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.

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.

Revaccination of renal transplant and hemodialysis recipients with pneumococcal vaccine.

Two years after pneumococcal vaccine was given to patients on a university renal transplant and hemodialysis service, vaccine failures began to occur. Serologic studies showed a threefold decrease in antibody levels during this period, from 913 ng of antibody nitrogen per milliliter to 315 ng/mL. The decrease was greater in patients undergoing hemodialysis than in renal transplant recipients (879 to 215 ng/mL vs 932 to 385 ng/mL). The lowest antibody levels were to types 4, 6A, and 19F. Patients were revaccinated, without serious reactions, and pneumococcal infections decreased as they had after the original vaccination program. After revaccination, there was a twofold increase in antibody levels (315 to 602 ng/mL), but the levels did not reach those seen after primary vaccination. The increase was greater in hemodialysis than in renal transplant recipients (215 to 757 ng/mL vs 385 to 536 ng/mL). This experience indicates that pneumococcal vaccines may be effective in patients undergoing hemodialysis and in asplenic renal transplant recipients, but these groups will require revaccination sooner than normal subjects to maintain immunity.

Response to pneumococcal vaccine in renal transplant and hemodialysis patients.

Because of the risk of serious pneumococcal infections in patients receiving a renal transplant, a study was undertaken to determine if pneumococcal vaccine could be administered before or after transplantation. Vaccine was given to recipients of transplants and to patients who were undergoing dialysis. Both groups responded to the vaccine, and although the mean antibody levels were lower than those reported for normal populations, the levels were in the range thought to be protective for most pneumococcal types. Antibody levels, both before and after vaccination, were substantially lower in patients with recent transplants than in patients who were undergoing hemodialysis. Patients who are awaiting renal transplantation can be immunized while they are undergoing hemodialysis. Further study is needed to determine how long antibody levels will persist after vaccination in both patients undergoing hemodialysis and those receiving a transplant.

Acute febrile cerebrovasculitis. A non-spotted fever group rickettsial disease.

In December 1985, a patient was seen with an illness that was clinically compatible with the recently described clinical syndrome of acute febrile cerebrovasculitis, including fever, headache, altered mentation, multifocal neurologic signs, and cerebrospinal fluid pleocytosis. An extensive medical evaluation failed to reveal a cause, until, retrospectively, she was shown to have antibodies to Rickettsia typhi. Detailed serologic analysis with enzyme immunoassays and protein immunoblots indicated that she was infected with a non-spotted fever group Rickettsia, most likely either R typhi or Rickettsia canada. Serum samples from a mouse trapped at her home contained antibody only to R canada. Evaluation of patients with acute febrile cerebrovasculitis in the future should include rickettsial blood cultures to attempt specific identification of the species involved.

Late onset of fatal cytomegalovirus infection after renal transplantation. Primary or reactivation infection?

Cytomegaloviurs (CMV) infections are a recognized problem in the first six months after renal transplantation. Studies have suggested that primary infections produce symptomatic disease, whereas reactivation infections are usually asymptomatic. Two patients are described who developed fatal CMV infections in the second year after transplantation. Both patients had typical CMV disease with fever, pneumonitis, and hepatitis. Results of serologic studies in one patient were characteristic of primary infection, with seroconversion at the time of disease and appearance of specific IgM antibodies. The other patient had a similar antibody response at the time of his illness, but serial antibody tests showed that he had had a transient seroconversion earlier, in the second month after transplanation, that was not associated with clinical symptoms. These patients indicate that CMV infection must be considered in the differential diagnosis of serious febrile illnesses even in the late posttransplantation period and may occur either as the result of primary or reactivation infection. Serologic studies at the time of illness may not allow distinction between the types of infection.

Emergence of acyclovir-resistant varicella zoster virus in an AIDS patient on prolonged acyclovir therapy.

We demonstrate for the first time the appearance of acyclovir resistance in serial varicella zoster isolates from a patient treated with acyclovir. We recovered varicella zoster virus three times over a period of 5 months from the skin lesions of this patient with AIDS who was treated with three courses of intravenous acyclovir and prolonged low-dose oral acyclovir. The isolate recovered from a typical zoster lesion before acyclovir, and one obtained from a hyperkeratotic lesion 2 months later, after intravenous and oral acyclovir, were sensitive to acyclovir and produced normal amounts of thymidine kinase. In contrast, virus recovered from lesions 5 months after the onset, when the patient had received repeated courses of acyclovir, was acyclovir-resistant and thymidine-kinase-deficient. Resistance to acyclovir was associated with persistence of lesions which failed to improve with intravenous acyclovir, but was not associated with new lesion formation.

Pathogenesis of varicella-zoster angiitis in the CNS.

A 20-year-old man with Hodgkin's disease experienced ophthalmic zoster with dissemination and CNS involvement. At autopsy, he was found to have granulomatous angiitis involving the basilar artery, and electron microscopy revealed virus-like particles in the outer layers of the vessel walls, but not the endothelium. This suggests that granulomatous angiitis of the CNS in varicella-zoster infections results from direct viral invasion of blood vessels, perhaps by contiguous spread from cranial nerves.

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.

Cytomegalovirus encephalitis associated with thymoma and immunoglobulin deficiency.

The clinical and immunologic findings in an elderly woman with thymoma and immunoglobulin deficiency in whom cytomegalovirus (CMV) encephalitis developed are described. The patient had absent serum immunoglobulins and no circulating immunoglobulin-bearing lymphocytes. Complement receptor-bearing lymphocytes were present in the peripheral blood, and circulating T lymphocyte numbers were within normal limits. She was anergic to a battery of skin test antigens, and her lymphocytes in vitro showed a selective unresponsiveness to CMV antigen while responding normally to phytohemagglutinin and streptokinase. The course of the encephalitis was progressive with quadriplegia, aphasia and coma developing within six months of onset of symptoms. This is the fifth reported case documenting an association between CMV infection and the syndrome of thymoma with immunoglobulin deficiency, but the first report of fatal CMV encephalitis in a patient with thymoma and immunoglobulin deficiency.

Herpesvirus hominis type 2 meningoencephalitis following renal transplantation.

Herpesvirus hominis (HVH) type 2 meningoencephalitis, confirmed by isolation of the virus from cerebrospinal fluid and brain biopsy specimens, is described in a 44 year old man following renal transplantation. An HVH type 2 genital infection developed two weeks after renal transplantation, which was followed by meningoencephalitis 10 days later. Subsequently an intracerebral hemorrhage developed with evidence of diffuse vasculitis on arteriography. In a second transplant patient a similar clinical syndrome also developed after an HVH type 2 genital infection, but viral studies were not made to confirm the etiology of the meningoencephalitis. HVH has been recognized as a cause ot mucocutaneous diseases in recipients of renal transplants, but involvement of the central nervous system has not been reported.

Measles immunity after revaccination: results in children vaccinated before 10 months of age.

Measles immunity was studied in children in a private pediatric practice who had been revaccinated because they had received their primary measles vaccination before 1 year of age. Antibody was measured in 72 of these children who had received the first injection of live measles virus vaccine at less than 10 months of age, and the second at greater than 1 year of age. Of the 72 children, 29 (40%) had no detectable antibody and the geometric mean titer for the group was approximately 1:4. Of the children with low antibody titers, 15 were given a third injection of measles vaccine and five (33%) still did not respond. Cell-mediated immunity as indicated by lymphocyte transformation to measles antigen was measured in 11 of the children. Five (45%) had responses to measles antigen, but the responses did not correlate with the presence or absence of antibody. This study confirms the observation that revaccination is unsuccessful in many children who received measles vaccine in the first year of life, and shows that even a third injection of vaccine may fail to produce a significant antibody response.

Antiviral chemotherapy and neonatal herpes simplex virus infecition: a pilot study--experience with adenine arabinoside (ARA-A).

Among 13 neonates with herpes simplex virus (HSV) infection, eight had disseminated disease, one localized CNS disease, and in four the infection was confined to the skin and eyes. Ara-A, a purine nucleoside with anti-viral activity against DNA-VIRUSES, WAS GIVEN (10 TO 20 MG/MG/DAY) BY A CONTINUOUS 12-HOUR INTRAVENOUS DRIP FOR 10 TO 15 DAYS. In all, ara-A administration was begun within three to eight days after the appearance of skin vesicles which represented the hallmark of the disease. Both diagnosis and ara-A treatment were much delayed in one infant without skin vesicles and four infants whose skin vesicles appeared late, long after the occurrence of CNS damage. In this group of infants with disseminated disease, four died and one infant was left with severe neurological deficits. Eight infants (four with disseminated and four with localized skin disease) with skin vesicles as the earliest sign of infection received ara-A early, within three days after the onset of neurologic signs. All survived with no neurologic deficit at 6 months to 1 year of age. There was no apparent toxicity of ara-A to the bonemarrow, liver, or kidney.

Cytomegalovirus in the bronchoalveolar lavage fluid of patients with AIDS.

This study investigated the significance of detecting cytomegalovirus in the bronchoalveolar lavage fluid of patients with human immunodeficiency virus infection. Bronchoscopy with BAL was performed on all patients. Lavage was examined for CMV by cytology, culture, and immunofluorescence. The lavage results were compared to clinical status at the time of bronchoscopy and the outcome of the respiratory event. Cytomegalovirus was detected in 51 percent of the BALs in the patients with HIV infection and 25 percent of the immunosuppressed patients without HIV. No association was found in the HIV infected patients between CMV and hypoxemia, abnormal chest roentgenogram, leukopenia, and increased mortality. As indicated by mortality, CMV did not significantly increase the severity of Pneumocystis carinii pneumonia. The study also suggested that CMV in BAL fluid reflected bronchopulmonary replication of the virus, and not contamination by virus in the blood. Cytomegalovirus does not appear to contribute directly to the pulmonary disease found in most patients with HIV infection.

Recovery of human immunodeficiency virus and detection of p24 antigen in bronchoalveolar lavage fluid from adult patients with AIDS.

Published reports indicate that HIV is recovered from BAL fluid of patients with AIDS who have LIP but not with other AIDS-related pulmonary disease. Our experience has been different. Ten BAL specimens from nine patients with AIDS were cultured directly in peripheral blood mononuclear cells, and all ten cultures were positive for HIV as indicated by examination of the culture supernatant by reverse transcriptase assay and enzyme immunoassay for HIV antigen. Five of the specimens were also positive for Pneumocystis carinii, and other pulmonary diagnoses included histoplasmosis, lymphoma, Kaposi's sarcoma, and aspiration pneumonia. Five additional BAL specimens were cultured after freezing at -70 degrees C, but only two were culture-positive for HIV (p = 0.022; FET). This study indicates that HIV can be recovered from the BAL fluid in most patients with AIDS, unrelated to the type of pulmonary disease. In contrast to cultures, HIV antigen was detected in the BAL fluid of only one patient, and that patient had LIP with noncaseating granulomas. Therefore, HIV culture is not useful in the diagnosis of LIP, but HIV antigen detection should be studied further. All BAL fluids should be considered potentially infectious.

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.

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.

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.

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.

Pneumococcal endophthalmitis after corneal transplantation: control by modification of harvesting techniques.

Between January and September 1986, 61 patients underwent corneal transplantation at a university hospital, and three (4.9%) of the patients developed endophthalmitis. Cultures of the donor cornea were positive for Streptococcus pneumoniae. The transplant program was stopped and an investigation begun. Review of corneal transplants in 1985 showed that S pneumoniae was recovered from only 1 (1.5%) of 66 donor corneas compared with 6 (9.8%) of 61 in 1986 (P = 0.045; Fisher's exact test). Investigation showed that major changes had occurred in the corneal transplant program in 1986 as a result of a new state law. Coroner's cases had become the source of most corneas; younger donors were available, and corneas, instead of whole eyes, were collected in the coroner's office, often by part-time technicians. All of the infected corneas had been harvested by part-time technicians, instead of the regular eye bank technician, and came from younger donors (mean age 11.8 years v 27.2; P less than or equal to 0.02). Based on these observations, collection techniques were modified to reduce contamination of corneas during harvesting. This included the use of surgical drapes and gloves, collecting the cornea without interruption, saline irrigation of the eye, and inversion of the eye chamber to ensure complete contact of the cornea with the antibiotic-containing media. The program was restarted, and there were no corneal infections with S pneumoniae during a one-year follow-up period.(ABSTRACT TRUNCATED AT 250 WORDS)