The Motor Neuron Diseases

The motor neuron diseases - detailed technical article.

motor neurone in motor neurone disease (MND)

Topics covered:

  • Essentials
  • Introduction
  • Combined upper and lower motor neuron syndromes
  • Lower motor neuron syndromes
  • Upper motor neuron syndromes
  • Further reading

Essentials

Motor neuron diseases are a family of conditions that lead to selective loss of function of the lower and/or upper motor neurons controlling the voluntary muscles of the limbs or bulbar region. Precise diagnosis is essential for prognosis, identification of those diseases with genetic implications, and for (in a very few cases) specific treatment.

Clinical features, diagnosis, and treatment

Clinical signs of lower motor neuron involvement are muscle wasting, fasciculation, and flaccid weakness; upper motor neuron involvement produces spasticity, clonus, extensor plantar responses and weakness. Sensation and cognition are generally normal on simple clinical assessment.

Accurate diagnosis depends on (1) clinical and electrophysiological classification as to whether the disease involves the upper or the lower motor neurons, or both; augmented by (2) the age of onset; (3) the rate of deterioration; and (4) whether there is familial occurrence.

Motor neuron diseases are incurable for the most part, hence treatment must aim to overcome, or minimize, the diverse disabilities.

Particular motor neuron diseases

Amyotrophic lateral sclerosis—a diffuse neurodegenerative disorder of (usually) unknown cause, with the brunt borne by motor neurons. Typically presents with (1) bulbar symptoms—dysphagia, dysphonia, and inhalation of foodstuffs; or (2) spinal symptoms—usually wasting and weakness of one limb. Upper and lower motor neuron signs in all three body regions are required for a definite diagnosis. There is no specific curative treatment: the disease progresses relentlessly, with few surviving beyond 5 years from diagnosis.

Lower motor neuron syndromes—these disorders generally follow a much more benign course than amyotrophic lateral sclerosis, and include (1) proximal childhood spinal muscular atrophy with SMN mutations, (2) other inherited spinal muscular atrophies, (3) hexosaminidase deficiency, (4) X-linked recessive bulbospinal neuronopathy (Kennedy’s disease), (5) hereditary bulbar palsy of infancy and childhood, (6) monomelic, focal, and segmental motor neuronopathies, (7) postirradiation lumbosacral radiculopathy, (8) postpolio syndrome, and (9) multifocal motor neuropathy with conduction block—which may improve with high-dose intravenous human immunoglobulin therapy.

Upper motor neuron syndromes—these are the rarest forms of motor neuron disease and include (1) primary lateral sclerosis, (2) hereditary spastic paraplegia, (3) lathyrism, and (4) konzo.

Introduction

Motor neuron diseases result from selective loss of function of the lower and/or upper motor neurons controlling the voluntary muscles of the limbs or bulbar region. The term ‘motor neuron disease’ is best used to describe a family of diseases within which there is extensive differential diagnosis (Table 1 below); in the past the term has been used synonymously with amyotrophic lateral sclerosis (ALS), one of the most serious of these conditions. Precise diagnosis is essential for prognosis, for identifying those diseases with genetic implications, and appropriate use of immunosuppressant therapy for patients with certain acquired lower motor neuron disorders.

Accurate diagnosis requires clinical and electrophysiological classification as to whether the disease involves the upper or the lower motor neurons, or both. This anatomical differentiation is augmented by the age of onset, the rate of deterioration, and familial occurrence. Sensation and cognition are generally normal on simple clinical assessment, but several motor neuron disorders manifest other neurological features, such as ALS with frontotemporal dementia.

Motor neuron diseases are incurable for the most part and hence treatment must aim to overcome, or minimize, the diverse disabilities. Malnutrition due to dysphagia can be circumvented by nasogastric tube feeding or percutaneous endoscopic gastrostomy (PEG). Various forms of assisted respiration offset respiratory muscle weakness, including intermittent positive pressure ventilation (NIPPV) via a nasal mask. Limb spasticity can be reduced by baclofen, dantrolene, or diazepam. Wheelchairs and arm appliances may overcome inadequate limb function. Electronic communication devices should be supplied to those whose speech is incomprehensible. Amitriptyline may help contain the embarrassing emotional lability of pseudobulbar palsy. Housing and workplace modifications can allow patients to maintain independence despite their disability.

The motor neuron diseases, particularly ALS, are a focus of intensive neuroscience research. Therapeutic discoveries from the study of the human disease and animal models may affect the course of this disease in the foreseeable future.

diagram of spine showing location of lower motor neurones

Combined upper and lower motor neuron syndromes

Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis occurs worldwide, usually with an incidence of about 2 per 100 000 population and a prevalence of 6 per 100 000. It is more common in men and the incidence increases with advancing age; it is unusual before the fifth decade of life. The cause of the common sporadic form of amyotrophic lateral sclerosis is quite unknown. Its incidence is particularly high in areas of the western Pacific, particularly in Guam and the Japanese Kii Peninsula, where it tends to occur in younger adults and can be associated with dementia or parkinsonism. However, it is generally agreed now that this is a different disease, characterized by tau pathology rather than ubiquitinated inclusions.

Autosomal dominant inheritance is evident in approximately 5% of patients with adult-onset amyotrophic lateral sclerosis. Roughly 20% of familial amyotrophic lateral sclerosis is associated with more than 100 different missense mutations of the Cu/Zn superoxide dismutase (SOD1) gene on chromosome 21, which catalyses conversion of toxic superoxide anion radicals to hydrogen peroxide. The disease associated with various SOD1 mutations shows varying degrees of penetrance and a variable phenotype. It tends to begin earlier in adulthood and may involve minor sensory symptoms. SOD1 mutations are thought to damage cells by toxic gain of function, although protein misfolding may cause intracellular inclusions. Mutations of other genes associated with amyotrophic lateral sclerosis include Alsin and senataxin in juvenile forms, and a variety of other loci have been identified.

Amyotrophic lateral sclerosis is increasingly viewed as a diffuse neurodegenerative disorder with the brunt borne by motor neurons, which are particularly large neurons supporting long axons. The process of neuronal cell death may reflect a cascade process variously involving genetic factors, oxidative stress, excitotoxicity due to glutamate, mitochondrial dysfunction, perturbed axonal transport and cytoskeleton formation, intracellular protein aggregation, inflammatory cascade, apoptotic cascades, and toxic factors. Until the triggering events are understood, the question of disease subtypes and the design of pharmacological interventions will remain elusive.

motor neurone disease - diagram of upper and lower motor nerone pathways

Pathology

Lower motor neurons are lost from clinically affected areas of the spinal cord and brain stem. Surviving neurons may show intracytoplasmic inclusions, both the almost invariable ubiquitinated form and eosinophilic Bunina bodies, and proximal axonal accumulations of neurofilaments (spheroids). The motor cortex is depleted of Betz cells and the pyramidal tracts degenerate. There is relative sparing of Onuf’s nucleus in the sacral spinal cord, and the brain-stem ocular motor nuclei, which explains the preservation of micturition control and eye movements respectively. It is becoming increasingly recognized that other populations of neurons can also degenerate in motor neuron disease even though this is not usually evident clinically. These include peripheral sensory neurons and Clarke’s column neurons. Up to 10% of patients develop a mild dementia, often of a frontal lobe type. These recent findings show that either amyotrophic lateral sclerosis is a generalized neurodegenerative disorder, in which the motor neurons take the vast brunt of the disease, or it sometimes overlaps with other neurodegenerations. However, for the practical purpose of clinical diagnosis early in the disease, amyotrophic lateral sclerosis should be regarded as having purely motor manifestations.

motor neuron

Clinical features

At presentation, patients have either bulbar or spinal symptoms, although both usually become evident as the disease progresses. The El Escorial research diagnostic criteria for amyotrophic lateral sclerosis require evidence of both upper and lower motor neuron signs in all three body regions for a definite diagnosis, with lesser involvements for probable or possible diagnosis. In everyday practice most diagnoses are made at these earlier, incomplete stages.

The bulbar form causes dysphagia, dysphonia, and inhalation of foodstuffs due to weakness of the tongue, pharynx, and larynx. The tongue is wasted, weak, and fasciculating, palatal movements are reduced, and the ability to cough explosively is lost due to vocal cord paralysis. This bulbar palsy is usually accompanied, or even preceded, by varying degrees of pseudobulbar involvement. The tongue is spastic and immobile with ‘hot potato’ speech and difficulty in inhibiting emotional responses such as laughing or crying. Ventilatory respiratory failure may develop due to weakness of the diaphragm and intercostal muscles. Occasionally, amyotrophic lateral sclerosis can present with dyspnoea. Diaphragm weakness can be detected clinically by noting that the upper abdomen is drawn inwards, rather than outwards, during the second half of inspiration. Furthermore, the forced vital capacity is substantially lower when the patient is lying down compared with standing, because the weight of the liver no longer assists diaphragmatic descent.

The spinal form of amyotrophic lateral sclerosis usually presents with wasting and weakness of one limb, usually as intrinsic hand muscle wasting or foot drop. Occasionally the initial weakness predominantly affects the musculature of the shoulder girdle. Asymptomatic involvement of other limbs is often evident on examination. It is diagnostically important to demonstrate combined upper and lower motor neuron signs in at least two limbs. Wasted fasciculating muscles exhibiting clonus or hyper-reflexia are also a helpful finding. With time the limbs become useless due to progressive denervation. Patients become wheelchair or bed bound, or unable to use their arms for grooming or feeding. Despite enforced recumbency, decubitus ulcers are relatively unusual because autonomic regulation of skin blood flow and secretion is unaffected. Sphincter control is not affected, although practical difficulties in excretion may result from immobility and abdominal wall weakness preventing the exertion of intra-abdominal pressure.

Table 1 Classification of the motor neuron diseases
Disease Inheritancea Age of onsetb
Combined upper and lower motor neuron syndromes
Amyotrophic lateral sclerosis:    
 sporadic A, E
 familial adult onset    
 familial juvenile onset AR C
Lower motor neuron syndromes
Hereditary
Proximal childhood SMA (with SMN mutations):    
 type I Werdnig Hoffman disease AR I
 type II intermediate form AR I
 type III Wohlfart–Kugelberg–Welander disease AR C
 type IV adult onset AR A
Acute infantile SMA (without SMN mutations) Vary C
Autosomal dominant proximal SMA AD A
Distal SMA:
with respiratory distress   C
 slowly progressive AR C, A
with upper limb predominance   C, A
with lower limb predominance AD C, A
with vocal fold paralysis   A
scapuloperoneal   C, A
Acquired
Monomelic, focal and segmental SMA   A
Multifocal motor neuropathy with conduction block   A, E
Acute poliomyelitis    
Postpolio syndrome    
Postirradiation    
Bulbar
Kennedy’s disease X A
Brown–Vialetto–van Laere syndrome AR I, C, A
Fazio–Londe disease   C
Upper motor neuron syndromes
Primary lateral sclerosis   A, E
Hereditary spastic paraplegia AD A, E
Lathyrism   A
Konzo   A

SMA, spinal muscular atrophy.

a Inheritance: AD, autosomal dominant; AR, autosomal recessive; X, X linked.

b Onset: I, infantile; C, childhood; A, adult (15–50 years); E, older person.

Clinical variants

Many consider progressive bulbar palsy and the pure lower and upper motor neuron variants, known as progressive muscular atrophy and primary lateral sclerosis, to be variants of amyotrophic lateral sclerosis. Segmental variants with head drop, flail arms, or progressive paraparesis seem to occur particularly in older people and often progress slowly to produce generalized muscle denervation late in the disease, if at all. The Madras form from southern India produces prominent arm and later leg involvement as part of a generalized motor neuron disease in young adults, half of whom also become deaf.

Prognosis

Amyotrophic lateral sclerosis progresses relentlessly, in both the severity and the extent of muscular involvement. Death commonly results from ventilatory respiratory failure or from inhalational pneumonia, and malnutrition often plays a part. The median survival from first symptoms in those with bulbar onset is approximately 20 months, with survival beyond 5 years being rare. The alternative diagnosis of X-linked bulbospinal neuronopathy should be considered in such long survivors. The median survival for those with spinal onset is approximately 29 months with almost 15% surviving 5 years. Although a subacute and reversible syndrome resembling spinal amyotrophic lateral sclerosis has been described, this is so extraordinarily rare that it should not influence the physician’s prognosis.

Differential diagnosis and investigation

A diagnosis of amyotrophic lateral sclerosis is usually depressingly obvious on simple clinical grounds. Often only electrophysiological investigation is necessary to confirm denervation and to exclude a potentially treatable myopathy or demyelinating neuropathy. Sometimes upper motor neuron involvement is not clinically demonstrable, particularly in patients with absent Babinski’s responses due to severely denervated toe extensor muscles. Unfortunately, measurement of central motor conduction after electromagnetic stimulation of the brain is less reliable for revealing upper motor neuron involvement in such cases than had been hoped. If patients present with the combination of arm denervation and upper motor neuron signs in the legs, the cervical spinal canal should be imaged with MRI to exclude a compressive lesion, most often spondylitic radiculomyelopathy.

The usual diagnostic problem lies in differentiating amyotrophic lateral sclerosis from other motor neuron diseases. A lack of upper motor neuron involvement should raise the possibility of alternative diagnoses. The postpolio syndrome causes slow deterioration in limb or bulbar function some decades after acute poliomyelitis. X-linked bulbospinal neuronopathy is much more slowly progressive than bulbar amyotrophic lateral sclerosis, grimacing usually evokes characteristic lower facial contractions; gynaecomastia, diabetes mellitus, or abnormal sensory nerve conduction is often evident, and other male family members may be affected. Multifocal motor neuropathy or neuronopathy usually develops insidiously, characteristically producing marked weakness with little wasting; it predominantly affects the arms, may be associated with paraproteinaemia or antiganglioside antibodies, and may involve motor nerve slowing or conduction block. Adult-onset proximal hereditary motor neuronopathy is very slowly progressive, with early and symmetrical involvement of the proximal muscles; it rarely involves the bulbar muscles. Benign fasciculation syndromes without evidence of denervation, usually affecting young adults, do not evolve into motor neuron disease. Myopathic disorders, particularly the bulbar presentations of inclusion body myositis and myasthenia gravis, should always be borne in mind. The possible occurrence of motor neuron disease as a paraneoplastic disorder is still in dispute.

Giving the diagnosis

Doctors or relatives are sometimes tempted on compassionate grounds not to tell patients about their diagnosis of amyotrophic lateral sclerosis. When patients eventually detect this conspiracy of secrecy it can lead to serious loss of trust at a time when death looms and trustworthy relationships are of inestimable value. When given the opportunity, patients usually indicate that they wish to know the name of the disease and the likely outcome, and they may even wish for a detailed discussion of the probable modes of death. Judgement is required to soften the blow of grim news while giving an honest appraisal of the condition. Of course, questions should be answered honestly, although sometimes it may be preferable to discuss them in stages with the partner present in order to soften the blow early on in the course of the disease. Once a patient has been told the diagnosis, the doctor must address the particular issues presented by that patient’s own brand of amyotrophic lateral sclerosis before he or she becomes upset by the summary information that they may glean from lay reference books, newspapers/magazines, or the internet.

Treatment

No treatment is known to cure amyotrophic lateral sclerosis. Trials of drug therapy have concentrated on slowing the downhill progression of disability or improving survival. The antiglutamate agent riluzole, administered orally, has been licensed for treatment of amyotrophic lateral sclerosis. The 100 mg dosage improved the chance of tracheostomy-free survival at 18 months by an extra 35%, although there was no significant benefit on muscle function. Criticisms of this study have included the nature of Cox’s model of statistical adjustment, and it should be noted that more of the placebo group had bulbar features at entry to the study. Riluzole is generally well tolerated by patients; nausea, gastrointestinal upset, and raised transaminase enzyme levels may occur and usually resolve with a dose reduction. Ineffective therapeutic trials have included mixtures of branched-chain amino acids, dextromorphan, total lymphoid irradiation, the free radical scavenger acetylcysteine, gabapentin, creatine, and vitamin E.

Much can be done to overcome disability and alleviate distress by the care team of speech and language therapist, physiotherapist, occupational therapist, social worker, and physician. The Motor Neuron Disease Association is often able to provide equipment promptly. Severe dysphagia is most effectively bypassed by percutaneous endoscopic gastrostomy. Preferably the patient or the carer should have good hand function and vision so that they can change nutrient bags at home. If video-swallow shows that cricopharyngeal spasm is responsible for dysphagia, cricopharyngeal myotomy may help. Speech failure can be circumvented by computer-assisted communication devices operated through a practical modality, such as pressure, blowing, head nodding, or blinking, depending on which muscles remain strong.

Decisions about the advisability of instituting assisted respiration pose complex practical and ethical dilemmas. Patients with diaphragm weakness and nocturnal dyspnoea may be helped by intermittent positive airway pressure delivered by facemask. Endotracheal intubation and ventilation are rarely to be recommended in a disease causing such ubiquitous and irreversible weakness.

Lower motor neuron syndromes

These forms of motor neuron disease generally follow a much more benign course than amyotrophic lateral sclerosis. They include syndromes previously described as spinal muscular atrophy and progressive muscular atrophy. Differential diagnosis within the lower motor neuron syndromes depends principally upon attention to the age of onset, the pattern of the weakness, and a possible family history.

Proximal childhood spinal muscular atrophy with SMN mutations

This group of lower motor neuron degenerations is associated with deletions at 5q13 of the SMN1 survival motor neuron gene. The variable phenotype is explained by the difference in copy number of an almost identical gene, SMN2. The precise role of SMN has not been elucidated, but ribonucleoprotein or gene-splicing regulation is a likely function.

Type I: acute infantile form (Werdnig–Hoffmann disease)

This is one of the most common fatal autosomal recessive disorders of children. The disease frequency of approximately 1 in 25 000 in England results from a gene frequency of 1 in 160. Before the age of 6 months, babies become inactive, weak, and hypotonic, feed poorly, and are slow to attain motor milestones. They may be born with limb deformities and, in retrospect, fetal movements have been often absent or sparse. The tongue is weak and may fasciculate. Head control is poor and the infant’s areflexic and proximally wasted limbs tend to assume a frog-like position. Respiratory movements are decreased with prominent involvement of the intercostal muscles. Half the infants die by 6 months, and almost all have succumbed by 18 months, usually to respiratory complications.

Type II: intermediate form

This produces muscle weakness before 18 months; children can sit but never walk, and usually die in adolescence.

Type III: chronic childhood form (Kugelberg–Welander disease)

This form develops at any time after the age of 18 months to the early teens. It is also autosomal recessive, may be genetically heterogeneous, and may start discordantly within families. It can resemble Werdnig–Hoffmann disease if the onset is early, but follows a comparatively benign course. More than 90% of patients are able to walk or sit unsupported at some time, although these abilities are often lost eventually. Tongue involvement occurs in only half, and significant dysphagia is unusual. Some patients develop respiratory insufficiency as a result of intercostal muscle involvement. The proximal limb weakness and wasting are only slowly progressive and may stabilize spontaneously. Those with severe early weakness often develop secondary spinal and joint deformities. The prognosis varies, although survival into middle age is usual. It is important, although initially difficult, to differentiate those with infantile onset and no family history from types I and II infantile-onset forms.

Type IV: adult-onset form

This unusual autosomal recessive adult form starts from 15 to 60 years of age, usually in the fourth decade. Slowly progressive proximal limb weakness ensues, but significant disability for walking does not usually occur until the sixth or seventh decade. Life expectancy is only slightly reduced. Distal muscles can also be involved and the tendon reflexes are usually lost, but bulbar involvement is uncommon. The lack of either upper motor neuron signs or bulbar involvement, and the rather indolent progression, distinguish this from amyotrophic lateral sclerosis.

Other inherited spinal muscular atrophies

Autosomal dominant forms are rare, and fall into two groups with onset in childhood and early middle age respectively. Mutations of the VAPB gene (vesicle-associated membrane protein) at 20q13.3 are present in some Brazilian families. The limb weakness is predominantly proximal. Bulbar involvement does occur, although it is unusual. The childhood form may stabilize at adolescence and some patients retain walking ability into middle or old age. The adult-onset form causes more severe disability. The lack of upper motor neuron signs distinguishes these conditions from hereditary amyotrophic lateral sclerosis.

Autosomal recessive and dominant distal spinal muscular atrophies not associated with SMN mutations occur. Some resemble the type II Charcot–Marie–Tooth disease polyneuropathy. Various forms are recognized with leg or arm predominance, respiratory distress, vocal fold paralysis, and scapuloperoneal distribution. Occasional acute infantile forms are part of more complex disorders, variously involving pontocerebellar hypoplasia, arthrogryposis, bone fractures, and lethal congenital contractures.

Hexosaminidase deficiency

Autosomal recessive GM2 gangliosidosis presents a variable neurological picture, occasionally as a pure motor neuron syndrome due to lower and, rarely, upper motor neuron involvement. More usually there are also other neurological abnormalities such as cerebellar ataxia or dementia. Hexosaminidase assays should be reserved for those patients with early onset of unusual motor neuron disorders, particularly in those of Ashkenazi Jewish extraction.

X-linked recessive bulbospinal neuronopathy (Kennedy’s disease)

This disorder occurs only in men, with onset in the third to fifth decades of life. It is due to a mutation causing CAG (cytosine–adenine–guanine) repeat sequences of increased length within the androgen receptor gene. Molecular genetic analysis now forms the basis of a diagnostic test. Weakness usually first affects hand or pelvic girdle muscles and the bulbar symptoms may not be evident until 20 years later, if at all. Cramps are prominent and fasciculations are usually visible in the limb, tongue, and facial muscles. Characteristically, muscle contractions around the chin are induced by pursing the lips or grimacing. The disorder is only slowly progressive. Most patients survive into their seventh or eight decade except when bulbar involvement is unusually severe. The disorder is often misdiagnosed as amyotrophic lateral sclerosis until the unusually slow deterioration is questioned. Unlike amyotrophic lateral sclerosis, there are no upper motor neuron signs and patients commonly show gynaecomastia, diabetes mellitus, and absent sensory nerve action potentials.

Hereditary bulbar palsy of infancy and childhood

The Brown–Violetto–van Laere syndrome presents in the teens with bilateral sensorineural deafness, followed some years later by bulbar, facial, limb, and sometimes respiratory muscle weakness. Fazio–Londe disease is an autosomal recessive bulbar palsy of childhood, without deafness, and respiratory muscle involvement may lead to death within a few years.

Monomelic, focal, and segmental motor neuronopathies

These conditions are also known as chronic asymmetrical or focal spinal muscular atrophy, or monomelic motor neuron disease. Currently, the disorder is generally known as monomelic amyotrophy. Although most commonly described in Asia, especially Japan, it is seen regularly elsewhere in the world. It usually occurs sporadically and most patients are young men. It presents with distal wasting and weakness of one hand or forearm. This progresses steadily for the first 2 years before either stabilizing or settling to a slow rate of subsequent progression. Initially there may be concern that this is the first presentation of amyotrophic lateral sclerosis, but the expected upper motor neuron and bulbar involvement fails to materialize, and spread to other limbs is unusual. Nerve conduction studies are necessary to exclude focal entrapment neuropathies or multifocal motor neuropathy with conduction block. MRI of the cervical spine will detect syringomyelia or other spinal cord disease. Forms affecting a leg have been described, particularly from India.

Postirradiation lumbosacral radiculopathy

This may follow months or years of inclusion of the lower thoracic and upper lumbar spine in irradiation fields treating testicular tumours or lymphomas. It usually affects both legs, although occasionally one, and later causes mild symptoms affecting the sphincters and sensation. It is painless, and electrophysiology does not reveal the myokymic discharges or abnormal sensory nerve action potentials of irradiation plexopathy. The normal imaging of the lumbosacral plexus and cauda equina, and the absence of pain, exclude tumour recurrence.

Postpolio syndrome

After two or more decades, very slowly progressive weakness may affect muscles previously involved by acute paralytic poliomyelitis. Although this predominantly affects the limbs, approximately half the cases also have mild choking or dysphagia and weakness of the respiratory muscles, which may lead to hypercapnic respiratory failure. The sluggish deterioration, lack of upper motor neuron involvement, and previous history serve to distinguish postpolio syndrome from amyotrophic lateral sclerosis. Electromyography reveals the giant motor units typical of extensive reinnervation during recovery from previous acute poliomyelitis. At least equally commonly, late deterioration after polio is due to a secondary degenerative arthritis or fibromyalgia.

Multifocal motor neuropathy with conduction block

Patients with these conditions may present at any stage of adult life with multifocal and slowly progressive muscle weakness for as long as 20 years. The clinical picture is immensely variable. Distal limb muscles are mainly involved, often notably asymmetrical. The first symptoms and most severe weakness usually affect the arms. A third present with drop of an individual finger. Characteristically, severely weakened muscles show little or no wasting. Reflex loss is generally restricted to markedly affected muscles. The condition is neurophysiologically heterogeneous, ranging from muscle denervation to multifocal conduction block in motor nerves, and occasionally a diffusely demyelinating, pure, motor peripheral neuropathy. Early cases may show no such diagnostic electrophysiological abnormality. Serum antibodies to GM1 gangliosides are detectable in a third of cases, but are of no proven pathogenic significance. This antibody assay currently lacks specificity as positives are sometimes found in other neurological diseases.

These motor neuropathies usually progress insidiously, sometimes in a stepwise manner. Spontaneous remissions occur only occasionally, and usually in the subacute subgroup. It is important to detect the subgroup of patients with either multifocal motor conduction block or diffuse demyelinating neuropathy, because improvement may follow immunosuppressant therapy. Although cyclophosphamide is reportedly effective, its potential toxicity should limit its use to those patients with severely disabling and progressive weakness. High-dose intravenous human immunoglobulin (IvIg) therapy can produce dramatic improvement lasting 6 to 8 weeks and repeated administration is the mainstay of treatment in severely symptomatic patients. With IvIg administered sufficiently regularly to prevent end-of-dose deterioration, progressive motor axonal loss can be largely or completely prevented. Unfortunately, steroid therapy does not improve multifocal motor neuropathy, and may precipitate further deterioration.

Upper motor neuron syndromes

The pure upper motor neuron syndromes are the rarest forms of motor neuron disease. They should be considered only after MRI has excluded structural or demyelinating disease of the spinal cord, foramen magnum, or brain. Severe spasticity often overshadows weakness in these purely upper motor neuron diseases, but unfortunately antispasticity medications are often relatively ineffective. Rarely, similar upper motor neuron syndromes may be seen with syphilis and HTLV-I (human T-lymphocytic virus type I) infection. Deficiencies of vitamins B12 and E need to be considered along with L-dopa-responsive dystonia and adrenomyeloneuropathy.

Primary lateral sclerosis

Generally considered as a variant of amyotrophic lateral sclerosis, this rare sporadic form of motor neuron disease has an average age of onset of 50 years, and slow progression thereafter for an average of 15 years. The clinical features are all attributable to symmetrical degeneration of the upper motor neurons destined for the spinal cord and of the bulbar motor neurons. Spasticity and weakness usually start insidiously in the legs and ascend ultimately to involve the bulbar muscles. Less commonly patients present with an isolated spastic dysarthria, a symptom of pseudobulbar palsy. Pseudobulbar emotional lability may be distressing for these patients, given their normal cognition, and it often responds well to amitriptyline. Bladder function is generally preserved, at least until the later stages. Electromyography does not reveal the muscle denervation expected in predominantly upper motor neuron forms of amyotrophic lateral sclerosis, although in many patients this develops belatedly. MRI may reveal atrophy of the precentral gyrus motor cortex, reflecting loss of the Betz cells from which the pyramidal tract originates. Central motor conduction is notably delayed after electromagnetic stimulation of the motor cortex.

Hereditary spastic paraplegia

Various forms of slowly progressive, symmetrical, spastic paraparesis may be inherited, most usually on an autosomal dominant basis with onset in the fourth to sixth decades. The degree of leg spasticity often outweighs the severity of the weakness. Bulbar involvement is very rare, and arm function may be well preserved despite severe leg involvement. The condition is slowly progressive. It may remain asymptomatic in some family members, coming to light only when a familial basis for the disease is sought. Sphincter control is not impaired, but sexual impotence can develop. More than 30 genetic loci are involved, with genes identified in half. Clinically the hereditary spastic paraplegias are most conveniently divided into ‘pure’ and ‘complicated’ forms, the latter involving various features such as distal amyotrophy, intellectual impairment, dementia, pigmentary retinopathy, optic atrophy, extrapyramidal features, sensory neuropathy, ataxia, or epilepsy.

The various genetic entities produce a range of neurodevelopmental and neurodegenerative disorders. The autosomal dominant disorders are usually ‘pure’ and involve abnormalities of various genes for proteins involved in intra-axonal trafficking, such as spastin, atlastin, or KIF5A, while other genetic mutations involved heat shock protein 60 and seipin. The less common autosomal recessive forms often produce ‘complicated’ phenotypes and mutations include those for paraplegin, spartin, and maspardin. X-linked mutations are rare and generally present in childhood with ‘complicated’ phenotypes.

Lathyrism

Neurolathyrism is a spastic paraparesis caused by regular consumption of the chickling pea (Lathyrus sativus) for some months. It is endemic in parts of India and outbreaks have occurred in China, Africa, and central Europe at times of famine. Patients, usually young men, present either subacutely or chronically with a spastic paraparesis and a characteristic scissoring gait in which the balls of the feet take most of the weight. Once it has developed, neurolathyrism is usually not progressive, but little or no recovery occurs even after chickling pea consumption ceases. A plant-derived excitotoxic amino acid, BOAA, is considered pathogenic.

Konzo

Konzo is a form of tropical myelopathy which can occur in epidemics at times of famine in sub-Saharan Africa. It seems to be due to dietary cyanogen consumption, resulting from insufficient soaking of the cassava roots used to produce flour. There is an abrupt onset of symmetrical spastic paraparesis, which is nonprogressive but permanent. Blood cyanide levels are raised at the onset of disease.

Further reading

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Atsuta N, et al. (2006). Natural history of spinal and bulbar muscular atrophy (SBMA): a study of 223 Japanese patients. Brain, 129, 1446–55.

Bowen J, et al. (1997). The post-irradiation lower motor neuron syndrome. Neuronopathy or radiculopathy? Brain, 119, 1429–39.

Lacomblez L, et al. (1996). Dose-ranging study of Riluzole in amyotrophic lateral sclerosis. Lancet, 347, 1425–31.

La Spada AR, et al. (1991). Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature, 352, 77–9.

Le Forestier N, et al. (2001). Does primary lateral sclerosis exist? A study of 20 patients and a review of the literature. Brain, 124, 89–99.

Ludolph AC, et al. (1987). Studies on the aetiology and pathogenesis of motor neuron diseases. I Lathyrism: clinical findings in established cases. Brain, 110, 149–66.

McShane MA, et al. (1993). Progressive bulbar paralysis of childhood. A reappraisal of Fazio–Londe disease. Brain, 115, 1889–900.

Ringholz GM, et al. (2005). Prevalence and patterns of cognitive impairment in sporadic ALS. Neurology, 65, 586–90.

Rosen DR, et al. (1993). Mutations in Cu-Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature, 362, 59–62.

Shaw PM (2009). The motor neuron disorders. In: Donaghy M (ed.) Brain’s diseases of the nervous system, 12th edition. Oxford University Press, Oxford.

Slee M, et al. (2007). Multifocal motor neuropathy: the diagnostic spectrum and response to treatment. Neurology, 69, 1680–7.

Trojan DA, Cashman NR (2005). Post-poliomyelitis syndrome. Muscle Nerve, 31, 6–19.

Tylleskär T, et al. (1992). Cassava cyanogens and Konzo, an upper motor neuron disease found in Africa. Lancet, 339, 208–11.