Tissue plasminogen activator reduces neurological damage after cerebral embolism.

Intravenous administration of tissue plasminogen activator immediately after the injection of numerous small blood clots into the carotid circulation in rabbit embolic stroke model animals caused a significant reduction in neurological damage. In vitro studies indicate that tissue plasminogen activator produced substantial lysis of clots at concentrations comparable to those expected in vivo, suggesting that this may be the mechanism of action of this drug. Drug-induced hemorrhages were not demonstrable. Tissue plasminogen activator may be of value for the immediate treatment of embolic stroke.

Endothelial dysfunction and the expression of endothelial nitric oxide synthetase in diabetic neuropathy, vascular disease, and foot ulceration.

We studied endothelial-mediated microvascular blood flow in neuropathic diabetic patients to determine the association between endothelial regulation of the microcirculation and the expression of endothelial constitutive nitric oxide synthetase (ecNOS) in the skin. Vasodilation on the dorsal foot in response to heating and iontophoresis of acetylcholine (endothelium-dependent) and sodium nitroprusside (endothelium-independent) were measured using single-point laser Doppler and laser Doppler imaging in diabetic patients with neuropathy (DN), with neuropathy and vascular disease (DI), with Charcot arthropathy (DA), and without complications (D), and in healthy control subjects (C). The response to heat was reduced in the DN (321 [21-629] percentage of increase over the baseline, median [interquartile range]) and DI (225 [122-470]) groups but was preserved in the DA (895 [359-1,229]), D (699 [466-1,029]), and C (810 [440-1,064], P < 0.0001) groups. The endothelial-mediated response to acetylcholine was reduced in the DN (17 [11-25]), DA (22 [2-34]), and DI (13 [2-30]) groups compared with the D (47 [24-58]) and C (44 [31-70], P < 0.001) groups. The non-endothelial-mediated response to sodium nitroprusside was also reduced in the DI (4 [0-18]), DN (17 [9-26]), and DA (21 [11-31]) groups compared with the D (37 [19-41]) and C (44 [26-67], P < 0.0001) groups. There was a significant reduction in vasodilation in the DI group compared with all other groups (P < 0.0001). Full thickness skin biopsies from the dorsum of the foot of 15 DN, 10 DI, and 11 C study subjects were immunostained with antiserum to human ecNOS, the functional endothelial marker GLUT1, and the anatomical endothelial marker von Willebrand factor. The staining intensity of ecNOS was reduced in both diabetic groups. No differences were found among the three groups in the staining intensity of von Willebrand factor and GLUT1. We conclude that the endothelium-dependent and endothelium-independent vasodilations are impaired in diabetic patients predisposed to foot ulceration and that neuropathy is the main factor associated with this abnormality. Reduced expression of ecNOS may be a major contributing factor for endothelial dysfunction. These data provide support for a close association of neuropathy and microcirculation in the pathogenesis of foot ulceration.

Cardiomyopathy of limb-girdle muscular dystrophy.

OBJECTIVES: This study sought to find an association between dilated cardiomyopathy and limb-girdle muscular dystrophy. BACKGROUND: Cardiomyopathy has been seen in various neuromuscular disorders, but it has not been recognized to be associated with limb-girdle muscular dystrophy. METHODS: We investigated three sisters with well documented limb-girdle dystrophy and congestive heart failure by the 3rd decade of life. All underwent noninvasive evaluation of left ventricular systolic function by both echocardiography and radionuclide scanning, and one also had cardiac catheterization. Deoxyribonucleic acid (DNA) linkage analysis was performed in these affected subjects and in the unaffected family members, and DNA was extracted from mononuclear cells with primer sequences for three chromosome 13q microsatellite markers. RESULTS: The parents had no evidence of clinical disease, but all three sisters had echocardiographic evidence of dilated cardiomyopathy. The sister with additional evidence of left ventricular dysfunction of cardiac catheterization had no coronary artery disease. The affected subjects had the same paternal allele for three potential markers of limb-girdle muscular dystrophy but different maternal alleles. The very small family size did not permit statistical confirmation or refutation of linkage for chromosome 13q markers. CONCLUSIONS: Demonstrable cardiomyopathy accompanying limb-girdle muscular dystrophy and its probable genetic associations require continued investigation by anticipating the cardiomyopathy in limb-girdle muscular dystrophy.

Eosinophilia-myalgia syndrome associated with L-tryptophan ingestion. Analysis of four patients and implications for differential diagnosis and pathogenesis.

Four patients fulfilling the case definition for eosinophilia-myalgia syndrome are described, including one whose disease began in 1986. Each displayed a variety of symptoms: one suffered principally from myalgia and recovered spontaneously on discontinuation of L-tryptophan therapy; one exhibited progressive sclerodermiform skin changes, neuropathy, and myopathy; a third had prominent neuromuscular disease and sclerodermiform skin changes; and the fourth experienced profound weight loss, an axonal polyneuropathy, and perivascular lymphoid infiltrates simulating a lymphoma. Evidence of T-cell activation was present in peripheral blood and affected tissues during the clinically active progressive phase of disease. Among other manifestations pleural effusion, cutaneous vasculitis, joint contractures, and bloody diarrhea were observed. A history of L-tryptophan ingestion should be sought in patients with myalgia, fatigue, or the above outlined symptoms.

Neuropathology of experimental spinal cord ischemia in the rabbit.

We studied a highly reproducible spinal cord model of focal central nervous system ischemia produced by occlusion of the abdominal aorta in the rabbit just below the renal arteries. The neuropathology of the lesion at one week or longer is characterized by: 1. Necrosis of gray matter and relative sparing of white matter throughout the lumbar and sacral cord with periods of ischemia between 45 minutes and 2 hours; and 2. Selective necrosis of elements within the anterior horns of the gray matter (neurons) in the lumbar cord with periods of ischemia between 15 and 30 minutes and in the transition zone between normal and infarcted gray matter with periods of ischemia between 45 minutes and 2 hours. Within the time period that causes irreversible damage (15 minutes to 1 hour), the distribution, size, and severity of infarcts is proportional to the duration of ischemia. The degree of functional impairment correlated closely with the extent of tissue damage. Previous work on ischemia of the spinal cord in experimental animals is critically reviewed. The segmental topographic distribution of the lesion and its histologic characteristics are discussed in relation to two important pathophysiological mechanisms of injury in central nervous system ischemia: the microcirculatory network, which in turn governs the adequacy of collateral flow, and the differential susceptibility of cells in nervous tissue. Sequential regional spinal cord blood flow determinations will be necessary to establish the precise relationship between levels of blood flow over time and space and neuropathology.

Selective necrosis and total necrosis in focal cerebral ischemia. Neuropathologic observations on experimental middle cerebral artery occlusion in the macaque monkey.

Temporary (15 minutes to 24 hours) or permanent focal cerebral ischemia was induced in 87 awake monkeys (Macaca mulatta and Macaca fasicularis) by transorbital snare ligation of the middle cerebral artery (MCA) and neuropathological evaluation was carried out two weeks later. The size, location and histology of lesions varied within each time-period of MCA occlusion. However, most animals that underwent long-term ischemia (eight hours to permanent) had a single, confluent infarct involving deep and sometimes cortical structures. These animals had total necrosis chracterized by: 1. indiscriminate involvement of white and gray matter, 2. relatively sharp margins containing astrocytic and mononuclear cells, 3. an inner zone of liquefaction, infiltrated with fat-laden macrophages and newly formed blood vessels. Animals that underwent moderate to short-term ischemia (30 minutes to four hours) showed multiple, non-confluent deep infarcts. These animals had selective necrosis characterized by: 1. involvement of gray matter and relative sparing of white matter, 2. poorly circumscribed, multiple and often perivascular lesions with incomplete tissue destruction, 3. preferential loss of neurons and proliferation of reactive astrocytes and microglia.

The intracerebral microcirculation of the rat in hemorrhagic shock.

The intracerebral microcirculation of the isocortex was studied in unanesthetized rats under hemorrhagic shock. To observe the microvessels, three markers were separately injected intravenously during the shock period: (a) Evans blue for fluorescence microscopic visualization of the vessels. (b) India ink for gross and light microscopic evidence of retention of carbon. (c) Horseradish peroxidase (HRP) for light and electron microscopic study. Lack of spontaneous recovery from shock was associated with: (a) 55-65% blood loss, a low blood pressure (30-40 mm Hg), and a dramatic increase in pulse rate; (b) marked Evans blue fluorescence along the vessels; (c) no retention of India ink in the microcirculation; (d) peroxidase activity on the luminal surface of the endothelium. Absence of India ink in the microcirculation of the isocortex during the shock period, as shown by light and electron microscopy, suggests that there is sufficient cerebral blood flow to clear the carbon particles from the blood stream and that there are no openings greater than 30 nm in the endothelial layer allowing seepage of carbon particles through or between endothelial cells. Vascular Evans blue fluorescence and peroxidase activity were both demonstrated on the luminal surface of the endothelial cells, by light microscopy, indicating that these markers are abnormally retained. Ultrastructural demonstration of increased HRP uptake and adherence onto the endothelial cells confirms these observations. These results show that regional endothelial alterations occur in this model of hemorrhagic shock.

Charcot-Marie-Tooth disease associated with hypertrophic neuropathy: a neuropathologic study of two cases.

The neuropathologic features of two cases of Charcot-Marie-Tooth disease associated with hypertrophic neuropathy are described. The peripheral nerves had a loss of myelinated fibers, endoneurial fibrosis, and numerous onion-bulb formations. The most severe changes were seen in the distal nerves. In the older of the two patients, advanced changes were also observed in the proximal nerves and anterior roots and were associated with neuronal degeneration in the anterior horns and dorsal root ganglia. The muscles were the site of chronic denervation atrophy, which was most severe in the distal portions of the lower extremities. In one of the cases, the autopsy findings were complemented by sural nerve biopsy studies, which confirmed the presence of segmental demyelination and remyelination, axonal degeneration, and Schwann cell proliferation in the form of onion bulbs. Our observations support the concept of a primary neuronal abnormality in the hypertrophic type of Charcot-Marie-Tooth disease (HN-CMT). The disorder appears to initially involve the distal axonal processes but, with progression of the disease, also involves the proximal axons, eventually leading to degeneration and loss of neurons in the anterior horns and dorsal root ganglia. Onion-bulb formation generally parallels nerve fiber degeneration, suggesting that segmental demyelination and onion bulbs may occur secondary to axonal degeneration. The possibility of a concomitant Schwann cell abnormality cannot be excluded, however, on the basis of our postmortem studies.

Human immunodeficiency virus (HIV) leukoencephalopathy and the microcirculation.

We studied the brains of three patients with acquired immune deficiency syndrome (AIDS), all of whom developed subacutely progressive dementia unassociated with opportunistic infection or neoplasm in the central nervous system. Computed tomographic (CT) scans of the head revealed cortical atrophy, ventricular dilation, and diffuse hypodensity of the centrum semiovale. On microscopic examination, the cerebral and cerebellar white matter in all cases showed diffuse and focal, angiocentric regions of myelin pallor, focal vacuolization, and extensive gliosis. Variable axonal loss and axonal spheroids were evident. The microvasculature showed striking changes, including mural thickening, increased cellularity, and enlargement and pleomorphism of endothelial cells with variable numbers of macrophages and multinucleated giant cells (MNGC), which often contained hemosiderin pigment. Human immunodeficiency virus type 1 (HIV-1) antigens were identified immunocytochemically within perivascular macrophages and MNGC and in some microglial cells. We suggest that the morphologic abnormalities of the microcirculation may be associated with an alteration of the blood-brain barrier. The increased vascular permeability could contribute to damage and loss of the white matter including both myelin and axons, and result in subcortical cerebral atrophy. The HIV-1 infected cells present in relation to the microvasculature may play a role in mediating the vascular injury.

The indusium griseum: is it involved in Alzheimer's disease?

The histopathology of the indusium griseum (IG), a displaced hippocampal anlage, was studied in five patients with Alzheimer's disease (AD) and five controls. In the AD group, the IG had occasional neurons with granulovacuolar change (GVD) and rare Hirano bodies (HB), but no senile plaques (SP), neurofibrillary tangles (NFT), or neurons staining for phosphorylated neurofilament antigen. There was a slight but not statistically significant diminution of neurons within the IG. In all AD cases, the hippocampus showed abundant AD-associated histopathology. In the control cases, only rare neurons with GVD were present in the IG. These findings indicate that although single neurons within the IG may show some of the cytologic changes seen in the hippocampal neurons in normal aging and AD, IG neurons do not express the full range and severity of histopathologic abnormalities characteristic of AD. This suggests that factors other than selective vulnerability of neurons of hippocampal origin might be operating to induce the neuropathologic picture of AD.

Spectrum of neurological deficits in experimental CNS ischemia. A quantitative study.

The sequence of events in focal cerebral ischemia has been difficult to study quantitatively in humans. Experimental investigation of these phenomena has been impeded because reproducible animals models that simulate human stroke are lacking. We have developed a rabbit spinal cord ischemia model that resembles human stroke patterns in many respects. Using this model, we have found that (1) brief ischemia produces completely reversible neurological deficits; (2) intermediate ischemic periods may produce transiently reversible deficits that later progress without further manipulation; (3) prolonged ischemia produces irreversible lesions in all animals. The model should be useful for studies of the pathophysiological mechanisms of CNS ischemia.

Vacuolar change in Alzheimer's disease.

A retrospective neuropathologic study of brains from 66 patients with Alzheimer's disease (AD) demonstrated the presence of a vacuolar change (VC) in 50 cases that was virtually indistinguishable histologically from the spongiform change characteristic of Creutzfeldt-Jakob disease (CJD). Indeed, in several instances, there was initial diagnostic confusion with CJD. Unlike the spongiform change in CJD, however, VC was almost entirely restricted to the medial temporal cortex and amygdala. Furthermore, the severity of VC was usually less intense than the spongiform change observed in cases of CJD with severe neurologic impairment. The VC could be readily distinguished from the fine microvacuolation of the upper layers of the isocortex reported in a number of different conditions, including AD. It also differed from the status spongiosus of the cerebral cortex that occurs in advanced AD and CJD as well as in other degenerative diseases. The artifactual rarefaction that occurs in improperly processed paraffin-embedded brain tissue was excluded as a contributory factor to the VC. Since VC does not invariably occur in AD, it conceivably could represent a subtype of this disorder or may represent a variant of the pathologic changes that can occur. Its relationship to CJD or other slow virus disorders is to date unknown but unlikely.

Tissue plasminogen activator. Reduction of neurologic damage after experimental embolic stroke.

Tissue plasminogen activator (tPA) has become available for pharmacologic use, and it appears to produce relatively fewer hemorrhagic complications than the previously available, less specific thrombolytic agents. We tested the effects of tPA in several models of embolic stroke and found that neurologic damage was reduced when the drug was administered as late as 45 minutes after cerebral embolic occlusion. The mechanism of therapeutic efficacy of tPA was probably thrombolysis. Drug-induced hemorrhages did not occur when therapy was started within four hours after the onset of vascular occlusion. These results suggest that tPA may be useful for thrombolytic therapy of embolic stroke if the drug is administered rapidly after the onset of vascular occlusion.

Pseudallescheria boydii infection of the central nervous system.

Pseudallescheria boydii is a rare cause of central nervous system infection characteristically presenting as a neutrophilic meningitis or multiple brain abscesses. Factors predisposing to central nervous system infection with this fungus include immunosuppression and near drowning. The organism is infrequently cultured from fluid obtained by lumbar puncture, delaying clinical recognition and appropriate antifungal therapy. All untreated patients with P boydii infection of the central nervous system died. We describe a patient who developed a persistent neutrophilic meningitis with focal neurologic deficits due to P boydii 6 months after a freshwater aspiration pneumonia. We also review the characteristic clinical and pathologic features of previously reported cases and emphasize the importance of early detection and treatment in the management of this frequently intractable disease.

Variability and reversibility of focal cerebral ischemia in unanesthetized monkeys.

To assess reversibility of focal cerebral ischemia, we performed a neurologic and pathologic study of 27 monkeys subjected to temporary middle cerebral artery occlusion. An implanted snare ligature occluded the artery in awake monkeys for 30 minutes, 4 hours, 8 hours, 16 hours, 24 hours, or permanently. Serial neurologic observations were made for 2 weeks, and systematic neuropathologic examination estimated extent of infarction. Deficits from ischemia were commonly reversible at 30 minutes and 4 hours, but were rarely reversible after 8 hours. Neurologic deficit and infarct size showed remarkable variability. Maximum irreversible infarction evolved in about 4 to 8 hours in most awake monkeys. Variability and reversibility of focal ischemia were probably related to variable collateral circulation. The results suggested that emergency surgical revascularization might help some cases of acute ischemic stroke.

Perineuritis and ulcerative colitis.

We describe the association of chronic polyneuropathy with ulcerative colitis. Electrophysiologic studies disclosed a severe neuropathy with both axonal and demyelinating features. The CSF protein content was 875 mg/dl. Sural nerve biopsy revealed perineuritis. Peripheral neuropathy with perineuritis may be an immunologically mediated extraintestinal manifestation of ulcerative colitis.

Thalamic dementia and motor neuron disease.

A 46-year-old woman developed a progressive neurologic disorder over the course of 30 months which was characterized by profound dementia complicated by a motor neuron disorder that became evident 10 months prior to death. Postmortem examination of the nervous system disclosed extensive neuronal loss and gliosis of the thalamus, predominantly involving the dorsomedial nuclei, as well as severe degeneration of the corticospinal tracts, spinal anterior horns, and hypoglossal nuclei. The disease could not be transmitted to experimental animals by intracerebral inoculation of the patient's brain tissue. This case represents a unique dementing disorder, possibly familial, with associated motor neuron disease.

Coexistence of Lambert-Eaton myasthenic syndrome and subacute cerebellar degeneration: differential effects of treatment.

A 61-year-old woman presented with two paraneoplastic neurologic disorders--Lambert-Eaton myasthenic syndrome (LEMS) and subacute cerebellar degeneration (SCD)--that antedated the diagnosis of small-cell carcinoma of the lung by 15 months. Plasmapheresis initiated before the identification of the tumor had a beneficial effect on LEMS but did not affect the SCD. Chemotherapy administered for treatment of the primary tumor was also associated with improvement of LEMS but, like plasmapheresis, had no effect on SCD. While the pathogenesis of both LEMS and SCD is thought to be mediated predominantly by humoral immune factors, a differential therapeutic response indicates that mechanisms of tissue damage or susceptibility to tissue injury, or both, differ in these two disorders.

Lobar atrophy with pontine neuronal chromatolysis ("ballooned" neurons).

A 64-year-old man developed progressive dementia over a period of 11 years. Postmortem examination showed severe atrophy of the temporal lobes of the brain with extensive neuronal loss and a remarkable alteration of the neuronal perikaryon--the "ballooned" neuron--restricted to the nuclei of the basis pontis. No neuritic plaques, neurofibrillary tangles, or Pick bodies were seen.

A model for quantitative evaluation of embolic stroke therapy.

We developed a small animal embolic stroke model for pharmacological screening trials. Microspheres are injected into the carotid circulations and group embolus dose-response relationships are calculated. Emboli quantity is related to neurologic injury, and small changes in neurologic function are detectable. Rabbits tolerated twice as many microspheres when cyproheptadine-treated after embolization. This demonstrated both the sensitivity of the model and the value of serotonin antagonists in reducing neurological injury.