The term motor neurone disease either can be used to describe the condition known as amyotrophic lateral sclerosis (ALS) or it can be a more general term for other motor neurone diseases including bulbar palsy and progressive muscular atrophy (PMA) which are closely allied to ALS and others such as Kennedy disease and Hirayama disease that have a less clear association. Conditions such as progressive bulbar palsy and PMA can develop into ALS although pure forms of these conditions also occur. The relationship of ALS to subtypes such as the ‘man in a barrel’ or flail arm MND (Vulpian–Bernhardt syndrome) and flail leg MND (pseudopolyneuritic MND) is not clear. PMA can either be a very slowly progressive disorder with an outlook better than for ALS or it can progress rapidly, sometimes over a few months, giving it a bimodal distribution of survival. Over half of all cases of PMA show the corticospinal tracts to be involved at autopsy and ubiquitin inclusions typical of MND are also found in the central nervous system (CNS).5 Bulbar symptoms and signs are seen in a minority of patients with PMA. This chapter deals largely with the ALS form of MND. Bulbar palsy remains a useful term referring to dysarthria and/or dysphagia being the presenting symptoms, but in most cases the condition eventually progresses to MND. The usefulness of the term bulbar palsy is a prognostic one—the life expectancy in bulbar palsy is significantly worse than that in limb-onset MND. A subcommittee of the World Federation of Neurology made a significant contribution to the definition of MND and ALS when it met in El Escorial, Spain, to formulate a set of internationally agreed diagnostic criteria.6 The El Escorial criteria for diagnosis of possible, probable and clinically definite MND have made it possible to compare directly the results of research investigations carried out in different countries. The criteria are summarized below:

• Definite ALS: Upper and lower motor neurone signs in bulbar and two spinal regions or in three spinal regions (cervical, thoracic and lumbosacral).
  
• Probable ALS: Upper and lower motor neurone signs in at least two regions with some of the upper motor neurone signs rostral to the lower motor neurone signs.
  
• Probable ALS/laboratory supported: Upper motor neurone signs in at least one region and lower motor neurone signs on electrodiagnostic testing in at least two regions.
  
• Possible ALS: Upper and lower motor neurone signs in one region (the same region) or upper motor neurone signs in two or three regions or upper and lower motor neurone signs in two regions with no upper motor neurone signs rostral to the lower motor neurone signs.

The term ‘suspected ALS’ was dropped in the 1998 revised criteria. It previously referred to a condition in which lower motor neurone signs were found in two or three regions. Certain clinical features were listed as deflecting one from the diagnosis (although not absolute exclusions). These included sensory dysfunction, sphincter disturbance, autonomic signs, visual abnormalities, involuntary movement disorder and cognitive dysfunction. The criteria require the exclusion of other diagnoses by imaging and other investigations. The Airlie revision6 also suggested that neurophysiological or pathological criteria could be used to identify lower motor neurone signs. The Awaji consensus7 clarified the neurophysiological features of acute denervation in MND. These criteria are widely supported and adoption of these revisions may drop the ‘probable ALS/laboratory supported’ entity. There remains a group of patients who do not satisfy these criteria but who are thought to have MND on clinical grounds. These are mainly lower motor neurone syndromes. They emphasize the point that the El Escorial criteria with their several revisions remain important research tools but do not replace clinical judgment.

MND is a progressive neurodegenerative disorder of the upper and lower motor neurones, resulting in weakness, muscle wasting, fasciculation and spasticity as a part of the clinical picture. There is a profound difference between the motor pathways, which are severely affected, and the sensory pathways, which are relatively preserved. Sensory pathway involvement is sufficiently unusual as to spark off a search for an alternative diagnosis. About one-third of patients with MND present with bulbar symptoms, the others with limb problems. Older patients and women are more likely to present with bulbar symptoms. Only a few have other initial presentations such as dementia or respiratory failure. These groups follow significantly different clinical courses and the distinction between them remains important. Furthermore, the diagnostic pitfalls in the two main modes of presentation may be completely different (see below). MND is slightly more common in men, although recent information suggests a narrowing of the male:female ratio. The mean age at presentation is about 57 years. This is a few years younger than the mean age for other neurodegenerative disorders of adult life, such as Parkinson’s disease (PD) and Alzheimer’s disease. A few patients with MND develop parkinsonism as well and a further few develop dementia. The dementia of MND is a frontotemporal one and distinct from Alzheimer’s disease. It is characterized by behaviour disturbance, impaired judgment, language and memory problems and a dysexecutive state.8 Only small numbers of patients develop these features but they do underline the point that common mechanisms of disease aetiology may be involved in these seemingly disparate disorders. In an even smaller number of cases, patients can present with simultaneous development of both ALS- and PD-like features.

Limb-Onset MND

This can arise in either arms or legs and common modes of presentation are with weakness, wasting, cramp, spasms secondary to spasticity and fasciculation. The symptoms are progressive usually over a period of months or occasionally over a few years. Loss of manual dexterity secondary to involvement of small hand muscles is a frequent presenting symptom, as is a disturbance in gait and, in older patients, falls. A cramp in muscles not normally thought of as being prone to cramp, for instance, forearm flexors or abductor pollicis brevis can be a useful clinical pointer. A history of progression is an essential requirement for the diagnosis. The disease commonly starts in just one limb. Clinical and prognostic separation of different limb-onset varieties of MND is still poorly developed, but distinct entities such as flail arms MND, hemiplegic MND and paraplegic MND are recognized. Pain, which is not uncommon in late disease, is usually not a problem at presentation and its early occurrence should encourage a search for alternative diagnoses. Although fasciculation is seen very commonly in MND, it is unusual for prominent fasciculation to be the sole presenting symptom in MND, but it is a common symptom in patients with benign fasciculation or those with a fear of developing MND. Patients with a family history of MND are exceptions, in that they frequently have fasciculation as a presenting symptom.

Bulbar-Onset MND

This occurs in about one-third of patients with MND and is more frequent in women. The first presentation is usually with dysarthria or anarthria. Older patients are also more likely to have bulbar onset disease. Progression from dysarthria to anarthria can, in some cases, be so rapid as to lead to an erroneous diagnosis of stroke. Dysphagia is also common in the disease but is a surprisingly infrequent presenting symptom. Recurrent aspiration pneumonitis should alert the physician to the possibility of MND. Choking spells are also uncommon at presentation. Dyspnea secondary to respiratory muscle weakness with or without aspiration pneumonitis is another rare mode of presentation but can become a more troublesome problem later in the disease, as discussed below. Emotional lability is often encountered but only rarely at first presentation and then not as troublesome as other bulbar symptoms.

In establishing a diagnosis of MND, the absence of certain symptoms is just as helpful as the presence of others. Sensory symptoms are usually absent at first presentation of MND and, when present, they are usually trivial in comparison with the motor problems. The presence of sensory symptoms in a patient at first presentation should activate a search for a condition other than MND. Clinically relevant sensory signs are even less common, and when they are found are often attributed to, but cannot always be explained by, the consequences of nutritional deprivation or pressure palsies secondary to profound wasting and weakness. Sophisticated electrophysiological measurements can demonstrate involvement of sensory pathways in up to 50% of patients. Urinary bladder function is generally preserved in MND. Urgency and frequency, encountered so commonly in other patients with limb spasticity, are uncommon in MND. Similarly, the anterior horn cells responsible for eye movements are relatively resistant to the diffuse process that damages other anterior horn cells in MND, with abnormalities being found occasionally in patients on long-term ventilatory support.

Familial MND

Up to 10% of MND is familial and largely inherited in an autosomal dominant pattern. The age of onset and the clinical course of this condition are similar to those of the sporadic disease, indicating that common mechanisms may be involved in disease causation. Missense and nonsense mutations in the gene encoding superoxide dismutase type 1 (SOD 1 or ALS 1) are found in about 10% of families with this disease.9 Some mutations (e.g. A4V) encode for more rapidly progressive disease than others (e.g. G37R).10 SOD 1 MND more commonly starts in the legs. Other genes have also been identified as causing MND but none are as well studied as SOD 1. SOD 1 toxicity is increased in experimental animals by the close proximity between mutation-carrying astrocytes and anterior horn cells. ALS 2 is a recessive disorder involving a gene encoding GEF signalling. Interest in other genetic causes of motor neurone disorders has focused on angiogenin, TAR DNA binding protein (TARDBP), vascular endothelial growth factor (VEGF), dynactin, senataxin, vesicle-associated membrane protein-associated protein B (VAPB), microtubule-associated protein tau (MAPT) and unknown loci on chromosome 9 linking MND with frontotemporal dementia.11 The ubiquitinated inclusions found in MND contain TDP43, the protein encoded by TARDBP. TARDBP mutations are found in 2–5% of patients with familial MND and in about 2% of sporadic MND cases.12 It is also controversially suggested that RNA processing defects play a role in MND. The X-linked disorder Kennedy disease or spinal bulbar muscular atrophy (SBMA) is an MND-like disorder with a better outlook than MND and should be considered in cases where maternal transmission of MND is likely or when specific clinical features (see the section on differential diagnosis below) alert one to the diagnosis. There are various genetic factors that may alter disease expression in sporadic MND. For instance, homozygous survival motor neurone 2 (SMN2) gene mutations are over-represented in the MND population. Mutations in the gene encoding vascular endothelial growth factor (VEGF)13 may also have a disease-modifying effect. Other potential genetic risk factors for MND include mutations in the apurinic/apyrimidinic endonuclease (APEX nuclease) gene, the neuronal apoptosis inhibitory polypeptide (NAIP) gene, cytochrome c oxidase gene and the APO E4 genotype. Young patients with an MND-like syndrome may have mutations in the hexosaminidase A gene, causing an accumulation in tissues of GM2 ganglioside. The principles of investigation and management of familial disease are the same as those of sporadic MND with the exception of issues of genetic counselling and perhaps additional psychological support for those patients who have previously nursed other family members through a distressing and ultimately fatal condition. Genetic counselling is made more difficult by the incomplete penetrance of the mutant gene. Where ethical considerations permit this, FALS may provide the best opportunity to study the effects of potentially neuroprotective strategies in altering the course of disease expression in presymptomatic individuals who are known to carry pathogenic disease mutations. The human SOD 1 mutant gene has made it possible to develop a very good mouse model of MND.14 This allows screening of potential therapeutic compounds before they are used in clinical settings.

Both bulbar-onset and limb-onset MND progress inexorably and are ultimately fatal. The rate of progression is variable but the clinical course is more predictable than for many other fatal conditions such as some of the malignant diseases. This point is important in enabling the healthcare needs of patients to be anticipated and planned for. Median survival in MND is approximately 3 years from the first symptom. Survival up to 5 years and beyond is certainly seen and 10% are said to survive over 10 years. However, survival to 10 years or beyond should activate a search for alternative diagnoses as some of the mimic syndromes have slower progression. Despite the anecdotal observation of more patients surviving to previously exceptional durations of disease, systematic studies do not show an overall increase in survival in MND. Although some patients appear to go through periods of relative stability, these are the exception rather than the rule in MND (except in young-onset MND where initial severe deterioration can be followed by prolonged stability). Each 6 month period usually sees an increase in disability. Women are over-represented in the bulbar-onset group and have a worse prognosis than men. Other prognostic factors include short latency between symptom onset and diagnosis (perhaps coding for more rapidly advancing disease), older age at presentation and poor social support network. MND patients with a spouse-carer live longer.15

MND does not have a diagnostic test or reliable biomarker and is a rapidly progressive condition. This makes it imperative to look for alternative diagnoses that may be more treatable or carry a better outlook. Diagnostic errors are more likely to occur if there is pressure for early diagnosis. This is happening now owing to advances in treatment and to increased publicity for the disease. Patients who have fasciculation either as a constant finding, or more often as an intermittent symptom, confined to one muscle or segment such as one calf worry about having MND. In the absence of other signs of a progressive disorder, these patients are likely to have benign fasciculation requiring explanation and reassurance but no other intervention. In an Irish study of diagnostic pitfalls, errors included patients regarded as having clinically definite or clinically probable MND who later turned out to have postpolio syndrome or Kennedy disease. The searches for a biomarker for MND may change diagnostic certainty in years to come.

Spinal root and cord compression by cervical and lumbar spondylosis is common. Root compression can lead to segmental muscle wasting and weakness and is a common cause of calf muscle fasciculation. In the elderly, multiple root compression can cause fairly widespread lower motor neurone signs. This, combined with the spasticity that can be caused by spinal cord compression, can mimic MND. However, sensory and bladder disturbances are common in spondylosis but are spared in MND. Neck pain and restriction of neck movements are also more common in spondylosis than in MND at its onset. Bulbar signs, when present, clearly point more strongly towards MND. Tongue wasting with fasciculation can be diagnostic in this setting and other bulbar signs can be suggestive—for instance, brisk jaw jerk or jaw clonus, spastic dysarthria or emotional lability.

Occasionally the distinction between MND and spinal conditions such as syringomyelia can be difficult (a few patients with syringomyelia present with motor rather than sensory features), but spinal MRI can distinguish between these conditions. Other intrinsic spinal pathology may also mimic MND but such cases are rare in the West. Cysticercosis of the spinal cord has been linked with an MND-like presentation and needs to be considered in endemic areas, particularly when the presentation is with a disturbance in one limb, so-called monomelic myelopathy or amyotrophy. Hirayama disease is a disorder of younger men causing distal and usually unilateral arm amyotrophy.16 It can be familial and may involve dynamic spinal cord compression during neck flexion, resulting in damage to genetically predisposed anterior horn cells. Inherited disorders of spinal neurones can be mistaken for MND including its familial form. Hereditary spastic paraparesis can be a predominantly motor disorder of the upper motor neurones and lower motor neurone disturbance is not a feature, but spontaneous clonus can mimic fasciculation and the unwary can be caught out. The prolonged history and relatively indolent clinical course are also powerful indicators away from MND. The term primary lateral sclerosis was coined to describe those patients who have a slowly progressive upper motor neurone disturbance without lower motor neurone features over at least a 3 year period of observation. The progression of this condition is slower than that of MND and the prognosis better. Spinal muscular atrophies, previously classified as forms of MND, are now recognized as distinct disorders with a more benign course. Kennedy disease or X-linked bulbospinal neuronopathy is a disorder characterized by lower motor neurone disturbance of spinal and bulbar neurones and was previously frequently mislabelled MND. This should happen less frequently now as features such as gynaecomastia, facial fasciculation and a family history of X-linked disorder should lead to the search for the trinucleotide repeat expansion in the androgen receptor gene.17 Other clues include finding low sensory action potentials on nerve conduction studies. Sandhoff disease, a variety of gangliosidosis with hexosaminidase A deficiency, can present in an MND-like fashion and needs to be considered as a possible diagnosis in any very young patient with apparent MND.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a radiculoneuropathy with predominantly motor symptoms and signs and without upper motor neurone pathology. It can mimic the lower motor neurone disturbance of MND but the finding of slowed nerve conduction velocities and elevated CSF protein should lead to the correct diagnosis of a neuropathy rather than an anterior horn cell disorder. This is a treatable disorder often responding well to immunomodulation such as with intravenous immunoglobulins (IVIG). A more patchy related disorder, multifocal motor neuropathy (MMN) with proximal conduction block, also causes confusion. In MMN, the response to steroids and plasmapheresis is poor and the response to IVIG is rather better to begin with (in 70%) than in CIDP. However, it may not be as sustained. It, too, is worth thinking about in the patient with few or no upper motor neurone signs and without bulbar involvement, with asymmetric onset often in upper limbs and with weakness out of proportion to wasting being important clinical clues. Those cases refractory to IVIG may respond to cyclophosphamide. Reflexes can be preserved and, although it is a neuropathy, fasciculation can be prominent. Limited autopsy studies suggest that anterior horn cells may also be affected. Antibody binding to the nodes of Ranvier indicates that this may be the site of damage. There is a syndrome of late deterioration in patients who have had polio in childhood or in early adult life. This postpolio syndrome can resemble MND but follows a different clinical course. Its recognition is easy if the history of pre-existing polio is known. Similarities between the viral condition and idiopathic MND have prompted searches for an aetiological association between the two disorders. Other enteroviruses have also been implicated in the aetiology of MND. Vasculitis affecting either the spinal cord or the spinal roots or both can resemble MND. Unusually marked sensory symptoms or other features of systemic vasculitis can act as clues. CSF examination can be helpful in this situation as the CSF protein concentration is often elevated in CNS vasculitis and there may be a pleocytosis even in the absence of clinical meningitis. The rise in CSF protein concentration is more marked than that usually seen in MND. The disturbance of anterior horn function associated with the vasculitides including polyarteritis nodosa may respond to immunosuppression.

Paraneoplastic neuropathy can mimic MND. Sometimes it is truly an MND-like disorder and on occasion even a Lambert–Eaton myasthenic syndrome (LEMS) has been mistaken for MND. Paraneoplastic disorders are associated with circulating antibodies, for example, voltage-gated calcium channel antibodies linked to LEMS. Sometimes it can be difficult even using electromyography (EMG) always to decide whether a lesion is just neurogenic or whether there is a combination of a neurogenic change and a myopathy. A rare myopathy that causes some difficulty is acid maltase deficiency, which can cause severe respiratory muscle compromise in mobile patients; a condition that is mimicked by a few sufferers of MND. A careful search for upper motor neurone signs may help to avoid diagnostic confusion. When it occurs in adults, lead toxicity can present a picture of a virtually pure motor neuropathy. No case of lead poisoning has been described in terms that could convincingly be recognized as MND. On current evidence, there is no case for treatment of MND with lead chelating agents. A similar controversy has surrounded the link between mercury and MND, but again there is no convincing evidence of an aetiological link. Porphyria and polyarteritis nodosa are causes of a motor neuropathy. Treatment of porphyria with avoidance of the precipitants of acute relapses and treatment of polyarteritis nodosa with immunosuppression can improve disease outcome remarkably. Some of the hereditary motor neuropathies (HMN2 and HMN5) can be mistaken for a predominantly lower motor neurone form of familial MND.

When bilateral tongue wasting and fasciculation are present, the diagnosis of MND is very likely to be correct. However, when the physical findings both in the limbs and in the mouth are equivocal, a diagnosis of myasthenia gravis must always be considered, as this is an eminently treatable condition. Usually, but not always, a history of fatigable ptosis or diplopia is helpful. These are not seen in ambulant patients with MND. A Tensilon test can aid diagnosis, but interpretation must be cautious as a weak positive Tensilon test can be found in MND. The major difficulty in making a diagnosis of myasthenia gravis is not thinking of the condition. Another rare cause of bulbar weakness and ptosis is the inherited disorder of older adults oculopharyngeal muscular dystrophy, for which there is now a reliable genetic test. A pseudobulbar presentation should activate a search for structural brain pathology such as cerebrovascular disease. It is common for the severe dysarthria or anarthria of MND to be thought of as dysphasia resulting from a stroke. The progressive history and the recognition that the patient’s ability to express himself/herself using gesture or writing is totally intact at a time when they are unable to make any sound should clarify whether the problem is dysphasic or anarthric. A proportion of MND patients develop dementia and in rare cases this can be a prominent feature at diagnosis. Frontotemporal dementia may of course present with dysphasia, but this is rare in MND. A combination of dementia and amyotrophy (muscle wasting) with fasciculation can rarely signify a prion protein disorder of Creutzfeldt–Jakob type.

The diagnosis of MND is a clinical one. The role of investigation is largely to look for other conditions that may mimic MND. These have been discussed above and, where appropriate, diagnostic tests have been suggested. All patients in whom a diagnosis of MND is considered should have nerve conduction studies and these may be combined with EMG. The EMG can confirm electrical evidence of denervation in marginal cases or may demonstrate denervation in clinically normal limbs, but more importantly, nerve conduction studies which should be normal in MND may point to alternative diagnoses such as a motor neuropathy as seen in CIDP or multifocal motor neuropathy with conduction block (MMN). Elevated plasma creatine phosphokinase (CK) is a non-specific marker of lower motor neurone damage. In other clinical settings it can help with the diagnosis of muscle disorders. CK elevations in MND are more modest than in muscle disease. Generally, values are only increased to no more than 10-fold above the normal upper limit. CSF examination for elevated protein concentrations or pleocytosis may also be helpful in swaying one away from the diagnosis. Having said this, slight increases in CSF protein are seen in MND so that the elevation has to be marked for it to be of significant negative predictive value. Antiganglioside antibodies are found in low titre in many patients with MND and are found more consistently and at higher titres in patients with MMN and CIDP. Paraproteins are found more frequently in the serum of MND patients. Treatment of the paraprotein in these cases does not influence the outcome of MND. Other tests, ranging from looking for antiacetylcholine receptor antibodies to magnetic resonance scanning of the cervical spine, may be appropriate in certain clinical settings as discussed above. Currently there are no biomarkers of a diagnosis of MND.

Discussion of the diagnosis of MND is an important step in the management of the condition. Nerve conduction tests, an electromyogram, imaging studies and any other tests indicated should of course be completed prior to mention of the words, motor neurone disease. A busy outpatient clinic is hardly a suitable setting for the unhurried imparting of bad news. Following the tests and preferably on the same day, the diagnosis can be discussed with the patient and their family by the doctor and a counsellor with an interest in MND. Any healthcare professional with a knowledge of and interest in MND and the time to be able to discuss matters unhurriedly could develop counselling skills and become an MND counsellor. Patients and their families usually appreciate written information and most appreciate receiving a transcript of or letter about the consultation. The hospice movement in particular and the experience of oncology in general have taught us much about imparting bad news. The principles of breaking bad news range from the use of a private room to fractionating the news so that the patient is not completely overwhelmed by the information and to remembering to emphasize some positive features, for instance, our increasing ability to help all the symptoms of the disease. In our unit, the MND nurse counsellor plays an important role in maintaining contact with the patient and their family, even when they are at home. This outreach function has proved invaluable in reducing the morbidity of the disease, decreasing unplanned hospital admissions and, later on, in facilitating discussions about end-of-life issues As the diagnosis of MND is essentially based on the clinical picture and as there is no one diagnostic test for it, most patients will appreciate the offer of a second neurological opinion. This may be a counsel of perfection as many parts of the world have difficulty with access to one neurologist, let alone two. However, wherever feasible, this course is to be recommended as confident acceptance of the diagnosis by the medical team and by the patient and their family forms the basis of all subsequent management.