MR imaging of encephalitis in children: infectious, noninfectious and mimics

1. MR imaging of encephalitis in children: infectious, noninfectious and mimics Nishard Abdeen MD1, Katya Rozovsky MD2, Nagwa Wilson MD3 Children’s Hospital of Eastern Ontario1 Winnipeg Children’s Hospital2 Montreal Children’s Hospital3 eEdE-190 Abstract 2935

2. Disclosures • We have no disclosures with respect to this presentation

3. Outline • Clinical presentation of encephalitis • Differential diagnosis • Viral encephalitis • Autoimmune encephalitis • ADEM • Limbic encephalitis • Rasmussens • Hashimoto’s encephalitis • Encephalitis Mimics: Vasculitis, Cerebritis, Drug Reaction, Metabolic disorders, Status epilepticus

4. Viral encephalitis Herpes Simplex type 1 Herpes simplex type 2 Enterovirus Parechovirus Epstein Barr Virus

5. Herpes simplex type 1 13 y.o. male with fever and altered consciousness. T2 hyperintensity (L) , with low signal intensity on ADC map ( middle) and hyperintensity on DWI ( right) in the right medial and lateral temporal lobes as well as periventricular area of left temporal lobe. Abnormal signal extended into the right insula ( not shown)

6. Herpes simplex encephalitis Adolescents and young adults presenting with fever ,seizure, behaviour changes, altered level of consciousness Early administration of acyclovir is vital FLAIR and T2 hyper-intensity with restricted diffusion involves limbic system: mesial temporal lobes, subfrontal areas, cingulate gyrus and amygdala. Variable enhancement. Typically bilateral but asymmetric Cortical and subcortical signal abnormality with relative sparing of white matter 95% of herpes encephalitis caused by type1

7. HSV type 2 encephalitis 6 week old boy with seizures. FLAIR hyperintensity (L) and T2 hyperintensity ( middle) in the left temporal lobe , with cortical enhancement in the mesial temporal lobe on coronal and axial t1 post Gad images ( right).

8. Neonatal herpes encephalitis • Neonatal herpes encephalitis is usually caused by HSV 2, transmitted from the mother. • Usually more widespread involvement including the cortex, white matter, basal ganglia and cerebellum though temporal involvement as in our case is not rare. • DWI shows restricted diffusion. Variable enhancement post Gadolinium.

9. Epstein Barr viral encephalitis 5 y boy with seizures. Marked swelling and T2 hyper-intensity of the basal ganglia ( left), with vasogenic edema extending into the internal capsules, thalami and external capsules bilaterally. Corresponding marked hypo-intensity and lack of enhancement on the T1 post Gd images ( middle) . DWI and ADC map ( above right and below right) show increased diffusivity and no restricted diffusion.

10. EBV encephalitis • Companion case in 14 y boy showing involvement of the caudate nucleii, anterior putamina and peri-sylvian cerebral cortex bilaterally in an adolescent boy who presented with seizures ( arrows, T2 w image , left). No corresponding restricted diffusion or enhancement on T1 w image ( middle) or DWI and ADC images ( right)

11. Epstein Barr viral encephalitis • EBV typically presents with bilaterally symmetric involvement of basal ganglia, thalami, cortex or brainstem • A variety of anatomical regions have been reported to be involved including holo-hemispheric, splenium of corpus callosum, basal ganglia ,thalami and brainstem • Variable presence of restricted diffusion • Patients with hemispheric involvement had a better prognosis than those with basal ganglia involvement. Patients with brainstem involvement had the most sequelae*. • In addition to encephalitis EBV can cause meningitis, transverse myelitis, ADEM and Guillain-Barre polyneuritis. • Diagnosis of acute infection is based on the presence of antibodies to Viral capsid antigen ( VCA ig G and Ig M) and absence of Epstein Barr Nuclear antigen ( EBNA Ig G) *J Child Neurol. 2009 Jun;24(6):720-6.

12. Parechovirus encephaliits • Newborn ( 7 days) girl with rash and seizures and serology proven parechovirus infection shows small T1 hyper-intense foci in the cerebral white matter ( arrows, T1 weighted image , left ) There are multiple foci of restricted diffusion in the frontal and parietal white matter on DWI ( right) and ADC map ( middle).

13. 7 day old term baby girl with parechovirus infection • Newborn girl with rash and seizures and serology proven parechovirus infection shows multiple and extensive foci of restricted diffusion in the frontal and parietal white matter as well as diffuse involvement of the genu and splenium of corpus callosum on DWI ( left) and ADC map ( right).

14. Enteroviral encephalitis • 25-day-old male neonate with right focal seizure and apnea. Possible sepsis with low blood pressure. Positive enterovirus PCR on nasopharyngeal swap in the context of bronchiolitis. T1 W images ( left) show patchy hyper-intensities in the frontal white matter bilaterally, corresponding to heterogeneous high and intermediate T2 signal ( right) . The splenium of the corpus callosum is T2 hyper-intense.

15. 25 day old boy with Enteroviral infection • Multiple areas of restricted diffusion ,including the bifrontal white matter lesions seen on T1 and T2 weighted images,. The splenium is diffusely involved.

16. Enteroviral encephalitis • Enteroviral encephalomyelitis EV-71 typically involves the posterior medulla, pons, midbrain dentate nuclei and spinal cord. • Parechovirus is a relatively new infection unitl recently desiganted echovirus 22 and 23 ans classified with the enteroviruses .They are now called human parechovirus 1 and 2 ( HPeV). HPeV presents clinically like enterovirus with a rash , fever and lethargy. It causes extensive white matter lesions with marked restricted diffusion, particularly in the periventricular white matter and the corpus callosum.* Our case shows the typical extensive restricted diffusion in the white matter and corpus callosum. *Ann Neurol. 2008 Sep;64(3):266-73.

17. Viral encephalitis • Viral encephalitis is caused by a large number of viruses and may presnt with different patterns of lesion distrbution. • Abnormal T2 and Flair hyper-intensity in grey matter or dep gey nucleii with relative sparing of white matter though not invariably • Imaging nonspecific often; DWI may be sensitive • HSV: limbic system • CMV: periventricular WM • Varicella: multifocal cortex • Eastern equine encephalitis: basal ganglia an d thalami • Japanese encephalitis: bilateral tghalami, brainstem,cerebellum, cerebral cortex • West Nile virus: Basal ganglia, thlami, brainstem cerebral WM , cerebellum • St Louis enncephalitis: substantia nigra *statdx.

18. Autoimmune encephalitis • Autoimmune encephalitides in children comprise a heterogeneous group with overlapping imaging appearances. • A variety of immune mediated mechanisms can lead to encephalitis: • 1. ADEM or acute demyelinating encephalomyelits, thought to be an immune reaction to infection or vaccination • 2. Presence of antibodies to antigens or proteins in the CNS which may or may not be linked to an underlying neoplasm • This category is large and growing and includes anti NMDA receptor antibody, anti aquaphorin 4antibody ( in Neuromyelitis optica ) and MOG or myelin oligodendrocyte glycoprotein antibody. • 3. Unusual encephalitides thought to hve an autoimmune mechanism but of unclear etiology eg Rasmussens encephalitis and Hashimotos encephalopathy *Ann Neurol. 2008 Sep;64(3):266-73.

19. Autoimmune encephalitis cases Acute demyelinating encephalomyelitis Limbic encephalitis MOG antibody associated encephalitis Rasmussens encephalitis Hashimotio’s encephalitis

20. Acute demyelinating encephalomyelitis ( ADEM) 6 year old boy with 2 days history of bilateral leg weakness (3/5). R/O cord compression, preceded by viral illness 2-3 weeks ago. Extensive FLAIR ( left ) and T2 ( rigth ) hyperintnsity and thckening of the frontal lobe grey and white matter , caudate heads, thalami, and insular cortex and external capsule

21. ADEM There are 3 central spinal cord lesions characterized by ill defined T2 hyperintensity. The first lesion is extending from the medulla to C-2. The second lesion is extending from C-7/T-1 to T-3 with expansion. The third lesion is extending from T-10/T-11 to the conus with expansion as well. Signal abnormality is predominantly central. There is no corresponding abnormal enhancement( not shown).

22. Anti-MOG* antibody associated encephalitis 7 y girl presenting with seizures , altered level of consciousness, leg weakness . T2 weighted image ( left) shows edema and hyperintensity of the putamina, globi pallidi and insular cortexbilaterally as well as left posterior thalamus .No enhancement on T1 post Gd image( middle) or retricted diffusion on ADC/DWI images ( right) *Myelin oligodendrocyte glycoprotein

23. MOG Anti-MOG antibody associated encephalitis Same patient has hyperintense lesions in the spinal cord at C4, and diffusely from T6 to the conus on T2 weighted images ( far left). There is patchy enhancement at C4 and at T11 and T12 on post gadolinum T1 weighted image ( left)

24. Anti-MOG antibody associated encephalitis Same patient presented 4 months later with decreased visual acuity in the right eye .Coronal T2 weighted image ( arrow, right)) shows thickened hyper-intense right optic which enhances avidly on the T1 post Gd image(arrow, left).

25. antiMOG antibody positive encephalitis • High levels of IgG antibodies to myelin oligodendrocyte glycoprotein occur in many pediatric encephalitis syndromes • These include ADEM, recurent optic neuritis and Neuromyelitis optica( NMO) like syndrome which is negative for aquaphorin-4 antibodies. • Distinct from aquaphorin 4 NMO( astrocyts affected) as antiMOG affects oligodendrocytes. • Given the clinical and radiologic overlap with ADEM, neuromyelitis optica and multiple sclerosis ( optic neuritic, myelitis and encephalitis), careful laboratory and clinical work up is required.

26. Viral Cerebellitis 3 year old girl with 3 day history ataxia, nausea &vomiting. Extensive T2 ( left ) hyper-intensity in the left cerebellar hemisphere with mass effect and loss of cerebellar sulci. No enhancement (middle, T1 post gad )or restricted diffusion (right, ADC/DWI). MRS at 144 ms ( bottom right) shows low NAA and high Choline peaks, mimicking a neoplasm. Patient recovered with steroid therapy

27. Hashimoto’s encephalitis • Hashimoto encephalitis (HE) is characterized by seizures, encephalopathy, tremors and myoclonus • Associated with elevated levels of anti-thyroid ( anti-microsomal and anti-thyroglobulin) antibodies • Responds to steroids • There is a wide range of MRI findings such as enlarged and hyper-intense unilateral or bilateral hippocampi, transient subcortical ischemia, cortical atrophy, and unilateral cerebral atrophy. Diffuse reversible white matter anomalies that mimic a leukodystrophy and resolve after treatment have also been reported. Epileptologie 2014; 31: 39 – 43

28. Hashimoto’s encephalitis 11year old girl with seizures and hypothyroidism. Axial DWI ( left) and ADC (middle) images show restricted diffusion in the posterior thalami bilaterally. Axial DWI ( top right) and ADC map ( bottom right) show restricted diffusion in the hippocampi

29. Hashimoto’s encephalitis 11year old girl with seizures and hypothyroidism. Coronal T2 weighted image (above left) shows bilateral symmetric T2 hyperintensity and enlargement of the hippocampi. Axial T2 weighted image ( above right) shows bilateral symmetric hyperintensity of the posterior thalami , without any enhancement on the post Gd T1 weighted image (right). The hippocampi showed low signal intensity on T1 but not enhance with Gd ( not shown)

30. Rasmussen’s encephalitis 6 y girl with partial complex seizures for two years, with persistent right posterior slowing on EEG. T2 weighted images ( left , middle) show volume loss of the right cerebral hemisphere and gliosis in the right frontal white matter. DWI and ADC images ( top /middle right) show no restricted diffusion. No enhancement post Gd ( bottom right)

31. Rasmussen encephalitis • Chronic inflammatory encephalitis of unknown cause , usually in a young child aged 6-8 years • Drug resistant epilepsy ( partial complex seizures, status epilepticus), progressive hemiplegia and cognitive deterioration • Imaging may be normal initially. Progressive cortical atrophy of one cerebral hemisphere, typically frontal and insular regions. • Increased T2 and FLAIR signal with no enhancement or diffusion restriction *Ann Neurol. 2008 Sep;64(3):266-73.

32. Limbic encephalitis 7 year old girl with recurrent focal complex seizures which responded to IVIG, plasmapheresis and steroids. Axial FLAIR (above left) and coronal T2 weighted ( middle) shows bilateral symmetric T2 hyper-intensity and enlargement of the hippocampi. Axial post GdT1 weighted image (above right) shows subtle left hippocampal enhancement. Restricted diffusion in the hippocampi on the ADC map and DWI images ( right).

33. Limbic encephalitis • Autoimmune encephalitis mediated by antibodies, of which limbic encephalitis is a subset, is being increasingly diagnosed in children • Antibodies include NMDAR ( NMDA receptor),VGKC ( voltage gated potassium channel) GAD ( glutamic acid decarboxylase ) , and Gly-R(glycine receptor).* The spectrum of antibodies is different from adults. • Anti NMDAR antibodies and limbic encephalitis can also be associated with ovarian teratoma in some cases • Clinical presentation is variable and may include cognitive decline, neuropsychiatric symptoms, movement disorders and seizures. • MRI findings include T2 hyperintensity in the hippocampi, basal ganglia white matter or cortex. A normal MRI does not exclude the diagnosis. • As treatment with intravenous immunoglobulin ( IVIG) and steroids may be effective, early diagnosis is important. *J Neurol Neurosurg Psychiatry doi:10.1136/jnnp-2012-303807

34. Disorders mimicking encephalitis • Bacterial cerebritis • CNS vasculitis • Metabolic diseases( mitochondrial disease, urea cycle disorders, aminoacidurias etc) • Drug reactions • Status epilepticus

35. Bacterial cerebritis 13 year with fever, headache and sinusitis. Axial T2 (above left) shows T2 hyper-intensity and thickening of the left frontal lobe, with a rim enhancing subdural collection and pachymeningeal enhancement on post Gd T1 weighted images ( middle, right).There is opacification of the frontal sinus. The subdural collection and the left frontal lobe show restricted diffusion on the ADC map and DWI images ( right), in keeping with subdural empyema and cerebritis.

36. Small vessel CNS vasculitis • 7 y girl with seizures. Axial T2 weighted images ( left , middle above) show thickening and hyper-intensity of the grey and subcortical white matter in both cerebra; hemispheres and basal ganglia with restricted diffusion (DWI/ADC map, right) but no enhancement on post Gd T1 weighted images( above right).

37. Status epilepticus 10 year old girl with left hemiplegia following status epilepticus. T2 weighted image ( left) shows cortical and subcortical hyperintensity and thickening in the right cerebral hemisphere. DWI ( middle) and ADC map ( right) show restricted diffusion in the corresponding distribution, particularly the juxtacortical and subcortical white matter. Questionable subtle restriction also in the left occipital lobe. The changes resolved on repeat scanning three days later and the patinet recovered

38. Gabapentin toxicity 2 year old girl with infantile spasms treated with gabapentin.T2 weighted image ( left) shows hyperintensity in the globi pallidi bilaterally with corresponding restricted diffusion on the DWI image( middle) and ADC map ( right). The signal abnormalities resolved on withdrawal of the drug. Diffuse volume effect is related to concurrent use of ACTH.

39. Mitochondrial disorder POLG1 mutation 10 year old girl with visual loss and seizures. T2 weighted image ( left) shows cortical and subcortical hyperintensity and thickening in the right occipital lobe. DWI ( middle) and ADC map ( right) show restricted. Prominent lactate peak at 1.3 ppm on MR spectroscopy inverted at 144 ms echo time( arrow, bottom right)