Impact and predictors of quality of life in adults diagnosed with a genetic muscle disorder: a nationwide population-based study.

OBJECTIVES: To determine the impact of genetic muscle disorders and identify the sociodemographic, illness, and symptom factors influencing quality of life. METHODS: Adults (aged 16-90 years) with a confirmed clinical or molecular diagnosis of a genetic muscle disorder identified as part of a nationwide prevalence study were invited to complete an assessment of the impact of their condition. Quality of life was measured using the World Health Organization Quality of Life questionnaire. Impact was measured via the prevalence of symptoms and comparisons of quality of life against New Zealand norms. Multivariate regression models were used to identify the most significant predictors of quality of life domains. RESULTS: 490/596 participants completed the assessment (82.2% consent rate). Quality of life was lower than the general population on physical (t = 9.37 p < 0.0001, d = 0.54) social (t = 2.27 p = 0.02, d = 0.13) and environmental domains (t = 2.28 p = 0.02, d = 0.13), although effect sizes were small. No difference was found on the psychological domain (t = - 1.17 p = 0.24, d = 0.07). Multivariate regression models (predicting 42%-64% of the variance) revealed personal factors (younger age, being in employment and in a relationship), symptoms (lower pain, fatigue, and sleep difficulties), physical health (no need for ventilation support, fewer activity limitations and no comorbidities), and psychosocial factors (lower depression, anxiety, behavioural dyscontrol and higher self-efficacy, satisfaction with health care and social support) contributed to improved quality of life. CONCLUSIONS: A range of factors influence the quality of life in adults diagnosed with a genetic muscle disorder and some may serve as targets for multi-faceted intervention.

A Nationwide, Population-Based Prevalence Study of Genetic Muscle Disorders.

BACKGROUND: Previous epidemiological studies of genetic muscle disorders have relied on medical records to identify cases and may be at risk of selection biases or have focused on selective population groups. OBJECTIVES: This study aimed to determine age-standardised prevalence of genetic muscle disorders through a nationwide, epidemiological study across the lifespan using the capture-recapture method. METHODS: Adults and children with a confirmed clinical or molecular diagnosis of a genetic muscle disorder, resident in New Zealand on April 1, 2015 were identified using multiple overlapping sources. Genetic muscle disorders included the muscular dystrophies, congenital myopathies, ion channel myopathies, GNE myopathy, and Pompe disease. Prevalence per 100,000 persons by age, sex, disorder, ethnicity and geographical region with 95% CIs was calculated using Poisson distribution. Direct standardisation was applied to age-standardise prevalence to the world population. Completeness of case ascertainment was determined using capture-recapture modelling. RESULTS: Age standardised minimal point prevalence of all genetic muscle disorders was 22.3 per 100,000 (95% CI 19.5-25.6). Prevalence in Europeans of 24.4 per 100,000, (95% CI 21.1-28.3) was twice that observed in NZ's other 3 main ethnic groups; Maori (12.6 per 100,000, 95% CI 7.8-20.5), Pasifika (11.0 per 100,000, 95% CI 5.4-23.3), and Asian (9.13 per 100,000, 95% CI 5.0-17.8). Crude prevalence of myotonic dystrophy was 3 times higher in Europeans (10.5 per 100,000, 9.4-11.8) than Maori and Pasifika (2.5 per 100,000, 95% CI 1.5-4.2 and 0.7 per 100,000, 95% CI 0.1-2.7 respectively). There were considerable regional variations in prevalence, although there was no significant association with social deprivation. The final capture-recapture model, with the least deviance, estimated the study ascertained 99.2% of diagnosed cases. CONCLUSIONS: Ethnic and regional differences in the prevalence of genetic muscle disorders need to be considered in service delivery planning, evaluation, and decision making.

Correcting for Body Surface Area Identifies the True Prevalence of Abdominal Aortic Aneurysm in Screened Women.

OBJECTIVE: Recently, the prevalence of abdominal aortic aneurysm (AAA) using screening strategies based on elevated cardiovascular disease (CVD) risk was reported. AAA was defined as a diameter ≥30 mm, with prevalence of 6.1% and 1.8% in men and women respectively, consistent with the widely reported AAA predominant prevalence in males. Given the obvious differences in body size between sexes this study aimed to re-evaluate the expanded CVD risk based AAA screening dataset to determine the effect of body size on sex specific AAA prevalence. METHODS: Absolute (26 and 30 mm) and relative (aortic size index [ASI] equals the maximum infrarenal aorta diameter (cm) divided by body surface area (m2), ASI ≥ 1.5) thresholds were used to assess targeted AAA screening groups (n = 4115) and compared with a self reported healthy elderly control group (n = 800). RESULTS: Male AAA prevalence was the same using either the 30 mm or ASI ≥1.5 aneurysm definitions (5.7%). In females, AAA prevalence was significantly different between the 30 mm (2.4%) and ASI ≥ 1.5 (4.5%) or the 26 mm (4.4%) thresholds. CONCLUSION: The results suggest the purported male predominance in AAA prevalence is primarily an artefact of body size differences. When aortic size is adjusted for body surface area there is only a modest sex difference in AAA prevalence. This observation has potential implications in the context of the ongoing discussion regarding AAA screening in women.

Clinical features of opticospinal multiple sclerosis with anti-aquaporin 4 antibody.

BACKGROUND: We have followed 9 Japanese patients with opticospinal multiple sclerosis (OSMS), some of whom showed longitudinally extensive spinal cord lesions, deep sensory disturbances and resistance to treatment. We investigated the patients for anti-aquaporin 4 (AQP4) antibodies and related this to their neuroimaging, clinical and laboratory features. METHODS: We studied the clinical course, neurological findings, cerebrospinal fluid (CSF), and electrophysiological findings, and determined the presence of anti-AQP4 antibody and human leukocyte antigen DPB1 and DRB1 alleles. RESULTS: Five patients (56.6%) had anti-AQP4 antibody. Antibody-positive patients displayed female predominance, longitudinally extensive spinal cord lesions, higher frequency of exacerbations, severe disability, and higher cell counts and total protein content without IgG oligoclonal bands in the CSF. They also showed poor steroid responsiveness and poor therapeutic response to interferon beta(1b). CONCLUSIONS: The presence of anti-AQP4 antibodies correlates with clinical severity and poor prognosis in OSMS.

Response inhibition in patients with functional neurological symptom disorder.

Abnormal response inhibition has been demonstrated in psychogenic movement disorders (PMD) and is a plausible mechanism for other forms of functional neurological symptom disorder (FNSD), in which response inhibition has not yet been investigated. Response inhibition was therefore studied in patients with FNSD, including patients with psychogenic non-epileptic seizures (PNES), functional weakness (FW) or both. Twenty-nine patients with FNSD and 29 age and sex-matched healthy volunteers underwent a go-nogo task, a stop-signal reaction time (SSRT) task, and a negative priming flanker task. The Attentional Resource Allocation Scale, the Beck Depression Inventory and the Spielberger State and Trait Anxiety Inventory were also administered. Mean hit rates on nogo trials, miss rates on go signals and discriminability index were higher and go signal reaction times were significantly longer in the FNSD group than in healthy controls. The presence of FW was associated with increased hit rates on nogo trials, suggesting a bias toward responding to nogo signals rather than missed go signals. SSRT and negative priming were not significantly different from healthy controls. It is unclear whether impaired performance on the go-nogo task reflects dysfunctional inhibitory processes, disordered attention, or impaired ability to discriminate between stimuli.

The New Zealand Neuromuscular Disease Patient Registry; Five Years and a Thousand Patients.

The New Zealand Neuromuscular Disease Patient Registry has been recruiting for five years. Its primary aim is to enable people with neuromuscular disease to participate in research including clinical trials. It has contributed data to large anonymised cohort studies and many feasibility studies, and has provided practical information and advice to researchers wanting to work with people with neuromuscular conditions. 1019 people have enrolled since the Registry's launch in August 2011 with over 70 different diagnoses. Of these; 8 patients have been involved in clinical trials, 134 in other disease-specific research and 757 have contributed anonymised data to cohort studies. As a result the Registry is now effectively facilitating almost all neuromuscular research currently taking place in New Zealand.

Theta Burst Stimulation of the Cerebellum Modifies the TMS-Evoked N100 Potential, a Marker of GABA Inhibition.

Theta burst stimulation (TBS) of the cerebellum, a potential therapy for neurological disease, can modulate corticospinal excitability via the dentato-thalamo-cortical pathway, but it is uncertain whether its effects are mediated via inhibitory or facilitatory networks. The aim of this study was to investigate the effects of 30Hz cerebellar TBS on the N100 waveform of the TMS-evoked potential (TEP), a marker of intracortical GABAB-mediated inhibition. 16 healthy participants (aged 18-30 years; 13 right handed and 3 left handed) received 30Hz intermittent TBS (iTBS), continuous TBS (cTBS) or sham stimulation over the right cerebellum, in three separate sessions. The first 8 participants received TBS at a stimulus intensity of 80% of active motor threshold (AMT), while the remainder received 90% of AMT. Motor evoked potentials (MEP) and TEP were recorded before and after each treatment, by stimulating the first dorsal interosseus area of the left motor cortex. Analysis of the 13 right handed participants showed that iTBS at 90% of AMT increased the N100 amplitude compared to sham and cTBS, without significantly altering MEP amplitude. cTBS at 80% of active motor threshold decreased the N100 amplitude and cTBS overall reduced resting MEP amplitude. The study demonstrates effects of 30Hz cerebellar TBS on inhibitory cortical networks that may be useful for treatment of neurological conditions associated with dysfunctional intracortical inhibition.

Deficit in late-stage contingent negative variation provides evidence for disrupted movement preparation in patients with conversion paresis.

Conversion paresis is the presence of unexplained weakness without detectable neuropathology that is not feigned. To examine the 'abnormal preparation' and 'disrupted execution' hypotheses proposed to explain the movement deficits in conversion paresis, electroencephalographic, electromyographic and kinematic measures were recorded during motor preparation and execution. Six patients with unilateral upper limb conversion weakness, 24 participants feigning weakness and 12 control participants performed a 2-choice precued reaction time task. Precues provided advance information about the responding hand or finger. Patients and feigners demonstrated similar diminished force, longer movement time and extended duration of muscle activity in their symptomatic limb. Patients showed significantly suppressed contingent negative variation (CNV) amplitudes, but only when the symptomatic limb was precued. Despite the similarity in performance measures, this CNV suppression was not seen in feigners. Diminished CNV for symptomatic hand precues may reflect engagement of an inhibitory mechanism suppressing cortical activity related to preparatory processes.

Theta priming of 1-Hz rTMS in healthy volunteers: effects on motor inhibition.

Originally derived from animal experiments, the concept of priming in repetitive transcranial magnetic stimulation (rTMS) experiments refers to a pretreatment or preprotocol stimulation that enhances the effect of the protocol. This means that previous stimulation or bout of activity predisposes the synapse for a second stimulation protocol to produce an enhanced depression. The purpose of this study was to investigate the use of theta priming with 1-Hz rTMS to the motor cortex to induce corticospinal inhibition. The main question was whether there was any benefit in using theta priming instead of simply a longer period of 1-Hz rTMS. To address this, the authors compared 1-Hz rTMS with and without theta priming, using a protocol in which the total period of stimulation was the same. Eleven healthy volunteers were given rTMS to the right primary motor cortex in three separate sessions, in which the participant received one of the three protocols: (1) 1-Hz rTMS for 10 minutes, (2) 5 minutes of 6-Hz theta burst priming followed by 5 minutes of 1-Hz rTMS, or (3) 10 minutes of 1-Hz sham rTMS using a placebo coil. There was a significant effect of active 1-Hz rTMS alone on both resting motor evoked potential and active motor evoked potential amplitude, P < 0.05: both were significantly decrease after 1-Hz rTMS compared with sham. Resting motor evoked potential amplitude was unchanged compared with sham rTMS after the priming protocol, P = 0.001; 1-Hz rTMS with and without theta priming significantly reduced right unimanual reaction time compared with sham. While theta priming abolished or interfered with the inhibitory effect of 1-Hz rTMS on corticospinal excitability, the effect on ipsilateral reaction times was unaffected. The negative effect of priming can be interpreted as a functional interference of the priming preprotocol with the 1 Hz protocol.

Distinct modulation of event-related potentials during motor preparation in patients with motor conversion disorder.

OBJECTIVE: Conversion paresis patients and healthy people feigning weakness both exhibit weak voluntary movement without detectable neuropathology. Uniquely, conversion patients lack a sense of conscious awareness of the origin of their impairment. We investigated whether conversion paresis patients show distinct electroencephalographic (EEG) markers associated with their unconscious movement deficits. METHODS: Six unilateral upper limb conversion paresis patients, 12 feigning participants asked to mimic weakness and 12 control participants performed a precued reaction time task, requiring movements of either hand, depending on precue information. Performance measures (force, reaction and movement time), and event-related EEG potentials (ERP) were compared, between groups and across hands or hemisphere, using linear mixed models. RESULTS: Feigners generated the same inter-hand difference in reaction and movement time as expressed by patients, even though no specific targets were set nor feedback given on these measures. We found novel ERP signatures specific to patients. When the symptomatic hand was precued, the P3 ERP component accompanying the precue was dramatically larger in patients than in feigning participants. Additionally, in patients the earlier N1 ERP component was diminished when the precue signalled either the symptomatic or asymptomatic hand. CONCLUSIONS: These results are consistent with previous suggestions that lack of awareness of the origin of their symptoms in conversion disorder patients may result from suppression of brain activity normally related to self-agency. In patients the diminished N1 to all precues is consistent with a generalised reduction in cognitive processing of movement-related precues. The P3 enhancement in patients is unlikely to simply reflect changes required for generation of impaired movements, because it was not seen in feigners showing the same behavioural deficits. Rather, this P3 enhancement in patients may represent a neural biomarker of unconscious processes, including additional emotional loading, related to active suppression of brain circuits involved in the attribution of self-agency.

The New Zealand Neuromuscular Disease Registry.

The development of effective treatments for neuromuscular diseases is a significant challenge due to difficulties in identifying adequate numbers of patients for clinical trials. Low patient numbers in these rare diseases also has an effect when establishing sound clinical practices based on experience gained from patients with similar diagnosis. The Muscular Dystrophy Association of New Zealand (MDA), working in consort with interested clinicians has established the New Zealand Neuromuscular Disease (NZ NMD) Registry in order to help address these problems. The NZ NMD Registry is exceptional in that it comprises one registry for all neuromuscular conditions and will significantly benefit both patients with neuromuscular disease and their clinicians.

A rat model of Urtica ferox neuropathy.

A species of stinging nettle, Urtica ferox, is indigenous to New Zealand and has caused deaths in animals and humans. We previously reported a human case of acute polyneuropathy due to U. ferox stings. We developed an experimental animal model of U. ferox toxin neuropathy to determine its neurophysiological and pathological characteristics. Male Wistar rats received either normal saline or fluid from U. ferox trichomes by injection into the epineurium of the left sciatic nerve. Neurophysiological and histological studies were carried out 5, 14 and 28 days after administration. Toxin-injected rats developed paresis of the left leg by 14 days with recovery by 28 days. Compound muscle action potentials amplitudes on the left side of toxin-administered rats at day 14 were significantly reduced compared to the right uninjected side. Toxin-injected nerves at days 5 and 14 showed a reduction in the number of myelinated fibres compared to the saline-injected nerves and frequency distributions of myelinated fibres showed a shift to smaller fibres. U. ferox neurotoxin thus produced a transient neuropathy in rat peripheral nerves with neurophysiological and pathological features suggestive of axonopathy. The identity and mechanism of action of the toxin responsible for neuropathy are uncertain.

Normative values for three clinical measures of motor performance used in the neurological assessment of sports concussion.

Postural control and motor coordination are essential components of normal athletic activity. Tasks involving balance and coordination are used to determine neurological function in sports-related concussion. Determining normative values for these tasks is therefore essential to provide sports medicine professionals with a frame of reference with which to interpret clinical measures obtained from players suspected of sustaining a concussion. One hundred and seventytwo healthy subjects (16-37 yrs) performed three timed tests: Tandem Gait (TG); Finger-to-Nose (FTN); Single-Leg-Stance (SLS) on firm and foam surfaces. Unadjusted geometric means (+/-SD) for each measure were averaged across three trials. Time to complete TG was 11.2+/-1.2s. FTN for the dominant and non-dominant arm were 2.9+/-1.1s and 3.0+/-1.2s, respectively. SLS values for dominant and non-dominant leg were 20.4+/-3.0s (firm), 3.4+/-1.6s (foam), and 21.0+/-2.9s (firm), 3.3+/-1.6s (foam), respectively. For TG, there was an order effect (P<.001) but no age, sex or BMI effects. FTN demonstrated a dominant arm preference (P<.001), sex (P=.006), BMI (P=.043) and order effects (P<.001). SLS demonstrated an order effect on the firm surface (P=.009) and an order (P<.001) and BMI (P=.001) effect on foam. Intra-rater reliability, as measured by ICC (3,3), demonstrated that TG and FTN had excellent reliability compared to SLS. FTN and TG should continue to be used in test batteries to determine neurological function in sports-related concussion.

Intravenous immunoglobulin therapy for neurological disorders.

AIM: To determine the extent to which the use of intravenous human immunoglobulin for neurological conditions complied with the guidelines of the Australian Health Minister's Advisory Council. METHODS: Patients treated with intravenous immunoglobulin in Otago over a 5.5-year period were identified from the records of the New Zealand Blood Service and the hospital files were reviewed. RESULTS: 200 patients received immunoglobulin therapy, of whom 57 had neurological conditions: myasthenia gravis, (15.8%), Guillain-Barre syndrome (36.8%), multiple sclerosis (10.5%), chronic inflammatory demyelinating polyneuropathy (17.5%), inclusion body myositis (7%), polymyositis (1.7%), miscellaneous disorders (stiff person syndrome, diabetic amyotrophy, neuropathy associated with paraproteinaemia, and hereditary neuropathy with liability to pressure palsies) (10.5). Thirty-one percent of the immunoglobulin was used in 27% of the patients for disorders lacking convincing evidence of benefit according to the guidelines of the Australian Health Minister's Advisory Council. These were multiple sclerosis, inclusion body myositis, and miscellaneous neuropathies. Good response occurred most often in patients with myasthenia gravis, Guillain-Barre syndrome, multiple sclerosis, and chronic inflammatory demyelinating polyneuropathy. CONCLUSIONS: Intravenous immunoglobulin was frequently used for indications not recommended by the Australian Health Minister's Advisory Council guidelines. However guidelines vary internationally, and there is a paucity of controlled studies to guide management of some uncommon conditions.

Urtica ferox neuropathy.

A 21-year-old student developed an acute, symmetrical, predominantly motor polyneuropathy within 48 h of walking through a patch of nettles (Urtica ferox). Two companions had similar but less severe symptoms. Nerve conduction studies demonstrated markedly reduced compound muscle action potentials and prolonged distal motor latencies. Recovery occurred over a period of a few weeks. This case demonstrates that cutaneous exposure to Urtica ferox can cause an acute polyneuropathy and that its stinging hairs contain an unidentified neurotoxin.

STIR MRI to direct muscle biopsy in suspected idiopathic inflammatory myopathy.

Successful management of the idiopathic inflammatory myopathies requires an early and accurate diagnosis. The muscle biopsy remains the definitive test. However, false-negative biopsy results are common, as the disease is typically patchy in distribution. The advent of short tau inversion recovery sequences now allows rapid magnetic resonance imaging of the whole body to be performed, enabling identification of the muscles most suitable for biopsy. It also provides further diagnostic information through the form and anatomic distribution of the pathology. We report 2 cases illustrating the advantages of whole-body short tau inversion recovery magnetic resonance imaging before muscle biopsy. We encourage clinicians to use the technique in this context.

Myotonic dystrophy in Otago, New Zealand.

AIMS: To determine the prevalence of myotonic dystrophy (DM) in Otago, the ethnic distribution of the disease, any founder effect, the complications and adequacy of health care, and the quality of life of sufferers in this region. METHODS: DM patients were identified through hospital records and assessed using a structured questionnaire, neurological examination, and review of hospital records. Quality of life was evaluated using the SF-36 Health Survey, and compared to patients with other neuromuscular conditions and New Zealand norms. RESULTS: 21 patients were identified, giving a prevalence of 11.6 per 100,000. All were of European descent. There was no evidence of a common ancestor. Not all patients had had essential investigations such as electrocardiogram and many had not been seen by the genetic service. DM patients had higher scores on the bodily pain subscale of the SF-36 Health Survey, compared to neuromuscular controls and the general population. Subjects differed significantly from New Zealand norms on four of the eight subscales. CONCLUSIONS: DM is relatively common in Europeans in Otago, but we found no cases in other ethnic groups. The disease affects aspects of quality of life, and management could be improved by use of a clinical care pathway.