Ekaterina A Stepanova, M.D., Ph.D.

• Assistant Professor of Psychiatry and Behavioral Sciences

https://www.hopkinsmedicine.org/profiles/results/directory/profile/10001197/ekaterina-stepanova

People without a family history but otherwise meeting the criteria are classified as having sporadic hemiplegic migraine erectile dysfunction pump buy 800mg viagra vigour with mastercard. Other causes of monocular visual loss (transient ischemic attacks erectile dysfunction drug types buy genuine viagra vigour line, optic neuropathy erectile dysfunction chicago purchase 800 mg viagra vigour visa, and retinal detachment) must be considered low cost erectile dysfunction drugs generic 800 mg viagra vigour mastercard. Neurologic and vestibular functions are normal between attacks erectile dysfunction treatment new zealand viagra vigour 800 mg low cost, as are imaging studies and electroencephalography erectile dysfunction heart attack cheap 800mg viagra vigour amex. When this condition occurs after childhood, the patients often have bouts of migraine during or independent of vertigo. Many risk factors contribute to the evolution of chronic migraine from episodic migraine (see Chapter 5). Risk factors include frequent episodic headaches, high levels of disability, allodynia, depression, traumatic head injury, and overuse of drugs, most importantly opioidand barbiturate-containing analgesics. The diag- nosis of chronic migraine in the setting of medication overuse is complex (see Chapter 10). The typical aura symptom or symptoms persist beyond 1 hour, and neurologic examination or neuroimaging or both confirms cerebral infarction. The location is bilateral, the quality is nonpulsating, the intensity is mild to moderate, and the headache is not aggravated by physical activity. Similarly, there is a paucity of associated symptoms: no nausea or vomiting, although either photophobia or phonophobia may be present, but not both. Not aggravated by routine physical activity, such as walking or climbing upstairs D. The pain may spread to adjacent areas of one side and is usually locked to the same side on repeated attacks. The pain, usually in or around one orbit, is excruciating and is typically boring, sharp, or stabbing. During the attack, one or more of the following associated features are present: ipsilateral redness and tearing of the eye, clogging or drainage from the nostril, and ptosis and miosis. During the headache, in contrast to the behavior during migraine, the patient cannot lie still but is impelled to move about or sit and rock. During these cluster periods, alcoholic beverages and other vasodilating agents may trigger an attack. Associated with these are some or all of the autonomic features of cluster headache. Ask whether or not some headache or discomfort is present between the severe attacks. This may lead to the diagnosis of hemicrania continua with exacerbations that resemble a migraine-like headache. The daily pain is of moderate intensity, but superimposed exacerbations often occur and may mimic migraine or cluster headache. Without inquiring about lesser daily headaches, the diagnosis of hemicrania continua may be missed. Formerly called "jabs and jolts," the pains last only one or a few seconds and occur at random without a consistent location. Headache associated with sexual activity may be preorgasmic, causing a dull ache in the head and neck, or orgasmic, which often has an explosive quality. The headache lasts from 1 to 10 days and may recur at random over weeks or months. The headaches begin within 3 days of the noted day and are constant for more than 3 months. Acute medication overuse must be first considered, and chronic migraine should also be ruled out before the diagnosis is made. As noted before, headaches secondary to organic disease or dysfunction must be ruled out before a diagnosis of primary headache disorder is established. Neurologic workup is not necessary with every new patient, but if the headache is atypical or has recently changed or there is a history of red flags, a search for underlying disease is warranted (Table 1. In formulating the differential diagnoses of the primary headaches, it is useful to follow a sequence of steps (Table 1. First, classify the headaches in to low or high frequency (less or more than 15 headache days per month). Finally, consider headaches of short duration of low or high frequency and the presence or not of triggering factors. Late life migraine accompaniments as a cause of unexplained transient ischemic attacks. Shortlasting unilateral neuralgiform headache attacks with conjunctival injection, tearing, sweating, and rhinorrhea. Although the vast majority of headache syndromes are benign, clinicians are faced with the crucial task of differentiating benign headache disorders from potentially life-threatening conditions. Given the broad range of disorders that present with headache, a focused and systematic approach is necessary to facilitate the prompt diagnosis and treatment of various kinds of head pain. In managing a patient with chronic, recurrent primary headaches, there must be a positive interrelationship between patient and doctor. During the initial evaluation, the patient and the doctor should get to know one another. If worrisome features or "red flags" are present either in the history or on examination, diagnostic testing may be necessary to exclude secondary headache disorders. Having determined that the condition is a primary headache, the specific headache type must be diagnosed. Once a diagnosis has been established, the general therapeutic options should be outlined in a treatment plan tailored to the patient. One should emphasize the need for the patient to be active in his or her own care. Realistic expectations should be established, and rarely will the initial plan be perfect. Follow-up visits are scheduled to modify the therapy and, if necessary, to reassess the diagnosis. History-taking is often complicated by the presence of more than one type of headache or by a change in the headache pattern over time. It is often helpful to begin with the current headache of greatest concern to the patient and subsequently explore other headache patterns and the evolution of those patterns. The doctor will have a general idea about the degree of disability after speaking to the patient. More specifically, we want to know how the headaches are impacting on family life, schoolwork or occupation, and social life. Age at onset and at presentation Most of the primary headache disorders begin in childhood or early adult life. Like migraine, tension-type headache and cluster headache may start in early childhood or later in life, but commonly occur between the ages of 20 and 30 years. Without an adequate history, unnecessary diagnostic and treatment interventions may be performed or, alternatively, crucial testing may not be obtained. Taking the headache history provides an opportunity to establish a rapport with the patient that will serve as the basis for an ongoing therapeutic relationship. Headache descriptors should first be sought with open-ended statements such as "Tell me about your headaches and how they impact your life. With advancing age, headache or facial pain may result from medications, systemic disorders, postherpetic neuralgia, trigeminal neuralgia, or disorders of the head, neck, eyes, ears, or nose. For these reasons, testing is indicated when older patients present with headaches of recent onset, headaches that have changed from a pre-existing pattern, or headaches that are associated with an abnormal examination. The location of headache in a patient with migraine may fluctuate over the course of an attack and between different attacks. However, the latter two headache types may last for days or may evolve in to a chronic form. The timing of headaches within a diurnal, monthly, or annual cycle is particularly important in the diagnosis of cluster headache. Changes in the frequency of headache may be the cause of the visit to the physician, as when relatively well-controlled attacks of migraine increase in frequency or transform in to a daily or near-daily headache. Frequent episodic and chronic headaches are managed differently from a rarely occurring headache. The frequency and timing of headache attacks within a longer period of time, such as months or a year or more, allow an understanding of the burden of headache for the individual. Infratentorial, occipitonuchal, and cervical spine pathology can refer pain to the forehead or eye because of the convergence of cervical nociceptive afferents at the second and third cervical levels with trigeminal afferents in the caudal trigeminal nucleus of the brainstem. As blood or pus tracks down the subarachnoid space, the acute headache of a subarachnoid hemorrhage or meningitis may be followed by pain that travels down the spinal column to the interscapular region or lower back. Burning or pulsating ocular or periorbital pain may reflect incipient ischemia in the vertebrobasilar territory, an expanding skull base aneurysm, extracranial or intracranial vascular dissection, dural sinus occlusion, or inflammation in the cavernous sinus. Ask the patient to grade the intensity on a scale of 1 to 10, with 1 as pain that can barely be appreciated and 10 as the worst pain possible. The intensity of a tension-type headache is rarely more than moderate, migraine is usually moderate to severe, and cluster headaches are unbearably severe. Premonitory and aura symptoms Patients with migraine can often predict the arrival of a headache because of premonitory symptoms that may occur hours or days preceding the headache. The latter precede the headache by minutes or as much as an hour, whereas sometimes the aura begins with the headache. Positive visual symptoms may be bright or complex patterns, such as zigzag scintillating scotomas, or photopsia such as floaters and flashes. However, progressive impairment of visual acuity with transient visual obscurations (with or without visual field cuts or papilledema) may be seen in patients with headaches caused by raised intracranial pressure. Amaurosis occurs in patients with anterior ischemic optic neuropathy secondary to vasculitis. Diplopia with head pain may be a manifestation of basilar-type migraine but often signifies a parasellar mass or a posterior communicating artery aneurysm. Cheiro-oral paresthesias, which "march" from a hand to the face, are common with migraine but may be a manifestation of a partial sensory seizure or a transient ischemic attack. Examples of this include headaches associated with sexual activity, cough, and exertion. A chronic recurrent or long-standing daily headache usually represents a primary disorder such as migraine, cluster headache, or tensiontype headache. Migraine and other primary headache disorders may only be diagnosed in retrospect after their episodic course becomes manifest and there is no evidence of an underlying lesion. Some physicians inform their female patients with migraine that their headaches will completely cease once they have reached menopause. Progressively worsening headaches (over weeks to months) suggest increasing intracranial pressure, medication overuse headache, or systemic disease. Patients with idiopathic intracranial hypertension, bilateral subdural hematomas, midline obstructive lesions, and chronic meningitic syndromes may exhibit a subacute progressive headache. Temporal profile the onset of the headache and its course over time has diagnostic and therapeutic implications. Primary stabbing headaches ("jabs and jolts") are fleeting, often multifocal cranial pains, which, despite their intensity, are benign. Abrupt-onset headaches suggest a vascular mechanism such as subarachnoid hemorrhage. Usually, features on examination will distinguish between these serious conditions. Other head- Associated features Noting the associated features of headache, or their absence, and their temporal relationship to the headache provides essential features of the history. They are not pathognomonic for migraine as elevated intracranial pressure, disturbances to the area postrema of the medulla, and systemic infection can cause vomiting. Similarly, phonophobia, photophobia, and osmophobia often accompany migraine, although these symptoms may also occur with meningitis. Visual disturbances are often associated with migraine but should also raise concerns of ischemic brain pathology. Pituitary adenoma or idiopathic intracranial hypertension may cause visual field cuts. Symptoms of an upper respiratory infection or toothache may be indicative of acute sinusitis as the cause of the headache, but nasopharyngeal symptoms are often misdiagnosed as "sinus headache" rather than migraine. On the other hand, sphenoid sinusitis may present with headache without nasal symptoms. The physician should differentiate between symptoms that are due to the underlying headache disorder and those due to treatment. For example, ergot agents and nonsteroidal antiinflammatory drugs may cause nausea. Relieving factors Typically, migraine is relieved by sleep or rest in a dark and quiet room. Cluster headache, on the other hand, induces patients to be active, typically pacing to and fro. Patients may use a variety of techniques to relieve their headaches, ranging from home remedies, such as cold or warm compresses and relaxation techniques, to herbs, prescription medications, and over-the-counter medications. Aggravating or precipitating factors Patients often have an understanding of headache triggers even before the visit to the healthcare provider. If the patient is not aware of specific triggers, headache diaries are helpful at elucidating them. When the headaches are associated with menses, ovulation, stress, hormonal supplements, fatigue, depression, food deprivation, or food sensitivity, migraine is likely. Similarly, environmental factors such as fumes, glare or flickering lights, perfume or chemical smells, or exercise may influence the headache pattern. Alcohol is a notorious trigger of cluster headache, and red wine is a classic instigator of migraine. Headaches aggravated by an upright posture suggest intracranial hypotension, which can occur spontaneously or iatrogenically. The supine position, or a change in position, may worsen the headaches of intracranial hypertension.

A sectional image represents a slice of anatomy found within the patient in a given plane of section erectile dysfunction medication ratings cheap viagra vigour 800mg on-line. Although the thickness may vary erectile dysfunction vitamins order viagra vigour in india, the image will represent a specific section of anatomy impotence female purchase viagra vigour canada, which is used to generate the image impotence yoga postures discount viagra vigour 800mg with visa. By generating high-frequency sound waves through the patient and then collecting the reflected sound wave erectile dysfunction vitamin deficiency buy viagra vigour 800 mg on line, echoes are recorded and displayed as a real-time visual image impotence uk purchase 800 mg viagra vigour free shipping. The arteries forming the circle of Willis are found between the arachnoid and pia mater in the subarachnoid space. The venous sinuses are formed by folds of the dura mater and many like the transverse sinus create grooves on the inside of the skull. Although most of the venous blood within the skull is drained in to the internal jugular veins, small amounts of venous blood also drain through the face to empty in to the external jugular veins. On the outside, the brain is covered with pia mater, whereas the dura mater lines the inside of the skull. The internal carotid artery begins at the bifurcation of the common carotid artery in to the internal and external carotid arteries in the neck near the level of C4. The artery passes through the carotid foramen within the petrous part of the temporal bone. Each internal carotid artery has branches that form the anterior cerebral and posterior communicating arteries. The continuation of the internal carotid artery after the branches originate is called the middle cerebral artery. The cerebral tissue supplied by the vessel will undergo ischemic necrosis or infarction. Because the bones are L-shaped, they also form part of the lateral walls and the floor of the nasal cavity. Deep within the temporal lobe, this curved sheet of gray matter extends upward in to the floor of the lateral ventricle. Considered part of the limbic system, the hippocampal formation is involved in the emotional aspects of behavior. Arising from the internal carotid artery near the hypothalamus, the artery extends laterally as it travels upward through the Sylvian fissure. The arteries forming the circle of Willis are found on the inferior surface of the brain between the midbrain and the upper part of the sphenoid bone found in the base of the skull. Clinically, this condition is called hydrocephalus and will appear as a progressive dilation of the ventricular system. Cisterns, which are enclosed spaces serving as a reservoir for cerebrospinal fluid. The middle layer is called the arachnoid mater because the weblike projections extend through the subarachnoid space, which is filled with cerebrospinal fluid. The structure is made up of nerve fibers radiating between the nuclei and the cerebral cortex. Altogether, the sheets of nerve fibers form a crown extending upward to the cerebral cortex. The C-shaped collection of gray matter forming the caudate nucleus can be described as lining the inner curvature of the lateral ventricle. The enlarged region of the brainstem sometimes called the belly is formed by nerve fibers from the cerebellum joining those from the cerebrum and spinal cord. The first and most atypical vertebra, because it lacks a body and a true spinous process, is roughly circular in shape. Yes, normally the cervical curvature causes C3 and C4 to be more anterior as compared to the surrounding vertebrae. It is easily distinguished in the body, which is long and extends cranially, forming the dens. Malignant cells lose their ability to adhere so some of the cells would be taken via the venous bloodstream in to the pulmonary veins. The cells would be carried to the heart and would pass through the left atrium and left ventricle. The malignant cells would leave the heart through the aorta and would ascend in to the neck via the common carotid artery. At about the level of C4, the cells would continue upward in the internal jugular artery and continue out in smaller branches until they became lodged within the deep neck. By comparison, the circle of Willis is just inferior to the midbrain and above the sphenoid bone in the base of the skull. The cerebellum is the lowermost part of the brain and is often described as being behind the face. The superior articular process is found anterior and lateral to the inferior articular process. The inferior articular process is locked in front of the superior articular facet. The facet is compressing the right nerve root containing both sensory and motor nerve fibers passing through the intervertebral foramen. Like the other meningeal layers, the dura mater forms a sheath around the nerve roots within the intervertebral foramen. The tough outer layer, surrounded by fat in the epidural space within the vertebral foramen. No, nerve cells are fully differentiated and are unable to revert to an undifferentiated or dividing state to replace cells that are lost as a result of injury. Outside the spinal cord, the fluid travels upward in the subarachnoid space to return to the top of the brain where it is reabsorbed in to the venous blood stream. The innermost meningeal layer continuous with the surface of the spinal cord and nerve roots. Lumbar vertebrae can be distinguished by their large size and the absence of costal facets (thoracic vertebrae) and transverse foramina (cervical vertebrae). Yes, when the vertebral body slides forward, the articular facets will also move forward, resulting in a pinching of spinal nerve roots passing through the intervertebral foramina. All of the spinal ligaments including the anterior longitudinal ligament, posterior longitudinal ligament, ligamentum flavum, interspinous ligament, etc. Yes, spondylolisthesis can occur between any two vertebrae but occurs most often at L5 to S1. Yes, when the vertebral body slides forward, the pedicles and laminae will also move forward, resulting in a narrowing of the spinal canal. No, the layer of dense connective tissue tightly attached to the anterior surfaces of vertebrae and intervertebral discs was probably intact because the vertebral column maintained its orderly staked arrangement. Yes, the layer of dense connective tissue tightly attached to the posterior surfaces of vertebrae and intervertebral discs was torn. Yes, the tearing of the posterior longitudinal ligament also resulted in damage to the intervertebral disc. The meningeal layers surrounding the spinal cord are encased by the ligaments and bony structures forming the vertebral foramen. Due to injury to these connective tissues, the subarachnoid space enlarged due to an outward bulging of the meningeal layers beyond the normal limits of the spinal foramen. Because the sensory nerves below the injury will be unable to provide signals, select sensory nerve cells above the injury site will no longer be functional. Phantom pains often occur due to a crossing over of nerve signals within the central nervous system. The internal carotid arteries ascend in the deep neck and travel through the base of the skull to supply blood to the middle and anterior cerebrum. The facial artery is a branch of the external carotid that extends over the lower edge of the mandible to supply blood to the external face. Yes, the bundle of lumbar and sacral nerves descending below the termination of the spinal cord would be compressed by the bulging discs. The conus medullaris is the caudal tip of the spinal cord found between L1 and L3. Yes, bulging discs will often narrow the intervertebral foramina and pinch spinal nerve roots resulting in numbness and a tingling sensation traveling down the legs and in to the feet. The posterior longitudinal ligament attached to the posterior surfaces of vertebrae and intervertebral disks. The common carotid artery ascends through the neck beside the posterior trachea and is found deep to the internal jugular vein. The external carotid artery ascends through the superficial upper neck to supply arterial blood to the external head including the face and scalp. The vertebral arteries originate from the subclavian arteries and ascend through the transverse foramina of C6 through C1 to enter the skull through the foramen magnum. In the images, the vertebral arteries are found medial and posterior to the common carotid arteries. The azygos vein is located inside the right posterior thoracic cage adjacent to the right side of the vertebral bodies. Located inferior to the larynx, the thyroid gland surrounds the upper region of the trachea. There are two lobes located on either side of the trachea, connected by a narrowed region called the isthmus. The thyroid gland wraps around the anterior surface of the trachea, whereas the esophagus lies near the midline posteriorly. The external jugular vein drains venous blood from the superficial structures of the head. The sternocleidomastoid muscle is a flat muscle band that originates from the sternum and clavicle and inserts on the mastoid process of the temporal bone. Located in the upper part of the larynx, the spoonshaped cartilage is folded over the opening of the larynx, moving food or drink in to the laryngeal pharynx. The aorta descends in the posterior mediastinum on the left side of the vertebral column. The esophagus descends in the posterior mediastinum and travels between the heart and the vertebral column. The gland lies just below the anterior liver and creates an impression on the lower or visceral surface. The spleen lies against the diaphragm on the upper left side of the abdomen within the thoracic cage. Its size and shape vary considerably, partially depending on the adjacent structures. The anterior surface is next to the stomach, the posterior surface is next to the left kidney, the superior surface is next to the diaphragm, and the inferior surface is next to the left splenic flexure of the colon. The celiac trunk, the superior mesenteric, the renal, the inferior mesenteric, and the common iliac arteries. The celiac trunk is the short (1 to 2 cm), first branch of the abdominal aorta originating just below the diaphragm between the lesser curvature of the stomach and the liver. The stomach is found within the upper left abdominal cavity just below the diaphragm. Near the center of the abdomen, the pancreas lies between the stomach and the vertebral column. The duodenum drains the contents of the stomach and is found on the right side below the liver. The duodenum joins with the jejunum, which is the small bowel generally located in the upper anterior abdominal cavity. The ileum is the last part of the small bowel and is generally located in the lower anterior abdominal cavity. The kidneys are found on either side of the vertebral column and typically are centered at the level of the first lumbar segment. They are located posterior to the peritoneum lining the abdominal cavity and are described as retroperitoneal. The right renal artery is usually longer because it passes posterior to the inferior vena cava. The portal system is a network of venous structures that drain nutrient-rich blood from the gastrointestinal tract in to the liver. Originating at the diaphragm, the aorta extends through the abdomen along the left side of the vertebral column to terminate as the common iliac arteries. Within the prostate, the seminal vesicle ducts join with the ductus (vas) deferens to join the prostatic urethra. During ejaculation, the seminal vesicles secrete an alkaline fluid rich in sugar that contributes to sperm viability. C A Above Posterior D the fundus is the dome-shaped roof of the uterus found above the oviduct. The cervix is the most inferior constricted region of the uterus opening in to the vagina. The first image must be above the iliac crest, and the last image must be below the ischium. The testicles are surrounded by the scrotal sack, and are located outside and below the bony pelvis. The ductus (vas) deferens extends from the testicle, and passes over the pubis and bladder to join within the prostate gland to the urethra. As they descend during fetal development, they move through the anterior abdominal wall so the spermatic cord will attach to the anterior abdominal wall to enter the greater pelvic cavity, above the symphysis pubis. Originating below the bladder, the urethra is about 20 cm in length and travels through the prostate, pelvic diaphragm, and penis. The urethra is found behind the pubis and traverses through the pelvic diaphragm to exit the lower pelvis. A vascular stent is a device used to maintain a vessel wall that will fuse with adjacent structures and maintain blood flow or perfusion of affected tissues. The abdominal aorta descends in to the greater pelvis where it divides in to the right and left common iliac arteries.

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Is the comorbidity of epilepsy and migraine due to a shared genetic susceptibility Comorbidity of migraine and psychiatric disorders-a national population-based study impotence herbs buy generic viagra vigour 800 mg line. Rates erectile dysfunction treatment levitra cheap 800mg viagra vigour free shipping, predictors erectile dysfunction recovery stories discount viagra vigour 800mg amex, and consequences of remission from chronic migraine to episodic migraine erectile dysfunction treatment viagra generic viagra vigour 800mg line. Migraine in junior high-school students: a prospective 3academic-year cohort study green tea causes erectile dysfunction order viagra vigour 800mg on-line. Looking to the future: research designs for study of headache disease progression impotence 10 cheap 800 mg viagra vigour mastercard. Factors associated with the onset and remission of chronic daily headache in a population-based study. Head or neck injury increases the risk of chronic daily headache: a population-based study. Major life changes before and after the onset of chronic daily headache: a population-based study. Periaqueductal gray matter dysfunction in migraine: cause or the burden of illness Does chronic daily headache arise de novo in association with regular use of analgesics Prevalence and characteristics of allodynia in headache sufferers: a population study. Cutaneous allodynia-a predictor of migraine chronification: a longitudinal population-based study. Obesity is a risk factor for transformed migraine but not chronic tension-type headache. Research diagnostic criteria for temporomandibular disorders: review, criteria, examinations and specifications, critique. Temporomandibular disorders and cutaneous allodynia are associated in individuals with migraine. Depression and risk of transformation of episodic to chronic migraine: results of the American Migraine Prevalence and Prevention Study. Outcomes and predictors of chronic daily headache in adolescents: a 2-year longitudinal study. Migrainous disorder and its relation to migraine without aura and Migraine with aura. The prevalence and characteristics of migraine in twins from the general population. Familial risk of migraine: variation by proband age at onset and headache severity. Catechol-O methyltransferase inhibition increases pain sensitivity through activation of both beta2and beta3-adrenergic receptors. Catechol-O methyltransferase gene polymorphisms are associated with multiple pain-evoking stimuli. Behavioral sleep modification may revert transformed migraine to episodic migraine. Openlabel, multicenter study of the efficacy and outcome of onabotulinumtoxin-A treatment in patients with chronic migraine and comorbid depressive disorders. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Assessing and managing all aspects of migraine: migraine attacks, migraine-related func- 121. Incidence and predictors for chronicity of headache in patients with episodic migraine. An understanding of the pathophysiology of mi graine should be based upon the anatomy and physiology of the painproducing structures of the cranium, integrated with a knowledge of their central nervous system modulation. Current views concerning migraine will be reviewed, con cluding that the disorder is a disturbance in the brain of the subcortical aminergic sensory mod ulatory systems, in addition to other brainstem, hypothalamic, and thalamic structures. Migraine-explaining the clinical phenotype Migraine is in essence a familial episodic disorder whose key marker is headache with certain asso ciated features (Tables 6. It is these features that give crucial clues to its pathophysi ology, and ultimately will provide insights leading to new treatments. It is clear from clinical practice that many patients have firstdegree relatives who also suffer from migraine. Transmission of migraine from parents to children has been Headache, First Edition. Genetic epidemiology Studies of twin pairs are the classical method to investigate the relative importance of genetic and environmental factors. A Danish study included 1013 monozygotic and 1667 dizygotic twin pairs of the same gender, obtained from a population based twin register. Both twin studies and population based epidemiologic surveys strongly suggest that migraine without aura is a multifactorial dis order, caused by a combination of genetic and environmental factors. An unexplained but epi demiologically wellestablished predisposition relates to a methyltetrahydrofolate reductase C677T gene mutation that is certainly over represented in migraine with aura. Remarkably, and importantly for patients and clinicians, the most recent populationbased epidemiologic data suggest that migraine carries no excess risk for cognitive function compared to age and sex matched controls. Indeed, the clinical phenotype does not associate par ticularly with the known mutations. Another less striking difference includes the fact that patients from chromosome 19linked fami lies are more likely to have attacks that can be triggered by minor head trauma or are that asso ciated with coma. The biologic basis for the linkage to chromo some 19 is mutations involving the Cav2. One effect of this change is to reduce or inactivate astrocytic glutamate transporters, leading to a buildup of synaptic glutamate. This mutation affects a highly conserved amino acid in a part of the channel that contributes to its rapid closure after opening in response to membrane depolarization (fast inactivation). This represents a gain of function: instead of the channel rapidly closing, allowing the membrane to repolarize fully after an action potential, the mutated channel allows a persist ent sodium influx. Taken together, the known mutations suggest that migraine, or at least the neurologic manifes tations currently called the aura, are ionopa thies. Further, studies of trigeminal durally evoked nociceptive activa tion using Fos protein expression in these knockin mice demonstrate reduced second order neuronal activation compared to wildtype animals and enhanced Fos protein expression in certain thalamic nuclei. The data suggest the brunt of the pathophysiologic burden in this mutation may fall on thalamocortical mechanisms. Migraine aura Migraine aura is defined as a focal neurologic dis turbance manifest as visual, sensory, or motor symptoms. Blood flow studies in patients have also shown that a focal hyperemia tends to precede the spreading oligemia, and again this is similar to what would be expected with spread ing depression. An area of controversy surrounds whether aura in fact triggers the rest of the attack, and is indeed painful. Tonabersat does not constrict isolated human blood vessels, but does inhibit trigeminally induced craniovas cular effects. These may suggest some way forward for the management of at least the most disabled group who have persistent or pro longed aura. Stimulation of the cranial vessels, such as the superior sagittal sinus, is certainly painful in humans. Human dural nerves that innervate the cranial vessels largely consist of smalldiameter myelinated and unmyelinated fibers that almost certainly subserve a nocicep tive function. Neurogenic plasma extrava sation can be seen during electrical stimulation of the trigeminal ganglion in the rat. In addition, there are structural changes in the dura mater that are observed after trigeminal ganglion stimulation. These include mast cell degranulation and changes in postcapillary venules including platelet aggregation. While it is generally accepted that such changes, and par ticularly the initiation of a sterile inflammatory response, would cause pain, it is not clear whether this is sufficient of itself, or requires other stimu lators or promoters. What neurogenic dural plasma extravasation fails to predict is whether new targets, when engaged, are effective in either the acute or preventive treatment of migraine. Headache-anatomy Trigeminal innervation of pain-producing intracranial structures Surrounding the large cerebral vessels, pial vessels, large venous sinuses, and dura mater is a plexus of largely unmyelinated fibres that arise from the ophthalmic division of the trigeminal ganglion, and in the posterior fossa from the upper cervical dorsal roots. A par ticularly interesting aspect is the demonstration of allodynia in the upper limbs ipsilateral and contralateral to the pain. This finding is consist ent with at least thirdorder neuronal involve ment, such as a sensitization of thalamic neurons, and firmly places the pathophysiology within the central nervous system. Sensitization in migraine may also have a peripheral component with a local release of inflammatory markers, which would certainly activate trigeminal nociceptors, although a peripheral component is not neces sary to explain the symptoms. More likely, in migraine there is a form of central sensitization, which may be classical central sensitization, or a form of disinhibitory sensitization with dysfunc tion of the descending modulatory pathways. Interestingly, the presence or absence of allody nia does not predict outcome after acute therapy in randomizedcontrolled trials. Inter estingly, given the variability, it will probably not provide a biomarker for migraine. Headache physiology-central connections the trigeminocervical complex Fos immunohistochemistry is a method for looking at activated cells by plotting the expres sion of Fos protein. Similarly, stimulation of a branch of C2, the greater occipital nerve, increases meta bolic activity in the same regions, i. In experimental animals, one can record directly from trigeminal neurons with both supraten to rial trigeminal input and input from the greater occipital nerve, a branch of the C2 dorsal root. Stimulation of the greater occipital nerve for 5 minutes results in substantial increases in responses to supratentorial dural stimulation, which can last for over an hour. Conversely, stim ulation of the dura mater over the middle menin geal artery with the Cfiber irritant mustard oil sensitizes responses to occipital muscle stimula tion. Moreo ver, stimulation of a lateralized structure, the middle meningeal artery, produces Fos expres sion bilaterally in both cat and monkey brain. These data demonstrate that trigeminovascu lar nociceptive information comes by way of the most caudal cells. This concept provides an ana tomic explanation for the referral of pain to the back of the head in migraine. These data further the concept that vascular mechanisms are not necessary for acute migraine treatments. The presence of iGluR5 subunits in the trigeminal ganglion neurons and at the presynaptic sites of primary afferents indicates a possible role of kainate receptors in trigeminovascular physiology. Taken together, these studies suggest a strong basis for pursuing glutamate targets, with some care for considering how to do this without attracting unwanted side effects. Higher order processing Following transmission in the caudal brainstem and high cervical spinal cord, information is relayed rostrally. This typical negative feedback system will be further considered later as a pos sible mechanism for the symptomatic manifesta tions of migraine. Another potential modulatory region activated by stimulation of nociceptive trigeminovascular input is the posterior hypothalamic gray. Moreover, the clinical features of the premoni tory phase, and other features of the disorder, suggest dopamine neuron involvement in some part. Orexinergic neurons in the posterior hypothalamus can have both pro and antinociceptive downstream effects and are activated when trigeminovascular nociceptive afferents are stimulated. The "vascular hypothesis"-a good story ruined by the facts For much of the later part of the 20th century, a rather straightforward concept dominated think ing about migraine. First proposed in some part by Willis and best articulated by Wolff, the theory explained the pain of migraine to be due to dila tion of the cranial vessels. By the later part of the 19th century, neuronal theories had been well articulated, and indeed Gowers seemed happy with that concept. It is now clear that the vascular hypothesis is untenable as an explanation for migraine pathophysiology, and some of the data behind this view are covered here. Another lynchpin of the vascular argument came from the behavior of cranial vessels in migraine sufferers. It had been shown that ergotamine could produce vasoconstriction in line with its efficacy in migraine. When this was more closely examined, it was shown that the vascular changes were unrelated to the phase of the attack, and indeed blood flow could be reduced or normal during the pain phase. Most recently, using high resolution 3 T magnetic resonance angiography, it has been reported that migraine triggered by nitroglycerin occurs without any continuing change in intracranial or extracranial vessels. Taken together, be it triggering, measuring, or inducing vascular change with therapies, vascu lar change is neither necessary, sufficient, nor needed in migraine-in short, it is an epiphe nomenon of the neural substrates that are acti vated by the underlying pathophysiology of the disorder. These areas are active immedi ately after successful treatment of the headache, but are not active interictally. Electrophysiology of migraine in humans Studies of evoked potentials and eventrelated potentials provide some link between animal studies and human functional imaging. Authors have shown changes in neurophysiologic meas ures of brain activation, but there is much discus sion of how to interpret such changes. Perhaps the most reliable theme is that the migrainous brain does not habituate to signals in a normal way, nor indeed does that of patients who have firstdegree relatives with migraine. Similarly, contingent negative variation, an eventrelated potential, is abnormal in migraineurs compared to controls. Attempts to correlate clinical phenotypes with electro physiologic changes may enhance further studies in this area. Patients complain of pain in the head that is throbbing, but there is no reliable relationship between the vessel diameter and the pain, or its treatment. They complain of discomfort caused by normal lights and the unpleasantness of routine sounds. Normal movement of the head causes pain, and many mention a sense of unsteadiness as if they have just stepped off a boat, having been nowhere near the water. The conver gence of cervical and trigeminal afferents explains why neck stiffness or pain is so common in primary headache. The genetics of chan nelopathies is opening up a plausible way to think about the episodic nature of migraine. Aura can be experienced without pain at all, and is seen in the other primary headaches. There is not a photon of extra light that migraine patients receive over others, so for that symptom, and phonophobia and osmophobia, the basis of the problem must be abnormal central processing of a normal signal.

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HbA2 levels are useful in identifying carriers of p thalassemia trait in high-risk communities. Molecular techniques are increasingly used for detection of individuals who are m ore likely to give birth to offspring with hereditary dis orders. Newborn Screening this is an example of secondary prevention by early diagnosis and treatment. Newborn infants are screened routinely for some endocrine disorders and inborn errors of metabolism in developed countries. This is of special value for detecting the affected cases during the newborn period, so that the handicap can be prevented or minimized by early treatment. Prenatal Diagnosis and Selective Termination of Affected Fetuses this is a successfully used modality for preventing birth of affected babies and reducing the load of lethal, chronically disabling, untreatable or difficult-to-treat genetic disorders in the community. Noninvasive techniques include fetal ultrasono graphy and maternal serum screening. If the risk of bearing a child with Down syndrome is more than 1:250, prenatal fetal karyotyping can be offered. Fetal ultrasonography helps to detect fetuses who are at high risk for chromosomal abnormalities. Important findings in the second trimester which are markers of Down syndrome include increased nuchal fold thickness (measured over the occiput and not the spine), short femur and humerus length and duodenal atresia. Ultrasound findings help in cow1seling, particularly if the parents have opted for initial screening with maternal serum markers. Both maternal serum screening and fetal ultrasound are screening techniques and cannot rule out Down syndrome. First trimester screening using dual markers have high detection rates, which improves further if ultrasound markers are com bined. Elevated alpha-fetoprotein level in maternal blood is also a very sensitive marker for fetuses affected with open neural tube defects. Invasive Prenatal Testing this includes chorionic villus biopsy (done at 10-12 weeks of gestation or later), amniocentesis (16-20 weeks) and cord blood sampling (after 18 weeks). Some common examples are thalassemia, sickle cell anemia, hemophilia, Duchenne muscular dystrophy and cystic fibrosis. Genetic Counseling Genetic counseling is a communication process, which deals with problems associated with the occurrence and recurrence of a genetic disorder in a family. Counseling should be undertaken by a physician with proper under standing of the genetic mechanisms. The metabolic error usually results in the deficiency of one or more enzymes required for the formation or transport of proteins. The diagnosis is often delayed, and requires a high index of suspicion, since symptoms are nonspecific, leading to evaluation for other pediatric illnesses like sepsis and hypoxic ischemic encephalopathy. Symptoms are often precipitated by catabolic state (fever, infections, immunization, dehydration or fasting). Defects in energy metabolism include conditions associated with deficient energy production or utilization within liver, muscle, heart and brain. Failure to thrive, hypo glycemia, hepatomegaly, hypotonia, cardiomyopathy, myopathy, high lactate, neurological symptoms, circulatory collapse or sudden death may be seen. Disorders of complex molecules include lysosomal storage diseases, peroxisomal disorders, a,-antitrypsin deficiency and congenital disorders of glycosylation. Symptoms are usually progressive and permanent and do not have precipitating factors. Acute Presentation Neonates with metabolic disorders appear normal at birth since the small intermediary metabolites are eliminated by the placenta during fetal life. In general, an early onset of clinical symptoms is associated with severe disease. An important clue to diagnosis is unexpected deterioration after normal initial period in afull term baby. Neonates with organic acidurias, urea cycle disorders and some arninoacidurias may present with lethargy, poor feeding, persistent vomiting, seizures, tachypnea, floppiness and body or urine odor. Common conditions such as sepsis, hypoxic ischemic encephalopathy and hypoglycemia should be excluded. Older children show acute unexplained, recurrent episodes of altered sensorium, vomiting, lethargy pro gressing to coma, stroke or stroke like episodes, ataxia, psychiatric features, exercise intolerance, abdominal pain, quadriparesis or arrhythmias. The symptom free period may be prolonged, often longer than a 1 yr and patients are normal in between the episodes. Intercurrent illnesses, high protein intake, exercise, fasting and drug intake (enzyme inducers) may precipitate symptoms. Physical examination may show altered sensorium, apnea or hyperpnea and hypotonia. Facial dysmorphism, structural anomalies of brain, cataract, retinopathy, deaf ness, hypertrophic or dilated cardiomyopathy, hepa to megaly, multicystic dysplastic kidneys, myopathy and peculiar urine odor suggest specific diagnoses. Following informed written consent, the following samples should be obtained postmortem to facilitate diagnosis. The excretion of toxic metabolites is enhanced by hemo dialysis or using alternative pathways for nitrogen excre tion. Immediate measures to decrease plasma levels of ammonia are necessary as the risk for irreversible cerebral damage is related to its concentration. The initial screening investigations include total and differential counts and blood levels of sugar, electrolytes, bicarbonate, calcium, transarninases, ammonia, lactate and pyruvate. If clinical improvement is observed and a final diagnosis is not established, some amino acid intake should be provided after 2-3 days of complete protein restriction. Appropriate amino acid formula (free of precursor amino acids) or protein free infant formula with breast milk is gradually introduced with careful clinical and laboratory monitoring. Expressed human milk is preferred as it can be measured and total protein intake quantified. Prompt recognition and avoidance of physiologic stresses (fever, infection, trauma, surgery, fasting) and changes in diet that may precipitate symptoms is important in pre venting metabolic decompensation. Chronic and Progressive Prese ntation this group of metabolic disorders is characterized by variable but insidious onset from birth to adulthood. Unexplained developmental delay with or without seizures, organomegaly, coarse facies, cataract, dislocated lens, chronic skin lesions, abnormal hair, abnormal urine color on standing and failure to thrive are important clues. These forms are divided in to subgroups depending upon the involvement of specific system. Neurologic findings are developmental delay or progressive psychomotor retardation, seizures, ataxia, spasticity, variable hearing and visual impairment, and extra- pyramidal symptoms. Psychomotor or developmental delay is the chief manifestation and tends to be global and progressive. Severe irritability, impulsivity, aggressiveness and hyperactivity and behavioral patterns such as au to matism, stereotypes, compulsive chewing of thumbs and fingers, self-mutilation and nocturnal restlessness are com mon. Complex partial or myoclonic seizures occur early in course of the disease and are often resistant to therapy. Differentiating between involvement of either gray matter or white matter is helpful in narrowing the differential diagnosis (Table. Movement disorders are intermittent or progressive, in form of ataxia, dystonia, choreoathetosis and Parkinsonism. Dysmorphic features are present in patients with Zellweger syndrome, glutaric aciduria type 2 and storage syndromes. The presence of cataract(s) suggests galactosemia, peroxi somal disorders, Lowe syndrome and Wilson disease. Corneal abnormalities are seen in mucopolysaccharidoses, Wilson disease and Fabry disease. Skin may show an eczematous rash associated with alopecia in biotinidase deficiency. Angiokeratoma are characteristic of Fabry disease, but can be seen in fucosi dosis and -mannosidosis. Evaluation Investigations should include complete hemogram, liver and renal function tests and serum electrolytes. Pancy to penia may be seen in patients with methylmalonic acidemia and propionic acidemia. Metabolic acidosis and evidence of proximal renal tubular dysfunction is present in patients with Lowe syndrome, cystinosis, Wilson disease and galactosemia. Investigations that enable specific diagnosis include neurological imaging and electrophysiological studies and skeletal survey. Specific enzyme assays and estimation of plasma levels of lactate, ammonia, very long chain fattyacids and amino acids are useful in certain cases. Management A multidisciplinary team of metabolic specialists, pediatric neurologists, clinical geneticist, cardiologist, orthopedic surgeon and physiotherapist is required to maximize the supportive care in these patients. Other treatment options include cofactor and megavitamin therapy, special diets, enzyme replacement therapy and organ transplantation. Muscular disorders presenting with myopathy are usually due to defects in energy metabolism. Hepatic presentations include the presence of unconju gated or conjugated jaundice, hypoglycemia and hepa to megaly with or without hepatocellular dysfunction. Disorders leading to cirrhosis include tyrosinemia, galactosemia, hereditary fructose intolerance and Wilson disease. There are five different phenotypes based on clinical findings and response to thiamine. By 48-72 hr, poor feeding, ketonuria, irritability and drowsiness develops followed by unexplained progressive coma. In advanced stage, intermittent apnea, bradycardia, hypothermia, generalized hypertonia, opisthotonus and involuntary movements such as fencing and bicycling may appear. Chronic progressive forms can present with variable manifestations such as developmental delay or progressive psychomotor retardation, seizures, failure to thrive, sleep disturbances, hyperactivity, mood swings and movement disorders. Treatment during acute stage should follow the abovementioned principles along with rapid removal of branched chain amino acids from body tissues and fluids using either peritoneal or hemodialysis. Cerebral edema is a common complication should be treated promptly in an intensive care setting with mannitol, hypertonic saline and diuretics. During recovery high calorie, branched chain amino acid free formula is initiated early with regular plasma amino acid monitoring. Affected individuals have profound and irreversible intellectual disability, microcephaly, epilepsy and behavioral problems. These patients often have a musty body odor and skin conditions such as eczema caused by excretion of excessive phenylalanine and its metabolites. Decreased skin, hair and eye pigmentation may also be present due to associated inhibition of tyrosinase and reduced melanin synthesis. It is a disorder of tyrosine metabolism, classically presents as severe liver disease in young infants. Severe forms present during infancy with vomiting, diarrhea, bleeding diathesis, hepatomegaly, jaundice, hypoglycemia, ascites and coagulopathy. Children older than six months of age may come to medical attention with variable degree of renal dysfunction, hypophosphatemic rickets and aminoaciduria. Untreated children may have repeated, often unrecognized, neurologic crises lasting 1-7 days that can include change in mental status, abdominal. Death in the untreated child usually occurs before age ten years, typically from liver failure, neurologic crisis or hepatocellular carcinoma. It blocks tyrosine degradation at an early step to prevent the production of downstream metabolites such as fumarylacetoacetate and succinylacetone. Dietary restriction of phenylalanine and tyrosine is required to prevent tyrosine crystals from forming in the cornea. In Western countries, prior to the availability of nitisinone, the only definitive therapy for tyrosinemia type I was liver transplantation, which now is reserved for those children who have severe liver failure at presentation and fail to respond to nitisinone therapy or have documented evidence of malignant changes in hepatic tissue. Classic Homocystinuria this occurs due to cystathionine -synthase deficiency leading to accumulation of homocysteine, which has deleterious effects on the central nervous system, vessels, skin, joints and skeleton. Two clinical variants exist: B6 (pyridoxine)-responsive homocystinuria and B6-non responsive homocystinuria. B6-responsive homocystinuria is typically, but not always, milder than the nonresponsive variant and has a better outcome than the nonresponsive ones. Quantitative plasma amino acid analysis showing increased levels of methionine, homocysteine with no cystathionine confirms the diagnosis. Treatment is directed towards lowering the plasma homocysteine levels as close to normal as possible. Patients nonresponsive to pyridoxine require lifelong methionine restricted diet with frequent biochemical monitoring. Alkaptonuria this was the first inborn error of metabolism described by Garrod in 1902 and is caused by defect of the enzyme homogentisate 1,2-dioxygenase (homogentisic acid oxidase). The disorder comes to attention due to change in color of urine to brownish black or staining of diapers. Pigment deposits irritate the articular cartilage, resulting in degeneration and osteoarthritis like changes. Intervertebral disks are degenerated, spaces are narrowed and calcification occurs.