Characteristics of hypersomnia due to inflammatory demyelinating diseases of the central nervous system

Abstract

Background: Neuromyelitis optica spectrum disorder (NMOSD) diagnostic criteria for inflammatory demyelinating central nervous system diseases included symptomatic narcolepsy; however, no relevant case-control studies exist. We aimed to examine the relationship among cerebrospinal fluid orexin-A (CSF-OX) levels, cataplexy and diencephalic syndrome; determine risk factors for low-and-intermediate CSF-OX levels (≤200 pg/mL) and quantify hypothalamic intensity using MRI.

Methods: This ancillary retrospective case-control study included 50 patients with hypersomnia and 68 controls (among 3000 patients) from Akita University, the University of Tsukuba and community hospitals (200 facilities). Outcomes were CSF-OX level and MRI hypothalamus-to-caudate-nucleus-intensity ratio. Risk factors were age, sex, hypersomnolence and MRI hypothalamus-to-caudate-nucleus-intensity ratio >130%. Logistic regression was performed for the association between the risk factors and CSF-OX levels ≤200 pg/mL.

Results: The hypersomnia group (n=50) had significantly more cases of NMOSD (p<0.001), diencephalic syndrome (p=0.006), corticosteroid use (p=0.011), hypothalamic lesions (p<0.023) and early treatment (p<0.001). No cataplexy occurred. In the hypersomnia group, the median CSF-OX level was 160.5 (IQR 108.4-236.5) pg/mL and median MRI hypothalamus-to-caudate-nucleus-intensity ratio was 127.6% (IQR 115.3-149.1). Significant risk factors were hypersomnolence (adjusted OR (AOR) 6.95; 95% CI 2.64 to 18.29; p<0.001) and MRI hypothalamus-to-caudate-nucleus-intensity ratio >130% (AOR 6.33; 95% CI 1.18 to 34.09; p=0.032). The latter was less sensitive in predicting CSF-OX levels ≤200 pg/mL. Cases with MRI hypothalamus-to-caudate-nucleus-intensity ratio >130% had a higher rate of diencephalic syndrome (p<0.001, V=0.59).

Conclusions: Considering orexin as reflected by CSF-OX levels and MRI hypothalamus-to-caudate-nucleus-intensity ratio may help diagnose hypersomnia with diencephalic syndrome.

Keywords: CSF; MRI; multiple sclerosis; sleep disorders.

Figure 1

Definition of the MRI hypothalamus-to-caudate-nucleus-intensity ratio. (A) Procedure for measuring the intensity levels. The Fiji screen is shown. The numbers indicate the steps. (1) Opening image files (File>Import>Image Sequence). (2) Processing the image before analysis: convert to 8-bit grayscale (Image>Type>8-bit). (3) Setting measurement items: select the mean gray value (Analyse>Set Measurements>Mean gray value (Mean)). (4) Designating and measuring the region of interest (ROI): select the segmented line (Area Selection Tools>Straight Line Selection Tool>Segmented Line) and view ROI manager (Analyse>Tools>ROI Manager). (5) Identifying and measuring the hypothalamus and caudate nucleus visually and manually, with the image enlarged to facilitate identification (Add>Measure). (6) Checking and saving the results. Permission was obtained for the images. (B) We defined the MRI hypothalamus-to-caudate-nucleus-intensity (MRI H/C) ratio (%) as the intensity level of the bilateral hypothalamus relative to that of the bilateral caudate nucleus. Quantification of the intensity levels was performed using the image analysis software Fiji. Data were processed via 8-bit grayscale conversion without segmentation and filtering. Identification and measurement of the hypothalamus and caudate nucleus were performed visually and manually by enlarging the images. The ROI was required to be set at an appropriate distance from the cerebrospinal fluid site to avoid interference of choroid plexus and cerebrospinal fluid artefacts. Anatomography was used to illustrate the location of the hypothalamus and caudate nucleus.

Figure 2

Violin plots of cerebrospinal fluid orexin-A (CSF-OX) levels of 118 patients with inflammatory demyelinating diseases of the central nervous system. The y-axis indicates the CSF-OX (hypocretin-1) levels. The dots indicate patients’ CSF-OX data. The thick lines indicate the medians, and the thin lines indicate the IQRs. The limit of detection for CSF-OX levels is 40 pg/mL. The median (IQR) CSF-OX level was 160.5 (108.4–236.5) pg/mL for the hypersomnia group and 282.3 (216.3–371.7) pg/mL for the control group. The Mann-Whitney U test revealed a significant difference between the two groups (p<0.001).

Figure 3

Correlation between the MRI hypothalamus-to-caudate-nucleus-intensity ratios and cerebrospinal fluid orexin-A (CSF-OX) levels. (A) Correlogram with dots representing individual cases projected by the MRI hypothalamus-to-caudate-nucleus-intensity (MRI H/C) ratios (x-axis) and the CSF-OX (hypocretin-1) levels (y-axis). Filled dots indicate the hypersomnia group; unfilled dots indicate the control group. The MRI H/C ratio is a quantified index of hypothalamic intensity data based on the caudate nucleus (figure 1). A significant negative correlation was observed between the MRI H/C ratio and CSF-OX levels (ρ=−0.42, p<0.001). Asterisks indicate cases with representative brain MRI data (a, control; b–f, hypersomnia). (B) Representative T2-weighted fluid-attenuated inversion recovery MRI of the brain in patients from two MRI H/C ratio categories and three CSF-OX level categories: MRI H/C ratio >130%, MRI H/C ratio ≤130%, low CSF-OX level (≤110 pg/mL), intermediate CSF-OX level (>110 to <200 pg/mL) and normal CSF-OX level (>200 pg/mL). a, Multiple sclerosis (MS), CSF-OX level 238.1 pg/mL, and MRI H/C ratio 115.0%. b, Neuromyelitis optica spectrum disorder (NMOSD), CSF-OX level 345.0 pg/mL, and MRI H/C ratio 147.8%. c, Acute disseminated encephalomyelitis, CSF-OX level 177.0 pg/mL and MRI H/C ratio 121.4%. d, MS, CSF-OX level 152.0 pg/mL and MRI H/C ratio 166.2%. e, NMOSD, CSF-OX level 20.9 pg/mL and MRI H/C ratio 122.6%. f, Myelin oligodendrocyte glycoprotein-antibody-associated disease, CSF-OX level 75.0 pg/mL and MRI H/C ratio 206.5%. Permission was obtained for all the images.

Figure 4

Violin plots of cerebrospinal fluid orexin-A (CSF-OX) levels by diagnosis for 50 patients with hypersomnia and 68 control patients with inflammatory demyelinating diseases of the central nervous system. Panels A and B show the results for the hypersomnia and control groups, respectively. The x-axis indicates diagnosis of inflammatory demyelinating diseases of the central nervous system, and the y-axis indicates CSF-OX (hypocretin-1) levels. Dots indicate patients’ CSF-OX data. The thick lines indicate the medians and the thin lines indicate the IQRs. The limit for detecting CSF-OX levels was defined as 40 pg/mL. Unclassifiable inflammatory demyelinating diseases of the central nervous system: autoantibody (eg, against aquaporin-4 or myelin oligodendrocyte glycoprotein) status was negative or untested, but the differential diagnosis could be excluded. The median (IQR) CSF-OX levels in the hypersomnia group were 157.0 (115.6–191.5) pg/mL for NMOSD, 81.0 (77.5–194.5) pg/mL for MOGAD, 265.0 (124.0–311.1) pg/mL for MS, 191.0 (174.8–295.8) pg/mL for ADEM and 57.5 (40.0–NA) pg/mL for unclassifiable IDDCNS. Differences in the CSF-OX levels between the five hypersomnia groups were compared using the Kruskal-Wallis H test and were found to be significant (p=0.033), but Bonferroni correction showed no difference by diagnosis. ADEM, acute disseminated encephalomyelitis; MOGAD, myelin oligodendrocyte glycoprotein-antibody-associated disease; MS, multiple sclerosis; NMOSD, neuromyelitis optica spectrum disorders.