Harry Alexopoulos

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.

A critical update on the immunopathogenesis of Stiff Person Syndrome

Eur J Clin Invest 2010; 40 (11): 1018–1025

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.

Immunology of stiff person syndrome and other GAD-associated neurological disorders

Antibodies against glutamic acid decarboxylase (GAD), the rate-limiting enzyme for the synthesis of GABA, are associated with an array of distinct, mostly autoimmune, neurological conditions. In all associated syndromes, namely stiff person syndrome, cerebellar ataxia, epilepsy, limbic encephalitis or abnormal eye movements, anti-GAD antibodies are detected at high titers and play a fundamental role in diagnosis, but do not correlate with disease severity, diversity of symptomatology or response to therapies. Despite considerable efforts, including in vitro (enzymatic assays) and in vivo (animal models) systems, the pathogenicity of anti-GAD antibodies has not been unequivocally proven for any specific condition. The search for the responsible autoantigen has revealed a few other antigenic targets, particularly for SPS, localized in the pre- or post-synaptic inhibitory neuronal synapses. Cumulative clinical and laboratory evidence indicates that anti-GAD and related antibodies define a novel group of syndromes, collectively known as ‘hyperexcitability disorders’.

Autoimmune antigenic targets at the node of Ranvier in demyelinating disorders

Mounting evidence suggests that autoantibodies contribute to the pathogenesis of demyelination in the PNS and CNS. Rapid reversal of electrophysiological blockade after plasmapheresis or intravenous immunoglobulin treatment for acute or chronic inflammatory demyelinating polyneuropathy is more likely to result from removal or neutralization of an antibody that impairs saltatory conduction than from remyelination. Although up to 30% of patients with acute or chronic inflammatory demyelinating polyneuropathy harbour autoantibodies, specific antigens have been identified in no more than 13% of cases. To date, autoantigens identified at the node of Ranvier include neurofascin 186, gliomedin and possibly moesin in the nodal domain, and contactin-1, Caspr1 and neurofascin 155 in the paranodal domain. In some patients with multiple sclerosis, paranodal CNPase and juxtaparanodal contactin-2 trigger a humoral response. This Review explores the molecular anatomy of the node of Ranvier, focusing on proteins with extracellular domains that could serve as antigens. The clinical implications of node-specific antibody responses are addressed, and the best approaches to identify antibodies that target nodal proteins are highlighted. Also discussed are the roles of these antibodies as either secondary, disease-exacerbating responses, or as a primary effector mechanism that defines demyelination or axonal degeneration at the node, identifies disease subtypes or determines response to treatments.

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.

GAD65 epitope mapping and search for novel autoantibodies in GAD-associated neurological disorders.

Antibodies against Glutamic-acid-decarboxylase (GAD65) are seen in various CNS excitability disorders including stiff-person syndrome, cerebellar ataxia, encephalitis and epilepsy. To explore pathogenicity, we examined whether distinct epitope specificities or other co-existing antibodies may account for each disorder. The epitope recognized by all 27 tested patients, irrespective of clinical phenotype, corresponded to the catalytic core of GAD. No autoantibodies against known GABAergic antigens were found. In a screen for novel specificities using live hippocampal neurons, three epilepsy patients, but no other, were positive. We conclude that no GAD-specific epitope defines any neurological syndrome but other antibody specificities may account for certain phenotypes.

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

Glycine receptor antibodies in stiff-person syndrome and other GAD-positive CNS disorders

Stiff-person syndrome (SPS) is characterized by stiffness in trunk and limb muscles, phobic anxiety, and sudden spasms. A disturbance in inhibitory GABAergic pathways, presumably by autoantibodies against GAD (the main GABA-synthesizing enzyme), is considered fundamental for SPS pathogenesis.1 As the precise role of anti-GAD antibodies in SPS remains unclear,2,3 several other candidate disease-specific autoantibodies associated with inhibitory pathways have been explored3,4 or are actively pursued. Recently, McKeon et al.5 described anti-glycine-α1 receptor (GlyR) antibodies in a subset of patients with SPS. Glycine is a neurotransmitter in spinal inhibitory interneurons and GlyR are primarily expressed in the spinal cord, brainstem, and cerebellum. Anti-GlyR antibodies have been associated with progressive encephalomyelitis with rigidity and myoclonus (PERM), a syndrome resembling SPS.6 Our aims were to search for GlyR antibodies in a large number of patients with well-characterized SPS and other CNS autoimmune controls and other GAD-positive disorders; and to correlate anti-GlyR titers with clinical symptomatology using quantitative scales of stiffness and spasms.7

Anti-aquaporin-4 autoantibodies in systemic lupus erythematosus persist for years and induce astrocytic cytotoxicity but not CNS disease

Anti-aquaporin-4 autoantibodies are specific for the neuromyelitis optica spectrum disorders (NMOSD) and they have also been described in patients with systemic lupus erythematosus (SLE) with neurological signs consistent with NMOSD. Our objective was to test for the presence and pathogenicity of anti-AQP4 antibodies in SLE patients without neurological disease. Sera from 89 non-CNS-SLE patients were screened for anti-AQP4 autoantibodies. Two of the 89 patients were positive. Archived samples dating back 11 years were also positive. A brain and spinal cord MRI did not reveal any NMOSD-compatible lesions. An in vitro cytotoxicity assay showed that either sera or purified IgG from these patients induced a complement-mediated damage in cultured astrocytes comparable to antibodies obtained from typical NMO patients. We conclude that AQP4-antibodies can be present in SLE patients and persist for many years, without concurrent clinical or radiological NMOSD signs. It is unclear why the anti-AQP4 antibodies did not induce CNS disease.