Clinical Characteristics of Tic Disorders in Children and Adolescents with the Chief Complaint of Abnormal Blinking

doi:10.21203/rs.3.rs-5280121/v1

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Research Article

Clinical Characteristics of Tic Disorders in Children and Adolescents with the Chief Complaint of Abnormal Blinking

https://doi.org/10.21203/rs.3.rs-5280121/v1

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Background

Abnormal blinking is a common symptom shared by allergic conjunctivitis (AC), dry eye disease (DED), and tic disorders (TD). This study explored clinical manifestations of TD in patients with the chief complaint of abnormal blinking; its goal was to reduce misdiagnosis and missed diagnosis.

Methods

In total, 1054 patients with the chief complaint of abnormal blinking completed a questionnaire and underwent comprehensive ophthalmic examinations and mental health assessments. Questionnaire data were compiled for patients with a confirmed diagnosis of TD; their clinical characteristics were analyzed.

Results

Of the 1054 patients presenting with abnormal blinking, 453 (42.98%) were diagnosed with a TD. Among these 453 patients, 253 (55.63%) had transient tic disorder (TTD). 121 (26.71%) patients initially were misdiagnosed (primarily with AC) or experienced a missed diagnosis; Patients with TTD were more likely to seek ophthalmologic care, whereas those with CTD or TS were more likely to visit a pediatrician(P < 0.001). The predominant eye tics were excessive and/or frequent blinking; 438 (96.69%) patients exhibited tics other than eye tics. Among the TD patients, 371 (81.90%) reported ocular symptoms, whereas 336 (74.17%) had comorbid eye diseases including AC and DED. TTD patients with AC had higher incidences of allergic rhinitis and asthma compared with patients displaying CTD and TS (P < 0.05).

Conclusions

TD are major causes of abnormal blinking, and TTD is the most common subtype. TD patients with abnormal blinking often have comorbid eye diseases, primarily AC and DED.

Clinical features

Abnormal blinking

Tic disorders

Allergic conjunctivitis

Dry eye disease

Tic disorders (TD) are common neurodevelopmental disorders that typically emerge during childhood or adolescence, with a peak incidence between the ages of 5 and 10. The primary clinical manifestations ofTD are sudden, involuntary, repetitive, stereotypical, and nonrhythmic motor and/or vocal tics. These tics often include abnormal blinking, nose wrinkling, facial grimacing, throat clearing, whole-body tics, and accompanying sounds or echoes; all display varying degrees of severity [1–2]. TD encompass a spectrum of conditions, ranging from transient tic disorder (TTD) to chronic tic disorder (CTD) and Tourette syndrome (TS). These conditions can be distinguished based on the type and duration of tic symptoms [3]. The global incidence ofTD has been increasing; the estimated prevalences of TS and TTD are 0.77% and 2.99%, respectively. Boys are more frequently affected, and the male-to-female ratio is approximately 3–4:1 [4]. In some children, TD symptoms persist into adolescence and adulthood, substantially influencing their quality of life. These individuals often experience behavioural difficulties, such as comorbid obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD). Consequently, TD can cause considerable distress for affected children and their families [1–3].

TD often initially manifest as eye tics (abnormal blinking), which can then gradually progress to facial tics or other types of tics [5–9]. Consequently, patients frequently present to paediatric ophthalmologists with the complaint of “abnormal blinking.” Eye diseases that may also involve abnormal blinking include allergic conjunctivitis (AC) [10] and dry eye disease (DED) [11]. Furthermore, these conditions can simultaneously occur with TD, but limited information is available regarding their prevalence in the context of abnormal blinking [5–9]. Additionally, ophthalmologists may not be sufficiently familiar with the initial symptoms of TD. All of these factors can hinder accurate identification of the cause of abnormal blinking, often leading to delayed diagnosis and misdiagnosis in paediatric ophthalmology clinics [12]. Therefore, paediatric ophthalmologists should understand the clinical characteristics of TD with abnormal blinking, particularly in the presence of comorbid eye diseases. This knowledge can facilitate early diagnosis, reducing the likelihood of missed diagnosis or misdiagnosis. This study aimed to summarise the clinical characteristics of TD in patients presenting with the chief complaint of abnormal blinking. It specifically focused on distinguishing between ocular disease-related and TD-associated abnormal blinking, with the goals of improving ophthalmologists’ diagnostic accuracy, reducing rates of misdiagnosis, and improving prevention and management.

Patients and protocol

This prospective study, conducted at the Eye Hospital of Wenzhou Medical University from 1 January 2022 to 31 August 2023, included children and adolescents aged 5 to 18 years who presented with the chief complaint of abnormal blinking. Written informed consent was obtained from the parents of all patients. The study adhered to the tenets of the 2013 Declaration of Helsinki and the CONSORT statement. The study protocol and informed consent forms were approved by the Medical Ethics Committee of the Eye Hospital, Wenzhou Medical University.

Abnormal blinking was defined as excessive blinking (including brow wrinkling or eye squeezing), frequent blinking, staring, unilateral blinking, or any combination of these symptoms. All patients presenting with the chief complaint of abnormal blinking completed a detailed questionnaire. This questionnaire collected data regarding age, gender, blink rate, blink duration, accompanying symptoms, past medical history, recurrence, and attempted treatments. It also included questions about allergies, allergen exposures, and medication history. All patients underwent a comprehensive ophthalmic evaluation, including assessments of visual acuity, medical optometry, intraocular pressure, and slit-lamp examination. All data were recorded using a standardised data collection form. Based on the recorded symptoms and signs, the clinician determined whether the patient had a TD and any accompanying eye diseases. If a diagnosis could not be established, the patient was scheduled for follow-up visits until a definitive diagnosis could be established. The diagnostic process is illustrated in Fig. 1.

Diagnostic criteria

TD diagnoses were made in accordance with the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) [3]. Diagnoses of eye diseases (e.g., AC and DED) were based on relevant guidelines or criteria, as determined by a combination of medical history, physical examination findings, and any necessary ancillary tests.

Diagnostic principles

To avoid overdiagnosis or misdiagnosis, we established the following diagnostic principles for TD. At the initial visit, TD were diagnosed in patients who presented with tics other than abnormal blinking or who presented with abnormal blinking alone but had a history of TD. These direct diagnoses of TD were made regardless of the presence or absence of accompanying eye diseases. During follow-up, TD were diagnosed in patients who presented with abnormal blinking alone if the blinking persisted or worsened, or if other tics emerged during the 1-year follow-up period. For patients with abnormal blinking and eye diseases (e.g., AC or DED), TD were diagnosed if abnormal blinking and/or other tics persisted despite successful treatment of the eye diseases. TD were excluded in patients who presented with abnormal blinking alone and showed a reduction in abnormal blinking during the 1-year follow-up period. They also were excluded in patients who presented with abnormal blinking and eye diseases if the abnormal blinking disappeared after successful treatment of the eye diseases.

Diagnoses of AC were based on a comprehensive assessment of typical symptoms and ocular signs, a history of allergic conjunctivitis or other allergic diseases, and allergen reports. If AC could not be definitively confirmed, the diagnosis was “suspected AC.” During follow-up, if standard anti-allergy treatment led to remission, the patient was diagnosed with AC; otherwise, the diagnosis of AC was excluded.

Considering the difficulty of performing the Schirmer I test in children, diagnoses of DED were based on symptoms, slit-lamp examination findings, tear meniscus height, corneal fluorescein staining, and tear film break-up time (TFBUT). Patients with abnormal TFBUT but no other symptoms were diagnosed with asymptomatic DED.

Therapy and follow-up

All patients with eye diseases received appropriate treatment. Patients with TTD alone primarily received mental health education and attended follow-up visits. Patients with CTD or TS were treated with Chinese herbs and/or acupuncture. All patients with suspected TD, including those with abnormal blinking alone or with eye diseases, underwent treatment and monitoring until a definite diagnosis or exclusion of TD was made during the 1-year follow-up period. Similarly, “suspected AC” was diagnosed or excluded based on the results of treatment.

Statistical analyses

Data were analysed using SPSS 25.0 software. Continuous variables are presented as means ± standard deviations; they were analysed using the independent Student’s t-test and one-way analysis of variance (ANOVA). Categorical variables are presented as frequencies and percentages; they were analysed using the Chi-square test. Multivariable logistic regression analysis was used to explore factors associated with the disease. P-values less than 0.05 were considered statistically significant.

Morbidities and demographic characteristics of TD patients

Of the 1054 patients who presented with the chief complaint of abnormal blinking, 508 were diagnosed with a TD or suspected TD. Among these 508 patients, 367 received a clear diagnosis at their initial visit, whereas 141 had a suspected TD. During follow-up, 86 of the 141 patients with suspected TD received a definitive diagnosis; the remaining patients could not be evaluated because their symptoms disappeared or resolved. Finally, 453 patients were diagnosed with TD, constituting 42.98% of the overall cohort; of these, 253 (55.63%) had TTD, 88 (19.43%) had CTD, and 53 (11.70%) had TS. Furthermore, 215 (47.46%) patients were visiting our hospital or another hospital's ophthalmology department for the first time; 238 (52.54%) patients had a history of visiting other hospitals' paediatric departments or had made repeated visits to both ophthalmology and paediatrics departments. Analysis via Chi-squared tests revealed that patients with TTD were more likely to seek ophthalmologic care, whereas patients with CTD or TS were more likely to visit a paediatrician (P < 0.0001). Additionally, 121 (26.71%) patients initially had a missed diagnosis or were misdiagnosed; TTD was the most common misdiagnosis (P < 0.05). Among the patients with missed or misdiagnosed conditions, 86 (71.07%) had allergic diseases (AC or AC and AR), 27 (22.31%) had DED, and eight (6.61%) had other eye diseases.

In total, 385 boys (84.99%) and 68 girls (15.01%) were included in the study. The age range was 4 to 18 years (mean, 8.43 ± 2.65 years). Analysis via Chi-squared tests revealed that patients with TTD were significantly younger (P = 0.000). The disease duration ranged from 1 week to 10 years (mean, 19.72 ± 22.28 months). Among the 453 patients diagnosed with TD, 240 had a past medical history of abnormal blinking. Of these 240 patients, 94 (37.30%) had TTD, 113 (47.08%) had CTD, and 33 (13.75%) had TS. Additionally, 176 patients had a past medical history of TD: 60 (34.09%) had TTD, 88 (50%) had CTD, and 28 (15.91%) had TS. Multinomial logistic regression models, using the TTD group as the control, showed that older age and a past medical history of abnormal blinking or TD were significantly associated with higher risks of CTD and TS (P < 0.05) (Table 2). Specific demographic characteristics are presented in Table 1 below.

Table 1

Morbidities and demographic characteristics of TD patients
Characteristic		TD (n = 453)	TTD (252)	CTD (148)	TS (53)	P
Age, years		4–18 8.43 ± 2.65	4–17 7.77 ± 2.39	4–18 9.20 ± 2.92	6–16 9.41 ± 2.20	F = 19.16 P = 0.000*******
Gender (%)	Male	385(84.99%)	191(75.79%)	126(85.14%)	48(90.57%)	χ² = 1.608 P = 0.448
Gender (%)	Female	68(15.01%)	41(34.21%)	22(14.86%)	5(9.43%)	χ² = 1.608 P = 0.448
Course of disease (M)		19.72 ± 22.28	3.72 ± 4.03	39.66 ± 18.88	40.40 ± 20.68	F = 418.96 P = 0.000*******
Depart- ment	paediatrics	238(52.54%)	93(36.90%)	111(75.00%)	34(64.15%)	χ² = 57.511 P = 0.000*******
Depart- ment	ophthalmology	215(47.46%)	159(63.10%)	37(25.00%)	19(35.85%)	χ² = 57.511 P = 0.000*******
past medical history of abnormal blinking		240(52.98%)	94(37.30%)	113(76.35%)	33(62.26%)	χ² = 59.125 P = 0.000*******
past medical history of TD		176(38.85%)	60(23.81%)	88(59.45%)	28(52.83%)	χ² = 54.816 P = 0.000*******
missed or misdiagnosed diseases		121(26.71%)	78(30.95%)	36(24.32%)	7(13.21%)	χ² = 7.683 P = 0.021*
One-way ANOVA revealed statistically significant differences in age and disease duration among all types of TD (P < 0.001). Chi-squared tests showed statistically significant differences in the location (department) of initial diagnosis, past medical history of abnormal blinking, and past medical history of TD (P < 0.001). : P < 0.05, **: P < 0.001.

Table 2

Associations between potential influencing factors and risks of TD according to multinomial logistic regression
Variable	CTD^a	TS^a	TS^b
Variable	aOR (95%CI)	aOR (95%CI)	aOR (95%CI)
Gender
Male	Reference	Reference	Reference
Female	1.06 (0.55,2.07)	0.58 (0.21,1.63)	0.55 (0.2,1.55)
Age	1.31 (1.19,1.43) ***	1.32 (1.17,1.48) ***	1.01 (0.90,1.13)
past medical history of abnormal blinking	4.12 (2.54,6.67) ***	3.26 (1.72,6.17) ***	0.79 (0.42,1.50)
past medical history of TD	5.99 (3.59,9.99) ***	3.02 (1.57,5.80) **	0.50 (0.25,1.01)
^a: TTD group as control group; ^b: CTD group as control group; aOR: adjusted odds ratio; CI: confidence interval; : P < 0.001; : P < 0.01.*

Clinical characteristics

Tic symptoms in TD patients: All 453 patients with TD exhibited eye tics (abnormal blinking: excessive blinking, frequent blinking, staring, unilateral blinking). Of these patients, 159 had both frequent and excessive blinking, 145 had frequent blinking, 104 had excessive blinking, 66 had staring, and 75 had unilateral blinking. There were no significant differences in the types of eye tics according to TD subtype. In terms of blink rate, 50 patients exhibited persistent blinking, 262 patients had frequent blinking, and 142 patients displayed occasional blinking. Among all patients, 438 (96.69%) experienced tics other than eye tics. In 98 cases, these other tics preceded the onset of abnormal blinking; in 271 cases, they occurred simultaneously with abnormal blinking; and in 69 cases, they followed the onset of abnormal blinking. The most common tics other than eye tics included nose wrinkling (169, 37.30%), facial grimacing (126, 27.81%), throat clearing (116, 25.61%), mouth tics (115, 25.39%), finger sucking (62, 13.69%), head nodding (61, 13.47%), shrugging (44, 9.71%), neck stretching (43, 9.49%), and other simple or complex tics. Analysis via Chi-squared tests revealed that patients with TS were more likely to experience other tic symptoms before the onset of eye tics (P = 0.014) (Table 3); they also had a higher number of combined tic symptoms in addition to eye tics (P = 0.000) (Table 4). Further details are presented in Tables 3 and 4.

Table 3

Eye tic characteristics in TD patients
Characteristic		TD (n = 453)	TTD (252)	CTD (148)	TS (53)
Type of eye tics	frequency blinking	145(32.01%)	81(32.14%)	46(31.8%)	11(20.75%)	χ² = 4.582 P = 0.101
	excessive blinking^△	104(22.96%)	55(21.83%)	39(26.35%)	18(33.96%)
	excessive & frequency blinking	159(35.09%)	90(35.71%)	48(32.43%)	21(39.62%)
	eye staring	66(14.57%)	39(15.48%)	21(14.19%)	6(11.32%)
	unilateral blinking	75(16.56%)	38(15.08%)	27(18.24%)	10(18.87%)
	other	14(3.09%)	9(3.57%)	4(2.70%)	1(1.89%)
	total^#	563^#	312^#	185^#	67^#
Rate of eye tics	persistently	50(11.03%)	25(9.92%)	17(11.49%)	8(15.09%)	χ² = 3.087 P = 0.543
	frequently	262(57.84%)	152(60.32%)	79(53.38%)	31(58.59%)
	occasionally	142(31.35%)	76(30.16%)	52(35.14%)	14(26.42%)
times of the other tics	before the blinking	98(21.63%)	55(21.83%)	24(16.22%)	21(39.62%)	χ² = 12.425 P = 0.014*
	simultaneously with the blinking	271(59.82%)	155(61.51%)	94(63.51%)	23(43.40%)
	after the blinking	69(15.23%)	35(13.89%)	22(14.86%)	9(16.98%)
^△Excessive blinking = brow wrinkling or eye squeezing; ^#Because some patients exhibited two or more types of abnormal blinking, the total number of abnormal blinking instances is not equal to the number of patients. : P < 0.05.*

Table 4

Other tic symptoms in TD patients
Characteristic	TD (n = 453)	TTD (252)	CTD (148)	TS (53)
nose wrinkling	169(37.30%)	95(37.70%)	55(37.16%)	19(35.85%)	χ² = 108.647 P = 0.000***
facial grimacing	126(27.81%)	73(28.97%)	38(25.68%)	15(28.30%)
throat clearing	116(25.61%)	55(21.83%)	14(9.46%)	47(88.68%)
mouth tic	115(25.39%)	58(23.02%)	48(32.43%)	9(16.98%)
fingers sucking	62(13.69%)	34(13.49%)	17(11.49%)	11(20.75%)
head nodding	61(13.47%)	31(12.30%)	22(14.86%)	8(15.09%)
shrugging	44(9.71%)	21(8.33%)	11(7.43%)	12(22.64%)
neck stretching	43(9.49%)	15(5.95%)	19(12.84%)	9(16.98%)
leg shaking	28(6.18%)	13(5.16%)	8(5.41%)	7(13.21%)
coprolalia	22(4.86%)	9(3.57%)	2(1.35%)	11(20.75%)
hand spinning	14(3.09%)	6(2.38%)	4(2.70%)	4(7.55%)
shriek	12(2.65%)	6(2.38%)	2(1.35%)	4(7.55%)
abdominal tics	11(2.43%)	5(1.98%)	1(0.68%)	5(9.43%)
aggressive behaviour	4(0.88%)	1(0.40%)	1(0.68%)	2(3.77%)
others	11(2.43%)	6(2.38%)	2(1.35%)	3(5.66%)
Total^#	832^#	428^#	244^#	160^#
^△Excessive blinking = eye squeezing or brow wrinkling; ^#Because some patients exhibited two or more types of tics, the total number of tic symptoms is not equal to the number of patients. **: P < 0.001.*

Accompanying ocular symptoms and signs

Among the 453 patients with TD, 371 (81.90%) reported ocular symptoms. The most common symptoms were itching (193, 42.60%), dryness (102, 22.52%), redness (82, 18.10%), fatigue (82, 18.10%), photophobia (58, 12.80%), and eye discharge (42, 9.27%). There were no significant differences in ocular symptoms according to TD subtype. Among these 371 patients, ocular symptoms preceded abnormal blinking in 82 cases, occurred simultaneously with abnormal blinking in 231 cases, and followed the onset of abnormal blinking in 58 cases. Further details are presented in Table 5.

Table 5

Ocular symptoms in TD patients
Characteristic		TD (n = 453)	TTD (252)	CTD (148)	TS (53)	P
No ocular symptoms		82(18.10%)	49(19.44%)	24(16.22%)	9(16.98%)	χ² = 13.932 P = 0.904
Itching		193(42.60%)	104(41.27%)	67(45.27%)	22(41.51%)
dryness		102(22.52%)	56(22.22%)	32(21.62%)	14(26.42%)
Redness		82(18.10%)	46(18.25%)	25(16.89%)	11(20.75%)
fatigue		82(18.10%)	41(16.27%)	27(18.24%)	14(26.42%)
photophobia		58(12.80%)	29(11.51%)	19(12.84%)	10(18.87%)
discharge of eye		42(9.27%)	24(9.52%)	11(7.43%)	7(13.21%)
sore numb		25(5.51%)	9(3.57%)	13(8.78%)	3(5.67%)
pain		24(5.29%)	10(3.97%)	9(6.08%)	5(9.43%)
foreign body sensation		22(4.86%)	14(5.56%)	6(4.05%)	2(3.77%)
visual blur		18(3.97%)	11(4.37%)	4(2.70%)	3(5.66%)
others		4(0.88%)	2(0.79%)	2(1.35%)	0(0)
times of the ocular symptoms	before the blinking	82(18.10%)	46(18.25%)	27(18.24%)	9(16.98%)	χ² = 2.311 P = 0.679
	simultaneously with the blinking	231(50.99%)	132(52.38%)	71(47.97%)	28(52.83%)
	after the blinking	58(12.80%)	27(10.71%)	22(14.86%)	9(16.98%)

Accompanying eye diseases

Excluding ametropia (146 cases, 32.23%), 336 TD patients (74.17%) had comorbid eye diseases; of these patients, 180 had TTD, 120 had CTD, and 36 had TS. Overall, ametropia, AC, and DED were the primary eye diseases accompanying TD. Specifically, 164 (36.20%) patients had AC, 92 (20.31%) patients had DED, and 52 (11.48%) patients had both. Analysis via Chi-squared tests revealed significant differences in AC and DED prevalence according to TD subtype. TS patients were more likely to have both AC and DED but less likely to have DED alone (P = 0.002) (Table 6). In contrast, patients with TTD and CTD were more likely to have DED alone. Further details are presented in Table 6.

Table 6

Accompanying eye diseases in TD patients
Characteristic		TD (n = 453)	TTD (252)	CTD (148)	TS (53)	p
Accompany-ing eye diseases	Ametropia	146(32.23%)	82(32.54%)	47(31.76%)	17(32.08%)
	AC	164(36.20%)	91(36.11%)	58(31.19%)	15(28.30%)	χ² = 17.505 P = 0.002**
	DED	92(20.31%)	50(19.84%)	38(25.68%)	5(9.43%)
	AC&DED	52(11.48%)	22(8.73%)	16(10.81%)	14(26.42%)
	asthenopia	14(3.09%)	9(3.57%)	3(2.03%)	2(3.77%)	χ² = 17.505 P = 0.002**
	trichiasis	20(4.42%)	11(4.37%)	7(4.73%)	2(3.77%)
	others	11(2.43%)	10(3.97%)	1(0.68%)	0(0)
	total^#	405^#	209^#	133^#	46^#
^#Because some patients had two or more comorbid diseases, the total number of comorbid eye diseases is not equal to the number of patients. **: P < 0.01.

Clinical characteristics of AC and DED in TD patients: Among 216 TD patients with AC (including 52 patients with both AC and DED), 83 exhibited frequent blinking, 71 exhibited excessive blinking, 95 exhibited both frequent and excessive blinking, and 47 exhibited staring. Other allergic diseases were common in this group: 120 patients had allergic rhinitis (AR), and 84 patients had allergic asthma. Analysis via Chi-squared tests showed that TTD patients were more likely to have other allergic diseases (P = 0.000). Allergen testing was performed in 94 patients, and 58 (59.18%) had identifiable allergens. These mainly included dust mites (37 cases), followed by milk (11 cases). Among 145 TD patients with DED (including 52 patients with both AC and DED), 51 exhibited frequent blinking, 32 exhibited excessive blinking, and 47 exhibited both frequent and excessive blinking. Furthermore, 109 of these 145 patients reported various ocular symptoms, such as dryness, fatigue, and itching. The remaining 36 patients had only a shortened TFBUT without any ocular discomfort. Further details are presented in Tables 7 and 8.

Table 7

Clinical characteristics of AC in TD patients
Characteristic		TD (n = 216)	TTD (113)	CTD (74)	TS (29)
types of blinking	excessive and frequency blinking	95(43.98%)	51(23.61%)	27(12.50%)	17(7.87%)	χ² = 8.568 P = 0.380
	frequency blinking	83(38.43%)	42(18.58%)	26(12.03%)	15(6.94%)
	excessive blinking	71(32.87%)	34(15.71%)	26(12.03%)	11(5.09%)
	eye staring	47(21.76%)	18(8.33%)	21(9.72%)	8(3.70%)
	others	37(17.13%)	23(10.65%)	12(5.55%)	2(0.93%)
allergic diseases	AR	120(55.56%)	64(29.63%)	35(16.20%)	21(9.72%)	χ² = 22.456 P = 0.000***
	allergic asthma	84(38.89%)	35(24.14%)	12(5.55%)	37(17.13%)
	others	20(9.26%)	11(4.66%)	7(4.73%)	2(3.77%)
allergens	number of allergens tested	98(45.37%)	41(16.27%)	37(25.0%)	20(30.73%)
	dust mites	37(17.13%)	14(6.48%)	15(6.94%)	8(3.70%)	χ² = 0.762 P = 0.943
	milk/beef	11(5.09%)	5(2.31%)	4(1.85%)	2(0.93%)
	others	16(7.41%)	8(3.70%)	5(2.31%)	3(1.39%)
***: P < 0.001.

Table 8

Clinical characteristics of DED in TD patients
Characteristic		TD (n = 145)	TTD (72)	CTD (54)	TS (19)
types of blinking	excessive and frequency blinking	47(32.41%)	23(15.86%)	18(12.41%)	6(4.14%)	χ² = 5.414 P = 0.713
	frequency blinking	51(35.17%)	26(17.93%)	17(11.72%)	8(5.52%)
	excessive blinking	32(22.07%)	17(11.72%)	12(8.28%)	3(2.07%)
	eye staring	22(15.17%)	7(4.83%)	7(4.83%)	4(2.76%)
	others	15(10.34%)	10(6.89%)	2(1.38%)	3(2.07%)
symptoms and signs	both signs and symptoms	62(42.76%)	36(24.83%)	21(14.48%)	5(3.45%)	χ² = 4.857 P = 0.302
	Only symptoms	47(32.41%)	33(22.76%)	11(7.59%)	3(2.07%)
	Only signs	36(24.83%)	18(12.41%)	15(10.34%)	3(2.07%)

Neurological and psychiatric disorders

Overall, varying severities of neurological and psychiatric disorders were exhibited by 267 patients (58.94%), including 183 (40.40%) with ADHD, 72 (15.89%) with OCD, 147 (32.45%) dysthymic disorder (e.g., irritability, anxiety, fear, and/or depression), and 35 (7.73%) with social dysfunction. Analysis via Chi-squared tests revealed significant differences in neurological and psychiatric disorder prevalence according to TD subtype; TS patients had the highest incidences of all types of neurological and psychiatric disorders (P < 0.01, P < 0.05). Details are presented in Table 9.

Table 9

Neurological and psychiatric disorders
Characteristic		TD (n = 453)	TTD (252)	CTD (148)	TS (53)	P
neurologic and psychiatric disorders	ADHD	183(40.40%)	90(35.71%)	59(39.86%)	34(64.15%)	χ² = 14.733 P = 0.001**
	OCD	72(15.89%)	29(11.51%)	24(16.22%)	19(35.85%)	χ² = 19.426 P = 0.000***
	dysthymic disorder	147(32.45%)	72(28.57%)	54(36.49%)	26(49.06%)	χ² = 9.090 P = 0.011*
	social dysfunction	35(7.73%)	13(5.16%)	10(6.76%)	12(22.64%)	χ² = 19.064 P = 0.000***
: P < 0.05, : P < 0.01, **: P < 0.001.

Therapy and follow-up

In total, 370 TD patients with eye diseases were treated according to the guidelines for their specific conditions. Of these patients, 256 (69.19%) experienced improvement or resolution of their tic symptoms. Among the 141 patients with suspected TD, 85 had eye diseases: 54 exhibited persistent eye or other tics after treatment and were ultimately diagnosed with TD, whereas 31 experienced symptom reduction after ocular disease treatment, leading to the exclusion of a TD diagnosis. Among the 56 patients who presented with abnormal blinking alone, 32 developed other tics or experienced persistently worsening abnormal blinking, resulting in a diagnosis of TD. Abnormal blinking spontaneously resolved in the remaining patients, leading to the exclusion of a TD diagnosis during the 1-year follow-up period. Additionally, 45 TTD patients displayed progression to CTD or TS during follow-up. In 146 TD patients with ametropia, tic symptoms did not improve after refractive correction.

TD and abnormal blinking

Eye blinking is a physiological motor act that can be spontaneous, voluntary, or reflexive. Typically, the blink rate is approximately 10 to 15 times per minute [13]. Abnormal blinking refers to a frequency and/or amplitude of blinking that exceeds this normal range. TD often initially present with abnormal blinking or eye tics; however, few studies have specifically focused on abnormal blinking in TD patients. A positive correlation between blink rate and tics has been reported. Comings and Comings [6] reviewed 250 cases of TS and found that the most frequent manifestations were facial tics; excessive blinking was the most common presenting symptom. Jankovic et al. [7] observed excessive blinking in 70% of 156 patients with TS. Tulen et al. [8] found that patients with TS exhibited more frequent blinking compared with healthy controls. In a study of 212 patients with TS, Martino et al. [9] found that 91.5% had an eyelid-related tic, such as blinking, winking, eye staring, or staring; these tics could sometimes be voluntarily controlled. Nilles et al. [2] examined the clinical characteristics of 203 children with TD, revealing that 56% had eye tics and 48% exhibited eye staring. Collectively, these findings highlight the common nature of abnormal blinking in TD.

Similarly, some authors have explored the characteristics of TD in children with abnormal blinking. In a study of 50 children with frequent eye blinking, Jung et al. [8] reported that 43 were diagnosed with TD, including 39 cases of TTD. In contrast, Coats et al. [14], examining the aetiology of disease in 99 children with excessive blinking, found that among 23 children with habitual tics, only two were diagnosed with TS. Bisker et al. identified TS in only one of 32 children with persistent eye tics [15]. Yasmin et al. reported that only two of 34 patients with excessive blinking had TS; they speculated that children experience episodic transient excessive blinking [16]. Similarly, Vrabec et al. [17] reviewed the records of 17 patients with excessive blinking and found that all had functional blinking, which spontaneously resolved in all cases. These conflicting results may be attributable to inconsistencies in the patient populations among studies. Some studies have only reported on the relationship between eye blinking and TS, not TD. Some authors may have diagnosed TD only in children with eye tics, which could also be either transient excessive blinking or functional blinking. Furthermore, manifestations of eye tics vary across studies; some authors have solely focused on excessive blinking, whereas others included various types of eye tics (e.g., frequent blinking, staring, and eye rolling).

To accurately assess the clinical characteristics of TD in patients presenting with the chief complaint of abnormal blinking, all patients in our cohort were diagnosed within an ophthalmology clinic. The clinical manifestations included various types of abnormal blinking (e.g., excessive blinking, frequent blinking, and staring) and met our established diagnostic criteria. This approach was intended to minimise overdiagnosis or misdiagnosis. Our results showed that 453 of 1054 patients (42.98%) had TD. Of these patients, 367 (81.02%) were diagnosed during their initial ophthalmology visit, 86 (18.98%) were diagnosed during follow-up, and 121 (26.71%) initially were misdiagnosed or experienced a missed diagnosis. We also found that TTD patients were more likely to visit an ophthalmology clinic and be misdiagnosed or experience a missed diagnosis; patients with CTD or TS were more likely to visit a paediatrician. These findings align with other results from our study, such as the associations of TS with more tic symptoms, more neurological and psychiatric disorders, and a greater likelihood of a past medical history of abnormal blinking or TD. Our findings also indicate that the symptoms of CTD and TS are generally more severe than those of TTD. Taken together, these observations suggest that parents of TD patients with abnormal blinking often initially choose to consult a paediatric ophthalmologist. However, they are more likely to consult a paediatrician when the patient exhibits repeated blinking or has a prior history of TD. When TD patients, especially those with TTD, also have eye diseases, misdiagnosis or missed diagnosis is more likely. In summary, TD are important causes of abnormal blinking. Ophthalmologists should recognise the clinical characteristics of TD with abnormal blinking and consider a diagnosis of TD when children present with blinking-related complaints, particularly in the presence of eye diseases. Referral to a specialist is warranted when patients exhibit repeated blinking or have a history of TD.

In addition to abnormal blinking and eye tics, we observed several other characteristics in our cohort of TD patients diagnosed in an ophthalmology setting. First, most TD patients (371, 81.90%) experienced ocular discomfort; the main symptoms were eye itching, dryness, redness, and fatigue. Correspondingly, 336 patients (74.17%) had comorbid eye diseases (excluding ametropia), primarily AC and DED. Tic symptoms showed varying degrees of improvement when DED and/or AC were treated. Therefore, a diagnosis of TD should not be excluded in patients presenting with the chief complaint of blinking and ocular discomfort, even if an ocular disease is diagnosed. Notably, 146 patients with ametropia did not experience any improvement in tic symptoms after refractive correction, suggesting that TD are more strongly associated with DED and AC than with ametropia. Second, TTD was the predominant TD subtype (252, 55.63%), indicating that most patients had a short course of disease. The tic symptoms primarily involved eye and facial tics, which likely explains why TD patients often seek ophthalmologic care and are misdiagnosed with an ocular disease. Third, tic symptoms were mainly motor tics and simple tics. Most patients presented with eye and facial tics, including excessive blinking, frequent blinking, staring, nose wrinkling, mouth tics, and facial grimacing. However, many children also exhibited nose and throat clearing, which may be related to the tendency for ophthalmic TD patients to have comorbid AC or AR. Complex tics were less common; only 22 children displayed coprolalia and four exhibited aggressive behaviour. Finally, neurological and psychiatric disorders were not uncommon. In our cohort, 40.40% of TD patients had ADHD, whereas 32.45% had dysthymic disorder. TS patients had the highest incidences of neurological and psychiatric disorders. These results appear to contradict previous literature, which has suggested that habitual tics and excessive blinking rarely have neurological or permanent sequelae [15–17].

TD, allergic diseases, and abnormal blinking

Abnormal blinking is one of the most common symptoms of both TD and AC, and there is increasing evidence that TD are closely associated with allergic diseases. Moreover, allergic diseases may be a primary cause of TD, considering that children with TD often exhibit conditions such as allergic eczema, AR, or AC. The presence of allergic diseases is associated with tic symptoms and TD severity [10, 18–20]. TD patients with allergic diseases have higher motor and vocal tic scores than such patients without allergic diseases [19]. Yuce et al. [21] discovered strong correlations between rhinitis or eczema and TS and/or OCD. Additionally, Chen et al. [22] found that patients with ADHD and TD had significantly higher prevalences of allergic diseases (e.g., asthma, AR, atopic dermatitis, and AC). In our clinical practice, we have observed that many TD patients also have allergic diseases and exhibit more severe tic symptoms.

Ocular and nasal symptoms such as blinking, wrinkling, and throat clearing are often the initial manifestations in children with TD and allergic diseases; these symptoms typically persist throughout the course of disease [10]. At disease onset, children with TD often present to ophthalmology clinics with complaints of abnormal blinking, nose wrinkling, or throat clearing. They may be misdiagnosed with AC, AR, or allergic asthma. Our study also showed that TD patients are likely to be misdiagnosed with AC. Furthermore, the clinical courses of TD and allergic diseases are similar, exhibiting cycles of exacerbation and remission. In patients with both conditions, tic symptoms tend to improve after allergy treatment [20]. All of these findings support a connection between TD and allergic diseases. Therefore, it is essential to obtain a detailed medical history, conduct a thorough physical examination, and perform any necessary auxiliary examinations to exclude eye diseases (especially allergic diseases) before making a diagnosis of TD [19]. Conversely, clinicians evaluating allergies in children should also consider the possibility of a TD. In patients with TD, allergic diseases should be actively managed and prevented [24]. Based on the close relationship between TTD and AC, Chen et al. [18] suggested that TTD is an entity distinct from other TD subtypes, such as TS. Therefore, ophthalmologists could play a crucial role in the management of TD. In clinical practice, effective control of allergic diseases can facilitate the prevention and management of TD, especially TTD.

The aetiologies of allergic diseases are complex, involving a combination of genetic factors, allergens, and various physical and chemical factors; they mirror the complexity of TD aetiologies [25]. Allergic diseases can cause considerable stress for patients; psychosocial stress has emerged as a strong predictor of the severities of future tics, OCD, and depressive symptoms. Moreover, stress can exacerbate the symptoms of both TS and allergic diseases [26]. Additionally, TD and various allergic diseases exhibit abnormalities in inflammatory markers such as interleukins and tumour necrosis factor, suggesting shared immune responses. Allergy-associated immune dysfunction may increase the severities of tics and other abnormal behaviours in children with TD [27]. The results of some immunological and genetic studies have supported this link. For example, Hartmann et al. [28] reported elevated histamine levels in patients with both TS and allergic diseases.

TD, DED, and abnormal blinking

Abnormal blinking also is a primary symptom of both TD and DED [1, 11]. There is evidence of a strong correlation between abnormal blinking and DED [29]. Even minor abnormalities in the ocular surface and tear film can increase blink rates. Frequent blinking is common in children with AC, especially when accompanied by DED [30]. In our clinical practice, we have identified both TD and DED in some patients who present with abnormal blinking as the chief complaint. Chen et al. [18] reported that AC was less prevalent than DED in TTD patients; their results indicated that the incomplete blinking induced by eye tics in children with TD led to tear film instability and DED. In children with TD, eye tics often involve frequent and excessive blinking. This abnormal blinking can result in inadequate tear lipid distribution and subsequent exposure of the inferior ocular surface, potentially increasing tear evaporation [31]. Moreover, incomplete blinking has been associated with decreased TFBUT, increased ocular surface disease index scores, and insufficient lipid layer thickness [32]. Patients with incomplete blinking reportedly have more severe meibomian gland loss and reduced tear film stability [33].

Importantly, the lack of research and consensus regarding normal tear film function parameters and ocular surface characteristics in children has hindered the early diagnosis of DED in this population, and data concerning normal values for ocular surface tests are limited [34]. A diagnosis of DED could be established in at least 33.3% of children based on the Tear Film and Ocular Surface Society Dry Eye Workshop II (TFOS DEWS II) criteria for adults [35]. This finding suggests that a lower TFBUT is more common in children than in adults and might not be the optimal basis for diagnosing DED in children [13]. However, higher prevalence rates of DED in children have been reported, emphasising the importance of conducting ocular surface tests in this population. The results of these tests can aid in the recognition, prevention, and prompt treatment of DED in children [36]. In the present study, tear film instability, as evidenced by decreased TFBUT, was observed in two-thirds (89/145) of children with TD and DED. Notably, more than one-third of these children (36/98) were asymptomatic.

AC and DED, common triggers of TD in children, can occur alone or in combination in TD patients. The recurrent nature of AC in children with TD can lead to tear film instability and ocular inflammation, predisposing them to DED. Chen et al. [37]. reported that the frequency of DED, as determined by TFBUT, was 97.5% in young children with AC. Additionally, an AC-associated form of DED was solely characterised by decreased TFBUT; affected individuals remained asymptomatic [18]. In the present study, tear film instability was evident in 24.07% (52/216) of TD patients with AC, but more than half of these children did not report any dry eye-related symptoms.

Differential diagnosis of TD with abnormal blinking

As we have discussed above, abnormal blinking is a common symptom shared by AC, DED, and TD, which can hinder effective differential diagnosis. Children with TD are often misdiagnosed with conditions such as AC, DED, AR, or habitual tics. On the basis of our extensive clinical experience, we believe that the first step towards accurate diagnosis involves gathering information about the clinical manifestations, including the types of abnormal blinking (e.g., excessive blinking, frequent blinking, wrinkling, and/or staring), blink rate and duration, presence of accompanying facial or other tics, and any past medical history of blinking or tics. Generally, excessive blinking or wrinkling, facial and other tics, and/or recurrent abnormal blinking are features that suggest the presence of a TD. The second step involves identifying the cause of abnormal blinking. A detailed history should be collected; an ophthalmic examination should be performed to determine whether the patient exhibits ocular symptoms and signs of DED, AC, or other eye diseases. If no ocular discomfort is present, the abnormal blinking is likely caused by a TD. If ocular discomfort is evident, further evaluation is needed to determine whether the abnormal blinking is due to an ocular disease alone or in conjunction with a TD. Third, in patients with both TD and eye diseases such as AC, abnormal blinking usually improves but does not completely resolve after appropriate treatment of the ocular condition. Therefore, children with abnormal blinking should be evaluated for TD when no organic abnormalities are found or when blinking persists despite appropriate treatment. Finally, when AC is accompanied by AR and asthma, excessive blinking, nose wrinkling, throat clearing, and other symptoms can be difficult to distinguish from TS. Consequently, many children with TS are misdiagnosed and undergo treatment for conjunctivitis or rhinitis. Prompt treatment of allergic diseases can help identify TD, especially in patients with comorbid allergic conditions. It also can prevent the exacerbation of tic symptoms, potentially influencing the patient’s somatic symptoms and attention. Therefore, a detailed medical history should be collected and a physical examination (including mental assessments and necessary auxiliary examinations) should be performed along with diagnostic treatment and follow-up as needed to ensure accurate diagnosis of TD, particularly in patients with allergic diseases.

To our knowledge, this is the largest cohort of TD patients diagnosed in an ophthalmology setting to date. Our results provide an accurate summary of the clinical characteristics of children with TD who present with the chief complaint of abnormal blinking [6–9]. Thereas this study had some limitations. First, we did not perform allergen tests in all patients with suspected AC; instead, we relied on their allergic disease histories and typical ocular signs. Second, because TD can spontaneously resolve in patients with AC or DED, even if all symptoms disappeared during treatment and follow-up, TD could not be definitively excluded. Therefore, we may have underestimated the prevalence of TD in patients with abnormal blinking. Third, allergic diseases and TD can occur in a seasonal manner; because this study used a recruitment period shorter than 1 year, selection bias may have been present. Finally, allergic diseases and DED are influenced by climate and geographic factors. The inclusion of patients only from southeast China may limit the generalisability of our findings to other populations.

In this study, we found that TD are major causes of abnormal blinking; TTD is the most common subtype, and patients with TTD are more likely (compared with other TD patients) to seek ophthalmologic care. Eye tics in TD mainly manifest as excessive and/or frequent blinking, and most patients exhibit tics other than eye tics. TD patients with abnormal blinking often have comorbid eye diseases, primarily AC and DED; these patients are likely to be misdiagnosed or experience missed diagnosis. Moreover, we established clear definitions for various types of abnormal blinking, including functional blinking, excessive blinking, frequent blinking, and habitual tics, based on previous literature. Importantly, patients with unclear diagnoses were monitored until a diagnosis of TD was confirmed or excluded. This also is the first cohort study of TD patients in an ophthalmology setting. Finally, this study highlights the fact that abnormal blinking is a common symptom shared by TD, AC, and DED. Accurate differential diagnosis of these conditions should be based on a comprehensive medical history, ophthalmic examination, and any necessary auxiliary examinations.

Ethics approval and consent to participate

All included patients provided oral and written informed consent. The study was approved by the Medical Ethics Committee of the Eye Hospital, Wenzhou Medical University (reference number 2022-031-K-23-01).

Consent for publication

Not applicable.

Availability of data and materials

The datasets generated and/or analysed during the current study are available

from the corresponding author upon reasonable request.

Competing interests

The authors declare that they have no competing interests, financial or otherwise.

Funding

This study was supported by the Zhejiang Province Traditional Chinese Medicine Modernization Special Project (2022ZX013) and the Natural Science Foundation of Zhejiang Province (LTGY24H270011).

Authors’ contributions

NT, YW, and XJ conducted case collection, summarised the questionnaire data, and drafted the manuscript. HL and YL assisted with case collection and data collation. JQ and SX designed and supervised the project, verified the data, and revised the manuscript. All authors have read and approved the final manuscript.

Acknowledgements

We thank Ryan Chastain-Gross, Ph.D., from Liwen Bianji (Edanz) (www.liwenbianji.cn) for editing the English text of a draft of this manuscript.

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No competing interests reported.

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Clinical Characteristics of Tic Disorders in Children and Adolescents with the Chief Complaint of Abnormal Blinking

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Background

Methods

Patients and protocol

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Diagnostic principles

Therapy and follow-up

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Results

Morbidities and demographic characteristics of TD patients

Clinical characteristics

Therapy and follow-up

Discussion

TD and abnormal blinking

TD, allergic diseases, and abnormal blinking

TD, DED, and abnormal blinking

Differential diagnosis of TD with abnormal blinking

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