Quantitative muscle ultrasound as a biomarker in Charcot-Marie-Tooth neuropathy.

OBJECTIVE: The utility of quantitative muscle ultrasound as a marker of disease severity in Charcot-Marie-Tooth (CMT) disease subtypes was investigated. METHODS: Muscle ultrasound was prospectively performed on 252 individual muscles from 21 CMT patients (9 CMT1A, 8 CMTX1, 4 CMT2A) and compared to 120 muscles from 10 age and gender-matched controls. Muscle ultrasound recorded echogenicity and thickness in representative muscles including first dorsal interosseus (FDI) and tibialis anterior (TA). RESULTS: Muscle volume of FDI and thickness of TA correlated with MRC strength. Muscle echogenicity was significantly increased in FDI (65.05 vs 47.09; p<0.0001) and TA (89.45 vs 66.30; p<0.0001) of CMT patients. In TA, there was significantly higher muscle thickness (23 vs 18 vs 16mm; p<0.0001) and lower muscle echogenicity (80 vs 95 vs 108; p<0.0001) in CMT1A compared to CMTX1 and CMT2A. This corresponded to disease severity based on muscle strength (MRC grading CMT1A vs CMTX1 vs CMT2A: 59 vs 48 vs 44; p=0.002). CONCLUSION: In CMT, quantitative muscle ultrasound of FDI and TA is a useful marker of disease severity. SIGNIFICANCE: The current findings suggest that quantitative muscle ultrasound has potential as a surrogate marker of disease progression in future interventional trials in CMT.

Amyotrophic lateral sclerosis and motor neuron syndromes in Asia.

While the past 2 decades have witnessed an increasing understanding of amyotrophic lateral sclerosis (ALS) arising from East Asia, particularly Japan, South Korea, Taiwan and China, knowledge of ALS throughout the whole of Asia remains limited. Asia represents >50% of the world population, making it host to the largest patient cohort of ALS. Furthermore, Asia represents a diverse population in terms of ethnic, social and cultural backgrounds. In this review, an overview is presented that covers what is currently known of ALS in Asia from basic epidemiology and genetic influences, through to disease characteristics including atypical phenotypes which manifest a predilection for Asians. With the recent establishment of the Pan-Asian Consortium for Treatment and Research in ALS to facilitate collaborations between clinicians and researchers across the region, it is anticipated that Asia and the Pacific will contribute to unravelling the uncertainties in ALS.

Relationship between ultrasonographic nerve morphology and severity of diabetic sensorimotor polyneuropathy.

BACKGROUND AND PURPOSE: In the current study, the aim was to characterize the nerve ultrasound cross-sectional areas (CSAs) of type 2 diabetic patients with diabetic sensorimotor polyneuropathy (DSP) of different severities. METHODS: A hundred symptomatic DSP patients and 40 age-matched healthy controls were prospectively recruited. DSP severity was ascertained through the Toronto Clinical Scoring System (TCCS). Nerve electrophysiology and ultrasound were performed on both lower limbs and the non-dominant upper limb. RESULTS: The sural nerve was inexcitable in 19.1% of mild, 40.0% of moderate and 69.0% of severe DSP groups. In contrast, CSAs were measurable in all nerves of DSP patients and were significantly larger compared to controls. Patients with severe DSP had significantly larger ulnar, peroneal, tibial and sural nerves compared to mild DSP patients. By receiver operating characteristic curve analysis, the cut-off value for the sural nerve at 2 mm(2) was a good discriminator (area under the curve 0.88) between the presence and absence of DSP (sensitivity 0.90; specificity 0.74) but performed less well in discriminating between the severity of DSP (cut-off 2.75 mm(2); area under the curve 0.62; sensitivity 0.59; specificity 0.73). Significant correlations were demonstrated between TCSS scores, most neurophysiology parameters and CSAs of the ulnar, peroneal, tibial and sural nerves. CONCLUSION: Nerve ultrasound in DSP reveals enlarged CSAs and these changes worsen with increasing disease severity, thus serving as a useful diagnostic tool especially when neurophysiology is unrevealing.

Mutation analysis of genes within the dynactin complex in a cohort of hereditary peripheral neuropathies.

The cytoplasmic dynein-dynactin genes are attractive candidates for neurodegenerative disorders given their functional role in retrograde transport along neurons. The cytoplasmic dynein heavy chain (DYNC1H1) gene has been implicated in various neurodegenerative disorders, and dynactin 1 (DCTN1) genes have been implicated in a wide spectrum of disorders including motor neuron disease, Parkinson's disease, spinobulbar muscular atrophy and hereditary spastic paraplegia. However, the involvement of other dynactin genes with inherited peripheral neuropathies (IPN) namely, hereditary sensory neuropathy, hereditary motor neuropathy and Charcot-Marie-Tooth disease is under reported. We screened eight genes; DCTN1-6 and ACTR1A and ACTR1B in 136 IPN patients using whole-exome sequencing and high-resolution melt (HRM) analysis. Eight non-synonymous variants (including one novel variant) and three synonymous variants were identified. Four variants have been reported previously in other studies, however segregation analysis within family members excluded them from causing IPN in these families. No variants of disease significance were identified in this study suggesting the dynactin genes are unlikely to be a common cause of IPNs. However, with the ease of querying gene variants from exome data, these genes remain worthwhile candidates to assess unsolved IPN families for variants that may affect the function of the proteins.

Anti-GQ1b antibody syndrome: anti-ganglioside complex reactivity determines clinical spectrum.

BACKGROUND AND PURPOSE: Anti-GQ1b antibodies have been found in patients with Miller Fisher syndrome as well as its related conditions. Our aim was to identify the mechanism by which autoantibodies produce various clinical presentations in 'anti-GQ1b antibody syndrome'. METHODS: Immunoglobulin G antibodies to ganglioside complex (GSC) of GQ1b or GT1a with GM1, GD1a, GD1b or GT1b were tested in sera from patients with anti-GQ1b (n = 708) or anti-GT1a (n = 696) IgG antibodies. Optical densities of the single anti-GQ1b or anti-GT1a antibodies were used as reference (100%), and those of anti-GSC antibodies were expressed in percentages to reference. The relationships between anti-GSC antibody reactivity and the corresponding clinical features were assessed by multivariate logistic regression analysis. RESULTS: Ophthalmoplegia and hypersomnolence were significantly associated with complex-attenuated anti-GQ1b and anti-GT1a antibodies. Ataxia was associated with GD1b- and GT1b-enhanced anti-GQ1b antibodies or GM1-enhanced anti-GT1a antibodies. Bulbar palsy was associated with GT1b-enhanced anti-GQ1b antibodies. Neck weakness was associated with GD1a-enhanced anti-GQ1b antibodies. Arm weakness was associated with GD1b-enhanced anti-GQ1b and GD1a-enhanced anti-GT1a antibodies. Leg weakness was associated with GD1a-enhanced anti-GQ1b and anti-GT1a antibodies. CONCLUSIONS: Differences in fine specificity of anti-GQ1b antibodies are associated with clinical features, possibly due to the different expression of gangliosides in different parts of the nervous system.

The value of comparing mortality of Guillain-Barré syndrome across different regions.

OBJECTIVE: To study the clinical profile of Guillain-Barré syndrome (GBS) patients who died in 4 Asian countries in order to understand factors underlying any variation in mortality. METHODS: Retrospectively reviewed medical records of GBS patients who died in 7 hospitals from 4 Asian countries between 2001 and 2012. Baseline characteristics, timing and causes of death were recorded. RESULTS: A total of 16 out of 261 GBS patients died. The overall mortality rate was 6%, with a range of 0 to 13%. The leading causes of death were respiratory infections, followed by myocardial infarction. The median age of our patients was 77 years. Half of the patients required mechanical ventilation and almost all had significant concomitant illnesses. A disproportionate number of patients in the Hong Kong cohort died (13%). Patients with advanced age, fewer antecedent respiratory infections and need for mechanical ventilation were at most risk. Most deaths occurred during the plateau phase of GBS and on the general ward after having initially received intensive care. CONCLUSIONS: There is considerable variability in mortality of GBS among different Asian cohorts. Although the risks factors for mortality were similar to Western cohorts, the timing and site of death differed. This allows specific measures to be implemented to improve GBS care in countries with higher mortality.

Successful treatment of chronic inflammatory demyelinating polyneuropathy (CIDP) in systemic lupus erythematosus (SLE) with oral cyclophosphamide.

Peripheral neuropathy is a known manifestation of systemic lupus erythematosus. However, the association of primary autoimmune inflammatory neuropathies such as chronic inflammatory demyelinating polyneuropathy (CIDP) with SLE is uncommon. We report a 26-year-old man who simultaneously presented with severe CIDP and photosensitive rash, but was unresponsive to intravenous immunoglobulin infusion and continued to progress. He was found to have underlying SLE and improved with combined corticosteroid and immunosuppressive therapy with oral cyclophosphamide. CIDP with underlying SLE may be more resistant to conventional therapy with IVIG, requiring the addition of other immunosuppressive agents.

Respiratory involvement in inherited primary muscle conditions.

Patients with inherited muscle disorders can develop respiratory muscle weakness leading to ventilatory failure. Predicting the extent of respiratory involvement in the different types of inherited muscle disorders is important, as it allows clinicians to impart prognostic information and offers an opportunity for early interventional management strategies. The approach to respiratory assessment in patients with muscle disorders, the current knowledge of respiratory impairment in different muscle disorders and advice on the management of respiratory complications are summarised.

Tubular aggregate myopathy presenting with acute type II respiratory failure and severe orthopnoea.

Acute hypercapnic respiratory failure (AHRF) is a common reason for hospital admission. Most patients have an underlying chronic lung disease such as chronic obstructive pulmonary disease. We report the case of a man who presented with AHRF secondary to tubular aggregate myopathy.

Thymectomy in myasthenia gravis: comparison of outcome in Santiago, Cuba and Nottingham, UK.

OBJECTIVES: We compared the outcome of thymectomy for myasthenia gravis (MG) in two healthcare systems. In Nottingham, UK, thymectomy is performed for thymic enlargement and considered in acetylcholine receptor (AchR) antibody positive patients. In Santiago, Cuba, thymectomy is considered in all generalised MG patients irrespective of their radiological findings or AchR antibodies. METHOD: 22 MG patients in Nottingham and 75 in Santiago who had a thymectomy were identified and their notes reviewed. We compared the median age, stage of disease, thymic histology and clinical outcome at two years post-thymectomy. RESULTS: The median ages for the Cuban and Nottingham patients were 25 and 35 years respectively. The median stage of disease was IIa by Osserman's classification in both. In Nottingham, 59% (13/22) showed an improvement compared with 88 % (66/75) in Santiago (p < 0.01). There were significantly more cases of thymoma in Nottingham whereas thymic hyperplasia and atrophy were a more frequent finding in Cuban patients. The majority of cases who improved post-thymectomy had thymic hyperplasia on histology in both Nottingham (46%) and Cuban (61%) patients. CONCLUSION: Selecting MG patients based on thymic enlargement alone or AchR antibody positivity may be inadequate and thymectomy should perhaps be considered in all patients with generalised myasthenia.

Thymectomy in myasthenia gravis: comparison of outcome in Santiago, Cuba and Nottingham, UK

OBJECTIVES: We compared the outcome of thymectomy for myasthenia gravis (MG) in two healthcare systems. In Nottingham, UK, thymectomy is performed for thymic enlargement and considered in acetylcholine receptor (AchR) antibody positive patients. In Santiago, Cuba, thymectomy is considered in all generalised MG patients irrespective of their radiological findings or AchR antibodies. METHOD: 22 MG patients in Nottingham and 75 in Santiago who had a thymectomy were identified and their notes reviewed. We compared the median age, stage of disease, thymic histology and clinical outcome at two years post-thymectomy. RESULTS: The median ages for the Cuban and Nottingham patients were 25 and 35 years respectively. The median stage of disease was IIa by Osserman's classification in both. In Nottingham, 59 percent (13/22) showed an improvement compared with 88 percent (66/75) in Santiago (p < 0.01). There were significantly more cases of thymoma in Nottingham whereas thymic hyperplasia and atrophy were a more frequent finding in Cuban patients. The majority of cases who improved post-thymectomy had thymic hyperplasia on histology in both Nottingham (46 percent) and Cuban (61 percent) patients. CONCLUSION: Selecting MG patients based on thymic enlargement alone or AchR antibody positivity may be inadequate and thymectomy should perhaps be considered in all patients with generalised myasthenia(AU)

Significance of Beevor's sign in facioscapulohumeral dystrophy and other neuromuscular diseases.

An atypical presentation of facioscapulohumeral dystrophy (FSH) is described, where the presence of a positive Beevor's sign led to genetic testing and subsequent probable diagnostic confirmation. This prompted evaluation of a further 68 patients for the presence of Beevor's sign. Among these, 19/20 patients with FSH had a positive Beevor's sign, compared with 2/28 with other muscle diseases, and 0/20 in a neurological control group. Beevor's sign should be considered as an additional criterion for the diagnosis of FSH.