Rapid disease course in African Americans with multiple sclerosis.

OBJECTIVE: To investigate utility of a Multiple Sclerosis Severity Scale (MSSS)-based classification system for comparing African American (AA) and white American (WA) multiple sclerosis (MS) subpopulations in the New York State Multiple Sclerosis Consortium (NYSMSC) database. MSSS is a frequency-rank algorithm relating MS disability to disease duration in a large, untreated reference population. Design/ METHODS: Distributions of patients in 6 MSSS-based severity grades were calculated for AA and WA registrants. RESULTS: There were 419 AA and 5,809 WA patients in the NYSMSC, who had EDSS recorded during years 1-30 since symptom onset. Median EDSS was not different in AA and WA (3.5 vs 3.0, p = 0.60), whereas median MSSS in AA was higher than in WA (6.0 vs 4.8, p = 0.001). AA patients were overrepresented in the 2 most severe grades (41.5% vs 29.3% for WA) and underrepresented in the 2 lowest grades (23.4% vs 35.4%; p < 0.001). In multivariable analysis (ordered logistic and median regression), MSSS for AA remained significantly higher than in WA after adjusting for age, gender, disease duration, disease type distribution, and treatment with disease-modifying therapies. CONCLUSIONS: The 6-tiered MSSS grading system is a powerful tool for comparing rate of disease progression in subpopulations of interest. MSSS-based analysis demonstrates that African ancestry is a risk factor for a more rapidly disabling disease course.

Multiple sclerosis characteristics in African American patients in the New York State Multiple Sclerosis Consortium.

The objective of this study was to determine the clinical characteristics of multiple sclerosis (MS) in African American (AA) patients in the New York State Multiple Sclerosis Consortium (NYSMSC) patient registry. The NYSMSC is a group of 18 MS centers throughout New York State organized to prospectively assess clinical characteristics of MS patients. AAs comprise 6% (329) of the total NYSMSC registrants (5602). Demographics, disease course, therapy, and socioeconomic status were compared in AA registrants versus nonAfrican Americans (NAA). There was an increased female preponderance and a significantly younger age at diagnosis in the AA group. AA patients were more likely to have greater disability with increased disease duration. No differences were seen in types of MS and use of disease modifying therapies. Our findings suggest a racial influence in MS. Further genetic studies that consider race differences are warranted to elucidate mechanisms of disease susceptibility.

Intranasal inoculation with the olfactory bulb line variant of mouse hepatitis virus causes extensive destruction of the olfactory bulb and accelerated turnover of neurons in the olfactory epithelium of mice.

Viral upper respiratory infections are the most common cause of clinical olfactory dysfunction, but the pathogenesis of dysosmia after viral infection is poorly understood. Biopsies of the olfactory mucosa in patients that complain of dysosmia after viral infection fall into two categories: one in which no olfactory epithelium is seen and another in which the epithelium is disordered and populated mainly by immature neurons. We have used intranasal inoculation with an olfactory bulb line variant of MHV to study the consequences of viral infection on peripheral olfactory structures. MHV OBLV has little direct effect on the olfactory epithelium, but causes extensive spongiotic degeneration and destruction of mitral cells and interneurons in the olfactory bulb such that the axonal projection from the bulb via the lateral olfactory tract is markedly reduced. Moreover, surviving mitral cells apparently remain disconnected from the sensory neuron input to the glomerular layer, judging from retrograde labeling studies using Dil. The damage to the bulb indirectly causes a persistent, long-term increase in the turnover of sensory neurons in the epithelium, i.e. the relative proportion of immature to mature sensory neurons and the rate of basal cell proliferation both increase. The changes that develop after inoculation with MHV OBLV closely resemble the disordering of the olfactory epithelium in some patient biopsies. Thus, damage to the olfactory nerve or bulb may contribute to a form of post-viral olfactory dysfunction and MHV OBLV is a useful model for studying the pathogenesis of this form of dysosmia.

Functional consequences following infection of the olfactory system by intranasal infusion of the olfactory bulb line variant (OBLV) of mouse hepatitis strain JHM.

The present study assessed the functional consequences of viral infection with a neurotropic coronavirus, designated MHV OBLV, that specifically targets central olfactory structures. Using standard operant techniques and a 'go, no-go' successive discrimination paradigm, six BALB/c mice were trained to discriminate between the presentation of an air or odor stimulus (three mice for each of the odorants propanol and propyl acetate). Two additional BALB/c mice were trained to discriminate between the presentation of air and the presentation of either vanillin or propionic acid. Following criterion performance, each mouse received an additional 2000 trials of overtraining. At completion of overtraining one mouse from the propanol and propyl acetate groups were allocated as untreated. The remaining six mice were inoculated with 300 microl of the OBLV stock per nostril for a total of 1.5 x 10(6) p.f.u. in 600 microl. Following a 1 month rest, untreated and inoculated animals were again tested on their respective air versus odor discrimination task. Untreated animals immediately performed at criterion levels. In contrast, inoculated animals varied in their capacity to discriminate between air and odorant. Five of the six inoculated mice showed massive disruption of the olfactory bulb, including death of mitral cells; the other was more modestly affected. In addition, the density of innervation of the olfactory mucosa by substance P-containing trigeminal fibers is also affected by inoculation. Those mice that remained anosmic to the training odorants had the most severe reduction in mitral cell number and substance P fiber density among the inoculated animals.

Serum insulin-like growth factor-I (IGF-I) does not correlate positively with isometric strength, fatigue, and quality of life in post-polio syndrome.

OBJECTIVES AND BACKGROUND: To determine if serum insulin-like growth factor-I (IGF-I) levels are associated with strength, body mass index (BMI), fatigue, or quality of life in post-poliomyelitis syndrome (PPS). PPS is likely due to a distal disintegration of enlarged post-polio motor units as a result of terminal axonal sprouting. Age-related decline in growth hormone and IGF-I (which support terminal axonal sprouts) is proposed as a contributing factor. METHODS: As part of the North American Post-Poliomyelitis Pyridostigmine Study (NAPPS), baseline data on maximum voluntary isometric contraction (MVIC), BMI, subjective fatigue (fatigue severity scale, Hare fatigue symptom scale), health-related quality of life (short form health survey-36; SF-36), and serum IGF-I levels were gathered on 112 PPS patients. Pearson correlation coefficients were calculated to evaluate the association between serum IGF-I and MVIC in 12 muscles, BMI, two fatigue scales, and SF-36 scale scores. RESULTS: There is a significant inverse correlation of IGF-I levels with MVIC in left ankle dorsiflexors (r=-0.30, P<0.01), and left and right knee extensors (r=-0.22, -0.25, P=<0.01, 0.01), but no significant correlations in other muscles. When men and women were evaluated separately, inverse correlations of IGF-I levels with MVIC were found only in men. IGF-I correlated inversely with BMI (r=-0.32, P=0006) and age (r=-0.32, P=0.0005). IGF-I did not correlate with the fatigue or SF-36 scales. CONCLUSIONS: In this exploratory study, we found that contrary to our expectations, IGF-I did not correlate positively with strength. IGF-I correlated negatively with strength in several lower extremity muscles, BMI, and age. IGF-I is likely not an important factor in the pathogenesis of fatigue and in determining quality of life in PPS, but its role on strength should be studied further.

A multicenter, randomized, double-blinded trial of pyridostigmine in postpolio syndrome.

BACKGROUND: Postpoliomyelitis syndrome (PPS) is likely due to degeneration and dysfunction of terminal axons of enlarged postpolio motor units. Age-related decline in growth hormone and insulin-like growth factor (IGF-I) may be a contributing factor. Neuromuscular junction abnormalities and decreased IGF-I levels may respond to the anticholinesterase pyridostigmine, with consequent improvement in strength, fatigue, and quality of life. OBJECTIVES: To determine the effect of pyridostigmine in PPS on health-related quality of life, isometric muscle strength, fatigue, and serum IGF-I levels; and to assess the safety of pyridostigmine in PPS. METHODS: The study was a multicenter, randomized, double-blinded, placebo-controlled trial of a 6-month course of pyridostigmine 60 mg three times per day in 126 PPS patients. The primary data analysis compared mean changes of outcomes between treatment and control groups at 6 months using an intention to treat approach. Secondary analyses included a comparison of outcomes at 6 and 10 weeks, and in compliant patients. RESULTS: The study showed no significant differences in pyridostigmine and placebo-treated patients with regard to changes in quality of life, isometric strength, fatigue, and IGF-I serum levels at 6 months in the primary analysis and in compliant patients. There were no differences in outcomes at 6 and 10 weeks between groups. However, very weak muscles (1 to 25% predicted normal at baseline) were somewhat stronger (p = 0.10, 95% CI of difference -9.5 to 73.3%), and in compliant patients IGF-I was somewhat increased (p = 0.15, 95% CI of difference -6.4 to 44.8 ng/mL) at 6 months with the medication. Pyridostigmine was generally well tolerated. CONCLUSIONS: This study showed no significant differences between pyridostigmine and placebo-treated PPS patients on measures of quality of life, isometric strength, fatigue, and serum IGF-I.

Post-polio syndrome: an update.

The PPS is now a well-recognized entity encompassing the late manifestations that occur because of previous poliomyelitis. Common signs and symptoms include fatigue, cold intolerance, joint deteriorations with pain, and prominent neurologic problems that include new weakness, muscle pain, atrophy, respiratory insufficiency, dysphagia, and sleep apnea. It is estimated that there are 1.63 million polio survivors in the United States and that half of them will develop PPS. PPS and PPMA usually begin 30 to 40 years after the acute illness and are very slowly progressive. The etiology is unclear, although premature exhaustion of the new sprouts that develop after acute poliomyelitis and of their motor neurons appears most likely. Less likely is a persistent polio-virus infection or an immune-mediated problem. Treatment is primarily supportive, although nonfatiguing strengthening exercise may improve strength over the short term. The long-term effects of this type of exercise remain to be clarified.

Motor neuron diseases and viruses: poliovirus, retroviruses, and lymphomas.

The viral theory of motor neuron disease (MND) has been rejuvenated in the last 5 years for several reasons. First, it is now recognized that enteroviruses and picornaviruses similar to poliovirus can persist and induce immune-mediated diseases. In some picornavirus animal models, the immune-mediated disease can occur and continue long after the infectious virus has been cleared, and in some cases of human MND an immune-mediated disease may occur. Second, the human retroviruses human immunodeficiency virus (HIV) and human T-cell lymphotrophic virus (HTLV) have caused isolated MND syndromes. Neither of these two specific viruses appear to be 'the amyotrophic lateral sclerosis (ALS) retrovirus', because they cause a plethora of neurologic syndromes unrelated to MND. Retroviruses of mice, however, can cause MND and lymphomas, and because there is an increased incidence of lymphomas in ALS patients, it has been suggested that retroviruses are another possible viral agent of human MND.

Susceptibility and resistance to poliovirus-induced paralysis of inbred mouse strains.

Susceptibility to human poliovirus-induced disease in different inbred mouse strains was analyzed after intracerebral inoculation of two mouse-adapted type 2 polioviruses, the attenuated W-2 strain and the virulent Lansing strain. In contrast to inoculation with the Lansing strain, which was invariably lethal, inoculation with the W-2 strain defined three groups of mice with high, intermediate, or low disease incidence. Those in the high-disease-incidence group, the DBA/1J and DBA/2J mice, exhibited a high level of virus replication in the spinal cord by day 2 postinfection, with no detectable neutralizing-antibody response. Mice in the intermediate- and low-incidence groups had lower levels of virus replication in the spinal cord and/or produced neutralizing antibodies. No correlation was observed between H-2 haplotype and the extent of virus replication, production of neutralizing or enzyme-linked immunosorbent assay-detectable antibodies, or T-cell-proliferative response. However, mice of the H-2k haplotype manifested a low incidence of disease.

Localization of genomic regions specific for the attenuated, mouse-adapted poliovirus type 2 strain W-2.

In order to begin to elucidate the genomic basis of the attenuation of mouse-adapted, poliovirus type 2 strain W-2 (PV2/W-2), we have cloned and sequenced the virus and compared it with the virulent, mouse-adapted PV2/Lansing strain. In addition, we have performed computer-generated comparisons of PV2/W-2 to the non-mouse-adapted, attenuated PV2/Sabin strain to determine whether mutational patterns occur that result in attenuation. The PV2/W-2 genome is 7434 nucleotides in length, which is three bases shorter than PV2/Lansing. The 5' non-coding region of PV2/W-2 is 747 nucleotides in length (compared to 744 in PV2/Lansing) and shares 98.8% identity with PV2/Lansing and 82.3% identity with PV2/Sabin. Overall, the PV2/W-2 polyprotein (2205 amino acids) is two amino acids shorter than that of either PV2/Lansing or PV2/Sabin (2207 amino acids). These contiguous deletions fall within the P3-D region (polymerase). Within these 2205 amino acid residues only 26 differences were observed between PV2/W-2 and PV2/Lansing (98.8% identity), whereas 92 occurred between PV2/W-2 and PV2/Sabin (95.8% identity). The 3' non-coding region of PV2/W-2 is 72 nucleotides in length and shares 100% identity with PV2/Lansing and 98.6% identity with PV2/Sabin. Amino acid changes in the capsid protein region occurred in neutralization sites 1 and 3, areas previously shown to be important for pathogenicity. The cleavage site between non-structural proteins P2-C/P3-A consisted of a glutamine-serine pair, in contrast to other sequenced polioviruses which have a glutamine-glycine dipeptide.

Cell-mediated immune responses to poliovirus II. Survey of delayed hypersensitivity and T-cell proliferative responses in inbred mouse strains.

Some epidemiological reports suggest a human genetic predisposition for susceptibility to the development of paralytic poliomyelitis. In a previous study of cell-mediated immune responses by mice to poliovirus (PV), we showed differences in the responses by BALB/c and C57BL/6 (B6) mice. The present study is a further analysis of the delayed hypersensitivity (DTH) and T cell proliferative (Tprlf) responses to PV in 17 different inbred strains of mice, to determine if these responses were under major histocompatibility complex (MHC) or other genetic control. Both DTH and Tprlf to PV did not correlate with MHC for responses to any of the three PV serotypes. Further, we found a lack of concordance of DTH and Tprlf responses to a given PV serotype. The cell-mediated immune responses by any one mouse strain to one PV serotype is not predictive of that mouse strain's response to another PV serotype.

Isoelectric focusing studies of serum and cerebrospinal fluid in patients with antecedent poliomyelitis.

The post-poliomyelitis syndrome (PPS) refers to symptoms of new weakness, fatigue, and pain years after recovery from acute poliomyelitis. Oligoclonal IgG bands have been reported in the cerebrospinal fluid (CSF) from PPS patients, suggesting that the syndrome is immune mediated or caused by persistent viral infection. We studied 15 paired serum and CSF samples and 6 unpaired CSF samples from a total of 21 patients with a prior history of poliomyelitis. Quantitative immune studies failed to show evidence for increased intrathecal IgG production relative to patients with noninflammatory central nervous system (CNS) disease. We found definite oligoclonal IgG bands in the CSF from only 1 patient, who also carried a diagnosis of multiple sclerosis. An isoelectric focusing poliovirus antigen overlay study showed evidence that suggested a CNS-specific antipoliovirus immune response in only 1 patient. Our results fail to support a dysimmune or persistent viral cause for post-poliomyelitis progressive muscular atrophy or PPS.

Anti-thymocyte serum delays clearance of poliovirus from the mouse central nervous system.

Antibody is of primary importance for protection from poliovirus-induced paralysis (poliomyelitis) and from other enterovirus infections. However, the components of the immune response involved in the clearance of an established enterovirus infection of the central nervous system (CNS) are not known. To assess the effect of thymus-dependent immune functions on a CNS poliovirus infection, adult BALB/c mice inoculated intracerebrally with the W-2 strain of human poliovirus type 2 (PV2) were treated with anti-thymocyte serum (ATS) and analyzed for clinical disease, virus persistence, antibody responses, and T-cell proliferation (Tprlf). Half (22 of 44) of the ATS-treated mice showed paralysis and death as compared to 27% (17 of 62) of control mice treated with normal rabbit serum. Virus persisted in the brain for 45 days after infection in 43% (13 of 30) of ATS-treated mice as compared to 3% (1 of 30) of controls. Tprlf to PV as well as Tprlf and antibody responses to control antigens were markedly reduced in ATS-treated mice. However, antibody responses to PV in ATS-treated mice were not suppressed, suggesting that PV may be a T-cell-independent antigen. These findings indicate that ATS-suppressible functions contribute to the clearance of PV from the mouse CNS, apparently via a sensitized T-cell mechanism.

Clearance of a persistent human enterovirus infection of the mouse central nervous system by the antiviral agent disoxaril.

Enteroviruses can cause persistent central nervous system (CNS) infections in agammaglobulinemic individuals. Because these infections are rarely cured by passive administration of antibody, a chemotherapeutic approach would be advantageous. In this study, the efficacy of the antienterovirus (and antipicornavirus) drug disoxaril was demonstrated in a murine model of persistent enterovirus infection. Disoxaril is a hydrophobic antiviral compound that blocks picornavirus uncoating. The W-2 strain of human poliovirus type 2 (PV2) persists in the CNS of immunosuppressed mice and causes late paralysis. Mice were inoculated intracerebrally with PV2, immunosuppressed with cyclophosphamide, and treated intragastrically with disoxaril at 50, 100, or 200 mg/kg per day in two divided doses beginning on postinfection day 20. At 200 mg/kg per day, disoxaril significantly decreased the incidence of clinical disease, i.e., paralysis and death. Assays for virus revealed more rapid clearance of virus from the CNS in the drug-treated group. No drug-associated toxicity was observed. Residual isolates of virus were not drug-resistant, suggesting that the appearance of drug resistance during prolonged treatment may not be a clinical problem.