Epidemiology of amyotrophic lateral sclerosis in Hordaland county, western Norway

The incidence, prevalence and prognosis of amyotrophic lateral sclerosis (ALS) in the county of Hordaland, western Norway were determined for the years 1978 through 1988. The average annual incidence rate was 1.60 per 100,000 population with a male to female ratio of 1.26 (95% confidence interval: 0.76-2.09). The maximal age-specific annual incidence was 8.12 per 100,000 and occurred in the age-group between 61 and 65 years. The prevalence of ALS was 3.67 per 100,000 on December 31, 1988. The average age at the onset of the disease was 60.9 years ranging from 34 to 82 years of age. Survival was studied with life table techniques. Median survival from the onset of symptoms was 28.0 months overall. In patients with bulbar onset the median survival was 24.0 months whereas it was 40 months in patients with spinal onset of disease (log rank test, P = 0.0004). The difference in survival between ALS with bulbar or spinal onset was not explained by age or sex differences in the two groups.     

The onset of amyotrophic lateral sclerosis

Two patients in whom both the neurological examination and electromyography (EMG) were normal prior to the onset of amyotrophic lateral sclerosis (ALS) are reported. In each patient, the onset of ALS some 18 months later was clearly defined clinically and confirmed by subsequent EMG studies. These unique observations show that ALS commences at a defined time, and that there is early generalisation with an initial phase of rapid progression.     

Impaired hypoxic sensor Siah‐1, PHD3, and FIH system in spinal motor neurons of an amyotrophic lateral sclerosis mouse model

We recently reported spinal blood flow–metabolism uncoupling in the Cu/Zn‐superoxide dismutase 1 (SOD1)‐transgenic (Tg) mouse model of amyotrophic lateral sclerosis (ALS), suggesting relative hypoxia in the spinal cord. However, the hypoxic stress sensor pathway in ALS has not been well studied. In the present work, we examined the temporal and spatial changes of hypoxic stress sensor proteins (Siah‐1, PHD3, and FIH) following motor neuron (MN) degeneration in the spinal cord of normoxic ALS mice. The expression of Siah‐1 and PHD3 proteins progressively increased in the surrounding glial cells of presymptomatic Tg mice (10 weeks, 10 weeks) compared with the large MN of the anterior horn. In contrast, a significant reduction in Siah‐1 and PHD3 protein expression was evident in end‐stage ALS mice (18 weeks, 18 weeks). Double‐immunofluorescence analysis revealed PHD3 plus Siah‐1 double‐positive cells in the surrounding glia of symptomatic Tg mice (14–18 weeks), with no change in the large MNs. In contrast, FIH protein expression decreased in the surrounding glial cells of Tg mice at end‐stage ALS (18 weeks). The present study suggests a partial loss in the neuroprotective response of spinal MNs in ALS results from a relative hypoxia through the Siah‐1, PHD3, and FIH system under normoxic conditions. This response could be an important mechanism of neurodegeneration in ALS. © 2012 Wiley Periodicals, Inc.     

Flail arm syndrome with cytoplasmic vacuoles in remaining anterior horn motor neurons: A peculiar variant of amyotrophic lateral sclerosis

Flail arm (FA) syndrome, a minor subtype of amyotrophic lateral sclerosis (ALS), is characterized by progressive weakness and upper girdle wasting, but the associated pathological changes remain unclear. A 59‐year‐old man was admitted to our hospital with a 3‐year history of upper girdle weakness. Bulbar symptom and gait disturbance gradually developed, and he was clinically diagnosed with FA syndrome. After a 10‐year disease course, he died of pulmonary adenocarcinoma. Neuropathological examination revealed severe motor neuronal loss in the brain stem and anterior horn of the cervical spinal cord with bilateral pyramidal tract degeneration. The histological findings were consistent with typical ALS, including Bunina bodies and Lewy body‐like and skein‐like inclusions. Cytoplasmic vacuoles were found in the remaining anterior horn motor neurons of the lumbar spinal cord. This is a unique autopsy case with a long‐standing clinical course that suggests that FA syndrome is an atypical form of ALS.     

Proximal-distal motor unit number estimation-dynamic changes in patients with amyotrophic lateral sclerosis A one-year follow-up

BACKGROUND:Amyotrophic lateral sclerosis (ALS) is the most common of all the motor neuron diseases and the absence of a biologic marker has made both diagnosis and tracking evolution of the disease difficult, Electrodiagnostic tests play a fundamental role in quantifying pathological changes in the motor unit pool.OBJECTIVE:We assessed distal-proximal Motor Unit (MU) loss and changes using the method of motor unit number estimation (MUNE).DESIGN, TIME AND SETTING:A case-control study was performed at the Department of Neuroscience, Pisa University Medical School, Italy from December 1999 to November 2009. PARTICIPANTS:A total of 50 ALS patients were recruited, 30 males:mean age (59.6 ± 13.3) years; 20 females:mean age (63.9 ± 11.7) years; range (30-82) years; all patients had probable or definite ALS. Thirty healthy volunteers were recruited from department staffs, including 20 males and 10 females; mean age (57.7 ± 13.8) years served as controls.METHODS:MUNE was performed for both the biceps brachii and abductor digiti minimi muscles of the same side. The technique used relayed substantially on manual incremental stimulation of the motor nerve, known as the McComas technique (50 ms sweep duration, a gain of 2 mV/Div for M wave, 0.5 mV/Div for each step; filters 10-20 kHz).MAIN OUTCOME MEASURES:MUNE results were measured.RESULTS:Functioning MU numbers, measured by MUNE, decreased in the biceps brachii and abductor digiti minimi muscles over the entire one-year follow-up period (one assessment every three months) compared with baseline determination, the rate of MU decrease was similar in both muscles, but steeper distally.CONCLUSION:MUNE is a feasible method for ALS patients both proximally and distally to track changes over time in muscle MUs during the disease's evolution.     

Familial amyotrophic lateral sclerosis

The increasing complexity of the pathways implicated in the pathogenesis of familial amyotrophic lateral sclerosis (ALS) has stimulated intensive research in many directions. Genetic analysis of familial ALS has yielded six loci and one disease gene (SOD1), initially suggesting a role for free radicals in the disease process, although the mechanisms through which the mutant exerts toxicity and results in selective motor neuron death remain uncertain. Numerous studies have focused on structural elements of the affected cell, emphasizing the role of neurofilaments and peripherin and their functional disruption in disease. Other topics examined include cellular homeostasis of copper and calcium, particularly in the context of oxidative stress and the processes of protein aggregation, glutamate excitotoxicity, and apoptosis. It has become evident that there is considerable interplay between these mechanisms and, as the role of each is established, a common picture may emerge, enabling the development of more targeted therapies. This study discusses the main areas of investigation and reviews the findings.     

T cells in amyotrophic lateral sclerosis

The inflammatory process in ALS involves infiltration of T cells and activation of antigen presenting cells co-localizing with motor neuron damage in the brain and spinal cord. The role of T cells in the pathogenic process is not settled. T cells may damage motor neurons by cell-cell contact or cytokine secretion, or contribute indirectly to motor neuron damage through activation of microglia and macrophages. Alternatively, T cell infiltration may be an epiphenomenon related to clearance of dead motor neurons. Lessons from animal models of neuroinflammation and neurodegeneration have shown that T cell responses can be neuroprotective or even enhance neurogenesis. Therefore, it is possible that T cells can be induced to slow motor neuron destruction and facilitate repair in ALS. The T cell modulating drug glatiramer acetate has shown promising results in animal models, and is being currently investigated in a phase II trial in ALS. This paper reviews the evidence for T cells as pathogenic players and therapeutic targets in ALS.     

Low-grade systemic inflammation in patients with amyotrophic lateral sclerosis

Objective – To prospectively determine the intensity of systemic low‐grade inflammation in patients with amyotrophic lateral sclerosis (ALS). Patients and methods – Patients with ALS and matched healthy controls underwent blood tests for inflammation‐sensitive biomarkers: erythrocyte sedimentation rate (ESR), quantitative fibrinogen, wide‐range C‐reactive protein (wrCRP) concentrations, leukocyte count and neutrophil‐to‐lymphocyte ratio (NLR). The correlation between these inflammatory biomarkers and disability status of the patients, expressed by the ALS Functional Rating Scale (ALSFRS‐R), was evaluated. Results – Eighty patients with ALS and 80 matched controls were included. wrCRP, fibrinogen, ESR and NLR values were significantly elevated in patients compared with controls. There was a significant correlation between the ALSFRS‐R score and wrCRP, ESR and fibrinogen levels. This correlation persisted on sequential examinations. Conclusions – A systemic low‐grade inflammation was detected in patients with ALS and correlated with their degree of disability. A heightened systemic inflammatory state is apparently associated with a negative prognosis in ALS.     

Bunina bodies in amyotrophic lateral sclerosis

Bunina bodies, which are small eosinophilic intraneuronal inclusions in the remaining lower motor neurons, are generally considered to be a specific pathologic hallmark of amyotrophic lateral sclerosis (ALS). One year before a publication by Bunina, van Reeth et al. described similar intracytoplasmic inclusions in the anterior horn cells in a patient with Pick's dementia with atypical ALS. At present, only two proteins have been shown to be present in Bunina bodies, one is cystatin C and the other is transferrin. Bunina bodies consist of amorphous electron‐dense material surrounded by tubular and vesicular structures on electron microscopy. Although the nature and significance of Bunina bodies in ALS are not yet clear, the bodies may be abnormal accumulations of unknown proteinous materials.     

Ultrastructural abnormalities with inclusions in Onuf's nucleus in motor neuron disease (amyotrophic lateral scIerosis)

This study describes an ultrastructural examination focused on motor neurons in Onuf's nucleus in the spinal cord of four control patients without neurological disease (45–70 years) and six motor neuron disease (MND) patients (38–79 years; duration 8 months-19 years) who showed no somato-vesical dysfunction. Prompted by recent studies suggesting some sphincteric motor neurons may succumb to MND, this study sought to determine whether the wider population of neurons in Onuf's nucleus display ultrastructural cytopathology which is normally undetectable in histological preparations. Spinal cords were removed 3–20 h after death, and 1 mm slices of cord rapidly fixed in modified Karnovsky medium were processed for both light- and electronmicroscopy. ‘Control motor neurons’ had intact neuronal and nuclear membranes. Nissl bodies chiefly comprised ordered structures of alternate lamellae of rough endoplasmic reticulum and arrays of polyribo-somes. The Golgi complexes consisted of multilamellated curvilinear stacks of ER. No intraneuronal filamentous or Bunina body inclusions were observed, but occasional axonal spheroids were seen in the neuropil. In MND. histological evidence of sparing in Onuf's nucleus was associated with abnormal ultrastructure of the motor neurons. Some sphincteric neurons were atrophic, whereas in the others, Nissl bodies were reduced in number, showed loss of structural organization or comprised polyribosomal aggregates. Golgi complexes had disrupted lamellated organization or consisted solely of distended ER. Intraneuronal filamentous Lewy-body or skein-like inclusions and Bunina bodies were identified in Onuf's nucleus of three subjects (duration of MND 8 months-2 years). The results of the present study indicate that Onuf's nucleus is vulnerable in MND, and preservation of sphincter function with qualitative histological evidence of ‘sparing’ does not necessarily imply a corresponding lack of ultrastructural cytopathology in this nucleus.     

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.     

Progressive motor neuron impairment in an animal model of familial amyotrophic lateral sclerosis

Mutations of Cu,Zn superoxide dismutase cause an autosomal dominant form of familial amyotrophic lateral sclerosis. An animal model of the disease has been produced by expressing mutant human SOD1 in transgenic mice (G93A). In order to quantify the dysfunction of the motor unit in transgenic mice, electromyographic recordings were performed during the course of the disease. The first alterations in neuromuscular function appeared between P63 and P90. The deficits became even more striking after P100; compound muscle action potentials in the hindlimb decreased by 80% of initial value. Spontaneous fibrillation potentials were measured in more than 50% of transgenic mice. The number of motor units in the gastrocnemius muscle was progressively reduced over time, down to 18% of the control value at P130. Moreover, distal motor latencies increased after P120. These data suggest that the initial dysfunctions of motor unit are related to a severe motor axonal degeneration, which is followed at later periods by myelin alteration. © 1997 John Wiley & Sons, Inc.     

Flail arm syndrome: a clinical variant of amyotrophic lateral sclerosis

We describe a case of a 65-year old patient diagnosed with amyotrophic lateral sclerosis. The clinical findings, with symmetric, predominantly proximal wasting and weakness of both arms (especially of the infra-, supraspinatus and deltoideus) leading to severe functional disability and contrasting with preserved independent ambulation and sparing of bulbar muscles, were consistent with the proposed criteria of the so-called flail arm syndrome. Based on our case we characterize the clinical features of flail arm syndrome and review the literature.     

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.     

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.