Читать книгу Large Animal Neurology - Joe Mayhew - Страница 106

Seizures, abnormal sleep patterns, myotonic episodes, and syncopal episodes can be difficult to distinguish apart. The last of these, occurring in the absence of heart failure, is incredibly rare but the first two are quite distinguishable if observed or preferably captured on video. Particularly because they both more often occur at quiet periods when patients are not being observed, 24‐h video recording can be useful to capture suspected episodes of sleep disorders and epilepsy when they are not otherwise overt. Exposure to stray electric currents can be the cause of unusual repetitive recumbency akin to epilepsy.¹ There are also many nonepileptic disorders imitating generalized idiopathic epilepsy that need to be considered when evaluating patients for repeated motor and hypotonic events. These include movement disorders classified as paroxysmal dyskinesia,² benign myoclonus, hypotension, hyperekplexia, and many metabolic and toxic insults.^3,4 Indeed, even severe Psoroptes ovis infestation (sheep scab) has been seen to induce convulsions in sheep⁵ and Otobius megnini (spinose ear tick) will cause fits in horses,^5b and both of these syndromes resolve with antiparasitic therapy.

Acquired metabolic derangements including hypomagnesemia, hypocalcemia, hyponatremia, hypernatremia, hepatoencephalopathy, hyperammonemia, and uremia all can result in seizures, as also seen with terminal events in many toxicities.

Dyskinesias, although not apparently confirmed in large animals, do deserve mention here.² These disorders are differentiated from epileptic seizures by there being no impairment to consciousness and no autonomic or postictal signs. Many of these phenotypic syndromes are yet to be specifically defined, but some involve genetic alterations to proteins involved in transmembrane conductance. Interestingly, the paroxysmal, familial ataxia in lambs (see Chapter 31) fits these criteria,⁶ but as with several inherited spinocerebellar ataxias in humans and dogs this disorder is likely a channelopathy.⁷ The onset of a myotonic episode in patients with myotonia (Chapter 31) can be exceedingly abrupt with whole body rigidity and recumbency that mimics a seizure, although again there is no loss of consciousness.

A seizure, fit, ictus, or convulsion is considered abnormal behavior. Seizures are the physical expression of abnormal, synchronous, electrical discharges spreading through forebrain neurons that reach the somatic and visceral motor areas to initiate spontaneous, paroxysmal, involuntary movements. These cerebral dysrhythmias tend to begin and end abruptly, having a finite duration⁸ and may be very brief. There may or may not be a preictal phase or aura for seconds to hours when the animal is distracted from its environment and is usually restless. The beginning of the ictus may be a localizing finding with one part of the body, usually part of the head, involved in motor activity first. If the seizure begins affecting one side of the face, head, or body, it can be referred to as a focal seizure and may or may not progress further (Figure 6.1). These muscle contractions can spread to the whole body, thus resulting in a generalized seizure with the animal falling to the ground. Initially, the motor event is one of tonic muscle contractions that then proceeds to clonic muscle contractions with the patient showing limb paddling while in lateral recumbency. Based on observations of absent responsiveness and extrapolating from human neurology studies, consciousness is lost in generalized seizures.⁹ Autonomic involvement expressed as urination or defecation may intervene at any time. A postictal phase of poor responsiveness, restlessness, and temporary blindness may last for minutes to hours, although central blindness may be apparent in foals for several days following severe generalized seizures. More than one seizure constitutes epilepsy and this, most often, is not an inherited condition in large animals. More than one seizure over several minutes to hours, without full normalcy between, is referred to as a cluster of seizures, and continuous seizure activity with seizures immediately following each other without an interictal period is status epilepticus that is always given a bad prognosis. Notwithstanding this, several cattle, sheep, and horses have been observed to have generalized tonic and clonic seizures with prolonged periods of having a startled expression, hyper‐responsiveness, and repetitive, jerky face, jaw, head, neck and trunk movements that ultimately resolved without therapy between epileptic attacks.

The onset of a focal or generalized seizure in large animals often begins with an altered facial expression such as grimacing.

Fortunately, large animals have a relatively high seizure threshold as it seems to take a considerable perturbation to forebrain function to precipitate convulsions. Notwithstanding, seizures often accompany many focal and diffuse acquired diseases of the forebrain, often as part of terminal syndromes.^10,11

Figure 6.1 Most cases of seizures and epilepsy in large animals are acquired. Some accompany inherited neurologic disorders (Chapter 31) and others are associated with metabolic problems including electrolyte disturbances and liver disease, and with some specific toxicities such as Tutu (Coriaria arborea) and metaldehyde poisoning. In neonates, seizures can accompany birth asphyxia in calves (A) and the hypoxic–ischemic encephalopathy syndrome in foals (B). The seizures in these two cases were heralded by tonic movements of the head and neck that were symmetric in the calf (A) and asymmetric in the foal (B), prior to generalizing to tonic and clonic contractions of the whole body. Focal seizures, and mild generalized seizures, where the patient does not lose consciousness to become recumbent, may be restricted only to the face and head as shown by the early ictal movements in two other foals (C and D). The consequences of generalized seizures are seen in a horse (E) that had epilepsy and focal seizures with secondary generalization causing self‐inflicted head trauma.

Neonatal animals, particularly foals, convulse more readily than adults, and foals frequently demonstrate mild generalized seizures seen as periods of jaw chomping (“chewing‐gum fit”),¹² tachypnea, tremor and grimacing of facial muscles, and jerky head movements without evolving from a focal seizure. Epilepsy may occur in conjunction with other signs of forebrain disease persistent during the interictal period. These may be quite subtle and consist of degrees of partial blindness seen as an asymmetric menace response, partial facial hypalgesia seen as asymmetric reactions to touching the sides of the nasal septum, an asymmetric hopping response on the thoracic limbs, and a tendency to drift to one side when blindfolded and verbally coaxed, but not led, to walk straight forward.

Evidence of prior self‐inflicted trauma over bony prominences or on the tongue or gums as seen here can herald the onset of epilepsy as seen by an upper lip lesion in this foal.

Large animals, especially horses, often become violent in response to painful processes and when attempting to regain their footing. These intermittent and sometimes continuous episodes of struggling and thrashing are difficult to distinguish from convulsions. Secondary head trauma often ensues, usually adding to the delirious state. Primary processes that fall in this category include colic, myopathy, vertebral injury, long bone fractures, and acute spinal cord, brainstem, and particularly vestibular disease.

Because suspected epilepsy does appear to be more frequently a presenting problem in horses, and some attempts have been made to classify these,^13,14 a few specific comments are warranted for that species. Repeated generalized seizures that persist, with no active underlying disease process identified, and occurring in families of purebred animals, are true or idiopathic epilepsy. This does not appear to have been demonstrated in adult horses, although it may have been seen in some breeds of cattle.¹⁵ However, a patient that has had one seizure from any cause is more likely to have another—a process referred to as kindling. Thus, epilepsy beginning in adulthood in horses can be regarded as acquired until proven otherwise. Any morbid or biochemical forebrain lesion potentially can act as a seizure focus, and the resulting epileptic syndrome may begin days to years after the initial lesion. Also, a nonprogressive cerebral lesion such as an old glial scar may result in epilepsy that resolves, progresses, or remains stable.

Repeated seizures in neonatal foals most frequently indicate sepsis or neonatal encephalopathy,^16–18 and a similar syndrome has been seen in calves suffering birth asphyxia with resuscitation (Figure 6.1). Equine familial isolated hypocalcemia (EFIH) in Thoroughbred foals, hypoglycemia, and possibly hyperbilirubinemic encephalopathy (kernicterus) should also be considered in young patients,^19,20 and in adults under appropriate situations.²¹ Adolescent foals, especially of the Arabian breed, can suffer from epilepsy that is of genetic origin^22,23 and can also suffer from severe seizures associated with the lethal Lavender foal syndrome.^22,24 In the genetic adolescent epilepsy, seizures are usually symmetrical and generalized, and the first seizure may accompany an episode of sepsis or other acquired diseases. Control of the seizures with medication is usually successful, and the patients appear to grow out of the condition. Finally, although not true epilepsy, foals and calves with severe cerebellar disease have been seen to have convulsive episodes regarded as cerebellar fits, but they are aware of their environment during these attacks.

On a practical note, the recommendation to proceed with straightforward epilepsy cases having no interictal signs to advanced diagnostic imaging is not really helpful unless everything possible, including heroic intracranial surgery, is to be entertained. The utility of electroencephalography and MR imaging in improving the outcome of such cases has been discussed,^25,26 but is not widely accepted.

Signs that may relate to a focal forebrain lesion that is a potential seizure focus must be searched for during an interictal—not postictal—neurologic examination. Such signs include asymmetric menace responses, asymmetric nasal sensation, anisocoria, a head deviation with or without blindfold applied, facial paresis and facial hypertonia, and asymmetry in hopping on the forelimbs. If an epileptic horse is essentially healthy with minimal or no neurologic signs evident between seizures, then most possible causes of forebrain disease that include viral encephalitis, hepatoencephalopathy, leukoencephalomalacia (Fusarium sp. mycotoxicosis), and other toxicities are exceedingly unlikely to be the cause of the epilepsy. Three diseases at least should however be given consideration as underlying specific causes in such situations. In horses that have been on the American continents, equine protozoal myeloencephalitis caused by Sarcocystis neurona or Neospora hughesi must be considered.²⁷ Serum and cerebrospinal fluid immunoassay tests can be performed so that appropriate treatment can be initiated and continued if the tests are positive. In most countries, consideration should be given to treatment for thromboembolic and migratory verminous encephalitis at the beginning of an epileptic syndrome using larvicidal doses of anthelmintics and short‐term nonsteroidal anti‐inflammatory or glucocorticosteroid therapy. And third, cases with bacterial granulomatous ependymitis and choroiditis, true brain abscesses, and cholinisteric granuloma can be insidious in their clinical progression, and one or more seizures may be the initial overt sign. Indeed, in an aged horse with epilepsy that may be responsive to glucocorticosteroid drugs for quite some time, cholinisteric granuloma must be given strong consideration.²⁸ Various surgical and antibacterial therapeutic regimens are feasible, but heroic approaches in such cases. Rare occurrences of ear tick infestation, hypoglycemia associated with pancreatic neoplasia, intracranial neoplasia, and vascular dysplasia might be considered.^29–31

Guidelines aimed at assisting in the handling of large animal epileptic patients and in advising owners are not available, thus recommendations are rather empiric. To begin with, it must at least be reported to the owner that a patient with epilepsy is unsafe to ride until seizure free and not on anticonvulsant medication for at least 6 months. Also, if the horse injures itself to require veterinary attention, and thus documentation of the injury for the record, then euthanasia must be considered (Figure 6.1). With respect to this decision, and in reporting to an insurance company, it is reassuring to have a video of one of the seizures and to have some, albeit subtle, interictal sign to corroborate the horse having epilepsy associated with an acquired intracranial morbid disease process. On the other hand, a sensible owner can be advised that the vast majority of seizures will occur at quiet times and not while working; however, the written report must state that the horse is unsafe to ride.

The following points are a guide to maintenance anticonvulsant therapy to help control seizures in epileptic adult horses:

 Have the owner keep a diary of seizure activity and all medication given.

 All anticonvulsant drugs are not licensed for use in large animals.

 Begin phenobarbital at 5 mg/kg BID, PO.

 Increase the dose about 20% every 2 weeks until persistent sleepiness occurs or seizures are not controlled.

 Reduce dose say by 20% and add KBr at 25–90 mg/kg SID, PO, with or without loading doses of 120–200 mg/kg SID, PO for 1–5 days.⁴¹

 Consideration then can be given to incorporating phenytoin, carbamazepine, gabapentin or levetiracetam, etc., to the regimen if further control required and/or side effects are unacceptable.

 After control, monitor serum concentrations and aim to keep them in the therapeutic ranges (e.g., phenobarbital, 15–40 μg/mL; bromide, 1000–4000 μg/mL).

 Seizure threshold may be lowered with estrogen, therefore anticonvulsant dosage may be increased prior to onset of and during estrus activity.

 If the patient is completely seizure free for 6 months. then slowly wean the patient off one drug at a time over 3 months. If seizures begin, raise the dose again.

 Interactions must be considered when other drugs are to be administered to an animal already on anticonvulsant therapy.

These guidelines may be extrapolated to other species. Metabolic disorders especially hypocalcemia and hypomagnesemia must be considered in ruminants. All ruminants that have seizures of uncertain cause should receive gram doses of thiamin immediately after any diagnostic samples have been drawn for red cell transketolase activity.

The client should be encouraged to keep an accurate diary of known and suspected seizure episodes particularly noting preictal signs, site on the body where the motor disturbance begins, and the severity and timed duration of each seizure. This will allow a best prediction as to whether the epilepsy is stable, resolving or progressing, to be made. Should individual seizures be occurring say fewer than one every month and the patient does not injure itself to require veterinary attention, then medication is probably not indicated. If there are cluster seizures, status epilepticus or more than one seizure a month, or if the patient injures itself to require veterinary attention and the client does not accept euthanasia as an option, then anticonvulsant therapy must be considered.

For acute control of seizures in adult horses, IV glucose should be administered if hypoglycemia is suspected. Then, 50 mg IV doses of diazepam or midazolam can be used.^{32, 33} Benzodiazepine drugs should not be left in a plastic container or syringe for more than a few minutes as they may become inactivated. If diazepam or an alternative benzodiazepine drug is not available, then standard doses of alpha‐2 agonist drugs, or IV levetiracetam can be used. If these are ineffective, then general anesthesia is indicated and at this stage euthanasia must be strongly considered. Midazolam can also be considered as first line therapy for neonatal seizures in foals,^32,34 and intranasal equivalent doses may expedite seizure control.³⁵

Pharmacokinetic and related drug disposition studies on phenobarbital,^36–39 potassium bromide^40,41 and phenytoin in horses,^42–44 potassium bromide in sheep,⁴⁵ and phenobarbital⁴⁶ and levetiracetam in foals have been published. Gabapentin,⁴⁸ pregabalin,⁴⁹ and imepitoin⁵⁰ may need to be considered if the starting drugs are ineffective at giving some seizure control. Several other human anticonvulsant drugs may be worth considering if control of seizures is unsatisfactory. Two drugs that have been tried in foals with unsubstantiated anticonvulsant results are carbamazepine (a sodium channel stabilizer) at 250–500 mg doses and triazoline (an excitatory amino acid antagonist) at 1 g doses. Discussions on the use of antiseizure medication in small animals⁵¹ and in humans⁵² are useful resources to consult.