Muscle biopsy practices in the evaluation of neuromuscular disease: A systematic literature review.

AIMS: Muscle biopsy techniques range from needle muscle biopsy (NMB) and conchotome biopsy to open surgical biopsy. It is unknown whether specific biopsy techniques offer superior diagnostic yield or differ in procedural complication rates. Therefore, we aimed to compare the diagnostic utility of NMB, conchotome and open muscle biopsies in the assessment of neuromuscular disorders. METHODS: A systematic literature review of the EMBASE and Medline (Ovid) databases was performed to identify original, full-length research articles that described the muscle biopsy technique used to diagnose neuromuscular disease in both adult and paediatric patient populations. Studies of any design, excluding case reports, were eligible for inclusion. Data pertaining to biopsy technique, biopsy yield and procedural complications were extracted. RESULTS: Sixty-four studies reporting the yield of a specific muscle biopsy technique and, or procedural complications were identified. Open surgical biopsies provided a larger tissue sample than any type of percutaneous muscle biopsy. Where anaesthetic details were reported, general anaesthesia was required in 60% of studies that reported open surgical biopsies. Percutaneous biopsies were most commonly performed under local anaesthesia and despite the smaller tissue yield, moderate- to large-gauge needle and conchotome muscle biopsies had an equivalent diagnostic utility to that of open surgical muscle biopsy. All types of muscle biopsy procedures were well tolerated with few adverse events and no scarring complications were reported with percutaneous sampling. CONCLUSIONS: When a histological diagnosis of myopathy is required, moderate- to large-gauge NMB and the conchotome technique appear to have an equivalent diagnostic yield to that of an open surgical biopsy.

Anti-LGI1-Associated Myopathy in the Setting of Neuromuscular Hyperexcitability Syndrome.

This case report describes a patient with anti­leucine-rich glioma-inactivated 1 (LGI1)­associated hyperexcitability syndrome associated with myopathy.

Eosinophilic myositis: could it be an adult-onset dystrophy?

A 40-year-old woman presented with a 20 kg weight loss and asymmetrical hip and shoulder girdle muscle weakness; she had a raised serum creatine kinase and mild peripheral blood eosinophilia. There was no evidence of a parasitic infection or vasculitis. A muscle biopsy showed eosinophilic myositis. Following treatment with oral corticosteroid, methotrexate and intravenous immunoglobulin infusion, her weakness initially mildly improved and her serum creatine kinase reduced. However, despite continued immunosuppression her condition progressed over 3 years. The pattern of muscle weakness suggested a muscular dystrophy. Genetic testing confirmed heterozygous calpain mutations consistent with limb girdle muscular dystrophy type 2A.

Efficacy and Safety of Bimagrumab in Sporadic Inclusion Body Myositis: Long-term Extension of RESILIENT.

OBJECTIVE: To assess long-term (2 years) effects of bimagrumab in participants with sporadic inclusion body myositis (sIBM). METHODS: Participants (aged 36-85 years) who completed the core study (RESILIENT [Efficacy and Safety of Bimagrumab/BYM338 at 52 Weeks on Physical Function, Muscle Strength, Mobility in sIBM Patients]) were invited to join an extension study. Individuals continued on the same treatment as in the core study (10 mg/kg, 3 mg/kg, 1 mg/kg bimagrumab or matching placebo administered as IV infusions every 4 weeks). The co-primary outcome measures were 6-minute walk distance (6MWD) and safety. RESULTS: Between November 2015 and February 2017, 211 participants entered double-blind placebo-controlled period of the extension study. Mean change in 6MWD from baseline was highly variable across treatment groups, but indicated progressive deterioration from weeks 24-104 in all treatment groups. Overall, 91.0% (n = 142) of participants in the pooled bimagrumab group and 89.1% (n = 49) in the placebo group had ≥1 treatment-emergent adverse event (AE). Falls were slightly higher in the bimagrumab 3 mg/kg group vs 10 mg/kg, 1 mg/kg, and placebo groups (69.2% [n = 36 of 52] vs 56.6% [n = 30 of 53], 58.8% [n = 30 of 51], and 61.8% [n = 34 of 55], respectively). The most frequently reported AEs in the pooled bimagrumab group were diarrhea 14.7% (n = 23), involuntary muscle contractions 9.6% (n = 15), and rash 5.1% (n = 8). Incidence of serious AEs was comparable between the pooled bimagrumab and the placebo group (18.6% [n = 29] vs 14.5% [n = 8], respectively). CONCLUSION: Extended treatment with bimagrumab up to 2 years produced a good safety profile and was well-tolerated, but did not provide clinical benefits in terms of improvement in mobility. The extension study was terminated early due to core study not meeting its primary endpoint. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT02573467. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with sIBM, long-term treatment with bimagrumab was safe, well-tolerated, and did not provide meaningful functional benefit. The study is rated Class IV because of the open-label design of extension treatment period 2.

Treatable lysosomal storage diseases in the advent of disease-specific therapy.

Lysosomal storage diseases (LSD) comprise a rare and heterogeneous group of nearly 50 heritable metabolic disorders caused by mutations in proteins critical for cellular lysosomal function. Defects in the activity of these proteins in multiple organs leads to progressive intra-lysosomal accumulation of specific substrates, resulting in disruption of cellular functions, extracellular inflammatory responses, tissue damage and organ dysfunction. The classification and clinical presentation of different LSD are dependent on the type of accumulated substrate. Some clinical signs and symptoms are common across multiple LSD, while others are more specific to a particular syndrome. Due to the rarity and wide clinical diversity of LSD, identification and diagnosis can be challenging, and in many cases diagnosis is delayed for months or years. Treatments, such as enzyme replacement therapy, haemopoietic stem cell transplantation and substrate reduction therapy, are now available for some of the LSD. For maximum effect, therapy must be initiated prior to the occurrence of irreversible tissue damage, highlighting the importance of prompt diagnosis. Herein, we discuss the clinical presentation, diagnosis and treatment of four of the treatable LSD: Gaucher disease, Fabry disease, Pompe disease, and two of the mucopolysaccharidoses (I and II). For each disease, we present illustrative case studies to help increase awareness of their clinical presentation and possible treatment outcomes.

Slug regulates the Dll4-Notch-VEGFR2 axis to control endothelial cell activation and angiogenesis.

Slug (SNAI2), a member of the well-conserved Snail family of transcription factors, has multiple developmental roles, including in epithelial-to-mesenchymal transition (EMT). Here, we show that Slug is critical for the pathological angiogenesis needed to sustain tumor growth, and transiently necessary for normal developmental angiogenesis. We find that Slug upregulation in angiogenic endothelial cells (EC) regulates an EMT-like suite of target genes, and suppresses Dll4-Notch signaling thereby promoting VEGFR2 expression. Both EC-specific Slug re-expression and reduced Notch signaling, either by γ-secretase inhibition or loss of Dll4, rescue retinal angiogenesis in SlugKO mice. Conversely, inhibition of VEGF signaling prevents excessive angiogenic sprouting of Slug overexpressing EC. Finally, endothelial Slug (but not Snail) is activated by the pro-angiogenic factor SDF1α via its canonical receptor CXCR4 and the MAP kinase ERK5. Altogether, our data support a critical role for Slug in determining the angiogenic response during development and disease.

Is it Pompe Disease? Australian diagnostic considerations.

Pompe Disease is a spectrum disorder with an evolving phenotype in which diagnostic delay is common. Contributing factors include the rarity of the disorder, its wide clinical spectrum, signs and symptoms that overlap with those of other neuromuscular disorders, variable diagnostic approaches, lack of awareness of the clinical manifestations and difficulties in completing the diagnostic inventory. International updates and recommendations have been published providing diagnostic guidelines and management criteria. However, questions remain in the Australian setting. A panel (two neurologists, one clinical geneticist) reviewed the literature, examined clinical questions of relevance to the Australian setting, and developed a framework for the guidance. A wider panel, comprising the initial panel plus eight additional members, critiqued the framework and contributed clinical guidance within the scope of their respective areas of clinical expertise. The resultant expert consensus recommendations build on currently available data to propose an appropriate management framework incorporating the diagnosis, classification, therapeutic approach, multidisciplinary care, and on-going monitoring of patients with Pompe Disease in the Australian setting. It is hoped that diagnostic delay can be reduced with appropriate recourse to evidence-based insights and practical advice on diagnosis and management tailored to the Australian setting.

Lymphoma, a great imitator in neurology.

The title "great imitator" refers to conditions which can cause varied manifestations and mimic many diseases. Lymphoma is worthy of this title. We describe three cases of lymphoma in which lymphoma mimicked other diseases causing neurological dysfunction, specifically sarcoidosis, vasculitis and infection respectively. Case 1 was a 66-year-old man with subacute progressive diplopia and gait disturbance and investigations revealing a supratentorial para-falcine soft tissue lesion, mid-thoracic cord enhancement and right axillary mass and an elevated serum ACE. Right axillary mass core biopsy was diagnostic of Burkitt lymphoma. Case 2 was a 50-year-old man with several weeks of constitutional symptoms and development of lower limb weakness and numbness, urinary retention and confusion while in hospital. MRI brain demonstrated multi-territory cerebral infarcts. Intravascular lymphoma was diagnosed on random skin biopsy. Case 3 was a 65-year-old man with several weeks of headache and diplopia on a background of previously treated Burkitt lymphoma. CSF analysis showed a lymphocytic pleocytosis and markedly low glucose with cytologic analysis negative for malignancy. Investigations for an infective cause were negative. FDG-PET demonstrated marked, disseminated spinal and cranial leptomeningeal disease and a multi-focal, intra-dural relapse of Burkitt lymphoma was diagnosed. The varied manifestations in our cases demonstrate the ability for lymphoma to mimic infective, inflammatory, granulomatous (including sarcoidosis) and neoplastic aetiologies. An elevated serum ACE appears insufficiently diagnostic to confirm sarcoidosis and tissue for histological examination should be sought whenever possible. When the diagnosis is uncertain, the possibility of this great imitator should be considered, especially for multi-focal disease.

Statin-induced anti-HMGCR antibody-related immune-mediated necrotising myositis achieving complete remission with rituximab.

Statin-induced immune-mediated necrotising myopathy (IMNM) is a rare but increasingly recognised myositis. Many cases have positive antibodies to 3-hydroxy-3-methylglutaryl coenzyme A reductase (anti-HMGCR). The current treatment is ceasing the statin, but often immunosuppressive therapy is required as the antibodies persist, causing muscle necrosis. Despite the use of immunosuppressive medications, most commonly prednisolone, methotrexate, plasma exchange and/or intravenous immunoglobulin, some patients do not respond. We report the successful treatment with rituximab therapy for three patients with IMNM with positive anti-HMGCR antibodies. All three patients with statin-induced IMNM were elderly, with a disease history of 7-9 years, and had failed several immunosuppressive agents. They responded well to rituximab (induction and maintenance) therapy. They remain in remission with no symptoms and normal creatine kinase. One patient had normalisation of anti-HMGCR antibody level, and one patient's antibody level reduced significantly. Rituximab is an effective immunosuppressive treatment for patients with refractory IMNM.

Safety and efficacy of intravenous bimagrumab in inclusion body myositis (RESILIENT): a randomised, double-blind, placebo-controlled phase 2b trial.

BACKGROUND: Inclusion body myositis is an idiopathic inflammatory myopathy and the most common myopathy affecting people older than 50 years. To date, there are no effective drug treatments. We aimed to assess the safety, efficacy, and tolerability of bimagrumab-a fully human monoclonal antibody-in individuals with inclusion body myositis. METHODS: We did a multicentre, double-blind, placebo-controlled study (RESILIENT) at 38 academic clinical sites in Australia, Europe, Japan, and the USA. Individuals (aged 36-85 years) were eligible for the study if they met modified 2010 Medical Research Council criteria for inclusion body myositis. We randomly assigned participants (1:1:1:1) using a blocked randomisation schedule (block size of four) to either bimagrumab (10 mg/kg, 3 mg/kg, or 1 mg/kg) or placebo matched in appearance to bimagrumab, administered as intravenous infusions every 4 weeks for at least 48 weeks. All study participants, the funder, investigators, site personnel, and people doing assessments were masked to treatment assignment. The primary outcome measure was 6-min walking distance (6MWD), which was assessed at week 52 in the primary analysis population and analysed by intention-to-treat principles. We used a multivariate normal repeated measures model to analyse data for 6MWD. Safety was assessed by recording adverse events and by electrocardiography, echocardiography, haematological testing, urinalysis, and blood chemistry. This trial is registered with ClinicalTrials.gov, number NCT01925209; this report represents the final analysis. FINDINGS: Between Sept 26, 2013, and Jan 6, 2016, 251 participants were enrolled to the study, of whom 63 were assigned to each bimagrumab group and 62 were allocated to the placebo group. At week 52, 6MWD change from baseline did not differ between any bimagrumab dose and placebo (least squares mean treatment difference for bimagrumab 10 mg/kg group, 17·6 m, SE 14·3, 99% CI -19·6 to 54·8; p=0·22; for 3 mg/kg group, 18·6 m, 14·2, -18·2 to 55·4; p=0·19; and for 1 mg/kg group, -1·3 m, 14·1, -38·0 to 35·4; p=0·93). 63 (100%) participants in each bimagrumab group and 61 (98%) of 62 in the placebo group had at least one adverse event. Falls were the most frequent adverse event (48 [76%] in the bimagrumab 10 mg/kg group, 55 [87%] in the 3 mg/kg group, 54 [86%] in the 1 mg/kg group, and 52 [84%] in the placebo group). The most frequently reported adverse events with bimagrumab were muscle spasms (32 [51%] in the bimagrumab 10 mg/kg group, 43 [68%] in the 3 mg/kg group, 25 [40%] in the 1 mg/kg group, and 13 [21%] in the placebo group) and diarrhoea (33 [52%], 28 [44%], 20 [32%], and 11 [18%], respectively). Adverse events leading to discontinuation were reported in four (6%) participants in each bimagrumab group compared with one (2%) participant in the placebo group. At least one serious adverse event was reported by 21 (33%) participants in the 10 mg/kg group, 11 (17%) in the 3 mg/kg group, 20 (32%) in the 1 mg/kg group, and 20 (32%) in the placebo group. No significant adverse cardiac effects were recorded on electrocardiography or echocardiography. Two deaths were reported during the study, one attributable to subendocardial myocardial infarction (secondary to gastrointestinal bleeding after an intentional overdose of concomitant sedatives and antidepressants) and one attributable to lung adenocarcinoma. Neither death was considered by the investigator to be related to bimagrumab. INTERPRETATION: Bimagrumab showed a good safety profile, relative to placebo, in individuals with inclusion body myositis but did not improve 6MWD. The strengths of our study are that, to the best of our knowledge, it is the largest randomised controlled trial done in people with inclusion body myositis, and it provides important natural history data over 12 months. FUNDING: Novartis Pharma.

Inferring the long duration response to levodopa in Parkinson's disease.

INTRODUCTION: The long duration response to levodopa in Parkinson's disease outlasts drug elimination by days to weeks. Though a substantive part of anti-parkinsonian motor benefit, it cannot easily be observed. OBJECTIVES: To infer the magnitude of the long duration response during the first decade of Parkinson's disease and identify factors that influence it. METHODS: Serial practically defined off scores of 24 patients from a longitudinal study of levodopa short duration response were used to establish their rate of motor progression. A line of notional untreated disability (as if drug treatment had never been given) with the same progression gradient was the basis for calculation of the long duration response. Predictors of mean long duration response amplitude were identified using a multiple linear regression model. RESULTS: Over a mean treatment period of 16.6 ±â€¯4.4 years, annual increase in motor disability was 2.3% of the maximum score. The long duration response composed 49% of total levodopa response during the first decade of treatment, and this proportion was significantly higher soon after commencing levodopa (p = 0.001). Higher pre-treatment motor score (r = 0.60) and lower MMSE (r = 0.60) were the main predictors of a larger long duration response. There was little correlation between long and short duration responses. CONCLUSIONS: Long duration responses contribute almost half of the total levodopa benefit during the first decade of treatment. An appreciation of both long and short duration components of drug symptomatic effects is important in clinical trial design to investigate possible neuroprotective treatments.

Multimodal emotion processing deficits are present in amyotrophic lateral sclerosis.

OBJECTIVE: Emotion processing abilities might be reduced in amyotrophic lateral sclerosis (ALS). Previous studies of emotion processing in ALS have inconsistent results, and are limited by variations in task difficulty, modalities examined, and participants' cognitive status. The current study used a battery of emotion processing tasks at differing levels of difficulty and across different modalities (facial affect and voice prosody) to assess the extent of emotion processing deficits in nondemented ALS. METHOD: 33 ALS participants with intact basic cognition and 22 healthy controls completed the abbreviated Comprehensive Affect Testing System (CATS), which assesses simple and complex facial affect recognition, affective prosody recognition, cross-modal face-prosody integration, and semantic comprehension of affect. Participants also completed measures of executive function, mood, and functional impairment. RESULTS: ALS participants showed impairments on complex facial affect recognition, affective prosody recognition, and cross-modal integration. In contrast, simple facial affect recognition and semantic comprehension of affect were intact. ALS participants did not have significant mood symptoms, and neither mood nor functional impairment was related to emotion processing. Performance on the cross-modal composite was related to executive function, however, this relationship was not apparent for facial or prosody recognition within a single modality. CONCLUSIONS: These results indicate that people living with ALS without dementia often have subtle difficulties with recognizing emotions in both faces and voices, even in the context of intact basic cognition. Clinicians should be aware of the potential for these emotion processing difficulties to be present in ALS and to affect interpersonal behavior and quality of life. (PsycINFO Database Record

Study of levodopa response in Parkinson's disease: Observations on rates of motor progression.

INTRODUCTION: It is important to understand how the rate of motor progression in PD relates to dopaminergic treatment. METHODS: The methods for this study comprised prospective defined off state measurements of the levodopa response at 3-year intervals over a mean 13.3-year period in 34 patients enrolled before treatment initiation. RESULTS: Despite worsening of on and off scores, the magnitude of the l-dopa short-duration response is maintained as the disease progresses. A linear mixed-effects regression analysis of off phase motor scores showed a yearly deterioration of 2.3% of the maximum disability score. Greater motor disability at the commencement of treatment was an independent predictor of faster progression. Demented patients had worse motor function than those without dementia (P = 0.02), and motor deficit appeared to accelerate toward the end of the disease course in patients who had died. CONCLUSIONS: These observations should inform clinical trial design for drugs with possible neuroprotective properties.

A role for partial endothelial-mesenchymal transitions in angiogenesis?

The contribution of epithelial-to-mesenchymal transitions (EMT) in both developmental and pathological conditions has been widely recognized and studied. In a parallel process, governed by a similar set of signaling and transcription factors, endothelial-to-mesenchymal transitions (EndoMT) contribute to heart valve formation and the generation of cancer-associated fibroblasts. During angiogenic sprouting, endothelial cells express many of the same genes and break down basement membrane; however, they retain intercellular junctions and migrate as a connected train of cells rather than as individual cells. This has been termed a partial endothelial-to-mesenchymal transition. A key regulatory check-point determines whether cells undergo a full or a partial epithelial-to-mesenchymal transitions/endothelial-to-mesenchymal transition; however, very little is known about how this switch is controlled. Here we discuss these developmental/pathological pathways, with a particular focus on their role in vascular biology.

A three-dimensional in vitro model of tumor cell intravasation.

Metastasis is the cause of over 90% of all human cancer deaths. Early steps in the metastatic process include: the formation of new blood vessels, the initiation of epithelial-mesenchymal transition (EMT), and the mobilization of tumor cells into the circulation. There are ongoing efforts to replicate the physiological landscape of human tumor tissue using three-dimensional in vitro culture models; however, few systems are able to capture the full range of authentic, complex in vivo events such as neovascularization and intravasation. Here we introduce the Prevascularized Tumor (PVT) model to investigate early events of solid tumor progression. PVT spheroids are composed of endothelial and tumor cells, and are embedded in a fibrin matrix containing fibroblasts. The PVT model facilitates two mechanisms of vessel formation: robust sprouting angiogenesis into the matrix, and contiguous vascularization within the spheroid. Furthermore, the PVT model enables the intravasation of tumor cells that is enhanced under low oxygen conditions and is also dependent on the key EMT transcription factor Slug. The PVT model provides a significant advance in the mimicry of human tumors in vitro, and may improve investigation and targeting of events in the metastatic process.

Interferon-induced transmembrane protein 1 regulates endothelial lumen formation during angiogenesis.

OBJECTIVE: It is well established that angiogenesis is a complex and coordinated multistep process. However, there remains a lack of information about the genes that regulate individual stages of vessel formation. Here, we aimed to define the role of human interferon-induced transmembrane protein 1 (IFITM1) during blood vessel formation. APPROACH AND RESULTS: We identified IFITM1 in a microarray screen for genes differentially regulated by endothelial cells (ECs) during an in vitro angiogenesis assay and found that IFITM1 expression was strongly induced as ECs sprouted and formed lumens. We showed by immunohistochemistry that human IFITM1 was expressed by stable blood vessels in multiple organs. siRNA-mediated knockdown of IFITM1 expression spared EC sprouting but completely disrupted lumen formation, in both in vitro and in an in vivo xeno-transplant model. ECs lacking IFITM1 underwent early stages of lumenogenesis (ie, intracellular vacuole formation) but failed to mature or expand lumens. Coimmunoprecipitation studies confirmed occludin as an IFITM1 binding partner in ECs, and immunocytochemistry showed a lack of occludin at endothelial tight junctions in the absence of IFITM1. Finally, time-lapse video microscopy revealed that IFITM1 is required for the formation of stable cell-cell contacts during endothelial lumen formation. CONCLUSIONS: IFITM1 is essential for the formation of functional blood vessels and stabilizes EC-EC interactions during endothelial lumen formation by regulating tight junction assembly.

Angiogenic sprouting is regulated by endothelial cell expression of Slug.

The Snail family of zinc-finger transcription factors are evolutionarily conserved proteins that control processes requiring cell movement. Specifically, they regulate epithelial-to-mesenchymal transitions (EMT) where an epithelial cell severs intercellular junctions, degrades basement membrane and becomes a migratory, mesenchymal-like cell. Interestingly, Slug expression has been observed in angiogenic endothelial cells (EC) in vivo, suggesting that angiogenic sprouting may share common attributes with EMT. Here, we demonstrate that sprouting EC in vitro express both Slug and Snail, and that siRNA-mediated knockdown of either inhibits sprouting and migration in multiple in vitro angiogenesis assays. We find that expression of MT1-MMP, but not of VE-Cadherin, is regulated by Slug and that loss of sprouting as a consequence of reduced Slug expression can be reversed by lentiviral-mediated re-expression of MT1-MMP. Activity of MMP2 and MMP9 are also affected by Slug expression, likely through MT1-MMP. Importantly, we find enhanced expression of Slug in EC in human colorectal cancer samples compared with normal colon tissue, suggesting a role for Slug in pathological angiogenesis. In summary, these data implicate Slug as an important regulator of sprouting angiogenesis, particularly in pathological settings.

Exploring sarcasm detection in amyotrophic lateral sclerosis using ecologically valid measures.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive condition involving degeneration of both upper and lower motor neurons. Recent research suggests that a proportion of persons with ALS show a profile similar to that of frontotemporal dementia (FTD), with this group of ALS patients exhibiting social cognitive deficits. Although social cognitive deficits have been partially explored in ALS, research has yet to investigate such changes using ecologically valid measures. Therefore, this study aimed to further characterize the scope of social cognitive and emotion recognition deficits in non-demented ALS patients using an ecologically valid measure of social cognition. A sample of 35 ALS patients and 30 age-and-education matched controls were assessed using the Addenbrooke's Cognitive Examination, the Brixton Spatial Anticipation Test, and The Awareness of Social Inference Test, where participants were required to discriminate between various emotions and decipher socially challenging scenarios enacted in video vignettes. Participants with ALS showed significant difficulties in recognizing both sarcastic and paradoxical sarcastic statements, but not sincere statements, when compared to controls. After controlling for executive difficulties, ALS patients still displayed significant difficulties on tasks that assessed their comprehension of both sarcastic and paradoxical sarcastic statements. The inability to read social cues and make social inferences has the potential to place significant strain on familial/interpersonal relationships in ALS. The findings of this study highlight the importance of employing a broader range of neuropsychological assessment tools to aid in early detection of frontal lobe impairment in non-demented ALS patients.

A further patient with parasitic myositis due to Haycocknema perplexum, a rare entity.

A new genus of nematode, Haycocknema perplexum, causing polymyositis in humans, was first described in two Australian patients from Tasmania in 1998. Three patients with myositis due to the same nematode were reported from northern Queensland in 2008. We report the sixth case from Australia, a 50-year-old man, also from Tasmania. He had a 2-year history of progressive weakness, weight loss of 10 kg and dysphagia. Muscle biopsy was initially interpreted as polymyositis with eosinophils. Maximum creatine kinase (CK) level was 5700 U/L and full blood examination was normal. He deteriorated after several months of treatment with prednisolone and methotrexate and review of the muscle biopsy showed intramyofibre parasites of H. perplexum. After 3 months of treatment with albendazole therapy, he made a very good clinical recovery and his CK decreased to 470 U/L. This uniquely Australian parasite can mimic polymyositis and leads to significant irreversible morbidity (two of the previous patients still have weakness and elevated CK after years) and even mortality (one died), if diagnosed late or after corticosteroids. Diagnosis can only be made by histopathology of muscle biopsy.

Longitudinal study of levodopa in Parkinson's disease: effects of the advanced disease phase.

Thirty-four patients have been studied from the time of initiation of pharmacological treatment in a long-term prospective study of levodopa effects and disease progression in Parkinson's disease. Objective motor scoring of the response to levodopa in defined off states was performed every 3 years. The mean time from the initiation of levodopa treatment to the most recent measurements was 18.2 years. Of 8 patients who are still alive, only 3 had none of the features of the advanced disease phase (dementia, hallucinations, frequent falling). Off-phase motor function worsened at a yearly rate of 1.9% of the maximum disability score, although the plots of the serial scores showed that the magnitude of the levodopa response is well preserved. There was little difference in the rate of progression between patients with tremor-dominant and non-tremor-dominant motor subtypes. Those who developed dementia had more rapid deterioration of motor scores, with significantly worse off-phase (P = .008) and on-phase (P = .03) motor function. A graph of serial scores of patients who have died, aligned for time of death, showed an upward curving trend of motor disability in the last 5 years of the disease course. Its advanced phase may reveal that Parkinson's disease has an exponential pattern of progression.