Granulomatous meningoencephalitis
Encyclopedia
Granulomatous meningoencephalitis (GME) is an inflammatory disease of the central nervous system
(CNS) of dog
s and, rarely, cat
s. It is a form of meningoencephalitis
. GME is likely second only to encephalitis
caused by canine distemper virus
as the most common cause of inflammatory disease of the canine CNS. The disease is more common in female toy dogs of young and middle age. It has a rapid onset. The lesions of GME exist mainly in the white matter
of the cerebrum
, brainstem
, cerebellum
, and spinal cord
. The cause is only known to be noninfectious and is considered at this time to be idiopathic
. Because lesions resemble those seen in allergic meningoencephalitis, GME is thought to have an immune-mediated
cause, but it is also thought that the disease may be based on an abnormal response to an infectious agent. One study searched for viral DNA
from canine herpesvirus
, canine adenovirus
, and canine parvovirus
in brain tissue from dogs with GME, necrotizing meningoencephalitis, and necrotizing leukoencephalitis (see below for the latter two conditions), but failed to find any.
(CSF) analysis shows a large number of white blood cell
s. Typically small mature lymphocyte
s are the majority of cells seen, with monocytes and neutrophils making up the rest. A CT scan
or MRI
will show patchy, diffuse, or multifocal lesions. For a number of years, the basic treatment was some type of corticosteroid
in combination with one or more immunosuppressive drugs, typically cytosine arabinoside
and/or cyclosporine
or other medications such as azathioprine
, cyclophosphamide
, or procarbazine
, of which were usually added one at a time to the corticosteroid until a successful combination was found. There is evidence that treatment with radiation therapy
for focal GME provides the longest periods of remission.
. The disease may be inherited in Pug
s and Maltese and has been diagnosed in other breeds as well (Yorkies, Chihuahuas). It differs in pathology
from GME by more tissue breakdown and increased eosinophil
s (white blood cells). CSF analysis is also unique among inflammatory CNS diseases in dogs in that the cells are predominately lymphocyte
s instead of a mixed population of mononuclear cells. In Maltese and Pugs there is extensive necrosis and inflammation of the gray matter
of the cerebrum and subcortical white matter. The most common early symptoms are related to forebrain
disease and include seizures and dementia
, and later circling, head tilt, and blindness with normal pupillary light reflexs may be seen.
s there can be severe mononuclear inflammation of the brainstem and periventricular
cerebral white matter. Because the condition in this breed frequently affects only the white matter, it has been called necrotizing leukoencephalitis. Symptoms of brainstem and central vestibular
disease predominate.
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(CNS) of dog
Dog
The domestic dog is a domesticated form of the gray wolf, a member of the Canidae family of the order Carnivora. The term is used for both feral and pet varieties. The dog may have been the first animal to be domesticated, and has been the most widely kept working, hunting, and companion animal in...
s and, rarely, cat
Cat
The cat , also known as the domestic cat or housecat to distinguish it from other felids and felines, is a small, usually furry, domesticated, carnivorous mammal that is valued by humans for its companionship and for its ability to hunt vermin and household pests...
s. It is a form of meningoencephalitis
Meningoencephalitis
Meningoencephalitis is a medical condition that simultaneously resembles both meningitis, which is an infection or inflammation of the meninges, and encephalitis, which is an infection or inflammation of the brain.-Causes:...
. GME is likely second only to encephalitis
Encephalitis
Encephalitis is an acute inflammation of the brain. Encephalitis with meningitis is known as meningoencephalitis. Symptoms include headache, fever, confusion, drowsiness, and fatigue...
caused by canine distemper virus
Canine distemper
Canine distemper is a viral disease that affects animals in the families Canidae, Mustelidae, Mephitidae, Hyaenidae, Ailuridae, Procyonidae, Pinnipedia, some Viverridae and Felidae...
as the most common cause of inflammatory disease of the canine CNS. The disease is more common in female toy dogs of young and middle age. It has a rapid onset. The lesions of GME exist mainly in the white matter
White matter
White matter is one of the two components of the central nervous system and consists mostly of myelinated axons. White matter tissue of the freshly cut brain appears pinkish white to the naked eye because myelin is composed largely of lipid tissue veined with capillaries. Its white color is due to...
of the cerebrum
Telencephalon
The cerebrum or telencephalon, together with the diencephalon, constitutes the forebrain. The cerebrum is the most anterior region of the vertebrate central nervous system. Telencephalon refers to the embryonic structure, from which the mature cerebrum develops...
, brainstem
Brain stem
In vertebrate anatomy the brainstem is the posterior part of the brain, adjoining and structurally continuous with the spinal cord. The brain stem provides the main motor and sensory innervation to the face and neck via the cranial nerves...
, cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
, and spinal cord
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
. The cause is only known to be noninfectious and is considered at this time to be idiopathic
Idiopathic
Idiopathic is an adjective used primarily in medicine meaning arising spontaneously or from an obscure or unknown cause. From Greek ἴδιος, idios + πάθος, pathos , it means approximately "a disease of its own kind". It is technically a term from nosology, the classification of disease...
. Because lesions resemble those seen in allergic meningoencephalitis, GME is thought to have an immune-mediated
Immune-mediated disease
Immune-mediated diseases are conditions which result from abnormal activity of the body's immune system. The immune system may over-react or start attacking the body . Autoimmune diseases are a subset of immune-mediated diseases....
cause, but it is also thought that the disease may be based on an abnormal response to an infectious agent. One study searched for viral DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
from canine herpesvirus
Canine herpesvirus
Canine herpesvirus ' is a virus of the family Herpesviridae which most importantly causes a fatal hemorrhagic disease in puppies less than two to three weeks old. It is known to exist in the United States, Canada, Australia, Japan, England and Germany...
, canine adenovirus
Infectious canine hepatitis
Infectious canine hepatitis is an acute liver infection in dogs caused by canine adenovirus type-1 . CAV-1 also causes disease in wolves, coyotes, and bears, and encephalitis in foxes. The virus is spread in the feces, urine, blood, saliva, and nasal discharge of infected dogs. It is contracted...
, and canine parvovirus
Canine parvovirus
Canine parvovirus type 2 is a contagious virus mainly affecting dogs. The disease is highly contagious and is spread from dog to dog by direct or indirect contact with their feces. It can be especially severe in puppies that are not protected by maternal antibodies or vaccination. It has two...
in brain tissue from dogs with GME, necrotizing meningoencephalitis, and necrotizing leukoencephalitis (see below for the latter two conditions), but failed to find any.
Types of GME
- Disseminated - This is a diffuse disease throughout the CNS. It was previously known as inflammatory reticulosis. There is an accumulation of mononuclear cellMonocyteMonocytes are a type of white blood cell and are part of the innate immune system of vertebrates including all mammals , birds, reptiles, and fish. Monocytes play multiple roles in immune function...
s and neutrophilNeutrophil granulocyteNeutrophil granulocytes are the most abundant type of white blood cells in mammals and form an essential part of the innate immune system. They are generally referred to as either neutrophils or polymorphonuclear neutrophils , and are subdivided into segmented neutrophils and banded neutrophils...
s around the blood vessels (perivascular) of the CNS. MeningitisMeningitisMeningitis is inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. The inflammation may be caused by infection with viruses, bacteria, or other microorganisms, and less commonly by certain drugs...
is seen with this form of GME and causes fever and neck pain. It has an acute progression over a few weeks. Symptoms include incoordination, nystagmus, head tilt, seizures, and depression. - Focal - The disease presents as a granulomaGranulomaGranuloma is a medical term for a tiny collection of immune cells known as macrophages. Granulomas form when the immune system attempts to wall off substances that it perceives as foreign but is unable to eliminate. Such substances include infectious organisms such as bacteria and fungi as well as...
, which mimics a tumor. It usually is found in the cerebrum or cerebellopontine angleCerebellumThe cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
. Symptoms may be acute or develop slowly over several months and depend on the location of the lesion. - Ocular - This is an uncommon form of GME and is characterized by sudden blindness caused by optic neuritisOptic neuritisOptic neuritis is the inflammation of the optic nerve that may cause a complete or partial loss of vision.-Causes:The optic nerve comprises axons that emerge from the retina of the eye and carry visual information to the primary visual nuclei, most of which is relayed to the occipital cortex of the...
. The disease is bilateral. Ocular GME is considered to be an extension of CNS disease. The blood vessels of the posterior segmentPosterior segmentThe posterior segment is the back two-thirds of the eye that includes the anterior hyaloid membrane and all of the optical structures behind it: the vitreous humor, retina, choroid, and optic nerve....
of the eye and anterior uveaUveaThe uvea , also called the uveal layer, uveal coat, uveal tract, or vascular tunic, is the pigmented middle of the three concentric layers that make up an eye. The name is possibly a reference to its reddish-blue or almost black colour, wrinkled appearance and grape-like size and shape when...
have the same infiltrates of inflammatory cells as the intracranial vessels. UveitisUveitisUveitis specifically refers to inflammation of the middle layer of the eye, termed the "uvea" but in common usage may refer to any inflammatory process involving the interior of the eye....
, retinal detachmentRetinal detachmentRetinal detachment is a disorder of the eye in which the retina peels away from its underlying layer of support tissue. Initial detachment may be localized, but without rapid treatment the entire retina may detach, leading to vision loss and blindness. It is a medical emergency.The retina is a...
, and secondary glaucomaGlaucomaGlaucoma is an eye disorder in which the optic nerve suffers damage, permanently damaging vision in the affected eye and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the eye...
may be seen.
Diagnosis and treatment
Cerebrospinal fluidCerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
(CSF) analysis shows a large number of white blood cell
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
s. Typically small mature lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
s are the majority of cells seen, with monocytes and neutrophils making up the rest. A CT scan
Computed tomography
X-ray computed tomography or Computer tomography , is a medical imaging method employing tomography created by computer processing...
or MRI
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
will show patchy, diffuse, or multifocal lesions. For a number of years, the basic treatment was some type of corticosteroid
Corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte...
in combination with one or more immunosuppressive drugs, typically cytosine arabinoside
Cytarabine
Cytarabine, or cytosine arabinoside, is a chemotherapy agent used mainly in the treatment of cancers of white blood cells such as acute myeloid leukemia and non-Hodgkin lymphoma. It is also known as Ara-C...
and/or cyclosporine
Ciclosporin
Ciclosporin , cyclosporine , cyclosporin , or cyclosporin A is an immunosuppressant drug widely used in post-allogeneic organ transplant to reduce the activity of the immune system, and therefore the risk of organ rejection...
or other medications such as azathioprine
Azathioprine
Azathioprine is a purine analogue immunosuppressive drug. It is used to prevent organ rejection following organ transplantation and to treat a vast array of autoimmune diseases, including rheumatoid arthritis, pemphigus, inflammatory bowel disease , multiple sclerosis, autoimmune hepatitis, atopic...
, cyclophosphamide
Cyclophosphamide
Cyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group....
, or procarbazine
Procarbazine
Procarbazine Procarbazine Procarbazine (Matulane (US), Natulan (Canada), Indicarb (India) is an antineoplastic chemotherapy drug for the treatment of Hodgkin's lymphoma and certain brain cancers (such as Glioblastoma multiforme). It is a member of a group of medicines called alkylating agents. It...
, of which were usually added one at a time to the corticosteroid until a successful combination was found. There is evidence that treatment with radiation therapy
Radiation therapy
Radiation therapy , radiation oncology, or radiotherapy , sometimes abbreviated to XRT or DXT, is the medical use of ionizing radiation, generally as part of cancer treatment to control malignant cells.Radiation therapy is commonly applied to the cancerous tumor because of its ability to control...
for focal GME provides the longest periods of remission.
Pug Dog encephalitis
Pug Dog encephalitis (PDE) is an idiopathic inflammatory disease primarily affecting the prosencephalon (forebrain and thalamus). It is also known as necrotizing meningoencephalitisNecrotizing meningoencephalitis
Necrotizing meningoencephalitis is an inflammatory disease of the central nervous system that occurs in young, small breed dogs. Necrotizing meingoencephalitis has been described in numerous small breeds, including the Pug, Maltese and Chihuahua....
. The disease may be inherited in Pug
Pug
The pug is a "toy" breed of dog with a wrinkly, short-muzzled face, and curled tail. The breed has a fine, glossy coat that comes in a variety of colors, and a compact square body with well-developed muscle. They have been described as multum in parvo , referring to the pug's personality and...
s and Maltese and has been diagnosed in other breeds as well (Yorkies, Chihuahuas). It differs in pathology
Pathology
Pathology is the precise study and diagnosis of disease. The word pathology is from Ancient Greek , pathos, "feeling, suffering"; and , -logia, "the study of". Pathologization, to pathologize, refers to the process of defining a condition or behavior as pathological, e.g. pathological gambling....
from GME by more tissue breakdown and increased eosinophil
Eosinophil granulocyte
Eosinophil granulocytes, usually called eosinophils or eosinophiles , are white blood cells that are one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. Along with mast cells, they also control mechanisms associated with...
s (white blood cells). CSF analysis is also unique among inflammatory CNS diseases in dogs in that the cells are predominately lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
s instead of a mixed population of mononuclear cells. In Maltese and Pugs there is extensive necrosis and inflammation of the gray matter
Grey matter
Grey matter is a major component of the central nervous system, consisting of neuronal cell bodies, neuropil , glial cells and capillaries. Grey matter contains neural cell bodies, in contrast to white matter, which does not and mostly contains myelinated axon tracts...
of the cerebrum and subcortical white matter. The most common early symptoms are related to forebrain
Prosencephalon
In the anatomy of the brain of vertebrates, the prosencephalon is the rostral-most portion of the brain. The prosencephalon, the mesencephalon , and rhombencephalon are the three primary portions of the brain during early development of the central nervous system...
disease and include seizures and dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
, and later circling, head tilt, and blindness with normal pupillary light reflexs may be seen.
Necrotizing leukoencephalitis
In Yorkshire TerrierYorkshire Terrier
The Yorkshire Terrier is a small dog breed of terrier type, developed in the 19th century in the county of Yorkshire, England to catch rats in clothing mills. The defining features of the breed are its size, to , and its silky blue and tan coat...
s there can be severe mononuclear inflammation of the brainstem and periventricular
Ventricular system
The ventricular system is a set of structures containing cerebrospinal fluid in the brain. It is continuous with the central canal of the spinal cord.-Components:The system comprises four ventricles:* right and left lateral ventricles* third ventricle...
cerebral white matter. Because the condition in this breed frequently affects only the white matter, it has been called necrotizing leukoencephalitis. Symptoms of brainstem and central vestibular
Vestibular system
The vestibular system, which contributes to balance in most mammals and to the sense of spatial orientation, is the sensory system that provides the leading contribution about movement and sense of balance. Together with the cochlea, a part of the auditory system, it constitutes the labyrinth of...
disease predominate.
Other types of noninfectious meningoencephalitis
- Steroid-responsive meningoencephalitis is any noninfectious meningoencephalitis that responds well to corticosteroidCorticosteroidCorticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte...
s and usually has an excellent prognosisPrognosisPrognosis is a medical term to describe the likely outcome of an illness.When applied to large statistical populations, prognostic estimates can be very accurate: for example the statement "45% of patients with severe septic shock will die within 28 days" can be made with some confidence, because...
. This could represent mild forms of GME or PDE, but there are two separate conditions recognized also.- Steroid-responsive meningitis/arteritis, also known as necrotizing vasculitis, is seen most commonly in BeagleBeagleThe Beagle is a breed of small to medium-sized dog. A member of the Hound Group, it is similar in appearance to the Foxhound, but smaller, with shorter legs and longer, softer ears. Beagles are scent hounds, developed primarily for tracking hare, rabbit, and other game...
s, BoxerBoxer (dog)Developed in Germany, the Boxer is a breed of stocky, medium-sized, short-haired dog. The coat is smooth and fawn or brindled, with or without white markings. Boxers are brachycephalic , and have a square muzzle, mandibular prognathism , very strong jaws and a powerful bite ideal for hanging on to...
s, Bernese Mountain DogBernese Mountain DogThe Bernese Mountain Dog, called in German the Berner Sennenhund, is a large breed of dog, one of the four breeds of Sennenhund-type dogs from the Swiss Alps. The name Sennenhund is derived from the German "Senne" and "hund" , as they accompanied the alpine herders and dairymen called Senn...
s, and German Shorthaired PointerGerman Shorthaired PointerThe German shorthaired pointer is a breed of dog developed in the 19th century in Germany for hunting.The breed is streamlined yet powerful with strong legs that make it able to move rapidly and turn quickly. It has moderately long floppy ears set high on the head. Its muzzle is long, broad, and...
s younger than two years of age. Many cases have fever, loss of appetite, and severe neck pain without other neurologic symptoms, although long-term cases may have incoordination and limb weakness or paralysis. CSF analysis shows predominantly neutrophils. In Beagles this condition is also known as Beagle pain syndrome. - Eosinophilic meningoencephalomyelitis is seen mainly in Golden RetrieverGolden RetrieverThe Golden Retriever is a medium-sized breed of dog. They were historically developed as gundogs to retrieve shot waterfowl such as ducks and upland game birds during hunting and shooting parties. As such, they were bred to have a soft mouth to retrieve game undamaged and have an instinctive love...
s. CSF analysis shows predominantly eosinophils.
- Steroid-responsive meningitis/arteritis, also known as necrotizing vasculitis, is seen most commonly in Beagle
- An acute progressive pyogranulomatous meningoencephalomyelitis is seen in mature PointerPointer (dog breed)The Pointer, often called the English Pointer, is a breed of dog developed as a gun dog. It is one of several pointing breeds.-Appearance:...
dogs. There is monocytic and neutrophilic infiltration of the leptomeningesMeningesThe meninges is the system of membranes which envelopes the central nervous system. The meninges consist of three layers: the dura mater, the arachnoid mater, and the pia mater. The primary function of the meninges and of the cerebrospinal fluid is to protect the central nervous system.-Dura...
. Symptoms include incoordination, reluctance to move, and neck rigidity.