A bstract : Antibodies to voltage‐gated potassium channels (VGKCs) appear likely to be the effector mechanisms in many patients with acquired peripheral nerve hyperexcitability (APNH) syndromes, a group of disorders that include neuromyotonia, cramp‐fasciculation syndrome, and Isaacs' syndrome. They may contribute to the associated autonomic changes. Through a central action, they may also be the effector mechanism in those with Morvan's syndrome and in some patients with limbic encephalitis. Evidence supporting this hypothesis includes the increased association of APNH with autoimmune diseases (in particular, myasthenia gravis and thymoma), the response to plasmapheresis, passive transfer of APNH to experimental animals by patients' plasma or immunoglobulins, the action of their serum on VGKC currents studied in vitro , and the presence in many patients of IgG antibodies to VGKCs.
The question of why many types of cells stop dividing and differentiate in the continuing presence of growth factors is a fundamental one in animal development. In the rat optic nerve, bipotential 0-2A progenitor cells give rise to oligodendrocytes and type-2 astrocytes on a precise schedule. Previous studies suggest that platelet-derived growth factor (PDGF) plays an important part in timing oligodendrocyte development and that the timing of oligodendrocyte differentiation is secondary to an intrinsic timing mechanism that controls when 0-2A progenitor cells become mitotically unresponsive to PDGF (Raff et al., 1988). This thesis examines the molecular basis of this intrinsic timing mechanism in 0-2A progenitor cells in vitro and looks at the relationship between mitosis and oligodendrocyte differentiation in vivo. 0-2A progenitor cells have a PDGF receptors, suggesting that these cells respond directly to PDGF. The receptors are initially retained when progenitor cells stop dividing in vitro and differentiate into oligodendrocytes. This indicates that receptor loss is not the reason that progenitor cells become mitotically unresponsive to PDGF. Many 0-2A progenitor cells, and newly formed oligodendrocytes which are no longer mitotically responsive to PDGF, show an increase in cytosolic Ca2+ in response to PDGF. A combination of a Ca2+ ionophore plus a phorbol ester mimics the effect of PDGF, both in stimulating 0-2A progenitor cell division and in reconstituting the normal timing of oligodendrocyte differentiation in culture, whereas the same drug combination does not stimulate newly formed oligodendrocytes to proliferate. These findings suggest that at least one reason why newly formed oligodendrocytes do not respond mitotically to PDGF is that there is a block or deficiency downstream from some of the early intracellular events that follow activation of the PDGF receptor. PDGF increases the expression of Fos and Jun in newly formed oligodendrocytes in vitro, suggesting that at least one intracellular signalling pathway to the nucleus is activated by PDGF in these cells even though PDGF does not stimulate them to synthesize DNA. 0-2A progenitor cells in the developing optic nerve, like those in optic nerve cultures, usually stop synthesizing DNA at least 6-12 hours before they express galactocerebroside, an early surface marker of differentiated oligodendrocytes, suggesting that in vivo differentiation follows loss of mitotic responsiveness, just as it does in vitro.
Objective: To determine the prevalence of serum antibodies to the ionotropic glutamate receptor 3 (GluR3) in patients with Rasmussen encephalitis (RE), a severe epileptic disorder, and to compare with serum from control subjects and patients with intractable epilepsy (IE). Methods: The authors looked for serum immunoglobulin (Ig) G antibodies to GluR3 in 30 patients with RE, including two patients who had plasma exchange and 12 who had been treated with IV Igs with varying results, and 49 patients with IE and 23 healthy individuals, using ELISA with GluR3B peptide, Western blot analysis of recombinant full-length GluR3, immunoprecipitation of [35S]- and [125I]-labeled GluR3 extracellular domains, immunohistochemistry on rat brain sections, and electrophysiology of GluR3 expressed in Xenopus oocytes. Results: Low levels of antibodies to the GluR3B peptide were detected using ELISA in only 4 of the 79 patients with epilepsy (2 with RE and 2 with IE); binding to GluR3B in other sera was shown to be nonspecific. One other patient with IE had antibodies to recombinant GluR3 on Western blot analysis. However, none of the sera tested precipitated either the [35S]- or the [125I]-labeled GluR3 domains; none bound to rat brain sections in a manner similar to rabbit antibodies to GluR3; and none of the nine sera tested affected the electrophysiologic function of GluR3. Conclusions: GluR3 antibodies were only infrequently found in Rasmussen encephalitis or intractable epilepsy.
Rasmussen syndrome (RS) is a focal, progressive, cortical inflammation affecting one cerebral hemisphere that usually presents with epilepsia partialis continua (EPC) that is resistant to antiepileptic drugs (AEDs). The encephalitis is often associated with ipsilateral cerebral hemisphere and basal ganglia atrophy.1 Patients can develop involuntary movements, including myoclonus, dystonia, and athetosis, usually in association with EPC.2 The encephalitis is probably autoimmune mediated, although the pathogenesis of the atrophy is unknown.3 We report a man with established RS who developed EPC and painful dystonia that improved with botulinum toxin A (BTX-A).
We described previously this 43-year-old, left-handed man.4 He sought treatment in 1989 for EPC followed by neurologic and cognitive deficits. The following therapies had no sustained effect: multiple AEDs, right corticectomy in 1990, infusions of sodium valproate or benzodiazepines into the corticectomy cavity in 1994, and right frontoparietal subcortical transection in 1995. Immunomodulatory therapy started in 1996, and his condition improved, although he continued to have intermittent bouts of left upper limb myoclonic jerking.4
He was stable until 2002 …
Abstract The neuromuscular junction (NMJ) is not only the site of myasthenia gravis, the main topic of this book, but also of the LambertEaton myasthenic syndrome (LEMS), which is caused by autoantibodies against the voltage-gated calcium channels on the presynaptic nerve terminal that are involved in neurotransmitter release (see Chapter 9). The pathophysiology of these disorders and the ability to study them by injecting immunoglobulins into mice or rats indicate that the motor nerve terminal and neuromuscular junction are extremely vulnerable to circulating antibodies. The approaches learned by studying myasthenia gravis and LEMS have now been applied to other disorders. In this chapter we shall concentrate on acquired neuromyotonia (NMT), which is caused by increased excitability of the nerve, here shown to be associated with autoantibod-ies to potassium channels. In addition, we shall summarize recent findings on the effects of sera and monoclonal antibodies from patients with antiganglioside-associated neuropathies on the function of the motor nerve and nerve terminal.
Mitochondrial cytopathies (MCs) result from a genetic defect in cells that leads to reduction in energy production. This can affect any organ, especially those with high-energy consumption. The authors highlight two cases of MCs who presented with isolated ptosis. The characteristics initially suggested myasthenia gravis. Subsequently the ptosis became progressive and the diagnosis was revised to MC because mitochondrial rearrangements were found in skeletal muscle DNA. Limb muscle biopsy was conclusive in one patient, but the other patient required periocular muscle to confirm the diagnosis. MC can present in this manner because heteroplasmy of mitochondrial DNA means that not all organs will exhibit clinical manifestations.
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