Does sex influence the natural history of idiopathic adult-onset dystonia?

BACKGROUND: Several earlier studies showed a female predominance in idiopathic adult-onset dystonia (IAOD) affecting the craniocervical area and a male preponderance in limb dystonia. However, sex-related differences may result from bias inherent to study design. Moreover, information is lacking on whether sex-related differences exist in expressing other dystonia-associated features and dystonia spread. OBJECTIVE: To provide accurate information on the relationship between sex differences, motor phenomenology, dystonia-associated features and the natural history of IAOD. METHODS: Data of 1701 patients with IAOD from the Italian Dystonia Registry were analysed. RESULTS: Women predominated over men in blepharospasm, oromandibular, laryngeal and cervical dystonia; the sex ratio was reversed in task-specific upper limb dystonia; and no clear sex difference emerged in non-task-specific upper limb dystonia and lower limb dystonia. This pattern was present at disease onset and the last examination. Women and men did not significantly differ for several dystonia-associated features and tendency to spread. In women and men, the absolute number of individuals who developed dystonia tended to increase from 20 to 60 years and then declined. However, when we stratified by site of dystonia onset, different patterns of female-to-male ratio over time could be observed in the various forms of dystonia. CONCLUSIONS: Our findings provide novel evidence on sex as a key mediator of IAOD phenotype at disease onset. Age-related sexual dimorphism may result from the varying exposures to specific age-related and sex-related environmental risk factors interacting in a complex manner with biological factors such as hormonal sex factors.

Status epilepticus: Is there a Stage 1 plus?

In status epilepticus (SE), "time is brain." Currently, first-line therapy consists of benzodiazepines (BDZs) and SE is classified by the response to treatment; stage 2 or established SE is defined as "BDZ-resistant SE." Nonetheless, this classification does not always work, especially in the case of prolonged convulsive SE, where many molecular changes occur and γ-aminobutyric acid signaling becomes excitatory. Under these circumstances, BDZ therapy might not be optimal, and might be possibly detrimental, if given alone; as the duration of SE increases, so too does BDZ resistance. Murine models of SE showed how these cases might benefit more from synergistic combined therapy from the start. The definition of Stage 1 plus is suggested, as a stage requiring combined therapy from the start, which includes prolonged SE with seizure activity going on for >10 min, the time that marks the disruption of receptor homeostasis, with increased internalization. This specific stage might require a synergistic approach from the start, with a combination of first- and second-line treatment.

Does thyroid diseases contribute to the natural history of idiopathic adult-onset dystonia? Data from the Italian Dystonia Registry.

A few earlier observations and recent controlled studies pointed to the possible contribution of thyroid diseases in idiopathic adult-onset dystonia (IAOD). The aim of this study was to investigate the association between thyroid status and clinical characteristics of IAOD, focusing on dystonia localization, spread, and associated features such as tremors and sensory tricks. Patients were identified from those included in the Italian Dystonia Registry, a multicentre dataset of patients with adult-onset dystonia. The study population included 1518 IAOD patients. Patients with hypothyroidism and hyperthyroidism were compared with those without any thyroid disease. In the 1518 IAOD patients, 167 patients (11%; 95% CI 9.5-12.6%) were diagnosed with hypothyroidism and 42 (2.8%; 95% CI 1.99-3.74) with hyperthyroidism. The three groups were comparable in age at dystonia onset, but there were more women than men in the groups with thyroid disease. Analysing the anatomical distribution of dystonia, more patients with blepharospasm were present in the hyperthyroidism group, but the difference did not reach statistical significance after the Bonferroni correction. The remaining dystonia-affected body sites were similarly distributed in the three groups, as did dystonia-associated features and spread. Our findings provided novel information indicating that the high rate of thyroid diseases is not specific for any specific dystonia subpopulation and does not appear to influence the natural history of the disease.

The Dark side of the White Matter. Diffuse subcortical White Matter Hypointensity on T2/FLAIR: A systematic review of a frequently underrecognized sign.

BACKGROUND AND OBJECTIVES: Many reversible brain MRI abnormalities have been described, among these the most frequently reported are cortical hyperintensities on FLAIR/T2 occurring during seizures. Much less attention has been given to those situations where White Matter goes Dark: subcortical white matter hypointensity on T2/FLAIR. Our aim is to identify the medical condition "Dark White Matter" (DWM) is more frequently associated with. This is the first systematic review on DWM. METHODS: PubMed was searched in August 2023. Included studies were those reporting Diffuse Subcortical White Matter Hypointensity on T2/FLAIR. Mainly case reports were included. Individual patient-level data was included whenever available. Frequency measures of the different diseases were calculated. RESULTS: 56 studies were included, 228 patients were eligible for analysis. DWM happened in isolation, with no cortical abnormalities, in 71 cases and was associated with seizures in >61.4% of cases. The most frequently DWM-associated disease was Non-Ketotic Hyperglycaemic hyperosmolar state (NKH), followed by Encephalitis, Moyamoya disease, Genetic Causes, and Subdural Hematoma. Frequency of NKH was 32%. NKH was associated with seizures in 100% of cases and the most frequently involved lobe was the occipital one. When considering only the subgroup of patients with seizures, DWM was indicative of NKH in 51.4% of cases and Encephalitis in 26.4% of cases. Key limitations are heterogeneity and missing data. DISCUSSION: DWM is frequently underdiagnosed. This sign can exist alone and it is not merely a consequence of cortical involvement. Moreover, it has important implications, both diagnostic and therapeutic, as it is more frequently associated with NKH, especially in the context of seizures, where anti-seizure medication is not the first line of treatment. We also discuss the pathogenesis of DWM by finding a common link between the most frequently associated diseases.

Elderly Onset of Functional Motor Disorders: Clinical Correlates from the Italian Registry.

BACKGROUND: Functional motor disorders (FMD) are a frequent neurological condition affecting patients with movement disorders. Commonly described in younger adults, their manifestation can be also associated to an elderly onset. OBJECTIVE: To assess the prevalence and describe the clinical manifestations of FMD with elderly and younger onset and their relationship with demographical and clinical variables. METHODS: We recruited patients with a "clinically definite" diagnosis of FMD from the Italian Registry of FMD. Patients underwent extensive clinical assessments. For elderly onset, we set a chronological cut-off at 65 years or older according to WHO definition. Multivariate regression models were implemented to estimate adjusted odds ratio of elderly FMD onset related to clinical characteristics. RESULTS: Among the 410 patients, 34 (8.2%) experienced elderly-onset FMD, with a mean age at onset of 70.9 years. The most common phenotype was tremor (47.1%), followed by gait disorders, weakness, and dystonia (29.4%, 23.5%, 14.7%, respectively). Eleven elderly patients had a combined phenomenology: 9 exhibited two phenotypes, 2 had three phenotypes. Weakness was isolated in 3/8 patients and combined with another phenotype in 5/8, manifesting as paraplegia (n = 4); upper limb diplegia (n = 2), hemiparesis/hemiplegia (n = 1), and tetraparesis/tetraplegia (n= 1). Non-motor and other functional neurological disorders occurred more frequently in the younger group (89.1%) than the elderly (73.5%). Neurological and non-neurological comorbidities were more prevalent in the elderly group (82.4%) as opposed to the younger (32.7%). In a multivariate regression analysis, elderly-onset FMD was significantly associated with neurological comorbidities, including parkinsonism (OR 6.73) and cerebrovascular diseases (OR 5.48). CONCLUSIONS: These results highlight the importance of achieving an accurate diagnosis of FMD in the elderly, as it is crucial for effectively managing FMD symptoms and addressing neurological comorbidities.

Regional Targeted Subcutaneous Injection of Botulinum Neurotoxin Type A in Refractory Chronic Migraine: A Randomized, Double-Blind, Placebo-Controlled Study.

In this randomized, double-blind, placebo-controlled study, we evaluated the efficacy of an individualized technique of subcutaneous injection of botulinum toxin type A (BoNT-A) targeted (SjBoT) to the occipital or trigeminal skin area in non-responder patients with chronic migraine (CM). Patients who had not previously responded to at least two treatments of intramuscular injections of BoNT-A were randomly assigned (2:1) to receive two subcutaneous administrations of BoNT-A (up to 200 units) with the SjBoT injection paradigm or placebo. Following the skin area where the maximum pain began, treatment was given in the trigeminal or occipital region bilaterally. The primary endpoint changed in monthly headache days from baseline to the last 4 weeks. Among 139 randomized patients, 90 received BoNT-A and 49 received placebo, and 128 completed the double-blind phase. BoNT-A significantly reduced monthly headache days versus placebo (-13.2 versus -1.2; p < 0.0001) in the majority of patients who had cutaneous allodynia. Other secondary endpoints, including measures for disability (Migraine Disability Assessment questionnaire from baseline 21.96 to 7.59 after treatment, p = 0.028), also differed. Thus, in non-responder patients with CM, BoNT-A significantly reduced migraine days when administered according to the "follow the origin of maximum pain" approach using SjBoT injection paradigm.

Do cerebrovascular risk factors impact the clinical expression of idiopathic isolated adult-onset dystonia?

BACKGROUND: Although acquired dystonia may develop following ischaemic/haemorrhagic stroke, the relationship between cerebrovascular disease and idiopathic dystonia has been poorly investigated. This cross sectional study aimed at evaluating the impact of cerebrovascular risk factors on the clinical expression of idiopathic adult onset dystonia (IAOD), with reference to dystonia localization and dystonia-associated features. METHODS: Data were obtained from the Italian Dystonia Registry. Patients with IAOD were stratified into two groups according to the presence of diabetes mellitus and/or arterial hypertension and/or dyslipidemia and/or heart disease. The two groups were compared for demographic features, dystonia phenotype, and dystonia-associated features (sensory trick, tremor, eye symptoms in blepharospasm, and neck pain in cervical dystonia). RESULTS: A total of 1108 patients participated into the study. Patients who reported one cerebrovascular factor or more (n = 555) had higher age and longer disease duration than patients who did not. On multivariable logistic regression analysis, blepharospasm was the only localization, and sensory trick was the only dystonia-associated feature that was significantly associated with cerebrovascular risk factors. Linear regression analysis showed that the strength of the association between cerebrovascular factors and blepharospasm/sensory trick increased with increasing the number of cerebrovascular factors per patient. CONCLUSIONS: Results of the present study showed that cerebrovascular risk factors may be associated with specific features of IAOD that is development of blepharospasm and sensory trick. Further studies are needed to better understand the meaning and the mechanisms underlying this association.