Chronic progressive myelopathy: investigation with CSF electrophoresis, evoked potentials, and CT scan.

Chronic progressive myelopathy (CPM) is a difficult clinical problem. Many patients who present with CPM turn out to have a spinal form of multiple sclerosis (MS), but until there is clear lesion dissemination, a definite clinical diagnosis cannot be made. We have looked for MS-related abnormalities in 72 patients with CPM. The mean age of onset was 42 years, mean duration was ten years, and mean Kurtzke disability rating was 4.5. Studies performed were cerebrospinal fluid electrophoresis for oligoclonal banding, pattern-reversal visual evoked responses, blink reflex latencies, and computerized axial tomography. Oligoclonal banding was found in 32 patients (44%), patterned visual evoked responses were abnormal in 32 (44%), and blink latencies were abnormal in 40 (56%). A least one of these studies was abnormal in 61 patients (85%) and at least two in 48 (66%). The CT scan was abnormal in 38 )53%), 36 with atrophy and 3 with low-density or enhancing lesions. These results suggest that at least 44% of patients with CPM may have MS that could be diagnosed by oligoclonal bands. Other physiological tests suggesting diffuse or disseminated disease bring the total to 85%. Only autopsy follow-up will tell us the exact diagnostic accuracy of these studies in this complex syndrome.     

Immunoglobulin abnormalities and measles antibody response in chronic myelopathy.

Patients with chronic myelopathy of unknown origin were separated into two groups on the basis of presence or absence of oligoclonal immunoglobulin G (lgG) in cerebrospinal fluid (CSF). Thirty-nine of 48 patients (81%) with oligoclonal lgG in CSF had measles virus antibodies in the CSF and 31 (65%) showed reduced serum/CSF measles virus antibody ratios, in comparison with the corresponding ratios of adenovirus, group-specific, penton hemagglutination-enhancement and poliovirus neutralization-enhancement antibodies. Of 25 patients with myelopathy, but without oligoclonal lgG in their CSF, three had detectable titers of measles CSF antibodies and one of these had a greatly reduced serum/CSF ratio. The conditions of patients with chronic myelopathy of unknown origin and oligoclonal lgG in CSF may be diagnosed as probable multiple sclerosis (MS), in contrast to patients with this disease who lack oligoclonal lgG IN CSF. However, the clinical features of the disease in these two groups do not differ substantially.     

Is myelopathy of unknown origin related with tropical spastic paraparesis and myelopathy associated with human T cell lymphotropic virus type I?

Paired cerebrospinal fluid (CSF) and serum samples from 52 Italian patients affected by myelopathy of unknown origin (MUO) were tested for the presence of antibodies to human T cell lymphotrophic virus type I (HTLV-I) by an enzyme-linked immunosorbent assay, in an attempt to demonstrate a common retroviral origin of MUO, tropical spastic paraparesis (TSP) and HTLV-I-associated myelopathy (HAM). All the patients complained of weakness to the legs, while weakness to the arms, mild sensory disturbances, impaired bladder and bowel functions, and impotence were present in different percentages. All CSF and serum samples were devoid of HTLV-I antibodies. The possible relations between MUO, TSP and HAM are discussed.     

MRI in the diagnosis of MS: a prospective study with comparison of clinical evaluation, evoked potentials, oligoclonal banding, and CT

We compared the diagnostic capabilities of MRI to CT, evoked potentials (EP), and CSF oligoclonal banding analysis in a prospective evaluation of 200 patients with suspected multiple sclerosis (MS). MRI was the best method for demonstrating dissemination in space. An abnormal appropriate EP in monosymptomatic disease was usually supported by MRI and CSF analysis as being predictive of MS as a clinical diagnosis. A normal appropriate EP study was not satisfactory because MRI and CSF analysis often did not support a diagnosis of non-MS. When there is agreement between three of these paraclinical studies, the diagnosis of MS is probably unequivocal. For use in research studies, laboratory-supported definite MS (LSDMS) could be diagnosed in 85 patients of the total 200 (42.5%), in 19/38 (50%) of optic neuritis (ON) patients, and in 24/52 (46%) of chronic progressive myelopathy (CPM) patients. MRI was 100% successful in identifying patients who qualified for LSDMS in the ON and CPM groups. In a short follow-up (less than 1 year), 19/200 (10%) went on to develop clinically definite MS (CDMS), and MRI predicted that diagnosis in 18/19 (95%). Only long-term follow-up will show how well these studies and the category of LSDMS predict the development of CDMS. The clinical diagnosis of MS (CDMS), even though only 95% accurate, must remain the gold standard.     

Immunoglobulin class and light chain type of oligoclonal bands in CSF in multiple sclerosis determined by agarose gel electrophoresis and immunofixation.

Agarose gel electrophoresis and immunofixation of CSF and serum from 39 patients with multiple sclerosis (MS) revealed oligoclonal IgG in the CSF in all cases and oligoclonal IgA and IgM in 1 patient each. IgG kappa bands only were found in 10 patients, while no patient had IgG lambda bands alone. IgG kappa bands predominated in 20 patients and IgG lambda bands in 5, while 4 patients had the same number of IgG kappa and IgG lambda bands. Twenty-seven patients also displayed IgG bands with kappa and lambda present simultaneously. Bands of free lambda chains were found in 7 patients, while free kappa chain bands were not seen. One or 2 faint IgG bands in 4 patients constituted the only serum abnormality. In 4 additional MS patients selected on the basis of normal findings on agarose gel electrophoresis of the CSF, immunofixation did not reveal oligoclonal Ig, while isoelectric focusing showed bands in 1. Immunofixation is recommended for proving the presence of oligoclonal Ig in CSF and for characterizing oligoclonal Ig into classes and types of light chains.     

Chronic progressive myelopathy associated with HTLV-I: oligoclonal IgG and anti-HTLV-I IgG antibodies in cerebrospinal fluid and serum

Among 22 patients with human T-lymphotropic virus type I (HTLV-I)-associated chronic progressive myelopathy, agarose isoelectric focusing (AIF) revealed oligoclonal IgG bands in 21: in 3 in CSF only; in 11 in CSF and to some extent in serum; and in 7, identical patterns in CSF and serum. By immunoblot after AIF of CSF and serum, we observed bands of anti-HTLV-I IgG antibodies in 19 patients: in 5 in CSF only; in 9 in CSF and partly in serum; and in 5, identical in CSF and serum. Oligoclonal anti-HTLV-I IgG antibody bands could only partly be traced to oligoclonal IgG bands. If, prior to AIF, serum and CSF were absorbed with HTLV-I antigen, practically all oligoclonal HTLV-I-specific IgG antibody activity was abolished, while the oligoclonal pattern of total IgG was affected only to a minor extent. Alongside with HTLV-I-specific oligoclonal B cell response, HTLV-I myelopathy is regularly accompanied by production of oligoclonal IgG of unknown antibody specificities.     

Two cases of atypical HTLV-I associated myelopathy (HAM)

We report two cases of HTLV-I associated myelopathy (HAM) who showed high HTLV-I antibody titers with clinically atypical neurological symptoms compared with typical HAM originally reported by Osame et al. Case 1 is a 59 year-old-woman who showed Shy-Drager syndrome-like symptoms such as a slowly progressive gait disturbance, pyramidal and extra-pyramidal symptoms, an orthostatic hypotension and a sweating disturbance. The anti HTLV-I antibody titer was highly positive in both her serum and cerebrospinal fluid (CSF), and there was also a high level of oligoclonal immunoglobulin in her CSF. These symptoms improved slightly with steroid therapy. Therefore, it was suspected that this neurological condition was associated with HTLV-I, which means that HTLV-I can be associated not only with myelopathy but also with various other neurological symptoms. The second case is a 52-year-old woman who had a myelopathy with a slowly progressive course. She had suffered from a transient optic neuritis 5 years before admission that had improved completely with steroid therapy. She had highly positive anti HTLV-I antibody in both her serum and CSF, and also showed a high level of oligoclonal immunoglobulin in her CSF. With administration of steroids, the sensory disturbances and abnormal findings in the CSF improved slightly. Koprowski et al reported that in some MS patients they found positive anti HTLV-I antibody and furthermore proved the presence of CSF cells which hybridized with a HTLV-I probe. They suggested the presence of an unknown HTLV-related agent which may be a pathogenic factor in some subtypes of MS. The transient optic neuritis responding to steroid therapy and the following transverse myelopathy, as seen in case 2, are highly characteristic of MS. Thus, some clinical features of HAM may be very similar to MS.     

Is Devic's neuromyelitis optica a separate disease? A comparative study with multiple sclerosis

Devic's neuromyelitis optica (NMO) associates optic neuritis and myelopathy without other neurological signs. Many patients with NMO may be diagnosed as having multiple sclerosis (MS). However, there have been no previous studies comparing these two pathologies and it is still unclear if NMO is a separate entity or a subtype of MS. In the present study, we compared a series of NMO patients with a series of MS patients for whom optic neuritis or myelopathy was the presenting symptom, in order to determine the place of NMO in the spectrum of MS. We retrospectively studied 30 patients diagnosed with NMO and we compared these patients with 50 consecutive MS cases revealed by optic neuritis or acute myelopathy. MS patients were only included if a relapse occurred demonstrating time and space dissemination. We compared the two groups in terms of clinical presentation, laboratory findings (MRI and CSF) and clinical outcome. NMO patients were older and more frequently women than MS patients but the difference was not significant. CSF and MRI data were clearly different: oligoclonal bands (OCB) were found in 23% of NMO cases and 88% of MS (P < 0.001), abnormal brain MRI data were observed in 10% of NMO cases and 66% of MS (P < 0.001) and a large spinal cord lesion was observed in 67% of NMO cases and 7.4% of MS cases (P < 0.001). Clinical outcome was evaluated as more severe in the NMO group (P < 0.001). On the basis of clinical data, all NMO patients but three had dissemination in time and space. When we included MRI parameters, only two of the NMO patients met criteria for MS and one of the MS patients met criteria for NMO. Our study demonstrates that NMO and MS should be considered as two different entities. The respective criteria for NMO and MS were able to distinguish these two pathologies but only when MRI data were applied. This finding could have implications for future therapeutic trials.     

Optic neuritis: findings on MRI,CSF examination and HLA class II typing in 60 patients and results of a short-term follow-up

Optic neuritis (ON) is a common first manifestation of multiple sclerosis (MS), and examination of patients with ON provides opportunities to study the early clinical stages of MS. This prospective study compares results of brain magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) examinations and HLA-Dw2 phenotyping in 60 consecutive patients with ON. At a median of 17 days after the onset of ON, 69% had oligoclonal IgG bands, and at a median on 79 days after onset, 53% had multiple ( 3) white matter lesions on MRI. Subgroup analyses revealed that MRI abnormalities and oligoclonal IgG bands were equally common in patients examined early or late after the onset of ON. Strong correlations were found between the presence of MRI abnormalities and oligoclonal IgG bands. The HLA-Dw2 phenotype was significantly increased in ON patients compared with controls, but also significantly different from a group of MS patients from the same geographical area. A significant relation was found between Dw2 phenotype and oligoclonal IgG bands. During a mean follow-up time of about 2 years, the diagnosis in 17 of the patients changed to clinically definite MS. Initially, 16 of them had oligoclonal IgG bands and 12 had three or more MRI lesions. Both MRI and CSF studies are important diagnostic tools in the work-up of ON patients.     

Prospective study of patients presenting with acute partial transverse myelopathy

Abstract. Background: The clinical and radiological characteristics of myelopathy in multiple sclerosis (MS) are relatively well known. Nevertheless, it remains difficult for the clinician to ascertain conversion to MS after a first episode of acute partial transverse myelopathy (APTM). Objective: The aims of this study were to define predictive factors for conversion to clinically definite MS after an APTM and to define predictive factors for disease severity. Patients and methods: Between 1994 and 2001, we prospectively included 55 patients presenting with a first episode of APTM. Three patients were lost during the follow-up. We evaluated clinical signs, spinal cord and brain MRI, cerebrospinal fluid (CSF) and visual evoked potentials on admission.After a mean followup of 35 months (range 12–86), we evaluated the diagnosis and, among the MS group, the severity of the disease. Results: Of the 52 APTM patients who completed the study, 30 became clinically definite MS. The predictive factors for conversion to MS were: initial sensory symptoms, latero-posterior spinal cord lesion, abnormal brain MRI and oligoclonal bands in CSF. In the MS group, the number of spinal cord lesions on MRI was the only predictive factor for a poor outcome, being statistically correlated with a higher number of relapses. Conclusion: On the basis of our results, we propose that, in patients with APTM, sensory symptoms, oligoclonal bands and brain MRI are predictive factors for subsequent conversion to clinically definite MS and that within the latter patients the number of spinal cord lesions on MRI is the only predictive factor for a poor outcome.     

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.     

Measles virus antibodies in serum and cerebrospinal fluid in patients with multiple sclerosis and other neurological disorders,with special reference to measles antibody synthesis within the central nervous system

Measles virus hemagglutination-inhibiting (HI) and gel precipitating (GP) antibodies were determined in sera and cerebrospinal fluids (CSF) from 65 patients with multiple sclerosis (MS) and 65 patients with other neurological diseases. The serological results were correlated to content of immunoglobulin-G (IgG) and electrophoretic patterns of sera and CSF.Measles GP antibodies, identified as directed against measles virus ribonucleoprotein antigens, were detected in sera and in CSF from a significantly higher proportion of MS than of non-MS patients. No significant difference between the 2 groups of patients was found for measles HI antibodies.Reduced serum/CSF HI and/or GP antibody ratios were found in about one half of the MS patients and in 2 patients with chronic myelopathy. All patients with reduced antibody ratios had evidence of IgG synthesis within the central nervous system (CNS), as inferred from oligoclonal IgG patterns of the CSF. Reduced ratios of measles GP antibodies were 3 times as common as reduced ratios of HI antibodies. Immuno-electrophoretic assays indicated that the CSF GP antibodies were electrophoretically restricted in a number of MS patients.The results indicate that measles virus may be an active immunogen within the CNS in many MS patients and in some patients with chronic myelopathy, giving rise to an oligoclonal IgG antibody response.     

Cytokine levels in the cerebrospinal fluid and serum of patients with multiple sclerosis

Interleukin (IL) 1 beta, tumor necrosis factor alpha (TNF alpha), and IL-6 are cytokines which mediate cellular responses during immune activation and inflammation. In multiple sclerosis (MS) they might be responsible for T-cell activation (IL-1 beta), for demyelination (TNF alpha), and for immunoglobulin (Ig) synthesis (IL-6) within the central nervous system. We studied IL-1 beta, TNF alpha, and IL-6 levels in the cerebrospinal fluid (CSF) of 34 patients with MS, 43 patients with non-inflammatory neurological diseases (NIND), and 19 patients with inflammatory neurological diseases (IND). IL-6 was found in the CSF of 29% of MS, 7% of NIND, and 47% of IND patients. TNF alpha was detected in the CSF of 23% of MS, 7% of NIND, and 29% of IND. CSF IL-6 and TNF alpha levels were significantly higher in MS and IND than in NIND. IL-1 beta was rarely detected in the CSF of any group. At least one cytokine was detected in 52% of MS CSF, 11% of NIND CSF, and 64% of IND CSF. In MS patients, no relationship was observed between the incidence or the amount of intrathecal IgG synthesis or oligoclonal bands and the presence of any cytokine. We also evaluated cytokine levels in paired sera from 11 MS and 13 NIND patients. Low levels of IL-6 were detected in most sera from MS and NIND patients. TNF alpha was detected in only two MS sera, and IL-1 beta was undetectable in any sample. Our results indicate that increased CSF levels of the cytokines IL-6 and TNF alpha occur frequently in MS and IND, but there is no obvious relationship to intrathecal Ig synthesis.     

Acute myelopathy. Retrospective clinical, laboratory, MRI and outcome analysis of 49 cases.

Forty nine consecutive cases of acute myelopathy were related to the following pathologies: 31 MS, four spinal cord infarction, four parainfectious, one antiphospolipid syndrome and nine of unknown origin. Sensory deficits were most frequent in MS and in myelopathy of unknown origin. In spinal cord infarction motor deficits and sphincter dysfunction were present in all cases. In parainfectious myelopathy sensory-motor deficits and sphincter dysfunction were most frequent. Myelopathy extended over less than two vertebral segments in MS and in myelopathy of unknown origin. Myelopathy extended over more than two vertebral segments in spinal cord infarction and in parainfectious myelopathy. The clinical outcome was good in MS, parainfectious myelopathy and myelopathy of unknown origin, but poor in spinal cord infarction. Our findings suggest that various aetiologies of acute myelopathy may be differentiated on the basis of distinct clinical, MRI, laboratory and outcome data.     

Cranial magnetic resonance imaging in the evaluation of myelopathy of undetermined etiology

The spinal form of MS is a clinical conundrum, the solution of which may yield many answers; to be certain that it is MS and not another disease causing the myelopathy is often difficult. We evaluated 20 patients with myelopathy of undetermined etiology (clinical findings limited to the spinal cord) using T2-weighted cranial magnetic resonance imaging (T2 MRI) and cranial computerized tomography (CT). Some patients were also studied with flash visual evoked responses (FVER) and spinal fluid analysis for myelin basic protein (MBP) and oligoclonal banding (OCB). Thirteen patients had T2 MRIs consistent with demyelinating disease (two or more areas of increased signal intensity, of appropriate size, in periventricular/subcortical white matter), while only one CT showed focal lesions. FVER were abnormal in 8 of 15 patients tested; spinal fluid OCB was present in 12 of 16 patients tested, only 1 of whom had elevated MBP. T2 MRI showed lesions typical of demyelination in the majority of study patients, was much more sensitive than CT, and was well correlated with evidence of demyelination by other tests. Although the specificity of T2 MRI in MS is unknown, it may be very high in this clinical setting.     

T cells from multiple sclerosis patients recognize immunoglobulin G from cerebrospinal fluid

Idiotopic sequences are created after V, D and J recombinations and by somatic mutations during affinity maturation of immunoglobulin (Ig) molecules, and may therefore be potential immunogenic epitopes. Idiotope-specific T cells are able to activate and sustain the B cells producing such idiotopes. It is therefore possible that idiotope-specific intrathecal T cells could help maintain the persisting intrathecal synthesis of oligoclonal IgG observed in patients with multiple sclerosis (MS). This study was undertaken to examine T-cell responses to cerebrospinal fluid (CSF) IgG. Peripheral blood mononuclear cells (PBMC) from 14 of 21 MS patients and four of 17 control patients with other neurological diseases proliferated upon stimulation with autologous CSF IgG, while five and three, respectively, responded to serum IgG. By comparison, responses to myelin basic protein were recorded in only four MS and three control patients. Data from a limited number of patients indicate that the CSF IgG responsive cells were CD4+ and human leucocyte antigen DR restricted, that PBMC also respond to CSF IgG from other MS patients and that the CSF may contain T cells responding to autologous CSF IgG. This suggests that CSF IgG, or substances bound to this IgG, may represent T-cell immunogens, which could contribute to the intrathecal immune response in MS.     

Intrathecal antibody (IgG) production against human herpesvirus type 6 occurs in about 20% of multiple sclerosis patients and might be linked to a polyspecific B–cell response

Human herpesvirus 6 (HHV–6) is one of many infectious agents that have been implicated in the pathogenesis of multiple sclerosis (MS). Intrathecal immunoglobulin (Ig) production with oligoclonal CSF bands are hallmarks of both MS and infections of the CNS. In neuroinfections the intrathecal Ig production is directed largely against the respective agent, while MS patients mount an intrathecal Ig production against different pathogens. In this study a total of 77 serum/CSF pairs were first analyzed for an intrathecal immune response against HHV–6. We found that 21% of the MS patients, but none of the control donors showed an intrathecal immunoglobulin (Ig) response against HHV–6 (p = 0.017). Patients with such an intrathecal Ig production had a significantly higher total amount of Ig (p = 0.007) and a higher cell number in the CSF (p = 0.03). In a second step, four of the MS–patients who showed a strong intrathecal Ig production against HHV–6 were examined for immune reactivity against other viruses (human herpesvirus type 1, measles virus, human cytomegalovirus, rubella virus, varicella zoster virus). All of these patients had an intrathecal Ig production against at least one other, unrelated virus. Together, our findings strongly argue that in the majority of MS patients without an intrathecal Ig response to HHV–6 (about 80 % in our study), this virus is not involved in the pathogenesis. In the other 20% the intrathecal Ig production to HHV–6 might reflect reactivation of HHV–6 or could be part of a polyspecific B cell activation.     

Detection of oligoclonal free kappa chains in the absence of oligoclonal IgG in the CSF of patients with suspected multiple sclerosis

BACKGROUND: Oligoclonal free kappa bands are present as frequently as oligoclonal IgG bands in the cerebrospinal fluid (CSF) from patients with definite multiple sclerosis (MS) and can even occur in the absence of oligoclonal IgG. As such, they too are markers of an ongoing intrathecal immune process. OBJECTIVES: To determine how frequently oligoclonal free kappa bands are detectable in the CSF from patients with clinical signs and symptoms suggestive of MS in the absence of CSF restricted oligoclonal IgG. METHODS: An immunoaffinity mediated immunoblotting technique specific for free kappa chains was used, after isoelectric focusing of paired CSF and serum samples from 33 patients with clinical signs and symptoms suggestive of MS but without CSF oligoclonal IgG. CSF data were correlated with MRI results in the context of the new diagnostic criteria from McDonald et al. RESULTS: Eighteen CSF samples contained oligoclonal free kappa bands (54%), mainly from patients with motor dysfunction (83%) and optic neuritis (64%). All patients with a positive MRI according to Barkhof's criteria (n = 6) had free kappa bands in their CSF. CONCLUSIONS: (1) Oligoclonal free kappa bands in the CSF are related to the dissemination of MS lesions; (2) such bands should be looked for in oligoclonal IgG negative CSF, and (3) the presence of free kappa bands in the CSF may be a substitute for oligoclonal IgG in the McDonald's criteria for diagnosis of MS.     

Viral antibody activity of oligodonal and polyclonal immunoglobulins synthesized within the central nervous system in multiple sclerosis

Thin-layer polyacrylamide gel isoelectric focusing (PAG IEF), a very high capacity method for separating immunoglobulins (Ig), was performed on cerebrospinal fluid (CSF) and serum. It was followed by antigen immunofixation with measles, mumps, herpes simplex (HSV), and rubella virus antigens and anti-human Ig autoradiography in order to demonstrate viral antibodies in separated Ig zones. Two of 11 control patients and 21 of 25 patients with multiple sclerosis (MS) displayed one or more zones of viral antibodies in the CSF without any counterpart, or with distinctly fainter zones, in the serum. Such reaction patterns were taken to indicate the possibility of intrathecal antibody synthesis. Antibody synthesis to measles was found in one to five zones in 76% of the patients with MS; antibody zones were found to HSV in 36% of the patients, to mumps in 12%, and to rubella in 12%. In 36% of the patients, two or three different antibody specificities (of which one was always measles) were found simultaneously in individual autoradiogram zones. For all viral antibodies detected in the CSF autoradiograms, their counterparts in oligoclonal or polyclonal IgG zones (or both) were demonstrable by PAG IEF of the corresponding CSF. The majority of patients with MS also had one or more oligoclonal CSF IgG zones without known antibody specificity. Antigen immunofixation and autoradiography are mainly qualitative. It is not known whether the viral antibodies present in oligoclonal or polyclonal IgG zones in MS CSF reflect a polyclonal B cell activation, a disease-specific immune reaction, or both.