Larger Hypothalamic Volume Seen in Narcolepsy Type 1 After H1N1 Infection

Patients with post-H1N1 narcolepsy type 1 (NT1), compared with control individuals, had larger hypothalamic volume, particularly in the tubular-inferior subregions. This could be indicative of neuroinflammation, gliosis, and/or changes in the numbers of different cell types among patients with NT1. These are the findings of a study published in the journal Sleep.

NT1 is a neurologic sleep disorder characterized by excessive daytime sleepiness and cataplexy. These symptoms have been linked to a deficiency in hypocretin and potentially to higher numbers of histaminergic neurons in the tuberomammillary nucleus of the hypothalamus. For the study, researchers used a fully automated tool for segmentation of the hypothalamus into 10 subregions to examine structural differences in the hypothalamus between patients with NT1 and healthy control individuals.

Patients with HLA-DQB1*06:02-positive NT1 were included in the study. Matched control individuals were included from ongoing studies coordinated by the Norwegian Centre for Mental Disorders Research (NORMENT), with the same magnetic resonance imaging (MRI) scanning protocol as patients with NT1. MRI imaging and polysomnography recordings were evaluated, with group differences calculated for the extracted volume measures for the whole hypothalamus, the left/right part of the hypothalamus, and 10 subregions of the hypothalamus. Age, sex, and standardized intracranial volume (ICV) were included in the model and a stepwise Bonferroni correction was performed.

A total of 54 patients with NT1 (women, n=39; mean age, 21.8±11.0) and 114 matched control individuals (women, n=77; mean age, 23.2±9.0) were included in the study. Permutation testing with models including age, sex, and ICV found larger hypothalamus volume among patients with NT1 compared with controls for the whole hypothalamus (Cohen’s d=.71; P =.0028) and for the left (d=.70; P =.0037) and right parts of the hypothalamus (d=0.65; P =.0075), respectively.

Compared with control individuals, patients with NT1 were also found to have larger volumes in the left (d=.72; P =.0036) and right tubular-inferior subregions (d=.71; P =.0037) of the hypothalamus. The researchers noted that the larger bilateral tubular-inferior hypothalamic subregions, “…could possibly be linked to gliosis due to neuroinflammation or increase in the numbers of histaminergic neurons in NT1.”

The researchers also compared the MRI-based volume of the hypothalamus among patients with NT1 and control individuals in vivo. They computed the volume of the whole hypothalamus, left and right part of the hypothalamus and 10 hypothalamic subregions using a segmentation tool based on deep learning. The researchers utilized permutation testing in Permutation Analysis of Linear Models to assess general linear models for differences among groups and evaluated after 10,000 permutations yielding 2-tailed P-values. They also conducted a stepwise Bonferroni correction following the division of the hypothalamus into smaller regions.

Permutation testing did not show any group differences for the:

• left (d=0.13; P =.60) and right anterior superior (d=.19; P =.43),
• left (d=0.41; P =.095) and right anterior-inferior (d=.43; P =.080),
• left (d=.41; P =.099) and right posterior (d=.15; P =.55), and
• right posterior (d=.15; P =.55) and left tubular-superior subregions (d=.26; P =.28).

In a multiple linear regression analysis of disease duration and hypothalamic volumes, the researchers found no significant results for the whole hypothalamus (d=.63), left (P =.55) or right part of the hypothalamus (P =.75) or the left (P =.49) or right tubular-inferior (P =.77).

After permutation testing, in a follow-up analysis, researchers noted that compared with control individuals, patients with comorbidities and a score of a least 5 on the apnea-hypopnea index (AHI), had larger volume for the whole hypothalamus (d=.57; P =.03), right (d=.60; P =.027) and left parts of the hypothalamus (d = .47; P =.077), and the left (d=0.52; P =.059) and right tubular-inferior (d=.61; P=.020) subregions.

“We believe our findings shed light on the disease processes occurring in the hypothalamus of NT1. Moreover, if structural brain changes are shown to be specific for hypocretin-deficient narcolepsy this could also in the future have potential to be used for noninvasive diagnostic purposes,” the researchers concluded.

Study limitations included the homogenous sample of participants and imperfectly adapted hypothalamic segmentation into subregions.

Disclosures: Several study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see original source for full list of disclosures.