Potential conflict of interest: Nothing to report.
Smooth pursuit eye movements (SPEM) are the conjugate movements used to track the smooth trajectory of small dots. Jerky or ‘saccadic’ ocular pursuit has been reported in patients with cirrhosis, but no formal assessment of SPEM has ever been undertaken. The aim of this study was to evaluate SPEM in patients with cirrhosis and varying degrees of hepatic encephalopathy. The patient population comprised 56 individuals (31 men, 25 women) of mean age 51.1 (range, 25–70) years, with biopsy-proven cirrhosis, classified, using clinical, electroencephalographic, and psychometric variables, as either neuropsychiatrically unimpaired or as having minimal or overt hepatic encephalopathy; patients were further categorized in relation to their treatment status. The reference population comprised 28 healthy volunteers (12 men, 16 women) of mean age 47.3 (range, 26–65) years. SPEM was assessed using an electro-oculographic technique. Visual inspection of the SPEM recordings showed clear disruption of smooth pursuit in the patients with minimal hepatic encephalopathy, and more pronounced disruption, if not complete loss, of smooth pursuit in patients with overt hepatic encephalopathy. The differences observed in quantifiable SPEM indices between the healthy volunteers/unimpaired patients and those with overt hepatic encephalopathy were significant (P < .05). In conclusion, SPEM performance is impaired in patients with hepatic encephalopathy in parallel with the degree of neuropsychiatric disturbance: the pathophysiology of these changes is unknown, but retinal, extrapyramidal, and attentional abnormalities are likely to play a role. Treatment status confounds the classification of neuropsychiatric status and should be taken into account when categorizing these patients. (HEPATOLOGY 2005;42:772–781.)
Hepatic encephalopathy is characterized by deficits in cerebral neurotransmission primarily of the glutamatergic, GABAergic, and endogenous opioid systems.1 Low-grade astrocyte swelling, which results in alterations in glial-neuronal communication, is also thought to play a role in the genesis of this syndrome.2 Similar low-grade swelling occurs in the retinal glial (Müller) cells, resulting in the development of morphological changes that mirror those of the cerebral astrocytes. The term ‘hepatic retinopathy’ has been coined to describe these histopathological alterations.3 The presence of hepatic retinopathy is associated with a number of functional abnormalities,4 including an alteration in critical flicker frequency (CFF), which is defined as the highest frequency at which the flicker of a flickering light source can be detected.5 The exact relationship between the changes in the retinal and cerebral glial cells has not been defined, but it has been suggested that alteration in the CFF threshold may serve as a diagnostic marker for hepatic encephalopathy.5
One of the key factors determining CFF integrity is the initial perception of velocity, or movement, across the retina.6 This facility is also key to the execution of smooth pursuit eye movements (SPEM), which are the conjugate movements used to track, or pursue, the smooth trajectory of small dots. Impaired pursuit occurs when individuals cannot track the dot trajectory accurately. In these instances, the trajectory of the eye is no longer smooth but interspersed with anticipatory and corrective catch-up saccades, resulting in a pattern of jerky or cogwheel pursuit.7 Unilateral or bilateral pursuit abnormalities can be observed in the presence of structural abnormalities of the pursuit pathways in the cerebral cortex, pons, and cerebellum,7 and in situations characterized by disruption in cerebral neurotransmission, for example, in Parkinsonism8 and schizophrenia,9 and during medication with various neuroactive drugs.7 Although ‘saccadic’ ocular pursuit has been observed in patients with cirrhosis, particularly in those with hepatic encephalopathy,10 no formal assessment of SPEM has been undertaken in this patient population.
Difficulties arise in delineating relationships between variables such as SPEM and the neuropsychiatric abnormalities observed in patients with chronic liver disease, particularly in determining the causality of any identified associations. This reflects, at least in part, the fact that there is no reference or ‘gold’ standard for the diagnosis of hepatic encephalopathy11 but also the fact that no guidance is available on the classification of patients receiving long-term maintenance treatment.11 Previous workers have tended to either exclude treated patients from their studies5 or else to classify them as having overt hepatic encephalopathy irrespective of their status on the day of study.12 Thus, here is a need to obtain a consensus on whether long-term maintenance treatment should be taken into account as a separate variable for classification purposes.
The aim of the current study was, therefore, to determine the integrity of SPEM in patients with cirrhosis with varying degrees of neuropsychiatric impairment, controlling for the possible confounding effect of long-term maintenance treatment for hepatic encephalopathy.
SPEM, smooth pursuit eye movements; CFF, critical flicker frequency; HMST, Hodkinson mental state test; MMST, ‘Mini-mental’ state test; NCT-A, Number Connection Test A; NCT-B, Number Connection Test B; DS, digit symbol test; EEG, electroencephalogram; TRMS, total root mean square; RMS, root mean square; SRMS, SPEM root mean square.
Patients and Methods
The patient population comprised 56 individuals (31 men, 25 women) of mean age 51.1 (range, 25–70) years, with biopsy-proven cirrhosis. The etiology of the liver lesion was determined on the basis of clinical, laboratory, and histological variables. The functional severity of the liver injury was assessed using Pugh's modification of the Child's grading system.13
Patients were excluded from the study if they were younger than 16 or older than 70 years of age, could not speak English or obey spoken commands, had misused alcohol in the preceding 3 months, had a history of insulin-dependent diabetes mellitus, significant head injury, cerebrovascular disease or arterial hypertension, or had impaired eye muscle function or visual acuity of less than 6/6, in either eye, with corrective lenses, or were taking neuroactive drugs.
The reference population comprised 28 healthy volunteers (12 men, 16 women) of mean age 47.3 (range, 26–65) years. None had a history, clinical or laboratory evidence of alcohol misuse or chronic liver disease; none drank alcohol in excess of 20 g/d, or was on long-term medication, had defective eye muscle function or impaired visual acuity.
All patients were clinically stable at the time of the study. Details of their neuropsychiatric history were recorded and confirmed by reference to a third party, usually a relative, in every case. Patients were examined and their mental state assessed using the West Haven criteria,14 the Hodkinson mental state test (HMST),15 and a modified version of the ‘Mini-mental state’ test (MMST).16 Psychometric performance was assessed, under standardized conditions, by the same observer, using Number Connection Tests A (NCT-A) and B (NCT-B),14 the digit symbol (DS) subtest of the Wechsler Adult Intelligence Scale,17 and the digit copying (DC) subtest of the Kendrick battery.18 Electroencephalograms (EEGs) were recorded, eyes closed, in a condition of relaxed wakefulness, using silver-silver chloride electrodes placed according to the International 10–20 system; the traces were analyzed visually by a single observer blinded to the subjects' clinical status.
Assessments were carried out in a darkened room by an operator who was blinded to the clinical status of the subject. An EEG electrode was placed at both the inner and outer canthus of each eye to record eye movements.19 Subjects were asked to sit comfortably with their eyes at approximately 30 cm from the computer monitor, and to eye-track the progress of a computer-generated, 1-cm diameter, white dot across the screen, without moving their head. The dot moved in a horizontal, pseudo-random, sinusoidal fashion at frequencies increasing from 0.2 Hz to 0.5 Hz at 0.1-Hz intervals, with interspersed pauses between frequency changes. Two complete sinusoids were randomly embedded within each set of dot movements for purposes of analysis (Fig. 1). The tracking positions of each eye were recorded and then superimposed on the digitally filtered trace of the dot (Fig. 1).
If the eye voltages exceeded the range of the analog-to-digital converter, no analyzable data could be obtained; recordings containing less than 90% of analyzable trace were excluded. SPEM can be differentiated from saccades and other fast eye movements on the basis of velocity; for purposes of this study, eye movements were qualified as SPEM if their velocity was below five times the maximum dot velocity.
The following indices were calculated, over the period of the two full sinusoids, separately for left and right eye and then averaged for each dot velocity:
SPEM time: the fraction of SPEM in the tracing, which ranges from 0 (none of the tracing qualified as SPEM) to 1 (all of the tracing qualified as SPEM). This index is a measure of tracking ability or compliance with the task because it represents the amount of time spent in appropriate tracking of the dot as opposed to fast eye movements such as saccades.
Total root mean square (TRMS): root mean square (RMS) of the error in each eye position compared with the dot position. TRMS was normalized to the RMS of the dot position for each sample used:
This index is a measure of the error between the positions of the eye and dot both during smooth pursuit movement and faster eye movements; it thus provides a measure of both tracking ability and tracking accuracy.
SPEM root mean square (SRMS): RMS of the error in each eye position compared with the dot position on the sections of the tracing qualified as SPEM. SRMS was normalized to the RMS of the dot position for each sample used:
This index is a measure of the error between the position of the eye and the dot in the sections of the tracing qualified as SPEM; it thus provides a measure of tracking accuracy.
Gain: the sum of the ratios of the eye and dot velocities when the dot velocity exceeds a threshold of 0.25 times its maximum in the sections of the tracing qualified as SPEM. The instantaneous Gain was normalized for dot velocity for each sample used; the sum of the instantaneous Gains was re-normalized by dividing by the number of samples used:
This index is a measure of the eye/dot velocity match and hence of tracking accuracy.20 Tracking would be qualified as abnormal both if Gain < 1-slow eye movement; the eye lags behind the dot-and if Gain >1-fast eye movement; the eye anticipates dot motion. To facilitate correlation analysis, an additional parameter, Gain2, ranging from 0 to 1, which qualified abnormal performance in one direction only, was defined:
Repeat studies were undertaken in 15 patients to monitor progress over time and/or the response to treatment with a non-absorbable disaccharide.
Age- and education-adjusted normative data for the psychometric tests used in this study are not available for the British population. NCT-A and NCT-B results were, therefore, scored in relation to age- and education-adjusted reference values obtained from a healthy Italian population21 and age-adjusted reference values obtained from a healthy German population22; the DS was scored with reference to age-adjusted values obtained from a healthy German population.22 The adjusted test results were considered abnormal if they exceeded two standard deviations from the mean. The DC test was defined as abnormal below a fixed score threshold of 124, corresponding to the completion of 100 copies or less in 120 seconds.18 Overall psychometric performance was classified as impaired if two or more of the individual tests were abnormal. The EEG was considered abnormal if the central-posterior mean frequency was < 9 Hz and/or there were significant bursts of slow activity in the theta/delta range.
Neuropsychiatric status on the day of the study was classified as (1) unimpaired: individuals who had no history or clinical evidence of hepatic encephalopathy and no defining EEG and/or psychometric test abnormalities; (2) minimal hepatic encephalopathy: individuals who showed no clinical evidence of hepatic encephalopathy but had an abnormal EEG and/or impaired psychometric performance; (3) overt hepatic encephalopathy: individuals with clinically evident neuropsychiatric disturbances14; these patients invariably demonstrated EEG and/or psychometric abnormalities. Patients were further classified, on the basis of long-term treatment with a non-absorbable disaccharide, as either treated or untreated.
The distributions of the neuropsychiatric variables, the laboratory parameters, and the SPEM indices were tested for normality using the Shapiro-Wilk's W test. Variables that were not normally distributed were Ln transformed or 1/Ln transformed and re-tested for normality. Ln NCT-A, 1/Ln NCT-B, DS, Ln SRMS, Ln TRMS, and Ln Gain2 were normally distributed at all dot frequencies. Differences between normally distributed group variables were examined by one-way ANOVA/ANCOVA, which included an age-adjustment; subsequent between groups comparisons were performed, where appropriate, using the Scheffé test. The results were represented as means and 95% confidence intervals (bars). Differences between non-normally distributed group variables were examined using the Kruskal-Wallis test; subsequent between-group comparisons were performed, where appropriate, using the Mann-Whitney U test, applying the Bonferroni correction for multiple comparisons. The results were represented as box and whisker plots (mean and standard error [box] and standard deviation [whisker]). Correlations between SPEM indices and the other variables were tested using the Pearson r.
The study was conducted according to the Declaration of Helsinki (Hong Kong Amendment) and Good Clinical Practice (European guidelines). The protocol and amendments were submitted to, and approved by, the Royal Free Hospital Ethics Committee. All participating subjects provided written, informed consent.
The etiology of the cirrhosis was alcohol in 46 (82%) of the 56 patients, hepatitis C in 5 (9%), cryptogenic in 3 (5.4%), and biliary in 2 (3.6%). Functionally, 32 (57.1%) were Child's grade A; 21 (37.5%), Child's grade B; and 3 (5.4%), Child's grade C.
On the day of study, 11 (19.6%) of the 56 patients were classified as neuropsychiatrically unimpaired, 20 (35.7%) as having minimal hepatic encephalopathy, and 25 (44.6%) as having overt hepatic encephalopathy; 9 of the individuals classified as having minimal and 8 classified as having overt hepatic encephalopathy had experienced one or more episodes of overt hepatic encephalopathy and were on long-term maintenance treatment with a non-absorbable disaccharide (Table 1).
Table 1. Demographic and Assessment Variables in the Reference Population and in the Various Patient Populations
The patients and healthy volunteers were of comparable age overall (Table 1).
There were no significant differences in psychometric and EEG performance between the healthy volunteers and the patients with cirrhosis classified as neuropsychiatrically unimpaired (Table 1). Patients with minimal hepatic encephalopathy performed significantly less well than the healthy volunteers and the unimpaired cirrhotic patients on a number of individual tests but significantly better than patients with overt hepatic encephalopathy (P < .05; Table 1). Patients with overt hepatic encephalopathy performed significantly less well than healthy volunteers and unimpaired cirrhotic patients on most individual tests (P < .05; Table 1). In general, treated patients showed less psychometric/neurophysiological impairment than their untreated counterparts (Table 1; Fig. 2).
SPEM Recording and Analysis.
Overall, 299 (89%) of the 336 initial individual frequency recordings were suitable for analysis. Only the data recorded at 0.4 and 0.5 Hz are presented.
No perceptible differences were observed, on visual inspection, between the SPEM recordings obtained from patients who were neuropsychiatrically unimpaired and the healthy volunteers (Fig. 3A–B). However, obvious impairment in pursuit movement was observed in the recordings obtained from the patients with both minimal and overt hepatic encephalopathy (Fig. 3C–D).
Significant differences were observed in measured SPEM indices between the healthy volunteers and the patients with cirrhosis in relation to both their neuropsychiatric and treatment status.
In the total patient population of 56 individuals, progressive impairment in neuropsychiatric performance was associated with a parallel deterioration in SPEM performance evidenced by increases in TRMS, SRMS, and Gain2 together with decreases in Gain, and SPEM time (Table 2; Fig. 4A). The patients with overt hepatic encephalopathy performed significantly less well than both the healthy volunteers and the unimpaired cirrhotic patients (Table 2; Fig. 4A).
Table 2. SPEM Indices in Healthy Volunteers and in Patients With Cirrhosis, by Degree of Current Neuropsychiatric and Treatment Status
Healthy Volunteers (n = 26 at 0.4; 25 at 0.5)
Unimpaired (n = 11)
Minimal HE All (n = 16)
Minimal HE Untreated (n = 8)
Patients With Cirrhosis Minimal HE Treated (n = 8)
Overt HE All (n = 22 at 0.4; 25 at 0.5)
Overt HE Untreated (n = 14 at 0.4; 17 at 0.5)
Overt HE Treated (n = 8)
Data are crude (non-Ln transformed) and expressed as mean ± 1 SD; *normal or normalized variables.
Significance of the difference between healthy volunteers and patients with overt HE:
P < .05;
P < .005;
P < .002.
Significance of the difference between unimpaired cirrhotic patients and patients with overt HE:
P < .05;
P < .02.
Significance of the differences between healthy volunteers and untreated patients with overt HE:
P < .05;
P < .01;
P < .002.
Significance of the difference between unimpaired cirrhotic patients and treated patients with minimal HE:
P < .02.
Significance of the difference between unimpaired cirrhotic patients and untreated patients with overt HE:
Seventeen of the 56 patients had a history of overt hepatic encephalopathy and were on maintenance treatment with a non-absorbable disaccharide; of these, 9 were categorized as having minimal and 8 as having overt hepatic encephalopathy, based on their current status. Subcategorization in relation to treatment status produced a much more complex picture of the relationship between SPEM performance and neuropsychiatric status (Table 2; Fig. 4B). Thus, significant differences were observed in SPEM variables between the untreated patients with overt hepatic encephalopathy and both the healthy volunteers and the unimpaired cirrhotic patients. However, no significant differences were found between SPEM variables in the treated patients with overt hepatic encephalopathy and the other patient groups (Table 2; Fig. 4B). In contrast, the patients with minimal hepatic encephalopathy on treatment performed less well than their untreated counterparts, although the intergroup differences were not significant (Table 2; Fig. 4B).
Significant correlations were observed between SPEM variables and the mental state test scores and psychometric test results, but not with the Pugh's score or the EEG mean frequency (Table 3). There were no significant differences in neuropsychiatric and SPEM variables in relation to the etiology of the liver injury.
Table 3. Correlations Matrix Between SPEM and Demographic/Neuropsychiatric Variables in the Healthy Volunteers and the Patients With Cirrhosis
Changes were observed in pursuit behavior in the 15 patients studied over time/in response to initiation of treatment, which mirrored the changes in clinical state and neuropsychometric performance, although, in general, the changes in SPEM variables occurred earlier (Table 4; Fig. 5).
Table 4. Assessment Variables in a Patient With Overt Hepatic Encephalopathy Before and During Treatment With Lactulose
Abnormalities in smooth pursuit were observed in patients with hepatic encephalopathy, reflecting impairment of both tracking ability and accuracy. The degree of SPEM impairment paralleled the changes in neuropsychiatric status, suggesting a common pathophysiology. Treatment status had a confounding effect on the classification of neuropsychiatric status.
SPEM and the Degree of Hepatic Encephalopathy.
There is no ‘gold standard’ for the diagnosis of hepatic encephalopathy. This creates significant difficulties in the evaluation of abnormalities such as those observed in SPEM, which are clearly related to the presence of neuropsychiatric dysfunction and may have diagnostic utility. Visual inspection of the SPEM recordings showed clear disruption of smooth pursuit in the patients with minimal hepatic encephalopathy, with interspersion of both corrective catch-up and anticipatory saccades, and more pronounced disruption, if not complete loss of smooth pursuit, in patients with overt hepatic encephalopathy. However, use of more objective performance measures did not provide the same degree of differentiation, and grading thresholds for SPEM performance, in relation to the degree of neuropsychiatric impairment, could not be defined.
Here are a number of possible explanations for the lack of quantifiable differences in SPEM performance between the population subgroups despite the obvious visual differences. The most obvious is that the eye detects differences in the traces that are not captured by the numerical analysis. The system for quantifying the SPEM traces assessed the most obvious measurement variables, but clearly more could be gained from the numerical analysis. Other factors that might help explain the lack of quantitative distinction between population subgroups include the rigor of the statistical analysis, the intrinsic limitations of the system used to assess neuropsychiatric status in this patient population, and the fact that abnormalities of the defining variables arise at differing stages of disease progression on an individual basis.
SPEM Performance in Relation to Treatment Status.
No guidelines exist for classifying neuropsychiatric status in patients receiving long-term maintenance treatment for hepatic encephalopathy. At any given time, these individuals, if tested, may still show evidence of overt hepatic encephalopathy, may appear clinically normal but with impaired psychometric and/or electrophysiological performance, thereby fulfilling the diagnostic criteria for minimal hepatic encephalopathy, or may even appear neuropsychiatrically unimpaired with no discernible clinical, psychometric, or electrophysiological abnormalities. Significant difficulties therefore arise in determining how these patients should be categorized, particularly in studies designed to test the potential diagnostic utility of established or novel test systems.
In the best of previous studies, workers have tended to determine status ‘on the day of study’ using a combination of clinical, psychometric, and/or electrophysiological variables, choosing to either exclude all treated patients5 or to classify them as having overt hepatic encephalopathy irrespective of their current status.12 Both these approaches are pragmatic and have merit but do not provide data that are applicable to the mixed population of treated and untreated patients encountered in a clinical setting.
In the current study, account was taken of the potential confounding effect of maintenance treatment on the classification of neuropsychiatric status and evidence obtained that the distinction between the treated and untreated patients clearly had significant implication for classification purposes. Treatment status should therefore be included as a separate variable when classifying neuropsychiatric status in this patent population
There was also evidence in the current study that the various changes in cerebral function observed in patients with hepatic encephalopathy may not occur synchronously and may improve at differing rates following treatment. Thus, the untreated patients with minimal hepatic encephalopathy showed greater impairment of psychometric performance but less disruption of SPEM performance than their treated counterparts, while in the serial studies SPEM parameters seemed to improve earlier than other neuropsychiatric variables in response to treatment.
SPEM and Hepatic Encephalopathy: Pathophysiology.
SPEM abnormalities were observed in patients with hepatic encephalopathy, reflecting impairment of both tracking ability and accuracy. The functional correlates of the abnormalities observed in SPEM performance and the relative utility of the indices used to qualify smooth pursuit remain unclear.23 Nevertheless, a number of possible explanations exist for the pursuit abnormalities observed in patients with cirrhosis exhibiting neuropsychiatric change:
Impairment in the Motor Control of Eye Movements.
In 1976, Plum and Hindfelt24 referred to ‘abnormal ocular motor and skeletal muscle movement control’ as features typical of chronic hepatic encephalopathy. In 1996, Krieger and colleagues10 identified abnormalities of saccadic ocular pursuit in 26 (51%) of 51 consecutive patients with cirrhosis with no clinical evidence of hepatic encephalopathy; the abnormalities were more common in those with a history of overt hepatic encephalopathy. Principle component analysis classified the ocular pursuit abnormalities, together with incoordination, alterations of muscle tone, and tremor, into a category of subcortical motor performance, which the authors claimed expressed the functioning of the striatopallidonigral and cerebellar systems controlling movement and posture.10 The neurological abnormalities Kreiger and his colleagues10 observed were assessed as dichotomized variables, and no further information on the eye movement abnormalities, in particular no formal assessment of ocular motor function, was included.
None of the patients in the current study had clinical evidence of oculomotor paresis or dysfunction. However, the changes observed in smooth pursuit might reflect more subtle abnormalities of motor control. Joebges and coworkers,25 for example, have recently shown that the abnormalities observed in patients with hepatic encephalopathy in the execution of diadochokinetic limb movements are due to a delay in movement initiation rather than a reduction in movement velocity. A deficit in movement initiation, perhaps reflecting dysfunction in the neural loops connecting the prefrontal cortex and the basal ganglia, would prolong the latency of the onset of tracking and could be a determinant in the generation of early corrective catch-up saccades.
Pursuit eye movements allow maintenance of the image of a moving object on the fovea and are controlled by visual feedback.26 Very little information is available currently on the functional correlates of the post-mortem and electroretinographic abnormalities described in the retinas of individuals with cirrhosis.3, 4 Significant lowering in the CFF threshold has been observed in patients with minimal hepatic encephalopathy and attributed to the presence of hepatic retinopathy.5 However, retinal function was not examined directly in this study,5 and although CFF undoubtedly reflects the efficacy of the visual apparatus, it also reflects the functional state of the cerebral cortex. None of the patients included in the current study had defective vision on routine testing. Nevertheless, the presence of subtle defects in visual feedback relating to the presence of hepatic retinopathy cannot be excluded. Studies combining assessments of retinal function, SPEM, and CFF are needed.
An Attentional Deficit.
Abnormalities in smooth pursuit are commonly found in patients with schizophrenia and are attributed, by some workers, to the presence of global attentional and inhibitory dysfunction.23, 27, 28 This attribution is supported by the observation that SPEM abnormalities can be reversed in schizophrenic patients, to a degree, by attention-enhancing techniques, and by the fact that at least one of the pathological components of SPEM performance, task-inappropriate intrusion of anticipatory saccades, has been conceptualized as a failure of inhibitory control.29, 30 However, the role of attentional and inhibitory dysfunction in the genesis of smooth pursuit abnormalities has been questioned, because adults with attention-deficit/hyperactivity syndrome do not exhibit pursuit abnormalities.30
There is considerable evidence that patients with cirrhosis, particularly those with evidence of hepatic encephalopathy, exhibit attentional dysfunction, more specifically, deficits of complex attentional skills.31–35 Their inability to disengage previously focused attention35 may play a role in their inability to track small moving objects.
It is highly likely that the abnormalities observed in smooth pursuit in patients with hepatic encephalopathy are multifactorial in origin, and the relative importance of each factor may vary in a given individual at different stages of their disease.
Quantifiable abnormalities are observed in smooth pursuit movement in patients with cirrhosis, which parallel the changes observed in neuropsychiatric status. The pathophysiology of the abnormalities in SPEM is unknown, but impairment of the motor control of eye movements, functional abnormalities associated with the development of hepatic retinopathy, and attentional dysfunction are all likely to play a role. Classification of the neuropsychiatric status of patients with cirrhosis, which is key to the assessment of the diagnostic utility of variables such as smooth pursuit, should take account of the patients' treatment status, a taxonomic category that has, to date, received little, if any, attention.