Social cognition in cervical dystonia.

Background: Whilst traditionally considered a movement disorder, it is now generally accepted that cervical dystonia (CD) presents with additional non-motor symptoms which significantly impact quality of life. Our study primarily aimed to explore social cognition and levels of psychological distress in individuals with CD, in comparison to age- and sex-matched healthy controls. Methods: 20 participants with CD attending a specialist movement disorders clinic were recruited. 20 age and sex matched neurologically healthy controls were recruited in parallel. Participants completed the Hospital Anxiety and Depression Scale, and two novel social cognition tasks: The Cambridge Mindreading Face-Voice Battery (CAFMB) and the Edinburgh Social Cognition Test (ESCoT). Results: Participants with CD exhibited poorer complex emotion recognition abilities for visual and auditory stimuli, compared to controls on the CAFMB task. Participants with CD did not differ significantly from controls on performance on cognitive or affective Theory of Mind tasks, or interpersonal or intrapersonal understanding of social norms, as measured by the ESCoT. The proportion of depressive symptoms was significantly higher for participants with CD than controls. 40% of participants with CD reported clinically elevated depressive symptoms, and 60% reported clinically elevated anxiety. Poorer understanding of emotional facial expressions was associated with higher levels of depression in the CD group. Conclusions: Significant between-group differences between participants with CD and controls suggests socio-cognitive dysfunction is an important aspect of the non-motor syndrome of CD. Findings highlight the need for assessment of and intervention for both social cognitive difficulties and psychological distress in individuals with CD.

Longitudinal Follow-Up of Mood in Cervical Dystonia and Influence on Age at Onset.

Background: Anxiety and depression are highly prevalent conditions in cervical dystonia and considered intrinsic to the disease mechanism. Psychiatric symptoms do not appear to be influenced by botulinum toxin therapy. Studies focusing on changes in mood disorder during the course of the disease are limited in this chronic, lifelong disorder. Objective: To assess the longitudinal prevalence of mood disorder, pain, and quality of life in patients with cervical dystonia attending a botulinum toxin clinic. Methods: Patients involved in phase I of our study were invited to be involved in reassessment using the Beck Depression Inventory, Second Revision; Beck Anxiety Index; Cervical Dystonia Impact Profile-58 (CDIP-58); and the Toronto Western Spasmodic Torticollis Rating Scale-2 Pain Scale (TWSTRS2-Pain). Results: A total of 53 participants took part after a mean study interval duration of 24 months. There were no significant differences between the 2 study time points in the prevalence of anxiety (P = 0.2919) and depressive symptoms (P = 0.5). Self-reported quality of life by CDIP-58 (P = 0.96) and pain by TWSTRS2-Pain (P = 0.9321) were unchanged. Men and women with significant symptoms of mood disorder had an earlier age of onset of cervical dystonia (P = 0.008). Conclusion: Anxiety and depressive symptoms persist in cervical dystonia, seem to be unrelated to pain severity, and need to be specifically targeted to improve quality of life. The relationship between mood disorder and age of onset suggest that mood disorder may be part of the disease pathophysiology.

Identification of a novel MAGT1 mutation supports a diagnosis of XMEN disease.

XMEN (X-linked immunodeficiency with magnesium defect) is caused by loss-of-function mutations in MAGT1 which is encoded on the X chromosome. The disorder is characterised by CD4 lymphopenia, severe chronic viral infections and defective T-lymphocyte activation. XMEN patients are susceptible to Epstein-Barr virus infections and persistently low levels of intracellular Mg2+. Here we describe a patient that presented with multiple recurrent infections and a subsequent diffuse B-cell lymphoma. Molecular genetic analysis by exome sequencing identified a novel hemizygous MAGT1 nonsense mutation c.1005T>A (NM_032121.5) p.(Cys335*), confirming a diagnosis of XMEN deficiency. Follow-up immunophenotyping was performed by antibody staining and flow cytometry; proliferation was determined by 3H-thymidine uptake after activation by PHA and anti-CD3. Cytotoxic natural killer cell activity was assessed with K562 target cells using the NKTESTTM assay. While lymphocyte populations were superficially intact, B cells were largely naive with a reduced memory cell compartment. Translated NKG2D was absent on both NK and T cells in the proband, and normally expressed in the carrier mother. In vitro NK cell activity was intact in both the proband and his mother. This report adds to the growing number of identified XMEN cases, raising awareness of a, still rare, X-linked immunodeficiency.

Reliability of DNMSQuest as a Screening Tool for Mood Disorders in Cervical Dystonia.

BACKGROUND: The high prevalence of mood disorders in cervical dystonia, often unaddressed in botulinum toxin clinics, is a major factor in impaired quality of life. There is a clear need for a brief screening method for identifying these disorders; the Dystonia non-motor symptoms questionnaire (DNMSQuest) has been proposed as such. OBJECTIVE: We aimed to assess the practical utility of the DNMSQuest and compare it with validated rating scales for anxiety, depression and quality of life. METHODS: In 88 patients with cervical dystonia, we compared results from the DNMSQuest with mood rating scales [Beck Anxiety Inventory (BAI), Beck Depression Index (BDI-II) and Hospital Anxiety and Depression Scale (HADS)], quality of life measures [European Quality of Life (EQOL) and European Quality of Life Visual Analogue Scale (EQOLVAS)] and with assessments of dystonia severity [Cervical Dystonia Impact Profile-58 (CDIP58) and Toronto Western Rating Scale for Spasmodic Torticollis (TWSTRS)]. RESULTS: Using a cut off score on the DNMSQuest of 5, we noted that DNMSQuest had a sensitivity of 85% for detecting anxiety and depression using the BAI and BDI-II, and 76% and 78% for anxiety and depression respectively using the HADS. The DNMSQuest correlated strongly with BAI (ρ = 0.715), BDI-II (ρ = 0.658), HADS-Anxiety (ρ = 0.616), HADS-Depression (ρ = 0.706), EQOL (ρ = 0.653) and CDIP-58 (ρ = 0.665). CONCLUSION: The DNMSQuest is a brief, sensitive and non-specific instrument for identifying patients that warrant further review for anxiety and depression and can easily be implemented in a neurologist-run botulinum toxin clinic.

Non-motor features of cervical dystonia: Cognition, social cognition, psychological distress and quality of life.

INTRODUCTION: Non-motor features of cervical dystonia (CD) have been identified, including depression, anxiety, and neuropsychological deficits. The aims were: to provide a clinical neuropsychological profile of CD patients with specific focus on social cognition; assess levels of psychological distress; and investigate the relationship between non-motor features of CD, including cognitive functioning, psychological distress, CD severity, pain, and health-related quality of life (HR-QoL). METHODS: A multi-domain neuropsychological assessment battery was administered to 46 participants with CD, examining cognitive and social cognitive domains. Clinical data on dystonia severity, pain, psychological distress and HR-QoL were collected. RESULTS: The majority of participants with CD performed within the average range across most tests of cognition. Scores were significantly lower than standardized norms in social cognition, processing speed, and aspects of memory. High levels of anxiety (Hospital Anxiety and Depression Scale [HADS-A] ≥ 11, 30%) and depression (HADS-D ≥ 11; 29%) were observed. Psychological distress, CD severity, pain and HR-QoL were not significantly associated with neuropsychological functioning after controlling for multiple comparisons. Low HR-QoL was associated with higher levels of pain and psychological distress, but not severity of motor symptoms. CONCLUSION: Results indicate that psychological distress and deficits in cognitive and social cognitive functioning are likely distinct features of CD. While motor symptoms do not appear to impact HR-QoL, pain and psychological distress were associated with low HR-QoL. Findings highlight the importance of addressing non-motor symptoms in the treatment of CD.

Adult onset dystonia: A disorder of the collicular-pulvinar-amygdala network.

Models attempting to explain the pathogenesis of adult onset idiopathic focal dystonia often fail to accommodate the entire spectrum of this disorder: the diverse motor and non-motor symptoms, psychiatric and cognitive dysfunction, as well as the sub-clinical, physiological and anatomical, abnormalities. We propose, and present the accumulating evidence, that the adult onset dystonia syndrome is due to disruption in the covert-attentional network, the unconscious sub-cortical mechanism for the detection of potentially environmentally threatening (salient) stimuli, involving the collicular-pulvinar-amygdala network. A critical consideration of this network indicates a number of hypothesis-generated research questions aimed at elucidating the pathogenesis of adult onset dystonia. Given the rarity of adult onset dystonia, international, multidisciplinary, multicentre studies are required to elucidate the prevalence of non-motor symptoms in unaffected relatives, in particular, using temporal discrimination. Research focussing on the non-motor symptoms and the collicular-pulvinar-amygdala pathway may be the key to understanding adult-onset idiopathic focal dystonias (AOIFD) pathophysiology.

Severe brachial plexopathy secondary to shingles (herpes zoster).

Varicella zoster reactivation ("shingles" or "herpes zoster") usually presents as a self-limiting, unilateral, dermatomal vesicular rash in older adults. We present the case of a 73 year-old woman with unilateral brachial plexopathy, an unusual but debilitating complication of shingles. Despite treatment with intravenous acyclovir and immunoglobulin she had a marked residual motor paresis that required an upper limb rehabilitation program after discharge.

We Must Talk about Sex and Focal Dystonia.

In a recent workshop on "Defining research priorities in dystonia,", there was absolutely no reference to sex as a factor in disease pathogenesis. In this viewpoint paper, we argue that the most distinctive aspects of adult onset isolated focal dystonia are the marked sex-related differences demonstrated by epidemiological, clinical, and laboratory studies in patients with adult onset dystonia, particularly in cervical dystonia, the most common presentation. We propose that the future focus of research should be on neurobiological mechanisms underlying the profound sexual dimorphism in this disorder. Targeting research into gamma aminobutyric acid (GABA)ergic function, which also shows similar sexual dimorphism, would be most productive in elucidating the pathogenesis of adult onset dystonia. © 2021 International Parkinson and Movement Disorder Society.

Trust the Patient Not the Doctor: The Determinants of Quality of Life in Cervical Dystonia.

Background: Mood disorder is common in cervical dystonia and can impact on quality of life. It often precedes the onset of cervical dystonia and does not improve with botulinum toxin therapy. Objective: To assess health-related quality of life in relation to mood disorder and measures of severity, disability and pain, in cervical dystonia patients receiving botulinum toxin therapy. Methods: In a single-center, University Hospital movement disorders clinic, we conducted a comprehensive, cross-sectional study of disease severity, non-motor symptoms, mood and health-related quality of life in patients with cervical dystonia receiving botulinum toxin therapy using TWSTRS-2 for pain, severity and disability; Beck Anxiety Inventory and Beck Depression Inventory. We assessed all variables in relation to health-related quality of life assessed by Cervical Dystonia Impact Profile-58 and the Euro-QoL Utility Index. Results: In 201 patients (136 women), mean age 61.5 years, significant determinants of impaired health related quality of life were: being a woman, reporting a history of anxiety or depression, prevalent pain, disability, anxiety and/or depression but not physician-assessed disease severity. Conclusion: Patient-reported measures of pain, disability and, most markedly, mood disorder, are significant factors affecting quality of life; these were totally unrelated to the neurologist-rated measure of disease severity. Mood disorders, the predominant predictor of quality of life, were not addressed in the botulinum toxin clinic.

Germline TET2 loss of function causes childhood immunodeficiency and lymphoma.

Molecular dissection of inborn errors of immunity can help to elucidate the nonredundant functions of individual genes. We studied 3 children with an immune dysregulation syndrome of susceptibility to infection, lymphadenopathy, hepatosplenomegaly, developmental delay, autoimmunity, and lymphoma of B-cell (n = 2) or T-cell (n = 1) origin. All 3 showed early autologous T-cell reconstitution following allogeneic hematopoietic stem cell transplantation. By whole-exome sequencing, we identified rare homozygous germline missense or nonsense variants in a known epigenetic regulator of gene expression: ten-eleven translocation methylcytosine dioxygenase 2 (TET2). Mutated TET2 protein was absent or enzymatically defective for 5-hydroxymethylating activity, resulting in whole-blood DNA hypermethylation. Circulating T cells showed an abnormal immunophenotype including expanded double-negative, but depleted follicular helper, T-cell compartments and impaired Fas-dependent apoptosis in 2 of 3 patients. Moreover, TET2-deficient B cells showed defective class-switch recombination. The hematopoietic potential of patient-derived induced pluripotent stem cells was skewed toward the myeloid lineage. These are the first reported cases of autosomal-recessive germline TET2 deficiency in humans, causing clinically significant immunodeficiency and an autoimmune lymphoproliferative syndrome with marked predisposition to lymphoma. This disease phenotype demonstrates the broad role of TET2 within the human immune system.

Sonography of musculoskeletal infection in children.

Musculoskeletal infection, especially in young children, often presents with non-specific clinical signs and symptoms necessitating early imaging to identify the source of infection. While MRI is the investigation of choice to demonstrate bone infection, it is expensive and often requires a general anaesthetic in the young child. Ultrasound can be a useful tool in the initial assessment due to its easy availability and portable equipment. It does not involve ionising radiation and is used to guide aspiration and drainage procedures. This review explains sonographic features of septic arthritis, osteomyelitis, pyomyositis and soft tissue infection in children and highlights advantages and limitations of sonography when assessing the child with suspected musculoskeletal infection.

A Case of Recurrent Painful Ophthalmoplegic Neuropathy with Associated Oculomotor Nerve Tumour.

Recurrent painful ophthalmoplegic neuropathy (RPON) replaced the term 'ophthalmoplegic migraine' as the condition behaves more like an inflammatory cranial neuropathy than a primary headache disorder. RPON may be associated with cranial nerve thickening on MR imaging and persistent oculomotor paresis. Oculomotor tumours have rarely been described in cases of relapsing painful ophthalmoplegia with and without persistent paresis. Here, we present a case of relapsing painful left ophthalmoplegia that gradually became persistent. MR imaging after 14 years of symptoms revealed an enhancing tumour of the left oculomotor nerve. It is unclear whether the tumour was the cause of the attacks or whether repeated cycles could lead to tumour development. MR imaging is indicated in patients with RPON who develop persistent deficits to screen for associated oculomotor tumour.

Slowed Luminance Reaction Times in Cervical Dystonia: Disordered Superior Colliculus Processing.

BACKGROUND: Abnormal temporal discrimination in cervical dystonia is hypothesized to be attributable to disrupted processing in the superior colliculus. The fast, luminance-based, retinotectal pathway, projects to the superior colliculus; chromatic stimuli responses, by the retino-geniculo-calcarine pathway, are up to 30 ms longer. OBJECTIVES: We sought to interrogate visual processing and reaction times in patients with cervical dystonia compared with healthy controls. We hypothesized that cervical dystonia patients would have impaired reaction times to luminance based stimuli accessing the retino-tectal pathway in comparison to healthy control participants. METHODS: In 20 cervical dystonia and 20 age-matched control participants, we compared reaction times to two flashing visual stimuli: (1) a chromatic annulus and (2) a luminant, noncolored annulus. Participants pressed a joystick control when they perceived the annulus flashing. RESULTS: Reaction times in control participants were 20 ms significantly faster in the luminant condition than the chromatic (P = 0.017). Patients with cervical dystonia had no reaction time advantage in response to the luminant stimulus. CONCLUSION: Cervical dystonia patients (compared to control participants) demonstrated no reduction in their reaction time to luminant stimuli, processed through the retinotectal pathway. This finding is consistent with superior colliculus dysfunction in cervical dystonia. © 2020 International Parkinson and Movement Disorder Society.

Mood disorder affects age at onset of adult-onset cervical dystonia.

INTRODUCTION: Mood disorder is common in cervical dystonia, affects quality of life and may precede the onset of the dystonia. There is controversy as to whether mood disorder is part of the primary process or secondary to the disability.We assessed the characteristics of cervical dystonia patients in relation to a past history of mood disorder. METHODS: At a University Hospital clinic, in all consenting patients with cervical dystonia, we uniformly collected demographic data, medical history, and prospectively, measures of prevalent mood disorder. RESULTS: In 193 patients (128 women and 65 men) mean age at onset was 43.9 years and mean duration of cervical dystonia was 17.5 years. Men had earlier age at onset of cervical dystonia than women (p = 0.0037). A history of a mood disorder was reported in 53/128 (41%) women with a significantly earlier median age at onset of cervical dystonia (42 years) than 75/128 (59%) women with no history of mood disorder (48 years) (p = 0.005); 33 (26%) women with mood disorder prior to dystonia also had an earlier age at onset of dystonia than the 75 without such a history (p = 0.0154). A history of mood disorder was more common in women (41%) than men (31%); 54/128 (42%) women and 21/65 (32%) men had current mood disorder symptoms. CONCLUSIONS: In our cervical dystonia clinic population significant differences in the age at onset in women with, and without, a history of mood disorder strongly indicates that anxiety and depression are primary non-motor (and premotor) symptoms of cervical dystonia.

Social cognition in cervical dystonia: A case-control study.

BACKGROUND: Although considered a motor disorder, adult onset isolated focal dystonia has many non-motor symptoms. There is a paucity of neuropsychological research on cognitive processing in adult onset focal dystonia. METHODS: We employed a battery of clinical and cognitive assessments, including basic and complex social cognition, and assessed 46 patients with adult-onset cervical dystonia, compared to 46 age-, sex-, education-, and premorbid IQ-matched healthy controls. RESULTS: Significant between-group differences were observed in relation to measures of memory encoding, recall and recognition, as well as multimodal measures of basic Social Cognition (emotion recognition: face and prosody), but not complex Social Cognition (mentalising). There were no deficits observed in multimodal measures of executive function. Controlling for mood did not affect performance. CONCLUSION: In this multi-dimensional assessment of cognition in cervical dystonia, we report deficits in memory encoding, and in social cognition. Further investigation of social cognitive processes, memory, and sustained attention are required. Longitudinal studies are also needed to further delineate the role of psychological distress on cognitive outcomes and document the cognitive profile over time.

Neural Correlates of Abnormal Temporal Discrimination in Unaffected Relatives of Cervical Dystonia Patients.

Background: An abnormal temporal discrimination threshold in cervical dystonia (CD) is considered to be a mediational endophenotype; in unaffected relatives it is hypothesized to indicate non-manifesting gene carriage. The pathogenesis underlying this condition remains unknown. Investigation of the neural networks involved in disordered temporal discrimination may highlight its pathomechanisms. Objective: To examine resting state brain function in unaffected relatives of CD patients with normal and abnormal temporal discrimination. We hypothesized that the endophenotype, an abnormal temporal discrimination, would manifest as altered connectivity in relatives in regions associated with CD, thereby illuminating the neural substrates of the link between temporal discrimination and CD. Methods: Rs-fMRI data was analyzed from two sex- and age-matched cohorts: 16 unaffected relatives of CD patients with normal temporal discrimination and 16 with abnormal temporal discrimination. Regional and whole brain functional connectivity measures were extracted via Independent Component Analysis (ICA), Regional Homogeneity (ReHo), and Amplitude of Low Frequency (ALFF) analyses. Results: Our ICA analysis revealed increased connectivity within both the executive control and cerebellar networks and decreased connectivity within the sensorimotor network in relatives with abnormal temporal discrimination when compared to relatives with normal temporal discrimination. The ReHo and ALFF analyses complimented these results and demonstrated connectivity differences in areas corresponding to motor planning, movement coordination, visual information processing, and eye movements in unaffected relatives with abnormal temporal discrimination. Conclusion: Disordered connectivity in unaffected relatives with abnormal temporal discrimination illuminates neural substrates underlying endophenotype expression and supports the hypothesis that genetically determined aberrant connectivity, when later coupled with unknown environmental triggers, may lead to disease penetrance.

Blood-brain barrier dysfunction in a boxer with chronic traumatic encephalopathy and schizophrenia.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative condition characterized by the perivascular deposition of phosphorylated τ (p-τ) protein aggregates resulting from repetitive mild traumatic brain injury (rTBI). Advances in the field have revealed the significance of repetitive head trauma in the pathogenesis of CTE in contact sports as well as military veterans. In this study we provide evidence of blood-brain barrier (BBB) disruption in regions of intense perivascular p-τ deposition in a former professional boxer diagnosed with CTE and schizophrenia. P-τ deposition was associated with loss of the tight junction protein claudin-5 and enhanced extravasation of endogenous blood components such as fibrinogen and IgG. We also provide evidence of tight junction disruption in individuals with schizophrenia, with discontinuous claudin-5 immunoreactivity in the parietal cortex. This data highlights a common phenotype of a dysfunctional BBB in individuals with CTE and schizophrenia and may represent a novel correlate of neural dysfunction in individuals at risk of developing CTE and schizophrenia.
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