Fion Bremner

Pupil evaluation as a test for autonomic disorders

Pupil tests provide a convenient and simple method for evaluation of autonomic function. Most patients with autonomic disorders show evidence of sympathetic or parasympathetic deficits in the pupil, and these can be detected using a combination of clinical signs, pupillometric tests (measuring the responses to light, or an accommodative effort, or a sudden noise) and pharmacological tests (using topically applied drugs both to confirm a deficit and to localize the lesion). Caution is needed in the interpretation of these tests, particularly if the deficits are mixed (i.e. sympathetic and parasympathetic) or bilateral. The pattern of autonomic disturbance in the pupils often correlates poorly with autonomic function elsewhere, but may have diagnostic value in discriminating between different underlying conditions.Pupil tests provide a convenient and simple method for evaluation of autonomic function. Most patients with autonomic disorders show evidence of sympathetic or parasympathetic deficits in the pupil, and these can be detected using a combination of clinical signs, pupillometric tests (measuring the responses to light, or an accommodative effort, or a sudden noise) and pharmacological tests (using topically applied drugs both to confirm a deficit and to localize the lesion). Caution is needed in the interpretation of these tests, particularly if the deficits are mixed (i.e. sympathetic and parasympathetic) or bilateral. The pattern of autonomic disturbance in the pupils often correlates poorly with autonomic function elsewhere, but may have diagnostic value in discriminating between different underlying conditions.

Pupil findings in a consecutive series of 150 patients with generalised autonomic neuropathy

Aim: To detect and characterise the pattern and extent of pupil abnormalities in patients with generalised autonomic failure. Methods: A consecutive series of 150 patients referred for investigation of symptomatic generalised autonomic failure underwent pupil investigations. Infra-red video pupillography was used to measure resting pupil diameters in light and dark, the light reflex response, the miosis associated with an accommodative effort, and responses to topical administration of various pharmacological agents. The results were compared with data recorded under identical conditions from a cohort of 315 age-matched and sex-matched healthy controls. Results: Overall, two thirds of patients had abnormal pupils (66%) with sympathetic deficit occurring twice as often as parasympathetic deficit. However, the prevalence and type of pupil abnormality showed wide variation according to aetiology—for example, almost all patients with amyloidosis had abnormal pupils, two thirds with pure autonomic failure but less than a quarter with multiple system atrophy. In most patients (85%), pupil abnormalities were bilateral and symmetrical, none had a Horner’s syndrome in one eye and a tonic pupil in the other. No significant correlation between the type of pupil abnormality and the predominant type of systemic autonomic deficit was seen in most conditions. Conclusions: The pupils are often affected in autonomic neuropathy, although this is not always apparent either to the patient or to their doctors. Considerable care is needed not only to detect these abnormalities but also to interpret correctly the results of pupil tests in this group of patients.

Pupillographic Findings in 39 Consecutive Cases of Harlequin Syndrome

Background: Harlequin syndrome is a curious phenomenon in which one half of the face fails to flush during thermal or emotional stress as a result of damage to vasodilator sympathetic fibers. Anecdotal reports suggest that some of these patients have abnormal pupils. In this study we set out to systematically investigate autonomic pupil disturbances in an unselected cohort of patients with harlequin syndrome. Methods: A consecutive series of 39 patients with harlequin syndrome who were referred to a tertiary autonomic function laboratory underwent slit-lamp examinations, testing of deep tendon reflexes, infrared video pupillography and, where needed, additional pharmacologic pupillary testing. Results were compared with a meta-analysis of all previously reported cases of harlequin syndrome (n = 39) identified from a literature search. Results: In 65% of patients, no underlying causative medical disturbance could be identified. In 64% of patients, there were abnormal pupils, most commonly Horner syndrome, which was always present ipsilateral to the side of the face with impaired facial sweating and flushing. The lesion was postganglionic in 9 of 10 patients tested pharmacologically. Five (13%) patients had tonic pupils, most of whom also had tendon areflexia but no other neurologic findings, a pattern consistent with Holmes-Adie syndrome. In 2 of these patients, tonic and Horner pupils coexisted. Normal pupils were present in 36% of patients. These results are similar to those for the 39 previously reported patients with harlequin syndrome. Conclusions: The frequent coexistence of harlequin and Horner syndromes without other neurologic deficits suggests pathologic changes affecting the superior cervical ganglion. Because either syndrome may occur alone, damage is apparently selective. Among the patients with harlequin syndrome who also have tonic pupils and tendon areflexia (Holmes-Adie syndrome), we postulate a ganglionopathy affecting not merely the (sympathetic) superior cervical ganglion, but also the (parasympathetic) ciliary and dorsal root ganglia. Because we found that more than 10% of patients had an undisclosed mass lesion in the chest or neck or a generalized autonomic neuropathy, we recommend a targeted evaluation in selected patients with harlequin syndrome.

Pupil assessment in optic nerve disorders

AbstractBackground 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.

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.

The ARSACS phenotype can include supranuclear gaze palsy and skin lipofuscin deposits

The autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) phenotype was first characterised in patients from Quebec, all of whom had young onset spasticity and gait ataxia. Other features included distal amyotrophy, extensor plantar responses, cerebellar speech, saccadic intrusion in smooth pursuit and hypermyelinated retinal nerve fibres.1 Seven percent had seizures. Spasticity and ataxia were progressive. Electromyography showed denervation. Nerve conduction studies showed reduced conduction velocities with absent sensory action potentials. Nerve biopsy showed a lack of large myelinated axons.2 Subsequent analysis of this cohort has shown two founder mutations in the SACS gene—c.6594delT and c.5254C>T.3 Identification of mutations in SACS as the cause of ARSACS facilitated the detection of further cases worldwide, revealing greater phenotypic variation. Vermeer et al screened 43 patients presenting with ataxia prior to age 25 (suggesting an autosomal recessive cause4), finding 16 patients with SACS mutations.5 One patient had onset aged 12, two showed dystonia. Baets et al 6 screened 85 patients with at least two of cerebellar ataxia, spasticity and peripheral neuropathy, finding 18 different mutations. In five of these patients, disease onset was at over 20 years, one patient had no signs of peripheral neuropathy, several patients presented primarily with peripheral neuropathy and only one had hypermyelinated retinal nerve fibres using standard fundoscopy. Two patients had mild cognitive impairment and one epilepsy. Breckpot et al 7 detected a deletion of SACS combined with a hemizygous SACS mutation causing early-onset ARSACS with hearing impairment. We describe a 37-year-old patient who first walked at 23 months. Aged seven, he had cerebellar ataxia and brisk reflexes in all limbs. Cognitive function has been normal but ataxia and spasticity have progressed. He also developed epilepsy, myoclonus and …

Retinal Imaging in Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

A case is described of autosomal recessive spastic ataxia of Charlevoix-Saguenay. Genetic analysis has shown that two mutant genes encoding the sacsin protein have been inherited one from each parent. In the proband the thickness of the nerve fibre layer is quantified using optical coherence tomography. An abnormally thick retinal nerve fibre layer has been previously described in this condition, ascribed to hypermyelination; the authors suggest that there is no evidence of abnormal myelination as the thickened nerve fibre layer is not opaque. Lesser degrees of nerve fibre layer thickening are seen in other family members who do not show any of the phenotypic features of the disorder.

Unilateral Light-Near Dissociation in Lesions of the Rostral Midbrain

Examination of the pupillary response to light and accommodation can provide precise information concerning the localization of a lesion within the sympathetic and parasympathetic pathways, the anterior visual pathway, or the brainstem (Table 1). Classical teaching has associated all lesions of the rostral midbrain with bilateral lightnear dissociation (LND), defined as attenuation of the pupil light reflex (PLR) with relative sparing of the near response, as one component of Parinaud syndrome. We describe 2 patients with rostral midbrain lesions in whom LND was clinically present only in the eye ipsilateral to the lesion. To our knowledge, this clinical phenomenon has not been previously reported. We provide an explanation for this observation and its implications for our understanding of the anatomy of the pupil light pathway. Report of Cases. Case 1. A 19-yearold Asian woman had symptoms of headache and diplopia. Oculomotor examination findings demonstrated a vertical gaze palsy with convergence-retraction nystagmus, noncomitant skew deviation, and convergence insufficiency but preservation of all other eye movements. Examination of the pupils revealed moderate anisocoria, with the right pupil being 0.50 mm larger than the left in both bright light and in the dark (Table 2). The light response (LR) and the near response in the left eye were equally brisk and normal; however, in the right eye there was attenuation of the light reflex but preservation of a normal brisk near response (LND). These findings were confirmed by formal measurement of the amplitudes of the LR and near response in each eye, recorded separately under monocular conditions, using infrared video pupillometry. In the left eye both the LR and the near response were normal wi th no LND (Figure 1A). Slitlamp examination showed no evidence of a tonic pupil (eg, irregular shape, sector palsy, tonic near response, delayed redilation on looking back into the distance) or anterior segment pathologic conditions, nor were there any clinical signs of a third cranial nerve palsy. Her visual acuity and color vision were normal. Magnetic resonance imaging of the brain showed a hyperintense lesion at the level of the rostral midbrain immediately to the right of the aqueduct of Sylvius, within the periaqueductal gray (Figure 2A and B). Case 2. A 31-year-old man had a sudden-onset headache, vomiting, and poor balance. He reported vertical diplopia and difficulty focusing on near targets. Oculomotor examination findings revealed a noncomitant skew deviation with right hypertropia on right gaze but full horizontal eye movements. Paresis of vertical eye movements and an up-gaze saccadic palsy with convergence-retraction nystagmus was present. Visual acuity and color vision were normal. Examination of the pupils under resting conditions showed a small degree of anisoco-

Benign alternating anisocoria

Aims: To characterise and compare the variability of anisocoria measurements in normal healthy subjects and patients with alternating anisocoria. Methods: Using flash photography or infra-red pupillometry, serial measurements of pupil diameter were made in two patients presenting with alternating anisocoria, both daughters of Patient 2, and eight normal subjects. In each individual the distribution of anisocoria measurements was compared with a Gaussian normal distribution using a Chi-squared test. Results: The distribution of anisocoria measurements was Gaussian in all control subjects but bimodal in both patients. The elder daughter of Patient 2 showed a bimodal distribution which weakly departed from normality (p = 0.101) and her younger sister showed a unimodal distribution. In all cases the pupils reacted normally to a light stimulus or an accommodative effort; visual function, and ocular and neurological examination were normal. Conclusion: Alternating anisocoria is a discreet entity not found in normal subjects but which may be present in more than one member of a family. Because it occurs in otherwise healthy individuals, we recommend it should be called benign alternating anisocoria. The neural mechanism underlying this phenomenon remains unclear.

Optical coherence tomography in autosomal recessive spastic ataxia of Charlevoix-Saguenay

Autosomal recessive spastic ataxia of Charlevoix-Saguenay is a rare neurodegenerative disorder caused by mutations in the SACS gene. Thickened retinal nerve fibres visible on fundoscopy have previously been described in these patients; however, thickening of the retinal nerve fibre layer as demonstrated by optical coherence tomography appears to be a more sensitive and specific feature. To test this observation, we assessed 292 individuals (191 patients with ataxia and 101 control subjects) by peripapillary time-domain optical coherence tomography. The patients included 146 with a genetic diagnosis of ataxia (17 autosomal spastic ataxia of Charlevoix-Saguenay, 59 Friedreichs ataxia, 53 spinocerebellar ataxias, 17 other genetically confirmed ataxias) and 45 with cerebellar ataxia of unknown cause. The controls included 13 asymptomatic heterozygotes for SACS mutations and 88 unaffected controls. The cases with autosomal recessive spastic ataxia of Charlevoix-Saguenay included 11 previously unpublished SACS mutations, of which seven were nonsense and four missense mutations. Most patients were visually asymptomatic and had no previous history of ophthalmic complaints and normal or near normal visual test results. None had visual symptoms directly attributable to the retinal changes. Twelve of the 17 cases (70.6%) had thickened retinal nerve fibres visible on fundoscopy. All patients with autosomal recessive spastic ataxia of Charlevoix-Saguenay had thickening of the peripapillary retinal nerve fibre layer on optical coherence tomography, whereas all the remaining cases and controls except one showed normal or reduced average peripapillary retinal nerve fibre layer thickness on optical coherence tomography. We propose a cut-off value of 119 µm in average peripapillary retinal nerve fibre layer thickness, which provides a sensitivity of 100% and specificity of 99.4% amongst patients affected with ataxia. This is the largest cohort of patients with this condition to undergo systematic evaluation by optical coherence tomography. This is a useful tool in identifying cases of autosomal recessive spastic ataxia of Charlevoix-Saguenay from other causes of ataxia. Visualization of thickened retinal fibres by direct fundoscopy is less sensitive. We therefore advocate the use of this technique in the assessment of possible cases of this condition.