: Venous occlusive intracranial disease is associated with oral contraceptive use the immediate post-partum period, and a wide range of hypercoagulable medical conditions. Significant cerebral venous thrombosis involves one or more of the major venous sinuses and typically results in parenchymal hemorrhage. By definition, the territories of the ischemic and hemorrhagic lesions are in a venous, rather than arterial, distribution. Involvement of the deep venous system (case study 3) carries a much worse prognosis than if only the superficial sinuses and/or cortical veins (1.20) are involved. Magnetic resonance venography (MRV) is commonly used to identify major venous sinus occlusions.

Pradaxa Lawsuit: The single mandated indication for neurosurgical decompression is cerebellar hemorrhage. Early craniotomy, prior to brainstem compression, is critical. The best surgical candidates are patients with an initial GCS <14 and hematoma volume >40 ml, while those with higher GCS and smaller lesions are likely to have a good outcome with conservative, non-surgical management. Neurosurgical evacuation of clot in primary hemispheric ICH has had mixed results in randomized and non­randomized clinical trials. The leading study, I-STICH (International Surgical Trial in Intracerebral Haemorrhage), identified neutral outcomes for early evacuation. Nonetheless, a role for neurosurgical decompression to reduce clot size may exist in highly selected patients, particularly younger patients (e.g., <60 years old) who have cerebellar hemorrhage, treated with neurosurgery. Head CT scan shows a large, primary ICH based in the cerebellar vermis, causing effacement of the basal cisterns around the pons and early obstructive hydrocephalus, with markedly enlarged temporal horns (arrows) (A). The patient underwent emergent craniotomy over the next few hours, and subsequent CT scan the following day (B) shows recovery of basal cisterns, reduction in ventricular size, and a pocket of air in the left cerebellar hemisphere (arrowhead), with some edema in the left middle cerebellar peduncle. Note the craniotomy defect from the left suboccipital approach.

Pradaxa Lawsuit: Less invasive surgical interventions, such as catheter-based clot aspiration or thrombolysis, are being studied. Intraventricular ICH may contribute to elevated intra­cranial pressure (ICP) by causing obstructive hydrocephalus. The amount of ventricular blood to cause hydrocephalus need not be great (1.22). In this setting, external drainage of cerebrospinal fluid via ventricular catheter may be indicated to reduce ICP.

Pradaxa Lawsuit

Commonly considered agents: beta-blockers (labetalol, esmo­lol), calcium channel blockers (nicardipine), angiotensin con­verting enzyme (ACE) inhibitors (enalapril), and hydralazine. Other agents such as nitroprusside are effective as second-line options but carry the risk of significant vasodilation.Mass effect causing significant elevation of ICP, with the risk for cerebral herniation syndromes, may be managed emergently with osmotic agents, such as mannitol and/or hypertonic saline, and hyperventilation.However, these approaches have never been formally studied in clinical trials. Seizures occur in 10% of patients with primary ICH, usually at onset or within the initial 24 hours, and reflect cortical involvement of the lesion.

Pradaxa Lawsuit:Anticonvulsant agents are empirically recommended for patients with significant hematomas in peripheral territories in the cerebral hemispheres. The appropriate duration of anticonvulsant use has not been established. For patients who are seizure- free, guidelines suggest discontinuation of the anti-epileptic drug after the first month post-hemorrhage. Neurointensivist management of ICH in an intensive care unit (ICU) setting may improve patient outcomes.

Pradaxa Lawsuit: News and Information from related Sources

Pradaxa Lawsuit: Various clinical trials, including SHEP (Systolic Hypertension in the Elderly Program)and PROGRESS (Perindopril Protection Against Recurrent Stroke Study), have documented the critical role of antihypertensive agents in both primary and secondary stroke prevention of ICH. The JNC-7 report (Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) provides an extensive overview of the role of HTN in stroke risk, specific drug classes, lifestyle modifications, and target blood pressures. In general, lower blood pressures are associated with a proportional reduction of recurrent stroke and stroke mortality.

Pradaxa Lawsuit

: By far the most important modifiable risk factor for spontaneous ICH is HTN.Primary hypertensive hemorrhage results from the rupture of small penetrating arteries originating in the anterior, middle (i.e., lenticulostriate), and posterior cerebral (i.e., thalamostriate) arteries and the pons (i.e., paramedian perforators). HTN causes vessel rupture at or near the bifurcation of affected vessels, where degeneration of components of the arterial wall (media and smooth muscle) are identified. The annual risk of recurrent hemorrhage is 2% without antihypertensive treatment. A hematoma incites local edema and neuronal damage in the adjacent brain parenchyma. This edema typically increases in size over an interval as long as 3 weeks following the initial bleeding, with the greatest growth rate over the first 2 days. Thrombin within the hematoma plays a central role in promoting perihematomal edema. Hemoglobin and its products, heme and iron, are potent mitochondrial toxins, thereby increasing cell death.

Hemorrhage may dissect from the brain parenchyma into the adjacent ventricular space, carrying a poor prognosis, Hemorrhage may also be isolated to the intraventricular space,and lesions can expand substantially by rupturing into the ventricular system. Ventricular involvement may cause obstructive hydrocephalus and can result in long-term cognitive impairment.

Significant clinical deterioration associated with PH is known as ‘symptomatic hemorrhage, an important outcome measure in acute stroke treatment. One common definition for symptomatic hemorrhage is a clinical deterioration of >4 points on the National Institutes of Health Stroke Scale (NIHSS) associated with hemorrhage seen on CT scan. Various predictors for symptomatic hemorrhage include hyperglycemia, concur­rent heparin use, the timing of successful recanalization, a history of diabetes and cardiac disease, leukoariosis, early signs of infarct on CT scans, and elevated pretreatment mean blood pressure. Neurosurgical evacuation typically is not a helpful treatment for symptomatic hemorrhage, because the lesion is frequently large and multifocal. Extra-ischemic hematomas are: located remotely from the initial ischemic stroke lesion; may be isolated or multifocal, with or without mass effect (1.17);²³ and associated with concurrent coagulopathy and previously occult vasculopathies, such as CAA, microhemorrhages, or hypertensive vasculopathy. In the NINDS (National Institute of Neurological Disorders and Stroke) trial of IV t-PA for AIS, the incidence of extra-ischemic cerebral hematomas was 1.3%.

Pradaxa Lawsuit

THYROID-ACTING AGENTS 465 not inducing developmental defects in guinea pigs and rabbits, the chemical did affect the thyroid in these species, causing atrophic thyroids and pituitaries in the former (Peterson, 1953) and goiter in the latter (Isono, 1960). Triatricol induced cardiac muscle malformations in rats that were elucidated by electron microscopy (Hawkey et al., 1981). Of the antithyroid compounds, only the substituted thiouracil agents, but not thiouracil itself, were teratogenic in animals (see Table 14-1). Methyl thiouracil induced eye defects in rats (Langman and vanFaassen, 1955), clubfoot in mice (Miyamoto, 1967), and brain and cardiovascular anomalies In chinchillas (Klosovskii, 1963). Only thyroid effects were obsen’ed in rabbits (Toriumi, 1959) and guinea pigs (Hagemann, 1955). Propylthiouracil caused loss of hearing in mice (Deol, 1973); three other species exhibited thyroid lesions only. Metbimazole had no teratogenic activity in the rabbit, but postnatal behavioral alterations have been described in both mice (Rice et al., 1987) and rats (Comer and Norton, 1982) from low-dose prenatal administration.

The former species is, in fact, a suitable model for behavioral test validation with this drug (Rice et al., 1987). 2′-Thiourea, given as a 0.2% aqueous solution ad lib to rats on gastation days 1-14 induced a wide variety of severe malformations (Kern et al, 1980). Notably, no congenital defects were obsen’ed with either thiouracil itself or iothiouracil. Virtually all of the antithyroid agents have shown the capacity to induce fetal goiter in animals, as would be expected. Sheep grazing on certain range plants manifested congenital goiter in an

older report (Sinclair and Andrews, 1958), presumably by ingestion of goitrogenic substances of unknown composition.

Several reports have been published that associate human use of thyroid drugs during pregnancy with congenital malformation. With thyroxinc, eye defects were observed in an infant after treatment

of the mother during gestation (Mayer and Hemmcr, 1956). Medication with this drug was also considered to be a risk factor for limb defects among ]08 cases analyzed (Polednak and Janerich,

1985). Heinonen and colleagues (1977) reported a suggestive association with cardiovascular malformations among some 537 women medicated during pregnancy with thyroxine. No further associations

with malformation have occurred with this drug in recent years, and reports of some 75 pregnancies found no increased incidence of birth defects (Harris and Podolsky, 1969; Pekonen et al.,

1984). With thyroid (extract), multiple defects were obsen’ed in a child whose mother received only one treatment with the drug, but drug therapy also included several other drugs (Degenhardt, 1968).

According to another publication, a child with unspecified defects was bom to one of five mothers who were taking thyroid extract during pregnancy (Castellanos, 1967). Two more cases of malformation

were reported from treatment with desiccated thyroid: one infant had central nervous system birth defects and the other had Down syndrome (Man et al., 1958). Some 22 normal births were reported with exposure to thyroid in one publication (Harris and Podolsky, 1969). In addition to the biological effect on the thyroid (see later discussion), a number of case reports have associated antithyroid drugs with the production of serious structural congenital malformations. MaiernaJ hyperthyroid status may be one of the factors involved in ihe etiology of malformations; thyroxin-binding globulin values were significantly lower at the I5th-16th weeks of pregnancy among women giving birth to infants with birth defects  172 cases (Sparre, 1989).

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