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Sjögren's Syndrome Neurological Aspects

Mary L. Olsen, MD

University of Texas Health Science Center - Houston 
Arthritis and Rheumatology Associates of Southwestern Texas

The following article is based on Dr. Olsen's presentations at the SSF symposia in Houston, Texas (March 1992) and New York City (September 1992)

* Reprinted with permission of the Sjögren Syndrome Foundation, Inc. (founded 1983)

"The Moisture Seekers" Newsletter. Vol. 11 No. 1, January 1993 pages 1 - 5

Introduction

Sjögren's Syndrome and the Peripheral Nervous System

Cause of Peripheral Neuropathy

Evaluation

Treatment

Sjögren's Syndrome and the Central Nervous System

Neurologic Evaluation

Study Design

Cause of CNS in SS

Evaluation for CNS in SS

Treatment

Summary

Introduction

Sjögren's Syndrome (SS) is a chronic autoimmune disorder.  The action of lymphocytes, a white blood cell component of the immune system, appears to be a major culprit in the formation of this autoimmune problem.  Lymphocytes can directly invade a body organ, such as the lacrimal or salivary glands, and interfere with their normal function, leading to the hallmark symptoms of dry eyes and dry mouth.  Lymphocytes can also produce abnormal proteins directed against components, called autoantibodies, which are carried by the bloodstream throughout the body.  Autoantibodies can invade the general antinuclear antibody (ANA) and rheumatoid factor (RF), or the more specific Sjögren's syndrome-related autoantibodies and anti-Ro (SS-A) and anti-La (SS-B).  Ro antibodies have been related to blood vessel inflammation, or vasculitis.

Sjögren's syndrome is a multi-system autoimmune disorder.  In other words, many of the body's organ systems can be involved in the inflammatory process by virtue of direct lymphocyte invasion or the effects of autoantibody production or vasculitis.  Therefore, some SS patients may have other symptoms in addition to oral and ocular dryness.  These additional symptoms will reflect other potential sites of organ inflammation, such as the lung, kidney, gastrointestinal or nervous system.

This article will address the current information regarding neurologic system involvement in SS.  The structural complexity of the nervous system is enormous.  However, it is important to have a slight understanding of its structure as the symptoms that can result from nervous system inflammation are directly related to the anatomical site of inflammation.

The nervous system is divided into the central nervous system (CNS) which is composed of the brain and spinal cord and the peripheral nervous system (PNS) composed of nerves extending out from the brain (cranial nerves) or out from the spinal cord (peripheral nerves).  If there is a specific site of inflammation in the brain, one could envision a stroke like presentation.  More diffuse brain involvement could result in psychiatric abnormalities, cognitive (thinking) dysfunction, or dementia (memory and intellectual decline).  A specific site of inflammation in the spinal cord could result in a paraplegia like presentation.  The cranial nerve component of the PNS is important in sensory functions such as smell, tasting, hearing, sight and facial sensation.  Therefore inflammation of the cranial nerve (e.g. Cranial Nerve V which innervates the face) could cause tingling in that area of the face.  Finally the peripheral nerves govern motor and sensory function in the limbs.  Their disruption could lead to such problems as foot drop or numbness and tingling in an arm or leg.

Sjögren's Syndrome and the Peripheral Nervous System

Peripheral nervous system involvement in Sjögren's is a well accepted phenomenon.  Initial descriptions date back to 1935 when Sjögren reported patients with transient sensory changes in the limbs (peripheral neuropathy) and bilateral facial palsy (cranial neuropathy).  In the 1960's Kaltrider and Talal brought further attention to involvement of the peripheral nerves, along with a focus on Cranial Nerve V (the Trigeminal nerve) dysfunction.  In the 1980's, a description of a pure sensory neuronopathy in Sjögren's syndrome was emphasized as well.  In a 1989 review of 33 Sjögren's syndrome patients with peripheral neuropathy by Mellgren et al at Mayo Clinic, Rochester, MN, two thirds of the patients had non painful paresthesias described as "asleep or prickling numbness" of a limb.  These generally occur in a "stocking and glove" type distribution of the limb.  Twenty percent had a "burning" or other painful component to the nerve paresthesia.  Only about 10% had a component of true motor weakness with the peripheral neuropathy.  Therefore the most common peripheral neuropathy is a tingling feeling with pain or true weakness less common.

The increasing impact of Sjögren's syndrome as a cause of peripheral neuropathy is underscored in a review article, directed toward neurologist, written by Kaplan et al in 1990, which stated "Our experience and review of the literature reveal that Sjögren's syndrome (SS) is an important, poorly recognized cause of peripheral neuropathy".  They note that the "clinical evidence of glandular involvement is often minimal to absent when patients with SS develop develop peripheral neuropathy" and the diagnosis of the underlying condition is elusive".

Cause of Peripheral Neuropathy

The cause of peripheral neuropathy in Sjögren's syndrome is related to the autoimmune effect of lymphocytes.  Nerve biopsy specimens frequently show a lymphocytic infiltrate in the small blood vessels serving the nerve.  Occasionally the inflammation can destroy the blood vessel wall (i.e. necrotizing vasculitis).  Disruption of the blood supply to the nerve interferes with its normal function.  In some cases the lymphocytes have been found to directly invade the substance of the nerve at an important nervous signal processing site called the dorsal root ganglion.  This dorsal root ganglionitis is found in that small percentage of Sjögren's syndrome patients with a pure sensory neuronopathy.

Evaluation

In evaluation for peripheral neuropathy in a patient with Sjögren's syndrome, the history often reveals complaints of burning, tingling paresthesias in a symmetrical stocking or glove distribution or in the face (Trigeminal Nerve V) area.  Physical examination may reveal sensory abnormalities (e.g. pain, light touch, position sense, or vibration components of sensation), but also potentially associated motor, reflex, and coordination abnormalities.  Diagnostic testing can include an electromyogram with nerve conduction study(EMG/NCS).  EMG/NCS uses a needle electrode and an electrical current stimulus to assess the functional status of a nerve and the area it supplies.  It has been shown to be much more sensitive in determining nerve involvement than simply physical examination.  Diagnostic testing also requires a concomitant evaluation for alternative causes of neuropathy (e.g. diabetes, Vitamin B12 deficiency, etc.) that may be coexistent in a patient with Sjögren's syndrome.  At times a nerve biopsy will be done to directly look for evidence of inflammation or vasculitis.

Treatment

The optimal treatment for peripheral neuropathy in Sjögren's syndrome is unknown.  There are no controlled studies of any treatment regimen.  Moreover, the use of immunosuppressive therapy (such as corticosteroids) has met with variable results in the currently reported cases.  Therefore, all therapy must be individualized such that the chance for potential benefit outweighs the risk of any proposed treatment.  In cases of the commonly occurring distal (fingers and toes) tingling paresthesias it is reasonable to treat conservatively with splints and physical therapy.  In progressive, disabling disease, especially with the sensory ataxia (loss of awareness of joint position) associated with dorsal root ganglionitis, then vigorous trials with steroids, cytotoxics and even plasmapheresis have been attempted.

Sjögren's Syndrome and the Central Nervous System

Central nervous system involvement with Sjögren's syndrome remains an area of controversy.  There were only rare case reports of a Sjögren's syndrome patient with a seizure or stoke-like presentation until the 1980's when a flurry of studies were published by Alexander and colleagues describing diffuse multifocal CNS involvement of the brain and spinal cord.  In 1986, Alexander reported, "Central nervous system disease has been recognized as a complication of primary Sjögren's syndrome and has occurred in approximately 20% of patients evaluated at our institution".  However, other centers failed to corroborate these findings.

In 1990, Andonopoulous reported "The present study suggests that peripheral nervous system involvement in primary Sjögren's syndrome is common and benign in the majority of affected subjects.  Central nervous system disease must be rare".  From a patient's perspective this dichotomy of views can be both confusing and frustrating.  However, there are many reasons for this disparity in research findings.

Referral bias is a likely explanation for the discrepancy regarding the frequency of CNS manifestations in SS patients.  As Alexander and colleagues interest in the potential CNS manifestations of Sjögren's syndrome became known, may patients with neurological manifestations were specifically referred to them for further study.  This "referral bias" acts to artificially increase the proportion of SS patients with neurological symptoms within the SS patient population as a whole.

Neurologic Evaluation

Another important factor in determining the status of neurologic disease in SS patients is the actual extent of the neurological evaluation.  A questionnaire or cursory physical examination for neurological symptoms will likely yield quite different results from comprehensive examinations by rheumatologists, neurologists and psychiatrists and the addition of sophisticated testing such as neuroimaging, cerebrospinal fluid, or neuro-electrophysiological testing.  Conversely, the extent of the evaluation for the presence of Sjögren's syndrome in a patient presenting with neurological symptoms is an important factor.  SS patients can often recall seeing various medical specialists for various organ system complaints prior to determining the underlying problem of Sjögren's syndrome.  Therefore if one seeks evaluation for neuropsychiatric symptoms and the treating physician is unaware of Sjögren's syndrome playing a role, it will remain undiagnosed.  This is further hampered by the observation that the glandular features of dry eyes and dry mouth may be minimal in the fact of florid neuropsychiatric manifestations.

Study Design

A final important factor is the retrospective vs. prospective study design.  In prospective data collection, information regarding the study variables are systematically sought and recorded in each study subject.  In retrospective data collection, one reviews the information available in the study of patient's old records.  One cannot definitively determine if a specific study variable was present or absent - only if it happened to be recorded or not.

Let's now look at the currently available studies regarding neurological manifestations in Sjögren's syndrome patients (Table 2).  These reflect formal studies (not simply case reports or observations) available in English language medical journals.  The international interest in CNS manifestations of SS is demonstrated by the diverse countries represented.  Although Alexander and coworkers were instrumental in the initial observations, there is a striking paucity of research from other centers in the United States.  Also, it will become evident that the findings of each study are directly related to the extent of neurologic evaluation.

 

Simplified Overview of the Nervous System

Structural Format

Central Nervous System Peripheral Nervous System
Brain Cranial Nerves
Spinal cord Peripheral nerves

Related Functional Abnormalities

Strokes Cranial neuropathies
Seizures Motor/sensory peripheral neuropathies
Movement disorders  
Cognitive dysfunction  
Dementia  
Psychiatric abnormalities  
Paraplegia  

Table 2.

In the earliest study by Mallow evaluating psychiatric symptoms and cognitive abilities, the findings were that of psychiatric symptoms and mild memory and concentration deficits.  Montecucco and Drosos also used psychiatric testing in a Sjögren's syndrome population and obtained similar results, with an emphasis on the finding of depression.

Rather that a direct manifestation of SS, one could envision depression, or either psychiatric symptoms, to simply reflect the consequences of living with a chronic illness.  The studies by Vitali and Tarter attempted to factor out the impact of neuropsychiatric symptoms related to a chronic disease by comparing results of SS patients to patients having such chronic diseases as osteoarthritis, diabetes mellitus and primary biliary cirrhosis (PBC).  Vitali did find moderate to severe depression to be present in 7% of diabetes mellitus patients and 20% of osteoarthritis patients.  However, 47% of the SS patients similarly studied were found to have moderate to severe depression.  Similarly, Tarter found that patients with PBC and SS performed worse on tests of cognitive function and had increased anxiety vs. patients with PBC alone.  These studies suggest that SS itself may be playing a role in cognitive and psychiatric manifestations.

As previously mentioned, results of studies regarding neurologic evaluation.  When Pal et al queried regarding headaches, 46% of SS patients were reported as having migraine headaches.  Similarly, when Andonopoulous employed the use of EMG/NCS, a sensitive measure for peripheral neuropathy, 51% of the SS patients studied were said to have findings of peripheral neuropathy.

Of all the studies regarding potential neurological symptoms in SS patients, that of Hietaharju, given its comprehensive approach, warrants special attention.  Almost all study subjects underwent physical examination, MMPI, and measures of brain function by electroencephalograph (EEG) and visual evoked potential (VEP).  Whenever possible, EMG/NCS, muscle biopsy, and cerebrospinal fluid (CFS) analysis were done.  In this more comprehensive evaluation, 17% were found to have CNS manifestations such as seizures, cognitive dysfunction, aseptic meningitis, etc.; 39% had peripheral nervous system involvement; and 77% had psychiatric manifestations.  Of interest 48% had an abnormal EEG, even without overt neurological symptoms.  The authors suggested that this reflects subclinical neurologic changes directly related to SS.

Another way to address a relationship between neurologic manifestations and Sjögren's syndrome is to look for the presence of SS in patients presenting with neurologic symptoms.  Alexander and colleagues have reported symptoms and laboratory findings (brain magnetic resonance imaging {MRI}, CSF and VEP) mimicking multiple sclerosis in SS patients.  This has prompted a variety of centers specializing in multiple sclerosis to look for occult Sjögren's syndrome.  Montecucco, Noseworthy, and Miro all found approximately 3% of their MS patients had evidence for Sjögren's syndrome.  As SS is estimated to occur in at least 2% of the population, their conclusions were that MS patients simply have coexistent SS.  This remains a point of controversy, as Dr. Alexander feels that rather than coexistent problems, these few patients may have their CNS disease due to the inflammation of SS rather than the demyelination problem of MS.  Brain biopsy could help settle this question but this information is not readily available.

A slightly different approach was taken by Olsen and colleagues who searched for sicca symptoms and autoantibody formation in 100 patients admitted to a hospital neurology service.  Thirty percent had sicca symptoms and 16% had ANA or RF positively suggesting a possible correlation of SS and diverse neurologic symptoms.  This study was limited in that only 4 patients underwent further evaluation for SS.  However 3 were found to have SS and presented with problems of dementia, neuro-psychiatric dysfunction, and stroke.

Cause of CNS in SS

The cause of CNS disease in SS is unknown, but it is likely immunologically mediated.  There have been case reports of brain biopsy or autopsy material documenting true vasculitis or perivascular inflammation of blood vessels of the brain and it's covering membrane (the leptomeninges) in SS patients with neurological disease.  Moreover, there is evidence to suggest that the brain, spinal cord, and leptomeninges may be infiltrated with inflammatory cells similar to that found in other organ systems involved with SS inflammation.

Evaluation for CNS in SS

In the evaluation for possible CNS manifestations in SS the clinical history needs to seek for the perhaps more subtle complaints of memory or concentration changes, depression, etc., as well as, other more "hard" neurologic complaints.  Physical examination needs to include a complete neurologic exam, including mental status testing.  A variety of diagnostic testing can be employed.  Neuro-psychometric testing assesses abnormalities of concentration, memory and other cognitive functions.  CSF evaluation is often done to evaluate for oligoclonal bands and elevated IgG index, or atypical cells to implicate CNS inflammation.  Neuroimaging studies look at brain structure.  Cranial computed tomograph (CT) or angiography are usually normal.  Brain MRI is often found to be abnormal with high intensity periventricular white matter lesions of unknown significance.  Electrophysiologic studies look at brain function.  EEG is often found to be abnormal and evoked potential testing may demonstrate abnormalities in the visual, auditory, or somatic sensory pathways.  Pathologic studies of brain and leptomeningeal biopsy material are sometimes done to directly assess potential vasculitis or focal inflammatory infiltrates.  It must also be emphasized that one must perform a thorough evaluation for alternative cause of CNS manifestations that may be coexistent in a patient with Sjögren's syndrome.  For example, if a patient with SS also smokes, has high blood pressure and high cholesterol levels, then the occurrence of a stroke in this setting could simply be due to these known stroke risk factors.

Treatment

The optimum treatment of CNS manifestations of SS is not known.  There are no controlled studies of any specific treatment regimen.  Because of the evidence for an immunologically mediated cause, immunosuppressive therapy (such as corticosteroids) is often tried.  If severe symptoms persist despite steroid use, then other immunosuppressive agents, such as cytoxan have been implemented.  Specific documented reports of treatment efforts are few.  A study of psychodynamic modified group therapy in 18 patients with SS showed these patients demonstrated an increased capacity for both introspection and outward expression of emotions; however, little to no physical or psyche improvement nor improvement in family or social relations were seen.  There have been case reports of benefit in the use of steroids with or without plasmapheresis in a few patients with transverse myelitis and optic neuropathy.  Finally, Casselli reported a SS patient with progressive dementia (mistaken for Alzheimer's disease) who was actually found to have perivascular inflammation on brain biopsy and who demonstrated rapid cognitive improvement following high dose steroid therapy.

Summary

In summary, peripheral nervous system involvement in Sjögren's syndrome is common with reports of peripheral and cranial neuropathy ranging from 12% (clinically detectable) to 51% (often subclinical with detection by nerve conduction studies only).  Central nervous system involvement is variable.  Psychiatric symptoms, especially depression, somatization, and anxiety are commonly reported (13% to 77%).  Although likely in part a reaction to the chronic disease of SS, these symptoms nevertheless have been reported more commonly in SS patients than in some other chronic disease patients.  Cognitive or memory problems have been found in up to 18% when formal psychometric testing has been performed.  Other CNS involvement such as seizures, vertigo, aseptic meningitis, etc., have been reported in up to 16%.

Study of the neurologic aspects of Sjögren's syndrome remains an exciting avenue for future research.  From a physician's perspective, the possibility of an inflammatory, and therefore potentially reversible cause of neurological symptoms, is especially gratifying.  Much more information is needed to determine the frequency of involvement, spectrum of symptoms, pathophysiologic causes and optimal evaluation and treatment approaches.  This will require patient and physician cooperation in comprehensive, multicenter studies.

SSF Disclaimer

* The articles identified as originally published in The Moisture Seekers Newsletter, are the only materials contained in this website that have been reviewed by the Sjogren's Syndrome Foundation.  The SSF in no way endorses any of the medications or treatments mentioned in these articles.  We strongly advise that you check any drugs, treatments or products mentioned with your own healthcare provider.
Introduction / SS and PNS / Causes of  PN / Evaluation  / PN Treatment / SS and CNS / Neurologic Evaluation / Study Design / Causes of CNS-SS / Evaluation for CNS-SS / CNS Treatment / Summary 
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