To determine whether rates and patterns of progression differ among Primary Lateral Sclerosis (PLS) patients.
50 patients fulfilling clinical criteria for PLS were classified on initial presentation into 3 subtypes: ascending, multifocal, and sporadic paraparesis (PLS-A, PLS-M or PLS-SP). Patients were surveyed annually. Measures of movement speed, clinical rating scales, and transcranial magnetic stimulation were re-assessed at 1–5 years intervals for spread to additional body regions and progression of severity within affected regions.
Forty-seven patients continued to fulfill criteria for PLS over a mean follow-up of 6.6 years, with a mean disease duration > 14 years. PLS-A patients had more predictable progression to additional body regions. Severity progressed faster in newly affected regions followed by stabilization in PLS-A or PLS-M subtypes.
Clinical progression in PLS does not occur steadily, but has periods of faster decline upon spreading to a newly affected region. Classification of PLS patients by subtype is more relevant to predicting the spread of disease, but not progression of severity.
primary lateral sclerosis; motor neuron disorders; spasticity; upper motor neuron syndrome
Amyotrophic lateral sclerosis (ALS) is characterized phenotypically by progressive weakness and neuropathologically by loss of motor neurons. Phenotypically, there is marked heterogeneity. Typical ALS has mixed upper motor neuron (UMN) and lower motor neuron (LMN) involvement. Primary lateral sclerosis has predominant UMN involvement. Progressive muscular atrophy has predominant LMN involvement. Bulbar and limb ALS have predominant regional involvement. Frontotemporal dementia has significant cognitive and behavioral involvement. These phenotypes can be so distinctive that they would seem to have differing biology. However, they cannot be distinguished, at least neuropathologically or genetically. In sporadic ALS (SALS), they are mostly characterized by ubiquitinated cytoplasmic inclusions of TDP-43. In familial ALS (FALS), where phenotypes are indistinguishable from SALS and similarly heterogeneous, each mutated gene has its own genetic and molecular signature. Overall, since the same phenotypes can have multiple causes including different gene mutations, there must be multiple molecular mechanisms causing ALS – and ALS is a syndrome. Since, however, multiple phenotypes can be caused by one single gene mutation, a single molecular mechanism can cause heterogeneity. What the mechanisms are remain unknown, but active propagation of the pathology neuroanatomically seems to be a principal component. Leading candidate mechanisms include RNA processing, cell-cell interactions between neurons and non-neuronal neighbors, focal seeding from a misfolded protein that has prion-like propagation, and fatal errors introduced during neurodevelopment of the motor system. If fundamental mechanisms could be identified and understood, ALS therapy could rationally target progression and stop the disease – a goal that seems increasingly achievable.
ALS; PLS; PMA; motor neuron disease; FTD
Patients with Amyotrophic lateral sclerosis (ALS) rely on a variety of support services during the course of their illness. Patients with Primary lateral sclerosis (PLS) have a slower progression of disease and different clinical spectrum. Their needs for allied health services and social support have not been well characterized. To investigate these needs, 25 patients with PLS and caregivers were surveyed about the use of assistive devices and support services. Needs for assistance changed as the disease progressed. Their greatest need was for gait assistive devices and home help for activities requiring mobility. As in other chronic diseases, there was a striking use of the internet to gather information and for patient support groups.
Amyotrophic lateral sclerosis; internet support groups; Primary lateral sclerosis; wheelchair; survival
Stiff Person Syndrome (SPS) is a disabling autoimmune CNS disorder characterized by progressive muscle rigidity and gait impairment with superimposed painful spasms that involve axial and limb musculature, triggered by heightened sensitivity to external stimuli. Impaired synaptic GABAergic inhibition resulting from intrathecal B-cell-mediated clonal synthesis of autoantibodies against various presynaptic and synaptic proteins in the inhibitory neurons of the brain and spinal cord is believed to be an underlying pathogenic mechanism. SPS is most often idiopathic, but it can occur as a paraneoplastic condition. Despite evidence that anti-GAD and related autoantibodies impair GABA synthesis, the exact pathogenic mechanism of SPS is not fully elucidated. The strong association with several MHC-II alleles and improvement of symptoms with immune-modulating therapies support an autoimmune etiology of SPS. In this review, we discuss the clinical spectrum, neurophysiological mechanisms, and therapeutic options, including a rationale for agents that modulate B cell function in SPS.
GABA; anti-GAD antibodies; stiff person syndrome; autoimmunity; paraneoplastic disorders
Magnetic resonance imaging measures have been proposed as objective markers to study upper motor neuron loss in motor neuron disorders. Cross-sectional studies have identified imaging differences between groups of healthy controls and patients with amyotrophic lateral sclerosis (ALS) or primary lateral sclerosis (PLS) that correlate with disease severity, but it is not known whether imaging measures change as disease progresses. Additionally, whether imaging measures change in a similar fashion with disease progression in PLS and ALS is unclear. To address these questions, clinical and imaging evaluations were first carried out in a prospective cross-sectional study of 23 ALS and 22 PLS patients with similar motor impairment and 19 age-matched healthy controls. Clinical evaluations consisted of a neurological examination, the ALS Functional rating scale-revised, and measures of finger tapping, gait, and timed speech. Age and ALSFRS score were not different, but PLS patients had longer duration of symptoms. Imaging measures examined were cortical thickness, regional brain volumes, and diffusion tensor imaging of the corticospinal tract and callosum. Imaging measures that differed from controls in a cross-sectional vertex-wise analysis were used as regions of interest for longitudinal analysis, which was carried out in 9 of the ALS patients (interval 1.26 ± 0.72 years) and 12 PLS patients (interval 2.08 ± 0.93 years). In the cross-sectional study both groups had areas of cortical thinning, which was more extensive in motor regions in PLS patients. At follow-up, clinical measures declined more in ALS than PLS patients. Cortical thinning and grey matter volume loss of the precentral gyri progressed over the follow-up interval. Fractional anisotropy of the corticospinal tracts remained stable, but the cross-sectional area declined in ALS patients. Changes in clinical measures correlated with changes in precentral cortical thickness and grey matter volume. The rate of cortical thinning was greater in ALS patients with shorter disease durations, suggesting that thickness decreases in a non-linear fashion. Thus, cortical thickness changes are a potential imaging marker for disease progression in individual patients, but the magnitude of change likely depends on disease duration and progression rate. Differences between PLS and ALS patients in the magnitude of thinning in cross-sectional studies are likely to reflect longer disease duration. We conclude that there is an evolution of structural imaging changes with disease progression in motor neuron disorders. Some changes, such as diffusion properties of the corticospinal tract, occur early while cortical thinning and volume loss occur later.
► In a cross-sectional study, ALS and PLS patients had thinning of the motor cortex compared to age-matched controls ► Progressive thinning and atrophy of the precentral gyrus were correlated with clinical progression over a 1- or 2-year longitudinal follow-up ► The rate of cortical thinning was faster in ALS patients with a shorter disease duration ► Fractional anisotropy of corticospinal tracts, though reduced at baseline in ALS and PLS patients remained stable over longitudinal follow-up ► Imaging changes evolve with disease progression in motor neuron disorders ► Changes in white matter diffusion properties occur early, while cortical thinning and atrophy occur later and over a longer time frame
ALS, amyotrophic lateral sclerosis; ALSFRS-R, ALS functional rating scale, revised; CC, corpus callosum; CST, corticospinal tract; DTI, diffusion tensor imaging; FA, fractional anisotropy; MD, mean diffusivity; MRI, magnetic resonance imaging; PLS, primary lateral sclerosis; UMN, upper motor neuron; Cortical thickness; Longitudinal studies; Motor neuron disease; Diffusion tensor imaging; FreeSurfer
Primary lateral sclerosis is a sporadic disorder characterized by slowly progressive corticospinal dysfunction. Primary lateral sclerosis differs from amyotrophic lateral sclerosis by its lack of lower motor neuron signs and long survival. Few pathological studies have been carried out on patients with primary lateral sclerosis, and the relationship between primary lateral sclerosis and amyotrophic lateral sclerosis remains uncertain. To detect in vivo structural differences between the two disorders, diffusion tensor imaging of white matter tracts was carried out in 19 patients with primary lateral sclerosis, 18 patients with amyotrophic lateral sclerosis and 19 age-matched controls. Fibre tracking was used to reconstruct the intracranial portion of the corticospinal tract and three regions of the corpus callosum: the genu, splenium and callosal fibres connecting the motor cortices. Both patient groups had reduced fractional anisotropy, a measure associated with axonal organization, and increased mean diffusivity of the reconstructed corticospinal and callosal motor fibres compared with controls, without changes in the genu or splenium. Voxelwise comparison of the whole brain white matter using tract-based spatial statistics confirmed the differences between patients and controls in the diffusion properties of the corticospinal tracts and motor fibres of the callosum. This analysis further revealed differences in the regional distribution of white matter alterations between the patient groups. In patients with amyotrophic lateral sclerosis, the greatest reduction in fractional anisotropy occurred in the distal portions of the intracranial corticospinal tract, consistent with a distal axonal degeneration. In patients with primary lateral sclerosis, the greatest loss of fractional anisotropy and mean diffusivity occurred in the subcortical white matter underlying the motor cortex, with reduced volume, suggesting tissue loss. Clinical measures of upper motor neuron dysfunction correlated with reductions in fractional anisotropy in the corticospinal tract in patients with amyotrophic lateral sclerosis and increased mean diffusivity and volume loss of the corticospinal tract in patients with primary lateral sclerosis. Changes in the diffusion properties of the motor fibres of the corpus callosum were strongly correlated with changes in corticospinal fibres in patients, but not in controls. These findings indicate that degeneration is not selective for corticospinal neurons, but affects callosal neurons within the motor cortex in motor neuron disorders.
diffusion tensor imaging; diffusion tensor tractography; motor neuron disorders; primary lateral sclerosis; corpus callosum
Patients usually require long-term training for effective EEG-based brain-computer interface (BCI) control due to fatigue caused by the demands for focused attention during prolonged BCI operation. We intended to develop a user-friendly BCI requiring minimal training and less mental load.
Testing of BCI performance was investigated in three patients with amyotrophic lateral sclerosis (ALS) and three patients with primary lateral sclerosis (PLS), who had no previous BCI experience. All patients performed binary control of cursor movement. One ALS patient and one PLS patient performed four-directional cursor control in a two-dimensional domain under a BCI paradigm associated with human natural motor behavior using motor execution and motor imagery. Subjects practiced for 5-10 minutes and then participated in a multi-session study of either binary control or four-directional control including online BCI game over 1.5 – 2 hours in a single visit.
Event-related desynchronization and event-related synchronization in the beta band were observed in all patients during the production of voluntary movement either by motor execution or motor imagery. The online binary control of cursor movement was achieved with an average accuracy about 82.1±8.2% with motor execution and about 80% with motor imagery, whereas offline accuracy was achieved with 91.4±3.4% with motor execution and 83.3±8.9% with motor imagery after optimization. In addition, four-directional cursor control was achieved with an accuracy of 50-60% with motor execution and motor imagery.
Patients with ALS or PLS may achieve BCI control without extended training, and fatigue might be reduced during operation of a BCI associated with human natural motor behavior.
The development of a user-friendly BCI will promote practical BCI applications in paralyzed patients.
EEG; brain-computer interface (BCI); event-related desynchronization (ERD); event-related synchronization (ERS); user-friendly; amyotrophic lateral sclerosis (ALS); primary lateral sclerosis (PLS); motor control
The statistical reliability of diffusion property measurements was evaluated in ten healthy subjects using deterministic fiber tracking to localize tracts affected in motor neuron disease: corticospinal tract (CST), uncinate fasciculus (UNC), and the corpus callosum in its entirety (CC), and its genu (GE), motor (CCM), and splenium (SP) fibers separately. Measurements of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (λ1), transverse diffusivity (λ⊥), and volume of voxels containing fibers (VV) were obtained within each tract. To assess intra-rater and inter-rater reliability, two raters carried out fiber tracking five times on each scan. Scan-rescan and longitudinal reliability were assessed in a subset of four subjects who had six scans, with two sets of three scans separated by one year. The statistical reliability of repeated measurements was evaluated using intra-class correlation coefficients (ICC) and coefficients of variation (CV). Spatial agreement of tract shape was assessed using the kappa (κ) statistic.
Repeated same-scan fiber tracking evaluations showed good geometric alignment (intra-rater κ > 0.90, inter-rater κ > 0.76) and reliable diffusion property measurements (intra-rater ICC > 0.92, inter-rater ICC > 0.77). FA, MD, and λ⊥ were highly reliable with repeated scans on different days, up to a year apart (ICC > 0.8). VV also exhibited good reliability, but with higher CVs. We were unable to demonstrate reproducibility of λ1. Longitudinal reliability after one year was improved by averaging measurements from multiple scans at each timepoint. Fiber tracking provides a reliable tool for the longitudinal evaluation of white matter diffusion properties.
diffusion tensor imaging; tractography; fiber tracking; corticospinal tract; corpus callosum; test-retest reliability
MUNE, a technique used in ALS clinical trials to quantitatively assess motor neuron loss, should also be valuable in assessing progression in spinal bulbar muscular atrophy (SBMA), an x-linked neuronopathy. In ALS, instability of single motor units (SMUP) prompted Shefner9 to modify the statistical MUNE method to exclude SMUPs ≤ 40μV. It is unknown if there is a similar SMUP instability in the more chronic degenerative disease of SBMA.
In this study, the standard parameter of excluding SMUP < 10 μV was compared with the exclusion of SMUP < 40 μV in the calculation of the statistical MUNE. The mean statistical MUNE, using the standard method and the Shefner method, was 60±21 to 47±23, respectively. Similar to ALS, SBMA showed an increased proportion (17%) of individual SMUPs ≤ 40 μV compared to normal controls.
In conclusion, excluding SMUPs ≤ 40 μV from the statistical MUNE calculations is appropriate for SBMA subjects because their SMUPs characteristics are similar to ALS. Exclusion of the low amplitude SMUPs reduces the calculated MUNE.
Spinal bulbar muscular atrophy; motor unit number estimation; motor neuron disease
Patients with corticospinal tract dysfunction have slow voluntary movements with brisk stretch reflexes and spasticity. Previous studies reported reduced firing rates of motor units during voluntary contraction. To assess whether this firing behavior occurs because motor neurons do not respond normally to excitatory inputs, we studied motor units in patients with primary lateral sclerosis, a degenerative syndrome of progressive spasticity. Firing rates were measured from motor units in the wrist extensor muscles at varying levels of voluntary contraction ≤10% maximal force. At each force level, the firing rate was measured with and without added muscle vibration, a maneuver that repetitively activates muscle spindles. In motor units from age-matched control subjects, the firing rate increased with successively stronger contractions as well as with the addition of vibration at each force level. In patients with primary lateral sclerosis, motor-unit firing rates remained stable, or in some cases declined, with progressively stronger contractions or with muscle vibration. We conclude that excitatory inputs produce a blunted response in motor neurons in patients with primary lateral sclerosis compared with age-matched controls. The potential explanations include abnormal activation of voltage-activated channels that produce stable membrane plateaus at low voltages, abnormal recruitment of the motor pool, or tonic inhibition of motor neurons.
Impaired axonal transport has been postulated to play a role in the pathophysiology of multiple neurodegenerative disorders. In this report, we describe the results of clinical and neuropathological studies in a family with an inherited form of motor neuron disease caused by mutation in the p150Glued subunit of dynactin, a microtubule motor protein essential for retrograde axonal transport. Affected family members had a distinct clinical phenotype characterized by early bilateral vocal fold paralysis affecting the adductor and abductor laryngeal muscles. They later experienced weakness and atrophy in the face, hands, and distal legs. The extremity involvement was greater in the hands than in the legs, and it had a particular predilection for the thenar muscles. No clinical or electrophysiological sensory abnormality existed; however, skin biopsy results showed morphological abnormalities of epidermal nerve fibers. An autopsy study of one patient showed motor neuron degeneration and axonal loss in the ventral horn of the spinal cord and hypoglossal nucleus of the medulla. Immunohistochemistry showed abnormal inclusions of dynactin and dynein in motor neurons. This mutation of dynactin, a ubiquitously expressed protein, causes a unique pattern of motor neuron degeneration that is associated with the accumulation of dynein and dynactin in neuronal inclusions.
Executive dysfunction occurs in many patients with amyotrophic lateral sclerosis (ALS), but it has not been well studied in primary lateral sclerosis (PLS). The aims of this study were to (1) compare cognitive function in PLS to that in ALS patients, (2) explore the relationship between performance on specific cognitive tests and diffusion tensor imaging (DTI) metrics of white matter tracts and gray matter volumes, and (3) compare DTI metrics in patients with and without cognitive and behavioral changes.
The Delis-Kaplan Executive Function System (D-KEFS), the Mattis Dementia Rating Scale (DRS-2), and other behavior and mood scales were administered to 25 ALS patients and 25 PLS patients. Seventeen of the PLS patients, 13 of the ALS patients, and 17 healthy controls underwent structural magnetic resonance imaging (MRI) and DTI. Atlas-based analysis using MRI Studio software was used to measure fractional anisotropy, and axial and radial diffusivity of selected white matter tracts. Voxel-based morphometry was used to assess gray matter volumes. The relationship between diffusion properties of selected association and commissural white matter and performance on executive function and memory tests was explored using a linear regression model.
More ALS than PLS patients had abnormal scores on the DRS-2. DRS-2 and D-KEFS scores were related to DTI metrics in several long association tracts and the callosum. Reduced gray matter volumes in motor and perirolandic areas were not associated with cognitive scores.
The changes in diffusion metrics of white matter long association tracts suggest that the loss of integrity of the networks connecting fronto-temporal areas to parietal and occipital areas contributes to cognitive impairment.
Motor neuron disease; Executive function; Diffusion tensor imaging
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by cortical and spinal motor neuron dysfunction. Routine magnetic resonance imaging (MRI) studies have previously shown hypointense signal in the motor cortex on T2-weighted images in some ALS patients, however, the cause of this finding is unknown. To investigate the utility of this MR signal change as a marker of cortical motor neuron degeneration, signal abnormalities on 3T and 7T MR images of the brain were compared, and pathology was obtained in two ALS patients to determine the origin of the motor cortex hypointensity. Nineteen patients with clinically probable or definite ALS by El Escorial criteria and 19 healthy controls underwent 3T MRI. A 7T MRI scan was carried out on five ALS patients who had motor cortex hypointensity on the 3T FLAIR sequence and on three healthy controls. Postmortem 7T MRI of the brain was performed in one ALS patient and histological studies of the brains and spinal cords were obtained post-mortem in two patients. The motor cortex hypointensity on 3T FLAIR images was present in greater frequency in ALS patients. Increased hypointensity correlated with greater severity of upper motor neuron impairment. Analysis of 7T T2*-weighted gradient echo imaging localized the signal alteration to the deeper layers of the motor cortex in both ALS patients. Pathological studies showed increased iron accumulation in microglial cells in areas corresponding to the location of the signal changes on the 3T and 7T MRI of the motor cortex. These findings indicate that the motor cortex hypointensity on 3T MRI FLAIR images in ALS is due to increased iron accumulation by microglia.
The Neurolaryngology Study Group convened a multidisciplinary panel of experts in neuromuscular physiology, electromyography, physical medicine and rehabilitation, neurology, and laryngology to meet with interested members from the American Academy of Otolaryngology Head and Neck Surgery, the Neurolaryngology Subcommittee and the Neurolaryngology Study Group to address the use of laryngeal electromyography (LEMG) for electrodiagnosis of laryngeal disorders. The panel addressed the use of LEMG for: 1) diagnosis of vocal fold paresis, 2) best practice application of equipment and techniques for LEMG, 3) estimation of time of injury and prediction of recovery of neural injuries, 4) diagnosis of neuromuscular diseases of the laryngeal muscles, and, 5) differentiation between central nervous system and behaviorally based laryngeal disorders. The panel also addressed establishing standardized techniques and methods for future assessment of LEMG sensitivity, specificity and reliability for identification, assessment and prognosis of neurolaryngeal disorders. Previously an evidence-based review of the clinical utility of LEMG published in 2004 only found evidence supported that LEMG was possibly useful for guiding injections of botulinum toxin into the laryngeal muscles. An updated traditional/narrative literature review and expert opinions were used to direct discussion and format conclusions. In current clinical practice, LEMG is a qualitative and not a quantitative examination. Specific recommendations were made to standardize electrode types, muscles to be sampled, sampling techniques, and reporting requirements. Prospective studies are needed to determine the clinical utility of LEMG. Use of the standardized methods and reporting will support future studies correlating electro-diagnostic findings with voice and upper airway function.