Quantitative oculomotor and nonmotor assessments in late-onset GM2 gangliosidosis.

OBJECTIVE: A cross-sectional study was performed to evaluate whether quantitative oculomotor measures correlate with disease severity in late-onset GM2 gangliosidosis (LOGG) and assess cognition and sleep as potential early nonmotor features. METHODS: Ten patients with LOGG underwent quantitative oculomotor recordings, including measurements of the angular vestibulo-ocular reflex (VOR), with results compared to age- and sex-matched controls. Disease severity was assessed by ataxia rating scales. Cognitive/neuropsychiatric features were assessed by the cerebellar cognitive affective syndrome (CCAS) scale, Cerebellar Neuropsychiatric Rating Scale, and sleep quality evaluated using subjective sleep scales. RESULTS: Oculomotor abnormalities were found in all participants, including 3/10 with clinically normal eye movements. Abnormalities involved impaired saccadic accuracy (5/10), abnormal vertical (8/10) and horizontal (4/10) pursuit, reduced optokinetic nystagmus (OKN) responses (7/10), low VOR gain (10/10), and impaired VOR cancellation (2/10). Compared to controls, the LOGG group showed significant differences in saccade, VOR, OKN, and visually enhanced VOR gains. Severity of saccadic dysmetria, OKN, and VOR fixation-suppression impairments correlated with ataxia scales (p < 0.05). Nine out of ten patients with LOGG had evidence of the CCAS (5/10 definite, 2/10 probable, 2/10 possible). Excessive daytime sleepiness was present in 4/10 and 8/10 had poor subjective sleep quality. CONCLUSIONS: Cerebellar oculomotor abnormalities were present in all patients with LOGG, including those with normal clinical oculomotor examinations. Saccade accuracy (dorsal cerebellar vermis localization), fixation suppression, and OKN gain (cerebellar flocculus/paraflocculus localization) correlated with disease severity, suggesting that quantitative oculomotor measurements could be used to track disease progression. We found evidence of the CCAS, suggesting that cerebellar dysfunction may explain the cognitive disorder in LOGG. Sleep impairments were prevalent and require further study.

Electroencephalographic patterns during sleep in children with chromosome 15q11.2-13.1 duplications (Dup15q).

Our objective was to define the EEG features during sleep of children with neurodevelopmental disorders due to copy number gains of 15q11-q13 (Dup15q). We retrospectively reviewed continuous EEG recordings of 42 children with Dup15q (mean age: eight years, 32 with idic15), and data collected included background activity, interictal epileptiform discharges, sleep organization, and ictal activity. Three patterns were recognized: Pattern 1: Alpha­delta sleep was noted in 14 children (33%), not associated with any clinical changes. Pattern 2: Electrical status epilepticus in sleep was noted in 15 children (35%), all diagnosed with treatmentresistant epilepsy. Thirteen of the 15 children had clinical seizures. Pattern 3: Frequent bursts of high amplitude bifrontal predominant, paroxysmal fast activity (12­15 Hz) during non-REM sleep was noted in 15 children (35%). All 15 children had treatment-resistant epilepsy. This is the first report of electroencephalographic patterns during sleep of children with Dup15q reporting alpha-delta rhythms, CSWS, and high amplitude fast frequencies. Alpha-delta rhythms are described in children with dysautonomia and/or mood disorders and CSWS in children with developmental regression. The significance of these findings in cognitive function and epilepsy for the children in our cohort needs to be determined with follow-up studies.

The utility of routine EEG in the diagnosis of sleep disordered breathing.

Sleep disordered breathing (SDB) is a common medical condition. Its manifestations of snoring, nocturnal choking, arousals, and sleep fragmentation can lead to excessive daytime sleepiness, neuropsychological slowing, lapses of consciousness, and accidents that can be misinterpreted as epileptic phenomena. Moreover, patients with documented epilepsy commonly exhibit similar symptomatology because of the undiagnosed coexistence of sleep apnea. Therefore, a large proportion of patients referred to the electroencephalogram (EEG) laboratory primarily to confirm or refute the diagnosis of epilepsy could suffer from latent sleep apnea and the routine EEG has the potential to divulge it. We retrospectively evaluated the reporting of sleep apnea symptomatology (snoring, choking, gasping/deep breath, apnea, desaturation, excessive drowsiness) in routine inpatient and outpatient adult EEG studies performed in our institution over the past 12 years (39,130 studies, approximately half of which recorded at least early stages of sleep). Comparisons were performed with the medical records to ascertain the coexistence of objectively diagnosed SDB with polysomnography before or after the EEG study and the importance of reporting variations in assisting with the diagnosis. Two illustrative examples are provided. Sixty-nine EEG studies were identified, performed primarily to confirm, or refute the diagnosis of epilepsy. The mean age of the subjects at EEG was 64 years (range 30-89), and 55 (80%) were male. 36% of them suffered from known epilepsy. Snoring was the most commonly reported sign in 48 (70%) of the studies, followed by arousals in 29 (42%), apnea in 16 (23%), excessive drowsiness in 13 (19%), gasping/deep breath in 9 (13%), and desaturation in 7 (10%). A sleep disorder was suggested in 25 (36%) of the interpretations and a direct recommendation for a sleep study was made in 22 of them (32%). This interpretation was included in the impression of the report in 21 (30%) of the cases, in the detail in 20 (30%) of the cases and in both in 28 (40%). Only 14 (20%) patients underwent polysomnography, and all of them were formally diagnosed with SDB. Seven (50%) of them were diagnosed with obstructive sleep apnea, 2 (14%) with central sleep apnea, 3 (22%) with both, 1 (7%) with upper airways resistance syndrome, and 1 (7%) with primary snoring. From these 14 patients, 9 (64%) were diagnosed with a sleep study performed after the EEG, 4 (29%) before the EEG interpretation, and 1 (7%) had a repeat study after the EEG. In the logistic regression model applied, with the exception of the presence of arousals (odds ratio = 4.63, P = 0.033), none of the aforementioned symptomatology or the reporting of suspicion for SDB or the location (impression vs. detail) of the reporting showed a statistically significant association with the completion of a sleep study. Routine EEG offers a unique opportunity of direct clinical observation along with electrophysiologic and cardiorespiratory monitoring. When sleep is recorded, it can help identify clinical and electrographic features of sleep apnea and prompt confirmation with a polysomnogram in the appropriate clinical context. It can therefore serve as a valuable, adjunctive tool for the diagnosis of SDB. Our data highlight that potential but unveil its decreased use in the neurology community. Increased awareness is required by the EEG technologists, interpreting neurologists, and referring physicians, regarding reporting and using sleep apnea features on the EEG.

An open label trial of donepezil for enhancement of rapid eye movement sleep in young children with autism spectrum disorders.

BACKGROUND: Rapid eye movement (REM) sleep is greatest in the developing brain, is driven by acetylcholine, and may represent a protected time for neuroplasticity. Recently published data from our lab observed that children with autism spent significantly less time in this state during a single night recording than did typically developing children and those with developmental delay without autism. The objective of this study was to determine whether or not donepezil can increase the REM % in children with diagnosed autism spectrum disorder (ASD) found to have REM % values of at least two standard deviations below expected for age. METHODS: Five subjects found to have an ASD (ages 2.5-6.9 years) and demonstrated deficits in REM sleep compared with within-lab controls were enrolled in a dose finding study of donepezil. Each subject was examined by polysomnography for REM sleep augmentation after drug administration. RESULTS: REM sleep as a percentage of Total Sleep Time was increased significantly and REM latency was decreased significantly after drug administration in all subjects. No other observed sleep parameter was changed significantly. CONCLUSIONS: Donepezil can increase the amount of time that children with an ASD spend in the REM sleep state. A double-blind, placebo-controlled trial is needed to assess the association between REM sleep augmentation and learning, cognition, and behavior in such children.

Decreased seizure activity in a human neonate treated with bumetanide, an inhibitor of the Na(+)-K(+)-2Cl(-) cotransporter NKCC1.

Neonatal seizures have devastating consequences for brain development and are inadequately treated by available antiepileptics. In neonates, gamma-aminobutyric acid (GABA) is an excitatory neurotransmitter due to elevated levels of intraneuronal chloride achieved by robust activity of the Na(+)-K(+)-2Cl( -) cotransporter (NKCC1). This depolarizing action of GABA likely contributes to the lowered seizure threshold, increased seizure propensity, and poor efficacy of GABAergic anticonvulsants among infants. The diuretic bumetanide inhibits NKCC1 and silences seizure activity in rodent models of neonatal seizures, but its effect on seizures in human neonates is unknown. Continuous electroencephalography (EEG) monitoring was used to quantify the number, duration, and frequency of seizures 2 hours before and after the administration of bumetanide in a neonate with intractable multifocal seizures. Significant reductions in mean seizure duration and frequency were noted following treatment, with no associated clinical side effects or metabolic imbalances. These results suggest bumetanide may exert antiepileptic effects in human neonates.

The effects of consecutive night shifts on neuropsychological performance of interns in the emergency department: a pilot study.

STUDY OBJECTIVE: We obtain preliminary information on the neuropsychological performance of house officers at the beginning and end of a shift while they worked consecutive night shifts in the emergency department. METHODS: We prospectively studied interns working 12-hour consecutive night shifts in an urban Level I trauma center ED. All consecutive non-emergency medicine interns rotating for 1 month were eligible except those older than 40 years and those with sleep disorders or depression (identified by using the Profile of Mood Scale, Sleep Diagnostic Questionnaire). We tested research subjects at the beginning of a day shift and at the beginning and end of night shifts 1 and 3 of 4 consecutive night shifts at times of estimated baseline wakefulness (10 PM) and maximum fatigue (3 AM). We used 3 standardized neuropsychological tests: (1) Delayed Recognition Span Test (visual memory capacity); (2) Continuous Performance Test (attentional function, vigilance); and (3) Santa Ana Form Board Test (psychomotor speed, coordination). We analyzed data with mixed-model analysis, with research subject as a random effect. RESULTS: Thirteen interns were eligible, and 1 declined. Twelve interns (6 men and 6 women; age range 25 to 35 years) were enrolled. The Delayed Recognition Span Test (number correct before first error) revealed significant deterioration from the beginning of the shift to the end of the shift (mean difference -2.2; 95% confidence interval -3.1 to -1.3). This represents an 18.5% decrease in visual memory capacity. There were no significant differences found for the other tests. CONCLUSION: Interns working nights demonstrated a significant reduction in visual memory capacity across the night shift. Research involving neuropsychological performance during night shifts in the ED is important. It might provide valuable insights into ways to improve our performance during night shifts.