Hirayama disease: three cases.

Hirayama disease is a rare, lower cervical myelopathy affecting young adults. It is responsible for pure distal motor impairment of the upper limbs, with slow progressive development in the metameric territories of C7 to T1. It is thought to be caused by movements involved in flexing the neck. Neutral position magnetic resonance imaging (MRI) looks for abnormal cervical curvature, atrophy with flattening of the cervical spine, anterior cord hyperintensity and especially a lack of posterior apposition of the dural sac. If the condition is suspected, an MRI in flexion should be performed to show anterior displacement of the cord and dural sac, enlargement of the posterior epidural space, an increase in flattening of the cord and congestion of the epidural veins. These dynamic abnormalities tend to disappear after evolving for 10 years. We report two confirmed cases and a probable case of Hirayama disease and discuss its physiopathology.

Polyneuropathy associated with IgG/IgA monoclonal gammopathy: a clinical and electrophysiological study of 15 cases.

Peripheral neuropathy has been widely reported in patients with monoclonal gammopathy (MG), more frequently immunoglobulin M (IgM) or IgG than IgA. Nevertheless, it remains unclear whether this association has clinical or pathogenic relevance. In order to clarify the possible role of IgG/IgA MG in neuropathy, we studied the clinical and electrophysiological features of 15 consecutive patients with polyneuropathy and IgG/IgA-MG, and compared them to those of 40 patients with polyneuropathy associated with IgM-MG, previously reported. Nine middle-aged patients (60%) had a chronic progressive or relapsing demyelinating polyneuropathy (DP) that was clinically and electrophysiologically indistinguishable from classic chronic inflammatory demyelinating polyneuropathy (CIDP) and frequently responded to immunosuppressive treatments, both characteristics supporting a dysimmune process. Six older patients (40%) had a chronic axonal distal polyneuropathy similar to the so-called chronic cryptogenic sensory polyneuropathy: there was no clear relationship with the MG in these patients and the response to immunosuppressive treatments was poor. Several features allowed us to distinguish between polyneuropathies associated with IgG/IgA-MG (IgG/IgA-PN) considered together and polyneuropathies associated with IgM-MG (IgM-PN). In the first group, the proportion of patients with a predominantly sensory clinical picture (27%) was less than that in the second group (75%), and there were fewer changes in nerve conduction studies. In addition, we found that the nine patients with DP associated with IgG/IgA-MG (IgG/IgA-DP) differed from the 31 with DP associated with IgM-MG (IgM-DP): clinical and electrophysiological studies clearly showed that the demyelinating pattern was more heterogeneous in IgG/IgA-DP than in IgM-DP. The spectrum of polyneuropathies associated with IgG/IgA-MG is heterogeneous, including DP, which is similar to classic CIDP, and axonal polyneuropathy, in which the pathogenic role of the MG remains elusive. In addition, IgG/IgA-DP differ from IgM-DP on clinical and electrophysiological grounds, suggesting probable different physiopathological mechanisms.

Missense CACNA1A mutation causing episodic ataxia type 2.

OBJECTIVES: To characterize the nature of CACNA1A mutation in a previously unreported family with episodic ataxia type 2 (EA2) and to better delineate EA2 clinical features. BACKGROUND: Episodic ataxia type 2 is an autosomal dominant disorder characterized by the recurrence of acetazolamide-responsive spells of cerebellar ataxia, usually starting during childhood or adolescence. The mutated gene, CACNA1A, is located on chromosome 19 and encodes the alpha1A subunit voltage-dependent calcium channel. So far, most CACNA1A mutations detected in patients with EA2 have led to a truncated CACNA1A protein, whereas missense mutations cause familial hemiplegic migraine. METHODS: All 47 exons of CACNA1A were screened by a combination of single-strand conformer polymorphism and sequencing analysis. RESULTS: A CACNA1A missense mutation, Glu 1757 Lys, was identified. It was absent in 200 control chromosomes. It is predicted to result in an amino acid substitution at a highly phylogenetically conserved position, within a domain that plays a major role in the function of the channel. CONCLUSIONS: The Glu 1757 Lys missense mutation is likely to be pathogenic, causing episodic ataxia within a family whose phenotype is indistinguishable from EA2 except for a slightly later age of onset. These data strongly suggest that additional work is needed to fully establish genotype/phenotype correlations for CACNA1A mutations.

Intravenous immunoglobulin therapy in multifocal motor neuropathy: a double-blind, placebo-controlled study.

We conducted a double-blind, placebo-controlled, study of 19 patients fulfilling eligibility criteria for multifocal motor neuropathy with persistent conduction block. They were enrolled and divided into two groups: those who had never been treated previously with intravenous immunoglobulins (IVIg) (Group 1: 10 patients) and those who presented recurrent symptoms after previously successful treatment with IVIg (Group 2: nine patients). They were randomized prospectively to receive either IVIg or placebo at a dose of 500 mg/kg/day for 5 consecutive days, once a month for 3 months. At month 4, patients found to be responders remained on the same treatment for the 3 following months, while non-responders were switched to the alternative study drug for the 3 following months. Clinical assessment was conducted with the MRC score in 28 muscles and a self-evaluation scale (five daily motor activities scored from 0 to 5). In Group 1, nine patients completed the study, of whom initially four received IVIg and five placebo; four patients responded to IVIg (two at months 4 and 7, and a further two at month 7 after switching treatment at month 4), two patients responded to placebo at months 4 and 7, and three patients did not respond to either treatment. In Group 2, nine patients completed the study. Five patients first received IVIg and all responded at months 4 and 7. Four patients first received placebo and none responded at month 4; all were then switched to IVIg and three responded at month 7. When the 18 patients were considered together, seven out of the nine patients who received IVIg first were responders at month 4, compared with two of the nine patients who received placebo first, a difference that was statistically significant (P = 0.03). On the other hand, there was no significant difference in MRC score but a significant difference in the self-evaluation score, at month 4, between IVIg patients and placebo patients. Electrophysiological studies did not show significant differences at month 4 in motor parameters between IVIg patients and placebo patients. IgM anti-GM1 titres did not change significantly in patients treated with IVIg compared with those who received placebo, between baseline, month 4 and month 7. However, of five patients who had significantly high anti-GM1 titres (>3200) at baseline, four responded to IVIg. This trial confirms that IVIg is a promising therapeutic option for multifocal motor neuropathy.

[Treatment of chronic immune-mediated polyneuropathies. State of the art and perspectives]. / Traitement des neuropathies périphériques dysimmunitaires chroniques.

Chronic immune-mediated polyneuropathies encompass chronic inflammatory demyelinating polyneuropathies, polyneuropathies associated with monoclonal gammopathy and multifocal motor neuropathy with persistent conduction blocks. Their diagnosis is made on clinical, electrophysiological and sometimes immunochemical and pathological criteria. The efficacy of short-term treatments (corticosteroids, plasma exchanges, intravenous immunoglobulins) depends on the type of the polyneuropathy, but these treatments may sometimes lead to prolonged improvement. The efficacy of long-term treatments needs further evaluation.

[What's new in primary lateral sclerosis?]. / Qu'en est-il de la sclérose latérale primitive ?

Primary lateral sclerosis as a nosological entity distinct from amyotrophic lateral sclerosis has been the subject of controversy since it was first described in the nineteenth century. Primary lateral sclerosis has been defined as a rare, non-hereditary disease characterized by highly progressive spinobulbar spasticity, related to the exclusive loss of precentral pyramidal neurons, with secondary pyramidal tract degeneration and preservation of anterior horn motor neurons. We carried out a study in nine patients with a diagnosis of primary lateral sclerosis. Our clinical, electrophysiological and pathological investigations provide evidence that the disease has a heterogeneous clinical presentation and that degeneration is not restricted to the central motor system but also affects the lower motor neuron. In view of this similarity with amyotrophic lateral sclerosis, primary lateral sclerosis may represent a slowly progressive syndrome closely related to motor neuron disease and amyotrophic lateral sclerosis.

Antiglycolipid antibodies in motor neuropathies.

In peripheral neuropathies with monoclonal gammopathy, mainly IgM, it appears clear from clinical, electrophysiological, and experimental data, that the target glycolipid or glycolipid epitope for the IgM is related to the type of neuropathy--purely sensory, predominantly sensory, or uniquely motor. Investigations have focused on chronic peripheral neuropathies associated with polyclonal IgM reactivity to glycolipids. Although IgM anti-GM1 antibodies are present in normal controls, there is a subgroup of motor neuropathies with high titer anti-GM1 antibodies, mainly multifocal neuropathies with conduction blocks (MMNCB). Another subgroup of MMNCB may include IgM anti-SGPG antibodies that do not cross-react with MAG. The importance of the fine structure of the epitope has to be considered in view of the pathogenicity of the antibody. It may bear consequences on its binding properties on the neuronal surfaces and on its biological implications.

Association between centromeric deletions of the SMN gene and sporadic adult-onset lower motor neuron disease.

The telomeric copy (t) of the survival motor neuron (SMN) gene is homozygously deleted in more than 90% of patients with infantile motor neuron disease (MND). In the general population, no homozygous SMNt deletion has been found, whereas 5% of centromeric SMN (SMNc) deletions can be observed. Although SMNt deletions appear causal for infantile and at least some adult-onset spinal muscular atrophy (SMA) (type IV), the respective role of SMN deletions remains unclear in adult-onset MNDs. We studied SMN gene in three different groups of patients with adult-onset MNDs. In sporadic amyotrophic lateral sclerosis (ALS; n = 177) and familial ALS (n = 66), no SMNt deletion had been found, and the frequency of SMNc deletions was not increased. Conversely, among the 14 patients with sporadic pure lower MND (LMND), we found 2 patients with homozygous SMNt deletions (14%) and 5 patients with homozygous SMNc deletions (36%). These data suggest that (1) SMNt deletions do not account for the major part, if any, of adult-onset LMND cases; and (2) SMNc deletions act as a susceptibility factor for LMNDs in adults. The clinical and genetic heterogeneity of LMND cases, including SMA type IV, are yet to be unexplained. Further studies on large groups of adult-onset LMND patients are warranted to refine its nosology.

Peripheral neuropathy associated with IgM monoclonal gammopathy: correlations between M-protein antibody activity and clinical/electrophysiological features in 40 cases.

Forty cases of polyneuropathy associated with IgM monoclonal gammopathy were retrospectively studied to investigate the relevance of clinical and electrophysiological features to M-protein antibody activity. There were 26 men and 14 women; mean age was 65 +/- 11.7 years at the time of the study. Thirty-nine patients had a symmetrical polyneuropathy, of whom 13 had a predominantly sensory and 17 a purely sensory neuropathy (i.e., 30 sensory neuropathies). The remaining patient had a multifocal mononeuropathy. Electrophysiological studies allowed the polyneuropathies to be classified as demyelinating in 33 cases (82.5%) and axonal in 6 cases. Antibody studies disclosed anti-MAG antibodies in 65% and anti-SGPG antibodies in 82.5% of patients. Anti-MAG antibodies were associated with only demyelinating polyneuropathies. Anti-SGPG antibodies were found in 91% of demyelinating polyneuropathies and 50% of axonopathies. In addition, anti-MAG/SGPG antibody activity was significantly correlated with the subgroup of sensory neuropathies (P < 0.01). Last, antisulfatide antibodies were found at significant titers in 18 cases, and their presence was significantly correlated with anti-MAG/SGPG antibody activity, but not with some clinical/electrophysiological features.

[Multifocal motor neuropathies with conduction blocks. 39 cases]. / Neuropathies motrices multifocales avec blocs de conduction. 39 cas.

Clinical, biological and electrophysiological features from a cohort of 39 multifocal motor neuropathies with conduction blocks (NMM with CB) have been studied. There were 29 males and 10 females with an average of 47.3. At the first evaluation, the mean duration of the symptoms was of 8 years with extremes between 1 and 28. Pain and paresthesias were present in respectively 10 and 18 p. 100 of the patients. Fasciculations and cramps were observed in more than 2/3 of the cases. Three patients had tremor at rest. Upper limb muscular weakness was the predominant initial symptom (84.6 p. 100). The weakness always affected distal and unilateral muscles. Radial and cubital nerve distribution are mainly affected and in half of the cases an unilateral motor deficit in the lower limb was associated. Muscle atrophy was frequent (74 p. 100) and rapidly developed in the first 2 years. Reflexes were decreased or absent in 64 p. 100. In 78 p. 100 of cases, biological study showed normal serum immunoelectrophoresis and CSF. IgM anti-GM1 antibodies were found in 24/36 patients. Very high titres were found in 5 cases. All patients had CB in upper limbs. The preferential localizations of the CB were equally at the median and ulnar nerves. Only 7 patients had CB localized to the lower limbs. In many cases, marked reduction of the motor amplitude prevented the detection of CB, marked reduction of the motor amplitude prevented the detection of CB. Moderate fibrillation potentials were found in 28 p. 100 of patients. Giant muscular unit potentials were frequent (21/39). F-waves in nerve with CB were always abnormal with marked increased latencies. Late responses sometimes seemed to be repeater F-waves. Axon reflexes were detected in 5 cases. The late responses abnormalities could precede the block. Clinical, biological and electrophysiological described arguments could may distinguish NMM with CB from motor neuron disease and relate them to the group of chronic demyelinating neuropathies.

[Sympathetic skin responses and variability of the R-R interval: correlation with the severity stages of diabetic polyneuropathy]. / Réponses cutanées sympathiques et variabilité de l'intervalle R-R: corrélations avec le stade de gravité de la polyneuropathie diabétique.

The sympathetic skin responses (SSR) and the variations of the R-R interval of the electrocardiogram (the difference between the maximum and minimum heart rates at rest, the ratio between the maximum and minimum heart rates during the Valsalva manoeuvre or Valsalva ratio, and during an active orthostatic test or orthostatic ratio) have been measured in 32 control subjects and 53 diabetic patients. These latter ones were classified according to the existence and the increasing severity of a polyneuropathy (PNP) into 4 grades (0 to III) based on Dyck's classification modified depending on the presence or the absence of cutaneous impairments in grade II. There was an important inter-individual variability for SSR as well as R-R interval results, in the control group. In the absence of PNP, the vegetative tests showed normal values. These tests were severely degraded in the diabetic patients with a PNP grade III, ov even could not be performed. The SSR amplitude was decreased in all diabetic patients. In the presence of clinical signs of dysautonomia, the SSR amplitude, the heart rate variability at rest and the orthostatic ratio were significantly different from those of the control subjects. The presence of trophic disorders appearing at PNP grade II did not significantly modify the results of the tests. Although they did not allow any differentiation of the PNP intermediary grades. SSR and R-R intervals are of interest in appreciating the infra-clinical existence and the importance of the neurovegetative disorders occurring during diabetic polyneuropathies.

Chronic dysimmune demyelinating polyneuropathy: a clinical and electrophysiological study of 93 patients.

OBJECTIVES: To identify clinical, electrophysiological, and immunological characteristics of chronic immune demyelinating polyneuropathy to define for each group the appropriate therapeutic strategies. METHODS: The clinical and electrophysiological data and the response to treatment of 93 patients with an acquired chronic dysimmune demyelinating polyneuropathy (CDDP) studied over a period of 10 years were reviewed. Two groups were identified: group 1, comprising 64 patients with an idiopathic CDDP, of whom 13 had serum monoclonal or polyclonal gammopathy without detectable antibodies directed against the "myelin associated glycoprotein" (MAG), and group 2, comprising 29 patients with an IgM monoclonal gammopathy of undetermined significance (MGUS) with antibodies binding to the MAG. RESULTS: Group 1 patients had either a progressive or relapsing course. The relapsing course had more pronounced distal slowing of motor conduction velocity. In group 1, there were no significant clinical or electrophysiological differences between patients with or without gammopathy. Patients with anti-MAG antibody (group 2) differed significantly from group 1 patients, especially on the basis of electrophysiological results. They had a more pronounced slowing of peroneal motor nerve conduction velocity, a lower frequency of conduction block, and a distal accentuation of conduction slowing, distinguishing them from those with idiopathic CDDP, Charcot-Marie-Tooth polyneuropathy type 1A, and control subjects. CONCLUSION: The idiopathic CDDP group is heterogeneous with probably different subgroups. Patients with IgM MGUS polyneuropathy and anti-MAG antibodies have characteristics which distinguish them significantly from other CDDP and suggest different immune mechanisms and responses to treatment.

[Peripheral neuropathies associated with IgM monoclonal gammopathy: clinical and electrophysiological aspects]. / Neuropathies périphériques associées à une gammapathie monoclonale IgM: aspects cliniques et électrophysiologiques.

Polyneuropathies associated with IgM monoclonal gammopathy (IgM-MG) are the most frequent type of peripheral neuropathy (PN) associated with monoclonal gammopathy. The pathogenic relevance of IgM-MG in PN is supported by several arguments, the more significants are pathological data on neuromuscular biopsies and the demonstration of IgM antibody activity to peripheral nerve antigens, mainly myelin-associated-glycoprotein (MAG) and sulfated glucuronyl paragloboside (SGPG). In addition recently reported series show that there is a significant correlation between clinical/electrophysiological data of PN, and IgM-MG antibody activity, in more than 75% of cases. Those features are in favour of an immune-mediated disease.

Partial restoration of blink reflex function after spinal accessory-facial nerve anastomosis.

Functional motor control requires perfect matching of the central connections of motoneurons with their peripheral inputs. It is not known, however, to what extent these central circuits are influenced by target muscles, either during development or after a lesion. Surgical interventions aimed at restoring function after peripheral nerve lesions provide an opportunity for studying this interaction in the mature human nervous system. A patient was studied in whom the spinal accessory nerve was anastomosed into a lesioned facial nerve, allowing voluntary contractions of the previously paralysed muscles. This procedure, in addition to replacing the facial neurons at peripheral synapses, allowed a new short latency trigeminospinal accessory reflex of the R1 blink reflex type to be demonstrated, implying that trigeminal neurons had sprouted towards spinal accessory motoneurons over a distance of at least 1 cm. These results show an unexpected influence of the periphery in remodelling central connectivity in humans. The motoneuronal excitability for this R1 reflex response was therefore studied to compare the convergent properties of facial motoneurons (normal side) with those of the spinal accessory motoneurons (operated side) using a classic double shock technique with variable interstimulus intervals (conditioning test stimulus). On the normal side, conditioning stimuli (to the ipsilateral or contralateral infraliminar supraorbital nerve) produced a clearcut facilitation of the R1 blink reflex when the interstimulus interval was 30-80 ms. By contrast, a similar procedure had no effect on the R1 blink reflex mediated via the trigeminal-spinal accessory reflex arc. These data indicate that despite the heterotopic sprouting of some axons from neurons in the XIth nucleus, motoneurons involved in the newly formed reflex arc remain totally inexcitable by other trigeminal afferents and seem unable to ensure a physiological functioning of the normal blink reflex. Thus the functional relevance of the recovered R1 blink response remains unclear.

Human immunoglobulin treatment of multifocal motor neuropathy and polyneuropathy associated with monoclonal gammopathy.

Intravenous human immune globulin (IVIg) has been proposed for the treatment of various peripheral neuropathies that are considered to be immunemediated. The results are reported of an open trial conducted in multifocal motor neuropathy and polyneuropathy associated with monoclonal gammopathy. Six cases with multifocal motor neuropathy, selected on clinical and electrophysiological criteria (four of six patients also had significantly high anti-GM1 titres), received IVIg monthly, at doses varying from 1.6 to 2.5 mg/kg, over three to 13 months. The initial response to treatment was dramatic in 3/6 cases (with improvement of at least two grades on the MRC scale in the five more severely affected muscles). The final evaluation showed a good result in 4/6 cases, but the conduction blocks were not significantly reduced. In 13 other cases with polyneuropathy associated with IgM monoclonal gammopathy of unknown significance, IVIg was of benefit, with improvement of at least one grade on the Prineas score, in 4/7 cases previously treated with immunosuppression and 2/3 cases not treated before IVIg. In the last group of four patients with polyneuropathy and IgG monoclonal gammopathy, IVIg was followed by clinical improvement in the two cases with a chronic demyelinating polyneuropathy.

[Neurological manifestations of monoclonal gammopathies]. / Manifestations neurologiques des gammapathies monoclonales.

The spectrum of peripheral neuropathy associated with monoclonal gammapathy is wide: peripheral neuropathy associated with IgM monoclonal gammapathy, in which serum antibody activity has been demonstrated against MAG (myelin-associated-glycoprotein) and SGPG, mainly presents as a chronic demyelinating sensory polyneuropathy, with predominant tremor and ataxia. Polyneuropathy reported in association with multiple myeloma or MGUS (monoclonal gammapathy of undetermined significance) IgG and IgA are more heterogenous: mainly axonal, mixed or sometimes demyelinating as in POEMS syndrome. The treatment of these polyneuropathies is evaluated in trials in progression using corticosteroids, plasma exchanges and IgIV (polyvalent immunoglobulins).