Neurology is often seen as a disengaging subject, with seizures representing a manifestation of the dysfunctional ‘black-box’ we know as the brain. Seizures in small and fragile juvenile patients can quickly become life-threatening, demanding critical attention and informed intervention. This, when combined with the emotions of the owner, can lead to a very stressful environment in which time is of the essence and clear thinking is the key to success. A structured approach to investigating the problem allows optimal management of these cases, giving these altricial patients every chance of success. This article will discuss some conditions that are specific to these patients, and explain how best to treat and manage them.
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EPILEPTIC seizures can be defined as primary, symptomatic or reactive (see pathophysiology of seizures article on p 3 of this supplement). Dogs presenting with recurrent epileptic seizures before 12 months of age most commonly suffer primary epilepsy (75 per cent), whereas symptomatic epilepsy and reactive seizures are less common (18 per cent and 7 per cent, respectively) (Arrol and others 2012). Given the high percentage of primary epilepsies, and the associated good prognosis with this condition, a good outcome would be anticipated in many juvenile patients presenting with seizures.
Is it an epileptic seizure?
Most consultations will begin with an owner declaring ‘my pet has had a seizure’ and this assumption should be challenged. Paroxysmal episodes are difficult to characterise because, by definition, they are episodic with long periods of normality. The paroxysmal nature of these events, combined with the possible presence of prodromal or postictal (before and after the seizure) changes, is usually suggestive of a neurological condition and makes many owners assume a seizure. However, with the advent of the smart phone, it is now possible to gain an insight into what the owner has observed through videos. This development has revolutionised the way we identify and manage dogs and cats with paroxysmal episodes and although a description may appear diagnostic of an epileptic seizure, the reality is often quite different.
Signs that are useful in distinguishing epileptic seizures from other paroxysmal disorders are discussed elsewhere in this supplement (see diagnostic evaluation of the patient with seizures article on p 10 of this supplement). Box 1 gives a summary of some of the questions that are advisable to ask the owner if there is any doubt as to whether the patient is having epileptic seizures or not.
Important questions to determine whether this is an epileptic seizure
▪ Can your pet respond to you during an episode?
▪ Does your pet urinate or salivate during an episode?
▪ How long do the episodes last?
▪ How quickly does your pet recover from the episode?
▪ Is your pet normal in between the episodes?
▪ Do all the episodes look the same?
▪ Does your pet go floppy during an episode?
Two scenarios that mimic epileptic seizures that should be considered in young patients include:
▪ Pain. Severe pain can result in yelping and scratching that could appear to be seizure activity to the untrained eye. Pain is a non-specific diagnostic feature, but the location of the pain can aid in determining the underlying disease process, for example, intermittent neck pain may suggest an atlantoaxial luxation.
▪ Paroxysmal dyskinesias (movement disorders). As these disorders become increasingly recognised, it is clear that they have a very similar appearance to seizures. However, a key distinguishing feature is that patients retain normal awareness during an episode. They are mostly seen in dogs, although cats can also suffer these conditions. In dogs, there are numerous breed-related conditions, but one of importance in juvenile patients is episodic falling syndrome in Cavalier King Charles spaniels. Episodes are triggered by exercise, stress or excitement and characterised by progressive hypertonicity in the thoracic and pelvic limbs, resulting in a characteristic ‘deer-stalking’ or ‘praying’ position. Episodes can begin in puppies as young as 14 weeks old, although patients may be as old as four years old when the disease first manifests. Affected dogs are typically normal in between episodes. Some dogs respond to the use of the carbonic anhydrase inhibitor acetazolamide (4 to 8 mg/kg every eight to 12 hours), although this is an off-license medication and should only be used if episodes are frequent. Diagnosis is by the recognition of an episode via video footage combined with genetic testing, as this is the first canine movement disorder to have its genetic mutation identified. The BCAN mutation, which causes the disease, is recessively inherited and codes for the brevican protein, which is important in brain function. Therefore, if a dog is found to be homozygous for this mutated gene then it is affected with this condition.
A lot of useful information is obtained by questioning the owner on unusual behaviour while observing the patient in the consultation room. Epileptic seizures suggest forebrain disease, therefore questions should focus on the possible presence of clinical signs related to forebrain disease, for example, an altered mentation, central blindness, relentless pacing/circling, head pressing and loss of learned behaviour (eg, toileting in the house having previously learnt to go outside). Careful questioning of the owner will answer whether any of these clinical signs are present in between the seizures (interictal period), suggesting whether there is a reactive or symptomatic cause for the epileptic seizures. Observation of the gait during history taking may also detect abnormalities that the owner has not noticed. A thorough history will determine if toxin exposure is a possibility.
Neurological and clinical examination
If clinical signs of forebrain disease are present then it is imperative that a neurological examination is performed, as abnormal findings lend support for metabolic or symptomatic causes for seizures. However, in the absence of these signs, structural forebrain disease cannot be excluded. Certain aspects of the neurological examination are particularly important in assessing forebrain function:
▪ Menace response. This is decreased or absent on the side opposite the lesion.
▪ Hopping response/postural reaction testing. Deficits are evident on the side opposite the lesion.
▪ Nasal sensation. Facial hypoalgesia is evident on the side opposite the lesion.
Neurological examination findings may reveal only forebrain dysfunction. In juvenile patients, however, it is possible to find evidence of a multifocal or diffuse disease process (ie, one affecting other structures, eg, the cerebellum, brainstem, spinal cord or neuromuscular system). Finding these clinical signs can further refine the list of differential diagnoses. A fundoscopic examination may show active or previous signs of chorioretinitis.
Extracranial causes are also termed ‘reactive’ seizures (ie, a ‘reaction’ of the normal forebrain to a systemic insult in the blood). These include metabolic diseases, such as hypoglycaemia, hypocalcaemia and hepatic encephalopathy, and toxicities, such as metaldehyde, permethrin, organophosphates and mycotoxin poisoning. Clinical pathology testing should include a complete blood count, serum biochemistry (consisting of glucose, sodium and calcium concentrations, renal and hepatic dysfunction [notably urea, creatinine, cholesterol and albumin]) and urinalysis, which should be performed in all seizuring patients. Abnormal findings may further support a metabolic or toxic cause of seizures. Based on clinicopathological abnormalities, additional diagnostic testing is indicated when specific organ pathology is suspected. Liver function tests, such as pre- and postprandial bile acid concentrations and blood ammonia concentration, can provide evidence of hepatic dysfunction.
If extracranial disease is ruled out then an intracranial problem is suspected. Additional testing can further determine the type and extent of intracranial pathology. Ultrasonography is useful in young animals with a persistent fontanelle to assess for hydrocephalus or intracranial arachnoid cyst and has the added advantage of not requiring general anaesthesia. If hydrocephalus is observed, this finding should be carefully interpreted because it may not be the inciting cause. Cross-sectional imaging such as CT or MRI is the gold standard for identifying intracranial lesions, with MRI being preferred due to its better sensitivity for identifying soft tissue structures (Box 2).
When to consider MRI?
▪ Abnormal behaviour before starting antiepileptic medication:
– Head pressing
– Toileting in the house
– Persistent blindness
▪ Abnormal neurological examination
▪ Failure to respond appropriately to antiepileptic medication
Cerebrospinal fluid analysis
Cerebrospinal fluid (CSF) analysis is particularly useful in identifying the presence of inflammatory central nervous system (CNS) disease. Because inflammatory disease is a more likely differential diagnosis than neoplasia in younger animals, CSF analysis may more often provide a greater diagnostic yield than imaging procedures alone. However, results of this evaluation are rarely pathognomonic for a specific aetiology when performed in isolation and are best interpreted in all patients alongside cross-sectional imaging findings. In doing this, it can give a clearer indication of whether an inflammatory or non-inflammatory process is present and in the light of signalment, history and other findings (eg, cross-sectional imaging, serology) leads to refinement of the diagnosis.
A further note of caution should be mentioned in relation to raised intracranial pressure (ICP). Many inflammatory CNS diseases have the potential to increase ICP and this is a contraindication to performing CSF collection. Therefore, CSF is best performed following exclusion of raised ICP based on MRI. Imaging findings compatible with increased ICP include foramen magnum herniation (the caudal vermis of the cerebellum herniates through the foramen magnum), or transtentorial herniation (compression of the caudal parts of the cerebral hemispheres beneath the tentorium cerebelli). In the absence of MRI, mentation is a useful indicator, with severely depressed mental status being associated with increased ICP.
Cerebrospinal fluid should ideally be collected caudal to the suspected lesion due to the caudal flow of the fluid within the CNS and therefore cerebellomedullary cistern puncture is most appropriate in seizuring patients due to the forebrain localisation. Analysis consists of performing a nucleated cell count, measuring the protein concentration, and performing cytological evaluation as soon as possible after collecting the sample.
PCR is a highly specific method for demonstrating the presence of an infectious agent within the CNS. The major drawback of this type of test is the low sensitivity as the CSF sample must contain a component of the infectious organism's DNA or RNA to be positive. A combination of PCR and serology improves the sensitivity and specificity of these tests than when used in isolation. PCR tests for feline infectious peritonitis, Toxoplasma gondii and Neospora caninum are the ones used most commonly within the UK.
Serology and infectious disease testing
Serology and immunological testing may indirectly lend further support to infectious causes. Overall, viral causes are difficult to definitively diagnose and results of serological testing are difficult to interpret in young animals because of the presence of circulating antibodies from maternal immunity, vaccination, or environmental exposure.
It is important to note that all the diseases discussed below may present with forebrain signs alone, although all these conditions may commonly involve other areas of the nervous system resulting in a neurological examination suggestive of a multifocal localisation (see Table 1). The exception to this is idiopathic epilepsy, which is suspected when a patient is normal in between the epileptic seizures (Box 3).
Canine idiopathic epilepsy
Canine idiopathic epilepsy most commonly starts between the ages of six months and six years. Therefore, if the seizures start outside of this age range, other causes for seizures should be considered. Another reason to consider a cause other than idiopathic epilepsy is if the patient is abnormal in between the seizures, for example, abnormal behaviour, lateralising neurological signs or loss of learned behaviour (for more information, see idiopathic epilepsy article on p 17 of this supplement).
Portosystemic shunts (PSS) are common congenital defects that can cause hepatic encephalopathy in dogs and cats. The pathogenesis of hepatic encephalopathy is unclear, with several potential causes, including increased ammonia concentration, false neurotransmitter synthesis, an increased manganese concentration, excessive TNF-α concentrations and increased brain concentrations of benzodiazepine-like neurotransmitters. Common clinical signs of hepatic encephalopathy include diffuse forebrain signs consisting of ataxia, circling, depression, behavioural changes, seizures and visual disturbances.
Diagnosis is achieved on the basis of clinical signs and biochemical evidence of liver dysfunction. Liver dysfunction is assessed by measuring glucose, urea, cholesterol and albumin concentrations with any decrease suggesting insufficiency. Hyperammonaemia is also a common finding (sensitivity and specificity is 80 to 85 per cent in dogs and cats) and therefore serum ammonia testing is advised if available. However, increased dynamic bile acids remain the best biochemical test for diagnosing PSS with a sensitivity of 93 per cent in dogs and 100 per cent in cats. The specificity is 67 per cent in dogs and 71 per cent in cats. A small increase in fasted bile acids is usually not enough to cause seizures, but if the concentration is over five times the reference range then this should be investigated, particularly if biochemistry supports liver dysfunction. Identification of a PSS is possible by ultrasonography or mesenteric portovenography.
Medical therapy for hepatic encephalopathy includes lactulose, antibiotic therapy and dietary modification. Lactulose (0.5 to 1 ml/kg orally every eight hours) is indicated as it acidifies the colonic environment resulting in conversion of ammonia into ammonium, which is not absorbed through the colonic mucosa. It also has a cathartic effect, increasing the frequency of bowel movements, producing osmotic diarrhoea, which eliminates colonic bacterial flora and decreases colonic ammonia production. Ampicillin (22 mg/kg orally every eight hours) or, if unavailable, metronidazole (7.5 mg/kg orally every 12 hours) are used to decrease ammonia-producing bacteria. Gastrointestinal ulceration is an increased risk in patients with PSS and may exacerbate encephalopathic signs; therefore, treatment with a proton-pump inhibitor such as omeprazole is recommended. Commercially available liver diets or home-cooked diets with high-quality low-protein content are advised, although complete protein restriction should be avoided as this could result in detrimental musculoskeletal development in such young patients. Antiepileptic medication is warranted if seizures are present and diazepam (0.5 mg/kg intravenously or up to 2 mg/kg per rectum) may be administered as a short-acting antiepileptic drug as a first line treatment. Levetiracetam (20 mg/kg orally or intravenously every eight hours) is a good choice for long-term management as it acts quickly (within 24 hours) and avoids hepatic metabolism. Surgical ligation/constriction is recommended once neurological signs are corrected.
Juvenile-onset hypoglycaemia is not a specific diagnosis, but it is a sign indicating a disorder of glucose metabolism reported in dogs. It has been reported in neonatal puppies less than three months old and some toy breeds. The pathogenesis of transient hypoglycaemia is unknown, but it may be related to hepatic enzyme immaturity that could result in depletion of substrate for gluconeogenesis or glycolysis (eg, ketones or glucose). These energy substrates are readily exhausted in neonatal patients because glycogen stores are small and easily depleted. Neonates with fasting hypoglycaemia tend to be toy breeds and so it must be considered that their inability to tolerate fasting is no more than an exaggeration of the neonate's normal inability to do so. Hypoglycaemia may be transient or persistent. Transient juvenile hypoglycaemia is commonly the result of hypothermia, low birthweight, fasting, hepatic insufficiency (eg, portosystemic shunting) or gastrointestinal disease (eg, parasitism). Persistent juvenile hypoglycaemia may also be the result of hereditary metabolic disorders such as glycogen storage disease (see ‘Storage diseases’ below). However, these hereditary metabolic disorders should never cause transient hypoglycaemia.
The most important therapeutic measure in juvenile hypoglycaemia is the administration of carbohydrates. An intravenous dextrose bolus (0.5 g/kg 50 per cent dextrose dilated 1:4 with 0.9 per cent saline) should be given and continued with a constant rate infusion of 2.5 to 5 per cent dextrose in isotonic fluid to maintain normoglycaemia. A 2.5 per cent solution is obtained by diluting 50 per cent dextrose in 0.9 per cent saline or Hartmann's solution (50 ml of 50 per cent dextrose in 500 ml saline creates a 5 per cent solution). Oral glucose syrup is a good emergency measure if intravenous access is not available. If possible, treatment of transient juvenile hypoglycaemia should also include specific treatment of the primary cause of the condition. If this is impossible or if the underlying disease is unknown, merely symptomatic treatment of the hypoglycaemia may still be rewarding.
Hydrocephalus is defined as any increase in the volume of CSF and although there are a number of causes, it is a common congenital disorder in toy and brachycephalic dogs. Congenital hydrocephalus is associated with malformations that interfere with the flow or absorption of CSF. The most commonly identified cause of congenital hydrocephalus is stenosis of the mesencephalic aqueduct associated with fusion of the rostral colliculi. In other cases, however, an obvious site of obstruction is not apparent. These cases may be due to a malformation of the arachnoid villi preventing normal CSF absorption. Alternatively, intraventricular obstruction may occur during a critical stage of development resulting in an enlargement of the lateral ventricles and cerebral atrophy. However, at birth this obstruction resolves leaving the legacy of hydrocephalus with normal ICP.
Hydrocephalus is commonly asymptomatic and therefore ventriculomegaly is a common incidental finding in toy and brachycephalic breeds. Clinical signs of hydrocephalus are secondary to loss of cortical neurons or neuronal function, alterations in intracranial pressure, or periventricular oedema. Clinical signs of hydrocephalus vary in type and severity but forebrain signs tend to predominate with vestibular and cerebellar signs being possible. Affected dogs often have a persistent fontanelle and a dome-shaped appearance to the head (see Fig 1). However, it is worthy of note that a persistent fontanelle is not always indicative of the presence of future development of hydrocephalus and many patients with congenital hydrocephalus may not have an open fontanelle. The course of disease is variable and difficult to predict. Neurological deficits can progress over time, remain static, or even improve after one to two years of age.
Diagnosis may be obtained by MRI or CT. If a fontanelle is persistent, ultrasonography can be used to confirm the presence of hydrocephalus. MRI provides the most detailed evaluation of this disorder and allows superior evaluation of the ventricular system and brainstem (see Fig 1). CSF analysis is indicated to rule out concurrent inflammatory or infectious causes for hydrocephalus if raised ICP is not a concern. There is always a question of whether the hydrocephalus is severe enough to cause seizures. However, if neurological signs of forebrain disease are present in addition to seizures and other causes for seizures are excluded then the hydrocephalus should be considered significant.
Medical therapies aim to reduce the severity of clinical signs by altering CSF production and reducing associated periventricular oedema. Antiepileptic medication is also indicated if seizures are present. Prednisolone may be started at 0.5 mg/kg administered orally twice and is tapered to the lowest effective dose to maintain a remission of clinical signs. Glucocorticoids decrease CSF production by decreasing Na-K-ATPase activity and may also have a beneficial effect on periventricular oedema. Although some dogs may be managed long term with medication, typically it provides only temporary relief of clinical signs. The goal of surgical management is shunting CSF from the ventricles to another body compartment, commonly the abdominal cavity. Surgical therapy via ventriculoperitoneal shunting may be used to treat dogs with progressive signs that are non-responsive to medical therapy. Shunts have not been proven to be more effective than medical therapy but do offer the possibility of long-term control of clinical signs. A study of 12 dogs that underwent ventriculoperitoneal shunting all had neurological improvement following the surgery, although three were euthanased because of lack of sustained improvement within the first six months (Shihab and others 2011). In children, however, only 50 per cent of shunts are still considered successful at one year. Potential complications of shunting include infection, occlusion of the shunt, under-shunting, over-shunting, shunt migration and valve fracture.
Porencephaly and hydranencephaly
These terms are used to describe large developmental cavities in the forebrain that communicate with the subarachnoid space and/or lateral ventricles (see Fig 2). Hydranencephaly describes almost complete loss of one or both cerebral hemispheres, whereas porencephaly relates to a less extensive defect within the cerebral cortex. The cause is uncertain but it is believed to be due to a maternal infection during fetal development with the extent of the lesion depending on the stage of development at which this infection occurs. Porencephaly is more commonly associated with seizures in dogs than hydranencephaly (Davies and others 2012). These seizures may occur in isolation or may be associated with other forebrain signs. Dogs are born normally and the clinical signs may be static or may slowly progress with time. If clinical signs do progress then ventriculoperitoneal shunt placement is a consideration. Medical management of the seizures should result in adequate seizure control and occasionally medication to reduce CSF production (see ‘Hydrocephalus’ section) may also aid in alleviating clinical signs.
Quadrigeminal cysts (also known as intracranial arachnoid cysts) represent intracranial cystic accumulations of CSF within the arachnoid mater at the level of the quadrigeminal cistern (see Fig 3). Controversy surrounds the clinical significance of quadrigeminal cysts. Quadrigeminal cysts may cause clinical signs of neurological disease by compressing the cerebellum or occipital lobe (part of the forebrain). Seizures are a sign of forebrain disease and therefore only occipital lobe compression would be likely to result in seizures. A recent study suggested that any cyst causing more than 14 per cent compression of the occipital lobe will result in seizure activity (Matiasek and others 2007) (Fig 3). In this study, cysts were considered significant, and forebrain compression and seizures were present. Therefore, the number of dogs with clinically significant quadrigeminal cysts is likely to have been overestimated in this study. Despite this, the measurement remains a useful guide to determine whether the cyst may be of significance.
These primary metabolic brain diseases are the direct result of a defect in cellular metabolism, either due to deficiencies of mitochondrial respiratory chain enzymes or, less commonly, cytosolic enzymes. This group of diseases is therefore most commonly referred to as mitochondrial disorders. Due to the brain's high metabolic demand, encephalopathic signs are commonly seen in energy metabolism disorders. Therefore, seizures are often seen alongside generalised brain involvement (brainstem and/or cerebellar signs may develop). Neurological signs typically develop in the first year of life with some as young as four months old and others as old as six years or more. Encephalopathies suspected to be caused by a mitochondrial disorder have been reported in the Alaskan husky, Yorkshire terrier, springer spaniel, shih-tzu, Jack Russell terrier, Shetland sheepdog and Australian cattle dog. However, the disease could potentially occur in any dog. The Alaskan husky encephalopathy was recently studied and a mutation in the SLC19A3 gene (encoding a thiamine transporter protein) was identified (Vernau and others 2013). These results suggest that the pathogenesis of this disease results from a genetic defect in a thiamine transporter and contrary to previous belief, it does not represent a primary mitochondrial encephalopathy. Thiamine is important to mitochondria in metabolism and therefore these results suggest that this disease is due to a thiamine deficiency resulting in a secondary mitochondrial disease.
Blood testing and urinalysis are usually within normal limits. A clinical suspicion can only be suspected using MRI. This is achieved by identifying characteristic bilateral symmetrical brain lesions on MRI compatible with a metabolic encephalopathy. Furthermore, urine organic acids may provide supportive evidence by excluding other biochemical disorders (eg, L-2-hydroxyglutaric aciduria [L2-HGA]) (see L2-HGA section below) as the underlying pathological process. Genetic testing is available for Alaskan husky encephalopathy (www.vgl.ucdavis.edu/services/AlaskanHuskyEncephalopathy.php). Unfortunately, there is no successful treatment for these disorders, with management consisting of supportive care and management of the seizures.
Inborn errors of metabolism, distinct from mitochondrial encephalopathies, are rarely reported in the veterinary medical literature. Organic acidurias are a group of such disorders for which L2-HGA is the best characterised.
L2-HGA is generally considered to be a progressive disease of insidious onset, affecting young dogs. The disorder is attributed to a build-up of L2-HGA in the brain, which may directly cause oxidative stress resulting in neurological dysfunction. There may also be some interference with creatine kinase activity in the cerebellum. In dogs, the disease has been reported in Staffordshire bull terriers, but also in a West Highland white terrier and a Yorkshire terrier. In addition to the forebrain signs, generalised ataxia, hypermetria and head/neck tremors are commonly seen as a result of cerebellar involvement.
Haematology, biochemistry and urinalysis are normal in affected dogs. MRI is therefore useful in revealing bilaterally symmetrical lesions in the grey matter of the forebrain, brainstem and cerebellum (Fig 4). A high concentration of urinary organic acids is invariably observed in the urine; most frequently L-2-hydroxyglutaric acid. L2-HGA is inherited in dogs as an autosomal recessive trait and therefore diagnosis is best confirmed through DNA testing for the mutation of the gene encoding L2HGDH (L-2-hydroxyglutarate dehydrogenase). There is currently no known treatment for L2-HGA and, as previously mentioned for mitochondrial encephalopathy, management is supportive only.
Storage diseases in which epileptic seizures are the only clinical sign are exceptionally rare. In general, storage diseases are caused by enzyme deficiencies that result in abnormal accumulations of various substrates. Most animals affected with storage diseases are normal at birth and gradually develop clinical signs within the first few weeks to months of life. It is beyond the scope of this article to detail each storage disease separately. Nevertheless, it is important to keep this group in mind when a juvenile patient is presented with seizures and diffuse progressive CNS signs with or without multisystemic disease. Seizures or tremors may be present in several storage diseases (Table 2). Other organ systems may also be affected with substrate accumulations in the liver or white blood cells. Diagnosis of storage diseases is ideally performed using DNA testing in those in which a mutation has been identified (Table 2). In the remainder, diagnosis may be based on the identification of abnormal accumulations in a blood smear, fine needle aspiration or biopsy of an affected organ. Currently, the prognosis for storage diseases is poor. Effective treatments are not yet available and so treatment is symptomatic.
Neoplasia, thiamine deficiency, infectious causes (eg, neosporosis, toxoplasmosis, canine distemper virus, Angiostrongylus vasorum infection and feline infectious peritonitis) and non-infectious inflammatory diseases (eg, meningoencephalitis of unknown origin) are all important diseases to consider in the juvenile patient.
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