Abstract
Background and purpose
We aimed to characterize hypothalamic involvement in myelin oligodendrocyte glycoprotein antibody‐associated disease (MOGAD) and compare it with neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS).
Methods
A retrospective study was performed to identify hypothalamic lesions in patients diagnosed with MOGAD, NMOSD, or MS from January 2013 to May 2020. The demographic, clinical, and radiological features were recorded. Hypothalamic dysfunction and prognosis were assessed through physical examination, biochemical testing, sleep monitoring, and magnetic resonance imaging.
Results
Hypothalamic lesions were observed in seven of 96 patients (7.3%) with MOGAD, 34 of 536 (6.3%) with NMOSD, and 16 of 356 (4.5%) with MS (p = 0.407). The time from disease onset to development of hypothalamic lesions was shortest in MOGAD (12 months). The frequency of bilateral hypothalamic lesions was the lowest in MOGAD (p = 0.008). The rate of hypothalamic dysfunction in MOGAD was 28.6%, which was lower than that in NMOSD (70.6%) but greater than that in MS patients (18.8%; p = 0.095 and p = 0.349, respectively). Hypothalamic dysfunction in MOGAD manifests as hypothalamic–pituitary–adrenal axis dysfunction and hypersomnia. The proportion of complete regression of hypothalamic lesions in MOGAD (100%) was much greater than that in NMOSD (41.7%) and MS patients (18.2%; p = 0.007 and p = 0.001, respectively). An improvement in hypothalamic dysfunction was observed in all MOGAD patients after immunotherapy.
Conclusions
MOGAD patients have a relatively high incidence of asymptomatic hypothalamic lesions. The overall prognosis of patients with hypothalamic involvement is good in MOGAD, as the lesions completely resolve, and dysfunction improves after immunotherapy.
Keywords: hypothalamus, MRI, multiple sclerosis, myelin oligodendrocyte glycoprotein antibody‐associated disease, neuromyelitis optica
INTRODUCTION
Myelin oligodendrocyte glycoprotein antibody‐associated disease (MOGAD) is an inflammatory demyelinating disease of the central nervous system (CNS) that is distinct from aquaporin‐4 antibody (AQP4‐IgG)‐positive neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) [1, 2]. Myelin oligodendrocyte glycoprotein (MOG) is a CNS‐specific myelin protein that is primarily expressed in the outermost layer of myelin and has high immunogenicity. Emerging evidence suggests that MOG antibodies (MOG‐IgGs) play a direct pathogenic role in MOGAD [1]. Manifestations of MOGAD vary and include relapsing optic neuritis, transverse myelitis, and encephalitis, among others. Recently, newly observed clinical phenotypes such as cerebral cortical encephalitis have also been reported [3], indicating a broader clinical spectrum of this disease entity.
The hypothalamus is a crucial component of human homeostasis and regulates several significant functions. The hypothalamus also serves as a vital interface between the immunological and endocrine systems of the CNS involving the hypothalamic–pituitary–adrenal (HPA) axis and its reactivity to immune system mediators [4]. Previous studies suggest that hypothalamic involvement occurs in 0%–27% of neuromyelitis optica/NMOSD patients [5, 6, 7, 8, 9, 10, 11] and in 5%–13% of individuals with MS [11, 12]. Hypothalamic lesions can cause a range of symptoms, including hypersomnia/narcolepsy, temperature dysregulation, and autonomic and neuroendocrine disorders [13, 14, 15, 16, 17].
Notably, there is scant information regarding the prevalence and specific features of hypothalamic involvement in MOGAD and how it diverges from NMOSD and MS. Furthermore, reports on hypothalamic dysfunction in MOGAD are scarce [18, 19]. Thus, hypothalamic involvement in MOGAD may be underrecognized and inadequately understood.
In this study, we described the demographic, clinical, and radiological features of MOGAD with radiological involvement of the hypothalamus and compared them to those observed in NMOSD and MS patients, with the aim of providing clinicians with valuable knowledge concerning the distinctive features of hypothalamic involvement in patients with MOGAD.
METHODS
Patients and antibody testing
We conducted a retrospective study to identify patients with hypothalamic lesions among those diagnosed with MOGAD, NMOSD, or MS at the Third Affiliated Hospital of Sun Yat‐Sen University from January 2013 to May 2020. We utilized an in‐house, cell‐based assay in live cells transfected with full‐length human MOG to test for serum MOG‐IgG following previously described methods [20]. Serum AQP4‐IgG was detected using an indirect immunofluorescence assay as recommended by the manufacturer (EUROIMMUN, Lübeck, Germany). Cerebrospinal fluid (CSF) samples were collected during acute attacks prior to steroid therapy.
The inclusion criteria for patients were as follows: (i) met the International Consensus Diagnostic Criteria for MOGAD [1, 2], NMOSD [21], or MS [22]; (ii) had available brain magnetic resonance (MR) images for clinical analysis; (iii) had detectable hypothalamic lesions upon radiological examination; and (iv) had complete data. A flowchart illustrating the detailed screening process for MOGAD, NMOSD, and MS patients is presented in Figure S1. Briefly, the formation of the cohort involved initially screening patients from the overall MOGAD, NMOSD, and MS cohorts who had available brain MR images. Subsequently, we individually analysed the brain MR images and selected patients with hypothalamic involvement for inclusion.
Clinical data were acquired via electronic medical records and regular follow‐ups. Hypothalamic dysfunction and patient prognosis were assessed through physical examination, biochemical testing, sleep monitoring (e.g., polysomnography or multiple sleep latency tests), and MR imaging (MRI). Dysfunction of the HPA axis was assessed by measuring abnormalities in the secretion of adrenocorticotropic hormone, cortisol, antidiuretic hormone, prolactin, luteinizing hormone, thyroid hormone, orexins, and others.
The ethics committee of the Third Affiliated Hospital of Sun Yat‐Sen University, Guangzhou, China, approved the study protocol. Because the data were analysed anonymously, written informed consent was not necessary. However, verbal informed consent was obtained from the included patients.
MRI scanning
Initial detection of hypothalamic involvement in patients was primarily achieved through MRI scans conducted during disease onset or relapse. Subsequent MRI follow‐up was carried out to specifically monitor any changes in hypothalamic lesions. For all patients, brain MRI was performed with a 3.0‐T scanner (Discovery MR750; GE Healthcare, Chicago, IL, USA). These scans included axial T1‐weighted imaging (T1WI), T2‐weighted imaging, fluid‐attenuated inversion recovery (FLAIR), contrast‐enhanced axial T1WI, and coronal/sagittal scanning. The slice thickness of the axial scans was 5.0 mm.
Two experienced neuroradiologists who were blinded to the diagnostic categorization and the patients' clinical characteristics independently analysed all the available MR images. The characteristics of the hypothalamic lesions were documented, and the diameter of these lesions was measured on the axial T2‐weighted FLAIR images. The final evaluations were reached through consensus.
Statistical analysis
Quantitative data were analysed using one‐way analysis of variance or pairwise comparison using the least significant difference test (test level a = 0.05). Independent sample rank‐sum tests were applied for data that did not meet the criteria for a normal distribution and homogeneity of variance in group comparisons. Qualitative data were analysed with the χ 2 test or Fisher exact test. The statistical analysis was performed using SPSS version 23.0. A two‐sided p‐value < 0.05 was considered to indicate statistical significance.
RESULTS
Participants
Brain MRI data were available for 96 patients with MOGAD, 536 patients with NMOSD, and 356 patients with MS. Hypothalamic lesions occurred in seven (7.3%), 34 (6.3%), and 16 (4.5%) patients, respectively (p = 0.407). Table 1 summarizes the demographic and clinical features of these patients. The disease course and follow‐up time were comparable among the three groups. Most patients with MOGAD and hypothalamic involvement were female (71.4%). The age at onset of hypothalamic lesions in MOGAD patients was similar to that in patients with NMOSD and MS. Patients with MOGAD had the highest number of relapses and annualized relapse rate but the lowest Expanded Disability Status Scale (EDSS) score at the last follow‐up (p = 0.018).
TABLE 1.
Demographic and clinical characteristics of patients with hypothalamic lesions.
| Characteristic | MOGAD, n = 7 | NMOSD, n = 34 | MS, n = 16 | p | p 1 | p 2 | p 3 |
|---|---|---|---|---|---|---|---|
| Gender, female, n (%) | 5 (71.4%) | 32 (94.1%) | 8 (50%) | 0.002 | 0.551 | 0.751 | 0.001 |
| Age at onset, years [median](range) | 29.4 ± 16.2; [25.0] (9–51) | 34.5 ± 13.3; [34.5] (11–62) | 23.0 ± 11.0; [20.0] (12–57) | 0.008 | 0.687 | >0.999 | 0.006 |
| Age at lesions, years a [median](range) | 30.0 ± 15.7; [27.0] (10–51) | 37.9 ± 13.6; [37.0] (12–62) | 25.0 ± 11.3; [21.5] (13–59) | 0.005 | 0.367 | >0.999 | 0.005 |
| Disease duration, months [median](range) | 63.3 ± 26.5; [59.0] (41–120) | 92.9 ± 59.4; [85.0] (13–264) | 72.2 ± 36.2; [66.0] (21–154) | 0.269 | – | – | – |
| Follow‐up, months [median](range) | 43.7 ± 14.1; [45.0] (26–61) | 64.7 ± 42.6; [66.0] (7–192) | 55.3 ± 31.3; [49.0] (13–142) | 0.292 | – | – | – |
| Relapsing course, n (%) | 5 (71.4%) | 31 (91.2%) | 16 (100%) | 0.083 | – | – | – |
| Relapse number [median](range) | 5.6 ± 4.4; [6.0] (0–11) | 4.2 ± 3.3; [4.0] (0–15) | 3.8 ± 2.3; [3.0] (1–9) | 0.632 | – | – | – |
| Annualized relapse rate [median](range) | 1.0 ± 1.5; [0.9] (0–2.7) | 0.6 ± 0.5; [0.6] (0–2.1) | 0.7 ± 0.4; [0.6] (0.2–1.8) | 0.415 | – | – | – |
| EDSS at last visit [median](range) | 1.1 ± 1.1; [1.0] (0–3) | 3.6 ± 3.0; [2.5] (0–10) | 2.1 ± 1.7; [2.0] (0–7) | 0.018 | 0.025 | 0.543 | 0.320 |
| AQP4‐IgG (+), n (%) | 0 (0%) | 29 (85.3%) | 0 (0%) | <0.001 | <0.001 | >0.999 | <0.001 |
| Concomitant autoantibody, n (%) | 3 (42.9%) | 23 (67.6%) | 4 (25%) | 0.016 | 0.418 | 0.260 | 0.012 |
| Other lesions on MRI, n (%) | |||||||
| Optic nerve | 3 (42.9%) | 23 (67.6%) | 6 (37.5%) | 0.101 | – | – | – |
| Optic chiasm | 2 (28.6%) | 12 (35.3%) | 0 (0%) | 0.025 | 0.924 | 0.083 | 0.005 |
| Thalamus | 6 (85.7%) | 26 (76.5%) | 14 (87.5%) | 0.613 | |||
| Cerebral hemisphere | 6 (85.7%) | 24 (70.6%) | 16 (100%) | 0.046 | 0.723 | 0.304 | 0.013 |
| Medulla oblongata | 5 (71.4%) | 19 (55.9%) | 4 (25.0%) | 0.057 | – | – | – |
| Midbrain/pons | 5 (71.4%) | 25 (73.5%) | 10 (62.5%) | 0.727 | – | – | – |
| Cerebellum | 5 (71.4%) | 6 (17.6%) | 6 (37.5%) | 0.013 | 0.014 | 0.124 | 0.125 |
| Spinal cord | 3 (42.9%) | 25 (73.5%) | 12 (75.0%) | 0.240 | – | – | – |
Note: p: comparison among the three groups, p 1 = MOGAD versus NMOSD, p 2 = MOGAD versus MS, p 3 = MS versus NMOSD.
Abbreviations: AQP4‐IgG, aquaporin 4 antibody; EDSS, Expanded Disability Status Scale; MOGAD, myelin oligodendrocyte glycoprotein antibody‐associated disease; MRI, magnetic resonance imaging; MS, multiple sclerosis; NMOSD, neuromyelitis optica spectrum disorder.
Age at presentation of hypothalamic lesions.
Clinical characteristics of patients with hypothalamic involvement
Hypothalamic symptoms were the first presentation for 14.3% of patients with MOGAD, 11.8% with NMOSD, and 6.3% with MS (p = 0.790). Table 2 compares hypothalamic involvement in patients with MOGAD, NMOSD, and MS. The time from first onset to the development of hypothalamic lesions was shortest for patients with MOGAD, but the difference was not significant (p = 0.165). EDSS scores were lower for patients with MOGAD and MS than for those with NMOSD when hypothalamic lesions were present, but the difference was not significant (p = 0.055). The rate of hypothalamic dysfunction was lower for patients with MOGAD and MS than for those with NMOSD (p = 0.095 and p = 0.002, respectively). Patients with MOGAD and MS tended to have HPA axis dysfunction, whereas those with NMOSD were more likely to have excessive daytime sleepiness or narcolepsy. The use of intravenous methylprednisolone (IVMP) was greater for patients with MOGAD than for those with NMOSD or MS when hypothalamic lesions were present, whereas the use of intravenous immunoglobulin and immunosuppressants was greater for patients with NMOSD than for those with MOGAD or MS. Patients with MOGAD were treated with immunotherapy according to the established guidelines, and hypothalamic lesions were incidentally found in some patients during treatment. In other words, we utilized conventional immunotherapy rather than specific immunotherapy for hypothalamic lesions to treat all seven patients with MOGAD with hypothalamic involvement. Encouragingly, all patients with MOGAD and hypothalamic symptoms improved or completely recovered after immunotherapy.
TABLE 2.
Comparison of hypothalamic involvement in patients with MOGAD, NMOSD, and MS.
| MOGAD, n = 7 | NMOSD, n = 34 | MS, n = 16 | p | p 1 | p 2 | p 3 | |
|---|---|---|---|---|---|---|---|
| First onset to hypothalamic lesions, months [median](range) | 12.0 ± 12.0; [9.0] (0–33) | 43.4 ± 54.7; [27.0] (1–252) | 28.7 ± 24.4; [22.0] (3–90) | 0.165 | – | – | – |
| EDSS, occurrence of hypothalamic lesions [median](range) | 2.9 ± 1.8; [2.0] (1.0–6.5) | 4.0 ± 2.3; [4.0] (0–8.5) | 2.6 ± 1.0; [2.5] (1–4) | 0.055 | – | – | – |
| Hypothalamic dysfunction, n (%) | 2 (28.6%) | 24 (70.6%) | 3 (18.8%) | 0.001 | 0.095 | 0.349 | 0.002 |
| Hypersomnia/narcolepsy | 1 (14.3%) | 18 (52.9%) | 0 (0%) | 0.001 | 0.147 | 0.304 | <0.001 |
| HPA axis impairment a | 1 (14.3%) | 9 (26.5%) | 2 (12.5%) | 0.473 | – | – | – |
| Amenorrhoea/irregular menstruation | 1 (14.3%) | 4 (11.8%) | 1 (6.3%) | 0.790 | – | – | – |
| Obesity | 0 (0%) | 5 (14.7%) | 0 (0%) | 0.157 | – | – | – |
| Temperature dysregulation | 0 (0%) | 4 (11.8%) | 1 (6.3%) | 0.554 | – | – | – |
| SIADH | 0 (0%) | 1 (2.9%) | 0 (0%) | 0.709 | – | – | – |
| Diabetes insipidus | 0 (0%) | 2 (5.9%) | 0 (0%) | 0.496 | – | – | – |
| Bradycardia/hypotension | 0 (0%) | 3 (8.9%) | 1 (6.3%) | 0.700 | – | – | – |
| Cognitive impairment | 0 (0%) | 5 (14.7%) | 0 (0%) | 0.157 | – | – | – |
| MRI features of hypothalamic lesions | |||||||
| Diameter, mm [median](range) | 17.1 ± 5.6; [16.9] (9.8–24.8) | 17.5 ± 5.5; [15.8] (7.2–29.1) | 15.6 ± 4.1; [13.9] (11.7–24.8) | 0.416 | – | – | – |
| Bilateral, n (%) | 5 (71.4%) | 34 (100.0%) | 15 (93.8%) | 0.008 | 0.026 | 0.190 | 0.320 |
| Gadolinium enhancement, n (%) | 0 (0%) | 9 (26.5%) | 0 (0%) | 0.027 | 0.150 | >0.999 | 0.021 |
| Therapy at the time of MRI scans, n (%) | |||||||
| IVMP | 7 (100%) | 30 (88.2%) | 9 (56.3%) | 0.011 | 0.460 | 0.047 | 0.029 |
| IVIg | 1 (14.3%) | 13 (38.2%) | 1 (6.3%) | 0.042 | 0.436 | 0.443 | 0.044 |
| PE or IA | 0 (0%) | 5 (14.7%) | 0 (0%) | 0.157 | – | – | – |
| Immunosuppressive agents | 1 (14.3%) | 28 (82.4%) | 3 (18.8%) | <0.001 | 0.002 | 0.443 | <0.001 |
| Disease‐modifying treatment | 1 (14.3%) | 0 (0%) | 7 (43.8%) | <0.001 | 0.171 | 0.163 | <0.001 |
| Repeated MRI after treatment, n (%) | 7 (100%) | 24 (70.6%) | 11 (68.8%) | 0.238 | – | – | – |
| Exacerbated | 0 (0%) | 2 (8.3%) | 1 (9.1%) | 0.722 | – | – | – |
| Alleviative | 0 (0%) | 11 (45.8%) | 2 (18.2%) | 0.039 | 0.029 | 0.359 | 0.093 |
| Disappeared | 7 (100%) | 10 (41.7%) | 2 (18.2%) | 0.003 | 0.007 | 0.001 | 0.129 |
| Unchanged | 0 (0%) | 0 (0%) | 6 (54.5%) | <0.001 | >0.999 | 0.025 | <0.001 |
| Dilated third ventricle | 5 (71.4%) | 10 (41.7%) | 4 (36.4%) | 0.299 | – | – | – |
Note: p: comparison among the three groups, p 1 = MOGAD versus NMOSD, p 2 = MOGAD versus MS, p 3 = MS versus NMOSD.
Abbreviations: EDSS, Expanded Disability Status Scale; HPA, hypothalamic–pituitary–adrenal axis; IA, immunoadsorption; IVIg, intravenous immunoglobulin; IVMP, intravenous methylprednisolone; MOGAD, myelin oligodendrocyte glycoprotein antibody‐associated disease; MRI, magnetic resonance imaging; MS, multiple sclerosis; NMOSD, neuromyelitis optica spectrum disorder; PE, plasma exchange; SIADH, syndrome of inappropriate antidiuretic hormone secretion.
Disorders of secretion of prolactin, luteinizing hormone, and thyroid hormone.
Radiological characteristics of hypothalamic involvement
The mean (SD) diameter of hypothalamic lesions was 17.1 (5.6) mm for patients with MOGAD. Bilateral hypothalamic lesions occurred less frequently in patients with MOGAD than in those with NMOSD or MS (p = 0.026 and p = 0.190, respectively). None of the hypothalamic lesions in patients with MOGAD showed gadolinium enhancement. The time interval between MRI scans in MOGAD patients did not significantly differ from that of NMOSD and MS patients (p = 0.270 and p > 0.999, respectively). Hypothalamic lesions resolved completely after treatment in patients with MOGAD more often than in those with NMOSD or MS (p = 0.007 and p = 0.001, respectively). Hypothalamic lesions remained unchanged more often for patients with MS than for those with MOGAD or NMOSD (p = 0.025 and p < 0.001, respectively).
Characteristics of patients with MOGAD and hypothalamic involvement
Table 3 presents the information of seven patients with MOGAD and hypothalamic involvement. The mean (SD) age at hypothalamic lesion onset was 30.0 (15.7) years. Most patients had a MOG‐IgG titre of 1:100 or higher. Only one patient had a hypothalamic lesion at the first episode. Although some patients had an EDSS score > 3 for hypothalamic lesions, most patients had a good prognosis. Figure 1 summarizes a representative case of MOGAD with a typical hypothalamic lesion on MRI. Figure 2 shows the radiological features of hypothalamic lesions before and after immunotherapy in the other six patients with MOGAD. The size and pattern of the lesions varied among patients. Serial MRI showed reversible changes in the hypothalamus and enlargement of the third ventricle.
TABLE 3.
MOGAD patients with hypothalamic involvement.
| Patient | Sex | Age, years a | MOG‐IgG titer a | First onset to hypothalamic lesions, months | Hypothalamic dysfunction | EDSS a | EDSS at last visit |
|---|---|---|---|---|---|---|---|
| 1 | F | 10 | 1:640 | 20 | N | 1 | 1 |
| 2 | F | 29 | 1:100 | 3 | Y | 2 | 0 |
| 3 | M | 51 | 1:32 | 9 | N | 2 | 1 |
| 4 | F | 17 | 1:32 | 17 | N | 2 | 2 |
| 5 | M | 27 | 1:640 | 33 | N | 3 | 3 |
| 6 | F | 51 | 1:100 | 2 | N | 6.5 | 1 |
| 7 | F | 25 | 1:320 | 0 | Y | 3.5 | 0 |
Abbreviations: EDSS, Expanded Disability Status Scale; F, female; M, male; MOGAD, myelin oligodendrocyte glycoprotein antibody‐associated disease; MOG‐IgG, MOG antibody; N, no; Y, yes.
At presentation of hypothalamic lesions.
FIGURE 1.
A representative case of myelin oligodendrocyte glycoprotein antibody‐associated disease with a typical hypothalamic lesion. FLAIR, fluid‐attenuated inversion recovery; fs, fat suppression; Gd, gadolinium; IVMP, intravenous methylprednisolone; MOG‐IgG, MOG antibody; MP, methylprednisolone; T1w, T1‐weighted; T2w, T2‐weighted.
FIGURE 2.
Representative brain lesions in the other six myelin oligodendrocyte glycoprotein antibody‐associated disease patients observed via axial T2 fluid‐attenuated inversion recovery magnetic resonance imaging. The first row shows hypothalamic lesions before immunotherapy. After immunotherapy, hypothalamic lesions completely regressed.
DISCUSSION
MOGAD is an inflammatory demyelinating disease of the CNS with distinct clinical, radiological, and pathological features, but it shares some similarities with NMOSD and MS. Hypothalamic dysfunction has been reported in NMOSD and MS patients. However, hypothalamic involvement in MOGAD patients has received little attention. Our study is one of the first to specifically compare hypothalamic involvement in patients with MOGAD, NMOSD, and MS, and the results were as follows: (i) MOGAD patients had the highest frequency of hypothalamic lesions but a lower percentage of hypothalamic dysfunction, (ii) MOGAD patients had the shortest interval between disease onset and hypothalamic lesion development, (iii) MOGAD with hypothalamic lesions was associated with HPA axis dysfunction and hypersomnia, and (iv) MOGAD patients showed complete resolution of hypothalamic lesions and improvement of dysfunction after immunotherapy.
Hypothalamic lesions in patients with MOGAD have been poorly studied. Previous articles that reported hypothalamic lesions in MOGAD patients were mostly reviews or small cohorts that summarized the radiological characteristics of MOGAD [23, 24, 25, 26, 27] and did not provide detailed information on the frequency, pathophysiology, or treatment of hypothalamic lesions. Only two recent case reports have described MOGAD patients with hypersomnia caused by hypothalamic lesions [18, 19] and a reduced CSF orexin (hypocretin) level [19].
We found that 7.3% of patients with MOGAD had hypothalamic lesions, a greater percentage than in NMOSD and MS patients, indicating that hypothalamic lesions are not rare in MOGAD. The interval between disease onset and hypothalamic lesion development in MOGAD patients was only 12 months, suggesting that MOGAD patients should be monitored closely for hypothalamic involvement after the first attack.
Notably, hypothalamic involvement in NMOSD can precede the development of other symptoms and diagnosis by several years. Patients who experienced hypothalamic involvement at an early stage without undergoing imaging at that time were not included in our study.
We detected hypothalamic involvement on brain MR images in seven patients with MOGAD, one of whom exhibited hypothalamic symptoms at disease onset. These symptoms included hypersomnia and abnormal secretion of luteinizing hormone, both of which are attributed to the hypothalamus. Additionally, this patient presented with visual impairment, dizziness, and headache. However, our speculation is that these symptoms may be indicative of a multifocal acute disseminated encephalomyelitis‐type illness. It is crucial to gather additional clinical data to further substantiate our hypothesis. In addition to the previously reported hypersomnia [18, 19], we also observed HPA axis dysfunction, including irregular menstruation and abnormal luteinizing hormone production, which has not been described before. Therefore, MOGAD patients should be aware of the potential for hypothalamic lesions if they have any of these clinical symptoms.
No cases of hypothalamic relapse were detected in patients with MOGAD or MS in this study. However, six patients with NMOSD exhibited either clinical symptoms or imaging relapse specifically attributed to the hypothalamus, which was accompanied by other typical clinical core symptoms. These observations indicate that involvement of the hypothalamus (whether clinically or radiologically) may be considered part of a more conventional pattern of relapse in NMOSD. Similar findings have also been reported in previous studies [28, 29, 30].
The diameter of hypothalamic lesions in MOGAD patients was similar to that in patients with NMOSD and MS, but the frequency of bilateral hypothalamic lesions was the lowest. Some patients had only unilateral hypothalamic involvement, which may explain the milder hypothalamic symptoms in MOGAD patients. In our case series, a greater percentage of MOGAD patients than NMOSD and MS patients received IVMP for treatment of hypothalamic lesions. In our study and previous case reports, immunotherapy, such as IVMP [18, 19] or plasma exchange [19], resulted in neurological recovery and hypothalamic lesion resolution, suggesting a generally favourable outcome of hypothalamic involvement in MOGAD.
All seven MOGAD patients in our study had enlarged third ventricles after immunotherapy, indicating possible hypothalamic atrophy in later stages. We suggest exercising caution in attributing the enlargement of the third ventricle to acute oedema in MOGAD, as our study revealed that this enlargement often occurred during the remission period following treatment. In a previous case report of NMOSD patients with hypothalamic lesions and dysfunction, the author observed the potential progression of hypothalamic lesions to hypothalamic atrophy after regression with concurrent dilation of the third ventricle, which may be attributed to both hypothalamic and thalamic atrophy [16]. Thus, it is plausible to propose a potential association between third ventricle enlargement in MOGAD patients and hypothalamic atrophy to a certain extent, indicating severe involvement of the hypothalamus. A previous study suggested that atrophy of the anterior hypothalamus and superior tubular subunit may worsen the prognosis of relapsing–remitting MS patients by impairing the HPA axis response in MS patients [31]. However, whether hypothalamic atrophy has a similar effect on the prognosis of MOGAD patients remains unclear.
We observed that a substantial percentage of patients with hypothalamic lesions did not have hypothalamic dysfunction in our study or in previous studies [8, 12]. A previous study suggested that CSF hypocretin (orexin) levels can be used to monitor hypothalamic dysfunction in MOGAD patients [19]. Hypocretin (orexin) is a neuropeptide produced by a small group of neurons in the lateral hypothalamus that regulates various functions, such as sleep, arousal, feeding, energy homeostasis, stress, and reward [32, 33, 34]. Hypocretin (orexin) neurons also interact with other neurotransmitter systems, such as dopamine, serotonin, and acetylcholine systems [35]. Prior animal research has shown that achieving a 50% reduction in CSF hypocretin‐1 requires the destruction of 73% of hypocretin (orexin) neurons [36]. Moreover, Wang and colleagues suggested that the paraventricular nucleus of the hypothalamus may play an essential role in the development of hypersomnia in MOGAD patients [18]. This implies that the involvement of multiple hypothalamic domains or damage to specific nuclei in the hypothalamus is required for overt hypothalamic dysfunction. Selective loss of hypocretin (orexin) neurons, disordered hypocretin (orexin) neurotransmission, and abnormal HPA axis activity may be potential mechanisms of hypothalamic dysfunction in MOGAD patients. Notably, the hypothalamus is not a region with high MOG expression, and further elucidation of the immunologic mechanisms that cause hypothalamic dysfunction in patients with hypocretin (orexin) deficiency and their association with MOGAD is needed.
Our study has several limitations. First, bias was inevitable because of the small sample size, single‐centre cohort and retrospective design. Second, patients who did not have brain MRI data were excluded, which might have affected the estimation of the frequency of hypothalamic lesions. Third, hypothalamic dysfunction was mainly determined by patient or physician reports, which might have led to missed or delayed diagnoses. Fourth, our study revealed that a significant proportion of MOGAD patients experienced a relapsing course and MRI‐confirmed brainstem involvement. This may be related to the majority of patients who sought treatment at our centre being individuals with challenging or severe conditions. We acknowledge that this may introduce potential biases in our findings. However, our findings add to the limited existing data on hypothalamic involvement in MOGAD patients, as we conducted the first comparative study of patients with hypothalamic lesions, including the frequency, clinical symptoms, MRI findings, and treatment. Future prospective studies with larger sample sizes and regular long‐term surveillance are needed to fully understand the spectrum of hypothalamic involvement in MOGAD patients.
CONCLUSIONS
Hypothalamic involvement in patients with MOGAD differs from that in patients with NMOSD and MS. MOGAD patients have a relatively high incidence of hypothalamic lesions, which are usually asymptomatic. After immunotherapy, the lesions resolve completely, and dysfunction improves.
AUTHOR CONTRIBUTIONS
Wei Qiu: Project administration; funding acquisition; conceptualization; writing – review and editing; supervision. Wenjing Luo: Methodology; formal analysis; funding acquisition; visualization; project administration; writing – original draft. Xiaonan Zhong: Methodology; investigation; visualization; formal analysis. Shishi Shen: Formal analysis; methodology; writing – original draft; visualization. Ling Fang: Investigation; methodology; visualization. Yiying Huang: Methodology; investigation; visualization. Yuge Wang: Investigation; methodology; visualization.
FUNDING INFORMATION
This work was supported by grants from the National Natural Science Foundation of China (Nos. 81971140, 82301525) and Guangxi Science and Technology Base and Talent Special Project (No. AD23026150).
CONFLICT OF INTEREST STATEMENT
The authors report no competing interests.
Supporting information
Figure S1.
ACKNOWLEDGEMENTS
The authors would like to thank Yi Du from the First Affiliated Hospital of Guangxi Medical University for his valuable support.
Luo W, Zhong X, Shen S, et al. A comparative study of hypothalamic involvement in patients with myelin oligodendrocyte glycoprotein antibody‐associated disease, neuromyelitis optica spectrum disorder, and multiple sclerosis. Eur J Neurol. 2024;31:e16377. doi: 10.1111/ene.16377
Wenjing Luo, Xiaonan Zhong, and Shishi Shen contributed equally to this work.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.