Clinical Characteristics And Risk Factors For Pruritus In Patients With Neuromyelitis Optica Spectrum Disorders

doi:10.21203/rs.3.rs-5001368/v1

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Clinical Characteristics And Risk Factors For Pruritus In Patients With Neuromyelitis Optica Spectrum Disorders

https://doi.org/10.21203/rs.3.rs-5001368/v1

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Objective This study aimed to investigate the clinical characteristics and risk factors for pruritus in patients with neuromyelitis optica spectrum disorders (NMOSD) and evaluate its impact on patient quality of life.

Methods Patients with NMOSD at the Department of Neurology of our hospital from December 2021 to August 2023 were followed up by outpatient visits or telephone interviews. The 5-D itch scale was used to evaluate pruritus intensity, the course of pruritus and pruritus-related interference in daily life during the entire disease course. We explored the factors correlated with pruritus by comparing the clinical features of patients with NMOSD with and without pruritus.

Results A total of 112 patients with NMOSD were enrolled. 32(28.6%) patients had pruritus. All of these patients had myelitis. 22 (68.8%) patients had pruritus for less than 6 hours/day, 26 (81.2%) had moderate or severe pruritus intensity, 16 (50%) had complete pruritus relief, and 30 (93.8%) had never or occasionally affected daily life. Compared with patients without pruritus, patients with pruritus were more common in males (P=0.030), younger in age (P=0.018), with a shorter course of disease (P=0.000), and with cervical cord lesions and longitudinally extensive transverse myelitis (P=0.013 and 0.022, respectively). Multivariate logistic regression analysis revealed that younger age (OR=0.031, 95% CI=0.002-0.421, P=0.009), short disease duration (OR=0.810, 95% CI=0.721-0.909, P=0.000), longitudinally extensive transverse myelitis (OR=7.346, 95% CI=1.172-46.052, P=0.033), and cervical lesions (OR=8.023, 95% CI=1.501-42.852, P=0.015) were independent factors correlated with pruritus in patients with NMOSD.

Conclusions Pruritus is a common clinical feature in patients with NMOSD, and it can be the initial symptom in some patients. A short disease course, younger age, cervical cord involvement and longitudinally extensive transverse myelitis are risk factors for NMOSD with pruritus. Pruritus has a minor effect on the quality of life for the majority of NMOSD patients.

Neuromyelitis Optica Spectrum Disorders

Pruritus

Quality of life

Neuromyelitis optica spectrum disorders (NMOSD) is an autoimmune-mediated inflammatory demyelinating disease of the central nervous system that mainly presents as optic neuritis, longitudinally extensive transverse myelitis (LETM), and area postrema syndrome [1]. NMOSD is characterized by a high frequency of recurrence and severe disability. Almost 60% of patients with NMOSD relapse within the first year, and 87% of patients with NMOSD relapse within 5 years after disease onset[2]. A single relapse had significant and sustained clinically meaningful worsening of neurological disability and health-related quality of life [3]. In addition to visual impairment, motor dysfunction, bowel and bladder dysfunction, pain, painful tonic spasm, sensory abnormalities, depression, anxiety and cognitive impairment strongly impact quality of life in patients with NMOSD [4, 5, 6].

Pruritus is described as an unpleasant cutaneous sensation provoking the desire to scratch. Although previous reports have suggested that pruritus occurs frequently and can be the initial symptom of myelitis in patients with NMOSD [7, 8, 9], the clinical characteristics of pruritus in patients with NMOSD and its impact on their quality of life are not yet clear. The 5-D itch Scale is a reliable, multidimensional measure of pruritus that has been validated in many diseases with pruritus [10]. To date, no study has evaluated pruritus in patients with NMOSD via this scale. Therefore, the purpose of this study was to explore the prevalence and intensity of pruritus and its impact on patients’ daily life in NMOSD patients using the 5-D itch scale and to investigate the factors correlated with pruritus by comparing the clinical characteristics of patients with and without pruritus.

Patient enrollment

We performed a cross-sectional study and enrolled patients who fulfilled the international consensus diagnostic criteria for NMOSD published in 2015 and were treated in the Department of Neurology of Hebei Medical University Third Hospital between December 2021 and August 2023[11]. The exclusion criteria included patients with alternative causes of pruritus, including primary skin lesions; systemic diseases, such as kidney disease or liver diseases; and incomplete medical records who were unwilling to participate in our study.

Data collection

Patient data were obtained through inpatient or outpatient medical records. Clinical, demographic, laboratory and MRI data, including gender, age at onset, current age, disease duration, initial symptoms at onset, number of attacks, annualized relapse rate, brain and spinal MRI results, aquaporin-4 antibody status, and presence of pain, were also collected. Disease duration was defined as the time interval between disease onset and the last follow-up. Brain and spinal MRI information was obtained through reports provided by neuroradiologists. All enrolled patients were invited to finish the 5-D itch scale questionnaire by outpatient visits or telephone interviews. The 5-D Itch Scale includes daily duration, degree, direction, disability and distribution during the disease course. Single-item domain scores (duration, degree and direction) are equal to the value indicated below the response choice. The score for the disability domain is achieved by taking the highest score on any of the four items.

Statistical analysis

All the data were analyzed using SPSS 24.0. The normality of the quantitative data distribution was evaluated using the Shapiro‒Wilk test. The data of the normal distribution were expressed as the means and standard deviations, and the t-test was used to compare statistical differences between the two groups. The median and interquartile range were used for those with skewed distribution data, and the Mann‒Whitney U rank-sum test was used to compare statistical differences between the two groups. Count data are expressed as percentages, and the chi-square test or Fisher exact test was used to compare statistical differences. Multiple logistic regression analysis was used to analyze risk factors, with P < 0.05 indicating statistical significance.

A total of 112 patients with NMOSD were included in this study; 105 were female, and 7 were male, with a female-to-male ratio of 1:15. The mean age at the time of follow-up was 54.4 ± 15.1 years, the mean age of onset was 45.1 ± 14.6 years, and the mean disease duration was 9.3 ± 6.3 years. The mean annual recurrence rate was 0.2 ± 0.2. Among the 112 patients, optic neuritis as the initial symptom in 26 patients (23.2%), myelitis in 71 (63.4%), neuromyelitis optica in 5 (4.5%), and other core clinical symptoms in 10 patients (8.9%). The AQP4 antibody results were positive in 108 patients and negative in 4 patients.15 patients had intracranial lesions, and 97 had spinal cord lesions.

Prevalence and characteristics of pruritus

Among the 112 patients with NMOSD, 32 patients (28.6%) reported having pruritus during the course of the disease, and this percentage increased to 33% if patients with myelitis were considered. There were 5 males and 27 females, with a mean age of 48.6 ± 16.6 years, and the mean age of the first episode was 42.9 ± 15.9 years. All 32 patients with pruritus had myelitis attacks, with LETM in 29 (90.6%) patients, and 31 (96.9%) were positive for AQP4 antibodies (Table 1). Among the 32 patients with pruritus, pruritus occurred as the initial symptom in 5 patients (15.6%), simultaneously with myelitis at the same time in 8 (25%), and later than myelitis in 19 (59.4%).18 patients (56.2%) with pruritus experienced symptoms of pain or painful spasms.22 (69%) patients experienced pruritus for less than 6 hours per day, 8 (25%) for 6–18 hours, and only 2 (6%) patients experienced pruritus continuously through the day (Fig. 1). 26 (81.2%) patients reported moderate to severe pruritus, and 6 (18.8%) patients reported mild intensity pruritus (Fig. 2). During the follow-up period, pruritus was completely relieved in 16 (50%) patients, partially relieved in 12 (37.6%), and remained unchanged or worsened in only 4 (12.5%) patients (Fig. 3). Pruritus never or rarely affected the daily life of 11 (34.4%) patients, and only 2 (6.2%) patients reported a significant impact on daily life. (Fig. 4)

Table 1

Comparison of the characteristics of NMOSD patients with and without pruritus
	NMOSD with pruritus (n = 32)	NMOSD without pruritus (n = 80)	P Value
Sex(M/F)	5/27	2/78	0.030
Age, years	48.63 ± 16.57	56.76 ± 13.96	0.018
Age at onset, years	42.91 ± 15.89	45.91 ± 14.11	0.355
Disease duration, years	5.60 ± 5.42	5.6 ± 5.42	0.000
ARR	0.05(0.00-0.39)	0.21(0.00-0.33)	0.143
Onset symptoms
Optic neuritis	6	20	0.646
Myelitis	20	51	1
Optic neuritis + myelitis	1	4	1
Others	5	5	0.228
intracranial lesions	3	14	0.429
Spinal cord lesions	32	65	0.020
LETM	29	54	0.022
Cervical cord lesions	27	41	0.013
Thoracic cord lesions	19	2	0.569
AQP4 antibody positive	31	77	1.000

The location of pruritus

Patients may have pruritus in a single area or multiple areas. Among the 32 patients with pruritus, 27 (84.4%) reported pruritus in fewer than 2 areas, whereas 5 patients reported pruritus in 3 or more areas. Pruritus was located mostly in the neck (34.4%) and upper limbs (34.4%), followed by the back, head, chest, abdomen, and lower limbs at 31.2%, 28.1%, 25%, 18.8% and 12.5%, respectively. Among the 11 patients with pruritus in the neck, 9 had cervical cord lesions, and 4 had thoracic cord lesions. Among the 11 patients with pruritus in the upper limbs, 10 had cervical cord lesions, and 6 had thoracic cord lesions. The pruritus locations were in accordance with the dermatomal distribution of the involved spinal cord segments in 22 (69%) patients(Fig. 5).

Factors correlated with pruritus in patients with NMOSD

A comparison of clinical data between patients with and without pruritus revealed that patients with pruritus were more likely to be males, be younger, have a shorter disease duration and have more frequent cervical cord lesions and LETM. However, differences in age of onset, annual relapse rate, initial clinical symptoms, brain lesions, and the AQP4 antibody positivity rate were not statistically significant (Table 1). Further logistic regression showed that the age, disease duration, cervical cord lesions, and LETM were potential correlated factors for pruritus in patients with NMOSD. Significantly more patients with pruritus had younger age and shorted disease duration than in the patients without pruritus (OR,0.03;95% CI,0.00 to 0.42;P = 0.009 and OR,0.81;95% CI,0.72 to 0.91;p = 0.00 respectively). Significantly more patients with pruritus had cervical cord involvement and LETM than in the patients without pruritus (OR,8.02;95% CI,1.50 to 42.89; P = 0.015 and OR,7.35;95% CI,.17 to 46.05; p = 0.033 respectively). (Table 2)

Table 2

Multivariate logistic analysis of potential correlated factors of pruritus
	OR	95%CI	P
Sex	0.98	0.95–1.02	0.35
age	0.03	0.00-0.42	0.01
Disease duration	0.81	0.72–0.91	0.00
LETM	7.35	1.17–46.05	0.03
Cervical cord lesions	8.02	1.50-42.89	0.02

We found that 28% of NMOSD patients experienced pruritus, with a higher proportion of pruritus in NMOSD patients with myelitis, reaching 33%. Furthermore, 16% of patients experienced pruritus before a myelitis episode, similar to previous reports[8, 9] but lower than the 62.3% reported by He et al.[7]. These largely varied pruritus reporting rates may be related to ethnicity, sample size, and recall bias of the retrospective studies. Studies have shown that 2–35% of multiple sclerosis (MS) patients may also experience pruritus [8, 12]. However, the degree of pruritus in MS patients at the first and second episodes is significantly lower than that in NMOSD patients [8], and 27–42% of pruritus in NMOSD patients occurs a few days to weeks before a myelitis episode [13]. Pruritus is rare for other types of myelitis. These results suggest that pruritus is a common and relatively specific manifestation in NMOSD patients and may be an initial symptom in some patients. Therefore, when patients with acute myelitis report pruritus symptoms, NMOSD should be highly suspected clinically, and the sudden occurrence of pruritus during the course of NMOSD should raise suspicion of a relapse.

We used the 5-D itch score to evaluate pruritus in NMOSD patients and found that the majority of patients experienced pruritus for less than 6 hours per day, with moderate to severe intensity. Pruritus was completely relieved in 50% of patients at the time of last follow-up. This finding is similar to those of previous reports in which most patients had episodic pruritus lasting a few minutes to weeks or months[7 14]. However, rare cases of pruritus persisting for a year had been reported [9]. During last follow-up, we found that 50% of our patients still experienced pruritus, with 12.5% reported no relief or worsening, and one patient reported pruritus for up to 5 years. We also observed that pruritus had a relative mild impact on daily life for the majority of patients (94.8%), with only 6.2% reporting a severe impact on daily activities. These findings suggest that pruritus may not be an important factor influencing patients’ quality of life compared with other functional impairments, such as motor dysfunction, visual impairment, bladder and bowel dysfunction, depression, anxiety, and pain. However, further research is needed to determine whether therapeutic intervention is necessary to improve the quality of life for patients with severe and persistent pruritus.

One patient may have had pruritus in multiple areas, and 84% of our patients had pruritus in one or two areas. The most common parts were the neck and upper limbs, followed by the head and chest. MRI-corresponding spinal cord lesions were found in 69% of patients with pruritus, supporting previous findings that the anatomic localization of pruritus does not necessarily correspond to the dermatome distribution of spinal cord lesions[8]. Lesions in the periaqueductal gray matter and trigeminal spinal tract nucleus in the midbrain may be involved in the pruritus mechanism of NMOSD[14], and facial or scalp pruritus in MS patients is related to T2 hyperintense lesions within the anterior pons/ventromedial medulla[12]. In our study, 9 patients with head pruritus, only 1 patient had brainstem lesion, and among 11 patients with upper limb pruritus,6 patients had thoracic spinal cord lesions. The mechanism of pruritus localization still requires further research.

The mechanism of pruritus in NMOSD is not fully understood, and the related risk factors for pruritus have not been reported. To the best of our knowledge, this is the first study to compare the clinical features of patients with NMOSD with and without pruritus. We found that younger age at follow-up, shorter disease duration, cervical spinal cord lesions, and LETM were independent risk factors for pruritus. A study of painful spasms in NMOSD patients revealed that patients with painful spasms tend to be older at onset and are accompanied by pruritus. However, there were no differences in age at follow-up, disease duration, spinal cord lesion location or lesion length[15].The studies of neuropathic pain in NMOSD patients and pruritus in MS patients have also not found any correlation with patient age or disease duration[12, 16]. Further study is needed to confirm whether the results of this study are due to patients with younger and shorter disease durations being more likely to recall various symptoms that occurred after the onset of the disease, thus having less recall bias. Additionally, studies have shown that the spinal dorsal horn neurons are involved in the pruritus mechanism [14, 17], and the MS patients with pruritus showing significantly more T2 high signal lesions in the posterior cervical cord compared to no-pruritus patients[12].These studies support the relevance of cervical spinal cord lesions in the pruritus of NMOSD patients.

Several limitations of our study should be noted. First, this was a single-center study, and selection bias and information bias were inevitable. Second, the assessment of pruritus in patients has a certain degree of subjectivity. Third, the long follow-up duration might cause some recall bias.

Pruritus is a common clinical feature in patients with NMOSD, and it can be the initial symptom in some patients. A short disease course, younger age, cervical cord involvement and longitudinally extensive transverse myelitis are risk factors for NMOSD with pruritus. Pruritus has a minor effect on the quality of life of the majority of NMOSD patients.

Ethics approval and consent to participate

This retrospective study was approved by the Ethics Committee of Hebei Medical University Third Hospital and the methods were carried out in accordance with the approved guidelines. All the patients have been informed before the experiments.(Approval number: 2024-07-03).

Consent for publication

Consent for publication was obtained from the participants.

Competing interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Funding

Not applicable

Author Contribution

RCS participated in the conception and design of the study. YTS performed the analysis and interpretation of data. MF contributed to drafting the article. SQR revised it critically for important intellectual content. XHL is the guarantor for the article who accepts full responsibility for the work and the conduct of the study, had access to the data, and oversaw the decision to publish.

Acknowledgements

Not applicable

Availability of data and materials

The datasets generated/analysed during the current study are available.

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You are reading this latest preprint version

Clinical Characteristics And Risk Factors For Pruritus In Patients With Neuromyelitis Optica Spectrum Disorders

Status:

Version 1

Abstract

Figures

Introduction

Materials and methods

Patient enrollment

Data collection

Statistical analysis

Results

Prevalence and characteristics of pruritus

The location of pruritus

Factors correlated with pruritus in patients with NMOSD

Discussion

Conclusion

Declarations

Competing interests

Funding

Author Contribution

Acknowledgements

Availability of data and materials

References

Additional Declarations

Status:

Version 1