MRI studies in the antiphospholipid syndrome may show evidence of vascular occlusion [41]. Multiple hyperintense, periventricular white matter lesions may be seen. Multiple unexplained infarctions in young individuals are suggestive of antiphospholipid syndrome. Locations in the cerebral white matter, internal capsule, corpus callosum, optic nerves (optic neuritis), middle cerebellar peduncles, brainstem, and spinal cord (transverse myelitis) may be affected. Antiphospholipid syndrome may be difficult to distinguish from MS or SS. However, a history of thrombosis or fetal loss, the presence of livedo reticularis, MRI findings that show an atypical distribution for MS, high levels of antiphospholipid antibodies, and response to anticoagulants point to the antiphospholipid syndrome. In addition, the presence of serological features of SLE suggest lupus or a lupus-like disorder with an associated antiphospholipid syndrome.

Progressive multifocal leukoencephalopathy (PML) is a rare and serious viral neurologic disease that occurs in the context of immunosuppression [42]. Although PML is not currently a problem in SS, the use of immunosuppressive and immunomodulatory treatments in SS is on the rise. PML has occurred in SLE and rheumatoid arthritis [42]. PML is caused by the JC virus, a polyoma DNA virus that commonly infects the general population. PML occurred during clinical trials of natalizumab for MS, a monoclonal antibody, in 2005. Subsequently, two cases of PML occurred in SLE patients who received off-label rituximab, a monoclonal antibody directed against CD20 that causes B cell depletion. Some trials of rituximab are ongoing in SS. The experience in SLE and MS suggests that concomitant immunosuppression may contribute to or be necessary for PML. PML tends to have a subacute onset over a period of weeks and a progressive course associated with an extremely high mortality. Unlike MS, PML does not respond to immunosuppressive treatment. Features of MS include optic neuritis, diplopia, paresthesia, paraparesis, and myelopathy, while those of PML include subacute cortical signs and symptoms, bilateral visual defects (cortical blindness), hemiparesis, and behavioral and neuropsychiatric manifestations. Both MS and PML may show cerebellar dysfunction. In SS, as treatments become more aggressive and increasingly directed toward controlling the underlying autoimmune disease as opposed to controlling symptoms, more adverse events and complications of treatment related to immunomodulatory and immunosuppressive therapies are likely to be seen, including the possibility of PML. In the context of immune-based therapies, cases PML are likely to be missed unless there is a high index of suspicion.

20.4Cranial Nerve Involvement

Dysfunction of the optic nerve, cranial nerve two, has been discussed above. Sense of smell and taste can also be impaired in SS [43]. It is not clear to what extent this relates to decreased secretions or neuropathy in the nasal passages and oral cavity. The olfactory nerve, cranial nerve one, mediates the sense of smell. Taste sensation in the anterior two thirds of the tongue is supplied by the facial nerve, cranial nerve seven. Taste in the posterior third of the tongue is supplied by the glossopharyngeal nerve, cranial

nerve nine. Decrease in salivary and tear secretions may relate in part to neuropathy or blockade of nerve action in the salivary and lacrimal glands. Parasympathetic innervation is supplied to the salivary glands via cranial nerves. The ninth cranial nerve supplies the parotid glands but the submandibular glands are innervated by cranial nerve seven. Trigeminal nerve neuropathy reflects, in most cases, sensory ganglionitis [35]. Sensorineural hearing loss has been reported in SS [44]. An early study noted that the majority of SS patients with hearing loss had anticardiolipin antibodies [45].

20.5 Diagnostic Algorithm of SS Patient with CNS Lesions, Myelitis, Meningitis

A description of the approach to CNS lesions in SS patients presenting with features similar to MS has been included earlier. However, patients may present with features of aseptic meningitis or myelitis. Aseptic meningitis refers to meningeal inflammation in which there is no identifiable bacterial pathogen in the CSF [46]. Aseptic meningitis is distinct from encephalitis, in which the brain parenchyma is affected, and from myelitis, which involves the spinal cord. The infectious causes of aseptic meningitis and meningoencephalitis overlap and must be excluded. Aseptic meningitis occurs in the setting of autoimmune diseases (e.g., SLE and SS), other systemic diseases such as vasculitides (e.g., Behcet’s syndrome and Wegener’s granulomatosis), and granulomatous disorders such as sarcoidosis and malignancies. Aseptic meningitis may also occur in association with vaccines and exposure to certain drugs, such as nonsteroidal anti-inflammatory drugs, and intravenous immunoglobulins. CSF shows mononuclear or polymorphonuclear pleocytosis, negative bacterial smears and cultures, normal to mildly elevated protein, and normal to slightly low glucose.

Viruses may cause acute myelitis [46]. Gray matter involvement results in acute flaccid paralysis without autonomic disturbances of bowel and bladder. This can be seen in West Nile virus infection. Involvement of the spinal white matter results in acute transverse myelitis. CSF should be tested to rule out viral, bacterial, and fungal causes. The differential diagnosis for myelitis includes SS, SLE, and antiphospholipid syndrome, vasculitides such as Behçet’s disease, granulomatous conditions such as sarcoidosis, and demyelinating diseases such as MS and NMO. In addition, metabolic derangements such as vitamin E or vitamin B12 deficiency and hereditary disorders such as Friedrich’s ataxia can present with features of chronic myelitis.

For rapidly progressing symptoms and signs of myelopathy, the presence of conditions requiring emergency surgical treatment, such as epidural metastasis or abscess, should be excluded by performing MRI of the entire spine [47]. If such lesions are identified, surgery is required to relieve the compression and prevent progression of the symptoms. For noncompressive causes, about half will represent inflammatory or demyelinating disorders. The most common disorders are demyelinating diseases (MS NMO), spinal cord infarction, parainfectious myelitis, and inflammatory disorders that include SS. Parainfectious myelitis is diagnosed when an infection occurs in

close temporal relationship to myelitis. Infectious causes for myelopathy include Herpes zoster, enteroviruses, Chlamydia, Mycoplasma, Lyme disease, tuberculosis, and parasitic infestations such as schistosomiasis. A history of fever, rash, meningismus, and recent travel may suggest infectious causes. Treatable conditions such as syphilis, HIV, tuberculosis, herpes viruses, and Lyme disease must be considered. Serologic testing and CSF polymerase chain reaction (PCR) studies can help to identify specific organisms. Cytology may help to identify malignant tumors.

The overall approach to a patient with SS with CNS manifestations includes the performance of an MRI examination and laboratory tests to establish the nature of the CNS lesions. If the patient presents solely with symptoms of myelitis, an MRI of the spine and of the brain should be performed to exclude CNS lesions. A sample of CSF should be obtained to evaluate whether pleocytosis is present and to determine protein and glucose levels. These may be helpful in some cases of aseptic meningitis caused by viruses. For SS, the IgG index may be elevated and oligoclonal bands may be present. However, these findings could also be present in SLE and MS. If the patient appears to have aseptic meningitis, a careful history should be taken to identify possible causes other than SS, including viral, bacterial or fungal infections and appropriate samples of body fluids, including serum and CSF should be sent for tests. Cultures, PCR, and other tests should be performed to rule out infectious causes. Serological testing to exclude SLE and the antiphospholipid syndrome is essential.

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Chapter 21

Peripheral Neuropathy

Pantelis P. Pavlakis and Marinos C. Dalakas

Contents

21.2Sensory or Sensorimotor Axonal Polyneuropathy with Objective Clinical

21.1Prevalence and Classification

The prevalence of peripheral neuropathy among Sjögren’s syndrome patients varies greatly between different published studies, with numbers ranging between 2% and 60% [1–14]. Such a large disparity is due to: (a) the use of different criteria for the diagnosis of Sjögren’s syndrome, and (b) the varying definition of peripheral neuropathy with inconsistent application of objective clinical or electrodiagnostic criteria. An example of the problem is one recent report, based on a large population of Sjögren’s syndrome patients, which estimates the frequency of peripheral neuropathy at 10% [5], without providing details on how the neuropathy was diagnosed.

P.P. Pavlakis • M.C. Dalakas (*)

Neuroimmunology Unit, Department of Pathophysiology,

Medical School, University of Athens, Athens, Greece