Artificial induction of immunity

From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Artificial_induction_of_immunity

Artificial induction of immunity is immunization achieved by human efforts in preventive healthcare, as opposed to (and augmenting) natural immunity as produced by organisms' immune systems. It makes people immune to specific diseases by means other than waiting for them to catch the disease. The purpose is to reduce the risk of death and suffering, that is, the disease burden, even when eradication of the disease is not possible. Vaccination is the chief type of such immunization, greatly reducing the burden of vaccine-preventable diseases.

Immunity against infections that can cause serious illness is beneficial. Founded on a germ theory of infectious diseases, as demonstrated by Louis Pasteur's discoveries, modern medicine has provided means for inducing immunity against a widening range of diseases to prevent the associated risks from the wild infections. It is hoped that further understanding of the molecular basis of immunity will translate to improved clinical practice in the future.

Variolation and smallpox

Main articles: Variolation and Smallpox

The earliest recorded artificial induction of immunity in humans was by variolation or inoculation, which is the controlled infection of a subject with a less lethal natural form of smallpox (known as Variola Minor) to make him or her immune to re-infection with the more lethal natural form, Variola Major. This was practiced in ancient times in China and India, and imported into Europe, via Turkey, around 1720 by Lady Montagu and perhaps others. From England, the technique spread rapidly to the Colonies, and was also spread by African slaves arriving into Boston.

Variolation had the disadvantage that the inoculating agent used was still an active form of smallpox and, although less potent, could still kill the inoculee or spread in its full form to others nearby. However, as the risk of death from inoculation with Variola Minor was just 1% to 2%, as compared to the 20% risk of death from the natural form of smallpox, the risks of inoculation were generally considered acceptable.

Vaccination

Main articles: Smallpox vaccine and Edward Jenner

In 1796, Edward Jenner FRS, a doctor and scientist who had practiced variolation, performed an experiment based on the folk-knowledge that infection with cowpox, a disease with minor symptoms which was never fatal, also conferred immunity to smallpox. The idea was not new; it had been demonstrated some years earlier by Benjamin Jesty, who had not publicized his discovery. In 1798, Jenner extended his observations by showing that cowpox could be passed from a lesion on one patient to others through four arm to arm transfers and that the last in the series was immune by exposing him to smallpox. Jenner described the procedure, distributed his vaccine freely, and provided information to help those hoping to establish their own vaccines. In 1798 he published his information in his famous Inquiry into the Causes and Effects...of the Cow Pox. He is credited with being the first to start detailed investigations of the subject and of bringing it to the attention of the medical profession. Despite some opposition vaccination took over from variolation.

Jenner, like all members of the Royal Society in those days, was an empiricist. The theory to support further advances in vaccination came later.

Germ theory

Main articles: Pasteur Louis Pasteur; Germ Theory: Germ theory of disease

In the second half of the 1800s Louis Pasteur perfected experiments which disproved the then-popular theory of spontaneous generation and from which he derived the modern theory of (infectious) disease. Using experiments based on this theory, which posited that specific microorganisms cause specific diseases, Pasteur isolated the infectious agent from anthrax. He then derived a vaccine by altering the infectious agent so as to make it harmless and then introducing this inactivated form of the infectious agents into farm animals, which then proved to be immune to the disease.

Pasteur also isolated a crude preparation of the infectious agent for rabies. In a brave piece of rapid medicine development, he probably saved the life of a person who had been bitten by a clearly rabid dog by performing the same inactivating process upon his rabies preparation and then inoculating the patient with it. The patient, who was expected to die, lived, and thus was the first person successfully vaccinated against rabies.

Anthrax is now known to be caused by a bacterium, and rabies is known to be caused by a virus. The microscopes of the time could reasonably be expected to show bacteria, but imaging of viruses had to wait until the development of electron microscopes with their greater resolving power in the 20th century.

Toxoids

Main article: Toxoid

Some diseases, such as tetanus, cause disease not by bacterial growth but by bacterial production of a toxin. Tetanus toxin is so lethal that humans cannot develop immunity to a natural infection, as the amount of toxin and time required to kill a person is much less than is required by the immune system to recognize the toxin and produce antibodies against it. However the tetanus toxin is easily denatured losing its ability to produce disease, but leaving it able to induce immunity to tetanus when injected into subjects. The denatured toxin is called a toxoid.

Adjuvants

Main article: Adjuvant

The use of simple molecules such as toxoids for immunization tends to produce a low response by the immune system, and thus poor immune memory. However, adding certain substances to the mixture, for example adsorbing tetanus toxoid onto alum, greatly enhances the immune response (see Roitt etc. below). These substances are known as adjuvants. Several different adjuvants have been used in vaccine preparation. Adjuvants are also used in other ways in researching the immune system.

A more contemporary approach for "boosting" the immune response to simpler immunogenic molecules (known as antigens) is to conjugate the antigens. Conjugation is the attachment to the antigen of another substance which also generates an immune response, thus amplifying the overall response and causing a more robust immune memory to the antigen. For example, a toxoid might be attached to a polysaccharide from the capsule of the bacteria responsible for most lobar pneumonia.

Temporarily induced immunity

Main article: Immunoglobulin

 

Platypus: monotremes lack placental transfer of immunity

Temporary immunity to a specific infection can be induced in a subject by providing the subject with externally produced immune molecules, known as antibodies or immunoglobulins. This was first performed (and is still sometimes performed) by taking blood from a subject who is already immune, isolating the fraction of the blood which contains antibodies (known as the serum), and injecting this serum into the person for whom immunity is desired. This is known as passive immunity, and the serum that is isolated from one subject and injected into another is sometimes called antiserum. Antiserum from other mammals, notably horses, has been used in humans with generally good and often life-saving results, but there is some risk of anaphylactic shock and even death from this procedure because the human body sometimes recognizes antibodies from other animals as foreign proteins. Passive immunity is temporary, because the antibodies which are transferred have a lifespan of only about 3–6 months. Every placental mammal (which includes humans) has experienced temporarily induced immunity by transfer of homologous antibodies from its mother across the placenta, giving it passive immunity to whatever its mother became immune to. This allows some protection for the young while its own immune system is developing.

Synthetic (recombinant or cell-clone) human immunoglobulins can now be made, and for several reasons (including the risk of prion contamination of biological materials) are likely to be used more and more often. However, they are expensive to produce and are not in large-scale production as of 2013. In the future it might be possible to artificially design antibodies to fit specific antigens, then produce them in large quantities to induce temporary immunity in people in advance of exposure to a specific pathogen, such as a bacterium, a virus, or a prion. At present, the science to understand this process is available but not the technology to perform it.

Immunity (medical)

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Immunity_(medical)

In biology, immunity is the capability of multicellular organisms to resist harmful microorganisms. Immunity involves both specific and nonspecific components. The nonspecific components act as barriers or eliminators of a wide range of pathogens irrespective of their antigenic make-up. Other components of the immune system adapt themselves to each new disease encountered and can generate pathogen-specific immunity.

Immunity is a complex biological system that can recognize and tolerate whatever belongs to the self, and to recognize and reject what is foreign (non-self).

Innate and adaptive

Scheme of a Fc receptor

The immune system has innate and adaptive components. Innate immunity is present in all metazoans, immune responses: inflammatory responses and phagocytosis. The adaptive component, on the other hand, involves more advanced lymphatic cells that can distinguish between specific "non-self" substances in the presence of "self". The reaction to foreign substances is etymologically described as inflammation while the non-reaction to self substances is described as immunity. The two components of the immune system create a dynamic biological environment where "health" can be seen as a physical state where the self is immunologically spared, and what is foreign is inflammatorily and immunologically eliminated. "Disease" can arise when what is foreign cannot be eliminated or what is self is not spared.

Innate immunity, also known as native immunity, is a semi-specific and widely distributed form of immunity. It is defined as the first line of defense against pathogens, representing a critical systemic response to prevent infection and maintain homeostasis, contributing to the activation of an adaptive immune response. It does not adapt to specific external stimulus or a prior infection, but relies on genetically encoded recognition of particular patterns.

Adaptive or acquired immunity is the active component of the host immune response, mediated by antigen-specific lymphocytes. Unlike the innate immunity, the acquired immunity is highly specific to a particular pathogen, including the development of immunological memory. Like the innate system, the acquired system includes both humoral immunity components and cell-mediated immunity components.

Adaptive immunity can be acquired either 'naturally' (by infection) or 'artificially' (through deliberate actions such as vaccination). Adaptive immunity can also be classified as 'active' or 'passive'. Active immunity is acquired through the exposure to a pathogen, which triggers the production of antibodies by the immune system. Passive immunity is acquired through the transfer of antibodies or activated T-cells derived from an immune host either artificially or through the placenta; it is short-lived, requiring booster doses for continued immunity.

The diagram below summarizes these divisions of immunity. Adaptive immunity recognizes more diverse patterns. Unlike innate immunity it is associated with memory of the pathogen.

History of theories

A representation of the cholera epidemic of the 19th century.

For thousands of years mankind has been intrigued with the causes of disease and the concept of immunity. The prehistoric view was that disease was caused by supernatural forces, and that illness was a form of theurgic punishment for "bad deeds" or "evil thoughts" visited upon the soul by the gods or by one's enemies. In Classical Greek times, Hippocrates, who is regarded as the Father of Medicine, diseases were attributed to an alteration or imbalance in one of the four humors (blood, phlegm, yellow bile or black bile). The first written descriptions of the concept of immunity may have been made by the Athenian Thucydides who, in 430 BC, described that when the plague hit Athens: "the sick and the dying were tended by the pitying care of those who had recovered, because they knew the course of the disease and were themselves free from apprehensions. For no one was ever attacked a second time, or not with a fatal result".

Active immunotherapy may have begun with Mithridates VI of Pontus (120-63 BC) who, to induce active immunity for snake venom, recommended using a method similar to modern toxoid serum therapy, by drinking the blood of animals which fed on venomous snakes. He is thought to have assumed that those animals acquired some detoxifying property, so that their blood would contain transformed components of the snake venom that could induce resistance to it instead of exerting a toxic effect. Mithridates reasoned that, by drinking the blood of these animals, he could acquire a similar resistance. Fearing assassination by poison, he took daily sub-lethal doses of venom to build tolerance. He is also said to have sought to create a 'universal antidote' to protect him from all poisons. For nearly 2000 years, poisons were thought to be the proximate cause of disease, and a complicated mixture of ingredients, called Mithridate, was used to cure poisoning during the Renaissance. An updated version of this cure, Theriacum Andromachi, was used well into the 19th century. The term "immunes" is also found in the epic poem "Pharsalia" written around 60 BC by the poet Marcus Annaeus Lucanus to describe a North African tribe's resistance to snake venom.

The first clinical description of immunity which arose from a specific disease-causing organism is probably A Treatise on Smallpox and Measles ("Kitab fi al-jadari wa-al-hasbah″, translated 1848) written by the Islamic physician Al-Razi in the 9th century. In the treatise, Al Razi describes the clinical presentation of smallpox and measles and goes on to indicate that exposure to these specific agents confers lasting immunity (although he does not use this term).

Until the 19th century, the miasma theory was also widely accepted. The theory viewed diseases such as cholera or the Black Plague as being caused by a miasma, a noxious form of "bad air". If someone was exposed to the miasma in a swamp, in evening air, or breathing air in a sickroom or hospital ward, they could catch a disease. Since the 19th century, communicable diseases came to be viewed as being caused by germs/microbes.

The modern word "immunity" derives from the Latin immunis, meaning exemption from military service, tax payments or other public services.

The first scientist who developed a full theory of immunity was Ilya Mechnikov who revealed phagocytosis in 1882. With Louis Pasteur's germ theory of disease, the fledgling science of immunology began to explain how bacteria caused disease, and how, following infection, the human body gained the ability to resist further infections.

Louis Pasteur in his laboratory, 1885 by Albert Edelfelt

In 1888 Emile Roux and Alexandre Yersin isolated diphtheria toxin, and following the 1890 discovery by Behring and Kitasato of antitoxin based immunity to diphtheria and tetanus, the antitoxin became the first major success of modern therapeutic immunology.

In Europe, the induction of active immunity emerged in an attempt to contain smallpox. Immunization has existed in various forms for at least a thousand years, without the terminology. The earliest use of immunization is unknown, but, about 1000 AD, the Chinese began practicing a form of immunization by drying and inhaling powders derived from the crusts of smallpox lesions. Around the 15th century in India, the Ottoman Empire, and east Africa, the practice of inoculation (poking the skin with powdered material derived from smallpox crusts) was quite common. This practice was first introduced into the west in 1721 by Lady Mary Wortley Montagu. In 1798, Edward Jenner introduced the far safer method of deliberate infection with cowpox virus, (smallpox vaccine), which caused a mild infection that also induced immunity to smallpox. By 1800, the procedure was referred to as vaccination. To avoid confusion, smallpox inoculation was increasingly referred to as variolation, and it became common practice to use this term without regard for chronology. The success and general acceptance of Jenner's procedure would later drive the general nature of vaccination developed by Pasteur and others towards the end of the 19th century. In 1891, Pasteur widened the definition of vaccine in honour of Jenner, and it then became essential to qualify the term by referring to polio vaccine, measles vaccine etc.

Passive immunity

Main article: Passive immunity

Passive immunity is the immunity acquired by the transfer of ready-made antibodies from one individual to another. Passive immunity can occur naturally, such as when maternal antibodies are transferred to the foetus through the placenta, and can also be induced artificially, when high levels of human (or horse) antibodies specific for a pathogen or toxin are transferred to non-immune individuals. Passive immunization is used when there is a high risk of infection and insufficient time for the body to develop its own immune response, or to reduce the symptoms of ongoing or immunosuppressive diseases. Passive immunity provides immediate protection, but the body does not develop memory, therefore the patient is at risk of being infected by the same pathogen later.

Naturally acquired passive immunity

A fetus naturally acquires passive immunity from its mother during pregnancy. Maternal passive immunity is antibody-mediated immunity. The mother's antibodies (MatAb) are passed through the placenta to the fetus by an FcRn receptor on placental cells. This occurs around the third month of gestation. IgG is the only antibody isotype that can pass through the placenta.

Passive immunity is also provided through the transfer of IgA antibodies found in breast milk that are transferred to the gut of a nursing infant, protecting against bacterial infections, until the newborn can synthesize its antibodies. Colostrum present in mothers milk is an example of passive immunity.

One of the first bottles of diphtheria antitoxin produced (dated 1895).

Artificially acquired passive immunity

See also: Temporarily induced immunity

Artificially acquired passive immunity is a short-term immunization induced by the transfer of antibodies, which can be administered in several forms; as human or animal blood plasma, as pooled human immunoglobulin for intravenous (IVIG) or intramuscular (IG) use, and in the form of monoclonal antibodies (MAb). Passive transfer is used prophylactically in the case of immunodeficiency diseases, such as hypogammaglobulinemia. It is also used in the treatment of several types of acute infection, and to treat poisoning. Immunity derived from passive immunization lasts for only a short period of time, and there is also a potential risk for hypersensitivity reactions, and serum sickness, especially from gamma globulin of non-human origin.

The artificial induction of passive immunity has been used for over a century to treat infectious disease, and before the advent of antibiotics, was often the only specific treatment for certain infections. Immunoglobulin therapy continued to be a first line therapy in the treatment of severe respiratory diseases until the 1930s, even after sulfonamide lot antibiotics were introduced.

Transfer of activated T-cells

Passive or "adoptive transfer" of cell-mediated immunity, is conferred by the transfer of "sensitized" or activated T-cells from one individual into another. It is rarely used in humans because it requires histocompatible (matched) donors, which are often difficult to find. In unmatched donors this type of transfer carries severe risks of graft versus host disease. It has, however, been used to treat certain diseases including some types of cancer and immunodeficiency. This type of transfer differs from a bone marrow transplant, in which (undifferentiated) hematopoietic stem cells are transferred.

Active immunity

Further information: immunological memory

 

The time course of an immune response. Due to the formation of immunological memory, reinfection at later time points leads to a rapid increase in antibody production and effector T cell activity. These later infections can be mild or even unapparent.

When B cells and T cells are activated by a pathogen, memory B-cells and T- cells develop, and the primary immune response results. Throughout the lifetime of an animal, these memory cells will "remember" each specific pathogen encountered, and can mount a strong secondary response if the pathogen is detected again. The primary and secondary responses were first described in 1921 by English immunologist Alexander Glenny although the mechanism involved was not discovered until later. This type of immunity is both active and adaptive because the body's immune system prepares itself for future challenges. Active immunity often involves both the cell-mediated and humoral aspects of immunity as well as input from the innate immune system.

Naturally acquired

Further information: Immune system

Naturally acquired active immunity occurs when a person is exposed to a live pathogen and develops a primary immune response, which leads to immunological memory. Many disorders of immune system function can affect the formation of active immunity such as immunodeficiency (both acquired and congenital forms) and immunosuppression.

Artificially acquired

Main articles: artificial induction of immunity and vaccination

See also: Pandemic prevention § CRISPR-based immune subsystems

Artificially acquired active immunity can be induced by a vaccine, a substance that contains antigen. A vaccine stimulates a primary response against the antigen without causing symptoms of the disease. The term vaccination was coined by Richard Dunning, a colleague of Edward Jenner, and adapted by Louis Pasteur for his pioneering work in vaccination. The method Pasteur used entailed treating the infectious agents for those diseases, so they lost the ability to cause serious disease. Pasteur adopted the name vaccine as a generic term in honor of Jenner's discovery, which Pasteur's work built upon.

Poster from before the 1979 eradication of smallpox, promoting vaccination.

In 1807, Bavaria became the first group to require their military recruits to be vaccinated against smallpox, as the spread of smallpox was linked to combat. Subsequently, the practice of vaccination would increase with the spread of war.

There are four types of traditional vaccines:

• Inactivated vaccines are composed of micro-organisms that have been killed with chemicals and/or heat and are no longer infectious. Examples are vaccines against flu, cholera, plague, and hepatitis A. Most vaccines of this type are likely to require booster shots.
• Live, attenuated vaccines are composed of micro-organisms that have been cultivated under conditions which disable their ability to induce disease. These responses are more durable, however, they may require booster shots. Examples include yellow fever, measles, rubella, and mumps.
• Toxoids are inactivated toxic compounds from micro-organisms in cases where these (rather than the micro-organism itself) cause illness, used prior to an encounter with the toxin of the micro-organism. Examples of toxoid-based vaccines include tetanus and diphtheria.
• Subunit, recombinant, polysaccharide, and conjugate vaccines are composed of small fragments or pieces from a pathogenic (disease-causing) organism. A characteristic example is the subunit vaccine against Hepatitis B virus.

In addition, there are some newer types of vaccines in use:

• Outer Membrane Vesicle (OMV) vaccines contain the outer membrane of a bacterium without any of its internal components or genetic material. Thus, ideally, they stimulate an immune response effective against the original bacteria without the risk of an infection.
• Genetic vaccines deliver nucleic acid that codes for an antigen into host cells, which then produce that antigen, stimulating an immune response. This category of vaccine includes DNA vaccines, RNA vaccines, and viral vector vaccines, which differ in the chemical form of nucleic acid and how it is delivered into host cells.

A variety of vaccine types are under development; see Experimental Vaccine Types.

Most vaccines are given by hypodermic or intramuscular injection as they are not absorbed reliably through the gut. Live attenuated polio and some typhoid and cholera vaccines are given orally in order to produce immunity based in the bowel.

Hybrid immunity

Hybrid immunity is the combination of natural immunity and artificial immunity. Studies of hybrid-immune people found that their blood was better able to neutralize the Beta and other variants of SARS-CoV-2 than never-infected, vaccinated people. Moreover, on 29 October 2021, the Centers for Disease Control and Prevention (CDC) concluded that "Multiple studies in different settings have consistently shown that infection with SARS-CoV-2 and vaccination each result in a low risk of subsequent infection with antigenically similar variants for at least 6 months. Numerous immunologic studies and a growing number of epidemiologic studies have shown that vaccinating previously infected individuals significantly enhances their immune response and effectively reduces the risk of subsequent infection, including in the setting of increased circulation of more infectious variants. ... "

Absence seizure

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Absence_seizure 

 

Absence seizure
Other names	Petit mal seizures
Pronunciation	/ˈæbsəns ˈsiːʒər/ or /ɑːbˈsɑːns ˈsiːʒər/
Specialty	Neurology

Absence seizures are one of several kinds of generalized seizures. These seizures are sometimes referred to as petit mal seizures (from the French for "little illness", a term dated in the late 18th century). Absence seizures are characterized by a brief loss and return of consciousness, generally not followed by a period of lethargy (i.e. without a notable postictal state). Absence seizure is very common in children. It affects both sides of the brain.

Epidemiology

Absence seizures affect between 0.7 and 4.6 per 100,000 in the general population and 6 to 8 per 100,000 in children younger than 15 years. Childhood absence seizures account for 10% to 17% of all absence seizures. Onset is between 4 and 10 years and peaks at 5 to 7 years. It is more common in girls than in boys.

Etiology

An absence seizure is specifically caused by multifactorial inheritance. The voltage-gated T-type calcium channel is regulated by GABRG2, GABRG3, and CACNA1A2 genes. Inheritance of these genes is involved in etiology of absence seizure. The factors that trigger an absence seizure are lack of sleep and compliance, drinking alcohol, and benzodiazepine withdrawal, and use of medication that reduces the threshold of seizure such as Isoniazid, antipsychotics.

Signs and symptoms

The clinical manifestations of absence seizures vary significantly among patients. Impairment of consciousness is the essential symptom, and may be the only clinical symptom, but this can be combined with other manifestations. The hallmark of the absence seizures is abrupt and sudden-onset impairment of consciousness, interruption of ongoing activities, a blank stare, possibly a brief upward rotation of the eyes. If the patient is speaking, speech is slowed or interrupted; if walking, they stand transfixed; if eating, the food will stop on its way to the mouth. Usually, the patient will be unresponsive when addressed. In some cases, attacks are aborted when the patient is called. The attack lasts from a few seconds to half a minute and evaporates as rapidly as it commenced. Absence seizures generally are not followed by a period of disorientation or lethargy (postictal state), in contrast to the majority of seizure disorders.

1. Absence with impairment of consciousness only as per the above description.
2. Absence with mild clonic components. Here the onset of the attack is indistinguishable from the above, but clonic components may occur in the eyelids, at the corner of the mouth, or in other muscle groups which may vary in severity from almost imperceptible movements to generalised myoclonic jerks. Objects held in the hand may be dropped.
3. Absence with atonic components. Here there may be a diminution in tone of muscles subserving posture as well as in the limbs leading to dropping of the head, occasionally slumping of the trunk, dropping of the arms, and relaxation of the grip. Rarely tone is sufficiently diminished to cause this person to fall.
4. Absence with tonic components. Here during the attack tonic muscular contraction may occur, leading to increase in muscle tone which may affect the extensor muscles or the flexor muscles symmetrically or asymmetrically. If the patient is standing, the head may be drawn backward and the trunk may arch. This may lead to retropulsion, which may cause eyelids to twitch rapidly; eyes may jerk upwards or the patients head may rock back and forth slowly, as if nodding. The head may tonically draw to one or another side.
5. Absence with automatisms. Purposeful or quasi-purposeful movements occurring in the absence of awareness during an absence attack are frequent and may range from lip licking and swallowing to clothes fumbling or aimless walking. If spoken to, the patient may grunt, and when touched or tickled may rub the site. Automatisms are quite elaborate and may consist of combinations of the above described movements or may be so simple as to be missed by casual observation.
6. Absence with autonomic components. These may be pallor, and less frequently flushing, sweating, dilatation of pupils and incontinence of urine.

Mixed forms of absence frequently occur. These seizures can happen a few times a day or in some cases, hundreds of times a day, to the point that the person cannot concentrate in school or in other situations requiring sustained, concentrated attention.

Risk factors

Typical absences are easily induced by hyperventilation in more than 90% of people with typical absences. This is a reliable test for the diagnosis of absence seizures: a patient suspected of typical absences should be asked to hyperventilate for three minutes, counting breaths. During hyperventilation, the oxygen and carbon dioxide level will become abnormal. This results in weakening of electrical signal which leads to a reduction in the seizure threshold. Intermittent photic stimulation may precipitate or facilitate absence seizures; eyelid myoclonia is a common clinical feature.

A specific mechanism difference exists in absence seizures in that T-type Ca⁺⁺ channels are believed to be involved. Ethosuximide is specific for these channels and thus it is not effective for treating other types of seizures. Valproate and gabapentin (among others) have multiple mechanisms of action including blockade of T-type Ca⁺⁺ channels, and are useful in treating multiple seizure types. Gabapentin can aggravate absence seizures.

Pathophysiology

The corticothalamic cortical circuit plays an important role in the pathophysiology of absence seizure. Some of the neurons are important in their occurrence. They are

• Cortical glutamatergic neurons
• Thalamic relay neurons
• Neurons of thalamic nucleus reticularis

Abnormal oscillatory rhythms develop in the thalamic nucleus reticularis. This causes inhibition of GABAergic neurotransmission and excitation of glutamate neurotransmission. Abnormal oscillatory spikes are produced by the low threshold T-type calcium channel. This explains how inheritance of gene code for T-type calcium channel leads to an absence seizure. Antiepileptic drugs such as Gabapentin, Tiagabine and Vigabatrin cause inhibition of GABA resulting in exacerbation of absence seizures.

Diagnosis

The primary diagnostic test for absence seizures is electroencephalography (EEG). However, brain scans such as by an MRI can help rule out other diseases, such as a stroke or a brain tumor.

During EEG, hyperventilation can be used to provoke these seizures. Ambulatory EEG monitoring over 24 hours can quantify the number of seizures per day and their most likely times of occurrence.

Absence seizures are brief (usually less than 20 seconds) generalized epileptic seizures of sudden onset and termination. When someone experiences an absence seizure they are often unaware of their episode. Those most susceptible to this are children, and the first episode usually occurs between 4–12 years old. It is very rare that someone older will experience their first absence seizure. Episodes of absence seizures can often be mistaken for inattentiveness when misdiagnosed, and can occur 50–100 times a day. They can be so difficult to detect that some people may go months or years before being given a proper diagnosis. There are no known before or after effects of absence seizures.

Absence seizures have two essential components:

• Clinical - the impairment of consciousness (absence)
• EEG - the EEG shows generalized spike-and-slow wave discharges

Absence seizures are broadly divided into typical and atypical types:

• Typical absence seizures usually occur in the context of idiopathic generalised epilepsies and an EEG shows fast >2.5 Hz generalised spike-wave discharges. The prefix "typical" is to differentiate them from atypical absences rather than to characterise them as "classical" or characteristic of any particular syndrome.
• Atypical absence seizures:
  • Occur only in the context of mainly severe symptomatic or cryptogenic epilepsies of children with learning difficulties who also have frequent seizures of other types, such as atonic, tonic and myoclonic.
  • Have slower onset and termination and changes in tone are more pronounced.
  • Have particular ictal characteristics: EEG is of slow (less than 2.5 Hz) spike and slow wave. The discharge is heterogeneous, often asymmetrical and may include irregular spike and slow wave complexes, fast and other paroxysmal activity. Background interictal EEG is usually abnormal.

Syndromes

Absence seizure syndromes are childhood absence epilepsy, epilepsy with myoclonic absences, juvenile absence epilepsy and juvenile myoclonic epilepsy. Other proposed syndromes are Jeavons syndrome (eyelid myoclonia with absences), and genetic generalised epilepsy with phantom absences.

Absence seizures are also known to occur to patients with porphyria and can be triggered by stress or other porphyrin-inducing factors.

Treatment

Treatment of patients with absence seizures only is mainly with ethosuximide or valproic acid, which are of equal efficacy controlling absences in around 75% of patients. Lamotrigine monotherapy is less effective, controlling absences in around 50% of patients. This summary has been recently confirmed by Glauser et al. (2010), who studied the effects of ethosuximide, valproic acid, and lamotrigine in children with newly diagnosed childhood absence epilepsy. Drug dosages were incrementally increased until the child was free of seizures, the maximal allowable dose was reached, or a criterion indicating treatment failure was met. The primary outcome was freedom from treatment failure after 16 weeks of therapy; the secondary outcome was attentional dysfunction. After 16 weeks of therapy, the freedom-from-failure rates for ethosuximide and valproic acid were similar and were higher than the rate for lamotrigine. There were no significant differences between the three drugs with regard to discontinuation because of adverse events. Attentional dysfunction was more common with valproic acid than with ethosuximide. If monotherapy fails or unacceptable adverse reactions appear, replacement of one by another of the three antiepileptic drugs is the alternative. Adding small doses of lamotrigine to sodium valproate may be the best combination in resistant cases.

Although ethosuximide is effective in treating only absence seizures, valproic acid is effective in treating multiple seizure types including tonic-clonic seizure and partial seizure, suggesting it is a better choice if a patient is exhibiting multiple types of seizures. Similarly, lamotrigine treats multiple seizure types including partial seizures and generalized seizures, therefore it is also an option for patients with multiple seizure types. Clonazepam (Klonopin, Rivotril) is effective in the short term but is not generally recommended for treatment of absence seizure because of the rapid development of tolerance and high frequency of side effects. If medication is not effective in treating absence seizures, surgical treatment such as deep brain stimulation can reduce seizure episodes.

Prevention

Medication alone cannot prevent absence seizure. It need to be supplemented by life-style changes such as exercise, stress reduction, good sleep hygiene, and healthy diet. Research shows that patient with ketogenic diet have 50% reduction in seizure episodes and 34% of patients become seizure free.

Medications that should not be used

Carbamazepine, vigabatrin, and tiagabine are contraindicated in the treatment of absence seizures, irrespective of cause and severity. This is based on clinical and experimental evidence. In particular, the GABA agonists vigabatrin and tiagabine are used to induce, not to treat, absence seizures and absence status epilepticus. Similarly, oxcarbazepine, phenytoin, phenobarbital, gabapentin, and pregabalin should not be used in the treatment of absence seizures because these medications may worsen absence seizures.

Data limitations

In the treatment of absence seizures there is often insufficient evidence for which of the available medications has the best combination of safety and efficacy for a particular patient. Nor is it easily known how long a medication must be continued before an off-medication trial should be conducted to determine whether the patient has outgrown the absence seizures, as is often the case in children. To date there have been no published results of any large, double-blind, placebo-controlled studies comparing the efficacy and safety of these or any other medications for absence seizures. A 2019 Cochrane review found that ethosuximide was the best mono-therapy for children and adolescents but noted that if absence seizures co-exist with tonic-clonic seizures then valproate should be preferred.

Autism and working memory

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Autism_and_working_memory 

 

Typical classroom activity requires much polytropic processing of stimuli

 

A monotropic way of teaching can be greatly helpful for students with autism.

 

Monotropic and polytropic learning

Autism is a neurodevelopmental disorder diagnosed as impaired social interaction and communication, and by restricted and repetitive behavior. In this article, the word autism is used for referring to the whole range of conditions on the autism spectrum, which is not uncommon.

Working memory is the system that actively holds multiple pieces of transitory information in the mind, where they can be manipulated. This system has a limited capacity. Working memory is a part of the executive functions (EF), an umbrella term for cognitive processes that regulate, control, and manage other cognitive processes, for instance planning and attention.

Research connections

A majority of the research has found that individuals with autism perform poorly on measures of executive function. A general decrease in working memory (WM) is one of the limitations, although some studies have found that working memory is not impaired in autistic children relative to controls matched for IQ. However, some evidence suggests that there may be minimal impairment in high-functioning autistic (HFA) individuals in that they have intact associative learning ability, verbal working memory, and recognition memory. In rare cases there are even instances of individuals possessing extremely good memory in constricted domains which are typically characterized as savants. Bennetto, Pennington and Rogers also suggest that WM deficits and limited EF is likely compounded by the onset of autism where early development yields hindrances in social interaction which typically (i.e. without impairment) improves both WM and EF. However, due to limited ability in interpreting social gestures and an impaired ability to process such information in a holistic and comprehensive manner, individuals with autism are subject to diminished and confounding instances of memory function and performance.

Physiological underpinnings

The physical underpinnings of the cause for differences in the working memory of autistic people has been studied. Bachevalier suggests a major dysfunction in the brain of an autistic individual resides in the neural mechanisms of the structures in the medial temporal lobe (MTL) and perhaps, more specifically the amygdaloid complex. This may have implications in their ability to encode information because of the role the MTL and especially the hippocampal areas play in information processing DeLong reinforces this by suggesting autism to affect hippocampal function. Because the hippocampus is pivotal in memory encoding and modulating memory consolidation, any impairment can drastically affect an autistic individual's ability to process (i.e. multi-modal) and retain information. Sumiyoshi, Kawakubo, Suga, Sumiyoshi and Kasai have suggested that it is possible that the attenuated neural activities in parahippocampal regions might have something to do with the abnormal organization of information of individuals within the autistic spectrum. The left parahippocampal region (including the parahippocampal gyrus) has an implied role in sorting, relating, and sending information to the hippocampus and thus any abnormal activity or dysfunction within these regions might be accountable for the degree of effectiveness autistic individuals organize information. This is in keeping with other findings that suggest unconventional activity or lack of activity within the hippocampal regions which have a role in explaining some aspects of ASD.

Further evidence suggests that there is abnormal circuitry in what Brothers calls the neural basis for social intelligence, or holistically interpreting people's expressions and intentions. The interaction between the amygdala, the orbitofrontal cortex (OFC), and the superior temporal sulcus and gyrus (STG) enables one to process social information for personal interaction. In the case of autistic individuals there seems to be a limitation in these structures such that facial expressions, body language and speech expressions (ex. sarcasm) go consciously unnoticed, it is theorized that this could have something to do with the sagittal stratum, which is sometimes referred to as the "sarcasm center". However, Frith and Hill suggest that through 'remediation' or training that attends to specific traits in expressions, social understanding can be partially improved. The possibility of training in social understanding has given hope that there is a path that can be taken to reduce the social divide that is between children with autism and children who are neurotypical.

Characteristics

Global working memory characteristics

Beversdorf finds that because autistic individuals are not as reliant on contextual information (i.e. comparing typically related schemas) to aid in memory consolidation, they are less likely to rely on semantically similar cues (ex. Doctor-Nurse vs. Doctor-Beach). Thus, an autistic individual would fare well on discriminating and recalling accurate items from false items.

Bennetto, Pennington and Rogers investigated the degree of cognitive impairment in autistic individuals with an emphasis on illuminating the latency in executive functioning. Findings suggested a hindrance in temporal order, source, free recall and working memory. However, their participants did exhibit capable short and long-term memory, cued recall and the capacity to learn new material. In sum, they suggested that there is both a general deficit in global working memory and a specific impairment in social intelligence where the former is exacerbated by the latter and vice versa.

Other evidence points towards unique mnemonic strategies used by autistic individuals wherein they rely less on semantic associative networks and are less constricted by conventional word-word associations (ex. Orange-Apple). This may be due to abnormalities in MTL regions. Thus, autistic individuals may have the capacity for more abstract but robust associations. Firth addresses this with the term "weak Central Coherence", meaning a reduced tendency for processing information in context and integration of higher-level meaning. This may explain why autistic individuals have a heightened capacity for noticing seemingly disjointed details. For example, in the Embedded Figures Test (EFT) autistic individuals exhibited a faster and heightened ability to locate the target because of their diminished reliance on global perception. In a study conducted on autistic children, it was shown that neurocognition influences word learning in autistic children. The process of syntactic development requires a child to match co-occurrences of words or parts of words (morphemes) and their meanings. This process can depend on working memory. The limited short term verbal memory paired with working memory may be the reason of language delay in children with autism. According to the result of this experiment the group with autism was able to perform the part of the test with nonlinguistic cues which depended on working memory but failed to pass short-term memory and the linguistic part of it. This explains the delay of language in autistic children and neurocognition is an important contributor to it.

Central executive or executive functioning

The symptoms associated with autism spectrum disorders are thought to be greatly impacted by a dysfunction in working memory. In examining autism through the lens of Baddeley & Hitch's model of working memory there have been conflicting results in research. Some studies have shown that individuals that fall within the spectrum have impaired executive functioning which means working memory does not function correctly. However, other studies have failed to find an effect in autistic people with a high level of functioning. Tests such as the Wisconsin Card Sorting Test have been administered to autistic individuals and the lower scores have been interpreted as indicative of a poor ability to focus on relevant information and thus a deficit within the central executive aspect of working memory. An aspect of ASD is that it might be present, to a certain extent, in first degree relatives. One study found that siblings of autistic individuals have limited ability to focus and conceptualize categories using updated information. Given these results, it is reasonable to suggest that these so-called deficits in cognitive ability are of the cognitive endophenotypes (i.e. relatives) of ASD.

Category integration

Given these findings it would appear as if autistic individuals have trouble categorizing. Studies have shown that category induction is in fact possible and can occur at the same cognitive level as non-autistic individuals, however. Given that category formation aspects such as discrimination and feature detection are enhanced among autistic individuals it is viable to state that although autistic individuals require more trials and or time to learn material, and also may employ different learning strategies than non-autistic individuals, once learned, the level of categorization displayed is on par with a non-autistic individual.

The idea that autistic individuals learn differently than those without autism can account for the delay in their ability to categorize. However, once they begin categorizing they are at an average level of cognitive ability as compared to those without autism. This, however, is only applicable to higher functioning individuals within the spectrum as those with lower IQ levels are notoriously difficult to test and measure.

In part with a different style of learning, individuals within the spectrum have also been proposed to have a weak central coherence. This theory meshes well with the general traits of individuals within the spectrum. Again though, this is explained through different learning styles. As opposed to viewing a forest as a collection of trees, those with autism see one tree, and another tree, and another tree and thus it takes an immense amount of time to process complex tasks in comparison with non-autistic people. Weak central coherence can be used to explain what is viewed as a working memory deficit in attention or inhibition, as autistic individuals possess an intense focus on single parts of a complex, multi-part concept and cannot inhibit this in order to withdraw focus and direct it on the whole rather than a singular aspect. Thus, this suggests that the decrement in working memory is partially inherited which is then exacerbated by further genetic complications leading to a diagnosis of autism.

Visual and spatial memory

Deficits in spatial working memory appear to be familial in people with autism, and probably even in their close relatives. Replication of movements by others, a task that requires spatial awareness and memory capacities, can also be difficult for autistic children and adults.

People with Asperger's Syndrome were found to have spatial working memory deficits compared with control subjects on the Executive-Golf Task, although these may be indicative of a more general deficit in non-verbal intelligence in people with ASD. Despite these results, autistic children have been found to be superior to typically developing children in certain tasks, such as map learning and cued path recall regarding a navigated real-life labyrinth. Steele et al. attempt to explain this discrepancy by advancing the theory that the performance of autistic people on spatial memory tasks degrades faster in the face of increasing task difficulty, when compared with normally developed individuals. These results suggest that working memory is related with an individual's ability to solve problems, and that autism is a hindrance in this area.

Autistic people appear to have a local bias for visual information processing, that is, a preference for processing local features (details, parts) rather than global features (the whole). One explanation for this local bias is that people with autism do not have the normal global precedence when looking at objects and scenes. Alternatively, autism could bring about limitations in the complexity of information that can be manipulated in short-term visual memory during graphic planning.

The difficulties that individuals with ASD often have in regards to facial recognition has prompted further questions. Some research has shown that the fusiform gyrus in ASD individuals acts differently from in non-ASD individuals which may explain the aforementioned troubles regarding facial recognition.

Research by Baltruschat et al. has shown that improvement in spatial working memory for autistic individuals may be possible. Adapting a behaviorist approach by using positive reinforcement could increase WM efficiency in young children with ASD.

Auditory and phonological memory

The research on phonological working memory in autism is extensive and at times conflicting. Some research has found that, in comparison with spatial memory, verbal memory and inner speech use remain relatively spared, while other studies have found limitations on the use of inner speech by autistic people. Others have found a benefit to phonological processing in autism when compared with semantic processing, and attribute the results to a similar developmental abnormality to that in savant syndrome.

In particular, Whitehouse et al. have found that autistic children, when compared with typically developing (TD) children of a similar mean verbal age and reading ability, performed better when asked to recall a set of pictures presented to them, but not as well when asked to recall a set of printed words presented interspersed with the pictures; a competing verbal task given to both sets of participants also worsened performance on control children more than it did on autistic children. They also reported that word length effects were greater for the control group. These results are contested by Williams, Happé, and Jarrold, who contend that it may be verbal IQ, rather than verbal ability, that is at issue, and Whitehouse et al.'s subjects were not matched on chronological age. Williams, Happé, and Jarrold themselves found no difference between autistic children and controls on a serial recall task where phonological similarity effects, rather than word length effects, were used as an alternate measure of inner speech use.

Joseph et al. found that a self-ordered pointing task in autistic children involving stimuli that could be remembered as words (e.g. shovel, cat) was impaired relative to comparison children, but the same task with abstract stimuli was not impaired in autistic children. In contrast, Williams et al. found that autistic children scored significantly lower than TD children on spatial memory tests. Williams et al. not only experimented with spatial memory tasks, but verbal memory as well. They discovered that in an experimental group and a control group of TD individuals, that while differences were found in spatial memory ability, no significant difference was seen between the groups regarding verbal memory. They ran their experiments with both children and adult participants. Autism is a developmental disorder, so it is possible that life experiences could alter the memory performance in adults who had grown up with autism. Williams et al. experimented with children separately to see if they had different results from their adult counterparts. They used a WRAML (Wide Range Assessment of Memory and Learning) test, a test specifically designed to test memory in children. Test results were similar across all age groups, that significant differences between TD and autistic participants are found only in spatial memory, not verbal working memory.

Gabig et al. discovered that children with autism, regarding verbal working memory and story retelling, performed worse than a control group of TD children. In three separate tasks designed to test verbal working memory, the autistic children scored well below the expected levels for their age. While results do show lower scores for autistic children, there was also information that suggested lack of vocabulary contributed to the lower scores, rather than working memory itself.

There is some evidence from an fMRI study that autistic individuals are more likely to use visual cues rather than verbal cues on some working memory tasks, based on the differentially high activation of right parietal regions over left parietal regions in an N-back working memory task with letters.

Opposing results

Some data has shown that individuals with ASD may not have WM impairments and that this supposed impairment observed is a result of testing. Nakahachi et al. argue that the vagueness of many tests measuring WM levels in people with ASD. They found that people with ASD only performed worse on WM tests if the test itself could have interfered with the completion of the test. These findings show that the type of test and the way it is presented given to individuals with ASD can strongly affect the results, therefore much caution should be taken in choosing the design of a study focusing on WM in people with ASD.

Ozonoff et al. have found similar results in their studies on working memory in individuals with ASD. Their research showed no significant difference between individuals with ASD and those without ASD in tests designed to measure various aspects of working memory. This supports the notion that Autism does not inhibit WM. Results from experiments that have shown lower WM facilities in ASD individuals may be due to the human interaction nature of these experiments as individuals with ASD exhibit low social functioning skills. Experiments utilizing computer rather than human interaction remove this problem and may head more accurate findings.

Further research by Griffith et al. also indicates that WM may not be impaired in those with autism. There may be some executive function impairments in these individuals, but not in working memory and rather in social and language skills, which can effect education early in life. Other research conducted by Griffith et al. on young autistic individuals did not measure verbal working abilities, but nonetheless found no significant difference between the executive functions in autistic and non-autistic individuals. Though there has been much research that alludes to low WM abilities in those with autism, these recent data weaken the argument that autistic individuals have little WM facilities.