Edit Bosnyák

Diabetic Neuropathies: Diagnosis and Management

Introduction: Changes in human behaviour and lifestyle over the last century have resulted in a dramatic increase in the incidence of diabetes worldwide. Neuropathy is a common and costly complication of both type 1 and type 2 diabetes. The prevalence of neuropathy is estimated to be about 8% in newly diagnosed patients and greater than 50% in patients with long-standing disease. There are two main types of diabetic neuropathies, named as sensorimotor and autonomic neuropathies. Sensorimotor neuropathy is marked by pain, paraesthesia and sensory loss, and autonomic neuropathy may contribute to myocardial infarction, malignant arrhythmia and sudden death. Methods: In this article we reviewed the pathogenesis, clinical manifestations diagnosis and treatment of diabetic neuropathies. Conclusion: Sensorimotor and autonomic neuropathies (cardiovascular, gastrointestinal and genitourinary autonomic neuropathies) are common in diabetic patients. Apart from strict glycaemic control, no further therapeutic approach exists in the prevention of this phenomenon. Intensive diabetes therapy, intensive multifactorial cardiovascular risk reduction and lifestyle intervention are recommended in patients with cardiovascular autonomic neuropathy. Gastroparesis is the most debilitating complication of gastrointestinal autonomic neuropathy and genitourinary autonomic neuropathy can cause sexual dysfunction and neurogenic bladder; these conditions are hard to manage. The symptomatic treatment of sensory symptoms includes tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors, gabapentin, pregabalin and opioids. Other treatment strategies are not so effective.

Bilateral Subthalamic Stimulation can Improve Sleep Quality in Parkinson's Disease

BACKGROUND Sleep problems are among the most common non-motor symptoms of Parkinsons disease (PD). The PD Sleep Scale 2nd version (PDSS-2) improved the original PDSS by adding more items on different aspects of sleep problems, making it a more robust tool to evaluate the severity of sleep disturbances. However, previous studies on deep brain stimulation (DBS) have not used the PDSS-2. OBJECTIVE To determine if the PDSS-2 could detect improvement reliably in sleep problems after bilateral subthalamic nucleus DBS for PD. METHODS In this prospective study, 25 consecutive patients undergoing DBS implantation were enrolled. Patients were examined twice: 1 week prior to the DBS implantation (baseline) and 12 months postoperatively. Severity of PD symptoms were assessed by the Movement Disorders Society Unified PD Rating Scale (MDS-UPDRS) and the Non-Motor Symptoms Scale (NMSS). Presence and severity of sleep disturbances were specifically measured by PDSS-2. RESULTS Total score of MDS-UPDRS improved from 81 (median, interquartile-range: 63-103) to 55 points (median, IQR: 46-75, p <  0.001). Health-related quality of life, measured by PDQ-39, also improved from 29 (IQR: 18-40) to 15 (IQR: 9-28) points (p = 0.002). Most domains of NMSS also improved. At baseline 13 patients reported sleep problems, but 1 year after DBS implantation only 3 did (p = 0.012). Although only 6 out of 15 items showed a significant decrease after DBS implantation, the total score of PDSS-2 decreased from 24 (IQR: 17-32) to 10 (IQR: 7-18) points (P <  0.001). CONCLUSIONS Based on our results, PDSS-2 can detect improvements in sleep quality reliably after DBS implantation.

Is the MDS-UPDRS a Good Screening Tool for Detecting Sleep Problems and Daytime Sleepiness in Parkinson’s Disease?

Movement Disorder Society-sponsored Unified Parkinsons Disease Rating Scale (MDS-UPDRS) has separate items for measuring sleep problems (item 1.7) and daytime sleepiness (1.8). The aim of our study was to evaluate the screening sensitivity and specificity of these items to the PD Sleep Scale 2nd version (PDSS-2) and Epworth Sleepiness Scale (ESS). In this nationwide, cross-sectional study 460 PD patients were enrolled. Spearmans rank correlation coefficients were calculated between the individual items, domains, and the total score of PDSS-2 and item 1.7 of MDS-UPDRS. Similarly, the items and the total score of ESS were contrasted to item 1.8 of MDS-UPDRS. After developing generalized ordinal logistic regression models, the transformed and observed scores were compared by Lins Concordance Correlation Coefficient. Only item 3 difficulties staying asleep and the “disturbed sleep” domain of PDSS-2 showed high correlation with “sleep problems” item 1.7 of the MDS-UPDRS. Total score of PDSS-2 had moderate correlation with this MDS-UPRDS item. The total score of ESS showed the strongest, but still moderate, correlation with “daytime sleepiness” item 1.8 of MDS-UPDRS. As intended, the MDS-UPDRS serves as an effective screening tool for both sleep problems and daytime sleepiness and identifies subjects whose disabilities need further investigation.

Visuospatial impairment in Parkinson's disease: The role of laterality

Asymmetry is one of the unique and mysterious features of Parkinsons disease (PD). Motor symptoms develop unilaterally either on the left (LPD) or the right side (RPD). Incongruent data are available whether the side of onset has an impact on cognition in PD. The objective of this study is to compare the visuospatial performance of RPD and LPD patients. Seventy-one non-demented, non-depressive and right-handed patients were categorized into RBD (n = 36) and LPD (n = 35) groups. Rey-Osterrieth Complex Figure Test (ROCF) was evaluated by both the Taylors and Lorings scoring systems. Subsequently, we also performed subgroup analyses on patients having short disease duration (≤5 years, 15 RBD and 15 LPD patients). The standard analysis of ROCF (Taylors system) did not reveal any differences; however, the utilization of the Lorings system demonstrated that LPD patients had significantly worse visuospatial performance than the RPD subjects (3.0 vs. 2.0 points, median, p = 0.002). Correlation between the number of spatial errors and the degree of asymmetry was significant (r = −0.437, p = 0.001). However, this difference could not be observed in PD patients with short disease duration. LPD patients had worse visuospatial performance than the RPD subjects and the number of errors tightly correlated with the degree of asymmetry and long disease duration.

Deep Brain Stimulation Can Preserve Working Status in Parkinson’s Disease

Objectives. Our investigation aimed at evaluating if bilateral subthalamic deep brain stimulation (DBS) could preserve working capability in Parkinsons disease (PD). Materials. We reviewed the data of 40 young (<60 year-old) PD patients who underwent DBS implantation and had at least 2 years of follow-up. Patients were categorized based on their working capability at time of surgery: “active job” group (n = 20) and “no job” group (n = 20). Baseline characteristics were comparable. Quality of life (EQ-5D) and presence of active job were evaluated preoperatively and 2 years postoperatively. Results. Although similar (approximately 50%) improvement was achieved in the severity of motor and major nonmotor symptoms in both groups, the postoperative quality of life was significantly better in the “active job” group (0.687 versus 0.587, medians, p < 0.05). Majority (80%) of “active job” group members were able to preserve their job 2 years after the operation. However, only a minimal portion (5%) of the “no job” group members was able to return to the world of active employees (p < 0.01). Conclusions. Although our study has several limitations, our results suggest that in patients with active job the appropriately “early” usage of DBS might help preserve working capability and gain higher improvement in quality of life.

Are Branded and Generic Extended-Release Ropinirole Formulations Equally Efficacious? : A Rater-Blinded, Switch-Over, Multicenter Study

The aim of this study was to compare the efficacy of the branded and a generic extended-release ropinirole formulation in the treatment of advanced Parkinsons disease (PD). Of 22 enrolled patients 21 completed the study. A rater blinded to treatment evaluated Unified Parkinsons Disease Rating Scale, Fahn-Tolosa-Marin Tremor Rating Scale, Nonmotor Symptoms Assessment Scale, and a structured questionnaire on ropinirole side effects. Besides, the patients self-administered EQ-5D, Parkinsons Disease Sleep Scale (PDSS-2), and Beck Depression Inventories. Branded and generic ropinirole treatment achieved similar scores on all tests measuring severity of motor symptoms (primary endpoint, UPDRS-III: 27.0 versus 28.0 points, P = 0.505). Based on patient diaries, the lengths of “good time periods” were comparable (10.5 and 10.0 hours for branded and generic ropinirole, resp., P = 0.670). However, generic ropinirole therapy achieved almost 3.0 hours shorter on time without dyskinesia (6.5 versus. 9.5 hours, P < 0.05) and 2.5 hours longer on time with slight dyskinesia (3.5 versus. 1.0 hours, P < 0.05) than the branded ropinirole did. Except for gastrointestinal problems, nonmotor symptoms were similarly controlled. Patients did not prefer either formulation. Although this study has to be interpreted with limitations, it demonstrated that both generic and branded ropinirole administration can achieve similar control on most symptoms of PD.

Serum L-arginine and dimethylarginine levels in migraine patients with brain white matter lesions

Background/Aim Migraine is a risk factor for the formation of silent brain white matter lesions (WMLs) that are possibly ischemic in nature. Although dysfunction of the L-arginine/nitric oxide (NO) pathway has been associated with oxidative stress and endothelial dysfunction in migraine, its role in WML development has not been specifically investigated. Thus, this prospective study aimed to measure the serum concentrations of the NO substrate L-arginine, the NO synthase inhibitor asymmetric dimethylarginine (ADMA), and the L-arginine transport regulator symmetric dimethylarginine (SDMA) in migraine patients in a headache-free period. Methods All participants underwent MR imaging to assess for the presence of WMLs on fluid-attenuated inversion recovery imaging. Altogether 109 migraine patients (43 with lesions, 66 without lesions) and 46 control individuals were studied. High-performance liquid chromatography was used to quantify L-arginine, ADMA and SDMA serum concentrations. Migraine characteristics were investigated, and participants were screened for risk factors that can lead to elevated serum ADMA levels independent of migraine. Results Migraine patients and controls did not differ in regard to vascular risk factors. Migraineurs with WMLs had a longer disease duration (p < 0.001) and a higher number of lifetime headache attacks (p = 0.005) than lesion-free patients. Higher L-arginine serum levels were found in both migraine subgroups compared to controls (p < 0.001). Migraine patients with WMLs showed higher ADMA concentrations than lesion-free patients and controls (p < 0.001, for both). In migraineurs, the presence of WMLs, aura and increasing age proved to be significant predictors of increased ADMA levels (p = 0.008, 0.047 and 0.012, respectively). SDMA serum levels of lesional migraineurs were higher than in nonlesional patients (p < 0.001). The presence of lesions and increasing age indicated an increased SDMA level (p = 0.017 and 0.001, respectively). Binary logistic regression analysis showed that ADMA level (p = 0.006), increasing age (p = 0.017) and the total number of lifetime migraine attacks (p = 0.026) were associated with an increased likelihood of exhibiting WMLs. There was no significant effect of age on ADMA and SDMA concentrations in controls. Conclusions Elevated ADMA levels may impact the pathogenesis of migraine-related WMLs by influencing cerebrovascular autoregulation and vasomotor reactivity. Higher SDMA concentrations may indirectly influence NO synthesis by reducing substrate availability. Elevated L-arginine serum levels might reflect an increased demand for NO synthesis.

Prognostic Molecular and Imaging Biomarkers in Primary Glioblastoma

Purpose Several molecular glioma markers (including isocitrate dehydrogenase 1 [IDH1] mutation, amplification of the epidermal growth factor receptor [EGFR], and methylation of the O6-methylguanine-DNA methyltransferase [MGMT] promoter) have been associated with glioblastoma survival. In this study, we examined the association between tumoral amino acid uptake, molecular markers, and overall survival in patients with IDH1 wild-type (primary) glioblastoma. Patients and Methods Twenty-one patients with newly diagnosed IDH1 wild-type glioblastomas underwent presurgical MRI and PET scanning with alpha[C-11]-L-methyl-tryptophan (AMT). MRI characteristics (T2- and T1-contrast volume), tumoral tryptophan uptake, PET-based metabolic tumor volume, and kinetic variables were correlated with prognostic molecular markers (EGFR and MGMT) and overall survival. Results EGFR amplification was associated with lower T1-contrast volume (P = 0.04) as well as lower T1-contrast/T2 volume (P = 0.04) and T1-contrast/PET volume ratios (P = 0.02). Tumors with MGMT promoter methylation showed lower metabolic volume (P = 0.045) and lower tumor/cortex AMT unidirectional uptake ratios than those with unmethylated MGMT promoter (P = 0.009). While neither EGFR amplification nor MGMT promoter methylation was significantly associated with survival, high AMT tumor/cortex uptake ratios on PET were strongly prognostic for longer survival (hazards ratio, 30; P = 0.002). Estimated mean overall survival was 26 months in patients with high versus 8 months in those with low tumoral AMT uptake ratios. Conclusions The results demonstrate specific MRI and amino acid PET imaging characteristics associated with EGFR amplification and MGMT promoter methylation in patients with primary glioblastoma. High tryptophan uptake on PET may identify a subgroup with prolonged survival.

Abstract 3730: Early metabolic response to tumor-treating fields in patients with recurrent glioblastoma

PURPOSE. Tumor-Treating Fields (TTFields) is an FDA-approved treatment approach for patients with both newly-diagnosed and recurrent glioblastoma. The main purpose of the present study was to explore if amino acid positron emission tomography (PET) is able to detect an early, objective metabolic tumor response during the first months of TTFields therapy. METHODS. Patients with MRI signs of recurrent glioblastoma eligible for TTFields along with maintenance temozolomide were recruited for PET scanning with alpha[C-11]-methyl-L-tryptophan (AMT) at baseline (before start of TTFields application) and up to 3 months later. Serial MRIs were also performed in 1-2 months intervals. AMT accumulation in the MRI-detected tumor mass was measured by standardized uptake values (SUVs), and PET-based tumor volumes were also calculated. Interval changes of these PET variables were compared to changes in areas of MRI enhancement. RESULTS. Out of 7 recruited patients, 5 showed appropriate compliance (>75%) with the device and underwent follow-up PET. Four of the 5 patients showed a clear metabolic response during TTF treatment on PET imaging. Two patients, who received TTFields treatment only (in addition to maintenance temozolomide), showed 25% and 100% decrease of PET-based tumor volumes, respectively. MRI was stable (patient #1) or showed increasing contrast enhancement (#2) during the same period. In this latter patient, TTFields was continued with bevacizumab treatment, leading to decreased contrast enhancement and further decrease of AMT uptake on a second follow-up PET. In two other patients (#3 and #4), TTFields were combined with bevacizumab rescue treatment. Patient #3 showed a markedly decreased tumoral AMT uptake and metabolic volume along with stable MRI enhancement. Patient #4 showed interval decrease of tryptophan PET uptake 2 months after initiation of TTFields therapy. Finally, patient #5 showed an interval expansion of the PET-based tumor volume along with MRI progression during a 2-month follow-up despite TTFields combined with bevacizumab and carboplatin. CONCLUSIONS. This is the first study to demonstrate an objective metabolic response of recurrent glioblastoma within 1.5-3 months after initiation of TTFields. The data suggest that amino acid PET can identify early responders to TTFields therapy. Citation Format: Sandeep Mittal, Geoffrey R. Barger, Edit Bosnyak, Varun B. Shah, Csaba Juhasz. Early metabolic response to tumor-treating fields in patients with recurrent glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3730. doi:10.1158/1538-7445.AM2017-3730

Contents Vol. 98, 2013

D.H. Abbott, Madison, Wisc. E. Arzt, Buenos Aires A.V. Babwah, London, Ont. T. Bartness, Atlanta, Ga. C.L. Bethea, Beaverton, Oreg. D.W. Brann, Augusta, Ga. B. Canny, Monash, Vic. M. Caplin, London K. Catt, Bethesda, Md. A. Chodobski, Providence, R.I. S.L. Dickson, Gothenburg J. Drouin, Montreal, Que. P.J. Enriori, Monash, Vic. W. Farrell, Keele M. Freeman, Tallahassee, Fla. A.C. Gore, Austin, Tex. K. Grove, Beaverton, Oreg. T. Harmar, Edinburgh A. Herbison, Dunedin J. Herman, Cincinnati, Ohio J.J. Hirst, Callaghan, N.S.W. T. Hökfelt, Stockholm U. Kaiser, Boston, Mass. G. Kaltsas, Athens K. Kim, Seoul J.Z. Kiss, Geneva A.C. Latronico, São Paulo G. Leng, Edinburgh J. Levine, Evanston, Ill. C. Libertun, Buenos Aires C. Llorens-Cortes, Paris A. Lomniczi, Beaverton, Oreg. A. Loudon, Manchester Z.-L. Lu, Edinburgh G. Martinez de la Escalera, Querétaro R. Melcangi, Milano I. Modlin, New Haven, Conn. Z. Naor, Tel Aviv M. Palkovits, Budapest I. Parhar, Kuala Lumpur D.W. Pfaff , New York, N.Y. T.M. Plant, Pittsburgh, Pa. J. Reul, Bristol R. Reynolds, Edinburgh E. Rissman, Charlottesville, Va. J.L. Roberts, San Antonio, Tex. I. Robinson, London P. Ruszniewski, Clichy W. Schlegel, Geneva D. Skinner, Laramie, Wyo. M. Sleeman, Clayton, Vic. J. Smith, Perth, W.A. E. Spinedi, La Plata R. Steiner, Seattle, Wash. E. Terasawa, Madison, Wisc. A. Tilbrook, Roseworthy, S.A. B. Walker, Edinburgh H. Watanobe, Chiba M. Watt, Clayton, Vic. K. Weston-Green, Wollongong, N.S.W. M.E. Wierman, Aurora, Colo. J. Wingfi eld, Seattle, Wash. S. Wray, Bethesda, Md. International Journal for Basic and Clinical Studies on Neuroendocrine Relationships