Meningoencephalomyelitis

Question 1

Define EME

Answer 1

eosinophilic meningoencephalitis (EME) is a disorder of unknown etiology that is characterised by infiltration of eosinophilis. It can be a component of fungal/protozoal/parasitic mening, but can be idiopathic as well.

Question 2

typical CSF findings in EME

Answer 2

eosinophilic pleocytosis (>20%)

Question 3

Pathophysiology of EME

Answer 3

an autoimmune etiology is suspected. A type I and/or type IV hypersensitivity reaction may be involved with eosinophils releasing neurotoxic substances

Question 4

Common MRI findings with idiopathic eosinophilic mening in dogs

Answer 4

• focal or multifocal intra-axial lesions are observed primarily within cortical grey matter and meninges +/- white matter lesions
• contrast enhanced meninges ( cortical atrophy or necrosis)
• cerebral sulci enlargement
• lesions are typically hyperintense on T2-weight images; hypo- to hyperintense on fluid-attenuated inversion recovery (FLAIR) images; hypo- to isointense on T1-weighted images; and may or may not contrast enhance
• can also be normal

Question 5

list potential infectious etiologies of EME in dogs

Answer 5

• canine distemper virus
• rabies
• neosporosis
• toxoplasmosis
• cryptococcosis
• protothecosis
• neural angiostrongylosis
• intracranial cuterebriasis
• dirofilarial larval migration
• bacterial infection

Question 6

typical signalment for eme

Answer 6

• large-breed dogs; goldens and rottweilers
• 4 months to 10 years
• males predisposed

Question 7

MOA of corticosteroids in EME

Answer 7

• immunosuppressive therapy; glucocorticoids enter the cell nucleus to interfere with transcription of products important to immune and inflammatory processes
• neuroprotective effects

Question 8

Prognosis of dogs with idiopathic EME

Answer 8

• good with treatment; 75% respond well to therapy
• relapses possible

Question 9

what is pug dog encephalitis?

Answer 9

necrotizing encephalitis

Question 10

What distinguishes NME and NLE?

Answer 10

lesion distribution;
- NME primarily affects cerebral gray matter
- NLE within subcortical + brainstem white matter

Question 11

what is NE?

Answer 11

necrotizing encephalitis; an aseptic inflammatory, necrotizing disease of the brain. Only reported in dogs.
- two discrete forms (1) necrotising meningoencephalitis (NME) + (2) necrotizing leukoencephalitis (NLE)

Question 12

etiology of Necrotizing meningitis

Answer 12

• thought to be an autoimmune disease targeting cellular components that are normally shielded
• no infectious organisms isolated
• pathogenesis likely multifactorial with genetic predisposition and aberrant immune system stimulation

Question 13

why is NME also known as pug dog mening?

Answer 13

• strong familial inheritance of NME has been documented in the pug; associated with risk loci on chromosome 15 and the dog leukocyte antigen (DLA) II region of chromosome 12

Question 14

Pathophysiology of NME

Answer 14

• thought to be a T-cell mediated autoimmune disease
• altered display of self-antigens to the immune system –> presentation of CNS self antigen to T-cells or cross-reaction of antibodies against a self-protein antigen.
• activated T-cells cause a cascade of changes; loss of blood-brain barrier integrity, cytokine activation and other inflammatory changes leading to oxidative stress, neurotoxicity, apoptosis, astrogliosis, microglial activation

Question 15

typical CSF findings in NME

Answer 15

• mononuclear or lymphocytic pleocytosis (most commonly)
  +/- increased protein concentration (disruption of blood/brain barrier) or intrathecal IgG production

Question 16

is genetic testing available for NME?

Answer 16

• testing for the DLA gene markers on chromosome 12 is commercially available in the USA and UK
• homozygous affected dogs have an observed risk of 12.75 for NME compared to normal or heterozygous (0-1.08)

Question 17

typical NME signalment

Answer 17

• young adult, small breed dogs
• pug (fawn, females), yorkshire terrier, maltese, chis, pekingese, papillon, shih tzu, coton de tulear, brussels griffon –> NME
• french bulldog + yorkshire terrier –> NLE

Question 18

common NLE CS

Answer 18

central blindness, seizures, central vestibular signs

Question 19

common NME CS

Answer 19

• forebrain signs; seizures, central blindness, circling, head pressing, altered mentation, head +/- cervical pain

Question 20

MOA of cyclosporine in NME

Answer 20

• kinase/phosphorylase inhibitors
• calcineurin inhibition stops translocation of nuclear factor of activated T-cells (NFAT) into the nucleus = inhibition of IL-2 + proinflammatory cytokines transcription
• only modified formulations of cyclosporine (Atopica, Neoral) are well absorbed (administer 1-2hrs before a meal)

Question 21

MOA of DNA Alkylators

Answer 21

• alter DNA conformation by insertion of alkyl group which interferes with DNA repair and replication, as well as inhibiting transcription. They are cell cycle nonspecific.
• Procarbazine, Lomustine, Cyclophosphamide penetrate into the CNS well

Question 22

examples of antimetabolites

Answer 22

• those affecting purine synthesis; mycophenolate and azathioprine
• those affect pyrimidine synthesis; cytosine arabinoside, leflunomide

Question 23

MOA of azathioprine

Answer 23

interferes with pathways for synthesis of purines; greatest effect on humoral immunity. Requires 8-12 weeks to achieve maximal immunosuppressive effects.

Question 24

MOA of leflunomide

Answer 24

• interferes with the pathways for synthesis of pyrimidines
• metabolized into its active form by intestinal mucosa – works by inhibiting dihydroorotate dehydrogenase thereby blocking T and B cell proliferation
• also has limited antiviral activity

Question 25

NME prognosis

Answer 25

• fatal without treatment
• approx. 44-75% dogs respond to therapy; 26% die within 7 days of diagnosis
• reported survival times; 1-1096 days

Question 26

negative prognostic indicators of NME

Answer 26

• presence of seizures, decreased mentation, mass effect
• higher CSF total nucleated cell count, increased neutrophil conc, abnormal CSF at 3 months post diagnosis

Question 27

What is the scientific name of rat lung worm?

Answer 27

Angiostrongylus cantonensis

Question 28

What is the life-cycle and transmission of A.cantonensis?

Answer 28

L1 passed in rat faeces –> ingested by slugs/snails and mature to L3 –> rats/other hosts ie. dogs ingest the slug –> L3 migrate from GIT to brain (develop into subadult) then migrate to pulmonary arteries –> mature and mate –> eggs hatch in lungs –> migrate to trachea and are coughed up and swallowed –> L1 pass in faeces

Question 29

CSF tests for A.cantonensis

Answer 29

• Anti-A.cantonensis IgG in the CSF can be detected via enzyme-linked immunosorbent assay (ELISA)
• PCR reaction
• loop-mediated isothermal amplification (LAMP) assays

Question 30

pathophysiology of A.cantonensis meninge

Answer 30

• L3 leave GIT via lymphatics and veins. L3 exhibit neurotropism and travel via peripheral nerves and nerve roots to CNS.
• Damage to CNS tissue occurs from mechanical damage from larval migration and haemorrhage
• severe eosinophilic meningoencephalitis occurs in response to larval antigens

Question 31

Treatment of A.cantonensis

Answer 31

high dose glucocorticoids for a minimum of 6-8 weeks - anthelmintics can worsen CS and result in death