Non-Epileptic Seizures

Non-epileptic seizures (NES) are paroxysmal events that clinically resemble epileptic seizures but are not caused by abnormal, excessive, or synchronous neuronal activity in the brain. They are also referred to as psychogenic non-epileptic seizures (PNES) in human medicine, but in veterinary medicine, the term encompasses a broader range of conditions including syncopal events, movement disorders, sleep disorders, and metabolic or toxic-induced episodes that mimic seizures. NES are characterized by transient alterations in consciousness, motor activity, or behavior that may be mistaken for epilepsy but have a distinct underlying pathophysiological mechanism. Accurate differentiation between epileptic seizures and NES is critical for appropriate therapeutic intervention and prognosis. In veterinary patients, NES are often underdiagnosed or misdiagnosed as epilepsy, leading to unnecessary antiepileptic drug (AED) therapy and potential adverse effects. The classification of NES includes cardiovascular events (e.g., syncope), metabolic disturbances (e.g., hypoglycemia, electrolyte imbalances), toxicities (e.g., certain plant or drug intoxications), and behavioral or psychogenic events (e.g., stereotypies, anxiety-related episodes). A thorough diagnostic workup is essential to identify the underlying cause and guide management.

The etiologies of non-epileptic seizures are diverse and can be categorized into several major groups: cardiovascular, metabolic, toxic, and behavioral/psychogenic. Cardiovascular causes include syncope due to arrhythmias (e.g., sick sinus syndrome, atrioventricular block, ventricular tachycardia), hypotension, or structural heart disease (e.g., hypertrophic cardiomyopathy, aortic stenosis). Metabolic disturbances that can precipitate NES include hypoglycemia (e.g., insulinoma, sepsis, hepatic insufficiency), hypocalcemia (e.g., hypoparathyroidism, eclampsia), hyperkalemia (e.g., urinary obstruction, hypoadrenocorticism), hyponatremia or hypernatremia, and hepatic encephalopathy. Toxic causes encompass exposure to various substances such as chocolate (theobromine), xylitol, lead, organophosphates, pyrethrins, and certain plants (e.g., lilies in cats). Behavioral or psychogenic causes include anxiety, fear, or stress-induced episodes, stereotypies (e.g., fly-biting, tail chasing), and compulsive disorders. Additionally, sleep disorders such as narcolepsy or REM behavior disorder can manifest as paroxysmal events. In some cases, the exact cause remains idiopathic. It is important to note that NES can coexist with epilepsy, complicating diagnosis and management.

Non-epileptic seizures are reported in both dogs and cats, though the exact prevalence is unknown due to diagnostic challenges. In dogs, syncope is the most common cause of NES, particularly in breeds predisposed to cardiac disease such as Boxers, Doberman Pinschers, and Cavalier King Charles Spaniels. Metabolic causes like hypoglycemia are more common in young puppies (e.g., toy breeds) and in animals with insulinomas (typically middle-aged to older dogs). Hypocalcemia is seen in lactating bitches and in cats with primary hypoparathyroidism. Toxic exposures are more common in younger animals due to indiscriminate ingestion. Behavioral NES are reported in both dogs and cats, with certain breeds (e.g., Bull Terriers for tail chasing) showing a predisposition. There is no clear sex predilection, but age varies with the underlying cause: cardiovascular events are more common in older animals, while metabolic and toxic causes may occur at any age. Geographic variation exists for certain toxicities (e.g., lead poisoning in urban areas). Overall, NES may account for up to 20-30% of cases referred for seizure-like activity, emphasizing the need for accurate diagnosis.

The pathophysiology of NES depends on the underlying cause. In syncope, a transient reduction in cerebral perfusion leads to global cerebral hypoxia, causing loss of consciousness and sometimes brief myoclonic jerks. This can result from cardiac arrhythmias (reduced cardiac output), vasovagal reflexes (bradycardia and vasodilation), or orthostatic hypotension. Metabolic disturbances disrupt neuronal function by altering ion gradients, neurotransmitter levels, or energy supply. For example, hypoglycemia deprives neurons of glucose, leading to energy failure and altered membrane potentials. Hypocalcemia increases neuronal excitability by affecting sodium channel permeability, while hyperkalemia impairs cardiac conduction and can cause muscle weakness. Hepatic encephalopathy involves accumulation of neurotoxins like ammonia, which interfere with neurotransmitter systems. Toxic agents may directly affect ion channels (e.g., pyrethrins prolong sodium channel opening) or neurotransmitter receptors (e.g., organophosphates inhibit acetylcholinesterase). Behavioral NES are thought to involve psychological stress and learned responses, with no identifiable organic brain lesion. In all cases, the final common pathway is a transient functional disturbance that mimics seizure activity but lacks the characteristic electroencephalographic (EEG) changes of epilepsy.

Predisposing factors for NES include breed-specific cardiac diseases (e.g., Boxer cardiomyopathy), age (young animals for hypoglycemia, older for cardiac syncope), sex (eclampsia in lactating females), and concurrent systemic diseases (e.g., diabetes mellitus, renal failure, hepatic insufficiency). Environmental factors such as access to toxins (e.g., chocolate, xylitol) increase the risk of toxic NES. Stress, anxiety, and behavioral disorders predispose to psychogenic NES. Animals with a history of head trauma or intracranial disease may have a lowered seizure threshold, making them more susceptible to metabolic or toxic triggers. Additionally, certain medications (e.g., diuretics causing electrolyte imbalances) can predispose to NES. In cats, hyperthyroidism can cause hypertension and syncope. Obesity and lack of exercise may contribute to cardiovascular events. A thorough history and physical examination are essential to identify these risk factors.

Clinical signs of NES vary depending on the underlying cause but generally include sudden collapse, loss of consciousness, and brief episodes of abnormal motor activity. Syncopal events are typically characterized by a prodrome of weakness, staggering, or vocalization, followed by collapse and recumbency. During syncope, the animal may be flaccid or have mild myoclonic jerks, but there is no tonic-clonic activity, and recovery is rapid (seconds to minutes) with no post-ictal phase. Metabolic NES may present with tremors, ataxia, disorientation, and in severe cases, collapse. Hypoglycemia often causes weakness, lethargy, and tremors that resolve with glucose administration. Hypocalcemia can lead to muscle fasciculations, tetany, and seizures-like episodes. Toxic NES may include vomiting, diarrhea, hypersalivation, and neurological signs such as tremors, ataxia, and seizures. Behavioral NES may manifest as episodes of abnormal behavior (e.g., fly-biting, tail chasing) without loss of consciousness or autonomic signs. It is crucial to obtain a detailed description of the event from the owner, including duration, triggers, and any post-event behavior, to differentiate NES from true epilepsy.

The primary differential diagnosis for NES is true epileptic seizures, which are caused by abnormal neuronal activity. Key distinguishing features include: epileptic seizures often have a pre-ictal phase (aura), a post-ictal phase (disorientation, blindness, pacing), and may involve autonomic signs (salivation, urination, defecation). Syncope is differentiated by its rapid onset, brief duration, and absence of post-ictal signs. Other differentials include: 1) Narcolepsy: sudden onset of sleep episodes, often triggered by excitement, with rapid recovery. 2) Vestibular disease: head tilt, nystagmus, and ataxia, but no loss of consciousness. 3) Neuromuscular disorders (e.g., myasthenia gravis): episodic weakness, but no altered consciousness. 4) Pain episodes (e.g., pancreatitis, discospondylitis): may cause recumbency and vocalization, but consciousness is preserved. 5) Movement disorders (e.g., paroxysmal dyskinesia): involuntary movements without loss of consciousness. 6) Toxicities (e.g., strychnine poisoning): severe muscle spasms and rigidity, but consciousness is maintained. 7) Metabolic diseases (e.g., hepatic encephalopathy): waxing and waning neurological signs, often associated with meals. 8) Intracranial diseases (e.g., brain tumors, encephalitis): may cause seizures but also other focal neurological deficits. A thorough diagnostic workup is essential to rule out these conditions.

The diagnostic approach to NES begins with a thorough history and physical examination, including a detailed description of the event (e.g., video recording by the owner). The next step is to rule out common metabolic and toxic causes via baseline blood work: complete blood count (CBC), serum biochemistry profile (including glucose, calcium, electrolytes, liver enzymes, bile acids), and urinalysis. If cardiovascular disease is suspected, thoracic radiographs, electrocardiography (ECG), and echocardiography are indicated. For suspected arrhythmias, a 24-hour Holter monitor may be necessary. If metabolic causes are ruled out and no cardiac abnormalities are found, advanced imaging of the brain (MRI) and cerebrospinal fluid (CSF) analysis may be considered to exclude structural intracranial disease. In cases where behavioral NES is suspected, a video recording and consultation with a veterinary behaviorist may be helpful. In some cases, an electroencephalogram (EEG) can be performed to differentiate epileptic from non-epileptic events, but this is not widely available in veterinary practice. The diagnostic algorithm should be tailored to the individual patient based on signalment, history, and clinical signs.

Laboratory findings in NES depend on the underlying cause. In hypoglycemia, blood glucose is typically below 60 mg/dL (3.3 mmol/L). Hypocalcemia is defined as total calcium < 8.0 mg/dL (2.0 mmol/L) or ionized calcium < 1.0 mmol/L. Hyperkalemia is seen with urinary obstruction or hypoadrenocorticism (potassium > 5.5 mEq/L). Hyponatremia (< 130 mEq/L) or hypernatremia (> 160 mEq/L) may be present. Hepatic encephalopathy may show elevated liver enzymes, hyperbilirubinemia, and elevated fasting or post-prandial bile acids. Toxicities may reveal specific abnormalities: for example, lead poisoning may show basophilic stippling on blood smear, and organophosphate toxicity may show decreased cholinesterase activity. In cardiac syncope, laboratory findings are often normal, but cardiac biomarkers such as NT-proBNP may be elevated. In behavioral NES, all laboratory tests are typically within normal limits. It is important to perform a comprehensive laboratory panel to identify the underlying cause and guide treatment.

Imaging findings in NES are variable. Thoracic radiographs may reveal cardiomegaly, pulmonary edema, or other signs of cardiac disease in syncope due to heart failure. Abdominal radiographs may show radiopaque foreign bodies in toxic ingestions. Echocardiography is essential for diagnosing structural heart disease (e.g., hypertrophic cardiomyopathy, valvular disease) and can identify dynamic outflow obstructions. Electrocardiography (ECG) may reveal arrhythmias such as atrial fibrillation, ventricular tachycardia, or heart block. Holter monitoring is useful for detecting intermittent arrhythmias. In cases of suspected intracranial disease, MRI of the brain is the imaging modality of choice and can identify structural lesions (e.g., tumors, inflammation, infarcts). CT may be used if MRI is unavailable. In metabolic NES, imaging is typically unremarkable. In behavioral NES, brain imaging is normal. Imaging should be guided by clinical suspicion and is not always necessary if a clear metabolic or toxic cause is identified.

Cytology and histopathology are not typically performed for the diagnosis of NES unless there is an underlying neoplastic or inflammatory process. For example, if a brain tumor is suspected, histopathology of a biopsy sample may be obtained. In cases of insulinoma, histopathology of the pancreatic mass may confirm the diagnosis. In inflammatory conditions (e.g., encephalitis), CSF analysis may show increased protein and nucleated cell count, and histopathology of brain tissue may reveal inflammatory infiltrates. However, in most cases of NES, cytology and histopathology are not indicated. If a toxic cause is suspected, analysis of gastric contents or liver tissue may be performed post-mortem. In behavioral NES, there are no specific cytological or histopathological findings.

Treatment of NES is directed at the underlying cause. For syncope due to cardiac arrhythmias, antiarrhythmic drugs (e.g., atenolol, sotalol, mexiletine) or pacemaker implantation may be necessary. For structural heart disease, appropriate cardiac medications (e.g., pimobendan, diuretics, ACE inhibitors) are used. Metabolic causes are treated by correcting the underlying abnormality: hypoglycemia is managed with glucose administration and treatment of the underlying cause (e.g., insulinoma surgery, dietary management). Hypocalcemia is treated with calcium supplementation (e.g., 10% calcium gluconate at 0.5-1.5 mL/kg IV slowly, followed by oral calcium and vitamin D). Hyperkalemia is managed with fluids, insulin/dextrose, and treatment of the underlying cause. Hepatic encephalopathy is treated with lactulose, antibiotics (e.g., neomycin), and dietary modification. Toxicities are managed with decontamination (e.g., emesis, activated charcoal) and specific antidotes if available (e.g., atropine for organophosphates). Behavioral NES may respond to behavior modification, environmental enrichment, and anxiolytic medications (e.g., fluoxetine, clomipramine). In all cases, supportive care, including fluid therapy and nutritional support, is important. Antiepileptic drugs are not indicated for NES unless the animal also has epilepsy.

The prognosis for NES depends on the underlying cause. For syncope due to cardiac disease, the prognosis is variable and depends on the severity of the cardiac condition; some arrhythmias are manageable, while others may have a guarded prognosis. Metabolic causes such as hypoglycemia due to insulinoma have a guarded prognosis if the tumor is malignant, but surgical removal can be curative in some cases. Hypocalcemia due to hypoparathyroidism is manageable with lifelong supplementation, and the prognosis is good with appropriate treatment. Toxicities have a good prognosis if treated early and the toxin is identified. Behavioral NES have a variable prognosis; some animals respond well to behavior modification and medication, while others may have persistent episodes. Overall, the prognosis is better for NES than for epilepsy, as the underlying cause is often treatable. However, misdiagnosis and inappropriate treatment with AEDs can lead to adverse effects and poor outcomes.

Follow-up for NES depends on the underlying cause. For cardiac syncope, regular rechecks with ECG and echocardiography are recommended every 3-6 months. For metabolic causes, monitoring of blood glucose, calcium, or electrolytes should be performed as needed. For toxicities, follow-up is usually short-term unless there are long-term sequelae. For behavioral NES, regular consultations with a behaviorist and medication adjustments may be necessary. In all cases, owners should be educated to recognize the signs of NES and to seek immediate veterinary care if episodes become more frequent or severe. A recheck examination is typically recommended 1-2 weeks after initial diagnosis to assess response to treatment, and then at regular intervals depending on the condition.

Pearls: 1) Always obtain a video recording of the event from the owner; this is invaluable for diagnosis. 2) Syncope is often triggered by excitement or exercise and is followed by rapid recovery. 3) Hypoglycemia should be ruled out in any young or small-breed dog with collapse. 4) Cardiac evaluation, including ECG and Holter monitoring, is essential in older animals with collapse. 5) Behavioral NES may be triggered by specific situations and may be reduced with environmental enrichment. Pitfalls: 1) Assuming all seizure-like events are epilepsy and starting AEDs without a thorough workup. 2) Missing a cardiac cause of syncope, which can be life-threatening. 3) Failing to consider toxic exposures, especially in young animals. 4) Overlooking metabolic causes such as hypocalcemia or hypoglycemia. 5) Not recognizing that NES can coexist with epilepsy, requiring a combined approach.

Drug protocols for NES are specific to the underlying cause. For cardiac syncope due to arrhythmias: Atenolol (0.25-1 mg/kg PO q12h) for supraventricular arrhythmias; Sotalol (1-2 mg/kg PO q12h) for ventricular arrhythmias; Mexiletine (4-8 mg/kg PO q8h) for refractory ventricular arrhythmias. For heart failure: Pimobendan (0.25-0.3 mg/kg PO q12h), Furosemide (1-4 mg/kg IV/PO q8-12h), Enalapril (0.5 mg/kg PO q12h). For hypoglycemia: Acute: 50% dextrose (1-2 mL/kg IV diluted 1:1 with saline) followed by CRI of 2.5-5% dextrose. Chronic: dietary management and treatment of underlying cause (e.g., surgery for insulinoma). For hypocalcemia: Acute: 10% calcium gluconate (0.5-1.5 mL/kg IV over 20-30 min with ECG monitoring). Chronic: oral calcium carbonate (25-50 mg/kg/day) and vitamin D (calcitriol 2.5-6.5 ng/kg/day). For hyperkalemia: 10% calcium gluconate (0.5-1 mL/kg IV over 10-20 min), regular insulin (0.1-0.2 U/kg IV) with dextrose (2 g/U insulin), and sodium bicarbonate (1-2 mEq/kg IV) if acidotic. For hepatic encephalopathy: Lactulose (0.5-1 mL/kg PO q8h), neomycin (20 mg/kg PO q8h), and a low-protein diet. For toxicities: Specific antidotes as indicated (e.g., atropine for organophosphates, pralidoxime for organophosphates, activated charcoal for many toxins). For behavioral NES: Fluoxetine (0.5-1 mg/kg PO q24h) or clomipramine (1-3 mg/kg PO q12h) in dogs; fluoxetine (0.5-1 mg/kg PO q24h) in cats. Always adjust dosages based on renal/hepatic function and monitor for adverse effects.

Evidence-based literature on NES in veterinary medicine is limited, but several studies highlight the importance of differentiating NES from epilepsy. A study by Berendt et al. (2004) evaluated dogs with seizure-like episodes and found that 20-30% had non-epileptic events, with syncope being the most common. Another study by Packer et al. (2015) emphasized the use of video recording to aid in diagnosis. ACVIM consensus statements on epilepsy (2021) recommend a thorough diagnostic workup to rule out reactive seizures and NES before initiating AED therapy. In human medicine, PNES is well-documented, and the diagnostic criteria include video-EEG monitoring. Veterinary studies on specific causes, such as insulinoma (e.g., Tappin et al., 2008) and cardiac syncope (e.g., Santilli et al., 2011), provide evidence for diagnostic and therapeutic approaches. Overall, the literature supports a systematic approach to diagnosing NES, with a focus on identifying the underlying cause to guide treatment and improve outcomes.