Clinical features, prognostic factors, and antibody effects in anti-mGluR1 encephalitis.

OBJECTIVE: To clinically characterize patients with anti-metabotropic glutamate receptor (mGluR) 1 encephalitis, to identify prognostic factors, and to study the immunoglobulin G (IgG) subclasses and effects of antibodies on neuronal mGluR1 clusters. METHODS: Clinical information on new and previously reported patients was reviewed. Antibodies to mGluR1 and IgG subclasses were determined with brain immunohistochemistry and cell-based assays, and their effects on mGluR1 clusters were studied on rat hippocampal neurons. RESULTS: Eleven new patients were identified (10 adults, 1 child);4 were female. In these and 19 previously reported cases (n = 30, median age 55 years), the main clinical manifestation was a subacute cerebellar syndrome that in 25 (86%) patients was associated with behavioral/cognitive changes or other neurologic symptoms. A tumor was found in 3 of 26 (11%). Brain MRI was abnormal in 7 of 19 (37%) at onset and showed cerebellar atrophy in 10 of 12 (83%) at follow-up. Twenty-five of 30 (83%) patients received immunotherapy. Follow-up was available for 25: 13 (52%) had clinical stabilization; 10 (40%) showed significant improvement; and 2 died. At the peak of the disease, patients with bad outcome at 2 years (modified Rankin Scale score > 2, n = 7) were more likely to have higher degree of initial disability, as reflected by a worse Scale for Assessment and Rating of Ataxia score, and more frequent need of assistance to walk. Antibodies to mGluR1 were mainly IgG1 and caused a significant decrease of mGluR1 clusters in cultured neurons. CONCLUSIONS: Anti-mGluR1 encephalitis manifests as a severe cerebellar syndrome, often resulting in long-term disability and cerebellar atrophy. The antibodies are pathogenic and cause significant decrease of mGluR1 clusters in cultured neurons.

Autoimmune Vestibulocerebellar Syndromes.

Autoimmune disorders affecting the vestibular end organs, vestibular pathways, vestibular nuclei, and vestibulocerebellum are often underrecognized as a cause of chronic dizziness and ataxia. Autoantibodies specific for cell-surface, synaptic, and intracellular neural antigens serve as biomarkers of these disorders. This article describes the epidemiology, clinical presentation, diagnostic considerations, imaging findings, treatment, and prognosis of autoimmune disorders, in which the vestibulocerebellar syndrome is the main or presenting clinical presentation. Antibodies specific for intracellular antigenic targets described in the article are PCA-1 (Purkinje cell cytoplasmic antibody type 1, also known as anti-Yo), ANNA-1 (antinuclear neuronal antibody type 1, also known as anti-Hu), ANNA-2 (antinuclear neuronal antibody type 2, also known as anti-Ri), Ma1/2 (anti-Kelch-like 11/12 antibody), Kelch-like 11, amphiphysin, CV2 (collapsin response 2, also known as collapsin response mediator protein-5 [CRMP5]), VGCC (voltage-gated calcium channel), GAD65 (glutamic acid decarboxylase 65-kDa isoform), AP3B2 (adaptor protein 3B2, also known as anti-Nb), MAP1B (microtubule-associated protein 1B antibody, also known as anti-PCA-2), and neurochondrin antibodies. Antibodies targeting cell-surface or synaptic antigenic targets described in the article include DNER (delta/notchlike epidermal growth factor related receptor; antigen to anti-Tr), CASPR2 (contactin-associated proteinlike 2), septin-5, Homer-3, and mGluR1 (metabotropic glutamate receptor 1). The vestibulocerebellar presentation is largely indistinguishable among these conditions and is characterized by subacute onset of cerebellar symptoms over weeks to months. The diagnosis of autoimmune vestibulocerebellar syndromes is based on a combination of clinical and serological features, with a limited role for neuroimaging. Subtle eye movement abnormalities can be an early feature in many of these disorders, and therefore a meticulous vestibulo-ocular examination is essential for early and correct identification. Cancer occurrence and its type are variable and depend on the autoantibody detected and other cancer risk factors. Treatment comprises immunotherapy and cancer-directed therapy. Acute immunotherapies such as intravenous immunoglobulin, plasma exchange, and steroids are used in the initial phase, and the use of long-term immunosuppression such as rituximab may be necessary in relapsing cases. Outcomes are better if immunotherapy is started early. The neurologic prognosis depends on multiple factors.

Advances in Therapies of Cerebellar Disorders: Immune-mediated Ataxias.

The identification of an increasing number of immune mediated ataxias suggests that the cerebellum is often a target organ for autoimmune insults. The diagnosis of immune mediated ataxias is challenging as there is significant clinical overlap between immune mediated and other forms of ataxia. Furthermore the classification of immune mediated ataxias requires further clarification particularly for those ataxias where no specific antigenic trigger and associated antibodies have been identified. Recognition of immune mediated ataxias remains imperative as therapeutic interventions can be effective, although given the relative rarity of this entity, large-scale treatment trials may not be feasible. This review will discuss advances in therapies for immune mediated ataxias based on what is currently available in the literature.

Cerebellar disease associated with anti-glutamic acid decarboxylase antibodies: review.

Several neurological syndromes have been recognized associated to GAD antibodies. Among those disorders, cerebellar ataxia (CA) is one of the most common, along with stiff-person syndrome. Patients with GAD associated CA present with a progressive pancerebellar syndrome, with a subacute or chronic evolution, along with other neurological manifestations such as stiffness, oculomotor dysfunction, epilepsy, and cognitive dysfunction. These symptoms may be preceded by the so-called "brainstem attacks", where manifestations consistent with transient dysfunction of the brainstem may be observed. These patients frequently have extra-neurologic autoimmune manifestations such as diabetes mellitus type 1, polyendocrine autoimmune syndrome, pernicious anemia, vitiligo, etc. A proportion of patients may present with an underlying neoplasia, but the course is less aggressive than in those patients with classical paraneoplastic CA with onconeural antibodies. The diagnosis is based on the present of high serum and CSF titers of GAD antibodies, with intrathecal production of such antibodies. Treatment is aimed to decrease the immunological response with intravenous immunoglobulin, steroids, rituximab and oral immunosuppressive drugs. A subacute presentation and rapid initiation of immunotherapy seem to be the predictors of a favorable clinical response.

The Complex Diagnostic Challenge in Children With Non-Central Nervous System Cancer and Cerebellar Mutism.

Multiple etiologies should be considered in the differential diagnosis of immunocompromised patients with non-central nervous system cancer and viral infections who develop mutism. Acute cerebellitis, caused by infections or by neurotoxicity resulting from chemotherapy; paraneoplastic cerebellar degeneration; atypical posterior reversible encephalopathy syndrome; and acute disseminated encephalomyelitis may all cause mutism in such patients. This condition warrants prompt recognition and may require treatment with immunotherapy, as it may be an immune-mediated process. We present 2 patients with leukemia and viral illness who developed cerebellar mutism in the setting of acute cerebellitis and responded to immunotherapy, suggesting that the condition involved a parainfectious immune-mediated response.

Purple patches in an immunocompromised patient: a report of secondary disseminated cutaneous mucormycosis in a man with chronic lymphocytic leukemia.

A 60-year-old man with chronic lymphocytic leukemiadeveloped a deeply violaceous annular patchwith a halo of erythema on the right thigh duringhospitalization for neutropenic fever. Associatedsymptoms included chronic cough and fatigue.Bilateral lung opacities with hilar lymphadenopathywere noted on chest computed tomographyscan. Punch biopsy and tissue culture confirmeda diagnosis of secondary disseminated cutaneousmucormycosis. Although rare, physicians shouldinclude mucormycosis in the differential diagnosisof purpuric patches in immunosuppressed patients.Prompt skin biopsy and tissue culture may optimizethe success of treatment.

Subtentorial cerebral nocardiosis in immunocompetent patients: CT and MR imaging findings.

PURPOSE: To describe the clinical presentation and computed tomography (CT) and magnetic resonance imaging (MRI) appearances of subtentorial nocardia cerebral abscesses developing in immunocompetent patients. PATIENTS AND METHODS: The clinical findings and the results of CT and MRI examinations of three immunocompetent patients with nocardiosis located initially only in the subtentorial region were studied. Three patients underwent CT examination and two patients had MRI. RESULTS: Clinically, two patients had cerebellar syndrome and the third had meningism with fever. The diagnosis of nocardiosis was bacteriologically confirmed by demonstrating the organism in lumbar puncture fluid in one patient and by an aspiration biopsy of the abscess in the other two. Two of the patients improved under targeted antibiotic therapy whereas the third patient died. The main imaging features of the lesions were a multiloculated appearance with peripheral enhancement after intravenous administration of iodinated contrast material on CT and a multicystic appearance on MRI, with a peripheral hypointense rim on T2-weighted images, a relatively minor mass effect and a multiloculated appearance on gadolinium-chelate enhanced T1-weighted images. CONCLUSION: The clinical presentation of cerebral nocardiosis is relatively non-specific. A microcystic lesion surrounded by hypointensity on T2-weighted MR images with a multiloculated pattern after gadolinium chelate administration on T1-weighted MR images in association with a relatively minor mass effect should suggest this diagnosis even if the lesion is single and in the absence of immunosuppression.

"Non-classical" paraneoplastic neurological syndromes associated with well-characterized antineuronal antibodies as compared to "classical" syndromes - More frequent than expected.

OBJECTIVES: Paraneoplastic neurological syndromes (PNSs) are rare disorders in association with cancer and sub-divided into "classical" and "non-classical" syndromes according to a 2004 consensus paper proposed by a panel of PNS experts. "Classical" PNSs are regarded to account for the vast majority of cases. However, systematic reports on clinical PNS manifestations are rare. Therefore, we analyzed the spectrum of PNS in our clinic. METHODS: We retrospectively investigated medical records from consecutive patients diagnosed with definite PNS and serological evidence of well-characterized onconeural antibodies (anti-Hu, Yo, Ri, CV2/CRMP5, Ma1, Ma2, and amphiphysin) analyzed between 1991 and 2014 in our clinic. RESULTS: Of the 50 patients identified with onconeural antibody-positive PNS, 28 patients (56.0%) had "classical" PNS, and 22 (44.0%) "non-classical" PNS. Subacute cerebellar degeneration was the most frequent "classical" syndrome, brainstem encephalitis and subacute sensorimotor neuronopathy the most frequent "non-classical" syndromes. Anti-Hu antibodies were most frequent in both groups. 86.1% of patients developed neurological symptoms before the cancer was known. No differences between "classical" and "non-classical" syndromes were detected with respect to age, tumor entities and median time to diagnosis. However, whereas most patients with "classical" syndromes were females, there was no gender predominance in patients with "non-classical" PNS and the latter had significantly more frequent peripheral neurological syndromes. CONCLUSIONS: The so-called "non-classical" PNSs in association with well-characterized onconeural antibodies were more common in our patient population than expected. Therefore, in neurological disorders of unclear etiology with a subacute onset and atypical presentation further diagnostic work-up including investigation of onconeural antibodies is necessary.

Membranous nephropathy and cerebellar degeneration with anti-GAD antibodies in type 2 diabetes mellitus.

AIMS: To study the potential pathogenic significance of the coexistence of membranous nephropathy, cerebellar degeneration and anti-glutamic acid decarboxylase (GAD) autoantibodies in patients with diabetes. METHODS: We performed a direct immunocytochemistry on human kidney slides, electron microscopy on human kidney biopsy, direct immunofluorescence on human kidney biopsy. Baboon and rat kidney cell lines were fractionated and subjected to western blotting with antibodies to GAD. RESULTS: In this patient we demonstrate the presence of autoantibodies to GAD, which is highly enriched in podocytes plasma membrane and tubular cells of the kidney as well as sub-endothelial IgG and complement C3 deposits in the glomerular basement membrane (GBM). CONCLUSIONS: We hypothesize the existence in this patient of a common autoimmune pathogenic mechanism with GAD as the autoantigenic determinant, underlying cerebellar degeneration and membranous nephropathy.

Non-stiff anti-amphiphysin syndrome: clinical manifestations and outcome after immunotherapy.

Amphiphysin antibody causes paraneoplastic stiff-person syndrome and can also result in a variety of neurological manifestations. Here, we investigated the clinical spectrum of 20 patients with non-stiff anti-amphiphysin syndrome and their responses to immunotherapy. The most common neurological manifestation was limbic encephalitis (n=10), followed by dysautonomia (n=9), and cerebellar dysfunction (n=6). Cancer was detected in only seven patients. Intravenous immunoglobulin or steroid treatment was effective in most patients, but three improved only after rituximab treatment. Our study suggests that anti-amphiphysin syndrome can manifest as non-stiff encephalomyelitis and is only partially associated with cancer. Active immunotherapy, including rituximab, would be beneficial.

A novel case of natural killer cell deficiency associated with Joubert syndrome.

Joubert syndrome (JS) is a rare, complex autosomal recessive inherited disorder mostly characterized by partial or complete agenesis of the cerebellar vermis. There is a wide clinical and genetic heterogeneity in the syndrome. The main clinical features of JS are hypotonia, ataxia, developmental delay, oculomotor apraxia, breathing abnormalities and peculiar neuroimaging findings. A lot of additional features have been reported. Here, we first reported a case of the syndrome with natural killer (NK) cell deficiency. NK cell deficiency in JS might be not an incidental phenomenon. NK cell deficiency might be associated with JS when there are additional features such as recurrent infections and tumors. NK cell deficiency may be part of the clinical spectrum of JS. Reduced cellular immunity in association with NK cell deficiency may be a feature in a subset of JS patients, especially if there is a history of recurrent infections, tumors and autoimmune disorders.

A case report of the efficient reduction of calcium channel antibodies by tryptophan ligand immunoadsorption in a patient with Lambert-Eaton syndrome.

Lambert-Eaton myasthenic syndrome (LEMS) is a neuromuscular transmission disease caused by autoantibodies directed against voltage-gated calcium channels (VGCC). We report on a patient with LEMS and a cerebellar syndrome associated with lymphatic proliferation in the thymus. As thymectomy and immunosuppressive therapy failed to efficiently reduce clinical symptoms and VGCC antibody titer, we performed immunoadsorption using a tryptophan-ligand column for the first time. Repeated treatments resulted in a considerable decrease in antibody levels and a marked subjective and objective amelioration of LEMS as well as of the cerebellar symptoms.

Metabotropic glutamate receptor type 1 autoantibody-associated cerebellitis: a primary autoimmune disease?

OBJECTIVES: To report the third case of subacute cerebellar ataxia associated with metabotropic glutamate receptor type 1 autoantibodies (mGluR1-Abs), an uncommon syndrome known to be part of the group of paraneoplastic cerebellar degeneration syndromes linked to antineuronal antibodies and previously reported in only 2 other patients with long-term remission of Hodgkin lymphoma, and to discuss the underlying immunopathogenesis. DESIGN: Case report. SETTING: University hospital. PATIENT: A 50-year-old woman admitted for acute severe isolated static and kinetic cerebellar syndrome. Magnetic resonance imaging of the brain showed diffuse abnormal hyperintensity in the whole cerebellum on fluid-attenuated inversion recovery and diffusion sequences. RESULTS: Results of the biological workup were negative for general inflammation, vitamin deficiency, and bacterial and viral infections. Immunohistochemical analysis of the serum and cerebrospinal fluid of the patient demonstrated staining for Purkinje cell bodies and the molecular layer of the cerebellum. Finally, mGluR1-Abs were detected in serum and cerebrospinal fluid by a cell-based assay. Complete clinical examination, thoracoabdominal-pelvic computed tomography, and whole-body fludeoxyglucose F 18-positron emission tomography failed to show any underlying tumor, including Hodgkin lymphoma. The disease was stabilized after a course of intravenous immunoglobulins and continuous mycophenolate mofetil treatment during a follow-up of 40 months. CONCLUSIONS: Cerebellitis associated with mGluR1-Abs should be considered in the differential diagnosis of patients with subacute cerebellar ataxia. This first case without any tumor found suggests a possible idiopathic autoimmune rather than a paraneoplastic mechanism. In consideration of this possible primitive autoimmune ataxia involving the directly pathogenic mGluR1-Abs, immunoactive therapy should be initiated as early as possible.