Thierry Kuntzer

Efficacy of lidocaine patch 5% in the treatment of focal peripheral neuropathic pain syndromes: a randomized, double-blind, placebo-controlled study

&NA; Peripheral neuropathic pain syndromes (PNPS) are difficult to treat because commonly used analgesics are often ineffective when, for example, touch‐evoked allodynia, hyperalgesia, and pain paroxysms are present. To investigate whether lidocaine patch 5% treatment is also effective in postherpetic neuropathy (PHN) and in other PNPS, 40 patients with various forms and localizations of PNPS completed a prospective, randomized, placebo‐controlled, two‐way, cross‐over study in three medical hospitals. Patients suffering from pain in a localized skin area with intensity above 40 mm visual analog scale (VAS) and a stable consumption of pain medication were included in this study. The study was divided into four phases: 3‐day run‐in phase, treatment phase 1, wash‐out period, and treatment phase 2, each lasting 1 week. At the discretion of the patients, up to four patches (covering a maximum of 560 cm2) were applied onto the maximally painful area for 12 consecutive hours daily, always either by day or at night. Throughout the four phases, ongoing pain, allodynia, quality of neuropathic symptoms, quality of sleep, and adverse events were assessed. When, after the wash‐out period, the pain intensity scores did not return to the pre‐treatment values (±20%), these patients were excluded from the study. The present study revealed that, as an add‐on therapy, the lidocaine patch 5% was clearly effective in reducing ongoing pain (P=0.017) and allodynia (P=0.023) during the first 8 h after application and that the patches also worked well over a period of 7 days (P=0.018) in diverse focal PNPS. Calculation of the numbers needed to treat (NNT) to obtain one patient with more than 50% relief of ongoing pain revealed that the NNT of 4.4 in the present study compared reasonably well with other studies of PHN, such as topically applied capsaicin (NNT: 5.3–∞) or systemic treatment with gabapentin (NNT: 3.2–5.0).

Clinical features and pathophysiological basis of sensory neuronopathies (ganglionopathies)

Sensory ganglionopathies have a frequent association with neoplastic disorders (paraneoplastic subacute sensory neuronopathy, or SSN) or dysimmune disorders (Sjögrens syndrome, SS; Miller Fisher syndrome; and Bickerstaffs brainstem encephalitis, BBE), with drugs, such as cisplatin or pyridoxine, and with inherited disorders with degeneration of dorsal root ganglion cells. Unsteady gait and pseudoathetoid movements of the hand are the distinctive signs encountered in these disorders. The chronic disorders are characterized by non–length‐dependent abnormalities of sensory nerve action potentials (SNAPs) and differ from other sensory neuropathies in showing a global, rather than distal, decrease in SNAP amplitudes. This review focuses on recent advances in defining the mechanisms involved in sensory ganglionopathies. Specific topics include a summary of their clinical features, pathological findings, and immunopathology. In SSN, early diagnosis by the detection of anti‐Hu antibodies and early treatment of the cancer gives the best chance of stabilizing the disorder. In SS sensory ganglionitis, response to treatment has been disappointing, but immunomodulating treatments are emerging. The immunological profile common to BBE and Fisher syndrome supports a common pathogenesis. In toxic sensory neuronopathy, no treatment is available. The differential diagnosis involves separating sensory ganglionopathies from other ataxic polyneuropathies, such as infectious neuropathies, sensory neuropathies with various autoantibodies, and the neuropathies seen in celiac disease. Muscle Nerve 30:255–268, 2004

Identification of an Agrin Mutation that Causes Congenital Myasthenia and Affects Synapse Function

We report the case of a congenital myasthenic syndrome due to a mutation in AGRN, the gene encoding agrin, an extracellular matrix molecule released by the nerve and critical for formation of the neuromuscular junction. Gene analysis identified a homozygous missense mutation, c.5125G>C, leading to the p.Gly1709Arg variant. The muscle-biopsy specimen showed a major disorganization of the neuromuscular junction, including changes in the nerve-terminal cytoskeleton and fragmentation of the synaptic gutters. Experiments performed in nonmuscle cells or in cultured C2C12 myotubes and using recombinant mini-agrin for the mutated and the wild-type forms showed that the mutated form did not impair the activation of MuSK or change the total number of induced acetylcholine receptor aggregates. A solid-phase assay using the dystrophin glycoprotein complex showed that the mutation did not affect the binding of agrin to alpha-dystroglycan. Injection of wild-type or mutated agrin into rat soleus muscle induced the formation of nonsynaptic acetylcholine receptor clusters, but the mutant protein specifically destabilized the endogenous neuromuscular junctions. Importantly, the changes observed in rat muscle injected with mutant agrin recapitulated the pre- and post-synaptic modifications observed in the patient. These results indicate that the mutation does not interfere with the ability of agrin to induce postsynaptic structures but that it dramatically perturbs the maintenance of the neuromuscular junction.

Carpal tunnel syndrome in 100 patients: Sensitivity, specificity of multi-neurophysiological procedures and estimation of axonal loss of motor, sensory and sympathetic median nerve fibers

This prospective study meets all six criteria recently recommended by a quality assurance committee of the AAEM and defines criteria of abnormality, sensitivity and specificity of 19 sensorimotor and sympathetic parameters in 100 patients who were suspected on clinical grounds of having carpal tunnel syndrome (CTS), and in 70 control subjects. Nine parameters reached a specificity of 97%, permitting the electrodiagnosis of CTS in 87% of the patients studied. The results in this study confirm that median sensory nerve conduction studies are more frequently abnormal than are studies of motor nerve conduction. The so far unknown usefulness of parameters such as median F-wave abnormalities and residual latency, terminal latency index and sensory nerve action potential (SNAP) amplitude was assessed; these parameters were not found sensitive enough, yet high specific (SNAP amplitude) or high sensitive yet low specific (F-wave abnormalities, residual latency and terminal latency index) and are therefore of little value in the early clinical electrodiagnostic evaluation of patients with CTS. Finally, in the patients studied, some degree of axonal loss for motor, sensory and sympathetic median nerve fibers was found in 42% of cases and 6 patients had a double-crush syndrome and 6 others had a concomitant ulnar neuropathy at the elbow.

Predictive value of anti-GM1 ganglioside antibodies in neuromuscular diseases: a study of 180 sera.

The incidence of anti-GM1 antibodies in the serum of 104 patients with neurological diseases, 35 patients with non-neurological diseases (NND) and 41 normal controls was determined by enzyme-linked immunosorbent assay (ELISA). Anti-GM1 antibodies were found in 90% of patients presenting with a motor neuropathy (all except one had multifocal conduction blocks). A large proportion (60%) of these patients displayed high antibody titer ranging from 101 to 788. A low incidence of anti-GM1 antibodies was found in the other groups of patients, i.e. 21% of amyotrophic lateral sclerosis (ALS), 26% of other neurological diseases (OND) and 23% of NND. High antibody titers ranging from 106 to 260 were found in two (5%) ALS patients, one (2%) OND patient (myasthenia gravis), and one (3%) NND patient (Waldenströms disease). This study shows that high titers of anti-GM1 antibodies are found in a large proportion of patients with motor neuropathy with multifocal conduction blocks. This argues for a possible autoimmune origin of this neuropathy. We suggest that anti-GM1 antibody determination should be included systematically in the evaluation of all patients with motor neuron diseases and predominantly motor neuropathies.

Early Onset Collagen VI Myopathies: Genetic and Clinical Correlations

Mutations in the genes encoding the extracellular matrix protein collagen VI (ColVI) cause a spectrum of disorders with variable inheritance including Ullrich congenital muscular dystrophy, Bethlem myopathy, and intermediate phenotypes. We extensively characterized, at the clinical, cellular, and molecular levels, 49 patients with onset in the first 2 years of life to investigate genotype‐phenotype correlations.

Early symptoms and outcome of Listeria monocytogenes rhombencephalitis: 14 adult cases.

Listeria monocytogenes rhombencephalitis has never been studied in a significant group of patients. We describe 14 adult cases who were seen over a 10-year period. A biphasic illness was characteristic: (1) prodromes (5–15 days) with malaise, fatigue, headache, nausea or vomiting, and fever; (2) cranial nerve palsy with facial palsy, diplopia, dysphagia, dysarthria, usually multiple. Meningism and hemi- or tetraparesis were present in 11 patients and cerebellar dysfunction in 9 patients. In 4 cases, CT showed widening of the brain stem with disappearance of the surrounding cisterns. The cerebrospinal fluid was abnormal in all patients in whom this investigation was done (pleocytosis, elevation in protein content). The patients received antibiotic therapy for 2–6 weeks. In the 9 patients who recovered, the neurological dysfunction improved within 2 days to 1 week of the initiation of therapy. There were 5 deaths. At autopsy in 2 cases, there was severe purulent meningitis and rhombencephalitis with predominantly polymorphonuclear cellular infiltration in 1 case, while numerous microabscesses in the midbrain, pons and medulla were observed in the other. We conclude thatL. monocytogenes infection should be considered in patients who develop fever and focal neurological signs particularly localized to the brain stem.

Clinical and prognostic features in unilateral femoral neuropathies

We have examined the clinical features of patients with femoral neuropathy and the factors that influence the prognosis. Of 80 consecutive patients referred for neurophysiological evaluations of proximal lower limb weakness, 32 fulfilled strict inclusion criteria and had adequate information, including estimates of axon loss (AxL) by stimulation of the bilateral femoral nerve. In 31, the Kaplan‐Meier method was used to describe the time course of the outcome, while logistic regression was employed to determine the contributing factors. Excellent, satisfactory, and poor outcomes were seen in 10 (31%), 11 (34%), and 10 (31%) patients, respectively. Logistic regression analysis of seven factors demonstrated that the estimate of AxL was the only significant variable. The best prognostic factor was an estimate of AxL ≤ 50%, with all patients fulfilling this criterion showing improvement within 1 year; fewer than half the patients with AxL >50% should be expected to improve. This study clearly shows that, irrespective of the cause of femoral neuropathy, functional improvement is seen in 2 out of 3 patients within 2 years and that the estimate of AxL is the only factor influencing prognosis.

New mutations of SCN4A cause a potassium-sensitive normokalemic periodic paralysis

Background: Periodic paralysis is classified into hypokalemic (hypoPP) and hyperkalemic (hyperPP) periodic paralysis according to variations of blood potassium levels during attacks. Objective: To describe new mutations in the muscle sodium channel gene SCN4A that cause periodic paralysis. Methods: A thorough clinical, electrophysiologic, and molecular study was performed of four unrelated families who presented with periodic paralysis. Results: The nine affected members had episodes of muscle weakness reminiscent of both hyperPP and hypoPP. A provocative test with potassium chloride was positive in two patients. However, repeated and carefully performed tests of blood potassium levels during attacks resulted in normal potassium levels. Remarkably, two patients experienced hypokalemic episodes of paralysis related to peculiar provocative factors (corticosteroids and thyrotoxicosis). Similarly to hyperPP, electromyography in nine patients revealed increased compound muscle action potentials after short exercise and a delayed decline during rest after long exercise as well as myotonic discharges in one patient. With use of molecular genetic analysis of the gene SCN4A, three new mutations were found affecting codon 675. They resulted in an amino acid substitution of a highly conserved arginine (R) to either a glycine (G), a glutamine (Q), or a tryptophan (W). Interestingly, hypoPP is caused by both mutations affecting nearby codons as well as the change of an arginine into another amino acid. Conclusion: A potassium-sensitive and normokalemic type of periodic paralysis caused by new SCN4A mutations at codon 675 is reported.

Meningovascular form of neuroborreliosis: similarities between neuropathological findings in a case of Lyme disease and those occurring in tertiary neurosyphilis

SummaryRecent observations have delineated the neurological manifestations of Lyme disease, but, to our knowledge, no detailed neuropathological study from autopsy cases has been reported. In this report we describe the neuropathological findings in a case of Lyme neuroborreliosis. The chronic meningitis, the occlusive meningo vascular and secondary parenchymal changes that we found are similar to those occurring in the meningovascular form of neurosyphilis. Thus, we suggest that the case described here represents the meningovascular form of tertiary Lyme neuroborreliosis.