Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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This article includes discussion of the neurologic complications of Sjögren syndrome, Gougerot-Sjögren syndrome, and Sicca complex. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Neurologic manifestations occur in 20% to 27% of patients with Sjögren syndrome, often preceding the diagnosis of this systemic autoimmune disease. The peripheral nervous system, skeletal muscles, and central nervous system may be involved. Sjögren syndrome has been associated with neuromyelitis optica with positive serum aquaporin autoantibody. The symptoms of neurologic Sjögren syndrome may also mimic multiple sclerosis. HTLV-1 infection and vitamin B12 deficiency can complicate Sjögren myeloneuropathies. In this article, the author reviews the clinical presentations and postulated pathogenesis of these complications and offers current treatment recommendations.
• Sjögren syndrome is a common autoimmune disease, particularly among postmenopausal women, and it is manifested by dry mouth, dry eyes, fatigue, and arthralgias.
• Neurologic symptoms occur in 20% to 27% of patients with Sjögren syndrome due to involvement of cranial nerves (Bell palsy, trigeminal neuralgia, diplopia), peripheral nerves (sensorimotor neuropathies), skeletal muscles (fibromyalgia, polymyositis), and the central nervous system.
• Sjögren syndrome can mimic the symptoms and radiographic features of multiple sclerosis.
• Sjögren syndrome is closely associated with neuromyelitis optica, a demyelinating disease of the central nervous system caused by antibodies to aquaporin-4 (NMO IgG).
• A high index of suspicion is required given the pleomorphic manifestations and the fact that neurologic symptoms often precede the clinical diagnosis of Sjögren syndrome.
In 1933, Henrik Sjögren described the association of keratoconjunctivitis sicca (filamentary keratitis) with arthritis (99). Morgan and Castleman noted the histopathological commonality between the keratitis described by Sjögren and the glandular enlargement described by Mikulicz (70; 67). By 1973, the term “Sjögren syndrome” became widely accepted as these disorders were considered variants of the same process (63). The name Gougerot-Sjögren syndrome is commonly used in the French literature (21) given that Henry Gougerot first reported, in Paris, the typical symptoms of xerostomia and xerophthalmia due to atrophy of salivary and lachrymal glands (33).
Sjögren syndrome is a chronic, multisystem autoimmune disorder. Primary Sjögren syndrome presents as dry eye and dry mouth secondary to autoimmune dysfunction of the exocrine glands. In secondary Sjögren syndrome, these manifestations occur in the presence of another autoimmune disease. Overall, there is no increased mortality in patients with primary Sjögren syndrome (61).
Systemic involvement in Sjögren syndrome includes: chronic fatigue affecting as many as 50% of patients; arthralgias present in 53%; esophageal dysmotility in 36%; hematological abnormalities including anemia and leukopenia (33%), increased erythrocyte sedimentation rate (22%), hypergammaglobulinemia (22%); inflammatory myalgias (22%); and skin lesions such as “burning skin” (18%), cutaneous vasculitis (10%), alopecia, vitiligo, papular lesions, and annular erythema (48; 88). Lymphoma may develop in 5% to 7% of patients with primary Sjögren syndrome, often associated with cutaneous purpura (115). Less common manifestations include lung involvement with lymphocytic alveolitis, lymphocytic interstitial pneumonitis, fibrosis, pulmonary pseudolymphoma, and pulmonary hypertension. Other less common manifestations include pericarditis, vascular lesions manifested by Raynaud phenomenon, renal tubular lesions, interstitial nephritis and glomerulonephritis, malabsorption due to lymphocytic infiltrates of the intestine, mild pancreatitis, and hepatitis. Exclusion criteria for the diagnosis of Sjögren syndrome include infections with HIV, HTLV-1, or hepatitis C virus (87). Table 1 summarizes the current consensus criteria for the diagnosis of Sjögren syndrome.
I. Ocular symptoms: A positive response to at least 1 of 3 validated questions:
1. Have you had daily, persistent, troublesome dry eyes for more than 3 months?
2. Do you have a recurrent sensation of sand or gravel in the eyes?
3. Do you use tear substitutes more than 3 times a day?
II. Oral symptoms: A positive response to at least 1 of 3 validated questions:
1. Have you had a daily feeling of dry mouth for more than 3 months?
2. Have you had recurrent or persistently swollen salivary glands as an adult?
3. Do you frequently drink liquids to aid in swallowing dry foods?
III. Ocular signs: Objective evidence of ocular involvement defined as a positive result to at least 1 of the following 2 tests:
1. Schirmer's test, performed without anesthesia (≥ 5 mm in 5 min)
2. Rose Bengal score or other ocular dye score (≥ 4 according to van Bijsterveld's scoring system)
IV. Histopathology: Focal lymphocytic sialoadenitis in minor salivary glands, with a focus score of 1.
V. Salivary gland involvement: Objective evidence of salivary gland involvement defined by a positive result to at least 1 of the following diagnostic tests:
1. Unstimulated whole salivary flow (≤ 1.5 mL in 15 min)
2. Parotid sialography showing the presence of diffuse sialectasis
3. Salivary scintigraphy showing delayed uptake, reduced concentration, and/or delayed excretion of tracer
VI. Autoantibodies - presence in the serum of the following autoantibodies:
1. Antibodies to Ro/SS-A or La/SS-B antigens, or both
• Past head and neck radiation treatment
For Primary Sjögren syndrome
a. Any 4 of the 6 items, as long as item IV (histopathology) or VI (serology) is positive
In patients with a potentially associated disease (for example, another well-defined connective tissue disease), the presence of item I or item II plus any 2 from among items III, IV, and V may be considered as indicative of secondary Sjögren syndrome (113).
The American College of Rheumatology, in consensus with the Sjögren’s International Collaborative Clinical Alliance (SICCA) investigators, proposed new provisional criteria to improve the criteria’s specificity for enrollment in trials for biologic agents and other therapies. These criteria require at least 2 of the following 3 findings:
1. Positive serum anti-SSA and/or anti-SSB or positive rheumatoid factors and ANA ≥ 1:320
2. Ocular staining score ≥ 3
3. Presence of focal lymphocytic sialadenitis with focus score ≥ 1 focus/4mm2 in labial salivary gland biopsies.
These criteria were found to have a sensitivity of 93% and a specificity of 95% (98).
A number of neurologic manifestations have been reported in about 20% of patients with Sjögren syndrome (range 6% to 70%) (56; 24; 21; 71). In most cases, neurologic symptoms precede the diagnosis (08; 71). Historically, the most common symptoms include involvement of the peripheral nervous system and skeletal muscles. More recent reports emphasize the involvement of the central nervous system that went underrecognized in the past, often mimicking the clinical symptoms of primary progressive or relapsing-remitting multiple sclerosis. An observational, single center study from Italy found that 5.8% of patients presenting to rheumatology clinic with a diagnosis of Sjögren syndrome had central nervous system involvement (64). Table 2 lists some of the most common neurologic manifestations of primary Sjögren syndrome.
Painful sensory neuropathy
Focal brain lesions
Stroke with motor or sensory deficits, associated with CNS vasculitis
Movement disorders and cerebellar syndromes
Diffuse nonfocal symptoms
Acute or subacute encephalopathy
Spinal cord involvement
Peripheral nervous system. Most studies report that the frequency of peripheral nervous system disease is between 5% and 20% (10). Mori and colleagues reviewed 92 patients (86% women, mean age 60 years) with Sjögren syndrome and found the following varieties of neuropathy: sensory ataxia (39%); sensory painful neuropathy (20%); trigeminal neuropathy (17%); multiple mononeuropathy (12%); multiple cranial neuropathies (5%); autonomic neuropathy (3%); and radiculoneuropathy (4%) (71).
Dyck described the following nerve fiber lesions in these cases (26). In the ataxic variety, large primary afferent neurons or fibers are selectively affected as suggested by inflammatory infiltrates found in spinal ganglia. In trigeminal neuropathy, all classes of sensory neurons or fibers are involved. In sensory and autonomic neuropathy affecting limb or trunk, all classes of sensory neurons or fibers are affected, but symptoms suggest predominant small fiber sensory involvement with either tactile (allodynia) or thermal hypersensitivity (hyperalgesia), as well as sudomotor abnormalities such as decreased sweating in toes and feet or in an asymmetrical, radicular pattern. These sensory and autonomic neuropathies may occur with minimal or no evidence of sicca symptoms (26).
Painful sensory neuropathy (without sensory ataxia). Painful sensory neuropathy can present as acute, subacute, or chronic onset of burning dysesthesias in the toes, feet, or hands, usually in either one limb or over the entire body, including the trunk and the face (71). Dysautonomia may also be present, although there is no evidence of dorsal column involvement. These patients had preserved motor and vibratory/proprioceptive function, with impairment only in pin-prick and temperature sensation on neurologic exam. Sural nerve biopsies show small-fiber loss suggesting predominant impairment of small sensory neurons with preservation of large-diameter sensory neurons (14). The measurements of intraepidermal nerve fiber densities in skin punch biopsy specimens show less than 3.4 fibers/mm, which is consistent with the morphological criteria for small-diameter nerve fiber neuropathy (32).
Axonal neuropathies. Between 17% and 39% of patients with Sjögren syndrome have minor symptoms of peripheral neuropathy (08; 26). The most common axonal forms are symmetrical sensory neuropathy and sensorimotor neuropathy (08; 56; 24; 26; 71). Vibration perception threshold and thermal perception are sensitive and useful methods of monitoring peripheral nerve function in these patients (08). The course is generally slowly progressive. Autonomic symptoms are rare. A common complication is carpal tunnel syndrome. Motor and sensory action potentials in the involved nerves are markedly reduced. Sural nerve biopsies have shown vasculitis of vasa nervorum, perivascular cellular infiltration, and necrotizing vasculitis, along with focal or multifocal axonal degeneration of large and small myelinated fibers and minor demyelination.
Sensory ataxic ganglionopathy. This is a distinctive type of sensory neuronopathy with a reported association with antiganglion neuronal antibodies in 1 study (75). The antigenic target of these antibodies is not known, and there are no posterior studies that confirmed this finding. The neuropathology of the sensory neuronopathy is characterized by lesions of the dorsal root ganglia with neuronal loss and presence of mononuclear cell infiltrates (ganglionitis) but without vasculitis (35; 75). Clinically, it is characterized by a profound loss of proprioception and vibratory perception leading to sensory ataxia, with a positive Romberg sign and global areflexia, without motor involvement. The sensory symptoms are usually asymmetrical, segmental, or multifocal, including trigeminal nerve involvement (71). Birnbaum and colleagues described dorsal root ganglion enlargement and T2 hyperintensity in early dorsal root ganglionitis (11), whereas Yoshida and colleagues detected atrophy of the dorsal root ganglion in chronic sensory ataxic ganglionopathy (123).
There is usually autonomic involvement manifested by abnormal pupillary responses including Adie pupils, anisocoria, and oval pupils; orthostatic hypotension decreases in 123I-MIBG cardiac uptake, hypohidrosis, and segmental anhidrosis of the trunk. Sensory potentials are absent, contrasting with normal motor potentials and normal peripheral nerve conduction velocities. Somatosensory evoked potentials are usually absent. Sural nerve biopsies show a selective loss of large myelinated fibers, with minimal inflammation or vasculitis. Cervical spinal cord MRI may show hyperintense T2-weighted signals corresponding to involvement of the fasciculus cuneatus and fasciculus gracilis in the dorsal columns, proportional to the severity of the damage (72). This form of neuropathy is chronic and progressive and is usually only minimally responsive to treatment (10).
Multiple cranial neuropathies. The most common cranial nerve affected in Sjögren syndrome is the trigeminal nerve, which is discussed in more detail in the next section. The facial nerve is the most commonly targeted motor nerve and can present bilaterally. Other symptoms include recurrent diplopia due to oculomotor and trochlear nerve involvement, swallowing problems due to compromise of the glossopharyngeal and vagus nerves, and less commonly, simultaneous lesions in multiple cranial nerves (71). Neurosarcoidosis should be included in the differential diagnosis in patients with multiple cranial nerve involvement (108).
Trigeminal neuralgia. A common form of pure sensory trigeminal neuropathy in Sjögren syndrome is trigeminal neuralgia, often with bilateral involvement. There is facial numbness, decreased corneal reflexes, and loss of pin prick and soft touch perception in the trigeminal nerve distribution, without motor trigeminal nerve involvement. Immune-mediated involvement of Gasserian ganglion neurons is suspected. Simultaneous sensory neuropathy of the trigeminal, glossopharyngeal, and vagus nerves has been reported (109).
Hearing loss. Sensorineural hearing loss, due to lesion of the vestibulocochlear nerve manifested by sudden or progressive deafness, has been reported in Sjögren syndrome. In some cases, hearing loss was associated with the presence of antiphospholipid antibodies (73).
Autonomic neuropathy. The peripheral sympathetic nervous system is severely involved in this form of neuropathy. These patients commonly present with sicca syndrome, orthostatic hypotension with syncope, anhidrosis, Adie pupil, neurogenic bladder, erectile dysfunction, as well as gastrointestinal symptoms such as abdominal pain, constipation, or diarrhea (24; 26; 71). In addition to the above, examination reveals reduced cardiac 123I-MIBG uptake, no plasma norepinephrine response after standing, and hypertensive response to minimal doses of norepinephrine (71). These patients usually have elevated titers of nicotinic ganglionic acetylcholine receptor autoantibody, a putative effector of autoimmune cholinergic dysautonomia (96).
Radiculoneuropathy. A demyelinating polyradiculoneuropathy is the most uncommon peripheral nervous system manifestation in patients with Sjögren syndrome. Patients present with progressive sensory disturbances in a glove-and-stocking distribution, muscle weakness, and sensory ataxia but without autonomic symptoms. CSF protein is elevated, and nerve conduction studies show reduced conduction velocities and temporal dispersion. Biopsies show histopathological evidence of remyelination. According to Mori and colleagues, the primary lesion in these patients is an inflammatory radiculoneuropathy (71).
Inflammatory myositis. Myalgias and diffuse musculoskeletal pain, without elevation of muscle enzymes or electromyographic changes, have been reported in 30% to 44% of patients with Sjögren syndrome (59); many of them fulfill criteria for fibromyalgia. Fibromyalgia is a diagnosis of exclusion for these patients, and vitamin D deficiency as well as thyroid disease should be ruled out prior to making the diagnosis (10). Inflammatory myopathies are uncommon in Sjögren syndrome, reported in 1% to 2% of cases of peripheral nervous system manifestations. Muscle biopsy results on this small subset of patients show signs of inflammation in 50% to 72% and evidence of polymyositis (inflammation combined with degeneration and regeneration of muscle fibers) in 47% (25). Some cases have symmetrical inclusion body myositis diagnosed by electron microscopy (59; 25). Myopathy due to medications such as steroids must be considered in the differential diagnosis.
Multiple sclerosis-like manifestations. Alexander and colleagues first reported the frequent occurrence of a relapsing remitting syndrome resembling multiple sclerosis associated with cutaneous vasculitis in patients with Sjögren syndrome (02). All cases had confirmed primary Sjögren syndrome by lip biopsy, and all cases met diagnostic criteria for clinically definite multiple sclerosis. Eighty nine percent of the patients had oligoclonal bands in the CSF, but occasionally the bands were lowered with corticosteroid therapy. Fifteen out of 19 patients had positive visual evoked potential testing. Many of these cases presented a combination of optic neuropathy and chronic myelopathy that could be confused with neuromyelitis optica or multiple sclerosis, as well as brainstem and cerebellar symptoms. Sjögren syndrome and multiple sclerosis share common immunologic dysregulation, as a dominant feature of the immunopathogenesis in Sjogren syndrome is B cell dysfunction and excessive BAFF (B cell activating factor). Self-reactive B cells as well as BAFF itself can stimulate T cells, which are implicated in the pathogenesis of multiple sclerosis (16). Peripheral nervous system involvement was seen in 55% of these patients, and perhaps this could help differentiate between multiple sclerosis and CNS Sjögren syndrome. There is no consensus in the medical literature to determine whether a patient has a relapsing remitting demyelinating disease of the CNS as a result of Sjögren syndrome or if Sjögren syndrome and multiple sclerosis can present independently. A cross sectional study of 68 patients with Sjögren syndrome and 68 healthy controls found no difference in white matter hyperintensity load or distribution between the 2 groups (37). However, in other autoimmune disorders such as lupus and APLA, cerebral white matter hyperintensities are fairly common. There is a low prevalence of primary Sjögren syndrome in relapsing remitting multiple sclerosis patients, comparable to the prevalence in the general population (62). However, the prevalence of primary Sjögren syndrome diagnosis in the primary progressive multiple sclerosis population was found to be 16.7% higher than that of the general population, and it has been argued that all primary progressive multiple sclerosis patients should be screened for Sjögren syndrome (22). The occurrence of Sjögren syndrome in patients with confirmed multiple sclerosis ranges from no cases among 192 patients (77) to about 5% (3 out of 64 cases) (69). In some geographic areas, a chronic myelitis due to infection with the human T-lymphotropic virus type 1 (HTLV-1) has been also associated with Sicca syndrome (76; 97).
Neuromyelitis optica. The combination of optic neuritis with concurrent myelitis is included in the diagnostic criteria for neuromyelitis optica, also known as Devic disease (100). More than 95% of neuromyelitis optica cases test positive to the disease-specific serum aquaporin autoantibody (119). Autoantibodies or other systemic autoimmune diseases are often found in patients with neuromyelitis optica, including Sjögren syndrome (84), and 7.7% to 12% of patients with neuromyelitis optica have anti-Ro/SS-A or anti-La/SS-B antibodies (39). In Korea, Kim and colleagues studied 8 patients with Sjögren myelopathy and demonstrated that most patients exhibited clinical, radiological, and immunological characteristics of neuromyelitis optica, including positive aquaporin autoantibody testing (52). Min and colleagues studied 12 women with primary Sjögren syndrome and recurrent cerebral manifestations (68). MRI showed lesions characteristic of neuromyelitis optica in the third and fourth ventricles and in the posterior limb of the internal capsule, along with cerebral or cerebellar lesions larger than 3 cm in size and with cavity-like formations. Aquaporin autoantibody was positive in 6 of 8 patients tested, and all the seropositive patients showed lesions with increased MRI diffusion, suggestive of vasogenic edema.
Javed and colleagues tested patients with neuromyelitis optica for concomitant Sjögren syndrome with labial biopsies. Although less than 20% of patients had symptoms that were suggestive of Sjögren syndrome, labial biopsy was positive for 9 of 12 patients with confirmed neuromyelitis optica and for 7 of 8 patients with longitudinally extensive transverse myelitis (45). These authors recommend testing for aquaporin autoantibody in all patients with Sjögren myelitis, followed by early aggressive immune therapies in these patients.
Spinal cord involvement. Following an initial report (117), at least 57 cases of spinal cord involvement in Sjögren syndrome have been reported, indicating that this neurologic complication is not uncommon (53; 120; 07; 38; 40; 104; 03; 80; 112; 29; 20; 85; 103; 106; 100; 50; 52). Furthermore, patients with primary progressive multiple sclerosis have a prevalence of Sjögren syndrome (16.6%) that is much higher than expected in the general population (1% to 5%) (22).
Acute transverse myelitis is the most frequent form of spinal cord involvement in Sjögren syndrome (117). The symptoms of acute transverse myelitis develop abruptly, usually with severe neck and thoracic back pain followed by sensory and motor deficits below the level of the lesion. In Sjögren syndrome, this form of myelopathy is thought to be due to vasculitis and carries a high morbidity and mortality.
Spinal cord involvement may also present as a progressive myelitis. A diagnosis of Sjögren myelopathy requires a high index of suspicion and should be considered especially in women over 45 years of age with progressive spastic paraparesis and abnormalities on spinal cord MRI, even with negative antiextractable nuclear antigen antibodies (Ro/SS-A or La/SS-B) (80). The presence of autoantibodies against fodrin also helps in differentiating myelopathy in Sjögren syndrome from primary progressive multiple sclerosis (23). A positive test has 70% sensitivity, 86.7% specificity, 63.6% positive predictive value, and 89.6% negative predictive value (23).
Less common is the combined involvement of pyramidal tracts and anterior horn cells resembling amyotrophic lateral sclerosis. Postmortem study of 2 cases confirmed in 1 patient a lower motor neuron syndrome combined with flaccid bladder and rectum, and in the other patient, unilateral hearing loss, sensory neuronopathy, Adie pupils, upper motor neuron signs, and autopsy-proven anterior horn cell degeneration (51). These cases demonstrate the wide multisystem neuronal involvement that may occur in Sjögren syndrome. A similar syndrome called pseudo-amyotrophic lateral sclerosis has been reported in patients with HTLV-1 infection (Roman et al 1991).
Focal encephalic manifestations. Focal manifestations may present acutely, with stroke-like features such as aphasia, hemiplegia, or numbness, consistent with a focal vasculitis (24). Intracerebral or subarachnoid hemorrhage may signal the presence of vasculitis. Recurrent or relapsing CNS symptoms may mimic multiple sclerosis as discussed above.
Occurrences of subacute development of cerebellar ataxia and tremor may be caused by demyelination. In 1 patient, an MRI showed T2-hyperintensities in the cerebellar white matter and the pons; severe necrotic lesions were found in the cerebellar white matter bilaterally, with several foci of perivenous demyelination in the periphery of the lesions and similar demyelinated areas in the pons; there was minimal granulomatous angiitis (42).
Other focal neurologic manifestations described in Sjögren syndrome include: internuclear ophthalmoplegia, nystagmus, dystonia, athetosis, and intention tremor; or aseptic meningitis with confusion, cerebellar involvement, and spastic tetraparesis (74). A rigid form of parkinsonism with preponderant akinesia but without tremor and resistance to L-DOPA treatment has been described (116). There are also rare cases of generalized chorea (111). Focal and generalized seizures may occur during relapses of cerebral vasculitis.
Sjögren syndrome may also present as limbic encephalitis. A case series of 3 patients describes limbic encephalitis occurring after the diagnosis of Sjögren syndrome was made, with or without other neurologic complications such as motor axonal neuropathy (17). Antineuronal antibodies were tested and were negative, thus suggesting Sjögren syndrome was the cause of these symptoms.
Meningoencephalitis. Meningoencephalitis is a relatively common neurologic complication of Sjögren syndrome (24). It begins with headache, myalgias, confusion, and meningeal signs without fever (94); in some cases, sensorineural deafness may occur. Focal neurologic signs may be present; brain MRI shows hyperintense multifocal inflammatory changes in the cerebral white mater and cortex. The CSF profile is consistent with an aseptic lymphocytic meningitis, with up to 900 cells/mm3. Recurrences occur, and changes associated with vasculitis may be demonstrated by angiography.
Psychiatric and cognitive disorders. Central nervous system involvement precedes the symptoms of Sjögren syndrome in 52% to 80% of patients (62). In many patients, symptoms of depression and anxiety may precede the diagnosis of Sjögren syndrome or become chronic accompaniments of the disease (110). Also common are cognitive changes with poor concentration and memory and abnormalities in neuropsychiatric testing, including executive dysfunction and frontal lobe deficits. The pathogenesis of these changes is not clearly understood, but it may be part of the so-called “vascular depression-vascular cognitive disorder,” resulting from ischemic interruption of prefrontal circuits important for mood and behavior (92). Sicca symptoms are more common in patients with cognitive disturbances and low inflammatory disease activity. A study comparing the risk of Alzheimer disease in primary Sjögren syndrome patients with healthy controls revealed a 2.68 fold higher risk in the primary Sjögren syndrome patients after 10 years (57).
Optic neuropathy. Patients with Sjögren syndrome can present with bilateral visual loss secondary to retrobulbar optic neuropathy (02; 24). In some cases, blindness secondary to bilateral optic neuropathy was the first manifestation of Sjögren syndrome (107; 86; 09). In about 12% to 15% of patients, the diagnosis was revealed by abnormal visual evoked potentials (24). The pathogenesis of optic nerve involvement in Sjögren syndrome is postulated to result from a combination of ischemic vasculitis and demyelination. The differential diagnosis should include multiple sclerosis ad neuromyelitis optica.
Complications are discussed in the clinical manifestations.
A 63-year-old woman developed paraplegia, urinary frequency, urgency, and incontinence; she had been experiencing sensory symptoms in her legs for the last 10 months. Neurologic examination revealed spastic paraparesis, lower limb hyperreflexia, and flexor plantar responses. No sensory level was noted, but she had hypoesthesia to pinprick in her left buttock and posterior thigh. MRI demonstrated abnormal focal signal intensities on T2-weighted images, enhancing with gadolinium on T1-weighted images, at the C5-6 and T8-9 levels and on the conus medullaris and cauda equina. MRI of the brain was unremarkable. CSF showed lymphocytic pleocytosis with 0.011 x109 cells/L, few atypical lymphocytes, a mildly elevated protein level (0.85 g/L), a nonreactive VDRL test, and absent oligoclonal bands. A second CSF had 0.006 x109 cells/L, a protein level of 0.72 g/L, and normal cytology. Serum and urine protein electrophoresis showed neither monoclonal gammopathy nor elevation of the angiotensin-converting enzyme level; serum B12 levels were normal. Antibodies to HIV and HTLV-1 were nonreactive. Chest x-ray was normal. A gallium body scan demonstrated increased activity in the lachrymal glands, regional lymph nodes, and right paratracheal region; there was no evidence of sarcoidosis.
Over the next 3 months, her paraparesis progressed to near paraplegia associated with a sensory level at the umbilicus and with left arm paresthesias. Antinuclear antibody ratio was 1:640; the erythrocyte sedimentation rate was 41 mm/h. Mild sicca symptoms (xerostomia and keratoconjunctivitis) were found on further questioning. Neurologic examination showed a left afferent pupillary defect, spastic paraplegia with hyperreflexia, crossed adductor responses, ankle clonus, and bilateral Babinski sign. Motor strength was 5/5 (MRC scale) in the upper extremities and 0/5 in the lower extremities, except for 1/5 for ankle dorsiflexors and plantar flexors. A T10 sensory level was found, along with decreased anal sphincter tone. MRI of the cervical, thoracic, and lumbar spine showed multifocal areas of increased T2-signal intensity, enhanced by gadolinium at the C5-7, T3-5, and T8-11 levels and on the conus medullaris. A third CSF sample had 0.035 x109 cells/L, a glucose level of 2.9 mmol/L (53 mg/dL), and a protein level of 0.62 g/L. Oligoclonal bands and myelin basic protein were absent, and the IgG index was normal (0.63). A second antinuclear antibody test was positive, with a titer of 1:2560; Ro/SS-A antibody was positive with a speckled pattern. Complement C3 was 1.78 g/L (reference range, 0.86 to 1.84 g/L) and C4, 0.23 g/L (reference range, 0.20 to 0.59 g/L). Visual evoked potentials were prolonged in the left eye. Examination of a minor salivary gland biopsy specimen showed chronic sialadenitis, with a focus score of 3. NMO antibody was negative.
The patient was diagnosed with CNS Sjögren syndrome because of the presence of Sicca syndrome, abnormal serological test results, and the salivary gland biopsy results, which fulfilled the American-European Consensus Criteria for Sjögren syndrome. The patient received a pulse dose of intravenous methylprednisolone sodium succinate, 1 g/d for 3 days, followed by oral prednisone, 60 mg/d. Rheumatology consultants recommended treatment with intravenous cyclophosphamide, 0.75 g/m2, followed by equal monthly doses for 6 months, along with oral prednisone, 20 mg/d. With this treatment, the patient experienced marked improvement in the strength of most of the muscles in her lower extremities, going from 0-1/5 to 3/5 (MRC scale). Furthermore, sensory complaints, particularly subjective paresthesias in the left upper extremity, slowly abated during the ensuing several weeks (117).
Sjögren syndrome is an autoimmune disorder manifested by alterations of B-cell and T-lymphocytes occurring in individuals with a genetic predisposition.
The pathogenesis of Sjögren syndrome has been reviewed by Fox (27). The exact mechanisms are still unknown, but the most prominent immunoregulatory alterations are B-cell hyperreactivity and enhanced levels of B-cell-activating factor/B-lymphocyte stimulator. The pathogenesis is multifactorial, whereby environmental factors activate glandular endothelial or epithelial cells, triggering inflammation in individuals with a genetic predisposition (HLA DR). The inappropriate B-cell activation can follow various stages of evolution, leading in extreme cases to malignant transformation of B-cells to produce lymphoma. Patients with Sjögren syndrome have a 6- to 44-fold increased risk for developing non-Hodgkin lymphoma (10).
Polyclonal B-cell hyperreactivity in Sjögren syndrome accounts for the hypergammaglobulinemia, circulating immune complexes, and multiple autoantibodies directed against both organ- and nonorgan-specific autoantigens. Clinically, the most important and best characterized are the autoantibodies anti-Ro (SS-A) and anti-La (SS-B) directed against cellular heterogeneous ribonucleoprotein complexes consisting of antigenic proteins (46). The antibodies recognize autoantigens, which bind to ribonucleoprotein particles consisting of a 60kD SS-A/Ro RNA binding protein and hY1 RNAs and 48 KD RNA binding protein, which facilitates maturation of RNA polymerase III transcripts, such as precursors to tRNA and 5S-RNA (54). These antibodies are found in approximately 50% of the patients with Sjögren syndrome and tend to be associated more with severe glandular and extraglandular manifestations (46; 54; 27).
There are also alterations of cellular immunity in Sjögren syndrome. Mononuclear cells (primarily T-lymphocytes) infiltrate salivary and lachrymal glands with partial destruction of acinar and ductal structures. The T-lymphocytes and also the glandular cells cause the release of cytokines (especially interleukin-1, interleukin-6, and tumor necrosis factor alpha) (27). These cytokines, along with autoantibodies and metalloproteinases, cause a decreased release of neurotransmitters and a diminished response of the residual glandular cells to available neurotransmitters, resulting in the symptoms commonly seen in Sjögren syndrome (28). Interaction between constitutional factors (hormones and major histocompatibility complex) and environmental factors (most likely viruses) are thought to be important in the etiology of Sjögren syndrome. Females are affected in a ratio of 9:1 compared to males. Hormones such as estrogens, reactive hypothalamic and hypophyseal peptide hormones and dehydroepiandrosterone may play a role. Sjögren syndrome is associated with HLA-DR 3 and linked genes B8, DQ 2, and the C4 null gene in about 50% of the patients. Postulated infectious agents capable of triggering the immune process include herpes viruses (particularly Epstein Barr virus, cytomegalovirus, and human herpesvirus-6), H pylori and human retroviruses, in particular HTLV-1.
HTLV-1 and Sjögren syndrome. Transgenic mice expressing the HTLV-1 tax gene develop an exocrinopathy similar to that seen in patients with Sjögren syndrome (34). The expression of sequences homologous to the HTLV-1 tax gene has been found in labial salivary glands of patients with Sjögren syndrome (60; 101). Kompoliti and colleagues described a patient with Sjögren syndrome, lymphocytic pneumonitis, and HTLV-1 myelitis (53). More recently in Japan, Nakamura and colleagues investigated the presence of Sjögren syndrome in patients with HTLV-1-associated myelopathy, including a histological examination of labial salivary glands; definite Sjögren syndrome was found in 65% (13/20) of patients (76). More severe inflammatory cell infiltration in labial salivary glands was found in patients with HTLV-1-seropositive Sjögren syndrome than in seronegative controls. Pot and colleagues reported a spectacular radiological and clinical recovery of a patient with HTLV-1 myelitis and Sjögren syndrome who was treated with combined antiretroviral drugs (lamivudine and tenofovir) plus immunosuppressant therapy with prednisone and mycophenolate mofetil (85). Based on the aforementioned findings, it is advisable to test for HTLV-1 antibodies in all patients with Sjögren syndrome who develop a myelopathy.
Population-based studies show that the prevalence of Sjögren syndrome ranges between 0.5% and 5%, with most of the cases presenting in postmenopausal women. Although the majority of cases present in midlife, there are reports of Sjögren syndrome in children and the elderly. In Olmstead County, Minnesota, the incidence rate has been estimated at 3.9 cases per 100,000 annually (83). Primary Sjögren syndrome is more common in women than men; the ratio of women to men in patients with neurologic manifestations ranges from 3.8 to 31 (15).
Neurologic manifestations have been reported traditionally in about 20% of patients with Sjögren syndrome (range 6% to 70%) (56; 24; 15). Goransson and colleagues performed a population-based study in Sweden and found that 27% of patients with Sjögren syndrome had neuropathy, including 31% with motor neuropathy, 13% with sensory neuropathy, and 11% with sensorimotor neuropathy (32). Central nervous system involvement ranges from 2% to 25% in hospitalized patients (31).
Ye and colleagues reviewed a large cohort of primary and secondary Sjögren syndrome patients in a cross-sectional study and found that low complement (C3) levels, xerophthalmia, positive ANA, cardiac involvement, and labial salivary gland histologic results were useful in predicting the risk of neurologic complications (122).
Depending on the form of neurologic presentation, the differential diagnosis of neurologic Sjögren syndrome include many processes that effect either the peripheral or central nervous system. As mentioned above, demyelinating diseases such as multiple sclerosis, neuromyelitis optica, and transverse myelitis are commonly on the differential for central nervous system Sjögren syndrome. Other multisystemic autoimmune disorders should be considered, as well as antineuronal antibody encephalitis and infectious processes (especially HLTV-1). The onset of transverse myelitis with thoracic back pain and rapid loss of motor function is reminiscent of nucleus pulposus herniation (Toro and Roman 1994). Serum levels of vitamin B12 and methylmalonic acid are diagnostic for subacute combined degeneration.
Peripheral nervous system presentations vary widely and, therefore, the diagnostic work up should be focused on the patient’s symptoms, dependent on the clinical presentation.
The differential diagnosis of Sjögren syndrome includes a past history of head and neck radiation therapy, hepatitis C infection, AIDS, preexisting lymphoma, sarcoidosis, graft-versus-host disease, and the recent use of anticholinergic drugs.
The diagnostic workup of Sjögren syndrome is outlined in tables 1a and 1b. There is no gold standard test for the diagnosis of neurologic Sjögren syndrome. However, it is important to note that inflammatory CSF changes are rarely found and if so, a pathognomic pattern does not exist. CSF analysis is often used to exclude other autoimmune and infectious processes (79).
Treatment of keratoconjunctivitis sicca includes tears replacement and conservative therapy, as well as topical ocular and systemic medications (81). Preservative-free preparations of artificial tears are preferred to avoid irritation and allergic reactions. In refractory cases, more concentrated, viscous solutions or hydroxypropyl cellulose pellets inserted under the lower eyelids may be used. Ointments are used only at night. In keratoconjunctivitis sicca, inflammation appears to have a role in the pathogenesis of the ocular surface epithelial disease. Clinical improvement has been observed after therapy with antiinflammatory agents including corticosteroids, cyclosporine, and doxycycline. Cyclosporine A emulsion was approved by the U.S. Food and Drug Administration (FDA) as therapy for dry eyes. Randomized placebo-controlled FDA clinical trials showed that cyclosporine A was superior to vehicle in stimulating aqueous tear production, decreasing corneal punctuate fluorescein staining, reducing symptoms of blurred vision, and decreasing artificial tears use in patients with keratoconjunctivitis sicca. No ocular or systemic toxicity was observed from this medication (95).
For the treatment of xerostomia, secretagogues such as pilocarpine may increase secretions in patients with sufficient exocrine tissue. Pilocarpine is usually given at a dose of 5 mg orally 4 times a day to a maximum dose of 30 mg (114). Adverse effects include feeling hot and flushed, increased perspiration, and increased bowel and bladder motility. Cevimeline is a muscarinic agonist with higher affinity for the M3 receptor site and decreased affinity for M2 receptors, which are found in cardiac tissue, minimizing the likelihood of cardiac stimulation. Cevimeline also has a much longer half-life than pilocarpine. Cevimeline augments not only the salivary flow rate but also the secretion rate of some digestive or defense factors from infections (102). Daily topical fluoride, antimicrobial mouth rinse, and frequent dental care are important to minimize progression of dental decay in patients with reduced salivary flow (19). Two phase III studies showed that the use of oral interferon-alpha by patients with Sjögren syndrome, given at low dosage by the oromucosal route can significantly increase unstimulated whole saliva flow in patients with primary Sjögren syndrome, without causing significant adverse events (18). Oral dryness could be ameliorated with the use of sugar-free chewing gum or candies, and patients should be counseled on dietary changes and restriction of sugar intake.
Vitamin B12 (cobalamin) deficiency. Andres and colleagues documented the common occurrence of vitamin B12 deficiency in 80 patients with primary Sjögren syndrome (04). Serum B12 levels below 200 pg/mL were found in 8.8% (7/80) of patients, and 56.2% of patients had B12 levels between 200 and 300 pg/mL, for an overall prevalence of B12 deficiency of 65%. In comparison, they found B12 deficiency in 5.3% of patients in an Internal Medicine clinic. In the general population, B12 deficiency occurs in 15% of people over 60 years of age (58). Cobalamin is first released from proteins in food by pepsin and stomach acid; then cobalamin is bound to the salivary vitamin B12 R-binder protein (55) before it can be attached to intrinsic factor. Andres and colleagues postulated that B12 deficiency from food-cobalamin malabsorption is the result of a lack of saliva, which is typical of Sjögren syndrome (06).
Vitamin B12 deficiency causes a number of neurologic manifestations (91) that could worsen the neurologic complications of Sjögren syndrome. The most common manifestations of cobalamin deficiency include: peripheral sensory neuropathy; subacute combined degeneration of the spinal cord presenting with sensory ataxia and pyramidal tract involvement with bilateral Babinski sign (05); cerebellar syndromes; cranial nerves neuropathies, including optic neuritis and optic atrophy; urinary or fecal incontinence; stroke and atherosclerosis from hyperhomocysteinemia with cognitive decline or dementia (30); parkinsonian syndromes; and depression. In practice, it is advisable to exclude and treat B12 (cobalamin) deficiency in patients with Sjögren syndrome and psychiatric or neurologic symptoms, including the several types of neuropathy and myelopathy described.
The treatment of neurologic complications in Sjögren syndrome is dictated by the clinical symptomatology, the clinical course, and the implicated pathogenetic mechanism.
Peripheral nervous system. The common symmetric, distal axonal sensory and sensorimotor neuropathy is believed to be caused by perivascular cellular infiltration and necrotizing vasculitis. These axonal neuropathies usually follow a slowly progressive and insidious course that is often treated with the usual symptomatic therapy of Sjögren syndrome (salicylates, nonsteroidal agents, hydroxychloroquine, oral corticosteroids). IVIg has been shown to improve sensorimotor or nonataxic sensory neuropathies, but not in ataxic neuropathies (89). In cases with mononeuritis multiplex, multiple cranial neuropathies, pseudo-amyotrophic lateral sclerosis forms, or with lesions suggestive of severe vasculitis, first-line treatment appears to be intravenous corticosteroid therapy; however, when the patient’s course fails to improve or deteriorates, a nonsteroidal immunosuppressant agent should be considered (66). Patients with vasculitis- or cryoglobulinemia-related neuropathies have had good response to rituximab treatment (65).
The sensory ataxic ganglionopathy with antiganglion neuron antibodies and the demyelinating polyradiculoneuropathy of Sjögren syndrome respond poorly to triple treatment with prednisolone, cyclosporine, and cyclophosphamide (49). There is 1 case report of a patient with sensory neuronopathy treated with infliximab (13). There was marked improvement in clinical and neurophysiologic deficits associated with the neuronopathy using a dose of 3 mg/kg given at weeks 0, 2, 6, and every 12 weeks thereafter. Plasmapheresis and rituximab may produce improvement, and there is occasional response to treatment with IVIG (0.4 g/kg for 5 days) (43). Yamada and colleagues reported excellent results with IFN-alpha treatment (3 MIU/day, 3 times weekly), resulting also in marked improvement of the clinical and laboratory manifestations of Sjögren syndrome (121). This treatment could potentially be useful also for predominantly autonomic neuropathies with elevated titers of ganglionic acetylcholine receptor autoantibody, trigeminal neuralgia, and for the painful neuropathy without sensory ataxia of Sjögren syndrome.
Skeletal muscle. Myalgias in patients with Sjögren syndrome may respond to hydroxychloroquine (6 to 8 mg/kg daily) (27). Additional treatments may include corticosteroids, azathioprine, and methotrexate.
Encephalic manifestations. Meningoencephalitis, focal manifestations, or seizures consistent with vasculitis should be treated with intravenous steroids (41). In severe cases, intravenous corticosteroids may be used in conjunction with cyclophosphamide, rituximab, azathioprine, cyclosporine, or methotrexate (78; 47). Plasmapheresis, or treatments with IVIG, are probably indicated, but there are minimal reported data with these therapeutic modalities (12).
Spinal cord involvement. Rogers and colleagues have reviewed this topic (90), but these data are based on anecdotal reports. Nonetheless, it seems clear that treatment of Sjögren syndrome myelopathy with intravenous steroids alone is not adequate (118; 90; 20). Combination therapy with agents such as cyclophosphamide, rituximab, azathioprine, cyclosporine, or methotrexate must be considered.
Cyclophosphamide is the historical agent of choice, given intravenously in pulse dosing (117; 20). Current treatment regimens consist of a monthly intravenous bolus of drug for 6 to 12 months (20); then, if needed, every 3 to 6 months for the second year. Doses used are 0.75 to 1.0 gm/m2. Caution is required due to the high frequency of lymphoma in Sjögren syndrome. The most common severe adverse effects associated with cyclophosphamide are hemorrhagic cystitis and myelosuppression. Hemorrhagic cystitis can be prevented by adequate hydration and use of mercapto ethane sulfonate sodium, a sulfhydryl compound that binds to the toxic metabolite formed by cyclophosphamide, thus, preventing it from binding to the bladder wall and causing damage. Myelosuppression may be dose-limiting, with the white blood cell nadir occurring 7 to 10 days after treatment. Owing to the aforementioned side effects, the use of mycophenolate mofetil is being explored as an alternative to cyclophosphamide in the treatment of vasculitis. Rituximab is being used more often now because of the more favorable side effect profile and similar efficacy to cyclophosphamide.
Azathioprine has been used for relapses or intolerance to cyclophosphamide therapy (38). In uncomplicated Sjögren syndrome, azathioprine by itself was ineffective in a dose of 1 mg/kg/d for 6 months. The most serious side effects are dose-related myelosuppression, gastrointestinal disturbances, stomatitis, and hepatotoxicity.
Cyclosporine in combination with corticosteroids may be effective in the treatment of optic neuritis. Cyclosporine is a potent immunomodulator that decreases cytokines involved in T-cell activation and has direct effects on B-cells and macrophages. The onset of effect of cyclosporine is 1 to 3 months. It is only available in an oral dosage form. Serious adverse effects are hypertension, hyperglycemia, nephrotoxicity, tremor, gastrointestinal intolerance, hirsutism, and gingival hyperplasia.
Methotrexate at a dose of 0.2 mg/kg/week tends to improve subjective oral and ocular symptoms, without objective changes. It is an antineoplastic and antiinflammatory agent. Serious adverse effects include thrombocytopenia, gastrointestinal intolerance, stomatitis, hepatotoxicity, and pulmonary toxicity.
Other nonsteroidal immunosuppressant agents should be considered, especially when lack of efficacy or intolerance to cyclophosphamide appears. Other symptoms may benefit from concomitant immunosuppressant treatment. In addition, plasmapheresis appears to be useful when acute relief of symptomatology is needed, such as in a patient with rapid deterioration who is waiting for an immunosuppressant to work. IVIG has been successfully used in Sjögren CNS vasculitis (12). The dose used in the patient was 400 mg/kg/d for 5 days along with corticosteroids, with additional monthly doses of IVIG for 6 months and then every 2 to 5 months as indicated by the patient’s neurologic symptoms.
Infliximab, chimeric human-mouse anti-tumor necrosis factor alpha antibodies, has not been used for myelopathy but has shown some usefulness in the treatment of peripheral nervous system manifestations of Sjögren syndrome (13).
Rituximab, a chimeric monoclonal antibody directed against the B cell differentiation marker CD20, has been used with some success in the treatment of primary Sjögren syndrome (44; 01). Most of the evidence consists of case reviews for treatment of extraglandular manifestations of Sjögren syndrome. To our knowledge, there are no randomized placebo-controlled clinical trials of infliximab or rituximab in the treatment of neurologic manifestations associated with Sjögren syndrome.
In a questionnaire-based study, primary Sjögren syndrome had no impact on pregnancy outcome before disease onset (36). The most important condition associated with primary Sjögren syndrome in anti-SSA-positive mothers was congenital heart block in the offspring. This condition is associated with high morbidity and mortality, and these patients should receive multidisciplinary care in a neonatal intensive care unit (82).
Veronica P Cipriani MD MS
Dr. Cipriani of the University of Chicago Medical Center received consulting fees from Genetech as an advisory board participantSee Profile
Francesc Graus MD PhD
Dr. Graus, Emeritus Professor, Laboratory Clinical and Experimental Neuroimmunology, Institut D’Investigacions Biomédiques August Pi I Sunyer, Hospital Clinic, Spain, has no relevant financial relationships to disclose.See Profile
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