Sex Disparities in the Self-Evaluation of Subthalamic Deep Brain Stimulation Effects on Mood and Personality in Parkinson's Disease Patients.

Changes in personality are one of the main concerns Parkinson's disease (PD) patients raise when facing the decision to undergo neurosurgery for deep brain stimulation (DBS) of the subthalamic nucleus (STN). While clinical instruments for monitoring functional changes following DBS surgery are well-established in the daily therapeutic routine, personality issues are far less systematically encompassed. Moreover, while sex disparities in the outcomes of STN-DBS therapy have been reported, little is known about the different effects that DBS treatment may have on mood and personality traits in female and male patients. To this aim, the effect of STN-DBS on personality traits was assessed in 46 PD patients (12 women and 34 men) by means of the Freiburg Personality Inventory. The Becks Depression Inventory (BDI-I) and the Parkinson's Disease Questionnaire were used to evaluate patients' level of depression and quality of life (QoL). Patients completed the questionnaires a few days before, within the first year, and 2 years after surgery. The 12 personality traits defined by the FPI-R questionnaire did not change significantly after STN-DBS surgery (p = 0.198). Women declared higher depression scores through all study stages (p = 0.009), but also showed a stronger QoL amelioration after surgery than male patients (p = 0.022). The BDI-I scores of female patients clearly correlated with their levodopa equivalent daily dose (LEDD; r = 0.621, p = 0.008). Remarkably, in both male and female patients, higher pre-operative LEDDs were related to worse post-operative QoL scores (p = 0.034). These results mitigate the concerns about systematic personality changes due to STN-DBS treatment in PD patients and encourage an early DBS approach, before severe levodopa-induced sequelae may irreparably compromise the patients' QoL. In the future, more focus should lie on sex-related effects, since female patients seem to profit more than male patients from STN-DBS, in terms of reduced depressive symptoms associated with a reduction of the LEDD and amelioration of QoL. These aspects may help to redress the sex imbalance in PD patients treated with DBS, given that women are still strongly under-represented.

Towards unambiguous reporting of complications related to deep brain stimulation surgery: A retrospective single-center analysis and systematic review of the literature.

BACKGROUND AND OBJECTIVE: To determine rates of adverse events (AEs) related to deep brain stimulation (DBS) surgery or implanted devices from a large series from a single institution. Sound comparisons with the literature require the definition of unambiguous categories, since there is no consensus on the reporting of such AEs. PATIENTS AND METHODS: 123 consecutive patients (median age 63 yrs; female 45.5%) treated with DBS in the subthalamic nucleus (78 patients), ventrolateral thalamus (24), internal pallidum (20), and centre médian-parafascicular nucleus (1) were analyzed retrospectively. Both mean and median follow-up time was 4.7 years (578 patient-years). AEs were assessed according to three unambiguous categories: (i) hemorrhages including other intracranial complications because these might lead to neurological deficits or death, (ii) infections and similar AEs necessitating the explantation of hardware components as this results in the interruption of DBS therapy, and (iii) lead revisions for various reasons since this involves an additional intracranial procedure. For a systematic review of the literature AE rates were calculated based on primary data presented in 103 publications. Heterogeneity between studies was assessed with the I2 statistic and analyzed further by a random effects meta-regression. Publication bias was analyzed with funnel plots. RESULTS: Surgery- or hardware-related AEs (23) affected 18 of 123 patients (14.6%) and resolved without permanent sequelae in all instances. In 2 patients (1.6%), small hemorrhages in the striatum were associated with transient neurological deficits. In 4 patients (3.3%; 0.7% per patient-year) impulse generators were removed due to infection. In 2 patients electrodes were revised (1.6%; 0.3% per patient-year). There was no lead migration or surgical revision because of lead misplacement. Age was not statistically significant different (p>0.05) between patients affected by AEs or not. AE rates did not decline over time and similar incidences were found among all patients (423) implanted with DBS systems at our institution until December 2016. A systematic literature review revealed that exact AE rates could not be determined from many studies, which could not be attributed to study designs. Average rates for intracranial complications were 3.8% among studies (per-study analysis) and 3.4% for pooled analysis of patients from different studies (per-patient analysis). Annual hardware removal rates were 3.6 and 2.4% for per-study and per-patient analysis, respectively, and lead revision rates were 4.1 and 2.6%, respectively. There was significant heterogeneity between studies (I2 ranged between 77% and 91% for the three categories; p< 0.0001). For hardware removal heterogeneity (I2 = 87.4%) was reduced by taking study size (p< 0.0001) and publication year (p< 0.01) into account, although a significant degree of heterogeneity remained (I2 = 80.0%; p< 0.0001). Based on comparisons with health care-related databases there appears to be publication bias with lower rates for hardware-related AEs in published patient cohorts. CONCLUSIONS: The proposed categories are suited for an unequivocal assessment of AEs even in a retrospective manner and useful for benchmarking. AE rates in the present cohorts from our institution compare favorable with the literature.

Adverse events in deep brain stimulation: A retrospective long-term analysis of neurological, psychiatric and other occurrences.

BACKGROUND AND OBJECTIVE: The extent to which deep brain stimulation (DBS) can improve quality of life may be perceived as a permanent trade-off between neurological improvements and complications of therapy, comorbidities, and disease progression. PATIENTS AND METHODS: We retrospectively investigated 123 consecutive and non-preselected patients. Indications for DBS surgery were Parkinson's disease (82), dystonia (18), tremor of different etiology (21), Huntington's disease (1) and Gilles de la Tourette syndrome (1). AEs were defined as any untoward clinical occurrence, sign or patient complaint or unintended disease if related or unrelated to the surgical procedures, implanted devices or ongoing DBS therapy. RESULTS: Over a mean/median follow-up period of 4.7 years (578 patient-years) 433 AEs were recorded in 106 of 123 patients (86.2%). There was no mortality or persistent morbidity from the surgical procedure. All serious adverse events (SAEs) that occurred within 4 weeks of surgery were reversible. Neurological AEs (193 in 85 patients) and psychiatric AEs (78 in 48 patients) were documented most frequently. AEs in 4 patients (suicide under GPI stimulation, weight gain >20 kg, impairment of gait and speech, cognitive decline >2 years following surgery) were severe or worse, at least possibly related to DBS and non reversible. In PD 23.1% of the STN-stimulated patients experienced non-reversible (or unknown reversibility) AEs that were at least possibly related to DBS in the form of impaired speech or gait, depression, weight gain, cognitive disturbances or urinary incontinence (severity was mild or moderate in 15 of 18 patients). Age and Hoehn&Yahr stage of STN-simulated PD patients, but not preoperative motor impairment or response to levodopa, showed a weak correlation (r = 0.24 and 0.22, respectively) with the number of AEs. CONCLUSIONS: DBS-related AEs that were severe or worse and non-reversible were only observed in PD (4 of 82 patients; 4.9%), but not in other diseases. PD patients exhibited a significant risk for non-severe AEs most of which also represented preexisting and progressive axial and non-motor symptoms of PD. Mild gait and/or speech disturbances were rather frequent complaints under VIM stimulation. GPI stimulation for dystonia could be applied with negligible DBS-related side effects.

Effectiveness, tolerability and acceptance of a low-dosed estradiol/dienogest formulation (Lafamme 1 mg/2 mg) for the treatment of menopausal complaints: a non-interventional observational study over 6 cycles of 28 days.

BACKGROUND: Concern and controversy characterize nowadays the use of hormone therapy for management of patients with menopausal complaints. This observational non-interventional study examined the use of a marketed oral formulation containing 1 mg estradiol valerate and 2 mg dienogest for treatment of menopausal symptoms in 1292 women visiting 243 gynecological practices in Germany. METHODS: Score changes in the Menopausal Rating Scale (MRS) after three and six 28-day cycles were primary endpoints. Subjective reports on skin- and hair-related complaints and satisfaction with treatment effects were assessed. The incidence of adverse drug reactions (ADRs), adverse events (AEs) and vaginal bleeding was evaluated. RESULTS: MRS total score decreased substantially and stronger than the clinically relevant change of 5 points (p < 0.0001) as compared with baseline. Subjective skin- and hair-related complaints declined. No unexpected ADRs were reported. AEs (including ADRs) were registered in 8.8% of the participants; most frequent AEs/ADRs were postmenopausal hemorrhage (2.9%) and drug ineffective (1.4%). Nearly 76% of the subjects remained amenorrheic. Approximately 90% of the patients rated the medication's effectiveness/tolerability as good/very good; 84% intended to continue the treatment. CONCLUSION: This low-dose estradiol/dienogest formulation proved efficient and well-tolerated option for the alleviation of menopausal symptoms associated with estrogen deficiency.

Effectiveness, tolerability and acceptance of an oral estradiol/levonorgestrel formulation for the treatment of menopausal complaints: a non-interventional observational study over six cycles of 28 days.

BACKGROUND: Use of hormone therapy for menopausal complaints is a subject of controversy and increased uncertainty and concerns. This non-interventional study aimed to investigate a marketed oral formulation containing 1 mg estradiol and 0.04 mg levonorgestrel for continuous treatment of menopausal symptoms for approximately 6 months in women visiting gynecological practices in Germany. METHODS: Changes in the menopause rating scale (MRS) total and sub-domain scores after three and six 28-d cycles served as primary endpoint. Skin- and hair-related complaints, quality of sexual life and subjective satisfaction with the treatment were assessed. Adverse drug reactions (ADRs), adverse events (AEs) and vaginal bleeding were evaluated. RESULTS: MRS scores improved significantly above 5 points of clinical relevance as compared to baseline (n = 736, p < 0.0001). Skin- and hair-related symptoms abated; quality of sexual life improved. AEs were registered in 9.9% of the participants. No unexpected ADRs were reported. Bleeding episodes consistently decreased; >75% of the subjects were amenorrheic throughout the study. Medication's effectiveness and tolerability was rated very good/good by >80% of the participants, who also continued treatment. CONCLUSION: This estradiol/low-dose levonorgestrel formulation safely alleviates menopausal symptoms in peri- and postmenopausal women with add-on benefits regarding dermatological and sexual life complaints.

Effect of extended-cycle regimen with an oral contraceptive containing 30 mcg ethinylestradiol and 2 mg dienogest on bleeding patterns, safety, acceptance and contraceptive efficacy.

BACKGROUND: The present study compared the efficacy and safety of a combined oral contraceptive containing 30 mcg ethinylestradiol and 2 mg dienogest (EE/DNG) in conventional and extended-cycle regimen over 1 year of treatment. STUDY DESIGN: In a phase III, randomized, prospective, open, two-arm, multicenter study, 1315 sexually active women (range, 18-40 years) were treated with EE/DNG either conventionally (21/7 days) or according to an extended-cycle regimen (84/7 days). Data were documented on volunteer diaries, and adverse events (AEs) were reported during five visits. RESULTS: In the extended-regimen group, the total number of days with bleeding progressively decreased over time, and overall, the volunteers had fewer numbers of days with bleeding/spotting compared to those treated conventionally. Intracyclic bleeding, on the other hand, was more frequent in the extended-cycle group, although its frequency considerably decreased over time. Both regimens offered reliable contraception, with an unadjusted Pearl Index of 0.489 for the conventional regimen and 0.495 for the extended regimen. The number of AEs was higher in the extended-cycle group, although the group differences tended to decrease over time. CONCLUSIONS: Extended-cycle use of EE/DNG was effective and mostly well tolerated, appearing to be a favorable option for women who need or wish to omit the pill-free interval.

Effects of an oral contraceptive containing 30 mcg ethinyl estradiol and 2 mg dienogest on lipid metabolism during 1 year of conventional or extended-cycle use.

BACKGROUND: The effects of extended regimens of combined oral contraceptives (COC) on lipid parameters are largely unknown. The present study compared the effects of a COC containing 30 mcg ethinyl estradiol and 2 mg dienogest (EE/DNG) in conventional and extended-cycle regimen over 1 year. STUDY DESIGN: Lipid parameters were measured in 59 women treated with EE/DNG either conventionally (21+7 days) or in extended-cycle regimen (84+7 days). Blood samples were taken in a control cycle and at 3 and 12 months of treatment. RESULTS: The mean levels of total cholesterol, HDL cholesterol and HDL(2) cholesterol underwent modest to moderate significant increases over time, while the significant increase in triglycerides and VLDL cholesterol was more pronounced with both regimens. LDL cholesterol decreased slightly in both regimen groups, whereas lipoprotein(a) was transiently decreased at 3 months only in the extended-cycle group. The changes reached a steady-state at latest at 3 months, but did not exceed the given normal ranges for any of the parameters. Notably, except for lipoprotein(a), the changes in mean lipid levels were not significantly different in the conventional and the extended-cycle regimen at 3 or 12 months of treatment. CONCLUSION: Use of EE/DNG in conventional or extended-cycle regimen resulted in comparable changes of lipid parameters.

Effects of conventional or extended-cycle regimen of an oral contraceptive containing 30 mcg ethinylestradiol and 2 mg dienogest on various hemostasis parameters.

BACKGROUND: The study was conducted to investigate the effect of a combined oral contraceptive (COC) containing 30 mcg ethinylestradiol and 2 mg dienogest with two different regimens on various hemostasis variables. STUDY DESIGN: Hemostatic parameters were measured in 59 women treated with a monophasic COC containing 30 mcg ethinylestradiol and 2 mg dienogest (EE/DNG) either conventionally (13 cycles with 21 days of treatment+7 days without hormones) or with an extended-cycle regimen (4 extended cycles with 84 days of continuous administration of EE/DNG, followed by a hormone-free interval of 7 days). Blood samples were taken on Days 21-26 of the preceding control cycle and on Days 19-21 of the 3rd and 13th conventional cycle or on Days 82-84 of the first and fourth extended cycle. RESULTS: After 3 and 12 months, significant increases in fibrinogen (20%), factor VII antigen (50-60%), factor VII activity (45%), activated factor VII (30-45%) and factor VIII activity (10-20%) occurred in both treatment regimens. In both groups, there was a small but significant decrease in the level and activity of antithrombin, a 20-25% decrease in total and free protein S and a 15-20% rise in the level and activity of protein C, but no significant change of the thrombin-antithrombin complex. A significant over-time rise by about 25% of prothrombin fragment 1+2 occurred only in the extended-cycle group, but this effect did not differ significantly from that observed during conventional treatment. Plasminogen was elevated by 50% in both groups, while tissue-plasminogen activator (t-PA) activity rose by 15% in the conventional group and by 25-30% in the extended-cycle group. In both groups, t-PA antigen was reduced by about 30% and plasminogen activator inhibitor-1 by 40-60%. The levels of the plasmin-antiplasmin complex rose by 30-40% and those of D-dimers by 20-55%. The prothrombin time was slightly increased and the activated partial thromboplastin time was slightly decreased. CONCLUSION: In general, these results were in agreement with those observed during treatment with other COCs. The study demonstrated that during conventional and extended-cycle treatment with EE/DNG, a steady-state in the effects on hemostasis variables was reached within 3 months, and that the effects observed after 3 and 12 months of treatment did not substantially differ between conventional and extended-cycle regimen.

Effects of an oral contraceptive containing 30 mcg ethinyl estradiol and 2 mg dienogest on thyroid hormones and androgen parameters: conventional vs. extended-cycle use.

BACKGROUND: This study was conducted to investigate the effects of an oral contraceptive containing 30 mcg ethinyl estradiol and 2 mg dienogest on thyroid hormones and androgen parameters. STUDY DESIGN: Thyroid and androgen parameters were measured in 59 women treated with a monophasic combined oral contraceptive containing 30 mcg ethinyl estradiol and 2 mg dienogest (EE/DNG) either conventionally (13 cycles with 21 days of treatment+7 days without hormones) or according to an extended-cycle regimen (four extended cycles with 84 days of continuous administration of EE/DNG, followed by a hormone-free interval of 7 days). Blood samples were taken on Days 21-26 of the preceding control cycle and on Days 19-21 of the 3rd and 13th conventional cycle, or on Days 82-84 of the first and fourth extended cycle. RESULTS: At both time points, the serum concentrations of thyroxine-binding globulin were elevated by about 65% in both treatment regimens. Likewise, both groups showed an increase in total triiodothyronine (T3) and total thyroxine (T4) by 30-40%, and no change in free T4. Until the 12th month of conventional treatment, the level of free T3 remained unchanged but decreased slightly during the extended-cycle regimen. In both groups there was a rise of sex hormone-binding globulin by 210-230% after 3 months and by 220-250% after 12 months. The levels of total testosterone were reduced by about 40% and those of free testosterone by 55-65% after 3 and 12 months. CONCLUSION: The results suggest that, during conventional and extended-cycle treatment with EE/DNG, a steady state in the effects on thyroid hormones and androgen parameters was reached within 3 months and that the changes in the various hormonal parameters did not substantially differ between conventional and extended-cycle regimen.

Fertility after discontinuation of treatment with an oral contraceptive containing 30 microg of ethinyl estradiol and 2 mg of dienogest.

OBJECTIVE: To examine the conception rate after cessation of a combination of 30 microg ethinyl E2 and 2 mg dienogest (EE/DNG). DESIGN: Prospective observational study. SETTING: Population-based cohort in Germany. PATIENT(S): Women who wished to become pregnant after cessation of an oral contraceptive (EE/DNG). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Cumulative conception rate within 1 year after termination of EE/DNG and time to pregnancy. RESULT(S): After 1 year of follow-up, the cumulative pregnancy rate was 86.6% (full analysis set; n = 706). When all participants with complete data were analyzed (n = 652), the cumulative pregnancy rate was 94.0%. More than 15% of the patients conceived in each of the first three cycles after termination of EE/DNG; the mean time to pregnancy was 3.5 cycles. The preceding duration of treatment with EE/DNG did not influence the conception rate. Except in the youngest age group (16-18 years), a certain delay was observed in the other age groups. CONCLUSION(S): The present prospective study revealed only a slight delay in regaining fertility during the first three cycles after cessation of EE/DNG. Thereafter, the cumulative rate of conception did not differ from that observed in fertile women who attempted to become pregnant without prior contraception.