Phantom auditory perception (tinnitus): mechanisms of generation and perception

✓ The mechanisms that give rise to ischemic brain damage have not been definitively determined, but considerable evidence exists that three major factors are involved: increases in the intercellular cytosolic calcium concentration (Ca++i), acidosis, and production of free radicals. A nonphysiological rise in Ca++i due to a disturbed pump/leak relationship for calcium is believed to cause cell damage by overactivation of lipases and proteases and possibly also of endonucleases, and by alterations of protein phosphorylation, which secondarily affects protein synthesis and genome expression. The severity of this disturbance depends on the density of ischemia. In complete or near-complete ischemia of the cardiac arrest type, pump activity has ceased and the calcium leak is enhanced by the massive release of excitatory amino acids. As a result, multiple calcium channels are opened. This is probably the scenario in the focus of an ischemic lesion due to middle cerebral artery occlusion. Such ischemic tissues ca...

Pathophysiology and treatment of focal cerebral ischemia. Part II: Mechanisms of damage and treatment.

Cerebral hypoxia-ischemia (asphyxia) occurring in the fetus and newborn infant is a major cause of acute mortality and chronic neurological disability in survivors. This review highlights many practical aspects of perinatal hypoxic-ischemic brain damage, including neuropathological features, obstetrical antecedents, and clinically important aspects of identification, management, and prognosis. Diagnostic techniques, including neuro-imaging, to diagnose hypoxic-ischemic encephalopathy also are discussed. A thorough knowledge of the clinical spectrum of perinatal hypoxic-ischemic encephalopathy should enable neonatologists to undertake appropriate management strategies and prognostic indicators.

Hypoxic-ischemic encephalopathy.

Evidence derived from a variety of tissues suggests that loss of calcium homeostasis in ischemia and related disorders (\"calcium overload\") is a major cause of cell death. The hypothesis of calcium-related tissue injury was originally proposed to explain damage to the ischemic heart,'-3 to ischemic or dystrophic muscle:5 to ischemic liver tissue: and to the traumatized spinal Some authors subsequently proposed that adverse, calcium-related reactions, elicited when the plasma membrane becomes unduly permeable to calcium, constitute more general mechanisms of cell necrosis.\"' At least in part, the evidence quoted in support was that removal of calcium from a suspension increases the viability of cells exposed to adverse conditions, cell viability being estimated by dye exclusion tests. It was then either assumed that calcium injured cells by causing overload and high-amplitude swelling of mitochondria, or caused structural and functional damage to plasma membranes and other targets by activating proteases and l i p a ~ e s . ~ * ' ~ . ' ~ One hypothesis proposed that the plasma membrane damage in muscle cells was more localized, being secondary to excessive agonistreceptor interaction^.^*'^ The hypothesis of calcium-related cell damage, as applied to brain disease, has some special feature^.'^-^' First, it proposes a common mechanism in the pathogenesis of ischemic, hypoglycemic, and epileptic brain damage.'6s'9*20 Second, it attempts to explain selective neuronal vulnerability in terms of the special characteristics of some burst-firing neurons which, by mechanisms related to calcium influx, have a strong proclivity to epileptic Third, it provides a likely mediator of the postsynaptic damage which has been ascribed to the presynaptic release of the excitatory amino acids glutamate and a ~ p a r t a t e . * ~ ~ ~ Fourth, some evidence suggests that delayed neuronal death could be caused by a lingering derangement of membrane calcium transport, providing a speculative explanation for why calcium antagonists, when given after the ischemic transient, may ameliorate the final ischemic damage.26 Recently, the hypothesis that ischemic injury is secondary to a flooding of cells with calcium has been ~ h a l l e n g e d . ~ ~ ~ ~ The main arguments raised against the hypothesis are the following. First, it has never been shown whether calcium accumulation in

Historical overview. Calcium, ischemia, and death of brain cells.

Recent investigations suggest that increased cellular calcium concentrations may be implicated in neuronal death after ischemia. To determine whether treatment with a calcium-channel blocker would improve survival and neurologic outcome in acute ischemic stroke, we enrolled 186 patients in a prospective, double-blind, randomized, placebo-controlled trial of nimodipine (30 mg every six hours), begun within 24 hours of the onset of symptoms of an acute ischemic stroke. During the four-week treatment period, mortality from all causes was significantly reduced with nimodipine as compared with placebo (8 deaths [8.6 percent] vs. 19 [20.4 percent]). The improvement in survival was restricted to men. During the follow-up period of six months, an additional eight patients in each group died. A significantly better neurologic outcome, as assessed by the Mathew scale of neurologic deficit, was also observed in the nimodipine group. The improvement in neurologic status was greatest in patients with a modera...

A controlled trial of nimodipine in acute ischemic stroke.

Twenty-seven pigtailed monkeys (Macaca nemestrina) were subjected to 17 min of complete cerebral ischemia followed by 96 h of intensive care treatment. Fourteen of the monkeys were assigned randomly to the treatment group and received nimodipine 10 μg·kg−1 5 min postischemia followed by 1 μg·kg−1·mi

John D. Michenfelder

Papers

Nimodipine improves outcome when given after complete cerebral ischemia in primates.