Exploring Factors That Prolong the Diagnosis of Myasthenia Gravis.

Background and Objectives: Myasthenia gravis (MG) is a condition with significant phenotypic variability, posing a diagnostic challenge to many clinicians worldwide. Prolonged diagnosis can lead to reduced remission rates and morbidity. This study aimed to identify factors leading to a longer time to diagnosis in MG that could be addressed in future to optimize diagnosis time. Methods: One hundred and ten patients from 3 institutions in Melbourne, Australia, were included in this retrospective cohort study. Demographic and clinical data were collected for these patients over the first 5 years from diagnosis and at 10 years. Nonparametric statistical analysis was used to identify factors contributing to a longer diagnosis time. Results: The median time for MG diagnosis was 102 (345) days. 90% of patients were diagnosed before 1 year. Female patients took longer than male patients to be diagnosed (p = 0.013). The time taken for first presentation after symptom onset contributed most to diagnosis time (median 17 [141] days), with female patients and not working as contributory factors. Neurology referral took longer if patients had diplopia (p = 0.022), respiratory (p = 0.026) symptoms, or saw an ophthalmologist first (p < 0.001). Outpatient management compared with inpatient was associated with a longer time to be seen by a neurologist from referral (p < 0.001), for the first diagnostic result to return (p = 0.001), and for the result to be reviewed (p < 0.001). Ocular MG had a median greater time to neurologist review than generalized MG (median 5 [25] days vs 1 [13] days, p = 0.035). Electrophysiology tests took longer for outpatients than inpatients (median 21 [35] days vs 2 [8] days, p < 0.001). Outpatients were also started on treatment later than inpatients (p < 0.001). There was no association of MG severity, ethnicity, age, medical and ocular comorbidities, and public or private health service on diagnosis time. There was also no impact of time to diagnosis on Myasthenia Gravis Foundation of America outcomes, number of follow-ups or hospitalizations, or prevalence of treatments used. This study is limited by low patient numbers and its retrospective nature. Discussion: This study identified several factors that can contribute to a prolonged diagnosis time of MG. Patient and clinician education about MG and outpatient diagnostic efficiency needs emphasis. Further studies are also needed to explore the delayed presentation time of women and nonworking patients in MG.

A single centre prospective study of three device-assisted therapies for Parkinson's disease.

Comparative studies assessing outcomes with the three device-assisted therapies could help to individualise treatment for patients living with Parkinson's disease. We designed a single-centre non-randomised prospective observational study assessing the quality of life (QoL), motor and non-motor outcomes at 6 and 12-months in patients treated with subcutaneous apomorphine continuous 16-hours infusion (APO), levodopa-carbidopa intestinal gel (LCIG) or subthalamic nucleus deep brain stimulation (STN-DBS). In this study, 66 patients were included (13 APO; 19 LCIG; 34 STN-DBS). At baseline, cognitive, non-motor and motor scores were significantly less severe in the STN-DBS group, whereas the LCIG group had a longer disease duration and higher non-motor scores. In the APO group, there were no statistically significant changes in non-motor, motor and QoL scales. The LCIG group had significant changes in QoL and motor scales that were significant after multiple comparison analysis at 6 and 12-months. The STN-DBS group showed improvement in QoL scores and non-motor and motor scores at 6 and 12-months after multiple comparison analysis. In this real-life prospective study, device-assisted therapies showed differences in their effects on QoL and motor and non-motor function at 12-months. However, there were also differences in baseline characteristics of the patient groups that were not based on pre-determined selection criteria. Differences in characteristics of patients offered and/or treatment with different device-assisted therapies may reflect within-centre biases that may, in turn, influence perceptions of treatment efficacy or outcomes. Treatment centres should be aware of this potential confounder when assessing and offering device-assisted treatment options to their patients and potential baseline differences need to be taken into consideration when comparing the results of non-randomised studies.

Efficacy of botulinum toxin type a in the targeted treatment of sleep bruxism: a double-blind, randomised, placebo-controlled, cross-over study.

Background: Intramuscular injections of botulinum toxin A (BTX-A) have been used in the treatment of sleep bruxism (SB) however controlled trials are limited and the optimal injection strategy and dose is not known. Methods: This double-blind, randomised, placebo-controlled, cross-over study evaluated the efficacy and safety of BTX-A in participants with SB. Average bruxism events per hour of sleep (Bruxism Index, BI) was calculated using surface electromyography. Participants with BI >5 were included and randomised by order of injection (active or placebo with the opposite 20 weeks later) and into one of three differing treatment groups: bilateral masseter (60 units(U)), bilateral masseter and temporalis (90U) and bilateral masseter, temporalis and medial pterygoid muscles (120U). Change in BI and subjective measures of headache, pain, and bruxism at 4 and 12 weeks was calculated following intervention, and differences between treatment groups analysed. Results: 41 participants were recruited, 35 randomised and data from 22 participants (14 female) were analysed. BI was significantly lower at 4 weeks after active treatment when compared with placebo (mean=-1.66, p=0.003), not sustained at 12 weeks. The difference was greater with higher doses injected and among those with greater baseline BI. There was no difference in subjective measures at any time point. Five participants injected had mild, transient side effects. Discussion: Targeted BTX-A injection is a safe and effective treatment for SB. A greater benefit may be achieved by administering BTX-A into more muscles and at higher total doses and among those with higher baseline BI. Trial registration number: ACTRN12618001430224.

Characterization of sedation and anesthesia complications in patients with alternating hemiplegia of childhood.

BACKGROUND: Alternating hemiplegia of childhood (AHC) pathophysiology suggests predisposition to sedation and anesthesia complications. GOALS: Hypotheses: 1) AHC patients experience high rates of sedation-anesthesia complications. 2) ATP1A3 mutation genotype positivity, age, and AHC severity correlate with more severe complications. 3) Prior short QTc correlates with cardiac rhythm complications. METHODS: Analysis of 34 consecutive AHC patients who underwent sedation or anesthesia. Classification of complications: mild (not requiring intervention), moderate (intervention), severe (intervention, risk for permanent injury or potential life-threatening emergency). STATISTICS: Fisher Exact test, Spearman correlations. RESULTS: These patients underwent 129 procedures (3.79 ± 2.75 procedures/patient). Twelve (35%) experienced complications during at least one procedure. Fourteen/129 procedures (11%) manifested one or more complications (2.3% mild, 7% moderate, 1.6% severe). Of the total 20 observed complications, six (33.3%) were severe: apneas (2), seizures (2), bradycardia (1), ventricular fibrillation that responded to resuscitation (1). Moderate complications: non-life-threatening bradycardias, apneas, AHC spells or seizures. Complications occurred during sedation or anesthesia and during procedures or recovery periods. Patients with disease-associated ATP1A3 variants were more likely to have moderate or severe complications. There was no correlation between complications and age or AHC severity. Presence of prior short QTc correlated with cardiac rhythm complications. After this series was analyzed, another patient had severe recurrent laryngeal dystonia requiring tracheostomy following anesthesia with intubation. CONCLUSIONS: During sedation or anesthesia, AHC patients, particularly those with ATP1A3 variants and prior short QTc, are at risk for complications consistent with AHC pathophysiology. Increased awareness is warranted during planning, performance, and recovery from such procedures.

Nitrous oxide-induced neurological disorders: an increasing public health concern.

BACKGROUND: Neurological presentations resulting from nitrous oxide (N2 O) abuse are increasing in Australia and worldwide. Despite known neuropsychiatric sequelae, N2 O canisters remain readily available and its use unregulated. AIMS: To examine the demographics, clinical and electrophysiological findings of patients presenting with neurological complications of N2 O abuse, and thus inform clinicians and public health decision-makers of the significant public health concerns of this increasing practice. METHODS: Consecutive patients presenting to a tertiary referral metropolitan hospital were included in this series. Patients were identified by a search of discharge summaries of patients admitted with acute or subacute neuropathy or myelopathy and a history of N2 O abuse, and from the electrophysiology database. RESULTS: Thirteen patients were identified, most presenting with subacute paraesthesia, sensory ataxia and lower limb weakness. Eleven had low serum vitamin B12 . Spinal magnetic resonance imaging was consistent with subacute combined degeneration in eight. Nerve conduction studies revealed a motor or sensorimotor axonal neuropathy (three with motor predominance). There was a bimodal demographic distribution consisting of socially isolated, international university students and local residents with a history of mental illness and polydrug abuse. CONCLUSIONS: Recreational N2 O use is an emerging health problem in Australia. International university students and patients with pre-existing mental illness or polydrug use appear to be at increased risk. A severe motor neuropathy may emerge following vitamin B12 replacement. Public health measures are required to limit the availability of N2 O and to educate adolescents and young adults about the potential for significant harm.

Oromandibular parafunction in chronic graft-versus-host disease: novel association and treatment approach.

Chronic graft-versus-host disease (cGVHD) complicating allogeneic haemopoietic stem cell transplantation rarely involves the nervous system; oromandibular parafunction has not been previously reported. We describe five patients with cGVHD, presenting with bruxism, limitation of mouth opening, jaw locking, pain and masseter hypertrophy. Pathophysiological mechanisms are discussed. Targeted botulinum toxin injections were an effective treatment with minimal side-effects.

Rest tremor correlates with reduced contralateral striatal dopamine transporter binding in Parkinson's disease.

INTRODUCTION: In vivo dopamine transporter imaging is a useful tool for distinguishing nigrostriatal pathologies (e.g. Parkinson's disease) from other causes of tremor. However, while many of the motoric features of Parkinson's disease (e.g. bradykinesia, rigidity, hypomimia) correlate well with reduced striatal dopamine transporter binding, the same relationship has not been demonstrated for tremor. We investigated the relationship between striatal dopamine transporter binding and quantitative measures of tremor. METHODS: 23 participants with Parkinson's disease underwent standardised clinical assessment including structured, videotaped clinical examination, tremor neurophysiology study of both upper limbs using accelerometry and surface EMG, and Technitium-99 m TRODAT-1 brain SPECT imaging. Normalised striatal uptake values were calculated. Tremor EMG and accelerometry time series were processed with Fourier transformation to identify peak tremor power within a window of 3-10Hz and to calculate the tremor stability index (TSI). RESULTS: Spearman correlation analyses revealed an association between tremor power and contralaterally reduced striatal uptake in a number of recording conditions. This association was strongest for rest tremor, followed by postural tremor, with the weakest association observed for kinetic tremor. Lower TSI was also associated with lower contralateral striatal uptake in a number of rest and postural conditions. CONCLUSION: These data suggest a relationship between Parkinsonian rest tremor and contralateral reduction in striatal dopamine binding. Use of quantitative neurophysiology techniques may allow the demonstration of clinico-pathophysiological relationships in tremor that have remained occult to previous studies.

Cerebellar Ataxia Followed by Stiff Person Syndrome in a Patient with Anti-GAD Antibodies.

Anti-GAD antibody syndrome is a result of the production of antibodies against glutamic acid decarboxylase (GAD), the main enzyme responsible for the production of gamma-aminobutyric acid (GABA). Several neurological manifestations including cerebellar ataxia and stiff person syndrome have been reported in association with anti-GAD antibodies. In this paper, we present a case of a young woman with anti-GAD antibodies who initially presented with cerebellar ataxia followed by stiff person syndrome three and a half years later. Having both cerebellar ataxia and stiff person syndrome is a rare occurrence in anti-GAD antibody syndrome. We emphasise the importance of long-term follow-up of patients with anti-GAD antibody syndrome, as delayed neurological manifestations can occur.

Validation of a precision tremor measurement system for multiple sclerosis.

BACKGROUND: Tremor is a debilitating symptom of Multiple Sclerosis (MS). Little is known about its pathophysiology and treatments are limited. Clinical trials investigating new interventions often rely on subjective clinical rating scales to provide supporting evidence of efficacy. NEW METHOD: We present a novel instrument (TREMBAL) which uses electromagnetic motion capture technology to quantify MS tremor. We aim to validate TREMBAL by comparison to clinical ratings using regression modelling with 310 samples of tremor captured from 13 MS participants who performed five different hand exercises during several follow-up visits. Minimum detectable change (MDC) and test-retest reliability were calculated and comparisons were made between MS tremor and data from 12 healthy volunteers. RESULTS: Velocity of the index finger was most congruent with clinical observation. Regression modelling combining different features, sensor configurations, and labelling exercises did not improve results. TREMBAL MDC was 84% of its initial measurement compared to 91% for the clinical rating. Intra-class correlations for test-retest reliability were 0.781 for TREMBAL and 0.703 for clinical ratings. Tremor was lower (p = 0.002) in healthy subjects. COMPARISON WITH EXISTING METHODS: Subjective scales have low sensitivity, suffer from ceiling effects, and mitigation against inter-rater variability is challenging. Inertial sensors are ubiquitous, however, their output is nonlinearly related to tremor frequency, compensation is required for gravitational artefacts, and their raw data cannot be intuitively comprehended. CONCLUSIONS: TREMBAL, compared with clinical ratings, gave measures in agreement with clinical observation, had marginally lower MDC, and similar test-retest reliability.

24-hour levodopa-carbidopa intestinal gel may reduce troublesome dyskinesia in advanced Parkinson's disease.

Levodopa-carbidopa intestinal gel (LCIG) is effective for the control of motor fluctuations in Parkinson's disease (PD). The objective of this study is to report the reduction of dyskinesias after transitioning from 16 to 24-h/day LCIG infusion. From a cohort of 74 PD patients treated with LCIG for motor fluctuations, we identified 12 patients that were treated with 24-h per day infusion with the aim to control troublesome daytime dyskinesia. Clinical, demographic, dyskinesia rating scales were evaluated. Daytime dyskinesia was reduced in 75% (9/12) patients following treatment with 24-h therapy, including 7 who were compared with 16-h therapy and 2 that were transitioned from oral dopaminergic therapy to 24-h LCIG. Combining the data from all 12 subjects, troublesome dyskinesias were reduced during 24-h LCIG; UPDRS 4.1 (time spent with dyskinesias) mean change was -1.5 ± 0.75, p = 0.010 (Wilcoxon signed-rank test) and UPDRS 4.2 (functional impact of dyskinesias) mean change was -1.7 ± 0.90, p = 0.016, without changing their UPDRS part 3 "ON" scores (p = 0.138) or H&Y (p = 0.157). In 5 patients, improvement in dyskinesia occurred despite an overall increase in the total daily levodopa dose. None of the patients had worsening of dyskinesia after a median follow-up of 28 months. 24-h per day infusion of LCIG may be a useful strategy in the management of troublesome dyskinesias in PD patients with disabling dyskinesias resistant to attempts to optimise 16-hours per day therapy. We postulate that this may be due to a pharmacodynamic as opposed to pharmacokinetic mechanism.

Cerebrovascular disease in HIV-infected individuals in the era of highly active antiretroviral therapy.

The widespread use of highly active antiretroviral therapy (HAART) in HIV-infected individuals mostly in developed countries has dramatically improved their prognosis. In such advantaged regions of the world, therefore, many patients are now transitioning from middle into older age, with altered patterns of disease. While previously a rare complication of HIV infection, cerebrovascular disease (particularly that associated with atherosclerosis) is becoming relatively more important in this treated group of individuals. This review summarises the evidence regarding the shifting epidemiology of cerebrovascular diseases affecting HIV-infected individuals. While outlining the association between HIV infection and AIDS and cerebrovascular disease, as well as opportunistic diseases and HIV-associated vasculopathies, the current evidence supporting an increase in atherosclerotic disease in treated HIV-infected individuals is emphasised and a management approach to ischaemic stroke in HIV-infected individuals is presented. Evidence supporting the important role of HAART and HIV infection itself in the pathogenesis of atherosclerotic disease is discussed, together with preventative approaches to this increasingly important disease process as the population ages. Finally, a discussion regarding the significant association between cerebrovascular disease and HIV-associated neurocognitive disorder is presented, together with possible mechanisms behind this relationship.