A TALE OF TWO DOGS: MENINGOENCEPHALITIS OF UNKNOWN ETIOLOGY (MUE)

Sarah Trub, DVM (Resident in Neurology & Neurosurgery)

Meningoencephalitis

• Inflammation of the brain and leptomeninges • Meningoencephalomyelitis if spinal cord is also

involved

2

Two groups of etiologies

• Infectious • Immune-mediated

Common infectious etiologies

• Protozoal • Toxoplasma • Neospora

• Viral • Distemper

4

• Rickettsial diseases • E. canis • Anaplasma spp • R. rickettsii (RMSF)

• Fungal • Cryptococcus spp • Coccidioides immitis

• Bacterial

Meningoencephalitis of Unknown Etiology • Encompasses all clinically diagnosed cases of

noninfectious inflammatory CNS disease • Does not include diseases without overt CNS

involvement (i.e. SRMA) • Histopathology is necessary for definitive

diagnosis of subtype

5

Granulomatous meningoencephalitis (GME) • T-cell mediated delayed-type hypersensitivity

reaction with organ-specific autoimmune disease

• Young adults (1-6 yrs), females and small breeds

6

GME: Distributions • Disseminated

• White matter of the cerebrum, caudal brainstem, cerebellum and cervical spinal cord

• +/- gray matter, leptomeninges, choroid plexus • Multifocal signs • Acute onset and rapid progression

• Focal • Solitary granuloma • Most common in cerebral white matter • More insidious progression

• Ocular • Retinal or post-retinal portions of the optic nerve • Acute visual dysfunction

7

GME: Histopathology

• Whorling, perivascular, disseminated or focal infiltrates of mononuclear cells in parenchyma and meninges of the CNS

• Acutely, equal distribution among gray and white matter

• Chronically, white matter lesions predominate

8

Necrotizing Encephalitis (NE)

• Necrotic lesions in cerebral white or gray matter

• Rapidly progressive neurologic signs • 6 mo - 7 yr, mean age 2.5 yr • Two subtypes: NME, NLE

9

Necrotizing meningoencephalitis (NME) • Young, small breeds • Pugs overrepresented

• Familial inheritance

10

NME: Distribution

• Most often affects the cerebrum and/or thalamus

• Lesions most often located at the junction between the gray and white matter

11

NME: Histopathology

• Extensive asymmetric regions of cerebral necrosis and non-suppurative inflammation

• Leptomeningeal involvement

• Loss of demarcation between gray and white matter

12

Necrotizing leukoencephalitis (NLE)

• Yorkshire Terrier • French bulldog

13

NLE: Distribution

• Forebrain • Brainstem

14

NLE: Histopathology

• Nonsuppurative leukoencephalitis

• Multiple necrotic and cavitated regions in white matter

• Minimal leptomeningeal involvement

15

Clinical presentation

• Varies based on lesion distribution

• Typically, fever is not present

16

Diagnostics: CBC/Chem

• Typically normal

17

Diagnostics: MRI

• Multifocal, single, or diffuse, ill-defined, intra-axial variably contrast-enhancing lesions, hyperintense on T2w and FLAIR

• +/- Leptomeningeal enhancement (NME) • +/- Perilesional edema • +/- Mass effect suggesting elevated ICP • +/- Ventriculomegaly • +/- Cavitary lesions (NE) • Normal (25%)

18

Diagnostics: CSF

• Mononuclear pleocytosis most common • Other pleocytoses possible

• Elevated protein concentration • Due to BBB disruption or intrathecal IgG

production • Nonspecific indicator of CNS disease

• Normal

19

Diagnostics: Rule out infection

• Toxoplasma IgG/IgM • Neospora IFA • Distemper PCR or serology • Tick PCR panel • Cryptococcus PCR or fungal profile • +/- CSF culture and sensitivity

20

Diagnostics: Biopsy (101)

• 82-100% accurate • Methods

• Stereotactic • Ultrasound-guided • Endoscopic-guided • CT-guided

• 6-29% mortality and morbidity • Not commonly performed

21

Treatment: Goal

• Achieve remission • Minimize adverse effects

22

Treatment: Treat the Cause • Empiric antibiotic therapy

• Clindamycin • Doxycycline or minocycline

• Immunosuppressive therapy • Corticosteroid therapy • Cytosine arabinoside • Cyclosporine • Procarbazine • Lomustine

23

Treatment: Treat the Symptoms • Anticonvulsant therapy • Maropitant, meclizine • Pain medications • IV fluids • Nutrition

24

Prognosis • MST

• Multimodal tx: 240-590 d

• Corticosteroid +/- lomustine: 28-357 d

• 56% die within 2 months of diagnosis • 31% (70% of those who live >2 m) have good to excellent long-term

outcomes • Patients that survive 3 months tend to live • Relapses are common (65%) • Most will require life-long therapy • Some may achieve remission and be able to be weaned off all medications

25

Prognosis

• Repeat diagnostics are helpful • MR + CSF more sensitive for predicting relapse • Discontinuing tx before resolution of MR lesions

always resulted in relapse • Abnormal CSF at 3 mo associated with increased risk

of relapse

26

Sophie • 5 yo FS Yorkshire Terrier • Presents for circling

27

History

• 1 week prior, unwilling to navigate stairs and would lose balance/tumble when attempted

• Progressed to worsened incoordination, leaning to the right, head tilt, lethargy, shaking, excessive panting, vomiting

• 1 day prior began circling tightly to the right

28

Examination Findings • Alert and appropriate, excitable

• Moderate head tilt (predominantly right-sided), undulating head and neck movements, intermittent predominantly right-sided head turn

• Ambulatory, moderate vestibulocerebellar ataxia with circling both tightly and widely in both directions (predominantly to the left), hypermetria x4

• Inconsistently slow placing and hopping on the left side

• Inconsistent menace OU (OD>OS)

• Decreased palpebral OD

• Intermittent spontaneous horizontal nystagmus (FFL) and positional vertical nystagmus

• Head pain

• T 103.1 F

29

Neurolocalization

• Central vestibular with paradoxical and dynamic signs, caudal fossa +/- forebrain

30

Differentials

• Meningoencephalitis • Congenital malformation • Neoplasia

31

Diagnostics: Preliminary

• CBC: Hct 59.51%, rbc 8.97, Hgb 18.2 g/dL • Chem: BUN 26 mg/dL, Glu 153 mg/dL • BP: 100 mmHg

32

Diagnostics: MRI

33

34

Diagnostics: MRI • Multifocal, ill-defined lesions involving the right frontal lobe, left

occipital lobe and pons, hyper intense on T2w and FLAIR images, moderately contrast-enhancing; most suggestive of inflammatory or neoplastic disease

• Meninges contrast-enhance • Mass effect with leftward shift of the medulla and mild FMH • Mild to moderate COMS, likely exacerbated by suspected inflammatory

disease • Hyperintense signal on T2w images within the cervical spine, likely pre-

syrinx formation or extension of inflammatory disease • Moderate hydrocephalus, likely congenital

35

Diagnostics: CSF

• Not performed due to mass effect and considerable brainstem disease

36

Diagnostics: Infectious Diseases

• Cryptococcus Ag: neg • Toxoplasma IgM/IgG: neg • Neospora IFA: neg

37

Treatment

• Cytosar CRI • Corticosteroid therapy • Doxycycline • Clindamycin

38

• IV fluids • Maropitant • Gabapentin • Famotidine

Progress • Gradual improvement • At discharge 48 hr later

• Mild, slow positional nystagmus (horizontal, FFL) • Circles widely to the left • Hypermetric • Right-sided head tilt and turn • Mildly decreased palpebral and menace OD

• 5d post-discharge • Near normal at home

39

Progress • 12d post-discharge

• Recurrance of vomiting, trouble jumping, lethargy, hugging walls, rubbing face on furniture

• Recheck exam: circling widely in both directions, tightly towards the left, mild positional ventral strabismus OS

• Added in cyclosporine • Gradual return to normal, still doing well today!

40

41

Ralphie

• 4 yo MN Chihuahua • Presented for fever and

head bobbing

42

History • 1 month ago fever and diffuse spinal pain, improved on

gabapentin and meloxicam • Signs recurred once meloxicam was discontinued, started

prednisone and improved • With tapering of prednisone, lethargic, inappetent, staring

off, coughing, febrile, head bobbing • Restarted prednisone, started doxycycline and clindamycin • Yesterday, tachypnic and hacking cough • Previous CBC, chem, 4DX, AUS and rads wnl

43

Examination Findings

• Hypersalivation • Ambulatory, occasionally lifts up LTL • Inconsistent menace OU (OD>OS) • Head and cervical pain

44

Neurolocalization

• C1-C5 • Forebrain • +/- Cerebellum

45

Differentials

• MUE • Neoplasia • Congenital malformation • Metabolic

46

Diagnostics: Preliminary

• CBC: wnl • Chem: ALT 483 U/L, Glu 131 mg/dL

47

Diagnostics: MRI

• Multifocal contrast-enhancing lesions throughout white matter of all regions of the brain, hyperintense on T2w and FLAIR images

48

FLAIR

T2w T2w

T1w + C

FLAIR

FLAIR T2w T1w + C

T1w + C

Diagnostics: CSF

• Protein: 300 mg/dL • Cell count: 2376 wbc/uL • Cytology: 44% lymphocytes, 30% neutrophils,

26% monocytes • Mixed/mononuclear pleocytosis

51

Diagnostics: Infectious Diseases

• Cryptococcus Ag: neg • Distemper PCR: neg

52

Treatment

• Cytosar CRI • Prednisone • Cyclosporine • Clindamycin • Doxycycline

53

• IV fluids • Gabapentin • Famotidine

Progress

• Signs waxed and waned for the next couple of months

• In general, steady decline • Persistent cough • Vestibular ataxia • Decreased gag • Dull • CP deficits

54

Progress

• Repeat CXR wnl • Repeat MRI

55

T2w T2w

FLAIR T1w + C

T2w FLAIR

T1w + C

Outcome

• Ralphie was euthanized

58

References • Adamo P, Adams W and Steinberg H. Granulomatous meningoencephalitis in dogs.

Compendium 2007;29(11):678-90.

• Coates J and Jeffery N. Perspectives on meningoencephalitis of unknown origin. Veterinary Clinics of North America: Small Animal Practice 2014;44(6),1157-1185.

• Flegel T, Boettcher IC, Matiasek K, et al. Comparison of oral administration of lomustine and prednisolone or prednisolone alone as treatment for granulomatous meningoencephalomyelitis or necrotizing encephalitis in dogs. J Am Vet Med Assoc 2011;238:337-45.

• Higginbotham M, Kent M and Glass E. Noninfectious inflammatory central nervous system diseases in dogs. Compendium 2007;29(8):488-97.

• Lamb CR, Croson PJ, Cappellow R, et al. Magnetic resonance imaging findings in 25 dogs with inflammatory cerebrospinal fluid. Vet Radiol Ultrasound 2005;46:17-22.

• Lowrie M, Smith PM, Garosi L. Meningoencephalitis of unknown origin: investigation of prognostic factors and outcome using a standard treatment protocol. Vet Rec 2013;172:527-34.

59

Acknowledgements

• Dr. David Brewer • Sophie and Ralphie’s committed owners

60