Karl Ng

Two Australian families with inclusion-body myopathy, Paget's disease of bone and frontotemporal dementia: novel clinical and genetic findings

We report the first Australian families with inclusion-body myopathy, Pagets disease of the bone and frontotemporal dementia (IBMPFD). The clinical characteristics of the two pedigrees are described including a previously undescribed phenotypic feature of pyramidal tract dysfunction in one family member. A novel mutation in the valosin-containing protein (VCP) gene (p.Arg155Leu) was found in one family while the other family had a previously reported mutation (p.Leu198Trp). Our findings broaden the phenotypic spectrum of IBMPFD and further emphasise the resemblance to amyotrophic lateral sclerosis in some cases.

A prospective study of predictors of prolonged hospital stay and disability after stroke.

This study examined predictors of prolonged hospitalisation (>30 days) and significant disability (modified Rankin Scale >2) in 257 patients with acute ischaemic stroke. These patients were assessed prospectively regarding stroke severity, comorbidities and complications in hospital. Multivariate logistic regression was used to select variables that best predicted prolonged hospital stay and significant disability on discharge. Four factors significantly predicted prolonged hospital stay: older age (>65); diabetes mellitus; in-hospital infection; and significant disability on discharge. Significant disability on discharge was in turn associated with diabetes, infection, premorbid disability, stroke in progression and atrial fibrillation. Diabetes and in-hospital infection, together with other factors, can significantly predict prolonged hospital stay and disability in stroke patients. These two potentially modifiable factors are possible targets for interventions to reduce the burden of illness and healthcare costs of stroke.

Cortical Function in Asymptomatic Carriers and Patients With C9orf72 Amyotrophic Lateral Sclerosis

IMPORTANCE The identification of the chromosome 9 open reading frame 72 (c9orf72) gene hexanucleotide repeat expansion represents a major advance in the understanding of amyotrophic lateral sclerosis (ALS) pathogenesis. The pathophysiological mechanism by which the c9orf72 gene expansion leads to neurodegeneration is not yet elucidated. Cortical hyperexcitability is potentially an important pathophysiological process in sporadic ALS and familial ALS (FALS). OBJECTIVE To investigate whether cortical hyperexcitability forms the pathophysiological basis of c9orf72 FALS using the threshold-tracking transcranial magnetic stimulation technique. DESIGN, SETTING, AND PARTICIPANTS Prospective case-control single-center study that took place at hospitals and outpatient clinics from January 1, 2013, to January 1, 2015. Clinical and functional assessments along with transcranial magnetic stimulation studies were taken on 15 patients with c9orf72 FALS and 11 asymptomatic expansion carriers of c9orf72 who were longitudinally followed up for 3 years. Results were compared with 73 patients with sporadic ALS and 74 healthy control participants. MAIN OUTCOMES AND MEASURES Cortical excitability variables, including short-interval intracortical inhibition, were measured in patients with c9orf72 FALS and results were compared with asymptomatic c9orf72 carriers, patients with sporadic ALS, and healthy control participants. RESULTS Mean (SD) short-interval intracortical inhibition was significantly reduced in patients with c9orf72 FALS (1.2% [1.8%]) and sporadic ALS (1.6% [1.2%]) compared with asymptomatic c9orf72 expansion carriers (10.2% [1.8%]; F = 16.1; P < .001) and healthy control participants (11.8% [1.0%]; F = 16.1; P < .001). The reduction of short-interval intracortical inhibition was accompanied by an increase in intracortical facilitation (P < .01) and motor-evoked potential amplitude (P < .05) as well as a reduction in the resting motor threshold (P < .05) and cortical silent period duration (P < .001). CONCLUSIONS AND RELEVANCE This study establishes cortical hyperexcitability as an intrinsic feature of symptomatic c9orf72 expansion-related ALS but not asymptomatic expansion carriers.

Up-regulation of slow K+ channels in peripheral motor axons: a transcriptional channelopathy in multiple sclerosis

Spinal lesions produce plastic changes in motoneuron properties. We have documented the excitability of motor axons in the median nerve of 12 patients with multiple sclerosis and 50 normal subjects, hypothesizing that plastic changes in the properties of spinal motoneurons might be reflected in the properties of peripheral motor axons and be demonstrable in vivo. In the patients, there were changes in physiological measures of axonal excitability attributable to increased slow K(+) channel activity. Other measures were within control limits. These changes could be modelled by an 11% increase in slow K(+) current, with compensatory changes in membrane potential, suggesting increased expression of the responsible channels. The changes cannot be explained solely by changes in membrane potential and are not those expected if peripheral nerve axons were involved in the inflammatory process of multiple sclerosis. They probably represent a transcriptional channelopathy, due to up-regulation of channel expression. The abnormalities do not imply that peripheral nerve function has been significantly compromised, but they do suggest that the properties of the parent motoneurons have changed. This study thus provides evidence for plasticity in motoneuronal properties at a molecular level, the first such evidence for intact human subjects.

Cortical excitability changes distinguish the motor neuron disease phenotypes from hereditary spastic paraplegia

Cortical hyperexcitability has been identified as an important pathogenic mechanism in motor neuron disease (MND). The issue as to whether cortical hyperexcitability is a common process across the MND phenotypes, including amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS), remains unresolved. Separately, the clinical distinction between PLS and ‘mimic disorders’ such as hereditary spastic paraparesis (HSP) may be difficult, potentially delaying diagnosis. Consequently, the aim of the present study was to determine the nature and spectrum of cortical excitability changes across the MND phenotypes, and to determine whether the presence of cortical dysfunction distinguishes PLS from HSP.

Thermal quantitative sensory testing: A study of 101 control subjects

Quantitative sensory testing is useful for the diagnosis, confirmation and monitoring of small fibre neuropathies. Normative data have been reported but differences in methodology, lack of age-specific values and graphical presentation of data make much of these data difficult to apply in a clinical setting. We have collected normative age-specific thermal threshold data for use in a clinical setting and clarified other factors influencing reference values, including the individual machine or operator. Thermal threshold studies were performed on 101 healthy volunteers (21-70 years old) using one of two Medoc Thermal Sensory Analyser II machines (Medoc, Ramat Yishai, Israel) with a number of operators. A further study was performed on 10 healthy volunteers using both machines and one operator at least 3 weeks apart. Thermal threshold detection increases with age and is different for different body regions. There is no significant difference seen in results between machines of the same make and model; however, different operators may influence results. Normative data for thermal thresholds should be applied using only age- and region-specific values and all operators should be trained and strictly adhere to standard protocols. To our knowledge, this is the largest published collection of normal controls for thermal threshold testing presented with regression data which can easily be used in the clinical setting.

The phenotypic spectrum of dystonia in Mohr–Tranebjaerg syndrome

Mohr–Tranebjaerg syndrome (MTS) is an X‐linked recessive disorder characterized by deafness and dystonia. However the phenotypic expression of dystonia has not been systematically defined. We report clinical, neurophysiological, and ophthalmological data on 6 subjects from 3 Australian kindreds, including 2 with novel mutations, together with a systematic review of the literature, in order to define the phenotypic expression of dystonia. Profound hearing impairment in affected males develops by infancy and precedes the development of dystonia, which varies in time of onset from the first to the sixth decades, with a peak in the second and third decades. Dystonia in MTS tends to be focal, segmental, or multifocal in distribution at onset, with a predilection for the upper body, variably involving the head, neck, and upper limbs. The majority of patients have progression or generalization of their dystonia regardless of age of onset. Within our 3 kindreds, we observed relative intrafamilial homogeneity but interfamilial variation. The median time to the development of moderate‐severely disabling dystonia in these subjects was 11 years. Associated features included progressive cognitive decline, pyramidal signs, and in 1 patient, gait freezing and postural instability. Optic atrophy and cortical visual impairment were both observed. We report for the first time a female patient who developed multiple disabling neurological complications of MTS. Our findings more clearly define and expand the phenotype of both the dystonia and other neurological features of MTS and have implications for the diagnosis and management of this condition.

Riluzole exerts transient modulating effects on cortical and axonal hyperexcitability in ALS

Abstract Riluzole is an established therapy for amyotrophic lateral sclerosis (ALS), although its effects are modest, prolonging survival by three months on average. While the neuroprotective effects of riluzole appear to be mediated by inhibition of glutaminergic transmission and antagonization of Na+ channel function, the duration of these effects remains to be elucidated. Consequently, the present study combined assessment of cortical and peripheral function to determine the longitudinal effects of riluzole in ALS patients. Assessment of cortical function by threshold tracking transcranial magnetic stimulation (TMS) combined with peripheral nerve function excitability studies were longitudinally undertaken on 19 sporadic ALS patients, with assessment occurring at baseline, four, eight, and 12 weeks post riluzole initiation. Baseline results were compared to 31 healthy controls. Results showed that, at baseline, cortical hyperexcitability was a feature of ALS as indicated by a marked reduction in averaged short interval intracortical inhibition [SICI] (3.6 ± 6.9%, p < 0.0001) and cortical silent period duration (p < 0.05) as well as an increase in motor evoked potential amplitude (p < 0.05). Riluzole therapy resulted in individual patient increase in SICI of 4.3% (p < 0.01) and 5.2% (p < 0.01) at four and eight weeks, respectively. At a peripheral level, riluzole therapy lead to a transient increase at four weeks in the relative refractory period (p < 0.05), superexcitability (p < 0.05) and late subexcitability (p < 0.05), all of which returned to baseline levels eight weeks after initiation of riluzole. In conclusion, the present study has established that riluzole exerts transient effects on cortical and axonal hyperexcitability, potentially accounting for the modest clinical effectiveness in ALS.

Electrical perceptual threshold testing: a validation study.

Abstract Background/Objective: To investigate inter-rater and intra-rater reliability of electrical perceptual threshold (EPT) testing in assessing somatosensory function in healthy volunteers. Study Design: Prospective experimental. Setting: Hospital-based spinal cord injuries unit. Methods: Cutaneous electrical stimulation of 4 dermatomes at ASIA sensory key points (C3, T1, L3, and S2) was performed on 40 control subjects. The lowest ascending stimulus intensity at which sensation was perceived was recorded as the EPT. Mean EPT values for each dermatome, as determined by 2 testers at 2 time points, were examined and plotted against a normative template. Differences and associations between intra- and inter-rater measurements and left-right measurements were studied. EPT results for 2 people with spinal cord injuries were also examined. Results: EPT measurements from left and right sides, obtained from the 2 time points and 2 testers, were found to be strongly associated, with the exception of left and right side measurements at the S2 dermatome. No significant differences in the mean EPT for tester or time period were found. The intra- and inter-rater reliability was good for all dermatomes tested. Mean EPT measurements fell within the range of a normative template at each of the 4 dermatomes tested. Conclusion: EPT is an objective, reproducible, and quantifiable method of assessing sensation in a control group. However, caution should be applied in certain dermatomes such as S2, where there was large variation between left and right side measurements.

Sequential fluctuating paraneoplastic ocular flutter–opsoclonus–myoclonus syndrome and Lambert–Eaton myasthenic syndrome in small-cell lung cancer

Paraneoplastic cerebellar degeneration may occur in association with Lambert–Eaton myasthenic syndrome (LEMS), but to our knowledge, the co-occurrence of paraneoplastic opsoclonus–myoclonus syndrome and LEMS has not been previously reported. A 67-year-old woman presented with a complex partial seizure and evolving ocular flutter, opsoclonus, myoclonus and ‘cerebellar’ signs, all of which improved spontaneously within 6 weeks. Approximately 8 weeks after symptom onset, the patient became encephalopathic, she had a further complex partial seizure, and she became areflexic with potentiation of deep tendon reflexes. Radiological, bronchoscopic and histological investigations revealed small-cell lung cancer, and neurophysiological investigations confirmed a diagnosis of LEMS. High-titre anti-P/Q-type voltage-gated calcium-channel antibodies were identified in the serum, which increased as the signs of opsoclonus and myoclonus resolved. The encephalopathy and clinical features of LEMS responded dramatically to chemotherapy and radiotherapy. Spontaneous improvement of paraneoplastic opsoclonus–myoclonus syndrome may occur, and this syndrome may occur in association with LEMS. Antivoltage-gated calcium-channel antibodies are not implicated in the pathogenesis of paraneoplastic opsoclonus–myoclonus syndrome.