Assessment of autonomic innervation of the foot in familial amyloid polyneuropathy.

BACKGROUND AND PURPOSE: Distal involvement of autonomic nerve fibers is critical in familial amyloid polyneuropathy (FAP) due to transthyretin (TTR) mutation. This study compares different methods for assessing autonomic foot innervation in TTR-FAP patients. METHODS: Three groups of seven TTR-FAP patients were included, according to disease severity: clinically asymptomatic, moderate or advanced neuropathy. The autonomic investigation included the eutectic mixture of local anesthetics test and laser Doppler flowmetry for vasomotor aspects and the Sudoscan® (measuring electrochemical skin conductance) and Neuropad® test for sudomotor aspects. Somatic innervation was assessed by performing nerve conduction studies, quantitative sensory testing [including vibration, cold and warm detection threshold (WDT) measurements] and laser evoked potentials. RESULTS: The results of all neurophysiological tests varied according to TTR-FAP severity (P ≤ 0.01, Kruskal-Wallis test), except for the eutectic mixture of local anesthetics test and laser Doppler flowmetry variables. In addition, the sudomotor tests (Sudoscan or Neuropad) or WDT measurement provided early markers of neuropathy in two of the seven asymptomatic carriers. Finally, all neurophysiological results correlated with the Neuropathy Impairment Score (r values between -0.88 and -0.66, P < 0.005, Spearman test), except the cold detection threshold. CONCLUSIONS: The Neuropad test could be used to detect TTR-FAP onset, but confirmation requires electrochemical skin conductance and WDT measurement. The Sudoscan technique, but not the Neuropad test (at least assessed at a fixed time point), could be valuable to follow the progression of the neuropathy. Follow-up investigation should also include large-fiber investigation (e.g. nerve conduction studies and vibration detection threshold). Conversely, reliable tests for assessing vasomotor disturbances in limb extremities of TTR-FAP patients are still awaited.

Diagnosis of small fiber neuropathy: A comparative study of five neurophysiological tests.

The diagnosis of small fiber neuropathy (SFN) is a challenge for clinical neurophysiology. Conventional nerve conduction studies are inappropriate for this purpose and therefore various neurophysiological tests have been proposed. In this study, we compared the diagnostic value of five of these tests in 87 patients with clinically definite (n=33) or possible (n=54) SFN related to amyloid neuropathy secondary to transthyretin gene mutation or monoclonal gammopathy (n=30), primary Sjögren's syndrome (n=20), Fabry's disease (n=2), or unknown cause (n=35). Neurophysiological tests included quantitative sensory testing with determination of warm and cold detection thresholds (WDT, CDT), recording of laser-evoked potentials (LEP) and sympathetic skin responses (SSRs), and measurement of electrochemical skin conductance (ESC) using Sudoscan(®) device. All tests were performed at the four extremities (hands and feet). All patients with clinically definite SFN and 70% of the patients with possible SFN had at least one abnormal test. The LEP was the most sensitive test (altered in 79% of the patients with at least one abnormal test), followed by ESC (61%), WDT (55%), SSR (41%), and CDT (32%). The combination of LEP, assessing A-delta sensory fibers, WDT, assessing sensory C fibers, and ESC, assessing autonomic C fibers, appears a relevant approach for the diagnosis of SFN. Compared to SSR and CDT, these three tests, LEP, WDT, and ESC, had a significantly better diagnostic sensitivity and their combination further improved diagnostic accuracy.

Analysis of tremor in multiple sclerosis using Hilbert-Huang Transform.

Tremor is frequently described in patients with multiple sclerosis (MS) but remains poorly characterized using neurophysiological techniques. Accelerometric (ACC) and electromyographic (EMG) recordings were performed in 26 MS patients complaining of clumsiness, associated (n = 16) or not associated (n = 10) with visible tremor. Seventeen healthy subjects with physiological tremor (PT) and eight patients with essential tremor (ET) served as controls. Signals were analyzed using non-linear Empirical Mode Decomposition (EMD) and related Hilbert-Huang Transform (HHT), compared to the standard linear spectral analysis using Fast Fourier Transform (FFT). The presence of cerebellar signs and motor deficit was assessed on clinical examination. Using FFT, tremor was found in all patients with ET and 12% of subjects with PT, but in none of the MS patients, even in the presence of visible tremor. In contrast, EMD-HHT analysis of ACC-EMG coupling showed common frequency peaks characterizing tremor related to a central generator in 62.5% of MS patients with visible tremor, 40% of MS patients without visible tremor, 29% of subjects with PT, and all patients with ET. In EMD-HHT analysis, tremor characteristics were similar in subjects with PT and MS patients, regardless of the presence of a visible tremor, but these characteristics clearly differed in patients with ET. A visible tremor in MS patients was associated with more frequent cerebellar signs and less motor deficit at the upper limb. The low-frequency tremor observed in MS patients could therefore originate in lesions of the brainstem (midbrain) or cerebellothalamic circuits, or may correspond to an enhanced PT, partly favored by cerebellar dysfunction and being more visible during movement execution in the absence of concomitant motor deficit.

Relapses in multiple sclerosis: effects of high-dose steroids on cortical excitability.

BACKGROUND AND PURPOSE: High-dose steroid administration is the usual treatment of multiple sclerosis (MS) relapse, but it remains to determine whether this treatment may act by changing the excitability of cortical circuitry. METHODS: The functional cortical effects of high-dose steroids in 21 MS patients before and after 3 days of intravenous administration of methylprednisolone (1 g/day) for the treatment of MS relapse were studied. Investigations included various clinical scales [Kurtzke Functional System Scale (KFSS), Expanded Disability Status Scale and Fatigue Severity Scale, 10-m walk] and transcranial magnetic stimulation (TMS) tests of cortical excitability [resting motor threshold, recruitment curve of motor evoked potentials, short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) at various interstimuli intervals (ISIs), cortical silent period and interhemispheric inhibition]. RESULTS: Following steroid administration, clinical improvement was significant for the KFSS pyramidal (motor) and total scores, whilst TMS showed a reduction of SICI (mean and maximum values) and an increase of ICF at 10 ms ISI. CONCLUSIONS: Very rapid functional changes in the excitability of cortical circuits involved in motor control can be induced by steroids, before any process of remyelination or axonal regeneration has time to occur. The net effect of steroids on the balance between intracortical GABAergic inhibition and glutamatergic facilitation was in favour of weaker inhibition or stronger facilitation, which could lead to improving the motor performance in MS patients.

Definition of DLPFC and M1 according to anatomical landmarks for navigated brain stimulation: inter-rater reliability, accuracy, and influence of gender and age.

The optimization of the targeting of a defined cortical region is a challenge in the current practice of transcranial magnetic stimulation (TMS). The dorsolateral prefrontal cortex (DLPFC) and the primary motor cortex (M1) are among the most usual TMS targets, particularly in its "therapeutic" application. This study describes a practical algorithm to determine the anatomical location of the DLPFC and M1 using a three-dimensional (3D) brain reconstruction provided by a TMS-dedicated navigation system from individual magnetic resonance imaging (MRI) data. The coordinates of the right and left DLPFC and M1 were determined in 50 normal brains (100 hemispheres) by five different investigators using a standardized procedure. Inter-rater reliability was good, with 95% limits of agreement ranging between 7 and 16 mm for the different coordinates. As expressed in the Talairach space and compared with anatomical or imaging data from the literature, the coordinates of the DLPFC defined by our algorithm corresponded to the junction between BA9 and BA46, while M1 coordinates corresponded to the posterior border of hand representation. Finally, we found an influence of gender and possibly of age on some coordinates on both rostrocaudal and dorsoventral axes. Our algorithm only requires a short training and can be used to provide a reliable targeting of DLPFC and M1 between various TMS investigators. This method, based on an image-guided navigation system using individual MRI data, should be helpful to a variety of TMS studies, especially to standardize the procedure of stimulation in multicenter "therapeutic" studies.

Analgesic effects of repetitive transcranial magnetic stimulation of the motor cortex in neuropathic pain: influence of theta burst stimulation priming.

BACKGROUND: 'Conventional' protocols of high-frequency repetitive transcranial magnetic stimulation (rTMS) delivered to M1 can produce analgesia. Theta burst stimulation (TBS), a novel rTMS paradigm, is thought to produce greater changes in M1 excitability than 'conventional' protocols. After a preliminary experiment showing no analgesic effect of continuous or intermittent TBS trains (cTBS or iTBS) delivered to M1 as single procedures, we used TBS to prime a subsequent session of 'conventional' 10 Hz-rTMS. METHODS: In 14 patients with chronic refractory neuropathic pain, navigated rTMS was targeted over M1 hand region, contralateral to painful side. Analgesic effects were daily assessed on a visual analogue scale for the week after each 10 Hz-rTMS session, preceded or not by TBS priming. In an additional experiment, the effects on cortical excitability parameters provided by single- and paired-pulse TMS paradigms were studied. RESULTS: Pain level was reduced after any type of rTMS procedure compared to baseline, but iTBS priming produced greater analgesia than the other protocols. Regarding motor cortex excitability changes, the analgesic effects were associated with an increase in intracortical inhibition, whatever the type of stimulation, primed or non-primed. CONCLUSIONS: The present results show that the analgesic effects of 'conventional' 10 Hz-rTMS delivered to M1 can be enhanced by TBS priming, at least using iTBS. Interestingly, the application of cTBS and iTBS did not produce opposite modulations, unlike previously reported in other systems. It remains to be determined whether the interest of TBS priming is to generate a simple additive effect or a more specific process of cortical plasticity.

[French guidelines on the use of repetitive transcranial magnetic stimulation (rTMS): safety and therapeutic indications]. / Recommandations françaises sur l'utilisation de la stimulation magnétique transcrânienne répétitive (rTMS) : règles de sécurité et indications thérapeutiques.

During the past decade, a large amount of work on transcranial magnetic stimulation (TMS) has been performed, including the development of new paradigms of stimulation, the integration of imaging data, and the coupling of TMS techniques with electroencephalography or neuroimaging. These accumulating data being difficult to synthesize, several French scientific societies commissioned a group of experts to conduct a comprehensive review of the literature on TMS. This text contains all the consensual findings of the expert group on the mechanisms of action, safety rules and indications of TMS, including repetitive TMS (rTMS). TMS sessions have been conducted in thousands of healthy subjects or patients with various neurological or psychiatric diseases, allowing a better assessment of risks associated with this technique. The number of reported side effects is extremely low, the most serious complication being the occurrence of seizures. In most reported seizures, the stimulation parameters did not follow the previously published recommendations (Wassermann, 1998) [430] and rTMS was associated to medication that could lower the seizure threshold. Recommendations on the safe use of TMS / rTMS were recently updated (Rossi et al., 2009) [348], establishing new limits for stimulation parameters and fixing the contraindications. The recommendations we propose regarding safety are largely based on this previous report with some modifications. By contrast, the issue of therapeutic indications of rTMS has never been addressed before, the present work being the first attempt of a synthesis and expert consensus on this topic. The use of TMS/rTMS is discussed in the context of chronic pain, movement disorders, stroke, epilepsy, tinnitus and psychiatric disorders. There is already a sufficient level of evidence of published data to retain a therapeutic indication of rTMS in clinical practice (grade A) in chronic neuropathic pain, major depressive episodes, and auditory hallucinations. The number of therapeutic indications of rTMS is expected to increase in coming years, in parallel with the optimisation of stimulation parameters.

Cloning and sequencing of a phenol hydroxylase gene of Pseudomonas pseudoalcaligenes strain MH1: a bacterium able to mineralize various aromatic compounds.

The phenol-degrading strain Pseudomonas pseudoalcaligenes MH1, identified by the rRNA approach, was isolated from wastewater enrichment culture. It utilized phenol up to 1.5 g/L as the sole source of carbon and energy. In addition, cresols (o-, m-, p-), 4-hydroxybenzoic acid, syringic acid, and vanillic acid were metabolized as sole substrates by phenol-grown cells of strain MH1. Using primers, designed on the basis of the sequence of the dmp operon of P. putida strain CF600, a gene encoding phenol hydroxylase, which catalyzes the hydroxylation of phenol to catechol, was detected in strain MH1. The whole phenol hydroxylase operon of strain MH1 was amplified in a polymerase chain reaction fragment of 5.207 kb that was cloned and sequenced. The total sequence revealed a cluster of six ATG starting open reading frames (ORFs). Analysis of the regulatory signals showed a putative promoter region, 40 bp upstream from the transcriptional start of ORF1, which have a strong homology to a set of positively controlled promoters. Comparison of the MH1 phenol hydroxylase gene sequence with those of other Pseudomonas strains revealed higher homology except in the 5' region. Thus, the deduced amino acid sequence of the first subunit of phenol hydroxylase of P. pseudoalcaligenes strain MH1 exhibited a difference at the N-terminal region (the first 10 amino acids) compared with that of known phenol hydroxylase of Pseudomonas strains.