Perampanel as a novel treatment for subcortical myoclonus in myoclonus-dystonia syndrome.

BACKGROUND: Myoclonus-dystonia (MD) is a syndrome characterized by subcortical myoclonus and milder dystonia. The main causative gene is the epsilon sarcoglycan gene (SGCE), but other genes may be involved. Response to medications is variable, with poor tolerability limiting their use. CASE PRESENTATION: We present the case of a patient with severe myoclonic jerks and mild dystonia since childhood. At first neurological visit at the age of 46 years old, she presented brief myoclonic jerks predominating in the upper limbs and neck, mild at rest and elicited by action, posture and tactile stimulus. Myoclonus was accompanied by mild neck and right arm dystonia. Neurophysiological tests suggested subcortical origin of myoclonus, brain MRI was unremarkable. Myoclonus-dystonia was diagnosed, and genetic testing identified a novel mutation in SGCE gene (c.907delC) in heterozygosis. Over time she assumed a large variety of anti-epileptics without beneficial effect on myoclonus and low tolerability. Add-on treatment with Perampanel was started, with a beneficial effect. No adverse events were reported. Perampanel is the first selective non-competitive AMPA receptor antagonist approved in add-on for focal and generalized tonic-clonic seizures. To our knowledge, this is the first trial of Perampanel in MD. CONCLUSIONS: We presented the case of a patient with MD due to SGCE mutation who was treated with Perampanel with beneficial effects. We propose Perampanel as a novel treatment for myoclonus in MD.

Positive DAT-SCAN in SPG7: a case report mimicking possible MSA-C.

BACKGROUND: Spastic Paraplegia type 7 (SPG7) is one of the most common autosomal recessive Hereditary Spastic Paraplegias (HSP); Spastic Paraplegias (SPGs) can present as hereditary ataxias. However, ataxia is frequently the symptom of presentation of many other hereditary/sporadic disorders, such as Multiple system atrophy type C (MSA-C), an α-synuclein sporadic neurodegenerative disorder, in which cerebellar ataxia is one of the main clinical features. Dopamine Transporter imaging (DAT-SCAN), associated with clinical features, can be a helpful tool in order to distinguish MSA-C from other causes of ataxia. CASE-PRESENTATION: We present the case of a 70-year-old man with gait difficulties over a period of 3 years and frequent backward/lateral falls. He also reported urinary urge incontinence, but no symptoms that are compatible with orthostatic hypotension. On neurological examination he showed ataxic gait, spasticity in the left lower limb and trunk and limb ataxia, especially on the left side. Mild hypokinesia was found in all 4 limbs, especially in the left foot. MRI revealed atrophy of the cerebellar hemispheres and vermis. DAT-SCAN imaging revealed bilateral nigro-striatal degeneration, which was compatible with a diagnosis of possible MSA-C. Considering the atypical disease course (the patient walked without any support after 3 years), we carried out a genetic investigation for Ataxia, and a mutation in SPG7 was found. CONCLUSIONS: DAT-SCAN imaging, evaluated together with the clinical findings, can be useful for differentiating MSA from other possible causes of adult-onset Ataxia. Indeed, patients with MSA-C generally show a decreased uptake of dopamine transporters in DAT-SCAN imaging. Ours is the first case reported in the literature of a patient with SPG7 mutation with nigrostriatal degeneration and a clinical presentation of a possible MSA-C. Performing genetic investigations in patients with an atypical disease course is important to avoid MSA-mimicries. Identifying the correct diagnosis is important not only for prognostic reasons, but also for possible future genetic therapies.

Theory of mind in Parkinson's disease: evidences in drug-naïve patients and longitudinal effects of dopaminergic therapy.

Theory of mind (ToM) is the ability to attribute mental states to one self and others and to understand that others have beliefs different from one's own. Different subcomponents of ToM have also been identified: cognitive and affective. Cognitive ToM refers to the capacity to infer others' beliefs and intentions, while affective ToM implies the ability to appreciate others' emotional states. The aim of this study was to explore ToM in drug-naïve Parkinson's disease (PD) patients and to investigate the effects of chronic dopaminergic therapy on different subcomponents of ToM during a 3 months and 1 year of follow-up. We examined 16 PD patients in three conditions: before (un-medicated) and after dopaminergic therapy (medicated 3 months: T1 and medicated 1 year: T2). We also compared our PD's ToM abilities with 11 healthy individuals. ToM was explored with 5 different tasks: Faux Pas Test, Picture Sequencing Task Capture Story, Emotion Attribution Task, Strange Stories Task, and Karolinska Directed Emotional Faces. Our study confirms that PD patients present deficits in cognitive components of ToM and preserved performances in the affective ones in early stages of disease. We also find a significant effect of dopaminergic therapy on ToM already after 3 months with a good persistency after 1 year of treatment.

Phenotypic Variability in Acquired and Idiopathic Dystonia.

Background: To date, a few studies have systematically investigated differences in the clinical spectrum between acquired and idiopathic dystonias. Objectives: To compare demographic data and clinical features in patients with adult-onset acquired and idiopathic dystonias. Methods: Patients were identified from among those included in the Italian Dystonia Registry, a multicenter Italian dataset of patients with adult-onset dystonia. Study population included 116 patients with adult-onset acquired dystonia and 651 patients with isolated adult-onset idiopathic dystonia. Results: Comparison of acquired and idiopathic dystonia revealed differences in the body distribution of dystonia, with oromandibular dystonia, limb and trunk dystonia being more frequent in patients with acquired dystonia. The acquired dystonia group was also characterized by lower age at dystonia onset, greater tendency to spread, lower frequency of head tremor, sensory trick and eye symptoms, and similar frequency of neck pain associated with CD and family history of dystonia/tremor. Conclusions: The clinical phenomenology of dystonia may differ between acquired and idiopathic dystonia, particularly with regard to the body localization of dystonia and the tendency to spread. This dissimilarity raises the possibility of pathophysiological differences between etiologic categories.

Event-based prospective memory in newly diagnosed, drug-naive Parkinson's disease patients.

The present study investigated memory for intention in individuals with Parkinson's disease (PD) who were newly diagnosed and not yet treated to avoid the effect of therapy as a potential confounding variable. A comprehensive neuropsychological battery and an event-based prospective memory task were administered to 41 subjects with de novo PD and 40 control subjects. Separate scores were computed for correct execution of intended action (prospective component) and recall of intention (retrospective component). PD patients performed marginally worse (p = .053) than controls on the prospective component of the task. On the other hand, the performance of the two groups was comparable for the retrospective component. Neuropsychological findings revealed lower performance of the PD group in episodic memory and in some measures of executive functions. These results suggested a subtle prospective memory dysfunction present at the initial stage of PD, which may be related to disruption of fronto-striatal circuitry.

Botulinum toxin for the treatment of dystonia and pain in corticobasal syndrome.

BACKGROUND: Dystonia is a key symptom in corticobasal syndrome (CBS), and upper limb dystonia is the most common phenotype. Dystonia-associated pain is frequently reported and can be disabling, with poor benefit from oral treatments. AIMS OF THE STUDY: To investigate the role of botulinum toxin A (BoTNA) in the treatment of dystonia and associated pain in CBS. METHODS: Ten consecutive patients with a clinical diagnosis of probable CBS and dystonia with/without associated pain were treated with BoTNA every 3 months. Treatment efficacy was assessed during the first follow-up visit, three months after the first injection, by means of caregiver impression (CI), evaluation of muscle tone with the Ashworth scale (AS), severity of pain measured with the visual analog scale (VAS). RESULTS: Nine subjects underwent at least three treatments, four patients discontinued for progressive reduction in efficacy or disease progression, five patients are ongoing with good response, and one completed the 10th treatment. No local or systemic side effects were reported, and levodopa equivalent daily dose remained unchanged in most cases during the observational period. Significant improvement of AS was recorded (from 2.9 ± 0.7 to 2.0 ± 0.5, p = 0.003). CI ranged from mild to moderate benefit. All patients reported efficacy on pain, with a significant reduction of VAS score (from 7.7 ± 1.7 to 1.7 ± 0.7 in the Pain group, p = 0.016). CONCLUSIONS: Our study confirms safety, efficacy, and tolerability of BoTNA in the treatment of dystonia associated with CBS. Local treatment should be considered as a valid alternative to oral treatment modulation mainly in the presence of associated pain.

Aerobic rehabilitation program for improving muscle function in Parkinson's disease.

BACKGROUND: Parkinson's Disease (PD) is characterized by progressive and disabling symptoms. An impaired oxidative metabolism efficiency was supposed to be involved in the systemic impairment. Rehabilitative treatment represents a valid tool in promoting skeletal muscle's adaptations, even if no solid studies on muscle metabolic features are still available. OBJECTIVE: To evaluate the efficiency of skeletal muscle oxidative metabolism in PD patients in comparison with age-matched controls and test the role of an intensive aerobic treatment on muscle oxidative metabolism and its clinical effects. METHODS: 60 PD patients and 32 age-matched healthy controls participated. Haematic lactate values were detected during and after a submaximal incremental exercise on treadmill. The number of steps completed during the exercise was recorded. From these patients 10 underwent to an intensive aerobic treatment on treadmill (4 sessions/week for 4 weeks). Haematic lactate values and functional scales were recorded before (T0) and after (T1) treatment. RESULTS: At rest no significant difference in hematic lactate values between PD and control subjects was found. Lactate blood levels were significantly higher (p < 0,001) after the aerobic exercise test in PD patients compared to controls. These values remained higher at any time during recovery period (p < 0,001). No significant relationship between lactate values and the number of completed steps was found. After the rehabilitation treatment haematic value of lactate showed a significant reduction (p < 0,05) at 0, 5 and 10 minutes of recovery period with a normalization of value at 30'. All functional scales showed an improvement trend at T1, in particular Berg Balance Scale and 6 Meter Walking Test showed a significant reduction (p < 0,001 and p < 0,05 respectively). CONCLUSION: Our data clearly show an impaired muscle oxidative efficiency in PD subjects. The intensive rehabilitation program on treadmill showed a beneficial effect on muscle oxidative metabolism, endurance and balance, confirming the focal role of rehabilitation in PD patients.

Social Cognition and Oxytocin in Huntington's Disease: New Insights.

This study is aimed at relating social cognition in Huntington's Disease (HD) to plasma levels of the social hormone oxytocin (OT). Indeed, HD patients commonly display reduced social skills and OT is involved in bonding behavior and improved recognition of facial emotions. Twelve mild-symptomatic HD patients (stage II Shoulson & Fahn) and 11 gender/age matched controls (healthy controls, HC), without concurrent psychiatric disorders, were investigated at baseline (T0) for OT plasma levels and social cognition through an extensive battery of neuropsychological tests. Social cognition was also re-examined after two years (T1) in 8 of the 12 patients. Results showed a trend for reduced T0-OT levels in HD vs. HC, mean ± stardard deviation: 6.5 ± 2.4 vs. 9.9 ± 7.2 pg/mL, without reaching statistical significance. At T0, patients showed significantly lower performances than controls at the "Faux-Pas" and "Strange Stories" tests (p < 0.05; p < 0.01); a reduced perception of visual emotions (p < 0.01) and verbal stimuli (p < 0.01) was also reported, involving anger, fear, and sadness (p < 0.05; p < 0.01). Additionally, in the HD population, OT concentrations positively correlated with T1-performances at Neutral\Faux-Pas test (p < 0.05), whereas the cognitive Montreal Cognitive Assessment (MoCA) and Mini Mental State Examination (MMSE) scores positively correlated with psychosocial perception at the "Strange Stories" and Karolinska Directed Emotional Faces (KDEF) tests (p < 0.05). This study, despite its limitations, supports correlations between OT and HD social cognition, suggesting a possible therapeutic use of this hormone. More subjects and additional body tissues/fluids, such as cerebrospinal fluid, should be investigated to confirm this hypothesis.

Efficacy of a combined therapeutic approach in the management of Pisa Syndrome.

BACKGROUND: Pisa syndrome (PS) represents an important source of disability in Parkinson's disease (PD). Currently no consensus has been reached on its definition or diagnostic criteria, and therapeutic approaches are unspecific and often futile. Recently the role of abdominal muscles, and in particular of the external oblique (EO), in the pathogenesis of PS was hypothesized. OBJECTIVES: To evaluate the role of EO and propose a combined therapeutic approach in the management of PS. METHODS: Ten PD patients with PS underwent a combined protocol based on repeated lidocaine injection in EO and rehabilitation program. RESULTS: Our data confirm the primary role of EO muscles in PS pathogenesis and showed an improvement in truncal flexion and balance with a positive impact on patients' quality of life after treatment. CONCLUSIONS: These data highlight the need for accurate characterization of PS focusing on the role of abdominal muscles and the need for a specific rehabilitation protocol for PS management.

Apomorphine hydrochloride for the treatment of Parkinson's disease.

Apomorphine (APO) is a potent D1 and D2 dopamine agonist. Plasma maximal concentration is reached in 8-16 min with a plasma half-life of 34-70 min. Bioavailability is close to 100%. It has a rapid antiparkinsonian action after subcutaneous (s.c.) administration with a size effect comparable with that of levodopa. Trials of s.c., oral, sublingual, intravenous, rectal, intranasal and iontophoretic transdermal administration of APO have been attempted in Parkinson's disease (PD), each of these routes have shown some potential for clinical effectiveness but the majority of studies indicate that APO intermittent s.c. administration, on which this review is mainly focused, is an effective therapy for the management of motor symptoms in PD, particularly in advanced phases mainly characterized by motor fluctuations, such as wearing OFF and unpredictable "off". Data on the effect of APO on non-motor symptoms in PD patients are limited but there is strong suggestion of a beneficial effect that warrants further investigation.

Nigral involvement and nigrostriatal dysfunction in Huntington's disease: evidences from an MRI and SPECT study.

BACKGROUND: Huntington disease (HD) is pathologically characterized by a selective neurodegeneration of vulnerable populations of neurons, with an early marked neuronal loss and atrophy in the neostriatum. Dopaminergic innervations of neostriatal neurons originate in the substantia nigra pars compacta. Few studies investigated the neuronal loss and the functional role of the substantia nigra in modulating clinical features in HD. METHODS: 12 patients and 12 age-matched controls underwent SPECT scans with (123)I-FP-CIT and a 1.5 T MRI scan with inversion recovery technique. The association between both clinical and neuropsychological features and striatal uptake and volume of substantia nigra was explored. RESULTS: Striatal (p < 0.05), caudate (p < 0.05), and putaminal (p < 0.01) uptake was significantly lower in patients with respect to controls. Further, the volume of substantia nigra was reduced in HD when compared to controls (p < 0.01). No relationship between the volume of SN and tracer striatal uptake was found as well as between clinical and neuropsychological features with the SPECT and MRI results. CONCLUSIONS: Our results confirm that the degeneration of nigrostriatal pathway may occur in symptomatic HD patients. If confirmed by larger studies, the lack of any kind of correlation between clinical and neuropsychological features with striatal uptake and volume of substantia nigra suggests that motor and cognitive aspects in HD are not directly related to nigrostriatal degeneration.

The hOGG1 Ser326Cys polymorphism and Huntington's disease.

Increasing evidence supports a role for oxidative DNA damage and impaired DNA repair mechanisms in the pathogenesis of age related neurodegenerative diseases. Within this context there is a current interest in the understanding of the role played by polymorphisms of DNA repair genes in the inter-individual risk to develop neurodegenerative pathologies, as well as in the onset and the progression of disease symptoms. Particularly, somatic CAG repeat expansion of the gene encoding for huntingtin has been observed in tissues of patients affected by Huntington's disease (HD), including blood and brain. Recent evidence suggests that somatic CAG repeat expansion in HD cells might contribute to disease age at onset and is mediated by the DNA repair OGG1 enzyme, during the removal of 8-oxoguanine (8-oxoG) from the DNA. There is also evidence that the expression of hMTH1, which removes 8-oxoG from the nucleotide pool, protects mice from HD-like symptoms, and progenitor striatal cells from the toxic effects of the mutant huntingtin. The hOGG1 Ser326Cys polymorphism results in reduced OGG1 activity and increased 8-oxoG formation. In the present study, performed on blood DNA from 91 HD subjects, we observed that bearers of the mutant Cys326 allele (Ser326Cys+Cys326Cys) tend to have an increased number of CAG repeats of the expanded HD allele (P=0.049); moreover bearers of at least one copy of the mutant Cys326 allele, mainly heterozygous subjects, showed a significant (P=0.041) earlier disease onset than Ser326Ser wild-type individuals, suggesting a possible role of the hOGG1 Ser326Cys polymorphism in HD phenotype.

"Parkinson-dementia" diseases: a comparison by double tracer SPECT studies.

We performed 123I-FP-CIT/SPECT and ECD/SPECT in 30 patients with Parkinson's disease with dementia (PDD) and 30 patients with dementia with Lewy bodies (DLB) to evaluate whether presynaptic nigro-striatal function and/or cerebral perfusional pattern is different in these diseases. The striatal uptake of DAT tracer was statistically significantly lower in PDD and DLB with respect to control data (p < 0.0005), however no significant difference was found between PDD and DLB. Patients with PDD and DLB showed a significant reduction of rCBF (p < 0.001) in parieto-occipital and frontal areas, with respect to controls, but the comparison between the two groups did not result in any significant difference by SPM analysis. Finally no correlation was found between any regional perfusional changes and nigro-striatal dysfunction. We conclude that neither studies with 123I-FP-CIT nor ECD/SPECT were able to discriminate between DLB and PDD in vivo.