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Autoimmune Dysautonomia Evaluation

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Published: February 2011

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Dr. McKeon reviews the diagnostic testing algorithm for autoimmune dysautonomia, define the clinical aspects, and describe interpretation of laboratory testing.

Presenter: Andrew McKeon, MB, BCh, MD

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Introduction

Welcome to Mayo Medical Laboratories' Hot Topics. These presentations provide short discussions of current topics and may be helpful to you in your practice.

Our presenter for this program is Andrew McKeon, MB BCh (N-AI), consultant in the Neuroimmunology Laboratory in the Division of Clinical Biochemistry and Immunology, Department of Laboratory Medicine and Pathology at Mayo Clinic in Rochester, Minnesota. Dr. McKeon will review the diagnostic testing algorithm for autoimmune dysautonomia, define the clinical aspects, and describe interpretation of laboratory testing.

New Profile

Today I am going to discuss a new antibody profile called "the autoimmune dysautonomia profile."

Autoimmune Dysautonomia

Autoimmune dysautonomia can target peripheral synapses, ganglionic neurons, autonomic nerve fibers or central autonomic pathways. This autoimmune disorder can be mediated by neuron specific IgG or effector T-cells. The disorder may be idiopathic or may be paraneoplastic, meaning that the disorder occurs in the context of an immune response to a systemic cancer.

When taking the history from a patient with autoimmune dysautonomia diagnostic clues may arise in the history, including a personal or family history of autoimmunity or cancer. One of the key reasons why diagnosing a paraneoplastic autoimmune dysautonomia is important is that when a cancer is detected in this setting it is usually a limited stage and is more easily treatable, thereby lessening morbidity from the cancer. Another reason for early detection of these disorders is that many of these patients improve considerably with immunotherapy or oncological therapies for a related cancer when the diagnosis is made early.

Autoimmune dysautonomia may present as a pandysautonomia meaning that multiple components of the autonomic nervous system are affected or may present with a limited dysautonomia where the disorder is restricted to one or two areas only. Oncological associations of autoimmune dysautonomias include small cell carcinoma, thymoma and other neoplasms. Over 60% of the patients improve with immunotherapy.

Pandysautonomia

Pandysautonomia usually occurs subacutely in onset in an autoimmune context and is usually severe and affects multiple systems. Symptoms and signs include an impaired papillary light reflex, loss of sweating, orthostatic hypotension leading to dizziness and syncope on standing up or sitting up, cardiac arrhythmias may occur, gastrointestinal dysmotility such as early satiety and vomiting, small bowel pseudo-obstruction and severe constipation may occur. The patients may also complain of dry eyes and dry mouth known as "sicca symptoms." Patients may develop bladder dysfunction.

Limited Dysautonomia

With limited dysautonomia the symptoms are confined to one or just a few of the domains mentioned in the last slide. These symptoms are often milder and may include sicca manifestations, postural orthostatism, cardiac arrhythmias, bladder dysfunction, or gastrointestinal dysmotility.

Objective Testing

The diagnosis of autoimmune dysautonomia may be aided by documenting objective abnormality on autonomic testing. Autonomic laboratory testing includes tilt table testing and testing of sweating through sudomotor responses and thermoregulatory sweat testing. Other studies which may be helpful include gastrointestinal motility studies and urodynamics.

Thermoregulatory Sweat Testing

By way of example, to illustrate some of the abnormalities that can be found in dysautonomia, I have some pictures from sweat testing. These images represent the degree of sweat loss in individual patients. A powder that changes color with sweating is applied all over the body, but spares the face. If the patient sweats normally the indicator powder changes to a purple color. The far left panel you can see has normal sweating throughout. The patient in the middle has evidence of more patchy hypohidrosis, particularly in the lower extremities whereas the patient on the far right side of the screen has widespread sweat loss or hypohidrosis affecting nearly the whole body. This is just to illustrate the varying degrees of dysautonomia that can be seen with these disorders.

Antibody Testing

Once a diagnosis of dysautonomia has been established and if an autoimmune cause is suspected then antibody testing can be further helpful. These neuron specific antibodies are markers of idiopathic or paraneoplastic dysautonomia. Multiple antibodies commonly coexist. A specific neoplasm may be predicted by the antibody profile. For example, a patient with ANNA-1 and anticalcium channel antibody this profile would predict small cell carcinoma.

Ganglionic Acetylcholine Receptor (AChR) Autoantibody

I will now talk in a little bit more detail about the ganglionic acetylcholine receptor autoantibody as this is the most commonly encountered antibody marker of autoimmune dysautonomia. The antibody value generally correlates with the disease severity also.

Antibody values greater than 1.0 nanomoles per liter are usually associated with profound dysautonomia and widespread dysautonomia. Values of 0.03 to 0.99 nanomoles per liter are often associated with more limited disorders. Cancer is detected in 30% of seropositive patients. These cancers can include adenocarcinomas, small cell lung carcinoma, thymoma or lymphoma.

Autoimmune Dysautonomia Antibody Profile

The autoimmune dysautonomia antibody profile consists of three classes of antibodies that aid the diagnosis. Firstly, there are the neuronal nuclear antibodies such as ANNA-1, also known as anti-hu antibody, which is associated with small cell carcinoma. Then there is the neuronal and muscle cytoplasmic antibody such as CRMP-5 IgG, GAD-65 antibody and striational antibody, and finally the third class is cation channel antibody such as the ganglionic alpha-3 neuronal acetylcholine receptor antibody that I have just discussed. The muscle acetylcholine receptor antibody, N and P/Q type calcium channel antibodies and voltage-gated potassium channel autoantibodies.

Autoimmune Dysautonomia Evaluation Testing Algorithm

The autoimmune dysautonomia testing evaluation algorithm is documented and discussed on this slide. Starting from the top, there is some testing that is always performed and these antibodies are listed and these are the ANNA-1 antibody, striational antibody, anticalcium channel antibody, acetylcholine receptor muscle binding antibody, acetylcholine receptor ganglionic neuronal antibody, neuronal voltage-gated potassium channel antibody, PQ-type calcium channel antibody, and GAD-65 antibody.

After this there may be no further testing to be performed. However, there are four situations in which additional testing may be done and these are illustrated at the bottom of the screen. I will discuss these from left to right. The first is the immunofluorescence pattern is indeterminate. In this situation there may be an antibody staining pattern suspicious for antineuronal nuclear antibody type-1, but not all of the characteristic features are present. In that setting additionally a paraneoplastic Western blot is performed to look for the characteristic Western blot pattern associated with this antibody.

The second setting and the third setting would occur where an antibody pattern suggestive of amphiphysin antibody or CRMP-5 IgG were detected. Then the presence of these antibodies would be confirmed with recombinant Western blots for the appropriate antibody either Amphiphysin or CRMP-5 IgG.

The final setting in which additional testing may be done would be where the acetylcholine receptor binding antibody or striational antibody were detected. Then the possibility of an antibody profile supportive of thymoma would come to mind. This could be further explored by doing testing for the acetylcholine receptor modulating antibody and CRMP-5 IgG by Western blot.

Clinical Utility of Autoimmune Dysautonomia Evaluation

So what is the clinic utility of autoimmune dysautonomia evaluation?

This testing is useful for investigating new onset dysautonomia symptoms. Seropositivity for one or more antibodies mentioned may direct the cancer search. The testing is also useful for investigating dysautonomia that appears during cancer therapy that is not explainable by recurrent cancer or metastasis.

Seropositivity can help distinguish autoimmune dysautonomia from chemotherapy side effects. Finally, a rise in antibody titer in a previously seropositive patient can suggest cancer recurrence.

Summary

In summary, the autoimmune dysautonomia serological evaluation aids the investigation of new onset dysautonomia where a paraneoplastic or idiopathic autoimmune cause is suspected. Detection of one or more of this profile of antibodies may lead to detection of unsuspected cancer and seropositivity will also indicate a potentially immunotherapy responsive disorder.

 


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