Multi-mission satellite remote sensing data for improving land hydrological models via data assimilation.

Satellite remote sensing offers valuable tools to study Earth and hydrological processes and improve land surface models. This is essential to improve the quality of model predictions, which are affected by various factors such as erroneous input data, the uncertainty of model forcings, and parameter uncertainties. Abundant datasets from multi-mission satellite remote sensing during recent years have provided an opportunity to improve not only the model estimates but also model parameters through a parameter estimation process. This study utilises multiple datasets from satellite remote sensing including soil moisture from Soil Moisture and Ocean Salinity Mission and Advanced Microwave Scanning Radiometer Earth Observing System, terrestrial water storage from the Gravity Recovery And Climate Experiment, and leaf area index from Advanced Very-High-Resolution Radiometer to estimate model parameters. This is done using the recently proposed assimilation method, unsupervised weak constrained ensemble Kalman filter (UWCEnKF). UWCEnKF applies a dual scheme to separately update the state and parameters using two interactive EnKF filters followed by a water balance constraint enforcement. The performance of multivariate data assimilation is evaluated against various independent data over different time periods over two different basins including the Murray-Darling and Mississippi basins. Results indicate that simultaneous assimilation of multiple satellite products combined with parameter estimation strongly improves model predictions compared with single satellite products and/or state estimation alone. This improvement is achieved not only during the parameter estimation period ([Formula: see text] 32% groundwater RMSE reduction and soil moisture correlation increase from [Formula: see text] 0.66 to [Formula: see text] 0.85) but also during the forecast period ([Formula: see text] 14% groundwater RMSE reduction and soil moisture correlation increase from [Formula: see text] 0.69 to [Formula: see text] 0.78) due to the effective impacts of the approach on both state and parameters.

A comparative study of brachial plexus sonography and magnetic resonance imaging in chronic inflammatory demyelinating neuropathy and multifocal motor neuropathy.

BACKGROUND AND PURPOSE: To compare the performance of neuroimaging techniques, i.e. high-resolution ultrasound (HRUS) and magnetic resonance imaging (MRI), when applied to the brachial plexus, as part of the diagnostic work-up of chronic inflammatory demyelinating neuropathy (CIDP) and multifocal motor neuropathy (MMN). METHODS: Fifty-one incident, treatment-naive patients with CIDP (n = 23) or MMN (n = 28) underwent imaging of the brachial plexus using (i) a standardized MRI protocol to assess enlargement or T2 hyperintensity and (ii) bilateral HRUS to determine the extent of nerve (root) enlargement. RESULTS: We found enlargement of the brachial plexus in 19/51 (37%) and T2 hyperintensity in 29/51 (57%) patients with MRI and enlargement in 37/51 (73%) patients with HRUS. Abnormal results were only found in 6/51 (12%) patients with MRI and 12/51 (24%) patients with HRUS. A combination of the two imaging techniques identified 42/51 (83%) patients. We found no association between age, disease duration or Medical Research Council sum-score and sonographic nerve size, MRI enlargement or presence of T2 hyperintensity. CONCLUSIONS: Brachial plexus sonography could complement MRI in the diagnostic work-up of patients with suspected CIDP and MMN. Our results indicate that combined imaging studies may add value to the current diagnostic consensus criteria for chronic inflammatory neuropathies.

The role of prior model calibration on predictions with ensemble Kalman filter.

This paper, based on a real world case study (Limmat aquifer, Switzerland), compares inverse groundwater flow models calibrated with specified numbers of monitoring head locations. These models are updated in real time with the ensemble Kalman filter (EnKF) and the prediction improvement is assessed in relation to the amount of monitoring locations used for calibration and updating. The prediction errors of the models calibrated in transient state are smaller if the amount of monitoring locations used for the calibration is larger. For highly dynamic groundwater flow systems a transient calibration is recommended as a model calibrated in steady state can lead to worse results than a noncalibrated model with a well-chosen uniform conductivity. The model predictions can be improved further with the assimilation of new measurement data from on-line sensors with the EnKF. Within all the studied models the reduction of 1-day hydraulic head prediction error (in terms of mean absolute error [MAE]) with EnKF lies between 31% (assimilation of head data from 5 locations) and 72% (assimilation of head data from 85 locations). The largest prediction improvements are expected for models that were calibrated with only a limited amount of historical information. It is worthwhile to update the model even with few monitoring locations as it seems that the error reduction with EnKF decreases exponentially with the amount of monitoring locations used. These results prove the feasibility of data assimilation with EnKF also for a real world case and show that improved predictions of groundwater levels can be obtained.

Multifocal motor neuropathy: association of anti-GM1 IgM antibodies with clinical features.

OBJECTIVE: To determine the prevalence and specificity of antibodies against single gangliosides and ganglioside complexes in serum from 88 patients with multifocal motor neuropathy (MMN) and to study the association with clinical features. METHODS: ELISA was used to detect immunoglobulin (Ig)M, IgG, and IgA antibodies against GM1, GM2, GD1a, GD1b, GM1b, GT1a, GT1b, GQ1b, GalNAc-GD1a, and the glycolipid SGPG; absorption studies were performed to study cross-reactivity. Presence of antibodies against ganglioside complexes consisting of any of combinations of GM1, GM2, GD1a, GD1b, GT1b, and GQ1b was also tested. RESULTS: Anti-GM1 IgM, IgG, and IgA antibodies were detected in serum from 43%, 1%, and 5% of patients with MMN. Anti-GM2 IgM antibodies were detected in 6% and anti-GD1b IgM antibodies in 9% of patients. Patients with MMN with anti-GM1 IgM antibodies had more severe weakness (p < 0.01), more disability (p < 0.01), and more axon loss (p = 0.05) than patients without anti-GM1 IgM antibodies. Anti-GM1 IgM antibody titers correlated with Medical Research Council scores (correlation coefficient = 0.43; p < 0.0001). Anti-GD1b IgM antibody activity was associated with reduced vibration sense (p < 0.01). Absorption studies showed that anti-GD1b and anti-GM2 IgM antibodies cross-reacted with GM1. Antibodies against ganglioside complexes were not detected. Complexes containing GD1a, GD1b, GT1b, or GQ1b with GM1 lowered antibody activity against GM1. CONCLUSION: Anti-ganglioside IgM antibodies in MMN display limited specificity and are associated with severity and clinical characteristics. Results of this study suggest that anti-GM1 IgM antibodies may play a role in MMN pathogenesis.

Correlates of outcome and response to IVIg in 88 patients with multifocal motor neuropathy.

OBJECTIVE: Identification and examination of all patients with multifocal motor neuropathy (MMN) in the Netherlands to document the clinical spectrum and response to IV immunoglobulin (IVIg) and to determine correlates of outcome. METHODS: A national cross-sectional descriptive study was performed. Ninety-seven patients were identified; 88 participated. Logistic regression analysis was used to study determinants of outcome. RESULTS: Age at onset was younger in men than in women (38 vs 45 years, p = 0.05). Onset of weakness was in distal arm (61%) or distal leg (34%), and occasionally in the upper arm (5%). Initial diagnosis was motor neuron disease in one-third of patients. Brisk, but not pathologic, reflexes in weakened muscles were found in 8%. Conduction blocks were most frequently detected in the ulnar (80%) and median (77%) nerves, but occasionally only between Erb and axilla (6%), or in the musculocutaneous nerve (1%). Ninety-four percent responded to IVIg therapy: nonresponders had longer disease duration before the first treatment (p = 0.03). Seventy-six percent received IVIg maintenance treatment at the time of this study (median duration 6 years; range 0-17): the median dose increased over the years from 12 to 17 g per week (p < 0.01). Independent determinants of more severe weakness and disability were axon loss (p < 0.001; p < 0.0001) and longer disease duration without IVIg (p = 0.03; p = 0.07). CONCLUSION: The results of this study may help aid recognition the clinical picture of MMN. Early IVIg treatment may help to postpone axonal degeneration and permanent deficits. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that IVIg improves muscle strength of patients with MMN and disability (defined as an increase of >or=1 Medical Research Council grade in at least 2 muscle groups without decrease in other muscle groups) in 94% (95% confidence interval, 86.8%-97.4%) of patients.

Prognosis of polyneuropathy due to IgM monoclonal gammopathy: a prospective cohort study.

BACKGROUND: The disease course of polyneuropathy associated with immunoglobulin M monoclonal gammopathy (IgM MGUSP) can be highly variable. In order to identify factors that influence long-term disease outcome, a prospective cohort study was performed of 140 patients with IgM MGUSP over a period of 23 years. METHODS: All patients with IgM MGUSP who were diagnosed in our tertiary referral center for polyneuropathy were eligible. All patients underwent nerve conduction studies and were tested for anti-MAG antibodies. The modified Rankin Scale, graded muscle strength, quantified sensory function, and laboratory testing were performed at 0, 1, 2, and 5 years and at last visit. The primary outcome measure was the risk of developing a modified Rankin Scale score of > or = 3 points. RESULTS: A total of 140 patients with IgM MGUSP fulfilled inclusion criteria (101 [72%] demyelinating, 39 [28%] axonal, 63 [44%] MAG positive). The median age at onset was 59 years (interquartile range 52-67), median disease duration at baseline was 3.2 years (interquartile range 1.9-6). Anti-MAG antibodies were associated with a lower risk of Rankin Scale score > or = 3. Demyelination and a higher age at onset were associated with a higher risk for Rankin Scale score > or = 3. Based on these 3 factors, a Web-based prognostic model was developed that directly allows clinicians to estimate the probability of developing disability (http://www.umcutrecht.nl/subsite/Prognosis-MGUS-Neuropathy). CONCLUSION: Higher age at onset and demyelination increase the risk, whereas anti-MAG antibodies decrease the risk, of developing Rankin Scale score > or = 3 in polyneuropathy associated with immunoglobulin M monoclonal gammopathy (IgM MGUSP). Our Web-based prognostic model allows determination of prognosis in IgM MGUSP.

Rituximab for polyneuropathy with IgM monoclonal gammopathy.

BACKGROUND: Polyneuropathy with IgM monoclonal gammopathy can be a disabling disorder necessitating treatment. METHODS: In a prospective open label trial, 17 patients with disabling IgM MGUS polyneuropathy were treated with rituximab, a chimeric anti-CD-20 monoclonal antibody. RESULTS: Rituximab induced an improvement of >or=1 point on the Overall Disability Sum Score in 2/17 patients, an improvement of >or=5% of the distal MRC sum score in 4/17 and the sensory sum score in 9/17 patients. Bone marrow investigations showed CD 20 B cell depletion in all patients. There were no serious adverse events. Compared with treatment with intermittent cyclophosphamide with prednisone or treatment with fludarabine, it shows a comparable response percentages but fewer side effects. The presence of anti-MAG and a disease duration shorter than 10 years may predict treatment response. CONCLUSION: Rituximab is a candidate for treatment of IgM MGUS polyneuropathy and should be further investigated in a double-blind randomised trial.

The realistic yield of lower leg SNAP amplitudes and SRAR in the routine evaluation of chronic axonal polyneuropathies.

OBJECTIVE: To assess the realistic yield of lower leg sensory nerve action potential amplitudes (SNAP) and the sural/radial nerve amplitude ratio (SRAR) in the routine evaluation of suspected distal axonal polyneuropathy. METHODS: Investigated were 721 people. In 393 referents without and 328 patients with chronic distal symmetrical polyneuropathy the SRAR, sural, superficial peroneal and dorsal sural SNAP were determined. RESULTS: The dorsal sural SNAP could not be elicited in 26 % of referents. Axonal polyneuropathy was confirmed by an abnormally low value of the sural or superficial peroneal SNAP or SRAR in 70 % of patients, and most often (68 %) by an absent sural or superficial peroneal SNAP. In 9 % of patients there was a normal sural but abnormal superficial peroneal SNAP, and 11 % had an abnormal sural but normal superficial peroneal SNAP. ROC curve analysis demonstrated equal accuracy of the sural and superficial peroneal SNAP. CONCLUSIONS: To confirm distal axonal polyneuropathy in routine clinical practice the sural and superficial peroneal SNAP had equal and complementary yield, whereas the SRAR and dorsal sural SNAP had limited additional yield.

Interpretation of electrodiagnostic findings in sporadic progressive muscular atrophy.

OBJECTIVE: We present the electrophysiologic data at baseline of 37 patients who were included in our prospective study on sporadic adult-onset progressive muscular atrophy (PMA). The aim was to correlate electrophysiological signs of lower motor neuron (LMN) loss with clinical signs of LMN loss, and to determine the prognostic value of the distribution of electrophysiological abnormalities in patients who presented clinically with only lower motor neuron signs. METHODS: Thirty-seven patients, who met our inclusion criteria for a prospective study on sporadic adult-onset PMA, underwent extensive standardized electrophysiological examination at baseline, consisting of concentric needle EMG in three regions (cervical, thoracic and lumbosacral) and standardized nerve conduction studies. RESULTS: Denervation on needle EMG was found in 88 % of clinically affected and in 40 % of clinically unaffected limb regions. All patients with a segmental or distal phenotype at baseline who developed generalized weakness had denervation in the thoracic region. Motor nerve conduction abnormalities were found in a substantial number of nerves and included reduced CMAP amplitude, increased distal motor latency, decreased motor conduction velocity, and F-wave abnormalities. Signs of demyelination and sensory nerve conduction abnormalities were rare. CONCLUSIONS: Our electrophysiological data in patients recently diagnosed with sporadic progressive muscular atrophy are consistent with widespread LMN loss. Progression in patients with a segmental or distal onset of PMA may be likely if denervation is found in clinically unaffected regions, including the thoracic region.

Electrophysiology in demyelinating polyneuropathies.

Demyelinating neuropathies are disorders of the peripheral nervous system in which the myelin sheath of axons is affected by immune-mediated or genetically determined processes. In single axons, demyelination yields conduction block due to extinction of action potentials or conduction slowing. Motor nerve conduction studies assess these phenomena in nerves, which consist of many axons. It is important to distinguish demyelinating from axonal polyneuropathies as this allows accurate diagnosis and institution of appropriate treatment. Immunological treatment in acquired demyelinating polyneuropathies is often successful. Criteria were developed for motor conduction velocity slowing and for conduction block, which assume demyelination if the findings cannot be explained by axon loss. Criteria-sets for the diagnosis of specific polyneuropathies require that several variables are consistent with demyelination in several nerves. However, these sets are based on expert opinion and have a low sensitivity such that treatable neuropathies may be underdiagnosed. Evidence-based sets are currently being developed. Axon loss is the main determinant of the clinical deficit in demyelinating neuropathies and, if its mechanisms are further elucidated, it may be prevented by pharmacological treatment. Excitability testing, which assesses axonal membrane potential and ion-channel activities, may reveal some of these mechanisms.

Intermittent cyclophosphamide with prednisone versus placebo for polyneuropathy with IgM monoclonal gammopathy.

BACKGROUND: The best treatment for polyneuropathy associated with IgM monoclonal gammopathy (MGUS) is unknown. Oral cyclophosphamide combined with prednisone showed limited efficacy in a previous open label pilot study. We therefore performed a double-blind, randomized, placebo-controlled study of combined oral cyclophosphamide and prednisone in IgM MGUS polyneuropathy. METHODS: Thirty-five patients with progressive IgM MGUS polyneuropathy were included. After stratification for anti-MAG antibodies patients were randomized to oral cyclophosphamide 500 mg once daily for 4 days combined with oral prednisone 60 mg once daily for 5 days (treatment) (n = 16), or placebo (n = 19), repeated every 28 days for six times. Primary outcome was improvement of the Rivermead Mobility Index (RMI). Secondary outcomes were improvement of the modified Rankin scale, Medical Research Council and sensory sum scores, levels of M protein, EMG, and Short Form-36 scale after treatment. Patients were examined at 0, 6, 12, 18, and 24 months. RESULTS: After 6 months of treatment and at later follow-up, no difference in change of the RMI between the two groups was observed. Change of the Rankin scale was similar in both groups. Other outcome parameters showed more improvement in the treatment group: the MRC sum score improved more from 6 to 24 months after treatment; the sensory sum score improved more at 6 months; the SF 36 mean health change score and physical role score improved more; and the median nerve distal conduction (abductor pollicis brevis muscle) improved more in the treatment group. The most common adverse event was nausea. CONCLUSIONS: Compared with placebo treatment, this first double-blind randomized trial with cyclophosphamide and prednisone in IgM MGUS polyneuropathy showed no beneficial effect on the functional scales, but a beneficial effect on muscle strength and sensation was observed.

Neurologic and hematologic response to fludarabine treatment in IgM MGUS polyneuropathy.

We studied the efficacy of fludarabine in 16 patients with immunoglobulin M monoclonal gammopathy of unknown significance polyneuropathy in a prospective uncontrolled trial. The modified Rankin scale improved in 5/16 patients, all of whom had a demyelinating polyneuropathy. The motor conduction velocity improved by more than 10% in two or more nerves for four of five of these patients. Hematologic response in bone marrow occurred in three of five of these patients, whereas two of five already had small polyclonal B cell populations. There were no serious side effects.

Criteria for conduction block based on computer simulation studies of nerve conduction with human data obtained in the forearm segment of the median nerve.

The finding of conduction block (CB) on nerve conduction studies supports the diagnosis of potentially treatable immune-mediated neuropathies. CB in a number of axons may result in reduction of the compound muscle action potential (CMAP) on proximal versus distal stimulation (decrement). Decrement may also result from increased temporal dispersion (TD) as this leads to desynchronization and phase cancellation of the motor unit action potentials (MUAPs) out of which the CMAP is built up; polyphasia of MUAPs possibly yields additional decrement. To prove the occurrence of CB, decrement has to be larger than can be explained by increased TD or increased phase cancellation. This was established previously by simulations using MUAPs recorded in rats assuming maximal TD. Unfortunately, criteria based on human data and criteria for nerves with limited TD are not available. In the present study, criteria for CB were derived using simulations with thenar surface recorded MUAPs affected by collateral reinnervation that were obtained in patients with lower motor neurone disease (LMND). The effect of TD on decrement was determined for a wide range of TDs in the forearm segment of the median nerve and the segment distal to this. Our criteria for CB were based on area decrement because this was less influenced by TD and more by CB than amplitude decrement. The maximal area decrement in the forearm segment increased as TD in the forearm segment increased but decreased as TD in the distal segment increased. This suggests that, when desynchronization and phase cancellation occur in the distal segment due to TD, less phase cancellation and, therefore, less decrement can occur due to TD in the forearm. The finding that duration prolongation on proximal versus distal stimulation reflected TD within the forearm segment and that distal duration reflected TD in the distal segment allowed proposal of a more flexible set of criteria for forearm segments when TD in the forearm segment is limited or TD in the distal segment is pronounced. A separate investigation showed that the maximal TD in chronic inflammatory demyelinating polyneuropathy was within the range of our simulations, indicating that these were realistic. Our criteria were validated retrospectively in patients with multifocal motor neuropathy and patients with LMND. In the forearm segment of the median nerve, our criteria were more sensitive and equally specific for CB as compared with criteria for CB based on the study using rats. Our criteria have to be evaluated prospectively.

The role of quantitative electromyography (EMG) in horses suspected of acute and chronic grass sickness.

REASONS FOR PERFORMING THE STUDY: Clinical evidence of motor neuron involvement in equine grass sickness (EGS) has not been reported. HYPOTHESIS: Quantitative electromyography (EMG) analysis can elucidate subtle changes of the lower motor neuron system present in horses with EGS, performed ante mortem. METHODS: Fourteen horses diagnosed clinically with acute, subacute or chronic EGS were examined and quantitative EMG performed. Previously published data on healthy horses and horses with proven lower motor neuron disease (LMND) were used as controls. In 8 horses post mortem examination was performed, and in 7 muscle biopsies of the lateral vastus muscle underwent histopathology and morphometry. RESULTS: Clinical electrophysiological evidence of neuropathy was present in 12 horses. Analysis of data from the first 4 horses resulted in 95% confidence intervals (CI) of nontransformed data for motor unit action potential (MUP) duration in subclavian, triceps and lateral vastus muscle of 11.0-13.7, 14.8-20.3 and 12.2-17.2 msecs, respectively, and for MUP amplitude 291-453, 1026-1892 and 957-1736 microV, respectively. For number of phases the 95% CI was 3.6-4.4, 2.9-3.6 and 2.9-3.4, respectively, and for number of turns 5.0-6.5, 4.3-5.3 and 3.7-4.6, respectively. No changes in duration of insertional activity were measured. Pathological spontaneous activity was observed in all horses. EGS as evidenced by degenerative changes in the autonomic ganglia in combination with minor degenerative changes of the spinal lower motor neurons was observed on post mortem examination in all 8 available autopsies. In muscle biopsies of 4 out of 7 horses changes consistent with slight neurogenic atrophy were found. CONCLUSIONS AND POTENTIAL RELEVANCE: EMG results demonstrated the presence of a neuropathy of skeletal muscles in all horses suspected to have EGS. The combination of clinical and electrophysiological evidence may aid differential diagnosis of neurogenic disease in cases of weight loss and colic.

Axon loss is an important determinant of weakness in multifocal motor neuropathy.

BACKGROUND: Multifocal motor neuropathy (MMN) is characterised by asymmetrical weakness and muscle atrophy, in the arms more than the legs, without sensory loss. Despite a beneficial response to treatment with intravenous immunoglobulins (IVIg), weakness is slowly progressive. Histopathological studies in MMN revealed features of demyelination and axon loss. It is unknown to what extent demyelination and axon loss contribute to weakness. Unlike demyelination, axon loss has not been studied systematically in MMN. Aims/ METHODS: To assess the independent determinants of weakness in MMN, 20 patients with MMN on IVIg treatment were investigated. Using a standardised examination in each patient, muscle strength was determined in 10 muscles. In the innervating nerve of each muscle, axon loss was assessed by concentric needle electromyography, and conduction block or demyelinative slowing by motor nerve conduction studies. Multivariate analysis was used to assess independent determinants of weakness. RESULTS: Needle electromyography abnormalities compatible with axon loss were found in 61% of all muscles. Axon loss, and not conduction block or demyelinative slowing, was the most significant independent determinant of weakness in corresponding muscles. Furthermore, axon loss and conduction block were independently associated with each other. CONCLUSION: Axon loss occurs frequently in MMN and pathogenic mechanisms leading to axonal degeneration may play an important role in the outcome of the neurological deficit in patients with MMN. Therapeutic strategies aimed at prevention and reduction of axon loss, such as early initiation of treatment or additional (neuroprotective) agents, should be considered in the treatment of patients with MMN.

Feasibility and cost efficiency of a diagnostic guideline for chronic polyneuropathy: a prospective implementation study.

BACKGROUND: Extensive investigations are often performed to reveal the cause of chronic polyneuropathy. It is not known whether a restrictive diagnostic guideline improves cost efficiency without loss of diagnostic reliability. METHODS: In a prospective multicentre study, a comparison was made between the workup in patients with chronic polyneuropathy before and after guideline implementation. RESULTS: Three hundred and ten patients were included: 173 before and 137 after guideline implementation. In all patients, the diagnosis would remain the same if the workup was limited to the investigations in the guideline. After guideline implementation, the time to reach a diagnosis decreased by two weeks. There was a reduction of 33% in the number and costs of routine laboratory investigations/patient, and a reduction of 27% in the total number of laboratory tests/patient, despite low guideline adherence. CONCLUSION: The implementation of a diagnostic guideline for chronic polyneuropathy can reduce diagnostic delay and the number and costs of investigations for each patient without loss of diagnostic reliability. Continuous evaluation strategies after guideline implementation may improve guideline adherence and cost efficiency.

Ultrasonography shows extensive nerve enlargements in multifocal motor neuropathy.

Using ultrasonography we found multiple sites with nerve enlargement along the course of the brachial plexus, median, ulnar, and radial nerves in the majority of 21 patients with multifocal motor neuropathy. Sonography and electrophysiologic studies showed more abnormalities than expected on purely clinical grounds. Moreover, sonography revealed nerve enlargement without clinical or electrophysiologic abnormalities.

Identification and characterisation of two runx2 homologues in zebrafish with different expression patterns.

Genome and gene duplications are considered to be the impetus to generate new genes, as the presence of multiple copies of a gene allows for paralogues to adopt novel function. After at least two rounds of genome/gene duplication, the Runt gene family consists of three members in vertebrates, instead of one in invertebrates. One of the family members, Runx2, plays a key role in the development of bone, a tissue that first occurs in vertebrates. The family has thus gained new gene function in the course of evolution. Two Runx2 genes were cloned in the vertebrate model system the zebrafish (Danio rerio). The expression patterns of the two genes differ and their kinetics differ up to four fold. In addition, splice forms exist that are novel when compared with mammals. Together, these findings comprise opportunities for selection and retention of the paralogues towards divergent and possibly new function.

Primary lateral sclerosis as a phenotypic manifestation of familial ALS.

Primary lateral sclerosis (PLS) is a diagnosis of exclusion in patients with progressive spinobulbar spasticity and could be part of the clinical spectrum of ALS. Unlike ALS, which is familial in 5 to 10% of the cases, PLS has been described as a sporadic disorder in adults. The authors report two patients with PLS from unrelated SOD1-negative familial ALS families. These observations provide further evidence that PLS can be linked pathophysiologically to ALS.