Xavier A. Preud'homme

Repetitive transcranial magnetic stimulation of the superior frontal gyrus modulates craving for cigarettes.

BACKGROUND Previous functional magnetic resonance imaging studies have shown strong correlations between cue-elicited craving for cigarettes and activation of the superior frontal gyrus (SFG). Repetitive transcranial magnetic stimulation (rTMS) offers a noninvasive means to reversibly affect brain cortical activity, which can be applied to testing hypotheses about the causal role of SFG in modulating craving. METHODS Fifteen volunteer smokers were recruited to investigate the effects of rTMS on subjective responses to smoking versus neutral cues and to controlled presentations of cigarette smoke. On different days, participants were exposed to three conditions: 1) high-frequency (10 Hz) rTMS directed at the SFG; 2) low-frequency (1 Hz) rTMS directed at the SFG; and 3) low-frequency (1 Hz) rTMS directed at the motor cortex (control condition). RESULTS Craving ratings in response to smoking versus neutral cues were differentially affected by the 10-Hz versus 1-Hz SFG condition. Craving after smoking cue presentations was elevated in the 10-Hz SFG condition, whereas craving after neutral cue presentations was reduced. Upon smoking in the 10-Hz SFG condition, ratings of immediate craving reduction as well as the intensity of interoceptive airway sensations were also attenuated. CONCLUSIONS These results support the view that the SFG plays a role in modulating craving reactivity; moreover, the results suggest that the SFG plays a role in both excitatory and inhibitory influences on craving, consistent with prior research demonstrating the role of the prefrontal cortex in the elicitation as well as inhibition of drug-seeking behaviors.

The association of fatigue with depression and insomnia in HIV-seropositive patients: a pilot study.

OBJECTIVE Fatigue is a pervasive symptom associated with HIV, resulting in significant functioning impairment; but little is known about its etiology or treatment. In patients with primary insomnia, data have shown improvement in fatigue following successful treatment of insomnia. However, little is known about the role of insomnia in patients with fatigue in HIV. This manuscript seeks to test the hypothesis that insomnia severity is correlated with increased fatigue in HIV-seropositive patients. METHODS Fifty-seven ambulatory HIV-seropositive patients, aged 18-60 years, with a DSM-IV-TR diagnosis of insomnia, were administered the Insomnia Severity Index (ISI), Piper Fatigue Scale (PFS), Hospital Anxiety and Depression scale, and Hamilton Depression Rating Scale (HAM-D). Their most recent CD4 count and time since diagnosis of HIV were recorded. Regression analysis was carried out with PFS as the dependent variable. RESULTS A higher ISI score correlated with higher PFS score, (R2 = 0.1713, P = 0.0042). Overall depression severity was not significantly correlated with PFS score, except in the most severely depressed subgroup, in which the HADS depression score was the strongest predictor of PFS (R2 = 0.182, P = 0.0009). In participants without depression, ISI accounted for most of the variance in fatigue (R2 = 0.6035, P = 0.0011). CONCLUSIONS Greater insomnia severity is associated with greater fatigue severity in HIV seropositive patients. Depression may contribute to both fatigue and insomnia. In the absence of depression, the treatment of insomnia may emerge as a treatment strategy to help alleviate fatigue. Further studies are needed to confirm these data. CLINICAL TRIAL INFORMATION Clinical Trials.Gov: The Treatment of Insomnia in Patients with HIV Disease. Registry Number: NCT00465972. URL: http://www.clinicaltrials.gov/ct2/show/NCT00465972?term = HIV+insomnia&rank = 1.

A randomized, double-blind, placebo-controlled trial of eszopiclone for the treatment of insomnia in patients with chronic low back pain.

STUDY OBJECTIVES Insomnia, which is very common in patients with chronic low back pain (LBP), has long been viewed as a pain symptom that did not merit specific treatment. Recent data suggest that adding insomnia therapy to pain-targeted treatment should improve outcome; however, this has not been empirically tested in LBP or in any pain condition treated with a standardized pain medication regimen. We sought to test the hypothesis that adding insomnia therapy to pain-targeted treatment might improve sleep and pain in LBP. DESIGN Double-blind, placebo-controlled, parallel-group, 1-mo trial. SETTING Duke University Medical Center Outpatient Sleep Clinic. PATIENTS Fifty-two adult volunteers with LBP of at least 3 mo duration who met diagnostic criteria for insomnia (mean age: 42.5 y; 63% females). INTERVENTIONS Subjects were randomized to eszopiclone (ESZ) 3 mg plus naproxen 500 mg BID or matching placebo plus naproxen 500 mg twice a day. MEASUREMENTS AND RESULTS ESZ SIGNIFICANTLY IMPROVED TOTAL SLEEP TIME (MEAN INCREASE: ESZ, 95 min; placebo, 9 min) (primary outcome) and nearly all sleep measures as well as visual analog scale pain (mean decrease: ESZ, 17 mm; placebo, 2 mm) (primary pain outcome), and depression (mean Hamilton Depression Rating Scale improvement ESZ, 3.8; placebo, 0.4) compared with placebo. Changes in pain ratings were significantly correlated with changes in sleep. CONCLUSIONS The addition of insomnia-specific therapy to a standardized naproxen pain regimen significantly improves sleep, pain, and depression in patients with chronic low back pain (LBP). The findings indicate the importance of administering both sleep and pain-directed therapies to patients with LBP in clinical practice and provide strong evidence that improving sleep disturbance may improve pain. TRIAL REGISTRATION clinicaltrials.gov identifier: NCT00365976.

Detrusor Overactivity Persisting at Night and Preceding Nocturia in Patients With Overactive Bladder Syndrome: A Nocturnal Cystometrogram and Polysomnogram Study

PURPOSE Nocturia, a common symptom of overactive bladder syndrome, is associated with substantial adverse consequences and yet its pathophysiology has hardly been studied and the capacity to treat it remains limited. We established methods to study the physiology of overactive bladder associated nocturia and better understand this phenomenon. MATERIALS AND METHODS We recorded simultaneous, time aligned, nocturnal cystometrogram and polysomnogram data during a single night at a sleep laboratory in 9 patients with overactive bladder and detrusor overactivity on daytime cystometrogram, in 10 patients with insomnia and in 5 healthy controls. RESULTS We safely recorded simultaneous polysomnography/nocturnal cystometrography data accurately during the sleep period. Nocturnal detrusor overactivity occurred significantly less often in patients with insomnia and controls than in patients with detrusor overactivity plus overactive bladder (p = 0.02) and only in the 10 minutes before nocturia events in the latter (0%, 0% and 67%, respectively, p = 0.002). Patients with detrusor overactivity plus overactive bladder were awake for a shorter period before nocturia events (p <0.001) and had a greater percent of nocturia associated awakenings. Patients with insomnia had more awakenings unrelated to nocturia. Nocturnal polyuria, another cause of nocturia, was not significantly associated with nocturnal detrusor overactivity. CONCLUSIONS Sleep and bladder pressure physiology may be safely monitored during the sleep period accurately. Nocturnal detrusor overactivity occurs in association with nocturia in most patients with detrusor overactivity plus overactive bladder, does not generally occur during sleep and is not due to sleep disturbance or nocturnal polyuria. This study may provide a foundation for research on overactive bladder related nocturia pathophysiology and treatment.

A case of delirium, motor disturbances, and autonomic dysfunction due to baclofen and tizanidine withdrawal: a review of the literature ☆

We report a case of delirium accompanied by extrapyramidal symptoms and autonomic dysfunction in a 59-year-old man following abrupt cessation of baclofen and tizanidine. An extensive search for the etiology was undertaken, but it was only after a careful history was taken that suspicion for baclofen and tizanidine withdrawal was raised. The delirium and motor disturbances resolved within 24 h of reintroduction of baclofen. Withdrawal from muscle relaxants requires a high index of suspicion but should be considered in patients who manifest signs and symptoms of withdrawal from the medications, particularly visual hallucinations, rigidity and autonomic dysfunction.

Pilot prospective study of post-surgery sleep and EEG predictors of post-operative delirium

OBJECTIVE Delirium is a common post-operative complication associated with significant costs, morbidity, and mortality. We sought sleep/EEG predictors of delirium present prior to delirium symptoms to facilitate developing and targeting therapies. METHODS Continuous EEG data were obtained in 12 patients post-orthopedic surgery from the day of surgery until delirium assessment on post-operative day 2 (POD2). RESULTS Diminished total sleep time (r=-0.68; p<0.05) and longer latency to sleep onset (r=0.67; p<0.05) on the first night in the hospital were associated with greater POD2 delirium severity. Patients experiencing delirium slept 2.4h less and took 2h longer to fall asleep. Greater waking EEG delta power (r=0.84; p<0.05) on POD1 and less non-REM sleep EEG delta power (r=-0.72; p<0.05) on night 2 also predicted POD2 delirium severity. CONCLUSIONS Loss of sleep on night1 post-surgery is an early predictor of subsequent delirium. EEG Delta Power alterations in waking and sleep appear to be later indicators of impending delirium. Further work is needed to evaluate reproducibility/generalizability and assess whether sleep loss contributes to causing delirium. SIGNIFICANCE This first study to prospectively collect continuous EEG data for an extended period prior to delirium onset identified EEG-derived indices that predict subsequent delirium that could aid in developing and targeting therapies.

A randomised trial of peri‐operative positive airway pressure for postoperative delirium in patients at risk for obstructive sleep apnoea after regional anaesthesia with sedation or general anaesthesia for joint arthroplasty

Previous pilot work has established an association between obstructive sleep apnoea and the development of acute postoperative delirium , but it remains unclear to what extent this risk factor is modifiable in the ‘real world’ peri‐operative setting. In a single‐blind randomised controlled trial, 135 elderly surgical patients at risk for obstructive sleep apnoea were randomly assigned to receive peri‐operative continuous positive airway pressure (CPAP) or routine care. Of the 114 patients who completed the study, 21 (18.4%) experienced delirium. Delirium was equally common in both groups: 21% (12 of 58 subjects) in the CPAP group and 16% (9 of 56 subjects) in the routine care group (OR = 1.36 [95%CI 0.52–3.54], p = 0.53). Delirious subjects were slightly older – mean (SD) age 68.9 (10.7) vs. 64.9 (8.2), p = 0.07 – but had nearly identical pre‐operative STOP‐Bang scores (4.19 (1.1) versus 4.27 (1.3), p = 0.79). Subjects in the CPAP group used their devices for a median (IQR [range]) of 3 (0.25–5 [0–12]) nights pre‐operatively (2.9 (0.1–4.8 [0.0–12.7]) hours per night) and 1 (0–2 [0–2]) nights postoperatively (1.4 (0.0–5.1 [0.0–11.6]) hours per night). Among the CPAP subjects, the residual pre‐operative apnoea–hypopnea index had a significant effect on delirium severity (p = 0.0002). Although we confirm that apnoea is associated with postoperative delirium, we did not find that providing a short‐course of auto‐titrating CPAP affected its likelihood or severity. Voluntary adherence to CPAP is particularly poor during the initiation of therapy.

Prolonged Delirium With Catatonia Following Orthotopic Liver Transplant Responsive to Memantine.

A 59-year-old man with nonalcoholic steatohepatitis cirrhosis underwent an orthotopic liver transplant and experienced a complicated postoperative course, including a prolonged delirium. After discharge to rehabilitation, he had 2 subsequent admissions for delirium. On the first readmission, the transplant team started the patient on risperidone and resumed treatment with sertraline. On his second readmission, neurology and psychiatry were consulted. On evaluation, the patient demonstrated signs of catatonia. On the basis of recommendations from psychiatry, the risperidone and sertraline were stopped, and the patient was started on mirtazapine. He failed to demonstrate improvement within the next 48 hours. Extensive work-up demonstrated a multifactorial etiology for his delirium, including calcineurin-related neuropsychiatric toxicity from tacrolimus leading to possible posterior reversible encephalopathy syndrome. However, after the initiation of memantine on hospital day 3—before the cessation of tacrolimus—the patient demonstrated marked improvement in mental status and motor symptoms. His magnetic resonance imaging, in addition to findings that raised concerns about posterior reversible encephalopathy syndrome, had demonstrated bilateral basal ganglia abnormalities on T1 imaging of uncertain origin. It is postulated that these findings served as predisposing factors for the patient’s catatonic symptoms. Although it has been described in case reports following liver transplant, catatonia remains an underrecognized neuropsychiatric complication following liver transplant. This case demonstrates the effectiveness of memantine, an N-methyl-D-aspartic acid antagonist that decreases glutamine excitotoxicity, as a potential treatment for catatonia in postliver transplant patients.

Topiramate-induced confusion following a single ingestion of 400 mg

BACKGROUND Topiramate is an anticonvulsant medication commonly used for a variety of neurological disorders including migraine prophylaxis. Broadened use of topiramate has brought an increased awareness of toxicity from this medication, particularly central nervous system side effects and metabolic acidosis. OBJECTIVE We describe a case of topiramate toxicity occurring in a 22-year-old female following the ingestion of two 200 mg tablets, which she was prescribed for the treatment of migraines. RESULTS During her outpatient cardiology evaluation for suspected postural orthostatic tachycardia syndrome (POTS), the patient experienced flushing and anxiety. Upon transfer to our hospital she was tachycardic, hypertensive, and confused. Her autonomic symptoms were consistent with her prior episodes of autonomic instability, while the confusion was new. Admission laboratory values revealed a metabolic acidosis with a mildly elevated anion gap. A blood topiramate level returned a value of 8.4 mg/L 15 h after the ingestion. Her symptoms cleared within 24 h following admission. CONCLUSION Clinicians should consider topiramate toxicity in their differential diagnosis for patients with neurological diseases presenting with acute-onset confusion and metabolic acidosis.

DOUBLE-BLIND, PLACEBO-CONTROLLED, CROSS-OVER, STUDY OF ARMODAFINIL TREATMENT OF DAYTIME SLEEPINESS ASSOCIATED WITH TREATED NOCTURIA.

Study Objectives Nocturia, voids which disturb sleep, is the most common cause of awakenings and is associated with daytime sleepiness. Because the standard treatments for the most common causes of nocturia are relatively ineffective, many treated patients with nocturia are left with residual sleepiness. We carried out this pilot study to evaluate the potential of armodafinil to be an effective means of addressing the sleepiness that persists in many nocturia patients, despite their receiving standard therapy. Methods This was a double-blind, placebo-controlled, crossover study carried out in 28 patients with nocturia who were receiving standard clinical therapy for their nocturia and who had an Epworth Sleepiness Scale (ESS) score of at least 10. Subjects received 4 weeks of both armodafinil (150-250 mg) and placebo with order randomized. Results Armodafinil led to statistically significant improvement in sleepiness compared to placebo as indicated by the ESS (the primary outcome; p < .002) as well as the Clinical Global Impression of Improvement in Sleepiness scale (key secondary outcome; p = .01). Armodafinil did not increase nocturic events or significantly increase adverse effects versus placebo. Conclusions This pilot study, the first double-blind, placebo-controlled trial assessing whether a wake-promoting therapy can improve residual daytime sleepiness in patients with treated nocturia, indicates the promise of armodafinil for addressing this residual sleepiness and provides impetus to carry out a large-scale study to definitively evaluate whether armodafinil is an effective therapy for the many patients with nocturia who experience daytime sleepiness that persists, despite their receiving standard therapy for this condition.