Anti-FGFR3 antibody epitopes are functional sites and correlate with the neuropathy pattern.

Antibodies against FGFR3 define a subgroup of sensory neuropathy (SN). The aim of this study was to identify the epitope(s) of anti-FGFR3 autoantibodies and potential epitope-dependent clinical subtypes. Using SPOT methodology, five specific candidate epitopes, three in the juxtamembrane domain (JMD) and two in the tyrosine kinase domain (TKD), were screened with 68 anti-FGFR3-positive patients and 35 healthy controls. The identified epitopes cover 6/15 functionally relevant sites of the protein. Four patients reacted with the JMD and 11 with the TKD, partly even in a phosphorylation-state dependent manner. The epitope could not be identified in the others. Patients with antibodies recognizing TKD exhibited a more severe clinical and electrophysiological impairment than others.

Sensorimotor dysfunction in a mild mouse model of cortical contusion injury without significant neuronal loss is associated with increases in inflammatory proteins with innate but not adaptive immune functions.

Traumatic brain injury is a leading cause of mortality and morbidity in the United States. Acute trauma to the brain triggers chronic secondary injury mechanisms that contribute to long-term neurological impairment. We have developed a single, unilateral contusion injury model of sensorimotor dysfunction in adult mice. By targeting a topographically defined neurological circuit with a mild impact, we are able to track sustained behavioral deficits in sensorimotor function in the absence of tissue cavitation or neuronal loss in the contused cortex of these mice. Stereological histopathology and multiplex enzyme-linked immunosorbent assay proteomic screening confirm contusion resulted in chronic gliosis and the robust expression of innate immune cytokines and monocyte attractant chemokines IL-1ß, IL-5, IL-6, TNFα, CXCL1, CXCL2, CXCL10, CCL2, and CCL3 in the contused cortex. In contrast, the expression of neuroinflammatory proteins with adaptive immune functions was not significantly modulated by injury. Our data support widespread activation of innate but not adaptive immune responses, confirming an association between sensorimotor dysfunction with innate immune activation in the absence of tissue or neuronal loss in our mice.

Case of primary Sjogren's syndrome preceded by dystonia.

There are only six cases in literature that describe development of dystonia with Sjogren's syndrome (SS). We describe a case of a 43-year-old woman who presented with symptoms including movement disorder, sensory neurogenic bladder, sensory loss and neuropathic pain, migraine like headaches, musculoskeletal pain, Raynaud's phenomenon and dysautonomia. Symptoms started in 2000, with weakness that progressed to dystonia in 2003. Diagnostic work-up was inconclusive with negative inflammatory serologies, cerebrospinal fluid and MRI for many years. After patient developed sicca syndrome with dry eyes and mouth in 2009, her rheumatoid factor titre was elevated (550 IU/mL), erythrocyte sedimentation rate, anti-Sjogrens syndrome-related antigen A (anti-Ro/SSA) and anti-SSB/La: anti-Sjogrens syndrome-related antigen B (anti-La/SSB) became positive. Lip biopsy confirmed diagnosis of SS. She was diagnosed with primary SS with neurological involvement. Her symptoms responded well to intravenous methylprednisolone. Symptoms stabilised with trials of immune-suppressive therapy. This is a case that demonstrates the delay of diagnosing SS with preceding unique neurological association.

Testing patients with non-specific symptoms for antibodies against Borrelia burgdorferi sensu lato does not provide useful clinical information about their aetiology.

The aim of this study was to determine whether patients with antibodies against Borrelia burgdorferi sensu lato or who report a history of erythema migrans (EM) or tick bite are more likely to have non-specific symptoms such as musculoskeletal pain, fatigue, sensory disorder, and headache. The study group comprised 423 subjects with non-specific symptoms tested for antibodies against B. burgdorferi sensu lato between July 2012 and December 2014 because of suspicion of Lyme borreliosis (LB). Of these, 285 were females (67%) and 138 were males (33%); the median age was 53 years (range, 7-89 years). Patients with a confirmed diagnosis of LB and patients with a known underlying disease that could influence the development of the symptoms were excluded from the evaluation. Subjects were assigned to the seronegative group or to one of three seropositive groups, and the history of EM and tick bite was also recorded. Statistical analysis was performed with single chi-square tests of independence and multiple logistic regression models. No differences in the occurrence of non-specific symptoms were observed between patients grouped according to antibody status. A history of EM showed no significant effect on any of the non-specific symptoms. A history of tick bite was weakly correlated with joint pain and joint swelling (p <0.05). In conclusion, it is highly unlikely that the complaints are related to a previous infection with B. burgdorferi sensu lato. The results show that testing patients with non-specific symptoms for antibodies against B. burgdorferi sensu lato in the everyday clinical setting does not provide any useful information about their aetiology.

The spectrum of immune-mediated autonomic neuropathies: insights from the clinicopathological features.

Although autonomic neuropathy may occur as a secondary consequence of various diseases, other patients without any obvious underlying diseases show profound autonomic dysfunctions from the early phase of the disease. These idiopathic or primary cases are divided into pure autonomic neuropathy, autonomic neuropathy with sensory impairment, and autonomic neuropathy with sensory and motor impairment based on the concomitance or absence of sensory or motor dysfunctions. The discovery of the antiganglionic acetylcholine receptor antibody suggested the involvement of immune mechanisms in idiopathic cases, especially in those cases with pure autonomic neuropathy. The ability to test for the presence of this antibody has significantly expanded the concept of autonomic neuropathy to include cases with a chronic progressive course that mimics pure autonomic failure. Recent work based on the antiganglionic acetylcholine receptor antibody has established autoimmune autonomic ganglionopathy as an isolated nosological entity. Other forms of primary autonomic neuropathies include acute autonomic and sensory neuropathy and acute autonomic sensory and motor neuropathy, although the nosological relationship of the latter to Guillain-Barré syndrome should be discussed. Although the possibility of infectious, metabolic or toxic aetiologies should be carefully excluded in these forms of autonomic neuropathy, the monophasic clinical course and the presence of antecedent infections suggest the involvement of immune mechanisms similar to Guillain-Barré syndrome. Neuronopathy in the autonomic ganglia is considered to be a common pathology in these autonomic neuropathies. In addition, clinically significant autonomic neuropathy may be associated with pre-existing immunological diseases such as paraneoplastic syndrome and Sjögren's syndrome. An overlap with autoimmune autonomic ganglionopathy has been suggested in these settings.

Beyond zoster: sensory and immune changes in zoster-affected dermatomes: a review*.

Neuroepidermal tropism of varicella-zoster virus accounts for cutaneous and nerve lesions following herpes zoster. Skin lesions heal in a few weeks and may or may not leave visible scars. Nerve lesions involve peripheral sensory fibres, sometimes causing permanent damage that results in partial denervation of the affected dermatome. The effects of the nerve injury involve the sensibility function, thus causing neuralgia, itch, allodynia, hypo- or anaesthesia, as well as the immune function that is related to neuropeptide release, thus altering immune control in the affected dermatome. The neuro-immune destabilization in the zoster-infected site paves the way for the onset of many and various immunity-related disorders along the affected dermatome.

Sensory neuropathy in patients with cryoglobulin negative hepatitis-C infection.

There is growing evidence that hepatitis-C virus (HCV) infection might cause peripheral neuropathy. We aimed to investigate the prevalence, clinical and electrophysiological features of sensory neuropathy in patients with cryoglobulin negative HCV infection. We studied 46 consecutive cryoglobulin negative HCV positive patients (24 of them with and 22 without neuropathic symptoms, NS) and compared to 28 age and gender matched controls. In all patients and controls, clinical neuropathy symptom (NSS) and neuropathy deficit scores (NDS) were assessed and standard nerve conduction velocity (SNCV) and pain related-evoked potentials (PREP) were recorded. Both, SNCV and PREP were abnormal in 13 NS positive patients (13/46, 28%). Abnormal PREP but normal SNCV were found in 5 (5/46, 11%) NS positive and in 2 NS negative patients (2/46, 4%). PREP abnormalities correlated positive with both clinical neuropathy scores (NSS r=0.62; p<0.001; NDS r=0.57; p<0.001), but not with the duration of the disease, current viral load, or the virus subtype. PREP abnormalities were more frequent (16/33, 48.5%) in HCV patients treated with interferon than in therapy naïve patients (4/13, 30.8%); the difference was, however, not significant. In our present study (1) all virus subtypes are capable of inducing neuropathy, (2) no differences were found between interferon therapy and treatment naive patients, (3) the prevalence of peripheral sensory neuropathy including small sensory fibers (20/46, 43.5%) is higher than previously reported and (4) we found that detection of HCV associated neuropathy depends on the evaluation method.

Sensory loss in multifocal motor neuropathy: a clinical and electrophysiological study.

Some patients fulfilling the criteria for the diagnosis of multifocal motor neuropathy with conduction block (MMN-CB) at the onset of disease may subsequently develop a sensory loss associated with electrophysiological sensory abnormalities. The latter could represent an overlap between MMN-CB and multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy. The objective was to specify the features of MMN-CB with sensory loss (MMN-CB-Se). Five patients in a series of 11 consecutive patients who fulfilled the criteria of the American Association of Neuromuscular and Electrodiagnostic Medicine for MMN-CB at the first examination and were treated periodically with intravenous immunoglobulin (IVIg) developed sensory loss in the course of the disease. In these five patients we compared the clinical, laboratory, and electrophysiological features found after the development of sensory loss with those at the first examination. The mean time to appearance of objective sensory signs was 7.2 years. In three of the five patients the sensory loss was preceded by intermittent paresthesias in the same nerve territories as the motor involvement. The most frequent electrophysiological abnormality was amplitude reduction of sensory nerve action potentials. There were no bilateral or symmetrical clinical and electrophysiological sensory abnormalities. Anti-GM1 IgM antibodies were positive in four patients. MMN-CB-Se could be an overlap between MMN-CB and MADSAM. It shares the distribution of the sensory disorders encountered in MADSAM, but it is closer to MMN-CB on clinical and therapeutic levels. Study of more patients would be useful to classify this subgroup more accurately.

Steroid-responsive paraneoplastic demyelinating neuropathy and myelopathy associated with breast carcinoma.

Paraneoplastic myeloneuropathy has rarely been reported with breast cancer. We report the case of a 59-year-old woman who presented with a peripheral neuropathy and cranial involvement and later developed a myelopathy. The neuropathy was found to be electrophysiologically and histologically demyelinating in nature. Magnetic resonance imaging studies failed to identify any structural brain or spinal cord abnormalities. The patient was diagnosed with breast carcinoma 4 months after initial presentation and underwent resective surgery, radiotherapy, and hormonotherapy. Paraneoplastic antibodies (anti-Hu, anti-Yo, anti-Ri, anti-CV2, anti-Ma, and anti-amphiphysin) were all negative. Her condition did not progress further after cancer treatment. Partial neurologic improvement occurred with oral steroid therapy, with subsequent deterioration on treatment withdrawal.

Sensory ataxic neuropathy and esophageal achalasia in a patient with Sjogren's syndrome.

We describe a patient who developed an ataxic sensory syndrome associated with xerophthalmia and progressive dysphagia with regurgitation. Electrophysiological findings were consistent with an axonal sensory neuropathy, and superficial peroneal nerve biopsy showed a reduction in number of myelinated fibers with epineurial inflammation. Rheumatoid factor, anti-SSA/SSB and antinuclear antibodies were positive and a diagnosis of Sjogren's syndrome was made. An endoscopic investigation revealed esophageal achalasia. We suggest that there may be a common autoimmune mechanism directed to different targets on the basis of this rare association.

Fine specificity of antibodies against phospholipids and beta-2-glycoprotein I in monoclonal gammopathy associated neuropathies.

Phospholipids are abundantly represented within the nervous system. Aim of our study was to evaluate the presence and fine specificity of anti phospholipid antibodies (aPLAb) among patients with monoclonal gammopathy associated neuropathy. Thirty nine percent of these patients had high titers of aPLAb, mostly associated with low levels of anti beta2 glycoprotein I, which suggests different antibody specificity compared to patients with anti phospholipid syndrome. Further 6/48 patients with dysimmune neuropathy without monoclonal gammopathy had positive aPLAb titers. APLAb strongly cross-reacted with sulfatide. These findings suggest an adjuntive role of aPLAb on nerve damage and may help to better understand the nerve binding properties of anti-sulfatide antibodies.

Adie's pupils in paraneoplastic ganglionopathy with ANNA-1.

Autonomic disturbances are common in patients with paraneoplastic syndromes associated with type-1 antineuronal nuclear autoantibodies (ANNA-1), although pupillary disturbances are infrequent. The authors describe a patient with ANNA-1 associated paraneoplastic sensory neuronopathy and bilateral Adie's pupils.

Polyneuropathy associated with interferon beta treatment in patients with multiple sclerosis.

Peripheral neuropathy has been reported as a side effect of interferon alpha, but not with interferon beta (IFNbeta) treatment. The authors assessed six patients with multiple sclerosis who developed polyneuropathy, or had exacerbation of previously subclinical neuropathy, during treatment with IFNbeta. In five patients the neuropathy improved after discontinuation of treatment and in two patients it relapsed upon rechallenge.

Primary AL (kappa-light chain) amyloidosis manifesting as peripheral neuropathy in a young male without increase in serum and urine immunoglobulin load: a diagnostic challenge.

Primary systemic or AL amyloidosis is a multisystem disorder characterized by diffuse extracellular infiltration of a fibrillar protein of monoclonal light chain origin (AL). Majority of the patients have monoclonal immunoglobulin in serum and/or urine and some have clonal proliferation of plasma cells in their bone marrow. This disease has the widest spectrum of organ involvement, most commonly affecting the kidneys, heart and liver. Involvement of peripheral nervous system is not infrequent and may be the presenting feature of the disease process. Thus, recognition of peripheral neuropathy and affecting the kidney as an early symptom of AL amyloidosis may widen the scope for therapeutic intervention. We describe here a rare case of primary amyloidosis (AL) kappa-light chain presenting with clinical features of peripheral neuropathy and affecting the kidney and heart at an early age of 18 years, hitherto unreported in literature. The case was further interesting as it was not associated with increased serum/urine immunoglobulins or plasma cells in bone marrow. Diagnosis was confirmed using immuno-electron microscopy on sural nerve biopsy.

Neuropathy resembling CIDP in patients receiving tumor necrosis factor-alpha blockers.

Tumor necrosis factor-alpha (TauNuFalpha) blockers are effective in the treatment of inflammatory arthritis but can induce autoimmune disorders including multiple sclerosis. Described are two patients who developed chronic inflammatory demyelinating polyneuropathy after initiation of anti-TNFalpha treatment.

Paraneoplastic sensory neuronopathy and spontaneous regression of small cell lung cancer.

BACKGROUND: Spontaneous tumour regression in small cell lung cancer has previously been suggested in patients with paraneoplastic neurologic syndromes. Rare documentation of this event has occurred in the literature. CASE REPORT: The authors report a patient with anti-Hu associated paraneoplastic sensory neuronopathy who had a spontaneous regression of her small cell lung cancer. CONCLUSIONS: This case supports the hypothesis that anti-Hu neurologic syndromes are the consequence of a misdirected immune response to small cell tumours.