A new perspective on positive symptoms: expression of damage or self-defence mechanism of the brain?

Usually, positive neurological symptoms are considered as the consequence of a mere, afinalistic and abnormal increase in function of specific brain areas. However, according to the Theory of Active Inference, which argues that action and perception constitute a loop that updates expectations according to a Bayesian model, the brain is rather an explorer that formulates hypotheses and tests them to assess the correspondence between internal models and reality. Moreover, the cerebral cortex is characterised by a continuous "conflict" between different brain areas, which constantly attempt to expand in order to acquire more of the limited available computational resources, by means of their dopamine-induced neuroplasticity. Thus, it has recently been suggested that dreams, during rapid eye movement sleep (REMS), protect visual brain areas (deprived of their stimuli during rest) from being conquered by other normally stimulated ones. It is therefore conceivable that positive symptoms also have a functional importance for the brain. We evaluate supporting literature data of a 'defensive' role of positive symptoms and the relevance of dopamine-induced neuroplasticity in the context of neurodegenerative and psychiatric diseases. Furthermore, the possible functional significance of idiopathic REMS-related behavioural disorder as well as phantom limb syndrome is examined. We suggest that positive neurological symptoms are not merely a passive expression of a damage, but active efforts, related to dopamine-induced plasticity, to maintain a correct relationship between the external world and its brain representation, thus preventing healthy cortical areas from ousting injured ones.

Idiopathic cervical dystonia and non-motor symptoms: a pilot case-control study on autonomic nervous system.

PURPOSE: Non-motor symptoms, such as sleep disturbances, fatigue, neuropsychiatric manifestations, cognitive impairment, and sensory abnormalities, have been widely reported in patients with idiopathic cervical dystonia (ICD). This study aimed to clarify the autonomic nervous system (ANS) involvement in ICD patients, which is still unclear in the literature. METHODS: We conducted a pilot case-control study to investigate ANS in twenty ICD patients and twenty age-sex-matched controls. The Composite Autonomic System Scale 31 was used for ANS clinical assessment. The laser Doppler flowmetry quantitative spectral analysis, applied to the skin and recorded from indices, was used to measure at rest, after a parasympathetic activation (six deep breathing) and two sympathetic stimuli (isometric handgrip and mental calculation), the power of high-frequency and low-frequency oscillations, and the low-frequency/high-frequency ratio. RESULTS: ICD patients manifested higher clinical dysautonomic symptoms than controls (p < 0.05). At rest, a lower high-frequency power band was detected among ICD patients than controls, reaching a statistically significant difference in the age group of ≥ 57-year-olds (p < 0.05). In the latter age group, ICD patients showed a lower low-frequency/high-frequency ratio than controls at rest (p < 0.05) and after mental calculation (p < 0.05). Regardless of age, during handgrip, ICD patients showed (i) lower low-frequency/high-frequency ratio (p < 0.05), (ii) similar increase of the low-frequency oscillatory component compared to controls, and (iii) stable high-frequency oscillatory component, which conversely decreased in controls. No differences between the two groups were detected during deep breathing. CONCLUSION: ICD patients showed ANS dysfunction at clinical and neurophysiological levels, reflecting an abnormal parasympathetic-sympathetic interaction likely related to abnormal neck posture and neurotransmitter alterations.

Levodopa Equivalent Dose of Safinamide: A Multicenter, Longitudinal, Case-Control Study.

Background: Effects of dopaminergic medications used to treat Parkinson's disease (PD) may be compared with each other by using conversion factors, calculated as Levodopa equivalent dose (LED). However, current LED proposals on MAO-B inhibitors (iMAO-B) safinamide and rasagiline are still based on empirical approaches. Objectives: To estimate LED of safinamide 50 and 100 mg. Methods: In this multicenter, longitudinal, case-control study, we retrospectively reviewed clinical charts of 500 consecutive PD patients with motor complications and treated with (i) safinamide 100 mg (N = 130), safinamide 50 mg (N = 144), or rasagiline 1 mg (N = 97) for 9 ± 3 months and a control group of patients never treated with any iMAO-B (N = 129). Results: Major baseline features (age, sex, disease duration and stage, severity of motor signs and motor complications) were similar among the groups. Patients on rasagiline had lower UPDRS-II scores and Levodopa dose than control subjects. After a mean follow-up of 8.8-to-10.1 months, patients on Safinamide 50 mg and 100 mg had lower UPDRS-III and OFF-related UPDRS-IV scores than control subjects, who in turn had larger increase in total LED than the three iMAO-B groups. After adjusting for age, disease duration, duration of follow-up, baseline values and taking change in UPDRS-III scores into account (sensitivity analysis), safinamide 100 mg corresponded to 125 mg LED, whereas safinamide 50 mg and rasagiline 1 mg equally corresponded to 100 mg LED. Conclusions: We used a rigorous approach to calculate LED of safinamide 50 and 100 mg. Large prospective pragmatic trials are needed to replicate our findings.

TeleNEwCARe: An Italian case-control telegenetics study in patients with Hereditary NEuromuscular and CARdiac diseases.

Telemedicine provides healthcare services remotely and represents a fundamental resource for the management of rare and fragile patients. Tele-health implementation is a main objective of the European Reference Networks (ERNs) mission to accelerate diagnosis for rare diseases. TeleNewCARe is a pilot case-control project which evaluates the efficacy and satisfaction of telegenetics for neuromuscular and cardiac adult patients, compared to face-to-face genetic counselling. The virtual sessions were co-hosted by a medical geneticist and a neurologist/cardiologist. Specific questionnaires (Clinical Genetics Satisfaction Questionnaire (CGS), Telemedicine Satisfaction Questionnaire (TSQ) and a Satisfaction Questionnaire for medical geneticists) were used to assess the effectiveness and fulfilment of telecounselling, both for patients and health care providers. Satisfaction expressed for telegenetics did not significantly differ from face-to-face counselling. The virtually enrolled patients declared they had the possibility to relate confidentially with the specialists, to share information and to be informed in an exhaustive way about their disease. Almost all patients declared themselves willing to reuse the telecounselling in the future. The multidisciplinary care was perceived as a significant added value. No overt technical problems were reported although the need for digital skills and tools can limit patients' compliance. Our experience supports telegenetics as a valid alternative to traditional genetic counselling in cardiac and neuromuscular patients. This innovative approach facilitates multidisciplinary care, grants a periodical follow up, without forcing patients to discomfortable travelling, and allows to maintain expert care. This result meets the ERNs needs to reduce patients' burden to access and monitor their healthcare.

Electrophysiological and neuropsychological assessment of cognition in spinocerebellar ataxia type 1 patients: a pilot study.

BACKGROUND: Event-related potentials (ERPs) reflect cognitive processing: negative early components (N100, N200) are involved in the sensory and perceptual processing of a stimulus, whereas late positive component P300 requires conscious attention. Both neuropsychological and affective disorders are present in patients with spinocerebellar ataxia type 1 (SCA1), but the underlying mechanisms need further clarification. MATERIALS AND METHODS: In this pilot study, we assessed cognitive processing by recording auditory ERPs in 16 consecutive SCA1 patients and 16 healthy controls (HC) matched for age and sex. Motor and nonmotor symptoms were evaluated using the Scale for the Assessment and Rating of Ataxia (SARA) and an extensive neuropsychological battery. ERPs were recorded using an oddball paradigm, and peak latency and amplitude of N100, N200, and P300 were measured in the averaged responses to target tones. RESULTS: We found in SCA1 significantly increased latencies of N200 and P300 (p=0.033, p=0.007) and decreased amplitudes of N100 and P300 (p=0.024, p=0.038) compared with HC. Furthermore, P300 latency had the highest AUC in the discrimination of SCA1 in ROC analysis. The expansion of trinucleotide repeats correlated with P300 latency (r=-0.607, p=0.048), whereas both P300 and N100 amplitudes correlated with the severity of motor symptoms (r=-0.692, p=0.003; r=-0.621; p=0.010). Significant correlations between P300 latency and the scores of Emotion Attribution Task (r=-0.633, p=0.027), as well as between N200 latency and the scores of Frontal Assessment Battery and Stroop test (r=-0.520, p=0.047; r=0.538, p=0.039), were observed. CONCLUSIONS: This research provides for the first time an extensive characterization of ERPs as useful electrophysiological markers to identify early cognitive dysfunction in SCA1.

AFG3L2 Biallelic Mutation: Clinical Heterogeneity in Two Italian Patients.

AFG3-like matrix AAA peptidase subunit 2 gene (AFG3L2, OMIM * 604,581) biallelic mutations lead to autosomal recessive spastic ataxia-5 SPAX5, OMIM # 614,487), a rare hereditary form of ataxia. The clinical spectrum includes early-onset cerebellar ataxia, spasticity, and progressive myoclonic epilepsy (PME). In Italy, the epidemiology of the disease is probably underestimated. The advent of next generation sequencing (NGS) technologies has speeded up the diagnosis of hereditary diseases and increased the percentage of diagnosis of rare disorders, such as the rare hereditary ataxia groups. Here, we describe two patients from two different villages in the province of Ferrara, who manifested a different clinical ataxia-plus history, although carrying the same biallelic mutation in AFG3L2 (p.Met625Ile) identified through NGS analysis.

Beyond canvas: behavioral onset of rfc1-expansion disease in an Italian family-causal or casual?

INTRODUCTION: Biallelic intronic AAGGG repeat expansion in the replication factor C subunit 1 (RFC1) gene was recently identified in two/third of patients with cerebellar ataxia, sensory neuropathy, and bilateral vestibular areflexia syndrome (CANVAS). The phenotypic spectrum has expanded since (i.e., parkinsonism, motor neuron involvement, cognitive decline); no behavioral symptoms have been reported yet. CASE REPORT: We report an Italian family that met the diagnostic criteria for CANVAS, and RFC1-expansion was detected in five of seven. All the affected members presented behavioral-psychiatric symptoms (anxiety, panic attacks, alcohol abuse) before the multisystemic RFC1-expansion manifestation. The disease course was progressive, with ataxia and behavioral-cognitive aspects as the most disabling symptoms. CONCLUSION: These behavioral-cognitive observations may broaden the RFC1-expansion phenotypic spectrum and highlight the importance of investigating the whole non-motor symptoms in ataxic patients.

Parkinson's disease-dementia in trans LRP10 and GBA variants: Response to deep brain stimulation.

We report on a patient with Parkinson's disease and dementia who underwent DBS with excellent response in motor features; the genotype is heterozygous for a novel LRP10 variant in trans with a GBA variant. He had a more severe phenotype compared to the father who only carries the LRP10 variant.

Levodopa-carbidopa intrajejunal infusion in Parkinson's disease: untangling the role of age.

OBJECTIVES: Levodopa-Carbidopa Intrajejunal gel (LCIG) infusion is an effective intervention for people with advanced Parkinson's disease (PD). Although age may not be a limiting factor for LCIG implant, no data are available on late elderly PD (LE-PD) subjects. In this cross-sectional, we aimed to demonstrate if older age may impact on quality of life (QoL), motor and non-motor symptoms severity, and profile of side effects in PD treated with LCIG. METHODS: Out of 512 PD subjects treated with LCIG at 9 Italian PD centers, we selected 25 LE-PD defined as age ≥ 80 years at last follow-up who were available to attend the study visit. Twenty-five PD patients (Control-PD, defined as age < 75 years at last follow-up) matched to LE-PD by disease and LCIG duration served as control group. The following motor and non-motor variables were ascertained: quality of life (PDQ-8), time spent in ON, wearing-off Questionnaire, Unified PD Rating Scale, freezing of gait questionnaire, Parkinson's disease sleep scale-2, Non Motor Symptoms Scale (NMSS), and MOCA. RESULTS: No statistically significant differences were found between LE-PD and Control-PD on PDQ-8 and several motor and non-motor variables. LE-PD had less frequent and milder impulsive-compulsive behaviors and milder dyskinesia. At multivariable regression, worse quality of life was associated with UPDRS-III and NMSS scores but not to age at study visit and age at LICG implant. Rate of adverse effects was similar in both groups. Drop-out rate calculated in the whole PD cohort was comparable between the two groups. CONCLUSION: Our data provide evidence that valuable LCIG infusion might be achieved in late elderly PD.

Impact of Supporting People with Advanced Parkinson's Disease on Carer's Quality of Life and Burden.

PURPOSE: The aim of this study was to assess the burden and the quality of life (QoL) perceived by caregivers assisting advanced Parkinson's disease (PD) patients. PATIENTS AND METHODS: Consecutive advanced PD patients treated with levodopa/carbidopa intestinal gel (LCIG) or continuous subcutaneous apomorphine infusion (CSAI) or care as usual (CU) and their care partners were recruited during routine visits according to a cross-sectional design. Caregiver's distress was assessed by Zarit Burden Interview (ZBI) and a QoL survey to evaluate and understand the burden experienced by care partners during family and working activities. RESULTS: A total of 126 patients (53 LCIG, 19 CSAI and 54 CU) and their care partners were enrolled. The ZBI score boxplot showed that LCIG and CU populations have a similar distribution (ZBI inter-quartile range [IQR] values respectively 18-42 for LCIG and 19-43 for CU group), while the CSAI group has a wider score range (IQR 16-52). Caregivers assisting patients in treatment with LCIG have more time to perform family or household duties (p=0.0022), or to engage in leisure activities (p=0.0073) compared to CU, while no difference was found when compared to CSAI group. Approximately 50% of the care partners showed mood changes in the last 6 months and LCIG and CSAI had less impact on caregiver's mood compared to CU. Patients treated with LCIG were more independent in taking a bath or shower without assistance and were more able to move and walk without assistance. CONCLUSION: Care partners of advanced PD patients treated with device-aided therapies have more time for their own life and a better perception of their QoL with a tendency to an improvement of mood compared with those of patients treated with CU.

Correction to: Caregiver burden and its related factors in advanced Parkinson's disease: data from the PREDICT study.

The original version of this article unfortunately contained a mistake. In the Figure.

Long-term effectiveness of levodopa-carbidopa intestinal gel on motor and non-motor symptoms in advanced Parkinson's disease: results of the Italian GLORIA patient population.

INTRODUCTION: The GLORIA registry included 375 advanced Parkinson's disease (PD) patients and evaluated the efficacy and safety of a 24-month levodopa-carbidopa intestinal gel (LCIG) treatment in routine medical care. This analysis focuses on the Italian population, 60 patients treated with LCIG in 7 specialised PD care centres. METHODS: Hours of "Off" and "On" time were assessed with a modified version of the Unified Parkinson's Disease Rating Scale (UPDRS) part IV items 39 and 32. Motor fluctuations, dyskinesia, non-motor symptoms, quality of life and safety were evaluated. RESULTS: Overall, 42 (70%) out of 60 patients completed the registry. LCIG treatment reduced "Off" time (- 3.3 ± 2.7 h at month 24 (M24), P < 0.0001), increased "On" time with dyskinesia (- 2.6 ± 5.2 h at M12, P = 0.0160), and improved UPDRS II and UPDRS III total scores at M24 (- 4.5 ± 10.6, P = 0.0333 and - 4.9 ± 11.7, P = 0.0229, respectively), Non-Motor Symptom Scale (NMSS) total score (- 21.8 ± 28.5, P < 0.0001) and Parkinson's Disease Questionnaire-8 item (PDQ-8) total score (- 12.5 ± 23.9, P = 0.0173) versus previous oral therapy. Adverse drug reactions (ADR) possibly or probably related to treatment were reported in 16 (28.6%) patients. Decreased weight (7.1%), polyneuropathy (7.1%) and abdominal pain (5.4%) were the most frequent ADRs while device malfunction (5.4%) and medical device change (5.4%) were the most reported device complaints. CONCLUSIONS: LCIG improved motor fluctuations, non-motor symptoms and quality of life over 24 months while tolerability was consistent with the established safety profile.

The TANDEM investigation: efficacy and tolerability of levodopa-carbidopa intestinal gel in (LCIG) advanced Parkinson's disease patients.

The TANDEM investigation was carried out in 17 Italian Movement Disorder centers on behalf of a joint initiative of neurologist members of the Italian Academy for Parkinson's disease and Movement Disorders (LIMPE-DISMOV Academy) and gastroenterologist members of the Italian Society of Digestive Endoscopy (SIED) to evaluate the efficacy and tolerability of levodopa-carbidopa intestinal gel (LCIG) in patients with advanced Parkinson's disease (PD) in routine medical care. Motor scores in "ON" and OFF" state (UPDRS-III), complications of therapy (UPDRS-IV), activities of daily living, sleep disorders and quality of life were evaluated at baseline and at two follow-up assessments (FUV1 and FUV2) within the initial 12-month LCIG treatment. In 159 patients (55% males) with a mean age of 69.1 ± 6.6 years and a diagnosis of PD since 13.6 ± 5.5 years, the UPDRS-III total score (in "OFF") decreased from baseline (45.8 ± 13.2) to FUV1 (41.0 ± 17.4; p < 0.001) and FUV2 (40.5 ± 15.5; p < 0.001), the UPDRS-IV total score decreased from baseline (8.8 ± 2.9) to FUV1 (5.1 ± 3.4; p < 0.001) and FUV2 (5.5 ± 3.2; p < 0.001). The percentage of patients exhibiting freezing, dystonia, gait/walking disturbances, falls, pain and sleep disorders was significantly reduced. Twenty-eight device complications were reported and 11 (6.9%) patients prematurely terminated the study. LCIG after 12-month treatment led to sustained improvement of time spent in "OFF", complications of therapy, PD-associated symptoms and sleep disorders. LCIG tolerability was consistent with the established safety profile of LCIG.

Motor and non-motor outcomes in patients with advanced Parkinson's disease treated with levodopa/carbidopa intestinal gel: final results of the GREENFIELD observational study.

INTRODUCTION: The GREENFIELD observational study assessed the effect of levodopa/carbidopa intestinal gel (LCIG) on motor and non-motor symptoms, and the related impact on patient quality of life and caregiver burden up to 8 years. METHODS: Final results of a large Italian cohort of patients who started LCIG in routine care between 2007 and 2014 are presented. Comparison between baseline (before LCIG) and follow-up visits on yearly basis (visit 2/3) is reported. Primary endpoint was Unified Parkinson's Disease Rating Scale (UPDRS-IV) Item 39; secondary endpoints were UPDRS I and II, dyskinesia items, PD Quality of Life Questionnaire-39, Parkinson's Disease Sleep Scale-2, Gait and Falls Questionnaire, Questionnaire on Impulsive Disorders, and Relative Stress Scale. RESULTS: Overall, 145 patients from 14 centers were assessed with a mean time since LCIG start of 2.8 ± 1.7 years at visit 2. The mean UPDRS-IV item 39 score showed significant reductions compared to baseline (mean score 2.0 ± 0.81) at visit 2 (mean score 0.9 ± 0.69; - 55%; p < 0.001) and at visit 3 (mean score 1.0 ± 0.75; - 50%; p < 0.001). At visit 3, significant reductions were observed for dyskinesia duration score (- 28%; p < 0.001), dyskinesia disability (- 40%; p < 0.001), and painful dyskinesia (- 50%; p < 0.001). Overall, 40 (27.6%) patients experienced 49 serious adverse events which were considered related to PEG/J procedure or to device in 16.3% of the cases. CONCLUSIONS: The results of this study support the long-term efficacy of LCIG on PD symptoms as well as on activities of daily living. The adverse events were consistent with the established LCIG safety profile.

Levodopa/Carbidopa Intestinal Gel Infusion Therapy: Focus on Gait and Balance.

BACKGROUND: Gait and balance disorders in advanced Parkinson's disease (aPD) heavily impact the disease burden. In this prospective observational open-label study, our aim was to evaluate the effectiveness of levodopa/carbidopa intestinal gel (LCIG) infusion on balance and gait over a long-term follow-up. METHODS: The motor status of 15 aPD patients with balance and gait symptoms was assessed with UPDRS (I-IV) and H&Y at baseline in OFF and ON conditions, and after 52 weeks of LCIG infusion. Berg Balance Scale (BBS), Tinetti Gait & Balance Score (TS), Gait and Falls Questionnaire (G&F-Q), FOG Questionnaire (FOG-Q), and New FOG Questionnaire (NFOG-Q) were used to specifically test balance and gait. RESULTS: UPDRS, H&Y, BBS, TS, G&F-Q, FOG-Q, NFOG-Q improved significantly. All FOG types benefited from LCIG. CONCLUSIONS: Our preliminary data show the beneficial effect of LCIG therapy not only on FOG, but also on gait and balance. Results need to be confirmed in larger cohort studies.

Caregiver burden and its related factors in advanced Parkinson's disease: data from the PREDICT study.

INTRODUCTION: Caring for a person with Parkinson's disease (PD) is associated with an increased risk of psychiatric morbidity and persistent distress. The objective of this study was to describe the burden and the related factors of caregivers of advanced PD (APD) patients either treated with continuous dopaminergic delivery systems or standard therapy. METHODS: This cross-sectional, epidemiologic study conducted in 13 Italian sites enrolled PD patients treated with continuous dopaminergic delivering systems [either levodopa/carbidopa intestinal gel (LCIG) infusion or continuous subcutaneous apomorphine infusion (CSAI)] or continuation of standard of care (SOC) with a caregiver. Patient quality of life (QoL) and caregiver burden were assessed using the Parkinson's Disease Questionnaire (PDQ-8) and Zarit Burden Inventory (ZBI), respectively. RESULTS: 126 patients (mean age 69.3 ± 8 years) and their caregivers (mean age 57.9 ± 12.9) were enrolled. Most caregivers were spouses. Fifty-three patients were treated with LCIG, 19 with CSAI, and 54 with SOC. Mean ZBI scores were 29.6 ± 14.4 for LCIG, 35.8 ± 20.2 for CSAI, and 31.4 ± 16.0 for SOC. Caregivers of LCIG, CSAI, and SOC patients showed no burden or mild/moderate burden in 74, 53, and 63% of the cases, respectively. Mean PDQ-8 scores were 11.25 ± 5.67, 11.26 ± 5.55, and 14.22 ± 6.51 in LCIG, CSAI, and SOC patients. Neurologists considered patients "very much or much improved" in 89, 58, and 13% of the LCIG, CSAI, and SOC groups using the Clinical Global Impression-Global Improvement Scale. Predictors significantly associated with caregiver burden were patients and caregivers' judgment of QoL and caregivers' need to change work. CONCLUSIONS: Caregiver burden showed a tendency to be lower when patients are treated with LCIG than with CSAI or SOC.

Epidemiological Study of Huntington's Disease in the Province of Ferrara, Italy.

BACKGROUND: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the abnormal expansion of CAG triplet repeat. We aimed to reappraise HD epidemiology in a northern Italian population, in relation to introduction of genetic testing. METHODS: Through ICD-9M code 333.4 and medical fare exemption code RF0080, HD cases were identified from administrative health data and medical records from the Units of Neurology and Genetics, Ferrara University Hospital, and from other provincial neurological structures. RESULTS: HD mean annual incidence rate in 1990-2009 was 0.3 per 100,000 (95% CI 0.2-0.5). All incident cases were found to have symptoms of the disease's classic form, and neither juvenile nor the rigid Westphal variant was detected. The mean (SD) age at onset was 50.2 (12.7 years; range 32-82 years), 54.9 (14.6) for men and 45.8 (9.4) for women. On prevalence day, December 31, 2014, HD prevalence was 4.2 per 100,000 (95% CI 2.4-7.0), with a male:female ratio of 1:2. CONCLUSIONS: The prevalence and incidence of HD in our population were lower than the prevalence and incidence reported for other European and Italian populations, but higher compared to those of Asia, Africa, and Eastern Europe. Compared to previous studies, HD incidence and prevalence did not change significantly.