Pick%27s disease

Pick's disease, a type of Frontotemporal Dementia, is a rare neurodegenerative disease that causes progressive destruction of nerve cells in the brain. Symptoms include dementia and loss of speech (aphasia). While some of the symptoms can initially be alleviated, the disease progresses and patients often die within two to ten years. A defining characteristic of the disease is build-up of tau proteins in neurons, accumulating into silver-staining, spherical aggregations known as "Pick bodies".

While the term Pick's disease was once used to represent a class of clinical syndromes with symptoms attributable to frontal and temporal lobe dysfunction, it is now used among professionals to mean a specific pathology that is one of the causes of frontotemporal lobar degeneration. Some people use the term Pick's disease to mean the more general clinical syndrome of frontotemporal lobar degeneration, but this has previously led to confusion among professionals and patients and so its use should be restricted to the specific pathological subtype described below. It is also known as Pick disease and PiD (not to be confused with pelvic inflammatory disease (PID) or Parkinson's disease (PD)).

Signs and symptoms

The symptoms of Pick's disease include difficulty in speech and thinking, efforts to dissociate from family, behavioral changes, unwarranted anxiety, impaired regulation of social conduct (e.g., breaches of etiquette, tactlessness, dis-inhibition, misperception), passivity, inertia, over-activity, pacing and wandering. The changes in personality allow doctors to distinguish between Pick's disease and Alzheimer's disease. Pick's disease is one of the causes of the clinical syndrome of frontotemporal lobar degeneration which has three subtypes. Pick's disease pathology is associated more with the frontotemporal dementia and progressive nonfluent aphasia subtypes than the semantic dementia subtype.

Causes

While other pathologies causing frontotemporal lobar degeneration are associated with a genetic cause, evidence is not conclusive in modern research on whether classical Pick's disease pathology has or does not have a direct genetic link, or whether it has been shown to run in families or certain ethnic or gender specific subgroups.

Pathophysiology

PiD was first recognized as a distinct disease separate from other neurodegenerative diseases because of the presence of large, dark-staining aggregates of proteins in neurological tissue as well as the aforementioned ballooned cells, which are known as Pick cells. Pick bodies are almost universally present in patients with PiD, but some new cases of atypical Pick’s disease have come to light that lack noticeable Pick bodies. A variety of stains can aid in the visualization of Pick bodies and Pick cells, but immunohistochemical staining using anti-tau and anti-ubiquitin antibodies have proven the most efficient and specific. Hematoxylin and eosin staining allows visualization of another population of Pick cells, which are both tau and ubiquitin protein negative. Several silver impregnation stains have been used, including the Bielschowsky, Bodian, and Gallyas methods. The latter two techniques are sensitive enough to allow PiD to be distinguished from Alzheimer's disease as the Bodian will bind preferentially to cells with PiD as compared to the Gallyas method, which preferentially binds to the cells with Alzheimer's.

Numerous areas of the brain are affected by PiD, but the specific areas that are affected allow for differentiation between PiD and Alzheimer’s disease. Pick bodies are almost always found in several places in the brain, including the dentate gyrus, the pyramidial cells of the CA1 sector and subiculum of the hippocampus, and the neocortex as well as a plurality of other nuclei. Interestingly, it is the location in the layers of the brain as well as the anatomical placement that demonstrates some of the unique features of PiD. A striking feature is that in the neocortex the Pick bodies are in the II and IV layers of the cortex, which send neurons within the cortex and to thalamic synapses, respectively. While layers III and V have very few if any Pick bodies they show extreme neuronal loss that can, in some cases, be so severe as to leave a void in the brain altogether. Other regions that are involved include the caudate, which is severely affected, the dorsomedial region of the putamen, the globus pallidus, and locus coeruleus. The hypothalamic lateral tuberal nucleus is also very severely affected. The cerebellar elements that are important in receiving input, including the mossy fibers as well as the monodendritic brush cells in the granule cell layer, and generating output signals, most notably the dentate nucleus, are stricken with lots of tau protein inclusions. Strangely, the substantia nigra is most often uninvolved or only mildly involved, but cases of extreme degeneration do exist.

PiD has several unique biochemical characteristics that allow for identification of Pick’s disease as opposed to other pathological subtypes of frontotemporal lobar degeneration. The most striking of these is that this disease, which has tau protein tangles present in many affected neurons, contains only one or as many as two of the six isoforms of the tau protein. All of these isoforms result from alternative splicing of the same gene. Pick bodies typically have the 3R isoform of tau proteins as not only the most abundant form but the only form of this protein, but a recent study has shown that a much greater number of tau isoforms including 4R and mixed 3R/4R can be present in the Pick bodies. Not only do these tangles have the 3R tau protein predominately, they are characteristically shaped with a round body; there is often an indentation in the area that faces the nucleus of the cell.

The Pick bodies are able to be labeled by N-terminal amyloid precursor protein segment, hyperphosphorylated tau, ubiquitin, Alz-50, neurofiliment proteins, clathrin, synaptophysin and neuronal surface glycoside (A2B5) specific stains. Moreover βII tubulin proteins are suspected in playing a role in the formation of phosphor-tau aggregates that are seen in PiD as well as AD.

Differences from Alzheimer’s disease

In Alzheimer's disease, all six isoforms of tau proteins are expressed. In addition, the presence of neurofibrillary tangles that are a hallmark of Alzheimer’s can be stained with antibodies to basic fibroblast growth factor, amyloid P, and heparan sulfate glycosaminoglycan.

Another difference is that in Pick's disease, a personality change occurs before any form of memory loss, unlike Alzheimer's, where memory loss typically presents first. This is used clinically to determine whether a patient is suffering from Alzheimer's or Pick's.

History

Pick's disease is named after Arnold Pick, a professor of psychiatry from the University of Prague who first discovered and described the disease in 1892 by examining the brain tissue of several deceased patients with histories of dementia. As a result, the characteristic histological feature of this diseaseâ€"a protein tangle that appears as a large body in neuronal tissueâ€"is named a Pick body. In 1911, Alois Alzheimer noted the complete absence of senile plaques and neurofilbrillary tangles as well as the presence of Pick bodies and occasional ballooned neurons.

Notable cases

• Don Cardwell (1935â€"2008), Major League baseball pitcher
• Rocco "Rocky" Catena (1929â€"2006), music industry executive, former senior VP, Capitol Records, in charge of marketing The Beatles and other top recording stars in the U.S. Suffered from Pick's disease for 20+ years.
• Jerry Corbetta (1947-), original lead singer and keyboardist for the group Sugarloaf
• Ted Darling (c.1935â€"1996), voice of the Buffalo Sabres
• Robert W. Floyd (1936â€"2001), computer scientist
• Colleen Howe (1933â€"2009), wife of Hockey Hall of Famer Gordie Howe
• Kazi Nazrul Islam (1899â€"1976), Bengali poet and musician (Known as rebel poet), who pioneered poetic works espousing intense rebellion against fascism and oppression, was a lifelong sufferer of this disease (approximately 1941â€"1976)
• Ralph Klein (1942â€"2013), former premier of Alberta, Canada
• Kevin Moore (1958â€"2013), English footballer
• Nic Potter (1951â€"2013), British bassist for Van der Graaf Generator
• David Rumelhart (1942â€"2011), American cognitive psychologist
• Colin Savage, father of footballer Robbie Savage
• Ernie Moss (born 1949), English footballer.

Radio frequency

Radio frequency (RF) is a rate of oscillation in the range of around 3 kHz to 300 GHz, which corresponds to the frequency of radio waves, and the alternating currents which carry radio signals. RF usually refers to electrical rather than mechanical oscillations; however, mechanical RF systems do exist (see mechanical filter and RF MEMS).

Although radio frequency is a rate of oscillation, the term "radio frequency" or its abbreviation "RF" are also used as a synonym for radio â€" i.e. to describe the use of wireless communication, as opposed to communication via electric wires. Examples include:

• Radio-frequency identification
• ISO/IEC 14443-2 Radio frequency power and signal interface

Special properties of RF current

Electric currents that oscillate at radio frequencies have special properties not shared by direct current or alternating current of lower frequencies.

• The energy in an RF current can radiate off a conductor into space as electromagnetic waves (radio waves); this is the basis of radio technology.
• RF current does not penetrate deeply into electrical conductors but tends to flow along their surfaces; this is known as the skin effect. For this reason, when the human body comes in contact with high power RF currents it can cause superficial but serious burns called RF burns.
• RF currents applied to the body often do not cause the painful sensation of electric shock as do lower frequency currents. This is because the current changes direction too quickly to trigger depolarization of nerve membranes.
• RF current can easily ionize air, creating a conductive path through it. This property is exploited by "high frequency" units used in electric arc welding, which use currents at higher frequencies than power distribution uses.
• Another property is the ability to appear to flow through paths that contain insulating material, like the dielectric insulator of a capacitor.
• When conducted by an ordinary electric cable, RF current has a tendency to reflect from discontinuities in the cable such as connectors and travel back down the cable toward the source, causing a condition called standing waves, so RF current must be carried by specialized types of cable called transmission line.

Radio communication

To receive radio signals an antenna must be used. However, since the antenna will pick up thousands of radio signals at a time, a radio tuner is necessary to tune into a particular frequency (or frequency range). This is typically done via a resonator â€" in its simplest form, a circuit with a capacitor and an inductor form a tuned circuit. The resonator amplifies oscillations within a particular frequency band, while reducing oscillations at other frequencies outside the band. Another method to isolate a particular radio frequency is by oversampling (which gets a wide range of frequencies) and picking out the frequencies of interest, as done in software defined radio.

The distance over which radio communications is useful depends significantly on things other than wavelength, such as transmitter power, receiver quality, type, size, and height of antenna, mode of transmission, noise, and interfering signals. Ground waves, tropospheric scatter and skywaves can all achieve greater ranges than line-of-sight propagation. The study of radio propagation allows estimates of useful range to be made.

Frequency bands

In medicine

Radio frequency (RF) energy, in the form of radiating waves or electrical currents, has been used in medical treatments for over 75 years, generally for minimally invasive surgeries, using radiofrequency ablation and cryoablation, including the treatment of sleep apnea. Magnetic resonance imaging (MRI) uses radio frequency waves to generate images of the human body.

Radio frequencies at non-ablation energy levels are sometimes used as a form of cosmetic treatment that can tighten skin, reduce fat, or promote healing.

RF diathermy is a medical treatment that uses RF induced heat as a form of physical or occupational therapy and in surgical procedures. It is commonly used for muscle relaxation. It is also a method of heating tissue electromagnetically for therapeutic purposes in medicine. Diathermy is used in physical therapy and occupational therapy to deliver moderate heat directly to pathologic lesions in the deeper tissues of the body. Surgically, the extreme heat that can be produced by diathermy may be used to destroy neoplasms, warts, and infected tissues, and to cauterize blood vessels to prevent excessive bleeding. The technique is particularly valuable in neurosurgery and surgery of the eye. Diathermy equipment typically operates in the short-wave radio frequency (range 1â€"100 MHz) or microwave energy (range 434â€"915 MHz).

Pulsed electromagnetic field therapy (PEMF) is a medical treatment that purportedly helps to heal bone tissue reported in a recent NASA study. This method usually employs electromagnetic radiation of different frequencies - ranging from static magnetic fields, through extremely low frequencies (ELF) to higher radio frequencies (RF) administered in pulses.

Effects on the human body

Extremely low frequency RF

High-power extremely low frequency RF with electric field levels in the low kV/m range are known to induce perceivable currents within the human body that create an annoying tingling sensation. These currents will typically flow to ground through a body contact surface such as the feet, or arc to ground where the body is well insulated.

Microwaves

Microwave exposure at low-power levels below the Specific absorption rate set by government regulatory bodies are considered harmless non-ionizing radiation and have no effect on the human body. However, levels above the Specific absorption rate set by the FCC are considered potentially harmful. See, Mobile phone radiation and health

Long-term exposure to high-levels of microwaves, is recognized, from experimental animal studies and epidemiological studies in humans, to cause cataracts. The mechanism is unclear but may include changes in heat sensitive enzymes that normally protect cell proteins in the lens. Another mechanism that has been advanced is direct damage to the lens from pressure waves induced in the aqueous humor.

High-power exposure to microwave RF is known to create a range of effects from lower to higher power levels, ranging from unpleasant burning sensation on the skin and Microwave auditory effect, to extreme pain at the mid-range, to physical burning and blistering of skin and internals at high power levels. Also, see Microwave burn.

General RF exposure

Canadian safety code 6, also, recommends electric field limits of 100 kV/m for pulsed EMF to prevent air breakdown and spark discharges. Additional rational for EMF restrictions is to avoid auditory effect and energy-induced unconsciousness in rats.

Also, See Electromagnetic radiation and health.

For high-power RF exposure see radiation burn.

For low-power RF exposure see Radiation-induced cancer.

As a weapon

A heat ray is a RF harassment device that makes use of microwave radio frequencies to create an unpleasant heating effect in the upper layer of the skin. A publically known heat ray weapon called the Active Denial System was developed by the US military as an experimental weapon to deny the enemy access to an area. Also, see death ray which is a heat ray weapon that delivers electromagnetic energy at levels that injure human tissue. The inventor of the death ray, Harry Grindell Matthews, claims to have lost sight in his left eye while developing his death ray weapon based on a primitive microwave magnetron from the 1920s. (Note that a typical microwave oven induces a tissue damaging cooking effect inside the oven at about 2 kV/m.)

Measurement

Since radio frequency radiation has both an electric and a magnetic component, it is often convenient to express intensity of radiation field in terms of units specific to each component. The unit volts per meter (V/m) is used for the electric component, and the unit amperes per meter (A/m) is used for the magnetic component. One can speak of an electromagnetic field, and these units are used to provide information about the levels of electric and magnetic field strength at a measurement location.

Another commonly used unit for characterizing an RF electromagnetic field is power density. Power density is most accurately used when the point of measurement is far enough away from the RF emitter to be located in what is referred to as the far field zone of the radiation pattern. In closer proximity to the transmitter, i.e., in the "near field" zone, the physical relationships between the electric and magnetic components of the field can be complex, and it is best to use the field strength units discussed above. Power density is measured in terms of power per unit area, for example, milliwatts per square centimeter (mW/cm²). When speaking of frequencies in the microwave range and higher, power density is usually used to express intensity since exposures that might occur would likely be in the far field zone.

Spina bifida

Spina bifida (Latin: "split spine") is a developmental congenital disorder caused by the incomplete closing of the embryonic neural tube. Some vertebrae overlying the spinal cord are not fully formed and remain unfused and open. If the opening is large enough, this allows a portion of the spinal cord to protrude through the opening in the bones. There may or may not be a fluid-filled sac surrounding the spinal cord. Other neural tube defects include anencephaly, a condition in which the portion of the neural tube that will become the cerebrum does not close, and encephalocele, which results when other parts of the brain remain unfused.

Spina bifida malformations fall into three categories: spina bifida occulta, spina bifida cystica with meningocele, and spina bifida cystica with myelomeningocele. The most common location of the malformations is the lumbar and sacral areas. Myelomeningocele is the most significant and common form, and this leads to disability in most affected individuals. The terms spina bifida and myelomeningocele are usually used interchangeably.

Spina bifida can be surgically closed after birth, but this does not restore normal function to the affected part of the spinal cord. Intrauterine surgery for spina bifida has also been performed, and the safety and efficacy of this procedure are currently being investigated. A study conducted with mothers who had prior spina bifida births indicates the incidence of spina bifida can be decreased by up to 70% when the mother takes daily folic acid supplements prior to conception.

Spina bifida meningocele and myelomeningocele are among the most common birth defects, with a worldwide incidence of about 1 in every 1000 births. The occulta form is much more common, but only rarely causes neurological symptoms.

Classification

Spina bifida occulta

Occulta is Latin for "hidden". This is the mildest form of spina bifida. In occulta, the outer part of some of the vertebrae is not completely closed. The splits in the vertebrae are so small that the spinal cord does not protrude. The skin at the site of the lesion may be normal, or it may have some hair growing from it; there may be a dimple in the skin, or a birthmark.

Many people with this type of spina bifida do not even know they have it, as the condition is asymptomatic in most cases. The incidence of spina bifida occulta is approximately 10-20% of the population, and most people are diagnosed incidentally from spinal X-rays. A systematic review of radiographic research studies found no relationship between spina bifida occulta and back pain. More recent studies not included in the review support the negative findings.

However, other studies suggest spina bifida occulta is not always harmless. One study found that among patients with back pain, severity is worse if spina bifida occulta is present.

Incomplete posterior fusion is not a true spina bifida, and is very rarely of neurological significance.

Meningocele

A posterior meningocele (pronounced /məˈnɪŋɡəˌsil/) or meningeal cyst (pronounced /mɪˈnɪndÊ'iÉ™l/ /sɪst/) is the least common form of spina bifida. In this form, the vertebrae develop normally, but the meninges are forced into the gaps between the vertebrae. As the nervous system remains undamaged, individuals with meningocele are unlikely to suffer long-term health problems, although cases of tethered cord have been reported. Causes of meningocele include teratoma and other tumors of the sacrococcyx and of the presacral space, and Currarino syndrome.

A meningocele may also form through dehiscences in the base of the skull. These may be classified by their localisation to occipital, frontoethmoidal, or nasal. Endonasal meningoceles lie at the roof of the nasal cavity and may be mistaken for a nasal polyp. They are treated surgically. Encephalomeningoceles are classified in the same way and also contain brain tissue.

Myelomeningocele

This type of spina bifida often results in the most severe complications. In individuals with myelomeningocele, the unfused portion of the spinal column allows the spinal cord to protrude through an opening. The meningeal membranes that cover the spinal cord form a sac enclosing the spinal elements. The term Meningomyelocele is also used interchangeably.

Myeloschisis

Spina bifida with myeloschisis is the most severe form of myelomeningocele. In this type, the involved area is represented by a flattened, plate-like mass of nervous tissue with no overlying membrane. The exposure of these nerves and tissues make the baby more prone to life-threatening infections such as meningitis.

The protruding portion of the spinal cord and the nerves that originate at that level of the cord are damaged or not properly developed. As a result, there is usually some degree of paralysis and loss of sensation below the level of the spinal cord defect. Thus, the more cranial the level of the defect, the more severe the associated nerve dysfunction and resultant paralysis may be. People may have ambulatory problems, loss of sensation, deformities of the hips, knees or feet, and loss of muscle tone.

Signs and symptoms

Physical complications

Physical signs of spina bifida may include:

• Leg weakness and paralysis
• Orthopedic abnormalities (i.e., club foot, hip dislocation, scoliosis)
• Bladder and bowel control problems, including incontinence, urinary tract infections, and poor renal function
• Pressure sores and skin irritations
• Abnormal eye movement

68% of children with spina bifida have an allergy to latex, ranging from mild to life-threatening. The common use of latex in medical facilities makes this a particularly serious concern. The most common approach to avoid developing an allergy is to avoid contact with latex-containing products such as examination gloves and condoms and catheters that do not specify they are latex free, and many other products, such as some commonly used by dentists.

The spinal cord lesion or the scarring due to surgery may result in a tethered spinal cord. In some individuals, this causes significant traction and stress on the spinal cord and can lead to a worsening of associated paralysis, scoliosis, back pain, and worsening bowel and/or bladder function.

Neurological complications

Many individuals with spina bifida have an associated abnormality of the cerebellum, called the Arnold Chiari II malformation. In affected individuals, the back portion of the brain is displaced from the back of the skull down into the upper neck. In about 90% of the people with myelomeningocele, hydrocephalus also occurs because the displaced cerebellum interferes with the normal flow of cerebrospinal fluid, causing an excess of the fluid to accumulate. In fact, the cerebellum also tends to be smaller in individuals with spina bifida, especially for those with higher lesion levels.

The corpus callosum is abnormally developed in 70-90% of individuals with spina bifida myelomeningocele; this impacts the communication processes between the left and right brain hemispheres. Further, white matter tracts connecting posterior brain regions with anterior regions appear less organized. White matter tracts between frontal regions have also been found to be impaired.

Cortex abnormalities may also be present. For example, frontal regions of the brain tend to be thicker than expected, while posterior and parietal regions are thinner. Thinner sections of the brain are also associated with increased cortical folding. Neurons within the cortex may also be displaced.

Executive function

Several studies have demonstrated difficulties with executive functions in youth with spina bifida, with greater deficits observed in youth with shunted hydrocephalus. Unlike typically developing children, youths with spina bifida do not tend to improve in their executive functioning as they grow older. Specific areas of difficulty in some individuals include planning, organizing, initiating, and working memory. Problem-solving, abstraction, and visual planning may also be impaired. Further, children with spina bifida may have poor cognitive flexibility. Although executive functions are often attributed to the frontal lobes of the brain, individuals with spina bifida have intact frontal lobes; therefore, other areas of the brain may be implicated.

Individuals with spina bifida, especially those with shunted hydrocephalus, often have attention problems. Children with spina bifida and shunted hydrocephalus have higher rates of ADHD than typically developing children (31% vs. 17%). Deficits have been observed for selective attention and focused attention, although poor motor speed may contribute to poor scores on tests of attention. Attention deficits may be evident at a very early age, as infants with spina bifida lag behind their peers in orienting to faces.

Academic skills

Individuals with spina bifida may struggle academically, especially in the subjects of mathematics and reading. In one study, 60% of children with spina bifida were diagnosed with a learning disability. In addition to brain abnormalities directly related to various academic skills, achievement is likely affected by impaired attentional control and executive functioning. Children with spina bifida may perform well in elementary school, but begin to struggle as academic demands increase.

Children with spina bifida are more likely than their typically developing peers to have dyscalculia. Individuals with spina bifida have demonstrated stable difficulties with arithmetic accuracy and speed, mathematical problem-solving, and general use and understanding of numbers in everyday life. Mathematics difficulties may be directly related to the thinning of the parietal lobes (regions implicated in mathematical functioning) and indirectly associated with deformities of the cerebellum and midbrain that affect other functions involved in mathematical skills. Further, higher numbers of shunt revisions are associated with poorer mathematics abilities. Working memory and inhibitory control deficiencies have been implicated for math difficulties, although visual-spatial difficulties are not likely involved. Early intervention to address mathematics difficulties and associated executive functions is crucial.

Individuals with spina bifida tend to have better reading skills than mathematics skills. Children and adults with spina bifida have stronger abilities in reading accuracy than in reading comprehension. Comprehension may be especially impaired for text that requires an abstract synthesis of information rather than a more literal understanding. Individuals with spina bifida may have difficulty with writing due to deficits in fine motor control and working memory.

Pathophysiology

Spina bifida is sometimes caused by the failure of the neural tube to close during the first month of embryonic development (often before the mother knows she is pregnant). Some forms are known to occur with primary conditions that cause raised central nervous system pressure, which raises the possibility of a dual pathogenesis

Under normal circumstances, the closure of the neural tube occurs around the 23rd (rostral closure) and 27th (caudal closure) day after fertilization. However, if something interferes and the tube fails to close properly, a neural tube defect will occur. Medications such as some anticonvulsants, diabetes, having a relative with spina bifida, obesity, and an increased body temperature from fever or external sources such as hot tubs and electric blankets may increase the chances of delivery of a baby with a spina bifida.

Extensive evidence from mouse strains with spina bifida indicates that there is sometimes a genetic basis for the condition. Human spina bifida, like other human diseases, such as cancer, hypertension and atherosclerosis (coronary artery disease), likely results from the interaction of multiple genes and environmental factors.

Research has shown the lack of folic acid (folate) is a contributing factor in the pathogenesis of neural tube defects, including spina bifida. Supplementation of the mother's diet with folate can reduce the incidence of neural tube defects by about 70%, and can also decrease the severity of these defects when they occur. It is unknown how or why folic acid has this effect.

Spina bifida does not follow direct patterns of heredity like muscular dystrophy or haemophilia. Studies show a woman having had one child with a neural tube defect such as spina bifida has about a 3% risk of having another child with a neural tube defect. This risk can be reduced to about 1% if the woman takes high doses (4 mg/day) of folic acid before and during pregnancy. For the general population, low-dose folic acid supplements are advised (0.4 mg/day).

Prevention

There is neither a single cause of spina bifida nor any known way to prevent it entirely. However, dietary supplementation with folic acid has been shown to be helpful in reducing the incidence of spina bifida. Sources of folic acid include whole grains, fortified breakfast cereals, dried beans, leaf vegetables and fruits.

Folate fortification of enriched grain products has been mandatory in the United States since 1998. The U.S. Food and Drug Administration, Public Health Agency of Canada and UK recommended amount of folic acid for women of childbearing age and women planning to become pregnant is at least 0.4 mg/day of folic acid from at least three months before conception, and continued for the first 12 weeks of pregnancy. Women who have already had a baby with spina bifida or other type of neural tube defect, or are taking anticonvulsant medication should take a higher dose of 4â€"5 mg/day.

Certain mutations in the gene VANGL1 are implicated as a risk factor for spina bifida: These mutations have been linked with spina bifida in some families with a history of spina bifida.

Pregnancy screening

Neural tube defects can usually be detected during pregnancy by testing the mother's blood (AFP screening) or a detailed fetal ultrasound. Increased levels of maternal serum alpha-fetoprotein (MSAFP) should be followed up by two tests - an ultrasound of the fetal spine and amniocentesis of the mother's amniotic fluid (to test for alpha-fetoprotein and acetylcholinesterase). AFP tests are now mandated by some state laws (including California). and failure to provide them can have legal ramifications. In one case a man born with spina bifida was awarded a $2 million settlement after court found his mother's OBGYN negligent for not performing these tests. Spina bifida may be associated with other malformations as in dysmorphic syndromes, often resulting in spontaneous miscarriage. In the majority of cases, though, spina bifida is an isolated malformation.

Genetic counseling and further genetic testing, such as amniocentesis, may be offered during the pregnancy, as some neural tube defects are associated with genetic disorders such as trisomy 18. Ultrasound screening for spina bifida is partly responsible for the decline in new cases, because many pregnancies are terminated out of fear that a newborn might have a poor future quality of life. With modern medical care, the quality of life of patients has greatly improved.

Treatment

There is no known cure for nerve damage caused by spina bifida. To prevent further damage of the nervous tissue and to prevent infection, pediatric neurosurgeons operate to close the opening on the back. The spinal cord and its nerve roots are put back inside the spine and covered with meninges. In addition, a shunt may be surgically installed to provide a continuous drain for the excess cerebrospinal fluid produced in the brain, as happens with hydrocephalus. Shunts most commonly drain into the abdomen or chest wall. However, if spina bifida is detected during pregnancy, then open or minimally-invasive fetal surgery can be performed.

In childhood

Most individuals with myelomeningocele will need periodic evaluations by a variety of specialists:

• Physiatrists coordinate the rehabilitation efforts of different therapists and prescribe specific therapies, adaptive equipment, or medications to encourage as high of a functional performance within the community as possible.
• Orthopedists monitor growth and development of bones, muscles, and joints.
• Neurosurgeons perform surgeries at birth and manage complications associated with tethered cord and hydrocephalus.
• Neurologists treat and evaluate nervous system issues, such as seizure disorders.
• Urologists to address kidney, bladder, and bowel dysfunction - many will need to manage their urinary systems with a program of catheterization. Bowel management programs aimed at improving elimination are also designed.
• Ophthalmologists evaluate and treat complications of the eyes.
• Orthotists design and customize various types of assistive technology, including braces, crutches, walkers, and wheelchairs to aid in mobility. As a general rule, the higher the level of the spina bifida defect, the more severe the paralysis, but paralysis does not always occur. Thus, those with low levels may need only short leg braces, whereas those with higher levels do best with a wheelchair, and some may be able to walk unaided.
• Physical therapists, occupational therapists, psychologists, and speech/language pathologists aid in rehabilitative therapies and increase independent living skills.

Transition to adulthood

Although many children's hospitals feature integrated multidisciplinary teams to coordinate healthcare of youth with spina bifida, the transition to adult healthcare can be difficult because the above healthcare professionals operate independently of each other, requiring separate appointments and communicate among each other much less frequently. Healthcare professionals working with adults may also be less knowledgeable about spina bifida because it is considered a childhood chronic health condition. Due to the potential difficulties of the transition, adolescents with spina bifida and their families are encouraged to begin to prepare for the transition around ages 14â€"16, although this may vary depending on the adolescent's cognitive and physical abilities and available family support. The transition itself should be gradual and flexible. The adolescent's multidisciplinary treatment team may aid in the process by preparing comprehensive, up-to-date documents detailing the adolescent's medical care, including information about medications, surgery, therapies, and recommendations. A transition plan and aid in identifying adult healthcare professionals are also helpful to include in the transition process.

Further complicating the transition process is the tendency for youths with spina bifida to be delayed in the development of autonomy, with boys particularly at risk for slower development of independence. An increased dependence on others (in particular family members) may interfere with the adolescent's self-management of health-related tasks, such as catheterization, bowel management, and taking medications. As part of the transition process, it is beneficial to begin discussions at an early age about educational and vocational goals, independent living, and community involvement.

Epidemiology

Spina bifida is one of the most common birth defects, with an average worldwide incidence of one to two cases per 1000 births, but certain populations have a significantly greater risk.

In the United States, the average incidence is 0.7 per 1000 live births. The incidence is higher on the East Coast than on the West Coast, and higher in white people (one case per 1000 live births) than in black people (0.1â€"0.4 case per 1000 live births). Immigrants from Ireland have a higher incidence of spina bifida than do natives. Highest rates of the defect in the USA can be found in Hispanic youth.

The highest incidence rates worldwide were found in Ireland and Wales, where three to four cases of myelomeningocele per 1000 population have been reported during the 1970s, along with more than six cases of anencephaly (both live births and stillbirths) per 1000 population. The reported overall incidence of myelomeningocele in the British Isles was 2.0â€"3.5 cases per 1000 births. Since then, the rate has fallen dramatically with 0.15 per 1000 live births reported in 1998, though this decline is partially accounted for because some fetuses are aborted when tests show signs of spina bifida (see Pregnancy screening above).

Parents of children with spina bifida have an increased risk of having a second child with a neural tube defect.

Fetal surgery research

• 1980 - Fetal surgical techniques using animal models were first developed at the University of California, San Francisco by Michael R. Harrison, N. Scott Adzick and research colleagues.

• 1994 - A surgical model that simulates the human disease is the fetal lamb model of myelomeningocele (MMC) introduced by Meuli and Adzick in 1994. The MMC-like defect was surgically created at 75 days of gestation (term 145 to 150 days) by a lumbo-sacral laminectomy. Approximately 3 weeks after creation of the defect a reversed latissimus dorsi flap was used to cover the exposed neural placode and the animals were delivered by cesarean section just prior term. Human MMC-like lesions with similar neurological deficit were found in the control newborn lambs. In contrast, animals that underwent closure had near-normal neurological function and well-preserved cytoarchitecture of the covered spinal cord on histopathological examination. Despite mild paraparesis, they were able to stand, walk, perform demanding motor test and demonstrated no signs of incontinence. Furthermore, sensory function of the hind limbs was present clinically and confirmed electrophysiologically. Further studies showed that this model, when combined with a lumbar spinal cord myelotomy leads to the hindbrain herniation characteristic of the Chiari II malformation and that in utero surgery restores normal hindbrain anatomy by stopping the leak of cerebrospinal fluid through the myelomeningocele lesion.

Surgeons at Vanderbilt University, led by Joseph Bruner, attempted to close spina bifida in 4 human fetuses using a skin graft from the mother using a laparoscope. Four cases were performed before stopping the procedure - two of the four fetuses died.

• 1998 - N. Scott Adzick and team at The Children's Hospital of Philadelphia performed open fetal surgery for spina bifida in an early gestation fetus (22 week gestation fetus) with a successful outcome. Open fetal surgery for myelomeningocele involves surgically opening the pregnant mother's abdomen and uterus to operate on the fetus. The exposed fetal spinal cord is covered in layers with surrounding fetal tissue at mid-gestation (19â€"25 weeks) to protect it from further damage caused by prolonged exposure to amniotic fluid. Between 1998 and 2003, Dr. Adzick, and his colleagues in the Center for Fetal Diagnosis and Treatment a The Children's Hospital Of Philadelphia, performed prenatal spina bifida repair in 58 mothers and observed significant benefit in the babies.

Surgeons at Vanderbilt University, led by Noel Tulipan, performed open fetal surgery at 28 to 30 weeks' gestation. All 4 fetuses were born premature but with evidence of reversal of their Chiari II malformation. Only 2 of the 4 required ventricular shunts after birth. Fetal surgery after 25 weeks has not shown benefit in subsequent studies.

Subsequently, 4 medical centers conducted 253 open spina bifida repairs prior to the Management of Myelomeningocele Study (MOMS) trial. The outcomes were mixed, and the only comparison groups were other children who had not undergone repair after birth in the past. To conclusively answer this question, the MOMS trial was launched in 2003 to determine the safety and efficacy of fetal surgery to close a myelomeningocele.

MOMS trial

Management of Myelomeningocele Study (MOMS) is a phase III clinical trial designed to compare two approaches to the treatment of spina bifida: surgery before birth (prenatal or fetal surgery) and surgery after birth (postnatal surgery).

Three fetal surgery centers participated in the trialâ€"at The Children’s Hospital of Philadelphia, Vanderbilt University, and the University of California San Francisco. The biostatistics center at George Washington University (GWU) served as the coordinating center and oversaw data collection and analysis, while the Eunice Kennedy Shriver National Institute of Child Health and Human Development sponsored the trial.

The MOMS study was a prospective, randomized clinical trial. One sign of its prominence is that all U.S. fetal surgery centers not participating in the trial agreed to perform no fetal surgery for spina bifida during the 7-year duration of the trial.

Throughout the trial, women whose fetuses had been diagnosed with spina bifida contacted the trial’s coordinating center at GWU if they chose to volunteer for the study. That center randomly assigned half of the eligible women to receive prenatal surgery, the other half to receive postnatal surgery.

Postnatal surgery entailed delivery by planned cesarean section at 37 weeks gestation, after which the surgical team repaired the opening in the newborn’s spine, usually within 24 hours after birth. In prenatal surgery, done between 19 and 26 weeks’ gestation, the surgical team made incisions in the mother and her uterus, then repaired the spina bifida lesion while the fetus was in the womb. Mothers in this group stayed near the center for ongoing monitoring, then underwent delivery by planned cesarean section at 37 weeks, or earlier, because many of the babies in the prenatal surgery group arrived prematurely. In both study groups, surgeons used the same technique to cover the myelomeningocele with multiple layers of the fetus’s own tissue.

Clinicians who were independent of the surgical teams and blinded (not informed which of the two surgeries a given child received) evaluated the children from the study at one year of age and again at age 30 months.

The MOMS trial was closed for efficacy in December 2010 based on comparing outcomes after prenatal and postnatal repair in 183 patients - 77 patients were treated at The Children’s Hospital of Philadelphia, 54 at Vanderbilt University and 52 at The University of California San Francisco.

Unfortunately the study failed to address the possibility that some of the benefit of surgery to central nervous system function in the intervention group may have been caused by early delivery from the intrauterine environment. This issue casts some doubt on the studies findings. A case controlled comparison of intervention vs conservative management would have been unethical because of the exposure of infants within a control group to the adversity of premature delivery.

The trial concluded that the outcomes after prenatal spina bifida treatment are improved to the degree that the benefits of the surgery outweigh the maternal risks. This conclusion requires a value judgment on the relative value of fetal and maternal outcomes on which opinion is still divided. Results were reported in the New England Journal of Medicine by Adzick et al.

To be specific, the study found that prenatal repair resulted in:

• Reversal of the hindbrain herniation component of the Chiari II malformation
• Reduced need for ventricular shunting (a procedure in which a thin tube is introduced into the brain’s ventricles to drain fluid and relieve hydrocephalus)
• Reduced incidence or severity of potentially devastating neurologic effects caused by the spine’s exposure to amniotic fluid, such as impaired motor function

At one year of age, 40 percent of the children in the prenatal surgery group had received a shunt, compared to 83 percent of the children in the postnatal group. During pregnancy, all the fetuses in the trial had hindbrain herniation. However, at age 12 months, one-third (36 percent) of the infants in the prenatal surgery group no longer had any evidence of hindbrain herniation, compared to only 4 percent in the postnatal surgery group.

At age 30 months, children in the prenatal group had significantly better scores in measurements of motor function. While the ability to walk depends on the level of the spina bifida lesion, the study found a twofold increase in the proportion of children able to walk without crutches or other assistive devicesâ€"42 percent in the prenatal group compared to 21 percent in the postnatal group. With the completion of the MOMS trial, open fetal surgery for myelomeningocele is now one standard of care option, at a handful of highly experienced centers, for appropriate patients.

In Europe, open fetal surgery for spina bifida was introduced in 2003 by the Polish pediatric surgeon Janusz Bohosiewicz in Katowice. Through the end of 2011, more than 40 fetuses with spina bifida were operated at this center.

After the publication of the initial results of the MOMS trial, the NICHD agreed to fund phase two of the Management of Myelomeningocele Study (MOMS 2). MOMS2 is currently underway - the 183 patient families from the initial trial continue to be monitored by participating clinical sites. The continuation of the study will provide valuable insight into the lasting outcomes of prenatal repair of spina bifida versus standard postnatal repair in children 6 to 9 years of age. This opportunity to compare long-term results will help clinicians to learn more about all children with spina bifida and allow both clinical teams and patients to make informed choices about the treatment options available in the future.

Endoscopic fetal surgery

In contrast to the open fetal operative approach performed in the MOMS trial, a minimally-invasive fetoscopic approach has been developed by the German pediatrician Thomas Kohl of the German Center for Fetal Surgery & Minimally-Invasive Therapy at the University of Giessen, Germany. This approach has been heavily criticized by the independent authors of a controlled study about this cohort and deemed unethical by others.

This approach under general materno-fetal anesthesia uses three trocars (small tubes) with an external diameter of 5 mm that are directly placed through the maternal abdominal wall into the uterine cavity under ultrasound guidance. Following intrauterine access, part of the amniotic fluid is removed and the uterus is insufflated with carbon dioxide (this technique provides superior visualization of fetoscopic spina bifida closure, is called PACI (partial amniotic fluid insufflation), and has been safe for mothers and fetuses alike in over 70 procedures on human fetuses). After fetal posturing, the neural cord is freed from pathological adhesions and covered with patch material. Watertight closure is demonstrated by intraoperative bulging of the patch. Accordingly, reversal of hindbrain herniation can be documented within days after most procedures.

The observations in mothers and their fetuses that were operated over the past two and a half years by the matured minimally invasive approach showed the following results: Compared to the open fetal surgery technique, fetoscopic repair of myelomeningocele results in far less surgical trauma to the mother, as large incisions of her abdomen and uterus are not required. In contrast, the initial punctures have a diameter of 1.2 mm only. As a result, thinning of the uterine wall or dehisscence which have been among the most worriesome and criticized complications after the open operative approach do not occur following minimally invasive fetoscopic closure of spina bifida aperta. The risks of maternal chorioamniotis or fetal death as a result of the fetoscopic procedure run below 5%. Operated women are discharged home from hospital one week after the procedure. There is no need for chronic administration of tocolytic agents since postoperative uterine contractions are barely ever observed. The current cost of the entire fetoscopic procedure, including hospital stay, drugs, perioperative clinical, ECG, ultrasound and MRI-examinations, is approximately €16,000.

In a cohort of 20 infants that underwent fetoscopic surgery on the lesion between July 2010 and December 2011 and were studied during the first six months of life, reversal of hindbrain herniation was observed in 18 (90%) and shunt insertion was required in only eight (40%). Normal to near normal leg function was observed in about two thirds of the infants. An abnormal foot position at birth was observed in only two. The fetuses that were operated at a mean of 24 weeks of gestation were born at a mean gestational age at delivery of about 33 weeks of gestation.

In 2012, these results of the fetoscopic approach were presented at various national and international meetings, among them at the 1st European Symposium “Fetal Surgery for Spina bifida“ in April 2012 in Giessen, at the 15th Congress of the German Society for Prenatal Medicine and Obstetrics in May 2012 in Bonn, at the World Congress of the Fetal Medicine Foundation in June 2012 and at the World Congress of the [[International Society of Obstetrics and Gynecology]] (ISUOG) in Copenhagen in September 2012, and published in abstract form. In contrast to the low maternal and fetal complication rates that can be achieved by the current fetoscopic approach, its clinical introduction was affected by technical difficulties and a number of adverse fetal outcomes: Three of the first 19 procedures could not be completed, three fetuses died, and the mean gestational age at delivery was 29 weeks of gestation. As a result, the approach was heavily criticized by the independent authors of a controlled study about this cohort and deemed unethical by others. Specifically, published in the January 2012 issue of Developmental Medicine & Child Neurology, David Shurtleff, Ph.D., stated that “the extremely high complication rates for mother and infant in this study and the principle of primum non nocere indicate that at this time it is unethical to pursue intrauterine endoscopic myelomeningocele repair in humans until the procedure has been perfected in animals. “ Additionally, VERBEEK, R. J.,et al., published in the same issue of Developmental Medicine & Child Neurology that “fetal endoscopic surgery is associated with spinal segmental neuroprotection, but it results in more complications. Before considering clinical implementation of fetal endoscopic myelomeningocele closure as standard care, the frequency of complications should be appropriately reduced and results assessed in larger groups over a longer period of time.”

In contrast, with the completion of the MOMS trial, open fetal surgery for myelomeningocele is now one standard of care option, at highly experienced centers, for appropriate patients.

Notable people

Notable people with spina bifida include:

• Tanni Grey-Thompson - Welsh Paralympic athlete, member of British House of Lords
• Blaine Harrison - lead singer, keyboards, rhythm guitarist and former drummer of the British band Mystery Jets
• Rene Kirby - US actor in films such as Shallow Hal and Stuck on You
• John Mellencamp - US rock and roll musician
• Karin Muraszko - chair of Department of Neurosurgery at University of Michigan, first woman appointed to such a position in the US
• Jeffrey Tate - British conductor
• Hank Williams - US country music singer-songwriter
• Lucinda Williams - US country music singer-songwriter
• Miller Williams - US poet
• Chandre Oram - Man who has a tail due to spina bifida.
• George Schapell - US country music singer. Conjoined twin with Lori Schapell, Together they are the oldest confirmed conjoined twins.
• Justin Yoder, soapbox driver and protagonist of the Disney Channel movie Miracle in Lane 2
• Billy Bridges, Canadian Paralympic ice sledge hockey and wheelchair basketball player
• Aaron Fotheringham, an extreme wheelchair athlete.

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