CHAPTER 18 Seizure Disorders
See Video 18-1 to introduce yourself to the subject of seizure disorders and so you can better appreciate the following discussion. This video shows Victory Forth, a 9-year-old female quarter horse, that has had a series of generalized seizures for the first few weeks after her last three foalings. Two seizures are shown on the video between which she was normal for approximately 1 hour.
Remember that a neuron is an excitable tissue constantly held in check. When this constant inhibition is interrupted, a seizure may be the result! Neurons communicate with each other via excitatory and inhibitory connections. Normal neuronal activity represents a balance of these excitatory and inhibitory influences. When imbalance results in excessive excitation, abnormal neuronal activity occurs and is manifested as a seizure. A seizure represents the uncontrolled synchronous discharge of neurons that is initiated in the prosencephalon. It is usually a brief episode as the brain usually rapidly corrects the imbalance in these neuronal influences. A seizure is the most common clinical complaint that involves the nervous system that a practicing veterinarian will encounter.
The terms seizure, convulsion, epilepsy, and fit are synonyms for a brain disorder expressed as a paroxysmal transitory disturbance of brain function that has a sudden onset, ceases spontaneously, has a tendency to recur, and originates in the prosencephalon. The term epilepsy is usually used for seizures that are recurrent. Those of unknown cause are called idiopathic epilepsy. The initial seizure focus may involve only a small number of highly unstable neurons that spontaneously discharge. This first episode may induce surrounding neurons to discharge, resulting in a progressive spread, or generalization, of the seizure. The pathogenesis of seizures has been and still is currently the subject of extensive investigation.*
The period of the seizure is known as the ictus, or the attack. The manifestation of the seizure is variable. Any unusual involuntary phenomenon that is episodic and recurrent in nature should be evaluated as a seizure disorder. Such phenomena include loss or derangement of consciousness, excessive or decreased voluntary muscle tone or movement, visceral muscle activity, and altered behavior.
Postictal depression refers to the period of recovery after a seizure when the patient may wander around in a state of confusion, may propulsively walk in circles or bump into objects because of its central blindness, or may sleep for a prolonged period or exhibit hyperphagia. This phase has the appearance of a patient whose neurons are exhausted from the excessive activity of the seizure. The length and form of postictal depression are variable. No correlation exists between the severity and length of the seizure and the severity, duration, or nature of the postictal phase. A short partial seizure may be followed by a longer, more complex postictus than a generalized seizure. As a rule, the postictal phase lasts less than an hour, but much longer periods of up to 1 to 2 days are possible. In horses, the postictal phase may last for 3 to 4 days.
The interictal period is the period between seizures after the patient has recovered from the postictal period. This phase is when the neurologic examination should be performed.
An isolated seizure is a seizure that occurs only once in a 24-hour period. Cluster seizures are when two or more seizures occur in 24 hours separated by normal interictal periods. Status epilepticus is when the seizure state is continual for more than 5 minutes or when a series of seizures occur without full recovery of consciousness between the seizures for 30 minutes.5,93 The seizure is continually repeated with no interictal period. Cluster seizures and status epilepticus are medical emergencies.
Descriptions of seizures usually include the terms aura and prodrome. The prodrome or prodromal period precedes the seizure and consists of a change in the sensorium of the patient that is exhibited in its behavior. The aura is defined as the initial focal motor or sensory signs that may precede a generalized seizure by a few seconds. If the aura is observed, it may suggest the site of the seizure focus. We do not regularly use these terms because they are often difficult to recognize in our patients. However, some owners will report recognizing a change in their pet’s behavior, a prodrome or aura, that is predictive of a seizure.
The classification of seizures in animals is controversial and cannot be directly correlated with that used in humans.80 We believe the following discussion best serves the experience we have had with seizures in domestic animals, which are most common in the canine species. Seizures can be classified as focal, partial, or general; those that begin as partial seizures may subsequently generalize.
A focal seizure is a nonclinical spontaneous discharge of a small group of prosencephalic neurons without any spread. It can be observed only on an electroencephalogram (EEG) and should not be confused with a partial seizure, which is a clinical entity. Focal seizures are sometimes present in the interictal period of dogs diagnosed as idiopathic epileptics. Notably, some clinicians use the terms focal and partial as synonyms, which is technically incorrect.
A partial seizure is a focal seizure that has a limited spread and is observed clinically. The nature of the clinical signs will reflect the area of the prosencephalon where the seizure focus is located and consists of varying degrees of abnormal motor and sensory behavior with or without loss of consciousness. Lateralizing clinical signs often indicate which side of the prosencephalon is affected. Most partial seizures occur in animals that have a structural lesion in the prosencephalon. Occasionally, partial seizures are idiopathic. Two categories are described for partial seizures.
A generalized seizure is the most common form that occurs in domestic animals and affects the brain diffusely. This form of seizure has been called a grand mal seizure. The petit mal seizures that are described in humans consist of brief lapses in the conscious state with a specific EEG pattern. These types of seizures have not been recognized in domestic animals. A generalized seizure is the form of seizure seen in the 9-year-old Quarter horse in the introductory video (Video 18-1) for this chapter. The initial seizure focus may be in one cerebral hemisphere that immediately spreads to the thalamus, which diffusely activates the entire cerebrum through its neurons that function in the diffuse cortical projection system, or the seizure may originate in this thalamic system. The result is a loss of the conscious state by the patient, a tonic contraction of most of the antigravity skeletal muscles, recumbency followed by periods of tonic muscle activity, and clonic muscle activity, which causes running-like movements of the limbs. Jaw clinching or chewing movements may occur along with sialosis, dilated pupils, hair erection, and sometimes urinary and fecal excretions. Apnea may occur during a tonic phase of the seizure. This form of seizure usually lasts from 30 seconds to 3 minutes, followed by a variable period of postictal clinical signs and then complete recovery.
To understand the basis for seizures, consider that neurons have what we call a seizure threshold. This neuronal threshold is determined by their environment, which is genetically determined. Seizures result when this neuronal environment is disturbed and the threshold is lowered. Most commonly, the seizure originates in disturbed prosencephalic neurons. Consider this neuronal threshold in the following simple graph diagram.
What comprises this neuronal environment? This concept is obviously very complex, but at the least it includes (1) the structure of the dendritic zones and all their synapses, as well as those on the neuronal cell body; (2) the neuronal lipoprotein cell membrane, including the plethora of ion channels that are influenced by the neurotransmitters and the enzymes involved with their activity, such as sodium-potassium-adenosine triphosphatase; (3) the ionic environment of the neurons that includes the availability of sodium, chloride, calcium, and potassium; and (4) the concentration of neurotransmitters that includes those concerned with excitation—glutamate, aspartate, and acetylcholine—and those concerned with inhibition—gamma aminobutyric acid, glycine, taurine, and norepinephrine. In addition, this neuronal environment includes the adjacent neurons and the astrocytes, which also have synapses with neurons and other astrocytes. Astrocytes regulate the transfer of metabolites and ions through the blood vessel walls and have a role in metabolizing many of the neurotransmitters.73Fig. 18-1 will help you appreciate the anatomic background of this neuronal environment. Alteration of any one or more of these components may lower the neuronal threshold enough to precipitate a seizure. These alterations comprise the differential diagnosis for seizures.
Figure 18-1 Neocortex showing some of the cellular components of the neuronal environment where seizures are initiated.
From: March PA: Seizures: Classification, etiologies, and pathophysiology, Clin Tech Sm Anim Pract 13:119–131, 1998.
Neuronal Environmental Alterations
Neuronal environmental alterations in the prosencephalon that precipitate seizures include intracranial (structural), extracranial (metabolic, toxic), and idiopathic disorders. Many of these disorders have already been described in this text. Remember that seizures are the result of uncontrolled discharge of living neurons in the prosencephalon. When necrosis occurs as part of a lesion, the live neurons associated with the disease process are the source of what we observe as seizure activity.
Intracranial in this discussion refers to structural disorders.101 A thorough neurologic examination will often reveal one or more neurologic deficits in the interictal examination, which indicates a structural lesion.
Extracranial causes of seizures are disorders that affect primarily other body systems that, in turn, affect the metabolism of neurons in the central nervous system (CNS). The interictal neurologic examination is usually normal in these patients. However, the physical examination may reflect a systemic abnormality that is related to the cause of the seizures. Some overlap exists with the intracranial group because some of these disorders cause degenerative lesions in the prosencephalon. This group emphasizes what needs to be considered when you study the history, do your physical examination, and order ancillary studies.
Idiopathic epilepsy, the most common cause of seizures in dogs,* is a syndrome characterized by repeated episodes of seizures for which no known demonstrable clinical or pathologic cause has been found. It is a diagnosis based on exclusion of all known causes of seizures. The interictal physical and neurologic examinations are normal, as are the blood studies, cerebrospinal fluid (CSF) evaluation, and imaging studies that rule out the intracranial and extracranial disorders that can cause seizures. Some of these patients may show an abnormality in their EEG readings during the interictal period, but this does not have diagnostic value. Much to the dismay of the owner of a patient with seizures, no conclusive diagnostic test is available for this disorder. In patients with idiopathic epilepsy, the alteration of the neuronal environment in the prosencephalon that lowers their threshold for seizures cannot be recognized by any laboratory procedure or microscopic examination of the brain. The development of this seizure threshold is likely genetically determined. The assumption is that dogs with idiopathic epilepsy have a lowered threshold as a result of a genetic alteration that may be inherited. Pedigree analysis and breeding studies have determined an inherited epilepsy in a large number of breeds that include the following: German shepherd (Alsatian),39 Belgian Turvuren,126 keeshond, beagle,35 English springer spaniel,107 dachshund, vizsla,108 Bernese mountain dog,66 Irish wolf hound,24 Finnish spitz,127 golden retriever,122 standard poodle,75 and Labrador retriever.15 The incidence is high in many other breeds that may yet be proven to be inherited, and idiopathic epilepsy also occurs in mixed-breed dogs. Where data is sufficient, it supports an autosomal recessive or polygenic recessive inheritance.
In idiopathic epilepsy, the seizures are usually generalized, but a variety of partial forms do occur. The onset of seizures is usually between 6 months and 6 years of age, but both younger and older onsets have been recognized. Owners may recognize a prodrome that is some subtle change in the behavior of their dog just before the seizure. The seizure usually lasts from 30 seconds to 3 minutes. If the seizure is a partial seizure, the form it takes is consistent and does not usually vary in an individual dog. Large breeds such as the German shepherd, Saint Bernard, and Irish setter often have very severe generalized seizures that may occur in clusters. Miniature and toy poodles may exhibit a mild form of generalized seizure but without loss of consciousness. They act disoriented and exhibit some loss of balance as they develop spasticity of their neck, trunk, and limbs and uncontrolled diffuse trembling but still try to move close to their owners. Their seizure may last for up to 30 minutes. We often see simple partial seizures in Labrador retrievers that we diagnose as idiopathic epilepsy. Idiopathic partial seizures are recognized in Finnish spitz dogs with normal magnetic resonance (MR) imaging127 and are documented in the standard poodle as an autosomal recessive inherited disorder.75 Most dogs with idiopathic epilepsy are depressed and occasionally blind in the immediate postictal period, which usually lasts for less than an hour. The interval between seizures varies from one or a few weeks to months. The frequency of the seizures may increase as the dog ages, and the dog may occasionally develop status epilepticus during which death can occur. In many of these dogs, the seizures can be controlled to an acceptable level for the owner with the use of anticonvulsant therapy.
Idiopathic epilepsy is a diagnosis of exclusion in which MR imaging plays a significant role in demonstrating the lack of structural lesions in the prosencephalon. However, dogs with presumptive idiopathic epilepsy occasionally have lesions on MR imaging that are likely the effect rather than the cause of the repetitive seizures. These dogs may have bilaterally symmetric to asymmetric lesions in the piriform lobe, the adjacent hippocampal portion of the temporal lobe, or both.3,40,83 Similar lesions have been reported in the frontal and parietal lobes and less commonly in the cingulate gyrus and the thalamus. The lesions are typically hypointense on T1-weighted images, hyperintense on T2-weighted and fluid-attenuated inversion-recovery (FLAIR) images, and may or may not have scant contrast enhancement. The margins are not well demarcated, and they lack any mass effect. These lesions are usually transient and not visible on repeat imaging once seizure control is achieved. On microscopic examination, these lesions consist of edema, vascular proliferation, neuronal loss, reactive astrogliosis, and occasionally necrosis. Similar findings are reported in humans and are presumed to be related to the excitotoxic effect of accumulated glutamic acid.
Idiopathic epilepsy occurs in cats but is much less common.12,67,70 It is uncommon in farm animals2 and the horse, except for the Arabian foals; an idiopathic seizure disorder occurs in Arabian foals.1 The onset is 3 to 9 months of age, and after a period of weeks the seizures may spontaneously cease. A familial basis is suspected. A form of idiopathic epilepsy has been observed in horses that may be related to the estrus period when the estrogen levels are increased. The horse in the introductory Video 18-1 for this chapter had seizures that occurred only in the first few weeks after foaling. A postpartum hormonal irregularity was presumed to be responsible, given that no lesions were found in the brain after euthanasia and necropsy when the horse was 10 years old. Occasionally, one or more seizures may occur in a patient over a few days with no identifiable cause and then cease spontaneously, which can occur at any age in dogs but more commonly occurs in puppies.
Terminology with seizures can be confusing. One term that will occasionally be seen in the literature is symptomatic epilepsy, which refers to recurrent seizures that have an intracranial or extracranial cause. Primary epilepsy is idiopathic epilepsy. Secondary epilepsy refers to recurrent seizures caused by a structural prosencephalic lesion, and reactive epilepsy refers to seizures caused by a metabolic disorder. We do not use these terms.
The following discussion is an example of a dog presented with the chief complaint of a possible seizure. This description demonstrates what the veterinarian should be considering and the historical information that needs to be obtained in attempting to diagnose the cause of the seizure.
Hypoglycemia of toy-breed puppies, hydrocephalus in toy and brachycephalic breeds, portosystemic shunt in Yorkshire terriers, neoplasm in boxers, idiopathic epilepsy in German shepherds and other breeds at risk (see earlier discussion), leukodystrophy in cairn and West Highland white terriers, neuronal storage disease in specific breeds (see Table 14-2), lissencephaly in the Lhasa apso, hyperlipidemia in miniature schnauzers, necrotizing meningoencephalitis in pug dogs, necrotizing leukoencephalitis in Yorkshire terriers
Mammary gland adenocarcinomas may metastasize to the brain. Seizure threshold may be lowered during estrus.
Obtain a complete description of the episode that is being considered as a seizure to be sure that the event is a seizure. Seizures rarely occur when you can see them, and if the description is questionable, have the owner video the episode for you to study. The motor activity in a simple partial seizure may be lateralizing and indicate the site of the seizure focus (i.e., frontoparietal lobes of one cerebral hemisphere). Most generalized seizures from many causes are symmetric and not lateralizing. These causes include toxins and idiopathic epilepsy. Bizarre behavioral abnormalities sometimes precede seizure generalization with lead intoxication. Seizures in cats with marked flexion of the neck and trunk occur with thiamin deficiency. Idiopathic epileptics usually have short generalized seizures.
Onset and Course
An explosive onset of cluster seizures or status epilepticus can occur with neoplasms, intoxications, or occasionally idiopathic epilepsy. A progressive course with increasing frequency and duration of seizures occurs with inflammations or neoplasms. Regular intervals are more common in idiopathic epilepsy. Hypoglycemic seizures often occur just before or shortly after feeding. Seizures often follow a high-protein meal in hepatic encephalopathy.
Littermates may also be affected with infectious diseases such as canine distemper. Multiple animals may be affected by a common toxin. Sources of lead include paint, linoleum, tarpaper, wall board, and roofing materials. Other intoxicants to consider are metaldehyde in snail bait, hexachlorophene soap, ethylene glycol antifreeze, chlorinated hydrocarbon and organophosphate insecticides, fluoroacetate (1080) rodenticide, fungicides with mercury, arsenicals in insecticides, and phenol and cresol germicides. We studied one young basset hound with seizures secondary to the ingestion of cement that contained ethylene glycol antifreeze, which prevents the cement from freezing during construction in cold weather.
An all-fish diet that contains thiaminase may precipitate thiamin deficiency, especially in cats. Cooking the food will deplete the thiamin and lead to a deficiency in small animals.
Seizures may follow the recovery from significant intracranial injuries by weeks to months. A febrile illness associated with the systemic clinical signs of canine distemper infection may precede the seizures from the subsequent encephalitis. A difficult parturition may cause cerebral hypoxia or brain injury. A delay of weeks may occur between smoke inhalation or radiation therapy overdose and the onset of encephalopathy with seizures. A previous diagnosis of neoplasia in another body system may herald a brain metastasis. The owner’s recognition of other neurologic dysfunction in the patient suggests a structural lesion. Evidence of a behavior change, polyuria, polydipsia, or a voracious indiscriminate appetite suggests possible hypothalamic involvement by a pituitary neoplasm. Clinical signs of hyperadrenocorticoidism may accompany a functional pituitary adenoma. A recent change in behavior often accompanies a frontal lobe neoplasm. Episodic behavioral alterations occur in the young dog with hepatic encephalopathy.
Extracranial causes of a seizure may reflect abnormal function of another organ system, which may be evident in your physical examination of these systems, as well as in the ancillary procedures. These organs include the liver, pancreas, kidney, and cardiorespiratory organs. Systemic disease may accompany the encephalitis caused by infectious agents.
To be reliable, the examination must be performed in the interictal period. Abnormalities in the interictal neurologic examination suggest intracranial structural brain disease. Focal clinical signs suggest a neoplasm, vascular compromise, previous injury, or focal infection (granuloma, abscess). See Chapter 14 for the discussion of prosencephalic disorders and the three clinical signs that can be recognized in your neurologic examination indicating a prosencephalic dysfunction. Recognition of any one of these in an otherwise normal patient is critical for the diagnosis of a structural lesion that is the cause of the seizures. See Video 14-6 and Video 14-7 that follow Case Example 14-5 in Chapter 14, in which seizures were the chief complaint. Patients with frontal lobe lesions may circle toward the side of the structural lesion (the adversive syndrome). This is a common clinical sign that helps locate the side of a prosencephalic disorder. Multifocal clinical signs suggest an inflammation or multiple neoplasms. Clinical signs of diffuse prosencephalic or brain dysfunction may occur with inflammations, degenerative diseases, or a metabolic disorder that is neuronal or extracranial in origin.
In the absence of interictal neurologic signs, the cause of the seizures can still be intracranial, as well as extracranial, in origin or idiopathic. Remember that large areas of prosencephalon may have a lesion causing neuronal dysfunction, but this dysfunction may not be reflected in the animal’s behavior or on its neurologic examination. We refer to these areas as “quiet areas” because we cannot test them for dysfunction in our neurologic examination. Most extracranial disorders do not cause interictal neurologic signs (i.e., hypoglycemia, hepatic encephalopathy, cardiac arrhythmias). The interictal neurologic examination is always normal in dogs with idiopathic epilepsy.
Further study to determine the cause of the seizure requires ancillary examinations.
Complete Blood Count and Differential Cell Count
Nucleated red blood cells, basophilic stippling, and a low packed cell volume may be present in lead poisoning. A microcytic anemia may occur with a portosystemic shunt. The complete blood count (CBC) is usually normal in viral encephalitis. Leucocytosis and neutrophilia may be present with suppurative meningoencephalitis. Leucocytosis may occur with portosystemic shunts. Polycythemia with a packed cell volume greater than 70 cells/mm3 may cause enough viscosity to result in a seizure.
The blood urea nitrogen (BUN) may be increased in chronic renal disease or decreased with portosystemic shunts. Most animals with hepatic encephalopathy will be hyperammonemic and show variable evidence of liver dysfunction on serum studies. Hypoglycemia or abnormal glucose-to-insulin ratios may be diagnostic for a pancreatic beta-cell neoplasm or other disease process. Electrolyte abnormalities may be recognized. Bile acid evaluation will be abnormal with diffuse liver disorders such as the portosystemic shunt. Hyperlipidemia may relate to seizure genesis.
The CSF is normal in all idiopathic epileptics and may be normal in many of the structural brain disorders. We do not routinely measure the CSF pressure and avoid obtaining CSF if we suspect that intracranial pressure may be markedly elevated. Whenever possible, we rely on the results of the MR imaging to dictate whether the CSF is obtained for evaluation.
By far the most reliable imaging for the recognition of prosencephalic disorders that cause seizures is MR imaging. Radiographs rarely show a structural lesion unless it involves the calvaria directly or indirectly. Meningiomas adjacent to the calvaria may cause a thickening of the bone. Computed tomographic (CT) imaging, using a soft tissue window, will reveal many prosencephalic lesions, but their characteristics to allow differentiation and further treatment options are much less useful when compared with MR imaging. Rectal scintigraphy may confirm a portosystemic shunt.
The extent of the examination for the cause of the seizure disorder depends on the number of seizures, the age of the patient at the time of the examination, the priority of the disorders in your differential diagnosis, and the cost of the ancillary procedures. All patients require a physical and neurologic examination. For a young dog with a single seizure and normal neurologic examination, this may be sufficient. In an older dog with a single seizure and normal neurologic examination, a CBC, differential cell count, and a complete blood chemistry panel should comprise the minimal database. Recurrent seizures with or without interictal neurologic signs require this minimal database, as well as consideration of a serum lead level and serum antibody levels for infectious diseases plus imaging studies, preferably MR imaging, if the owner can afford the expense. CSF evaluation is dependent on whether imaging studies are performed and your consideration of its value in determining the clinical diagnosis.
The following case examples exemplify the four major conclusions from the neurologic examination of a patient with the chief complaint of seizures.
Signalment: 6-year-old female Boston terrier
History: Seven weeks before this examination, she had her first episode of generalized seizures, which occurred as a cluster over 2 hours. Clusters of seizures recurred at 10 days and 2 days before this examination, as well as in the hour before this examination. The owners described her as being normal between these clusters of seizures.
Examination: On the initial examination when she was presented to the hospital, she was depressed and blind, with normal pupil size and response to light. She drifted to either side as she walked and had slow postural reactions in all four limbs.
Anatomic Diagnosis: Diffuse brain but primarily the prosencephalon bilaterally
Because of the history of a seizure just before hospitalization and this examination, the concern was that these clinical signs represented the postictal effects of that seizure, and the examination should be repeated if and when she reached an interictal stage.
Second Examination: This examination was performed 24 hours after the initial examination. She was alert, responsive, and visual, and she had a normal gait. Hopping was consistently slow in the right limbs. Hypalgesia was found on the right side of the nasal septum.
Anatomic Diagnosis: Left prosencephalon, possibly the left frontoparietal lobe region that spared the left central visual pathway
Differential Diagnosis: Structural disease: neoplasm, necrotizing meningoencephalitis or leukoencephalitis, granulomatous meningoencephalitis, abscess, vascular compromise
Progressive seizures in a brachycephalic breed at this age suggest a neoplasm. Necrotizing encephalitides are uncommon in this breed. A focal form of the lymphoproliferative granulomatous meningoencephalitis is a possibility. A bacterial or fungal abscess or granuloma is uncommon. Be aware of brain infections with Coccidioides immitis in the southwestern states. Vascular compromise is unlikely to only cause a seizure at the onset and then cause progressive seizures.
Imaging procedures are necessary to define the clinical diagnosis further. Advanced imaging was not available at the time of this study. CSF contained 2 white blood cells (WBCs)/mm3 (normal <5) and 39 mg/dl of protein (normal <25), which supported a structural disorder and suggested that a neoplasm was more likely than an inflammatory process.
The patient was euthanized, and necropsy revealed a well-defined astrocytoma in the left side of the diencephalon at its junction with the telencephalon (Fig. 18-2).
Figure 18-2 Transverse section of the preserved brain from the 6-year-old Boston terrier in this case example. Note the astrocytoma in the left side of the diencephalon.