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ObjectiveTo 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.MethodsClinical 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.ResultsEleven 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.ConclusionsAnti-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.

In 1881, Carl Wernicke1 described a “polioencephalopathia haemorrhagica superior” in 3 alcoholic patients with gray matter hemorrhages in the mammillary bodies.

To assess dysphagia, the authors examined 12 patients with Kearns-Sayre syndrome (KSS) or chronic progressive external ophthalmoplegia (CPEO) due to mitochondrial DNA (mtDNA) deletion by videofluoroscopy and manometry. Cricopharyngeal achalasia was documented in nine of 12 patients (75%), whereas deglutitive coordination problems were found in one patient. Cricopharyngeal myotomy may be an effective treatment in selected cases with severe cricopharyngeal obstruction.

Autosomal recessive limb-girdle muscular dystrophy (LGMD) 2L is caused by mutations in the anoctamin-5-gene ( ANO5 ) that encodes a calcium-activated chloride channel.1,2 Limb-girdle muscle weakness can also be caused by an immune-mediated necrotizing myopathy (IMNM) with antibodies against 3-hydroxy-3-methylglutaryl-coenzyme-A-reductase (HMGCR), which catalyzes a rate-limiting step in cholesterol biosynthesis and is inhibited by statins.3,4 We report on a patient with LGMD2L and HMGCR-associated IMNM without previous statin exposure. The authors thank the technical personnel of the Departments of Neuropathology, Neurology, and Radiology, RWTH University Aachen, Germany, for technical assistance; and Dr. A. Vigneron (D-Tek, Mons, Belgium, specialized in the development of diagnostic tests in autoimmune disorders) for performing the myositis-specific and myositis-associated antibody assays, including HMGCR.

Objective: To report the metabotropic glutamate receptor 5 (mGluR5) as the autoantigen of antibodies from 2 patients with Hodgkin lymphoma (HL) and limbic encephalopathy (Ophelia syndrome). Methods: Immunohistochemistry with brain tissue and cultures of rat hippocampal neurons were used to demonstrate antibodies. Immunoprecipitation, mass spectrometry, and mGluR5 -null mice served to identify the antigen. HEK293 cells transfected with mGluR5 or mGluR1 were used to determine immunologic crossreactivity. Results: Both patients developed symptoms consistent with limbic encephalopathy; one had MRI findings typical of this disorder and the other had more extensive radiologic involvement, including parietal and occipital cortex. Patients9 sera had antibodies that predominantly reacted with the neuropil of hippocampus and cell surface of live hippocampal neurons. Immunoprecipitation from cultured neurons and mass spectrometry demonstrated that the antigen was mGluR5, a receptor involved in processes of learning and memory. The reactivity of patients9 sera was abrogated in brain of mGluR5 -null mice, further confirming the antibody specificity. Studies with a large number of controls including 2 patients with cerebellar ataxia and mGluR1 antibodies showed that mGluR5 was only identified by sera of the 2 patients with the Ophelia syndrome, and that despite the homology of this receptor with mGluR1 each autoantigen was specific for a distinct syndrome. Conclusions: Antibodies to mGluR5 should be considered in patients with symptoms of limbic encephalitis and HL (Ophelia syndrome). Recognition of this disorder is important because it can affect young individuals and is reversible.

Necrotizing myopathy with pipestem capillaries defines an immune-mediated disorder of skeletal muscle characterized by minimal cellular infiltration, muscle fiber necrosis, and microangiopathy with complement membrane attack complex (MAC; C5b9) deposition. Thickened, hyalinized (“pipestem”) vessels, ultrastructurally embedded in amorphous material, and capillary loss are further features.1 The rare patients reported showed proximal weakness and high creatine kinase,1,–,4 frequently associated with myalgia. They presented with other symptoms suggesting autoimmune disorders (including cerebral vasculitis) or cancer and an overall unfavorable prognosis,1,2 despite the response of muscle symptoms to immunosuppressive treatments. A pathophysiologic concept to link these multiorgan symptoms is not known, possibly because only one sample outside muscle has so far been taken for comparison of histopathologic features. That skin probe showed “mild fibrosis and lymphocytic perivascular cuffs in superficial dermis.”2 A 57-year-old normotensive, nondiabetic man presented with rapid onset edema of the distal legs, dysesthesia, loss of ankle reflex, and bilateral foot drop (Medical Research Council grade 0). Proximal and upper limb strength and reflexes were intact. Neurophysiologic examination demonstrated loss of compound muscle action potentials (CMAPs) of both peroneal nerves and the left tibial nerve, reduced CMAP amplitude of the right tibial nerve, and loss of sensory nerve action potentials of both sural nerves. Neurography of the right median and ulnar nerves showed normal results. Needle myography showed abnormal spontaneous activity and only a few recordable muscle unit potentials in the tibialis anterior …

Objective: To present 2 families with maternally inherited severe epilepsy as the main symptom of mitochondrial disease due to point mutations at position 616 in the mitochondrial tRNA Phe ( MT-TF ) gene. Methods: Histologic stainings were performed on skeletal muscle slices from the 2 index patients. Oxidative phosphorylation activity was measured by oxygraphic and spectrophotometric methods. The patients9 complete mitochondrial DNA (mtDNA) and the relevant mtDNA region in maternal relatives were sequenced. Results: Muscle histology showed only decreased overall COX staining, while a combined respiratory chain defect, most severely affecting complex IV, was noted in both patients9 skeletal muscle. Sequencing of the mtDNA revealed in both patients a mutation at position 616 in the MT-TF gene (T>C or T>G). These mutations disrupt a base pair in the anticodon stem at a highly conserved position. They were apparently homoplasmic in both patients, and had different heteroplasmy levels in the investigated maternal relatives. Conclusions: Deleterious mutations in the mitochondrial tRNA Phe may solely manifest with epilepsy when segregating to homoplasmy. They may be overlooked in the absence of lactate accumulation and typical mosaic mitochondrial defects in muscle.

Arthrogryposis multiplex congenita (AMC) is defined by congenital contractures of 2 or more major joints1 and thought to be caused by prolonged fetal immobility, probably regardless of the underlying cause. It is one typical sign of the fetal akinesia deformation sequence (FADS) or Pena-Shokeir syndrome.2 Among the underlying conditions, 2 are known fetal myasthenic syndromes involving the γ-subunit of the fetal nicotinergic acetylcholine receptor (AChR): mutations in the CHRNG gene encoding the γ-subunit3 and placental transfer of maternal antibodies specific for γ-subunit-containing fetal AChR.4 Because the γ-subunit is replaced by adult-specific e before birth,5 these antibodies do not to cause myasthenic symptoms in the newborn. The mother may be unaffected if she does not have significant antibodies to the adult AChR.6 ### Case report. Muscle biopsy (vastus lateralis) of a 2-week-old preterm (32nd week) boy was sent for diagnostic evaluation for possible AMC. A previous pregnancy had been aborted at the 26th week due to signs of FADS. Standard histology showed immaturity roughly in accord with gestational age (see e-Methods in appendix e-1 and figure e-1, A and B, on the Neurology ® Web site at www.neurology.org), without signs of other disease processes. Staining for cholinesterase and with rhodamine-conjugated α-bungarotoxin, reacting with the α-subunit of both adult and fetal AChR, demonstrated normal reactivities at the neuromuscular endplates (figure, A and E). Double immunolabeling with monoclonal antibodies against the AChR γ-subunit and the membrane attack complex (C5b9; e-Methods) detected activated complement deposition at most endplates …