Feeling unreal: a functional imaging study in patients with Kleine-Levin syndrome

Abstract

Kleine-Levin syndrome is characterized by relapsing-remitting episodes of severe hypersomnia, cognitive impairment, apathy, derealization and behavioural disturbances. Between episodes, patients have normal sleep, mood and behaviour. Functional imaging studies performed in small series of patients with Kleine-Levin syndrome with visual or semi-quantitative, uncontrolled analysis yielded equivocal brain changes. Using whole brain voxel-based group analysis, we compared brain perfusion scintigraphy during and between episodes in consecutive patients with Kleine-Levin syndrome versus healthy control subjects and correlated perfusion changes with disease severity and symptoms, focusing on less studied but disabling symptoms, such as apathy and derealization. During asymptomatic periods, 41 patients (mean age of 22.3 ± 8.1 years, 56.1% male) and 15 age- and sex-matched healthy control subjects underwent single-photon emission computed tomography scanning with technetium-99m ethyl cysteinate dimer. Eleven patients repeated the test during a symptomatic period. Compared with controls, patients during asymptomatic periods had persistent hypoperfusion in the hypothalamus, the thalamus (mainly the right posterior part), the caudate nucleus, and cortical associative areas, including the anterior cingulate, (Brodmann area 25), the orbito-frontal (Brodmann area 11) and the right superior temporal cortices (Brodmann area 22), extending to the insula (P < 0.001 in all area). Two additional hypoperfused areas emerged during symptomatic periods (P < 0.001), located in the right dorsomedial prefrontal cortex (Brodmann area 8) and the right parieto-temporal junction (Brodmann areas 22 and 39). These two areas were more affected between episodes, when the mean episode duration was longer (r = -0.53; P < 0.001). The score for the Depersonalization/Derealization Inventory during symptomatic periods strongly correlated with the hypoperfusion of the right (r = -0.74, P < 0.001) and left (r = -0.59, P < 0.005) parieto-temporal junctions. No hyperperfusion was found. Because the parieto-temporal junction (including the angular gyrus) is involved in cross-modal association between somatosensory (body knowledge), auditory and visual information, the robust hypoperfusions and correlations observed in this area may underlie the striking derealization reported by patients during episodes. Defects in the dorsomedial prefrontal cortex may cause apathy. Persistent hypoperfusion in the diencephalic and associative cortical area during asymptomatic periods is a marker of the disease, suggestive of a scenario wherein patients compensate for these deficient circuitries.

Preliminary results on CSF biomarkers for hypothalamic dysfunction in Kleine–Levin syndrome

“…Our findings suggest that episodic hypothalamic dysfunction and state-dependent variations in hypocretin levels might occur in KLS, concurring with some functional neuroimaging findings [2,3,9,10]. Intermittent alteration of the diencephalic system may vary in degree between patients and between episodes, depending on the phenotype and its severity.…”

Serum cytokine levels in Kleine–Levin syndrome

“…This is supported by functional imaging studies during episodes, showing changes in activity in thalamic and hypothalamic regions, and in the frontal and temporal lobes [1,[3][4][5]. Analysis of case reports suggest that KLS has a genetic component [1,[6][7][8].…”

PANDAS and Comorbid Kleine–Levin Syndrome

“…Mixed evidence suggests hypothalamic dysfunction in KLS (Koerber et al 1984;Gadoth et al 1987;Fernábdez et al 1990;Chesson et al 1991;Malhotra et al 1997;Mayer et al 1998;Kas et al 2014). Evidence for thalamic involvement also exists; Tc-99m ethyl cysteinate dimer (ECD) single-photon emission CT analysis during symptomatic periods of KLS has demonstrated thalamic hypoperfusion (Huang et al 2005;Hong et al 2006;Huang et al 2012b;Kas et al 2014).…”

“…Evidence for thalamic involvement also exists; Tc-99m ethyl cysteinate dimer (ECD) single-photon emission CT analysis during symptomatic periods of KLS has demonstrated thalamic hypoperfusion (Huang et al 2005;Hong et al 2006;Huang et al 2012b;Kas et al 2014). MRI assessment of PANDAS youth has demonstrated enlarged basal ganglia (Giedd et al 1996(Giedd et al , 2000, and positron emission tomography has demonstrated increased activated microglial cells, which are suggestive of neuroinflammation, in bilateral caudate nuclei and bilateral lentiform in youth with PANDAS (Kumar et al 2014).…”