Tau gene mutation in familial progressive subcortical gliosis.

Familial forms of frontotemporal dementias are associated with mutations in the tau gene. A kindred affected by progressive subcortical gliosis (PSG), a rare form of presenile dementia, has genetic linkage to chromosome 17q21-22. This kindred (PSG-1) is included in the 'frontotemporal dementias and Parkinsonism linked to chromosome 17' group along with kindreds affected by apparently different forms of atypical dementias. Some of these kindreds have mutations in the tau gene. We report here that PSG-1 has a tau mutation at position +16 of the intron after exon 10. The mutation destabilizes a predicted stem-loop structure and leads to an over-representation of the soluble four-repeat tau isoforms, which assemble into wide, twisted, ribbon-like filaments and ultimately result in abundant neuronal and glial tau pathology. The mutations associated with PSG and other atypical dementias can be subdivided into three groups according to their tau gene locations and effects on tau. The existence of tau mutations with distinct pathogenetic mechanisms may explain the phenotypic heterogeneity of atypical dementias that previously led to their classification into separate disease entities.

Nineteenth-century contributions to the mechanical recording of postural sway.

In the first half of the 19th century, European physicians, including Marshall Hall, Bernardus Brach, and Moritz Romberg, described loss of postural control in darkness by patients with severely compromised proprioception. Late 19th-century neurologists developed instruments to measure and record postural sway in patients with neurologic disease. Principal American contributors were the neurologist Silas Weir Mitchell from Philadelphia, Pa, and his trainees Morris Lewis and Guy Hinsdale. The efforts of these neurologists anticipated later physiologic studies and ultimately the development of computerized dynamic platform posturography.

William Hammond, the dynamometer, the dynamograph.

The dynamometer came into general use by neurologists in the late 19th century. Various dynamometers were developed and adopted by neurologists at that time to measure muscle strength, in keeping with the general trend of adopting instrumentation to distinguish our specialty and aid observation and diagnosis. Many dynamometers were adaptations of the French Mathieu dynamometer, which was initially promoted by American neurologist William Hammond. Another variation, the Mathieu dynamograph, used to graphically record measurements made with a dynamometer, was also initially studied, used, and promoted by Hammond. The high cost of the dynamograph and the lack of demonstrated clinical utility contributed to its limited dissemination. The history of the dynamometer and the dynamograph illustrate both the practical difficulties associated with developing a new instrument, and the numerous modifications that such an instrument goes through, some of which have little to do with practical application.

The suspension therapy for tabes dorsalis. A case history of a therapeutic fad.

The suspension therapy of tabes dorsalis was introduced by Motschutkovsky in 1883, popularized by Charcot and Gilles de la Tourette in 1889, and subsequently rapidly and widely disseminated on the basis of enthusiastic case series. Dissemination was facilitated by endorsements of eminent neurologists, widespread publicity in professional journals and lay press, and the apparent simplicity and safety of the procedure. However, increasingly critical reports appeared, indicating much lower success rates, frequent postprocedure deterioration, and occasional serious complications. The disparity between early and later studies resulted from a placebo effect, from disregard of the natural history of the condition, from misdiagnosis, and from biased observation and reporting. By the end of 1890, the procedure was largely abandoned, despite proponents' attempts to modify the technique or to identify a more responsive subgroup of patients.

Conditions associated with Huntington's disease at death. A case-control study.

To identify conditions associated with reduced survival in patients with Huntington's disease, we studied all 1978 US death certificates on which Huntington's disease (331.0 in the International Classification of Diseases, eighth revision) was listed. For each of the 495 cases identified, two control deaths were matched by age, race, sex, county, and year of death. Pneumonia, choking, nutritional deficiencies, and chronic skin ulcers were increased in cases relative to controls.

Causative factors for suicide attempts by overdose in epileptics.

We investigated possible causative factors for the high epileptic suicide rate by reviewing the cases of 22 patients with idiopathic epilepsy found among 711 patients hospitalized for a suicide attempt by overdose. Suicide attempts occurred with increased seizure activity in one epileptic; otherwise, no relationships were found with seizure-related variables. When matched by age, sex, and race with 44 nonepileptic controls from the same population, the epileptics had more borderline personality disorders with multiple impulsive suicide attempts (45.5% vs 13.6%), more psychotic disturbances, including command hallucinations (31.8% vs 9.1%), fewer adjustment disorders (18.2% vs 45.5%), and a comparable frequency of depression (13.6% vs 25%). We conclude that suicide attempts in epileptics are primarily associated with interictal psychopathologic factors, such as borderline personality disorder and psychosis, rather than with specific psychosocial stressors, seizure variables, or anticonvulsant medications.

Indications for thymectomy in myasthenia gravis.

Fifty-six board-certified neurologists with interest and expertise in myasthenia completed a survey of indications for thymectomy in myasthenia gravis. Thymectomy was advocated for virtually all patients with thymoma, for a variable subset of patients with generalized myasthenia without thymoma, and occasionally for selected patients with disabling ocular myasthenia.

The history of reflex hammers.

Following the simultaneous description of muscle stretch reflexes by Heinrich Erb and Carl Westphal in 1875, neurologists used direct finger taps or chest percussion hammers to elicit these phenomena. Because of inadequacies of chest percussion hammers for eliciting muscle stretch reflexes, a variety of hammers were developed specifically for this purpose. In 1888, J. Madison Taylor, working for S. Weir Mitchell at the Philadelphia Orthopedic Hospital, designed the first such "reflex hammer." Taylor's hammer had a triangular rubber head and a short, flattened metal handle. Krauss (1894), Berliner (1910), Troemner (1910), Babinski (1912), and Wintle (1925) also designed popular reflex hammers. Many of these hammers and several others are still in use.

Diagnosis of thymoma in myasthenics using anti-striated muscle antibodies: predictive value and gain in diagnostic certainty.

Assay of anti-striated muscle antibodies (StrAb) is used as a diagnostic test for thymoma in individuals with myasthenia gravis. Unfortunately, false positive results are common, and their effect on test accuracy is magnified by the relatively low frequency of thymoma in myasthenics. We estimated the predictive values of positive and negative StrAb assays (PV+ and PV-) and gain in diagnostic certainty using values for sensitivity, specificity, and thymoma frequency previously reported in the literature. Sensitivity for indirect immunofluorescence assays ranged from 0.83 to 0.84 (pooled estimate = 0.84; n = 68). Specificity ranged from 0.73 to 0.88 (pooled estimate = 0.77; n = 898). Frequency of thymoma ranged from 0.07 to 0.17 (pooled estimate = 0.12; n = 4,515). The expected gain in diagnostic certainty from StrAb was minimal in those aged 0 to 20 and those aged 60+. In those aged 20 to 60, a negative test helped to exclude thymoma, and a positive test raised diagnostic suspicion but was not sufficient to establish a diagnosis of thymoma (PV+ = 0.46).

Stages in the recognition of epidemic pellagra in the United States: 1865-1960.

Recognition of the U.S. pellagra "epidemic" in the early part of this century occurred in stages. The recognition process distorted impressions of magnitude, rate of spread, and virulence. Unrecognized cases: Endemic pellagra developed from dietary deficiencies after the Civil War. Initially, cases were misdiagnosed as other more traditional disorders. Tradition and authority inhibited recognition. Recognition of severe cases: Beginning in 1907, outbreaks were reported in asylums. Existing severe cases came rapidly to medical attention, inflating the apparent rate of spread. Recognized cases had a fulminant course and a high case fatality. Expanded spectrum: Milder cases were increasingly recognized, leading to an exaggerated rate of increase in number of cases and a decrease in case fatality and apparent virulence. Greater sensitivity resulted largely from a shift in diagnostic thresholds, with loss of specificity and increase in false positive diagnoses. Standardization of diagnosis: Although no suitable diagnostic marker test was developed, diagnosis was ultimately standardized by development of a workable case definition and by assessment of response to an effective therapy (nicotinic acid) applied to presumptive cases.

Dementia mortality in the United States. Results of the 1986 National Mortality Followback Survey.

This study sought to determine nationally representative estimates of mortality from or with dementia in the United States, to compare rates derived from various sources of ascertainment, and to estimate the contribution of dementia to morbidity and facility usage in the last year of life. National Mortality Followback Survey (NMFS) data were analyzed. The NMFS is based on a nationwide probability sample of persons aged 25 and over who died in the United States in 1986. For sampled decedents, information was obtained from death certificates, detailed questionnaires and interviews of family members, and from abstracted records of health facilities that provided care during the last year of life. Rates varied by age, race, and source of ascertainment. Rates based on death certificate diagnoses were generally an order of magnitude smaller than rates based on other sources. Alzheimer's disease was the most frequently reported cause of dementia. In the last year of life, most demented patients required assistance with multiple basic activities of daily living, had severe impairments in cognitive functioning, and received some care in general medical-surgical hospitals. Dementia is an extremely common cause of morbidity and mortality. Rates vary widely depending on the method of ascertainment; in particular, ascertainment based on death certificates grossly underestimates the magnitude of the problem.

Geographic distribution of stroke mortality in the United States: 1939-1941 to 1979-1981.

I used data from the National Center for Health Statistics to map the geographic distribution of age-adjusted, race- and gender-specific stroke mortality rates in the United States from 1939-1941 to 1979-1981. Over this interval, stroke mortality rates declined dramatically with convergence of age-adjusted, state-specific stroke rates both within and between the various race-gender groups. For each race-gender group, high age-adjusted stroke mortality rates were significantly clustered in the southeastern United States, particularly in the South Atlantic census division, with persistent extreme rates in Georgia and the Carolinas. For whites, low-rate states were concentrated in the Mountain census division and along the northern Atlantic coast. The nonrandom distribution of stroke mortality across the United States, the large magnitude of the difference between high- and low-rate areas, the persistence of the pattern over more than four decades, the similarity of the distribution for different race-gender groups, the lack of delimitation by administrative or political boundaries, and results of national cooperative studies completed in the late 1960s and early 1970s together suggest that the pattern of excess stroke mortality is not an artifact of different diagnostic and reporting practices. Some of the observed geographic variation may be due to both the effects of selective migration and variations in the distributions of stroke risk factors.

Geographic distribution of hospitalization rates, case fatality, and mortality from stroke in the United States.

We analyzed state-specific stroke-hospitalization, case-fatality, and mortality rates for the US Medicare population for 1989, using national data resources of the Health Care Financing Administration (HCFA), the National Center for Health Statistics, and the Bureau of the Census. State-specific hospital admission rates for stroke ranged from 0.66 to 1.26%, compared with the national value of 0.94%. Both hospital-usage rates and deviations of observed rates from predicted values (based on statistical models of the HCFA) showed significant spatial autocorrelation, with high rates clustered in the southeastern United States and low rates clustered in the Mountain census division of the West and also somewhat in the Northeast. Case-fatality rates increased nationally from 14.9% at 15 days after hospital admission to 31.2% at 180 days after hospital admission. State-level case-fatality rates showed relatively little interstate variation and no clear or consistent spatial pattern, although there was statistically significant spatial autocorrelation at several intervals after hospital admission. Admission rates and case-fatality rates were not significantly associated at any interval after admission to 180 days, suggesting that variation in case-fatality rates was not simply a result of differences in severity-of-illness thresholds for hospital admission. State-specific stroke-mortality rates ranged from 294.5 to 523.5 per 100,000 population, compared with the national value of 415.3 per 100,000 population. State-specific mortality rates for stroke showed significant spatial autocorrelation, with high rates clustered in the South and low rates clustered in the Northeast and the Mountain census division of the West. The spatial distribution of stroke-mortality rates strongly resembled the spatial distribution of hospitalization rates but did not resemble the spatial distribution of case-fatality rates at any interval from 15 to 180 days after hospital admission. Indeed, in univariate spatial-regression models fitted to the data using a maximum likelihood procedure and weighted for non-constant variances, the best predictor of state-level stroke-mortality rates was the hospital-utilization rate for stroke; attempts to improve the model by including case fatality at various intervals and interaction terms did not yield a significant improvement. These data suggest that factors determining stroke occurrence and hospital utilization are more important than factors determining case fatality in terms of explaining the long-standing distribution of stroke mortality in the United States. Factors affecting only case fatality but not hospitalization, such as the quality of medical care provided in the hospital, cannot explain the geographic distribution of stroke mortality in the United States.

Romberg's sign: development, adoption, and adaptation in the 19th century.

In the first half of the 19th century, European physicians-including Marshall Hall, Moritz Romberg, and Bernardus Brach-described loss of postural control in darkness of patients with severely compromised proprioception. Romberg and Brach emphasized the relationship between this sign and tabes dorsalis. Later, other neurologists evaluated the phenomenon in a broader range of neurologic disorders using a variety of simple but increasingly precise and sensitive clinical tests. Although now known as Romberg's sign, among neurologists in the late 19th century this phenomenon was sometimes credited to Romberg, sometimes to both Brach and Romberg, and sometimes discussed without attribution.

Benign paroxysmal positioning vertigo: classic descriptions, origins of the provocative positioning technique, and conceptual developments.

The original description of benign paroxysmal positioning vertigo (BPPV) has been variously attributed to Bárány, Adler, and others. In addition, the proper eponymic designation for the provocative positioning test used to diagnose BPPV has been unclear, because authors use a variety of different terms, including Bárány, Nylén-Bárány, Nylén, Hallpike, Hallpike-Dix, and Dix-Hallpike to refer to the procedure in current use. Based on a review of the extant medical literature, Bárány was the first to describe the condition in detail, and Dix and Hallpike were the first to clearly describe both the currently used provocative positioning technique and the essential clinical manifestations of benign paroxysmal positioning vertigo elicited by that technique. Nevertheless, despite their important contributions, neither Bárány nor Dix and Hallpike understood the pathophysiology of BPPV nor did they appreciate that the positioning techniques they used actually demonstrated pathology in the semicircular canals rather than the utricle. The modern understanding of the pathophysiology of BPPV began with Schuknecht's proposal that the dysfunction resulted from the gravity-dependent movement of loose or fixed dense material within the posterior semicircular canal ("cupulolithiasis"). Although Schuknecht's formulations were not consistent with all clinical features of the disease, they led to the modern "canalolithiasis theory" and highly effective canalith repositioning or "liberatory" maneuvers for BPPV.

Seasonal variation in stroke mortality rates.

OBJECTIVE: To identify possible contributors to the seasonal variation in stroke mortality. BACKGROUND: Stroke and respiratory disease mortality rates were calculated from vital statistics and census data for the United States from 1938 to 1988. State-specific average temperatures by month were derived from data obtained from the National Climatic Data Center for 1938 to 1987. METHODS: Each time series was decomposed into a trend, a seasonal effect, and a residual effect. Multiple regression was used to fit both a trend and a seasonal harmonic series. Cross-correlation was used to assess the relationship between the residual time series. RESULTS: There is a strong and consistent seasonal pattern of high stroke and respiratory disease mortality in the colder winter months. Stroke mortality was significantly and independently both positively associated with respiratory disease mortality and inversely associated with temperature. The sharp initial increases in both respiratory disease and stroke mortality in the late fall and early winter are synchronous, and the amplitudes are strongly associated, except for a saturation effect with extreme respiratory disease amplitudes. CONCLUSIONS: Seasonal change in stroke mortality is associated with seasonal variation in both respiratory disease and temperature. Respiratory disease and temperature may influence stroke mortality nonspuriously by affecting stroke case fatality, incidence, or both.

In-hospital mortality following carotid endarterectomy.

OBJECTIVES: To determine population-based estimates of in-hospital mortality following carotid endarterectomy (CEA) and identify potential risk factors for in-hospital death. METHODS: Data from the Healthcare Cost and Utilization Project (HCUP-3) were analyzed for the year 1993. Nationally representative estimates of risk were calculated by age, sex, race, income, census region, hospital location (urban versus rural), teaching status of hospital, number of hospital beds, hospital ownership, third-party payer, principal procedure, and presence of surgical complications. Multivariate models were developed using stepwise logistic regression and a logit model fit by generalized estimating equations. RESULTS: There were 228 deaths among 18,510 CEAs performed in 17 states of the United States in 1993, yielding an estimated in-hospital mortality rate of 1.2%. Multivariate analysis showed that age, principal procedure, and presence of any surgical complication were significant predictors of in-hospital mortality. Mortality increased with increasing age (from 0.9% in those younger than 65 years to 1.7% in those age 75 and older) and was markedly higher with CEA performed as a secondary procedure (6.1% versus 0.9%) or with any surgical complication (5.9% versus 0.9%). CONCLUSIONS: Increasing age, CEA performed as a secondary procedure, and surgical complications are important predictors of in-hospital mortality following CEA.

Stroke and intracranial venous thrombosis during pregnancy and puerperium.

OBJECTIVES: To determine nationally representative estimates of the incidence of stroke and intracranial venous thrombosis during pregnancy and the puerperium, and to identify potential risk factors for these conditions. METHODS: National Hospital Discharge Survey data were analyzed for the period 1979 to 1991. Nationally representative estimates of risk were calculated by age, race, presence of pregnancy-related hypertension, census region, hospital ownership, and number of hospital beds. Multivariate models were developed using logistic regression. RESULTS: There were an estimated 8,918 cases of stroke and 5,723 cases of intracranial venous thrombosis during pregnancy and the puerperium in the United States among 50,264,631 deliveries, giving risks of 17.7 cases of stroke and 11.4 cases of intracranial venous thrombosis per 100,000 deliveries. In the multivariate models, stroke was associated strongly with pregnancy-related hypertension, larger hospital size, and proprietary hospital ownership, and inversely associated with living in the South. Intracranial venous thrombosis was associated with maternal age. CONCLUSIONS: Stroke and intracranial venous thrombosis are relatively common complications of pregnancy and the puerperium. Collectively, rates for these conditions are about 50% greater for the entire period of pregnancy and the puerperium than for the immediate peripartum period.

Surgeon characteristics associated with mortality and morbidity following carotid endarterectomy.

PURPOSE: To identify surgeon characteristics associated with mortality or morbidity, following carotid endarterectomy (CEA). METHODS: Data on all inpatient discharges from the 284 nonfederal Pennsylvania hospitals were obtained from the Pennsylvania Health Care Cost Containment Council for the period from 1994 to 1995. Physician data were obtained from the Physicians List of the American Medical Association, including name, gender, specialty, year of birth, board certified, and year of licensure. Cases were selected if any of six procedures codes were ICD-9-CM rubric 38.12, indicating CEA. RESULTS: Among the 12,725 cases studied, in-hospital mortality was 0.7%, nonfatal morbidity was 3.0%, and the total bad outcome rate was 3.7%. Surgeons who performed 1 to 2 CEAs over 2 years had the highest mortality (2.0%) and total bad outcome (9.2%) rates. For surgeons performing three or more cases in 2 years, increased volume was not associated with better outcomes. A greater number of years since the surgeon was licensed was associated with greater mortality (p = 0.001), but not with morbidity or bad outcome rates. In regression analyses that adjusted for patient risk, both years since licensure and specialty predicted surgical mortality rate, but only volume predicted surgical bad outcome rate. CONCLUSIONS: More years since licensure and very low patient volume are associated with worse patient outcomes following CEA.

Syphilitic polyradiculopathy in an HIV-positive man.

We report a case of syphilitic lumbosacral polyradiculopathy in an HIV-positive, 22-year-old bisexual man with a recent history of secondary syphilis treated with intramuscular penicillin. He presented with rapidly progressive pain and weakness, and muscle wasting in the legs. CSF was under increased pressure and showed a marked pleocytosis (1,130 cells/mm3), hypoglycorrhachia (19 mg/dl), and very elevated protein (1,000 mg/dl). Serum and CSF VDRL serologies were positive. In the legs, nerve conduction studies and needle EMG were consistent with an asymmetric lumbosacral polyradiculopathy with active denervation. His clinical state, CSF, and electrophysiologic studies all improved promptly and markedly after intravenous penicillin. This report documents an uncharacteristically aggressive case of neurosyphilis accompanied by marked changes in the CSF in an HIV-positive patient. While the immunologic effects of HIV and syphilis in combination are not yet fully understood, the cellular immunity defect associated with HIV may alter the natural history of syphilis in patients with concomitant infection, producing unusually aggressive forms or atypical presentations of neurosyphilis.