remitting relapsing carbamazepine overdosage mimicking vertebrobasilar transient ischemic attacks

The objective of this article is to describe an atypical, remitting-relapsing presentation of carbamazepine toxicity due to its interaction with nebivolol. The method we use is a case report of an elderly epileptic patient in treatment with antiepileptic drugs (AEDs) and antihypertensive drugs, manifesting transient neurological symptoms in association with high blood pressure values. The case report is of a 72-year-old male by forty years of age had tonicclonic seizures related to the presence of a cerebral arteriovenous malformation. Seizures had been successfully controlled for many years by the same dosage of carbamazepine and lamotrigine, and recently total serum carbamazepine levels resulted within the "therapeutic range." He had also a history of controlled essential hypertension, but lately he manifested a scarce control of his blood pressure values. Few days after a modification of his antihypertensive therapy, the patient had two transient episodes of dysarthria, ataxia, and dizziness. At the emergency department, his blood pressure values were 190/110 mmHg, ECG and routine blood tests were normal, and a brain CT did not show acute lesions; about two hours later, his neurological examination was normal. Morning fasting carbamazepine serum levels were "normal" too; therefore, his symptoms were initially interpreted as vertebrobasilar transient ischemic attacks. However, the recurrence of similar episodes despite the normalization of his blood pressure suggested a carbamazepine intoxication. Indeed, its dosage resulted too high just in occasion of one of his attacks. A moderate reduction of carbamazepine was followed by cessation of toxicity. This case reminds us to be aware of adverse consequences of other drugs in patients assuming carbamazepine: in this case, its toxicity was consequential to a likely metabolic interaction with nebivolol

The cerebellar topography of attention sub-components in Spinocerebellar Ataxia Type 2

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease characterized by a progressive cerebellar syndrome and multiple-domain cognitive impairments. The cerebellum is known to contribute to distinct functional networks related to higher-level functions. The aims of the present study were to investigate the different sub-components of attention and to analyse possible correlations between attention deficits and specific cerebellar regions in SCA2 patients. To this purpose, 11 SCA2 patients underwent an exhaustive attention battery that evaluated several attention sub-components. The SCA2 group performed below the normal range in tasks assessing selective attention, divided attention, and sustained attention, obtaining negative Z-scores. These results were confirmed by non-parametric Mann-Whitney U tests that showed significant differences between SCA2 and control subjects in the same sub-components of the attention battery, allowing us to speculate on cerebellar involvement when a high cognitive demand is required (i.e., multisensory integration, sequencing, prediction of events, and inhibition of inappropriate response behaviours). The voxel-based morphometry analysis showed a pattern of significantly reduced grey matter volume in specific cerebellar lobules. In particular, the SCA2 patients showed significant grey matter loss in bilateral regions of the anterior cerebellar hemisphere (I-V) and in the posterior lobe (VI-IX) and posterior vermis (VI-IX). Statistical analysis found significant correlations between grey matter reductions in the VIIb/VIIIa cerebellar lobules and impairments in Sustained and Divided Attention tasks and between grey matter reduction in the vermal VI lobule and impairment in the Go/NoGo task. For the first time, the study demonstrated the involvement of specific cerebellar lobules in different sub-components of the attention domain, giving further support to the inclusion of the cerebellum within the attention network

Brain connectomics' modification to clarify motor and nonmotor features of myotonic dystrophy type 1

The adult form of myotonic dystrophy type 1 (DM1) presents with paradoxical inconsistencies between severity of brain damage, relative preservation of cognition, and failure in everyday life. This study, based on the assessment of brain connectivity and mechanisms of plasticity, aimed at reconciling these conflicting issues. Resting-state functional MRI and graph theoretical methods of analysis were used to assess brain topological features in a large cohort of patients with DM1. Patients, compared to controls, revealed reduced connectivity in a large frontoparietal network that correlated with their isolated impairment in visuospatial reasoning. Despite a global preservation of the topological properties, peculiar patterns of frontal disconnection and increased parietal-cerebellar connectivity were also identified in patients' brains. The balance between loss of connectivity and compensatory mechanisms in different brain networks might explain the paradoxical mismatch between structural brain damage and minimal cognitive deficits observed in these patients. This study provides a comprehensive assessment of brain abnormalities that fit well with both motor and nonmotor clinical features experienced by patients in their everyday life. The current findings suggest that measures of functional connectivity may offer the possibility of characterizing individual patients with the potential to become a clinical tool

Heritability and Demographic Analyses in the Large Isolated Population of Val Borbera Suggest Advantages in Mapping Complex Traits Genes

Isolated populations are a useful resource for mapping complex traits due to shared stable environment, reduced genetic complexity and extended Linkage Disequilibrium (LD) compared to the general population. Here we describe a large genetic isolate from the North West Apennines, the mountain range that runs through Italy from the North West Alps to the South.The study involved 1,803 people living in 7 villages of the upper Borbera Valley. For this large population cohort, data from genealogy reconstruction, medical questionnaires, blood, anthropometric and bone status QUS parameters were evaluated. Demographic and epidemiological analyses indicated a substantial genetic component contributing to each trait variation as well as overlapping genetic determinants and family clustering for some traits.The data provide evidence for significant heritability of medical relevant traits that will be important in mapping quantitative traits. We suggest that this population isolate is suitable to identify rare variants associated with complex phenotypes that may be difficult to study in larger but more heterogeneous populations

Neurofilaments in spinocerebellar ataxia type 3: blood biomarkers at the preataxic and ataxic stage in humans and mice

With molecular treatments coming into reach for spinocerebellar ataxia type 3 (SCA3), easily accessible, cross-species validated biomarkers for human and preclinical trials are warranted, particularly for the preataxic disease stage. We assessed serum levels of neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in ataxic and preataxic subjects of two independent multicentric SCA3 cohorts and in a SCA3 knock-in mouse model. Ataxic SCA3 subjects showed increased levels of both NfL and pNfH. In preataxic subjects, NfL levels increased with proximity to the individual expected onset of ataxia, with significant NfL elevations already 7.5 years before onset. Cross-sectional NfL levels correlated with both disease severity and longitudinal disease progression. Blood NfL and pNfH increases in human SCA3 were each paralleled by similar changes in SCA3 knock-in mice, here also starting already at the presymptomatic stage, closely following ataxin-3 aggregation and preceding Purkinje cell loss in the brain. Blood neurofilaments, particularly NfL, might thus provide easily accessible, cross-species validated biomarkers in both ataxic and preataxic SCA3, associated with earliest neuropathological changes, and serve as progression, proximity-to-onset and, potentially, treatment-response markers in both human and preclinical SCA3 trials.Acknowledgements: This work was supported by the Horizon 2020 research and innovation programme (grant 779257 Solve-RD to MS and RS), the National Ataxia Foundation (grant to CW and MS), the Wilhelm Vaillant Stiftung (grant to CW), the EU Joint Programme—Neurodegenerative Disease Research (JPND) through participating national funding agencies, and the European Union’s Horizon 2020 research and innovation programme under grant agreement No 643417. BM was supported in part from the grant NKFIH 119540. HJ was funded by the Medical Faculty of the University of Heidelberg. CB was funded by the University of Basel (PhD Program in Health Sciences). The funding sources had no role in the study design, data collection, data analysis, data interpretation or writing of the manuscript

Development of a psychiatric disorder linked to cerebellar lesions

Cerebellar dysfunction plays a critical role in neurodevelopmental disorders with long-term behavioral and neuropsychiatric symptoms. A 43-year-old woman with a cerebellum arteriovenous malformation and history of behavioral dysregulation since childhood is described. After the rupture of the cerebellar malformation in adulthood, her behavior morphed into specific psychiatric symptoms and cognitive deficits occurred. The neuropsychological assessment evidenced impaired performance in attention, visuospatial, memory, and language domains. Moreover, psychiatric assessment indicated a borderline personality disorder. Brain MRI examination detected macroscopic abnormalities in the cerebellar posterior lobules VI, VIIa (Crus I), and IX, and in the posterior area of the vermis, regions usually involved in cognitive and emotional processing. The described patient suffered from cognitive and behavioral symptoms that are part of the cerebellar cognitive affective syndrome. This case supports the hypothesis of a cerebellar role in personality disorders emphasizing the importance of also examining the cerebellum in the presence of behavioral disturbances in children and adults

Molecular, clinical, and muscle studies in myotonic dystrophy type 1 (DM1) associated with novel variant CCG expansions

We assessed clinical, molecular and muscle histopathological features in five unrelated Italian DM1 patients carrying novel variant pathological expansions containing CCG interruptions within the 3'-end of the CTG array at the DMPK locus, detected by bidirectional triplet primed PCR (TP-PCR) and sequencing. Three patients had a negative DM1 testing by routine long-range PCR; the other two patients were identified among 100 unrelated DM1 cases and re-evaluated to estimate the prevalence of variant expansions. The overall prevalence was 4.8 % in our study cohort. There were no major clinical differences between variant and non-variant DM1 patients, except for cognitive involvement. Muscle RNA-FISH, immunofluorescence for MBNL1 and RT-PCR analysis documented the presence of ribonuclear inclusions, their co-localization with MBNL1, and an aberrant splicing pattern involved in DM1 pathogenesis, without any obvious differences between variant and non-variant DM1 patients. Therefore, this study shows that the CCG interruptions at the 3'-end of expanded DMPK alleles do not produce qualitative effects on the RNA-mediated toxic gain-of-function in DM1 muscle tissues. Finally, our results support the conclusion that different patterns of CCG interruptions within the CTG array could modulate the DM1 clinical phenotype, variably affecting the mutational dynamics of the variant repeat

Does the cerebellum shape the spatiotemporal organization of muscle patterns? Insights from subjects with cerebellar ataxias

The role of the cerebellum in motor control has been investigated extensively, but its contribution to the muscle pattern organization underlying goal-directed movements is still not fully understood. Muscle synergies may be used to characterize multimuscle pattern organization irrespective of time (spatial synergies), in time irrespective of the muscles (temporal synergies), and both across muscles and in time (spatiotemporal synergies). The decomposition of muscle patterns as combinations of different types of muscle synergies offers the possibility to identify specific changes due to neurological lesions. In this study, we recorded electromyographic activity from 13 shoulder and arm muscles in subjects with cerebellar ataxias (CA) and in age-matched healthy subjects (HS) while they performed reaching movements in multiple directions. We assessed whether cerebellar damage affects the organization of muscle patterns by extracting different types of muscle synergies from the muscle patterns of each HS and using these synergies to reconstruct the muscle patterns of all other participants. We found that CA muscle patterns could be accurately captured only by spatial muscle synergies of HS. In contrast, there were significant differences in the reconstruction R2 values for both spatiotemporal and temporal synergies, with an interaction between the two synergy types indicating a larger difference for spatiotemporal synergies. Moreover, the reconstruction quality using spatiotemporal synergies correlated with the severity of impairment. These results indicate that cerebellar damage affects the temporal and spatiotemporal organization, but not the spatial organization, of the muscle patterns, suggesting that the cerebellum plays a key role in shaping their spatiotemporal organization.NEW & NOTEWORTHY In recent studies, the decomposition of muscle activity patterns has revealed a modular organization of the motor commands. We show, for the first time, that muscle patterns of subjects with cerebellar damage share with healthy controls spatial, but not temporal and spatiotemporal, modules. Moreover, changes in spatiotemporal organization characterize the severity of the subject's impairment. These results suggest that the cerebellum has a specific role in shaping the spatiotemporal organization of the muscle patterns