Posterior reversible encephalopathy syndrome in neuromyelitis optica spectrum disorders

Posterior reversible encephalopathy syndrome (PRES) is a neurologic disorder with neuroimaging features of reversible subcortical vasogenic edema, typically without infarction, that usually symmetrically and preferentially affects posterior head regions. Clinical manifestations include encephalopathy, seizures, headache, and visual symptoms.^1–3 PRES is precipitated by hypertensive crises such as eclampsia, and by immunosuppressive agents.^4–7 It has not been previously associated with neuromyelitis optica spectrum disorders (NMOSDs).

Neuromyelitis optica (NMO) is an idiopathic, inflammatory CNS demyelinating disease characterized by a predilection for the spinal cord and optic nerves, although symptomatic brain lesions are known to occur in children.⁸ Typically, spinal cord lesions are longer than three vertebral segments at the time of acute myelitis attacks, brain lesions are absent at the onset of disease, and aquaporin-4 (AQP4)-specific immunoglobulin G (IgG) (NMO-IgG) autoantibody is positive.^9–11 NMOSDs include limited or inaugural forms of NMO, such as recurrent longitudinally extensive transverse myelitis (LETM) or recurrent optic neuritis (ON) in NMO-IgG seropositive patients.^12–14

NMO-IgG binds to the extracellular domain of AQP4, the dominant water channel in the CNS that controls bidirectional water flux in the brain.¹⁵

We and others have previously reported that brain MRI lesions may develop in patients with NMO. These lesions are most commonly nonspecific and asymptomatic subcortical white matter T2 hyperintensities, but occasionally are detected in periventricular, diencephalic, or brainstem locations, and may be symptomatic.^16–19 We describe clinical and radiographic findings diagnostic of PRES in patients with NMOSD that implicate a role for AQP4 channelopathy in the pathogenesis of some cases of PRES.

METHODS

RESULTS

Clinical presentation.

All patients experienced confusion or impaired consciousness. Coma developed in three. Three patients had visual abnormalities, including nystagmus and diplopia (n = 1), cortical blindness (n = 1), and diplopia alone (n = 1). The encephalopathic syndrome resolved completely in all patients, with a median recovery time of 4 days (range 1 to 7 days). None experienced seizures. Blood pressure recordings were not available for one of the patients at the onset of PRES who was evaluated at another institution and subsequently referred to Mayo Clinic for evaluation. Patient 3 had a blood pressure of 220/140 mm Hg, potentially contributing to PRES (table). Three patients were treated for the PRES episode: one patient received five sessions of PLEX, one received IVMP with concurrent withholding of midodrine pressor therapy administered for orthostatic hypotension, and one received IVIg and IVMP.

Laboratory investigations.

NMOSD group.

NMO-IgG was detected by indirect immunofluorescence in all five patients (median titer 7,680; range 120 to 7,680). CSF analyses at the time of PRES revealed lymphocytic pleocytosis in all four with available data (median leukocytes 23; range 4 to 69) and elevated protein in two patients (median 80 mg/dL; range 76 to 84; normal reference 14–45 mg/dL). Oligoclonal bands were detected in none.

Unselected PRES group.

Thirteen of 14 patients in the previously ascertained PRES cohort were NMO-IgG seronegative. The 14th seropositive patient was reported in the original series as a patient with NMO and PRES, and in our NMOSD series is patient 3.²⁰ Thus, none of the patients who had PRES but who did not have an NMOSD were seropositive for NMO-IgG.

Neuroimaging.

MRI studies, performed within 24 hours from onset of encephalopathy in all five patients, revealed T2W hyperintense signal abnormalities, Gd enhancement in three of four patients with available studies, DWI restriction in three of three patients, and increased ADC signal in two of three patients (patients 2 and 3) (figure and figure e-1 on the Neurology® Web site at www.neurology.org). None had decreased ADC signal to suggest infarction. Areas of T2W signal abnormality included frontal (n = 4), parieto-occipital (n = 5), thalami (n = 1), corpus callosum (n = 3), and cerebellum (n = 3). Lesions in all patients were bilateral and were very symmetric in patients 1, 2, and 3. Neuroimaging was repeated in all patients (median delay 10 days; range 4 days to 10 months) and revealed complete resolution of T2W signal abnormalities (n = 1), partial resolution (n = 3), and no resolution (n = 1). Complete resolution of Gd enhancement was observed in two of two patients with available follow-up T1W+Gd studies. Follow-up imaging revealed complete resolution of DWI restriction detected at the PRES episode in one of two patients.

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Figure Neuroimaging of three patients with neuromyelitis optica spectrum disorder–posterior reversible encephalopathy syndrome (PRES)

Images are displayed according to the following MRI sequences, as available: diffusion-weighted imaging (DWI), apparent diffusion coefficient, fluid-attenuated inversion recovery/T2-weighted (T2W), T1W+Gd. The top rows represent neuroimaging at time of PRES, and the bottom rows represent post-PRES repeat neuroimaging. DWI (patient 1) reveals changes consistent with vasogenic edema; T2 signal abnormalities resolved completed as did DWI signal abnormality over the imaging interval. Gadolinium enhancement resolved completely and T2 signal abnormalities partially in patient 4. Patient 5 had large asymmetric, enhancing lesions; there is minimal resolution of T2 signal abnormalities. Figure e-1 (at www.neurology.org) shows neuroimaging of patients 2 and 3.

DISCUSSION

In most respects, patients in our series had typical characteristics of PRES, including encephalopathy, visual disturbances, and rapidly reversible changes consistent with vasogenic edema on MRI. Although some patients in this series had features considered to be atypical for PRES, it is now accepted that the clinicoradiographic spectrum of PRES is broader than previously appreciated and includes irreversible clinical features, atypical neuroimaging features such as frontal involvement,^20–22 gray matter/cortical lesions,²⁰ unilateral lesions,^20–22 asymmetric lesions,²¹ basal ganglia lesions,^21,22 deep white matter and holohemispheric watershed lesions,²¹ hemorrhage,^20,22 Gd enhancement,^20,22,23 confluent lesions,²⁰ brainstem and cerebellar involvement,^20–22 and corpus callosum lesions.²¹ Foci of irreversible MRI signal abnormality occur in approximately 26% of patients.²⁰ In our series, clinical resolution was complete in all patients within 7 days of PRES onset, and no recurrent clinical episodes were reported. Resolution of neuroimaging abnormalities was incomplete; one of five patients had complete resolution of T2W signal abnormality and two of two had complete resolution of Gd enhancement after a median interval of 7 days. Resolution of Gd enhancement likely precedes resolution of T2W hyperintensity. The optimal timing for repeat imaging to document resolution has not been established.²⁰ The presence of Gd-enhancing lesions in two patients with available T1W+Gd studies suggests that PRES in the setting of an NMOSD can be accompanied by brain inflammation, with superimposed disruption of water channel physiology resulting in vasogenic edema. Further support for inflammation comes from the CSF pleocytosis that was present in three of four patients with available data. Additionally, patient 5, who experienced rapidly reversible coma with extensive vasogenic edema and patchy enhancement accompanied by asymmetric lesions between the right and left hemispheres, was found to have focal demyelination and extensive macrophage infiltration with relative axonal preservation in a brain biopsy specimen.

This study’s retrospective nature and potential referral bias of atypical cases do not allow us to confidently state that PRES occurs with a higher frequency in patients with AQP4 autoimmunity as compared to those with other acute illnesses in which treatments may result in blood pressure fluctuations or osmotic or fluid stresses (e.g., IVIg or PLEX). However, in the interval during which these patients were ascertained, a total of 70 patients evaluated at Mayo Clinic sites were found to be NMO-IgG seropositive. PRES is generally considered a rare disorder, but was diagnosed in 5 of 70 (7%) consecutive NMO-IgG-positive patients identified at Mayo Clinic. This suggests that the co-occurrence of NMOSD and PRES is not coincidental. Two of 5 (40%) patients who were NMO-IgG seropositive among an Israeli cohort of 10 patients with clinical NMOSD developed what was interpreted as an acute disseminated encephalomyelitis-like syndrome. The clinical characteristics and radiologic evolution were consistent with a PRES-like syndrome. The authors speculated that interference with water channels by aquaporin-4 specific IgG may have contributed to the development of these lesions.²⁴ It is also conceivable that severe AQP4 functional impairment by IgG can cause a knock-out phenotype and an increase in brain edema in these patients.

Despite advances in its neuroimaging characterization and consensus about its clinical context, the pathogenesis of PRES remains enigmatic. The most widely accepted mechanism is that rapid changes in cerebral perfusion in patients with increased blood–brain permeability, especially in posterior head regions that are relatively deficient in sympathetic innervation, compromise autoregulation.²⁵ Alteration in CNS water flux due to AQP4 autoimmunity may predispose to PRES especially in the setting of rapid fluctuations in cerebral perfusion and therapies altering blood pressure or osmotic gradients. AQP4-null mice have reduced blood–brain barrier water permeability and consequently less cytotoxic edema compared to wild-type animals.²⁶ However, AQP-null mice also develop higher intracranial pressure and brain water content when challenged by continuous intraparenchymal fluid infusion.²⁷ Thus AQP4 is critical both for development of cytotoxic edema and resolution of vasogenic edema. We propose that autoimmune-mediated disruption of the CNS AQP4 water channel function predisposes to a higher frequency of PRES relative to other illnesses that produce comparable levels of acute illness. The uniform NMO-IgG seronegativity that we found in this study among stored serum from a previously reported PRES cohort ascertained by clinical presentation²⁰ suggests that NMO accounts for only rare cases of PRES, specifically in individuals with a preexisting NMOSD.

Brain lesions in NMO are heterogenous and the spectrum ranges from completely reversible symmetric or diffuse lesions causing primarily encephalopathy to bilateral but asymmetric lesions, as in patients 4 and 5, accompanied by focal neurologic syndromes, such as aphasia, and prominent Gd enhancement on neuroimaging. This spectrum may illustrate the dual nature of the pathogenesis of brain lesions in NMO: functional perturbation of brain water channels and blockade of water flux from the CNS leading to diffuse and symmetric cerebral vasogenic edema vs inflammatory attack of target aquaporin-4 leading to areas of persistent T2 signal abnormality and possibly focal neurologic signs at the other extreme. Inflammatory lesions associated with immune complex deposition may be both destructive and demyelinating as well as nondestructive and nondemyelinating, as we have reported previously.²⁸ The role of AQP4-specific antibodies in the pathogenesis of these latter two lesion types is supported by the selective abolition of AQP4 immunoreactivity²⁹ as well as by the in vitro effects of the autoantibody on cells expressing AQP4.^29,30