The role of stroke-induced immunosuppression as a predictor of functional outcome in the neurorehabilitation setting.

Stroke affects the interconnection between the nervous and immune systems, leading to a down-regulation of immunity called stroke-induced immunosuppression (SII). The primary aim of this study is to investigate SII role as a predictor of functional, neurological, and motor outcomes in the neurorehabilitation setting (NRB). We conducted a prospective observational study enrolling post-acute stroke patients hospitalized for neurorehabilitation. At NRB admission (T0) and discharge (T1), we assessed presence of SII (defined by a neutrophil-to-lymphocyte ratio ≥ 5) and we evaluated functional independence (Functional Independence Measure-FIM, Barthel Index-BI), motor performances (Tinetti Score, Hauser Ambulation Index) and neurological impairment (NIHSS). We enrolled 96 patients (45.8% females, 70.6 ± 13.9 years, 88.5% ischemic stroke). At T0, 15.6% of patients (15/96) had SII. When compared to immunocompetent patients (IC), the SII group was characterized by worse baseline functional independence, motor performances and neurological disability. The same was confirmed at T1 (FIM p = 0.012, BI p = 0.007, Tinetti p = 0.034, NIHSS p = 0.001). Neurological disability demonstrated a less pronounced improvement in SII (ΔNIHSS: SII: - 2.1 ± 2.3 vs. IC: - 3.1 ± 2.5, p = 0.035). SII group presented a higher percentage of infectious complications during the neurorehabilitation period (SII 80% vs. IC 25.9%; p = 0.001). SII may represent a negative prognostic factor in the neurorehabilitation setting. SII patients were characterized by poorer functional, motor, neurological performances and higher risk of infectious complications. ClinicaTrial registration: NCT05889169.

Non-Invasive Neuromodulation in the Rehabilitation of Pisa Syndrome in Parkinson's Disease: A Randomized Controlled Trial.

Background: Pisa syndrome (PS) is a frequent postural complication of Parkinson's disease (PD). PS poorly responds to anti-parkinsonian drugs and the improvement achieved with neurorehabilitation tends to fade in 6 months or less. Transcranial direct current stimulation (t-DCS) is a non-invasive neuromodulation technique that showed promising results in improving specific symptoms in different movement disorders. Objectives: This study aimed to evaluate the role of bi-hemispheric t-DCS as an add-on to a standardized hospital rehabilitation program in the management of PS in PD. Methods: This study included 28 patients with PD and PS (21 men, aged 72.9 ± 5.1 years) who underwent a 4-week intensive neurorehabilitation treatment and were randomized to receive: i) t-DCS (t-DCS group, n = 13) for 5 daily sessions (20 min-2 mA) with bi-hemispheric stimulation over the primary motor cortex (M1), or ii) sham stimulation (sham group, n = 15) with the same duration and cadence. At baseline (T0), end of rehabilitation (T1), and 6 months later (T2) patients were evaluated with both trunk kinematic analysis and clinical scales, including UPDRS-III, Functional Independence Measure (FIM), and Numerical Rating Scale for lumbar pain. Results: When compared to the sham group, the t-DCS group achieved a more pronounced improvement in several variables: overall posture (p = 0.014), lateral trunk inclination (p = 0.013) during upright standing position, total range of motion of the trunk (p = 0.012), FIM score (p = 0.048), and lumbar pain intensity (p = 0.017). Conclusions: Our data support the use of neuromodulation with t-DCS as an add-on to neurorehabilitation for the treatment of patients affected by PS in PD.

The Effects of Intensive Neurorehabilitation on Sequence Effect in Parkinson's Disease Patients With and Without Freezing of Gait.

Background: The sequence effect (SE), defined as a reduction in amplitude of repetitive movements, is a common clinical feature of Parkinson's disease (PD) and is supposed to be a major contributor to freezing of gait (FOG). During walking, SE manifests as a step-by-step reduction in step length when approaching a turning point or gait destination, resulting in the so-called destination sequence effect (dSE). Previous studies explored the therapeutic effects of several strategies on SE, but none of them evaluated the role of an intensive rehabilitative program. Objectives: Here we aim to study the effects of a 4-week rehabilitative program on dSE in patients with PD with and without FOG. Methods: Forty-three patients (30 males, 70.6 ± 7.5 years old) with idiopathic PD were enrolled. The subjects were divided into two groups: patients with (PD + FOG, n = 23) and without FOG (PD - FOG, n = 20). All patients underwent a standardized 4-week intensive rehabilitation in-hospital program. At hospital admission (T0) and discharge (T1), all subjects were evaluated with an inertial gait analysis for dSE recording. Results: At T0, the dSE was more negative in the PD + FOG group (-0.80 ± 0.6) when compared to the PD - FOG group (-0.39 ± 0.3) (p = 0.007), even when controlling for several clinical and demographic features. At T1, the dSE was reduced in the overall study population (p = 0.001), with a more pronounced improvement in the PD + FOG group (T0: -0.80 ± 0.6; T1: -0.23 ± 0.4) when compared to the PD - FOG group (T0: -0.39 ± 0.3; T1: -0.22 ± 0.5) (p = 0.012). At T1, we described in the overall study population an improvement in speed, cadence, stride duration, and stride length (p = 0.001 for all variables). Conclusions: dSE is a core feature of PD gait dysfunction, specifically in patients with FOG. A 4-week intensive rehabilitative program improved dSE in PD patients, exerting a more notable beneficial effect in the PD + FOG group.

Deep brain stimulation and cognitive functions in Parkinson's disease: A three-year controlled study.

There is debate over the cognitive and behavioral effects of deep brain stimulation (DBS) of the subthalamic nucleus (STN) in advanced Parkinson's disease (PD). To evaluate these effects, we performed a prospective, naturalistic controlled, 3-year follow-up study. A total of 65 PD patients were enrolled, of whom 32 underwent STN-DBS (PD-DBS) and 33, even though eligible for this treatment, declined surgery and chose other therapeutic procedures (PD-control). Motor and neuropsychological functions were assessed in all the subjects at baseline (T0) and 36 months (T36). The PD-DBS patients were also evaluated at 1, 6, 12, and 24 months after surgery (T1, T6, T12, and T24). At T1, compared with T0, the PD-DBS patients recorded worse logical executive function task and verbal fluency (FAS) scores, whereas their performance of memory tasks remained stable. At T12, their cognitive profile had returned within the pre-DBS range, thereafter remaining stable until T36. FAS scores at T36 were significantly worse in the PD-DBS compared with the PD-control patients. This is the first long-term naturalistic controlled study of cognitive functions in PD patients submitted to STN-DBS. Our results confirm previous reports of a worsening of verbal fluency after DBS, but show that STN-DBS seems to be relatively safe from a cognitive standpoint, as the short-term worsening of frontal-executive functions was found to be transient.

Hyperhomocysteinemia in levodopa-treated patients with Parkinson's disease dementia.

Dementia is a frequent non-motor feature of Parkinson's disease (PD). Elevated plasma homocysteine (Hcy) levels have been associated with both cognitive impairment and dementia. Increased Hcy levels have been observed in levodopa-treated patients with PD. The objective of our study was to evaluate the association between plasma Hcy levels and dementia in PD. We performed a multicenter cross-sectional study on patients with PD with (PDD) and without (PDnD) dementia and age- and sex-matched healthy controls. We compared Hcy levels in patients with PDD and PDnD and healthy controls, and we performed logistic regression analysis to search for an association between the presence of dementia and increased Hcy levels in PD. Patients with PD (121), PDD (42), and PDnD (79), and age- and sex-matched controls (154) were enrolled. Hcy levels were higher in patients with PD compared to controls (17.5 micromol/L +/- 10.2 vs. 11 +/- 4.1; P < 0.00001). Among patients with PD, Hcy levels were higher in the PDD group compared to the PDnD group (20.7 micromol/L +/- 12.1 vs. 15.8 +/- 8.5; P = 0.002). In a multivariate logistic regression model, higher Hcy levels [Odds ratios comparing the top (>18.9 micromol/L) with the bottom tertile (<12.4 micromol/L): 3.68; 95% CI: 1.14-11.83] were significantly associated with dementia. These data support the association between elevated Hcy levels and the presence of dementia in PD.

Plasma melatonin pattern in chronic and episodic headaches: evaluation during sleep and waking.

To look for a relationship between pineal function in chronic migraine (CM), cluster headache (CH) (during active and remission periods), chronic tension-type headache (CTTH) patients and controls during NREM sleep, REM sleep and waking, we performed serial sampling of plasma melatonin in the different sleep stages during the first half of the night, in order to avoid chronobiological interferences. Plasma melatonin levels did not show a normal curve either in the CTTH or in the CM patients and no significant differences between these groups were found in any of the sleep stages studied. Plasma melatonin values of CH patients during the cluster period showed an abnormal pattern. The curve showed a pathological lack of peaks during the active period, melatonin levels remaining within normal daytime range throughout the study. A trend to normalization of the curve during the remission period was observed. On the basis of these different melatonin secretion patterns, it might be hypothesized that the involvement of the hypothalamus in chronic-type headaches differs from that displayed in episodic forms.

Body Weight Support Combined With Treadmill in the Rehabilitation of Parkinsonian Gait: A Review of Literature and New Data From a Controlled Study.

Background: Gait disorders represent disabling symptoms in Parkinson's Disease (PD). The effectiveness of rehabilitation treatment with Body Weight Support Treadmill Training (BWSTT) has been demonstrated in patients with stroke and spinal cord injuries, but limited data is available in PD. Aims: The aim of the study is to investigate the efficacy of BWSTT in the rehabilitation of gait in PD patients. Methods: Thirty-six PD inpatients were enrolled and performed rehabilitation treatment for 4-weeks, with daily sessions. Subjects were randomly divided into two groups: both groups underwent daily 40-min sessions of traditional physiokinesitherapy followed by 20-min sessions of overground gait training (Control group) or BWSTT (BWSTT group). The efficacy of BWSTT was evaluated with clinical scales and Computerized Gait Analysis (CGA). Patients were tested at baseline (T0) and at the end of the 4-weeks rehabilitation period (T1). Results: Both BWSTT and Control groups experienced a significant improvement in clinical scales as FIM and UPDRS and in gait parameters for both interventions. Even if we failed to detect any statistically significant differences between groups in the different clinical and gait parameters, the intragroup analysis captured a specific pattern of qualitative improvement associated to cadence and stride duration for the BWSTT group and to the swing/stance ratio for the Control group. Four patients with chronic pain or anxious symptoms did not tolerate BWSTT. Conclusions: BWSTT and traditional rehabilitation treatment are both effective in improving clinical motor functions and kinematic gait parameters. BWSTT may represent an option in PD patients with specific symptoms that limit traditional overground gait training, e.g., severe postural instability, balance disorder, orthostatic hypotension. BWSTT is generally well-tolerated, though caution is needed in subjects with chronic pain or with anxious symptoms. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03815409.

Botulinum toxin A modifies nociceptive withdrawal reflex in subacute stroke patients.

OBJECTIVES: The aims of this study were to evaluate the pattern of the nociceptive withdrawal reflex (NWR) of the upper limb at rest and after injection of Botulinum toxin type A (BoNT-A) in poststroke subacute hemiparetic patients. METHODS: Fourteen patients with poststroke subacute hemiparesis underwent clinical and instrumental evaluation and BoNT-A injection. Painful electrical stimulation was applied to induce the NWR. Baseline EMG activity and NWR recordings (EMG and kinematic response) were performed at T0, one month (T1), and three months (T2) after the BoNT-A injection, as were Modified Ashworth Scale (MAS) and Functional Independence Measure (FIM) scores. RESULTS: Comparison of results at T0, T1, and T2 revealed significant changes in the MAS score for the elbow (p < 0.001) and wrist joints (p < 0.001) and in the FIM score at T0 and T2. BoNT-A injection had a significant effect on both NWR amplitude and baseline EMG activity in the posterior deltoid (PD) and flexor carpi radialis (FCR) muscles as well as in all averaged muscles. Analysis of elbow kinematics before and after treatment revealed that the reflex probability rates were significantly higher at T1 and T2 than at T0. CONCLUSION: Injection of BoNT-A in the subacute phase of stroke can modify both the baseline EMG activity and the NWR-related EMG responses in the upper limb muscles irrespective of the site of injection; furthermore, the reflex-mediated defensive mechanical responses, that is, shoulder extension and abduction and elbow flexion, increased after treatment. BoNT-A injection may be a useful treatment in poststroke spasticity with a potential indirect effect on spinal neurons.

Different effects of tibolone and low-dose EPT in the management of postmenopausal women with primary headaches.

OBJECTIVE: The present randomized prospective study aimed to compare the effect of tibolone (T) with conventional low-dose estrogen-progestogen therapy (EPT) administered in a combined continuous regimen on the course of primary headaches in postmenopausal women requesting hormone therapy (HT) for climacteric complaints. DESIGN: Forty women presenting for clinical evaluation of headache (migraine without aura and episodic tension-type headache) were enrolled. The observational period lasted 7 months during which women kept a diary of the clinical characteristics of headache attacks and analgesic use. Climacteric symptoms and both anxiety and depression were also measured. After a 1-month run-in period, women received two different HT regimens: 1 mg 17beta-estradiol + 0.5 mg norethisterone acetate (EPT) or 2.5 mg T. Follow-up evaluations were planned after 3 and 6 months of treatment. RESULTS: Although T did not affect the number of days with migraine without aura, it significantly reduced the number of hours during which pain intensity prohibited daily activities (P < 0.001) and the number of analgesics (P < 0.001) after 3 months. Conventional low-dose EPT administered in a combined continuous regimen was confirmed to have a mild, but negative, effect on the course of migraine without aura by increasing the number of days with head pain (P < 0.001) and the number of analgesics (P < 0.001). Interestingly, both treatments were effective in the management of episodic tension-type headache, significantly reducing the number of days with head pain, severity, and analgesic consumption. CONCLUSIONS: In postmenopausal headache sufferers, analgesics are more effective in alleviating severe head pain when women are treated with T in comparison with low-dose EPT for climacteric complaints.

Secondary cervical dystonia in iatrogenic hypoparathyroidism associated with extensive brain calcifications.

Cervical dystonia (CD) is usually idiopathic, without a known aetiology. Hypoparathyroidism, both primary and secondary, can be associated with brain calcifications and various clinical neurological features. Anecdotal evidence suggests that patients affected by hypoparathyroidism show a rapid-onset oral dyskinesia after use of neuroleptic drugs. We report the case of a 60-year-old woman with CD, iatrogenic hypoparathyroidism and extensive brain calcifications. On the basis of the clinical features and the localization of the brain calcifications we suppose that they may have played a role in the development of this CD. This case may prove to be, after a review of literature, the first report of CD secondary to iatrogenic hypoparathyroidism in a patient with extensive brain calcifications.

Family-based association study of 5-HTTLPR, TPH, MAO-A, and DRD4 polymorphisms in mood disorders.

Variants of the functional polymorphism in the serotonin transporter (upstream regulatory region: 5-HTTLPR), the tryptophan hydroxylase (TPH), the monoamine oxidase A (MAO-A), and the dopamine receptor D4 (DRD4) genes have all been associated with mood disorders. The aim of this study was to test those hypotheses by using a family-based association approach. Both diagnoses and psychopathology were used for phenotype definitions. A total of 134 nuclear families with mood disorders, with probands affected by bipolar (n = 103) or major depressive (n = 58) disorders, were included in the study. All subjects were typed for the above-mentioned gene variants using polymerase chain reaction (PCR) technique. No significant transmission disequilibrium was found in the overall sample for any polymorphism. A separate analysis of bipolar subjects only, or the use of continuous psychopathologic traits as affectation status did not influence the observed results. Our study did not support the involvement of 5-HTTLPR, TPH, MAO-A, or DRD4 polymorphisms in mood disorders.

Multicentre Italian family-based association study on tyrosine hydroxylase, catechol-O-methyl transferase and Wolfram syndrome 1 polymorphisms in mood disorders.

OBJECTIVE: The aim of the present study was to investigate tyrosine hydroxylase, catechol-O-methyl transferase and Wolfram syndrome 1 genes in mood disorders using a family-based association approach. METHODS: The sample included 134 nuclear mood disorder families, with subjects affected by bipolar disorder (n=103) or major depressive disorder (n=58). All subjects were genotyped using polymerase chain reaction techniques. RESULTS: No significant transmission disequilibrium was found in the overall sample for any polymorphism. Analysis considering bipolar subjects only, or psychopathology traits as affection status did not influence the observed results. CONCLUSIONS: The study could not support the involvement of tyrosine hydroxylase, catechol-O-methyl transferase and Wolfram syndrome 1 polymorphisms in mood disorders.

Long-term evaluation of the effect of quetiapine on hallucinations, delusions and motor function in advanced Parkinson disease.

OBJECTIVES: Mental disorders (MDs) are disabling complications of Parkinson disease (PD). We set out to demonstrate the short- and long-term efficacy of quetiapine, an antipsychotic drug, in controlling hallucinations and delusions in parkinsonian patients without worsening their motor function. Since current guidelines recommend that dopaminergic drugs be decreased or even withdrawn altogether upon the appearance of MDs, we also sought to establish whether quetiapine enables a modification of this common course of action, and hence improve the management of pre-existing motor complications in affected subjects. METHOD: Thirty-five PD patients with disabling MDs were enrolled in this open-label study. Motor function, MDs and cognitive state were evaluated before starting quetiapine therapy and after 1, 3, and 12 months of treatment. RESULTS: MDs significantly improved after 1, 3, and 12 months of quetiapine treatment. At the end of the study the mean daily dose of quetiapine (185 mg) did not produce significant changes in motor or cognitive function. Isolated hallucinations responded to low doses of quetiapine (110 mg daily), while delusions needed 265 mg daily. After 12 months, global dopaminergic therapy was reduced in 3 patients, modified (purely in terms of its components) in 17 patients, and increased in 15 patients. CONCLUSIONS: Quetiapine was effective in the treatment of hallucinations and delusions in PD. It did not worsen motor functions and allowed the dopaminergic treatment in PD patients affected by MDs to be managed safely.

A questionnaire on sleep and mental disorders in Parkinson's disease (QSMDPD): development and application of a new screening tool.

Psychiatric, cognitive and sleep disorders are the most frequent and disabling non-motor complications of Parkinson's disease (PD). To improve the description of sleep and mental disorders in PD patients, we set out to develop a simple and reliable data collection tool (questionnaire) for the screening of large samples of PD patients. The first draft of the questionnaire was administered to a consecutive series of 120 PD patients from the outpatient department of our unit, who were instructed to fill it in with the help of their caregivers. Subsequent drafts of the questionnaire were evaluated together with the patients and their caregivers, until a final, satisfactory version was obtained. This final version was named the Questionnaire on Sleep and Mental Disorders in PD (QSMDPD). This questionnaire--we used the Italian version, named Questionario sui Disturbi del Sonno e Mentali nella Malattia di Parkinson, ODSMMP--consists of 119 questions with multiple-choice answers. The QSMDPD was mailed or handed to 400 PD patients followed at our unit's outpatient department. Three hundred and twenty (80%) were returned to us. A review of these completed questionnaires, conducted by a neurologist together with the patients, showed 90% of them (289) to be complete and to provide reliable data. This high compliance suggests that the QSMDPD is a promising tool for collecting data on sleep and mental disorders in large samples of PD patients. A short version will be administered as a follow-up tool.

REM sleep behavior disorder, hallucinations, and cognitive impairment in Parkinson's disease.

The objective of this study was to evaluate the relationship between REM sleep behavior disorder (RBD), hallucinations, and cognitive impairment in Parkinson's disease (PD). One hundred and ten PD patients, divided into three groups (without RBD or hallucinations; with RBD but no hallucinations; with RBD and hallucinations), were submitted to neuropsychological evaluation. The group without RBD and hallucinations showed normal neuropsychological tests when compared to normal controls. The group with hallucinations was characterized by a more severe cognitive impairment affecting both short- and long-term memory, logical abilities, and frontal functions, while the RBD-only group presented frontal impairment. The hypothesis that RBD in PD can be considered a risk factor not only of the hallucinations but also of more severe and diffuse cognitive abnormalities needs to be strengthened through a longitudinal evaluation.