Canine Encephalopathies - Sugar Land Veterinary Specialists

Canine
Encephalopathies:
Nervous System Meltdowns
Emily G. Davis, DVM Neurology/Neurosurgery Sugar Land Veterinary Specialists DrDavis@SLVetSpecialists.com November 16, 2014 Encephalopathy-­‐ Clinical ManifestaIons •  Cerebrum/diencephalon-­‐ •  Altered mental status, seizures, head pressing, visual impairment, circling, propriocep7ve deficits •  Brainstem-­‐ •  Stupor/coma, CN deficits (III-­‐XII), propriocep7ve deficits, gait abnormali7es, central ves7bular dysfunc7on •  Cerebellum-­‐ •  Normal menta7on (if only structure affected), inten7on tremor, hypermetria, paradoxical ves7bular dysfunc7on Disorders of the Brain • Trauma7c • Congenital • Degenera7ve • Metabolic/Toxic • Vascular • Neoplas7c • Inflammatory àInfec7ous à Non-­‐infec7ous Congenital
•  Hydrocephalus www.vet.ohio-­‐state.edu-­‐486
Brain MRI Normal lateral ventricle Grossly dilated lateral ventricle Normal Brain Hydrocephalic Brain Congenital • Caudal Occipital Malforma7on Syndrome (COMS) Chiari-­‐like Malforma/on Syringomyelia Syrinx •  SM COMS •  Young adults •  Secondary syringomyelia (SM/syrinx) in cervical spinal cord •  Cervical pain •  Scratching at ears and neck •  Ataxia x 4à tetraparesis Normal Caudal Fossa & Cervical MRI COMS/SM MRI Treatment
Medical
Analgesics Reduc7on CSF Steroids Surgical Subocciptal Craniectomy Dorsal C1 laminectomy hYp://cavalierhealth.org/syringomyelia.htm DegeneraIve • Lysosomal storage diseases and leukodystrophies •  Young (few weeks to a year depending on the disease) •  Typically breed related •  Usually autosomal recessively inherited •  Absence of or defect in enzymes needed to remove intracellular products of metabolism •  Rare Leukoencephalomyelopathy Globoid Cell Leukodystrophy Neoplasia •  Median age for dogs to develop primary brain tumors is 9 years old •  Animal may present with variety of clinical neurologic signs depending on loca7on and severity of lesion (mild seizuresàcoma) •  Signs usually insidious, progressive •  Occasionally acutely decompensate neurologically without previous symptomology (edema, hemorrhage) T1W post-­‐contrast Meningioma Neoplasia Treatment •  Medical •  Steroids-­‐ reduc7on in cytotoxic edema, strictly pallia7ve •  PPI •  Surgical •  Extra-­‐axial tumors most amenable to resec7on •  Radia7on •  Chemotherapy Surgery alone or in combinaIon with radiaIon therapy for treatment of intracranial meningiomas in dogs: 31 cases. (Axlund TW, 2002) •  In dogs, although meningiomas are histologically benign, the tumors are not well encapsulated and difficult to remove micro-­‐ and even macroscopic disease in some cases •  Dogs that underwent tumor resec7on alone for meningioma MST-­‐ 7 mo. (range 0.5-­‐22 mo.) •  Tumor resec7on + RT MST 16.5 mo (range 3-­‐58 mo.) Prognosis aXer surgical excision of cerebral meningiomas in cats: 17 cases. (Gallagher JG, 1993) • Long-­‐term follow-­‐up informa7on was obtained for cats with cerebral meningiomas treated by surgical excision. • 11 cats (78.6%) did not develop evidence of local tumor recurrence within follow-­‐up period • MST 27 months Bacterial MeningoencephaliIs •  Primary CNS bacterial infec7ons small animal species are uncommon •  Secondary-­‐ iatrogenic (Epidural, CSF puncture, Sx), wounds, O77s media/interna, nasal (fungal more commonly), FB •  No clinical studies on efficacy of an7bio7cs on CNS infec7ons in veterinary pa7ents •  Extrapola7ons from human literature Most Common E7ologies of Bacterial Meningoencephali7s Streptococcus Staphylococcus Enteric gram nega7ve bacilli (E. coli, Klebsiella pneumoniae) Diagnosis •  The brain being a “protected space” from the rest of the immune system, no changes may be seen on rou7ne blood chemistries or CBC •  Fever 40% •  Cervical pain 20% •  Almost all causes of encephali7s (infec7ous, inflammatory, neoplas7c, etc.) can have the same symptoms, therefore the same “neuro workup” is omen recommended •  MRI in bacterial CNS infec7on may show signs of brain and/or meningeal inflamma7on, abscessa7on, and edema/hernia7on CSF Analysis
•  Important to obtain samples BEFORE any administra7on of an7bio7cs when possible •  Obtain samples for: •  Cytology •  WBC/RBC counts and differen7al •  Protein levels •  Aerobic and anaerobic culture and an7bio7c suscep7bility •  Increased # WBC in CSF= Pleocytosis Protein Level Total Nucleated Cell Count Normal Abnormal >25 mg/dl (AO) >25 mg/dl <5 WBC/µl >5 WBC/µl CSF in Bacterial InfecIon •  Abnormal cytology in over 90% of bacterial CNS infec7ons •  Neutrophilic Pleocytosis •  Degenerate Neutrophils •  Intracellular Bacteria •  Nega7ve culture does not rule out infec7on (Bacterial Meningoencephalomyeli7s in Dogs: A Retrospec7ve Study of 23 Cases (1990-­‐1999) Radaelli, JVIM 2002) http://www.vetmed.auburn.edu/media/pathobiology/cytology-and-histopathology/cytology-histopath-pkg44
DifficulIes in TreaIng CNS InfecIons • Blood Brain Barrier • Blood-­‐CSF barrier • Low protein content of CSF • Low levels phagocy7c cells • Low an7body levels AnIbioIc Use in Brain, Spine and Meningeal InfecIons Achieve adequate CNS conc. Do NOT achieve adequate CNS conc. 3rd generaIon Cephalosporins 1st and 2nd generaIon Cephalosporins Carbapenams Penicillins Metronidazole Aminoglycosides Trimethoprim Fluoroquinolones rd
3 generaIon Cephalosporins Cefotaxime preferred drug in small animals •  Gram nega7ves and Strep •  30-­‐80 mg/kg IV q 8 hr Cemazidime •  Psuedomonas •  20-­‐30 mg/kg IV q 8 hr Trimethoprim •  Trimethoprim-­‐sulfadiazine •  Trimethoprim-­‐sulfamethoxazole •  Ac7ve against bacteria and protozoa •  Persist longer within 7ssues than in plasma •  Mul7ple possible adverse side effects •  Dosage for bacterial CNS infec7on 15-­‐30 mg/kg PO q 12 hr Metronidazole •  Anaerobes only (Bacteroides fragilis) •  Lipophilic •  10 mg/kg PO, IV q 12 hr •  Beware of dose related neurotoxicity •  Ves7bular, seizures, paresis •  Adverse neurologic SE typically seen at >60 mg/kg/day or with chronic use Surgical Treatment •  In cases in which CT or MRI can localize an accessible abscess, surgical sampling, culture and debridement is indicated •  Cases of infec7ous o77s media/interna with secondary intracranial extension should be addressed surgically ASAP for best chance of recovery Brain abscess in seven cats due to a bite
wound: MRI findings, surgical management and
outcome
by Holger Volk, JFMS 20011.
Protozoal InfecIons •  Toxoplasma gondii •  Dogs and cats •  Neospora caninum •  Dogs only Transmission •  Ver7cal •  Inges7on of 7ssue cyst in intermediate host •  Occur most commonly in young or immunocompromised pa7ents Toxoplasmosis • Clinical disease is rare • Seroposi7vity rates high Overall 40.6% felines in US (Lappin, 2006) Ø 
• Generalized systemic disease • Meningi7s, encephali7s, myeli7s • Choriore7ni7s, uvei7s Toxoplasmosis Diagnosis • Bloodwork-­‐ anemia, neutropenia, increase liver enzymes • Chest radiographs-­‐ inters77alàbronchoalveolar • CSF Analysis-­‐ variable (PMN, monocytes), rarely Toxoplasma organisms observed • MRI Brain and/or spine-­‐ solitary or mul7ple mass lesions in CNS, meningeal enhancement Segmental Meningomyeli7s in 2 Cats Caused by Toxoplasma gondii (L. Alves, 2011) TI-post
contrast
TI
Fig 3. T1-weighted dorsal section of the spinal cord pre- and postcontrast.
Extension of the intramedullary lesion between T5 and T9 with
strong contrast uptake.
Toxoplasmosis Diagnosis • IFA Ø 
Ø 
IgM indicates ac7ve infec7on IgG indicates exposure • PCR Ø 
Ø 
CSF, Aqueous Humor, Tissues Prone to false posi7ve and false nega7ves • Tissue Histology SuggesIve of Clinical Toxoplasma InfecIon Correla7ng clinical signs AND 1.  Any posi7ve CSF an7body 7ter or 2. Serum IgM >1:64 or 3. 4x or greater increase in serum IgG 7ters Tx and prognosis •  Clindamycin 12.5-­‐25 mg/kg PO BID x 4 wks •  TMS 15 mg/kg PO BID x 4 wk •  + Pyrimethamine 0.5-­‐1.0 mg/kg/day x 2 wk •  + Folic acid •  Neurologic signs typically improve with treatment (best treated early!) •  Infec7on is unlikely to be cleared from the animal •  Will remain seroposi7ve •  Relapses possible •  Overall prognosis guarded Neospora canis Prevalence •  Neosporosis is found world-­‐wide •  In the United States, 10.3-­‐60.6% of dairy caYle (n=8,342) and 5.2-­‐79% of beef caYle. Transmission in dogs •  Inges7on of bradyzoite-­‐laden 7ssues of caYle, par7cularly placenta and fetal membranes •  Transplacental transmission •  Raw meat Neospora-­‐ Two Main Forms 1.  EncephalomyeliIs • 
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Any age dog Focal or mul7focal CNS signs Cerebellar signs common Seizures, obtunda7on CN deficits Ataxia, paresis Propriocep7ve deficits 2. MyosiIs-­‐PolyradiculoneuriIs • <6 mo old • Organisms have predilec7on for lumbosacral nerve roots • Progressive, ascending paraparesis, -­‐plegia • Hindlimb rigidity and hyperextension • Muscle atrophy and immobile joints Clinical Symptoms Neospora caninum infection in three dogs. C. Knowler and S. J. Wheeler. JSAP 2008
Neosporosis and hammondiosis in dogs. JSAP Volume 48, Issue 6, 2007
DiagnosIcs • +/-­‐ elevated CK and AST • Brain MRI • CSF-­‐ mixed cell pleocystosis, few eosinosphils, elevated protein • Serology •  Neospora 7ter •  no cross reac7vity with Toxoplasma immunoglobulins CerebelliIs MRI • Muscle biopsy-­‐ non-­‐suppura7ve inflamma7on, tachyzoites within myocytes Neutrophils, macrophages and eosinophils
infiltrate the same muscle
small tachyzoites of Neospora in skeletal
muscle (arrow)
http://www.vet.uga.edu/ivcvm/courses/vpat5215/musculoskeletal/mus/inflammatory03.htm
Neosporosis Treatment •  Clindamycin 12.5-­‐25 mg/kg PO BID x 4 wks •  Trimethoprim-­‐Sulfa (TMS) 15 mg/kg PO BID x 4 wk •  + Pyrimethamine 0.5-­‐1.0 mg/kg/day x 2 wk •  + Folic acid Prognosis • Good to guarded if treated early • Poor to grave if muscle atrophy, joint immobility/rigidity, paraplegia present Photo courtesy Shel Steinberg, VMD
Neospora PrevenIon • Prevent contamina7on of livestock feed with canine feces. • Do not allow dogs to ingest bovine placental 7ssues, fetal membranes, or other raw meats. • Do not breed bitches that have previously developed clinical neosporosis or have whelped affected pups in the past. *Neospora is not a known zoonoIc disease threat Rickeesial MeningoencephaliIs • Ehrlichia spp. • Ricke?sia ricke?sii (RMSF) • Obligate intracellular parasites • TransmiYed via bites of infected 7cks Symptoms •  Encephalopathy •  Meningi7s secondary to vasculi7s and hemorrhage •  Ataxia, seizures, paresis, ves7bular dysfunc7on, obtunda7on, cerebelli7s • Petechia, ecchymosis • Fever • Uvei7s • Polymyosi7s, polyarthri7s • Lethargy, Wt. loss Clinicopathologic findings
•  Thrombocytopenia •  Mild non-­‐regenera7ve anemia •  Neutropenia •  Eosinophilia •  Morulae in granulocytes or monocytes •  CSF*-­‐ mononuclear, neutrophilic, or mixed pleocytosis Cerebrospinal Fluid PCR and AnIbody ConcentraIons against Anaplasma phagocytophilum and Borrelia burgdorferi sensu lato in Dogs with Neurological Signs (Jagerlund, JVIM 2009) • 54 dogs with CNS disease divided into two groups-­‐ • Dogs with inflammatory/infec7ous CNS disease • Dogs with other causes of CNS disease • Serology and PCR for Lyme disease and Anaplasma run on serum and CSF in both groups Groups of Dogs Inflammatory CNS diseases Non-­‐inflammatory CNS disease % Borrelia AnIbody PosiIve 0.0 10.3 % Anaplasma %PCR posiIve AnIbody PosiIve 0.0 0.0 20.5 0.0 • Neuroborreliosis is reported in humans and infrequently in equids
• Dogs experimentally infected with Borrelia fail to develop
neuroborreliosis
• Anaplasma and Lyme disease are unlikely causes of neurologic
disease in dogs
Diagnosis Rickseesial MeningiIs •  Serology •  Seroprevalance rate high, esp. Ehrlichia •  May have clinical signs of disease prior to seroconversion (up to 28 days) •  If nega7ve IFA and strongly suspect infec7on, repeat 7ters in 2-­‐3 weeks •  PCR •  Amplifies DNA of infec7ng organisms circula7ng in blood •  False nega7ves-­‐ low circula7ng numbers of pathogens, prior an7bio7c administra7on •  Nega7ve PCR does not rule out infec7on Consensus Statement on Ehrlichial Disease of Small Animals from the Infectious
Disease Study Group of the ACVIM 2002
Treatment •  Doxycycline 10 mg/kg PO q 12 hr x 28 days (Ehrlichia or RMSF) RMSF Only •  Enrofloxacin 5 mg/kg PO BID x 14 days •  Chloramphenicol 20-­‐30 mg/kg PO q 8 hr x 14 days Prognosis •  Good •  Response to treatment usually rapid for dogs treated during the acute phase of disease Fungal MeningoencephaliIs •  Cryptococcus •  Coccidioides •  Blastomyces •  Aspergillus •  Histoplasmosis •  Cladosporium •  phaeohyphomycosis spp. Neuroinfec<ve Pathogenesis
•  Animals most frequently infected following inhala7on of the organisms •  Spread to CNS via hematogenous route or erosion through cribriform plate •  Forebrain signs (head pressing, altered behavior, seizures, blindness) to brainstem lesions Clinical and Magne<c Resonance Imaging Features of Central Nervous System Blastomycosis in 4 Dogs. (L. Lipitz, JVIM 2010)
MRI Brain
Sagittal TI-W
postcontrast image
Lesions in the nasal cavity and frontal cortex enhance strongly and
homogenously with an area of ring enhancement (arrow).
IMAGING DIAGNOSIS—INTRACRANIAL CRYPTOCOCCAL MASS IN A CAT (Hammond, VRUS, 2011) Diagnosis •  Surgical biopsy of CNS or nasal granuloma(s) •  ID of fungal organisms on CSF cytology •  Coccidioides immi/s Ab 7ters IgG/IgM •  Cryptococcus Ag (CSF, very sensi7ve) •  Blastomyces/Histoplasma Ab (Urine or CSF, cross-­‐reac7vity) Treatment
• Surgical debulking granulomas • Amphotericin B-­‐ penetra7on into CNS limited • Oral therapy-­‐ Fluconazole achieves higher CSF concentra7ons than ketoconazole or itraconazole Ø 
Preferred treatment for Aspergillosis: itraconazole +/-­‐ amphotericin Ø  Prognosis poor to grave for CNS infec7on • Fluconazole •  Dogs 5 mg/kg PO BID •  Cats 50 mg/cat PO BID • Dura7on of treatment typically very prolonged (months to over a year) • Dependent on reduc7on in 7ters, resolu7on of MRI lesions, and clinical signs • Overall prognosis varies depending on infec7ng genus and severity of clinical signs •  Cryptococcus and Coccidioides tend to respond more favorably Canine Viral EncephaliIs •  Distemper •  Rabies •  Herpesvirus •  Pseudorabies •  Adenovirus •  West Nile Virus •  Parvovirus Canine Distemper Virus Polioencephalomyelopathy Leukoencephalomyelopathy < 1 year old Mature dogs Gray maYer disease Inflammatory demyelina7ng white maYer disease Forebrain signs Brainstem, cerebellum, spinal cord Ataxia, myoclonus, “chewing gum” fits, NOT always preceded by extraneural signs seizures common, NOT always preceded by extraneural signs Distemper diagnosis • Conjunc7val scraping/urine sediments-­‐ typically unrewarding • Buffy count smear-­‐ intracytoplasmic inclusions WBC • Serum Ab 7ter alone •  Very difficult to interpret due to interference from CDV vaccine/
maternal AB •  If posi7ve 7ter obtained from unvaccinated dog >4 mo old with sugges7ve clinical signs, an ac7ve infec7on is likely Distemper diagnosis
• Paired Serum and CSF Ab Titers •  An7bodies should be too large to cross an intact BBB and should not be found in CSF •  Comparison of serum to CSF 7ters can be helpful •  Even in previously vaccinated animal, CSF 7ter should not be higher than serum 7ter Treatment and Prognosis • An7convulsants when indicated • Mexili7ne or procainamide for myoclonus • Prognosis poor to grave Non-­‐infecIous Inflammatory EncephaliIdes • Granulomatous MeningoencephaliIs (GME) • NecroIzing LeukoencephaliIs (NLE) • Eosinophilic MeningoencephaliIs GME • Idiopathic inflammatory disease of CNS in dogs • Evidence this disease represents an autoimmune disorder • Delayed T-­‐cell mediated hypersensi7vity reac7on • Autoan7bodies directed against astrocytes • Histologically: perivascular cellular infiltrates CNS GME/NME • Any breed and any sex CAN be affected • Small breeds and terriers predisposed (GME) • Pugs, Yorkies, Maltese (NME, NLE) • Young to middle aged (median age 5 years) • Can be rapidly fatal Danger!
=
Medical Neurological Emergency
GME-­‐ Three Main Forms 1. MulIfocal/Diffuse • 
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Most common Acute, rapidly progressive White maYer disease Cerebrumà Seizures, behavioral change Brainstemà CN, paresis, obtunda7on Cerebellumà ataxia, tremor Cervical Spinal Cordà paresis, pain @
TIW postcontrast
T2W
Fig. 2. Images of the brain of a 6-year-old dachshund with granulomatous meningoencephalomyelitis. Extensive
signal abnormalities are present throughout the gray and white matter of the cerebellum. Strong ring enhancing
lesions are present in the cerebellum. Swelling is suggested by the lack of visible cerebellar folia. (Vite. VRUS 2011)
2.  Focal Less common Insidious onset Progressive clinical signs Predilec7on for forebrain and pons/medulla Mass lesion(s) on MRI 3. Ocular Rare Op7c Neuri7s Acute mydriasis No PLR Papilledema Right and left fundus photographs. Notice the indistinct
margins of the optic nerve, the peripapillary edema, and the
swollen optic nerve heads.
NecroIzing EncephaliIdes • NecroIzing meningoencephaliIs (NME) •  Pug dog encephali/s •  Maltese encephali/s •  Mostly cerebral cortex •  Gray and white maYer disease • NecroIzing LeukoencephaliIs (NLE) •  Yorkshire terrier Encephali/s •  Gray and white maYer disease •  Cerebrum and brainstem MRI TTIR:
Cavitated region
white matter left
frontal cortex
MRI T1W:
Same level as
image A. Right
frontal cortex.
Cavitated region
with ring of
contrast
enhancement
Multifocal cystic
cavitations
confined to the
subcortical white
matter
MAGNETIC RESONANCE
IMAGING AND PATHOLOGIC
FINDINGS ASSOCIATED WITH
NECROTIZING ENCEPHALITIS IN
TWO YORKSHIRE TERRIERS.
Ferdinand. VRUS 2006.
Diagnosis • Histopathology only way to make defini7ve diagnosis •  Stereotac7c or surgical biopsy •  Necropsy • Ante-­‐mortem diagnosis based upon: •  Characteris7c signalment •  Clinical findings •  Diagnos7c test results Diagnosis •  Idiopathic inflammatory encephali7s remains a diagnosis of exclusion in many cases •  Changes on MRI and CSF are omen most consistent with GME/NME but could be caused by other e7ologies (i.e. infec7ous disease) •  Diagnosis can become very challenging as well if pa7ents are presented for diagnos7cs having previously been treated with immunosuppressive/ an7-­‐inflammatory drugs •  Steroids •  NSAIDs Diagnosis • CSF • Can provide very useful diagnos7c informa7on antemortem • Mononuclear pleocytosis • Variable amounts of neutrophils (mean 20%) • Up to 25% of cases with MRI changes consistent with GME may have normal CSF analysis • Elevated protein levels • No infec7ous organisms Diagnosis • CSF • Brain MRI • Serology •  Toxoplasma, Neospora •  Ehrlichia, RMSF •  Cryptococcus, Coccidioides •  +/-­‐Distemper •  +/-­‐CSF culture “Chili”
3 year old FS
Brussels Griffon
Presented for a 2 day
history progressive
obtundation and
ataxia. 1 day history
cluster seizures.
Neuro Exam Menta7on: Mildly obtunded in examina7on room Gait: normal gait, wide circles to L CN: no menace OD, diminished response facial s7mula7on R Propriocep7on: postural reac7on deficits R TL/PL Segmental reflexes: normal No spinal hyperpathia noted Normal anal tone, normal muscle tone NeurolocalizaIon: Lem cerebrum L
CSF Analysis (AO Tap) Color-­‐ none (none) Clarity-­‐ clear (clear) TP-­‐ 38 mg/dl (<25 mg/dl)
RBC-­‐ 2/µL (0) TNCC-­‐ 78/µL (<5/µL) DifferenIal cell count Neutrophils 14% Lymphocytes 35% Monocytes/Macro 46% Other
5% No infecIous organisms noted DiagnosIcs • Brain MRI-­‐ Mul7focal T2 & FLAIR hyperintense cor7cal lesions • CSF-­‐ mononuclear pleocytosis, elevated protein • Infec7ous disease serology-­‐ all nega7ve • Chemistries/CBC-­‐ no signs of metabolic disease • Typical signalment GME until proven otherwise
Treatment and Prognosis • CorIcosteroids only •  MST 14 days •  Dogs with focal GME had longer MST than dogs with mul7focal disease • Procarbazine & Prednisone •  An7neoplas7c drugs that crosses BBB •  MST 14 mo. •  Myelosuppression •  Hemorrhagic gastroenteri7s Treatment and Prognosis • Cytosine Arabinoside & Prednisone •  Synthe7c nucleoside analog that crosses BBB •  MST 1.5 yr •  Myelosuppression •  Hepatotoxicity • Cyclosporine & Prednisone •  Does not typically cross BBB, vasculi7s in GME may allow entry •  MST 2.5 yr •  Vomi7ng, shedding, gingival hyperplasia Ø 1/3 dogs do not survive discharge from the hospital Ø 1/3 achieve ini7al remission and later succumb to their disease Ø 1/3 achieve remission and over period of several months-­‐year can discon7nue treatment Chili
Prednisolone 2 mg/kg/day
Cyclosporine 5 mg/kg BID
Cytosine 300 mg/m2 CRI q 3 weeks
Phenobarbital
Keppra
She achieved clinical remission and doses of
immunosuppressants were slooowly tapered over several
months. At 3 months into tx, a repeat CSF analysis was
normal.
5.5 months into tx, presented for cluster seizures, circling,
stupor, ataxia, vestibular dysfunction and did not respond
to an increase in immunosuppressants.
Summary • Serological tes7ng measures an7body levels only and must be interpreted along with clinical signs and other diagnos7c findings. • It is rare that clinical signs of encephalopathy will indicate a specific disease process thus extensive diagnos7cs are indicated in many cases. • Although the outward signs of CNS disease are omen disturbing to the owner and clinician, they are just an external manifesta7on of internal disease and not necessarily a poor prognos7c indicator. QuesIons? Cases?