Limbic Encephalitis as a Late Complication of Relapsing Polychondritis: A Case Report and Review of the Literature

Corresponding Author: Dimitris Katsifis-Nezis Internal Medicine, Peripheral General Hospital of Peiraias Tzaneio Afentouli and Zanni Str., Peiraias 18536 E-mail: dimitris.katsifis@yahoo.com INTRODUCTION Relapsing polychondritis (RP) is a rare connective tissue disease characterized by recurrent inflammation of cartilaginous and proteoglycan-rich tissues. Auricular and nasal chondritis, as well as oligoor polyarthritis are the clinical hallmarks of the disease, presenting in over 80% of cases. However, multiple organs can be affected, such as the eyes, the cardiovascular system, the skin and the nervous system, highlighting the systemic nature of the disease. In the majority of patients RP shows an abrupt onset with a progressive course and frequent relapses, resulting in destruction and functional impairment of the affected structures. Its incidence is estimated between 0.71 and 3.5 cases per million, while both genders are equally affected.1 The exact pathogenesis of the disease remains unknown. Current understanding implicates both cell mediated and humoral immune systems. HLADR4 is identified as a key allele, though no ethnic or familial clustering have been noted. To date, diagnosis relies on diagnostic criteria proposed by McAdam and colleagues in 1976 and their modification by Damiani et al. and Michet et al.2,3,4 Laboratory, histological, or imaging methods are supportive but lack diagnostic specificity.5 Central nervous system (CNS) involvement in RP is a life-threatening, but infrequent manifestation of the disease accounting for 3% of the reported cases.6 Neurologic involvement manifests with heterogenous features including limbic encephalitis, aseptic meningoencephalitis, dementia, and cranial nerve palsies. We report a case of a patient with known RP of distant onset that presented with rapidly progressive dementia (RPD) secondary to limbic encephalitis and concomitant parenchymal vasculitis. In our knowledge this is the first reported case of CNS involvement in RP with presentation ten years after disease onset, exemplifying the diversity of this condition in terms of clinical appearance and time course.

irritation.Signs of active auricular or nasal inflammation were absent.However, the pinna on both sides seemed flattened and atrophic, whereas his voice was hoarse.Overt focal deficits were not observed.On standing and walking, a wide-based gait with a positive Romberg test were noted.During the examination the patient remained alert, however he showed a euphoric disposition, often displaying agitation and expressing inappropriate remarks.Neuropsychological testing revealed pronounced disturbances in short-term memory, as well as recall, orientation, and executive functions.Brain MRI showed diffuse small-diameter focal lesions in T2 and FLAIR sequences located in the sub-cortical and deep white matter, as well as hyperintensity in both medial temporal lobes (Figure 1A).Diffusion weighted imaging was negative for recent infarction.Cerebral MR angiography with complementary high-resolution vessel wall imaging excluded the presence of aneurysms or arterial stenoses in the circle of Willis.Vessel wall enhancement was not noted.Initial laboratory investigations were unremarkable except for a mild elevation of the erythrocyte sedimentation rate (40 mm/hr).A lumbar puncture was performed, and cerebrospinal fluid (CSF) examination demonstrated a lymphocytic pleocytosis (118/mm 3 , lymphocytes=83%) with increased total protein (100mg/dl) and marginally reduced glucose concentration (53 mg/dl, serum glucose: 117 mg/dl).A comprehensive investigation for infectious agents was negative, including herpes simplex virus I and II, CMV, Epstein-Bar virus, Varicellazoster virus, Human herpesviruses 6, 7 and 8, Listeria Monocytogenes, Cryptococcus Neoformans, JC virus, Borrelia burgdorferi/miyamotoi and Mycobacterium Tuberculosis.CSF cytology did not detect malignant cells.Notably, Quantitative immunoglobulin analysis revealed intrathecal IgG synthesis (IgG index =1.14, presence of oligoclonal bands).Serum screening for HIV, syphilis, or hepatitis was negative.Further investigations, such as serum angiotensin-converting enzyme, Mantoux reaction, and interferon-γ assay, testing for autoimmune diseases (ANA, ANCA, C3/C4, RF, Ig4, ENA), antibodies for paraneoplastic (Anti-Amphiphysin, Anti-CV2, Anti-Hu, Anti-PNMA2, Anti-Recoverin, Anti-Ri, Anti-SOX1, Anti-Yo, Anti-zic4, AntiTr) and autoimmune encephalitides (NMDAR, GAD, ΑMPAR, GABAR, DPPX, GluR5, Αnti-CASPR2, Anti-LGI1, Anti-VGKC) were also without positive results.Finally, an extensive screening for systemic malignancy, including gastroscopy/colonoscopy and computed tomography of the chest and abdomen was unfruitful.Based on the clinical features, the MRI and CSF findings, as well as on the exclusion of pertinent alternative diagnoses, we concluded that limbic encephalitis secondary to relapsing polychondritis was an important consideration.
Therapy was promptly initiated with seven daily pulses of intravenous methylprednisolone (MP) (1gr/day), followed by oral prednisone (60mg/d).On follow-up one month later, our patient showed substantial clinical response, with improved orientation and attention on testing with cognitive batteries and a significant attenuation of CSF pleocytosis (18/mm 3 ) with still increased total protein (80mg/dl) and normal glucose concentration (86mg/ dl, serum glucose 113mg/dl).Surprisingly, a new brain MRI displayed further enlargement of the hyperintense areas in the medial temporal lobes, with signs of atrophy.Additionally, lesion bulk in the white matter and basal ganglia was increased, strongly indicating a vasculitic process (Figure 1B).Deterioration on imaging prompted the addition of a second-line immunomodulatory agent.Cyclophosphamide was initiated as induction therapy (750mg/m2 monthly for 6 months) and after completion, it was substituted with azathioprine as maintenance treatment (3mg/kg/d).A follow-up brain MRI two months into treatment with cyclophosphamide demonstrated a significant reduction of vasculitic lesions (Figure 1C).However, the progression of atrophy in the hippocampi and temporal horns was not halted, possibly reflecting the inevitable end-product of a long-lived inflammatory process.Currently, three years after initial presentation, the patient is clinically stable, still displaying anterograde amnesia.However, he is able to carry out rudimentary daily activities with minimal supervision.He remains on azathioprine therapy and prednisone was slowly tapered to 5mg/day.

DISCUSSION
Relapsing polychondritis is an uncommon disease first described in 1923 by Jaksch-Wartenhorst.The term was coined by Pearson and colleagues in 1960, in order to describe the undulating course of this condition. 7,8NS involvement is rare, affecting approximately 3% of patients.It can appear as part of the initial clinical syndrome, 9 occasionally as the presenting symptom, 10,11 or, in the case of our patient, as a late complication of the disease.Due to the long period separating the time of initial RP diagnosis and the onset of cognitive symptoms (10 years), as well as the lack of apparent disease activity, a direct association could not be drawn.Initially, our differential diagnosis included vascular, metabolic, autoimmune, systemic, infectious, malignant, and degenerative causes (Figure 2).Due to the rarity of the syndrome most data are derived from case reports, while only a few case series exist. 15,16urrently, there are no diagnostic criteria of CNS involvement in RP; hence, it is a diagnosis by exclusion.The pathophysiology underlying CNS involvement remains unknown and prevailing theories favour a vasculitic process. 17,18In 2017, Ellis et al. reported two RP cases complicated by cognitive decline that reflected

TITLE LIMBIC ENCEPHALITIS AS A LATE COMPLICATION OF RELAPSING POLYCHONDRITIS:
A CASE REPORT AND REVIEW OF THE LITERATURE two separate etiopathogeneses.The first case described a patient with fulminant cognitive dysfunction displaying vasculitic parenchymal foci on MRI and histopathologic evidence of small-vessel infiltration from atypical multinucleate giant cells.In contrast, the second case noted a more insidious course with behavioural changes and memory deficits resembling the clinical complex of limbic encephalitis.Brain MRI in this patient showed atrophy of the medial temporal lobes. 19Interestingly, our patient, presented with a combination of these two phenotypes, expressing both the neuropsychiatric features and medial temporal lobe pathology of limbic encephalitis, together with wide-spread vasculitic lesions on MRI.
We searched PubMed, Web of Science and Google Scholar in December 2021 using "relapsing polychondritis" AND ("limbic encephalitis" OR "encephalitis" AND "limbic system") AND "case reports" as the keywords.
We retrieved a total of 20 articles, where 13 met the inclusion criteria (English, limbic encephalitis) (Table 1).
The titles and abstracts were screened by 2 authors and those that did not meet the inclusion criteria were discarded.Full texts of the remaining citations were obtained and examined for eligibility.Reference lists of retrieved articles were manually screened for potentially relevant case reports.As shown in Table 1, the mean age of RP patients with a syndrome of limbic encephalitis is 59 years (range 43-72 years).There is a pronounced male predominance with no female cases of limbic encephalitis due to RP reported in medical literature.This is an interesting finding considering that RP is known to present in similar rates in both genders.Clinical presentation encompasses heterogenous features, including memory loss, behavioural changes, disorientation, apathy, extrapyramidal symptoms, and speech difficulties.Although seizures are a frequent symptom of limbic encephalitis, they are reported from only three authors.All patients indicated increased inflammatory markers and mononuclear pleocytosis in CSF, with only one reporting polymorphonuclear predominance.The preferred imaging modality was MRI, whilst in one case report PET/CT was used.MRI studies demonstrated mostly lesions in the temporal lobes, hippocampi, basal ganglia, as well as the deep brain white matter.A common late finding was atrophy of the affected structures.Of note, in two case reports initial MRI scans were free of abnormal findings, highlighting the importance of follow-up imaging.We too found the temporal lobes and hippocampi to be the most affected sites.However, our patient also displayed a progressive confluence of vasculitic lesions located in the periventricular white matter, deep gray matter and subcortical areas mimicking small-vessel disease.Eventually, the progressive atrophy of the medial temporal structures was responsible for the most devastating sequelae in our patient involving memory function.
As far as the CSF analysis is concerned, the available data from the most cases demonstrate pleocytosis with lymphocytic predominance, increased protein levels and normal glucose concentration.Our patient's marginally low CSF glucose levels from the first lumbar puncture was an unexpected finding.Nevertheless, the negative infectious disease workup along with the second lumbar puncture's findings (normal CSF glucose concentration) made the possibility of a CNS infection seem more distant.
Additionally, nine out of twelve reported cases tested antibodies for paraneoplastic and/or autoimmune encephalitides.It is important to note that only Kashihara et al. found a patient positive for GluR N2B antibodies, both in CSF and serum, while Kondo et al. identified GluR N2B and GluRδ2 only in CSF (22; 25).These antibodies, which are subunits of the NMDA receptor, have been associated with other forms of limbic encephalitis, such as non-paraneoplastic, non-herpetic and ovarian teratoma associated limbic encephalitides.Although we did not test for these antibodies directly, the lack of positive NMDAR antibodies in our patient strongly advocates against their presence.The role of NMDAR subunits and their relation to central nervous system involvement in RP, remains to be elucidated.

TITLE
Treatment of RP associated limbic encephalitis is empirical, based on previous reports.The majority of patients are initially treated with high dose corticosteroids showing good response. 18,20,27Nevertheless, a small number of cases report slight improvement or failure of initial treatment. 18,22Fewer reports exist regarding the treatment of refractory disease.Infliximab, cyclophosphamide, and IVIg have all been tried giving inconsistent results.Accordingly, we chose glucocorticoids as initial therapy.However, later on, radiological progression of the disease necessitated the use of 2 nd line drugs.We chose cyclophosphamide as induction therapy, followed by azathioprine for long-term treatment, both well studied therapies for refractory autoimmune encephalitides and other systemic rheumatological diseases with neuropsychiatric manifestations (eg, systemic lupus erythematosus). 31This therapeutic intervention was associated with decreased number of lesions depicted serially on MRI imaging, disappearance of pleocytosis in CSF, as well as significant improvement in neuropsychological testing.
In conclusion, we presented a case of relapsing polychondritis with a late presentation on CNS involvement that traversed the clinical and imaging spectrum of the disease displaying features of limbic encephalitis and small-vessel vasculitis.Importantly, we share our experience of effectively treating refractory limbic encephalitis in the context of RP with the use of cyclophosphamide and azathioprine intending to contribute to the limited data available so far in the literature.

Figure 1A -
Figure 1A-1B-1C.Α) MRI findings on presentation: T2-weighted and fluid-attenuated inversion recovery (FLAIR) images reveal hyperintensity in the medial temporal lobes, non-specific hyperintense small-diameter lesions in subcortical and deep white matter, Β) Cerebral MRI one month after initiation of corticosteroid therapy showing expansion of hyperintense areas in the medial temporal lobes with accompanying atrophy, increased lesion load in periventricular and deep white matter, C) Cerebral MRI two months later after initiating cyclophosphamide showing decreased lesion load in periventricular and deep white matter, attenuated hyperintensity in temporal lobes accompanied by significant atrophy.

Table 1 .
Articles retrieved within inclusion criteria.

Table 1 .
Articles retrieved within inclusion criteria.