Antineuronal Nuclear Autoantibody Research Articles

Paraneoplastic seesaw nystagmus and opsoclonus provides evidence for hyperexcitable reciprocally innervating mesencephalic network

Seesaw nystagmus is characterized by the rhythmic combination of vertical and torsional dysconjugate oscillations where one eye moves up and inward while the other moves down and outward. Common association of seesaw nystagmus with accessory optic track lesions lead to traditional hypothesis that it is due to the mismatch in the vision and vestibular systems. Here we propose a novel mechanism for seesaw nystagmus. We hypothesize that reverberations due to abnormal increases in the excitability of the reciprocally innervating circuit of excitatory burst neuron in the midbrain interstitial nucleus of Cajal causes the seesaw nystagmus. Analogous oscillations of the brainstem burst generators may be responsible for generation of saccadic oscillations or opsoclonus. The key difference is that the interstitial nucleus of Cajal lacks inhibitory burst neurons, hence the lack of post-inhibitory rebound, and relatively lower frequency of the oscillatory cycles causing pendular seesaw nystagmus. In contrast the brainstem burst generator, with reciprocally innervating excitatory and inhibitory burst neurons, and further inhibitory influence of the omnipause neurons results in the post-inhibitory rebound at the burst neurons, hence high oscillation frequency. This novel concept is supported by a unique observation in a patient with antineuronal nuclear autoantibody type 2 due to breast cancer who had combined seesaw nystagmus and superimposed saccadic oscillations. The patient neither had cerebellar deficits typically thought to cause paraneoplastic opsoclonus nor visual deficits that are known cause of seesaw nystagmus. We propose that hyperexcitability of the burst neurons in the interstitial nucleus of Cajal due to paraneoplastic antibody caused pendular seesaw nystagmus. On the other hand, increased excitability of brainstem burst generators and reduced efficacy of the omnipause neurons caused saccadic oscillations.

Breast cancer-related paraneoplastic neurologic disease.

Paraneoplastic neurologic disease (PND) is an aberrant immune-mediated response against the nervous system triggered by malignancy. Given the rarity, a paucity of data describing breast cancer-related PND (BC-PND) exists; we sought to further examine this specific patient population. We retrospectively identified patients at our institution from 1997 to 2016 with BC-PND. Retrospective review with a descriptive analysis determined factors associated with PND and BC, which were compared to national breast cancer median of age (61years) and average stage at diagnosis (60% local disease). BC-PND was diagnosed in 56 female patients at a median age of 52.8years. Only 20% of invasive cancer patients had local disease. The majority of patients were hormone receptor positive and Her2 negative. Neurological symptoms presented prior to BC diagnosis in 57.1% of patients. Of all patients, 30 (53.6%) had autoantibodies detected: Purkinje Cell Cytoplasmic Autoantibody Type-1 (PCA-1[anti-Yo]), n=10; amphiphysin-IgG, n=9; Anti-Neuronal Nuclear Autoantibody Type-2 (ANNA-2[anti-Ri]), n=5; and others, n=6. The most common neurologic findings were cerebellar ataxia, myelopathy, and myopathy. Immunotherapy benefit was found to be robust (21.6%), mild to moderate (52.9%), absent (17.6%), or indeterminate (7.8%). PND symptoms often presented prior to BC diagnosis, with the BC biologic subtype characteristics typical of the general BC population. BC diagnoses were often made at younger ages than that of the general BC population and with later-stage disease. Roughly 75% of patients benefited from immunotherapy. These data provide helpful information to providers treating this population of patients.

Breast cancer-related paraneoplastic neurologic disease.

11559 Background: Paraneoplastic neurologic disease (PND) is an aberrant immune-mediated response against the nervous system triggered by occult malignancy. Given the rarity of this disease, a paucity of data exists describing breast cancer (BC)-related PND; thus, we sought to further examine this specific population of patients. Methods: Using an institution specific clinical search tool, we identified all patients at our institution from 1997-2016 with a diagnosis of BC-related PND, verified by an international expert. Retrospective review was used to record tumor and treatment factors associated with PND and BC. A descriptive analysis was performed of the characteristics associated with BC-related PND. Results: BC-related PND was diagnosed in 58 female patients. Average age at BC diagnosis was 54.0±10.3 years. Most had invasive cancer of Stage II or higher [Stage 0 (10.3%), I (10.3%), II (44.8%), III (13.8%), IV (6.9%), unknown (13.8%)]. Most patients were hormone receptor (HR)+ (63.8%), while 4 (6.9%) were HR-, and 17 (29.3%) were unknown. Of the 34 patients where Her2/neu (Her2) data was available, 7 (20.6%) were Her2+ and 27 (79.4%) were Her2-. The majority (62.1%) had neurological symptoms prior to BC, 5.2% were concurrent, and 32.7% developed PND after initial BC. The interquartile range for time from PND to BC diagnosis was -8.5 to 10.5 months. Of the 58 patients, 29 (50%) had autoantibodies detected: Purkinje Cell Cytoplasmic Autoantibody Type-1 (PCA-1[anti-Yo]) (10), amphiphysin-IgG (n = 9), Anti-Neuronal Nuclear Autoantibody Type-2 (ANNA-2[anti-Ri]) (n = 5), and other (n = 5). The most common syndromes were cerebellar ataxia (n = 14), myelopathy (n = 11), and myopathy (n = 11). Immunotherapy was used for PND in 53 of 58 (91.4%) patients; benefit from immunotherapy was assessed as complete 0 (0%), robust 11 (20.8%), mild to moderate 28 (52.8%), none 9 (17%), and indeterminate 5 (9.4%). Conclusions: BC-related PND is rare, with only 58 cases over 20 years at a large academic institution. Paraneoplastic symptoms often present prior to BC diagnosis and BC characteristics are typical of the general population. Over 75% of patients benefit from immunotherapy. These data may provide helpful information to providers treating this population of patients.

Chapter 18 - Autoimmune sleep disorders

A number of autoantibodies, some paraneoplastic, are associated with sleep disorders. Morvan syndrome and limbic encephalitis, associated with voltage-gated potassium channel-complex antibodies, principally against CASPR2 and LGI1, can result in profound insomnia and rapid eye movement sleep behavior disorder (RBD). Patients with aquaporin-4 antibodies and neuromyelitis optica may develop narcolepsy in association with other evidence of hypothalamic dysfunction, sometimes as the initial presentation. Central sleep apnea and central neurogenic hypoventilation are found in patients with anti-N-methyl-d-aspartate receptor antibody encephalitis, and obstructive sleep apnea, stridor, and hypoventilation are prominent features of a novel tauopathy associated with IgLON5 antibodies. In addition, paraneoplastic diseases may involve the hypothalamus and cause sleep disorders, particularly narcolepsy and RBD in those with Ma1 and Ma2 antibodies. Patients with antineuronal nuclear autoantibodies type 2 may develop stridor. Several lines of evidence suggest that narcolepsy is an autoimmune disorder. There is a strong relationship with the human leukocyte antigen (HLA) DQB1*06:02 haplotype and polymorphisms in the T-cell receptor alpha locus and purinergic receptor P2Y11 genes. Patients with recent-onset narcolepsy may have high titers of antistreptococcal or other antibodies, although none has yet been shown to be disease-specific but, supporting an immune basis, recent evidence indicates that narcolepsy in children can be precipitated by one type of vaccination against the 2009-2010 H1N1 influenza pandemic.

Chapter 14 - Autoimmune dementia and encephalopathy

Autoimmune dementia and encephalopathies (ADE) are complex disorders that can cause immune-mediated cognitive deficits and have confusing nomenclature. Presentation varies from acute limbic encephalitis to subacute or chronic disorders of cognition mimicking neurodegenerative dementia. It may occur as a paraneoplastic phenomenon or an idiopathic autoimmune phenomenon. The presence of a personal/family history of autoimmunity, inflammatory spinal fluid, serologic evidence of autoimmunity (neural or nonorgan-specific), or mesial temporal magnetic resonance imaging abnormalities are clues to diagnosis. Bedside cognitive assessment and/or detailed neuropsychologic testing are useful. Neural-specific autoantibodies, mostly discovered in the past two decades, may bind antigens on the cell surface (e.g., N-methyl-d-aspartate receptor autoantibodies) and are likely to be pathogenic, with treatment aimed at antibody-depleting agents often with success, while antibodies binding intracellular antigens (e.g., antineuronal nuclear autoantibody type 1 (ANNA1 or anti-Hu)) are a marker of a T-cell-mediated process and treated with T-cell-depleting immunotherapies, with variable responses. Detection and treatment of cancer (when present) are essential. High-dose corticosteroids are the initial treatment in most patients and may serve as a diagnostic test when the diagnosis is uncertain. Repeat cognitive testing after immunotherapy helps document objective improvements. Maintenance immunotherapy is recommended in those at risk for relapse. Prognosis is variable, but paraneoplastic ADE with antibodies to intracellular antigens have a worse prognosis. The field is still developing and future studies should provide guidelines for diagnosis and treatments.

High prevalence of antineuronal antibodies in Tunisian psychiatric inpatients.

The authors aimed to determine the prevalence of antineuronal antibodies in 103 psychiatric inpatients and 41 control subjects with no history of malignancies or neurological disorders. All sera were tested by indirect immunofluorescence and positive sera by immunoblot. Using immunofluorescence, antineuronal nuclear autoantibodies were detected in 20 patients and none of the control subjects, and antibodies reacted with the cytoplasm of Purkinje cells in six patients and two control subjects. The immunoblot confirmed well-characterized antineuronal antibodies only in five patients: two had anti-Ri and three had anti-Yo antibodies. After a follow-up of 5 years, none of these patients developed neurological disorder or malignancy.

Presence of paraneoplastic antibodies in non-carcinomatous patients with neurological involvements of unknown cause

BackgroundParaneoplastic antibodies (PAs) play a crucial role in the diagnostic approach of paraneoplastic neurological syndrome (PNS). We clarified the frequency and the clinical profile of PA-positive non-carcinomatous patients with neurological involvements of unknown cause. MethodsPAs were analyzed in sera of 222 consecutive non-carcinomatous patients (122 men and 100 women) defined as acute or subacute onset of unknown-causative symptoms involving the neuromuscular junction, the central and/or the peripheral nervous system between 2006 and 2009. PAs contained antineuronal nuclear autoantibody type 1, 2, 3, Purkinje cell cytoplasmic autoantibody type 1, 2, anti-Tr, amphiphysin, CRMP-5, P/Q-type, N-type voltage-gated calcium channels (VGCC), voltage-gated potassium channel complex (VGKCC) and neuronal acetylcholine receptor (nAChR) antibodies. PA-seropositive patients received detailed examination of carcinoma in the whole body for the following 2years. ResultsNine patients were PA-positive. VGKCC antibodies were found in four patients, P/Q-type VGCC antibodies in two, N-type VGCC antibodies in two and nAChR antibodies in one. Neurological features revealed limbic encephalitis in four patients, sensorimotor neuropathy in three and Lambert–Eaton myasthenic syndrome in two. One year later, 2 patients developed myelodysplastic syndrome and lung adenocarcinoma (one patient each). ConclusionWe conclude that PA-seropositive frequency is 4.1% in non-carcinomatous neurological patients at examination. VGKCC, P/Q-type and N-type VGCC, and nAChR antibodies have benefits for screening non-carcinomatous PNS patients with acute or subacute neurological deficits of unknown cause.

High prevalence of anti-neuronal antibodies in Tunisian psychiatric inpatients.

Event Abstract Back to Event High prevalence of anti-neuronal antibodies in Tunisian psychiatric inpatients. Lilia Laadhar1*, Oussama Sidhom2, Mondher Zitouni1, Nadia Sassi1, Maryam Kallel-Sellami1, Zouheir Elhechimi2 and Sondes Makni1 1 Immunology Department, La rabta hospital, Tunisia 2 Razi hospital, Psychiatry F, Tunisia Purpose: Antineuronal autoantibodies are associated with paraneoplastic syndrome. They may target nuclear or cytoplasmic antigens. We aimed in this study to determine the prevalence of anti-neuronal antibodies in Tunisian psychiatric inpatients. Subjects and methods: We enrolled in this prospective study, 103 psychiatric inpatients and 41 healthy, age and sex matched blood donors. Patients and controls had no history of malignancies or neurological disorders. For all subjects, we performed indirect imunofluorescence on primate cerebellum sections. Positive sera by immunofluorescence were also tested by an immonoenzymatic test combining a western blot of primate cerebellum extract and recombinant antigens. Results: Using indirect immunofluorescence, antineuronal nuclear autoantibodies were detected in 17 patients and none of controls (p=0.003) and antibodies reacting with cytoplasm of Purkinje cells in 6 patients and 2 controls. There was no difference of the prevalence of autoantibodies across the 4 groups of patients.The immunoblot confirmed well-characterized antineuronal antibodies only in 5 patients: two had anti-Ri (1 man and 1 woman with schizophrenia) and 3 had anti-Yo antibodies (3 men, 2 with bipolar disorder and 1 with schizophrenia). After a mean follow-up of 5 years, none of these patients developed neurological disorder or malignancy. Conclusion: In our knowledge, our study is the first one assessing the prevalence of antineuronal antibodies in psychiatric patients. The high prevalence of these antibodies in our patients may highlight the possible contribution of neuronal autoantigens in the physiopathology of some psychiatric disorders. Further studies on a larger cohort are needed to confirm this hypothesis. Keywords: Autoantibodies, antineuronal, Psychiatry, Schizophrenia, prognosis Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Immune-mediated disease pathogenesis Citation: Laadhar L, Sidhom O, Zitouni M, Sassi N, Kallel-Sellami M, Elhechimi Z and Makni S (2013). High prevalence of anti-neuronal antibodies in Tunisian psychiatric inpatients.. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00243 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 12 Mar 2013; Published Online: 22 Aug 2013. * Correspondence: Dr. Lilia Laadhar, Immunology Department, La rabta hospital, Tunis, Tunisia, lilia_laadhar@yahoo.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Lilia Laadhar Oussama Sidhom Mondher Zitouni Nadia Sassi Maryam Kallel-Sellami Zouheir Elhechimi Sondes Makni Google Lilia Laadhar Oussama Sidhom Mondher Zitouni Nadia Sassi Maryam Kallel-Sellami Zouheir Elhechimi Sondes Makni Google Scholar Lilia Laadhar Oussama Sidhom Mondher Zitouni Nadia Sassi Maryam Kallel-Sellami Zouheir Elhechimi Sondes Makni PubMed Lilia Laadhar Oussama Sidhom Mondher Zitouni Nadia Sassi Maryam Kallel-Sellami Zouheir Elhechimi Sondes Makni Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Excessive Blinking and Ataxia in a Child With Occult Neuroblastoma and Voltage-Gated Potassium Channel Antibodies

A previously healthy 9-year-old girl presented with a 10-day history of slowly progressive unsteadiness, slurred speech, and behavior change. On examination there was cerebellar ataxia and dysarthria, excessive blinking, subtle perioral myoclonus, and labile mood. The finding of oligoclonal bands in the cerebrospinal fluid prompted paraneoplastic serological evaluation and search for an occult neural crest tumor. Antineuronal nuclear autoantibody type 1 (anti-Hu) and voltage-gated potassium channel complex antibodies were detected in serum. Metaiodobenzylguanidine scan and computed tomography scan of the abdomen showed a localized abdominal mass in the region of the porta hepatis. A diagnosis of occult neuroblastoma was made. Resection of the stage 1 neuroblastoma and treatment with pulsed corticosteroids resulted in resolution of all symptoms and signs. Excessive blinking has rarely been described with neuroblastoma, and, when it is not an isolated finding, it may be a useful clue to this paraneoplastic syndrome. Although voltage-gated potassium channel complex autoimmunity has not been described previously in the setting of neuroblastoma, it is associated with a spectrum of paraneoplastic neurologic manifestations in adults, including peripheral nerve hyperexcitability disorders.

Paraneoplastic isolated myelopathy

To report the clinical phenotype and outcome of isolated paraneoplastic myelopathy. We systematically reviewed clinical, serologic, and MRI data for 31 patients (20 female) who presented with an isolated myelopathy and coexisting cancer: carcinoma (lung, 9; breast, 7; kidney, 2; thyroid, 2; ovary/endometrium, 2), melanoma (2), or other cancer (3), or a paraneoplastic autoantibody with strong cancer association (amphiphysin-immunoglobulin G [IgG], 9; collapsin response-mediator protein 5-IgG, 9; Purkinje-cell cytoplasmic autoantibody type 1, 2; antineuronal nuclear autoantibody [ANNA]-1, 1; ANNA-3, 1). Of 31 patients who presented with a progressive myelopathy, symptom onset was subacute in 16 (52%). The median age was 62 years. CSF abnormalities included elevated protein (>45 mg/dL), 22; pleocytosis, 15; excess oligoclonal bands (normal <4), 7. MRI cord abnormalities identified in 20 patients were longitudinally extensive (>3 vertebral segments), 14; symmetric tract or gray matter-specific signal abnormality, 15 (enhancing in 13). Myelopathy preceded cancer diagnosis in 18 patients (median interval 12 months; range 2-44). After myelopathy onset, 26 patients underwent oncologic treatment, immunosuppressive treatment (median delay to commencing immunotherapy 9.5 months [range 1-54]), or both; only 8 improved (31%). At last neurologic evaluation (median interval after onset 17 months; range 1-165 months), 16 patients (52%) were wheelchair-dependent (median time from onset to wheelchair 9 months [range 1-21]). Ten patients died after a median of 38 months from symptom onset (range 7-152). Symmetric, longitudinally extensive tract or gray matter-specific changes on spinal MRI should raise suspicion for a paraneoplastic myelopathy. Resulting disability is often severe. Only a minority of patients improve with treatment.

Paraneoplastic Jaw Dystonia and Laryngospasm With Antineuronal Nuclear Autoantibody Type 2 (Anti-Ri)

Opsoclonus-myoclonus syndrome and breast carcinoma were initially described as neurologic and oncologic accompaniments of antineuronal nuclear autoantibody type 2 (ANNA-2, also known as anti-Ri). However, the neurologic spectrum of ANNA-2 autoimmunity is broader, includes a syndrome of jaw dystonia and laryngospasm, and can be accompanied by lung carcinoma. To describe clinically (with a video) ANNA-2-associated jaw dystonia and laryngospasm, its pathologic correlates, and therapeutic outcomes. Retrospective case series with prospective clinical follow-up. Mayo Clinic's Neuroimmunology Laboratory, Rochester, Minnesota. Consecutive patients with ANNA-2 seropositivity identified since January 1, 1990. Clinical (in 9 patients) and neuropathologic (in 2 patients) findings were reviewed. Of 48 patients with ANNA-2 seropositivity, 9 (19%) had multifocal neurologic manifestations that included jaw dystonia and laryngospasm. Among 6 patients with jaw dystonia, 5 had severely impaired nutrition, causing profound weight loss. Five patients had documented laryngospasm, which contributed to 1 patient's death. Neuropathologic examination revealed diffuse infiltration by CD8(+) T lymphocytes, with axonal loss and gliosis in brainstem and descending spinal cord tracts. Some patients improved symptomatically after immunosuppressant or cytotoxic therapies; 1 patient improved after treatment with botulinum toxin. One patient who underwent tracheostomy because of recurrent laryngospasm was alive and well longer than 3 years after symptom onset. Jaw dystonia and laryngospasm are common accompaniments of ANNA-2 autoimmunity and are associated with significant morbidity. We propose that selective damage to antigen-containing inhibitory fibers innervating bulbar motor nuclei by CD8(+) T lymphocytes (histopathologically observed infiltrating brainstem reticular formation) is the proximal cause of this syndrome. Early and aggressive therapy offers the prospect of neurologic improvement or stabilization.

Neuronal autoantibodies excite guinea pig myenteric neurons

The role of IgG in effecting gastrointestinal (G.I.) dysmotility associated with neurologic autoimmunity (idiopathic or paraneoplastic) remains poorly defined. Serum IgG prepared from patients with anti-neuronal nuclear autoantibody type 1 (ANNA-1 [aka anti-Hu], n=7) or ganglionic nicotinic acetylcholine receptor (α3AChR, n=6) autoantibody were tested on myenteric neurons in longitudinal muscle myenteric plexus (LMMP) preparations from the ileum of 38 guinea pigs. IgG prepared from healthy subjects or neurologic patients (n=7) without G.I. symptoms served as controls. Action potential discharges in all neurons of a ganglion in response to acute application of IgG were monitored by fast imaging using a voltage-sensitive dye. Data were analysed as% neurons per ganglion responding and frequency of action potential discharge. Only 0.7±1.2% of 708 neurons (26 ganglia) responded to 2 of 7 control IgG samples (mean action potential frequency 0.5±0.9Hz). Six of 7 samples containing ANNA-1-IgG evoked a response in 7.4±5.7% of 1266 neurons (45 ganglia) (P&lt;0.05) with a significantly higher action potential discharge (1.8±1.1Hz, P&lt;0.05). We observed no correlation between ANNA-1 titer and the percentage of responding neurons or action potential frequency. Four of 6 samples containing α3AChR-IgG evoked a response in a smaller number of neurons (6.5±9.9% of 612 neurons (32 ganglia)) with an action potential frequency of 1.9±1.5Hz.

Reversible Extralimbic Paraneoplastic Encephalopathies With Large Abnormalities on Magnetic Resonance Images

To describe reversible extralimbic paraneoplastic encephalopathies with large, lobar lesions on magnetic resonance imaging (MRI). Case series. Autoimmune Neurology Clinic, Mayo Clinic, Rochester, Minnesota. Three patients had large confluent areas of signal abnormality on T2-weighted MRI, including frontal in 2 and frontal and occipital in 1. Patient 1, a woman aged 63 years, experienced hemiparesis with hemianopia 3 years after a diagnosis of adenocarcinoma of the breast. Nine years later, rapidly progressive dementia developed. Patient 2, a woman aged 79 years, presented with monoparesis and epilepsia partialis continua, 1 year after a diagnosis of adenocarcinoma of the breast. Patient 3, a man aged 65 years, had paraneoplastic sensory neuronopathy, limbic encephalitis, antineuronal nuclear autoantibody type 1 (ANNA-1), and squamous cell carcinoma of the lung. He was stable for 3 years after treatment. Subacute onset of aphasia, delirium, worsening seizures, and rising ANNA-1 titers led to a diagnosis of recurrent limited carcinoma. Brain MRI abnormalities in all patients improved dramatically after immunotherapy. Two patients had sustained clinical remission. Recognition of paraneoplastic extralimbic lobar encephalopathies is important because these disorders and their underlying cancers are treatable.

Serologic Profiles Aiding the Diagnosis of Autoimmune Gastrointestinal Dysmotility

Autoimmune gastrointestinal dysmotility is a limited autoimmune dysautonomia occurring idiopathically or in the context of an anatomically remote neoplasm, previously documented or unsuspected. Here we report 24 Mayo Clinic patients in whom the profile of serum autoantibodies aided this diagnosis. All patients were ascertained serologically in the course of service evaluation for autoantibodies consistent with neurologic autoimmunity. Review of their histories, motility studies, and laboratory findings revealed that all had presented with subacute gastrointestinal dysmotility. Recorded motility abnormalities included esophageal dysmotility 8 (6 had achalasia), delayed gastric emptying 12, slow small intestinal transit 7, slow colonic transit 4, and pelvic floor dyssynergia 4. Four patients underwent abdominal surgery; 2 commenced total parenteral nutrition. Plasma membrane cation channel autoantibodies were detected in 23 patients: neuronal voltage-gated calcium channel (5 N-type and 1 P/Q-type), acetylcholine receptor (11 ganglionic-type and 4 muscle-type), and neuronal voltage-gated potassium channel autoantibodies (4). Two patients had antineuronal nuclear autoantibodies, type 1. Approximately half of the patients had neural autoantibodies (including skeletal muscle striational and glutamic acid decarboxylase, 65kd isoform) or other antibody markers of organ-specific autoimmunity (thyroid or gastric parietal cell specificities). Neoplasia was diagnosed in 11 patients (9 recent, 2 remote): lung, breast and endometrial, gastrointestinal and thymoma. Moderate to dramatic improvement in gastrointestinal symptoms was reported after immunotherapy in 4 of 4 patients treated and after pyridostigmine treatment in 2 of 2 patients treated. Autoimmune serology aids the diagnosis of autoimmune gastrointestinal dysmotility, both paraneoplastic and idiopathic, and might guide management.

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.

Paraneoplastic antibodies coexist and predict cancer, not neurological syndrome

Paraneoplastic autoimmune disorders are usually regarded as syndromic (for example, paraneoplastic optic neuropathy with CRMP5 antibody, opsoclonus with ANNA-2 (antiRI) antibodies. However, for most paraneoplastic antibodies, the spectrum of clinical manifestations is broader than what was initially described in syndromic patients. This study evaluated coexisting autoantibodies in sera of 553 patients with a neurological presentation and one or more paraneoplastic neuronal nuclear or cytoplasmic autoantibodies: antineuronal nuclear autoantibody type 1 (ANNA-1), ANNA-2, ANNA-3; Purkinje cell cytoplasmic autoantibody type 1 (PCA-1), PCA-2; and CRMP-5-immunoglobulin G or amphiphysin-immunoglobulin G. Except for PCA-1, which occurred alone, 31% of sera had more than one of these autoantibodies. In addition, 25% of sera had neuronal calcium channel (P/Q-type or N-type), potassium channel, ganglionic acetylcholine receptor, muscle acetylcholine receptor, or striational antibodies. The authors conclude that the autoantibody profiles observed in patients with paraneoplastic disorders imply the targeting of multiple onconeural antigens and predict the patient’s neoplasm, but not a specific neurological syndrome. They emphasize that optimal serological evaluation for the detection of autoantibody profiles predictive of cancer requires broad screening for autoantibodies. Indeed, diagnostically important autoantibodies are often missed if a single or limited number of individual antibodies are tested.—Valérie Biousse

Paraneoplastic dysmotility: loss of interstitial cells of Cajal

Autoimmune impairment and destruction of the enteric nervous plexus are thought to play a central role in the pathogenesis of paraneoplastic motility disorders. We present a case of a small-cell lung carcinoma-related paraneoplastic motility disorder associated with abnormal interstitial cells of Cajal networks. Antibodies against c-Kit and protein gene product 9.5 were used to selectively stain interstitial cells of Cajal and the enteric nervous plexus, respectively. A 68-yr-old man presented with anorexia, early satiety, nausea, and weight loss. Investigations revealed gastroparesis, delayed small intestinal transit, and mediastinal lymphadenopathy. The patient was seropositive for type 1 antineuronal nuclear autoantibody and P/Q-type calcium channel antibody. Biopsy of mediastinal lymph nodes revealed metastatic small-cell carcinoma cells that were immunoreactive for c-Kit. Immunohistochemical staining of a full-thickness small intestinal biopsy revealed a relatively intact myenteric plexus but a sparse and disorganized interstitial cells of Cajal network. The histopathology of this case suggests that interstitial cells of Cajal may be a target in the pathogenesis of paraneoplastic motility disorders.

55-Year-Old Man With a Lung Lesion and Hemidysesthesia

55-Year-Old Man With a Lung Lesion and Hemidysesthesia

55-Year-Old Man With a Lung Lesion and Hemidysesthesia

55-Year-Old Man With a Lung Lesion and Hemidysesthesia

Antibody recognition and RNA binding of a neuronal nuclear autoantigen associated with paraneoplastic neurological syndromes and small cell lung carcinoma

The PLE21/HuC neural protein is an autoantigen for anti-neuronal nuclear autoantibodies (ANNA-1/anti-Hu/Type IIa antibodies) from a patient with paraneoplastic limbic encephalomyelitis and small cell lung carcinoma. This antigen belongs to the Hu/ELAV-like protein family, contains three RNA recognition motifs (RRMs) and has RNA binding capacity. In many autoimmune diseases mediated by autoantibodies, antibodies often interfere with the biological functions of their target antigens. To investigate the influences of the autoantibodies on the biological function of the antigen, we mapped the regions which were required for the antibody recognition and for the RNA binding. Deletion analysis of the antigen revealed that the epitopes for the antibodies were localized in the regions of 12 residues, amino acids 161–172, and eight residues, amino acids 29–38, of the first and second RRMs. It was also shown that the eight residues, amino acids 29–38, and the 10 residues, amino acids 187–194, were required for the RNA binding. Although amino acids 29–38 were necessary for both the antibody recognition and the RNA bindings, pre-incubation of the PLE21 antigen with the antibodies did not inhibit the formation of the complex of PLE21, the antibodies and RNA. Thus, the regions required for the antibody recognition are not identical with those for the RNA binding, and it seems unlikely that the autoantibodies interfere with RNA binding of the antigen.