What is leukoencephalopathy of the brain: types, diagnosis and treatment. Canine Necrotizing Meningoencephalitis Treatment and Prognosis
Description:
It belongs, like all leukoencephalitis, to the group of demyelinating diseases of the nervous system, the pathomorphological feature of which is diffuse or nested myelin breakdown with the relative preservation of axial cylinders. The predominant lesion of the white matter of the brain determined the name of this disease as leukoencephalitis.
According to the nature of myelin damage, myelinoclastic and leukodystrophic types of demyelinating diseases are distinguished. In the first case, myelin is destroyed, in the second, myelin metabolism is disturbed due to a hereditary enzymatic defect. Leukoencephalitis is of the myelinoclastic type. In the process of elucidating the etiology of leukoencephalitis, an opinion arose about the involvement of this disease in slow infections associated with the latent long-term survival of the virus in the body (herpes simplex virus, etc.). Its activation is influenced by a number of factors. When they enter the nervous system, activated slow viruses cause the development of an acute or chronically progressive process. In addition to white matter damage in leukoencephalitis, dystrophic changes are also observed in nerve cells.
Symptoms:
The most characteristic localization of the process is the basal nuclei. The associative connections between the lobes of the brain are affected, which determines the dominant role of mental disorders in the clinical picture of leukoencephalitis.
The disease affects mainly children's age. It starts slowly, usually after some kind of infection. Children become lethargic, their memory gradually decreases, higher cortical functions (writing, counting, praxis, etc.) are disturbed, dementia increases. IN individual cases schizophrenia-like syndrome develops - negativism, autism, paradoxical emotions.
An early and typical symptom of leukoencephalitis is epileptiform seizures with rapid personality disintegration (even with rare and mild seizures). With leukoencephalitis, a variety of motor disorders are observed: spastic paralysis and paresis, pseudobulbar and bulbar syndromes.
The course of the disease is steadily progressive. The average duration is 1.5-2 years. Lethal outcome occurs with symptoms of decerebrate rigidity, central respiratory disorders.
There are several clinical forms of leukoencephalitis. Van Bogart's leukoencephalitis and Schilder's leukoencephalitis are more common. Van Bogart's leukoencephalitis is characterized primarily by progressive dementia, epileptiform seizures, and extrapyramidal symptoms. With Schilder's leukoencephalitis, more often paresis and paralysis, visual impairment either due to demyelination of the optic nerve fibers (retrobulbar), or due to damage to the subcortical white matter of the occipital lobe.
Causes of occurrence:
It is assumed that Van Bogart's panencephalitis is caused by the measles virus, which can persist in brain neurons for a long time and become activated under certain conditions. Schilder's leukoencephalitis is considered by some researchers as an option in children. Acute hemorrhagic leukoencephalitis often occurs after prophylactic vaccinations. The pathogenesis is not clear. A hyperergic autoimmune process is assumed, in which viruses play the role of a trigger.
Treatment:
For treatment appoint:
For the treatment of leukoencephalitis, anti-inflammatory, desensitizing agents, anticonvulsants, vitamins, amino acids are used.
Degenerative-demyelinating lesion of the brain, accompanied by the formation of large or confluent zones of demyelination. It has a steadily progressive course with a non-specific and polymorphic clinical picture, which may include mental disorders, pyramidal and extrapyramidal syndromes, cognitive deficits, damage to the cranial nerves, episyndrome. Schilder's leukoencephalitis is diagnosed according to clinical criteria and MRI results after the exclusion of other pathologies with similar manifestations. Therapy is carried out with glucocorticosteroids, anticonvulsants, muscle relaxants and psychotropic drugs. However, the treatment is ineffective.
ICD-10
G31.0 Limited brain atrophy
General information
Schilder's leukoencephalitis was first considered as an independent nosology in 1912 by a psychoneurologist, whose name was firmly fixed in the name of the disease, although the author himself designated the pathology described by him with the term "periaxial diffuse leukoencephalitis". Later, descriptions of other clinical forms of leukoencephalitis were presented by various researchers: in 1941 - hemorrhagic leukoencephalitis, in 1945 - subacute sclerosing leukoencephalitis. Since the main pathomorphological substrate of the disease is diffuse zones of white matter demyelination, Schilder's leukoencephalitis is included in the group of demyelinating diseases.
The predominant age of manifestation of Schilder's disease is still a controversial issue. Foreign experts in the field of neurology consider the onset in the age period from 7 to 12 years to be characteristic, and some authors propose to classify the disease as a childhood form of multiple sclerosis. Observations of domestic neurologists, on the contrary, indicate an equal degree of damage to persons of different age categories.
Causes of Schilder's leukoencephalitis
The etiopathogenesis of Schilder's disease is under study. From the name of the disease, it can be seen that the inflammatory etiology of the cerebral lesion, i.e., encephalitis, was originally implied. A viral theory of the disease is assumed according to the type of slow infections. Among the possible infectious agents, the role of measles, herpes infection, myxoviruses, which may trigger the process of autoimmune cerebral inflammation, is discussed. However, unsuccessful attempts to isolate the pathogen led to the emergence of a different etiopathogenetic theory. The latter suggests a connection between Schilder's leukoencephalitis and dysfunction of the regulatory mechanisms of lipid metabolism, which brings the disease closer to hereditary leukodystrophy.
Morphological changes consist in the formation in the white cerebral substance of the hemispheres of significant zones of demyelination, which have clear pointed outlines and are often asymmetrically located. In some cases, such lesions form in the cerebellum and brain stem. In patients who fell ill in the pubertal period and in adulthood, cases are described when, along with areas of extensive demyelination, rounded plaque-like foci are observed, resembling plaques of multiple sclerosis.
Symptoms of Schilder's leukoencephalitis
The disease is characterized by the presence of nonspecific and polymorphic symptoms. It can manifest gradually developing mental disorders: mood lability, apathy, behavioral disorders, episodes of arousal with a hallucinatory syndrome. Intellectual decline progresses up to dementia. Agraphia, acalculia, alexia, agnosia, apraxia are observed. Due to demyelination of the cranial nerves, optic neuritis, ophthalmoplegia, hearing loss, decreased vision, and bulbar disorders occur. When the cerebellum is damaged, cerebellar ataxia, chanted speech, and intentional tremor appear. The defeat of the visual zone of the cortex leads to hemianopsia, cortical amaurosis. Extrapyramidal disorders are possible in the form of hyperkinesis, torsion dystonia, etc. Pyramidal disorders are usually observed in the later stages of leukoencephalitis in the form of mono-, hemi- and tetraparesis. Often there is a convulsive syndrome (like Jacksonian epilepsy or with generalized epileptic seizures), characterized by the absence of a specific EEG pattern.
The variability of combinations of various symptom complexes is so pronounced that it does not allow one to single out a typical variant of the course of Schilder's disease. In some cases, the clinic is similar to the progressive variant of multiple sclerosis, in others it has a pseudotumorous character, in the third it resembles a psychiatric pathology. In the latter case, patients may be treated by a psychiatrist until the development of overt neurological symptoms.
Diagnosis of Schilder's leukoencephalitis
It is very difficult to diagnose Schilder's leukoencephalitis in vivo. This task requires the neurologist to carefully compare the anamnestic, clinical and tomographic data, and carefully conduct differential diagnostics with similar diseases. In order to examine the visual and auditory analyzers, an ophthalmologist and an otolaryngologist may be involved in consultations.
Electroencephalography reveals signs of diffuse cerebral damage: a decrease in alpha activity and disorganization of the rhythm; epileptiform activity is often determined. In the study of cerebrospinal fluid, an increase in the level of gamma globulin is found against the background of a decrease in the specific gravity of the albumin fraction. The most informative method of instrumental diagnosis is MRI of the brain. Schilder's disease confirms the presence of at least one large or a pair of confluent foci of demyelination in the cerebral white matter.
To establish the final diagnosis, many neurologists are guided by the criteria of C.M. Poser 1985: according to MRI data, there are 1-2 rounded demyelination zones with a size of at least 2x3 cm; no pathology of the adrenal glands; exclusion of any other cerebral pathology (multiple encephalomyelitis, stroke, etc.); compliance with the norm of the level of fatty acids in the blood serum; identification of areas of diffuse chronic sclerosis at autopsy. In some cases, only histological studies of the cerebral tissues of the affected area allow to distinguish Schilder's leukoencephalitis from leukodystrophy.
Treatment and prognosis of Schilder's leukoencephalitis
The lack of clear ideas about the etiopathogenesis of Schilder's disease has not yet allowed the development of more or less effective methods for its treatment. Some effect of glucocorticosteroid therapy was noted, in connection with which many patients are prescribed methylprednisolone, initially parenterally at a loading dose, and then orally with a gradual dose reduction. In parallel, a course of neuroprotective, antioxidant and vascular therapy is carried out, if necessary, anticonvulsant treatment (carbamazepine, diazepam), muscle relaxants (amantadine, tolperison, amidine), decongestants (furosemide, acetazolamide, magnesium sulfate), psychotropic pharmaceuticals are prescribed.
Timely treatment can only slightly delay the progression of the pathology. However, despite its implementation, all patients die. The time of onset of death varies from several months to 3 years from the onset of leukoencephalitis.
Viral etiology. Leukoencephalitis is characterized by a predominant lesion of the white matter of the brain. Leukoencephalitis in the form of subacute sclerosing encephalitis (see) occurs mainly in children aged 4-16 years.
clinical course. The disease develops gradually. General infectious and cerebral symptoms are rare. The picture of the disease consists of gradually developing (dementia), hyperkinesis (involuntary movements) and autonomic disorders. The earliest symptom is mental disorders that progress rapidly. Already in the early period, epileptiform seizures occur, but more often they appear against the background of a detailed picture of the disease. After 1.5 -2 months. involuntary movements appear, and hyperkinesias are varied, tonic muscles of the trunk and limbs are often observed, leading to peculiar rotational movements. Often there is a type of sensory or motor aphasia (see). Patients have violent laughter and crying. Vegetative disorders are manifested by greasiness of the skin, sweating, salivation, changes in vascular reactions. Weight loss gradually develops, often to the extent of cachexia. The disease is progressive. Death occurs after several months, and in some cases several years from the onset of the disease.
Treatment. Rational treatment of the disease currently does not exist. Some effect may be with treatment (under the supervision of a physician). Restorative treatment, vitamin therapy (0.01 g per 1 year of life per day), etc. are shown. Careful care should be taken for patients (they need to be fed, wipe the skin, make sure that they do not appear).
Leukoencephalitis (from the Greek leukos - white + encephalitis) is an inflammatory disease of the brain with damage to the white matter. For a long time, leukoencephalitis was opposed to encephalitis with an isolated lesion of the gray matter (polioencephalitis). Recently, the boundary between these two types of encephalitis has been gradually blurred, and now we can only talk about the predominance of the inflammatory process in the white or gray matter of the brain.
At first, various lesions of the nervous system, both inflammatory and degenerative, were attributed to leukoencephalitis. As the nature of encephalitis was studied, secondary post-infectious encephalitis was identified from this polymorphic group, which was observed mainly in acute childhood infections (measles, rubella, etc.), vaccinal and allergic encephalitis, as well as systemic demyelinating diseases of a degenerative nature, such as diffuse sclerosis (Schilder's disease). , familial progressive leukodystrophy, etc.). The remaining primary leukoencephalitis is still difficult to recognize due to the lack of an accurate etiological classification. Their diagnosis is possible only according to the features of the clinic and pathohistology.
The most accurately studied group of primary leukoencephalitis, called subacute sclerosing leukoencephalitis with a progressive course. As an independent nosological unit, they were first isolated by L. van Bogaert in 1945. It turned out that a number of encephalitis, previously described under various names, can be fully classified as subacute sclerosing leukoencephalitis. They are only variants of this form and differ in the presence or absence of intracellular inclusions, the duration of the course and the intensity of the demyelinating process.
The etiology of subacute sclerosing leukoencephalitis has not yet been established. Intracellular inclusions testify in favor of the viral nature, but the virus cannot be isolated. The disease has no seasonality and epidemic foci. There has been an increase in cases of subacute disease in many countries. Initially, it was believed that the disease occurs only in childhood. Recently, it has also been described in adults, but much less frequently and proceeds less typically.
Pathologically, subacute sclerosing leukoencephalitis is characterized by demyelinating lesions in the white matter of the cerebral hemispheres and brainstem. The process of demyelination in some cases spreads diffusely, but more often affects the conduction systems of the brain in a certain sequence. The association systems of the cerebral hemispheres, the cortico-strio-pallidar pathways and the pontocerebellar wiring connections are the first to suffer. The pyramidal system is involved in the process in the later stages of the disease. Fibrous glial proliferation accompanying demyelination and inflammatory changes vary with the duration of the disease. They are more pronounced with a longer duration. In cases of a rapid course, along with a weak development of demyelination, the proliferation of fibrillar glia comes to the fore, which gave reason to call encephalitis sclerosing. In fast-flowing forms, intranuclear eosinophilic inclusions of type A are also more often found.
The clinical picture is extremely stereotypical. The disease proceeds in three main stages. The earliest symptoms (first stage) include changes that appear in children who were previously completely healthy in somatic and mental terms and not burdened by pathological heredity. Severe degradation of intellect with the phenomena of agnosia, apraxia and speech disorders is rapidly growing. Mutism and a complete lack of contact with others develop.
The second stage is accompanied by a kind of hyperkinesis. They may initially have the character of choreiform or myoclonic, but very quickly acquire the type of large-scale ballism, an extremely stereotyped appearance, with simultaneous contraction of a number of muscles of the proximal limbs, trunk and neck. They are distinguished by strict rhythm (from 4 to 12 in 1 min.). In the future, a kind of hyperkinesis of the eyeballs joins: forcible abduction of them to the sides and up synchronously with hyperkinesis of the limbs; Simultaneously, forced opening of the mouth and extrusion of the tongue occur, coinciding with the rhythm of the rest of the motor discharges. These strictly rhythmic and complex hyperkinesias give subacute leukoencephalitis a peculiarity that makes it possible to distinguish it from a number of other subacute encephalitis. Between attacks of motor discharges, at first, neither paralysis of the limbs nor disorders of the cranial nerves are detected; only muscle hypotonia is noted.
The third stage of the disease is characterized by the cessation of hyperkinesis and the gradual development of decerebrate rigidity. There are vegetative disorders and hyperthermic crises with an increase in temperature up to 40 ° and above. By this time, pyramidal symptoms develop in the form of foot clonuses and pathological reflexes. In the cerebrospinal fluid, globulin fractions of the protein increase, while the level of gamma globulin in the blood may not increase. The fundus of the eye is normal in all cases. Especially characteristic are changes in the electrical activity of the brain with periodic high-voltage discharges observed in all leads synchronously for both hemispheres. These peculiar EEG changes may distinguish this form from other encephalitis.
The disease is steadily progressing; the process lasts from several months to 2 years, in all cases ending in death. Treatment unsuccessful. See also Encephalitis.
Author: Georgina Child, BVSc, DACVIM (Neurology) / Specialty Clinic for Small Animals, 1 Richardson Pl, North Ryde NSW 2113Inflammatory diseases of the CNS affect the brain, meninges and/or spinal cord. Most of the pathological processes that cause meningitis also lead to concomitant encephalitis and/or myelitis. In dogs, non-infectious and (presumably) immune-mediated forms of meningoencephalomyelitis are much more common than infectious forms.
The causes of most immune-mediated disorders have not been established.
Immune-mediated diseases are believed to include corticosteroid-responsive meningoencephalitis, granulomatous meningoencephalomyelitis (GME), necrotizing vasculitis, necrotizing meningoencephalitis (NME) in certain breeds (Pug, Maltese, Chihuahua), and necrotizing leukoencephalitis (in yorkshire terriers).
The final diagnosis is made according to the results of histological examination; in most cases, it is not possible to make an intravital diagnosis without histological examination, since clinical signs and laboratory findings are often nonspecific and indistinguishable from those of infectious meningoencephalomyelitis, vascular disease, and some CNS tumors. Differences in the histologic pattern in non-inflammatory meningoencephalitis may or may not reflect different causes or immunologic mechanisms.
Corticosteroid-responsive meningitis (polyarteritis, necrotizing vasculitis, beagle pain syndrome)
Steroid-responsive meningitis occurs predominantly in young dogs of large breeds (mean age 1 year), although it can also occur in smaller breeds (eg, polyarteritis in Beagles (also called Beagle Pain Syndrome), New Scotia Retrievers, and Italian Greyhounds, noted in Lately).
Symptoms characteristic of meningitis include back pain, unnatural posture, stiff gait, lethargy, and lethargy. Fever is common, and leukocytosis may be detected in a general clinical blood test. Clinical signs range from acute and severe to episodic. Neurological disorders (paresis / paralysis) are rare, but possible with damage to the spinal cord or, in rare cases, the brain. Cases of necrotizing vasculitis of the pial and arachnoid vessels of the spinal cord have been described in young Beagles, German Shorthair Pointers and Bernese Mountain Dogs, sometimes occurring in other breeds.
Clinical signs are similar to those seen in steroid-responsive meningitis, but symptoms of multiple or focal spinal cord involvement may be present.
Treatment is similar to that used for meningitis, but the prognosis depends on the degree of spinal cord involvement.
CSF usually shows marked pleocytosis with neutrophils up to >10,000/mcL. Between episodes, CSF results may be normal. Microorganisms in the CSF are absent, culture results are negative. Some animals develop concomitant polyarthritis. Treatment consists of a long-term course of corticosteroids at an initial dose of 2–4 mg/kg per day, which is gradually reduced over 3–6 months.
Animals with only symptoms of meningitis have a good prognosis, although relapses are common. If corticosteroids do not work or the animal does not tolerate side effects well, azathioprine can be used.
Steroid-responsive meningitis occasionally occurs in cats.
For a more accurate designation of the diagnosis, the term "meningoencephalitis (or meningoencephalomyelitis) of unknown etiology (or origin)" (MNE or MNP) has been proposed. Other proposed or previous terms include nonpathogenic meningoencephalomyelitis, noninfectious inflammatory disease of the CNS, nonsuppurative meningoencephalitis, reticulosis, and others.
In this paper, the term GME will be used to describe all non-infectious inflammatory diseases of the CNS (even if it is incorrect), since it is generally accepted. These diseases are widespread throughout the world and can account for up to 25% of all cases of CNS disease in dogs.
GME is most common in toy and small breeds, especially Maltese, Toy Poodles, and all terriers (including Staffordshire and Airedale Terriers). However, it can develop in any breed of dog, including large dogs and mestizos. The disease is most common in middle-aged dogs (rarely in dogs<2 лет или >10 years). The disease occurs in both sexes, but it is possible that females get sick more often.
Diagnosis of noninfectious inflammatory disease of the CNS is based on clinical signs and exclusion of infectious causes—often by serology, CSF analysis, and brain imaging studies. However, in many cases, a presumptive diagnosis is made based on the best guess based on breed, age, history, and clinical signs. For an inflammatory disease of the central nervous system, an acute development of symptoms of multiple lesions of the central nervous system (brain or spinal cord) and / or hyperesthesia (in the cervical or lumbothoracic region) is typical. Clinical signs include forebrain symptoms (changes in mental state, compulsive circling, seizures) and/or caudal fossa (ataxia, vestibular disorders, cranial nerve disorders) and/or spinal cord lesions (at any level). In many cases, it is difficult to determine the anatomical localization of the lesion. However, the disease is chronic, progressive, and in some cases appears episodic, with a significant number of dogs presenting with focal neurological symptoms. Animals with meningitis often suffer from severe neck pain, a hunched posture, unwillingness to move, and a stiff "stilted" gait. Many owners of small dogs report that the animal hides, whines or screams for no apparent reason when trying to pick it up. Often there are back pains of uncertain localization. However, signs of back pain are not observed in all cases.
There may be symptoms of focal lesions of the spinal cord (any department, but most often the cervical), including paresis or paralysis. A form of GME associated with optic neuritis has been described, but is rare. Clinical signs may be acute and rapidly progressive, or insidious and slowly progressive over weeks or months.
In general, GME can have any history, be accompanied by any neurological symptoms, and develop in dogs of any age and breed!
Attempts have been made to classify forms of GME as disseminated, focal, or proceeding with damage to the optic nerve. This is very difficult to do in vivo and does not always matter for diagnosis, treatment and prognosis. Breed necrotizing meningoencephalitis (in Pugs, Maltese, Chihuahuas, and Yorkshire Terriers) can develop at a young age (<1 года, особенно у мальтийских болонок и мопсов), но встречается и у собак старше (особенно у чихуахуа). Обычно такой энцефалит развивается остро с симптомами тяжелого поражения переднего мозга, включая судороги. Неврологические нарушения часто быстро прогрессируют. Эти заболевания у разных пород классифицируются в зависимости от поражения оболочек, преимущественного поражения белого вещества и локализации (большие полушария или ствол мозга, или обе части). Такие различия могут отражать разные патологические процессы либо различия иммунного ответа, возможно, генетические.
Usually, clinical examination, clinical and biochemical blood tests of dogs with any form of non-infectious inflammatory diseases of the central nervous system do not show abnormalities. Fever is possible, but rare.
CSF analysis usually shows mild to moderate pleocytosis with a predominance of mononuclear cells and varying degrees of protein elevation. The total concentration of leukocytes varies from<10 до >5000 cells. The protein concentration can be from normal to 4 g/l. Neutrophils usually make up less than 50% of all detected cells. Sometimes there are macrophages and single eosinophils. In some dogs (sometimes more than 10%), CSF analysis shows no abnormalities. Changes in the composition of the CSF may indicate inflammation, which is the basis for suspicion of GME, but a similar pattern of CSF is possible in other diseases, including infectious, vascular (heart attack), and neoplasms. In most cases, CSF analysis is not sufficient to make a definitive diagnosis, but it can provide clarifying information when looking for a likely diagnosis in cases of spinal cord or brain damage. CSF analysis detects inflammation, but only if the inflammation involves the meninges, the ependymal lining, or tissues close to the CSF pathways. Nonspecific changes in the CSF are often observed in vascular, traumatic, degenerative, neoplastic and inflammatory diseases of the central nervous system.
In animals with elevated intracranial pressure (ICP), CSF sampling is associated with significant risk and may result in brain herniation at the incision of the cerebellar tentorium or herniation of the cerebellum at the foramen magnum. CSF sampling is also risky in severe brain disease, including without increased intracranial pressure, when changes in brain perfusion and reduced brain capacity for self-regulation can lead to further deterioration of neurological status.
Unfortunately, it is in these animals that CSF analysis often provides the most valuable diagnostic information. Clinical signs of elevated ICP include dizziness, stupor, dyspnea, head-butting, bradycardia, and elevated blood pressure. Some animals with elevated intracranial pressure have no obvious clinical signs.
CSF withdrawal from the cisterna also carries the risk of damage to structures of the nervous system (spinal cord or medulla oblongata), especially in small animals or in animals with CSF flow obstruction at the level of the cerebellar cistern.
Most dogs with GME are small breeds, some of which are predisposed to craniocervical junctional malformations, such as Chiari type malformations.
I do not practice routine CSF sampling in dogs with a high likelihood of GME, especially those with neurological abnormalities suggestive of brain damage. CSF analysis is useful for evaluating animals with spinal cord or meningeal involvement (I usually use lumbar puncture).
It is also possible to identify changes characteristic of an inflammatory disease using visual methods for examining the brain; MRI is considered the treatment of choice for GME. Magnetic resonance imaging (MRI) is the most sensitive technology for visual diagnosis of diseases of the brain and spinal cord. MRI units with powerful magnets 1.0 T, 1.5 T allow better visualization of inflammatory lesions than units with weak magnets. However, there is no “typical” MRI pattern, and changes may be indistinguishable from those observed in infectious, vascular, or neoplastic diseases. Solitary or multiple lesions can be found in any part of the central nervous system, they can be hypointense on T1-weighted images and hyperintense on T2-weighted and FLAIR images. The degree of contrast enhancement varies. It is possible to increase the contrast of the meninges. However, the most typical multifocal lesion. Imaging also helps rule out other causes of brain or spinal cord involvement, such as neoplasms or vascular abnormalities, although focal granulomas in GME may show a pattern very similar to neoplasms and infarctions, as the inflammation sometimes looks very similar to vascular abnormalities from other causes.
With necrotizing encephalitis in Chihuahuas, pugs, Maltese lapdogs, etc., characteristic multiple foci are found in the cerebral hemispheres with an erased border between gray and white matter and areas of hyperintensity on T2-weighted / hypointensity on T1-weighted images corresponding to areas of necrosis.
In some cases of inflammatory diseases of the CNS, MRI does not show changes.
Computed tomography (CT) is less sensitive, especially when examining lesions in the caudal fossa (artifact of increased beam stiffness). Displacement of the falx medulla or change in its normal anatomy as a result of compression by a bulky neoplasm can be either visible or invisible on CT or MRI images.
The final diagnosis of GME is possible only on the basis of the results of histological examination of the brain - which is obviously difficult to do in vivo. Microscopically, GME is characterized by tissue infiltration along the vessels by lymphocytes and/or macrophages. Such foci may merge into granulomas, visible macroscopically.
A presumptive diagnosis of HME is often made by exclusion of other causes (by serology/CSF culture in some circumstances) and, in many cases, by treatment outcome. To exclude infectious causes of meningoencephalitis, serum can be tested to determine the titers of cryptococcal antigen, antibodies to toxoplasma gondii and neospora caninum (in some cases, CSF is also examined). CSF cultures are often negative, even with bacterial and fungal infections.
When an animal has severe neurological symptoms, the benefits of diagnostic testing, especially CSF, should be weighed against the risks of the procedure.
The causes of GME are unknown, but most likely it is an autoimmune process based on T-cell mediated hypersensitivity.
It's hard to make a prediction. GME can be an acute, rapidly progressive, and fatal disease despite treatment, but in many cases of suspected GME, treatment works well and animals remain in remission for months or years. In most published sources, the prognosis for GME is indicated as unfavorable or hopeless, but in practice there are cases of successful treatment. Since the diagnosis is based on the results of histological examination, the authors of published works usually rely on cases of confirmed diagnosis (i.e., post-mortem).
The prognosis does not depend on the severity of clinical symptoms at admission, as well as on the severity of changes in the analysis of CSF or imaging of the brain.
Corticosteroids (mainly prednisolone) in immunosuppressive doses remain the mainstay of treatment. In many cases (for financial reasons and/or due to the risk of further diagnostic tests) treatment is given empirically without further confirmation of the diagnosis.
Initial dose of prednisolone 1–2 mg/kg every 12 hours Small dogs (<12 кг) следует давать 2 мг/кг каждые 12 ч. Собакам с весом <2,5 кг следует давать такую же дозу, как для собак весом 2,5 кг, а с весом <5 кг – такую же, как для собак весом 5 кг. Доза для более крупных собак (>40 kg) corresponds to a dose for dogs weighing 40 kg, in general, I would not recommend giving more than 40 mg every 12 hours for a long time. Response to corticosteroid therapy may take several days.
The dose of prednisolone is gradually reduced over at least 6 months, depending on the clinical response. The first time the dose is reduced after 2-4 weeks. After achieving remission, a maintenance dose of prednisolone (0.5–1 mg/kg every other day or 2–3 times a week) is used for 1–2 years. It is difficult to establish whether an animal has “cured”. If a dog receiving low-dose prednisolone 2-3 times per week has no neurological symptoms for >6 months, treatment may be discontinued. However, the side effects of corticosteroids, especially in large dogs, can be a significant problem in the long term. Long-term use of corticosteroids leads to iatrogenic hyperadrenocorticism, accompanied by significant wasting of muscle mass and calcification of the skin. In addition, treatment predisposes to gastrointestinal ulceration, pancreatitis, diabetes mellitus, infections (especially of the urinary tract), and ligament and tendon injuries.
Small dogs often tolerate high doses well, but animals that experience a relapse of neurological symptoms while on corticosteroid therapy, require high doses of corticosteroids (>1 mg/kg) for long periods of time to relieve neurological symptoms, or have significant side effects should consider using other immunosuppressants.
For large dogs, timely supplementation is recommended because many animals do not tolerate high doses of corticosteroids. All dogs with severe neurologic impairment associated with spinal cord injury should receive additional therapy, such as cytarabine, early in treatment. The addition of other immunosuppressants can reduce the dose of prednisolone, but the need for a certain dose of prednisolone remains in most animals.
Azathioprine (Imuran) - an immunosuppressant that suppresses the function of T-cells. In healthy dogs, it does not cross the blood-brain barrier. While this drug may be effective in steroid-responsive meningitis, especially in young large breed dogs, it is not useful in GME in my opinion. However, other clinicians recommend imuran and describe successful use of azathioprine in combination with prednisolone, which allowed the dose of the latter to be reduced. This drug causes almost no side effects, the main problem at high doses is the suppression of bone marrow activity. The recommended dose is 0.5–1.0 mg/kg every 48 hours. For the first 5–7 days, it can be given at a dose of 2 mg/kg every 24 hours.
Cytosine arabinoside (cytarabine, ara-C) - a drug used as an antineoplastic agent for dogs and humans, for example, for the treatment of CNS lymphoma. Its mechanism of action is unknown. Since this drug crosses the blood-brain barrier and is an immunosuppressant, it was proposed approximately 6 years ago as a possible treatment for GME. Most authors recommend using it at a dose of 50 mg/m2 subcutaneously twice a day for 2 consecutive days, repeating this cycle every 3 weeks. This dose is lower than the usual dose for cancer chemotherapy. The number of side effects of cytarabine is small. Bone marrow suppression has been described (usually 10 to 14 days after the start of treatment), but this usually does not lead to clinical impairment. It is recommended to periodically do a complete blood count, but not necessarily at each cycle. After treatment, vomiting, diarrhea and/or loss of appetite may occur. Cytarabine is inexpensive (when purchased in 10 ml vials) and suitable for outpatient treatment, however, protective gloves must be worn when administering this drug and handling/disposing of urine and faeces. Cytarabine is used in combination with prednisolone; if the neurological status of the animal remains stable, I usually gradually reduce the dose of prednisolone every 2 cycles of cytarabine. Cytarabine can be used indefinitely.
Leflunomide (Arava) - an immunosuppressant, used in medicine mainly for the treatment of rheumatoid arthritis. Successful use in the treatment of dogs has been described, first in combination with corticosteroids, and then alone (for uncontrolled adverse reactions to corticosteroids). The initial dose is 2 mg/kg per day. In my practice, animals relapsed or did not improve. This drug does not cause any significant side effects and is given by mouth. Can be combined with prednisone.
Cyclosporine - has also been proposed for the treatment of GME due to the latter's presumed autoimmune T-cell nature. Cyclosporine is a powerful immunosuppressant that suppresses T-cell immune responses. In healthy animals, the permeability of the blood-brain barrier to cyclosporine is low. However, since HME occurs with damage to the tissues around the vessels and a possible violation of the blood-brain barrier, it is assumed that the concentration of cyclosporine in the affected areas of the CNS may be higher. My experience with this drug is limited, with two dogs failing to respond to prednisone and cytarabine therapy.
Procarbazine - an antitumor agent that is lipid soluble and easily penetrates the blood-brain barrier; It is mainly used in medicine for the treatment of lymphoma. A dose of 25–50 mg/m2 per day is recommended. Procarbazine often causes side effects, including bone marrow suppression (30%), hemorrhagic gastroenteritis (15%), nausea, vomiting, and liver dysfunction. I have no experience with this drug, and its effectiveness has not been proven. Side effects and low availability limit its use.
Lomustine (CCNU) - an antitumor alkylating drug of the nitrosourea class, highly soluble in lipids and penetrating the blood-brain barrier. Doses used to treat GME are relatively arbitrary, but high doses are not recommended. Treatment with lomustine has been associated with significant, in some cases life-threatening, bone marrow suppression, gastrointestinal ulceration, and hepatotoxicity. The frequency of side effects increases with increasing dose, but such effects sometimes occur at an initial relatively low dose. Sepsis is a significant risk factor for bone marrow suppression. Toxicity is unpredictable and I do not recommend routine use of this drug for primary treatment.
Seizures require anticonvulsants.
Sick animals should not be vaccinated unless absolutely necessary. Vaccination may lead to recurrence of clinical symptoms. In addition, a low-fat diet is recommended.
Response to therapy is usually assessed by the reduction or disappearance of clinical symptoms. Repeated analysis of CSF is usually not recommended, since the severity of changes (or their absence) weakly correlates with the severity of CNS inflammation.
In my experience, at least 60% of dogs with suspected GME or steroid-responsive noninfectious meningoencephalitis respond well to corticosteroid monotherapy and can eventually be phased out without further relapse. However, relapse may occur days, weeks, months, or years after the first onset of clinical signs. If neurologic symptoms persist despite high doses of corticosteroids and/or prednisolone, and if the dose is reduced<2 мг/кг в сутки после нескольких месяцев терапии наступает рецидив, долговременный прогноз менее благоприятный.
Animals that require high doses of corticosteroids for a long time to reduce neurological symptoms can be supplemented with cytarabine; this will reduce the dose of prednisolone and achieve an acceptable quality of life for several months and even >1 year.
Other types of idiopathic meningoencephalitis have been described in several small breeds, including pug encephalitis, necrotizing encephalitis of Yorkshire terriers (necrotizing leukoencephalitis), Chihuahuas, and Maltese lapdogs (necrotizing meningoencephalitis).
Necrotizing encephalitis is also found in other toy breeds.
Histological sections reveal extensive inflammation and predominant necrosis of the cerebral cortex. Often, these pedigree inflammatory diseases present with a pattern of necrosis and cavities in the brain parenchyma, with meningeal lesions may or may not be present, and changes on MRI scans closely match lesions found post-mortem. The prognosis in all such cases is very cautious.
Treatment is the same as for GME, although response to treatment is often poorer.
For the first time, a disease from the Leukoencephalitis group was described by J. Danson in 1933 under the name "subacute form of lethargic encephalitis". In 1939, Pette and Dering (N. Pette, G. Doring) reported encephalitis with a chronic progressive course, somewhat different in clinical and pathomorphological manifestations, calling it nodular panencephalitis. In 1945, the same disease was described by L. Van Bogaert as "subacute sclerosing leukoencephalitis". Subsequently, Van Bogart carefully studied the clinic and morphology of this chronic progressive form of encephalitis. The diffuse periaxial encephalitis and hemorrhagic Leukoencephalitis described in 1912 by P. F. Schilder and reported by E. W. Hurst B 1941 are also similar to the Leukoencephalitis group.
Etiology and pathogenesis. It is assumed that Leukoencephalitis are diseases of an infectious-allergic nature. The role of myxoviruses, measles, rabies and Herpes zoster viruses as trigger factors of hyperergic autoimmune process is discussed.
Classification. The following clinical and morphological forms of leukoencephalitis are distinguished: subacute sclerosing Van Bogart leukoencephalitis, Schilder's periaxial leukoencephalitis, acute hemorrhagic leukoencephalitis. With Leukoencephalitis, the demyelinating process is usually combined with damage to neurons to one degree or another, therefore, for some of its forms, the term "panencephalitis" is also used.
Pathological anatomy. Macroscopic examination of the brain with leukoencephalitis reveals the expansion of the furrows and atrophy of the gyri. On a section of the hemispheres, areas of destruction and demyelination of various sizes are determined in all parts of the brain, mainly in the white matter, but involving different areas of the gray matter of the cortex (Figure 1). In the most affected areas, the brain has a spongy texture, the ventricles of the brain are moderately dilated.
The histological picture is characterized by a diffuse subacute inflammatory reaction with perivascular infiltration of lymphocytes and plasma cells and focal demyelination (Figure 2). Inflammatory changes are predominantly localized in the white matter of the brain, sometimes in the cortex, subcortical ganglia, meninges. Normally formed myelin is destroyed (myelinoclastic type of lesion). The degree of demyelination and destruction of the nervous tissue varies in different foci. Separate small foci can merge. At the edges of the focus of demyelination, oligodendrocytes are enlarged, contain amphophilic inclusions, in more affected areas they completely disappear. In addition, there are many large bizarre astrocytes with hyperchromatic multilobed or multiple nuclei. Axons remain relatively intact in the early stages of the process, later they may have dystrophic changes. The neurons of the cerebral cortex can contain inclusions of two types: spherical particles with a diameter of 30-40 micrometers and oblong, or tubular, structures of a slightly smaller diameter. Inclusions are more common with a short duration of the disease. Histochemical studies reveal a large amount of protein in the inclusions. In most cases, a proliferative reaction of glia is found. Gliosis can be small nodular or in the form of large foci (pseudotumor). Diffuse growth of fibrous glia sometimes leads to compaction of the medulla, so that the brain on the cut has a cartilaginous consistency. The walls of the arteries and veins are thickened, with an excess of reticular fibers in the adventitia.
clinical picture. Neuropsychiatric disorders are the earliest manifestation of the disease. Initially, there are complaints of increased fatigue, lethargy, irritability, mood instability. Gradually, the range of neuropsychiatric disorders is expanding. Malice, affectivity, greed, selfishness, cruelty, indiscipline, inertia of thinking appear. Patients often commit unmotivated acts, lose their neatness skills.
Against the background of mental disorders, focal neurological symptoms gradually progress over several weeks or months: practical disorders leading to loss of self-service skills (see the full body of knowledge Apraksin); gnostic violations (see the full body of knowledge of Agnosia); there are disorders of reading, writing, counting. Some patients experience visual and auditory hallucinations. Motor disorders are initially represented mainly by extrapyramidal disorders: rigidity, the “cogwheel” phenomenon is revealed (see Trembling Paralysis). There are polymorphic hyperkinesis of the muscles of the face, limbs, torso - tremor (see the full body of knowledge Trembling), torsion spasm (see the full body of knowledge Torsion dystonia), Hemiballismus (see the full body of knowledge Hyperkinesis), myoclonus (see the full body of knowledge). Pyramidal disorders in typical cases develop at later stages in the form of mono-, hemi or tetraparesis and paralysis (see Paralysis, paresis). Common symptoms of a focal lesion include static and locomotor ataxia (see full body of knowledge) of the cerebellar or frontal type. Bilateral damage to the cortical-nuclear pathways leads to impaired phonation and swallowing. Bulbar palsy develops quite rarely.
Seizures are a constant symptom of the disease (see full body of knowledge). They can appear at different stages of the disease. The most characteristic are small and abortive convulsive seizures, less often generalized grand mal seizures. In the late stage of the disease, trophic and autonomic disorders develop: cachexia, bedsores, thermoregulation disorders, profuse sweat, and so on. In the terminal stage, patients are immobilized, sometimes there is decerebrate rigidity (see full body of knowledge).
The course of leukoencephalitis can be steadily progressive or remittent. In the latter case, the clinical picture may resemble multiple sclerosis (see full body of knowledge).
With electroencephalography, periodic paroxysmal activity is recorded with an interval of 5-15 seconds simultaneously in most leads in the form of slow (1-2 per 1 second) high-voltage waves.
In the blood, leukocytosis is determined, an increase in the fraction of gamma globulin, the titer of antibodies to the measles virus or to myxoviruses (virus jc, sv-40) is usually increased.
In the cerebrospinal fluid, in most cases there is no cytosis and no increase in protein content. However, during the electrophoretic study of proteins, it is found that gamma globulin makes up to 40 percent or more of the total amount of protein, and the albumin fraction is reduced. Colloidal reactions give maximum flocculation in the first test tubes (paralytic type of Lange reaction).
Treatment must be comprehensive. Hormonal and symptomatic therapy is indicated. A positive effect is obtained with the appointment of corticosteroids. Treatment with glucocorticoids (prednisolone) should be started at an early stage of the pathological process, taking into account the rhythm of the hormonal activity of the adrenal glands. Hormonal therapy is supplemented with antiallergic (diphenhydramine, pipolfen, suprastin, diazolin) and anticonvulsant drugs. Showing drugs that reduce muscle tone (mydocalm, amedin, midantan, cyclodol and others), B vitamins and other symptomatic agents. The use of active therapy can delay the course of the disease and promote remissions for several years.
Forecast. With a steadily progressive course, patients die 2-12 months after the onset of the first symptoms. With a relapsing course, the disease lasts up to 3 years or more, and remissions can last from several months to several years, during which the symptoms of the disease are almost or completely absent.
Features of individual forms of leukoencephalitis. Subacute sclerosing leukoencephalitis Van Bogrammart. Pathomorphological examination of the brain of patients with this form of leukoencephalitis, as a rule, reveals intracellular inclusions. The degree of damage decreases in the direction from the cortex to phylogenetically more ancient formations, but more often than in other forms, the trunk and spinal cord are affected.
Clinical, a feature of this form of leukoencephalitis is the early manifestation and predominance of extrapyramidal disorders (hyperkinetic form), which are joined only at later stages by pyramidal symptoms. Epileptic seizures are not typical.
Schilder's periaxial diffuse leukoencephalitis. A pathological feature compared to other leukoencephalitis and multiple sclerosis is the relatively early axonal dystrophy. This form differs from the previous one in the predominance of pyramidal symptoms and frequent epileptic seizures. Large seizures are usually observed. The development of retrobulbar optic neuritis or the central form of blindness associated with demyelination of the occipital lobes is characteristic (see Schilder's disease).
Acute hemorrhagic leukoencephalitis. According to clinical and pathological features, this form of leukoencephalitis is similar to viral and post-vaccination encephalitis. Pathological anatomical examination reveals cerebral edema, on sections in the substance of the brain - large foci of soft pinkish-gray or yellowish color with multiple petechial hemorrhages. Gisto l. the picture is characterized by fibrinous necrosis of the walls of small vessels, mainly venules, surrounded by fibrin exudate, inflammatory cells and ring-shaped hemorrhagic zones. In the same perivascular zones - demyelination with moderate or severe destruction of axons. At the earliest stages, perivascular infiltrates are represented mainly by neutrophils, but many lymphocytes and plasma cells are found in older lesions.
The clinic of acute hemorrhagic leukoencephalitis is characterized by an extremely acute onset, a lightning-fast increase in the severity of symptoms of brain damage. Persons of both sexes aged from 20 to 40 years get sick. The duration of the course is from 2 days to 2 weeks An extended clinical picture is preceded by catarrhal phenomena in the pharynx, fever with leukocytosis in the peripheral blood. After 2-4 days, a headache, stiffness of the neck muscles appear, consciousness is disturbed, sometimes a coma develops. Characterized by focal or generalized convulsions, movement disorders in the form of hemi or tetraplegia, pseudobulbar paralysis. On the fundus - swelling of the disk (nipple) of the optic nerve. Rarely observed subacute and chronic forms. EEG and arteriography can detect focal changes. In the cerebrospinal fluid - pronounced pleocytosis due to polymorphonuclear leukocytes, there are also lymphocytes; the protein content is increased to 1 gram/liter or more; xanthochromia of cerebrospinal fluid is often detected, single erythrocytes can be detected microscopically.
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