Emergency and Critical Care of the Veterinary Patient with Acute Brain Inflammation

The term for inflammation of brain parenchyma is encephalitis, which can develop on its own or concurrently with inflammation of other tissues within the central nervous system (CNS). For example, inflammation of the meninges is called meningitis; inflammation of the spinal cord is called myelitis; inflammation of the brain, spinal cord, and meninges is called meningoencephalomyelitis. This article will focus on multiple aspects of acute brain inflammation and will use meningoencephalomyelitis as an all-encompassing term.

Etiologies of Meningoencephalomyelitis

The most common causes of meningoencephalomyelitis are immune-mediated and infectious agents, with neoplastic causes being the least common (FIGURE 1).

Figure 1. Etiology tree of the various causes of acute brain inflammation. Immune-mediated causes are described for dogs only. Immune-mediated causes are exceedingly rare and not as well understood or classified in cats.

Immune-Mediated Causes

The noninfectious causes of meningoencephalomyelitis are characterized by nonsuppurative inflammation of the CNS. These are suspected to be immune-mediated in origin though the pathogenesis is most likely multifactorial. Breed, age, exposure to (or lack of) infectious agents, familial inheritance, and environmental factors are presumed to be contributing factors. The most common forms of immune-mediated meningoencephalomyelitis are often referred to as meningoencephalomyelitis of unknown origin/etiology (MUO/MUE). Some examples of MUO/MUE include granulomatous meningoencephalitis, necrotizing meningoencephalitis, and necrotizing leukoencephalitis. Other forms of immune-mediated inflammatory conditions of the CNS include steroid-responsive meningitis–arteritis, eosinophilic meningoencephalitis, and corticosteroid-responsive tremor syndrome. These conditions are well documented in dogs but are exceedingly rare and not well understood or classified in cats.

Each of these forms of immune-mediated brain inflammation has its own unique features and histopathologic findings. Female toy and terrier breeds, approximately 3 through 6 years of age, tend to be the most commonly diagnosed with MUO/MUE. However, any breed, sex, or age can be affected. An antemortem diagnosis of MUO/MUE is made by evaluating signalment, history, and clinical findings—specifically magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) analysis in combination with negative infectious disease screening. Histopathologic evaluation of neuroparenchymal tissue is necessary for a definitive diagnosis.^1-3

Infectious Causes

A myriad of infectious agents has been associated with causing meningoencephalomyelitis:  bacterial, fungal (e.g., Cryptococcus, Aspergillus), viral (e.g., rabies, canine distemper virus, pseudorabies, canine herpes virus), protozoal (e.g., Toxoplasma gondii, Neospora caninum, Sarcocystis), rickettsial (e.g., Rickettsia rickettsii, Ehrlichia canis, Anaplasma platys), and verminous (e.g., Cuterebra, Taenia solium, Dirofilaria). Collecting a thorough medical history that includes vaccination status, travel history, exposure to other animals, and diet (including indiscretions) is essential for these cases. A patient with an infectious cause of meningoencephalomyelitis may display similar clinical signs as a patient with MUO/MUE. MRI findings can be similar as well, yet some findings such as intracranial abscessation or empyema can be strong indicators of infection. Occasionally, patients with infectious causes of meningoencephalomyelitis are febrile and/or have CBC abnormalities. Many of these patients experience a rapid decline in their health and need critical care.^1,2

Neoplastic Causes

Occasionally, patients with lymphosarcoma will display similar clinical signs and advanced imaging findings as patients with meningoencephalomyelitis. Sometimes, neoplastic cells can be observed in CSF if they have exfoliated well enough. Ultrasonography of the spleen, kidneys, and abdominal lymph nodes can be useful. Regional lymph nodes, if enlarged or abnormal, can be aspirated to obtain a diagnosis through cytology. Patients with lymphosarcoma of the CNS have a poor to grave prognosis. Other tumors of the brain, such as histiocytic sarcoma, can cause meningitis but tend to have additional advanced imaging findings that are consistent with mass formation, thus making meningoencephalomyelitis unlikely as the primary diagnosis.^4,5

Clinical Signs of Meningoencephalomyelitis

A patient with acute brain inflammation can display a wide variety of clinical signs, some of which indicate a more urgent concern. The clinical signs of meningoencephalomyelitis depend on the part of the CNS that is affected and are often separated into 2 categories—forebrain (cerebrum, thalamus) and hindbrain (cerebellum, brainstem). The brainstem is the site of decussation (where neuronal pathways cross over) for the majority of the forebrain, thus leading to contralateral neurologic deficits. Contrarily, hindbrain lesions are anatomically caudal to this major site of decussation, leading to ipsilateral neurologic deficits.

Clinical signs of forebrain lesions include seizures, circling/pacing, visual deficits, behavior changes (e.g., dementia, mania), and proprioceptive deficits (contralateral). Clinical signs of hindbrain lesions include vestibular or cerebellar ataxia, mentation changes (e.g., dull, obtunded, semicomatose, comatose), nystagmus, head tilt, proprioceptive deficits (ipsilateral), facial paralysis, and pharyngeal/laryngeal changes (e.g., dysphonia, laryngeal paralysis, dysphagia, lingual paresis).⁶

Patients with meningoencephalomyelitis often have multifocal lesions or diffuse disease and, therefore, a combination of the clinical signs listed above. If clinical signs indicate a multifocal neurolocalization, meningoencephalomyelitis should be considered.

Seizures

Seizure activity can have many different appearances, and keen monitoring is an important component of care. Generalized seizure activity can include loss of consciousness, tonic-clonic movements, urination, defecation, salivation, jaw movement, and/or jaw clenching. However, these are not the only signs of seizure activity. If a patient’s seizure activity is focal (e.g., left-sided facial twitching), this may be more difficult to detect. Documentation of a patient’s specific signs of seizure activity on cage cards, treatment sheets, and/or electronic care boards can be very helpful to effectively communicate across shifts and among staff. Bells may be placed loosely around a patient’s neck to serve as a helpful auditory indicator of distress or seizure activity. An immediate intervention plan (e.g., “midazolam 3 mg [0.6 mL] IV in the event of seizure”) should be displayed on cage cards, treatment sheets, and/or electronic care boards to enable any clinical staff member to intervene if the attending clinician is unavailable.

The first occurrence of seizure activity is considered an emergency, and the patient should be immediately evaluated. A single seizure less than 2 to 3 minutes in duration with a short postictal period may not be life threatening. Cluster seizures, defined as multiple seizures in a 24-hour period with a return to normal behavior between seizures, are considered an emergency that necessitates immediate care. Status epilepticus, defined as seizure activity longer than 5 minutes in duration or multiple seizures in a row without return to normal behavior between seizures, is also considered an emergency. Status epilepticus is life threatening without immediate intervention, and medical intervention is most likely required to stop seizure activity.^7,8

Mentation Changes

Mentation is defined as a level of consciousness and is mediated by the ascending reticular activating system (ARAS) of the brainstem. Mentation should not be confused with behavior, which is defined as learned patterns that are stored and enacted by the cerebrum. The brain is entirely enclosed by a rigid skull with merely 1 place for pressure to be released, the foramen magnum. Therefore, inflammation of the brain can lead to increased intracranial pressure (ICP), which can be life threatening. Inflammation of the brain can also lead to swelling of the parenchyma, formation of edema, and obstruction of CSF outflow—all of which increase ICP. The ARAS can also be directly affected by inflammation without having concurrently elevated ICP. The brain can compensate for a slight increase of ICP. When the brain can no longer compensate for increased ICP, the ARAS becomes physically inhibited by pressure and the patient’s mentation will change.⁹

Changes in mentation can indicate significant increases of ICP and mandate close monitoring. Scales, such as the modified Glasgow Coma Scale, can be used to remove subjectivity and bias (TABLE 1). A simpler mentation scale can also be used to monitor changes (TABLE 2). A hospitalized patient with CNS dysfunction should be closely monitored for changes in mentation at least every hour, if not more frequently. The attending clinician should be informed immediately of any changes in mentation.

The Cushing’s Response and Cushing’s Triad

Other indicators of increased ICP are the Cushing’s response and Cushing’s triad. Cushing’s response is a physiologic compensatory response to increased ICP characterized by increased blood pressure (systolic > 160 mm Hg) and bradycardia (< 60 beats per minute in dogs, < 130 beats per minute in cats). This physiologic response of increased blood pressure and reflex bradycardia is an effort by the body and brain to maintain adequate cerebral perfusion pressure and cerebral blood flow. Cushing’s triad is described as a Cushing’s response with an abnormal respiratory pattern (e.g., ataxic respirations, Cheyne–Stokes) and serves as a dire indicator of severely elevated ICP and imminent brain herniation and/or respiratory arrest. Ataxic respiration is characterized by an irregular rate, rhythm, and depth of breaths and is the respiratory pattern typically associated with brainstem compromise. Cheyne–Stokes respiration is characterized by cycles of increasing and decreasing tidal volume with periods of apnea between cycles. This abnormal respiratory pattern is typically associated with severe cerebral disease yet can also indicate elevated ICP.^10,11

Diagnostics for Meningoencephalomyelitis

Before advanced diagnostics are performed, thorough physical and neurologic exams are necessary. A CBC and serum chemistry (including electrolytes) are also essential. Thoracic radiographs may be considered before anesthesia in older patients or patients of which underlying cardiac disease is a concern (echocardiogram may also be indicated for these patients). MRI, combined with CSF analysis, is the gold standard for diagnosing meningoencephalomyelitis.

MRI Findings

Many CNS diseases have the same MRI findings, and these findings do not differentiate the underlying causes of immune-mediated, infectious, or neoplastic meningoencephalomyelitis. However, a few specific MRI findings can differentiate the underlying cause. For example, cribriform plate involvement is typically seen with fungal encephalitis. Inflammation that extends from the inner and middle ear structures into the brainstem may indicate otogenic meningitis, which is often bacterial (FIGURE 2).^1,2,12

FIGURE 2. Sagittal T2-weighted magnetic resonance image of a canine brain with hyperintensity of the olfactory bulb and involvement of the cribriform plate (arrow). There is also severe ventriculitis resulting in obstructive hydrocephalus. This patient had cryptococcal meningoencephalomyelitis, diagnosed by cerebrospinal fluid analysis and latex agglutination of cryptococcal antigens.

The following MRI findings are typically seen with meningoencephalomyelitis:

• Lesions of the neuroparenchyma are usually multifocal, involving the forebrain and hindbrain regions, and can also be seen across the left and right brain hemispheres.
• Lesions are irregularly shaped with ill-defined margins.
• Concurrent meningeal contrast enhancement is common and indicates meningitis.
• Lesions can have uniform hyperintensity on specific MRI sequences (T2 weighted and fluid-attenuated inversion recovery).
• Lesions will be isointense or hypointense on specific MRI sequences (T1 weighted).
• Mass effect is not commonly associated with these lesions.
• Lesions are not strongly contrast enhancing (mild, incomplete contrast enhancement is occasionally noted).

Cerebrospinal Fluid Analysis

CSF analysis is an essential diagnostic tool for confirming meningoencephalomyelitis. CSF is collected by passing a spinal needle through the atlanto-occipital junction into the cerebellomedullary cistern or into the thecal sac, where CSF gathers at the end of the spinal cord. Lumbar puncture is typically performed between L4 and L5 in large dogs and L5 and L6 in smaller dogs or cats. CSF reference ranges vary according to the area of collection (TABLE 3).^1,2,4

Some cases of meningoencephalomyelitis will not exfoliate cells into the CSF, and CSF analysis can be within normal limits. If a primary autoimmune disease is the cause of meningoencephalomyelitis, CSF analysis will often detect a mild to markedly elevated white blood cell count, called pleocytosis. Mild to markedly elevated total protein can also be noted within the CSF. The various forms of MUO/MUE can trend towards certain types of pleocytosis and total protein levels (TABLE 4). For infectious causes, pleocytosis is typically marked to severe with a similarly severe elevation of total protein. Infectious agents may be seen via CSF analysis, which is confirmatory for the infectious disease.^1,2,13

Treatment of Meningoencephalomyelitis

Although treatment is dependent upon the cause of brain inflammation, general treatment considerations include minimizing inflammation (typically with glucocorticoids) and mediating neurologic manifestations (e.g., seizures, increased ICP).^1,2 Infectious causes also require treatment of the infectious agent itself, if the causative agent can be identified and a targeted therapy exists.

Glucocorticoid therapy (usually prednisone or dexamethasone) is a mainstay of treating brain inflammation as glucocorticoids can mediate and suppress an immune response as well as reduce inflammation. The dose, ranging from immunosuppressive to anti-inflammatory, is determined by the underlying cause of inflammation and clinician preference. Glucocorticoid therapy may be initiated at the time of diagnosis and can be used as a monotherapy for the treatment of MUO/MUE or as 1 component of a multimodal treatment plan if the disease is severe or there are significant glucocorticoid side effects.^1,2,14

Other immunomodulating drugs (e.g., cytarabine [cytosine arabinoside], mycophenolate, leflunomide, azathioprine, cyclosporine) may be used concurrently; however, reports of their effectiveness have been evaluated only by small-scale studies.

Hyperosmolar agents can be used to treat increased ICP in addition to glucocorticoids.^1,2 Hypertonic saline (e.g., 3% NaCl, 7.2% NaCl, 23.4% NaCl) is a hyperosmolar agent that causes immediate expansion of the intravascular spaces by creating a change in the osmotic gradient of the vasculature, thus drawing water out of the interstitial spaces and into the intravascular spaces. In the brain, this movement of water from the extracellular spaces into the vasculature encourages a reduction of cerebral edema and, thereby, reduces ICP. Hypernatremia can develop with repeated boluses of hypertonic saline, and close monitoring of electrolytes is required for any patient that receives boluses.^11,15,16

Mannitol is an osmotic diuretic that has been used to reduce ICP for a long time. Mannitol is filtered by the kidneys yet is not resorbed by the renal tubules; thus it increases osmotic pressure within the vasculature and forces water to move extracellularly. Mannitol also has free radical scavenging properties, which can reduce tissue damage from cerebral hypoxia. Because mannitol initiates significant diuresis, the hydration status of a patient should be established before administering mannitol. If a patient is not well-hydrated, ideally, fluids are administered before mannitol to prevent iatrogenic kidney injury. However, there may not be time to do so for a critical patient with meningoencephalomyelitis. Intravenous fluid therapy—during administration of mannitol and immediately after—is necessary for those patients. To prevent iatrogenic kidney injury, intravenous fluid therapy should be continued after mannitol administration, especially for recumbent patients for which oral water intake is decreased, impossible, or dangerous (i.e., high risk of aspiration). The suggested dose for mannitol is 0.5 to 1 g/kg IV, administered over 15 to 20 minutes, which can be repeated every 6 to 8 hours if intravenous fluid therapy and strict monitoring of electrolytes are being performed. Warming mannitol before administration can prevent crystallization. An in-line filter of ≤ 5 microns should be used in the event of microscopic crystallization.^11,17 If repeated boluses of mannitol are given, higher fluid rates should be considered to maintain adequate hydration and prevent kidney injury. Monitoring a patient’s hydration, urination, and electrolyte levels—while ensuring fluid overload does not develop—is imperative.

Seizure management drug choice varies among clinicians. Injectable midazolam and diazepam are often used to quickly stop seizure activity in emergency/critical care settings; however, these drugs are not meant to be used for daily or long-term antiepileptic therapy. Oral phenobarbital and levetiracetam are commonly used for daily antiepileptic therapy. In emergency/critical care settings, the benefits of phenobarbital and levetiracetam include parenteral administration and the ability to use loading doses to reach steady states more rapidly. Potassium bromide can also be considered for daily antiepileptic therapy, and an oral solution of potassium bromide can be administered rectally if a patient is unable to consume oral medications.^7,8

Monitoring for Meningoencephalomyelitis

Patients with brain inflammation will have some degree of increased ICP and should be closely monitored. These patients may benefit from monitoring via electrocardiography, doppler ultrasonography, and/or pulse oximetry, which provide visual and auditory aids for the nursing team that may not be directly beside the patient. Changes in various tones, volumes, and speeds in accordance with heart rate, breath, and/or perfusion can indicate increasing ICP. For example, if a patient’s brain begins to herniate, the patient will display acute tachycardia quickly followed by respiratory arrest. Changes in auditory notifications from an electrocardiogram, doppler ultrasound, or pulse oximeter reading can signal the need for immediate intervention, which can be lifesaving.

Blood gas analysis can be helpful to monitor for changes in CO₂ levels. Maintaining normocapnia in a patient with increased ICP is critical, and some patients may require intubation and manual or mechanical ventilation to maintain normocapnia. When ICP increases, respiratory centers in the brainstem can become compromised, leading to hypoventilation. The exchange of respiratory gases is reduced in a hypoventilating patient, which leads to increasing CO₂ levels. This CO₂ accumulation reduces blood pH, which triggers vasodilation and, in turn, increases cerebral blood flow, which further increases ICP. Improving the ventilation of a patient will reduce CO₂ levels and, thereby, reduce ICP. The goal is to maintain a partial pressure of CO₂ (PaCO₂) between 35 mm Hg and 45 mm Hg. Short periods of mild hypocapnia (PaCO₂ of 30 to 35 mm Hg) may be used to reduce ICP and may aid in regaining control of respiratory centers. However, prolonged periods of hypocapnia are not recommended as the resulting vasoconstriction can lead to reduced cerebral blood flow.^10,11

Most patients with significantly increased ICP will display mentation changes and, thus, may also be recumbent. Elevating the heads of these patients to an approximately 30° angle, using caution to not occlude the jugular vein with blankets or other props, can be helpful. Compression of the jugular vein can lead to reduced venous drainage of the CNS and subsequently increase ICP. Transient compression of the jugular vein for venipuncture can cause brain herniation if the ICP is severely elevated. Clot formation in the jugular vein after venipuncture can obstruct drainage from the CNS. For these reasons, jugular venipuncture should not be performed on these patients unless all other vessel options have been exhausted.^10,11

Prognosis of Meningoencephalomyelitis

Disease severity, therapy responsiveness, and disease recrudescence contribute to a patient’s long-term prognosis.^1,2 For most patients with MUO/MUE, prognosis is often considered fair to poor. One study found that the use of glucocorticoids as a monotherapy for MUO/MUE resulted in a median survival time of 570 days (range of 2 to 3540 days). In that same study, the 1-year median survival rate was 56%, the 3-year median survival rate was approximately 30%, and the 5-year median survival rate was approximately 11%.¹⁸ Patients with corticosteroid-responsive tremor syndrome or acute steroid-responsive meningitis–arteritis generally have a more favorable prognosis than noninfectious causes of meningoencephalomyelitis. For patients with an infectious etiology, prognosis is generally considered guarded to poor.^1,2 Mass effect, loss of cerebral gyral-sulcal pattern, and foramen magnum herniation are considered negative prognostic indicators of survival (FIGURES 3 AND 4).¹⁹

Figure 3. Sagittal T2-weighted magnetic resonance image of a canine brain. The arrow highlights cerebellar herniation through the foramen magnum from increased intracranial pressure. The brainstem is visibly compressed and has areas of hyperintensity.

Figure 4A. Axial T2-weighted and matching axial T2-weighted FLAIR (fluid-attenuated inversion recovery) magnetic resonance images of a canine brain. The arrows highlight moderate subfalcine herniation resulting from mass effect from inflamed neuroparenchyma.

Figure 4B. Axial T2-weighted and matching axial T2-weighted FLAIR (fluid-attenuated inversion recovery) magnetic resonance images of a canine brain. The arrows highlight moderate subfalcine herniation resulting from mass effect from inflamed neuroparenchyma.

Summary

A patient with meningoencephalomyelitis can be in critical condition and challenging to manage. The role of a veterinary nurse becomes imperative in the treatment of these patients. Understanding how elevated ICP can affect a patient and recognizing clinical signs of deterioration are essential for timely interventions. A veterinary nurse’s goals for patient care will focus on managing ICP, monitoring for changes in mentation, addressing other neurologic signs (e.g., seizure activity), and providing comfort and attentive care to a most likely recumbent or semirecumbent patient. Because of the intensive care that is required by many of these patients, an attentive, detail-oriented veterinary nurse can drastically improve the care, comfort, and outcome of these critically ill patients.