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Brain Damage, Brain Repair$

James W. Fawcett, Anne E. Rosser, and Stephen B. Dunnett

Print publication date: 2002

Print ISBN-13: 9780198523376

Published to Oxford Scholarship Online: March 2012

DOI: 10.1093/acprof:oso/9780198523376.001.0001

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(p.387) Appendix 2 Amyotrophic lateral sclerosis (ALS)/Motor neurone disease

(p.387) Appendix 2 Amyotrophic lateral sclerosis (ALS)/Motor neurone disease

Source:
Brain Damage, Brain Repair
Publisher:
Oxford University Press

History

  • 1850 Aran used the term progressive muscular atrophy, but attributed this to a muscle disorder.

  • 1853 Bell and Cruveilhier noted the thinness of the anterior spinal roots in this condition and regarded it as a myelopathic condition.

  • 1858 Description of labioglossolaryngeal paralysis by Duchenne.

  • 1859 Term changed to progressive bulbar palsy by Wachsmuth.

  • 1869 Charcot studied the pathological features, and noted the involvement of the corticospinal tracts, suggested the term Amyotrophic Lateral Sclerosis (ALS) and, with Joffroy, recognised relation ship to progressive bulbar palsy.

  • 1882 Relationship of progressive bulbar palsy to ALS established by Déjerine.

  • 1883 Brain introduced the term motor neurone disease in recognition of the relationship between ALS, progressive bulbar palsy, and progressive muscular atrophy, depending on the topography of anterior horn cell loss. Identification of familial cases.

  • 1991 Linkage to chromosome 21 by Siddique et al.

  • 1992 Identification of involvement of mutations in exon 2 and 4 of CuZn SOD gene by Rosen.

  • 1993 Identification of other mutations within this gene by Deng et al.

Symptoms

Motor neurone disease (MND) is a progressive disorder of motor neurones in the spinal cord, brainstem, and cortex — the precise clinical picture depending on whether all of these groups of motor neurones, or only a subset, are affected by the disease progress. In the most common type there is degeneration of both the lower motor neurones in the spinal cord and the descending corticospinal and corticobulbar tracts. This produces both hypotonia and muscle wasting due to the lower motor neurone lesion, and rigidity and hyper-reflexia due to the upper motor neurone lesion. This form is also termed amyotrophic lateral sclerosis (amyotrophy refers to the muscle weakness and wasting due to the dennervation of that muscle), and one of its hallmarks is a combination of both upper (rigidity and hyperreflexia) and lower (weakness, wasting, and fasciculation) motor neurone signs in one body part. If the weakness and wasting predominates in the muscles innervated by the lower cranial nerve nuclei, the condition is often termed progressive bulbar palsy. In a much rarer form, the descending tracts are principally affected, and if there appears to be involvement of descending tracts only, over an extended period of time, the condition is known as primary lateral sclerosis, although there is not universal acceptance that this is definitely related to other forms of MND. As the disease progresses (usually over 2–5 years), there is progressive weakness and loss of muscle bulk until the patient is wheelchair or bed-bound, mute, and unable to swallow. Muscles controlling sphincter action are usually unaffected, even in the later stages, and sensory symptoms are essentially absent. Respiratory muscle weakness is common in the latter stages and frequently is the cause of death.

(p.388) Neuropathology

The principal pathology is loss of neuronal cells in the anterior horns of the spinal cord, lower cranial nerve nuclei, and Betz cells in the motor cortex. Many remaining neurones in these regions are shrunken and small, and filled with lipofuscin. There is also evidence of astrocytosis. Secondary to the loss of these cell bodies, there is thinning of the anterior spinal roots and degeneration in the corticospinal and corticobulbar tracts. There are a small number of cases associated with dementia, in which there is also neuronal loss and gliosis in the superior frontal gyri and inferolateral cortex of the temporal lobes.

Genetics

Of MND cases, 5–10% are familial. Most of these familial cases show autosomal dominant inheritance, although a few are autosomal recessive. Apart from the family history, on the whole the condition is identical to the sporadic form, although some familial cases show degeneration of posterior columns and spinocerebellar tracts. The familial condition was linked to chromosome 21 and since then 10–20% of familial disease has been linked to a number of mutations in the gene encoding Cu, Zn super oxide. Genes responsible for the other familial forms have yet to be identified.

Cellular pathology and pathogenesis

In common with a growing number of neurodegenerative diseases (see Huntington's disease and Alzheimer's disease), there is evidence of altered proteins in vulnerable neurones in the form of intracellular inclusions, although their role in the pathogenesis is as yet unclear, and the cellular and molecular steps leading to the neuroneal degeneration seen in MND are as yet unknown. In terms of familial MND due to the CuZn SOD mutation, it is thought likely that the mutation impairs the activity of the CuZn SOD enzyme leading to increased generation of superoxide radicals and that motor neurones are particularly sensitive to oxidative damage. It is not known whether cell death in sporadic MND is by similar mechanisms, and a number of theories have been put forward for the mechanism of cell including: environmental toxins; premature ageing, as motor neurone death also occurs with normal ageing; interruption of the endogenous production of trophic factors necessary for motor neurone maintenance; viral infection of motor neurones; metabolic abnormalities (a wide range of relatively minor metabolic abnormalities have been reported in ALS); and autoimmune destruction.

Current treatments

Currently there is no specific treatment for this disease other than supportive measures. Riluzol has been shown to lengthen life-expectancy by a number of months, although it was not shown to improve quality of life in these studies, and insulin-like growth factor (IGF-1) also prolongs survival. A number of other experimental approaches are ongoing, for example, ciliary neurotrophic factor (CNTF) delivered by means of genetically-engineered cells housed within a semi-permeable polymer membrane in within the spinal canal have not proved helpful in small scale trials, but with modification may still prove to be useful.