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Congenital and Inherited Cerebral Disorders

By Rebecca A. Packer, MS, DVM, DACVIM (Neurology), Assistant Professor, Neurology/Neurosurgery, Department of Veterinary Clinical Sciences, and Department of Basic Medical Sciences, School of Veterinary Medicine, Purdue University

Large Animals

Anencephaly means that the brain is largely absent at birth. It is a rare disorder but is seen sporadically in calves; the cause is unknown. Because the pituitary gland may also be absent, prolonged gestation (see Prolonged Gestation in Cattle and Sheep) of affected calves can occur. Signs include profound lethargy, head pressing, and blindness with normal pupillary reflexes. Cerebral aplasia in calves is usually associated with complete absence of both cerebral hemispheres, and CSF may leak out of a small opening on the midline between the frontal bones.

Exencephaly means that the brain is exposed through a large defect in the skull (cranium bifida). The brain (encephalocele), meninges (meningocele), or both (meningoencephalocele) may protrude through this opening. Encephalocele and meningocele are seen in many species and are known to be inherited in pigs. Defects may be closed or open in terms of communication with the environment through skin defects. Too little information exists to reliably predict outcome and resolution of any deficits. Good surgical outcomes have been achieved in rare case reports of closed meningoencephaloceles; however, safety and quality-of-life issues must be considered, as with any ataxic, seizuring, or mentally inappropriate large animal. When the defects openly communicate externally, CNS infection should be presumed unless proved otherwise.

In hydranencephaly, there is a marked loss of cerebral cortical tissue (primarily the neocortex) within a cranial vault of normal conformation. The resultant cavity communicates with the ventricular system, has an incomplete ependymal cell lining, and is filled with CSF. Clinical signs may include lethargy, propulsive circling, head pressing, and blindness. Hydranencephaly develops as a result of the destruction of developing neural tissues and is sometimes accompanied by cerebellar hypoplasia and arthrogryposis. Hydranencephaly is seen sporadically or as an epidemic in calves, lambs, and less commonly in piglets. Known causes include infection in utero with a number of viruses, including Akabane virus (see Akabane Virus Infection) in ruminants in Australia, Japan, and Israel; bluetongue virus (see Bluetongue) in sheep and cattle in North America; Rift Valley fever virus (see Rift Valley Fever) and the virus of Wesselsbron disease (see Wesselsbron Disease) in sheep and cattle in Africa; the Cache Valley virus in sheep in the USA; and the Chuzan virus in calves in Japan. Rarely, bovine viral diarrhea (see Bovine Viral Diarrhea and Mucosal Disease Complex) and border disease virus (see Border Disease) produce hydranencephaly in lambs and calves. Hydranencephaly and porencephaly (cystic cavities in the cerebrum) are seen sometimes in lambs with in utero copper deficiency (swayback). It also is seen in a syndrome of prolonged gestation in sheep in Scotland (cause unknown).

Hydrocephalus, an increase in volume of the CSF, can appear similar to hydranencephaly, but in hydrocephalus the ventricles retain a complete ependymal lining. Clinical signs can vary from mild to severe and include seizures, lethargy, or other forebrain abnormalities. There may be extensive expansion of the lateral ventricles in the frontal lobes. Hydrocephalus is seen sporadically in all large animals, although it is relatively common in calves, in which inheritance and vitamin A deficiency have been implicated.

Cyclopia is characterized by a single orbital fossa. One cause in lambs is ingestion by the gestating dam of plant alkaloids from Veratrum californicum. This malformation also is seen in pigs.

Idiopathic or familial epilepsy has been described in many species. Benign epilepsy is seen in young foals, particularly Arabians, up to 12 mo of age. The foal may present for seizures, head injuries, or postictal blindness. Foals usually recover spontaneously within a few months, but anticonvulsant therapy (phenobarbital, 100–500 mg, PO, bid, for a 50-kg foal) is probably advisable for 1–3 mo, followed by withdrawal over 2 wk. Epilepsy beginning by 1 yr of age has been recorded in Brown Swiss and Swedish Red cattle. Seizures are also seen in young Aberdeen Angus calves; if these calves survive, they show cerebellar signs but become clinically normal by 2 yr of age.

Metabolic disorders and lysosomal storage disorders often cause signs of forebrain dysfunction, along with other neurologic deficits, and are discussed further under multifocal disorders (see Congenital and Inherited Multifocal Disorders of the Nervous System). Cerebral signs seem to be most prominent in citrullinemia.

Citrullinemia is a fatal hereditary metabolic defect of Holstein-Friesian calves (mainly in Australia and New Zealand) associated with cerebral cortical edema. It is due to increased citrulline in plasma, caused by deficiency of the urea cycle enzyme argininosuccinate synthetase. Affected calves appear healthy at birth but die of acute neurologic disease in 1–4 days. Signs are sudden in onset and consist of depression, aimless wandering, blindness, seizures, opisthotonos, and recumbency.

Narcolepsy, a disorder of sleep-wake control (typically characterized by excessive sleepiness or sudden paroxysmal attacks of flaccid paralysis with conservation of consciousness), has been reported in several equine breeds, particularly Shetland ponies. The animal is otherwise healthy. During narcoleptic episodes, rapid eye movements occur, and at the same time, the animal may also show cataplexy or sudden loss of muscle tone with collapse.

Small Animals

The same structural anomalies of the brain as described for large animals (see Large Animals) are also found in small animals.

Hydranencephaly has been described mainly in kittens after in utero exposure to feline panleukopenia virus/parvovirus (see Feline Panleukopenia). Brain stem malformations and cerebellar hypoplasia may be seen concomitantly.

Hydrocephalus is most common in dogs, particularly in toy and brachycephalic breeds. It can be classified as communicating (nonobstructive), in which CSF can flow freely into the subarachnoid space, or noncommunicating (obstructive). Known causes of noncommunicating hydrocephalus include atresia of the mesencephalic aqueduct, perinatal encephalitis, or adhesions caused by intraventricular hemorrhage at birth. Clinical signs of hydrocephalus usually indicate cerebral dysfunction and often progress, although some animals may remain asymptomatic. The fontanelles are often patent, and affected animals may have ventrolateral strabismus. Blindness due to polymicrogyria (excessive number of smaller gyri) and asymmetric dilatations of the lateral ventricles have been described in Standard Poodles. Hydrocephalus has been observed in Saint Bernard puppies in association with aphakia (absence of the lens) and multiple ocular defects. Imaging by ultrasonography (through the fontanelle), CT, or MRI can provide the diagnosis, and CSF analysis should identify encephalitis. Treatment relies on omeprazole to reduce CSF production or, if necessary, corticosteroids, or surgery to shunt CSF into the peritoneum.

Lissencephaly, an absence or reduction of cerebral gyri, is a rare disorder seen in Lhasa Apsos. It is also seen in association with cerebellar hypoplasia in Irish Setters, Wirehaired Fox Terriers, and Samoyeds and in Korat cats with microencephaly. Clinical signs consist of mild behavioral abnormalities and seizures.

Pug encephalitis is an ultimately fatal disease that may have a familial basis. Affected Pugs show behavioral changes, seizures, and CSF pleocytosis. A similar nonsuppurative, necrotizing encephalitis has been reported in several other toy breed dogs, including Yorkshire Terriers, Chihuahuas, and Maltese Terriers.

Neonatal encephalopathy is an inherited genetic disorder that has been described in Standard Poodles. Poodles appear stunted and weak from birth and begin seizuring at 4–5 wk of age. The disease is fatal. A genetic test is available for diagnosis of this disease in Standard Poodles.

Polymicrogyria is an inherited disease identified in Standard Poodles that results in focal areas of the brain having smaller and more gyri than normal, resulting in disruption of function. The most common clinical signs are visual disturbances, but ataxia, behavioral problems, and hydrocephalus can also be seen. Clinical signs are attributable to the portion of the brain affected by the abnormal gyri.

Idiopathic epilepsy may be inherited in certain breeds, including Beagles, Keeshonden, Irish Setters, Belgian Tervurens, Siberian Huskies, Springer Spaniels, Labrador Retrievers, Golden Retrievers, and German Shepherds. A specific type of seizure known as temporal lobe epilepsy appears to be familial in Cavalier King Charles Spaniels and is characterized by behavioral manifestations such as "fly biting." The diagnosis of idiopathic epilepsy depends on eliminating other causes of seizures, particularly structural brain abnormalities (such as hydrocephalus or juvenile tumors), encephalitis, or metabolic causes (such as hepatic encephalopathy).

Hepatic encephalopathy is usually caused by a congenital portosystemic shunt. The shunt may be a single large vessel, or there may be microscopic shunting of blood within the liver. Breeds often affected include Miniature Schnauzers, Yorkshire Terriers, Cairn Terriers, Australian Cattle Dogs, Old English Sheepdogs, and Maltese Terriers. The clinical signs are usually noticed before 6 mo of age and primarily reflect cerebral dysfunction, including staring into space, inappropriate vocalizing, aggression, and agitation. Advanced neurologic alterations can cause depression, blindness, myoclonus, stupor, coma, or seizures. In cats, these signs are often accompanied by excessive salivation. A rare cause of hepatic encephalopathy is a deficiency of hepatic urea cycle enzymes. Pre- and postprandial bile acid tests may support the diagnosis. Definitive diagnosis may be facilitated by use of radiographic imaging techniques, such as positive contrast portography, CT, transcolonic portal scintigraphy, or diagnostic gray-scale ultrasonography. Blood tests such as the ammonia tolerance test (see Hepatic Function Tests in Small Animals) should be used with caution in cases of suspected hepatic encephalopathy because of risk of causing an encephalopathic crisis. Resting ammonia levels can be performed; however, ammonia levels have been poorly correlated with both the diagnosis and presence of clinical signs.

Lysosomal storage disorders that commonly cause cerebral signs include ceroid lipofuscinosis and fucosidosis, although there are many other forms of lysosomal storage disorders as well as other inborn errors of metabolism (see Congenital and Inherited Multifocal Disorders of the Nervous System). Genetic and enzymatic testing is available for some of these disorders. When specific tests are not available, organic acid screens may support the general diagnosis of metabolic error.

Puppy hypoglycemia is an idiopathic syndrome in toy breeds of dogs that is seen in the first 6 mo of life. It seems to relate to a relative immaturity of the liver, which affects glycogenolysis and can usually be managed by providing frequent meals of a commercial puppy diet. The problem usually resolves as the puppy matures.

Narcolepsy or cataplexy is inherited in Doberman Pinschers, Labrador Retrievers, and Dachshunds and has been described in additional canine breeds. It is rare in cats. Attacks are often stimulated by excitement. It must be differentiated from various types of syncope. Physostigmine (0.025–0.1 mg/kg, IV) potentiates the frequency and severity of cataleptic attacks. Imipramine (0.5–1 mg/kg, PO, tid) can be used to control the severity of the cataplexy.

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