An Exciting New Avenue For Epilepsy Treatment Development

A ketogenic diet, high in fat and low in carbohydrate, has been used in the treatment of drug-resistant (refractory) childhood epilepsy since the 1920s. It forces the body to burn fats instead of carbohydrates, and this leads to a build-up of molecules called ketone bodies in the blood, which are thought to be responsible for the diet’s anti-convulsant effect in some people.

The ketogenic diet does, however, have a number of unpleasant side-effects, such as constipation, bone fracture and delayed growth; and it is generally not well tolerated by adults (who find it difficult to persevere with). Research efforts are therefore ongoing to gain a better understanding of the anti-convulsant mechanisms of the diet, so that a drug that has its benefits but avoids its side-effects can be developed to replace it. Such a treatment might also be a viable option for adults with refractory epilepsy.

Clinical studies have now shown that there is, in fact, no link between blood ketone body levels and seizure control; and this suggests that other factors must be at the root of the diet’s anti-convulsant effect. Researchers at Royal Holloway University London (RHUL) have recently made exciting progress in identifying these.

In their latest study, the team focused on molecules known as medium chain fatty acids (MCFAs), which also accumulate in the blood during the the ketogenic diet. Fatty acids are the building blocks of fats, and there are many different types depending on their structure. The reason the scientists were interested in MCFAs is because valproate (a widely prescribed anti-epileptic drug) is also a type of fatty acid; although it is a short-chain fatty acid, not a medium chain one.

Valproate has a number of unpleasant side-effects, and it poses considerable risks to the development of unborn babies if their mothers take it during pregnancy (this is referred to as teratogenicity). MCFAs are significantly different to short-chain fatty acids in terms of their size and structure, and the scientists hoped that they would find at least one that could stop seizures as effectively as valproate (if not more) AND have fewer side-effects.

The group began by identifying three MCFAs: two that are known to accumulate in the ketogenic diet (ethanoic acid and decanoic acid), and one that is also found naturally but does not tend to increase during the diet (nonanoic acid). They tested each one (at a range of doses) using cell cultures to find out i) their ability to stop seizure activity ii) whether they were toxic to liver cells and iii) their teratogenic risk, and then compared them to valproate.

The results of the first assessment showed that decanoic acid and nonanoic acid were superior to valproate in stopping experimental seizures (they required a lower dose to achieve the same effect); but this was not the case with ethanoic acid. When an ethanoic acid derivative called 4-methylethanoic acid was tested, however, it too out-performed valproate. This compound was therefore included in subsequent assessments.

Liver toxicity is notoriously difficult to assess in cell cultures, and whilst none of the molecules showed significantly greater toxicity compared to valproate, it was not easy to determine from the results whether any were less toxic.

In terms of teratogenicity, both nonanoic acid and 4-methylethanoic showed minimal risk (at all doses tested); however decanoic acid appeared to be as teratogenic as valproate at some clinical doses.

After considering these findings and weighing the benefits of each MCFA against their potential side-effects; the researchers decided to take 4-methylethanoic acid and nonanoic acid forward for further testing, in animals. Here, they assessed the tendency of each to cause drowsiness/sedation (which can be extremely debilitating to daily life) and their ability to protect neurons from damage caused by status epilepticus (SE), and again they compared them to valproate. Interestingly they found that nonanoic acid caused less sedation than valproate in the animals, but that with 4-methylethaonic acid, sedation was more pronounced. Furthermore, neither 4-methylethanoic acid nor valproate protected the brain from neuronal damage during SE, whereas in animals treated with nonanoic acid, this damage was markedly reduced.

These results are very promising, because they pinpoint nonanoic acid as a molecule that is superior to valproate in terms of seizure control and side-effects, and suggest that it might also offer protection to neurons during seizures. In time, drugs that mimic nonanoic acid’s function could potentially replace the ketogenic diet and become a viable treatment for both adults and children. They may even prove to be safer and more effective than some existing anti-epileptic drugs in certain types of epilepsy.

πηγή http://www.epilepsyresearch.org.uk/an-exciting-new-avenue-for-epilepsy-treatment-development/

High-Fat Ketogenic Diet Misunderstood, Underused

Two Johns Hopkins Children’s Center neurologists say persistent misunderstandings among physicians and patients about the high-fat ketogenic diet may have led to its underuse and are urging both its wider application for seizure disorders and further research into its therapeutic promise for brain cancer, Alzheimer’s and other diseases.

The opinion is contained in a review article in the journal Advances in Pediatrics by pediatric neurologists John Freeman, M.D., and Eric Kossoff, M.D.
 “Several persistent myths and half-truths seem to discourage both doctors and patients from trying a diet that, in many children, is more effective than medication and has fewer cognitive side effects,” says Freeman, professor emeritus of pediatrics and neurology at The Johns Hopkins School of Medicine.
The ketogenic diet has been used since 1921 to successfully treat several forms of epilepsy in patients who don’t respond to anti-seizure medications. Made up of high-fat foods and very few carbohydrates, the diet works by triggering biochemical changes that eliminate seizure-causing short circuits in the brain’s signaling system. Even though it has been used primarily in children, the diet has shown therapeutic promise in adults with epilepsy.
Anecdotal evidence also suggests the diet may be useful in the treatment of brain tumors, Alzheimer’s, stroke and Parkinson’s disease, and several human and animal studies have found tumor reduction after treatment with the ketogenic diet. The suspected mechanism is that cancer cells require glucose for survival, and the ketogenic diet deprives them of this essential fuel. One report described two children with inoperable brain cancer, whose tumors shrank remarkably after treatment with the ketogenic diet, leading to long-term survival of both patients. This evidence indicates that the diet may affect the body’s chemistry on a far more basic level than once believed, with effects far more profound than now thought, and requires further research, the authors say.
What has been well-established is that when it comes to seizures, the diet’s therapeutic effects are often longer lasting than those of medication, and it has resulted in a full cure of seizures in at least some children, the researchers say. Yet, the diet has remained somewhat misunderstood and underused, they say.
The most common misconceptions about the diet are that it causes dangerous biochemical changes, is inappropriate for use in infants and very young children, causes weight gain and fatty build-up in the arteries or that it should be a treatment of last resort. All of these, the authors note, are partly or entirely false.
The diet does require rigorous monitoring by a neurologist and a dietitian, which also may discourage patients and health-care providers from using it.
Several studies have documented the effectiveness of the ketogenic diet in reducing or completely eliminating seizures. In a 2001 Hopkins study, 75 out of 83 children who were on the diet for a year experienced full resolution or partial reduction of seizures. Many of them continued to do well even years after stopping the diet. A 2009 study in the journal Lancet reported nearly 40 percent (28) in a group of 54 children experienced greater than 50 percent reduction in the number of seizures on the diet. Five of the 54 had more than 90 percent fewer seizures after starting the diet. These were all children with drug-resistant epilepsy, whose seizures had not improved with two medications.
The diet is not without side effects, Kossoff and Freeman caution. These include vomiting and constipation, and a temporary moderate spike in cholesterol, which goes down after one to two years on the diet and returns to normal once the diet is stopped. A Hopkins Children’s study showed that one in 20 children on the diet develops kidney stones, but most cases can be prevented or treated with the supplement potassium citrate.
Kossoff and Freeman recommend the diet as a first-line treatment in two rare metabolic conditions — GLUT-1 deficiency and pyruvate dehydrogenase deficiency, both marked by seizures and other neurological problems. The diet, they say, may be a good earlier option for treating infantile spasms,myoclonic seizures, tuberous sclerosis, myoclonic-static epilepsy, Dravet syndrome, Rett syndrome and Lennox-Gastaut syndrome, all of which traditionally do not respond well to anti-seizure medication. In other seizure disorders, the diet should be considered after two medications have failed to resolve the seizures.

Βρεφικών Σπασμοί ...Σύνδρομο West

West syndrome or West's Syndrome is an uncommon to rare epileptic disorder in infants. It is named after the English physician, William James West (1793–1848), who first described it in an article published in The Lancet in 1841. The original case actually described his own son, James Edwin West (1820–1840) [1]. Other names for it are "Generalized Flexion Epilepsy", "Infantile Epileptic Encephalopathy", "Infantile Myoclonic Encephalopathy", "jackknife convulsions", "Massive Myoclonia" and "Salaam spasms". The term "infantile spasms" can be used to describe the specific seizure manifestation in the syndrome, but is also used as a synonym for the syndrome itself. West syndrome is the triad of infantile spasms, a pathognomonic EEG pattern (called hypsarrhythmia), and mental retardation - although the international definition requires only two out of these three elements.

The syndrome is age-related, generally occurring between the third and the twelfth month, generally manifesting around the fifth month. There are various causes ("polyetiology"). The syndrome is often caused by an organic brain dysfunction whose origins may be prenatal, perinatal(caused during birth) or postnatal.

Prevalence is around 1:3200 to 1:3500 of live births. Statistically, boys are more likely to be affected than girls at a ratio of around 56:44. In 45 out of every 50 children affected, the spasms appear for the first time between the third and the twelfth month of age. In rarer cases, spasms may occur in the first two months or during the second to fourth year of age.

It is still unknown which bio-chemical mechanisms lead to the occurrence of West syndrome. It is conjectured that it is a malfunction of neurotransmitter function, or more precisely, a malfunction in the regulation of the GABA transmission process. Another possibility being researched is a hyper-production of the Corticotropin-releasing hormone (CRH). It is possible that more than one factor is involved. Both hypotheses are supported by the effect of certain medications used to treat West syndrome.

Symptomatic

If a cause presents itself, the syndrome is referred to as symptomatic West syndrome, as the attacks manifest as a symptom of another problem. Almost any cause of brain damage could be associated, and these are divided into prenatal, perinatal, and post-natal. The following is a partial list:

• In around one third of the children, there is evidence of a profound organic disorder of the brain. This includes:
  • microcephaly
  • cortical dysplasia
  • cerebral atrophy
  • lissencephaly
  • bacterial meningitis
  • phakomatoses (e.g. tuberous sclerosis)
  • Aicardi syndrome
  • cephalhematoma and
  • vascular malformation.

• Furthermore, other causes increasingly being named in the literature are:
  • Incontinentia pigmenti
  • Foix-Chavany-Marie syndrome
  • Patau syndrome (trisomy 13)
  • Sturge-Weber syndrome
  • neurometabolic diseases
  • congential infections (e.g. Cytomegalovirus)
  • hypoglycemia
  • brain damage due to asphyxiation or hypoxia (lack of oxygen, e.g. during birth), periventricular leukomalacia, cephalhematoma, cerebrovascular accident or brain damage of various types as well as that caused by premature birth.

• There are known cases in which the spasms occurred for the first time after vaccination against Measles, Mumps and Rubella or Tetanus, Pertussis, Diphtheria, Polio, Hepatitis B andHaemophilus influenzae Type B. However, there is no causal relationship between immunization and West syndrome, since stress of any kind is a common trigger for seizures, and the immunization occurs during the time-frame in which many typical cases become conspicuous.

West syndrome in babies with Down's syndrome

West syndrome appears in 1% to 5% of infants with Down's syndrome. This form of epilepsy is relatively difficult to treat in children who do not have the chromosomal abnormalities involved in Down's syndrome. However, in children with Down's syndrome, the syndrome is often far more mild, and the children often react better to medication. The German Down Syndrom InfoCenter noted in 2003 that what was normally a serious epilepsy was in such cases often a relatively benign one.

EEG records for children with Down's syndrome are often more symmetrical with fewer unusual findings. Although not all children can become entirely free from attacks with medication, children with Down's syndrome are less likely to go on to develop Lennox-Gastaut syndrome or other forms of epilepsy than those without additional hereditary material on the 21st chromosome. The reason why it is easier to treat children with Down's syndrome is not known.

If, however, a child with Down's syndrome has seizures that are difficult to control, the child is at risk to develop an autistic spectrum disorder.

Cryptogenic

When a direct cause cannot be determined but the children has other neurological disorder, the case is referred to as cryptogenic West syndrome, where an underlying cause is most likely but even with our modern means cannot be detected. Currently the cryptogenic group is often combined with idiopathic while referred to as "cryptogenic".

Sometimes multiple children within the same family develop West syndrome. In this case it is also referred to as cryptogenic, in which genetic and sometimes hereditary influences play a role. There are known cases in which West syndrome appears in successive generations in boys; this has to do with X-chromosomal heredity.

Idiopathic

Occasionally the syndrome is referred to as idiopathic West syndrome, when a cause cannot be determined. Important diagnostic criteria are:

• Regular development until the onset of the attacks or before the beginning of the therapy
• no pathological findings in neurological or neuroradiological studies
• no evidence of a trigger for the spasms

Those are becoming rare due to modern medicine.

Clinical presentation

The epileptic seizures which can be observed in infants with West syndrome fall into three categories, collectively known as infantile spasms. Typically, the following triad of attack types appears; while the three types usually appear simultaneously, they also can occur independently of each other:

• Lightning attacks: Sudden, severe myoclonic convulsions of the entire body or several parts of the body in split seconds, and the legs in particular are bent (flexor muscle convulsions here are generally more severe than extensor ones).
• Nodding attacks: Convulsions of the throat and neck flexor muscles, during which the chin is fitfully jerked towards the breast or the head is drawn inward.
• Salaam or jackknife attacks: a flexor spasm with rapid bending of the head and torso forward and simultaneous raising and bending of the arms while partially drawing the hands together in front of the chest and/or flailing. If one imagined this act in slow motion, it would appear similar to the oriental ceremonial greeting (Salaam), from which this type of attack derives its name.

Therapy 

Compared with other forms of epilepsy, West syndrome is difficult to treat. To raise the chance of successful treatment and keep down the risk of longer-lasting effects, it is very important that the condition is diagnosed as early as possible and that treatment begins straight away. However, there is no guarantee that therapy will work even in this case.Insufficient research has yet been carried out into whether the form of treatment has an effect upon the long-term prognosis. Based on what is known today, the prognosis depends mainly on the cause of the attacks and the length of time that hypsarrhythmia lasts. In general it can be said that the prognosis is worse when the patient does not react as well to therapy and the epileptic over-activity in the brain continues. Treatment differs in each individual case and depends on the cause of the West syndrome (etiological classification) and the state of brain development at the time of the damage.

Due to their side-effects, two drugs are currently being used as the first-line treatment: ACTH and Vigabatrin.

ACTH

• ACTH - Use primarily in United States
  • Side effects are: Weight gain, especially in the trunk and face, hypertension, metabolic abnormalities, severe irritability, osteoporosis, sepsis, and congestive heart failure.

Vigabatrin

• Vigabatrin (Sabril) - Approved in several countries, including most of Europe, Canada, Mexico, and more recently the United States.
  • Side effects are: Somnolence, headache, dizziness, fatigue, weight gain, decreased vision or other vision changes

Vigabatrin is known for being effective, especially in children with tuberous sclerosis, with few and benign side effects. But due to some recent studies showing visual field constriction (loss of peripheral vision), it was not approved in the United States until mid-2009. It is currently debated that a short use (6 months or less) of Vigabatrin will not affect vision. Also, considering the effect of frequent seizures on day to day life and mental development, some parents prefer to take the risk of some vision loss.

Other

When those two are proving ineffective, other drugs may be used in conjunction or alone. From those, corticosteroids (prednisone) are often used. In Japan, there is a good experience with pyridoxine therapy. Further, topiramate (Topamax), lamotrigine (Lamictal), levetiracetam (Keppra) and zonisamide (Zonegran) are amongst those drugs most widely used.

The ketogenic diet has been shown to be effective in treating infantile spams, up to 70% of children having a 50% or more reduction in seizure.

Prognosis

It is not possible to make a generalised prognosis for development due to the variability of causes, as mentioned above, the differing types of symptoms and etiology. Each case must be considered individually.

The prognosis for children with idiopathic West syndrome are mostly more positive than for those with the cryptogenic or symptomatic forms. Idiopathic cases are less likely to show signs of developmental problems before the attacks begin, the attacks can often be treated more easily and effectively and there is a lower relapse rate. Children with this form of the syndrome are less likely to go on to develop other forms of epilepsy; around two in every five children develop at the same rate as healthy children.

In other cases, however, treatment of West syndrome is relatively difficult and the results of therapy often dissatisfying; for children with symptomatic and cryptogenic West syndrome, the prognosis is generally not positive, especially when they prove resistant to therapy.

Statistically, 5 out of every 100 children with West syndrome do not survive beyond five years of age, in some cases due to the cause of the syndrome, in others for reasons related to their medication. Only less than half of all children can become entirely free from attacks with the help of medication. Statistics show that treatment produces a satisfactory result in around three out of ten cases, with only one in every 25 children's cognitive and motoric development developing more or less normally.

A large proportion (up to 90%) of children suffer severe physical and cognitive impairments, even when treatment for the attacks is successful. This is not usually because of the epileptic fits, but rather because of the causes behind them (cerebral anomalies or their location or degree of severity). Severe, frequent attacks can (further) damage the brain.

Permanent damage often associated with West syndrome in the literature include cognitive disabilities, learning difficulties and behavioural problems, cerebral palsy (up to 5 out of 10 children), psychological disorders and often autism (in around 3 out of 10 children). Once more, the etiology of each individual case of West syndrome must be considered when debating cause and effect.

As many as 6 out of 10 children with West syndrome suffer from epilepsy later in life. Sometimes West syndrome turns into a focal or other generalised epilepsy. Around half of all children develop Lennox-Gastaut syndrome.