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Educational Case: Multiple sclerosis

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see https://www.journals.elsevier.com/academic-pathology/news/pathology-competencies-for-medical-education-pcme . 1

Primary objective

Objective NSC3.3: Multiple sclerosis. Describe the pathogenesis, clinical presentation, and gross and microscopic pathologic features of multiple sclerosis.

Competency 2: Organ System Pathology; Topic NSC: Nervous System – Central Nervous System; Learning Goal 3: Spinal Cord Disorders.

Secondary objective

Objective NSC6.1: Autoimmune mechanisms in multiple sclerosis. Describe the autoimmune mechanism mediated by CD4 + T cells that react against self-myelin antigens in multiple sclerosis and outline the clinicopathologic features of the disease.

Competency 2: Organ System Pathology; Topic NSC: Nervous System – Central Nervous System; Learning Goal 6: Demyelinating Disorders.

Patient presentation

A 32-year-old woman with no past medical history presents to the emergency room with a 6-month history of waxing and waning unilateral visual impairment and facial numbness. She was well until 6 months ago when she noticed the onset of right-sided facial numbness and blurred vision lasting several weeks. She states that three episodes have occurred during the past 6-month time period. There was no associated muscle weakness of the facial muscles. Earlier today, upon waking up, the patient noted a sudden onset of blurry vision in her right eye and numbness on the right side of her face. She states she has not observed any muscle weakness, gait disturbance, fever, or urinary incontinence.

Diagnostic findings, Part 1

Physical examination reveals a well appearing, anxious woman. Vital signs are temperature: 98.6 °F, heart rate: 82 beats per minute, blood pressure: 116/84 mmHg, respiratory rate: 16 breaths per minute. Neurologic exam reveals 20/20 vision in the left eye and 20/100 vision in the right eye. Muscle strength is 5/5 in all extremities. There is unilateral loss of sensation on the entire right half of the face; otherwise, all other cranial nerves are intact. Romberg sign is negative, and no gait disturbances are noted. Cardiac, pulmonary, and abdominal examinations are unremarkable.

Questions/discussion points, Part 1

What is the differential diagnosis based on the clinical findings.

Relapsing-remitting visual deficits are suggestive of optic neuritis which, along with new-onset facial neuropathy manifesting as numbness, are most suggestive of a central nervous system (CNS) demyelinating disease. Demyelinating disorders that affect the CNS can be grouped by their etiologies, which includes inflammatory, infectious, and toxic-metabolic-nutritional ( Table 1 ). Among inflammatory disease processes, the relapsing-remitting nature of vision deficits in a woman in her 30s raises multiple sclerosis (MS) highest in the differential diagnosis, discussed below. In addition to MS, other demyelinating disorders in the differential include neuromyelitis optica spectrum disorder (NMOSD) and acute disseminated encephalomyelitis (ADEM). NMOSD present with relapsing-remitting neurological symptoms and lesions on magnetic resonance imaging (MRI) studies are similar to those in MS. However, lesions in NMOSD are characteristically limited to the spinal cord and optic nerves, whereas MS characteristically has cranial involvement in addition to the spinal cord and optic nerves. ADEM is rarely confused with MS as it is usually a monophasic, self-limiting, post-viral, or rarely post-vaccination disease of childhood. It typically presents with acutely evolving, multifocal CNS disease, whereas in MS, the neurological deficits during initial presentation or a relapse are usually limited to a single site or a few sites. ADEM can rarely manifest with relapses, although, in this setting, MRI lesions are typically more extensive and symmetric than MS.

Table 1

Disorders that may present with myelin loss in the central nervous system, peripheral nervous system, or both.

Abbreviations: CNS, central nervous system; PNS, peripheral nervous system.

Infectious etiologies of CNS demyelination include progressive multifocal leukoencephalopathy, Lyme disease, and neurosyphilis. Progressive multifocal leukoencephalopathy is an infection of oligodendroglial cells by the JC virus leading to demyelination in the setting of immunodeficiency (e.g., acquired immunodeficiency disease or iatrogenic immunosuppression). The optic nerve is myelinated by oligodendroglial cells; therefore, the optic nerve is affected in progressive multifocal leukoencephalopathy and not in peripheral nervous system (PNS) demyelinating diseases like Guillain-Barré syndrome or chronic inflammatory demyelinating polyradiculoneuropathy. Early disseminated stage 2 lyme disease can present with recurrent cranial neuropathies in the context of meningitis.

Inherited toxic-metabolic-nutritional disorders that lead to loss of myelin (leukodystrophy) include the lysosomal storage diseases Krabbe disease and metachromic leukodystrophy, as well as the peroxisomal disease adrenoleukodystrophy. These disorders typically present in childhood with a slow, progressive course, eventually leading to symptoms in both the CNS and PNS due to loss of myelin. Adrenoleukodystrophy also leads to adrenal cortex dysfunction due to steroid hormone production deficits, manifesting clinically as Addison disease. The leukodystrophies are inherited, with an autosomal recessive inheritance in Krabbe disease and metachromic leukodystrophy and an X-linked pattern of inheritance in adrenoleukodystrophy.

Inflammatory disorders that can mimic MS include cerebral vasculitis, systemic lupus erythematosus, Sjogren syndrome, and neurosarcoidosis. These disorders only rarely present initially with neurological symptoms, and systemic signs and symptom characteristics of these disorders are usually present. MRI studies and laboratory testing performed on blood and cerebrospinal fluid (CSF) can help differentiate between an inflammatory demyelinating disorder and infectious and inflammatory disease processes. Arteriovenous malformations can result in relapsing-remitting, single-site neurological symptoms similar to MS, but MRI and computed tomography angiography can distinguish vascular malformation from other disorders. Similarly, tumors in certain locations can mimic MS symptoms. Pituitary adenomas, craniopharyngiomas, and meningiomas can occur in the sella turcica region and compress on the optic chiasm and optic nerves resulting in visual deficits, although characteristically with a progressive loss of vision rather than with relapsing and remitting symptoms. 2 , 3

Define the different clinical subtypes (phenotypes) of multiple sclerosis

In 1996, the US National MS Society defined three phenotypes of MS, which were later refined by Lublin et al., in 2013: relapsing-remitting (RRMS), secondary-progressive (SPMS), and primary-progressive (PPMS). 4 RRMS is defined as having relapses that last at least 24h and have complete or partial remission of symptoms between attacks. RRMS can transform into SPMS, which is where symptoms are no longer stable between relapses and instead there is progressive accumulation of disability. PPMS is when a patient initially presents with a progressive accumulation of disability, without a period of RRMS beforehand.

In addition to refining the definitions of the MS phenotypes, Lublin et al. introduced a new category: the clinically isolated syndrome (CIS). A CIS is defined as the first clinical presentation of a disease that could be MS but has yet to fulfill the dissemination in time (DIT) criteria required to diagnose MS. DIT will be described in more detail below, but as it requires at least two attacks to have occurred, MS cannot be diagnosed at the initial presentation. The inclusion of CIS as a subgroup of MS allows patients with probable MS to begin treatment earlier than before its inclusion. Another concept the Lublin group added was active vs. not active MS. Active MS is defined as a patient with clinical evidence of a relapse or a new gadolinium-enhancing lesion on a current MRI. Conversely, not active MS is a patient without clinical evidence of a relapse or a new lesion on MRI. “Active” and “not active” are used as modifiers to the MS phenotype; thus, a patient can have RRMS – active, or SPMS – not active. Lublin et al. used 1 year as the minimum time frame to assess for activity; thus, if the annual MRI for MS activity showed no new lesions, and there were no clinical relapses in the past year, the patient would have “not active” MS. However, no recommendation for what time frame to use was given in this article, and in 2020, Lublin et al. published an article to clarify the necessity of defining a time frame in which to define activity or else this modifier would have little meaning. 5

What are the diagnostic criteria for multiple sclerosis?

The diagnosis of MS incorporates a combination of clinical, imaging, and laboratory criteria, which are compiled by an expert panel and then revised periodically, most recently in 2010 and 2017. 6 , 7 These criteria are termed the McDonald criteria, after the lead author on the paper detailing the criteria that were originally composed in 2001. 8 Due to the reliance on the combination of information, as there is no single laboratory test that can diagnose MS, consideration and exclusion of alternative disease processes is critical to the diagnostic workup. To diagnose MS, you must demonstrate dissemination of lesions in the CNS in space and time (DIS/DIT). DIS and DIT are defined as either clinical or radiologic evidence of greater than one lesion at different anatomical locations, separated in time by a period of complete or partial remission. The McDonald criteria define different ways DIS and DIT can be demonstrated to make the diagnosis. In a patient with a relapsing-remitting presentation of MS, DIS can be demonstrated through either:

  • - Objective, clinical evidence of ≥2 lesions or
  • - ≥ 1 symptomatic or asymptomatic MS-typical T2 lesions in 2 or more areas of the CNS: periventricular, juxtacortical/cortical, infratentorial, or the spinal cord.

DIT can be demonstrated through either:

  • - ≥ 2 typical MS attacks separated by a period of remission,
  • - The simultaneous presence of both enhancing and non-enhancing symptomatic or asymptomatic MS-typical MRI lesions,
  • - A new T2-enhancing MRI lesion compared to a baseline scan, or
  • - The presence of CSF-specific oligoclonal bands.

If, however, a patient initially presents with a continual progression of disability, MS can still be diagnosed if they have had at least 1 year of disability progression and two of the following:

  • - ≥ 1 symptomatic or asymptomatic MS typical T2 lesions (periventricular, juxtacortical/cortical, or infratentorial),
  • - ≥ 2 T2 spinal cord lesions, or
  • - The presence of CSF-specific oligoclonal bands. 6

What imaging is indicated and what results would support a diagnosis of MS?

An MRI of the brain and spinal cord is extremely important in the diagnosis of MS as it is very sensitive in detecting white matter abnormalities. To diagnose MS there should be at least one typical MS lesion in at least two areas that are characteristic of MS. A typical MS lesion is a focal hyperintensity on a T2 weighted sequence, round/ovoid in shape, ranges from a few millimeters to 1–2 cm in size, and is at least 3 mm in its long axis. Characteristic locations include periventricular (in direct contact with the lateral ventricles, without intervening normal white matter), juxtacortical/cortical (in direct contact with the cortex, without intervening normal white matter), infratentorial (in the brainstem, cerebellar peduncles, or cerebellum), or anywhere in the spinal cord (the cervical cord is the most frequently involved). Another feature characteristic of MS lesions is gadolinium enhancement. Gadolinium enhancement is seen in acute MS lesions and is transient, usually lasting 4 weeks or less. This feature can help support the DIT criteria of diagnosis, as the presence of gadolinium-enhancing and nonenhancing lesions confirms the presence of new and chronic lesions. 9

What laboratory testing is indicated and what results would support a diagnosis of MS?

CSF analysis and serum antibody testing can be useful, especially when the clinical picture is not “classic” for MS to support or cast doubt on the diagnosis of MS. In the workup of MS, CSF analysis should include white blood cell count, red blood cell count, protein concentration, glucose level, immunoglobulin G (IgG) index, and oligoclonal band testing. The white blood cell count, protein concentration, and glucose levels are helpful in ruling out MS; white blood cell counts can be mildly elevated in MS, but very high counts (>50/mm 3 ), low glucose level, and high total protein are more indicative of infection than MS. A high red blood cell count likely indicates a traumatic tap, which may make the other tests uninterpretable, so a CSF analysis with high red blood cells should be interpreted with caution. An IgG index (IgG CSF /IgG Serum )/(Albumin CSF /Albumin Serum ) is indicative of how much IgG is being produced in the CSF and is used instead of just measuring the level of IgG in the CSF because peripherally produced IgG can cross the blood–brain barrier and be measured in the CSF. Another method to detect CSF-specific IgG is oligoclonal bands. Through isoelectric focusing and immunoblotting, antibodies can be visualized as dark bands. Oligoclonal bands are antibodies seen only in the CSF and not in the patient's serum. Two or more oligoclonal bands in the CSF suggest intrathecal production of IgG (as seen in MS) rather than a systemic production of IgG that is being leaked into the CSF. In the latter case, the bands of IgG antibodies being detected in the serum would be observed in the CSF as well. 10 Another laboratory test that is sometimes used in the workup of MS is testing the serum for the presence of antibodies. There is no specific antibody associated with MS, but detection of specific antibodies can help rule out MS. Antibodies against an aquaporin-4 water channel in astrocytes is seen in NMOSD and can help rule out MS if present. Anti-myelin oligodendrocyte glycoprotein (anti-MOG) targets one of the proteins found in myelin, and though once thought to be indicative of MS, it has been discovered to be a separate entity, termed anti-MOG syndrome. The clinical course of anti-MOG syndrome is like ADEM in pediatric patients, whereas adults typically show optic neuritis and brainstem encephalitis. Importantly though, pediatric and adult patients with seropositive anti-MOG titers don't ever fulfill diagnostic criteria for MS, further solidifying anti-MOG syndrome as a separate entity from MS. 11

What electrophysiologic testing could be performed and what results would support a diagnosis of MS?

Evoked potentials (EPs) are used to measure electrical activity in areas of the brain and spinal cord. There are different types of EPs, and the ones most used in MS are visual (testing the optic nerve) and motor EPs. There are certain situations EPs can be helpful: when the MRI is equivocal or to predict the aggressiveness of the disease. MRI is more sensitive than an EP and is better at diagnosing MS, but if the MRI is equivocal, an EP can be used to help support or rule out the diagnosis. Second, EPs are better at predicting the clinical course of MS as it can detect early or even subclinical demyelination prior to its visualization on MRI. EPs can be used to monitor a patient, and if an EP is positive, more aggressive treatment can be initiated. 12

Diagnostic findings, Part 2

Lumbar puncture and blood draw are performed, and CSF and serum obtained for additional studies. The results are listed in Table 2 , Table 3 . T2 FLAIR MRI images of the brain, optic nerves, and spinal cord are also obtained ( Fig. 1 ). Focal hyperintensities are seen in the brain, right optic nerve, and spinal cord. The clinical presentation, imaging, and lab data are consistent with MS as the diagnosis.

Table 2

Cerebrospinal fluid (CSF) values.

Table 3

Additional results.

Abbreviation: CSF, cerebrospinal fluid.

Fig. 1

Parasagittal MRI image demonstrates several periventricular demyelinating plaques (red arrowheads) referred to as Dawson fingers in multiple sclerosis. Reproduced with permission from Harrison Klause, MD, EVMS, Norfolk, VA. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Questions/discussion points, Part 2

Describe the epidemiologic features of ms.

MS is a disorder that leads to disability in young adults. Patients are usually between 15 and 45 years of age when symptoms present. The mean age of onset is from 28 to 31 years. The age of onset varies among the clinical subtypes (phenotypes). RRMS has an earlier onset, averaging between 25 and 29 years, with SPMS presenting at a mean age between 40 and 49 years of age. The estimated male to female ratio is 1.4–2.3 to 1. Geographic variation exists with MS more common in northern latitudes. In the US, the estimated prevalence is 1–1.5 per 1000 individuals. 2 , 13

How does autoimmunity play a role in the mechanism of MS?

Normally, when a dendritic cell detects a foreign antigen, it presents the antigen to CD4 + T cells and releases cytokines that induce inflammation and helps shape the adaptive immune system. In MS, dendritic cells are overactivated and migrate through the blood–brain barrier to induce Th1 and Th17 differentiation in the CNS. The proportion of Th17 to Th1 cells is also increased in the peripheral blood of MS patients during acute relapses. Th17 releases matrix metalloproteinase and granulocyte macrophage colony-stimulating factor, which increases blood–brain barrier permeability and recruits bone marrow-derived monocytes, respectively. Th1 and Th17 are both involved in ectopic lymphoid follicle formation and play a role in activating B-cells. In MS patients, B-cells produce autoantibodies that mediate demyelination and axonal disruption. Also, memory B-cells differentiate into CSF plasma cells, which produce antibodies that manifest as oligoclonal bands on protein electrophoresis. B-cells are important regulators of the immune system, and this regulatory function is defective in MS patients, leading to autoreactive B-cells and an overactive immune system. In addition to B-cells and T-cells, astrocytes, the gut microbiome, and dieting patterns are also thought to play a role in the immune response in MS patients. Astrocytes play an important role in maintaining the blood–brain barrier and regulate the activity of microglia and oligodendrocytes. Dysfunction in these processes is thought to contribute to demyelination, axonal damage, and infiltration of pro-inflammatory leukocytes into the CNS. 2 , 14

Describe the gross and histological findings observed in the brain from a patient with multiple sclerosis

Fig. 2 is a picture from an autopsy patient with MS who died of an unrelated cause. There are several well-circumscribed, gray-tan, irregularly shaped paraventricular and juxtacortical plaques (arrows), representing chronic MS plaques that are demyelinated. On histology, active plaques can be recognized by the presence of foamy macrophages, which are stripping myelin from axons and digesting it in lysosomes ( Fig. 3 , Fig. 4 ). In chronic plaques, there is little to no myelin left, which is highlighted with the Luxol fast blue stain which stains myelin blue ( Fig. 5 , Fig. 6 , Fig. 7 ). 2

Fig. 2

Multiple sclerosis. In a coronal section of brain, multiple sharply defined, tan-gray plaques are identified in the white matter, adjacent to the right ventricle (paraventricular), involving the cortex at the gray matter-white interface (juxtacortical), and in other locations (arrows).

Fig. 3

Active MS plaque shows abundant foamy macrophages, which are ingesting the myelin breakdown products, accompanied by an intense lymphocytic perivascular infiltrate (perivascular cuffing) (H&E stain, intermediate magnification).

Fig. 4

Foamy macrophages (arrowheads) are distended with myelin breakdown product (Luxol fast blue stain, high magnification). Reproduced with permission from Suzanne Zein-Powell, MD, Methodist Hospital, Houston, TX. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 5

A c oronal section of midbrain at the interface between the pons and midbrain shows several areas of demyelination, most notably centrally within the cerebral peduncle, within the corticospinal fiber tract (arrowhead) (Luxol fast blue stain, no magnification). Reproduced with permission from the College of American Pathologists. AUB, 1996 Education Programs. Northfield, IL: College of American Pathologists; 1996. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 6

On histological examination, the brain shows an area of demyelination with axonal preservation (arrowhead) seen as the tan-gray plaque on gross examination. (Luxol fast blue stain, intermediate magnification). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 7

Chronic plaque at interface with normal white matter. The axons are retained within the plaque; however, many have not been remyelinated. In addition, macrophages and lymphocytes are decreased in number in a chronic plaque, so the cellularity within a chronic plaque is less than in an active/acute plaque ( Fig. 3 , Fig. 4 ). (Luxol fast blue stain, intermediate magnification). Courtesy of Philip Boyer, MD, PhD, Brody School of Medicine, Greenville, NC. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Do a patient's acute exacerbation symptoms correlate with pathologic findings?

Clinical symptoms of acute exacerbations are correlated histopathologically with focal inflammatory demyelinating white matter lesions. Inflammatory cells recruited from the circulation, mostly T-cells and macrophages, accumulate in the lesions and eventually lead to partial/complete demyelination. Overall, white matter demyelination and peripheral immune cell accumulation are pathological hallmarks of an acute plaque and correlate with clinical symptoms. Additionally, edema associated with the inflammatory lesion likely contributes to the observed functional deficits, especially in regions with low swelling capacity, such as the spinal cord. Both demyelination and compression of nerve fibers lead to reduced conduction velocity and sometimes complete conduction block. 15

Describe the pathological hallmarks of progressive disease

Although there is likely some crossover, disease progression is characterized more by neurodegeneration than focal, autoimmune-driven inflammation like that of acute relapses. In the later chronic stages of MS, all aspects of the neuron undergo degenerative changes including axons, cell bodies, dendrites, spines, and neurotransmitter metabolism. The direct mechanism leading to neurodegeneration is unknown, but possible mechanisms include microglia activation, reactive oxygen species, and mitochondrial dysfunction. The triggers of neurodegeneration seen in chronic, progressive MS are the “normal appearing” white matter (NAWM) lesions and tissue damage in the gray matter. NAWM appears normal in routine stains and imaging; however, detailed histological studies reveal diffuse gliosis, microglial activation, vascular fibrosis, perivascular cuffing by inflammatory cells, perivascular lipofuscin, abnormal endothelial tight junctions, blood–brain barrier breakdown, and/or vessels containing proliferating endothelial cells. Axonal loss has also been observed in NAWM. Notably, NAWM lesions correlate better with clinical disability than focal inflammatory white matter lesions. In addition to white matter, gray matter is damaged in progressive MS. Damage can extend throughout the cortex and subcortical regions. An important element of gray matter damage is meningeal inflammation. Lymphoid structures resembling B-cell follicles form in the meninges. They are found extensively in patients with primary progressive MS who exhibit a more severe clinical course. 16 , 17

Describe remyelination in MS

Remyelination in the CNS is accomplished by oligodendrocytes, and in MS patients, they contribute to the complete or partial resolution of clinical symptoms in RRMS. Remyelination is dependent on adult oligodendrocyte progenitor cells (OPC) as preexisting, mature oligodendrocytes cannot add to the pool of myelinogenic oligodendrocytes. It is thought that the main reason remyelination fails in MS is because OPC become quiescent and unable to differentiate, but there are likely other factors that contribute to the failure to remyelinate. For example, reactive astrocytes secrete inhibitors of remyelination at the site of demyelination. Similarly, clearance of myelin debris is an important step in remyelination since it contains remyelination inhibitors. The macrophages and activated microglia that are responsible for phagocytosis of debris also secrete various neutrophilic factors. There is also an age dependent decline in remyelination, and this is more clearly due to decreased differentiation of OPC. Mechanistically, it is thought that aged OPC become less responsive to factors that induce differentiation through dysfunction of the mTOR pathway. Finally, remyelination also depends on the location in the CNS. For example, periventricular lesions are less amenable to remyelination than subcortical lesions. Overall, as patients age and the disease progresses, there is less remyelination of lesions, correlating with progressive clinical dysfunction. 18

How is MS treated?

Treatment is multifactorial including counseling, physical therapy, exercise and pharmacotherapy. Pharmacotherapy consists of medications directed at immunosuppression or immunomodulation. 2 Although not curative, pharmacotherapy may ameliorate symptoms. Disease modifying therapeutic agents depends on which clinical subtype (phenotype) (CIS, RRMS, SPMS, and PPMS) the patient presents with. Monoclonal antibodies (natalizumab, ocrelizumab, rituximab, ofatumumab, and alemtuzumab) may be indicated for active disease. Fumarates (e.g. dimethyl fumarate) and sphingosine 1-phosphate receptor modulators (e.g. fingolimod) are other considerations along with injectable agents, such as recombinant human interferon beta-1b, recombinant human interferon beta-1a, and glatiramer acetate. Healthcare workers need to consider the risk benefit of selected agents, given the potential adverse effects including infection. 2 , 19 , 20 , 21

Teaching Points

  • • Multiple sclerosis (MS) is a chronic demyelinating disorder of autoimmune etiology in which the clinical findings are separated in both time and space.
  • • MS presents with symptoms usually between 15 and 45 years of age. It is twice as common in women and has a prevalence between 1/1000 persons in the US.
  • • The diagnosis of MS incorporates a combination of clinical, imaging, and laboratory data to show dissemination of lesions in space and time, along with the consideration and exclusion of alternative diagnoses.
  • • Laboratory testing contributes to the diagnostic workup of a patient with MS in the differential diagnosis; however, no single laboratory test, in isolation, is diagnostic of MS.
  • • The most characteristic finding seen on MRI are T2-hyperintense and/or gadolinium contrast-enhancing T1 cerebral hemisphere periventricular, juxtacortical, infratentorial, and spinal cord white matter lesions.
  • • The presence of CSF-specific oligoclonal bands can substitute for MRI data demonstrating dissemination in time.
  • • Autoimmunity is thought to play an important role in the pathogenesis of MS, involving T and B cell dysfunction.
  • • Acute exacerbations are characterized by demyelination, inflammation, and edema.
  • • Chronic, progressive disease is characterized by neurodegeneration, axonal damage, normal appearing white matter lesions, and gray matter abnormalities.
  • • Remyelination is thought to play a role in the partial or complete recovery of neurological function in relapsing-remitting MS.
  • • As MS progresses and patients age, remyelination lessens and neurological dysfunction becomes permanent.
  • • Treatment of MS is multifactorial including counseling, physical therapy, exercise, and pharmacotherapy.

Conflict of interest

The author(s) declare no potential conflicts of interest with respect to research, authorship, and/or publication of this article.

The author(s) received no financial support for the research, authorship, and/or publication of this article.


Fig. 2 , Fig. 3 , Fig. 6 were obtained during the scope of US government employment for Dr. Conran.

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 study patient with multiple sclerosis

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

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

\nKatharina Breitkopf,,

  • 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.


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.


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.


We acknowledge support by the Heinrich Heine University Düsseldorf.


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.

1. Lucchinetti CF, Gavrilova RH, Metz I, Parisi JE, Scheithauer BW, Weigand S, et al. Clinical and radiographic spectrum of pathologically confirmed tumefactive multiple sclerosis. Brain. (2008) 131:1759–75. doi: 10.1093/brain/awn098

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3. Le Guennec L, Mokhtari K, Chauvet D, Dupuis N, Roos-Weil D, Agut H, et al. Human Herpesvirus 6 (HHV-6) necrotizing encephalitis, a rare condition in immunocompromised patients: the importance of brain biopsy associated with HHV-6 testing. J Neurol Sci. (2017) 377:112–5. doi: 10.1016/j.jns.2017.04.003

4. Arbuckle JH, Medveczky MM, Luka J, Hadley SH, Luegmayr A, Ablashi D, et al. The latent human herpesvirus-6A genome specifically integrates in telomeres of human chromosomes in vivo and in vitro . Proc Natl Acad Sci USA. (2010) 107:5563–8. doi: 10.1073/pnas.0913586107

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

6. Luppi M, Barozzi P, Maiorana A, Marasca R, Torelli G. Human herpesvirus 6 infection in normal human brain tissue. J Infect Dis. (1994) 169:943–4. doi: 10.1093/infdis/169.4.943

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

8. Faissner S, Hoepner R, Lukas C, Chan A, Gold R, Ellrichmann G. Tumefactive multiple sclerosis lesions in two patients after cessation of fingolimod treatment. Ther Adv Neurol Disord. (2015) 8:233–8. doi: 10.1177/1756285615594575

9. Jander S, Turowski B, Kieseier BC, Hartung HP. Emerging tumefactive multiple sclerosis after switching therapy from natalizumab to fingolimod. Multiple Scler. (2012) 18:1650–2. doi: 10.1177/1352458512463768

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.

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Research Article

Critical Illness in Patients with Multiple Sclerosis: A Matched Case-Control Study

Affiliation Department of Neurology, Christian Doppler Medical Center, Paracelsus Medical University, and Center for Cognitive Neuroscience, Salzburg, Austria

Affiliation Department of Anesthesiology, Perioperative and General Intensive Care Medicine, University Hospital Salzburg and Paracelsus Medical University, Salzburg, Austria

Affiliation Department of Biostatistics and Epidemiology, Perelman School of Medicine University of Pennsylvania, PA, United States of America

Affiliation Department of Psychiatry, Christian Doppler Medical Center, Paracelsus Medical University, Salzburg, Austria

* E-mail: [email protected]

Affiliations Department of Neurology, Christian Doppler Medical Center, Paracelsus Medical University, and Center for Cognitive Neuroscience, Salzburg, Austria, Department of Neurology, Klinikum rechts der Isar, Technische Universität München, Germany

  • Anush Karamyan, 
  • Martin W. Dünser, 
  • Douglas J. Wiebe, 
  • Georg Pilz, 
  • Peter Wipfler, 
  • Vaclav Chroust, 
  • Helmut F. Novak, 
  • Larissa Hauer, 
  • Eugen Trinka, 
  • Johann Sellner


  • Published: May 31, 2016
  • https://doi.org/10.1371/journal.pone.0155795
  • Reader Comments

Fig 1

Over the course of multiple sclerosis (MS) several conditions may arise that require critical care. We aimed to study the reasons for admission and outcome in patients with MS admitted to a neuro-intensive care unit (NICU).

We retrospectively searched the electronic charts of a 9-bedded NICU in a tertiary hospital for patients with a diagnosis of multiple sclerosis (MS) from 1993–2015, and matched them to NICU controls without MS based on age and gender. Conditional logistic regression was used to compare admission causes, Charlson’s Comorbidity Index, indicators of disease severity, and survival between MS and non-MS patients.

We identified 61 MS patients and 181 non-MS controls. Respiratory dysfunction was the most frequent reason for NICU admission among MS patients (34.4%), having infectious context as a rule. In a matched analysis, after adjusting for co-morbidities and immunosuppressive medications, patients with MS were more likely to be admitted to the NICU because of respiratory dysfunction (OR = 7.86, 95% CI 3.02–20.42, p<0.001), non-respiratory infections (OR = 3.71, 95% CI 1.29–10.68, p = 0.02), had a higher rate of multiple NICU admissions (OR = 2.53, 95% CI 1.05–6.05, p = 0.04) than non-MS patients. Mortality after NICU admission at a median follow-up time of 1 year was higher in MS than control patients (adjusted OR = 4.21, 95% CI 1.49–11.85, p = 0.04).

The most common reason for NICU admission in MS patients was respiratory dysfunction due to infection. Compared to non-MS patients, critically ill MS patients had a higher NICU re-admission rate, and a higher mortality.

Citation: Karamyan A, Dünser MW, Wiebe DJ, Pilz G, Wipfler P, Chroust V, et al. (2016) Critical Illness in Patients with Multiple Sclerosis: A Matched Case-Control Study. PLoS ONE 11(5): e0155795. https://doi.org/10.1371/journal.pone.0155795

Editor: Martin Sebastian Weber, Klinikum rechts der Isar der Technischen Universitaet Muenchen, GERMANY

Received: March 7, 2016; Accepted: May 4, 2016; Published: May 31, 2016

Copyright: © 2016 Karamyan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper.

Funding: This study was in part supported by an unrestricted grant from Merck. JS has received research funding from the Paracelsus Medical University, Bayer, Biogen-Idec, Merck and Novartis, has acted as paid consultant to Novartis and Genzyme, and has received speakers’ honoraria from Biogen-Idec, Ever Neuropharma, Genzyme, Novartis and Teva-Ratiopharm. There was no additional external funding received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: JS has received research funding from the Paracelsus Medical University, Bayer, Biogen-Idec, Merck and Novartis, has acted as paid consultant to Novartis and Genzyme, and has received speakers’ honoraria from Biogen-Idec, Ever Neuropharma, Genzyme, Novartis and Teva-Ratiopharm. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials. There are no restrictions on sharing of data and/or materials related to this work.


Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system, which is recognized as a leading cause of disability in working-age adults [ 1 , 2 ]. Immobility, involvement of vital neurological structures that may result in dysphagia and respiratory dysfunction as well as current MS medications pose a potential risk for the development of fatal complications [ 3 , 4 ]. While many of these conditions require critical care, the pattern of neuro-intensive care unit (NICU) admissions among MS patients has so far not been sufficiently studied. A recent study has reported a higher risk of critical care admission and 1-year mortality in MS patients as compared to the general population [ 5 ]. Given that both long-term and acute critical care of MS patients are very cost intensive [ 6 , 7 ], targeted interventions to reduce the need for consumption of critical care in MS patients would be paramount. To this end, it is important to better understand the reasons leading these patients to critical care presentation, as well as their outcome after admission.

The aim of this study was to describe clinical characteristics, reasons for admission and disease severity in MS patients requiring NICU admission. In addition, we compared MS patients to a matched group of NICU patients without MS. We hypothesized that critically ill MS patients would differ from non-MS patients in their admission diagnoses and mortality rate.

Study design and setting

This analysis was designed as a retrospective, matched case-control study. It was conducted in a 9-bed NICU of a tertiary university teaching hospital. The study protocol was reviewed and approved by the local Ethics Committee (Ethikkommision für das Bundesland Salzburg; 415-EP/73/534-2015). No written consent was needed due to the retrospective study design. Patient records were anonymized and de-identified prior to analysis.

Study population and data collection

From January 1, 1993 until December 31, 2015, the electronic records of the NICU were reviewed for patients admitted with the diagnosis of MS, excluding those under 18 years of age or admitted for palliative care. Then, the same database was searched for non-MS patients who were matched to MS patients based on age, gender and admission year. Doing so, up to eight control subjects per MS case were identified. NICU patients admitted because of other demyelinating diseases were not considered as control matches.

The following data were extracted from the prospectively collected electronic NICU and hospital records: age (at the time of first NICU admission), gender, reason for NICU admission, use of any immunosuppressive therapy such as cyclophosphamide, methotrexate, azathioprine prior to admission (yes vs no), the Simplified Acute Physiology Score II as an indicator of disease severity during the first 24 hours after NICU admission [ 8 ], resource utilization quantified with Therapeutic Intervention Scoring System (TISS-28) [ 9 ], need for and duration of mechanical ventilation, length of NICU stay (for the initial admission), cumulative length of NICU stay (in case of re-admissions), number of NICU admissions. For each patient we retrospectively calculated the Charlson’s Comorbidity Index (CCI) as a measure of comorbidity. In MS patients, the duration of disease as well as the degree of disability at the time of NICU admission as evaluated by the Expanded Disability Status Scale (EDSS) [ 10 ], were recorded.

Reasons for NICU admission

In MS patients, reasons for NICU admission were categorized as (1) pre-planned admissions for intensive therapeutic interventions (therapeutic plasma exchange, baclofen pump implantation); or (2) unplanned admissions due to critical illness complicating MS. In order to compare the study cohort with matched controls, reasons for admission were grouped into the following categories: respiratory dysfunction including infections; cardio-/cerebrovascular disease, neuro-/psychiatric disease, non-pulmonary infection, and planned interventions. A separate category of “other causes” included admissions for intoxication, trauma and progressive multifocal leukoencephalopathy.

Short- and long-term mortality

The mortality status of study and control patients was determined at NICU and hospital discharge, as well as 3, 6 and 12 months after the first NICU admission, by reviewing their hospital charts until the last documentation of using medical services. We repeated the mortality analysis, excluding MS patients who were admitted to the NICU for scheduled interventions or planned drug administration, as this may have underestimated true NICU mortality.

Statistical analysis

We report median (IQR) for continuous variables, and frequency (percent) for categorical variables. Correlations were determined using Spearman rank correlation test (r) with stratification by age, sex and CCI score.

For each study variable we used an univariate conditional logistic regression analysis to compare MS and non-MS NICU patients. To increase the power, we stratified the cohorts by 10-year age groups. We then performed multivariate conditional logistic regression analyses to control for the influence of potential confounders.

All reported p-values were two-tailed and considered statistically significant at <0.05. All statistical analyses were conducted using R statistical software version 3.2.3.

Over the 22-years observation period, 7124 NICU admissions occurred, of which 5911 were primary admissions. Sixty-one patients were admitted with a diagnosis of MS (1.03%) resulting in 86 NICU admissions with a diagnosis of MS ( Fig 1 ).


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*Admissions for plasmapheresis series (usually a total of 5 exchanges administered every other day) were considered as a single admission. **After excluding admissions for a planned intervention and adjusting the matching for mortality analysis.


Clinical characteristics in MS patients

Reasons for NICU admission and clinical characteristics of MS patients are summarized in Table 1 . Respiratory insufficiency due to pulmonary or non-pulmonary infection was the most common reason for NICU admission (34.4%). Thirteen (21.3%) patients were admitted for plasma exchange by refractory or complicated course of the disease. MS exacerbation with infectious complications (such as decubitus) was observed in 3 (4.9%) patients, another 3 patients were admitted for MS related drug administration (e.g. cyclophospahamide, baclofen pump implantation). Less frequent causes included natalizumab associated PML (n = 3), sepsis (n = 2), trauma and severe urinary infection (n = 1). As MS patients were matched to non-MS controls based on age and gender, we compared these two parameters between MS and general non-MS NICU populations. Doing so, MS patients were younger (48 (16.7) years vs. 62 (13.7), p<0.001) and more often female (65% vs. 42%, p<0.001).



Both the duration of MS history (r = 0.5, p<0.001) and the EDSS (r = 0.5, p<0.001) were associated with the SAPS II at NICU admission. The EDSS score was further associated with the length of NICU stay both for the initial admission (r = 0.32; p = 0.04), the overall length of NICU stay in case of re-admissions (r = 0.41, p = 0.008), and the number of NICU admissions (r = 0.41, p = 0.009). All associations remained significant when corrected for age, gender, the Charlson’s Comorbidity Index, and the reasons for NICU admission.

Comparisons between MS and matched cohorts

We identified 181 matched controls in total. Relative prevalences of NICU admission reasons in both populations are shown in Table 2 . MS patients had a higher relative prevalence of NICU admissions because of respiratory insufficiency, infections and therapeutic interventions. Admissions for cerebro-/cardiovascular and neuro-/psychiatric diseases, on the contrary, were less prevalent in MS patients compared to the controls. After adjusting for prior immunosuppressive treatment and comorbidities the admission rates for respiratory infections remained substantially higher in MS patients (OR = 7.86, 95% CI 3.02–20.42, p<0.001).



Mortality analyses

The median follow-up time for MS and matched controls was one year. In MS patients, mortality at NICU discharge, hospital discharge, 3 months, 6 months and 1 year following NICU admission was 11.5%, 11.5%, 11.5%, 13.1%, and 14.8%, respectively. The mortality rate during the observation period was 20%. In the age and gender stratified conditional regression analyses controlling for comorbidity index, MS patients had a 5.6-fold (95% CI 1.2–25.6, p = 0.03) increased risk of dying in the NICU compared to non-MS patients. When we stratified the cohorts by age in 10-year increments, the mortality remained higher in the MS cohort. In a multivariate model only the number of NICU re-admissions proved to be an independent predictor of NICU mortality (OR = 2.7, 95% CI 1.2–6.3, p = 0.02) in MS patients, while the Charlson’s Comorbidity Index, reasons for admission causes, SAPS II and prior immunosuppressive therapy were not ( Table 2 ). Including the variable indicating years of admission for each patient into the model did not influence the results.

To the best of our knowledge, this is the first hospital-based study focusing on NICU admissions and outcome of MS patients. Our results indicate that MS patients were admitted to the NICU mainly because of respiratory insufficiency related to infections. The need for medical interventions such as therapeutic plasma exchange, baclofen pump implantation was another common reason for NICU admission in this population, and is observed to a much lesser extent in the remaining ICU population. Infections of non-respiratory nature, taken separately, are more frequent in the MS population compared to demographically similar ICU population without MS, as well. Whatever the cause of admission, the MS population is younger on average than the overall ICU population, and has higher ICU, 1-year, as well as the study period mortality adjusted for comorbid state.

Prior work on critically ill patients with MS is sparse. Our findings are consistent with the report from Marrie et al. suggesting that infections constitute the most common cause for ICU admissions in MS patients [ 4 ]. In their population-based study they estimated 1.7-fold adjusted OR (95% CI 1.01–2.90) for the risk of admission for infection in the MS compared to the general population. Notably, a Swedish study reported an adjusted relative risk of 4.26 (95% CI 4.13–4.40) for MS patients vs. general population to be admitted to the hospital due to infections [ 11 ]. In their study on autoimmune diseases in the ICU Bernal-Macias et al. observed the main causes of admission to be infections and disease flare up (36% and 24%, respectively) [ 12 ]. In our cohort, the admissions for only respiratory infections were 7.86-fold (95% CI 3.02–20.42, p<0.001), and for other infections 3.71-fold (95% CI 1.29–10.68, p = 0.02) more frequent, as compared to the general ICU population. In this setting the finding has not been previously reported. Nevertheless, the literature suggests frequent occurrence of respiratory dysfunction in patients with MS, particularly in advanced stages of the disease [ 13 ].

Our cohort was demographically different from the entire ICU population having particularly younger age at admission, and consisting predominantly of women. The latter might be the reflection of the increasingly high female to male ratio in the MS population [ 14 , 15 ]. On the other hand, the literature provides several reports on male predominance among the ICU population [ 16 ], and mean age of 62.3±17.6 years [ 17 ], similar to the demographic pattern of our ICU.

The positive correlations between the MS duration and ICU scores allow us to assume that patients with MS become susceptible to more severe critical illness in later stages of the disease. The SAPS II score, which is designed to predict mortality in critically ill patients, correlated with longer MS duration, suggesting that patients admitted to the ICU with longer prior history of MS appear to be more severely ill, as assessed by SAPS II scores. A study at one large NICU found TISS-28 scores at admission to be independent predictors of unfavorable outcome in a neurocritical care population as well [ 18 ]. Interestingly, TISS-28 and SAPS II scores did not correlate with mortality in our MS cohort. Therefore we suppose that the instruments might be not enough accurate for the MS population. Whatever the case, validation studies are necessary.

A number of studies have reported higher mortality rates in MS patients compared to the general population [ 19 , 20 , 21 ]. In a population-based cohort study Lalmohamed et al. estimated a 3,5-fold increased all-cause mortality rate among patients with MS, compared with referent subjects, and particularly the highest mortality hazard ratio (HR) for infectious/respiratory-related deaths (HR 7.69, 95% CI 4.92–12.02) [ 21 ]. Furthermore, there are reports on increased mortality risk of ICU admitted patients in the subsequent years after discharge as compared with the general population [ 22 ]. In current study we estimated the mortality in the ICU admitted MS cohort to be higher than in the ICU population. In addition, we found an increased risk of readmissions in the MS cohort, which was an independent predictor of ICU mortality among them. Similarly, in their multicenter cohort study Metnitz and colleagues describe an ICU subpopulation with higher rate of readmissions, which had a fourfold risk of hospital mortality [ 23 ].

Our work has several limitations. As a retrospective cohort study it might be subject to various unknown confounders because of the lack of necessary adjustments. Hospital-based data derived from a single center, and the relatively small sample size, on the other hand, might carry a potential bias. However, the center is unique in its nature serving a large region of the country. We performed a matched analysis within the admissions of each year separately to minimize the impact of temporal changes in management and outcomes. We did not perform subgroup analyses within the MS cohort due to the limited sample size. Nevertheless, despite these limitations, our study provides clear evidence of unfavorable short- and long-term outcome of MS patients admitted to the ICU. Further larger multicenter studies are required to confirm our findings.


MS patients comprise a non-negligible subpopulation in the ICU with specific demographic and clinical characteristics that differ from the overall ICU population. Even though these patients make up a relatively small proportion in the ICU, but are prominent with their younger age at admission, higher mortality despite relatively less severe chronic status and higher re-admission rate. Therefore increased alertness of healthcare providers towards this population and reduction of potentially preventable conditions leading to severe illness such as respiratory infections is necessary.

Author Contributions

Conceived and designed the experiments: AK JS. Performed the experiments: AK. Analyzed the data: AK DJW. Wrote the paper: AK. Critically reviewed the manuscript: MD DJW HFN ET JS. Read and approved the final version: MD DJW GP PW VC HFN LH ET JS.

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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.

case study patient with multiple sclerosis

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


  • 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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    Background Over the course of multiple sclerosis (MS) several conditions may arise that require critical care. We aimed to study the reasons for admission and outcome in patients with MS admitted to a neuro-intensive care unit (NICU). Methods We retrospectively searched the electronic charts of a 9-bedded NICU in a tertiary hospital for patients with a diagnosis of multiple sclerosis (MS) from ...

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