Neurological Disorders In Patients Research Articles

Neurologic Disorders in Patients With Celiac Disease: Are They Mediated by Brain Perfusion Changes?

To the Editor .— We read with great interest the recent study reported by Zelnik et al1 on the relationship between celiac disease (CD) and neurologic disorders. The authors screened patients with CD and showed a strong association not only between CD and specific neurologic disorders such as cerebral ataxia, chronic neuropathies, myoclonic ataxia, progressive leukoencephalopathy, and dementia but also between CD and milder and more common neurologic conditions such as headache, learning disabilities and attention-deficit/hyperactivity disorder, development delay, and hypotonia. In the discussion section the authors suggest that chronic immune-mediated inflammation, lymphocytic infiltration, or vasculitis of the central …

Neurologic Disorders in Patients With Celiac Disease: Are They Mediated by Brain Perfusion Changes?: In Reply

Neurologic Disorders in Patients With Celiac Disease: Are They Mediated by Brain Perfusion Changes?: In Reply

Celiac Disease in Children With Migraine

To the Editor. In an interesting article, Zelnik et al1 recently investigated the presence of neurologic disorders in patients with celiac disease (CD). They found those disorders to be more common in children with CD (51.4%) than in controls (19.9%). The authors also demonstrated therapeutic benefit with gluten-free diet only in patients with hypotonia or migraine. On the other hand, Gabrielli et al2 reported positive serology for CD in a significantly higher percentage of patients with migraine than in a control …

Neurologic Complications of Celiac Disease

Source: Zelnik N, Pacht A, Obeid R, et al. Range of neurologic disorders in patients with celiac disease. Pediatrics. 2004;113:1672–1676.Investigators at the Carmel Medical Center in Haifa, Israel, sought to study the neurologic complications of celiac disease (CD) among a cohort of patients evaluated between 1977 and 2001. Patients with celiac disease [n=111] and controls [n=211] matched for age and gender were questioned regarding neurologic disorders, had their charts reviewed, and received neurologic evaluations, including brain imaging or electroencephalography, if indicated. Prior to 1988, diagnosis of CD was based on 3 consecutive intestinal biopsies. After 1988, the diagnostic approach was simplified and was based on immunoglobulin A antiendomysial antibodies and 1 intestinal biopsy. The mean age of patients and controls was 20.1 ± 9 years, and the male to female ratio was 2:3. The CD was classical infantile (diagnosed at 1.8 years) in 58 (52.3%) patients and later in onset (diagnosed at 14.8 years) in 53 (47.7%) patients. Neurologic disorders were found in 57/111 (51.4%) of patients with CD, whereas only 42/211 (19.9%) control subjects had abnormal neurologic findings. Patients with late-onset CD had more neurologic complications than the classical CD group (54.7% versus 48.3%), but the difference was not significant. Neurologic abnormalities and their frequency compared to controls included: hypotonia, 21.6% versus 3.8% (P<.01); developmental delay, 15.5% versus 3.3% (P<.01); seizures, 7.2% versus 0.8% (P<.09); learning disabilities and ADHD, 20.7% versus 10.5% (P<.01); headache, 27.9% versus 8.1% (P<.01); ataxia, 5.4% versus 0% (P<.01); and tics, 0.9% versus 2.4% (P=.67). Seizure disorders were more frequent with CD but not significantly, and tic disorders showed no increased prevalence. The gluten-free diet only benefited those CD patients with infantile hypotonia and migraine headache.The range of neurologic disorders associated with CD is wider than previously reported and includes chronic migraine headache, developmental delay, hypotonia in infants, learning disabilities, ADHD,1,2 and seizures. Apart from cases of epilepsy with occipital calcifications, recurrent seizures were not significantly correlated with CD.In occipital lobe seizures related to CD, the CD may be clinically asymptomatic.3 The incidence of silent CD in children with idiopathic localization epilepsies and the indications for routine CD screening were established in a study of 72 patients (mean age, 12.6 years) observed over a 5-year period.4 Two (8%) of 25 patients with childhood partial epilepsy with occipital paroxysms (CPEO) had positive IgA-antiendomysium antibodies, and jejunal biopsies showed villous atrophy and crypt hyperplasia, confirming the diagnosis of CD. Brain CT showed occipital calcifications in one. Seizures were controlled by treatment with a gluten-free diet, and no brain calcifications developed in the patient with a normal CT after a 3-year follow-up on a gluten-free diet.Forty-seven patients with childhood partial epilepsy with centrotemporal spikes (CPEC) had negative antibody tests for CD.4 CD screening is recommended in children with CPEO but not in those with CPEC and extraoccipital spikes. Early diagnosis and dietary intervention may reverse the tendency to seizures and brain calcifications. The gluten-free diet was also successful in the relief of migraine headaches. Wheat cereal is a known migraine trigger in some children5 and positive reactors should be screened for CD.The underlying pathophysiology linking gluten to neurologic disorders is not well characterized in this study, which refers only to its non-specific immunologic and inflammatory effects. Nonetheless, the association between gluten and brain disorders appears to be very strong, and some patients’ neurologic symptoms remit when gluten is removed from their diet. Thus, to separate the wheat of celiac disease-associated neurologic disorders from the chaff of the truly idiopathic, we must consider celiac disease as a possible etiology for a variety of neurologic presentations.

Range of neurologic disorders in patients with celiac disease.

During the past 2 decades, celiac disease (CD) has been recognized as a multisystem autoimmune disorder. A growing body of distinct neurologic conditions such as cerebellar ataxia, epilepsy, myoclonic ataxia, chronic neuropathies, and dementia have been reported, mainly in middle-aged adults. There still are insufficient data on the association of CD with various neurologic disorders in children, adolescents, and young adults, including more common and "soft" neurologic conditions, such as headache, learning disorders, attention-deficit/hyperactivity disorder (ADHD), and tic disorders. The aim of the present study is to look for a broader spectrum of neurologic disorders in CD patients, most of them children or young adults. Patients with CD were asked to fill in a questionnaire regarding the presence of neurologic disorders or symptoms. Their medical charts were reviewed, and those who were reported as having neurologic manifestations underwent neurologic examination and brain imaging or electroencephalogram if required. Their neurologic data were compared with that of a control group matched for age and gender. Patients with CD were more prone to develop neurologic disorders (51.4%) in comparison with control subjects (19.9%). These disorders include hypotonia, developmental delay, learning disorders and ADHD, headache, and cerebellar ataxia. Epileptic disorders were only marginally more common in CD. In contrast, no difference was found in the prevalence of tic disorders in both groups. Therapeutic benefit, with gluten-free diet, was demonstrated only in patients with transient infantile hypotonia and migraine headache. This study suggests that the variability of neurologic disorders that occur in CD is broader than previously reported and includes "softer" and more common neurologic disorders, such as chronic headache, developmental delay, hypotonia, and learning disorders or ADHD. Future longitudinal prospective studies might better define the full range of these neurologic disorders and their clinical response to a gluten-free diet.

Neurologic disorders in 432 consecutive patients with small cell lung carcinoma.

Neurologic complications are an important cause of morbidity and possibly also mortality in patients with small cell lung carcinoma (SCLC). The current study was undertaken to prospectively investigate survival and the frequency of neurologic disorders in patients with SCLC. Between October 1980 and September 2001, 432 consecutive patients with microscopically proven SCLC were included in the current study. Patients underwent neurologic examinations on a regular basis prior to, during, and after treatment. Routine imaging of the brain (computed tomography or magnetic resonance imaging) was performed before and after systemic therapy. A neurologic disorder was diagnosed in approximately 56% of the SCLC patients. In nearly half of the cases, the neurologic disorder already was present at the time of diagnosis. Brain metastases (BM) were diagnosed most frequently. Seventy-four patients (18%) had BM at the time of diagnosis; in 20 of these patients, the BM did not demonstrate clinical signs. Another 101 patients developed BM during follow-up. The 2-year cumulative risk of BM reached 49% for patients with limited disease (LD) and 65% for patients with extensive disease (ED). Patients with BM as the only site of disease dissemination were found to have a poorer survival compared with LD patients. The majority of the nonmetastatic disorders preceded the diagnosis of SCLC. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) was diagnosed most frequently. In this prospective study, neurologic disorders were diagnosed in greater than half of the patients with SCLC. BM were detected most frequently. Approximately 18% of the patients were found to have BM at the time of diagnosis. In approximately 33% of the cases, these BM did not cause symptoms. BM were found to have a negative effect on survival in patients with SCLC.

Neurological disorders in patients with Kallmann's syndrome

Neurological disorders in patients with Kallmann's syndrome

Seek Neurosyphilis Aggressively in HIV Patients

High rates of symptomatic neurosyphilis have been reported in patients with HIV infection, even after standard treatment for primary or secondary syphilis, but experts disagree on the criteria that should prompt a proactive search for neurologic disease in patients with both infections. A national consortium of researchers enrolled 326 patients with syphilis and a high clinical probability of neurosyphilis in a prospective trial …

Ubiquitin-positive inclusions in ependymal cells.

Ubiquitin-positive inclusions (UbIs) have not been well studied in ependymal cells. Since we detected such UbIs in the central canals of the medulla and spinal cord while investigating UbIs in neurodegenerative diseases, we studied UbIs in the entire ependymal system of 42 patients with various neurological diseases and of 10 non-neurological controls. UbIs were located in the cytoplasm of the ependymal cells, and were round to oval in shape, measuring 4-11 microm in diameter. The UbIs were non-argyrophilic and undetectable by hematoxylin and eosin staining, but mildly reactive to periodic acid-Schiff staining with and without digestion. The UbIs were variably immunoreactive for anti-epithelial membrane antigen (EMA) antibody, but did not react with several other antibodies. The co-existence of ubiquitin and EMA was confirmed by confocal laser microscopy. Throughout the ependymal system, UbIs were variably found in ependymal cells as well as in subependymal cells. There was no significant difference in the overall incidence of either ependymal or subependymal UbIs between the patients with neurological diseases and controls. However, ependymal UbIs in the central canal were more frequent in the neurological disease patients than in controls, although there was no disease specificity. This is the first comprehensive report to show common occurrence of UbIs in the ependymal cells of adult human brains.

Abnormal response to glutamate of T lymphocytes from multiple sclerosis patients

Multiple sclerosis (MS) is an immune-mediate, inflammatory and demyelinating disease of the central nervous system (CNS). Since glutamate (Glu) is a modulator of T lymphocyte function and Glu excitotoxicity has been proposed as one of the mechanisms of the demyelination, we studied the responses of T lymphocytes from normal controls (NC), MS or other non-inflammatory neurological disease (ONND) patients to Glu, by measuring phytohemagglutinin-induced intracellular Ca 2+ ([Ca 2+] i) rise (Fura-2 method) and cell proliferation (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide colorimetric assay). No differences in the Glu (1 μM)-induced potentiation of the [Ca 2+] i rise were measured in T lymphocytes from all groups of subjects, while a significant decrease in the Glu (1 mM)-induced inhibition of cell proliferation was observed in T lymphocytes from MS patients. These data demonstrate that MS T lymphocytes abnormally respond to Glu.

Dr. Hayward and Colleagues Reply

Back to table of contents Previous article Next article Letter to the EditorFull AccessDr. Hayward and Colleagues ReplyCHRIS HAYWARD, M.D., Ph.D., BENJAMIN H. FLORES, M.D., H. BRENT SOLVASON, M.D., PENELOPE ZEIFERT, Ph.D., and BRENT T. HARRIS, M.D., Ph.D., CHRIS HAYWARDSearch for more papers by this author, M.D., Ph.D., BENJAMIN H. FLORESSearch for more papers by this author, M.D., H. BRENT SOLVASONSearch for more papers by this author, M.D., PENELOPE ZEIFERTSearch for more papers by this author, Ph.D., and BRENT T. HARRISSearch for more papers by this author, M.D., Ph.D., Stanford, Calif.Published Online:1 Feb 2003https://doi.org/10.1176/appi.ajp.160.2.391-aAboutSectionsView EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Dr. Stone and colleagues make an excellent point: there can be a reluctance among psychiatrists to make the diagnosis of conversion disorder for fear the patient will develop a neurological disease that better explains the presentation of the illness. Dr. Stone and colleagues express concern that the case conference might reinforce an idea that development of a neurological disease in patients with a presentation most consistent with conversion initially is a common occurrence.The case presentation was directed toward demonstrating how difficult it can be to establish a diagnosis of a neurological disease before there is a signature sign and how illness-related behavior, and interpretations of secondary gain, may sadly confound the clinician. It is helpful that a CSF assay for the 14-3-3 protein is now available, making a diagnosis of Creutzfeld-Jacob disease more straightforward in patients with otherwise ambiguous symptoms. In the case presented, there were no T2-weighted hyperintensities in the basal ganglia or elsewhere on the MRI of the patient’s head. Furthermore, at that time, diffusion-weighted scans were not available, although they appear to be a relatively sensitive marker for Creutzfeld-Jacob disease (1). Fortunately, other individuals with conversion disorder whom we have seen on our unit had an illness that was far clearer in presentation and responded to treatment.It was not our intention to generalize the experience with this case conference in a way that would prevent a reasonable diagnosis of conversion in a patient with medically unexplained symptoms. However, a cautionary note is inherent in the history of the case we presented. It is expected that any diagnosis made on the basis of an apparent exclusion of other causes, as is the case with conversion disorder, be held with some degree of suspended disbelief. Clinical vigilance, as we noted, is essential.Reference1. Murata T, Shiga Y, Higano S, Takahashi S, Mugikura S: Conspicuity and evolution of lesions in Creutzfeldt-Jakob disease at diffusion-weighted imaging. AJNR Am J Neuroradiol 2002; 23:1164-1172Medline, Google Scholar FiguresReferencesCited byDetailsCited byNone Volume 160Issue 2 February 2003Pages 391-a-392 Metrics History Published online 1 February 2003 Published in print 1 February 2003

Multiple sclerosis and optic neuritis: CCR5 and CXCR3 expressing T cells are augmented in blood and cerebrospinal fluid.

A role for chemokines as mediators of Th1 cell recruitment to the central nervous system (CNS) is probable in MS. Therefore we studied expression of Th1-related CCR5 and CXCR3 chemokine receptors in patients with MS and controls. Patients with untreated MS had elevated percentages of CCR5 and CXCR3 expressing T cells vs. healthy controls (HC) in blood, and vs. other non-inflammatory neurological diseases (OND) patients in CSF. Such elevation was not found in MS patients examined during ongoing treatment with IFN-beta. Patients with optic neuritis (ON), a common first manifestation of MS, had elevated percentages of CXCR3 expressing T cells in blood compared with HC, and of CCR5 expressing T cells in CSF compared with OND patients. High chemokine receptor expression may be one prerequisite for Th1 cells to migrate to the CNS. Inhibition of chemokine receptor expression may constitute a potentially important therapeutic effect of IFN-beta.

Focal neurological disease in patients with acquired immunodeficiency syndrome.

Focal neurological disease in patients with acquired immunodeficiency syndrome may be caused by various opportunistic pathogens and malignancies, including Toxoplasma gondii, progressive multifocal leukoencephalopathy (PML), cytomegalovirus (CMV), and Epstein-Barr virus-related primary central nervous system (CNS) lymphoma. Diagnosis may be difficult, because the findings of lumbar puncture, computed tomography (CT), and magnetic resonance imaging are relatively nonspecific. Newer techniques have led to improved diagnostic accuracy of these conditions. Polymerase chain reaction (PCR) of cerebrospinal fluid specimens is useful for diagnosis of PML, CNS lymphoma, and CMV encephalitis. Recent studies have indicated the diagnostic utility of new neuroimaging techniques, such as single-photon emission CT and positron emission tomography. The combination of PCR and neuroimaging techniques may obviate the need for brain biopsy in selected cases. However, stereotactic brain biopsy, which is associated with relatively low morbidity rates, remains the reference standard for diagnosis. Highly active antiretroviral therapy has improved the prognosis of several focal CNS processes, most notably toxoplasmosis, PML, and CMV encephalitis.

Relation between depression and anxiety in dystonic patients: implications for clinical management.

Past clinical research has identified depression as the most common psychiatric disorder associated with cervical dystonia (CD). The purpose of our study is to document different patterns of psychopathology, the frequency of psychiatric disorders, and possible correlation with the neurological disorder in patients with CD. Forty patients with CD were investigated to assess levels of psychopathology on two self-rated scales: the Beck Depression Inventory (BDI) and Symptom Check List (SCL-90). To determine the presence of psychiatric disorders, the patients were evaluated using the standard instrument in the DSM-III-R (Structured Clinical Interview Schedule, SCID). A small group of dystonic patients (12%) had higher levels of psychopathology, with significant amounts of concomitant anxiety and depression on the BDI and SCL-90. SCID criteria for at least one psychiatric disorder were fulfilled in 22 patients (55%), including both the lifetime and current diagnoses. The most frequent diagnostic categories were anxiety (40%) and major depressive disorders (37.5%). In 17 patients (42.5%), criteria for at least one lifetime diagnosis were fulfilled prior to the onset of CD. Psychiatric evaluation does not indicate one specific disorder associated with CD. The presence of anxiety and depression symptoms before and during the course of dystonia, without a possible causal relationship, could mean that the alteration of a chain of physiological events in the central nervous system may not lead to a single clinical picture. The relatively high overall lifetime prevalence of anxiety and depressive disorders may indicate the need for a broader diagnostic and therapeutic approach to patients with focal dystonia.

Clinical features and survival pattern of central nervous system leukemia in children with acute lymphoblastic leukemia

Infiltration of leukemic cells into the central nervous system (CNS) is one of the causes of neurological disorders in patients with acute lymphoblastic leukemia (ALL) that worsen the prognosis. This retrospective cohort study aimed to review the clinical manifestations of children with CNS leukemia, their survival pattern and the role of early CNS leukemial. The survival curve was developed by Kaplan-Meier method, while the comparison of survival curves was done with log-rank test. Among 128 new ALL patients, 23 (18.0%) patients suffered from CNS leukemia, while 13 (10.2%) suffered from early CNS leukemia and 10 (7.8%) suffered from relapsing CNS leukemia. CNS leukemia was more common in male, in those aged less than 2 years, in those with white blood cell (WBC) count above 50,000/µl, and in patients type FAB-L2 ALL. The clinical manifestations most commonly found were decrease of consciousness (61%), vomiting (48%), cranial nerve palsy (44%), seizures (39%), and headache (26%). Relapsing CNS leukemia was more common in high risk (12.5%) compared with standard risk leukemia (5.7%). Patients with early CNS leukemia had a lower survival rate than those without early CNS leukemia (p = 0.0005). The percentage of patients with early CNS leukemia surviving up to 3 years was 26%. We conclude that early CNS leukemia could cause low survival ALL patients. (Paediatr Indones 2001; 41:247-252)

Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study.

The appropriate duration of oral anticoagulation after a first episode of venous thromboembolism (VTE) is uncertain and depends upon VTE recurrence rates. To estimate VTE recurrence rates and determine predictors of recurrence. Patients in Olmsted County, Minnesota, with a first lifetime deep vein thrombosis or pulmonary embolism diagnosed during the 25-year period from 1966 through 1990 (N = 1,719) were followed forward in time through their complete medical records in the community for first VTE recurrence. Four hundred four patients developed recurrent VTE during 10,198 person-years of follow-up. The overall (probable/definite) cumulative percentages of VTE recurrence at 7, 30, and 180 days and 1 and 10 years were 1.6% (0.2%), 5.2% (1.4%), 10.1% (4.1%), 12.9% (5.6%), and 30.4% (17.6%), respectively. The risk of recurrence was greatest in the first 6 to 12 months after the initial event but never fell to zero. Independent predictors of first overall VTE recurrence included increasing age and body mass index, neurologic disease with paresis, malignant neoplasm, and neurosurgery during the period from 1966 through 1980. Independent predictors of first probable/definite recurrence included diagnostic certainty of the incident event and neurologic disease in patients with hospital-acquired VTE. Recurrence risk was increased by malignant neoplasm but varied with concomitant chemotherapy, patient age and sex, and study year. Venous thromboembolism recurs frequently, especially within the first 6 to 12 months, and continues to recur for at least 10 years after the initial VTE. Patients with VTE with neurologic disease and paresis or with malignant neoplasm are at increased risk for recurrence, while VTE patients with transient or reversible risk factors are at less risk.

Cross‐reactive idiotypy in cerebrospinal fluid immunoglobulins in multiple sclerosis

The presence of oligoclonal bands in cerebrospinal fluid (CSF) in multiple sclerosis (MS) indicates a restricted heterogeneity of immunoglobulin (Ig). The portion of myelin basic protein encompassing residues 80–96 contains epitopes frequently recognized by T and B cells of MS patients. To define further this restricted heterogeneity and to direct further efforts to identify an antigenic target of CSF oligoclonal bands, the presence of idiotope (Id)-bearing antibodies sharing an Id with a murine monoclonal antibody to myelin basic protein peptide 80–89 was examined in the CSF of MS patients. CSF samples from 57 patients with clinically definite MS and 45 patients with other neurological diseases were standardized for amount of IgG and analyzed by immunoblotting for detection of Id-bearing antibodies. Id-bearing Ig was detected in the CSF of 79% of MS patients and 16% of other neurological disease patients. Further statistical analysis revealed an 84% specificity, an 86% positive predictive value, and a 76% negative predictive value of the test. The probability that a positive screening result indicated MS was 81%. Thus, antibodies containing a cross-reactive Id are present preferentially in the CSF of patients with MS compared with those with other neurological diseases. An immune network that has limited V region gene usage likely exists in the CSF and central nervous system of patients with MS and may provide evidence about antigens relevant to the pathogenesis of MS. Ann Neurol 2000; 47:87–92

Cross-reactive idiotypy in cerebrospinal fluid immunoglobulins in multiple sclerosis

The presence of oligoclonal bands in cerebrospinal fluid (CSF) in multiple sclerosis (MS) indicates a restricted heterogeneity of immunoglobulin (Ig). The portion of myelin basic protein encompassing residues 80-96 contains epitopes frequently recognized by T and B cells of MS patients. To define further this restricted heterogeneity and to direct further efforts to identify an antigenic target of CSF oligoclonal bands, the presence of idiotope (Id)-bearing antibodies sharing an Id with a murine monoclonal antibody to myelin basic protein peptide 80-89 was examined in the CSF of MS patients. CSF samples from 57 patients with clinically definite MS and 45 patients with other neurological diseases were standardized for amount of IgG and analyzed by immunoblotting for detection of Id-bearing antibodies. Id-bearing Ig was detected in the CSF of 79% of MS patients and 16% of other neurological disease patients. Further statistical analysis revealed an 84% specificity, an 86% positive predictive value, and a 76% negative predictive value of the test. The probability that a positive screening result indicated MS was 81%. Thus, antibodies containing a cross-reactive Id are present preferentially in the CSF of patients with MS compared with those with other neurological diseases. An immune network that has limited V region gene usage likely exists in the CSF and central nervous system of patients with MS and may provide evidence about antigens relevant to the pathogenesis of MS.

A physical model describing the mechanism for formation of gas microbubbles in patients with mitral mechanical heart valves.

This study was aimed at developing a physical model, supported by experimental observations, to describe the formation and growth of microbubbles seen in patients with mitral mechanical heart valves (MHV). This phenomenon, often referred to as high intensity transient signals (HITS), appears as bright, intense, high-velocity and persistent echoes detected by Doppler ultrasonography at the instant of closure. The long-term clinical implications of HITS has yet to be determined. However, there are reports of a certain degree of neurological disorder in patients with mitral MHV. The numerical analysis has shown the existence of a twofold process (1) nucleation and (2) microbubble growth as a result of cavitation. While mild growth of nuclei is governed by diffusion, explosive growth of microbubbles is controlled by pressure drop on the atrial side of mitral MHV. It was demonstrated that there exist limits on both microbubble size and regurgitant velocity, above which microbubbles grow explosively, and below which growth is almost nonexistent. Therefore, prevention of excessive pressure drops induced by high closing velocities related to the dynamics of closure of mitral MHV may offer design changes in the future generations of mechanical valves.

Impaired interleukin-12 production in multiple sclerosis patients.

Multiple Sclerosis (MS), a disease of the human central nervous system, is believed to be a T cell mediated autoimmune disorder with genetic and environmental influences. Interleukin-12 (IL-12), a proinflammatory cytokine produced primarily by antigen presenting cells is a potent inducer of interferon-gamma (IFN-gamma) and other Th1 cytokines that may play an important role in MS pathogenesis. We have investigated IL-12 production induced by the T cell independent pathway in untreated and IFN-beta treated MS patients, healthy individuals and other neurological disease (OND) patients in response to the human pathogen Staphylococcus aureus. We report that peripheral blood mononuclear cells (PBMC) from untreated MS patients produce normal amounts of the biologically active IL-12 p70 heterodimer but significantly less free IL-12 p40 heavy chain than PBMC from both healthy and disease controls when challenged in vitro with Staphylococcus aureus. Both mRNA expression of the inducible IL-12 p40 chain and protein levels were found to be reduced in untreated MS patients. No decrease in the production of the IL-12 p40 was seen in MS patients on IFN-beta therapy. The decreased production of IL-12 p40 heavy chain is not attributed to increased IL-10 secretion, a defect in the production of cytokines by macrophages or the number of cytokine producing cells. The factor(s) responsible for the decrease in p40 remain to be determined. Since IL-12 p40 antagonizes the biological activity of IL-12 in vitro and in vivo, identification of a defect in the 'natural' antagonist of IL-12, may provide the basis for immune therapy.