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Biomedical subjects

Paul Maddison

Publications and source records attributed to Paul Maddison.

8 recordsLinked to original sources
PubMed2006

Neuromyotonia.

Neuromyotonia is a rare condition of spontaneous and continuous muscle fibre activity of peripheral nerve origin. It represents the more severe phenotype of peripheral nerve hyperexcitability, and when acquired is often associated with antibodies to voltage-gated potassium channels. There are no specific published electromyographic or clinical diagnostic criteria for this disorder. This review highlights the classical clinical, electrophysiological and immunological features of this disorder from what is currently known in the literature to date, and also from the author's own patients' studies. Neuromyotonia is best classified as a moderately severe disorder of peripheral nerve hyperexcitability, with electromyographic features of spontaneous, continuous, irregularly occurring doublet, or multiplet single motor unit (or partial motor unit) discharges, firing at a high intraburst frequency (30-300Hz). Invariably, patients develop persistent muscle contraction, often worse following exercise. About 40% of patients with acquired neuromyotonia will have detectable voltage-gated potassium-channel antibodies. Clinical, electrophysiological and immunological measurements are important in defining the phenotype of neuromyotonia, and other, milder forms of peripheral nerve hyperexcitability.

Animals↗
PubMed2006

Clinical electrophysiological characterization of the acquired neuromyotonia phenotype of autoimmune peripheral nerve hyperexcitability.

Acquired autoimmune neuromyotonia is regarded as part of the spectrum of peripheral nerve hyperexcitability disorders. We aimed to use clinical neurophysiological measurements to study the extent, distribution, and characteristics of spontaneous motor unit potentials in 11 patients with acquired neuromyotonia. Investigations revealed that most spontaneous discharges recorded were motor unit, or partial motor unit potentials of normal size. Bursts of motor unit potentials arose more commonly from distal portions of the peripheral nerve and had abnormal absolute and relative refractory periods. Spontaneous discharges in some patients occurred in semirhythmic bursts in certain muscles. No patient had neurophysiological abnormalities detectable in first-order neurons of the central nervous system when using transcranial magnetic stimulation to estimate the threshold for corticomotor excitation and determine central motor conduction time. Only patients with coexistent myasthenia gravis had neurophysiologically detectable defects in neuromuscular transmission. The pathogenic region of abnormality in peripheral nerve hyperexcitability disorders therefore seems to lie within the terminal branches of peripheral motor nerves.

Action Potentials↗
PubMed2004

HLA and smoking in prediction and prognosis of small cell lung cancer in autoimmune Lambert-Eaton myasthenic syndrome.

Patients with small cell lung cancer (SCLC) survive longer if they have the antibody-mediated Lambert-Eaton myasthenic syndrome (LEMS), making this autoimmune disorder a prototype disease for studying cancer immunosurveillance. Patients with nontumor LEMS (NT-LEMS) never develop SCLC but are otherwise indistinguishable clinically. Therefore, we have compared immunogenetic factors in SCLC-LEMS and NT-LEMS and studied their role in the pathogenesis of LEMS and survival from SCLC. In 48 British and 29 Dutch Caucasian LEMS patients, we studied clinical symptoms, antibody titers, HLA types and alleles at six nearby located microsatellite loci. Highly significant associations were found in NT-LEMS, which appeared strongest with HLA-B8, but also involved HLA-DQ2, -DR3 and six flanking microsatellite alleles. SCLC-LEMS patients were not different from controls. Smoking was a strong predictor of SCLC. In contrast, HLA-B8 positivity correlated with a decreased risk of SCLC even among the smokers. Moreover, in SCLC-LEMS patients, HLA-B8 positivity correlated with prolonged survival after LEMS onset. We propose that two distinct immunopathogenetic routes can lead to one clinically and serologically indistinguishable autoimmune myasthenic syndrome. HLA-DR3-B8 is strongly associated with LEMS in nontumor patients only. In other LEMS patients, SCLC apparently provides a powerful autoimmunogenic stimulus that overrides HLA restrictions in breaking tolerance to calcium channels. Moreover, negativity for HLA-B8 combined with smoking behavior points more strongly to an underlying SCLC and predicts a worse prognosis in SCLC-LEMS patients.

Adolescent↗
PubMed2003

Autoimmune disorders of neuronal potassium channels.

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.

Action Potentials↗
PubMed2002

Acute rhabdomyolysis and brachial plexopathy following alcohol ingestion.

An unusual case of brachial plexopathy following alcohol-induced rhabdomyolysis is presented. The patient's rhabdomyolysis developed during sleep after an acute alcohol binge and there was no history of muscle trauma. It is thought that the brachial plexopathy developed due to direct compression of the plexus from swollen muscles of the shoulder girdle. The lack of similar reported cases despite the common clinical scenario of prolonged unconsciousness following excess alcohol intake suggests that other factors may be important in the development of muscle and nerve damage in susceptible individuals.

Acute Disease↗
PubMed2002

A novel mitochondrial DNA tRNA(Ile) (A4267G) mutation in a sporadic patient with mitochondrial myopathy.

We describe a novel mutation in the mitochondrial tRNA(Ile) gene, an A to G transition at nucleotide position 4267, in a 37-year-old woman with myopathy, ataxia and sensorineural hearing loss. The A4267G mutation was heteroplasmic in several of the proband's tissues and single fibre analysis revealed significantly higher levels of mutated mitochondrial DNA in cytochrome c oxidase-deficient fibres than cytochrome c oxidase-positive fibres. It is predicted to disrupt a highly conserved base pair within the aminoacyl acceptor stem of the tRNA causing functional impairment, and as such fulfils all the accepted criteria for pathogenicity. Moreover, we were unable to detect the A4267G mutation in lymphocytes, buccal epithelia and hair of the patient's mother and two siblings, implying that the A4267G transition represents a sporadic, germline mutation.

Adult↗
PubMed2002

Phenotypic variants of autoimmune peripheral nerve hyperexcitability.

Clinicians use many terms including undulating myokymia, neuromyotonia, Isaacs' syndrome and Cramp-Fasciculation Syndrome to describe the motor manifestations of generalized peripheral nerve hyperexcitability (PNH). Our previous findings in a selected group of patients with undulating myokymia or neuromyotonia, and EMG doublet or multiplet ('myokymic') motor unit discharges, indicated that an autoantibody-mediated potassium channelopathy was likely to be the cause of their disorder. This prompted us to search for a common pathogenesis in a wider spectrum of PNH syndromes. We studied the clinical, autoimmune and electrophysiological features of 60 patients presenting with acquired PNH. Patients were grouped according to an EMG criterion: the presence (group A, n = 42) or absence (group B, n = 18) of doublet or multiplet myokymic motor unit discharges. The average ages of onset in the two groups were 45 and 48 years respectively. The relative frequency and topography of the clinical features were similar in both groups. Serum voltage-gated potassium channel (VGKC) antibodies were detected using a (125)I-alpha-dendrotoxin immunoprecipitation assay in 38% of group A and in 28% of group B. Autoimmune disease and other autoantibodies were present in both groups more frequently than would be expected by chance (59 and 28%, respectively)-particularly myasthenia gravis and acetylcholine receptor (AChR) antibodies. The neurological disorder in both groups could occur as a paraneoplastic condition. Thymoma was detected in 19 and 11%, respectively, and lung cancer in 10 and 6%, respectively. An axonal neuropathy was present in six (14%) of group A and in one (6%) of group B patients. Thus, despite the discrete EMG distinction, both groups share clinical features often associated with autoimmune-related diseases, which can occur as paraneoplastic disorders and, importantly, have an increased frequency of VGKC antibodies. We conclude that autoimmunity, and specifically VGKC antibodies in many cases, are strongly implicated in the pathogenesis of both groups, and that the EMG features reflect quantitative rather than qualitative differences between the diverse clinical syndromes. These findings also have relevance for disease management. A classification is proposed that distinguishes immune-mediated PNH (irrespective of whether VGKC antibodies are detectable by standard assays) from non-immune forms of PNH that include toxins, anterior horn cell degeneration in motor neurone disease and genetic disorders.

Age of Onset↗