Диагностика множественных склерозов: из материалов Конференции Национального общества по проблемам множественных склерозов.

Case Presentation

In June 2023, a 28-year-old Black woman with a four-year history of unspecified mood disorder, migraine without aura, type 2 diabetes, obesity, hereditary factor VIII deficiency with recurrent unprovoked deep venous thrombosis (DVT)/pulmonary embolism (PE), and hidradenitis suppurativa presented to an outside facility with neurologic symptoms. Her psychiatric diagnosis was based on 4 years of labile mood culminating in a manic episode with psychosis and 3 previous suicide attempts. On presentation, she reported bilateral leg, right hand, and tongue paresthesia and numbness that developed over several days. Neurologic examination was remarkable for hyperalgesia to pinprick and temperature sensation in the right hemibody below the neck, including upper and lower extremities and the trunk. She also complained of dyspnea and pleuritic chest pain and was noted to have sinus tachycardia. She was found to have a recurrent PE on CT angiogram of the chest and was placed on anticoagulation therapy with rivaroxaban. Two months before, she had a presumed self-limited viral illness characterized by fevers, chills, nausea, and nonintractable, nonbilious emesis lasting 7–10 days. She tested negative for common respiratory viruses including coronavirus disease 2019 (COVID-19). The clinical timeline is outlined in Figure 1 .

Clinical Timeline

Key events in the diagnosis and treatment of a 28-year-old woman with multimorbidity including mood disorder who was ultimately diagnosed with multiple sclerosis. Time is represented on the “x” axis (not to scale) while diagnostic events are shown above the axis and therapeutic events shown below. The relative overt inflammatory activity of the patient's disease is represented in the color-coded graph; red: more active; yellow: quiescent. DMT = disease-modifying therapy; MS = multiple sclerosis; OCB = oligoclonal band; PE = pulmonary embolism.

Brain MRI revealed an oblong, faintly incomplete ring-enhancing, left frontal periventricular T2-hyperintense lesion (estimated to be a little over 2 cm in diameter; Figure 2 ), a nonenhancing inferior temporal periventricular lesion, and an enhancing punctate inferior temporal lesion. Spinal MRI showed an equivocal short-segment lesion at the right dorsolateral C5-C6 level that was not visualized on sagittal sequences ( Figure 3A ), raising concern for artifact. CSF analyses revealed an elevated white blood cell count (WBC) of 21 cells/mm 3 (62% lymphocytes, 22% monocytes), red blood cell count (RBC) of 3 cells/mm 3 , glucose of 136 mg/dL, >2 CSF-restricted oligoclonal bands, and elevated IgG index of 1.6. She also underwent a CT scan of the chest, which did not show features of sarcoidosis or malignancy. In follow-up at the multiple sclerosis (MS) clinic 1 month after presentation, her neurologic examination demonstrated a flat affect with vague recollection of her medical history, decreased light touch and pinprick in the right more than the left lower extremity, mild intention tremor in both arms, and mild truncal ataxia. Extensive workup for mimics of MS was completed including negative aquaporin-4 and myelin oligodendrocyte glycoprotein (MOG)-IgG antibodies, as well as negative serology testing pertinent to rheumatologic diseases (systemic lupus erythematosus, antiphospholipid antibody syndrome, rheumatoid arthritis, Sjögren syndrome), along with negative tests for HIV, Toxoplasma, syphilis, Lyme disease, and tuberculosis. Optical coherence tomography was normal. Owing to the equivocal spinal cord lesion, relatively nonspecific appearance of some of her brain lesions, and vague remote history, serial clinical and MRI observations were recommended before confirming a diagnosis of MS and starting disease-modifying therapy (DMT).

MRI Brain Findings at Initial Presentation

(A) Axial T2-FLAIR sequences showing T2-hyperintense lesions in the left frontal periventricular region and in the inferior left temporal subcortical white matter (one of which was enhancing, not shown). (B) The dominant left frontal periventricular lesion is estimated to measure 2.15 cm in longest diameter, with T1 postgadolinium sequences showing faint incomplete ring enhancement within the lesion (B, arrows).

MRI Spine Findings at Initial Presentation and Follow-Up

(A) T2-weighted axial sequences showing an equivocal lesion at C5-C6 in the right dorsolateral intramedullary cord, which was not readily apparent on sagittal short tau inversion recovery (STIR) sequences at the time of initial presentation. (B) After presenting with new or recrudescent symptoms suggestive of cervical origin, a more clearly defined short-segment T2-hyperintense lesion is seen dorsolaterally at C5-C6 on the right.

In October 2023, the patient developed numbness, tingling, and a cramping sensation in her bilateral upper and lower extremities. She described a squeezing sensation across the chest over 3–5 days concerning for either new spinal cord activity or recrudescence of symptoms related to an old spinal cord lesion (pseudorelapse). Updated MRI scans demonstrated resolution of enhancement of the left frontal brain lesion, no new brain lesions, and a more compelling T2-hyperintense, short-segment lesion in the right dorsolateral spinal cord at C5-C6 ( Figure 3B ). Given the more apparent spinal cord lesion together with exclusion of alternative diagnoses, it was determined that she had relapsing MS. Due to a variety of factors (discussed further), she was started on ublituximab in February 2024. She had a minor infusion reaction without receiving premedication with methylprednisolone with the first ublituximab induction dose. With the second induction dose, she received methylprednisolone 125 mg, in addition to diphenhydramine and acetaminophen, and noted worsening of her mood with pervasive suicidal ideation in the subsequent month. Under the care of psychiatry, olanzapine was started resulting in improvement in her mood. She received a lower dose of methylprednisolone for premedication with future ublituximab infusions to prevent further exacerbations of her mood disorder.

From an MS disease activity perspective, she has remained clinically and radiologically stable for approximately 6 months after starting ublituximab. She noted transient worsening of leg spasticity and dysesthesias in the context of a hidradenitis suppurativa flare, which was treated with oral antibiotics and later improved. This was consistent with an MS pseudorelapse.

Diagnostic Considerations and Treatment Decisions

Although a pressing diagnostic concern in this case was for demyelinating CNS lesions due to MS, there were a few factors on presentation that underscored consideration of differential diagnoses. First, the neuroimaging findings including a dominant left frontal periventricular lesion measuring just over 2 cm in diameter could be considered borderline tumefactive. 1 The differential diagnosis for tumefactive MS brain lesions is broad and includes other CNS autoimmune conditions such as neuromyelitis optica spectrum disorder (NMOSD), MOG antibody-associated disease (MOGAD), neurosarcoidosis, vasculitis, and other systemic inflammatory conditions affecting the brain such as lupus cerebritis. 2 , 3 Primary and secondary CNS neoplasms are on the differential but were not further pursued in this case because of lack of mass effect, lack of associated edema, and improvement in enhancement on follow-up imaging all being inconsistent with tumor in addition to the lesion's moderate size. Moreover, her MRI scans did not demonstrate lesions in typical areas consistent with metastatic disease, and body CT did not demonstrate an obvious primary source of cancer. Opportunistic CNS infections and brain abscess were less likely because of the patient's immunocompetent status and lack of pertinent exposures or risks and also because of MRI scans showing incomplete ring enhancement with minimal edema. 2 The patient was hypercoagulable due to constitutive factor VIII elevation, 4 which may have predisposed her to cerebral venous thrombosis or DVT accompanied by paradoxical embolism causing ischemic stroke. Both venous infarction and subacute ischemic stroke can produce blood-brain barrier disruption and enhancement, although the subacute symptom onset and lack of conformity of MRI lesions to specific vascular territories in this case rendered vascular causes less likely. 2

At the time of initial assessment, there was clinical concern for cervical myelitis but spinal MRI was inconclusive. It was not until the patient presented with subsequent symptoms localizing to the spinal cord where reimaging showed a short-segment cervical cord lesion more clearly. Given the resemblance of these symptoms to her index attack and the concern for a possible cervical spinal cord lesion on her first set of MRI scans, it is not entirely clear whether her second event represented recrudescence from a previous lesion or a genuinely new site of spinal cord inflammation. Nevertheless, the patient's course over time along with negative workup for mimics and the presence of CSF-restricted OCBs helped to collectively establish the diagnosis of MS. 5 Although the sensitivity of CSF-restricted OCBs in the diagnosis of MS is low, the presence of OCBs has a specificity of approximately 90% in patients presenting with demyelinating disease who fulfill criteria for dissemination in space. 6 This can help exclude mimics such as NMOSD and MOGAD, which have a comparably lower rate of CSF-restricted OCBs (<15%). 7

A second series of factors that affected both diagnosis and treatment in this case relates to psychiatric comorbidity. The presence of unspecified mood disorder (resembling either schizoaffective or bipolar disorder), which featured both negative cognitive symptoms and positive psychotic symptoms at various time points during the patient's illness, made it exceedingly difficult for her to recount a history of any typical demyelinating events. In addition, she did not have access to a supportive caregiver for collateral history or to support adherence to prescribed treatments. Although this patient's psychiatric diagnosis may be independent from MS, it is generally worth considering whether ongoing neuropsychiatric symptoms are due to MS, primary psychiatric disorder, or both. Administrative health data from Canada have shown that the incidence rate of bipolar disorder in individuals with MS is about double that of controls. 8 , 9 In addition, there are increased rates of depression, anxiety, bipolar, and psychotic disorders up to 5 years before typical MS symptom onset, which may be part of the MS prodrome . 10 With the causal relationship between MS and psychiatric disorders difficult to discern in most patients, their co-occurrence should not always be considered coincidental. For example, mania can rarely be a presenting symptom of a focal demyelinating attack in MS. 11 , 12 This may lead to erroneous bipolar disorder diagnoses in some cases because brain MRI scans may not be routinely obtained, particularly in young adults with otherwise typical psychiatric presentations.

In this patient, along with being of Black race, a documented risk factor of greater MS disease burden, 13 the presence of mood disorder is an independent risk factor of poorer outcomes in MS. 14 Having a mood or anxiety disorder increases the risk of a higher Expanded Disability Status Scale score at 10 years when adjusted for disease duration, sex, socioeconomic status, and DMT use. 14 This patient also had negative prognostic factors including comorbidities (e.g., obesity), spinal cord involvement, incomplete recovery from attacks, and gadolinium-enhancing lesions on MRI brain. 15 Based on these collective factors, we recommended ublituximab, a high-efficacy DMT. Ublituximab can be administered intravenously every 6 months and may have minor advantages over other infused anti-CD20 therapies (e.g., ocrelizumab and rituximab). The infusion time of ublituximab is shorter and theoretically may be associated with a lower rate of infusion reactions based on relatively greater antibody-dependent cellular cytotoxicity vs complement-dependent cytotoxicity, although these benefits have not been established in long-term studies or head-to-head studies with other infused anti-CD20 therapies. 16 This is of particular relevance in this case, because of the desire to minimize the predosing of steroids so as to not inadvertently worsen this patient's mood. Corticosteroids may result in various neuropsychiatric alterations including depressed mood, anxiety, mania, psychosis, delirium, and suicidality. 17 This patient experienced a decline in her mood and increase in suicidal ideation in the context of 125-mg methylprednisolone use, which required tailoring of her premedication regimen with reduction of steroids going forward. This may similarly apply to people with comorbidities that may be exacerbated in other ways by corticosteroids including those with diabetes, poorly controlled hypertension, osteoporosis, and recurrent infections. 18 , 19 To this effect, reported data suggest that a subcutaneous (SC) formulation of ocrelizumab administered every 6 months is noninferior to the intravenously administered form and may require only low-dose oral corticosteroid premedication. 20 This may be a future option for patients who require anti-CD20 therapy but do not tolerate frequent SC dosing (as with ofatumumab) or IV corticosteroid premedication.

Based on the patient's history of suicidality, she requested avoiding self-administered (oral or injectable) therapies. Owing to concerns for adherence, natalizumab was also not a good DMT choice in this case because of the requirement for monthly infusions and risk of rebound with nonadherence. Currently on a population level, there is controversy about whether starting high-efficacy DMT at the time of MS diagnosis may be superior to the traditional approach of an escalation paradigm for preventing future disability. 21 As demonstrated in this case, taking into consideration individual prognostic factors, comorbidities, and patient preferences is of paramount importance.

Certain limitations in this case are worth discussing. First, we did not have access to documentation from the time of the patient's psychiatric diagnoses. It would have been helpful to know whether her psychiatric presentation was in any way atypical to suggest the possibility of MS onset years earlier. Second, because we have followed this patient for approximately 1 year (with only approximately 6 months on DMT), it is difficult to predict long-term tolerance and response to therapy. Despite this, breakthrough disease and severe adverse events are uncommon with anti-CD20 therapies, with the main concern being an increased risk of infections particularly with long-term exposure and hypogammaglobulinemia. 16 , 22 Finally, this case highlights the limited specificity and technical limitations associated with brain and spinal cord MRI with sequences used in routine clinical practice. Ongoing validation of MRI biomarkers highly specific for MS lesions including the central vein sign and paramagnetic rim lesions and novel, more sensitive MRI sequences to overcome inherent limitations may be instrumental to help facilitate earlier MS diagnosis in many people. 23 , 24

Conclusions

This case report illustrates unique challenges that can arise in the diagnosis and management of MS when multiple complicating factors coalesce. Although the person in this case presented with typical demyelinating symptoms, the presence of (1) atypical imaging findings, (2) systemic comorbidities, and (3) mental health comorbidity contributed to a broader differential diagnosis and required longitudinal follow-up to clarify diagnosis. Once the diagnosis became clear, the treatment plan included starting a high-efficacy DMT with less frequent administration when considering individual patient circumstances and personal preferences. This case highlights differential diagnostic considerations and the importance of individualized treatment decision-making for people with MS.