Diagnostic approach to patients with signs of encephalopathy (Proceedings)

The word encephalopathy literally means "disease or disorder" of the brain. One can see that this would be an extremely vast topic if all disorders were discussed. The word also does not denote an etiology, and therefore, from a clinical standpoint the important learning issues for the clinician are: 1) what are the clinical signs associated with encephalopathy 2) what is the clinical problem solving approach to these patients 3) what diagnostics are generally required and 4) are there any breed related disorders. These four points will be addressed in general and not with detailed specifics because this topic is too vast. The clinician should grasp the concept of how to develop a "problem solving approach" to this neurologic presentation and then later focus on the specific disorders that can result in an encephalopathic patient.

Clinical presentation for encephalopathy

One can imagine that the neurologic deficits can be quite broad and diverse when the entire brain is included in this discussion. Some historical information may be beneficial to establish a category of disease and for initial development of a differential diagnosis list.

Clinical signs can be present as a focal, diffuse or multifocal encephalopathy. Focal encephalopathy often will result in asymmetric abnormalities on neurologic examination. Diffuse encephalopathy will show symmetric or bilateral neurologic deficits often with more severe changes in mentation. Metabolic and toxic disorders commonly have signs of a diffuse encephalopathy. Multifocal encephalopathy consists of multiple lesions within the CNS. Inflammatory diseases have this type of lesion distribution.

Time of onset of clinical signs will assist with ascertaining differentials. Specific disorders are associated with acute progressive, acute non-progressive and chronic time courses. Toxic, metabolic, and inflammatory causes have acute progressive clinical presentations. Disorders with an acute non-progressive time course include vascular insults and trauma. Degenerative, anomalous, neoplastic, and nutritional disorders often have chronic presentations. Obtaining an accurate history from the pet-owner is crucial for establishing a clinical time course, but also for gathering indirect evidence of brain disease.

Differentiation between clinical signs that reflect forebrain and brainstem dysfunction aids with the neuroanatomic localization. The forebrain processes input associated with responses or reactions to an external stimulus and serves to initiate specific reactions (Table 1). Clinical signs of forebrain dysfunction include altered mentation (obtunded, stupor, or coma), behavioral changes, head-pressing, wide-circling, head turn toward the side of the lesion, visual field deficits, and hemi-neglect (aversive syndrome). Gait often is normal with forebrain dysfunction, but may be aimless and without purpose. Postural reaction deficits are contralateral to the side of the lesion. Seizures also are a sign of cerebral or diencephalic dysfunction.

Table 1: Neurologic Signs of Forebrain Dysfunction

Clinical signs for diencephalic disease are similar to cerebral disease buy may show clinical signs of diffuse forebrain dysfunction. Alterations in mentation are more severe because of its close association with the ascending reticular activating system (ARAS). The gait can be normal and not manifest signs of asymmetry such as circling. Cranial nerve evaluation often shows menace response deficits with abnormal pupillary light reflex reflective of a CN II lesion. This relates to proximity of the diencephalon to the optic chiasm. Hypothalamic signs include endocrine dysfunction, abnormal eating patterns (polyphagia or anorexia), and temperature dysautoregulation. It is not uncommon for clinical signs of diencephalic disease to be vague making the lesion localization difficult.

Clinical signs of brainstem dysfunction reflect lesions of the midbrain through the medulla (Table 2). Mentation is more severely affected often causing stupor or coma as a result of direct involvement to the ARAS. Ipsilateral postural reaction deficits, vestibular dysfunction, and multiple cranial nerve deficits are characteristic of brainstem dysfunction.

Table 2: Neurologic Signs of Brainstem Dysfunction

Diagnostic approach

Step 1- Neurologic Examination: If the neurologic exam reveals findings that are very compatible with focal cortical/thalamic or brainstem disease (see above), then one can be fairly certain that organic brain disease exists and that there is an intracranial cause for the signs. In this scenario, CSF analysis and special imaging (CT, MRI) will usually be required and this information can be relayed to the owner. In this instance, CBC, Chem panel, UA are usually performed as a pre-anesthetic work-up but are not usually beneficial in establishing a definitive diagnosis.

Step 2- If the neurologic exam points to a more diffuse cortical dysfunction without focal localizing signs, then a CBC, Chem panel, UA, blood lead, endocrine testing, bile acids, etc. should be performed to search for a metabolic, endocrine, or toxic reason for the encephalopathic signs. In addition, these are very non-invasive tests.

Step 3- If the diagnostics in step 2 are normal, then it is very likely that the patient has intracranial disease causing the encephalopathic signs. At this point, CSF, CT, MRI and CSF serology will be required to further establish a cause for the encephalopathy.

CSF analysis abnormalities in conjunction with encephalopathic signs indicate intracranial disease. Many times CSF will reflect an inflammatory or infectious disease etiology based on a neutrophilic or mononuclear pleocytosis, but unfortunately, a definitive etiology is not always found. The CSF changes are present but yet they may be non-specific. Unless organisms are detected such as fungal, protozoal, or bacterial, then the CSF may only tell us an intracranial problem exists but not always the exact cause. This is an important concept to explain to the client. One must always be cognizant of the limitation of any test.

The student is expected to know how to clinically approach a patient with signs compatible with an encephalopathy, i.e. the diagnostic approach. Table 3 lists the more common intracranial and extracranial causes (which the student can use as a reference guide), but the only specific diseases which will be discussed in this lecture include:

Table 3: Intra-cranial and Extra-cranial Causes of Encephalopathies

1. GME (granulomatous meningoencephalitis)

2. Yorkie, Maltese, Pug, Chihuahua, French bulldog necrotizing encephalitis

3. Canine distemper

GME

Signalment

Primarily seen in toy and small breed dogs and as a general rule the problem is manifested in the young to middle aged patient. In some reports females and toy poodles are over represented.

Etiology

This is an inflammatory disorder of the brain with an unknown etiology or inciting cause. It is sporadic but in the small breed dog with signs of intracranial disease, it should always be high on the differential list. The two most common forms are the disseminated and focal form. The disseminated form is the most common and by its description results in multiple lesions which then cause multi-focal neurologic deficits. In contrast, the focal form is caused by a coalescing of inflammatory cells which then form a "nodule" or "mass". This tissue then acts as a space occupying lesion, and the resultant signs are focal neurologic deficits.

History

The onset of disseminated GME is usually acute with a progressive course over a 1-8 week period. In about 25%, the owner will notice rapid deterioration in a week. The focal form of GME has a more insidious onset and slowly progresses over weeks to months. Depending on the location of the brain involvement, cortical versus brainstem, the signs may be so dramatic that the owner seeks veterinary care for their pet very soon after onset of signs.

Clinical/neurologic indings

Disseminated form

1. Reflect several neuroanatomic syndromes since it is a multi-focal disorder (i.e. cerebral, brainstem, and spinal cord syndromes.

2. Common signs include: incoordination, ataxia and falling, cervical spinal pain, head tilt, nystagmus, circling, visual deficits.

3. The vestibular system is a common location for GME, and therefore central vestibular signs are very common.

Focal form

1. Neurologic deficits reflect the location of the space occupying mass. Therefore, the signs will vary according to this location.

2. As with disseminated form, the vestibular system in the brainstem is commonly affected.

3. Due to focal nature though, the signs could be confused with any other space occupying lesion.

Diagnosis

1. A tentative diagnosis of GME may be suggested by the signalment, history, clinical signs, and course of problem.

2. All the usual lab tests such as CBC, Chem panel, UA are normal.

3. CSF analysis is the most helpful test to provide strong support for GME. The typical findings include:

a. Elevated protein (> 30 mg/dl)

b. Mild to pronounced pleocytosis, ranging from 25 to over a 1,000 wbc cells/ul

c. WBC differential typically consists of mononuclear cells (lymphocytes, monocytes) and macrophages. There are a few neutrophils but these are the minority.

d. Lymphocytes- 60-90%

e. Monocytes- 10-20%

f. Macrophages- 10-25%

g. *Note- if there are mostly neutrophils (>70%) in the CSF it is unlikely that GME is the diagnosis. Also, previous glucocorticoid therapy may decrease the amount of pleocytosis. Therefore, it is always best to perform CSF analysis prior to any therapy.

h. Canine distemper encephalitis may also result in a lymphocytic pleocytosis and therefore the most likely differential diagnosis that can be confused with GME based on the CSF findings is distemper.

1. The clinician must realize that a TRUE and absolute diagnosis is made only with histopath. Therefore, brain biopsy ante-mortem or necropsy post-mortem is needed to arrive at a definitive answer. The client should understand this dilemma that we face as clinicians.

2. So, in the end, most of the time the presumptive or tentative diagnosis of GME is made with a combination of history, breed, clinical signs, and CSF analysis.

3. CT/MRI can be helpful in defining focal lesions of GME. Some characteristic changes on MRI when coupled with the CSF findings may be helpful to increase the specificity of a presumptive diagnosis of GME. More research is needed in this area.

Differential diagnosis

1. Other breed specific encephalopathies

2. Canine distemper

3.Toxoplasmosis/Neospora

4. Systemic mycotic disease

5. Rickettsial disease

6. Possibly cervical disc disease, if main symptoms are cervical column pain

Treatment/prognosis

1. For years, glucocorticoids have been the primary conventional treatment and really still are. Prednisone is the usual maintenance drug, but dexamethasone may be used initially as a parenteral source of treatment. The dexamethasone dose should be 1/6 to 1/7th of the calculated prednisone dose. Prednisone dose is 2-4 mg/kg/day for 7-10 days and then a slow taper over weeks to months.

2. Permanent recovery from GME is very unlikely and most dogs require lifelong treatment although the dosages for medications may be much reduced from the initial regimen.

3. Other drugs that might be useful but do not have controlled studies assessing their efficacy include:

4. Leflunomide (Arava) - 2mg/kg/day orally

5. Procarbazine (Matulane) - 25-50 mg/m2/day orally

6. Cyclosporine- 3mg/kg twice daily

7. Cytosine arabinoside (Cytosar) - 50 mg/m2 SQ BID for 2 consecutive days, then repeat every 3-4 weeks at same dose schedule. Dilute with saline 2:1 to reduce irritation of tissues.

8. Prognosis:

9. Most dogs that truly have GME have a poor prognosis for long term survival. Most will be euthanized due to progressive disease within 6-8 months of initial diagnosis. Therefore, this should be stressed to the owner. Many dogs respond very well to treatment during the first few weeks only to have worsening of signs after a few months of therapy.

10. Of the newer drugs, Leflunomide and Procabazine have shown the most success. In one study, Procarbazine achieved a median survival time of 15 months compared to conventional therapy.

Pug, yorkshire terrier, maltese, chihuahua, french bulldog necrotizing encephalitis

Several small breeds have a unique, non-infectious inflammatory disorder of the brain referred to as breed-specific meningoencephalitis. The diseases are not exactly the same in each breed but I will group them all together for this lecture topic. The important points to realize is that these are pure bred dogs, small breeds and all are young dogs when presented.

The common pathologic features consist of non-suppurative necrotizing meningoencephalitis. In the Pug, Maltese and Chihuahua the lesions are more commonly located in the cerebrum, while in the Yorkshire terrier there tends to be more of a brainstem (medulla) location.

Clinical signs

1. Mentation changes: dull, inattentive, less playful

2. Grand mal seizures

3. Central vestibular signs: weakness, circling, head tilt, nystagmus

4. Cortical blindness

5. Postural test reaction deficits

Diagnosis

1. These breed specific necrotizing encephalitis patients must have GME, distemper, hydrocephalus, infectious causes, and some metabolic, toxic disorders as differentials

2. Therefore, CSF analysis, CSF serology, CSF culture, Chem panel and blood lead levels, may be needed to rule out other causes of cortical disorders.

3. MRI may assist in some breeds such as Yorkshire terrier and Pug by defining hypointense T1 weighted multifocal lesions in the brain. These dogs can almost have a "Swiss cheese" appearance to brain, with multi-focal cavitations. Hydrocephalus is another common MRI finding.

4. CSF analysis may also be abnormal and consists of elevated protein, and pleocytosis which is comprised of primarily small lymphocytes. (71-98% of the nucleated cells).

5. Histopathology is the only definitive diagnosis.

Treatment/prognosis

1. The response of these idiopathic necrotizing encephalitis cases to treatment is much less rewarding than GME.

2. The same drugs listed for the treatment of GME can be used but in the author's opinion the response is less than optimal.

3. Many dogs continue to have seizure activity and need to be treated symptomatically with anticonvulsants.

4. One should not expect these dogs to survive more than 6-10 months after the diagnosis. Due to the persistence of signs most owners will elect euthanasia sometime during these months.

Canine distemper encephalitis

Canine distemper virus encephalitis is the most common infectious inflammatory cause of intracranial disease in the dog. Even though the disease has been recognized for years and quality vaccines have been available for quite some time, it remains a problem in everyday practice.

History/signalment

Distemper encephalitis is most likely to affect the dog less than one year of age and one which has not developed good immunity. There are neurotrophic strains of distemper virus that may result in CNS involvement without other systemic involvement such as pulmonary or gastrointestinal disease. Vaccination does not guarantee protection against CNS distemper and therefore, should never be used as a sole reason to rule out CNS distemper infection. Certainly a vaccinated dog is less likely to acquire distemper but never guarantee protection to the owner or rule out distemper simply because the dog has been vaccinated.

Clinical/neurologic findings

Those related to the nervous system will only be discussed here. Once must realize that multi-focal disease is common with distemper since it is an infectious disease.

1. Grand mal seizures

2. "Chewing gum" focal motor seizures

3. Mentation changes which include: obtunded, disoriented, "stares" into space, stand in corners, loss of playful habits

4. Tetraparesis due to brainstem involvement

5. Multiple cranial nerve deficits, with vestibular system being a common location.

6. In summary, the best way to think of distemper with regard to clinical/neurologic signs is that it can cause ANY neurologic deficit or abnormality

7. Myoclonus is a fairly specific involuntary muscle movement that is seen almost exclusively with distemper. It consists of a rhythmic one per second jerk of a muscle group or groups. It may be the only sign present that points to distemper infection. It is present at all times even during sleep. It will persist for years and many dogs will not have any further neurologic signs develop.

Differential diagnosis

1. Any of the other inflammatory/infectious diseases of the CNS

2. Lead toxicity

3. Developmental disorders of the brain if patient is less than one year of age

4. Hypoglycemia

Diagnosis of CNS distemper infection

1. FA testing on conjunctival smears: only positive during the first 7-14 days of infection then becomes negative. If positive and neurologic signs are present, then a positive diagnosis can be made. This test is only positive in 10-15% of cases though. Fa on footpad biopsies may be positive on occasion in dogs with "hardpad" disease.

2. CSF analysis with antibody/PCR

a) CSF analysis: typical finding is a lymphocytic pleocytosis with mild protein evaluations.

b) Protein- 30-60 mg/dl

c) WBC count-10-50 cells/ul and 70-90% are small lymphocytes

d) CSF serology for canine distemper virus: positive in approximately 40% of cases of CNS distemper infection. A negative test does not rule out distemper. A positive test most of the time should confirm diagnosis.

e) CSF RT-PCR for distemper virus: positive test strongly supports a diagnosis of CNS distemper infection.

Treatment/prognosis

1. No specific therapy, antiviral drugs have not shown any benefits.

2. Supportive care only.

3. Anticonvulsants if seizure activity is present.

4. Prognosis is very poor for recovery since most cases are progressive in nature. Euthanasia is the usual outcome in these dogs.