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THE BARE ESSENTIALS
The existence of a large number of neurological diseases in which the motor neuron is the principal site of pathology suggests that these cells and their neuronal networks have a specific set of vulnerabilities. Recent research, largely based on relatively rare genetic forms of motor neuron disease, indicates that these cells are vulnerable to defects in excitotoxicity, RNA transport and splicing, axonal protein transport, mitochondrial function, protein misfolding and oxidative stress. The most important motor neuron disease is a largely sporadic, late onset, degenerative condition, known simply as motor neuron disease (MND) or more widely as amyotrophic lateral sclerosis (ALS), which currently remains untreatable and uniformly fatal.
The core features of MND
In essence, MND is a progressive motor syndrome with clinical evidence of upper motor neuron dysfunction (spasticity, brisk reflexes, extensor plantar responses) and denervation (muscle wasting, weakness and fasciculation). It is typically asymmetrical in onset and progresses in a non-random pattern suggesting a pathological process with a focal onset and anatomically contiguous spread. Although predominantly a motor disorder, there is evidence of multisystem involvement (especially cognitive, but occasionally sensory or autonomic). The diagnosis is clinical, although imaging is usually necessary to exclude structural pathology mimicking MND. Neurophysiology should not be considered to be a diagnostic test but can provide support for the presence of denervation and exclude other conditions such as pure motor inflammatory demyelinating neuropathies.
The incidence of MND is approximately 2/100 000 population per year and there is no convincing evidence of geographical variation, although studies to date are limited to developed societies with predominantly European genetic heritage. Approximately 1/1000 death certificates list MND as the cause of death. There is no indication that MND is increasing in frequency.
The prevalence is approximately 7/100 000. General practitioners in the UK might encounter a patient with MND less than once every 10 years.
The average age of onset of patients attending specialist clinics with unbiased referral patterns is roughly 65 years; approximately 10% present below the age of 45 years and 20% over the age of 70 years.
There is a consistently observed male preponderance which is almost completely accounted for by younger onset patients and approaches a 1:1 male to female ratio after the age of 70 years.
Approximately one-third of patients present with upper limb symptoms, one-third with lower limb symptoms and slightly less than one-third with disorders of speech and swallowing; 1–2% of patients present, usually to chest physicians, with isolated respiratory failure. A few people present with axial weakness leading to non-specific gait disturbance or a “dropped head”.
Clinically significant frontotemporal dementia occurs in less than 5%, but 40–50% have some evidence of executive dysfunction on formal testing. Conversely, about 10% of patients presenting with frontotemporal dementia go on to develop MND.
5–10% of patients report a history of MND in a first degree relative.
Natural history and prognosis
It is important, but clinically challenging, to offer an individualised prognosis to patients rather than adopting the usual practice of quoting the “average survival” as 2–3 years from diagnosis. Many factors determine overall survival, and evidence about prognosis, derived from large clinical case series, is often difficult to apply to individual patients. The following statements are therefore generalisations:
The disease progression is approximately linear, as measured by the ALS Functional Rating Scale, and forced vital capacity once it starts to decline. Apparently abrupt changes in specific functions such as walking, standing and transferring are best explained by a failure of compensatory muscle power, rather than by a sudden acceleration in disease activity. Thus, in an individual, a disease that is slowly progressive in the initial phase will remain so.
50% of patients with MND die within 30 months from first symptoms, 15–20% are alive at 5 years and a small percentage survive beyond 10 years. The reasons for this variation are not known. Long survivors cannot be easily identified early in the disease and do not appear to have a pathologically distinct condition at autopsy.
Diagnostic delay is the most robust surrogate marker of survival; early presentation to tertiary services is associated with rapid progression and a worse survival.
Bulbar onset, early respiratory muscle weakness and disease in the elderly are associated with shorter survival.
Although there are clinical subtypes of MND that have on average a better prognosis, within each subtype there are rapid and slow progressors.
Timing of death is generally predictable, but a significant minority of patients die suddenly, often during sleep, from causes such as pulmonary embolism or cardiorespiratory arrest. Conversely other patients may remain in the terminal phase for an unexpectedly long period of time, making care planning difficult.
Differential diagnosis and investigation
The average delay in diagnosis from first symptoms is >1 year due to the insidious nature of the disease onset and the fact that early signs are often subtle. Only as the disease generalises does the diagnosis become obvious. The commonest presentation, weakness in one limb (often referred to as “spinal onset ALS”), has a wide differential diagnosis. Although neurologists are naturally worried about getting the diagnosis wrong due to its grave implications, misdiagnosis is very unusual in specialist settings. Population based studies, however, suggest that 8% of patients who are initially diagnosed with MND eventually turn out to have another condition, emphasising one of many reasons for specialist follow up—to ensure that another diagnosis has not been missed.
The literature contains a very large number of conditions which apparently mimic MND but many of these are unique examples. The commonest cause of misdiagnosis is degenerative cervical spine disease in which spondylotic myelopathy and radiculopathy combine to give upper motor neuron signs in the lower limbs and lower motor neuron signs in the upper limbs. Other occasional causes include inclusion body myositis (which can give a “neurogenic” pattern on EMG), multiple sclerosis and rare forms of motor neuropathy. Progressive wasting and fasciculation of the tongue is almost always due to MND.
The El Escorial ALS diagnostic criteria scheme is used to standardise inclusion in research studies but is not a sensitive or useful tool for diagnosis in a clinical setting. There is no category which allows for pure lower motor neuron disease, despite evidence that progressive muscular atrophy is within the ALS pathological spectrum. Significant numbers of patients do not fulfil the criteria at a stage when most MND experts would consider the diagnosis almost certain, and when the patient would be an ideal candidate for clinical trials of interventions to delay if not prevent progression. Terms used in the scheme such as “probable” and “possible” do not help patients who, understandably, look to their physicians for diagnostic clarity.
El Escorial diagnostic criteria (revised)
Upper motor neuron signs and lower motor neuron signs in three regions (bulbar, arm, leg).
Upper motor neuron signs and lower motor neuron signs in two regions with at least some upper motor neuron signs rostral to lower motor neuron signs.
Probable ALS—laboratory supported
Upper motor neuron signs in one or more regions and lower motor neuron involvement defined by electromyography in at least two regions.
Upper motor neuron signs and lower motor neuron signs in one region.
Upper motor neuron signs in two or more regions.
Upper motor neuron signs and lower motor neuron signs in two regions with no upper motor neuron signs rostral to lower motor neuron signs.
Essential investigations in suspected MND
Full blood count and erythrocyte sedimentation rate
Full biochemical profile, including calcium
Creatine kinase (usually mildly raised or normal, >1000 iu/l is very unusual in MND)
Nerve conduction studies and EMG
MRI spine/brain as indicated by clinical signs
Additional investigations in selected cases
Blood B12 level
Antineuronal antibodies for paraneoplastic syndrome
Antiacetylcholine receptor antibodies
The subtypes of MND
MND can be regarded as a syndrome comprising a range of clinical phenotypes, reflecting the pattern and progression of the underlying progressive degenerative motor neuronopathy. The justification for considering these phenotypes as part of the same disease entity is: (a) they all share common pathological features; (b) any of the phenotypes can occur as part of familial MND with mutations in the same gene; and (c) initial atypical presentations usually progress to a more generalised ALS clinical picture. It is however useful to distinguish the following clinical patterns in order to guide management and prognostication.
Amyotrophic lateral sclerosis
Fundamental to the diagnosis is progressive weakness with mixed upper and lower motor neuron signs. Brisk reflexes in the presence of local wasting is a strong clue to the diagnosis. Patients report weakness, clumsiness, stiffness or wasting. Visible fasciculations (often, unlike benign fasciculations, not noticed by the patient) are usually prominent but tend to fade as the illness progresses. There are upper motor neuron predominant as well as lower motor neuron predominant forms, which must be distinguished from primary lateral sclerosis and progressive muscular atrophy, respectively (see below). Unequivocally, pathological reflexes (eg, extensor plantar responses, Hoffman’s reflex and corticobulbar reflexes such as a brisk jaw jerk, with jaw clonus, facial jerks, pout and the glabellar tap) are useful clinical signs. Emotional lability is due to loss of the normal suppression of reflex laughter and crying; although commoner in patients with clinical or subclinical cognitive dysfunction, it mostly occurs in people with normal cognitive function. Respiratory involvement may be an early or late feature, with prognosis generally poor when early. At least 80% of patients develop clinically significant bulbar involvement, with speech affected before swallowing in >90% of cases. Conditions to consider in the differential diagnosis of spinal onset ALS are cervical spondylotic myeloradiculopathy and paraneoplastic neuromuscular syndromes. Bulbar onset ALS with wasting and fasciculation of the tongue does not have a significant differential diagnosis.
Progressive muscular atrophy
Progressive muscular atrophy is the least well defined subtype of MND which is reflected in the widely varying incidence in different studies. True pure lower motor neuron MND is rare because many patients develop upper motor neuron signs at some point in the disease and are probably best classified as lower motor neuron predominant ALS. However, there are undoubtedly patients who present with asymmetrical weakness and wasting, often in the legs, which coalesces into four limb lower motor neuron involvement. The degree of wasting is often out of proportion to the level of weakness, which has led to speculation that hypermetabolism may be present. Although there are very rapidly progressive cases, the overall survival is about 5 years, and there is an excess of long survivors. The differential diagnosis includes conduction block neuropathy, paraneoplastic neuropathy, X linked spinobulbar muscular atrophy (Kennedy’s syndrome) and adult onset spinal muscular atrophy.
Primary lateral sclerosis
Primary lateral sclerosis is rare and accounts for 1–2% of MND. It is characterised by an ascending spastic tetraparesis with involvement of speech in the majority by 3 years. Although there is a broad age of onset, the average is lower than typical ALS. Some patients with apparent primary lateral sclerosis develop wasting within 4 years, become reclassified as upper motor neuron predominant ALS and have a worse prognosis than primary lateral sclerosis but still longer than typical ALS. Urinary urgency is common. Cognitive involvement is the exception. Although it is a slowly progressive condition, consistent with survival for decades, the burden of disability is high.
Flail arm variant
Bilateral weakness and wasting of the proximal upper limb which may not spread to other regions for a number of years is sometimes associated with a dropped head. Despite the proximity of the affected segments to the respiratory neurons, vital capacity may be unaffected until late in the disease. Males appear to be affected much more frequently.
Lower limb onset
Lower limb onset was often referred to in the past as “the creeping paralysis” or the pseudopolyneuritic variant of MND. Patients present with gradually ascending distal weakness. It may remain confined to the leg for 3–5 years and overall survival is 5–8 years.
Progressive bulbar palsy
Progressive bulbar palsy is a term which has fallen in and out of favour but it does provide a clinically useful distinction from “bulbar onset ALS” in which speech and swallowing are early features of a condition which rapidly generalises to the limbs and respiratory muscles and has a poor prognosis. Patients with progressive bulbar palsy are more often women over the age of 65 years and typically progress to complete anarthria in 6–12 months despite normal limb strength. Upper motor neuron features (slow spastic tongue with a jaw jerk) usually predominate. The EMG is frequently normal which should not prevent a diagnosis of MND being made and supportive treatment with enteral feeding and communication aids being instituted as early as possible. The prognosis varies from 2 to 4 years and depends on the timing of respiratory and limb involvement.
Ubiquitinated inclusions are present in the spinal cord of all patients with a clinical diagnosis of sporadic ALS.
TAR (transactive response) DNA binding protein (TDP-43) is the major protein constituent of ubiquinated inclusions. It is translocated from its normal position in the nucleus so that in affected motor neurons in the spinal cord it accumulates in the cytoplasm. Adjacent oligodendroglia also stain positive for ubiquitin and TDP-43.
Bunina bodies are a characteristic form of ubiquitin inclusion which are thought by some to be pathognomonic of sporadic ALS but are only present in about 85% of cases. These small eosinophilic, paracrystalline inclusions are immunoreactive for the proteinase inhibitor cystatin C.
Hyaline inclusions are less compact cytoplasmic inclusions which are less frequent than ubiquitinated inclusions and are immunoreactive for neurofilaments. These are particularly characteristic of some familial superoxide dismutase 1 (SOD1) mutation cases.
Most familial cases also have TDP-43 pathology. However, SOD1 related ALS appears to be pathologically different and TDP-43 staining is absent.
The relative uniformity of the clinical spectrum and presentation of MND in widely differing geographical areas, the unvarying incidence in population studies, and the absence of consistent associations between MND and individual exposures (eg, heavy metals, pesticides, physical trauma, etc) in case-control studies argue that environmental influences either have a minimal effect on disease risk or there are many complex risk factors operating at the individual level, which have low explanatory power considered across the disease as a whole. There are no convincing examples of population clusters, and there is no increased risk in spouses. “Guamanian ALS” is evidence that environmental factors can in principle have a major influence on the risk of neurodegeneration but this disease is pathologically distinct (a “tauopathy”) from sporadic ALS. The only established risk factors for ALS are therefore: age, male gender and a family history of the disease.
A number of clinic based studies suggest that athleticism is associated with the risk of ALS while population based studies have yielded conflicting or negative results. There is a suggestion of an excess of sufferers in ex-service personnel and competitive athletes. Perhaps a genetic profile which promotes physical prowess in youth is deleterious to the aging motor system, rather than exercise causing a specific effect leading to cell injury.
Between 5% and 10% of patients attending MND clinics have a history of a first degree relative with MND. Given the low incidence of MND this is unlikely to be a chance association and suggests a genetically inherited form of MND, usually autosomal dominant. Similarly, a family in which the disease appears to skip a generation is more likely to indicate reduced penetrance of a familial form of MND, rather than two sporadic cases in one family, although in this situation calculating the risk to other family members is much more difficult. It is important to take a detailed family history in all patients with ALS, paying particular attention to any neurological disease and questioning labels such as “multiple sclerosis”, “Alzheimer’s” and older terms for MND like “creeping paralysis” (which often appeared on death certificates).
The absence of a family history usually allows a confident diagnosis of sporadic ALS to be made. Early reassurance that the disease is not likely to be transmitted to children can be very important. Whether there is, in fact, a slightly increased relative risk (but still a low absolute risk) to first degree relatives is unknown.
Familial ALS is clinically indistinguishable from sporadic disease in individual cases. Median age of onset is about 10 years younger than sporadic ALS. Interestingly all subtypes of ALS can be found in the familial ALS population which argues for significant overlap in pathophysiology between sporadic and familial ALS. The individual phenotypes of ALS, frontotemporal dementia or their combination can occur in the same pedigree, supporting the notion that both conditions are part of a clinicopathological spectrum.
For each gene that has been identified as causing familial ALS, rare variants in those genes have also been described in a significant number of patients with “sporadic ALS”. As these do not appear to occur in the non-MND population, it is likely that they are relevant to the disease and act as rare risk alleles (in which the presence of a mutation confers a variable and individual risk in conjunction with other genetic and non-genetic factors).
A number of other conditions (table 1) have been designated as “familial ALS” but are phenotypically quite different from sporadic ALS and cause young onset, slowly progressive, atypical motor neuron degeneration. While understanding these conditions may provide insight into the general nature of motor neuron vulnerability, forms of familial ALS which are indistinguishable from sporadic ALS on clinical grounds are the main focus for current basic research in the molecular pathophysiology of MND.
Functional analysis of mutations in genes associated with familial ALS have implicated a number of pathways in the pathophysiology of motor neuron degeneration. Both cell culture and animal work indicate that there are a large number of potential interacting pathways which could serve as drug targets in MND. However, it is unclear which, if any, of these diverse pathways are a primary part of the trigger to motor neuron degeneration, or maybe they are simply part of the phenomenology of motor neuron death. Therapeutic efforts using a SOD1 mouse model of ALS have generated some promising results but these have not translated into successful trials in humans. The reasons for this include the poor methodology in animal studies which introduce biases and false positive results, the distortion of the normal pathophysiology of the disease by overexpressing transgenic protein to high levels which may recruit pathways which are responsive to treatment but are not part of the human disease, the fact that animals are often treated at a much earlier stage than is currently possible in humans, and also the fact that MND clinical trials are probably being carried out in a heterogeneous patient population which contains people who have the disease for a large number of different reasons. Recent evidence that SOD1 cases do not demonstrate TDP-43 staining, now considered by many to be the neuropathological “signature” of ALS, also raises doubts about the SOD1 mouse model as a tool for translational research.
The cornerstone of management of MND is regular individualised follow-up to assess the rate of change of the disease and facilitate planning and patient choice and, where possible, to maintain well-being. Patients with ALS progressing at a typical rate should be seen about every 3 months by a multidisciplinary clinic team consisting of:
Neurologist: diagnosis, assessment of disease progression, coordination of research and management.
Care coordinator: often a nurse, liaison between patients and clinical and paraclinical team to ensure interventions are appropriate and timely. Provision of information and support to patients and carers. Education and outreach for allied health care professionals.
Physiotherapist: assessment of motor dysfunction and provision of ankle–foot orthoses, collars and aids to walking. Teaching exercises to prevent cramps and secondary disability.
Occupational therapist: specialist in posture management and assessment for wheelchairs and other mobility and posture aids.
Psychologist: assessment of cognitive dysfunction, management of adjustment reactions and support, and counselling for patients and relatives.
Respiratory team: specialist nurse and physician for assessment of nocturnal sleep fragmentation with overnight oximetry and provision of non-invasive ventilation equipment.
Dietician and enteral feeding specialist team: initially advice about changes to oral diet (softened and pureed food), then planning of percutaneous endoscopic gastrostomy (PEG) or radiologically inserted gastrostomy (RIG) and subsequent follow-up.
Speech and language therapist: initial advice about how to avoid choking episodes and how to improve intelligibility. In selected patients with major communication problems, aids to communication such as the Lightwriter or voice synthesis software can be critical in maintaining personal autonomy.
A summary of the symptomatic management in patients with MND is given in table 2.
Riluzole is currently the only drug licensed for the treatment of MND. Because the original clinical trials used the El Escorial inclusion criteria for ALS, whether other forms of MND such as progressive lateral sclerosis and progressive muscular atrophy benefit has never been formally addressed. Prescribing practice for these forms is therefore variable.
Evidence for benefit comes from randomised trials which included >900 patients, taking oral riluzole 50 mg twice daily.
Overall, the probability of survival at 1 year after starting the drug is 9% greater than placebo; this equates to about 2–3 months greater life expectancy.
It is well tolerated, with about 10% of patients stopping the drug because of nausea or lethargy (probably a greater risk in the elderly).
Monitoring with monthly liver function and full blood count (possibility of marrow suppression).
A minority of patients have a 2–3-fold rise in liver enzymes which often reaches a plateau; if they continue to rise the drug must be stopped.
There is no evidence of any effect on quality of life, or improvement in specific symptoms
Weight loss in MND is not just due to difficulty swallowing but also to a complex mixture of:
Reduced food intake due to dysphagia, fear of choking and social embarrassment
Physical disability (eg, upper limb weakness) leading to dependence on others for food preparation and feeding
Increased calorie requirements and hypermetabolism
Psychological factors (eg, reduced appetite with low mood and cognitive impairment)
Recurrent chest infections
Nutritional status should be assessed at each clinic visit. A skilled multidisciplinary team will be able to anticipate which patients are likely to benefit from PEG feeding, and they will support the patient in making a choice to have early PEG insertion before weight loss occurs. An RIG can be placed without the need for endoscopy or significant sedation and is the preferred method in higher risk patients with poor respiratory function (forced vital capacity <50% of predicted). However, neither of these procedures should be performed late in the disease when the risks are higher and the period of benefit much shorter.
The provision of non-invasive ventilation for patients with MND has been a major advance in symptom management and is likely to significantly extend life in selected patients. However, the mode of death for the overwhelming majority of MND patients is still respiratory failure and not all patients need symptom palliation. In some, especially those with significant bulbar problems, non-invasive ventilation is not tolerated.
A symptom enquiry should be carried out at each clinic visit specifically asking about breathlessness when lying flat, broken sleep, early morning headache and nausea, daytime somnolence and general fatigue.
Respiratory muscle weakness is most easily monitored by measuring forced vital capacity; a fall of 15–20% on lying flat indicates diaphragmatic weakness.
In patients with bulbar and corticobulbar involvement measuring forced vital capacity is technically difficult and may be unreliable.
An early morning blood-gas estimation with a raised bicarbonate is probably the earliest sign of significant respiratory compromise.
Overnight oximetry (which can easily be carried out in the patient’s home) should be performed in all patients with symptoms and in those with evidence of significant diaphragm weakness. The presence of significant nocturnal desaturations and arousals is a marker of the need for non-invasive ventilation.
The provision and management of non-invasive ventilation is best done jointly between a neurologist and respiratory team.
MND is an aetiologically complex disease and so the search for an overarching single cause is probably misguided.
There is pathological overplap between MND and frontotemporal dementia, through the presence of TDP-43 positive ubiquitinated inclusions at autopsy; MND is now best considered as a multisystem neurodegenerative disease.
While there has been no real progress in identifying environmental triggers, there has been a dramatic increase in our knowledge of the genetic determinants of both familial ALS and some cases of sporadic ALS.
The risk of diagnostic error in specialist settings is very low.
Advances in multidisciplinary care, with access to enteral feeding and non-invasive ventilation, have improved quality of life and probably prolonged survival to a greater extent than the single available drug, riluzole.
Since most patients are only diagnosed after the disease has been firmly established, there is an urgent need for some method of improving early diagnosis, for example through imaging or blood biomarkers; whether a susceptible population will ever be identified using complex genetic typing remains an open question.
Restoring neurological function by reconstituting nervous connections, for example through stem cell treatment, remains a distant prospect.
Diagnostic “red flags”
Symptoms and signs consistent with a lesion at a single anatomical site
No progression, or major fluctuations in function
Unusual or very prominent sensory symptoms, or objective sensory signs
Dysphagia precedes dysarthria
Major bladder or bowel involvement
Fasciculation without weakness
Symptoms remain confined to one limb
Limb weakness without wasting
MRI of relevant area
Exclude local structural pathology
Consider other spinal cord diseases
Consider other causes of fasciculation such as cramp fasciculation syndrome or potassium channelopathies
Consider causes of a plexopathy
Consider conduction block neuropathy
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