Motor neuron disease

Published on 02/04/2015 by admin

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Last modified 22/04/2025

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69 Motor neuron disease

Instruction

Examine this patient’s cranial nerves.

Examine this patient’s upper limbs.

Examine this patient’s lower limbs.

Salient features

History

• Fasciculations and cramps: these may precede other symptoms by months

• Painless, asymmetrical weakness of muscles of the upper limb or lower limb

• Dysarthria and dysphagia

• Emotional lability if there is bulbar involvement.

Diagnosis

This patient has a combination of upper and lower motor neuron signs (lesions) caused by motor neuron disease (aetiology), although I would like to exclude cervical cord compression. The patient is wheelchair bound as a result of the disease (functional status).

Questions

What important cause should be ruled out before making a firm diagnosis of motor neuron disease?

Cord compression may produce a similar clinical picture and hence it is important to do an MRI scan of the spine and/or a myelogram to exclude it.

Advanced-level questions

What are the characteristic features of this disease?

• It rarely begins before the age of 40 years

• Presence of upper and lower motor neuron involvement of a single spinal segment, and motor dysfunction involving at least two limbs or one limb and bulbar muscles

• Sensory symptoms or signs are not seen

• Ocular movements are not affected

• There are never cerebellar or extrapyramidal signs

• Sphincters are involved late, if at all

• Remission is unknown and the disease is fatal within 5 to 7 years (caused by bronchopneumonia).

What are the clinical patterns of motor neuron disease?

• Bulbar: bulbar or pseudobulbar palsy (in 25%)

• Amyotrophic lateral sclerosis (ALS; in 50%): flaccid arms and spastic legs

• Progressive muscular atrophy (in 25%): a lesion in the anterior horn cells affecting distal muscles. Characteristically there is retention of deep tendon reflexes in the presence of severe muscular atrophy

• Primary lateral sclerosis (rare): signs progress from an upper motor neuron to a lower motor neuron type

• Others conditions affect lower motor neurons:

• Werdnig–Hoffman’s disease: presents in the neonatal period as a ‘floppy infant’ and known as infantile progressive spinal muscular atrophy

• X-linked spinal muscular atrophy: the patient has associated testicular atrophy resulting in oligospermia and gynaecomastia; it is associated with the amplification of a trinucleotide repeat in the coding sequence of the androgen receptor gene and disease severity is directly related to the number of repeats present

• Spinal muscular atrophy: linked to locus on the large arm of chromosome 5.

What are the other types of motor neuron disease?

• Madras motor neuron disease, common in southern India, where the onset is early (before the age of 30), with asymmetrical limb weakness and wasting; bulbar and facial involvement occurs along with sensorineural deafness. The course is more benign than the disorder observed in Europe and America (Srinivas K, Jagannathan K, Valmikinathan K. The spectrum of motor neuron disease in Madras. In Rose FC (ed.) Research Progress in Motor Neuron Disease. London: Pitman, 1984, p. 142).

• ALS associated with a parkinsonism–dementia complex in Guam (Science 1987;237:517). It also tends to have an earlier onset and a more protracted course than the sporadic cases seen in Europe and America.

What are the criteria for diagnosis of amyotrophic lateral sclerosis?

Summary of revised El Escorial criteria:

• Definite: lower motor neuron and upper motor neuron signs in three regions

• Probable: lower motor neuron and upper motor neuron signs in two regions

• Probable with laboratory support: lower motor neuron and upper motor neuron signs in one region or upper motor neuron signs in one or more regions with electromyography evidence of acute denervation in two or more limbs

• Possible: lower motor neuron and upper motor neuron signs in one region

• Suspected: lower motor neuron signs only in one or more regions or upper motor neuron signs only in one or more regions.

All categories need evidence of disease progression and absence of sensory signs not explicable on the basis of comorbidity.

What is the pathology of motor neuron disease?

The clinical manifestations result from degeneration of Betz cells, pyramidal tracts, cranial nerve nuclei and anterior horn cells. Both upper and lower motor neurons may be involved, but sensory involvement is not seen.

What is the explanation for fasciculation?

It is the result of spontaneous firing of large motor units formed by branching fibres of surviving axons that are striving to innervate muscle fibres that have lost their nerve supply.

What are the cerebrospinal fluid changes in the disease?

Usually normal; protein may be slightly raised.

What do you know about the heredity of amyotrophic lateral sclerosis?

Most cases are sporadic but 5–10% are familial. Familial ALS is linked to a gene on the long arm of chromosome 21 (N Engl J Med 1991;324:1381), with various missense mutations identified in different families. This genetic locus appears to encode a copper–zinc-binding superoxide dismutase (SOD). Therapy that ameliorate symptoms in the Sod1 mutant mouse have consistently failed in humans suggesting other mechanisms. It has been shown that a muscle-specific microRNA (miR-206) in the Sod1 mouse delays disease progression and promotes regeneration of neuromuscular synapses by boosting the secretion of a growth factor-binding protein into the extracellular matrix indirectly; this, in turn, potentiates growth factors that promote presynaptic innervation at the neuromuscular junction (Science 2009;326:1549–54). [Micro-RNAs are endogenous, small RNAs (~22 nucleotides in length) that target and downregulate, in a sequence-specific manner, messenger RNA.]

Mutations in additional genes (encoding alsin, angiogenin, dynactin 1, senataxin and vesicle-associated protein B) have also been associated with a motor neuron disease (although often not a typical ALS phenotype) in a few families.

How are DNA chips (microarrays) used in genetic analysis?

The DNA chip or the microarray is able to genotype hundreds of thousands of single-nucleotide polymorphisms (SNPs) simultaneously in a single experiment. (SNPs are single-nucleotide variations in the DNA sequence that can be used as markers for neighboring genetic variation.) Comparing the prevalence of a specific SNP in patients and controls, the chromosomal region represented by the SNP associated with a disease can be determined. This approach is known as a high-density genomewide association study. Using one such study, a recent group of investigators reported that variants of FLJ10986 may confer susceptibility to sporadic ALS. FLJ10986 and 50 other candidate loci warrant further investigation for their potential role in conferring susceptibility to the disease (Lancet Neurol 2007;6:322–8, N Engl J Med 2007;357:775–88).

Is there any treatment for motor neuron disease?

No treatment has been shown to influence the course of the disease. Riluzole, a glutamate antagonist, is being used in limb or bulbar palsy (N Engl J Med 1994;330:585–91). Patients often require treatment for painful muscle cramps, constant drooling, severe fatiguability, sleep problems, incipient contractures, subluxation of the shoulder joint, dysphagia and neuralgia—all of which can be ameliorated. Patients often have extreme lability of emotion, particularly in the early stages of ALS. In order to alleviate distress before or during respiratory failure, which is usually the terminal event, narcotic drugs should not be withheld.

What is the rationale for using riluzole?

The suggestion that accumulation of toxic levels of glutamate at synapses may cause neuronal death through a calcium-dependent pathway. Riluzole has been shown to be useful in patients with disease of bulbar onset but not in those with disease of spinal onset. The risk of death or tracheostomy is lower with 100 mg riluzole than placebo in limb or bulbar onset disease (Lancet 1996;347:1425–31), but it is debatable whether this translates into an improved quality of life.

What is the role of beta-lactam antibiotics in amyotrophic lateral sclerosis?

More recently beta-lactam antibiotics have been shown to enhance astroglial transport of glutamate in vitro by enhancing the surface expression of the glutamate transporter GLT1 and they do so at levels that are routinely achieved during the treatment of CNS infections (Nature 2005;433:73–7). Long-term ceftriaxone treatment slows the course of disease in mouse models of ALS caused by transgenic expression of mutant SOD. When administered at high doses at the onset of the disease, ceftriaxone preserves grip strength, slows weight loss and increased the overall duration of survival from 122 to 132 days. The slowing of motor neuron death is accompanied by a marked increase in the expression of GLT1 protein in the mice. The US National Institutes of Health has approved funding for a multicentre trial of ceftriaxone in patients with ALS.

What is the role of microglia in motor neuron disease?

Recent data suggest that the expression of mutant SOD1 in microglia accelerates the death of motor neurons in murine models of SOD1-linked ALS (Science 2006;312:1389–92). The aetiology may be toxin production or the transfer of toxins to nearby motor neurons or astrocytes by mutant microglia, or the mutant protein may damage the microglia and prevent them from producing protective factors. Other possibilities exist, including the production of diffusible toxins (such as ions or cytokines) by damaged microglia.

Is there any test to monitor the rate of disease progression?

Antibodies to L-type voltage-gated calcium channels are present in the serum of patients with sporadic AML, and antibody titres correlate with the rate of disease progression (N Engl J Med 1992;327:1721–8).

What is the role of magnetic cortical stimulation in amyotrophic lateral sclerosis?

Magnetic cortical stimlation uses time-varying magnetic fields to induce electrical currents within the brain painlessly. It is said to activate cortical motor neurons trans-synaptically through thalamocortical and corticocortical afferents, and allows detection of degeneration of cortical Betz cells. In patients with AML, the sensitivity of this technique to detect upper motor neuron involvement in those with clinical signs is high, but the sensitivity of the technique in those without clinical signs is unknown.

Is there any animal model for amyotrophic lateral sclerosis?

Transgenic mouse model possessing mutations in the gene encoding the cytosolic form of the enzyme copper–zinc SOD (Nature 1993;362:59).

Further reading

Radunović A, Mitsumoto H, Leigh PN. Clinical care of patients with amyotrophic lateral sclerosis. Lancet Neurol. 2007;6:913-925.

Lou Gehrig, the American baseball player, died from AML 50 years ago.

Charcot gave a detailed clinical and pathological description of AML in 1865.

Professor Stephen Hawking, the Cambridge theoretical physicist, is the most famous sufferer of motor neuron disease. It claimed the lives of the actor David Niven, the football manager Don Revie and the wartime pilot Sir Leonard Cheshire, VC.

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