, using scanning laser Doppler flowmetry. Br J Ophthalmol 2001;85: 12981302.
  • 26
    Hosking SL, Embleton SJ, Kagemann L, Chabra A, Jonescu-Cuypers C, Harris A. Detector sensitivity influences blood flow sampling in scanning Laser Doppler flowmetry. Graefes Arch Clin Exp Ophthalmol 2001;239: 40710.
  • 27
    Galassi F, Nuzzaci G, Sodi A, et al. Possible correlations of ocular blood-flow parameters with intraocular-pressure and visual-field alterations in glaucoma: a study by means of color Doppler imaging. Ophthalmologica 1994;208: 3048.
  • 28
    Nicolela MT, Drance SM, Rankin SJA, et al. Color Doppler imaging in patients with asymmetric glaucoma and unilateral visual field loss. Am J Ophthalmol 1996;121: 50210.
  • 29
    Michelson G, Langhans M, Dichtl A, et al. Impaired perfusion of the juxtapapillary retina and the neuroretinal rim area precede visual field loss in primary open angle glaucoma (POAG). Invest Ophthalmol Vis Sci 1996;37: 21011.
  • 30
    Quigley HA, Nickells RW, Kerrigan LA, et al. Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis. Invest Ophthalmol Vis Sci 1995;36: 77486.
  • 31
    Levin LA. Direct and indirect approaches to neuroprotective therapy of glaucomatous optic neuropathy. Surv Ophthalmol 1999;43: S98101.
  • 32
    Dreyer EB, Grosskreutz CL. Excitatory mechanisms in retinal ganglion cell death in primary open angle glaucoma (POAG). Clin Neurosci 1997;4: 2703.
  • 33
    Lloyd GK, Gillenwater G. Epilepsy and antiepileptic drugs. In: MunsonPL, ed. Principles of pharmacology. New York: Chapman & Hall, 1995: 36398.
  • 34
    Michelson G, Welzenbach J, Pal I, et al. Automatic full field analysis of perfusion images gained by scanning laser Doppler flowmetry. Br J Ophthalmol 1998;82: 1294300.
  • 35
    Chauhan BC, Smith FM. Confocal scanning laser Doppler flowmetry: experiments in a model flow system. J Glaucoma 1997;6: 23745.
  • 36
    Bohdanecka Z, Orgül S, Prünte C, et al. Influence of acquisition parameters on hemodynamic measurements with the Heidelberg retina flowmeter at the optic disc. J Glaucoma 1998;7: 1517.