Chapter 24 - Degenerative diseases of the nervous system
The degenerative disorders generally are characterized by the loss of neurons and secondary gliosis (scarring) without evidence of major inflammation or necrosis of tissue. Many diseases previously classified as degenerative are now known to be associated with specific metabolic deficiencies or have other definite causes (Table 24-1). Others are transmitted by infectious agents (see Chapter 25). However, we are still left with a large number of progressive diseases of unknown etiology, and their classification is based on pathologic and clinical findings. This is true of many of the disorders of the basal ganglia and the rest of the extrapyramidal system. However these disorders will be discussed in Chapter 26 . As time passes, it is quite likely that the specific biochemical and pathophysiological processes underpinning many of these diseases will be elucidated and their classifications will change.
In this chapter we discuss the more common of these conditions (designated by asterisks in Tables 24-2). They range from extremely common (Alzheimer disease) to quite rare (the spinocerebellar degenerations). Many are devastating conditions that often affect people in the prime of life. Certainly these are important to discuss in any course on neurology.
Spinocerebellar ataxias (SCAs) are a large and growing number of rare conditions that share the characteristics of being hereditary, of being progressive and of producing ataxia as a dominant symptom. A full treatment of these conditions is beyond the scope of this text. Friedreich ataxia is by far the most common of these conditions and we will consider it as a prototype of this group of conditions. This disease is an autosomal recessive condition that usually begins in late childhood, but whose onset can be delayed until early adulthood. Several spinal cord pathways are progressively damaged including the dorsal columns and the lateral columns (upper motor neurons) as well as cerebellar pathways. After a reasonably normal early childhood, progressive clumsiness of gait and skeletal deformity (such as scoliosis) are noted, typically with progression to a wheelchair after about 10 years of symptoms. Ultimately, in 1996, this condition was shown to result from a defective gene producing a mitochondrial protein, frataxin. This leads to iron deposition in the mitochondria and cell damage and patients die from cardiomyopathy, typically 30-40 years after onset of symptoms. The other SCAs have different genetic abnormalities (not all of which are known).
Friedreich ataxia has its onset in childhood or adolescence, with ataxia that is due to a combination of proprioceptive loss and cerebellar ataxia. There is atrophy of the small muscles of the feet, indicating a peripheral neuropathy. Mild spastic weakness and upgoing toes may be seen later. Severe disability and death usually occur by the third or fourth decades; however, mild forms, or formes frustes, of the disease are not infrequent. Extraneurologic signs include pes cavus, kyphoscoliosis, and cardiomyopathy, which may result in terminal congestive heart failure.
The lesions in Friedreich's ataxia involve the dorsal root ganglia, with secondary lesions in the peripheral nerves and dorsal columns. In addition, lesions are present in Clarke's column and in the lateral columns and the cerebellum.
Most of the other spinocerebellar ataxias begin in adulthood. The best known
of these are the autosomal dominant SCAs, where specific genes and, for many,
gene products are known. This list is growing and there are also autosomal
recessive SCAs to add to the list but the taxonomy is complicated and evolving
as more becomes known about the specific dysfunctional genes. These conditions
enter into the differential diagnosis of a slowly progressive neurologic disorder
presenting with severe ataxic symptoms.
Alzheimer described a presenile dementing illness characterized pathologically by neurofibrillary accumulation in the neurons as well as senile plaques containing substantial amounts of beta amyloid configured proteins. Since the pathologic changes are identical in most cases of old-age dementia (occurring over the age of 65), we use the term Alzheimer disease to include this common form of dementia, which affects approximately 5-10% of adults over 65 and possibly as many as 40% of individuals over 85. The disease has a familial tendency in some families and is associated with mutations in the beta amyloid gene. Also, risk of Alzheimer disease is higher in individuals with the epsilon 4 version of apolipoprotein. This risk is particularly high in individuals who are homozygous for this.
The pathologic changes in persons with Alzheimer's disease are most severe in the hippocampi. This is the reason that loss of recent memory (i.e., learning new material) is an early clinical feature. The posterior temporo-parietal association area is often affected early, as well. Therefore, mild anomia (trouble finding nouns) and constructional apraxia are also common early signs. There is early loss of cholinergic neurons in the nucleus basalis (of Meynert) and drugs that inhibit central nervous system acetylcholinesterase (increasing the amount of acetylcholine available in the brain) improve symptoms of the condition modestly. As the illness progresses it involves more of the cortex, with more severe cognitive loss and eventually frontal lobe disturbances become prominent. However, paresis, sensory loss, or visual field defects are not seen. Despite trouble finding the right words, repetition of even complex phrases is preserved (a transcortical aphasia).
Alzheimer disease is the most common cause of dementia of age. Older persons with dementia are often diagnosed as having "cerebral arteriosclerosis" when, in fact, they have Alzheimer disease. Vascular dementia does occur in association with Alzheimer's disease but is frequently associated with clear findings indicative of prior strokes (spasticity, paresis, pseudobulbar palsies, aphasia, etc). Amyloid also collects in arterial walls in Alzheimer disease patients and may contribute to a coexisting vascular dementia (amyloid angiopathy).
Unfortunately, there is no definitive diagnostic test for Alzheimer disease. Pathologic diagnosis is still the only way to definitively diagnose the condition. Imaging is insensitive (although is often useful to rule out other conditions that can cause dementia). Some functional imaging studies have shown promise at defining abnormalities in function of the temporal and posterior parietal lobes, however this has not been widely applied in clinical practice. Investigators have been looking at certain components in the CSF (particularly tau proteins and beta amyloid) as a possible diagnostic test. However there are still many questions about the utility of these tools. Obviously, methods for definitive diagnosis will be more important if a specific therapy is proven effective.
Recent data suggest that accumulation of amyloid deposits in the characteristic Alzheimer's plaques is the active pathology of the disease. There are animal models of the condition that are improved by vaccination against amyloid in an attempt to stimulate the immune system to help clear away amyloid. However, this approach has yet to produce an effective human treatment. Epidemiologic and a few prospective studies suggest that there may be some element of inflammation in the condition and some have suggested excess oxidation as a contributing factor. Despite some limited therapeutic trials, there are no proven methods for arresting the progression of the condition.
Pick's disease (also known as frontotemporal dementia) is a rare condition that can run in families and results in degeneration of the frontal and temporal lobes of the brain. This can be severe in some cases, permitting reasonably accurate diagnosis on the basis of imaging. However, most cases are not so easy to diagnose, especially at the onset. This condition tends to present in one of two ways. Firstly, it may present as disordered behavior (usually either with disinhibited behavior or with apathy). The disinhibited behaviors include agitation, socially inappropriate behavior or impulsivity. There is usually a lack on insight into their condition and a lack of empathy. The second presentation is dominated by language problems, usually accompanied by behavioral problems. Despite these deficits, memory and spatial skills remain intact. Pathology does not show the changes of Alzheimer disease, but rather shows the presence of intraneuronal "Pick bodies". There is no effective therapy for Pick's disease other than, perhaps, psychotropic medications and behavior modification to control the worst of the behavioral issues. This condition tends to be more aggressive than Alzheimer disease, usually resulting in death in 2-10 years.
- Walton, J.N.: Disorders of Voluntary Muscle, ed. 3. Edinburgh, Churchill and Livingstone, 1974.
- Engel, A.G. and Banker, B.Q.: Myology. New York, McGraw-Hill, Inc., 1986.
- Whitehouse, P.J..: Dementia, Philadelphia, F.A. Davis Co., 1993.