Chapter 24 - Degenerative diseases of the nervous system
In this chapter we will discuss conditions that have historically been classified as degenerative. These 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 Chap. 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.
Amyotrophic lateral sclerosis (ALS) is one of a number of degenerative conditions that selectively involve the motor system, collectively termed "motor neuron disease." There are two inherited conditions (Werdnig-Hoffmann disease in infants and Kugelberg-Welander disease in children and young adults) that are characterized by anterior horn cell degeneration only. In ALS, which affects mainly adults 40-60 years of age, there is degeneration not only of the anterior horn cells and some of the cranial nerve motor nuclei, but also of the corticobulbar and corticospinal tracts. Clinically, therefore, one sees a combination of lower motor neuron findings (atrophy, and fasciculations) along with upper motor neuron findings (spasticity and hyperactive reflexes). Therefore, although weakness without sensory change is the hallmark, this weakness is of two types and may express quite differently in the arms and in the legs of a single patient. The disease may start asymmetrically, but usually within months it involves many muscle groups on both sides of the body. The average patient survives three years with death resulting from weakness of the bulbar and respiratory musculature and resultant superimposed infection.
There are some variants of the condition that selectively involve either upper motor neurons or the lower motor neurons. In primary lateral sclerosis, the upper motor neuron signs predominate, but eventually there is some evidence of lower motor neuron involvement, so that this entity is no longer felt to be distinct from ALS. The course tends to be longer than in the usual variety of ALS, with some persons surviving ten years or longer. There is also a variant that involves only lower motor neurons and one that selectively involves the cranial musculature (termed progressive bulbar palsy). Again, with time these variants often show signs of evolution to a more typical ALS pattern.
Motor neuron disease is a very active field of research. There has been great interest in the possible contribution of environmental toxins to the condition. This has partially been based on identified clusters of ALS and a very clear example of toxin-induced motor neuron disease (ALS-dementia complex of Guam). The finding of certain families of patients with clearly hereditary ALS stimulated research identifying neuronal deficit of the antioxidant superoxide dismutase as a cause. This has lead to research into free-radical destruction of motor neurons. There is also some research suggesting the involvement of inflammatory cytokines in the condition (despite the absence of major inflammation in most cases). Despite these preliminary findings, extensive research has yet to lead to any effective therapy.
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.
Collectively, these conditions result in non-inflammatory degeneration of muscles
This is the most common type and is a sex-linked recessive trait. It affects young boys, in whom pseudohypertrophy of the calves and weakness of the hip and shoulder girdles progress from early childhood. Levels of serum muscle enzymes (CPK and aldolase) are extremely high. The children are usually confined to a wheelchair by the age of 10, and they usually die in the second to third decade. It is due to a mutation in the gene for an inappropriately-named normal protein named dystrophin. A less severe mutation in this same gene is responsible for a somewhat later onset dystrophy, Becker dystrophy. No effective therapy is known, although steroids may slightly prolong the course.
This is a heterogeneous group of conditions that usually appear in adolescence or adult life with proximal limb weakness. The weakness usually progresses slowly, but it may arrest spontaneously. There are at least 15 different mutations that contribute to this presentation and some are passed on recessively while others have dominant inheritance.
This condition also can be recessive or dominant and appears to have at least several different genetic abnormalities producing this phenotypically distinct pattern of weakness and wasting. Symptoms usually appear in adolescence or very early adult life with weakness of face muscles and of muscles attached to the scapula and proximal upper limb. The weakness usually progresses slowly and life expectancy is normal. Mental retardation is common and there may be abnormalities of cardiac rhythm.
In this disease myotonia (delayed relaxation of muscles) is combined with dystrophy (muscle atrophy not secondary to peripheral nerve or anterior horn cell involvement). The disease, which is transmitted as an autosomal dominant condition, usually begins in childhood or young adult life (possibly infancy with maternal transmission). There are cases where it has been unrecognized until advanced ages, however. It is due to repeats in the sequence of the myotonic protein kinase gene. These repeats often get longer in sequential generations, with earlier onset of symptoms.
Myotonic dystrophy, as opposed to most forms of myopathy, is distal, affecting the muscles of the hands before more proximal musculature. In addition, facial and neck musculature are involved early. Evidence points to an abnormality of membranes that is not restricted to muscle. Numerous non-neurologic problems are found: frontal balding, testicular atrophy, diabetes, cardiac arrhythmias, and others. It progresses slowly. Many victims succumb to respiratory failure and superimposed infection by the fifth decade.
These conditions are discussed in Chapter 25 on infectious diseases. The group of diseases are caused by abnormal proteins (scrapie, kuru, Creutzfeldt-Jakob disease, bovine spongiform encephalopathy) and the primary pathologic change is neuronal degeneration and reactive gliosis. These conditions are transmissible, but the "infectious agent" in these cases appears to be an abnormal protein rather than a virus, bacteria or parasite. It appears that some cases can be sporadic due to de-novo configurational changes in proteins.
- 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.