книги студ / Color Atlas of Pathophysiology (S Silbernagl et al, Thieme 2000)

Diseases of the Basal Ganglia

the substantia nigra (p. c.) must have been destroyed.

The loss of cells in the substantia nigra (p.c.) decreases the corresponding dopaminergic innervation of the striatum (→B1). This leads, first of all, to disinhibition of glutamatergic neurons in the subthalamic nucleus and thus to an increased activation in the internal part of the pallidum and of the pars reticulata of the substantia nigra. Secondly, the dopaminergic activation of the striatal neurons ceases. It normally directly inhibits neurons in the substantia nigra (p.r.) and the internal part of the pallidum. Together these processes ultimately lead to excessive inhibition of the thalamus

(GABA transmitter).

Inhibition of the thalamus suppresses voluntary movement (→B2). Patients have difficulty initiating movement or can do so only as a reaction to external stimuli (hypokinesia). Muscle tone is greatly increased (rigor). In addition, resting tremor (4 – 8 per second) is common, with alternating movements especially of the hands and fingers (a movement similar to that used when counting money). Hypokinesia typically forces the patient to adopt a moderately bent posture with slightly angled arms and legs. It also leads to a rather rigid facial expression, micrographia, and soft, monotone, and indistinct speech. Finally, other disturbances occur, for example, increased salivation, depression, and dementia. These are caused by additional lesions (death of neurons in the nucleus of the median raphe, of the locus coeruleus, or of the vagus nerve).

In treating Parkinson’s disease (→B3) the attempt is made to increase the dopamine formation of the nigrostriatal neurons by administering L-dopa, a precursor of dopamine (which cannot itself pass the blood–brain barrier). Amphetamines can stimulate the release of dopamine as well as inhibit the reuptake of dopamine in the nerve endings. This also increases the synaptic concentration of dopamine. Finally, dopamine breakdown can be delayed by inhibitors of monoaminooxidase (MAO inhibitor) or the effect of dopamine can be imitated by dopamine-like drugs.

In addition to increasing dopamine formation or its effect, transplantation of dopamine-

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producing cells into the striatum has been tried with the aim of increasing local dopamine concentration. The symptoms of Parkinson’s disease can also be improved by inhibiting cholinergic neurons in the striatum. These neurons stimulate those striatal neurons that are normally inhibited by dopamine.

Glutamate antagonists and lesions of the subthalamic nucleus or the internal part of the pallidum can also cause disinhibition of the thalamus, and thus an improvement in the clinical picture of the disease. Attempts have also been made to delay the apoptotic death of the nigrostriatal neurons by means of antioxidatively-acting drugs and of growth factors.

Hyperkinesias

Chorea is the most common hyperkinetic disease of the basal ganglia. It is largely a disease of the striatum.

The inherited variant of the disease (Huntington’s chorea; →C1) becomes manifest in the fourth or fifth decade of life and leads to an irreversible progressive destruction of striatal neurons. The responsible gene is on the short arm of chromosome 4. It is thought that the genetic defect results in the cellular increase of a protein (huntingtin) that is difficult to break down. Cell death is accelerated by the effect of the excitatory neurotransmitter glutamate, which stimulates neurons by activating calcium-permeable ionic channels. The cell is damaged by excessive entry of Ca2+.

In Sydenham’s chorea, contrary to Huntington’s chorea there is largely reversible damage to the striatal neurons (→C2). It is caused by the deposition of immunocomplexes in the course of rheumatic fever, and it occurs mainly in children.

In rare cases the striatal neurons have been damaged by ischemia (atherosclerosis), tumor, or inflammation (encephalitis).

The result of the destruction of striatal neurons is chiefly an increased inhibition of neurons in the subthalamic nucleus that normally activate inhibitory neurons in the substantia nigra (p. r.). This leads to disinhibition of cells in the thalamus, resulting in sudden, erratic, and involuntary movements that are normally suppressed by the basal ganglia.

Hemiballism. After destruction of the subthalamic nucleus (by ischemia or tumor) sudden flinging movements occur. They are thought to be due to decreased stimulation of inhibitory GABAergic neurons in the internal part of the pallidum and substantia nigra (p. r.). It leads to disinhibition of neurons in the thalamus.

Tardive dyskinesia (dystonia) is caused by longer-term treatment with neuroleptics, which displace dopamine from receptors (→D2). These drugs are used as antipsychotics (→p. 352). They cause sensitization of those neurons that express increased numbers of dopamine receptors in the subsynaptic membrane. The activity of the subthalamic nucleus is suppressed via disinhibition of neurons in the external part of the pallidum. Nonactivation of the subthalamic nucleus and increased inhibition by striate neurons decrease the activity of neurons in the internal part of the pallidum and in substantia nigra (p.r.). This results in disinhibition of the thalamus and involuntary movements. In addition to the increased expression of receptors, apoptosis of those neurons that are normally inhibited by dopamine is also important.

Lesions of the striatum and pallidum additionally lead to athetosis, a hyperkinesia marked by excruciatingly slow, screw-like movements. Lesions in the pallidum and thalamus cause dystonia (prolonged torsions and twists; also regarded as proximal athetosis).

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Lesions of the Cerebellum

Lesions of the cerebellum may be caused by poisoning (especially by alcohol, but also DDT, piperazine, 5-fluorouracil, lithium, or diphenylhydantoin), heat stroke, hypothyroidism, malabsorption as well as by genetic defects of enzymes or transport (hexosaminidase, glutamate dehydrogenase, pyruvate dehydrogenase, α-oxidation, DNA repair, transport of neutral amino acids), partially hereditary degenerative processes, inflammation (e.g., multiple sclerosis [→p. 302], viruses, prions), cerebellar and extracerebellar tumors (paraneoplasia; →p.16). In hereditary Friedreich’s ataxia, cerebellar function is indirectly affected, for example, by degeneration of the spinocerebellar tracts. The effects of cerebellar lesions depend on their location.

The lateral cerebellar hemispheres (cerebrocerebellum; →A, yellow) store programs for voluntary movements (manual dexterity). In voluntary movements, associative cortical areas (→A1) activate, via pontine nuclei (→A2), neurons in the hemispheres (→A3) whose efferent impulses (orange) project, via the dentate nucleus (→A4) and thalamus (→A5), to the motor cortex (→A5). From here spinal motoneurons are activated via the pyramidal tract (violet). Lesions in the hemispheres or in structures connected with them thus impair initiation and planning of movements.

The intermediate part of the hemisphere

(spinocerebellum, light blue) is mainly responsible for the control of movement. Via spinocerebellar afferents (blue) it receives information about the state of the motor apparatus. Neurons of the spinocerebellum project to the red nucleus (→A9) and thalamus via the nuclei emboliformis and globosus (→A8). Spinal motoneurons are influenced by the red nucleus via the rubrospinal tract and by the thalamus via the motor cortex and the pyramidal tract. Disorders of the spinocerebellum impair the execution and control of voluntary movements.

The vestibulocerebellum, comprising flocculus and nodulus and portions of the vermis (bright green), is responsible for control of balance. Neurons in the flocculus receive direct afferents from the vestibular organ (→A10). In addition, the flocculus, nodulus, and vermis

receive direct afferent signals via spinocerebellar fibers (→A7) as well as information on the movements of the eye muscles. The neurons of this part of the cerebellum project directly to the vestibular nucleus (→A11) as well as via the nuclei fastigii (→A12) to the thalamus, to the reticular formation (→A13), and to the contralateral vestibular nucleus (→A14). Spinal motoneurons receive impulses via the vestibulospinal and reticulospinal tracts, via the thalamocortical and corticospinal tracts. Lesions in the flocculus, nodulus, and vermis mainly affect balance and body posture as well as the muscles of the trunk and face.

Clinical manifestations of lesions in the cerebellum are delayed onset and stoppage of movements. There are no coordinated movements (dyssynergia) and often the required force, acceleration, speed, and extent of movements is misjudged (dysmetria). The patient cannot immediately withdraw the muscle action when a resistance is suddenly reduced (rebound phenomenon), nor able to perform rapid and consecutive antagonistic movements (dysdiadochokinesia). An intention tremor (3 – 5 oscillations per second) develops on moving the hand toward an object, the oscillations becoming increasingly marked the nearer the object gets. Movements are discontinuous and divided into separate components (decomposition of movement). Less active resistance is exerted against passive movements (hypotonia). On holding an object the muscle tone cannot be maintained, and patients can only stretch out their arms for a relatively short time (positioning attempt). Muscle stretch reflexes are diminished (hyporeflexia).

Speech is slow, explosive, staccato, and slurred. The control of balance is disturbed; patients stand with their legs apart and walk uncertainly (ataxia). Sitting and standing are also made more difficult by tremors of the trunk muscles (titubation, 2 –3 oscillations per second). Abnormal control of the eye muscles causes dysmetria of the eye movements and coarse nystagmus (→p. 330) in the direction of the lesion. It increases when patients direct their gaze toward the lesion and decreases when their eyes are closed.

Abnormalities of the Sensory System

loss of gross mechanoreceptor function, temperature and pain sensation (dissociated disorder of sensation). Additionally, there will be ipsilateral loss of the descending motor functions (lower motoneuron paralysis; →p. 310).

An interruption in the dorsal column (→ A4) stops adequate vibratory sensation and diminishes the ability to precisely define mechanical stimuli in space and time, and accurately to determine their intensity. Proprioception is also affected, which means that it is mainly information from the muscle spindles which is impaired, and thus the control of muscular activity. One of the effects is ataxia. In a lesion within the dorsal tracts their topographical arrangement is of importance. The cervical tracts lie most posterior, the sacral ones medial.

A lesion in the anterolateral tract (→A5) especially impairs pressure, pain, and temperature sensation. Anesthesia, hypesthesia, hyperesthesia, paraesthesia and dysesthesia may occur. Movements of the vertebral column can, by stimulating the damaged afferent nerves, cause corresponding sensations (Lhermitte’s sign: sudden, electric shock-like, paresthesia in upper limbs and trunk on forward neck flexion).

Lesions in the somatosensory cortex (→A6) impair the ability to separate sensations in time and space; the sense of position and movement have been lost, as has the ability to judge the intensity of a stimulus.

Lesions in the association tracts or cortical areas (→A7) lead to abnormal processing of sensory perception. This results, for example, in the inability to recognize objects by feeling or touching them (astereognosis) and topagnosis (inability to identify the exact spot where a sensation is felt). Abnormalities of body image and position may also occur. Another function that may be lost is the ability to discriminate between two simultaneously presented stimuli (deletion phenomenon). Hemineglect (ignoring the contralateral half of the body and its environment) may also result from such a lesion.

A. Disorders of the Sensory System

Anterior

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Pain

Pain stimuli are received by nociceptors in the skin and the viscera which are excited by highintensity, non-noxious stimuli (distension, temperature) as well as by tissue lesions (→A). Necrotic cells release K+ and intracellular proteins. An increase in extracellular K+ concentration depolarizes the nociceptors, while the proteins and, in some circumstances, infiltrating microorganisms may cause an inflammation. As a result, pain-producing mediators are released (→p. 294ff.). Leukotrienes, prostaglandin E2, and histamine sensitize the nociceptors so that even otherwise subthreshold noxious and harmless stimuli can produce pain (hyperalgesia or allodynia). Tissue lesions also activate blood clotting and thus the release of bradykinin and serotonin (→p. 294). If there is vascular occlusion, ischemia occurs and the resulting extracellular accumulation of K+ and H+ further activates the sensitized nociceptors. The mediators histamine, bradykinin, and prostaglandin E2 have a vasodilator effect and increase vascular permeability. This results in local edemas; the tissue pressure rises and this also stimulates the nociceptors. Their stimulation releases the peptide substance P (SP) and the calcitonin gene-related peptide (CGRP), which promote the inflammatory response and also produce vasodilatation and increase vascular permeability.

Vasoconstriction (by serotonin), followed by vasodilatation, is probably also responsible for migraine attacks (recurring severe headache, often unilateral and associated with neurological dysfunctions due, in part at least, to cerebral vasomotor abnormalities).

Afferents from organs and the surface of the skin are intertwined in parts of the spinal cord, i.e., the afferent nerves converge upon the same neurons in the spinal cord (→B). Excitation of the nociceptors in an organ then triggers pain sensations in those areas of the skin whose afferents make connections in the same spinal cord segment (referred pain; →B1). In myocardial infarction, for example, pain radiates into the left shoulder and left arm (Head’s zones).

Projected pain is produced by stimulation of a nerve (e.g., of the ulnar nerve in the ulnar sulcus; →B2). The perception of pain is pro-

jected to the innervation area of the nerve. A special form of projected pain is phantom pain of an amputated limb or part thereof. In neuralgia continued abnormal stimulation of a nerve or posterior root results in chronic pain in the area of innervation.

The impulses along the afferent nerves synapse in the spinal cord and pass via the anterolateral tracts to the thalamus and from there to, among others, the somatosensory cortex, the cingular gyrus, and the insular cortex (→C). Appropriate connections produce various components of pain sensation: sensory (e.g., perception of localization and intensity), affective (ailment), motor (protective reflex, muscle tone, mimicry), and autonomic (changes in blood pressure, tachycardia, pupillary dilatation, sweating, nausea). The connections in the thalamus and spinal cord are inhibited by the descending tracts from the cortex, midbrain periaqueductal gray matter, and raphe nucleus, these tracts employing norepinephrine, serotonin, and especially endorphines. Lesions of the thalamus, for example, can produce pain through an absence of these inhibitions (thalamus syndrome).

To counteract pain, the activation of pain receptors can be inhibited, for example, by cooling of the damaged area and by prostaglandin synthesis inhibitors (→C1). The transmission of pain can be inhibited by cooling and by Na+ channel blockers (local anesthetics; →C2). Transmission in the thalamus can be inhibited by anesthesia and alcohol (→C5). Attempts have now and again been made to interrupt pain transmission by means of surgical nerve transection (→C6). Electroacupuncture and transcutaneous nerve stimulation act via activation of the descending, pain-inhibiting tracts (→C3). The endorphine receptors are activated by morphine and related drugs (→C4). Endogenous pain-inhibiting mechanisms can be aided by psychological methods of treatment.

An absence of pain brought about by pharmacological means or the very rare congenital condition of congenital analgesia interrupt these warning functions. If the cause of the pain is not removed, the consequences can be life-threatening.