Destructive course of multiple sclerosis under the mask of progressive multifocal leukoencephalopathy (case report)
DOI: 10.32364/2587-6821-2023-7-10-12
A.A. Ershova1, A.S. Kotov2
1Moscow Regional Veteran's Hospital, Solnechnogorsk, Russian Federation
2M.F. Vladimirskiy Moscow Regional Research and Clinical Institute, Moscow, Russian Federation
The article presents a retrospective case study concerning demyelinating disease in a 44-year-old female patient. The disease onset was in 2019 with minor clinical manifestations, however, it led to an exacerbation, clinically similar to acute disseminated encephalomyelitis, manifested by facial asymmetry, speech disorder, gait, and pelvic floor dysfunction. Diagnosis was significantly hindered, since the female patient herself was not sufficiently aware of the disease severity and was not interested in further treatment due to concomitant depressive disorder. The presented clinical case shows the importance of a multidisciplinary approach and the earliest possible diagnosis. Despite the fact that multiple sclerosis was suspected at the time of the disease's onset, diagnosis and treatment began only 2 years later, when persistent disabling disorders developed in female patient that required the use of a differential diagnostic sets with such nosologies as progressive multifocal leukoencephalopathy, acute disseminated encephalomyelitis, secondary encephalitis, levamisole-induced multifocal inflammatory leukoencephalopathy. The possibilities of laboratory and instrumental methods necessary for this disease verification were analyzed as part of the case study.
Keywords: multiple sclerosis, progressive multifocal leukoencephalopathy, acute disseminated encephalomyelitis, differential diagnosis, case study.
For citation: Ershova A.A., Kotov A.S. Destructive course of multiple sclerosis under the mask of progressive multifocal leukoencephalopathy (case report). Russian Medical Inquiry. 2023;7(10):687–692 (in Russ.). DOI: 10.32364/2587-6821-2023-7-10-12.
Background
Multiple sclerosis (MS) is now the best studied demyelinating disease of the central nervous system. MS was first described in 1835 by J. Cruvelier as a "spotted" or "islet" sclerosis. The priority for describing the clinical presentation belongs to J. Charcot (1868), who characterised the disease as a combination of spastic paraplegia, intention tremor, dysarthria, visual disturbances and nystagmus [1].
Approaches to the treatment of MS have changed over time. Currently, disease-modifying therapy (DMT), which alters the course of MS, reduces relapse rates and slows progression, is considered the most effective treatment. More recently, treatments for primary progressive MS have been developed [2].
In contrast to MS, research into progressive multifocal leukoencephalopathy (PML) began much later. PML was first described in 1958 by K.E. Astromet et al [3]. Data on this entity have accumulated over time. In 1971, B.L. Padgett et al. isolated a virus from the brain of a patient who had died of PML (John Cunningham). This virus was named after the first letters of his name (JC virus) [4]. The JC virus is a circular, double-stranded DNA virus that infects humans, usually those with severe immunodeficiency.
Despite tremendous advances in the diagnosis and treatment of demyelinating diseases in recent decades, many questions remain unanswered, as the following case report illustrates.
Case report
A 42-year-old woman presented to the Scientific Centre for Neurology for the first time in 2019. After medical history and neurological examination, the patient was referred for brain MRI (see Fig. 1).
Although a demyelinating disease was suspected at that time, no evidence of a hereditary family history was obtained, and the final diagnosis was not established because the patient refused to undergo further examination and lumbar puncture. According to her mother, she was depressed but had never seen a psychiatrist.
In 2020, the woman moved to Brazil to look for work. A year later, she returned to Russia with no signs of infection. After her return, her general condition deteriorated and she became depressed, which gradually led to her withdrawal from her usual physical activities.
In January 2022, over the course of a week, the patient gradually developed facial asymmetry, speech and gait disturbances, and pelvic floor dysfunction. She was referred to the neurological unit for patients with acute cerebrovascular events, where she remained from January 15, 2022 to January 28, 2022 with a preliminary diagnosis of a demyelinating disease of the CNS (MS? PML? Unspecific encephalitis?).
Brain CT scan (January 15, 2022): motion artefacts, no acute lesions in visible parts of the brain.
Brain CT angiography (January 18, 2022): motion artefacts, no lesions of intracranial and brachiocephalic vessels.
Contrast-enhanced brain CT (January 21, 2022): Isolated areas of glial density in both cerebral hemispheres. No areas of pathological contrast enhancement were seen.
Contrast-enhanced brain MRI (January 27, 2022, see Fig. 2).
In February 2022, the patient was admitted to the adult neurological unit of the M.F. Vladimirskiy Moscow Regional Research and Clinical Institute in serious condition.
Neurological status: conscious, gross cognitive and mental disorders (disorientation in his own personality, time, space, lack of disease recognition), delayed response to questions, does not follow instructions, adequate response to pain stimuli. No meningeal signs. Cranial nerves: symmetric slits, fixed gaze on hammer but does not follow it. No convergence. No nystagmus. Reliable assessment of movement, sensation and coordination was not possible due to the severity of the condition. Mixed hypertonus in extremities. Abnormal movements in the lower limbs (hyperkinesis?). Tendon and periosteal reflexes of the hands are increased (D>S), and knee reflexes (D>S), increased with the extension of the reflexogenic zones. Achilles reflexes D=S, active.
Contrast-enhanced brain MRI (see Fig. 3) showed no changes in the brain lesions compared to the non-contrast-enhanced brain MRI performed on January 27. 2022.
Complete blood count (February 02, 2022): no abnormalities.
Blood biochemistry (February 02, 2022): urea 10.9 mmol/L (reference range 2.9–7.5 mmol/l), no other abnormalities.
HbsAg, antibodies against HIV, HCV, and Treponema pallidum (February 02, 2022): negative.
The results of the cerebrospinal fluid (CSF) examination are listed in Table 1.
CSF analysis (February 18, 2022): no Listeria monocytogenes DNA was detected.
CSF PCR for Chlamydia trachomatis, Ureaplasma urealyticum, Candida albicans, Cytomegalovirus, Herpes simplex I, II, Mycoplasma hominis, Mycobacterium tuberculosis, EBV, Toxoplasma gondii, JC polyomavirus, and human polyomavirus (February 24, 2022): negative.
In view of the clinical and paraclinical findings, the patient underwent lumbar puncture (February 24, 2022) and the oligoclonal band pattern was classified as type 1.
The findings are therefore not typical of MS, but do not exclude this diagnosis. The absence of pleocytosis supports the non-infectious origin of the disease.
After a pulse of methylprednisolone (1000 mg for five consecutive days), the patient was discharged with improvement. The diagnosis was CNS demyelinating disease and psycho-organic syndrome. EDSS 8 points (G37.8).
The patient was readmitted to the neurological department of the M.F. Vladimirskiy Moscow Regional Research and Clinical Institute on April 19, 2022 with complaints of leg weakness, walking fatigue, and frequent urination.
Neurological status: Cranial nerves are intact. Limb movements are intact. Upper extremity muscle strength was 5 points on the right and 4 points on the left, and lower extremity muscle strength was 4 points. Tendon and periosteal reflexes of the hands are increased (D>S), and knee reflexes are increased with expansion of reflexogenic zones (D>S). Achilles reflexes are increased (D>S). Pathological reflexes: Trömner’s sign is positive. Mild ataxia on Romberg's test. Gait is atactic. EDSS 4.5 points. Brain MRI (29 February 2022): Given the signal characteristics, a progressive focal leukoencephalopathy cannot be ruled out (see Fig. 4). CSF analysis was performed (see Table).
Discussion
The differential diagnosis of MS, PML, secondary viral encephalitis, acute disseminated encephalomyelitis and levamisole-induced inflammatory leukoencephalopathy was discussed during the clinical discussion.
According to the 2017 McDonald criteria, evidence of spatial and temporal dissemination should be demonstrated to establish the diagnosis of MS. Spatial dissemination implies the presence of ≥1 symptomatic and/or asymptomatic T2 hyperintense foci (≥3 mm along the long axis) typical of MS [5]. Given the subcortical location of demyelinating lesions, brain MRI over time is required.
Spread over time can be determined in two ways [5]:
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detection of a new T2 hyperintense or paramagnetic accumulating focus compared with the previous MRI (however long ago);
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the simultaneous presence of contrast-enhancing and non-contrast-enhancing T2 hyperintense foci on any MR scan [5].
In this case report, contrast-enhanced neuroimaging showed no evidence of contrast enhancement, which did not confirm MS. Contrast-enhanced MRI of the cervical spine is required.
Detection of IgG oligoclonal bands is an additional method to determine distribution over time based on the 2017 McDonald criteria. This woman was found to have type 1, which does not confirm MS but occurs in 13% of MS patients [6].
However, in the presence of ≥2 lesions and objective clinical signs, no additional data are required to establish a diagnosis of MS based on the same criteria.
Given that the EDSS decreased from 8 points (at first admission) to 4.5 points (after 2 months), the course of MS is most likely remitting.
Given the MR signs and the pattern of exacerbations in January 2022, it is necessary to differentiate between MR and PML. In most patients, PML is a manifestation of acquired immunodeficiency. In other patients, the JC virus is activated in the context of immunosuppressive therapy. Brain MRI is probably the most sensitive diagnostic tool for the detection of PML, as it identifies lesions even in the absence of clinical signs ("asymptomatic PML") and/or detection of JC virus DNA in the cerebrospinal fluid. T2-weighted sequences (including T2-FLAIR) are a standard for PML screening, diagnosis and monitoring in clinical practice, and T2-FLAIR is particularly sensitive for detecting PML foci [7]. In addition, PML is characterized by a typical MRI pattern (milky way sign) and visualizes multiple punctate areas of high T2 signal surrounding the core of a new lesion [8]. In addition to MRI, the patient underwent CSF PCR to detect JC virus DNA. Given the negative PCR and HIV test results and the absence of immunomodulatory therapy, this diagnosis is unlikely.
Suspicion of viral encephalitis was ruled out because of normal cytosis on clinical CSF analysis and negative CSF PCR for infection.
Acute disseminated encephalomyelitis (ADEM) has been associated with infection, vaccination, MS, vasculitis and other unspecified causes. However, the relationship between triggering events and ADEM is controversial, and possible mechanisms include either molecular mimicry or direct inflammatory damage to the myelin sheath [9]. Clinical diagnostic criteria include symptoms such as fever. As this diagnostic sign is atypical for MS, it can confirm the diagnosis of ADEM [10]. However, in adults, this diagnostic sign is somewhat blurred due to age-related changes in the immune response. No fever was reported in this woman. CSF analysis showed no abnormalities, whereas pleocytosis and elevated protein levels are usually seen in ADEM [11]. Typical brain MRI findings include diffuse, poorly defined and large (>1-2 cm) T2 hyperintense lesions predominantly in the cerebral white matter. To rule out disease activity suggestive of another diagnosis (other than ADEM), some investigators have suggested reassessing patients with at least two additional MRI scans (3 and 9/12 months after clinical manifestation), as monophasic ADEM is not associated with the appearance of new foci 3 months after onset. Persistent hypointense foci of white matter lesions are not common in monophasic ADEM and suggest an alternative diagnosis such as MS [12].
Levamisole-induced leukoencephalopathy should also be considered as a differential diagnosis because of the similarity in clinical presentation and pattern of cerebral lesions. Studies have reported a prevalence of active or recent helminthiasis of 15%, which is much higher than most recently reported prevalences of helminthiasis (<2%) in urban areas of Brazil [13]. Given the patient's residence in helminth-endemic areas of Brazil, a history of helminth invasion and consequent levamisole therapy cannot be ruled out. In levamisole-induced leukoencephalopathy, brain MRI shows multifocal demyelinating lesions with no prevalence over time, as in this case report. The history taken after improvement did not support this notion. Furthermore, the lesions detected by brain MRI in 2019 (before travelling to Brazil) also contradict this assumption.
Conclusions
The lack of compliance and the presence of a severe depressive disorder make the diagnosis difficult in this patient. MS was suggested at the first request for medical care, but the diagnostic process was not completed. The disease history was 3 years. The level of disability increased significantly during this period.
Although MS is now a well-studied disease, the final diagnosis is often difficult, partly because of the lack of highly specific MS biomarkers. The search for genes that may determine predisposition to the disease continues. A human leukocyte antigen (HLA) region is known to be the strongest MS susceptibility locus, but genome-wide association studies have recently identified new susceptibility genes [14]. With the development of genome sequencing, more MS susceptibility loci are being discovered every day. Further advances in genetic diagnosis will allow diagnosis at an earlier stage, before the onset of clinically irreversible symptoms. Alternative diagnoses (PML, viral encephalitis, ADEM, levamisole-induced leukoencephalopathy) are unlikely in this patient.
Therefore, the patient remains under surveillance with a diagnosis of MS and receives appropriate treatment. Contrast-enhanced MRI of the brain and cervical spine every 6 months, re-analysis for oligo-clonal band patterns and second-line DMT to achieve disease control (with the consent of the woman) are planned.
About the authors:
Anna A. Ershova — neurologist of the Department of Neurology, Moscow Regional Veteran's Hospital; G/1, Zhilino, Moscow region, 141551, Russian Federation; ORCID iD 0000-0002-6846-7876.
Alexey S. Kotov — Dr. Sc. (Med.), Associate Professor, Leading Researcher of the Department of Neurology for Adults, M.F. Vladimirskiy Moscow Regional Research and Clinical Institute; 61/2, Shchepkin str., Moscow, 129110, Russian Federation; ORCID iD 0000-0003-2988-5706.
Contact information: Anna A. Ershova, e-mail: anna.yer.96@mail.ru.
Financial Disclosure: no authors have a financial or property interest in any material or method mentioned.
There is no conflict of interest.
Received 01.02.2023.
Revised 28.02.2023.
Accepted 24.03.2023.
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