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There remains an important and unmet need for fully effective and acceptable treatments in obstructive sleep apnea (OSA). At present, there are no approved drug treatments. Dronabinol has shown promise for OSA pharmacotherapy in a small dose-escalation pilot study. Here, we present initial findings of the Phase II PACE (Pharmacotherapy of Apnea by Cannabimimetic Enhancement) trial, a fully blinded parallel groups, placebo-controlled randomized trial of dronabinol in people with moderate or severe OSA.By random assignment, 73 adults with moderate or severe OSA received either placebo (N = 25), 2.5 mg dronabinol (N = 21), or 10 mg dronabinol (N = 27) daily, 1 hour before bedtime for up to 6 weeks.At baseline, overall apnea-hypopnea index (AHI) was 25.9 ± 11.3, Epworth Sleepiness Scale (ESS) score was 11.45 ± 3.8, maintenance of wakefulness test (MWT) mean latency was 19.2 ± 11.8 minutes, body mass index was 33.4 ± 5.4 kg/m2, and age was 53.6 ± 9.0 years. The number and severity of adverse events, and treatment adherence (0.3 ± 0.6 missed doses/week) were equivalent among all treatment groups. Participants receiving 10 mg/day of dronabinol expressed the highest overall satisfaction with treatment (p = .04). In comparison to placebo, dronabinol dose-dependently reduced AHI by 10.7 ± 4.4 (p = .02) and 12.9 ± 4.3 (p = .003) events/hour at doses of 2.5 and 10 mg/day, respectively. Dronabinol at 10 mg/day reduced ESS score by -3.8 ± 0.8 points from baseline (p.0001) and by -2.3 ± 1.2 points in comparison to placebo (p = .05). MWT sleep latencies, gross sleep architecture, and overnight oxygenation parameters were unchanged from baseline in any treatment group.These findings support the therapeutic potential of cannabinoids in people with OSA. In comparison to placebo, dronabinol was associated with lower AHI, improved self-reported sleepiness, and greater overall treatment satisfaction. Larger scale clinical trials will be necessary to clarify the best potential approach(es) to cannabinoid therapy in OSA.

Symptoms of narcolepsy tend to arise during adolescence or young adulthood, a formative time in human development during which people are usually completing their education and launching a career. Little is known about the impact of narcolepsy on the social aspects of health-related quality of life in young adults. The purpose of this study was to examine relationships between health-related stigma, mood (anxiety and depression) and daytime functioning in young adults with narcolepsy compared to those without narcolepsy. Young adults (age 18–35) with narcolepsy (N = 122) and without narcolepsy (N = 93) were mailed a packet that included questionnaires and a self-addressed postage paid envelope. The questionnaire included demographic information and a composite of instruments including the SF 36, Functional Outcomes of Sleep Questionnaire (FOSQ), Fife Stigma Scale (FSS), Epworth Sleepiness Scale (ESS) and Hospital Anxiety and Depression Scale (HADS). Variable associations were assessed using descriptive statistics, ANOVA, Mann-Whitney U Test, correlations, stepwise multiple regression and path analysis. Young adults with narcolepsy perceived significantly more stigma and lower mood and health-related quality of life than young adults without narcolepsy (p

In order to study spontaneous, slow oscillations of regional oxidative metabolism and blood flow in the normal, unanesthetized cortex, adult rabbits were implanted with bilateral cortical windows and electrodes for polysomnography. Relative changes in the cortical intramitochondrial redox state of cytochrome aa3 (CYT) and blood volume (CBV) were monitored by dual-wavelength reflectance spectrophotometry. Continuous, non-stationary oscillations (< 0.5 Hz) of both CYT and CBV were observed during waking and non-REM sleep. Cross-correlation analysis revealed a predominant interhemispheric synchrony of these oscillations which were unrelated to the heart rate, breathing, or electrocorticogram pattern. These findings suggest a dynamic linkage of slowly varying metabolic and vascular processes between unanesthetized cortical regions of 50 mm2 surface area.

A 19 year-old man presented with pharyngitis and cervical lymphadenopathy, followed by vomiting and acute cerebellar ataxia. Serologic studies were consistent with a recent Epstein-Barr virus infection. Although contrast-enhanced brain computed tomography and MRI scans were normal, brain perfusion single photon emission tomography (SPECT) examination using 99mTc-HMPAO, performed on the 15th day of illness, showed marked cerebellar hyperperfusion, suggesting a diagnosis of acute post-infectious cerebellitis. After treatment with intravenous human immunoglobulin (IVIg, 2 g kg-1 over three days), progressive neurologic improvement occurred over two weeks. A brain SPECT study repeated after two additional weeks demonstrated a normal perfusion pattern. We conclude that brain perfusion SPECT examination is useful in identifying post-infectious cerebellitis and in monitoring its clinical course. In addition, IVIg may be helpful in treating this condition.

The effect of folic acid (1 mg/day orally) on phenytoin steady-state pharmacokinetics was studied in four male folate-deficient epileptic patients who were treated with only one anticonvulsant. Each patient served as his own control before and after starting folic acid replacement therapy. The Michaelis-Menten parameters, Vmax and Km, were calculated for each patient, and compliance with the single anticonvulsant drug (phenytoin) regimen was documented. Blood and urine samples were collected just before (day 1) and after 180 or 300 days of vitamin administration. Total and free phenytoin were measured in plasma; and phenytoin, 5-(p-hydroxyphenyl)-5-phenylhydantoin (p-HPPH), 5-(3,4-dihydroxyphenyl)-5-phenylhydantoin (DHD) were measured in 24-h urine. After the addition of folic acid, total phenytoin plasma concentration decreased 7.5-47.6% in three of the four patients, and the extent of this change correlated with Km (r2 = 0.99). Ratios of urinary metabolites to parent drug increased in those patients showing a decrease in plasma phenytoin caused by folic acid supplementation. This indicated that a folic acid-associated increase in phenytoin oxidative metabolism had occurred.

To study the changes in cortical oxidative metabolism and blood volume during behavioral state transitions, we employed reflectance spectrophotometry of the cortical cytochrome c oxidase (cyt aa3) redox state and blood volume in unanesthetized cats implanted with bilateral cortical windows and EEG electrodes. Continuous oscillations in the redox state and blood volume (∼9/min) were observed during waking and sleep. These primarily metabolic oscillations of relatively high amplitude were usually synchronous in homotopic cortical areas, and persisted during barbiturate-induced electrocortical silence. Their mean amplitude and frequency did not vary across different behavioral/EEG states, although the mean levels of cyt aa3 oxidation and blood volume during rapid eye movement (REM) sleep significantly exceeded those during waking and slow-wave sleep. These data suggest the existence of a spontaneously oscillating metabolic phenomenon in cortex that is not directly related to neuroelectric activity. A superimposed increase in cortical oxidative metabolism and blood volume occurs during REM sleep. Experimental data concerning cerebral metabolism and blood flow that are obtained by clinical methods that employ relatively long sample acquisition times should therefore be interpreted with caution.

Five members in three generations of a family were affected by an illness that had many clinical features of the hypokalemic form of periodic paralysis (HPP). The serum potassium was either moderately reduced or normal during attacks, and there was no evidence of myotonia or cold-intolerance. All of the patients improved to a variable degree with oral potassium supplements, and 3 responded favorably to triamterene. The usually beneficial drug acetazolamide, however, invariably caused weakness in these patients, an effect previously described in only one other family with HPP. In addition, amphetamine-like sympathomimetic drugs effectively aborted or prevented paralysis in several members. Muscle biopsy in two patients revealed some unusual features, and electromyography showed myopathic potentials. There was no evidence of diabetes. The urine electrolyte concentrations during glucose tolerance tests, however, were different from those previously reported in HPP. This family may represent a variant form of HPP.

The relationship between the oxidation of intramitochondrial NADH and increased oxygen utilization previously described in various preparations has not yet been directly studied in large areas of the cerebral cortex during generalized seizures. In the present study, changes in the NADH fluorescence of one or both cortical hemispheres were measured with a television fluorometer during Metrazol seizures in normotensive and hypotensive states. Fluorescein fluorescence was used as a reference signal. Combined with measurements of sagittal sinus blood flow and oxygen saturation, this technique demonstrated generalized ictal decreases in NADH fluorescence, the time integrals of which linearly related to the integrals of simultaneous increases in relative cortical O 2 consumption during seizures occurring at normal blood pressures. Seizures observed during systemic hypotension and probable cerebral hypoperfusion, however, were characterized by generalized increases in NADH fluorescence, the integrals of which were not related to the integrals of relatively delayed increases in cortical O 2 consumption. Similar anomalous NADH increases during seizures were also occasionally seen in certain cortical areas in normotensive animals, suggesting local ischemia. In addition. NADH fluorescence and cortical O 2 consumption were found to be affected by changes in blood pressure in the absence of ictal activity. These observations suggest that cortical NADH fluorescence is dependent both on metabolic demand and O 2 availability, and consequently may be validly utilized as an indicator of activated cortical oxidative metabolism during seizures only under conditions of adequate cortical oxygenation.

We describe a versatile optical system that enables the simultaneous monitoring of the redox state of cytochrome c oxidase (cytochrome aa3) in two homologous cortical areas under chronically implanted windows in cats. A single light source, broad bandpass primary filters, light-conducting rods, and narrow-bandpass interference detecting filters are employed. We observed reproducible responses of the cytochrome redox state and blood volume to carotid occlusion and terminal anoxia during anesthesia, and to graded doses of pentobarbital in awake animals.

Computerized tomography revealed extensive bilateral hypodensity of the thalamus after an episode of severe arterial hypertension and convulsions in a patient with systemic lupus erythematosus. Radiologic and neurologic abnormalities were substantially resolved 1 week later. The unusual radiologic findings are discussed in relation to possible unique characteristics of vascular permeability in the thalamus.

Changes in cortical extracellular potassium activity ([K+]0), NADH fluorescence, and oxygen consumption were studied in anesthetized cats during pentylenetetrazol seizures. The effects of partial ischemia induced by either hypotension or intermittent carotid artery occlusion on these parameters were investigated. Nonischemic seizures were characterized by gradual generalized decreases in cortical NADH fluorescence and increases in O2 consumption, along with rapid increases in [K+]0, which then usually fell slightly as the ictal discharge continued. Ischemic seizures, on the other hand, were accompanied by complex changes in NADH fluorescence, by smaller delayed maximal increases in O2 consumption that lasted beyond the end of ictal activity, and by more sustained increases in [K+]0. The decay of [K+]0 after the termination of seizures in both nonischemic and moderately ischemic animals was not a monoexponential function: plots of ln delta [K+]0 versus time showed an initial linear decline (of slope M1) that rather abruptly slowed (to slope M2) after 2 to 5 sec and then often increased to the original rate. Both M1 and M2 were proportionately decreased by ischemia. In addition, the rate of [K+]0 removal could be slowed by acute ischemia induced either during or after the end of ictal activity. The initial rate of postictal [K+]0 removal (M1) was found to be linearly and inversely related to the level of cortical NADH fluorescence at the time of seizure termination. The results of this study suggest that an O2-dependent transport mechanism plays a major role in the removal of [K+]0 during and following the termination of generalized pentylenetetrazol seizures in the cat.

A causal relationship has been suggested between the altered electrical cortical activity and the increases in both cortical metabolism and blood flow which follow experimental reticulocortical activation. To further study this hypothesis, cortical O2 consumption, NADH fluorescence, and blood flow were monitored simultaneously with aortic blood pressure and ECoG after the electrical stimulation of the pontomesencephalic reticular formation (MRF) in anesthetized cats. Reversible increases in blood pressure, cortical blood flow, and O2 consumption, and decreases in NADH fluorescence were induced by MRF stimulation. All these changes were linearly related to each other as a function of stimulus intensity; they were often but not always associated with an increase in the ECoG frequency. MRF stimulation after ganglionic suppression with hexamethonium chloride revealed a dissociation of the resulting changes in the ECoG from the changes in cortical blood flow and metabolism. In addition, pharmacologically induced acute elevations of blood pressure caused changes in the experimental parameters similar to those which followed MRF stimulation but without a significant effect on the ECoG. We conclude that (i) acute increases in cortical blood flow and oxidative metabolism after electrical MRF stimulation may be more related to the simultaneous elevations of blood pressure than to changes in the ECoG; and (ii) an acute increase in cortical blood flow may by itself stimulate cortical oxidative metabolism in the anesthetized cat.

In 1962 Chance demonstrated the feasibility of monitoring intramitochondrial NADH levels in vivo. NADH serves as an indicator of oxidative metabolism because it fluoresces at 475 nm while its oxidized form NAD+ does not fluoresce significantly. We have designed a long focal length television fluorometer for the direct measurement of NADH fluorescence in the operating room on a practical basis. It enables a comparison of simultaneous metabolic changes in several anatomic areas. The 30-cm working distance of the system permits metabolic measurements to be made with a minimum of interference with normal operating procedures and other instrumentation. The tissue is illuminated at 360 nm by a mercury arc lamp, and the resulting fluorescence is monitored by a television system. Fluorescence variations are then analyzed by video densitometric techniques to localize metabolic changes that occur on a regional basis. Intravenous sodium fluorescein provides a reference fluorescence at 529 nm to compensate for the absorption of the ultraviolet excitation light by the hemoglobin in the blood. The difference between the fluorescence at 475 nm and 529 nm represents a corrected NADH fluorescence signal related to local oxidative metabolism. By employing this system in conjunction with other instrumentation, we have demonstrated a strong correlation among NADH fluorescence, oxygen consumption, and potassium kinetics in exposed cerebral cortex. Additionally, some effects of ischemia on NADH fluorescence were studied in both cortex and myocardium.© (1977) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

The effect of folic acid supplementation on the disposition of phenytoin and the resultant loss of seizure control in a male folate-deficient epileptic is reported. Due to the increase in tonic-clonic seizures after the initiation of folic acid (1 mg, orally) the sodium phenytoin dosage was increased by 130 mg until control was achieved. Because of these dosage changes, the Vmax and Km were calculated before and after initiation of the folic acid. The Vmax remained relatively the same, but the Km decreased after folate supplementation.

In a double-blind trial with a placebo phase, low-dose bromocriptine therapy (average dose, 15 mg per day) produced a significant improvement in 25 idiopathic parkinsonian patients. Tremor and bradykinesia were equally and significantly improved in both the levodopa-treated and the de novo patients. Rigidity was most improved in the levodopa-treated subjects. Age was not a factor in determining the dose of bromocriptine or the degree of improvement. Adverse effects occurred in 30% but were mild and dose-dependent. Four subjects, unable to tolerate initial doses of bromocriptine, withdrew from the trial. A low initial dose (1 mg per day) and slow escalation in dosage produced an optimal, though delayed improvement. Low-dose bromocriptine therapy is effective, does not induce significant dyskinesia nor on-off phenomenon, and is probably an alternative to levodopa as a drug of first choice in Parkinson disease.

Many investigators have identified localized cortical involvement in subacute sclerosing panencephalitis (SSPE) by clinical and electrophysiologic criteria. Some investigators have reported such abnormalities in the posterior cerebrum early in the course of the disease, but without radiologic correlation. Recently, magnetic resonance imaging has been used to follow the progression of SSPE. The largest reported study of SSPE utilizing magnetic resonance imaging indicated that focal abnormalities were distinctly rare and actually mitigated against the diagnosis of SSPE. We report an SSPE patient with focal cerebral dysfunction and magnetic resonance imaging evidence of distinctly focal inflammatory disease early in the course of the illness.

The postabsorptive distribution of cimetidine is described. Assays by high pressure liquid chromatography (HPLC) of postmortem samples of cerebrospinal fluid, serum, and solid tissues were used to determine pharmacokinetic parameters as well as mean tissue: serum concentration (T:S) ratios in seven patients with renal and liver dysfunction. Correlations were calculated between the T:S ratio and the volume of distribution, and between the T:S concentration ratio and the time of sampling after death. The highest T:S ratios occurred in the eliminating organs, the liver and kidneys, and the lowest in fat. As the time of autopsy increased after death, the T:S ratios decreased.

• Epileptic aphasia in adults is a rarely described syndrome. Its occurrence in individuals without a clear-cut history of seizures raises diagnostic difficulties with important therapeutic implications. Two such cases are reported in which the diagnosis was confirmed by EEG with a dramatic therapeutic response to anticonvulsant medication. The EEG criteria leading to detection of the epileptic nature of the syndrome are detailed. Maintaining a high index of suspicion in cases with fluctuating symptoms remains crucial for early diagnosis and management, especially in terms of differentiating epileptic aphasia from transient ischemic phenomena.