A 32-year-old female with relapsing remitting multiple sclerosis (MS) diagnosed 6 years previously presents at hospital in November 2015. She reports difficulty walking, which she says has worsened steadily over the past 3 weeks. She explains that this has been accompanied by twitching facial muscles, and “strange sensations” all over her body.
Clinical assessment identifies mild weakness and sensory changes on the left side of her body, along with mild truncal ataxia and exaggerated deep tendon reflexes affecting both sides of her body. Brain magnetic resonance imaging (MRI) shows minimal new changes (Figure 1A, 1D, 1G), and her lymphocyte count is 400 cells/ mL.
Her treatment history began at the time of her MS diagnosis with interferon-beta-1b. She was switched to natalizumab less than a year later in response to numerous relapses and an increasing lesion load on MRI. About one and a half years later, her serum tested positive for John Cunningham polyoma virus (JCV) antibodies, with an index of 0.57. Because of this, in addition to her plan to relocate to an area where natalizumab is unavailable, the patient was switched to fingolimod. Her disease remained stable for the following several years.
She explains that about 6 months before her current symptoms developed, she began having sensory changes, including mild tingling in her extremities. At that time, she says she also started to experience increased urinary frequency, especially at night, and urinary urgency with occasional incontinence. Her medical records show an Expanded Disability Status Scale (EDSS) score of 1.5, no new lesions on MRI, and a lymphocyte count of 700 cells/mL.
Her symptoms suggest a probable relapse, and the patient is treated with 5 sessions of 1 g intravenous (IV) methylprednisolone (MP). When she returns for follow-up one month later, her mobility has worsened and she is found to have had a generalized tonic clonic seizure. She is started on carbamazepine.
At her next appointment, her husband reports that she is experiencing disrupted sleep. She is also uncharacteristically irritable, even with their young daughter. He is also concerned because her speech is becoming difficult to understand, and her memory seems to be deteriorating.
Examination findings include:
- Marked cognitive impairment, with short attention span and significant working memory deficit
- Mini-mental state examination (MMSE) score of 25
- Mild motor dysphasia and dysarthria
- Severe asymmetric bilateral pyramidal weakness
- MRC scale score 4/5; worse in the left side with truncal ataxia
- EDSS of 4.5
This evidence of subacute progressive focal neurological deficits, in addition to her previous seizure and current behavioral and cognitive changes, suggests a diagnosis of progressive multifocal leukoencephalopathy (PML). Although her MRI findings are not characteristic of PML, the patient’s fingolimod is discontinued in January 2016. One month later, despite some debate with the attending neuroradiologists, clinicians order analysis of the patient’s CSF. PCR for JCV is positive with 11 copies/mL.
Treatment and Outcome
On confirmation of PML, the patient begins treatment with mirtazepine 30 mg twice daily and mefloquine 250 mg once weekly. This fails to generate any improvement in symptoms. Almost 5 weeks after fingolimod treatment has been stopped, the patient develops acute left-sided paralysis and she is no longer able to walk without assistance. She is readmitted to the hospital.
Her EDSS on admission is 6.5. Brain MRI reveals several, even mass-like new enhancing lesions. These findings suggest that she has had a severe MS rebound (Figure 1B, 1E, 1H, 1J). Mefloquine is stopped and mirtazepine dose is reduced to 30 mg at night. She receives 2 consecutive courses of 5 sessions of 1 g IV MP followed 2 weeks later by a course of 30 g daily for 5 days of IV immunoglobulins (IVIG). Further deterioration is noted. In April 2016, MRI reveals even more new enhancing lesions sparing cortical areas (Figure 1C, 1F, 1I, 1K), and her lymphocyte count is 1,200 cells/mL.
These developments lead clinicians to suspect she has immune reconstitution inflammatory syndrome (IRIS). She receives a further 5 sessions of IV methylprednisone, followed by another course of IVIG. At this point, she begins to stabilize clinically and slowly show some improvement in symptoms.
By August 2016, she demonstrates significant improvements and she is started on rituximab. Her mobility improves and her EDSS improves to 5. She continues to improve and show no signs of relapse. In August 2018, she is given her fifth dose of rituximab; her EDSS is 4.
Progressive multifocal leukoencephalopathy (PML), a serious opportunistic infectious disease, has increased in incidence in multiple sclerosis (MS) patients since disease modifying drugs were introduced.
Clinicians reporting this case1 write that MRI plays an important role in differentiating MS from PML.2,3 They caution that PML can present with a variety of atypical changes on MRI, such as small, non-confluent and enhancing lesions4,5 or minimal brain changes6 that can easily be mistakenly attributed to MS.
Such misinterpretations can result in delayed diagnosis and inappropriate and potentially harmful treatment with high dose steroids.7 They add that in PML, small and enhancing lesions may occur early in the disease and have been associated with a better outcome.8
In this case, clinicians note that MRI evidence of new involvement of periventricular white matter (also more characteristic of new MS lesions), basal ganglia, and pons caused their initial suspicion of PML to be strongly questioned.
While MRI is a key diagnostic criterion for PML, it is not required for diagnosis. The American Academy of Neurology diagnostic criteria for PML include typical clinical presentation and characteristic MRI findings along with a positive JCV PCR in the CSF.9 In the absence of either of these latter features, the diagnosis is labeled probable PML, which is managed in the same way as definite PML at the discretion of the attending neurologist.
Typical clinical features of PML10:
- dysphasia or dysarthria
- progressive weakness
The patient reported here had subacute progressive cognitive dysfunction associated with dysarthria and hemiparesis, marked by non-remitting symptoms progressing over many weeks,11 and seizures which, while rare in MS, affect up to 18% of patients with PML.12
PML associated with fingolimod is rare, with an estimated risk of 0.069 per 1,000.13 In suspected PML, diagnosis should be confirmed by CSF analysis for JCV, authors noted. JCV PCR is a rapid, reproducible, and highly specific test (95%-100% specificity; 70% sensitivity.14,15 As in this patient’s case, copy count may be low early stages of the disease, and may predict a better prognosis.16
Natalizumab-associated PML is associated with significant morbidity and a mortality rate of 20% or more.17 Because there are no specific treatments for PML, outcome is largely dependent on early diagnosis based on awareness and clinical vigilance – that is, more frequent serum JCV antibody assessment, brain MRI, and earlier CSF analysis for JCV PCR for high-risk patients.18
Case authors reference numerous papers suggesting that the effectiveness of treatments for PML such as mirtazepine and mefloquine, among others, is unclear, while maraviroc and interleukin-7 have shown promising but inclusive results.
They add that they suspect that this patient had PML-IRIS, given her significant clinical deterioration accompanied by excessive new MRI enhancing lesions after 5 weeks of withdrawal from fingolimod.
This is typically linked with prior use of natalizumab.19 The case authors cite clinicians reporting the one other case of PML-IRIS related to fingolimod alone,20 who suggested its rarity may be due to the relatively slow immune reconstitution that follows fingolimod withdrawal compared with the rapid immune system recovery after the urgent removal of natalizumab.
Clinicians concluded that in patients presenting with typical clinical symptoms of PML without characteristic MRI findings, JCV PCR should be performed to avoid a potential delay in diagnosis, with probable detrimental effect to the patient.
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