SEIZURE

INVESTIGATION

References:

Davis KA, Sturges BK, Vite CH, Ruedebusch V, Worrell G, Gardner AB, Leyde K, Sheffield WD, Litt B (2011) A novel implanted device to wirelessly record and analyze continuous intracranial canine EEG. Epilepsy Res. 96(1-2):116-22. Epub 2011 Jun 14. - PubMed -

 

Levitski RE, Trepanier LA (2000) Effect of timing of blood collection on serum phenobarbital concentrations in dogs with epilepsy. JAVMA 217, 200-204. - PubMed -

 

Raith K, Steinberg T, Fischer A (2010) Continuous electroencephalographic monitoring of status epilepticus in dogs and cats: 10 patients (2004-2005). J Vet Emerg Crit Care (San Antonio). 20(4):446-55. - PubMed -

 

 

 

  • Overview

    1. Overview

    1.1 Clinical signs/definition

    A seizure is defined as a paroxysmal, transitory disturbance of brain function that has sudden onset, ceases spontaneously and tends to recur.

    An epileptic seizure is the physical manifestation of an excessive and⁄or hypersynchronous abnormal neuronal activity within the cerebral cortex. Epilepsy is not a specific disease but a chronic condition characterised by recurrent epileptic seizures. A patient having a single epileptic seizure does not have epilepsy as the seizures are not recurrent. It is important to recognise that an epileptic seizure is not a disease entity in itself but a clinical sign generally indicative of a forebrain disorder.

    Seizures can be classified into two major categories: partial and generalised.

    In dogs, generalised seizures are the most common. Generalised seizures indicate initial involvement of both cerebral hemispheres. Consciousness is impaired and motor manifestations are bilateral.

    Cats more commonly exhibit partial (focal) seizures. This type of seizure indicates abnormal neuronal activity in one region of the cerebral hemisphere. Any part of the body can be affected by a focal seizure depending on the region of the brain affected.

    There are 3 phases to an epileptic seizure:
    Pre-ictal phase: abnormal behavior for a period of hours or more prior to the episode.
    Ictus: rhythmic limb movements, salivation, chewing, defecation and urination.
    Post-ictal phase: altered behavior lasting a period of hours after the episode.

     

    1.2 Lesion location

    Seizures are usually the result of a forebrain disorder.

    The underlying cause for the seizure can be found outside the brain (metabolic or toxic causes) or inside the brain (structural or functional causes).

     

    1.3 Pathophysiology

    The normal brain cell maintains an unevenly distributed electrical charge across the cell membrane. The interior of the cell is negative with respect to the exterior, and this charge difference is maintained in the resting state primarily via the sodium/potassium ATPase pump that extrudes 3 Na ions in exchange for moving 2 K ions into the cell. This pump requires energy to maintain the interior of the cell approximately 70-85 mv negative with respect to the exterior.

    When the cell is excited, this resting membrane potential moves toward positive until threshold is reached (depolarization), and an action potential is generated (primarily via Na ions entering the cell). After threshold is reached and the action potential is generated, Na ions will be extruded, the molecular charge at the cell membrane will become more negative, and the cell will repolarise to its resting membrane potential.

    •  Two basic processes are occurring at the cellular level:
    a) The cell can be excited by excitatory post-synaptic potentials resulting in depolarization.
    b) In opposition the cell may be inhibited or prevented from depolarizing by stimulation from inhibitory
    post-synaptic potentials.

    Therefore, a battle may occur between the two, with a winner, or a neutral solution.

    The basic pathophysiological processes that result in seizures are excessive excitation or loss of inhibition (disinhibition):

    •  Hypoglycemia causes loss of energy substrate for the sodium/potassium ATPase pump, failure to extrude Na ions, and the cell moving toward positivity and depolarization (excessive excitation).

    •  In a disease process where inhibitory transmitters are unable to function (hepatic encephalopathy?), the lack of inhibition will allow for unregulated depolarization.

    A seizure can occur when brain cells spontaneously depolarise. For a seizure to be propagated, a cell or group of cells must depolarise (paroxysmal depolarization shift (PDS)). Normal neurons display sporadic, low-frequency activity. The brain normally handles these minor electrical events without our knowledge. In seizure foci, the firing pattern is one of regular recurrent high-frequency bursts of action potentials.

    •  Even with abnormal electrical events the PDS usually remain localised to a small area. The brain is able to control much of this activity by surrounding inhibition.

    When a depolarization is of a sufficient magnitude, the impulse will be conducted (most likely through normal anatomic connections), to the entire brain and a generalised seizure will be produced. This spread can occur in milliseconds and a generalised seizure will be seen from the onset or, if the spread is slower, an initial focal seizure (confined to one body part/area), may eventually generalise. If the spread of the electrical discharge is stopped, a focal seizure occurs. Focal seizures may become generalised through normal brain interconnections, or may become generalised by synchronised depolarizations controlled from the thalamus and other subcortical structures. This centrencephalic theory of seizure propagation suggests that generalised seizure activity originates in structures in the brain stem and thalamus, which is then projected to the cortex. Experimental evidence suggests that both brain stem and cortical stimulation may result in seizure activity.

    Two interesting phenomena that occur due to seizure activity are:

    Mirror focus - where a seizure focus creates similar activity in a homologous area of the contralateral hemisphere.

    Kindling is simply the fact that seizure can cause further seizure.

    With time both mirror foci and kindled foci may become autonomous and form a new, independent seizure focus.

    Why seizures terminate as rapidly as they begin is also unknown. Metabolic exhaustion of neurons is not an adequate explanation. Extracortical inhibitory centers, such as within the cerebellum, may play a role (ablations of the cerebellum facilitates seizure activity). Phenytoin, a commonly used anticonvulsant in human beings, dramatically increases the rate of firing of Purkinje neurons. Other areas such as the caudate and parts of the thalamus and reticular formation may also help to terminate seizure activity.

    It is often noted that seizures occur in the middle of the night in dogs. One explanation is that during low levels of awareness, drowsiness and dreamless sleep, decreased activity in the reticular formation allows for reverberating circuits between the thalamus and the cortex to synchronise. Additionally, groups of neurons which are only mildly hyperactive in the awake state become excitable and fire consistently during sleep.

     

    1.4 Differential diagnoses

    •  Seizures can be mimicked by:

    •  Syncope

    •  Weakness

    •  Narcolepsy

    •  Scottie cramp

    •  Vestibular disease

    •  Myasthenia gravis

    •  Painful focus

  • Approach to evaluation

    2. Approach to evaluation

    2.1 History - important questions

    A number of questions are important to narrow down differential diagnosis

    Age at the onset of the first seizure (may help to narrow likely differential diagnosis list as different forms of disease more likely at different ages).

    Owner's description of these episodes from start to end (may help to confirm the epileptic nature of the events and aid recognition of conditions that mimic an epileptic seizure).

    Frequency of seizures (the aim of anti-epileptic treatment is not to cure the animal of his epilepsy but to "control" the seizures with "acceptable" side effects - decision to start treatment should be based on the frequency of the seizures.

    Warning: There is no correlation between the actual seizure frequency and underlying disease process as an animal with idiopathic epilepsy might experience seizures on a weekly basis while an animal in the early stage of a brain tumour might be presented with only one recorded seizure event.

    What was the animal doing just before the episode occurred (dogs with idiopathic epilepsy typically seizure when they are at rest or sleeping - seizures at exercise or associated with excitement are more common with cardiovascular disease or metabolic disease eg hypoglycemia).

    Relationship of episodes to feeding (metabolic causes of seizures such as congenital porto-systemic shunt may be associated with feeding or fasting).

    Behavior, mental status, gait between episodes ie interictal period (should be normal in case of idiopathic epilepsy. The presence of inter-ictal abnormality is suggestive of a metabolic or structural intracranial cause for the seizure).

    Presence of other systemic signs.

    Previous medical history (sudden cessation of anticonvulsant drugs can trigger seizure activity, hepatotoxic drugs can result in liver damage and hepatic encephalopthy, some drugs have neurological side effects).

    Vaccination status (some infectious viral diseases can result in seizures but are prevented by vaccination).

    Travel history (some diseases potentially causing seizures are more common or only present abroad).

    Any familial history of seizures (epilepsy may be proven or suspected to be inherited in some breeds eg Labrador retriever, Golden Retriever, Border Collie, German Shepherd Dog)..

     

    2.2 Examination

    2.2.1 General physical examination

    In all patients, the neurological examination should be preceded by a thorough examination of all other body systems. This is essential in detecting abnormality in other body systems that might also affect the nervous system (e.g. animal with liver disease presented for epileptic seizures and abnormal mentation), mimic a primary neurologic disorder (e.g. severe cardiovascular disease causing syncope) or could influence the prognosis.

     

    2.2.2 Specific examination

    An epileptic seizure is not a disease entity in itself but a clinical sign generally indicative of a forebrain disorder. Seizure etiology can be classified as intracranial or extracranial. Intracranial causes are further subdivided into those where a structural lesion is identified (vascular, inflammatory⁄infectious, traumatic, anomalous, neoplastic disease) and those where no such lesion is present, that is primary (functional or idiopathic) epilepsy.

    The detection of forebrain signs on neurological evaluation in the inter-ictal period generally rules-out primary epilepsy. The only exception to this rule is ischemic necrotic brain lesions secondary to violent seizures (excitotoxicity phenomenon). Such lesions are particularly found in cats in the NMDA receptor-rich brain region such as the hippocampus. Inter-ictal neurological deficits frequently observed include mainly behavioral changes (aggression, fear, hyperexcitability, uncontrolled biting, chasing) as well as other signs referring to forebrain involvement (circling, uni- or bilateral central blindness, decreased mental status).

    Most animals with structural forebrain disorders show neurological signs in the interictal period. These signs are often asymmetric and can localise the lesion. They can refer to a forebrain disorder (ipsilateral circling, contralateral postural reaction deficit, contralateral menace response loss with normal papillary light reflex, contralateral abnormal response to stimulation of the nostril, abnormal behavior) or to a multifocal disorder (cranial nerve or spinal cord involvement).

    The exception to this is a structural lesion in a "silent area" of the brain (region of the brain which causes only seizures with no other localizing signs such as the olfactory lobe or prefrontal lobes) or in the early stage of an enlarging (and eventually slowly growing) mass.

    In case of metabolic or toxic causes, the animal may have normal or abnormal neurological examination in the interictal period. If neurological signs are seen, they are typically symmetrical and non-localizing in term of anatomic diagnosis.

     

    2.3 Clinical pathology

    The least invasive diagnostic tests should be performed first. Blood tests are indicated to investigate metabolic causes. Brain imaging, CSF analysis, PCR and serology for infectious disease are then indicated to investigate structural brain diseases.

    Tip: The diagnosis of primary (idiopathic) epilepsy is a diagnosis of exclusion after elimination of extracranial causes (metabolic or toxic) and structural intracranial causes. There is no definitive diagnostic test to confirm this condition.

     

    2.3.1 Routine screening tests

    Aim to rule-out extracranial metabolic causes:

    liver enzymes (AST, ALT, ALP and bile acid stimulation test (to rule out hepatic encephalopathy)

    Urea and creatinine (to rule-out uremic encephalopathy)

    Glucose (To rule out hypoglycemia)

    Calcium (to rule-out hypocalcalcemia)

    PCV (to rule-out anemia⁄polycythemia)Electrolytes eg sodium, potassium (to rule-out electrolyte imbalance)

     

    2.3.2 Advanced/specific tests

    2.3.2.1 Assay for toxins

    Lead assays and cholinesterase assays are possible.

    Opioids

     

    2.3.2.2 Toxoplasma and neospora titers

    PCR on CSF and blood for Distemper, Toxoplasma, Neospora (to rule-out infectious causes).

     

    2.3.2.3 Endocrine test

    Thyroid evaluation (tT4, fT4, endogenous TSH) to rule-out hypothyroidism.

     

    2.3.2.4 CSF analysis

    Examination of CSF may show evidence of an inflammatory response. CSF results should be interpreted in light of the neurological examination and clinical findings (suspected etiological diagnosis) and results of other tests (such as MRI and infectious disease titer).

    Warning: Taken on their own, CSF results are relatively poorly sensitive and poorly specific.

     

    2.4 Diagnostic imaging

    Imaging of the brain, preferentially MRI scanning, is the cornerstone of the investigation of possible structural brain causes.

     

    2.4.1 Routine imaging

    Thoracic and abdominal radiographs to rule out systemic conditions causing seizures. Warning: Skull radiographs are rarely helpful. Ultrasonography may be useful to further investigate suspected cardiovascular or metabolic disease eg portosystemic shunts.

     

    2.4.2 Specific/advanced tests

    MRI and MRI angio studies to investigate the possibility of structural brain disease (vascular, inflammatory⁄infectious, neoplastic, anomalous, traumatic).Computed tomography (CT) of brain. PET scans.

     

    2.5 Specific tests

    EEG is rarely useful. Absolute confirmation of the epileptic nature can only be obtained by observing simultaneously the characteristic EEG changes and physical manifestation of the seizures. The incidence of abnormal EEG in dogs with idiopathic epilepsy in the interictal period is low. EEG recording can help to detect structural brain disease. Apart from rare cases (such as hydrocephalus), the specificity of such findings is low.

    ECG may be indicated for suspected cardiac disease.

  • Etiology

    3. Etiology

    3.1 Degenerative

    Storage diseases

    Age-related senile disease

    In-born errors of metabolism

     

    3.2 Developmental/structural abnormality

    3.2.1 Congenital

    Hydrocephalus

     

    3.2.2 Inherited

     

    3.3 Metabolic

    Electrolyte abnormality (hypoglycemia, hypocalcemia)

    Hepatic encephalopathy

    Uremia

    Hyperproteinemia

    Hyperlipidemia

    Hypothyroidism

    Hypoxia (cardiac or respiratory insufficiency)

    Anemia

     

    3.4 Neoplastic

     

    3.4.1 Primary

    Brain tumor

     

    3.4.2 Secondary

    Brain metastases eg mammary adenocarcinoma

     

    3.5 Idiopathic

    Idiopathic epilepsy

     

    3.6 Inflammation

     

    3.6.1 Infectious

     

    3.6.1.1 Bacterial

    Bacterial meningitis

     

    3.6.1.2 Viral

    Distemper

     

    3.6.2 Immune-mediated

    GME

     

    3.7 Toxic

    Lead

    Metaldehyde

    Ethylene glycol

    Strychnine

    Chocolate

    Chlorinated hydrocarbons

     

    3.8 Trauma

     

    3.8.1 Acute

    Head trauma

     

    3.8.2 Delayed onset

    Head trauma (traumatic epilepsy).

     

  • Treatment

    4. Treatment

    4.1 Emergency care

    Status epilepticus is an emergency

     

    Immediate treatment is necessary because status epilepticus (SE) can cause permanent neurological sequela or even death. There is some evidence to suggest that early aggressive treatment of prolonged seizures results in their termination with smaller doses of medication and less overall risk to the patient than would be incurred by delaying therapy. In addition, profound hemodynamic and metabolic abnormalities commonly occur during seizures and may cause significant morbidity despite appropriate treatment of the seizures. Moreover, administration of anticonvulsants may also contribute to the hemodynamic instability. Therefore, management of SE requires a prompt, comprehensive, and dynamic approach and should be individualised, depending on the animal's clinical status.

    IV anticonvulsants (see seizure management).

    Anesthetise dog if seizures continue uncontrolled.

     

    4.2 General principles of management

    4.2.1 Symptomatic therapy

    Anticonvulsant therapy should be given if seizures severe, frequent or cannot treat underlying cause. Further details can be found in seizure management.

    Phenobarbitol

    Primidone

    Bromide

    Diazepam

    Phenytoin

     

    4.2.2 Monitoring

    Anticonvulsant therapy requires monitoring

    Monitoring progression of underlying disease

  • Most likely etiology

    4. Treatment

    4.1 Emergency care

    Status epilepticus is an emergency

     

    Immediate treatment is necessary because status epilepticus (SE) can cause permanent neurological sequela or even death. There is some evidence to suggest that early aggressive treatment of prolonged seizures results in

     

    5. Most likely etiology

    5.1 Intracranial Causes

    Functional

    Generalised seizures (rarely partial)

    Initially low frequency

    Normal neurological examination in interictal period

    Normal CSF analysis

    Normal brain imaging

    Structural

    Partial or generalised seizures

    Variable frequency

    Neurological deficits in inter-ictal period (except lesion in silent area of the brain or in early stage)

    Normal or abnormal CSF analysis

    Often abnormal brain imaging

     

    5.2 Extracranial Causes

    Metabolic or toxic

    Generalised seizures

    Often high frequency

    Often abnormal neurological examination in the inter-ictal period (diffuse and symmetric deficits - can wax and wane) or the period preceding the seizure (muscular weakness with hypoglycemia, tremor with hypocalcemia, abnormal mental status and behavior with hepatic encephalopathy)Abnormal biochemical findings (hypoglycemia, hypocalcemia, uremia, electrolyte imbalance, elevated pre- and post-prandial bile acids)

    Documented exposure to toxins

     

    5.3 Interictal signs

    5.3.1 Normal

    Normal inter-ictal examination

     

    Primary epilepsy

    Structural brain disease (especially tumor) in silent area of the forebrain or at early stages

    Metabolic disease (clinical signs can wax and wane with hypoglycemia, hypocalcemia or portosystemic

     

    5.3.2 Abnormal

    Abnormal inter-ictal examination and symmetrical deficits

    Metabolic disease

    Intoxication

    Hydrocephalus (congenital or acquired)

    Midline structural brain disease (pituitary tumor, diencephalic tumor)

    (Degenerative disease)

     

    Abnormal inter-ictal examination and asymmetrical deficits
    Structural brain disease (tumor, inflammation⁄infection, cerebrovascular accident, old or recent head trauma, malformation)

     

    5.4 Age

    5.4.1 Immature

    Immature (less than 6 month old)

    Portosystemic shunt

    Intoxication

    Infectious CNS disease (distemper, neosporosis)

    Malformation

    Hypoglycemia

    Head trauma

     

    5.4.2 Young Adult

    Young adult (between 6 month and 6 year old)

    Primary epilepsy

    Cerebrovascular accident

    Inflammatory⁄infectious CNS disease

    Head trauma

    Metabolic disease

    Intoxication

    (Tumor rare in this age range except in brachycephalic breed)

     

    5.4.3 Older

    Adult (more than 6 year old)

    Tumor

    Metabolic disease (especially hypoglycemia secondary to insulinoma)

    Inflammatory CNS disease

    Head trauma

    Intoxication

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