Recurrent seizures in cats: Diagnostic approach – when is it idiopathic epilepsy?

Abstract

Practical relevance:

Seizures are one of the most common neurologic problems recognized in cats, affecting approximately 1–3% of the general population. Treatment options and prognosis are closely related to the underlying cause, so it is important that veterinarians are familiar with the diagnostic approach to cats with seizures and options for medical management.

Series outline:

This is the first of a two-part article series that reviews the diagnosis and treatment of seizures in cats. Part 1 outlines the classification and terminology used to describe epilepsy and epileptic seizures in cats, and discusses some of the most common and unique causes of recurrent seizures in cats. The diagnostic approach to cats with recurrent seizures is addressed, as are criteria for the diagnosis of idiopathic epilepsy.

Audience:

This review of recurrent seizures in cats is intended for all veterinarians who are facing the challenges of seizure diagnosis and management in the feline patient.

Evidence base:

Recommendations for diagnosis and management of feline seizure disorders have historically been extrapolated from the canine and human literature. The information and guidance provided in this two-part series is based on a review of the recent published literature addressing seizure disorders and antiepileptic treatment in cats, as well as the authors’ clinical experience.

Epilepsy terminology and classification

A seizure is the clinical manifestation of excessive or hypersynchronous abnormal electrical activity in the brain.^1–5 Epilepsy is, by definition, a brain disorder where paroxysmal abnormal activity occurs in neuronal networks, causing recurrent seizures.^1,3,5,6

Classification of seizures and epilepsy into a universally accepted scheme has been an ongoing process in human and veterinary medicine, and there is still no clear acceptance of terminology for seizure type. Publications describing classification schemes for veterinary patients have borrowed from (but not entirely adopted) the terminology used for humans.^2–9 Some pertinent definitions are listed in the box on page 812, together with descriptions of seizure phases.

Seizure manifestations

Generalized seizures

Generalized epileptic seizures originate from both cerebral hemispheres and usually comprise bilaterally symmetrical tonic, clonic or tonic–clonic movements.^3,6,10,11 During a generalized seizure a cat typically experiences a period of extremely increased extensor muscle tone (tonus), falls into lateral recumbency in opisthotonus with its limbs extended and then has periods of tonus alternating with periods of limb flexion (clonus).^5,7,11 This rhythmic alternation of tonic and clonic contractions is manifested as paddling or jerking of the limbs and chewing movements [see videos 1 and 2 in supplementary material – details on page 821]. ¹¹ The animal loses consciousness during the convulsive episode and autonomic signs such as salivation, urination, defecation and mydriasis are common.^3,6,10,11

Focal seizures

Focal seizures (also known as partial seizures) originate from abnormal activity in one region of a cerebral hemisphere, resulting in asymmetric signs initially.^3,8,10,11 Motor manifestations of a focal seizure may include abnormal movements (automatisms) such as turning of the head to one side, rhythmic contractions of a limb or facial muscles, ear and / or whisker twitching, lip smacking or chewing movements [see videos 3 and 4 in supplementary material].^5,8 Circling, rapid running or climbing activity are also common in cats with focal seizures and may suggest temporal lobe involvement.^4,10,12–14 Tail chasing, limb chewing and fly biting are focal seizure manifestations that are presumed to result from abnormal sensory experiences such as tingling, pain or visual hallucinations. Less commonly, focal seizures cause strictly autonomic signs, with episodes of vomiting, drooling, diarrhea and apparent abdominal discomfort, or rhythmic pupillary dilation and constriction (hippus).^5,10,13

Complex focal seizures (formerly called psychomotor seizures) are focal seizures with altered mentation, resulting in excessive vocalization, growling, head pressing, pacing, aimless walking and occasionally unprovoked aggression or extreme fearfulness.^3,5,8,11 Some cats with complex focal seizures will be described by owners as acting as if they are ‘possessed’ or in a trance during the seizure, while others may be severely obtunded and non-responsive. ¹¹

Focal seizures sometimes progress into a generalized tonic–clonic seizure and the secondary spread can be so rapid that the initial focal component is missed and the seizure is misclassified as a generalized-onset seizure.^4,5,14

Reflex seizures

Reflex seizures are seizures that can be consistently provoked by specific stimuli or events. ³ The most common precipitating factor in people is a flickering light, but certain sounds and eating have also been identified as triggers. ⁵ Reflex seizures in humans may occur with any seizure etiology and are reported to be generalized or focal, with myoclonic jerks being most common.

Seizures that were consistently provoked by specific high-pitched sound stimuli have been described in 96 cats, characterizing a disorder of feline audiogenic reflex seizures.^21–23 The sounds that served as triggers for the seizures were varied and included the crinkling of tin foil, the sound of a metal spoon hitting a bowl or glass, paper or plastic bag crinkling, the clinking of coins or keys and the clicking of an owner’s tongue. All cats developed generalized tonic–clonic seizures and 94% also developed myoclonic jerks with the noise stimulus. No underlying cause for the seizures could be identified with metabolic and intracranial evaluation. Neurologic examinations between seizures were normal, except that 50% of the cats were hearing impaired or deaf and 21% were visually impaired. Cats ranged from 10 to 19 years of age at the onset of their seizures (median age 15 years) and a degenerative brain condition was suspected. Birman cats were over-represented. In therapeutic trials, levetiracetam was more successful than phenobarbital at controlling both the generalized tonic–clonic seizures (69% vs 27%) and the myoclonic seizures (93% vs 7%).^21,22

Table 1

Etiologic differential diagnosis for recurrent seizures in cats

	Differential diagnoses
Extracranial causes (reactive seizures)
Metabolic	Hepatic encephalopathy, hypoglycemia, hyperthyroidism, severe hypertension*, uremic encephalopathy, hypocalcemia, polycythemia*, electrolyte imbalance, severe anemia, hyperlipidemia*, thiamine deficiency*
Toxic	Many
*Denotes an extracranial cause that typically results in hypoperfusion of the brain or hemorrhage in the brain
Intracranial causes (structural epilepsy)
Neoplastic	Primary or metastatic
Inflammatory	FIR non-suppurative meningoencephalitis of unknown etiology, toxoplasmosis, cryptococcosis, parasite migration, FeLV infection, FIV infection, West Nile virus infection, rabies, bacterial infection, bacterial or fungal granuloma/abscess/empyema, others
Vascular	Thromboembolic disease, infarct, feline ischemic encephalopathy, thrombocytopenia, coagulopathy, severe hypertension
Degenerative	Hippocampal necrosis, storage diseases
Anomalous	Hydrocephalus, lissencephaly, porencephaly, other developmental anomalies
Traumatic	Acquired epilepsy (previous brain injury)
Idiopathic epilepsy (cause unknown)

FIP = feline infectious peritonitis; FeLV = feline leukemia virus; FIV = feline immunodeficiency virus

Seizures of extracranial origin

Seizures with an extracranial cause are known as reactive seizures. A reactive seizure occurs as a response from a normal brain to a transient metabolic or toxin-induced disturbance in cerebral function.^1,6,14,23 The seizure disorder is usually reversible when the cause or disturbance is resolved. ⁶ Reactive seizures have been reported to account for approximately 15–25% of all seizure disorders in cats.^7,12

Neurologic abnormalities are common interictally in cats with reactive seizures because of diffuse thalamocortical impairment, but diffuse or symmetric signs are much more common than lateralizing signs. Behaviour changes, altered mentation, cortical blindness, diminished facial sensation and impaired proprioceptive placing can all be seen. ¹ Cats with reactive seizures are usually middle-aged or older (mean 8.2 years) when they are presented with their first seizure and they have an increased risk of status epilepticus or cluster seizures compared with cats diagnosed with IE. ¹

The most common causes of reactive seizures in veterinary patients are hypoglycemia due to insulin overdose or insulinoma, hepatic encephalopathy (see below) and intoxications.^1,7,12 Other causes include hyperthyroidism, hyperviscosity syndromes (polycythemia or multiple myeloma), severe hypertension, chronic uremia and severe electrolyte disturbances.^3,10,11,16 Less commonly, severe anemia, hypocalcemia and hyperlipidemia can cause reactive seizures in cats. ⁷

Clinical management is directed at identifying and addressing the underlying problem. Most of these patients do not require or benefit from chronic antiepileptic drug (AED) therapy.

Hepatic encephalopathy

Hepatic encephalopathy is an important cause of reactive seizures in cats, but the diagnosis can be easily missed if a high index of clinical suspicion is not maintained (see ‘Case notes’ below). The hepatic disorder most commonly associated with seizures in cats is a congenital portosystemic shunt (PSS).

Most cats with PSSs are younger than 1 year of age at the time of presentation and have had clinical signs present for months.^24–26 Small body size and golden or copper-colored irises are observed in approximately 50%. ²⁷ Signs of hepatic encephalopathy can be limited to seizures or may include episodes of drooling, altered mentation, circling, head pressing, visual deficits, ataxia and disorientation.^7,12,24–27

Classical clinicopathologic abnormalities include decreased BUN, albumin and glucose; but, although these changes are very consistent in dogs with PSSs, many cats with a PSS have no abnormalities on a biochemistry profile.^24,26 This means that a clinician will have to strongly suspect a PSS in order to proceed with a correct diagnostic work-up to include pre- and post-prandial bile acids and abdominal ultrasound. Failure to consider hepatic encephalopathy in a cat with seizures can result in an unnecessary intracranial work-up or potentially inappropriate treatment with antiepileptic medication when an incorrect presumptive diagnosis of IE is made in a cat with a PSS.

Seizures of intracranial origin

Seizures caused by intracranial pathology (structural epilepsy, also called secondary epilepsy or symptomatic epilepsy) account for 40–70% of all recurrent seizure disorders in cats.^{7,12,20,28,29} Lesions producing seizures are located in the forebrain, most often in the cerebral cortex, but occasionally in the subcortical regions of the brain, particularly the thalamus. ⁸

Approximately 75% of cats with structural epilepsy have interictal neurologic abnormalities suggesting structural disease of the thalamocortex, including unilateral or asymmetric menace deficits, paresis, decreases in proprioceptive placing, circling and subtle changes in personality or behavior (see box above, Case notes on page 816, and video 5 in supplementary material). ¹⁶ Lesions of the olfactory lobe, rostral frontal lobe or midline thalamus can, however, remain clinically silent for some time, other than causing seizures. Raimondi et al recently reported that 23% of cats older than 6 years at seizure onset with a normal interictal neurologic examination had a significant structural abnormality on MRI causing their seizure disorder. ³⁰

The most common causes of structural epilepsy in cats include neoplasia, inflammatory disorders, and vascular disorders such as infarcts or hemorrhage.^{1,7,11,16,17,20} Congenital anomalies, degenerative disorders, storage diseases and thiamine deficiency have also been reported. Hippocampal necrosis may additionally be an important cause of recurrent seizures in cats. In most patients with an intracranial cause for their seizures, MRI and potentially cerebrospinal fluid (CSF) collection and analysis will be needed to reach a diagnosis. ³ Medical management of seizures with AEDs may be recommended while attempting to treat the underlying disease process or whenever the structural disease that is identified cannot be treated. ¹

Neoplasia

Approximately 25% of cats with intracranial neoplasia experience seizures.

Generalized tonic–clonic seizures are observed in approximately 60% of cats seizuring due to intracranial neoplasia, with the rest showing both generalized and focal seizures or complex focal seizures alone.^17,18 MRI confirms the presence of a mass and provides information to aid in the diagnosis of tumor type (Figure 1). A variety of primary and metastatic forebrain tumors can cause recurrent seizures in cats, but meningiomas and lymphoma are the most common.^7,11,16,18 Meningiomas are usually very slow growing and histologically benign, causing seizures in middle-aged or older cats (median >9 years), while cats with intracranial lymphoma tend to be significantly younger (mean age of 5.6 years) with more rapidly progressive signs.^11,18 Reportedly 18% of cats with intracranial lymphoma are feline leukemia virus (FeLV) positive. ³¹

Figure 1

Transverse magnetic resonance images from a 12-year-old cat with an 8 month history of behavioral changes and decreased vision. MRI revealed a large extra-axial mass within the left cerebrum. A craniectomy was performed and the mass was removed. Histopathology confirmed the mass as being a meningioma. (a) T1-weighted image showing a large isointense, well-circumscribed mass within the left cerebrum, extending past the midline. (b) There is moderate enhancement of the mass following the administration of gadolinium. Images courtesy of Mary Smith, DVM, DACVIM (Neurology)

Inflammatory disease

Studies report a variable contribution of inflammatory disorders as a cause of recurrent seizures in cats, ranging from rare to common.^{7,11,12,15,16,31–33}

Feline infectious peritonitis

Feline infectious peritonitis (FIP) is widely considered to be the most common inflammatory disorder affecting the feline brain, and 25% of cats with confirmed neurologic FIP experience seizures.^17,31,32 Most cats with neurologic FIP are young (median 12 months).^32–35 Neurologic findings in addition to seizures may include altered mentation, ataxia, proprioceptive deficits and central vestibular signs.^32,36 Systemic manifestations of pyogranulomatous inflammation in cats with neurologic FIP can include fever, lethargy, icterus, uveitis, chorioretinitis and hypergammaglobulinemia. MRI commonly reveals meningitis and ventricular dilatation due to obstructive hydrocephalus.^31,32,34,36 Cisternal CSF can be normal but typically reveals a neutrophilic or mixed cell pleocytosis (neutrophils, lymphocytes, macrophages) with markedly increased protein.^33,36 Measurement of feline corona-virus (FCoV) antibodies in CSF relative to blood, and RT-PCR detection of FCoV in CSF can aid diagnosis, but definitive diagnosis usually requires post-mortem demonstration of FCoV within neural tissues.^31,32,34,36

Although some limited success has been reported with targeted antiviral treatment of cats with certain presentations of FIP, neurologic FIP is uniformly fatal.^36,37

Non-suppurative meningoencephalitis of unknown origin

Non-suppurative meningoencephalitis of unknown origin (viral non-FIP encephalitis) has also been documented as a common cause of seizures in cats.^{7,17,31,33,35,38,39} In one report investigating cats with recurrent seizures, 47% of the animals had non-suppurative meningoencephalitis that was suggestive of a viral infection but no infectious agent could be identified. ¹⁷ Young cats (less than 2 years of age) may be most commonly affected and clinical signs are progressive over 3–5 weeks. In addition to seizures, affected cats may develop ataxia, nystagmus, head tremor and fever.^31,33 CSF is normal or mildly inflammatory with a mononuclear pleocytosis.^31,33 The disorder is usually acute and rapidly progressive, but some cats will have a more chronic course and show partial or complete recovery.^31,33,39,40 Histologic lesions include meningitis, neuronal degeneration and variable lymphohistiocytic perivascular infiltrates suggesting a viral etiology.^{10,31,33,41,42} Routine testing for a wide range of known infectious agents has been negative.^{18,33,35,41,42}

Other infectious agents

Other infectious agents may cause diffuse or multifocal meningoencephalitis or focal granulomas or abscesses, all of which can be a cause of recurrent seizures. Most affected cats will exhibit other concurrent neurologic abnormalities, but occasionally seizures are the only finding. Toxoplasma, Cryptococcus and Bartonella species, feline immunodeficiency virus (FIV), FeLV, West Nile virus, bacterial agents and rabies virus have all been reported to cause seizures in cats.^{7,31,33,35,41–43}

Vascular disorders

Cerebrovascular accidents (CVAs) are disruptions in cerebral blood flow leading to neurologic dysfunction.^44,45 Infarction and hemorrhage are important causes of seizures in cats.^{3,7,11,20,44,45} Cerebral infarction classically causes a peracute onset of forebrain signs that are non-progressive after the initial 24 h.^44,45 Signs depend on the cerebral vessel affected, and therefore the amount and region of brain affected, but may include seizures, blindness, behavior change, circling and loss of proprioception. ⁴⁴ When performed within 72 h of the onset of clinical signs, MRI may reveal focal, well demarcated, characteristic parenchymal lesions.^44,45 Most cats experiencing an ischemic CVA improve neurologically within days to weeks unless their clinical presentation or underlying systemic disease is very severe.^44,45

Hypertension related to renal disease or hyperthyroidism is recognized as a major risk factor for ischemic feline CVA. ⁴⁵ Cerebral cuterebriasis, systemic neoplasia, cardiomyopathy-associated thromboembolic disease, sepsis, vasculitis and vascular degeneration have also been implicated, but in many cases no underlying cause is identified.^20,44–48

Feline ischemic encephalopathy

Feline ischemic encephalopathy, a disorder caused by aberrant migration of Cuterebra species larvae in the brain, occurs in young cats (usually <4 years of age) that have access to the outdoors in the summer months.^46–49 The larvae migrate through the nares and sinus, potentially causing rhinitis and sinusitis, and then through the cribriform plate. Migration of the parasite through the brain results in hemorrhage, necrosis and secondary vasospasm in response to a substance released by the parasite or from the damaged host brain parenchyma.^47,49 The areas normally perfused by the middle cerebral artery are infarcted, causing acute forebrain signs.

Diagnosis is suspected based on the per-acute onset of forebrain signs in a geographical region where Cuterebra flies are known to exist, but definitive diagnosis is difficult even with post-mortem examination. MRI can be performed to document localized inflammation and infarction. Treatment is largely supportive with oxygen, AEDs as needed, mannitol if warranted, and fluid therapy. Some advocate treating with ivermectin, prednisolone and diphenhydramine. ⁴⁹ A few cats will die but others will show a dramatic recovery within a few days, followed by a more gradual recovery over 4–6 weeks. Behavior changes (especially aggression) may be permanent, and some cats will have acquired epilepsy and require chronic AED treatment.

Hemorrhage

Intraparenchymal hemorrhage causing compression or distortion of brain parenchyma can lead to a peracute onset of forebrain signs including seizures. In cats this is most often caused by primary hypertension, hypertension secondary to hyperthyroidism or renal disease, primary or metastatic neoplasia, trauma, thiamine deficiency, thrombocytopenia and acquired coagulopathies secondary to anticoagulant intoxication or hepatic lipidosis.^11,20,46

Hippocampal necrosis

Feline hippocampal necrosis (FHN) is a severe structural abnormality in the brain that has been associated with seizures in cats.^7,20,50–54 It is uncertain whether this hippocampal pathology serves as an epileptogenic focus to cause seizures or if the FHN occurs secondarily to severe seizure activity.^7,51 Hippocampal neurons are very sensitive to hypoxia, hypoglycemia, hyperglycemia and glutamate excitotoxicity, potentially leading to ischemic injury and necrosis following severe seizures.^7,50,52–54 In humans and dogs, prolonged seizure activity can cause hippocampal ischemia that is initially reversible but can be perpetuated by ongoing seizure activity, leading to necrosis.^50,51,54 Hippocampal sclerosis has a strong association with temporal lobe epilepsy in humans. ⁵¹

Hippocampal necrosis occurs in 6–30% of seizuring cats and is most prevalent in cats with severe seizure disorders that have had at least one observed episode of cluster seizures or status epilepticus.^{16,20,50,51,55} Cats with focal-onset seizures with secondary generalization that develop status epilepticus after a prolonged history of recurrent seizures may be at highest risk. ²⁰ Many epileptic cats with FHN have no other structural brain disease identified, suggesting either that the FHN is causing their seizures or that they have IE and secondary hippocampal ischemia and necrosis.^19,20,54 There is one report of two cats with no MRI evidence of FHN at the onset of their seizure disorders, but severe FHN at re-evaluation and repeat MRI 7 months (case a) and 32 months (case b) later, after experiencing a severe worsening of seizure activity for 3–4 days and abnormal behavior and mentation. ⁵⁰ In one large study evaluating 93 cats with epilepsy, however, the risk of FHN was highest in cats with inflammatory or neoplastic causes for their severe seizure disorder, and all cats with bilateral FHN had neoplastic or inflammatory infiltrates invading both hippocampi. ²⁰

Most cats with FHN are presented because of a rapidly progressive acute cluster of generalized or complex focal seizures together with interictal abnormalities, suggesting a fore-brain lesion. Complex focal seizures with orofacial involvement are most common, including salivation, facial twitching, lip smacking, chewing, licking and swallowing. Behavior changes that persist between seizures often include staring into space, disorientation, aggression, rapid running, hyperexcitability and fearfulness.^19,50–54 MRI shows moderate T2 hyperintensity within the hippocampus and the piriform lobe that is often bilaterally symmetric, with signal alterations most apparent on fluid-attenuated inversion recovery (FLAIR) sequences (Figure 2).^19,50–53 Contrast enhancement is variable. ⁵³ Similar MRI changes occur in humans and dogs following severe seizure activity, presumably corresponding to ischemic injury, but the changes resolve completely on follow-up MRI. ⁵⁵ The potential for spontaneous resolution of acute hippocampal damage in cats with FHN is uncertain.

Figure 2

Transverse magnetic resonance images at the level of the sella turcica from a cat with behavioral changes and seizures. This cat continued to have seizures despite phenobarbital therapy and was euthanized. Post-mortem examination revealed hippocampal necrosis. (a) T2-weighted image; there is moderate bilateral symmetric hyperintensity in the entire hippocampus and the area of the piriform lobe. (b) T1-weighted image; mild hypointensity is seen in the area of the hippocampus and piriform lobe. (c) Contrast-enhanced T1-weighted image: there is marked contrast enhancement along the hippocampus and within the piriform lobe. Reproduced, with permission, from Schmied et al ⁵³

Early reports suggested that FHN had a poor prognosis, as all cats died or were euthanized when initial antiepileptic therapy was ineffective. ⁵⁴ Even when seizures can be controlled acutely, the neurologic and behavioral abnormalities may persist for several months and recurrent seizures can be a problem. ⁵³ There have, however, been reports of a few cats with FHN that gradually returned nearly to normal, with few neurologic deficits and well controlled seizures, suggesting that the long-term outcome can occasionally be good to excellent. ¹⁹ In 2012, Pakozdy et al reported that in some cats with clinical and MRI features of FHN, antibodies could be detected against proteins of the voltage-gated potassium channel complex, suggesting that the disorder could be a manifestation of autoimmune limbic encephalitis. Ten of 14 cats experienced full remission (ie, became seizure-free) after antiepileptic, supportive and corticosteroid treatment. ⁵⁶

Thiamine deficiency

Thiamine (vitamin Bl) is an essential component of a number of metabolic pathways and cats are particularly dependent on dietary thiamine.^57–60 Thiamine deficiency causing a progressive encephalopathy has been described in cats eating diets preserved with sulphur dioxide, commercial diets that have been inadequately supplemented, diets where thiamine is degraded by heating and diets containing thiaminase ^57–60 Neurologic signs may include impaired vision, mydriasis, ataxia, ventroflexion of the head and neck, vestibular signs, seizures, coma and even death ^57–59

Seizures are common in thiamine-deficient cats but are often accompanied by other neurologic signs.^57–60 Seizures occurred in 10 /17 cats (59%) fed a thiamine-deficient diet, and 80% of those seizuring cats experienced cluster seizures or status epilepticus. ⁵⁹ MRI of the brain can be normal in cats with neurologic signs due to thiamine deficiency or can reveal bilaterally symmetric hyperintense foci in the lateral geniculate nuclei, caudal colliculi, facial nuclei, cerebellar nodulus and medial vestibular nuclei on T2-weighted and FLAIR images (Figure 3).^57–60 These grey matter regions correspond to sites of hemorrhage and edema seen on neuropathology. ⁵⁷ Whole blood thiamine concentrations can be measured to confirm the diagnosis; and supplementation with parenteral and oral thiamine, and changing the diet to include adequate thiamine, will usually result in a rapid recovery and resolution of all neurologic signs including seizures.^57–60

Figure 3

(a)Transverse T2-weighted (T2W) magnetic resonance image at the level of the thalamus and (b) dorsal T2W image at the level of the caudal colliculi in a cat that presented with seizures and blindness caused by thiamine deficiency. There are bilaterally symmetric hyperintense lesions affecting the lateral geniculate nuclei (arrow in [a]) and caudal colliculi (arrow in [b]). Reproduced, with permission, from Chang etal ⁵⁹

Idiopathic epilepsy

The diagnosis of IE (primary epilepsy or unknown epilepsy) is one of exclusion and in dogs and cats is traditionally made based on typical signalment and seizure history, unremarkable interictal physical and neurologic examination, exclusion of underlying metabolic and toxic causes, and inability to find an intracranial cause (Table 2).^{1,3,5,6,10,14,23,29,30,61,62} These criteria for diagnosis have been problematic in cats, however, because until recently the published reports describing cats with IE have been very limited.

Table 2

Diagnostic evaluation of cats with recurrent seizures

Assessment	Inclusions and considerations
History	Including: behavioral, vaccination and diet history; potential for toxin exposure; onset and frequency of seizures; seizure description; postictal signs; interictal systemic signs
Physical examination
Complete ophthalmic examination
Blood pressure measurement
Neurologic examination	Including: mentation; posture, gait and postural reactions; spinal reflexes; assessment of neck/spinal pain; cranial nerve examination Neurologic examination can be abnormal for 12–24 h after seizure activity
Laboratory tests	Including: CBC; biochemistry profile; urinalysis; liver function tests (pre- and post-prandial serum bile acids or ammonia tolerance test); T4; FeLV/FIV; other infectious disease screening (Toxoplasma species serology, LCAT, etc)
Cancer screening	For older cats Including: thoracic radiographs and abdominal ultrasound
Advanced imaging: MRI	MRI can be abnormal for at least 7–14 days after seizure activity, with regional T2 hyperintensity likely representing cytotoxic and vasogenic edema
CSF analysis	Including: cytology; protein; ancillary tests CSF collection may only be recommended when MRI evaluation suggests inflammatory disease or lymphoma because of the risk of collection and lack of diagnostic specificity of CSF analysis. A mild pleocytosis and increased protein can be seen on cytology after repetitive seizures

CBC = complete blood count; CSF = cerebrospinal fluid; LCAT = latex cryptococcal antigen test; MRI = magnetic resonance imaging; T4 = thyroxine; FeLV = feline leukemia virus; FIV = feline immunodeficiency virus

Historically, IE was considered to be an uncommon cause of seizures in cats.^11,17,40,63 There was a perception that all cats with epilepsy must have an intracranial cause for their seizures, so when no cause could be readily found these cats were categorized as having ‘probable symptomatic’ or ‘cryptogenic’ epilepsy with no identifiable underlying cause. ¹⁷ Contributing to the confusion was the use of the term IE to describe familial epilepsy in dogs. Although there is proven inheritance of IE in several dog breeds, and inheritance is suspected in many others based on high breed prevalence or familial occurrence, there is really very little evidence to support a genetic cause in most cats with IE.^6–8,14

Studies have reported IE in 22–57% of cats with recurrent seizures,^{4,7,12,13,16,28–30,61,62,64} suggesting that IE should be considered an important differential diagnosis in such cases. The diagnosis of IE in these studies was based on normal interictal physical and neurologic examinations, normal metabolic testing and, in most cases, unremarkable MRI or postmortem histopathology of the brain. In a few cats, no advanced imaging or brain histopathology was performed, but the cats were observed for more than 12 months while they continued to have recurrent seizures and none developed interictal neurologic abnormalities, which would be expected if there was a progressive structural lesion in the brain causing the recurrent seizures.^7,16,65

Since intracranial disease has been reported to be the most common cause of seizures in cats and the typical clinical features of feline IE have not been well described previously, most investigators and clinicians recommend comprehensive diagnostic evaluation of all cats with recurrent seizures, looking for important metabolic and intracranial causes (Table 1).^{1,7,8,12,14,16–20,28,65} An additional important tool in the diagnosis of epileptic syndromes in humans is electroencephalographic recording (EEG) to identify interictal paroxysmal electrical discharges in the brain; however, this test has not yet been demonstrated to be a reliable clinical tool for identifying epileptic cats or differentiating cats with IE from those with structural epilepsy. ⁶⁶ Cats with IE are typically younger than cats with structural epilepsy. In several studies the mean age for seizure onset in cats with IE was between 3 and 5 years, while cats with intracranial disease did not usually start experiencing seizures until they were older than 8 years of age.^{1,4,7,10,11,16,30,61,62,64,65} There are, of course, exceptions as congenital disorders, FIP, non-suppurative meningoencephalitis of unknown etiology and feline ischemic encephalopathy predominantly affect young cats, while neoplasia is more common in the older cat population. Although there is considerable overlap between groups, a young adult cat is more likely to have IE than structural intracranial disease.^{4,7,16,30,61,64} A recent study by Raimondi et al found that seizure onset at less than 6 years of age without neurologic deficits was highly suggestive of IE, while the likelihood of having structural epilepsy confirmed by MRI increased substantially in cats older than 6 years at first seizure, even if the interictal neurologic examination was normal. ³⁰ The current authors suspect that most older cats that present for an acute onset of seizures with a normal interictal neurologic examination and negative extensive evaluation for intracranial disease do not actually have primary epilepsy but have instead a non-progressive, difficult to diagnose, acquired cause of seizures such as a small CVA.

Cats with IE can have generalized seizures, focal seizures or focal seizures with secondary generalization. tonic–clonic generalized seizures may be most frequent, but approximately 50% of cats with IE have both focal and generalized seizures.^{4,7,12,13,16–18,64,65} Audiogenic reflex seizures in older cats are also considered idiopathic. Salivation during a seizure has been reported to be more likely and ictal vocalization less likely in cats with IE than in cats with structural intracranial disease. ⁶¹

Seizure duration is usually 1–3 mins. Seizures in cats with IE are reported to occur most frequently during resting conditions, perhaps because there is an increase in cortical neuronal synchronization during sleep, decreasing the seizure threshold.^4,16 Status epilepticus rarely occurs during the first presentation of cats with IE, but progression from a cluster of seizures to status epilepticus will occur in 10–20% of cats with IE during a lifetime (vs 40% for other seizure etiologies) and is associated with a poor prognosis for survival.^7,16,20,65 Cluster seizures are common in cats with IE (53%) but their prevalence is not different from that of cats with other causes of seizures. ¹⁶

IE is the most likely diagnosis in a cat with a normal interictal neurologic examination, an age of onset between 1 and 5 years, and regularly recurring seizures that last 1–3 mins (see box on page 820). Physical and fundoscopic examinations are unremarkable and metabolic testing (including liver function and thyroid function) returns normal results. ⁴ Intracranial examination (MRI and CSF analysis) should always be performed if there are factors making IE less likely, such as age of seizure onset younger than 1 year or older than 5 years, interictal behavioral abnormalities or neurologic deficits, the occurrence of status epilepticus at seizure onset, or failure to respond adequately to chronic AEDs. These guidelines are similar to those recommended for the evaluation of dogs with recurrent seizures.^4,23

Key Points

• Recurrent seizures affect up to 3% of the feline population and can be classified according to their cause as being extracranial or intracranial in origin or idiopathic.

• Reactive seizures should always be ruled out prior to proceeding with an intracranial work-up.

• Cats with structural epilepsy often have an abnormal neurologic examination interictally.

• Unique underlying causes for structural epilepsy in cats include FIR non-suppurative meningoencephalitis of unknown origin, feline ischemic encephalopathy, hippocampal necrosis and thiamine deficiency.

• IE is the most likely diagnosis in a cat with a normal interictal neurologic examination, an age of onset between 1 and 5 years, and regularly recurring seizures that last 1–3 mins. Diagnosis is by exclusion of metabolic and intracranial causes.

• Cats with IE can have generalized seizures, partial seizures or partial seizures with secondary generalization.