Herbert Schreiber

Cognitive function in bulbar- and spinal-onset amyotrophic lateral sclerosis. A longitudinal study in 52 patients.

AbstractWe performed a longitudinal study of frontal and temporal lobe functions in patients with amyotrophic lateral sclerosis (ALS) and compared the evolution of cognitive performance with that of motor deficits in patients with spinal and bulbar–onset of the disease. Fifty two patients suffering from sporadic ALS according to the El Escorial criteria were examined; 37 patients had a spinal, 15 a bulbar onset of the disease. The data profile included examinations at entry (E1), every four months at follow–up (E2, E3, E4) and after 18 months (E5), if possible. Neuropsychological testing covered the domains of executive functions, memory and attentional control. ALS patients showed executive dysfunctions that were most prominently represented by deficits of non–verbal and verbal fluency and concept formation. Memory–related deficits were also present but less expressed. The same held true for phasic and tonic alertness and divided attention. In contrast to motor functions declining concomitantly with disease progression, cognitive deficits appeared in early disease, were essentially present at initial testing and did not substantially decline on follow–up. A subgroup analysis revealed that bulbar–onset ALS patients performed consistently poorer in many cognitive tests than spinalonset ones with special reference to verbal and non–verbal fluency and interference control. This subgroup difference persisted or even increased throughout follow–up. We conclude that there is a fronto–temporal pattern of cognitive dysfunction in ALS expressing itself early in the course of the disease and mainly with bulbar forms. The cognitive deficits do not progress in synchrony with motor decline, but distinctly more slowly. We suggest that cognitive dysfunctions reflect functional and possibly morphological deficits outside the primary motor system that is specific for the nature and evolution of the disease and might also give clues to etiopathogenesis.

Cognitive function in bulbar– and spinal–onset amyotrophic lateral sclerosis

AbstractWe performed a longitudinal study of frontal and temporal lobe functions in patients with amyotrophic lateral sclerosis (ALS) and compared the evolution of cognitive performance with that of motor deficits in patients with spinal and bulbar–onset of the disease. Fifty two patients suffering from sporadic ALS according to the El Escorial criteria were examined; 37 patients had a spinal, 15 a bulbar onset of the disease. The data profile included examinations at entry (E1), every four months at follow–up (E2, E3, E4) and after 18 months (E5), if possible. Neuropsychological testing covered the domains of executive functions, memory and attentional control. ALS patients showed executive dysfunctions that were most prominently represented by deficits of non–verbal and verbal fluency and concept formation. Memory–related deficits were also present but less expressed. The same held true for phasic and tonic alertness and divided attention. In contrast to motor functions declining concomitantly with disease progression, cognitive deficits appeared in early disease, were essentially present at initial testing and did not substantially decline on follow–up. A subgroup analysis revealed that bulbar–onset ALS patients performed consistently poorer in many cognitive tests than spinalonset ones with special reference to verbal and non–verbal fluency and interference control. This subgroup difference persisted or even increased throughout follow–up. We conclude that there is a fronto–temporal pattern of cognitive dysfunction in ALS expressing itself early in the course of the disease and mainly with bulbar forms. The cognitive deficits do not progress in synchrony with motor decline, but distinctly more slowly. We suggest that cognitive dysfunctions reflect functional and possibly morphological deficits outside the primary motor system that is specific for the nature and evolution of the disease and might also give clues to etiopathogenesis.

Event-related potential correlates of impaired selective attention in children at high risk for schizophrenia

Auditory event-related potentials (ERPs) associated with selective attention were recorded in 21 children at high-risk for schizophrenia and in 21 matched controls. The subjects performed a selective listening task. For behavioral evaluation, target counts on the selective listening task and on cognitive performance were assessed. Group-specific differences of ERP components could be demonstrated, as reflected by significant amplitude reductions of the frontally located negative difference wave (Nd) and of the P3 component, following selectively attended stimuli, in the high-risk children. P3 latencies tended to be prolonged in the high-risk group. Reduced Nd was found in 14 and reduced P3 in 16 high-risk children among the 21 matched pairs. Significant correlations between the ERP reductions and psychometric deficit (counting accuracy) were observed. Mismatch negativity (MMN), an ERP component associated with automatic processing of physically deviant stimuli, did not differentiate significantly between groups, but was distinctly reduced in the high-risk group. The Nd and P3 reductions suggest deficits of selective attention in a considerable number of the subjects genetically at risk for schizophrenia. The present findings are discussed with respect to their relevance as indicators of a predisposition to schizophrenia.

Longitudinal effects of noninvasive positive-pressure ventilation in patients with amyotrophic lateral sclerosis

Butz M, Wollinsky KH, Wiedemuth-Catrinescu U, Sperfeld A, Winter S, Mehrkens HH, Ludolph AC, Schreiber H: Longitudinal effects of noninvasive positive-pressure ventilation in patients with amyotrophic lateral sclerosis. Am J Phys Med Rehabil 2003;82:597–604. ObjectiveTo evaluate the duration of benefit on symptoms, quality of life, and survival derived from the use of noninvasive positive-pressure ventilation by patients with amyotrophic lateral sclerosis. DesignIn this prospective, cohort study, 30 of 36 consecutively referred symptomatic patients tolerated nightly noninvasive positive-pressure ventilation and undertook pulmonary function testing and 12 symptom and quality-of-life instruments concerning sleep quality, daytime sleepiness, physical fatigue, mental fatigue, and depression that were administered during a 10-mo period. ResultsWith treatment, there was a significant improvement in the majority of patients in sleep quality, daytime sleepiness, physical fatigue, and depression; however, significant improvements lasted for up to 10 mo only in sleep quality. Partial pressure of arterial oxygen, partial pressure of arterial carbon dioxide, and oxyhemoglobin saturation remained stable or even improved for up to 7 mo during use of part-time noninvasive positive-pressure ventilation. A total of 14 patients had survival prolonged by continuous dependence on noninvasive positive-pressure ventilation. ConclusionsNoninvasive positive-pressure ventilation provides a long-lasting benefit on symptoms and quality of life indicators for amyotrophic lateral sclerosis patients and should be offered to all patients with symptoms of sleep disordered breathing or inspiratory muscle dysfunction. It can also prolong tracheostomy-free survival.

Variable reduction of caveolin-3 in patients with LGMD2B/MM

Abstract.Mutations in the human dysferlin gene (DYSF) cause autosomal recessive muscular dystrophies characterized by degeneration and weakness of proximal and/or distal muscles: limb girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy (MM). Recently, an interaction between caveolin-3 and dysferlin in normal and dystrophic muscle (primary caveolin-3 deficiency; LGMD1C) was shown. In this study, clinical,morphological and genetic analysis was carried out in four independent LGMD2B/MM patients. All patients presented with an adult-onset, slowly progressive muscular dystrophy with variable involvement of proximal and distal muscles. We found complete lack of dysferlin in the four LGMD2B/MM patients. Secondary reduction of caveolin-3 was detected in three out of the four patients. Regular caveolae were detected along the basal lamina in two patients by electron microscopy. We provide further evidence that dysferlin and caveolin-3 interact in human skeletal muscle. It remains to be elucidated whether the loss of this interaction contributes to pathogenic events in muscular dystrophy.

Muscle MRI findings in limb girdle muscular dystrophy type 2L

Limb girdle muscular dystrophy type 2L (LGMD2L) is an adult-onset slowly progressive muscular dystrophy associated with recessive mutations in the ANO5 gene. We analysed the muscle MRI pattern in a cohort of 25 LGMD2L patients in order to understand the extent and progression of muscle pathology in LGM2L and assess if muscle MRI might help in the diagnostic work-up of these patients. Our results showed a homogeneous pattern of muscle pathology on muscle MRI, with a predominant involvement of the posterior compartment muscles in both the thighs and calves. The muscles of the anterior compartments in the leg together with the sartorius and gracilis muscles were best preserved, which partially overlaps with patterns observed for other recessive LGMDs. Muscle MRI therefore does not appear to be as useful in the diagnostic work up of LGMD2L as for other neuromuscular diseases, such as Bethlem myopathy or myofibrillar myopathy.

Endogenous event-related brain potentials and psychometric performance in children at risk for schizophrenia.

Two independent groups of high-risk children for schizophrenia and their matched control children were submitted to the following experiments: an auditory oddball paradigm registrating late event-related potentials (ERPs) and a psychometric test battery including the assessment of Wechsler Intelligence Scales, reaction times (after regular and irregular preparatory intervals), and the d2-attention test. The study was intended to clarify whether long-latency ERPs and the selected psychometric tests would contribute to reliably differentiating between these groups. The results showed significantly prolonged latencies of the P3 component of the ERPs to rare, task-relevant target stimuli in both high-risk groups compared with the controls. Similarly, the N2 latencies were delayed in both groups. By contrast, ERP patterns to frequent, nontask-relevant stimuli were very similar, with no significant differences between high-risks and normals; nor did any ERP amplitudes show significant differences. The data are interpreted as a reflection of a subtle deficit in maintaining attention and a subsequent impairment of stimulus discrimination in high-risk children. This is consistent with the psychometric findings of higher error scores in target counts and d2-test, and significantly prolonged reaction times after regular preparatory intervals (PIs) in the high-risks. The findings may hint at a vulnerability for schizophrenia in high-risk children. Given the high prevalence of the attentional dysfunctions in both high-risk groups, however, it is hypothesized their presence does not necessarily imply an unequivocal manifestation of schizophrenia.

ANO5 gene analysis in a large cohort of patients with anoctaminopathy: confirmation of male prevalence and high occurrence of the common exon 5 gene mutation

Limb girdle muscular dystrophy type 2L or anoctaminopathy is a condition mainly characterized by adult onset proximal lower limb muscular weakness and raised CK values, due to recessive ANO5 gene mutations. An exon 5 founder mutation (c.191dupA) has been identified in most of the British and German LGMD2L patients so far reported. We aimed to further investigate the prevalence and spectrum of ANO5 gene mutations and related clinical phenotypes, by screening 205 undiagnosed patients referred to our molecular service with a clinical suspicion of anoctaminopathy. A total of 42 unrelated patients had two ANO5 mutations (21%), whereas 14 carried a single change. We identified 34 pathogenic changes, 15 of which are novel. The c.191dupA mutation represents 61% of mutated alleles and appears to be less prevalent in non‐Northern European populations. Retrospective clinical analysis corroborates the prevalently proximal lower limb phenotype, the male predominance and absence of major cardiac or respiratory involvement. Identification of cases with isolated hyperCKaemia and very late symptomatic male and female subjects confirms the extension of the phenotypic spectrum of the disease. Anoctaminopathy appears to be one of the most common adult muscular dystrophies in Northern Europe, with a prevalence of about 20%–25% in unselected undiagnosed cases.

Signs of impaired selective attention in patients with amyotrophic lateral sclerosis

The evidence for involvement of extramotor cortical areas in non-demented patients with amyotrophic lateral sclerosis (ALS) has been provided by recent neuropsychological and functional brain imaging studies. The aim of this study was to investigate possible alterations in selective attention, as an important constituent part of frontal brain function in ALS patients. A classical dichotic listening task paradigm was employed to assess event-related EEG potential (ERPs) indicators of selective attention as well as preattentive processing of mismatch, without interference by motor impairment.A total of 20 patients with sporadic ALS according to the revised El Escorial criteria and 20 healthy controls were studied. Additionally a neuropsychological test battery of frontotemporal functions was applied.Compared with the controls, the ALS patients showed a distinct decrease of the fronto-precentral negative difference wave (Nd), i.e., the main ERP indicator of selective attention. Analysis of the P3 component of the ERPs indicated an increased processing of non-relevant stimuli in ALS patients confirming a reduced focus of attention. We conclude impaired selective attention reflects a subtle variant of frontotemporal dementia frequently observed in ALS patients at a relatively early stage of the disease.

Comparative assessment of saccadic eye movements, psychomotor and cognitive performance in schizophrenics, their first-degree relatives and control subjects

This study is aimed at detecting biological markers for schizophrenia. For this purpose, a total of 70 subjects (21 schizophrenic patients, 27 first‐degree relatives and 22 controls) performed a series of tests assessing various attentional, psychomotor and cognitive functions and saccadic eye movements. The schizophrenics performed significantly poorer than both high‐risk and control subjects in most of the tests demanding attention, concentration and psychomotor speed (d2 concentration test, reaction times and Stroop test of perceptual interference) as well as cognition (Wechsler intelligence scales). On the other hand, these tests did not differentiate between the high‐risk and control subjects. This distinction, however, could be made by two other parameters: hypometria score of saccadic eye movements and ratio of verbal to performance intelligence scores. Both parameters were significantly increased in both the schizophrenic and the high‐risk group, distinguishing both from the control group. The relevance of these findings in indicating a schizophrenic disposition is discussed.