Cerebellar degeneration associated with Sjögren's syndrome.
ABSTRACT Neurologic manifestations of primary Sjögren's syndrome (PSS) have been reported to vary from sensory polyneuropathy to encephalopathy or psychiatric problems. However, marked cerebellar degeneration associated with PSS has rarely been reported.
We describe a patient with Sjögren's syndrome who exhibited rapidly progressive cerebellar ataxia, nystagmus, cognitive decline, and psychiatric problems. Brain magnetic resonance imaging revealed marked atrophy of the cerebellum, and (18)F-fluorodeoxyglucose positron-emission tomography demonstrated glucose hypometabolism of the cerebellum.
Our PSS patient exhibited a progressive course of cerebellar syndrome, as evidenced by cerebellar atrophy on serial brain images.
- SourceAvailable from: rheumatology.oxfordjournals.org[show abstract] [hide abstract]
ABSTRACT: Sjogren's syndrome (SS) is a systemic autoimmune disease that mainly affects the exocrine glands and usually presents as persistent dryness of the mouth and eyes due to functional impairment of the salivary and lacrimal glands (1, 2). The common histolopathological feature of all organs affected is a potentially progressive lymphocytic infiltration. Salivary glands are the most studied organs because they are affected in almost all patients and are easily accessible. Microscopic examination of the salivary glands reveals a benign lymphoepithelial lesion, characterized by lymphocytic replacement of the salivary epithelium and the presence of epimyoepithelial islands com- posed of keratin-containing epithelial cells. The predominant cells in the minor labial salivary gland infiltrates are T cells, with a bias towards CD4þ cells rather than CD8þ suppressor cells (CD4/CD8 ratio of 3:1-5:1). B cells constitute approximately 20% of the total infiltrating population, while natural killer (NK) cells are observed less often (5%) (3). The aetiopathogenesis of primary SS is probably a sequential, multistep process that leads to selective damage of the exocrine glands, with consequent target organ dysfunction. Although the exact mechanisms involved in this aetiopathogenic process are not well known, the autoimmune origin of the disease (autoimmune epithelitis (4)) is probably the aetiopathogenic hypothesis most commonly postulated in primary SS. In this review we have summarized the current concepts on autoimmune aetiopathogenesis of primary SS and reviewed alternative aetiopathogenic mechanisms that have recently been postulated.Rheumatology 12/2005; 44(11):1354-67. · 4.21 Impact Factor
- Advances in internal medicine 02/2001; 47:191-217.
- [show abstract] [hide abstract]
ABSTRACT: Objectives:To study the clinical and laboratory profile evolution, as well as morbidity and mortality impact, of primary Sjögren's syndrome (pSS), in a large cohort of patients followed-up longitudinally.Methods:We studied the evolution of the clinical picture and laboratory profile of pSS, the incidence and predictors for systemic sequelae, and the impact of pSS on overall survival in a prospective cohort study of 261 patients with pSS. Analyses included calculation of incidence rates, Cox proportional hazards predictive models, and estimation of standardized mortality ratios (SMRs) compared with the general Greek population, adjusting for age and sex.Results:Glandular manifestations of the syndrome were typically present at the time of diagnosis. Systemic manifestations such as arthritis, Raynaud's phenomenon, purpura, interstitial nephritis, and liver involvement, as well as the serological profile, also did not change substantially during subsequent follow-up. Incidence rates for peripheral neuropathy, glomerulonephritis, and lymphoproliferative disorders were 3.3, 6.6, and 12.2 per 1,000 person-years, respectively. Glomerulonephritis and lymphoma tended to co-exist in the same patients (relative risk, 34.0; P < .0001). The development of lymphoproliferative disorders was associated with low levels of C4 complement (relative risk, 7.5; P = .0016), the presence of mixed monoclonal cryoglobulins (relative risk, 7.9; P = .0012), and purpura (relative risk, 3.9; P = .037). Low levels of C4 was the strongest predictor for mortality after adjusting for age (relative risk, 6.5; P = .0041). Patients with pSS had an SMR of 2.07 (95% Cl, 1.03 to 3.71). However, when patients with adverse predictors were excluded, the mortality rate was identical to that of the general population (SMR 1.02).Conclusions:The initial presentation of pSS determines subsequent outcome.Purpura, decreased C4 complement levels, and mixed monoclonal cryoglobulinemia are adverse prognostic factors. The overall mortality of patients with pSS compared with the general population is increased only in patients with adverse predictors.Seminars in Arthritis and Rheumatism 04/2000; · 3.81 Impact Factor
Copyright © 2012 Korean Neurological Association 155
Print ISSN 1738-6586 / On-line ISSN 2005-5013
J Clin Neurol 2012;8:155-159
Cerebellar Degeneration Associated with Sjögren’s Syndrome
Mi Jung Kim,a,b Myoung Chong Lee,b,c Jae-Hong Lee,b Sun Ju Chungb
aDepartment of Health Screening and Promotion Center, Asan Medical Center, Seoul, Korea
bDepartment of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
cDepartment of Neurology, Cheongshim International Medical Center, Gapyeong, Korea
Received? July 12, 2010
Revised? September 8, 2010
Accepted? September 8, 2010
Sun Ju Chung, MD, PhD
Department of Neurology,
Asan Medical Center,
University of Ulsan College
of Medicine, 88 Olympic-ro 43-gil,
Songpa-gu, Seoul 138-736, Korea
BackgroundzzNeurologic manifestations of primary Sjögren’s syndrome (PSS) have been re-
ported to vary from sensory polyneuropathy to encephalopathy or psychiatric problems. How-
ever, marked cerebellar degeneration associated with PSS has rarely been reported.
Case ReportzzWe describe a patient with Sjögren’s syndrome who exhibited rapidly progres-
sive cerebellar ataxia, nystagmus, cognitive decline, and psychiatric problems. Brain magnetic
resonance imaging revealed marked atrophy of the cerebellum, and 18F-fluorodeoxyglucose
positron-emission tomography demonstrated glucose hypometabolism of the cerebellum.
ConclusionszzOur PSS patient exhibited a progressive course of cerebellar syndrome, as evi-
denced by cerebellar atrophy on serial brain images.
J Clin Neurol 2012;8:155-159
Key Wordszz Sjögren’s syndrome, cerebellar degeneration, ataxia, cognitive impairment.
cc This is an Open Access article distributed under the terms of the Cre-
ative Commons Attribution Non-Commercial License (http://creative-
commons.org/licenses/by-nc/3.0) which permits unrestricted non-com-
mercial use, distribution, and reproduction in any medium, provided the ori-
ginal work is properly cited.
Sjögren’s syndrome is a chronic autoimmune disorder of un-
known etiology and pathogenesis. It is characterized mainly
by mononuclear cell infiltration of the exocrine glands, which
leads to dryness of the eyes and mouth.1 Although the disor-
der has a strong predilection toward women (females : males,
9 : 1), both sexes and all ages may be affected.2 Approximately
one-third of patients with primary Sjögren’s syndrome (PSS)
present with systemic manifestations,3 but the prevalence of
neurologic manifestations in PSS remains controversial.4-6 Pe-
ripheral neuropathy is reportedly the most common neurolog-
ic complication of PSS, followed by cranial nerve neuropathy
and focal or multifocal involvement of the central nervous
system (CNS).4 Although ataxia due to PSS has also been de-
scribed,7,8 marked cerebellar atrophy associated with PSS has
rarely been reported.
We describe herein a patient with PSS who exhibited rapid-
ly progressive ataxia accompanied by cerebellar atrophy.
A 46-year-old woman was admitted to our neurologic clinic
due to progressive gait disturbance. Three months before ad-
mission, she developed vitiligo in her right anterior neck area,
and she noticed unsteadiness of her gait. There was no family
history of neurologic disorders and the patient had no expo-
sure to toxins such as alcohol or drugs.
A neurological examination revealed that she had cerebel-
lar dysfunction: dysarthria, nystagmus, and ataxia. Ataxia was
observed in all four extremities, but was worse in the left limbs
and trunk. The patient had marked gait disturbance due to
ataxia. Speech analysis revealed that her speech disturbance
was a mixed type of dysarthria with ataxic, hyperkinetic, and
flaccid components. Gaze-evoked nystagmus of both eyes was
found in all directions. Motor power and sensory examina-
tions were normal. She had no parkinsonian features, her
deep-tendon reflexes were normoactive, and her plantar re-
sponses were flexor bilaterally. She had mild depression and
persecutory delusions related to her husband.
Laboratory tests were positive for speckled-type antinuclear
antibody, anti-Ro/SSA (4.5 S/C ratio), and anti-La/SSB (1.0 S/
C ratio). Her antinuclear antibody titer was elevated by 1 : 160.
Cerebellar Degeneration in Sjögren’s Syndrome
156 J Clin Neurol 2012;8:155-159
The following parameters were all normal: complete blood
counts, biochemical screening, erythrocyte segmentation rate,
C-reactive protein, thyroid function test, anti-hepatitis C virus,
Venereal Disease Research Laboratory test, serum C3, C4, and
CH50, anti-ds-DNA, lupus anticoagulant, anticardiolipin anti-
body, cytoplasmic antineutrophil cytoplasmic antibodies, peri-
nuclear antineutrophil cytoplasmic antibodies, serum folate,
vitamin B12, anti-human immunodeficiency virus (HIV) anti-
body, HIV antigen, and paraneoplastic antibodies (anti-Hu,
anti-Ri, anti-Yo, and anti-CRMP5). The following malignancy
screening procedures produced unremarkable results: whole-
body 18F-fluorodeoxyglucose positron-emission tomography
(18F-FDG PET), tumor markers (alpha fetoprotein, carcinoem-
bryonic antigen, CA-125, CA-19-9, and CA 15-3), cerebrospi-
nal fluid cytology, mammography, and abdomen-pelvic com-
puted tomography scan. The findings of brain magnetic reso-
nance imaging (MRI) were normal (Fig. 1A-D).
Her ataxia and gait disturbance progressively worsened over
the next 6 months. She had mild cognitive impairment and
scored 25 on the Korean version of the Mini Mental Status
Examination. Her Montreal Cognitive Assessment9 score was
14. The patient exhibited impairment in frontal executive func-
tion, visuospatial function, attention, calculation, and delayed
recall on bedside examination. Oculomotor examination re-
vealed mild saccadic pursuit eye movements and saccadic
dysmetria. Positional nystagmus of both eyes was purely hor-
izontal, and was triggered by an apogeotropic head position,
which was not associated with vertigo. The nystagmus was
not improved by repetitive canalith-repositioning maneuvers.
She suffered from moderate xerostomia and xerophthalmia.
Follow-up brain MRI revealed marked cerebellar atrophy
with an enlarged fourth ventricle and cisterna magna (Fig.
Fig. 2. Salivary scan and biopsy of the salivary gland. A: Salivary scan showing no uptake of the parotid and submandibular glands. B: Bi-
opsy of a minor salivary gland showing focal lymphocytic infiltration. ANT: anterior, RAO: right anterior oblique, Rt. LAT: right lateral.
Post IV 40 min
Fig. 1. Brain MRI and 18F-FDG PET results for the patient. A-D: Initial brain MRI was unremarkable. E-H: Follow-up brain MRI, performed 6
months later, revealed marked cerebellar atrophy and an enlarged fourth ventricle and cisterna magna without cerebral cortical atrophy. I:
18F-FDG PET, performed at the same time as the follow-up MRI, revealed decreased glucose metabolism in the bilateral cerebellum. 18F-
FDG PET: 18F-fluorodeoxyglucose positron-emission tomography.
Kim MJ et al.
1E-H). Brain 18F-FDG PET revealed decreased glucose me-
tabolism in the bilateral cerebellum (Fig. 1I). Mutation analy-
sis for dentatorubral-pallidoluysian atrophy and spinocerebel-
lar ataxia types 1, 2, 3, 6, and 7 were negative. A salivary scan
revealed no uptake of the parotid and submandibular glands
(Fig. 2A). Biopsy of a minor salivary gland revealed focal
lymphocytic infiltration involving exocrine glands (Fig. 2B).
The result of Schirmer’s test was strongly positive. The patient
was diagnosed with PSS according to American and European
Intravenous methylprednisolone (500 mg/day) was admin-
istered for 3 days and then maintenance therapy with oral
methylprednisolone (1 mg/kg/day) was continued for 1 month.
Hydroxychloroquine (200 mg, t.i.d.), quetiapine (12.5 mg/
day), escitalopram (5 mg/day), and buspirone (10 mg, t.i.d.)
were also administered. However, there was no improvement
in her neurological and psychiatric abnormalities. Unfortu-
nately, her gait disturbance and dysarthria progressed further,
with persistent psychiatric symptoms during the 18-month fol-
Primary cerebellar degeneration is extremely rarely associated
with PSS. We evaluated possible causes of primary cerebellar
degeneration in our patient, including alcohol, drug abuse, nu-
tritional deficiency, genetic causes of cerebellar ataxia, parane-
oplastic marker, autoimmune disorders, and a rare manifesta-
tion of HIV infection.11 Diagnosis by exclusion ultimately led
to the belief that her cerebellar degeneration was related to
Our patient with established PSS exhibited rapidly progres-
sive cerebellar ataxia and subacute development of cerebellar
atrophy. In contrast to the uniform features of the peripheral
nervous system complications of PSS, CNS abnormalities are
associated with a much wider spectrum of manifestations.5
Our patient had severe pancerebellar dysfunction that did not
respond to medical treatment.
The pathophysiologic mechanisms underlying the CNS in-
volvement in PSS remain unclear. Previous studies have sug-
gested that ischemia plays a role because CNS lesions in PSS
were found to be associated with mononuclear inflammation
and cerebral ischemic vasculopathy, resulting in micro or
macro infarcts.6,12,13 Other studies found that abnormalities in
humoral and cellular immunity, including antineuronal anti-
body, might be involved in the pathogenesis of the CNS man-
ifestations of Sjögren’s syndrome.8,13 In addition, the direct in-
volvement of anti-Ro/SSA antibodies has been suggested.6
Table 1. Previous reports of cerebellar degeneration associated with autoimmune disease
Owada et al.8
55 F Cerebellar and cerebral
MRI Neurologic deficits
Motor weakness, ataxia,
Ataxia, dysarthria, vertigo
Terao et al.25
61 M Cerebellar and frontal
lobe atrophy, multiple
F Cerebellar atrophy
Manto et al.26
27Gait and limbs ataxia,
Bilateral ataxia of limbs,
Gait ataxia, diplopia,
Shimomura et al.27
47F Cerebellar atrophySLEAntineuronal
Gardner et al.28
16F Cerebellar atrophy,
M Mild cerebellar
atrophy, pons high
Hirose et al.29
47 Gait ataxia,
41 Truncal and limb ataxia,
Gait and limb ataxia,
Kim et al. 2012*46 F Cerebellar atrophyParaneoplastic
*The present study.
Ab: antibody, F: female, M: male, SLE: systemic lupus erythematosus, (+): positive, (-): negative.
Cerebellar Degeneration in Sjögren’s Syndrome
158 J Clin Neurol 2012;8:155-159
Interestingly, other autoimmune diseases, such as Behçet’s
disease and systemic lupus erythematosus, have also been re-
ported to present with cerebellar atrophy (Table 1).
Our patient exhibited mild neuropsychiatric dysfunction.
The most frequently observed CNS disorders in PSS are non-
focal involvements such as memory loss, cognitive dysfunc-
tion, visual disturbance, dizziness, and reduced performance
in concentration and attention.14 The incidence of mild-to-
moderate psychiatric and cognitive dysfunction may be as
high as 80% in patients with CNS manifestations in PSS.15
Psychiatric disorders are common in PSS, including atypical
mood disorder, psychosis, paranoia, and depression, all of
which were found in our patient.4,15 Cerebral white-matter hy-
perintensities on MRI, or cerebral hypoperfusion in the fron-
tal, parietal, and temporal cortices in functional studies have
been found to be correlated with mild cognitive dysfunction in
PSS.15,16 A recent published evaluation of cognitive dysfunc-
tion in PSS described executive and visuospatial dysfunctions
in PSS even in patients with no history of neurological involve-
ment.16 However, in our case there were no cerebral parenchy-
mal abnormalities, and cerebral glucose metabolism was pre-
served, suggesting that another pathophysiologic mechanism
was responsible for her neuropsychiatric manifestation.
It is reported that the cerebellum modulates cognitive and
affective functioning.17 The term “cerebellar cognitive affec-
tive syndrome” has been suggested to describe the disturbance
of executive function, impaired spatial cognition, personality
change, and linguistic difficulties.17 In addition, cognitive im-
pairment and psychiatric symptoms, including depression,
personality change, anxiety, and psychosis, were noted in 51%
of patients with cerebellar degeneration.18 It was suggested
that the cerebellar feedback loop through the thalamus to the
cerebral cortex is directed not only to the sensorimotor corti-
ces but also to the associative cerebrocerebellar circuitry, in-
cluding the dorsolateral cortex, dorsomedial prefrontal cortex,
parietal cortex, and limbic system.17 In our patient there was
no evidence of supratentorial abnormalities on brain MRI or
18F-FDG PET. Therefore, the cognitive and neuropsychiatric
manifestations of our patient may have been related to the
functional disconnection of associative cerebellar circuits.
Positional nystagmus in our patient was one of the charac-
teristic manifestations of marked cerebellar degeneration.
Various diseases involving the fourth ventricle or cerebellar
vermis, such as stroke, multiple sclerosis, multiple system at-
rophy, and tumor, have been reported to cause positional nys-
tagmus.19-23 Paroxysmal direction-changing positional nystag-
mus has been also reported in patients with the horizontal
canal variant of benign positional vertigo.24 Our patient had
other oculomotor dysfunctions, including saccadic pursuit, hy-
permetric saccade, and gaze-evoked nystagmus without verti-
go, and did not benefit from repetitive canalith-repositioning
maneuvers, suggesting positional nystagmus with a central or-
In summary, the reported PSS patient exhibited a progres-
sive course of cerebellar syndrome, which was demonstrated
by cerebellar atrophy on serial MRI and 18F-FDG PET. Fur-
ther experimental studies are needed to clarify the precise
pathogenic mechanism underlying marked cerebellar degen-
eration in PSS.
Conflicts of Interest
The authors have no financial conflicts of interest.
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