CNS manifestations of Sjogren Syndrome

1. Diana Girnita MD PhD
Rheumatology Fellow

2. 
 1898 –Miculicz-Radecki J.(Polish
surgeon) -First lacrimal and salivary
glands enlargement
 1925 –Gougerot H. (French
dermatologist) -Few cases of atrophy of
the salivary glands with dryness of eyes,
mouth and vagina
 1933- Sjögren H. (Swedish
ophthalmologist) – Doctoral thesis
described keratoconjunctivitis sicca, and
his description became a basis for pSS
picture.
History

3. 
 May be primary or secondary to connective tissue
disease (mainly SLE, Rheumatoid Arthritis,
Scleroderma).
 Primary SS (pSS) occurs from 0.1 to 3.0 % in general
population.
 Female/male ratio 9:1
 Ages of 40–60
Sjögren Syndrome (SS)

4. 
 Keratoconjuctivitis sicca
 Pathology: mononuclear
infiltration and destruction of
salivary and lacrymal glands
leading to xerostomia and
xerophthalmia.
 Similar mononuclear infiltrates
invading visceral organs or
vasculitic lesions can give
extraglandular manifestations.
Definition of Sjögren

6. 

7. 
Antibody Prevalence Association
Ro/SSA
La/SSb
60-80% With severe glandular manifestations, longer duration of
the disease, presence of splenomegaly,
lymphadenopathy, vasculitis and high infiltration of
salivary glands.
ANA 80% predictor of internal organ involvement and the
development of lymphoproliferative disorders
RF
Anti -CCP
74%
rare
early stage of disease and onset of the disease at a
younger age, extraglandular symptoms (arthritis)
ACA
(anticentromere)
17% Specific for limited systemic sclerosis; overlap sdr.
M3 muscarinic rec
Ab
high specificity 95% but relatively low sensitivity
43% (Deng C et al, 2015)
Other Ab rare AMA (anti -mitocondrial)
CAII(anti -carbonic anhidrase) + RTA
Anti cytoskeletal proteins-α and β fodrin
Anti protein 1 (SP-1), carbonic anhydrase 6 (CA6) and
parotid secretory protein (PSP)
Anti-TPO anti- TG -thyroid disease in pSS patients in up
to 30 % compared with 4 % of the control group (diseases
may coexist)

8. 
Diagnostic criteria

9. 
Exclusion criteria

11. 
 Neurologic involvement has been reported in pSS since its
initial clinical description 1935
 Varies between 10-60% in primary SS (pSS)
 PNS involvement is relatively well documented
 CNS manifestations are still a matter of discussion.
Prevalence
Alexander EL, Provost TT, Stevens MB, Alexander GE. Neurologic complications of primary Sjogren’s syndrome. Medicine (Baltimore).
1982;61:247–257.Alexander EL. Central nervous system (CNS) manifestations of primary Sjogren’s syndrome: an overview. Scand J Rheumatol
Suppl. 1986;61: 161–165. Delande S, et al. Neurologic manifestations in primary Sjogren syndrome: a study of 82 patients. Medicine (Baltimore)
2004;83:280–291. Lafitte C et al Neurological complications of primary Sjogren’s syndrome. J Neurol. 2001;248:577–584.

13. 

14. 
CNS manifestations

15. 
 Mostly females
 Age 40-50 yo
 Duration of disease aprox 10-11 years
 Prevalence 3.2 % to 79%
CNS involvement

16. 
Authors Pts % CNS Type of CNS manifestation
Teixeira et al, 2015 93 15 Headaches
Spinal cord involvement
Seizures
NMO
Movement disorders
Morreale et al, 2014 120 79 Headaches
Cognitive deficits
Mood disorders
Delalande et al, 2004 83 68 Spinal cord involvement
Motor neuron disease
Focal/multifocal brain involvement
Optic neuritis
Lafitte et al, 2001 25 17 Spinal cord dysfunction
Transverse myelitis
Seizures, tetrapiramydal sdr; cerebellar sdr
Anaya et al, 2000 95 3.2 MS like sdr;
Optic neuritis
Epilepsy
Escudero et al, 1995 48 23 Focal neurological deficits
Moll et al, 1993 48 9 Transverse myelitis
Stroke
Bell palsy
Pyramidal signs
Binder et al., 1988 50 6 Epilepsy
Vertigo
Recurrent TIAs
Alexander et al, 1986 20 MS-like sdr

17. 
Focal vs
 The main CNS manifestation
 Motor/sensory loss with
hemiparesis
 Aphasia
 Dysatria
 Seizures
 Movement disorders
 Cerebellar syndrome
 Subacute transverse myelitis
 Spinal cord disorders
(progressive myelopathies,
neurogenic bladder)
 Optic neuritis
 Large tumefactive brain lesion
Diffuse
 Encephalopathy
 Cognitive
dysfunction(frontal
executive dysfunction,
impairment in attention
control, intellectual
decline, and
deterioration of
instrumental abilities)
 Dementia
 Psychiatric
abnormalities
 Aseptic
meningoencephalitis

18. CNS
Teixeira F et al. ACTA REUMATOL PORT. 2013;38:29-36
Moreira I, Teixeira F et al. Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35:289–294
14/93
patients
(15%)

19.  81/120 (67%) CNS + PNS
involvement
 64 pts with CNS (79%) vs
17 PNS disease (p 0.001).
 64 pts
 Headache (46.9%)
 Cognitive (44.4%)
dysfunction
 Mood disorders (38.3%)
Morreale M et al (2014) Neurological Involvement in Primary Sjogren Syndrome: A Focus on Central Nervous System. PLoS ONE
9(1): e84605.

20. 
 82 patients
 25 (30%) both
CNS + PNS
involvement
 31 (38%) had
isolated CNS
Delalande S et al. Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 2004;83:280–291)

21. 
Extraglandular
manifestations
Accompanying CNS

22. Common
extraglandular
manifestations in
association with
CNS
manifestations
 Sicca symptoms
 Raynauds
 MSK manifestations
 Autoimmune Thyroiditis
 Lung involvement

23. 
Morreale M, et al. (2014) Neurological Involvement in Primary Sjogren Syndrome: A Focus on Central Nervous System. PLoS
ONE 9(1): e84605.

24. 
Delalande S et al. Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 2004;83:280–291)

25. 
Moreira I, Teixeira F et al. Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35:289–294
All pts Pts w/out CNS Pts w/CNS p value

26. 
More frequent extraglandular
manifestations in PNS-Sjogren
NeuroSS with
PNS involvement
is more frequently
associated with
-dermatologic
-Raynauds
-pulmonary
-hematologic
manifestations

27. 
Sicca vs
Neurologic manifestations
-who is first?

28. 
 Neurologic involvement frequently preceded the
diagnosis of pSS in 12 (46%) patients (was the first
symptom of the disease)
Neurologic symptoms before sicca
Teixeira F et al. ACTA REUMATOL PORT. 2013;38:29-36
Moreira I, Teixeira F et al. Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35:289–294

29. 
 Neurologic symptoms occurring at onset of SS involved the
CNS more frequently than the PNS (p = 0.005)
 CNS manifestations preceded sicca symptoms more
frequently than did PNS manifestations (p = 0.02).
Neurologic symptoms before sicca
Delalande S et al. Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 2004;83:280–291)
47%
15%
38%
before
same time
after

31. CSF
Serology
(antibodies)
Brain/Spi
nal MRI
SPECT/P
ET
Cerebral
Angio
graphy
Meet
Sjögren
Criteria

32.  Lymphocytosis
 usually -50cells/mm3 with higher counts ( up to 30%) in
aseptic lymphoid meningitis
 IgG index
 raised (33% -ALL with CNS involvement)
 Oligoclonal bands
 <2;
 These bands have been reported in about 20 to 25% of pSS
compared to more than 90% in MS patients
 Only 1/7 (14%) with isolated PNS involvement had CSF
abnormalities (increased cell count).
CSF in active CNS disease
Delalande S et al. Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 2004;83:280–291)
Alexander L et al. “Primary Sjo gren’s syndrome with central nervous system disease mimicking multiple sclerosis,” Annals of Internal Medicine, vol.
104, no. 3, pp. 323–330, 1986. M. Vrethem, et al. “Immunoglobulins within the central nervous system in primary Sjo ̈gren’s syndrome,” Journal of
the Neurological Sciences, vol. 100, no. 1-2, pp. 186–192, 1990.

33. 
Serology

34. 
Labs
Lymphopenia, hypergammaglobulinemia, ANA, cryoglobulins, complement
were more frequent in cases with pSS and PNS than in those with CNS
involvement.
Delalande S et al. Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 2004;83:280–291)

35. 
Role of Antibodies
Antibody Prevalence Authors
Ro/SSA
La/SSB
40-50%
6% (CNS) vs 19% (PNS)
Delalande et al, 2004
Anti-alpha-
fodrin (IgA and
IgG)
64% (of 31 pts);
no difference between pts with or without
neurologic sx
De Seze J et al, 2004
Anti-GM1 (IgM
and IgG)
12 pts ( 6 with/ 6 without neuropathy)
No difference
Giordano N et al, 2003
Antineuronal Ab
Antiganglion
neuron Ab
882 pts with neurological disorders –detected
also in patients with pSS
Murata et al, 2005
Vianello M et al, 2004
Anti-GW182 Patients with mixed motor and/or
sensory neuropathy without pSS and
neurological pSS (18/200 patients -9%)
Eystathioy T et al. ,2003

36. 
 Anti-Ro + associated with the severity of CNS
disease as well as with findings on cerebral
angiography suggestive of small vessel angiitis.
 Therefore in a patient with known SS who presents
with CNS manifestations testing for anti-Ro
antibodies is of prognostic rather than diagnostic
value.
Anti-Ro have prognostic values
Alexander EL. Neurologic disease in Sjogren’s syndrome: mononuclear inflammatory vasculopathy affecting central/peripheral nervous
system and muscle. A clinical review and update of immunopathogenesis. Rheum Dis Clin North Am 1993;19:869–908.
Alexander EL et al Anti-Ro (SS-A) autoantibodies in central nervous system disease associated with Sjo gren’s syndrome (CNS-SS):
clinical, neuroimaging, and angiographic correlates. Neurology 1994;44:899–908.

37. 
 Abnormal in 61% of the patients tested.
 Confirmed optic neuritis in patients with a history of
visual loss (13)
 Can define additional patients with subclinical
optic neuritis (12)
Visual evoked potential
Delalande S et al. Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 2004;83:280–291)

38. 
 Limited value
 Abnormal in ½ patient with pSS+severe progressive CNS
disease.
 Pts with
 Focal deficits - focal slow wave activity, decreased
amplitude, or spikes.
 Epilepsy - seizure discharges
 Encephalopathy or dementia -diffuse slow wave activity.
 Useful in detecting sublinical abnormalities that precede
the development of clinical pSS- CNS.
EEG
Delalande S et al. Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 2004;83:280–291)

39. 
 MRI are more sensitive than CT scans to detect
anatomical abnormalities in pSS-CNS
 Multiple areas of increased signal intensity (T2
weighted images) predominantly in subcortical and
periventricular white matter
 Lesions were found more frequently in patients with
CNS (80%) vs patients without CNS involvement
(25%; p = 0.008).
 These findings have been observed in both patients
with and those without CNS impairment
MRI
Delalande S et al. Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 2004;83:280–291)
Pierot L, Sauve C, Leger JM, et al. Asymptomatic cerebral involvement in Sjögren’s syndrome: MRI findings of 15 cases. Neuroradiology 1993; 35:
378–380 Morgen K, McFarland HF, Pillemer SR. Central nervous system disease in primary Sjögren’s syn- drome: the role of magnetic resonance
imaging. Semin Arthritis Rheum 2004; 34:623–630

40. 
Brain MRI
Delalande S et al. Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 2004;83:280–291)
 MRI brain -FLAIR showing white matter
lesions and severe atrophy suggestive of but
not specific to multiple sclerosis in a patient
with relapsing-remitting symptoms.

41. 
Cerebral Venous Thrombosis
Mercurio A et al –cerebral venous thrombosis revealing pSS-report f 2 cases; case reports in medicine, 2013

42. 
Cerebral Venous Thrombosis
Mercurio A et al –cerebral venous thrombosis revealing pSS-report f 2 cases; case reports in medicine, 2013

43. A and B, Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing
frontoparietal tumefactive lesion with edema and mass effect.
J. Sanahuja et al. AJNR Am J Neuroradiol 2008;29:1878-
1879
©2008 by American Society of Neuroradiology

44. 
‘MRI detects focal CNS but not
always diffuse CNS disease’’
 19 patients with SS +neuropsychological abnormalities
mostly frontal lobe syndrome and memory problems –
None had abnormal brain MRI (Berlin et al, 1999)
 Alexander et al -5/8 patients with psychiatric or
cognitive dysfunction had abnormalities on brain MRI
Belin C et al. Central nervous system involvement in Sjogren’s syndrome: evidence from neuropsychological testing and HMPAO- SPECT.
Ann Med Interne (Paris) 1999;150:598–604.
Alexander EL et al. MRI of cerebral lesions in patients with the Sjogren syndrome. Ann Intern Med 1988;108:815–23.

45. 
Spinal MRI
 Spinal cord involvement showed T2-weighted
hyperintensities
 Involvement
 Cervical in 82%
 Dorsal in 47%
 Lumbar in 12%
 65% with a single lesion
 40% with centromedullar lesions
 35% with extended lesions (cases of acute myelopathy)
Delalande S et al. Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 2004;83:280–291)

46. 
Spinal MRI
Spinal cord MRI ( T2-weighted) showing an
extended hypersignal in the cord in a
patient with acute myelopathy.
Delalande S et al. Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 2004;83:280–291)

47. 
Extensive transverse myelitis
Longitudinal extensive transverse myelitis—it's not all neuromyelitis optica Corinna Trebst et al.Nature Reviews Neurology 7, 688-698
(December 2011)
a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22. b | MRI scan taken 3
days after the initial examination; the hyperintensities are almost unchanged. Follow-up scans taken at c | 2
weeks and d | 1.5 years after the initial examination show progressive spinal cord atrophy.

48. 
 Dg optic neuritis were +
anti- Aquaporin4 (AQ4)
antibodies
 Spinal cord MRI:
extensive centromedular
lesion from C2 to C5/C7;
 Brain MRIs were normal.
Neuromyelitis
optica (NMO)
Teixeira F et al. ACTA REUMATOL PORT. 2013;38:29-36
Moreira I, Teixeira F et al. Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35:289–294

49. 
Neuromyelitis optica (NMO)
Bhattacharyya S,
Helfgott S.
Semin Neurol
2014;34:425–436.

50. 
 Voxel-based morphometry (VBM) is a method
commonly used for quantitative and objective
evaluation of differences in regional cerebral volume
between groups
 53 patients vs controls (18 systemic sclerosis, 35
healthy) and evaluated for differences in brain
volume
MRI and Voxel-Based Morphometry
Good CD et al.. A voxel-based morphometric study of ageing in 465 normal adult human brains. Neuroimage 2001; 14:21–36

51.  38/53 patients with pSS had White
matter hyperintensities (WMHIs)
vs 6/18 with scleroderma; 17/35 of
healthy controls
 The numbers of WMHIs ≥ 2 mm
were higher in patients with pSS
than in controls (≥ 2 mm, p = 0.004).
Voxel-Based Morphometry
Good CD et al.. A voxel-based morphometric study of ageing in 465 normal adult human brains. Neuroimage 2001; 14:21–36

52. 
pSS had
decreased gray
matter volume in
the cortex, deep
gray matter, and
cerebellum.
Associated loss of
white matter
volume was ob-
served in areas
corresponding to
gray matter
atrophy and in
the corpus
callosum (p <
0.05).

53. 
Patients with pSS have
WMHIs and gray and white
matter atrophy, probably
related to cerebral
vasculitis.

54. 
 Brain hypoperfusion has been associated with brain
atrophy
 SPECT and PET studies have shown reduced cerebral
blood flow and decreased glucose metabolism in
patients with pSS
SPECT/PET
Kao CH, Ho YJ, Lan JL, ChangLai SP, Chieng PU. Regional cerebral blood flow and glucose metabolism in Sjögren’s syndrome. J Nucl
Med 1998; 39:1354–1356
Huang WS, Chiu PY, Kao A, Tsai CH, Lee CC. Detecting abnormal regional cerebral blood flow in patients with primary Sjögren’s
syndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain: a preliminary report.
Rheumatol Int 2003; 23:174–177

55.  10 F(<55 years old), with pSS defined using EA criteria, +anti-SSA and/or anti-
SSB, no history of neurological involvement were prospectively investigated
vs 10 healthy controls
 within 1 month, brain MRI, neuropsychological testing, including overall
evaluation and focal cognitive function assessment, and (99m)Tc-ECD brain
SPECT.
 (99m)Tc-ECD brain SPECT abnormalities were significantly more common in
patients with pSS (10/10) than controls (2/10; p<0.05).
 Cognitive dysfunctions (executive and visuospatial disorders) were also
significantly more common in patients with pSS (8/10) than controls (0/10;
p<0.01).
 MRI abnormalities in patients and controls did not differ significantly.
 CONCLUSIONS: Neuropsychological testing and (99m)Tc-ECD brain SPECT
seem to be the most sensitive tools to detect subclinical CNS dysfunction in
pSS.
Neuropsychological testing and
(99m)Tc-ECD brain SPECT
Le Guern V, Belin C et al. Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primary
Sjogren syndrome: a case-control Study. Ann Rheum Dis. 2010 Jan;69(1):132-7.

56. 
(99m)Tc-ECD brain SPECT
Chang CP et al. Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjögren’s
syndrome and normal findings on brain magnetic resonance imaging . Ann Rheum Dis 2002;61:774–778

57. 
 Exclude other causes of CNS disease (arteriovenous
malformations, congenital aneurysms, and other
vascular abnormalities and cerebrovascular disease)
 Up to 45% of highly selected pSS with active CNS
disease have angiographic findings suggestive of
small vessel vasculitis (stenosis, dilatation, or
occlusion of small cerebral blood vessels)
Cerebral angiography
Alexander EL. Neurologic disease in Sjogren’s syndrome: mononuclear inflammatory vasculopathy affecting central/peripheral
nervous system and muscle. A clinical review and update of immunopathogenesis. Rheum Dis Clin North Am 1993;19:869–908.

58. 
Differential Diagnosis
Multiple sclerosis
SLE
Vasculitis
Sarcoidosis
Behçet’s disease
Infectious –Lyme,
syphilis, PMLE,
HTLV-1 infection,
herpes zoster
Genetic (lysosomal
disorders,
adrenoleucodystrop
hy, mitochondrial
disorders)
Metabolic (vitamin
B12 deficiency)
CNS lymphoma,
Spinal (degenerative
and vascular
malformations)
Dementia,
AML sclerosis
Parkinson’s disease
Dorsal root
ganglionitis

59. Multiple Sclerosis
(MS)

60. 
 Hard to differentiate, even for experienced clinicians
 CNS –SS seems to mimic “relapsing- remitting MS “
or in patients with chronic myelopathies seems to
mimic “primary progressive” MS
 Features found in common:
 both tend to involve the spinal cord, brain, and the
optic tract
CNS-SS mimics MS

61. 
CNS-SS vs MS
Delalande S et al. Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 2004;83:280–291)

62. 
 The pattern “primary-progressive” more frequent in pSS
(gradual period of deterioration, reflecting progressive
myelitis)
 pSS
 when peripheral or cranial nerve involvement occurs, the
diagnosis of MS is less likely.
 may have less brain disease on MRI (pSS rarely touch the
basal ganglia or the cerebral cortex)
 may have lesser amounts of protein in CSF (less
“oligoclonal” bands <2; in MS > 3)
 ANA, SSA/SSB, RF more frequent in SS vs MS
 SICCA simptoms
Red Flags against MS

63. 
SLE vs CNS-SS
 Onset abrupt
 Autoimmune features—
rash, serositis,
polyarthritis or nephritis
 Younger patients
 MRI : grey matter disease
 Antibody profile: anti-
Sm and anti-dsDNA
 +APL ab
 Insidious, subtle, waning
and waxing in SS
 Sicca symptoms
 Older patients
 MRI: white matter
disease
 Autoantibody profile:
anti- Ro; -La
 +APL Ab

65. 
Nocturne, G. & Mariette, X. (2013) Advances in understanding the pathogenesis of primary Sjögren’s syndrome Nat. Rev.
Rheumatol. doi:10.1038/nrrheum.2013.110
• Innate
immunityactivate
pDC  high levels
of INF stimulates
BAFF (B cell
activating
factor)autoantibo
dies and promotes
the survival and
maturation of B
cells, polyclonal
activation
• Epithelium is
infiltrated mainly by
CD 4+ lim- phocytes
T subtype and
immune response is
balanced toward
Th1 response and
also Th17—with
interleukin 17(IL-17)
as a main cytokine.

66. 
Hypothesis CNS-SS
CNS-
SS
CNS
lymphocytic
infiltration
Small
vessel
vasculitis
Antibodies
–AntiRo,
anti-M3

67. 
1. CSF analysis of patients with active CNS disease reveals
evidence of lymphocytosis, elevated IgG index, and
oligoclonal bands (Alexander et al., 1986)
1. Lymphocytic CNS infiltration
Gono T, Kawaguchi Y, Katsumata Y et al. Clinical manifestations of neurological involvement in primary Sjögren’s syndrome.
Clin Rheumatol 2011; 30:485–490.
Chai J, Logigian E. Neurological manifestations of primary Sjogren’s syndrome. Current Opinion in Neurology 2010, 23:509–
511.

68. 
2. Vascular injury may be related to the presence of
antineuronal and anti-Ro antibodies or due to ischemia
secondary to diffuse small vessel vasculitis (angiographic
studies -Alexander et al., 1994).
1. SPECT – reveal hypoperfusion (parietal and temporal lobes)
(Kao et al., 1998; Chang et al., 2002).
2. Significant correlation between cortical hypoperfusion and
cognitive dysfunction (Le et al., 2010).
3. Necrotizing vasculitis has been associated with spinal cord
complication (sensory ataxia and transverse myelitis (Mori et
al., 2001).
4. MRI findings in CNS-SS with diffuse small foci of
hyperintensity suggestive of small vessel disease (Segal et al.,
2008)
2. Small vessel vasculitis

69. 3. May bind to the brain cells and mediate (at least
partially) small vessel changes
1. anti-Ro/SS-A Ab shown to correlate with CNS
disease severity and abnormal neuroimaging (small-
vessel angiitis) (Alexander et al., 1994).
2. anti-Ro/SS-A overexpressed in the brain
microvascular compartment (Shusta et al., 2003).
3. CNS SS patients with anti-Ro/SS-A antibodies in the
CSF  ? pathogenic role (Megevand et al., 2007).
3. Antibodies roles
Minesh Kapadia, Boris Sakic *Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301–333
Shusta EV et al. The Ro52/SS-A autoantigen has elevated expression at the brain microvasculature. Neuroreport. 2003 Oct 6;14(14):1861-5.
Megevand P et al. Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogren's syndrome with central nervous system involvement. Eur Neurol.
2007;57(3):

70.  Autoantibodies that recognize M3 muscarinic
acetylcholine receptors (mAChR;IgG)
 cause dysfunction of of exocrine glands (Dawson et
al., 2006)
 interact with cerebral mAChRs expressed on the
surface of cells in the frontal cortex (Reina et al.,
2004)
 M3 mAChR activationpromoting NO and
prostaglandin biosynthesis (Orman et al., 2007).
M3-mAchR antibodies
Reina S et al. Human mAChR antibodies from Sjögren syndrome sera increase cerebral nitric oxide synthase activity and nitric
oxide synthase mRNA level. Clin Immunol. 2004 Nov;113(2):193-202.
Orman B et al. Anti-brain cholinergic auto antibodies from primary Sjögren syndrome sera modify simultaneously cerebral nitric oxide and
prostaglandin biosynthesis.Int Immunopharmacol. 2007 Dec 5;7(12):1535-43. Epub 2007 Aug 16.

72. 
 No consensus
 Corticosteroids -usually first initiated in high dose
 45% pts with durable neurologic amelioration or
stabilization
 Ineffective mostly in patients with spinal cord
involvement
Treatment CNS-SS
Delalande S et al. Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 2004;83:280–291)
Teixeira F et al. ACTA REUMATOL PORT. 2013;38:29-36 Moreira I, Teixeira F et al. Frequent involvement of CNS in primary
SS -Rheumatol Int (2015) 35:289–294

73. 
 Immunosuppressive therapy
 Cyclophosphamide- monthly (700 mg/m2 IV for 6 or
12 months )
 It resulted in a partial recovery or stabilization treated
patients with spinal cord involvement
Treatment CNS-SS
Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide. Arch Neurol.
2001;58:815–819;

74. 
 Plasmapheresis efficacy (+prednisone) reported in a
sporadic case of acute transverse myelopathy.
 In severe cases, IVIG have been used successfully in
a small sample of patients with ganglionopathy
Treatment CNS-SS
Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary
Sjogren’s syndrome. Arthritis Rheum. 1987; 30:339 –344. Takahashi Y et alBenefit of
IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS. Neurology. 2003;60:503–505.

75. 
 Neurologic involvement (CNS) is common in pSS
and often precede the diagnosis.
 The accurate prevalence of these manifestations is
difficult to assess, because the heterogeneity of the
series.
 Could be disabling disease with severe consequences
 Prospective, controlled studies are needed with large
numbers of patients to assess treatment
Conclusion

77.  J Clin Rheumatol. 2012 Dec;18(8):389-92. doi: 10.1097/RHU.0b013e318277369e.
 Neurosjögren: early therapy is associated with successful outcomes.
 Santosa A1, Lim AY, Vasoo S, Lau TC, Teng GG.
 Author information
 Abstract
 BACKGROUND:
 Primary Sjögren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 0.6%. The frequency of neurologic manifestations in PSS varies widely from 0% to 60%.
 METHODS:
 We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore. Eight consecutive women (median age, 51 years [range, 38-67 years]) with neurologic
manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations.
 RESULTS:
 Six of 8 patients with neurosjögren had their neurologic manifestation at time of PSS diagnosis. The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years,
respectively. Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients. All our patients received early aggressive therapy with pulse corticosteroids and intravenously
administered cyclophosphamide. The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days). All achieved good recovery regardless of the type or site of neurologic involvement,
initial erythrocyte sedimentation rate, immunoglobulin and complement levels.
 CONCLUSIONS:
 Neurologic disease, when present, is a strong contributor to disease activity and damage. Confirmatory tests should be conducted early regardless of the presence of sicca symptoms. Vigilance for the development
of new neurologic symptoms is imperative even in chronic, apparently stable patients. It is likely that early initiation of treatmentcontributed to good recovery in our patients.
 Lupus. 2007;16(7):521-3.
 Successful treatment of refractory neuroSjogren with Rituximab.
 Yamout B1, El-Hajj T, Barada W, Uthman I.
 Author information
 Abstract
 We report a 47-year-old female with Sjogren's syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy, who was treated with the monoclonal anti CD-20 antibody
rituximab at a weekly dose of 375 mg/m2 for four consecutive weeks. Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with
progressive resolution of the paresthesias and dysesthesias. The improvement was sustained and progressive and eight months after the last dose, she was able to walk for 60 meters without aid or rest. Rituximab
may be considered as an effective and promising novel therapy in SS patients with neurological involvement.

78.  Fingolimod (INN, trade name Gilenya, Novartis) is an immunomodulating drug, approved for treating multiple sclerosis. It has reduced the rate of relapses in relapsing-remitting multiple sclerosis by
approximately one-half over a two-year period.[1] Fingolimod is a sphingosine-1-phosphate receptor modulator, which sequesters lymphocytes in lymph nodes, preventing them from contributing to an autoimmune reaction.


 Send to:
 See comment in PubMed Commons below
 Acta Neurol Scand. 2015 Feb;131(2):140-3. doi: 10.1111/ane.12357.
 Fingolimod efficacy in multiple sclerosis associated with Sjogren syndrome.
 Signoriello E1, Sagliocchi A, Fratta M, Lus G.
 Author information
 1Multiple Sclerosis Center, II Division of Neurology, Department of Clinical and Experimental Medicine, Second University of Naples, Naples, Italy.
 Abstract
 BACKGROUND:
 Sjogren syndrome (SS) is a common autoimmune disease characterized by lymphocytic infiltration of the exocrine glands with neurological involvement in about 20% of patients. The neurological manifestations in
the central nervous system CNS may vary and include a multiple sclerosis (MS)-like disease, and the treatments with immunosuppressive drugs have been undertaken.
 CASE PRESENTATION:
 We describe a case of 40-year-old woman with clinical and instrumental evidence of an MS characterized by numerous relapses and demyelinating lesions prevailing in the infratentorial and spinal cord.
Immunological analysis showed biological data that were consistent with an SS. The treatment with fingolimod showed not only an optimal response to the demyelinating events but also biological parameters.
 CONCLUSION:
 These data allow us to hypothesize possible combined efficacy of treatment with fingolimod in SS associated with definite MS.
 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
 KEYWORDS:
 Sjogren syndrome; fingolimod; multiple sclerosis




 In two Phase III clinical trials, fingolimod reduced the rate of relapses in relapsing-remitting multiple sclerosis by over half compared both to placebo and to the active comparator interferon beta-1a.[37]
 A double-blind randomized control trial comparing fingolimod to placebo[38] found the drug reduced the annualized frequency of relapses to 0.18 relapses per year at 0.5 mg/day or 0.16 relapses per year at 1.25
mg/day, compared to 0.40 relapses per year for those patients taking the placebo. The probability of disease progression at 24 month followup was lower in the fingolimod groups compared to placebo (hazard
ratio 0.70 at 0.5 mg and 0.68 at 1.25 mg). Fingolimod patients also had better results according to MRI imaging of new or enlarged lesions at 24 month followup. Side effects leading to discontinuation of the study
drug were more common in the higher dose group (14.2% of patients) than at the lower dose (7.5%) or placebo (7.7%). Serious adverse events in the fingolimod group included bradycardia, relapse, and basal-cell
carcinoma. Seven episodes of bradycardia occurred during the monitoring period after administration of the first dose, and were asymptomatic in six of these cases. There was a higher rate of lower respiratory tract
infections (including bronchitis and pneumonia) in the fingolimod groups (9.6% at 0.5 mg, 11.4% at 1.5 mg) than the placebo group (6.0%). Other adverse events reported on the study drug included macular
edema, cancer, and laboratory abnormalities.[39]
 Diana M. Girnita, MD, PhD
 E-mail: dianagirnita@gmail.com
 Phone: 513-917-0908
Fingomolid

79. 1. No consensus on the definition of CNS involvement( some include psychiatric disease,
headache or mood disturbances, some not)
2. The diagnostic criteria used for SS are not uniform ( Some include confirmatory
salivary gland biopsies, whereas others have included patients with probable SS)
3. Confounding factors that may increase the risk for cerebrovascular disease (DM, HTN,
HLD) or factors that may be associated with psychiatric disease such as thyroid
disease ( high incidence of autoimmune endocrinopathies in patients with pSS)
4. Referral bias may occur in tertiary centres, where complex cases with severe disease
are referred (This may lead to overdiagnosis of CNS; Underdiagnosis may be a
result of symptoms being dismissed by the assessing physician; Patients may also
fail voluntarily to report symptoms.; neurological complications in elderly patients
with SS may be attributed to their age)
5. The incidence of MS increases with latitude, and therefore coexistence of SS with MS
may explain the high incidence of MS-like disease reported in North America and
Scandinavia compared with the low incidence in south European countries
6. To solve the controversy, prospective, controlled studies are needed with large
numbers of patients, because the prevalence of specific neurological syndromes in the
general population is low
Why this variability in CNS disease prevalence in pSS?

80. 
Extraglandular
manifestations