New DNA Map May Help Cure Congenital Heart Defects

Reasearchers from Gladstone Institute in California have created a blueprint map of how the heart developes in time. The purpose of this study was to create a genomic and epigenomic blueprint in order to reveal the exact sequence and timing of all the changes a heart goes through, from the embryonic stem cell stage to the grown adult heart.

Thanks to the recent data found by the researchers from Gladstone, new treatments can now be developed for people suffering from congenital heart defects, the most common type of birth defects. Heart defects like ventricular septal defects or arrhythmias occur at a genetic level. However, by what means these defects have developed are still yet to be found.

The study only focuses on a particular set of genes, that give the heart cells their unique identity, explained senior investigator and team leader Benoit Bruneau. In order to create a new heart, the scientists put embryonic stem cells from mice in a culture similar to an embryonic development enviroment. Afterwards the embryonic stem cells were reprogrammed to grow and form beating heart cells.

The next step was to study the epigenomic signatures. Using a gene-sequencing tool, called CHIP-seq, they managed to create a detailed map which shows how the genes switch on and off during different stages of the growth process. After finding these epigenomic signatures, researchers had to decipher the genetic information encoded in the genes. They used all the data collected  by the Gladstone Bioinformatics Core and organized it into a concise blueprint, explained dr Jeffrey Alexander, co-lead author.

congenital Heart Defect

The scientists found important, new groups of genes which are believed to be involved in the development of the heart. They also discovered a link between the newly discovered groups of genes and the previously known genes.  Moreover significant information about the working mechanism of the genes from heart stem cells was discovered. The genes seem to turn on and off together at the exact stages of the embryonic heart development.

Thanks to the detailed map of how the genes work, scientists are convinced they can figure out how a disease can interfere with the normal growth process of the heart cells. Awearness of the complexityof genetic and epigenetic patters will help researchers prevent, intervene or oppose the appearance of a disease.

Doctor Bruneau, also professor of pediatrics at UCSF said that their main focus will be on finding a treatment plan for children born with congenital heart defects. He also pointed out that their next step towards finishing the study will be to “pinpoint the specific genetic disruption that caused their heart defect”.

After identifying the genetic disruption, Bruneau and his team can start restoring normal gene function during the early stages of heart development. As a result, the number of babies born with congenital heart defects will be significantly reduced , Doctor Bruneau added.

Primary Biliary Cirrhosis – Causes, Symptoms, Diagnosis And Treatment

Primary biliary cirrhosis is a chronic and progressive cholestatic disease of the liver of unknown etiology, although is presumed to have an autoimmune etiology. Primary biliary cirrhosis evolves with chronic cholestasis, progressive destruction of intrahepatic bile ducts, portal inflammation and final evolution to cirrhosis and liver failure. Inflammation particularly affects small and medium bile ducts, reason for which the disease was also called destructive non-suppurative cholangitis.

Clinical picture of primary biliary cirrhosis was first described in 1851 by Addison and Gull, noting the presence of progressive obstructive jaundice in the absence of mechanical obstruction of the large bile ducts. In 1950, Ahrens and colleagues named this condition  primary biliary cirrhosis and in 1969, Doniach and Walker first reported the association between primary biliary cirrhosis and mitochondrial antibodies.

Primary Biliary Cirrhosis

Primary biliary cirrhosis is more prevalent in the white population, accounting for 2% of deaths due to cirrhosis. The disease is more frequent in women than in men, thee incidence of the disease has been estimated as 4.5 cases for women and 0.7 cases for men per 100,000 population. Primary biliary cirrhosis symptoms may affect patient’s quality of life and may induce incapacitation. Various therapeutic approaches have been implemented with variable results, but liver transplantation is the only treatment option for the terminal stages of the disease. It was observed that after this procedure, primary biliary cirrhosis has a relatively high recurrence rate despite immunosuppressive therapy.

Primary Biliary Cirrhosis Causes

The exact cause of primary biliary cirrhosis is not known exactly, but is assumed that liver damage is the result of two phenomena: immunological abnormalities interest both cellular and humoral  immunity. It was observed that in patients with primary biliary cirrhosis is an impaired regulation of both B and T lymphocytes, serum titers of immunoglobulin M (IgM) is greatly increased and mitochondrial antibodies are present in about 95% -100% of cases. Primary biliary cirrhosis is associated with several autoimmune diseases such as lupus erythematosus, scleroderma, dermatomyositis, autoimmune thyroiditis, rheumatoid arthritis, ankylosing spondylitis.

The second phenomenon is represented by continuous destruction of small and medium bile ducts mediated by activated CD4 and CD8 lymphocytes. As a result, chronic cholestasis is the prominent clinical and laboratory finding and once destroyed, the regeneration of bile ducts is either not possible or inefficient. The result of intrahepatic bile ducts destruction, is the disruption of the normal bile flow which leads to retention and deposition of toxic substances, that are normally excreted into bile. The retention of toxic substances, such as bile acids and copper, can cause a further secondary destruction of the bile ducts and of the hepatocytes.

Primary Biliary Cirrhosis

Primary Biliary Cirrhosis Symptoms

Half of patients diagnosed with primary biliary cirrhosis are asymptomatic, but all patients present signs of cholestasis: increased alkaline phosphatase and gammaglutamyl transpeptidase.

In symptomatic forms of the disease, the onset is insidious. Fatigue is the main symptom and can cause disability in some patients. It was observed that fatigue may be associated with depression and obsessive-compulsive behavior. Fatigue etiology is unknown, but however, sleep abnormalities, particularly excessive daytime somnolence was identified in an increased proportion of patients and may be associated with the degree of fatigue. Pruritus is present in 55% of patients with primary biliary cirrhosis and 10% of patients experience severe pruritus. The cause of this symptom is unknown, but it seems that pruritus appears unrelated to the deposition of bile acids in the skin. Right upper quadrant discomfort occurs in 8-17% of patients.

In patient with primary biliary cirrhosis, physical examination findings depend on the stage of the disease. In the first stages of the disease, physical examination findings are normal. As the disease evolves, excoriations of the skin, xanthelasmata, cirrhosis signs, such as hepatomegaly, skin hyperpigmentation, splenomegaly, jaundice, spider nevi, palmar erythema, ascites, temporal and proximal muscle wasting, and peripheral edema  may be present. Sicca syndrome, consisting of xerophthalmia (dry eyes) and xerostomia (dry mouth) may be present in 50%-75% of patients with primary biliary cirrhosis.

Biliary system

Primary Biliary Cirrhosis Diagnosis

In most patients with primary biliary cirrhosis elevated levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) may be identified, but elevated levels of the alkaline phosphatase (ALP), gammaglutamyl transpeptidase (GGTP), and immunoglobulin levels (mainly IgM) are usually the most prominent findings. Serum lipids levels and cholesterol levels (especially HDL fraction) are also elevated, explaining the low risk of these patients for atherosclerosis. Increased erythrocyte sedimentation rate may be present and as the disease progresses to cirrhosis, elevated bilirubin level, prolonged prothrombin time, and decreased albumin level may be present. Increased bilirubin level represent an indicator factor for liver transplantation.

Immunological abnormalities are highlighted by the presence of antimitochondrial antibodies (AMA) which are found in 90%-95% of patients with primary biliary cirrhosis and poses a specificity of 98% for this condition. Antinuclear antibodies (ANA) were reported in 20%-50% of cases.

Imaging studies such as abdominal ultrasonography, computed tomography (CT) and magnetic resonance imaging (MRI) do not show specific modifications for primary biliary cirrhosis, but are useful in excluding biliary obstruction. FibroScan (impulsional elastography) is useful in detecting the degree of liver fibrosis.

Liver biopsy is the gold-standard diagnosis method for primary biliary cirrhosis because can confirm the diagnosis and provides information about disease stage and prognosis.

Primary Biliary Cirrhosis

Primary Biliary Cirrhosis Treatment

Treatment of primary biliary cirrhosis has the following objectives: to alleviate symptoms, to slow the immune process and disease progression.

Ursodeoxycholic acid (UDCA) is very effective, especially in the early stages of primitive biliary cirrhosis. This drug is administered lifelong and studies suggest that UDCA delays the need for transplantation or delays death.

Immunosuppressive agents such as methotrexate, corticosteroids and cyclosporine inhibit immune reactions that mediate disease progression.

Pruritus is the most disturbing symptom and is often refractory to treatment. In the early stages of primary biliary cirrhosis, pruritus is alleviate with antihistamines, but this class of drugs has short-term effects. Cholestyramine is also effective in the treatment of pruritus and posses the capacity to sequester bile salts in the enteric lumen. In primary biliary cirrhosis with pruritus refractory to treatment phenobarbital may be administered and ultraviolet therapy or plasmapheresis may be tempted.

As the disease progress to cirrhosis, liver transplantation should be considered because seems to represented the only life-saving procedure.

Primary biliary cirrhosis has a slow and progressive evolution to cirrhosis. Average survival in asymptomatic forms disease is over 10 years and in symptomatic forms is approximately 7 years. Along with cirrhosis development, primary biliary cirrhosis prognosis becomes reserved.

Soy Consumption Associated With Congenital Hypothyroidism

According to a case report published in Pediatrics, soy products are linked to congenital hypothyroidism, an endocrinologic disorder. Congenital hypothyroidism is a rare disease that affects 1 in 4000 infants. There are multiple causes that can lead hypothyroidism, the most common being iodine deficiency, but sometimes defects in the formation of thyroid hormones can have the same consequence. Another cause is lack of thyroid (thyroid aplasia or hypoplasia). Without hormone replacement therapy, hypothyroidism cause delays in development, not only physical but also mental development (mental retardation or cretinism). There are several signs and symptoms of congenital hypothyroidism such as  exaggerated jaundice, excessive sleeping, constipation, low body temperature. Other signs of hypothyroidism are macroglossia (enlarged tongue), enlarged anterior fontanelle and others.

Soy

The observation was made in two female patients by doctors at University of California San Diego in La Jolla. They found that thyroid function in patients, diagnosed with congenital hypothyroidism and treated with hormone replacement, did not improve. It was noticed that the two patients were also receiving a soy formula.  Instead, after stopping soy formula, thyroid function improved.
Hypothyroidism is an endocrine disorder in which the thyroid does not produce enough thyroid hormone. This disorder can be congenital or acquired.

There are many causes that determine such impairment because there are several glands and nervous structures that control thyroid hormone levels. Hypothyroidism can be induced by thyroid gland, pituitary gland or hypothalamus. When the thyroid is involved, it is called primary hypothyroidism, if  pituitary gland (which produces TSH, tyroid stimulating hormone)is implied,  there the hypothyroidism is secondary, and if it is involved the hypothalamus (that produces tyrotropin releasing hormone) the disorder is called tertiary hypothyroidism. But most often hypothyroidism is related to iodine deficiency.

Hypothyroidism is characterized by increased TSH levels while levels of free T4 (thyroxine) are low. Signs and symptoms of hypothyroidism include bradycardia (low heart rate), intolerance to cold, fatigue, weight gain, dry skin due to water retention and edema (myxedema), depression, gastrointestinal disorders (constipation), infertility.

Hypothyroidism can be kept under control if diagnosed early and treated appropriately. As far as congenital hypothyroidism is concerned, there is a newborn screening  showing what children suffer from hypothyroidism and who do not. Hormone replacement therapy (levothyroxine) begins in the first weeks of life. Doses of hormones increases as the child grows. It is important to note that hormone replacement therapy lead to normal development of the child, even in those with athyreosis (lack of development of the thyroid gland).

Tension Headache

Tension headache is a syndrome of uncertain pathogenesis and is one of the most common forms of headache. Although, much more common than migraine, the exact cause of this disease is not fully known and the symptoms are not as well shaped as in the case of migraine.

Tension headache is characterized by recurrent episodes of headache of moderate intensity, self-limited, and usually responsive to nonprescription drugs, episodes that are lasting from few minutes to several weeks. Usually vomiting is not typical for tension headache, but photophobia and phonophobia may be present. To be considered tension headache, cephalalgia should exclude the following causes: head trauma, cerebrovascular disorders, non-vascular brain disorders, non-encephalitis inflammatory process, the use of certain drugs, metabolic disorders, eye, neck, ears, nose, sinuses, teeth and mouth injuries or other facial or cranial injuries.

Tension Headache Causes

The International Headache Society (IHS) proposed in 1988 a classification of tension headache based on cephalalgia episodes in episodic and chronic form. In episodic tension headache, painful accesses occur for up to 15 days per month and a higher frequency of this episodes represents a diagnostic criterion for chronic tension headache. Clinical manifestations are similar to both forms of headache, but the treatment differs. Another criterion for classification of tension headache is the presence or the absence of pericranial muscle disorders, both in episodic and in chronic form. Pericranial muscle disorders are considered to be present when these muscles are under tension and are establish either by palpation or by electromyographic (EMG) testes. It is worth noting, that pericranial muscle tension occurs in most patients with tension headache, but can also occur in other situations such as fibromyalgia, migraine or low back pain.

Tension Headache

A subdivision of tension headache can be done according to the possible etiologic factors, thus the disease may be associated with one of the following conditions: oromandibular dysfunction, psychosocial stress, anxiety, depression, psychogenic headache, drug overdose and muscle contraction.

Oromandibular dysfunction is often concomitant with tension headache, but is not exactly  know if this condition may represent one of the causes of tension headache, because both diseases have a higher prevalence. Psychosocial stress may be incriminated as etiologic factor, but it was observed that represents a precipitating factor both for tension headache and migraine.

Although, in some cases of tension headache was observed a depressed mood, it was not a real depressive illness. Epidemiological studies have shown that depression and anxiety are frequently associated with migraine and less with tension headache.

Muscle contraction, especially of pericranial  muscles seems to be an important cause of tension headache, especially in episodic forms. Menstruation appears to be a precipitating factor for tension headache.

Tension headache represents between 30% and 80% of all headaches cases. The disease may debuts in childhood, at the age of 10 years or later and females are more affected than males. It was observed that the prevalence of disease has a tendency to decrease with aging.

Tension Headache Symptoms

The main symptom of disease is headache and in 99% of patients  has moderate intensity, but pain intensity may increase along with frequency in episodic form. In most cases, the headache does not interfere with normal daily activities. Pain is usually bilateral, occipitonuchal or bifrontal and approximately in 89% of cases the pain is localized fronto-temporal than fronto-occipital and is described as a dull ache, tightness/squeezing, pressure or “bandlike/viselike”(nonpulsatile quality). Although most patients have no symptoms associated, photophobia and phonophobia may be described, nausea and in very rare cases vomiting. As associated phenomena have been described anxiety, abdominal distension, left chest pain, lumbar or coccygeal pain  and indigestion All these associated phenomena are considered to be psychosomatic symptoms. No focal neurological signs are present.

Tension Headache

Headache is often precipitated by sleep deprivation. In general population, tension headache is common in people who have sleep disturbances, compared with migraine subjects. It was noted that sleep apnea is associated with a type of headache that mimic tension headache.

Headache onset usually occurs during the day and gradually increase in intensity in the second part of the day. In some cases, especially in forms of episodic tension headache, pain occurs in relation to a state of stress. In the chronic forms of tension headache, pain may begin early in the morning or shortly after this time and may persist throughout the day and is not influenced by the patient’s daily activities. Pain intensity varies depending on the type of individual behavior, being more severe in depressed patients. The duration of a painful access is variable, with a minimum of 30 minutes, up to 72 hours, but with a average of 12 hours.

Tension Headache Treatment

Medical Treatment

Medical treatment of tension headache can be divided into short-term, long-term and prophylactic therapy.

NSAIDs (nonsteroidal anti-inflammatory drugs) are drugs of first choice especially in short-term treatment regimens. The most effective NSAIDs are represented by ibuprofen and naproxen. Ketoprofen and indomethacin are also effective, but have been much less studied. In some cases, the combination of NSAIDs with caffeine, sedatives or tranquilizers was more effective than the combination of NSAIDs with analgesics such as acetaminophen. It is generally recommended to avoid long-term use of analgesics because they produce addiction and chronic headache. Muscle relaxant drugs, such as baclofen, diazepam and myolastam can be useful.

Tricyclic antidepressants are recommended as preventive therapy, amitriptyline is considered to be more effective than doxepin, mianserin and maprotiline. New generation antidepressants such as citalopram, which selectively blocks the serotonin reuptake are indicated especially in obese patients.

Tension Headache

Non-pharmacological treatment

Refers to relaxation and biofeedback therapy or cognitive behavioral interventions such as stress control programs that have proven to be effective if were associated. The results of these therapies are less effective in patients who excessively use analgesics or ergotamine, in patients with continuing headache and in depressive patients or with other psychiatric disorders. This type of therapy produces slower improvement than drug therapy, improvements that are lasting longer.

Other methods of therapy are represented by physical therapy, ergonomics training and transcutaneous nerve electrical stimulation. In some patients the oromandibular treatment may be useful.

Skin Cancer

Skin cancer, melanoma treatment could benefit from the results of a research conducted at Western University, Canada. The discovery made by Silvia Penuel and Dale Laird, was published in the Journal of Biological Chemistry. Specifically, scientists found that skin cancer overexpressed a protein channel, Pannexin 1 (Panx1). Furthermore it seems that by reducing the number of these proteins, cells could return to normal. Laird, a Professor in the Department of Anatomy and Cell Biology, and Canada Research Chair in Gap Junctions and Disease, believes that Panx 1 is involved in melanoma aggressiveness and metastatic capacity.

Researchers now consider conducting studies in collaboration with Dr. Muriel Brackstone and Other clinicians at the London Health Sciences Centre, in order to verify the therapeutic potential of this discovery. To test whether Panx1 is a marker of melanoma, researchers need to relate their research with biopsies taken from patients with melanoma.

Skin Cancer

Melanoma is a type of skin cancer associated with a poor prognosis. Melanoma is derived from melanocytes, skin cells that contain melanocytes. Although this cancer occurs most commonly in the skin, it can also occur anywhere in the body where melanocytes are found. An important factor in developing melanoma is sun exposure.  Although it is less often than other skin cancers, almost 80% of skin cancer related deaths are due to melanoma. Once the diagnosis of melanoma by histopathological examination, it must be removed surgically. Of course, treatment is determined depending on the particular cancer (cancer type, stage, metastasis) and the patient’s condition. Surgical excision should be performed in oncological safety limits, and may be followed by chemotherapy or other adjuvant therapy, immunotherapy, etc.. Another treatment  option, radiation therapy, may be an alternative in some cases,  such as after surgical resection or in patients with metastases (as palliative method).

Similar studies for finding new melanoma treatment options have been also performed in the past, when researchers tried to target different cancer characteristics. One of the therapeutic targets is B-Raf gene mutation. Inhibitors, such as vemurafenib, can cause tumor reduction in patients who have this mutation. Another alternative in terms of melanoma treatment is and gene therapy. Gene therapy involves the transfer of genes that encode T cell receptors (T cell receptor). Once genes have been transferred to T lymphocytes in patients with melanoma, these lymphocytes attack and destroy tumor cells.

New Function of Astrocytes

A recent study has discovered a new role for astrocytes. Astrocytes are the most abundant cell found in the human brain. Formerly, it was considered that astrocytes are the help cells of the neurons. Some of their functions are biochemical support of endothelial cells, maintaining the extracellular ion balance and providing nutrients for the nervous tissue. A research team led by Dr Katsuhiko Mikoshiba from the RIKEN (Rikagaku Kenkyujo – The Institute of Physical and Chemical Research) Brain Science Institute in Wako, Japan, has discovered that astrocytes have another role, that of transmitting chemical signals to neurons, vascular cells and other astrocytes.

Astrocytes are cells shaped like stars, having a central ‘soma’ and many extensions that connect the astrocyte to the neighboring cells that it regulates. Healthy astrocytes use their extensions (know as processes) to send individual Ca2+ signals. This process was previously discovered to be regulated by a receptor found in the cellular membrane – mGluR5 (metabotropic glutamate receptor 5). However, researchers weren’t certain about the way each signal was confined to an individual extension. Understanding this process could be important for the future therapy of Alzheimer’s disease or epilepsy. Astrocytes from patients suffering from these conditions send out global signals, instead of sending out individual signals.

Astrocytes

In order to understand the regulation of astrocyte signaling, researchers used quantum dots (semiconductors that emit light when excited) to mark the mGluR5 receptors. Researchers observed that the marked receptors didn’t pass from the extension to the soma. Normal astrocytes contain a mGluR5-selective barrier that allowed the extensions to regulate their signals through Ca2+ dissociation.

Dr. Mikoshiba’s team used an over-expression of the mGluR5 receptor in order to overwhelm the barrier and note its characteristics. They concluded that the barrier is made of proteins that interact with the mGluR5 receptor. Each protein contained by the barrier only interacts with a single molecule of mGluR5 receptor, thus preventing it from crossing to the soma. Because the number of barrier proteins is limited, an abundance of mGluR5 causes an overflow, thus some receptors cross the barrier into the soma. This leads to the global propagation of signals sent by the astrocyte.

A series of experimental models of Alzheimer’s and epilepsy have shown an increased concentration of mGluR5 in astrocytes. The team of scientists suggest that comprehending the molecular characteristics of the barrier can offer new treatment methods for the aforementioned conditions. “We are very curious to know the effect of global astrocytic Ca2+ signaling on the neuronal network and neuro-vascular coupling”, says Dr Mikoshiba.

 Longevity Boosting Protein and Diabetes

A new study led by a research team from the Massachusetts Institute of Technology (MIT) reveals that a protein that is responsible for slowing down the aging process in laboratory mice might also have an effect against diabetes.

More than 10 years ago, biology professor Leonard Guarente, from MIT, discovered the anti-aging properties of the SIRT1 (Silent Information Regulator) gene, which is found in sirtuin proteins. In his most recent study, published in the journal Cell Metabolism, on the 8th of August, he examined what happens if the gene is missing from the adipose cells (the cells which make up the body fat).

For these results, the team used laboratory mice, which were kept on high-fat meals. The mice which were lacking the SIRT1 protein were found to develop several metabolic disorders, including diabetes, whilst the mice who weren’t lacking the protein developed these disorders later in time.

“We see them as being poised for metabolic dysfunction. You’ve removed one of the safeguards against metabolic decline, so if you now give them the trigger of a high-fat diet, they’re much more sensitive than the normal mouse”, said professor Guarente.

Diabete

 The results of the study suggest that medication what enhances the activity of the SIRT1 protein could be used to treat metabolic diseases linked to obesity. Professor Guerente is the one who discovered the effects of both SIRT1 and other sirtuin proteins. The role of the sirtuin proteins is to keep the cells alive through the coordination of regulatory proteins, hormonal networks and the coordination of other genes.

Professor Guarente and his research team deleted the gene from the brain and the liver in order to better study its effects. Previous studies have shown that SIRT1 protects against the neurodegeneration that comes along with diseases such as Alzheimer’s, Parkinson’s or Huntington’s. The team of researchers has shown that the protective abilities of the SIRT1 protein are obtained through the process of deacetylation.

The team found that a high percentage of the hundreds of genes that were studied in the mice lacking the SIRT1 protein (which were on a normal diet) were also found in the normal mice that received a high-fat diet. Professor Guarente says that the results of his study suggest that the onset of metabolic disorders is composed of two steps, the first step being the inactivation of the SIRT1 protein.

A closer look into the process revealed that the SIRT1 protein is proteolitically cleaved by the caspase-1 enzyme. This enzyme is also related to inflammation, whether it’s induced by high-fat diets or not. However, the process through which high-fat diets induce inflammation is still unknown.

“What our study says is that once you induce the inflammatory response, the consequence in the fat cells is that SIRT1 will be cleaved”, said professor Guarente.

Generalized Tonic-Clonic Epilepsy Seizures (Grand Mal Seizures) – Clinical Presentation

Epilepsy is a chronic cerebral disorder characterized by recurrent and spontaneous seizures that are typically unprovoked and unpredicteble.

An epilepsy seizure represents a transient episode of supratentorial origin, characterized by an abrupt and temporary alteration of cerebral function, due to an abnormal paroxysmal discharge of cerebral neurons caused by cortical hyperexcitability. According to The International Classification of Seizures, epilepsy seizures are divided into partial seizures ( focal or localization-related seizures) and generalized seizures.

Partial seizures are subdivided into simple partial seizures in which there is no loss of consciousness and into complex partial seizures which are always associated with loss of consciousness. Partial seizures are the result of an abnormal paroxysmal discharge of cerebral neurons within a particular brain region and they manifest focal symptoms an may progress to generalized seizures.

Epilepsy Seizures

Generalized seizures are the result of an paroxysmal discharge that probably begins in thalamus and then spreads to other brain structures, but on electroencephalographic (EEG) recordings, they appear to start simultaneously in both cerebral hemispheres. Generalized seizures are always associated with loss of consciousness and generalized symptoms.

Generalized Tonic-Clonic Epilepsy Seizures (Grand Mal Seizures)

Grand mal seizures or primary generalized seizures represent the most frequent form of epilepsy seizures and typically include four phases, out of which the first two phases may be absent, but the third phase is always present. This four phases are represented by prodromal phase, aura, tonico-clonic phase and postictal phase.

Prodromal Phase or Prodrome

This phase is present in 20%-30% of patients with epilepsy and may last for several hours up to maximum two days. Patients may experience mood changes, headache, depression, irritability, euphoria, paresthesia, hypoacusia, palpitation, pollakiuria (abnormally frequent urination), diffuse myoclonia, sleep disturbances and difficulty concentrating. This symptoms are sometimes observed by family members and not by the patient.

Aura

This phase is present in 50% of patients with epilepsy and lasting seconds (5-15 seconds). Aura predicts the loss of consciousness an patients may experience symptoms such as palpitations, paresthesias, photopsias (the presence of perceived flashes of light), tinnitus, olfactory or taste hallucinations. Sensory-autonomic symptoms such as abdominal pain, facial pallor, headache or stereotypical ictal cry are more common and are followed by the loss of consciousness.

Epilepsy Seizures

Aura symptoms warn about the imminent crisis and patient may lay down before losing consciousness, thus avoiding a trauma caused by an eventual fall. Aura occurs every time  in the same manner in the same individual.

Tonico-Clonic Phase

Tonic-clonic phase of convulsive stage has a brutal onset with loss of consciousness and fall, with the possibility of injury occurrence. It evolves in two subphases: the tonic phase that lasts 15-20 seconds and the clonic phase that lasts 30-40 seconds.

Tonic phase begin with generalized muscle contracture, during which the patient utters a cry (due to forced expiration with closed glottal orifice).  Tonic phase is associated with loss of consciousness and is followed by an unprotected fall. The tonic phase begins with flexion of the trunk and elevation and abduction of the elbows. Subsequent extension of the back and neck is followed by extension of arms and legs. This events are accompanied by apnea which is leading to cyanosis, due to intense oxygen consumption induced by muscle contraction.

Autonomic signs are characteristic for this phase and are represented by profuse sweating, tracheobronchial hypersecretion, increase in pulse rate and in blood pressure. Although urinary bladder pressure is increasing during tonic phase, voiding does not occur due to sphincter muscle contraction.

Grand Mal Seizure

Clonic phase follows the tonic phase, in which the tonic muscles relax intermittently for a variable period of time and is characterized by saccadic and sychronous convulsive movements. This convulsive movements are initially reduced in amplitude and in speed and become increasingly ampler while the general hypertonia subsides. This atonic phases alternate with repeated violent flexor spasms and each spasm is accompanied by pupillary contraction and dilation. Patient may bite its tongue or cheeks.

Due to atonia which is characteristic for the end of this phase, voiding may occur as sphincter muscles relax. In clonic phase cyanosis subsides as respiration is regained.

Postictal Phase

This phase is considered a postcritic coma state and lasts from 1-5 minutes up to 20-25 minutes. This phase is always present in epilepsy grand mal seizures. The postictal phase is accompained  by a variable period of unconsciousness during which the patient becomes quiet and breathing resumes. The patient gradually awakens and after a period of stupor or sleep may present obnubilation, spatial and temporal disorientation, motor automatism, aggressivity and motor restlessness. Head ache and muscle weakness are common during this phase.

Generalized Tonic-Clonic Epilepsy Seizures Clinical Forms

In medical practice, particular variants of generalized tonic-clonic epilepsy seizures are encountered, such as:

1. In newborns, sychronous muscle contraction are substituted by chaotic muscle contraction of different body segments, due to cerebral immaturity;
2. In children, tonic phase is prolonged and may lead to sever functional consequences due to cerebral anoxia and respiratory failure during the crisis or grand mal crisis may be represented by an akinetic crisis associated with loss of consciousness and of muscle tone ;
3. In older patients, with vascular epilepsy, grand mal crisis present only the clonic phase which is not so dangerous as the tonic phase is absent.

Trigeminal Neuralgia – Causes, Symptoms And Treatment

Trigeminal neuralgia is the most common facial pain syndrome with paroxysmal character, representing one of the most unbearable pain. Also known as tic douloureux, trigeminal neuralgia has an incidence of 4.5 cases per 100,000 inhabitants and is characterized by recurrent episodes of pain, which starts in a small area of the face. Onset is most common in middle age, but have been reported cases with onset in childhood or in adolescence.

Trigeminal nerve is the largest of all the cranial nerves, is a mixed nerve and presents two components: a sensory component which is formed by somatic sensory fibers that carry pain, temperature and touch sensations from the face and a motor component formed by motor fibers that supply temporalis, pterygoid, tensor tympani, tensor palati, mylohyoid, and anterior belly of the digastric muscle.

Trigeminal Neuralgia Causes

The exact pathophysiology of trigeminal neuralgia is not well known, in most cases the cause is not evident, being an idiopathic trigeminal neuralgia. In a small percentage of cases, trigeminal neuralgia may occur due to structural lesions of the trigeminal nerve.

In most cases, trigeminal neuralgia is probably caused by the compression of an aberrant arterial or venous loop on the nerve root, produced where trigeminal root is entering into the pons. This mechanism first described by Jannetta in 1967 is still incriminated in 80% -90% of cases.

Trigeminal Neuralgia

Pulsations of arterial or venous vascular loops that produce aberrant trigeminal root compression, are responsible for the appearance of demyelination areas in the trigeminal root, which causes a non-synaptic transmission between sensory, thick , myelinated fibers and small, thin fibers that transmit pain. Aberrant arterial loops most often originate from superior cerebellar artery and anterior inferior cerebellar artery.

In a lower proportion of cases, trigeminal neuralgia may be caused by a primary demyelination, as occurs in approximately 2% of cases of multiple sclerosis that is associated with trigeminal neuralgia.

Trigeminal Neuralgia Symptoms

The disease usually appears after age of 40 years, between 50 and 58 years, and most commonly affects females, the female/male ratio being 1,6:1 for women.

Trigeminal neuralgia is characterized by a paroxysmal, repetitive, very strong and lancianting pain that is lasting a few seconds, described by the patient as a sensation of electrical shocks that starts suddenly. Attacks occur daily for several weeks or months, followed by a period of remission that may last for years and then attacks may recur. The pain is always located unilaterally, is so strong and sudden that the patient is frightened, may grimace, wince, or make an aversive head movement, reason why trigeminal neuralgia is also called tic douloureux.

Paroxysmal pain attack lasts a few seconds, up to 20-30 seconds, rarely up to several minutes and during the day or night painful attacks can occur several times. The attack appear and disappear suddenly. Pain may occur spontaneously or is triggered by stimulation of specific areas located on the face, called trigger zones. Trigger zones are stimulated by low intensity stimuli, especially tactile or activities like teeth washing, yawning, talking, shaving and laughing. Pain may be precipitated by loud noises or bright stimuli. Most often the trigger zone is located on the nose or lips. After the active period of the disease, remissions can last for months or years, and recurrence of painful paroxysms  is unpredictable.

Trigeminal Neuralgia

Neuralgia occurs mostly on maxillary and mandibular branch, but were reported exceptional cases were neuralgia was located in the ophthalmic branch of the trigeminal nerve.

Neurological examination reveals no changes in trigeminal nerve territory, which is an argument for the diagnosis of idiopathic trigeminal neuralgia. In evolution, trigeminal neuralgia tends to deterioration, painful attacks have the tendency to increase in frequency and severity.

Trigeminal Neuralgia Treatment

Trigeminal neuralgia benefit from medical treatment and neurosurgical treatment. Because trigeminal neuralgia affects patients older than 50 years, medical treatment should represent the initial therapy. Medical therapy is often sufficient and effective, allowing surgical consideration only if pharmacologic treatment fails.

Medical Therapy

Carbamazepine is the drug of choice in the treatment of trigeminal neuralgia. Dose should be increased gradually to obtain a maximum effect of the drug. After several weeks of symptoms improvement, the dose of carbamazepine may be decreased gradually. The most common side effects of carbamazepine are represented by skin rash, liver problems, ataxia and dizziness. Oxycarbamazepine has fewer side effects compared with carabamazepina and represent an other choice in trigeminal neuralgia.

Phenytoin, clonazepam, baclofen, gabapentin and lamotrigine may be used either alone or in combination with carbamazepine.

Baclofen is the second choice in the treatment of trigeminal neuralgia, especially in relapse cases. Dose should be increased gradually to obtain a maximum effect and can be administered alone or in combination with phenytoin or carbamazepine.

Neurosurgical Procedures

Trigeminal Neuralgia

Neurosurgical procedure are applied to cases that are unresponsive to drug therapy and consist of:

• Microvascular decompression;
• Percutaneous radiofrequency rhizotomy;
• Percutaneous radiofrequency trigeminal gangliolysis;
• Percutaneous microcompression with balloon inflation;
• Gamma knife surgery.