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Neurological diseases (usually) affecting
Juveniles and Adults
Bacterial Otitis interna and meningoencephalitis Listeriosis Clostridial - botulism
Viral Equine herpes viral encephalomyelitis – endemic in Wyoming WNV endemic in Wyoming
Parasitic Equine protozoal myelitis – very rare in WY Nervous coccidiosis – common in cattle Taenia multiceps – common in sheep
Rare / uncommon due to effective vaccines
WNV – endemic in Wyoming WEE – historically present, but rare in Wyoming EEE – not in WY – not discussed Rabies - can occur in very young also
- neurological symptoms are quite variable
- own lecture by Dr. O’Toole
- very important zoonosis
- vaccine used in some horses
Toxic and Nutritional Nigropallidal encephalomalacia – occurs in WY Polioencephalomalacia – common in cattle in WY Hepatic encephalopathy – occurs world-wide; toxic causes vary with locality
Prion diseases Scrapie BSE
Organization of lecture
• Diseases with brain stem involvement
• Diseases primarily affecting cerebral
hemispheres
• Diseases primarily affecting spinal cordDi i il ff ti i l d
• Clostridial diseases
• Prion disease
- Species: seen most commonly in calves, but not
neonates
- Pathogenesis: typically an ascending bacterial infection
of the nasopharynx
Nasopharynx
Otitis interna (± brain stem meningoencephalitis) 1.
Nasopharynx
Eustachian tube
Middle ear
Inner ear
Brain stem and associated meninges
Isolates
- Mycoplasma species*
- Actinomyces pyogenes
- Staphylococcus aureus
- Streptococcus species
Otitis media / interna (± brain stem meningoencephalitis) 2.
Right facial nerve damage in otitis media / interna
Facial nerve passes through middle ear
Diagnosis: unilateral or bilateral, facial nerve paralysis, deafness, head tilt, pyrexia.
Treatment:
- Antibiotics, supportive (shelter, nutrition)
Prevention:
- If housed – clean environment is important
Otitis interna (± brain stem meningoencephalitis) 3.
p
- Don’t feed mastitic milk to calves
Listeriosis 1.
Species: ruminants >>> horses and man Zoonotic potential: associated with abortion, CNS infection
Cause: Listeria monocytogenes infects the brain-stem in ruminants. However, it is important to remember that this pathogen can also cause ocular infections, mastitis, abortion due to metritis and septicemia. The disease often occurs in winter in association with feeding of silage, butg g cases do occur also in animals at pasture. Pathogenesis:
Ruminants: L. monocytogenes gains access to the hind-brain by travelling up axons of the facial or trigeminal nerves. It is thought to cross the oral mucosa through minor abrasions before entering axons. Lm is a hardy bacterium and replicates easily in poor quality silage where the pH is >5. Disease often occurs in outbreaks. Horses: disease rare in horses. Usually diffuse encephalitis.
Listeriosis 2.
Clinical signs: - Ear droop, prehension, mastication
(chewing) and swallowing problems. Circling.
Necropsy:
-Bacterial culture from brain stem.
-Characteristic lesions. Microabscess (containCh t i ti l i Mi b ( t i
predominantly neutrophils) in the medulla oblongata and
pons. Inflammation is also present in the trigeminal
ganglion. Bacteria are Gram positive and may be intra-
cellular.
Treatment: antibiotics.
Prevention: No vaccine available in USA. Ensure good
quality silage.
Nigro-pallidal encephalomalacia 1.
Species: This disease affects horses only. Cause: It is caused by ingestion of either Yellow star thistle ( Centaurea solstitialis ) or Russian knapweed ( Centaurea repens ). Disease is typically found in summer and fall. The dried plants in hay are also toxic.
Yellow Star Thistle and Russian Knapweed – native to Eurasia, introduced into USA in 19 th^ century
Nigro-pallidal encephalomalacia 2.
Pathogenesis: The plants contain a toxic principle, repin, that mediates the effects of the disease. Repin causes degeneration of a brain region called the substantia nigra and globus pallidus. The substantia nigra is in the front end of the brain stem. This region also degenerations in Parkinson’s disease.
Midbrain of horse with NPEM
Symptoms: The brain regions involved are important in the control of movement. Problems with prehension, mastication, swallowing. Tongue protrudes. Weight loss dehydration, aimless wandering.
Treatment: Once neurons have been lost in the affected areas there is no regeneration. Mildly affected cases may make a small recovery.
Prevention: Grazing and pasture management. Avoid making hay from contaminated pastures.
Substantia nigra liquefaction
Polioencephalomalacia (aka. cerebral cortical
necrosis, thiamine-responsive encephalopathy) 1
Species: cattle, sheep and goats
Cause:
- thiamine-responsive PEM
- hydrogen sulfide toxicity [does not respond to thiamine]
- [lead poisoning or salt poisoning – may cause lesions similar to PEM]
Pathogenesis:Pathogenesis: cerebral cortex is metabolically very active and iscerebral cortex is metabolically very active and is
sensitive to defects of energy metabolism; thiamine deficiency and H 2 S interfere with cellular energy metabolism.
Symptoms: These are the same regardless of whether thiamine
responsive. Classically, opisthotonus (star gazing), central blindness due to involvement of visual part of cortex, recumbency, seizures. There should be no pyrexia.
There is cerebro-
cortical laminar necrosis
and brain swelling (A).
The brain has a very high
content of unsaturated
Polioencephalomalacia 2 – lesions
A
content of unsaturated
lipids. There is abundant
brain lipid oxidation in
PEM and this results in
the generation of lipid
oxidation products that
fluoresce with UV light
(B).
B
Polioencephalomalacia 3- thiamine-responsive
- A subset of cases respond to intra-venous thiamine [only
if thiamine administered in early stages of clinical
disease]
- This does not necessarily mean that animals are
thiamine deficient (hence the term thiamine-responsive)
- True thiamine deficiency may be important in some
cases howevercases however
- Potential origins of thiamine deficiency
- Thiaminase containing plants e.g. bracken ( Pteridium aquilinum )
- Thiaminase producing bacteria in intestines e.g. some Bacillus species
Distribution of Pteridium aquilinum in Wyoming by county [NB – most cases of thiamine-responsive PEM are not thought to be associated with specific thiaminase containing plants]
Xanthium strumarium
‘Cocklebur’
Senecio jacobea
‘Ragwort’
Many causes of hepatotoxicity – have plant expert evaluate pasture, need to rule out other sources of toxins – e.g. baled hay, water, drugs, man-made chemicals
Senecio jacobea is present in WY Xanthium strumarium is present in WY
Invasive species [not indigenous to USA] Cocklebur is native to USA
Coenuriasis
- Caused by the intermediate stage of the tapeworm
Taenia multiceps , usually causes brain lesions, variable
in location, occasionally spinal cord lesions
- Sheep>>goats, cattle, horses, humans
- • Disease symptoms develop 2 8 months after sheepDisease symptoms develop 2-8 months after sheep
ingests eggs
- Symptoms are variable, depend on cyst location, most
common site is in one cerebral hemisphere
- Circling is common, usually to one side
Dog is definitive host (also foxes, coyotes)
Life Cycle of Taenia multiceps
How may the life-cycle of this parasite be broken?
Sheep are important intermediate hosts
Cystic intermediate stage in brain of sheep – the cystic stage is called ‘Coenurus cerebralis’
Nervous coccidiosis
- Neurologic syndrome in calves-cattle affected with enteric coccidiosis
- Caused by Eimeria spp. of coccidia.
- Neurologic symptoms in up to 30% of infected animals
- Twitching, muscle incoordination, seizures
- Mortality rate of 70-90% for neurologic syndrome
- The exact cause of the neurologic syndrome is unknown-
- Electrolyte abnormalities secondary to intestinal diseaseElectrolyte abnormalities secondary to intestinal disease
- Toxin produced by coccidial species has been demonstrated by one group
- Treatment
- Coccidiostats
- To reduce incidence of seizures – keep animal in a quiet, dark area
- Supportive – shelter, fluids
- Prevention
- Cocciodiostats – medication in drinking water
- If housed – clean environment and fresh bedding
Locoweed poisoning 1.
- Species: horses more susceptible than ruminants
- Cause: ingestion of several plants of the genus Oxytropis
(and also Astralagus ) – 24 Oxytropis species ‘produce’ the
toxic principle called swainsonine – most are present in WY.
- For example: Predisposing factors-
White locoweed [ O. sericea ] Wyoming locoweed [ O. nana ]
Predisposing factors
- Access to plants
- Swainsonine concentration in plant
- Insufficient grazing
- No salt lick
Locoweed poisoning 2 – pathogenesis
Complex sugars
Swainsonine ingestion
Neuronal accumulation
α-mannosidase
p g
Simple sugars
Disease manifestation
Neuronal dysfunction and loss
Locoweed poisoning 3
Diagnosis
- History of exposure
- Consistent clinical findings – in horses – excessive salivation, wandering, altered gait, weight loss, hypersensitive to stimuli, mania, weight loss, infertility and abortion. Similar findings in cattlein cattle.
- Vacuolation of white blood cells
Management
- Prevent access to plants
- Good nutrition
- Recovery may take some time
- Why do you think that full recovery may not be complete in some animals?
West Nile Encephalitis 1
- History of West Nile Encephalitis (WNE) in USA: is a
mosquito borne viral infection that was first identified in
the USA in 1999. The disease occurs in horses (birds,
humans and less commonly in other species).
- Symptoms: Clinical symptoms in horses are varied.
Most cases have mainly spinal involvement.y p
- depression and violent behavior (forebrain involvement)
- ataxia, lameness, toe dragging, prayer posture, sensitivity to touch (spinal cord involvement)
- fever.
- Initial symptoms may resemble rabies
- Causes: WNV is an RNA virus in the flavivirus genus. Other flavi-
viruses also cause encephalitis e.g.^ tick borne encephalitis
in Europe.
WNV in birds in 2008 (^) WNV in horses in 2008
Pink=positives Green=submitted Yellow=not involved in surveillance, or did not submit samples
WNV in humans in 2008
Consider the whole of WY to be endemic for WNV, less surveillance than a few years ago
West Nile Encephalitis 2 – CNS lesions
Spinal gray matter lesions Spinal perivascular infiltrates
WNV antigen in spinal cord neurons and glial cells
Proliferation of glial cells
Non-suppurative polioencephalomyelitis
West Nile Encephalitis 3
- Diagnosis:
- Disease occurs during the mosquito season [May to October – peak in August].
- Suggestive clinical findings
- Antibody ELISA: serum IgM; CSF IgM – need to know vaccination status
- Positive on serum indicates recent exposure, may not be cause of disease
- Long term-effect of vaccine is an IgG response
- PCR on clinical samples such as CSF
- Necropsy: spinal cord examination is critical. There is non-suppurative perivascular inflammation affecting primarily gray matter (spinal cord > brain stem midbrain thalamus and basal nuclei) Confirmatory diagnostic toolsstem, midbrain, thalamus and basal nuclei). Confirmatory diagnostic tools include CNS immunohistochemistry and rt PCR.
- Treatment: Supportive care. The survival rate is about 50%. Recovery to athletic status in competition / working horses may not occur. Why do you think that this may be the case?
- Prevention: An effective vaccine is available. Mosquito control.
- Precautions: No documented direct animal to human transmission has been documented. When handling a suspect WNV horse take routine precautions – no direct exposure to body fluid, wear latex gloves and protective clothing, wash hands.
- Equine rabies can present with symptoms resembling WNV infection
Equine protozoal myelitis 2. Diagnosis
Post-mortem diagnosis
- Spinal cord lesions may not be apparent macroscopically hemorrhage and necrosis in spinal cord
- Parasite detection on routine sections or by IHC or PCR
Ante-mortem diagnosis (tentative)
- Clinical findings (can be variable)
- spinal ataxia / weakness
- exclude musculoskeletal disorders e.g. injuries
- uncommonly brain / brainstem
- Antibody detection in serum
•~50% of horses have high serum titers
- CSF analysis
- CSF anti-S.neurona IgG
- CSF PCR
- CSF cytology and protein – may be normal, unlike WNV
- Rule out WNV and EHV1 Lesions are not usually this prominent – this horse was given immunosuppressive therapy to aid isolation of the agent
Treatment
- Combination antibiotic treatment [ Trimethoprim Sulfa and pyrimethamine]
60% of horses respond to therapy
- May not recover to previous athletic level – why do you
Equine protozoal myelitis 3: treatment
think?
Control
- Secure horse food i.e. lids
- Prevent access of opossums to horse stables
- A vaccine is available – no need to use for WY horses
Clostridial enterotoxemia (aka.
overeating disease)
Species : mainly sheep and goats. 4 weeks – 2 years. Cause : Clostridium perfingens type D. Pathogenesis : The bacteria proliferate in the intestines and produce the toxin that enters the blood stream. One effect of epison toxin is to damage blood vessels resulting in edema (accumulation of fluid within tissues) and hemorrhage in tissue including brain. SymptomsSymptoms :: Found dead; usually peracuteFound dead; usually peracute disease course dead in 1-2 hours. Abnormal posturing. Occasionally may present as subacute to chronic disease. Diagnosis : Necrosis or edema in basal ganglia or other brain regions, lung edema, ±enteritis. Culture and demonstration of toxin by PCR Treatment : Penicillin and antitoxin (C&D) if outbreak occurs – poor prognosis. Prevention : Vaccination program – all sheep, cattle and goats should be vaccinated for this disease (these vaccines are multivalent and cover other clostridial diseases including blackleg, botulism, lamb dysentery, tetanus and braxy).
Tissue death and hemorrhage in brain stem
Tetanus 1.
• Species: all farm mammals, horses (and humans)
• Cause: Clostridium tetani toxin (tetanospasmin)
- Pathogenesis:
- Bacterium gains entry to body through wound e.g. navel, tail docking, castration, ear tag, nose ring, foot injuryg g j y
- Proliferates in anaerobic environment and produces toxin
- Toxin enters body fluids
- Toxin enters nervous system at neuromuscular junction
- Transport up axons into CNS
- Inhibits inhibitory transmitters (glycine and γ-ABA in CNS)
- Dis-inhibition results in excess muscle tone over extensor groups
- Toxin has similar mechanism of action as botulinum toxins, but acts at a different location in the nervous system – see later
Tetanus 2 – clinical diagnosis
History - no vaccination, often infected deep wound Clinical signs
Ears back Raised tail head ‘Saw horse stance’ Chronic bloat
• Treatment
– Penicillin, antitoxin injection – poor prognosis
• Prevention
Cl li d i i l d
Tetanus 3
– Cleanliness during surgical procedures
– Vaccination is very effective; vaccinate dam to
generate maternally derived immunity in calves,
foals, lambs
– Prompt treatment of infections, injuries, wounds
Botulism 1
- Species: any mammal or bird.
- Cause: Clostridium botulinum toxins. The bacterium is often in the gastrointestinal tract of healthy animals.
- Pathogenesis – there are three forms of disease
- Toxin is ingested (forage poisoning) - This form usually occurs as a disease outbreak. In this scenario, the bacterium grows in a certain substrate and produces its toxins. It is then ingested. For example, an outbreak has occurred in sheep through spreading poultry litter on pasture (illegally). Symptoms 1-7 days after ingestion. Association with phosphorus deficiency which causes pica (depraved appetite) and feeding silage containing dead animals e.g. rodents. This is the most common form of the disease in cattle, sheep and horses.
- Toxico-infectious – The bacteria grow and produces toxins in intestinal tract. Shaker foal syndrome - 3-8 weeks of age.
- Wound botulism – bacterium grows in wound, this form may be more common in foals / horses. Most likely one animal involved. Least common form of disease.
Botulism 2 - toxins.
- Eight different forms of botulinum toxin. They all have two protein chains joined by a disulfide linkage.h i j i d b di lfid li k
- Heavy chain targets to location within CNS
- Light chain is a protease
- Botulinum toxins are targeted to the neuromuscular junction
- Cleavage of synaptobrevin / syntaxin / SNAP-25 prevents release of acetylcholine in response to an action potential
Botulinum toxin inhibits transmission of chemical signals at the neuromuscular junction
Botulism 3
- What symptoms would you predict to occur with botulism?
- Paresis (weakness), difficulty to rise, loss of tongue tone, muscle fasciculations.
- How can you confirm a diagnosis? Demonstration of pre-formed toxin is best
- Mouse inoculation [wasp waist breathing due to contraction of abdominal muscles – can be difficult to interpret]
- Wound form – can try culture – need ‘100%’ anaerobic equipment
- Treatment – supportive, antibiotics if wound form, antitoxin if know strain
- PreventionPrevention
- Vaccine is very effective, if used properly (multivalent or monovalent)
- Treat wounds
- Rodent control
- Disposal of carcasses
- Don’t feed contaminated foods
- Large hay bales provide anaerobic centers, difficult to see carcasses with automated farming methods
- Don’t feed silage to horses
- Public health – toxin is destroyed by heat, spores are highly resistant to heat
Summary: Clostridial disease
involving the nervous system
• Definitive diagnosis: difficult for botulism and
tetanus - as extreme anaerobes
• Prognosis is poor for tetanus, botulism and
enterotoxemia
• VVaccines are highly effective and cheap; there is i hi hl ff ti d h th i
no excuse for not vaccinating
• Horses are generally only vaccinated for tetanus
(of the clostridial diseases)
• Can protect young animals by vaccinating
pregnant mothers and rely on maternally derived
immunity for early protection
Prion Diseases – transmissible
spongiform encephalopathies 1
• Prions are misfolded proteins that are infectious in
the absence of DNA
• Prion diseases are neurodegenerative in nature
• Species in which prion diseases have been
describeddesc bed
- Cattle – bovine spongiform encephalopathy
- Sheep and goats - scrapie
- Humans – kuru, CJD
- Mink – transmissible mink encephalopathy
- Mule deer / Elk / White-tailed deer
• There is potential for cross-species transmission
e.g. bovine prion disease is transmissible to man
Prion diseases 2
- Cattle [bovine spongiform encephalopathy]
- Outbreak in UK in mid-1980’s through 1990’s
- At peak several hundred cattle / month developed disease; destroyed export market of live animals and meat
- A case in USA was from an animal imported from Canada – disease not present in USA, as far as we know – surveillance programs are in place
- Transmissible to man - >100 cases reported in UK (nvCJD) from early 1990’s Tissues excluded from human food chain Disease outbreak in cattle is thought to have derived from the feeding of processed sheep offal in cattle concentrations Feeding animal meat / offal to other animals is now banned in UK and USA
Now unable to buy bovine / ovine brains for human consumption
Tissues excluded from human food chain
