JoAnne M. Sangal

Subjective sleepiness ratings (Epworth sleepiness scale) do not reflect the same parameter of sleepiness as objective sleepiness (maintenance of wakefulness test) in patients with narcolepsy

OBJECTIVE To evaluate whether subjective (Epworth Sleepiness Scale or ESS) and objective (Maintenance of Wakefulness Test or MWT) tests of sleepiness are equally useful in patients with narcolepsy. METHODS Correlational study evaluating the relationship between ESS and MWT as measures of sleepiness. SETTING Multi-center. PATIENTS 522 patients (17-68 year old men and women) with a current diagnosis of narcolepsy. INTERVENTIONS None. RESULTS Correlations were: MSLT and MWT, r = 0.52 (P<0.001); MWT and ESS, r = -0.29 (P<0.001); MSLT and ESS, r = -0.27 (P<0.001). Regression curve estimation using linear and curvilinear models revealed no difference among linear and curvilinear models between MWT and MSLT, and between MSLT and ESS. However, curvilinear models were better at explaining the relationship between MWT and ESS, with the cubic model being the best. As the level of severe sleepiness (as measured by the MWT) changed, the ESS remained stable. CONCLUSIONS In a large narcolepsy sample, the MWT and ESS are not equally useful, and do not measure the same parameter of sleepiness.

Subjective and objective indices of sleepiness (ESS and MWT) are not equally useful in patients with sleep apnea.

To understand the relationship between subjective and objective indices of sleepiness, we studied the relationship of the Epworth Sleepiness Scale (ESS) and the Maintenance of Wakefulness Test (MWT) in 41 consecutive patients complaining of snoring and excessive day-time sleepiness. The correlation between ESS and MWT was significant but small (rho = -0.39). There was considerable discordance between the two tests. The Lowess fit line between the ESS and the MWT indicates that the ESS falls as the MWT rises to about 4 min. It then stays at a plateau until the MWT rises to about 12 min. Thereafter, it resumes its downward slope as the MWT rises further. Thus, in patients who are severely sleepy on the MWT, the ESS may not be sensitive to different levels of sleepiness. We conclude that the ESS and the MWT are not equally useful in assessing sleepiness in patients with sleep apnea.

P300 Latency: Abnormal in Sleep Apnea with Somnolence and Idiopathic Hypersomnia, but Normal in Narcolepsy

To evaluate cognitive abnormalities in excessive daytime sleepiness (EDS) using cognitive evoked potentials (P300), and to evaluate if P300 measures differentiate among disorders of EDS, a series of EDS subjects were administered a polysomnogram, auditory and visual P300 testing using 31 scalp electrodes, and a multiple sleep latency test. P300 variables were compared with those of normal subjects. Forty normal subjects ages 16 to 65 years, and 69 EDS patients ages 16 to 65 years were used. Of these, 39 had profound obstructive sleep apnea (OSA, Respiratory Disturbance Index or RDI > 80/h sleep) with severe somnolence (Mean Sleep Latency < 5 min). Twenty-two had idiopathic hypersomnia (IH). Eight had narcolepsy. The normals and the three EDS groups did not differ in age. IH and profound OSA patients had longer visual P300 latency than normals or narcolepsy patients (p < 0.05). (p < 0.05). IH and profound OSA patients had longer auditory P300 latency than normals. They had smaller auditory P300 amplitude than narcolepsy patients. There were visual P300 latency topographic differences between normals and profound OSA patients. In conclusion, IH and profound OSA patients show cognitive evoked potential evidence of cognitive dysfunction. Narcolepsy patients do not show such evidence. Visual P300 latency differentiates among disorders of EDS.

Obstructive Sleep Apnea and Abnormal P300 Latency Topography

This study was conducted to evaluate cognitive abnormalities in obstructive sleep apnea (OSA) using cognitive evoked potentials (P300), and to clarify if such cognitive dysfunction is related to the OSA itself or to the hypersomnolence in OSA. Subjects were administered a polysomnogram, auditory and visual P300 testing using 31 scalp electrodes, and the multiple sleep latency test. There were 40 normal subjects ages 26 to 75. Of 143 consecutive OSA patients ages 26 to 75, 56 had severe OSA (Respiratory Disturbance Index or RDI 40-80/h sleep) with objective somnolence (Mean Sleep Latency < 5 min). Thirty-three had severe OSA without objective somnolence. Fifty-four had profound OSA (RDI > 80/h sleep) with or without objective somnolence. The normals and the three OSA groups did not differ in age. Patients with profound OSA or with severe OSA without somnolence had longer visual P300 latency than normals. The groups also differed in visual P300 latency topography. OSA patients had significantly longer latencies frontally than normals. Thus, OSA, even in the absence of hypersomnolence, is associated with abnormalities in cognitive evoked potentials. Visual P300 latency at frontal electrodes seems to be a neurophysiological index of dysfunction in OSA that is independent of tests of sleepiness.

Attention-deficit/hyperactivity disorder: cognitive evoked potential (P300) topography predicts treatment response to methylphenidate.

OBJECTIVE Auditory cognitive evoked potential (P300) topography predicts robust response to the stimulant pemoline in patients with attention-deficit/hyperactivity disorder (ADHD). Patients with a right fronto-central to parietal (FC2:P4) auditory P300 amplitude ratio >0.5 respond robustly to pemoline, whereas others do not. This study was performed to demonstrate whether the same test and ratio predict treatment response to methylphenidate. METHODS Patients aged 6-12 with DSM-IV diagnosis of ADHD were administered auditory and visual cognitive evoked potential (P300) testing. They then underwent single-blind treatment with an extended-release version of methylphenidate. Robust response was defined as a 60% decrease from baseline in a parent rated ADHD rating scale. RESULTS Nine of 20 subjects responded robustly. They did not differ from the non-robust responders in age, baseline attention or hyperactivity ratings, or any P300 parameter except auditory P300 topography. A FC2:P4 auditory P300 amplitude ratio >0.5 predicted robust response with a positive predictive value of 0.67 and a negative predictive value of 0.73. CONCLUSIONS The ratio of right fronto-central to parietal auditory P300 amplitude predicts response to stimulants in patients with ADHD. As non-stimulant treatments are approved for the treatment of ADHD, tests such as this may help pinpoint whether to use a stimulant or a medicine with some other mechanism of action.

Longer Auditory and Visual P300 Latencies in Patients with Narcolepsy

To compare auditory and visual P300 amplitude and latency magnitudes and topographies in patients with narcolepsy and normal subjects, 20 patients with polysomnographically-confirmed narcolepsy and 40 normal subjects were administered auditory and visual P300 testing using 31 evenly spaced scalp electrodes. Patients with narcolepsy were then administered baseline polysomnograms and objective (MSLT, Maintenance of Wakefulness Test or MWT) and subjective tests (Epworth Sleepiness Scale, Clinical Global Impression) of daytime sleepiness. Patients had longer 31-electrode mean age-adjusted auditory P300 latencies (406.0 +/- 27.8 vs. 385.7 +/- 28.9 ms, p = 0.012) and visual P300 latencies (427.3 +/- 29.0 vs. 411.4 +/- 27.7 ms., p = 0.044) than 40 normal subjects in the same age range. Age-adjusted auditory P300 latency was correlated with MWT (r = -0.49, p = 0.028), but not with any other clinical variable or measure of sleepiness. Age-adjusted visual P300 latency was not correlated with any clinical variable or measure of sleepiness. Patients with narcolepsy had longer auditory and visual P300 latencies than normal subjects.

Topography of Auditory and Visual P300 in Normal Adults

Auditory and visual P300 recordings were performed on 40 normal, right-handed individuals from age 16 through 65, using 31 evenly spaced scalp electrodes. Amplitude at the P300 peak and latency to this peak at each electrode site were measured. Age was significantly correlated with the 31-electrode mean for auditory and visual P300 amplitudes and auditory and visual P300 latencies. The younger age group (16-40) had shorter auditory and visual P300 latencies than the older group (41-65). Visual P300 amplitudes were of an overall larger magnitude than auditory P300 amplitudes. There were no other differences in P300 amplitudes or latencies by gender, modality, or side of scalp, and no significant topographical differences in P300 amplitudes or latencies by gender, age-group, modality, or side of scalp. Radial current density maps on group-averaged auditory and visual P300 waveforms at the group mean P300 latency at Cz, showed a right centroparietal sink surrounded by sources. This suggests a major right centroparietal P300 generator. Except for the change in P300 amplitudes with age, and the direction of the change in P300 latencies with age, these data on adults are similar to our previous description of P300 topography in normal children. Description of the normal topography of the P300, and demonstration of the lack of topographic differences by gender, age group, modality, or side of scalp, may facilitate the meaningful examination of P300 topography in cognitive disorders. Such an examination might lead to better diagnostic tools and more appropriate treatment of cognitive disorders in adults.

P300 latency and age: a quadratic regression explains their relationship from age 5 to 85.

The use of P300 latency to demonstrate cognitive dysfunction is important. P300 latency decreases with age in children and then increases with age in adults. It has been debated whether the relationship between age and P300 latency is linear or quadratic. If the relationship is linear, then at least two regression equations in opposite directions are required for children and for adults, and perhaps a third for the elderly. This is a report of data from an age-stratified sample of 97 normal individuals ages 5 through 85. The best regression equation is quadratic, using log transformed age, with accurate projection of 95% confidence limits for P300 latency by age. This quadratic regression simplifies the application of P300 latency across the life-span in the management of disorders affecting cognition, such as Traumatic Brain Injury, Attention Deficit-Hyperactivity Disorder, and Obstructive Sleep Apnea.

Visual P300 latency predicts treatment response to modafinil in patients with narcolepsy.

OBJECTIVE To evaluate the hypothesis that visual P300 latency (VL) predicts treatment response to modafinil (a new wake-promoting agent) in patients with narcolepsy. METHODS DESIGN Comparison of responders and non-responders in a double-blind randomized placebo-controlled trial. SETTING Private practice referral sleep disorders center. PATIENTS Twenty one patients with narcolepsy (ages 17-65 years). INTERVENTIONS Auditory and visual P300 testing using 31 evenly spaced scalp electrodes, and baseline polysomnograms and objective and subjective tests of daytime sleepiness, followed by modafinil treatment for 9 weeks. Polysomnograms and tests of sleepiness were then repeated. MAIN OUTCOME MEASURE The Maintenance of Wakefulness Test (MWT). Response defined as a final MWT > 7.3min (normative sample mean - 3 SD), plus an increase > 1SD based on normative sample (3.6 min) over baseline MWT. RESULTS Non-responders had longer age-adjusted 31-electrode mean VL (448.4 ms vs. 410.8 ms, P = 0.024), and larger auditory P300 amplitude, with no topographical P300 differences. Non-responders and responders did not differ on any other baseline clinical variable. Using a cut-off of 0.5 SE from normal regression constant, shorter age-adjusted VL predicted modafinil response, with specificity of 0.71 and sensitivity of 0.86. CONCLUSIONS VL predicts treatment response to modafinil in patients with narcolepsy.

Topography of auditory and visual P300 in normal children.

Auditory and visual P300 recordings were performed on 39 normal, right-handed individuals from age 6 through 15, using 31 evenly spaced scalp electrodes. Amplitude at the P300 peak and latency to this peak at each electrode site were measured. Age was significantly correlated with the 31-electrode mean for auditory and visual P300 latencies, but not for amplitudes. The younger age group (6-10) had longer auditory and visual P300 latencies than the older age group. Visual P300 amplitudes were of an overall larger magnitude than auditory amplitudes. There were no other differences including significant topographical differences in P300 amplitudes or latencies by gender, age group, modality, or side of scalp. Radial current density maps on group-averaged auditory and visual P300 waveforms at the group mean P300 latency at Cz, showed a right centroparietal sink surrounded by sources. This suggests a major right centroparietal P300 generator. Description of the normal topography of the P300, and demonstration of the lack of topographic differences by gender, age group, modality, or side of scalp, may facilitate the meaningful examination of P300 topography in cognitive disorders. Such an examination might lead to better diagnostic tools and more appropriate treatment of cognitive disorders in children.