Criteria For Multiple Sclerosis Research Articles

Should Spinal MRI Be Routinely Performed in Patients With Clinically Isolated Optic Neuritis?

Should Spinal MRI Be Routinely Performed in Patients With Clinically Isolated Optic Neuritis?

Optimal Intereye Difference Thresholds in Retinal Nerve Fiber Layer Thickness for Predicting a Unilateral Optic Nerve Lesion in Multiple Sclerosis.

The optic nerve is a frequent site for involvement in multiple sclerosis (MS). Optical coherence tomography (OCT) detects thinning of the retinal nerve fiber layer (RNFL) in eyes of patients with MS and in those meeting criteria for clinically or radiologically isolated demyelinating syndromes. Current international diagnostic criteria for MS do not include the optic nerve as an imaging lesion site despite the high prevalence of acute optic neuritis (ON), or occult optic neuropathy, among early MS and clinically isolated syndrome patients; as well as most MS patients over the course of the disease. We sought to determine optimal thresholds for intereye difference in peripapillary RNFL thickness that are most predictive of a unilateral optic nerve lesion. We analyzed spectral domain OCT data of 31 healthy volunteers and 124 patients with MS at a single center as part of an ongoing collaborative investigation of visual outcomes. Intereye differences in peripapillary (360°) RNFL thickness were calculated as the absolute value of the difference. First, we determined the 95th percentile value of intereye difference for the healthy volunteers. This value was applied to the convenience sample group of MS patients as a validation cohort determining how well this threshold could distinguish patients with vs without a history of unilateral ON. The relation of intereye differences in peripapillary RNFL thickness to binocular low-contrast letter acuity scores was also examined. Among healthy volunteer participants (n = 31), the 95th percentile value for intereye difference (upper boundary of expected for normal controls) was 6.0 μm. This value was applied to the convenience sample group of MS patients (n = 124, validation cohort). Positive predictive value, negative predictive value, sensitivity, and specificity for identifying MS patients with a history of unilateral ON were calculated for the 6-μm threshold value in a 2 × 2 table analysis with the application of χ tests (P < 0.0001). The 6-μm threshold was predictive of worse binocular low-contrast acuity scores at 2.5% (P = 0.03) and 1.25% (P = 0.002 by linear regression analyses). A receiver operating characteristic curve analysis demonstrated an optimal intereye difference threshold of 5 μm for identifying unilateral ON in the MS cohort. An intereye difference of 5-6 μm in RNFL thickness is a robust structural threshold for identifying the presence of a unilateral optic nerve lesion in MS.

Evaluation of interferon β-1b therapy effects on the level and abnormal nature of immunoglobulin G in patients with multiple sclerosis

Aim : to study and evaluate the interferon β-1b (INF) therapy efficiency on the level and abnormal nature of immunoglobulin G in patients with multiple sclerosis (MS). Materials and methods . This scientific work was performed at the Neurology Department and the Department of Histology, Cytology and Embryology of theLvivNationalMedicalUniversity named after Danylo Halytsky and in theLvivRegionalResearchCenter for the Study of Multiple Sclerosis and Other Demyelinating Diseases on the basis of theLvivRegionalClinicalHospital. The inclusion criteria for patients were age between 18 and 65 years as well as definite diagnosis of MS according to McDonald Diagnostic Criteria for MS (2010). 32 patients with MS and 23 practically healthy persons were enrolled in the study. After a written informed consent obtaining from the patient there was a peripheral venous blood sampling using a blood-collection tube system Vacuette. Serum samples were prepared for antibodies to myelin basic protein (MBP) determination and identification of immunoglobulin glycosylation by means of lectin-immunoenzymatic assay. Results. Elevated levels of anti-MBP IgG and IgM in the treatment-naive MS patients were determined in comparison with the healthy persons. At the same time, higher exposure of anti-inflammatory sialic acid residues on IgG molecules and associated native immune complexes were observed in the group of patients who received INF therapy as well as higher exposure of fucosylated tri-mannose residues on measles IgG molecules and associated native immune complexes in comparison with the untreated patients. Conclusions: The blood serum of MS patients who received INF therapy were characterized by lower levels of IgG and IgM antibodies to MBP and higher exposure of sialic acid terminal residues on IgG and IgM molecules in comparison with the untreated patients. It is reasonable to assume that INF therapy could lead to anti-inflammatory native IgG complexes formation and / or decrease in IgG and IgM autoantibodies against the nervous system components, as it has been shown for autoantibodies to MBP.

Diagnosis of Multiple Sclerosis: 2017 McDonald Diagnostic Criteria

Multiple sclerosis (MS) is a diagnosis of exclusion and the lesions or objective findings should disseminate in space and time to diagnose MS. The diagnostic criteria of MS have continuously evolved overtime. The McDonald criteria were originally proposed in 2001, and the revised 2010 McDonald criteria have been used widely. Scientific advances in the past 7 years since 2010 induced the revised 2017 McDonald criteria. All revisions relied entirely on the available evidences, and not expert opinion. In this review, we will provide an overview of the way to diagnose MS and the 2017 McDonald criteria. Key Words: Multiple sclerosis, Diagnosis

Factors Related to Long Term Motor, Behavioral, and Scholastic Outcome in Children with Acute Disseminated Encephalomyelitis

ObjectiveWe studied the long-term outcome of Acute disseminated encephalomyelitis (ADEM). MethodsWe performed a retrospective cohort study among children diagnosed with ADEM (fulfilling IPMSSG criteria). Major outcome variables were motor deficit, scholastic underperformance, and behavioral abnormality. ResultsThe inclusion criteria were fulfilled by 102 children. Three died in hospital. The follow-up ranged from one to 10 years (median 4 years). Motor deficit was seen in 17(17.2%), attention deficit in 25 (25.3%), behavioral abnormality in 13(13.1%), persistent seizures in seven (7%) invididuals and poor learning skills in 22 (22.2%). Recurrence of demyelination occurred in seven (7.1%). Two individuals had a recurrent demyelinating disorder (a chronic relapsing demyelinating disorder) that could not be classified as multiple sclerosis (MS), two had ADEM with sequential optic neuritis and three had multiphasic ADEM. At follow-up, the mean (SD) modified Rankin Scale (mRS) score was 0.556 (1.36) and Expanded Disability Status Scale score was 1.71(2.22). On multivariate analysis, the mRS score at discharge (p<0.01) and thalamic lesions on magnetic resonance imaging (MRI) (p<0.01) were associated with motor sequelae; poor learning skills with ADEM with concomitant polyneuropathy (p<0.02); and behavioral abnormality with tumefactive demyelination (p<0.02). ConclusionsChildren who had ADEM may have motor or cognitive sequelae, seizures or recurrent demyelinating events on follow-up. We identified a few risk factors for these sequelae. Factors that affected outcome on discharge from hospital did not affect chances of having long-term sequelae. On follow-up, none of the children fulfilled the diagnostic criteria for MS, suggesting that the chance of conversion of ADEM to MS is less likely.

Childhood multiple sclerosis: clinical features and recent developments on treatment choices and outcomes.

Multiple sclerosis (MS) is an inflammatory idiopathic autoimmune disease causing demyelination of central nervous system (CNS). The incidence of pediatric MS is relatively rare, affecting 0.2 to 0.64/100,000 subjects; cases with MS onset before age 10-12 years, account for less than 1% of all MS cases, while 2.7 to 10.5% of all MS cases worldwide are seen in children <18 years of age, with a strong female preponderance. The disease course of MS varies from a benign type with relatively low level of disability after a long duration (15 years) of the disease, to a malignant type of MS with severe disability or even death within few months following onset. Diagnostic criteria for pediatric MS include ≥ 2 clinical events involving more areas of CNS inflammation in the absence of encephalopathy, separated by > 30 days, along with the involvement of brainstem. Pediatric MS generally presents relapsing-remittent form of MS, with majority of the patients recovering from the first attack. Major histocompatibility complex, more specifically, mutations in the human leukocyte antigen (HLA) DRB1*15 allele, are considered most important genetic factors that are contributory to the disease. Treatment choices for pediatric MS include many disease-modifying therapies (DMT) that are currently being used for adult MS and these are interferon-β 1a/1b (IFN-β1a/1b), glatiramer acetate, teriflunomide, dimethyl fumarate, alemtuzumab, etc. However, most of these have not gone through complete testing in randomized, placebo-controlled clinical trials for pediatric MS and are being prescribed off-label by clinicians. As these studies are progressing, it is important to address if these approaches of treating pediatric MS patients have any long-term impact on patients, in particular, physical, cognitive, developmental and social outcomes of the children.

Evaluation of brain lesion distribution criteria at disease onset in differentiating MS from NMOSD and MOG-IgG-associated encephalomyelitis

Objectives: We aimed to evaluate the utility of the recently described brain lesion distribution criteria to differentiate multiple sclerosis (MS) from aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein immunoglobulin G-associated encephalomyelitis (MOG-EM) at disease onset in an Asian cohort. Methods: A total of 214 patients who fulfilled the published criteria for MS, NMOSD, or MOG-EM and underwent brain magnetic resonance imaging (MRI) within 3 months of disease onset were enrolled. The brain lesion distribution criteria were defined as the presence of a lesion adjacent to the body of the lateral ventricle and in the inferior temporal lobe, or an S-shaped U-fiber lesion, or a Dawson’s finger-type lesion. Results: Brain lesions were identified in the initial MRI scans of 166/214 patients. The distribution criteria were applied to these scans (MS (n = 94), NMOSD (n = 64), and MOG-EM (n = 8)). The sensitivity, specificity, and positive and negative predictive values of the criteria for MS versus NMOSD were 79.8%, 87.5%, 90.4%, and 74.7%, and for MS versus MOG-EM these were 79.8%, 100%, 100%, and 29.6%, respectively. Conclusion: These findings suggest that the brain lesion distribution criteria are helpful in distinguishing MS from NMOSD and MOG-EM in an Asian population, even at disease onset.

The early diagnosis and treatments in multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system that leads to neurological disability. The diagnosis of MS relies on the MRI criteria, which can demonstrate dissemination in space and time. Exclusion of other demyelinating mimics is essential because there are no specific biomarker for MS and MRI criteria are still have imperfect. There is incremental improvements in MS treatment option that have contributed to the delay of disease progression. The early initiation of DMT may ameliorate the neurological disability. In this review, we discusses the new diagnostic MS criteria and summarize the evidences supporting the early treatment in the course of MS.

Cervical vestibular-evoked myogenic potentials in patients with multiple sclerosis: sensitive in detecting brainstem involvement?

Cervical vestibular-evoked myogenic potentials (cVEMPs) are accepted to demonstrate the vestibulo-collic reflex. However, the brainstem pathway is still not fully understood. The aim of the study was to evaluate the contribution of cVEMPs to detection of brainstem involvement in multiple sclerosis (MS). Thirty patients fulfilling the criteria for definite MS were included in the study. All were newly diagnosed cases, admitted due to an attack with active lesions on MRI. Thirty-one age- and sex-matched healthy controls constituted the control group. The latencies of peaks p13 and n23 and peak-to-peak amplitude of p13-n23 were measured. Brainstem lesions on MRI were present in 13 of the patients (43.4%). Comparison of the overall results recorded from patients with the healthy controls did not reveal a statistically significant difference in any of the parameters studied (p > 0.05). A significant inter-side difference was not also present between groups (p > 0.05). When p13 and n23 latencies exceeding 2.5 standard deviations (SD) were taken into consideration, it was seen that there were seven patients (23.3%) with prolonged latencies mainly involving the p13 peak. Five of them had brainstem signs on examination and had brainstem lesions on MRI. In the other eight patients with abnormal MRI, normal results were recorded indicating that in only 38% of patients with brainstem lesions, cVEMPs were altered. Absence of a correlation between cVEMPs and brainstem clinical or MRI lesions defies their role in identifying lower brainstem involvement.

MAGNET RESONANCE IMAGING FINDINGS AND DIFFERANTIAL DIAGNOSIS OF MULTIPLE SCLEROSIS

Multiple sclerosis (MS) is the most common inflammatory demyelinating disease of the central nervous system in young and middle-age adults and diagnosis is very complicated. According to the McDonald criteria for MS, the diagnosis requires objective evidence of lesions disseminated in time and space. In clinically isolated syndrome suggestive of MS to prove dissemination in time or space in order to fulfill the McDonald criteria, brain MRI is indicated. The diagnosis of MS requires demonstration of dissemination of lesions in space and time and elimination of more likely diagnoses with MRI of brain and spinal cord. Gadolinium is administered at the start of the examination.

Consistent increase in the prevalence and female ratio of multiple sclerosis over 15 years in northern Japan.

The prevalence of multiple sclerosis (MS) is considered to be lower in East Asia than in Western countries. An increasing trend has been reported globally for the prevalence of MS. We investigated the changes in the prevalence and clinical characteristics of MS in the Tokachi province of Hokkaido, northern Japan from 2001 to 2016. Prevalence was determined on 31 March 2016. Data-processing sheets were collected from all MS-related institutions in Tokachi province. We applied Poser's diagnostic criteria for MS as used in our previous three studies. Cases of neuromyelitis optica spectrum disorders were excluded. In 2016, the crude MS prevalence was 18.6/100 000 (95% confidence interval, 14.3-23.8) in northern Japan. Over the last 15 years, the prevalence of MS in the same area was 8.1, 12.6 and 16.2 in 2001, 2006 and 2011, respectively. The female:male ratio was 3.57, which increased from 2.63 in 2001. The ratios of primary progressive, relapsing-remitting and secondary progressive MS types were 2%, 84% and 14%, respectively. Our results demonstrated a consistent increase in MS prevalence among the northern Japanese population, particularly in females, and relatively lower rates of progressive MS in northern Japan than in Western countries.

A population-based prospective study of optic neuritis

Background: Optic neuritis (ON) is often associated with multiple sclerosis (MS). Early diagnosis is critical to optimal patient management. Objective: To estimate the incidence of acute ON and the rates of conversion to MS and antibody-mediated ON. Method: Population-based prospective study was performed in patients with ON from three ophthalmological departments and 44 practicing ophthalmologists from 2014 to 2016. Ophthalmological and neurological examination, magnetic resonance imaging (MRI), determination of aquaporin-4(AQP4)-IgG and myelin-oligodendrocyte glycoprotein (MOG)-IgG were investigated blindly. Results: In all, 63 patients were evaluated and 51 fulfilled the criteria for ON. All were Caucasian, with female:male ratio of 2.2:1 and a median age of 38 years (16–66); 44 (86%) had a single episode of ON (four bilateral), while 7/51 (14%) had recurrent ON. The overall age-specific incidence was 3.28 (2.44–4.31) per 100,000 person years, 2.02 for men and 4.57 for women. At follow-up, 20 patients met the diagnostic criteria for MS, MRI lesions disseminated in space and time in 17/20 patients. AQP4-IgG was detected in none, MOG-IgG was detected in two patients. Conclusion: The prospective incidence of ON was estimated. MRI enabled a diagnosis of MS in a subgroup of patients. Antibody-mediated ON with specificity for MOG was detected in 4% of cases.

Application of the McDonald criteria in Latin America.

The diagnosis of multiple sclerosis (MS) is based on neurological symptoms and signs, alongside evidence of dissemination of central nervous system (CNS) lesions in space and time. In the absence of a sensitive and specific diagnostic test, diagnostic criteria are needed for diagnosing MS. The caveat to the application of the McDonald criteria is that alternative diagnoses must be excluded. The prevalence, clinical phenotype and the differential diagnosis of MS may have variations in different populations, especially in Latin America (LATAM). Considering that MS diagnostic criteria were developed with data gathered largely from adult Caucasian European and North American populations, their applicability and accuracy in ethnical/genetic diverse populations may be affected. There are scarce data in our region about the reliability of MS criteria.

Dysregulation of cytokine pathways in chronic fatigue syndrome and multiple sclerosis

ABSTRACT Background: Cytokine studies in chronic fatigue syndrome (CFS) have yielded mixed findings. Purpose: This investigation evaluated whether network analysis of cytokine production differs between patients with CFS and multiple sclerosis (MS) as compared to a reference group of healthy controls. Methods: Three subgroups (N = 109) were included: 15 participants who met diagnostic criteria for CFS, 57 participants meeting criteria for MS, and 37 controls. Peripheral blood was obtained and production of a select cytokine profile was determined from stimulated and unstimulated mononuclear cells. Data were generated through the use of a multi-analyte bead suspension array. Pairwise associations were determined for each group, and these associations were used to create a graphical representation of the data. The graph was clustered using an eigenvector community algorithm and results visualized using edges to model the correlations by color and thickness to show direction and strength. Results: The control and MS groups produced a three-neighborhood relationship regardless of cell condition. While producing a three-neighborhood relationship, the MS group differed significantly from the control group as it displayed stronger relationships among pro-inflammatory cytokines. In contrast, the CFS group displayed a three-neighborhood solution when unstimulated. However, when cells from the CFS group were stimulated, a two-neighborhood model was found that exhibited stronger inter-cytokine correlations. The model found in CFS was significantly different from that found in the control and MS groups. Conclusion: CFS was characterized by a pattern of global immunologic activation using network analysis, fundamentally different from those found for either MS or control groups.

Letter re: The contemporary spectrum of multiple sclerosis misdiagnosis: A multicenter study.

We read with interest the multicenter observational study by Solomon et al.,1 which assessed the prevalence and possible causes of multiple sclerosis (MS) misdiagnosis. We are concerned about the interpretation of the results and the assertion of the conclusion that misinterpretation and misapplication of MS criteria are substantial contemporary contributors to misdiagnosis.

Importance of cerebrospinal fluid analysis in the era of McDonald 2010 criteria: a German-Austrian retrospective multicenter study in patients with a clinically isolated syndrome.

The majority of patients presenting with a first clinical symptom suggestive of multiple sclerosis (MS) do not fulfill the MRI criteria for dissemination in space and time according to the 2010 revision of the McDonald diagnostic criteria for MS and are thus classified as clinically isolated syndrome (CIS). To re-evaluate the utility of cerebrospinal fluid (CSF) analysis in the context of the revised McDonald criteria from 2010, we conducted a retrospective multicenter study aimed at determining the prevalence and predictive value of oligoclonal IgG bands (OCBs) in patients with CIS. Patients were recruited from ten specialized MS centers in Germany and Austria. We collected data from 406 patients; at disease onset, 44/406 (11 %) fulfilled the McDonald 2010 criteria for MS. Intrathecal IgG OCBs were detected in 310/362 (86 %) of CIS patients. Those patients were twice as likely to convert to MS according to McDonald 2010 criteria as OCB-negative individuals (hazard ratio = 2.1, p = 0.0014) and in a shorter time period of 25 months (95 % CI 21–34) compared to 47 months in OCB-negative individuals (95 % CI 36–85). In patients without brain lesions at first attack and presence of intrathecal OCBs (30/44), conversion rate to MS was 60 % (18/30), whereas it was only 21 % (3/14) in those without OCBs. Our data confirm that in patients with CIS the risk of conversion to MS substantially increases if OCBs are present at onset. CSF analysis definitely helps to evaluate the prognosis in patients who do not have MS according to the revised McDonald criteria.

Consensus definitions for pediatric MS and other demyelinating disorders in childhood.

In light of the published 2012 International Pediatric Multiple Sclerosis Group definitions for pediatric multiple sclerosis (MS) and related disorders and given that pediatric-onset MS is now formally included in the 2010 McDonald criteria for MS, we sought to review these criteria and summarize their application in children with acquired CNS demyelination. In addition, proposals are made for definitions of no evidence of disease activity and inadequate treatment response that are important because of new therapeutic options and trials.

A study of cognitive fatigue in Multiple Sclerosis with novel clinical and electrophysiological parameters utilizing the event related potential P300

BackgroundAlthough cognitive fatigue plays a significant part in Multiple Sclerosis (MS) related impairment, knowledge regarding it is largely lacking. Until now, not many tools are available to a clinician to detect cognitive fatigue. The subjective tools of fatigue have never been reliable.tabl ObjectivesTo assess the prevalence and clinical/ demographic profile of cognitive fatigue in MS using novel clinical and electrophysiological measures and to find their accuracy. We also aimed to test the three leading hypotheses - the temporal fatigue, cognitive load and cognitive domain hypotheses of cognitive fatigue in MS. Methods50 consecutive MS patients attending the Neurology OPD in Madras Medical College, Chennai from May 2015 to February 2016 satisfying the 2010 revised McDonald criteria for MS with an equal number of matched controls were recruited. Modified versions (a shorter version, and longer and more demanding versions) of the Stroop test, symbol digit modalities test, and serial addition tests were used in addition to modified tests of P300 latency and amplitude each specifically tailored to reveal cognitive fatigue. ResultsOut of the seven measures of cognitive fatigue used, 46% (n=23) of MS patients had impairment in two or more of the scores compared to that of 8% (n=4) in the healthy control group. The Expanded disability status scale (EDSS) scores were significantly higher for MS patients with cognitive fatigue compared to those without. All the clinical and electrophysiological measures used in this study had a relatively high sensitivity and specificity. In addition, all the clinical measures correlated with the electrophysiological measures of cognitive fatigue in this study. Our data also supported all three hypotheses implying that cognitive fatigue in MS may be a multifaceted entity. ConclusionCognitive fatigue is widely prevalent in MS and can be detected with specific tools. The tools developed and described in this study may be used as an effective means of detecting cognitive fatigue in MS patients and thus allowing patients to realise their limitations. Institution of appropriate remedial measures like advising such patients to break up a more cognitively demanding task into smaller subtasks may help to improve their quality of life.

Quality of Life-Spasticity-Fatigue Score in Patients With Multiple Sclerosis and Serum Vitamin D Level

Background: Vitamin D (VitD) is being increasingly studied in multiple sclerosis (MS). Association of VitD deficiency and MS risk, progression, disability and severity has been shown in previous studies. Our objective was to prospectively investigate if 25-hydroxyvitamin D (25(OH)D) levels are associated with duration of disease, the number of joint involvement, level of spasticity, and quality of life (QoL) in MS. Methods: The study was performed on 40 patients who fulfilled the Poser criteria for primary progressive MS (PPMS), repeater MS (RRMS) or diagnosed with secondary progressive MS (SPMS). Serum samples of all participants were collected for 25(OH)D measurement. 25(OH)D levels were divided into three groups: VitD deficient (serum level below 20 ng/mL), VitD insufficient (serum level between 21 and 29 ng/mL), and normal VitD (serum level higher than 30 ng/mL). Demographic characteristics and medical history of the patients were recorded. Modified Ashworth scale was used to assess spasticity. As a measure of QoL, the MS international quality of life (MUSIQOL) questionnaire and MS fatigue scores were used. Results: We found that VitD levels in patients with attack type MS were significantly lower than the primary and progressive MS types. In addition, serum VitD level was associated with the level of the disability and the duration of disease. According to the results of our study, there is a significant relationship between mean VitD levels and the mean score of spasticity and also of MS fatigue scores. Conclusion: VitD levels are associated with duration of disease, the number of joint involvement, level of spasticity, and QoL in MS. J Neurol Res. 2016;6(1):18-23 doi: http://dx.doi.org/10.14740/jnr372e

Combined central and peripheral demyelination: Clinical features, diagnostic findings, and treatment

Combined central and peripheral demyelination (CCPD) is rare, and current knowledge is based on case reports and small case series. The aim of our study was to describe the clinical features, diagnostic results, treatment and outcomes in a large cohort of patients with CCPD. Thirty-one patients entered this retrospective, observational, two-center study. In 20 patients (65%) CCPD presented, after an infection, as myeloradiculoneuropathy, encephalopathy, cranial neuropathy, length-dependent peripheral neuropathy, or pseudo-Guillain-Barré syndrome. Demyelinating features of peripheral nerve damage fulfilling European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) electrodiagnostic criteria for CIDP were found in 23 patients (74%), and spatial dissemination of demyelinating lesions on brain MRI fulfilling the 2010 McDonald criteria for multiple sclerosis (MS) in 11 (46%). Two thirds of the patients had a relapsing or progressive disease course, usually related to the appearance of new spinal cord lesions or worsening of the peripheral neuropathy, and showed unsatisfactory responses to high-dose corticosteroids and intravenous immunoglobulins. The clinical presentation of CCPD was severe in 22 patients (71%), who were left significantly disabled. Our data suggest that CCPD has heterogeneous features and shows frequent post-infectious onset, primary peripheral nervous system or central nervous system involvement, a monophasic or chronic disease course, inadequate response to treatments, and a generally poor outcome. We therefore conclude that the current diagnostic criteria for MS and CIDP may not fully encompass the spectrum of possible manifestations of CCPD, whose pathogenesis remains largely unknown.