Acute Disseminated Encephalomyelitis

Acute Disseminated Encephalomyelitis

80 PART V Infection 10 Acute Disseminated Encephalomyelitis Girish Bathla, Bruno Policeni INTRODUCTION Acute disseminated encephalomyelitis (AD...

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PART V Infection

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Acute Disseminated Encephalomyelitis Girish Bathla, Bruno Policeni

INTRODUCTION Acute disseminated encephalomyelitis (ADEM) is a rare, usually monophasic, immunologically mediated inflammatory disease of the central nervous system (CNS) with characteristic polyfocal involvement of the neuroaxis on imaging. It may occur at any age but is most commonly seen in the pediatric population, with the mean age at presentation between 5 and 8 years. It has a reported incidence of 0.007 to 0.64 per 100,000 persons per year in the pediatric population and shows seasonal variation, with increased incidence during winter and spring. There is slight male predilection (M:F::1.4–2.3:1). A preceding history of infection, or less likely, vaccination may be elicited in approximately 67% to 93% of patients, with an upper respiratory infection being most commonly associated.

Although a number of infectious agents and vaccines have been implicated, ADEM is most frequently associated with measles and rubella infection and immunization with Semple form of rabies vaccine. The duration between the antigenic trigger and initial symptoms of ADEM varies between 4 and 12 days but may be delayed by up to 6 weeks. The relationship between ADEM and multiple sclerosis (MS) is complex and approximately 6% to 18% of pediatric ADEM patients eventually progress to MS. Risk factors for progression to MS include age greater than 10 years at first presentation, absence of encephalopathy or antecedent infection, presence of oligoclonal bands in cerebrospinal fluid (CSF) or characteristic periventricular lesions on magnetic resonance imaging (MRI), optic neuritis, and positive family history of MS.

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Under the revised International Pediatric Multiple Sclerosis Study Group (IPMSSG) criteria, a clinical encephalopathic syndrome must exist for ADEM to be diagnosed. Absence of encephalopathy, or encephalopathy secondary to fever, leads to a diagnosis of clinically isolated syndrome (CIS). Besides encephalopathy, other presenting symptoms include long tract or brainstem dysfunction, ataxia, seizures, optic neuritis, and cranial nerve palsy. Respiratory failure secondary to brainstem involvement may occur in 11% to 16% of cases. Once ADEM develops, any fluctuation in the clinical features or imaging findings within the first 3 months is considered a part of the monophasic illness.

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The lesions can virtually occur anywhere along the neuroaxis but show a predilection for the juxtacortical or deep WM. Involvement of the cortical ribbon, basal ganglia, thalami, and brainstem is also well described (Fig. 10.7). When present, optic nerve involvement is commonly bilateral, unlike MS, which is often unilateral

PATHOPHYSIOLOGY AND HISTOLOGY It is generally agreed that ADEM is an autoimmune response to myelin because pathologically similar changes may be induced in a variety of animal models following immunization with myelin proteins or peptides (experimental allergic encephalomyelitis model). This may occur through molecular mimicry wherein the antigen shares a structural similarity to myelin (Fig. 10.1). The ensuing immune response cross-reacts with myelin, inadvertently resulting in an autoimmune CNS injury. Similarity of myelin basic protein (MBP) to several viral sequences and enhanced T-cell response to MBP in patients with ADEM lend support to the theory. Another potential explanation is activation of preexisting myelin reactive T cells through a nonspecific inflammatory process. Lastly, a less appealing hypothesis is CNS involvement by a neurotropic infectious agent resulting in systemic leakage of autoantigens, thereby triggering an autoimmune response. Histopathologically, the lesions show perivenous “sleeves” of demyelination dominated by T lymphocytes and macrophages, a finding felt to be characteristic of ADEM (Fig. 10.2).

IMAGING APPEARANCE ADEM lesions predominantly involve the white matter (WM), are large and asymmetric, and have ill-defined margins (Fig. 10.3). Neuroimaging findings may lag behind clinical presentation, rarely by up to 8 weeks. Lesions resolve over a course of few days to weeks, often completely, although partial resolution or residual volume loss may be seen (Figs. 10.4 and 10.5). Computed tomography (CT) imaging often shows hypodense lesions involving the cerebral WM (Fig. 10.6). Although CT is often abnormal, MRI is generally preferred, given the superior soft tissue detail and improved characterization.

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Figure 10.1. Illustration depicting proposed pathogenesis of acute disseminated encephalomyelitis (ADEM), including molecular mimicry, neurotropic infection, and nonspecific activation. MS, Multiple sclerosis.

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Figure 10.2. (A and B) Photomicrographs of Luxol fast blue–stained sections of brain parenchyma showing perivascular demyelination (10×) (A) and mild lymphocytic inflammation admixed with abundant foamy macrophages (20×) (B). (Images courtesy Dr. Sarika Gupta, University of Iowa Hospitals and Clinics, IA.)

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Figure 10.3. (A–C) Axial FLAIR images at the level of centrum semiovale obtained on day 1 (A), day 5 (B), and after 3 months (C). Initial images show characteristic bilateral demyelinating lesions (A), which are more confluent and widespread on day 5 (B). On follow-up imaging (C), lesions show complete resolution.

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Figure 10.4. (A and B) Axial FLAIR images at admission (A) and 3-month follow-up (B). There are typical demyelinating lesions involving bilateral central semiovale (A), which only partially resolve on follow-up imaging (B).

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Figure 10.5. (A and B) Axial FLAIR images at the level of basal ganglia obtained during admission (A) and after 4 months (B). There is T2 prolongation involving the right corpus striatum (A). Follow-up imaging (B) reveals resolution of signal changes with residual volume loss.

Figure 10.6. Axial noncontrast computed tomography image in a patient with acute disseminated encephalomyelitis shows nonspecific bilateral white matter hypodense lesions involving the centrum semiovale.

Figure 10.7. Axial FLAIR image in a patient with acute disseminated encephalomyelitis reveals diffuse pontine involvement.

(Fig. 10.8). Occasionally, lesions may involve periventricular WM and corpus callosum. Although ADEM by definition is polyfocal, rare cases may show only a solitary lesion or isolated brainstem involvement (Fig. 10.9). MRI typically shows multiple, asymmetric supratentorial and infratentorial lesions that are iso- to hypointense on T1-weighted imaging (T1WI) and show T2 prolongation. Some authors have described dominant patterns on imaging, which include: (1) ADEM with small lesions (<5 mm) (Fig. 10.10), (2) ADEM with large, confluent, or tumefactive lesions (Fig. 10.11), (3) ADEM with additional bithalamic involvement (Fig. 10.12), and (4) acute hemorrhagic encephalomyelitis (see later). On diffusion-weighted imaging (DWI), the advancing edge of the demyelination may show some restriction, a finding attributed to increased cellular infiltrate in the demyelinating zone (Fig.

10.13). Contrast enhancement is highly variable and has been reported in 10% to 95% of patients, a finding likely affected by the time of acquisition and steroid administration. The enhancement characteristics are also variable and may have a nodular, ring, or incomplete rim pattern (Fig. 10.14). Involvement of the spinal cord is variable and has been reported in up to 28% in pediatric series and up to 83% in adults. The higher incidence in adult population was noted with routine MR evaluation in patients with ADEM and may reflect a more accurate incidence of spinal involvement that includes clinically asymptomatic lesions. Clinically, the myelopathy is often complete, unlike MS where it is often partial. The extent of involvement is variable and may range from a short segment to confluent lesions spanning across multiple vertebral levels. Rarely, holocord Text continued on p 88

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Figure 10.8. (A and B) Acute disseminated encephalomyelitis with bilateral optic neuritis. Axial postcontrast fat-suppressed T1WI (A) reveals thickened and enhancing optic nerves bilaterally. Axial FLAIR image (B) shows nonspecific T2 prolongation involving the right middle cerebral peduncle. Both findings resolved on follow-up imaging.

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Figure 10.9. (A–C) Solitary acute disseminated encephalomyelitis. Axial FLAIR image reveals a solitary demyelinating focus involving the left corona radiata. Axial DW (B) and ADC image (C) show true restricted diffusion along the periphery of the lesion with T2 shine-through centrally.

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Figure 10.10. (A and B) Axial T2WI at the level of centrum semiovale (A) and midbrain (B) show multiple small demyelinating foci in a patient with acute disseminated encephalomyelitis.

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Figure 10.11. (A–C) Acute disseminated encephalomyelitis with confluent lesions. Axial FLAIR (A) image reveal extensive bilateral T2 prolongation involving the periventricular white matter with scattered nodular enhancement post contrast (B). Follow-up image after 2 months reveals interval improvement and residual white matter changes (C).

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C Figure 10.12. (A–C) Axial FLAIR images at presentation (A and B) reveal T2 prolongation involving bilateral thalami that completely resolve on follow-up imaging (C). (Images courtesy Dr. Amit Agarwal, Penn State University College of Medicine, PA.)

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Figure 10.13. (A and B) Axial DW (A) and ADC image (B) at the level of basal ganglia show multiple foci of peripherally restricted diffusion bilaterally. Note that two of the lesions are along the splenium of corpus callosum, a site not commonly involved with acute disseminated encephalomyelitis.

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Figure 10.14. (A–C) Contrast enhancement patterns in acute disseminated encephalomyelitis. Axial postcontrast image (A, same patient as Fig. 10.4) shows nodular enhancement in the right centrum semiovale lesion. Axial postcontrast image (B, same patient as Fig. 10.13) shows ring enhancement. Coronal postcontrast image (C) in another patient reveals incomplete rim enhancement.

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Figure 10.15. (A–D) Sagittal (A) and axial (B) T2WI reveal short segment T2 prolongation involving the thoracic cord (A), with involvement of both the gray and white matter (B). Sagittal postcontrast T1WI (C) shows ring enhancement within the lesion. Axial FLAIR (D) image at the level of centrum semiovale shows typical demyelinating lesions.

involvement may occur. On imaging, lesions are most frequently seen in the thoracic cord, are large and edematous, often involve the WM, and may enhance (Fig. 10.15). MR spectroscopy (MRS) in the acute phase may reveal reduced myoinositol to creatinine ratio with elevated lipids. N-acetylaspartate (NAA) and choline are typically normal. As the lesions evolve, there may be transient reduction in NAA and elevation of choline, which subsequently normalize with resolution of conventional imaging abnormalities.

VARIANTS Multiphasic Acute Disseminated Encephalomyelitis As per the revised IPMSSG criteria, multiphasic ADEM is defined as two episodes of demyelination occurring more than 3 months apart (Fig. 10.16). The latency between the episodes may vary, and the timing in relation to steroids is no longer pertinent. The clinical presentation and imaging findings during relapse may or may not resemble the initial episode. Neuroimaging characteristics are otherwise similar to demyelinating foci of ADEM. Occurrence of more than two episodes is felt to be inconsistent with ADEM and is more likely to represent underlying MS or neuromyelitis optica (NMO).

Tumefactive Acute Disseminated Encephalomyelitis A mass-like focus of demyelination, referred to as tumefactive demyelination, may occur in approximately 5% to 8% of ADEM patients. Occasionally, it may cross the corpus callosum and mimic a “butterfly” glioblastoma or lymphoma. Findings favoring underlying demyelination include predominant WM involvement, peripheral restricted diffusion, lack of mass effect, and incomplete rim enhancement (Fig. 10.17). In challenging cases, MRS may be used as a problem-solving modality.

Acute Hemorrhagic Encephalomyelitis (Weston-Hurst Disease) It is believed to be a rare hyperacute variant of ADEM, affecting approximately 2% of patients, with a rapid and often fatal

clinical course. It often follows an upper respiratory tract infection. Pathologically, lesions show neutrophilic infiltration, unlike ADEM, which typically has leukocytic infiltrates. When compared with ADEM, lesions are often larger, have greater mass effect and edema, may be symmetric, and show hemorrhage (Fig. 10.18). Prognosis is often dismal but may be improved with aggressive immunomodulatory therapy early in the course of the disease.

Poststreptococcal Acute Disseminated Encephalomyelitis Initially described by Dale et al., poststreptococcal ADEM is associated with group A beta-hemolytic streptococcal infection and elevated anti–basal ganglia antibodies. Patients frequently exhibit extrapyramidal symptoms, otherwise uncommon in ADEM. On imaging, the basal ganglia involvement is often asymmetric and statistically more common (when compared with ADEM without preceding streptococcal infection), being seen in up to 80% of these patients (Fig. 10.19).

COMPLICATIONS • Large ADEM lesions may be associated with elevated intracranial pressure (ICP) and may result in midline shift, transtentorial or tonsillar herniation. Although mortality in ADEM is low (<5%), persistently raised ICP refractory to medical therapy is usually the major culprit. • Respiratory failure may occur in patients with brainstem lesions, secondary to involvement of the respiration centers in the medulla.

Mimics and Differential Diagnosis A number of CNS pathologies may mimic ADEM, both clinically and on imaging. These are summarized in Box 10.1. The more pertinent differential diagnoses are discussed next.

Multiple Sclerosis As mentioned earlier, some patients with ADEM eventually progress to MS. At first presentation, the two entities may be indistinguishable, and at times, only follow-up imaging may be able to distinguish

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E Figure 10.16. (A–E) Multiphasic acute disseminated encephalomyelitis. Axial FLAIR images at initial presentation (A–C) and during the second clinical episode (D and E). Initial images reveal foci of demyelination involving the left centrum semiovale (A) and right hippocampal tail (B). Note that the posterior fossa is unremarkable (C). Subsequent images during the second episode reveal interval involvement of the posterior fossa (D) and resolution of the hippocampal lesion (E).

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E Figure 10.17. (A–E) Tumefactive acute disseminated encephalomyelitis. Axial FLAIR (A), DW (B), and postcontrast (C) images reveal a solitary demyelinating lesion involving the left centrum semiovale (A) with peripheral restricted diffusion medially (B) and incomplete rim enhancement medially (C). Single voxel spectroscopy (D) obtained at long TE (144 ms) shows mildly elevated myoinositol peak at 3.5 ppm and an inverted lactate peak at 1.3 ppm but no elevation of choline or reduction in N-acetylaspartate at 3.2 ppm or 2.0 ppm, respectively. Spectroscopy findings are not diagnostic of demyelination but do support the diagnosis. Follow-up FLAIR image (E) at 1 year reveals significant interval improvement. Subsequent follow-up imaging (not shown) revealed stable residual changes with no new lesions, consistent with monophasic demyelination. (Images courtesy Dr. Daniel Noujaim, Lahey Hospital and Medical Center, MA.)

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Figure 10.18. (A–C) Acute hemorrhagic encephalomyelitis (AHEM). Axial T2WI (A and B) reveal abnormal T2 prolongation involving bilateral occipital lobes (A) and cerebellar hemispheres (B). Axial T1WI (C) reveals T1 shortening along bilateral occipital lobes, consistent with hemorrhage. (Images courtesy Dr. Toshio Moritani, University of Iowa Hospitals and Clinics, IA.)

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Figure 10.19. (A and B) Poststreptococcal acute disseminated encephalomyelitis. Axial FLAIR (A) and DW (B) images reveal asymmetric T2 prolongation involving bilateral basal ganglia (A) with associated peripheral diffusion restriction (B).

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BOX 10.1  Imaging-Based Differential Diagnosis of Acute Disseminated Encephalomyelitis MULTIFOCAL WHITE MATTER LESIONS • Other demyelinating diseases like MS and NMO • Neurosarcoidosis • CADASIL • With encephalopathy: • PRES • Hashimoto encephalitis • Postictal encephalopathy • Extrapontine myelinolysis • Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) • Paraneoplastic encephalitis • Susac syndrome BITHALAMIC/BISTRIATAL LESIONS • Acute necrotizing encephalopathy • Japanese encephalitis • Deep cerebral venous thrombosis • Uremic encephalopathy • Bithalamic glioma • West Nile virus encephalitis • Leigh disease DIFFUSE WHITE MATTER LESIONS • Toxic leukoencephalopathies • Leukodystrophies • Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) TUMEFACTIVE LESIONS • Astrocytoma • Lymphoma CADASIL, Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; MS, multiple sclerosis; NMO, neuromyelitis optica; PRES, posterior reversible encephalopathy syndrome.

one from another (Fig. 10.20). When compared with ADEM, MS is more common in females, usually involves the corpus callosum and periventricular WM, and often shows lesion distribution in time. In addition, MS lesions can demonstrate T1 hypointense foci (“black holes”) in acute and chronic phases, whereas ADEM typically resolve. Within the spine, MS more frequently involves the cervical cord and lesions are often peripheral and involve fewer vertebral segments. Optic neuritis, when present, is typically unilateral in MS, whereas it may be unilateral or bilateral in ADEM. CSF oligoclonal bands may be seen with MS but are typically absent in ADEM.

Acute Necrotizing Encephalopathy This is a rare, fulminant form of necrotizing encephalopathy predominantly affecting infants and children. A history of preceding viral illness is often present, and the illness is felt to be immune mediated, similar to ADEM. On imaging, characteristic findings include T2 hyperintense symmetric lesions involving the thalami, brainstem tegmentum, periventricular WM, putamina, and cerebellum (Fig. 10.21). Lesions may show hemorrhage, necrosis, and postcontrast enhancement. Other lesions with bithalamic distribution that may mimic ADEM include bithalamic glioma, infectious encephalitis, or venous sinus thrombosis (Figs. 10.22–10.24). Rarely, venous congestion secondary to dural arteriovenous (AV) fistula may mimic bithalamic ADEM (Fig. 10.25).

Posterior Reversible Encephalopathy Syndrome Posterior reversible encephalopathy syndrome (PRES) is more common in adults and presents as regions of predominantly symmetric vasogenic edema along the watershed territories, with a parieto-occipital predominance. Lesions show T2 prolongation and usually do not enhance. On the other hand, ADEM is more common in the pediatric population, does not have a predilection for the watershed territories, is often asymmetric, and may involve the spinal cord. Rarely, both ADEM and PRES may coexist (Fig. 10.26).

Encephalitis/Encephalopathy Occasionally, ADEM may be mimicked both clinically and radiologically by a number of conditions such as infective encephalitis, toxin-induced leukoencephalopathy, extrapontine myelinolysis, uremic encephalopathy (Fig. 10.27), and inflammatory (neurosarcoidosis) or immune-mediated encephalitis (Hashimoto, anti-Nmethyl-D-aspartate [NMDA] encephalitis). Most of these entities present with focal or diffuse WM lesions, which show T2 prolongation along with variable enhancement. Although neuroimaging helps to narrow the differential considerations, the final diagnosis may require lumbar puncture or even brain biopsy. This highlights the importance of clinical history, CSF correlation, and radiologic follow up to confirm expected imaging evolution.

Vascular Causes ADEM may also be mimicked, both clinically and radiologically by vasculitis. However, lesions in vasculitis often involve the gray matter, conform to a vascular distribution, may show hemorrhage, and evolve into gliosis, unlike ADEM where lesions often resolve. Thrombosis of the deep venous system may present with widespread signal abnormalities of the basal ganglia and thalamus and mimic ADEM, as discussed previously (see Figs. 10.24–10.25). MRI may reveal hemorrhage within the deep nuclei and absence of venous sinus contrast opacification.

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C Figure 10.20. (A–C) Multiple sclerosis (MS). Axial FLAIR (A) and postcontrast (B) images at presentation reveal demyelinating foci involving bilateral centrum semiovale (A) with nodular and rim enhancement (B). Note that the appearance is indistinguishable from acute disseminated encephalomyelitis. The patient however had recurrent demyelinating episodes. Follow-up sagittal FLAIR (C) image at 2 years reveals periventricular lesions characteristic of MS.

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Figure 10.21. (A and B) Axial T2W (A) and DW (B) images in a patient with acute necrotizing encephalopathy reveal symmetrical areas of T2 prolongation involving bilateral thalami, basal ganglia, and corona radiate (A), which show increased DW signal (B).

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Figure 10.22. (A and B) Bithalamic glioma. Axial T2 (A) and FLAIR (B) images reveal enlarged and bulky thalami. Note the associated hydrocephalus. (Images courtesy Dr. Daniel Noujaim, Lahey Hospital and Medical Center, MA.)

Figure 10.23. Axial T2WI in a patient with Japanese encephalitis reveals symmetric bithalamic T2 prolongation.

Figure 10.24. Deep cerebral venous thrombosis. Axial FLAIR image reveals abnormal T2 prolongation involving bilateral thalami, internal capsules, and left caudate nucleus. T2 shortening involving bilateral medial thalami corresponds to foci of hemorrhage. Also note blood-CSF levels along bilateral lateral ventricles. (Image courtesy Dr. Achint Singh, University of Texas Health Science Center, TX.)

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Figure 10.25. (A–D) Axial FLAIR (A), T1W precontrast, (B) and postcontrast (C) images reveal relatively symmetric T1/T2 prolongation and enhancement involving bilateral thalami. Sagittal MIP image of computed tomography angiogram (D) reveals dilated deep venous system and vascular congestion in the posterior fossa. Conventional angiogram (not shown) revealed dural AV fistula. The thalamic signal changes were felt to be secondary to venous congestion and ischemia. (Images courtesy Dr. Daniel Noujaim, Lahey Hospital and Medical Center, MA; [A–C] from Borja MJ, Schaefer PW, Boulter DJ. Case of the season: dural arteriovenous fistula mimicking a bithalamic neoplasm or viral encephalitis. Semin Roentgenol. 2014;49[1]:4–9.)

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Figure 10.26. Posterior reversible encephalopathy syndrome (PRES) with acute disseminated encephalomyelitis. Axial FLAIR images (same patient as Fig. 10.13) obtained at admission (A) and after few days (B) following further clinical deterioration. Initial image reveals characteristic bilateral demyelinating foci. Subsequent image (B) reveals superimposed areas of T2 prolongation involving bilateral frontal and occipital lobes, basal ganglia and thalami, consistent with PRES.

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Figure 10.27. (A and B) Axial T2WI images in a patient with uremia and altered mental status reveal asymmetric T2 prolongation involving bilateral corona radiata and gangliothalamic regions, consistent with uremic encephalopathy.

SUGGESTED READING

Alper G. Acute disseminated encephalomyelitis. J Child Neurol. 2012;27(11):1408–1425. Berzero G, Cortese A, Ravaglia S, et al. Diagnosis and therapy of acute disseminated encephalomyelitis and its variants. Expert Rev Neurother. 2015;1–19. [Epub ahead of print]. Bester M, Petracca M, Inglese M. Neuroimaging of multiple sclerosis, acute disseminated encephalomyelitis, and other demyelinating diseases. In: Seminars in Roentgenology. Vol. 49. No. 1. WB Saunders; 2014:76–85. Dale RC, Church AJ, Cardoso F, et al. Poststreptococcal acute disseminated encephalomyelitis with basal ganglia involvement and auto-reactive antibasal ganglia antibodies. Ann Neurol. 2001;50(5):588–595.

Koelman DLH, Mateen FJ. Acute disseminated encephalomyelitis: current controversies in diagnosis and outcome. J Neurol. 2015;1–2. Marin SE, Callen DJA. The magnetic resonance imaging appearance of monophasic acute disseminated encephalomyelitis. Neuroimaging Clin N Am. 2013;23(2):245–266. Rossi A. Imaging of acute disseminated encephalomyelitis. Neuroimaging Clin N Am. 2008;18(1):149–161.