CASPR2 autoimmunity in children expanding to mild encephalopathy with hypertension.

OBJECTIVE: To delineate autoimmune disease in association with contactin-associated protein 2 (CASPR2) antibodies in childhood, we reviewed the clinical phenotype of children with CASPR2 antibodies. METHODS: Retrospective assessment of patients recruited through laboratories specialized in autoimmune CNS disease. RESULTS: Ten children with serum CASPR2 antibodies were identified (age at manifestation 18 months to 17 years). Eight children with CASPR2 antibody titers from ≥1:160 to 1:5,120 had complex autoimmune diseases with an age-dependent clinical phenotype. Two children with structural epilepsy due to CNS malformations harbored nonspecific low-titer CASPR2 antibodies (serum titers 1:80). The clinical symptoms of the 8 children with high-titer CASPR2 antibodies were general weakness (8/8), sleep dysregulation (8/8), dysautonomia (8/8) encephalopathy (7/8), neuropathic pain (7/8), neuromyotonia (3/8), and flaccid paresis (3/8). Adolescents (3/8) showed pain, neuromyotonia, and encephalopathy, whereas younger children (5/8) displayed severe hypertension, encephalopathy, and hormonal dysfunction mimicking a systemic disease. No tumors were identified. Motor symptoms remitted with immunotherapy. Mild behavioral changes persisted in 1 child, and autism spectrum disorder was diagnosed during follow-up in a young boy. CONCLUSION: High-titer CASPR2 antibodies are associated with Morvan syndrome in children as young as 2 years. However, CASPR2 autoimmunity mimics systemic disease and hypertensive encephalopathy in children younger than 7 years. The outcome following immunotherapy was mostly favorable; long-term behavioral impairment may occur in younger children.

Morvan Syndrome and Diffuse Large B-Cell Lymphoma in the Central Nervous System.

INTRODUCTION: The origin of contactin-associated protein-like 2 (Caspr2) antibodies in patients with Morvan syndrome is currently unknown. This case report investigated a possible association between the production of Caspr2 antibodies and aberrant proliferation of B lymphocytes. CASE REPORT: We admitted a critically ill 65-year-old female patient with a suspected infection of the central nervous system (CNS). In addition to acquired neuromyotonia and CNS involvement, Caspr2 antibodies detected in her serum led to the presumptive diagnosis of Morvan syndrome. However, steroid and immunoglobulin treatment did not result in a satisfactory therapeutic outcome. On the basis of findings from immunohistochemistry, flow cytometric analysis, and immunoglobulin/T-cell receptor gene rearrangement detection of cerebrospinal fluid cells, we also made a concurrent diagnosis of diffuse large B-cell lymphoma in the CNS of this patient. The patient then received 4 cycles of rituximab and methylprednisolone therapy with an interval of 2 weeks, which temporarily led to a near-complete remission of her symptoms. Upon follow-up, her symptoms relapsed at 3 months after the last treatment with rituximab and methylprednisolone. CONCLUSIONS: This is a first reported case of a patient who was concurrently diagnosed with Morvan syndrome and diffuse large B-cell lymphoma in the CNS. Additional studies are needed to determine whether aberrantly proliferating B lymphocytes are responsible for the production of Caspr2 antibodies.

A Previously Healthy Adolescent With Acute Psychosis and Severe Hyperhidrosis.

A previously healthy 15-year-old boy presented with 3 months of progressive psychosis, insomnia, back and groin pain, and hyperhidrosis. On examination, the patient was disheveled, agitated, and soaked with sweat, with systolic blood pressure in the 160s and heart rate in the 130s. Aside from occasional auditory and visual hallucinations, his neurologic examination was normal. The patient was admitted for an extensive workup, including MRI of the brain and spine and lumbar puncture, which were normal. Through collaboration with various pediatric specialists, including psychiatry and neurology, a rare diagnosis was ultimately unveiled.

Using machine learning to understand neuromorphological change and image-based biomarker identification in Cavalier King Charles Spaniels with Chiari-like malformation-associated pain and syringomyelia.

BACKGROUND: Chiari-like malformation (CM) is a complex malformation of the skull and cranial cervical vertebrae that potentially results in pain and secondary syringomyelia (SM). Chiari-like malformation-associated pain (CM-P) can be challenging to diagnose. We propose a machine learning approach to characterize morphological changes in dogs that may or may not be apparent to human observers. This data-driven approach can remove potential bias (or blindness) that may be produced by a hypothesis-driven expert observer approach. HYPOTHESIS/OBJECTIVES: To understand neuromorphological change and to identify image-based biomarkers in dogs with CM-P and symptomatic SM (SM-S) using a novel machine learning approach, with the aim of increasing the understanding of these disorders. ANIMALS: Thirty-two client-owned Cavalier King Charles Spaniels (CKCSs; 11 controls, 10 CM-P, 11 SM-S). METHODS: Retrospective study using T2-weighted midsagittal Digital Imaging and Communications in Medicine (DICOM) anonymized images, which then were mapped to images of an average clinically normal CKCS reference using Demons image registration. Key deformation features were automatically selected from the resulting deformation maps. A kernelized support vector machine was used for classifying characteristic localized changes in morphology. RESULTS: Candidate biomarkers were identified with receiver operating characteristic curves with area under the curve (AUC) of 0.78 (sensitivity 82%; specificity 69%) for the CM-P biomarkers collectively and an AUC of 0.82 (sensitivity, 93%; specificity, 67%) for the SM-S biomarkers, collectively. CONCLUSIONS AND CLINICAL IMPORTANCE: Machine learning techniques can assist CM/SM diagnosis and facilitate understanding of abnormal morphology location with the potential to be applied to a variety of breeds and conformational diseases.

Morvan syndrome: clinical and serological observations in 29 cases.

OBJECTIVE: A study was undertaken to describe the clinical spectrum, voltage-gated potassium channel (VGKC) complex antibody specificities, and central nervous system localization of antibody binding in 29 patients diagnosed with Morvan syndrome (MoS). METHODS: Clinical data were collected using questionnaires. Radioimmunoassay, cell-based assays, and mouse brain immunohistochemistry were used to characterize the serum antibodies. RESULTS: Neuromyotonia (100%), neuropsychiatric features (insomnia 89.7%, confusion 65.5%, amnesia 55.6%, hallucinations 51.9%), dysautonomia (hyperhidrosis 86.2%, cardiovascular 48.3%), and neuropathic pain (62.1%) were the most common manifestations. A total of 93.1% of MoS patients were male. VGKC-complex antibodies were present in 23 of 29 (79%) MoS patients at referral; 24 of 27 available sera had CASPR2, LGI1, or both CASPR2 and LGI1 antibodies (3 also with contactin-2 antibodies). CASPR2 antibodies were generally higher titer than LGI1 antibodies. Tumors (41.4%), mainly thymomas, were associated with CASPR2 antibodies and a poor prognosis, whereas LGI1 antibodies were associated with serum hyponatremia. In brain tissue regions including the hypothalamus, raphe, and locus coeruleus, commercial antibodies to LGI1 bound to neuronal cell bodies including the antidiuretic hormone-secreting and orexin-secreting hypothalamic neurons, whereas CASPR2 commercial antibodies bound more often to the neuropil. MoS antibodies bound similarly, but there was evidence of additional antibodies in some sera that were not adsorbed by LGI1- or CASPR2-expressing cells and bound to mouse Caspr2(-/-) tissue. INTERPRETATION: MoS is clinically distinct from other VGKC-complex antibody-associated conditions, and usually is associated with high-titer CASPR2 antibodies, often accompanied by lower-titer LGI1 antibodies. CASPR2 and LGI1 antibodies bind to multiple brain regions, which helps to explain the multifocal clinical features of this disease, but other antibodies are likely to play a role in some patients and need to be characterized in future studies.

A lumped-parameter model of the cerebrospinal system for investigating arterial-driven flow in posttraumatic syringomyelia.

Fluid transport in syringomyelia has remained enigmatic ever since the disease was first identified some three centuries ago. However, accumulating evidence in the last decade from animal studies implicates arterial pulsations in syrinx formation. In particular, it has been suggested that a phase difference between the pressure pulse in the spinal subarachnoid space and the perivascular spaces, due to a pathologically disturbed cerebrospinal fluid (CSF) or blood supply, could result in a net influx of CSF into the spinal cord (SC). A lumped-parameter model is developed of the cerebrospinal system to investigate this conjecture. It is found that although this phase-lag mechanism may operate, it requires the SC to have an intrinsic storage capacity due to the collapsibility of the contained venous reservoir. This net flux is associated with a higher mean pressure in the SC than the SSS which is maintained in the periodic steady state. According to our simulations the mechanical perturbations of arachnoiditis exacerbate the phase-lag effect, which may be partially alleviated by the presence of a posttraumatic syrinx and more completely by a syringo-subarachnoid shunt.

Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan's syndrome and acquired neuromyotonia.

Antibodies that immunoprecipitate (125)I-alpha-dendrotoxin-labelled voltage-gated potassium channels extracted from mammalian brain tissue have been identified in patients with neuromyotonia, Morvan's syndrome, limbic encephalitis and a few cases of adult-onset epilepsy. These conditions often improve following immunomodulatory therapies. However, the proportions of the different syndromes, the numbers with associated tumours and the relationships with potassium channel subunit antibody specificities have been unclear. We documented the clinical phenotype and tumour associations in 96 potassium channel antibody positive patients (titres >400 pM). Five had thymomas and one had an endometrial adenocarcinoma. To define the antibody specificities, we looked for binding of serum antibodies and their effects on potassium channel currents using human embryonic kidney cells expressing the potassium channel subunits. Surprisingly, only three of the patients had antibodies directed against the potassium channel subunits. By contrast, we found antibodies to three proteins that are complexed with (125)I-alpha-dendrotoxin-labelled potassium channels in brain extracts: (i) contactin-associated protein-2 that is localized at the juxtaparanodes in myelinated axons; (ii) leucine-rich, glioma inactivated 1 protein that is most strongly expressed in the hippocampus; and (iii) Tag-1/contactin-2 that associates with contactin-associated protein-2. Antibodies to Kv1 subunits were found in three sera, to contactin-associated protein-2 in 19 sera, to leucine-rich, glioma inactivated 1 protein in 55 sera and to contactin-2 in five sera, four of which were also positive for the other antibodies. The remaining 18 sera were negative for potassium channel subunits and associated proteins by the methods employed. Of the 19 patients with contactin-associated protein-antibody-2, 10 had neuromyotonia or Morvan's syndrome, compared with only 3 of the 55 leucine-rich, glioma inactivated 1 protein-antibody positive patients (P < 0.0001), who predominantly had limbic encephalitis. The responses to immunomodulatory therapies, defined by changes in modified Rankin scores, were good except in the patients with tumours, who all had contactin-associated-2 protein antibodies. This study confirms that the majority of patients with high potassium channel antibodies have limbic encephalitis without tumours. The identification of leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 as the major targets of potassium channel antibodies, and their associations with different clinical features, begins to explain the diversity of these syndromes; furthermore, detection of contactin-associated protein-2 antibodies should help identify the risk of an underlying tumour and a poor prognosis in future patients.

Experimental model of syringomyelia in rabbits.

We studied the possibility of reproducing syringomyelia in rabbits by injection of serum from patients with syringomyelia. Clinical signs of syringomyelia and morphological changes in the central nervous system (cavities, dilatation of the cerebrospinal channel, neurodegeneration, gliosis) developed in laboratory animals over 60-120 days. This laboratory model is easily reproducible, stable, and maximally similar to the natural disease, which suggests it for the studies of the pathogenesis and development of new therapeutic methods.

Growth hormone insensitivity syndrome associated with syringomyelia and type I Chiari malformation.

A 49-year-old man with syringomyelia and a Type I Arnold-Chiari malformation (Chiari-I) was diagnosed with growth hormone insensitivity syndrome (GHIS). He was short in stature, had high circulating levels of GH, and low circulating levels of insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3). His GH responses to the administration of growth hormone-releasing hormone (GHRH) and L-DOPA were normal, but his levels of IGF-I and IGFBP-3 did not increase after the administration of exogenous GH. Direct genomic DNA sequencing revealed neither a mutation nor deletion in this patient's GH receptor (GHR) gene, though one polymorphism was detected, indicating that his GHR gene was normal. This is the first reported case of an association of GHIS with syringomyelia and Chiari-I malformation.

The association of hypopituitarism with small pituitary, invisible pituitary stalk, type 1 Arnold-Chiari malformation, and syringomyelia in seven patients born in breech position: a further proof of birth injury theory on the pathogenesis of "idiopathic hypopituitarism".

We report seven cases of hypopituitarism all having a history of breech delivery, asphyxia at birth, and syringomyelia. A small pituitary gland was found on MRI or CT in six cases, invisible pituitary stalk on MRI in five cases, and type 1 Arnold-Chiari malformation in six cases. A constellation of these abnormalities are best explained by traction of brain and spinal cord of the subjects exerted during breech delivery and further support the primary role of birth trauma in the genesis of "idiopathic hypopituitarism".

Increased growth of myoblasts from hypertrophic muscles in syringomyelia.

Proliferation and differentiation of myoblasts from hypertrophic muscles were studied "in vitro" in two cases of syringomyelia with muscle hypertrophy (MH). Their myoblast growth was compared with that of muscle cells sampled on the contralateral side in the same patients and in control subjects. The effect of a circulating factor was tested using patient sera in place of fetal calf and horse sera. The results showed that MH cells were morphologically abnormal (giant and granular). MH myoblasts proliferated more rapidly than contralateral and normal myoblasts, their fusion was accelerated and the resulting myotubes synthesized higher levels of protein. MH sera increased these effects. Serum factors are therefore likely to be involved in "in vivo" muscle hypertrophy. These findings suggest that the pathogenesis of muscle hypertrophy in syringomyelia involves acquired abnormalities due to molecules released in response to neural lesions.