Important sources of variability in clinical studies of neutralizing antibodies against interferon beta.

Interferon (IFN) beta treatment of relapsing-remitting multiple sclerosis (RRMS) stimulates production of neutralizing antibodies (NAbs) in some patients. However, clinical data supporting the hypothesis that NAbs to IFN beta adversely affect patient outcomes are not consistent across multiple studies or different forms of IFN beta. Only the PRISMS trial has produced data showing a negative impact of NAbs to IFN beta-1a (Rebif) across multiple study endpoints. No such data are available for IFN beta-1b (Betaseron) despite completion of a large registry study. Biological factors affecting the development of NAbs to IFN beta include protein structure, product formulation, administration frequency and/or dosing, and patients' immunological responses. Technical factors affecting interpretation of clinical trial data on NAbs include inadequate randomization; differences in the methods used to measure NAbs and in definitions of NAb positivity; selection of NAb-positive patient subpopulations according to titer and duration of NAb response; lack of power to detect differences in patient subgroups; and different trial durations. Given the complexity of NAb studies, it is not possible to generalize from current data regarding the potential impact of NAbs on the clinical efficacy of all IFN beta therapies. Differences between IFN beta products and their specific trials should be considered when evaluating the evidence on this topic.

Jugular bulb saturation and cognitive dysfunction after cardiopulmonary bypass.

Inadequate cerebral oxygenation during cardiopulmonary bypass may lead to postoperative cognitive dysfunction in patients undergoing cardiac operations. A psychological test battery was administered to 255 patients before cardiac operation and just before hospital discharge. Postoperative impairment was defined as a decline of more than one standard deviation in 20% of tests. Variables significantly (p < 0.05) associated with postoperative cognitive impairment are baseline psychometric scores, largest arterial-venous oxygen difference, and years of education. Jugular bulb hemoglobin saturation is significant if it replaces arterial-venous oxygen difference in the model. Factors correlated with jugular bulb saturation at normothermia were cerebral metabolic rate of oxygen consumption (r = -0.6; p < 0.0005), cerebral blood flow (r = 0.4; p < 0.0005), oxygen delivery (r = 0.4; p < 0.0005), and mean arterial pressure (r = 0.15; p < 0.05). Three measures were significantly related to desaturation at normothermia and at hypothermia as well: greater cerebral oxygen extraction, greater arterial-venous oxygen difference, and lower ratio of cerebral blood flow to arterial-venous oxygen difference. We conclude that cerebral venous desaturation occurs during cardiopulmonary bypass in 17% to 23% of people and is associated with impaired postoperative cognitive test performance.

Effect of aging on cerebral autoregulation during cardiopulmonary bypass. Association with postoperative cognitive dysfunction.

BACKGROUND: Age is a predictor of cognitive dysfunction after cardiac surgery, but the mechanism is unknown. The purpose of our study was to determine whether age-related decrements in cognition are associated with cerebral blood flow (CBF) autoregulation during cardiopulmonary bypass (CPB). METHODS AND RESULTS: Cognitive function testing was completed before surgery and before hospital discharge in 215 patients undergoing elective coronary artery bypass grafting (CABG) surgery. The battery consisted of seven tests with nine measures designed to evaluate memory, mood changes, and visuomotor speed and function. Pressure-flow and metabolic-flow cerebral autoregulation during hypothermic cardiopulmonary bypass were determined using the 133Xe clearance CBF method and radial artery and jugular bulb effluent to calculate cerebral metabolic rate (CMRO2) and cerebral AV difference (C[AV]O2). Pressure-flow autoregulation was tested by using two CBF measurements at stable hypothermia: one at stable mean arterial pressure (MAP) and the second 15 minutes later when MAP had increased or decreased > or = 20%. Metabolism-flow autoregulation was tested by varying the temperature (CMRO2) and measuring the coupling of CBF and CMRO2. Individual patient autoregulation was correlated with changes in cognitive measures. Cognitive performance declined in 6 of 9 measures after CABG surgery. Age predicted cognitive decline in 7 of 9 measures; short-term memory showed the greatest effect of age. Pressure-flow autoregulation during hypothermic CPB showed a small but significant (P < .0001) effect of pressure on CBF. There was no effect of age on the slope of CBF response to changes in MAP (pressure-flow autoregulation). There was a major effect of temperature on CBF during CPB (P < .0001). Coupling CBF and CMRO2 with changing temperature was unaffected by age. Changes in cognition were not associated with measures of cerebral autoregulation. However, increasing C(AV)O2 is associated with cognitive deficits in 5 of 9 measures; these associations were independent of age. CONCLUSIONS: Increased age predisposes to impaired cognition after cardiac surgery. This decline in cognitive function in the elderly is not associated with age-related changes in cerebral blood flow autoregulation. The association of increased oxygen extraction with decline in some measures of cognitive function suggests that an imbalance in cerebral tissue oxygen supply, which is unrelated to age, contributes to acute cognitive dysfunction after cardiac surgery. Cognitive dysfunction after CPB in the elderly cannot be explained by impaired CBF autoregulation.

Detection of sequences homologous to human retroviral DNA in multiple sclerosis by gene amplification.

Twenty-one patients with multiple sclerosis, chronic progressive type, were examined for DNA sequences homologous to a human retrovirus. Genomic DNA from peripheral blood mononuclear cells was analyzed for the presence of homologous sequences to the human T-cell leukemia/lymphoma virus type I (HTLV-I) long terminal repeat, 3' gag, pol, and env domains by the enzymatic in vitro gene amplification technique, polymerase chain reaction. Positive identification of homologous pol sequences was made in the amplified DNA from six of these patients (29%). Three of these six patients (14%) also tested positive for the env region, but not for the other regions tested. In contrast, none of the samples from 35 normal individuals studied was positive when amplified and tested with the same primers and probes. Comparison of patterns obtained from controls and from patients with adult T-cell leukemia or tropical spastic paraparesis suggests that the DNA sequences identified are exogenous to the human genome and may correspond to a human retroviral species. The data support the detection of a human retroviral agent in some patients with multiple sclerosis.

Atrial septal aneurysm: association with cerebrovascular and peripheral embolic events.

Patient records in 36 consecutively identified patients with typical echocardiographic findings of atrial septal aneurysm were reviewed. Ten of the 36 (28%) had cerebrovascular events. Of these 10, 5 had completed strokes of definite embolic origin on the basis of clinical, angiographic, and computed tomographic findings; 2 had transient ischemic attacks of probable embolic origin. One of the 36 patients had a definite peripheral vascular embolus. Thus, 6 of 36 consecutively identified patients with atrial septal aneurysm (17%) had definite embolic events and 8 of 36 (22%) had definite or possible embolic events. The cause of the association between atrial septal aneurysm and emboli is unknown. While aneurysm-associated thrombus has been suggested, the high proportion (90%) of patients with interatrial shunting demonstrated by contrast echocardiography in this study suggests paradoxical embolization as a potential cause. Whatever its mechanism, the high prevalence of embolic events in this series strongly supports the premise that atrial septal aneurysm is a cardiac abnormality with embolic potential.

Early-onset Alzheimer's disease: clinical predictors of institutionalization and death.

Follow-up observations were made of 92 white patients with early-onset Alzheimer's disease to determine the demographic, clinical, and neuropsychological factors predictive of institutionalization or death. The cumulative mortality rate 5 years after entry into the study was 23.9%, compared with an expected rate of 9.5%. The 5-year cumulative rate of admission to nursing homes was 62.8%. The language ability of the patients on entry to the study, their scores on a brief screening test of cognitive function, and their overall ratings of clinical dementia were found to be predictors of subsequent institutional care and death. The age of the patients had a significant modifying effect on these predictive factors, resulting in a greater risk of institutionalization and death in younger patients with severe cognitive impairment as compared with older individuals with the same degree of dysfunction.

Comparison of amaurosis fugax and transient cerebral ischemia: a prospective clinical and arteriographic study.

We compared the clinical associations, arteriographic findings, and long-term outcome of 93 patients with amaurosis fugax and 212 patients with focal cerebral ischemia (transient ischemic attacks [TIAs]). The group of patients with cerebral TIAs included a significantly larger proportion of blacks and had a higher prevalence of hypertension than the group with amaurosis. Operable atherosclerotic lesions of the carotid arteries were more often associated with amaurosis (66%) than with cerebral TIAs (51%). The seven-year cumulative rate of cerebral infarction, however, was less in patients with amaurosis (14%) than in those with cerebral TIAs (27%; p less than 0.02). This difference in outcome persisted after adjustment for race, hypertension, and type of therapy. There were no significant differences, however, in the cumulative rates either of recurrent TIAs or of myocardial infarction or sudden death in the two groups of patients.

Risk of ischemic heart disease in patients with TIA.

A prospective study was made of the morbidity and mortality from ischemic heart disease in 390 patients with focal TIA caused by atherosclerotic vascular disease. The 5-year cumulative rate of myocardial infarction or sudden death in these patients was 21.0%, a rate only slightly less than that of fatal or nonfatal cerebral infarction (22.7%). Risk factors including diabetes, angina, and ECG abnormalities were associated with an increase in morbidity and mortality from ischemic heart disease. A major factor associated with these cardiac events was the presence of atherosclerotic obstructive or ulcerative lesions in the carotid arteries. These observations indicate that focal TIA caused by carotid atherosclerosis is a predictor not only of cerebral infarction, but also of serious cardiac disease and death.

Dysautonomia in Guillain-Barré syndrome with dorsal root ganglioneuropathy, wallerian degeneration, and fatal myocarditis.

An acute Guillain-Barré syndrome presenting as dysautonomia is described in a 12-year-old boy. The patient died of intractable cardiac arrhythmias and cardiac failure. A severe myocarditis with destruction of dorsal root ganglion cells and wallerian degeneration of dorsal roots and peripheral nerves was apparent postmortem. Segmental demyelination and inflammatory cellular infiltrations were not present at these sites.

Alzheimer's disease: genetic aspects and associated clinical disorders.

Genetic aspects and associated clinical disorders were studied in a consecutive series of 68 men and women in whom Alzheimer's disease appeared at or before age 70. Secondary cases of dementia were found in 17 (25%) of the families, affecting 22 of the probands' siblings and parents. The cumulative incidence of Alzheimer's disease in these relatives was approximately 14% at age 75. An increased frequency of Down's syndrome was observed among relatives of the probands: a rate of 3.6 per 1,000, as compared with an expected rate of 1.3 per 1,000. A history of thyroid disease was established in 9 (19.6%) of the 46 female probands, a frequency greater than that reported in the general population. There was no excess of hematological malignancies among the blood relatives, and parental age at the time of birth of the probands did not differ from the norm. The results of this study indicate that early-onset Alzheimer's disease is associated with a genetic factor manifested in a substantial familial aggregation of dementia, a probable excess of Down's syndrome in the probands' relatives, and a possible association with thyroid dysfunction in women with this form of dementia.

Degeneration of the central nervous system associated with celiac disease.

The following report describes a 57-year-old man with celiac disease who developed a progressive and fatal neurologic disorder despite intensive medical and nutritional care. The clinical and pathological CNS findings in this patient are compared with those of 9 previously reported patients with well documented celiac disease in whom a progressive CNS disorder was carefully studied both pre-and postmortem. An entity of CNS degeneration associated with celiac disease appears to emerge from the study of these 10 cases. This disorder affects predominantly the cerebellum, deep gray masses, certain brain stem nuclei, and spinal cord; its cause and pathogenesis are unknown.

Progressive sensory neuropathy in patients without carcinoma: a disorder with distinctive clinical and electrophysiological findings.

Seven patients with severe progressive impairment of kinesthetic sense, mild dysfunction of cutaneous sense, and sparing of motor function were examined during a 3-year period. The clinical and electrophysiological findings are described in detail. None of these seven has had evidence of cancer despite a thorough investigation and a 3- to 16-year (average, 7 years) period of symptoms. These patients' symptoms were indistinguishable from those of patients with sensory neuropathy and coexistent carcinoma, suggesting that progressive sensory neuropathy is not invariably associated with carcinoma.

The effect of oral glycerol on intraventricular pressure in man.

Oral glycerol was administered to eight patients with meningeal carcinomatosis or acute leukemia in whom ventricular catheters and Ommaya reservoirs had been implanted for the purpose of intrathecal chemotherapy or chemoprophylaxis. Intraventricular pressure was monitored continuously via the Ommaya reservoirs before and after single doses of 0.5, 1.0 or l.5 gm per kilogram of body weight. The interrelationship between initial pressure, change in pressure, serum osmolarity, and duration of action was investigated, and the ratio of CSF-to-plasma osmolarity was determined 4 to 5 hours after glycerol administration. The effects of chronic 6-hourly and 4-hourly 1 gm per kilogram glycerol doses were studied in a patient with meningeal carcinomatosis and increased intracranial pressure. Our data suggest that as a cerebral dehydrating agent oral glycerol is most effective in patients with markedly increased intracranial pressure. A single 1 gm per kilogram dose is adequate to lower raised intraventricular pressure acutely, but its effect is short-lived. Continuous oral administration must be carefully monitored to avoid the establishment or a reverse osmotic gradient, secondarily increased intracranial pressure, and clinical deterioration.