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Review Article: Diagnosis and Management of Inflammatory CNS Disease

Introduction

Inflammatory CNS disease comprises a range of conditions which can prove challenging to both diagnose and manage effectively.  Presenting signs are often vague and shifting in character, particularly in the early stages of the disease.  A variety of possible primary causes should be considered;

fig.1 - transverse T2W MR-scan of cat skull showing left-sided subdural empyema

Infectious

  • Bacterial e.g. discospondylitis, subdural empyema, extension of septic process – e.g. otitis interna, cat bite abscess (see figs. 1 & 2)
  • Iatrogenic/ nosocomial – e.g. post CSF tap/ surgery
  • protozoal – e.g. Toxoplasma, Neospora
  • Viral – e.g. Distemper, FIP
  • Arthropod-bourne – e.g. Lyme disease, erlichiosis
  • Fungal (rare in UK, but aspergillus may erose through cribiform plate to affect meninges overlying frontal lobes).
Non-infectious
  • Sterile/ Steroid responsive meningitis/ encephalititis/myelitis/ arteritis (see figs.3 & 4).
  • Post ischaemic/ concussive malacia
  • Idiopathic – e.g. trigeminal neuritis

However, timely diagnosis and aggressive treatment can often achieve excellent outcomes.

History & Clinical Signs

fig.2 - intraoperative photograph showing tooth-hole through parietal bone of skull, resulting in CNS infection

As with any disease process involving the central nervous system, signs vary according to the location (solitary lesion, diffuse or multifocal), severity, and speed of onset, as well as the current health status of the patient.  The majority of inflammatory conditions typically have an insidious onset, with a non-linear progression.  However, ‘acute-on-chronic’ situations (e.g. bacterial infection, see figs. 1 & 2) may have an acute or per-acute presentation.  On close questioning however, owners often recollect previous, milder episodes such as subtle changes in behaviour, not necessarily attributable to CNS disease at that time.

Overall, infectious causes are relatively rare in the small animal population; the majority of cases are found to be sterile at presentation.  However, this still leaves open the possibility that there are (or were) unidentified primary agents not detected on routine bacteriology, cytology or serology. 

In summary, inflammatory CNS disease should be considered as a differential diagnosis in any animal presenting with neurological deficits or unexplained pain once non-neurological causes have been eliminated – see list of examples below:

Some differential diagnoses of

CNS inflammatory disease:

  • Metabolic – e.g. Hepatic encephalopathy, azotaemia, hypocalcaemia, Addison’s, etc.
  • Orthopaedic – e.g. bilateral laemenss (CCL), polyarthropathy
  • Cardiovascular – e.g. shock, anaemia, iliac thrombus
  • Peripheral neuropathy/ neuromuscular disease – e.g. masticatry myositis, distal denervating disease, myesthenia, dysautonomia
  • Toxic – e.g. tetanus, botulism, methaemaglobinaemia, carboxyhaemaglobinaemia
  • Referred pain – e.g. abdominal (urolithiasis, chronic pancreatitis, prostatitis).
  • Neoplastic – e.g. lymphoma, meningioma,neurofibroma, malignant peripheral nerve sheath tumour, metastatic disease

 

Diagnosis

fig.3 - transverse T2W MR-scan of brain showing patchy inflammation of brain tissue

Aside from routine work-up (history, clinical examination, complete blood counts, urinalysis, coagulation, thyroid/ liver function testing), the mainstay for the diagnosis of inflammatory conditions is MRI (T2W + fat suppression sequences – e.g. STIR – are most useful) and CSF analysis.

Ideally, MR-scanning to check for evidence of raised intracranial pressure (cerebellar coning) should be performed prior to CSF collection to reduce the risk of respiratory arrest secondary to brainstem herniation.  If this complication is encountered, IPPV and mannitol administration should be considered. 

Gross examination of CSF is not sufficient to rule out increased cell counts, and samples should be submitted for detailed analysis as a routine in every non-surgical CNS case. Frustratingly, some cases of sterile inflammatory CNS disease may show minimal or non-specific changes on MR-scanning and/ or CSF analysis.  Antemortem diagnosis of meningoencephalomyelitis of unknown aetiology (MUA) and related disorders is therefore sometimes based on excluding other causes of disease and assessment of the patient’s response to trial therapy.

Treatment

fig.4 - Sagittal T2W MR-scan of cervical spinal cord showing increased signal within cord substance - diagnosis MUA

For infectious causes, antimicrobials should be used at the correct dose (e.g. protozoal infections may require clindamycin at up to 25mg/kg q12h for 7 days), based on the results of sensitivity/ serological testing of CSF/ tissue samples obtained surgically.  Acute presentation may necessitate initial broad-spectrum cover, based on drugs known to have good CNS distribution (e.g. trimethoprim-sulphonamide at 15 mg/kg q8h) or a choice based on likely in vivo sensitivity (e.g. cat-bite abscesses usually grow Pasteurella).  Treatment of MUA can be challenging, given the problems with achieving a definitive diagnosis in some cases, combined with the potential side-effects and idiosyncratic response to particular drugs in the individual patient.  Numerous regimes have been proposed, all of which focus on immunosuppression.  Steroids, cyclosporine, cytosine arabinoside (cytarabine), azathioprine and cyclophosphamide have all been use with varying degrees of success. 

Following the ‘cascade’ principle of prescribing licensed drugs, we would consider using prednisolone as a first-line treatment, at doses of 0.5-2.0mg/kg divided, q24h P.O. This can be used as a sole agent, or combined with other drugs, such as cytarabine 50mg/m2 q12h S.C. for four doses, azathioprine 2mg/kg q24h or cyclophosphamide 50mg/m2 q48h.

In summary, there is no single regime that can be recommended for every case.  Typically, one might expect to see a rapid and sustained improvements in clinical signs; if no response is seen, the diagnosis should be revisited, and consideration given to alternative drugs.  

Where a favourable response has been achieved, drugs should be withdrawn slowly over several weeks/ months.  Some animals may experience recurrence of signs on cessation of treatment, and some mat require life-long maintenance therapy.  Sadly, approximately 20% of cases will have a disappointing  response to treatment, necessitating consideration of euthanasia.  However, the majority of cases will respond well and can be very satisfying to treat.

References

Dong-in Jung, et al (2007):  A comparison of combination therapy (cyclosporine plus prednisolone) with sole prednisolone therapy in 7 dogs with necrotizing meningoencephalitis. Journal of Veterinary Medical Science. 69(12):1303-6.

Greene CE (1998): Infectious Diseases of the Dog and Cat 261.

Menaut P, et al (2008): Treatment of 11 dogs with meningoencephalomyelitis of unknown origin with a combination of prednisolone and cytosine arabinoside. The Veterinary Record. 162(8):241-5.

Zarfoss M et al (2006): Combined cytosine arabinoside and prednisone therapy for meningoencephalitis of unknown aetiology in 10 dogs. Journal of Small Animal Practice. 47(10):588-95.