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Pathology the disease affects principally the cerebral and cerebellar cortices symptoms of mono discount donepezil 10mg on-line, generally in a diffuse fashion medicine joint pain generic donepezil 10 mg with visa, although in some cases the occipitoparietal regions are almost exclusively involved treatment xanthelasma eyelid purchase 10 mg donepezil with amex, as in those described by Heidenhain medicine quinine donepezil 10mg generic. In others, such as the cases of Brownell and Oppenheimer, the cerebellum has been most extensively affected, with early and prominent ataxia. The degeneration and disappearance of nerve cells is associated with extensive astroglial proliferation; ultrastructural studies have shown that the microscopic vacuoles, which give the tissue its typically spongy appearance, are located within the cytoplasmic processes of glial cells and dendrites of nerve cells. Despite the fact that the disease is due to a transmissible agent, the lesions show no evidence of an inflammatory reaction and no viral particles are seen. Not infrequently, however, we have been surprised by a "typical" case that proves to be some other disease. Also, diagnosis may be difficult in patients who present with dizziness, gait disturbance, diplopia, or visual disturbances until the rapidly evolving clinical picture clarifies the issue. Special isolation rooms are not necessary, and the families of affected patients and nursing staff can be reassured that casual contact poses no risk. Needle punctures and cuts are not thought to pose a risk but some uncertainty remains. The transmissible agent is resistant to boiling, treatment with formalin and alcohol, and ultraviolet radiation but can be inactivated by autoclaving at 132 C at 15 lb/in. Workers exposed to infected materials (butchers, abattoir workers, health care workers) should wash thoroughly with ordinary soap. Needles, glassware, needle electrodes, and other instruments should be handled with great care and immersed in appropriate disinfectants and autoclaved or incinerated. The performance of a brain biopsy or autopsy requires that a set of special precautions be followed, as outlined by Brown (see References). Obviously such patients or any others known to have been demented should not be donors of organs for transplantation or blood for transfusion. It begins insidiously in midlife and runs a chronic course (mean duration, 5 years). The main characteristics are a progressive cerebellar ataxia, corticospinal tract signs, dysarthria, and nystagmus. Brain tissue from patients with this disease, when inoculated into chimpanzees, has produced a spongiform encephalopathy (Masters et al). Molecular genetic studies of affected members demonstrate a mutation of the prion protein gene. Fatal Familial Insomnia this is another very rare familial disease; it is characterized by intractable insomnia, sympathetic overactivity, and dementia, leading to death in 7 to 15 months (see also page 340). The pathologic changes, consisting of neuronal loss and gliosis, are found mainly in the medial thalamic nuclei. Studies of a few families have shown a mutation of the prion protein gene, and brain material was found to contain a protease-resistant form of the gene. Transmission of the disease by inoculation of infected brain material has not been accomplished (Medori et al). Kuru this disease, which occurs exclusively among the Fore linguistic group of natives of the New Guinea highlands, was the first slow infection due to a nonconventional transmissible agent to be documented in human beings. Clinically the disease takes the form of an afebrile, progressive cerebellar ataxia, with abnormalities of extraocular movements, weakness progressing to immobility, incontinence in the late stages, and death within 3 to 6 months of onset. In some ways it is similar to the ataxic (Brownell-Oppenheimer) variant of Creutzfeldt-Jakob disease. The remarkable epidemiologic and pathologic similarities between kuru and scrapie were pointed out by Hadlow (1959), who suggested that it might be possible to transmit kuru to subhuman primates. This was accomplished in 1966 by Gajdusek and coworkers; inoculation of chimpanzees with brain material from affected humans produced a kuru-like syndrome in chimpanzees after a latency of 18 to 36 months. Since then the disease has been transmitted from one chimpanzee to another and to other primates by using both neural and nonneural tissues. Kuru has gradually disappeared, apparently because of the cessation of ritual cannibalism by which the disease had been transmitted. At least 50 percent of the neurologic disorders in a general hospital are of this type. At some time or other, every physician will be required to examine patients with cerebrovascular disease and should at least know something of the common types- particularly those in which there is a reasonable prospect of successful medical or surgical intervention or the prevention of recurrence. There is another advantage to be gained from the study of this group of diseases- namely, that they have traditionally provided one of the most instructive approaches to neurology. Fisher has aptly remarked, house officers and students learn neurology literally "stroke by stroke. It must also be noted that, in the last two decades, new and extraordinary types of imaging technology have been introduced that allow the physician to make physiologic distinctions between normal, ischemic, and infarcted brain tissue. This biopathologic approach to stroke will likely guide the next generation of treatments and has already had a pronounced impact on the direction of research in the field. Salvageable brain tissue to be protected in the acute phase of stroke can be delineated by these methods. To identify this ischemic but not yet infarcted tissue virtually defines the goal of modern stroke treatment. Which of the sophisticated imaging techniques will contribute to improved clinical outcome is still to be determined, but certain ones, such as diffusionweighted imaging, have already proved invaluable in stroke work. First, all physicians have a role to play in the prevention of stroke by encouraging the reduction in risk factors such as hypertension and the identification of signs of potential stroke, such as transient ischemic attacks, atrial fibrillation, and carotid artery stenosis. Second, careful bedside clinical evaluation integrated with the newer testing methods mentioned above still provide the most promising approach to this category of disease. Finally, the last decade or two have witnessed a departure from the methodical clinicopathologic studies that have been the foundation of our understanding of cerebrovascular disease. Increasingly, randomized studies involving several hundred and even thousands of patients and conducted simultaneously in dozens of institutions have come to dominate investigative activity in this field. These multicenter trials have yielded highly valuable information about the natural history of a variety of cerebrovascular disorders, both symptomatic and asymptomatic. However, this approach suffers from a number of inherent weaknesses, the most important of which is that the homogenized data derived from an aggregate of patients may not be applicable to a specific case at hand. Moreover, many large studies show only marginal differences between treated and control groups. Each of these multicenter studies will therefore be critically appraised at appropriate points in the ensuing discussion. Since 1950, coincident with the introduction of effective treatment for hypertension, there has been a substantial reduction in the frequency of stroke. This was most apparent three decades ago, as treatment for high blood pressure became a public health focus. During this period, the incidence of coronary artery disease and malignant hypertension also fell significantly. In the last decade, according to the American Heart Association, the mortality rate from stroke has declined by 12 percent, but the total number of strokes may again be rising. Definition of Terms As discussed below, the term stroke is applied to a sudden focal neurologic syndrome, specifically the type due to cerebrovascular disease. The term cerebrovascular disease designates any abnormality of the brain resulting from a pathologic process of the blood vessels. Pathologic process is given an inclusive meaning- namely, occlusion of the lumen by embolus or thrombus, rupture of a vessel, an altered permeability of the vessel wall, or increased viscosity or other change in the quality of the blood flowing through the cerebral vessels. The vascular pathologic process may be considered not only in its grosser aspects- embolism, thrombosis, dissection, or rupture of a vessel- but also in terms of the more basic or primary disorder, i. Equal importance attaches to the secondary parenchymal changes in the brain resulting from the vascular lesion. These are of two main types- ischemia, with or without infarction, and hemorrhage- and unless one or the other occurs, the vascular lesion usually remains silent. The only exceptions to this statement are the local pressure effects of an aneurysm, vascular headache (migraine, hypertension, temporal arteritis), multiple small vessel disease with progressive encephalopathy (as in malignant hypertension or cerebral arteritis), and increased intracranial pressure (as occurs in hypertensive encephalopathy and venous sinus thrombosis). Also, persistent acute hypotension may cause ischemic necrosis in regions of brain between the vascular territories of cortical vessels, even without vascular occlusion. The many types of cerebrovascular diseases are listed in Table 34-1, and the predominant types during each period of life, in Table 34-2.
A lesion of the afferent limb of the light reflex pathway will not affect the near responses of the pupil medicine bobblehead fallout 4 buy 5mg donepezil with amex, and lesions of the visual pathway caudal to the point where the light reflex fibers leave the optic tract will not alter the pupillary light reflex treatment lower back pain discount donepezil 5mg on-line. Following initial constriction medicine in the middle ages discount 5 mg donepezil free shipping, the pupil may normally dilate slightly in spite of a light shining steadily in one or both eyes 10 medications doctors wont take donepezil 5mg cheap. Slowness of response along with failure to sustain pupillary constriction, or "pupillary escape," is sometimes referred to as the Marcus-Gunn pupillary sign (not to be confused with the Gunn jaw synkinesis mentioned earlier); a mild degree of it may be observed in normal persons, but it is far more prominent in cases of damage to the retina or optic nerve. A variant of this pupillary response may be used to expose mild degrees of retrobulbar neuropathy (relative afferent pupillary defect). This is best tested in a dimly lighted room with the patient fixating on a distant target. If a light is shifted quickly from the normal to the impaired eye, the direct light stimulus is no longer sufficient to maintain the previously evoked consensual pupillary constriction and both pupils dilate. These abnormal pupillary responses form the basis of "the swinging-flashlight test," in which each pupil is alternately exposed to light at 3-s intervals and the pupil on the side of an optic neuropathy displays a paradoxical dilation just as the light is brought to that side. Hippus, a rapid alternation in pupillary size, is common in metabolic encephalopathy but has no particular significance. The entire complex is called the Horner syndrome, Bernard-Horner syndrome, or oculosympathetic palsy (see also page 464). It may be due to ipsilateral lesions of the sympathetic tract in the medulla or cervical cord or to peripheral lesions. The pattern of sweating may be helpful in localizing the lesion in the following manner: with lesions at the level of the common carotid artery, loss of sweating involves the entire side of the face. With lesions distal to the bifurcation, loss of sweating is not found or is confined to the medial aspect of the forehead and side of the nose (see Morris et al). Retraction of the eyeball (enophthalmos), traditionally considered a component of the syndrome, is probably an illusion created by narrowing of the palpebral fissure. A hereditary form (autosomal dominant) of the Horner syndrome is known, usually but not always associated with a congenital absence of pigment in the affected iris (heterochromia iridis) (see Hageman et al). Bilateral Horner syndrome is a rare occurrence; usually it is found in autonomic neuropathies and in high cervical cord transection. Although difficult to appreciate, it may be detected (using pupillometry) by noting a lag in the redilation of the initially small pupils when light is withdrawn (Smith and Smith). Use is made of this phenomenon in the testing of the ciliospinal pupillary reflex, which is evoked by pinching the neck (afferent, C2, C3) and is effected through the efferent sympathetic fibers. Extreme constriction of the pupils (miosis) is commonly observed with pontine lesions, presumably because of bilateral interruption of the pupillodilator fibers. Interruption of the parasympathetic fibers causes an abnormal dilatation of the pupils (mydriasis), often with loss of pupillary light reflexes; this is frequently the result of midbrain lesions and is a common finding in cases of deep coma (the "blown" or Hutchinson pupil, described in Chap. As an ancillary test to determine the cause of changes in the size of the pupils, the functional integrity of the sympathetic and parasympathetic nerve endings in the iris may also be determined by the use of certain drugs. Atropinics dilate the pupils by paralyzing the parasympathetic nerve endings; physostigmine and pilocarpine constrict the pupils, the former by inhibiting cholinesterase activity at the neuromuscular junction and the latter by direct stimulation of the sphincter muscle of the iris. Epinephrine and phenylephrine dilate the pupils by direct stimulation of the dilator muscle. Cocaine dilates the pupils by preventing the reabsorption of norepinephrine into the nerve endings. In diabetes mellitus, where autonomic spinal and cranial nerves are often involved, the pupils are affected in the majority of cases. They are smaller than would be expected for age due to involvement of pupillodilator sympathetic fibers, and mydriasis is excessive upon instillation of sympathomimetic drugs. The light reflex, mediated by parasympathetic fibers (which are also damaged), is reduced, usually to a greater degree than constriction on accommodation (Smith and Smith). Some of these abnormalities require special methods of pupillometry for their demonstration. Argyll-Robertson Pupil In the forms of late syphilis, particularly tabes dorsalis, the pupils are usually small, irregular, and unequal; they fail to react to light, although they do constrict on accommodation (light-near dissociation) and do not dilate properly in response to mydriatic drugs. The exact locality of the lesion is not certain; it is generally believed to be in the tectum of the midbrain proximal to the oculomotor nuclei where the descending pupillodilator fibers are in close proximity to the light reflex fibers. The possibility of a partial third nerve lesion extending to the ciliary ganglion seems more plausible to us. A similar pupillary abnormality has been observed in the meningoradiculitis of Lyme disease and in diabetes. A dissociation of the light reflex from the accommodation-convergence reaction is also sometimes observed with a variety of midbrain lesions-. Adie Tonic Pupil (Holmes-Adie Syndrome) Another interesting pupillary abnormality is the tonic reaction, also referred to as the Adie pupil. This syndrome is due to a degeneration of the ciliary ganglia and the postganglionic parasympathetic fibers that normally constrict the pupil and effect accommodation. The patient may complain of unilateral blurring of vision or may have noticed that one pupil is larger than the other. The affected pupil is slightly enlarged in ambient light and the reaction to light is absent or greatly reduced if tested in the customary manner, although the size of the pupil will change slowly with prolonged light stimulation. Once the pupil has constricted, it tends to remain tonically constricted and redilates very slowly. Once dilated, the pupil remains in this state for many seconds, up to a minute or longer. Light and near paralysis of a segment or segments of the pupillary sphincter is also characteristic of the syndrome; this segmental irregularity can be seen with the high plus lenses of an ophthalmoscope. The affected pupil constricts promptly in response to the common miotic drugs and is unusually sensitive to a 0. The tonic pupil usually appears during the third or fourth decade of life and is much more common in women than in men; it may be associated with absence of knee or ankle jerks (Holmes-Adie syndrome) and hence be mistaken for tabes dorsalis. From all available data, it represents a special form of mild inherited polyneuropathy. An acquired type of tonic pupil has also been attributed, sometimes on uncertain grounds to diabetes, viral infection, and trauma. Springing Pupil Finally, mention should be made of a rare pupillary phenomenon characterized by transient episodes of unilateral mydriasis for which no cause can be found (the "springing pupil"). These episodes of mydriasis, which are more common in women, last for minutes to days and may recur at random intervals. Oculomotor palsies and ptosis are notably lacking, but sometimes the pupil is distorted during the attack. Some patients complain of blurred vision and head pain on the side of the mydriasis, suggesting an atypical form of ophthalmoplegic migraine. In children, following a minor or major seizure, one pupil may remain dilated for a protracted period of time. The main consideration in an awake patient is that the cornea has inadvertently (or purposefully) been exposed to mydriatic solutions, among them vasopressor agents used in cardiac resuscitation. As stated above, in dealing with anisocoria, it is worth noting that at any given examination, 20 percent of normal persons show an inequality of 0. This is "simple" or physiologic anisocoria, and it may be a source of confusion in patients with small pupils. Its main characteristic is that the same degree of asymmetry in size is maintained in low, ambient, and bright light conditions. It is also variable from day to day and even from hour to hour and often will have disappeared at the time of the second examination (Loewenfeld; Lam et al). In first dealing with the problem of pupillary asymmetry, one has to determine which of the pupils is abnormal. If it is the larger one, the light reaction will be muted on that side; if it is the smaller pupil, it will fail to enlarge in response to shading both eyes. More simply stated, light exaggerates the anisocoria due to a third-nerve lesion, and darkness accentuates the anisocoria in the case of a Horner syndrome. A persistently small pupil always raises the question of a Horner syndrome, a diagnosis that may be difficult if the ptosis is slight and facial anhidrosis undetectable. In darkness, the Horner pupil dilates more slowly and to a lesser degree than the normal one because it lacks the pull of the dilator muscle (dilation lag). The diagnosis can be confirmed by placing 1 or 2 drops of 2 to 10% cocaine in each eye; the Horner pupil dilates not at all or much less than the normal one- a response that can be documented by photos taken after 5 and 15 s of darkness.
In recent years symptoms kidney buy donepezil 5mg on line, it has come to be appreciated from serologic studies that the enteric organism Campylobacter jejuni is the most frequent identifiable antecedent infection but it accounts for only a relatively small proportion of cases symptoms type 1 diabetes buy 5mg donepezil with visa. Trauma and surgical operations may precede the neuropathy symptoms magnesium deficiency cheap donepezil 5mg overnight delivery, but a causal association to them remains uncertain symptoms ringworm discount 10 mg donepezil fast delivery. Historical Background the earliest description of an afebrile generalized paralysis is probably that of Wardrop and Ollivier, in 1834. Subsequently, Asbury, Arnason, and Adams (1969) established that the essential lesion, from the beginning of the disease, is a perivascular mononuclear inflammatory infiltration of the roots and nerves. More recently it has been found that complement deposition on the myelin surface may be the earliest immunologic event. For details of the historical and other aspects of this disease, see the monographs by Ropper and colleagues and by Hughes. It is generally nonseasonal and nonepidemic but isolated seasonal outbreaks have been recorded in rural China following exposure of children to C. Year after year, between 15 and 25 patients are admitted to each of our institutions. The age range of our consecutive patients has been 8 months to 81 years, with attack rates highest in persons 50 to 74 years of age. Paresthesias and slight numbness in the toes and fingers are the earliest symptoms; only infrequently are they absent throughout the illness. The major clinical manifestation is weakness that evolves more or less symmetrically over a period of several days to a week or two, or somewhat longer. The weakness progresses in about 5 percent of patients to total motor paralysis with respiratory failure within a few days. In severe cases the ocular motor nerves are paralyzed and even the pupils may be unreactive. More than half of the patients complain of pain and an aching discomfort in the muscles, mainly those of the hips, thighs, and back; these symptoms are frequently mistaken for lumbar disc disease, back strain, and various orthopedic diseases. A few describe burning in the fingers and toes and if this appears as an early symptom, it may become a persistent management problem. Sensory loss occurs to a variable degree during the first days and may be barely detectable. By the end of a week, vibration and joint position sense in the toes and fingers are usually reduced; when such loss is present, deep sensibility (touch-pressure-vibration) tends to be more affected than superficial (pain-temperature). At an early stage, the arm muscles may be less weak than the leg muscles, and in a few cases, they are spared almost entirely. Facial diplegia occurs in more than half of cases, sometimes bilaterally at the same time, or sequentially over days. Other cranial nerve palsies, if they occur, usually come later, after the arms and face are affected; infrequently they are the initial signs in a variant pattern of disease as described below. Disturbances of autonomic function (sinus tachycardia and less often bradycardia, facial flushing, fluctuating hypertension and hypotension, loss of sweating, or episodic profuse diaphoresis) are common in minor form, and only infrequently do these abnormalities become pronounced or persist for more than a week. Urinary retention occurs in about 15 percent of patients soon after the onset of weakness, but catheterization is seldom required for more than a few days. There are in addition numerous medical complications secondary to immobilization and respiratory failure, as discussed further on, under "Treatment. Whereas in most patients the paralysis ascends from legs to trunk, arms, and cranial muscles and reaches a peak of severity within 10 to 14 days, occasionally the pharyngeal-cervical-brachial muscles are affected first or constitute the entire illness, creating difficulty in swallowing as well as neck and proximal arm weakness (Ropper, 1986). The differential diagnosis then includes myasthenia gravis, diphtheria, and botulism and a lesion affecting the central portion of the cervical spinal cord and lower brainstem. The ophthalmoplegic pattern raises the possibility of myasthenia gravis, botulism, diphtheria, tick paralysis, and basilar artery occlusion. Bilateral but asymmetrical facial and abducens weakness, coupled with distal paresthesias or with proximal leg weakness, are other fairly common variants in our experience (Ropper, 1994). Paraparetic, ataxic, and purely motor or purely sensory forms of the illness have also been observed. Less difficulty attends these diagnoses if paresthesias in the acral extremities, progressive reduction or loss of reflexes, and relative symmetry of weakness appear after several days of signs. There has been a recent tendency to separate a group of cases with presumed diffuse axonal damage on the basis of an abrupt and explosive onset, severe paralysis, minor sensory features, and the electrophysiologic finding of inexcitability of nerves. In a few patients the weakness continues to evolve for 3 to 4 weeks or even longer. In their initial report they described five patients, all with a rapid evolution of polyneuropathy and very slow and poor recovery. Others, however, have questioned the specificity of this finding since the inability to excite motor nerves may also signify a distal demyelinating block, from which complete recovery is possible (Triggs et al). Postmortem examinations in these cases have disclosed severe axonal degeneration in nerves and roots, with minimal inflammatory changes and little demyelination, even early in the disease. Based on prominent deposits of complement and the presence of macrophages in the periaxonal space, a humoral antibody directed against some component of the axolemma has been postulated by Griffin and associates. Visser and colleagues reported similar findings in a series of acute motor polyneuropathies from Holland. The outbreaks of motor neuropathy that occur seasonally in rural China have many of the same characteristics. A chronic form of this illness, termed multifocal motor neuropathy, is more common and better understood (see further on). It should be reemphasized that the presence of electrically inexcitable nerves alone may be due to conduction block and give a misleading impression of axonal damage; the prognosis for cases with conduction block may be quite good. The differential diagnosis includes critical illness polyneuropathy and the rarer entities of porphyric neuropathy and tick paralysis. Usually, the protein content is normal during the first few days of symptoms, but then it begins to rise, reaching a peak in 4 to 6 weeks and persisting at a variably elevated level for many weeks. The most frequent early electrodiagnostic findings are a reduction in the amplitude of muscle action potentials, slowed conduction velocity, and conduction block in motor nerves singly or in combination (see Chap. Prolonged distal latencies (reflecting distal conduction block) and prolonged or absent F-responses (indicating involvement of proximal parts of nerves and roots) are other important diagnostic findings, all reflecting focal demyelination. The H-reflex is almost always very delayed, or more often absent, but this does little more than confirm the loss of ankle reflexes. Although a limited electrodiagnostic examination may be normal early in the illness, a more thorough study, which includes measurement of late responses, almost invariably shows disordered conduction in an affected limb within days of the first symptom. T-wave and other electrocardiographic changes of minor degree are reported frequently but are evanescent. Hyponatremia occurs in a proportion of cases after the first week, especially in ventilated patients. Sparse focal infiltrates of inflammatory cells (lymphocytes and other mononuclear cells) may also be found in lymph nodes, liver, spleen, heart, and other organs. Swelling of nerve roots at the site of their dural exit has been emphasized by some authors and theorized to cause root damage. Variations of this pattern of peripheral nerve damage have been observed, each perhaps representing a different immunopathology. Rarely, in a clinically typical case, there may be widespread demyelinative changes and only a paucity of perivascular lymphocytes. In patients whose electrophysiologic tests display severe axonal damage early in the illness as discussed later, the pathologic findings corroborate the predominantly axonal nature of the disease with secondary myelin damage and little inflammatory response. An occasional case has shown an inflammatory process with primary axonal damage rather than demyelination (Honovar et al). Pathogenesis and Etiology Most of the evidence supports a cell-mediated immunologic reaction directed at peripheral nerve. Brostoff and colleagues suggested that the antigen in this reaction is a basic protein, designated P2, found only in peripheral nerve myelin. Subsequent investigations by these authors indicated that the neuritogenic factor might be a specific peptide in the P2 protein.
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