multiple sclerosis case study

Clinical Presentation: Case History # 1 Ms. C is a 35 year old white female. She came to Neurology Clinic for evaluation of her long-term neurologic complaints. The patient relates that for many years she had noticed some significant changes in neurologic functions, particularly heat intolerance precipitating a stumbling gait and a tendency to fall. Her visual acuity also seemed to change periodically during several years. Two months ago the patient was working very hard and was under a lot of stress. She got sick with a flu and her neurologic condition worsened. At that time, she could not hold objects in her hands, had significant tremors and severe exhaustion. She also had several bad falls. Since that time she had noticed arthralgia on the right and subsequently on the left side of her body. Then, the patient abruptly developed a right hemisensory deficit after several days of work. The MRI scan was performed at that time and revealed a multifocal white matter disease - areas of increased T2 signal in both cerebral hemispheres. Spinal tap was also done which revealed the presence of oligoclonal bands in CSF. Visual evoked response testing was abnormal with slowed conduction in optic nerves.    (Q.1)    (Q. 2)    (Q.3) Today, the patient has multiple problems related to her disease: she remains weak and numb on the right side; she has impaired urinary bladder function which requires multiple voids in the mornings, and nocturia times 3. She became incontinent and now has to wear a pad during the day.   (Q.4)   She also has persistent balance problems with some sensation of spinning, and she is extremely fatigued. REVIEW OF SYSTEMS is also significant for a number of problems related to her suspected MS. The patient has a tendency to aspirate liquids and also solids.    (Q.5)   (Q.6) She complains of tinnitus which is continuous and associated with hearing loss, more prominent on the left. She has decreased finger dexterity and weakness of the hands bilaterally. She also complains of impaired short-term memory and irritability. FAMILY HISTORY is significant for high blood pressure, cancer and heart disease in the immediate family. PERSONAL HISTORY is significant for mumps and chicken pox as a child, and anemia and allergies with hives later in life. She also had a tubal ligation. NEUROLOGIC EXAMINATION: Cranial Nerve II - disks are sharp and of normal color. Funduscopic examination is normal. Cranial Nerves III, IV, VI - no extraocular motor palsy or difficulties with smooth pursuit or saccades are seen. Remainder of the cranial nerve exam is normal except for decreased hearing on the left, and numbness in the right face, which extends down into the entire right side. The Weber test reveals greater conductance to the right. Rinne's test reveals air greater than bone bilaterally.   (Q.7) The palate elevates well. Swallow appears to be intact. Tongue movements are slowed, but tongue power appears to be intact. Motor examination reveals relatively normal strength in the upper extremities throughout. However, rapid alternating movements are decreased in both upper extremities and the patient has dysdiadochokinesia in the left hand.   (Q.8) Mild paraparesis is noted in both legs without severe spasticity. Deep tendon reflexes are +2 and symmetrical in the arms, +3 at the ankles and at the knees. Bilateral extensor toe sign are present. Sensory exam reveals paresthesia on the right to touch and decreased pin sensation on the right diffusely. The patient has mild vibratory sense loss in the distal lower extremities. Romberg's is negative.   (Q.9) Tandem gait is mildly unstable. Ambulation index is 7.0 seconds for 25 feet. (The patient takes 7.0 seconds to walk 25 feet.) Diagnosis: Multiple Sclerosis with laboratory support.   ©   John W.Rose, M.D.,   Maria Houtchens, MSIII,   Sharon G. Lynch, M.D.

Case Studies in Multiple Sclerosis

• © 2017
• Paul S. Giacomini 0

McGill University , MONTREAL, Canada

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• A collection of case studies illustrating the complex, unpredictable nature of multiple sclerosis and its many presentations and disease courses
• Case studies submitted from clinicians from some of the world's leading neurology departments
• Edited by Dr Paul Giacomini of McGill University, a leading expert in the field of multiple sclerosis
• Includes supplementary material: sn.pub/extras

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Table of contents (19 chapters)

Front matter, clinically isolated syndrome, optic neuritis.

• Mahtab Ghadiri

Early Multiple Sclerosis

Disease-modifying therapies.

• Anne-Marie Trudelle

Management of relapses with corticosteroids

Established relapsing-remitting multiple sclerosis, breakthrough disease.

• Chris Eckstein

Progressive multifocal leukoencephalopathy

Induction therapy, primary progressive multiple sclerosis, diagnosing primary progressive multiple sclerosis.

• Scott D. Newsome

Symptomatic care in primary progressive multiple sclerosis

Secondary progressive multiple sclerosis, diagnosing secondary progressive multiple sclerosis.

• Sarah Morrow

Walking disability in multiple sclerosis

Cognitive impairment, pediatric multiple sclerosis and related disorders, acute disseminated encephalomyelitis.

• Sunita Venkateswaran
• Case studies
• Clinically isolated syndrome
• Multiple sclerosis
• Primary progressive multiple sclerosis
• Relapse remitting multiple sclerosis

About this book

Editors and affiliations.

Paul S. Giacomini

About the editor

Bibliographic information.

Book Title : Case Studies in Multiple Sclerosis

Editors : Paul S. Giacomini

DOI : https://doi.org/10.1007/978-3-319-31190-6

Publisher : Adis Cham

eBook Packages : Medicine , Medicine (R0)

Copyright Information : Springer International Publishing Switzerland 2017

Softcover ISBN : 978-3-319-31188-3 Published: 21 October 2016

eBook ISBN : 978-3-319-31190-6 Published: 06 October 2016

Edition Number : 1

Number of Pages : XVII, 149

Number of Illustrations : 14 b/w illustrations

Topics : Neurology , Neuroradiology , Primary Care Medicine

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BRIEF RESEARCH REPORT article

Case report: a case of severe clinical deterioration in a patient with multiple sclerosis.

• 1 German Center for Vertigo and Balance Disorders, Ludwig Maximilian University of Munich, Munich, Germany
• 2 Department of Neurology, Ludwig Maximilian University of Munich, Munich, Germany
• 3 Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
• 4 Department of Neuroradiology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
• 5 Institute of Neuropathology, University Medical Center Göttingen, Göttingen, Germany
• 6 Institute of Neuropathology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

Tumefactive multiple sclerosis (MS) is a rare variant of MS that may lead to a rapidly progressive clinical deterioration requiring a multidisciplinary diagnostic workup. Our report describes the diagnostic and therapeutic approach of a rare and extremely severe course of MS. A 51-year-old man with an 8-year history of relapsing-remitting MS (RRMS) was admitted with a subacute progressive left lower limb weakness and deterioration of walking ability. After extensive investigations including repeated MRI, microbiological, serological, cerebrospinal fluid (CSF) studies, and finally brain biopsy, the diagnosis of a tumefactive MS lesion was confirmed. Despite repeated intravenous (IV) steroids as well as plasma exchanges and IV foscarnet and ganciclovir owing to low copy numbers of human herpesvirus 6 (HHV-6) DNA in polymerase chain reaction (PCR) analysis, the patient did not recover. The clinical presentation of tumefactive MS is rare and variable. Brain biopsy for histopathological workup should be considered in immunocompromised patients with rapidly progressive clinical deterioration with brain lesions of uncertain cause.

Introduction

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) characterized by multiple lesions disseminated in time and space. Tumefactive MS is a rare variant of MS presenting with a large intracranial lesion, >2 cm in diameter with mass effect and perilesional edema and/or ring enhancement with gadolinium ( 1 ).

The rapidly progressive clinical deterioration of the MS patient presented here posed a diagnostic challenge requiring a multidisciplinary diagnostic workup. In the literature, various case reports describing the challenging diagnostic procedure of tumefactive MS due to varied clinical presentations as well as clinical courses can be found. Our report describes the diagnostic and therapeutic approach of a rare and at the same time extremely severe course of MS. It demonstrates that brain biopsy may be necessary for differential diagnosis in an immunocompromised MS patient with progressive brain lesions.

Case Presentation

A 51-year-old man of Mediterranean origin with an 8-year history of relapsing-remitting MS (RRMS) was admitted to our hospital on suspicion of a relapse.

After diagnosis in 2009, the patient had initially been treated with glatiramer acetate. The family medical history offered that the patient's mother and uncle (blood related) both suffered from MS. The patient's uncle died at the age of 52 years after being bedridden for a longer time. The patient had four relapses under glatiramer acetate necessitating treatment with intravenous (IV) steroids initially with a good treatment response. The first relapse leading to the diagnosis of a clinically isolated syndrome (CIS) was an acute central vestibular syndrome leading to dizziness and an ataxic gait dysfunction. At this time, MRI already revealed multiple white matter lesions in the supratentorium, cerebellum, and cervical as well as thoracic spinal cord.

In 2012, owing to an increasing relapse rate and incomplete clinical remissions, the medication was changed to natalizumab. At this time, the last relapses under glatiramer acetate had led to a residual paraparesis with emphasis on the left and a left side internuclear ophthalmoplegia. At the last relapse, brain MRI scan of the brain showed multiple white matter lesions with a cystic aspect and incomplete ring-like gadolinium enhancement. After the medication was switched to natalizumab, the disease course stabilized, and he suffered no more relapses. However, when the anti-JC virus (JCV) antibody level index (Stratify™) rose to 4.5, natalizumab was discontinued early in 2017. Subsequently, fingolimod was started 3 months prior to admission and 4 weeks after discontinuation of natalizumab.

The first symptoms appeared 8 days before admission: a progressive left lower limb weakness and deterioration of walking ability became evident. At that time, the patient was able to stand without help and walk a few steps with unilateral assistance [Expanded Disability Status Scale (EDSS) 6.0].

At this time (after treatment with natalizumab and rising anti-JCV antibody level index), the differential diagnoses were an MS relapse or progressive multifocal leukoencephalopathy (PML). The MRI scan of the brain on the day of admission showed bihemispheric confluent T2 white matter lesions without changes, typical for PML ( Figure 1A ). Cerebrospinal fluid (CSF) analysis revealed a normal white blood cell count (2/μl) with mildly increased lactate and glucose levels. The albumin quotient was normal, but oligoclonal bands were positive with intrathecal synthesis of immunoglobulins G and M. Polymerase chain reaction (PCR), microbiological, and serological study findings were all negative (including JCV PCR, JCV CSF/serum antibody index, HSV-1 PCR, HSV-2 PCR, VZV PCR, EBV PCR, and HIV PCR). Evoked potentials revealed an impairment of the corticospinal tract to the right leg, bilaterally impaired tibial nerve somatosensory reactions, and evidence of a bilateral affection of the visual system.

Figure 1 . From left to right: sagittal, axial MRI T2-weighted sequences and axial gadolinium contrast T1-weighted sequences. (A) On the day of admission. (B) Three days after admission. (C) Forty-one days after admission.

On suspicion of an MS relapse, the patient was treated with IV methylprednisolone 1,000 mg once daily for five consecutive days. In response to this therapy, his walking ability slightly improved. However, 2 days later, the patient's clinical status dramatically worsened, necessitating his transfer to the intensive care unit (ICU): he became somnolent and mutistic, exhibiting a bilateral horizontal gaze palsy. In addition, he became tetraplegic and had bilaterally positive Babinski signs corresponding to an EDSS score of 9.5. MRI scan of the brain at that time showed progressive bihemispheric confluent white matter lesions ( Figure 1B ). The patient developed a severe aspiration pneumonia with respiratory failure requiring intubation and subsequent tracheostomy for mechanical ventilation.

The progressive white matter lesions were judged as the radiological correlate of a clinical MS relapse.

After antibiotic treatment for pneumonia had led to a reduction of the leukocytosis and C-reactive protein, IV steroids were applied for 6 days. However, as no clinical improvement was observed on IV steroids, seven cycles of plasma exchange (PLEX) were performed. Another follow-up MRI scan of the brain revealed further progression of gadolinium enhancement and T2 lesion load.

Despite high-dose IV steroids and PLEX, the clinical condition of the patient deteriorated further. With negative laboratory results, and radiological findings atypical for PML, other differential diagnoses had to be considered. Characteristic imaging findings in PML are one or more regions of FLAIR/T2 showing hyperintense confluent white matter lesions, inconsistent in size and shape, typically involving subcortical U-fibers and sparing the cortex, leading to a sharp border between lesion and cortex. MS lesions typically present a periventricular distribution, whereas PML lesions more commonly involve the subcortical white matter.

The following differential diagnoses were considered for our patient:

• tumefactive MS relapse,

• neurocysticercosis,

• neurosarcoidosis,

• intracerebral lymphoma,

• atypic PML, and

• other viral encephalitis.

The negative results of the CSF analysis and serology argued against a neurocysticercosis, lymphoma, or PML. Cysticercosis is the most common parasitic infection of the CNS. However, the presentation on MRI imaging was judged unusual. Electroencephalography (EEG) was normal. For sarcoidosis, a CT scan of the chest and laboratory tests for ACE and sIL2R were added; both proved negative. The negative CSF findings and radiological presentation also argued against an intracerebral lymphoma but did not definitely exclude one. A tumefactive MS relapse is a rare course and commonly presents with a large intracerebral lesion (>2 cm) with mass effect and perilesional edema and/or ring enhancement with gadolinium.

To further differentiate between a tumefactive MS relapse and a less likely intracerebral lymphoma, a stereotactic biopsy of a lesion in the right frontal lobe was performed. The biopsy revealed a sharply demarcated inflammatory demyelinating lesion consistent with MS. Inflammatory infiltrates within the lesion consisted of CD3 dominated by CD8-positive T cells as well as CD138-positive plasma cells ( Figure 2 ). Deposits of complement and immunoglobulins identified the lesion as an antibody/complement mediated type of MS, described previously as pattern II MS ( 2 ). PCR analysis revealed low copy numbers of human herpesvirus 6 (HHV-6) DNA in tissue (32 copies/μg DNA). However, axons were preserved, thus ruling out a necrosis. Also, no evidence was found for lymphoma.

Figure 2 . Histology showed an active demyelinating multiple sclerosis (MS) lesion corresponding to immunopathological pattern II. Arrows indicate the sharply demarcated inflammatory subcortical plaque on the left; the cerebral cortex is present on the right [H&E stain, ×10 (A) ]. Axons were preserved within the lesion [Bielschowsky silver stain, ×10 (B) ], whereas myelin was lost [proteolipid protein, ×10 (C) ; cyclic nucleotide phosphodiesterase stain, ×40 (D) ]. The lesion showed early active demyelination as indicated by the presence of major (C) and minor myelin proteins (D) within the macrophages. Complement [c9neo complement stain, ×40 (E) ] and immunoglobulin G [IgG; IgG stain ×40 (F) ] were found within the macrophages, suggesting a complement and immunoglobulin-mediated demyelination (pattern II).

Given the diagnostic uncertainty between HHV-6 encephalitis and tumefactive MS lesions, we opted for a polypragmatic approach and induced a therapy with IV foscarnet and ganciclovir ( 3 ) along with another course of high-dose IV steroids for 5 days. The final neuropathologic results were suggestive of a pattern II MS lesion according to Lassmann et al. ( 2 ).

The MRI scan of the brain after therapy showed progression of the T2 lesion load; however, the regression of gadolinium enhancement suggested remission of acute inflammation ( Figure 1C ). The neurological status remained severely impaired: the tetraplegia slightly improved by developing into a severe tetraparesis of 2/5 at the upper and persisting plegia of lower limbs (EDSS 8.5).

Subsequently, the patient was transferred to a neuro-rehabilitation center. His clinical status did not improve, even after 3 months of rehabilitation. Currently, the patient is tetraparetic and lives in a special-care home where he spontaneously breathes through tracheostomy and receives enteral long-term nutrition via percutaneous endoscopic gastrostomy (PEG).

After fingolimod was discontinued during the acute phase, the possibility of administering a new highly active preventive MS treatment such as ocrelizumab or alemtuzumab in order to avoid further relapses was discussed with the patient's relatives but was discarded owing to fear of infectious complications and the patient's poor clinical status and prognosis. Unfortunately, no further MRI imaging has been performed after discharge from our clinic.

The rapid clinical deterioration posed a diagnostic challenge. Because of increasing anti-JCV index upon treatment with natalizumab, we speculated that PML might have occurred. However, the MRI findings were atypical (uncommon mass effect and degree of gadolinium enhancement). CSF analyses including PCR, microbiological, and serological studies were all negative. In view of the absence of clinical improvement and radiological progression despite high-dose IV steroids and PLEX, further differential diagnoses were considered. However, CSF findings argued against neurocysticercosis, lymphoma, or PML. Negative CSF findings for JCV (PCR) did not completely exclude PML because viral loads can be very low (<100 copies/mL); the detection threshold of commercial tests is about 200 copies/mL. With no signs of mediastinal lymphadenopathy in the CT scan of the chest and nonelevated serum ACE and sIL2-R levels, neurosarcoidosis seemed less likely. The negative CSF findings as well as the radiological presentation made the possibility of an intracerebral lymphoma or HHV-6 encephalitis less likely but could not rule them out. Therefore, a stereotactic biopsy was needed. The histopathological results yielded an inflammatory demyelinating MS lesion with low titers of HHV-6 DNA quantified by PCR. There were no morphological features of a necrotizing HHV-6-encephalitis. In correlation with low copies of HHV-6-DNA, an HHV-6 encephalitis seemed very unlikely.

HHV-6 belongs to the Herpesviridae family. In the general population, virus latency in adenoid tissues/tonsils is almost 100%, usually acquired during childhood. Cells persist in a latent viral state mainly in leukocytes and can directly integrate their DNA into host cells ( 4 ). The prevalence of integrated HHV-6 DNA in healthy blood donors is 0.5% ( 5 ). Thus, detection in a blood sample does not definitely indicate an active infection. The same applies to infection and replication in the CNS; studies have revealed the presence of HHV-6 DNA even in healthy brain tissues ( 6 ).

HHV-6 encephalitis is characterized by necrotizing brain lesions and typically high copy numbers of virus DNA in CSF and/or brain tissue. Although the disease is a rare event, it should be taken into account in an immunocompromised patient with necrotizing brain lesions. Brain biopsy should be considered because it is important that patients receive a proper diagnosis in order to possibly benefit from an antiviral therapy combining foscarnet and ganciclovir ( 3 ). In this context, advanced imaging modalities like FET-PET or MRI spectroscopy may be of help and should be further investigated for their usefulness in making the differential diagnosis.

Conclusions

In our patient, the results of the brain biopsy finally confirmed the diagnosis of a tumefactive MS lesion. All pathological features of MS were fulfilled including inflammatory demyelination, relative axonal preservation, and gliosis. The early active demyelinating nature of the lesion allowed us to classify the lesion as having the immunopathological pattern II, which has recently been shown to improve clinically in 55% in response to apheresis therapy ( 7 ). Our case exemplifies that treatment response can be dramatically negative. Possible explanations include that the onset of PLEX at 13 days after relapse onset may have been too late and/or that the damage was too severe.

Severe MS rebounds after highly effective treatment with fingolimod as well as natalizumab were previously reported ( 8 ). The differentiation between a recurrence of disease activity and a rebound, implying a more severe disease course than before natalizumab treatment, is difficult. On histological grounds, the present biopsy showed an MS lesion with an inflammatory infiltrate not exceeding the MS typical inflammation. However, a rebound can be assumed based on the clinical and MRI findings. Switching from natalizumab to fingolimod might increase the risk of tumefactive MS ( 9 ). Predictive factors to identify risk groups are warranted.

Data Availability Statement

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

Ethics Statement

Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

Author Contributions

KB gave the idea of case reporting, analyzed the case, and drafted the manuscript for intellectual content. AA revised the figures and critically reviewed the manuscript. MF, NG, HH, OA, and H-PH critically reviewed the manuscript. BK prepared the MRI scans as figures and critically reviewed the manuscript. DH critically reviewed the manuscript and revised the MRI sequences for interpretation. BT critically reviewed the manuscript and interpreted the MRI sequences. IM, WB, and GR critically reviewed the manuscript and interpreted the neuropathology results. PA critically reviewed the manuscript. All authors contributed to the article and approved the submitted version.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

We acknowledge support by the Heinrich Heine University Düsseldorf.

Abbreviations

ACE, angiotensin-converting enzyme; CNS, central nervous system; CSF, cerebrospinal fluid; EBV, Epstein–Barr virus; EDSS, expanded disability status scale; EEG, electroencephalography; FET-PET, 18 F-fluoro-ethyl-tyrosine positron emission tomography; HHV-6, human herpesvirus 6; HIV, human immunodeficiency virus; HSV-1/HSV-2, herpes simplex virus type 1/type 2; ICU, intensive care unit; IV, intravenous; JCV, John Cunningham virus; MRI, magnet resonance imaging; MS, multiple sclerosis; PCR, polymerase chain reaction; PEG, percutaneous endoscopic gastrostomy; PLEX, plasma exchange; PML, progressive multifocal leukoencephalopathy; RRMS, relapsing-remitting multiple sclerosis; sIL-2-R, soluble interleukin-2-receptor; VZV, varicella zoster virus.

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5. Geraudie B, Charrier M, Bonnafous P, Heurte D, Desmonet M, Bartoletti MA, et al. Quantitation of human herpesvirus-6A,−6B and−7 DNAs in whole blood, mononuclear and polymorphonuclear cell fractions from healthy blood donors. J Clin Virol. (2012) 53:151–5. doi: 10.1016/j.jcv.2011.10.017

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7. Stork L, Ellenberger D, Beissbarth T, Friede T, Lucchinetti CF, Bruck W, et al. Differences in the reponses to apheresis therapy of patients with 3 histopathologically classified immunopathological patterns of multiple sclerosis. JAMA Neurol. (2018) 75:428–35. doi: 10.1001/jamaneurol.2017.4842

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Keywords: multiple sclerosis, tumefactive multiple sclerosis, demyelinating disease, multiple sclerosis rebound, immunocompromised multiple sclerosis patient, progressive brain lesions

Citation: Breitkopf K, Aytulun A, Förster M, Kraus B, Turowski B, Huppert D, Goebels N, Hefter H, Aktas O, Metz I, Brück W, Reifenberger G, Hartung H-P and Albrecht P (2020) Case Report: A Case of Severe Clinical Deterioration in a Patient With Multiple Sclerosis. Front. Neurol. 11:782. doi: 10.3389/fneur.2020.00782

Received: 17 May 2020; Accepted: 25 June 2020; Published: 18 August 2020.

Reviewed by:

Copyright © 2020 Breitkopf, Aytulun, Förster, Kraus, Turowski, Huppert, Goebels, Hefter, Aktas, Metz, Brück, Reifenberger, Hartung and Albrecht. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Philipp Albrecht, phil.albrecht@gmail.com

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Diagnosis and management of multiple sclerosis: case studies

Affiliation.

• 1 Multiple Sclerosis Program, Department of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9036, USA.
• PMID: 16684629
• DOI: 10.1016/j.ncl.2006.01.002

Although substantial capabilities have emerged in the ability to globally manage patients who have MS, clinicians continue to be confronted with formidable challenges. Reduction in disease activity and its impact on dis-ability progression remains the central objective of disease-modifying therapy and most current MS research initiatives. Nevertheless, the principal factors that determine the day-to-day limitations on functional capabilities(activities of daily living, work performance, quality of life, and so forth)are a derivative of the pathophysiology of the disease process itself. The substrate for these limitations is inherent in the pathology of demyelination and axonal dysfunction. Identifying measures that can optimize the performance and fidelity of axonal conduction mechanisms may translate into a reduction in MS-related symptoms. Chronic neurologic disease management (with MS representing a signature example) can be optimized when all members of the care team (including patients and their families) collaborate in the co-ordination of interdisciplinary care models that address all aspects of suffering.

Publication types

• Case Reports
• Adjuvants, Immunologic / therapeutic use*
• Anti-Inflammatory Agents / therapeutic use*
• Brain / pathology
• Diagnosis, Differential
• Disease Progression
• Interferon beta-1b
• Interferon-beta / therapeutic use*
• Magnetic Resonance Imaging
• Middle Aged
• Multiple Sclerosis / drug therapy*
• Multiple Sclerosis / pathology*
• Multiple Sclerosis, Relapsing-Remitting / pathology
• Multiple Sclerosis, Relapsing-Remitting / therapy
• Optic Neuritis / pathology
• Adjuvants, Immunologic
• Anti-Inflammatory Agents
• Interferon-beta

• Open access
• Published: 10 April 2024

“So at least now I know how to deal with things myself, what I can do if it gets really bad again”—experiences with a long-term cross-sectoral advocacy care and case management for severe multiple sclerosis: a qualitative study

• Anne Müller   ORCID: orcid.org/0000-0002-2456-2492 1 ,
• Fabian Hebben   ORCID: orcid.org/0009-0003-6401-3433 1 ,
• Kim Dillen 1 ,
• Veronika Dunkl 1 ,
• Yasemin Goereci 2 ,
• Raymond Voltz 1 , 3 , 4 ,
• Peter Löcherbach 5 ,
• Clemens Warnke   ORCID: orcid.org/0000-0002-3510-9255 2 &
• Heidrun Golla   ORCID: orcid.org/0000-0002-4403-630X 1

on behalf of the COCOS-MS trial group represented by Martin Hellmich

BMC Health Services Research volume  24 , Article number:  453 ( 2024 ) Cite this article

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Metrics details

Persons with severe Multiple Sclerosis (PwsMS) face complex needs and daily limitations that make it challenging to receive optimal care. The implementation and coordination of health care, social services, and support in financial affairs can be particularly time consuming and burdensome for both PwsMS and caregivers. Care and case management (CCM) helps ensure optimal individual care as well as care at a higher-level. The goal of the current qualitative study was to determine the experiences of PwsMS, caregivers and health care specialists (HCSs) with the CCM.

In the current qualitative sub study, as part of a larger trial, in-depth semi-structured interviews with PwsMS, caregivers and HCSs who had been in contact with the CCM were conducted between 02/2022 and 01/2023. Data was transcribed, pseudonymized, tested for saturation and analyzed using structuring content analysis according to Kuckartz. Sociodemographic and interview characteristics were analyzed descriptively.

Thirteen PwsMS, 12 caregivers and 10 HCSs completed interviews. Main categories of CCM functions were derived deductively: (1) gatekeeper function, (2) broker function, (3) advocacy function, (4) outlook on CCM in standard care. Subcategories were then derived inductively from the interview material. 852 segments were coded. Participants appreciated the CCM as a continuous and objective contact person, a person of trust (92 codes), a competent source of information and advice (on MS) (68 codes) and comprehensive cross-insurance support (128 codes), relieving and supporting PwsMS, their caregivers and HCSs (67 codes).

Conclusions

Through the cross-sectoral continuous support in health-related, social, financial and everyday bureaucratic matters, the CCM provides comprehensive and overriding support and relief for PwsMS, caregivers and HCSs. This intervention bears the potential to be fine-tuned and applied to similar complex patient groups.

Trial registration

The study was approved by the Ethics Committee of the University of Cologne (#20–1436), registered at the German Register for Clinical Studies (DRKS00022771) and in accordance with the Declaration of Helsinki.

Peer Review reports

Introduction

Multiple sclerosis (MS) is the most frequent and incurable chronic inflammatory and degenerative disease of the central nervous system (CNS). Illness awareness and the number of specialized MS clinics have increased since the 1990s, paralleled by the increased availability of disease-modifying therapies [ 1 ]. There are attempts in the literature for the definition of severe MS [ 2 , 3 ]. These include a high EDSS (Expanded disability Status Scale [ 4 ]) of ≥ 6, which we took into account in our study. There are also other factors to consider, such as a highly active disease course with complex therapies that are associated with side effects. These persons are (still) less disabled, but may feel overwhelmed with regard to therapy, side effects and risk monitoring of therapies [ 5 , 6 ].

Persons with severe MS (PwsMS) develop individual disease trajectories marked by a spectrum of heterogeneous symptoms, functional limitations, and uncertainties [ 7 , 8 ] manifesting individually and unpredictably [ 9 ]. This variability can lead to irreversible physical and mental impairment culminating in complex needs and daily challenges, particularly for those with progressive and severe MS [ 5 , 10 , 11 ]. Such challenges span the spectrum from reorganizing biographical continuity and organizing care and everyday live, to monitoring disease-specific therapies and integrating palliative and hospice care [ 5 , 10 ]. Moreover, severe MS exerts a profound of social and economic impact [ 9 , 12 , 13 , 14 ]. PwsMS and their caregivers (defined in this manuscript as relatives or closely related individuals directly involved in patients’ care) often find themselves grappling with overwhelming challenges. The process of organizing and coordinating optimal care becomes demanding, as they contend with the perceived unmanageability of searching for, implementing and coordinating health care and social services [ 5 , 15 , 16 , 17 ].

Case management (CM) proved to have a positive effect on patients with neurological disorders and/or patients with palliative care needs [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. However, a focus on severe MS has been missed so far Case managers primarily function as: (1) gatekeeper involving the allocation of necessary and available resources to a case, ensuring the equitable distribution of resources; as (2) broker assisting clients in pursuing their interests, requiring negotiation to provide individualized assistance that aligns as closely as possible with individual needs and (3) advocate working to enhance clients’ individual autonomy, to advocate for essential care offers, and to identify gaps in care [ 25 , 26 , 27 , 28 , 29 ].

Difficulties in understanding, acting, and making decisions regarding health care-related aspects (health literacy) poses a significant challenge for 54% of the German population [ 30 ]. Additionally acting on a superordinate level as an overarching link, a care and case management (CCM) tries to reduce disintegration in the social and health care system [ 31 , 32 ]. Our hypothesis is that a CCM allows PwsMS and their caregivers to regain time and resources outside of disease management and to facilitate the recovery and establishment of biographical continuity that might be disrupted due to severe MS [ 33 , 34 ].

Health care specialists (HCSs) often perceive their work with numerous time and economic constraints, especially when treating complex and severely ill individuals like PwsMS and often have concerns about being blamed by patients when expectations could not be met [ 35 , 36 ]. Our hypothesis is that the CCM will help to reduce time constraints and free up resources for specialized tasks.

To the best of our knowledge there is no long-term cross-sectoral and outreaching authority or service dedicated to assisting in the organization and coordination of the complex care concerns of PwsMS within the framework of standard care addressing needs in health, social, financial, every day and bureaucratic aspects. While some studies have attempted to design and test care programs for persons with MS (PwMS), severely affected individuals were often not included [ 37 , 38 , 39 ]. They often remain overlooked by existing health and social care structures [ 5 , 9 , 15 ].

The COCOS-MS trial developed and applied a long-term cross-sectoral CCM intervention consisting of weekly telephone contacts and monthly re-assessments with PwsMS and caregivers, aiming to provide optimal care. Their problems, resources and (unmet) needs were assessed holistically including physical health, mental health, self-sufficiency and social situation and participation. Based on assessed (unmet) needs, individual care plans with individual actions and goals were developed and constantly adapted during the CCM intervention. Contacts with HCSs were established to ensure optimal care. The CCM intervention was structured through and documented in a CCM manual designed for the trial [ 40 , 41 ].

Our aim was to find out how PwsMS, caregivers and HCSs experienced the cross-sectoral long-term, outreaching patient advocacy CCM.

This study is part of a larger phase II, randomized, controlled clinical trial “Communication, Coordination and Security for people with severe Multiple Sclerosis (COCOS-MS)” [ 41 ]. This explorative clinical trial, employing a mixed-method design, incorporates a qualitative study component with PwsMS, caregivers and HCSs to enrich the findings of the quantitative data. This manuscript focuses on the qualitative data collected between February 2022 and January 2023, following the Consolidated Criteria for Reporting Qualitative Research (COREQ) guidelines [ 42 ].

Research team

Three trained authors AM, KD and FH (AM, female, research associate, M.A. degree in Rehabilitation Sciences; KD, female, researcher, Dr. rer. medic.; FH, male, research assistant, B.Sc. degree in Health Care Management), who had no prior relationship with patients, caregivers or HCSs conducted qualitative interviews. A research team, consisting of clinical experts and health services researchers, discussed the development of the interview guides and the finalized category system.

Theoretical framework

Interview data was analyzed with the structuring content analysis according to Kuckartz. This method enables a deductive structuring of interview material, as well as the integration of new aspects found in the interview material through the inductive addition of categories in an iterative analysis process [ 43 ].

Sociodemographic and interview characteristics were analyzed descriptively (mean, median, range, SD). PwsMS, caregivers and HCSs were contacted by the authors AM, KD or FH via telephone or e-mail after providing full written informed consent. Participants had the option to choose between online interviews conducted via the GoToMeeting 10.19.0® Software or face-to-face. Peasgood et al. (2023) found no significant differences in understanding questions, engagement or concentration between face-to-face and online interviews [ 44 , 45 ]. Digital assessments were familiar to participants due to pandemic-related adjustments within the trial.

Out of 14 PwsMS and 14 caregivers who were approached to participate in interviews, three declined to complete interviews, resulting in 13 PwsMS (5 male, 8 female) and 12 caregiver (7 male, 5 female) interviews, respectively (see Fig.  1 ). Thirty-one HCSs were contacted of whom ten (2 male, 8 female) agreed to be interviewed (see Fig.  2 ).

Flowchart of PwsMS and caregiver participation in the intervention group of the COCOS-MS trial. Patients could participate with and without a respective caregiver taking part in the trial. Therefore, number of caregivers does not correspond to patients. For detailed inclusion criteria see also Table  1 in Golla et al. [ 41 ]

Flowchart of HCSs interview participation

Setting and data collection

Interviews were carried out where participants preferred, e.g. at home, workplace, online, and no third person being present. In total, we conducted 35 interviews whereof 7 interviews face-to-face (3 PwsMS, 3 caregivers, 1 HCS).

The research team developed a topic guide which was meticulously discussed with research and clinical staff to enhance credibility. It included relevant aspects for the evaluation of the CCM (see Tables  1 and 2 , for detailed topic guides see Supplementary Material ). Patient and caregiver characteristics (covering age, sex, marital status, living situation, EDSS (patients only), subgroup) were collected during the first assessment of the COCOS-MS trial and HCSs characteristics (age, sex, profession) as well as interview information (length and setting) were collected during the interviews. The interview guides developed for this study addressed consistent aspects both for PwsMS and caregivers (see Supplementary Material ):

For HCSs it contained the following guides:

Probing questions were asked to get more specific and in-depth information. Interviews were carried out once and recorded using a recording device or the recording function of the GoToMeeting 10.19.0® Software. Data were pseudonymized (including sensitive information, such as personal names, dates of birth, or addresses), audio files were safely stored in a data protection folder. The interview duration ranged from 11 to 56 min (mean: 23.9 min, SD: 11.1 min). Interviews were continued until we found that data saturation was reached. Audio recordings were transcribed verbatim by an external source and not returned to participants.

Data analysis

Two coders (AM, FH) coded the interviews. Initially, the first author (AM) thoroughly reviewed the transcripts to gain a sense of the interview material. Using the topic guide and literature, she deductively developed a category system based on the primary functions of CM [ 25 , 26 , 27 , 28 , 29 ]. Three interviews were coded repeatedly for piloting, and inductive subcategories were added when new themes emerged in the interview material. This category system proved suitable for the interview material. The second coder (FH) familiarized himself with the interview material and category system. Both coders (AM, FH) independently coded all interviews, engaging in discussions and adjusting codes iteratively. The finalized category system was discussed and consolidated in a research workshop and within the COCOS-MS trial group and finally we reached an intercoder agreement of 90% between the two coders AM and FH, computed by the MAXQDA Standard 2022® software.

We analyzed sociodemographic and interview characteristics using IBM SPSS Statistics 27® and Excel 2016®. Transcripts were managed and analyzed using MAXQDA Standard 2022®.

Participants were provided with oral and written information about the trial and gave written informed consent. Ethical approvals were obtained from the Ethics Committee of the University of Cologne (#20–1436). The trial is registered in the German Register for Clinical Studies (DRKS) (DRKS00022771) and is conducted under the Declaration of Helsinki.

Characteristics of participants and interviews

PwsMS participating in an interview were mainly German (84.6%), had a mean EDSS of 6.8 (range: 6–8) and MS for 13.5 years (median: 14; SD: 8.1). For detailed characteristics see Table  3 .

Most of the interviewed caregivers (9 caregivers) were the partners of the PwsMS with whom they lived in the same household. For further details see Table  3 .

HCSs involved in the study comprised various professions, including MS-nurse (3), neurologist (2), general physician with further training in palliative care (1), physician with further training in palliative care and pain therapist (1), housing counselling service (1), outpatient nursing service manager (1), participation counselling service (1).

Structuring qualitative content analysis

The experiences of PwsMS, caregivers and HCSs were a priori deductively assigned to four main categories: (1) gatekeeper function, (2) broker function, (3) advocacy function [ 25 , 26 , 27 , 28 , 29 ] and (4) Outlook on CCM in standard care, whereas the subcategories were developed inductively (see Fig.  3 ).

Category system including main and subcategories of the qualitative thematic content analysis

The most extensive category, housing the highest number of codes and subcodes, was the “ Outlook on CCM in standard care ” (281 codes). Following this, the category “ Advocacy Function ” contained 261 codes. The “ Broker Function ” (150 codes) and the “ Gatekeeper Function ” (160 codes) constituted two smaller categories. The majority of codes was identified in the caregivers’ interviews, followed by those of PwsMS (see Table  4 ). Illustrative quotes for each category and subcategory can be found in Table  5 .

Persons with severe multiple sclerosis

In the gatekeeper function (59 codes), PwsMS particularly valued the CCM as a continuous contact person . They appreciated the CCM as a person of trust who was reliably accessible throughout the intervention period. This aspect, with 41 codes, held significant importance for PwsMS.

Within the broker function (44 codes), establishing contact was most important for PwsMS (22 codes). This involved the CCM as successfully connecting PwsMS and caregivers with physicians and therapists, as well as coordinating and arranging medical appointments, which were highly valued. Assistance in authority and health and social insurance matters (10 codes) was another subcategory, where the CCM encompassed support in communication with health insurance companies, such as improving the level of care, assisting with retirement pension applications, and facilitating rehabilitation program applications. Optimized care (12 codes) resulted in improved living conditions and the provision of assistive devices through the CCM intervention.

The advocacy function (103 codes) emerged as the most critical aspect for PwsMS, representing the core of the category system. PwsMS experienced multidimensional, comprehensive, cross-insurance system support from the CCM. This category, with 43 statements, was the largest within all subcategories. PwsMS described the CCM as addressing their concerns, providing help, and assisting with the challenges posed by the illness in everyday life. The second-largest subcategory, regaining, maintaining and supporting autonomy (25 codes), highlighted the CCM’s role in supporting self-sufficiency and independence. Reviving personal wellbeing (17 codes) involved PwsMSs’ needs of regaining positive feelings, improved quality of life, and a sense of support and acceptance, which could be improved by the CCM. Temporal relief (18 codes) was reported, with the CCM intervention taking over or reducing tasks.

Within the outlook on CCM in standard care (84 codes), eight subcategories were identified. Communications was described as friendly and open (9 codes), with the setting of communication (29 codes) including the frequency of contacts deemed appropriate by the interviewed PwsMS, who preferred face-to-face contact over virtual or telephone interactions. Improvement suggestions for CCM (10 codes) predominantly revolved around the desire for the continuation of the CCM beyond the trial, expressing intense satisfaction with the CCM contact person and program. PwsMS rarely wished for better cooperation with the CCM. With respect to limitations (7 codes), PwsMS distinguished between individual limitations (e.g. when not feeling ready for using a wheelchair) and overriding structural limitations (e.g. unsuccessful search for an accessible apartment despite CCM support). Some PwsMS mentioned needing the CCM earlier in the course of the disease and believed it would beneficial for anyone with a chronic illness (6 codes).

In the gatekeeper function (75 codes), caregivers highly valued the CCM as a continuous contact partner (33 codes). More frequently than among the PwsMS interviewed, caregivers valued the CCM as a source of consultation/ information on essential individual subjects (42 codes). The need for basic information about the illness, its potential course, treatment and therapy options, possible supportive equipment, and basic medical advice/ information could be met by the CCM.

Within the broker function (63 codes), caregivers primarily experienced the subcategory establish contacts (24 codes). They found the CCM as helpful in establishing and managing contact with physicians, therapists and especially with health insurance companies. In the subcategory assistance in authority and health and social insurance matters (22 codes), caregivers highlighted similar aspects as the PwsMS interviewed. However, there was a particular emphasis on assistance with patients' retirement matters. Caregivers also valued the optimization of patients’ care and living environment (17 codes) in various life areas during the CCM intervention, including improved access to assistive devices, home modification, and involvement of a household support and/ or nursing services.

The advocacy function, with 115 codes, was by far the broadest category . The subcategory multidimensional, comprehensive, cross-insurance system support represented the largest subcategory of caregivers, with 70 statements. In summary, caregivers felt supported by the CCM in all domains of life. Regaining, maintaining and supporting autonomy (11 codes) and reviving personal wellbeing (8 codes) in the form of an improved quality of life played a role not only for patients but also for caregivers, albeit to a lower extend. Caregivers experienced temporal relief (26 codes) as the CCM undertook a wide range of organizational tasks, freeing up more needed resources for their own interests.

For the Outlook on CCM in standard care , caregivers provided various suggestions (81 codes). Similar to PwsMS, caregivers felt that setting (home based face-to-face, telephone, virtual) and frequency of contact were appropriate (10 codes, communication setting ) and communications (7 codes) were recognized as open and friendly. However, to avoid conflicts between caregiver and PwsMS, caregivers preferred meeting the CCM separately from the PwsMS in the future. Some caregivers wished the CCM to specify all services it might offer at the beginning, while others emphasized not wanting this. Like PwsMS, caregivers criticized the CCM intervention being (trial-related) limited to one year, regardless of whether further support was needed or processes being incomplete (13 codes, improvement suggestions ). After the CCM intervention time had expired, the continuous contact person and assistance were missed and new problems had arisen and had to be managed with their own resources again (9 codes, effects of CCM discontinuation ), which was perceived as an exhausting or unsolvable endeavor. Caregivers identified analogous limitations (8 codes), both individual and structural. However, the largest subcategory, was the experienced potential of CCM (27 codes), reflected in extremely high satisfaction with the CCM intervention. Like PwsMS, caregivers regarded severe chronically ill persons in general as target groups for a CCM (7 codes) and would implement it even earlier, starting from the time of diagnosis. They considered a CCM to be particularly helpful for patients without caregivers or for caregivers with limited (time) resources, as it was true for most caregivers.

Health care specialists

In the gatekeeper function (26 codes) HCSs particularly valued the CCM as a continuous contact partner (18 codes). They primarily described their valuable collaboration with the CCM, emphasizing professional exchange between the CCM and HCSs.

Within the broker function (43 codes), the CCM was seen as a connecting link between patients and HCSs, frequently establishing contacts (18 codes). This not only improved optimal care on an individual patient level (case management) but also at a higher, superordinate care level (care management). HCSs appreciated the optimized care and living environment (18 codes) for PwsMS, including improved medical and therapeutic access and the introduction of new assistive devices. The CCM was also recognized as providing assistance in authority and health and social matters (7 codes) for PwsMS and their caregivers.

In the advocacy function (43 codes), HCSs primarily reported temporal relief through CCM intervention (23 codes). They experienced this relief, especially as the CCM provided multidimensional, comprehensive, and cross-insurance system support (15 codes) for PwsMS and their caregivers. Through this support, HCSs felt relieved from time intensive responsibilities that may not fall within their area of expertise, freeing up more time resources for their actual professional tasks.

The largest category within the HCSs interviews was the outlook on CCM in standard care (116 codes). In the largest subcategory, HCSs made suggestions for further patient groups who could benefit (38 codes) from a CCM. Chronic neurological diseases like neurodegenerative diseases (e.g. amyotrophic lateral sclerosis), typical and atypical Parkinson syndromes were mentioned. HCSs considered the enrollment of the CCM directly after the diagnosis of these complex chronic diseases. Additionally, chronic progressive diseases in general or oncological diseases, which may also run chronically, were regarded worthwhile for this approach. HCSs also provided suggestions regarding improvement (21 codes). They wished e.g. for information or contact when patients were enrolled to the CCM, regular updates, exchange and collaborative effort. On the other hand, HCSs reported, that their suggestions for improvement would hardly be feasible due to their limited time resources. Similar to patients and caregivers, HCSs experienced structural limits (13 codes), which a CCM could not exceed due to overriding structural limitations (e.g. insufficient supply of (household) aids, lack of outreach services like psychotherapists, and long processing times on health and pension insurers' side). HCSs were also asked about their opinions on financial resources (14 codes) of a CCM in standard care. All interviewed HCSs agreed that CCM would initially cause more costs for health and social insurers, but they were convinced of cost savings in the long run. HCSs particularly perceived the potential of the CCM (20 codes) through the feedback of PwsMS, highlighting the trustful relationship enabling individualized help for PwsMS and their caregivers.

Persons with severe multiple sclerosis and their caregivers

The long-term cross-sectoral CCM intervention implemented in the COCOS-MS trial addressed significant unmet needs of PwsMS and their caregivers which previous research revealed as burdensome and hardly or even not possible to improve without assistance [ 5 , 6 , 9 , 10 , 33 , 35 , 46 ]. Notably, the CCM service met the need for a reliable, continuous contact partner, guiding patients through the complexities of regulations, authorities and the insurance system. Both, PwsMS and their caregivers highly valued the professional, objective perspective provided by the CCM, recognizing it as a source of relief, support and improved care in line with previous studies [ 37 , 47 ]. Caregivers emphasized the CCM’s competence in offering concrete assistance and information on caregiving and the fundamentals of MS, including bureaucratic, authority and insurances matters. On the other hand, PwsMS particularly appreciated the CCMs external reflective and advisory function, along with empathic social support tailored to their individual concerns. Above all, the continuous partnership of trust, available irrespective of the care sector, was a key aspect that both PwsMS and their caregivers highlighted. This consistent support was identified as one of the main components in the care of PwsMS in previous studies [ 5 , 33 , 35 ].

As the health literacy is inadequate or problematic for 54% of the German population and disintegration in the health and social care system is high [ 30 , 31 , 32 ], the CCM approach serves to enhance health literacy and reduce disintegration of PwsMS and their caregivers by providing cross-insurance navigational guidance in the German health and social insurance sector on a superordinate level. Simultaneously PwsMS and caregivers experienced relief and gained more (time) resources for all areas of life outside of the disease and its management, including own interests and establishing biographical continuity. This empowerment enables patients to find a sense of purpose beyond their illness, regain autonomy, and enhance social participation, reducing the feeling of being a burden to those closest to them. Such feelings are often experienced as burdensome and shameful by PwsMS [ 6 , 48 , 49 , 50 ]. Finding a sense of purpose beyond the illness also contributes to caregivers perceiving their loved ones not primarily as patient but as individuals outside of the disease, reinforcing valuable relationships such as partners, siblings, or children, strengthening emotional bonds. These factors are also highly relevant and well-documented in a suicide-preventive context, as the suicide rate is higher in persons diagnosed with neurological disorders [ 19 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 ] and the feeling of being a burden to others, loss of autonomy, and perceived loss of dignity are significant factors in patients with severe chronic neurological diseases for suicide [ 50 , 57 ].

The temporal relief experienced by the CCM was particularly significant for HCSs and did not only improve the satisfaction of HCSs but also removed unfulfilled expectations and concerns about being blamed by patients when expectations could not be met, which previous studied elaborated [ 35 , 36 ]. Moreover, the CCM alleviated the burden on HCSs by addressing patients’ concerns, allowing them to focus on their own medical responsibilities. This aspect probably reduced the dissatisfaction that arises when HCSs are expected to address issues beyond their medical expertise, such as assistive devices, health and social insurance, and the organization and coordination of supplementary therapies, appointments, and contacts [ 35 , 36 , 61 ]. Consequently, the CCM reduced difficulties of HCSs treating persons with neurological or chronical illnesses, which previous research identified as problematic.

HCSs perceive their work as increasingly condensed with numerous time and economic constraints, especially when treating complex and severely ill individuals like PwsMS [ 36 ]. This constraint was mentioned by HCSs in the interviews and was one of the main reasons why they were hesitant to participate in interviews and may also be an explanation for a shorter interview duration than initially planned in the interview guides. The CCM’s overarching navigational competence in the health and social insurance system was particularly valued by HCSs. The complex and often small-scale specialties in the health and social care system are not easily manageable or well-known even for HCSs, and dealing with them can exceed their skills and time capacities [ 61 ]. The CCM played a crucial role in keeping (temporal) resources available for what HCSs are professionally trained and qualified to work on. However, there remains a challenge in finding solutions to the dilemma faced by HCSs regarding their wish to be informed about CCM procedures and linked with each other, while also managing the strain of additional requests and contact with the CCM due to limited (time) resources [ 62 ]. Hudon et al. (2023) suggest that optimizing time resources and improving exchange could involve meetings, information sharing via fax, e-mail, secure online platforms, or, prospectively, within the electronic patient record (EPR). The implementation of an EPR has shown promise in improving the quality of health care and time resources, when properly implemented [ 63 , 64 ]. The challenge lies ineffective information exchange between HCSs and CCM for optimal patient care. The prospect of time saving in the long run and at best for a financial incentive, e.g., when anchoring in the Social Security Code, will help best to win over the HCSs.If this crucial factor can be resolved, there is a chance that HCSs will thoroughly accept the CCM as an important pillar, benefiting not only PwsMS but also other complex patient groups, especially those with long-term neurological or complex oncological conditions that might run chronically.

Care and case management and implications for the health care system

The results of our study suggest that the cross-sectoral long-term advocacy CCM in the COCOS-MS trial, with continuous personal contacts at short intervals and constant reevaluation of needs, problems, resources and goals, is highly valued by PwsMS, caregivers, and HCSs. The trial addresses several key aspects that may have been overlooked in previous studies which have shown great potential for the integration of case management [ 17 , 47 , 62 , 65 , 66 ]. However, they often excluded the overriding care management, missed those patient groups with special severity and complexity who might struggle to reach social and health care structures independently or the interventions were not intended for long-term [ 22 , 37 ]. Our results indicate that the CCM intervention had a positive impact on PwsMS and caregivers as HCSs experienced them with benefits such as increased invigoration, reduced demands, and enhanced self-confidence. However, there was a notable loss experienced by PwsMS and caregivers after the completion of the CCM intervention, even if they had stabilized during the intervention period. The experiences of optimized social and health care for the addressed population, both at an individual and superordinate care level, support the integration of this service into standard care. Beyond the quantitatively measurable outcomes and economic considerations reported elsewhere [ 16 , 20 , 21 ], our results emphasize the importance of regaining control, self-efficacy, self-worth, dignity, autonomy, and social participation. These aspects are highlighted as preventive measures in suicidal contexts, which is particularly relevant for individuals with severe and complex illnesses [ 19 , 50 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 ]. Our findings further emphasize the societal responsibilities to offer individuals with severe and complex illnesses the opportunity to regain control and meaningful aspects of life, irrespective of purely economic considerations. This underscores the need for a comprehensive evaluation that not only takes into account quantitative measures but also the qualitative aspects of well-being and quality of life when making recommendations of a CCM in standard care.

The study by J. Y. Joo and Huber (2019) highlighted that CM interventions aligned with the standards of the Case Management Society of America varied in duration, ranging from 1 month to 15.9 years, and implemented in community- or hospital-based settings. However, they noted a limitation in understanding how CM processes unfold [ 67 ]. In contrast, our trial addressed this criticism by providing transparent explanations of the CCM process, which also extends to a superordinate care management [ 40 , 41 ]. Our CCM manual [ 40 ] outlines a standardized and structured procedure for measuring and reevaluating individual resources, problems, and unmet needs on predefined dimensions. It also identifies goals and actions at reducing unmet needs and improving the individual resources of PwsMS and caregivers. Importantly, the CCM manual demonstrates that the CCM process can be structured and standardized, while accounting for the unique aspects of each individual’s serious illness, disease courses, complex needs, available resources, and environmental conditions. Furthermore, the adaptability of the CCM manual to other complex chronically ill patient groups suggests the potential for a standardized approach in various health care settings. This standardized procedure allows for consistency in assessing and addressing the individual needs of patients, ensuring that the CCM process remains flexible while maintaining a structured and goal-oriented framework.

The discussion about the disintegration in the social and health care system and the increasing specialization dates back to 2009 [ 31 , 32 ]. Three strategies were identified to address this issue: (a) “driver-minimizing” [Treiberminimierende], (b) “effect-modifying” [Effektmodifizierende] and (c) “disintegration-impact-minimizing” [Desintegrationsfolgenminimierende] strategies. “Driver-minimizing strategies” involve comprehensive and radical changes within the existing health and social care system, requiring political and social pursuit. “Disintegration-impact-minimizing strategies” are strategies like quality management or tele-monitoring, which are limited in scope and effectiveness. “Effect-modifying strategies”, to which CCM belongs, acknowledges the segmentation within the system but aims to overcome it through cooperative, communicative, and integrative measures. CCM, being an “effect-modifying strategy”, operates the “integrated segmentation model” [Integrierte Segmentierung] rather than the “general contractor model” [Generalunternehmer-Modell] or “total service provider model” [Gesamtdienstleister-Modell] [ 31 , 32 ]. In this model, the advantage lies in providing an overarching and coordinating service to link different HCSs and services cross-sectorally. The superordinate care management aspect of the CCM plays a crucial role in identifying gaps in care, which is essential for future development strategies within the health and social care system. It aims to find or develop (regional) alternatives to ensure optimal care [ 17 , 23 , 24 , 68 , 69 ], using regional services of existing health and social care structures. Therefore, superordinate care management within the CCM process is decisive for reducing disintegration in the system.

Strengths and limitations

The qualitative study results of the explorative COCOS-MS clinical trial, which employed an integrated mixed-method design, provide valuable insights into the individual experiences of three leading stakeholders: PwsMS, caregivers and HCSs with a long-term cross-sectoral CCM. In addition to in-depth interviews, patient and caregiver reported outcome measurements were utilized and will be reported elsewhere. The qualitative study’s strengths include the inclusion of patients who, due to the severity of their condition (e.g. EDSS mean: 6.8, range: 6–8, highly active MS), age (mean: 53.9 years, range: 36–73 years) family constellations, are often underrepresented in research studies and often get lost in existing social and health care structures. The study population is specific to the wider district region of Cologne, but the broad inclusion criteria make it representative of severe MS in Germany. The methodological approach of a deductive and inductive structuring content analysis made it possible to include new findings into an existing theoretical framework.

However, the study acknowledges some limitations. While efforts were made to include more HCSs, time constraints on their side limited the number of interviews conducted and might have biased the results. Some professions are underrepresented in the interviews. Complex symptoms (e.g. fatigue, ability to concentrate), medical or therapeutic appointments and organization of the everyday live may have been reasons for the patients’ and caregivers’ interviews lasting shorter than initially planned.

The provision of functions of a CCM, might have pre-structured the answers of the participants.

At current, there is no support system for PwsMS, their caregivers and HCSs that addresses their complex and unmet needs comprehensively and continuously. There are rare qualitative insights of the three important stakeholders: PwsMS, caregivers and HCSs in one analysis about a supporting service like a CCM. In response to this gap, we developed and implemented a long-term cross-sectoral advocacy CCM and analyzed it qualitatively. PwsMS, their caregivers and HCSs expressed positive experiences, perceiving the CCM as a source of relief and support that improved care across various aspects of life. For patients, the CCM intervention resulted in enhanced autonomy, reviving of personal wellbeing and new established contacts with HCSs. Caregivers reported a reduced organizational burden and felt better informed, and HCSs experienced primarily temporal relief, allowing them to concentrate on their core professional responsibilities. At a higher level of care, the study suggests that the CCM contributed to a reduction in disintegration within the social and health care system.

The feedback from participants is seen as valuable for adapting the CCM intervention and the CCM manual for follow-up studies, involving further complex patient groups such as neurological long-term diseases apart from MS and tailoring the duration of the intervention depending on the complexity of evolving demands.

Availability of data and materials

Generated and/or analyzed datasets of participants are available from the corresponding author on reasonable request to protect participants. Preliminary partial results have been presented as a poster during the EAPC World Congress in June 2023 and the abstract has been published in the corresponding abstract booklet [ 70 ].

Abbreviations

Amyotrophic lateral sclerosis

• Care and case management

Case management

Central nervous system

Communication, Coordination and security for people with multiple sclerosis

Consolidated criteria for reporting qualitative research

German register for clinical studies

Extended disability status scale

Electronic patient record

Quality of life

Multiple sclerosis

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Acknowledgements

We would like to thank all the patients, caregivers and health care specialists who volunteered their time to participate in an interview and the trial, Carola Janßen for transcribing the interviews, Fiona Brown for translating the illustrative quotes and Beatrix Münzberg, Kerstin Weiß and Monika Höveler for data collection in the quantitative study part.

COCOS-MS Trial Group

Anne Müller 1 , Fabian Hebben 1 , Kim Dillen 1 , Veronika Dunkl 1 , Yasemin Goereci 2 , Raymond Voltz 1,3,4 , Peter Löcherbach 5 , Clemens Warnke 2 , Heidrun Golla 1 , Dirk Müller 6 , Dorthe Hobus 1 , Eckhard Bonmann 7 , Franziska Schwartzkopff 8 , Gereon Nelles 9 , Gundula Palmbach 8 , Herbert Temmes 10 , Isabel Franke 1 , Judith Haas 10 , Julia Strupp 1 , Kathrin Gerbershagen 7 , Laura Becker-Peters 8 , Lothar Burghaus 11 , Martin Hellmich 12 , Martin Paus 8 , Solveig Ungeheuer 1 , Sophia Kochs 1 , Stephanie Stock 6 , Thomas Joist 13 , Volker Limmroth 14

1 Department of Palliative Medicine, Faculty of Medicine and University Hospital, University of Cologne, Cologne, Germany

2 Department of Neurology, Faculty of Medicine and University Hospital, University of Cologne, Cologne, Germany

3 Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), University of Cologne, Cologne, Germany

4 Center for Health Services Research (ZVFK), University of Cologne, Cologne, Germany

5 German Society of Care and Case Management e.V. (DGCC), Münster, Germany

6 Institute for Health Economics and Clinical Epidemiology (IGKE), Faculty of Medicine and University Hospital, University of Cologne, Cologne, Germany

7 Department of Neurology, Klinikum Köln, Cologne, Germany

8 Clinical Trials Centre Cologne (CTCC), Faculty of Medicine and University Hospital, University of Cologne, Cologne, Germany

9 NeuroMed Campus, MedCampus Hohenlind, Cologne, Germany

10 German Multiple Sclerosis Society Federal Association (DMSG), Hannover, Germany

11 Department of Neurology, Heilig Geist-Krankenhaus Köln, Cologne, Germany

12 Institute of Medical Statistics and Computational Biology (IMSB), Faculty of Medicine and University Hospital, University of Cologne, Cologne, Germany

13 Academic Teaching Practice, University of Cologne, Cologne, Germany

14 Department of Neurology, Klinikum Köln-Merheim, Cologne, Germany

Open Access funding enabled and organized by Projekt DEAL. This work was supported by the Innovation Funds of the Federal Joint Committee (G-BA), grant number: 01VSF19029.

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Anne Müller, Fabian Hebben, Kim Dillen, Veronika Dunkl, Raymond Voltz & Heidrun Golla

Department of Neurology, Faculty of Medicine and University Hospital, University of Cologne, Cologne, Germany

Yasemin Goereci & Clemens Warnke

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• Anne Müller
• , Fabian Hebben
• , Kim Dillen
• , Veronika Dunkl
• , Yasemin Goereci
• , Raymond Voltz
• , Peter Löcherbach
• , Clemens Warnke
• , Heidrun Golla
• , Dirk Müller
• , Dorthe Hobus
• , Eckhard Bonmann
• , Franziska Schwartzkopff
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• , Gundula Palmbach
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• , Isabel Franke
• , Judith Haas
• , Julia Strupp
• , Kathrin Gerbershagen
• , Laura Becker-Peters
• , Lothar Burghaus
• , Martin Hellmich
• , Martin Paus
• , Solveig Ungeheuer
• , Sophia Kochs
• , Stephanie Stock
• , Thomas Joist
•  & Volker Limmroth

Contributions

HG, KD, CW designed the trial. HG, KD obtained ethical approvals. HG, KD developed the interview guidelines with help of the CCM (SU). AM was responsible for collecting qualitative data, developing the code system, coding, analysis of the data and writing the first draft of the manuscript, thoroughly revised and partly rewritten by HG. FH supported in collecting qualitative data, coding and analysis of the interviews. KD supported in collecting qualitative data. AM, FH, KD, VD, YG, RV, PL, CW, HG discussed and con-solidated the finalized category system. AM, FH, KD, VD, YG, RV, PL, CW, HG read and commented on the manuscript and agreed to the final version.

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Ethics approval and consent to participate.

Participants were provided with oral and written information about the trial and provided written informed consent. Ethical approval was obtained from the Ethics Committee of the University of Cologne (#20–1436). The trial is registered in the German Register for Clinical Studies (DRKS) (DRKS00022771) and is conducted under the Declaration of Helsinki.

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Competing interests.

Clemens Warnke has received institutional support from Novartis, Alexion, Sanofi Genzyme, Janssen, Biogen, Merck and Roche. The other authors declare that they have no competing interests.

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Müller, A., Hebben, F., Dillen, K. et al. “So at least now I know how to deal with things myself, what I can do if it gets really bad again”—experiences with a long-term cross-sectoral advocacy care and case management for severe multiple sclerosis: a qualitative study. BMC Health Serv Res 24 , 453 (2024). https://doi.org/10.1186/s12913-024-10851-1

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DOI : https://doi.org/10.1186/s12913-024-10851-1

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Multiple Sclerosis Case Study

Janet has experienced periodic episodes of tingling in her extremities, dizziness, and even episodes of blindness. After 12 years, doctors have finally given her a diagnosis. Follow Janet through her journey and find out why her disease is so difficult to diagnose.

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Groundbreaking study reveals potential diagnostic marker for Multiple sclerosis years before symptom onset

A new study published today in Nature Medicine unveils a significant breakthrough in the understanding and early detection of multiple sclerosis (MS). Researchers have identified a unique autoantibody signature present in approximately 10% of patients with MS years before the onset of clinical symptoms.

Danillo Augusto , Ph.D., an assistant professor in biology at UNC Charlotte and a co-author of the study, stated, "This study sheds light on the preclinical phase of MS and provides a promising avenue for early detection and intervention. Identifying patients at high risk of developing MS before symptom onset could revolutionize patient care and treatment strategies."

Autoantibodies are basically antibodies that are supposed to fight off invaders but end up turning against one’s own body, causing problems like autoimmune diseases. Utilizing the U.S. Department of Defense Serum Repository, a cohort encompassing more than 10 million individuals, researchers conducted whole-proteome autoantibody profiling on hundreds of MS patients’ samples collected before and after symptom onset. They discovered a distinct cluster of patients exhibiting an autoantibody signature targeting a common recognizable pattern. Notably, these patients showed antibody reactivity years before developing any MS symptoms and had elevated levels of serum neurofilament light (sNfL), indicating early neuroaxonal injury.

Further validation of this autoantibody signature was conducted on samples from a separate MS cohort, confirming its high specificity for patients diagnosed with MS. This finding marks a significant milestone in MS research, potentially paving the way for the development of antigen-specific biomarkers for high-risk individuals with clinically or radiologically isolated neuroinflammatory syndromes.

The study, led by Michael Wilson, M.D., a professor of neurology at the University of California, San Francisco, offers hope for improved early diagnosis and intervention in MS, potentially leading to better patient outcomes. Further research is underway to elucidate the underlying immunological mechanisms and explore additional diagnostic and therapeutic implications.

Inside UNC Charlotte is produced and maintained by the Office of University Communications. Faculty and staff members can submit news or story/video ideas for consideration via the online form or email  [email protected] .

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• What is multiple sclerosis? An expert explains

Learn more from neurologist Oliver Tobin, M.B., B.Ch., B.A.O., Ph.D.

I'm Dr. Oliver Tobin, a neurologist specializing in multiple sclerosis at Mayo Clinic. In this video, we'll be covering the basics of multiple sclerosis. What is it? Who gets it? The symptoms, diagnosis, and treatment. Whether you're looking for answers about your own health or that of someone you love, we're here to provide you with the best information available. Multiple sclerosis is a disorder in which the body's immune system attacks the protective covering of the nerve cells in the brain, optic nerve and spinal cord, called the myelin sheath. And this sheath is often compared to the insulation on an electrical wire. When that covering is damaged, it exposes the actual nerve fiber, which can slow or block the signals being transmitted within it. The nerve fibers themselves might also be damaged. The body can repair damage to the myelin sheath, but it's not perfect. The resulting damage leaves lesions or scars, and this is where the name comes from: multiple sclerosis, multiple scars. Now everyone loses brain cells and spinal cord cells as they get older. But if part of the brain or spinal cord has been damaged by MS, the nerve cells in that area will die off faster than the areas around it that are normal. This happens very slowly, usually over decades and typically shows up as gradual walking difficulty happening over several years. When you read about multiple sclerosis, you may hear about different types -- the most frequent being relapsing-remitting multiple sclerosis. And this is characterized by attacks, or relapses.

We don't know what causes MS, but there are certain factors that may increase the risk or trigger its onset. So while MS can occur at any age, it mostly makes its first appearance in people between the ages of 20 and 40. Low levels of vitamin D and low exposure to sunlight, which enables our body to make vitamin D, are associated with an increased risk of developing MS. As people who have MS who have low vitamin D tend to have more severe disease. So people who are overweight are more likely to develop MS and people who have MS and are overweight tend to have more severe disease and a faster onset of progression. People who have MS and who smoke tend to have more relapses, worse progressive disease, and worse cognitive symptoms. Women are up to three times as likely as men to have relapsing-remitting MS. The risk for MS in the general population is about 0.5%. If a parent or sibling has MS, your risk is about twice that or about 1%. Certain infections are also important. A variety of viruses have been linked to MS, including Epstein-Barr virus, which causes mono. Northern and southern latitudes have a higher prevalence, including Canada, the northern US, New Zealand, southeastern Australia, and Europe. White people, especially of northern European descent, are at the highest risk. People of Asian, African, and Native American ancestry have the lowest risk. A slightly increased risk is seen if a patient already has autoimmune thyroid disease, pernicious anemia, psoriasis, type 1 diabetes, or inflammatory bowel disease.

Symptoms of a relapse usually come on over 24 to 48 hours, last for a few days to a few weeks and then improve in the region of 80 to a 100 percent. Those symptoms include loss of vision in an eye, loss of power in an arm or leg or a rising sense of numbness in the legs. Other common symptoms associated with MS include spasms, fatigue, depression, incontinence issues, sexual dysfunction, and walking difficulties.

There's currently no single test to make a diagnosis of MS. However, there are four key features which help to secure the diagnosis. Firstly, are there typical symptoms of multiple sclerosis? Again, those are loss of vision in an eye, loss of power in an arm or leg, or sensory disturbance in an arm or leg lasting for more than 24 hours. Secondly, do you have any physical examination findings consistent with MS? Next, is the MRI of your brain or spine consistent with MS? Now here it's important to note that 95 percent of people over the age of 40 have an abnormal brain MRI, just the same as many of us have wrinkles on our skin. Lastly, are the results of the spinal fluid analysis consistent with MS? Your doctor may recommend blood tests to check for other diseases that share the same symptoms. They may also recommend an OCT test or optical coherence tomography. This is a short scan of the thickness of the layers at the back of your eye.

So the best thing to do when living with MS is to find a trusted interdisciplinary medical team that can help you monitor and manage your health. Having a multidisciplinary team is essential for addressing the individual symptoms that you're experiencing. If you have an MS attack or relapse, your doctor may prescribe you corticosteroids to reduce or improve your symptoms. And if your attack symptoms do not respond to steroids, another option is plasmapheresis or plasma exchange, which is a treatment similar to dialysis. About 50 percent of people who do not respond to steroids have a significant improvement with a short course of plasma exchange. There are over 20 medications currently approved for prevention of MS attacks and prevention of new MRI lesions.

As learning to function with MS can be challenging, there are medical experts ready to work with you to help you manage it, so you can still live a full life. Consulting with a physiatrist, physical or occupational therapist can help you deal with physical difficulties. Physical activity is strongly recommended for all people with MS. Mental health is also an important consideration. So keeping up personal connections with friends and family and trying to stay involved with your hobbies is important. But also be kind to yourself and realistic about what you're up for. This can change from day to day, so it's okay to give yourself permission if something seems like too much or if you need to cancel plans. You may also find support groups helpful to connect with people who understand what you are going through and discuss your feelings and concerns with a doctor or a counselor. Meanwhile, scientists are hard at work, expanding our understanding of this disease and developing new treatments and medications which are ever more effective. If you want to learn more, watch more of our videos or visit mayoclinic.org. We wish you well.

In multiple sclerosis, the protective coating on the nerve fibers (myelin) is damaged and may eventually be destroyed. Depending on where the nerve damage occurs, MS can affect vision, sensation, coordination, movement, and bladder or bowel control.

Multiple sclerosis (MS) is a potentially disabling disease of the brain and spinal cord (central nervous system).

In MS , the immune system attacks the protective sheath (myelin) that covers nerve fibers and causes communication problems between your brain and the rest of your body. Eventually, the disease can cause permanent damage or deterioration of the nerve fibers.

Signs and symptoms of MS vary widely between patients and depend on the location and severity of nerve fiber damage in the central nevous system. Some people with severe MS may lose the ability to walk independently or ambulate at all. Other individuals may experience long periods of remission without any new symptoms depending on the type of MS they have.

There's no cure for multiple sclerosis. However, there are treatments to help speed the recovery from attacks, modify the course of the disease and manage symptoms.

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• Myelin damage and the nervous system

In multiple sclerosis, the protective coating on nerve fibers (myelin) in the central nervous system is damaged. This creates a lesion that, depending on the location in the central nervous system, may cause symptoms such as numbness, pain or tingling in parts of the body.

Multiple sclerosis signs and symptoms may differ greatly from person to person and over the course of the disease depending on the location of affected nerve fibers.

Common symptoms include:

• Numbness or weakness in one or more limbs that typically occurs on one side of your body at a time
• Electric-shock sensations that occur with certain neck movements, especially bending the neck forward (Lhermitte sign)
• Lack of coordination
• Unsteady gait or inability to walk
• Partial or complete loss of vision, usually in one eye at a time, often with pain during eye movement
• Prolonged double vision
• Blurry vision
• Problems with sexual, bowel and bladder function
• Slurred speech
• Cognitive problems
• Mood disturbances

When to see a doctor

See a doctor if you experience any of the above symptoms for unknown reasons.

Disease course

Most people with MS have a relapsing-remitting disease course. They experience periods of new symptoms or relapses that develop over days or weeks and usually improve partially or completely. These relapses are followed by quiet periods of disease remission that can last months or even years.

Small increases in body temperature can temporarily worsen signs and symptoms of MS . These aren't considered true disease relapses but pseudorelapses.

At least 20% to 40% of those with relapsing-remitting MS can eventually develop a steady progression of symptoms, with or without periods of remission, within 10 to 20 years from disease onset. This is known as secondary-progressive MS .

The worsening of symptoms usually includes problems with mobility and gait. The rate of disease progression varies greatly among people with secondary-progressive MS .

Some people with MS experience a gradual onset and steady progression of signs and symptoms without any relapses, known as primary-progressive MS .

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The cause of multiple sclerosis is unknown. It's considered an immune mediated disease in which the body's immune system attacks its own tissues. In the case of MS , this immune system malfunction destroys the fatty substance that coats and protects nerve fibers in the brain and spinal cord (myelin).

Myelin can be compared to the insulation coating on electrical wires. When the protective myelin is damaged and the nerve fiber is exposed, the messages that travel along that nerve fiber may be slowed or blocked.

It isn't clear why MS develops in some people and not others. A combination of genetics and environmental factors appears to be responsible.

Risk factors

These factors may increase your risk of developing multiple sclerosis:

• Age. MS can occur at any age, but onset usually occurs around 20 and 40 years of age. However, younger and older people can be affected.
• Sex. Women are more than 2 to 3 times as likely as men are to have relapsing-remitting MS .
• Family history. If one of your parents or siblings has had MS , you are at higher risk of developing the disease.
• Certain infections. A variety of viruses have been linked to MS , including Epstein-Barr, the virus that causes infectious mononucleosis.
• Race. White people, particularly those of Northern European descent, are at highest risk of developing MS . People of Asian, African or Native American descent have the lowest risk. A recent study suggests that the number of Black and Hispanic young adults with multiple sclerosis may be greater than previously thought.
• Climate. MS is far more common in countries with temperate climates, including Canada, the northern United States, New Zealand, southeastern Australia and Europe. Your birth month may also affect the chances of developing multiple sclerosis, since exposure to the sun when a mother is pregnant seems to decrease later development of multiple sclerosis in these children.
• Vitamin D. Having low levels of vitamin D and low exposure to sunlight is associated with a greater risk of MS .
• Your genes. A gene on chromosome 6p21 has been found to be associated with multiple sclerosis.
• Obesity. An association with obesity and multiple sclerosis has been found in females. This is especially true for female childhood and adolescent obesity.
• Certain autoimmune diseases. You have a slightly higher risk of developing MS if you have other autoimmune disorders such as thyroid disease, pernicious anemia, psoriasis, type 1 diabetes or inflammatory bowel disease.
• Smoking. Smokers who experience an initial symptom that may signal MS are more likely than nonsmokers to develop a second event that confirms relapsing-remitting MS .

Complications

People with multiple sclerosis may also develop:

• Muscle stiffness or spasms
• Severe weakness or paralysis, typically in the legs
• Problems with bladder, bowel or sexual function
• Cognitive problems, like forgetfulness or word finding difficulties
• Mood problems, such as depression, anxiety or mood swings
• Seizures, though very rare
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• FDA approves new oral drug to treat multiple sclerosis. U.S. Food and Drug Administration. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm634469.htm. Accessed June 2, 2022.
• Kappos L, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): A double-blind, randomized, phase 3 study. The Lancet. 2018; doi: 10.1016/S0140-6736(18)30475-6.
• Marin Collazo IV (expert opinion). Mayo Clinic, Rochester, Minn. April 2, 2019.
• AskMayoExpert. Multiple sclerosis. Mayo Clinic; 2020.
• AskMayoExpert. Medication monitoring guidelines. Mayo Clinic; 2020.
• Vumerity. National MS Society. https://www.nationalmssociety.org/Treating-MS/Medications/Vumerity. Accessed March 16, 2020.
• Gianfrancesco M, et al. Obesity during childhood and adolescence increases susceptibility to multiple sclerosis after accounting for established genetic and environmental risk factors. Obesity Research and Clinical Practice. 2014; doi.org/10.1016/j.orcp.2014.01.002.
• Pantavou KG, et al. Season of birth and multiple sclerosis: A systematic review and multivariate meta-analysis. Journal of Neurology. 2020; doi:10.1007/s00415019-09346-5.
• Cifu DX, et al., eds. Multiple sclerosis. In Braddom's Physical Medicine and Rehabilitation. 6th ed. Elsevier; 2021 https://www.clinicalkey.com. Accessed Jun. 2, 2022.
• Langer-Gould AM, et al. Racial and ethnic disparities in multiple sclerosis prevalence. Neurology. 2022; doi:10.1212/WNL.0000000000200151.
• Kasper LH, et al. Immunomodulatory activity of interferon-beta. Annals of Clinical and Translational Neurology. 2014; doi:10.1002/acn3.84.
• Goldschmidt CH, et al. Re-evaluating the use of IFN-B and relapsing multiple sclerosis: Safety, efficacy and place in therapy. Degenerative Neurological and Neuromuscular Disease. 2020; doi:10.2147/DNND.S224912.
• Kieseie BC. The mechanism of action of interferon-B in relapsing multiple sclerosis. Central Nervous System Drugs. 2011; doi:10.1007/s10067-008-0972-3.
• Betaseron. Bayer AG; 1993. www.bayer.com. Accessed Jun. 1, 2022.
• Hauser SL, et al. Ofatumumab versus teriflunomide in multiple sclerosis. The New England Journal of Medicine. 2020; doi:10.1056/NEJMoa1917246.
• Kesimpta. Novartis; 2020. www.novartis.com. Accessed Jun. 1, 2022.
• Marin Collazo V (expert opinion). Mayo Clinic. June 13, 2020.
• Olek MJ. Treatment of progressive multiple sclerosis in adults. https://www.uptodate.com/contents/search. Accessed Jun. 2, 2022.
• Wingerchuk DM, et al. Disease modifying therapies for relapsing multiple sclerosis. British Medical Journal. 2016; doi:10.1136/bmj.i3518.
• Saadeh RS, et al. CSF kappa free light chains: Cutoff validation for diagnosing multiple sclerosis. Mayo Clinic Proceedings. 2022; doi:10.1016/j.mayocp.2021.09.014.
• Goldschmidt C, et al. Advances in the treatment of multiple sclerosis. Neurologic Clinics. 2021; doi:10.1016/j.ncl.2020.09.002.
• Bafiertam. Banner Life Sciences LLC; 2013. www.bannerls.com. Accessed Jun. 1, 2022.
• Baliertam delayed release capsule. Banner Life Sciences LLC; 2013. www.bannerls.com. Accessed Jun. 1, 2022.
• Oral ponesimod versus teriflunomide in relapsing multiple sclerosis (OPTIMUM). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02425644. Accessed Jun. 2, 2022.
• Ponvory. Janssen Pharmaceuticals; 2021. www.janssen.com. Accessed Jun. 1, 2022.
• Torke S, et al. Inhibition of Bruton's tyrosine kinase as a novel therapeutic approach in multiple sclerosis. Expert Opinion on Investigational Drugs. 2020.
• Nash RA, et al. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for relapsing-remitting multiple sclerosis (HALT-MS): A 3-year interim report. Journal of the American Medical Association Neurology. 2015; doi:10.1001/jamaneurol.2014.3780.
• Reston, et al. Autologous hematopoietic cell transplantation for multiple sclerosis: A systematic review. Multiple Sclerosis. 2011; doi:10,1177/1352458510383609.
• Petrou P, et al. Beneficial effects of autologous mesenchymal stem cell transplantation in active progressive multiple sclerosis. Brain. 2020; doi:10.1093/brain/awaa333.
• Liang J, et al. Allogenic mesenchymal stem cell transplantation in the treatment of multiple sclerosis. Multiple Sclerosis. 2009; doi:10.1177/1352458509104590.
• Wingerchuk DM, et al. Multiple sclerosis: Current and emerging disease-modifying therapies and treatment strategies. Mayo Clinic Proceedings. 2014; doi:101016/j.mayocp.2013.11.002.
• Multiple sclerosis information page. National institute of neurological disorders and stroke. https://www.ninds.nih.gov/Disorders/All-Disorders/Multiple-Sclerosis-Information-Page. Accessed Jun. 2, 2022.
• Sadovnick AD. Genetic background of multiple sclerosis. Autoimmunity Reviews. 2012; doi:10.1016/j.autrev.2011.05.007.
• Acetyl-L-carnitine: Can it relieve MS fatigue?
• Demyelinating disease: What can you do about it?
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• Explaining multiple sclerosis
• Infographic: Multiple Sclerosis
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Multiple Sclerosis is the most common immune-mediated inflammatory demyelinating disease of the central nervous system. Educational gaps involving early symptom identification and diagnosis, misdiagnosis, current concepts of neurologic reserve and benefits of early treatment, a rapidly evolving treatment landscape, and increasing goals of therapy create real-world challenges for HCPs that threaten the long-term prognosis of individuals living with MS.

Lucas Kipp, MD

Dr. Kipp specializes in the diagnosis and treatment of neuroimmunological disorders, particularly demyelinating conditions such as multiple sclerosis and neuromyelitis optica. He is interested in translational research connecting expert MS clinicians, world-renown immunology laboratories, and advanced neuroimaging techniques to identify biomarkers of disease and treatment response.

Have you encountered a patient with Multiple Sclerosis? This disease affects 2.8 million people worldwide, with a disproportionate number in the United States. In this interactive module about Multiple Sclerosis, explore four case studies that illustrate the importance of early diagnosis and optimal treatment of patients. Providers can learn how to diagnose efficiently and best provide early interventional treatment to Multiple Sclerosis patients.

Have you encountered a patient with Multiple Sclerosis? This disease affects 2.8 million people worldwide, with a disproportionate number in the United States. Listen to recent research that has increased understanding of the connection between Epstein-Barr Virus and Multiple Sclerosis. Topics discussed include the basics of Multiple Sclerosis genetic predisposition, risk factors, potential triggers, and ways to modify behavior and diet to reduce disease progression.

How is Multiple Sclerosis accurately diagnosed? This second lecture in the Multiple Sclerosis Series explores how to use a 4 step process to confirm if a patient has MS. Listen and examine 2 case studies and learn common barriers to a correct diagnosis. Learn why there are consequences to misdiagnosing MS in patients. This activity will appeal to all healthcare providers that want expert instruction about the diagnostic criteria, best practices in examination, careful interpretation of MRI scans, and common mistakes to avoid.

What are the early treatment possibilities for Multiple Sclerosis? In the third lecture of the MS Lecture Series, learn about MS phenotypes, the importance of early intervention, and maximizing neurological reserve in patients. Treatments for Multiple Sclerosis continue to evolve, so watch this video to learn the latest concepts and best practices for treating MS patients quickly after diagnosis.

How can providers best provide timely treatment to Multiple Sclerosis patients? Watch the fourth lecture in the MS Series to learn about how to choose disease-modifying treatment options, the importance of monitoring patients at regular intervals to evaluate signs of disease activity, and how to balance patients' risks and comorbidities with the advantages of treatments. Listen in to examine the available data about treating with the escalation approach or early induction approach.

What are the new innovative treatment strategies indicated for the treatment of MS? Watch the fifth and final lecture in the MS Series to learn about the novel therapies that are at the precipice of transforming the field in patient care. In this talk, Dr. Lucas Kipp explores the mechanisms of progressive MS, remyelination, and Epstein Barr Virus treatments.

Presented by: Jeffrey Edward Dunn, MD

Presented by: Emmanuelle Waubant, MD

Presented by: Lawrence Steinman, MD

This educational activity is supported in part by an educational grant from Novartis Pharmaceuticals Corporation.

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Chief complaint:  “When I woke up yesterday my legs felt so stiff, I could barely walk. My hands shake every time I try to paint. I feel uncoordinated, exhausted,  and just not like myself lately.”

History of present illness:  Ms. N.S. is a 29 yo white female, who was referred to the neurology clinic by her PCP after complaining of frequent episodes of weakness, fatigue, and a tingling sensation in different areas of her body. She states she first started noticing symptoms about 2 weeks ago and has been feeling progressively worse. Patient has also reported some urinary frequency, but she has been attributing it to her recent childbirth.

Past medical history

• Tonsillectomy, age 5 years
• Epstein-Barr virus, age 14 years
• Reports a “precancerous mole” that was removed at age 18 years with no complications
• Gave birth to first child 3 months ago with no complications

Pertinent family history:

• Mother alive and healthy at age 58 years
• Father alive, patient reports he takes medication for blood pressure but otherwise is healthy at age 59 years
• Patient has no siblings
• Maternal Aunt alive, living with multiple sclerosis, age 54 years
• Paternal grandfather died after suffering a stroke 2 years ago

Pertinent social history:

• Former smoker, patient quit at age 23
• Recently moved to Columbus, Ohio from Toronto, Canada
• Social drinker with approx. 1-2 alcoholic beverages per week
• Patient is an artist, enjoys going to the gym 2-3 times per week, and is currently working part time in an art gallery
• Patient likes being outdoors and states she recently returned from a several day hiking trip
• None known to patient

Medications:

• Pt states takes Tylenol “occasionally only for headaches”

Focused physical exam:

• Height 5′ 6″
• Weight 135 lb.
• Skin: clear with no lesions or rashes
• Heart Sounds: S1, S2 Regular
• Lungs: Clear in all fields, respirations regular and unlabored
• Abdomen: Soft, nontender, active bowel sounds. Pt reports last BM was this morning.
• Genitourinary: Patient reports urinary frequency, states urine is clear and yellow with no foul odor
• Patient is alert, oriented x 4 to person, place, time, situation
• Pupils are equal, round, and reactive
• Strength equal bilaterally in all extremities, patient has a slight intention tremor present in both hands
• Patient reports feeling “pins and needles” in her left and right lower legs
• Distal pulses are palpable in all extremities with no abnormalities

Vital Signs:

• Temperature: 37.0 degrees celsius
• Respiratory rate: 18
• Blood pressure: 108/76
• Oxygen saturation: 99% on room air
• Pain: 0/10 pt states: “No pain, I just feel tired and my legs are tingling”

Lab Values/Imaging:

• CBC: unremarkable
• Antinuclear antibodies (ANA) test: negative
• Enzyme-linked immunosorbent assay (ELISA) test: negative
• Urinary analysis: unremarkable
• Urine culture: pending
• CT Scan: unremarkable
• MRI with IV contrast: results are positive for inflammation in areas of the brain and spinal cord

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April 19, 2024

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Signs of multiple sclerosis show up in blood years before symptoms, study finds

by University of California, San Francisco

In a discovery that could hasten treatment for patients with multiple sclerosis (MS), UC San Francisco scientists have discovered a harbinger in the blood of some people who later went on to develop the disease.

In about 1 in 10 cases of MS, the body begins producing a distinctive set of antibodies against its own proteins years before symptoms emerge. These autoantibodies appear to bind to both human cells and common pathogens, possibly explaining the immune attacks on the brain and spinal cord that are the hallmark of MS.

The findings were published in Nature Medicine on April 19.

MS can lead to a devastating loss of motor control, although new treatments can slow the progress of the disease and, for example, preserve a patient's ability to walk. The scientists hope the autoantibodies they have discovered will one day be detected with a simple blood test , giving patients a head start on receiving treatment.

"Over the last few decades, there's been a move in the field to treat MS earlier and more aggressively with newer, more potent therapies," said UCSF neurologist Michael Wilson, MD, a senior author of the paper. "A diagnostic result like this makes such early intervention more likely, giving patients hope for a better life."

Linking infections with autoimmune disease

Autoimmune diseases like MS are believed to result, in part, from rare immune reactions to common infections.

In 2014, Wilson joined forces with Joe DeRisi, Ph.D., president of the Chan Zuckerberg Biohub SF and a senior author of the paper, to develop better tools for unmasking the culprits behind autoimmune disease. They took a technique in which viruses are engineered to display bits of proteins like flags on their surface, called phage display immunoprecipitation sequencing (PhIP-Seq), and further optimized it to screen human blood for autoantibodies.

PhIP-Seq detects autoantibodies against more than 10,000 human proteins, enough to investigate nearly any autoimmune disease. In 2019, they successfully used it to discover a rare autoimmune disease that seemed to arise from testicular cancer .

MS affects more than 900,000 people in the US. Its early symptoms, like dizziness, spasms, and fatigue, can resemble other conditions, and diagnosis requires careful analysis of brain MRI scans.

The phage display system, the scientists reasoned, could reveal the autoantibodies behind the immune attacks of MS and create new opportunities to understand and treat the disease.

The project was spearheaded by first co-authors Colin Zamecnik, Ph.D., a postdoctoral researcher in DeRisi's and Wilson's labs; and Gavin Sowa, MD, MS, former UCSF medical student and now internal medicine resident at Northwestern University.

They partnered with Mitch Wallin, MD, MPH, from the University of Maryland and a senior author of the paper, to search for autoantibodies in the blood of people with MS. These samples were obtained from the U.S. Department of Defense Serum Repository, which stores blood taken from armed service members when they apply to join the military.

The group analyzed blood from 250 MS patients collected after their diagnosis, plus samples taken five or more years earlier when they joined the military. The researchers also looked at comparable blood samples from 250 healthy veterans.

Between the large number of subjects and the before-and-after timing of the samples, it was "a phenomenal cohort of individuals to look at to see how this kind of autoimmunity develops over the course of clinical onset of this disease," said Zamecnik.

A consistent signature of MS

Using a mere one-thousandth of a milliliter of blood from each time point, the scientists thought they would see a jump in autoantibodies as the first symptoms of MS appeared.

Instead, they found that 10% of the MS patients had a striking abundance of autoantibodies years before their diagnosis.

The dozen or so autoantibodies all stuck to a chemical pattern that resembled one found in common viruses, including Epstein-Barr Virus (EBV), which infects more than 85% of all people, yet has been flagged in previous studies as a contributing cause for MS.

Years before diagnosis, this subset of MS patients had other signs of an immune war in the brain. Ahmed Abdelhak, MD, co-author of the paper and a postdoctoral researcher in the UCSF laboratory of Ari Green, MD, found that patients with these autoantibodies had elevated levels of neurofilament light (Nfl), a protein that gets released as neurons break down.

Perhaps, the researchers speculated, the immune system was mistaking friendly human proteins for some viral foe, leading to a lifetime of MS.

"When we analyze healthy people using our technology, everybody looks unique, with their own fingerprint of immunological experience, like a snowflake," DeRisi said. "It's when the immunological signature of a person looks like someone else, and they stop looking like snowflakes that we begin to suspect something is wrong, and that's what we found in these MS patients."

A test to speed patients toward the right therapies

To confirm their findings, the team analyzed blood samples from patients in the UCSF ORIGINS study. These patients all had neurological symptoms and many, but not all, went on to be diagnosed with MS.

Once again, 10% of the patients in the ORIGINS study who were diagnosed with MS had the same autoantibody pattern. The pattern was 100% predictive of an MS diagnosis. Across both the Department of Defense group and the ORIGINS group, every patient with this autoantibody pattern had MS.

"Diagnosis is not always straightforward for MS, because we haven't had disease specific biomarkers," Wilson said. "We're excited to have anything that can give more diagnostic certainty earlier on, to have a concrete discussion about whether to start treatment for each patient."

Many questions remain about MS, ranging from what's instigating the immune response in some MS patients to how the disease develops in the other 90% of patients. But the researchers believe they now have a definitive sign that MS is brewing.

"Imagine if we could diagnose MS before some patients reach the clinic," said Stephen Hauser, MD, director of the UCSF Weill Institute for Neurosciences and a senior author of the paper. "It enhances our chances of moving from suppression to cure."

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Risk Factors Associated with Multiple Sclerosis: A Case-Control Study in Damascus, Syria

Faculty of Medicine, Damascus University, Damascus, Syria

Farah Al Ahmad

Mohammad karim ercksousi, ghassan hamza, associated data.

The raw data supporting the results reported in this article is available upon reasonable request by contacting the corresponding author.

To assess the probable risk factors associated with Multiple sclerosis among Syrian patients in the city of Damascus.

In a case-control study conducted from May to September 2020, 140 MS patients and 140 healthy controls were selected from two main hospitals in Damascus. Data regarding risk factors associated with MS was collected via a structured questionnaire and complementary laboratory tests. The statistical analysis was carried out by the SPSS Statistical Software Version 26.

Factors such as smoking, family history of MS, migraine, and vitamin D deficiency were associated with a higher risk of developing MS: Smoking (OR = 2.275 95% CI (1.348-3.841) P = 0.002). Family history of MS (OR = 3.970 95% CI (1.807-8.719) P ≤ 0.001). Migraine (OR = 3.011 95% CI (1.345-6.741) P = 0.005). Vitamin D deficiency (OR = 4.778 95% CI (2.863-7.972) P ≤ 0.001). However, factors such as diabetes, hypertension, a surgical history of appendectomy, tonsillectomy, and being the first-born in a family were statistically irrelevant: Diabetes (OR = 0.652 95% CI (0.226-1.882) P = 0.426). Hypertension (OR = 1.445 95% CI (0.724-2.885) P = 0.295) Appendectomy (OR = 1.269 95% CI (0.486-3.317) P = 0.626) Tonsillectomy (OR = 1.280 95% CI (0.576-2.843) P = 0.544). First-born Child (OR = 0.933 95% CI (0.558-1.562) P = 0.793).

Our study suggests that smoking, vitamin D deficiency, family history of MS, and migraine are probable risk factors for multiple sclerosis. Therefore, engaging in outdoor activities and maintaining a healthy diet—for females in particular—is highly recommended.

1. Introduction

Multiple sclerosis is an inflammatory, autoimmune demyelinating disease of the central nervous system affecting more than 2 million people around the world- with an estimated overall prevalence of 51.52/100000 in the Middle East alone [ 1 ]. Previous studies have shown that different genetic, immunological, and environmental factors play a role in the pathogenesis of this disease. However, the underlying cause and mechanisms behind MS remain unclear. The epidemiology of MS is changing, despite the increasing awareness raised against chronic diseases and the accessibility of new diagnostic procedures. Recent data has reflected an increase in the prevalence of the disease across Europe, Latin America, and the Mediterranean Basin [ 2 ]. Factors including geographic latitude, amount of daylight exposure, viruses, smoking, and nutritional habits—among others—were linked with MS in several studies [ 3 – 6 ]. In addition, clinically significant depressive symptoms were found in 41.8% of MS subjects in a study conducted by Chwastiak et al. [ 7 ]. The study demonstrated that as a disease, MS tends to be mentally draining, not only for the patients but also for their families and the greater community as well. Our study aims to evaluate the relationship between probable risk factors and MS by using a case-control study design in Syria. Taking into consideration that few studies have addressed this topic in our region, it was necessary to investigate the environmental triggers of MS in order to achieve a better understanding of how this disease functions.

2. Material and Methods

We selected a total number of 140 MS patients and 140 healthy controls who were matched for gender and age (±1 year) from two main hospitals in Damascus: Al-Assad University Hospital and Ibn Al-Nafees Hospital. Our inclusion criteria for MS cases consisted of patients who were able to fulfill the McDonald 2017 criteria had been diagnosed or admitted in either of the hospitals within the past year (2019-2020) and were 18 years or older. Exclusion criteria for MS cases consisted of patients who were not able to fulfill the McDonald 2017 criteria were less than 18 years old or were unable to understand the questionnaire and provide detailed answers. The total number of cases that matched our criteria reached approximately 250 patients. However, to avoid any sampling bias, the 250 patients were divided into two groups based on gender, from which we then randomly selected the subjects who would be included in our study until we reduced our sample size to 140 cases. While doing this, we made sure to take into consideration the importance of maintaining the same female to male ratio of the initial population. For the controls, we approached the healthy companions of the patients in other hospital departments—excluding the Neurology Department—while following our exclusion criteria for the controls (subjects with a history of MS, under 18 years of age, or who were unable to understand the questionnaire and provide detailed answers).

For this study, we adopted a structured questionnaire which included several questions about demographics, neurological symptoms, family history, smoking, vitamin D deficiency, weight, height, history of chronic illnesses, and history of surgical procedures. We assessed our questionnaire's validity by conducting several pilot surveys. In addition, we presented the questionnaire to different neurologists to consider their opinions and feedback. To evaluate our questionnaire's reliability, we used a test-retest method, administering the same questionnaire to the same group of people at different times and, thereafter, assessing the degree of similarity between the two sessions of the questionnaire. Through the questionnaire, we collected data from both the cases and the controls regarding the following factors: smoking, family history of MS, tonsillectomy, and appendectomy. For the data regarding vitamin D deficiency, migraine, hypertension, and diabetes, we revised the patients' medical history folders in the hospitals' archives for every patient who was included in the study.

From these folders, the necessary data was collected after assessing the laboratory and clinical tests that had been performed on the respective patients after their admission to the hospital. If there was any lack or insufficient information in the patients' medical archives, the proper clinical and/or laboratory tests were performed on the subjects. As for controls, we conducted all the clinical and/or laboratory tests needed for the study. After confirmation of the protocol by the Ethics Committee of Damascus University Faculty of Medicine, all data was collected carefully under close supervision to address any inquiries and to assess whether any question was left unanswered. Table 1 shows a detailed explanation of each variable composing the Inclusion Criteria that was used in the study.

Detailed inclusion criteria for each risk factor included in the study.

To reach the goal of our study, a univariate analysis method was implemented, which consisted of assessing the relationship between each factor individually, and the risk of developing MS from it. Frequency percentage values were reported to demonstrate the nominal and categorical variables, and the median value was used to describe numeric variables. The Chi-Square test and the Fisher's exact test were both used to test the association between categorical variables, and the corresponding odds ratios (OR) and its 95% confidence interval (CI) were computed for each variable. In all analytical procedures, a p value of ˂0.05 was considered statistically significant. The statistical analysis was carried out by the SPSS Statistical Software Version 26.

A total number of 140 MS patients and 140 controls were enrolled in this study. The cases were matched with the controls for gender and age, with females outnumbering males on a 2.2 : 1 female to male ratio, and the mean age was 34 years of age for both genders. The demographic comparison between the two groups is demonstrated in Table 2 .

Detailed comparison of the demographics between the cases and the controls.

The most common subtype of MS was relapsing-remitting (RRMS) with a percentage of 60.4%. Our results showed a potential risk in the relationship between smoking and MS (OR = 2.275 95% CI (1.348-3.841) P = 0.002), as well as indicated a relationship between family history of MS and the risk of having the disease (OR = 3.970 95% CI (1.807-8.719) P ≤ 0.001). The risk of MS was also significantly higher among those who suffered from migraine (OR = 3.011 95% CI (1.345-6.741) P = 0.005), and an association was found between vitamin D deficiency and MS (OR = 4.778 95% CI (2.863-7.972) P ≤ 0.001). Results of the comparison between the two groups are summarized in Table 3 .

Detailed comparison of the result values for each risk factor between the two groups.

Findings concerning the association between diabetes and risk of MS, however, were statistically irrelevant (OR = 0.652 95% CI (0.226-1.882) P = 0.426). High-blood pressure did not show any statistical significance for an increased risk of MS (OR = 1.445 95% CI (0.724-2.885) P = 0.295), and further assessments also showed no significant difference between the two groups regarding the appendectomy and tonsillectomy surgical procedures (OR = 1.269 95% CI (0.486-3.317) P = 0.626) and (OR = 1.280 95% CI (0.576-2.843) P = 0.544), respectively. Moreover, the results for being a first-born child were also statistically insignificant (OR = 0.933 95% CI (0.558-1.562) P = 0.793).

4. Discussion

The findings in our study indicated that smoking, a family history of MS, a positive history of migraine, and suffering from vitamin D deficiency are statistically more significant in MS cases than in the controls. However, variables such as suffering from hypertension, diabetes mellitus, a surgical history of tonsillectomy, appendectomy, or being the first-born child in a family showed no relation with MS and were statistically irrelevant.

Our study displayed a 2.2 : 1 female to male ratio. A similar study conducted in Syria by Almallouhi and Almallouhi [ 8 ] stated that the female to male ratio had increased from 1.8 : 1 in 2010 to 3.4 : 1 in 2015. In the greater region, other studies also reported similar ratios. For example, a study conducted in Lebanon, Yamout et al. [ 9 ] found that females outnumbered males with a female to male ratio of 1.8 : 1.

Regarding marital status, 60% of the cases were married, 35.7% were single, and the remaining cases were either divorced or widowers. Similar results are reported by Yamout et al. [ 9 ] with two-thirds of their cases having been married, while the remaining were either single or divorced.

In our study, the most common subtype of MS was relapsing-remitting multiple sclerosis (RRMS) with 60.4%, followed by progressive-relapsing multiple sclerosis (PRMS) with 22.9%. Similarly, Daif et al. [ 10 ] found that the clinical course in their study was 60.7% RRMS and 20.2% PRMS.

The clinical symptoms for MS primarily consisted of motor symptoms (34.15%), followed by sensory symptoms (24.98%), visual symptoms (21.14%), and brainstem and cerebellar symptoms (19.7%). In a study conducted by El-Salem et al. [ 11 ], visual symptoms were more common than sensory ones.

Our study suggests that there is a positive relationship between smoking and MS. Likewise, Halawani et al. [ 4 ] concluded that smoking significantly increases the risk of MS. On the other hand, Abbasi et al. [ 5 ] showed no relation between MS risk and cigarette consumption. Through further research, however, we were able to find a study by Mitrovic et al. [ 12 ], which stated that oligodendrocytes—the myelin-producing cells—are sensitive to nitric oxide exposure. Therefore, any exposure to nitric oxide will ultimately lead to cell death by either apoptosis or necrosis. This study supports the notion that the nitrogen oxide in cigarettes may be causing degeneration, demyelination, and oligodendrocytes necrosis.

The risk of MS was also higher among people with a family history of MS, which emphasizes the fact that both genetic and environmental factors play a role in the development of MS. This finding is consistent with many MS studies such as one conducted in Saudi Arabia by Al Jumah et al. [ 13 ], which reported that approximately 21% of MS patients have had a family history of MS. Unlike other studies, however, our study did not distinguish the differences between first, second, and third-degree relatives. Each individual with a family history of MS was taken into account, regardless of their degree of relationship to the family member who had MS.

In addition, our data shows more frequency of migraine in MS patients compared with the control group. While the pathogenesis behind this relation is not clear, many studies have proven the coexistence of the two diseases. Rolak and Brown [ 14 ] showed that 21% of patients with MS had migraine (22 out of 104); other studies suggested that headaches were associated with the usage of IFN beta as a treatment for MS. La Mantia et al. [ 15 ] exhibited a higher prevalence of headaches in patients treated with IFN beta (72%), compared to patients who were treated with other agents (54%). We believe that the relationship between migraine and MS is not clear to this day. Migraine may act as a risk factor for MS in some cases, while in other cases, MS itself could be the cause of migraine. It may also be possible that the two diseases just happen to coexist with one another. Due to this uncertainty, we encourage other researchers to assess this relationship to come to a better understanding of both MS and migraine.

Vitamin D is well-known to have many immunoregulatory elements and substantially interferes with a wide range of autoimmune diseases. Goldsmith [ 16 ] suggested that vitamin D may serve as an endogenous brake to inflammation. A study by Waschbisch et al. [ 17 ] also demonstrated how vitamin D induces the expression of the inhibitory receptor ILT-3, which controls the T cell activation that is essential to prevent autoimmunity. Thus, it is suggested that vitamin D cotreatment with IFN beta could contribute beneficial effects to the management of the disease. With that being said, in our study, lower serum levels of vitamin D were found to be associated with a higher risk of MS. This finding certainly stems from the overall low daylight exposure in the cases group, which led to the deficiency. This observation was also supported by other studies including Ramagopalan et al. [ 18 ] which showed that decreased UVB exposure correlates with an increased incidence of MS.

There is no clear relationship between diabetes mellitus and MS, a result which was also reflected in our investigation of the relationship between hypertension and MS. A study by Nielsen et al. [ 19 ] claimed that patients with Type 1 diabetes were at more than a threefold increased risk for the development of MS. Whereas Abbasi et al. [ 5 ] reported that diabetes mellitus appeared to be related with a decreased risk of MS. Regarding hypertension, a study conducted by Saroufim et al. [ 20 ] stated that MS cases were 48% more likely to have ever had hypertension than the controls. These unclear results regarding diabetes and hypertension in our study may be caused by the high prevalence of these two diseases in the Syrian community, which may be due to different genetic factors as well as other behavioral habits.

A surgical history of appendectomy or tonsillectomy were also statistically irrelevant in our study. However, other studies have had mixed results while studying these factors. A meta-analysis of several case controls conducted by Lunny et al. [ 21 ] suggested that there is a small yet statistically significant increased risk for developing MS for those who have undergone an appendectomy and tonsillectomy, and who are 20 years old or younger. Another study by Broadley et al. [ 22 ] claimed that no evidence was found to suggest that tonsillectomy affects the susceptibility to multiple sclerosis. The study by Eftekharian et al. [ 23 ] had the closest results to ours—showing no significant association between appendectomy and tonsillectomy, and MS—and also suggested that if more people were included in the study groups, the results could potentially show greater significant differences.

Our study also showed no statistical evidence that being the first-born child in the family represents a risk factor for MS. However, a study by Al Wutayd et al. [ 6 ] suggested the opposite by demonstrating that being the first-born child of a family is associated with an increased risk of MS. The inconsistency in these results may be due to different sets of beliefs, as well as sociodemographic characteristics such as education levels and awareness of birth control usage (both elements which may receive more emphasis in some countries than others).

Finally, our study had potential limitations. First, the lack of previous research on MS in Syria did not provide us the ability to follow an existing theoretical framework or methodology through which we could ultimately compare our results with previous studies. We believe that this factor would have enabled us to further understand how MS characteristics have evolved throughout time in Syria. Additionally, we were hindered by severe transportation limitations at the time this article was written due to the ongoing war in Syria, and thus, we were only able to sample from two hospitals. We believe that sampling from more hospitals would have enabled us to access a larger population with a broader range and/or diversity of sociodemographic characteristics, a critical factor which could have potentially led to more accurate results.

5. Conclusion

Data availability, conflicts of interest.

The authors have no conflicts of interest to declare.