Neurological complications may affect 10- 20% of those with Sjögren’s disease and range from cognitive difficulties to burning toes and feet.
Introduction to the Nervous System
The nervous system is divided into two anatomic compartments:
- The “Central Nervous System” – or CNS – includes the brain and the spinal cord;
- The “Peripheral Nervous System” – or PNS – includes larger and smaller nerves, connecting muscles to the spinal cord.
Sjögren’s disease can cause inflammation and damage to both the CNS and PNS.
Peripheral Neuropathy of Sjögren’s Disease
What is neuropathy?
Neuropathy, which means inflammation and/or damage to the peripheral nerves, can occur in 5-10% of people with Sjögren’s disease. Neuropathy can cause various symptoms, from “numbness,” to “coldness”; in its most severe, neuropathy has been described as “burning”, “lancinating”, or “feeling like my skin is on fire.” Neuropathy can also cause weakness and clumsiness.
How is neuropathy diagnosed?
The evaluation begins with a careful history and physical examination. The pattern and description of symptoms, which may include pain and weakness, could suggest damage to the peripheral nerves. A neurological examination provides objective evidence of peripheral neuropathy. Weakness may be present, which is typically greater in the toes and fingers than in the larger muscle groups of the arms and legs. During the examination, a reflex hammer typically elicits emphatic lurches of arms and legs when tapped against a muscle tendon. However, patients with neuropathy may not have any reflexes. Your ability to appreciate temperature, a sharp pin, and vibration is also tested. If the neurological examination confirms a peripheral neuropathy, then you may have a nerve-conduction test, looking at the electrical integrity and activity of nerves and muscles.
Why is Neuropathy Under-Diagnosed or Under-Treated in Sjögren’s Disease?
1. Sjögren’s disease may uniquely target nerves which are not tested on normal nerve-conduction tests.
Neuropathy can target nerves either of larger or smaller caliber, respectively referred to as a “large-fiber” neuropathy and a “small-fiber” neuropathy. Symptoms of large-fiber neuropathy include weakness and poorly localizable numbness and are associated with abnormalities on nerve-conduction tests. In contrast, patients with small-fiber neuropathy may have symptoms of pain, burning, and prickling, even without weakness. The nerve-conduction test can detect damage to the large-fiber nerves. but not to the small-caliber nerves.
Skin biopsies are obtained when a patient has symptoms of a small-fiber neuropathy but has normal nerve-conduction tests. The skin biopsy allows quantification of the small sensory nerve fibers that innervate the skin. A reduced density of these nerve fibers is an indication of a small fiber sensory neuropathy, a common form in Sjögren’s disease.
2. The lack of any definitive blood tests
Sjögren’s disease is an example of an autoimmune disorder in whichthe immune system, normally protecting the body from infection and cancer, may cause injury to the body’s own tissues. In addition to the nervous system, organs which may be targeted in Sjögren’s disease include the eye, lung, heart, kidney, and joints. Many patients with Sjögren’s disease have autoantibodies, which bind to the body’s organ tissue and cells. Some examples of autoantibodies in Sjögren’s disease include anti-Ro (or SS-A antibodies) and anti-La (or SS-B antibodies).
However, patients with neurological manifestations of Sjögren’s disease may not have these autoantibodies. In patients who have neuropathy and symptoms of dry eyes and dry mouth, negative blood tests for SS-A and SS-B antibodies do not exclude the diagnosis of Sjögren’s disease. In the context of these dryness symptoms, further diagnostic studies are warranted, including a Schirmer’s test and a minor salivary gland biopsy.
What Other Neuropathies can occur with Sjögren’s Disease?
1. Autonomic Neuropathy
Sjögren’s disease can cause nerve damage which regulates the coordination of heartbeat, respiration, and gastric motility. This is called an “autonomic neuropathy.” Symptoms include lightheadedness when standing, decreased or increased sweating, and feeling full despite eating small meals.
2. Trigeminal Neuralgia and Glossopharyngeal Neuralgia
Sjögren’s disease can cause numbness or burning of the face, called “trigeminal neuralgia.” Pain in the back of the throat, which may worsen while swallowing, is called “glossopharyngeal neuralgia.” Patients with trigeminal or glossopharyngeal neuralgia can have agonizing mouth and facial pain. These neuropathies may co-exist with other neuropathies in different parts of the body. For example, up to 20% of patients with a “small-fiber” neuropathy may also have trigeminal neuropathy.
Medicines which may help alleviate symptoms in small-fiber neuropathy may also have efficacy in trigeminal neuralgia. Such medications include a class of agents which are typically used to treat seizures, such as gabapentin, topiramate, and pregabalin. In seizure disorders, paroxysmal and irregular bursts of electrical activity in brain nerves may lead to propagation of seizures. Similarly, in Sjögren’s neuropathy, irritative electrical signals produced by nerves in the skin instead of the brain, may similarly contribute to pain. Just as anti-seizure medicines can dampen electrical activity of brain cells, the dampening of electrical activity produced by pain fibers may ameliorate burning pain. It is important to note that use of these symptomatic medications does not target the neuroinflammation which may be contributing to neuropathy. In such cases, judicious use of immunosuppressant medications has to be considered.
3. Mononeuritis Multiplex
“Mononeuritis multiplex” refers to deficits in both motor and sensory function in at least two different parts of the body innervated by specific peripheral nerves. These episodes of numbness or weakness, often developing abruptly, necessitate a thorough diagnostic evaluation, both by nerve-conduction tests and often by biopsy of nerve and/or muscles. Mononeuritis multiplex occurs when there is inflammation of small blood-vessels that nourishmuscles and nerves. As a result of the inflammation, blood flow may be impaired, leading to focal nerve injury and damage. In such cases, ameliorating symptoms of pain is not sufficient – immunosuppressant therapy is always warranted.
The pace of recovery from mononeuritis multiplex can be frustratingly slow. In some cases, it may be difficult to determine whether the slow pace of recovery is a manifestation of the slow process of healing and “rewiring,” or is due to ongoing and ineffectively treated inflammation. Repeat nerve-conduction tests may help in this differentiation. Immunosuppressant medications which may be used in the treatment of mononeuritis multiplex includerituximab, cyclophosphamide, azathioprine, as well as prednisone.
How is the Neuropathy of Sjögren’s Disease Treated?
In general, a neurologist and/or rheumatologist must determine the “pattern” of neuropathy (i.e. mononeuritis multiplex versus small-fiber neuropathy). Distinguishing between these patterns is important to determine the best therapeutic strategy. The pain of neuropathy can be especially severe and may require different analgesics and anti-seizure medications. However, symptomatic treatment of pain should not preclude the institution of immune-suppressant medications, when there is evidence of ongoing neuroinflammation.
CNS or Central Nervous System Complications of Sjögren’s Disease
Myelitis
Patients with Sjögren’s disease may have “myelitis,” which is inflammation of the spinal cord. Myelitis can cause weakness, numbness, and difficulty with urination and/or defecation. Myelitis can present quickly (i.e. within hours). However, symptoms due to inflammation of the spinal cord may evolve more slowly, progressing over weeks or months. This slower progression may be difficult to distinguish from Multiple Sclerosis (MS). Unfortunately, patients with myelitis and Sjögren’s disease can be misdiagnosed with MS. Appropriate tests, which may include spinal tap and MRI of the brain/spinal cord, can lead to diagnostic clarity. Distinguishing between Multiple Sclerosis and Sjögren’s is important since some treatments for MS may actually lead to “flares” of Sjögren’s disease.
Patients with Sjögren’s disease may have another autoimmune disorder called Devic’s syndrome, or neuromyelitis optica (NMO). NMO causes inflammation of the nerves connecting the eyes to the brain, or “optic neuritis,” as well as myelitis. The pattern of myelitis which can occur in NMO is much different than Multiple Sclerosis. Typically, the myelitis in NMO is more severe, causing severe weakness, and may cause future relapses.
Concern for Neuromyelitis Optica is heightened when there are especially severe episodes of myelitis (i.e. associated with inability to lift the arms or legs in the air), multiple relapses, occurrence of “optic neuritis” along with the myelitis, and magnetic resonance imaging of the spine that shows the myelitis extending longitudinally over the span of three or more vertebral bodies.
Any patient with Sjögren’s disease, a history of myelitis, and one of these features should have a blood test which may assist in the diagnosis of Neuromyelitis Optica. The name of this blood test is the NMO-IgG antibody. It detects Neuromyelitis Optica in 70 percent of cases. This means that it is not a perfect blood test and will be negative in 30 percent of cases. In such cases, consultation with a neurologist is crucial.
Multiple Sclerosis
Multiple Sclerosis has different subtypes, each with a different presentation and tempo. The most common subtype is called “relapsing-remitting” MS and is punctuated by episodes of unequivocal deterioration (called “flares”), and then periods of clear improvement and quiescent disease. However, a different subtype of MS may be confused with Sjögren’s disease. This pattern is called “primary-progressive” MS. In such cases, the episodic worsening and improvement typical of “relapsing-remitting” MS are not evident. Instead, there may be a slower and more gradual period of deterioration, reflecting inflammation and damage in the spine (i.e. progressive myelitis).
It is often difficult to distinguish between primary-progressive MS and Sjögren’s disease. Patients with Sjögren’s disease may have less brain disease on MRI compared to patients with primary-progressive MS. In addition, patients with Sjögren’s disease may have lesser amounts of protein in the spinal fluid, called “oligoclonal” bands.
Conclusions
The most common CNS complications of Sjögren’s disease include myelitis and optic neuritis, which are syndromes that can occur in MS. Because of this symptomatic overlap, patients with Sjögren’s disease may erroneously receive a diagnosis of MS. When the myelitis is particularly severe, associated with optic neuritis, or involves extensive regions of the spine, then the diagnosis of Neuromyelitis Optica should be considered. Spinal taps and brain MRIs may help in the distinction between primary-progressive MS and Sjögren’s disease.
