DYNAMIC MOTION OF HIV AS IT READIES AN ATTACK

Researchers at Weill Cornell Medical College have developed technologies that allow investigators, for the first time, to watch what they call the "dance" of HIV proteins on the virus' surface, which may contribute to how it infects human immune cells. Their discovery is described in the Oct. 8 issue of Science, and is also a part of a study published the same day in Nature.

The new technology platform opens new possibilities for devising an approach to prevent HIV infection, says Dr. Scott Blanchard, an associate professor of physiology and biophysics at Weill Cornell, and one of three co-lead authors on the Sciencestudy. He is also an author on the Nature paper that describes a three-dimensional structure of one of the shapes, or conformations of the HIV protein.

"Making the movements of HIV visible so that we can follow, in real time, how surface proteins on the virus behave will hopefully tell us what we need to know to prevent fusion with human cells -- if you can prevent viral entry of HIV into immune cells, you have won," says Dr. Blanchard, who is also associate director of Weill Cornell's chemical biology program.

"What we have shown in the Science study is that we now have the means to obtain real-time images of processes happening on the surface of intact HIV particles, which we now plan to use to screen the impact of drugs and antibodies that can shut it down," he says.

"We desperately need solutions to prevent HIV infection, which, to date, has infected or killed more than 70 million people worldwide," Dr. Blanchard says. If this technology proves useful in HIV management, it could potentially be used to decode infection processes for other viruses, he says.

Using Light to Watch HIV Dance

In the Science study, Dr. Blanchard worked with Dr. Walther Mothes, a HIV specialist at the Yale University School of Medicine, and with Dr. James Munro, who was Dr. Blanchard's first graduate student and who is now an assistant professor at Tufts University School of Medicine. Drs. Mothes and Munro are the two other co-lead investigators.

Dr. Blanchard adapted an imaging technique that uses fluorescence to measure distance on molecular scale -- single-molecule fluorescence resonance energy transfer (smFRET) imaging -- to study viral particles. His group developed fluorescent molecules (fluorophores) -- which he dubs "beacons" -- and the team inserted them into the virus's outer covering, known as the envelope. With two of these special beacons in place, smFRET imaging can be used to visualize how the molecules move over time, when the virus proteins change conformation. The approach provides a measure of distances, on the order of a billionth of an inch, between two beacons glowing in different colors, and this can be used to detect shape shifting as it occurs and the attached beacons move.

The team used the technology to study motions of proteins on the surface of the HIV virus (called envelope proteins) that are key to the virus's ability to infect human immune cells carrying CD4 receptor proteins. (CD4 receptor proteins help HIV bind to a cell.) The envelope consists of three gp120 and gp41 proteins positioned close together, and referred to as "trimers," that open up like a flower in the presence of CD4, exposing the gp41 subunit that is essential for subsequent aspects of the mechanism that causes infection.

"There are 10-20 such envelope trimers on the surface of each HIV particle, and they mutate rapidly, thereby evading typical immune responses. This is why it is so difficult for humans to mount an effective immune response and why it is challenging for researchers to develop vaccines targeting the HIV envelope proteins," Dr. Blanchard says. The researchers were able to study proteins from two different strains of HIV, which contained beacons that did not alter the biology of the particles.

Then they watched.

They saw that the gp120 proteins' virus particles changed shape constantly and that the timing and nature of their movements were both similar and distinct. "This answered the first big question of how opening of the envelope trimer is triggered," Dr. Blanchard says. "Many scientists believe that the particles remain in one conformation until they come across a CD4-positive cell. But we saw that the proteins dance when no CD4 was present -- they change shape all the time."

The researchers were then able to watch how the viruses responded when synthetic CD4 was introduced. They also saw that antibodies known to exhibit some effectiveness acted to prevent gp120 from opening, and that these effects correlated with a decrease in the virus' ability to infect cells. Similar things happened when they introduced a small molecule now under development to prevent HIV infection.

"The practical outcome from this technology is that we can begin to understand how the biological system moves. So far we have detected three different conformations of the envelope trimer. We are working now to improve the technology to achieve the imaging precision we need to make broadly effective therapies," Blanchard says.

Technologies Work Hand in Hand

The Nature study, led by researchers at the National Institute of Allergy and Infectious Diseases, used X-ray crystallography to capture a three-dimensional structure of one of the conformations revealed in the Science paper. The protein constructs used in this investigation were originally developed by a team of researchers headed by Dr. John Moore, professor of microbiology and immunology at Weill Cornell.

"The antibodies used in the crystallography study are ones that we observed to stop the dance of the HIV envelope proteins, pushing the trimer assembly into a quiescent, ground state," Dr. Blanchard says.

"This concrete, atomic resolution picture of what the pre-fusion machinery looks like and where these antibodies bind provides an important step forward to understanding HIV's biology," he says.

Dr. Blanchard believes both techniques -- smFRET and X-ray crystallography -- can work hand in hand to help scientists describe the functions of molecules from the perspective motion, including the other two distinct conformations identified in the smFRET study.

"The approach is really a breakthrough for science because most research is done in a test tube where billions of molecules are present, all behaving independently. It is very difficult to extract direct information about these types of movements from indirect observations," such as those that don't use imaging technology, he says. "The single-molecule approach allows practical, interpretable, real-time information to be obtained about molecular processes in complex biological systems."

Neuropathy As A Side Effect Of Lyme Disease

Today's post from lymeneteurope.org (see link below) is possibly not for every reader as it talks about neuropathy caused by Lyme Disease. It's a very long (hence the smaller than normal typeface) and technical post, consisting of complex abstracts from many studies but if you have Lyme disease and/or neuropathy caused by Lyme disease, then there is a vast amount of useful information for you to digest here. Tics that cause Lyme disease are spreading rapidly in many parts of the world and you may not be aware that you have been bitten at all. If you're not already aware of the general facts about how this condition is caused, there are other shorter and simpler articles here on the blog (use the search button to the right) or you may want to Google Lyme disease itself. I am very grateful to Rita A for collecting all this information in one place - it will help a lot of people to understand the connection between Lyme disease and neuropathy.

Older Articles re LD and Neuropathy
by RitaA Sun 22 Jan 2012
I was reading about Lyme disease and peripheral neuropathy earlier, and did a bit of digging for published articles about the topic. Neuropathy does seem to be a common finding in both early and late Lyme disease. I've also included a couple of articles dealing with Lyme disease from a neuropsychiatric point of view:

Neurology. 1987 Nov;37(11):1700-6.
Lyme disease: cause of a treatable peripheral neuropathy.
Halperin JJ, Little BW, Coyle PK, Dattwyler RJ.
Source
Department of Neurology, State University of New York, Stony Brook 11794.
Abstract
Peripheral nerve dysfunction was demonstrated in 36% of patients with late Lyme disease. Of 36 patients evaluated, 14 had prominent limb paresthesias. Thirteen of these had neurophysiologic evidence of peripheral neuropathy; neurologic examinations were normal in most. Repeat testing following treatment documented rapid improvement in 11 of 12. We conclude that this neuropathy, which is quite different from the infrequent peripheral nerve syndromes previously described in this illness, is commonly present in late Lyme disease. This neuropathy presents with intermittent paresthesias without significant deficits on clinical examination and is reversible with appropriate antibiotic treatment. Neurophysiologic testing provides a useful diagnostic tool and an important measure of response to treatment.

PMID: 3670609 [PubMed - indexed for MEDLINE]

Neurology. 1989 Jun;39(6):753-9.
Lyme neuroborreliosis: central nervous system manifestations.
Halperin JJ, Luft BJ, Anand AK, Roque CT, Alvarez O, Volkman DJ, Dattwyler RJ.
SourceDepartment of Neurology, State University of New York, Stony Brook.
Abstract
We evaluated 85 patients with serologic evidence of Borrelia burgdorferi infection. Manifestations included encephalopathy (41), neuropathy (27), meningitis (2), multiple sclerosis (MS) (6), and psychiatric disorders (3). We performed lumbar punctures in 53, brain MRI in 33, and evoked potentials (EPs) in 33. Only patients with an MS-like illness had abnormal EPs, elevated IgG index, and oligoclonal bands in the cerebrospinal fluid. Twelve of 18 patients with encephalopathy, meningitis, or focal CNS disease had evidence of intrathecal synthesis of anti-B burgdorferi antibody, compared with no patients with either MS-like or psychiatric illnesses, and only 2/24 patients with neuropathy. MRIs were abnormal in 7/17 patients with encephalopathy, 5/6 patients with an MS-like illness, and no others. We conclude that (1) intrathecal concentration of specific antibody is a useful marker of CNS B burgdorferi infection; (2) Lyme disease causes an encephalopathy, probably due to infection of the CNS; (3) MS patients with serum immunoreactivity against B burgdorferi lack evidence of CNS infection with this organism.

Comment in
Neurology. 1990 Jan;40(1):189-91.
Neurology. 1991 Jun;41(6):952-3.

PMID:2542840[PubMed - indexed for MEDLINE]

Rev Infect Dis. 1989 Sep-Oct;11 Suppl 6:S1499-504.
Abnormalities of the nervous system in Lyme disease: response to antimicrobial therapy.Halperin JJ.
Source
Department of Neurology, State University of New York, School of Medicine, Stony Brook 11794.
Erratum in
Rev Infect Dis 1990 May-Jun;12(3):566.
Abstract
Objective measures of neurologic function were used to assess response to treatment in patients with late Lyme borreliosis. Neurophysiologic evidence of peripheral neuropathy was present in 64 of 137 patients tested. Measures of distal axon function (sensory amplitude and conduction velocity, motor terminal latency) were most affected.Repeat studies following 60 patients receiving antimicrobial therapy demonstrated significant improvement in these values. Before and after therapy 17 patients with late Lyme borreliosis and prominent subjective cognitive dysfunction underwent neuropsychologic tests of memory, conceptual ability, concentration, psychomotor function, overlearned intellectual abilities, and mood. Significant abnormalities were evident before treatment; all reversed with antimicrobial therapy. Many patients with this encephalopathy had specific abnormalities revealed by magnetic resonance imaging of the brain and had evidence of intrathecal synthesis of antibody to Borrelia. These findings indicate that late Lyme borreliosis commonly causes nervous system abnormalities that are reversible with appropriate antibiotic therapy.

PMID: 2682962 [PubMed - indexed for MEDLINE]

Brain. 1990 Aug;113 ( Pt 4):1207-21.
Lyme neuroborreliosis. Peripheral nervous system manifestations.
Halperin J, Luft BJ, Volkman DJ, Dattwyler RJ.
SourceDepartment of Neurology, State University of New York, Stony Brook 11794.
Abstract
An ever increasing number of apparently unrelated peripheral nervous system (PNS) disorders has been associated with Lyme borreliosis. To ascertain their relative frequency and significance, we studied prospectively 74 consecutive patients with late Lyme disease, with and without PNS symptoms: 53% had intermittent limb paraesthesiae, 25% the carpal tunnel syndrome, 8% painful radiculopathy, and 3% Bell's palsy; 39% had disseminated neurophysiological abnormalities. To assess the interrelationships among these syndromes, we reviewed the neurophysiological findings in all 163 such patients that we have studied to date. Reversible abnormalities of distal conduction were the most common finding. Demyelinating neuropathy was extremely rare. The pattern of abnormality was similar in all patient groups, regardless of whether the symptoms suggested radiculopathy, Bell's palsy, or neuropathy. We conclude that (1) reversible PNS abnormalities occur in one-third of our patients with late Lyme borreliosis, and (2) the pattern of electrophysiological abnormalities is the same in all and is indicative of widespread axonal damage, suggesting that these different presentations reflect varying manifestations of the same pathological process.
PMID:2168778[PubMed - indexed for MEDLINE]

N Engl J Med. 1990 Nov 22;323(21):1438-44.
Chronic neurologic manifestations of Lyme disease.
Logigian EL, Kaplan RF, Steere AC.
SourceDepartment of Neurology, Tufts University School of Medicine, Boston, MA 02111.
Abstract
BACKGROUND AND METHODS: Lyme disease, caused by the tick-borne spirochete Borrelia burgdorferi, is associated with a wide variety of neurologic manifestations. To define further the chronic neurologic abnormalities of Lyme disease, we studied 27 patients (age range, 25 to 72 years) with previous signs of Lyme disease, current evidence of immunity to B. burgdorferi, and chronic neurologic symptoms with no other identifiable cause. Eight of the patients had been followed prospectively for 8 to 12 years after the onset of infection.

RESULTS: Of the 27 patients, 24 (89 percent) had a mild encephalopathy that began 1 month to 14 years after the onset of the disease and was characterized by memory loss, mood changes, or sleep disturbance. Of the 24 patients, 14 had memory impairment on neuropsychological tests, and 18 had increased cerebrospinal fluid protein levels, evidence of intrathecal production of antibody to B. burgdorferi, or both. Nineteen of the 27 patients (70 percent) had polyneuropathy with radicular pain or distal paresthesias; all but two of these patients also had encephalopathy. In 16 patients electrophysiologic testing showed an axonal polyneuropathy. One patient had leukoencephalitis with asymmetric spastic diplegia, periventricular white-matter lesions, and intrathecal production of antibody to B. burgdorferi. Among the 27 patients, associated symptoms included fatigue (74 percent), headache (48 percent), arthritis (37 percent), and hearing loss (15 percent). At the time of examination, chronic neurologic abnormalities had been present from 3 months to 14 years, usually with little progression. Six months after a two-week course of intravenous ceftriaxone (2 g daily), 17 patients (63 percent) had improvement, 6 (22 percent) had improvement but then relapsed, and 4 (15 percent) had no change in their condition.

CONCLUSIONS: Months to years after the initial infection with B. burgdorferi, patients with Lyme disease may have chronic encephalopathy, polyneuropathy, or less commonly, leukoencephalitis. These chronic neurologic abnormalities usually improve with antibiotic therapy.

Comment in
N Engl J Med. 1991 Apr 18;324(16):1137.
PMID:2172819[PubMed - indexed for MEDLINE] Free full text

Scand J Infect Dis Suppl. 1991;77:74-80.
North American Lyme neuroborreliosis.
Halperin JJ.
SourceDepartment of Neurology, State University of New York, Stony Brook 11794.
Abstract
Clinical, neurophysiologic and laboratory findings obtained in American patients with nervous system Lyme borreliosis were compared to published observations in European neuroborreliosis patients. In both populations, Borrelia burgdorferi infection is commonly associated with neurologic abnormalities. European reports have emphasized dramatic clinical phenomena, such as painful radiculitis (Garin-Bujadoux-Bannwarth syndrome) and chronic progressive spastic paraparesis. North American patients seem to develop milder forms of nervous system involvement. Peripheral nervous system manifestations take a variety of forms, ranging from mild, intermittent sensory symptoms, to typical painful radiculitis. Despite the range of clinical presentations, neurophysiologic and morphologic analyses indicate these all represent different manifestations of the same pathophysiologic process, which, in turn, is similar to what has been described in Garin-Bujadoux-Bannwarth syndrome. Similarly, central nervous system (CNS) symptoms vary widely, ranging from a mild confusional state to a severe encephalitis. The encephalitis is probably due to direct CNS infection. In some instances the confusional state may also be due to CNS infection but it is likely that in many patients it is not. As in European patients, the most reliable indicator of CNS infection appears to be the intrathecal production of anti-B burgdorferi antibodies. Although North American Lyme borreliosis patients may often develop milder forms of nervous system involvement that their European counterparts, there is considerable overlap, and the underlying pathophysiologic mechanisms are probably identical.

PMID:1658921[PubMed - indexed for MEDLINE]

Scand J Infect Dis Suppl. 1991;77:64-73.
Neurological manifestations of Lyme borreliosis: clinical definition and differential diagnosis.
Kristoferitsch W.
SourceDepartment of Neurology, Wilhelminen-Spital der Stadt Wien, Vienna, Austria.

Abstract
Neurological manifestations occur in early disseminated Lyme Borreliosis and in the chronic late stage. Two of them, Bannwarth's syndrome and acrodermatitis chronica atraphicans-associated neuropathy, were known as well defined clinical entities many years prior to the detection of their causative agent. Soon after B. burgdorferi was identified and serologic tests became available, many reports were published which attributed to a large variety of different neurological disorders to Lyme borreliosis. In many cases the diagnosis was primarily based on serodiagnostic results. Yet some scepticism is indicated since 10-30% of the population in endemic areas have been found to be seropositive. While prior to 1983 and before the availability of serodiagnostic tests neurological manifestations of Lyme borreliosis were recognized by a minority of neurologists, they now seem to be overdiagnosed. Therefore clear diagnostic criteria have to be set up. They include the clinical picture, other preceding or concomitant diseases of the Lyme borreliosis complex, serodiagnostic results, cerebrospinal fluid findings, demonstration of intrathecal specific antibody synthesis, results of nerve biopsies, response to adequate antibiotic therapy and exclusion of other diseases. The significance of each of these criteria depends on the clinical involvement and on the stage of Lyme borreliosis.

PMID:1947814[PubMed - indexed for MEDLINE]

Arch Neurol. 1991 Nov;48(11):1125-9.
Cognitive functioning in late Lyme borreliosis.
Krupp LB, Masur D, Schwartz J, Coyle PK, Langenbach LJ, Fernquist SK, Jandorf L, Halperin JJ.
SourceDepartment of Neurology, State University of New York, Stony Brook 11794.
Abstract
Lyme borreliosis, a tick-borne multisystem disease, may cause a variety of neurologic complications, including meningoencephalitis and encephalopathy. To evaluate neurobehavioral function following treated Lyme borreliosis, 15 patients with Lyme disease and complaints of persistent cognitive difficulty a mean of 6.7 months following antibiotic treatment underwent neuropsychological evaluation and were compared with 10 healthy controls, matched in aggregate for age and education, who underwent the identical neuropsychological assessment.Compared with controls, patients with Lyme disease exhibited marked impairment on memory tests and particularly on selective reminding measures of memory retrieval. The memory impairment did not correlate with serum or cerebrospinal fluid anti-Borrelia burgdorferi antibody titers and was not explained by magnetic resonance imaging findings or depression. The cause of this encephalopathy is currently unknown; however, indirect effects of systemic infection or other toxic-metabolic factors may be partly responsible.

Comment in
Arch Neurol. 1992 Oct;49(10):1011.
PMID:1953395[PubMed - indexed for MEDLINE]

Ital J Neurol Sci. 1992 Dec;13(9 Suppl 14):85-90.
Neurological complications of Lyme borreliosis.
Meier C.
SourceDepartment of Neurology, University of Berne, Switzerland.
Abstract
Lyme disease, like syphilis, a spirochetal infection, can appear with exacerbations and remissions in different stages. The clinical picture is marked by dermatological, neurological, rheumatic and cardiological complications.PNS complications appear in the second and third stage. Tick bite meningoradiculoneuritis neuritis (Garin-Bujadoux-Bannwarth-Syndrome), characterized by painful asymmetrical sensory and motor dysfunctions and inflamed CSF, is a typical manifestation of the second stage. Mononeuritis multiplex appearing in conjunction with acrodermatitis chronica atrophicans is a typical PNS manifestation of the third stage. CNS involvement may also occur in early and late stages of Lyme-Borreliosis, presenting as myelitis or progressive encephalomyelitis. Lyme-Borreliosis is a treatable condition, which should not be missed in the differential diagnosis of PNS and CNS disorders.PMID:1345745[PubMed - indexed for MEDLINE]

Am J Phys Med Rehabil. 1996 Jul-Aug;75(4):314-6.
Lyme borreliosis neuropathy. A case report.
Deltombe T, Hanson P, Boutsen Y, Laloux P, Clerin M.
Source
Department of Physical Medicine and Rehabilitation, University Hospital of Mont-Godinne UCL, Yvoir, Belgium.

Abstract
Lyme borreliosis is responsible for a large variety of peripheral neurologic manifestations including axonal polyneuropathy, radiculopathy, and facial nerve palsy. The prevalence of the disease must draw our attention on the possible responsibility of Borrelia burgdorferi in the pathogenesis of such symptomatology. Electrophysiologic studies demonstrate a proximal and distal axonal involvement, whereas neuropathologic studies suggest that vasculitis might be one of the primary pathophysiologic mechanisms. Electromyography provides a useful diagnostic tool and an important measure of response to treatment. Although peripheral neuropathy usually improves, our case report confirms the fact that chronic neurologic manifestations may not consistently resolve with appropriate treatment.

PMID:8777029[PubMed - indexed for MEDLINE]

Semin Neurol. 1997 Mar;17(1):25-30.
Peripheral nervous system Lyme borreliosis.
Logigian EL.
SourceHarvard Medical School, Clinical Neurophysiology Laboratory, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Abstract
There are acute and chronic Lyme neuropathies. The seasonal acute syndromes of cranial neuritis or radiculoneuritis are generally quite distinctive, but may cause diagnostic difficulty when one syndrome occurs without the other, when erythema migrans is absent or missed, and when meningeal signs are minimal or absent. The chronic Lyme radiculoneuropathies are less severe, and less distinctive. Their recognition depends on eliciting a history of earlier classical manifestations of Lyme disease and by laboratory testing. In both acute and chronic Lyme radiculoneuropathy, electrophysiologic testing often proves the presence of a sensorimotor, axon loss polyradiculoneuropathy. Both acute and chronic Lyme radiculoneuropathy have similar pathologic features and can be classified as a nonvasculitic mononeuritis multiplex. The pathogenesis is uncertain; both direct infection as well as parainfectious mechanisms may play a role. The treatment with which we have the most experience is intravenous ceftriaxone 2 g/day for 2 to 4 weeks. Improvement occurs rapidly over days to weeks in early Lyme neuroborreliosis, but slowly over many months in chronic neuroborreliosis.

PMID:9166956[PubMed - indexed for MEDLINE]

Here is one of the webpages that prompted my search for peer-reviewed, published articles:

http://peripheralneuropathycenter.uchic ... ease.shtml


Types of Peripheral Neuropathy – Inflammatory

Lyme Disease

Lyme disease is an inflammatory disease that rapidly progresses. Transmitted by the bite of an infected deer tick, Lyme disease is most common in the Northeast section of the United States. However, the disease has also appeared in the upper East coast, in the upper Midwest, and along the coasts of northern California and Oregon.

Signs of Lyme disease include skin rash and painful inflammation of joints (particularly the knees), accompanied by flu-like symptoms. The symptoms of Lyme disease increase in severity as the disease spreads though the body.

Early diagnosis and treatment are important to stop the progression of the disease. If untreated, the disease can result in neurological disorders such as peripheral neuropathy, including Bell's palsy, as well as pain, numbness or weakness in the limbs. The onset of peripheral neuropathy typically develops weeks, months or years later, if the disease is left untreated.

While potentially serious, Lyme disease can be treated, especially in the early stages. It is important to take preventive measures when outdoors in areas known to have infected deer ticks. Some helpful steps include: wearing enclosed shoes and light colored clothing; checking clothing and exposed skin frequently for ticks; and using insect repellant containing DEET (Diethyl-meta-toluamide) on skin or clothes.

SYMPTOMS

(Not all symptoms and signs may be present.)

Lyme disease progresses in three stages of severity:

First Stage:

Fatigue
Fever and chills
Muscle and joint pain
Red circular rash
Stiff neck
Swollen lymph nodes

Second Stage:

Facial paralysis (Bell's palsy)
Irregular heartbeat
Meningitis (fever, stiff neck, severe headaches)
Numbness and pain in arms and legs
Stiff neck
Poor coordination

Third Stage:

Chronic arthritis and swelling in large joints, especially the knees
Chronic pain in muscles
Problems with sleeping
Numbness and pain in arms and legs
Nervous system problems
Difficulty concentrating
Memory loss
Numbness and tingling
Peripheral neuropathy
Pain, numbness and tingling in limbs
Paralysis of facial muscles (Bell's palsy)

EVALUATION AND TESTS
(Not all evaluation and tests may be necessary.)

Neurological exam
Electromyography
Nerve conduction velocity test
Blood tests, including tests for antibody against the agent that causes Lyme disease and tests to detect the agent itself.

TREATMENT AND THERAPY
(Not all treatments and therapies may be indicated.)

Antibiotics
Intravenous therapy
[snip]

Lyme disease is curable, if treated early

And here is the other website that contains more detailed information about peripheral neuropathy in general, as well as what research is currently underway:

(I snipped out the parts having to do with HIV/AIDS, diabetes, cancer, etc)

http://www.ninds.nih.gov/disorders/peri ... opathy.htm


What is peripheral neuropathy?

Peripheral neuropathy describes damage to the peripheral nervous system, the vast communications network that transmits information from the brain and spinal cord (the central nervous system) to every other part of the body. Peripheral nerves also send sensory information back to the brain and spinal cord, such as a message that the feet are cold or a finger is burned. Damage to the peripheral nervous system interferes with these vital connections. Like static on a telephone line, peripheral neuropathy distorts and sometimes interrupts messages between the brain and the rest of the body.

Because every peripheral nerve has a highly specialized function in a specific part of the body, a wide array of symptoms can occur when nerves are damaged. Some people may experience temporary numbness, tingling, and pricking sensations (paresthesia), sensitivity to touch, or muscle weakness. Others may suffer more extreme symptoms, including burning pain (especially at night), muscle wasting, paralysis, or organ or gland dysfunction. People may become unable to digest food easily, maintain safe levels of blood pressure, sweat normally, or experience normal sexual function. In the most extreme cases, breathing may become difficult or organ failure may occur.

Some forms of neuropathy involve damage to only one nerve and are called mononeuropathies. More often though, multiple nerves affecting all limbs are affected-called polyneuropathy. Occasionally, two or more isolated nerves in separate areas of the body are affected-called mononeuritis multiplex.

In acute neuropathies, such as Guillain-Barré syndrome, symptoms appear suddenly, progress rapidly, and resolve slowly as damaged nerves heal. In chronic forms, symptoms begin subtly and progress slowly. Some people may have periods of relief followed by relapse. Others may reach a plateau stage where symptoms stay the same for many months or years. Some chronic neuropathies worsen over time, but very few forms prove fatal unless complicated by other diseases. Occasionally the neuropathy is a symptom of another disorder.

How are the peripheral neuropathies classified?

More than 100 types of peripheral neuropathy have been identified, each with its own characteristic set of symptoms, pattern of development, and prognosis. Impaired function and symptoms depend on the type of nerves-motor, sensory, or autonomic-that are damaged. Motor nerves control movements of all muscles under conscious control, such as those used for walking, grasping things, or talking. Sensory nerves transmit information about sensory experiences, such as the feeling of a light touch or the pain resulting from a cut. Autonomic nerves regulate biological activities that people do not control consciously, such as breathing, digesting food, and heart and gland functions. Although some neuropathies may affect all three types of nerves, others primarily affect one or two types. Therefore, doctors may use terms such as predominantly motor neuropathy, predominantly sensory neuropathy, sensory-motor neuropathy, or autonomic neuropathy to describe a patient's condition.

What are the symptoms of peripheral nerve damage?

Symptoms are related to the type of affected nerve and may be seen over a period of days, weeks, or years.Muscle weakness is the most common symptom of motor nerve damage. Other symptoms may include painful cramps and fasciculations (uncontrolled muscle twitching visible under the skin), muscle loss, bone degeneration, and changes in the skin, hair, and nails. These more general degenerative changes also can result from sensory or autonomic nerve fiber loss.

Sensory nerve damage causes a more complex range of symptoms because sensory nerves have a wider, more highly specialized range of functions. Larger sensory fibers enclosed in myelin (a fatty protein that coats and insulates many nerves) register vibration, light touch, and position sense. Damage to large sensory fibers lessens the ability to feel vibrations and touch, resulting in a general sense of numbness, especially in the hands and feet. People may feel as if they are wearing gloves and stockings even when they are not. Many patients cannot recognize by touch alone the shapes of small objects or distinguish between different shapes. This damage to sensory fibers may contribute to the loss of reflexes (as can motor nerve damage). Loss of position sense often makes people unable to coordinate complex movements like walking or fastening buttons, or to maintain their balance when their eyes are shut. Neuropathic pain is difficult to control and can seriously affect emotional well-being and overall quality of life. Neuropathic pain is often worse at night, seriously disrupting sleep and adding to the emotional burden of sensory nerve damage.

Smaller sensory fibers without myelin sheaths transmit pain and temperature sensations. Damage to these fibers can interfere with the ability to feel pain or changes in temperature. People may fail to sense that they have been injured from a cut or that a wound is becoming infected. Others may not detect pains that warn of impending heart attack or other acute conditions. (Loss of pain sensation is a particularly serious problem for people with diabetes, contributing to the high rate of lower limb amputations among this population.) Pain receptors in the skin can also become oversensitized, so that people may feel severe pain (allodynia) from stimuli that are normally painless (for example, some may experience pain from bed sheets draped lightly over the body).

Symptoms of autonomic nerve damage are diverse and depend upon which organs or glands are affected. Autonomic nerve dysfunction can become life threatening and may require emergency medical care in cases when breathing becomes impaired or when the heart begins beating irregularly. Common symptoms of autonomic nerve damage include an inability to sweat normally, which may lead to heat intolerance; a loss of bladder control, which may cause infection or incontinence; and an inability to control muscles that expand or contract blood vessels to maintain safe blood pressure levels. A loss of control over blood pressure can cause dizziness, lightheadedness, or even fainting when a person moves suddenly from a seated to a standing position (a condition known as postural or orthostatic hypotension).

Gastrointestinal symptoms frequently accompany autonomic neuropathy. Nerves controlling intestinal muscle contractions often malfunction, leading to diarrhea, constipation, or incontinence. Many people also have problems eating or swallowing if certain autonomic nerves are affected.

What causes peripheral neuropathy?

Peripheral neuropathy may be either inherited or acquired. Causes of acquired peripheral neuropathy include physical injury (trauma) to a nerve, tumors, toxins, autoimmune responses, nutritional deficiencies, alcoholism, and vascular and metabolic disorders. Acquired peripheral neuropathies are grouped into three broad categories: those caused by systemic disease, those caused by trauma from external agents, and those caused by infections or autoimmune disorders affecting nerve tissue. One example of an acquired peripheral neuropathy is trigeminal neuralgia (also known as tic douloureux), in which damage to the trigeminal nerve (the large nerve of the head and face) causes episodic attacks of excruciating, lightning-like pain on one side of the face. In some cases, the cause is an earlier viral infection, pressure on the nerve from a tumor or swollen blood vessel, or, infrequently, multiple sclerosis. In many cases, however, a specific cause cannot be identified. Doctors usually refer to neuropathies with no known cause as idiopathic neuropathies.

Toxins can also cause peripheral nerve damage. People who are exposed to heavy metals (arsenic, lead, mercury, thallium), industrial drugs, or environmental toxins frequently develop neuropathy. Certain anticancer drugs, anticonvulsants, antiviral agents, and antibiotics have side effects that can include peripheral nerve damage, thus limiting their long-term use.

Infections and autoimmune disorders can cause peripheral neuropathy. Viruses and bacteria that can attack nerve tissues include herpes varicella-zoster (shingles), Epstein-Barr virus, cytomegalovirus, and herpes simplex-members of the large family of human herpes viruses. These viruses severely damage sensory nerves, causing attacks of sharp, lightning-like pain. Postherpetic neuralgia often occurs after an attack of shingles and can be particularly painful.

[snip]

Lyme disease, diphtheria, and leprosy are bacterial diseases characterized by extensive peripheral nerve damage.Diphtheria and leprosy are now rare in the United States, but Lyme disease is on the rise. It can cause a wide range of neuropathic disorders, including a rapidly developing, painful polyneuropathy, often within a few weeks after initial infection by a tick bite.

Viral and bacterial infections can also cause indirect nerve damage by provoking conditions referred to as autoimmune disorders, in which specialized cells and antibodies of the immune system attack the body's own tissues. These attacks typically cause destruction of the nerve's myelin sheath or axon (the long fiber that extends out from the main nerve cell body).

Some neuropathies are caused by inflammation resulting from immune system activities rather than from direct damage by infectious organisms. Inflammatory neuropathies can develop quickly or slowly, and chronic forms can exhibit a pattern of alternating remission and relapse. Acute inflammatory demyelinating neuropathy, better known as Guillain-Barré syndrome, can damage motor, sensory, and autonomic nerve fibers. Most people recover from this syndrome although severe cases can be life threatening. Chronic inflammatory demyelinating polyneuropathy (CIDP), generally less dangerous, usually damages sensory and motor nerves, leaving autonomic nerves intact. Multifocal motor neuropathy is a form of inflammatory neuropathy that affects motor nerves exclusively; it may be chronic or acute.

How is peripheral neuropathy diagnosed?

Diagnosing peripheral neuropathy is often difficult because the symptoms are highly variable. A thorough neurological examination is usually required and involves taking an extensive patient history (including the patient’s symptoms, work environment, social habits, exposure to any toxins, history of alcoholism, risk of HIV or other infectious disease, and family history of neurological disease), performing tests that may identify the cause of the neuropathic disorder, and conducting tests to determine the extent and type of nerve damage.

A general physical examination and related tests may reveal the presence of a systemic disease causing nerve damage. Blood tests can detect diabetes, vitamin deficiencies, liver or kidney dysfunction, other metabolic disorders, and signs of abnormal immune system activity. An examination of cerebrospinal fluid that surrounds the brain and spinal cord can reveal abnormal antibodies associated with neuropathy. More specialized tests may reveal other blood or cardiovascular diseases, connective tissue disorders, or malignancies. Tests of muscle strength, as well as evidence of cramps or fasciculations, indicate motor fiber involvement. Evaluation of a patient’s ability to register vibration, light touch, body position, temperature, and pain reveals sensory nerve damage and may indicate whether small or large sensory nerve fibers are affected.

Based on the results of the neurological exam, physical exam, patient history, and any previous screening or testing, additional testing may be ordered to help determine the nature and extent of the neuropathy.

What treatments are available?

No medical treatments now exist that can cure inherited peripheral neuropathy. However, there are therapies for many other forms. Any underlying condition is treated first, followed by symptomatic treatment. Peripheral nerves have the ability to regenerate, as long as the nerve cell itself has not been killed. Symptoms often can be controlled, and eliminating the causes of specific forms of neuropathy often can prevent new damage.

Neuropathic pain is often difficult to control. Mild pain may sometimes be alleviated by analgesics sold over the counter. Several classes of drugs have recently proved helpful to many patients suffering from more severe forms of chronic neuropathic pain. These include mexiletine, a drug developed to correct irregular heart rhythms (sometimes associated with severe side effects); several antiepileptic drugs, including gabapentin, phenytoin, and carbamazepine; and some classes of antidepressants, including tricyclics such as amitriptyline. Injections of local anesthetics such as lidocaine or topical patches containing lidocaine may relieve more intractable pain. In the most severe cases, doctors can surgically destroy nerves; however, the results are often temporary and the procedure can lead to complications.

What research is being done?

The National Institute of Neurological Disorders and Stroke (NINDS), a component of the Federal government's National Institutes of Health (NIH) within the U.S. Department of Health and Human Services, has primary responsibility for research on peripheral neuropathy. Current research projects funded by the NINDS involve investigations of genetic factors associated with hereditary neuropathies, studies of biological mechanisms involved in diabetes-associated neuropathies, efforts to gain greater understanding of how the immune system contributes to peripheral nerve damage, and efforts to develop new therapies for neuropathic symptoms.

Scientists have found that the destructive effects of abnormal immune system activity cause many neuropathies for which a cause could not previously be identified. However, the exact biological mechanisms that lead to this nerve damage are not yet well understood. Many NINDS-sponsored studies are studying inflammatory neuropathies, both in research animals and in humans, to clarify these mechanisms so that therapeutic interventions can be developed.

Neuropathic pain is a primary target of NINDS-sponsored studies aimed at developing more effective therapies for symptoms of peripheral neuropathy. Some scientists hope to identify substances that will block the brain chemicals that generate pain signals, while others are investigating the pathways by which pain signals reach the brain.

Studies of neurotrophic factors represent one of the most promising areas of research aimed at finding new, more effective treatments for peripheral neuropathies. These substances, produced naturally by the body, protect neurons from injury and encourage their survival. Neurotrophic factors also help maintain normal function in mature nerve cells, and some stimulate axon regeneration. Several NINDS-sponsored studies seek to learn more about the effects of these powerful chemicals on the peripheral nervous system and may eventually lead to treatments that can reverse nerve damage and cure peripheral nerve disorders.

So as not to raise false hope, here is a link to a Science-Based Medicine article by Dr. Steven Novella on November 9, 2011:

http://www.sciencebasedmedicine.org/ind ... c-factors/

Scientific medicine is not easy. By this point we have largely picked the low hanging fruit, and continued improvements are mostly incremental and hard won. In order to get the most out of our limited research dollars, and optimize medical practice with the safest and most effective treatments, we need to use all available scientific evidence in the proper way. That is the essence of SBM.

There are those, however, that misuse or abuse the scientific evidence — whether to promote an ideology, out of innocent ignorance, or for nefarious purposes. In order to be truly science-based a medical intervention should be plausible, or at least not implausible, based upon basic science evidence, and it should actually be safe and effective when tested in people. Therefore, medical practices can fail to be scientific for one of two broad reasons: they can be scientifically implausible, or they can lack proper clinical evidence for safety and efficacy (or even have evidence for lack of efficacy). Some modalities (like homeopathy) fail on both counts.

The more pernicious medical claims are those that seem highly plausible, that can be extrapolated from basic science, but simply lack adequate clinical evidence. Stem cell clinics are an example — they can easily dazzle desperate patients with scientific descriptions of how stem cells work, and even cite published basic-science papers showing the potential of this technology. But what they cannot do is provide clinical evidence that the specific intervention they are offering is safe and effective for the specific disease or condition they are treating.

[snip]

Neurotrophic factors are generally proteins that bind to cells and cause them to grow, proliferate, or just maintain their functionality. Some nervous system cells would die without a steady supply of the needed neurotrophic factors. The discovery of neurotrophic factors and their role in nervous system function was certainly very important to our understanding of neurological diseases. This knowledge has also led to a great deal of speculation about the potential of neurotrophic factors in treating neurological diseases.

After a couple decades of clinical research, however, the reality has not lived up to the promise. As is often the case, highly plausible ideas do not pan out in clinical research. Several neurotrophic factors, for example have been studied in diseases like ALS without any measurable clinical benefit. They are just another reminder that the body is complex, and even when we have a very compelling picture of why a treatment should work, that picture is almost certainly incomplete. We cannot know what the net effect will be of a treatment until we do rigorous clinical trials.

Another way to look at this is that the body has evolved complex mechanisms of self-regulation. It is not easy to push or pull on one piece of this complex system and predict the net effect. There are many reasons why a treatment that we predict should work, doesn’t.

[snip]

Conclusion

The public needs to be aware of the types of misleading claims that are made by clinics, centers, and marketers of health products that can seem very scientific when they are not. The use of pre-clinical evidence to make clinical claims, the use of research methods for clinical diagnosis, and the use of supplements without any consideration of bioavailability are chief among them. Patients and their families are cautioned to be skeptical of any clinic or center that claims to offer a unique service. Further, any clinical claims being made should be backed by well-designed clinical trials of the specific claims published in respected peer-reviewed journals.

Anything less than this is likely to be selling false hope, not a legitimate treatment.

http://www.lymeneteurope.org/forum/viewtopic.php?f=5&t=3629

SYSTEM REVEALS HOW OUR BRAINS BODIES CHANGE AS WE FALL ASLEEP

Massachusetts General Hospital (MGH) investigators have developed a system to accurately track the dynamic process of falling asleep, something has not been possible with existing techniques. In their report in the October issue of the open-access journal PLOS Computational Biology, the research team describes how combining key physiologic measurements with a behavioral task that does not interfere with sleep onset gives a better picture of the gradual process of falling asleep. In addition to being a powerful tool for future research, the system could provide valuable insight into diagnosing and understanding sleep disorders.

"While our personal experience tells us that falling asleep is a gradual process, current clinical methods only define a single point in time at which one has fallen asleep," says Michael Prerau, PhD, of the MGH Department of Anesthesia, Critical Care and Pain Management, lead author of the report. "Our new research shows that it's not simply when you fall asleep that's important, it's how you fall asleep that really matters. We now have the power to chart the entire trajectory of your neurological, physiological and behavioral activity as you transition from wake to asleep, rather than simply reporting the time it takes."

In their report, the investigators describe developing a method that continuously estimates the degree to which an individual is awake at each point during the sleep onset process. "This is a real paradigm shift in the way we study sleep onset," says Patrick Purdon, PhD, MGH Department of Anesthesia, Critical Care and Pain Management and senior author of the study. "By quantifying the dynamic changes in brain activity and behavior during the transition from wakefulness to sleep, we now have a rigorous framework with which to study disorders of sleep onset, such as insomnia or narcolepsy."

To link changes in brain activity to loss of consciousness during sleep onset, the investigators developed a new, minimally disruptive means of tracking behavior as someone falls asleep. Earlier methods either used tasks in which a participant was asked to respond to auditory cues, something that could disrupt falling asleep, or actigraphy -- the method of measuring movement used in most clinical sleep devices and consumer wearables, which cannot distinguish between sleep and motionless wakefulness. To get around these problems the investigators developed an ingenious new behavioral task that is accurate without disturbing sleep.

Instead of responding to a sound, a participant holds a small rubber "stress ball" in one hand and is asked to squeeze the ball with every intake of breath and release it when exhaling. A special glove on that hand and electrodes on the forearm measure both the timing and the force of each squeeze. In this way, the participant's own breathing acts as the stimulus, and the squeezes act as the behavioral response. Tracking how well ball squeezes are aligned with an individual's breathing reflects a gradual process during which more and more squeezes are mistimed or totally absent. Measuring the force exerted by the forearm muscle also reflects how the strength of the squeezing motion drops with sleep onset.

At the same time as the ball-squeeze measurements are taken, EEG readings track three brain wave patterns previously associated with falling asleep, decreasing power in the alpha frequency range and increasing power in delta and theta frequencies. The combination of all of these measures -- the timing and strength of ball squeezes and the change in brain wave levels -- is used to calculate what the investigators call the wake probability, an estimate of the degree to which a participant is awake during the process of sleep onset.

Testing their model in healthy volunteers over several nights not only provided more accurate results than did traditional methods of sleep determination, it also revealed differences in the way sleep onset occurs in different individuals. Current clinical criteria define sleep as beginning when the power of an individual's alpha-range brainwaves disappears. While seven of the nine study participants followed this pattern, two participants continued to correctly time their ball squeezes for several minutes after alpha levels had dropped. Only when the power in their brainwaves at the theta and delta frequencies had risen did both the behavioral and physiological measures indicate that they were asleep.

"These participants continued to respond to the task, even though current clinical measures would say they were still asleep, which was clearly not the case," says Prerau. "These results suggest that it is the presence of delta and theta power, rather than the lack of alpha power, that is necessary for the cessation of behavior. We may need to carefully re-examine the way sleep onset is defined, since behavior is an essential component of the story that is not measured clinically."

By characterizing the trajectory of the sleep onset process in healthy individuals, Prerau and Purdon believe this study will ultimately shed light on what happens in patients who have trouble falling asleep, leading to an improved ability to understand and diagnose sleep disorders as well as to more precisely measure the effect of sleep medications. This method could also be used to track drowsiness in situations in which alertness is vital.