Multiple Sclerosis and Related Disorders (2014) 3, 728–731

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Posterior reversible encephalopathy syndrome masquerading as progressive multifocal leukoencephalopathy in rituximab treated neuromyelitis optica Joseph R. Bergern, Janna Neltner, Charles Smith, Franca Cambi Departments of Neurology and Pathology, University of Kentucky College of Medicine, Lexington, KY 40536-0284, United States Received 9 May 2014; received in revised form 23 August 2014; accepted 25 August 2014




Progressive multifocal leukoencephalopathy; Posterior reversible encephalopathy syndrome; Rituximab; Neuromyelitis optica; JC virus

Both progressive multifocal leukoencephalopathy (PML) and posterior reversible encephalopathy syndrome (PRES) have been reported as complications of rituximab therapy. These disorders may appear indistinguishable on magnetic resonance imaging (MRI). We report on a 42 year old woman with neuromyelitis optica (NMO) of 10 years duration who developed extensive white matter disease affecting chiefly both parietal lobes 6 months after her first and only dose of rituximab. The MRI findings suggested the diagnosis of PML, but her history was more consistent with PRES. Ultimately, a brain biopsy was performed which was consistent with the diagnosis of PRES. PRES and PML may have overlapping symptomatology and be indistinguishable on MRI. An approach to distinguishing between these two disorders is addressed. & 2014 Published by Elsevier B.V.


The experience of progressive multifocal leukoencephalopathy (PML) with natalizumab has heightened awareness of this

n Correspondence to: Department of Neurology, Perelman School of Medicine, University of Pennsylvania School of Medicine, 3400 Spruce St., 3 W Gates, Philadelphia, PA 19104, United States. Tel.: +1 215 349 8304; fax: +1 215 349 5579. E-mail address: [email protected] (J.R. Berger). 2211-0348/& 2014 Published by Elsevier B.V.

disorder with other therapeutic agents. At least 5 drugs or monoclonal antibodies, including rituximab, an anti-CD20 monoclonal antibody, carry “black box” warnings for PML. Therefore, when new symptoms accompany white matter lesions on MRI in patients being treated with these agents, concern is rightfully raised about PML. We report a patient who developed new neurological symptoms and MRI abnormalities indistinguishable from PML 6 months after her initial treatment with rituximab for neuromyelitis optica (NMO). Our patient is illustrative of manifold issues confronting the clinician when a patient develops new neurolo-

PRES masquerading as PML gical symptoms and MRI findings consistent with PML after receiving a therapy that has been linked to the disorder. PML can mimic PRES radiographically. Clinically clues that suggested PRES in our patient were the rather acute onset of symptoms, the associated headache and confusion, and visual complaints that could not be ascribed to a visual field defect. All of these features are observed with PRES (Fugate et al., 2010); however, none excludes PML (Berger, 2014). A negative CSF PCR for JCV does not fully exclude the diagnosis of PML, but is quite unlikely in the face of extensive disease when performed with ultrasensitive PCR techniques as the sensitivity of the test exceeds 95% (Berger, 2014). Similarly, seronegativity for JCV antibody should argue against the diagnosis of PML, as the experience with natalizumabassociated PML indicates that newer generation ELISA studies are rarely, if ever, negative in the months before diagnosis (Lee et al., 2013). Importantly, the risk of PML developing with therapeutic agents varies greatly. There is a unique association between PML and the administration of natalizumab and efalizumab, a monoclonal antibody used in the treatment of psoriasis that has been removed from the market (Zaheer and Berger, 2012). The risk of PML with rituximab is several orders of magnitude lower than with natalizumab and has almost always occurred in the context of disorders that already increase the likelihood of developing PML (Zaheer and Berger, 2012).


Case report

This 42 year old white female with a past medical history of Sjogren's syndrome, chronic liver disease, and Felty's syndrome (rheumatoid arthritis, splenomegaly and neutropenia) developed left optic neuritis in 2004. She was diagnosed with probable multiple sclerosis and started on interferon β1b subcutaneously every other day. The therapy was discontinued the following year due to increasing arthralgias. In 2006, following recurrent episodes of optic neuritis, a diagnosis of NMO was considered. That diagnosis was

729 confirmed in January 2008, when new myelopathic features were associated with hyperintense lesions within the parenchyma of the spinal cord from C4-T1 and T3-T11 on FLAIR and T2 weighted MRIs of cervical and thoracic spine and serological testing showed positive NMO antibodies. CSF examination revealed 206 WBCs/cu mm (88% polymorphonuclear cells), myelin basic protein 48 ng/mL, and no oligoclonal bands (OCBs). She improved with parenteral corticosteroids. Despite mycophenolate mofetil and azathioprine therapy, optic neuritis recurred in the ensuing years. Nonetheless, she remained independent in all activities of daily living and retained useful sight in her right eye. In August 2013, she received her first dose of rituximab and was scheduled to receive a course of rituximab every 6 months thereafter. On January 14, 2014, she developed left hand and foot tingling and 2 weeks later new onset headache, confusion, worsening vision, and severe imbalance. Her boyfriend and mother reported that she had a difficult time finding food on her plate and could not get a fork to her mouth. Physical examination showed a depressed, anxious female who was crying inconsolably. She had a blood pressure of 124/78 and pulse of 78. She was alert and appropriately oriented, but slow to respond to commands and questions. Pupils were 5 mm with a left Marcus Gunn pupil. There was no light perception in the left eye and at least 20/200 in the right. Both optic disks were chalky white. The cranial nerves were otherwise normal. Profound weakness of the left leg was noted and reflexes were 1+ to 2+ throughout with a right Babinski. There was a questionable sensory loss at T2. Cranial MRI revealed extensive confluent white matter lesions of both parietal lobes, greater on the right side, that were hyperintense on fluid attenuated inversion recovery (FLAIR) and T2 weighted image (T2WI) sequences and hypointense on T1WI. There was no contrast enhancement or mass effect demonstrated. These lesions were not seen on a cranial MRI from August 26, 2013, which showed only a small hyperintense signal abnormality on T2WI and FLAIR adjacent to the left lateral ventricle. By February 2, 2014, she had developed increased weakness in all four extremities but retained useful movement of

Figure 1 MRI of the brain. (A) FLAIR image shows extensive involvement of the posterior regions of both hemispheres sparing the gray matter and unassociated with mass effect. (B) T1WI with contrast showing bilateral signal hypointensities and no contrast enhancement.


J.R. Berger et al.

the right arm. No facial weakness was apparent and her vision had not changed. A C5 sensory level to pinprick was

detected. Her affect was pseudobulbar and she reported visual hallucinations. CSF examination was performed and showed normal opening pressure, clear colorless fluid, 2 WBCs, protein 48 mg/dL, and no OCBs. CSF PCR for HSV and JCV were negative. Flow cytometry and cytology were negative. JCV serology was positive. An MRI from February 10, 2014, showed slight increase in the size of the lesions previously observed (Figure 1). On February 15, 2014, a brain biopsy was performed of the right parietal lobe white and gray matter. The biopsy revealed some minimally reactive endothelial cells, with focal lipohyalinosis and perivascular pigment laden macrophages, (Figure 2) but was otherwise unremarkable. There was no inflammation, demyelination, bizarre astrocytes, or enlarged oligodendroglial nuclei to suggest either NMO or PML. Immunohistochemistry for JC virus was also negative. The final diagnosis was compatible with posterior reversible encephalopathy syndrome (PRES). Methotrexate 15 mg weekly was initiated in place of rituximab for her NMO. In the ensuing months, her behavioral problems resolved and she demonstrated significant improvement in her extremity strength. By June 14, 2014, her right arm and leg strength was normal, left upper extremity strength was 3/5 distally and 4/5 proximally and left lower extremity was 3/5 proximally and 4/5 distally.


Figure 2 Excisional biopsy of the parietal cortex. (A) Some focal small vessel changes, including pigment laden macrophages and lipohyalinosis (H&E, 100  ). (B) The lack of demyelination within the biopsy. (Luxol fast blue, 100  ).


There have been at least 7 instances of PRES associated with NMO (Fugate et al., 2010; Sanchez-Carteyron et al., 2010; Magana et al., 2009) and a handful of case reports of rituximab associated PRES (Fugate et al., 2010; Sanchez-Carteyron et al., 2010; Haefner et al., 2007; Kur and Esdaile, 2006; Mavragani et al., 2004; Siddiqi, 2011). With respect to the

Table 1 Magnetic Resonance Imaging Features of PML vs PRES. The imaging features are largely overlapping, emphasizing the importance of the clinical findings in differentiating these two conditions.

T2-weighted hyperintensity T1-weighted hypointensity Mass effect gadolinium enhancement Diffusion restriction Subcortical WM location Parieto-occipital Frontal Temporal Cerebellum Brainstem Symmetric lesions Unilateral lesions Gray-matter sparing Associated autoimmune disease a

PML(Bergui et al., 2004; Post et al., 1999; Yousry et al., 2012; Berger et al., 1998)

PRES(Fugate et al., 2010)

Present, patchy or confluent May be present 10%; usually late or in IRIS 2.2–15% (41% natalizumab PML) Rim of restriction in some cases

Present, patchy or confluent Usually present Usually absent 5–17% 9–29%a

93% (52% occipital) 76% 33% 57% 89% Rare 8.3% (HIV PML); 44.8% (natalizumab PML) 44% 90%

94% 77% 64% 53% 27% 52% 1%

Excludes sepsis and renal failure.

90% 45%

PRES masquerading as PML association of PRES and aquaporin 4 antibody, Magana et al. (2009) reported 5 women with NMO who developed PRES. None had been treated with rituximab. In on small series, extensive brain lesions with NMO were attributable to PRES in 6.25% (Cheng et al., 2013). Kim et al. (2011) reported on reversible clinical and MRI features in 8 of 15 patients with NMO that resembled either PRES or acute disseminated encephalomyelitis; however, as the disorder recurred in seven of eight patients, they were reluctant to attribute it to either and believed that the condition was part of NMO itself. Interestingly, our patient developed symptomatic spinal cord disease during the course of PRES. The spinal cord symptoms were unremitting and despite the bland CSF, we believe that it was likely the consequence of an NMO relapse rather than PRES, though the latter has occurred in association with radiographic abnormalities of the spinal cord (Matiello et al., 2010). Water flux impairment due to the aquaporin 4 autoimmunity was suggested as a potential predisposing cause of PRES (Mavragani et al., 2004) (Table 1). The attribution of PRES to rituximab is tenuous as both the underlying conditions, e.g., systemic lupus erythematosus (Martinez-Martinez and Abud-Mendoza, 2012), and the other treatments employed for these disorders may contribute to the development of PRES. The association of rituximab and PRES has occurred with SLE (Kur and Esdaile, 2006; Mavragani et al., 2004), diffuse large B cell lymphoma (Haefner et al., 2007; Siddiqi, 2011), and neuromyelitis optica (Fugate et al., 2010; Sanchez-Carteyron et al., 2010). In one large series of 120 cases of PRES, 45% had an underlying autoimmune disease and the authors suggest that this likely contributes to the underlying endothelial dysfunction that leads to PRES (Fugate et al., 2010). In at least 2 cases, PRES developed within one day of rituximab infusion (Sanchez-Carteyron et al., 2010; Mavragani et al., 2004). In one instance, the blood pressure was normal (Sanchez-Carteyron et al., 2010) and in the other elevated to 210/120 (Mavragani et al., 2004). One cannot rely on radiographic imaging to establish the diagnosis of PML; confirmatory evidence must include demonstration of JC virus in the CSF or the brain (Berger et al., 2013). Careful history and physical examination are extremely helpful in suggesting the correct diagnosis. Diagnosing PML in patients treated with rituximab for neurological disorders should be made very cautiously as rituximab-associated PML is a disorder largely confined to persons with underlying diseases that predispose to PML.

Conflict of interest/role of funding sources The authors report no conflict of interests with respect to this case description. No external funding was used for this report.

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Posterior reversible encephalopathy syndrome masquerading as progressive multifocal leukoencephalopathy in rituximab treated neuromyelitis optica.

Both progressive multifocal leukoencephalopathy (PML) and posterior reversible encephalopathy syndrome (PRES) have been reported as complications of r...
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