There are many inflammatory, infectious, and degenerative diseases that produce multifocal
central nervous system (CNS) signs and often simultaneous systemic disease. These
disorders are categorized as multifocal, systemic, or diffuse diseases. Initially,
some of these diseases may start with focal CNS signs, but they progress to affect
other areas.
Lesion Localization
The key to recognition of these diseases is a neurologic examination that indicates
the involvement of two or more parts of the nervous system that are not closely related
anatomically. The most obvious example is an abnormality in both the brain and the
spinal cord. All the possible combinations of signs of diffuse or multifocal diseases
are too extensive to list, but Box 15-1
lists some of the more common ones.
BOX 15–1
Examples of Systemic or Multifocal Signs
Lower motor neuron (LMN) signs (more than one location, may include cranial nerves):
diffuse LMN diseases, polyneuropathy (see Chapter 7)
Brain and spinal cord signs: pelvic limb paresis and seizures
Systemic disease and CNS signs: fever, anorexia, ataxia, or seizures
Generalized pain: meningitis
Cerebral cortex and brainstem: cerebrum seizures and cranial nerve deficits, blindness,
severe gait deficits, head tilt, circling
Forebrain: blindness with normal pupils (may be seen with brain swelling, hydrocephalus)
(see Chapter 11)
Cerebellum and paresis: head tremor, ataxia, severe gait deficits, paresis
Ascending paralysis: pelvic limb paresis progressing to tetraparesis (focal cervical
spinal cord lesion must be ruled out)
Anytime abnormalities identified on the neurologic examination cannot be attributed
to a single lesion, a multifocal neuroanatomic localization should be made. Etiologically,
this group of diseases becomes more likely.
Diseases
The major disease categories that produce systemic or multifocal signs are degenerative,
metabolic, nutritional, inflammatory, toxic, and sometimes neoplastic and vascular
disorders.
Diseases that are primarily skeletal in origin are mentioned but not discussed. Neoplastic
and vascular disorders of the brain are further discussed in Chapter 12. Asymmetry
often is associated with inflammatory, immune-mediated, neoplastic, and ischemic disorders.
Diffuse and symmetric involvement is seen with degenerative, metabolic, and toxic
disorders. The acute or chronic onset and the rate of progression may be of some help
in establishing the diagnosis (Table 15-1
).
TABLE 15-1
Etiology of Systemic Diseases∗
Classification
Acute Progressive
Chronic Progressive
Degenerative
Myelinolytic disorders
Storage disease, abiotrophy
Metabolic
Hepatic encephalopathy
Hepatic encephalopathy
Hypoglycemia
Endocrine disease
Endocrine disease
Renal disease
Neoplastic
Metastatic
Primary metastatic
Nutritional
Methionine deficiency
Hypovitaminosis
Hypervitaminosis
Inflammatory
Infectious and noninfectious
Infectious (usually viral) and noninfectious
Toxic
Most toxins
Heavy metals
Other toxins, chrome exposure
Modified with permission from Oliver JE, Hoerlein BF, Mayhew IG: Veterinary neurology,
Philadelphia, 1987, WB Saunders.
Degenerative Diseases
Many degenerative diseases that are systemic or multifocal are either congenital and/or
hereditary. However, the cause is still unknown for some of the spongiform and metabolic
encephalopathies and dysautonomia. Congenital refers to a disease or malformation
present at birth. It includes conditions that may be genetic or a result of exposure
to toxins, malnutrition, or infection in utero. Not all congenital conditions are
inherited and conversely, not all inherited conditions are congenital. The congenital
malformations are discussed in Chapter 12 for the cerebrum and in Chapter 8 for the
cerebellum.
Breed predilection and stereotypic clinical presentation for many of these disorders
often suggest an inherited basis. Careful study of affected litters and pedigrees
is required to determine the inheritance pattern. Selection processes used by breeders
include inbreeding, linebreeding, and outcrossing. While selecting for a particular
trait, inbreeding and linebreeding practices result in a reduction of genetic variability
and an increase in homozygous and recessive traits. Simple inheritance (Mendelian)
patterns have served as the basis for determining modes of inheritance of many genetic
disorders. Many of these hereditary diseases have an autosomal recessive inheritance
pattern. Dominant traits are more easily eliminated from the breeding pool of a breed
by not breeding affected dogs. Determining inheritance pattern is more difficult for
polygenetic and complex traits. Polygenetic inheritance refers to when proper development
relies on sequential activation of genes or for traits of variable penetrance that
result in a variety of phenotypes for a given genotype. Complex traits are determined
by the interaction between environment and polygenetic predisposition. Having an understanding
of the hereditary basis for these degenerative diseases is important because (1) they
are genetic disorders and can be eliminated by selective breeding; (2) they may be
confused with conditions of nongenetic origin, such as viral diseases; and (3) they
can serve as excellent models of similar human diseases.
Differential Diagnosis
Many of these diseases have a similar clinical history and course. Clinical signs
of conditions like the lysosomal storage diseases and some metabolic encephalopathies
are delayed until the animal is older (usually within a few months after birth) because
of the time required for build up of byproduct. Abiotrophies, disorders of premature
neuronal degeneration, and other degenerative diseases affecting the axons and myelin
can manifest signs within a few months or late in life. These disorders are often
insidious and progressive. However, some diseases such as the storage and myelin disorders
can have an acute onset once the neuron or myelin reaches a critical threshold of
dysfunction.
The findings on neurologic examination may indicate a predominance of signs referable
to the forebrain, cerebellum, spinal cord, or neuromuscular junction. These findings,
and the age and breed of the animal, should suggest a small number of possibilities.
Early in the disease course, neuronal cell body diseases often can be differentiated
from demyelinating diseases. Proprioceptive positioning is commonly affected in demyelinating
diseases but is rarely involved in the early stages of neuronal disease. Neuronal
cell body, diseases (storage disease, abiotrophy) are more likely to have forebrain
or cerebellar involvement. Axonal and myelin diseases of the sensory and motor tracts
of the spinal cord are more likely to have general proprioceptive (GP) ataxia and
paresis of an upper motor neuron (UMN) type. If the nerve or neuronal cell body is
involved, signs of LMN weakness predominate. Weakness is not a predominant feature
of pure demyelinating or cerebellar disorders. However, limb and whole body tremor
is a feature of myelin and cerebellar diseases.
The degenerative diseases also must be differentiated from inflammatory (infectious
and noninfectious), neoplastic, and toxic disorders. Specific diagnostic tests are
available for most of these conditions and are discussed later in this chapter.
This section on degenerative diseases will focus on those that are multifocal (storage
disorders) or have an unknown etiology. The metabolic encephalopathies that are of
primary brain origin are discussed in Chapter 12. Other degenerative disorders involving
the spinal cord and brain (myeloencephalopathies), which predominate as spinal cord
diseases, are discussed in Chapters 6 and 7Chapter 6Chapter 7. Those that present
primarily with LMN signs that involve the axon, myelin, and the neuronal cell body
(motor neuron) are discussed also in Chapter 7. Diseases that are discussed in this
chapter include (1) storage disorders, (2) abiotrophies, (3) multiple system degenerations,
and (4) degenerative disorders that are of unknown cause.
Storage Disorders
Storage disorders are characterized pathologically by the accumulation of metabolic
products in cells (Table 15-2
and Figure 15-1
).
TABLE 15-2
Lysosomal Storage Disorders in Domestic Animals
Disease Subgroup
Storage Disease(Human Disease)
Enzyme Deficiency
Species—Breed (age at onset)
Clinical Signs; Diagnosis
Inheritance
Reference
Glycoproteinoses
Fucosidosis
α-L-Fucosidase
C-English springer spaniel (6 mo-3 yr)
Cerebellar ataxia, behavioral change, dysphonia, dysphagia, seizures; DNA testing,
enzyme assay
AR
215., 216., 217., 218., 219.
Mannosidosis(α-Mannosidosis)
α-d-mannosidase
F-DSH (7 mo), DLH, Persian (8 wk); B-Galloway, Murray gray, Aberdeen Angus (birth)
Cerebellar ataxia, tremor, corneal opacity, skeletal anomalies, neuropathy; B-cerebellar
ataxia, aggressiveness; urine screening, enzyme assay, DNA testing
AR
220., 221., 222., 223., 224., 225., 226.
Mannosidosis(β-Mannosidosis)
β-d-Mannosidase
B-Salers; G-Anglo nubian (birth-1 yr)
Cerebellar ataxia, recumbency, skull and limb deformities; urine screening, enzyme
assay
AR
227., 228.
Lafora disease
α-Glucosidase
C-Beagle (5-9 mo), basset hound (3 yr), poodle (9-12 yr), wire-haired miniature dachshund
(5-8 yr); F-DSH
Myoclonic seizures, dullness; muscle biopsy, DNA testing
AR
229., 230., 231., 232., 233., 234., 235.
Oligosaccharidoses Glycogenoses
GSD type 1(von Gierke disease)
Glucose-6-phosphatase
C-Silky terrier, Maltese, other toy breeds (weeks); F-DSH
Weakness, seizures, stupor; urine screening
AR?
236., 237.
GSD type 2(Pompe disease)
α-Glucosidase
C-Swedish Lapland dog (1.5 yr); F-DSH; B-beef shorthorn, Brahman (3-9 mo); O-Corriedale
(6 mo)
Ataxia, muscle weakness, exercise intolerance, cardiac; muscle/liver biopsy, urine
screening
AR
238., 239., 240., 241., 242., 243., 244., 245., 246.
GSD type 3(Cori disease)
Amylo-1,6-glucosidase
C-German shepherd (2 mo), curly-coated retriever (IIIA) (1 yr)
Lethargy, exercise intolerance, organomegaly; muscle/liver biopsy, DNA testing
AR
247., 248.
GSD type 4(Andersen disease)
Branching enzyme
F-Norwegian forest cat (5 mo)
Cerebellar ataxia, muscle weakness, tremor, neuromuscular, organomegaly; muscle biopsy,
enzyme assay, DNA testing
AR
249., 250., 251.
GSD type 5
Myophosphorylase
B-Charolais (weeks)
Exercise intolerance
AR
252
GSD type7(Tarui disease)
Phosphofructose kinase
C-English springer spaniel (8-12 mo)
Exercise intolerance
AR
253., 254.
Mucolipidosis
Mucolipidosis II(I-cell disease)
N-acetylglucosamine-1-phosphotransferase
F-DSH
Facial dysmorphism, dullness, retinal, ataxia; DNA testing
Unknown
255., 256.
Sphingolipidoses
GM1-gangliosidosis type 1(Norman-Landing disease)
β-d-Galactosidase
C-Beagle cross (4-7 mo), Portuguese water dog (4-5 mo), English springer spaniel (4-5
mo), Alaskan husky, Shiba dog; F-DSH (2-3 mo); B-Friesian (birth); O-Coopworth Romney
(1 mo), Suffolk (4 mo)
C, F-Cerebellar ataxia, corneal clouding, tremor, seizures, paralysis, skeletal, facial
dysmorphism; B, O-ataxia, recumbency; enzyme assays, DNA testing
AR
257., 258., 259., 260., 261., 262., 263., 264.
GM1-gangliosidosis type 2(Derry disease)
β-d-Galactosidase
F-Siamese, Korat (7 mo), DSH; O-Suffolk (4-6 mo)
Same; O-rapid progression
AR
265., 266., 267.
GM2-gangliosidosis(Tay-Sachs disease)(Variant B)
β–n-acetyl hexosaminidase A (α-subunit)
C-German shorthair pointer (6-12 mo)
Cerebellar ataxia; urine screening; enzyme assay
Unknown
268., 269.
GM2-gangliosidosis(Sandhoff disease)(Variant O)
β–n-acetyl hexosaminidase B (β-subunit)
C-Golden retriever; toy poodle, F-DSH-Japan, Korat, Burmese-Europe (2-3 mo); S-Yorkshire
Same; S-cerebellar ataxia, weakness
Unknown
270., 271., 272., 273., 274.
GM2AB-gangliosidosis(Bernheimer-Seitelberger disease)(Variant AB)
GM2 activator protein deficiency
C-Japanese spaniel (18 mo); F-Korat (18 mo)
Same
Unknown
275., 276.
Galactosialidosis
Galactosialidosis with α-neuraminidase
C-Schipperke (5 yr)
Cerebellar ataxia
Unknown
278
Glucocerebrosidosis(Gaucher disease)
β-d-Glucocerebrosidase
C-Sydney silky dog (6-8 mo); O-unknown; S-unknown
Cerebellar ataxia; enzyme assay; biopsy
AR(S)
279., 280., 281.
Globoid cell leukodystrophy(Krabbe disease)
β-d-galactosyl ceramidase (accumulation of psychosine)
C-West Highland white terrier (2-5 mo), Cairn terrier (2-5 mo), beagle (4 mo), poodle
(2 yr), basset hound (1.5-2 yr), blue tick hound (4 mo), pomeranian (1.5 yr), Irish
setter (6 mo); F-DSH, DLH (5-6 wk); O-Dorset (4-18 mo)
Cerebellar ataxia, tremor, paraparesis, neuropathy; muscle/nerve biopsy, enzyme assay;
DNA testing
AR or unknown
282., 283., 284., 285., 286., 287., 288., 289., 290., 291., 292.
Metachromatic leukodystrophy
Arylsulfatase A
F-DSH (2 wk)
Progressive motor dysfunction, seizures, opisthotonus, neuropathy
Unknown
293
Sphingomyelinosis(Niemann-Pick disease type A)
Sphingomyelinase
C-Miniature poodle (2-4 mo); F-Balinese, Siamese (2-3 mo); B-Hereford (5 mo)
Cerebellar ataxia, tremor, paraparesis, neuropathy; biopsy
Unknown, AR-Siamese
294., 295., 296., 297., 298.
(Niemann-Pick disease type C)
Cholesterol esterification deficiency
C-Boxer (9 mo); F-DSH (2-4 mo)
C-Cerebellar ataxia, hepatomegaly, neuropathy; F-cerebellar ataxia, hepatic; enzyme
testing, DNA testing
Unknown
299., 300.
Mucopoly-saccharidoses
MPS I(Hurler syndrome)
α-L-iduronidase
C-Plott hound (3-6 mo), mixed-breed (3-6 mo); F-DSH (10 mo)
Growth retardation, facial deformity, lameness, corneal opacity, cardiac; urine screening,
enzyme testing, DNA testing
AR
301., 302.
MPS II
Iduronate-2-sulfate sulfatase
C-Labrador retriever (5 yr)
Cerebellar ataxia, exercise intolerance, corneal opacity, facial dysmorphism; urine
screening, enzyme assay
AR
303
MPS III (A, B, D)
Sulfamidase A-heparin sulphamidase B-N-acetyl-alpha-D-glucosaminidase C-acetyl-CoA-alpha-glucosaminide
N-acetyltransferase D-n-acetylglucosamine 6-sulphatase
C- Huntaway dog (IIIA) (18 mo), Schipperke (IIIB) (3 yr) wire-haired dachshund (IIIA)
(3); B-breed unknown-Australia (IIIB) (2 yr); G-nubian (IIID) (birth)
Cerebellar ataxia, tremor, retinal degeneration, corneal opacity; G-weakness; urine
screening, enzyme assay, DNA testing
AR
304., 305., 306., 307., 308., 309., 310., 311., 312.
MPS VI(Maroteaux-Lamy disease)
N-acetylgalactosamine 4-sulfase (arylsulfatase B)
C-Miniature pinscher (6 mo); F-Siamese cat, DSH (4-7 mo)
Growth retardation, facial deformity, corneal opacity, spinal fusion; urine screening,
enzyme testing, DNA testing
AR
313., 314., 315.
MPS VII(Sly syndrome)
β–d-glucouronidase
C-Mixed breed; F-DSH
C-Paraparesis, cardiac; F-growth retardation, facial deformity, corneal opacity, spinal
fusion, cardiac; urine screening, enzyme testing, DNA testing
AR
316., 317.
Proteinoses Ceroid Lipofuscinoses (Batten Disease)
All-Visual deficits, cerebellar ataxia, myoclonus, seizures of varying degree; tissue
biopsy (autofluorescence)
CLN 1
Palmitoyl protein thioesterase I
C-Dachshund (mo)
AR(S)
Katz ML personal communication
CLN 2
Tripeptidyl-peptidase
C-Dachshund (4-5 mo)
AR
318
CLN 4 (not confirmed)
Unknown
C-Tibetan terrier (4-6 yr)
AR
319., 320.
CLN 5
Soluble lysosomal membrane protein
C-Border collie (2 yr); O-borderdale (15 mo); B-Devon (12 mo)
AR
321., 322., 323.
CLN 6
Endoplasmic reticulum membrane protein
C-Australian shepherd (1-2 yr) O-South Hampshire (3 mo), Merino (7 mo)
Unknown or AR (O)
324., 325., 326., 327.
CLN 8
Membrane protein of the endoplasmic reticulum
C-English setter (2 yr)
AR
328., 329.
CSTD
Cathepsin D
C-American bulldog (2-4 yr); O-White Swedish landrace
AR
330., 331., 332.
CLN4 (Kuf’s disease)
Arylsulfatase G
C-American Staffordshire terrier (>1 yr variable)
AR
335., 334.
Unknown
C-Australian cattle dog (1-2 yr), Australian shepherd (more than one NCL), Chihuahua
(2 yr), cocker spaniel (1.5-6 yr), collie, dachshund (4.5 yr), dalmatian (6 mo-1 yr),
golden retriever (2 yr), Japanese retriever (3 yr), Labrador retriever, miniature
schnauzer, poodle, Polish lowland sheepdog (0.5-4.5 yr), saluki (2 yr), spitz, Welsh
corgi (6-8 yr); F- Siamese cat, Japanese DSH, European DSH (<1 yr); B-beefmaster (12
mo), Devon (12 mo), Holstein (adult); O-Rambouillet (4 mo); G-nubian (4 mo); E-Icelandic
× Peruvian paso
Unknown
335., 336., 337., 338., 339., 340., 341., 342., 343., 344., 345., 346., 347., 348.,
349., 350., 351., 352., 353., 354., 355., 356.
AR, Autosomal recessive; AR(S), autosomal suspect; CLN, ceroid lipofuscinosis; CTSD,
cathepsin D gene; GSD, glycogen storage disease; GM, gangliosidosis; Mps, mucopolysaccharidosis.
Breeds in italics signify mutation discovered; C, canine; F, feline; B, bovine; O,
ovine; S, swine; G, goat; E, equine.
Modified from Oliver JE, Hoerlein BF, Mayhew IG: Veterinary neurology, Philadelphia,
1987, WB Saunders, Table 6-1; Mayhew IG: Large Animal Neurology, Ames, IA, 2009 Wiley-Blackwell,
Table 30-2.
Figure 15-1
Bovine neuronal ceroid-lipofuscinosis. Luxol fast blue stain of the cerebellar cortex
of a Devon cow with intense storage evident in Purkinje cells (arrow).
(Courtesy Cornell University College of Veterinary Medicine.)
A genetically based deficiency of a key enzyme causes accumulation of the product
in neurons, glia, or other cell types. The effects of the disease may be caused by
the accumulation of the product or may be a direct result of the metabolic disturbance.
1
Because the clinical signs and the progression of the disease depend on the pathologic
process, many of the conditions present in a similar fashion with multifocal CNS signs
and sometimes also with peripheral neuropathy. Two groups are commonly recognized:
neuronal storage diseases, in which the product accumulates in neurons, and leukodystrophies.
2
In general, leukodystrophy refers to inherited conditions of younger animals in which
myelin synthesis or function is defective and cannot be maintained and may include
storage disease pathogenesis. Globoid cell leukodystrophy is a storage disease caused
by a deficiency of galactocerebroside activity, resulting in intracellular accumulation
of a metabolite toxic to myelin-forming oligodendrocytes and Schwann cells (Figure
15-2
).
Figure 15-2
Canine globoid cell leukodystrophy. Note large globoid cells in white matter of cerebral
cortex. The cells are filled with myelin breakdown products.
(Courtesy Cornell University College of Veterinary Medicine.)
The storage byproducts usually can be found in the lysosomes of neurons. Lysosomal
storage diseases are characterized by accumulation of sphingolipids, glycolipids,
oligosaccharides, or mucopolysaccharides within lysosomes.
3
The neuronal ceroid lipofuscinoses involve the accumulation of hydrophobic proteins
but the pathogenesis remains unclear (see Figure 15-1).
3
The storage diseases are rare, but several have been reported in domestic animals.
2
Most have been recognized in specific breeds of dogs or cats.3., 4. Animals are usually
normal at birth, but they fail to grow normally. Signs typically occur within the
first few months of life but may be delayed until adulthood with some conditions such
as some of the neuronal ceroid lipofuscinoses.
5
Many of the storage disorders affect multiple organs and regions of the nervous system.
Others affect only the myelin and only neurologic signs occur. Often neurologic signs
include cerebellar ataxia, myelopathy, and encephalopathy. Cerebellar signs are often
the first sign of storage diseases because of the complex integration of the fast
conducting sensory and motor pathways (see Chapter 8).
4
The cerebellum also is particularly sensitive to disorders affecting myelin. Seizure
events that occur with some storage disorders usually manifest at the end stage of
the disease process. Storage disorders for which seizure activity is a predominant
clinical feature include ceroid lipofuscinosis, glycoproteinoses, and leukodystrophies.
4
Most of the diseases that have been studied have a recessive mode of inheritance,
and so only a portion of the litter is affected (see Table 15-2). Lysosomal storage
diseases will have signs in other organs including the retina. Skeletal and facial
malformations are prominent in the mucopolysaccharidoses. In general, lysosomal storage
disorders tend to be slowly progressive and lead to the animal’s death.
4
Enzyme replacement, small molecule, gene, and cell-based therapies may have value
in some conditions and have only been used experimentally in affected animals.3.,
6. Genetic testing may be available for some of these disorders. Colonies of animals
for some of these diseases have been established at research institutions.
Abiotrophies and Other Degenerative Diseases
The normal neuron is not capable of dividing and reproducing itself but has the capacity
to survive for the life of the animal. Abiotrophy is a process by which cells develop
normally but later degenerate due to an intrinsic cellular defect.
7
The degeneration of the neuronal cell body can primarily involve the neurons of the
cerebellum, cerebrum, nerve, or multiple systems (Figure 15-3
; see Chapters 7 and 8Chapter 7Chapter 8).
Figure 15-3
Folium from a dog with cerebellar cortical abiotrophy. The cerebellar cortex is almost
devoid of Purkinje neurons. A single purkinje neuron is visible (arrow). Subjectively
there are few granule cell neurons than normal. Gliosis is also pressent (10× mag).
Right inset, Higher magnification of a purkinje neuron. Left inset, Folia are smaller
than normal.
The multisystem disorders are further characterized as to the primary site of the
degenerative process—cell body, axon, myelin, and so forth that also involve other
anatomic regions of the CNS or the peripheral nervous system (PNS). Clinical signs
relate to the predominant region of the nervous system affected. The motor neuron
degenerations are rare and usually occur in young growing animals with an insidious
and progressive clinical disease course of neuromuscular weakness and generalized
LMN signs (see Chapter 7). Myelin disorders cause ataxia and tremor that progresses
to paresis. Diffuse myelinopathies occur with inherited, metabolic, and toxic disorders.
Primary cerebellar cortical degeneration refers to degeneration and loss of Purkinje
cells and/or granule cells. Pathologic processes of cerebellar degeneration are classified
microscopically as atrophy, abiotrophy, and transsynaptic neuronal degeneration. Atrophy,
a term that lacks specificity, refers to loss of cerebellar mass often as a result
of a degenerative process (Figure 15-4
).2., 8.
Figure 15-4
Sagittal T2W MRI from the dog in Figure 15-3. The cerebellum is small. There is atrophy
of the folia as evidenced by increase amount of cerebrospinal fluid overlying the
folia as well as within the fourth ventricle.
Cerebellar degenerative disorders cause clinical signs of cerebellar ataxia and intention
tremor (see Chapter 8). The progression of these abiotrophies and degenerative processes
is generally slow (over months) but unrelenting. Like the storage diseases, they are
rare, usually inherited, and in most instances eventually fatal. The course of disease
is usually insidious but can be rapid.
Multisystem Neuronal Degenerations
These disorders often first cause cerebellar cortical degeneration and later involve
other neuronal populations. A multisystem degeneration in rottweilers characterized
by neuronal vacuolation has been recognized in young rottweiler dogs.
9
Affected dogs develop progressive GP ataxia, tetraparesis, cerebellar dysfunction,
and laryngeal paralysis. Intracytoplasmic vacuoles are prominent in the cerebellar
nuclei and other brainstem nuclei and ganglia. There is bilaterally symmetric degeneration
in the spinal cord. Young Cairn terriers show a progressive GP ataxia, tetraparesis,
and cerebellar signs.
10
Histopathology reveals neuron degeneration in the spinal cord, brainstem, and thalamus,
and degenerative changes in the tracts of the spinal cord and brainstem. A multisystem
degeneration recognized in young cocker spaniels manifests cerebellovestibular and
forebrain signs.
11
Histopathology shows widespread neuronal degeneration in the cerebellum and brain
with presence of swollen axons. Recently, a multisystem degeneration has been described
in golden retrievers that show tremor, progressive tetraparesis, and generalized LMN
signs.
12
The spinal cord had changes consistent with axonopathy; there was loss of cranial
nerve motor nuclei; and nerves had evidence of Wallerian degeneration.
Multisystem degenerations also involve the basal ganglia, such as the caudate nucleus
and substantia nigra, that cause movement disorders similar to Huntington and Parkinson
disease in humans. These disorders have been recognized in Kerry blue terriers and
Chinese crested dogs.13., 14. In these breeds, cerebellar ataxia begins between 3
and 6 months of age. As the basal nuclei degenerate, affected dogs have increasing
difficulty initiating movements and maintaining balance. These disorders are autosomal
recessive and have been linked to a locus on chromosome 1.
14
Dysautonomia
In veterinary medicine, the term dysautonomia refers to acute or subacute idiopathic
panautonomic failure involving both the parasympathetic and sympathetic systems. Dysautonomia
is also described in Chapters 3, 9, and 11Chapter 3Chapter 9Chapter 11. It is a progressive
degenerative disease of the ganglia of the autonomic nervous system. The general somatic
efferent system is not affected except for involvement of the anal sphincter. Dysautonomia
was first recognized in horses in Scotland (grass sickness) and then described in
cats in the United Kingdom and Europe in the early 1980s.15., 16. Dysautonomia was
first described in dogs from southwest Missouri and Wyoming in 1988 and continues
to be reported in Missouri and surrounding states.17., 18., 19. The etiology is still
unknown but a toxico-infectious etiology resulting from Clostridium botulinum type
CD has been proposed in horses. Acute or subacute autonomic neuropathy of people is
similar to the animal forms and studies suggest an immune-mediated basis for this
disease.
In dogs, dysfunction of the parasympathetic nervous system predominates, although
signs related to the sympathetic nervous system may be present as well.
20
The disease is most common in young adult free-roaming dogs (median age of 18 months)
and tends to affect medium- to large-breed dogs. Many affected dogs are from rural
environments but the disease has been documented in dogs maintained strictly in kennel
environments. The peak incidence in Missouri is from late winter to early spring.
The following clinical signs develop and are progressive over 2 to 3 weeks. All signs
may not be present in all dogs.
•
Dysuria, distended urinary bladder: The pelvic nerve is a parasympathetic nerve that
innervates the detrusor muscle. Detrusor muscle dysfunction is a common finding.
•
Mydriasis and absent pupillary light reflexes: Pupillary constriction is a function
of the parasympathetic fibers contained in the oculomotor nerves.
•
Elevated third eyelid: This sign is present in about 50% of cases, suggesting some
dysfunction of the sympathetic nervous system.
•
Dry mucous membranes, decreased tear production: Dry mouth, nose, and eyes are common
findings. Secretions are largely the function of the parasympathetic nervous system.
•
Vomiting, regurgitation: Megaesophagus is a common finding. The vagus nerve (parasympathetic)
innervates the esophagus and stomach and plays a major role in esophageal and gastric
motility.
•
Decreased anal (perineal) reflex: The external anal sphincter is innervated by the
pudendal nerve, a general somatic efferent nerve. This is the only sign of somatic
dysfunction.
•
Intestinal ileus: Distention of the intestinal tract is a less common finding. Constipation
and diarrhea may be seen in some dogs.
•
Weight loss, muscle wasting, and decreased appetite
•
Gait, postural reactions, and spinal reflexes are not affected
Dysautonomia also has been reported in cats but no clear risk factors have been identified.
21
Cats have clinical signs similar to dogs.
Dysautonomia should be suspected from the cluster of clinical signs. Although myasthenia
gravis and botulism cause some of these signs, the presence of weakness in the skeletal
muscles is not observed in dysautonomia. One of the best clinical procedures for confirming
dysautonomia is to demonstrate denervation hypersensitivity to the pupils. Pilocarpine
ophthalmic solution (1%) is diluted to a concentration of 0.05% with normal saline.
One to two drops are placed in one eye and the pupils are observed every 15 minutes.
Dogs with dysautonomia have rapid pupillary constriction compared with normal dogs
who either do not respond at all or show delayed responses. If no response is seen
in 90 minutes, the test is repeated with 1% pilocarpine. Unless parasympatholytic
drugs (atropine) or toxins are present, rapid pupillary constriction should occur.
Lack of innervation causes an upregulation of the postsynaptic receptors with denervation
supersensitivity in neurotransmission.
Thoracic radiographs frequently show megaesophagus and abdominal radiographs reveal
distention of the urinary bladder and sometimes intestinal ileus. Unless detrusor
atony is present from prolonged detrusor paralysis, dogs may void urine in response
to low doses of bethanechol.
No definitive treatment is available. Symptomatic therapy includes bethanechol, pilocarpine
to increase tear production and to reduce photophobia from dilated pupils, metoclopramide
to stimulate gastrointestinal motility, and frequent evacuation of the bladder. The
mortality rate in canine dysautonomia is approximately 90%. There are isolated reports
of dogs developing partial recovery.
Metabolic Disorders
Normal nervous system function depends on a closely regulated environment. Conversely,
homeostasis is coordinated by the nervous system through the neuroendocrine, autonomic,
and somatic systems. Systemic disorders altering homeostasis often have profound effects
on the nervous system.
Hepatic Encephalopathy
Hepatic encephalopathy (HE) is a complex metabolic disorder resulting from abnormal
liver function.
Pathophysiology
HE has been reported in four types of liver disease: (1) severe parenchymal liver
damage, either acute or chronic (cirrhosis, neoplasia, toxicosis); (2) anomalous portal
venous circulation (rare in large animals); (3) microvascular dysplasia, and (4) congenital
urea-cycle enzyme deficiencies (rare).
22
Parenchymal liver diseases other than cirrhosis (fatty infiltration, chronic active
hepatitis, and so forth) usually do not cause hepatic encephalopathy except in the
terminal stages of the disease. Pyrrolizidine alkaloids in certain plants such as
Senecio spp. and Crotalaria spp. cause parenchymal liver damage and hepatic encephalopathy
in herbivores. Parenchymal disease severely reduces the capacity of the liver to perform
its normal metabolic functions. Portosystemic venous shunts divert a significant portion
of the portal blood past the liver into the vena cava. Potentially toxic substances
that normally are absorbed from the gastrointestinal (GI) tract and detoxified in
the liver enter the systemic circulation. Similar to portosystemic venous shunting,
the pathophysiology in microvascular dysplasia involves shunting of portal blood into
the systemic circulation but occurs within the liver vasculature on a microscopic
level. Urea-cycle enzyme deficiencies prevent the metabolism of ammonia to urea.
The metabolic changes that cause the clinical syndrome of hepatic encephalopathy result
from failure of the liver to (1) remove toxic products of gut metabolism and (2) synthesize
factors necessary for normal brain function.
22
The exact cause of hepatic encephalopathy is unknown, but current theories of the
pathogenesis include (1) ammonia as the primary putative neurotoxin, although other
synergistic toxins may be involved; (2) disorders of aromatic amino acid metabolism
resulting from alterations in monoamine neurotransmitters; (3) disorders of gamma-aminobutyric
acid (GABA) or glutamate; and (4) increased cerebral concentrations of an endogenous
benzodiazepine-like substance.
23
Ammonia is probably the most important toxic substance, although the level of ammonia
in the blood does not necessarily correlate with the severity of the CNS disturbance.
24
Clinical Signs
Most animals with liver disease severe enough to produce HE have other clinical signs
indicative of hepatic failure, such as vomiting, anorexia, weight loss, retarded growth,
ascites, polyuria-polydipsia, and sometimes icterus. The neurologic signs are frequently
worse after feeding, especially if high-protein food is given. The release of nitrogenous
materials into the portal circulation exacerbates the signs. Obtundation that may
progress to stupor and coma is the most common neurologic sign. Other signs of forebrain
involvement such as behavior change, continuous pacing and head pressing, blindness,
and seizures also are common. Frequently, the clinical picture is that of a waxing
and waning diffuse encephalopathy. The postural reactions and reflexes are only minimally
involved except when the animal is nearly comatose. The cranial nerves are not markedly
affected except that vision may be impaired (decreased menace response with normal
pupillary light reflexes [PLRs]). Ptyalism is common, especially in cats.
A variety of factors can precipitate the neurologic signs of HE in an animal with
marginal liver function (Table 15-3
).
TABLE 15-3
Management of Hepatic Encephalopathy (HE)
Factors That Exacerbate HE
Management of HE
Increased dietary protein and fatty acids
Low-protein, low-fat diet
Bacterial production of ammonia in large bowel
Diet, antibiotics
Constipation leading to bacterial production of ammonia in large bowel
Diet, laxatives, enemas in acute lactulose
Gastrointestinal hemorrhage
Monitoring and treatment of ulcers, bleeding disorders, hookworms, whipworms
Hypokalemia, hypovolemia, alkalosis—aggravated by diuretics
Monitoring and correction of fluid and electrolyte imbalance, use of potassium-sparing
diuretics with caution or not at all
Transfusion of stored blood
Use fresh blood
Sedatives, narcotics, anesthetics
Use depressant drugs with extreme caution (in lowest possible dosages), and monitor
carefully
Infections, fever
Monitoring and supportive treatment
Any source of protein in the digestive tract is a common cause. Hemorrhage in the
gastrointestinal (GI) tract, constipation, or increased fatty acids also may precipitate
a crisis. Alterations in fluids, electrolytes, or pH may increase the blood and tissue
ammonia levels. Decreased renal function reduces elimination of ammonia and other
metabolites. Fever and infection cause increased tissue catabolism and increased nitrogen
release. Stored blood for transfusions may have an excess of ammonia. Depressant drugs
directly affect the brain and frequently are metabolized in the liver. The first evidence
of hepatic dysfunction often is slow recovery from anesthesia. Diuretics used to treat
ascites may cause HE through their effect on potassium, renal output of ammonia, and
alkalosis.
A range of clinicopathologic abnormalities may be present, depending on the cause.
Microcytosis with normochromic erythrocytes, ammonium biurate crystals in the urine,
and lowered cholesterol, blood glucose, and vitamin K dependent clotting factor levels
may be seen with liver failure. Frequently, serum albumin and serum urea nitrogen
levels are low. Parenchymal disease often causes elevations in liver enzymes, such
as serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline
phosphatase (ALP). These enzymes usually are not elevated significantly in portacaval
shunts.
25
Hepatic dysfunction may be confirmed with tests such as the ammonia tolerance test
or preprandial and postprandial serum bile acids measured after a 12-hour fast.26.,
27. Hepatic ultrasonography (US) is a sensitive indicator of liver size, but the definitive
diagnosis of anomalous portal vein circulation requires US, contrast-enhanced radiography
or computed tomography (CT), or nuclear medicine. Depending on the experience of the
operator, abdominal US has a sensitivity of about 80% and a specificity of about 65%
for the detection of extrahepatic portosystemic shunts (PSS). The sensitivity for
detection of intrahepatic shunts is nearly 100%.
28
Radiocolloid scintigraphy using technetium-99m sulfur colloid (TcSC) is used to evaluate
liver size and shape. Transcolonic TcSC procedures have been described for the diagnosis
of macrovascular shunts in dogs, cats, and potbellied pigs.29., 30. Biopsy is required
for confirmation of parenchymal disease.
The successful medical management of HE depends on the cause of the liver disorder
and the degree of liver malfunction. Animals with marginal liver function may be managed
by reducing the sources of nitrogenous products in the GI tract (see Table 15-3).
A high-carbohydrate, low-fat, low-protein diet with high biologic value is indicated.
If dietary management alone is inadequate, then oral, nonabsorbable antibiotics (such
as neomycin) may be given to reduce the bacterial flora that split urea. Mild laxatives
or lactulose (a nonabsorbable disaccharide) may be helpful.31., 32. In addition to
its laxative effects, lactulose creates an acid environment in the colon that allows
NH3 to be trapped as NH4+ in the gut lumen.
Acute crises of hepatic encephalopathy require more vigorous treatment. Protein sources
must be removed completely. Enemas and laxatives are used to remove all nitrogenous
material from the GI tract. Sedative drugs, methionine, and diuretics are discontinued.
Sources of GI hemorrhage are corrected if they are present. Administration of antibiotic
aimed at altering the GI bacterial flora in an attempt to reduce ammonia production
should be considered. Antibiotics can be given parenterally or as a retention enema
in animals unable to receive oral medications. Dehydration, hypokalemia, and alkalosis
are managed with intravenous (IV) fluid therapy. Renal output must be maintained to
eliminate nitrogenous products. Oxygen therapy may be necessary, especially in cases
of coma. The prognosis for herbivores with hepatic encephalopathy from pyrrolizidine
toxicity is poor.
Specific treatment of the cause is instituted, if possible. Unfortunately, most chronic
liver diseases and the urea-cycle enzyme deficiencies cannot be treated specifically.
Portosystemic shunts may be corrected surgically if portal circulation to the liver
is adequate. Partial occlusion of the shunt may be effective. Seizures and neurologic
complications following PSS attenuation have been well documented.33., 34. Potential
risk factors for neurologic complications include older dogs and dogs with single
extrahepatic and portoazygos shunts.
35
For details of the management of hepatic encephalopathy, the reader should consult
the references.23., 24., 32., 35., 36., 37., 38., 39.
Ketonemic Syndromes
Ketosis
These diseases occur primarily in ruminants and are characterized by hypoglycemia
and the accumulation of ketones in body fluids. Conditions that have been recognized
include bovine ketosis (acetonemia) and pregnancy toxemia of cattle, sheep, and goats.
Unlike most monogastric animals, ruminants produce most of their glucose supplies
from the gluconeogenesis of volatile fatty acids (acetic, propionic, and butyric acids).
Nearly 50% of the glucose in a cow is normally derived from dietary propionic acid
that is converted to glucose in the gluconeogenic pathway. Reduction of propionic
acid production in the rumen can result in hypoglycemia and the subsequent mobilization
of free fatty acids and glycerol from fat stores. The liver has a limited ability
to use these fatty acids because the levels of oxaloacetate are low. Acetyl coenzyme
A therefore is not incorporated into the tricarboxylic acid cycle and is converted
into the ketone bodies acetoacetate and ß-hydroxybutyrate. When the production of
ketones by the liver exceeds peripheral use, pathologic ketosis results.
Both ketosis and primary hypoglycemia are involved in the development of the clinical
signs. The most common signs include depression, partial to complete anorexia, weight
loss, and decreased milk production. The neurologic signs present in some cows include
ataxia, apparent blindness, salivation, tooth grinding, excessive licking, muscle
twitching, head pressing, and hyperesthesia. Cows may charge blindly if they are disturbed.
The diagnosis of bovine ketosis is based on the presence of elevated ketone levels
in blood and milk with concomitant hypoglycemia. The odor of ketones may be perceived
on the breath and in the urine. The immediate therapy is an IV injection of glucose,
followed by oral administration of 125 to 250 g of propylene glycol twice a day. Corticosteroids
are also beneficial in cows that are not septic. Cows with severe neurologic signs
can be treated with 2 to 8 g of chloral hydrate orally twice a day for 3 to 5 days.
Pregnancy/Toxemia
Pregnancy toxemia is a condition that is closely related pathophysiologically to bovine
ketosis. It occurs in ewes during the last 6 weeks of pregnancy, when the demand for
glucose by developing fetuses is large. Pregnancy toxemia occurs in pastured or housed
beef cows during the last 2 months of pregnancy. Overweight cows or those bearing
twin calves are especially susceptible. In ewes and cows, the basic cause is nutrition
insufficient to maintain normal blood glucose concentrations when fetal glucose demands
are high. Hypoglycemia precipitates the ketosis, as has been described earlier in
this section.
In sheep, clinical signs may develop in a flock and may extend for several weeks.
Ewes become depressed and develop weakness, ataxia, and loss of muscle tone. Terminally,
recumbency and coma develop. Neuromuscular disturbances include fine muscle tremors
of the ears and the lips. In some cases, seizures develop. “Stargazing” postures and
grinding of the teeth are common. The neurologic signs in cattle include depression,
excitability, and ataxia. The diagnosis of pregnancy toxemia is based on the history,
clinical signs, and presence of ketosis and hypoglycemia.
In sheep, flock treatment consists of increasing the availability of glucose precursors
in the diet or drenching affected ewes twice daily with 200 mL of a warm 50% glycerol
solution. The anabolic steroid trenbolone acetate also is beneficial given in 30-mg
doses administered intramuscularly (IM). Induction of parturition or fetal removal
by cesarean section also may be needed to reduce the metabolic drain on the ewe. Cattle
are treated by the method described for bovine ketosis. Pregnancy toxemia can be prevented
by ensuring adequate nutrition during pregnancy.
Renal Failure
The terminal stages of renal failure may cause tetany or seizures. Chronic renal disease
may be associated with vomiting, diarrhea, anorexia, muscle wasting, and weakness.
Encephalopathy, polyneuropathy, and polymyopathy have been seen in humans with chronic
renal disease, especially those receiving hemodialysis. Renal encephalopathy has been
reported in cows and dogs.40., 41., 42. Alterations in parathyroid hormone levels
and electrolyte metabolism, especially calcium and potassium, may cause signs that
are related to the nervous system (discussed later in this chapter). Parathyroid hormone
can have a primary neurotoxic effect and secondarily cause hypercalcemia.
Endocrine Disorders
Endocrine disorders that affect electrolyte and glucose homeostasis may produce neurologic
signs in affected animals. Hormonal excess or deficiency may affect the function of
nerves or muscles directly. Pituitary lesions may cause signs of hormonal and forebrain
dysfunction if the disease extends into the hypothalamus (Figure 15-5
).
Figure 15-5
A, Older toy poodle showing head pressing behavior from pituitary macroadenoma. B,
Brain from dog in
A.
Note mass at the base of the hypothalamus arising from the pituitary gland. C, Cross
section of brain from
B.
Note the large mass invading the hypothalamus.
In this section, specific endocrine and metabolic diseases that produce prominent
neurologic signs of weakness are discussed. Those that cause involuntary movements
such as tetany or constant, repetitive myoclonus (tremor) are discussed in Chapter
10. Readers should seek other textbooks for in-depth descriptions of each disorder.
Many endocrine and metabolic diseases cause electrolyte disorders that result in weakness
because they affect neuromuscular functions. With certain conditions, clinical signs
improve with rest and are exacerbated by exercise. The term episodic weakness has
been applied to this condition (see Chapter 7).
Hypocalcemia
Parturient Paresis
Parturient paresis, or milk fever, is a hypocalcemic metabolic disorder that occurs
in mature dairy cows, sows, sheep, and, rarely, horses, usually within 48 hours of
parturition. The affected cows are usually older than 5 years of age, and incidence
is increased in the heavy milk producers and Jersey breed. Many dairy cows are marginally
hypocalcemic at parturition, and any factor that decreases the metabolic adjustment
to this hypocalcemia may cause paresis. Such factors include milk yield versus calcium
mobilization from bone and gut, the ratios of calcium to phosphorus in the diet, anorexia
and decreased intestinal motility, and dietary pH.
The onset of parturient paresis (stage 1) is often missed and is characterized by
apprehension, anorexia, ataxia, and limb stiffness. Stage 2 is marked by progressive
muscular weakness, recumbency, and depression. The head is usually turned to the flank,
and an S-shaped curvature of the neck may be present. Other signs include dilated
pupils, decreased pupillary light reflexes, reduced anal reflex, decreased defecation
and urination, no ruminal motility, protrusion of the tongue, and frequent straining.
Stage 3 occurs in about 20% of cases and is characterized by lateral recumbency; severe
depression or coma; subnormal temperature; a weak, irregular heart rate; and slow,
irregular, shallow respirations. The pupils are dilated and unresponsive to light.
Bloating may occur. Changes in serum ions include hypocalcemia, hypophosphatemia,
and hypomagnesemia. With prolonged anorexia, serum sodium and potassium levels may
decrease.
Intravenous calcium salts (Ca, 1 g per 45 kg of body weight) are usually effective.
Calcium borogluconate is commonly used; a 25% solution contains 10.4 g of calcium
per 500 mL. Milk fever can be prevented in susceptible cows or herds by the administration
of vitamin D or its analogs or by the manipulation of the prepartum dietary calcium
and phosphorus levels.
Dogs and Cats
Hypocalcemic syndromes are well documented in dogs and cats (also see Chapter 10).
43
In both species, primary hypoparathyroidism is a documented cause of chronic hypocalcemia.
In cats, hypoparathyroidism is sometimes caused by inadvertent surgical resection
of the parathyroid glands during thyroidectomy for the treatment of hyperthyroidism.
Hypocalcemia may be associated with chronic renal disease in dogs and cats. It is
the major biochemical abnormality in dogs with eclampsia and may be observed in animals
receiving blood transfusions containing calcium-chelating anticoagulants. Enema solutions
that contain phosphate may cause hypocalcemia in cats. Ionized hypocalcemia occurs
in critically ill dogs; especially dogs with sepsis.
44
When the total serum calcium concentration falls below 6 to 7 mg/dL (ionized <0.6
to 0.7 mmol/L), the clinical signs of hypocalcemia are likely to occur.
45
Hypocalcemia increases membrane hyperexcitability by decreasing the membrane threshold
to more easily elicit an action potential. Tetanic muscle contractions are the most
common clinical signs, but some dogs develop muscle weakness early in the disease.
Hypocalcemia should be investigated when the total serum calcium concentration is
less than 7.0 mg/dL and the serum albumin concentration is normal. Serum ionized calcium
concentrations help to confirm the diagnosis. Once the diagnosis of hypocalcemia is
confirmed, the underlying cause should be identified. The diagnosis of both eclampsia
and iatrogenic hypoparathyroidism is usually obvious from the history and physical
findings. Primary hypoparathyroidism may be confirmed through parathormone (PTH) assays
conducted at specialized laboratories.
Animals experiencing seizures should be given 10% calcium gluconate solution IV at
a dose of 0.5 to 1.5 mL/kg. The dosage should be slowly infused over a 10- to 20-minute
period, and the heart rate and Q–T interval should be closely monitored with an electrocardiogram
(ECG) recording. The calcium dose can be repeated every 6 to 8 hours as a bolus injection.
Oral maintenance therapy is instituted when the total serum calcium concentration
is consistently less than 7.0 mg/dL. Calcium gluconate or calcium lactate is administered
orally in doses of 1 to 4 g for dogs and 0.5 to 1.0 g for cats. In parathyroid deficiency,
vitamin D therapy is required. Dihydrotachysterol (DHT) is a synthetic vitamin D that
is active in the absence of PTH. The loading dose is 0.03 mg/kg daily administered
orally for 3 to 4 days.
46
The maintenance dose is 0.01 to 0.02 mg/kg per day. Calcitriol is a vitamin D analog
that is used to treat subacute and chronic hypocalcemia in dogs. The initial dose
is 10 to 15 ng/kg twice a day for 3 to 4 days. Then the dose is reduced to 2.5 to
7.5 ng/mg twice a day. Animals should be closely monitored because hypercalcemia may
be a complication of vitamin D therapy, especially when supplemental calcium salts
are administered.
46
Diabetes Mellitus
Diabetes mellitus may result in a variety of neurologic signs. Insulin deficiency
results in failure of glucose transport into muscle and adipose tissue. An early sign
of diabetes mellitus may be exercise intolerance and weakness. As insulin deficiency
progresses, ketonemia develops from a marked increase in lipolysis and serum fatty
acids. The ensuing metabolic acidosis results in depressed cerebral function that
culminates in coma and death. In the untreated ketoacidotic dog or cat, hyperkalemia
can cause flaccid muscles by depressing neuromuscular and cardiovascular functions.
With therapy and correction of the acidosis, potassium ions reenter cells, and hypokalemia
may be a complication that fosters muscle weakness and depression. In some animals,
the hyperglycemia may be severe, even though acidosis is absent. This syndrome is
called hyperosmolar nonketotic coma. Clinical signs result from the hyperosmolar effects
of glucose on the cerebral cortex. Diabetic animals, especially cats, may also develop
neuropathy with associated LMN signs (see Chapter 7).
The comatose diabetic animal is a difficult therapeutic challenge. The clinician must
exercise great care in performing insulin, acid-base, electrolyte, and fluid therapy.
Interested readers should consult other texts for an in-depth discussion of the diagnosis
and management of the diabetic patient.
Hypothyroidism
Deficiencies of thyroxine result in a marked decrease in forebrain function and basal
metabolic rate. Severely hypothyroid dogs may become obtunded or may appear dull and
unresponsive. Coma also known as myxedema coma may occur in severe cases.47., 48.,
49. A very low voltage electroencephalogram (EEG) usually is seen. The forebrain signs
improve dramatically after replacement thyroid medication. Polyneuropathy and myopathy
have been recognized in dogs without the usual signs of hypothyroidism.50., 51. Clinical
signs of polyneuropathy include laryngeal paralysis, vestibular dysfunction, and paresis
involving various peripheral and cranial nerves (Figure 15-6
).50., 52. Hypothyroidism may cause hyperlipidemia and atherosclerosis, conditions
that are risk factors for CNS infarction.
50
Figure 15-6
Older cocker spaniel dog with myxedematous hypothyroidism and facial nerve paralysis.
The fact that the animal has a polyneuropathy rather than a single problem may be
defined by electromyography (EMG) or other electrodiagnostic tests. Measurement of
free thyroxine and thyroid-stimulating hormone (TSH) concentrations or TSH response
testing are necessary to confirm a diagnosis.53., 54. Many of these animals respond
well to thyroid hormone supplementation, but weeks to months may be required for nerve
function to recover.
55
Hyperadrenocorticism
Hyperadrenocorticism (Cushing disease/syndrome) occurs in dogs, horses, and cats.
In dogs and horses, pituitary adenomas that hypersecrete adrenocorticotropic hormone
(ACTH) are the most common cause, but functional cortisol-secreting adrenal tumors
also produce this syndrome in dogs and cats. The clinical signs are caused by the
metabolic effects of hypercortisolemia. Generalized muscle weakness resulting from
the catabolic effects of glucocorticoids is a common finding. Some dogs develop muscle
degeneration, known as steroid-induced myopathy (see Chapters 7 and 10Chapter 7Chapter
10). This condition produces spontaneous muscle contractions (pseudomyotonia) and
a stiff gait.
Pituitary adenomas (macroadenomas) may create neurologic signs by growth and expansion
into the hypothalamus (see Figure 15-5, A through C).
56
Signs of pituitary macroadenomas are usually vague and include depression, confusion,
circling, ataxia, and seizures.
57
Macroadenomas are more common in older, large-breed dogs. Pituitary tumors causing
hyperadrenocorticisms may be present without causing neurologic signs.
57
In dogs and cats, hyperadrenocorticism is confirmed with screening tests such as the
low-dose dexamethasone suppression test, the ACTH stimulation test, or the urine cortisol:creatinine
ratio. Pituitary-dependent hyperadrenocorticism is differentiated from functional
adrenocortical tumors with the high-dose dexamethasone suppression test or ACTH assay
or both. Similar tests and measurement of increased plasma ACTH concentrations are
useful in the diagnosis of equine Cushing disease.
58
Abdominal US may also be helpful in the diagnosis of adrenal gland disease. Macroadenomas
can be accurately diagnosed with MRI or CT.
59
In dogs, pituitary-dependent hyperadrenocorticism is usually treated medically with
mitotane or trilostane.
60
Mitotane causes necrosis of the adrenal cortex, primarily the zona fasciculata and
reticularis, and results in markedly decreased cortisol production. If the dosage
is carefully monitored, aldosterone secretion is much less affected. Side effects
include vomiting, diarrhea, anorexia, weight loss, and depression. Trilostane reduces
synthesis of cortisol, aldosterone, and adrenal androgens. It also can be used in
dogs, cats, and horses for pituitary and adrenal-dependent hyperadrenocorticism. It
is well tolerated and has fewer side effects than mitotane. However, it may not produce
long-term control of clinical signs. Readers are encouraged to consult internal medicine
textbooks or veterinary drug handbooks for dosages and correct regimens for each drug.
In dogs and cats with pituitary macrotumors, treatment also is directed at control
of the pituitary mass (see Chapter 12). Adrenalectomy is recommended for adrenocortical
neoplasia.
Hypercalcemic Syndromes
An increased concentration of serum calcium may result in neuromuscular, cardiovascular,
and renal dysfunction. Hypercalcemia (>14 mg/dL) increases membrane threshold (making
it more difficult to depolarize the membrane) resulting in hypoexcitability of the
muscle membrane. CNS reflex and response activities and muscles become sluggish and
weak. Hypercalcemia decreases the Q–T interval of the ECG and decreases myocardial
function. Hypercalcemia impairs renal concentrating ability. In prolonged hypercalcemia,
mineralization of soft tissue may occur. The syndrome of hypercalcemic nephropathy
is well documented in animals and culminates in chronic renal failure. In dogs calcium
levels above 12.5 mg/dL may result in hypercalcemic signs. Ionized calcium concentrations
should be measured to confirm hypercalcemia. In some cases, muscle weakness may be
worse during exercise.
Several causes of hypercalcemia exist, including primary hyperparathyroidism, paraneoplastic
syndromes, vitamin D rodenticide intoxication, hypoadrenocorticism, and iatrogenic
calcium therapy.
61
Primary hyperparathyroidism results from autonomously functioning parathyroid adenomas.
These tumors secrete PTH in the presence of increasing serum calcium concentrations.
Certain nonendocrine tumors such as lymphosarcoma, anal sac adenocarcinoma, squamous
cell carcinoma, and thymoma secrete substances with PTH-like activity that results
in hypercalcemia.62., 63., 64. This syndrome is called the hypercalcemia of malignancy
and is the most common cause for hypercalcemia in dogs and cats.
64
Rodenticides that contain analogues of vitamin D promote increased absorption of calcium
and may produce hypercalcemia.
65
The symptomatic therapy of hypercalcemia includes IV diuresis with 0.9% saline and
furosemide. Corticosteroids also are beneficial because they promote the renal excretion
of calcium. Clinicopathologic data for the diagnosis of lymphoma should be obtained
before administration of corticosteroids as these drugs can induce remission confounding
the diagnosis of lymphosarcoma. Salmon calcitonin may also be given to decrease serum
calcium concentrations.
66
Hyperkalemia
Increased serum concentrations of potassium (>6.5 mEq/L) decrease the resting membrane
potential causing an increase in membrane excitability. Eventually, the muscle is
unable to repolarize and the muscle fatigues. Excessive extracellular potassium causes
cardiac flaccidity and decreases the conduction of impulses through the atrioventricular
(AV) node. Thus, heart rate and cardiac output may be severely depressed. Hyperkalemia
therefore manifests as generalized weakness that may worsen with exercise.
Adrenal Insufficiency
Hyperkalemia may occur secondary to severe acidosis; however, the usual cause is adrenal
insufficiency. Adrenal insufficiency, a chronic immune-mediated adrenalitis, may result
in aldosterone deficiency secondary to atrophy of the zona glomerulosa. Hyperkalemia
and hyponatremia contribute to the typical signs of depression, anorexia, vomiting,
diarrhea, weakness, bradycardia, and hypotension secondary to decreased cardiac output.
The disease responds well to fluid therapy and replacement adrenocortical hormone
therapy.
Hyperkalemic periodic paralysis
Hyperkalemic periodic paralysis (HPP), an episodic syndrome of muscular weakness and
fasciculations, occurs in young, adult quarter horses (see Chapter 7).
67
This is an autosomal dominant inherited disease caused by a genetic mutation in the
α-subunit of the equine adult sodium-channel gene.
68
It is associated with marked hyperkalemia without major acid-base imbalance or high
serum activity of enzymes derived from muscle. The episodes occur spontaneously or
can be induced by administration of potassium chloride orally. Electromyographic changes
include fibrillation potentials, positive sharp waves, and complex repetitive discharges.
Histologic changes in muscle are minimal but may include vacuolation of type-2b fibers
or mild degenerative changes. Hyperkalemia or normokalemia may occur during episodes.
Intravenous administration of calcium, glucose, or bicarbonate results in recovery.
Administration of acetazolamide, 2.2 mg/kg orally every 8 to 12 hours, prevents the
episodes. Decreasing the potassium content of the feed may also be effective. This
can be done by feeding oat hay, feeding grain two to three times daily, and providing
free access to salt.
67
Hypokalemia
Decreased serum concentrations of potassium decrease the activity of skeletal muscle
because the membranes are hyperpolarized. In other words, decreased extracellular
potassium causes a decrease in membrane sensitivity by increasing the resting membrane
potential. Muscle weakness and even paralysis may occur. The primary causes of hypokalemia
include diuretic therapy, vomiting, diarrhea, alkalosis, excessive mineralocorticoid
therapy for adrenal insufficiency, renal failure, and diabetic ketoacidosis. Hypokalemic
myopathy is well documented in cats with renal failure, in cats with chronic anorexia,
and in cats receiving low-potassium diets. Most patients respond well to potassium
supplementation (see Chapter 7).
Hypoglycemia
Hypoglycemia causes altered CNS function similar to that associated with hypoxia.
The blood glucose concentration is of prime importance for normal neuronal metabolism
because glucose oxidation is the primary energy source. No glycogen stores are present
in the CNS. Glucose enters nervous tissue by noninsulin dependent transport mechanisms.
Hypoglycemia at glucose concentrations less than 40 mg/dL can precipitate signs of
hypoglycemia. Neurologic signs of hypoglycemia are manifested by dullness, hypothermia,
weakness, seizures, and coma. Factors responsible for clinical signs include rate
of decrease, level, and duration of hypoglycemia. The severity of the CNS signs may
be related more to the rate of decrease than to the actual concentration of glucose.
Sudden drops in glucose levels are more likely to cause seizures, whereas slowly developing
hypoglycemia may cause weakness, paresis, behavioral changes, or stupor.
Neonatal Hypoglycemia
Studies in puppies have shown that during hypoglycemia, lactic acid is not only incorporated
into the perinatal brain but also consumed to the extent that the metabolite can support
up to 60% total cerebral energy required for metabolic processes.
69
Although the neonatal brain can readily metabolize ketone bodies, lack of body fat
and prolonged time necessary to produce ketones prevent this mechanism from protecting
neonates from acute hypoglycemia. Hypoglycemia in young animals may be secondary to
malnutrition, parasitism, stress, or some GI abnormality. Puppies are frequently extremely
depressed or comatose. Serum glucose should be determined, and IV glucose is administered
immediately (2 to 4 mL of 20% glucose per kilogram of body weight). Diazepam often
will have no effect on halting hypoglycemic seizures. Continued signs of stupor or
coma indicate brain swelling and are treated with hypertonic solutions (see Chapter
12). Dietary regulation, including tube feeding if necessary, must be established
to maintain normoglycemia.
Hypoglycemia in puppies also occurs because of immature hepatic enzyme systems, deficiency
of glucagon, and deficiency of gluconeogenic substrates. Fatty liver syndrome causes
hypoglycemia in toy breed puppies at 4 to 16 weeks of age.
70
Persistent and recurrent hypoglycemia, hepatomegaly, acidosis, and ketosis suggest
a glycogen storage disorder.
71
Liver and muscle biopsies are required to make a definitive diagnosis. The management
of these cases is frequently unsuccessful.
Insulinoma
Adult-onset hypoglycemia usually is caused by a functional tumor of the pancreatic
β-islet cells commonly called insulinomas.72., 73., 74. Excessive insulin produces
an increased transfer of blood glucose into the nonneuronal cellular compartments,
resulting in hypoglycemia and abnormal CNS metabolism. Although insulinomas are relatively
rare, increasing awareness has resulted in more frequent diagnosis. Most insulinomas
in dogs have metastasized to the local lymph node (stage II) or liver (stage III)
and other sites by the time a definitive diagnosis is made. In addition to hypoglycemia,
insulinomas may also induce peripheral neuropathies (see Chapter 7). Other neoplasms
(e.g., leiomyosarcoma) also may induce hypoglycemia.
75
Seizures associated with insulinomas are more frequently related to exercise, fasting
(or, conversely, eating), and excitement. Other signs such as weakness, facial and
muscle tremors, disorientation, and behavioral changes are also common. The signs
are episodic until irreversible neuronal damage occurs. LMN paresis can be detected
in dogs with peripheral neuropathies.
Blood glucose concentrations after a 12-hour fast are usually below normal (<60 mg/dL).
Longer fasts (24 to 48 hours) may be necessary in some cases, but animals should be
monitored closely during this time. serum insulin levels are more specific for making
a diagnosis.
76
Serum insulin concentrations are near zero when serum glucose concentrations are less
than or equal to 30 mg/dL. Serum insulin levels should be measured when the blood
glucose concentrations are below 60 mg/dL. Normal or increased serum insulin concentrations
in hypoglycemic dogs are strongly suggestive of insulinoma. An amended insulin:glucose
ratio greater than 30 is supportive of an insulinoma. The glucagon tolerance test
may be used as an alternative procedure, but it carries a greater risk of profound
hypoglycemia during the test. Abdominal ultrasonography, CT, or MRI may detect pancreatic
masses in some cases and help localize the lesion for surgical resection.
The management of patients in coma and status epilepticus is discussed in Chapters
12 and 13Chapter 12Chapter 13, respectively. Surgical removal of the tumor is indicated
when the patient’s condition has stabilized. The reported incidence of malignancy
ranges from 56% to 82%; therefore the prognosis is poor even with successful removal
of the pancreatic focus.72., 73. Animals with insulinoma should be fed several small
meals each day. Diets high in simple sugars should be avoided. Symptomatic treatment
with glucocorticoids such as prednisolone, given at a dosage of 0.25 to 0.50 mg/kg
per day, help to normalize the blood glucose concentration because of their antiinsulin
effects. Streptozotocin is effective in dogs with even metastatic disease. Concurrent
saline diuresis should be given to prevent renal toxicity. Seizures may persist because
of prior neuronal injury even though serum glucose levels have been normalized.
76
Nutritional Disorders
Nervous system disorders caused by nutritional deficiencies or excesses are uncommon
in companion animals, but they are more common in food animals. Severe malnutrition
can cause a variety of abnormalities that are related to multiple deficiencies.
Vitamin A Deficiency
Deficiencies in vitamin A can produce night blindness. Hypovitaminosis A in young
animals may cause excessive thickening of the skull and the vertebrae with secondary
compression of nervous tissue (especially of the cranial nerves as they pass through
the foramina). Decreased absorption of CSF may result in communicating hydrocephalus.
77
Skull malformation and cerebellar herniation have been reported in exotic cats fed
a vitamin A–deficient diet.
78
Hypovitaminosis A is rare or rarely recognized in companion animals but has been reported
in food animals.77., 78., 79., 80. Blindness in cattle with vitamin A deficiency is
caused by several pathologic mechanisms.
81
Papilledema occurs in adult animals secondary to increased CSF pressure, which is
secondary to decreased absorption. Photoreceptor abnormalities, especially affecting
the rods, lead to night blindness. Similar changes occur in growing calves, but, in
addition, the optic nerves are compressed by narrowing of the optic canals, resulting
in ischemia and direct interference with the nerve.
Vitamin E Deficiency
A noninflammatory myopathy may be produced by vitamin E deficiency; however, vitamin
E deficiency is rare in companion animals. Calves and sheep have a myopathy associated
with a deficiency in vitamin E and selenium. Swine may die suddenly because of degeneration
of cardiac muscle. Retinal degeneration may occur secondary to vitamin E deficiency
(see Chapter 11). Low vitamin E blood levels have been associated with degenerative
myeloencephalopathy and motor neuron disease in horses (see Chapter 7).82., 83.
Vitamin B Complex–Thiamine Deficiency (Polioencephalomalacia)
Deficiencies in B vitamins can cause pathologic changes in both the CNS and PNS. Thiamine
deficiency has been reported in dogs, cats, and ruminants.79., 84., 85., 86., 87.
The syndrome in dogs progresses from anorexia to paraparesis, tetraparesis, seizures,
and coma in approximately 1 week.
87
Malacia and hemorrhage were found in multiple sites in the brain and the spinal cord,
with the most severe lesions in the brainstem. Animals treated with thiamine recovered.
A peripheral neuropathy with LMN paralysis can occur.
84
Cats with thiamine deficiency often have characteristic ventral flexion of the head
and the neck, sometimes causing the mandible to touch the sternum. Vestibular ataxia
and seizures may be present. The pathologic lesions are similar to those that occur
in dogs.
79
The deficiency in dogs was produced by a diet consisting entirely of cooked meat or
a specific thiamine-deficient diet.
87
Cat foods with fish as the primary ingredient contain thiaminase, which destroys thiamine
in the diet.
79
Treatment should be instituted immediately for any animal suspected of having thiamine
deficiency. In dogs and cats, 50 to 100 mg of thiamine should be given IV and then
repeated IM daily until a response is obtained or another diagnosis is established.
Polioencephalomalacia (symmetric necrosis of the cerebral cortex) is caused by thiamine
deficiency in young ruminants (feedlot calves and lambs). The deficiency results from
increased breakdown of thiamine in the rumen by thiaminase-secreting bacteria or from
sulfur toxicity. Animals have usually been moved from a marginal pasture to a lush
pasture, are in a feedlot, or have had some similar change in feeding patterns. Feedlot
diets high in sulfates decrease thiamine production in the rumen and may inhibit the
production of ATP. Animals younger than 2 years of age are most commonly affected.
86
Clinical signs are primarily forebrain in origin and include depression, pacing, head
pressing, blindness, ataxia, teeth grinding, opisthotonos, and seizures. Dorsomedial
strabismus has been attributed to trochlear nerve (cranial nerve [CN] IV) paralysis.
Increased intracranial pressure is common and may lead to transtentorial herniation.
Symmetric laminar cortical necrosis is the most prominent pathologic finding (Figure
15-7
).
Figure 15-7
Polioencephalomalacia in a calf. There is acute cortical necrosis evidenced by locally
extensive softening and discoloration (left image) and highlighted by fluorescence
under ultraviolet light.
(Courtesy Cornell University College of Veterinary Medicine.)
Edema of the brain with flattening of the gyri may be present. Measurement of transketolase,
the thiamine-dependent coenzyme, is helpful for making a diagnosis. Autofluorescence
of the cut surface of the cerebral cortex under ultraviolet light may assist diagnosis
(see Figure 15-7).
The condition should be treated with thiamine, 250 to 1000 mg administered IV or IM
for 3 to 5 days. Corticosteroids should be given if CNS signs are severe. Severely
affected animals may have permanent cortical damage.
88
Niacin and riboflavin deficiencies are less common, but because animals with thiamine
deficiency also may have deficiencies in these vitamins, multiple B-complex preparations
are indicated. The diet should be corrected to prevent recurrences.
Vitamin A Toxicity
Increased levels of vitamin A have been reported in cats fed predominantly liver diets.
Hypertrophic vertebral bone formation causes ankylosing spondylosis, usually of the
cervical vertebrae but in some cases extending to the lumbar region. The clinical
signs relate primarily to the rigidity of the vertebral column. A compressive neuropathy
occurs in severely affected cats. Dietary correction stops the progression of the
spondylosis but does not significantly reduce the existing spondylosis that is present.
Antiinflammatory and analgesic drugs have been recommended but must be used with caution,
especially in cats.
79
Toxic Disorders
Toxicities causing CNS dysfunction are common in both small and large animals. Many
cause biochemical changes and are potentially reversible, whereas others produce structural
damage. The more common toxicants are listed in Table 15-4
.
TABLE 15-4
Common Toxicants
Use
Toxicant
Primary Effect
Pesticides
Chlorinated hydrocarbons
CNS stimulation
Organophosphates
Binding of acetylcholinesterase
Carbamates
Binding of acetylcholinesterase
Pyrethrins
Blocking of nerve conduction and GABA inhibition
Metaldehyde
CNS stimulation
Arsenic
GI irritation
Rodenticides
Strychnine
Blocking of inhibitory interneurons (glycine)
Thallium
GI irritation, CNS stimulation, peripheral neuropathy, skin lesions
α-Naphthylthiourea (ANTU)
GI irritation, pulmonary edema, depression,coma
Sodium fluoroacetate (1080)
CNS stimulation
Warfarin
Anticoagulation
Zinc phosphide
GI irritation, depression
Phosphorus
GI irritation, CNS stimulation, coma
Cholecalciferol
CNS depression, cardiac depression
Bromethalin
Acute—CNS stimulation; chronic—CNS depression
Herbicides and fungicides
Numerous
GI irritation, CNS depression, some are stimulants
Heavy metals
Lead (see arsenic and thallium)
GI irritation, CNS stimulation or depression (see above)
Drugs
Narcotics
CNS depression
Amphetamines
CNS stimulation
Barbiturates
CNS depression
Tranquilizers
CNS depression
Aspirin
GI irritation, coma
Marijuana
Abnormal behavior, depression
Anthelmintics
GI irritation, CNS stimulation
Ivermectin
Depression, tremors, ataxia, coma
Garbage
Staphylococcal toxin
GI irritation, CNS stimulation
Botulinum toxin
LMN paralysis
Poisonous plants
Various
Various
Antifreeze
Ethylene glycol
GI irritation, CNS stimulation, renal failure
Detergents and disinfectants
Hexachlorophene
CNS stimulation or depression, tremors
Phenols
GI irritation, CNS degeneration
Animal origin
Snake bite
Necrotizing wound, shock, CNS depression
Toad (Bufo spp.)
Digitoxin-like action, CNS stimulation
Black widow spider
Initial signs—spasms, pain tremor initally; later signs—LMN paralysis
Lizards
GI irritation, CNS stimulation or depression
Tick paralysis (Dermacentor spp. Ixodes in Australia)
LMN paralysis
Toxicologic disorders, including those caused by poisonous plants, are discussed in
detail in several texts.79., 89., 90. A helpful information resource about toxic agents
and treatment protocols is the ASPCA’s National Animal Poison Control Center (http://www.napcc.aspca.org).
Diagnosis
A history of exposure to a toxin is the most important factor in establishing the
diagnosis in cases of poisoning. Neurologic signs of intoxication include (1) seizures;
(2) depression or coma; (3) tremors, ataxia, and paresis; and (4) LMN signs. Animals
that show any of these four signs must be considered as possible poisoning victims
until proved otherwise. Metabolic and inflammatory disorders are most commonly confused
with toxicosis.
Toxins can cause imbalances of neurotransmitter in the CNS to cause tremor. In particular
neurotoxic agents that stimulate the CNS will manifest signs of hyperactivity, hyperesthesia,
muscle tremor and fasciculation, and behavior changes. Toxicants affecting the autonomic
nervous system induce clinical signs by interference with cholinergic neurotransmission.
Stimulation of the cholinergic neurotransmission will result in bronchoconstriction,
muscle tremors, exocrine gland stimulation, bradycardia, and other CNS effects. Toxins
may exert effects at the neuromuscular junction through increased release of acetylcholine
and increased receptor stimulation and subsequent muscular fatigue. Blockade of cholinergic
neurotransmission depends upon the type of cholinergic receptor involved. Muscarinic
receptor blockade causes CNS depression. Nicotinic receptor blockade results in skeletal
muscle paralysis and often tremor. Toxins such as bromethalin and hexachlorophene
affect myelin causing intramyelinic edema and alter conduction of the action potential.
When an animal shows signs suggestive of poisoning, the owner must be questioned carefully
to find a possible source. Animals in status epilepticus must be treated immediately,
and the history must be obtained later (see Chapter 13). Direct questions regarding
agents that are capable of producing the signs must be asked. Owners usually are aware
of common agents such as insecticides and rodenticides, but they may have difficulty
identifying a source of lead poisoning and may be reluctant to admit a source of illicit
drug intoxication.
The clinical signs may be sufficient for the clinician to establish a presumptive
diagnosis (e.g., intoxication from strychnine and organophosphates). Other agents,
such as lead and drugs, may require laboratory confirmation (TABLE 15-5, TABLE 15-6,
TABLE 15-7, TABLE 15-8
) or tissue analysis.
TABLE 15-5
Common Toxicants Causing Seizures
Toxicants
Diagnosis
Management
Prognosis
Organochlorines
Exposure; muscle fasciculations common; laboratory confirmation difficult
Removal of toxicant—washing, gastric lavage; sedation or anesthesia with barbiturates
Poor with seizures
Organophosphates and carbamates
Exposure; salivation, diarrhea, constricted pupils, muscle weakness; blood cholinesterase
level decreased; tissue analysis poor
Removal of toxicant; atropine; pralidoxime chloride (2-PAM) (not for carbamates)
Good if treated early
Pyrethrins
Exposure; tremor, salivation, ataxia, seizures; analysis of tissues
Removal of toxicant; sedation
Good if treated early
Strychnine
Exposure; tetany without loss of consciousness, increased by stimulation or noise;
laboratory analysis of stomach contents, urine, tissues
Removal of toxicant—gastric lavage or emesis; sedation—barbiturates; respiratory support
if needed
Good if treated early
Bromethalin
Exposure; high dose—excitement, tremor, seizures; low dose—tremor, depression, ataxia
Removal of toxicant—activated charcoal; corticosteroids, mannitol
Fair if treated vigorously for several days
Sodium fluoroacetate (1080)
Exposure; seizures are clonic and severe; laboratory confirmation difficult
Removal of toxicant; sedation—barbiturates
Poor with seizures
Thallium
Exposure; GI signs, seizures only in severe poisonings; laboratory analysis of urine
and tissues
Removal of toxicant; diphenylthiocarbazone (Dithion) early, ferric ferrocyanide (Prussian
blue) late late
Poor with seizures, fair with other signs, good with treatment
Lead
Exposure (may be difficult to document); chronic intoxication may cause intermittent
seizures, behavioral change, tremor, GI signs; blood lead level >0.4 ppm; basophilic
stippling, nucleated red blood cells (RBCs) with no anemia
Removal of toxicant; calcium ethylenediaminetetraacetic acid, 2,3-dimercaptosuccinic
acid
Good with treatment
Staphylococcal toxin
Exposure to garbage; severe GI signs; isolation of toxins and testing in laboratory
animalslaboratory animals
Removal of toxicant; sedation
Poor with seizures; animals usually die rapidly
Toad (Bufo spp.—reported only in southern Florida)
Exposure; severe buccal irritation
Wash mouth; sedation—anesthesia
Fair if treated within 15-30 min, otherwise poor
Amphetamines
Exposure to prescription or “street” drugs; hyperactivity, dilated pupils; analysis
of urine
Removal of toxicant; sedation or anesthesia—barbiturates
Good if treated early
Metaldehyde
Exposure to snail bait; tremor, ataxia, salivation; seizures are tonic, similar to
strychnine, but not changing with stimuli; laboratory analysis of stomach contents
Removal of toxicant; sedation or anesthesia; support respiration
Fair if treated early
Caffeine and other methylxanthines
Ataxia, tachycardia, seizures, coma; laboratory analysis of stomach contents and tissues
Removal of toxicant; sedation, fluids
Fair with treatment
Zinc phosphide
Exposure to rodenticide; behavioral changes, hysteria followed by seizures; GI irritation;
analysis of stomach contents and tissues
Removal of toxicant; oral and intravenous bicarbonate; sedation—barbiturates
Poor
TABLE 15-6
Common Toxicants Causing Behavioral Changes, CNS Depression, or Coma
Toxicants
Diagnosis
Management
Prognosis
Drugs—narcotics, barbiturates, tranquilizers, marijuana
Degree of depression depends on dose; source of pharmaceuticals or “street” drugs;
laboratory analysis of blood or urine
Removal of toxicant, narcotic antagonists, diuresis, support respiration
Good with treatment
α-Naphthylthiourea (ANTU)
Exposure; pulmonary edema; depression and coma terminal; laboratory analysis of stomach
contents and tissues
Removal of toxicant, treatment of pulmonary edema
Poor
Ethylene glycol
Exposure; GI irritation, renal failure; oxalate crystals in urine
IV ethanol (30%) with sodium bicarbonate; alternative for dogs—4-methylpyrazole
Poor with coma, fair to good if treated early
Cholecalciferol
Exposure; depression, weakness, cardiac depression, renal failure
Removal of intoxicant; IV saline diuresis, furosemide, corticosteroids
Fair with treatment
Many poisons produce coma terminally
TABLE 15-7
Common Toxicants Causing Tremor, Ataxia, or Paresis
Toxicants
Diagnosis
Management
Prognosis
Hexachlorophene
Exposure; usually young, nursing animal; large dose causes GI irritation, severe depression;
chronic exposure causes cerebellar signs and CNS edema
Removal of toxicant, supportive care; treatment for cerebral edema
Fair; may be residual effects
Lead
Chronic lead poisoning may produce cerebellar signs and dementia (see Table 15-5)
See Table 15-5
Good
Organophosphates
Chronic low doses (flea collars, dips) may produce tremor and weakness (see Table
15-5)
See Table 15-5
Good
Organochlorines
Low-dose exposure may produce weakness and muscle fasciculation (see Table 15-5)
See Table 15-5
Fair to good
Tranquilizers
Ataxia common with tranquilizers (see Table 15-5)
None needed
Good
Marijuana
Behavioral changes and ataxia common
Removal of toxicant
Good
Ergot alkaloids
Cattle and other herbivores grazing on Dallis grass or ryegrass; ataxia, uncoordinated
gait
Removal from pasture
Good
Nitro-bearing plants (e.g., Astragalus spp., locoweed)
Cattle, sheep, horses; ataxia, weakness or hyperexcitability, death
Removal from pasture
Fair in ruminants; may be permanent CNS damage
Yellow star thistle
Horses have an acute onset of rigidity of muscles of mastication and involuntary movement
of the lips; ataxia, circling, and pacing may occur; lesions are necrosis of the globus
pallidus and substantia nigra
No treatment known
Poor
TABLE 15-8
Common Toxicants Causing LMN Signs
Toxicants
Diagnosis
Management
Prognosis
Botulinum toxin
Exposure to contaminated food, carrion, and so forth; ascending LMN paralysis (see
Chapter 7)
See Chapter 7
Good
Tick paralysis (Dermacentor spp., Ixodes species in Australia)
Presence of ticks; ascending LMN paralysis (see Chapter 7)
Removal of ticks (see Chapter 7)
Good in the United States of America; poor in Australia
Drug reaction (nitrofurantoins, doxorubicin, vincristine)
Exposure; rare in animals
Removal of source
Fair
Cyanide (from Sorghum spp. grass)
Cauda equina syndrome with dysuria, flaccid anus and tail, prolapsed penis; may progress
to paraplegia; usually occurs in horses
Removal from pasture; no treatment available
May improve after removal from source; residual deficits common
Organophosphates
Chronic exposure may cause LMN signs; axonopathy affecting pelvic limbs first
Removal of source; atropine and pralidoxime if acute signs present; no treatment for
peripheral neuropathy
Fair to poor
Heavy metals (lead, arsenic, mercury, thallium)
Chronic exposure, rare in animals (see Table 15-5)
See Table 15-5
See Table 15-5
Industrial chemicals (acrylamide, carbon disulfide, polychlorinated biphenyls)
Not reported in animals; presumably could cause distal axonopathy
Removal from source
Unknown
Toxicants Causing Seizures
The most common sign of poisoning in small animals is seizures (see Table 15-5). The
CNS is primarily or secondarily involved with a variety of toxic substances. Dorman
reported that seizures occurred in 8.2% of all cases of suspected toxicosis.
91
Toxins induce seizures through a number of different mechanisms: increased excitation,
decreased inhibition, and interference with energy metabolism.
92
The animal may show (status epilepticus) or cluster seizures (e.g., from organophosphates,
strychnine) or may have a history of intermittent seizures (e.g., from lead). Animals
in status epilepticus must be treated immediately (see Chapter 13).
Tetany
The tetany produced by strychnine is differentiated from the seizures produced by
other agents in this group. Tetany is a period of sustained muscular contraction with
intermittent periods of relaxation. Despite the severe muscle contractions, the animal
is conscious. Tetany caused by strychnine may be confused with hypocalcemic tetany
seen in lactating animals of all species or in tetanus. Intravenous calcium provides
immediate relief in cases of hypocalcemia. The term tetanus is associated with the
toxic effects of Clostridium tetani. Tetanus is much slower in onset than is strychnine
poisoning and generally causes more continuous contraction of the muscles. Seizures
from other agents produce clonus (alternating flexion and extension).
Insecticides
Organophosphates may be distinguished from organochlorines by their profound effect
on the autonomic nervous system, producing profuse salivation, constricted pupils,
and diarrhea. Organochlorines frequently produce fine-muscle fasciculations, even
between seizures. Pyrethrins and pyrethroid insecticides alter both sodium and chloride
conductance causing tremor and seizures. The seizure may be preceded by tremors, ataxia,
salivation, and other signs. Class I and II pyrethrins and pyrethroid compounds act
on voltage-gated sodium channels in nerve and muscle, causing persistent depolarization
and failure of membrane repolarization. Class II pyrethroids also inhibit binding
of GABA to the GABAA receptor, which prevents influx of chloride.
Miscellaneous Stimulants
Ingestion of products containing caffeine and other methylxanthines, including chocolate,
may also cause seizures. Metaldehyde, a common snail bait, can cause continuous seizures.
91
Both bromethalin and hexachlorophene are toxins that result in intramyelinic edema
and demyelination. Bromethalin is a rodenticide that uncouples oxidative phosphorylation
depleting cellular ATP.93., 94. Clinical signs include ataxia; conscious proprioceptive
deficits; paresis/paralysis; depression, which can progress to stupor; focal or generalized
seizures; decerebrate posture; and vocalization.
Metronidazole
Central nervous system signs of lead intoxication are seen most often in cases of
chronic exposure.95., 96., 97., 98., 99. The seizures are intermittent. The differential
diagnosis of seizure disorders is discussed in Chapter 13. Laboratory analysis of
the blood for evidence of lead is diagnostic. If the blood lead values are in the
high normal range and lead poisoning is suspected, treatment followed by measurement
of urine lead levels is diagnostic. Other toxicants causing seizures are seen infrequently.
Metronidazole is an antimicrobial, antiprotozoal agent that is lipophilic readily
penetrating the blood-brain barrier and causes neurotoxicity in dogs and cats.100.,
101., 102. The drug is also used in the chronic treatment of inflammatory bowel disease.
Neurologic signs include seizures, tremors, ataxia, blindness, hyperactivity, and
vestibular dysfunction. Doses of metronidazole reported to be toxic in cats ranged
from 111 mg/kg of body weight per day for 9 weeks to 58 mg/kg of body weight per day
for 6 months.
101
The neurologic signs resolved within days of drug withdrawal and supportive treatment.
In dogs, doses as low as 67.3 mg/kg of body weight per day for 3 to 14 days caused
neurotoxicity.
100
In a report of five dogs, two were euthanized because of severe CNS disease, and three
recovered after several months.
100
Most dogs recover within 7 to 14 days. Diazepam may be effective in treatment of the
neurologic signs because it facilitates the effects of GABA, a potent inhibitory neurotransmitter.
102
Diazepam, 0.43 mg/kg PO every 8 hours for 3 days, decreased response time from 4.25
days for untreated dogs to 13.4 hours for treated dogs. In addition, the time to recovery
was reduced from 11 days to 38.8 hours.
102
Ivermectin
Ivermectin is widely used as an antiparasitic agent and heartworm preventative. It
is also used in higher doses for the treatment of sarcoptic and demodectic mange in
dogs. In most breeds of dogs, ivermectin has a wide margin of safety. Collies, Australian
shepherds, Shetland sheepdogs, and Old English sheepdogs have an increased sensitivity
to ivermectin and related compounds. These breeds have a genetic mutation that results
in a nonfunctional P-glycoprotein.103., 104. P-glycoprotein plays an important neuroprotective
role in the blood-brain barrier in that it enhances the transport of drugs from the
CSF back into circulation. Ivermectin is a GABA agonist that inhibits activity at
presynaptic and postsynaptic neurons in the CNS. Clinical signs of ivermectin neurotoxicity
include depression, disorientation, tremors, ataxia, blindness, mydriasis, retinopathy,
seizures, and coma.104., 105., 106., 107. Clinical signs are dose dependent in that
susceptible breeds rarely develop clinical signs at 6 μg/kg once a month, which is
the standard dose for heartworm prevention. Doses exceeding 200 μg/kg may cause clinical
signs in susceptible breeds and doses above 400 μg/kg may cause death.
105
The recovery period may take more than 3 weeks. There is no specific anecdote for
ivermectin toxicity. Three adult horses developed neurologic signs 18 hours after
oral administration of ivermectin paste.
108
Signs included depression, ataxia, drooping of the lips, mydriasis, decreased pupillary
light reflexes, absent menace responses and muscle fasciculations. Two horses recovered
following symptomatic therapy.
Toxicants Causing Behavioral Change, Stupor, or Coma
Stupor or coma may be seen with almost any poison in the terminal stages. Drugs such
as narcotics, barbiturates, and tranquilizers most frequently cause stupor or coma
and also may cause behavioral changes in smaller doses (see Table 15-6). Some other
agents such as chlorpyrifos and lead also can produce behavioral changes with chronic
intoxication.99., 109. The diagnosis may be obvious if the source is known (e.g.,
with accidental overdosing with an antiepileptic drugs or ingestion by an animal of
its owner’s tranquilizers). Reports of animals that have ingested illicit drugs are
not uncommon, and the owner is usually reluctant to admit the source of the intoxication
in these cases. Laboratory analysis of blood or urine may be necessary to confirm
the diagnosis.
Leukoencephalomalacia (Moldy Corn Toxicity)
Leukoencephalomalacia is caused by the mycotoxin fumonisin B1 found in contaminated
corn. The toxin creates a severe liquefactive necrosis and degeneration of the cerebrum,
brainstem, and spinal cord. The disease has a worldwide distribution and typically
occurs in the late fall through early spring. Neurologic (most common) and hepatoxic
syndromes are recognized. Clinical signs develop 3 to 4 weeks after daily ingestion
of contaminated corn. The onset of clinical signs is rapid with death occurring in
2 to 3 days. The CNS signs are similar to other equine encephalopathies. The hepatotoxic
syndrome is associated with swelling of the lips and nose, somnolence, severe icterus,
petechia of mucous membranes, abnormal breathing, and cyanosis. Diagnosis is based
on histopathology. Analysis for the toxin in feed is recommended. There is no treatment
and mortality is high.
Toxicants Causing Tremors, Ataxia, and Paresis
Chronic organophosphate poisoning from flea collars and topical or systemic insecticides
frequently causes signs that are suggestive of cerebellar disease or muscle weakness
(see Table 15-8). The finding of weakness is not consistent with pure cerebellar disease,
so when both are present, poisoning must be considered.
110
Organophosphates bind acetylcholinesterase to cause muscle weakness through effects
on the neuromuscular junction (see Chapter 7) and have direct CNS effects causing
seizure. Tremor and fasciculation associated with muscle weakness occur as a depolarizing
neuromuscular junction blockade effect take place. Atropine is used to counteract
the muscarinic effects of the organophosphate. Pralidoxime chloride (2-PAM) is a drug
that acts specifically on the organophosphate-enzyme complex and freeing the enzyme.
Hexachlorophene toxicity has been seen in puppies with signs of tremor and ataxia.111.,
112., 113. Severe depression may follow. The usual source has been repeated washing
of the bitch’s mammary glands with a soap containing hexachlorophene. Bathing young
dogs or cats of any age in hexachlorophene soap also has produced the syndrome. Hexachlorophene
is rarely available now.
Metaldehyde poisoning, which produces tremor and ataxia progressing to depression
and coma, is seen frequently in areas where the substance is used for snail bait.
Chronic lead poisoning (see Chapter 10) and numerous plant toxicities cause tremor
and ataxia (Table 15-7). Mycotoxins also can cause severe tremors and seizures in
dogs (see Chapter 10).
Toxicants Causing LMN Signs
Botulism and tick paralysis cause generalized LMN paralysis by blockade of the neuromuscular
junction (see Table 15-8). These conditions are discussed in Chapter 7. Some drugs
(e.g., nitrofurans and chemotherapeutic drugs and some chronic toxicities (such as
lead, organophosphate, and arsenic poisoning) can produce peripheral neuropathies.
Other signs usually predominate, however.
Toxic Plants
Toxic plants causing neurologic syndromes of herbivores are summarized in Table 15-9
.
TABLE 15-9
Examples of Several Plant (and Fungal) Toxicoses of Domestic Herbivores That Can Result
in Syndromes Characterized by Neurologic Signs
Plant
Species Affected
Neurologic Signs
Pathophysiology
Neural Legions
Treatment
Prognosis
Ryegrass
Sheep, cattle, horses
Ataxia, tremor, tetany
Penitrem and fumi tremorgenic mycotoxins from Penicillium spp.
Secondary Purkinje cell degeneration
Diazepam
Good
Phalaris spp.
Sheep, cattle
Ataxia, tremor, weakness, seizures
Dimethyltryptamine alkaloids act as monoamine oxidase inhibitors
Neuronal pigmentation (indole melanins)
?Diazepam
Poor
Paspalum, Dallis grass
Cattle, sheep
Ataxia, tremor
Claviceps paspali ergot alkaloids probably neurotoxic
None
—
Good
Swainsona spp. and locoweeds
Sheep, cattle, horses
Weight loss, ataxia, aggressiveness
Indolizidine alkaloid (swainsonine) induces α-mannosidosis
Neuroaxonal dystrophy, neurovisceral storage products
Reserpine (locoweed)
Fair to very good
Sorghum spp.
Horses, cattle, sheep
Ataxia, bladder paralysis
Possibly HCN or lathyrogenic toxins
Spinal cord degeneration
—
Poor to fair
Solanum esuriale
Sheep
Exercise intolerance, weakness, arched back (humpyback)
Unknown (suspected toxin in S. esuriale)
Spinal cord fiber degeneration; myopathy
—
Poor
Solanum fastigiatum, S. dimidiatum, S. kwebense
Cattle
Cerebellar ataxia, “cerebellar seizures”
Suspected induction of gangliosidosis
Purkinje cell vacuolation and degeneration
—
Poor
Cycad palms
Cattle, goats, horses
Ataxia, recumbency
Possibly toxic glycosides, cycasin and macrozamin
Spinal cord degeneration
—
Poor
Melochia pyramidata
Cattle
Ataxia, recumbency
Unknown
Spinal cord and nerve degeneration
—
Poor
Tribulus terrestris
Sheep
Asymmetric pelvic limb weakness
Possibly neuromuscular process
None
—
Poor
Karwinskia humboldtiana
Goats
Hypermetria, weakness
Unknown
Peripheral neuropathy, central neuroaxonal dystrophy, myopathy
—
Poor
Nardoo fern, Marsilea drummondii
Sheep
Depression, blindness, convulsions
Probably a thiaminase
Polioencephalomalacia
Thiamine
Good if early
Birdsville indigo, Indigofera linnaei
Horses
Weight loss, ataxia, weakness
Arginine antagonist alkaloids; indospicine, canavine
None
Arginine-rich feeds (gelatin, Lucerne)
Good
Mexican fireweed, Kochia scoparia
Cattle
Blindness (nephrosis, hepatitis)
Saponins, alkaloids, oxalates; possibly thiaminase
Polioencephalomalacia
—
Poor
Buckeye, Aesculus spp.
Cattle
Staggering, convulsions
Glycosides and alkaloids described
Unknown
—
Fair
Helichrysum argyrosphaerum
Sheep, cattle
Peripheral blindness, nystagmus, weakness
Unknown
Patchy status spongiosus, white matter
—
Fair for life, poor for vision
Yellow star thistle, Centaurea solstitialis
Horses
Depression, pacing, dystonia of muscles of prehension, mastication, and deglutition
Uknown
Nigropallidal encephalomalacia
Tube feed
Poor, starve
Modified from Kornegay JN, Mayhew IG: Metabolic, toxic, and nutritional diseases of
the nervous system. In Oliver JE, Hoerlein BF, Mayhew IG, editors: Veterinary neurology,
Philadelphia, 1987, WB Saunders.
Treatment
Removal of the toxic substance is the most important part of the treatment for many
toxicities. Agents that have entered the animal through the skin, such as insecticides,
should be removed by thorough washing and rinsing. Ingested agents may be removed
by inducing emesis, performing gastric lavage, or administering laxatives or enemas.
Diuresis may promote excretion when absorption has occurred. Activated charcoal is
an effective adsorbing agent.
114
Electrolyte imbalances and other secondary metabolic disorders are treated symptomatically
and by managing the underlying disease process. Status epilepticus is a life-threatening
emergency and must be treated accordingly (see Chapter 13).
Specific treatments for the various toxicities are outlined in TABLE 15-5, TABLE 15-6,
TABLE 15-7, TABLE 15-8, TABLE 15-9. The reader should consult the references for details.79.,
89., 90., 115. Toxins causing spasticity can be counterbalanced with use of muscle
relaxants. Diazepam (0.25 to 1.0 mg/kg IV or per rectum) is a centrally acting muscle
relaxant and can relieve acute-onset tremor disorders. However, diazepam should be
avoided in cats with organophosphate toxicity as it may potentiate muscle tremor,
and other muscarinic signs. Methocarbamol also a centrally acting muscle relaxant
can be administered. Often a dark, quiet room is necessary to remove external stimuli
associated with CNS stimulants (strychnine, bromethalin, etc.). Frequent patient monitoring
and other measures of supportive care are important. Fluid therapy maintains electrolyte
concentration and normovolemia. Oxygenation, blood pressure, electrolytes, and glucose
should be monitored. In severe cases of respiratory muscle weakness, assisted ventilation
may be necessary.
Inflammatory Diseases
The inflammatory diseases of the nervous system are caused by infectious and parasitic
organisms or are immune mediated. Canine distemper, feline infectious peritonitis,
equine protozoal myeloencephalitis, West Nile encephalomyelitis, alphaviral encephalomyelitis,
and bacterial infections, including thromboembolic meningoencephalitis and listeriosis,
are common infectious causes of CNS inflammatory disease. Some fungal diseases are
common in endemic areas. Most of the other diseases are relatively uncommon. Infectious
diseases are discussed in many textbooks.116., 117., 118., 119., 120., 121. Granulomatous
meningoencephalomyelitis, steroid-responsive meningoencephalitis, and other breed-specific
meningoencephalitides are common noninfectious or immune causes of CNS inflammatory
disease. The differential diagnosis is discussed in the next section. The more common
inflammatory diseases are outlined in TABLE 15-10, TABLE 15-11, TABLE 15-12, TABLE
15-13, Table 15-14, TABLE 15-15, TABLE 15-16, TABLE 15-17
.
TABLE 15-10
Bacterial Diseases of the Nervous System
Disease
Cause
Incidence
Clinical Signs and Pathology
Course and Prognosis
Diagnostic Tests
Treatment
Meningitis
Staphylococcus, Pasteurella, others
Variable, but generally uncommon
Generalized or localized (especially cervical) hyperesthesia; degree of illness variable;
temperature and white blood cell (WBC) count may be normal count may be normal
Usually acute onset, but may be chronic; prognosis good with early treatment
CSF (protein often >200 mg/dL, increased cells, primarily neutrophils), culture and
sensitivity testing
Antibiotics according to sensitivity: ampicillin, trimethoprim, chloramphenicol
Meningoencephalo-myelitis
As in meningitis
Uncommon
As in meningitis, plus signs of brain or spinal cord disease; often includes blindness,
seizures, ataxia, cranial nerve deficits
Usually acute: prognosis good with early treatment, but neurologic deficits are common
Same as meningitis; EEG may indicate encephalitis; cross-sectional imaging
Same as for meningitis; seizures—diazepam, phenobarbital; acute cerebral edema—mannitol,
hypertonic saline
Abscess
As in meningitis
Rare
May have focal signs or focal signs plus signs of meningitis or meningoencephalitis
May be chronic; progression may be rapid once signs are obvious
Same as in meningoencephalitis
Same as for meningoencephalitis
Vertebral osteomyelitis, discospondylitis (see Chapter 6)
Staphylococcus, Brucella canis, others
Moderately frequent in dogs
Pain, usually focal; may have spinal cord compression; usually clinically ill, often
over weeks to months
Chronic, may become acute when spinal cord is compressed
Radiography, cross-sectional imaging, Brucella serology; blood and urine culture and
sensitivity
Antibiotics, preferably bactericidal; curettage, decompression if spinal cord is compressed
Tetanus
Clostridium tetani
Rare except in horses
Extensor rigidity of all limbs, often with opisthotonos; contraction of facial muscles,
prolapsed nictitating membrane; usually infected wound; toxin blocks glycine release
Acute onset, often lasts 1-2 wk, animals may die; prognosis fair if treated
Signs, history, isolation of organism from wound
Penicillin, metronidazole, tetanus antitoxin, tranquilizers or muscle relaxants; quiet
environment; treat wound, nursing
Botulism
Clostridium botulinum
Sporadic
LMN-type paralysis. often beginning with pelvic limbs, progressing to tetra- paresis
in less than 24 hr; caused by toxin blocking neuromuscular transmission
Acute onset, lasts about 2 wk; good prognosis unless respiratory paralysis is present
early
Serum, fecal analysis, history, EMG, and nerve conduction velocity
Enemas and laxatives early, supportive care, antitoxin usually not effective
Thromboembolic meningoencephalitis
Histophilus somni
Cattle, primarily young in feedlot
Fever, depression, blindness, lack of coordination, cranial nerve signs, seizures
Acute progressive; fair prognosis with early treatment
History, CSF (increased protein, increased neutrophils), culture
Antibiotics, vaccine available
Listeriosis
Listeria monocytogenes
Sporadic in ruminants
Depression, asymmetric ataxia and paresis, cranial nerve signs, central vestibular
signs
Acute progressive in sheep and goats, more chronic in cattle; poor prognosis if CNS
signs are present
History, signs, CSF (increased protein, increased mononuclear cells), histopathology,
fluorescent antibody, isolation of organism
Antibiotics (penicillin, sulfonamides, tetracyclines) for 2-4 wk
TABLE 15-11
Mycotic and Actinomycetes Infections of the Nervous System
Disease
Cause
Incidence
Clinical Signs and Pathology
Course and Prognosis
Diagnostic Tests
Treatment
Cryptococcosis
Cryptococcus neoformans
Low; primarily in eastern and midwestern United States but not reported throughout
United States
Nose and sinuses usually are infected, with extension to brain; ocular lesions and
blindness common; CNS involvement common
Chronic; guarded prognosis
Cytology and culture of exudates, serology, antigen test, CSF (increased protein,
increased cells, neutrophils and mononuclear cells, possibly organisms)
Itraconazole, fluconazole∗
Blastomycosis
Blastomyces dermatitidis
Low; primarily in eastern and midwestern United States
Rarely involves CNS; pyogranulomatous encephalitis or single or multifocal granulomas;
frequently involves lungs, skin, and eyes
Chronic; poor prognosis
PCR, serology, cytology
Amphotericin B,∗ 5-fluorocytosine, ketoconazole, itraconazole, fluconazole
Histoplasmosis
Histoplasma capsulatum
Low, primarily in central United States
CNS involvement uncommon; involves reticuloendothelial cells of most viscera
Chronic; guarded prognosis
PCR, serology, cytology
Amphotericin B,∗ 5-fluorocytosine, ketoconazole, itraconazole, fluconazole
Coccidioidomycosis
Coccidioides immitis
Can be relatively common in endemic areas of southwestern United States
CNS involvement uncommon; pulmonary infection common
Chronic; poor prognosis
PCR, serology, cytology
Amphotericin B,∗ 5-fluorocytosine, ketoconazole, itraconazole, fluconazole
Nocardiosis
Nocardia sp.
Low throughout United States
Systemic disease, signs similar to canine distemper, respiratory or cutaneous forms;
CNS abscesses and vertebral osteomyelitis reported
Chronic; poor prognosis
Smears, cultures, CSF (increased protein, increased cells, neutrophils)
Penicillin, sulfonamides, trimethoprim
Actinomycosis
Actinomyces sp.
Low throughout United States
Similar to nocardiosis
Chronic; poor prognosis
Similar to nocardiosis
Penicillin, clindamycin, erythromycin, lincomycin
Paecilomycosis
Paecilomyces sp.
Rare
Disseminated form of discospondylitis
Chronic; poor prognosis
Culture, biopsy
None
Aspergillosis
Aspergillus sp.
Primarily in large animals
Encephalitis can develop after immunosuppression or guttural pouch infection
Chronic; poor prognosis
Culture, CSF, cytology
Amphotericin B,∗ 5-fluorocytosine, ketoconazole, itraconazole, fluconazole
Phaeohyphomycosis
Cladosporium sp.
Rare
Encephalitis with granulomas has been reported in dogs and cats
Chronic; poor prognosis
Culture, biopsy
Amphotericin B,∗ 5-fluorocytosine, ketoconazole, itraconazole, fluconazole
∗
Itraconazole and fluconazole have been used effectively in some cats with cryptococcal
encephalitis and are the preferred treatment. Data for other fungal CNS infections
are largely lacking.
TABLE 15-12
Protozoal Diseases of the CNS
Disease
Cause
Incidence
Clinical Signs and Pathology
Course and Prognosis
Diagnostic Tests
Treatment
Toxoplasmosis
Toxoplasma gondii
Common infection but infrequent clinical problem
Clinical manifestations usually associated with another disease or immunosuppression;
CNS, eyes, lungs, gastrointestinal tract and skeletal muscles often affected
Chronic; fair to poor prognosis
Serology, oocysts in stool (cats), biopsy, CSF (increased protein, mononuclear cells
and neutrophils)
Sulfonamides, pyrimethamine, clindamycin
Neosporosis
Neospora caninum
Uknown frequency, cases of toxoplasmosis reported in past were sometimes Neospora;
reported in dogs and rarely in cats, cattle, and horses
Similar to toxoplasmosis; ascending paralysis of limbs with extension of the pelvic
limbs is frequent in young pups
Chronic progressive; fair to poor prognosis
CSF, biopsy, isolation of organism, serology
Sulfonamides, pyrimethamine, clindamycin are probably effective if given early
Babesiosis
Babesia spp.
Rare in United States
Parasite of red blood cells; rarely causes CNS disease, hemorrhage; more severe with
other infections, such as Ehrlichia
Acute to chronic; poor prognosis
Peripheral blood smears, serology
Diminazene, phenamidine, or imidocarb
Encephalitozoonosis
Encephalitozoon cuniculi
Rare; primarily affects dogs <2 mo old
Acute encephalitis, ataxia, tremors, behavioral changes
Acute; poor prognosis
Serology, culture, histopathology
None
Trypanosomiasis
Trypanosoma cruzi
Rare in United States
Parasite of red blood cells; rarely causes CNS disease
Chronic, fair prognosis with treatment
Peripheral blood smears
Nifurtimox
Equine protozoal myeloencephalitis
Sarcocystis neurona (Sarcocystis falcatula)
Fairly common in horses
Systemic, multifocal, involving almost any part of the nervous system: commonly spinal
cord, cauda equina, and cranial nerve signs
Chronic, progressive; guarded prognosis; treatment may be effective
CSF: Western blot, ELISA, IFA, and PCR
Pyrimethamine, trimethoprim-sulfonamide, diclazuril, ponazuril, nitazoxanide
Coccidiosis
Several species
Common enteric, rare CNS, several species of animals affected
Enteric coccidiosis is reported to cause CNS signs in some cases; Sarcocystis spp.
may cause myopathy
Variable
Fecal identification, organism in muscle biopsy or necropsy
Sulfonamides, amprolium
Hepatozoonosis
Hepatozoon canis
Rare; dogs
Muscle pain and gait abnormalities may be seen
Chronic; guarded prognosis
Biopsy, PCR
Possibly sulfonamides, pyrimethamine (efficacy not known)
TABLE 15-13
Viral Diseases of the CNS
Disease
Cause
Incidence
Clinical Signs and Pathology
Course and Prognosis
Diagnostic Tests
Treatment
Prevention
Multiple Species
Rabies
Rhabdovirus
Variable; all mammals
Rare; more common in cats
Initially behavioral changes; rapid progression to either furious or dumb form; atypical
variants are common in large animals (colic in horses and tenesmus in cattle)
Furious: restlessness, wandering, biting, aggression, seizures
Dumb: severe depression, pharyngeal and hypoglossal paralysis, progressive paralysis
Paralytic: Ascending paralysis; progresses to include other brain signs
Acute, progresses to death in 3-10 days from onset
Necropsy: FA of brain
None
Vaccine
Postvaccinal: Inadequate attenuated virus; rare; progressive ascending paralysis to
diffuse CNS signs
Acute, progressive, poor prognosis
Necropsy: FA
None
Use proper vaccine
Pseudorabies
Herpesvirus
Rare; eradicated in domestic swine in United States
Swine: subclinical in adults; neonates: seizures, tremors, ataxia, death
Other animals: excitement, intense pruritus and self-mutilation at site of viral entry;
rapid progression to coma and death; contact with swine
Acute; progression to death in 1-2 days
Necropsy: FA on brain and spinal cord
None
Avoid contact with infected swine
Dogs
Canine distemper
Morbillivirus
Common; dogs.
Also large cats, raccoons, ferrets, marine mammals
Acute: young dogs; systemic illness; respiratory and gastrointestinal signs; CNS:
acute seizures
Chronic: Young or mature dogs. Demyelination of cerebellum, cerebral peduncles, optic
nerves and tracts, and spinal cord. May begin with focal signs and progress to multifocal
lesions. CNS signs occur weeks to months after systemic illness or without systemic
signs.
Old dog encephalitis: Mature or older dogs. Necrosis of cerebral gray matter. Forebrain
signs predominate.
Acute to chronic; poor prognosis
CSF, FA on CSF, serology. Histopathology
Supportive; anticonvulsants
Vaccine
Postvaccinal: see chronic distemper
1-2 wk postvaccination; acute and progressive
See distemper
None
Infectious canine hepatitis
Canine adenovirus type I
Rare
Affects vascular endothelium, which may cause CNS signs; primarily affects liver,
kidney, and lung. Can cause hepatoencephalopathy
Acute to chronic
Clinical pathology profile (liver)
Supportive
Vaccine
Canine herpesvirus
Canine herpesvirus
Sporadic; neonates and young puppies
In utero or early postwhelping exposure; polysystemic signs: depression, diarrhea,
rhinitis, coma, opisthotonus, seizures
Acute progressive to death
Virus isolation; histopathology
Supportive
Colostrum; hyper-immune serum
Cats
Feline infectious peritonitis
Coronavirus
Relatively common in cats
Effusive form (wet): diffuse, fibrinous peritonitis
Noneffusive (dry) form: disseminated pyogranulomatous lesions in viscera, CNS, and
eye. CNS signs can be focal or disseminated. Meningeal involvement and secondary hydrocephalus
are common.
Slowly progressive; eventually fatal
Neutrophilic leukocytosis; increased serum globulins; CSF; mixed pleocytosis and increased
protein
Supportive
Vaccine; marginally effective. Isolate infected cats
Feline panleukopenia
Parvovirus
Sporadic; neonatal cats
In utero or early postnatal CNS infection causing cerebellar hypoplasia (see Chapter
8)
Present at birth; nonprogressive
Necropsy
None
Vaccine
Feline leukemia virus (FLV)
Retrovirus
Common; cats
Epidural lymphoma causes spinal cord signs; diffuse brain disease may be present;
systemic involvement and immunosuppression are common
Chronic progressive
Imaging, CSF, ELISA, FA, PCR
Combination chemotherapy
Vaccine
Feline immunodeficiency virus (FIV)
Lentivirus
Rare for neurologic signs
Behavioral signs
Chronic
ELISA, histopathology
None
Vaccine
Feline paramyxovirus
Paramyxovirus
Rare
Similar to canine distemper; demyelination; myoclonus reported
Chronic progressive
Virus isolation
None
None
Horses
Encephalomyelitis (Western, Eastern, Venezuelan)
Togavirus (alphaviruses)
Variable; sporadic outbreaks in United States
Depression, fever, anorexia, ataxia, pacing, and circling; cranial nerve involvement
in some cases
Acute progressive; guarded prognosis
CSF; serology; virus isolation; histopathology
Supportive
Vaccine mosquito control
West Nile virus
Togavirus (flavivirus)
Variable outbreaks; horses, birds and humans; sometimes other species including dogs
and cats
Fever, paresis, ataxia, and muscle fasciculations. Lesions most severe in spinal cord;
usually asymmetric and multifocal. Abnormal mentation and cranial nerve abnormalities
occur in 44% to 67% of affected horses.
Acute progressive; guarded prognosis
CSF; plaque reduction neutralization tests (PRNTs); IgM capture ELISA test
Supportive
Vaccine
Equine herpesvirus
Equine herpesvirus 1 (EHV 1)
Variable
Upper respiratory infection, abortion, ataxia, urinary incontinence, paresis, signs
more severe in pelvic limbs, sometimes cranial nerve signs
Acute progressive; fair to good prognosis
CSF, serology
Supportive Acyclovir
Vaccine ± isolation
Equine infectious anemia (EIA)
Retrovirus
Rare CNS signs
Behavioral changes, blindness, ataxia, weakness
Chronic progressive
Coggin test
Supportive
None
Cattle
Infectious bovine rhinotracheitis (IBR) 1 and 5
Bovine herpesvirus types 1 and 5
Rare form of IBR
Calves <6 wk of age most susceptible. Fever, depression, respiratory signs, salivation,
ataxia, circling, nystagmus, blindness, coma
Acute progressive; fatal
CSF; virus isolation; FA; immunoper- oxidase; histo- pathology
Supportive
Vaccine
Malignant catarrhal fever
Herpesvirus
Sporadic
Adult cattle: depression, blindness, pacing, seizures, death; nasal and ocular discharge
Acute progressive to death
Histopathology
Supportive
None
Swine
Enteroviral encephalomyelitis
Enterovirus
Variable
Pelvic limb paresis and ataxia, paralysis, seizures
Acute progressive; recovery or death in 1-3 wk
Virus isolation, serology
Supportive
Vaccine
Hemagglutinating encephalomyelitis virus
Coronavirus
Sporadic
Young swine: depression, ataxia, seizures, hyperesthesia
CNS form is acute
Serology; virus isolation
None
None
Porcine para- myxovirus
Paramyxovirus
Rare
Nursing piglets: depression, ataxia, seizures, weakness, tremor, blindness, and panophthalmitis
Acute progressive; fatal
Viral isolation; histopathology
None
None
Sheep and Goats
Visna, maedi
Lentivirus
Variable; sheep >2 yr old; horizontal transmission
Visna: ataxia, pelvic limb paresis; progressive to tetraparesis; facial tremors, blindness
Maedi: progressive pneumonia
Chronic progressive; fatal in 1-2 yr
CSF, virus isolation, serology, histopathology
None
Culling carriers, chronically infected sheep
Louping ill (ovine encephalomyelitis)
Togavirus
Ireland; tick vector (Ixodes). Young sheep; sometimes horses, wildlife and other ruminants
Ataxia of head, trunk, and limbs. Rabbit hopping gait, blindness, seizures
Acute progressive; 50% fatal
Serology, virus isolation, presence of ticks
Supportive
Vaccine
Caprine arthritis-encephalitis virus (CAE virus)
Retrovirus (lentivirus)
Kids 2-6 mo old (virus shed in colostrum)
Persistent asymptomatic infection in adults. Progressive ataxia and paresis worse
in pelvic limbs, tremors, opisthotonus. Evidence of arthritis, pneumonia, and mastitis
(hard bag) in herd.
Acute to chronic progressive; fatal in kids
Agar gel immunodiffusion (AGID) blood
None
Culling chronically infected adults; heat treat colostrum
Border disease (hairy shaker lamb)
Pestivirus (similar to BVD of cattle)
Lambs (transmission is vertical and horizontal). Can affect goats and cattle
In utero infection before 50 days of gestation. Hairy wool, tremors of head and neck,
ataxia. Flock history of abortion, infertility, deformed lambs. Goats: abortion and
muffied fetus. Cattle: early abortion
Chronic; persistent infections
PCR, serology
None
Remove persistently infected animals
Table 15-14
Rickettsial and Chlamydial Diseases of the CNS
Disease
Cause
Incidence
Clinical Signs and Pathology
Course and Prognosis
Diagnostic Tests
Treatment
Rocky Mountain spotted fever
Rickettsia rickettsii
Fairly common in endemic areas of United States; dogs
Meningitis, ataxia, other CNS signs, can look like canine distemper
Acute; good prognosis with treatment
History of ticks, signs; thrombocytopenia, serology
Doxycycline, chloramphenicol
Ehrlichiosis
Ehrlichia canis
Rarely CNS signs in dogs
Meningitis, encephalitis
Acute to chronic; good prognosis if treated early
Pancytopenia, thrombocytopenia, serology
Doxycycline, chloramphenicol
Salmon poisoning
Neorickettsia helminthoeca
Rare, Pacific Northwest United States
Depression and convulsions terminally; paresis of pelvic limbs less common; nonsuppurative
meningoencephalitis
Acute; fair to good prognosis if treated early
History of eating salmon, fluke eggs in feces
Doxycycline, chloramphenicol
Sporadic bovine encephalomyelitis (Buss disease)
Chlamydia psittaci
Sporadic, young cattle
Respiratory disease, polyarthritis, diffuse cerebral signs
Acute progressive; mortality approximately 50%
History, signs, CSF (increased protein, increased mononuclear cells), serology
Tetracycline, tylosin
Neuroborreliosis (Lyme disease)
Borrelia burgdorferi
Rare, except in endemic areas
Depression, meningitis
Acute to chronic (poorly characterized)
Antibodies to B. burgdorferi (especially in CSF)
Third-generation cephalosporins, tetracyclines
TABLE 15-15
Parasitic Diseases of the CNS
Disease
Cause
Incidence
Clinical Signs and Pathology
Course and Prognosis
Diagnostic Tests
Treatment
Dirofilariasis
Dirofilaria immitis, microfilaria or aberrant adult
Rare, areas with heartworm disease
CNS signs rare; microfilaria or migrating adult heartworms may cause infarction; seizures
and other cerebral signs
Acute onset; prognosis guarded
Blood smear or serology to confirm heartworm disease, CSF (increased eosinophils suggestive),
difficult to prove antemortem
None proven
Larva migrans
Toxocara canis and other species
Rare
Granulomas in brain or spinal cord from migrating larvae; signs related to location
of lesion
Acute or chronic; prognosis depends on severity of signs
None, necropsy
None
Cuterebrosis
Cuterebra spp.
Rare
CNS signs depend on location of lesion
Acute to chronic; guarded prognosis
None, necropsy
None
Coenurosis
Coenurus spp.
Rare; most often reported in sheep
CNS signs depend on location of lesion
Acute to chronic; poor prognosis
None, sheep have softening of skull that can be palpated or seen on radiographs
Surgical removal in sheep
TABLE 15-16
Immune-Mediated Diseases of the CNS
Disease
Cause
Incidence
Clinical Signs and Pathology
Course and Prognosis
Diagnostic Tests
Treatment
Coonhound paralysis
Probable immune reaction to transmissible agent in raccoon saliva or environment
Fairly high in some areas; dogs
Ascending LMN paralysis; may last approximately 6 wk; ventral roots and peripheral
nerves have segmental demyelination and some axon loss
Acute onset, lasts approximately 6 wk; good prognosis with good nursing
History, EMG, nerve conduction studies
Supportive
Postvaccinal rabies
CNS tissues in vaccine
Rare—these vaccines are no longer used
Ascending paralysis; demyelination from immune reaction to myelin in brain-origin
vaccines
Acute onset, progressive; poor prognosis
None
None
TABLE 15-17
Unclassified (noninfectious) Inflammatory Diseases of the CNS in Dogs and Cats
Disease
Cause
Incidence
Clinical Signs and Pathology
Course and Prognosis
Diagnostic Tests
Treatment
Steroid-responsive Meningitis-Arteritis (SRMA)
Unknown
Uncommon. Dogs less than 2 yr of age. Large-breed dogs: boxers, Bernese mountain dogs
Severe cervical hyperesthesia from inflammation of meninges and arteries. Sometimes
associated with immune-mediated polyarthritis.
Acute and progressive; fair to good prognosis
CSF: neutrophilic pleocytosis and increased protein; increase IgA in serum and CSF
Immunosuppressive doses of prednisone
Necrotizing vasculitis
Unknown
Likely a severe form of SRMA. Seen in young beagles, Bernese mountain dogs and German
short-haired pointers
Severe necrotizing vasculitis of the meninges, especially in cervical region. Signs
similar to SRMA but more likely to have paresis. Spinal cord infarction reported in
Bernese mountain dogs
Acute progressive; guarded prognosis
CSF: see SRMA
See SRMA
Pyogranulomatosis meningoencephalo- myelitis
Unknown
Rare; reported in pointers
Mixed mononuclear-neutrophil infiltration of meninges and parenchyma of brain and
spinal cord. Severe cervical pain, atrophy of cervical muscles, mild ataxia
Acute progressive; guarded to poor prognosis
CSF: neutrophilic pleocytosis; histopathology
See SRMA; some dogs respond to antibiotics
Granulomatous meningoencephalo-myelitis (GME)
Unknown; probably type IV hypersensitivity
Relatively common in small-breed dogs
Granulomatous infiltrates in meninges, perivascular spaces, and brain parenchyma.
Lesions may be disseminated, focal, or multifocal. Signs depend on lesion distribution.
Cervical pain is common.
Chronic progressive; guarded prognosis, relapses are common
CSF: presence of macrophages is useful; histopathology, MRI
Prednisone, cytosine arabinoside, cyclosporine, other immunosuppressants
Necrotizing meningoencephalitis (NME); necrotizing leukoencephalitis (NLE)
Unknown; possibly immune mediated
Rare disease reported in young pugs, Maltese, Pekingese, Chihuahua, Yorkshire terrier,
shih-tzu, French bulldog; West Highland white terrier, Boston terrier, Japanese Chin,
miniature pinscher
Lymphoplasmacytic perivascular infiltrates in cerebrum and meninges. Multifocal necrosis
in cerebrum. Seizures and other forebrain signs. Brainstem signs occur more with NLE.
Chronic progressive; poor prognosis
CSF (lymphocytic pleocytosis, increased protein); MRI
See GME; responds poorly to immunosuppressants
Feline polioencephalomyelitis
Unknown
Rare
Pelvic limb paresis, tremors, hyperesthesia. Spinal cord neurons and white matter
primarily affected; brain lesions are scattered
Chronic progressive; poor prognosis
Histopathology; some cats have leukopenia and nonregenerative anemia
None
Principles of Diagnosis
Most of the inflammatory diseases are characterized by an acute onset. All are progressive,
and some are chronic-progressive. Diffuse or multifocal involvement is characteristic
of most of the diseases in this group, but localized signs also occur. The minimum
database (see Chapters 1 and 4Chapter 1Chapter 4) may provide evidence of systemic
infection (e.g., alterations in white blood cell [WBC] count), although many primary
CNS inflammatory diseases do not produce a systemic response. Therefore, positive
findings in laboratory data are useful, but negative findings do not rule out infectious
disease. Focal deficits should be investigated according to the location of the lesion
(see Chapters 5 through 15Chapter 5Chapter 6Chapter 7Chapter 8Chapter 9Chapter 10Chapter
11Chapter 12Chapter 13Chapter 14).
Analysis of CSF is a useful test for establishing the diagnosis of inflammatory disease
(see Chapter 4). Increases in CSF protein concentrations range from low (50 to 100
mg/dL) in chronic viral diseases to very high (>300 mg/dL) in bacterial and fungal
infections. Characteristic cell changes are increased mononuclear cells in viral diseases;
increased neutrophils in bacterial diseases; increased numbers of both mononuclear
cells and neutrophils in mycotic and protozoal diseases and feline infectious peritonitis;
and increased numbers of mononuclear cells, neutrophils, and some eosinophils in parasitic,
fungal, and immune-mediated diseases. Exceptions are common. For example, chronic
bacterial infections may cause a mononuclear cell response, especially increases in
macrophages, whereas some viral diseases cause increased neutrophils in the CSF. The
presence of a few neutrophils in the CSF is not necessarily abnormal. The only cell
whose presence in the CSF seems consistently abnormal is the macrophage. The CSF can
be normal in CNS inflammation.
Clinical suspicion of an infection is an adequate indication for bacterial and fungal
cultures and bacterial sensitivity tests. The presence of antibodies in the CSF to
specific viruses or to other infectious agents provides evidence of infection because
they are not present in normal, vaccinated animals or those with systemic infection
but without CNS disease (also see Chapter 4).
92
In CSF samples contaminated by blood (hemorrhage), serum albumin and antibody concentrations
should be compared with concentrations in the CSF. When the level of CSF antibodies
exceeds that of serum, CNS infection is more likely. Inflammation may increase the
permeability of the blood-brain barrier, allowing serum antibodies to leak into the
CSF.
Principles of Medical Treatment
Medical treatment is most commonly indicated for infections involving the nervous
system. Physical therapy also is necessary for rehabilitation (see Chapter 14). Seizures
(see Chapter 13) and other diseases requiring specific treatment are covered in the
descriptions of the diseases. The management of CNS edema resulting in increased intracranial
pressure is discussed in Chapter 12 in the section on brain trauma. Management of
pain is reviewed in Chapter 14.
Effective therapy for CNS infections depends on the identification of the cause and
selection of the appropriate antimicrobial agent. Identification is based on CSF analysis
in which the organism may be observed (albeit rarely), culture and when available,
polymerase chain reaction (PCR) testing, and measurement of antibody or antigen titers.
Selection of the appropriate antimicrobial agent depends on two principles: (1) the
agent must be effective against the microbial target without severely injuring the
patient; and (2) it must be delivered to, and must penetrate, the CNS. Unfortunately,
anatomic and physiologic barriers to successful therapy for CNS infections exist,
especially when certain drugs are used. The combined effects of these obstacles create
a functional blood-brain barrier.
The combined functions of the CNS capillaries and the choroid plexus create a barrier
to the movement of drugs from the capillary or pericapillary fluid into nervous tissue
or CSF. Discrepancies between serum and CNS drug concentrations occur because of two
factors: those promoting drug accumulation in the CNS (the secretory selectivity of
the choroid plexus) balanced against those preventing drug accumulation (the special
anatomy of CNS capillaries and drug efflux pumps such as P-glycoprotein). In capillaries
outside the CNS, drugs and other agents pass from the blood through clefts between
endothelial cells and through fenestrations in the capillary basement membrane. In
the CNS, capillary endothelial cells are joined by tight junctions that seal the intercellular
clefts. The capillary basement membrane has no fenestrations and glial cell foot processes
surround the capillaries helping create a barrier to diffusion.
In the CNS, a drug must penetrate an inner bimolecular lipid membrane, the endothelial
cell cytoplasm, an outer lipid membrane, and a basement membrane and then traverse
the glial foot processes.
122
Penetration of a drug is largely a function of its endothelial membrane solubility.
Membrane solubility is favored by (1) a low degree of ionization at physiologic pH,
(2) a low degree of plasma protein binding, and (3) a high degree of lipid solubility
of the unionized drug.123., 124. Certain highly lipid-soluble drugs bind strongly
to tissue sites in the brain, permitting high concentrations to be achieved within
nervous tissue.
Regulation of CSF solutes occurs at the choroid plexus. Plasma dialysate that filters
through fenestrated capillaries is selectively secreted by choroid epithelial cells.
Certain CSF constituents also are actively reabsorbed by the choroidal epithelial
cell, which tends to clear these substances from the CSF and from nervous tissue.
This active transport system for weak organic acids removes drugs such as penicillin
and gentamicin. Inflammation may block this system, allowing drug concentrations in
the nervous tissue to increase. In addition, inflammation may increase the permeability
of endothelial membranes to certain antibiotics, allowing these drugs to penetrate
nervous tissue in cases of disease. In the normal animal, these antibiotics penetrate
poorly. As the inflammation decreases, penetration of the antibiotic also decreases.
Antimicrobial Agents in Treating Infections
Antimicrobiocidal agents are grouped by their capacity to achieve concentrations in
CSF sufficient to inhibit microorganisms throughout the period of therapy.
124
Table 15-18
lists these drugs relative to achievable concentrations in CSF.
TABLE 15-18
Antimicrobial Drugs: Ability to Penetrate the Blood-Brain Barrier∗
Good
Intermediate
Poor
Microbicidal
Trimethoprim
Penicillin G†
Penicillin G Benzathine
Moxalactam
Ampicillin†
Cefotaxime
Methicillin†
Cephalosporins§
Ceftazidime
Nafcillin†
Aminoglycosides
Metronidazole
Carbenicillin†
Enrofloxacin
Oxacillin
Vancomycin
Microbistatic
Chloramphenicol
Tetracycline
Amphotericin B
Sulfonamides
Flucytosine
Erythromycin║
Isoniazid
Clindamycin
Minocycline‡
Doxycycline‡
Rifampin
∗
Drugs prohibited for use in all food-producing animals: Chloramphenicol, clenbuterol,
diethylstibestrol (DES), dimetridazole, ipronidazole and other nitroimidazoles, furazolidone,
nitrofurazone, and other nitrofuans, sulfonamide drugs in lactating dairy cattle (except
approved use of sulfadimethoxine, sulfabromomethazine, sulfaethoxypyridazine), fluoroquinolones,
glycopeptides (http://www.fda.gov).
†
High intravenous doses are needed to achieve the maximal effect.
‡
Lipid-soluble tetracyclines that achieve higher concentrations in CSF than do other
tetracyclines.
§
First and second generation, may be effective early in bacterial meningitis; concentrations
dramatically decrease with repair of the blood-brain barrier.
║
Penetration in the face of inflammation is unpredictable.
Microbicidal drugs are preferred to microbiostatic drugs whenever possible. Antibiotics
such as the aminoglycosides diffuse poorly, even in the presence of inflammation.
Intrathecal administration may be required for adequate CSF concentrations to be achieved,
but this route is rarely used in animals because of the necessity for anesthesia with
each injection. Placement of intraventricular catheters can facilitate the injection
of drugs into the CSF.
Infectious Inflammatory Disease
Bacterial Infections (See Table 15-10)
Bacterial Meningoencephalomyelitis
The pathogenesis, pathophysiology, and implications of treatment of bacterial meningitis
in humans and experimental animals have been reviewed.
100
Bacteria must be able to survive in the intravascular space, penetrate the blood-brain
barrier, and colonize in the meninges or CSF. Breakdown of the blood-brain barrier
causes exudation of albumin into the CSF and facilitates the development of brain
or spinal cord edema. Experiments in rats suggest that bacteria in the CSF elicit
the release of endogenous inflammatory mediators that are important in the development
and progression of clinical signs.
125
Experimental studies in rabbits reveal that the inflammatory process causes brain
edema, probably secondary to loss of cerebrovascular autoregulation, direct cytotoxicity,
and increased CSF outflow resistance.
101
These findings may have important therapeutic implications. Rapidly acting bactericidal
therapy delivered into the CSF is mandatory because only bactericidal therapy is associated
with a cure in humans and experimental animal models. Rapid destruction of bacteria
could release high concentrations of inflammatory bacterial toxins (lipopolysaccharides),
which might exacerbate the inflammatory process.126., 127., 128.
These studies also suggest that adjunctive therapy with antiinflammatory agents may
be beneficial in bacterial meningitis.
101
In animals with experimental Streptococcus pneumoniae meningitis, methylprednisolone
reduced CSF outflow resistance and both methylprednisolone and dexamethasone reduced
brain edema.
101
Pretreatment with dexamethasone followed in 15 to 20 minutes with third-generation
cephalosporins resulted in decreased inflammatory mediator release in laboratory animals
with Haemophilus influenzae CNS infections.
127
Several controlled studies in children with bacterial meningitis demonstrated the
benefits of adjunctive corticosteroid therapy, especially when corticosteroids were
administered 15 to 20 minutes before bactericidal antibiotic therapy.
128
In these studies, dexamethasone was given 15 to 20 minutes before cefotaxime therapy
and was continued every 6 hours for 4 days.
Other antiinflammatory agents that might be useful include indomethacin, pentoxifylline,
and superoxide dismutase. Specific monoclonal antibodies have shown promise in experimental
models of bacterial meningitis, especially when dexamethasone is also administered.
129
Although these studies may have therapeutic implications for bacterial meningitis
in domestic animals, controlled studies regarding these species have not been published.
Furthermore, these studies involve specific neurotrophic bacteria in humans that may
behave differently than the agents producing meningitis in animals. Ultimately, the
use of corticosteroids in animals with confirmed or suspected CNS infection should
be done judiciously and with caution. Despite the obvious counterintuitive rationale
for their use, corticosteroids may be beneficial to reduce edema and alleviate clinical
signs. When used, the dosage of corticosteroids should be tailored to the least amount
necessary to control clinical signs. When possible, rapid tapering of the dosage should
be prescribed based on continued response to therapy in an effort to restrict the
administration of corticosteroids to short-term usage.
Bacterial Meningoencephalomyelitis in Dogs and Cats
Bacterial meningoencephalomyelitis is not common in dogs and cats. It usually occurs
in association with bacteremia secondary to endocarditis, urinary tract infections,
and pulmonary infections. Critically ill patients may have added risk of CNS infection.
Meningitis may also occur from extension of infection in structures adjacent to the
nervous system, such as the nasal passages, sinuses, and internal ears as well as
direct penetration into the CNS such as occurs with bite wounds. Aerobic bacteria
associated with bacterial meningitis in dogs and cats include Pasteurella multocida,
Staphylococcus Pseudintermedius, Streptococcus spp., and Escherichia coli.
124., 130., 131. Uncommonly, Proteus, Pseudomonas, Salmonella, and Klebsiella organisms
may be the causative agents. These gram-negative organisms are more common in nosocomial
infections of critically ill patients. Bartonella sp. may also cause CNS disease in
dogs.
132
Anaerobic bacteria isolated from dogs and cats with CNS infection include Bacteroides,
Fusobacterium, Peptostreptococcus, and Eubacterium.
133
Definitive treatment of bacterial meningitis is based on isolation of the organism
from the CSF and determination of its antibiotic sensitivity. Other diagnostic tests
include serology and PCR testing. The identification and elimination of the source
of infection are imperative to successful treatment. Blood and urine cultures may
be useful to identify the causative agent. Pending the outcome of CSF cultures, the
initial antibiotic therapy in small animals is based on clinical findings of concomitant
infection and the most likely causative agent present. Broad-spectrum bacteriocidal
antibiotics that penetrate the CSF are chosen.
Trimethoprim-sulfonamide combinations and enrofloxacin are good initial choices. Both
are available to veterinarians, penetrate the CSF in good concentrations, cover a
broad spectrum of bacterial agents, and are not expensive compared with third-generation
cephalosporins. Enrofloxacin has greater activity against gram-negative bacteria and
very little activity against anaerobes.
134
Clindamycin hydrochloride may be used concurrently to provide anaerobic and gram-positive
coverage. For animals unable to receive oral medications, parenteral formulations
of enrofloxacin and clindamycin hydrochloride are available. The dose for enrofloxacin
in dogs is 2.5-5.0 mg/kg PO, IM, SC, IV every 12 hours. Enrofloxacin should be used
with care in dogs 2 to 12 months of age to avoid cartilage damage. The dose of enrofloxacin
in cats is 5 mg/kg once a day PO or 2.5 mg/kg IM every 12 hours. Rare incidence of
retinal toxicity in cats have been reported at doses >15 mg.kg/day. The dose for clindamycin
in dogs and cats is 3-11 mg/kg PO, IV, IM SC every 8 hours. Gastroenteritis is the
most common side effect of clindamycin therapy in dogs and cats. The initial dose
for trimethoprim-sulfonamides is 30 mg/kg every 12 hours for 5 to 7 days and then
15 mg/kg every 12 hours for 10 to 14 days.
Third-generation cephalosporins such as cefotaxime and ceftazidime penetrate the CSF
in good concentrations and are effective against many resistant gram-negative bacteria.
135
They are usually effective against anaerobes but have reduced activity against gram-positive
cocci. Ceftiofur, approved for use in animals, does not cross the blood-brain barrier
unless inflammation is present, and, in this regard, is similar to the aminopenicillins.
When gram-negative sepsis is suspected as the cause of the meningitis, the third-generation
cephalosporins are the drugs of choice.
Meningitis caused by gram-positive bacteria may respond to high doses of aminopenicillins.
131
Many isolates of S. Pseudintermedius and S. aureus secrete beta lactamase, which inactivates
most aminopenicillins. Aminopenicillins combined with clavulanic acid and lactamase-resistant
penicillins such as methicillin or oxacillin are better choices for staphylococcal
infections. Rifampin is bactericidal, readily penetrates the CSF, and has very good
activity against staphylococci.
136
It is also effective against many gram-negative bacteria. Bacterial resistance to
rifampin develops readily, especially when it is given as a single agent. For staphylococcal
infections, rifampin is best combined with β-lactam antibiotics. The human dose of
10 mg/kg daily produces a concentration in canine serum four times that required in
people to inhibit bacteria but also causes adverse side effects in dogs. A dose less
than 10 mg/kg daily is recommended, but definitive pharmacologic studies have not
been published.
136
Rifampin also may be useful in treating chronic abscesses and pyogranulomatous infections.
Imipenem is a β-lactam compound that belongs to the carbapenem family of antibiotics.
It has broad-spectrum activity against most gram-positive and gram-negative aerobes
and anaerobes. Imipenem is useful in the treatment of nosocomial gram-negative infections
that do not respond to other antibiotic regimens.135., 137. After intravenous administration,
imipenem penetrates the CSF in good concentrations.
Occasionally, systemic infection with Brucella canis extends to the nervous system.
While most animals are euthanized due to zoonotic issues, brucellosis can be treated
with combination of streptomycin and minocycline. Streptomycin should be administered
for 2 weeks by parenteral injection. Minocycline should be given orally for 4 weeks
in combination with the 2-week course for streptomycin.138., 139. It is difficult
to eradicate brucella infections in animals.
Bacterial Meningoencephalomyelitis in Horses
Bacterial meningitis occurs most commonly in septicemic foals that do not acquire
passive transfer of immunity.140., 141., 142. Common primary sites of infection include
the GI tract, lung, and umbilicus. Pneumonia, peritonitis, hypopyon, septic arthritis,
and omphalophlebitis are common. Extension to the brain and spinal cord frequently
occurs if treatment is not aggressive.
The diagnosis of meningitis in foals is confirmed by cytologic evaluation and bacterial
culture of the CSF. A neutrophilic pleocytosis is typical, and cell counts may exceed
1000 cells/uL (normal <5 cells/uL).142., 143. The total CSF protein level is usually
more than 100 mg/dL. E. coli and Klebsiella spp. are the most frequently isolated
organisms.142., 143.
Although definitive antibiotic therapy is based on bacterial culture and antimicrobial
sensitivity testing, initial empiric therapy is based on the assumption that gram-negative
enteric bacteria are the most likely cause. Third-generation cephalosporins are the
antimicrobials recommended in foals. These include cefotaxime sodium (40 mg/kg IV
q8h) and ceftazidime (50 mg/kg IV q12h). Ceftiofur (2 to 4 mg/kg IV q12h) is available
to veterinarians but does not penetrate the CSF in normal horses. Although very expensive,
these antibiotics can rapidly sterilize the CSF and may shorten the total treatment
time and thus reduce overall costs of therapy.
140
Trimethoprim-sulfonamide combinations may be effective but are less so than the third-generation
cephalosporins previously described.
Adjunctive antiinflammatory therapy and other supportive care are used in foals with
progressive neurologic dysfunction. Corticosteroids (dexamethasone, 0.15 mg/kg q6h
IV) are used with caution in septic foals because corticosteroid therapy can cause
rapid bacterial dissemination.
140
Dimethyl sulfoxide (1 g/kg IV q24h) may help to reduce CNS inflammation and edema
and protect against reperfusion injury when cerebral ischemia is present. Mannitol
(0.25 to 1.0 g/kg IV q24h) helps reduce CNS edema. Plasma transfusions (1 to 2 L IV)
and enteral hyperalimentation may be indicated. Diazepam (0.2 to 0.5 mg/kg every 15
minutes) or phenobarbital (10 to 20 mg/kg IV q8h) or both can be given to control
seizures.
115
Bacterial Meningoencephalomyelitis in Cattle
Bacterial meningitis is the most common CNS disease in neonatal calves.
119
It develops secondary to septicemia and bacteremia associated with failure of passive
transfer of colostral antibodies. A presumptive diagnosis of bacterial meningitis
with failure of passive transfer is based on presence of omphalophlebitis or septic
arthritis, fever and signs suggestive for meningoencephalomyelitis (obtundation, tetraparesis,
hyperesthesia, and multiple cranial nerve deficits) (Figure 15-8
).
Figure 15-8
Suppurative meningitis in a calf. Note the cloudy and thickened meninges that tend
to obscure engorged (inflamed) blood vessels (arrow).
(Courtesy Dr. Roger Panciera, Oklahoma State University College of Veterinary Medicine.)
Neutrophilic pleocytosis and increased protein are present in the CSF of 60% to 70%
of affected calves. Mononuclear pleocytosis may be present in chronic disease. The
identification of bacteria in the CSF is less than 50% of cases examined. E. coli
is the organism most frequently responsible in clinical cases.
119
Isolates may be resistant to trimethoprim-sulfonamides, and many, if not most, are
now resistant to triple sulfonamide drugs. Other bacterial agents include Salmonella
sp. and Arcanobacterium pyogenes. Most affected calves die or are euthanized, usually
within 2 to 3 days after diagnosis and initiation of therapy.
Treatment of bacterial meningitis in calves is difficult and the mortality rate is
high.
144
Selection of antimicrobial drugs is based on culture and sensitivity of bacteria from
the CSF; however, their use is often empirical. The antimicrobial regimen should be
broad spectrum against gram-negative and gram-positive bacteria. Although trimethoprim-sulfonamides
and triple sulfonamide drugs are frequently chosen to treat bacterial meningitis in
calves, studies indicate an emerging resistance of gram-negative bacteria to these
drugs. Ampicillin (10 to 20 mg/kg IV q8h) has been used in combination with other
antimicrobials. Although expensive, the third-generation cephalosporins (such as ceftiofur,
5 to 10 mg/kg IV or IM q12h) are rational empiric drugs for treatment. Because of
their cost, the use of these drugs may not be economically feasible in many cases.
Adequate amounts of colostrum and early recognition and treatment of bacterial infections
is essential for prevention of bacterial meningitis in calves.
Thromboembolic Meningoencephalitis (TEME)
Histophilus somni (formerly Haemophilus somnus) is the major cause of TEME in cattle.
145
Exposure to this organism is widespread, and up to 25% of cattle may harbor serum
antibodies to the organism. H. somni persists in the urinary and reproductive tracts
of cattle and is shed in urine and reproductive secretions. The disease is most common
in weaned calves, and outbreaks of TEME occur 1 to 2 weeks after cattle arrive at
the feedyard.
146
Bronchopneumonia is the most common form of hemophilosis, but arthritis, myelitis,
retinitis, myocarditis, laryngitis, otitis media or otitis interna, and conjunctivitis
also occur. TEME usually follows the occurrence of pneumonia by 1 to 2 weeks. Morbidity
is low, and mortality is high. Diagnosis is based on history and physical examination.
Changes in CSF reflect a bacterial infection that often is hemorrhagic. Necropsy findings
provide a definitive diagnosis with presence of hemorrhagic infarcts in the brain
and spinal cord. Histology reveals vasculitis, thrombosis, and neutrophilic infiltrates
(Figure 15-9
).
Figure 15-9
A, Extensive hemorrhages in the cerebral cortex are typical gross lesions of thromboembolic
meningoencephalomyelitis. B, Note the multiple hemorrhagic lesions seen in cross section
of the brain in A.
(A and B, Courtesy Dr. Roger Panciera, Oklahoma State University College of Veterinary
Medicine.)
As with the neurotrophic bacteria that infect people, H. somni possesses several virulent
factors (mucopolysaccharide capsule, outer membrane proteins, and endotoxin concentrated
in the cell wall) that enhance its penetration into, and subsequent injury to, the
CNS. H. somni colonizes the small vessels of the meninges, brain, and spinal cord.
Fibrin thrombi and brain infarction cause the neurologic signs. The most effective
antibiotics for TEME include the aminopenicillins, ceftiofur, oxytetracycline, and
florfenicol. All are approved for use in food animals and penetrate the CSF when active
inflammation is present. Parenteral oxytetracycline is used for non-CNS infections.
Treatment of animals that progress to recumbency is often not effective. When a case
is suspected, the other animals in contact should be closely monitored to detect and
treat at the early disease stage.
Listeriosis (Circling Disease)
Listeria monocytogenes is a resistant and ubiquitous bacterium that causes CNS disease
in people and domestic animals (listeriosis, circling disease, silage disease).
147
Ruminants appear more susceptible to infection than do other domestic animals. The
organism can be transmitted in silage and other feed. Food-borne infection is common
in humans. Outbreaks usually occur in the winter. In cattle and sheep, the organism
penetrates the oral mucosa via wounds and is transmitted to the brain in a retrograde
fashion via the trigeminal nerve. Signs related to infection of the rostral medulla
(trigeminal, facial, and vestibulocochlear nerve dysfunction) are common. Although
meningitis and encephalitis are the classic manifestations of listeriosis in ruminants,
spinal cord disease, abortion, and mastitis also occur. Clinical signs of encephalitis
are often more severe in small ruminants. The most useful antemortem diagnostic test
is CSF analysis. Characteristic findings include increased protein concentration and
nucleated cell count with mononuclear cells predominating. Definitive diagnosis is
made by histopathology. Gross necropsy findings are not very remarkable. Histopathology
reveals multifocal areas of necrosis with infiltrations of macrophages and neutrophils.
Diagnosis is confirmed by isolation of the organism from body fluids or tissues. Warm
or cold enrichment methods are used to isolate the organism but immunohistochemistry
is more successful than bacteriologic culture for detecting L. monocytogenes in brain
tissue. Treatment is initiated early and involves long-term parenteral antibiotic
therapy (penicillin, ampicillin, amoxicillin, or oxytetracycline). Prevention is aimed
a limiting fecal contamination of the feed from ruminants and wildlife.
Bacterial Brain Abscess
Brain abscesses are more common in large animals than in dogs and cats. Neurologic
signs relate to the specific location of the abscess and compression or necrosis of
surrounding neurologic structures. Large abscesses may create signs similar to any
other intracranial mass. Increased intracranial pressure, cerebral edema, and brain
herniation may occur (Figure 15-10
).
Figure 15-10
Large brain abscess in a sheep.
(Courtesy Cornell University College of Veterinary Medicine.)
The pituitary abscess syndrome has been described in cattle, goats, sheep, and swine
(Figure 15-11
).
148
Figure 15-11
A large and destructive pituitary abscess in a cow (black arrow). Inset figure shows
abscess extending into the hypothalamus.
(Courtesy Cornell University College of Veterinary Medicine.)
The anatomy of the rete mirabilis and its close association to the pituitary gland
may explain the predilection for pituitary abscesses in cattle. The primary clinical
signs include depression, ataxia, blindness, absence of the pupillary light reflex,
dysphagia, dropped jaw, head pressing, bradycardia, nystagmus, and strabismus. The
CSF may contain increased total protein concentrations and pleocytosis. Bacterial
cultures of CSF are usually negative. Arcanobacterium pyogenes and Pasteurella multocida
are most commonly isolated from abscesses at necropsy.
148
Infection at other sites with the same organisms occurs in about 50% of cases. The
mortality rate is nearly 100%, and successful therapy is rare.
In horses, brain abscesses are usually caused by Streptococcus equi, but other streptococci
are occasionally isolated.
149
The prognosis is generally poor. If diagnosed by CT, successful surgical drainage
is possible.
150
Brain abscesses are rare in dogs and cats but may result from extension of purulent
otitis media/interna, rhinitis, sinusitis, open skull fractures, and foreign-body
penetration of the brain. The causative agents are usually Staphylococcus spp., Streptococcus
spp., and Pasteurella spp. Anaerobes may also be isolated in some cases. Localization
of the abscess with CT or MRI may allow surgical drainage or excision. Methicillin,
oxacillin, and rifampin may be useful for gram-positive infections. Clindamycin and
metronidazole may be given in anaerobic infections. A guarded prognosis should be
made.
Cats may have meningitis secondary to abscesses that are caused by anaerobic bacteria.
Penicillin or amoxicillin is effective and reasonable in cost. Clindamycin or metronidazole
is a good alternative for resistant infections.
151
If accessible, surgical drainage of intracranial infections should be considered.
Discospondylitis (also see Chapter 6)
The most common cause of bacterial discospondylitis in dogs is Staphylococcus pseudintermedius;
occasionally Brucella canis organisms are the source.
152
The disease may be associated with urinary tract infection and bacteremia. In staphylococcal
discospondylitis, penicillinase-resistant antibiotics should be chosen. Cephalosporin,
methicillin, or oxacillin is usually effective. Antibiotic therapy should be continued
for 4 to 6 weeks. If medical treatment is not successful, surgery is recommended to
obtain a biopsy and culture. Animals with severe paresis may require decompression.
In B. canis discospondylitis, therapy is expensive and may not eradicate the infection
effectively. Streptomycin-minocycline combinations are used as described for meningitis.
114
Affected dogs should be neutered and isolated from other dogs.
Mycotic Infections (see Table 15-11)
The more common mycotic infections of the CNS are caused by Cryptococcus neoformans,
Blastomyces dermatitidis, and Coccidioides immitis. They produce polysystemic disease,
including granulomatous meningoencephalomyelitis or neuritis (Figure 15-12
).
Figure 15-12
Multifocal cryptococcosis in a dog. Note the thickened meninges (black arrows) and
extension of the infection into the brain surface (red arrow).
A definitive diagnosis is made by isolation or identification of the organism in the
CSF or other body secretions. Treatment regimens are similar for the various deep
mycotic agents, as discussed below.
Therapy
Cryptococcal Meningitis
For many years the mainstay of therapy for the deep mycotic pathogens has been amphotericin
B. This drug is poorly absorbed from the GI tract and must be given IV for a full
therapeutic effect. Amphotericin B diffuses poorly into the CSF. For this reason,
although amphotericin B has value in fulminating systemic infections, agents such
as itraconazole and fluconazole are preferred for cryptococcal meningitis. Several
therapeutic regimens of amphotericin B have been described.
Flucytosine, when combined with amphotericin B, acts synergistically in vitro against
C. neoformans. It achieves satisfactory concentrations in the CSF. The oral dose of
flucytosine is 50 to 75 mg/kg every 8 hours.153., 154. The rate of relapse is considerably
lower with the combined therapy. Side effects include leukopenia, thrombocytopenia,
vomiting, and diarrhea.
Successful management of cryptococcal meningitis has been reported with the azole
and triazole antifungal compounds.130., 131. At usual concentrations achieved in the
plasma these compounds are considered fungistatic, but at higher concentrations they
may be fungicidal.
155
The azoles and triazoles inhibit synthesis of ergosterol in the fungal cell membrane.
Ketoconazole, itraconazole, and fluconazole have been studied in dogs and cats. All
are well absorbed from the GI tract. Absorption of itraconazole is enhanced by food
in the intestinal tract.
Ketoconazole does not penetrate the CSF in adequate concentrations to be effective,
and yet reports exist of success with this agent in the treatment of cryptococcal
meningitis, especially when combined with flucytosine.
157
Ketoconazole therapy is associated with hepatic dysfunction, elevated liver enzymes,
and suppression of endogenous steroid synthesis. It has a slow onset of action, and
in life-threatening conditions ketoconazole is often combined with amphotericin B
to provide immediate fungicidal activity in all tissues except the eye and the CNS.
The dose of ketoconazole for dogs and cats is 10 to 15 mg/kg daily.
Itraconazole has a broad spectrum of activity against many fungal organisms and has
been effective in the treatment of cryptococcal meningitis in cats.
158
In systemic blastomycosis, itraconazole produces a cure rate equal to or greater than
that of combined therapy with ketoconazole and amphotericin B. Itraconazole is less
toxic than ketoconazole but is more expensive. Fluconazole is a bistriazole compound
with broad-spectrum antifungal activity. It is well absorbed from the GI tract and
has a bioavailability greater than 90%.
156
It penetrates into the meninges and CSF with or without inflammation. Fluconazole
is the drug of choice in the treatment of cryptococcal meningitis in humans and is
used in dogs and cats with mycotic infections of the CNS. Serious side effects are
uncommon. The recommended dose in dogs and cats for both itraconazole and fluconazole
is 10 mg/kg daily divided twice daily for 2 to 3 months beyond the resolution of all
signs.
159
The successful resolution of cryptococcal meningitis and optic neuritis with fluconazole
has been reported in the horse. The dose was 5 mg/kg per day and the horse was treated
for 197 days.
160
Coccidioidal Meningitis
Coccidioides immitis is not susceptible to the synergistic activity of combined amphotericin
B and flucytosine therapy but may respond to ketoconazole administered at 10 mg/kg
every 24 hours for 9 to 12 months.
136
Although in some cases treatment resolved the clinical signs, recurrences were common
when treatment was discontinued. Similar results were found in a few cases treated
with itraconazole and fluconazole.
161
Other Systemic Fungal Infections
Histoplasma capsulatum, Blastomyces dermatitidis, Aspergillus spp., Candida spp.,
and Sporothrix schenckii occasionally are involved in meningitis. Treatment is the
same as for cryptococcosis and coccidioidomycosis.162., 163., 164., 165.
Actinomycetes Infections (see Table 15-1)
Tuberculous Meningitis
Although it is nearly nonexistent in dogs and cats, tuberculous meningitis occurs
occasionally in primates. Most of the antituberculous drugs readily penetrate the
CNS. A combination of isoniazid and ethambutol is suggested. Other effective drugs
include rifampin, ethionamide, pyrazinamide, and cycloserine.
Nocardiosis
The drugs of choice have been triple sulfonamides or trimethoprim-sulfa combinations.
Their in vitro effect, however, has not been duplicated in vivo. The drugs should
be given in high doses, and precautions should be taken to prevent nephrotoxicity.
Alternative drugs include minocycline, amikacin, and erythromycin combined with ampicillin.
166
Actinomycosis
The drug of choice is ampicillin given IV at 10 to 20 mg/kg every 6 hours.
166
Therapy is continued with clindamycin, chloramphenicol, or minocycline.
Protozoan Infections (see Table 15-12)
Toxoplasmosis
Toxoplasma gondii is an intracellular coccidian parasite that produces systemic infection
in dogs and cats and occasionally in other domestic animals. Cats are the definitive
host and pass oocysts in the feces. In cats infection may occur through ingestion
of any of the three life stages of the organism or transplacentally.
167
The organism may infect the muscle, CNS, liver, lung, and eye. A variety of clinical
signs may occur, including uveitis, retinitis, myositis, pneumonia, and encephalitis.
The diagnosis of clinically active toxoplasma infection is based on suggestive clinical
signs, demonstration of T. gondii tachyzoites or bradyzoites in tissue biopsy sections,
or immune testing for antibodies or antigen in serum, ocular fluid, or CSF. Although
several immunologic tests are commercially available, the T. gondii-specific immunoglobulin
M (IgM) and IgG enzyme-linked immunosorbent assay (ELISA) are most often used in dogs
and cats. IgM levels tend to increase within 2 to 4 weeks of infection but are negative
by 16 weeks.
168
IgM titers more than 1:256 indicate recent or active infection. A fourfold increase
in IgG titers also indicates recent or active disease. Both IgG and IgM titers can
be assessed in samples of CSF and compared with serum concentrations of albumin, IgG,
and IgM. When the levels in CSF exceed those in serum, active or recent CNS infection
should be suspected.
Clindamycin hydrochloride is the primary antimicrobial selected to treat clinical
toxoplasmosis in dogs and cats. The dose in cats is 12.5 to 25 mg/kg orally or IM
every 12 hours. The dose in dogs is 10 to 20 mg/kg orally or IM every 12 hours. Although
clindamycin does not adequately penetrate the CSF of humans, the drug may penetrate
the CSF of cats in sufficient levels to be effective for neurologic disease.
169
Transient vomiting is a common side effect in some cats. Cats should be treated for
at least 4 to 5 weeks.
Neosporosis
Neosporosis is caused by the protozoan Neospora caninum. Natural infections have been
reported in dogs and calves. The muscles and the CNS are the most common sites of
infection. Affected animals typically develop nonsuppurative encephalomyelitis, polyradiculoneuritis,
and myositis. A positive diagnosis is based on demonstration of the organism in blood,
CSF, or tissues. A fluorescent antibody test can detect N. caninum–specific antibodies.
Clinical experience with treatment is limited, but treatment with clindamycin should
be tried early in the course of illness. Sulfadiazine may also be effective (see also
Chapter 7).
167
Equine Protozoal Myeloencephalitis (EPM)
EPM is described in Chapter 6 because clinical signs commonly manifest as spinal cord
dysfunction. It is the most common neurologic disease in horses with multifocal or
asymmetric neurologic deficits. Infection of the CNS may occur anywhere, but the spinal
cord is most commonly affected.170., 171., 172., 173. EPM is most commonly caused
Sarcocystis neurona. A small number of EPM cases have been attributed to infection
by Neospora hughesi. The opossum is the definitive host for S. neurona and harbors
the sexual stages of the protozoa within its gastrointestinal tract. Natural intermediate
hosts for S. neurona that have been identified include the skunk, raccoon, cat, Pacific
harbor seal, and nine-banded armadillo. The horse is an aberrant dead-end host. Horses
are most likely infected by fecal-oral transmission. The diagnosis and treatment of
EPM are discussed in Chapter 6.
Viral Infections
The viral diseases causing encephalomyelitis are summarized in Table 15-13. Viral
infection of the CNS may fit into one of three categories: (1) viral invasions resulting
in inflammation (viral meningitis, encephalitis, encephalomyelitis, or poliomyelitis);
(2) postinfectious, noninflammatory encephalopathic states; and (3) postinfectious
and postvaccinal inflammatory states (“old dog” encephalitis, perhaps polyradiculoneuritis,
brachial plexus neuropathy).
Rabies
Rabies is caused by a rhabdovirus that results in a fatal encephalomyelitis in mammals.
Common sources of infection include bites from skunks, bats, raccoons, foxes, and
coyotes. The virus is transmitted via infected saliva (animal bites, contamination
of wounds) and is transmitted by retrograde axonal transport to the brain and spinal
cord. Lesions in the nervous system are most severe in the midbrain, cervical spinal
cord, and cranial nerve ganglia and include perivascular cuffs of plasma cells and
lymphocytes. The Negri body, found in neurons, is the classical inclusion body of
rabies virus (Figure 15-13
).
Figure 15-13
Brain from a horse with rabies. Note the prominent Negri bodies (arrows) in a neuron.
(Courtesy Cornell University College of Veterinary Medicine.)
Three forms of rabies have been described in domestic animals: furious, dumb, and
paralytic. Initially, infected animals often develop behavioral changes with rapid
progression to one of the three forms. The furious form is characterized by restlessness,
wandering, aggression, and seizures. The dumb form is characterized by progressive
paralysis, pharyngeal and hypoglossal paralysis, depression, and head pressing. The
paralytic form occurs more commonly in large animals than in dogs and cats. It is
a progressive ascending paralysis that may begin as a shifting leg lameness. In cattle,
the most common clinical signs are salivation, bellowing, aggressiveness, paresis/paralysis,
and straining. Colic, aggressiveness, hyperesthesia, and ataxia are common clinical
signs in horses. Sheep will commonly manifest hyperesthesia, tremors, and salivation.
Goats and pigs also manifest mainly aggressiveness, hyperexcitability, and squealing.
It is important to keep in mind that rabies can clinically present with any neurologic
sign.
Definitive diagnosis is a positive fluorescent antibody test performed on brain tissue.
There is no effective treatment. Infected animals and those suspected to be infected
should be euthanized and brain submitted for fluorescent antibody (FA) examination.
Given the human health hazard, FA examination of the brain should be pursued in every
suspected case in which there has been significant risk of exposure to humans. If
uncertainty exists, a state health official should be contacted for advice. Vaccines
are available and very effective in domestic animals. Despite their efficacy, rabies
infection can occur in vaccinated animals.
172
Pseudorabies
Pseudorabies (Aujeszky disease, mad itch) is caused by a neurotrophic α-herpesvirus.
The virus can be latent or subclinical in adult swine and pigs are thought to be the
source of infection in other animal species. After a pig bite, the virus enters the
skin and travels to the brain or spinal cord by retrograde axonal transport. The incubation
period is 90 to 156 days. Piglets show seizures, tremors, ataxia, and death. In other
species, severe pruritus, dermal abrasions, swelling, and alopecia develop at the
site of virus inoculation (Figure 15-14
).
Figure 15-14
Dog with pseudorabies. Note the extensive self-mutilation of the head secondary to
severe pruritus.
(Courtesy Dr. Joan Coates, Texas A&M University College of Veterinary Medicine.)
Other signs include ataxia, paresis, circling, aggression, depression, and seizures.
Diagnosis is based on viral isolation and histopathology. There is no effective treatment.
Pseudorabies has been eradicated from domestic swine in the United States.
Canine Distemper Virus
Canine distemper is a common polysystemic disease of dogs that may infect the CNS.
The virus is also pathogenic in ferrets, raccoons, big cats, and other animal species.
There are three neurologic syndromes. Acute distemper occurs in susceptible young
dogs and respiratory and digestive signs predominate. Neurologic signs may occur later
in the clinical course but many dogs die before these signs develop. Seizures are
the most common neurologic manifestation. Lesions most commonly represent a polioencephalomyelitis.
Chronic distemper encephalomyelitis occurs in young dogs that survive the acute stages
of the disease and in mature dogs without signs of system disease. Chronic distemper
is a multifocal severe demyelinating meningoencephalomyelitis. Lesions are most common
in the cerebellum, cerebellar peduncles, cervical spinal cord, optic tracts, and periventricular
white matter (Figure 15-15
).
Figure 15-15
Canine distemper encephalomyelitis. Cerebellar folial white matter with perivascular
lymphocytes and plasma cells, numerous macrophages and vacuolated neuroparenchyma.
(Courtesy Cornell University College of Veterinary Medicine.)
Clinical signs include progressive and severe ataxia, paresis, depression, and generalized
or “chewing gum” seizures (focal seizures involving biting movements of the mandible).
Constant repetitive myoclonus, twitching of temporal or appendicular muscles, occurs
in some dogs and is supportive of the diagnosis. Distemper virus may cause chorioretinitis
and optic neuritis and visual deficits may develop.
Old dog encephalitis is a rare form of canine distemper that appears to be a manifestation
of chronic viral infection after years of latent brain infection. The clinical signs
result from necrosis of cerebral gray matter and are typical of other forebrain disorders.
The diagnosis of canine distemper is based on positive FA tests on neural tissue,
cerebrospinal fluid cells (infected lymphocytes), or other lymphoid tissues. Other
supporting findings include ophthalmologic evidence of chorioretinitis, increased
lymphocytes and protein in CSF, and distemper myoclonus.
There is no definitive treatment. Seizures can be managed with anticonvulsants drugs
such as phenobarbital but control is difficult. Vaccines are highly protective against
both system and neurologic signs.
Feline Infectious Peritonitis Virus (FIP)
The noneffusive (dry) form of FIP virus includes neurologic signs in some cats. The
FIP virus induces a vasculitis involving the meninges, ependymal lining, and choroid
plexus (Figure 15-16
).
Figure 15-16
Neurologic feline infectious peritonitis with extensive periventricular inflammation
and protein effusion into the ventricular lumen.
(Courtesy Cornell University College of Veterinary Medicine.)
Characteristic histopathologic lesions are a pyogranulomatous meningoencephalitis
and lymphoplasmacytic periventriculitis. The lesions are most severe around the third
ventricle of the brain resulting in an obstructive hydrocephalus. Ataxia related to
vestibular dysfunction is the most common neurologic sign. Intention tremor and fine
head tremor have been associated with cerebellar and meningeal disease. Forebrain,
cerebellar, and thoracolumbar spinal cord signs are also common. Signs are slowly
progressive and eventually fatal. Affected cats frequently have an anterior uveitis.
Diagnosis is based on clinical signs, presence of ocular lesions, cytology of abdominal
effusion if present, and CSF analysis (neutrophilic-lymphocytic pleocytosis and increased
protein). There is no effective treatment.
Equine Herpesvirus-1 (EHV-1)
Equine herpesvirus type 1 causes a diffuse multifocal myeloencephalopathy and is discussed
in detail in Chapter 6.
West Nile Virus
West Nile virus is a flavivirus that causes acute polioencephalomyelitis in birds,
horses, and humans and rarely in other animal species.173., 174., 175. In horses the
most common clinical signs are fever, paresis, ataxia, and muscle fasciculations.
173
The lesions are most severe in the spinal cord and are usually asymmetric and multifocal.
Abnormal mentation and cranial nerve abnormalities occur in 44% to 67% of affected
horses.
173
See Chapter 6 for discussion of diagnosis and treatment.
Western, Eastern, and Venezuelan Equine Encephalomyelitis (WEE, EEE, VEE)
A group of mosquito-transmitted alphaviruses cause encephalomyelitis in horses (Eastern,
Western, and Venezuelan equine encephalomyelitis). Descriptions have been mainly reported
in humans, horses, and in a number of other mammalians, including dogs, cats, cattle,
camelids, rodents, and pigs.176., 177., 178. The causative agents are single-stranded
enveloped RNA viruses, Alphavirus genus of the family Togaviridae. Birds are involved
in application of the disease. Susceptible horses, usually younger, show clinical
signs 2 to 3 weeks after viral infection of birds. Times for peak infection are June
to August in the southern states and September in the northern states. The clinical
signs include mild to severe pyrexia, anorexia, stiffness, propulsive walking, depression,
hyperesthesia, aggression, and excitability.
179
Obtundation is the most common clinical sign and seizures occur in one third of the
cases. Neurologic signs are variable and occur as diffuse or multifocal forebrain
disease with brainstem and spinal cord involvement. The signs are peracute to acute
in onset and progressive. Mortality rates are highest with EEE. Histopathology reveals
gray matter predominance with multifocal to diffuse meningoencephalomyelitis. Diagnosis
is made via serology (CF, HI, SN, and IgM capture ELISA). Results of CSF analysis
are distinctive and reveal very high protein concentrations and severe neutrophilic
pleocytosis. Treatment is mostly supportive care, which includes corticosteroids or
nonsteroidal antiinflammatory agents and physical therapy. Long-term antiinflammatory
therapy may be important for neurologic recovery. Efficacious vaccines are available
but twice yearly vaccination is recommended. Mosquito control is important in reducing
risk of infection.
Antiviral Therapy
Few reports address the use of antiviral agents in animals. Acyclovir is an antiherpes
viral agent that inhibits the enzyme thymidine kinase and thus inhibits deoxyribonucleic
acid (DNA) synthesis. This effect is 200 times greater for the viral enzyme than for
the enzyme in mammalian cells.
180
Acyclovir can be given orally and intravenously. It penetrates into the CSF and aqueous
humor at 30% to 50% of the plasma concentration. In human herpes encephalitis, the
IV dose is 10 mg/kg every 8 hours. The dose should be reduced with renal failure because
the drug is excreted in the urine. Encephalopathy is a rare side effect with high
doses.
Foscarnet is effective against herpesvirus, cytomegalovirus, and the human immunodeficiency
virus. It penetrates the CNS in good concentrations.
180
The Transmissible Spongiform Encephalopathies (TSE)
The TSE are a group of slowly progressive, neurodegenerative diseases of the CNS.
The group includes bovine spongiform encephalopathy (BSE, mad cow disease), scrapie
in goats and sheep, chronic wasting disease in elk and deer, transmissible mink encephalopathy,
and feline spongiform encephalopathy. The cause is a particle in which nucleic acids
have not been demonstrated. These particles may represent infectious proteins derived
from the normal host. Normal prion proteins (PrP) are located in nervous system membranes
and are suspectable to proteases. Abnormal PrP are protease resistant (PrP-res). Protease
resistant prions accumulate in the neurons and interfere with cell function and cause
vacuole formation (Figure 15-17
). There is a long latency period before clinical signs develop. The TSE are reportable
diseases.
Figure 15-17
Spongiform change (vacuoles) in the caudal brainstem gray matter of a cow with bovine
spongiform encephalopathy (left image) and large vacuoles in a large neuron (right
image).
(Courtesy Cornell University College of Veterinary Medicine.)
Bovine Spongiform Encephalopathy (BSE)
BSE was first reported in dairy cattle in the United Kingdom. Infection was tied to
the consumption of meat and bone meal contaminated with BSE-infected nervous tissue.
BSE has been sporadically reported in Canada and a few cases have been reported in
the United States. The incubation period can be long (2 to 8 years). The clinical
signs include nervousness, aggression, frequent licking at the muzzle, muscle fasciculations,
and bruxism. Cows are hypersensitive to external stimuli. Locomotor signs include
ataxia, hypermetria, paresis, falling, and recumbency. There is no antemortem diagnostic
test. Postmortem diagnosis includes histopathology, immunohistochemistry, and Western
blot or ELISA on the brain. There is no treatment or vaccine. Human TSE, variant Creutzfeldt-Jakob
disease, has been linked to consumption of brain and spinal cord tissue from BSE-infected
cattle.
Scrapie
Scrapie is a TSE that affects sheep and goats. The prion is transmitted by ingestion
or direct or indirect contact with infected placenta and birth fluids. The incubation
is 1 to 7 years with clinical signs usually present at 2 to 5 years of age. Scrapie
is most common in black-faced sheep (Suffolk, Cheviot, Hampshire). These breeds are
genetically susceptible to the prion proteins. In addition to the signs described
for cattle, sheep develop tremors, pruritus, wool break, and inducible nibbling reflex.
When startled, sheep may tremble and fall down in a seizure. The signs progress slowly
to recumbency and death (6 weeks to 1 year). The clinical signs in goats are similar.
About 33% of infected goats regurgitate rumen contents.
The antemortem diagnosis of scrapie is based on clinical signs and third eyelid biopsy
for immunohistochemistry of PrP-res. Postmortem diagnosis is made from histopathology
of brain (vacuolation of gray matter) and immunohistochemistry of brain and/or lymphoid
tissue. There is no treatment. The disease can be prevented by selecting ewes and
rams that are genetically resistant to scrapie and by maintaining closed herds.
Feline Spongiform Encephalopathy
Spongiform encephalopathy has been reported to cause tremor in cats. A 7-year-old
spayed female domestic shorthair cat presented for a 4-month history of progressive
aggressive behavioral changes, tremor, and pelvic limb ataxia.
181
Histopathology revealed diffuse vacuolation of the neuropil and neuronal cell bodies
most marked in the frontal lobe of the cerebral cortex. Due to the lack of plaques,
which are associated with transmissibility, it is unclear if this is a true example
of transmissible spongiform encephalopathy. Spongiform change was also reported in
an 8-month-old female domestic shorthair cat that had a 2-week history of generalized
ataxia and lethargy.
182
Neurologic examination also revealed head tilt, cervical spine ventroflexion, tetraparesis,
tremor, and visual deficits. Histopathology revealed generalized vacuolation of the
gray matter of the brain and spinal cord.
Rickettsial Infections (see Table 15-14)
The agents that cause Rocky Mountain spotted fever (RMSF) and canine ehrlichiosis
may cause meningitis and encephalitis in addition to vasculitis and hematologic disorders.183.,
184. Both diseases are transmitted by ticks and are limited to areas harboring the
appropriate vector. Dogs with RMSF may have acute cervical pain and minimal signs
related to brain or spinal cord disease. Dogs with neurologic ehrlichiosis usually
have signs related to brainstem or spinal cord lesions. CSF may be normal or reveal
increased protein and a mixed pleocytosis.
183
Confirmation of ehrlichiosis may be difficult in some dogs and is based on serologic
tests and isolation of the organism.
185
Treatment is with tetracycline, minocycline, or doxycycline. Doxycycline is preferred
because it penetrates the CSF in good concentrations. For doxycycline, a dose is 5
to 10 mg/kg every 12 hours IV or orally.
Parasitic Infections
Parasitic disease of the nervous system is uncommon. The most common parasitic diseases
are summarized in Table 15-15.
Noninfectious Inflammatory Diseases
Immune Mediated Diseases
Polyradiculoneuritis (see Chapter 7) is probably an immune-mediated reaction to a
transmissible agent in raccoon saliva. Postvaccinal rabies is rare (see Table 15-13).
Both conditions are summarized in Table 15-16.
Meningoencephalomyelitis of Unknown Etiology (MUE) (see Table 15-17)
Several nonseptic inflammatory diseases may respond to medical therapy.186., 187.,
188. The causes of these diseases are not currently known, but immune-mediated mechanisms
are suspected. Accordingly, corticosteroids and other immunosuppressive drugs may
be beneficial with certain diseases. Differentiating these diseases from bacterial
or viral infections is difficult because the clinical signs and CSF findings may be
similar with both types of inflammation (see Chapter 4).
Steroid-Responsive Meningitis-Arteritis (SRMA)
Steroid-responsive meningitis-arteritis occurs in large-breed dogs, usually less than
2 years of age (Figure 15-18
).
Figure 15-18
Canine juvenile polyarteritis (steroid responsive meningitis-arteritis). Note the
prolific arterial inflammation with neutrophils.
(Courtesy Cornell University College of Veterinary Medicine.)
Cervical spinal hyperesthesia occurs in more than 90% of affected dogs. Neutrophilic
leukocytosis with left shift and fever occurs in two thirds of affected dogs. Boxers,
Bernese mountain dogs, beagles, weimaraners, and Nova Scotia duck tolling retriever
dogs may be predisposed to this disease.187., 188., 189., 190., 191., 192., 193. Dogs
with noninfectious, nonerosive, idiopathic immune-mediated polyarthritis (IMPA) commonly
have spinal pain, and about 50% of these dogs have concurrent SRMA.
188
Analysis of CSF usually reveals marked increases in protein and neutrophils. Bacterial
cultures from the CSF are negative. IgA concentrations are increased in both the plasma
and the CSF. Measurement of acute phase proteins in CSF may also aid in the diagnosis
and management of affected dogs.194., 195. Most dogs respond dramatically to prednisone,
2 to 4 mg/kg every 24 hours.
194
In dogs not responding to prednisone alone, additional immunosuppressive therapy may
be needed. Once the signs are controlled, the dose of prednisone is decreased to alternate-day
therapy, and then the total dose is gradually reduced over months. Relapses are common
when the corticosteroid dose is too low or is discontinued.
Necrotizing Meningeal Vasculitis
Necrotizing meningeal vasculitis is a severe form of SRMA.186., 187., 194. Necrotizing
vasculitis also occurs in young dogs, especially beagles, Bernese mountain dogs, and
German shorthaired pointers. Although the prognosis in affected beagles is guarded,
other breeds may respond well to prednisone at 2 to 4 mg/kg every 24 hours using the
aforementioned reducing-dosage regimen.
Granulomatous Meningoencephalomyelitis (GME)
GME is a common nonseptic inflammatory disease that affects young to middle-aged small-breed
dogs.186., 187., 188., 196., 197. Females are more often affected.
188
The exact cause is unknown, but studies of inflammatory cells in dogs with GME suggest
a T cell–mediated delayed type of hypersensitivity.
198
Neurologic signs may be acute or chronic. Clinically, GME has been characterized into
three clinical presentations: focal, disseminated, or ocular.199., 200. Cervical pain
is a common finding. About 50% of affected dogs have focal signs referable to the
forebrain, and about 50% have forebrain and brainstem disease.
196
Central vestibular signs are common manifestations of acute disease.
197
Rarely, involvement of the peripheral nervous system may be observed.
201
A definitive diagnosis is based on histopathologic examination of the CNS. Microscopically,
the hallmark of GME is perivascular cuffs of granulomatous inflammation (Figure 15-19
).
202
Figure 15-19
Perivascular cuffs of lymphocytes, plasma cells, and histiocytes in the cerebral white
matter of a dog. These lesions are typical of granulomatous meningoencephalomyelitis.
(Courtesy Cornell University College of Veterinary Medicine.)
Presumptive antemortem diagnosis is based on a combination of signalment, anamnesis,
clinicopathologic data, and exclusion of other disease capable of producing similar
clinical signs. Since the definitive diagnosis of GME necessitates histologic evaluation
of CNS tissue, the term meningoencephalomyelitis of unknown etiology (MUE) has been
used to describe dogs without a definitive diagnosis.
The diagnosis of MUE should be pursued in a logical manner (see Chapter 4). Briefly,
minimum database (complete blood count, chemistry profile, and urinalysis) often discloses
nonspecific abnormalities. Analysis of CSF is critical to establishing a presumptive
antemortem diagnosis. Mononuclear pleocytosis, activated macrophages, occasionally
neutrophils, and rarely mast cells with increases in protein content are common CSF
abnormalities. Cross-sectional imaging also is important in the diagnostic workup.
MRI of the brain is the imaging modality of choice. With MRI, multifocal hyperintensities
on T2-weighted and fluid attenuated inversion recovery sequences predominantly affecting
the white matter are observed. Enhancement patterns vary on T1-weighted sequences
after administration of contrast media. A focal space occupying mass or abnormalities
involving the optic nerves may be observed in animals with the focal or ocular forms,
respectively.
203
Abnormal findings from CSF analysis and MRI of the brain can be found in other forms
of MUE. Therefore, the value in pursuing these diagnostics tests is not only in documenting
abnormalities but in excluding other disease processes; the greatest importance of
which is eliminating infectious disease from consideration. Given the treatment of
GME is centered on immunosuppression, misdiagnosis may be devastating in animals with
infectious disease. Therefore, depending on the clinician’s index of suspicion, further
diagnostic testing aimed at the identification of an infectious etiology may be warranted.
Likewise, CNS lymphoma may occur with clinical signs of multifocal signs and have
MRI findings and lymphocytic pleocytosis that are difficult to differentiate from
GME. PCR for the antigen receptor rearrangements may be useful in the diagnosis of
CNS lymphoma.
Response to prednisone therapy is highly variable. Some dogs respond to prednisone
(2 to 4 mg/kg every 24 hours, using the aforementioned reducing-dosage regimen), but
relapses and progression of neurologic signs are common in many dogs. Cytosine arabinoside,
given as a single agent or in combination with prednisone, is a more effective treatment.204.,
205. In one study of 10 dogs treated with cytosine arabinoside and prednisone, all
dogs achieved partial or complete remission and the median survival time was 531 days;
five dogs were still alive at the end of the study.
206
Cytosine arabinoside is administered in cycles. Each cycle consists of administering
the drug at a dose of 50 mg/m2 given subcutaneously twice a day for 2 consecutive
days. Cycles are initially repeated every 3 weeks. With time, gradual lengthening
of the interval between cycles can be done. In severely affected animals, initial
administration of 600 mg/m2 given as a constant rate infusion over 2 days may be beneficial.
207
To monitor for myelosuppression, a CBC should be performed 10 to 14 days following
the first course of treatment and every 2 to 3 months throughout the course of therapy.
Cyclosporine may also be effective in treating GME. Two protocols have been reported.205.,
208. In one, cyclosporine was administered at 10 mg/kg every 24 hours for 6 weeks.
The dose was then reduced to 5 mg/kg per day. Prednisone was also administered at
2 to 4 mg/kg daily for 3 to 4 weeks. In another protocol, cyclosporine was administered
at 3 to 10 mg/kg every 12 hours. Serum cyclosporine levels were followed but the drug
was not detected in the CSF, even in dogs with good clinical response. In one study
of 10 dogs treated with cyclosporine and prednisone, all dogs responded and the median
survival time was 930 days.
208
Procarbazine has also been used as an adjunctive therapy combined with prednisone.
209
The dosage administered was 25 to 50 mg/m2 orally once daily. The combination of procarbazine
and prednisone in 21 dogs provided a median survival time of 14 months. Seven dogs
experienced myelosuppression and three dogs had hemorrhagic gastroenteritis. Other
immunosuppressive drugs used in the treatment of GME include mycophenolate mofetil
(20 mg/kg orally twice daily) and leflunomide (1.5 to 4.0 mg/kg orally once daily).
210
Radiation treatment is effective for dogs with focal GME.
173
The prognosis for survival is better for dogs with focal disease.
196
Necrotizing Meningoencephalitis (NME) and Necrotizing Leukoencephalitis (NLE)
These breed-specific diseases are seen most commonly in young adult dogs. They are
fatal disorders that cause a nonsuppurative inflammation and necrosis of the brain.
Variants have been reported in the pug, Yorkshire terrier, Maltese, Pekingese, French
bulldog, Chihuahua, and shih-tzu.
211
NME is most common in the pug and Maltese and NLE is most common in Yorkshire terriers
and French bulldogs. In pugs, the mean age of onset of clinical signs is 18 months
(range 4 to 113 months). Females are more commonly affected than males. Most pugs
with NME have a mononuclear pleocytosis.
As with GME, definitive diagnosis requires histopathologic evaluation of the brain.
Gross evaluation of the brain in dogs with NME discloses abnormalities limited to
the gray/white matter junction of the cerebrum (Figure 15-20
).
Figure 15-20
Brain from Maltese dog treated for intractable seizures. Note the laminar loss of
cortical tissue (black arrows) and cribriform changes in the white matter (green arrows).
These are the lesions of necrotizing meningoencephalitis.
(Courtesy Cornell University College of Veterinary Medicine via Dr. R. Higgins, University
of California, Davis.)
Microscopically, the lesion affects gray and white matter, meninges, and choroid and
consists of inflammatory infiltrate composed of lymphocytes, plasma cells, and macrophages.
In addition, areas of liquefactive necrosis and cavitation occur. In dogs with NLE,
gross lesions predominate in the deep white matter of the cerebrum and thalamus. Similar
to NME, inflammation composed of lymphocytes, plasma cells, and macrophages exist
along with necrosis and cavitation of the white matter. Typical white matter lesions
involve the thalamus, internal capsule, centrum semiovale, and corona radiata.
Although there are gross anatomic differences in the distribution of the lesions in
NME and NLE, these diseases may represent a spectrum of a single disease process rather
than separate entities. In fact, although NME or NLE has been reported to affect specific
breeds, occasionally NLE has been observed in a breed normally thought to be affected
with NME and vice versa.212., 213.
Presumptive diagnosis can be relatively accurately established based on signalment
(specifically breed), clinicopathologic data, and exclusion of other disease processes
that may result in similar clinical signs. Importantly, a relatively accurate presumptive
diagnosis can be made based on MRI findings. Magnetic resonance imaging characteristics
and topography of the lesion mirrors the gross and histologic findings (Figure 15-21
).212., 213.
Figure 15-21
Axial T2W image of the brain of an adult Dachshund dog with meningoencephalitis of
unknown origin. There is excessive hyperintensity of the white matter (internal capsule,
centrum semiovale, and corona radiate) of the left cerebrum (arrows). There is also
edema in internal capsule of the right cerebrum (arrowhead).
Treatment is pursued using the same drug combinations as with GME. Overall, the prognosis
is guarded depending on the severity of clinical signs and extent of necrosis of the
brain. The mean survival time in one study was 93 days.
211
Eosinophilic Meningoencephalomyelitis (EME)
Eosinophils are rarely found in CSF. When the percentage is less than 5%, it is a
nonspecific finding and can be found in several CNS disorders. When eosinophil counts
exceed 20%, an eosinophilic pleocytosis exists and the most common causes are parasitic
migration, cryptococcosis, neosporosis, and idiopathic EME. Idiopathic EME occurs
in both large- and small-breed dogs with a median age of 3.5 years.
214
There is no gender bias and about 75% of dogs respond to prednisone therapy (0.33
to 1 1 mg/kg q12h).
Case Studies
Key: 0, Absent; +1, decreased; +2, normal; +3, exaggerated; +4, very exaggerated or
clonus: PL, pelvic limb; TL, thoracic limb; NE, not evaluated.
CASE STUDY 15-1
CASEY veterinaryneurologycases.com
Signalment
Mastiff, female spayed, 1.5 years old
History
Clinical signs began several days ago. Dog has experienced vomiting, diarrhea, dry
eyes and nose, urinary incontinence, and weight loss. All vaccinations are current.
Physical Examination Findings
Dog is dull and dehydrated. The bladder is distended and easily expressed. Gas-filled
intestinal loops can be palpated. Both eyes are very dry and the planum nasale is
dry and crusted. Both pupils are widely dilated and do not respond to a strong light
source. Third eyelids are prolapsed.
Neurologic Examination
Mental status
Dull
Gait and posture
Normal
Postural reactions
Normal
Spinal reflexes
Normal except the perineal reflex is weak and anal tone is reduced.
Cranial nerves
Pupils are dilated and do not respond to strong light source.
Sensory evaluation
Normal
Lesion Localization
Generalized disease of autonomic nervous system
Differential Diagnosis
1.
Dysautonomia
2.
Botulism
Diagnostic Plan
Dilute pilocarpine in left eye (immediate constriction); poor wheal and flare to intradermal
histamine phosphate injection.
Diagnosis
Dysautonomia
Treatment
Dilute pilocarpine in each eye daily. Cisapride was administered twice a day to promote
esophageal motility.
Outcome
This case responded poorly to treatment,
CASE STUDY 15-2
MCCOY veterinaryneurologycases.com
Signalment
Pus, female spayed, 3 years old
History
Two months prior to presentation, the dog was brought in because of a paralyzed tail.
A cauda equina syndrome was presumptively diagnosed and the dog seemed to respond
to nonsteroidal antiinflammatory drugs. On this visit, the dog was seen for severe
ataxia. Owner declined diagnostic testing and the dog was placed on prednisone and
doxycycline. Three days later, the dog’s condition had worsened and seizures developed.
The dog was treated with phenobarbital and referred. All vaccinations are current.
Physical Examination Findings
See neurologic examination.
Neurologic Examination
Mental status
Dull and poorly responsive to auditory stimuli
Gait and posture
Unable to stand without assistance. She is very ataxic and falls both left and right.
Left head tilt is present.
Postural reactions
1.
Proprioceptive placing: normal in left front leg and very depressed in all other limbs
2.
Hopping: +1 in thoracic limbs and 0 in pelvic limbs
Spinal reflexes
1.
Patellar: +3 in both limbs
2.
Withdrawal: normal
Cranial nerves
Menace response: reduced
Palpebral reflex: normal
Pupils: very dilated and no PLRs absent
Vertical nystagmus
Sensory evaluation
Normal
Lesion Localization
Forebrain based on seizures
Left cranial medulla based on vestibular signs and postural deficits
Retina/optic nerves bilateral based on reduced menace responce and absent PLRO
Differential Diagnosis
1.
Viral encephalitis
2.
Pug dog encephalitis
3.
Protozoal encephalitis
4.
Rickettsial encephalitis
Diagnostic Plan
CSF and immunocytochemistry analysis; cross-sectional imaging and serology
Results
CSF: mild increase in protein; normal cell count; CSF cells positive on immunofluorescent
antibody for canine distemper; MRI and serology not performed
Diagnosis
Canine distemper encephalomyelitis
Treatment
Euthanasia
CASE STUDY 15-3
RASCAL veterinaryneurologycases.com
Signalment
Abyssinian cat, male castrated, 1 year old
History
The cat had severe paraparesis. Clinical signs began 3 weeks ago with lameness of
the right thoracic limb that was managed with NSAIDs. Weakness and ataxia also became
evident in the pelvic limbs. Muscular atrophy developed rapidly in the pelvic limbs.
The cat has had two episodes of pyrexia and anorexia. Vaccinations are current.
Physical Examination
The rectal temperature is normal. Cat is thin with generalized muscle atrophy. Enlarged
popliteal lymph nodes are present.
Neurologic Examination
Mental status
Alert and responsive
Posture
Normal
Gait
Severe paraparesis. The tail is paralyzed.
Postural reactions
Hopping and proprioceptive deficits are noted in both pelvic limbs. Hopping is decreased
in the right thoracic limb.
Spinal reflexes
Spinal reflexes are increased in all limbs except the left pelvic limb where the patellar
reflex is absent and hock flexion is decreased during flexion. Perineal reflex is
absent.
Cranial nerves
The menace response is reduced and the pupils are widely dilated (medication to examine
retinas). Pupillary light reflexes cannot be evaluated due to administration of cycloplegic
drugs.
Palpation
The urinary bladder is distended.
Sensory evaluation
Hyperesthesia is noted in the LS region. Noxious stimuli are poorly perceived from
the tail.
Lesion Localization
At least two and maybe three spinal cord lesions are present. In addition, disease
of multiple spinal nerves (neuritis) or muscle may also be present to explain the
generalized muscle atrophy.
1.
T3-L3 based on paraparesis and increased spinal reflexes
2.
Left L4-S2 based on absent patellar and flexor reflexes
3.
Cauda equina based on sensory examination of tail and decreased perineal reflex
Differential Diagnosis
There are multifocal lesions making inflammatory disease much more likely than degenerative
or neoplastic processes.
1.
Protozoal myelitis-neuritis (toxoplasmosis and neosporosis)
2.
Mycotic myelitis-neuritis (cryptococcosis, histoplasmosis, blastomycosis, aspergillosis)
3.
FIP
4.
Lymphoma
Diagnostic Plan
1.
CBC
2.
Fine-needle lymph node biopsy
3.
Thoracic and LS radiographs
4.
MRI
5.
CSF analysis
Results
Fundic examination revealed severe bilateral chorioretinitis. Lymph node aspirate
isolated histoplasma organisms. Radiographs of the lumbosacral spine did not reveal
any skeletal lesions. Cross-sectional imaging and CSF analysis not performed.
Diagnosis
Histoplasmosis with myelitis and neuritis (likely fungal granulomas)
Treatment
Itraconazole (cat greatly improved and regained ability to urinate)
CASE STUDY 15-4
SADIE veterinaryneurologycases.com
Signalment
Boxer, 9-month-old female intact
History
The dog has a 2-day history of anorexia, decreased activity, and stiff gait. There
is no history of trauma. She lives in northeastern Kansas, is well vaccinated, and
eats a premium dog food. The dog was examined in early September.
Physical Examination Findings
The abnormalities include a stiff gait and rectal temperature of 104.5° F. Ticks are
present on the dog.
Neurologic Examination
Mental status
Responsive to her environment
Gait and posture
Discomfort evident when handled or picked up. A stiff gait and reluctance to walk
are noted. There is no head tilt circling, or ataxia.
Postural reactions
Normal
Spinal reflexes
Normal
Cranial nerves
Normal
Sensory evaluation
Marked hyperesthesia is elicited upon palpation over the thoracolumbar and cervical
vertebral column.
Lesion Localization
There are no findings suggestive of intramedullary spinal cord disease, especially
with the presence of paraspinal pain. The hyperesthesia suggests disease involving
the TL and cervical vertebra or meningeal disease. Muscles and joints also have pain
sensitive fibers.
Differential Diagnosis
1.
Steroid responsive meningitis-arteritis
2.
Rickettsial (RMSF) meningitis
3.
GME
4.
Discospondylitis
5.
Metastatic neoplasia
6.
Intervertebral disk disease
7.
Polymyositis
8.
Polyarthritis
Diagnostic Plan
1.
CBC, biochemical profile, UA
2.
Thoracic radiographs and abdominal ultrasound to rule-out metastatic disease; spinal
radiography
3.
Serology: RMSF and Ehrlichia canis
4.
CSF analysis
Results
1. The primary abnormality on the CBC was a platelet count of 90,000. The biochemical
profile and UA were normal.
2. Thoracic radiographs and abdominal ultrasound within normal limits;
3. Negative serology for RMSF and Ehrlichia canis
4. No CSF analysis was performed
Diagnosis
Given the clinical signs and the presence of ticks, RMSF meningitis was suspected.
Treatment
Dog was placed on oral doxycycline. The dog dramatically responded to treatment. Convalescence
RMSF titers were 1:256.
CASE STUDY 15-5
VICTOR veterinaryneurologycases.com
Signalment
Miniature schnauzer, intact male, 14 months old
History
The dog has been anorexic and lethargic for the past 2 days. He vomited one to two
times in last 48 hours. Dog has right head tilt, circles and falls to the right, and
bumps into objects on the right side. Owners report that the dog is reluctant to open
his mouth and whines when his mouth is opened. Another veterinarian also found a mild
fever and modest thrombocytopenia (165,000 platelets/μL).
Physical Examination Findings
The liver was not palpable on abdominal palpation. Rectal temperature at admission
was 103.2° F.
Neurologic Examination
Mental status
Dull, confused, and disoriented
Gait and posture
Right head tilt; drifts and falls to the right, right hemiparesis, circles both directions
but mostly to the right side. Visual deficits are suspected on right side.
Postural reactions
Very decreased on the right side
Spinal reflexes
All spinal reflexes are intact
Cranial nerves
Menace response: OD—absent; OS—normal
Palpebral reflex: normal
PLR: intact
Physiologic nystagmus is intact. There is no pathologic nystagmus but a ventrolateral
strabismus is observed in the right eye
Facial sensation: normal
Swallowing/gag: normal
Tongue movement: normal
Sensory perception
Normal
Lesion Localization
Left cerebral cortex; right brainstem (rostral medulla—central vestibular disease)
Differential Diagnosis
1.
Rickettsial encephalitis
2.
Viral encephalitis
3.
Meningoencephalomyelitis of unknown origin
4.
Fungal encephalitis
5.
Toxoplasmosis/neosporosis
6.
Hepatoencephalopathy
Diagnostic Plan
1.
Fundic examination
2.
CBC, biochemical profile, UA
3.
Bile acids
4.
Abdominal radiographs/ultrasonography
5.
MRI
6.
CSF analysis
Results
1.
CBC: platelets 162,000 (200,00 to 500,000 cells/µL); CK 501 (22 to 491); ALT 76 (3
to 69)
2.
UA: normal
3.
Abdominal radiographs: small liver
4.
Bile acids: pre-5.3; postprandial 23.8 (5 to 23)
5.
CSF: WBC—488; RBC—173; Total protein—94.39; cytology—100% lymphocytes
6.
PCR and serology for Ehrlichia: negative
7.
Toxoplasma gondii and Neospora caninum: negative titers (IFA) at 1:50
8.
MRI not performed
Diagnosis
Meningoencephalitis of unknown etiology; possibly GME
Treatment
Initially chloramphenicol and prednisone was administered. The dog was maintained
on an immunosuppressive dose of prednisone.
Outcome
1.Recheck 1 month: Improved
2.Recheck 2 months: Much improved
3.Recheck 3 months: Signs in remission. The dog developed severe iatrogenic Cushing.
The dose of prednisone was reduced to every other day. Other immunosuppressive agents
(e.g., cytosine arabinoside) were considered.
CASE STUDY 15-6
OTTO veterinaryneurologycases.com
Signalment
Miniature schnauzer, male, 16 weeks old
History
Otto developed clinical signs at 8 weeks of age and signs have progressively worsened.
There are no other clinical signs. He eats, drinks, and is growing normally. Owner
describes clumsy gait and falling right and left.
Physical Examination Findings
No abnormalities found except for neurologic examination findings.
Neurologic Examination
Mental status
Alert and responsive
Gait and posture
There was a base wide stance. Gait showed severe cerebellal ataxia, hypermetria, and
falling to right. Intention tremors were evident upon eating.
Postural reactions
+1 hopping in left thoracic and pelvic limbs.
Cranial nerves
Normal
Spinal reflexes
Patellar reflex on left side is +3. All other reflexes are normal.
Sensory evaluation
Normal
Lesion Localization
The prominent clinical signs localized to the cerebellum. Dog probably has either
brainstem and/or cervical spinal cord lesion to explain the postural reaction deficits.
Differential Diagnosis
1.
Cerebellar abiotrophy
2.
Lysosomal storage disease
3.
Canine distemper virus
4.
Other infectious inflammatory disease
Diagnostic Plan
1.
CSF analysis
2.
Serology for distemper, toxoplasmosis, neosporosis, and rickettsial agents.
3.
MRI
4.
Urine organic acid screening
Results
1.
CSF: Normal
2.
Serology results were for negative infectious agents
3.
MRI and urine screening not performed
Treatment
No treatment was administered because dog most likely has a neurodegenerative disease
Outcome
Dog developed rapid progression of neurologic signs and was euthanized at 6 months
of age. Necropsy and histopathology confirmed cerebellar abiotrophy with degenerative
lesions also in the brainstem.