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Bacterial and Fungal Disease of the CNS

Simon R Platt BVM&S MRCVS Dipl. ACVIM (Neurology) Dipl. ECVN

College of Veterinary Medicine University of Georgia, Athens, USA

Introduction

n  Meningitis / Encephalitis / Myelitis n  Abscess – enclosed collection of

liquefied tissue known as pus; can be sterile or septic

n  Granuloma – mass of chronically inflamed tissue; can infectious or sterile

n  Empyema – pus in a cavity, space or potential space

Brain Abscess n  Liquefactive necrosis n  Surrounding brain is edematous n  May present with progressive

focal deficits & general signs of raised intracranial pressure

n  CSF may contain normal to slight increased number of wbcs and increased protein

n  May lead to herniation or rupture into CSF

Juliana de Castro Cosme et al, Rev Bras Med Vet 2015

Stages of Abscess Formation

n  Britt et al; Canine model - J of Neurosurg 1981 1.  Early cerebritis – days 1-3; perivascular

inflammation / neutrophil invasion / edema 2.  Late cerebritis – days 4-9; central area of

necrosis and peripheral fibroblast accumulation 3.  Early capsule – days 10-14; well vascularized

tissue with further fibroblast migration 4.  Late capsule - >day 14; collagen fiber and

granulation tissue deposition thickens capsule

Entry of CNS Infections

n  Hematogenous spread n  most common n  Especially if immunosuppressed

n  Direct implantation – usually traumatic

n  Local extension – secondary to infection in ear / nose / sinus / tooth root

Pathogenesis of Hematogneous Bacterial CNS Infection

1.  Colonization in body system / adhesion to mucosa

2.  Mucosal invasion & penetration into bloodstream

3.  Cross the blood brain barrier usually at endothelium of choroid plexus into ventricular fluid

4.  Multiply in CSF / inflammatory response

5.  Cerebral edema

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Otogenic Origin CNS Infections

n  Meningitis and abscesses n  Associated with long standing

otitis media-interna n  Can be acute or chronic in

onset n  CT can demonstrate skull

defects n  MRI ideal for caudal fossa soft

tissue abnormalities

Clinical Signs in Dogs n  Acute to chronic n  Progressive n  Asymmetric, multifocal n  Cranial nerve / Visual deficits n  Altered mentation n  Paresis n  Seizures n  Postural reaction deficits n  Neck pain n  Pyrexia

DIFFERENTIAL DIAGNOSIS for Inflammatory Disease

Subacute-chronic, progressive, asymmetric +- pain n  V Vascular n  I n  T Trauma, Toxin n  A Anomalous (developmental) n  M Metabolic n  I Idiopathic n  N Neoplastic, Nutritional n  D Degenerative

Diagnosis of Inflammatory Disease

Minimum Data Base n  Good history – travel / in contacts? n  Physical exam n  Neurological exam n  Fundic exam n  Hematology / Serum chemistry n  Urinalysis n  Bile acids n  Thoracic and abdominal imaging n  Infectious disease titers / PCR

Diagnosis of Inflammatory Disease

n  Skull radiography n  Computed tomography n  Magnetic resonance n  Cerebrospinal fluid n  + / - Electroencephalography n  +/- Tissue biopsy????

CSF ANALYSIS n  Requires anesthesia n  Requires technical experience n  Requires immediate laboratory

analysis n  Add hetastarch or autologous

serum and store at 4°C n  Rarely specific but very

sensitive

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CSF ANALYSIS

n  Ideal to obtain cisternal and lumbar samples

n  Subjective qualities n  Cell count n  Protein level n  Cytology n  Titers & PCR n  Culture n  Electrophoresis

CT Scan

n  Excellent for imaging bone

n  CT can demonstrate significant abnormalities of parenchyma

n  Contrast enhancement can help

n  Poor imaging of caudal fossa

Bilderback et al J Vet Emerg Crit Care 2009

MRI n  Excellent soft tissue detail n  Extent of disease can be assessed n  Not specific n  76% sensitive compared to CSF (Lamb 2005)

MRI Brain Abscess n  T1W

n  Central hypointensity (hyperintense to CSF) n  Peripheral low intensity – vasogenic edema n  Ring enhancement n  +- ventriculitis and hydrocephalus

n  T2W / FLAIR n  Central hyperintensity (hypointense to CSF) n  Does not attenuate on FLAIR n  Peripheral high intensity – vasogenic edema n  Abscess capsule may be visible as intermediate to slightly low signal

thin rim n  Differentials include neoplasia, infarction, hematoma, granuloma

Bahn et al J Kor Neurosurg Soc 2010

2 yr Old Mix CN – CT & MRI

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Bacterial Disease

n  Dogs can have infection spread from ear / nose / skin / abdomen

n  Plethora of organisms – staph / strep / pasteurella / actinomyces/ nocardia / e. coli

n  11/23 pyrexic in one study & 5/23 had neck pain

n  Brain > Spine (empyema) n  Can lead to secondary hydrocephalus

n  Guarded prognosis

Bacterial Disease

n  CSF tap imperative n  Possibly purulent n  Neutrophilic pleocytosis -70% dogs (18-10,850)

n 7% humans /2-16% dogs no pleocytosis

n  Multiplex PCR bacterial genome n Not affected by prior antibiotics

n  Gram stain n  Culture (13-31% positive in dogs) n  CSF lactate levels

Antibiotic Therapy

2-3 months oral therapy if no surgery n  Ampicillin n  Clavulanated Amoxicillin n  Enrofloxacin n  Third generation cephalosporins n  Metronidazole n  Trimethoprim-sulphadiazine n  Doxycycline

First 2-3 days

Empirical therapy of brain abscess

Steroidal Therapy

n  Decreases host defense and decreases penetration of some antimicrobials

n  May result in improvement of neuro signs n  Useful if:

n  Associated edema and mass effect n  Progressive neuro deterioration

n  Short term & anti-inflammatory doses n  Start before or same time as antibiotics

Surgical Therapy

n  Optimal approach to humans with bacterial abscess

n  Aspiration after bur-hole placement or complete excision with craniotomy

n  Intra-operative ultrasound assisted

n  Bulla osteotomy if otogenic n  In humans, recurrence rates after

aspiration 0-24%

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Indications for Initial Surgical Treatment

n  Significant mass effect n  (>2.5cm diameter) n  Proximity to ventricle n  Elevated ICP n  Poor neuro status n  Traumatic origin n  Fungal abscess n  Multiloculated

Pus Aspirated - What Next? Stains •  Gram stain •  Acid-fast stain for mycobacterium •  Special fungal stains

(methenamine silver)

Cultures •  Routine cultures – aerobic /

anaerobic •  Fungal cultures

Treatment of Empyema Fungal Infections of the CNS n  Usually associated with immunosuppression due to

drugs, age, breed or other diseases n  Mostly hematogenous dissemination

n  Rare direct extension (mucormycosis)

n  Yeasts - Leptomeningitis n  Hyphae - Hemorrhagic infarcts

From: Neuropathology Illustrated 1.0

Cryptococcal Encephalomyelitis

n  Common fungal CNS disease n  May also involve eyes, nose or skin n  C. neoformans (dogs) & gattii (cats) n  Spread to CNS from nose or blood

n  6-42% cats n  26-68% dogs

n  Often diffuse / multifocal neuro signs n  Neck pain in dogs and TL pain

in cats

Cryptococcal Encephalomyelitis

n  Culture and Ag testing is necessary but not

100% sensitive n  Organisms not always in CSF

n  9/11 cats and 11/15 dogs

n  CSF analysis variable but cytology essential n  Mean wbc 200-300/il n  Median wbc 21-67/ul n  Median protein 39-161 mg/dl

n  Mixed or granulomatous pleocytosis in dogs n  Neutrophilic in cats n  Cryptococcal capsular antigen in serum or

CSF

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Cryptococcosis n  Meningitis versus gelatinous

pseudocysts n  Dilation of Virchow-Robin Space

n  MRI characteristics depend on whether there is meningo-encephalitis, pseudocysts or cryptococcomas

Cryptococcal Encephalomyelitis

n  Fluconazole 5-15 mg/kg PO bid for 6 months >>Itraconazole

n  Amphotericin B SQ 16mg/kg n  Glucocorticoid use after diagnosis

improves 10 day survival n  Altered mentation associated with a

negative outcome n  32% cats and dogs remission >1yr n  55% dogs successfully treated but

recrudesce n  > 6mo median survival possible if

survive >4 days after diagnosis Sykes et al J Vet Int Med 2010 O’Brien CR, et al: Aust Vet J 2006

Aspergillus Encephalitis

n  Soil or plant saprophyte causing disseminated infection

n  A. fumigatus / flavus – sino-nasal / lung

n  A. terreus / deflectus - disseminated n  More common in GSDs n  Often young dogs (median 3yrs) n  Mostly females? n  May be extension of nasal dz n  Multifocal / often vestibular

Aspergillus Encephalitis

n  Galactomannan EIA test n  Urine, blood, CSF, tissue

culture n  CSF

n  Neutrophilic pleocytosis n  Increased protein

n  MRI may be normal n  Mass lesions n  Multifocal n  Contrast enhancing n  Hemorrhagic infarctions Taylor et al J Vet Int Med 2015

Aspergillus Encephalitis

n  No topical treatment if cribriform is damaged

n  Voriconazole 5mg/kg PO bid n  +- terbinafine 6.25mg/kg PO bid

n  Itraconazole 5mg/kg PO bid n  +- anti-inflammatory steroids n  Disseminated disease carries poor

prognosis (0-25 mo)

Coccidioidomycosis n  Soil organisms endemic to SW USA n  Inhalation leads to lung infections

n  Osteomyelitis in dogs n  Skin and disseminated in cats

n  Diffuse or focal CNS disease n  2/7 animals had normal CSF wbc count n  MRI lesions could be intra or extra-axial

– granulomas n  Need histo / cyto diagnosis

Bentley et al Vet Radiol US 2015

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Summary

n  Bacterial and fungal CNS disease has a poor prognosis

n  Originates locally or systemically n  May form focal or diffuse lesions n  May require surgery and or medical therapy n  Requires a combination of imaging and CSF

analysis to get close to diagnosis n  Only definitive is often histopathology