The motor cortex and amyotrophic lateral sclerosis

On theoretical grounds, abnormalities of the motor cortex in patients with amyotrophic lateral sclerosis (ALS) could lead to anterograde ("dying-forward") transneuronal degeneration of the anterior horn cells as suggested by Charcot. Conversely, retrograde ("dying-back") degeneration of the corticospinal tracts could affect the motor cortex. Evidence derived from clinical, neuropathological, static, and functional imaging, and physiological studies, favors the occurrence of anterograde degeneration. It is hypothesized that transneuronal degeneration in ALS is an active excitotoxic process in which live but dysfunctional corticomotoneurons, originating in the primary motor cortex, drive the anterior horn cell into metabolic deficit. When this is marked, it will result in more rapid and widespread loss of lower motor neurons. In contrast, slow loss of corticomotoneurons, as occurs in primary lateral sclerosis (PLS), precludes excitotoxic drive and is incompatible with anterograde degeneration. Preservation of slow-conducting non-M1 direct pathways in PLS is not associated with excitotoxicity, and anterior horn cells survive for long periods of time.     

Prevalence of depression in amyotrophic lateral sclerosis and other motor disorders

Background: Research suggests the prevalence of severe depression in ALS is <20%. In contrast, studies have reported that severe depression affects 40–50% of patients with other neurodegenerative motor conditions (e.g. multiple sclerosis, Parkinson’s disease and Huntington’s disease). The comparison with such disorders has generated a clinical impression that patients with ALS have surprisingly low rates of depression. However, comparisons with such disorders do not take into account the markedly different pathological, physical and behavioural profiles associated with these disorders. To assess further the extent to which ALS is associated with a low prevalence of depression, we compared the prevalence of depression in patients with ALS to that in patients with neuromuscular disorders with more comparable disease profiles. Methods: The Beck Depression Inventory‐II (BDI‐II), the Major Depression Inventory (MDI), the Hospital Anxiety and Depression Scale (HADS) and the ALS Functional Rating Scale‐Revised were sent to 212 patients from a tertiary referral Motor Nerve Clinic in London, UK. Results: Data were obtained from 51 people with ALS and 39 with other neuromuscular disorders. The non‐ALS group included patients diagnosed with disorders that are characterized by motor neurone dysfunction and/or a decline in everyday function. Analyses revealed no between‐group differences on severity and prevalence rates of depression according to the BDI‐II, HADS Depression Subscale and MDI. Conclusions: Our findings do not support the impression that patients with ALS have lower rates of depression than patients with other varied neuromuscular disorders.     

Duration of amyotrophic lateral sclerosis is age dependent

Since 1985, we prospectively followed 246 patients with ALS. The relation ship between the age of developing neurological impairment and disease duration was analyzed in 138 patients (86 men and 52 women) who died. Mean disease duration was 4.0 ± 3.8 years for men and 3.2 ± 2.5 years for women. There was an inverse, exponential, relationship between onset age and duration (goodness-of-fit P > 0.05). Mean duration at onset age 40 years was 8.2 ± 5.0 years compared with 2.6 ± 1.4 years for patients aged 61 to 70 years (P > 0.001). The ratio of young (40 years) men to women was 3.6:1. When matched for age, disease duration was the same for patients with bulbar and nonbulbar onsets. We conclude that onset age, but no sex, is the most significant predictor determining disesae duration in ALS. Longer survival in younger patients probably reflects their greater neuronal reserve. © 1993 John Wiley & Sons, Inc.     

Riluzole and amyotrophic lateral sclerosis survival: a population-based study in southern Italy

Riluzole is to date the only treatment that prolongs amyotrophic lateral sclerosis (ALS) survival. However, results on the efficacy of riluzole in observational population‐based studies with a longer follow‐up are conflicting and it is still unclear if the effect of the drug is limited to an early stage of the disease and to some specific subgroups of patients. The objective is: (i) to evaluate the effect of riluzole on ALS survival in a cohort of incident cases; (ii) to examine whether bulbar‐ALS benefits from the medication to a greater extent and (iii) to assess the efficacy of the drug in elderly patients. Source of the study was a prospective population‐based registry of ALS established in Puglia, Southern Italy. We examined survival of 126/130 incident ALS cases diagnosed during the period 1998–1999. Seventy‐three patients were prescribed riluzole and the remaining 53 were not. Riluzole therapy increased survival rates at 12 months by approximately 10% and prolonged survival by 6 months (18.2 months vs. 12.4; peto‐test: 2.78; P = 0.09). This beneficial effect was present amongst bulbar‐onset ALS (peto‐test: 4.11; P = 0.042), but not in subjects with limb‐onset (peto‐test: 0.48; P = 0.4). In patients aged >70 years riluzole treatment was associated with an 8 months longer median survival time [15.4 months vs. 7.1] and a reduction in mortality rate at 12 months by 27%, regardless of site of symptoms onset. In multivariate analysis, riluzole use was an independent predictor of survival at 12 months from the diagnosis with borderline significance (P = 0.06). Riluzole was effective amongst cases with bulbar‐onset ALS (P = 0.04), whereas in subjects with limb‐onset there was no effect on survival at 12 months (P = 0.5). In each model riluzole did not influence survival at 24 months. Conversely, riluzole use was associated with an improvement in survival amongst elderly patients both at 12 (P = 0.07), at 24 months (P = 0.03) and in the entire follow‐up period (P < 0.04). In this population‐based series, we found that riluzole therapy improves ALS survival. The efficacy of the drug was present amongst bulbar‐onset ALS and older patients, but not in subjects with limb‐onset. The favourable effect of the drug was transient, as it was lost in prolonged follow‐up. Our observations support the use of riluzole at an early stage of ALS in bulbar and elderly patients. However, the appropriate duration of riluzole treatment remains to be established.     

Telephone follow-up for patients with amyotrophic lateral sclerosis

The relentless evolution of amyotrophic lateral sclerosis (ALS), a severe neurodegenerative disorder of the upper and lower motoneurons, leads to an increasing level of disability. Most patients, during the course of the disease, become unable to attend the tertiary clinical care center and are thus prevented from enrolling in clinical trials or benefiting from specialized care and management. The main objective of this study was to verify whether the ALS functional rating scale (ALSFRS) could be reliably administered by telephone to patients, when unable to attend the ALS clinic, or to their caregivers. ALSFRS is a validated instrument that assesses the functional status and the disease progression in ALS. We first administered the functional rating scale directly in the clinic to 30 patients, with definite or probable ALS, and to their respective caregivers, and found a very high agreement between the two groups for the total score and the majority of the rating items. Next, we showed, in both patients and caregivers, a high degree of correlation between the total score of the ALSFRS measured by telephone and that reported in the clinic. This indicates that ALSFRS is a reliable instrument for monitoring the disease progression in homebound patients, even when the person contacted by telephone is the caregiver. We also performed a telephone clinic, based on an unstructured interview, with 16 ALS patients at an advanced stage of the disease and unable to attend the ALS clinic. On some occasions, the person interviewed was the caregiver. The symptoms most frequently reported were a worsening of muscle strength, swallowing and breathing problems, constipation, and inability to clear lung secretions. Several patients asked for assistive and adaptive equipment. All patients and caregivers found the telephone clinic very useful and considered it a good complement to the management and care programme.     

Brain-computer interfaces for amyotrophic lateral sclerosis

A brain-computer interface (BCI) is a device that detects signals from the brain and transforms them into useful commands. Researchers have developed BCIs that utilize different kinds of brain signals. These different BCI systems have differing characteristics, such as the amount of training required and the degree to which they are or are not invasive. Much of the research on BCIs to date has involved healthy individuals and evaluation of classification algorithms. Some BCIs have been shown to have potential benefit for users with minimal muscular function as a result of amyotrophic lateral sclerosis. However, there are still several challenges that need to be successfully addressed before BCIs can be clinically useful.     

Cognitive impairment in amyotrophic lateral sclerosis and its relation to motor disabilities

The performance of patients with amyotrophic lateral sclerosis (ALS) on selective neuropsychological tests was examined in regard to the applicability of such examinations to diagnosis. Eighteen patients with ALS, and 15 age- and education-matched controls were given a battery of tests designed to assess motor and intellectual functions. The ALS group displayed significantly lower scores on all tests than those in the control group. Correlation analyses on the several motor and neuropsychological results in ALS group revealed that there was a significant negative correlation between upper motor symptoms and mini-mental state examination, as well as memory tests.     

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.     

Phenotypic and genotypic heterogeneity of dominantly inherited amyotrophic lateral sclerosis

Twenty-seven cases of hereditary amyotrophic lateral sclerosis (ALS), belonging to 8 families, are reported. The analysis of the pedigrees suggests an autosomal dominant transmission, apparently with incomplete penetration. The mean age at onset of symptoms was 50.3 (SD 12.4) years. The mean duration of the disease was 31.2 (SD 20.4) months, ranging from 9 to 86. The median survival time was 24 months. The degree of variation of some quantitative characters, both within and among families, was statistically analyzed. The results support the hypothesis of a phenotypic and genetic heterogeneity of autosomal dominant transmitted ALS.     

Diagnostic problems and delay of diagnosis in amyotrophic lateral sclerosis

Objective

Initial symptoms of amyotrophic lateral sclerosis (ALS) mimic several neurological syndromes that may decelerate a correct diagnosis. The aim of our study was to investigate if diagnostic and therapeutic parameters have influence on the time of diagnosis.

Methods

We retrospectively reviewed the medical records of 100 consecutive ALS patients focusing on clinical and diagnostic data, the timing of diagnosis and treatments attributed to the onset of symptoms of ALS.

Results

Among 100 consecutive patients with ALS, 12% underwent surgery due to symptoms retrospectively attributable to ALS. The comparison of duration from first symptoms to correct diagnosis showed a significant difference between operated and non-operated patients. 35% of all ALS patients had bulbar onset symptoms. The mean time from first symptoms to diagnosis was 9 months in this group. In patients without bulbar onset it was 16.4 months which also represents a significant difference. In 44% of patients other diagnoses were considered and medically treated previous to correct diagnosis, but there was no significant delay of diagnosis.

Conclusion

Our study confirms that diagnosis of ALS is still a common clinical problem and shows the need of sensitive and specific diagnostic tests.     

Golgi apparatus of the motor neurons in patients with amyotrophic lateral sclerosis and in mice models of amyotrophic lateral sclerosis

We examined the Golgi apparatus (GA) of motor neurons of patients with ALS and in mice models of ALS by immunohistological method using antiserum against MG160 and against components of the trans‐Golgi network (TGN46). The GA of half of the remaining spinal cord motor neurons of patients with sporadic ALS showed fragmentation, where the GA were dispersed or fragmented into numerous small, isolated elements. The GA of Betz cells in sporadic ALS were fragmented similar to that of anterior horn cells, and the GA of spinal cord motor neurons of those with familial ALS and of those with ALS with basophilic inclusions were fragmented or diminished. The GA in the majority of the motor neurons contained Bunina bodies, basophilic inclusions and superoxide dismutase 1 (SOD1)‐positive aggregates were fragmented. The motor neurons in transgenic mice expressing G93A mutation of the SOD1 gene showed the fragmentation of the GA months before the onset of paralysis. These findings suggest that the fragmentation of GA may be related to the neuronal degeneration in patients with ALS.     

Multimodality evoked potentials in amyotrophic lateral sclerosis

Visual, brainstem auditory and somatosensory evoked potentials to medial nerve stimulation were recorded in 27 patients affected by amyotrophic lateral sclerosis. VEP N75, P100, N140, N75-P100 latencies and P100 amplitude, BAEP I-III, III-V and I-V interpeak-latencies were within normal limits in all ALS patients. Somatosensory evoked potentials were abnormally delayed in 8 patients: in 3 arms because of a delayed N9-N13 latency, in 9 arms because of a delayed N13-N19 latency.     

Amygdala abnormalities across disease stages in patients with sporadic amyotrophic lateral sclerosis

To examine selective atrophy patterns and resting‐state functional connectivity (FC) alterations in the amygdala at different stages of amyotrophic lateral sclerosis (ALS), and to explore any correlations between amygdala abnormalities and neuropsychiatric symptoms. We used the King''s clinical staging system for ALS to divide 83 consecutive patients with ALS into comparable subgroups at different disease stages. We explored the pattern of selective amygdala subnucleus atrophy and amygdala‐based whole‐brain FC alteration in these patients and 94 healthy controls (HCs). Cognitive and emotional functions were also evaluated using a neuropsychological test battery. There were no significant differences between ALS patients at King''s stage 1 and HCs for any amygdala subnucleus volumes. Compared with HCs, ALS patients at King''s stage 2 had significantly lower left accessory basal nucleus and cortico‐amygdaloid transition volumes. Furthermore, ALS patients at King''s stage 3 demonstrated significant reductions in most amygdala subnucleus volumes and global amygdala volumes compared with HCs. Notably, amygdala‐cuneus FC was increased in ALS patients at King''s stage 3. Specific subnucleus volumes were significantly associated with Mini‐Mental State Examination scores and Hamilton Anxiety Rating Scale scores in ALS patients. In conclusions, our study provides a comprehensive profile of amygdala abnormalities in ALS patients. The pattern of amygdala abnormalities in ALS patients differed greatly across King''s clinical disease stages, and amygdala abnormalities are an important feature of patients with ALS at relatively advanced stages. Moreover, our findings suggest that amygdala volume may play an important role in anxiety and cognitive dysfunction in ALS patients.     

Ischemic resistance of cutaneous afferents and motor axons in patients with amyotrophic lateral sclerosis

Compared with control subjects, patients with amyotrophic lateral sclerosis (ALS) have been reported to experience less or no paresthesias during and after release of ischemic compression of the upper arm for 10 min. This is reminiscent of the resistance to ischemia of diabetic patients, in whom sensory and motor axons undergo less ischemic depolarization and less postischemic hyperpolarization than in control subjects. The present study compared the changes in axonal excitability produced by ischemia for 10 min in 21 patients with ALS and 14 age-matched control subjects. Fewer patients reported intraischemic or postischemic paresthesias and the intensity of paresthesias was less, but this was significant only for postischemic paresthesias. There were quantitatively similar changes in refractoriness, supernormality, and strength-duration time constant during ischemic compression, but the increase in excitability of motor axons was less during the second half of ischemia in the patients. After release of ischemia the postischemic hyperpolarization was greater in the ALS patients, the opposite of what occurs in diabetes. These changes could reflect reduced intraneural K⁺ accumulation due to loss of motor axons or an alteration in nerve metabolism or membrane properties. Either way, the present study has failed to confirm previous reports of “ischemic resistance” in ALS, and indicates that the changes in axonal properties in ALS are not analogous to those in diabetes mellitus. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21: 1692–1700, 1998     

The management of amyotrophic lateral sclerosis

The terms amyotrophic lateral sclerosis (ALS) or motor neuron disease (MND) refer to a condition characterized by motor system degeneration with relative preservation of other pathways. Although there have been advances in symptomatic treatment, ALS remains an incurable condition. Advances in ALS management prolong survival but simultaneously raise challenging ethical dilemmas for physicians, patients and their families. Here, we review current practice in the management of ALS including pharmacological treatment, nutritional management, respiratory care, and evolving strategies in the management of cognitive impairment.