Bilateral tonic pupils: Holmes Adie syndrome or generalised neuropathy?

AIM: To compare the pupil signs in patients with bilateral pupillotonia caused by Holmes-Adie syndrome or generalised peripheral neuropathy. METHODS: Infrared video pupillographic techniques were used to measure a number of pupil variables in patients with Holmes-Adie syndrome, generalised neuropathy (various aetiologies) and healthy age-matched control subjects. RESULTS: Regardless of aetiology, the patients generally had pupil signs typical of pupillotonia (small dark diameters, large light diameters, tonic near responses, attenuated light responses with light-near dissociation, and sector palsy). However, significant differences were found in the prevalence and magnitude of several pupil variables in the two patient groups. In particular, sector palsy and anisocoria exceeding 1 mm (in the light) were seen much more commonly in Holmes-Adie patients than patients with generalised neuropathy. The presence of both these pupil signs can be used to distinguish between these diagnoses with a sensitivity of 58% and a specificity of 90%. CONCLUSIONS: The tonic pupils of patients with Holmes-Adie syndrome are significantly different to those found in patients with generalised neuropathy; recognition of these differences may allow distinction between these diagnoses.

Subretinal membranes are associated with abnormal degrees of pupil "evasion": an index of clinical macular dysfunction.

AIM: To assess whether macular dysfunction caused by unilateral subretinal neovascular membranes (SRNs) is associated with pupil "evasion" (that is, increased initial rate of re-dilation following a brief light stimulus). METHODS: Comparative observational series. 20 eyes of 10 participants, all with unilateral SRNs and healthy fellow eyes. Dynamic infrared pupillography at seven stimulus intensities (duration 1100 ms, intensities over 2 log unit range). Pupil evasion ratio (PEVR; defined as the ratio of light response amplitude to amount of recovery at the mid-time point of re-dilation expressed as a percentage) was calculated for each stimulus intensity (mean of five recordings). RESULTS: Inter-eye PEVR is significantly reduced in eyes with SRN (that is, greater pupil evasion in SRN eyes: range p = 0.002 to p = 0.05 (paired t test)) and is most apparent at higher stimulus intensities. CONCLUSIONS: PEVR is a novel parameter that is analogous to the pupil escape ratio, but measured following a short rather than a sustained light stimulus. PEVR is significantly altered by macular disease. Clinically PEVR may be used to detect occult unilateral or asymmetric maculopathy in situations such as ocular media opacities like cataract, when pupil reactions are unaffected or augmented, while other tests of retinal function are diminished. PEVR represents altered neuronal firing in cones and macular ganglion cells.

Pupil assessment in optic nerve disorders.

BACKGROUND: The normal pupillary constriction to light is an involuntary reflex that can be easily elicited and observed without specialized equipment or discomfort to the patient. Attenuation of this reflex in optic nerve disorders was first described 120 years ago. Since then, pupil examination has become a routine part of the assessment of optic nerve disease. CLINICAL TECHNIQUES: The original cover/uncover test compares pupillomotor drive in the two eyes, but requires two working pupils and is relatively insensitive. The swinging flashlight test is now the standard clinical tool to detect pupillomotor asymmetry. It requires only one working pupil, is easily quantified, and has high sensitivity in experienced hands, but interpretation of the results needs care. Measurement of the pupil cycle time is the only clinical test that does not rely on comparison with the fellow eye, but it can only be measured in mild to moderate optic nerve dysfunction, is more time consuming, and less sensitive. LABORATORY TECHNIQUES: Infrared video pupillography allows recordings to be made of the pupil responses to full-field or perimetric light stimulation under tightly controlled conditions with a high degree of accuracy. Frustratingly, there is a wide range in reflex gain in normal subjects limiting its usefulness unless comparison is made with the fellow eye or stimulation of unaffected adjacent areas of the visual field. CORRELATION WITH OTHER TESTS: In general, pupillomotor deficit shows good correlation with visual field deficit. However, some diseases of the optic nerve are associated with relative sparing either of pupil function or visual function implying that pupil tests and psychophysical tests may assess function in different subpopulations of optic nerve fibres. Less is known of the relationship between pupil measurements and electrodiagnostic tests. USES IN CLINICAL PRACTICE: Pupil assessment is invaluable when distinguishing functional from organic visual loss. Its usefulness in distinguishing between different causes of optic neuropathy and as a prognostic sign is gradually emerging.

Genotypic and phenotypic heterogeneity in familial microcoria.

AIMS: To describe the clinical features and genetic findings in two families presenting with microcoria inherited as an autosomal dominant trait. METHODS: Both affected and unaffected members of two families displaying familial microcoria were examined. Flash photography or infrared pupillography were used to assess pupils, and a full ophthalmic examination including visual acuity and field testing, refraction, biomicroscopy of anterior and posterior segments, and measurement of intraocular pressure were performed. DNA from the blood of affected and unaffected family members was investigated using standard markers to look for a possible gene defect in the chromosome 13q31-q32 region. RESULTS: All affected members of both families had pinpoint pupils which responded normally to light and accommodation. None of these subjects exhibited any other ocular abnormality. The iris of affected members showed stromal thinning and apparent absence of the iris dilator muscle in the first family, but was smooth and lacked all trabecular structure in the second family. The microcoria was present at birth in the first family but developed progressively at a later age in the second family. Haplotype analysis suggested the gene defect is not located in the chromosome 13q31-q32 region in the first family but the evidence was not conclusive in the second family. CONCLUSION: Although both families presented with similar pupil abnormalities inherited as an autosomal dominant trait, they show important phenotypic and genotypic differences suggesting that this is a heterogeneous condition. The possible mechanisms underlying the microcoria are discussed.

Pupil perimetry in the diagnosis of functional visual field loss.

The diagnosis of functional visual loss-reduced visual performance in the absence of an organic cause-is usually made by exclusion. We conducted a pilot study to evaluate pupil perimetry in three patients (aged 14, 43 and 50) with visual field loss presumed to be functional on clinical grounds and having no cause identified by visual electrophysiology or magnetic resonance imaging. A modified automated perimeter was used to examine visual and pupil responses to a light stimulus (size 1.7 degrees ) presented at five locations in the visual field (fixation and in each of the four quadrants). In each patient, the pupil responses were normal in those test quadrants which showed apparent visual field loss. Pupil perimetry provides objective evidence for a diagnosis of functional visual field loss in selected patients and may circumvent the need for other investigations.

The pupil in dominant optic atrophy.

PURPOSE: To compare visual and pupil afferent function in dominant optic atrophy (DOA). METHODS: Patients with DOA who belonged to families showing evidence of linkage to the locus on chromosome 3q28-qter were recruited from the Moorfields Genetic Register. Patients and healthy control subjects underwent visual and pupil perimetry using a modified automated perimeter (Octopus 1-2-3; Interzeag, Schlieren, Switzerland). Five stimulus locations were tested: fixation, and at 17 degrees eccentricity along the 45 degrees and 135 degrees meridians in all four quadrants. The visual deficit (difference in decibels between the patient's luminance threshold and that in age-matched healthy control subjects) was compared directly with the pupil deficit (difference in decibels between the stimulus intensity giving the patient's pupil response and that giving an equivalent pupil response in healthy control subjects) at each test location. RESULTS: Visual deficits and pupil afferent deficits were found at all five locations. The visual deficits were significantly greater than the pupil deficits at the four peripheral locations (median difference = 6.3 dB, P: < 0.001). At fixation, the difference was not significant (median difference = 2.3 dB, P: = 0.407). CONCLUSIONS: Pupil function appears less affected than visual function at four of five locations tested. This result provides evidence that the retinotectal fibers serving the pupil light reflex are less susceptible to damage from the OPA1 genetic defect than the retinogeniculate fibers serving vision.

Comparing pupil function with visual function in patients with Leber's hereditary optic neuropathy.

PURPOSE: To compare pupil function with visual function in patients with Leber's hereditary optic neuropathy (LHON) and age-matched normal control subjects. METHODS: Visual function was assessed by measuring the perceptual thresholds at five central locations in the visual field using automated static perimetry. Pupil function was assessed by recording the pupil responses to a standard intensity light stimulus (size equivalent to a Goldmann V target) presented at the same five locations in the visual field. The extent of the pupil afferent defect in LHON patients was quantified by establishing the relationship between stimulus intensity and the size of the pupil response in normal subjects and then interpolating the equivalent luminance deficit in LHON patients from the size of their pupil responses. RESULTS: At all five locations tested, the pupil responses were significantly reduced in amplitude, and the perceptual thresholds were significantly raised in LHON patients compared with normal control subjects. A nonparametric analysis of perceptual and pupil responses to perithreshold stimuli showed that a stimulus that was not perceived was three times more likely to be followed by a pupil response in a LHON patient than in a normal subject (P < 0.001). A quantitative comparison showed that the visual deficits exceeded the pupil deficits by on average 7.5 dB at all tested locations. CONCLUSIONS: Although both visual and pupil function are abnormal in LHON, there appears to be relative sparing of the pupil afferent fibers.

The frequency content of common synaptic inputs to motoneurones studied during voluntary isometric contraction in man.

1. The discharges of pairs of individual motor units were recorded from intrinsic hand muscles in man. Single motor unit recordings were obtained either when both members of the motor unit pair were within first dorsal interosseous muscle (1DI:1DI recordings) or where one motor unit was within 1DI and the other in second dorsal interosseous muscle (1DI:2DI recordings). The pairs of motor unit spike trains were cross-correlated in the time domain and the results compared to those of coherence analysis performed on the same spike train data. Central peaks were present in the cross-intensity functions, indicating the presence of common synaptic input to the motoneurone pair. Coherence analysis of these data indicated significant association between motor unit firing in the frequency ranges 1-12 and 16-32 Hz. 2. Analysis of sequential non-overlapping segments of data recorded from individual motor unit pairs, demonstrated that both the central cross-intensity peak and coherence in the frequency bands 1-12 and 16-32 Hz were consistent features throughout a long recording. In these sequential recordings, the size of the central cross-intensity peak and the maximal value of coherence in the frequency band 16-32 Hz covaried from segment to segment. Analysis of the entire population of motor unit pairs confirmed a positive relationship between the magnitude of peak coherence and the size of the central cross-intensity peak. 3. Voluntary sinusoidal co-modulation of the firing rates of pairs of individual motor units recorded from within 1DI was found to produce significant values of coherence corresponding to the frequency of the common modulation. However, firing rate co-modulation was not found to affect either the size of the central cross-intensity peak or the maximum value of coherence in the frequency band 16-32 Hz. 4. Pairs of single motor units were recorded from within 1DI and biceps brachii muscles of healthy subjects. The number and size of the central cross-intensity peaks and coherence peaks detected were compared for the two muscles. The incidence and size of central cross-intensity peaks and the incidence and magnitude of 16-32 Hz coherence peaks were both found to be greater for 1DI recordings when compared to biceps brachii recordings. 5. Single motor unit recordings were made from the intrinsic hand muscles of a patient with severe peripheral deafferentation. Time- and frequency-domain analysis of these recordings revealed cross-intensity peaks and frequency bands of coherence similar to those seen in healthy subjects.(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of task on the degree of synchronization of intrinsic hand muscle motor units in man.

1. Recordings were made of the firing of pairs of intrinsic hand muscle motor units active under different task conditions in man. The different tasks were defined as isometric contractions producing force in one of three different directions: finger abduction, finger extension, or finger flexion. The degree of motor-unit synchronization associated with each of these task conditions was compared with the use of cross-correlation analysis. 2. The average amount of synchronization between the firing of motor units recorded from within first dorsal interosseous muscle (IDI) was greater during index finger extension than during index finger abduction (n = 8 motor-unit pairings, 3 subjects). In addition, for another sample population of motor units, the average amount of synchronization was greater during index finger abduction than during index finger flexion (n = 11 motor-unit pairings, 4 subjects). 3. In a further series of experiments, one motor unit of each pair was recorded from second dorsal interosseous muscle (2DI), whereas the other motor unit of each pair was recorded from 1DI. The average amount of synchronization for these motor-unit pairings was greater during extension of the index and middle fingers than during abduction of the index and middle fingers (n = 8, 4 subjects). For another sample population of such motor-unit pairings, the average amount of synchronization was found to be greater during abduction of the index and middle fingers than during flexion of the index and middle fingers (n = 11, 4 subjects). 4. In approximately one-third of cases, it was not found possible to maintain the same firing rates from two motor units in 1DI when active under different task conditions. For instance, the "reference" motor unit might consistently fire at a faster rate than the "response" motor unit when active during index finger extension but consistently fire at a slower rate than the response motor unit when active during index finger abduction. Where such motor-unit pairs have been studied in detail, the pattern of task dependence in their synchronization was found to be similar to that described above for motor-unit pairs in which the firing rates remained constant under the different task conditions.(ABSTRACT TRUNCATED AT 400 WORDS)

Correlation between the discharges of motor units recorded from the same and from different finger muscles in man.

1. Cross-correlation analysis of the discharges of individual motor units recorded from various different finger muscles has been performed during weak, isometric, voluntary contractions in man. 2. The dominant feature in 88% of the cross-correlograms studied was a narrow, central peak, the area of which significantly exceeded that expected for independent processes (P less than 0.001). The highest bin counts in these central peaks were mostly within 5 ms of time zero in the histograms, and the base of these peaks extended between 5 and 31 ms (modal value = 13 ms with 90% of the values lying between 8 and 18 ms). The width and displacement of the central cross-correlogram peaks were similar irrespective of whether the contributory spike trains were recorded from motor units active in the same finger muscle or recorded from motor units in different, co-activated finger muscles. 3. The time course of the central peaks in this study was found to be consistent with the hypothesis that it is generated by the joint occurrence of EPSPs evoked in motoneurones by branches of common stem presynaptic fibres using the theoretical model developed by Kirkwood (Kirkwood & Sears, 1978). The model parameters providing the best fit with our experimental data imply that synaptic contacts on motoneurones made by these common inputs lie on average peripherally in the dendritic tree and generate small (less than 300 microV) EPSPs superimposed on a high level of background synaptic noise. 4. Minima (troughs) were found either side of the central peak in 27% of the cross-correlograms studied, and their appearance was invariably associated with a large central peak. These secondary features could not be modelled with the same operator parameters that describe the central peaks. Their presence was particularly noticed in association with very regular discharges from the output motoneurones. 5. Smaller and broader secondary peaks symmetrically displaced 30-55 ms either side of the large, narrow central peak were observed in 7% of the cross-correlograms studied. We suggest that these secondary features which were found at lags shorter than the interspike interval of the contributory motor unit spike trains reflect the autocorrelation functions of the spike trains of common input fibres. On this basis the observed displacement of these secondary peaks from the primary feature in the cross-correlogram indicate firing rates for common input fibres in the range 18-33 impulses s-1. 6. In a small number of cases (1.4%) the cross-correlogram was flat and indistinguishable from the results of cross-correlating independent spike train data.

Variation in the degree of synchronization exhibited by motor units lying in different finger muscles in man.

1. Cross-correlation analysis was performed on the discharges of motor units recorded from the same or from different finger muscles during weak, voluntary isometric contractions in man. 2. In 88% of cases such cross-correlograms contained a narrow central peak indicating synchronization between the firing of the contributory motor units. Expressed in terms of the synchronization index, b (peak area/total number of reference plus response spikes) the amount of synchronization found in these different recordings ranged from b = 0.0057 to b = 0.1436 (n = 1230). The duration of the synchronization (measured across the base of the peak) ranged from 5 to 31 ms (mode = 13 ms). 3. For each pair of motor units examined the amount of synchronization between their firing varied from minute to minute of a long recording. In around half the cases studied this variation appeared to correspond to variation in the firing rates of the two motor units whereas in the other half of cases tested no relationship was found between the firing rates and the amount of synchronization. 4. Some motor unit pairings consistently showed more synchronization than other motor unit pairings within the same muscle. A frequency histogram of the synchrony measurements from all of the motor unit pairings tested in that muscle showed a unimodal and continuous distribution. 5. Some subjects consistently showed two or three times more motor unit synchronization than others in equivalent recordings. This rank order of motor unit synchronization in different subjects was found to be the same in all muscle pairings tested. 6. A similar distribution in the amount of motor unit synchronization found in different muscle pairings was found in all subjects tested. In the first place the firing of motor units which act on widely separated fingers was less synchronized than the firing of motor units acting on adjacent fingers. Secondly, motor units acting on the lateral fingers (thumb, index) showed less synchronization in their discharges than motor units acting on medial fingers (ring, little). Finally the firing of motor units in the finger flexor muscles were less synchronized than the firing of motor units in either the finger abductor or the finger extensor muscles. 7. The synchronization of motor unit activity in different muscles indicates the presence of a widespread projection pattern for the branches of some last-order input fibres to finger muscle motoneurones.(ABSTRACT TRUNCATED AT 400 WORDS)