User talk:The Call of Cthulhu/sandbox 2

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Stiff person syndrome (SPS) is a rare neurologic disorder of unclear etiology characterized by progressive rigidity and stiffness. The stiffness primarily affects the truncal muslcles and is superimposed by spasms, resulting in postural deformities. Chronic pain, impaired mobility, and hyperlordosis are common symptoms. Spasms can be violent and unpredictable, sometimes breaking bones and often leave sufferers afraid to leave the home. Patients become very sensitive to touch and sound, which can sometimes trigger spasms. The exact mechanism of the condition is unclear. It has been established that SPS patients generally have anti-glutamic acid decarboxylase antibodies, which seldom occur in the general population. The antibodies are often thought to be the cause of the condition.

SPS is difficult to diagnose because there is no specific laboratory test that confirms its presence. CSF and EMG tests can help confirm the condition's presence by finding antibodies against GAD and involuntary motor unit firing. Early recognition and treatment slow the disease's progression, but a majority of patients eventually are unable to function independently. Benzodiazepine-class drugs are the most common treatment; they are used for symptom relief from stiffness. Other common treatments include Baclofen and Intravenous immunoglobin. SPS occurs in about one in a million people and is most commonly found in middle-aged people. A small minority have the paraneoplastic variety of the condition. Another variant of the condition, stiff-limb syndrome, primarily affects a specific limb. The condition was first described in 1956. Diagnostic criteria were proposed in the 1960s and refined two decades later. In the 1990s and 2000s the roles of antibodies in the condition became more clear.

Cause
Patients with SPS generally have high amounts of high anti-glutamic acid decarboxylase antibody titers. About 80 percent of SPS patients have anti-GAD antibodies, compared with about one percent of the general population. GAD, a presynaptic autoantigen, is generally thought to play a key role in the condition, but exact details of the way that autoantibodies affect SPS patients are not known. Most SPS patients with high-titer GAD antibodies also have antibodies that inhibit GABA-receptor-associated protein. Amphiphysin and gephyrin also sometimes occur in SPS patients. The antibodies appear to interact with antigens in the brain neurons and the spinal cord synapses, causing a functional blockade with gamma-aminobutyric acid. This leads to GABA impairment, which probably causes the stiffness and spasms that characterizes SPS. There are low GABA levels in the motor cortexes of SPS patients.

It is not known why GAD autoimmunity occurs in SPS patients. It is also unknown whether these antibodies are pathogenic. The amount of GAD antibody titers found in SPS patients does not correlate with disease severity, thus titre levels need not be monitored. It has not been proven that anti-GAD antibodies are sole cause of SPS, and the possibility exists that they are a marker or an epiphenomenon of the cause of the condition.

In SPS patients, motor unit neurons fire involuntarily in a way that resembles a normal contraction. Motor unit potentials fire while the patient is at rest, particularly in the stiff muscles. The excessive firing of motor neurons may be cause by malfunctions in spinal and supra-segmental inhibitory networks that utilize GABA. Involuntary actions show up as voluntary on EMG scans; even when the patient tries to relax, there are agonist and antagonist contractions.

In a minority of patients with SPS, breast, ovarian, or lung cancer manifests paraneoplasticly as proximal muscle stiffness. These cancers are associated with the synaptic proteins amphiphysin and gephyrin. Paraneoplastic SPS with anti-amphiphysin antibodies and breast adenocarcinoma tend to occur together. These patients tend not to have anti-GAD antibodies. Passive transfer of the disease by plasma injection has been shown in paraneoplastic SPS but not classical SPS.

There is evidence of genetic risk of SPS. The HLA class II locus makes patients susceptible to the condition. Most SPS patients have the the DQB1* 0201 allele. This allele is also associated with type 1 diabetes. - It may work by impairing endocytosis. In these cases, some evidence suggests that the anti-amphiphysin antibodies maybe be pathogenic. Anti-amphiphysin can be found in the spinal cords of SPS patients.

Neonates of SPS mothers do not necessarily develop the disease, even when they have high anti-GAD antibodies.

SPS is caused by synaptic proteins that inhibit synaptic transmission. GAD is a cytoplasmic enzyme that synthesizes GABA, a neurotransmitter, in the brain and spinal cord. GAD65, not GAD67, is targeted by GAD antibodies in SPS. The two GAD isoforms are encoded by separate genes. GAD65 occurs in synaptic vesicles and occurs as apoenzyme. It plays a key role in GABA release. Amphiphysin is also a presynaptic autoantigen and often play a role, as do the postsynaptic autoantigens GABARAP and gephyrin. These form a pharmacological blockade of autoantigens. They probably do not change the structure of GABAergic neurons. Amphiphysin contains proline and is a hydrophilic protein that occurs in the CNS. It often occurs in anti-GAD negative patients. GABARAP and gephyrin play a role in the synthesis of GABAA receptors. A GABAergic deficit can be found in vivo using brain imaging. It is a subject of discussion whether impaired GABAergic transmission is a result of a reduction is presyaptic transmitter synthesis, destruction of inhibitory interneurons, or a reduction in postsynaptic receptors.

These are synthesized intrathecally and occur in the periphreal blood and CNS CSF. They react with GAD65 and GAD67, and they inhibit GAD enzymes. It must be confirmed with animal studies. Animal studies have confirmed that anti-GAD antibodies do inhibit GABAergic transmission. The autoantibodies may undermine the central nervous system. They disrupt GABA production in vitro. Experiments show that the inhibitory synapse of the spinal cord neurons are affected. MRI shows that the antibodies cause synapse dysfunction rather than total destruction. GAD antibodies are detected clinically by RIA or ELISA. GABARAP plays a role in endocytosis. Seventy percent of patients with anti-GAD65 also have GABARAP. It is not known which aspects of dysfunction are caused by either of these. The autoimmune response may initially develop in the periphery, before affecting the CNS, or it may develop in the CNS itself. The autoimmune response seems to be humorally mediated. The disease appears to be B-cell dependent.

Failure of reciprocal inhibition of agonist and antagonist muscles also occurs and can help diagnose the disease.

Startle responses are inhibited and stimulation of cutaneous nerves can cause electromyography (EMG) responses in distant limbs.

Insulin-dependant diabetes mellitus is often associated with SPS. About half of SPS diabetes sufferers developed it after SPS. GAD is a major antigen in IDDM, but IDDM patients generally have 50 to 100 fold less titers of anti-GAD antibodies than SPS patients. The overwhelming majority of patients with diabetes and anti-GAD antibodies do not contract SPS, indicating that systematic synthesis of the antibody does not alone cause SPS. It is very difficult to distinguish SPS from other neurological syndromes associated with anti-GAD antibodies or IDDM because there is no clear electrophysiological tests. The epitope specificity of GAD65 is in SPS patients is different from that of people with diabetes who do not have SPS. Other autoantibodies can be observed in a variety of organs and clinical presentations. Anti-nuclear, anti-thyroid, anti RNP, anti-gliadin, and anti-intrinsic factor antibodies have also been found in SPS patients. Autopsies of SPS patients generally show no inflammation and typical neuronal numbers. Some have shown neuron loss though. They do indicate that T-cells may cause some tissue damage in some SPS patients though. Some SPS patients do have anti-GAD reactive T-Cells.

Deficient GABAergic inhibition plays a role in the mechanism of the condition. Glycenergic inhibition also occurs in the spine, but the Renshaw inhibition does not. Nerve block, anesthesia, and sleep decrease motor unit firing, indicating that there is a central origin to the firing. Neuropsychological aspects of the disease may be caused by conditioned response and dysregulation of the hippocampus. Decreases in GABA may lead to increased phobias, though fears are often realistic. The condition appears to be similar to myasthenia gravis in that the immune system targets specific organs. Dysregulation of the amygdala and hippocampus may cause fears and phobias in SPS patients.

Cross-reactive binding of antibodies may occur, thus disrupting GABAergic neurons. The possibility that SPS could be mediated by T-cells has also been raised. Whether SPS qualifies as a neuro-autoimmune disorder has also been questioned.

Autoimmune diseases, including thyroiditis, Graves' disease, pernicious anemia, and vitiligo are found in about 5 to 10 percent of patients with SPS. About ten percent have ataxia or epilepsy.