Expansion of CD27high plasmablasts in transverse myelitis patients that utilize VH4 and JH6 genes and undergo extensive somatic hypermutation.

Patients with the autoimmune disease multiple sclerosis (MS) typically present with the clinically isolated syndromes (CIS) transverse myelitis (TM) or optic neuritis (ON). B-cell disturbances have been well documented in patients with MS and CIS patients with ON, but not in CIS patients with TM, despite the fact that these patients have the worst clinical outcome of all CIS types. The goal of this study was to characterize the B-cell populations and immunoglobulin genetics in TM patients. We found a unique expansion of CD27(high) plasmablasts in both the cerebrospinal fluid and periphery of TM patients that is not present in ON patients. Additionally, plasmablasts from TM patients show evidence for positive selection with increased somatic hypermutation accumulation in VH4(+) B cells and receptor editing that is not observed in ON patients. These characteristics unique to TM patients may impact disease severity and progression.

Sudomotor dysfunction in autoimmune autonomic ganglionopathy.

BACKGROUND: Autoimmune autonomic ganglionopathy is characterized by impairment of multiple autonomic domains of which sudomotor function is among the most common. Many patients with this disorder have difficulties with thermoregulation and anhidrosis. Our objective was to characterize the distribution and severity of sudomotor dysfunction in this disorder. METHODS: Sudomotor function was analyzed in a cohort of 21 patients with ganglionic alpha3 nicotinic acetylcholine receptor (nAChR) antibody positive autoimmune autonomic ganglionopathy. Standard measurements of sudomotor function were used including the Thermoregulatory Sweat Test and Quantitative Sudomotor Axon Reflex Test. RESULTS: The clinical presentation in all patients was characterized by widespread sudomotor dysfunction. Sudomotor impairment was predominantly postganglionic in 17 of the 21 patients studied. Higher ganglionic alpha3 nAChR antibody levels resulted in progressive postganglionic predominant dysfunction (postganglionic, r = 0.637, p = 0.002; mixed ganglionic, r = 0.709, p < 0.001). The pattern of anhidrosis on Thermoregulatory Sweat Testing was consistent with a ganglionopathy in the majority of patients (14 of 21) and a distal pattern in a minority of patients (8 of 21). These patterns of anhidrosis coupled with increasing postganglionic dysfunction in a proximal to distal pattern (foot > distal leg > proximal leg > forearm) indicate lesions at both the ganglia and distal axon of the postganglionic sudomotor sympathetic neuron. CONCLUSIONS: Our data characterize the unique sudomotor dysfunction in autoimmune autonomic ganglionopathy as widespread, predominantly postganglionic, and a result of lesions at both the ganglia and distal axon. This study provides important support to the hypothesis that this disorder represents a ganglionic neuropathy.

Efficacy of immunotherapy in seropositive and seronegative putative autoimmune autonomic ganglionopathy.

OBJECTIVE: To evaluate the efficacy of immunotherapy in the treatment of patients with seropositive and seronegative putative autoimmune autonomic ganglionopathy (AAG) using validated autonomic function tests and instruments. BACKGROUND: AAG is an immune-mediated disorder characterized by prominent and selective involvement of autonomic nerve fibers or ganglia. Treatment with i.v. immunoglobulin (IVIg) or plasma exchange (PE) has been reported to be effective in single case reports. METHODS: We studied six patients, four with seropositive and two with seronegative putative AAG, who underwent autonomic function tests and completed two validated questionnaires, to assess autonomic symptoms before and after immunomodulatory treatment. Patients were treated with standard doses of IVIg, PE, or immunosuppressants in a specific sequential therapy protocol depending on clinical response. RESULTS: Of the six patients (all women, mean ages 49.3 +/- 10.6 years), four patients were ganglionic (alpha3) AChR autoantibody positive and two were autoantibody negative. All patients showed clinical improvement after treatment. Sudomotor function assessed by quantitative sudomotor axon reflex test and thermoregulatory sweat test improved in four patients after treatment. CONCLUSIONS: Immunomodulatory treatment can be effective in both seropositive and seronegative putative autoimmune autonomic ganglionopathy. Plasma exchange or combined therapy with immunosuppressive agents should be considered in patients who do not benefit from i.v. immunoglobulin alone.

Autoimmune autonomic ganglionopathy with late-onset encephalopathy.

A 47-year old female presented with a 4 month history of early satiety, constipation, light sensitivity, orthostatic intolerance, siccca, and anhydrosis. Her examination revealed dilated, unreactive pupils with dry eyes and mouth but normal strength, phasic reflexes, and sensation. After 3 min of quiet standing her systolic pressure dropped 70 mmHg with a fixed heart rate of 74 bpm. Her alpha3 ganglionic AChR level was 2060 pmol/L (normal < or = 50). Orthostatic symptoms significantly improved within 10 days of completing 2.0 g/kg IVIg. Her supine norepinephrine (NE) level improved over baseline but remained low (i.e., 0.36 à 0.61 nmol/L). Persisting gut inertia prompted a trial of plasma exchange (PLEx) which restored her supine NE level (2.18 nmol/L), bowel patterns, and pupillary reactivity. Five months later, while her AAG was well controlled, she developed gait unsteadiness, confusion, horizontal and vertical nystagmus, bladder retention, and long tract motor signs. A contrast MRI head was normal. Further serum testing demonstrated binding avidity for neuronal alpha4 and alpha7 nAChRs. She responded to high-dose steroid and immunomodulation. This is the first case report of AAG presenting with antibodies directed against both peripheral and central nAChRs. It is tempting to speculate that CNS alpha4 or alpha7 antibodies may have precipitated the treatment-responsive encephalopathy.

Autoimmune autonomic ganglionopathy: IgG effects on ganglionic acetylcholine receptor current.

BACKGROUND: Autoimmune autonomic ganglionopathy (AAG) is an acquired immune-mediated form of diffuse autonomic failure. Many patients have serum antibodies that bind to the ganglionic acetylcholine receptors (AChRs) that mediate fast synaptic transmission in autonomic ganglia. Previous clinical studies and observations in animal models suggest that AAG is an antibody-mediated neurologic disorder. METHODS: Using whole-cell patch clamp techniques, we recorded ganglionic AChR currents in cultured human IMR-32 cells and examined the effects of bath application of IgG derived from patients with AAG. RESULTS: IgG from seven patients with AAG all produced a progressive decline in whole-cell ganglionic AChR current, whereas IgG from control subjects had no effect. The effect was abolished at low temperature. Fab antibody fragments had no effect unless a secondary antibody was added concurrently. IgG from one patient also produced a more immediate reduction of ganglionic AChR current. CONCLUSIONS: The characteristics of antibody-mediated inhibition of ganglionic acetylcholine receptor (AChR) current are consistent with modulation and blocking of the membrane AChR, analogous to the effects of muscle AChR antibodies in myasthenia gravis. Our observations demonstrate that antibodies in patients with autoimmune autonomic ganglionopathy (AAG) cause physiologic changes in ganglionic AChR function and confirm that AAG is an antibody-mediated disorder.

Potentially reversible autoimmune limbic encephalitis with neuronal potassium channel antibody.

OBJECTIVES: To describe the clinical features and coexisting serum autoantibodies in seven patients with encephalitis associated with autoantibodies to alpha-dendrotoxin-sensitive voltage-gated potassium channels (VGKCs), and to compare this disorder with other autoimmune encephalopathies. METHODS: Clinical information was obtained from a retrospective review of medical records and telephone interviews. All autoantibody testing was performed in a single laboratory. RESULTS: The seven patients were examined for subacute cognitive and behavioral changes. Seizures, usually temporal-onset complex partial type, were documented in six patients, and all seven patients had EEG abnormalities. None had symptoms or signs of neuromuscular hyperexcitability. One described hypersalivation. Four patients had additional autoantibody markers of neurologic autoimmunity (muscle acetylcholine receptor, striational, P/Q-type calcium channel, or GAD65), and two had thyroperoxidase antibodies. Two patients had a history of cancer: one had active prostate adenocarcinoma, and the second had a remote history of tongue carcinoma. Cranial MRI demonstrated mesial temporal lobe abnormalities in all patients. One patient improved spontaneously, and six were treated with IV methylprednisolone. Three improved remarkably with treatment. At follow-up evaluation, one had no cognitive deficits, four had mild persistent short-term memory dysfunction, and two had persistent disabling behavioral deficits. CONCLUSIONS: Voltage-gated potassium channel antibodies are a valuable serologic marker of a potentially reversible autoimmune encephalopathy. The neurologic manifestations of this disorder are indistinguishable from paraneoplastic limbic encephalitis but are distinct from Morvan syndrome and Hashimoto encephalopathy.

Persistent facial myokymia associated with K(+) channel antibodies.

A 58-year-old woman developed bilateral facial myokymia in 1978, persisting for the next 23 years and associated with high titers of voltage-gated K(+) channel (VGKC) antibodies. Brain imaging failed to show a pontine lesion. The clinical facial myokymia and electromyographic doublets and multiplets (43 to 250 Hz) were milder and more restricted than those seen in generalized neuromyotonic disorders with VGKC antibodies. This case and another reported recently represent a focal VGKC antibody syndrome.

ANNA-3 anti-neuronal nuclear antibody: marker of lung cancer-related autoimmunity.

Two anti-neuronal nuclear antibodies (ANNA-1 and ANNA-2) are markers of paraneoplastic neurological autoimmunity related to small-cell carcinoma. ANNA-2 is also related to breast carcinoma. Here we define a third IgG specificity (ANNA-3), identified in 11 patients (10 adults) by immunofluorescence screening of sera from approximately 68,000 patients with suspected paraneoplastic neurological syndromes. ANNA-3 binds prominently to nuclei of cerebellar Purkinje neurons, not to cytoplasm, granular neurons, or enteric neurons, but distinctively to renal glomerular podocytes. Western blots revealed an approximately 170 kDa antigen, in cerebellum and small-cell carcinoma. IgG eluted from this protein reproduced Purkinje and podocyte nuclear staining. ANNA-2 in 8 of 32 cases bound to podocyte nuclei but not to the 170 kDa protein. Healthy subjects and control neurological and cancer patients lack ANNA-3. Neurological accompaniments, subacute and usually multifocal, included sensory/sensorimotor neuropathies, cerebellar ataxia, myelopathy, brain stem and limbic encephalopathy. All of 9 adults followed had an intrathoracic neoplasm, seven biopsied within 7 months (five small-cell lung carcinomas and two adenocarcinomas, one lung, one esophagus) and two imaged, one early, the other 3 years later. Thus, immunohistochemical and Western blot criteria can now identify six IgG markers of neurological autoimmunity related to small-cell carcinoma, their frequency being ANNA-1 > collapsin response-mediator protein-5 > amphiphysin > Purkinje cell cytoplasmic antibody-2 = ANNA-2 = ANNA-3.

Myasthenia gravis with autoimmune autonomic neuropathy.

The autoantibodies that impair neuromuscular junction transmission in myasthenia gravis are specific for the nicotinic acetylcholine receptor (AChR) of muscle. Antibodies specific for AChRs in ganglionic neurons are found in a majority of patients with subacute autonomic neuropathy. Dysautonomia is not a recognized feature of myasthenia gravis, but there have been rare reports of myasthenia gravis coexisting with autonomic failure, usually in association with thymoma. Here we report seven patients who had myasthenia gravis with subacute autonomic failure. Their autonomic dysfunction ranged from isolated gastroparesis to severe panautonomic failure. Gastrointestinal dysmotility was a common feature. All had antibodies against muscle AChR, and three (all of whom had thymoma) had antibodies against neuronal ganglionic AChRs. In several patients, gastrointestinal function improved clinically after administration of an acetylcholinesterase inhibitor. These observations support a rare but definite clinical association between myasthenia gravis and autonomic failure and strengthen the concept that subacute autonomic neuropathy is an autoimmune disorder.

Paraneoplastic and metastatic neurologic complications of Merkel cell carcinoma.

Merkel cell carcinoma is a rare primary cutaneous neuroendocrine tumor that is locally aggressive and frequently accompanied by distant metastases. Neurologic complications of Merkel cell carcinoma are rare. We describe a 69-year-old man who presented with Lambert-Eaton myasthenic syndrome and was found to have Merkel cell carcinoma. The paraneoplastic syndrome improved with initial treatment of the malignancy. He subsequently developed a solitary brain metastasis and died of leptomeningeal carcinomatosis.

Fulminant autoimmune cortical encephalitis associated with thymoma treated with plasma exchange.

A 55-year-old man presented with fever, malaise, dysarthria, and intermittent twitching of his right hand. He progressed rapidly to aphasia, intractable myoclonic seizures, and unresponsiveness. Magnetic resonance imaging (MRI) of the head demonstrated multiple nonenhancing areas of signal abnormality involving the cortex of both cerebral hemispheres. Extensive evaluation revealed no infectious cause for his symptoms. Muscle acetylcholine receptor binding and modulating antibodies, striational antibodies, and a neuronal autoantibody specific for collapsin response-mediator protein were detected. An invasive thymoma was discovered and resected. Brain biopsy revealed microglial activation, gliosis, and scant perivascular lymphocytic inflammation. His condition worsened despite treatment with anticonvulsants, intravenous corticosteroids, and antimicrobials. Plasma exchange was performed. The myoclonus stopped; he regained consciousness and gradually improved to the point that he could talk and ambulate with assistance. An MRI revealed regression of the lesions with residual cortical atrophy. This case demonstrates that paraneoplastic encephalitis may occur with thymoma and may extend to cortical regions outside the limbic system.

Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies.

BACKGROUND: Idiopathic autonomic neuropathy is a severe, subacute disorder with a presumed autoimmune basis. It is indistinguishable from the subacute autonomic neuropathy that may accompany lung cancer or other tumors. Autoantibodies specific for nicotinic acetylcholine receptors in the autonomic ganglia are potentially pathogenic and may serve as serologic markers of various forms of autoimmune autonomic neuropathy. METHODS: We tested serum from 157 patients with a variety of types of dysautonomia. Immunoprecipitation assays with iodine-125-labeled epibatidine and solubilized human neuroblastoma acetylcholine receptors were used to detect autoantibodies that bound to or blocked ganglionic receptors. RESULTS: Ganglionic-receptor-binding antibodies were found in 19 of 46 patients with idiopathic or paraneoplastic autonomic neuropathy (41 percent), in 6 of 67 patients with postural tachycardia syndrome, idiopathic gastrointestinal dysmotility, or diabetic autonomic neuropathy (9 percent), and in none of 44 patients with other autonomic disorders. High levels of the binding antibodies correlated with more severe autonomic dysfunction (including the presence of tonic pupils). Levels of these antibodies decreased in patients who had clinical improvement. All seven patients with ganglionic-receptor-blocking antibodies had ganglionic-receptor-binding antibodies and had idiopathic or paraneoplastic autonomic neuropathy. CONCLUSIONS: Seropositivity for antibodies that bind to or block ganglionic acetylcholine receptors identifies patients with various forms of autoimmune autonomic neuropathy and distinguishes these disorders from other types of dysautonomia. The positive correlation between high levels of ganglionic-receptor antibodies and the severity of autonomic dysfunction suggests that the antibodies have a pathogenic role in these types of neuropathy.

New Purkinje cell antibody (PCA-2): marker of lung cancer-related neurological autoimmunity.

Neuron-restricted autoantibodies are important markers of neurological autoimmunity related to cancer. We identified a new paraneoplastic IgG, PCA-2 (Purkinje cell cytoplasmic antibody type 2), in 10 patients. Nine had mixed subacute neurological presentations (5 brainstem or limbic encephalitis, 3 cerebellar ataxia, 2 Lambert-Eaton myasthenic syndrome, 1 autonomic neuropathy, and 1 motor neuropathy). All 9 were smokers, and 8 had definite or probable lung cancer (7 with biopsy-confirmed small cell lung carcinoma [SCLC]; 1 imaged only). One patient had no follow-up information. A 10th patient was among 58 with uncomplicated SCLC. PCA-2 binds to a cytoplasmic antigen in neurons and SCLC cells. Its immunostaining pattern in mouse tissues is distinct from that of the paraneoplastic autoantibodies PCA-1 (anti-Yo, marker of immune response initiated by ovarian or breast carcinoma) and PCA-Tr (anti-Tr, immune response marker of Hodgkin's lymphoma). PCA-2 binds to cerebellar Purkinje somata and dendrites, neurons in internal granular layer and dentate nucleus, and neuronal elements in gut and kidney. Western blots of reduced/denatured cerebellar and SCLC proteins reveal a common antigenic band, of approximately 280 kd. PCA-2 is the seventh IgG neuronal autoantibody marker of paraneoplastic autoimmunity identifiable unambiguously by standardized immunofluorescence criteria.

Myasthenia, thymoma, presynaptic antibodies, and a continuum of neuromuscular hyperexcitability.

BACKGROUND: Autoantibodies specific for the nicotinic acetylcholine receptor (AChR) of skeletal muscle impair neuromuscular transmission in myasthenia gravis (MG). Autoantibodies specific for alpha3 neuronal AChRs or voltage-gated potassium channels have been reported in patients with Isaacs syndrome, an acquired disorder of continuous muscle fiber activity characterized by neuromyotonia. OBJECTIVE: To report the neuromuscular autoantibody profiles of three patients with a syndrome of MG and neuromuscular hyperexcitability. RESULTS: All three patients reported here had clinical and electrophysiologic evidence of MG and neuromuscular hyperexcitability. None had neuromyotonia. Thymoma was proven in two patients and suspected in the third. One had MG and thymoma and subsequently developed cramp-fasciculation syndrome; MG and rippling muscle syndrome appeared simultaneously in the other two. All patients had muscle and neuronal AChR binding antibodies and striational antibodies. Only one had antibodies reactive with alpha-dendrotoxin-complexed potassium channels. CONCLUSIONS: The coexistence of cramp-fasciculation syndrome and acquired rippling muscle syndrome with MG, thymoma, and neuronal AChR autoantibodies suggests that there is a continuum of autoimmune neuromuscular hyperexcitability disorders related pathogenically to Isaacs syndrome. Manifestations of neuromuscular hyperexcitability may be altered and less apparent in the context of MG because of the coexisting defect of neuromuscular transmission.

Coma in fulminant pneumococcal meningitis: new MRI observations.

We report a 45-year-old man with fulminant pneumococcal meningitis. Fluid attenuated inverse ratio MR images showed the ravaging consequences of occlusive vasculopathy and a transient purulent basal exudate. Bilateral thalamic lesions may have explained the failure to awaken despite appropriate antibiotic therapy.

Neuronal nicotinic ACh receptor antibody in subacute autonomic neuropathy and cancer-related syndromes.

BACKGROUND: Autoantibodies specific for the acetylcholine receptor (AChR) of skeletal muscle (containing the alpha1 subunit) impair neuromuscular transmission in myasthenia gravis (MG). AChRs mediating fast synaptic transmission through autonomic ganglia are structurally similar to muscle AChR, but contain the alpha3 subunit. We propose that ganglionic AChR autoimmunity may cause dysautonomia. OBJECTIVE: To test serum of patients with autonomic neuropathy for autoantibodies of neuronal ganglionic AChR specificity. METHODS: We developed an immunoprecipitation radioassay by complexing epibatidine (125I-labeled high affinity agonist) to a Triton X-100-solubilized AChR antigen from peripheral neuroblastoma membranes. Monoclonal rat immunoglobulins (IgG) specific for muscle or neuronal AChRs validated the assay's specificity. We tested serum from 52 healthy subjects, 12 patients with subacute autonomic neuropathy, and 248 patients with other neurologic disorders. RESULTS: Twelve patients had antibodies that bound unequivocally to ganglionic AChR. Five had subacute autonomic neuropathy, and three (of six tested) had Isaacs' syndrome; four of these eight had a carcinoma (lung, bladder, rectum, thyroid). The remaining four seropositive patients (two Lambert-Eaton syndrome, one dementia, one sensory neuronopathy) all had Ca2+ channel antibodies and three had small cell lung carcinoma. No healthy subject had ganglionic AChR antibodies, nor did 62 patients with MG and muscle AChR antibodies. CONCLUSION: Neuronal AChR antibodies are a novel serologic marker of neurologic autoimmunity. The pathogenicity of neuronal AChR autoantibodies in autonomic neuropathy, Isaacs' syndrome, or other neurologic disorders remains to be shown, as has been demonstrated for muscle AChR antibodies in MG. An autoimmune and potentially paraneoplastic etiology is implicated in seropositive patients.

Postpartum thrombotic thrombocytopenic purpura complicated by Budd-Chiari syndrome.

BACKGROUND: Thrombotic thrombocytopenic purpura is an infrequent but devastating complication of pregnancy, often difficult to differentiate from severe preeclampsia and the syndrome of hemolysis, elevated liver enzymes, and low platelets (HELLP). To our knowledge, the combination of thrombotic thrombocytopenic purpura and hepatic vein thrombosis has not been reported previously in pregnancy. CASE: A 33-year-old woman, a multigravida, was delivered at 36 weeks' gestation because of pregnancy-induced hypertension and HELLP syndrome. Postpartum, the patient became obtunded, disoriented, and anuric. Her laboratory values revealed a Coombs-negative, microangiopathic hemolytic anemia, modestly abnormal coagulation studies, and thrombocytopenia. She also had elevated liver enzymes, lactate dehydrogenase, and creatinine. The largest plasma von Willebrand factor multimeric forms were relatively decreased in her ethylenediaminetetra-acetic acid-platelet-poor plasma. A diagnosis of thrombotic thrombocytopenic purpura was made. The patient received plasma exchange, hemodialysis, blood transfusion, and glucocorticoids. She responded to therapy, but was later noted to have increasing hepatosplenomegaly, rising levels of bilirubin, and elevated alkaline phosphatase. A Doppler study and magnetic resonance imaging demonstrated the absence of flow in the middle and left hepatic veins, secondary to thrombosis (Budd-Chiari syndrome). She was maintained on warfarin therapy and was discharged on postpartum day 50. CONCLUSION: The early recognition of thrombotic thrombocytopenic purpura is crucial for the initiation of appropriate treatment as soon as possible. The avoidance of platelet transfusion and early plasma-exchange therapy may be lifesaving.

Quantitative measurement of calcium flux through muscle and neuronal nicotinic acetylcholine receptors.

A new approach was developed to determine quantitatively the fraction of current carried by Ca2+ through an ion channel under physiological conditions. This approach entails the simultaneous measurement of membrane current and intracellular Ca2+ for single cells. Whole-cell patch-clamp techniques were used to measure current, and intracellular Ca2+ was monitored with the fluorescent indicator fura-2. To obtain a quantitative measure of the fraction of current carried by Ca2+, a cell-by-cell calibration method was devised to account for differences among cells in such factors as cellular volume and Ca2+ buffering. The method was used to evaluate the Ca2+ flux through muscle and neuronal nicotinic ACh receptors (nAChRs). In a solution containing 2.5 mM Ca2+ at a holding potential of -50 mV, Ca2+ carries 2.0% of the inward current through muscle nAChRs from BC3H1 cells and 4.1% of the inward current through neuronal nAChRs from adrenal chromaffin cells. The Ca2+ flux through neuronal nAChRs of adrenal chromaffin cells is insensitive to alpha-bungarotoxin. The influx of Ca2+ is voltage dependent, and because of the Ca2+ concentration difference across the cellular membrane, there is Ca2+ influx into the cell even when there is a large net outward current. At both muscle and neuronal cholinergic synapses, activity-dependent Ca2+ influx through nicotinic receptors produces intracellular signals that may have important roles in synaptic development, maintenance, and plasticity.