Integrative oncology: evidence-based medicine - The multidisciplinary experience of the Integrative Medicine Research Group (IMRG).

The purpose of this conference was to explain the relationship between the integrative and complementary medicine and cancer disease through evidence-based medicine. The topics covered are numerous and are characterized by the multidisciplinary approach of the researchers involved in this complex scenario. The Integrative Medicine Research Group (IMRG) studies the complementary and integrative approach in cancer patients with the aim to highlight the risk of drug and nutraceutical interactions and, at the same time, improve the quality of life in this particular set of patients. Our auspicious is to have an integrative medicine approach to all chronic diseases, oncological included.

Consistent skin α-synuclein positivity in REM sleep behavior disorder - A two center two-to-four-year follow-up study.

OBJECTIVE/METHODS: Phosphorylated alpha-synuclein (p-syn) in dermal nerves of patients with isolated REM sleep behavior disorder (iRBD) is detectable by immunofluorescence-labeling. Skin-biopsy-p-syn-positivity was recently postulated to be a prodromal marker of Parkinson's disease (PD) or related synucleinopathies. Here, we provide two-to four-year clinical and skin biopsy follow-up data of 33 iRBD patients, whose skin biopsy findings at baseline were reported in 2017. RESULTS: Follow-up biopsies were available from 25 patients (18 positive at baseline) and showed consistent findings over time in 24 patients. One patient converted from skin-biopsy-negativity to -positivity. P-syn-positivity was observed in iRBD patients who still had a normal FP-CIT-SPECT two years later. Clinically, five of the 23 at baseline skin-biopsy-positive patients (21.7%) had converted to PD or dementia with Lewy bodies at follow-up, but none of the skin-biopsy-negative patients. CONCLUSIONS: Dermal p-syn in iRBD is most probably an early consistent marker of synucleinopathy and may support other indicators of conversion to manifest disease state.

Pain in focal dystonias - A focused review to address an important component of the disease.

Focal dystonia is characterized by involuntary muscle contractions that cause abnormal postures and/or twisting movements in a segment of the body. Motor symptoms have a major impact on disability in this condition, but the presence of pain represents an additional source of impairment and poor quality of life. Notwithstanding that pain occurs in up to 70% of patients with cervical dystonia and in a relevant proportion of subjects with focal dystonia of the limbs, it has received very little attention from researchers and controlled trials are scant. The aim of this review is to summarize the current knowledge on the clinical assessment and management of pain in focal dystonias. The search results will inform on the types of pain reported in focal dystonias, on the tools that are used to quantify pain and on the efficacy of pharmacological and non-pharmacological approaches. The collated data will hopefully improve the clinical management of focal dystonia and also stimulate future research on dystonia-associated pain. Optimization of the outcome indeed requires the identification and the management of all the factors that determine disability and hence relies on a multidisciplinary approach.

Tremor induced by Calcineurin inhibitor immunosuppression: a single-centre observational study in kidney transplanted patients.

INTRODUCTION: Tremor is the most frequent and disabling neurological side effect under Calcineurin inhibitor-induced immunosuppression, but no studies have defined its phenomenology, severity, distribution, the impact on quality of life, as well as of other neurological symptoms associated. METHODS: 126 consecutive kidney-transplanted patients, under treatment with Cyclosporin A, Tacrolimus and non-Calcineurin inhibitors, within therapeutic range, were enrolled. Participants underwent a deep neurological examination by two blinded to the treatment raters, and a blood sampling to assess plasmatic immunosuppressant level and nephrological function tests. Tremor and cerebellar signs were scored according to the Fahn-Tolosa-Marin and the SARA scale. Parkinsonism was excluded applying the UPDRS (part III). RESULTS: Tremor was more common and severe in the Tacrolimus group, similar to impairment in ADL. Regardless of treatment, tremor involved both upper and lower limbs and was activated by action, but in about 50% of cases presented in action and rest condition. Plasmatic level of Tacrolimus was higher in patients with tremor than in those without, while cholesterol was significantly lower. Cerebellar and neuropathic signs were overall mild and were not significantly different across the three groups comparing patients with and without tremor. CONCLUSIONS: Non-Calcineurin inhibitors such as Sirolimus have the lowest propensity to induce tremor and with a milder severity, while Calcineurin inhibitors, especially Tacrolimus, the highest, and regardless of the formulation. Plasmatic concentration of Tacrolimus was higher in tremulous patients; further research needs to validate the role of cholesterol plasmatic concentration in predicting the occurrence of tremor in patients on Tacrolimus.

Correction to: The Italian Dystonia Registry: rationale, design and preliminary findings.

In the original article, Gina Ferrazzano was affiliated to Department of Neurology and Psychiatry, Neuromed Institute IRCCS, Sapienza University of Rome, Pozzilli, Italy.The corrected affiliation should be: Neuromed Institute IRCCS, Pozzilli, IS, Italy.

Pain in Parkinson's disease: facts and uncertainties.

Pain is one of the most common and troublesome non-motor symptoms of Parkinson's disease (PD). It can appear at any time during the disease and is often present before diagnosis. However, there is little or no consensus on its definition. An expert group of clinicians with relevant research experience met to review the existing evidence and to identify gaps in our understanding leading towards AUTHOR: 'understanding towards' has been changed to 'understanding leading towards'. Please check and confirm that this is appropriate an optimized therapy of pain in PD. Key findings from epidemiologic, neurophysiologic, neuroimaging and clinical studies are reviewed. In each case, the evidence base is limited by wide variations in the definitions of pain applied, study methodologies and populations evaluated. Disease-related and medical conditions trigger spontaneous pain in patients with PD, which is then abnormally processed and results in painful manifestations in specific body parts. Dopaminergic medications, such as rotigotine, as well as opiate analgesics, such as oxycodone, have shown positive results but future studies with more detailed pain characterization at inclusion are warranted.

Non-invasive brain stimulation for dystonia: therapeutic implications.

Dystonia is characterized by excessive muscle contractions giving rise to abnormal posture and involuntary twisting movements. Although dystonia syndromes are a heterogeneous group of disorders, certain pathophysiological mechanisms have been consistently identified across different forms. These pathophysiological mechanisms have subsequently been exploited for the development of non-invasive brain stimulation (NIBS) techniques able to modulate neural activity in one or more nodes of the putative network that is altered in dystonia, and the therapeutic role of NIBS has hence been suggested. Here all studies that applied such techniques as a therapeutic intervention in any forms of dystonia, including the few works performed in children, are reviewed and emerging concepts and pitfalls of NIBS are discussed.

Metabolic and kinematic parameters during walking with poles in Parkinson's disease.

In healthy people, energy expenditure is generally higher during walking with poles (WP) than during conventional walking (W). In persons with Parkinson's disease (PD), walking is slower and may be associated with greater energy consumption, stride-to-stride variability, and difficulty in regulating stride length. The aim of this study was to determine whether treadmill WP at three different speeds could induce changes in gait kinematics and oxygen consumption in PD patients. The study sample was 20 patients with mild-to-moderate PD and 20 age-matched healthy controls. Subjects underwent 5-min W and WP treadmill tests at three different speeds (2.5, 3.5, and 4.5 km/h). Metabolic and gait parameters (ventilation, gas exchange, stride count and length) were recorded. As compared with the healthy controls, higher energy consumption (P < 0.05) (and other metabolic parameters), shorter stride, and reduced cadence (P < 0.05) were observed for the PD patients, independent of the walking technique. All subjects were noted to take longer strides during WP (P < 0.001), especially at the lowest treadmill speed. However, significantly higher energy consumption was observed only for the healthy controls (P < 0.05). No changes in metabolic parameters during WP were recorded; however, a substantial improvement in gait cycle length was noted for the PD patients.

Relationship between pain and motor and non-motor symptoms in Parkinson's disease.

BACKGROUND AND PURPOSE: Although female gender, depressive symptoms and medical conditions predisposing to pain are more common in patients with Parkinson's disease (PD) with pain, no study has yet explored the relationship between pain and other non-motor symptoms (NMS). METHODS: A total of 321 consecutive patients with PD [190 men/131 women aged 68.3 (SD 9.2) years] attending four Italian movement disorder clinics were studied. Demographic/clinical data were obtained by a standardized interview and the NMS scale. The association of pain with motor and NMS was assessed by multivariable logistic regression models. RESULTS: At the time of the study, 180 patients with PD (56%) reported chronic pain that, in most cases, was described as being muscular or arthralgic pain. Pain preceded the onset of motor signs in 36/180 patients. In the main-effect model, factors independently associated with pain were female sex [odds ratio (OR), 2.1; P = 0.01], medical conditions predisposing to pain (OR, 2.9; P < 0.001), Hoehn-Yahr staging (OR, 1.9; P = 0.04), motor complications (OR, 4.7; P = 0.04) and NMS belonging to the sleep/fatigue (OR, 1.6; P = 0.04) and mood/cognition (OR, 1.6; P = 0.03) domains. Most explanatory variables in the multivariable analysis were similarly distributed in patients in whom pain may have been related to PD or to a cause other than PD. CONCLUSIONS: We confirm that pain in PD is more frequent in women and in subjects with medical conditions predisposing to painful symptoms. Moreover, this strengthens the association between pain and motor severity measures and NMS domains, particularly sleep and mood disturbances.

The Italian Dystonia Registry: rationale, design and preliminary findings.

The Italian Dystonia Registry is a multicenter data collection system that will prospectively assess the phenomenology and natural history of adult-onset dystonia and will serve as a basis for future etiological, pathophysiological and therapeutic studies. In the first 6 months of activity, 20 movement disorders Italian centres have adhered to the registry and 664 patients have been recruited. Baseline historical information from this cohort provides the first general overview of adult-onset dystonia in Italy. The cohort was characterized by a lower education level than the Italian population, and most patients were employed as artisans, builders, farmers, or unskilled workers. The clinical features of our sample confirmed the peculiar characteristics of adult-onset dystonia, i.e. gender preference, peak age at onset in the sixth decade, predominance of cervical dystonia and blepharospasm over the other focal dystonias, and a tendency to spread to adjacent body parts, The sample also confirmed the association between eye symptoms and blepharospasm, whereas no clear association emerged between extracranial injury and dystonia in a body site. Adult-onset dystonia patients and the Italian population shared similar burden of arterial hypertension, type 2 diabetes, coronary heart disease, dyslipidemia, and hypothyroidism, while hyperthyroidism was more frequent in the dystonia population. Geographic stratification of the study population yielded no major difference in the most clinical and phenomenological features of dystonia. Analysis of baseline information from recruited patients indicates that the Italian Dystonia Registry may be a useful tool to capture the real world clinical practice of physicians that visit dystonia patients.

A prospective evaluation of taste in Parkinson's disease.

It is well known that Parkinson's disease is characterized by a variety of non-motor symptoms. A gustatory deficit is hypothesized to be one of them although few and only cross-sectional studies are available. The aim of our pilot study was to prospectively investigate the taste function in Parkinson's disease patients after some years from the first evaluation (mean follow-up 4.35 ± 0.49 years; time range 3.5-5.6 years). A group of 26 patients was re-examined (16 males and 10 females; mean age 70.9 ± 8.4 years, range 54-88 years). Taste function was assessed in one session, by means of the Whole Mouth Test (WMT) and Taste Strips Test (TST). Olfaction was also evaluated with the Sniffin' Sticks Identification Test (SST). All these tests are commercially available (Burghart Company, Germany). All patients were able to understand and complete the procedure. Although scores decreased over time, no significant difference was found between global taste scores of first and second evaluation, neither comparing every single taste quality (WMT: p = 0.234, Mann-Whitney U test; TST: p = 0.747, Mann-Whitney U test; McNemar chi-square in the range of 0-1.455). These results confirm a persistent but slight and stable taste impairment, in patients with Parkinson's disease. Future studies on a much larger sample of patients are certainly required.

Functional facial and tongue movement disorders.

Functional movement disorders (FMDs) affecting the eyelids, tongue, and other facial muscles are often underrecognized because their phenomenology has not been fully characterized. Nevertheless, these disorders are more common than previously thought. In this chapter we will discuss the phenomenology as well as the clinical and instrumental diagnosis of facial FMDs. Facial FMDs should be considered when a patient exhibits any combination of the following features: (1) fixed unilateral facial contractions, especially with lower lip, with or without ipsilateral jaw involvement, of maximal severity at onset; (2) inconsistent features such as changes in side and pattern during or between examination; (3) associated somatoform or nonphysiologic sensory or motor findings; (4) reduction or abolition of facial spasm with distraction; (5) response to suggestion or psychotherapy; (6) rapid onset and/or spontaneous remissions; and (7) normal neurologic examination. Supportive features are young age, female gender, and associated medical conditions such as depression, headaches, facial pain, fibromyalgia, or irritable-bowel syndrome. Finally, the differential diagnosis with the organic counterparts will be also addressed, particularly with respect to blepharospasm, oromandibular dystonia, and hemifacial spasm.

Rehabilitation procedures in the management of gait disorders in the elderly.

Gait disorders are common and very disabling in elderly people, leading to an increase of risk of falling and reductions in quality of life. So far, many clinical classifications of gait disorders in the elderly population have been proposed. Here we suggest a novel categorization of gait disorders in elderly people, which takes into account the several resources required during gait. The biomechanical constraints, movement and sensory strategies, orientation in space, control of dynamics and cognitive processing are essential to perform safely gait. Moreover, the strictly connection between gait and balance has been discussed. According to this perspective, a literature search was performed including studies investigating the rehabilitation procedures in the management of balance and gait disorders in elderly people. Training aimed at improving muscle strength and flexibility, movement strategies, sensorimotor integration and sensory reweighting processes, balance in static and dynamic conditions and cognitive strategies have been proposed as possible therapeutic approaches in elderly people affected by gait disorders. Moreover, the role of new technological devices in improving balance and gait control has been also described. A multidisciplinary and interdisciplinary approach is fundamental for the management of gait disorders in elderly people. Rehabilitation procedures should take into consideration all the potential constraints involved in gait disorders in order to select the most appropriate intervention.

A randomized clinical trial to evaluate the effects of rasagiline on depressive symptoms in non-demented Parkinson's disease patients.

BACKGROUND AND PURPOSE: Depressed mood is a common psychiatric problem associated with Parkinson's disease (PD), and studies have suggested a benefit of rasagiline treatment. METHODS: ACCORDO (see the ) was a 12-week, double-blind, placebo-controlled trial to evaluate the effects of rasagiline 1 mg/day on depressive symptoms and cognition in non-demented PD patients with depressive symptoms. The primary efficacy variable was the change from baseline to week 12 in depressive symptoms measured by the Beck Depression Inventory (BDI-IA) total score. Secondary outcomes included change from baseline to week 12 in cognitive function as assessed by a comprehensive neuropsychological battery; Parkinson's disease quality of life questionnaire (PDQ-39) scores; Apathy Scale scores; and Unified Parkinson's Disease Rating Scale (UPDRS) subscores. RESULTS: One hundred and twenty-three patients were randomized. At week 12 there was no significant difference between groups for the reduction in total BDI-IA score (primary efficacy variable). However, analysis at week 4 did show a significant difference in favour of rasagiline (marginal means difference ± SE: rasagiline -5.46 ± 0.73 vs. placebo -3.22 ± 0.67; P = 0.026). There were no significant differences between groups on any cognitive test. Rasagiline significantly improved UPDRS Parts I (P = 0.03) and II (P = 0.003) scores versus placebo at week 12. Post hoc analyses showed the statistical superiority of rasagiline versus placebo in the UPDRS Part I depression item (P = 0.04) and PDQ-39 mobility (P = 0.007) and cognition domains (P = 0.026). CONCLUSIONS: Treatment with rasagiline did not have significant effects versus placebo on depressive symptoms or cognition in PD patients with moderate depressive symptoms. Although limited by lack of correction for multiple comparisons, post hoc analyses signalled some improvement in patient-rated cognitive and depression outcomes.

Prevalence and associated features of self-reported freezing of gait in Parkinson disease: The DEEP FOG study.

Freezing of Gait (FOG) is a common and disabling symptom in patients with Parkinson disease (PD). The relationship between FOG and dopaminergic medication is complex. The aim of the present study was to estimate the prevalence of self-reported FOG, its associated clinical features, and its relationship with wearing-off in a wide PD population. This is an observational multicenter study of 634 consecutive non-demented PD patients. Patients were identified either as freezers or non-freezers based on item-3 of the Freezing of Gait-Questionnaire. FOG was then classified as on, off and onoff freezing based on its relationship with wearing-off. Patients were assessed with Unified Parkinson's Disease Rating Scale, Hoehn and Yahr scale, 8-item Parkinson's disease Questionnaire, Mini-Mental State Examination. Data from 593 patients were analyzed, 325 (54.3%) were freezers of whom 200 (61.6%) experienced FOG only during off state (off-freezers), 6 (1.8%) only during on state and 119 (36.6%) either in on and off states or independently of dopaminergic response-related symptoms (onoff-freezers). Overall, freezers vs non-freezers had longer disease duration, more advanced disease and greater disability. Moreover, freezers more frequently reported wearing-off and experienced worse quality of life. Onoff-freezers vs off-freezers were older, more severely disabled, less likely to experience wearing-off, treated with lower levodopa equivalent daily dose and with poorer cognitive performance. Self-reported FOG is mainly recognizable in advanced PD and is associated with more disability and worse quality of life. Onoff-FOG may represent the result of under-treatment or rather interpretable as a distinct clinical entity.

Trigeminal laser-evoked potentials: a neurophysiological tool to detect post-surgical outcome in trigeminovascular contact neuralgia.

BACKGROUND: The aim of this study was to explore the nociceptive system of patients affected by trigeminal neuralgia (TN) secondary to documented vascular contact who underwent microvascular decompression. For that purpose, we used the classical trigeminal reflexes and the trigeminal laser-evoked potentials (tLEPs) before and after surgery, in order to verify any possible change after decompression and determine if there was any correlation between the neurophysiological parameters and the clinical outcome. METHODS: Eleven patients affected by TN caused by trigeminovascular contact and 10 age-matched controls underwent conventional trigeminal reflexes (bilateral Blink Reflex/BR and Masseter Inhibitory Reflex stimulating infraorbital and mental nerves/MIR V2 and V3) and tLEPs. Patients repeated neurophysiological tests one week after surgery. RESULTS: Short-latency BR and MIR were normal in all patients before surgery and there was no statistical difference before and after surgery. Conversely, in patients before surgery, tLEPs' amplitudes were significantly lower in the affected than in the healthy side (p = 0.017 for V2 and 0.037 for V3 branches). After surgery, on the affected side, tLEP amplitude increased and the pre/post-operative difference was significant (p = 0.017 for V2 and 0.028 for V3 divisions). Nine patients referred satisfactory pain relief and the favourable clinical outcome correlated with the neurophysiological recovery. CONCLUSIONS: This study demonstrates that TN caused by trigeminovascular compression may be related to Aδ fibres impairment, and tLEPs are more sensitive than conventional trigeminal reflexes to reveal small fibre dysfunction and to monitor the post-surgical outcome in these patients.

[¹²³I]FP-CIT SPECT (DaTSCAN) may be a useful tool to differentiate between Parkinson's disease and vascular or drug-induced parkinsonisms: a meta-analysis.

BACKGROUND AND PURPOSE: Differentiating idiopathic Parkinson's disease from secondary parkinsonian syndromes is crucial since their management and prognosis differ considerably. Functional imaging of the dopaminergic pathway by means of [¹²³I]FP-CIT SPECT (DaTSCAN) might be useful in this regard, but its role is still controversial. The accuracy of DaTSCAN in the differential diagnosis between Parkinson's disease and vascular or drug-induced parkinsonism was therefore systematically reviewed. METHODS: MEDLINE and CENTRAL were searched for studies aiming to determine accuracy measures (sensitivity, specificity, diagnostic odds ratio, positive and negative likelihood ratios) of DaTSCAN in differentiating between Parkinson's disease and vascular or drug-induced parkinsonism. RESULTS: Five studies were included. Pooled accuracy measures in differentiating between Parkinson's disease and vascular or drug-induced parkinsonism were relatively high, with sensitivity and specificity values above 85% and 80%, respectively. CONCLUSIONS: DaTSCAN might accurately differentiate between early Parkinson's disease and secondary parkinsonian conditions, namely vascular or drug-induced, in patients with clinically unclear parkinsonism. However, all the studies reviewed here show several methodological limits, which prevent definitive conclusions on the role of DaTSCAN being drawn in this context. Further studies are needed to confirm our results and definitely evaluate the utility of DaTSCAN in differentiating between Parkinson's disease and vascular or drug-induced parkinsonism.

Early DEtection of wEaring off in Parkinson disease: the DEEP study.

OBJECTIVE: Assessing the frequency of Wearing-Off (WO) in Parkinson's disease (PD) patients, and its impact on Quality of Life (QoL). METHODS: Consecutive ambulatory patients, who were on dopaminergic treatment for ≥ 1 year, were included in this multicentre, observational cross-sectional study. In a single visit, WO was diagnosed based on neurologist assessment as well as using the validated Italian version of a patient self-rated 19-question Wearing-Off Questionnaire (WOQ-19); WO was defined for scores ≥ 2. QoL was evaluated by the 8-item Parkinson's Disease Questionnaire (PDQ-8). RESULTS: 617 subjects were included, with a mean anti-Parkinson treatment duration of 6.6 ± 4.6 years, 87.2% were on levodopa treatment. Neurologists identified presence of WO in 351 subjects (56.9%), whereas 415 subjects (67.3%) were identified by the self-administered WOQ-19. In patients with a <2.5 years disease duration, WO was diagnosed in 12 subjects (21.8%) by neurologists and in 23 subjects (41.8%) by the WOQ-19. The most frequent WO symptoms, as identified by WOQ-19, were "slowness of movements" (55.8%) and "reduced dexterity" (48.8%). Younger age, female gender, Unified Parkinson's Disease Rating Scale (UPDRS) part II score and duration of anti-Parkinson treatment were found significantly associated with WO. The number of motor (p < 0.0001) and non-motor (p < 0.0001) WO symptoms correlated with PDQ-8 total score. CONCLUSIONS: WO is common already at the early stages of PD and is underestimated by routine neurological clinical evaluation. The number of WO symptoms, both motor and non motor, increases along with disease duration and has a negative impact on patients QoL.

Behavioral and neurophysiological investigation of the influence of verbal suggestion on tactile perception.

Recently we demonstrated that it is possible to influence tactile perception by applying a placebo manipulation consisting of verbal suggestion and conditioning and that this influence is associated to changes in the late components (N140 and P200) of somatosensory-evoked potentials (SEPs) (Fiorio et al., 2012). Due to the powerful effects of words in changing symptoms perception in the clinical domain, aim of this study was to investigate whether even in the tactile modality, perception can be changed by the mere use of persuasive words in a specific context. To this purpose, we adopted the same experimental setting of our previous study, apart from the conditioning procedure. A group of subjects (experimental group) has been verbally suggested about the effect of an inert cream in enhancing tactile perception, while a control group was informed about the inefficacy of the cream. In order to unveil the neurophysiological underpinnings of this effect, we compared the amplitude of late SEPs (P100, N140, P200), before and after treatment. Results showed that the experimental group did not perceive an increase of tactile sensation after the treatment and no modification occurred in the late SEPs. This study proves that verbal suggestion alone is not sufficient to induce enhanced tactile perception (at least with this experimental setting), suggesting that a conditioning procedure may be necessary in the tactile modality. The absence of changes in the late SEP components could reflect the lack of strong expectation following the placebo procedure.

How pain arises in Parkinson's disease?

In recent years, increasing attention has centred on pain in Parkinson's disease (PD). Pain in PD is heterogeneous in quality and body distribution. To clarify how the various pain types relate to PD and to propose plausible treatment strategies, in this paper we reviewed psychophysical, neurophysiological and imaging data reported in parkinsonian patients with and without pain. Most available evidence supports abnormal central nociceptive input processing that probably reflects an impairment in the lateral and medial pain pathways. Changes in central pain processing probably underlie all the different pain types and also intervene in patients with PD without pain. Thus, altered pain processing might predispose patients with PD to spontaneous pain that is variable in quality. These background pain-processing abnormalities may interact with additional factors (such as contractures secondary to marked rigidity/bradykinesia, dystonia and medical conditions associated with painful symptoms), thus causing pain to manifest itself clinically in various ways and providing candidate targets for pain treatment in PD.