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Neoplasia and the Nervous System

These are primarily a problem of aged animals. Classification is based on histological and cytological criteria, growth characteristics, and degree of differentiation.

Tumors are divided into CNS (central nervous system) and PNS (peripheral nervous system).

They can then be further divided into primary and secondary tumors.

Secondary tumors originate from extraneural organs (i.e. “outside of nerves” i.e. from elsewhere in the body) and reach the brain by extension or metastasis (i.e. “growth” and “spread” of a tumor).

CELLS OF THE NERVOUS SYSTEM:

These are....

Neurons

Glia cells (oligodendrocytes, astrocytes, microglial)

Ependyma and choroid plexus

Endothelial cells

Pericytes of blood vessels

Meninges

These cells can have tumors!

1. Astrocytoma

This is one of the most common primary intracranial tumors in dogs. Brachycephalic breeds such as bulldogs appear predisposed.

Histologically, it is classified as:

- Low-grade astrocytoma (cells which are still well-differentiated i.e. mild)

- Medium-grade astrocytoma (anaplastic - a term to describe cells which have lost their mature/specialised features)

- High-grade astrocytoma (glioblastoma - fast growing!)

What is its significance?

Astrocytes are support cells of the central nervous system. They play very important roles such as maintaining normal CNS physiology and critically control the response to brain injury and neurological diseases. However, problems arise if they grow out of control such as in a astrocytoma.

Astrocytomas can cause seizures due to the tumour pressing onto cranial nerves, anorexia, loss of appetite, collapse, disorientation, and even blindness.

What is the cause?

The actual cause of astrocytoma is not known. However, possible causes could include genetics, radiation exposure, pesticides, trauma or injury.

2. Oligodendroglioma

The second most common primary brain tumours.

Oligodendrocytes main role is to produce myelin. Myelin is made up of protein and fats, which allows quick transmission of impulses through neurons.

This is mainly reported in dogs. It grossly appears as a well-demarcated, grey, soft and almost fluctuating mass.

All are considered malignant.

3. Oligoastrocytoma

This is a mixed glial tumor!

It is composed of both neoplastic astrocytes and oligodengroglia.

4. Ependymoma

These are tumors derived from the lining epithelium of the ventricles and central canal of the spinal cord. Most of them arise in the third ventricle.

Significance? It can be a space-occupying lesion in the brain.

5. Choroid plexus tumours

These may be papillomas or carcinomas according to cellular atypia (i.e. how abnormal) and invasiveness.

6. Meningioma

This is the most common type of intracranial tumor in the cat. It is relatively common in dogs, but rare in other species. The tumor arises within the meninges and grows expansively.

In cats, common locations include the tela choroidea of the third ventricle and the supratentorial meninges.

Most intracranial meningiomas are benign, while extracranial meningiomas tend to be locally aggressive.

7. Tumours of the peripheral nervous system

Benign forms: Schwannoma, neurofibroma

Malignant form: Malignant schwannoma, neurofibrosarcoma

Schwannomas may be largely solitary infiltrating lesions at any site on a nerve trunk.

Malignant tumors have a highly variable histologic image and may be indistinguishable from other soft tissue neoplasms.

Neurofibromatosis of cattle is a well-recognised Schwannoma.

8. Cholesterol granulomas in horses

Cholesterol granulomas occur in 15-20% of old horses.

Pathogenesis suggests that repeated episodes of hemorrhage and congestion in the choroid plexuses are responsible for the development of cholesterol granulomas. In some cases, they may attain the large size and obstruct the interventricular foramen leading to hydrocephalus.

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Idiopathic inflammatory, degenerative, metabolic and toxic diseases of the CNS

1. “Idiopathic” refers to “an unknown cause”.

An example below....

1a. Neuritis of the cauda equina of horses

The “cauda equina” are a collection of nerves at the end of the spinal cord. The sacrococcygeal nerves are part of these collection of nerves. These affected nerves in this idiopathic disease leads to the presenting clinical signs seen such as tail paralysis, urinary incontinence, faecal retention, weakness, atrophy of coccygeal muscles and, in chronic cases, atrophy of the muscles of the hind limbs. 

The sacral and coccygeal nerve roots are thickened and discoloured. These are due to recent or accumulation of old hemorrhages.

Microscopically, there is granulomatous inflammation with extensive fibrosis. 

2. Malacia

“Malacia” refers to softening or necrosis of tissues of the CNS. 

The types of malacia which can occur are described below. 

Encephalomalacia refers to necrosis in the brain, while myelomalacia refers to the spinal cord.

Poliomalacia refers to softening of gray matter. 

Leukomalacia refers to softening of white matter. 

Each may qualified as to whether there is cerebral (encephalo-) or spinal (myelo-) involvement.

More specific examples are described below.

2a. Laminar cortical necrosis (polioencephalomalacia) 

Again, “polio” refers to the gray matter, and “enceph-” refers to the brain. 

A specific example of laminar cortical necrosis is polioencephalomalacia of ruminants.  This is a degenerative disease of ruminants characterised by oedema and laminar necrosis. 

The disease is attributed to an induced thiamine deficiency i.e. changes in the diet that induce changes in ruminal flora. Too much dietary sulphur, sulphates and sulphites may also induce PEM. 

Clinical signs include blindness, twitches, convulsions, nystagmus and head pressing. 

2b. Focal symmetrical encephalomalacia (FSE)

This disease can be seen in lambs and calves on high starch diets. High starch diets causes C.perfringens type D overgrowth, leading to production of epsilon toxins. These toxins cause endothelial damage, causing the walls of blood vessels to leak (i.e. increased vascular permeability). This results in oedema, brain hypoxia and necrosis. 

The disease is characterised by bilaterally symmetrical areas of malacia and haemorrhage in the internal capsule, the mid-brain and cerebellar peduncles.

2c. Mycotoxic leukoencephalomalacia of horses

Occurs in horses fed moldy corn for a month or longer. There can be a sudden onset of neurological signs (drowsiness, impaired vision, partial or complete pharyngeal paralysis, weakness, staggering, tendency to circle). 

The mycotoxin responsible is fumonisin B1, a product of Fusarium verticilloides (Fusarium moniliforme) and F. proliferatum, which grow on corn in warm, moist, environments. 

3. Metabolic disorders

3a. Hepatic encephalopathy 

This disease refers to a metabolic disturbance that may result from diminished hepatic (liver) function, urea cycle enzyme deficiency, or shunting of portal blood around the liver. Although this condition affects the brain, there are no gross CNS changes.

Under histopathology, there is diffuse polymicrocavitation of myelin at various levels of the brain, especially in the cerebral cortex, ischaemic neuronal degeneration of the cerebral cortex, presence of Alzheimer type II astrocytes (direct toxic effect of ammonia in these cells). 

4. Nutritional diseases

4a. Copper deficiency (swayback, enzootic ataxia)

The effects of copper deficiency on the central nervous system occur in utero and during early neonatal life.

Clinical swayback in lambs occurs in a congenital form and a delayed form, also known as “enzootic ataxia”. 

Clinical signs include staggering and ataxia, inability to stand. 

5. Toxic diseases

5a. Perennial rye-grass staggers

This is a common mycotoxicosis which affects sheep, cattle and horses. 

It occurs during summer and autumn on dry, short pastures of Lolium perenne. 

Clinical signs appear 5-10 days following exposure. These include fine head tremors, head nodding and weaving, stiff-legged, incoordinate gait. 

The disease is due to lolitrems produced by the endophytic fungus Neotyphodium lolii. 

Microscopic change is limited to the occurrence of fusiform enlargement of the proximal axons of some cerebellar Purkinje cells. 

6. Peripheral axonopathies

6a. Equine laryngeal hemiplegia

This condition refers to the denervation atrophy of the intrinsic muscles on the left side of the larynx. In simple words, there are no nerves supplying those muscles of the larynx. This means that the horse would not be able to adduct the arytenoid cartilage nor the vocal fold. This leads to partial obstruction of the airway on inspiration, and inspiratory stridor on exertion (roaring).

The underlying lesion is idiopathic degeneration of the left recurrent laryngeal nerve.

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Fungal Disease and the Brain

Fungal diseases are usually opportunistic infections in immunocompromised individuals. “Opportunistic infections” are infections which occur under certain conditions such as when the immune system of an animal is compromised in a certain way, allowing fungus/algae to invade and affect the health of the animal. 

In general, when animals are infected with such organisms, the inflammatory response which occurs are granulomatous or pyogranulomatous with neutrophils, macrophages and multinucleated giant cells. 

Among the different types of fungi which affects animals, only Cryptococcus neoformans has affinity for the central nervous system. 

Cryptococcus neoformans

This fungus mainly affects cats, dogs, and horses.

The organism enters the host through the cribriform plate, after nasal or sinus infections or via leukocytic trafficking.

These result in the formation of multiple small “cysts” in the brain. 

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Pathology of the Nervous System: What makes the nervous system special?

Understanding how the nervous system reacts to injury

When attempting to understand how the nervous system of animals react to injury, we must note some important points about what makes this system special when it comes to disease.

1. The central nervous system has low resistance to infection and injury. i.e. it is easily hurt!

2. Cells of the central nervous system vary in their susceptibility to injury. NEURONS (these are your brain cells) are the most susceptible, followed by oligodendroglia (companion cells of neurons which help to form myelin to insulate neurons - important for fast transmission), astrocytes (repair cells), microglia (immune cells) and blood vessels.

3. Neurons have limited energy stores thus if blood flow to the brain were to stop, this can be lethal! 4. Neurons cannot regenerate once damaged. 

5. Nerve fibres in the central nervous system have little to no regenerative capacity. However, those of the peripheral nervous system can regenerate under certain conditions.

6. Wounds deep in the central nervous system heal by proliferation of astrocytes’ processes (i.e. they become bigger, more numerous). In contrast, wounds which are superficial (i.e. on the surface) or those that extend throughout the meninges (these are your protective coverings of your brain) heal by deposition of collagen by fibroblasts. 

Some basic terminology:

Encephalitis - Inflammation (-itis) of the brain (enceph-)

Encephalopathy - Degenerative (-pathy) disease process of the brain

Leukoencephalitis - Inflammation of the white matter (”leuko”-) of the brain

Malacia - Softening of CNS tissue, usually the result of necrosis

Myelitis - Inflammation of the spinal cord (mye-)

Myelopathy - Degenerative disease process of the spinal cord (mye-)

Neuronophagia - Accumulation of microglial cells (-phagia) around a dead neuron

Polioencephalomalacia - Softening/necrosis of the grey matter (polio-) of the brain

Polioenaphalomyelitis - Inflammation of the grey matter of the brain AND spinal cord

Poliomyelomalacia - Softening (necrosis) of the grey matter of the spinal cord

Radiculoneuritis (polyradiculoneuritis) - Inflammation of a spinal nerve rootlet 

Satellitosis - Accumulation of oligodendroglia around neuronal cell bodies

Congenital Malformations

These are abnormalities of the nervous system which animals are BORN WITH. 

Some common ones include:

1. Cerebellar hypoplasia

The term “hypoplasia” means an incomplete development or under-development of a tissue or organ. The “cerebellum” refers to a structure which is located at the back of the brain. Thus, cerebellar hypoplasia means an incomplete development/under-development of the cerebellum. The cerebellum is important for movement and co-ordination.

Cerebellar hypoplasia can be caused by certain viruses such as parvovirus and pestivirus. 

These viruses (an example being FELINE PANLEUKOPAENIA VIRUS) can infect a pregnant female, and then enter and target neuroblast cell precursors. These are responsible for the development of the cerebellum. Thus, as these precursors are infected by viruses, the development of the cerebellum is affected, resulting in cerebellar hypoplasia. 

Affected animals have trouble moving properly as a result. 

2. Hydrocephalus

This abnormality refers to the abnormal accumulation of cerebral spinal fluid (the fluid in your brain which provides it with nutrients) in the cranial cavity. 

This can either be congenital (born with - especially in brachycephalic puppies such as bulldogs), acquired (which is almost always secondary to obstruction to the flow) or caused by a viral infection (leading to stenosis i.e. “stop” of the flow through the mesencephalic duct, which means that the fluid cannot be drained away).

Thus, accumulation of this fluid would cause an enlarged brain! 

This is a serious, life-threatening condition as the excess CSF in the brain can put pressure on sensitive brain tissues, leading to brain damage.

Infectious Diseases of the Central Nervous System

These can either be bacterial, viral, or parasitic. 

Bacterial infections:

These can also be called “pyogenic” infections. The term “pyogenic” means involving the formation of pus.

1. Abscess 

Sometimes, abscesses can be formed within the central nervous system in response to a bacterial infection. An “abscess” is the immune system’s attempt to “wall off” an infection.

These can either be from a hematogenous spread (blood flow) from other sites, direct extension, trauma, or direct incidental injection (also called “iatrogenic”).

2. Neonatal bacterial suppurative meningitis

“Suppurative” as in “pus formation”, “meningitis” as in inflammation (”-itis”) of the meninges (the protective coverings of the brain). 

Grossly, you can see cloudiness and opacity of the meninges. 

3. Listeriosis

This is an interesting one. The disease is caused by the bacteria called Listeria monocytogenes. Animals are at risk of contracting the disease if they are fed contaminated silage. 

The bacteria enters the mouth of the animal and invade the trigeminal nerve, which allows it to travel up axons to the brain. It likes to localise in the brainstem. 

The bacterial infection can cause three main syndromes in ruminants like cows:

- Infection of the pregnant uterus leading to abortions and stillbirths.

- Septicaemia (i.e. blood poisoning with the bacteria)

- Meningoencephalitis (i.e. inflammation of the brain and meninges). 

Neurological signs include depression, head tilt, head pressing, and circling. This is because infected animals have trouble co-ordinating their movements.

4. Infectious thrombotic meningoencephalitis 

This disease is caused by the bacteria Histophilus somni. Interestingly enough, the bacteria forms part of the NORMAL flora of the bovine genital and upper respiratory tract!

Calves are infected by cows in the first months of life, and disseminate the infection in feedlots. 

The bacteria can attack vessels, causing vasculitis (inflammation of blood vessels) leading to thrombus formation (i.e. blood clots). The formation of these blood clots can stop blood flow to the brain. The bacteria can also cause a septicaemia which may result in acute death or may cause subacute or chronic fatal or non-fatal disease.

Clinical signs include ataxia, circling and head pressing.  

Viral infections:

1. Rabies

When a rabid animal bites another, the virus is transferred from the infected animal’s saliva into the victim’s monocytes around the wound. The virus then invades the neuromuscular junction (the space between a nerve innervating a particular muscle group - i.e. to allow muscle contraction) and ascend to the central nervous system. It then replicates there, before spreading to major “exit portals” such as adrenal glands, nasal mucosa, and salivary glands.

The virus causes non-suppurative (i.e. non-pus forming) encephalomyelitis, ganglioneuritis and parotid adenitis.

2. Canine distemper virus

Canine distemper is a type of paramyxovirus which affects multiple organ systems of dogs such as the respiratory, gastrointestinal and central nervous system, including conjunctival membranes of the eye.

The virus is able to spread to the brain from the bloodstream, affecting astrocytes and microglia. Astrocytes are “repair cells” of the central nervous system and microglia are “immune cells” of the CNS. When these are affected, they cannot carry out their functions i.e. inability to repair the nervous system nor fight off infections. The virus also affects oligodendrocytes, leading to abnormal myelin formation.

As a result, affected dogs may present with sneezing, coughing, and thick mucus coming from the eyes. They may also have fever, depression, diarrhoea and vomiting. CNS signs develop 1-3 weeks after systemic signs, or may occur after a subclinical infection. 

Dogs with adequate humoral and cell-mediated immunity may recover within 14 days. However, dogs with intermediate or poor immunity may develop the severe disease symptoms described above.

3. Feline infectious peritonitis

Feline infectious peritonitis is caused by a feline corona virus. 

There are two types:

The effusive form is characterized by serositis (inflammation of serous membranes),  fluid accumulation in the abdominal cavity and varying degrees of pyogranulomatous inflammation. 

The non-effusive form is characterised by leptomeningitis, chorioependymitis, focal encephalomyelitis and ophthalmitis. 

Parasitic infections:

1. Equine protozoal myelonencephalitis

This disease is caused by the protozoa sarcocystis neurona. 

Prevalence is low, but affected horses present with ataxia, limb weakness, lameness and seizures. 

Gross lesions are only present in severe cases. 

2. Neosporosis

This disease is caused by an apicomplexan parasite and its effects on animals depends on if the host is a cow or a dog. 

In a cow (bovine), neosporosis can cause abortions. Cattle can become infected by ingesting sporulated oocyst-contaminated food, water, or soil. However, the principal route for infection in cattle is transplacental. 

In dogs, neosporosis causes neuromuscular disease. Dogs can become infected by eating tissues contaminated with cysts. Once infected, they then shed oocysts in faeces. 

Young dogs in utero are most severely affected; resulting in muscle atrophy, dysphagia and heart failure. Clinical signs include ataxia, head tilt, hind limb paresis, rigidity and progressive paralysis.

3. Toxoplasmosis

This is a disease which affects cats. Cats can become infected by ingesting tissues contaminated with tissue cysts. Infected cats shed oocysts in their faeces. 

The encephalitic form of toxoplasmosis is most likely to occur in immunosuppressed dogs and cats.