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


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  2. Abstract

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.


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  2. Abstract


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)

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).


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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


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  2. Abstract

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.


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