Inhibition of HERV-K (HML-2) in amyotrophic lateral sclerosis patients on antiretroviral therapy.

Reactivation of Human Endogenous Retrovirus K (HERV-K), subtype HML-2, has been associated with pathophysiology of amyotrophic lateral sclerosis (ALS). We aimed to assess the efficacy of antiretroviral therapy in inhibiting HML-2 in patients with ALS and a possible association between the change in HML-2 levels and clinical outcomes. We studied the effect of 24-weeks antiretroviral combination therapy with abacavir, lamivudine, and dolutegravir on HML-2 levels in 29 ALS patients. HML-2 levels decreased progressively over 24 weeks (P = 0.001) and rebounded within a week of stopping medications (P = 0.02). The majority of participants (82%), defined as "responders", experienced a decrease in HML-2 at week 24 of treatment compared to the pre-treatment levels. Differences in the evolution of some of the clinical outcomes could be seen between responders and non-responders: FVC decreased 23.69% (SE = 11.34) in non-responders and 12.71% (SE = 8.28) in responders. NPI score decreased 91.95% (SE = 6.32) in non-responders and 53.05% (SE = 10.06) in responders (P = 0.01). Thus, participants with a virological response to treatment showed a trend for slower progression of the illness. These findings further support the possible involvement of HML-2 in the clinical course of the disease.

A Compound Heterozygous Mutation in Calpain 1 Identifies a New Genetic Cause for Spinal Muscular Atrophy Type 4 (SMA4).

Spinal Muscular Atrophy (SMA) is a heterogeneous group of neuromuscular diseases characterized by degeneration of anterior horn cells of the spinal cord, leading to muscular atrophy and weakness. Although the major cause of SMA is autosomal recessive exon deletions or loss-of-function mutations of survival motor neuron 1 (SMN1) gene, next generation sequencing technologies are increasing the genetic heterogeneity of SMA. SMA type 4 (SMA4) is an adult onset, less severe form of SMA for which genetic and pathogenic causes remain elusive.Whole exome sequencing in a 30-year-old brother and sister with SMA4 identified a compound heterozygous mutation (p. G492R/p. F610C) in calpain-1 (CAPN1). Mutations in CAPN1 have been previously associated with cerebellar ataxia and hereditary spastic paraplegia. Using skin fibroblasts from a patient bearing the p. G492R/p. F610C mutation, we demonstrate reduced levels of CAPN1 protein and protease activity. Functional characterization of the SMA4 fibroblasts revealed no changes in SMN protein levels and subcellular distribution. Additional cellular pathways associated with SMA remain unaffected in the patient fibroblasts, highlighting the tissue specificity of CAPN1 dysfunction in SMA4 pathophysiology. This study provides genetic and functional evidence of CAPN1 as a novel gene for the SMA4 phenotype and expands the phenotype of CAPN1 mutation disorders.

Cortical inexcitability defines an adverse clinical profile in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: In amyotrophic lateral sclerosis, studies using threshold-tracking transcranial magnetic stimulation (TMS) have identified corticomotoneuronal dysfunction as a key pathogenic mechanism. Some patients, however, display no motor response at maximal TMS intensities, termed here an 'inexcitable' motor cortex. The extent to which this cortical difference impacts clinical outcomes remains unclear. The aim of this study was to determine the clinical profile of patients with inexcitability to TMS. METHODS: Motor cortex excitability was evaluated using TMS. Patients in whom a motor evoked potential could not be recorded in one or more limbs at maximal TMS intensities were classified as four-limb or partially inexcitable. Demographic information, clinical variables and survival data were analysed. RESULTS: From 133 patients, 40 were identified with inexcitability. Patients with four-limb inexcitability were younger (P = 0.03) and had lower-limb disease onset (64%), greater functional disability (P < 0.001) and faster disease progression (P = 0.02), particularly if inexcitability developed within 1 year of symptoms (P < 0.01). Patients with partial inexcitability had higher resting motor thresholds compared to the excitable cohort (P < 0.01), but averaged short-interval intracortical inhibition was similar (P = 0.5). Mean survival was reduced if inexcitability involved all limbs within 12 months of symptom onset (P = 0.04). CONCLUSION: Amyotrophic lateral sclerosis patients with inexcitability of all four limbs to TMS have a distinct clinical profile of younger age and lower-limb onset. Importantly, these patients display a more malignant disease trajectory, with faster progression, greater functional disability and reduced survival when occurring in early disease. This measure may provide an important prognostic marker in amyotrophic lateral sclerosis.

Changes in long term peripheral nerve biophysical properties in childhood cancer survivors following neurotoxic chemotherapy.

OBJECTIVE: In the context of increasing numbers of childhood cancer survivors (CCS), this study aimed to enhance understanding of the biophysical basis for long term chemotherapy induced peripheral neuropathy from different chemotherapy agents in CCS. METHODS: Detailed cross-sectional neurophysiological examination, using median nerve axonal excitability studies, alongside clinical assessments, in 103 long term CCS (10.5 ± 0.6 years post-treatment). RESULTS: Cisplatin treated CCS (n = 16) demonstrated multiple sensory axonal excitability changes including increased threshold (P < 0.05), alterations in depolarising and hyperpolarising threshold electrotonus (P < 0.05) and reduction in resting and minimum IV slope (P < 0.01). Vincristine treated CCS (n = 73) were comparable to controls, except for prolonged distal motor latency (P = 0.001). No differences were seen in the non-neurotoxic chemotherapy group (n = 14). Abnormalities were more evident in the cisplatin subgroup with greater clinical neuropathy manifestations. CONCLUSION: Persistent long term changes in axonal biophysical properties vary with different chemotherapy agents, most evident after cisplatin exposure. Longitudinal studies of nerve function during chemotherapy treatment are required to further evaluate these differences and their mechanistic basis. SIGNIFICANCE: This study provides a unique biophysical perspective for persistent cisplatin related neurotoxicity in children, previously under recognised.

Sonographic assessment of nerve blood flow in diabetic neuropathy.

AIMS: To undertake sonographic assessment of nerve blood flow in people with Type 2 diabetes and correlate the findings with neuropathy severity scores and electrophysiological measurements. METHODS: Median and tibial nerve ultrasound scans were undertaken in 75 people with diabetes and 30 aged-matched controls without diabetes, using a high-resolution linear probe at non-entrapment sites. Nerve blood flow was quantified using power Doppler techniques to obtain the vessel score and the maximum perfusion intensity. Neuropathy severity was assessed using a total neuropathy score. RESULTS: Diabetic nerves had higher rates of nerve blood flow detection (28%) compared to the control group (P < 0.0001). Significant correlations were found between nerve blood flow measurements and nerve size (P <0.001), reported sensory symptoms (P < 0.05) and neuropathy severity scores (P < 0.001). The cohort with diabetes had significantly larger median (8.5 ± 0.3 mm2 vs 7.2 ± 0.1 mm2 ; P < 0.05) and tibial nerves (18.0 ± 0.9 mm2 vs 12.8 ± 0.5 mm2 ; P < 0.05) compared with controls. CONCLUSION: Peripheral nerve hypervascularity is detectable by ultrasonography in moderate to severe diabetic neuropathy with prominent sensory dysfunction.

Respiratory function and cognitive profile in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is increasingly recognized as a multisystem disorder with 30%-50% of patients exhibiting cognitive impairment. The pathophysiological mechanisms of cognitive dysfunction are probably multifactorial although hypoventilation secondary to respiratory dysfunction may contribute to cognitive decline. The current study aimed to identify the relationship between respiratory function in ALS patients and the presence and degree of cognitive impairment. METHODS: Amyotrophic lateral sclerosis patients were prospectively recruited from a multidisciplinary ALS clinic. Baseline clinical assessments including respiratory function as assessed by spirometry were recorded with forced vital capacity (FVC) ≤ 75% considered to be reduced respiratory function. Cognitive testing was performed utilizing the Addenbrooke's Cognitive Examination (ACE) and the Mini-Mental State Examination (MMSE). RESULTS: From a cohort of 100 ALS patients, 48% were categorized as having impaired respiratory function (FVC = 58.24% ± 2.15%) whilst 52% had normal function (88.65% ± 1.27%). Compared to the group with normal respiratory function (ACE 90.68 ± 0.89, MMSE 28.22 ± 0.21), patients with respiratory dysfunction had significantly reduced cognitive function (ACE 86.83 ± 1.5, P = 0.025; MMSE 26.29 ± 0.45, P = 0.029). Furthermore, subscores demonstrated significant differences between the groups with respect to domains in memory (P = 0.003) and attention (P = 0.05) with a trend observed in fluency (P = 0.082). There was a significant correlation between patient baseline FVC and ACE scores as well as between FVC and memory and fluency subscores (P < 0.01). CONCLUSION: Amyotrophic lateral sclerosis patients with respiratory compromise were more likely to develop reduced cognitive function. In addition to improving physical function, it remains plausible that non-invasive ventilation may alter the progression of cognitive impairment in ALS patients and potentially improve overall quality of life and carer burden.

Conduction block in immune-mediated neuropathy: paranodopathy versus axonopathy.

BACKGROUND AND PURPOSE: Conduction block is a pathognomonic feature of immune-mediated neuropathies. The aim of this study was to advance understanding of pathophysiology and conduction block in chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). METHODS: A multimodal approach was used, incorporating clinical phenotyping, neurophysiology, immunohistochemistry and structural assessments. RESULTS: Of 49 CIDP and 14 MMN patients, 25% and 79% had median nerve forearm block, respectively. Clinical scores were similar in CIDP patients with and without block. CIDP patients with median nerve block demonstrated markedly elevated thresholds and greater threshold changes in threshold electrotonus, whilst those without did not differ from healthy controls in electrotonus parameters. In contrast, MMN patients exhibited marked increases in superexcitability. Nerve size was similar in both CIDP groups at the site of axonal excitability. However, CIDP patients with block demonstrated more frequent paranodal serum binding to teased rat nerve fibres. In keeping with these findings, mathematical modelling of nerve excitability recordings in CIDP patients with block support the role of paranodal dysfunction and enhanced leakage of current between the node and internode. In contrast, changes in MMN probably resulted from a reduction in ion channel density along axons. CONCLUSIONS: The underlying pathologies in CIDP and MMN are distinct. Conduction block in CIDP is associated with paranodal dysfunction which may be antibody-mediated in a subset of patients. In contrast, MMN is characterized by channel dysfunction downstream from the site of block.

Predictors of survival and progression in behavioural variant frontotemporal dementia.

BACKGROUND AND PURPOSE: Predicting the course of behavioural variant frontotemporal dementia (bvFTD) remains a major clinical challenge. This study aimed to identify factors that predict survival and clinical progression in bvFTD. METHODS: Consecutive patients with clinically probable bvFTD were prospectively followed up over an 8-year period. Baseline neuropsychological variables, presence of a known pathogenic frontotemporal dementia gene mutation and a systematic visual magnetic resonance imaging assessment at baseline were examined as candidate predictors using multivariate modelling. RESULTS: After screening 121 cases, the study cohort consisted of 75 patients with probable bvFTD, with a mean age of 60.8 ± 8.5 years, followed up for a mean duration of 7.2 ± 3.5 years from symptom onset. Median survival time from disease onset was 10.8 years and median survival, prior to transition to nursing home, was 8.9 years. A total of 25 of the 75 patients died during the study follow-up period. Survival without dependence was predicted by shorter disease duration at presentation (hazard ratio, 0.49, P = 0.001), greater atrophy in the anterior cingulate cortex (hazard ratio, 1.75, P = 0.047), older age (hazard ratio, 1.07, P = 0.026) and a higher burden of behavioural symptoms (hazard ratio, 1.04, P = 0.015). In terms of disease progression, presence of a known pathogenic frontotemporal dementia mutation (ß = 0.46, P < 0.001) was the strongest predictor of progression. Deficits in letter fluency (ß = -0.43, P = 0.017) and greater atrophy in the motor cortex (ß = 0.51, P = 0.03) were also associated with faster progression. CONCLUSIONS: This study provides novel clinical predictors of survival and progression in bvFTD. Our findings are likely to have an impact on prognostication and care planning in this difficult disease.

Apathy and its impact on patient outcome in amyotrophic lateral sclerosis.

Apathy is one of the most common behavioural symptoms of amyotrophic lateral sclerosis (ALS), yet there are few studies that have investigated the relationship between apathy and quality of life (QOL) as they are experienced by the patient. A cohort of 60 ALS patients were evaluated using the Apathy Evaluation Scale which measured cognitive, behavioural, emotional and non-specific symptoms of apathy combined with the Personal Wellbeing Index, a multidimensional measure of QOL. The relationship between patient-rated apathy and QOL scores, controlling for potential clinical and psychological confounders were analysed using univariate and multivariate methods. Apathy was identified in 30% of ALS patients. Patients with apathy reported higher levels of depression (p = 0.0001). Compared to non-apathetic patients, patients with apathy had lower overall QOL (p = 0.001), most pronounced in the domains related to achievements in life (p = 0.001) and community-connectedness (p = 0.0001). Of the cognitive, behavioural, emotional and non-specific manifestations of apathy, only the emotional symptoms explained a significant amount of variance in achievements in life (p = 0.003) and community-connectedness (p = 0.001). As such, emotional manifestations of apathy may underlie worse QOL in ALS patients presenting with behavioural impairment. Patient-reported outcomes, particularly those assessing psychosocial functioning may be important for demonstrating the efficacy of interventions designed to improve QOL in ALS patients with behavioural impairment.

Brain functional connectome abnormalities in amyotrophic lateral sclerosis are associated with disability and cortical hyperexcitability.

BACKGROUND AND PURPOSE: The present study utilized a multimodal approach encompassing connectome networks combined with brain volume analysis, and assessment of cortical excitability to provide novel insights into amyotrophic lateral sclerosis (ALS) pathogenesis. METHODS: Magnetic resonance images were acquired using a 3.0-Tesla Signa HDx scanner (GE Healthcare, Milwaukee, WI, USA), using an eight-channel head coil. Magnetic resonance images for the resting-state scan were acquired using an echo-planar imaging magnetic resonance sequence, acquiring 40 contiguous axial/oblique slices. Structural magnetic resonance imaging three-dimensional T1-weighted images were acquired in the sagittal plane using three-dimensional spoiled gradient echo sequences. For structural imaging, a T1-weighted high-resolution (3.0-Tesla) magnetic resonance imaging scan was used. Cortical excitability was assessed by using the threshold-tracking transcranial magnetic stimulation paradigm. Network-based statistics and whole-brain functional topology (using graph theoretical approaches) assessed functional connectivity. RESULTS: Using a global network-based statistical analysis approach, functional connectivity was increased in 12 network edges connecting 14 nodes (P < 0.05) within the frontal, temporal, parietal and subcortical regions. Analysis of local connectedness disclosed dichotomous effects with reduced connectivity in frontal regions and increased connectivity in occipital regions in ALS. Cortical hyperexcitability was evident in patients with ALS, negatively correlated with functional connectivity changes in the pre-central gyrus (P < 0.01). Connectivity changes in the frontal regions were negatively associated with functional disability (P < 0.05). CONCLUSIONS: Multimodal assessment of cortical function in patients with ALS identified deficits in functional connectivity associated with cortical hyperexcitability that correlated with patient disability. Novel integration of functional brain assessment further contributes to the understanding of disease pathogenesis in ALS.

Autoantibody responses to nodal and paranodal antigens in chronic inflammatory neuropathies.

Autoantibodies to nodal/paranodal proteins have been reported in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). To determine the frequency of anti-paranodal antibodies in our cohort of CIDP patients and to validate the presence anti-nodal antibodies in MMN, sera were screened for IgG against human neurofascin 155, contactin-1, neurofascin 186 and gliomedin using ELISA. In CIDP patients, 7% were anti-NF155 IgG4 positive and 7% were anti-CNTN1 IgG4 positive. Positive results were confirmed using cell based assays and indirect immunofluorescence on teased nerve fibres. We did not detect IgG autoantibodies against these nodal/paranodal antigens in MMN patients.

Cortical hyperexcitability and disease spread in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is characterized by focal disease onset with a predominantly contiguous pattern of disease spread. The pathophysiological mechanisms underlying disease progression in ALS have not been elucidated. Given that cortical hyperexcitability has been identified as an important pathogenic mechanism in ALS, the aim of the present study was to determine whether changes in cortical function could mediate disease spread in ALS. METHODS: Threshold-tracking transcranial magnetic stimulation was undertaken in 50 patients with sporadic ALS with recording of responses over both abductor pollicis brevis muscles, with results matched to clinical assessments and concurrent neurophysiological investigation of lower motor neuron function. Subsequently, patients were followed longitudinally to map patterns of clinical disease progression. RESULTS: Cortical dysfunction was evident over both motor cortices, with hyperexcitability more prominent over the dominant motor cortex, contralateral to the site of disease onset, with reduction of resting motor threshold (F = 3.83, P < 0.05), short-interval intracortical inhibition (F = 15.0, P < 0.0001) and cortical silent-period duration (F = 8.01, P < 0.01), along with an increase in motor evoked potential amplitude (F = 5.66, P < 0.01). In addition, patterns of cortical change were consistent with a contiguous pattern of disease progression. CONCLUSIONS: Cortical hyperexcitability appears to be more prominent over the dominant motor cortex, contralateral to the side of symptom onset, and contributes to a contiguous pattern of spread in sporadic ALS.

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.

Cognition and eating behavior in amyotrophic lateral sclerosis: effect on survival.

It is increasingly recognized that metabolic factors influenced by eating behavior, may affect disease progression in neurodegeneration. In frontotemporal dementia (FTD), which shares a significant overlap with Amyotrophic lateral sclerosis (ALS), patients are well known to develop changes in eating behavior. Whether patients with pure ALS and those with cognitive and behavioral changes associated with ALS also develop similar changes is not known. The current study aimed to examine caloric intake, eating behavioral changes, body mass index, and using cox regression analyses survival across the spectrum of 118 ALS-FTD patients (29 pure ALS, 12 ALS-plus and 21 ALS-FTD, 56 behavioral variant FTD), compared with 25 control subjects. The current study found contrary to previous assumptions eating changes are not restricted to FTD, but a spectrum of eating behavioral changes occur in ALS, present in those with pure ALS and worsening as patients develop cognitive changes. ALS patients with cognitive impairment exhibited changes in food preference, with caloric intake and BMI increasing with the development of cognitive/behavioral changes. Both pure ALS and those with cognitive impairment demonstrated increased saturated fat intake. Survival analyses over the mean patient follow-up period of 6.9 years indicated that increasing eating behavioral changes were associated with an improved survival (threefold decrease risk of dying). Changes in eating behavior and metabolism occur in ALS in association with increasing cognitive impairment, perhaps exerting a protective survival influence. These changes provide insights into the common neural networks controlling eating and metabolism in FTD and ALS and provide potential targets to modify disease prognosis and progression.

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.

Apathy is associated with poor prognosis in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Apathy is the most commonly reported behavioural change in amyotrophic lateral sclerosis (ALS). However, the degree to which it affects prognosis and overlaps with depression in this population is unknown. The present study examined the relationship between level of apathy, mortality and survival time and whether apathy was linked to specific symptom clusters of depression. METHODS: A cohort of 76 consecutive ALS patients attending specialized multidisciplinary clinics were classified according to level of apathy. The effects of clinical factors and apathy on survival time were analysed using univariate and multivariate methods. RESULTS: The majority of patients with moderate to severe apathy died during the study (P = 0.003) and had a median survival time of 21.7 months, considerably shorter than patients with mild apathy (46.9 months) and no apathy (51.9 months) (P = 0.0001). Apathy remained a significant predictor of survival even after controlling for clinical factors and symptom duration at the time of study entry (hazard ratio 3.8, 95% confidence interval 1.9-7.5, P = 0.0001). Depression with demoralization was not associated with level of apathy (P = 0.172) whereas depression with anhedonia was more common in patients with apathy than in those without apathy (P = 0.006). CONCLUSIONS: The presence of severe apathy is an independent, negative prognostic factor in ALS.

Motor function and behaviour across the ALS-FTD spectrum.

BACKGROUND: Behavioural/functional disturbances, characteristic of frontotemporal dementia (FTD), are also a feature of amyotrophic lateral sclerosis (ALS) and patients with combined ALS and FTD (FTD-ALS). AIM OF THE STUDY: To investigate the progression of behavioural disturbances in ALS and FTD using the FTD functional rating scale (FTDFRS). METHODS: Patients with ALS, FTD-ALS and FTD were recruited from specialist clinics. Baseline assessments included the FTDFRS and the ALS functional rating scale-revised (ALSFRS-R). Baseline assessments were included, as were longitudinal assessments in a proportion of patients. RESULTS: In total, 21 ALS, 12 FTD-ALS and 14 behavioural variant FTD (bvFTD) patients were included in the study. Moderate or severe behavioural disturbance was common in patients with ALS at baseline (47.6%), although less frequent than in bvFTD patients; patients with FTD-ALS displayed intermediate impairment. The ALSFRS-R showed the opposite pattern and did not correlate with the FTDFRS. During the follow-up period, significant (P < 0.05) behavioural deterioration was demonstrated in patients with bvFTD and FTD-ALS, with a trend for decline in patients with ALS (P = 0.06). CONCLUSION: Motor disturbance is the primary marker of disease severity in ALS, but behavioural and functional impairment are common, and may decline independently of motor function. As such, the FTDFRS may provide valuable information in the assessment and monitoring of ALS.

Ion Channel Modulation as a Therapeutic Approach in Multiple Sclerosis.

Ion channel dysfunction has been identified as a contributor to symptom development and neurodegeneration in multiple sclerosis (MS). The molecular insights have been translated into new lines of research, with ion channel modulation now representing a therapeutic approach in MS. Studies of Na+ channel function have demonstrated pathological blockade of Na(+) channels during an acute inflammatory attack. Relapses are typically associated with subsequent alterations in Na+ channel expression and structure. However, these compensatory changes may also be deleterious. Specifically, increased Na(+) channel expression may contribute to neuronal energy insufficiency and a cascade of events that may ultimately lead to neurodegeneration and apoptosis. Pharmacological blockade of Na(+) channels in animal models of MS demonstrated encouraging results, although mixed results were obtained in subsequent clinical trials in MS patient cohorts. The process involved in demyelination, a characteristic event in MS pathology, may also induce complex structural changes mediated by K(+) channels that may in turn hinder neural transmission. From a therapeutic perspective, the potent K(+) channel blocker, 4-aminopyridine (4-AP), has demonstrated neurophysiological and functional improvements in animal models of demyelination. Clinical translation of these results was recently achieved with the advent of Fampridine PR, a modified release form of 4-AP, with phase III clinical trials that demonstrated improvement in neurological symptoms including fatigue, walking speed and strength in MS patients.

Motor neuron disease: current management and future prospects.

Motor neuron disease (MND) is characterised by progressive neurological deterioration and coexistence of upper and lower motor neuron signs. Over the past decade, evidence has emerged of unique pathophysiological processes, including glutamate-mediated excitotoxicity, which has resulted in the development of novel diagnostic investigations and uncovered potential therapeutic targets. Advances in genetics, including the recently discovered C9orf72 gene, have radically changed the pathological mindset, from MND being classified as a neuromuscular disease to one that MND forms a continuum with other primary neurodegenerative disorders, including frontotemporal dementia. The present review will highlight the improvements that have occurred in clinical care, in conjunction with recent scientific developments.