BRAIN - inflammatory Flashcards
In MUO, focal signs are associated with an increased survival compared to dogs with multifocal signs: true or false?
False
(a study from 1998 found this association, but 3 more recent studies didn’t found this result)
Cornelis, 2019
Give molecules with following action:
- Regulation of gene expression
- DNA Alkylation (antiproliferatives)
- Antimetabolites: purine & pyrimidine
- Kinase and Phosphorylase Inhibitors
- Inhibition of microtubule formation
Regulation of Gene Expression
Enter nucleus to interfere directly with transcription of gene products.
Glucocorticoids, vitamin D analogues
DNA Alkylation (antiproliferatives)
Interfere directly with the structure of DNA in order to block subsequent replication, which is required for cell proliferation.
Cyclophosphamide, lomustine, procarbazine, chlorambucile
Antimetabolites
Interfere with pathways responsible for the synthesis of the purine (adenine, guanine) or pyrimidine (thymine, cytosine) molecules necessary for DNA synthesis and cell proliferation, or with enzymes involved in other processes critical to cell survival or proliferation.
Inhibits purine synthesis: 6-mercaptopurine, azathioprine, mycophenolate mofetil
Inhibits pyrimidine synthesis: Cytosine arabinoside, leflunomide
Kinase and Phosphorylase Inhibitors
The most common enzyme inhibited is calcineurin, which belongs to the serine/threonine phosphatase superfamily and acts to dephosphorylate nuclear factor of activated T cells (NFAT). This interferes with the translocation of NFAT into the nucleus of activated T cells, impairing a number of important functions, such as the production of IL-2 and other proinflammatory cytokines.
Cyclosporine A
Inhibition of microtubule formation in mitotic spindle
Arrest of dividing cells at the metaphase stage
Vincristine
Which autoantibodies can be found in Pugs with MUO?
GFAP in CSF
Which factors are associated with the short-term prognosis in MUO?
1. Decreased mentation at presentation
2. Presence of seizures
3. Increased percentage of neutrophils on CSF analysis
4. Bodyweight
5. Duration of clinical signs and treatment prior to diagnosis
1,2,3
Gene associated with risk for NME
dog leucocyte antigen MHC class II (chromosome 12)
polymorphism in chromosome 15 Pug, 4 Maltese
how many Pug carry at-risk gene for NME
2/3 of pug carry at least 1 DLA at-risk haplotype, 6-18% carry the high risk homozygous DLA haplotype
most common sign of early NME/clinical NME
early NME: multifocal spinal hyperesthesia, paw placement deficit, reduced menace response (90%), mild lethargy (75%), proprioceptive ataxia (65%)
clinical NME: seizure, circling, visual deficits, behavior change , lethargy
MRI/csf change in early/clinical NME
MRI change in 90% of ealry form: meningeal enhancement, focal contrast-enhancing lesion within parenchyma, T2 hyperintense lesion (early necrosis)
abnormal CSF in 50%
clinical: loss W/G matter distinction, parenchymal inflam/necrotic lesion, leptomeningeal enhancement. Maj in parietal/occipital lobe
abnormal CSF 90-80% (lymphocytic pleocytosis)
frequency + risk factors for postencephalitic epilepsy development?
% developing resistant epilesy
23% develop PEE
1/ Acute symptomatic seizures = seizures at the early stage of the disease
2/ MRI lesions in the hippocampus
They were younger when compared with those without PEE and had shorter MST.
Among PEE, 21% develop drug-resistant epilepsy
,
What are the risk factors for dying with MUO?
During first week:
Decreased mentation
Seizures
Increased neutrophils in CSF
After: obtundation
Note: large breed dogs present more commonly decreased mentation than small and medium breed dogs, but no overall difference in MST
Dogs with NE are usually older than dogs with GME: true or false?
False
NE: <4 yo
GME: 4-8 yo
What is the clinical sign that is most common in large breed dogs than small breed dogs with MUO?
Decreased mentation
What are the 3 genetic risk factors identified for NME in dogs?
∼75% of Pugs with NME have a specific combination of alleles coding for major histocompatibility complex class II (MHC II) molecules on chromosome 12 containing exons for the dog leukocyte antigen and conferring on them a relative risk of 5.45 of developing the disease
In Maltese dogs, ILR7 on chromosome 4
FBXW7 on chromosome 15 in Pugs + Maltese
6-18% Pugs carry high risk homozyg haplotype
In MUO, seizures or altered mentation are associated with significantly shorter ST: true or false?
True
They have also a significantly higher risk of dying within the first week after diagnosis.
What are the most common location of lesions of NME in MRI?
The most common MRI abnormalities reported in dogs with NME are asymmetrical, multifocal and located in the forebrain (more severe lesions in parietal and occipital lobes); are hyperintense on T2W and FLAIR images; and typically affect the cortical grey and subcortical white matter with loss of grey/white matter demarcation and variable degrees of contrast enhancement of the parenchymal lesions on T1W postcontrast images,
However, cerebellar and brainstem lesions were also detected in 4/18 and 3/18 cases in one study, respectively,
Meningeal enhancement can also be present, accompanied by mass effect and varying degrees of ventriculomegaly
A younger age at time of diagnosis with MUO is associated with improved survival: true or false?
true
In MUO, oligoclonal bands in CSF are indicative of B cell response? T cell response?
Dogs with MUO were 9.9 times more likely to show CSF-specific OCBs than all other diseases together.
MUO showed the highest prevalence of CSF-specific OCBs, indicating an inflammatory B cell response.
What is the most common presentation of LGI1 positive autoimmune encephalitis in cat?
Similar to human cases, most cats with LGI1-antibodies had a history of focal seizures (83%), clustering in the majority (88%), with interictal behavioural changes (73%).
1/ Pug dog encephalitis is described as a seasonal disease with a CSF neutrophilic pleocytosis
2/ Affected dogs are predominantly male dogs less than one year old and the lesions are widely distributed in the brain as it is observed in the chihuahua
3/ Affected dogs are predominantly young adult female dogs and the lesions are most commonly seen in the prosencephalon although up to 40% of the dog have cerebellum lesions
4/ Pug dog encephalitis is strongly suspected to be more likely to occur following rabies vaccination
3
What of the following statements is incorrect?
- Dogs with optic neuritis as part of a multifocal MUO respond significantly less well to treatment than dogs with isolated optic neuritis.
- Median CSF TNCC in dogs with isolated optic neuritis is 5 cells and median TP 35, with over 50% of the dogs having normal CSF analysis
- Males were slightly more represented in the group of isolated optic neuritis, contrary to what is the case for the MUO group
- Overall, between 65 and 73% of cases remained blind despite treatment.
1
What of the following statements is incorrect?
- The environment of dogs, urban vs rural has not been proven to be a risk factor for development of MUO
- The presence of Prevotellaceae in the digestive tract of dogs has been positively correlated with development of MUO
- A haplotype in the CFA 12 containing the regions for canine leukocyte antigen class II has been identified as a risk factor for NME in Pugs.
- Pugs with MRI having a heavier lesion burden in MRI have longer time from disease onset to MRI
2
Which factors were associated with complete recovery in optic neuritis (isolated or with MUO)?
Reactive PLR
Absence of fundoscopic lesion
Younger age
Lower CSF TNCC
The 2 last were more significantly associated with I-ON compared to MUO group.
What type of serological abnormality can be detected in cats with suspected limbic encephalitis?”
High levels of voltage-gated potassium channel complex antibodies
What is the risk of previous corticosteroid therapy in case of discospondylitis?
Prior steroid therapy was associated with an increased risk of progressive neurological dysfunction
Factors associated with outcome in MUO
1/ decreased mentation at presentation
2/presence of seizures
3/ increased percentage of neutrophils on CSF analysis
4/ bodyweight
5/duration of clinical signs and treatment prior to diagnosis
1,2,3
risk factor for NME
female
young (<6y)
fawn
genetic fact (dog leuco antigen MHC II chr12, chr15 (pug) /4 (maltese)
inflammatory cells in NME/MUO/NLE/GME
- CD3+ T cells adhered astrocyte in NME/GME
- CD20+ B cells in NME, NLE, GME
- IgG positive cytoplasm and astrocytic process in NME>NLE
in which inflam pathol are indentified
1. oligoclonal bands
2. GFAP
3. serum cytokines
4. glutamate
5. neurofil light chain in CSF and blood
6. fecal microbiome
- MUO
- NME and healthy Pugs
- IL 10 in normal at risk Pug, IFN gamma in NME, IL17 in MUO
- NME
- MUO + decrease in treat responder, increase in non respond
- Prevotellaceae less abundant in MUO
elevated CRP and MUO
blood CRP assoc with duration clinical signs
most frequent sign with neospora caninum
cerebello-vestibular
46% multifocal
complete improvement 5%, relapse 30%
GFAP and Pug myelopathy
anti GFAP antibody and CSF GFAP but no serum GFAP (only in NME)
neutro/lympho ratio cutoff for MUO
4.16 sensit 71% specif 83% from dog with other forebrain disease
human disease simmilar to NME
multiple sclerosis
human leucocyte antigen DR15
young female
maj T cells (CD4+ acute, 8+ chronic)
demyelination
oligoclonal bands ans k-free light chain in CSF
cytokines in asymptomatic pug at risk of NME
lower proportion of CD4+
higher plasma IL10 concent
MRI fidings to differenciate granuloma from glioma
unusual for glioma:
- dural contact,
- T2-hypointensity,
- concomitant meningeal-enhancement,
- minor changes in the contralateral brain,
- caudal location,
- severe mass effect/perilesional edema,
- homogenous enhancement.
Lack of pronounced cerebrospinal fluid pleocytosis does not exclude granuloma.
eosinohilic MUO
1/ def
2/ affect young/old, small/big
3/ associated with which infectious cause
4/ MRI lesion
1/ eosino >10% CSF
2/ young large breed
3/ Neospora, Toxoplasma, Angiostrongylus, Prototheca, Cryptococcus, distemper, rabies, Bacterial
4/ multifocal symm GM T2 hyper, meningeal enhanct
MRI method for evaluate BBB permeability
dynamic contrast enhancement
substraction enhancement analysis
% BBB dysfunction in MUO dogs
50%
dogs with BBBD has higher seizure preval
albumine extravasation =>activ TGNFbeta => activ astrocytes, degrad extracel matrix, decrease inhib synaptic transm, generation excit synapse
factor for recovery in optic neuritis
young age, reactive PLR, no fundoscopic lesion, low TNCC CSF
duration blindness not assoc with outcome
complete recov vision 20-30%
antibodies detected in encephalitis
anti GFAP in CSF of dogs with GME and NE
anti LGI1 in cat with limbic encephalitis
anti NMDAR in dogs with MUO
causes of hyperammoniemia
1) cong or acquired (portal hypert, cirrhosis) portosystemic shunt (PSS)
2) hepatic insufficiency
3) aquired urea cycle amino-acid deficiency
4) cobalamin deficiency/malabsorption and accum of methylmalonic acid
4) metabolic disorders of organic acids
5)** xylitol, 5-fluoouracil**
6) congenital urea cycle enzyme def as ornithine transcarbamylase def
7) cat arginine deficiency (can be secondary to lipidosis)
8) azotemic cat
Clinical features, treatment, and outcome of juvenile dogs with meningoencephalitis of unknown etiology:
1. clinical signs
2. localisation
3. outcome
- Altered mentation (71%), ataxia (44%), seizures (29%), and circling (26%) were the most common presenting complaints
- forebrain (38%), multifocal (35%), brainstem (18%), and cerebellum (12%).
- 31% were alive at the time of data collection with a follow-up range of 135 to 2944 days. median survival time for all-cause death of 84 days.
CSF velocity:
1. Dogs with body weight >20 kg had higher CSF peak velocity compared with dogs <10 kg within the ventral and dorsal subarachnoid space at the FM and C2
- Dogs ≤2 years of age had significantly lower CSF peak flow velocity at the ventral SAS of the FM.
- Females had significantly lower CSF peak flow velocity within the ventral SAS of FM.
- true
- false (higher)
- true
MUO at 6 months:
1.% alive, % persistant signs, % relapse during treat
2.factor neg associated with survival
3.fact assoc with peristant deficit
4.fact assoc with relapse
5.fact assoc with all
- 63% alive, 40% persistant def, 50% relapse
- pug, epil, paresis, NDS
- neurodisab score
- incomplete resolution, longer dur clinical signs, NDS
- higher neurodisability score
most common signs in MUO
Proprioceptive deficits 70%
Obtundation 60%
Ataxia 55%
Visual deficits 53%
neurodisability sclae in MUO
ambulatory status
cerebral function (coma)
cerebellar
BS
visual function
posture abnomalities
seizures
median survival time in dog <52w with MUO
84 days
Altered mentation (71%), ataxia (44%), seizures (29%), and circling (26%) were the most common presenting complaints
% MUE with normal MRI, prognosis
26% were classified as normal MRI cases
survival was significantly longer in the normal MRI group
Death caused by MUE occurred in 1/19 (5%) normal MRI dogs and 18/54 (33%) abnormal MRI dogs
side effect cyclosporine
gastroi-intest+
gingival hyperplasia (treatment with azithromycin), opportunistic infections, hepatotoxicity, anaphylaxis, thromboembolic complications, and lymphoproliferative disorders
substrate of cytochrome P450 enzyme CYP3A
substrate P-glycoprotein
in cats, decreased cyclosporine concentrations occurred with
cyclosporine co-administrated with phenobarbital
breed with higher/lower activity of azathioprine
lower TMPT activity in giant schnauzers and higher TMPT activity in Alaskan malamutes
side effect azathioprine
GI upset (vomiting and diarrhea), myelosuppression (3m, 10%), hepatotoxicity (2w, 15%), and pancreatitis
allopurinol increase toxicity
side effect chorambucyl
Cytotoxic myelosuppression
GI toxicity
reversible myoclonus with overdose
