A neuropsychological investigation of dementia in motor neurone disease (MND)

Different clinical criteria for diagnosing dementia were compared in a sample of 69 patients with motor neurone disease (MND). Participants’ performances on a computerised battery of neuropsychological tests were evaluated to assess the usefulness of these tests in predicting dementia in MND. The results indicated that when diagnostic criteria for frontotemporal (FTD) were used as part of a questionnaire method of diagnosing dementia the incidence of dementia in MND was considerably greater than traditional estimates suggest. Through a series of logistic and multiple regressions the results demonstrated that neuropsychological test performance related well to diagnostic classifications of dementia. MND patients with a clinical diagnosis of dementia were likely to demonstrate impaired new learning; poor working memory and planning; slowness in information processing and rigidity in thinking. These features, which are typical of cases of FTD, suggest that the dementia of MND is usefully characterised as a form of FTD. The finding that neuropsychological impairment correlated with behavioural features of dysexecutive impairment in daily living, indicates that the management focus in MND must be broadened to include cognitive/behavioural issues.     

Development of a patient-specific dyspnoea questionnaire in motor neurone disease (MND): the MND dyspnoea rating scale (MDRS)

Motor neurone disease (MND) is a progressive, unremitting and fatal disease. Respiratory dysfunction is common and a significant cause of morbidity. The relationship between subjective dyspnoea and objective measures of lung function have been unexplored in MND. Increasing interest in the specific treatment of respiratory symptoms in MND has highlighted the need for simple, reliable and valid measures to quantify the degree of dyspnoea in this condition. Several generic questionnaires have been developed to rate subjective breathlessness but are inappropriate for use in MND patients as they often assess dyspnoea by exercise-limitation. As yet, there are no published disease-specific measures to assess dyspnoea in MND. In order to accurately and reproducibly measure the subjective experience of dyspnoea in this patient group, we have developed and validated a novel patient-specific dyspnoea questionnaire, the MND dyspnoea rating scale (MDRS). It comprises three domains covering dyspnoea, emotion and mastery and is valid for use in MND patients at all stages of disease progression. In our cohort of 40 unselected patients with MND we have shown that the patients subjective experience of dyspnoea is closely related to emotion and psychological control over the disease. Dyspnoea is not related to objective measures of lung function such as vital capacity, irrespective of limb or bulbar presentation. In conclusion, vital capacity, although useful prognostically, is only one aspect of respiratory function in MND. The MDRS is a reliable and valid tool to rate subjective dyspnoea in MND.     

Cognitive change in motor neurone disease/amyotrophic lateral sclerosis (MND/ALS)

A motor neuronopathy complicating frontotemporal dementia (FTD) has been recognised and designated FTD/motor neurone disease (MND). FTD is characterised by profound character change and altered social conduct, and executive deficits, reflecting focal degeneration of the frontal and temporal neocortex. The motor neuronopathy comprises bulbar palsy and limb amyotrophy. The major histological change is typically of microvacuolation of the cerebral cortex, with atrophy of the bulbar neurones and anterior horn cells of the spinal cord. Ubiquitinated inclusion bodies occur in large pyramidal cortical neurones and in surviving cranial nerve nuclei and anterior horn cells. Evidence is emerging that some patients with classical MND/amyotrophic lateral sclerosis (ALS), who are thought not to be demented, develop cognitive deficits in the realm of frontal executive functions. Moreover, frontal lobe abnormalities have been demonstrated by neuroimaging. The findings point to a link between FTD/MND and cMND/ALS and suggest that a proportion of patients with cMND/ALS go on to develop FTD. Patients with cMND/ALS may not be equally vulnerable. The hypothesis is that patients who present with bulbar palsy and amyotrophy, rather than corticospinal and corticobulbar features, may be most susceptible to the development of FTD.     

Spontaneous lower motor neuron disease in rabbits (Oryctolagus cuniculus)

Summary Spontaneous neurologic disease was observed in 6 to 8-week-old rabbits. Both males and females from several different litters were affected but all were sired by the same male. Clinically, the disease was characterized initially by posterior weakness and incoordination which progressed to tetraplegia within 3–4 weeks. With light microscopy there was neuronal degeneration and loss within the ventral horns of the spinal cord and brain stem and type-II fiber atrophy of skeletal muscles. Ultrastructurally the neuronal degeneration was charactered by accumulations of 100 Å neurofilaments within the perikaryon. These findings are compared to diseases with neurofibrillary accumulation in animals and man.This work was supported in part by NIH grant RR00685-05 and by the Scott-Ritchy Research Fund of Auburn University     

Central motor conduction in motor neuron disease

Central motor conduction was assessed in 13 patients with motor neuron disease and in 15 control subjects. All patients with motor neuron disease, even those without clinical pyramidal signs, had slowed central motor conduction, and in some the delays were asymmetrical. Evoked motor potentials represent a new and reliable method to detect physiological abnormalities of central motor pathways early in the course of motor neuron disease.     

Voluntary activation and fiber density of fasciculations in motor neuron disease.

Two hundred voluntarily activated motor units and 211 fasciculations were recorded in the biceps of 10 patients with motor neuron disease with the Macro EMG technique. Twenty-two fasciculations, in nine of 10 muscles, had a potential of closely similar shape, amplitude, and area to that of a voluntary unit. Fasciculating units that could not be activated voluntarily had a higher mean number of spikes in their triggering single fiber potentials than units that could only be activated voluntarily, but statistically similar Macro EMG parameters. The mean number of single fiber spikes, and Macro EMG parameters, of fasciculations activated voluntarily, were similar to those of units that were only activated voluntarily. A positive correlation between fiber density and Macro EMG median amplitude and area in individual patients, and between number of single fiber spikes and Macro EMG amplitudes and areas in the pooled data, was found for fasciculations but not for voluntary units. At least 10% of fasciculations in patients with motor neuron disease may originate near or above the point of axonal branching and a proportion of those without evidence of voluntary activation may have a higher number of smaller muscle fibers, or more closely packed muscle fibers, of similar or greater size, than voluntarily activated motor units. Differences in the peripheral microanatomy of a number of fasciculation units not activated voluntarily may underlie ectopic impulse generation in the terminal axonal arborization, endplate zone, or muscle fibers of these units.     

Flaviviruses in motor neuron disease

Sporadic motor neuron disease (MND) causes a progressive loss of motor neurons. West Nile virus can attack motor neurons, so we examined whether flavivirus infection could be detected in MND cases. Spinal cord sections from 22 MND cases were stained immunohistochemically with a flavivirus-specific antibody. No staining for flavivirus was seen in any case. Sporadic MND does not appear to arise from a recent infection with a flavivirus.     

Ocular motor function in motor neuron disease.

We studied ocular motor function in 34 patients with motor neuron disease (MND) and in 18 age-matched controls. This included the latency, accuracy, and amplitude-velocity relationships of saccades. We also examined ocular pursuit, the slow phases of optokinetic nystagmus, and the ability to suppress the vestibulo-ocular reflex (VOR) with visual fixation of a head-mounted target. Five of the subjects with MND had pronounced parkinsonian features on neurologic examination. The nonparkinsonian MND subjects had normal ocular motor function for all measures. Most subjects suppressed the VOR completely. The parkinsonian-MND patients had impairment of both saccadic and pursuit eye movements, and one parkinsonian-MND patient with poor pursuit was unable to suppress the VOR. We conclude that ocular motor function is generally spared in MND. The occasional appearance of ocular motor dysfunction probably reflects the incidence of secondary abnormalities such as parkinsonism.     

Central motor conduction in cerebrovascular disease and motor neuron disease

Conduction in the central motor pathways was studied in 9 patients with cerebrovascular disease (CVD), 13 with amyotrophic lateral sclerosis (ALS) and 3 with spinal progressive muscular atrophy (SPMA). Motor responses evoked in the limb by cortical, cervical and lumbar stimulations were recorded. The central conduction time (CCT) was calculated for each muscle. In patients with CVD, responses to cortical stimulation were unobtainable or delayed in the paretic limb muscles. In patients with ALS the abnormality of central motor conduction had significant correlation with the extensor plantar response. The CCTs were normal in patients with SPMA. This technique demonstrated a subclinical lesion in some patients. We conclude that the new technique of examining motor conduction along the corticospinal tract may be useful to detect a subclinical lesion in the corticospinal tract.     

Clinically undetected motor neuron disease in pathologically proven frontotemporal lobar degeneration with motor neuron disease

BACKGROUND: Frontotemporal lobar degeneration with motor neuron disease (FTLD-MND) is a pathological entity characterized by motor neuron degeneration and frontotemporal lobar degeneration. The ability to detect the clinical signs of dementia and motor neuron disease in pathologically confirmed FTLD-MND has not been assessed. OBJECTIVES: To determine if all cases of pathologically confirmed FTLD-MND have clinical evidence of frontotemporal dementia and motor neuron disease, and to determine the possible reasons for misdiagnosis. METHOD: Review of historical records and semiquantitative analysis of the motor and extramotor pathological findings of all cases of pathologically confirmed FTLD-MND. RESULTS: From a total of 17 cases of pathologically confirmed FTLD-MND, all had clinical evidence of frontotemporal dementia, while only 10 (59%) had clinical evidence of motor neuron disease. Semiquantitative analysis of motor and extramotor pathological findings revealed a spectrum of pathological changes underlying FTLD-MND. Hippocampal sclerosis, predominantly of the subiculum, was a significantly more frequent occurrence in the cases without clinical evidence of motor neuron disease (P<.01). In addition, neuronal loss, gliosis, and corticospinal tract degeneration were less severe in the other 3 cases without clinical evidence of motor neuron disease. CONCLUSIONS: Clinical diagnostic sensitivity for the elements of FTLD-MND is modest and may be affected by the fact that FTLD-MND represents a spectrum of pathological findings, rather than a single homogeneous entity. Detection of signs of clinical motor neuron disease is also difficult when motor neuron degeneration is mild and in patients with hippocampal sclerosis.     

运动神经元病血清特异抗原成分的检测

目的检测运动神经元病（ＭＮＤ）病人血清中是否存在运动神经元特异抗原成分，并探索ＭＮＤ潜在的诊断标志物。方法制备５株抗运动神经元单克隆抗体，并证明其对大鼠脊髓前角运动神经元具有高度特异的免疫组织化学反应。应用抗运动神经元单克隆抗体２４Ｂ０－ＭｃＡｂ，用ＥＬＩＳＡ法对２５例运动神经元病病人血清中的特异抗原成分进行检测。根据临床表现将２５例病人分为肌萎缩侧索硬化（ＡＬＳ）、脊肌萎缩症（ＳＭＡ）及进行性球麻痹（ＰＢＰ）３组，再按年龄段分３个亚组（＜２０岁组、２０～３９岁组、＞４０岁组）。结果发现８５％（２２／２５）临床确诊的ＭＮＤ病人存在较高浓度的特异抗原成分，ＭＮＤ病人与正常对照组对２４Ｂ０－ＭｃＡｂ的反应性差异有显著性意义（Ｐ＜０．０５），ＡＬＳ、ＳＭＡ及ＰＢＰ亚型之间差异也有显著性意义（Ｐ＜０．０５），而年龄组之间差异虽有显著性意义，其临床意义尚需进一步研究。性别组之间的差异无显著性意义。结论ＭＮＤ病人血清中存在运动神经元特异抗原成分。用抗运动神经元单克隆抗体以ＥＬＩＳＡ法检测运动神经元特异抗原可以作为诊断ＭＮＤ的辅助检查。     

New insights in motor neuron disease

In motor neuron disease there is a characteristic pattern of nerve cell loss and degeneration of related pathways. In surviving anterior horn cells several morphologically distinct, but generally non-specific, intracytoplasmic inclusion bodies have been recognized. Recently accumulations of previously unrecognized ubiquitinated material have been described in surviving neurons, which cannot be demonstrated with routine histological methods. These changes appear unique to this disease, and provide a new insight into the underlying pathology that may help understand the pathogenesis of this intriguing disorder. In this article we review the new information on the clinical, toxicological and pathological features of the disease.     

Oculomotor abnormalities in motor neuron disease

To determine whether there are oculomotor abnormalities in motor neuron disease (MND), electrooculographic recordings were performed prospectively in 16 MND patients and the results compared with age-matched healthy controls. Parameters analysed included random and fixed saccades (latency, velocity and accuracy), smooth pursuit (gain, total harmonic distortion and number of saccadic intrusions) and optokinetic nystagmus (maximal and mean slow component velocity). Increased saccadic latencies and decreased smooth pursuit gain were the main alterations in the MND group. Correlation with clinical variables showed a positive relationship between smooth pursuit saccadic intrusions and the bulbar clinical score and the rate of progression and a lower optokinetic nystagmus maximal velocity in patients with pseudobulbar syndrome. Our results demonstrate the presence of subclinical supranuclear abnormalities in MND, and support the notion that MND is not merely a degeneration of the motor system.     

Pain in motor neuron disease.

Twenty-seven of 42 patients with motor neuron disease had significant pain. The nature and duration of the pain are described along with an illustrative case-report. The aetiology and most effective treatment of this common complication of motor neuron disease remain unclear.