Chapter 126 Diseases of the Brain and Cranial Nerves
The brain may be anatomically and functionally divided into three major compartments, the brain stem, cerebellum, and cerebrum. Cranial nerves have their cell bodies within the brain, but most of their nerve fibers course outside the brain. Diseases of the brain and cranial nerves may be neoplastic, infectious, idiopathic, vascular, traumatic, metabolic, toxic, congenital, or degenerative in origin. These disorders may result in dysfunction of a focal, regionally specific brain area or may produce more diffuse or multifocal deficits. Because many different diseases can affect similar areas causing very similar clinical signs, the first portion of this chapter discusses clinical signs of lesions in each brain region. The remainder of the chapter discusses important brain diseases within each etiologic category. Diagnosis of neurologic disease is discussed in Chapter 125, and management of seizures is discussed in Chapter 127.
CLINICAL SIGNS AND NEUROLOCALIZATION
Brain Stem Lesions
• The brain stem contains the midbrain, pons, and medulla in the caudal fossa (below the tentorium cerebelli or infratentorial) and diencephalon in the more rostral middle fossa (above the tentorium cerebelli or supratentorial). Signs associated with lesions in the infratentorial brain stem are discussed below. Signs associated with the diencephalic (thalamic and hypothalamic) lesions are similar to those associated with cerebral lesions and so are discussed in the cerebral lesion section.
• Cranial nerve dysfunction is a common sign of brain stem disease. The brain stem contains cranial nerve 3 through cranial nerve 12 (CN3–CN12). Multiple or single cranial nerves may be involved in a disease process; signs are typically asymmetrical. CN5 through CN12 in the pons and medulla are more commonly affected than CN3 and CN4 in the midbrain.
• Head tilt, circling, falling, disequilibrium, and nystagmus indicate damage to vestibular nuclei of CN8. Head tilts usually occur toward the side of the lesion. Paradoxical vestibular syndrome is characterized by a head tilt opposite the side of the lesion.
• Dysfunction of muscles of facial expression (CN7) and mastication (CN5) are common. Disorders of swallowing (CN9 and CN10), laryngeal function (CN9 and CN10), and tongue mobility (CN12) can occur but are less common.
• Oculomotor weakness, strabismus, and resting pupillary changes occur with CN3, CN4, and CN6 involvement.
• Injury to ascending white matter tracts in the brain stem results in ipsilateral conscious proprioceptive deficits and other abnormalities in postural reactions. Occasionally, ataxia, dysmetria, and exaggerated postural reactions may be seen.
• Injury to descending upper motor neuron (UMN) nuclei and their tracts in the brain stem causes tetraparesis or paralysis characterized by increased extensor muscle tone and exaggerated reflexes. The weakness or paresis is usually more severe in limbs on the same side as the lesion.
• Severe brain stem lesions can result in disruption of the ascending reticular activating system. Clinical signs of progressively decreasing levels of consciousness (depression, obtundation, stupor, coma) correlate with the severity of the injury.
Cerebellar Lesions
• Ataxia of gait: Cerebellar lesions produce pronounced limb incoordination during voluntary movements. Exaggerated range and force of limb movement is common. Hypermetria and limb circumduction can be seen. Strength and conscious proprioception (CP) are preserved. Postural reactions often are preserved but exaggerated.
• Truncal ataxia: Truncal swaying and a wide-based stance are typical of cerebellar disease. Affected patients may fall to one side. Dysmetric head bobbing with overshooting and undershooting occurs. Forward and backward movements of the trunk (titubation) may be seen.
• Intention tremor: A fine oscillating tremor of the head and sometimes the body is seen during highly controlled movements, such as eating or visually fixating on an object.
• Menace deficit: The menace response is lost ipsilateral to the cerebellar lesion. Vision and facial nerve function are intact.
• Vestibular signs: The cerebellum contains the flocculonodular lobe, which is considered part of the vestibular system. Lesions in this area of the cerebellum may produce pathologic (and often positional) nystagmus, head tilt, and circling. Occasionally, a pendular nystagmus (rhythmic but rapid horizontal oscillation of the eyes) is seen with cerebellar disease.
• Opisthotonus (extension of the head and neck) and thoracic limb extensor rigidity may be seen with severe cerebellar disease or with cerebellar herniation.
Forebrain Lesions
• Forebrain diseases can affect the cerebrum or diencephalon either bilaterally (diffusely) or unilaterally (focally). Both diffuse and focal forebrain disorders can cause the following:
• Dullness, agitation, or otherwise inappropriate responses to environmental stimuli (abnormal mentation or “dementia”)
• Focal diencephalic lesions may cause lethargy; inappetence; altered mentation and behavior; circling, listing, and/or head turn toward the side of the lesion; and hemi-inattention. These deficits may occur in the absence of proprioceptive, visual, or facial sensory and motor deficits.
Herniation from Space-Occupying Brain Lesions
• Space-occupying lesions in the forebrain and cerebellum may grow rapidly, may be accompanied by extensive edema, or may result in acute hemorrhage or infarction due to invasion of local blood vessels. Intracranial tissue and fluid compartments (parenchyma, blood, cerebrospinal fluid [CSF]) can compensate for space-occupying lesions up to a point. Beyond this critical threshold, brain shift or herniation occurs. Sudden changes in clinical signs not referable to the original neurolocalization suggest brain herniation and warrant emergency treatment.
• The two most common types of herniation are caudal transtentorial herniation due to an expanding forebrain mass and foramen magnum herniation due to an expanding cerebellar lesion.
• Clinical signs of transtentorial herniation include extensor rigidity in all four limbs and cervical musculature (decerebrate rigidity), pupillary constriction followed by dilatation or fixed, midrange pupils, loss of the vestibulo-ocular reflex (doll’s eye reflex), and a stuporous or comatose state.
• Clinical signs of foramen magnum herniation include opisthotonus (extended head and neck), thoracic limb rigidity (usually without rigidity of the pelvic limbs), pupillary changes (usually miosis), and either severely irregular respirations or apnea.
NEOPLASIA
Etiology
Primary Brain Tumors in the Canine
Primary tumors of the canine brain arise spontaneously and may grow slowly or rapidly.
Clinical Signs
• The onset and progression of clinical signs depend on the type of tumor and its location. Extra-axial meningiomas grow slowly and clinical signs are gradual in onset and progression. Intra-axial gliomas grow rapidly and cause a more rapid clinical deterioration. Secondary tumors also tend to progress rapidly. An exception to this is the trigeminal neurofibroma, which exhibits very slow growth (months to years).
• Early clinical signs of forebrain tumors may be vague and include increased irritability, behavior change, pacing, head and neck pain, and increased lethargy. Head pain or headache in dogs can be recognized by gently applying bilateral pressure across the temporal aspects of the head and skull.
• Some forebrain tumors may be clinically “silent” or may only cause seizures. These tumors can be located in the olfactory, temporal, or occipital cerebral lobes.
• Diffuse cerebral signs may occur secondary to a tumor obstructing CSF flow. This results in fluid accumulation in the lateral ventricles of the cerebrum and secondary hydrocephalus.
• Herniation syndromes may occur with tumors of the forebrain or cerebellum (see under “Herniation from Space-Occupying Brain Lesions”).
• Brain stem tumors usually occur in the pontomedullary area and typically cause central vestibular and other cranial nerve and long tract (e.g., limb proprioception and paresis) deficits.
• Cerebellopontomedullary angle tumors (choroid plexus papillomas, ependymomas, neurofibromas, meningiomas, and other tumor types) may invade the flocculonodular lobe of the cerebellum or the cerebellar peduncles. If this occurs, a “paradoxical vestibular syndrome” is seen. Signs are head tilt with possible circling and ataxia (rolling, falling, stumbling) away from the side of the lesion. The fast phase of nystagmus is often toward the side of the lesion. Long tract signs (e.g., limb proprioception and paresis), however, are ipsilateral to the lesion. If other cranial nerves are involved (e.g., CN5 and CN7), those deficits will be on the same side as the lesion.
• Cavernous sinus syndrome is a sporadic syndrome due to a lesion in the cavernous sinus along the floor of the rostral fossa (beneath the forebrain and just caudal to the orbital fissure). Neoplastic masses occupying this area will compress CN3, CN4, CN6, the ophthalmic branch of CN5, and the sympathetic nerve going to the eye. The result is an ipsilateral fixed pupil, absent corneal and eyelid sensation, and ocular immobility.
Diagnosis
Laboratory Testing
• Perform a complete blood count (CBC), chemistry profile, and urinalysis to rule out extracranial causes of brain dysfunction prior to pursuing tests for intracranial disease.
• Because most patients with brain tumors are older, run a geriatric screen of liver and kidney function.
Electrodiagnostic Testing
• An electroencephalogram (EEG) may detect asymmetries in brain activity or actual epileptiform complexes if a seizure focus is present. See Chapter 125 for a more thorough description of the EEG and its uses.
• A brain stem auditory evoked response (BAER) may aid in localizing a brain stem lesion. See Chapter 125 for additional information.
Radiography
• An area of bone sclerosis or lysis may be visible in the skull immediately adjacent to a feline meningioma.
Computed Tomography and Magnetic Resonance Imaging
• Tumor margins and neuroanatomic location can be more precisely defined with computed tomography (CT) or magnetic resonance imaging (MRI). Peritumoral edema is also visible. Parenchyma definition, especially in brain stem areas, is best identified with MRI.
• Intravenous contrast agents (meglumine iothalamate for CT and gadolinium diethylenetriamine pentaacetic acid for MRI) highlight areas of blood-brain barrier disruption. Patterns of enhancement are not pathognomonic for tumor type but aid in making a tentative diagnosis.
• Inflammatory or other non-neoplastic lesions may mimic a neoplastic lesion on both CT and MRI. A CSF tap and biopsy of the mass are sometimes needed to confirm the underlying process.
Cerebrospinal Fluid Analysis
For CSF tap technique and normal values, see Chapter 125.
• CSF analysis may be useful in distinguishing inflammatory from neoplastic processes (see also “Inflammatory Brain Diseases”).
• The majority of brain tumors are characterized by no cytologic abnormalities (normal cell count and differential) on CSF analysis. CSF pleocytosis may be seen if the tumor is necrotic and has a secondary inflammatory component. Neoplastic lymphocytes in CSF are typically seen in dogs with CNS lymphoma.
• Protein levels are usually elevated for all tumor types. Elevated protein with a normal cell count is called albuminocytologic dissociation.
Treatment
Corticosteroids
• Corticosteroids primarily help in resolving vasogenic edema and often benefit patients with peritumoral edema. Administer prednisone at a dosage of 0.25 to 0.5 mg/kg every 12 hours as maintenance therapy for peritumoral edema.
• Meningiomas in cats may show a partial clinical response to corticosteroids in the short term (several weeks or months).
Hyperosmotic Solutions and Diuretics
• In the euvolemic patient, mannitol at 1 g/kg IV over 20 minutes will draw fluid out of more normal areas of brain and temporarily lower ICP.
Anticonvulsant Therapy
Phenobarbital at a dosage of 2.2 to 2.5 mg/kg PO every 12 hours is indicated if seizures are part of the clinical picture (see Chapter 127). Potassium bromide is often required as an additional anticonvulsant if seizures are recurrent.
Specific Chemotherapy
• Controlled clinical trials in dogs and cats have not been done to assess the true efficacy of different chemotherapeutic agents in the treatment of brain tumors.
• Nitrosoureas (lomustine, carmustine) appear to be beneficial in the treatment of some canine gliomas and meningiomas. Longer survival and even temporary tumor regression have been reported. Lomustine is also frequently effective against CNS lymphoma and malignant histiocytosis. Nitrosoureas are unique in that they cross the blood-brain barrier, the limiting factor for most chemotherapeutic agents. Give 50 to 80 mg/m2 of body surface area every 4 to 6 weeks. For conversion of body weight to surface area (m2), see Table 26-4 in Chapter 26.
• Cytosine arabinoside reaches therapeutic CSF concentrations after large intravenous doses in normal dogs. Intrathecal and IV infusions of cytosine arabinoside have been used in dogs with CNS lymphoma. A dosage of 300 to 400 mg/m2 of body surface area intravenously over 4 to 12 hours is recommended.
Surgery
• Craniotomy or craniectomy with tumor excision is a treatment option for extra-axial tumors involving the cerebrum or cerebellum. Refer the patient to a neurosurgical specialist.
• It is usually years before clinically significant regrowth occurs after meningioma excision in cats. Survival periods of 6 months to 1 year are reported following meningioma excision in dogs. Postoperative radiation therapy extends the survival period in the canine (1-2 years).
Radiation Therapy
• Longest survival times for dogs with meningiomas are obtained when radiation therapy is combined with surgery.
• Clinical signs of neurologic dysfunction often improve rapidly (within 2-8 weeks) following radiation therapy. Tumor shrinkage is delayed (>4 months) and is not associated with early clinical improvement.
Stereotactic Radiosurgery
• Stereotactic radiosurgery is the application of a single high dose of radiation delivered to a stereotactically defined target volume.
• The procedure utilizes multiple, non-coplanar beams originating from a radiation source that rotates in an arc around the patient’s tumor. All beams are focused on the target in non-intersecting planes using a stereotactic image-based system.
• This radiation procedure reduces radiation exposure of normal brain tissue and so avoids adverse effects associated with conventional radiation therapy.
INFLAMMATORY BRAIN DISEASES
Infectious Meningoencephalitis
Etiology
• Infectious diseases are a common cause of acute to subacute, rapidly progressive neurologic dysfunction in dogs and cats and tend to occur in young adults.
• Major etiologic categories include viral, fungal, rickettsial, and protozoal agents. Bacterial diseases of the CNS can also occur but are less common. Klebsiella, Escherichia coli, Streptococcus, Enterococcus, Staphylococcus, Pasteurella, Actinomyces, Nocardia, and various anaerobic species are the most common bacterial isolates. Some of the more important causes of infectious meningoencephalitis and their clinical and clinicopathologic features in the dog and cat are listed in Tables 126-1 and 126-2.
Diagnosis
• Due to frequent multisystemic involvement seen with many infectious brain disorders, diagnostic testing should include ophthalmic exam, CBC, chemistry profile, urinalysis, thoracic radiographs, and sometimes abdominal ultrasound or echocardiography, and ophthalmologic examination. Both anterior uveitis and chorioretinitis are common with toxoplasmosis, rickettsial, and feline infectious peritonitis (FIP) infections. Chorioretinitis and optic neuritis may also be observed with cryptococcal and distemper infections.
• Cytologic evaluation of skin lesions, nasal exudates, liver and splenic aspirates, lymph node and bone marrow aspirates, joint fluid, and CSF can sometimes identify the offending pathogen. Histopathologic evaluation of skin and muscle biopsies may also be useful to diagnose fungal and protozoal infections.
• CSF analysis in CNS infectious diseases frequently reveals a moderate to severe pleocytosis and elevated protein. Bacterial meningoencephalitis typically produces a neutrophilic pleocytosis with or without toxic changes in the neutrophils. Intracellular organisms are rarely observed. Blood, urine, and CSF cultures are indicated when bacterial infections are suspected even though CSF cultures are usually falsely negative. CSF characteristics of other CNS infections are described in Tables 126-1 and 126-2.
• CSF titers are preferred for diagnosis of distemper, cryptococcosis, and toxoplasmosis. An immunoglobulin G (IgG) ratio or intrathecal antibody coefficient for canine distemper virus (CDV) and toxoplasmosis can be determined using CSF and serum samples from affected animals. These methods correct for possible blood-CSF barrier breakdown by comparing CSF-to-serum ratios of pathogen-specific antibodies against ratios of vaccine-associated (usually adenovirus or calicivirus) antibodies. Non-paired serum titers for toxoplasmosis are unreliable in the dog and cat due to persistence of high antibody titers long after exposure. The antibody coefficient calculation may also be useful to diagnose CNS FIP, although false-negative cases of CNS FIP have been reported. Cryptococcal antigen-specific titers can be run on serum, but CSF titers provide a more definitive diagnosis of CNS involvement. Cryptococcal antibody titers may be falsely negative due to an inadequate humoral immunologic response to the encapsulated organism. Serum titers are useful for diagnosis of neosporosis and rickettsial diseases. Neospora caninum serum antibody titers are usually very high (>1:800) in infected dogs and do not crossreact with toxoplasmosis titers. Dogs exposed to the organism but without clinical signs of infection may also have high titers.
• MRI features of CNS infectious diseases include patchy edema and focal to multifocal contrast-enhancing lesions of the parenchyma. Some fungal and protozoal granulomas and bacterial abscesses can ring enhance. Edema can be severe with bacterial encephalitis. Meningeal enhancement is common, especially with bacterial meningoencephalitis. FIP is often characterized by periventricular and meningeal contrast enhancement and ventricular dilatation due to secondary hydrocephalus. Fungal granulomas and bacterial abscesses may resemble intracranial tumors due to their patterns of enhancement and perilesional edema.
Treatment
• Medical therapy for infectious brain diseases is presented in Table 126-3. Protozoal and fungal infections frequently require prolonged therapy. The recommended treatment duration for CNS cryptococcal and coccidioidal infections with fluconazole is 9 to 12 months. In dogs, treatment of cryptococcal infections is stopped after two consecutive negative titers are obtained at least 4 weeks apart. Relapses are common if fluconazole therapy is stopped too early.
• Initial treatment of bacterial meningoencephalitis is most effective if parenteral antibiotics are administered. Parenteral (usually intravenous) administration allows rapid therapeutic CNS and CSF drug concentrations to be achieved. Penicillin or ampicillin in combination with third-generation cephalosporins have a broad antimicrobial spectrum and are bactericidal (see Table 126-3). Many third-generation cephalosporins also cross the blood-CSF and blood-brain barrier in both the presence and the absence of inflammation. Concurrent low-dose dexamethasone therapy (0.15 mg/kg IV every 6-8 hours for 4 days) has been shown to be beneficial in human bacterial meningoencephalitis. After 3 to 5 days of parenteral therapy, inflammation resolves and the barrier to the entry of many antibiotics is restored. Extended therapy is then instituted with broad-spectrum oral antibiotics that penetrate non-inflamed meninges. These drugs include trimethoprim-sulfonamide, chloramphenicol, florfenicol, and fluoroquinolones. Metronidazole is often added if an anaerobic component to the infection is suspected.
IDIOPATHIC INFLAMMATORY BRAIN DISORDERS
Granulomatous Meningoencephalomyelitis
Clinical Signs
• GME is primarily a disease of toy and small breeds between 1 and 8 years of age. Large-breed dogs may occasionally be affected (e.g., Airedale terriers).
• Onset and progression of clinical signs may be more rapid (several days) in the disseminated form compared with the focal form (1-3 weeks).
• Central vestibular signs are common and may be paradoxical (see “Neoplasia”). Long tract signs (proprioceptive deficits and paresis) and other cranial nerve deficits (CN5 and CN7) may be present.
• Focal or multifocal areas of intramedullary spinal cord inflammation (myelitis) may cause tetraparesis or caudal paresis.
Diagnosis
• A marked mononuclear pleocytosis consisting of lymphocytes, plasma cells, monocytes, macrophages, and multinucleated giant cells is usually evident on CSF analysis. Neutrophils may be present. Rarely, CSF cytology is normal. Protein is usually elevated.
• CT or MRI may reveal focal or multifocal contrast-enhancing lesions (homogeneous or heterogeneous) with edema in white matter adjacent to the lesions.
Treatment
• Prednisone at 2 mg/kg every 12 hours for 2 weeks, then 1 mg/kg every 12 hours for 1 to 2 months followed by a gradual taper over several months, will usually result in temporary remission of clinical signs in the focal form. The disseminated form has a less favorable response to therapy. The optic form, if treated in the early stages, can result in recovery of vision.
• Other therapies for GME include lomustine, azathioprine, cytosine arabinoside, procarbazine, cyclophosphamide, and cyclosporine. I prefer lomustine as maintenance therapy. The dosage is 60 mg/m2 of body surface area every 4 to 6 weeks for 12 to 24 months. Lomustine therapy can be initiated early in the course of corticosteroid therapy.
Necrotizing Encephalitis
Clinical Signs
• Seizures, dementia, blindness, neck pain, and ataxia are seen in the acute form. Over 1 to 2 weeks, signs may or may not progress to coma and/or status epilepticus.
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