Sjögren’s syndrome (SS) is characterized by chronic inflammation of exocrine glands, such as lachrymal and salivary glands, leading to xerophthalmia and xerostomia [
The pathogenic mechanisms responsible for SS neurological involvement are unknown. Many hypotheses have been considered, namely, the direct infiltration of the central nervous tissue by lymphocytic cells, the vascular injury due to antineuronal and anti-SSA antibodies, and/or the ischemia secondary to small vessel vasculitis [
In the present paper, we described two patients with SS, who presented mononeuritis: the first patient presented optic neuritis preceding the clinical onset of SS and the second developed a very unusual neuritis of the right phrenic nerve. Finally, a review of the literature on cervicocranial neuritis in the course of SS was carried out.
A 40-year-old woman referred to our Rheumatology Unit in January 2012, in the suspicion of an autoimmune disorder. Since 2006, she presented episodes of left optic mononeuritis, responsive to steroids; thus, she was undergoing a neurologic follow-up for a hypothetical multiple sclerosis. The first magnetic resonance (MR) of the brain and the spine showed a solitary T2-hyperintense, gadolinium enhancing lesion of the retrobulbar and intracanalicular left optic nerve, suggestive for demyelinated plaque; anyway, the subsequent yearly MRs did not show other lesions. Since 2006, positivity for antinuclear antibodies (ANA) at the titre of 1 : 640 (speckled) was detected, along with reduced lymphocyte counts (500–600 cells/
Only after the patient referred to our Rheumatology Centre, a deeper check-up was performed, namely, salivary glands scintigraphy that showed mild salivary hyposecretion basally and after lemon juice stimulation and Schirmer’s test that was bilaterally positive (<5 mm). On these bases, a diagnosis of SS, classified according to the new American College of Rheumatology/Sjögren’s International Collaborative Clinical Alliance (ACR/SICCA) criteria [
No chronic treatment was prescribed, except steroids in the case of the further two episodes of mild optic neuritis.
A 54-year-old woman with diagnosis of SS-scleroderma overlap syndrome from 2005 referred to our Rheumatology Unit in January 2013. She did not present skin involvement, while an overt sicca syndrome was observed. Serum anticentromere autoantibodies were present, without anti-ENA specificity; Schirmer’s test was clearly positive (<1 mm). Videocapillaroscopy revealed an “early” scleroderma pattern; salivary glands echography evidenced a complete atrophy, while chest high-resolution computed tomography did not show interstitial lung disease, but only hypotonia of oesophagus. A labial salivary gland biopsy was not performed, since the patient refused it; thus, the diagnosis of primary SS, classified according to ACR/SICCA criteria [
Since 2012, the patient progressively complained of fatigue and dyspnoea in the absence of new radiological pulmonary alterations; therefore, oxygen therapy (3 L/min) was necessary. Forced vital capacity was 50% of normal value, whereas heart echography was normal. In November 2012, the diagnosis of paralysis of right diaphragm was suspected on the bases of clinical symptoms and radiological alterations at standard chest X-ray and then confirmed by the detection of mixed demyelinated/axonal damage of right phrenic nerve at electromyographic examination. A modest axonal polyneuropathy of the arms and the legs was also present, while neck MR excluded compressions of nerve roots. Treatment with steroids at 1 mg/kg/day was prescribed without significant improvement; thus the patient was referred to our Rheumatology Unit, where an immune-mediated mononeuritis of the right phrenic nerve was suspected. Therapy with monthly cycles of intravenous immunoglobulin (50 g/day, for 3 consecutive days) was decided. After the third cycle, the patient experienced reduction of dyspnoea (from 10/10 to 6/10 of modified Borg scale), improved physical performance, and tapering of daily oxygen therapy, without disease exacerbation up to date.
An exhaustive revision of the literature was done by including all case reports and case series of SS patients with cervical-cranial neuritis present in PubMed database (Table
Review of the literature regarding Sjögren's syndrome (SS) patients with cranial neuritis.
First authors/year | Ref. | No. pts. | Age/gender | Onset of neuritis versus diagnosis of SS (years)* | Nerves involved/clinical features | Follow-up |
---|---|---|---|---|---|---|
Sjogren/1935 | [ |
1 | n.d. | n.a. | bil. VII | n.a. |
|
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Weber/1945 | [ |
1 | n.a. | n.a. | III | n.a. |
|
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Spillane/1959 | [ |
1 | 58 F | n.a. | bil. V | n.a. |
|
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Attwood/1961 | [ |
1 | 50 F | n.a. | III–V–VII–IX | Improv. with Cs |
|
||||||
Kaltreider/1969 |
[ |
4 | 45 F, 48 F, |
+6; +2; |
sV (3), bil. (pt. 3); bil. I + PNS involv. (pt. 4) | 1: chronic course, onset during Cs; 2, 4: Cs inefficacy; 3: response to Cs |
1 | 55 F | +8 | I | remission within 1 year | ||
|
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Whaley/1972 | [ |
1 | 27 F | n.a. | V | Response to Cs and P.E. |
|
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Hull/1984 | [ |
1 | 33 F | 0 | V + PNS | n.a. |
|
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Vincent/1985 | [ |
1 | 53 F | +7 | V–VII–IX-diplopia | Recurrent ep. (6 in 7 years) |
|
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Alexander/1986 | [ |
16 | Mean 50 F | n.a. | 7 II, 2 III, 1 V, 6 VI, 1 VII, 1 VIII | n.a. |
|
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Shimode/1986 | [ |
1 | n.a. | n.a. | II | n.a. |
|
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Serratrice/1986 | [ |
1 | 58 F | +4 | V | Cs 20 mg/day ineffective |
|
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Malinow/1986 | [ |
1 | F | n.a. | V + d.r. ganglionitis | n.a. |
|
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Mauch/1994 | [ |
1 | n.a. | n.a. | V | n.a. |
|
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Hankey/1987 | [ |
1 | 78 F | + (several years) | V + PNS involv. | n.a. |
|
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Wise/1988 | [ |
3 | F | − (1–6) | II | n.a. |
|
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Laloux/1988 | [ |
1 | 81 F | n.a. | V + d.r. ganglionitis | n.a. |
|
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Graus/1988 | [ |
2 | 58 F, 75 F | n.a. | sV | n.a. |
|
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Phanthumchinda/ |
[ |
1 | 28 F | 0 | Multiple | Resolved with Cs |
|
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Uchihara/1989 | [ |
1 | n.a. | n.a. | bil. VII | n.a. |
|
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Mellgren/1989 | [ |
5 | n.a. | n.a. | V | n.a. |
|
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Andonopoulos/ |
[ |
3 | n.a. | n.a. | V | n.a. |
|
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Flint/1990 | [ |
1 | n.a. | n.a. | bil. sV | n.a. |
|
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Mukai/1990 | [ |
5 | n.a. | n.a. | V | n.a. |
|
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Semah/1990 | [ |
1 | 57 F | −11 | V | Chronic course |
|
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Berman/1990 | [ |
1 | 10 F | 0 | II + CNS vasculitis | Improv. with immunosuppressors |
|
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Berault-Dupont/1992 | [ |
1 | 59 F | 0 | VII | Improv. to high dosage Cs |
|
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Tesar/1992 | [ |
3 | 20 F, 35 F, 41 F | 0; −1; −2 | II, bil. III-IV–VI (pt. 1), bil. II (pt. 2), II–IX-diplopia + CNS involv. (pt. 3) | Resolution with high dosage Cs (pt. 1); |
|
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Soubrier/1993 | [ |
4 | n.a. | n.a. | V | n.a. |
|
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Pou Serradell/1993 | [ |
1 | 63 F | − (n.a.) | III (8 ep.), multiple (5 ep.) | Recurrent, responsive to Cs |
|
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Güell/1993 | [ |
1 | n.a. | 0 | V | n.a. |
|
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Mauch/1987 | [ |
1 | n.a. | n.a. | sV | n.a. |
|
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Bakouche/1994 | [ |
1 | 49 M | − (n.a.) | Diplopia-V-tinnitus | Recurrent (3 ep.) solving within 3 weeks |
|
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Matsukawa/1995 | [ |
1 | 56 F | 0 | V then IV–VI | The first ep. autoresolved; the second with Cs |
|
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Harada/1995 | [ |
1 | n.a. | − (n.a.) | II + acute transv. myelopathy | Resistant to Cs |
|
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Tajima/1997 | [ |
9 | Mean 54.9 F; 51 F | n.a. | 8 V, 4 bil.; 1 II | n.a. |
|
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Rojas-Rodriguez/1998 | [ |
1 | 8 F | − (n.a.) | II | Visual impairment not responsive to Cs, IVIG, CYC pulses |
|
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Govoni/1999 | [ |
2 | 51 F, 24 F | +6; +2 | VIII; III + cerebellar ataxia | n.a. |
|
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Dumas/1999 | [ |
1 | 41 F | n.a. | sV | n.a. |
|
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Kuhl/1999 | [ |
1 | 54 F | +8 | IV | Improv. spontaneously within few weeks |
|
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Touze/1999 | [ |
1 | 34 F (first ep.) | −35; −2; 0; |
VI, VII, IX, laryngeal | Recurrent ep., not improv. with Cs |
|
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Oketani/1999 | [ |
1 | 52 F | +2 | II | Improv. to pulse Cs |
|
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Wingerchuk/1999 | [ |
4 | n.a. | n.a. | II | n.a. |
|
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Chu/2000 | [ |
1 | 54 F | 0 | IV-V | Resolution with Cs and Aza within 4 weeks |
|
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Urban/2001 | [ |
1 | 53 F | +1 | V–IX-X | Chronic course |
|
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Hadithi/2001 | [ |
1 | 41 F | 0 | VII | Autoresolution after several days |
|
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Lafitte/2001 | [ |
1 | n.a. | n.a. | V | n.a. |
|
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Kadota/2002 | [ |
1 | 63 F | 0 | II | Autoresolution within 6 months |
|
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Maeda/2002 | [ |
1 | 21 F | 0 | II | Autoresolution |
|
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Anaya/2002 | [ |
1 | n.a. | n.a. | II | n.a. |
|
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Yanagihara/2002 | [ |
1 | 39 F | 0 | III | n.a. |
|
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Font/2003 | [ |
6 | Mean 58 F | −4 to 0 | V | Chronic course besides oral Cs |
|
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Delalande/2004 | [ |
30 | n.a. | n.a. | 2 I, 13 II, 5 V, 4 VII, 6 VIII | n.a. |
|
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Mori/2005 | [ |
20 | Mean 55.6 | − (n.a.) | 15 V, 1 VII, 5 multiple (III, V, VI, VII, IX, X, XII) | 4/7 patients improv. with Cs |
|
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Rousso/2005 | [ |
1 | 40 F | 0 | VII | Recurrent ep. that autoresolved, in 1 pt. with Cs/vit. B12 within 12 days |
|
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Oishi/2007 | [ |
1 | 65 M | 0 | VI | Autoresolved within 5 months |
|
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Cardoso/2006 | [ |
1 | 9 F | −9; 0 | bil. II | 2 ep. 9 years apart, irreversible visual loss after initial response to Cs |
|
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Galbussera/2007 | [ |
1 | 79 F | 0 | III | Resolution with Cs and IGIV within 2 months |
|
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Pournaras/2007 | [ |
1 | 38 M | 0 | bil. II | Improv. with Cs |
|
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Gökçay/2007 | [ |
1 | 20 F | −10 | II | Cs/Aza resistant, switch to CYC |
|
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Arabshahi/2006 | [ |
1 | 11 F | 0 | bil. II + transv. myelitis | Recurrent ep., transient improv. with Cs |
|
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Barroso/2007 | [ |
1 | 34 F | −9 | II + CNS involv. | Recurrent ep., responsive to iv Cs |
|
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Teo/2008 | [ |
1 | 52 F | 0 | III | n.a. |
|
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Béjot/2008 | [ |
1 | 53 F | + (n.a.) | bil. II + aseptic meningitis | Improv. with CYC |
|
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Lui/2008 | [ |
1 | 59 M | 0 | III | Resolved with Cs/Aza within 2 weeks |
|
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Ii/2008 | [ |
1 | 49 F | 0 | II | Improv. with IVIG |
|
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Javed/2008 | [ |
2 | n.a. | n.a. | II | n.a. |
|
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Pittock/2008 | [ |
6 | n.a. | n.a. | II | n.a. |
|
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Min/2009 | [ |
6 | n.a. | n.a. | II | n.a. |
|
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Ashraf/2009 | [ |
1 | 47 F | 0 | V–IX–XII | Resolved with Cs and MTX |
|
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Kato/2009 | [ |
1 | 25 F | + (2) | II + CNS involv. | Improv. with high-dosage Cs |
|
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Dellavance/2009 | [ |
2 | n.a. | n.a. | II | n.a. |
|
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Kim/2009 | [ |
7 | n.a. | n.a. | II | Poor prognosis for high relapse rate |
|
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Alhomoud/2009 | [ |
10 | Mean 40 F | n.a. | 9 II + CNS involv.; 1 VII | n.a. |
|
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Rabadi/2010 | [ |
1 | 23 F | 0 | II | n.a. |
|
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Sakai/2010 | [ |
1 | 77 M | 0 | III-bil.V-VI-VII | Improv. with Cs |
|
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Imbe/2010 | [ |
1 | 31 F | 0 | II + acute myelitis | Improv. with Cs/P.E. |
|
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Nascimento/2010 | [ |
2 | n.a. | −10; −0.5 | V | n.a. |
|
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Chourkani/2010 | [ |
2 | 43 F, 48 F | 0 | II (bil. 1 pt.) | Improv. with Cs/immunosuppressors |
|
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Massara/2010 | [ |
3 | 48, 50, 74 F | +5, +6, |
2 II, 1 VII | Resolution with iv Cs |
|
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Cojocaru/2011 | [ |
1 | 50 F | +0.7; +2 | II then V | 1° ep.: improv. with Cs/IVIG; 2° ep.: Cs-resistant |
|
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Niţescu/2011 | [ |
2 | n.a. | + (n.a.) | II | n.a. |
|
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Yadav/2011 | [ |
1 | 26 F | + (several years) | bil. II | n.a. |
|
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Koga/2011 | [ |
1 | 31 F | 0 | II + acute myelitis | Improv. with P.E., Cs-resistant |
|
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Gono/2011 | [ |
7 | Mean 44 F | n.a. | 3 II (1 + CNS involv.), 2 V, 1 VII, 1 IX-X | n.a. |
|
||||||
Kolfenbach/2011 | [ |
6 | n.a. | n.a. | II | Recurrent ep. |
|
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Estiasari/2012 | [ |
10 | n.a. | n.a. | II | n.a. |
|
||||||
Horai/2012 | [ |
8 | 63 F, 52 M, 43 F, 61 F, |
0 (first case); n.a. | V (4 bil.) | Improv. with Cs/tacrolimus (1); Improv. with Cs (1); |
|
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Tan/2012 | [ |
1 | 56 F | 0 | bil. II | Permanent visual impairment |
|
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Maruta/2012 | [ |
1 | 89 F | 0 | II | Improv. with iv Cs |
|
||||||
Mallucci/2012 | [ |
1 | 74 F | 0 | bil. II | n.a. |
|
||||||
Teixeira/2013 | [ |
4 | Mean 47.9 F | n.a. | 2 II, V, VI, 2 VII | Cs almost effective |
|
||||||
Briani/2013 | [ |
1 | 66 F | +5 | V | n.a. |
|
||||||
Flanagan/2013 | [ |
1 | 64 M | 0 | V | n.a. |
|
||||||
Tang/2013 | [ |
8 | Mean 34.7 F | 0 | II | Recurrent (3 pts), response to Cs/immunosuppressors |
|
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Present cases | 2 | 40 F, 54 F | −6; +8 | II; phrenic nerve | Improvement with Cs (40 F), with IVIG (54 F) | |
|
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TOTAL |
|
|
|
(*) 0: diagnosis of SS and neuritis were contemporary; + (yrs): neuritis onset after diagnosis of SS; − (yrs): neuritis onset before diagnosis of SS. (
Alterations of the I cranial nerve were rarely observed; to date, only 4 cases were described [
The review of the literature revealed that optic neuritis represents the 46.4% (124/267) of cranial neuritis in SS patients [
The majority of published papers refer to case reports. Among cohort studies, Alexander et al. [
Diplopia is one of the most evident features related to alterations of cranial nerves, namely, oculomotor, trochlear, and abducens. Specific involvement of the III nerve in SS patients was described in 9 cases [
Trigeminal injury is the second more frequently described feature among cranial neuritis in SS patients; in fact, trigeminal neuropathy was observed in 102/267 (38%) cases, isolated or associated with other cranial nerve involvement [
Considering large cohort studies, Mellgren et al. [
In 1935, Henrik Sjögren himself was the first author to mention cranial nerve involvement in SS patients, describing a case with bilateral facial palsy [
Neuropathy of the cochlear nerve is rarely reported in the literature. Except one [
A few reports described SS patients who presented difficulty of swallowing, which is a symptom of glossopharyngeal neuropathy [
Phrenic nerve is not a cranial nerve; it originates in the neck from C3–C5 cervical nerves, containing motor efferent fibres to diaphragm and sensitive fibres from pericardium and visceral pleura.
The research in PubMed database of “Phrenic nerve”
In the present report, two SS patients with optic and phrenic mononeuritis were described. The coexistence of a cranial neuritis in the course of SS is in keeping with the world literature reporting a number of anecdotal cases and a few cohort studies describing SS patients with cranial neuritis [
Involvement of cranial nerves in SS is much less common with respect to peripheral neuropathy [
Synoptic view of cranial nerve involvement in the course of Sjögren’s syndrome (SS).
Cranial nerve(s) | Frequency of involvement (%) | Key points |
---|---|---|
I | 1 | Probably underdiagnosed because of the concomitant olfactory dysfunction secondary to mucosal dryness. |
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II | 46 | Possible feature of neuromyelitis optica spectrum disorder, associated with SS, otherwise, autoimmune neuritis in patients with possibly misdiagnosed SS. |
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III, IV, VI | 12 | Clinically evident as diplopia, this neuritis is generally responsive to steroids. |
|
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V | 38 | Autoimmune damage of the Gasser ganglion could be suspected. Neuritis tends to be recurrent or to stabilize and to be less frequently responsive to steroids than other cranial neuritis. |
|
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VII | 5 | Neuritis isolated or associated with another nerve involvement, with good prognosis. |
|
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VIII | 3 | Neuritis rarely reported as tinnitus, often isolated. |
|
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IX, X, XI, XII | 4 | Transient, often recurrent neuritis episodes, generally responsive to steroids. The IX nerve was always reported in cases of multineuritis, while the XI was never mentioned in literature. |
Cranial nerves are named with their Roman numerals. The frequencies of involvement refer to the cases illustrated in Table
A pure sensory trigeminal neuropathy has been described in patients with SS [
In many cases described in literature, as well as in our patient number 1, SS was diagnosed contemporary or even after the onset of cranial neuritis. These patients are commonly referred to neurology or ophthalmology centres, where sicca syndrome or other SS manifestations, such as arthralgias and/or mild arthritis, may be underestimated or not even mentioned by the patients. Consequently, a correct diagnosis of the underlying connective tissue disease is often delayed or overlooked entirely. Nonetheless, patients with CNS involvement and/or optic neuritis may be misdiagnosed as multiple sclerosis. Thus, in patients with cranial nerve involvement it is recommendable to keep in mind the possibility of associated SS that may be easily diagnosed by standard clinicoserological assessment.
With regard to our patient number 2, the diagnosis of overlapping SS and systemic sclerosis was based on the presence of typical SS clinical manifestations, plus anticentromere autoantibodies, esophagus involvement, and scleroderma capillaroscopic pattern [
In conclusion, SS patients may be affected by cranial neuropathy, mainly optic neuritis or trigeminal neuropathy, which could represent the first symptom of subclinical connective tissue disease. In addition, the first observation of phrenic neuritis in a woman affected by SS and scleroderma in overlap was also described. Overall, careful clinical evaluation is recommendable in such conditions, particularly in individuals with apparently isolated cervicocranial nerve involvement.
None of the authors have any conflict of interests to declare.