Clinical Vignette
Kwash, a 13-year-old male DSH cat, is presented for a dull attitude of several weeks and a recent onset of “seizure” activity. Kwash is strictly an indoor cat and has been so for 10 years. The owners have no other pets. Kwash has been less active and reclusive for the past several weeks. Three episodes are described in which Kwash has fallen onto his side, been unresponsive, and had paddling movements with all four limbs. These last about 45 seconds and he is very subdued for several hours afterward. Kwash appears normal upon physical examination although he is more quiet than normal. When you observe Kwash walk, no abnormalities (strength is good, no ataxia, and no posture abnormalities) are noticed. Upon neurologic examination you find the following: (1) postural test reactions are delayed and much slower on the left side; (2) normal pupil size and pupillary light reflexes; (3) poor vision and menace response in the left eye; (4) paces constantly and is not as responsive to external environmental stimuli.
Is the history more consistent with seizures or syncope? What are your differentials for the potential collapsing episodes? What do the neurologic examination findings tell you about the cause of the potential seizures? Where have you localized the lesion? What tests would you select for determining the cause of Kwash’s abnormalities?
Problem Definition and Recognition
There are three major categories or general mechanisms for sudden collapse: seizures, syncope, and narcolepsy–cataplexy. All are characterized by a sudden onset and many times with loss of consciousness. All three have more than one cause.
Seizure, fit, and ictus are terms that describe stereotypical alterations in behavior resulting from paroxysmal abnormal brain function. Convulsion usually refers to a seizure with generalized tonic–clonic muscle activity. One or more of the following behavioral changes are present during seizure activity: (1) loss or derangement of consciousness, (2) alteration of muscle tone or movement, (3) alteration of sensation, (4) disturbance of autonomic function, and (5) other psychic manifestations. The term “epilepsy” refers to a patient which has recurring seizures. The term “epilepsy” does not truly denote cause or type of seizure by definition, but in the veterinary literature “epilepsy” is most commonly used to describe patients with recurring seizures of unknown etiology or idiopathic or primary epilepsy.
Syncope is a sudden loss of consciousness caused by inadequate oxygenation of the brain, particularly the cerebral cortex. The episodes are usually brief (last seconds to minutes), have no prodromal signs, and recovery is quick without any residual neurologic deficits. Cardiac arrhythmias are the most common mechanism for syncope.
Narcolepsy–cataplexy is a syndrome that includes excessive sleep (narcolepsy) during inappropriate times and/or sudden loss of muscle tone (cataplexy). Cataplexy is the prominent sign in affected animals and even though the animal cannot stand it remains mentally alert. The animal suddenly drops to the ground and lies immobile for varying periods unless disturbed. In many instances, touching or calling the animal usually results in an immediate return to normal behavior.
Pathophysiology
Seizures
The basic cellular event in seizures is paroxysmal discharge of a group of neurons, called a seizure focus. The focus may be single or multiple in any individual. Some neurons are capable of a large depolarization of the membrane (20–50 mV) that can last 50–100 ms. The large depolarization may lead to multiple action potentials in a short time. This depolarization is called the paroxysmal depolarizing shift (PDS). Following the PDS, the membrane usually has a prolonged after-hyperpolarization (AHP). The AHP tends to stabilize the population, preventing further discharge for a period of time. Some neurons have a prolonged after-depolarization (ADP), which may lead to ictal behavior. Apparently, both synaptic and ionic changes contribute to these events. Alterations in inhibitory neurotransmitters such as a gamma aminobutyric acid may be a factor in the seizure mechanism as well.
Spread of the hyperpolarized activity from a focus is necessary for a seizure to occur. The activity can spread both locally to adjacent neurons and to other areas by axonal propagation. Eventually other seizure foci will develop. The reticular activating system (RAS) has a role in the genesis of seizures, although the exact mechanism is not clear. Many seizures occur during sleep when the RAS is least active and, experimentally, decreasing the output of the RAS increases seizure activity.
Termination of seizure activity is primarily a function of the AHP and inhibitory feedback circuits from the cerebellum, thalamus, caudate nuclei, and possibly other areas of the brain. The concept of “metabolic exhaustion” of the neurons is probably not valid.
Susceptibility to seizure activity varies among populations of neurons and individuals. For example, the neurons of the hippocampus easily develop ictal activity, and the thresholds for seizures vary among individuals within a species. A genetic predisposition for seizures may be simply a low threshold. The threshold may also be lowered by a variety of internal and external factors such as sleep and increased estrogen levels. Alterations in energy substrates, electrolytes, and many endogenous and exogenous toxins may precipitate seizures.
The occurrence of seizures increases the probability of additional seizures. The synaptic changes have been compared to “learning mechanisms” responsible for memory. There is also a pathologic change in neurons after seizures, primarily in the structure of the dendrites. These changes range from minor distortions, to the virtual absence of processes in the neuron, to the eventual death of the neuron. Prevention of these changes is a major consideration in the decision of whether to treat an animal for seizures.
Seizures may be classified according to a modification of the international classification of human epilepsy (Table 44-1.). Other authors have recently described classification schemes in the dog (Podell et al. 1995; Berendt and Gram 1999). If an underlying cause cannot be identified, the seizures are defined as primary epileptic seizures (idiopathic or cryptogenic).
TABLE 44-1. Classification of seizures
| Clinical Manifestations | Comments |
| Generalized seizures Tonic–clonic (grand mal, major motor) | Most common type May be caused by organic brain disease, toxins, or metabolic disorders Idiopathic form is inherited in some breed |
| Absences with or without motor phenomenon (petit mal) | Rare in animals, true petit mal seizures are considered to not occur in dogs and cats |
| Partial seizures | Focal signs during seizures may generalize to tonic–clonic seizure |
| Partial motor (focal motor) Psychomotor | Usually, indicates an acquired brain lesion Complex behavioral activity that is stereotyped and similar each time. Exact anatomical location not determined. Better terminology may be to describe this activity as simply “paroxysmal repeating events” as opposed to seizure activity. |
If the seizures result from structural cerebral lesions, they are defined as secondary epileptic seizures. If seizures are a reaction of the normal brain to transient systemic insult or physiologic stress, they are defined as reactive epileptic seizures (Podell et al. 1995). Differentiating partial and generalized seizures is important because partial seizures are more likely to be caused by a focal brain lesion; therefore, they are generally acquired and not idiopathic. However, there is a paucity of information in the veterinary literature to support this statement. Therefore, far-reaching statements regarding the etiology of partial seizures in veterinary patients should be tempered with caution. Partial seizures may generalize secondarily; consequently, the seizures must be seen from the onset to ascertain the presence of a focal component. Idiopathic seizures are usually generalized, but not all generalized seizures are idiopathic. Idiopathic seizures may be inherited and Table 44-2 lists the breeds that have been studied by controlled breeding programs and those reported as frequently having idiopathic seizures.
TABLE 44-2. Breed susceptibility to collapse
| Seizures | Narcolepsy | Syncope |
| Inherited | Inheritance suspected | Inherited |
| Beagle | Doberman pinscher | Pugs |
| Dachshund | Miniature poodle | |
| German shepherd (Alsatian) | Labrador | |
| Horak’s laboratory dogs | ||
| Keeshond | ||
| Tervuren shepherd (Belgian) | ||
| High incidence | Reported cases | High incidence |
| Cocker spaniel | Afghan hound | Boxer |
| Collie | Airedale | Doberman pinscher |
| Golden retriever | Corgi | Miniature schnauzer |
| Irish setter | Dachshund | |
| Labrador retriever | Irish setter | |
| Miniature schnauzer | Malamute | |
| Poodle | Poodle | |
| St. Bernard | Springer spaniel | |
| Siberian husky | Wire-haired griffon | |
| Wire-haired fox terrier | Mix breed |
TABLE 44-3. Causes of seizures
| Category | Diseases |
| Degenerative | Storage diseases |
| Anomalous | Hydrocephalus |
| Lissencephaly | |
| Metabolic | Hypoglycemia |
| Hypocalcemia | |
| Renal failure | |
| Hepatic failure | |
| Hypothyroid | |
| Neoplastic | Brain tumors (primary and metastatic) |
| Nutritional | Thiamine deficiency |
| Parasitism (multiple factors) | |
| Idiopathic | Unknown |
| Genetic | |
| Inflammatory | Viral: canine distemper, rabies, feline infectious peritonitis |
| Bacterial: any | |
| Mycotic: any | |
| Protozoan: toxoplasma, neospora | |
| Inflammatory: granulomatous meningoencephalitis, immune | |
| meningoencephalitis, breed-specific necrotizing encephalitis | |
| syndromes (pugs, Maltese, French bulldog, Yorkshire terriers) | |
| Traumatic | Acute head injury |
| Posttraumatic: weeks to months after injury | |
| Vascular | Infarctions |
| Arrhythmias |
Table 44-3 lists the major causes of seizure disorders in small animals.
Syncope
Transient loss of consciousness is caused by a temporary deprivation of oxygen to the brain. It is usually of short duration but the cardiac arrhythmia could lead to sudden death. Syncope is the result of (1) impaired cerebral circulation, (2) a transient decrease in cardiac output, (3) decreased systolic blood pressure, or (4) inadequate delivery of energy substrates to the brain. The causes of syncope are summarized in Table 44-4. The various causes of syncope are discussed in detail in Chapter 22.
Narcolepsy–Cataplexy
Narcolepsy is a disorder of the sleep mechanism of the brain. The primary complaint in humans, excessive daytime sleepiness, is not usually recognized in animals. However, it has been documented in laboratory studies (Foutz et al. 1980). Cataplexy can be readily recognized in affected animals. The animal has a sudden loss of muscle tone, resulting in complete collapse. Usually consciousness is maintained and the animal remains alert, but they simply cannot move their muscles and therefore lie limp. Many times the episodes may be stimulated by food intake or other environmental stimuli.
TABLE 44-4. Causes of syncope
| General Cause | Pathophysiology | Disease or Problem |
| Decreased cerebral circulation | Vascular obstruction or insufficiency | Thrombus, embolus, atherosclerosis, neoplasia, trauma |
| Decreased cardiac output (most common) | Abnormal heart rate or rhythm (see Chapter 17) Obstruction (see Chapters 17 and 18) | Dysrhythmias Impulse conduction Impulse formation Congenital heart diseases Acquired heart diseases |
| Decreased blood pressure | Decreased blood volume (see Chapter 19) Increased vascular resistance (see Chapter 19) | Blood loss Postural, drugs, hyperventilation, carotid sinus |
| Metabolic | Decreased oxygen (see Chapters 19, 21, 54, and 57) Decreased glucose (see Chapter 55) | Cardiopulmonary dysfunction, abnormal hemoglobin, anemia Insulin-secreting tumors, insulin overdose, glycogen storage disease, inadequate nutrition (mostly toy breeds, young animals) |
The physiology of sleep is poorly understood, so it is not surprising that the pathophysiology of sleep disorders is still largely unknown. Normal sleep has two distinct stages, rapid eye movement (REM) sleep, and non-rapid-eye-movement sleep (NREM). REM sleep is characterized by atonic muscles, occasional fasciculation of distal and facial muscles, and rapid eye movements. The EEG is of low voltage with mixed frequency. NREM sleep has two components. Light slow-wave sleep is characterized on the EEG by higher voltage slow waves, with at least one 10- to 14-Hz spindle per 30 seconds. Deep slow-wave sleep has even higher voltage slow waves (<4 Hz) with spindles. REM sleep normally occurs after about 90 minutes of NREM sleep and reoccurs intermittently thereafter. It accounts for 11–13% of the sleep cycle (Hendricks 2005).
Narcoleptic dogs have significantly less REM sleep than normal dogs, but they have episodes of cataplexy that have some of the features of REM sleep. There are other changes in the pattern of sleep, suggesting that narcoleptic dogs have a disruption of the sleep–wake cycle, rather than hypersomnia (Baker et al. 1983).
Most cases of narcolepsy are idiopathic. Inheritance has been established in Doberman pinschers and Labrador retrievers. A variety of breeds of other dogs, horses, and ponies have been recognized to have narcolepsy (Table 44-2).
Diagnostic Plan
A database for animals with collapse (see Table 44-5) should be adequate to differentiate syncope and narcolepsy from true seizure activity.
The plan is based on the assumption that seizures may result from three major categories of disease: (1) extracranial abnormalities, such as metabolic, endocrine, and toxic disorders; (2) intracranial disease, such as encephalitis, brain tumors, or trauma; and (3) idiopathic or primary generalized epilepsy. The causes of syncope are extracranial: cardiovascular, pulmonary, or metabolic (hypoglycemia). Narcolepsy is considered idiopathic, although it may occur subsequent to a primary brain disorder such as tumor located in the hypothalamic region.
TABLE 44-5. Database for collapse
| I. Minimum database: one or more episodes |
| A. Patient profile: species, breed, age, sex |
| B. History |
| 1. Environment |
| 2. Immunizations: kind, dates, by whom |
| 3. Previous or present illness or injury |
| C. Description of collapse |
| 1. Age of onset |
| 2. Frequency, course |
| 3. General or partial; duration; aura; postictus; time of day; relation to exercise, food, sleep or stimuli |
| D. Behavioral changes |
| E. Physical examination |
| 1. Special attention to cardiovascular and nervous systems |
| F. Fundoscopic examination |
| G. Neurologic examination |
| 1. If collapse was within 24–48 hours and neurologic examination is abnormal, repeat in 24 hours |
| H. Laboratory tests |
| 1. Complete blood count |
| 2. Urinalysis |
| 3. Chemistries (at least) |
| a. Blood urea nitrogen |
| b. Alanine aminotransferase |
| c. Alkaline phosphatase |
| d. Calcium |
| e. Fasting blood glucose |
| I. Other tests |
| 1. Electrocardiogram |
| 2. Blood lead |
| II. Complete database |
| If seizures are not controlled, there is evidence of central nervous system disease on neurologic examination, or animal has first seizures starting at 5 years of age or older, then the following are justified: |
| A. Brain scan: computed tomography, magnetic resonance imaging |
| B. Cerebrospinal fluid analysis: cell count, total and differential; protein levels |
| C. EEG |
| D. Skull radiographs: advanced imaging superior to plain radiographs |
Modified from Lorenz and Kornegay (2004).
The minimum database should identify most extracranial causes of collapse. The findings may only be suggestive of these causes and, therefore other specific tests may be required in order to make a definitive diagnosis. If abnormal findings are found on the neurologic examination this usually points to intracranial disease and generally necessitate the tests listed under “complete database” to arrive at a final diagnosis. Brain tumors, for instance, should be considered as a likely diagnosis in animals which are 5 years of age or older before their first seizure occurs. Therefore, computed tomography (CT) or magnetic resonance imaging (MRI) will ultimately be necessary in these patients.
Clinical Vignette Answers and Conclusion
(1) The history is most consistent with grand mal seizure activity. The loss of consciousness and falling could be seen with either syncope or seizure but the finding of tonic–clonic muscle movements would not be expected with syncope. Occasionally a syncopal patient may have rigid limbs and have stiffened muscles during the episode, but they should not have the tonic–clonic movements. In addition, most grand mal seizure patients will not be normal immediately after the episode while this is common in syncope.
(2) The age of onset of the seizures eliminates congenital or idiopathic causes for the seizures. Since Kwash is strictly an indoor cat then infectious disease is very unlikely. Therefore, neoplastic, inflammatory, or vascular disorders would be most likely. Also, the neurologic examination gives clues (see 3 and 4 below).
(3) The fact that the owner recognizes that Kwash has interictal abnormalities and your neurologic examination has defined neurologic deficits, these both point to organic brain disease. The focal nature of the neurologic examination findings also strongly supports a structural lesion in the brain.
(4) Right cortical or thalamic lesion. Why? Kwash has a normal gait, posture, and strength but yet has very asymmetric postural test reaction deficits. Remember, a dog or cat does not need cortical function to walk because they are “brain stem walkers” but yet they do need cortical and thalamic function to initiate postural test reactions (de Lahunta and Glass 2009). Kwash is the hallmark patient for this location. The neurologic deficitsare always contralateral to the lesion when a cortical or thalamic lesion exists. This is because all the conscious proprioceptive sensory information from the left side of the body crosses over to the right cortex and vice versa. In addition, Kwash had cortical blindness in the left eye. This means he had normal pupillary light reflexes but was blind in the left eye. The absent menace response in the left eye was secondary to a right cortical lesion affecting the optic radiations on the right side. The pacing and dull mentation were additional signs of cortical or thalamic dysfunction. Therefore, this case exemplifies how important it is to perform a complete neurologic examination in a seizure patient. The neurologic examination essentially proved the fact that a localized lesion was present and this localization could also easily explain the seizure activity.
(5) Since a localized lesion was defined from the neurologic examination, advanced imaging is indicated. An MRI was performed and a right cortical meningioma was found (Figs. 44-1 and 44-2). The meningioma was excised and Kwash lived another 2 years without any further neurologic dysfunction. The blindness remained in the left eye and after 6 months of anticonvulsant therapy with phenobarbital and no seizure activity, the phenobarbital was discontinued.
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