Isolated opsoclonus heralding neuromyelitis optica spectrum disorder.

Opsoclonus is an ocular motility disorder characterized by spontaneous, arrhythmic conjugate saccades of varying amplitude occurring in all directions of gaze without normal intersaccadic interval. Etiological spectrum of opsoclonus encompasses paraneoplastic and neoplastic conditions, infectious and para-infectious encephalitis, autoimmune, metabolic and toxic encephalopathies, drugs, motor neuron diseases, multiple sclerosis and rarely neuromyelitis optica spectrum disorder (NMOSD). Opsoclonus has never been reported as a presenting manifestation heralding NMOSD. We herein report a previously healthy 37-year-old Asian Indian woman who presented with oscillopsia and opsoclonus, followed, 12 h later, by right-sided hemiparesis, right-sided appendicular ataxia, and left-sided lower motor neuron type facial palsy and dysarthria. Brain magnetic resonance imaging revealed hyperintense lesions in brainstem and thalamus in T2-weighted and fluid attenuated inversion recovery-weighted images, quite suggestive of NMOSD. Serum and cerebrospinal fluid samples were positive for anti-aquaporin-4 antibodies, which clinched the diagnosis of seropositive NMOSD. After completion of a course of intravenous methylprednisolone 1 g/day for 5 days, her opsoclonus disappeared completely. There was significant improvement in her speech and weakness within the first week of therapy and no objective deficit after day 20 of admission. After one-and-a-half-year follow-up, the patient was maintaining well on rituximab as secondary prophylaxis without any further attack. Our case highlights that isolated opsoclonus can be the presenting feature of NMOSD.

Anti-glutamic acid decarboxylase antibody positive neurological syndromes.

A rare kind of antibody, known as anti-glutamic acid decarboxylase (GAD) autoantibody, is found in some patients. The antibody works against the GAD enzyme, which is essential in the formation of gamma aminobutyric acid (GABA), an inhibitory neurotransmitter found in the brain. Patients found with this antibody present with motor and cognitive problems due to low levels or lack of GABA, because in the absence or low levels of GABA patients exhibit motor and cognitive symptoms. The anti-GAD antibody is found in some neurological syndromes, including stiff-person syndrome, paraneoplastic stiff-person syndrome, Miller Fisher syndrome (MFS), limbic encephalopathy, cerebellar ataxia, eye movement disorders, and epilepsy. Previously, excluding MFS, these conditions were calledhyperexcitability disorders. However, collectively, these syndromes should be known as "anti-GAD positive neurological syndromes." An important limitation of this study is that the literature is lacking on the subject, and why patients with the above mentioned neurological problems present with different symptoms has not been studied in detail. Therefore, it is recommended that more research is conducted on this subject to obtain a better and deeper understanding of these anti-GAD antibody induced neurological syndromes.

A novel treatment-responsive encephalitis with frequent opsoclonus and teratoma.

Among 249 patients with teratoma-associated encephalitis, 211 had N-methyl-D-aspartate receptor antibodies and 38 were negative for these antibodies. Whereas antibody-positive patients rarely developed prominent brainstem-cerebellar symptoms, 22 (58%) antibody-negative patients developed a brainstem-cerebellar syndrome, which in 45% occurred with opsoclonus. The median age of these patients was 28.5 years (range = 12-41), 91% were women, and 74% had full recovery after therapy and tumor resection. These findings uncover a novel phenotype of paraneoplastic opsoclonus that until recently was likely considered idiopathic or postinfectious. The triad of young age (teenager to young adult), systemic teratoma, and high response to treatment characterize this novel brainstem-cerebellar syndrome.

Glycine receptor antibodies are detected in progressive encephalomyelitis with rigidity and myoclonus (PERM) but not in saccadic oscillations.

Glycine receptor (GlyR) antibodies were recently identified in a few patients with progressive encephalomyelitis with rigidity and myoclonus (PERM); none of these patients had antibodies against glutamic acid decarboxylase (GAD). An inhibitory glycinergic transmission defect has also been implicated in the mechanism underlying saccadic oscillations, including ocular flutter or opsoclonus; GlyR antibodies have not been reported in these patients. The purpose was to determine whether GlyR antibodies are found in patients with PERM, ocular flutter syndrome (OFS), and opsoclonus-myoclonus syndrome (OMS). GlyR antibodies were first measured in archived sera and CSF from five patients, including one patient with GAD antibody-positive PERM, two patients with OFS, and two patients with OMS. GlyR antibodies were also measured in archived sera from nine other adult patients with OMS. GlyR antibodies and GAD antibodies were both found at high titers in the serum and CSF of the patient with PERM, and their levels paralleled disease activity over time. GlyR antibodies were not found at significant levels in 13 patients with saccadic oscillations. GlyR and GAD antibodies can co-exist in PERM and follow the clinical course. Although saccadic oscillations are a feature of this condition, GlyR antibodies are not commonly found in patients with isolated saccadic oscillations.

Narcolepsy, REM sleep behavior disorder, and supranuclear gaze palsy associated with Ma1 and Ma2 antibodies and tonsillar carcinoma.

OBJECTIVE: To describe a patient with diencephalic and mesencephalic presentation of a Ma1 and Ma2 antibody-associated paraneoplastic neurological disorder. DESIGN: Case report. SETTING: The Colorado Neurological Institute Movement Disorders Center in Englewood, Colorado, and the Mayo Clinic in Rochester, Minnesota. PATIENT: A 55-year-old man with a paraneoplastic neurological disorder characterized by rapid eye movement sleep behavior disorder, narcolepsy, and a progressive supranuclear palsy-like syndrome in the setting of tonsillar carcinoma. INTERVENTION: Immunotherapy for paraneoplastic neurological disorder, surgery and radiotherapy for cancer, and symptomatic treatment for parkinsonism and sleep disorders. MAIN OUTCOME MEASURES: Polysomnography, multiple sleep latency test, and neurological examination. RESULTS: The cancer was detected at a limited stage and treatable. After oncological therapy and immunotherapy, symptoms stabilized. Treatment with modafinil improved daytime somnolence. CONCLUSIONS: Rapid onset and progression of multifocal deficits may be a clue to paraneoplastic etiology. Early treatment of a limited stage cancer (with or without immunotherapy) may possibly slow progression of neurological symptoms. Symptomatic treatment may be beneficial.

[Pseudo-internuclear ophthalmoplegia in myasthenia gravis]. / Oftalmoplegia pseudo-internucleara din miastenia gravis.

Myasthenia Gravis is an organ-specific autoimmune disorder generaly thought to be caused by an antibody-mediated attack against the skeletal muscle nicotinic acetylcholine receptor (AChR) at the neuromuscular junction. Not infrequently there may be other diseases accompanying myasthenia, that can give different neuro-ophtalmological manifestations or neurological syndromes with autoimmune substrate. By these autoimmmune diseases we note:Autoimmune thyroiditis, Systemic lupus erythematous, Dermatomyositis, i.e. The extraocular muscle weakness is present at 90% of myastenia patients. While anti-AChR are detectable in the majority of patients with generalized myasthenia, at patients with ocular myasthenia these antibodies are nearly undetectable. On the another hand, epidemiological, clinical and immunoserological studies, suggests that the ocular myasthenia and generalized myasthenia are two separate disorders. Both Myasthenia Gravis forms could be associated with other autoimmune disturbances with ocular impact, for example such as Autoimmune thyroiditis Ophtalmopathy.

Additional triggers of endothelial disfunction modulate antiphospholipid-mediated microangiopathy in a central nervous system-cutaneous syndrome.

It is now recognised that the spectrum of antiphospholipid (aPL)-mediated syndromes includes end-organ injury due to microangiopathic manifestations. In the central nervous system (CNS), the clinical and radiographic appearance of microangiopathic lesions can be notoriously difficult to distinguish from multiple sclerosis (MS). A patient is presented who developed white-matter lesions in the brain and spinal-cord, shortly after receiving toxic doses of radiation for an arterio-venous malformation. The institution of interferon therapy for presumptive MS not only led to worsening neurologic deficits, but triggered a cutaneous syndrome with pleomorphic stigmata of microvascular injury (livedo reticularis rash, splinter haemorrhages). Subsequent workup revealed persistently elevated high-titer antiphospholipid of multiple isotypes. Treatment with corticosteroids and immunosuppressant therapy afforded improvement in locomotor function. We hypothesise that radiation injury and treatment with interferon-therapy constituted iatrogenic 'hits' of endothelial injury, and potentiated aPL-mediated microangiopathic disease affecting the CNS and the skin.

Ocular neuromyotonia in a 15-year-old girl after radiation therapy.

A 15-year-old girl, previously treated with radiation, chemotherapy, and surgery for a posterior fossa medulloblastoma and parasellar metastasis at age 8, presented with a 10-month history of episodic horizontal diplopia. She was diagnosed with ocular neuromyotonia and successfully treated with oral carbamazepine. Given the strong association between peripheral neuromyotonia and the presence of autoimmune antivoltage-gated potassium channels, the patient's blood was tested and found negative for these autoantibodies. This is the first time this has been verified in a person with ocular neuromyotonia.

Ocular flutter, generalized myoclonus, and trunk ataxia associated with anti-GQ1b antibodies.

OBJECTIVE: To describe a movement disorder characterized by ocular flutter, trunk ataxia, and mild generalized myoclonus associated with anti-GQ1b antibodies. DESIGN: Case report. SETTING: University hospital. PATIENT: A 37-year-old woman presented with rapid, conjugated, and periodic oscillations of the eyes with a strict preponderance for the horizontal plane (ocular flutter); trunk ataxia; and occasional arrhythmic muscle jerks (myoclonus) most pronounced at the neck. RESULTS: Brain magnetic resonance imaging results were normal. Cerebrospinal fluid examination revealed mild lymphocytic pleocytosis. Results of extensive serological tests on viral, bacterial, and fungal infections from blood and cerebrospinal fluid samples were unremarkable. Results of screening examinations for neoplasms and paraneoplastic antibodies, including whole-body fludeoxyglucose F18 positron emission tomography, were normal. Positive titers of IgG and IgM anti-GQ1b antibodies were found. CONCLUSIONS: This is the first description of an association between the clinical syndrome of ocular flutter, mild stimulus sensitive myoclonus, and trunk ataxia and anti-GQ1b antibodies. The association with ganglioside antibodies lends further support to the notion of an autoimmune-associated pathology of the syndrome.

Opsoclonus-myoclonus-ataxia syndrome with autoantibodies to glutamic acid decarboxylase.

Opsoclonus-myoclonus-ataxia syndrome (OMS) is a rare neurological disorder of probably autoimmune origin. Most cases are associated with a remote neoplasm or a viral infection; however in some instances no underlying aetiology can be demonstrated. We report the presence of anti-glutamic acid decarboxylase antibodies (anti-GAD Abs) in the serum and CSF of a patient with idiopathic OMS. Treatment with intravenous immunoglobulin led to a remarkable clinical improvement with parallel reduction of anti-GAD titers. Anti-GAD Abs have been associated with several neurological syndromes. They could also be responsible for the clinical triad of OMS, by impairing GABAergic transmission in specific brainstem and cerebellar circuits. We propose that testing for anti-GAD Abs should be performed in OMS, especially when no other aetiological association can be demonstrated.

Neuro-ophthalmologic manifestations of paraneoplastic syndromes.

Paraneoplastic syndromes with neuro-ophthalmologic manifestations may involve the central nervous system, cranial nerves, neuromuscular junction, optic nerve, uvea, or retina. Most of these disorders are related to immunologic mechanisms presumably triggered by the neoplastic expression of neuronal proteins. Accurate recognition is essential to appropriate management.

Factors associated with insensitivity to pyridostigmine therapy in Thai patients with ocular myasthenia gravis.

The objective of this study was to determine factors associated with pyridostigmine therapy in patients with ocular myasthenia gravis (OMG). This retrospective study included eighty-five patients with OMG who have been treated with pyridostigmine. Patients were excluded if they were diagnosed as generalized myasthenia gravis within a month after diagnosis or were treated with other medications. Forty-two patients responded to pyridostigmine and 43 patients did not. There were no significant differences in gender, age, the duration of symptoms before treatment, the dosage of pyridostigmine, and the initial presentations of ptosis or diplopia between the two groups. However, an initial presentation of concurrent ptosis and diplopia and the presence of systemic involvement after follow up were significant factors associated with an insensitivity to pyridostigmine in patients with OMG (p = 0.001 and p = 0.01, respectively). Determining these factors could help predict the pyridostigmine response in patients with OMG.

Ataxia-oculomotor apraxia 2 patients show no increased sensitivity to ionizing radiation.

Mutations in senataxin have been described recently in 24 cases of French-Canadian descent with ataxia-oculomotor apraxia 2. This recessive ataxia is associated with an elevation in alpha-fetoprotein as in ataxia-telangiectasia. Because ataxia-telangiectasia cells are highly radiosensitive, we used a colony survival assay to measure the radiosensitivity of lymphoblastoid cell lines derived from five French-Canadian patients with ataxia-oculomotor apraxia 2. Two were homozygous for the common French-Canadian L1976R SETX missense mutation; the three others were compound heterozygotes for the common mutation and three different missense mutations. Overall, lymphoblastoid cell lines derived from these cases did not show significant variation from a normal response to 1 Gray of ionizing radiation but the two patients who were homozygous for the common L1976R mutation fell in the intermediate or non-diagnostic range.

An update on opsoclonus.

PURPOSE OF REVIEW: The aim of this article is to review opsoclonus, with particular emphasis on its immunopathogenesis and pathophysiology. RECENT FINDINGS: Infections (West Nile virus, Lyme disease), neoplasms (non-Hodgkin's lymphoma, renal adenocarcinoma), celiac disease, and allogeneic hematopoietic stem cell transplantation can cause opsoclonus. Newly identified autoantibodies include antineuroleukin, antigliadin, antiendomysial, and anti-CV2. Evidence suggests that the autoantigens of opsoclonus reside in postsynaptic density, or on the cell surface of neurons or neuroblastoma cells (where they exert antiproliferative and proapoptotic effects). Most patients, however, are seronegative for autoantibodies. Cell-mediated immunity may also play a role, with B and T-cell recruitment in the cerebrospinal fluid linked to neurological signs. Rituximab, an anti-CD20 monoclonal antibody, seems efficacious as an adjunctive therapy. Although changes in synaptic weighting of saccadic burst neuron circuits in the brainstem have been implicated, disinhibition of the fastigial nucleus in the cerebellum, or damage to afferent projections to the fastigial nucleus, is a more plausible pathophysiologic mechanism which is supported by functional magnetic resonance imaging findings in patients. SUMMARY: There is increasing recognition that both humoral and cell mediated immune mechanisms are involved in the pathogenesis of opsoclonus. Further studies are needed to further elucidate its immunopathogenesis and pathophysiology in order to develop novel and efficacious therapy.

Neuroimmunology of dancing eye syndrome in children.

Clinical, histopathological, and laboratory evidence suggest that dancing eye syndrome/opsoclonus-mycoclonus syndrome is an immune-mediated and probably autoimmune disorder. There is a clear, but not invariable, association with neuroblastoma or ganglioneuroma in children, and with a miscellany of neoplasms in adults. Direct support, i.e. the identification of antibodies against cell-surface antigens in neurons, is lacking but the nature of other evidence is such that the case for use of immunomodulatory therapeutic strategies is compelling. Because at least 85% of children affected by the condition are left with permanent cognitive deficits, notwithstanding a favourable initial neurological response to, say, steroid or adrenocorticotrophic hormone, therapeutic stakes are high. There is an urgent need for controlled therapeutic trials which, because of the comparative rarity of the condition in children, will require international collaboration to expedite studies.

Recent advance in immunological tests in paraneoplastic neurological syndrome.

Paraneoplastic neurological syndromes are uncommon, however; their diagnosis is of major practical importance. Any portion of the nervous system may be involved in paraneoplastic syndromes. There is increasing evidence that the pathogenesis of many paraneoplastic neurological syndromes appears to be an immune reaction against antigen shared by the cancer and the nervous system. The identification of antibodies in the serum or cerebrospinal fluid in the central nervous system of paraneoplastic syndrome patient confirms the clinical diagnosis of paraneoplastic syndrome, and allows early identification of an underlying tumor at a stage when it is localized and more amenable to treatment. Cancer therapy (surgery, radiotherapy, chemotherapy) seems to be the most efficient treatment for the paraneoplastic neurological symptoms. Immunomodulatory therapy (intravenous immunoglobulin, plasmapheresis, immunosuppression) can halt or even reverse the neurological syndrome. The recent advances in understanding of the autoimmune pathology of these disorders should lead to more effective treatment options.

Neuro-ophthalmology and paraneoplastic syndromes.

PURPOSE OF REVIEW: To describe the neuro-ophthalmological manifestations of paraneoplastic syndromes and their immunological associations. RECENT FINDINGS: Neuro-ophthalmological signs and symptoms are usually present in paraneoplastic syndromes of the central nervous system. Unlike opsoclonus, less characteristic eye movement abnormalities are difficult to recognize as presenting symptoms of paraneoplastic syndromes. In this setting, the detection of several antibodies, including anti-Hu, Yo, Ma2, Ri, Tr, CV2/CRMP5 or voltage-gated calcium channel antibodies may help to establish that the neuro-ophthalmological disorder is paraneoplastic. Among the recently characterized antibodies, those against the Ma proteins often associate with brainstem encephalitis and vertical gaze paralysis. A small subset of patients with opsoclonus and ataxia harbor anti-Ri antibodies. In other patients, there is preliminary evidence that the autoantigens of opsoclonus reside in the postsynaptic density, but no dominant antibody marker has been identified. Uveitis and optic neuritis are rare accompaniments of paraneoplastic encephalomyelitis; some of these patients harbor anti-CV2/CRMP5 in association with other antibodies. Studies on paraneoplastic retinopathy indicate that immunity to retinal proteins other than recoverin can result in a similar syndrome to that associated with recoverin antibodies, and that melanoma-associated retinopathy may associate with several retinal antibodies. SUMMARY: There is increasing recognition of an extensive variety of neuro-ophthalmological abnormalities as manifestations of paraneoplastic syndromes and of several antineuronal antibodies as clinical markers of these disorders. Basic immunological studies support the pathogenic role of some of these antibodies, and are elucidating the pathogenic mechanisms that underlie these and other antibody-associated paraneoplastic syndromes.

Opsoclonus-myoclonus-dysequilibrium syndrome: cytological and immunological dynamics in the serial cerebrospinal fluid in two patients.

A peculiar clinical presentation characterized by the triad of opsoclonus,myoclonus and ataxia, mainly in a form of dysequilibrium, is usually associated with infectious or paraneoplastic processes. Serial cerebrospinal fluid (CSF) analysis in two patients with opsoclonus-myoclonus-dysequilibrium syndrome suggestive of viral encephalitis were performed from disease onset for up to 8 months. A cell count, cytology, total protein and glucose concentrations in CSF, the blood-CSF barrier function, intrathecal synthesis of immunoglobulins (Ig) in class M, G and A expressed as IgM, IgG and IgA indices and oligoclonal IgG bands were monitored. Cellular and humoral alterations in both patients were slight at the onset becoming more pronounced a month later. The kinetics of the CSF changes mirrored the subacute clinical deterioration and subsequent recovery. The delayed response in the CSF measures and the gradual clinical deterioration suggest the development of subacute brain inflammation. A mononuclear pleocytosis, including macrophages and plasma cells, increased within the first month and then normalized during the following weeks. Intrathecally synthesized IgM occurred only transiently after one month of illness, whereas intrathecal IgG production increased during the first month and persisted for at least eight months. An increasing number of oligoclonal IgG bands during the course, indicative of expanding local intrathecal synthesis, was noted. The dynamics of these CSF changes supports the hypothesis that opsoclonus-myoclonus syndrome is a post-infectious immune- mediated condition.

Complicated paraneoplastic neurological syndromes: a report of two patients with small cell or non-small cell lung cancer.

Paraneoplastic neurological syndromes are frequently associated in patients with small cell lung cancer (SCLC) and antineuronal antibodies are involved in the autoimmune mechanism. Multiple syndromes are sometimes complicated in a single patient with SCLC. However, little is known about non-SCLC-associated neurological manifestations. We report two patients with complicated paraneoplastic neurological syndromes. Patient 1 showed paraneoplastic limbic encephalitis (PLE), paraneoplastic sensory neuropathy (PSN) and Lambert-Eaton myasthenic syndrome (LEMS) associated with SCLC. Patient 2 developed opsoclonus-ataxia and probable PLE associated with non-SCLC. Analysis of various antineuronal antibodies revealed that anti-Hu and P/Q-type voltage-gated calcium channel (VGCC) antibodies were positive in Patient 1 but any antibodies were not in Patient 2. Brain MRI demonstrated high intensity signals in temporal lobes particularly on fluid-attenuated inversion recovery (FLAIR) or diffusion-weighted images. These findings suggest that complicated paraneoplastic neurological syndromes occur in non-SCLC as well as SCLC and that unidentified antineuronal autoantibodies may underlie the pathophysiology.