Objectives: Autoimmune encephalitis (AE) is increasingly recognized as an important cause of subacute cognitive decline, seizures, and encephalopathy, with an ever-broadening clinical phenotype. Sleep disturbances are reported in AE patients, including rapid eye movement sleep behavior disorder, hypersomnia, fragmented sleep, and sleep-disordered breathing; however, the prevalence of sleep disturbances and contributions to outcomes in AE patients remain unknown. There is a need to determine the prevalence of sleep disturbances in AE patients, and to clarify the relationship between specific autoantibodies and disruptions in sleep. Methods: Clinical history, results of serum and cerebrospinal fluid testing, electroencephalography, and neuroimaging were reviewed from 26 AE patients diagnosed and managed at our tertiary care hospital. Polysomnography was performed in patients with clinical indications, yielding data from 12 patients. Results: The median age of AE patients was 53 years (range, 18-83). Autoantibodies against intracellular antigens (including Ma and Hu autoantibodies) were identified in 6/26 (23%) patients, while autoantibodies against cell-surface neuronal antigens (including NMDAR and LGI1) were identified in 20/26 (77%) patients. New sleep complaints were reported by 19/26 (73%) AE patients, including gasping or snoring (9/19, 47%), dream enactment behavior (6/19, 32%), insomnia (5/19, 29%), hypersomnia (4/19, 21%), other parasomnias (4/19, 21%), and dream-wake confusional states (2/19, 11%). Dream enactment behaviors were particularly common in AE associated with LGI1 autoantibodies, reported in 4/7 (57%) patients.

Chemotherapy-associated PRES is an increasingly encountered syndrome. Both neurologists and non-neurologists should be familiar with the most commonly implicated agents, symptoms, risk factors, and clinical course of chemotherapy-associated PRES, given its favorable prognosis with appropriate management.

There are sex differences in free-running rhythms, activity level and activity distribution that are attributed, in part, to the action of gonadal hormones. We tested the hypothesis that non-classical estrogenic signaling pathways at estrogen receptor subtype 1 (ESR1) modify the amplitude and phase of activity. We used ESR1 knock-out mice (ERKO) and non-classical estrogen receptor knock-in mice (NERKI). ERKO animals are unable to respond to estrogen at the ESR1 and NERKI animals lack the ability to respond to estrogens via the estrogen response element-mediated pathway, but can still respond via non-classical mechanisms. We compared intact male and female ERKO, NERKI and wildtype (WT) mice with respect to total wheel-running activity, activity distribution across the 24-h day, phase angle of activity onset and free-running period (τ ) and the duration of activity in constant conditions. WT females had significantly greater activity than WT males, and this activity was more consolidated to the dark phase of the light:dark cycle. These sex differences were absent in the NERKI and ERKO animals. Among females, NERKI and ERKO animals had greater activity during the light phase than WT counterparts. Additionally, we have identified a novel contribution of non-classical estrogen signaling pathways on the distribution of activity. Our data suggest that total activity is ESR1-dependent and daily activity patterns depend on both classical and nonclassical actions of estrogens. These data will aid in identifying the mechanisms underlying sex differences in sleep-wake cycles and the influence of steroid hormones on circadian patterns.

Steroid hormones including estrogens modulate the expression of daily activity and circadian rhythms, including free-running period, phase angle of activity onset, and response to light. The mechanisms underlying these effects, however, are not fully understood. We tested the hypothesis that estrogen signaling is required for photic responsiveness of the circadian timing system. We used estrogen receptor subtype 1 (ESR1) knock-out mice (ERKO) and nonclassic estrogen receptor knock-in mice (NERKI). ERKO animals are unable to respond to estrogen at ESR1, and NERKI animals lack the ability to respond to estrogens via estrogen response element-mediated transcription but still respond via nonclassical mechanisms. We analyzed behavioral shifts in activity onset in response to 1-h light pulses given across the subjective 24-h day in gonadally intact male and female NERKI, ERKO, and wild-type (WT) littermates. We also examined Fos protein expression in the suprachiasmatic nucleus, the site of the master circadian pacemaker, at 2 times of day. We found a significant effect of genotype on phase shifts in response to light pulses given in the subjective night. Female WT mice had a significantly larger phase response than ERKO females during the early subjective night (phase shift of 98 min and 58 min, respectively; p < 0.05). NERKI females were intermediate to WT and ERKO females, suggesting a contribution of nonclassical estrogen signaling on circadian timekeeping functions. This genotype effect is not observed in males; they did not have a difference in phase shifts following a light pulse at any time point. WT males, however, shifted an average of 47 min less than did females at zeitgeber time (ZT) 16 (ZT 0 lights-on and ZT 12 lights-off). These data indicate that estrogens modify the response of the circadian timekeeping system to light via classical and nonclassical signaling pathways.

Estradiol influences the level and distribution of daily activity, the duration of the free-running period, and the behavioral phase response to light pulses. However, the mechanisms by which estradiol regulates daily and circadian rhythms are not fully understood. We tested the hypothesis that estrogens modulate daily activity patterns via both classical and "non-classical" actions at the estrogen receptor subtype 1 (ESR1). We used female transgenic mice with mutations in their estrogen response pathways; ESR1 knock-out (ERKO) mice and "non-classical" estrogen receptor knock-in (NERKI) mice. NERKI mice have an ESR1 receptor with a mutation in the estrogen-response-element binding domain, allowing only actions via "non-classical" genomic and second messenger pathways. Ovariectomized female NERKI, ERKO, and wildtype (WT) mice were given a subcutaneous capsule with low- or high-dose estradiol and compared with counterparts with no hormone replacement. We measured wheel-running activity in a light:dark cycle and constant darkness, and the behavioral phase response to light pulses given at different points during the subjective day and night. Estradiol increased average daily wheel-running, consolidated activity to the dark phase, and shortened the endogenous period in WT, but not NERKI and ERKO mice. The timing of activity onset during entrainment was advanced in all estradiol-treated animals regardless of genotype suggesting an ESR1-independent mechanism. We propose that estradiol modifies period, activity level, and distribution of activity via classical actions of ESR1 whereas an ESR1 independent mechanism regulates the phase of rhythms.

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