A Rare Case Of Sjögren's Syndrome Associated With Intracranial .
International Journal ofClinical RheumatologyCase ReportA rare case of Sjögren's Syndromeassociated with Intracranial Hemorrhagecase report and literature reviewAbstract: Sjögren Syndrome (SS) is an autoimmune rheumatic disease, whose hallmark is ocular andmouth dryness secondary to autoimmune exocrinopathy. Rarely, SS can affect both peripheral nervoussystem (PNS) as well as central nervous system (CNS). When CNS is involved, SS is usually diagnosed afterpatients present with neurologic symptoms. Both ischemic and hemorrhagic stroke can present as firstmanifestation of primary SS. Stroke is described in literature as a rare entity associated with primary SS,and only few cases were reported. In some cases, CNS involvement was thought to be related to CNSvasculitis, but most of the times remains questionable. We present a rare case of intracranial hemorrhageas first manifestation of primary SS and a review of the pertinent literature.Diana M. Girnita*1, Elena I.Obreja2, Teresa Sosenko3,Andrew J. Ringer4 & LeonardCalabrese5Department of Rheumatology, TrihealthPhysician Partners, Cincinnati, Ohio, USA1Internal Medical Resident, Weiss MemorialHospital, Chicago, IL, USA2Internal Medical Resident, GoodSamaritean Hospital, Cincinnati, Ohio, USA3Trihealth Neuroscience Institute,Cincinnati, OH, USA4IntroductionSjögren Syndrome (SS) is an autoimmunerheumatic disease, whose hallmark is ocularand mouth dryness secondary to autoimmuneexocrinopathy [1]. These symptoms are due toexcessive lymphocyte infiltration. SS typicallyaffects women after 40 years of age, but ithas also been reported in young adults andadolescents. Serologic markers are positive Ro/SSA, La/SSB and antinuclear (ANA) antibodies.SS can also affect extra glandular systems suchas neurologic system. While Peripheral NervousSystem (PNS) involvement is often described,CNS manifestations are controversial andextremely rare [2]. The incidence of stroke inpatients with primary SS is about 2% [3]. Basedon a PubMed search, only 15 cases of stroke weredescribed in primary SS since 1982. Out of thesecases, five patients presented with subarachnoidhemorrhage and two patients with intracranialhemorrhage (ICH). Here we report a case ofICH as first manifestation of primary SS.Case presentationA 61-year-old Caucasian female with a pastmedical history significant for Hashimotothyroiditis, cervical cancer, osteoarthritis andmigraines presented in the emergency room forworsening headaches. Patient was treated forone year with sumatriptan and topiramate formigraines. Within the previous year, she hadboth Computed Tomography (CT) head andmagnetic resonance imaging MRI brain thatwere reportedly normal. Despite treatment,headaches worsened and interfered with herwork as an accountant. On the day of admission,she also complained of dizziness, nausea andvomiting, photophobia. On examination,patient was confused, lethargic and requiringrepeated stimulation to answer questions.Neurologic exam revealed 5/5 strength in allextremities, no pronator drift, no change insensation, patellar deep tendon reflexes (DTR)2 bilaterally and negative bilateral Babinski.Electroencephalogram (EEG) was negativefor acute seizures. CT head without contrastrevealed subarachnoid hemorrhage (SAH)(Figures 1 and 2). Brain MRI was obtainedand was consistent with SAH in left posteriorfossa, bifrontal intracranial hemorrhage (ICH)and no evidence of midline shift (Figures 3-5).Neurosurgery was consulted, and cerebralangiogram was performed which revealednormal four vessel cerebral angiogram. MRVenogram of brain was negative for thrombosis.Neurosurgery performed right craniotomy andevacuation of the right frontal hematoma withcortical and dural biopsies. Following that, adetailed review of systems revealed long historyof eye dryness (she had laser surgery and wasapplying lubricant drops in her eyes for manyyears), mouth dryness (using very frequent mintdrops) and occasionally parotid gland swelling,along with multiple tooth decays, cavities, andhalitosis. Over the past two to three months, thepatient also noticed an unintentional 20-poundweight loss, decreased appetite, night sweats, jawand axilla pain and short term memory loss.Cleveland Clinic's Department ofRheumatic and Immunologic Diseases,Cleveland, OH, USA5*Author for correspondence:Diana girnita@trihealth.comDue to concern of CNS vasculitis process,an autoimmune work up was performed andrevealed positive ANA (titer 1: 160, speckledInt. J. Clin. Rheumatol. (2018) 13(4), 239-244ISSN 1758-4272239
Case ReportGirnita et al.Figure 3. MRI without contrast, T2.Figure 1. CT head without contrast.Figure 4. MRI without contrast , T1.Figure 2. CT head without contrast.pattern) and SSA. All other autoantibodieswere negative (Table 1). Complement levelswere normal. Both Erythrocyte SedimentationRate (ESR) and C-Reactive Protein (CRP)were elevated. Salivary gland biopsy confirmedlymphocytic infiltration consistent with adiagnosis of primary SS (Figure 6). Given thesudden onset of intracranial hemorrhage andnewly diagnosed primary SS, the suspicion ofassociated CNS vasculitis persisted. Furtherwork up with brain and leptomeningeal biopsywas negative for vasculitis, amyloid deposition orneoplasia.During this time, patient was started on high doseIV methylprednisolone for three days, followedprednisone 60 mg daily. Within the first week,the patient mentation improved significantly.She was discharged to acute rehabilitation onprednisone taper, levetiracetam and all previous240Int. J. Clin. Rheumatol. (2018) 13(4)Figure 5. MRI without contrast, GRE.home medications. Repeat cerebral angiogramwas performed in one month after dischargefrom the hospital and was also normal with noevidence for primary CNS vasculitis.
A rare case of sjögren's syndrome associated with intracranial hemorrhage- case report and Case Reportliterature reviewcord dysfunctions, MS-like syndrome and CNSvasculitis [1].CNS involvement occurs mostly in women,with a mean age of 40-50-years-old. It usuallymanifests after 10-11 years of disease. Thefocal manifestation is the most common CNSmanifestation [1]. The initial work-up thatshould be done when neurologic primary SS issuspected consists of autoimmune serologies.Anti-Ro antibodies are associated with severity ofdisease as well as abnormal findings suggestive ofsmall vessel angiitis seen on cerebral angiography[4].Figure 6. Salivary gland biopsy.DiscussionNeurologic and psychiatric involvement inprimary SS varies between 0%-70% according toreports and depends on their clinics, but generallyaffects 20% of the patients [1]. PNS involvementcan manifest as axonal polyneuropathies, iber neuropathy, multiple mononeuritis,trigeminal and other cranial neuropathies,autonomic neuropathies, or demyelinatingpolyradiculoneuropathy [1].CNS involvement can be divided into focal(seizures, movement disorders, cerebellarsyndrome, optic neuropathy, etc.), ntia, aseptic meningoencephalitis), spinalLumbar puncture may be considered, however isnonspecific. Cerebrospinal fluid (CSF) analysismay show increased lymphocytosis, oligoclonalbands number and increased IgG index [5-7].EEG has limited value and is more useful indetecting subclinical abnormalities that precedethe development of clinical primary SS withCNS manifestations [5].In terms of imaging studies, MRI is moresensitive than CT scan. MRI findings includeanatomical abnormalities, increased signalintensity (T2) predominantly in subcortical andperiventricular white matter, cerebral venousthrombosis or transverse myelitis.MRI is also useful for detecting focal CNSinvolvement, more than diffuse CNS disease[5,8,9]. Cerebral angiography is helpful toexclude other causes of CNS disease howeveronly about 45% of patients with primary SS andCNS disease have findings suggestive of smallTable 1. Autoimmune work up.LabResultReference ValueCRP343-24 mg/LESR540-30 mm/hANAPositive, titers 1: 160 homogenousNegativeAnti SSA/Ro antibody730-40 AU/mLAnti SSB/La antibody20-40 AU/mLAnti dsDNA antibodyNegativeNegativeAnti-Smith antibody00-40 AU/mLRheumatoid factor 20 20 IU/mLAnti CCP antibody140-19UAnti Scl antibody20-40 AU/mLAnti-centromere antibody10-40 AU/mLAnt phospholipid antibodiesnegativenegativeAnti RNP antibody10-40 AU/mLANCA 1: 20 1: 20Complement C39379-152 mg/dLComplement C41816-38 mg/dLCRP C-reactive protein; ESR erythrocyte sedimentation rate, ANA antinuclear antibody, dsDNA doublestranded DNA, CCP cyclic citrullinated peptide, RNP ribonucleic protein, ANCA antineutrophilic cytoplasmicantibodies241
Case ReportGirnita et al.Table 2. Complete blood count with differential.LabResultReference ValueWBC15.83.60 -10.50 thou/mcLRBC4.323.80-5.20 thou/mcLHemoglobin12.812.0-15.2 g/dLHematocrit3836%-46%MCV8882-97 fLPlatelet273140-375 thou/mcLAbsolute neutrophil count14.601.80-7.70 thou/mcLAbsolute lymphocyte count0.901.00-4.00 thou/mcLAbsolute monocyte count0.400.20-0.90 thou/mcLAbsolute eosinophil count0.000.03-0.45 thou/mcLAbsolute basophil count0.000.00-0.20 thou/mcLWBC white blood cell count, RBC red blood cell count, MCV mean corpuscular ucoseCalciumTable 3. Basic Metabolic Panel.Result1343.71012290.781679.2Reference Value135-145 mEq/L3.6-5.1 mEq/L101-111 mEQ/L24-36 mEq/L8-26 mg/dL0.44-1.03 mg/dL70-99 mg/dL8.5-10.5 mg/dLLabUPEPSPEPHomocysteineCold agglutininsTable 4. Additional Work Up.ResultNegativeNegative7.4 1:32Reference ValueNegativeNegative 11 mcmol/L 1: 32Year and Author Name1982, Alexander1994, Bragoni1994, Urban1995, Giordano1996, Nagahiro2002, Koh2009, Klingler2010, Hayashi2012, Asai2012, Ishizaka2013, Wang2013, Mercurio2013, Mercurio2016, Ho TH2018, present patientTable 5. List of case reports.Patient demographics37, F44, F41, F55, F17, F50, F46, F54, F52, F66, F39, F43, F44, F50, F61, FType of CNS involvementSAHIschemic strokeVenous sinus thrombosisSAHIschemic strokeIschemic strokeSAHSAHThalamic hemorrhageSAHICHVenous sinus thrombosisVenous sinus thrombosisVenous sinus thrombosisICHvessel vasculitis.Stroke is an extremely rare manifestation ofprimary SS It can be ischemic or hemorrhagic.Since 1982, fifteen cases have been reportedincluding ours [3,10-21]. Out of these, sixpatients presented with SAH, three patients with242Int. J. Clin. Rheumatol. (2018) 13(4)cerebral infarction, four patients with venoussinus thrombosis, two patients with ICH andone of them with thalamic hemorrhage [3]. Inall these reported cases, patients were females(Tables 2-5).One of the causes of ischemic stroke is internal
A rare case of sjögren's syndrome associated with intracranial hemorrhage- case report and Case Reportliterature reviewcarotid atherosclerosis. There have beenseveral studies showing a strong connectionbetween systemic rheumatic disease and earlyatherosclerosis [22]. A non-randomized studydone by Ciccone et al. evaluated the differencesin carotid intima-media thickness (C-IMT) inpatients affected by autoimmune diseases [23]. Acomparison between systemic Scleroderma (SSc)patients versus other connective tissue diseasepatients (such as systemic lupus erythematosus,polymyositis/dermatomyositis, antiphospholipidsyndrome, mixed connective tissue disease,Sjogren’s syndrome) versus control patientsshowed no differences of incidence in terms ofatheromatous plaques in both SSc and otherconnective tissue diseases with higher number ofplaques than control group. These investigatorsdemonstrated the abnormal function of theendothelial layer in SSc group predisposesto macrovascular changes such as increasedC-IMT (which can lead to ischemic events)and microvascular changes (which can lead toRaynaud’s phenomenon). Thus, patients withsystemic rheumatic disease are at risk for ischemicevents by the increased number of atheromatousplaques compared to general population but notby increased thickness of the carotid intimamedia.Our patient was a middle age female withnew onset of cognitive issues and headachesthat developed ICH with secondary SAH.Although the cerebral angiogram and brain andleptomeningeal biopsies were negative for CNSvasculitis, this could not be excluded since thispatient had no risk factors that could cause theICH (such as diabetes, hypertension, cerebralaneurism or vessel spasm, exposure to NSAIDs),Bifrontal lobe involvement was also unusual.Previous reports regarding small CNS vesselvasculitis reported a sensitivity of only 75% forleptomeningeal biopsy [24].Currently there is no standard of care forSS with CNS involvement; previous reportsdescribed the use of immunosuppressive therapyinvolving high dose pulse steroids, Rituximab orCyclophosphamide [24]. Our patient did receivemethylprednisolone 1 g for 3 consecutive days,followed by oral prednisone 1 mg/ kg that wastapered down over the course of 4 months. Thepatient’s mentation improved in one week andthe confusion resolved. She remains without anyneurological deficits.ConclusionOur case emphasizes the importance of a taking adetailed history in ICH cases, which may detectan autoimmune etiology. Although extremelyrare, ICH can be seen in patients with primarySS and CNS involvement. Increasing awarenessabout the neurologic manifestations of SS maylead to prompt treatment and better prognosisof these patients.Conflicts of interest'NoneFundingNoneAcknowledgementNo oneReferences1.Tobon GJ, Pers JO, Devauchelle-Pensec V, et al.Neurological Disorders in Primary Sjogren’s Syndrome.Autoimmune Dis. 2012, 11 (2011).2.Baer AN, Fox R, Romain PL. Clinical manifestations ofSjogren’s syndrome: Extraglandular disease.3.Hayashi K, Morofuji Y, Suyama K, et al. Recurrenceof Subarachnoid Hemorrhage Due to the Ruptureof Cerebral Aneurysms in a Patient With Sjogren’sSyndrome. Neurol. Med. Chir. 50(8), 658–661 (2010).4.Alexander EL. Neurologic disease in Sjögren’ssyndrome: mononuclear inflammatory vasculopathyaffecting central/peripheral nervous system and muscle.A clinical review and update of immunopathogenesis.Rheum. Dis. Clin. North. Am. 19(4), 869–908 (1993).5.Delalande S, de Seze J, Fauchais AL, et al. Neurologicmanifestations in primary Sjögren syndrome: a study of82 patients. Med. 83(5), 280–291 (2004).6.Alexander EL, Malinow K, Lejewski JE, et al. PrimarySjögren’s Syndrome with Central Nervous SystemDisease Mimicking Multiple Sclerosis. Ann. Intern.Med. 104(3), 323–330 (1986).7.Vrethem M. Immunoglobulins within the centralnervous system in primary Sjogren’s syndrome. J.Neurol. Sci. 100(1-2), 186–192 (1990).8.Pierot L. Asymptomatic cerebral involvement inSjögren’s syndrome: MRI findings of 15 cases.Neuroradiology 35(5), 378–380 (1993).9.Morgen K. Central nervous system disease in primarySjogrens syndrome: the role of magnetic resonanceimaging. Semin. Arthritis. Rheum. 34(3), 623–630(2004).10. Alexander EL, Craft C, Dorsch C, et al. Necrotizingarteritis and spinal subarachnoid hemorrhage in Sjögrensyndrome. Ann. Neurol. 11(6), 632–635 (1982).11. Bragoni M, Di Piero V, Priori R, et al. Sjogren’sSyndrome Presenting as Ischemic Stroke. Stroke.25(11), 2276–2279 (1994).12. Urban E, Jabbari B, Robles H. Concurrent cerebralvenous sinus thrombosis and myeloradiculopathy inSjögren’s syndrome. Neurology. 44(3), 554–556 (1994).13. Giordano MJ, Commins D, Silbergeld DL. Sjogren’scerebritis complicated by subarachnoid hemorrhageand bilateral superior cerebellar artery occlusion: casereport. Surg. Neurol. 43(1), 48–51 (1995).243
Case ReportGirnita et al.14. Nagahiro S, Mantani A, Yamada K, et al. Multiplecerebral arterial occlusions in a young patient withSjögren’s syndrome: case report. Neurosurgery. 38(3),592–595 (1996).20. Mercurio A, Altieri M, Saraceni VM, et al. CerebralVenous Thrombosis Revealing Primary SjögrenSyndrome: Report of 2 Cases. Case. Rep. Med. 2013,1–4 (2013).15. Koh MS, Goh KY, Chen C, et al. Cerebral infarctmimicking glioma in Sjogren’s syndrome. Hong Kong.Med. J. 8(4), 292–294 (2002).21. Ho TH, Hsu YW, Wang CW, et al. Cerebral VenousSinus Thrombosis in A Patient with Sjögren’s Syndromewith Atypical Antibodies: A Case Report. Acta. Neurol.Taiwan. 25(2), 65–69 (2016).16. Klingler JH, Glasker S, Shah MJ, et al. Rupture of aspinal artery aneurysm attributable to exacerbatedSjögren syndrome: case report. Neurosurgery. 64(5),E1010–E1011 (2009).17. Asai Y, Nakayasu H, Fusayasu E, et al. Moyamoyadisease presenting as thalamic hemorrhage in a patientwith neuromyelitis optica and Sjögren’s syndrome. J.Stroke. Cerebrovasc. Dis. 21(7), 619.e7–619.e9 (2012).23. Ciccone MM, Scicchitano P, Zito A, et al. Evaluationof differences in carotid intima-media thickness inpatients affected by systemic rheumatic diseases. Intern.Emerg. Med. 10(7), 823–830 (2015).18. Ishizaka S, Hayashi K, Otsuka M, et al. Syringomyeliaand arachnoid cysts associated with spinal arachnoiditisfollowing subarachnoid hemorrhage. Neurol. Med.Chir. 52(9), 686–690 (2012).24. Haji-Ali RA, Calabrese LH. Primary angiitis of thecentral nervous system in adults.19. Wang GQ, Zhang WW. Spontaneous intracranialhemorrhage as an initial manifestation of primarySjögren’s syndrome: a case report. BMC. Neurol. 13,100 (2013).24422. Kurmann RD, Mankad R. Atherosclerotic vasculardisease in the autoimmune rheumatologic woman.Clin. Cardiol. 41, 258–263 (2018).Int. J. Clin. Rheumatol. (2018) 13(4)
1994, Bragoni 44, F Ischemic stroke 1994, Urban 41, F Venous sinus thrombosis 1995, Giordano 55, F SAH 1996, Nagahiro 17, F Ischemic stroke 2002, Koh 50, F Ischemic stroke 2009, Klingler 46, F SAH 2010, Hayashi 54, F SAH 2012, Asai 52, F Thalamic hemorrhage 2012, Ishizaka 66, F SAH 2013, Wang 39, F ICH 2013, Mercurio 43, F Venous sinus thrombosis
series b, 580c. case farm tractor manuals - tractor repair, service and case 530 ck backhoe & loader only case 530 ck, case 530 forklift attachment only, const king case 531 ag case 535 ag case 540 case 540 ag case 540, 540c ag case 540c ag case 541 case 541 ag case 541c ag case 545 ag case 570 case 570 ag case 570 agas, case
Nine Lives Stealer (any sword) Yes Very Rare 36,000 gp DMG 183 Oathbow (longbow) Yes Very Rare 13,000 gp DMG 183 Scimitar of Speed Yes Very Rare 7,500 gp DMG 199 Spear of Backbiting (spear or javelin) Yes Very Rare 6,500 gp TYP 229 Sword of Sharpness (slashing swords) Yes Very Rare 42,000 gp DMG 206 Bookmark (dagger) Yes Legendary 30,000 gp TA 206
LINEAR REGRESSION WITH RARE EVENTS The term rare events simply refers to events that don’t happen very frequently, but there’s no rule of thumb as to what it means to be “rare.” Any disease incidence is generally considered a rare event (van Belle (2008)).
The logistic regression shows important drawbacks when we study rare events data. Firstly, when the dependent variable represents a rare event, the logistic regression could underestimate the probability of occurrence of the rare event. Secondly, com-monly used data collection strategies are inefficient for rare event data (King and Zeng, 2001).
A Rare Barometer survey - June 2021 6 / 45 4. A call for research that benefits every rare disease and that involves patient organisations When asked about research priorities, respondents' answers showed that they would like research to benefit every rare disease, including diseases with:
case 721e z bar 132,5 r10 r10 - - case 721 bxt 133,2 r10 r10 - - case 721 cxt 136,5 r10 r10 - - case 721 f xr tier 3 138,8 r10 r10 - - case 721 f xr tier 4 138,8 r10 r10 - - case 721 f xr interim tier 4 138,9 r10 r10 - - case 721 f tier 4 139,5 r10 r10 - - case 721 f tier 3 139,6 r10 r10 - - case 721 d 139,8 r10 r10 - - case 721 e 139,8 r10 r10 - - case 721 f wh xr 145,6 r10 r10 - - case 821 b .
12oz Container Dome Dimensions 4.5 x 4.5 x 2 Case Pack 960 Case Weight 27.44 Case Cube 3.21 YY4S18Y 16oz Container Dome Dimensions 4.5 x 4.5 x 3 Case Pack 480 Case Weight 18.55 Case Cube 1.88 YY4S24 24oz Container Dome Dimensions 4.5 x 4.5 x 4.17 Case Pack 480 Case Weight 26.34 Case Cube 2.10 YY4S32 32oz Container Dome Dimensions 4.5 x 4.5 x 4.18 Case Pack 480 Case Weight 28.42 Case Cube 2.48 YY4S36
The National Strategic Action Plan for Rare Diseases is the first nationally coordinated effort to address rare diseases in Australia. Due to the great complexity, significant unmet need and critical urgency associated with rare diseases, systemic reform is required. While there are many dif
