Michalis L. Kosmidis

Peripheral neuropathies in Sjögren’s syndrome: A critical update on clinical features and pathogenetic mechanisms

Sjögrens syndrome is a systemic autoimmune disease that, apart from exocrine glands, may affect every organ or system. Involvement of different sections of the peripheral nervous system results in a wide spectrum of neuropathic manifestations. Based on distinct clinical, electrophysiological and histological criteria, the types of neuropathies seen in Sjögrens syndrome include: a) pure sensory which presents with distal symmetric sensory loss due to axonal degeneration of sensory fibers; sensory ataxia due to loss of proprioceptive large fibers (ganglionopathy); or with painful dysethesias (small fiber sensory neuropathy) due to degeneration of cutaneous axons. The latter appears to be the most common neuropathy in Sjögrens syndrome and requires skin biopsy for diagnosis to document loss or reduction of nerve fiber density; b) sensorimotor polyneuropathy affecting sensory and motor axons, often associated with severe systemic or pro-lymhomatous manifestations, such as palpable purpura and cryoglobulinemia, and c) rare types that include autoimmune demyelinating neuropathy, mononeuropathy, mononeuropathy multiplex and autonomic neuropathy. In this review, the frequency, prevalence and diagnostic criteria for each neuropathy subset are discussed and possible pathogenetic mechanisms are outlined.

Incidence and prevalence of major central nervous system involvement in systemic lupus erythematosus: a 3-year prospective study of 370 patients.

Background The incidence and prevalence of CNS involvement in SLE remains unclear owing to conflicting results in the published studies. The aim of the study was to evaluate the incidence and prevalence of major definite CNS events in SLE patients. Methods 370 SLE patients with no previous history of CNS involvement were prospectively evaluated in a tertiary hospital referral center for 3 years. Major CNS manifestations were codified according to ACR definitions, including chorea, aseptic meningitis, psychosis, seizures, myelopathy, demyelinating syndrome, acute confusional state and strokes. Minor CNS events were excluded. ECLAM and SLEDAI-SELENA Modification scores were used to evaluate disease activity and SLICC/ACR Damage Index was used to assess accumulated damage. Results 16/370 (4.3%) patients presented with a total of 23 major CNS events. These included seizures (35%), strokes (26%), myelopathy (22%), optic neuritis (8.7%), aseptic meningitis (4.3%) and acute psychosis (4.3%). Incidence was 7.8/100 person years. Among hospitalizations for SLE, 13% were due to CNS manifestations. Epileptic seizures were associated with high disease activity, while myelopathy correlated with lower disease activity and NMO-IgG antibodies (P≤0.05). Stroke incidence correlated with APS coexistence (P = 0.06). Overall, CNS involvement correlated with high ECLAM and SLEDAI scores (P<0.001). Conclusions Clinically severe CNS involvement is rare in SLE patients, accounting for 7.8/100 person years. CNS involvement correlates with high disease activity and coexistence of specific features that define the respective CNS syndromes.

Reduction of Intraepidermal Nerve Fiber Density (IENFD) in the skin biopsies of patients with fibromyalgia: A controlled study

OBJECTIVES Fibromyalgia (FM) is one of the most common chronic pain syndromes. Various pathogenetic mechanisms have been implicated but none is proven. Our scope was to determine if Intraepidermal Nerve Fiber Density (IENFD) is reduced in the skin of FM patients, as observed in patients with painful small fiber sensory neuropathy (SFSN). DESIGN, SETTING AND PARTICIPANTS We prospectively studied 46 FM patients (5 men and 41 women), aged 29 to 76 (mean: 52.5) years, diagnosed according to the ACR 2010 criteria, and 34 controls (18 women and 16 men) aged 19 to 84 (mean: 31.7) years. IENFD was measured using published guidelines and immune markers were sought immunocytochemically. In 30 FM patients, pain intensity was assessed with the Neuropathic Pain Symptom Inventory (NPSI), a scale validated for neuropathic pain. RESULTS 15 of 46 (32.6%) FM patients had reduced IENFD [range: 0.6-12.5 fibers/mm (mean: 4.83 SD: 2.5)], compared to healthy controls [2.8-11.5 fibers/mm (mean: 7.35, SD: 1.85)] (p<0.0001). No significant correlation was noticed between NPSI scores and IENFD. No difference in the Langerhans cells, the major Antigen Presenting Cells (APCs) in the epidermis, or in IL-6 staining, was noted between FM and controls. IENFD was equally reduced in a subset of FM patients who also had another autoimmune disease. CONCLUSION This is one of the largest series of FM patients demonstrating a significant reduction of IENFD in their skin biopsies. The findings indicate that in a subset of FM patients, the pain syndrome is, at least partially, of neuropathic origin. Skin biopsy may prove a useful tool and a potential biomarker in future studies of FM patients.

The effect of anakinra, an IL1 receptor antagonist, in patients with sporadic inclusion body myositis (sIBM): A small pilot study

In sIBM, an inflammatory process mediated by cytotoxic T cells and cytokines in conjunction with a degenerative process, deposits of beta amyloid and misfolded proteins appear to be the main culprits in disease pathogenesis. IL-1β may play a key role because it is upregulated in sIBM myofibers, co-localizes with Amyloid Precursor Protein (APP) and promotes the production of APP and amyloid deposits. We performed a small, pilot study to examine whether anakinra, an IL1 receptor antagonist could benefit sIBM patients. Four patients with biopsy-proven sIBM received anakinra for a mean period of 7.7 months. No improvement in muscle strength or stabilization was noted in any of the patients based on grip strength and MRC measurements. The treatment failure may be due to insufficiency of anakinra to suppress the intramuscular IL1, the short study period, or the irrelevance of IL1 in the disease process.

Paraneoplastic anti-NMDAR encephalitis: long term follow-up reveals persistent serum antibodies

Encephalitis associated with antibodies to N-methyl-Daspartate receptor (NMDAR) is a severe but treatable condition [3]. It is often paraneoplastic, affecting mostly women harboring ovarian teratomas. Its characteristic clinical picture includes confusion, agitation, psychiatric manifestations, memory loss, seizures and abnormal movements, and often leads to decreased level of consciousness, autonomic instability, and central hypoventilation [1, 5]. We present the long term follow-up of a patient with paraneoplastic anti-NMDAR encephalitis diagnosed several months after symptom onset who was in a comatose state for 1 year. A prolonged recovery followed after tumor resection and immunotherapy. Two notable observations are the absence of a detectable tumor at an early stage of the disease, and the persistent detection of serum NMDAR antibodies 4 years after disease onset. A 42-year-old woman suffering from headaches 2 months before disease onset, was admitted to an Athens hospital with neck pain, nausea, dizziness and high fever. She was alert and oriented. Her initial work up (brain and spinal MRI, chest and abdominal CT, routine laboratory tests) was normal. Lumbar puncture revealed pleiocytosis (421 lymphocytes/ mm) but no oligoclonal bands. CSF and serum cultures for bacterial, fungal and viral infections were negative. Two days after admission she became delusional with visual hallucinations, confusion, central hypoventilation and a progressive consciousness decline that led to a coma requiring ventilation 10 days after admission. Her EEG was slowing, disorganized, with no basic rhythm but without epileptic foci. The initial diagnosis was viral encephalitis with non convulsive status epilepticus and she was treated with antibiotics, antivirals and antiepileptics. Her condition worsened with episodes of hyperpyrexia, agitation, orofacial dyskinesias, stiffness, and seemingly violent movements of her upper arms. These episodes diminished significantly with dantrolene. A transvaginal echo was normal. She was treated with steroids and one course of IVIg but she remained unresponsive. In ICU the patient had multiple episodes of septicemia but she responded well to therapy. Seven months after disease onset she was transferred to our institution in a comatose state with tracheostomy and gastrostomy. Repeated CSF analysis for bacterial and viral infections was negative. Other systemic autoimmune causes were excluded and all autoantibody tests were negative (ANA, Ro, La, cANCA, pANCA, rheumatoid factor). Brain MRI was normal. An upper and lower abdominal MRI (looking for ovarian tumors) was negative. A suspected immune mediated encephalitis was treated with IVIg infusions, 2 g/ kg/36 h per month. A month later (month 9 from disease onset), a CT re-examination of the lower abdomen revealed a cystic formation at the left ovary. Following resection, pathology revealed a mature ovarian teratoma. NMDAR autoantibodies were detected in the serum and CSF using a qualitative assay (Fig. 1a). The patient started to communicate 40 days after tumor resection. IVIg infusions continued monthly for 7 months and she continued to improve slowly. No steroids, cyclophosphamide or plasmapheresis were added due to H. Alexopoulos M. L. Kosmidis M. C. Dalakas (&) Neuroimmunology Unit, Department of Pathophysiology, Faculty of Medicine, National and Kapodistrian University of Athens, 75 Mikras Asias St, 11527 Athens, Greece e-mail: mdalakas@med.uoa.gr

THU0159 Incidence and prevalence of major central nervous system (CNS) involvement in systemic lupus erythematosus (SLE): A 3 year prospective evaluation and clinical correlations in 370 patients

Background Incidence and prevalence of CNS involvement in SLE is highly variable in all published series. Minor and non-specific symptoms such as headaches, mild cognitive dysfunction or depression, collectively labeled neuropsychiatric lupus, are clouding the true incidence of specific CNS events. Objectives To evaluate the incidence and prevalence of definite and severe CNS involvement in SLE patients. Methods From a cohort of 1093 SLE patients, fulfilling the 1997 ACR criteria, 458 were prospectively evaluated in our department (July 2008 to June 2011). 370 of them had no previous history of CNS involvement attributed to SLE and were finally enrolled in the study. Major and objective CNS manifestations were codified according to ACR definitions excluding minor CNS events such as headaches, mild depression or unspecified cognitive impairment. European Consensus Lupus Activity Measurement score (ECLAM) and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) SELENA Modification, were used to evaluate disease activity. The SLICC/ACR Damage Index was used to assess accumulated damage due to the disease. We used the Chi-Square test for categorical and the Mann-Whitney test for quantitative variables to evaluate differences between subgroups of patients with CNS involvement. Binary logistic regression models were used to assess differences between patients with and without CNS involvement. Results After excluding the non-specific and minor CNS events, only 16/370 (4.3%) patients remained with a total of 19 definite CNS events. These included seizures (42.1%), strokes (31.6%), myelopathy (21%), optic neuritis (5.3%) and acute psychosis (5.3%). Incidence was evaluated among newly diagnosed SLE patients and was 7.8/100 person years. Among hospitalizations for SLE, 13.7% were due to CNS involvement. Epileptic seizures were associated with high disease activity scores and early onset during the disease course, while myelopathy correlated with lower disease activity scores and NMO-IgG antibodies (P≤0.05). Stroke incidence correlated with APS coexistence (P=0.06). When these patients were compared with the 354 SLE patients without neurologic manifestations, CNS involvement correlated with high ECLAM and SLEDAI scores (P<0.001). Conclusions Clinically severe CNS involvement is rare in SLE patients, accounting for 7.8/100 person years. CNS involvement correlates with disease activity and coexistence of specific autoantibodies (NMO) that define the respective CNS syndromes. Disclosure of Interest None Declared