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.

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.

High lumbar disc: diagnostic and treatment dilemma.

The high lumbar disc refers to a disc herniation involving the upper lumbar discs (L2-4). Radiculopathy caused by an upper lumbar disc is occasionally difficult to diagnose secondary to ambiguous presenting symptoms. Once accurately diagnosed, the treatment program is straight-forward but specific for the high nerve root pathology. A series of three cases of high lumbar radiculopathies managed with an aggressive conservative approach are presented. This case series will review the diagnostic and treatment strategies that are useful in the identification and management of a high lumbar radiculopathy. Various pitfalls in the management of these cases are reviewed, all of which may worsen the patient's clinical situation. A high index of suspicion is necessary to elucidate this entity.

Mandatory clerkship in physical medicine and rehabilitation: effect on medical students' knowledge of physiatry.

OBJECTIVE: To study the effect of a 2-week clerkship on the perceptions and knowledge of physical medicine and rehabilitation (PM&R) among fourth-year medical students. DESIGN: Survey of fourth-year medical students before and after completion of a mandatory clerkship. RESULTS: Knowledge of PM&R by fourth-year medical students is marginal, but a clerkship increases the awareness of the practice of physiatry. CONCLUSIONS: Mandatory clerkships can help expose future physicians to the benefits of physiatric services and should be pursued by academic PM&R departments.

Impaired phagocytosis of Staphylococcus aureus in complete tetraplegics.

Accumulating evidence implicates the sympathetic nervous system as a modulator of immune function. Immune alteration has been observed in survivors of cervical level spinal cord injury, possibly because of dysregulation of the sympathetic outflow tracts. The majority of immune studies in the spinal cord-injured population have focused on lymphocytes. Because of the high incidence of infections in this population, we hypothesized that the immune alteration would extend to the cells of the myeloid lineage. This hypothesis was tested by analyzing the phagocytic and bactericidal function of circulating neutrophils in response to Staphylococcus aureus. A group of ten individuals with complete cervical spinal cord injury, a group of eight paraplegics with injuries below the majority of sympathetic outflow (T-10 and below), and age- and gender-matched controls for each subject were studied. In addition, a psychiatric screening for depression was completed by all subjects and controls. Paired t test revealed significantly impaired phagocytic ability in the tetraplegic group compared with their controls. The paraplegic group did not demonstrate these findings. Our results suggest that individuals who have sustained complete cervical spinal cord injury have alteration in immune function compared with neurologically intact controls, whereas those with lesions at or below T-10 do not. This in vitro finding may be related to infection after cervical spinal cord injury. The mechanism may involve dysregulation of the sympathetic arm of the autonomic nervous system.

Effect of timing of stabilization on length of stay and medical complications following spinal cord injury.

This retrospective study examines length of acute hospital stay (LOS) and the development of medical complications in 64 patients with cervical, thoracolumbar or cauda equina injuries divided into two groups according to whether they underwent spinal stabilization < 24 hours after injury or > 24 hours after injury. The mean length of stay for the early stabilization group was 37.5 days (SD +/- 34.2) and for the late stabilization group 54.7 days (SD +/- 40.1). This difference was statistically significant by Mann Whitney U test (Z = 2.53, P = 0.01). There was no statistically significant difference between the early and the late groups with respect to the occurrence of common medical complications. There was a statistically significant difference in age in the early group (mean of 32.4 years) versus the late group (mean of 41.9 years) (t = 2.36, P = 0.02); however we do not feel that this age difference is clinically significant. There was not a statistically significant difference between the early group (17.9, SD = +/-7.2) and the late group (21.3, SD = +/- 8.3) (t = 1.71, p = 0.10) in mean injury Severity Scores (ISS). Also the correlation between length of stay and ISS scores was not significant (r = 0.18, P = 0.2). Timing of spinal stabilization appears to be an important factor in the management of spinal cord injury survivors. Our limited retrospective study suggests that when spinal stabilization is indicated, performance < 24 hours after injury is associated with a significantly shorter length of stay in the hospital. We suspect this is due to earlier mobilization of the patient. Medical complication rates were not significantly affected.

Practice and career satisfaction among physiatrists. A national survey.

To evaluate physiatrist career satisfaction and current practice patterns, a 15-page survey was mailed randomly to 400 fellow members of the American Academy of Physical Medicine and Rehabilitation. The 208 questionnaires (52%) returned revealed respondents' level of satisfaction with career choice, current practice, relationships with other physicians, their own residency training, and problems experienced that impede their practice. Factor analysis identified six areas of satisfaction: time demands, organizational support, current practice, current specialty, profession, and training. Problems with work consisted of four factors: external intrusions into practice, having to deal with non-rehabilitation problems, dealing with PM&R problems, and insufficient time for patients. Results showed that 75% of physiatrists were satisfied with their practice/profession. Satisfaction with current practice was greater with fewer external intrusions into practice, a larger percentage of income from traditional non-managed payment sources (including Medicaid), and less competition. Changes in health care, such as managed care, competition, and increased external regulations, appear to interfere with current practice. Variation in satisfaction was not significantly correlated with size of community, variation in rates of payment denials, workloads of greater than 50 hours per week, and a number of other factors that one might expect to affect satisfaction. Physiatrists had made many changes in their practice in response to the changes in the health care environment but had not cut care for indigent patients. Needs for greater residency training in outpatient clinics, physicians' offices, managed care, and long-term care settings were expressed. This is the first comprehensive published report on physiatric satisfaction in a changing health care environment. Further research in some of the areas will be required.

Computed tomography--guided aspiration of a ganglion cyst of the anterior cruciate ligament: a case report.

This report describes the case of a ganglion cyst of the anterior cruciate ligament in a 26-year-old man who had long-standing intermittent knee pain with locking. The cyst was successfully aspirated under computed tomography guidance, with complete resolution of symptoms. A literature review is presented along with diagnostic and treatment approaches for this uncommon finding.

Silent autonomic dysreflexia during voiding in men with spinal cord injuries.

PURPOSE: We determined whether symptoms of autonomic dysreflexia correlated with elevations in blood pressure in men with spinal cord injuries. MATERIALS AND METHODS: During a routine yearly urodynamic evaluation 45 consecutive men with complete spinal cord injuries above T6 underwent simultaneous monitoring of blood pressure and symptoms of autonomic dysreflexia. Those with systolic blood pressure of greater than 160 mm. Hg or diastolic blood pressure of greater than 90 mm. Hg during voiding were assigned to the hypertensive group. During voiding 35 men (78%) had significant hypertension. RESULTS: Before voiding there was no statistical difference in mean systolic blood pressure between men with and without hypertension (117 versus 110 mm. Hg, p = 0.28). During uninhibited contractions and voiding mean systolic blood pressure of the normotensive group (131 mm. Hg) versus the hypertensive group (169 mm. Hg) was statistically significant (p < 0.0001). Of the 35 hypertensive patients 15 (43%) had no symptoms of autonomic dysreflexia. There was no correlation of autonomic dysreflexia with length of injury, maximum voiding pressure or bladder capacity (p = 0.59, 0.85 and 0.34, respectively). CONCLUSIONS: Urodynamics are helpful to detect symptomatic and asymptomatic autonomic dysreflexia. Significant elevations in blood pressure can occur without the symptoms of autonomic dysreflexia.

Factors influencing the specialty choice of the physical medicine and rehabilitation graduating class of 1994 and the entering class of 1995.

To understand better how career choices are made by physiatrists, a 16-item, 7-page questionnaire was sent to all 1994 graduating physical medicine and rehabilitation (PM&R) resident physicians in the United States. Of the 343 senior residents, 202 completed the questionnaire for a response rate of 59%. The questionnaire focused on the following areas: timing of the decision to enter PM&R; and how the medical school curriculum, certain groups of people, and certain specific factors influenced their choices. There were 130 factors modeled after the American Association of Medical Colleges (AAMC) annual medical student questionnaire that the recipients were asked to grade on a numerical scale: 1 = unimportant to 5 = very important. Of the graduating residents, 60.1% (119/198) made the decision to enter PM&R in their 3rd or 4th yr of medical school, 13.1% (26/198) in the first 2 yr, and 11.1% (22/198) after starting another residency. The five factors ranked most important in the decision were (mean rank score): sufficient time/flexibility for family obligations (4.60); opportunity to make a difference in peoples lives (4.57); interest in helping people (4.55); types of patient problems encountered (4.50); and consistency with personality (4.49). We also obtained the AAMC's 1993 annual data on medical students choosing PM&R. Their top five factors were the same as those listed by the graduating residents, but in a slightly different rank order. Profiles have also been derived on those graduating PM&R residents who chose an academic career (n = 68) v nonacademic (n = 133) and fellowship (n = 34) v nonfellowship (n = 163).

Critical evaluation of clinical research.

This focused review contains a suggested core of material that will help residents or practicing physiatrists critically review research papers published in the medical literature. Before accepting the results of a clinical trial, physiatrists must critique the experimental methods and study design carefully to decide whether to include these new ideas into their clinical practice. Medical research relies on statistical methodology, and statistics pervade the medical literature. This article begins with an introduction to rudimentary statistics. Fortunately, most studies depend on a rather small body of statistical concepts. The elements of experimental design--clinical trials, randomization, single-subject design, meta-analysis, epidemiological studies--are presented in a concise review. Finally, the elements of statistics and experimental design are integrated into a step-by-step method strategy for reading the medical literature.

Alteration of immune system function in tetraplegics. A pilot study.

Over the past 20 yr, evidence has accumulated that implicates the autonomic nervous system as a central modulator of immune function. We hypothesized that injury to the cervical spinal cord would affect immune function by dysregulation of the sympathetic outflow tract. To test this hypothesis, peripheral blood lymphocytes were obtained from five individuals with complete cervical spinal cord injury (SCI) and from five age- and sex-matched neurologically intact controls. Immunologic parameters studied included cell counts by flow cytometry, lymphocyte proliferation response to three mitogens and a natural killer cell cytotoxicity assay. In addition the Ilfeld Psychiatric Symptom Index was completed by all subjects and controls. Repeated measures analysis of variance revealed an impaired lymphocyte proliferation response in the SCI group. Our results suggest that individuals who have sustained complete cervical SCI have alteration in immune function as compared with neurologically intact controls. This may contribute to infections after spinal cord injury. The mechanism may involve dysregulation of the sympathetic arm of the autonomic nervous system.

Clarification of the pronator reflex.

The pronator reflex has been used in evaluating the 6th and 7th cervical roots. It has been described as a muscle stretch reflex of the pronator muscles; however, a review of the literature did not elucidate which muscles are active in this reflex. We examined 10 healthy subjects with surface electromyograms recorded over the pronator quadratus and pronator teres and used a Teca reflex hammer to produce a muscle stretch and trigger the electromyogram sweep. A reproducible response was found in all patients when recordings were made over the pronator teres (mean latency, 9.7 +/- 1.8 ms). No response was found in any of the subjects when recordings were made over the pronator quadratus. We conclude that the pronator reflex represents a muscle stretch reflex of the pronator teres (and not the pronator quadratus), which would make it helpful in evaluating C6 and C7 root lesions.

Methods used in the evaluation of clinical competency of physical medicine and rehabilitation residents.

A 17-item questionnaire was designed to determine how physical medicine and rehabilitation (PM&R) training directors assess their residents' clinical competency. A response rate of 83% (62/75) was obtained. Seventy-nine percent (49/62) have a written resident supervision policy, and 73% (45/62) have a written resident probation policy. Ninety-four percent (58/62) believe that their system of evaluating residents' clinical competency is effective, although many commented that it could be improved. 76% (47/62) of the residency training directors made the final decision regarding residents' clinical competency. Fifty-two percent (32/62) have a departmental written examination, and 23% (14/62) have formal oral examinations. Eighteen percent (11/62) use an objective structured clinical examination (OSCE), 8% (5/62) use standardized patients and 3% (2/62) use videotaped patient encounters. Forty percent (25/62) use medical record audits. Fifty percent of the programs have rated at least one resident unsatisfactory during a clinical rotation in the past 3 yr, and 11% (7/62) have reported to the American Board of Physical Medicine and Rehabilitation that the overall clinical evaluation of one resident was unsatisfactory in the past 3 yr. Forty-seven percent (29/62) of the programs have asked at least one resident to leave their program in the past 3 yr. The OSCE is emerging as the state-of-the-art method for assessing clinical skills, although it is expensive. The measurement of clinical competency is important in the certification and recertification process, and our specialty needs better methods to assess these performance skills.

Factors used by physical medicine and rehabilitation residency training directors to select their residents.

A 17-item questionnaire was designed to assess the relative importance of various factors to physical medicine and rehabilitation (PM&R) training directors when ranking PM&R resident applicants during the National Resident Match. The questionnaire was sent to all PM&R residency training directors. The recipients were asked to grade most selection factors based on a numerical scale: 1, unimportant; 2, some importance; 3, important; 4, very important; 5, critical. The specific factors addressed in the questionnaire were: academic criteria, letters of recommendation, individual applicant characteristics and aspects of the interview process. Twelve yes-or-no questions were also designed to determine the weight that residency training directors place on certain academic criteria. A response rate of 88% (66/75) was obtained. The most important academic criteria were grades in a PM&R clerkship in their facility (4.1 +/- 0.8), followed by grades in a PM&R clerkship in another facility (3.6 +/- 0.9). The most important letters of recommendation were from a PM&R faculty member in the respondent's department (4.0 +/- 0.8), followed by the dean's letter (3.7 +/- 1.0) and the PM&R chairman's letter (3.7 +/- 1.0). The three most important applicant characteristics evaluated during the interview were compatibility with the program (4.4 +/- 0.8), the ability to articulate thoughts (4.2 +/- 0.8) and the ability to work with the team (4.2 +/- 0.8). Most program directors used multiple criteria to complete their rank list, but the most important were based upon the interview (4.5 +/- 0.9), letters of recommendation (3.7 +/- 0.9), medical school transcript (3.6 +/- 0.8) and the dean's letter (3.6 +/- 1.1).(ABSTRACT TRUNCATED AT 250 WORDS)

Prevalence of urinary incontinence after brain injury.

There is little reported in the literature describing the prevalence of voiding dysfunction after brain injury. A prospective study was conducted, 54 consecutive admissions to our brain injury unit from September 1992 through January 1993 were screened for signs and symptoms of voiding dysfunction. Signs and symptoms were noted in 24 patients (44.4%). There was no statistically significant difference in symptom prevalence based on age, sex, hemisphere (right or left) injured, or presence or absence of a frontal lobe injury. Those functioning at a lower cognitive level (Rancho Los Amigos Scale VI or less) had a higher symptom prevalence than the VII-VIII group (p = 0.004, Chi Square Test).