Inventory of Non-Ataxia Signs (INAS): validation of a new clinical assessment instrument.

Although ataxia is by definition the prominent symptom of ataxia disorders, there are various neurological signs that may accompany ataxia in affected patients. Reliable and quantitative assessment of these signs is important because they contribute to disability, but may also interfere with ataxia. Therefore we devised the Inventory of Non-Ataxia Signs (INAS), a list of neurological signs that allows determining the presence and severity of non-ataxia signs in a standardized way. INAS underwent a rigorous validation procedure that involved a trial of 140 patients with spinocerebellar ataxia (SCA) for testing of inter-rater reliability and another trial of 28 SCA patients to assess short-term intra-rater reliability. In addition, data of the ongoing EUROSCA natural history study were used to determine the reproducibility, responsiveness and validity of INAS. Inter-rater reliability and short-term test-retest reliability was high, both for the total count and for most of the items. However, measures of responsiveness, such as the smallest detectable change and the clinically important change were not satisfactory. In addition, INAS did not differentiate between subjects that were subjectively stable and those that worsened in the 2-year observation period. In summary, INAS and INAS count showed good reproducibility, but unsatisfactory responsiveness. The present analysis and published data from the EUROSCA natural history study suggest that INAS is a valid measure of extracerebellar involvement in progressive ataxia disorders. As such, it is useful as a supplement to the measures of ataxia, but not as a primary outcome measure in future interventional trials.

The natural history of spinocerebellar ataxia type 1, 2, 3, and 6: a 2-year follow-up study.

OBJECTIVE: To obtain quantitative data on the progression of the most common spinocerebellar ataxias (SCAs) and identify factors that influence their progression, we initiated the EUROSCA natural history study, a multicentric longitudinal cohort study of 526 patients with SCA1, SCA2, SCA3, or SCA6. We report the results of the 1- and 2-year follow-up visits. METHODS: As the primary outcome measure we used the Scale for the Assessment and Rating of Ataxia (SARA, 0-40), and as a secondary measure the Inventory of Non-Ataxia Symptoms (INAS, 0-16) count. RESULTS: The annual increase of the SARA score was greatest in SCA1 (2.18 ± 0.17, mean ± SE) followed by SCA3 (1.61 ± 0.12) and SCA2 (1.40 ± 0.11). SARA progression in SCA6 was slowest and nonlinear (first year: 0.35 ± 0.34, second year: 1.44 ± 0.34). Analysis of the INAS count yielded similar results. Larger expanded repeats and earlier age at onset were associated with faster SARA progression in SCA1 and SCA2. In SCA1, repeat length of the expanded allele had a similar effect on INAS progression. In SCA3, SARA progression was influenced by the disease duration at inclusion, and INAS progression was faster in females. CONCLUSIONS: Our study gives a comprehensive quantitative account of disease progression in SCA1, SCA2, SCA3, and SCA6 and identifies factors that specifically affect disease progression.

Responsiveness of different rating instruments in spinocerebellar ataxia patients.

OBJECTIVE: To determine the longitudinal metric properties of recently developed clinical assessment tools in spinocerebellar ataxia (SCA). METHODS: A subset of 171 patients from the EUROSCA natural history study cohort (43 SCA1, 61 SCA2, 37 SCA3, and 30 SCA6) were examined after 1 year of follow-up. Score changes and effect size indices were calculated for clinical scales (Scale for the Assessment and Rating of Ataxia [SARA], Inventory of Non-Ataxia Symptoms [INAS]), functional tests (SCA Functional Index [SCAFI] and components), and a patient-based scale for subjective health status (EQ-5D visual analogue scale [EQVAS]). Responsiveness was determined in relation to the patient's global impression (PGI) of change and reproducibility described as retest reliability for the stable groups and smallest detectable change. RESULTS: Within the 1-year follow-up period, SARA, INAS, and SCAFI but not EQVAS indicated worsening in the whole group and in the groups with subjective (PGI) worsening. SCAFI and its 9-hole pegboard (9HPT) component also deteriorated in the stable groups. Standardized response means were highest for 9HPT (-0.67), SARA (0.50), and SCAFI (-0.48) with accordingly lower sample size estimates of 143, 250, or 275 per group for a 2-arm interventional trial that aims to reduce disease progression by 50%. SARA and EQVAS performed best to distinguish groups classified as worse by PGI. All scales except EQVAS reached the criterion for retest reliability. CONCLUSION: While both the Scale for the Assessment and Rating of Ataxia and the SCA Functional Index (SCAFI) (and its 9-hole pegboard component) had favorable measurement precision, the clinical relevance of SCAFI and 9-hole pegboard score changes warrants further exploration. The EQ-5D visual analogue scale proved insufficient for longitudinal assessment, but validly reflected patients' impression of change.

Transient change in GABA(A) receptor subunit mRNA expression in Lurcher cerebellar nuclei during Purkinje cell degeneration.

BACKGROUND: Lurcher mice suffer from a complete Purkinje cell (PC) loss in the first four postnatal weeks. Parallel to this degeneration, GABAergic synapses in the deep cerebellar nuclei (DCN), the major recipient of the inhibitory PC projection, increase synaptic conductance. Here, we further investigated this phenomenon, using real-time RT-PCR to assess GABAA receptor subunit gene expression during PC degeneration. RESULTS: We observed a specific reduction in gamma2 subunit gene expression, while alpha1-5, beta1-2, gamma1,3 and delta subunits were unaffected. We made two further specific findings. First, the difference in gene expression was shown in tissue from DCN only. Neither the hippocampus nor coronal sections through the forebrain showed such effects. Furthermore, the involvement of different levels of corticosterone, a possible humeral trigger for differences in gene expression, could be excluded. Second, like the known potentiation of GABAergic synapses, the gamma2 down-regulation was present only after the onset of degeneration at p14. The difference in gamma2 mRNA expression, however, appeared transient, since it was no longer detectable in adult Lurcher mice. CONCLUSION: In conclusion, the down-regulation of gamma2 subunits may be related to differences in synaptic efficacy and, as such, may reflect the initial phase of adaptive responses of DCN tissue to massive GABAergic deafferentation. Its transient course, however, does not support the idea that modulations in GABAergic transmission are at the basis of the well-known DCN-based functional benefit of Lurcher mice present throughout their life.

Lurcher mice exhibit potentiation of GABA(A)-receptor-mediated conductance in cerebellar nuclei neurons in close temporal relationship to Purkinje cell death.

In heterozygous Lurcher mice (Lc/+), the Purkinje cells (PCs) degenerate almost totally during postnatal development. On the other hand, their projection target, the deep cerebellar nuclei (DCN), shows few signs of degeneration and seems to play an important role in maintaining a residual cerebellar function in Lc/+. We asked whether the DCN in Lc/+ develop cellular adaptations allowing them to cope with the loss of GABAergic PC input. Using whole-cell patch-clamp recordings, we measured inhibitory postsynaptic currents from DCN of Lc/+ and wild-type mice (WT). In experiments on phenotypically striking Lc/+ studied well after the onset of the PC degeneration, we found enlarged average synaptic conductances (g(syn)) compared with WT. We next investigated postnatal mice before and after the onset of PC death. In younger animals

Tubulointerstitial nephritis due to a mutant polyomavirus BK virus strain, BKV(Cin), causing end-stage renal disease.

A renal biopsy from a 36-year-old man with AIDS showed a severe tubulointerstitial nephritis with intranuclear inclusions in epithelial cells. Electron microscopy revealed the characteristic findings of a polyomavirus (PyV) infection, and immunofluorescence indicated the presence of BK virus (BKV) antigen. Inoculation of rhesus monkey kidney cell cultures both with urine and with buffy coat blood cells resulted in a cytopathic response which was subsequently confirmed to be due to BKV. Further characterization of the viral DNA from the kidney by PCR amplification and Southern blot analysis with PyV and strain-specific primers and probes indicated that the virus was closely related to the BK(Dun) strain but different in its apparent sequence arrangement. Subsequent cycle sequencing showed a dinucleotide mutation of TG-->AA which substitutes hydrophilic Gln for hydrophobic Leu in a sequence homologous to an origin DNA-binding domain of simian virus 40 T antigen. It is suggested that the mutation and a coding region rearrangement of this strain of BKV designated BKV(Cin) has the potential to alter viral DNA replication and enhance pathogenicity.

Control of methicillin-resistant Staphylococcus aureus in a neonatal intensive-care unit: use of intensive microbiologic surveillance and mupirocin.

OBJECTIVE: To describe the epidemiology and the interventions used to control two methicillin-resistant Staphylococcus aureus (MRSA) epidemics involving 46 infants with two fatalities in a neonatal intensive care unit (NICU). SETTING: A 50-bed, level III NICU in a university hospital. INTERVENTIONS: After traditional interventions failed to stop the first epidemic, an intensive microbiologic surveillance (IMS) program was developed. Cultures were obtained on all infants each week, and those colonized with MRSA were isolated. When an infant was found to be colonized with MRSA, cultures immediately were obtained on all surrounding infants. This was continued until no MRSA-colonized infants were found in the area. During the first epidemic, mupirocin was used in an attempt to eradicate the organism from the unit. RESULTS: All infants, colonized and noncolonized, and parents of and personnel working with colonized infants were treated simultaneously with 5 days of mupirocin. This failed to eradicate MRSA in colonized infants. The spread of MRSA ceased in the unit, but a second epidemic occurred 4 months later. This time, IMS alone was successful in quickly containing the epidemic, and MRSA disappeared from the unit after all colonized infants were discharged. Plasmid analysis demonstrated that the same strain was responsible for both outbreaks. CONCLUSIONS: IMS and isolation are effective in containing the spread of MRSA in an NICU. The use of mupirocin failed to eradicate the organism.

The relationship between cytomegalovirus retrieved by bronchoalveolar lavage and mortality in patients with HIV.

STUDY OBJECTIVE: To evaluate mortality over 6 months of patients with HIV with cytomegalovirus (CMV) cultured from bronchoalveolar lavage (BAL) compared with those without CMV and to assess the significance of CMV cytologic study, CD4+ counts, and coexistent Pneumocystis carinii pneumonia. DESIGN: Retrospective evaluation of HIV-infected patients undergoing bronchoscopy with BAL. The 40 most recent HIV-positive patients undergoing bronchoscopy with BAL were included for each of three categories: CMV by cytologic study; CMV by culture only; and CMV absent. Patients for whom survival status at 6 months was unknown were excluded from analysis. SETTING: University hospital, tertiary care center. PATIENTS: Group 1 consisted of 36 patients with positive CMV culture and cytologic study and group 2 consisted of 38 patients with only a positive culture for CMV. Group 3 consisted of 40 patients with no evidence of CMV by BAL. RESULTS: On comparison of the groups, there was no difference in 3-week survival (from date of bronchoscopy). There was a statistically significant increase in mortality in group 1 patients compared with group 3 patients at both 3 and 6 months. Between groups 2 and 3, there was a difference in mortality that approached but did not reach significance at 3 months but did at 6 months. The mortality in group 1 at 3 months = 28%, at 6 months = 47%, whereas mortality in group 2 at 3 months = 26% and at 6 months = 45%. Group 3 had a 3-month mortality of 10% and a 6-month mortality of 15%. While those patients with positive CMV cytologic study had lower mean CD4+ counts, within the group, CD4+ counts were no different between the 3-month survivors and nonsurvivors (survivors, CD4/mm3 median = 38 [0 to 141]; and nonsurvivors, CD4/mm3 median = 16 [3 to 224]). Coinfection with P carinii did not increase mortality at 3 months. CONCLUSIONS: The CMV retrieved by BAL in HIV-infected patients was associated with significantly greater 3- and 6-month mortality. The CMV cytologic study did not predict a higher mortality and the difference in mortality between patients with and without CMV in BAL fluid was not directly attributed to lower CD4+ counts or P carinii coinfection.

Hepatitis C virus infection in healthcare workers: risk of exposure and infection.

OBJECTIVES: To determine the incidence of hepatitis C virus (HCV) infection among healthcare workers (HCWs) at a university hospital, the proportion of HCWs having non-A, non-B hepatitis (NANBH) who were anti-HCV positive, and the rate of HCV transmission following a HCV-positive needlestick injury. DESIGN: Longitudinal analysis of a dynamic (cohort) population. MEASUREMENTS: From 1980 through 1989, HCWs who had clinical NANBH were identified, and from 1987 through 1989, HCWs who reported a blood or body fluid exposure and the patients who were the source of the exposure were screened for antibodies to HCV. SETTING: A 732-bed, university hospital and outpatient clinics. RESULTS: Over the 10-year period, six cases of occupationally acquired NANBH were observed, for an incidence of 21 cases per 100,000 HCWs per year (standardized incidence ratio, 2.96; 95% confidence interval [CI95], 1.83 to 4.36). Four of the six cases were confirmed to be HCV infection. From 1987 through 1989, 176 (12.7%) of 1,387 patients who were the source of an exposure were anti-HCV positive. Exposures that occurred in the emergency department were more likely to be anti-HCV positive than were exposures from all other locations (relative risk [RR] = 1.7; P = 0.009). Of HCWs who had an HCV-positive needlestick injury and whose serum had been tested for anti-HCV at least 5 months after the exposure, 3 (6.0%) of 50 seroconverted. From 1987 through 1989, the incidence of HCV infection among HCWs was 54 cases per 100,000 HCWs per year. CONCLUSION: The incidence of clinical NANBH among HCWs in this study is approximately three times higher than that of non-HCWs. HCWs are at significant risk for exposure to and acquisition of HCV.

Recovery of viruses other than cytomegalovirus from bronchoalveolar lavage fluid.

STUDY DESIGN: To determine the yield and diagnostic significance of performing viral cultures on specimens obtained by bronchoalveolar lavage (BAL) in immunocompromised patients. DESIGN: Review of all BAL specimens submitted for viral culture over a six-year period. SETTING: Referral laboratory within a university hospital. The majority of specimens came from the university hospital, and for those cases, review of the patient's underlying disease, clinical presentation, and outcome was performed. PATIENTS: Over 95 percent of the patients had recognized underlying immunosuppression. INTERVENTION: None. MEASUREMENTS AND RESULTS: Cultures were done on 1,199 BAL specimens for viruses, and in 90 (8 percent), non-cytomegalovirus (CMV) viruses were recovered. These included herpes virus (53), influenza (11), parainfluenza (7), rhinovirus (12), adenovirus (5), enterovirus (1), and respiratory syncytial virus (1). Complete medical records were available for 1,020 (85 percent) of the BAL specimens, and the 77 patients with non-CMV viral pneumonia were studied in more detail. In 31 (40 percent) patients, virus was the only potential pathogen recovered. CONCLUSION: The recovery of respiratory viruses followed epidemic trends in the community and was often associated with self-limited illnesses without an increased mortality. The isolation of herpesvirus in patients without AIDS was associated with increased mortality in comparison with patients with AIDS (p < 0.01). This study demonstrates that viruses other than CMV may be recovered from BAL of patients with lower respiratory disease and may be the only pathogen recovered.

Recurrent epidemics caused by a single strain of erythromycin-resistant Staphylococcus aureus. The importance of molecular epidemiology.

OBJECTIVE--To compare the accuracy of clinical epidemiologic findings with results of molecular epidemiologic analysis in identifying the source of recurrent epidemics of erythromycin-resistant Staphylococcus aureus (ERSA) infections in a well-baby nursery. DESIGN--Epidemic investigations with retrospective and prospective microbiological surveillance. Staphylococcus aureus isolates were evaluated by plasmid analysis and genotyping. SETTING--A well-baby nursery in a 700-bed university teaching hospital with approximately 250 deliveries per month. PATIENTS--Newborn infants who developed ERSA infections during 1990 and 1991. INTERVENTION--Traditional infection control measures, including cohorting of infected infants and hand washing, were implemented. Personnel were cultured for nasal carriage of S aureus during both epidemics. Employees carrying ERSA were removed from the nursery and treated with mupirocin. RESULTS--In the first epidemic, 15 infants were infected with ERSA. A nursing assistant who cared for most of the infants was found to be a carrier of ERSA. She was removed from the nursery and the epidemic resolved. Fifteen months after the first epidemic ended, an epidemic that involved 11 infants began. The attending physician had a facial furuncle and was found to be a carrier of ERSA. The physician was treated and the epidemic resolved. Plasmid and genotyping showed the ERSA organisms from both epidemics were the same. The employee implicated in the first epidemic did not have the epidemic strain, but the physician who attended during both epidemics did. CONCLUSIONS--Traditional epidemic investigations may lead to false conclusions that can only be recognized with molecular epidemiologic techniques. For these techniques to be useful in the control of outbreaks, plasmid analysis and/or genotyping must be readily available.

Decline of clinical hepatitis B in workers at a general hospital: relation to increasing vaccine-induced immunity.

Hepatitis B is a well-recognized occupational hazard of health-care workers that can be prevented with vaccination. However, because data on the current epidemiology of hepatitis B virus (HBV) in this population are limited, no consensus exists regarding the requirement for immunization. In 1980-1989, 4,908 exposures of health-care workers to patients' blood and/or other body fluids were reported and evaluated at a general hospital. During this period, 4.8% of patients to whom health-care workers were exposed were positive for hepatitis B surface antigen (HBsAg). In exposed workers, the rate of protective immunity to HBV (measured by antibody to HBsAg) increased from 14% in 1980 to 55% in 1989. Hepatitis B vaccine became available at this hospital in 1983. The increase in antibody to HBsAg was not associated with an increase in antibody to HBV core antigen; this finding suggests that the increase in immunity was primarily vaccine induced. The incidence of reported clinical hepatitis B in health-care workers decreased from 82/100,000 in 1980-1984 to zero in 1985-1989 (odds ratio = 20.06; P = .0012). Thus, in this study, a program of hepatitis B immunization for health-care workers was associated with a significant decline in clinical HBV infection despite continued exposure to patients positive for HBsAg.

Yersinia enterocolitica infections in hospitalized patients: the problem of hospital-acquired infections.

OBJECTIVE: To study the epidemiology of Yersinia enterocolitica infections in hospitalized patients and to determine the frequency of hospital-acquired infection and the modes of transmission within the hospital. DESIGN: Descriptive study in which the clinical microbiology laboratory reported all positive Yersinia cultures to the infection control department; each case was investigated to determine the source of infection. SETTING: A 700-bed university teaching hospital. PARTICIPANTS: All patients who were culture-positive for Y enterocolitica after admission to the University of Cincinnati Hospital during the 4-year period between 1987 and 1990. RESULTS: Of 18 patients who were diagnosed with Yersinia infections, 8 (44%) were community-acquired. These patients were admitted with gastrointestinal symptoms and had their first positive cultures between days 1 and 5 of their hospitalizations. Five patients (28%) had hospital-acquired infections, having developed diarrhea after admission for unrelated problems, and became culture-positive between days 18 and 66. The remaining 5 patients could not be classified as either community- or hospital-acquired. These patients had gastrointestinal symptoms at the time of admission, but these could have been explained by other diseases. Their first positive stool cultures were not obtained until the second week or later during hospitalization, and 3 of these patients had negative stool cultures prior to a positive culture. CONCLUSIONS: Although Y enterocolitica has not previously been recognized as a common hospital problem, at least 28% of our patients acquired their Yersinia infections in the hospital. In some cases, cross infections, transmitted by healthcare workers, occurred between patients. Four of the 18 infections occurred in patients with acquired immunodeficiency syndrome.

Reemergence of epidemic methicillin-resistant Staphylococcus aureus in a general hospital associated with changing staphylococcal strains.

An epidemic of methicillin-resistant Staphylococcus aureus (MRSA) infections involving 323 patients occurred at the University of Cincinnati Hospital from 1977 to 1981. Subsequently, endemic MRSA persisted in the hospital for 6 years, until 1987, when a new epidemic began with 223 patients becoming infected over 3 years. Between the two epidemics, there was a major change in the MRSA recovered from infected patients, as demonstrated by three epidemiologic markers. Antibiograms showed that the tetracycline-resistant MRSA involved in the first epidemic was replaced by tetracycline-susceptible MRSA in the second epidemic; bacteriophage typing indicated that the original epidemic strain, D11/83A/85, had been replaced by new strains, many of which were susceptible to phage 54; and restriction endonuclease analysis of plasmid DNA confirmed that a single strain was involved in the first epidemic and that multiple strains were present in the second epidemic. The epidemiology of MRSA infections in the hospital changed with the change in staphylococcal strains. The first epidemic was hospital based with most infections occurring in surgical patients, and the burn unit was the major reservoir. In contrast, 28% of the patients in the second epidemic had community-acquired infections, and nursing home patients were an important source of these infections. Also, 29% of the hospital-acquired infections in this epidemic occurred in nonsurgical patients. This time the burn unit was not a reservoir of infection, but other intensive care units were. The increased diversity of strains of MRSA in the second epidemic might be related to increased transmission in the community and more widespread transmission in the hospital.

Isolation of human immunodeficiency virus type 1 in cutaneous blister fluid.

The human immunodeficiency virus type 1 (HIV-1) has been isolated from a number of body fluids, including semen, tears, cerebrospinal fluid, saliva, breast milk, alveolar fluid, and vaginal fluid, but it has not been isolated from fluid-containing skin lesions. We report the isolation of HIV-1 from cutaneous blister fluid in a patient with concomitant HIV-1 infection and porphyria cutanea tarda. Although transmission of HIV-1 through casual contact has not been reported, appropriate precautions should be taken to avoid direct contact with cutaneous fluid-containing lesions in HIV-1-positive patients.

Effect of educational programs, rigid sharps containers, and universal precautions on reported needlestick injuries in healthcare workers.

OBJECTIVE: To evaluate the effect of infection control programs on reported needlestick injuries in a general hospital. DESIGN: Surveillance of all reported needlestick injuries at the University of Cincinnati Hospital was maintained by the infection control department for five years, from 1985 through 1989. Data on individual workers were collected, tabulated on a monthly basis, and reviewed continually to monitor trends in injuries. During this time, the effects of each of three new infection control programs on reported injuries were evaluated sequentially. SETTING: A 700-bed general hospital that serves as the main teaching hospital of the University of Cincinnati. PARTICIPANTS: All employees of University Hospital who reported to personnel health for management of needlestick injuries. INTERVENTIONS: In 1986, an educational program to prevent injuries was initiated and continued throughout the surveillance period. In 1987, rigid sharps disposal containers were placed in all hospital rooms. In 1988, universal precautions were introduced with an intensive inservice. RESULTS: Surveillance identified 1,602 needlestick injuries (320/year) or 104/1,000/year. After the educational program began, reported injuries increased rather than decreased, and this was attributed to increased reporting. Subsequently, after installation of the new disposal containers, reported injuries returned to the levels seen prior to the educational program, but recapping injuries showed a significant decrease from 63/year to 30, or 20/1,000/year to 10. This decrease was observed in nurses but not in other healthcare workers. After universal precautions were instituted, total injuries increased slightly, but recapping injuries remained at 50% of the levels reported prior to the use of rigid sharps disposal containers. CONCLUSIONS: The three infection control programs failed to produce a major reduction in reported needlestick injuries, except for a decrease in recapping injuries associated with the placement of rigid sharps disposal containers in all patient rooms. These observations indicate that new approaches are needed to reduce needlestick injuries.