There are erectile dysfunction medication and heart disease 100mg kamagra gold with amex, in addition high cholesterol causes erectile dysfunction generic kamagra gold 100 mg fast delivery, a few patients who have true myoclonic jerks in the leg or trunk muscles erectile dysfunction treatment miami cheap kamagra gold 100 mg online, often associated with dyskinesias that are difficult to characterize but may include walking-like movements and arrhythmic abduction-adduction of one or both legs or of an arm erectile dysfunction q and a discount kamagra gold 100 mg online, as discussed in a later section erectile dysfunction depression treatment order kamagra gold 100 mg with visa. In a few patients impotence sexual dysfunction purchase kamagra gold 100 mg amex, mainly older ones with a severe form of the nighttime disorder, these movements and the myoclonus spill over into wakefulness and are accompanied by such movements as abnormal spasms, foot stamping, body rocking, and marching in place that are only partly under voluntary control. Treatment Several medications have proved helpful in the treatment of both the restless legs syndrome and periodic leg movements. Most physicians, as a first choice, favor treatment with dopamine agonists such as bromocriptine (1. Numerous other drugs seem to be helpful in certain patients: baclofen, opioids, carbamazepine, and gabapentin- but they are infrequently required. A lengthy list of medications that have been effective is given in the comprehensive review by Earley. Curiously, a single infusion of iron is said to suppress the movements for several weeks (Earley et al). When painful paresthesias are prominent, patients may benefit from gabapentin or opiate-derivatives such as propoxyphene. Caution is urged with the use of benzodiazepines, as these may worsen coexisting sleep apnea. Other Causes of Secondary Insomnia Acroparesthesias, a predominantly nocturnal tingling and numbness of the fingers and palms due to tight carpal ligaments (carpal tunnel syndrome), may awaken the patient at night (see further on, under "Sleep Palsies"). Cluster headaches characteristically awaken the patient within 1 to 2 h after falling asleep (page 155). Among the secondary insomnias, those due to some type of psychologic disturbance are particularly common. Under these circumstances the main difficulty is in falling asleep, with a tendency to sleep late in the morning. These facts emphasize that, to a certain degree, conditioning and environmental factors (social and learned) are normally involved in readying the mind and body for sleep. Illnesses in which anxiety and fear are prominent symptoms also result in difficulty in falling asleep and in light, fitful, or intermittent sleep. If anxiety is combined with depression, there is a tendency for both the above patterns to be observed. These people sink into bed and sleep through sheer exhaustion, but they awaken early with their worries and are unable to get back to sleep. Furthermore, a form of drug-withdrawal or rebound insomnia may actually occur during the night in which the drug is administered. The drug produces its hypnotic effect in the first half of the night and a worsening of sleep during the latter half of the night, as the effects of the drug wear off; the patient and the physician may be misled into thinking that these latter symptoms require more of the hypnotic drug or a different one. A wide variety of other pharmacologic agents may give rise to sporadic or persistent disturbances of sleep. Caffeine-containing beverages, corticosteroids, bronchodilators, central adrenergic blocking agents, amphetamines, certain "activating" antidepressants such as fluoxetine, and cigarettes are the most common offenders. The sleep rhythm may be totally deranged in acute confusional states and especially in delirium, and the patient may doze for only short periods, both day and night, the total amount and depth of sleep in a 24-h period being reduced. The senile patient tends to catnap during the day and to remain alert for progressively longer periods during the night, until sleep is obtained in a series of short naps throughout the 24 h; the total amount of sleep may be increased or decreased. Treatment of Insomnia In general, a sedative-hypnotic drug for the management of insomnia should be prescribed only as a shortterm adjuvant during an illness or some unusual circumstance. For patients who have difficulty falling asleep, staying asleep, or both, a quick-acting, fairly rapidly metabolized hypnotic is useful. The ones most commonly used have been flurazepam (Dalmane), 15 to 30 mg; triazolam (Halcion), 0. Barbiturates are no longer used because they so often produce dependence and, after a few consecutive nights, unpleasant aftereffects. All of these drugs are more or less equally effective in inducing and maintaining sleep, although they affect sleep stages somewhat differently. If flurazepam or triazolam are given for longer than a week or two, they may have a cumulative effect and lead to daytime drowsiness and dependence or withdrawal symptoms including anxiety attacks. Melatonin (300 to 900 mg) is sometimes as effective as the sedative-hypnotics and may cause fewer short-term side effects. Amitriptyline (25 to 50 mg at bedtime) appears to be a sleep-enhancing drug even in those who are not anxious or depressed. When pain is a factor in insomnia, the sedative may be combined with a suitable analgesic. Nonprescription drugs, such as Nytol and Sleepeze, contain diphenhydramine (Benadryl) or doxylamine, which are minimally effective in inducing sleep but may impair the quality of sleep and lead to drowsiness the following morning. The chronic insomniac who has no other symptoms should not be permitted to use sedative drugs as a crutch on which to limp through life. One should search out and correct, if possible, any underlying situational or psychologic difficulty, using medication only as a temporary measure. Patients should be encouraged to regularize their daily schedules, including their bedtimes, and to be physically active during the day but to avoid strenuous physical and mental activity before bedtime. It has been suggested that illumination from broad-spectrum light (television) in the late evening is detrimental. A number of simple behavioral modifications may be useful, such as using the bedroom only for sleeping, arising at the same time each morning regardless of the duration of sleep, avoiding daytime naps, and limiting the time spent in bed strictly to the duration of sleep. Disorders of Sleep Due to Neurologic Disease Many neurologic conditions seriously derange the total amount and patterns of sleep (see Culebras). Lesions in the upper pons, near the locus ceruleus, are particularly prone to do so. Lesser degrees of tegmental damage- as might occur with Chiari malformations, unilateral medullary infarction, syringobulbia, or poliomyelitis- may cause sleep apnea and daytime drowsiness. Patients with large hemispheric strokes may also be left with daytime lethargy on the basis of inversion of sleep-wake rhythm. Certain instances of mesencephalic infarction that are characterized by vivid visual hallucinations (peduncular hallucinosis) may be associated with disruption of sleep. Von Economo encephalitis, now an extinct illness, was usually associated with a hypersomnolent state but caused persistent insomnia in some instances. The latter was related to a predominance of lesions in the anterior hypothalamus and basal frontal lobes, in distinction to hypersomnia, which was related to lesions mainly in the dorsal hypothalamus and subthalamus. This subject and other forms of hypersomnia are elaborated further on, under "Excessive Sleep. The cerebral changes consist mainly of profound neuronal loss in the anterior or anteroventral and mediodorsal thalamic nuclei. These cases are thought to represent a familial form of prion disease similar to diseases that cause subacute spongiform encephalopathy and Gerstmann-Straussler-Scheinker disease (see Ё Chap. Interestingly, the alcoholic form of the Korsakoff amnesic state, associated with less severe lesions in the same thalamic nuclei, is also characterized by a sleep disturbance, taking the form of an increased frequency of intermittent periods of wakefulness (Martin et al). This sequence usually presages the change from a state of coma to one of wakefulness. Organized sleep activity is absent in virtually all types of coma that are the result of anatomic damage to the brain. A possible exception occurs in the unusual condition known as "spindle coma," in which persistent coma and the electrographic features of sleep coexist. This particular combination of events has been described after head trauma and rarely in association with profound metabolic encephalopathies. Disturbed sleep patterns have been described in patients with Alzheimer disease, Huntington chorea, olivopontocerebellar degeneration, and progressive supranuclear palsy (Parkes). The peculiarities of sleep in Parkinson disease have been extensively studied; many patients in early stages of the disease complain of fragmented and unrestful sleep, particularly in the early morning hours. The loss of natural body movements and the alerting effects of L-dopa contribute to the insomnia. Also, the directly acting dopaminergic agonist drugs used for the treatment of Parkinson disease may have the side effect of a pronounced and often rapid daytime sleepiness; however, a similar problem arises in some patients with advancing disease alone. Migraine, cluster headaches, and paroxysmal hemicrania all have been linked to certain sleep stages. Additionally, patients with epilepsy and myasthenia gravis and motor neuron disease may have sleep-related complaints; in the latter two the cause can be traced to mild respiratory failure or to pharyngeal weakness leading to apneic periods or aspiration. A variety of sleep disturbances may accompany brain tumors or follow surgical resection of an intracranial tumor. These include excessive daytime sleepiness, sleep apnea, and, rarely, nocturnal epilepsy. The location of the lesion, rather than the tumor type, is predictive of such a disturbance; thus tumors affecting the hypo- thalamus and pituitary are associated with excessive daytime drowsiness, whereas medullary lesions cause respiratory disturbances that may affect sleep (Rosen et al). A symptomatic form of narcolepsy has been associated with tumors located adjacent to the third ventricle and midbrain (see below). Schwartz and associates have reported transient cataplexy following surgery for a craniopharyngioma, but a delirious state has been more common in the few cases we have followed. Disorders of Sleep Associated with Changes in Circadian Rhythm Sleep is also disturbed and diminished when the normal circadian rhythm of the sleep-wake cycle is exogenously altered. This is observed most often in shift workers, who periodically change their work schedule from day to night, and as a result of transmeridional air travel- i. The consequent fatigue is a product of both sleep deprivation and a phase change required by changing time zones. Melatonin is also used for this purpose, but its effects have not been studied extensively. Exposure to light during the extended day is helpful in entraining the sleep cycle; this adjustment is also accomplished more easily when traveling west than east. Shifting of the circadian rhythm in animals suggests that brief exposure to light at crucial times effectively resets the sleep-wake cycle; apparently the period just before 4 A. The delayed-sleep-phase syndrome is a chronic inability to fall asleep and to arise at conventional clock times. The advanced-sleep-phase syndrome is characterized by an earlyevening sleep onset (8 to 9 P. Simply delaying the onset of sleep usually fails to prevent early-morning awakening. This pattern is not uncommon among healthy elderly persons (and also among college students), in whom it should probably not be dignified as an insomnia syndrome. Still other persons show a completely irregular sleep-wake pattern; sleep consists of persistent but variable short or long naps throughout the night and day, with a nearly normal 24-h accumulation of sleep. Somnolescent (Sleep, Hypnic) Starts As sleep comes on, certain motor centers may be excited to a burst of insubordinate activity. It may involve one or both legs or the trunk (less often, the arms) and may be associated with a frightening dream or sensory experience. If the start occurs repeatedly during the process of falling asleep and is a nightly event, it may become a matter of great concern to the patient. The starts are more apt to occur in individuals in whom the sleep process develops slowly; they are especially frequent under conditions of tension and anxiety. Polygraphic recordings have shown that these bodily jerks occur at the moment of falling asleep or during the early stages of sleep. It is probable that some relationship exists between these brusque nocturnal jerks and the sudden isolated jerk of a leg, or arm and leg, that occurs occasionally in a healthy, fully conscious person. Nor should these "somnolescent starts" be referred to as nocturnal myoclonus, a term that has also been used incorrectly to designate the relatively mild, repetitive leg movements that occur during sleep, mainly in stages 3 and 4 (see above, under "Insomnia"). A small proportion of otherwise healthy infants exhibit rhythmic jerking of the hands, arms, and legs or abdomen, both at the onset and in the later stages of sleep (benign neonatal myoclonus). Sensory Paroxysms Sensory centers may be disturbed in a similar way to the above described sleep starts, either as an isolated phenomenon or in association with motor phenomena. The patient, dropping off to sleep, may be roused by a sensation that darts through the body, a sudden flash of light, or a sudden crashing sound or thunderclap sensation- "the exploding head syndrome" (Pearce). Sometimes there is a sensation of being turned or lifted and dashed to the ground; conceivably these are sensory paroxysms involving the labyrinthine-vestibular mechanism. Though apparent causes for concern by some patients, these sensory paroxysms are benign. Sometimes the patient appears awake and has a fearful or astonished expression, or there are repetitive utterances and an appearance of distress, similar to what is seen in night terrors, discussed further on. The attacks may begin at any age, affect both sexes alike, and are usually nonfamilial. Two forms of this disorder have been recognized: in one, the attacks last 60 s or less; they may be diurnal as well as nocturnal; some patients in addition have epileptic seizures of the more usual type; and all respond to treatment with carbamazepine. Except for the lack of familial incidence and occurrence only during sleep, the disorder is very much the same as the "familial paroxysmal dystonic choreoathetosis" decribed by Lance (see page 68). Sleep Paralysis Curious paralytic phenomena, referred to as preand postdormital paralyses, may occur in the transition from the sleeping to the waking state. Sometimes in the morning and less frequently when falling asleep, otherwise healthy persons- though awake, conscious, and fully oriented- are seemingly unable to activate their muscles. Respiratory and diaphragmatic function and eye movements are usually not affected, although a few patients have reported a sensation of being unable to breathe. They lie as though still asleep, with eyes closed, and may become quite frightened while engaged in a struggle for movement. They have the impression that if they could move one muscle, the paralysis would be dispelled instantly and they would regain full power. Such attacks are observed in patients with narcolepsy (discussed later in this chapter) and with the hypersomnia of the pickwickian syndrome and other forms of sleep apnea. Usually the attacks are brief (minutes) and transient; if they occur in isolation and only on rare occasions, they are of no special significance. If frequent, as in narcolepsy, they can be prevented by the use of tricyclic antidepressants, particularly clomipramine, which has serotonergic activity.
The deficiency results in the accumulation of galactocerebroside; a toxic metabolite erectile dysfunction hypnosis 100mg kamagra gold otc, psychosine erectile dysfunction injections treatment buy kamagra gold 100 mg with visa, leads to the early destruction of oligodendrocytes and depletion of lipids in the cerebral white matter impotence by age 100 mg kamagra gold otc. The globoid cell reaction impotence sentence buy generic kamagra gold 100mg on-line, however doctor of erectile dysfunction 100mg kamagra gold free shipping, indicates that impaired catabolism of galactosylceramide is also important erectile dysfunction causes infertility generic kamagra gold 100 mg without prescription. Gross examination of the brain discloses a marked reduction in the cerebral white matter, which feels firm and rubbery. Microscopically, there is widespread myelin degeneration, absence of oligodendrocytes, and astrocytic gliosis in the cerebrum, brainstem, spinal cord, and nerves. The characteristic globoid cells are large histiocytes containing the accumulated metabolite. Visual failure with optic atrophy and a normal electroretinogram is an early finding. Later there is ataxia as well as spastic weakness of the legs, mental regression, and finally decerebration. Adams, a progressive quadriparesis with mild pseudobulbar signs, slowly progressive impairment of memory and other mental functions, dystonic posturing of the arms, and preserved sphincteric control constituted the clinical picture. We have observed another rare variant, beginning in adult years, with spastic quadriparesis (asymmetrical) and optic atrophy. The nerve conduction velocities in the late-onset form may be either normal or abnormal. Kolodny and colleagues have reported 15 cases of even later onset (ages 4 to 73 years); pes cavus, optic pallor, progressive spastic quadriparesis, a demyelinating sensorimotor neuropathy, and symmetrical parieto-occipital white matter changes (on imaging studies) were the main features. Galactocerebrosidase levels were not as much reduced as in the infantile form; possibly these late-onset variants represent a structural mutation of the enzyme (see Farrell and Swedberg). In this disease, as well as others described in this chapter, it has become clear that different mutations involving the same enzyme or metabolic pathway can produce strikingly different phenotypes and that there is a wide range in the age of onset in what had been considered, until relatively recently, a disease confined to infancy and early childhood. The onset is in the first weeks of life, with a hoarse cry due to fixation of laryngeal cartilage, respiratory distress, and sensitivity of the joints, followed by characteristic periarticular and subcutaneous swellings and progressive arthropathy, leading finally to ankylosis. Usually there is severe psychomotor retardation, but a few patients have appeared neurologically normal. The diagnostic abnormality is a deficiency of ceramidase, leading to accumulation of ceramide. Seitelberger has obtained pathologic verification of this lesion in cases beginning as late as adult years. This disease and Cockayne syndrome are the only leukodystrophies in which nystagmus has been an invariable finding. Koeppen and Robitaille, in a current and thorough review of the subject, summarize the present-day understanding of the pathogenesis, based on misfolding of myelin proteins. Unclassifiable Sporadic and Familial Sudanophilic Leukodystrophies There are two types of such disorder, one with early and the other with late onset. In the former, onset is before 3 months, with survival of less than 2 years; in the latter type, onset is from 3 to 7 years and the course is chronic. Psychomotor regression; spastic paralysis; incoordination; blindness and optic atrophy; seizures (rare); severe microcephaly; and absence of skeletal, visceral, and hematologic evidence of the metabolic abnormality are the main features. Rabinowicz, a brother and sister living to adolescence, the destroyed white matter was widely cavitated. Sudanophilic Leukodystrophies and Pelizaeus-Merzbacher Disease these are a heterogeneous group of disorders that have in common a defective myelination of the cerebrum, brainstem, cerebellum, spinal cord, and peripheral nerves. Morphologic peculiarities and genetic features separate a certain group called Pelizaeus-Merzbacher disease; other types have been artificially delineated; as a result, a relatively meaningless terminology has been introduced. Pelizaeus-Merzbacher Disease this is predominantly an Xlinked disease of infancy, childhood, and adolescence and includes other closely related pathologic entities with different modes of inheritance. Koeppen and associates have offered evidence of a defective synthesis of this protein. The onset of symptoms is most often in the first months of life; other cases begin later in childhood. The first signs are abnormal movements of the eyes (rapid, irregular, often asymmetrical pendular nystagmus), jerk nystagmus on extremes of lateral movements, upbeat nystagmus on upward gaze, and hypometric saccades (Trobe et al). There is spastic weakness of the limbs, optic atrophy (often with unexplained retention of pupillary light reflex), ataxia of limb movement and intention tremor, choreiform or athetotic movements of the arms, and slow psychomotor development with delay in sitting, standing, and walking. In later-developing cases, pendular nystagmus, choreoathetosis, corticospinal signs, dysarthria, cerebellar ataxia, and mental deterioration are the major manifestations. There are milder cases of later onset with behavioral peculiarities and loss of tendon reflexes and, rarely, pure spastic paraparesis. In the most severe cases, Seitelberger has observed an absence of oligodendrocytes and myelinated fibers. It is hypothesized that proteolipids accumulate in the endoplasmic reticulum of the oligodendrocytes, resulting in apoptosis. One group of cases resembles the Cockayne syndrome (page 824), with photosensitivity of skin, dwarfism, cerebellar ataxia, corticospinal signs, cataracts, retinitis pigmentosa, and deafness. Pathologically, islands of preserved myelin impart a tigroid pattern of degenerated and Spongy Degeneration of Infancy (Canavan-van Bogaert-Bertrand or Canavan Disease) this is an autosomal recessive disease described in 1931 by Canavan as a form of Schilder disease (see Chap. Onset is early, usually recognizable in the first 3 months of life and sometimes in the first neonatal weeks. There is either a lack of development or rapid regression of psychomotor function, loss of sight and optic atrophy, lethargy, difficulty in sucking, irritability, reduced motor activity, hypotonia followed by spasticity of the limbs with corticospinal signs, and an enlarged head (macrocephaly). There are no visceral or skeletal abnormalities, but a variable sensorineural hearing loss has been found (Ishiyama et al). An interesting but unexplored aspect of the disease is the occurrence of blond hair and light complexion in affected members, in contrast to the darker hair and complexion of their normal siblings (Banker and Victor). Instead, after a long period of constipation, sleep disorder, and orthostatic hypotension during adolescence, bulbar symptoms (dysarthria, dysphonia, and dysphagia), seizures, and in some cases ataxia gradually emerged during adult years. Alpers Disease this is a progressive disease of the cerebral gray matter, known also as progressive cerebral poliodystrophy or diffuse cerebral degeneration in infancy. A familial form (probably autosomal recessive) as well many sporadic cases has been reported. In both groups there is a certain uniformity of clinical features- loss of smile and disinterest in the surroundings, sweating attacks, seizures and diffuse myoclonic jerks beginning in early infancy and followed by incoordination of movements; progressive spasticity of limb, trunk, and cranial muscles; blindness and optic atrophy; growth retardation and increasing microcephaly; and finally virtual decortication. In some instances, the late onset of jaundice and fatty degeneration or cirrhosis of the liver have been described (Alpers-Huttenlocher syndrome); the hepatic changes are distinctive and probably not related to the use of anticonvulsant drugs, as had been hypothesized (Harding et al). The nature of this combined hepatic-cerebral degeneration remains unexplained, but some instances have been connected to the mitochondrial disorders, as noted below. Neuropathologic examination shows marked atrophy of the cerebral convolutions and cerebellar cortex, with loss of nerve cells and fibrous gliosis ("walnut brain"). In some cases, the spongiform vacuolization of the gray matter of the brain resembles that seen in Creutzfeldt-Jakob disease. Hypoglycemic, hypoxic, and hypotensive encephalopathies must always be considered in the diagnosis but can usually be eliminated by knowledge of the clinical circumstances at the onset of the illness. A number of biochemical abnormalities have been identified in patients with Alpers disease, including pyruvate dehydrogenase deficiency, decreased pyruvate utilization, dysfunction of the citric acid cycle, and decreased cytochromes a and aa3. The biochemical and pathologic changes suggest a relationship to Leigh encephalomyelopathy and a mitochondrial transmission. Many authoritative texts classify it with the mitochondrial diseases, but its nosologic status is in our opinion still uncertain (see Shaffner and Wallace). The abnormal white matter appears hyperintense and extends to the cortex without sparing of the arcuate fiber. Adachi and coworkers have demonstrated an abnormal vacuolar accumulation of fluid in astrocytes and between split myelin lamellae; they have suggested that the loss of myelin is secondary to these changes. Alexander Disease this distinctive disease shares certain features with the leukodystrophies and also with gray matter diseases (poliodystrophies), both clinically and pathologically. The onset is in infancy with a failure to thrive, psychomotor retardation, spasticity of the craniospinal musculature, and seizures. Alexander was the first to call attention to the enlargement of the brain, the extensive loss of cerebral white matter, and highly characteristic inclusions (the so-called Rosenthal fibers noted below) in astrocytes, and subpial and periventricular regions. Pathologically, there are severe destructive changes in the cerebral white matter, most intense in the frontal lobes. Distinctive eosinophilic hyaline bodies, most prominent just below the pia and around blood vessels, are seen throughout the cerebral cortex, brainstem, and spinal cord. These have been identified as Rosenthal fibers and probably represent glial degradation products. The astrocytic changes have been traced to a mutation in the glial fibrillary protein, according to Gorospe et al. This gene abnormality gives rise to the intermediate filament protein in astrocytes and, presumably, to the Rosenthal fiber inclusions. On the Congenital Lactic Acidosis this uncommon disease of the neonatal period or early infancy has many biochemical etiologies. The important laboratory findings are acidosis with an anion gap and high serum lactate levels and hyperalaninemia. Defects can be found in the pyruvate dehydrogenase complex of enzymes and the electron transport chain complexes, which function in the oxidative decarboxylation of pyruvate to acetyl CoA, relating the disease to defects in the mitochondrial respiratory chain enzymes. Indeed, lactic acidosis is a feature of several of the mitochondropathies discussed later in this chapter. Cases examined postmortem have shown necrosis and cavitation of the globus pallidus and cerebral white matter. It must be distinguished from the several diseases of infancy that are complicated secondarily by lactic acidosis, especially the organic acidopathies. Cases of benign transient infantile lactic acidosis have been reported, but their etiology is unclear. The Oculocerebrorenal (Lowe) Syndrome Here the mode of inheritance is probably X-linked recessive, although sporadic cases have been reported in girls. The clinical abnormalities comprise bilateral cataracts (which may be present at birth), glaucoma, large eyes with megalocornea and buphthalmos, corneal opacities and blindness, pendular nystagmus, hypotonia and absent or depressed tendon reflexes, corticospinal signs without paralysis, slow movements of the hands, tantrums and aggressive behavior, high-pitched cry, occasional seizures, and psychomotor regression. The characteristic biochemical abnormality is a renal tubular acidosis, and death is usually from renal failure. Additional laboratory findings include demineralization of bones and typical rachitic deformities, anemia, metabolic acidosis, and generalized aminoaciduria. The neuropathologic changes are nonspecific; inconstant atrophy and poor myelination have been described in the brain and tubular abnormalities in the kidneys. The primary genetic defects are in the gene encoding inositol polyphosphate phosphatase of the Golgi complex. Treatment programs include anticonvulsant medication, correction of electrolyte disorders, and removal of cataracts. Cerebrohepatorenal (Zellweger) Disease (Peroxisomal Disorder) this disease, estimated to occur once in every 100,000 births, is inherited as an autosomal recessive trait. It has its onset in the neonatal period or early infancy and as a rule leads to death within a few months. Motor inactivity and hypotonia, dysmorphic alterations of the skull and face (high forehead, shallow orbits, hypertelorism, high arched palate, abnormal helices of ears, retrognathia), poor visual fixation, multifocal seizures, swallowing difficulties, fixed flexion posture of the limbs, cataracts, abnormal retinal pigmentation, optic atrophy, cloudy corneas, hepatomegaly, and hepatic dysfunction are the usual manifestations. Stippled, irregular calcifications of the patellae and greater trochanters are highly characteristic. Pathologically, there is dysgenesis of the cerebral cortex and degeneration of white matter as well as a number of visceral abnormalities- cortical renal cysts, hepatic fibrosis, intrahepatic biliary dysgenesis, agenesis of the thymus, and iron storage in the reticuloendothelial system. Moser and coworkers have demonstrated a fivefold increase of very-long-chain fatty acids, particularly hexacosanoic acid, in the plasma and cultured skin fibroblasts from 35 patients with Zellweger disease. A similar abnormality was found in cultured amniocytes of women at risk of bearing a child with Zellweger disease, thus permitting prenatal diagnosis. The findings of Moser and colleagues are in keeping with current notions about the basic abnormality in Zellweger syndrome- namely, that it is due to a lack of liver peroxisomes (oxidase-containing, membrane-bound cytoplasmic organelles), in which the very-long-chain fatty acids are normally oxidized (Goldfischer et al). Currently, a spectrum of at least 12 disorders of peroxisomal function is recognized, all of them characterized by deficiencies in the peroxisomal enzyme of fatty-acid oxidation-a veritable peroxisomal assembly. The most widely recognized are neonatal adrenoleukodystrophy and infantile Refsum disease, but the Zellweger cerebrohepatorenal syndrome can be considered the prototype. Each variant can be identified by its characteristic profile of elevated longand very-long-chain fatty acids, and the specific diagnosis can be confirmed by enzymology of cultured fibroblasts or amniocytes. For an authoritative discussion of peroxisomal biogenesis, the reader is referred to the article by Gould and Valle. Menkes Disease (Kinky- or Steely-Hair Disease; Trichopoliodystrophy) this is a rare disorder, inherited as a sex-linked recessive trait. Poor feeding and failure to gain weight, instability of temperature (mainly hypothermia), and seizures become apparent in early infancy. The hair is normal at birth, but the secondary growth is lusterless and depigmented and feels like steel wool; hairs break easily and under the microscope they appear twisted (pili torti). Radiologic examination shows metaphysial spurring, mainly of the femurs, and subperiosteal calcifications of the bone shafts. Arteriography discloses tortuosity and elongation of the cerebral and systemic arteries and occlusion of some. The combination of intracerebral hemorrhage and metaphysial bone spurs, which may be interpreted as "corner fractures," has led in some cases to the erroneous diagnosis of child abuse. There is no discernible neurologic development, and rarely does the untreated child survive beyond the second year. Treated with copper histidine, patients may survive to adolescence, but they remain profoundly impaired and hypotonic and require gastric feeding; the seizures may abate. There was a diffuse loss of neurons in the relay nuclei of the thalamus, the cerebral cortex, and the cerebellum (granule and stellate cells) and of dendritic arborizations of residual neurons of the motor cortex and Purkinje cells. The manifestations of this disease are attributable to a deficiency of several copper-dependent enzymes, including cytochrome oxidase, resulting in a failure of absorption of copper from the gastrointestinal tract and a profound deficiency of tissue copper (Danks et al). Further, since copper fails to cross the placenta, a severe reduction of copper in the brain and liver is evident from birth.
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By contrast erectile dysfunction causes in young men discount kamagra gold 100mg otc, if the muscles are briskly stretched bpa causes erectile dysfunction discount kamagra gold 100 mg overnight delivery, the limb moves freely for a very short distance (free interval) erectile dysfunction prevalence age buy kamagra gold 100mg overnight delivery, beyond which there is an abrupt catch and then a rapidly increasing muscular resistance up to a point; then erectile dysfunction nitric oxide cheap kamagra gold 100mg on line, as passive extension of the arm or flexion of the leg continues erectile dysfunction drugs over the counter canada kamagra gold 100mg low price, the resistance melts away erectile dysfunction jokes cheap kamagra gold 100mg overnight delivery. With the limb in the extended or flexed position, a new passive movement may not encounter the same sequence; this entire pattern of response constitutes the lengthening and shortening reaction. Thus the essential feature of spasticity is a velocity-dependent increase in the resistance of muscles to a passive stretch stimulus. Although a clasp-knife relaxation following peak resistance is highly characteristic of cerebral hemiplegia, it is by no means found consistently. In some cases, the arm flexors and leg extensors are spastic, while the antagonist muscles show an even resistance throughout the range of passive movement- i. In some cases, severe weakness may be associated with only the mildest signs of spasticity, detectable as a "catch" in the pronators on passive supination of the forearm and in the flexors of the hand on extension of the wrist. Contrariwise, the most extreme degrees of spasticity, observed in certain patients with cervical spinal cord disease, may so vastly exceed paresis of voluntary movement as to indicate that these two states depend on separate mechanisms. Indeed, the selective blocking of small gamma neurons is said to abolish spasticity as well as hyperactive segmental tendon reflexes but to leave motor performance unchanged. Until recently, it was taught that the heightened myotatic or stretch reflexes ("tendon jerks") of the spastic state are "release" phenomena- the result of interruption of descending inhibitory pathways. Animal experiments have demonstrated that this aspect of the spastic state is also mediated through spindle afferents (increased tonic activity of gamma motor neurons) and, centrally, through reticulospinal and vestibulospinal pathways that act on alpha motor neurons. The clasp-knife phenomenon appears to derive at least partly from a lesion (or presumably a change in central control) of a specific portion of the reticulospinal system. Brown, in a discussion of the pathophysiology of spasticity, has emphasized the importance of two systems of fibers: (1) the dorsal reticulospinal tract, which has inhibitory effects on stretch reflexes, and (2) the medial reticulospinal and vestibulospinal tracts, which together facilitate extensor tone. He postulates that in cerebral and capsular lesions, cortical inhibition is weakened, resulting in spastic hemiplegia. In spinal cord lesions that involve the corticospinal tract, the dorsal reticulospinal tract is usually involved as well. If the latter tract is spared, only paresis, loss of support reflexes, and possibly release of flexor reflexes (Babinski phenomenon) occur. Pantano and colleagues have suggested that primary involvement of the lentiform nucleus and thalamus is the feature that determines the persistence of flaccidity after stroke, but the anatomic and physiologic evidence for this view is insecure. Numerous monographs and articles have been written about the sign: a quite comprehensive one, by van Gijn, and a classic but more arcane one by Fulton and Keller. A movement resembling the Babinski sign is present in normal infants, but its definite persistence or emergence in late infancy and childhood or later in life is an invariable indicator of a lesion at some level of the corticospinal tract. In its essential form, the sign consists of extension of the large toe and extension and fanning of the other toes during and immediately after stroking the lateral plantar surface of the foot. The stimulus is applied along the dorsum of the foot from the lateral heel and sweeping upward and across the ball of the foot. Several dozen surrogate responses (with numerous eponyms) have been described over the years, most utilizing alternative sites and types of stimulation, but all have the same significance as the classic response. Clinical and electrophysiologic observations indicate that the extension movement of the toe is a component of a larger synergistic flexion or shortening reflex of the leg- i. The nociceptive spinal flexion reflexes, of which the Babinski sign is a part, are common accompaniments but not essential components of spasticity. They, too, are exaggerated because of disinhibition or release of motor programs of spinal origin. Important characteristics of these responses are their capacity to be induced by weak superficial stimuli (such as a series of pinpricks) and their tendency to persist after the stimulation ceases. In their most complete form, a nocifensive flexor synergy occurs, involving flexion of the knee and hip and dorsiflexion of the foot and big toe (triple flexion response). With incomplete suprasegmental lesions, the response may be fractionated; for example, the hip and knee may flex but the foot may not dorsiflex, or vice versa. In the more chronic stages of hemiplegia, the upper limb is characteristically held stiffly in partial flexion. The hyperreflexic state that characterizes spasticity may take the form of clonus, a series of rhythmic involuntary muscular contractions occurring at a frequency of 5 to 7 Hz in response to an abruptly applied and sustained stretch stimulus. It is usually designated in terms of the part of the limb to which the stimulus is applied. The frequency is constant within 1 Hz and is not appreciably modified by altering peripheral or central nervous system activities. Clonus depends for its elicitation on an appropriate degree of muscle relaxation, integrity of the spinal stretch reflex mechanisms, sustained hyperexcitability of alpha and gamma motor neurons (suprasegmental effects), and synchronization of the contraction-relaxation cycle of muscle spindles. The cutaneomuscular abdominal and cremasteric reflexes are usually abolished in these circumstances, and a Babinski sign is usually but not invariably present. Spread, or irradiation of reflexes, is regularly associated with spasticity, although the latter phenomenon may be observed to a slight degree in normal persons with brisk tendon reflexes. Tapping of the radial periosteum, for example, may elicit a reflex contraction not only of the brachioradialis but also of the biceps, triceps, or finger flexors. This spread of reflex activity is probably due not to an irradiation of impulses in the spinal cord, as is often taught, but to the propagation of a vibration wave from bone to muscle, stimulating the excitable muscle spindles in its path (Lance). The same mechanism is probably operative in other manifestations of the hyperreflexic state, such as the Hoffmann sign and the crossed adductor reflex of the thigh muscles. Also, reflexes may be "inverted," as in the case of a lesion of the fifth or sixth cervical segment; here the biceps and brachioradialis reflexes are abolished and only the triceps and finger flexors, whose reflex arcs are intact, respond to a tap over the distal radius. In addition to hyperactive phasic myotatic reflexes ("tendon jerks"), certain lesions, particularly of the cervical segments of the spinal cord, may result in great enhancement of tonic myotatic reflexes. These are stretch reflexes in which a stimulus produces a prolonged asynchronous discharge of motor neurons, causing sustained muscle contraction. As the patient stands or attempts voluntary movement, the entire limb may become involved in intense muscular spasm, sometimes lasting for several minutes. Presumably there is both an interruption of lateral reticulospinal inhibitory influences on the anterior horn cells and a release of the medial reticulospinal facilitatory effects needed in antigravity support (Henneman). With bilateral cerebral lesions, exaggerated stretch reflexes can be elicited in cranial as well as limb and trunk muscles because of interruption of the corticobulbar pathways. These are seen as easily triggered masseter contractions in response to a brisk downward tap on the chin (jaw jerk) and brisk contractions of the orbicularis oris muscles in response to tapping the philtrum or corners of the mouth. In advanced cases, weakness or paralysis of voluntary movements of the face, tongue, larynx, and pharynx are added (bulbar spasticity or "pseudobulbar" palsy; see pages 426 and 445). There have been many investigations of the biochemical changes that underlie spasticity and the mechanisms of action of antispasticity drugs. Since glutamic acid is the neurotransmitter of the corticospinal tracts, one would expect its action on inhibitory interneurons to be lost. Actually, none of these agents is entirely satisfactory in the treatment of spasticity when administered orally; the administration of baclofen intrathecally may have a more beneficial effect. Glycine is the transmitter released by inhibitory interneurons and is measurably reduced in quantity, uptake, and turnover in the spastic animal. There is some evidence that the oral administration of glycine reduces experimentally induced spasticity, but its value in patients is uncertain. Interruption of descending noradrenergic, dopaminergic, and serotonergic fibers is undoubtedly involved in the genesis of spasticity, although the exact mode of action of these neurotransmitters on the various components of spinal reflex arcs remains to be defined. Table 3-1 summarizes the main attributes of upper motor neuron lesions and contrasts them with those of the lower motor neuron. Motor Disturbances Due to Lesions of the Parietal Lobe As indicated earlier in this section, a significant portion of the pyramidal tract originates in neurons of the parietal cortex. Pause and colleagues have described the motor disturbances due to lesions of the parietal cortex. The patient is unable to maintain stable postures of the outstretched hand when his eyes are closed and cannot exert a steady contraction. Exploratory movements and manipulation of small objects are impaired, and the speed of tapping is diminished. Posterior parietal lesions (involving areas 5 and 7) are more detrimental in this respect than anterior ones (areas 1, 3, and 5), but both regions are affected in patients with the most severe deficits. Viewed objectively, the conscious and sentient human organism is continuously active- fidgeting, adjusting posture and position, sitting, standing, walking, running, speaking, manipulating tools, or performing the intricate sequences of movements involved in athletic or musical skills. Others have been learned and mastered through intense conscious effort and with long practice have become habitual- i. Still others are complex and voluntary, parts of a carefully formulated plan, and demand continuous attention and thought. What is more remarkable, one can be occupied in several of these variably conscious and habitual activities simultaneously, such as driving through heavy traffic while dialing a cellular phone and engaging in animated conversation. Moreover, when an obstacle prevents a particular sequence of movements from accomplishing its goal, a new sequence can be undertaken automatically for the same purpose. As stated above, these activities, in the scheme of Hughlings Jackson, represent the third and highest level of motor function. Neuropsychologists, on the basis of studies of large numbers of patients with lesions of different parts of the cerebrum, believe that the planning of complex activities, conceptualizing their final purpose, and continuously modifying the individual components of a motor sequence until the goal is achieved are initiated and directed by the frontal lobes. Lesions of the frontal lobes have the effect of reducing the impulse to think, speak, and act. The term apraxia is applied to a state in which a clear-minded patient with no weakness, ataxia, or other extrapyramidal derangement, and no defect of the primary modes of sensation, loses the ability to execute highly complex and previously learned skills and gestures. This was the meaning given to apraxia by Liepmann, who introduced the term in 1900. It was his view, on the basis of case studies, that apraxia could be subdivided into three types- ideational, ideomotor, and kinetic. His anatomic data indicated that planned or commanded action is normally developed not in the frontal lobe, where the impulse to action arises, but in the parietal lobe of the dominant hemisphere, where visual, auditory, and somasthetic information is integrated. Presumably the formation of ensembles of skilled movements depends on the integrity of this part of the brain; if it is damaged, the patterns cannot be activated at all or the movements are faltering and inappropriate. The failure to conceive or formulate an action, either spontaneously or to command, was referred to by Liepmann as ideational apraxia. Involved are connections from sensory areas 5 and 7 in the dominant parietal lobe and the supplementary and premotor cortices of both cerebral hemispheres, wherein reside the innervatory mechanisms for patterned movement. Or, the patient may know and remember the planned action, but because these areas or their connections are interrupted, he cannot actually execute it with either hand. Certain tasks are said to differentiate ideomotor from ideational apraxia, as discussed further on, but the distinction is so subtle at times that it has largely eluded us. A third disorder, kinetic limb apraxia, involves clumsiness and maladroitness of a limb, usually the right, or dominant, hand, in the performance of a skilled act that cannot be accounted for by paresis, ataxia, or sensory loss (see also Chap. A historical perspective that outlines the development of these concepts is given by Faglioni and Basso. These high-order abnormalities of learned movement patterns have several unique features. Seldom are they evident to the patient himself, and therefore they are not sources of complaint; or, if they are appreciated by the patient, he has difficulty describing the problem except in narrow terms of the activity that is impaired, such as using a phone or dressing. Their evocation requires special types of testing that may be difficult because of the presence of other neurologic deficits. Obviously, if the patient is confused or aphasic, spoken or written requests to perform an act will not be understood and one must find ways of persuading him to imitate the movements of the examiner. Moreover, the patient must be able to recognize and name the articles that he attempts to manipulate; i. In practical terms, the lesion responsible for ideomotor apraxia that affects both arms usually resides in the left parietal region. Kertesz and colleagues have provided evidence that the lesions responsible for aphasia and apraxia are different, though the two conditions are frequently associated because of their origin in the left hemisphere. The exact location of the parietal lesion, whether in the supramarginal gyrus or in the superior parietal lobe (areas 5 and 7) and whether subcortical or cortical, is still uncertain. Clinically there is a motor speech disorder, a right hemiparesis, and this type of apraxia of the nonparalyzed hand, which has been termed sympathetic apraxia. If the lesion in the deep white matter separates the language areas from the right motor cortex but not from the left, the patient can write with the right hand but not with the left, or he may write correctly with the right hand and aphasically with the left. That such a syndrome is attributable to interruption of a pathway that traverses the genu of the corpus callosum, as depicted by Geschwind, is questionable, insofar as sympathetic apraxia has not been observed in patients with lesions (or surgical sections) confined to the anterior third of the corpus callosum (see page 395). Perhaps surprisingly, there are but a few cases of apraxia of any type with proven prefrontal lesions. Of a somewhat different nature is a facial-oral apraxia, which is probably the most common of all apraxias in practice. It may occur with lesions that undercut the left supramarginal gyrus or the left motor association cortex and may or may not be associated with the apraxia of the limbs described above. Such patients are unable to carry out facial movements to command (lick the lips, blow out a match, etc. With lesions that are restricted to the facial area of the left motor cortex, the apraxia will be limited to the facial musculature and may be associated with a verbal apraxia or cortical dysarthria (page 418). The terms dressing apraxia and constructional apraxia are used to describe certain manifestations of parietal lobe disease. These abnormalities are not apraxias in the strict sense of a loss of previously learned behavior but are instead symptoms of contralateral extinction or neglect of the body schema and of extrapersonal space (anosognosia, page 401). First, one observes the actions of the patient as he engages in such tasks as dressing, washing, shaving, and using eating utensils. Second, the patient is asked to carry out familiar symbolic acts- wave goodbye, salute the flag, shake a fist as though angry, or blow a kiss. Finally, he is asked to show how he would hammer a nail, brush his teeth, take a comb out of his pocket and comb his hair, cross himself, and so forth, or to execute a more complex act, such as lighting and smoking a cigarette or opening a bottle of soda, pouring some into a glass, and drinking it. These last actions, involving more complex sequences, are said to be tests of ideational apraxia; the simpler and familiar acts are called tests of ideomotor apraxia. To perform these tasks in the absence of the tool or utensil is always more demanding because the patient must mentally formulate a plan of action rather than engage in a habitual motor sequence. One may think of such an ideomotor deficit, if it can be singled out from confusion or a defect in comprehension, as a kind of amnesia for certain learned patterns of movement, analogous to the amnesia for words in aphasia. Children with cerebral diseases that retard mental development are often unable to learn the sequences of movement required in hopping, jumping over a barrier, hitting or kicking a ball, or dancing.
Basilar Artery the branches of the basilar artery may be instructively grouped as follows: (1) paramedian impotence bicycle seat discount kamagra gold 100 mg without prescription, 7 to 10 in number impotence of organic nature purchase kamagra gold 100 mg without prescription, supplying a wedge of pons on either side of the midline; (2) short circumferential erectile dysfunction co.za purchase 100 mg kamagra gold amex, 5 to 7 in number chewing tobacco causes erectile dysfunction discount kamagra gold 100 mg, supplying the lateral two-thirds of the pons and the middle and superior cerebellar peduncles; (3) long circumferential erectile dysfunction qof buy kamagra gold 100 mg low price, 2 on each side (the superior and anterior inferior cerebellar arteries) erectile dysfunction treatment bodybuilding cheap 100mg kamagra gold mastercard, which run laterally around the pons to reach the cerebellar hemispheres. These interpeduncular and other short proximal branches of the posterior cerebral artery have been described above. The picture of basilar artery occlusion due to thrombosis may arise in several ways: (1) occlusion of the basilar artery itself, usually in the lower or middle third at the site of an atherosclerotic plaque and superimposed thrombosis; (2) occlusion of both vertebral arteries; and (3) occlusion of a single vertebral artery when it is the only one of adequate size. Also, thrombosis may involve a branch of the basilar artery rather than the trunk (basilar branch occlusion). When there is embolism, the clot usually lodges at the upper bifurcation of the basilar or in one of the posterior cerebral arteries, since the embolus, if it is small enough to pass through the vertebral artery, easily traverses the length of the basilar artery, which is of greater diameter than either vertebral artery. The syndrome of basilar artery occlusion, as delineated by Kubik and Adams, reflects the involvement of a large number of structures: corticospinal and corticobulbar tracts, cerebellum, middle and superior cerebellar peduncles, medial and lateral lemnisci, spinothalamic tracts, medial longitudinal fasciculi, pontine nuclei, vestibular and cochlear nuclei, descending hypothalamospinal sympathetic fibers, and the third through eighth cranial nerves (the nuclei and their segments within the brainstem). The complete basilar syndrome comprises bilateral long tract signs (sensory and motor) with variable cerebellar, cranial nerve, and other segmental abnormalities of the brainstem. Often the patient is comatose because of ischemia of the high midbrain reticular activating system. Others are mute and quadriplegic but conscious, reflecting interruption of descending motor pathways in the base of the pons but sparing of the reticular activating system ("lockedin" syndrome; see page 305). Midbasilar disease may also cause coma if the posterior communicating arteries are inadequate to perfuse the distal basilar artery territory. In the presence of the full syndrome, it is usually not difficult to make the correct diagnosis. The aim should be, however, to recognize basilar insufficiency long before the stage of total deficit has been reached. Basilar Branch Occlusion Occlusion of branches at the bifurcation (top) of the basilar artery results in a remarkable number of complex syndromes that include, in various combinations, somnolence or coma, memory defects, akinetic mutism, visual hallucinations, ptosis, disorders of ocular movement (convergence spasm, paralysis of vertical gaze, retraction nystagmus, pseudoabducens palsy, retraction of upper eyelids, skew deviation of the eyes), an agitated confusional state, and visual defects. These have been reviewed by Petit and coworkers and Castaigne and associates as paramedian thalamic, subthalamic, and midbrain infarction syndromes and by Caplan as the "top of the basilar" syndrome. The main signs of occlusion of the superior cerebellar artery are ipsilateral cerebellar ataxia of the limbs (middle and/or superior cerebellar peduncles); nausea and vomiting; slurred speech; and loss of pain and thermal sensation over the opposite side of the body (spinothalamic tract). Partial deafness, static tremor of the ipsilateral upper extremity, an ipsilateral Horner syndrome, and palatal myoclonus have also been reported, but we have not seen these. The principal findings are vertigo, vomiting, nystagmus, tinnitus and sometimes unilateral deafness; facial weakness; ipsilateral cerebellar ataxia (inferior or middle cerebellar peduncle); an ipsilateral Horner syndrome and paresis of conjugate lateral gaze; and contralateral loss of pain and temperature sense of the arm, trunk, and leg (lateral spinothalamic tract). If the occlusion is close to the origin of the artery, the corticospinal fibers may also be involved, producing a hemiplegia; if distal, there may be cochlear and labyrinthine infarction. Cerebellar swelling has not occurred in our cases or in the 20 collected by Amarenco and Hauw. The most characteristic manifestation of all these branch or division brainstem infarcts is the "crossed" cranial nerve and long tract sensory or motor deficit. Another feature of note is that it is not possible to distinguish a hemiplegia of pontine origin from one of deep cerebral origin on the basis of motor signs alone. With brainstem lesions as with cerebral ones, a flaccid paralysis gives way to spasticity after a few days or weeks, and there is no satisfactory explanation for the variability in this period of delay or for the occurrence in some cases of spasticity from the onset of the stroke. There may also be a combined hemiparesis and ataxia of the limbs on the same side. With a hemiplegia of pontine origin, the eyes may deviate to the side of the paralysis, i. A dissociated sensory deficit over the ipsilateral face and contralateral half of the body usually indicates a lesion in the lower brainstem, while a hemisensory loss including the face and involving all modalities indicates a lesion in the upper brainstem, in the thalamus, or deep in the white matter of the parietal lobe. When position sense, two-point discrimination, and tactile localization are affected relatively more than pain or thermal and tactile sense, a cerebral lesion is suggested; the converse indicates a brainstem localization. Bilaterality of both motor and sensory signs is almost certain evidence that the lesion lies in the brainstem. When hemiplegia or hemiparesis and sensory loss are coextensive, the lesion usually lies supratentorially. Additional manifestations that point unequivocally to a brainstem site are rotational dizziness, diplopia, cerebellar ataxia, a Horner syndrome, and deafness. The several brainstem syndromes illustrate the important point that the cerebellar pathways, spinothalamic tract, trigeminal nucleus, and sympathetic fibers can be involved at different levels, and "neighboring" phenomena must be used to identify the exact site. A myriad of proper names have been applied to the brainstem syndromes, as noted in Tables 34-3 and 47-1 (page 1180). Most of them were originally described in relation to tumors and other nonvascular diseases. The diagnosis of vascular disorders in this region of the brain is not greatly facilitated by a knowledge of these eponymic syndromes; it is much more profitable to memorize the anatomy of the brainstem. Fisher and used in all previous editions of this book, present both medial and lateral syndromes at four levels of the medulla and pons. Other syndromes can usually be identified as fragments or combinations of the major ones. In almost all clinical and pathologic material, there has always been a strong relationship between the lacunar state and a combination of hypertension and atherosclerosis and, to a lesser degree, with diabetes. Sacco and colleagues (1991), in a population-based study in Rochester, Minnesota, found hypertension in 81 percent of patients with lacunar infarctions. In our view, the basis of the lacunar state is unusually severe atherosclerosis that has extended into the finest branches of large arteries. When Fisher examined a series of such lesions in serial sections, from a basal parent artery up to and through the lacuna, he found atheroma and thrombosis at the mouth of the branch vessels and less often embolic occlusion of small vessels to be the basic abnormality in some (usually the larger) lacunae, and a lipohyalin degeneration and occlusion in the initial course of small vessels in the smaller ones. In some, lipohyalinotic changes had resulted in false aneurysm formation, resembling the Charcot-Bouchard aneurysms that underlie brain hemorrhage (see further on). In a series of 1042 consecutive adults whose brains were examined postmortem in past decades, Fisher observed one or more lacunae in 11 percent. Lacunae are situated, in descending order of frequency, in the putamen and caudate nuclei, thalamus, basis pontis, internal capsule, and deep hemispheral white matter. The cavities range from 3 to 15 mm in diameter, and whether they cause symptoms depends entirely on their location. Pure motor hemiplegia Pure sensory stroke Clumsy hand dysarthria Ipsilateral hemiparesis ataxia Lacunar Syndromes As one might surmise, small penetrating branches of the cerebral arteries may become occluded, and the resulting infarcts may be so small or so situated as to cause no symptoms whatsoever. Early in the twentieth century, Pierre Marie confirmed the occurrence of multiple deep small cavities of this type, first described by Durant-Fardel in 1843. He distinguished these lesions from a fine loosening of tissue around thickened vessels that enter the anterior and posterior perforated spaces, a change to which he gave the name etat crible. Symptoms may be abrupt in onset or evolve over several hours, but in some instances (10 of 34 cases, according to Weisberg) the neurologic deficit evolves stepwise and relatively slowly, over as long a period as 2 to 3 days, thereby simulating a small hemorrhage. Recovery, which may begin within hours, days, or weeks, is sometimes nearly complete, even in the face of a severe initial stroke. However, many patients are left with some degree of clumsiness or slowness of movement of the affected side. Similarly, a lacuna of the lateral thalamus or (less often of the parietal white matter) presents as a pure hemisensory defect involving the limbs, face, and trunk extending to the midline, a pure sensory stroke. Medial inferior pontine syndrome (occlusion of paramedian branch of basilar artery) a. On side of lesion (1) Paralysis of conjugate gaze to side of lesion (preservation of convergence) (2) Nystagmus (3) Ataxia of limbs and gait (4) Diplopia on lateral gaze b. On side opposite lesion (1) Paralysis of face, arm, and leg (2) Impaired tactile and proprioceptive sense over half of the body 2. Lateral inferior pontine syndrome (occlusion of anterior inferior cerebellar artery) a. On side of lesion (1) Horizontal and vertical nystagmus, vertigo, nausea, vomiting, oscillopsia (2) Facial paralysis (3) Paralysis of conjugate gaze to side of lesion (4) Deafness, tinnitus (5) Ataxia (6) Impaired sensation over face b. On side opposite lesion (1) Impaired pain and thermal sense over half the body (may include face) 3. On side of lesion (1) Ataxia of limbs and gait (more prominent in bilateral involvement b. On side opposite lesion (1) Paralysis of face, arm, and leg (2) Deviation of eyes (3) Variably impaired touch and proprioception when lesion extends posteriorly. On side of lesion (1) Ataxia of limbs (2) Paralysis of muscles of mastication (3) Impaired sensation over side of face Structures involved Middle cerebellar peduncle Corticobulbar and corticospinal tract Medial lemniscus Middle cerebellar peduncle Motor fibers or nucleus of fifth nerve Sensory fibers or nucleus of fifth nerve As mentioned, in the ventral pons, the lacunar syndrome may be one of pure motor hemiplegia, mimicking that of internal capsular infarction except for relative sparing of the face and the presence of an ipsilateral paresis of conjugate gaze in some cases; or there is a combination of dysarthria and clumsiness of one hand; in the latter case the lacune is located in the paramedian midpons on the side opposite the clumsy limb. Occasionally a lacunar infarction of the pons, midbrain, internal capsule, or parietal white matter gives rise to a hemiparesis with ataxia on the same side as the weakness (Fisher; Sage and Lepore). There are many other, less frequent lacunar syndromes, too numerous to tabulate here. Multiple lacunar infarcts, involving the corticospinal and corticobulbar tracts, are by far the most common cause of pseudobulbar palsy. Undoubtedly, an accumulation of lacunes deep in both hemispheres can give rise to gait disorders and also to mental dulling sometimes referred to as multi-infarct dementia (see further on and pages 373, 691, and 707). The main differential diagnostic considerations are then normal-pressure hydrocephalus (Chap. In all these cases of lacunar infarction, the diagnosis depends essentially on the occurrence of the aforementioned unique stroke syndromes of limited proportions: to recapitulate, pure motor hemiplegia, pure sensory stroke, clumsy-hand with dysarthria, and ataxic hemiparesis are the main ones. On side of lesion (1) Cerebellar ataxia (2) Internuclear ophthalmoplegia (3) Rhythmic myoclonus of palate, pharynx, vocal cords, respiratory apparatus, face, oculomotor apparatus, etc. On side opposite lesion (1) Paralysis of face, arm, and leg (2) Rarely touch, vibration, and position senses are affected 2. On side of lesion (1) Ataxia of limbs and gait, falling to side of lesion (2) Dizziness, nausea, vomiting (3) Horizontal nystagmus (4) Paresis of conjugate gaze (ipsilateral) (5) Loss of optokinetic nystagmus (6) Skew deviation (7) Miosis, ptosis, decreased sweating over face (Horner syndrome) b. On side opposite lesion (1) Impaired pain and thermal sense on face, limbs, and trunk (2) Impaired touch, vibration, and position sense, more in leg than in arm (there is a tendency to incongruity of pain and touch deficits) Structures involved Superior and/or middle cerebellar peduncle Medial longitudinal fasciculus Central tegmental bundle Corticobulbar and corticospinal tract Medial lemniscus Middle and superior cerebellar peduncles, superior surface of cerebellum, dentate nucleus Vestibular nuclei Territory of descending branch to middle Vestibular nuclei cerebellar peduncle (occlusion of Uncertain superior cerebellar artery) Uncertain Uncertain Descending sympathetic fibers Spinothalamic tract Medial lemniscus (lateral portion) "big three," along with the criteria for diagnosis and the confirmatory laboratory tests for each, are considered here in separate sections. This classification has the disadvantage of not providing for disorders such as reversible ischemia, hypertensive encephalopathy, and venous thrombosis; these are considered in separate sections later in the chapter. The frequency of the different types of cerebrovascular disease has been difficult to ascertain. Obviously clinical diagnosis is not always correct, and clinical services are heavily weighted with acute strokes and nonfatal cases of uncertain type. For comparison, we have included an autopsy series of 740 cases, examined during the year 1949 by Fisher and Adams; of these, 179 (nearly 25 percent) had some form of cerebrovascular disease. Interestingly, in both series the ratio of infarcts to hemorrhages was 4:1 and embolism accounted for approximately one-third of all strokes. Atherothrombotic Infarction Most cerebrovascular disease can be attributed to atherosclerosis and chronic hypertension; until ways are found to prevent or control them, vascular disease of the brain will continue to be a major cause of morbidity. Atherosclerosis, by reducing the resilience of large arteries, induces systolic hypertension. In turn, sustained hypertension worsens atherosclerosis, seemingly "driving" it into the walls of small branch arteries (0. All the coats of the vessel become impregnated with a hyaline-lipid material, a process that Fisher has called lipohyalinosis. The segment so affected may also weaken and allow the formation of a small dissecting aneurysm (Charcot-Bouchard aneurysm), which most neuropathologists hold responsible for the hypertensive brain hemorrhage. The atheromatous process in brain arteries is identical to that in the aorta, coronary, and other large arteries. In general the process in the cerebral arteries runs parallel to but is somewhat less severe than that in the aorta, coronary, and lower limb vessels. Adams in an examination of 740 brains during the year 1949 at Mallory Institute of Pathology, Boston City Hospital. Hypertensive encephalopathy, cerebral vein thrombosis, meningovascular syphilis, and polyarteritis nodosa. Although atheromatosis is known to have its onset in childhood and adolescence, only in the middle and late years of life is it likely to have clinical effects. Added to these well-established risk factors is a theorized role of an excess of homocystine and an even more speculative role for chronic inflammation or and intracellular infection of uncertain origin within plaques (Chlamydia pneumoniae has been implicated in some studies). Clinical experience indicates that there are families with a predilection for the development of cerebral atherosclerosis, independent of these welldefined risk factors. There is a tendency for atheromatous plaques to form at branchings and curves of the cerebral arteries. The most frequent sites are in the internal carotid artery, at its origin from the common carotid; in the cervical part of the vertebral arteries and at their junction to form the basilar artery; in the stem or at the main bifurcation of the middle cerebral arteries; in the posterior cerebral arteries as they wind around the midbrain; and in the anterior cerebral arteries as they pass anteriorly and curve over the corpus callosum. It is rare for the cerebral arteries to develop plaques beyond their first major branching. Also, it is unusual for the cerebellar and ophthalmic arteries to show atheromatous involvement except in conjunction with hypertension. The common carotid and vertebral arteries at their origins from the aorta are frequent sites of atheromatous deposits, but because of abundant collateral arterial pathways, occlusions at these sites are not commonly associated with cerebral ischemia. The atheromatous lesions develop and grow silently for 20, 30, or more years; only in the event of a thrombotic complication do they become symptomatic. Although atheromatous plaques may narrow the lumen of an artery, causing stenosis, complete occlusion is nearly always the consequence of superimposed thrombosis ("atherothrombosis"). In general, the more severe the atheromatosis, the more likely the thrombotic complication, but the two processes do not always run in parallel. One patient with only scattered atheromatous plaques may thrombose a vessel, whereas another with marked atherosclerosis may have only a few thrombosed vessels or none at all. Atheromatous lesions may regress to some extent under the influence of diet and certain drugs. Hennerici and colleagues followed a series of patients with carotid stenoses for a period of 18 months and observed spontaneous regression in nearly 20 percent of the lesions. In the large majority of cases, however, atherosclerosis is a progressive disease. Degeneration of the wall of a sclerotic vessel or hemorrhage into the wall (from rupture of the vasa vasorum) may damage the endothelium. This is known to occur particularly in the walls of the internal carotid arteries (and the coronary arteries, where it is a main cause of vessel occlusion). The lesion in the atheromatous plaque apparently excites an inflammatory reaction.
