2012).
Acute post-encephalitic seizures (PES), defined by the International League Against Epilepsy (ILAE) as seizures occurring within 7 days of an acute central nervous system (CNS) infection, have been reported in 2–67% of patients with encephalitis. Late (>7 days) PES usually develop within the first 5 years following encephalitis, but can occur up to 20 years later. The pathogen causing the encephalitis appears important in predicting the likelihood of later developing post-encephalitic epilepsy (PEE). Studies from Western industrialized countries show that patients with encephalitis are overall about 16 times more likely than the general population to develop late PES (Michael and Solomon, 2012). Data on incidence and risk factors for encephalitis-associated seizures are unavailable in veterinary medicine.
Several potential pathophysiologic mechanisms can explain the development of seizures in patients with encephalitis. Experimental evidence indicates a significant role for inflammatory and immune mediators in initiation of seizures and epileptogenesis (Friedman and Dingledine, 2011; Kramer et al., 2012). The inflammatory response and in particular inflammatory mediators (including cytokines such as interleukins (IL), chemokines, prostaglandins and complement factors) produced by astrocytes and microglia are increasingly recognized to promote excitatory neurotransmitter release and consequent depolarization. These inflammatory mediators can have both acute and long-term effects on seizure threshold (Vezzani et al., 2011; Michael and Solomon, 2012). Glial cells, as well as neurons, can over-express receptors for inflammatory molecules, including receptors for proinflammatory cytokines (e.g. IL-1β, IL-6 and tumour necrosis factor-α), as well as toll-like receptors. Cytokines or prostaglandins can induce post-translational changes in receptor-coupled or voltage-dependent ion channels leading to increased glutamatergic neurotransmission or reduced GABA-mediated effects. Proinflammatory cytokines also can decrease glutamate reuptake by astrocytes and can increase the release of excitatory gliotransmitters by activated glial cells, possibly also contributing to neuronal network hyperexcitability. Long-term effects of inflammatory mediators involve gene transcription of proinflammatory genes, which may perpetuate inflammation in brain tissue, and play a role in alterations in blood–brain barrier (BBB) permeability properties. A compromised BBB in turn contributes to decrease seizure threshold by inducing ionic imbalance in the extracellular milieu, as well as astrocytes and microglia dysfunctions. In addition, recent data suggest that cytotoxic T-cells and antibody-mediated complement activation may have a role in neural tissue degeneration and subsequently epileptogenesis (Bauer et al., 2012).
In people, there is currently no evidence to support prophylactic anti-epileptic treatment in all patients with encephalitis. Patients with encephalitis should be closely monitored and administed AEMs promptly if seizures occur. PEE should be treated similarly to other types of structural epilepsy. People with PEE are frequently refractory to AEMs and may require combination therapy or neurosurgery to attempt to control seizures (Michael and Solomon, 2012).
Diagnostic investigations
Haematology may sometimes provide evidence of systemic infection (e.g. alterations in white blood-cell count), and serum biochemistry may reveal changes consistent with involvement of other organs. Cerebrospinal fluid analysis often reveals increased white blood-cell (WBC) count (pleocytosis) and increased protein concentration. CSF pleocytosis has been classified as mild (6–50 WBC/μl), moderate (51–200 WBC/μl), or marked (>200 WBC/μl), and as mononuclear, neutrophilic, eosinophilic, or mixed based on the predominant cell type on cytological examination (Tipold, 2003).
The type of CSF pleocytosis may be suggestive of a particular aetiology or disease group (Table 5.2).
CSF may be normal when the CNS inflammation does not involve the leptomeninges or the ependymal lining of the ventricular system or if the animal has been treated with anti-inflammatory medications (particularly corticosteroids) prior to CSF collection. Additional tests on CSF (such as polymerase chain reaction (PCR), antibody or antigen titres, immunofluorescence and culture) can help to reach an aetiologic diagnosis. Occasionaly, certain microorganisms (e.g. bacteria, Ehrlichia morulae, fungi, protozoa or parasites) can be visualized on CSF cytology.
Table 5.2. Cerebrospinal fluid characteristics of canine and feline inflammatory CNS disease.
| Disease | Type of pleocytosis | Total protein concentration |
| Viral meningoencephalitis (CDV or other; FIP excluded) | None or mild to moderate mononuclear | Normal to markedly elevated |
| FIP meningoencephalitis | Moderate to marked neutrophilic or mixed, occasionally eosinophilic | Markedly elevated |
| Rickettsial meningoencephalitis | Mild to moderate mononuclear or mixed. Can be neutrophilic with granulocytic ehrlichiosis or anaplasmosis | Mildly to markedly elevated |
| Bacterial meningoencephalitis | Moderate to marked neutrophilic (toxic changes in cell morphology) in acute and subacute infections; mixed in chronic infections; sometimes mononuclear following antibiotic treatment | Mildly to markedly elevated |
| SRMA | Moderate to marked neutrophilic in acute SRMA, mononuclear or mixed in chronic SRMA | Mildly to markedly elevated |
| Protozoal meningoencephalitis | Moderate mixed, occasionally eosinophilic, rarely mononuclear | Mildly to markedly elevated |
| Fungal meningoencephalitis | Moderate to marked mixed, occasionally eosinophilic | Markedly elevated |
| Algal (Prototheca) | Moderate to marked mixed or eosinophilic | Markedly elevated |
| Parasitic meningoencephalitis | Mild to moderate mixed, often eosinophilic | Mildly to markedly elevated |
| GME | None or moderate to marked mononuclear or mixed | Mildly to markedly elevated |
| Necrotizing meningoencepahlitis/ leukoencephalitis | Mild to marked mononuclear | Mildly elevated |
| Eosinophilic meningoencephalitis | Mild to marked eosinophilic | Mildly to markedly elevated |
Inflammatory CNS disease can cause increased intracranial pressure (ICP) and CSF collection may be contraindicated due to the risk of cerebral herniation and death. Progression from obtundation to stupor, a diminished or absent vestibulo-ocular reflex, the development of unilateral or bilateral midriasis and loss of the pupillary light reflexes are suggestive of increased ICP and transtentorial brain herniation. Any time increased ICP is suspected, MRI of the brain should be performed before considering CSF collection.
MRI of the brain can reveal changes suggestive of inflammatory CNS disease such as multifocal, diffuse or sometimes focal lesions within the brain parenchyma that typically appear hyperintense on T2-weighted and FLAIR images, iso- to hypointense on T1-weighted images and show variable contrast enhancement sometimes with meningeal involvement following administration of contrast medium. The MRI findings sometimes may support the ante-mortem diagnosis of a particular aetiology (e.g. FIP). The MRI features of various inflammatory CNS diseases have been reviewed (Hecht and Adams, 2010b). Sensitivity and specificity of high-field MRI for classifying brain diseases as inflammatory are 86.0 and 93.1% without provision of clinical data and 80.7 and 95.4% with provision of clinical data, respectively (Wolff et al., 2012). Sensitivity and specificity of high-field MRI are lower for detection of specific inflammatory CNS aetiologies (Wolff et al., 2012).
Treatment
Treatment of CNS infections depends on the identification of the aetiologic agent and selection of the appropriate antimicrobial or anti-fungal agent (see Tables 5.5–5.9). Treatment of viral CNS infections is mostly supportive and symptomatic. Treatment of non-infectious inflammatory CNS disorders involves immunosuppressive medications. Anti-epileptic treatment of both acute and late PES is performed as for other types of structural brain disorders (see section on encephalitic-related seizures, introduction to this chapter and
