redazione@vetpedia.it +39-0372-40-35-36/37/47

Meningoencephalomyelitides of unknown aetiology (GME, NME, NLE)

Details
Category: Schede
Hits: 10
  • Disciplina: Neurologia
  • Specie: Cane e Gatto

The term meningitis is used to define an inflammation of the meninges. The terms encephalitis and myelitis instead define, respectively, an inflammation of the encephalon and of the spinal cord. Given their specific pathogenetic mechanisms, inflammatory forms of the Central Nervous System (CNS) often involve more than one region, earning the name of meningoencephalitis or meningoencephalomyelitis.

The name “meningoencephalitis” or “meningoencephalomyelitis of unknown aetiology” (MUE) is used to define a group of inflammatory disorders of the central nervous system which are quite common in the dog, united by the fact that they have an unknown origin and a pathogenetic mechanism of probable immune-mediated origin. These meningoencephalitides seem to be caused by an aberrant immune response directed against components of the CNS. Even though they have been known for many years, their precise aetiopathogenesis remains unclear, although several studies indicate a possible role for environmental triggers (pathogens, vaccinations, etc.) and genetic factors.

The names by which these diseases are known in the veterinary field, Granulomatous Meningoencephalomyelitis (GME), Necrotising Meningoencephalitis (NME) and Necrotising Leukoencephalitis (NLE) reflect an anatomo-pathological classification defined on the basis of distinctive histopathological characteristics, rather than on aspects of a specific set of symptoms.

Since the diagnostic confirmation is only possible at the anatomo-pathological table, ante-mortem diagnosis is practically impossible due to the overlapping of clinical and diagnostic characteristics common to various forms of meningoencephalitis. For this reason, for some years, the suspected diagnosis of a form of “sterile” meningoencephalitis, established by way of a multimodal approach which integrates signalment data, clinical characteristics, results of cerebrospinal fluid examination and advanced diagnostic imaging, is defined with the term Meningoencephalitis of unknown aetiology (MUE). The treatment protocol for all these inflammatory forms of the CNS, which do not have an infectious or parasitic aetiology, is common and is based upon immunosuppression of the immune system in affected animals.

Based upon the foregoing, this article provides an integrated and common clinical and diagnostic approach for the different types of meningoencephalitis of unknown aetiology and then defines the distinctive aspects of each of them in more depth. For the reasons set out above, the treatment protocol is also described in an integrated way for the various meningoencephalitides.

 

CLINICAL AND DIAGNOSTIC APPROACH TO MUEs

Ante-mortem diagnosis of a specific meningoencephalitis may not be simple due to the varied clinical presentation, often also common to other diseases, and due to the impossibility of obtaining diagnostic confirmation, other than in necropsy. Despite this, the reasoned integration of signalment data, clinical presentation and advanced diagnostic imaging and laboratory testing provides sufficient data to develop a proper treatment protocol.

Signalment and clinical presentation - MUEs tend to affect animals belonging to specific breeds (for example, Necrotising Meningoencephalitis (NME) particularly affects breeds such as the Pug, Maltese and Pinscher; Necrotising Leukoencephalitis (NLE) affects the Yorkshire Terrier; Granulomatous Meningoencephalomyelitis (GME) affects toy breed dogs) and tends to occur in young/adult subjects, with an acute onset and a progressive course. The neurological deficits identified by the owners and confirmed upon neurological examination vary greatly depending upon the affected neuroanatomical region. Characteristically, the neuroanatomical localisation of the lesion is multifocal, although necrotising meningoencephalitides (ME) tend to have pre-eminently prosencephalic signs (Video 1).

In GME, it is also possible for the spinal cord to be primarily affected (Video 2). Upon neurological examination, therefore, prosencephalic deficits may be present, such as alterations in consciousproprioception, menace response deficits and compulsive gait (Videos 3 and 4) or brain stem signs, such as, for example, multiple deficits of the cranial nerves(Video 5). In the presence of suspected spinal GME, the most frequently identified clinical signs are spinal pain accompanied, to greater or lesser degrees, by neurological deficits.

Video 1Video 2

Video 3Video 4

 

Video 5

 

 

 

 

 

 

 

 

 

 

As often happens with inflammatory forms of the CNS, extra-neurological systemic signs, such as fever and leukocytosis, are not frequently found. The differential diagnostic clinical hypotheses are many, including, along with MUEs, infectious meningoencephalitides, neoplasms and toxic-metabolic diseases.

Diagnostic protocol - Given the broad spectrum of clinical presentations and the numerous differential diagnostic possibilities, the diagnosis of MUE should be based upon a reasonable amount of information deriving from blood test results (including eventual serological tests) and especially from the results of the cerebrospinal fluid examination  (CSF) and Magnetic Resonance Imaging (MRI).

The typical picture of the CSF examination in an animal affected by MUE is that of a mixed pleocytosis with an increased proportion of proteins.

The severity of the pleocytosis is of no prognostic value and, in some cases of MUE, the CSF examination may even prove to be normal. Serological and PCR tests of the CSF may be of help in ruling out inflammatory diseases of infectious aetiology. While an increase in the number of cells in the CSF is common in MUEs, it is rare for this finding to be able to differentiate the origin of the pathological process. The comparison of data from the cytological examination of the fluid and the visible lesions at MRI can help the clinician to restrict the field of possible differential diagnoses. MRI is also helpful in distinguishing between the different non-infectious meningoencephalitides, as it reproduces the topography and typology of the lesions which, at necropsy, allow for the formulation of a definitive diagnosis. The topography of the lesions, combined with the presence or absence of necrosis, may help to differentiate GME from necrotising encephalitis.

Nuclear Magnetic Resonance plays a decidedly important role in the ante-mortem diagnosis of the inflammatory processes of the CNS. Before MRI became available, in the veterinary field it was practically impossible to obtain suitable images which could demonstrate the presence of an inflammation of the nervous parenchyma. The sole exception was constituted by Computerised Tomography (CT), which was able to reveal, in post-contrast sequences, the presence of space-occupying lesions in GME.

 

GRANULOMATOUS MENINGOENCEPHALOMYELITIS– GME

Aetiopathogenesis – Even though the first description (then known as “reticulosis”) of granulomatous meningoencephalomyelitis dates back to 1962, i.e. more than 40 years ago, no light has yet been shed upon its origin. Over time, several aetiopathogenetic theories have been advanced which have involved, from time to time, a neoplastic, immune-mediated, infectious and genetic origin. Some studies have demonstrated the presence of infectious agents in nervous tissue samples of animals affected by GME, although the interpretation of this positivity is controversial. Other studies have documented the existence of findings compatible with an autoimmune disease of the CNS related to mechanisms of delayed hypersensitivity. Finally, some authors consider that the focal form of GME is a lymphoproliferative diseasethat shares inflammatory and neoplastic features.

At present, the most accepted hypothesis considers GME to be the result of a non-specific immune response modulated by factors of genetic predisposition and possibly provoked by infectious/environmental triggers.

Clinical presentation - GME is more prevalent in young adult toy breeds and in small-sized dogs, with an apparent predilection for poodles and terriers and for females.  Typically, GME presents with an acute onset and a progressive course, and with symptoms which depend upon the anatomical site affected (it is often multifocal). Among the most frequently reported signs, along with seizures and visual function disturbances, are those affecting the caudal fossa and the cervical spinal cord. The involvement of the spinal cord is evidenced by meningeal signs of pain (also extremely marked) along with gait deficits resulting in ataxia and paresis. Vestibular-cerebellar signs are a distinctive feature of the caudal fossa involvement (see Video 2). 

Traditionally, along with the form principally affecting the spinal cord, GME may affect the intracranial structures with three sufficiently distinct clinical-pathological forms:

  • Disseminated GME - This is the most frequent clinical form. The clinical signs have an acute onset and a rapid progression indicative of a multifocal lesion of the CNS which mainly affects the prosencephalon, brain stem, cerebellum and cervical spinal cord (see Video 3). 
  • Focal GME- This is a rarer occurrence, with an acute or insidious onset and slow progression, which causes clinical signs indicating a space-occupying lesion and which can be correlated to the formation of a granulomatous-like lesion of significant dimensions, primarily localised in the prosencephalon and pontomedullary region.
  • Ocular GME - This form is characterized by the acute onset of visual deficits, caused by an acute onset optic neuritis, which causes pupil dilation (usually unresponsive to light stimulation), papillary oedemaof variable intensity and occasional chorioretinitis (Fig. 2). Ocular GME may be found in association with the disseminated form, or it may precede it.

Advanced diagnostic imaging - In T2-W and FLAIR MRI images, the disseminated form of GME presents with disseminated hyperintense lesions, with irregular margins and an infiltrative pattern which affect both the white and grey matter. These lesions are usually associated with oedema, which is clearly evident in T2-W images. In T1-W images the lesions tend to be iso-hypointense and the use of a contrast medium produces extremely variable increases of intensity (Fig. 3).

The focal form of GME appears as a single space-occupying lesion, difficult to distinguish from a neoplasm (Fig. 4).

The ocular form may be evidenced by the enlargement of the optic chiasm and a good uptake of the contrast medium. Spinal GME forms are evidenced in T2-W images, in which they appear as diffuse hyperintensities with indistict margins (Fig. 5).

Neuropathology - GME presents very peculiar neuropathological characteristics, which can be summarised in the finding of non-suppurative inflammatory lesions which primarily affect the white matter of the encephalon and of the spinal cord. These lesions, which invade and infiltrate the adjacent cerebral tissue, have a very precise morphology, characterized by the mixed proliferation of inflammatory cells (lymphocytes, plasma cells, histiocytes and monocytes)  around a blood vessel, which earns them the name of “perivascular cuffs” (Fig. 6).

 

NECROTISING MENINGOENCEPHALITIDES: NECROTISING MENINGOENCEPHALITIS (NME) AND NECROTISING LEUKOENCEPHALITIS (NLE)

Necrotising meningoencephalitis (NME) and necrotising leukoencephalitis (NLE) share with GME the unknown aetiology, but they stand out as they are characterized by necrosis of the affected nervous tissue.

Aetiopathogenesis - Traditionally, NME was attributed to the Pug, while NLE to the Yorkshire Terrier. More recently, it has been shown that these two diseases can affect both breeds as well as other types of dogs. It therefore seems necessary, in the absence of histopathology confirmation, to call these pathological entities necrotising encephalitides (NE). NEs are considered diseases with a multifactorial aetiology. The latest theories involve the action of environmental and infectious triggers on a major substrate of genetic susceptibility. The hypothesised mechanisms, particularly for NME, are those of an exaggerated immune-mediated reaction.

Clinical Presentation- NME has an acute onset and a progressive course; apart from the Pug, it is also found in the Yorkshire Terrier, Maltese and sporadically in other small-sized breeds (Chihuahua, Pekinese, West Highland white terrier, Boston terrier, Japanese Spitz and Pinscher). It affects young/adult dogs, which are usually between 6 months and 7 years old. NLE can occur at an age between 4 months and 10 years and presents with clinical characteristics similar to NME. Both pathologies are characterized by very severe signs which mainly involve the prosencephalon (see Video 1) although NLE may affect the brain stem structures. Frequently reported clinical signs are therefore represented by convulsive crises, depression, circling and visual deficits. Vestibular cerebellar signs are identified particularly in NLE. If untreated, these illnesses rapidly progress, ending in the death of the animal. Treatment significantly slows down the course of the disease which, however, continues to progress, sometimes with relapses that can even be very severe. Affected animals may survive for several months, often maintaining neurological deficits that are the result of the nervous tissue lesions (Video 6).

  Video 6

 

 

 

 

 

Diagnostic Imaging: Magnetic Resonance - Magnetic resonance imaging allows to visualise the parenchymal lesions produced by NEs and, based on the pattern of distribution, can help in differentiating the diagnosis (Fig. 7).

Typically, in T2-W images NME produces asymmetrical and hyperintense prosencephalic lesions. In T1-W images these lesions, which involve the white and grey matter, are iso-hypointense, and the uptake of the contrast medium is variable. In NLE forms, the lesions present characteristics similar to those of NME, but are not limited to the prosencephalon and may affect the brain stem. It is relatively common, particularly in protracted forms of NLE, to find cystic lesions even of significant dimensions.

Neuropathology - At a neuropathological level, the distinctive mark of necrotising meningoencephalitides is the finding of non-suppurative inflammatory lesions associated with asymmetrical necrosis of the cerebral tissue.

Both NME and NLE appear as a non-suppurative meningoencephalitis, with asymmetrical bilateral cerebral necrosis. The former is characterized by lesions generally located in the cerebral hemispheres and in the subcortical white matter, with intense inflammation, constituted by lymphocytes, plasma cells and occasional histiocytes, which extend from the leptomeninges to the corona radiata, through the cerebral cortex. Malacic and necrotic areas are present, with possible liquefaction and cavitation. Protracted cases may present areas with neuronal loss and gliosis (Fig. 8).

NLE has only mild leptomeningeal and cortical infiltrations, while it presents a greater involvement of the periventricular white matter and an extension of the lesions to the brain stem. The neurons of the grey matter appear to be unaffected by the phlogistic process. The necrotic areas and cavitation are of greater magnitude than NME (Fig. 9).

 

TREATMENT PROTOCOL

Although there are no doubts about the need for an immunosuppressive treatment, scientific works dealing with the therapeutic aspects of animals affected by MUE are scarce and are often based on a limited number of cases. Therefore, at present, there are no clear operating procedures, and information about the usefulness of certain drugs is not well proven or describes an experience gained on a limited number of cases. Current treatment guidelines involve the use of corticosteroids at immunosuppressive doses, more or less associated with other immunosuppressive drugs. At the moment it is not possible to assess whether one protocol is better than another due to what has been explained above.

In the first instance the treatment strategy involves the use of prednisone (or prednisolone) used first at immunosuppressive doses and then gradually tapered. Since MUEs are most likely to embody very diverse pathological entities, the response to treatment is extremely variable. Some dogs respond extremely positively to the administration of corticosteroids, with an almost complete recovery of the neurological function and do not relapse when the dosages are reduced or even when the treatment is stopped. Conversely, other animals only show a partial improvement and the results achieved are not maintained when the dosages are reduced. Necrotising meningoencephalitides are the form which responds less well to treatment attempts.

Below is an example of the treatment protocol with prednisone, as described by Schatzberg in the most recent review published on the topic:

  • 1.5 mg/kg twice a day for three weeks;
  • 1.0 mg/kg twice a day for six weeks;
  • 0.5 mg/kg twice a day for three weeks;·0.5 mg/kg once a day for three weeks;
  • 0.5 mg/kg once every two days indefinitely (this dosage can be further reduced to 0.25 mg/kg).

Various chemotherapeutic drugs have been used alongside corticosteroids, with the aim of maintaining adequate immunosuppression by using the minimum effective dose of steroids. Relapses should be treated aggressively because they do not always respond to drugs.  In literature, it is possible to find reports on the clinical use of cytosine arabinoside, procarbazine, cyclosporine, lomustine and mycophenolate mofetil.

Cytosine arabinosideis administered at a dose of 50 mg/m2 every 12 hours subcutaneously for two consecutive days and at intervals of 3-6 weeks, indefinitely. Reported survival times are extremely variable, but it is commonly thought that the prednisone-cytosine arabinoside cocktail is one of the most effective, also encouraged by the limited number of reported side effects.

Procarbazineis administered orally at a dose of 25-50 mg/m2 once a day. Reported side effects include nausea, vomiting, myelosuppression and liver disorders.

Cyclosporine has been used as monotherapy for MUE at a dosage of 6 mg/kg per os twice a day based upon its suppressive action on cell-mediated immunity. Dose-dependent vomiting and diarrhoea have been reported. The combined use of cyclosporine and ketoconazole (at a dosage, respectively, of 5 mg/kg once a day and 8 mg/kg once a day per os) allows a reduction in treatment costs. The microemulsion formulation of cyclosporine is preferred.

The use of lomustine seems justified by the results of two studies presented at a conference. The proposed dose was 40-60 mg/m2per os every six weeks repeated several times. Information on mycophenolate mofetil is even more limited.

In summary, the use of immunomodulating drugs to be used in association with prednisone still needs to be sufficiently documented both from the perspective of treatment protocols and its actual effectiveness. It is hoped that a rigorous double-blind trial will soon be conducted which will include different centres of reference and will assess the real effectiveness of the various proposed treatment protocols.

 

 

Suggested readings

  1. Adamo PF, Adams WM, Steinberg H.::  Granulomatous meningoencephalomyelitis in dogs - Compend Contin Educ Vet. 2007 Nov;29(11):678-90.
  2. Coates JR, Barone G, Dewey CW, et al.: Procarbazine as adjunctive therapy for treatment of dogs with presumptive antemortem diagnosis of granulomatous meningoencephalomyelitis: 21 cases (1998–2004). J Vet Intern Med 2007;21:100–6.
  3. Cherubini G, Platt S, Anderson T, et al.: Characteristics of magnetic resonance images of granulomatous meningoencephalomyelitis in 11 dogs. Vet Rec 2006; 159; 110-5
  4. Flegel T, Henke D, Boettcher IC, Aupperle H, Oechtering G, Matiasek K: Magnetic resonance imaging in histologically confirmed pug dog encephalitis -Radiology & Ultrasound, Vol. 49, No. 5, 2008, pp 419–424.
  5. Granger N, Smith PM, Jeffery ND: Clinical findings and treatment of non-infectious meningoencephalomyelitis in dogs: a systematic review of 457 published cases from 1962 to 2008 - http://www.ncbi.nlm.nih.gov/pubmed/19410487Vet J. 2010 Jun;184(3):290-7
  6. Higgins RJ, LeCouteur RA: GME, NME, and breed-specific encephalitis and allied disorders: variations of the same theme or different diseases? A clinical and pathological perspective. In: 20th Annual Symposium of the European College of Veterinary Neurology. Bern (Switzerland) 2007. p. 35–37
  7. Munana KR, Luttgen PJ: Prognostic factors for dogs with granulomatous meningoencephalomyelitis: 42 cases (1982–1996). J Am Vet Med Assoc 1998;212: 1902–6.
  8. Schatzberg SJ: Idiopathic Granulomatous and Necrotizing Inflammatory Disorders of the Canine Central Nervous System - Vet Clin North Am Small Anim Pract. 2010 Jan;40(1):101-20
  9. Schwab S, Herden C, Seeliger F, Papaioannou N, Psalla D, Polizopulou Z, Baumgärtner W.: Non-suppurative meningoencephalitis of unknown origin in cats and dogs: an immunohistochemical study http://www.ncbi.nlm.nih.gov/pubmed/17275833J Comp Pathol -2007 Feb-Apr; 136(2-3):96-110.
  10. Suzuki M, Uchida K, Morozumi M, et al.: A comparative pathological study on canine necrotizing meningoencephalitis and granulomatous meningoencephalomyelitis. J Vet Med Sci 2003;65:1233–9.
  11. Talarico LR, Schatzberg SJ: Idiopathic granulomatous and necrotising inflammatory disorders of the canine central nervous system: a review and future perspectives http://www.ncbi.nlm.nih.gov/pubmed/19814766J Small Anim Pract. 2010 Mar;51(3):138-49..
  12. Tipold A: Diagnosis of inflammatory and infectious diseases of the central nervous system in dogs: a retrospective study. J Vet Intern Med 1995;9:304–14.
  13. Vite CH: Inflammatory Diseases of the Central Nervous System. In: Braund’s Clinical Neurology in  Small Animals: Localization, Diagnosis and treatment, Ed: International Veterinary Information Service, Ithaca NY (www.ivis.org), 2005
  14. Zarfoss M, Schatzberg SJ, Venator K, et al.: Combined cytosine arabinoside and prednisone therapy for meningoencephalitis of unknown aetiology in 10 dogs. J Small Anim Pract 2006;47:588–95.