Key Point
The common feature of diseases of the basal ganglia is a movement disorder in which there is either too much or too little movement, that is, an excess or deficiency of movement impulse, movement automaticity, and/or muscle tone (see section ▶ 5.5.2).
In general, such diseases are characterized by the following:
Disturbances of the process or movement (always).
Abnormally increased or diminished muscle tone (usually).
Involuntary movements (often).
Associated neuropsychological manifestations (sometimes).
Increased muscle tone is often associated with paucity of movement, and, conversely, diminished muscle tone with excessive movement. Thus, there are two main classes of extrapyramidal syndrome:
Hypertonic–hypokinetic extrapyramidal syndromes (above all, parkinsonian syndromes and related neurodegenerative disorders, which will be discussed in this section).
Hypotonic-hyperkinetic extrapyramidal syndromes (e.g., chorea, athetosis, ballism, and dystonia, which will be discussed in the next section).
Note
In hypertonic–hyperkinetic syndromes, elevated muscle tone is typically manifest as rigidity. Paucity of movement, depending on its severity, is termed either hypokinesia (= diminished movement) or akinesia (= complete lack of movement). A third so-called “cardinal manifestation,” tremor, is also commonly present. This clinical triad, called the parkinsonian syndrome (or parkinsonism), is typically found in idiopathic Parkinson disease. Often, postural instability (= tendency to fall) occur as a fourth cardinal manifestation.
Parkinson disease, however, is only one possible cause of parkinsonism; there are many others besides. Parkinsonism may be due to an underlying illness or condition other than idiopathic Parkinson disease (symptomatic parkinsonian syndromes). In addition, several systemic neurodegenerative diseases cause parkinsonism. These rare diseases are marked by a loss of neurons not only in the basal ganglia, but also in other areas of the CNS, and thus are clinically characterized not only by extrapyramidal manifestations, but also by neurologic deficits localizable to other regions of the brain. The most important diseases in this category, multisystem atrophy (MSA) and corticobasal degeneration (CBD), will be discussed further in this chapter. Lewy body dementia belongs in this category as well but will be discussed later in the subsection on dementia (section ▶ 6.12).
Definition Parkinson disease is defined by its clinical manifestations (characteristic body posture and gait, with hypokinesia, rigidity, and, usually, rest tremor) and their pathologic correlates in the brain: Lewy bodies containing α-synuclein and degeneration of dopaminergic neurons in the pars compacta of the substantia nigra (a pigmented nucleus in the midbrain).
Epidemiology and etiology Parkinson disease has an overall prevalence of 0.15%. Its age-specific prevalence rises with increasing age, to 1% in persons older than 60 years and 3% in persons older than 80 years. Most cases are idiopathic, that is, without any identifiable cause.
Familial clustering of Parkinson disease is seen in 5 to 15% of cases (so-called hereditary Parkinson disease); patients who develop Parkinson disease at an unusually young age are particularly likely to have a problem of this type. To date, 18 genetic loci (PARK1 through PARK18) and at least 7 genes have been identified whose mutations can cause a hereditary parkinsonian syndrome. The mode of inheritance can be autosomal dominant with variable penetrance or autosomal recessive. A special type is the familial Parkinson–dementia complex seen on the island of Guam. The combination of parkinsonism and dementia also sometimes exhibits familial clustering.
Pathogenesis The neuropathologic hallmark of idiopathic Parkinson disease is degeneration of the dopaminergic neurons of the substantia nigra and the locus ceruleus. Hyaline inclusion bodies, called Lewy bodies, are found within the degenerated neurons. The loss of dopaminergic neurons leads to a degeneration of the (inhibitory) nigrostriatal dopaminergic pathway and, therefore, to dopamine deficiency in the striatum. This, in turn, leads to enhanced activity of the striatal glutamatergic neurons, which produces the clinical manifestations of the disease.
Additional Information
In the Braak system of Parkinson disease there are six neuropathologic stages that trace the temporal progression of intraneuronal Lewy body formation from lower to higher neural centers in the brain. In stages 1 and 2, before any clinical manifestations of the disease have arisen, Lewy bodies are present only in certain areas of the brainstem and the olfactory system. The first symptoms arise in stages 3 and 4 when Lewy bodies begin to appear in the substantia nigra. Finally, in stages 5 and 6, Lewy bodies are found in diffuse areas of the cerebral cortex.
The clinical picture of idiopathic Parkinson disease and of hereditary parkinsonian syndromes ( ▶ Fig. 6.55) is typically characterized by:
Hypokinesia, i.e., slowing of movement.
Increased muscle tone (rigidity).
Abnormal body posture (stooped head and trunk, flexion at the knees).
Impaired postural reflexes, sometimes leading to falls.
Often tremor.
Later, neuropsychological deficits and certain vegetative/autonomic disturbances such as oily (seborrheic) face and bladder dysfunction.
Practical Tip
The motor signs are often only unilateral, or more marked on one side, when the disease first appears. They can be aggravated by emotional stress.
Fig. 6.55 Parkinson disease. (a) Typical posture with stooped head and upper body and lightly flexed elbows, hips, and knees. (b) Hypomimia (paucity of facial expression) and the asymmetry of manifestations that is typical in idiopathic Parkinson disease (the right elbow is somewhat more strongly flexed than the left).
Hypokinesia Hypokinesia manifests itself as paucity of facial expression (mask-like facies), reduced frequency of blinking, and speech disturbances (dysphonia, i.e., slow, monotonous, unmodulated speech, and repetitions). There is little spontaneous movement, and the normal accessory movements (e.g., arm swing during walking) are diminished or absent. The patient’s handwriting becomes progressively smaller (micrographia). Repeated or alternating movements (e.g., finger-tapping) are performed slowly and with smaller excursions (dysdiadochokinesia; cf. ▶ Fig. 3.19). Axial movements, such as turning around while standing or turning over in bed, are difficult to perform. Very severe hypokinesia is sometimes called akinesia.
Gait A parkinsonian gait is characterized by a mildly stooped posture, with the head jutting forward, and a small-stepped, often shuffling gait, without accessory arm movements ( ▶ Fig. 6.56). To turn around while standing, the patient makes many small turning steps.
Fig. 6.56 Typical parkinsonian posture while walking: inclined head, slightly stooped upper body, flexed elbows, and lightly flexed hips and knees.
Increased muscle tone This is primarily evident as rigidity ( ▶ Fig. 3.24), felt by the examiner during large-amplitude, passive flexion and extension of the joints. Rigidity is sometimes easier to detect when the patient voluntarily contracts the muscles on the opposite side of the body. Often, during passive movement, the examiner may feel a small, brief, periodically recurring diminution of muscle tone, known as the cogwheel phenomenon, which is usually most evident at the wrist ( ▶ Fig. 3.25). The patient’s postural tone, too, is elevated; if, for example, the head is lifted off the bed and let go, it may remain suspended in midair for some time (the Wartenberg sign; the classic literature spoke of a “coussin psychique,” i.e., a virtual pillow).
Practical Tip
Another test for the objectification of rigidity is the so-called swinging test: the examiner grasps and shakes the patient’s forearm back and forth. Rigidity markedly diminishes the swinging (pendular) motion of the wrist. The test can also be performed at the elbow or knee joint.
Tremor Three-quarters of patients with Parkinson disease have tremor sooner or later in the course of their disease, typically a distal rest tremor at a frequency of 5 Hz. A pronation–supination (“pill-rolling”) tremor is highly characteristic. The tremor is present at rest and generally disappears on voluntary movement; it is sometimes increased by mental exertion, deep concentration, or walking. Some patients have postural and intention tremor in addition to rest tremor (see ▶ Fig. 3.22).
The risk of falling An impairment of postural reflexes, combined with hypokinesia, has the consequence that changes of body posture and orientation in space can no longer be compensated for by reflexive, rapid corrective movements. The most obvious manifestations of this problem are pro- and retropulsion. If the patient is pushed while standing still, or stumbles over an obstacle, the movements made to regain balance are too small and too slow, and a fall may result.
Practical Tip
The patient’s postural reflexes and possible tendency to fall can be tested with the pull test and the push-and-release test. In the former, the examiner stands behind the patient and pulls back on both shoulders; in the latter, the patient is propped up in a standing position from behind by the examiner’s hands, which are then suddenly released. (Obviously, when performing these tests, the examiner must make sure that the patient can be caught in case of a fall.)
Impaired olfaction An impaired sense of smell is almost universal in patients with idiopathic Parkinson disease but rare in patients with symptomatic parkinsonism.
neuropsychological deficits When the first symptoms of Parkinson disease arise, the patient’s cognitive functions are generally normal or only mildly impaired. As the disease progresses, however, neuropsychological deficits almost always arise. Memory is impaired, cognitive processes are slowed (bradyphrenia), and there is a tendency toward perseveration. Rapid changes in thought content are difficult to achieve, and the planning and execution of actions and behaviors is impaired (so-called dysexecutive syndrome).
Psychiatric manifestations Depression affects one-third to one-half of all patients over the course of the disease and is treatable. Isolated apathy (without depression) can also arise. Impulse-control disorders, such as compulsive shopping, gambling, or hypersexuality, are usually side effects of dopaminergic drugs. The patient’s perceptions and thought processes can become abnormal over the course of the disease, because of either the disease itself or its dopaminergic treatment; hallucinations and overt psychoses can result.
Disturbances of autonomic and vegetative function Such disturbances arise partly as a by-product of hypokinesia and partly because of direct involvement of the autonomic nervous system. These include seborrhea (an oily face, caused by excessive fat production in the skin), hypersalivation, cold intolerance, a tendency toward orthostatic hypotension and constipation, urinary urgency (possibly causing incontinence), and sexual dysfunction (altered libido, erectile dysfunction). Insomnia and behavioral disturbances during REM sleep (see section ▶ 10.4) are often seen early on in the course of disease; the patient’s sleep can also be disturbed by restless legs syndrome (see section ▶ 10.2.2) or spontaneous pain in the limbs.
The nonmotor manifestations of Parkinson disease are summarized in ▶ Table 6.30.
|
Autonomic/vegetative |
Cognitive |
Psychiatric |
|
|
|
Classification and grading of manifestations The manifestations described are present to variable extents in different patients with Parkinson disease. Generally speaking, the disease has three main clinical variants:
The akinetic-rigid type (without tremor).
The tremor-dominant type (with little hypokinesia and rigidity).
The mixed or “equivalence” type (with roughly equal severity of all three cardinal manifestations—rigidity, hypokinesia, and tremor).
Individual clinical manifestations can be graded on pseudoquantitative scales, if this is desired for long-term follow-up or for research purposes, for example, with the Webster Rating Scale ( ▶ Table 6.31) or the very detailed Unified Parkinson's Disease Rating Scale (UPDRS), which is not reproduced here. Cognitive function can be assessed with the MOCA test or the Mini-Mental State Examination (MMSE; see ▶ Table 3.11).
|
1. Bradykinesia of hands, including handwriting |
0 = normal 1 = mild slowing 2 = moderate slowing, handwriting severely impaired 3 = severe slowing |
|
2. Rigidity |
0 = none 1 = mild 2 = moderate 3 = severe, present despite medication |
|
3. Posture |
0 = normal 1 = mildly stooped 2 = arm flexion 3 = severely stooped; arm, hand, and knee flexion |
|
4. Arm swing |
0 = good bilaterally 1 = unilaterally impaired 2 = unilaterally absent 3 = bilaterally absent |
|
5. Gait |
0 = normal, turns without difficulty 1 = short steps, slow turn 2 = markedly shortened steps, both heels slap on floor 3 = shuffling steps, occasional freezing, very slow turn |
|
6. Tremor |
0 = none 1 = amplitude < 2.5 cm 2 = amplitude > 10 cm 3 = amplitude > 10 cm, constant, eating and writing impossible |
|
7. Facial expression |
0 = normal 1 = mild hypomimia 2 = marked hypomimia, lips open, marked drooling 3 = mask-like facies, mouth open, marked drooling |
|
8. Seborrhea |
0 = none 1 = increased sweating 2 = oily skin 3 = marked deposition on face |
|
9. Speech |
0 = normal 1 = reduced modulation, good volume 2 = monotonous, not modulated, incipient dysarthria, difficulty being understood 3 = marked difficulty being understood |
|
10. Independence |
0 = not impaired 1 = mildly impaired (dressing) 2 = needs help in critical situations, all activities markedly slowed 3 = cannot dress him- or herself, eat or walk unaided |
|
Source: Webster DD. Critical analysis of the disability in Parkinson disease. Mod Treat 1968;5(2):257–282. Note: The sum of the scores indicates the degree of severity of Parkinson disease: 0–10 mild, 10–20 moderate, 20–30: severe. |
|
Note
The diagnosis of Parkinson disease is based on the typical clinical manifestations and characteristic findings on neurologic examination.
History Important points to be addressed in clinical history-taking include the following:
Has the patient had difficulty with fine motor activities such as writing, getting dressed, or eating?
Is the patient’s gait less steady than before, perhaps with stumbling or falls?
Has the patient noticed any difference between the right and left sides of the body?
Does the patient suffer from pain or disturbed sleep?
Has there been any impairment of the sense of smell or any difficulty swallowing?
Neurologic examination In addition to hypokinesia, rigidity, tremor, and propulsion/retropulsion, the examination generally reveals the following:
Weak convergence (movements to focus the eyes are slowed).
A persistent glabellar reflex (i.e., lack of habituation of the reflex after repeated glabellar tapping).
Saccadic ocular pursuit movements.
Impaired olfaction.
The intrinsic muscle reflexes are normal, however, as are all somatosensory modalities.
For numerical grading, see the preceding paragraphs and ▶ Table 6.31.
Imaging studies CT and MRI of the head reveal no abnormalities and are generally performed only to rule out competing diagnoses, for example, symptomatic parkinsonian syndromes. The loss of dopaminergic afferent input to the striatum can be demonstrated with positron emission tomography (PET) or single-photon emission computed tomography (SPECT) after the administration of 18fluorodopa ( ▶ Fig. 6.57). Cerebral ultrasonography can reveal early changes in the substantia nigra.
Fig. 6.57 An 18F-DOPA-PET scan in a normal person (left, top and bottom) and in a patient with incipient Parkinson disease, worse on the left side of the body (right, top and bottom). The basal ganglia are seen in axial and coronal section (upper and lower rows of images, respectively). The patient with Parkinson disease has a more than 20% reduction in the activity of dopamine decarboxylase in the right putamen (particularly in its dorsal aspect), with relatively normal activity in the caudate nucleus. (Image provided courtesy of Dr. F. Jüngling, PET/CT-Zentrum NW-Schweiz, St. Claraspital, Basel, Switzerland.)
Note
Idiopathic Parkinson disease is always a diagnosis of exclusion, that is, all varieties of symptomatic parkinsonism must be ruled out before this diagnosis can be made.
Testing of olfaction Impairment of the sense of smell early on in the course of disease is supporting evidence for idiopathic or genetically triggered Parkinson disease. Smell is tested with small samples of various substances (coffee, etc.).
Genetic testing In young patients with a positive family history, genetic testing can help secure the diagnosis and enable a more accurate prognosis.
Treatment, complications, and prognosis Effective treatment alleviates the manifestations of the disease, moving the symptomatic progression curve to the right by some 3 to 5 years, but does not affect the disease process as such. The putative early neuroprotective effect of certain antiparkinsonian drugs has not yet been confirmed.
Pharmacotherapy The goal of drug therapy is to replace the missing dopamine in the striatum.
Note
The most important antiparkinsonian drug is still levodopa (L-DOPA), which is metabolized to dopamine in the CSF. At the beginning of treatment, only small doses are needed to alleviate the clinical manifestations; later on, however, higher doses are needed, and side effects such as dyskinesia and on–off motor fluctuations commonly arise. Therefore, efforts are often made to delay the administration of L-DOPA to younger patients by giving alternative drugs first.
MAO-B inhibitors are increasingly used as drugs of first choice because of their putative neuroprotective effect. These include selegiline and rasagiline (a long-acting selegiline derivative). They inhibit the degradation of dopamine to homovanillic acid and thereby ameliorate parkinsonian manifestations.
Amantadine, an NMDA-receptor antagonist, is sometimes used very early in the course of disease; it is thought to enhance dopamine release from nerve terminals.
If these agents are no longer sufficiently effective, nonergot dopamine agonists (e.g., ropinirole, pramipexole, or rotigotine) can be used in younger patients; their effectiveness, however, matches that of L-DOPA only in the early stages of the disease.
In older patients, L-DOPA is used from the outset. This agent, unlike dopamine itself, crosses the blood–brain barrier; it is converted to dopamine in the CSF.
L-DOPA is always given in combination with a decarboxylase inhibitor (e.g., benserazide [HCl] or carbidopa) to prevent its premature degradation in the periphery.
The combination of L-DOPA with a COMT inhibitor, such as entacapone or tolcapone, can further increase dopamine bioavailability. Tolcapone, however, is occasionally hepatotoxic and is therefore reserved for otherwise intractable cases. Entacapone is sold as a combination drug together with L-DOPA and a decarboxylase inhibitor.
Anticholinergic drugs, such as biperiden, are mainly effective against tremor. Note: their anticholinergic effect can also induce or worsen confusion and/or dementia.
Note
The following should be borne in mind as rules of thumb for the dosing of antiparkinsonian drugs, particularly L-DOPA:
Give as much as necessary and as little as possible.
The drug regimen should be as simple as possible to promote compliance.
Drug side effects and complications Prolonged treatment with L-DOPA and other antiparkinsonian drugs can cause several problems:
Fluctuations in drug effect (on–off fluctuations, end-of-dose akinesia) can often be improved by the use of sustained-release L-DOPA preparations, division of the daily dose into smaller individual doses at more frequent intervals (perhaps with the use of water-soluble L-DOPA preparations), and/or the addition of dopamine agonists or COMT inhibitors. Water-soluble L-DOPA takes effect very rapidly and can shorten off-phases or prevent imminent off-phases. Deep brain stimulation is another therapeutic possibility (see later).
Drug-induced dyskinesias, for example, peak-dose dyskinesia or hyperkinesia (often involving choreiform involuntary movements; see section ▶ 6.10), are seen in 40% of patients after 6 months of L-DOPA treatment, in 60% after 2 years, and in nearly all after 6 years. They are usually more disturbing to patients’ families than to the patients themselves, but they can be disabling if severe and may be untreatable except by deep brain stimulation.
Painful foot dystonia can be managed with the use of sustained-release preparations in the evening and perhaps with apomorphine injections.
“Freezing,” that is, sudden arrest of movement, is not directly related to the serum concentration of L-DOPA. Various mental techniques can help (carrying a briefcase, stepping over real or imagined obstacles, etc.).
Psychosis and other psychiatric disturbances (e.g., hypersexuality, illusions, hallucinations, delusions, compulsive gambling, food cravings) usually arise as side effects of drugs, especially dopamine agonists (ropinirole, pramipexole). They may respond to a reduction of the dose or to the addition of an atypical neuroleptic drug (clozapine, risperidone).
An akinetic crisis is a prolonged phase of extreme rigidity causing complete immobility and accompanied by hyperthermia, hyperhidrosis, other autonomic disturbances, and dysphagia. Such crises can be precipitated, for example, by abrupt discontinuation of antiparkinsonian drugs, errors in drug-taking or drug-prescribing, the use of neuroleptic drugs, surgical procedures, or infection. They can be treated with water-soluble L-DOPA (given by nasogastric tube), amantadine (by intravenous infusion), or apomorphine (by subcutaneous injection).
Further side effects that can be induced by any dopaminergic drug include nausea (especially at the beginning of treatment; it can be counteracted with an antiemetic dopamine antagonist that has a purely peripheral effect, such as domperidone), fatigue, and orthostatic hypotension.
Note
Movement disorders that are caused by L-DOPA:
On-dyskinesia (also called peak-dose or plateau hyperkinesia); choreatiform movements that arise as the serum L-DOPA concentration increases (see section ▶ 6.10).
Off-dystonia (also called early-morning dystonia): painful dystonia, for example, in one or both feet, that arises as the serum L-DOPA concentration falls.
Deep brain stimulation Neurosurgical treatment, consisting of the stereotactic implantation of stimulating electrodes into the thalamus (nucleus ventrointermedius), globus pallidus, or subthalamic nucleus for chronic electrical stimulation, can markedly alleviate the manifestations of the disease; its indication depends on their severity and intractability in the individual patient. Each stimulating electrode has multiple metallic contacts, at which the intensity, pulse width, and frequency of the applied current can be independently controlled to optimize the clinical effect. This method has now largely replaced earlier destructive methods involving the creation of permanent lesions. It was once considered a treatment of last resort but is now increasingly used for patients in intermediate stages of the disease. An overview of the expected effects of deep brain stimulation in each of the three currently used target structures is provided in ▶ Table 6.32.
|
Target structure |
Best effect |
Remarks |
|
Subthalamic nucleus |
Reduction of hypokinesia, less frequent and less intense off-phases |
The L-DOPA dose can be markedly reduced. Dyskinesia and tremor improve as well |
|
Globus pallidus internus |
Reduction of dyskinesia during on-phases |
Hypokinesia and rigidity improve as well, but less than with stimulation in the subthalamic nucleus |
|
Nucleus ventrointermedius of the thalamus |
Reduction of tremor |
Little effect on hypokinesia or dyskinesia |
Further types of treatment Aside from drugs and surgery, physical therapy and regular exercise (sports, walking, hiking) can help improve and maintain mobility. Speech therapy may be helpful as well.
Moreover, adequate psychological support for patients and their families is important. Self-help groups can be valuable in this regard.
Course and prognosis L-DOPA treatment can shift the symptomatic progression curve to the right by 6 to 7 years. It is hard to predict which patients will eventually become dependent on the help of others or on around-the-clock nursing care. This tends to occur after approximately 20 years of illness.
The tremor-dominant type has a relatively favorable prognosis. The prognosis is worse for older patients, men as opposed to women, and patients with severe disease (in terms of both motor and nonmotor manifestations). Parkinson disease can shorten the patient’s life span.
Note
Parkinson disease is a progressive disease whose manifestations can be alleviated by drugs, deep brain stimulation, and physiotherapy.
|
Cause of parkinsonism |
Examples |
|
Arteriosclerotic parkinsonism |
|
|
Drug-induced parkinsonism |
|
|
Parkinsonism of infectious origin |
|
|
Normal pressure hydrocephalus (also called malresorptive hydrocephalus) |
|
|
Toxic parkinsonism |
|
|
Trauma |
|
|
Metabolic diseases |
|
|
Neurodegenerative diseases (see also ▶ Table 1.1) |
|
|
Hereditary diseases that can have prominent parkinsonian manifestations |
|
|
Further causes |
|
Tremor, hypokinesia, and rigidity can also be expressions of diseases other than Parkinson disease, including symptomatic parkinsonian syndromes.
Note
The main differential diagnoses of idiopathic Parkinson disease are: neuroleptic side effects and other neurodegenerative systemic diseases causing abnormal movements: Lewy body dementia, MSA, progressive supranuclear palsy (PSP), malresorptive hydrocephalus, and subcortical arteriosclerotic encephalopathy.
Neuroimaging now enables the recognition of some of these entities by their typical MRI findings:
Ventricular enlargement in malresorptive hydrocephalus (also called “normal pressure hydrocephalus”).
“Hot-cross-bun” sign in MSA.
Midbrain atrophy with the “Mickey Mouse” and/or “hummingbird” signs, along with frontal atrophy, in PSP.
An overview of these and other differential diagnoses is provided in ▶ Table 6.33.
There are several clinical conditions that resemble idiopathic Parkinson disease but have a different underlying cause or pathophysiologic mechanism. The clue to such a condition may be a history of a precipitating event (e.g., intoxication, drug use, trauma, or infection) or a structural abnormality of the basal ganglia or other brain areas (e.g., multiple arteriosclerotic changes, hydrocephalus) revealed by CT or MRI. A further characteristic of symptomatic parkinsonism is its relative resistance to treatment with L-DOPA, in contrast to idiopathic Parkinson disease, which usually responds very well to L-DOPA, at least at first. Moreover, some forms of symptomatic parkinsonism present with symmetric manifestations, while idiopathic Parkinson disease generally presents asymmetrically.
This disease is also known as Steele–Richardson–Olszewski syndrome.
Etiology and pathology A polymorphism in the tau protein gene (chromosome 17) causes deposition of an abnormally phosphorylated tau protein in the cells of the basal ganglia. This “tauopathy,” in turn, leads to cellular degeneration in the substantia nigra, globus pallidus, subthalamic nucleus, periaqueductal area of the midbrain, and other brain nuclei.
Clinical features The clinical features of PSP include the following:
Paucity of movement.
Gait disturbance early in the course of the disease.
Predominantly axial rigidity, often with a permanently extended cervical spine (head turned upward).
Frequent falls with a tendency to fall backward.
Progressive dementia.
Impaired vertical gaze movements (particularly downward), with nystagmus.
Diagnostic evaluation PSP is diagnosed from its typical clinical features. MRI reveals midbrain atrophy.
Treatment and course This disease presents between ages 50 and 70 years, mainly in men. Its manifestations tend to respond only weakly to L-DOPA, or not at all. PSP progresses rapidly and causes death within a few years.
This term subsumes a collection of rare diseases that were previously described as separate entities:
Olivopontocerebellar atrophy (OPCA), now also called MSA-C (cerebellar type).
Striatonigral degeneration (SND), now also called MSA-P (parkinsonian type).
Shy–Drager syndrome (SDS).
Mixed forms of these.
Pathology The neuropathologic lesion consists of intracellular inclusion bodies (with α-synuclein; synucleinopathy) in glial cells as well as cellular degeneration and gliosis in the substantia nigra, striatum, pons, inferior olive, and cerebellum.
Clinical features The main clinical features of MSA are present to varying extents in its different forms of MSA, each of which has its own characteristic initial presentation:
Parkinsonism: bradykinesia, akinesia, rigidity, and rest tremor (seen early in the course of MSA-C and MSA-P).
Autonomic dysfunction, including orthostatic hypotension, incontinence, and erectile dysfunction in men (seen early in the course of SDS).
Ataxia and other cerebellar signs (prominent in OPCA, i.e., MSA-C).
Pyramidal tract signs such as pathologic reflexes and spasticity.
In some cases, dementia and/or frontal signs.
Diagnostic evaluation These conditions are diagnosed from their clinical features. The diagnosis of MSA may be supported by an MRI finding of focal brain atrophy, for example, cerebellar atrophy or a loss of fiber connections in the pons (the “hot-cross-bun” sign with cross-shaped hypointensity in the pons).
Treatment MSA generally responds poorly to treatment; dopamine agonists tend to be more effective than L-DOPA. The disease usually leads to severe disability and death within a few years of onset.
Pathology The neuropathologic lesion in this disease consists of cellular degeneration and gliosis in the substantia nigra and in the pre- and postcentral gyri. The cerebral peduncles are correspondingly diminished in size. Like PSP, CBD is a type of tauopathy.
Clinical features The manifestations of CBD, which are asymmetrically distributed, include:
Impaired fine motor control of an arm (early in the course of the disease).
Progressive rigidity and akinesia.
Weakness.
Central sensory disturbances.
(Sometimes) apraxia.
(Sometimes) dystonia.
Treatment and course L-DOPA is generally not very effective and patients usually become severely disabled within a few years of the onset of the disease.
This disease is described later in the section on dementia (section ▶ 6.12.3).
Key Point
These disturbances, unlike Parkinson disease, are characterized by “too much” movement, often in combination with diminished muscle tone. The different clinical types of hyperkinesia include chorea, athetosis, ballism, and dystonia, and mixed forms. Each of these movement disturbances may be due to a variety of underlying diseases. Thus, the hyperkinetic extrapyramidal syndroms are a diverse group both in their clinical features and in their causes.
An overview of the hyperkinetic extrapyramidal syndroms is provided in ▶ Table 6.34. The more important ones are described in greater detail in the text that follows.
|
Syndrome |
Etiology |
Remarks |
|
Chorea: sudden, usually rapid, distal, brief, irregular involuntary movements; hypotonia |
||
|
Chorea minor |
Autoimmune; streptococcal infection |
Often a sequela of streptococcal pharyngitis, most commonly in girls aged 6 to 13 y |
|
Chorea mollis |
Autoimmune; streptococcal infection |
Hypotonia is prominent |
|
Chorea gravidarum |
Third to fifth month of pregnancy |
Usually during first pregnancy, often with prior history of chorea minor |
|
Chorea due to antiovulatory drugs |
Antiovulatory drugs |
Rare, reversible with discontinuation of the drug |
|
Huntington disease |
Autosomal dominant |
Onset usually at age 30 to 50 y; associated with progressive dementia |
|
Benign familial chorea |
Autosomal dominant |
Onset in childhood, no further progression, no dementia |
|
Choreoacanthocytosis |
Autosomal recessive |
Mainly orofacial, tongue-biting, elevated CK, hyporeflexia, acanthocytosis |
|
Postapoplectic chorea |
Vascular (prior stroke) |
Sudden hemichorea and hemiparesis, often combined with hemiballism |
|
Senile chorea |
Vascular and degenerative |
Occasional presenile onset, often more severe on one side, occasionally with dementia |
|
Athetosis: slow, exaggerated movements against resistance of antagonist muscles, mainly distal; seem uncomfortable and cramped |
||
|
Status marmoratus |
Perinatal asphyxia |
Soon after birth, increasingly severe athetotic hyperkinesia, often cognitive impairment, sometimes also spasticity |
|
Status dysmyelinisatus |
Kernicterus of the newborn |
Onset immediately after birth, often with other signs of perinatal brain damage; further progression |
|
Pantothenate kinase–associated neurodegeneration |
autosomal recessive disorder of pigment metabolism |
Choreoathetotic movements beginning at age 5 to 15 y, rigidity, dementia, and retinitis pigmentosa in one-third of cases; progressive, with characteristic joint hyperflexion/hyperextension; death by age 30 y |
|
Hemiathetosis |
Focal lesion of pallidum and striatum |
Unilateral, may come about some time after the causative lesion |
|
Ballism/hemiballism: unilateral, lightning-like, high-amplitude flinging movements of multiple limb segments |
Ischemic or neoplastic lesion of the subthalamic nucleus |
Sudden onset, usually with hemiparesis as well |
|
Dystonic syndromes |
||
|
Torsion dystonia: slow, tonic contractions of muscles or muscle groups, of shorter or longer duration, usually against the resistance of antagonist muscles |
Familial types |
Often in Ashkenazi Jewish families, onset before age 20 y with focal dystonia; later, rotatory movements of the head and trunk, as well as limb movements and athetotic finger movements |
|
Symptomatic types |
For example, in Wilson disease, Huntington disease, pantothenate kinase–associated neurodegeneration |
|
|
L-DOPA-sensitive dystonia: usually arises in childhood with dystonia of variably localization and fluctuation over the course of the day; progresses over the years |
Sometimes due to familial tyrosine hydroxylase deficiency |
Responds well to L-DOPA; can be difficult to distinguish from juvenile Parkinson disease with dystonia |
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Spasmodic torticollis: slow contraction of cervical and nuchal musculature against antagonist resistance, with rotatory movements of the head |
Idiopathic, occasionally after cervical spine trauma and various other causes |
One-third spontaneous recovery, one-third no change, one-third progression to torsion dystonia |
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Localized dystonia (see section ▶ 6.10.5) |
For example, writer's cramp, faciobuccolingual dystonia, oromandibular dystonia |
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Abbreviation: CK, creatine kinase. |
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Etiology Huntington disease (chorea major) is a genetic disorder of autosomal dominant inheritance caused by an unstable CAG trinucleotide repeat expansion on the short arm of chromosome 4.
Pathology The neuropathologic correlate of the disease is loss of small ganglion cells, mainly in the putamen and the caudate nucleus.
Clinical features The disease generally becomes symptomatic between the ages of 30 and 50 years. As a rule, choreiform movements appear first, followed by progressive dementia. Patients who inherited the defective gene from their father tend to develop overt disease at an earlier age, sometimes with rigidity and pyramidal tract signs as the initial manifestations.
Note
Chorea consists of irregular, sudden, involuntary movements that are usually more pronounced at the distal end of the limbs.
In some patients, these movements are of low amplitude and look almost normal, resembling nonpathologic “fidgetiness;” in others, they are massive and highly disturbing.
Chorea can be unilateral (“hemichorea,” ▶ Fig. 6.58) or bilateral.
Muscle tone is normal or diminished.
There is no weakness or sensory deficit, and pyramidal tract signs are absent.
The intrinsic muscle reflexes are normal, except that they may have a second extension phase (Gordon phenomenon) if elicited at the same time as an incipient choreiform movement.
Fig. 6.58 Senile hemichorea. Drawings from video stills.
Practical Tip
Chorea, like other hyperkinesias (see later), is typically enhanced by goal-directed movement, mental stress, or concentration, and subsides in sleep and under general anesthesia.
Treatment, course, and prognosis Huntingtonchorea progresses chronically, generally ending in death 10 to 15 years after the onset of symptoms. There is no treatment other than palliative, symptomatic management. The abnormal movements can be alleviated to some extent with perphenazine, tetrabenazine, tiapride, and other neuroleptic drugs. Depression can be treated with an SSRI or sulpiride; anxiety, agitation, and insomnia with benzodiazepines; and psychosis with neuroleptic drugs, preferably atypical ones such as olanzapine.
Epidemiology Chorea minor is the most common disease associated with choreiform movements. It mainly strikes school-aged girls.
Etiology and pathogenesis This disease arises after an infection with β-hemolytic group A streptococci and is caused by an autoimmune reaction in which antibodies are generated that cross-react with neurons.
Clinical features Within a few days or weeks after an attack of “strep throat,” or within a few weeks or months of an attack of rheumatic fever, the patient develops choreiform motor unrest (mainly in the face, pharynx, and hands), combined with irritability and other mental abnormalities.
Treatment, course, and prognosis The treatment is with high-dose penicillin for at least 10 days. The manifestations resolve spontaneously in a few weeks or months.
Pathology The neuropathologic basis of athetosis is loss of neurons in the striatum, the globus pallidus, and, less commonly, the thalamus.
Etiology and types of athetosis Congenital and perinatally acquired lesions of the basal ganglia (status marmoratus, status dysmyelinisatus, severe neonatal jaundice = kernicterus) cause bilateral athetosis (athétose double), sometimes in conjunction with other signs of brain damage. Choreoathetosis and dystonia are prominent manifestations of iron deposition in the basal ganglia in pantothenate kinase–associated neurodegeneration. Focal brain lesions, too, for example, an infarct, can produce hemiathetosis.
Clinical features Athetosis generally consists of slow, irregular movements mainly affecting the distal ends of the limbs, causing extreme flexion and extension at the joints and correspondingly bizarre postures, particularly of the hands ( ▶ Fig. 6.59). The interphalangeal joints may be hyperextended to the point of subluxation (“bayonet finger”). Athetosis is often found in combination with chorea (“choreoathetosis”).
Fig. 6.59 Hand posture in athetosis.
Practical Tip
Athetosis can be hard to distinguish from dystonia and is often designated as such. Athetosis can be considered a form of dystonia that is most prominent at the distal end of the limbs.
Pathology The neuropathologic substrate of ballism is a lesion of the contralateral subthalamic nucleus (corpus Luysii) and/or its fiber connections to the thalamus.
Etiology Ballism is usually due to focal ischemia, and less commonly due to a space-occupying lesion. It may also be the result of severe neonatal jaundice or of a hereditary degenerative disease; it is typically bilateral in such patients.
Clinical features Rapid, propulsive, large-amplitude, unbraked flinging movements of the limbs are seen on one side of the body (hemiballism) or both. Unlike chorea, these movements occur mainly in the proximal joints. The limbs may be hurled against walls, etc., causing injury.
Treatment Haloperidol and chlorpromazine can alleviate ballism. Stereotactic neurosurgical procedures are sometimes necessary.
Pathology and etiology There are no characteristic neuropathologic abnormalities in dystonia. To date, only a few of the disorders that cause dystonia have a known pathophysiologic basis (e.g., L-DOPA-sensitive dystonia). Precipitating factors of symptomatic dystonia are likewise only rarely identifiable. Often, the etiology of dystonia remains unclear.
Clinical features Dystonia consists of slow, long-lasting contractions of individual muscles or muscle groups. The trunk, head, and limbs assume uncomfortable or even painful positions and maintain them for long periods of time. The various clinical types of dystonia are classified as either focal, that is, affecting isolated, individual (small) muscle groups, or generalized.
Treatment In the treatment of generalized dystonia, baclofen, carbamazepine, and trihexyphenidyl are used, either as monotherapy or in combination, often with only limited success. For some types of dystonia, a trial of L-DOPA treatment may be worthwhile. Focal dystonias can be successfully treated with botulinum A toxin injections. In some cases of dystonia, deep brain stimulation can be highly effective; the preferred target structure is the globus pallidus internus.
Torsion dystonia This category of dystonia is characterized by slow, forceful, mainly rotatory movements of the trunk and head, usually accompanied by athetotic finger movements. Muscle tone is diminished at the onset of the disease. In some cases, hyperkinesia gradually ceases and gives way to hypertonia with a rigidly maintained dystonic posture (myostatic type). The various types of primary torsion dystonia are mostly of autosomal dominant inheritance, with low penetrance, and have been localized to genes on various chromosomes. The early-onset form is particularly common among Jews of Ashkenazi (Eastern European) ancestry and is due to a genetic defect at the 9p34 locus.
L-DOPA-sensitive dystonia (Segawa disease) This is an autosomal recessive disorder due to a genetic defect on chromosome 14q. It usually presents in young girls as a gait disturbance characterized by dystonic postures or movements of the legs that fluctuate widely in severity over the course of the day. It is liable to misdiagnosis as a psychogenic disorder. It typically responds to low doses of L-DOPA (250 mg, or a little more, per day). A therapeutic test of L-DOPA is worthwhile in any young patient with dystonia, even if no other family members are affected.
Focal dystonia is much more common than generalized dystonia. The abnormal movements are restricted to individual parts of the body or muscle groups. The main types of focal dystonia are the following:
Spasmodic torticollis In this disorder, slow contraction of individual muscles of the neck and shoulder girdle produce tonic rotation of the head to one side or the other ( ▶ Fig. 6.60). It is usually the contralateral sternocleidomastoid muscle that is most strongly contracted. Only one-third of all patients with “wry neck” due to spasmodic torticollis undergo spontaneous remission; a further third go on to develop other dystonic manifestations. The etiology usually remains unclear; there are probably multiple causes.
Fig. 6.60 Spasmodic torticollis. (a) A 32-year-old man whose head is spontaneously lightly turned to the right. (b) Torticollis with tonic, involuntary head rotation to the right. Note the hypertrophic left sternocleidomastoid muscle. (c) The patient can bring his head back to the neutral position by pressing gently on the lower jaw with a fingertip.
Blepharospasm This consists of bilateral tonic contraction of the orbicularis oculi muscles, often with very long-lasting involuntary eye closure, during which the patient cannot voluntarily open his or her eyes. Blepharospasm tends to affect older patients, mainly women. Eye closure may be forceful, with visible contraction of the orbicularis oculi muscle, or weak, with a relatively normal external appearance. Cases of the latter type are alternatively designated lid-opening apraxia. Misdiagnosis as a psychogenic disturbance is, unfortunately, common.
Dystonia affecting multiple muscles of the head The various types of focal dystonia that come under this heading are not rare when taken together; they include facio-bucco-lingual dystonia, oromandibular dystonia, and Brueghel or Meige syndrome. There may also be a relatively isolated dystonia of the mouth, pharynx, and tongue, particularly in patients who have been treated with neuroleptics. An acute form can appear as a complication of antiemetic drugs such as metoclopramide.
Isolated dystonia Isolated dystonias have been described for practically every muscle group in the body. Dystonia of this type may be idiopathic or may arise in connection with occupational overuse of the muscle group in question. Well-known examples include writer’s cramp, hand dystonia in musicians, and foot dystonia in certain other occupations. Spastic dysphonia is a focal dystonia of the laryngeal musculature.
Types of tremor The main phenomenological distinction is between the following:
Rest tremor.
Action tremor.
Action tremor, in turn, is subdivided into the following:
Postural tremor.
Isometric tremor (appearing when a muscle is contracted against constant resistance).
Kinetic tremor (appearing only during movement). Intention tremor is a kinetic tremor that worsens as the limb nears its target.
Tremor can also be classified etiologically as shown in ▶ Table 6.35.
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Designation |
Characteristics |
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Physiologic tremor |
Seen in normal individuals; intensified by pain, anxiety, cold, caffeine ingestion, etc. |
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Thyrogenic tremor |
Hyperthyroidism also intensifies physiologic tremor through the mediation of catecholamines. The tremor appears as a fine trembling of the hands |
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Essential tremor |
See text. This hereditary condition is sometimes misdiagnosed as Parkinson disease |
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Orthostatic tremor |
Similar to essential tremor bur arises only when the patient is standing, manifesting itself as shaking of the legs; mainly seen in the elderly. Other muscle groups can be similarly affected when under tonic stress |
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Parkinsonian tremor |
See the discussion of Parkinson disease (see section ▶ 6.9.2). Usually consists of rest tremor, e.g., of the hand or fingers when resting on a solid surface, or of the hand when the arm is dependent |
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Psychogenic tremor |
Sudden attacks of tremor, e.g., in acute stress disorder; often highly variable in intensity; coarse; of demonstrative quality |
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Holmes tremor |
Unilateral, low-frequency rest, postural, and intention tremor (becomes stronger as the movement nears its target) |
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Cerebellar tremor |
Intention tremor arising after cerebellar injury (becomes stronger as the movement nears its target) |
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Dystonic tremor |
Tremor and movement disturbance due to dystonia (section ▶ 6.5.10) |
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Asterixis (“flapping tremor”) |
Sudden loss of postural tone, mainly seen in hepatic encephalopathy but also in other liver diseases, e.g., Wilson disease |
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Alcohol-related tremor |
Fine rest and intention tremor, worse during alcohol withdrawal, improves after consumption of alcohol (but note: essential tremor often improves with alcohol as well) |
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Tremor induced by drugs, hormones, or toxic substances |
Resembling physiologic tremor, but more intense |
Essential tremor This is the most common type of tremor and often runs in families. Genetic defects causing familial essential tremor have been found on chromosomes 2p22– p25 and 3q. It usually arises between the ages of 35 and 45 years. It is a predominantly postural and sometimes also kinetic tremor of the hands; a pure intention tremor is seen in 15% of patients (see ▶ Fig. 3.22). It may also affect the head in isolation (nodding or shaking tremor of the “yes” or “no” type), sometimes including the chin and/or vocal cords.
Practical Tip
Essential tremor typically improves after the consumption of a small amount of alcohol and worsens with nervousness or stress.
“Essential tremor plus” is a combination of this entity with another neurologic disorder (e.g., Parkinson disease, dystonia, myoclonus, polyneuropathy, restless legs syndrome).
Diagnostic evaluation Thorough history-taking and a precise neurologic examination often yield important clues to the etiology of tremor; further studies (e.g., imaging studies) are only rarely necessary. In some cases, electrophysiologic testing is needed to pinpoint the correct diagnosis (e.g., in suspected orthostatic tremor). Laboratory testing may also be needed to exclude underlying disease.
Treatment If the tremor is severe enough to interfere with the patient’s everyday activities, a β-blocker such as propranolol can be tried; this drug is particularly effective against essential tremor. Primidone, benzodiazepines, and clozapine are further alternatives. A tremor accompanied by dystonia may respond well to botulinum toxin injections. Deep brain stimulation through an electrode that has been stereotactically implanted in the nucleus ventrointermedius of the thalamus is highly effective but is reserved for severe, medically intractable cases.
Differential diagnosis Involuntary movements arising from diseases of the basal ganglia must be differentiated from a variety of other movement disorders, which are listed in ▶ Table 5.3.