Amyotrophic lateral sclerosis

Lokesh C Wijesekera; P Nigel Leigh

doi:10.1186/1750-1172-4-3

Review

Open Access

Amyotrophic lateral sclerosis

Lokesh C Wijesekera†¹ and
P Nigel Leigh†¹Email author

†Contributed equally

Orphanet Journal of Rare Diseases20094:3

https://doi.org/10.1186/1750-1172-4-3

Received: 22 October 2008

Accepted: 03 February 2009

Published: 03 February 2009

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by progressive muscular paralysis reflecting degeneration of motor neurones in the primary motor cortex, corticospinal tracts, brainstem and spinal cord. Incidence (average 1.89 per 100,000/year) and prevalence (average 5.2 per100,000) are relatively uniform in Western countries, although foci of higher frequency occur in the Western Pacific. The mean age of onset for sporadic ALS is about 60 years. Overall, there is a slight male prevalence (M:F ratio~1.5:1). Approximately two thirds of patients with typical ALS have a spinal form of the disease (limb onset) and present with symptoms related to focal muscle weakness and wasting, where the symptoms may start either distally or proximally in the upper and lower limbs. Gradually, spasticity may develop in the weakened atrophic limbs, affecting manual dexterity and gait. Patients with bulbar onset ALS usually present with dysarthria and dysphagia for solid or liquids, and limbs symptoms can develop almost simultaneously with bulbar symptoms, and in the vast majority of cases will occur within 1–2 years. Paralysis is progressive and leads to death due to respiratory failure within 2–3 years for bulbar onset cases and 3–5 years for limb onset ALS cases. Most ALS cases are sporadic but 5–10% of cases are familial, and of these 20% have a mutation of the SOD1 gene and about 2–5% have mutations of the TARDBP (TDP-43) gene. Two percent of apparently sporadic patients have SOD1 mutations, and TARDBP mutations also occur in sporadic cases. The diagnosis is based on clinical history, examination, electromyography, and exclusion of 'ALS-mimics' (e.g. cervical spondylotic myelopathies, multifocal motor neuropathy, Kennedy's disease) by appropriate investigations. The pathological hallmarks comprise loss of motor neurones with intraneuronal ubiquitin-immunoreactive inclusions in upper motor neurones and TDP-43 immunoreactive inclusions in degenerating lower motor neurones. Signs of upper motor neurone and lower motor neurone damage not explained by any other disease process are suggestive of ALS. The management of ALS is supportive, palliative, and multidisciplinary. Non-invasive ventilation prolongs survival and improves quality of life. Riluzole is the only drug that has been shown to extend survival.

Keywords

Amyotrophic Lateral SclerosisPercutaneous Endoscopic GastrostomyAmyotrophic Lateral Sclerosis PatientRiluzoleMotor Neurone

Disease names

Amyotrophic lateral sclerosis (ALS), Motor neurone disease (MND), Charcot's disease, Lou Gehrig's disease

Included diseases

Amyotrophic lateral sclerosis (ALS) is a term used to cover the spectrum of neurodegenerative syndromes characterised by progressive degeneration of motor neurones. However, it is also the term used in modern clinical practice to indicate the commonest form of the disease, Classical (Charcot's) ALS. Other syndromes related to this spectrum of disorders include, Progressive bulbar palsy (PBP), Progressive muscular atrophy (PMA), Primary lateral sclerosis (PLS), Flail arm syndrome (Vulpian-Bernhardt syndrome), Flail leg syndrome (Pseudopolyneuritic form) and ALS with multi-system involvement (e.g., ALS-Dementia). Lord Russell Brain proposed the term Motor neurone disease (MND) to incorporate these conditions into a single spectrum of disorders [1]. The terms 'bulbar onset ALS' and 'spinal onset ALS' have largely replaced the terms PBP and Charcot's ALS in current practice. These syndromes share a common molecular and cellular pathology comprising of motor neurone degeneration and the presence of characteristic ubiquitin-immunoreactive (Ub-IR) and TDP-43 immunoreactive (TDP43-IR) intraneuronal inclusions, as described later [2–4].

Another group of neurodegenerative motor neurone disorders referred to as adult-onset spinal muscular atrophies (e.g., Kennedy's syndrome) which, while affecting anterior horn cells of the spinal cord and/or brainstem, are not considered in this article as they have a distinct molecular pathology unrelated to ALS, and have a more benign disease course.

Definition and diagnostic/classification criteria

ALS can be defined as a neurodegenerative disorder characterised by progressive muscular paralysis reflecting degeneration of motor neurones in the primary motor cortex, brainstem and spinal cord. "Amyotrophy" refers to the atrophy of muscle fibres, which are denervated as their corresponding anterior horn cells degenerate, leading to weakness of affected muscles and visible fasciculations. "Lateral sclerosis" refers to hardening of the anterior and lateral corticospinal tracts as motor neurons in these areas degenerate and are replaced by gliosis [5].

Despite advances in investigative medicine over the past century, the diagnosis of ALS is based on the presence of very characteristic clinical findings in conjunction with investigations to exclude "ALS-mimic" syndromes (e.g. Cervical radiculomyelopathy). The latter conditions lead to diagnostic error in 5–10% of cases [6, 7]. The clinical finding of signs suggestive of combined upper motor neurone (UMN) and lower motor neurone (LMN) that cannot be explained by any other disease process (evident on electrophysiological, imaging, cerebrospinal fluid (CSF) or serological studies), together with progression compatible with a neurodegenerative disorder, is suggestive of ALS. Thus, investigation results alone (e.g., evidence of chronic denervation on electromyography (EMG)) are not adequate for achieving a diagnosis, and must be interpreted in light of the patient's history and clinical findings.

The World Federation of Neurology (WFN) Research Group on Motor Neuron Diseases have developed the 1994 'El Escorial' diagnostic criteria [8] and the revised 2000 'Airlie House' criteria [9] to aid in diagnosing and classifying patients for research studies and drug trials. The revised Airlie House criteria are shown in Table 1, and based on these criteria patients can be classified into 'Clinically definite', 'Clinically probable', 'Clinically probable-Laboratory supported' and 'Clinically possible' categories. In the previous 1994 classification, patients with a pure LMN syndrome were classified into the 'Clinically suspected' category, which was removed from the revised criteria. However, it is well recognised that a significant number of patients who either have a pure LMN syndrome or who early in the course of the disease do not have obvious UMN signs, will undoubtedly have ALS (or a variant) but will not fall into these categories in the revised criteria. Therefore, these criteria are probably more useful for research purposes and therapeutic trials, rather than day-to-day clinical practice. A recent rationalisation of the El Escorial Criteria (the Awaji consensus, see below) [10] simplifies the criteria and in our opinion should be adopted.

Table 1

Summary of Revised El Escorial Research Diagnostic Criteria for ALS (Brooks et al., 2000)

The diagnosis of ALS requires:
1 Evidence of LMN degeneration by clinical, electrophysiological or neuropathological examination;
2 Evidence of UMN degeneration by clinical examination, and
3 Progressive spread of symptoms or signs within a region or to other regions, as determined by history or examination,
Together with the absence of:
[1] Electrophysiological and pathological evidence of other disease that might explain the signs of LMN and/or UMN degeneration, and
[2] Neuroimaging evidence of other disease processes that might explain the observed clinical and electrophysiological signs
Categories of clinical diagnostic certainty on clinical criteria alone
Definite ALS
• UMN signs and LMN signs in 3 regions Probable ALS
• UMN signs and LMN signs in 2 regions with at least some UMN signs rostral to LMN signs
Probable ALS – Laboratory supported
• UMN signs in 1 or more regions and LMN signs defined by EMG in at least 2 regions
Possible ALS
• UMN signs and LMN signs in 1 region (together), or
• UMN signs in 2 or more regions
• UMN and LMN signs in 2 regions with no UMN signs rostral to LMN signs

UMN signs: clonus, Babinski sign, absent abdominal skin reflexes, hypertonia, loss of dexterity.

LMN signs: atrophy, weakness. If only fasciculation: search with EMG for active denervation.

Regions reflect neuronal pools: bulbar, cervical, thoracic and lumbosacral.

Epidemiology

The incidence of sporadic amyotrophic lateral sclerosis (SALS) in the 1990's is reported to be between 1.5 and 2.7 per 100,000 population/year (average 1.89 per 100,000/year) in Europe and North America [11], with a uniform incidence across these countries. The point prevalence in the 1990's ranges from 2.7 to 7.4 per 100,000 (average 5.2 per 100,000) in western countries [11]. The lifetime risk of SALS by the age of 70 has been estimated at 1 in 1,000 [12, 13] but a more accurate estimate is more likely to be 1 in 400 [14, 15]. A consistent finding in studies is that there is a slight excess of males are affected more than females, with a M:F ratio about 1.5:1, although more recent data suggests that the gender ratio may be approaching equality [11, 16–18]. Explanations for this male excess have been attributed to possible protective hormonal factors in women, increased likelihood of males being exposed to putative risk factors and under ascertainment of elderly women in some population registers [19, 20]. A review published in 2001 found the mortality rates of ALS in the 1990's ranged from 1.54 to 2.55 per 100,000/year and a more recent study estimated the figure to be 1.84 per 100,000 persons in the US population [11, 21]. The mean age of onset for sporadic ALS (SALS) varies between 55–65 years with a median age of onset of 64 years[22, 23]. Only 5% of cases have an onset before the age of 30 years [23], although juvenile sporadic onset cases are being increasingly recognised [24]. Bulbar onset is commoner in women and in older age groups, with 43% of patients over the age of 70 presenting with bulbar symptoms compared to 15% below the age of 30 [23, 25, 26].

Although most cases of ALS are sporadic, about 5% of cases have a family history of ALS (Familial ALS; FALS) [27]. There is an often Mendelian inheritance and high penetrance, with most cases having autosomal dominant pattern of inheritance, although autosomal recessive pedigrees have been reported [28, 29]. The ages of onset of FALS is about a decade earlier than for sporadic cases, affects males and female equally, and have a shorter survival [28, 30, 31]. Age of onset in FALS has a normal Gaussian distribution, whereas SALS has an age dependant incidence [32]. Juvenile onset ALS (jALS) is a term used when age of onset is less than 25 years [33]. Most cases are autosomal recessive although dominant inheritance linked to chromosome 9q34 (ALS4, senataxin) has been reported [34]. Recessive forms have been mapped to chromosome regions 2q33 (ALS2, alsin), and 15q12-21 [35, 36].

Geographic loci of the Western Pacific form of ALS, where the prevalence is 50–100 times higher than elsewhere world have been reported, although the cause of these aggregations remains elusive [37]. These populations include the Chamorro people of Guam and Marianas island, the Kii peninsula of Honshu Island, and the Auyu and Jakai people of south west New Guinea, in whom ALS is associated with the Parkinsonism and dementia (ALS-PD complex) [38, 39]. More recent studies however have shown a decrease in incidence of both ALS and PDC in these areas over the past 40 years, although the incidence of PDC slightly increased during the eighties and nineties [37, 40–42].

Clinical features

The features of ALS were first clearly described as a clinico-pathological entity by Jean Martin Charcot in 1869 and in subsequent articles in 1874 [43, 44]. However, before that Bell (1824), Aran (1850), Duchenne (1851), and Cruveilher (1853) made important observations that contributed to the understanding of the clinical and pathological syndrome [45–50].

Approximately two thirds of patients with typical ALS have a spinal form of the disease (classical 'Charcot ALS'). They present with symptoms related to focal muscle weakness where the symptoms may start either distally or proximally in the upper limbs and lower limbs. Rarely, patients may notice focal muscle wasting before onset of weakness, and some patients may present with a spastic paraparesis. Patients may have noticed fasciculations (noticed as involuntary muscle twitching) or cramps preceding the onset of weakness or wasting for some months (or years), but rarely are these the presenting symptoms. The weakness is usually of insidious onset, and patients may notice that symptoms are exacerbated by cold weather. Although it is usually asymmetrical at onset, the other limbs develop weakness and wasting sooner or later, and most patients go on to develop bulbar symptoms and eventually respiratory symptoms (although not necessarily in that sequence). Gradually, spasticity may develop in the weakened atrophic limbs, affecting manual dexterity and gait. During late stages of the disease patients may develop 'flexor spasms', which are involuntary spasms occurring due to excess activation of the flexor arc in a spastic limb. Occasionally encountered symptoms include new bladder dysfunction (such as urgency of micturition), sensory symptoms, cognitive symptoms and multi-system involvement (e.g. dementia, parkinsonism).

Patients with bulbar onset ALS usually present with dysarthria of speech, which may initially only be apparent after ingestion of small amount of alcohol. Rarely, patients may present with dysphagia for solid or liquids before noticing speech disturbances. Limbs symptoms can develop almost simultaneously with bulbar symptoms and in the vast majority of cases will occur within 1–2 years. Almost all patients with bulbar symptoms develop sialorrhoea (excessive drooling) due to difficulty swallowing saliva and mild UMN type bilateral facial weakness which affects the lower part of the face. 'Pseudobulbar' symptoms such as emotional lability and excessive yawning are seen in a significant number of cases.

About 5% of cases with ALS present with respiratory weakness without significant limb or bulbar symptoms [51, 52]. These patients present with symptoms of type 2 respiratory failure or nocturnal hypoventilation such as dyspnoea, orthopnoea, disturbed sleep, morning headaches, excessive day time somnolence, anorexia, decreased concentration and irritability or mood changes [53].

The examination early in the course of limb onset disease usually reveals focal muscle atrophy especially involving the muscles of the hands, forearms or shoulders in the upper limbs, and proximal thigh or distal foot muscle in the lower limbs. Fasciculations are usually visible in more than one muscle group. Spasticity is evident in the upper limbs by increased tone and a supinator 'catch', and in the lower limbs with a patellar 'catch' and clonus together with hypertonia. Tendon reflexes are pathologically brisk in a symmetrical manner, including the finger jerks in the upper limbs and positive crossed adductor reflex in the lower limbs. Abnormal spread of tendon reflexes beyond the stimulated muscle group may be evident. The Hoffmann's sign may be positive in the upper limbs and plantar response is often extensor. In patients with bulbar dysfunction, dysarthria may arise from either LMN pathology or pseudobulbar palsy from UMN disorder, leading to slow slurred speech or a nasal quality. On examining the cranial nerves, the jaw jerk may be brisk, especially in bulbar-onset disease. An upper motor neurone type facial weakness affects the lower half of the face causing difficulty with lip seal and blowing cheeks, but often varying degrees of UMN and LMN facial weakness coexist. The gag reflex is preserved and is often brisk while the soft palate may be weak. Patients develop fasciculations and wasting of the tongue, and tongue movements are slowed due to spasticity. The rest of the cranial nerves remain intact, although in late stages of the disease patients may very rarely develop a supranuclear gaze palsy [54, 55]. Sensory examination is almost always unremarkable. As disease progresses, patients develop the characteristic picture of the combination of upper motor neurone and lower motor neurone signs coexisting within the same central nervous system region, affecting the bulbar, cervical, thoracic and lumbar territories. Respiratory failure and other pulmonary complications are the usual cause of death in ALS. However, patients who are kept alive by tracheostomy assisted ventilation are found to eventually develop a profound state motor paralysis termed the 'totally locked-in state' (TLS), were there is paralysis of all voluntary muscles and varying degrees of oculomotor impairment [56, 57].

Clinical features of variant disorders

Variants of MND have differing clinical presentations, rate of progression and prognosis. Opinion is divided as to whether these syndromes should be classed as separate entities from ALS, although there is evidence that the may be a common molecular pathology.

The syndrome of progressive muscular atrophy (PMA) accounts for 5–10% of patients with MND, and indicates a pure lower motor neurone syndrome without accompanying upper motor neurone signs [58]. It is almost always of limb onset, but patients may eventually develop swallowing difficulties. It is reported that up to 50% of patients may develop UMN signs and go on to develop typical ALS picture [59].

The "flail arm" and "flail leg" variants are initially localised forms with a predominantly lower motor neuron presentation. In the flail arm variant (which also is known as the Vulpian-Bernhardt syndrome [60] and Brachial amyotrophic diplegia [61]), weakness and wasting predominantly affects the proximal upper limb in a symmetrical pattern, leading to severe wasting around the shoulder girdle and the arms hanging flaccidly either side. Typically, the tendon reflexes in the upper limbs are depressed or absent, but patients may have retained reflexes or focal brisk reflexes especially in the unaffected limb when the disease is asymmetrical at the onset. The lower limbs remain strong for some years but eventually spasticity and wasting develops. Swallowing difficulties and diaphragmatic weakness are usually late features [62, 63]. In the flail leg syndrome (also known as the Pseudopolyneuritic form of ALS) [64], weakness and wasting begins in the distal lower limbs affecting both lower limbs in a symmetrical manner. Again the clinical features are of a lower motor neurone syndrome with hypotonia and depressed tendon reflexes. Pyramidal signs are usually absent, although it is not unusual for these patients to have focal brisk reflexes in the unaffected limb when the disease is asymmetrical [65]. The unusual clinical picture together with lack of neurophysiological evidence of denervation in other regions can lead to considerable diagnostic delays. These two variants characteristically show slower progression compared to more typical forms of ALS [61, 62, 66–68].

Primary lateral sclerosis is a clinically progressive pure upper motor syndrome that cannot be attributed to another disease process. There is ongoing debate as to whether this syndrome is in fact an entirely separate disorder to ALS, but there is evidence from pathological studies that hallmarks of ALS such as ubiquitinated inclusions are present in this condition. Patients present with a pure upper motor neurone syndrome with either absent or minimal lower motor neurone signs. It can be difficult to differentiate PLS from ALS during the early stages as some patients with typical ALS may only manifest UMN signs. For this reason, some authors have suggested that LMN signs must be absent for 3 years from onset to confidently diagnose PLS [69]. However, there may be electrophysiological evidence of LMN involvement in PLS patients despite the absence of clinical LMN signs, and some patients may develop wasting of small muscles of the hands, adding to the diagnostic confusion [70, 71], a condition called by some authors as "UMN-dominant ALS" [72, 73]. Prognosis for PLS is considerably better than for typical ALS [72].

It is recognised that patients with ALS may exhibit a range of cognitive abnormalities ranging from impaired frontal executive dysfunction in 20–40% of patients, to overt fronto-temporal dementia (FTLD) in approximately 5% of cases [74]. Cognitive abnormalities may precede or occur after the onset of motor symptoms. Neuropathological and neuroimaging studies have indicated that this subset of patients with ALS-dementia may represent a part of spectrum between patients with pure FTLD and ALS [75, 76].

Aetiology

The cause of ALS/MND is unknown although some genetic risk factors have been identified. Recent reviews on the role of environmental risk factors in the causation of ALS have concluded that there is no consistent association between a single environmental factor and risk of developing ALS. Most authors favour a hypothesis of complex genetic-environmental interaction as the causal factor for motor neuron degeneration [77, 78].

Putative exogenous risk factors associated with development of ALS investigated in case-control studies have been reviewed, and are summarised in Appendix 1 [19, 39]. By applying an evidenced based approach, it was found that only smoking is likely to be associated with developing ALS, while other risk factors were weakly related. More recent case-control studies have estimated the relative risk (RR) of ALS of 0.8–1.67 in smokers compared to non-smokers [79, 80], and an odds ratio (OR) of 1.6 independent of age, level of education and occupation [81].

Pathogenesis of motor neurone degeneration in ALS

The exact molecular pathway causing motor neurone degeneration in ALS is unknown, but as with other neurodegenerative diseases, is likely to be a complex interplay between multiple pathogenic cellular mechanisms which may not be mutually exclusive [77, 78]. These include:

1. Genetic factors

20% of cases with autosomal dominant FALS and 2% of patients with SALS show mutations in the Copper-Zinc superoxide dismutase (SOD1) gene [82]. Mutations in the gene are though to cause disease through a toxic gain of function rather than causing impairment of the antioxidant function of the SOD1 enzyme [77]. Other genes causing familial MND include alsin (ALS2) [83, 84], senataxin (ALS4) [85], Vesicle associated membrane protein (VAPB, ALS8) [86], Angiogenin [87, 88] and a mutation in the p150 subunit of dynactin (DCTN1) [89, 90]. Recently, mutations in TARDBP gene (encoding the TAR-DNA binding protein TDP-43) located on chromosome 1p36.22 have been linked to familial and sporadic ALS [91–93]. Several other gene mutations have been identified in sporadic cases which may increase susceptibility to ALS, such as mutations in the KSP repeat region in the NEFH gene (encoding neurofilament heavy subunit) [94, 95], apolipoprotein E ∑4 genotype (APOE) [96], decreased expression of EAAT2 protein [97, 98] and alterations in the Vascular endothelial growth factor (VEGF) gene [99] to name a few (See Table 2).

Table 2

Familial ALS (fALS) gene mutations and clinical features

Familial ALS type	Locus (gene address)	Gene	Inheritance	Clinical pattern	Mutations	Causes sporadic disease
ALS1	21q	SOD1	AD	Classical	> 120	yes
ALS2	2q33	ALSIN	AR	Young onset, UMN	10	no
ALS3	18q21		AD	Classical	not known	not known
ALS4	9q34	SETX	AD	Young onset, slow	3	Probably not
ALS5	15q15	not known	AR	Young onset	not known	Probably not
ALS6	16q21	not known	AD	Classical	not known	not known
ALS7	20ptel-p13	not known	AD	Classical	not known	not known
ALS8	20q13.3	VAPB	AD	Varied	1	no
ALS-FTD	9q21-q22	not known	AD	With FTD	not known	not known
ALS-FTD	9p21.3	not known	AD	With FTD	not known	not known
ALS	14q11.2	Angiogenin	AD	Classical	6	Yes
FTD (FTD3)	3	CHMP2B	AD	FTD (ALS)	2	not known
ALS	1	TDP43	AD	ALS	14	Yes
LMND	2p13	DCTNI	AD	LMND	1 (+ 4 in ALS?)	Yes?

AD = autosomal dominant; AR = autosomal recessive; CHMP2B = Chromatin modifying protein 2B; DCTNI = dynactin; FTD = frontotemporal lobe dementia; LMND = lower motor neuron disease; SETX = senataxin

VAPB = Vesicle associated membrane protein.

2. Excitotoxicity

This is the term for neuronal injury induced by excessive glutamate induced stimulation of the postsynaptic glutamate receptors such as cell surface NMDA receptors and AMPA receptors [77, 100]. This over stimulation of glutamate receptors is thought to result in massive calcium influx into the neurons, leading to increased nitric oxide formation and thereby neuronal death. Glutamate levels in CSF are elevated in some patients with ALS [101, 102]. This elevation has been attributed to the loss of the glial cell excitatory amino acid transporter EAAT2 [103].

3. Oxidative stress

Oxidative stress has longed been linked to neurodegeneration and it is known that accumulation of reactive oxygen species (ROS) cause cell death. As mutations in the anti-oxidant enzyme superoxide dismutase 1 (SOD1) gene can cause familial ALS, there is significant interest in this mechanism underlying neurodegenerative process in ALS. This hypothesis is supported by the finding of biochemical changes reflecting free radical damage and abnormal free radical metabolism in CSF and post mortem tissue samples of ALS patients [104–107]. In addition, fibroblasts cultured from ALS patients shows increased sensitivity to oxidative damage controls [108].

4. Mitochondrial dysfunction

Abnormalities in mitochondrial morphology and biochemistry have been reported in sporadic ALS patients, SOD1 transgenic mice and cellular models [109–115]. Mitochondria from ALS patients show elevated calcium levels and decreased activity of respiratory chain complexes I and IV, implicating defective energy metabolism [112, 116]. Mitochondrial DNA mutations have been described in ALS patients [117–119].

5. Impaired axonal transport

Motor neuron axons may reach up to one metre in length in humans, and rely on efficient intracellular transport systems. These systems consist of anterograde (slow and fast) and retrograde transport systems, and rely on molecular 'motors', the kinesin complex of proteins (for anterograde) and the dynein-dynactin complex (for retrograde) [120]. SOD1 transgenic mouse models of ALS show evidence of slowed anterograde transport and retrograde transport [121–124]. Although no such findings have been observed in humans with ALS, mutations in the kinesin genes are known to cause neurodegenerative motor nerve diseases in humans such as hereditary spastic paraplegia and Type 2A Charcot-Marie-Tooth disease [125, 126]. Mutations in the dynactin complex cause a lower motor neuron disorder with vocal cord paralysis in humans [89].

6. Neurofilament aggregation

Abnormal assembly with accumulation of neurofilaments are commonly seen in several neurodegenerative conditions including SALS and FALS [111, 127, 128]. In addition, mutations in KSP repeat region of the neurofilament heavy (NFH) gene are found in about 1% of sporadic cases [94, 95, 129]. Neurofilament proteins together with Peripherin (an intermediate filament protein) are found in the majority of axonal inclusions motor neurones of ALS patients [130]. A toxic isoform of peripherin (peripherin 61), has been found to be toxic to motor neurones even when expressed at modest levels and is detectable in spinal cords of ALS patients but not controls [131].

7. Protein aggregation

Intra-cytoplasmic inclusions are a hallmark of both sporadic and familial ALS (See histopathology section). However, it is still unclear as to whether aggregate formation directly causes cellular toxicity and have a key role in pathogenesis, if aggregates may be innocent by-products of the neurodegeneration process, or if formation of the aggregates may actually be a being a beneficial process by being part of a defence mechanism to reduce intracellular concentrations of toxic proteins [77, 78].

8. Inflammatory dysfunction and contribution of non-neuronal cells

Although ALS is not primarily a disorder of autoimmunity or immune dysregulation, there is considerable evidence that inflammatory processes and non-neuronal cells may play a part in pathogenesis of ALS. Microglial and dendritic cell activation is a prominent pathology in human ALS and transgenic SOD1 mice [132–136]. These activated non-neuronal cells produce inflammatory cytokines such as interleukins, COX-2, TNFα and MCP-1, and evidence of upregulation is found in CSF or spinal cord specimens of ALS patients or in vitro models [137–140]. Despite this evidence, immunomodulatory therapies are yet to show promise as neuroprotective agents in clinical trials of ALS.

9. Deficits in neurotrophic factors and dysfunction of signalling pathways

Decreased levels of neurotrophic factors (e.g. CTNF, BDNF, GDNF and IGF-1) have been observed in ALS patients post-mortem and in in vitro models [141–143]. In addition, deletion of the hypoxia-response element in the vascular endothelial growth factor (VEGF) gene was found to cause a motor neurone disease in mice [144]. In humans, three mutations in the VEGF gene were found to be associated with increased risk of developing sporadic ALS [99], although a recent meta-analysis by the same authors failed to show an association between VEGF haplotypes and increase the risk of ALS in humans [145].

The final process of cell death in ALS motor neurones is thought to closely resemble a programmed cell death pathway (apoptosis). Biochemical markers of apoptosis are detected in the terminal stages of human and models of ALS [146–150]. Key elements of the normal apoptotic pathway are found to be involved in cell death in ALS, including the caspase family of proteolytic enzymes, the Bcl2 family of oncoproteins (anti-apoptotic and proapoptotic oncogenes) and the apoptosis inhibitor family of proteins (IAPs) [77, 151, 152].

Histopathological features

The pathological hallmarks of ALS are the degeneration and loss of motor neurones with astrocytic gliosis and the presence of intraneuronal inclusions in degenerating neurones and glia. Upper motor neurone pathology in ALS is indicated by depopulation of the Betz cells in the motor cortex (Brodmann area 4), variable astrocytic gliosis affecting both the grey matter and underlying subcortical white matter of the motor cortex, and axonal loss within the descending pyramidal motor pathway associated with myelin pallor and gliosis of the corticospinal tracts [153, 154].

Lower motor neurone pathology primarily affects the ventral horn motor neurones of the spinal cord and brainstem. There is relative sparing of the motor nucleus of Onufrowicz in the S2 spinal segment and the cranial nerve oculomotor nuclei [4, 155]. The number of lower motor neurones can be reduced by up to 50% at autopsy [156] but there is considerable variation both between cases and between different spinal levels within cases [154]. The remaining neurones are atrophic and contain intraneuronal inclusions such as:

1. Bunina bodies

These are small eosinophilic, hyaline intracytoplasmic inclusions that stain positive for cystatin and transferring [157, 158], and are present in 70–100% of cases [4, 159, 160]. Also present in Betz cells and subthalamic nuclei. Rarely seen in other conditions.

2. Ubiquitinated inclusions or ubiquitin-immunoreactive (UBIs; Ub-IR)

Can be divided according to morphology into skein-like inclusions (SLIs) which have a filamentous profile, and more compact spherical bodies (with a rounded appearance). The compact spherical bodies have also been termed "Lewy-body like" inclusions due to the similarity in their appearance to Lewy bodies found in Parkinson's disease. They are almost universal in ALS and its variants, where it can be seen in up to 95% of cases [2, 3, 161, 162]. It has recently been found that the TAR DNA binding protein 43 (TDP-43) is the major protein constituent in the ubiquitin positive inclusions [163–166].

3. Hyaline conglomerate (Neurofilament) inclusions (HCIs)

Associated with FALS and rarely seen in sporadic ALS. These are argyrophilic inclusions seen in spinal cord motor neurones that stain for phosphorylated and non-phosphorylated neurofilaments [167]. They have been also described in other neurodegenerative diseases and normal subjects and are not as specific UBIs [168].

Contrary to early belief that ALS was a disease exclusive to the motor system, there is now significant evidence to suggest that ALS is in fact a multisystem disorder. Extra motor pathology is found in regions such as the frontotemporal cortex, hippocampus, thalamus [169], substantia nigra [170], spinocerebellar pathways [171], dorsal columns [172] and peripheral sensory nerves [173, 174].

ALS variant syndromes seem to share a common molecular pathology as suggested by the findings of ubiquitinated inclusions in PLS [175, 176], PMA [161], Flail arm syndrome [177, 178], Flail leg [179], ALS-dementia [180, 181] and Guam ALS-PDC [182]. A recent finding is that the TAR DNA binding protein 43 (TDP-43) has been shown to be a major protein constituent in the ubiquitin positive (tau and α-synuclein negative) inclusions found in upper and lower motor neurones in ALS, frontotemporal lobar degeneration with MND (FTLD-MND) and frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U) [163]. TDP-43 positive inclusions were also detected in one of two cases of PLS but appear to be negative in the inclusions seen in SOD1 positive familial ALS [183–185].

Differential diagnosis

ALS must be differentiated from the "ALS mimic syndromes" which are unrelated disorders that may have a similar presentation and clinical features to ALS or it's variants [5, 74]. The most important conditions are shown in Table 3.

Table 3

Diagnostic errors and most common 'ALS mimic syndromes'. (Modified from Kato et al., with permission)

Final diagnosis	Characteristic features	Distinguishing diagnostic features and investigations
Cerebral lesions	Focal motor cortex lesions very rarely mimic ALS, but frontal lesions with co-existent cervical or lumbo-sacral root damage may cause confusion.	MRI/CT; no EMG evidence of widespread chronic partial denervation (CPD) in limbs
Skull base lesions	Lower cranial nerve signs (bulbar symptoms and signs; wasting of tongue, often asymmetrical); seldom significant long tract signs unless foramen magnum involved in addition	MRI; CT with bone windows; no EMG evidence of CPD in limbs unless wasting of C8/T1 muscles (rare, but present in some lesions at foramen magnum or high cervical level)
Cervical spondylotic myelopathy	Progressive limb weakness. Asymmetrical onset; combined UMN and LMN signs in arm(s); spastic paraparesis; occasionally fasciculations in arms.	Pain in root distribution, but pain may not be severe and may resolve quickly; often progression followed by clinical stabilisation; no bulbar involvement; MRI evidence of spinal cord and root compression; no evidence of CPD on EMG (NB: patients may have co-existent lumbo-sacral motor radiculopathy with lower limb denervation)
Other cervical myelopathies • Foramen magnum lesions • Intrinsic and extrinsic tumours • Syringomyelia	Progressive weakness; foramen magnum lesions and high cervical cord lesions may be associated with focal (C8/T1) wasting; syringomyelia usually associated with LMN signs and dissociated sensory loss	Usually involvement of cerebellar and/or sensory pathways; MRI of head and cervical spine reveal pathology
Conus lesions and lumbo-sacral radiculopathy	Progressive mixed UMN and LMN syndrome	Usually significant sensory symptoms if not signs; bladder involvement; MRI thoracic and lumbo-sacral region; EMG evidence of radiculopathy
Inclusion body myositis (IBM)	Progressive weakness; bulbar symptoms; sometimes respiratory muscle weakness	Characteristic wasting and weakness of deep finger flexors and quadriceps femoris; EMG evidence of myopathy; muscle biopsy as definitive test (rimmed vacuoles)
Cramp/fasciculation/myokymia syndromes	Cramps, undulating muscle contractions, +/- weakness, stiffness (Isaac's syndrome; peripheral nerve hyper-excitability syndrome)	EMG evidence of myokymia; ~30% VGKC antibodies; ~20% associated with thymoma or lung cancer; association with other autoimmune diseases
Multifocal motor neuropathy (MFMN)	Focal asymmetrical onset, often upper limb; pure LMN syndrome; may stabilise for months or years; M:F 4:1;	Conduction block on nerve conduction studies (NCS); weakness often out of proportion to wasting; improvement with intravenous immunoglobulin (IVIG) in ~70%
Kennedy's disease (X-linked bulbar and spinal muscular atrophy)	Males symptomatic; slowly progressive bulbar and limb weakness	Family history; fasciculations of facial muscles; gynaecomastia; proximal symmetrical weakness in addition to foot drop; mild sensory neuropathy on NCS; positive DNA test for CAG repeat mutation in exon 1 of androgen receptor gene

Diagnostic methods

Electrophysiological studies

Patients in whom a diagnosis of ALS is suspected on clinical grounds should have electrophysiological studies primarily to document lower motor dysfunction in clinically involved and uninvolved regions, and secondarily to exclude other disease processes. The first published criteria for electrodiagnosis of ALS were by Lambert in 1957 and 1969 [186, 187]. The revised El-Escorial criteria [9] have proposed electrophysiological criteria for the diagnosis of ALS, which have been future refined in December 2006 at an consensus conference on Awaji Island, Japan [10]. It is important to bear in mind that clinical neurophysiological examination is used in the diagnosis of ALS when the diagnosis is clinically suspected, and suggestive neurophysiological abnormalities alone cannot clinch the diagnosis without clinical support.

1. Nerve conduction studies (motor and sensory)

Nerve conduction studies are required for the diagnosis principally to define and exclude other disorders of peripheral nerve, neuromuscular junction and muscle that may mimic or confound the diagnosis of ALS, and these studies should generally be normal or near normal, unless the compound muscle potential is small [9]. In ALS, the distal motor latency (DML) and motor conduction velocity (MCV) remain almost normal, never falling below 70% of the upper or lower limit of normal [188–190]. Motor studies are also important in excluding multifocal motor neuropathy, by the detection of partial conduction block. A marked reduction of proximal amplitude or negative-peak area as compared with the distal ones (over 50%), in short segments, (excluding entrapment sites) implies partial conduction block [191]. F-wave studies are particularly useful in assessing proximal conduction and abnormalities have been reported in ALS. These include increased F-wave latency with normal frequency and increased amplitude, and slowing of F-wave velocity with decreased F-wave frequency. Prominent UMN features may be associated with an increased F-wave frequency [188].

The sensory nerve conduction studies can be abnormal in the presence of entrapment syndromes and coexisting peripheral nerve disease [9]. There is also recent evidence sub-clinical involvement of the sensory system in 10–20% of patients with ALS, suggesting an additional polyneuropathy or sensory ganglionopathy [192, 193].

2. Conventional electromyography

Concentric needle electromyography (EMG) provides evidence of LMN dysfunction which is required to support a diagnosis of ALS, and should be found in at least two of the four CNS regions: brainstem (bulbar/cranial motor neurons), cervical, thoracic, or lumbosacral spinal cord (anterior horn motor neurons). For the brainstem region it is sufficient to demonstrate EMG changes in one muscle (e.g. tongue, facial muscles, jaw muscles). For the thoracic spinal cord region it is sufficient to demonstrate EMG changes either in the paraspinal muscles at or below the T6 level or in the abdominal muscles. For the cervical and lumbosacral spinal cord regions at least two muscles innervated by different roots and peripheral nerves must show EMG changes [9].

The revised El-Escorial criteria require that both evidence of active or ongoing denervation and chronic partial denervation is required for the diagnosis of ALS, although relative proportions vary from muscle to muscle [9]. Signs of active denervation consist of:

1. fibrillation potentials

2. positive sharp waves

Signs of chronic denervation consist of:

1. large motor unit potentials of increased duration with an increased proportion of polyphasic potentials, often of increased amplitude

2. reduced interference pattern with firing rates higher than 10 Hz (unless there is a significant UMN component, in which case the firing rate may be lower than 10 Hz)

3. unstable motor unit potentials.

Fasciculation potentials are an important characteristic finding in ALS, although they can be seen in normal muscles (benign fasciculations) and are not present in all muscles in ALS patients. In benign fasciculations the morphology of the fasciculation potentials are normal, whereas in fasciculation potentials associated with neurogenic change there are abnormal and complex morphology [10, 194]. The Awaji group suggest that the presence of abnormal complex fasciculation potentials in a muscle showing neurogenic change, can be considered equivalent in importance to fibrillation potentials or positive sharp waves [10].

3. Transcranial magnetic stimulation and Central motor conduction studies

Transcranial magnetic stimulation (TMS) allows a non-invasive evaluation of corticospinal motor pathways, and allows detection of UMN lesions in patients who lack UMN signs. Motor amplitude, cortical threshold, central motor conduction time and silent periods can be easily evaluated using this method [195]. Central motor conduction time (CMCT) is often marginally prolonged to muscles of at least one extremity in ALS patients. Electrophysiological features compatible with UMN involvement include [9]:

1. Up to a 30% increase in central motor conduction time determined by cortical magnetic stimulation and

2. Low firing rates of motor unit potentials on maximal effort.

Marked prolongation in the CMCT is seen in FALS patients with D90A SOD1 mutations and patients with the flail arm and flail leg variants [196–198].

4. Quantitative electromyography

Motor unit number estimation (MUNE) is a special electrophysiological technique that can provide a quantitative estimate of the number of axons innervating a muscle or group of muscles. MUNE consists of a number of different methods (incremental, multiple point stimulation, spike-triggered averaging, F-wave, and statistical methods), with each having specific advantages and limitations. Despite the lack of a perfect single method for performing MUNE, it may have value in the assessment of progressive motor axon loss in ALS, and may have use as an end-point measure in clinical trials [199].

Neuroimaging studies

The most important use of neuroimaging is in the diagnosis of ALS to exclude treatable structural lesion that mimics ALS by producing varying degrees of UMN and LMN signs, especially in those with clinically probable or possible ALS. The WFN revised criteria state that imaging studies are not required in cases that have clinically definite disease with bulbar or pseudobulbar onset as it is unlikely that structural lesions can mimic clinically definite disease [9]. Magnetic resonance imaging (MRI) can be used in revealing lesions in the corticospinal tracts in ALS. The most characteristic finding in ALS is hyperintensity of the corticospinal tracts on T2-weighted, proton density weighted and FLAIR-weighted MRI, and is best visualised in the brain and brainstem and to a lesser extent in the spinal cord [200–203]. T2 weighted MRI may also show hypointensity of the primary motor cortex, usually along the posterior bank of the precentral gyrus, although this is an inconsistent and non-specific finding [204].

More advanced neuroimaging modalities such as magnetic resonance spectroscopy, diffusion weighted imaging (DWI)/diffusion tensor imaging (DTI), magnetic resonance voxel-based morphometry and functional imaging techniques (fMRI, PET and SPECT) have a limited role in routine clinical practice but have shown promise in understanding pathophysiology of the disease in vivo, identification of potential biomarkers of disease progression and identifying disease changes earlier in the course of the disease facilitating earlier diagnosis [205–210].

Muscle biopsy and neuropathalogical studies

Biopsy of skeletal muscle or other tissues is not required for diagnosis, unless to rule out a mimic syndrome (e.g. Inclusion body myositis). In addition, muscle biopsy may be used to demonstrate LMN dysfunction in a body region when clinical or electrophysiological findings do not support this. Histological findings that are compatible with the diagnosis of ALS include [9]:

• Scattered hypertrophied muscle fibres.

• No more than a moderate number of target or targetoid fibres.

• Fibre type grouping of no more than mild-to-moderate extent.

• The presence of a small number of necrotic muscle fibres.

Other laboratory studies

There are few other investigations that may be considered mandatory in the work-up of an ALS patient. Clinical laboratory tests that may be abnormal in otherwise typical case of ALS include [9]:

• Muscle enzymes (serum creatine kinase [unusual above ten times upper limit of normal], ALT, AST, LDH)

• Serum creatinine (related to loss of skeletal muscle mass)

• Hypochloremia, increased bicarbonate (related to advanced respiratory compromise)

• Elevated CSF protein (uncommonly more than 100 mg/dl)

Management

The management of ALS/MND has considerably changed over the past two decades, with a emphasis on coordinated multidisciplinary care between specialist, community based therapists and palliative care teams. Although the condition is considered incurable, many of the symptoms arising during the course of the disease are treatable, and all efforts should be made to improve quality of life and help maintain the patient's autonomy for as long as possible. Advanced directives on end of life care, respiratory and nutritional management during late stages of life are important issues, and should be discussed with patients and relatives at the earliest opportunity that they are willing to do this. Patients with ALS and their relatives are likely to suffer from depression, feelings of hopelessness and anxiety regarding end-of-life issues following the diagnosis or as the disease progresses [211, 212]. Therefore, psychological support in the form of counselling and palliative care should be offered to the patients and relatives early [74, 213].

Symptomatic treatments

Symptomatic treatments aim to improve quality of life of patients and care givers. The main symptoms encountered in ALS and their management are shown in Table 4.

Table 4

Symptomatic treatments for ALS (with permission from Radunović et al. 2007)

	Drugs	Other treatments
Cramps	• Carbamazepine	• Physiotherapy
	• Phenytoin	• Physical exercise
	• Quinine (removed from US market)	• Massage
		• Hydrotherapy
Spasticity	• Baclofen	• Physiotherapy
	• Tizanidine	• Hydrotherapy
	• Dantrolene	• Cryotherapy
	• Botulinum toxin type A
Excessive watery saliva	• Atropine	• Home suction device
	• Hyoscine hydrobromide	• Dark grape juice
	• Hyoscine butylbromide	• Sugar-free citrus lozenges
	• Hyoscine scopoderm	• Nebulisation
	• Glycopyrronium	• Steam inhalation
	• Amitriptyline	• Injections of botulinum toxin into parotid glands
		• Irradiation of the salivary glands
Persistent saliva and bronchial secretions	• Carbocisteine	• Home suction device
	• Propranolol	• Assisted cough insufflator-exsufflator
	• Metoprolol	• Rehydration (jelly or ice)
		• Pineapple or papaya juice
		• Reduced intake of diary products, alcohol, and caffeine
Excessive or violent yawning	Baclofen
Laryngospasm	Lorazepam	Reassurance
Pain	• Simple analgesics	Comfort (seating, sleeping, day and night care)
	• Non-steroidal anti-inflammatory drugs
	• Opioids
Emotional lability	• Tricyclic antidepressant
	• Selective serotonin-reuptake inhibitors
	• Levodopa
	• Dextrometorphan and quinidine
Communication difficulties		• Speaking techniques
		• Low-tech augmentative and alternative communication tools
		• Voice amplifiers
		• Light writers
		• Scanning systems operated by switches
		• Brain-computer interfaces
Constipation	• Lactulose	• Hydration
	• Senna	• Increased fibre intake
Depression	• Amitriptyline	• Psychological support, counselling
	• Citalopram
Insomnia	• Amitriptyline	Comfort, analgesia
	• Zolpidem
Anxiety	Lorazepam	Psychological support, counselling
Fatigue	Modafinil

Ventilatory management

Respiratory insufficiency occurs commonly in patients with ALS and is a major cause of mortality. The presenting symptoms of respiratory muscle weakness include dyspnoea on exertion or talking, orthopneoa, disturbed sleep, excessive daytime somnolence, morning headaches, fatigue, anorexia, depression, poor concentration, vivid nightmares and nocturia. Clinical signs evident on examination include tachypnoea, use of accessory breathing muscles, paradoxical movement of the abdomen, weak cough and rarely papilloedema [74, 214].

Measurements of the forced vital capacity (FVC) or relaxed (slow) vital capacity (SVC) are the most widely available measures for detecting respiratory decline. Measurement of the Sniff nasal inspiratory pressure (SNIP) is a good measure of diaphragmatic strength and is probably more accurate than vital capacity, although both measurements underestimate respiratory function in patients with bulbar impairment. The American Academy of Neurology (AAN) ALS Practice Parameter (1999) recommends starting non-invasive ventilation when forced vital capacity declines to 50% of the predicted value [215]. However, patients can develop respiratory failure with a forced vital capacity above 70% of the predicted value, therefore a forced vital capacity of 75% or less is probably more appropriate as a threshold for closer monitoring of respiratory symptoms [216–218]. A SNIP of 32% (~25 cms H2O) or less is highly predictive of respiratory failure [219]. Overnight oximetry can reveal episodes of desaturation consistent with nocturnal hypoventilation. Abnormalities of arterial or venous (ear lobe) blood gases, such as respiratory acidosis are a late but important finding that signifies the need for respiratory support.

Respiratory support is usually provided by non-invasive ventilation (NIV) or invasive ventilation via tracheotomy. Bi-level positive pressure devices (BiPAP) are the commonly used form of NIV, whereas continuous positive pressure (CPAP) ventilation is not usually helpful [220]. The timing of initiating NIV treatment varies between counties and centres, but most published international guidelines such as those by the EALSC's work shop group [221] and EFNS task force [222], suggest the criteria proposed by the European ALS/MND Consortium and European Neuromuscular Centre workshop on non-invasive ventilation in MND in May 2002, and are shown in Table 5[74].

Table 5

Suggested criteria for non-invasive ventilation (NIV): Provisional European consensus criteria for NIV (European ALS/MND Consortium and European Neuromuscular Centre workshop on non-invasive ventilation in MND, May 2002) [with permission from Leigh et al. 2003]

Symptoms related to respiratory muscle weakness. At least one of
• Dyspnoea
• Orthopnoea
• Disturbed sleep (not caused by pain)
• Morning headache
• Poor concentration
• Anorexia
• Excessive daytime sleepiness (ESS > 9)
AND	Evidence of respiratory muscle weakness (FVC ≤ 80% or SNP ≤ 40 cmH2O)
AND	Evidence of EITHER:
	significant nocturnal desaturation on overnight oximetry
	OR
	morning ear lobe blood gas pCO₂ ≥ 6.5 kPa

ESS, Epworth sleepiness scale

NIV is usually initially used for intermittent nocturnal support to alleviate symptoms of nocturnal hypoventilation, although as respiratory function worsens, patients tend to require increasing daytime support and eventually continuous support. Observational studies and a recent randomised controlled trial involving 92 ALS patients show that NIV improves survival and quality of life [223, 224]. In patients with severe bulbar impairment, NIV improves sleep-related symptoms, but is unlikely to confer a large survival advantage [223].

Nutritional management

Dysphagia is a common symptom of ALS and leads to increased risk of aspiration, malnutrition, weight loss and dehydration. Malnutrition and dehydration can also occur inpatients whom have severe upper limb weakness, especially if they live alone, as this leads to difficulties in meal preparation or prolonged meal times. ALS is associated with a hyper metabolic state, therefore patients require increased calorie intake [225, 226]. Early management of dysphagia includes dietary advice, modification of food consistency (blending solid, adding thickening agents to liquids) and educating patients on special swallowing techniques (such as supraglottic swallowing and postural changes ('Chin tuck manoeuvre') [74, 222].

Most guidelines state that supplementary enteral feeding should be considered when body weight falls by > 10% of the pre-diagnostic or baseline weight [74, 222]. The three options available for enteric feeding include percutaneous endoscopic gastrostomy (PEG), percutaneous radiologic gastrostomy (PRG) or radiologically inserted gastrostomy (RIG), and nasogastric tube (NGT) feeding. PEG is the standard procedure for enteral feeding, although the procedure requires mild sedation and therefore has implications in patients with respiratory weakness. To minimise risks, evidence suggests that PEG should be performed before VC falls below 50% of predicted [74, 227]. Although it may be possible to insert PEG with NIV assistance, PRG/RIG insertion is a better alternative in these patients [228–230]. NGT is a relatively non-invasive option, but is limited by discomfort and problems associated with long term use such as frequent replacement, and should only be considered in patients who cannot undergo PEG or RIG insertion.

Disease modifying treatments

Despite many clinical trials and various advances in the understanding of ALS, there has been little success in the search for disease modifying or neuroprotective agents. Riluzole is the only approved drug that has been shown to have a modest effect on prolonging life in ALS patients [231–237]. The mechanism of action of riluzole is not entirely certain but is though to include interference with N-methyl-D-aspartate (NMDA) receptor mediated responses, stabilisation of the inactivated state of voltage-dependent sodium channels, inhibition of glutamate release from pre-synaptic terminals, and increasing of extracellular glutamate uptake [238]. The conclusion of a recent Cochrane Collaboration meta-analysis stated that riluzole at 100 mg probably prolongs median survival by 2–3 months when taken for a 18 month duration (in patients clinically probable or definite El Escorial ALS, with symptoms less than 5 years, FVC > 60% and age < 75 years) [239]. The absolute risk reduction with the 100 mg dose at 12 months was 9%, with the numbers needed-to-treat to delay one death (NNT) after 12 months is 11 [239]. The drug is generally well tolerated with the most common side effects being asthenia, nausea, gastrointestinal upset and abnormal liver function tests, and therefore liver function should be regularly monitored during therapy [240].

Over 100 other neuroprotective agents have been studied in animal models and humans. Some agents that have been evaluated in phase II or III human clinical trials and have shown inconclusive evidence or failed to demonstrate effectiveness for routine clinical practice include:

• Subcutaneous recombinant human insulin-like growth factor (IGF-1, ormyotrophin), neurotrophins including brain derived neurotrophic factor, ciliary neurotrophic factor, glial cell line derived neurotrophic factor and oral xaliproden [241–245]

• Ceftriaxone [246]

• Talampanel (8-methyl-7H-1,3-dioxolo(2,3)benzodiazepine)

• Tamoxifen [247]

• Minocycline [248]

• TCH346 [249]

• Coenzyme Q10 [250]

• Vitamin E [251, 252]

• Celecoxib [253]

• Creatine [254, 255]

• Copaxone [256]

• ONO 2506 – A randomised placebo-controlled investigate efficacy and safety of ONO-2506PO in the presence of riluzole was negative overall in 2004 but showed a trend towards improved survival in those who started the drug within 14 months of onset.

The use of gene therapy approach to deliver neurotrophic factors directly to neurons by means of genetically engineered adeno-associated viruses (AAV) expressing neurotrophic factor genes has been evaluated in SOD1 mouse models with some promising results [257], but human studies are not yet underway. Another approach is the use of autologous stem cell transplantation, but to date there have been no convincing results from human studies [258, 259]. The recent discovery of the ability to re-programme human skin fibroblast generate pluripotent stem cells (Induced pluripotent stem cells; iPS) [260] would allow patient and disease specific stem cells to produced, leading to better disease models and eventually better autologous cell replacement therapies.

Prognosis

Analysis of large patient samples drawn from clinic based populations or population registries consistently show that the overall median survival from onset of symptoms for ALS ranges between 2–3 years for bulbar onset cases and 3–5 years for limb onset ALS cases [12, 58, 261]. Large clinic cohort studies have shown 3 year and 5 year survival tares to be around 48% and 24% respectively, with approximately 4% surviving longer than 10 years [262, 263], whereas 5 year survival reported in population based studies is much lower and ranges from 4–30% [12].

Important prognostic indicators of survival consistently arising from population based studies and clinic cohort studies include clinical phenotype (PMA and Flail arm have better prognosis than typical forms) [264], site of onset (bulbar vs. limb onset) [17, 261, 264–266], age of symptom onset [58, 261, 264–267], shorter time from symptom onset to diagnosis [266], baseline FVC decline [261, 265, 268], El Escorial category at presentation [17, 267] and riluzole use [265, 269].

Appendix 1 – Some exogenous risk factors implicated in sporadic ALS

• Age at menopause (females) [270, 271]

• Dietary factors [272]

• Electrical injury [273]

• Family history of non-ALS neurodegenerative disease (Parkinson's or Alzheimer's disease) [274]

• Geographical residence (rural, suburban or urban) [275]

• Gulf war service (Male veterans) [276–278]

• Maternal age [279], Number of births (in females) & Birth order [81, 279, 280], Loss of child [281]

• Occupation [81, 282]

• Physical activity [283, 284],

• Playing football professionally [285–287]

• Previous poliomyelitis infection [288]

• Race/ethnicity [289]

• Smoking [79–81, 290, 291]

• Toxin exposure (agricultural chemicals, lead) [282, 292]

• Trauma (e.g. Head injury) [274, 285, 293]

• Years of education [81]

Notes

Abbreviations

(ALS):: Amyotrophic lateral sclerosis

(UMN):: upper motor neurone

(LMNs):: lower motor neurone

(Ub-IR):: ubiquitin-immunoreactive

(TDP43-IR):: TDP-43 immunoreactive

(EMG):: electromyography

(PMA):: progressive muscular atrophy

(PLS):: primary lateral sclerosis, (MND): motor neurone disease

(PBP):: progressive bulbar palsy

(PMA):: progressive muscular atrophy

(CSF):: cerebrospinal fluid

(WFN):: World Federation of Neurology

(FALS):: familial ALS

(SALS):: sporadic ALS

(jALS):: juvenile onset ALS

(ALS-PD complex):: ALS associated with the Parkinsonism and dementia

(TLS):: 'totally locked-in state'

(FTLD):: fronto-temporal dementia

(RR):: relative risk

(OR):: odds ratio

(VEGF):: vascular endothelial growth factor

(ROS):: reactive oxygen species

(SOD1):: superoxide dismutase 1

(NFH):: neurofilament heavy

(IAPs):: inhibitor family of proteins

(UBIs):: ubiquitinated inclusions

(SLIs):: skein-like inclusions

(TDP-43):: TAR DNA binding protein 43

(HCIs):: hyaline conglomerate inclusions

(FTLD-MND):: frontotemporal lobar degeneration with MND

(FTLD-U):: frontotemporal lobar degeneration with ubiquitin inclusions

(DML):: distal motor latency

(MCV):: motor conduction velocity

(TMS):: transcranial magnetic stimulation

(CMCT):: central motor conduction time

(MUNE):: motor unit number estimation

(DWI):: diffusion weighted imaging

(DTI):: diffusion tensor imaging

(FVC):: forced vital capacity

(SVC):: slow vital capacity

(SNIP):: sniff nasal inspiratory pressure

(AAN):: American Academy of Neurology

(NIV):: non-invasive ventilation

(BiPAP):: bi-level positive pressure devices

(CPAP):: continuous positive pressure

(PEG):: percutaneous endoscopic gastrostomy

(PRG):: percutaneous radiologic gastrostomy

(RIG):: radiologically inserted gastrostomy

(MRI):: magnetic resonance imaging

(NGT):: nasogastric tube

(NMDA):: N-methyl-D-aspartate

(AAV):: adeno-associated viruses

(iPS):: induced pluripotent stem cells.

Declarations

Acknowledgements

We are grateful to the MRC, Wellcome Trust, MND Association, ALS association, and The European Union for support over the last 10 years and to the MND Association for co-funding the King's MND Care and Research Centre. We thank especially the many people affected by MND who have altruistically and cheerfully contributed to our research over the years.

Authors’ Affiliations

(1)

MRC centre for Neurodegeneration Research, Department of Clinical Neuroscience, Box 41, Institute of Psychiatry, Kings College London, UK

References

Brain WR, Walton JN: Brain's diseases of the nervous system. London: Oxford university press; 1969.Google Scholar
Leigh PN, Anderton BH, Dodson A, Gallo JM, Swash M, Power DM: Ubiquitin deposits in anterior horn cells in motor neurone disease. Neurosci Lett. 1988, 93: 197-203.PubMedGoogle Scholar
Lowe J, Lennox G, Jefferson D, Morrell K, McQuire D, Gray T, Landon M, Doherty FJ, Mayer RJ: A filamentous inclusion body within anterior horn neurones in motor neurone disease defined by immunocytochemical localisation of ubiquitin. Neurosci Lett. 1988, 94: 203-210.PubMedGoogle Scholar
Kato S, Shaw P, Wood-Allum C, Leigh PN, Shaw CE: Amyotrophic lateral sclerosis. Neurodegeneration: The molecular pathology of dementia and movement disorders. Edited by: Dickson DW. ISN Neuropath press; 2003:350-371.Google Scholar
Rowland LP, Shneider NA: Amyotrophic lateral sclerosis. N Engl J Med. 2001, 344: 1688-1700.PubMedGoogle Scholar
Traynor BJ, Codd MB, Corr B, Forde C, Frost E, Hardiman O: Amyotrophic lateral sclerosis mimic syndromes: a population-based study. Arch Neurol. 2000, 57: 109-113.PubMedGoogle Scholar
Davenport RJ, Swingler RJ, Chancellor AM, Warlow CP: Avoiding false positive diagnoses of motor neuron disease: lessons from the Scottish Motor Neuron Disease Register. J Neurol Neurosurg Psychiatry. 1996, 60: 147-151.PubMed CentralPubMedGoogle Scholar
Brooks BR: El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. Subcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases and the El Escorial "Clinical limits of amyotrophic lateral sclerosis" workshop contributors. J Neurol Sci. 1994, 124 (Suppl): 96-107.PubMedGoogle Scholar
Brooks BR, Miller RG, Swash M, Munsat TL: El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000, 1: 293-299.PubMedGoogle Scholar
de Carvalho M, Dengler R, Eisen A, England JD, Kaji R, Kimura J, Mills K, Mitsumoto H, Nodera H, Shefner J, Swash M: Electrodiagnostic criteria for diagnosis of ALS. Clin Neurophysiol. 2008, 119: 497-503.PubMedGoogle Scholar
Worms PM: The epidemiology of motor neuron diseases: a review of recent studies. J Neurol Sci. 2001, 191: 3-9.PubMedGoogle Scholar
Chancellor AM, Slattery JM, Fraser H, Swingler RJ, Holloway SM, Warlow CP: The prognosis of adult-onset motor neuron disease: a prospective study based on the Scottish Motor Neuron Disease Register. J Neurol. 1993, 240: 339-346.PubMedGoogle Scholar
Traynor BJ, Codd MB, Corr B, Forde C, Frost E, Hardiman O: Incidence and prevalence of ALS in Ireland, 1995–1997: a population-based study. Neurology. 1999, 52: 504-509.PubMedGoogle Scholar
Johnston CA, Stanton BR, Turner MR, Gray R, Blunt AH, Butt D, Ampong MA, Shaw CE, Leigh PN, Al-Chalabi A: Amyotrophic lateral sclerosis in an urban setting: a population based study of inner city London. J Neurol. 2006, 253: 1642-1643.PubMedGoogle Scholar
Table 2: Deaths by age, sex and underlying cause, 2003 registrations. Death registrations in England and Wales ed.: Office of National statistics. 2003, [http://www.statistics.gov.uk/STATBASE/ssdataset.asp?vlnk=8257]Google Scholar
Abhinav K, Stanton B, Johnston C, Hardstaff J, Orrell RW, Howard R, Clarke J, Sakel M, Ampong MA, Shaw CE: Amyotrophic lateral sclerosis in South-East England: a population-based study. The South-East England register for amyotrophic lateral sclerosis (SEALS Registry). Neuroepidemiology. 2007, 29: 44-48.PubMedGoogle Scholar
Zoccolella S, Beghi E, Palagano G, Fraddosio A, Guerra V, Samarelli V, Lepore V, Simone IL, Lamberti P, Serlenga L, Logroscino G: Analysis of survival and prognostic factors in amyotrophic lateral sclerosis: a population based study. J Neurol Neurosurg Psychiatry. 2008, 79: 33-37.PubMedGoogle Scholar
Logroscino G, Traynor BJ, Hardiman O, Chio' A, Couratier P, Mitchell JD, Swingler RJ, Beghi E, for EURALS: Descriptive epidemiology of amyotrophic lateral sclerosis: new evidence and unsolved issues. J Neurol Neurosurg Psychiatry. 2008, 79: 6-11.PubMedGoogle Scholar
Armon C: An evidence-based medicine approach to the evaluation of the role of exogenous risk factors in sporadic amyotrophic lateral sclerosis. Neuroepidemiology. 2003, 22: 217-228.PubMedGoogle Scholar
Nelson LM, McGuire V, Longstreth WT, Matkin C: Population-based case-control study of amyotrophic lateral sclerosis in western Washington State. I. Cigarette smoking and alcohol consumption. Am J Epidemiol. 2000, 151: 156-163.PubMedGoogle Scholar
Sejvar JJ, Holman RC, Bresee JS, Kochanek KD, Schonberger LB: Amyotrophic lateral sclerosis mortality in the United States, 1979–2001. Neuroepidemiology. 2005, 25: 144-152.PubMedGoogle Scholar
Leigh PN: Amyotrophic lateral sclerosis. Motor Neuron Disorders and related diseases. Edited by: Eisen AA, Sham PJ. 2007, Amsterdam: Elsevier, 82: 249-268. [Aminoff MJ, Boller F, Swaab DF (Series Editor): Handbook of Clinical Neurology]Google Scholar
Haverkamp LJ, Appel V, Appel SH: Natural history of amyotrophic lateral sclerosis in a database population. Validation of a scoring system and a model for survival prediction. Brain. 1995, 118 (Pt 3): 707-719.PubMedGoogle Scholar
Gouveia LO, De Carvalho M: Young-onset sporadic amyotrophic lateral sclerosis: A distinct nosological entity?. Amyotroph Lateral Scler. 2007, 1-5.Google Scholar
Beghi E, Millul A, Micheli A, Vitelli E, Logroscino G: Incidence of ALS in Lombardy, Italy. Neurology. 2007, 68: 141-145.PubMedGoogle Scholar
Forbes RB, Colville S, Swingler RJ: The epidemiology of amyotrophic lateral sclerosis (ALS/MND) in people aged 80 or over. Age Ageing. 2004, 33: 131-134.PubMedGoogle Scholar
Anderson PM: Genetic Aspects of Amyotrophic Lateral Sclerosis/Motor Neurone Disease. Motor Neuron Disorders Volume 28. Edited by: Shaw PJ, Strong MJ. Philadelphia: Butterworth Heinemann; 2003:207-208.Google Scholar
Mulder DW, Kurland LT, Offord KP, Beard CM: Familial adult motor neuron disease: amyotrophic lateral sclerosis. Neurology. 1986, 36: 511-517.PubMedGoogle Scholar
Gros-Louis F, Gaspar C, Rouleau GA: Genetics of familial and sporadic amyotrophic lateral sclerosis. Biochim Biophys Acta. 2006, 1762: 956-972.PubMedGoogle Scholar
Li TM, Alberman E, Swash M: Comparison of sporadic and familial disease amongst 580 cases of motor neuron disease. J Neurol Neurosurg Psychiatry. 1988, 51: 778-784.PubMed CentralPubMedGoogle Scholar
Veltema AN, Roos RA, Bruyn GW: Autosomal dominant adult amyotrophic lateral sclerosis. A six generation Dutch family. J Neurol Sci. 1990, 97: 93-115.PubMedGoogle Scholar
Strong MJ, Hudson AJ, Alvord WG: Familial amyotrophic lateral sclerosis, 1850–1989: a statistical analysis of the world literature. Can J Neurol Sci. 1991, 18: 45-58.PubMedGoogle Scholar
Ben Hamida M, Hentati F, Ben Hamida C: Hereditary motor system diseases (chronic juvenile amyotrophic lateral sclerosis). Conditions combining a bilateral pyramidal syndrome with limb and bulbar amyotrophy. Brain. 1990, 113 (Pt 2): 347-363.PubMedGoogle Scholar
Chance PF, Rabin BA, Ryan SG, Ding Y, Scavina M, Crain B, Griffin JW, Cornblath DR: Linkage of the gene for an autosomal dominant form of juvenile amyotrophic lateral sclerosis to chromosome 9q34. Am J Hum Genet. 1998, 62: 633-640.PubMed CentralPubMedGoogle Scholar
Hentati A, Bejaoui K, Pericak-Vance MA, Hentati F, Speer MC, Hung WY, Figlewicz DA, Haines J, Rimmler J, Ben Hamida C: Linkage of recessive familial amyotrophic lateral sclerosis to chromosome 2q33-q35. Nat Genet. 1994, 7: 425-428.PubMedGoogle Scholar
Hentati A, Ouahchi K, Pericak-Vance MA, Nijhawan D, Ahmad A, Yang Y, Rimmler J, Hung W, Schlotter B, Ahmed A: Linkage of a commoner form of recessive amyotrophic lateral sclerosis to chromosome 15q15-q22 markers. Neurogenetics. 1998, 2: 55-60.PubMedGoogle Scholar
Steele JC, McGeer PL: The ALS/PDC syndrome of Guam and the cycad hypothesis. Neurology. 2008, 70: 1984-1990.PubMedGoogle Scholar
Shaw CE, Arechavala-Gomeza V, Al-Chalabi A: Familial amyotrophic lateral sclerosis. Motor Neuron Disorders and Related Diseases. Edited by: Eisen AA, Shaw PJ. 2007, Elsevier, 82: 279-280. [Aminoff MJ, Boller F, Swaab DF (Series Editor): Handbook of Clinical Neurology]Google Scholar
Armon C: Epidemiology of Amyotrophic Lateral Sclerosis/Motor Neuron Disease. Motor Neuron Disorders. Butterworth Heinemann. 2003, 28: 195-197.Google Scholar
Plato CC, Garruto RM, Galasko D, Craig UK, Plato M, Gamst A, Torres JM, Wiederholt W: Amyotrophic lateral sclerosis and parkinsonism-dementia complex of Guam: changing incidence rates during the past 60 years. Am J Epidemiol. 2003, 157: 149-157.PubMedGoogle Scholar
Waring SC, Esteban-Santillan C, Reed DM, Craig UK, Labarthe DR, Petersen RC, Kurland LT: Incidence of amyotrophic lateral sclerosis and of the parkinsonism-dementia complex of Guam, 1950–1989. Neuroepidemiology. 2004, 23: 192-200.PubMedGoogle Scholar
Kuzuhara S, Kokubo Y: Atypical parkinsonism of Japan: amyotrophic lateral sclerosis-parkinsonism-dementia complex of the Kii peninsula of Japan (Muro disease): an update. Mov Disord. 2005, 20 (Suppl 12): S108-113.PubMedGoogle Scholar
Charcot J-M: De la sclérose latérale amyotrophique. Prog Med. 1874, 23; 24; 29: 235-237. 341–232; 453–235Google Scholar
Charcot J-M, Joffroy A: Deuxcas d'atrophie musculaire progressive avec lésions de la substance grise et de faisceaux antérolatéraux de la moelle épinière. Arch Physiol Norm Pathol. 1869, 1: 354-357. 352:628–649; 353:744–757Google Scholar
Tyler HR, Shefner J: Amyotrophic lateral sclerosis. Handb Clin Neurol. 1991, 169-215.Google Scholar
Aran FA: Recherches sur une maladie non encore décrite du systemé musculaire (atrophie musculaire progressive). Arch Gen Med. 1850, 14: 5-35. 172–214Google Scholar
Duchenne de Boulogne GB: Recherches électro-physiologiques et thérapeutiques. Comp Rend Seances Acad Sci. 1851, 32: 506.Google Scholar
Cruveilhier J: Sur le paralysie musculaire, progressive, atrophique. Bull Acad Med. 1853, 18: 490-501. 546–583Google Scholar
Goetz CG: Amyotrophic lateral sclerosis: Early contributions of Jean-Martin Charcot. Muscle & Nerve. 2000, 23: 336-343.Google Scholar
Rowland LP: How Amyotrophic Lateral Sclerosis Got Its Name: The Clinical-Pathologic Genius of Jean-Martin Charcot. Arch Neurol. 2001, 58: 512-515.PubMedGoogle Scholar
de Carvalho M, Matias T, Coelho F, Evangelista T, Pinto A, Luis ML: Motor neuron disease presenting with respiratory failure. J Neurol Sci. 1996, 139 (Suppl): 117-122.PubMedGoogle Scholar
Chen R, Grand'Maison F, Strong MJ, Ramsay DA, Bolton CF: Motor neuron disease presenting as acute respiratory failure: a clinical and pathological study. J Neurol Neurosurg Psychiatry. 1996, 60: 455-458.PubMed CentralPubMedGoogle Scholar
Polkey MI, Lyall RA, Moxham J, Leigh PN: Respiratory aspects of neurological disease. J Neurol Neurosurg Psychiatry. 1999, 66: 5-15.PubMed CentralPubMedGoogle Scholar
Okuda B, Yamamoto T, Yamasaki M, Maya K, Imai T: Motor neuron disease with slow eye movements and vertical gaze palsy. Acta Neurol Scand. 1992, 85: 71-76.PubMedGoogle Scholar
Kobayashi M, Ikeda K, Kinoshita M, Iwasaki Y: Amyotrophic lateral sclerosis with supranuclear ophthalmoplegia and rigidity. Neurol Res. 1999, 21: 661-664.PubMedGoogle Scholar
Hayashi H, Kato S: Total manifestations of amyotrophic lateral sclerosis: ALS in the totally locked-in state. Journal of the Neurological Sciences. 1989, 93: 19-35.PubMedGoogle Scholar
Sasaki S, Tsutsumi Y, Yamane K, Sakuma H, Maruyama S: Sporadic amyotrophic lateral sclerosis with extensive neurological involvement. Acta Neuropathol. 1992, 84: 211-215.PubMedGoogle Scholar
Norris F, Shepherd R, Denys E, U K, Mukai E, Elias L, Holden D, Norris H: Onset, natural history and outcome in idiopathic adult motor neuron disease. J Neurol Sci. 1993, 118: 48-55.PubMedGoogle Scholar
Traynor BJ, Codd MB, Corr B, Forde C, Frost E, Hardiman OM: Clinical features of amyotrophic lateral sclerosis according to the El Escorial and Airlie House diagnostic criteria: A population-based study. Arch Neurol. 2000, 57: 1171-1176.PubMedGoogle Scholar
Vulpian A: Maladies du système nerveux (moelle épinière).Volume 2. Paris: Octave Dion; 1886: 346.Google Scholar
Katz JS, Wolfe GI, Andersson PB, Saperstein DS, Elliott JL, Nations SP, Bryan WW, Barohn RJ: Brachial amyotrophic diplegia: a slowly progressive motor neuron disorder. Neurology. 1999, 53: 1071-1076.PubMedGoogle Scholar
Hu MT, Ellis CM, Al-Chalabi A, Leigh PN, Shaw CE: Flail arm syndrome: a distinctive variant of amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 1998, 65: 950-951.PubMed CentralPubMedGoogle Scholar
Couratier P, Truong C, Khalil M, Deviere F, Vallat JM: Clinical features of flail arm syndrome. Muscle Nerve. 2000, 23: 646-648.PubMedGoogle Scholar
Patrikios JS: Contribution à l'Étude des Formes Cliniques et de l'Anatomie Pathologique de la Sclérose Latérale Amyotrophique. Paris University; 1918.Google Scholar
Alema G, Brusa A, Pastorino P, Sacco G: [On 3 cases of the pseudopolyneuritic form of amyotrophic lateral sclerosis. Anatomic and electromyographic study]. J Neurol Sci. 1967, 4: 241-257.PubMedGoogle Scholar
Salemi G, Fierro B, Arcara A, Cassata M, Castiglione MG, Savettieri G: Amyotrophic lateral sclerosis in Palermo, Italy: an epidemiological study. Ital J Neurol Sci. 1989, 10: 505-509.PubMedGoogle Scholar
Guidetti D, Bondavalli M, Sabadini R, Marcello N, Vinceti M, Cavalletti S, Marbini A, Gemignani F, Colombo A, Ferrari A: Epidemiological survey of amyotrophic lateral sclerosis in the province of Reggio Emilia, Italy: influence of environmental exposure to lead. Neuroepidemiology. 1996, 15: 301-312.PubMedGoogle Scholar
Talman P, Forbes A, Mathers S: Clinical phenotypes and natural progression for motor neuron disease: Analysis from an Australian database. Amyotrophic Lateral Sclerosis. 2008, 99999: 1-6.Google Scholar
Pringle CE, Hudson AJ, Munoz DG, Kiernan JA, Brown WF, Ebers GC: Primary lateral sclerosis. Clinical features, neuropathology and diagnostic criteria. Brain. 1992, 115 (Pt 2): 495-520.PubMedGoogle Scholar
Le Forestier N, Maisonobe T, Spelle L, Lesort A, Salachas F, Lacomblez L, Samson Y, Bouche P, Meininger V: Primary lateral sclerosis: further clarification. J Neurol Sci. 2001, 185: 95-100.PubMedGoogle Scholar
Le Forestier N, Maisonobe T, Piquard A, Rivaud S, Crevier-Buchman L, Salachas F, Pradat PF, Lacomblez L, Meininger V: Does primary lateral sclerosis exist? A study of 20 patients and a review of the literature. Brain. 2001, 124: 1989-1999.PubMedGoogle Scholar
Gordon PH, Cheng B, Katz IB, Pinto M, Hays AP, Mitsumoto H, Rowland LP: The natural history of primary lateral sclerosis. Neurology. 2006, 66: 647-653.PubMedGoogle Scholar
Tartaglia MC, Rowe A, Findlater K, Orange JB, Grace G, Strong MJ: Differentiation between primary lateral sclerosis and amyotrophic lateral sclerosis: examination of symptoms and signs at disease onset and during follow-up. Arch Neurol. 2007, 64: 232-236.PubMedGoogle Scholar
Leigh PN, Abrahams S, Al-Chalabi A, Ampong MA, Goldstein LH, Johnson J, Lyall R, Moxham J, Mustfa N, Rio A: The management of motor neurone disease. J Neurol Neurosurg Psychiatry. 2003, 74 (Suppl 4): iv32-iv47.PubMed CentralPubMedGoogle Scholar
Ince PG, Lowe J, Shaw PJ: Amyotrophic lateral sclerosis: current issues in classification, pathogenesis and molecular pathology. Neuropathol Appl Neurobiol. 1998, 24: 104-117.PubMedGoogle Scholar
Phukan J, Pender NP, Hardiman O: Cognitive impairment in amyotrophic lateral sclerosis. Lancet Neurol. 2007, 6: 994-1003.PubMedGoogle Scholar
Shaw PJ: Molecular and cellular pathways of neurodegeneration in motor neurone disease. J Neurol Neurosurg Psychiatry. 2005, 76: 1046-1057.PubMed CentralPubMedGoogle Scholar
Cozzolino M, Ferri A, Carri MT: Amyotrophic lateral sclerosis: from current developments in the laboratory to clinical implications. Antioxid Redox Signal. 2008, 10: 405-443.PubMedGoogle Scholar
Weisskopf MG, McCullough ML, Calle EE, Thun MJ, Cudkowicz M, Ascherio A: Prospective study of cigarette smoking and amyotrophic lateral sclerosis. Am J Epidemiol. 2004, 160: 26-33.PubMedGoogle Scholar
Fang F, Bellocco R, Hernan MA, Ye W: Smoking, snuff dipping and the risk of amyotrophic lateral sclerosis – a prospective cohort study. Neuroepidemiology. 2006, 27: 217-221.PubMedGoogle Scholar
Sutedja NA, Veldink JH, Fischer K, Kromhout H, Wokke JH, Huisman MH, Heederik DJ, Berg Van den LH: Lifetime occupation, education, smoking, and risk of ALS. Neurology. 2007, 69: 1508-1514.PubMedGoogle Scholar
Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O'Regan JP, Deng HX: Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993, 362: 59-62.PubMedGoogle Scholar
Hadano S, Hand CK, Osuga H, Yanagisawa Y, Otomo A, Devon RS, Miyamoto N, Showguchi-Miyata J, Okada Y, Singaraja R: A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat Genet. 2001, 29: 166-173.PubMedGoogle Scholar
Yang Y, Hentati A, Deng HX, Dabbagh O, Sasaki T, Hirano M, Hung WY, Ouahchi K, Yan J, Azim AC: The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nat Genet. 2001, 29: 160-165.PubMedGoogle Scholar
Chen YZ, Bennett CL, Huynh HM, Blair IP, Puls I, Irobi J, Dierick I, Abel A, Kennerson ML, Rabin BA: DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet. 2004, 74: 1128-1135.PubMed CentralPubMedGoogle Scholar
Nishimura AL, Mitne-Neto M, Silva HC, Richieri-Costa A, Middleton S, Cascio D, Kok F, Oliveira JR, Gillingwater T, Webb J: A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet. 2004, 75: 822-831.PubMed CentralPubMedGoogle Scholar
Greenway MJ, Alexander MD, Ennis S, Traynor BJ, Corr B, Frost E, Green A, Hardiman O: A novel candidate region for ALS on chromosome 14q11.2. Neurology. 2004, 63: 1936-1938.PubMedGoogle Scholar
Greenway MJ, Andersen PM, Russ C, Ennis S, Cashman S, Donaghy C, Patterson V, Swingler R, Kieran D, Prehn J: ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis. Nat Genet. 2006, 38: 411-413.PubMedGoogle Scholar
Puls I, Jonnakuty C, LaMonte BH, Holzbaur EL, Tokito M, Mann E, Floeter MK, Bidus K, Drayna D, Oh SJ: Mutant dynactin in motor neuron disease. Nat Genet. 2003, 33: 455-456.PubMedGoogle Scholar
Munch C, Sedlmeier R, Meyer T, Homberg V, Sperfeld AD, Kurt A, Prudlo J, Peraus G, Hanemann CO, Stumm G, Ludolph AC: Point mutations of the p150 subunit of dynactin (DCTN1) gene in ALS. Neurology. 2004, 63: 724-726.PubMedGoogle Scholar
Yokoseki A, Shiga A, Tan CF, Tagawa A, Kaneko H, Koyama A, Eguchi H, Tsujino A, Ikeuchi T, Kakita A: TDP-43 mutation in familial amyotrophic lateral sclerosis. Ann Neurol. 2008, 63: 538-542.PubMedGoogle Scholar
Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B, Ackerley S, Durnall JC, Williams KL, Buratti E: TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science. 2008, 319: 1668-1672.PubMedGoogle Scholar
Kabashi E, Valdmanis PN, Dion P, Spiegelman D, McConkey BJ, Velde Vande C, Bouchard JP, Lacomblez L, Pochigaeva K, Salachas F: TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet. 2008, 40: 572-574.PubMedGoogle Scholar
Figlewicz DA, Krizus A, Martinoli MG, Meininger V, Dib M, Rouleau GA, Julien J-P: Variants of the heavy neurofilament subunit are associated with the development of amyotrophic lateral sclerosis. Hum Mol Genet. 1994, 3: 1757-1761.PubMedGoogle Scholar
Tomkins J, Usher P, Slade JY, Ince PG, Curtis A, Bushby K, Shaw PJ: Novel insertion in the KSP region of the neurofilament heavy gene in amyotrophic lateral sclerosis (ALS). Neuroreport. 1998, 9: 3967-3970.PubMedGoogle Scholar
Al-Chalabi A, Enayat ZE, Bakker MC, Sham PC, Ball DM, Shaw CE, Lloyd CM, Powell JF, Leigh PN: Association of apolipoprotein E epsilon 4 allele with bulbar-onset motor neuron disease. Lancet. 1996, 347: 159-160.PubMedGoogle Scholar
Meyer T, Fromm A, Munch C, Schwalenstocker B, Fray AE, Ince PG, Stamm S, Gron G, Ludolph AC, Shaw PJ: The RNA of the glutamate transporter EAAT2 is variably spliced in amyotrophic lateral sclerosis and normal individuals. J Neurol Sci. 1999, 170: 45-50.PubMedGoogle Scholar
Trotti D, Aoki M, Pasinelli P, Berger UV, Danbolt NC, Brown RH, Hediger MA: Amyotrophic Lateral Sclerosis-linked Glutamate Transporter Mutant Has Impaired Glutamate Clearance Capacity. J Biol Chem. 2001, 276: 576-582.PubMedGoogle Scholar
Lambrechts D, Storkebaum E, Morimoto M, Del-Favero J, Desmet F, Marklund SL, Wyns S, Thijs V, Andersson J, van Marion I: VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nat Genet. 2003, 34: 383-394.PubMedGoogle Scholar
Pasinelli P, Brown RH: Molecular biology of amyotrophic lateral sclerosis: insights from genetics. Nat Rev Neurosci. 2006, 7: 710-723.PubMedGoogle Scholar
Rothstein JD, Tsai G, Kuncl RW, Clawson L, Cornblath DR, Drachman DB, Pestronk A, Stauch BL, Coyle JT: Abnormal excitatory amino acid metabolism in amyotrophic lateral sclerosis. Ann Neurol. 1990, 28: 18-25.PubMedGoogle Scholar
Shaw PJ, Forrest V, Ince PG, Richardson JP, Wastell HJ: CSF and plasma amino acid levels in motor neuron disease: elevation of CSF glutamate in a subset of patients. Neurodegeneration. 1995, 4: 209-216.PubMedGoogle Scholar
Rothstein JD, Van Kammen M, Levey AI, Martin LJ, Kuncl RW: Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol. 1995, 38: 73-84.PubMedGoogle Scholar
Pamela J, Shaw PGI, Falkous Gavin, Mantle David: Oxidative damage to protein in sporadic motor neuron disease spinal cord. Annals of Neurology. 1995, 38: 691-695.Google Scholar
Ferrante RJ, Browne SE, Shinobu LA, Bowling AC, Baik MJ, MacGarvey U, Kowall NW, Brown RH, Beal MF: Evidence of increased oxidative damage in both sporadic and familial amyotrophic lateral sclerosis. J Neurochem. 1997, 69: 2064-2074.PubMedGoogle Scholar
R Glenn Smith YKH, Mark P Mattson, Stanley H Appel: Presence of 4-hydroxynonenal in cerebrospinal fluid of patients with sporadic amyotrophic lateral sclerosis. Annals of Neurology. 1998, 44: 696-699.Google Scholar
Hideo Tohgi TA, Kinya Yamazaki, Takahiko Murata, Eri Ishizaki, Chiaki Isobe: Remarkable increase in cerebrospinal fluid 3-nitrotyrosine in patients with sporadic amyotrophic lateral sclerosis. Annals of Neurology. 1999, 46: 129-131.Google Scholar
Aguirre LvDB T, Goetschalckx K, Tilkin P, Mathijis G, Cassiman JJ, Robberecht W: Increased sensitivity of fibroblasts from amyotrophic lateral sclerosis patients to oxidative stress. Annals of Neurology. 1998, 43: 452-457.Google Scholar
Atsumi T: The ultrastructure of intramuscular nerves in amyotrophic lateral sclerosis. Acta Neuropathol. 1981, 55: 193-198.PubMedGoogle Scholar
Afifi AK, Aleu FP, Goodgold J, MacKay B: Ultrastructure of atrophic muscle in amyotrophic lateral sclerosis. Neurology. 1966, 16: 475-481.PubMedGoogle Scholar
Hirano A, Donnenfeld H, Sasaki S, Nakano I: Fine structural observations of neurofilamentous changes in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol. 1984, 43: 461-470.PubMedGoogle Scholar
Siklos L, Engelhardt J, Harati Y, Smith RG, Joo F, Appel SH: Ultrastructural evidence for altered calcium in motor nerve terminals in amyotropic lateral sclerosis. Ann Neurol. 1996, 39: 203-216.PubMedGoogle Scholar
Kong J, Xu Z: Massive mitochondrial degeneration in motor neurons triggers the onset of amyotrophic lateral sclerosis in mice expressing a mutant SOD1. J Neurosci. 1998, 18: 3241-3250.PubMedGoogle Scholar
Krasnianski A, Deschauer M, Neudecker S, Gellerich FN, Muller T, Schoser BG, Krasnianski M, Zierz S: Mitochondrial changes in skeletal muscle in amyotrophic lateral sclerosis and other neurogenic atrophies. Brain. 2005, 128: 1870-1876.PubMedGoogle Scholar
Hirano M, Angelini C, Montagna P, Hays AP, Tanji K, Mitsumoto H, Gordon PH, Naini AB, DiMauro S, Rowland LP: Amyotrophic lateral sclerosis with ragged-red fibers. Arch Neurol. 2008, 65: 403-406.PubMedGoogle Scholar
Wiedemann FR, Winkler K, Kuznetsov AV, Bartels C, Vielhaber S, Feistner H, Kunz WS: Impairment of mitochondrial function in skeletal muscle of patients with amyotrophic lateral sclerosis. J Neurol Sci. 1998, 156: 65-72.PubMedGoogle Scholar
Dhaliwal GK, Grewal RP: Mitochondrial DNA deletion mutation levels are elevated in ALS brains. Neuroreport. 2000, 11: 2507-2509.PubMedGoogle Scholar
Falk R Wiedemann GM, Christian Mawrin, M Flint Beal, Eric A Schon: Mitochondrial DNA and respiratory chain function in spinal cords of ALS patients. Journal of Neurochemistry. 2002, 80: 616-625.PubMedGoogle Scholar
Ro LS, Lai SL, Chen CM, Chen ST: Deleted 4977-bp mitochondrial DNA mutation is associated with sporadic amyotrophic lateral sclerosis: a hospital-based case-control study. Muscle Nerve. 2003, 28: 737-743.PubMedGoogle Scholar
Grierson AJ, Miller C: Axonal transport and amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis. Edited by: Brown Jr RH, Swash M, Pasinelli P. 2006, Informa healthcare, 309-318. 2Google Scholar
Williamson TL, Cleveland DW: Slowing of axonal transport is a very early event in the toxicity of ALS-linked SOD1 mutants to motor neurons. Nat Neurosci. 1999, 2: 50-56.PubMedGoogle Scholar
Borchelt DR, Wong PC, Becher MW, Pardo CA, Lee MK, Xu ZS, Thinakaran G, Jenkins NA, Copeland NG, Sisodia SS: Axonal transport of mutant superoxide dismutase 1 and focal axonal abnormalities in the proximal axons of transgenic mice. Neurobiol Dis. 1998, 5: 27-35.PubMedGoogle Scholar
Murakami T, Nagano I, Hayashi T, Manabe Y, Shoji M, Setoguchi Y, Abe K: Impaired retrograde axonal transport of adenovirus-mediated E. coli LacZ gene in the mice carrying mutant SOD1 gene. Neurosci Lett. 2001, 308: 149-152.PubMedGoogle Scholar
De Vos KJ, Grierson AJ, Ackerley S, Miller CCJ: Role of Axonal Transport in Neurodegenerative Diseases. Annual Review of Neuroscience. 2008, 31: 151-173.PubMedGoogle Scholar
Reid E, Kloos M, Ashley-Koch A, Hughes L, Bevan S, Svenson IK, Graham FL, Gaskell PC, Dearlove A, Pericak-Vance MA: A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10). Am J Hum Genet. 2002, 71: 1189-1194.PubMed CentralPubMedGoogle Scholar
Zhao C, Takita J, Tanaka Y, Setou M, Nakagawa T, Takeda S, Yang HW, Terada S, Nakata T, Takei Y: Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bbeta. Cell. 2001, 105: 587-597.PubMedGoogle Scholar
Carpenter S: Proximal axonal enlargement in motor neuron disease. Neurology. 1968, 18: 841-851.PubMedGoogle Scholar
Hirano A, Nakano I, Kurland LT, Mulder DW, Holley PW, Saccomanno G: Fine structural study of neurofibrillary changes in a family with amyotrophic lateral sclerosis. J Neuropathol Exp Neurol. 1984, 43: 471-480.PubMedGoogle Scholar
Al-Chalabi A, Andersen PM, Nilsson P, Chioza B, Andersson JL, Russ C, Shaw CE, Powell JF, Leigh PN: Deletions of the heavy neurofilament subunit tail in amyotrophic lateral sclerosis. Hum Mol Genet. 1999, 8: 157-164.PubMedGoogle Scholar
Corbo M, Hays AP: Peripherin and neurofilament protein coexist in spinal spheroids of motor neuron disease. J Neuropathol Exp Neurol. 1992, 51: 531-537.PubMedGoogle Scholar
Robertson J, Doroudchi MM, Nguyen MD, Durham HD, Strong MJ, Shaw G, Julien J-P, Mushynski WE: A neurotoxic peripherin splice variant in a mouse model of ALS. J Cell Biol. 2003, 160: 939-949.PubMed CentralPubMedGoogle Scholar
Troost D, Oord van den JJ, de Jong JM, Swaab DF: Lymphocytic infiltration in the spinal cord of patients with amyotrophic lateral sclerosis. Clin Neuropathol. 1989, 8: 289-294.PubMedGoogle Scholar
Troost D, Oord Van den JJ, Vianney de Jong JM: Immunohistochemical characterization of the inflammatory infiltrate in amyotrophic lateral sclerosis. Neuropathol Appl Neurobiol. 1990, 16: 401-410.PubMedGoogle Scholar
Kawamata T, Akiyama H, Yamada T, McGeer PL: Immunologic reactions in amyotrophic lateral sclerosis brain and spinal cord tissue. Am J Pathol. 1992, 140: 691-707.PubMed CentralPubMedGoogle Scholar
Henkel JS, Engelhardt JI, Siklos L, Simpson EP, Kim SH, Pan T, Goodman JC, Siddique T, Beers DR, Appel SH: Presence of dendritic cells, MCP-1, and activated microglia/macrophages in amyotrophic lateral sclerosis spinal cord tissue. Ann Neurol. 2004, 55: 221-235.PubMedGoogle Scholar
Hall ED, Oostveen JA, Gurney ME: Relationship of microglial and astrocytic activation to disease onset and progression in a transgenic model of familial ALS. Glia. 1998, 23: 249-256.PubMedGoogle Scholar
Almer G, Guegan C, Teismann P, Naini A, Rosoklija G, Hays AP, Chen C, Przedborski S: Increased expression of the pro-inflammatory enzyme cyclooxygenase-2 in amyotrophic lateral sclerosis. Ann Neurol. 2001, 49: 176-185.PubMedGoogle Scholar
Robertson J, Beaulieu JM, Doroudchi MM, Durham HD, Julien JP, Mushynski WE: Apoptotic death of neurons exhibiting peripherin aggregates is mediated by the proinflammatory cytokine tumor necrosis factor-alpha. J Cell Biol. 2001, 155: 217-226.PubMed CentralPubMedGoogle Scholar
Sekizawa T, Openshaw H, Ohbo K, Sugamura K, Itoyama Y, Niland JC: Cerebrospinal fluid interleukin 6 in amyotrophic lateral sclerosis: immunological parameter and comparison with inflammatory and non-inflammatory central nervous system diseases. J Neurol Sci. 1998, 154: 194-199.PubMedGoogle Scholar
Wilms H, Sievers J, Dengler R, Bufler J, Deuschl G, Lucius R: Intrathecal synthesis of monocyte chemoattractant protein-1 (MCP-1) in amyotrophic lateral sclerosis: further evidence for microglial activation in neurodegeneration. J Neuroimmunol. 2003, 144: 139-142.PubMedGoogle Scholar
Anand P, Parrett A, Martin J, Zeman S, Foley P, Swash M, Leigh PN, Cedarbaum JM, Lindsay RM, Williams-Chestnut RE: Regional changes of ciliary neurotrophic factor and nerve growth factor levels in post mortem spinal cord and cerebral cortex from patients with motor disease. Nat Med. 1995, 1: 168-172.PubMedGoogle Scholar
Elliott JL, Snider WD: Motor neuron growth factors. Neurology. 1996, 47: S47-53.PubMedGoogle Scholar
Oppenheim RW: Neurotrophic survival molecules for motoneurons: an embarrassment of riches. Neuron. 1996, 17: 195-197.PubMedGoogle Scholar
Oosthuyse B, Moons L, Storkebaum E, Beck H, Nuyens D, Brusselmans K, Van Dorpe J, Hellings P, Gorselink M, Heymans S: Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nat Genet. 2001, 28: 131-138.PubMedGoogle Scholar
Lambrechts D, Poesen K, Fernandez-Santiago R, Al-Chalabi A, Del Bo R, Van Vaught PW, Khan S, Marklund S, Brockington A, Van Marion I: Meta-analysis of VEGF variations in ALS: increased susceptibility in male carriers of the -2578AA genotype. J Med Genet. 2008Google Scholar
Guegan C, Przedborski S: Programmed cell death in amyotrophic lateral sclerosis. J Clin Invest. 2003, 111: 153-161.PubMed CentralPubMedGoogle Scholar
Pasinelli P, Borchelt DR, Houseweart MK, Cleveland DW, Brown RH: Caspase-1 is activated in neural cells and tissue with amyotrophic lateral sclerosis-associated mutations in copper-zinc superoxide dismutase. Proc Natl Acad Sci USA. 1998, 95: 15763-15768.PubMed CentralPubMedGoogle Scholar
Pasinelli P, Houseweart MK, Brown RH, Cleveland DW: Caspase-1 and -3 are sequentially activated in motor neuron death in Cu, Zn superoxide dismutase-mediated familial amyotrophic lateral sclerosis. Proc Natl Acad Sci USA. 2000, 97: 13901-13906.PubMed CentralPubMedGoogle Scholar
Li M, Ona VO, Guegan C, Chen M, Jackson-Lewis V, Andrews LJ, Olszewski AJ, Stieg PE, Lee JP, Przedborski S, Friedlander RM: Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model. Science. 2000, 288: 335-339.PubMedGoogle Scholar
Vukosavic S, Dubois-Dauphin M, Romero N, Przedborski S: Bax and Bcl-2 interaction in a transgenic mouse model of familial amyotrophic lateral sclerosis. J Neurochem. 1999, 73: 2460-2468.PubMedGoogle Scholar
Sathasivam S, Ince PG, Shaw PJ: Apoptosis in amyotrophic lateral sclerosis: a review of the evidence. Neuropathol Appl Neurobiol. 2001, 27: 257-274.PubMedGoogle Scholar
Pasinelli P, Brown RH: Molecular biology of amyotrophic lateral sclerosis: insights from genetics. Nat Rev Neurosci. 2006, 7: 710-723.PubMedGoogle Scholar
Wharton S, Ince PG: Pathology of Motor Neurone Disorders. Motor Neuron Disorders. Edited by: Shaw PJ, Strong MJ. 2003, Philadelphia: Butterworth Heinemann, 28: 17-41.Google Scholar
Ince PG, Wharton SB: Cytopathology of the motor neuron. Motor neurone disorders and related diseases. Edited by: Eisen AA, Shaw PJ. 2007, Amsterdam: Elsevier, 89-110. [Aminoff MJ, Boller F, Swaab DF (Series Editor): Handbook of clinical neurology]Google Scholar
Iwata M, Hirano A: Sparing of the Onufrowicz nucleus in sacral anterior horn lesions. Ann Neurol. 1978, 4: 245-249.PubMedGoogle Scholar
Ince PG: Neuropathology. Amyotrophic lateral sclerosis. Edited by: Brown RJ, Meininger V, Swash M. 2000, London: Martin Dunitz, 83-112.Google Scholar
Koichi Okamoto YM, Yukio Fujita: Bunina bodies in amyotrophic lateral sclerosis. Neuropathology. 2008, 28: 109-115.PubMedGoogle Scholar
Mizuno Y, Amari M, Takatama M, Aizawa H, Mihara B, Okamoto K: Transferrin localizes in Bunina bodies in amyotrophic lateral sclerosis. Acta Neuropathologica. 2006, 112: 597-603.PubMedGoogle Scholar
Bunina TL: [On intracellular inclusions in familial amyotrophic lateral sclerosis.]. Zh Nevropatol Psikhiatr Im S S Korsakova. 1962, 62: 1293-1299.PubMedGoogle Scholar
Piao YS, Wakabayashi K, Kakita A, Yamada M, Hayashi S, Morita T, Ikuta F, Oyanagi K, Takahashi H: Neuropathology with clinical correlations of sporadic amyotrophic lateral sclerosis: 102 autopsy cases examined between 1962 and 2000. Brain Pathol. 2003, 13: 10-22.PubMedGoogle Scholar
Ince PG, Evans J, Knopp M, Forster G, Hamdalla HHM, Wharton SB, Shaw PJ: Corticospinal tract degeneration in the progressive muscular atrophy variant of ALS. Neurology. 2003, 60: 1252-1258.PubMedGoogle Scholar
Leigh PN, Whitwell H, Garofalo O, Buller J, Swash M, Martin JE, Gallo JM, Weller RO, Anderton BH: Ubiquitin-immunoreactive intraneuronal inclusions in amyotrophic lateral sclerosis. Morphology, distribution, and specificity. Brain. 1991, 114 (Pt 2): 775-788.PubMedGoogle Scholar
Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM: Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006, 314: 130-133.PubMedGoogle Scholar
Tan C-F, Eguchi H, Tagawa A, Onodera O, Iwasaki T, Tsujino A, Nishizawa M, Kakita A, Takahashi H: TDP-43 immunoreactivity in neuronal inclusions in familial amyotrophic lateral sclerosis with or without SOD1 gene mutation. Acta Neuropathologica. 2007, 113: 535-542.PubMedGoogle Scholar
Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, Mann D, Tsuchiya K, Yoshida M, Hashizume Y, Oda T: TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochemical and Biophysical Research Communications. 2006, 351: 602-611.PubMedGoogle Scholar
RM Liscic LTG, J Zidar, MA Gitcho, NJ Cairns: ALS and FTLD: two faces of TDP-43 proteinopathy. European Journal of Neurology. 2008, 15: 772-780.Google Scholar
Warton S, Ince PG: Pathology of Motor Neuron Disorders. Motor neuron disorders. Edited by: Shaw PJ, Strong MJ. 2003, Philadelphia: Butterworth Heinemann, 17-41.Blue books of practical neurology,Google Scholar
Leigh PN, Dodson A, Swash M, Brion JP, Anderton BH: Cytoskeletal abnormalities in motor neuron disease. An immunocytochemical study. Brain. 1989, 112 (Pt 2): 521-535.PubMedGoogle Scholar
Brownell B, Oppenheimer DR, Hughes JT: The central nervous system in motor neurone disease. J Neurol Neurosurg Psychiatry. 1970, 33: 338-357.PubMed CentralPubMedGoogle Scholar
Al-Sarraj S, Maekawa S, Kibble M, Everall I, Leigh N: Ubiquitin-only intraneuronal inclusion in the substantia nigra is a characteristic feature of motor neurone disease with dementia. Neuropathol Appl Neurobiol. 2002, 28: 120-128.PubMedGoogle Scholar
Swash M, Leader M, Brown A, Swettenham KW: Focal loss of anterior horn cells in the cervical cord in motor neuron disease. Brain. 1986, 109 (Pt 5): 939-952.PubMedGoogle Scholar
Lawyer T, Netsky MG: Amyotrophic lateral sclerosis. AMA Arch Neurol Psychiatry. 1953, 69: 171-192.PubMedGoogle Scholar
Dyck PJ, Stevens JC, Mulder DW, Espinosa RE: Frequency of nerve fiber degeneration of peripheral motor and sensory neurons in amyotrophic lateral sclerosis. Morphometry of deep and superficial peroneal nerves. Neurology. 1975, 25: 781-785.PubMedGoogle Scholar
Bradley WG, Good P, Rasool CG, Adelman LS: Morphometric and biochemical studies of peripheral nerves in amyotrophic lateral sclerosis. Ann Neurol. 1983, 14: 267-277.PubMedGoogle Scholar
Konagaya M, Sakai M, Matsuoka Y, Konagaya Y, Hashizume Y: Upper motor neuron predominant degeneration with frontal and temporal lobe atrophy. Acta Neuropathol. 1998, 96: 532-536.PubMedGoogle Scholar
Tan CF, Kakita A, Piao YS, Kikugawa K, Endo K, Tanaka M, Okamoto K, Takahashi H: Primary lateral sclerosis: a rare upper-motor-predominant form of amyotrophic lateral sclerosis often accompanied by frontotemporal lobar degeneration with ubiquitinated neuronal inclusions? Report of an autopsy case and a review of the literature. Acta Neuropathol. 2003, 105: 615-620.PubMedGoogle Scholar
Sasaki S, Iwata M: Atypical form of amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 1999, 66: 581-585.PubMed CentralPubMedGoogle Scholar
Sasaki S, Iwata M: Motor neuron disease with predominantly upper extremity involvement: a clinicopathological study. Acta Neuropathol. 1999, 98: 645-650.PubMedGoogle Scholar
Ota S, Tsuchiya K, Akiyama H: "Forme fruste" of amyotrophic lateral sclerosis with dementia: a report of five autopsy cases without dementia and with ubiquitinated intraneuronal inclusions. Neuropathology. 2005, 25: 326-335.PubMedGoogle Scholar
Okamoto K, Hirai S, Yamazaki T, Sun XY, Nakazato Y: New ubiquitin-positive intraneuronal inclusions in the extra-motor cortices in patients with amyotrophic lateral sclerosis. Neurosci Lett. 1991, 129: 233-236.PubMedGoogle Scholar
Wightman G, Anderson VER, Martin J, Swash M, Anderton BH, Neary D, Mann D, Luthert P, Leigh PN: Hippocampal and neocortical ubiquitin-immunoreactive inclusions in amyotrophic lateral sclerosis with dementia. Neuroscience Letters. 1992, 139: 269-274.PubMedGoogle Scholar
Matsumoto S, Hirano A, Goto S: Ubiquitin-immunoreactive filamentous inclusions in anterior horn cells of Guamanian and non-Guamanian amyotrophic lateral sclerosis. Acta Neuropathol. 1990, 80: 233-238.PubMedGoogle Scholar
Dickson DW, Josephs KA, Amador-Ortiz C: TDP-43 in differential diagnosis of motor neuron disorders. Acta Neuropathol. 2007, 114: 71-79.PubMedGoogle Scholar
Robertson J, Sanelli T, Xiao S, Yang W, Horne P, Hammond R, Pioro EP, Strong MJ: Lack of TDP-43 abnormalities in mutant SOD1 transgenic mice shows disparity with ALS. Neurosci Lett. 2007, 420: 128-132.PubMedGoogle Scholar
Mackenzie IR, Bigio EH, Ince PG, Geser F, Neumann M, Cairns NJ, Kwong LK, Forman MS, Ravits J, Stewart H: Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol. 2007, 61: 427-434.PubMedGoogle Scholar
Lambert EH, Mulder DW: Electromyographic studies in amyotrophic lateral sclerosis. Proc Staff Meet Mayo Clin. 1957, 32: 441-446.PubMedGoogle Scholar
Lambert E: Electromyography in amyotrophic lateral sclerosis. Motor neuron disease. Edited by: Norris F, Kurland L. 1969, New York: Grune and Stratton, 135-153.Google Scholar
de Carvalho M, Swash M: Nerve conduction studies in amyotrophic lateral sclerosis. Muscle Nerve. 2000, 23: 344-352.PubMedGoogle Scholar
Mills KR, Nithi KA: Peripheral and central motor conduction in amyotrophic lateral sclerosis. J Neurol Sci. 1998, 159: 82-87.PubMedGoogle Scholar
Cornblath DR, Kuncl RW, Mellits ED, Quaskey SA, Clawson L, Pestronk A, Drachman DB: Nerve conduction studies in amyotrophic lateral sclerosis. Muscle Nerve. 1992, 15: 1111-1115.PubMedGoogle Scholar
de Carvalho M, Johnsen B, Fuglsang-Frederiksen A: Medical technology assessment. Electrodiagnosis in motor neuron diseases and amyotrophic lateral sclerosis. Neurophysiol Clin. 2001, 31: 341-348.PubMedGoogle Scholar
Isaacs JD, Dean AF, Shaw CE, Al-Chalabi A, Mills KR, Leigh PN: Amyotrophic lateral sclerosis with sensory neuropathy: part of a multisystem disorder?. J Neurol Neurosurg Psychiatry. 2007, 78: 750-753.PubMed CentralPubMedGoogle Scholar
Pugdahl K, Fuglsang-Frederiksen A, de Carvalho M, Johnsen B, Fawcett PR, Labarre-Vila A, Liguori R, Nix WA, Schofield IS: Generalised sensory system abnormalities in amyotrophic lateral sclerosis: a European multicentre study. J Neurol Neurosurg Psychiatry. 2007, 78: 746-749.PubMed CentralPubMedGoogle Scholar
Janko M, Trontelj JV, Gersak K: Fasciculations in motor neuron disease: discharge rate reflects extent and recency of collateral sprouting. J Neurol Neurosurg Psychiatry. 1989, 52: 1375-1381.PubMed CentralPubMedGoogle Scholar
Eisen AA, Shtybel W: AAEM minimonograph #35: Clinical experience with transcranial magnetic stimulation. Muscle Nerve. 1990, 13: 995-1011.PubMedGoogle Scholar
Osei-Lah AD, Turner MR, Andersen PM, Leigh PN, Mills KR: A novel central motor conduction abnormality in D90A-homozygous patients with amyotrophic lateral sclerosis. Muscle Nerve. 2004, 29: 790-794.PubMedGoogle Scholar
Vucic S, Kiernan MC: Abnormalities in cortical and peripheral excitability in flail arm variant amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2007, 78: 849-852.PubMed CentralPubMedGoogle Scholar
Cappellari A, Ciammola A, Silani V: The pseudopolyneuritic form of amyotrophic lateral sclerosis (Patrikios' disease). Electromyogr Clin Neurophysiol. 2008, 48: 75-81.PubMedGoogle Scholar
Bromberg MB, Brownell AA: Motor Unit Number Estimation in the Assessment of Performance and Function in Motor Neuron Disease. Physical Medicine and Rehabilitation Clinics of North America. 2008, 19: 509-532.PubMedGoogle Scholar
Goodin DS, Rowley HA, Olney RK: Magnetic resonance imaging in amyotrophic lateral sclerosis. Ann Neurol. 1988, 23: 418-420.PubMedGoogle Scholar
Thorpe JW, Moseley IF, Hawkes CH, MacManus DG, McDonald WI, Miller DH: Brain and spinal cord MRI in motor neuron disease. J Neurol Neurosurg Psychiatry. 1996, 61: 314-317.PubMed CentralPubMedGoogle Scholar
Abe K, Fujimura H, Kobayashi Y, Fujita N, Yanagihara T: Degeneration of the pyramidal tracts in patients with amyotrophic lateral sclerosis. A premortem and postmortem magnetic resonance imaging study. J Neuroimaging. 1997, 7: 208-212.PubMedGoogle Scholar
Waragai M: MRI and clinical features in amyotrophic lateral sclerosis. Neuroradiology. 1997, 39: 847-851.PubMedGoogle Scholar
Oba H, Araki T, Ohtomo K, Monzawa S, Uchiyama G, Koizumi K, Nogata Y, Kachi K, Shiozawa Z, Kobayashi M: Amyotrophic lateral sclerosis: T2 shortening in motor cortex at MR imaging. Radiology. 1993, 189: 843-846.PubMedGoogle Scholar
Ellis CM, Simmons A, Andrews C, Dawson JM, Williams SC, Leigh PN: A proton magnetic resonance spectroscopic study in ALS: correlation with clinical findings. Neurology. 1998, 51: 1104-1109.PubMedGoogle Scholar
Ellis CM, Simmons A, Jones DK, Bland J, Dawson JM, Horsfield MA, Williams SC, Leigh PN: Diffusion tensor MRI assesses corticospinal tract damage in ALS. Neurology. 1999, 53: 1051-1058.PubMedGoogle Scholar
Kalra S, Arnold D: Neuroimaging in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis. 2003, 4: 243-248.PubMedGoogle Scholar
Turner MR, Kiernan MC, Leigh PN, Talbot K: Biomarkers in amyotrophic lateral sclerosis. The Lancet Neurology. 2009, 8: 94-109.PubMedGoogle Scholar
Turner MR, Cagnin A, Turkheimer FE, Miller CC, Shaw CE, Brooks DJ, Leigh PN, Banati RB: Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study. Neurobiol Dis. 2004, 15: 601-609.PubMedGoogle Scholar
Turner MR, Leigh PN: Positron emission tomography (PET) – its potential to provide surrogate markers in ALS. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000, 1 (Suppl 2): S17-22.PubMedGoogle Scholar
Averill AJ, Kasarskis EJ, Segerstrom SC: Psychological health in patients with amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis. 2007, 8: 243-254.PubMedGoogle Scholar
Wicks P, Abrahams S, Masi D, Hejda-Forde S, Leigh PN, Goldstein LH: Prevalence of depression in a 12-month consecutive sample of patients with ALS. European Journal of Neurology. 2007, 14: 993-1001.PubMedGoogle Scholar
Mitsumoto H, Rabkin JG: Palliative care for patients with amyotrophic lateral sclerosis: "prepare for the worst and hope for the best". Jama. 2007, 298: 207-216.PubMedGoogle Scholar
Heffernan C, Jenkinson C, Holmes T, Macleod H, Kinnear W, Oliver D, Leigh N, Ampong MA: Management of respiration in MND/ALS patients: an evidence based review. Amyotroph Lateral Scler. 2006, 7: 5-15.PubMedGoogle Scholar
Miller RG, Rosenberg JA, Gelinas DF, Mitsumoto H, Newman D, Sufit R, Borasio GD, Bradley WG, Bromberg MB, Brooks BR: Practice parameter: The care of the patient with amyotrophic lateral sclerosis (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 1999, 52: 1311.PubMedGoogle Scholar
Lechtzin N, Wiener CM, Shade DM, Clawson L, Diette GB: Spirometry in the supine position improves the detection of diaphragmatic weakness in patients with amyotrophic lateral sclerosis. Chest. 2002, 121: 436-442.PubMedGoogle Scholar
Gruis KL, Brown DL, Schoennemann A, Zebarah VA, Feldman EL: Predictors of noninvasive ventilation tolerance in patients with amyotrophic lateral sclerosis. Muscle Nerve. 2005, 32: 808-811.PubMedGoogle Scholar
Schmidt EP, Drachman DB, Wiener CM, Clawson L, Kimball R, Lechtzin N: Pulmonary predictors of survival in amyotrophic lateral sclerosis: use in clinical trial design. Muscle Nerve. 2006, 33: 127-132.PubMedGoogle Scholar
Lyall RA, Donaldson N, Polkey MI, Leigh PN, Moxham J: Respiratory muscle strength and ventilatory failure in amyotrophic lateral sclerosis. Brain. 2001, 124: 2000-2013.PubMedGoogle Scholar
Radunovic A, Mitsumoto H, Leigh PN: Clinical care of patients with amyotrophic lateral sclerosis. Lancet Neurol. 2007, 6: 913-925.PubMedGoogle Scholar
Andersen PM, Borasio GD, Dengler R, Hardiman O, Kollewe K, Leigh PN, Pradat PF, Silani V, Tomik B: Good practice in the management of amyotrophic lateral sclerosis: clinical guidelines. An evidence-based review with good practice points. EALSC Working Group. Amyotroph Lateral Scler. 2007, 8: 195-213.PubMedGoogle Scholar
Andersen PM, Borasio GD, Dengler R, Hardiman O, Kollewe K, Leigh PN, Pradat PF, Silani V, Tomik B: EFNS task force on management of amyotrophic lateral sclerosis: guidelines for diagnosing and clinical care of patients and relatives. Eur J Neurol. 2005, 12: 921-938.PubMedGoogle Scholar
Bourke SC, Tomlinson M, Williams TL, Bullock RE, Shaw PJ, Gibson GJ: Effects of non-invasive ventilation on survival and quality of life in patients with amyotrophic lateral sclerosis: a randomised controlled trial. Lancet Neurol. 2006, 5: 140-147.PubMedGoogle Scholar
Bourke SC, Bullock RE, Williams TL, Shaw PJ, Gibson GJ: Noninvasive ventilation in ALS: Indications and effect on quality of life. Neurology. 2003, 61: 171-177.PubMedGoogle Scholar
Desport JC, Preux PM, Magy L, Boirie Y, Vallat JM, Beaufrere B, Couratier P: Factors correlated with hypermetabolism in patients with amyotrophic lateral sclerosis. Am J Clin Nutr. 2001, 74: 328-334.PubMedGoogle Scholar
Kasarskis EJ, Berryman S, Vanderleest JG, Schneider AR, McClain CJ: Nutritional status of patients with amyotrophic lateral sclerosis: relation to the proximity of death. Am J Clin Nutr. 1996, 63: 130-137.PubMedGoogle Scholar
Mathus-Vliegen LM, Louwerse LS, Merkus MP, Tytgat GN, Vianney de Jong JM: Percutaneous endoscopic gastrostomy in patients with amyotrophic lateral sclerosis and impaired pulmonary function. Gastrointest Endosc. 1994, 40: 463-469.PubMedGoogle Scholar
Chio A, Galletti R, Finocchiaro C, Righi D, Ruffino MA, Calvo A, Di Vito N, Ghiglione P, Terreni AA, Mutani R: Percutaneous radiological gastrostomy: a safe and effective method of nutritional tube placement in advanced ALS. J Neurol Neurosurg Psychiatry. 2004, 75: 645-647.PubMed CentralPubMedGoogle Scholar
Heffernan C, Jenkinson C, Holmes T, Feder G, Kupfer R, Leigh PN, McGowan S, Rio A, Sidhu P: Nutritional management in MND/ALS patients: an evidence based review. Amyotroph Lateral Scler Other Motor Neuron Disord. 2004, 5: 72-83.PubMedGoogle Scholar
Shaw AS, Ampong MA, Rio A, McClure J, Leigh PN, Sidhu PS: Entristar skin-level gastrostomy tube: primary placement with radiologic guidance in patients with amyotrophic lateral sclerosis. Radiology. 2004, 233: 392-399.PubMedGoogle Scholar
Bensimon G, Lacomblez L, Meininger V, The ALS/Riluzole Study Group: A Controlled Trial of Riluzole in Amyotrophic Lateral Sclerosis. N Engl J Med. 1994, 330: 585-591.PubMedGoogle Scholar
Lacomblez L, Bensimon G, Leigh PN, Guillet P, Powe L, Durrleman S, Delumeau JC, Meininger V: A confirmatory dose-ranging study of riluzole in ALS. ALS/Riluzole Study Group-II. Neurology. 1996, 47: S242-250.PubMedGoogle Scholar
Bensimon G, Lacomblez L, Delumeau JC, Bejuit R, Truffinet P, Meininger V: A study of riluzole in the treatment of advanced stage or elderly patients with amyotrophic lateral sclerosis. J Neurol. 2002, 249: 609-615.PubMedGoogle Scholar
Meininger V, Lacomblez L, Salachas F: What has changed with riluzole?. J Neurol. 2000, 247: 19-22.PubMedGoogle Scholar
Mitchell JD, O'Brien MR, Joshi M: Audit of outcomes in motor neuron disease (MND) patients treated with riluzole. Amyotroph Lateral Scler. 2006, 7: 67-71.PubMedGoogle Scholar
Guidance on the use of riluzole for the treatment of motor neuron disease. [http://www.nice.org.uk/nicemedia/pdf/RILUZOLE_full_guidance.pdf]
Turner MR, Parton MJ, Leigh PN: Clinical trials in ALS: an overview. Semin Neurol. 2001, 21: 167-175.PubMedGoogle Scholar
Distad BJ, Meekins GD, Liou LL, Weiss MD, Carter GT, Miller RG: Drug Therapy in Amyotrophic Lateral Sclerosis. Physical Medicine and Rehabilitation Clinics of North America. 2008, 19: 633-651.PubMedGoogle Scholar
Miller RG, Mitchell JD, Lyon M, Moore DH: Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev. 2007, CD001447-Google Scholar
Bensimon G, Doble A: The tolerability of riluzole in the treatment of patients with amyotrophic lateral sclerosis. Expert Opin Drug Saf. 2004, 3: 525-534.PubMedGoogle Scholar
Mitchell JD, Wokke JH, Borasio GD: Recombinant human insulin-like growth factor I (rhIGF-I) for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst Rev. 2007, CD002064.Google Scholar
JHP G Miller Robert, Bryan Wilson, Armon Carmel, Barohn Richard, Goodpasture Jessie, Hoagland Rebecca, Parry Gareth, Ross Mark, Stromatt Scott, rhCNTF ALS Study Group: A placebo-controlled trial of recombinant human ciliary neurotrophic (rhCNTF) factor in amyotrophic lateral sclerosis. Annals of Neurology. 1996, 39: 256-260.Google Scholar
A double-blind placebo-controlled clinical trial of subcutaneous recombinant human ciliary neurotrophic factor (rHCNTF) in amyotrophic lateral sclerosis. ALS CNTF Treatment Study Group. Neurology. 1996, 46: 1244-1249.Google Scholar
Ochs G, Penn RD, York M, Giess R, Beck M, Tonn J, Haigh J, Malta E, Traub M, Sendtner M, Toyka KV: A phase I/II trial of recombinant methionyl human brain derived neurotrophic factor administered by intrathecal infusion to patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000, 1: 201-206.PubMedGoogle Scholar
Meininger V, Bensimon G, Bradley WR, Brooks B, Douillet P, Eisen AA, Lacomblez L, Leigh PN, Robberecht W: Efficacy and safety of xaliproden in amyotrophic lateral sclerosis: results of two phase III trials. Amyotroph Lateral Scler Other Motor Neuron Disord. 2004, 5: 107-117.PubMedGoogle Scholar
Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE, Jin L, Dykes Hoberg M, Vidensky S, Chung DS: [beta]-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature. 2005, 433: 73-77.PubMedGoogle Scholar
Clinical Trial of Tamoxifen. [http://www.alsa.org/patient/drug.cfm?id=671]
Gordon PH, Moore DH, Miller RG, Florence JM, Verheijde JL, Doorish C, Hilton JF, Spitalny GM, MacArthur RB, Mitsumoto H: Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol. 2007, 6: 1045-1053.PubMedGoogle Scholar
Miller R, Bradley W, Cudkowicz M, Hubble J, Meininger V, Mitsumoto H, Moore D, Pohlmann H, Sauer D, Silani V: Phase II/III randomized trial of TCH346 in patients with ALS. Neurology. 2007, 69: 776-784.PubMedGoogle Scholar
High-Dose Coenzyme Q10 Shows No Benefit in ALS. [http://www.als-mda.org/research/news/080423coenzyme.html]
Desnuelle C, Dib M, Garrel C, Favier A: A double-blind, placebo-controlled randomized clinical trial of alpha-tocopherol (vitamin E) in the treatment of amyotrophic lateral sclerosis. ALS riluzole-tocopherol Study Group. Amyotroph Lateral Scler Other Motor Neuron Disord. 2001, 2: 9-18.PubMedGoogle Scholar
Graf M, Ecker D, Horowski R, Kramer B, Riederer P, Gerlach M, Hager C, Ludolph AC, Becker G, Osterhage J: High dose vitamin E therapy in amyotrophic lateral sclerosis as add-on therapy to riluzole: results of a placebo-controlled double-blind study. J Neural Transm. 2005, 112: 649-660.PubMedGoogle Scholar
JMS E Cudkowicz Merit, Schoenfeld David, Zhang Hui, Andreasson Katrin, Rothstein Jeffrey, Drachman Daniel, Northeast ALS Consortium: Trial of celecoxib in amyotrophic lateral sclerosis. Annals of Neurology. 2006, 60: 22-31.Google Scholar
Groeneveld GJ, Veldink JH, Tweel Van der I, Kalmijn S, Beijer C, De Visser M, Wokke JHJ, Franssen H, Berg Van den LH: A randomized sequential trial of creatine in amyotrophic lateral sclerosis. Annals of Neurology. 2003, 53: 437-445.PubMedGoogle Scholar
Shefner JM, Cudkowicz ME, Schoenfeld D, Conrad T, Taft J, Chilton M, Urbinelli L, Qureshi M, Zhang H, Pestronk A: A clinical trial of creatine in ALS. Neurology. 2004, 63: 1656-1661.PubMedGoogle Scholar
Teva Provides Update On Glatiramer Acetate 40 mg For Amyotrophic Lateral Sclerosis (ALS). [http://www.medicalnewstoday.com/articles/100725.php]
Kaspar BK, Llado J, Sherkat N, Rothstein JD, Gage FH: Retrograde viral delivery of IGF-1 prolongs survival in a mouse ALS model. Science. 2003, 301: 839-842.PubMedGoogle Scholar
Mazzini L, Mareschi K, Ferrero I, Vassallo E, Oliveri G, Boccaletti R, Testa L, Livigni S, Fagioli F: Autologous mesenchymal stem cells: clinical applications in amyotrophic lateral sclerosis. Neurol Res. 2006, 28: 523-526.PubMedGoogle Scholar
Mazzini L, Mareschi K, Ferrero I, Vassallo E, Oliveri G, Nasuelli N, Oggioni GD, Testa L, Fagioli F: Stem cell treatment in Amyotrophic Lateral Sclerosis. J Neurol Sci. 2008, 265: 78-83.PubMedGoogle Scholar
Dimos JT, Rodolfa KT, Niakan KK, Weisenthal LM, Mitsumoto H, Chung W, Croft GF, Saphier G, Leibel R, Goland R: Induced Pluripotent Stem Cells Generated from Patients with ALS Can Be Differentiated into Motor Neurons. Science. 2008, 321: 1218-1221.PubMedGoogle Scholar
Logroscino G, Traynor BJ, Hardiman O, Chio A, Couratier P, Mitchell JD, Swingler RJ, Beghi E: Descriptive epidemiology of amyotrophic lateral sclerosis: new evidence and unsolved issues. J Neurol Neurosurg Psychiatry. 2008, 79: 6-11.PubMedGoogle Scholar
Testa D, Lovati R, Ferrarini M, Salmoiraghi F, Filippini G: Survival of 793 patients with amyotrophic lateral sclerosis diagnosed over a 28-year period. Amyotroph Lateral Scler Other Motor Neuron Disord. 2004, 5: 208-212.PubMedGoogle Scholar
Turner MR, Parton MJ, Shaw CE, Leigh PN, Al-Chalabi A: Prolonged survival in motor neuron disease: a descriptive study of the King's database 1990–2002. J Neurol Neurosurg Psychiatry. 2003, 74: 995-997.PubMed CentralPubMedGoogle Scholar
Preux PM, Couratier P, Boutros-Toni F, Salle JY, Tabaraud F, Bernet-Bernady P, Vallat JM, Dumas M: Survival prediction in sporadic amyotrophic lateral sclerosis. Age and clinical form at onset are independent risk factors. Neuroepidemiology. 1996, 15: 153-160.PubMedGoogle Scholar
Chio A, Mora G, Leone M, Mazzini L, Cocito D, Giordana MT, Bottacchi E, Mutani R: Early symptom progression rate is related to ALS outcome: A prospective population-based study. Neurology. 2002, 59: 99-103.PubMedGoogle Scholar
del Aguila MA, Longstreth WT, McGuire V, Koepsell TD, van Belle G: Prognosis in amyotrophic lateral sclerosis: a population-based study. Neurology. 2003, 60: 813-819.PubMedGoogle Scholar
Millul A, Beghi E, Logroscino G, Micheli A, Vitelli E, Zardi A: Survival of patients with amyotrophic lateral sclerosis in a population-based registry. Neuroepidemiology. 2005, 25: 114-119.PubMedGoogle Scholar
Magnus MBT, Giess R, Puls I, Naumann M, Toyka KV: Disease progression in amyotrophic lateral sclerosis: Predictors of survival. Muscle & Nerve. 2002, 25: 709-714.Google Scholar
Traynor BJ, Alexander M, Corr B, Frost E, Hardiman O: An outcome study of riluzole in amyotrophic lateral sclerosis – a population-based study in Ireland, 1996–2000. J Neurol. 2003, 250: 473-479.PubMedGoogle Scholar
Chio A, Meineri P, Tribolo A, Schiffer D: Risk factors in motor neuron disease: a case-control study. Neuroepidemiology. 1991, 10: 174-184.PubMedGoogle Scholar
Popat RA, Eeden Van Den SK, Tanner CM, Bernstein AL, Bloch DA, Leimpeter A, McGuire V, Nelson LM: Effect of reproductive factors and postmenopausal hormone use on the risk of amyotrophic lateral sclerosis. Neuroepidemiology. 2006, 27: 117-121.PubMedGoogle Scholar
Morozova N, Weisskopf MG, McCullough ML, Munger KL, Calle EE, Thun MJ, Ascherio A: Diet and amyotrophic lateral sclerosis. Epidemiology. 2008, 19: 324-337.PubMedGoogle Scholar
Abhinav K, Al-Chalabi A, Hortobagyi T, Leigh PN: Electrical injury and amyotrophic lateral sclerosis: a systematic review of the literature. J Neurol Neurosurg Psychiatry. 2007, 78: 450-453.PubMed CentralPubMedGoogle Scholar
Cruz DC, Nelson LM, McGuire V, Longstreth WT: Physical trauma and family history of neurodegenerative diseases in amyotrophic lateral sclerosis: a population-based case-control study. Neuroepidemiology. 1999, 18: 101-110.PubMedGoogle Scholar
Govoni V, Granieri E, Fallica E, Casetta I: Amyotrophic lateral sclerosis, rural environment and agricultural work in the Local Health District of Ferrara, Italy, in the years 1964–1998. Journal of Neurology. 2005, 252: 1322-1327.PubMedGoogle Scholar
Horner RD, Grambow SC, Coffman CJ, Lindquist JH, Oddone EZ, Allen KD, Kasarskis EJ: Amyotrophic lateral sclerosis among 1991 Gulf War veterans: evidence for a time-limited outbreak. Neuroepidemiology. 2008, 31: 28-32.PubMedGoogle Scholar
Miranda ML, Alicia Overstreet Galeano M, Tassone E, Allen KD, Horner RD: Spatial analysis of the etiology of amyotrophic lateral sclerosis among 1991 Gulf War veterans. Neurotoxicology. 2008Google Scholar
Horner RD, Kamins KG, Feussner JR, Grambow SC, Hoff-Lindquist J, Harati Y, Mitsumoto H, Pascuzzi R, Spencer PS, Tim R: Occurrence of amyotrophic lateral sclerosis among Gulf War veterans. Neurology. 2003, 61: 742-749.PubMedGoogle Scholar
Fang F, Kamel F, Sandler DP, Sparen P, Ye W: Maternal Age, Exposure to Siblings, and Risk of Amyotrophic Lateral Sclerosis. Am J Epidemiol. 2008, 167: 1281-1286.PubMed CentralPubMedGoogle Scholar
Vivekananda U, Johnston C, McKenna-Yasek D, Shaw C, Leigh P, Brown R, Al-Chalabi A: Birth order and the genetics of amyotrophic lateral sclerosis. Journal of Neurology. 2008, 255: 99-102.PubMedGoogle Scholar
Fang F, Ye W, Fall K, Lekander M, Wigzell H, Sparen P, Adami H-O, Valdimarsdottir U: Loss of a Child and the Risk of Amyotrophic Lateral Sclerosis. Am J Epidemiol. 2008, 167: 203-210.PubMedGoogle Scholar
Armon C, Kurland LT, Daube JR, O'Brien PC: Epidemiologic correlates of sporadic amyotrophic lateral sclerosis. Neurology. 1991, 41: 1077-1084.PubMedGoogle Scholar
Longstreth WT, McGuire V, Koepsell TD, Wang Y, van Belle G: Risk of Amyotrophic Lateral Sclerosis and History of Physical Activity: A Population-Based Case-Control Study. Arch Neurol. 1998, 55: 201-206.PubMedGoogle Scholar
Veldink JH, Kalmijn S, Groeneveld GJ, Titulaer MJ, Wokke JH, Berg van den LH: Physical activity and the association with sporadic ALS. Neurology. 2005, 64: 241-245.PubMedGoogle Scholar
Armon C: Sports and trauma in amyotrophic lateral sclerosis revisited. Journal of the Neurological Sciences. 2007, 262: 45-53.PubMedGoogle Scholar
Chio A, Benzi G, Dossena M, Mutani R, Mora G: Severely increased risk of amyotrophic lateral sclerosis among Italian professional football players. Brain. 2005, 128: 472-476.PubMedGoogle Scholar
Al-Chalabi A, Leigh PN: Trouble on the pitch: are professional football players at increased risk of developing amyotrophic lateral sclerosis?. Brain. 2005, 128: 451-453.PubMedGoogle Scholar
Okumura H, Kurland LT, Waring SC: Amyotrophic Lateral Sclerosis and Polio: Is There an Association?. Annals of the New York Academy of Sciences. 1995, 753: 245-256.PubMedGoogle Scholar
Cronin S, Hardiman O, Traynor BJ: Ethnic variation in the incidence of ALS: A systematic review. Neurology. 2007, 68: 1002-1007.PubMedGoogle Scholar
Nelson LM, McGuire V, Longstreth WT, Matkin C: Population-Based Case-Control Study of Amyotrophic Lateral Sclerosis in Western Washington State. I. Cigarette Smoking and Alcohol Consumption. Am J Epidemiol. 2000, 151: 156-163.PubMedGoogle Scholar
Kamel F, Umbach DM, Munsat TL, Shefner JM, Sandler DP: Association of cigarette smoking with amyotrophic lateral sclerosis. Neuroepidemiology. 1999, 18: 194-202.PubMedGoogle Scholar
Kamel F, Umbach DM, Hu H, Munsat TL, Shefner JM, Taylor JA, Sandler DP: Lead exposure as a risk factor for amyotrophic lateral sclerosis. Neurodegener Dis. 2005, 2: 195-201.PubMedGoogle Scholar
Chen H, Richard M, Sandler DP, Umbach DM, Kamel F: Head Injury and Amyotrophic Lateral Sclerosis. Am J Epidemiol. 2007, 166: 810-816.PubMed CentralPubMedGoogle Scholar

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Amyotrophic lateral sclerosis

Abstract

Keywords

Disease names

Included diseases

Definition and diagnostic/classification criteria

Epidemiology

Clinical features

Clinical features of variant disorders

Aetiology

Pathogenesis of motor neurone degeneration in ALS

1. Genetic factors

2. Excitotoxicity

3. Oxidative stress

4. Mitochondrial dysfunction

5. Impaired axonal transport

6. Neurofilament aggregation

7. Protein aggregation

8. Inflammatory dysfunction and contribution of non-neuronal cells

9. Deficits in neurotrophic factors and dysfunction of signalling pathways

Histopathological features

1. Bunina bodies

2. Ubiquitinated inclusions or ubiquitin-immunoreactive (UBIs; Ub-IR)

3. Hyaline conglomerate (Neurofilament) inclusions (HCIs)

Differential diagnosis

Diagnostic methods

Electrophysiological studies

1. Nerve conduction studies (motor and sensory)

2. Conventional electromyography

3. Transcranial magnetic stimulation and Central motor conduction studies

4. Quantitative electromyography

Neuroimaging studies

Muscle biopsy and neuropathalogical studies

Other laboratory studies

Management

Symptomatic treatments

Ventilatory management

Nutritional management

Disease modifying treatments

Prognosis

Appendix 1 – Some exogenous risk factors implicated in sporadic ALS

Notes

Abbreviations

Declarations

Acknowledgements

Authors’ Affiliations

References

Copyright

Orphanet Journal of Rare Diseases

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