Kotagal, Suresh

Abstract Introduction Orexin deficiency in cerebrospinal fluid (CSF) was first reported in human narcolepsy in 2001, included in diagnostic criteria for narcolepsy in 2014, and made clinically available at the Mayo Clinic in 2019. The purpose of this publication is to report orexin test utilization and results, and other clinically relevant findings from patients evaluated at Mayo Clinic. Methods We retrospectively reviewed CSF orexin samples and clinical records from patients evaluated at Mayo Clinic from 2019 to 2021. Results A total of 98 internal samples (Rochester, n=56; Arizona, n=25, and Florida, n=17) from 95 patients (mean age 32.4 +/- 16.6 years with 20 %, 52 %, and 28 % of patients < 18, 18 – 40, and > 40 years, respectively, at time of CSF collection; 62 % female) have been submitted for CSF orexin measurement (mean CSF orexin 335.17 +/- 158.3 pg/ml; deficient < 110 pg/ml, n=11, 64 % <=40 years with mean age 32.9 +/- 17.0 years; intermediate 110 – 200 pg/ml, n=8, 100 % <= 40 years with mean age 21.1 +/- 12.8 years; normal > 200 pg/ml, n=79, 57 % <=40 years with mean age 33.5 +/- 16.7). No significant correlation was found between orexin levels, and time of collection (i.e., diurnal variation), gender, or age. Repeat testing was performed on three individuals (ages 10, 14, and 19 years) with a change in category of orexin level found in one patient from an intermediate to a normal level. Conclusion Orexin deficiency was found in 12 % of the patients (64 % of the deficient samples were found at ages <= 40 years). This result may reflect the fact that this test is frequently pursued in clinical patients presenting with inconclusive findings and/or comorbidities. Intermediate orexin levels found in 8 % of the samples (100 % <= 40 years). Although most of the patients tested were female (62.2%) and most were 40 years or younger (72%), no significant correlation was found between orexin levels, and time of collection (i.e., diurnal variation), gender, or age. Support (If Any) none

Abstract Introduction Moebius syndrome (MBS) is a rare disorder characterized by failure of development of the 6th and 7th cranial nerve nuclei located in the pons. Though the congenital lesion abuts the pontine tegmentum, sleep architecture has not been evaluated in MBS. Methods We report the clinical features of three children with MBS, and discuss implications for “developmental” RBD. Results Three clinically and MRI brain scan-confirmed MBS children, age 0.5 to 16 years, mean 8.5 ± 6.3 years, were evaluated for disrupted sleep, with repetitive crying (1/3), yelling (2/3), agitation in sleep (2/3), and injuring a co-sleeping sibling (1/3); 3/3 had REM sleep without atonia while 2/3 had RBD. REM sleep was reduced in all three: 21.7% in the infant (reference REM percentage value in infancy is about 40%), 11.4% in subject 2 and 3% in subject 3. Treatment with clonazepam (patients 2 and 3) or melatonin (patient 1) had variable results. Conclusion Children with Moebius syndrome have both quantitative (reduced percentage) and qualitative abnormalities of REM sleep (RSWA/RBD). The association of MBS with RSWA/RBD suggests more extensive involvement than published in literature, with extension into the sub-laterodorsal pontine tegmentum and “REM-off” neurons. Moebius syndrome might serve as a model for study of “developmental” REM sleep behavior disorder. Support (if any):

Abstract Introduction Pediatric Restless Legs Syndrome (RLS)/Periodic Limb Movement Disorder (PLMD) are treatable disorders affecting quality of life. The first line therapy is oral iron, which may have gastrointestinal side effects or suboptimal absorption. Consequently, parenteral iron preparations are needed, but have been insufficiently studied in children. This study evaluates the response to intravenous ferric carboxymaltose (FCM) in pediatric RLS/PLMD. Methods We performed a retrospective chart review of children who received FCM between May 2018 and January 2019 for treating RLS/PLMD. Serum ferritin before and after the infusion were compared. Where possible, the Clinical Global Impressions of Improvement (CGI-I) was evaluated. Side effects documented in the charts were extracted. The median administered dose of FCM was 10.1 mg/kg (range 9.6–20.8) over 0.6 to2 hours. Results There were 27 patients, with mean age of 10.0 +/-4.2 years. 52% were female. 24 had RLS and 3 had PLMD. 20/27 (69.7%) had prior oral iron therapy; 4/20 (26.0%) experienced side effects. Adverse events from FCM infusion included procedure-related anxiety in 4/27, nausea in 1/27, infusion site pain in 2/27, and tachycardia in 1/27. One patient developed subcutaneous extravasation of iron with brownish skin discoloration and a resulting adjustment disorder. Three patients had phosphorus checked following infusion; all were normal. Serum ferritin was available both before and after the infusion for 17 patients. Mean serum ferritin prior to infusion was 27.2 +/-15.7 µg/L (range 6–58) and after the infusion it was 109.8 +/-49.34 µg/L (range 27–192). Mean ferritin increase was 82.6 +/-41.5 µg/L (range 14–160; p=0.0001). Post-infusion ferritin was over 50 µg/L for all but 2 of the subjects, with follow up ranging from 31–266 days (mean 120 days). A larger increase was seen at higher doses (p=0.01). Ferritin increase was not impacted by age, gender, symptom severity, PLMI or prior ferritin level. CGI-I was applied to 15 patients with sufficient follow-up documentation and showed improvement in 86%, with 79% much or very much improved. Conclusion The administration of FCM in children with RLS/PLMD is associated with a satisfactory rise in serum ferritin and modest symptomatic improvement. Support (if any):

Abstract Background: Spinal muscular atrophy (SMA) type 3 is an autosomal recessive neurological disorder associated with a deletion/mutation in the survival motor neuron gene, with gradually progressive degeneration of the motor neurons of the spinal cord and brainstem, which causes muscle weakness responsible for impairment of swallowing, breathing, and mobility. Report of case: We report an 11-year-old girl with SMA type 3 with moderate to severe obstructive sleep apnea (OSA) syndrome refractory to adenotonsillectomy and noninvasive ventilatory support. She was started on nusinersen, which is a novel disease modifying therapy for SMA. This new treatment led to improvement of the OSA in a short period, likely from better respiratory muscle function. Conclusions: The improvement in OSA supports the role of nusinersen in sleep-related upper respiratory muscle function in SMA type 3.

Secondary narcolepsy occurs as a consequence of lesions involving the hypothalamic region that subserve wakefulness. Although observations on the characteristics of secondary narcolepsy have been published in adults, information on this topic in children is sparse. This is a retrospective study of characteristics and outcome of secondary narcolepsy in children. The medical records of 10 children with this condition at Mayo Clinic, Rochester, were reviewed. Characteristics of the underlying neurologic disorder, narcolepsy subtype, multiple sleep latency tests, medications used and outcome were extracted. Age at diagnosis of narcolepsy was between 6 and 17 years. Five of 10 patients had onset of excessive sleepiness within 1 year of diagnosis of the primary neurologic disorder. Six of 10 patients had type 1 narcolepsy (with cataplexy) whereas 4/10 had type 2 (without cataplexy). The clinical course was variable, with 8/10 continuing to require treatment for sleepiness at a mean period 6.6±6.2 years after diagnosis. One patient with narcolepsy type 1 due to Niemann Pick type C disease had died. One patient with narcolepsy type 2 due to craniopharyngioma had spontaneous remission of sleepiness. The 5/10 patients surviving with narcolepsy type 1 have continued to require pharmacotherapy for both sleepiness and cataplexy. This study draws attention to an important chronic sequel of childhood brain lesions that has variable, etiology-specific outcome. The rare occurrence of spontaneous resolution of childhood narcolepsy symptoms, not previously described, is also discussed.

Objective: To determine if Angelman syndrome patients with sleep complaints have an increased risk of iron deficiency, and if iron therapy improves their sleep difficulties. Background: About two-thirds of Angelman syndrome patients experience sleep difficulties, which are likely multifactorial. Because iron deficiency can contribute toward restlessness in sleep, we investigated whether it might be a contributing factor in this special population. Methods: This retrospective study involved medical record review of Angelman syndrome patients <18 years old who had attended our multidisciplinary Angelman syndrome clinic and had sleep complaints. Serum ferritin levels were compared to age- and sex-matched controls. Sleep history and nocturnal polysomnogram findings of the Angelman syndrome patients were also characterized. Results: Nineteen Angelman syndrome patients (9 female, mean age 6.2±4.4 years) were identified. All 19 reported sleep difficulties. The mean serum ferritin level was 19.9±8.5 μg/L, while that in controls was 27.8±17.8 μg/L ( P value .13). The odds ratio of iron deficiency in Angelman syndrome compared to controls was 4.17 (95% confidence interval 1.23-14.10), using normal serum ferritin level of 24 μg/L based on literature. Fifteen Angelman syndrome patients underwent nocturnal polysomnogram with 9/15 showing an elevated periodic limb movement index (overall mean 9.8±10.4). Seventeen of 19 received iron therapy. Twelve had follow-up after iron therapy, with parents reporting improved sleep quality. Eight had serum ferritin levels rechecked after iron therapy, showing a mean increase of 24±5.1 μg/L. Conclusions: Sleep difficulties in Angelman syndrome, though multifactorial, may in part be related to iron deficiency. Treatment with iron improved sleep to a modest degree in this population.