Impact of sleep disorder treatment on fatigue in multiple sclerosis.

BACKGROUND: We recently reported that sleep disorders are significantly associated with fatigue in multiple sclerosis (MS). OBJECTIVE: The objective of this paper is to assess the effects of sleep disorder treatment on fatigue and related clinical outcomes in MS. METHODS: This was a controlled, non-randomized clinical treatment study. Sixty-two MS patients completed standardized questionnaires including the Fatigue Severity Scale (FSS), Multidimensional Fatigue Inventory (MFI), Epworth Sleepiness scale (ESS) and Pittsburgh Sleep Quality Index (PSQI), and underwent polysomnography (PSG). Patients with sleep disorders were offered standard treatment. Fifty-six subjects repeated the questionnaires after ≥ three months, and were assigned to one of three groups: sleep disorders that were treated (SD-Tx, n=21), sleep disorders remaining untreated (SD-NonTx, n=18) and no sleep disorder (NoSD, n=17). RESULTS: FSS and MFI general and mental fatigue scores improved significantly from baseline to follow-up in SD-Tx (p <0.03), but not SD-NonTx or NoSD subjects. ESS and PSQI scores also improved significantly in SD-Tx subjects (p <0.001). Adjusted multivariate analyses confirmed significant effects of sleep disorder treatment on FSS (-0.87, p = 0.005), MFI general fatigue score (p = 0.034), ESS (p = 0.042) and PSQI (p = 0.023). CONCLUSION: Treatment of sleep disorders can improve fatigue and other clinical outcomes in MS.

Obstructive sleep apnea is associated with fatigue in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) patients often suffer from fatigue. OBJECTIVE: We evaluated the relationship of obstructive sleep apnea (OSA) to fatigue and sleepiness in MS patients. METHODS: Ambulatory MS patients without known sleep disorders and healthy controls underwent diagnostic polysomnography and a multiple sleep latency test (objective sleepiness measure). Fatigue was measured with the Fatigue Severity Scale (FSS) and the Multidimensional Fatigue Inventory (MFI), and subjective sleepiness by Epworth Sleepiness Scale. Covariates included age, sex, body mass index, Expanded Disability Status Scale (EDSS), depression, pain, nocturia, restless legs syndrome, and medication. RESULTS: OSA (apnea-hypopnea index ≥ 15) was found in 36 of 62 MS subjects and 15 of 32 controls. After adjusting for confounders, severe fatigue (FSS ≥ 5) and MFI-mental fatigue (>group median) were associated with OSA and respiratory-related arousals in MS, but not control subjects. Subjective and objective sleepiness were not related to OSA in either group. In a multivariate model, variables independently associated with severe fatigue in MS were severe OSA [OR 17.33, 95% CI 2.53-199.84], EDSS [OR 1.88, 95% CI 1.21-3.25], and immunomodulating treatment [OR 0.14, 95% CI 0.023-0.65]. CONCLUSIONS: OSA was frequent in MS and was associated with fatigue but not sleepiness, independent of MS-related disability and other covariates.

The Global Adherence Project (GAP): a multicenter observational study on adherence to disease-modifying therapies in patients with relapsing-remitting multiple sclerosis.

BACKGROUND: most disease-modifying therapies (DMTs) for multiple sclerosis (MS) are self-injectable medications that must be taken on an ongoing basis to reduce disease activity. Thus, adherence to therapy becomes an important challenge that must be addressed to maximize benefits of therapy. This study evaluated rates of adherence to prescribed treatment and explored factors affecting adherence amongst patients with relapsing-remitting MS. METHODS: this was an observational, multicenter, multinational, phase 4 study. Patients and physicians received paper questionnaires regarding adherence to DMTs approved at the time of the study, including intramuscular interferon beta-1a (IFNß-1a), subcutaneous IFNß-1a, IFNß-1b, and glatiramer acetate. Quality of life and cognition data also were collected. Multivariate analysis was conducted to identify factors associated with adherence to long-term DMTs. RESULTS: two thousand six hundred and forty-eight patients were studied, revealing an average treatment duration of 31 months. Seventy-five percent of patients (n = 1923) were adherent to therapy. The most common reasons for non-adherence were forgetting to administer the injection (50.2%) and other injection-related reasons (32.0%). Adherent patients reported better quality of life (P < 0.05) and fewer neuropsychological issues (P < 0.001) than non-adherent patients. Adherent patients had significantly shorter duration of disease (P < 0.001) and shorter duration of therapy (P = 0.005) than non-adherent patients. Women were more likely than men to adhere to treatment. CONCLUSION: identifying factors that affect adherence to prescribed treatments is the first step in improving adherence of patients with MS to therapy, thereby helping maximize the benefits of long-term DMTs.

Comparative tolerance of IFN beta-1a regimens in patients with relapsing multiple sclerosis. The EVIDENCE study.

The EVIDENCE study was a direct comparative study of two dose regimens of interferon (IFN) beta-1a used in the treatment of relapsing-remitting multiple sclerosis (RRMS): 30 mcg intramuscularly once weekly (qw; n=338) and 44 mcg subcutaneously three times weekly (tiw; n=339). The study continued for an average of 64 weeks. The safety population consisted of all patients receiving at least one dose of study drug. Clinical assessments occurred every 4 weeks for 24 weeks and then every 12 weeks. Blood tests for safety were taken at baseline and at weeks 4 and 12, and every 12 weeks thereafter. Overall adverse events were more common with the 44 mcg tiw regimen (p=0.007), and were due predominantly to differences in injection-site reactions. The majority of adverse events were rated mild by investigators. Hepatic and haematological adverse events and asymptomatic laboratory abnormalities were more common with 44 mcg tiw (p<0.001),with no difference seen for severe events. Flu-like symptoms were more common with 30 mcg qw (p=0.031), were more severe and persisted for longer. Serious adverse events were comparable for both groups, as were drug discontinuations. In conclusion, although adverse events were more common with high-dose, high-frequency IFN therapy, differences were primarily for mild events and did not affect treatment adherence. Based on superior clinical and magnetic resonance imaging outcomes over an average of 64 weeks, coupled with modest safety differences, the risk-benefit ratio for IFN therapy in RRMS favours the 44 mcg tiw regimen over this period of time.

High false-positive rate of questionnaire-based restless legs syndrome diagnosis in multiple sclerosis.

BACKGROUND/OBJECTIVES: Restless legs syndrome (RLS) is diagnosed by self-reported symptoms. Multiple sclerosis (MS) patients have disease-related symptoms which could mimic RLS. This study assessed the: (1) false-positive rate for questionnaire-based RLS diagnosis in MS patients and (2) utility of periodic leg movements during wakefulness (PLMW) on overnight polysomnography (PSG) in identifying true-positive RLS patients. METHODS: Ambulatory MS patients without known sleep disorders were recruited. Subjects completed the International RLS Study Group (IRLSG) diagnostic questionnaire (IRLDQ) and underwent full overnight PSG. IRLDQ-positive patients underwent clinical evaluation to confirm the diagnosis and completed the RLS severity scale (IRLS). RESULTS: Seventy-one MS patients (mean age 46.8 ± 10.4 years) were evaluated. Thirty-eight had a positive IRLDQ. RLS diagnosis was confirmed in 22, yielding a false-positive rate of 42% [95% confidence interval (CI) 26-59%], predominantly attributable to paresthesiae (n = 7), and cramps and/or muscle spasms (n = 4). IRLS scores were not significantly different between subjects with confirmed and nonconfirmed RLS. The PLMW index was significantly higher in patients with confirmed RLS (55.4 ± 41.9 vs. 29.7 ± 18.8, p = 0.03). The sensitivity of a PLMW index >70/h for true-positive IRLDQ was 8/22 = 36%, 95% CI: 17.2-59.3, and the specificity was 16/16 = 100%, 95% CI: 79.4-100. CONCLUSIONS: MS patients have a high false-positive rate of RLS diagnosis using a standardized questionnaire largely attributable to MS-related sensorimotor symptoms. While detailed clinical evaluation is essential for confirming RLS diagnosis, the PLMW index may provide useful adjunctive information.

Electrophysiological and behavioral correlates of psychomotor responsivity in depression.

Psychomotor retardation is a frequently observed clinical feature of depressive states. This study attempted to assess the relationship between response slowness and central nervous system (CNS) activity by examining cortical evoked potentials (EPs) during psychomotor task performance. Patients consisted of 21 women who met Research Diagnostic Criteria (RDC) and exhibited a minimum Hamilton Rating Scale for Depression score of 18 at the end of a drug washout period, the scheduled time of testing. The same number of normal women with no history of psychiatric illness were employed as controls. Cortical EPs from Cz and integrated electromyogram (EMG) from the dominant forearm extensor were recorded and time-locked to warning and imperative stimuli of a standard, two-choice, fixed foreperiod reaction time (RT) task, which yielded behavioral measures of decision time (DT) and movement time (MT). Analysis focused on behavioral RTs, latency and amplitudes of EMG, sensory and slow cortical (CNV) EPs, and measures of input time (IPT), central processing time (CPT), and motor execution time (MET), derived from combinations of EP and EMG peak latencies. Patients exhibited slower DT and MT response times, delayed EMG latencies, and attenuated EP amplitudes. The derived CPT measure was also significantly longer in patients. These findings support the view that a central dysfunction is implicated in psychomotor retardation, and the results are discussed in relation to information processing theory.

Phenelzine and exposure in the treatment of phobias.

A double-blind study was carried out on 40 agoraphobic and socially phobic patients, matched, then randomly assigned to one of four treatment groups; phenelzine-exposure, phenelzine-no exposure, placebo-exposure, and placebo-no exposure. Exposure consisted of encouraging the patient to face the phobic situation a predetermined number of times. Assessments, made at the beginning and end of 8 weeks of therapy and 8 weeks thereafter, showed that the phobia ratings of groups decreased significantly. The combined exposure group improved significantly more than the combined no exposure group during treatment. At 8 weeks follow-up there was some deterioration in the phenelzine-exposure and placebo-no exposure groups. Exposure, with or without phenelzine, was the superior treatment modality. The antiphobic effect of phenelzine was not supported, although it seemed to reduce subjective anxiety during exposure experiences. The possibility that effect of phenelzine is dose-related is discussed.

Erythrocyte membrane sodium-potassium and magnesium ATPase in primary affective disorder.

Erythrocyte membrane Mg2+ ATPase and Na+-K+ ATPase were measured in patients with affective disorder, their well relatives, and normal controls during euthymic moods. On the average, the Mg2+ ATPase activity was high in subjects belonging to affective disorder families. However, the difference between normal and affective disordered individuals was not statistically significant. Only the well individuals from affective disorder pedigrees as a group had significantly higher than normal Mg2+ ATPase activity (p less than 0.05). The Na+-K+ ATPase activity was similar for all the groups, including normal, bipolar manic-depressive (with or without lithium), unipolar depressive, and well individuals. Lithium treatment did not seem to have any effect on Mg2+ ATPase. Even though the values of Na+-K+ ATPase in the lithium-treated group were high, it is not certain that this was due to lithium per se.

Effects of cholinergic and GABAergic drugs on apomorphine-induced gnawing behavior in rats.

The effects of cholinergic and GABAergic agonist and antagonist were studied on the apomorphine-induced gnawing behavior in rats. Physostigmine (0.5 mg/kg) decreased the biting scores, whereas atropine (5 mg/kg) had an opposite effect. Picrotoxin potentiated the physostigmine inhibitory action on gnawing responses. This inhibitory gnawing effect was antagonized by prior treatment with atropine. Pretreatment with amino-oxyacetic acid (25 mg/kg) also potentiated the inhibitory effect of physostigmine on gnawing behavior in animals. Such an additive inhibitory response could be antagonized by simultaneous pretreatment with cholinergic and GABAergic blockers such as atropine and picrotoxin, respectively. These findings indicate that the modulatory action of cholinergic neurons on DA system is probably influenced by changes in the GABAergic system.

Determination of the optimal concentration of lithium for the prophylaxis of manic-depressive disorder.

A group of 29 bipolar manic-depressives completed a 12-month double-blind cross-over trial of low-dose and high-dose lithium prophylaxis. Twelve patients relapsed, and significantly more of the relapses occurred during the low-dose 6-month phase of the trial. There was a trend for relapse to occur within 2 months of an abrupt drop in plasma lithium level, and to occur more often in women than in men. The efficacy of low-dose lithium prophylaxis and the significance of rebound relapse are discussed.

Frequency of long allele in serotonin transporter gene is increased in depressed suicide victims.

BACKGROUND: There is evidence indicating that serotonin uptake and density of 5-HT2A receptors are altered in brain regions of depressed suicide victims and in platelets of depressed suicidal subjects. The present investigation tested the hypothesis that these changes in the serotonergic system in depressed suicide victims are trait rather than state markers and associated with a polymorphism in respective candidate genes. METHODS: Two polymorphic variants (102T/C polymorphism and His452Tyr functional polymorphism) of the 5-HT2A receptor gene and a functional polymorphism in the 5' regulatory region of the 5-HT transporter gene, have been determined in genomic DNA obtained from postmortem brain samples of 24 depressed suicide victims and 31 control subjects of the same ethnic background. In a subset of subjects, density (Bmax) of 5-HT uptake sites (labeled with 3H-paroxetine) and of 5-HT2A receptors (labeled with 3H-ketanserin) was also determined in prefrontal cortex samples. RESULTS: The major finding of this study was a significantly higher frequency of the 5-HT transporter gene long (L) allele (chi 2 = 3.9, df = 1; p = .048) in depressed suicides. No significant differences between suicides and controls were observed for the 102T/C polymorphism and His452Tyr polymorphism of 5-HT2A receptor gene. The density of 3H-paroxetine binding sites tended to be higher in subjects expressing the short (S) allele of 5-HT transporter gene. Furthermore, there was a significant difference in serotonin transporter binding sites between the genotype S/S and combined genotypes S/L and L/L. CONCLUSIONS: Our finding provides the first evidence suggesting that a functional polymorphism in the regulatory region of serotonin transporter gene may be associated with suicide in depressed subjects.

Mianserin kinetics in depressed patients.

We studied mianserin kinetics after a single (60 mg) dose in eight inpatients suffering from depression. There was a considerable interpatient variability in plasma levels. Mean peak plasma levels (+/- SEM) were 114 +/- 26 ng/ml and were reached between 1 and 3 hr. The decline of mianserin levels in plasma was biphasic. The mean elimination t 1/2 was 21.6 +/- 3.1 hr and ranged from 10.7 to 40.8 hr. The estimated first-pass loss ranged from 26% to 48% (mean, 37%) and was lower than that reported for tertiary amine tricyclic antidepressants. The mean apparent volume of distribution (15.7 +/- 2.2 l/kg; 9.7 to 28.8 l/kg) was in the range of that for imipramine but somewhat lower than for maprotiline. Apparent total body clearance ranged from 0.33 to 0.81 l/hr/kg (mean +/- SEM, 0.52 +/- 0.05 l/hr/kg) and was of the order of that after maprotiline. Our results indicate that mianserin kinetics are in most respects similar to those of tertiary amine tricyclic antidepressants (e.g., imipramine) and the tetracyclic maprotiline.

A controlled study of penfluridol in the treatment of chronic schizophrenia.

Twenty patients were treated with penfluridol and 21 with fluphenazine for a period of up to 1 year. Penfluridol, an oral neuroleptic administered weekly was as efficacious as fluphenazine administered twice daily and appeared to be superior to fluphenazine in improving emotional withdrawal and anergia. The low incidence of side effects and other signs of toxicity, coupled with an effective prophylactic activity, suggests that penfluridol is an important addition to our therapeutic armamentarium for the treatment of chronic schizophrenia.

Hypothalamic pathology in the neuroleptic malignant syndrome.

The pathogenesis of the neuroleptic malignant syndrome is currently unclear, and no specific morphological abnormalities in the CNS of victims of neuroleptic malignant syndrome have been described. The authors report a case of neuroleptic malignant syndrome with recent foci of necrosis in the anterior and lateral hypothalamic nuclei. They discuss the role of tricyclic antidepressants, monoamine oxidase inhibitors, and neuroleptics in the development of this syndrome. They conclude that although the pathogenesis of the neuroleptic malignant syndrome is still not clear, necrosis of the hypothalamic nuclei may be pathognomonic for this syndrome.

Neurophysiological correlates of sibling pairs discordant for bipolar affective disorder.

Eleven sibling pairs discordant for bipolar disorder were compared on the basis of computerized EEGs and auditory evoked potentials. The findings suggest that CNS overarousal may be characteristic of trait bipolar disorder.

Platelet serotonin measures in primary dysthymia.

Serotonergic function in 22 patients with primary dysthymia and 22 normal volunteers was evaluated by measuring [3H]serotonin uptake and [3H]paroxetine binding in platelets. A significantly lower maximum rate of serotonin uptake was noted in the dysthymic patients than in the normal subjects, indicating a possible serotonergic dysfunction in dysthymia. However, the values for parameters of paroxetine binding were similar in the two groups.

Varicella-zoster virus DNA in CSF and arteries in delayed contralateral hemiplegia: evidence for viral invasion of cerebral arteries.

A 78-year-old woman presented with a right basal ganglia infarct 6 weeks after a left herpes zoster ophthalmicus. MR angiography showed focal segmental stenosis of the proximal segments of the anterior, middle, and posterior cerebral arteries. Varicella DNA was detected in the CSF by polymerase chain reaction (PCR). Treated with dexamethasone and acyclovir without improvement, she died 1 month later. There was focal endarteritis in the left anterior, middle, and posterior cerebral arteries at autopsy. Varicella DNA was detected by PCR of extracts from these vessels but not from the arteries on the right side. This study provides further evidence that the vasculopathy after herpes zoster ophthalmicus results from direct viral invasion of the vessel wall.

Intermittent cyclophosphamide pulse therapy in progressive multiple sclerosis: final report of the Northeast Cooperative Multiple Sclerosis Treatment Group.

Previous studies reported that a 2- to 3-week course of IV cyclophosphamide plus adrenocorticotropic hormone (ACTH) induction can temporarily halt progressive MS for a period of 12 months in the majority of patients treated, after which reprogression occurs. The Northeast Cooperative Multiple Sclerosis Treatment Group was formed to determine whether outpatient pulse cyclophosphamide therapy could affect reprogression and whether there were differences between a modified induction regimen and the previously published regimen. Two hundred fifty-six progressive MS patients were randomized into four groups to receive IV cyclophosphamide/ACTH via the previously published versus a modified induction regimen, with or without outpatient IV cyclophosphamide boosters (700 mg/m2 every other month for 2 years). There were blinded evaluations performed every 6 months. Results demonstrate that (1) there were no differences between the modified and the published induction regimens either in terms of initial stabilization or subsequent progression; (2) without boosters, the majority of patients continued to progress; and (3) in patients receiving boosters, there was a statistically significant benefit at 24 months and 30 months (p = 0.04). Time to treatment failure after 1 year was also significantly prolonged in the booster versus the nonbooster group (p = 0.03). Age was the most important variable that correlated with response to therapy in that amelioration of disease progression occurred primarily in patients 40 years of age or younger. Boosters had a significant benefit on time to treatment failure in patients ages 18 to 40, p = 0.003, but not in patients ages 41 to 55, p = 0.97.(ABSTRACT TRUNCATED AT 250 WORDS)

Alterations in brain 5-hydroxytryptamine metabolism during the 'withdrawal' phase after chronic treatment with diazepam and bromazepam.

1 Daily administration of diazepam or bromazepam (10 mg/kg) for 22 days significantly increased the activity of mid-brain tryptophan hydroxylase by 36% and 39%, respectively. The concentration of tryptophan was also enhanced in the mid-brain region of rats subjected to benzodiazepine treatment.2 Chronic therapy with either of the two anti-anxiety agents enhanced the endogenous levels of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in cerebral cortex, hypothalamus, pons-medulla, mid-brain and striatum.3 Whereas diazepam treatment decreased (13%) the activity of monoamine oxidase in mid-brain, bromazepam failed to exert any effect, suggesting that the observed elevation in 5-hydroxy-indoleacetic acid levels is not associated with enhanced deamination of 5-hydroxytryptamine.4 Discontinuation of treatment for 48 h significantly decreased the activity of mid-brain tryptophan hydroxylase to levels that were significantly lower than those seen for benzodiazepine-treated and normal rats. The concentrations of mid-brain tryptophan and 5-hydroxytryptamine were also reduced in various brain regions examined.5 Withdrawal from diazepam or bromazepam therapy further augmented the levels of brain 5-hydroxyindoleacetic acid.6 The results demonstrate that the depressant effects on behaviour of these agents are accompanied by increased metabolism of 5-hydroxytryptamine in the brain. Withdrawal from these minor tranquillizers, on the other hand, reduces the synthesis of this indoleamine.

A review of trimipramine. 30 years of clinical use.

The hybrid chemical structure of trimipramine incorporates an imipramine nucleus and levomepromazine side chain. This structure predicts much of the clinical profile of trimipramine. The initial studies on trimipramine date back nearly 30 years. It now has a well-recognised clinical profile with some characteristics akin to other tricyclic antidepressants (TCA) and others which are quite distinct. It is well established as a highly effective antidepressant with an efficacy profile similar to the other TCAs. Clinically, its anxiolytic and sedative properties distinguish it from most other TCAs. Its effects on sleep architecture are unique and explain some of its unique properties. The side effect profile of trimipramine is in some ways similar to those of the tertiary amine TCAs with a preponderance of anticholinergic and sedative effects. Its cardiotoxic properties are minimal, with some findings suggesting a very favourable profile. Interactions with other drugs, psychotropic or non-psychotropic, are compatible with its pharmacological profile. These are reviewed with its clinical applications in mind. The pharmacokinetic characteristics of trimipramine differ from those of many of the other TCAs. The application of this to clinical situations is addressed. Based on experience using trimipramine, a profile of 'ideal' patient characteristics has been built up. Finally, the use of trimipramine in selected patient populations is reviewed.