It is estimated that five percent of persons older than 65 years have severe dementia and that 10 percent have mild to moderate dementia. This high prevalence, combined with the rapid rate of growth of the elderly segment of the population, makes dementia one of the most important public health problems. Alzheimer's disease accounts for the majority of cases of dementia. There are, however, more than 50 recognized causes of dementia,[1] and it is important to consider the possibility of a treatable cause when evaluating patients with dementia. A potentially reversible cause was identified in eight percent of cases in one series of 200 consecutive patients referred for dementia.2]
Reversible causes in this series were hydrocephalus, brain tumor, and hypothyroidism; these conditions generally were found in patients younger than 65 years. Potentially treatable causes were detected in 10 percent of 500 consecutive patients investigated by computed tomography (CT).[3] These statistics indicate that selected laboratory studies should accompany a careful historical, physical, and nutritional evaluation of patients with dementia. Among the laboratory tests, I would routinely include a specific serologic test for syphilis, blood counts, tests of thyroid function, a general chemistry panel, and CT of the head. Tests to detect human immunodeficiency virus (HIV) infection should be performed when appropriate.
Another critical aspect of the evaluation of apparently demented patients is the mental status examination. Depression may present as an apparent disorder of cognitive function or may coexist with dementia. Most patients with the pseudodementia associated with depression give more lucid accounts of their illness and complain more actively of memory loss than patients with dementia.[4] Dementia may also be overdiagnosed, particularly in patients who are elderly or educationally disadvantaged.[5] Folstein and colleagues have devised a mini-mental state examination that is often useful in distinguishing between dementia and affective disorders.[6] The examination takes about 10 minutes to administer [see Table 1]. Patients with affective disorders usually score above 24; those with dementia score well below this level.[7]
| Orientation | What is the year, season, date, day, month?
(5 points) Where are we: state, county, town, hospital, floor? (5 points) |
10 |
| Registration | Name three objects and ask the patient to
repeat the names of the objects. (correct response = 1
point) Repeat the names of the three objects until the patient learns them. |
3 |
| Attention and Calculation | Ask the patient to recite serial 7's backward from 100. Stop the patient after five responses. (correct response = 1 point) | 5 |
| Recall | Ask the patient to repeat the names of the three objects learned above. (correct response = 1 point) | 3 |
| Language | Show the patient two common objects (e.g.,
a pencil and a watch) and ask the patient to identify them. (2
points) Ask the patient to repeat "no ifs, ands, or buts." (1 point) Instruct the patient to follow the three-stage command: "take a paper in your right hand, fold it in half, and put it on the floor." (3 points) Ask the patient to read and obey the following: "close your eyes." (1 point) Instruct the patient to write a sentence. (1 point) Ask the patient to copy a design. (1 point) |
9 |
Alzheimer's disease is the most common cause of chronic dementia. It has been estimated that about two million people in the United States have Alzheimer's disease and that 100,000 people die of it each year.[8] Although once regarded as a condition of middle age, it is now known that the histopathologic lesions of Alzheimer's disease--neuritic or senile amyloid plaques, neurofibrillary degeneration, and granulovacuolar neuronal degeneration--are also found in the brains of elderly people with dementia. The relative abundance of such lesions correlates with the degree of intellectual deterioration. The designation senile dementia of Alzheimer type (SDAT) has been used to describe cases in elderly persons.
Alzheimer's disease usually arises spontaneously, although there is some evidence that genetic factors may be important. Families in which Alzheimer's disease is inherited in an autosomal dominant pattern have been reported.[9] In addition, the histopathologic lesions of Alzheimer's disease are regularly found in the brains of older patients dying of Down's syndrome (trisomy 21). Patients with Down's syndrome have an extra copy of chromosome 21 and as a result show increased expression of genes on that chromosome. Increased expression of one such gene, the b-amyloid gene, may regulate the formation of amyloid plaques in these patients. One group reported increased expression of the b-amyloid gene in patients with Alzheimer's disease, leading to the hypothesis that duplication of a segment of chromosome 21 may represent the genetic defect in Alzheimer's disease. [10] Several subsequent reports, however, failed to find evidence of duplication of chromosome 21 genes in patients with Alzheimer's disease.[11,12,13]
The etiology and pathogenesis of Alzheimer's disease are not known.[14] Cytoarchitectural studies of the cerebral cortex have shown that neurofibrillary changes occur in neurons within specific cortical laminae, especially in the temporal lobe in layers II and IV of the entorhinal cortex and in the subiculum of the hippocampus. Researchers have prepared a monoclonal antibody, Alz-50, that is directed against a soluble protein extracted from brain tissue of patients with Alzheimer's disease. The antibody is immunoreactive not only against neurons showing neurofibrillary degeneration but also against neurons that do not show such degeneration but that are located in cortical laminae, where such changes are likely to occur.[15] It is possible that Alz-50 could be used as a marker to detect prestructural pathologic changes in cells and that such studies could provide important new insights into the pathogenesis of Alzheimer's disease. Neurochemical studies of the cerebral cortex have shown a relatively specific reduction in choline acetyltransferase (CAT), the enzyme required for synthesis of the neurotransmitter acetylcholine (ACh). The degree of reduction of ACh correlates with the severity of dementia. This finding may reflect loss of the neurons in the substantia innominata of the basal forebrain that form the cholinergic projection to the hippocampus and cerebral cortex.[16] Degeneration of the terminals of these neurons may initiate the formation of amyloid plaques.
The disease usually begins after 45 years of age and is equally frequent in men and women. [This statement is questionable, studies show greater prevalence in women.] Symptoms at onset often suggest depression: moodiness, decreased sociability, and lack of enthusiasm and drive. In some cases, hypomanic behavior is prominent. The behavioral changes are soon accompanied by symptoms of intellectual decline. Family and associates of a patient may note errors of judgment and an inability to make decisions. The patient may retain sufficient insight to feel markedly anxious about these symptoms. As the disease progresses, memory loss gradually becomes more profound. At first, retention of new information is impaired; later, events of the recent past are easily forgotten; and finally, there is global dementia. Somatic neurologic signs or aphasic disturbances are usually absent until the disease is well advanced. Myoclonic jerks may be seen late in the course, but convulsive seizures are rare. The disease reduces life expectancy, generally by several years. It is important that the practicing physician be familiar with guidelines for the evaluation and general care of patients with Alzheimer's disease, including pharmacotherapy for insomnia, depression, and agitation; behavioral management techniques; and family assistance.[17]
Pick's disease is a rare cause of dementia that cannot be clinically distinguished from Alzheimer's disease. The tempo of progression may be more rapid in Pick's disease, and focal neurologic signs of aphasia and hemiparesis may be more prominent. The diagnosis is usually made at autopsy based on the findings of lobar atrophy, particularly of the frontal and temporal lobes, and the presence of argentophilic intraneuronal inclusions and swollen achromatic neurons. Some patients have shown a striking loss of neurons in the substantia innominata, as in Alzheimer's disease.[18] There is no specific therapy.
The term multi-infarct dementia is used to distinguish between demented patients with reduced cerebral blood flow and patients with Alzheimer's disease, who have normal cerebral blood flow. The pathologic findings in patients with multi-infarct dementia are atherosclerosis of small arteries and patchy cerebral infarction. The clinical features differ somewhat from those of Alzheimer's disease and suggest cerebrovascular occlusive disease: onset is often abrupt, the progression may be stepwise, and the course tends to fluctuate. Somatic neurologic signs are often found, and signs of generalized vascular disease are frequent.
The syndrome of occult hydrocephalus with normal cerebrospinal fluid (CSF) pressure has attracted much attention because the associated dementia can potentially be reversed by ventriculoatrial shunting. The pathophysiology of this disorder is not well understood. Normally, CSF is produced within the cranium at a rate of about 500 ml/day. The choroid plexuses in the ventricles are the major site of CSF production. Fluid flows through the outlet foramens of the fourth ventricle and over the surface of the brain; it is largely reabsorbed into the dural venous sinuses through arachnoidal granulations.
Obstruction within the ventricular system, most commonly at the aqueduct of Sylvius, leads to a noncommunicating hydrocephalus that dilates only the portion of the ventricular system proximal to the obstruction. Obstruction within the subarachnoid spaces or arachnoidal granulations leads to a communicating hydrocephalus in which all of the ventricles are dilated. In adults, occult hydrocephalus is usually of the communicating type and may result from a low-grade defect in CSF reabsorption. At times, the syndrome follows a known episode of meningitis, trauma, or subarachnoid hemorrhage.
The minimal clinical criteria required for a diagnosis of occult hydrocephalus are progressive dementia, gait disorder, and urinary incontinence. Diagnostic tests include CT scanning to demonstrate ventricular enlargement and radionuclide injection into the CSF, followed by brain scanning, to reveal the pattern of CSF flow. Even these tests do not provide a completely reliable method for identifying those patients who will benefit from a shunt. An improvement in psychomotor responses that persists for a few hours after the removal of 40 to 50 ml of CSF is said to be a good predictor of benefit following ventricular shunting.[19] The response to ventricular shunting varies, and there is a high frequency of postoperative complications, including stroke, subdural hematoma, and shunt malfunction.[20]
Parkinson's disease (paralysis agitans) is a degenerative disorder of the basal ganglia of unknown etiology. The prevalence of the disease has been cited as varying between 60 and 187 per 100,000 population. A positive family history is present in about five percent of patients, but genetic factors are not thought to be important determinants of the disease. In one survey, only one of 43 monozygotic twin pairs was found to be concordant for Parkinson's disease.[21] Several environmental factors induce symptoms of parkinsonism, and it has been suggested that most cases of the disease result from the combination of neuronal loss from aging and exposure to toxic environmental factors.[22] Parkinsonism was a common sequela of von Economo's encephalitis lethargica, which was pandemic during the first quarter of this century. Intoxication by carbon monoxide, carbon disulfide, or manganese or chronic ingestion of many psychotropic drugs can also induce parkinsonism.
In 1983, parkinsonism was reported to have developed in several patients after intravenous administration of a product of meperidine-analogue synthesis, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).[23] It was found that use of MPTP in monkeys provided an excellent animal model of Parkinson's disease, quite faithfully reproducing the clinical, pathologic, and chemical changes that occur in human disease. MPTP itself turned out to be nontoxic; instead, its oxidation product, 1-methyl-4-phenylpyridinium ion (MPP+), was found to be highly toxic, especially for neurons containing melanin pigment, such as those in the substantia nigra. MPTP is oxidized to MPP+ by monoamine oxidase (MAO) type B, the isoenzyme that catabolizes dopamine. Both the oxidation and the toxic effects of MPTP may be blocked in animals by the administration of deprenyl, an MAO B inhibitor. Furthermore, the distribution of MAO B in human brains has now been monitored by positron emission tomography (PET) after injection of radioactive 11C-deprenyl.[24] Such noninvasive imaging may play an important role in the design and evaluation of therapy.
The principal pathologic feature of Parkinson's disease is degeneration of the substantia nigra, particularly the zona compacta. Degenerative changes are also found in other brainstem nuclei, especially the locus ceruleus and dorsal motor nucleus of the vagus. An unusual inclusion, the Lewy body, is found in degenerating neurons in most cases of idiopathic Parkinson's disease. Pathologic changes occur less predictably in the globus pallidus, striatum, and cortex.
Neurons of the substantia nigra project to the corpus striatum (caudate nucleus and putamen), where they release the neurotransmitter dopamine. Loss of the striatal dopamine is the principal biochemical defect in Parkinson's disease. In turn, neurons from the striatum project back to the substantia nigra to form a feedback loop for intrinsic control. These feedback neurons appear to reduce the activity of nigral neurons by liberating the transmitter g-aminobutyric acid (GABA) and to increase their activity by liberating the peptide substance P. Cholinergic neurons appear to be largely intrastriatal. An imbalance of dopaminergic and cholinergic activity has been proposed to explain clinical phenomena in diseases of the basal ganglia. A relative excess of dopaminergic activity produces involuntary movements; a relative excess of cholinergic activity produces akinesia and rigidity.
As a rule, the symptoms of Parkinson's disease are first recognized in a patient's middle years, although it is often difficult to know when they began. Early in the disease, when symptoms are mild and confined to one side of the body, diagnosis may pose a problem. In its fully developed form, Parkinson's disease is unmistakable. The principal features are generalized slowness and poverty of spontaneous movement, rigidity of the limbs, facial immobility, disorders of posture and gait, and a rhythmic resting tremor. Most disabling to the patient are muscle rigidity and bradykinesia. The patient often describes these symptoms as tiredness and weakness, but it is usually not the power of muscles but their speed of movement that is primarily affected. The gait is generally slow and shuffling. A loss of associated arm swinging and a tendency to turn en bloc develop as well.
Rigidity first appears in proximal limbs and nuchal muscles. If the limbs or head are passively moved, an increase in muscle tone can be felt in flexors, extensors, and rotators. Such an increase in tone is uniform throughout the range of motion (plastic rigidity), except for periodic interruptions in tone, which give rise to the cogwheel phenomenon. In these respects, extrapyramidal rigidity differs from the sudden catch-and-release responses to muscle stretch found in disorders of the corticospinal system.
Facial immobility, characterized by infrequent blinking, a paucity of expressive responses to emotional stimuli, and a loss of crispness of features, produces a stony and staring countenance. An abnormal glabellar reflex (persistent blinking on tapping the forehead) may be present.
Tremor is usually first noted as a rhythmic, alternating flexion and extension of the thumb and digits at a frequency of four to five cycles a second--the so-called pill-rolling tremor. The tremor is prominent in the resting limb, disappears briefly during the course of the movement, and reappears when the limb is held in a static unsupported posture. Tremor of the head, lips, tongue, and feet may also occur.
Less easily defined symptoms include a tendency for the patient's voice and handwriting to be diminutive, especially at the end of a sentence. Seborrhea, greasy skin, pupillary abnormalities, tics, diaphragmatic spasms, repetitive speech, and oculogyric crises are features more typical of postencephalitic parkinsonism. Mild dementia and troublesome depression are noted in well-established cases of paralysis agitans. Some patients have coexisting Alzheimer's disease. The differential diagnosis of parkinsonism is not difficult. The course of the postencephalitic variety progresses slowly. Diffuse cerebrovascular arteriosclerosis may give rise to a syndrome consisting of pronounced extrapyramidal rigidity, dementia, hyperreflexia, and extensor plantar responses. Progression of this syndrome is often stepwise. Exposure to toxins and drugs should be sought in the history. Patients frequently do not know what drugs they are taking, and thus, they should be asked to bring samples for inspection to eliminate the possibility of adverse reactions to reserpine, phenothiazines, or butyrophenones.
The principal pharmacologic agent for treating Parkinson's disease is levodopa. The rationale is to provide a precursor for dopamine synthesis in the basal ganglia; dopamine itself does not cross the blood-brain barrier. The drug is usually administered in combination with carbidopa, an aromatic amino acid decarboxylase inhibitor, to prevent enzymatic conversion of levodopa to dopamine in peripheral tissues. Carbidopa does not interfere with brain synthesis of dopamine, because it does not cross the blood-brain barrier.
Controversy exists over whether to initiate levodopa therapy at the time of diagnosis of Parkinson's disease or to reserve the drug for patients with more advanced symptomatology.[25] Proponents of the latter option argue that the frequency of undesirable side effects increases with duration of levodopa treatment. Proponents of early therapy cite evidence to suggest that mortality may be lowered in patients who are treated early.[26] The issue is an important one that remains to be resolved.
Many neurologists continue to treat mild cases of Parkinson's disease or drug-induced parkinsonism with anticholinergic and antihistaminic agents such as trihexyphenidyl, 2 mg orally three or four times daily, and chlorphenoxamine, 50 mg orally three times daily. When the symptoms become more pronounced, amantadine, which stimulates the release of dopamine from nerve terminals, may be tried in an oral dosage of 100 mg two or three times a day.
In more advanced cases of Parkinson's disease or cases in which symptoms interfere with the patient's quality of life, the treatment of choice is levodopa combined with carbidopa. Three combinations of levodopa plus carbidopa (Sinemet) are available: 100 mg/10 mg, 100 mg/25 mg, and 250 mg/25 mg. Initial and subsequent dosages must be individualized; it is desirable to start with a low dose and increase it gradually. Treatment commonly starts with an oral dosage of 100 mg of levodopa and 10 or 25 mg of carbidopa, two to four times a day. Severe cases may require an oral dosage of 250 mg of levodopa and 25 mg of carbidopa, six times a day.
The intervals between doses should also be individualized. Some patients require medication as often as every hour or two. In other patients, the dosing intervals have to be adjusted based on the time of day and level of physical activity. Tailoring a medication program in this fashion may obviate an abrupt wearing off of the therapeutic effect. However, giving frequent doses that contain inadequate amounts of levodopa may worsen the so-called on-off phenomenon.[27]
Whenever possible, levodopa-carbidopa should be taken without food because amino acids derived from ingested proteins interfere with intestinal absorption of the drug. In fact, the response to therapy may be improved by severely limiting protein intake until dinner; dinner and evening snacks would then provide the recommended daily allowance of protein (0.8 g/kg of body weight).[28]
The toxic and adverse effects of levodopa are plentiful. Because the drug may induce such major systemic reactions as cardiac arrhythmias and gastrointestinal hemorrhage, great care is required with persons predisposed to these problems.
Furthermore, psychiatric symptoms occur in 30 percent of patients on long-term therapy. Such symptoms include sleep disorders, confusion, agitation, depression, and hallucinations. Symptoms are usually reversed by a reduction in drug dosage.
The most serious problem, the full extent of which is not known, is the emergence of an involuntary movement disorder that may take practically any form. Facial-lingual-pharyngeal dystonia, chorea, and athetosis are common.
Dyskinesias appear in about 80 percent of patients, usually after about a year of treatment with levodopa. At first, involuntary movements are little more than an annoyance to the patient, but gradually, they become more perverse. In 15 to 20 percent of patients, alternating periods of hyperkinesia and hypokinesia develop (on-off phenomenon). When full-blown, this phenomenon takes the form of disabling involuntary movements that abruptly give way to severe akinesia, with frozen postural attitudes and fixed facies. The transition can occur within minutes and is often preceded by anxiety, pallor, sweating, tachycardia, and other autonomic manifestations.
In general, the development of severe fluctuations in motor performance requires a change in therapy. Gradually reducing the dosage of levodopa while substituting bromocriptine may help.
Bromocriptine, a synthetic ergoloid that acts as a dopamine-receptor agonist, is started at a dosage of 1.25 mg orally twice daily, and the dosage is increased by 2.5 mg/day every two weeks until the desired response is achieved. Dosages that exceed 75 mg/day are not warranted. Another ergoloid, pergolide, which has not yet been approved by the FDA, has been shown to help some patients who do not respond to bromocriptine.[29]
Various other therapeutic approaches are being studied. One approach consists of the administration of deprenyl, with or without vitamin E, to prevent the accumulation of unknown oxidized metabolites that might progressively damage neurons in the substantia nigra. Another approach is the transplantation of adrenal medullary autografts into the lateral ventricle.[30] Although groups from Mexico and China have reported beneficial results using such transplants, the outcome in 85 patients who underwent the procedure at several centers in the United States has been disappointing.[31] Transplantation of substantia nigra tissue obtained from human fetuses into the brains of patients with Parkinson's disease has great scientific appeal, and its application in monkeys with MPTP-induced parkinsonism has met with early success.[32] However, the technique raises many novel ethical questions. In May 1988, the United States Public Health Service instituted a moratorium on research utilizing human fetal tissue obtained from induced abortions for therapeutic transplantations. The restriction does not apply to fetal tissue from spontaneous abortions or stillbirths.
Huntington's disease is a progressive degenerative disease of the basal ganglia that is inherited as an autosomal dominant trait. The prevalence is estimated to be three to four per million population among whites and considerably lower among blacks and Orientals.
The defective gene is located in the distal region of the short arm of chromosome 4. In 1983, a DNA fragment linked to the Huntington's disease locus (termed a restriction fragment length polymorphism) was discovered. This discovery led to the development of a test that uses DNA linkage analysis to identify persons who are at risk of carrying the defective gene and hence of eventually manifesting the disease. However, the opportunity for presymptomatic diagnosis raises many ethical questions, particularly because the accuracy of a positive or negative test result is only 85 to 95 percent.[33,34] A DNA segment much more tightly linked to the Huntington's disease locus has since been identified, which will improve the accuracy of predictive testing.[35]
Huntington's disease appears to result from the premature death of certain systems of neurons. Neurons in various general regions of the brain are selectively vulnerable to cell death; the most profound degeneration occurs in the corpus striatum (caudate nucleus and putamen). In addition, specific cell types within the corpus striatum are selectively vulnerable to loss.
Medium-sized spiny neurons appear to be the first cells affected. These cells contain the neurotransmitters GABA, substance P, and the enkephalins; the levels of these neurotransmitters are markedly reduced in the brains of patients with Huntington's disease. Large aspiny neurons, which contain acetylcholine, are also affected. Other aspiny neurons, which contain the peptides somatostatin and neuropeptide Y, as well as the enzyme nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d), are spared; concentrations of somatostatin and neuropeptide Y may even be increased in patients with Huntington's disease.[36] Neurons that contain dopamine are also unaffected.
It has been known for many years that excessive neuronal stimulation by excitatory neurotransmitters such as glutamate may cause cell death. More recently, it has been shown that the same selectivity of striatal cell loss that is found in Huntington's disease may be produced in rats by intrastriatal injection of quinolinic acid, an excitatory compound that is a naturally occurring metabolite of tryptophan.[37] Neurons containing NADPH-d, which are spared in Huntington's disease, are also selectively resistant to quinolinic acid.[38]
The neurotoxic effects of quinolinic acid in rats may be prevented by the administration of a drug that blocks the receptor to which quinolinic acid attaches. Dementia figures prominently in Huntington's disease, but unlike in Alzheimer's disease, the cholinergic system in the cerebral cortex appears to remain relatively intact and the nucleus basalis of the substantia innominata is uninvolved.[39] Thus, different mechanisms appear to underly the dementia of Alzheimer's disease and that of Huntington's disease.
The typical case of Huntington's disease is unmistakable; if the family history is positive, the disorder cannot be confused with any other. Symptoms consist of progressive dementia combined with choreoathetosis. These two aspects usually advance together, but on occasion, one symptom may precede the other by several years. When chorea appears long after dementia, diagnosis can be difficult. In some families, the disorder is characterized by progressive rigidity and akinesia, rather than chorea. This form of Huntington's disease begins more often in childhood than in adulthood, and it is almost always inherited from affected fathers.
Although knowledge of the neurochemical defects in Huntington's disease has advanced rapidly, effective therapy has not yet been developed. Efforts to relieve symptoms by the administration of precursors or medications that raise the levels of acetylcholine or GABA in the brain have failed. Therapeutic trials with baclofen to block glutamate-mediated excitation and cysteamine to lower levels of somatostatin in the brain are in progress.[36]
The most useful therapy for the control of involuntary movements still consists of drugs that block dopaminergic transmission. Haloperidol (up to 5 mg q.i.d.) or chlorpromazine (50 mg q.i.d.) may be helpful for many patients. Similar to levodopa therapy for Parkinson's disease, therapy for Huntington's disease addresses neither the primary degenerative process nor the nonmotor aspects of the disease. Therefore, such pharmacologic modifications of synaptic activity in the basal ganglia are likely to provide only partial symptomatic relief.
Essential tremor is one of the most commonly encountered disorders of movement. It is called familial tremor when there is a hereditary pattern. Neither the pathology nor the underlying mechanisms are known. In a sense, essential tremor represents an exaggeration of the physiologic tremor that occurs at times of stress, such as after drinking too much coffee. It may start at any age, commonly in childhood, and tends to progress slowly. It predominantly affects the hands; the trunk and legs are infrequently involved. A nodding head tremor and tremulousness of speech are often observed. The tremor is characteristically an action tremor, prominent during the maintenance of a static posture or during fine manipulative activity such as handwriting. It will be accentuated by such activities as pouring water from one test tube to another. When the arm is completely supported, the tremor tends to disappear. Frank cerebellar disturbances such as ataxia, dysmetria, or adiadochokinesia are absent.
The distinction between resting (parkinsonian) tremor and essential tremor is not always easy to make. Parkinson's disease is the more likely diagnosis when bradykinesia, impassive facies, and rigidity are present.
The treatment of choice is propranolol. A dosage of 40 to 60 mg orally four times a day is usually required. Long-acting propranolol in a dosage of 240 mg orally once a day is equally effective and may prove to be more convenient. [40] The mechanism of action of propranolol is not clear, but blockade of beta-adrenergic receptors in either the central nervous system or the muscles has been proposed. Trials with various selective (beta1 ) and nonselective (beta1 and beta2 ) antagonists have not provided a clear explanation for the drug's mode of action, but current data favor blockade of peripheral beta2 receptors. Some patients do not respond to propranolol; in such cases, modest amounts of wine or diazepam, 5 to 10 mg orally three times a day, may be helpful.
Dystonia refers to a disorder of movement, usually resulting from disturbed functioning of the extrapyramidal motor system, that is characterized by postural abnormalities and writhing, twisting, and grimacing movements. Some dystonic disorders, (e.g., writer's cramp) are restricted and develop in response to a specific task, whereas others are generalized and severely disabling. Both hereditary and environmental factors are involved in the pathogenesis of these disorders, but little is known about the fundamental mechanisms involved. Treatment approaches are similar for each of the disorders discussed below.
Idiopathic torsion dystonia, or dystonia musculorum deformans, is marked by abnormal movements that start in one limb or in truncal or nuchal muscles. Onset occurs most often before 15 years of age. The disorder may be inherited as an autosomal dominant or a recessive trait, the latter mode of inheritance occurring in Ashkenazic Jews. The disorder usually progresses during a period of about 10 years to involve all of the limbs, leading to profound disability. This outcome is particularly likely if the abnormal movements start in the legs. When onset occurs in adulthood, the condition tends to be much less incapacitating. Curiously, no specific pathologic changes in the brain have been found. Alterations in catecholamine concentration, especially decreased levels of norepinephrine in the diencephalon and brainstem, may be clues to the pathophysiology.[41]
Spasmodic torticollis may be the first symptom of idiopathic torsion dystonia, but it is much more commonly a localized movement disorder that remains restricted to nuchal muscles. In young adults, torticollis may last several years and then resolve spontaneously; remission is less likely when onset occurs during middle age.[42] The principal symptom is involuntary turning of the head, which at first is subtle and intermittent but later becomes forceful and persistent. The movements are accentuated while walking or during activities that require ocular fixation, such as reading or playing golf. The sternocleidomastoid muscle may hypertrophy. Other nuchal muscles are invariably involved, and the coordinated action of agonist and antagonist muscles is lost.
Meige syndrome consists of involuntary movements of muscles innervating the face, tongue, and jaws. Such movements produce blepharospasm, facial grimacing, jaw opening, and occasionally, dysphonia and torticollis. Sometimes only certain features, such as blepharospasm, are present. The mean age at onset is about 50 years; the syndrome occurs more frequently in women.[43]
Occupational cramp is a localized disturbance of voluntary contraction of muscle groups involved in a specific activity, usually a skilled task. Writer's cramp is the most common syndrome; professional musicians are also susceptible to such cramps.[44]
Approaches to treatment have been largely empiric and generally unsatisfactory. Many different kinds of drugs have been used to treat dystonia, including diazepam, carbamazepine, baclofen, clonazepam, propranolol, lithium, haloperidol, levodopa, bromocriptine, tricyclic antidepressants, and anticholinergics. The anticholinergic agents, given at a very high dosage, appear to be the most helpful.
It has been recommended that adults be treated with trihexyphenidyl, starting with 2 mg three times a day orally and gradually increasing the dosage to as much as 50 mg daily in divided doses (average dose, 24 mg/day). Alternatively, ethopropazine may be tried, starting with 25 mg once or twice daily and increasing the dosage slowly to a level as high as 800 mg/day in divided doses (average dose, 350 mg/day).[45] A newer therapy, widely applied in uncontrolled trials, consists of local injections of botulinum toxin into muscles that exhibit abnormal fiber discharge. Botulinum toxin is a potent neurotoxin that prevents the release of acetylcholine at the neuromuscular junction and paralyzes muscle fibers at the site of local injection. In placebo-controlled trials, injection of botulinum toxin has reportedly afforded temporary relief to patients with spasmodic torticollis or blepharospasm.[46,47]
The development of involuntary movements frequently complicates the use of antipsychotic drugs such as phenothiazines, butyrophenones, and thioxanthenes. Three very different syndromes may be seen in patients receiving such therapy.
The syndrome of acute dystonia consists of the abrupt development of oral, lingual, and pharyngeal involuntary movements, often with trismus, opisthotonos, and writhing dystonia. The reaction may follow one dose or at most a short course of antipsychotic drugs and is most common in adolescents. It is quite frightening to both the patient and the unsuspecting physician. Involuntary movements may often be relieved by an intravenous injection of diphenhydramine, 25 to 50 mg. Neuroleptic drugs should be stopped.
The parkinsonian symptoms of bradykinesia, involuntary restlessness (akathisia), and mild cogwheel rigidity occur in about 10 percent of patients on chronic antipsychotic drug therapy. These symptoms generally subside after the drug is stopped and may be controlled with anticholinergic agents such as benztropine, 1 to 2 mg orally three times a day.
The distressing syndrome of tardive dyskinesia occurs in about 20 percent of patients who have been treated with antipsychotic drugs for prolonged periods (months or years). Involuntary grimacing and chewing movements are the most characteristic features, but choreoathetotic and ballistic movements of the extremities may occur as well. The disorder may be so severe that speaking and swallowing are impeded. The involuntary movements are thought to result from an increased turnover of dopamine, combined with an increased sensitivity of dopaminergic receptors.[48] The disorder may develop either during therapy with the antipsychotic drug or shortly after the agent has been discontinued. Management of this difficult problem has been reviewed.[49] Withdrawal of antipsychotic medication is the most important measure. In most patients, the dyskinesia will gradually subside during a period of weeks or months. In some patients, however, the disorder appears to be irreversible. If serious impairment of respiration or swallowing develops or if the psychiatric disturbance becomes unmanageable, it may be necessary to reinstitute antipsychotic drug therapy. If so, the smallest possible dose should be used.
Shy and Drager described patients whose principal symptoms were autonomic insufficiency combined with signs of parenchymatous degeneration of the central nervous system.[50] Pathologic changes were found in the putamen, substantia nigra, cerebellum, brainstem, and intermediolateral gray column of the spinal cord. Men and women are equally affected.
Onset of symptoms occurs between 40 and 75 years of age. Early symptoms are related to autonomic failure and include hypotension, urinary and bowel dysfunction, sexual impotence, and diminished sweating. Postural hypotension is often severe enough to cause syncope. The plasma norepinephrine concentration is normal when the patient is in the supine position but fails to rise when the patient stands, a defect that presumably reflects degeneration of central sympathetic pathways.
This noradrenergic abnormality contrasts with the defect in idiopathic orthostatic hypotension, in which the plasma concentration of norepinephrine is abnormally low in the resting state as a result of postganglionic adrenergic failure.[51] The most conspicuous neurologic signs are those of parkinsonism, but these are often accompanied by signs of pyramidal and cerebellar motor systems involvement. Thus, the clinical picture of postural hypotension, urinary retention, extrapyramidal rigidity, intention tremor and ataxia, and hyperactive tendon reflexes is quite distinctive.
The disease is steadily progressive, with a fatal outcome in seven to eight years. Respiratory arrest from laryngeal obstruction, especially during sleep, may be an important cause of death. Selective atrophy of the posterior cricoarytenoid muscles, which abduct the vocal cords, has been found. Denervation of these muscles can be detected by surface electromyography, a procedure that may help identify patients needing tracheostomy.[52]
No specific treatment exists for the Shy-Drager syndrome. Levodopa rarely relieves extrapyramidal symptoms. Postural hypotension may be helped by fludrocortisone (0.1 mg orally t.i.d) or indomethacin (50 mg orally t.i.d.), and the patient should wear compressive stockings. Urinary retention may respond to bethanechol (10 mg orally t.i.d.).
Progressive supranuclear palsy is an uncommon but distinctive disorder of unknown etiology that affects men twice as often as women.[53] Symptoms usually begin between 50 and 70 years of age. Early complaints are slowness of movement, imbalance and falling, and impaired vision.
Patients often complain of difficulty in negotiating sidewalk curbs or stairs. These complaints relate to impairment of vertical gaze, which is the hallmark of the disease. Patients cannot look up or down voluntarily, although reflex movements are relatively well preserved. Impairment of horizontal saccadic movements and of convergence eventually develops. In addition, there are signs of parkinsonism, with axial rigidity, loss of associated movements, and bradykinesia.
The head and eyes follow after the trunk when the patient turns, in contrast to the en bloc turning in Parkinson's disease. The countenance is expressionless and fixed, facial and jaw reflexes are increased, and speech is forced and slurred.
The mental changes of apathy and dementia develop only late in the disease. There are no helpful laboratory tests, but the clinical diagnosis is usually clear-cut. The disease progresses steadily during a period of six to eight years. Histopathologic features consist of neuronal loss and gliosis, with neurofibrillary and granulovacuolar neuronal changes in the diencephalon, brainstem, and cerebellum.
A review of treatment trials in 91 patients showed generally disappointing results, but dopaminergic, anticholinergic, or antiserotonergic drugs have all been reported to help some patients.[54]
Wilson's disease is a rare metabolic disorder inherited as an autosomal recessive trait. The principal metabolic feature is excessive deposition of copper in various tissues but chiefly in the brain, liver, kidney, and cornea. Copper levels have also been elevated in cultured skin fibroblasts. Defective biliary excretion causes the copper to begin accumulating in body tissues in the first years of life. Symptoms generally appear in late childhood or early adulthood and may present as jaundice or an illness resembling hepatitis, as acute hemolytic anemia, or as neurologic disturbances. Early neurologic symptoms are often manifested as behavioral change and deterioration of school performance, falsely suggesting a psychiatric disturbance.
The diagnosis is suggested when signs of intention tremor, dysarthria, dystonia, and choreoathetosis develop. A fixed facial expression is characteristic in well-marked cases, often taking the form of a persistent grin. The pathognomonic clinical feature is the Kayser-Fleischer ring, which is found in all cases with neurologic involvement. Detection may require a careful slit-lamp examination. The main laboratory test abnormalities are decreased serum ceruloplasmin, decreased serum copper, and increased urinary excretion of copper. The copper content measured in liver biopsy specimens exceeds 100 mg/g of dry weight. Some or all of these abnormalities may be found in the asymptomatic homozygous patient. CT scanning commonly shows atrophy of the cortex and brainstem and ventricular enlargement. Striking lucencies in the regions of the basal ganglia are seen in about 50 percent of cases.
Treatment consists of eliminating copper-rich foods and using drugs to lessen the absorption of copper and to promote its excretion. The drug of choice is penicillamine, a chelator of copper, given in a daily dosage of 1 to 3 g orally in four divided doses. Pyridoxine, 50 mg/day orally, should also be taken because penicillamine tends to inhibit pyridoxal-dependent enzymes.
A transient hypersensitivity reaction to penicillamine may develop, consisting of skin rash, fever, and leukopenia. Corticosteroids and small desensitizing doses of penicillamine may be helpful if treatment is to be continued. Penicillamine treatment has been associated with the development of a variety of autoimmune conditions, including myasthenia gravis. With treatment, which must be continued indefinitely, the majority of patients improve to the extent that they can lead relatively normal lives. Many patients on penicillamine have had successful pregnancies. Early treatment of asymptomatic patients is widely recommended to prevent the clinical signs of the disease from appearing.
Patients with Wilson's disease who cannot tolerate penicillamine may be treated successfully with trientine, a newer chelating agent. It is given in an oral dosage of 1 to 2 g/day in three or four divided doses. [55] Zinc sulfate, given in an oral dosage of 100 to 300 mg three times daily, may provide an alternative mode of treatment if chelation therapy fails. [56]
Gilles de la Tourette's syndrome is a disorder of unknown etiology that usually begins in childhood. It is characterized by repetitive involuntary motor movements, by multiple tics of the vocal apparatus, which produce barking and grunting, and often by the involuntary utterance of vulgarities (coprolalia). A family history of tics or obsessive-compulsive disorder is often obtained. Evidence favors an autosomal dominant mode of transmission influenced by sex; there is a 3:1 male preponderance.[57] Treatment is with dopamine antagonists. Haloperidol is the drug of choice. It should be started at a daily dosage of 0.5 mg orally; the dosage should be increased gradually until adverse side effects develop or until a therapeutic effect has been achieved. Pimozide is an alternative agent and is initiated at an oral dosage of 1 mg/day.
Trifluoperazine, thiothixene, and fluphenazine have also been advocated. Switching from one drug to another may help refractory cases.[58]
Amyotrophic lateral sclerosis has a worldwide distribution, with a prevalence of about 1 per 100,000 population. Five to 10 percent of cases are familial and show an autosomal dominant pattern of inheritance.[59] The main pathologic feature is degeneration of pyramidal motor neurons accompanied by secondary changes in muscle. Morphometric studies of sensory nerves suggest that sensory fibers may also undergo degenerative changes, although overt symptoms related to sensory impairment are not found in the disorder. A syndrome resembling amyotrophic lateral sclerosis is occasionally found in association with other conditions, including paraproteinemias,[60] lymphomas, and adult hexosaminidase deficiency states.
Current knowledge of the pathophysiology and treatment of amyotrophic lateral sclerosis has been reviewed.[61] Various immunologic, virologic, exogenous toxic, and endogenous metabolic factors have been proposed as causes, but all remain unproved.
Clues to the pathogenesis are provided by a variant of the disease, the amyotrophic lateral sclerosis-parkinsonism-dementia complex, which affects the Chamorro natives of Guam and which has been linked to ingestion of a seed from the Cycas circinalis plant, a traditional source of food and medicine. The disease was once very common in Guam, but since 1955, as American acculturation has increased and use of the seed among natives has decreased, it has shown a gradual decline in incidence. A neurotoxic amino acid found in the seed, b-N -methylamino-L-alanine, produces a condition resembling amyotrophic lateral sclerosis when it is ingested by monkeys.[62]
Amyotrophic lateral sclerosis presents in a variety of ways. Most often, weakness begins in the intrinsic muscles of the hands and after weeks or months spreads to the forearms, shoulder girdle, and cranial musculature. Asymmetric involvement is not unusual at the onset. Formerly, the terms progressive bulbar palsy and progressive muscular atrophy were used to describe cases in which the main involvement was of lower motor neurons in the brainstem and spinal cord, respectively.
Pseudobulbar palsy and primary lateral sclerosis referred to those cases in which upper motor neuron involvement predominated. Symptoms of aching and cramping of the muscles are common, but other sensory symptoms are absent, and there is no bladder or bowel impairment. Patients with prominent bulbar involvement complain of choking and regurgitation, a nasal or hoarse dysarthria, and difficulty chewing. There are no visual complaints, because the ocular motor neurons are never involved. The earliest manifestation may be a pseudobulbar palsy: the patient experiences uncontrolled laughing or crying and explosive dysarthria or aphonia. Examination typically reveals signs of upper and lower motor neuron involvement. Wasting of muscles with commensurate weakness occurs, combined with hyperreflexia and, at times, extensor plantar responses. With bulbar involvement, the tongue is furrowed at its lateral margin, and protrusion is incomplete. Masseter and facial weakness may be evident, and the palate does not rise on phonation.
Pseudobulbar signs include increased jaw jerk, snout reflex, and hyperactive gag reflex. A hallmark of the disease is fasciculations of the muscles, although this sign should not be considered diagnostic. These twitches represent abnormal motor-unit discharges and tend to disappear in advanced disease. They occur randomly and may be provoked by muscle exercise, percussion, or cold. Fasciculations of the intrinsic muscles of the hand may cause small choreic movements of the fingers. Fasciculations of the tongue may be the earliest sign of bulbar involvement.
Laboratory aids to the diagnosis include electrophysiologic studies and muscle biopsy. The electromyogram shows signs of denervation. The muscle biopsy shows small, angulated, atrophic fibers, often occurring in groups. The serum creatine kinase level is normal or only slightly elevated, distinguishing amyotrophic lateral sclerosis from chronic polymyositis.
In practical terms, the important alternative diagnosis is cervical spinal cord compression from either a tumor or cervical disk disease. Compression of the cervical cord may produce weakness, atrophy, and fasciculations in the arms, together with spasticity and hyperreflexia in the legs. Radicular pain and sensory loss may be inconspicuous in midline cervical disk disease. Magnetic resonance imaging (MRI) is invaluable in determining whether this potentially remediable disorder is present.
There is no satisfactory treatment for amyotrophic lateral sclerosis. Therapeutic trials have been performed based on a range of experimental evidence.[61] Efforts have included the use of several modes of immunosuppression, thyrotropin-releasing hormone, testosterone, chelation with penicillamine, interferon, and gangliosides; however, no dramatic results have been reported. The course of the disease depends to some extent on the site of pathology. The life expectancy of patients with predominantly spinal disease is about three years; for patients with predominantly bulbar disease, it is about 18 months. On occasion, survival for 10 or more years is possible.
The hereditary ataxias constitute a large group of heterogeneous, often overlapping, familial neurologic disorders that share progressive ataxia as the most prominent manifestation. These disorders include several rare inborn errors of amino acid and lipid metabolism as well as a number of conditions of unknown etiology that are well characterized clinically and pathologically. Studies of the metabolic errors in many of these conditions have been reviewed,[63] and a new classification for the hereditary ataxias has been proposed.[64]
Spinocerebellar degenerations are hereditary disorders in which cerebellar and spinal motor and sensory systems undergo progressive degeneration. Three main hereditary groups are identifiable. Inheritance may be dominant or recessive.
Friedreich's ataxia[64] has its onset in childhood. The neurologic signs are quite constant and consist of proprioceptive sensory loss, areflexia, ataxia of the limbs, and Babinski's sign. Skeletal anomalies, including pes cavus and scoliosis, are usually present. A cardiomyopathy is regularly present and is often the cause of death.
Onset of olivopontocerebellar atrophy occurs during early or middle adult years. The signs of neurologic involvement are generally widespread and include ataxia, spasticity, extrapyramidal rigidity, and inconstant sensory loss. Degenerative changes are found in the spinal cord, brainstem, and cerebellum. A deficiency of glutamate dehydrogenase in leukocytes has been reported in some cases, but measurement of glutamate and malate dehydrogenase activity in postmortem brain-tissue samples has revealed that the levels of these enzymes are normal.[65]
Onset of symptoms in late corticocerebellar atrophy may be delayed until late in life. In some families, there is a pure cerebellar syndrome; in others, ataxia is variably combined with other manifestations, including retinal degeneration, optic atrophy, ophthalmoplegia, dementia, myoclonus, and deafness.[64]
Joseph's disease, an autosomal dominant condition affecting Portuguese families of Azorean descent, was named for the family in which it was fully characterized. Neuropathologically, the disorder involves multiple motor systems. The principal clinical features consist of ataxia, progressive ophthalmoplegia, pyramidal and extrapyramidal signs, and distal muscle wasting.[64]
Occasionally, identifiable metabolic defects, some of which may be treatable, produce a clinical syndrome of spinocerebellar degeneration. Such defects include adult hexosaminidase A deficiency, adrenomyeloneuropathy, and vitamin E deficiency.[66] In most cases, however, there is no known therapy, and relentless progression is to be expected.
Neurocutaneous disorders, or phakomatoses, are genetically determined dysplasias of neural and cutaneous ectoderm.[67] Numerous syndromes have been described, but the principal neurocutaneous disorders are neurofibromatosis, tuberous sclerosis, angioblastomatosis, craniofacial nevus, and ataxia-telangiectasia. Most of these conditions have their onset in childhood.
Neurofibromatosis is inherited as an autosomal dominant trait and has a prevalence of about 35 per 100,000 population.[68] There are two distinct forms of the disease.
Neurofibromatosis-1 (von Recklinghausen's disease) is characterized by cutaneous café au lait spots, axillary freckles, multiple subcutaneous nodules, and hamartomas of the iris (Lisch nodules). The subcutaneous nodules represent peripheral nerve tumors of Schwann cell and fibroblast origin. Tumors also arise in the spinal canal, where they may cause cord compression. Other central nervous system neoplasms (e.g., meningiomas, gliomas, and sarcomas) may be found; MRI is the procedure of choice for detection and follow-up of such lesions. The gene responsible for neurofibromatosis-1 is believed to be located near the centromere of chromosome 17.[69]
Neurofibromatosis-2 is characterized by the presence of bilateral acoustic neuromas.[70] Café au lait spots and subcutaneous nodules may also be found. Slit-lamp examination reveals the presence of lenticular opacities in 50 percent of patients; such lesions could be used as a marker to assist in presymptomatic diagnosis and genetic counseling. Tumors of the eighth cranial nerve usually develop between 10 and 30 years of age and are best detected by periodic audiometry and MRI. Treatment must be individualized. Neurofibromatosis-2 is believed to result from the deletion of genetic material (possibly an antioncogene) from chromosome 22.[71]
Tuberous sclerosis (Bourneville's disease) is a rare disorder with a variable pattern of inheritance and an estimated incidence of one to two per 100,000 population. The classical diagnostic triad consists of facial adenoma sebaceum, mental retardation, and epilepsy. Depigmented nevi, café au lait spots, and shagreen patches are other cutaneous manifestations. Treatment is directed at alleviation of symptoms.
Angioblastomatosis (von Hippel-Lindau disease) is a very rare disorder; it is probably inherited as an autosomal dominant trait with variable penetrance. The principal lesions are hemangioblastomas of the cerebellum and retina, although concurrence at these two sites is uncommon. Occasionally, the tumor is located in the medulla or cervical spinal cord. Cysts and neoplasms of the liver, pancreas, and kidneys may also be found. Onset of symptoms most commonly occurs in adulthood. Headache, ataxia, and increased intracranial pressure signal the presence of a cerebellar lesion (Lindau's disease). A retinal hemangioblastoma may produce no symptoms when it first arises but will ultimately cause a progressive loss of vision (von Hippel's disease). The neurologic tumors are treated surgically or by radiotherapy, depending on location.
Craniofacial nevus (Sturge-Weber syndrome) is also very rare and generally sporadic in occurrence. Infants are born with a capillary angioma (port-wine stain) of the face, most often the upper face. There is an associated homolateral meningeal and cortical angiomatous malformation, usually in the parieto-occipital region, that may produce symptoms of hemiparesis, hemianopsia, epilepsy, and mental retardation. Treatment is directed at easing symptoms.
Ataxia-telangiectasia (Louis-Barr syndrome) is a rare multisystem disorder inherited as an autosomal recessive trait. Infants and young children acquire progressive ataxia, disturbance of conjugate gaze, insulin-dependent diabetes, oculocutaneous telangiectasia, and recurrent sinopulmonary infections. Patients show fundamental defects in cell-mediated immunity, cell growth, and DNA repair mechanisms. There is no treatment for the primary defect.
The stiff-man syndrome is a rare disorder characterized by slow onset of rigidity and painful spasms of truncal and nuchal muscles, gradual spread to limb muscles, and ultimate severe impairment of volitional movement. Electromyography discloses continuous muscle fiber activity. The pathophysiology of this disorder is unknown; a defect in inhibitory spinal pathways mediated by GABA has been proposed.[72] In one case, investigators found antibodies to glutamic acid decarboxylase, the enzyme that converts glutamic acid to GABA, in the cerebrospinal fluid.[73] The most satisfactory treatment is high-dose diazepam (up to 50 mg/day), a drug that potentiates GABA-mediated neural inhibition.