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Paresis after spinal cord injury (SCI) is caused by damage to upper and lower motoneurons (LMNs) and may differentially impact neurological recovery. This prospective monocentric longitudinal observational study investigated the extent and severity of LMN dysfunction and its impact on upper extremity motor recovery after acute cervical SCI. Pathological spontaneous activity at rest and/or increased discharge rates of motor unit action potentials recorded by needle electromyography (EMG) were taken as parameters for LMN dysfunction and its relation to the extent of myelopathy in the first available spine magnetic resonance imaging (MRI) was determined. Motor recovery was assessed by standardized neurological examination within the first four weeks (acute stage) and up to one year (chronic stage) after injury. Eighty-five muscles of 17 individuals with cervical SCI (neurological level of injury from C1 to C7) and a median age of 54 (28-59) years were examined. The results showed that muscles with signs of LMN dysfunction peaked at the lesion center (Χ2 [2, n = 85] = 6.6, p = 0.04) and that the severity of LMN dysfunction correlated with T2-weighted hyperintense MRI signal changes in routine spine MRI at the lesion site (Spearman ρ = 0.31, p = 0.01). Muscles exhibiting signs of LMN dysfunction, as indicated by pathological spontaneous activity at rest and/or increased discharge rates of motor unit action potentials, were associated with more severe paresis in both the acute and chronic stages after SCI (Spearman ρ acute = -0.22, p = 0.04 and chronic = -0.31, p = 0.004). Moreover, the severity of LMN dysfunction in the acute stage was also associated with a greater degree of paresis (Spearman ρ acute = -0.24, p = 0.03 and chronic = -0.35, p = 0.001). While both muscles with and without signs of LMN dysfunction were capable of regaining strength over time, those without LMN dysfunctions had a higher potential to reach full strength. Muscles with signs of LMN dysfunction in the acute stage displayed increased amplitudes of motor unit action potentials with chronic-stage needle EMG, indicating reinnervation through peripheral collateral sprouting as compensatory mechanism (Χ2 [1, n = 72] = 4.3, p = 0.04). Thus, LMN dysfunction represents a relevant factor contributing to motor impairment and recovery in acute cervical SCI. Defined recovery mechanisms (peripheral reinnervation) may at least partially underlie spontaneous recovery in respective muscles. Therefore, assessment of LMN dysfunction could help refine prediction of motor recovery after SCI.

Elektromyografie (EMG) und Elektroneurografie (ENG) gelten als bewährte Methoden, deren Anfänge aber schon Jahrzehnte zurückliegen. In dieser Arbeit werden jüngere Entwicklungen beschrieben und die Rolle von EMG und ENG in wichtigen Situationen diskutiert, nämlich bei traumatische Nervenläsionen, Nervenkompressionssyndromen, Polyneuropathien, Motoneuronerkrankungen, Myopathien, neuromuskulären Transmissionsstörungen und bei muskulärer Überaktivität.

International audience; Background: Rasagiline, a monoamine oxidase B inhibitor with neuroprotective potential in Parkinson's disease, has shown a disease-modifying effect in the SOD1-Gly93Ala low-expressing mouse model of amyotrophic lateral sclerosis, both alone and in combination with riluzole. We sought to test whether or not rasagiline 1 mg/day can prolong survival in patients with amyotrophic lateral sclerosis also receiving riluzole.Methods: Patients with possible, probable, or definite amyotrophic lateral sclerosis were enrolled to our randomised, placebo-controlled, parallel-group, double-blind, phase 2 trial from 15 German network for motor neuron diseases (MND-NET) centres (university hospitals or clinics). Eligible patients were aged at least 18 years, had onset of progressive weakness within the 36 months before the study, had disease duration of more than 6 months and less than 3 years, and had a best-sitting slow vital capacity of at least 50%. After a 4-week screening period, eligible patients were randomly assigned (1:1) to receive either rasagiline (1 mg/day) or placebo in addition to riluzole (100 mg/day), after stratification for site of onset (bulbar or spinal) and study centre. Patients and all personnel assessing outcome parameters were masked to treatment allocation. Patients were followed up 2, 6, 12, and 18 months after randomisation. The primary endpoint was survival time, defined as the time to death or time to study cutoff date (ie, the last patient's last visit plus 14 days). Analyses of primary outcome and safety measures were done in all patients who received at least one dose of trial treatment (intention-to-treat population). The trial is registered with ClinicalTrials.gov, number NCT01879241.Findings: Between July 2, 2013, and Nov 11, 2014, 273 patients were screened for eligibility, and 252 patients were randomly assigned to receive rasagiline (n=127) or placebo (n=125). 126 patients taking rasagiline and 125 taking placebo were included in the intention-to-treat analysis. For the primary outcome, the survival probability at the end of the study was 0·43 (95% CI 0·25-0·59) in the rasagiline group (n=126) and 0·53 (0·43-0·62) in the placebo group (n=125). The estimated effect size (hazard ratio) was 0·91 (one-sided 97·5% CI -infinity to 1·34; p=0·31). Rasagiline was well tolerated, and most adverse events were due to amyotrophic lateral sclerosis disease progression rather than treatment; the most frequent of these were dysphagia (32 [25%] taking rasagiline vs 24 [19%] taking placebo) and respiratory failure (25 [20%] vs 31 [25%]). Frequency of adverse events were comparable between both groups.Interpretation: Rasagiline was safe in patients with amyotrophic lateral sclerosis. There was no difference between groups in the primary outcome of survival, although post-hoc analysis suggested that rasagiline might modify disease progression in patients with an initial slope of Amyotrophic Lateral Sclerosis Functional Rating Scale Revised greater than 0·5 points per month at baseline. This should be confirmed in another clinical trial.Funding: Teva Pharmaceutical Industries.

Objective: Developing an integrative approach to early treatment response classification using survival modeling and bioinformatics with various biomarkers for early assessment of filgrastim (granulocyte colony stimulating factor) treatment effects in amyotrophic lateral sclerosis (ALS) patients. Filgrastim, a hematopoietic growth factor with excellent safety, routinely applied in oncology and stem cell mobilization, had shown preliminary efficacy in ALS. Methods: We conducted individualized long-term filgrastim treatment in 36 ALS patients. The PRO-ACT database, with outcome data from 23 international clinical ALS trials, served as historical control and mathematical reference for survival modeling. Imaging data as well as cytokine and cellular data from stem cell analysis were processed as biomarkers in a non-linear principal component analysis (NLPCA) to identify individual response. Results: Cox proportional hazard and matched-pair analyses revealed a significant survival benefit for filgrastim-treated patients over PRO-ACT comparators. We generated a model for survival estimation based on patients in the PRO-ACT database and then applied the model to filgrastim-treated patients. Model-identified filgrastim responders displayed less functional decline and impressively longer survival than non-responders. Multimodal biomarkers were then analyzed by PCA in the context of model-defined treatment response, allowing identification of subsequent treatment response as early as within 3 months of therapy. Strong treatment response with a median survival of 3.8 years after start of therapy was associated with younger age, increased hematopoietic stem cell mobilization, less aggressive inflammatory cytokine plasma profiles, and preserved pattern of fractional anisotropy as determined by magnetic resonance diffusion tensor imaging (DTI-MRI). Conclusion: Long-term filgrastim is safe, is well-tolerated, and has significant positive effects on disease progression and survival in a small cohort of ALS patients. Developing and applying a model-based biomarker response classification allows use of multimodal biomarker patterns in full potential. This can identify strong individual treatment responders (here: filgrastim) at a very early stage of therapy and may pave the way to an effective individualized treatment option.

ZusammenfassungDie Transthyretin-Amyloidose (ATTR-Amyloidose) ist eine seltene, rasch verlaufende neurodegenerative Erkrankung, verursacht durch Mutationen im Transthyretin-Gen. Aufgrund der Seltenheit ist sie wenig bekannt mit der Folge, dass die Diagnose in vielen Fällen nicht oder für eine effektive Therapie zu spät gestellt wird. Therapeutisch steht seit Anfang der 1990er-Jahre die Lebertransplantation zur Verfügung, seit 2011 der oral einzunehmende Transthyretinstabilisator Tafamidis. Weitere Substanzen sind in der klinischen Prüfung oder stehen vor der Zulassung. Hierzu zählen die gentherapeutischen Substanzen Inotersen und Patisiran, die auf dem Boden der RNA-Interferenz wirken, für die Behandlung der Polyneuropathie und Tafamidis zur Behandlung der Kardiomyopathie bei ATTR-Amyloidosen. Die vorliegende Arbeit deutschsprachiger Experten gibt Empfehlungen zu Diagnostik, Management und Therapie von ATTR-Amyloidosen und soll helfen, diese erbliche, heute aber gut behandelbare, Erkrankung einem weiteren Kreis von Ärzten bekannt zu machen.

ZusammenfassungDie Anzahl funktionstüchtiger motorischer Einheiten stellt nach wie vor das ideale Maß zur Verlaufsbeurteilung bei Erkrankungen mit Verlust motorischer Einheiten dar. Die absolute Zahl motorischer Einheiten (ZME) sowie deren Verlauf über die Zeit erlauben neben der Beschreibung des Krankheitsverlaufes Aussagen über Regenerationsmechanismen wie Reinnervation durch kollaterale Aussprossung oder Reinnervation durch Axonwachstum. Eine exakte Bestimmung der Zahl motorischer Einheiten ist leider auch heute nicht möglich, eine Schätzung funktionstüchtiger motorischer Einheiten hingegen mit elektrophysiologischen Methoden durchführbar. Der apparative und zeitliche Aufwand älterer Methoden zur Schätzung der Anzahl motorischer Einheiten ist außerordentlich hoch und bedarf spezieller Untersucher-Erfahrung. Die 2004 erstbeschriebene Methode MUNIX hingegen ist einfach durchführbar und deutlich weniger zeitaufwendig. MUNIX eignet sich hervorragend zur Verlaufsbeurteilung der ZME bei bekanntem Verlust motorischer Einheiten. Neue Untersuchungen hingegen zeigen, dass MUNIX als diagnostische Methode per se ungeeignet ist.

Introduction: Neurographic data on Wallerian degeneration (WD) following motor nerve injury are available only from animal studies and from human case reports of 9 patients altogether. A precise knowledge of neurographic features of WD would be highly relevant for diagnostic, prognostic, therapeutic, and forensic aspects of traumatic lesions. Methods: We prospectively studied WD in patients with a peripheral nerve injury. They underwent sequential neurographic examinations beginning no later than 3 days after the injury until a plateau of the amplitude of compound muscle action potential was reached. Results: We examined 20 injured nerves from 16 patients. Four days after injury, all nerves showed amplitude decay to some extent while 85% had reached their plateau at day 8. A length dependency of WD could be demonstrated. Conclusion: In humans, WD starts no later than day 4, shows length dependency and is finished at day 8 in most nerves. This article is protected by copyright. All rights reserved.

Objective: Electroneurography has been an essential method for assessing peripheral nerve disorders for decades. During this procedure, a nerve is briefly electrically excited, and nerve conduction properties are identified by indirect means from the behavior of the innervated muscle. The magnetic field of the resulting muscle response can also be recorded by novel, uncooled magnetometers, which have become very attractive for different medical applications over recent years. These highly sensitive magnetometers are called optically pumped magnetometers. Methods: We performed unaveraged and averaged magnetic signal detection of electrically evoked muscle responses using optically pumped magnetometers. We then discussed the suitability of this procedure for clinical applications in the context of diagnostic value and in direct comparison with the current electrical gold standard. Results: The magnetic detection of muscle responses is possible using optically pumped magnetometers. Our magnetic results (averaged and unaveraged) closely match those from electrical measurements. Conclusion: Optically pumped magnetometers provide an alternative, contactless technology for electrode-based motor studies, but they are currently not ready for routine clinical use. This costly technology requires additional earth magnetic shielding because this is a prerequisite for proper operation. Currently, there are no diagnostic advantages over electrical measurements. Additionally, the required measurement setup and procedure are much more complicated. Significance: In contrast to already published proof-of-principle studies for magnetomyography, we report in detail the results of the magnetic measurements of electrically evoked muscle responses in a shielded environment by applying supramaximal stimulation and finally validate our findings with electroneurography data as a reference.

Objective: Electroneurography is a well-established diagnostic test for supporting the diagnosis of disorders of myelinated peripheral nerves. Neurophysiological quantities are automatically calculated and are used to determine the pathology of the nerve (axonal damage) or its sheath (myelin damage). Specific differential diagnostic criteria are derived from time-domain normative data, which result primarily from a computer simulation in the early 1990s based on animal data, namely rats. However, the rat signals studied differ significantly from those of humans because of anatomical differences. Methods: We present a model-based simulation of nerve conduction in healthy and pathological motor nerves. In contrast to earlier simulations, the present model is based on motor unit action potentials extracted from real human measurements facilitating the generation of realistic signals, starting from a conduction velocity distribution. In addition to the modeling of healthy nerves, we model a hereditary peripheral nerve disease as well as an acute and a chronic inflammatory demyelinating condition. Results: Quantitative signal differences based on standard variables in the time-domain are presented. The findings for the demyelinating conditions demonstrate amplitude reductions of 71% and 65% between the distal and proximal responses, which result from an increase in the variance of the nerve fiber conduction velocities. Conclusion: The simulation results closely match those of empirical measurements, indicating that the signal model captures relevant pathological mechanisms. An amplitude reduction of more than 50% in demyelinating conditions is in accordance with routine measurements and shows that temporal dispersion is quite well-modeled compared to previous simulation models. Significance: The simulation outcomes can serve as the basis for an improved pathophysiological understanding of peripheral nerve disorders and should aid neurophysiologists to refine their diagnostic armamentarium resulting in a more precise differential diagnosis.

Introduction: This prospectively designed study analyzed the correlation of a new, non-invasive neurophysiological method (Motor Unit Number Index – MUNIX) with two established Motor Unit Number Estimation (MUNE) methods. Methods: MUNIX and incremental stimulation MUNE (IS-MUNE) were done in the abductor digiti minimi muscle (ADM), while MUNIX and spike-triggered averaging MUNE (STA-MUNE) were tested in the trapezius muscle. Twenty healthy subjects and 17 patients with amyotrophic lateral sclerosis (ALS) were examined. Results: MUNIX and MUNE values correlated significantly (ADM: n =108; Spearman-Rho; r =0.88; p n =49; Spearman-Rho; r =0.46; p Discussion: MUNIX indeed reflects the number of motor units in a muscle, and may sensibly be recorded from the trapezius muscle. With MUNIX being both much more patient friendly and much more rapid to assess than MUNE, the results support the use of MUNIX when motor unit number assessment is desired.

ZusammenfassungTrotz des Vordringens der Bildgebung und der enormen Fortschritte der molekulargenetischen Diagnostik hat die Elektromyografie mit der (konzentrischen) Nadelelektrode einen festen Stellenwert in der Diagnostik und Differenzialdiagnostik neuromuskulärer Erkrankungen. Dies gilt insbesondere für die Frühdiagnostik (z. B. ALS, axonale PNP), den Nachweis einer axonalen Schädigung, von myotonen Serien, die Diagnostik von Myopathien, die zeitliche Zuordnung neurogener Schädigungen, die Differenzierung peripherer vs. zentraler Parese, und die frühzeitige Erfassung einer Reinnervation.

ZusammenfassungBildgebende Verfahren machen der Elektroneurografie scheinbar Konkurrenz, scheinen sie manchenorts in den Hintergrund zu verdrängen. Dies ist zum Schaden der Patienten, da beide Methoden einander vortrefflich ergänzen. Besonders hilfreich ist die Elektroneurografie auch „heute noch“ zum Nachweis und zur Lokalisation von neurogenen Prozessen oder Nervenverletzungen, Nachweis von Demyelinisierung, bei der Ermittlung der Art einer Nervenläsion, Beurteilung des zeitlichen Verlaufs nach einer Nervenläsion, Objektivierung von Läsionen, Diagnostik neuromuskulärer Transmissionsstörungen.

Zusammenfassung Die „ALS Ice Bucket Challenge“ hat das Interesse weiter Kreise an der Krankheit Amyotrophe Lateralsklerose (ALS) geweckt. Dieser Beitrag will Fragen zur ALS beantworten, namlich: Was ist ALS? Wie verlauft ALS? Wer bekommt ALS? Wie haufig ist ALS? Wie wird ALS diagnostiziert? Welche ahnlichen Erkrankungen gibt es? Wie wird ALS behandelt?

Background Adult and pediatric patients suffering from MuSK (muscle-specific kinase) -antibody positive myasthenia gravis exhibit similar features to individuals with acetylcholine receptor (AChR) antibodies, but they differ in several characteristics such as a predominant bulbar, respiratory and neck weakness, a generally worse disease severity and a tendency to develop muscle atrophy. Muscle atrophy is a rare phenomenon that is usually restricted to the facial muscles. Results We describe a girl with MuSK-antibody positive myasthenia gravis who developed a myopathy with severe generalized muscular weakness, muscle atrophy, and myopathic changes on electromyography. Conclusion This is the first published example of a generalized myopathic syndrome in myasthenia gravis. We review the relevant literature and discuss the hypothesis of a mitochondrial myopathy as a pathogenic mechanism in MuSK-antibody positive myasthenia gravis.

Periphere Nervenubererregbarkeitssyndrome sind seltene Erkrankungen die sich je nach Schweregrad und Auspragung durch verschiedene klinische und elektrophysiologische Befunde auszeichnen. Bei dem Krampf-Faszikulationssyndrom (KFS) finden sich entsprechend Muskelkrampfe und Faszikulationen, die sich auch elektromyografisch nachweisen lassen. Die Neuromyotonie (NMT) ist klinisch durch Muskelkrampfe, Muskelzuckungen, Myokymien, verzogerte Muskelrelaxation, Parasthesien und vermehrtes Schwitzen gekennzeichnet und elektromyografisch finden sich neben Doublets, Triplets und Multiplets die charakteristischen hochfrequenten neuromyotonen Entladungen. Das Morvan Syndrom erweitert die Neuromyotonie um Dysautonomie, Veranderungen der Kognition und des Verhaltens. Autoantikorper, die nicht gegen die VGKC selbst gerichtet sind, sondern gegen Proteine, die mit den VGKC einen Komplex bilden (Contactin-2, CASPR-2 und LGI-1) finden sich in bis zu 25% beim KFS, in bis zu 50% bei der NMT und bis zu 90% beim Morvan Syndrom. NMT und Morvan Syndrom kommen als paraneoplastische Syndrome vor, vor allem assoziiert mit Thymom oder kleinzelligem Bronchuskarzinom. Bei paraneoplastischen Formen kann die Behandlung des Tumors zu Besserungen der neuromyotonen Symptome fuhren. Zur symptomatischen Behandlung werden Na-Kanal Blocker wie z. B. Carbamazepin eingesetzt, zur Behandlung autoimmuner Formen intravenose Immunglobuline oder Plasmapharese.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neuronal disease resulting in a loss of the upper and lower motor neurons and subsequent death within three to four years after diagnosis. Mouse models and preliminary human exposure data suggest that the treatment with granulocyte-colony stimulating factor (G-CSF) has neuro-protective effects and may delay ALS progression. As data on long-term administration of G-CSF in patients with normal bone marrow (BM) function are scarce, we initiated a compassionate use program including 6 ALS patients with monthly G-CSF treatment cycles. Here we demonstrate that G-CSF injection was safe and feasible throughout our observation period up to three years. Significant decrease of mobilization efficiency occurred in one patient and a loss of immature erythroid progenitors was observed in all six patients. These data imply that follow-up studies analyzing BM function during long-term G-CSF stimulation are required.

A 49-year-old man with no significant medical history was seen by a neurologic consultant in eastern Bavaria, Germany, after he developed weakness of both arms. A few days earlier he had been referred to the internal medicine department with flu-like symptoms lasting for 2 weeks, which improved only transiently with trimethoprim/sulfamethoxazole for suspected urinary tract infection. The neurologic examination revealed an alert and oriented patient who was febrile (39.8°C, 103.6°F) but without meningeal signs or headache. He had normal cranial nerves and weakness of the shoulder girdle and both proximal arms. He had no sensory deficits, was hyporeflexic, and had flexor plantar responses. Gait was unsteady. Bladder function was reportedly normal. The patient was a passionate mushroom hunter and had no sick contacts. The authors thank the patient, Dr. G. Schuierer for providing the MRI, and Dr. L. Walter for comments on the manuscript.

Objective Clinical electroneurography, the diagnostic standard for the assessment of thickly myelinated peripheral nerves, is of limited spatial resolution since it provides only average data (nerve conduction velocity [NCV], nerve or muscle action potential amplitude) on relatively large nerve segments. Accordingly, different distribution patterns of axonal or myelin pathologies cannot be distinguished. But precisely this is relevant to ensure correct diagnosis and therapies. These can pose a relevant burden on the patient ranging from spontaneous recovery over surgical to medical, partly highly expensive, treatment. Hence, our main objective is to optimize the diagnostic specificity via a multichannel neurographical approach. By adding ultrasound data, a functional-structural model can be developed as a novel basis for medical decision making. Methods Based on ultrasound, eight electrodes are positioned along the course of the median and ulnar nerve, respectively, and nerve depth (distance to skin) profiles are recorded. Bipolar direct current stimulation is applied close to the M. abductor pollicis brevis and the M. abductor digiti minimi, resulting in the excitation of both motor and sensory nerve fibers (mixed nerve technique) ( Buschbacher, 1999 ) such that eight mixed nerve action potentials (NAPs) can be recorded along the nerve. We performed reference measurements in 10 healthy volunteers. Results Median nerve depth ranged from 2 to 23 mm, and we recorded reproducible signals at all locations with a maximum of 8 averages (at 20 mm) in good correspondence with previously published values ( Fig. 1 ) ( Watson et al., 2002 ). Fig. 2 reports the (inverse) relationship between NAP amplitudes and depth. Discussion Using the setup described, we reliably obtain NAP and their latencies of two peripheral nerves along their course with slight or no averaging. The interesting question is, if and how different pathologies influence the amplitude level. The next step will be the assessment of nerve pathologies to test that diagnostic and therapeutic decision making benefits from structural-functional nerve mapping with high spatial resolution.

5. Cox JJ, Sheynin J, Shorer Z, Reimann F, Nicholas AK, Zubovic L,et al. Congenital insensitivity to pain: novel SCN9A missense andin-frame deletion mutations. Hum Mutat 2010;31:E1670–1686.6. Drenth JP, Waxman SG. Mutations in sodium-channel gene SCN9Acause a spectrum of human genetic pain disorders. J Clin Invest2007;117:3603–3609.7. Han C, Hoeijmakers JG, Ahn HS, Zhao P, Shah P, Lauria G, et al.Nav1.7-related small fiber neuropathy: impaired slow-inactivation andDRG neuron hyperexcitability. Neurology 2012;78:1635–1643.8. Han C, Dib-Hajj SD, Lin Z, Li Y, Eastman EM, Tyrrell L, et al. Early-and late-onset inherited erythromelalgia: genotype–phenotype corre-lation. Brain 2009;132:1711–1722.9. Ahn HS, Dib-Hajj SD, Cox JJ, Tyrrell L, Elmslie FV, Clarke AA, et al.A new Nav1.7 sodium channel mutation I234T in a child with severepain. Eur J Pain 2010;14:944–950.10. Estacion M, Dib-Hajj SD, Benke PJ, Te Morsche RH, Eastman EM,Macala LJ, et al. NaV1.7 gain-of-function mutations as a continuum:A1632E displays physiological changes associated with erythromelal-gia and paroxysmal extreme pain disorder mutations and producessymptoms of both disorders. J Neurosci 2008;28:11079–11088.11. Fukuoka T, Noguchi K. Comparative study of voltage-gated sodiumchannel alpha-subunits in non-overlapping four neuronal popula-tions in the rat dorsal root ganglion. Neurosci Res 2011;70:164–171.12. Cook-Norris RH, Tollefson MM, Cruz-Inigo AE, Sandroni P, DavisMD, Davis DM. Pediatric erythromelalgia: a retrospective review of 32cases evaluated at Mayo Clinic over a 37-year period. J Am Acad Der-matol 2012;66:416–423.13. Rossignol E, Mathieu J, Thiffault I, Tetreault M, Dicaire MJ,Chrestian N, et al. A novel founder SCN4A mutation causes painfulcold-induced myotonia in French-Canadians. Neurology 2007;69:1937–1941.14. Morinville A, Fundin B, Meury L, Jureus A, Sandberg K, Krupp J,et al. Distribution of the voltage-gated sodium channel Na(v)1.7 inthe rat: expression in the autonomic and endocrine systems. J CompNeurol 2007;504:680–689.15. Segerdahl AR, Xie J, Paterson K, Ramirez JD, Tracey I, Bennett DL.Imaging the neural correlates of neuropathic pain and pleasurablerelief associated with inherited erythromelalgia in a single subjectwith quantitative arterial spin labelling. Pain 2012;53:1122–1127.

Neurographic data on Wallerian degeneration (WD) after motor nerve injury are available only from animal studies and human case reports of 9 patients altogether. A precise knowledge of neurographic features of WD would be highly relevant for diagnostic, prognostic, therapeutic, and forensic aspects of traumatic lesions.We prospectively studied WD in patients with a peripheral nerve injury. They underwent sequential neurographic examinations beginning no later than 3 days after the injury until a plateau of the amplitude of compound muscle action potential was reached.We examined 20 injured nerves from 16 patients. Four days after injury, all nerves showed amplitude decay to some extent, whereas 85% had reached their plateau at day 8. A length dependency of WD could be demonstrated.In humans, WD starts no later than day 4, shows length dependency, and is completed at day 8 in most nerves. Muscle Nerve 56: 247-252, 2017.

A 67-year-old man was admitted to the medical intensive care unit at a hospital in eastern Bavaria. The patient presented with back pain, fever (38.7°C, 101.7°F), disorientation regarding time, place, and his own identity, and drowsiness, all of which had developed in recent weeks. Apart from these findings, the neurologic examination was unremarkable. One day before admission, the patient had been placed on an IV broad-spectrum antibiotic regimen of ceftriaxone and combined piperacillin and tazobactam in response to increased infection parameters. In addition to the man's febrile temperature, his leukocyte count was elevated to 12,500/μL; however, examinations of urea, electrolytes, blood sugar, and liver and thyroid functions yielded unremarkable findings. In the absence of a specific focus from the internal medicine perspective, the possibility of meningoencephalitis was considered. A cranial CT study detected diffuse subarachnoid pneumocephalus with generalized accumulation of gas in the cranial cavities (figure 1). There was no recognizable point of entry for the gas.

Objective Demyelination may cause a uniform reduction of the conduction velocity of all fibres of a peripheral nerve segment, or may affect only certain nerve fibres in a non-uniform way while sparing others. This study was done to improve the detection of non-uniform conduction slowing by using the high-frequency attenuation (HFA) method. Methods Nerve conduction data from patients with early inflammatory demyelinating neuropathy (non-uniform demyelination, n=20), hereditary neuropathy (uniform demyelination, n=9), motor neuron disease (axon loss, n=20), and from healthy control subjects (n=20) were analysed. Results HFA, compound muscle action potential (CMAP) amplitude decay, and F-wave chronodispersion correlated significantly. Among these variables both HFA and amplitude decay most sensitively identified non-uniform demyelination (35%). In the patients with uniform demyelination, the most frequent finding was a reduced nerve conduction velocity (NCV) (100%). The most specific marker of non-uniform demyelination was HFA. For uniform demyelination it was NCV. Conclusions The pattern of correlations between the variables studied confirms that NCV and F-min are indicators of uniform conduction slowing. HFA, amplitude decay, and F-wave chronodispersion indicate non-uniform conduction slowing, for which HFA is both sensitive and specific. Significance The HFA method improves both the diagnostic sensitivity and specificity of nerve conduction studies in patients with non-uniform demyelination.

Despite extensive clinical experience and published data regarding botulinum toxin, questions remain about the clinical substitution of one botulinum toxin formulation for another. In the case of Dysport® and Botox®, doseequivalence ratios ranging from 1:1 to 6:1 (Dysport:Botox) have been advocated. This dose-ranging, electroneurographic study investigated the dose equivalence, diffusion characteristics (spread) and safety of these two type-A toxins in 79 volunteers. Dysport and Botox caused significant and similar reductions in compound muscle action potential (CMAP) amplitude in the target muscle (extensor digitorum brevis, EDB) 2 weeks after injection, with effects persisting to the 12-week timepoint. For both products, the reduction in amplitude was increased with increasing doses and with increasing concentration. The effects of toxin on neighbouring muscles were much smaller and of a shorter duration than those on the target muscle, implying a modest spread of toxin. Unlike the target muscle, the effects were greater with the higher volume, suggesting this volume led to greater diffusion from the EDB. No adverse events were reported. Statistical modelling with CMAP amplitude data from the target muscle gave a bioequivalence of 1.57 units of Dysport:1 unit of Botox (95 % CI: 0.77–3.20 units). The data indicate that a dose-equivalence ratio of 3:1 was within the statistical error limits, but ratios over 3:1 are too high.

Occipital stimulation in a small group of refractory chronic migraine and cluster headache patients has been suggested as a novel therapeutic approach with promising results. In an earlier study we have shown that a drug-induced block of the greater occipital nerve (GON) inhibits the nociceptive blink reflex (nBR). Now, we sought to examine the effects of low-frequency (3 Hz) short-time nociceptive stimulation of the GON on the trigeminal system. We recorded the nBR responses before and after stimulation in 34 healthy subjects. Selectivity of GON stimulation was confirmed by eliciting somatosensory evoked potentials of the GON upon stimulation. In contrast to an anaesthetic block of the occipital nerve, no significant changes of the R2-latencies and R2-response areas of the nBR can be elicited following GON stimulation. Various modes of electrical stimulation exist with differences in frequency, stimulus intensity, duration of stimulation and pulse width. One explanation for a missing modulatory effect in our study is the relatively short duration of the stimulation.

Botulinum toxin effectively blocks the release of acetylcholine from motor nerve terminals. Thus, botulinum toxin injections are well established in the treatment of disorders in which patients are impaired by involuntary muscle contractions. A remarkable pain reduction was frequently observed in these patients, and in vitro studies showed that botulinum toxin reduces not only the release of acetylcholine, but also the release of neuropeptides involved in pain perception. It was therefore hypothesized that botulinum toxin may help patients with pain not caused by muscular contractions, such as migraine or chronic daily headache, which includes chronic migraine. So far, the results of randomized, double-blind, placebo controlled trials on botulinum toxin in a total of 2,612 patients with migraine or with chronic daily headache were published. A superiority of botulinum toxin compared with placebo injections could not clearly be confirmed in any of the studies. One hypothesis derived from these results was that subgroups of patients with migraine can be defined in whom botulinum toxin may be efficacious. This hypothesis awaits confirmation. Interestingly, the efficacy of both botulinum toxin and placebo injections was found to be significant and similar to the efficacy of established oral migraine treatment. This finding may help explain the enthusiasm that followed the first open-label use of botulinum in patients with migraine. Drug Dev Res 68:397–402, 2007. © 2008 Wiley-Liss, Inc.

The objective of this study was to investigate whether injections of botulinum toxin into the soft palate reduce snoring in a subgroup of patients that present an active process causing habitual snoring. The study was conducted in eight patients with habitual snoring but without evidence of obstructive sleep apnea. Polysomnography was performed for diagnostic purposes and to monitor sleep quality before and after treatment. The patients and their partners completed a questionnaire before and after treatment. Recordings of snoring noise before and after treatment were evaluated on a visual analog scale by a blinded assessor. Doses of 20 U of botulinum toxin type A (Dysport®) were injected unilaterally into the muscles of the soft palate. Snoring was reduced in eight cases. The patients reported no major adverse effects. These results justify further studies of botulinum toxin therapy in patients with habitual snoring. The scheme presented for injections of botulinum toxin into the levator veli palatini muscle provides a rational basis for the design of such studies. Therapy with botulinum toxin for habitual snoring is safe, non-invasive, easy to perform, fully reversible, and thus warrants investigation under placebo-controlled, double-blind conditions. This treatment is appropriate for a disorder that is of paramount social importance but does not pose a medical threat to the individuals affected.

A genuine peripheral antinociceptive and anti-inflammatory effect of Botulinum neurotoxin type A (BoNT/A) has been proposed but could not be demonstrated in humans so far. Therefore, 100 mouse units of Botulinum toxin A (Dysport) and placebo were injected in a double blind paradigm in defined skin areas of 50 subjects. At baseline and after 4 and 8 weeks allodynia was induced in the skin areas with capsaicin ointment. Heat and cold pain threshold temperatures were measured with quantitative sensory testing, and threshold intensities upon electrical stimulation with a pain specific surface electrode were determined. No BoNT/A related differences in pain perception were found at any quality. There is neither a direct peripheral antinociceptive effect nor a significant effect against neurogenic inflammation of BoNT/A in humans.

Supplemental Digital Content is available in the text., Background: In a previous study, a single cross-lip flap (Abbe flap) combined with Johanson’s step technique for repair of defects of more than 2/3 of the lower lip was superior, in terms of aesthetic and functional outcome, compared with Bernard Webster–related techniques (cheek advancement). Herewith, a double cross-lip flap (Stein procedure) is proposed for repair of subtotal lower lip defects. A systematic review of the Stein procedure is provided. Methods: Two patients underwent a paramedian double cross-lip flap, preserving the aesthetic subunit philtrum column combined with the Johanson’s step technique. The aesthetic and functional outcomes and the surgical steps are demonstrated in the videos. An electromyographic study was performed 6 months and 4 years after surgery. A PubMed and a Google Scholar search were performed for the Stein procedure published in 1848. Results: Lip competence was achieved directly after sectioning of the cross-lip pedicles in both patients. Lips progressivity expanded in the first 6 months. No microstomia was observed. Electromyography showed successful reinnervation of the transplanted muscles at 6 months. Four years after surgery, the electromyographic findings were consolidated. Since 1975, 7 articles on the double cross-lip procedure have been published: 4 in English, 1 in French, and 2 in Japanese. None of those articles reported on any supplemental lower lip advancement or on any electromyographic study. Conclusions: The rationale of using 2 cross-lip flaps and a lip-cheek advancement according to Johanson seems to achieve functionally and aesthetically superior results compared with other techniques described for subtotal lower lip reconstruction.

We report the clinical, structural, functional and genetic characterization of a 37-year-old Caucasian female, presenting as a sporadic case of complicated spastic paraplegia with thin corpus callosum (CC), cognitive impairment, amyotrophy of the hand muscles and a sensorimotor neuropathy and review the literature for spastic paraplegia with thin CC. Magnetic resonance imaging (MRI) examination revealed a thin CC with fronto-parietal cortical atrophy. 18Fluordesoxyglucose positron emission tomography (FDG–PET) showed reduced cortical and thalamic metabolism. By transcranial magnetic stimulation, we delineated a severe impairment of transcallosal inhibition. Sequence analysis did not reveal disease causing mutations in the genes SLC12A6 (Andermann), Spastin (SPG 4), BSCL2 (SPG 17) and Spartin (SPG 20). We reviewed the literature for HSP with thin CC and found 113 HSP patients with thin CC previously described (35 with linkage to chromosome 15q13–15). Thin CC and peripheral neuropathy often appear together in spastic paraplegia and might be indicative for combined degeneration mechanism of central and peripheral axons.

Although the gene for facioscapulohumeral muscular dystrophy (FSHD) has not been identified so far, 4q35 deletion represents a diagnostic marker of the disease. In the present study, 46 consecutive symptomatic patients with 4q35 FSHD deletions or typical FSHD clinical features were evaluated. The patients were divided into three groups: 33 patients (72%) with typical FSHD phenotype and 4q35 FSHD deletion, eight (17%) with atypical (non-Landouzy-Dejerine) FSHD phenotype but with 4q35 FSHD deletion, and five patients (11%) with the typical FSHD phenotype but without FSHD 4q35 deletion. Apparently, the 4q35 deletion is associated not only with Landouzy-Dejerine FSHD but also with a variety of "atypical" FSHD forms. On the other hand, the Landouzy-Dejerine FSHD phenotype is possibly a polyetiological syndrome caused in some patients by other genetic effects than 4q35 deletion.

11. Kornegay JN, Bogan DJ, Bogan JR, Childers MK, Cundiff DD, Pet-roski GF, et al. Contraction force generated by tarsal joint flexionand extension in dogs with golden retriever muscular dystrophy. JNeurol Sci 1999;166:115–121.12. Dowling JJ, Vreede AP, Low SE, Gibbs EM, Kuwada JY, BonnemannCG, et al. Loss of myotubularin function results in T-tubule disorga-nization in zebrafish and human myotubular myopathy. PLoS Genet2009;5:e1000372.13. Buj-Bello A, Laugel V, Messaddeq N, Zahreddine H, Laporte J, Pel-lissier JF, et al. The lipid phosphatase myotubularin is essential forskeletal muscle maintenance but not for myogenesis in mice. ProcNatl Acad Sci U S A 2002;99:15060–15065.14. Al-Qusairi L, Weiss N, Toussaint A, Berbey C, Messaddeq N, Kretz C,et al. T-tubule disorganization and defective excitation-contractioncoupling in muscle fibers lacking myotubularin lipid phosphatase.Proc Natl Acad Sci U S A 2009;106:18763–18768.15. Yamaguchi N, Prosser BL, Ghassemi F, Xu L, Pasek DA, Eu JP,et al. Modulation of sarcoplasmic reticulum Ca2þ release in skele-tal muscle expressing ryanodine receptor impaired in regulation bycalmodulin and S100A1. Am J Physiol Cell Physiol 2011;300:C998–C1012.16. Tang W, Ingalls CP, Durham WJ, Snider J, Reid MB, Wu G, et al.Altered excitation-contraction coupling with skeletal muscle specificFKBP12 deficiency. FASEB J 2004;18:1597–1599.

Objectives: The aim of this study was to evaluate the time course of S-100β and neuron-specific enolase serum levels after cardiac surgery and their clinical relevance in predicting postoperative adverse neurologic outcomes; the 2 proteins are only released in peripheral blood in association with nervous system lesions. Methods: We neurologically assessed 190 consecutive patients undergoing elective cardiac operations for coronary artery bypass (n = 147), valve replacement (n = 29), or both (n = 14), before as well as after the operation. Postoperative outcome was classified as type I (uncomplicated), type II (confusion, agitation, disorientation, or epileptic seizures), or type III (stroke, stupor, or coma). Levels of S-100β and neuron-specific enolase were evaluated in venous blood samples drawn preoperatively and then daily in the first 5 postoperative days. Results: Levels of S-100β and neuron-specific enolase differed significantly among the 3 groups (type III > type II > type I) throughout the postoperative period and had a diagnostic specificity and specificity of 89% and 79%, respectively, in identifying patients with type III outcome. S-100β (but not neuron-specific enolase) levels were identified as significant independent predictors for type II and III outcomes (odds ratio 16.2, P < .0004). The same was true for duration of cardiopulmonary bypass (odds ratio 1.02, P < .006). Conclusions: Serum levels of S-100β are reliable markers for adverse neurologic outcomes after cardiac surgery. (J Thorac Cardiovasc Surg 2000;119:138-147)

Peripheral nerve entrapment syndromes are associated with hereditary neuropathy with liability to pressure palsies and a variety of rheumatic and endocrinological diseases.We report a patient with entrapment syndromes of multiple nerves associated with chronic graft-versus-host-disease (GVHD) after allogeneic hematopoietic stem cell transplantation. Nerve ultrasound, histology, and ultrastructural changes were assessed.The 51-year-old man had developed severe deep dermal sclerosis due to chronic GVHD with a progressive polyneuropathy and entrapment syndromes of multiple nerves. Pre-stenotic enlargement was shown by nerve ultrasound. Histology demonstrated fibrosis of the epineurium with scarce infiltration of macrophages. Electron microscopy demonstrated alterations of the myelin sheaths and marked depletion of normal-sized myelinated nerve fibers.In addition to polyneuropathy, chronic GVHD can be associated with peripheral nerve entrapment syndromes and should be added to the differential diagnosis of compressive neuropathies.

\(\it Objective\): Graft-versus-host disease (GVHD) is an immune-mediated multisystemic disorder and the leading cause of morbidity after allogeneic hematopoietic stem cell transplantation. Peripheral nervous system manifestations of GVHD are rare but often disabling. Whereas immune-mediated neuropathies are an established feature of GVHD, muscle cramps are not well characterized. \(\it Methods\): In a single-centre retrospective cohort we studied 27 patients (age 23 to 69 years) with GVHD (acute n = 6, chronic n = 21) who complained of symptoms suggestive of peripheral nervous system complications. Clinical, laboratory and neurophysiological findings were evaluated by descriptive statistics and regression analysis to detect factors associated with muscle cramps. Patient’s sera were examined for anti-neuronal antibodies. \(\it Results\): Nine patients had polyneuropathy, 4 had muscle cramps, and 14 had both. Median onset of polyneuropathy and muscle cramps was 6 and 9 months after allogeneic hematopoietic stem cell transplantation, respectively. Neurophysiology revealed a predominantly axonal polyneuropathy in 20 of 26 patients. In 4 of 19 patients electromyography showed signs of myopathy or myositis. Muscle cramps were more frequent during chronic than acute GVHD and affected muscles other than calves in 15 of 18 patients. They typically occurred daily, lasted 1 to 10 minutes with medium to severe pain intensity, compromised daily activity or sleep in 12, and were refractory to therapy in 4 patients. Muscle cramps were less likely with tacrolimus treatment and signs of severe polyneuropathy, but more likely with myopathic changes in electromyography and with incipient demyelinating polyneuropathy, shown by increased high frequency attenuation of the tibial nerve. Serological studies revealed antinuclear or antimitochondrial antibodies in a subset of patients. Two of 16 patients had a serum reactivity against peripheral nervous tissue. \(\it Conclusion\): Muscle cramps are associated with chronic GVHD, often compromise daily activity, and correlate negatively with axonal polyneuropathy and positively with myopathy and incipient demyelination.