Multiple sclerosis (MS) is a chronic autoimmune disorder affecting movement, ensation, and bodily functions. It is caused by destruction of the myelin insulation covering nerve fibers (neurons) in the central nervous system (brain and spinal cord).
MS is a nerve disorder caused by destruction of the insulating layer surrounding neurons in the brain and spinal cord. This insulation, called myelin, helps electrical signals pass quickly and smoothly between the brain and the rest of the body. When the myelin is destroyed, nerve messages are sent more slowly and less efficiently. Patches of scar tissue, called plaques, form over the affected areas, further disrupting nerve communication. The symptoms of MS occur when the brain and spinal cord nerves no longer communicate properly with other parts of the body. MS causes a wide variety of symptoms and can affect vision, balance, strength, sensation, coordination, and bodily functions.
Multiple sclerosis affects more than a quarter of a million people in the United States. Most people have their first symptoms between the ages of 20 and 40; symptoms rarely begin before 15 or after 60. Women are almost twice as likely to get MS as men, especially in their early years. People of northern European heritage are more likely to be affected than people of other racial backgrounds, and MS rates are higher in the United States, Canada, and Northern Europe than in other parts of the world. MS is very rare among Asians, North and South American Indians, and Eskimos.
Causes and symptoms
Multiple sclerosis is an autoimmune disease, meaning its cause is an attack by the body's own immune system. For unknown reasons, immune cells attack and destroy the myelin sheath that insulates neurons in the brain and spinal cord. This myelin sheath, created by other brain cells called glia, speeds transmission and prevents electrical activity in one cell from short-circuiting to another cell. Disruption of communication between the brain and other parts of the body prevent normal passage of sensations and control messages, leading to the symptoms of MS. The demyelinated areas appear as plaques, small round areas of gray neuron without the white myelin covering. The progression of symptoms in MS is correlated with development of new plaques in the portion of the brain or spinal cord controlling the affected areas. Because there appears to be no pattern in the appearance of new plaques, the progression of MS can be unpredictable.
Despite considerable research, the trigger for this autoimmune destruction is still unknown. At various times, evidence has pointed to genes, environmental factors, viruses, or a combination of these.
The risk of developing MS is higher if another family member is affected, suggesting the influence of genetic factors. In addition, the higher prevalence of MS among people of northern European background suggests some genetic susceptibility.
The role of an environmental factor is suggested by studies of the effect of migration on the risk of developing MS. Age plays an important role in determining this change in risk—young people in low-risk groups who move into countries with higher MS rates display the risk rates of their new surroundings, while older migrants retain the risk of their original home country. One interpretation of these studies is that an environmental factor, either protective or harmful, is acquired in early life; the risk of disease later in life reflects the effects of the early environment.
These same data can be used to support the involvement of a slow-acting virus, one that is acquired early on but begins its destructive effects much later. Slow viruses are known to cause other diseases, including AIDS
. In addition, viruses have been implicated in other autoimmune diseases. Many claims have been made for the role of viruses, slow or otherwise, as the trigger for MS, but as of 2001 no strong candidate has emerged.
How a virus could trigger the autoimmune reaction is also unclear. There are two main models of virally induced autoimmunity. The first suggests the immune system is actually attacking a virus (one too well-hidden for detection in the laboratory), and the myelin damage is an unintentional consequence of fighting the infection. The second model suggests the immune system mistakes myelin for a viral protein, one it encountered during a prior infection. Primed for the attack, it destroys myelin because it resembles the previously-recognized viral invader.
Either of these models allows a role for genetic factors, since certain genes can increase the likelihood of autoimmunity. Environmental factors as well might change the sensitivity of the immune system or interact with myelin to provide the trigger for the secondary immune response. Possible environmental triggers that have been invoked in MS include viral infection, trauma, electrical injury, and chemical exposure, although controlled studies do not support a causative role.
The symptoms of multiple sclerosis may occur in one of three patterns:
- The most common pattern is the "relapsing-remitting" pattern, in which there are clearly defined symptomatic attacks lasting 24 hours or more, followed by complete or almost complete improvement. The period between attacks may be a year or more at the beginning of the disease, but may shrink to several months later on. This pattern is especially common in younger people who develop MS.
- In the "primary progressive" pattern, the disease progresses without remission or with occasional plateaus or slight improvements. This pattern is more common in older people.
- In the "secondary progressive" pattern, the person with MS begins with relapses and remissions, followed by more steady progression of symptoms.
Between 10-20% of people have a benign type of MS, meaning their symptoms progress very little over the course of their lives.
Because plaques may form in any part of the central nervous system, the symptoms of MS vary widely from person-to-person and from stage-to-stage of the disease. Initial symptoms often include:
- Muscle weakness, causing difficulty walking
- Loss of coordination or balance
- Numbness, "pins and needles," or other abnormal sensations
- Visual disturbances, including blurred or double vision.
Later symptoms may include:
- Muscle spasticity and stiffness
- Speech or swallowing difficulty
- Loss of bowel and bladder control
- Incontinence, constipation
- Sexual dysfunction
- Cognitive changes.
Weakness in one or both legs is common, and may be the first symptom noticed by a person with MS. Muscle spasticity, or excessive tightness, is also common and may be more disabling than weakness.
Double vision or eye tremor (nystagmus
) may result from involvement of the nerve pathways controlling movement of the eye muscles. Visual disturbances result from involvement of the optic nerves (optic neutritis) and may include development of blind spots in one or both eyes, changes in color vision, or blindness. Optic neuritis
usually involves only one eye at a time and is often associated with movement of the effected eye.
More than half of all people affected by MS have pain during the course of their disease, and many experience chronic pain, including pain from spasticity. Acute pain occurs in about 10% of cases. This pain may be a sharp, stabbing pain especially in the face, neck, or down the back. Facial numbness and weakness are also common.
Cognitive changes, including memory disturbances, depression, and personality changes, are found in people affected by MS, though it is not entirely clear whether these changes are due primarily to the disease or to the psychological reaction to it. Depression may be severe enough to require treatment in up to 25% of those with MS. A smaller number of people experience disease-related euphoria, or abnormally elevated mood, usually after a long disease duration and in combination with other psychological changes.
Symptoms of MS may be worsened by heat or increased body temperature, including fever
, intense physical activity, or exposure to sun, hot baths, or showers.
There is no single test that confirms the diagnosis of multiple sclerosis, and there are a number of other diseases with similar symptoms. While one person's diagnosis may be immediately suggested by her symptoms and history, another's may not be confirmed without multiple tests and prolonged observation. The distribution of symptoms is important: MS affects multiple areas of the body over time. The pattern of symptoms is also critical, especially evidence of the relapsing- remitting pattern, so a detailed medical history is one of the most important parts of the diagnostic process. A thorough search to exclude other causes of a patient's symptoms is especially important if the following features are present: 1) family history of neurologic disease, 2) symptoms and findings attributable to a single anatomic location, 3) persistent back pain, 4) age of onset over 60 or under 15 years of age, or 5) progressively worsening disease.
In addition to the medical history and a standard neurological exam, several lab tests are used to help confirm or rule out a diagnosis of MS:
- Magnetic resonance imaging (MRI) can reveal plaques on the brain and spinal cord. Gadolinium enhancement can distinguish between old and new plaques, allowing a correlation of new plaques with-new symptoms. Plaques may be seen in several other-diseases as well, including encephalomyelitis, neurosarcoidosis, and cerebral lupus. Plaques on MRI may be difficult to distinguish from small strokes, areas of decreased blood flow, or changes seen with trauma or normal aging.
- A lumbar puncture, or spinal tap, is done to measure levels of immune proteins, which are usually elevated in the cerebrospinal fluid of a person with MS. This test may not be necessary if other tests are diagnostic.
- Evoked potential tests, electrical tests of conduction speed in the nerves, can reveal reduced speeds consistent with the damage caused by plaques. These tests may be done with small electrical charges applied to the skin (somatosensory evoked potential), with light patterns flashed on the eyes (visual evoked potential), or with sounds presented to the ears (auditory evoked potential).
The clinician making the diagnosis, usually a neurologist, may classify the disease as "definite MS," meaning the symptoms and test results all point toward MS as the cause. "Probable MS" and "possible MS" reflect less certainty and may require more time to pass to observe the progression of the disease and the distribution of symptoms.
The three major drugs previously approved for the treatment of MS affect the course of the disease. None of these drugs is a cure, but they can slow disease progression in many patients.
Known as the ABC drugs, Avonex and Betaseron are forms of the immune system protein beta interferon, while Copaxone is glatiramer acetate (formerly called copolymer-1). All three have been shown to reduce the rate of relapses in the relapsing-remitting form of MS. Different measurements from tests of each have demonstrated other benefits as well: Avonex may slow the progress of physical impairment, Betaseron may reduce the severity of symptoms, and Copaxone may decrease disability. All three drugs are administered by injection
Two major clinical studies were recently completed that focused on the question of whether disease-modifying therapy known to slow the disease, can postpone the development of clinically definitive MS in high risk patients. Data presented at the annual meeting of the American Academy of Neurology in May, 2000, highlighted the different effects of interferon therapy when it was initiated at the earliest recognizable stages of MS versus later. Previous studies with interferon beta-1b (Betaseron) and interferon beta-1a (Avonex, Rebif) clearly demonstrated benefits in patients with relapsing forms of MS. Moreover, previous treatment with High-dose corticosteroids
also delays, but does not prevent the ultimate development of MS. The encouraging message from the CHAMPS study in the United states and the ETOMS study in Europe is that early intervention can reduce the probability of developing clinically definitive MS.
Although the ABC drugs stop relapses and may keep patients in relatively good health for the short-term, their long-term success has not been proven and they don't work well for patients who have reached a steadily progressive stage of MS. In the meantime, new approaches to using current therapies are being researched especially using combinations of different types of agents when one agent alone is not effective. Clinical trials are now evaluating the safety and efficacy of combining cyclophosphamide (Cytoxan) and methylprednisolone (Medrol) in patients who do not respond to the ABC drus, and of adding mitoxantrone (Novantrone), prednisone (Prelone), azathioprine (Imuran), or methotrexate (Rheumatrex) to betainterferon for further benefit.
In addition, Miloxzantrone HCI (novantrone), a drug approved for cancer
treatment, has been approved for treating patients with advanced or chronic multiple scelereosis.In clinical trials, mitoxantrone reduced the number of relapse episodes and slowed down the disease. Reserved for progressive forms of MS, it is given intravenously by a doctor to help maintain mobility and reduce the number of flare-ups. However, there are serious side effects with the drug including heart problems, nausea, and hair thinning.
As reported in the Spring, 2001, Volume 19, No 2 issue of InsideMS, the FDA recently approved the Copaxone Autoject and the Mixject vial adapters to help people using Copaxone self administer the drug. The autoject keeps the syringe steady and hides the needle. The same syringe may be used for both mixing
Multiple sclerosis (MS) is an autoimmune disease in which immune cells attack and destroy the myelin sheath which stimulates neurons in the brain and spinal cord. When the myelin is destroyed, nerve messages are sent more slowly and less efficiently. Scar tissue then forms over the affected areas, disrupting nerve communication. MS symptoms occur when the brain and spinal cord nerves cease to communicate properly with other parts of the body.
(Illustration by Electronic Illustrators Group.)
and injecting with the Mixject vial adapters. A similar device is available for patients using Betassseron. Some patients are using the needlefree Biojector 2000 which uses a CO2
cartridge to deliver doses of medication through the skin. The FDA has not approved its use and patients should discuss this with their physician for its use with either Copaxone or Betaseron. Avonex must be injected in the muscle.
have been used for many years to treat acute exacerbations (relapses). Drugs used include corticosteroids such as prednisone and methylprednisone; the hormone adrenocorticotropic hormone (ACTH); and azathioprine. Recent studies indicate that several days of intravenous methylprednisone may be more effective than other immunosuppressant treatments for acute symptoms. This treatment may require hospitalization.
MS causes a large variety of symptoms, and the treatments for these are equally diverse. Most symptoms can be treated and complications avoided with good care and attention from medical professionals. Good health and nutrition
remain important preventive measures. Vaccination
can prevent respiratory complications, and contrary to earlier concerns, is not associated with worsening of symptoms. Preventing complications such as pneumonia
, bed sores, injuries from falls, or urinary infection requires attention to the primary problems which may cause them. Shortened life spans with MS are almost always due to complications rather than primary symptoms themselves.
Physical therapy helps the person with MS to strengthen and retrain affected muscles; to maintain range of motion to prevent muscle stiffening; to learn to use assistive devices such as canes and walkers; and to learn safer and more energy-efficient ways of moving, sitting, and transferring. Exercise
and stretching programs are usually designed by the physical therapist and taught to the patient and caregivers for use at home. Exercise is an important part of maintaining function for the person with MS. Swimming is often recommended, not only for its low-impact workout, but also because it allows strenuous activity without overheating.
Occupational therapy helps the person with MS adapt to her environment and adapt the environment to her. The occupational therapist suggests alternate strategies and assistive devices for activities of daily living, such as dressing, feeding, and washing, and evaluates the home and work environment for safety and efficiency improvements that may be made.
Training in bowel and bladder care may be needed to prevent or compensate for incontinence. If the urge to urinate becomes great before the bladder is full, some drugs may be helpful, including propantheline bromide (Probanthine), oxybutynin chloride (Ditropan), or imipramine (Tofranil). Baclofen (Lioresal) may relax the sphincter muscle, allowing full emptying. Intermittent catheterization is effective in controlling bladder dysfunction. In this technique, a catheter is used to periodically empty the bladder.
Spasticity can be treated with oral medications, including baclofen and diazepam (Valium), or by injection with botulinum toxin (Botox). Spasticity relief may also bring relief from chronic pain. Other more acute types of pain may respond to carbamazepine (Tegretol) or diphenylhydantoin (Dilantin). Low back pain
is common from increased use of the back muscles to compensate for weakened legs. Physical therapy and over-the-counter pain relievers may help.
Fatigue may be partially avoidable with changes in the daily routine to allow more frequent rests. Amantadine (Symmetrel) and pemoline (Cylert) may improve alertness and lessen fatigue. Visual disturbances often respond to corticosteroids. Other symptoms that may be treated with drugs include seizures, vertigo, and tremor.
Myloral, an oral preparation of bovine myelin, has recently been tested in clinical trials for its effectiveness in reducing the frequency and severity of relapses. Preliminary data indicate no difference between it and placebo.
Bee venom has been suggested as a treatment for MS, but no studies or objective reports support this claim.
In British studies, marijuana
has been shown to have variable effects on the symptoms of MS. Improvements have been documented for tremor, pain, and spasticity, and worsening for posture and balance. Side effects have included weakness, dizziness, relaxation, and incoordination, as well as euphoria. As a result, marijuana is not recommended as an alternative treatment.
Some studies support the value of high doses of vitamins
, minerals, and other dietary supplements for controlling disease progression or improving symptoms. Alpha-linoleic and linoleic acids, as well as selenium and vitamin E, have shown effectiveness in the treatment of MS. The selenium and vitamin E act as antioxidants. In addition, the Swank diet (low in saturated fats), maintained over a long period of time, may retard the disease process.
Removal of mercury fillings has been touted as a possible cure, but is of no proven benefit.
Studies have also shown that t'ai chi can be an effective therapy for MS because it works to improve balance and increase strength.
There are conflicting views about Echinacea
and its benefit to MS. Some medicine books recommend Echinacea for people with MS. However, Echinacea appears to stimulate different parts of the immune system, particularly immune cells known as macrophages. In MS these cells are very active already and further stimulation could worsen the disease.
It is difficult to predict how multiple sclerosis will progress in any one person. Most people with MS will be able to continue to walk and function at their work for many years after their diagnosis. The factors associated with the mildest course of MS are being female, having the relapsing-remitting form, having the first symptoms at a younger age, having longer periods of remission between relapses, and initial symptoms of decreased sensation or vision rather than of weakness or incoordination.
Less than 5% of people with MS have a severe progressive form, leading to death
from complications within five years. At the other extreme, 10-20% have a benign form, with a very slow or no progression of their symptoms. The most recent studies show that about seven out of 10 people with MS are still alive 25 years after their diagnosis, compared to about nine out of 10 people of similar age without disease. On average, MS shortens the lives of affected women by about six years, and men by 11 years. Suicide
is a significant cause of death in MS, especially in younger patients.
The degree of disability a person experiences five years after onset is, on average, about three-quarters of the expected disability at 10-15 years. A benign course for the first five years usually indicates the disease will not cause marked disability.
There is no known way to prevent multiple sclerosis. Until the cause of the disease is discovered, this is unlikely to change. Good nutrition; adequate rest; avoidance of stress
, heat, and extreme physical exertion; and good bladder hygiene may improve quality of life and reduce symptoms.
Kraft, Georg H., and Marci Catanzaro. Living with Multiple Sclerosis: A Wellness Approach. Demos Medical Publishing, 2000.
— All new drugs undergo clinical trials before approval. Clinical trials are carefully conducted tests in which effectiveness and side effects are studied, with the placebo effect eliminated.
— Tests that measure the brain's electrical response to stimulation of sensory organs (eyes or ears) or peripheral nerves (skin). These tests may help confirm the diagnosis of multiple sclerosis.
— A layer of insulation that surrounds the nerve fibers in the brain and spinal cord.
— Patches of scar tissue that form where the layer of yelin covering the nerve fibers is destroyed by the multiple sclerosis disease process.
— A pattern of symptoms of multiple sclerosis in which the disease progresses without remission, or with occasional plateaus or slight improvements.
— A pattern of symptoms of multiple sclerosis in which symptomatic attacks occur that last 24 hours or more, followed by complete or almost complete improvement.
— A pattern of symptoms of multiple sclerosis in which there are relapses and remissions, followed by more steady progression of symptoms.
Gale Encyclopedia of Medicine. Copyright 2008 The Gale Group, Inc. All rights reserved.
manifold; occurring in various parts of the body at once.
a malignant neoplasm of plasma cells
in which the plasma cells proliferate and invade the bone marrow, causing destruction of the bone and resulting in pathologic fracture and bone pain. It is the most common type of monoclonal gammopathy
, characterized by presence of a monoclonal immunoglobulin
(immunoglobulin recognized as a single protein), Bence Jones proteins
in the urine, anemia, and lowered resistance to infection. Called also plasma cell myeloma
Diagnostic procedures to confirm suspected multiple myeloma include blood analyses, quantitative immunologic assays of serum and urine, urinalysis, bone marrow aspiration and biopsy, and skeletal x-rays. Findings indicative of the disease are an increased number of plasma cells in the bone marrow (usually over 10 per cent of the total), anemia
due to release of calcium from deteriorating bone tissue, and elevated blood urea nitrogen
, Bence Jones protein in the urine, and osteolytic lesions that give the bone a honeycomb appearance on x-ray and lead to vertebral collapse.
Treatment. Treatment of multiple myeloma involves chemotherapy and radiation to relieve pain and manage the acute lesions of the spinal column. High-dose chemotherapy followed by blood cell rescue has shown some efficacy in certain situations. Individuals diagnosed with multiple myeloma who show no symptoms do not usually receive treatment.
. Major problems presented by the patient with multiple myeloma are related to anemia
, bone pain and pathologic fractures, and emotional distress created by trying to cope with the day-to-day physiologic and emotional aspects associated with the diagnosis of a malignant disease. The more common complications to be avoided are infection, renal failure
, and the sequelae of spinal cord compression.
Transfusions with packed red blood cells
can help alleviate and minimize some of the more severe symptoms of anemia
. It is important that the patient be adequately hydrated to improve viscosity of the blood and circulation, to help avoid hypercalcemia
, and to maintain kidney function for excretion of the products of protein metabolism. Continued ambulation and moderate exercise help slow down the loss of minerals, especially calcium, from the bones. Other problems are related to the administration of highly toxic antineoplastic drugs.
Multiple myeloma. Radiographs of the skull, ribs, and vertebrae show multiple punched out lesions. There is anemia secondary to bone marrow lesions that replace red blood cell precursors. Kidney failure is the most common cause of death. The urine contains Bence Jones protein. From Damjanov, 2000.
multiple organ dysfunction syndrome
(multiple organ failure
) failure of two or more organ systems in a critically ill patient because of a complex and interrelated series of events.
The pathogenesis of multiple organ failure. From Datex Medical Instrumentation, Inc., Tewksbury, MA.
an intracutaneous test in which the material used (such as tuberculin
) is introduced into the skin by pressure of several needles or pointed tines or prongs. This procedure is used in mass screenings, but it is not as accurate as other tests because of lack of precise measurement of the amount of medication actually entering the skin.
(MS) a chronic neurologic disease in which there are patches of demyelination
scattered throughout the white matter
of the central nervous system, sometimes extending into the gray matter
. The disease primarily affects the myelin
and not the nerve cells themselves; any damage to the neurons is secondary to destruction of the myelin
covering the axon. The symptoms caused by these lesions are typically weakness, incoordination, paresthesias, speech disturbances, and visual disturbances, particularly diplopia. More specific signs and symptoms depend on the location of the lesions and the severity and destructiveness of the inflammatory and sclerotic processes.
The course of the disease is usually prolonged, with remissions and relapses over many years. Brief exacerbations, even with acute and severe symptoms, are thought to be the result of a transient inflammatory depression of neural transmission. Recovery occurs when there has been no permanent damage to the myelin sheath during the attack. Repeated attacks can, however, eventually permanently denude the axons and leave the yellow sclerotic plaques that are characteristic of the disease. Once the disease process reaches the stage of sclerosis the affected axons cannot recover and there is permanent damage.
The prevalence of MS is not certain because the disease is not one that is reported, and mild cases can be either misdiagnosed or never brought to the attention of a health care provider. It is far more common in the temperate zones of the world than in tropical and subtropical climates. The onset of symptoms most often occurs between the ages of 20 and 40 years, and the disease affects both sexes about equally.
The cause of multiple sclerosis is unknown. It is likely that an inherited immune response
is somehow responsible for the production of autoantibodies
that attack the myelin sheath. Some authorities believe that infection by one of the slow viruses occurs during childhood and after some years of latency the virus triggers an autoimmune response. Others believe there is an antigen or environmental trigger for the disease.
The diagnosis of multiple sclerosis is difficult because of the wide variety of possible clinical manifestations and the resemblance they bear to other neurological disorders. There is no definitive diagnostic test for the condition, but persons with objectively measured abnormalities of the central nervous system, a history of exacerbation and remission of symptoms, and demonstrable delayed blink reflex and evoked visual response are diagnosed as having either possible or probable multiple sclerosis. With time and progressive worsening of symptoms the diagnosis can become definite.
. A multidisciplinary approach is required to diagnose the condition and help patients and their families cope with the attendant problems. Multiple sclerosis has an impact on physical activity and life style, role, and interpersonal relationships; therefore, vocational guidance, counseling, and group therapy are helpful. It is important that the patient with severe disability maintain a positive attitude, focusing on functional abilities rather than disabilities. Regeneration of the damaged neural tissue is not possible but retraining and adaptation are. Stress due to trauma, infection, overexertion, surgery, or emotional upset can aggravate the condition and precipitate a flare-up of symptoms.
Supportive measures include a regimen of rest and exercise, a well-balanced diet, avoidance of extremes of heat and cold, avoidance of known sources of infection, and adaptation of a life style that is relatively unstressful while still being as productive as possible.
Therapeutic measures include medications to diminish muscle spasticity; measures to overcome urinary retention (such as credé's method
or intermittent catheterization
); speech therapy; and physical therapy to maintain muscle tone and avoid orthopedic deformities. Management of MS has been greatly enhanced by the availability of interferons beta-1a
. Research support is strong that these medications reduce the frequency and severity of relapses.
Many multiple sclerosis patients and their families receive valuable support and encouragement from communication with others coping with the condition. A local chapter of the National Multiple Sclerosis Society is within reach of most persons in the United States. Information and assistance in all phases of the disease are available by writing to The National Multiple Sclerosis Society, 733 Third Ave., 6th floor, New York, NY 10017, or consulting their web site at http://www.nmss.org.
, especially of a part from inflammation, or in disease of the interstitial substance. The term is used chiefly for such a hardening of the nervous system due to hyperplasia of the connective tissue or for hardening of the blood vessels. Called also induration
. adj., adj
lateral sclerosis a form seated in the lateral columns of the spinal cord. It may be primary, with spastic paraplegia, rigidity of the limbs, and increase of the tendon reflexes but no sensory disturbances, or secondary to myelitis, with paraplegia and sensory disturbance.
tuberous sclerosis a congenital heredofamilial disease, transmitted as an autosomal dominant trait, characterized principally by the presence of hamartomas of the brain (tubers), retina (phakomas), and viscera, mental retardation, seizures, and adenoma sebaceum, and often associated with other skin lesions.
Miller-Keane Encyclopedia and Dictionary of Medicine, Nursing, and Allied Health, Seventh Edition. © 2003 by Saunders, an imprint of Elsevier, Inc. All rights reserved.