Peripheral nerve hyperexcitability syndrome: A clinical, electrophysiological, and immunological study.

INTRODUCTION: Peripheral nerve hyperexcitability syndrome (PNHS) is characterized by muscle fasciculations and spasms. Nerve hyperexcitability and after-discharges can be observed in electrophysiological studies. Autoimmune mechanisms play a major role in the pathophysiology of primary PNHS. METHODS: We retrospectively conducted a case-control study recruiting patients with clinical and electrophysiological features of PNHS. Control patients were diagnosed with other neuronal or muscular diseases. Contactin-associated protein2 (CASPR2) and leucine-rich glioma-inactivated1 (LGI1) antibodies were examined. RESULTS: A total of 19 primary PNHS patients and 39 control patients were analyzed. The most common symptoms for the case group were fasciculations (11/19) and muscle spasms (13/19). Case group patients were likely to demonstrate electrodiagnostic findings of nerve hyperexcitability (17/19) and after-discharges in the tibial nerve (19/19). We found high prevalence of CASPR2 (9/19) and LGI1 (6/19) antibodies in the case group. DISCUSSION: Primary PNHS patients were likely to show after-discharges in the tibial nerve. The pathogenesis of PNHS is autoimmune CASPR2 and LGI1 antibodies are possible pathogenic antibodies for primary PNHS.

Late-onset seropositive Isaacs' syndrome after Guillain-Barré syndrome.

Acquired neuromyotonia, or Isaacs' syndrome, has been described in combination with a variety of other autoimmune disorders; however there has never been a report of seropositive Isaacs' syndrome in a patient with a history of Guillain-Barré syndrome (GBS). Both conditions involve antibody-mediated autoimmune effects on the peripheral nervous system, although the clinical manifestations are quite different. We present a man who experienced an episode of GBS at the age of 21 and subsequently developed Isaacs' syndrome at the age of 24 which was positive for anti-voltage-gated potassium channel (VGKC) antibodies. When treated with intravenous immunoglobulins (IVIg) he developed an eczematous rash that differed markedly in pattern and duration from the usual presentation for this IVIg reaction.

Advances in the pathogenesis and treatment of patients with stiff person syndrome.

Advances in the clinical diagnosis, prognosis, pathogenesis, and therapies for stiff person syndrome (SPS), based on observations in more than 50 consecutive patients, are presented. The syndrome varies from mild to severe, but if untreated it can be progressive and disabling. SPS remains a largely underdiagnosed condition. Anti-glutamic acid decarboxylase (GAD) antibodies provide an excellent diagnostic marker, but their role in disease pathogenesis is uncertain. Research focused on identifying new autoantigens has provided evidence that gamma-aminobutyric acid (GABA)(A) receptor-associated protein (GABARAP), a 14-kD protein localized at the postsynaptic regions of GABAergic synapses, is a new antigenic target. In up to 65% of SPS patients, there are circulating anti-GABARAP antibodies that inhibit the GABA(A) receptor expression on GABAergic neurons. This review examines the diagnostic criteria for SPS, SPS variants, common errors in diagnosis, and a step-by-step therapeutic approach, including new advances in therapy.

Satoyoshi syndrome has antibody against brain and gastrointestinal tissue.

Satoyoshi syndrome is a rare postnatal disorder with muscle spasms, alopecia, and diarrhea of unknown etiology. Nutritional deficiency seems to influence lifespan. We present a patient with this syndrome having a unique "mesh-like" mucosal change radiographically and white granules endoscopically in the gastrointestinal tract. A common antibody against brain, stomach, and duodenal tissue, according to Western blot analysis, was detected in the sera of two patients with this syndrome. These findings suggest that Satoyoshi syndrome is a systemic autoimmune disease involving the nervous, endocrine, and gastrointestinal systems.

Rigidity and spasms from autoimmune encephalomyelopathies: stiff-person syndrome.

Stiff-person syndrome (SPS) is a disorder characterized by progressive muscle rigidity with superimposed painful muscle spasms and gait impairment due to continuous motor activity. Evidence has accumulated in favor of SPS representing an autoimmune, predominantly encephalomyelopathic disorder resulting from B-cell-mediated clonal production of autoantibodies against presynaptic inhibitory epitopes on the enzyme glutamic acid decarboxylase (GAD) and the synaptic membrane protein amphiphysin. Recognition of the clinical spectrum of SPS is important, particularly the upper-limb, cervical, and cranial nerve involvement that occurs in paraneoplastic variants. The correlation between antibody levels and severity of disease offers evidence for a pathogenic role for the anti-GAD and anti-amphiphysin autoantibodies. The scarcity of neuropathological correlates stand in sharp contrast with the severity of the disability in affected individuals and suggests that functional impairment of inhibitory circuits without structural damage is sufficient to develop the full clinical spectrum of SPS. The rarity of this condition limits the feasibility of controlled clinical trials in the treatment of SPS, but the available evidence suggest that drugs that increase cortical and spinal inhibition such as benzodiazepines and drugs that provide immune modulation such as intravenous immunoglobulin, plasmapheresis, and prednisone are effective treatments.

Lactobacillus paracasei normalizes muscle hypercontractility in a murine model of postinfective gut dysfunction.

BACKGROUND & AIMS: The effects of probiotics on gut dysfunction in postinfective irritable bowel syndrome are unknown. We tested whether probiotics influence persistent muscle hypercontractility in mice after recovery from infection with Trichinella spiralis and analyzed the underlying mechanisms. METHODS: Mice were gavaged with Lactobacillus paracasei, Lactobacillus johnsonii, Bifidobacterium longum, or Bifidobacterium lactis in spent culture medium from days 10 to 21 after infection. Additional mice received heat-inactivated Lactobacillus paracasei, Lactobacillus paracasei -free spent culture medium, or heat-inactivated Lactobacillus paracasei -free spent culture medium. Lactobacilli enumeration, immunohistochemistry, and cytokine detection (enzyme-linked immunosorbent assay) were performed. Mice were also treated with Lactobacillus paracasei or Lactobacillus paracasei -free spent culture medium from days 18 to 28 after infection. Contractility was measured on days 21 and 28 after infection. RESULTS: Lactobacillus paracasei, but not Lactobacillus johnsonii, Bifidobacterium lactis, or Bifidobacterium longum, attenuated muscle hypercontractility. This was associated with a reduction in the Trichinella spiralis -associated T-helper 2 response and a reduction in transforming growth factor-beta1, cyclooxygenase-2, and prostaglandin E 2 levels in muscle. Attenuation of muscle hypercontractility by Lactobacillus paracasei -free spent culture medium was abolished after heat treatment. Improvement of muscle hypercontractility at day 28 after infection was also observed after the administration of Lactobacillus paracasei or Lactobacillus paracasei -free spent culture medium from day 18 after infection. CONCLUSIONS: Probiotics show strain-dependent attenuation of muscle hypercontractility in an animal model of postinfective irritable bowel syndrome. This likely occurs via both a modulation of the immunologic response to infection and a direct effect of Lactobacillus paracasei or a heat-labile metabolite on postinfective muscle hypercontractility. Lactobacillus paracasei may be useful in the treatment of postinfective irritable bowel syndrome.

Stiff man syndrome and related conditions.

The stiff man syndrome (SMS) and its variants, focal SMS, stiff limb (or leg) syndrome (SLS), jerking SMS, and progressive encephalomyelitis with rigidity and myoclonus (PERM), appear to occur more frequently than hitherto thought. A characteristic ensemble of symptoms and signs allows a tentative clinical diagnosis. Supportive ancillary findings include (1) the demonstration of continuous muscle activity in trunk and proximal limb muscles despite attempted relaxation, (2) enhanced exteroceptive reflexes, and (3) antibodies to glutamic acid decarboxylase (GAD) in both serum and spinal fluid. Antibodies to GAD are not diagnostic or specific for SMS and the role of these autoantibodies in the pathogenesis of SMS/SLS/PERM is the subject of debate and difficult to reconcile on the basis of our present knowledge. Nevertheless, evidence is emerging to suggest that SMS/SLS/PERM are manifestations of an immune-mediated chronic encephalomyelitis and immunomodulation is an effective therapeutic approach.

Stiff-person syndrome associated with invasive thymoma: a case report.

We report a case of a 40-year-old female with continuous muscle stiffness and painful muscle spasms. The symptoms worsened over a two-week period after onset. Electrophysiological examinations revealed continuous muscle discharge, which was markedly reduced by intravenous administration of diazepam. High levels of anti-glutamic acid decarboxylase (GAD) antibodies were detected in both serum and cerebrospinal fluid, suggesting that the patient suffered from stiff-person syndrome. Steroid pulse therapy and immunoadsorption therapy alleviated the clinical symptoms and decreased the anti-GAD antibody titer. A chest CT revealed the presence of an invasive thymoma. Neither anti-acetylcholine receptor (AChR) antibodies nor symptoms of myasthenia gravis (MG) were observed. The patient underwent a thymectomy and postoperative radiotherapy. These treatments further alleviated the clinical symptoms. The present case is the first that associates stiff-person syndrome with invasive thymoma, and not accompanied by MG. The autoimmune mechanism, in this case, may be triggered by the invasive thymoma.

[A case of progressive continuous muscular rigidity and painless and rhythmic muscle spasm associated with autoantibody against glutamic acid decarboxylase].

We described a 60-year-old man with 5-year history of insulin dependent diabetes mellitus who developed continuous rigidity of truncal muscle and painless, rhythmic muscular spasm of trunk and proximal lower and upper extremities. The rigidity continued even in sleep. The painless muscle spasm was often precipitated by volitional movement and emotional stimuli. Intravenous administration of diazepam strongly attenuated the muscle spasm as well as truncal rigidity. Surface electromyography showed the continuous contraction of abdominal and paraspinal muscles. The rhythmic, clonic spasm of shoulder, triceps brachii, intercostal, abdominal, paraspinal and quadriceps femoris muscle induced by voluntary neck flexion was not compatible with typical stiff-man syndrome. Antibody against glutamic acid decarboxylase (GAD) was detected in the serum and cerebrospinal fluid of this patient. His condition was getting well with oral intake of sodium valproate. While painless, rhythmic spasm and persistent rigidity during sleep ruled out the patient from typical stiff-man syndrome, he was supposed to have the same pathophysiological mechanism as the anti-GAD autoantibody positive stiff-man syndrome.

Serum antibody production to botulinum A toxin.

PURPOSE: Conflicting data have been reported regarding development of serum antibodies to botulinum A toxin. The purpose of this study is to determine conclusively whether antibody production to this toxin occurs in humans, and, if so, to determine its relationship, if any, to length of treatment, total cumulative dose, and clinical response to treatment. METHODS: Sixty-five sera samples from 42 adults treated with botulinum A toxin for essential blepharospasm, hemifacial spasm, or spasmodic torticollis were analyzed via a sphere-linked immunodiagnostic assay for antibody production. Results were plotted against length of treatment, number of injections, cumulative dose, and treatment effect produced. RESULTS: Twenty-four (57%) of the 42 patients produced antibodies in all three diagnostic groups. No significant differences were found between antibody producers and nonproducers with respect to age (P = 0.216), length of treatment (P = 0.586), number of injections (P = 0.619), or total cumulative dose (P = 0.286). Within the antibody-producing group, there was no significant correlation between amount of antibody and length of treatment (P = 0.081), number of injections (P = 0.134), or cumulative dose (P = 0.250). The presence of demonstrable antibodies in serum did not affect the clinical responsiveness to injection. CONCLUSION: Antibody production is present in a majority of patients treated with botulinum A toxin. The sphere-linked immunodiagnostic assay is a reliable and reproducible method for detecting and quantifying these antibodies. When antibody production occurs, it is likely due to variations in individual immune responsiveness and appears to have no direct effect on the patient's clinical response to treatment.

Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff-man syndrome.

Stiff-man syndrome is a rare disorder of the central nervous system of unknown pathogenesis. We have previously reported the presence of autoantibodies against glutamic acid decarboxylase (GAD) in a patient with stiff-man syndrome, epilepsy, and insulin-dependent diabetes mellitus. GAD is an enzyme selectively concentrated in neurons secreting the neurotransmitter gamma-aminobutyric acid (GABA) and in pancreatic beta cells. We subsequently observed autoantibodies to GABA-ergic neurons in 20 of 33 patients with stiff-man syndrome. GAD was the principal autoantigen. In the group of patients positive for autoantibodies against GABA-ergic neurons, there was a striking association with organ-specific autoimmune diseases, primarily insulin-dependent diabetes mellitus. These findings support the hypothesis that stiff-man syndrome is an autoimmune disease and suggest that GAD is the primary autoantigen involved in stiff-man syndrome and the associated insulin-dependent diabetes mellitus. Our findings also indicate that autoantibodies directed against GABA-ergic neurons are a useful marker in the diagnosis of the disease.

Autoantibodies to glutamic acid decarboxylase in a patient with stiff-man syndrome, epilepsy, and type I diabetes mellitus.

Stiff-man syndrome is a rare disorder of the central nervous system consisting of progressive, fluctuating muscle rigidity with painful spasms. It is occasionally associated with endocrine disorders, including insulin-dependent diabetes, and with epilepsy. We investigated the possible existence of autoimmunity against the nervous system in a patient with stiff-man syndrome associated with epilepsy and Type I diabetes mellitus. Levels of IgG, which had an oligoclonal pattern, were elevated in the cerebrospinal fluid. The serum and the cerebrospinal fluid produced an identical, intense staining of all gray-matter regions when used to stain brain sections according to an indirect light-microscopical immunocytochemical procedure. The staining patterns were identical to those produced by antibodies to glutamic acid decarboxylase (the enzyme responsible for the synthesis of gamma-aminobutyric acid). A band comigrating with glutamic acid decarboxylase in sodium dodecyl sulfate-polyacrylamide gels appeared to be the only nervous-tissue antigen recognized by cerebrospinal fluid antibodies, and the predominant antigen recognized by serum antibodies. These findings support the idea that an impairment of neuronal pathways that operate through gamma-aminobutyric acid is involved in the pathogenesis of stiff-man syndrome, and they raise the possibility of an autoimmune pathogenesis.

Lymphocyte subset abnormalities in patients with spasmodic torticollis.

The aetiology of spasmodic torticollis is unknown but the patients form a heterogeneous group among which are cases apparently precipitated by a viral illness and others associated with autoimmune disease. We therefore decided to investigate the immunoregulatory lymphocyte subsets in our 11 cases. A significant decrease of both helper and suppressor lymphocytes was identified in the group, together with in vitro evidence of depressed suppressor cell function. Disturbance of the immune response may play a role in this puzzling disorder.

Absence of antibody production in patients treated with botulinum A toxin.

To test the possibility of the formation of an antibody to botulinum A toxin after multiple injections of this potent neurotoxin, we collected serum samples from 28 patients who received 57 doses. These injections over a nine-month period with as much as 50 units per injection formed no detectable antibody.