Dysphagia in neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein antibody disease as a surrogate of brain involvement?
Abstract
Background and purpose
Neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD) are demyelinating disorders that typically affect the optic nerves and the spinal cord. However, recent studies have demonstrated various forms of brain involvement indicating encephalitic syndromes, which consequently are included in the diagnostic criteria for both. Swallowing is processed in a distributed brain network and is therefore disturbed in many neurological diseases. The aim of this study was to investigate the occurrence of oropharyngeal dysphagia in NMOSD and MOGAD using flexible endoscopic evaluation of swallowing (FEES) as a surrogate parameter of brain involvement.
Methods
Thirteen patients with NMOSD and MOGAD (mean age 54.2 ± 18.6 years, six men) who received FEES during clinical routine were retrospectively reviewed. Their extent of oropharyngeal dysphagia was rated using an ordinal dysphagia severity scale. FEES results were compared to a control group of healthy individuals. Dysphagia severity was correlated with the presence of clinical and radiological signs of brain involvement, the Expanded Disability Status Scale (EDSS) and the occurrence of pneumonia.
Results
Oropharyngeal dysphagia was present in 8/13 patients, including six patients without other clinical indication of brain involvement. Clinical or subclinical swallowing impairment was significantly more severe in patients with NMOSD and MOGAD compared to the healthy individuals (p = 0.009) and correlated with clinical signs of brain involvement (p = 0.038), higher EDSS (p = 0.006) and pneumonia (p = 0.038).
Conclusion
Oropharyngeal dysphagia can occur in NMOSD and MOGAD and might be associated with pneumonia and disability. FEES may help to detect subclinical brain involvement.
INTRODUCTION
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune, demyelinating disease spectrum of the central nervous system, predominantly affecting the optic nerves and spinal cord. Myelin oligodendrocyte glycoprotein (MOG) antibody disease (MOGAD) has recently been proposed as a distinct disease entity that shares many clinical features with NMOSD and multiple sclerosis [1] but is considered to differ in some key immunopathogenic aspects [2]. Against this background, international recommendations on diagnosis and antibody testing have been published which help to distinguish MOGAD from other neuroimmunological diseases [3]. In recent years, several studies have drawn attention to brain involvement in both diseases [4-6], resulting in the inclusion of area postrema syndrome, symptomatic narcolepsy, acute diencephalic clinical syndrome, symptomatic cerebral syndrome and acute brainstem syndrome in the diagnosis criteria of NMOSD [7]. The latter two syndromes, which indicate encephalitis, are also used as clinical criteria for MOGAD [3]. Due to the potentially recurrent nature of both diseases, early diagnosis and appropriate treatment are generally considered important, although clear treatment regimes for MOGAD are still lacking and are part of a scientific debate [3, 8, 9]. However, especially in aquaporin-4-negative cases the diagnosis may be challenging because of the necessity of two clinical core symptoms and additional radiological lesions. The latter, however, are not easily detectable by conventional imaging techniques [10]. Irrespective of the underlying disease, oropharyngeal dysphagia is highly prevalent in disorders featuring cerebral lesions and, in particular, brainstem involvement[11]. It is therefore not surprising that dysphagia can be a clinical hallmark of NMOSD [12] and MOGAD [5]. In fact, it has even been described as a leading symptom in individual cases [13]. Since dysphagia symptoms are not necessarily perceived by patients, instrumental diagnostics, for example flexible endoscopic evaluation of swallowing (FEES), are mandatory to objectively assess the safety and efficiency of swallowing.
The aim of this study was therefore to investigate the occurrence of oropharyngeal dysphagia in NMOSD and MOGAD and to examine whether FEES could be useful as a surrogate marker of brain involvement.
METHODS
Study cohort
This retrospective pilot study included both patients with NMOSD according to the International Panel for Neuromyelitis Optica Diagnosis criteria [7] and MOGAD cases [3] who had received a FEES between January 2015 and August 2020 at the University Hospital Muenster, Germany. As part of the structured dysphagia screening, all patients with NMOSD and MOGAD were offered FEES diagnostics, regardless of whether swallowing complaints existed or not. Thirteen consecutive patients were included. Patients were excluded if they had dysphagia due to another diagnosed disease. As a control group, all FEES videos available in our clinic on healthy subjects (control participants from previous studies) were pooled (n = 101). This pool of videos was divided into subjects over 50 and under 50 years. For each NMOSD or MOGAD patient over 50 years, two healthy subjects over 50 years were randomly selected. For patients under 50 years of age the same procedure was applied. The study design was approved by the local ethics committee (2016-391-f-S).
Data collection
The FEES examination was performed by a speech-language therapist together with a trained neurologist. Three swallowing trials were performed with the following consistencies in the given order: 8 ml of semisolid pudding, 5 ml of blue dyed liquid and approximately 3 × 3 × 0.5 cm solid white bread. The following clinical parameters were determined for every patient: age at FEES, sex, core clinical symptoms, Expanded Disability Status Scale (EDSS), presence of antibodies, signs for magnetic resonance imaging (MRI) brain involvement, signs of clinical brain involvement (area postrema, other brainstem, diencephalic or cerebral presentations), prevalence of dysphagia, history of pneumonia and the Functional Oral Intake Scale [14].
Assessment of FEES videos
All patients were classified on the following ordinal dysphagia severity scale: 0, no signs of dysphagia; 1, mild dysphagia without penetration or aspiration but premature bolus spillage at least into the piriform sinus in at least two out of three swallows of at least one consistency or/and pharyngeal residue greater than coating in at least two out of three swallows of at least one consistency; 2, moderate dysphagia with penetration or aspiration of at least one consistency; 3, severe dysphagia with penetration or aspiration of more than one consistency.
Statistical analysis
Metric data are presented as mean ± standard deviation and ordinal or nominal data as frequencies.
The ordinal dysphagia severity scale was compared with a Mann–Whitney U test between the patients and the healthy subjects. Dysphagia severity in the patient group was correlated with clinical signs of brain involvement, MRI signs of brain involvement and pneumonia using the Fisher’s exact test (two-sided). Also, dysphagia severity was correlated with the EDSS using the Spearman correlation coefficient (one-sided). Further, age was compared between patients and control subjects using an independent sample t test and sex distribution using a chi-squared test.
RESULTS
Overall, 8/13 of NMOSD and MOGAD patients showed signs of oropharyngeal dysphagia, with three patients showing clinically relevant moderate or severe dysphagia with penetrations and aspirations resulting in food limitation; two of them required tube feeding and had a history of pneumonia. Moderate and severe dysphagia was symptomatic in 2/3 patients, while slight swallowing abnormalities without penetrations and aspirations were always asymptomatic. Table 1 summarizes the clinical data and dysphagia characteristics of the patients. Table 2 shows the results of the comparison of the patients with healthy subjects. Dysphagia severity was associated with clinical signs of brain involvement (p = 0.038) but not with MRI signs of brain involvement (p = 0.845). Further, dysphagia was associated with a higher EDSS (Spearman's ρ = 0.68; p = 0.006) and with pneumonia (p = 0.038).
| Age, sex and disease | Clinical characteristics (core symptom, EDSS and antibody status) | MRI findings | Clinical brain involvement | Dysphagia characteristics (severity, perception, pneumonia history, oral intake) |
|---|---|---|---|---|
| 61 years; female; NMOSD |
Core symptom: optic neuritis and acute myelitis EDSS 6.5 Antibody AQ4 (1:640) |
|
No |
Severity: 1, mild, residue without penetration or aspiration Perception: no symptoms Pneumonia history: no FOIS 7 |
| 78 years; male; NMOSD |
Core symptom: acute myelitis EDSS 8.0 Antibody AQ4 (1:160) |
|
No |
Severity: 1, mild, residue without penetration or aspiration Perception: no symptoms Pneumonia history: no FOIS 6 |
| 60 years; male; MOGAD |
Core symptom: optic neuritis EDSS 1.5 Antibody MOG (1:320) |
|
No |
Severity: 1, mild, residue without penetration or aspiration Perception: no symptoms FOIS 7 |
| 35 years; male; MOGAD |
Core symptom: acute myelitis EDSS 2.0 Antibody MOG (1:1000) |
|
No |
Severity: 0, no dysphagia Pneumonia history: no FOIS 7 |
| 30 years; female; MOGAD |
Core symptom: optic neuritis EDSS 0 Antibody MOG (1:320) |
|
No |
Severity: 0, no dysphagia Pneumonia history: no FOIS 7 |
| 34 years; female; NMOSD |
Core symptom: acute brainstem syndrome and acute myelitis EDSS 8.0 Antibody: no antibody |
|
Yes: oculomotor dysfunction, anarthria |
Severity: 2, moderate, penetration/aspiration of one consistency Perception: symptomatic Pneumonia history: yes FOIS 2 |
| 46 years, male; MOGAD |
Core symptom: optic neuritis and acute myelitis EDSS 8.0 Antibody MOG (1:320) |
|
No |
Severity: 0, no dysphagia Pneumonia history: no FOIS 7 |
| 66 years; female; NMOSD |
Core symptom: optic neuritis EDSS 2.0 Antibody AQ4 (1:160) |
|
No |
Severity: 0, no dysphagia Pneumonia history: no FOIS 7 |
| 80 years; male; NMOSD |
Core symptom: acute myelitis EDSS 7.0 Antibody AQ4 (1:160) |
|
No |
Severity: 1, mild, residue without penetration or aspiration Perception: no symptoms Pneumonia history: no FOIS 7 |
| 35 years; female; NMOSD |
Core symptom: optic neuritis and acute myelitis EDSS 8.5 Antibody AQ4 (1:320) |
|
Yes: oculomotor dysfunction |
Severity: 3, severe, penetration/aspiration of multiple consistencies Perception: symptomatic Pneumonia history: yes FOIS 1 |
| 49 years; male; NMOSD |
Core symptom: acute myelitis and optic neuritis EDSS 8.5 Antibody: no antibody |
|
No |
Severity: 2, moderate, penetration/aspiration of one consistency Perception: no symptoms Pneumonia history: no FOIS 7 |
| 48 years; female; MOGAD |
Core symptom: acute myelitis and optic neuritis EDSS 5.0 Antibody MOG (1:320) |
|
No |
Severity: 1, mild, residue without penetration or aspiration Perception: no symptoms Pneumonia history: no FOIS 7 |
| 83 years; female; NMOSD |
Core symptom: acute myelitis EDSS 5.0 Antibody AQ4 (1:640) |
|
No |
Severity: 0, no dysphagia Pneumonia history: no FOIS 7 |
Note
- Clinical brain involvement is defined as area postrema, other brainstem, diencephalic or cerebral presentations.
- For serum AQ4- and MOG-IgG testing, a fixed cell-based assay (Euroimmun, Luebeck, Germany) was used at the time of diagnosis of NMOSD or MOGAD exactly according to the manufacturer’s instructions. In the case of seropositivity, titres are given in parentheses. ‘No brain lesion’ is defined as the absence of visible structural damage to the cerebral parenchyma with exclusion to abnormalities in the afferent visual system (optic nerve, optic tract and optic chiasm).
- Abbreviations: AQ4, aquaporin-4; EDSS: Expanded Disability Status Scale; FOIS, Functional Oral Intake Scale; Gd, gadolinium; MOG, myelin oligodendrocyte glycoprotein; MOGAD, myelin oligodendrocyte glycoprotein antibody disease; MRI, magnetic resonance imaging; NMOSD, neuromyelitis optica spectrum disorder.
| NMOSD/MOGAD patients | Control subjects | p value | |
|---|---|---|---|
| Age in years, mean ± SD | 54.2 ± 18.6 | 52.5 ± 25.0 | 0.823 |
| Men, n | 6/13 | 11/26 | 0.819 |
| Dysphagia, n | |||
| No dysphagia | 5/13 | 20/26 | *0.009 |
| Mild | 5/13 | 6/26 | |
| Moderate | 2/13 | 0/26 | |
| Severe | 1/13 | 0/26 | |
- Abbreviations: MOGAD, myelin oligodendrocyte glycoprotein antibody disease; NMOSD, neuromyelitis optica spectrum disorder.
DISCUSSION
The main finding of this study is that dysphagia may occur in both NMOSD and MOGAD patients, even if the patients do not perceive swallowing impairment. Interestingly, swallowing abnormalities also occurred in six patients who had no other clinical evidence of brain involvement. This, in combination with the association of dysphagia severity with clinical brain involvement, suggests that swallowing impairment assessed with FEES could possibly be used as a surrogate parameter of brain involvement in patients with NMOSD and MOGAD. Such an approach would be of clinical importance, as brain lesions occur in more than half of the cases in both aquaporin-4-positive and MOG-positive patients [15, 16], which also applied for our patient cohort. However, in some patients with cerebral MRI lesions there is no clinical correlate of brain involvement [15]. Brain involvement as a clinical core criterion in both diseases appears to be heterogeneous and includes different forms of encephalitic syndromes such as brainstem involvement. Considering that dysphagia is often not noticed by patients, FEES in this context may possibly show subclinical impairment of swallowing function.
The association of dysphagia severity with pneumonia suggests that swallowing impairment in this patient group may contribute to morbidity. This corroborates the results from several studies of other forms of neurogenic dysphagia, for example stroke, Parkinson's disease and neuromuscular disorders. Finally, the positive correlation of dysphagia severity with EDSS indicates that dysphagia might be associated with a higher disability in advanced disease stages, similarly to the association of dysphagia with increased EDSS in patients with multiple sclerosis [17].
As a decisive limitation, it must be taken into account that mild abnormalities of swallowing function can also occur in healthy individuals—especially at an advanced age. Therefore, well-validated and age-adjusted diagnostic criteria would be mandatory in order to differentiate between normal and abnormal swallowing function when using FEES as a surrogate parameter of brain involvement in the future. Based on this pilot study, only moderate dysphagia with penetration or aspiration seems to reliably indicate brain involvement, as it did not occur in the control group. Further limitations are the retrospective design as a source of selection bias in combination with the small sample size and the mixed cohort of NMOSD and MOGAD patients. Therefore, all results of this pilot study should be considered explorative. Future prospective studies are necessary to confirm the results.
ACKNOWLEDGEMENTS
There was no funding for this study. Open Access funding enabled and organized by Projekt DEAL.
CONFLICT OF INTEREST
All authors declare no conflict of interest regarding the content of the paper.
Open Research
DATA AVAILABILITY STATEMENT
The data supporting the results of this study are all listed in the paper.
