Non-infectious inflammatory diseases of the central nervous system in dogs

Transcription

1 Non-infectious inflammatory diseases of the central nervous system in dogs Inflammatory diseases of the CNS present as progressive diseases, often with a collection of neurological deficits reflecting multifocal involvement of the CNS. The most common signalment (middle-aged small-breed dogs, more commonly females) can provide a high index of suspicion, combined with neurological findings, CSF analysis and imaging studies. The prognosis is guarded, and some dogs will deteriorate rapidly despite therapy, while others can live for years with or without medication, which reflects currently our lack of understanding of this group of diseases /coan ??? Darren Carwardine BVSc(Hons) MRCVS Nicolas Granger DVM PhD Dip ECVN MRCVS School of Veterinary Sciences, University of Bristol, Langford House, Langford, North Somerset, BS40 5DU and Langford Veterinary Services Small Animal Hospital. Key words: Dog Neurology Inflammatory Brain Central nervous system Meningoencephalomyelitis corresponds to an inflammation of the central nervous system (CNS). Inflammatory conditions affecting the CNS of dogs are common and include infectious diseases and non-infectious diseases. Infectious causes are rarer in the UK and include infection from viral (e.g. Distemper), protozoal (e.g. Toxoplasma, Neospora), fungal (e.g. Cryptococcus) and bacterial organisms. Non-infectious meningoencephalomyelitis is more common and includes diseases such as granulomatous meningoencephalomyelitis (GME), necrotising encephalitis (NE) and, more rarely reported, eosinophilic encephalomyelitis. Diagnosis of these diseases is based on neuropathological distribution and characteristics of the lesions from examination of CNS tissue. When CNS tissue is not available, these diseases can only be suspected and the diagnosis relies on clinical findings. In these cases, the term meningoencephalomyelitis of unknown origin (MUO) is preferable. Other non-infectious conditions include steroidresponsive meningitis arteritis, which primarily affects the meninges rather than brain parenchyma and will not be covered in this review. We will briefly review in this article MUO, GME and NE. In a practical sense, diagnosis of MUO ante-mortem is based on the history (onset and progression of the disease), signalment of the animal, neurological examination, cerebrospinal fluid (CSF) analysis and advanced imaging studies. Histopathological examination, to further reach a definitive diagnosis, can be made on brain biopsy specimens. Brain biopsy is perfectly feasible for forebrain lesions, but remains an expensive diagnostic test that is not widely available. There is currently no drug of choice to treat MUO, GME or NE, and the treatment is based around immunomodulation. The prognosis remains guarded and the outcome is variable. Some cases have very long periods free of clinical signs (years), while others, although they usually respond to immunomodulation in the first instance, relapse or deteriorate. Definitions Inflammation of the: zmeninges = Meningitis zbrain = Encephalitis zbrain (White Matter) = Leucoencephalitis zbrain (Grey Matter) = Polioencephalitis zspinal Cord = Myelitis zmeninges and Brain = Meningoencephalitis zmeninges and Spinal Cord = Meningomyelitis zmeninges, Brain, Spinal Cord = Meningoencephalomyelitis 198 Companion animal December 2013, Volume 18 No 10

2 Granulomatous meningoencephalomyelitis (GME) Adult (<8 years old) small-breed dogs are largely over-represented, the most commonly reported breeds being Miniature Poodle, Maltese, Dachshund, West Highland White Terrier (Figures 1a, b, d) and Chihuahuas (Granger et al, 2010). Females tend to be at higher risk. Three different forms of GME have been described (Cuddon and Smith-Maxie, 1984; Munana and Luttgen, 1998; Summers et al, 1995): disseminated, focal and ocular. The clinical signs are caused by the development of granuloma-like lesions around blood vessels, leading to focal deficits and diffuse oedema of the white matter. Therefore, neurological deficits depend on the localisation of lesions, which can occur at varied locations within the brain or spinal cord. Ranging from seizures, forebrain signs, cranial nerves deficits and occasionally paresis, plegia and spinal pain (Figure 1c). The disseminated form occurs in one third of cases. The focal form represents the majority of other cases, affecting the forebrain in one third of cases and the brainstem in one third of cases. The spinal cord is rarely the sole part of the CNS involved (in only 5% of the cases) (Granger et al, 2010). Finally, the ocular form remains rarely reported. It presents with acute onset visual impairment. The pupils are typically dilated and unresponsive, and affected cases can have optic disc oedema and chorioretinitis on fundic examination. The ocular form can progress to a disseminated form concomitantly or with time (Braund, 1985; Summers et al, 1995). Necrotising encephalitis (NE) The main two necrotising forms are necrotising meningoencephalitis (NME) and necrotising leukoencephalitis (NLE). These are historically referred to as Pug dog encephalitis (Cordi et al, 1989) and necrotising encephalitis of Yorkshire Terriers (Kuwamura et al, 2002), respectively. The encompassing term NE is commonly used on an ante-mortem basis for cases with typical signalment and presenting signs. NE is strongly breed associated, affecting predominantly the Pug, Yorkshire Terrier, Maltese, Chihuahua, Shih Tzu and Boston Terrier but there are sporadic descriptions of West Highland White Terrier, Papillon, Japanese Spitz and Miniature Pinscher breeds being affected. The age of presentation is typically younger than dogs with GME (<4 years of age). In a series of 60 Pugs with NE (Levine et al, 2008), the median age was 18 months. Both NME and NLE are characterised by inflammation of the subcortical white matter leading to cerebral necrosis. NME predominantly affects the cerebral hemispheres and subcortical white matter whereas NLE predominantly affects the periventricular white matter and brainstem. As a result of this difference in neuropathology, cases of NME present with forebrain signs such as seizures, depression, circling and visual deficits, whereas cases of NLE can present with caudal brainstem signs, such as crainial nerve deficits of neurological examination. Figure 1. Clinical signs in dogs with MUO: (a) A dog exhibiting a right head turn, characteristic of a right forebrain lesion; (b) Same case as in (a) exhibiting a left head tilt (the left ear pinna is lower than the right), characteristic of a vestibular lesion and demonstrating the multifocal aspect of the disease. The left forelimb is also placed outside the normal centre of mass, characteristic of a proprioceptive deficit; (c) a dog exhibiting a lowered head carriage characteristic of neck pain; (d) a dog exhibiting hypermetria of the right hindlimb (black arrow head). This would be a characteristic of cerebellar involvement. Meningoencephalomyelitis of unknown origin (MUO) The common non-infectious inflammatory diseases of the CNS have been discussed above (GME, NE). They require histopathology to be diagnosed. The terminology MUO is used to classify non-infectious inflammatory diseases of the CNS clinically, when histopathological is lacking. Dogs with MUO are usually small, middle-aged (between 4 and 8 years of age), female, and the most commonly affected breeds are: Chihuahua; West Highland White Terrier; and Dachshund. But the breeds cited for GME and NE are affected as well and the difference in signalment between MUO and GME/NE is most likely the lack of histopathological diagnosis. MUO can present with multifocal signs, (40% of the cases) or signs affecting the forebrain alone (15%) or brainstem alone (30%). The cerebellum or spinal cord are rarely affected alone. Clinical approach to GME, NE and MUO As with any neurological condition, the aim of the examination is to answer the following questions: zdoes the patient have a neurological problem? zcan we localise the origin of the neurological problem? zwhat is the most likely differential diagnoses, and which tests are appropriate to investigate the disease? In general terms, inflammatory diseases tend to be: zacute to sub-acute in onset zwaxing and waning (short term) zprogressive (long term) zmultifocal zasymmetrical. Companion animal December 2013, Volume 18 No

3 zvestibular ataxia (asymmetrical loss of balance and incoordination) zconscious proprioceptive deficits (knuckling, paw placement deficits). Cerebellar signs: zabsent menace response zspasticity and tremors zcerebellar ataxia (hypermetria: Figure 1d) Main cranial nerve deficits encountered: zloss of gag reflex zabnormal pupillary light reflexes zabnormal facial sensation (including corneal reflex) and facial movements. Figure 2. MRI of dogs with MUO: (a) dorsal T1W image following intravenous gadolinium (contrast) injection demonstrating a focal hyperintense contrast enhancing lesion in the right cerebral hemisphere (white arrowhead). This is an example of the focal form of MUO; (b) transverse T2W image demonstrating diffuse hyperintensity in the right cerebral hemisphere (white arrowheads), along the white matter tracts; (c) sagittal T2W image demonstrating a hyperintense region in the brainstem (black star) and cervical spinal cord (black arrowhead), illustrating the presence of multifocal lesions throughout the CNS. Animals with inflammatory disease of the CNS do not always present with typical systemic signs of inflammation (e.g. pyrexia, anorexia) or even changes in their leukogram. Therefore, these inflammatory diseases should not be discounted on this basis alone or on normal blood work results. A thorough neurological examination, with particular attention made to the cranial nerve examination is very useful to detect multifocal involvement of the CNS. The history can also help to suspect forebrain involvement, with some owners reporting loss of habits, incontinence, depression, tremors, photophobia, visual impairment, etc. Common clinical signs with GME, NE and MUO The following signs are not specific for inflammatory diseases of the CNS but form the majority of the signs usually encountered. Forebrain signs: zseizures zdepression zcircling (Figure 1a) zhead pressing zvisual deficits Central vestibular signs: zhead tilt (Figure 1b) znystagmus zstrabismus Myelopathic signs: zspinal pain zparesis zplegia. Remember that postural reaction deficits indicate involvement of the nervous system and confirm that the animal has a neurological condition but are not used to localise the origin of the problem. It is only the cranial nerve examination and spinal reflexes that will help to localise the lesions within the CNS. Diagnostic tests for GME, NE and MUO Cerebrospinal fluid (CSF) analysis Cerebrospinal fluid is collected in a sterile manner under general anaesthesia from either the cisterna magna or lumbar region and following imaging of the CNS. It is usually taken from the cisterna magna in suspected cases of MUO, i.e. as close as possible to the lesions. Laboratory analysis is performed on samples to give the: ztotal nucleated cell count (TNCC) (<5 cells/μl), obtained immediately after collection on a fresh sample preserved with EDTA zprotein concentration (this can be sampled in a plain tube and analysed later) zdifferential cell count (this requires cytospin preparation of the CSF in the lab within a few hours of CSF collection). There is a large overlap in CSF abnormalities between GME, NE and MUO. In the majority of cases, the TNCC and protein concentration will be elevated (Figure 3). Lymphocytes are usually the predominant cell type (40 70% of the cases) but monocytes can predominate (especially with NE); more rarely, neutrophils are predominant. These changes in the CSF can occur with other conditions affecting the CNS such as with infectious conditions (e.g. Distemper, Neospora, etc.). Unfortunately, in one review, 22% of MUO cases had a normal TNCC and 16% of histopathologically confirmed GME cases had a normal TNCC (Granger et al, 2010). This highlights the need to interpret CSF findings along with the neurological examination and other diagnostics. On the basis of an inflammatory CSF, common practice is to rule out infectious diseases using a range of PCRs and serology on serum and CSF. The panel can, for example, include serology for Toxolplasma and Neospora, Cryptococcus and PCR 202 Companion animal December 2013, Volume 18 No 10

4 on CSF for Distemper. This largely depends on geographical variations. If a bacterial cause is suspected (e.g. large number of neutrophils on CSF analysis) then CSF culture has to be considered. Imaging: Magnetic Resonance Imaging (MRI) versus Computed Tomography (CT) MRI remains the most reliable way to image intracranial structures. CT can provide imaging of intracranial structures but the parenchymal detail is less than with MRI and CT suffers from artifacts caused by the bony calvarium, especially in the region of the brainstem. The neuropathology caused by the non-infectious inflammatory CNS diseases often allows pathological lesions to be viewed within the CNS. Intraparenchymal lesions appear hyperintense on T2-weighted images and often, but not always, take up contrast medium following intravenous injection. The lesion distribution can be multifocal or focal, affecting the forebrain, brainstem, cerebellum and spinal cord. T2-weighted images often also reveal white matter oedema. The Fluid attenuated inversion recovery (FLAIR) MRI image acquisition sequence is useful in demonstrating the presence of multifocal CNS lesions. Contrast uptake of the meninges can also be seen. NE cases usually have multifocal asymmetrical cortical cystic lesions that are hyperintense on T2-weighted images. This corresponds with the cortical necrosis seen on histopathology. CT images can show contrast enhancement of intra-parenchymal lesions, although again, contrast uptake is not always detected. The contrast uptake tends to be diffuse for the inflammatory diseases, and in an intra-axial location as opposed to discrete contrast uptake and extra-axial for example in a meningioma. MRI is more sensitive than CT at detecting these lesions (especially if small) and remains the gold standard imaging technique. This is mainly because of its superiority in imaging the brainstem and cerebellum due to osseous structures covering these regions interfering with CT images. Treatment of GME, NE and MUO The mainstay of treatment is immunomodulation: GME and NE are suspected to be immune-mediated diseases with still unknown triggers. Corticosteroids remain the most reliable treatment modality but the best option for long-term survival is still being investigated. Box 1 outlines some different treatment options that have been used. Proposed prednisolone treatment protocol: z2 mg/kg twice a day for three weeks z1.5 mg/kg twice a day for three weeks z1.0 mg/kg twice a day for three weeks z0.5 mg/kg twice a day for three weeks z0.5 mg/kg once a day for three weeks z0.5 mg/kg every other day up until six months following therapy start date. Medication is stopped at this stage and cases are monitored for signs of recurrence. Figure 3. CSF from cases of MUO (a) a macroscopic sample of xanthochromic (yellow colour) CSF. This can be caused by the breakdown of red blood cells in CSF releasing bilirubin and in the presence of inflammation within the CNS; (b) microscopic view of CSF; there is a marked pleocytosis with lymphocytes, monocytes and neutrophils present This protocol can be started on its own or in combination with a second immunomodulating drug, given orally, intravenously or injected into the CSF (from one author (NG) personal experience). To date, there is no set guideline as to which treatment can provide the best outcome. However, it has recently been suggested that finding an abnormal CSF analysis and presence of MRI lesions three months into treatment is associated with an increased chance of relapse (Lowrie et al, 2013). Prognosis of GME, NE and MUO The prognosis for GME and NE is thought to be guarded to poor without adequate treatment. There have been multiple studies to try and establish the prognosis with varying treatment protocols, including corticosteroids +/- a second immunosuppressive agent, but most of them are observational (for a review, see Granger et al, 2010 and Talarico and Shatzberg, 2009). The survival times in studies vary from 1 day to 2469 days. It is this variability in survival times that makes predicting the course of the disease very difficult. Most studies performed will not have achieved a histopathological diagnosis, Box 1. Published treatment modalities for dogs with GME, NE or MUO (for a review see Granger et al, 2010 and Talarico and Shatzberg, 2009) Published treatment modalities zcorticosteroids zcorticosteroids + cyclosporine zcorticosteroids + lomustine zcorticosteroids + cytarabine zcorticosteroids + procarbazine zcorticosteroids + mycophenolate zcorticosteroids + leflunomide zcorticosteroids + azathioprine zcorticosteroids + radiation therapy Companion animal December 2013, Volume 18 No

5 which renders comparison of the studies difficult since the cohort of cases might be composed of different subtypes of inflammatory CNS disease. This is a limitation of clinical studies in general, where collection of pathological specimens is difficult. It is the authors experience that some cases respond well to initial corticosteroid treatment alone and can go on for many years, sometimes without the need for further immunosuppression. Some cases on the other hand will continue to acutely deteriorate and are often euthanised within the first week of presentation. This has recently been outlined by Lowrie and colleagues (2013) who reported that most dogs with a poor outcome deteriorated within 52 days. Stereotactic biopsy A technique that has received much interest in dogs with MUO is stereotactic biopsy of the CNS. This involves taking a sample of CNS tissue via a minimally invasive technique guided by advanced imaging modalities such as CT or MRI (Flegel et al, 2012; Troxel and Vite, 2008). It allows for a definitive ante-mortem diagnosis to be achieved, which can give more accurate prognostic information and guide treatment decisions for each individual case. Collecting samples prior to initiation of treatment will also allow direct comparison of similar cases with varying treatments, and is likely to guide future decisions on the most effective treatments for cases of GME or NE. The procedure comes with significant risks and is limited to biopsy of the forebrain. Attempting to biopsy the brainstem carries a too high risk of causing iatrogenic damages. Darren Carwardine is sponsored by the Elisabeth Blackwell Institute for Health Research, University of Bristol, and the Langford Trust and Nicolas Granger is sponsored by the Kennel Club and PetPlan Charitable Trust. References Cordy DR, Holliday TA (1989) A necrotizing meningoencephalitis of pug dogs. Vet Pathol 26(3): Cuddon P, Smith-Maxie L (1984) Reticulosis of the central nervous system in the dog. Compend Contin Educ Vet 6: 23 9, 32 3 Flegel T, Boettcher IC, Matiasek K et al (2011) Comparison of oral administration of lomustine and prednisolone or prednisolone alone as treatment for granulomatous meningoencephalomyelitis or necrotizing encephalitis in dogs. J Am Vet Med Assoc 238(3): Flegel T, Oevermann A, Oechtering G et al (2008) Diagnostic yield and adverse effects of MRI-guided free-hand brain biopsies through a mini-burr hole in dogs with encephalitis. J Vet Intern Med 26(4): Granger N, Smith PM, Jeffery ND et al (2010) Clinical findings and treatment of noninfectious meningoencephalomyelitis in dogs: A systematic review of 457 published cases from 1962 to Vet J 184(3): Levine JM, Fosgate GT, Porter B et al (2008) Epidemiology of necrotizing meningoencephalitis in Pug dogs. J Vet Intern Med 22(4): Kuwamura M, Adachi T, Yamate J et al (2002) Necrotising encephalitis in the Yorkshire terrier: a case report and literature review. J Small Anim Pract 43(10): Lowrie M, Smith PM, Garosi L et al (2013) Meningoencephalitis of unknown origin: investigation of prognostic factors and outcome using a standard treatment protocol. Vet Rec 172(20): 527 Muñana KR, Luttgen PJ (1998) Prognostic factors for dogs with granulomatous meningoencephalomyelitis: 42 cases ( ). J Am Vet Med Assoc 212(12): Summers BA, Cumings, JF., De Lahunt A (1995) Veterinary Neuropathology. Mosby, St. Louis, MO, USA Talarico LR, Schatzberg SJ (2009) Idiopathic granulomatous and necrotising inflammatory disorders of the canine central nervous system: a review and future perspectives. J Small Anim Pract 51(3): Troxel MT, Vite CH (2008) CT-guided stereotactic brain biopsy using the kopf stereotactic system. Vet Radiol Ultrasound 49(5): KEY POINTS zgranulomatous meningoencephalomyelitis (GME) commonly affects small breed female dogs under 8 years of age zthree different forms of GME exist: disseminated; focal and ocular znecrotising encephalitis commonly affects small breed dogs under 4 years of age and Pugs are over represented zmeningoencephalomyelitis of unknown origin (MUO) is the appropriate term for suspected cases of GME, NE or other causes of non-infectious meningoencepahlomyelitis when no histopathology is available zmagnetic resonance imaging (MRI) and Cerebrospinal fluid (CSF) analysis are the most useful diagnostic tests available on an ante mortem basis Continuing Professional Development In order to test your understanding of this article, answer these multiple choice questions, or if you are a subscriber, go online at and find many more multiple choice questions to test your understanding. Adjunctive tests 1. Which anatomical structure is affected in cases with steroid responsive meningitis arteritis (SRMA)? a. Brain parenchyma b. Meninges c. Spinal Cord d. Brain parenchyma and spinal cord 2. Which of the following are non-infectious causes of meningoencephalomyeltis? a. Granulomatous meningoencephalomyelitis b. Necrotising meningoencephalitis c. Necrotising leukoencephalitis d. All of the above 3. Meningoencephalomyelitis describes inflammation of the: a. Brain and spinal cord b. Meninges and Brain c. White matter of the brain and meninges d. Brain, spinal cord and meninges For answers please see page??? Call for papers Companion animal welcomes the submission of articles, please contact jessica.daniels@markallengroup.com Companion animal December 2013, Volume 18 No 10