Chapter 26- Disorders of basal ganglia function
There is no definitive list of structures that are included in the extrapyramidal system, but all lists would include the basal ganglia (caudate, putamen, and globus pallidus), and the subthalamic nucleus. The substantia nigra is an associated structure with important basal ganglia interconnections. The cerebellum and, perhaps also, the red nucleus play an important role in some abnormalities associated with basal ganglia disorders. Important interconnections of the basal ganglia are the nigrostriatal pathway, and the ansa and fasciculus lenticularis, and the fasciculus thalamicus, which interconnect the globus pallidus and the ventral lateral and ventral anterior (VL-VA) nuclei of the thalamus, and the VL-VA thalamocortical fibers, the subthalamopallidal pathway, striatopallidal fibers, and cerebellothalamic interconnections (Figure 26-1).
The normal functions of the human basal ganglia have largely been deduced from study of functional problems associated with destructive or irritative lesions. To a large degree, the deficits are in motor function and therefore, the extrapyramidal system and basal ganglia have been associated with movement disorders. For the most part, these clinical understandings have been supported and expanded by basic science investigations, although it is becoming increasingly evident that these brain regions are involved in a greater array of functions than was heretofore obvious. Although far from complete, this understanding has permitted development of some effective therapies for movement disorders.
In lower vertebrates the basal ganglia are a major motor control system. With progressive evolution of the brain in higher vertebrates, culminating in humans, the pyramidal system and the neocerebellar cortices have assumed a greater level of importance in motor control. However, as is true in many brain functions, the "more primitive" portions of the brain have not been discarded, but rather remain in control of some of the more primitive functions of the nervous system.
In primates and other neomammalian species, the basal ganglia appear to be important in the process of initiation of movement and the maintenance of stereotyped movements once they are initiated. Postural control, resting muscle tone, automatic associated movements (e.g., swinging the arms while walking), and possibly emotional motor expression (e.g., smiling, frowning, laughing, crying, etc.) appear to be important functions of the basal ganglia.
Some deficits observed with basal ganglia disease reflect loss of the preceding functions. However, other manifestations fit less easily into a scheme of lost normal function. One can only conclude that they reflect how the remaining normal brain functions when components of the basal ganglia are missing.
There are two major disorder complexes associated with disease of the basal ganglia and related structures: the parkinsonian syndrome and the choreas. Athetosis and the dystonias, also basal ganglia disorders, are much less common, with the exception of spasmodic torticollis and dystonias produced by certain neuroleptic drugs.
"Parkinsonism" is a relatively common complex of neurologic symptoms that can be seen with many types of extrapyramidal disease. This constellation of symptoms appears as the end product of many degenerative disorders of the brain, although some produce the symptoms much earlier in the course than others. For example, most patients with a generalized dementing condition of the brain will eventually develop symptoms of parkinsonism. However, this occurs quite late in the course of the disease for most of these conditions. Cerebrovascular disease can also target the extrapyramidal system (especially when diffuse), leading to parkinsonian symptoms. On the other hand, symptoms occur relatively early in conditions that selectively target the basal ganglia and related structures. Examples include progressive supranuclear palsy, cortico-basal ganglionic degeneration, striatonigral degeneration, multi-system atrophy and diffuse Lewy body disease.
In the case of idiopathic Parkinson's disease, the constellation has been related specifically to deficient function of the nigrostriatal dopaminergic systems. In this case, the major underlying pathologic abnormality is either a degeneration of neurons of the substantia nigra pars compacta (which are the source of the dopamine in the striate nuclei), or a drug-induced suppression of dopamine effectiveness. The latter is a common cause of the parkinsonian syndrome because of the widespread use of certain neuroleptic (tranquilizing) drugs (phenothiazines, butyrophenones, and reserpine) and it can be easily reversed by discontinuation of the drug.
A rare cause of acute and irreversible parkinsonism is poisoning with the "designer drug" MPTP, a derivative of the narcotic analgesic meperidine. The free radical breakdown product of MPTP, MPP+ appears to be the toxic molecule, which destroys the pigmented dopaminergic cells in the substantia nigra. A major experimental model has arisen from this tragic discovery (monkeys and other mammals also develop the parkinsonian syndrome when exposed to this toxin). The toxicity can be blocked by antioxidant therapy (Vitamin E, etc.) and a monoamine inhibitor, deprenyl. This has led to speculation concerning the etiology of parkinsonism and to clinical trials of both entities to determine a possible prophylactic effect in idiopathic parkinsonism.
Ameliorative but not curative medical therapy is now available for Parkinson's patients, mainly in the form of dopamine repletion or deep brain stimulation.
Parkinsonism is characterized by varying degrees of: (1) rigidity, (2) bradykinesia, (3) tremor, and (4) postural defects. Dementia, usually appearing late and less severe than the other abnormalities, is also relatively common (approximately 20%) and considered secondary to degeneration of cerebral cortical neurons that can be involved in a more diffuse degenerative process (as in diffuse Lewy body disease). Parkinsonism may also be part of a more prominent dementing process such as Alzheimer's Disease, presumably because the degenerative process also affects the basal ganglia.
Rigidity is plastic in nature and present in all ranges of passive manipulation and active movement. This appears to be due to overactivity in descending motor pathways from the brain stem. The gamma motor system probably is not involved because cutting the dorsal roots does not modify the rigidity. The rigidity has a superimposed cogwheel halting character if tremor is part of the syndrome.
Bradykinesia is actually not a slowness of movement so much as an inability to initiate or carry out movements despite the presence of adequate strength. An illustration of this presumed dyspraxia is seen in the parkinsonian patient who, frozen with bradykinesia, leaps from their wheelchair and runs with full coordination from a burning house and then safe, settles back to an inability to initiate volitional locomotion. The capability for catastrophe motivated, well-learned, and relatively automatic behavior is present, but volitional behavior is defective. Once movement is initiated, it can often be continued with reasonable speed. Bradykinesia and rigidity are additive in hindering movement and are usually present together. Bradykinesia is, however, not dependent on or necessarily proportional to rigidity, and vice versa. There is a small population of patients who have pure bradykinesia without other characteristic parkinsonian deficits. They have been described as having a pure "ignition" syndrome.
Also included by many under bradykinesia is the characteristic depression, or loss, of associated movements, such as arm swinging while walking, and emotional expression --e.g., an immobile face when the patient is happy or sad despite the ability to grimace voluntarily. Facial muscle rigidity can also partly or completely account for the "masked facies."
The tremor of parkinsonism is a rhythmic (four to eight per second) oscillation of opposing muscle groups, which is particularly prominent in the distal portions of the extremities. The upper extremities are affected earlier than the lower extremities. The neck and cranial muscles may also be involved.
Early in parkinsonism the tremor may begin in one extremity, so may rigidity and bradykinesia. In the absence of tremor, the presentation of parkinsonism may be erroneously diagnosed as hemiparesis. The absence of true weakness, the character of rigidity (full range instead of clasp knife) and the decrease in associated movements help to differentiate the two. Generalization to both sides of the body ultimately occurs in most patients with parkinsonism. The tremor has been erroneously considered a tremor at rest, but actually it is a tremor of postural or resting muscle tension. When the patient is completely at rest and relaxed (which is nearly impossible for most patients with Parkinson's disease), the tremor disappears. It is most characteristic that a parkinsonian tremor may be seen with the hands folded in the lap or when walking with the hands hanging by the sides.
The postural (e.g., arm held in position demanding muscle tone) or resting muscle tension tremor of parkinsonism is to be differentiated from the tremor of cerebellar damage, which is not present until the patient directs their limbs into purposeful activity (i.e., intention tremor). The tremor of Parkinson's disease is suppressed by the initiation of voluntary movement. As the disease progresses, however, many patients may begin to develop a coexisting intention tremor, which supports a hypothesis that involvement of the cerebellar system is important in the pathogenesis of parkinsonian tremor. All forms of tremor, and indeed most adventitious movement abnormalities, are increased by anxiety or any other stress that increases muscle tension; they are reduced to varying degrees by relaxation or sedation.
Postural deficits are less well studied and understood. However, it is characteristic for a person with parkinsonism to have difficulty adjusting to postural change. This can be demonstrated by seating the patient on the edge of a tilt table. When the table is tilted, the normal response is to lean uphill, thus preserving one's balance. The parkinsonian patient tilts with the table without adjusting and topples over (Figure 26-2). If the patient is given a good shove backward, instead of normally catching their balance s/he tends to fall back like a tree. In some patients this retropulsion can be initiated by simply having the patient attempt to look up or back up. Patients with moderately advanced parkinsonism frequently have a flexed (stooped) posture, which may well be a compensation for the postural imbalance that causes retropulsion. Falling is a common problem for parkinsonian patients because of the combination of their rigid/bradykinetic shuffling gait and the postural adjustment deficit. They are unable to make the appropriate kinetic-postural adjustment necessary to prevent them from falling. A bizarre but typically parkinsonian fall occurs when the patient is unable to initiate stepping movement with their feet although s/he has already initiated forward movement of the trunk. To avoid falling on their face, s/he usually drops to the knees.
Parkinson disease (PD) is the single most common (and most treatable) condition that produces parkinsonism. Most cases are sporadic, although there are some clearly defined families with autosomal dominant inheritance patterns. Most of these families have inherited defective genes for one of several intracellular proteins. The ultimate pathology in PD is the presence of Lewy bodies (ubiquitin-containing granules) in the cytoplasm of neurons in the degenerating substantia nigra pars compacta (the region of dopaminergic neurons projecting to the substantia nigra). Because there are some small clusters of Parkinson’s disease and because of cases of poisoning with MPTP (a byproduct of amateur attempts at synthesis of meperidine), there are some suspicions of environmental factors in the genesis of the disease. It appears that compounds that generate free radicals when oxidatively metabolized have a particular predilection for damaging the substantia nigra (due to the high oxidative functions of these neurons).
Although PD can occur at any age, it is rare before the 30s, and increases in frequency with advancing age. This can be explained by gradual, age-related loss of neurons in the substantia nigra.
Most often, the symptoms begin asymmetrically. There is a variable constellation of tremor, bradykinesia, rigidity, difficulty initiating movements and delayed postural corrections. The condition can present with tremor or with rigidity. Rarely, it can primarily present with balance issues in the absence of other symptoms. These cases are particularly difficult to diagnose.
The fundamental pathology in pure cases of PD is a deficiency of dopamine in the striatum of the basal ganglia (the caudate and putamen). Dopamine has the effect of stimulating the direct circuit through the basal ganglia, while inhibiting the indirect pathway. Ultimately, since the direct pathway is facilitatory to movement and the indirect pathway is inhibitory, the net effect of dopamine is to increase the excitability of the motor areas of the cerebral cortex and increase movement (see this discussion of functional anatomy if you desire further elucidation). Therefore, when the tonic activity of dopamine is lost, the motor and premotor cortex are less excitable and the patient is less mobile, with slower responses and less spontaneous movement.
As our understanding has progressed, it has become apparent that some patients have a pure dopamine deficiency. These patients have near-complete resolution of their symptoms when dopamine is replaced. However, there are also patients with additional degeneration of the extrapyramidal system. These patients usually have incomplete resolution of symptoms, with improvement based on how much additional damage has been done.
Treatment of PD is often initiated with the combination of levodopa (a dopamine precursor that crosses the blood-brain barrier) and carbidopa (an inhibitor of dopa decarboxylase that does not cross the BBB). This latter medication prevents conversion of levodopa to dopamine outside the brain, thereby minimizing dopaminergic side effects and assuring as much delivery of dopamine as possible to the brain. The entry of dopamine to the brain can be diminished by competition with other amino acids, and some patients have their response to levodopa blocked by a protein meal.
Levodopa is easily converted to dopamine in the brain and results in an increased concentration and storage of dopamine in dopaminergic neurons. Although the levodopa is typically quite short-lived in the peripheral circulation, the fact that it boosts dopamine storage in the brain can result in improvement of symptoms lasting many hours. However, as the condition progresses, the capacity to store dopamine declines and the duration of action becomes shorter (sometimes only persisting for the hour or two of high blood levels). This progressive decline in dopamine storage results in “wearing off” of the drug that can occur at progressively shorter intervals and, eventually, severely fluctuating symptoms. These fluctuation can result in “on-off” periods that can occur quite abruptly. The patient can even freeze in place unpredictably.
After long-term administration of levodopa, over-responsiveness to dopamine may develop. Striatal neurons appear to become particularly sensitive to dopamine after years of exposure to levodopa (and, to a lesser extent, other Parkinson’s treatments) due to proliferation of dopamine receptors. This can result in the “peak-dose dyskinesia” that is seen as choreoathetosis (see below).
Other complications of Parkinson’s treatment include nausea (due to stimulation of peripheral dopamine receptors), hypotension (which can also occur due to PD, itself) and hallucinations/nightmares. These latter are typically visual in nature.
Other treatments for PD include anticholinergic medications (these have limited effect and many side-effects), direct dopamine agonists (drugs that stimulate the dopamine receptors directly) and medications that slow the breakdown of dopamine (either by blocking centrally-acting monoamine oxidase or catechol-O-methyl transferase). Other methods of delivery of levodopa are being explored and, if medications are producing excessively variable responses, neurosurgical procedures (mostly either destruction of the medial globus pallidus or stimulator implantation into the subthalamic nucleus) are often used (see Figure 26-1 for the anatomical relationships of these structures).
Symptoms are invariably progressive, although there has been great interest (and slight evidence) for neuroprotective approaches to prevent this progression. Eventually, most patients develop less response to medication, coupled with increased side-effects. This probably occurs due to degeneration extending to other neuronal cell populations as well as proliferation of dopamine receptors on remaining neurons.
There are some conditions characterized by symptoms of Parkinson’s disease plus areas of degeneration. Multiple system atrophy (MSA) commonly has additional pyramidal signs (spasticity and upgoing toes), autonomic dysfunction (bladder and blood pressure control) and cerebellar findings along with symptoms of Parkinson’s disease. This is associated with a very specific pathology, the presence of glial cytoplasmic inclusions, in many brain regions (accounting for diffuse symptoms). There are 3 main variants of this condition, all with similar neuronal pathology, each of which has its greatest effect in different brain regions. When the extrapyramidal system is mostly affected, this is termed “striatonigral degeneration”. When the cerebellar systems are mostly affected, the diagnosis is “olivopontocerebellar atrophy”. And when the autonomic preganglionic neurons are targeted, the condition has been called Shy-Drager syndrome. This latter condition produces profound orthostasis and bladder dysfunction as early symptoms. With progression of any of these variants, elements of the other conditions may come out. None of these conditions are as responsive to treatment as is Parkinson’s disease (and side-effects to medications are typically greater).
As we described previously, any condition that results in sufficient degeneration of the extrapyramidal system can result in "parkinsonism". However, there are several specific causes of parkinsonism that deserve a little more discussion. These are all characterized by some appearance of the above-described symptoms of parkinsonism, especially rigidity and bradykinesia.
Progressive supranuclear palsy (PSP) is a condition of degeneration, with prominent accumulation of neurons containing tau proteins in many areas including the rostral midbrain. Symptoms usually start in the 50s or 60s. Most of these patients have early gait difficulty and there is often a significant dysarthria early in the course. Voluntary vertical gaze is also affected very early in the course. The patient has trouble looking up and down although the eyes can be moved much further by oculocephalic tests. Many patients eventually develop retrocollis (a dystonic extension of the neck) and they often develop severe swallowing troubles (that can lead to pneumonia). Emotional lability, personality change and cognitive problems usually occur a little later. This condition progresses more rapidly than does Parkinson’s disease and death is due to pneumonia or the effects of debility. There is little response to Parkinson’s medications.
Cortical basal ganglionic degeneration (CBD) is a rare, degenerative condition that results in degeneration of both the fronto-parietal region of the cerebral cortex and various structures of the extrapyramidal system. There may be large, ballooned neurons and other neurons containing neurofibrillary tangles. This condition usually begins in the 50s and 60s and presents with asymmetrical motor difficulties that can include prominent apraxia of a limb (“I just can’t make it do what I want to”). Sometimes this is so severe that it has been termed “alien hand.” Dystonia of one limb is a common symptom. Patients usually don’t have significant memory loss but may have “executive” function problems (i.e., distractible, trouble planning movements, deficient judgment, etc). Patients may also have trouble with graphesthesia despite intact sensations. There is no effective treatment other than palliation.
Diffuse Lewy body disease (DLBD) is a condition where neurons in the cerebral cortex and extrapyramidal system are undergoing degeneration with prominent ubiquitin-containing inclusions (Lewy bodies). This condition is most remarkable for vivid and severe hallucinations early in the condition, along with confusion, a progressive dementia and parkinsonian features. These patients are very sensitive to the older antipsychotic medications which are often administered in an attempt to quell the hallucinations, that are often accompanied by paranoid delusions. Some of the newer antipsychotics are significantly better in this regard (such as quetiapine and clozapine). Some of the anticholinergic treatments (as used for Alzheimer’s disease) may be helpful, but only for a short period.
Chorea is the term for a type of involuntary movement disorder characterized by irregular and fleeting movements of the limbs and/or axial musculature also including the muscles of the face, jaw and tongue. The intensity of movement varies from very minimal buccolingual chorea characteristic of long-term neuroleptic toxicity to the wild and exhausting limb-flailing chorea called hemiballism.
Degenerative and destructive processes in the striatum or striatal inhibition (due to certain classes of drugs) are the major pathologic substrates of chorea. Superficially it appears paradoxical that the most common causes of choreiform movement disorders are the same neuroleptic drugs (phenothiazines, butyrophenones, and reserpine) that are the most common causes of parkinsonian disability. Unfortunately the choreiform abnormalities are not so easily reversible and may be permanent in some cases.
The model for choreiform disorders is Huntington's chorea. This condition is a rare, inherited (autosomal dominant), degenerative process involving the striatum, particularly the small-cell population (the large-cell neurons are relatively spared), and also the cerebral cortex, giving rise to a combination of progressive limb and axial chorea and dementia. Sometimes, early in the disease, a parkinsonian syndrome with rigidity and bradykinesia precedes the chorea, presumably because of involvement of the dopamine system of the striatum. This changes to chorea with progression. When this unfortunate process is recognized in a family, genetic counseling becomes paramount as an exercise in prevention.
Sydenham's or rheumatic chorea is a mild, self-limited limb and axial disorder associated with rheumatic fever in children. The decreasing incidence of rheumatic fever may soon make Sydenham's chorea an historical curiosity. It is occasionally exacerbated or uncovered in adult women who are pregnant (chorea gravidarum) or taking birth control pills. Because it is reversible and not progressive or fatal, very little is known of the pathophysiology. However, it is presumed that the substrate is striatal dysfunction, because the same drugs that to some degree ameliorate Huntington's chorea are also effective against Sydenham's chorea.
A variety of metabolic conditions are associated with choreiform movements. Among these are hyperthyroidism, lupus erythematosus (presumably the vasculitis affects the arteries supplying the striatum), atropine poisoning, anticonvulsant toxicity (e.g., phenytoin, carbamazepine, and phenobarbital), and L-dopa therapy for parkinsonism. Relief coincides with clearing of the metabolic derangement.
Hemiballism is a violent, flailing chorea of the limbs opposite a lesion in the subthalamic nucleus or, rarely, the striatum. With few exceptions the pathogenesis is infarction, less often hemorrhage, and rarely tumor. Fortunately, in most cases the disease is self-limited because the process (e.g., ischemia) resolves or because the lesion enlarges to involve either the cerebral peduncle or the internal capsule, causing weakness from involvement of the pyramidal system; the chorea, which is expressed through an intact pyramidal system, disappears.
Athetosis is a rare movement disorder characterized by involuntary, slow, twisting, writhing movements of the trunk and limbs. It frequently has associated erratic choreiform components. Striatal injury, particularly prominent in the putamen, has been considered the pathophysiologic substrate; however, widespread brain damage is usually present and confounds any clear analysis. The most common causes are perinatal hyperbilirubinemia, which involves the brain (kernicterus) and prematurity (which can result in damage to developing forebrain, often with periventricular hemorrhage). These leave the infant with cortical and prominent basal ganglia damage, with subsequent choreoathetosis and, usually, mental retardation.
With one exception, the dystonias are uncommon disorders. They are characterized by torsion spasms of the limbs, trunk, and neck. They may be progressive or static and are related to past encephalitis in a few cases but are usually idiopathic. In a few individuals who were well studied post mortem, either no pathology or various combinations of basal ganglia lesions were seen. Spasmodic torticollis is the most common idiopathic form and is characterized by intermittent excessive and involuntary contractions of the sternomastoid muscle on one side (rarely bilateral giving retrocollis). Interestingly, the head can be guided back to a neutral position with very gentle pressure on the side of the face. The head drifts back to its distorted position when the pressure is released. Therapy with anticholinergic medications has had a minimal positive effect on dystonic disorders. Recently, intramuscular injections of weak solutions of botulinum toxin, a powerful neuromuscular transmission blocking agent, have been shown to be useful in relieving dystonia for periods up to four to six months.
The one frequently seen dystonia is related to an overdose of neuroleptic drugs and is always reversible when the drug is withdrawn or counteracted by anticholinergic drugs. Involuntary and occasionally severe tonic contraction of axial muscles is most common, ranging from jaw clenching similar to the trismus (lockjaw) of tetanus to severe opisthotonic posturing (back and neck in sustained extension) similar to that seen in decerebration. Recognition of this easily reversible cause of these otherwise ominous signs is obviously important. A good history can usually clarify the situation, and reversal of the dysfunction with anticholinergic medication confirms the diagnosis.
Tardive dyskinesia is the term given to the iatrogenic axial chorea seen most often in women exposed to long-term neuroleptic use. The neuroleptic drugs (phenothiazines and butyrophenones), among many other effects, block both dopamine and, to a lesser degree, acetylcholine systems and usually cause parkinsonian side effects; dystonia is caused by acute overdose. On withdrawing the drugs or decreasing the dose, these difficulties usually clear. In its mildest form, constant mouthing with protrusion of the lips, mandible and tongue is seen, not unlike the movements of some very elderly persons and individuals who continually adjust loose upper dental plates. In more advanced stages the trunk muscles are involved and there is a characteristic irregular, incessant pelvic thrusting, which can cause the patient to become a recluse. Unfortunately, after chronic use, axial and, occasionally, limb choreiform movements are uncovered in some cases and persist. Treating these patients with the same dopamine-blocking neuroleptics is usually successful in improving symptoms for a while, presumably on the basis of production of parkinsonian side effects. Unfortunately, the choreiform-causing changes continue to occur and finally break through the parkinsonian effects so that the dose of the drug must continually be increased. Withdrawing the drug leaves a worse choreiform problem.
The mechanism of tardive dyskinesia appears to be due to a compensatory increase in the number of dopamine receptor sites following long-term administration of neuroleptic drugs, producing hypersensitivity. When the drugs are withdrawn, uncovering blocked dopamine receptor sites or increasing dopamine levels toward normal, the total number of active sites may become so great that there is an excessive dopaminergic response (chorea) to normal levels of dopamine elaboration in the striatum.
Some of the newer "atypical neuroleptic" drugs are less likely to do this but most still can result in dyskinesia. Antioxidant prophylaxis and therapy has recently shown some promise in preventing and, to a lesser degree, reversing tardive dyskinesia. However, this may not be as effective as was first suspected. Nonetheless, it might be prudent to include antioxidants concomitantly with chronic neuroleptic therapy.
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Define the following terms:extrapyramidal, oxidative stress, parkinsonism, Parkinson disease, bradykinesia, delayed postural reflexes, resting tremor, cogwheel, festination, chorea, athetosis, hemiballismus, dystonia, "wearing off", "on-off", hypophonia.
26-1. What are the functions of the extrapyramidal system?
26-2. What is the cause of Parkinson disease?
26-3. What are the symptoms of Parkinson disease?
26-4. What is the pathology of Parkinson disease?
26-5. What are the treatments for Parkinson disease?
26-6. What problems complicate treatment of Parkinson patients?
26-7. What surgical treatments are available for Parkinson disease?
26-8. What is essential tremor?
26-9. How do you recognize essential tremor?
26-10. What are the available treatments for essential tremor?
26-11. What are potential causes of chorea and athetosis?