Large-scale survey of naturally occurring HBV polymerase mutations associated with anti-HBV drug resistance in untreated patients with chronic hepatitis B.

Drug resistance is a major limitation for the long-term efficacy of antiviral therapy with nucleos(t)ide analogues (NAs) in chronic hepatitis B (CHB). Antiviral resistance mutations may pre-exist in the overall viral population of untreated patients. We aimed to assess the prevalence of such hepatitis B virus (HBV) variants in a large cohort of NAs-naïve patients with CHB and to explore possible association with viral and host variables. Serum samples from 286 NAs-naïve consecutive patients with CHB were tested for serum HBV-DNA, and 255 of them having HBV-DNA > 1000 IU/mL were further analysed for drug resistance mutations by INNO-LiPA HBV DRv2/v3. NAs-naïve patients analysed were mainly men (73%), Caucasians (85%), hepatitis B e Antigen (HBeAg) negative (79%) and genotype D (69%), with a mean age of 43.2 ± 13.4 years. HBV mutations associated with antiviral drug resistance were detected in 13 (5%) patients: three patients infected with HBV genotype C had the rtM204V + rtL180M mutations associated with lamivudine (LMV) resistance. Four patients had the rtI233V mutation that may reduce sensitivity to adefovir, and three patients had the rtM250L/V mutation typical of entecavir resistance. LMV compensatory mutations rtL80V and rtV173L were seen in two and one patients, respectively. No relationship was seen between presence of resistant or compensatory mutations and HBV-DNA levels, HBeAg/anti-HBe status or previous IFN therapy. These results confirm that HBV mutations, which confer resistance against currently available anti-HBV NAs, may already exist in patients who have never received the drug.

Vascular comorbidity is associated with more rapid disability progression in multiple sclerosis.

BACKGROUND: Vascular comorbidity adversely influences health outcomes in several chronic conditions. Vascular comorbidities are common in multiple sclerosis (MS), but their impact on disease severity is unknown. Vascular comorbidities may contribute to the poorly understood heterogeneity in MS disease severity. Treatment of vascular comorbidities may represent an avenue for treating MS. METHODS: A total of 8,983 patients with MS enrolled in the North American Research Committee on Multiple Sclerosis Registry participated in this cohort study. Time from symptom onset or diagnosis until ambulatory disability was compared for patients with or without vascular comorbidities to determine their impact on MS severity. Multivariable proportional hazards models were adjusted for sex, race, age at symptom onset, year of symptom onset, socioeconomic status, and region of residence. RESULTS: Participants reporting one or more vascular comorbidities at diagnosis had an increased risk of ambulatory disability, and risk increased with the number of vascular conditions reported (hazard ratio [HR]/condition for early gait disability 1.51; 95% confidence interval [CI] 1.41-1.61). Vascular comorbidity at any time during the disease course also increased the risk of ambulatory disability (adjusted HR for unilateral walking assistance 1.54; 95% CI 1.44-1.65). The median time between diagnosis and need for ambulatory assistance was 18.8 years in patients without and 12.8 years in patients with vascular comorbidities. CONCLUSIONS: Vascular comorbidity, whether present at symptom onset, diagnosis, or later in the disease course, is associated with a substantially increased risk of disability progression in multiple sclerosis. The impact of treating vascular comorbidities on disease progression deserves investigation.

Serial combination therapy: is immune modulation in multiple sclerosis enhanced by initial immune suppression?

BACKGROUND: Although the concept that an initial course of immune-suppression facilitates subsequent immune-modulation (such as Th1 to Th2 deviation) is attractive for several autoimmune diseases, such a mechanism for serial-combination therapy has never been formally demonstrated. Recently, brief mitoxantrone induction-chemotherapy followed by immune-modulation with glatiramer acetate (GA) was significantly more effective at reducing multiple sclerosis disease activity than with GA alone. OBJECTIVE: To examine whether the benefit of initial immune suppression with mitoxantrone before GA treatment is associated with more efficient immune modulation. METHODS: IgG1/IgG4 GA-reactive antibody profiles, previously established as markers of GA-induced Th2 immune-deviation, were prospectively measured in vivo in patients treated with GA alone or with mitoxantrone induction therapy followed by GA. RESULTS: Significant and sustained increase in IgG4 antibodies (and the anticipated reversal of the IgG1/IgG4 ratio) was seen in patients treated with GA alone. Combination therapy resulted in lesser IgG4 induction (and no reversal of IgG1/IgG4 ratio). Thus, the enhanced efficacy of mitoxantrone-GA combination regimen was associated with decreased, rather than increased, efficiency of shifting the GA-reactive IgG1/IgG4 antibody profile. CONCLUSION: These results provide important insights into mechanisms of combination therapy and therapeutic strategies for autoimmune diseases.

The burden of mental comorbidity in multiple sclerosis: frequent, underdiagnosed, and undertreated.

BACKGROUND: Mental comorbidity is common in multiple sclerosis (MS), but some studies suggest that mental comorbidity may be underrecognized and undertreated. OBJECTIVE: Using the North American Research Committee on MS Registry, we assessed the frequency of mental comorbidities in MS and sociodemographic characteristics associated with diagnosis and treatment of depression. METHODS: We queried participants regarding depression, anxiety, bipolar disorder, and schizophrenia. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (CESD); a score>or=21 indicated probable major depression. RESULTS: Mental comorbidity affected 4264 (48%) responders; depression most frequently (4012, 46%). Among participants not reporting mental comorbidity, 751 (16.2%) had CESD scores>or=21 suggesting undiagnosed depression. Lower socioeconomic status was associated with increased odds of depression (Income $15,000-30,000 vs >$100,000 OR 1.34; 1.11-1.62), undiagnosed depression (Income $15,000-30,000 vs >$100,000 OR 1.52; 1.08-2.13), and untreated depression (

Comorbidity delays diagnosis and increases disability at diagnosis in MS.

BACKGROUND: Comorbidity is common in the general population and is associated with adverse health outcomes. In multiple sclerosis (MS), it is unknown whether preexisting comorbidity affects the delay between initial symptom onset and diagnosis ("diagnostic delay") or the severity of disability at MS diagnosis. OBJECTIVES: Using the North American Research Committee on Multiple Sclerosis Registry, we assessed the association between comorbidity and both the diagnostic delay and severity of disability at diagnosis. In 2006, we queried participants regarding physical and mental comorbidities, including date of diagnosis, smoking status, current height, and past and present weight. Using multivariate Cox regression, we compared the diagnostic delay between participants with and without comorbidity at diagnosis. We classified participants enrolled within 2 years of diagnosis (n = 2,375) as having mild, moderate, or severe disability using Patient Determined Disease Steps, and assessed the association of disability with comorbidity using polytomous logistic regression. RESULTS: The study included 8,983 participants. After multivariable adjustment for demographic and clinical characteristics, the diagnostic delay increased if obesity, smoking, or physical or mental comorbidities were present. Among participants enrolled within 2 years of diagnosis, the adjusted odds of moderate as compared to mild disability at diagnosis increased in participants with vascular comorbidity (odds ratio [OR] 1.51, 95% CI 1.12-2.05) or obesity (OR 1.38, 95% CI 1.02-1.87). The odds of severe as compared with mild disability increased with musculoskeletal (OR 1.81, 95% CI 1.25-2.63) or mental (OR 1.62, 95% CI 1.23-2.14) comorbidity. CONCLUSIONS: Both diagnostic delay and disability at diagnosis are influenced by comorbidity. The mechanisms underlying these associations deserve further investigation.

High frequency of adverse health behaviors in multiple sclerosis.

BACKGROUND: Health behaviors influence chronic disease risks in the general population, and may influence health outcomes independently of comorbid diseases. Health behaviors receive less attention in multiple sclerosis (MS) than in the general population. We assessed health behaviors among participants in the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry and the demographic characteristics associated with particular health behaviors. METHODS: In October 2006, we surveyed NARCOMS participants regarding smoking using questions from the Behavioral Risk Factor Surveillance Survey; physical activity using questions from the PEPI study, alcohol use using the AUDIT-C; and height and weight. To determine the independent demographic predictors of health behaviors, we used multivariable logistic regression, either binary or polytomous as appropriate. RESULTS: Of 8983 responders, 4867 (54.2%) ever smoked; 1542 (17.3%) currently smoked. On the basis of the AUDIT-C, 1632 (18.2%) were at risk for alcohol abuse or dependence. A quarter of participants were obese (n = 2269), and 2780 (31.3%) were overweight. Fewer than 25% of participants reported moderate or heavy leisure-time physical activity. Generally, lower socioeconomic status was associated with a higher frequency of adverse health behaviors accounting for other demographic factors. With increasing levels of disability, the reported intensity of physical activity was lower, and the frequency of overweight or obesity was higher. CONCLUSIONS: Patients with MS exhibit frequent adverse health behaviors, increasing the risk of other chronic diseases. Further research is needed to determine how these behaviors influence disability progression, quality of life, and other MS-related outcomes.

Glatiramer acetate after mitoxantrone induction improves MRI markers of lesion volume and permanent tissue injury in MS.

BACKGROUND: Glatiramer acetate (GA) therapy following brief, low-dose induction with mitoxantrone was safe and more effective than GA alone in suppressing inflammatory disease activity, as determined by a significant reduction in gadolinium (Gd)- enhancing MRI lesions, in a 15- month, randomized, single-blind study of relapsing-remitting multiple sclerosis (RRMS) patients. OBJECTIVE: To determine whether effects on MRI markers of disease burden and tissue damage support and extend data on the benefits of mitoxantrone induction therapy before initiation of long-term GA therapy. DESIGN/METHODS: 40 RRMS patients, aged 18 to 55 years, with 1-15 Gd-enhancing lesions on screening MRI and EDSS score 0-6.5 were randomized to receive GA (20 mg/d SC), starting 2 weeks after the last of 3 monthly mitoxantrone infusions (36 mg/m2 total; n = 21), or to GA alone (20 mg/d SC; n = 19), for a total of 15 months. MRIs were obtained at baseline and months 6, 9, 12, and 15. RESULTS: At baseline, mean (+/- SD) age was 37.2 +/- 9.7 years; disease duration, 3.5 +/- 4.8 years; EDSS score, 2.3 +/- 1.1; and number of Gd-enhancing lesions, 3.75 +/- 3.95. Reductions in Gd-enhancing lesions (RR = 0.30, 95 % CI, 0.11-0.86, p = 0.0147) and relapse activity favoring mitoxantrone- GA were accompanied by significant differences in changes in T2w lesion volume (p = 0.0139), T1w hypointense lesion volume (p = 0.0303), and proportion of Gdenhancing lesions that evolved into black holes (p = 0.0023) compared with GA alone. CONCLUSIONS: Longterm continuous GA after brief, low-dose mitoxantrone induction is safe and more effective than GA alone. A trend toward decreased clinical disease activity was accompanied by major effects on MRI measures of disease burden and severe tissue injury.

Comorbidity, socioeconomic status and multiple sclerosis.

OBJECTIVE: Multiple sclerosis (MS) is associated with substantial morbidity. The impact of comorbidity on MS is unknown, but comorbidity may explain some of the unpredictable progression. Comorbidity is common in the general population, and is associated with adverse health outcomes. To begin understanding the impact of comorbidity on MS, we need to know the breadth, type, and frequencies of comorbidities among MS patients. Using the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry, we aimed to describe comorbidities and their demographic predictors in MS. METHODS: In October 2006, we queried NARCOMS participants regarding physical comorbidities. Of 16,141 participants meeting the inclusion criteria, 8983 (55.7%) responded. RESULTS: Comorbidity was relatively common; if we considered conditions which are very likely to be accurately self-reported, then 3280 (36.7%) reported at least one physical comorbidity. The most frequently reported comorbidities were hypercholesterolemia (37%), hypertension (30%), and arthritis (16%). Associated with the risk of comorbidity were being male [females vs. males, odds ratio (OR) 0.77; 0.69-0.87]; age (age >60 years vs. age < or = 44 years, OR 5.91; 4.95-7.06); race (African Americans vs. Whites, OR 1.46; 1.06-2.03); and socioeconomic status (Income <$15,000 vs. Income >$100,000, OR 1.37; 1.10-1.70). CONCLUSIONS: Comorbidity is common in MS and similarly associated with socioeconomic status.

Glatiramer acetate after induction therapy with mitoxantrone in relapsing multiple sclerosis.

Forty relapsing multiple sclerosis patients with 1-15 gadolinium (Gd)-enhancing lesions on screening brain magnetic resonance imaging (MRI) and Expanded Disability Status Scale (EDSS) scores 0-6.5 were randomized to receive short-term induction therapy with mitoxantrone (three monthly 12 mg/m(2) infusions) followed by 12 months of daily glatiramer acetate (GA) therapy 20 mg/day subcutaneously for a total of 15 months (M-GA, n = 21) or daily GA 20 mg/day for 15 months (GA, n = 19). MRI scans were performed at months 6, 9, 12 and 15. The primary measure of outcome was the incidence of adverse events; secondary measures included number of Gd-enhanced lesions, confirmed relapses and EDSS changes. Except age, baseline demographic characteristics were well matched in both treatment arms. Both treatments were safe and well tolerated. M-GA induction produced an 89% greater reduction (relative risk (RR) = 0.11, 95% confidence interval (CI): 0.04-0.36, p = 0.0001) in the number of Gd-enhancing lesions at months 6 and 9 and a 70% reduction (RR = 0.30, 95% CI: 0.11-0.86, p = 0.0147) at months 12 and 15 versus GA alone. Mean relapse rates were 0.16 and 0.32 in the M-GA and GA groups, respectively. Short-term immunosuppression with mitoxantrone followed by daily GA for up to 15 months was found to be safe and effective, with an early and sustained decrease in MRI disease activity.

Altered innate immunity following spinal cord injury.

STUDY DESIGN: Cross-sectional, paired cohort study. OBJECTIVES: To replicate the finding of impaired immunocyte function following spinal cord injury (SCI). To determine whether cellular immune function in SCI subjects with decentralized sympathetic nervous system (SNS) (T6 and above) varies from SCI subjects with intact SNS (below T6). SETTING: University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ, USA. METHOD: In vitro immune assays: (1) natural killer (NK) cell cytotoxicity using a K562 target cell line in a 4-h chromium(51) release assay. The mean of three samples for each effector-to-target (E:F) ratio (25:1, 50:1, 100:1) was used in the analyses. (2) Cell enumeration was performed using commercially available antibodies and standard flow cytometry techniques. RESULTS: Participation of 36 SCI subjects and 36 individually age- and sex-matched healthy controls. SCI subjects were stratified into two groups, that is, neurologic level of injury (NLI) at T6 or above (26 subjects) and NLI below T6 (10 subjects). No statistically significant differences were identified between NLI T6 and above and NLI below T6 groups for the NK cytotoxicity assay. There was a statistically significant reduction in NK cell numbers in all subjects with SCI as compared to their paired controls. There was a statistically significant reduction in NK cell cytotoxicity in SCI subjects, relative to the controls for E:F ratio of 100:1 (F=6.18, d.f.=34, P=0.02). CONCLUSION: We replicated the finding of decreased NK cell number and cytotoxicity in SCI subjects. The mechanism behind these findings needs to be further investigated, with the long-term goal of developing therapeutic strategies to improve immune function.

IL-21 modulates CD4+ CD25+ regulatory T-cell homeostasis in experimental autoimmune encephalomyelitis.

The homeostasis of CD4+ CD25+ regulatory T cells (Tregs) depends on the cytokine interleukin (IL)-2. As IL-21 shares sequence homology with IL-2 and the IL-21 receptors contain a gamma-chain common to IL-2, we hypothesized that IL-21 could also affect the homeostasis of Tregs. We tested this hypothesis in experimental autoimmune encephalomyelitis (EAE), an animal model of relapsing-remitting human multiple sclerosis. We show that blockade of IL-21 in SJL/J mice before and after the induction of EAE enhances the influx of inflammatory cells into the central nervous system (CNS). The blockade of IL-21 leads to proliferation of proteolipid peptide (PLP(139-151))-autoreactive CD4+ T cells, which are capable to cause severe EAE in adoptively transferred recipient mice. Conversely, Tregs from mice where IL-21 was blocked, lose their capacity to prevent EAE induced PLP(139-151)-reactive T cells. Notably, direct effects of IL-21 on Tregs are confirmed by studies of blockade of IL-21 in mice expressing a green fluorescent protein 'knocked' into a Foxp3 allele, in which a reduction of the number of Tregs and a downregulation of their frequency and expression of Foxp3 are observed. These data suggest a role of the IL-21/IL-21R axis in the homeostasis of Tregs in CNS autoimmunity.

CD4(+)CD25(+) regulatory T cells contribute to the therapeutic effects of glatiramer acetate in experimental autoimmune encephalomyelitis.

CD4(+)CD25(+) regulatory T cells (Tregs) are potent immunosuppressors that are pivotal in the maintenance of self-tolerance. The involvement of Tregs in therapies for immune-mediated diseases has been proposed, but direct supporting evidence is still lacking. While investigating mechanisms underlying the clinical benefits of glatiramer acetate (GA) in an animal model of multiple sclerosis (MS), i.e., experimental autoimmune encephalomyelitis (EAE), we recently demonstrated that GA can protect mice deficient in the Th(2) cytokines IL-4, IL-10 and IL-4/IL-10 from acquiring EAE, suggesting that mechanisms other than Th(2) cells may be responsible for the therapeutic effects of GA. Here we demonstrate that GA treatment boosts the expression of Foxp3 on Tregs during EAE. Furthermore, adoptive transfer of purified Tregs from GA-treated EAE mice is more effective in preventing EAE development than Tregs from untreated EAE controls. Thus, our current data provide evidence that Tregs may be the major contributor to GA's therapeutic action in EAE and, possibly, MS. Further mechanistic studies to reveal the molecular events linking GA with Tregs may optimize GA treatment and lead to the development of new, even more effective therapies that utilize this mechanism of action.

Disparities in the management of multiple sclerosis-related bladder symptoms.

BACKGROUND: Participants enrolled in the North American Research Committee on Multiple Sclerosis (NARCOMS) registry report disability status using Performance Scales (PS), a self-report measure. The bladder/bowel subscale (PSB) of PS has not been validated. It is also unknown whether ethnic or socioeconomic disparities exist in bladder care. OBJECTIVE: We aimed to validate the bladder/bowel subscale used by the NARCOMS registry and to describe urologic symptoms, investigations, and treatments received by registry participants. METHODS: In the Fall 2005 update questionnaire, we collected the Bowel Control Scale (BWCS) and Urogenital Distress Inventory-6 (UDI-6) as criterion measures and urologic investigations and treatments. We measured associations between investigations, treatments, and symptoms with clinical and sociodemographic variables using chi(2) tests for categorical variables and Kruskal-Wallis tests for continuous variables, followed by multivariable logistic regression. RESULTS: Nine thousand six hundred eighty-eight participants completed the survey. For the UDI-6, the median (interquartile range) score was 33.3 (16.7 to 50.0), for the BWCS 3 (1 to 6), and for the PSB 1 (1 to 3). The correlation between the PSB and the UDI-6 was r = 0.67 and between the PSB and the BWCS r = 0.53 (both p < 0.0001). Participants had increased odds of receiving medication for bladder symptoms if they had health insurance (odds ratio [OR] 1.90; 1.07 to 3.35). Participants who were white (OR 1.5; 1.16 to 1.94) and had health insurance (OR 2.0; 1.3 to 3.07) had increased odds of undergoing urologic investigations. CONCLUSION: The Performance Scales bladder question has adequate criterion and construct validity in multiple sclerosis (MS). There are ethnic and socioeconomic disparities in bladder management in MS.

Validation of the NARCOMS registry: diagnosis.

The North American Research Committee on Multiple Sclerosis (NARCOMS) Registry is a patient registry, wherein the diagnoses of multiple sclerosis (MS) are unverified. We compared self-reported diagnoses of registry participants to physician-reported diagnoses, and with diagnoses based on medical records review. Registry participants with more than one of the following: age of onset <10 or >50 years, no bladder symptoms or fatigue, or zero or more than four relapses in the last year, were considered atypical. All others were considered typical. We sent letters to participants describing the study, surveyed treating physicians regarding the participants' diagnosis, and reviewed medical records. Diagnosis was classified by the McDonald and Poser criteria. Of the 240 participants sampled, 109 were in active registry status with accurate contact information. Of these, 52 consented, 29 refused and 28 did not respond (weighted response rate 76.3+/-4.5%). Some 37 of 38 physician surveys confirmed the diagnosis of MS (98.8+/-1.2%). After reviewing 41 medical records, we classified 53.2+/-8.9% of participants as definite MS, 16.9+/-6.8% as possible MS, while the remainder had insufficient data for diagnostic confirmation. We confirmed a diagnosis of MS in 98.7+/-1.3% of participants based on records review, physician survey or telephone interview, supporting the validity of the diagnoses reported by NARCOMS participants.

Does multiple sclerosis-associated disability differ between races?

OBJECTIVE: To investigate differences in disability between African American and Caucasian patients with multiple sclerosis (MS) by comparing the relationship between current age and disability between races and by assessing the effect of adjustment for socioeconomic status (SES) on the associations. METHODS: The authors selected US participants from the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry with an age at symptom onset of 10 to 60 years, who reported their race as Caucasian or African American (n = 21,557). They classified participants as having mild, moderate, or severe disability in the domains of mobility, hand function, cognition, and vision using Patient Determined Disease Steps and Performance Scales and assessed the association of disability with race using polytomous logistic regression. RESULTS: Disability increased more rapidly with increasing disease duration in older patients, but there was no interaction between race and age. African Americans had increased odds of severe vs mild disability in all four domains (odds ratio [OR] [95% CI]: hand 1.35 [1.10 to 1.64]; vision 1.75 [1.37 to 2.27]; cognition 1.32 [1.04 to 1.67]; mobility 1.32 [1.11 to 1.56]). Adjustment for all covariates, including SES, attenuated these associations (OR [95% CI]: hand 1.27 [1.00 to 1.61]; vision 1.59 [1.19 to 2.08]; cognition 0.98 [0.74 to 1.30]; mobility 1.37 [1.11 to 1.67]). Lack of adjustment for SES produced stronger associations. After enrollment in NARCOMS, disability progression did not differ between the groups. CONCLUSIONS: African Americans experience greater multiple sclerosis-associated disability than Caucasians. Failure to account for socioeconomic status leads to overestimation of these differences. Disease progression is similar in African Americans and Caucasians after diagnosis.

Changes in the ascertainment of multiple sclerosis.

OBJECTIVE: With diagnostic criteria alterations, increased MRI availability, and awareness of therapies, temporal changes in incidence and prevalence rates may occur, with an increase in the proportion of mildly affected persons diagnosed with multiple sclerosis (MS). The authors assessed temporal trends in the delay from symptom onset to diagnosis (DONDX), and determined whether the degree of disability at diagnosis differs by year of symptom onset (YONSET), using the NARCOMS Registry. METHODS: The authors selected US participants with an age at symptom onset of 10 to 60 years, and YONSET > or = 1980 (n = 16,581). The authors divided YONSET into 5-year groups and compared DONDX between groups using multivariate Cox regression. The authors classified participants enrolled within 2 years of diagnosis (n = 5,548) as having mild, moderate, or severe disability using Patient Determined Disease Steps, and assessed the association of disability with YONSET using polytomous logistic regression. RESULTS: DONDX decreased with later YONSET (r = -0.43, p < 0.0001). This association remained after adjustment for demographic factors in a multivariate Cox model. Later YONSET was associated with increased odds of having mild disability at diagnosis as compared to severe disability (OR = 1.10 per year; 1.09 to 1.11). CONCLUSION: The delay from symptom onset to diagnosis is steadily decreasing in MS. An increasing proportion of patients with MS have mild disability at diagnosis after accounting for confounders. As the effectiveness of therapies is influenced by disease duration, this has implications for comparison of treatment effects in modern clinical trials to earlier study results.

High-dose methylprednisolone may do more harm for spinal cord injury.

Because of the National Acute Spinal Cord Injury Studies (NASCIS), high-dose methylprednisolone became the standard of care for the acute spinal cord injury. In the NASCIS, there was no mention regarding the possibility of acute corticosteroid myopathy that high-dose methylprednisolone may cause. The dosage of methylprednisolone recommended by the NASCIS 3 is the highest dose of steroids ever being used during a 2-day period for any clinical condition. We hypothesize that it may cause some damage to the muscle of spinal cord injury patients. Further, steroid myopathy recovers naturally and the neurological improvement shown in the NASCIS may be just a recording of this natural motor recovery from the steroid myopathy, instead of any protection that methylprednisolone offers to the spinal cord injury. To our knowledge, this is the first discussion considering the possibility that the methylprednisolone recommended by NASCIS may cause acute corticosteroid myopathy.

Technique for studying conduction in the lateral cutaneous nerve of calf.

We describe a novel technique for assessing conduction in the lateral cutaneous nerve of the calf (LCNC), a branch of the common peroneal nerve, based on a study of 32 healthy subjects. Both antidromic and orthodromic techniques were used in each of the 64 limbs to obtain a sensory nerve action potential (SNAP) of the LCNC over a distance of 12 cm. In 60 limbs (93.7%) a SNAP was obtainable with either the antidromic or orthodromic technique. In 21 limbs (32. 8%), the SNAP was obtained both antidromically and orthodromically. In 33 limbs (51.6%), the SNAP was obtained only antidromically, and in 6 (9.4%), only orthodromically. In four limbs, the response was unobtainable. Mean antidromic onset latency was 2.1 ms +/- SD 0.3, peak latency was 2.6 ms +/- SD 0.4, amplitude (without averaging) was 4.3 microV +/- SD 2.5, and conduction velocity was 60 m/s +/- SD 10. Mean orthodromic onset latency was 2.3 ms +/- SD 0.3, peak latency was 2.7 ms +/- SD 0.3, amplitude was 5.0 microV +/- SD 2.2, and conduction velocity was 52 m/s +/- SD 5. Utilization of this technique allows for more detailed localization of common peroneal nerve injury based on whether it is proximal or distal to the origin of the LCNC.

Influence of neurological level on immune function following spinal cord injury: a review.

Due to the high incidence of lifelong infections in persons with spinal cord injury (SCI), the authors examined level of injury-related immune characteristics in a cohort of subjects with chronic SCI. Since the sympathetic nervous system and the endocrine system are known to be modulators of immune function, one possible explanation for heightened incidence of infections includes dysregulation of sympathetic outflow tracts in individuals with tetraplegia or high paraplegia. Natural killer cell cytotoxicity (NKCC) and bactericidal function of circulating neutrophils were assayed in a group of 10 individuals with chronic complete cervical SCI, a group of 8 individuals with paraplegia with injuries below the main sympathetic outflow (T-10 and below) and a group of 18 age- and sex-matched controls. In addition, a psychiatric assessment of depression was performed as well as assays of pituitary and adrenal functions. Analyses revealed no significant differences in immune function between all subjects with SCI combined and their matched controls. Further analyses stratifying based on presence or absence of sympathetic dysregulation revealed significantly impaired phagocytic ability and a trend toward reduced NKCC in the group with tetraplegia compared with their controls. Hormonal assays showed that dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DS) were higher in individuals with tetraplegia than controls, but no such differences were observed in individuals with paraplegia compared with their controls. The results of this study suggest that individuals sustaining complete cervical SCI experience alterations in immune function, while those with lesions at or below T-10 do not. These findings of level of injury related immune alteration could not be explained by mood differences. This paper is a review of previously published work and the authors' current thinking regarding increased acquisition of infections in this population.

Adrenal and pituitary hormone patterns after spinal cord injury.

Current evidence indicates that the neuroendocrine system is the highest regulator of immune/inflammatory reactions. We hypothesized that immune alterations, which were related to the level of injury, found in a cohort of spinal cord-injured subjects may be influenced by altered hormonal patterns postinjury. Therefore, we investigated aspects of both pituitary and adrenal function in the same cohort of spinal cord-injured subjects. We found significant elevations in both cortisol and dehydroepiandrosterone sulfate in chronic spinal cord-injured survivors compared with their able-bodied age- and gender-matched controls. Levels of dehydroepiandrosterone, adrenocorticotropin, and prolactin were not different in spinal cord-injured subjects overall compared with their controls. Both dehydroepiandrosterone sulfate and dehydroepiandrosterone were higher in tetraplegics compared with their controls, but we found no such differences in paraplegics compared with their controls. When the two groups of spinal cord-injured subjects were compared with each other, we also found differences between these two subject groups in dehydroepiandrosterone sulfate and dehydroepiandrosterone (higher in the tetraplegics compared with paraplegics). We found no differences between either group of spinal cord-injured subjects and their controls for adrenocorticotropin, prolactin, or cortisol. These data suggest that some hormonal differences between subjects and their controls may be further related to the level of injury (specifically dehydroepiandrosterone and dehydroepiandrosterone). Finally, we investigated correlations within subjects for the above hormones. Dehydroepiandrosterone sulfate and prolactin were highly correlated (the higher the dehydroepiandrosterone sulfate, the higher the prolactin) but only in the tetraplegic subjects.