 A SYSTEMATIC APPROACH TO DISEASE OF THE NERVOUS SYSTEM OF LIVESTOCK Dr Peter A W Harper, VFO Bicol FMD Task Force, Pili, Philippines; email: [email protected] |
A SYSTEMATIC APPROACH TO DISEASE OF THE NERVOUS SYSTEM OF LIVESTOCK Dr Peter A W Harper, VFO Bicol FMD Task Force, Pili, Philippines; email: [email protected] |
INTRODUCTION TO THE CLINICOPATHOLOGICAL APPROACH
BRIEF MODEL OF ANATOMY & PHYSIOLOGY OF NERVOUS SYSTEM
A LITTLE UNDERSTANDING OF NEUROPATHOGENESIS
CLINICAL & NEUROLOGICAL EXAMINATION
PATHOLOGICAL EXAMINATION OF THE CNS
PATHOLOGICAL EXAMINATION OF THE CNS
Livestock are dependent on locomotion to survive and produce, so an intact nervous system is of critical importance to our food and fiber-producing animals. As the nervous system is arguably the most complex interactive anatomical and physiological component of the body, neurological disorders present the clinician with one of the most challenging yet scientifically rewarding of diagnostic exercises.
This paper presents and discusses a systematic approach to neurological disorders. Essentially, it is suggested that applying a basic knowledge of neuroanatomy and physiology to assessment of a disorder can significantly assist the clinical scientist to make a more accurate appraisal of the dysfunctional areas of the nervous system. Knowledge of the diseases most likely to be found in those dysfunctional areas will then make assembly of a differential diagnosis a less exhaustive procedure, and provide a more rational approach to a definitive diagnosis and ultimately disease control and therapy.
It is convenient to have a global (? holistic) "mind model" of the nervous system that commences with so-called "higher" central nervous system (CNS) functions of the brain with it's multitude of poorly recognized functional cortical areas (e.g. motor cortex, optic cortex etc). The cerebrum is closely associated anatomically with the cerebellar, optic, vestibular and pontomedullary functional areas, and are connected by the ventricular system (especially third and fourth ventricles and choriod plexus) that bathe the brain internally with cerebrospinal fluid (CSF). Externally the brain and spinal cord is bathed with CSF by the leptomeninges. The cranial nerves I to XII are: oflactory, optic, occulomotor, trochlear, trigeminal, abducens, facial, auditory, glossopharyngeal, vagus, accessory, and hypoglossal.
The medulla or brainstem then leads on to the "lower" central nervous system functions of the spinal cord which coordinates the peripheral nervous system (PNS), which together are concerned primarily with locomotion. The PNS is connected to the CNS at the brachial plexus and lumbosacral intumescence which determine the function of the fore and hind limbs respectively, by neurotransmission via motor end plates to muscles. The animal is also affected by a superimposed autonomic nervous system and to a lesser degree by an interactive neuroendocrine system in close proximity to the thalamic region.
Thus we can conveniently separate the nervous system into the above anatomical components that tend to have different and identifiable functions. However the explosion of recent knowledge of neurochemistry reminds us that the whole system is operating as a complex of information transmitted between neurons as electrical impulses along fibers or axons, promoting chemical or neurotransmitter release into synapses between fibers and eventually to neuroreceptors. An important component of this process is myelin, which "insulates" the axons and facilitates the rapid transmission of impulses along nerve fibers.
Because the majority of neural function involves chemical and electrical neurotransmission, it is only reasonable to expect that many disorders, particularly in the acute phases of a disease, will be the result of a disorder of neurochemistry, and produce spectacular clinical deficits with no evidence of gross or microscopic pathology. Neurochemical disorders can produce clinical signs of nervous system disease by a number of mechanisms, including:
Mechanisms of neurochemical pathology
� failure of neurotransmitter release as occurs in hypocalcaemia,
� blocking of the receptor as occurs in tetanus and strychnine poisoning (which bind to the glycine receptor in the spinal cord),
� loss of receptor function (as occurs with GABA receptors in hyperammonaemia...see below)
� failure of neurotransmitter metabolism as occurs in organophosphate poisoning (due to anticholinesterase action) so that there is excessive neurotransmitter action.
As the disease progresses, morphological changes may ensue which lead to further changes in neurochemical action. These mechanisms can be illustrated by consideration of the actions of the popular acute human neurointoxicant alcohol, which adversely impacts on numerous neurotransmitter systems. However chronic intoxication may severe "secondary " neuropathology as a result of a disorder produced elsewhere in the body such as the liver as is seen in alcoholism. Liver failure results in a complex pathogenesis combining intoxication by endogenous products of metabolism (e.g. ammonia) and deficiency of essential components for neural function (e.g. vitamin B12), so the clinical neurological disease eventually reflects both disordered neurotransmitter systems and substantial cerebral neuron loss.
Plant poisonings due to intoxication with the pyrrolizidine alkaloids (e.g. Senecio species or Fireweeds; Crotalarias etc) causing liver failure and secondary hepatic encephalopathy are common in livestock and horses in Australia and other parts of the world, with animals presenting with severe higher CNS failure (depression, convulsions) and lesions of oedema in the myelinated fibers of the brain. Interestingly, congenital inherited failure of the urea cycle (e.g. citrullinaemia) in calves produces symptoms of acute higher cerebral failure (head-pressing, depression, convulsions) due to hyperammonaemia, however lesions of oedema are mild and located in oligodendrocytes with sparing of the myelin. Hyperammonaemia is a feature of dogs with congenital portosystemic shunts where blood returning to the liver is inadequately "deammoniated".
In the Philippines any clinical examination is clearly preceded by an assessment of the mental state (demeanor) and recent history of the animal as the clinician quickly does a risk assessment as to whether he may be dealing with rabies. With such a serious zoonotic disease endemic here, many neurological patients should prompt the clinician to treat such cases as rabies until proven otherwise, despite familiarity with the disease.
The neurological examination should examine and record responses to a number of tests that assist localizing a lesion:
� history: onset, duration, intermittent, progressive, non-progressive, epidemiology
� clinical signs and cardinal measurements (HR, RR, Temp)
� mental state: hypo or hyperaesthesia
� head position (cn VII): vestibular , opisthotonos
� ocular (cn II, III) : response to "menace", pupillary light reflex, horners syndrome
� auditory (cn VIII) : response to sound
� other cranial nerves: I nasal irritation, V facial response, VIII & XII pharyngeal response
� gait and posture: paresis (weakness) v paralysis, hypo or hypermetria (decreased or increased)
� muscle tone hypo or hypertonia (decreased or increased)
� reflexes: patellar and withdrawal (decreased or increased)
� postural tests: placement deficits
� proprioceptive tests: awareness deficits
One of the early decisions required during the examination is to decide whether the animal in fact has neurological disease or just appears so because of skeletal or muscular disease. Alternatively there may be disease of more than one system that is related e.g. spinal osteomyelitis can cause pathological spinal fracture and disruption of the cord, with signs and degree of paralysis reflecting the site and severity of the bone lesion. Similarly, young calves and lambs in selenium deficient areas may be assumed to have nervous system disease causing paralysis when their white muscle disease is exclusively a degenerative myopathy causing severe paresis.
The systematic clinical examination includes an assessment of mental (demeanor) and motor function (locomotion) as well as measurement of cardinal signs and temperature. The former) should quickly identify if a patient displaying generalized or higher central CNS disease is suffering from an acute inflammatory process, such as meningitis or meningoencephalitis. Examination of CSF by lumbosacral or cervical puncture will assist the diagnosis, with increased fluid pressure and turbidity supporting suspicion of inflammatory cell influx into the CNS. Ocular examination may also reveal extension of the inflammation via the optic tracts and possibly oedema of the optic disks. Localized inflammation usually eventually presents as a space occupying lesion, such as a spinal or pituitary abscess in younger animals, with older aged animals more likely to be affected by tumours.
Recognition of defects of the vestibular system is important in young animals as hydrocephalus (due to blockage of CSF flow from the ventricles), hydranencephaly (due to dissolution of brain tissue by intrauterine viral infection), meningocoele and spina bifida (expansion of anterior cervical and lumbosacral meninges usually with loss of spinal tissue respectively due to failure of occipital bone or dorsal vertebral arch fusion) and other CNS defects are common in most species (and even selected for in some e.g. hydrocephalus in Chihuahua dogs).
Generalized central neurological disease is often reflected by predominantly cerebral signs, and can present as a release of inhibition, which produces excitatory signs (hyperaesthesia, epilepsy, convulsions, tremors etc) or by excessive inhibition (depression, head pressing) followed by neural exhaustion (collapse, coma). Examples include lactating cattle, particularly dairy cows with extreme nutritional requirements and heavy production loads, metabolic failures can produce quite different clinical pictures; as in the excitation seen in ketosis due to disordered metabolism of glycogen reserves producing acetonaemia, and grass tetany associated with hypomagnesaemia, compared to the flaccidity of milk fever associated with hypocalcaemia.
However such metabolic diseases are frequently complex and the clinical picture variable, as in pregnancy toxaemia or twin lamb disease in sheep associated with energy depletion, and polioencephalomalacia or cerebrocortical necrosis of ruminants associated with thiamine deficiency as a result of an insufficient dietary source (as in diets containing elevated sulphides) or where thiaminases are present or produced (e.g. amprolium in coccidiostats is a thiaminolytic).
With the exception of epilepsy and brain tumours in small animals, focal disease of the cerebrum often remains undetected until terminal stages, particularly in livestock. This may reflect anatomical differences between primates and other species, the primates having long pyramidal tracts that commence in the cerebrum and synapse with motor neurons in the spinal cord, after decussation in the brainstem, so that disease in one side of the brain produces motor deficits in the contralateral limb innervated. Direct cortical motor neurotransmission in other species appears limited.
In livestock much of the cranial motor coordination is thought to be via the extrapyramidal tracts such as the rubrospinal tract from the red nucleus in the brainstem, with considerable intersegmental neurotransmission along the spinal cord. Swayback due to copper deficiency in sheep and goats is associated with Wallerian-type degeneration of spinal cord nerve fibers and characteristic lytic lesions in the neurons in the red nucleus.
Cerebellar disease is relatively easily recognized by the release of upper motor neuron inhibition that produces the characteristic goose-stepping gait produce d by hypermetria, particularly of the forelimbs. In severe cases the motor release is extreme, causing opisthotonos ("star-gazing"). Cerebellar disease is also most often associated with a head tremor (the latter appears variable between species however probably reflects differences in pathology). The lesions are most usually due to loss of cerebellar purkinje cell and efferent neural fiber function, and in advanced cases there is clearly loss of these cells.
| Congenital cerebellar disorders occur as a result of intrauterine infection with neurotropic viruses presumably at the time of peak cerebellar development e.g. pestivirus (MD-BVD) in cattle and panleucopaenia virus (enteritis virus) in cats, although there are numerous inherited cerebellar disorders described in many species. |
| Acquired cerebellar disorders include several neurotoxicities which may affect more than just the cerebellum, but the characteristic cerebellar signs predominate e.g. drunken sailor syndrome in arsenic poisoning of pigs, xanthorrhoea poisoning of cattle and chronic "cancer toxicity" in humans etc. |
Blindness can be difficult to recognize clinically and is often first observed as behavioural changes (e.g. bumping into objects, head held in a fixed "listening" position). Examination of the eye includes ensuring there are no eye or eyelid position irregularities (e.g. Horner's syndrome) and that the pupillary eye reflex and "menace" response are intact. Opthalmoscopic examination is a "window to the CNS" and can reveal pathology of both the optic nerve (e.g. vitamin A deficiency causes optic disk oedema, Seponver toxicity causes optic nerve necrosis) and internal eye structures (e.g. detached retina, retinitis etc). Note that extended grain feeding (210 days) of cattle for the Japanese feedlot Kobe beef market without vitamin supplementation produces blindness and limb vasculoapthy due to deficiencies of vitamins A and E.
A head tilt and tendency to circle may reflect vestibular disease as a result of pathology of the middle and internal ear structures or their extension to the brain via cranial nerve VIII. Otitis media and space occupying lesions in this site (e.g. metastatic ocular squamous cell carcinoma in Hereford and Friesian cattle) are not uncommon causes, the former being particularly common in rabbits due to Pasteurella multocida.
The brainstem consists of the pons and medulla which contain the most important neuroactive centers, many of the cranial nerves are located here, and motor and sensory tracts to and from the spinal cord are coordinated in "basal nuclei" structures at this site. Of note is that neurotropic pathogens that use axons for peripheral to central transmission such as rabies and Listeria monocytogenes, produce much of their pathology here, the latter affecting central vestibular mechanisms and causing circling disease (in humans Listeriosis can damage the respiratory centers and produce Ondine's curse where the patient must be continually respirated manually).
As in cerebella disease, lesions in the posterior brainstem may produce release of upper motor neuron inhibition so there is extension of the limbs with hypertonia and a hyperextended posture, and in extreme cases opisthotonos.
Disease of the cervical and thoracic regions of the spinal cord produce disruption in neurotransmission at this site; the site and extent of the lesion determining whether there is release of upper motor neuron inhibition or cessation of the local reflex arc. If there is flaccidity it is likely that the lesion is at the site of brachial plexus, disrupting the reflex arc. In some spinal injured animals there may be observed the Schiff-Sherrington syndrome with forelimb extension due to release of inhibition of motor neurons innervating the limb from a lesion in the thoracolumbar area caudal to the limb.
Disease of the lumbosacral regions of the spinal cord produce disruption in neurotransmission to the hind limb and tail; again the site and extent of the lesion determining whether there is release of upper motor neuron inhibition or cessation of the local reflex arc. If there is flaccidity it is likely that the lesion is at the site of the main innervation of the limb, disrupting the reflex arc. In many spinal injured animals the lesion is anterior to the lumbar intumescence such as at the thoracolumbar junction (e.g. Dachshunds with intervertebral disc disease) so there may be hind limb extension due to release of upper motor neuron inhibition i.e. neurons in the reflex arc can excessively innervate the limb.
The peripheral nerves are extensive and commonly traumatized; so most clinicians are familiar with radial nerve paralysis in the forelimb or tibial nerve paralysis of the hind limbs. In British and European cattle, dystocia is all too common and most livestock practitioners have been frustrated by the difficult calving paralysis cases which can have variable pathology from pelvic fractures or muscular contusions causing obturator and other nerve palsies. The functions of motor and plates is realized in disorder which block this neurotransmission, as in ascending placid paralysis of Ixodes tick intoxication.
Primary neuropathies of the PNS appear uncommon in domestic animals compared to man, however this may reflect difficulty of diagnosis, as increasingly, a significant number of central neuropathies are being described in animals, many either identical or with striking similarities to those described in man. Of course this would be expected with genetic disease where mutations in the genome of any species produce the same deficiency of gene product e.g. neuroactive enzyme or structural protein.
The sympathetic and parasympathetic nervous systems are best recognized by their "fright, flight, fight" and "comfort, coffee, cognac" responses respectively.
There are few recognized syndromes of primary disease of the autonomic nervous system, exceptions being Key-Gaskell syndrome in cats and grass sickness in horses, the latter defined by a digestive disorder associated with inflammatory lesions in mesenteric ganglia, of poorly understood pathogenesis.
As an important part of the neuroendocrine system, the pituitary gland is located within the cranial cavity and it with the adrenal and thyroid glands clearly has an important role to play in neural function (e.g. epinephrine production, basal metabolism, growth etc plus impacts on the limbic system i.e. emotion), and a complete clinicopathological assessment of an animal should include this system. Congenital defects of the pituitary are not uncommon (e.g. persistent Rathkes pouch) and frequently present as disorders of growth hormone production. Also, abscesses are commonly located in the pituitary fossa, particularly as a result of suppurative infections draining to this site from horn injuries, as are tumours.
The systematic neurological examination can indicate the likely site of a lesion and thus is of considerable benefit to the surgeon seeking to focus further diagnostic aids to a particular site (e.g. radiography, CAT and MRI scans etc). However as many animal neurological patients end up as a necropsy subjects, the neurological examination becomes more of a tool in furthering our understanding of nervous system function and dysfunction (i.e. disease processes), with pathological studies leading the way to this knowledge. Pathology is about accurate observation and recording, and as Goethe stated:
Thinking is more interesting than knowing but less interesting than looking.
The necropsy should be performed systematically with sequential examination of all body systems so that no relevant information is missed. Removal of brain and cord can be laborious however becomes easier with practice and there are numerous techniques to make the job easier, depending on species and age (I expect many veterinarians in the Philippines have had some experience of this with rabies cases). Pathological examination leads to a morphological diagnosis, which should include a statement of the duration, severity, extent, nature and character of the lesion, plus qualifying observations specific to that lesion. For example, a typically positive rabies case could be reported as:
Acute (subacute, chronic) mild (moderate, severe) locally extensive (focal, diffuse) non-suppurative (suppurative, granulomatous, necrotising, etc) encephalitis with intraneuronal negri bodies and FAT positive staining, characteristic rabies virus infection.
As with any disease investigation, the systematic recording of historical, epidemiological, clinical and pathological information, the latter summarized as a morphological diagnosis, should lead to an analytical process that can construct a differential diagnosis of aetiological probabilities and possibilities. For the differential diagnosis, to be exhaustive and thus accurate, extensive knowledge of the diseases present in that environment and capable of producing that particular clinicopathological scenario is required.
For example a cow with intermittent quadraparesis progressing to severe paralysis and recumbency, necropsied and found to have a focal 3cm diameter circumscribed grey soft mass in the cervical spinal canal in the vicinity of C2 to C3 causing spinal cord compression, has a:
� morphological diagnosis of chronic moderate focal spinal necrosis due to compression from a space occupying lesion in the cervical spinal canal, and may have a
� differential diagnosis of schwanoma (neurofibroma), lymphosarcoma (?enzootic bovine leucosis i.e. EBL), spinal abscess (e.g. Actinomyces sp.) or granuloma. Therein is a role for the histopathologist who can identify cell types involved and the serologist who can determine if the cow is an EBL case!
� aetiological diagnosis of neoplasia ie schwannoma
This is an only brief introduction to the complex subject of neurological disease diagnosis, however outlines a systematic approach that will hopefully assist the veterinarian to more accurately observe and record the pieces of the puzzle that fit together to arrive at a satisfactory conclusion to a disease investigation. Even the most experienced of veterinarians should wisely and regularly seek the counsel of colleagues, laboratory tests, textbooks and other literature and computer programs to assist them in the learning process we call disease investigation, and so continue the development of their skills as veterinary scientists.