Introduction

Horner syndrome (HS) comprises a group of symptoms caused by an interruption in the oculosympathetic pathway, which starts in the hypothalamus and runs through the spinal cord to the level between the last cervical and the second thoracic vertebra, where the synapses between the first and the second neuron are located. The second neuron leaves the vertebra, then passes the lung apex and the subconjunctival artery to the superior cervical ganglion where the third neuron starts. The postganglionic fibres innervate Muller’s muscle, the dilator of the pupil dilator, fascial vessels, and sweat glands on one side. Consequently, HS manifests with unilateral ptosis, miosis, and anhidrosis, which is observed in postganglionic cases [1]. Enophthalmos, once considered part of the syndrome, is no longer recognised as present, because its symptoms are only apparent [2]. However, cases of atypical manifestations are also reported in the literature. Furthermore, in some patients the symptoms are recurrent [3].

HS may also be associated with Harlequin syndrome, which is characterised by unilateral flushing of the face and neck and occasionally of the lower parts of the body on the opposite side to the HS, as a response to physical activity or stress. It results from damage to the fibres leaving the spinal cord at the level of the 2^nd and 3^rd vertebrae [4, 5].

According to the literature, HS does not affect vision; however, it may be a primary symptom of other life-threatening conditions. In children, the most important cause is mediastinal or cervical neuroblastoma (NBL) [6, 7]. Therefore, it is essential to improve the understanding of its manifestations. The objective of our study was to observe the clinical image of HS and monitor its changes over time.

Material and methods

The study was based on an ophthalmological examination of patients diagnosed with HS and a retrospective analysis of their past ophthalmological examinations. We included 12 patients under 18 years of age with HS who presented to our clinic between 2022 and 2024. The ophthalmological examination consisted of a visual acuity test (age-dependent method), intraocular pressure (I-care) as well as anterior and posterior segment evaluation, assessment of refractive error after cycloplegia, measurements of pupil diameters using a pupilometer (Spot Vision Screener, Welch Allyn Inc., USA), and margin-reflex distance 1 (MRD1; distance from the upper eyelid to the central light corneal reflex). In addition, we collected records of previous ophthalmological examinations and performed a retrospective analysis.

For statistical purposes, we used PQStat version 1.8.6. The normal distribution was assessed using the Shapiro-Wilk test. Group comparisons were performed with the Mann-Whitney U test. A significance level of p = 0.05 was adopted. Children with incomplete data were excluded from each analysis.

Results

In 9 participants HS was associated with NBL, and in 55.56% of these cases HS appeared following surgical removal of the tumour. In one child it occurred after cardiac surgery, in another after a jugular vein incision, and in one it was a consequence of birth trauma. The median age of HS onset in the entire cohort was 1.73 months (mean 5.19 months), and in 27.27% of subjects HS was congenital. In half of the patients HS developed on the right side.

In cases of tumour-induced HS, the authors analysed whether any changes in the clinical picture occurred after surgical removal of the lesion; in 4 out of 6 children improvement in pupil size and eyelid position was noted. In two cases, no changes were observed. This assessment was based on the parents’ opinion and reports from paediatricians.

In 7 out of 12 patients recently examined in our clinic, the follow-up period (time between the first and last appointment) was longer, ranging from 8 months to 9 years. In 5 cases, we were unable to schedule further check-ups. The mean observation period from the onset of HS to the last appointment was 60.72 months, and it fluctuated between 5 months and 13 years. In one case a test with apraclonidine was performed with a positive result, and in another patient phenylephrine and adrenaline tests resulted in the diagnosis of postganglionic HS.

During the first examination in our clinic after HS diagnosis, anisocoria was found in all patients, whereas ptosis was noted in 80.00%. At the last appointment, anisocoria was present in the entire cohort, and narrowing of palpebral fissure occurred in 45.45% of children.

We interviewed the parents of 9 patients regarding the symptoms associated with HS. In 22.22% of patients, parents reported that HS symptoms were variable – ptosis was more prominent after physical exertion. Moreover, parents observed a reduction of symptoms over time in 44.44% of cases. Anhidrosis occurred in half of the children, while Harlequin syndrome was found in 40.00% of the patients. Interestingly, in 3 out of 4 cases with Harlequin syndrome, parents noted flushing and sweating on one half of the face on the ipsilateral side to HS following exertion. In one case, Harlequin syndrome preceded HS and was the first symptom of NBL,
the removal of which resulted in HS.

Heterochromia (lighter colour of the iris in the eye affected by HS, Figure 1) occurred in 25.00% of the examined patients. The mean age of children with heterochromia at onset of HS was 1.97 months (median 2.83 months), which was lower than in the rest of the group (6.4 months; median 0.00). The difference between the groups was not statistically significant (p = 0.917961). Our cohort also included a patient with HS that was reported following surgery performed at 13 months of age, who presented with sunset eye sign prior to surgery.

No disorders of the anterior (despite heterochromia) or posterior segments of the eye were reported in our research group, with the exception of one patient with retinopa-
thy of prematurity with peripheral laser scars on the retina in both eyes. The conducted ophthalmological examination revealed that HS had no impact on visual function. Refractive errors were observed in 3 patients – 2 patients suffered from hyperopia, and one child was diagnosed with myopia in the right eye. Moreover, intraocular pressure was measured in 6 cases, and it was found to be lower in the eye affected by HS in 4 patients, although the differences were small (from 1 to 3 units).

We examined 9 children with a pupilometer, and measured MRD1 in 12 patients. The mean difference in pupil diameter was 1.17 mm in the light and 0.93 mm in the dark. The mean MRD1 amounted to 1.18 mm. The results of pupil diameter and MRD1 measurements, as well as their changes over time, are presented in Figures 2–4. Additionally, pupil diameters were measured repeatedly in 4 children, and MRD1 was assessed in 7 patients. In 3 out of 4 subjects, when anisocoria was measured using a pupilometer, it became less apparent over time. In 3 out of 7 children, MRD1 measurements decreased over time, while in 1 case they increased; in 3 cases ptosis remained unchanged.

Discussion

The clinical picture of HS is not stable. In fact, our research indicates that HS manifestations may vary over time. Moreover, Nutt et al. [3] in their study reported 4 atypical cases of HS and noted that isolated ptosis or anisocoria may be observed in some patients, or the symptoms may be transient.

The incidence of miosis and ptosis in our research is in line with the retrospective analysis results of Maloney et al. [8],
who found anhidrosis in 4% of HS cases, whereas in our cohort it was 50%. However, as they emphasised, no active research was performed to verify the incidence of this symptom. We also did not conduct any additional analyses to assess the occurrence of anhidrosis.

Interestingly, we observed that ptosis occurred less frequently than anisocoria and, in some cases, decreased or even disappeared over time. This is encouraging, particularly in terms of the possible psychological influence of this symptom on the wellbeing of the patients. Furthermore, it should also be considered before deciding whether to perform ptosis surgery.

In the acute phase of HS, hemifacial flushing and sweating may occur on the ipsilateral side is the form of miosis and ptosis, due to sympathetic denervation. Nevertheless, in long-lasting HS, these symptoms may appear on the opposite side and are referred to as Harlequin syndrome, caused by supersensitivity of the facial vessels to the adrenergic substances [9].
The cases presented in our paper paradoxically featured skin flushing of the ipsilateral side to HS, despite long-term oculosympathetic dysfunctions. This may be attributed to the anomalous vagal connections in the superior cervical ganglion with the third neuron of this pathway [10]. A similar atypical case was reported by Johann Horner [5]. Moreover, in patients with isolated Harlequin syndrome, positive results of the pharmacological tests with cocaine led to the detection of pupil disorders [4, 11]. This raises the question of whether the patient from our cohort who suffered from Harlequin syndrome as an NBL manifestation and subsequently developed HS had oculosympathetic neuron disorders prior to surgery. It is noteworthy that both Harlequin syndrome and HS in children should always be investigated thoroughly because they may be manifestations of underlying tumours [12].

Heterochromia develops in children with congenital HS due to sympathetic deficiency, which affects the activity of melanocytes in the iris stroma [13, 14]. However, in our study group, 3 children had heterochromia despite suffering from acquired HS. The oldest patient with heterochromia developed HS at 13 months of age. There are reports of heterochromia in patients with HS that appeared in adulthood, although such cases are rare [13, 15]. Notably, our analysis found no difference between the age of HS onset in patients with or without heterochromia.

Our study was limited by the number of participants in the research group. Additionally, we were unable to conduct follow-up examinations in all of patients; thus, some data were analysed retrospectively. Another limitation was the different ages of the children involved, which also had an impact on the selected patient examination methods. Contrary to the data in the sources, we did not find that anisocoria was more prominent in the dark as compared to the light [9]. However,
it should be noted that we did not measure the time, and in most cases we maintained a 15-second pause between turning off the light and conducting measurements. This period is required to achieve a full effect, due to delayed pupil dilation on the affected side [9]. Furthermore, the pupilometer we used requires time to adjust to the conditions, so it is impossible to measure pupils instantly after turning off the light. It also uses colourful lights to focus the patient’s attention on the test, which may affect the results. Nevertheless, to the best of the authors’ knowledge, this is the first study to assess HS changes over time.

In conclusion, our findings indicate that the clinical picture of HS may vary significantly between patients, and its symptoms may also change with time. Therefore, as clinicians, we should be particularly careful when examining patients with anisocoria or ptosis, and we should consider HS even in cases with atypical manifestations. Of note, heterochromia may occur in cases of acquired HS, and Harlequin syndrome may frequently accompany HS. Moreover, decisions regarding ptosis surgery should be considered carefully because in certain cases the condition resolves without any additional procedures.

STATEMENTS

The authors declare no conflict of interest.

This work received no external funding.

This study was approved by the local Bioethics Committee of Poznan University of Medical Sciences (Approval No. 557/22). Written informed consent for publication of the images was obtained from the patient’s parents.

References