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

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 234.

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.

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 67. 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.

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 1213 but a more accurate estimate is more likely to be 1 in 400 1415. 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 11161718. 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 1920. 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 1121. The mean age of onset for sporadic ALS (SALS) varies between 55–65 years with a median age of onset of 64 years2223. 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 232526.

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 2829. 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 283031. 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 3536.

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) 3839. 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 37404142.

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 4344. 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 454647484950.

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 5152. 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 5455. 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 5657.

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 6263. 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 6162666768.

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 7071, a condition called by some authors as "UMN-dominant ALS" 7273. 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 7576.

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 7778.

Putative exogenous risk factors associated with development of ALS investigated in case-control studies have been reviewed, and are summarised in Appendix 1 1939. 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 7980, and an odds ratio (OR) of 1.6 independent of age, level of education and occupation 81.

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 7778. These include:

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 153154.

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 4155. 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:

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 574. The most important conditions are shown in Table 3.

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 211212. Therefore, psychological support in the form of counselling and palliative care should be offered to the patients and relatives early 74213.

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 1258261. 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 262263, 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) 17261264265266, age of symptom onset 58261264265266267, shorter time from symptom onset to diagnosis 266, baseline FVC decline 261265268, El Escorial category at presentation 17267 and riluzole use 265269.

(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.

In the last 5 years PNL has received support for conducting clinical trials, educational grants, and occasional honoraria from Sanofi-Aventis, Novartis, Exonhit, ONO Pharma, Teva, Trophos, and GlaxoSmithKline. He has served on advisory boards and/or trial steering committees for Sanofi-Aventis, ONOPharma, Teva, Roche, Trophos, and GlaxoSmithKline. He has received research funding from the MRC, Wellcome Trust, UK Department of Health, MND Association, ALS association, and The European Union.

• Age at menopause (females) 270271

• 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) 276277278

• Maternal age 279, Number of births (in females) & Birth order 81279280, Loss of child 281

• Occupation 81282

• Physical activity 283284,

• Playing football professionally 285286287

• Previous poliomyelitis infection 288

• Race/ethnicity 289

• Smoking 798081290291

• Toxin exposure (agricultural chemicals, lead) 282292

• Trauma (e.g. Head injury) 274285293

• Years of education 81