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Cavernous sinus thrombosis may be unilateral, but the good collateralization between the cavernous sinuses usually leads to bilateral symptoms, while extension of the thrombosis into the large sinuses is the exception. Most cases of cavernous sinus thrombosis are due to ascending infection from the orbita, the paranasal sinuses or other structures of the viscerocranium and are accompanied by signs of local or systemic infection. Epileptic seizures, focal neurological signs, impairment of the level of consciousness and psychotic symptoms can occur. Septic thrombosis of other sinuses is found as a complication of bacterial infection. Aseptic thrombosis of the cavernous sinus leading to painful uni- or bilateral ophthalmoplegia has to be differentiated from the Tolosa-Hunt syndrome. Unenhanced cranial computed tomography scan showing an atypical right temporal hemorrhagic venous infarction in a patient with isolated cortical venous thrombosis. Chapter 11: Cerebral venous thrombosis intravenous application of iodinated contrast media, the dura mater of the sinuses will show a distinct enhancement, and the non-enhancing intravenous thrombus may be discriminated as a triangle ("empty triangle" or "Delta-sign", in analogy to the design of the Greek capital letter Delta [D]). Magnetic resonance imaging (T1-weighted images after intravenous injection of paramagnetic contrast media) in a patient with thrombosis of the superior sagittal, straight and right transverse sinus. During the second week after clot formation, red blood cells are destroyed, and deoxyhemoglobin is metabolized into methemoglobin, and the thrombus yields a hyperintense signal on both T1- and T2-weighted images. After 2 weeks, the thrombus becomes hypointense on T1- and hyperintense on T2-weighted images, and recanalization may occur with the re-appearance of flow void signaling. They allow direct imaging of the thrombus; the signal intensity depends on clot age. Acute thrombosis may be suspected if the D-dimers, a fibrinogen degradation product, are found to be elevated. Digital subtraction angiography in a patient with isolated thrombosis of the right inferior anastomotic vein of Labbe (right), in contrast to physiological imaging of the cerebral vein findings of the contralateral hemisphere (left). Thrombophilia screening should be performed especially in patients with recurrent thromboembolic events. Impaired consciousness and cerebral hemorrhage on admission are associated with a poor outcome. The treatment priority in the acute phase is to stabilize the patient and to prevent herniation, followed by the initiation of anticoagulant treatment and the treatment of underlying causes, especially bacterial infections. Acute management: stabilization of the patient prevention of herniation initiation of anticoagulant treatment treatment of underlying causes, especially bacterial infections. The first study was terminated after inclusion of 10 patients in each group, as an interim analysis documented a beneficial effect of heparin treatment on morbidity and mortality. Both studies were criticized for inadequately small sample size [8] or baseline imbalance favoring the placebo group [6]. Patients with intracranial hemorrhage were included in both studies, and no new symptomatic cerebral hemorrhage occurred in either treatment group. Immediate anticoagulation is recommended, even in the presence of hemorrhagic venous infarcts. There are insufficient data to determine the optimal duration of oral anticoagulation with vitamin K antagonists. If no underlying disease is identified that justifies the continuation of oral anticoagulation, treatment with vitamin K antagonists should be stopped and antiplatelets. Regular follow-up visits should be performed after termination of anticoagulation and patients should be informed about early signs and symptoms. In addition, treatment and assessment were non-blind, leading to a possible bias in outcome assessment [14]. If patients deteriorate despite adequate anticoagulation and other causes of deterioration have been ruled out, thrombolysis may be a therapeutic option in selected cases, possibly in those without hemorrhagic infarction or intracranial hemorrhage. Severe headache may require treatment with opioids, but dose titration should be performed cautiously in order to avoid over-sedation. Concomitant nausea requires parenteral antiemetic treatment with metoclopramide, minor neuroleptics. If sedation of agitated patients is required, firstchoice drugs are major neuroleptics. Thrombolysis Despite immediate anticoagulation, some patients show a distinct deterioration of their clinical condition, and this risk seems to be especially high in patients presenting with focal neurological signs and reduction of the level of consciousness. For the same reason, effective drug plasma levels should be achieved as soon as possible. A hemorrhagic lesion in the acute brain scan was the strongest predictor of post-acute seizures [22]. Late seizures are more common in patients with early symptomatic seizures than in those patients with none. Epileptic seizures should be treated with parenterally administered antiepileptic drugs (phenytoin, valproic acid, levetiracetam). This intervention is usually followed by a rapid improvement of headache and visual function. Although controlled data are lacking, acetazolamide should be considered in patients not responding to lumbar puncture. In the case of severe brain swelling, anti-edema treatment should follow the general rules for the treatment of raised intracranial pressure, i. Osmodiuretics may thus reduce venous drainage and should therefore be used with caution only. Volume restriction should be avoided, as dehydration may further increase blood viscosity. Steroids cannot be generally recommended for treatment of elevated intracranial pressure, since their efficacy is unproven and their administration may be harmful, as steroids may promote the thrombotic process [1, 23]. In single patients with impending herniation due to unilateral hemispheric lesion, decompressive hemicraniectomy can be life-saving and even allow a good functional recovery, but evidence is anecdotal [24]. Increased intracranial pressure in most cases responds to improved venous drainage after anticoagulation. Until the results of microbiological cultures are available, third-generation cephalosporins. The main causes of acute death are transtentorial herniation secondary to a large hemorrhagic lesion, multiple brain lesions or diffuse brain edema. Other causes of acute death include status epilepticus, medical complications and pulmonary embolism. Deterioration after admission occurs in about 23% of patients, with worsening of mental status, headache or focal deficits, or with new symptoms such as seizures. Fatalities after the acute phase are predominantly associated with the underlying disorder. Antithrombotic prophylaxis during pregnancy is probably unnecessary, unless a prothrombotic disorder has been diagnosed. However, women on vitamin K antagonists should be advised not to become pregnant because of the teratogenic effects of these drugs [14]. The vast majority of neonates present with an acute illness at the time of diagnosis, most often dehydration, cardiac defects, sepsis or meningitis. Leading clinical symptoms are epileptic seizures in two-thirds and respiratory distress or apnea in one-third of the neonates. A significant number of children are left with a considerable impairment (motor or cognitive deficits, epilepsy). Treatment is mostly symptomatic and comprises rehydration, antibiotics in the case of sepsis, and antiepileptic therapy. Treatment of epileptic seizures with parenterally administered antiepileptic drugs (phenytoin, valproic acid, levetiracetam). In general, these patients presented with clinical symptoms and signs different from those in younger patients: isolated intracranial hypertension was uncommon, whereas disturbances of mental status, alertness and the level of consciousness were common.

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Drugs in which the functional groups are appended to an aromatic ring have marked conformational rigidity. In the realm of neurologic drug design, the use of tricyclic structures containing aromatic rings is extremely common in major antipsychotics. Although they are superb for achieving planarity and rigidity, polyaromatic systems may come accompanied with the risk of a side-effect-carcinogenicity. Owing to the enormously more complex nature of macromolecular structure, less is known about such changes. Many examples of conformational changes of enzymes during their reactions with substrates have been well studied and described in the literature, including those of carboxypeptidase, dihydrofolate reductase, and acetylcholinesterase (see section 7. At times, a large, bulky substituent appended to a fragment within a drug molecule may physically impede the geometry of interaction between a drug and its receptor. Another classical measure of the molecular geometry of substituents is the Verloop steric parameter. This is calculated from bond angles and atomic dimensions-primarily the lengths of substituent groups and several measures of their width. Trivial as this may sound, the consideration of molecular "bulk" is an important and often neglected factor in making multiple quantitative correlations of structure and pharmacological activity. This means that there is a difference in action between stereoisomers of the same compound, with one isomer showing pharmacological activity while the other is more or less inactive. In 1860, Louis Pasteur was the first to demonstrate that molds and yeasts can differentiate between (+)- and (-)-tartarates, utilizing only one of the two isomers. Therefore, complementarity between an asymmetric drug and its asymmetric receptor is often a criterion of drug activity. The effects of highly active or highly specific drugs depend more upon such complementarity than do those of weakly active drugs. Occasionally, the stereoselectivity of a drug is based on a specific and preferential metabolism of one isomer over the other, or on a biotransformation that selectively removes one isomer. Since this hydroxylated metabolite is pharmacologically active, the stereochemical circumstances of the activation process are crucial, not only for the extent of the activation but also for the rate of elimination of the metabolite. The basic aspects of optical isomerism are discussed in various textbooks of organic chemistry. Optical isomers (enantiomers) may have different physiological activities from each other provided that their interaction with a receptor or some other effector structure involves the asymmetric carbon atom of the enantiomeric molecule and that the three different substituents on this carbon atom interact with the receptor. Qualitatively, dextrorphan is not an analgesic at all, but a very effective antitussive (cough suppressant), an action entirely different from analgesia. It should be emphasized that the mere sign (+ or -) of the optical rotation produced by an enantiomer is not biochemically decisive to the action of such a molecule. Stereoisomerism may also occur around double bonds, producing cis or trans orientations of the substituents on either face of the double bond. Even though enantiomeric drug pairs quite often show different potencies, they are seldom antagonists of each other, since the differences in their action are due to differences in their binding properties; antagonists (see section 2. Diastereomeric drugs-those having two or more asymmetric centers-are usually active in only one configuration. Unlike enantiomers, which have identical physicochemical properties, the absorption, distribution, receptor binding, metabolism, and every other aspect that influences the pharmacological activity of a drug are different for each diastereomer. Because of widespread misconceptions, the distomer of a racemate is often considered "inactive" and of no consequence to pharmacological activity, an idea reinforced by the fact that resolution (i. The distomer should therefore be viewed as an impurity constituting 50% of the total amount of a drug-an impurity that in the majority of cases is by no means "inert. However, there are instances in which the use of a racemate has advantages; sometimes it is more potent than either of the enantiomers used separately. However, now that we are in the 21st century, the need for optically active drugs capable of stereospecific interactions with drug receptors is a recognized prerequisite in drug design. These isomers are not mirror images and have very different physicochemical properties, as reflected in their pharmacological activity. Because the functional groups in these molecules are separated by different distances in the different isomers, they cannot as a rule bind to the same receptor. Therefore, geometric isomerism as such may be of interest to the medicinal chemist. In biological systems, there are a number of examples of the importance of cis/trans isomerization. Rod cells and cone cells are the two types of light-sensitive receptor cells in the human retina. The three million rod cells enable vision in dim light; the 100 million cone cells permit colour perception and vision in bright light. However, after the priority of substituents on each carbon atom is determined (using the sequence rules), the configuration in which the two substituents of higher priority lie on the same side is called the Z isomer (for zusammen, meaning "together" in German). The configuration in which these substituents lie on opposite sides is designated as the E isomer (for entgegen, which means "opposite"). The chemical structure of a drug molecule, its chemical reactivity, and its ability to interact with receptors ultimately depend on its electronic structure-the arrangement, nature, and interaction of electrons in the molecule. In general, the effect of electron distribution in organic compounds can be direct (short range) or indirect (long range). Direct electronic effects primarily concern covalent bonding, which involves the overlap of electron orbitals. The "strength" of covalent bonds, the interatomic distances spanned by these bonds, and dissociation constants are all direct consequences of the nature of covalent electrons. The nonbonding electron pairs of such heteroatoms as O, N, S, and P also play an important role in drug characteristics. They are the basis of such noncovalent interactions as hydrogen bonding (which, as already discussed, has a profound effect on the hydrophilic or lipophilic characteristics of a molecule), chargetransfer complex formation, and ionic bond formation. Indirect electronic effects occur over a longer range than direct effects, requiring no orbital overlap. Such inductive forces as van der Waals bonds and dipole moments are the results of polarization or polarizability-the permanent or induced distortion of the electron distribution within a molecule. Hammet correlations were among the first to be used and represent the classical way of quantifying electronic properties. The Hammet correlations (Hammet, 1970) express quantitatively the relationship between chemical reactivity and the electron-donating or electron-accepting nature of a substituent. The value of also varies according to whether the substituent is in the meta or para position. Ortho substituents are subject to too many interferences and are not used in calculating. Detailed tables of values can be found in the works of Chu (1980) and Albert (1985). In the case of benzoic acids, direct conjugation is not possible, but in one resonance hybrid, as shown in figure 1. The electron-donating phenolic hydroxyl group, on the other hand, destabilizes the carboxylate anion by charge repulsion, making the substituted acid weaker. The pKa of a drug is important to its pharmacological activity since it influences both the absorption and the passage of the drug through cell membranes.

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Initially, the disease most often involves the muscles of the eye and the pharynx, and the symptoms can be relieved with rest. In the progressive form of the disease, the weakness becomes steadily worse, and ultimately death occurs. The condition is an autoimmune disorder in which antibodies are the condition is an autoimmune disorder in which antibodies are produced against the nicotinic acetylcholine receptors on the postsynaptic membrane. The size of the junctional folds is also reduced, and the width of the synaptic cleft is increased. The condition can be temporarily relieved by anticholinesterase drugs such as neostigmine, which potentiates the action of acetylcholine. In adults with myasthenia gravis, about 70% show evidence of hyperplasia of their thymus glands. It is in the thymus that T cells, which mediate immune protection, undergo maturation. Excessive synthesis of thymic hormones that stimulate the development of T cells may contribute to the autoimmune response. A rare congenital form of myasthenia gravis may exist from birth, and in this form, there is no abnormal antibody present. Hypokalemic Periodic Paralysis and Hyperkalemic Paralysis Hypokalemic periodic paralysis and hyperkalemic paralysis are diseases due to decreased or increased blood potassium levels. It is known that the ability of acetylcholine to initiate electrical changes in the postsynaptic membrane of the neuromuscular junction can be greatly influenced by the level of blood potassium, and it is this blood change that is responsible for the paralysis in these patients. Action of Drugs on Neuromuscular Junctions in Smooth Muscle, Cardiac Muscle, and Nerve Endings on Secretory Cells It has been stated that in normal body physiology, acetylcholine released from postganglionic parasympathetic fibers can bring about depolarization and resulting contraction of smooth muscle fibers. Acetylcholine, however, is a useless drug to be administered by the physician, because it is rapidly destroyed by the cholinesterases. By slightly changing the structure, as in the case of methacholine chloride or carbachol, the drugs are less susceptible to destruction by the cholinesterases but still possess the ability to react with the receptors. Atropine and scopolamine are drugs that compete with acetylcholine for the same receptors. These drugs are competitive antagonists of acetylcholine at receptor sites of smooth muscle, cardiac muscle, and various secretory cells. Norepinephrine is released from postganglionic sympathetic fibers and can bring about depolarization of smooth muscle in the walls of arteries, for example, resulting in their contraction. The functions associated with alpha receptors are vasoconstriction, mydriasis (dilatation of the pupil), and relaxation of the smooth muscle of the intestine. Beta receptors are associated with vasodilatation, cardioacceleration, bronchial relaxation, and intestinal relaxation. Phenoxybenzamine has been found to block alpha receptors, while propranolol blocks beta receptors. Abnormalities in Sensory Perception Abnormalities in sensory perception should be looked for on the face, trunk, and limbs. Areas of diminished pain sensation (hypalgesia) or touch sensation (hypesthesia) or heightened sensation (hyperesthesia) should be identified. Abnormal sensations (paresthesia), such as pins and needles, may be experienced by a patient who has a lesion located anywhere along the sensory pathway from the peripheral nerve to the cerebral cortex. The areas of sensory abnormality should be precisely defined and recorded, with each modality being recorded separately. Some individuals try to assist the examiner by wrongfully anticipating the correct response. Other patients find it difficult to understand exactly what information is required of them. The physician must always be aware of the possibility of hysteria, which is when a patient complains of sensory loss that has no neuroanatomical explanation. For example, a total loss of skin sensation on one side of the face, including the angle of the jaw, would infer that the patient has a lesion involving the fifth cranial nerve in the pons and the greater auricular nerve (C2-3), which is anatomically very unlikely. Patience and objectivity are required, and if doubt exists as to the accuracy of the assessment, the patient should be reexamined on another occasion. Segmental Innervation of the Skin Because large nerve plexuses are present at the roots of the upper and lower limbs, it follows that a single spinal nerve may send both motor and sensory fibers to several peripheral nerves, and conversely, a single peripheral nerve may receive nerve fibers from many spinal nerves. Moreover, it follows that a lesion of a segment of the spinal cord, or posterior root, or spinal nerve will result in a sensory loss that is different from that occurring after a lesion of a peripheral nerve. The area of skin supplied by a single spinal nerve and, therefore, a single segment of the spinal cord is called a dermatome. A physician should remember that dermatomes overlap and that in the trunk, at least three contiguous spinal nerves have to be sectioned to produce a region of complete anesthesia. A physician should remember also that the degree of overlap for painful and thermal sensations is much greater than that for tactile sensation. A physician should have a working knowledge of the segmental (dermatomal) innervation of skin, since with the help of a pin or a piece of cotton, he or she can determine whether the sensory function of a particular spinal nerve or segment of the spinal cord is normal. When examining the dermatomal charts, one should note that because of the development of the upper limbs, the anterior rami of the lower cervical and first thoracic spinal nerves have lost their cutaneous innervation of the trunk anteriorly, and at the level of the second costal cartilage, the fourth cervical dermatome is contiguous with the second thoracic dermatome. In the sensory innervation of the head, the trigeminal (fifth cranial) nerve supplies a large area of the face and scalp, and its cutaneous area is contiguous with that of the second cervical segment. Since the dermatomes run longitudinally along the long axis of the upper limbs, sensation should be tested by dragging a wisp of cotton or a pin along the long axis of the medial and lateral borders of the limbs. On the trunk, the dermatomes run almost horizontally, so the stimulus should be applied by moving in a vertical direction. Segmental Innervation of the Muscles It is important to remember that most skeletal muscles are innervated by more than one spinal nerve and, therefore, by the same number of segments of the spinal cord. Complete destruction of one segment of the spinal cord as the result of trauma or pressure from a tumor will cause weakness of all the muscles that are innervated from that segment. To paralyze a muscle completely, several adjacent segments of the spinal cord have to be destroyed. Because of the presence of the cervical, brachial, and lumbosacral plexuses, the axons of motor anterior gray column cells are redistributed into a number of peripheral nerves. A physician, knowing this, is able to distinguish between a lesion of a segment of the spinal cord, an anterior root, or a spinal nerve on the one hand and a lesion of a peripheral nerve on the other hand. The segmental innervation of the biceps brachii, triceps, brachioradialis, muscles of the anterior abdominal wall, quadriceps femoris, gastrocnemius, and soleus should be memorized, as it is possible to test them easily by eliciting their reflex contraction (see p. Muscle Tone Skeletal muscle tone is due to the presence of a few muscle fibers within a muscle being in a state of full contraction all the time. Muscle tone is controlled reflexly from afferent nerve endings situated in the muscle itself. It follows, therefore, that any disease process that interferes with any part of the reflex arc will abolish the muscle tone. Some examples are syphilitic infection of the posterior root (tabes dorsalis); destruction of the motor anterior gray column cells, as in poliomyelitis or syringomyelia; destruction of a segment of the spinal cord by trauma or pressure from a tumor; section of an anterior root; pressure on a spinal nerve by a prolapsed intervertebral disc; and section of a peripheral nerve, as in a stab wound. Although it has been emphasized that the basic mechanism underlying muscle tone is the integrity of the spinal segmental reflex, it must not be forgotten that this reflex activity is influenced by nervous impulses received by the anterior horn cells from all levels of the brain and spinal cord. Spinal shock, which follows injury to the spinal cord and is caused by loss of functional activity of neurons, will result in diminished muscle tone. Cerebellar disease also results in diminished muscle tone because the cerebellum facilitates the stretch reflex. The reticular formation normally tends to increase muscle tone, but its activity is inhibited by higher cerebral centers. Therefore, it follows that if the higher cerebral control is interfered with by trauma or disease, the inhibition is lost and the muscle tone is exaggerated (decerebrate rigidity). It must not be forgotten that primary degeneration of the muscles themselves (myopathies) can cause loss of muscle tone. Posture the posture of an individual depends on the degree and distribution of muscle tone and, therefore, on the activity of the motor neurons that supply the muscles. The motor neurons in the anterior gray columns of the spinal cord are the points on which converge the nervous impulses from many posterior nerve roots and the descending fibers from many different levels of the brain and spinal cord. The successful coordination of all these nervous influences results in a normal posture. When one is in the standing posture, there is remarkably little muscular activity taking place in the muscles of the limbs and trunk.

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These matters are considered below, much deriving from accounts by Denison (1996) and Wilmshurst (1997). A 26-year-old man was rendered unconscious for several hours after sustaining a shock from bare wires which had made contact with his forehead. On recovery he had throbbing headache, was sluggish in cerebration, and complained of feeling depressed and irritable for several weeks thereafter. Two months later he was still vague and forgetful with delayed responses to questions. Five months after the accident he showed significant impairment of memory, lability of mood and psychomotor retardation. His girlfriend described a marked change of personality, with argumentativeness and occasional aggressive behaviour. He had lost his ability to speak German, which he had learned during the previous 3 years. Two years later his memory remained impaired and he was still mentally sluggish and rather vacuous in appearance. His mother confirmed a marked change of personality from a bright extroverted person to one who was slow, sullen and withdrawn. Though no longer depressed he was distractible, and had abandoned his reading and former hobbies. Gas toxicity the gases breathed during submersion must be delivered at the same pressure as the surrounding water. The breathing of pure oxygen does not solve the problem, because oxygen is toxic to the lungs when alveolar pressure exceeds 50 kPa (0. Deeper dives are accomplished using a mix of oxygen and helium and this has allowed divers to reach astonishing depths (below 600 m). However, deeper than 160 m the risk of high-pressure nervous syndrome increases considerably, resulting in tremor, myoclonic jerks, nausea, vomiting, fatigue, postural instability, somnolence and cognitive dysfunction and other symptoms (Bennett & McLeod 1984). In the course of the ascent such gases come out of solution as the ambient pressure falls, tending to form bubbles within the tissues and the blood (gas nucleation). Provided the ascent is sufficiently gradual the extra load of gas diffuses into the bloodstream and out of the lungs, but if it is too rapid the bubbles increase in size and number and may come to block blood vessels. Pulmonary symptoms consist of sudden chest pain, dyspnoea and cough due to bubble formation within the pulmonary circulation. Neurological symptoms, which occur in about half of cases, consist chiefly of spinal cord syndromes, visual disturbances or vertigo, although central focal deficits may occur. The range of severity is wide, from slight dysaesthesiae, ataxia and ophthalmoplegia to paraparesis, quadriparesis, dysphasia and confusion. The episodes are sometimes recurrent, in general resembling thromboembolic cerebrovascular disease except for commonly affecting the cord. The symptoms usually develop some minutes to hours after the dive is over, and must be treated immediately by recompression and the administration of oxygen. In an examination of the spinal cords of 11 divers, mostly dying from diving accidents, they found distended empty blood vessels, sometimes with perivascular haemorrhages, and minor chronic changes with foci of gliosis and hyalinisation of blood vessels. In three cases Marchi staining showed tract degeneration, variously affecting the posterior, lateral or anterior columns of the cord. Examination of the brains of 25 divers, again mostly dying from diving accidents, showed distended empty vessels in two-thirds of subjects, presumably caused by gas bubbles (Palmer et al. Perivascular lacunae were present in one-third, presumably due to bubble occlusion, along with hyalinisation of blood vessels which may have accrued from periodic rises in luminal pressure. Foci of necrosis were sometimes observed in the cerebral grey matter, and vacuolation in the white matter extending to status spongiosis. Sequelae of diving A well-known long-term effect of diving is the presence of aseptic infarcts in the long bones, evident on radiography and presumably due to gas embolism. Infarcts near the articular surfaces can be severely disabling, and crippling dysbaric osteonecrosis may occasionally ensue. At the time of examination 20% had stopped diving and six had lost their licenses because of neurological problems; 12 (8%) had had problems with vision, vertigo or reduced skin sensitivity in non-diving situations, and six had been referred to neurological clinics on account of seizures, transient cerebral ischaemia or transient amnesia attacks. On examination significantly more showed hand tremor, or signs indicative of cord damage such as reduced touch and pain sensation in the feet. In a study of construction divers matched to controls, the divers had significantly different error rates in tasks of reference memory and navigation behaviours (Leplow et al. Shallow water diving is a variant used professionally for collection of shellfish and recreationally, where instead of using scuba equipment the divers hold their breath. In a large study of professional abalone divers the incidence of deficits in visual function, psychomotor abilities and recent memory was related to individual characteristics in the divers and attributed to their diving technique (Williamson et al. Nevertheless, the possibility arises that divers with right-to-left shunts may be at particular risk of accumulating microinfarcts in the brain. The great majority of such shunts are likely to reflect a patent foramen ovale, which may well become functional only under the abnormal pressure conditions of diving. Others could be due to small atrial septal defects or pulmonary arteriovenous shunts. The radiological picture is of thickening of the inner tables of the frontal bones, with smooth rounded exostoses projecting into the cranial cavity. Part of the problem in discerning any putative clinical associations lies with the frequency of the condition and with the occurrence of minor variations. It may be found at any age from adolescence upwards, increasing markedly from the third or fourth decades onwards. While the pattern of inheritance is not understood, it does occur in families and identical twin-pairs have been reported (Koller et al. As the bone abnormalities are so easily identified in skeletal remains, the condition has frequently been diagnosed in ancient populations, medieval and prehistoric (Hershkovitz et al. In most reviews the main features have been headache, obesity, hirsutism and menstrual disorders (Capraro et al. Thirst, water retention, sleep disturbances and a variety of rather minor endocrine changes are also described. Among mental features neurotic complaints figure prominently, also disturbances of personality, memory impairment and occasionally dementia. Agenesis of the corpus callosum Absence of the corpus callosum, in whole or in part, occurs as a developmental abnormality, perhaps in as many as 1 in 4000 births (Paul et al. In complete agenesis other associated defects may be present: hydrocephalus, microgyria, heterotopias, arachnoid cysts, spina bifida or meningomyelocele. The anterior and hippocampal commissures may be intact even when the corpus callosum is entirely missing. Most cases have been reported in children, although the condition can come to light at any age. It usually presents by virtue of symptoms attributable to other cerebral malformations: seizures, mental retardation or hydrocephalus. There are some indications that it may be commoner than chance expectation in patients with organic psychosyndromes. Other Disorders of the Nervous System 893 the course of neuroradiological investigations carried out for some other purpose. The discovery of asymptomatic cases is likely to increase now that brain imaging is so frequently performed. It appears sometimes to be the result of intrauterine metabolic disturbances such as hyperglycinaemia, or intrauterine exposure to infections and toxins. Epilepsy, spasticity and other motor defects are common, likewise varying grades of mental subnormality especially in cases of partial agenesis and when associated with other conditions. However, when patients with other malformations are excluded, intelligence is usually in the normal range.

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In contrast, invasive malignancies are characterized by infiltration of the stroma, which may produce 420 Pathology a desmoplastic response within the stroma (schirrous carcinoma). Infiltrating ductal carcinomas also produce yellow-white chalky streaks that result from the deposition of elastic tissue around ducts (elastosis). Other patterns of invasion that produce specific results include infiltration of cells in a single file in infiltrating lobular carcinoma, and mucin production in colloid carcinoma. Lobular carcinoma in situ is characterized histologically by proliferation of cells of the terminal duct lobular unit, which fills and expands the lobules. Unlike the case with intraductal carcinoma, papillary and cribriform structures are not formed and neither is central necrosis present. Invasive lobular carcinoma is distinguished by its tendency to infiltrate the stroma in a single file. This pattern is not seen with invasive ductal carcinoma, which tends to cause a marked desmoplastic response, causing a schirrous carcinoma. The term does not refer to the presence of inflammatory cells, abscess, or any special histologic type of breast carcinoma; rather, it refers to more of a clinical phenomenon, in that the breast is swollen, erythematous, and indurated and demonstrates a marked increase in warmth. These changes are caused by widespread lymphatic and vascular permeation within the breast itself and in the deep dermis of the overlying skin by breast carcinoma cells. The clinical induration and erythema are presumably related to lymphatic-vascular blockage by tumor cells; if present, these findings mean a worse prognosis. Eczematous dermatitis of the nipples is a major differential diagnosis, but is usually bilateral and responds rapidly to topical steroids. Mammary fibromatosis is a rare, benign spindle cell lesion affecting women in the third decade. It should be treated by local excision with wide margins since there is risk of local recurrence. A 42-year-old man presents because recently he has had to change his shoe size from 9 to 101/2. She delivered her first child several months ago and has been breast-feeding since then. She also says that lately she has been tired and has been "feeling cold" all of the time. What is the classic visual disturbance produced early by a large pituitary adenoma (>1 cm) that compresses the central portion of the optic chiasm? Bitemporal hemianopsia Homonymous hemianopsia Homonymous inferior field defect Homonymous superior field defect Mononuclear anopsia 403. Which one of the listed individuals is most likely to have a prolactinsecreting tumor of the anterior pituitary? A 25-year-old female with amenorrhea, galactorrhea, and a negative pregnancy test b. A 45-year-old female with coarse facial features, large hands and feet, and headaches d. A 54-year-old male with central obesity, purple abdominal stria, and mental changes 404. A 49-year-old man who smokes two packs of cigarettes a day presents with a lung mass on x-ray and recent weight gain. Serum Sodium Hypernatremia Hypernatremia Hyponatremia Hyponatremia Normal Urine Low osmolarity and low specific gravity High osmolarity and high specific gravity Low osmolarity and low specific gravity High osmolarity and high specific gravity Normal osmolarity and normal specific gravity 406. A lesion that originates within and selectively destroys the ventromedial nucleus of the hypothalamus would most likely result in a. Decreased appetite Increased appetite Increased urination Paralysis of the extraocular muscles Tunnel vision 407. Physical examination reveals a small infant with dry, rough skin; a protuberant abdomen; periorbital edema; a flattened, broad nose; and a large, protuberant tongue. A perimenopausal woman presents with increasing swallowing difficulty and fatigue. No thyroidstimulating immunoglobulins are identified in the serum, but antimicrosomal antibodies are present. Intense lymphoplasmacytic infiltrate with lymphoid follicles and scattered oxyphilic cells c. Hyperplasia of follicular cells with scalloping of colloid at the margin of follicles d. Granulomatous inflammation with multinucleated giant cells surrounding fragments of colloid. Central obesity, "moon" face, and abdominal striae Hyperthyroidism, exophthalmus, and pretibial myxedema Polyuria, polydipsia, and hyponatremia Polyuria, polydipsia, and polyphagia Progressive lethargy, cold intolerance, and myxedema Endocrine System 427 411. Histologic sections of a follicular carcinoma of the thyroid would characteristically reveal a. Diagnostic nuclear changes including "Orphan Annie eyes," nuclear grooves, and intranuclear inclusions d. Histologic examination of the mass in this 37year-old male reveals organoid nests of tumor cells separated by broad bands of stroma, as seen in the photomicrograph below. The stroma stains positively with Congo red stain and demonstrates yellow-green birefringence. Follicular carcinoma Papillary carcinoma Squamous cell carcinoma Medullary carcinoma Anaplastic carcinoma Endocrine System 429 414. Which one of the listed signs or symptoms is more characteristic of hypocalcemia than of hypercalcemia? Calcium stones in the urine Metastatic calcification Peptic ulcers Psychiatric changes Tetany 415. A 52-year-old female presents with nausea, fatigue, muscle weakness, and intermittent pain in her left flank. Laboratory examination reveals an increased serum calcium and a decreased serum phosphorus. Primary hyperparathyroidism Primary hypoparathyroidism Pseudohypoparathyroidism Secondary hyperparathyroidism Secondary hypoparathyroidism 416. A 65-year-old male presents with bone pain and is found to have hypocalcemia and increased parathyroid hormone. Surgical exploration of his neck finds all four of his parathyroid glands to be enlarged. Without any other information, which one of the following is most likely the cause of the enlargement of the parathyroid glands? Primary hyperplasia Parathyroid adenoma Chronic renal failure Parathyroid carcinoma Lung carcinoma 430 Pathology 417. A 65-year-old female presents with numbness and tingling of her hands, feet, and lips. Which one of the labeled boxes in the graph below best depicts the expected serum levels of calcium and parathyroid hormone in this individual? A 10-year-old female with mental retardation presents with cramping in her legs and numbness and tingling around her mouth. Physical examination reveals a short, obese young female who has several subcutaneous calcified masses. X-rays of her hands and feet reveal shortened fourth and fifth metacarpal and metatarsal bones. Physical examination reveals decreased blood pressure, while laboratory examination reveals a serum sodium level of 132 meq/L. Which box in the schematic below represents the most likely serum findings for an individual on long-term exogenous glucocorticoid administration? Which one of the following combinations of findings is most likely to be present in an individual with primary hyperaldosteronism? Serum Renin Decreased Decreased Increased Increased Increased Serum Aldosterone Increased Increased Decreased Increased Increased Serum Sodium Decreased Increased Decreased Decreased Increased Serum Potassium Increased Decreased Increased Increased Decreased 423. Physical examination reveals a slightly decreased blood pressure along with a diffuse increase in skin pigmentation. A benign adenoma of the adrenal cortex A malignant tumor of the adrenal medulla Autoimmune destruction of the adrenal cortex Bilateral hyperplasia of the adrenal cortex Tuberculosis of the adrenal medulla 424. A 35-year-old male who presents with a neck mass is found to have a serum calcium level of 11. Extensive workup reveals the presence of a medullary carcinoma of the thyroid, a pheochromocytoma, and hyperplasia of the parathyroid glands. A 34-year-old female presents with recurrent episodes of severe headaches, palpitations, tachycardia, and sweating.

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The need to know urgently for the protection of staff or other patients is likely to apply only in patients showing aggressive or seriously disinhibited behaviour. In essence the test should be carried out with awareness that the decision may have to be defended in court. However, if after full discussion the patient refuses, his request for privacy should normally be respected. The exception is when failure of disclosure could put the health of any carer at serious risk although this needs to be considered in the context of the legal framework of the jurisdiction of the test. This is particularly so when the patient is incapacitated and cannot give consent. A careful multidisciplinary discussion and consultation with both an occupational health consultant and legal advice should be sought when making complex testing decisions. Similarly, disclosure to a spouse or partner without consent is warranted only when there is a serious and identifiable risk to a specific individual who, if not informed, would be exposed to infection. Treatment General aspects General aspects of management include the need for support and counselling, not only for the infected person but often also for the family, partners and friends. Even in the asymptomatic stage it is important to allow full discussion of the disease and its significance, including the likelihood that there may be considerable delay before symptoms make an appearance. Prophylactic drug treatment is often undertaken to ward off opportunistic infections such as Pneumocystis carinii, 420 Chapter 7 tuberculosis and toxoplasmosis (Beiser 1997). Problems over employment and coping with negative reactions from associates will often need attention. Many patients will benefit from regular follow-up, when weight and blood counts can be checked routinely and enquiry made about general health and fitness. Referral to local self-help organisations will usually be of very considerable assistance. For this reason, low doses and slow titrations of antipsychotics are advised, with careful monitoring for metabolic syndrome (Repetto & Petitto 2008). Ritonavir has been shown to decrease plasma concentrations of olanzapine (Penzak et al. Carbamazepine and lamotrigine are both known to have effects on the enzyme systems also utilised by antiretrovirals, resulting in altered serum concentrations of both mood stabiliser and/or antiretroviral. Zidovudine has been shown to have a protective influence against mania (Mijch et al. Ferrando and Freyberg (2008) critically review the treatment of depression and identify the confounding factors in appraising the literature. Other antidepressants, including mirtazapine, have also shown promise in open label studies. When prescribing antidepressants it is always important to consider interactions with antiretrovirals. Protease inhibitors and nucleoside reverse transcriptase inhibitors can affect cytochrome P450 activity, resulting in altered metabolism of some antidepressant medications. Group psychological interventions have been more extensively investigated, both alone and in combination with antidepressants, and have suggested an effect of psychotherapies alone, at least in mild to moderate depressive episodes (Targ et al. The differential diagnosis is often wide, infections can be multiple and investigations may need to be extensive. Oral candidiasis may be kept in check with nystatin suspension or amphotericin lozenges; oesophageal and severe oral infection will require ketoconazole. Details of treatment for these and other systemic infections are given in textbooks of medicine. Toxoplasma brain infection will often respond, both clinically and radiologically, to pyrimethamine and sulfadiazine, occasionally with complete resolution of symptoms and control of the disease. Cryptococcal infection is usually treated with amphotericin, with or without 5-flucytosine, followed by maintenance therapy with fluconazole (Manji & Connolly 1992). Inflammatory neuropathies are sometimes considered best treated with plasmapheresis because of the risks of steroid therapy in the immunocompromised patient. Others, however, use steroids on the basis that autoimmune mechanisms are at work. A full review of their mechanisms of action and the evidence that supports their use can be found in Warnke et al. The most frequent adverse effect of zidovudine is bone marrow suppression, resulting in anaemia or neutropenia, which may dictate dose reduction or cessation of treatment. Other side effects include nausea, anorexia, abdominal pain, rashes, headache and insomnia, largely restricted to the early weeks of treatment. Stavudine has been shown to further ameliorate neurological symptoms in patients previously treated with zidovudine (Arendt et al. However, efavirenz has also been associated with a number of neuropsychiatric side effects including dizziness, agitation, hallucinations, amnesia, insomnia, nightmares and deterioration in existing psychiatric illness. Of interest to the psychiatrist, it has also been shown to produce false-positive results in testing for cannabinoids. Several new classes of antiretroviral have been, or are in the process of being, developed. Despite the mandatory surveillance of sexually transmitted diseases in many countries, very little detailed information is available regarding the epidemiology of neurosyphilis. Primary (infectious) syphilis had already shown a gradual decline from the time of the First World War onwards. A new peak arose during the Second World War but this subsided rapidly in the years that followed. However, it was feared that late manifestations would ultimately rise again, due to unwitting partial treatment in the early stages when penicillin was given for other conditions, but this did not occur. There has also been a pronounced shift away from parenchymatous neurosyphilis (general paresis and tabes dorsalis) towards meningovascular syphilis, which now accounts for most of the new cases encountered (Nieman 1991). By the early 1990s case numbers had stabilised and although both low incidence and prevalence were evident, syphilis had not been altogether eliminated. In 1997, there were reports of an outbreak of syphilis among heterosexuals in Bristol and a subsequent increase in incidence (Simms et al. Paradoxically, the success of treatment brings its own particular risks, since as the disease becomes increasingly rare it runs the hazard of being more often overlooked. The psychiatrist must continue to bear it in mind, to check regularly with serological tests and look carefully for cardinal signs in the pupillary reactions and tendon reflexes. Whether the existing nomenclature for classifying cases of neurosyphilis is adequate has been questioned by Timmermans and Carr (2004) in their discussion of a recently reported case series. They propose a clinically based, syndromic classification whereby cases would be identified by their associated clinical presentations, i. For practical purposes the clinical presentations of neurosyphilis can also be divided into early and late (Marra et al. Meningovascular syphilis can appear in the secondary or tertiary stages, and even with primary infections the nervous system is sometimes involved without overt signs of disorder. In more recent cohorts neuropsychiatric presentations have been identified as the most frequently reported cluster, with 50% of cases presenting symptoms such as psychosis, delirium or dementia (Timmermans & Carr 2004). The effects of syphilis on the spinal cord (myelitis, cervical pachymeningitis and syphilitic amyotrophy) are the province of neurology and are not dealt with here. Thus it appears that a meningeal reaction can set in very early in a surprising number of cases and without producing overt disorder. When adequate treatment is given the disturbance dies out within a year or two and proves to have been benign. In some cases the prognosis is favourable even when treatment has been inadequate (Hahn & Clark 1946b), though in others the changes probably have implications for the later development of quaternary neurosyphilis. Acute syphilitic meningitis In rare cases infection of the nervous system may be overwhelming, with the production of an acute meningitis. This usually develops within the first 2 years, and can even accompany the secondary rash within a month or two of the primary infection. The illness is indistinguishable from other forms of acute meningitis until specific tests are performed.

Diseases

  • Neuronal intranuclear inclusion disease
  • Craniosynostosis fibular aplasia
  • Neurofibrillary tangles
  • Fascioliasis
  • Chromosome 1, monosomy 1q4
  • Mievis Verellen Dumoulin syndrome
  • Amnesia, lacunar

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Areas such as the hippocampus have only 3 layers, the entorhinal cortex has 3 to 5 layers, and the neocortex (idiotypic isocortex and homotypical isocortex) such as the primary motor cortex contains 6 layers. Layers of the neocortex are defined in large part by the neuronal cell types they contain; the major distinction is 181 182 Section I. Heteromodal parietal association cortex has a forward projection to prefrontal heteromodal association cortex and a backward connection to paralimbic regions. Similar connection patterns exist for all the modal networks (vision, hearing, motor, balance, and probably more primitive sensory networks for chemoreception [eg, smell and taste]) (Figure 21. The combination of cytoarchitecture, cellular components, thalamocortical and corticocortical connections, and neurochemistry defines regions within the cortical mantle as unique areas and leads to the creation of cortical maps. The Brodmann areas representing the primary sensorimotor areas include area 4 (primary motor cortex, precentral gyrus), areas 3, 2, 1 (primary somatosensory cortex, postcentral gyrus), area 17 (primary visual cortex), and areas 41 and 42 (primary Primary cortex Unimodal association Heteromodal association Paralimbic Limbic Figure 21. Cytoarchitectonic subdivisions of the lateral, medial, and inferior aspects of the cerebral cortex on the basis of phylogenetic origin, differentiation of cortical layers, and connectivity patterns. Primary cortex, unimodal association cortex, and heteromodal association cortex constitute neocortex. Left, Laminar structure of the neocortex as shown with Golgi (A) and Nissl staining (B). Right, Basic excitatory connectivity pattern within a functional column of neocortex. Input from a thalamic relay nucleus terminates primarily in layer 4, which contains spiny stellate excitatory neurons that project to pyramidal neurons in layers 2 and 3. These neurons project to pyramidal neurons in layer 5, which in turn activate pyramidal neurons in layer 6. The excitatory interactions within a column are controlled by different types of local interneurons (not shown), which also mediate lateral inhibition of surrounding columns. The apical dendrites of pyramidal cells reach layer 1, where they receive input from other cortical areas, thalamic intralaminar nuclei, and cholinergic and monoaminergic systems of the brainstem, hypothalamus, and basal forebrain. Cortical pyramidal cells give rise to extrinsic connections: layer 2 cells to intrahemispheric corticocortical association fibers, layer 3 cells to interhemispheric commissural fibers, layer 5 cells to corticostriate, corticorubral, corticopontine, corticobulbar, and corticospinal fibers, and layer 6 cells to corticothalamic fibers. Most studies using brain anatomy use the Brodmann classification scheme, and, depending on the area of inquiry, other regions are often mentioned. Finally, although poorly understood, there is an important laterality effect such that the left hemisphere in essentially all right-handed persons and in roughly 75% of left-handed persons supports language, whereas the right hemisphere in such cases appears to be dominant for spatial skills. Some left-handed persons have mixed language dominance, and a small subset are completely right hemisphere language dominant. Neuroscience and Neuroanatomy Primary sensory cortex Unimodal sensory association cortex Heteromodal association cortex Paralimbic cortex Limbic cortex Primary motor cortex Premotor cortex Hypothalamus Extrapersonal space Internal milieu Figure 21. Sensory information is processed serially from primary sensory, to unimodal sensory, to heteromodal sensory association areas in the posterior parietal and lateral temporal cortices. These areas project to both heteromodal association areas of the frontal lobe (prefrontal cortex) and paralimbic areas, which provide input to the hippocampus and amygdala. The prefrontal cortex projects to premotor areas (unimodal motor association areas), which activate primary motor cortex. Note the feedback connections between the paralimbic, heteromodal, and unimodal areas. The cortex then projects back to wide regions of the central nervous system including the cortex, thalamus, basal nuclei, cerebellum, brainstem, and cord. The types of fibers connecting areas of the central nervous system are designated based on regions they connect. For instance, the fibers connecting the cortex to subcortical structures are called projection fibers. Multiscale Organization the human brain is a complex information processing system whose proper functioning depends on the organization of its processing units. The scale of these processing units spans multiple levels from the genetic to systems level (Figure 22. A complete understanding of any 1 of these levels necessitates understanding each level because they are interdependent. For example, the genetic expression of a signal neuron determines the protein composition of that neuron, which, in turn, influences its firing pattern within a microcircuit. Thus, the firing pattern of neurons within circuits changes, which leads to a change in the genetic expression within individual neurons in order to optimally respond to this new firing pattern. The complex interaction between these various levels is typically summarized as an interaction between genes and environment. At any point in time, it is impossible to know every piece of information necessary to fully characterize the complexity within these systems. However, general principles of this multiscale organization are emerging via interdisciplinary investigations of complex adaptive systems. These principles can be more easily characterized and used to understand the brain in health and disease. A discussion of these complex network principles is beyond the scope of this chapter, but the structural, functional, and behavioral aspects of this multiscale system are reviewed in more detail. Therefore, the basic bipartite functional unit (ie, 2 neurons) is supported by a basic tripartite structural unit (ie, neuron, astrocyte, and a vascular endothelial cell). The laminar organization of the cortex is the basic structural substrate of cortical functional units at the microcircuit level. The cerebral cortex is composed of 6 possible cortical layers, with regional variability in the presence of these layers and their cellular composition, commonly referred to as the cytoarchitectonics of the region (see Chapter 21, "Cortex Topography and Organization"). Neurovascular coupling related to this bipartite functional and tripartite structural arrangement allows for the identification of regions of the brain that are functionally connected at the systems level. Anterior and Posterior Limbic Circuits: Emotion and Memory the structures involved in the anterior and posterior limbic systems are evolutionarily primitive, which speaks to their critical role in fundamental aspects of behavior, with higher neocortical functions arising with the need to modulate these primitive circuits. The brain evolved only once in evolutionary history, and all subsequent organisms with nervous systems share a common ancestor. Bilaterally symmetric mobile muticellular organisms driven to interact with the extrapersonal environment first developed a primitive olfactory sensory system in order to efficiently guide movements to sources of sustenance. The circuitry involved in coordinating this driven behavior evolved into the anterior limbic circuit. The anterior limbic circuit is involved in coordinating motivational drives (eg, hunger, thirst, procreation, emotion), and complex cognitive processes and motor plans satisfy those drives through certain behaviors. More complex memory-related modulation of behavioral responses is accomplished through the semantic, visual-spatial, and autobiographic memory processes mediated by the posterior limbic circuit. The function of these circuits has led to the tight association of the limbic system with emotion, cognition, and memory. The connections between the nidus of the anterior limbic circuit (ie, the amygdala) and sensory processes are bidirectional, and ongoing sensory information influences anterior limbic activity and limbic activity also influences sensory processing. This interaction is true for all major sensory domains (ie, extrapersonal, personal, and intrapersonal). Key regions of the anterior (purple) and posterior (cyan) limbic circuit are highlighted in the center illustration. Regions of positive (yellow) and negative (blue) functional connectivity within these systems are shown on surface renderings highlighting these structures. The color bars encode the strength of connectivity, with red being the strongest and purple the weakest. The information in the anterior and posterior limbic circuits is integrated not only by the reciprocal connections between the amygdala and the hippocampus but also by subcortical-cortical loops that interact in the cingulate gyrus to connect these 2 pathways via the cingulate fasciculus (Figure 22. The details of the posterior limbic circuit and its associated neocortical systems are discussed in detail below, followed by the neocortical associations of the anterior limbic system. The classic circuit of Papez constitutes the major posterior limbic subcortical-cortical loop. Hippocampal outputs from the subiculum travel via the fornix to the mammillary bodies then via the mammillothalamic tract to the anterior nucleus of the thalamus, which sends efferents to the cingulate gyrus (see Chapter 16, "The Limbic System"). From here the information can be integrated with anterior circuit activity in the anterior cingulate via the cingulate fasciculus, travel to the precuneus or other posterior association cortices, or return to the hippocampus via the cingulum bundle. Lesions anywhere along this circuit may impair new memory formation for autobiographic events, semantic knowledge, or visual-spatial information.

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This found that the estimated risk of having symptomatic early neurosyphilis in this group was 1. Of the cases, 75% had presented with visual disturbance or new-onset headache, 12% with acute meningitis and 50% with no other signs or symptoms of syphilis whatsoever. False positives may be obtained in certain diseases, notably leprosy, systemic lupus erythematosus, thyroiditis, haemolytic anaemia and some cases of rheumatoid arthritis. The tests may also be positive for a while after some viral infections, after vaccination, during pregnancy and in an appreciable proportion of drug addicts. The cardiolipin Wassermann reaction uses a purer antigen and gives fewer false positives in these situations. An initial diagnosis of dissociative disorder was made and the opinion of a psychiatrist sought. Features of the mental state at this stage included confabulation, perseveration, social disinhibition and grandiosity. Differential diagnosis the forms of neurosyphilis are so variable in presentation that serological tests should be considered in all patients admitted to psychiatric units. In the outpatient clinic there must be a readiness to perform such tests when the index of suspicion is high. Roberts and Emsley (1992) reported 21 patients admitted to acute psychiatric units with neurosyphilis, in only three of whom the diagnosis had been considered before the results of routine serology were known. The initial diagnoses had encompassed schizophrenia, depression, mania and hysteria, in addition to delirium and dementia. At the very minimum the pupil reactions and tendon reflexes should be examined at every new consultation. However, clinical examination without serology is not always enough to avoid errors in diagnosis; this was illustrated by Steel (1960) in patients in a psychiatric observation ward and by Joffe et al. A history of change of personality, impaired emotional control and intellectual decline will immediately suggest general paresis, and the presence of tremor, dysarthria or pupillary or reflex abnormalities will almost suffice to confirm the diagnosis. However, such well-established cases are nowadays rare at the time of initial presentation. The most common initial diagnoses were depressive illness, dementia, confusional states, schizophrenia, hypomania and epilepsy. General paresis must obviously be considered in all patients who present with organic impairment of intellect, and no patient should be diagnosed as suffering from a primary dementia until syphilis has been excluded. Among older arteriopathic patients mistakes are particularly likely to be made, since tremor and dysarthria are then not entirely unexpected. However, pupillary abnormalities are rarely seen in cerebral arteriosclerosis or other dementing illnesses. Where routine serological testing is not possible the principal safeguard must lie in careful and systematic examination of the nervous system, and due attention to any organic mental impairments which emerge. There is a special risk of overlooking the diagnosis in alcohol-dependent patients. Emotional instability or expansiveness may be attributed to alcoholic deterioration, likewise social lapses, facile behaviour, tremulousness and dysarthria. General paresis may be confused with cerebral tumour when headache is marked and the personality attributes of 430 Chapter 7 frontal lobe damage conspicuous. An anterior basal meningioma may mimic the disease closely when compression of the optic pathways leads to pupillary changes and optic atrophy. General paresis must also be borne in mind in the differential diagnosis of epilepsy of late onset, and in all acute organic reactions when other causes are not immediately obvious. Finally it is necessary to distinguish between general paresis and other neurosyphilitic diseases, in particular chronic meningovascular syphilis and asymptomatic neurosyphilis. In chronic meningovascular syphilis the prognosis is much better than in general paresis. Meningovascular syphilis tends to occur earlier than general paresis, shows a more acute development, and fluctuations in its course are usually marked. Insight is generally better preserved, the personality less deteriorated and focal neurological signs somewhat more common. The reaction may consist of malaise and fever alone or result in exacerbation of symptoms, sometimes with seizures. Oral prednisone given the day before and during the first few days of treatment helps to prevent its occurrence. Where patients are penicillin sensitive, consideration should be given to penicillin desensitisation procedures (Arroliga & Pien 2003). Fortunately, spirochaetal resistance to penicillin does not appear to have developed; all early syphilis continues to respond and it is unlikely that other antibiotics confer extra benefit. Treatment Adequate treatment of syphilis in the primary stage prevents the development of general paresis later. Penicillin therapy For the treatment of established general paresis, penicillin alone is generally agreed to be adequate and can eliminate syphilitic infection in the brain in the great majority of cases. Benzylpenicillin is the preparation of choice and must be given by intramuscular injection; as procaine benzylpenicillin it can be given by daily injections. However, benzathine benzylpenicillin, given as a single injection per week, will not suffice. Because of this, these Other treatment Antipsychotic drugs are indicated for the control of excitement, agitation or florid delusions or hallucinations as in any other psychotic illness and there are case reports of the use of atypicals being effective (Taycan et al. It must be borne in mind that a small proportion of cases may represent a coincidence between asymptomatic neurosyphilis and an independent psychotic illness, and the latter will then warrant full psychiatric management in its own right. Sudden worsening with focal signs of neurological defect has been reported to follow electroconvulsive therapy in such cases, and Dewhurst (1969) provides data that suggest the possibility of an impaired overall prognosis. The complete care of the patient will include planned rehabilitation when deficits persist, in the knowledge that they may show continued slow improvement for up to 2 years following arrest of the disease. If abnormalities in cells or protein persist, a second course should be given immediately. In this situation the essential step is re-evaluation of the diagnosis, since syphilitic infection may have been coincidental with other disease. A persistently elevated protein is not of the same significance, and can usually be disregarded if cell counts remain low and there is no clinical evidence of progression. However, rising titres in the blood serology should cause concern and may point to continuing activity or reinfection. Clinical evidence of progression of the disease will always raise the possibility of the need for retreatment, especially when the initial response was good. Outcome of treatment the outcome that can be expected was comprehensively described by Hahn et al. Their general conclusion is of great importance, namely that success depends essentially on early diagnosis and prompt administration of a fully adequate course of treatment. Of mild or early cases, 80% obtained clinical remission and proved capable of resuming work. The prognosis for ability to work and to live in the community was directly proportional to the severity of the illness and the duration of decreased work capacity at the time of treatment. However, even severely affected institutionalised patients were still capable of considerable benefit, and stood a one in three chance of improving sufficiently for rehabilitation and ultimate return to work. Certain symptoms were associated with a poor overall prognosis, including incontinence, inability to dress and neglect of personal hygiene. In patients over 60 years old, remission or improvement became much less frequent, probably because of the presence of cerebrovascular changes. The more active the fluid in terms of cell count, the greater the chance of a good clinical response; at the same time, however, the likelihood of clinical progression was then also increased in certain cases. The latter is less susceptible to treatment but also less likely to result in clinical progression.

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Bibliography Abenhaim L, Moride Y, Brenot F et al: Appetite-suppressant drugs and the, risk of primary pulmonary hypertension. Subject to statutory exception and to the provision of relevant collective licensing agreements, no reproduction of any part may take place without the written permission of Cambridge University Press. Every effort has been made in preparing this publication to provide accurate and up-to-date information which is in accord with accepted standards and practice at the time of publication. Although case histories are drawn from actual cases, every effort has been made to disguise the identities of the individuals involved. Nevertheless, the authors, editors and publishers can make no warranties that the information contained herein is totally free from error, not least because clinical standards are constantly changing through research and regulation. The authors, editors and publishers therefore disclaim all liability for direct or consequential damages resulting from the use of material contained in this publication. Readers are strongly advised to pay careful attention to information provided by the manufacturer of any drugs or equipment that they plan to use. Lees 219 230 6 17 Management of acute ischemic stroke and its complications 243 Natan M. Bornstein and Eitan Auriel v Contents 18 Infections in stroke 258 Achim Kaasch and Harald Seifert 19 Secondary prevention 272 Hans-Christoph Diener and Greg W. It is targeted at "beginning specialists", either medical students with a deeper interest or medical doctors entering the field of specialized stroke care. Therefore the text contains what is considered essential for this readership but, in addition, goes into much greater depth. The textbook leads the reader through the many causes of stroke, its typical manifestations, and the practical management of the stroke patient. We have tried to keep the clinical aspects to the fore, giving relative weight to those chapters that cover clinically important issues; however, the pathological, pathophysiological and anatomical background is included where necessary. The book benefits from the experience of many specialized authors, thereby providing expert coverage of the various topics by international authorities in the field. In places this leads to some differences of opinion in the approach to particular patients or conditions; as Editors we have tried not to interfere with the individual character of each chapter, leaving only duplicate presentations when they were handled from different topological or didactic aspects. The development of this textbook has been triggered by the "European Master in Stroke Medicine Programme" held at Danube University in Austria. This program has been fostered by the European Stroke Organisation and has been endorsed by the World Stroke Organization. Thus, we hope to satisfy the needs of students and young doctors from many different countries, both within and outside Europe. Thanks also to Nick Dunton and his team at Cambridge University Press for their help and patience. Changes in the vessel wall lead to obstruction of blood flow, by interacting with blood constituents they may cause thrombosis and blockade of blood flow in this vessel. In addition to vascular stenosis or occlusion at the site of vascular changes, disruption of blood supply and consecutive infarcts can also be produced by emboli arising from vascular lesions situated proximally to otherwise healthy branches located more distal in the arterial tree or from a source located in the heart. At the site of occlusion, the opportunity exists for thrombus to develop in anterograde fashion throughout the length of the vessel, but this event seems to occur only rarely. Changes in large arteries supplying the brain, including the aorta, are mainly caused by atherosclerosis. Middle-sized and intracerebral arteries can also be affected by acute or chronic vascular diseases of inflammatory origin due to subacute to chronic infections. In some diseases affecting the vessels of the brain the etiology and pathogenesis are still unclear. All these vascular disorders can cause obstruction, and lead to thrombosis and embolizations. Small vessels of the brain are affected by hyalinosis and fibrosis; this "small-vessel disease" can cause lacunes and, if widespread, is the substrate for vascular cognitive impairment and vascular dementia. Atherosclerosis is the most widespread disorder leading to death and serious morbidity including stroke. The basic pathological lesion is the atheromatous plaque, and the most commonly affected sites are the aorta, the coronary arteries, the carotid artery at its bifurcation, and the basilar artery. Atherosclerosis starts at a young age, and lesions accumulate and grow throughout life and become symptomatic and clinically evident when end organs are affected [1]. Atherosclerosis: atheromatous plaques, most commonly in the aorta, the coronary arteries, the bifurcation of the carotid artery and the basilar artery. The initial lesion of atherosclerosis has been attributed to the "fatty streaks" and the "intimal cell mass". Those changes occur in childhood and adolescence and do not necessarily correspond to the future sites of atherosclerotic plaques. Fatty streaks are focal areas of intracellular lipid collection in both macrophages and smooth muscle cells. Various concepts have been proposed to explain the progression of such precursor lesions to definite atherosclerosis [1, 2], the most remarkable of which is the response-to-injury 1 Section 1: Etiology, pathophysiology and imaging Figure 1. In this complex process of growth, progression and finally rupture of an atherosclerotic plaque a large number of matrix modulators, inflammatory mediators, growth factors and vasoactive substances are involved. This fibrous cap covers the deep lipid core with a massive accumulation of extracellular lipids (atheromatous plaque) or fibroblasts and extracellular calcifications may contribute to a fibrocalcific lesion. During the development of atherosclerosis the entire vessel can enlarge or constrict in size [7]. However, once the plaque enlarges to >40% of the vessel area, the artery no longer enlarges, and the lumen narrows as the plaque grows. In vulnerable plaques thrombosis forming on the disrupted lesion further narrows the vessel lumen and can lead to occlusion or be the origin of emboli. Less commonly, plaques have reduced collagen and elastin with a thin and weakened arterial wall, resulting in aneurysm formation which when ruptured may be the source of intracerebral hemorrhage (Figure 1. Injury hypothesis of progression to atherosclerosis: fatty streaks (focal areas of intra-cellular lipid collection)! Thromboembolism Immediately after plaque rupture or erosion, subendothelial collagen, the lipid core and procoagulants such as tissue factor and von Willebrand factor are exposed to circulating blood. Atherosclerotic thrombi are also the source of embolisms, which are the primary pathophysiological mechanisms of ischemic strokes, especially from carotid artery disease or of cardiac origin. Small-vessel disease usually affects the arterioles and is associated with hypertension. It is caused by subendothelial accumulation of a pathological protein, the hyaline, formed from mucopolysaccharides and matrix proteins. Often it is associated with fibrosis, which affects not only arterioles, but also other small vessels and capillaries and venules. Lipohyalinosis also weakens the vessel wall, predisposing it to the formation of "miliary aneurysms". Status lacunaris is characterized by small irregularly shaped infarcts due to occlusion of small vessels; it is the pathological substrate of lacunar strokes and vascular cognitive impairment and dementia. In status cribrosus small round cavities develop around affected arteries due to disturbed supply of oxygen and metabolic substrate. The etiology and pathophysiology of the various specific vascular disorders are discussed in specialist articles and handbooks [14]. The most reliable numbers come from the in-hospital assessment of stroke in the Framingham study determining the frequency of complete stroke: 60% were caused by atherothrombotic brain infarction, 25. Ischemic strokes are caused by a critical reduction of regional cerebral blood flow and, if the critical blood flow reduction lasts beyond a critical duration, they are caused by atherothrombotic changes of the arteries supplying the brain or by emboli from sources in the heart, the aorta or the large arteries. The pathological substrate of ischemic stroke is ischemic infarction of brain tissue; the location, extension and shape of these infarcts depend on the size of the occluded vessel, the mechanism of arterial obstruction and the compensatory capacity of the vascular bed.

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The classical division of bacteria into Gram-positive and Gram-negative groups on the basis of specific staining procedures also depends on cell wall components. The Grampositive organisms have a rigid cell wall that is covered with an outer layer containing teichoic acids, whereas the wall of Gram-negative bacteria is covered with a smooth, soft lipopolysaccharide. During the biosynthesis of the cell wall, the muropeptide is formed from acetylmuramylpentapeptide, which terminates in a D-alanyl-D-alanine. During the crosslinking of the pentapeptide precursor, the terminal fifth alanine must be split off by a transpeptidase enzyme. This last reaction in cell wall synthesis is inhibited by the -lactam antibiotics, Table 9. In contrast to this inhibition of the last step of a reaction sequence, the feedback inhibition of enzymatic reactions normally occurs at the first step in a sequence, avoiding any wastage of precursor substances; if it occurs late, biochemical efficiency is seriously jeopardized. First, the antibacterial agent has to penetrate the outer membrane of the Gram-negative bacteria, which are less susceptible to antibiotics. This membrane consists of lipopolysaccharides, phospholipids, lipoproteins, and proteins. The -lactam antibiotics (penicillins, cephalosporins) cross this diffusion-resistant membrane through porin channels, trimeric proteins that traverse the membrane. The next hurdle the antibiotic has to surmount involves the -lactamase enzymes in the periplasmic space, between the outer and inner membranes; these can deactivate the antibiotic (Gram-positive bacteria excrete the lactamase into the medium). Beyond that is the peptidoglycan cell wall with the associated penicillinbinding proteins, which are the essential transpeptidases, transglycosylases, and D-alanine carboxykinases involved in cell wall synthesis. The history of penicillin became a story of legendary proportions, illustrating the case of a serendipitous discovery combined with brilliant development; it also marks the beginning of the modern chemotherapy of infectious diseases. The most important and still used among these is benzylpenicillin or penicillin G, a singularly nontoxic compound highly active against Gram-positive infections such as staphylococcal sepsis, meningitis, and gonorrhea. Structurally, the -lactam ring fused with the thiazolidine ring is most unusual, since -lactam rings were unknown before the discovery of penicillin. The penam ring can be considered as a dipeptide composed of a cysteine and a valine residue. Owing to the strain of the four-membered -lactam, the ring is easily cleaved by acid hydrolysis and alcoholysis, and by heavy metals such as Zn2+, Cu2+, and Pb2+. The resulting penicilloic acid is inactive and undergoes a complex series of rearrangements. For example, phenoxymethyl penicillin is more resistant to acid cleavage than benzylpenicillin, and is therefore more suitable for oral use. The high reactivity of the -lactam ring is the key to the biological activity of the -lactam antibiotics. It acts as an irreversible inhibitor of the bacterial transpepticlase because it acylates the enzyme protein near the active site through opening of the lactam ring (see figure 9. By means of its highly reactive lactam ring, penicillin is able to deactivate the transpeptidase enzyme. This in turn leads to a halting of cell wall construction within the bacterium, ultimately leading to bacterial death. The most serious threat to antibiotic therapy, and to the use of -lactam antibiotics in particular, is the emergence of resistant bacterial strains. The primary reason for this resistance is the production of an enzyme, -lactamase (penicillinase), which in Gram-positive bacteria is excreted into the growth medium but in Gram-negative bacteria remains contained in the cell. Thus, Gram-positive organisms quickly destroy the antibiotic in the surrounding solution by hydrolysis, converting it to the inactive penicilloic acid. Since production of penicillinase enzymes is under plasmid control, resistant bacteria can transfer their resistance. Hence, bacterial species that were in the past easily controlled with penicillin have increasingly become a serious medical problem. They have a relatively narrow activity spectrum, primarily inhibiting Gram-positive bacteria only. They are acid- and lactamase-sensitive, and in a small percentage of patients they cause allergic side effects. All of these limitations could potentially be overcome by molecular modifications during the biosynthesis of these drugs. Unfortunately, however, the fermentation process used in penicillin production is not very flexible and does not permit the incorporation of very many amide side chains into the molecule. Although the total synthesis of penicillins was accomplished by Sheehan and his co-workers in 1953, and although some other approaches have also been successful, the syntheses are of limited practical value; nevertheless, they do allow modification of the ring system. The parent compound carries the aminoadipate side chain, which can be cleaved to supply the 7-amino-cephalosporanic acid. This amine can easily be acylated and thus forms the basis of many useful derivatives. However, it is remarkably resistant to enzymatic hydrolysis and becomes highly concentrated in the urine, which makes it useful in urinary tract infections caused by Gram-negative organisms. It is lactamase resistant because of its hydroxyethyl side chain but is not absorbed orally as it is highly polar. The monocyclic nocardicins represent the ultimate "simplification" of the -lactam structure, containing the azetidinone ring by itself, with a side chain resembling that of cephalosporin C. The sulfur atom can be replaced (moxalactam) or omitted (thienamycin), and the entire ring itself is, in fact, unnecessary (nocardicin). The carboxyl group, previously deemed essential, can be replaced by a tetrazolyl ring (as a bioisostere), which results in increased activity and lactamase resistance. The amide side chain, so widely varied in the past, is also unnecessary, as shown in the example of thienamycin. These natural products are antibacterial, killing bacteria by lethally altering the transmembrane ion flux. Such antibacterial molecules are called ionophores, or ion carriers, in contrast to other antibacterials, such as polyene antibiotics, which simply produce leakage through the cell membrane. Ionophoric antibiotics can function either as "cage" carriers of an ion or as channel formers. A channel former simply provides a polar tunnel that allows the migration of a polar ion across an otherwise impenetrable lipid layer. This cyclic peptide lactone consists of three molecules each of L-valine, D-hydroxyisovaleric acid, and L-lactate. The six highly polarized lactone carbonyl oxygens line the inside of the ring, whereas the nonpolar alkyl groups point to the outside of the molecule. Thus the polar interior can accommodate a nonhydrated potassium ion and surround it with an apolar bracelet. The selectivity of valinomycin for K+ over Na+ is very high, the ratio being about 104:1. In this way, valinomycin will increase the K+ conductivity of lipid membranes at concentrations as low as 10-9 M. The high K+ selectivity is due to the relative ease of dehydration of this ion: with its larger diameter, the potassium ion holds hydrate water less firmly than does sodium; consequently, whereas the hydrated sodium ion does not fit the valinomycin "doughnut," the dehydrated K+ does bind easily, with the bonding energy providing a further energy advantage for the selective reaction. A hydrated sodium ion is larger than a potassium ion with or without a hydrate envelope. It induces the transmembrane transport of protons, alkalimetal ions, and thallium ions at concentrations as low as 10-10 M, even though it is unable to complex these ions in solution. For example, two molecules of gramicidin form a "head-tohead" helix, spanning the total width of the cell membrane. The helix creates a pore lined with hydrophilic groups, permitting ion transport across the otherwise impermeable lipid barrier of the membrane. The movement of ions in the pore has been simulated in silico, using elaborate molecular modeling calculations. Colicins, bacteriostatic peptides encoded by bacterial plasmids, have been crystallized and investigated by X-ray crystallographic methods. They have a mass of 79,000 daltons and an axial ratio of 1:10, giving these peptides a length of about 20 nm. They are capable of forming a transmembrane channel with a diameter so large that glucose molecules can pass through. Of course, this fatally disrupts the membrane potential of the bacterial cell, with consequent bacteriostatic activity.

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