PET Study of Microglial Activation in Kleine-Levin Syndrome.

OBJECTIVES: Kleine-Levin syndrome (KLS) is a rare recurrent hypersomnolence disorder associated with cognitive and behavioral disturbances, of unknown origin, but inflammatory mechanisms could be involved. We aimed to explore in vivo microglia activation using [18F]DPA-714 PET imaging in patients with KLS compared with controls, and during symptomatic vs asymptomatic periods. METHODS: Patients with KLS and controls underwent a standardized clinical evaluation and PET imaging, using a radiolabeled ligand specific to the 18 kDa translocator protein. Images were processed on the PMOD (peripheral module) interface using a standard uptake value (SUV). Five regions of interest (ROIs) were analyzed: hypothalamus, thalamus, frontal area, cerebellum, and whole brain. SUV ratios (SUVr) were calculated by normalizing SUV with cerebellum uptake. RESULTS: Images of 17 consecutive patients with KLS (7 during episodes, 10 out of episodes) and 14 controls were analyzed. We found no SUV/SUVr difference between KLS and controls, between patients in and out episodes in all ROIs, and no correlation between SUVr and episode duration at the time of PET scan. No association was found between SUVr and sex, disease duration, or orexin levels. DISCUSSION: Our findings do not support the presence of neuroinflammation in KLS. Further research is needed to identify relevant biomarkers in KLS.

Can Quantitative Electroencephalography and Functional Near-Infrared Spectroscopy be a Good Guide in Kleine-Levin Syndrome?

There is scarce literature on functional neuroimaging data in Kleine-Levin syndrome. The current case report presents the electrical and metabolic status of cortical activity utilizing functional near-infrared spectroscopy (fNIRS) and quantitative electroencephalography (qEEG) before and after treatment of symptomatic phase of illness with modafinil.

Self-representation in Kleine-Levin syndrome: a single case fMRI study.

Kleine-Levin syndrome (KLS) is characterized by recurrent episodes of hypersomnia, compulsive hyperphagia, disinhibition, hypersexuality and self modifications. To investigate the Self, we used afunctional magnetic resonance imaging paradigm evaluating Self-reference processing (SRP) and Self-reference effect (SRE) in a17-year-old male adolescent at the end of an episode. We observed enhanced activations in right hemisphere and posterior areas- associated with physical Self representations- during the SRP condition, while during the SRE condition, enhanced activations in bilateral but prevailing left frontal areas- associated with the conceptual Self. These results suggest amodified Self during aKLS episode being more physically grounded.

Neuroimaging of Narcolepsy and Primary Hypersomnias.

Advances in neuroimaging open up the possibility for new powerful tools to be developed that potentially can be applied to clinical populations to improve the diagnosis of neurological disorders, including sleep disorders. At present, the diagnosis of narcolepsy and primary hypersomnias is largely limited to subjective assessments and objective measurements of behavior and sleep physiology. In this review, we focus on recent neuroimaging findings that provide insight into the neural basis of narcolepsy and the primary hypersomnias Kleine-Levin syndrome and idiopathic hypersomnia. We describe the role of neuroimaging in confirming previous genetic, neurochemical, and neurophysiological findings and highlight studies that permit a greater understanding of the symptoms of these sleep disorders. We conclude by considering some of the remaining challenges to overcome, the existing knowledge gaps, and the potential role for neuroimaging in understanding the pathogenesis and clinical features of narcolepsy and primary hypersomnias.

Neuroimaging in the Kleine-Levin Syndrome.

PURPOSE OF REVIEW: The purpose was to review the most recent literature on neuroimaging in the Kleine-Levin syndrome (KLS). We aimed to investigate if frontotemporal and thalamic dysfunction are key KLS signatures, and if recent research indicates other brain networks of interest that elucidate KLS symptomatology and aetiology. RECENT FINDINGS: In a comprehensive literature search, we found 12 original articles published 2013-2018. Most studies report deviations related to cerebral perfusion, glucose metabolism, or blood-oxygen-level-dependent responses in frontotemporal areas and/or the thalamus. Studies also report dysfunction in the temporoparietal junction and the oculomotor network that also were related to clinical parameters. We discuss these findings based on recent research on thalamocortical networks and brain stem white matter tracts. The hypothesis of frontotemporal and thalamic involvement in KLS was confirmed, and additional findings in the temporoparietal junction and the oculomotor system suggest a broader network involvement, which can be investigated by future high-resolution and multimodal imaging.

IV steroids during long episodes of Kleine-Levin syndrome.

OBJECTIVE: To retrospectively compare the benefits (episode cessation) and risks of IV methylprednisolone (IV-MP) vs abstention during prolonged Kleine-Levin syndrome (KLS) episodes. METHODS: A total of 26 patients with KLS received 1 g/d IV-MP for 3 days during 1 to 6 episodes each (totaling 43 IV-MP sessions). The change of episode duration with IV-MP (vs previous episode duration) was compared with the change duration between 2 consecutive episodes in 48 untreated patients matched for age, sex, age at KLS onset, number of episodes, and disease duration (more treated than untreated patients had long episodes). RESULTS: Eleven patients (42.3%) had an episode that was at least 1 week shorter than the preceding one when they received IV-MP therapy, whereas shorter episodes were significantly less frequent (10.4%) in the untreated group. This benefit was more marked (65.5% responders, 12 fewer days in an episode vs 0 days in the untreated patients) when IV-MP was infused before the 10th day of the episode. Mild, transient adverse effects (insomnia, muscle pain, nervousness/restlessness, but no manic switching) were reported by 61.3% of patients. No specific responder profile was identified. CONCLUSION: In this open-labeled, naturalistic study, early IV-MP (following the protocol for multiple sclerosis relapses) had a good benefit/risk ratio during KLS episodes in patients with long episodes (with half of the patients having an early cessation of episodes). CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with long episodes of KLS, IV steroids decrease the duration of KLS episodes.

The "Known Unknowns" of Kleine-Levin Syndrome: A Review and Future Prospects.

Kleine-Levin syndrome (KLS) is a rare, homogeneous, debilitating sleep disorder characterized by episodic hypersomnia, cognitive impairment, and behavioral changes. The etiology, pathophysiology, and optimal management of KLS remain uncertain. We identify the 5 key areas requiring urgent attention: KLS immunopathogenesis studies, next-generation genetics, multimodal functional imaging, biomarker discovery, and clinical drug trials. A centralized registry of afflicted individuals must be established. Disease uniformity should make the identification of associated genetic or imaging biomarkers easier, but clinical efforts require laboratory-based research to model the disease and generate preclinical data for clinical translation.

Neuroimaging of Narcolepsy and Kleine-Levin Syndrome.

Narcolepsy is a chronic neurologic disorder with the abnormal regulation of the sleep-wake cycle, resulting in excessive daytime sleepiness, disturbed nocturnal sleep, and manifestations related to rapid eye movement sleep, such as cataplexy, sleep paralysis, and hypnagogic hallucination. Over the past decade, numerous neuroimaging studies have been performed to characterize the pathophysiology and various clinical features of narcolepsy. This article reviews structural and functional brain imaging findings in narcolepsy and Kleine-Levin syndrome. Based on the current state of research, brain imaging is a useful tool to investigate and understand the neuroanatomic correlates and brain abnormalities of narcolepsy and other hypersomnia.

Kleine-Levin syndrome elicited by encephalopathy with reversible splenial lesion.

Kleine-Levin syndrome is a rare sleep disorder of unknown etiology characterized by repetitive episodes of hypersomnia between asymptomatic periods. We report the case of a 13-year-old girl who presented with drowsiness triggered by influenza A as the first episode. Magnetic resonance imaging (MRI) on day 6 showed transient reduction of diffusion in the corpus callosum splenium. The patient was diagnosed with encephalopathy with a reversible splenial lesion. The symptoms resolved after 10 days, but additional episodes of hypersomnia lasting 5-10 days occurred 1, 5, 6, 11, 13, and 25 months after the first episode. MRI during hypersomnia indicated no lesions, and sleep duration and cognition were normal between episodes. The patient was diagnosed with Kleine-Levin syndrome. Electroencephalographic and clinical findings during the first episode were similar to those during the other episodes. Encephalopathy with a splenial lesion and Kleine-Levin syndrome may have similar pathological mechanisms causing a disturbance in consciousness.

Kleine-Levin syndrome; An update and mini-review.

Since 1962, when Critchley and Hoffman coined the term Kleine-Levin Syndrome (KLS) for the triad of hypersomnia, excessive eating and "often abnormal behavior" which they have observed in 11 adolescent boys, the number of patients recognized with this rare syndrome expanded, the spectrum of the clinical presentation, disease course, prognosis, gender specificity and the presence of familial cases were established. However, in spite of the progress made in neuroscience, the search for the cause, neuroanatomy, pathophysiology and drug treatment of KLS is still ongoing. In this mini-review we will describe in some detail the scientific efforts made to understand in depth the complex symptomatology of KLS and refer also to updated findings reached up till now.

FDG Brain PET/CT Revealing Bilateral Thalamostriatal Activation During a Symptomatic Episode in a Patient With Kleine-Levin Syndrome.

We report the case of a 14-year-old girl with clinically diagnosed Kleine-Levin syndrome. Electroencephalogram and brain MRI were unremarkable. An FDG PET/CT scan was acquired during a symptomatic episode, while she was asleep, and another PET scan was obtained when she was asymptomatic, awake, and quiet. Comparison of both examinations demonstrated a bilateral activation of thalami, caudate nuclei, and lenticular nuclei. These findings may be linked to the implication of thalamostriatal structures in the regulation of sleep and wakefulness.

Do the Symptoms of Kleine-Levin Syndrome Correlate With the Hypometabolism of the Thalamus on FDG PET?

A 15-year-old adolescent boy had experienced intermittent, recurrent hypersomnia lasting for 1 week to 3 weeks for more than 3 years. He was diagnosed with Kleine-Levin Syndrome clinically. The brain MRI, video EEG, and serum and cerebrospinal fluid analysis did not show any abnormality. An FDG PET/CT scanning was acquired when the patient was symptomatic, showing marked symmetric hypometabolism in the thalamus and hypothalamus in the symptomatic phase, as well as mild homogeneous decreased glucose metabolism in the cortex. Interestingly, another FDG PET/CT scan acquired when the patient was asymptomatic found much less severe hypometabolism in the thalamus and hypothalamus.

Widespread hypermetabolism in symptomatic and asymptomatic episodes in Kleine-Levin syndrome.

BACKGROUND: No reliable biomarkers are identified in KLS. However, few functional neuroimaging studies suggested hypoactivity in thalamic and hypothalamic regions during symptomatic episodes. Here, we investigated relative changes in regional brain metabolism in Kleine-Levin syndrome (KLS) during symptomatic episodes and asymptomatic periods, as compared to healthy controls. METHODS: Four drug-free male patients with typical KLS and 15 healthy controls were included. 18-F-fluorodeoxy glucose positron emission tomography (PET) was obtained in baseline condition in all participants, and during symptomatic episodes in KLS patients. All participants were asked to remain fully awake during the whole PET procedure. RESULTS: Between state-comparisons in KLS disclosed higher metabolism in paracentral, precentral, and postcentral areas, supplementary motor area, medial frontal gyrus, thalamus and putamen during symptomatic episodes, and decreased metabolism in occipital and temporal gyri. As compared to healthy control subjects, KLS patients in the asymptomatic phase consistently exhibited significant hypermetabolism in a wide cortical network including frontal and temporal cortices, posterior cingulate and precuneus, with no detected hypometabolism. In symptomatic KLS episodes, hypermetabolism was additionally found in orbital frontal and supplementary motor areas, insula and inferior parietal areas, and right caudate nucleus, and hypometabolism in the middle occipital gyrus and inferior parietal areas. CONCLUSION: Our results demonstrated significant hypermetabolism and few hypometabolism in specific but widespread brain regions in drug-free KLS patients at baseline and during symptomatic episodes, highlighting the behavioral state-dependent nature of changes in regional brain activity in KLS.

Lower dopamine transporter density in an asymptomatic patient with Kleine-Levin syndrome.

BACKGROUND: Kleine-Levin syndrome (KLS) is a rare disorder whose pathophysiological mechanisms remain unknown. PATIENTS AND METHODS: To investigate dopamine abnormalities in KLS, a [99mTc]-TRODAT-1 single photon emission computerized tomography (SPECT) was performed in a patient with KLS during the asymptomatic period and compared with three matched healthy controls. RESULTS: The patient had 14% lower striatal dopamine transporter binding potential (DAT-BP) compared to the mean DAT-BP of three healthy controls. CONCLUSION: This study provides in vivo evidence for abnormalities in the DAT-BP, suggesting an involvement of the dopaminergic system in the pathophysiology of KLS.

Episodic diencephalic hypoperfusion in Kleine-Levin syndrome.

A 22 year-old woman suffered from recurrent episodes of hypersomnia, apathy, and hyperphagia. The symptoms occurred 3 to 4 times per year, and each attack lasted 2 to 3 weeks. 99mTc-ethylcysteinate dimer brain single photon emission computed tomography (SPECT) was performed during symptomatic and asymptomatic periods. To localize brain regions with perfusion changes during symptomatic period, asymptomatic SPECT was subtracted from symptomatic SPECT. The subtracted SPECT showed significant hypoperfusion in the left hypothalamus, bilateral thalami, basal ganglia, bilateral medial and dorsolateral frontal regions, and left temporal lobe during the symptomatic period. These cerebral hypoperfusion areas support the diencephalic hypothesis and clinical symptoms of Kleine-Levin syndrome.