How Cognition and Motivation "Freeze" the Motor Behavior in Parkinson's Disease.

OBJECTIVE: Freezing of gait (FoG) is a debilitating problem in patients with PD. The multifactorial pathogenesis of FoG remains poorly understood. We aimed to find which factors are most strongly associated with the occurrence of FoG. METHODS: Three hundred five PD patients were enrolled and subdivided according to the presence (FoG +, n = 128) or absence (FoG-, n = 177) of FoG. Several clinical, functional, and neuropsychological data were collected and compared between groups. The association between the probability of presence of FoG and possible explanatory variables was assessed by logistic regression analysis. RESULTS: FoG + patients were younger at the diagnosis (p = 0.04), and their mean daily dose of dopaminergic drugs (p < 0.0001) was higher in comparison with FoG- patients. FoG + patients get worse in Frontal Assessment Battery (p = 0.005), had higher scores in Apathy Evaluation Scale (p = 0.03), and were much more impaired on Wisconsin Card Sorting Test (WCST) (p = 0.018), Trail Making Test A (p = 0.0013), and Ray Auditory Verbal Learning Test (p = 0.012). Levodopa equivalent dose, age (direct), age at disease onset (inverse), and WCST were significant predictors of FoG (p = 0.01, p = 0.0025, p = 0.0016, and p = 0.029, respectively). CONCLUSION: FoG + patients show more deficits in executive functions and in motivation. The main explanatory variables of FoG occurrence are levodopa equivalent dose, age, age at disease onset, and WCST. These data suggest that a specific involvement of frontal cortical circuits in PD is responsible for certain cognitive-behavioral alterations related to the occurrence of FoG.

Severe Constipation in Parkinson's Disease and in Parkinsonisms: Prevalence and Affecting Factors.

Background: constipation is one of the most common and disabling non-motor symptoms of Parkinson Disease (PD) and Parkinsonisms (PS). Few studies evaluate the difference of prevalence between PD and PS and the cause leading to a severe constipation in this diseases. Objective: Aim of our study is to evaluate the prevalence of constipation in a population of patients with PD and PS and to evaluate which factors influence the development of severe constipation. Methods: Two hundred and fifty outpatients with PD and 39 with PS were enrolled. Sixty five age-matched healthy subjects served as control. Constipation was assessed using the "Constipation Scoring System" (CSS). All patients underwent a global clinical, functional and neuropsychological assessment including: Unified Parkinson's disease Rating Scale (UPDRS), 6-min Walk Test (6MWT), and Mini-Mental State Examination (MMSE). Results: Data confirm the high prevalence of constipation among patients with PD and PS. Severe constipation affects much more patients with PS. A significant association between total CSS and age, H and Y stage, 6MWT, MMSE, total UPDRS, and UPDRS III was found in PD. In PS patients total CSS was associated with age, 6MWT, total UPDRS, and UPDRS III. Multivariable regression analysis showed that the only variables significantly and independently associated with total CSS in PD patients were age and total UPDRS, both with direct relationship. Conclusions: The reduction of motor performance seems to be the primary cause for developing severe constipation in PD and PS patients. These data suggest that maintain a good quality of gait and endurance may be helpful to reduce the risk of constipation.

Focused and Sustained Attention Is Modified by a Goal-Based Rehabilitation in Parkinsonian Patients.

Rehabilitation for patients with Parkinson's disease (PD) is based on cognitive strategies that exploit attention. Parkinsonians exhibit impairments in divided attention and interference control. Nevertheless, the effectiveness of specific rehabilitation treatments based on attention suggests that other attentional functions are preserved. Data about attention are conflicting in PD, and it is not clear whether rehabilitative treatments that entail attentional strategies affect attention itself. Reaction times (RTs) represent an instrument to explore attention and investigate whether changes in attentional performances parallel rehabilitation induced-gains. RTs of 103 parkinsonian patients in "on" state, without cognitive deficits, were compared with those of a population of 34 healthy controls. We studied those attentional networks that subtend the use of cognitive strategies in motor rehabilitation: alertness and focused and sustained attention, which is a component of the executive system. We used visual and auditory RTs to evaluate alertness and multiple choices RTs (MC RTs) to explore focused and sustained attention. Parkinsonian patients underwent these tasks before and after a 4-week multidisciplinary, intensive and goal-based rehabilitation treatment (MIRT). Unified Parkinson's Disease Rating Scale (UPDRS) III and Timed Up and Go test (TUG) were assessed at the enrollment and at the end of MIRT to evaluate the motor-functional effectiveness of treatment. We did not find differences in RTs between parkinsonian patients and controls. Further, we found that improvements in motor-functional outcome measures after MIRT (p < 0.0001) paralleled a reduction in MC RTs (p = 0.014). No changes were found for visual and auditory RTs. Correlation analysis revealed no association between changes in MC RTs and improvements in UPDRS-III and TUG. These findings indicate that alertness, as well as focused and sustained attention, are preserved in "on" state. This explains why Parkinsonians benefit from a goal-based rehabilitation that entails the use of attention. The reduction in MC RTs suggests a positive effect of MIRT on the executive component of attention and indicates that this type of rehabilitation provides benefits by exploiting executive functions. This ensues from different training approaches aimed at bypassing the dysfunctional basal ganglia circuit, allowing the voluntary execution of the defective movements. These data suggest that the effectiveness of a motor rehabilitation tailored for PD lies on cognitive engagement.

Land Plus Aquatic Therapy Versus Land-Based Rehabilitation Alone for the Treatment of Balance Dysfunction in Parkinson Disease: A Randomized Controlled Study With 6-Month Follow-Up.

OBJECTIVES: To assess whether a specific land-based physical intervention with the inclusion of aquatic therapy is more effective than land-based rehabilitation alone for the treatment of balance dysfunction in patients with Parkinson disease (PD), immediately after therapy and at 6 months' follow-up. DESIGN: Randomized controlled study with 6-month follow-up. SETTING: A PD and brain injury rehabilitation department in a general hospital. PARTICIPANTS: Patients (N=34) with moderate-stage PD. INTERVENTION: Seventeen patients underwent a land-based rehabilitation protocol called multidisciplinary intensive rehabilitation treatment (MIRT), and 17 underwent MIRT plus aquatic therapy (MIRT-AT). MAIN OUTCOME MEASURES: The primary outcome measure was the Berg Balance Scale (BBS); secondary outcome measures were the Unified Parkinson Disease Rating Scale parts II and III (UPDRS II/III) and the Timed Up and Go (TUG) test. These measures were assessed in both groups at admission, at discharge, and after 6 months. RESULTS: BBS improved after treatment in both groups. Even though no statistically significant difference between groups was observed at each observation time, BBS scores at follow-up were significantly higher than at baseline in MIRT-AT patients. Both groups also showed an improvement in UPDRS II/III and TUG at the end of treatment compared with baseline, but these findings were lost at the 6-month follow-up. CONCLUSIONS: Aquatic therapy added to land-based rehabilitation could provide a contribution to the treatment of balance dysfunction in patients with moderate-stage PD.

A cola-induced hypokalemic rhabdomyolysis with electromyographic evaluation: A case report.

OBJECTIVE: To report a rare case of hypokalemic rhabdomyolysis induced by the heavy and prolonged ingestion of cola-based beverages, and its uneventful recovery after kalemia normalization. METHODS: We report a 38-year-old Caucasian male presented in our emergency room with a recent and progressive weakness of the lower limbs proximal muscles. RESULTS: A dietary history revealed a prolonged ingestion of cola-based beverages. Blood tests showed severe hypokalemia and marked increase in serum creatine phosphokinase. The analysis of cerebrospinal fluid resulted normal. Electromyography was suggestive for a myopathy. The clinical, laboratory and neurophysiological data were evocative for a cola-induced hypokalemic rhabdomyolysis. After kalemia normalization, the improvements of the electromyographic findings paralleled the clinical recovery. CONCLUSION: Chronic consumption of large amount of cola-based soft drinks may result in severe symptomatic hypokalemia, eventually leading in turn to myopathy. To our knowledge, this is the first description of the electromyographic findings of the cola-induced hypokalemic rhabdomyolysis. An early diagnosis and a prompt treatment appear to be crucial for a benign clinical course.

Dopamine Replacement Therapy, Learning and Reward Prediction in Parkinson's Disease: Implications for Rehabilitation.

The principal feature of Parkinson's disease (PD) is the impaired ability to acquire and express habitual-automatic actions due to the loss of dopamine in the dorsolateral striatum, the region of the basal ganglia associated with the control of habitual behavior. Dopamine replacement therapy (DRT) compensates for the lack of dopamine, representing the standard treatment for different motor symptoms of PD (such as rigidity, bradykinesia and resting tremor). On the other hand, rehabilitation treatments, exploiting the use of cognitive strategies, feedbacks and external cues, permit to "learn to bypass" the defective basal ganglia (using the dorsolateral area of the prefrontal cortex) allowing the patients to perform correct movements under executive-volitional control. Therefore, DRT and rehabilitation seem to be two complementary and synergistic approaches. Learning and reward are central in rehabilitation: both of these mechanisms are the basis for the success of any rehabilitative treatment. Anyway, it is known that "learning resources" and reward could be negatively influenced from dopaminergic drugs. Furthermore, DRT causes different well-known complications: among these, dyskinesias, motor fluctuations, and dopamine dysregulation syndrome (DDS) are intimately linked with the alteration in the learning and reward mechanisms and could impact seriously on the rehabilitative outcomes. These considerations highlight the need for careful titration of DRT to produce the desired improvement in motor symptoms while minimizing the associated detrimental effects. This is important in order to maximize the motor re-learning based on repetition, reward and practice during rehabilitation. In this scenario, we review the knowledge concerning the interactions between DRT, learning and reward, examine the most impactful DRT side effects and provide suggestions for optimizing rehabilitation in PD.

Balance Dysfunction in Parkinson's Disease: The Role of Posturography in Developing a Rehabilitation Program.

Balance dysfunction (BD) in Parkinson's disease (PD) is a disabling symptom, difficult to treat and predisposing to falls. The dopaminergic drugs or deep brain stimulation does not always provide significant improvements of BD and rehabilitative approaches have also failed to restore this condition. In this study, we investigated the suitability of quantitative posturographic indicators to early identify patients that could develop disabling BD. Parkinsonian patients not complaining of a subjective BD and controls were tested using a posturographic platform (PP) with open eyes (OE) and performing a simple cognitive task [counting (OEC)]. We found that patients show higher values of total standard deviation (SD) of body sway and along the medio-lateral (ML) axis during OE condition. Furthermore, total and ML SD of body sway during OE condition and total SD of body sway with OEC were higher than controls also in a subgroup of patients with normal Berg Balance Scale. We conclude that BD in Parkinsonian patients can be discovered before its appearance using a PP and that these data may allow developing specific rehabilitative treatment to prevent or delay their onset.

Mutations in PRRT2 result in familial infantile seizures with heterogeneous phenotypes including febrile convulsions and probable SUDEP.

Mutations of PRRT2, which encodes proline-rich transmembrane protein 2, are associated with heterogeneous phenotypes including benign familial infantile seizures (BFIS) and/or familial paroxysmal kinesigenic dystonia (PKD). Here, we performed mutation screening of PRRT2 in six Italian families with BFIS/PKD phenotypes. The mutation, c.649dupC (p.Arg217ProfsX8), was found in two families with BFIS phenotype. In a third BFIS family, a missense mutation, c.718C/T (R240X), was identified. All these mutations co-segregated with the disease and were not observed in 100 controls of matched ancestry. In one BFIS family that carried the c.649dupC mutation, one affected member developed afebrile focal seizures and died at age of 14 years of probable sudden unexpected death in epilepsy, while his brother also had simple febrile convulsions (FC) and performed poorly on complex psychomotor functioning. In another family carrying the c.718C/T mutation, two of three affected members also had simple FC. This study enlarges the clinical spectrum related to PPRT2 mutations and underscores the complexity of the phenotypic consequences of mutations in this gene.

A functional genetic variation of the 5-HTR2A receptor affects age at onset in patients with temporal lobe epilepsy.

The 1354C>T polymorphism of the 5-hydroxytryptamine receptor 2A gene (5-HTR2A) was implicated in human memory performance. We investigated the relationship between this polymorphism and cognitive function in patients with temporal lobe epilepsy (TLE). We also evaluated if this polymorphism could influence the phenotype. There were 138 patients with TLE: 25% (34/138) of them found to be cognitively impaired, while the remaining 104 of 138 (75%) were found to be cognitively preserved after a comprehensive neuropsychological evaluation. dHPLC followed by DNA sequencing was used to detect the genetic variation. The distribution of 1354C>T did not differ between these two TLE groups, both in the comparison of genotype distribution (P= 0.177) and allele frequencies (P = 0.065). Nonetheless, patients with the T allele had a significantly earlier age at onset of the disease (P= 0.006). This effect was even stronger in patients with impaired memory (P= 0.00015). A second independent sample of 86 individuals with TLE satisfactorily confirmed the relationship between T allele and age at epilepsy onset. The results of this study have demonstrated that the T variant of 5-HTR2A may influence an earlier age of onset of TLE, especially in those with impaired memory. Nonetheless, this polymorphism has no major impact on memory functions in such TLE patients.

Tacrolimus-induced polyneuropathy after heart transplantation.

Tacrolimus has been often described to induce neuropathy in liver-, pancreas-, and renal-transplanted patients. Here, we report the first case of a 56-year-old woman who developed a progressive symmetric demyelinating sensorimotor polyneuropathy in the distal muscles of the lower limbs after therapy with tacrolimus because of heart transplantation. This condition suddenly reverted after the tacrolimus was stopped.