Cutaneous silent periods - Part 1: Update on physiological mechanisms.

Testing of exteroceptive electromyographic modulation of ongoing voluntary muscle activity is of interest in normal human physiology and in diagnostic clinical neurophysiology in normal and pathological conditions. The cutaneous silent period (CSP) is a robust and reproducible nociceptive EMG suppression, mediated at the spinal level by small-diameter A-delta afferents. This critical review surveys the literature on applied stimulation and recording techniques, physiological principles, involved fiber types, spinal circuitry, supraspinal modulation, neurotransmitters and pharmacology of CSPs. Understanding the principles of CSP testing is fundamental for a valid and thoughtful clinical application of CSPs (reviewed in part 2) (Kofler et al., 2019).

Does astroglial protein S100B contribute to West Nile neuro-invasive syndrome?

The clinical spectrum of West Nile Virus (WNV) infection ranges from a flu-like febrile condition to a more severe neuro-invasive disease that can cause death. The exact mechanism of neurodegeneration in neuro-invasive form of WNV infection has not been elucidated; however, a destructive role played by glial cells in promoting WNV mediated neurotoxicity has widely been speculated. The clinical studies revealed that the astroglial protein S100B is significantly elevated in the blood and CSF of patients with WNV infection, even in the absence of neuro-invasive disease. Therefore, the present study was designed to explore the potential role of S100B in the pathophysiology of WNV infection. The overarching hypothesis was that WNV primes astroglia to release S100B protein, which leads to a cascade of events that may have deleterious effects in both acute and chronic stages of WNV disease. To justify our hypothesis, we first ascertained increased levels of S100B in post-mortem tissue samples from WNV patients. Next, we looked at the effects of UV-inactivated WNV particles on astroglia using astroglial cell lines or primary cultures. Astroglial activation was measured as an increase in the expression of S100B and was analyzed by immunofluorescence and real-time PCR. Further, the in vitro effects of purified S100B protein on neutrophil migration and glutamate uptake were also determined in astroglial cell lines or primary cultures. We found that incubation of cultured astroglial cells with UV-inactivated WNV particles caused induction of S100B both at the mRNA and protein levels. Varying concentrations of S100B stimulated neutrophil migration in vitro. In addition, varying amounts of S100B caused inhibition of glutamate uptake in astroglia in a dose-dependent manner. Our data suggest that inactivated WNV particles are capable of inducing S100B synthesis in astroglia in vitro. We speculate that S100B release by activated astroglia may have multiple roles in the pathophysiology of WNV neuro-invasive disease, including induction of neutrophil migration to the sites where blood brain barrier is disrupted as well as glutamate neurotoxicity. To further elucidate the WNV-S100B neurotoxic pathway, in vivo studies using mouse models are warranted.

Neuronal and glial cerebrospinal fluid protein biomarkers are elevated after West Nile virus infection.

Neurotrophic West Nile virus (WNV) disease is a severe arbovirus infection in which neuronal loss is the likely anatomical substrate for the high morbidity and mortality. We investigated whether cerebrospinal fluid (CSF) protein biomarkers were elevated in vivo and related to disease severity in patients with WNV infection. This exploratory study included 114 patients (24 acute WNV, 77 noninflammatory controls, six peripheral neuropathies, seven aseptic meningoencephalitis). CSF levels of neuronal (neurofilaments, NfH-SMI35) and glial (glial fibrillary acidic protein, GFAP, S100B) biomarkers were measured by enzyme-linked immunosorbent assay (ELISA). Immunocytochemistry was performed in two fatal WNV cases. A significant proportion of patients with WNV had pathological CSF levels for NfH-SMI35 (58%, median concentration 1.01 ng/mL), GFAP (58%, 10 pg/mL), and S100B (90%, 1.29 ng/mL). The results were consistent with postmortem evidence for neuronal death and astrogliosis. Surprisingly, CSF protein biomarker levels were also found to be pathological in a considerable proportion of patients who presented with WNV fever only (100% for GFAP and S100B and 43% for NfH-SMI35). Elevated CSF protein biomarker levels are suggestive of neuronal death and glial pathology in human WNV infection. The results indicate the presence of neuroinvasive disease across the spectrum of WNV disease, including WNV fever.

Cutaneous silent periods are not affected by the antihistaminic drug cetirizine.

OBJECTIVE: Noxious digital nerve stimulation leads to transient suppression of the electromyographic activity in isometrically contracted hand muscles, known as the "cutaneous silent period" (CSP). To date, neurotransmitters potentially involved in mediating this electromyographic (EMG) suppression remain unknown. Anecdotal observation lead to the hypothesis that antihistaminic medication may counteract nociceptive EMG suppression, as CSPs in one male subject who was accustomed to CSP recordings were temporarily lost following ingestion of an antihistaminic drug for acute rhinitis. A second otherwise healthy male subject, who was on long-term cetirizine for allergic rhinitis, presented without clearly defined CSPs when volunteering for normal values. METHODS: We undertook a systematic study in five healthy subjects (including the one with temporarily lost CSPs) who underwent serial CSP testing after ingestion of 10 mg cetirizine. CSPs were elicited in thenar muscles following digit II and digit V stimulation (20 times sensory threshold, 100 sweeps rectified and averaged) before and 90, 180, and 360 min following intake of medication. RESULTS: CSP onset latency, CSP end latency and CSP duration, as well as the index of suppression did not change significantly following ingestion of 10 mg cetirizine. Repeat study in the subject with no clearly defined CSPs on long-term treatment revealed persistently absent CSPs after a 5-week withdrawal from cetirizine. CONCLUSION: CSPs are not affected by therapeutic doses of the H1 antihistaminic cetirizine. SIGNIFICANCE: Our findings suggest that histamine plays no major role as a neurotransmitter of CSPs.

Modulation of upper extremity motor evoked potentials by cutaneous afferents in humans.

The excitability of motoneurons controlling upper limb muscles in humans may vary with cutaneous nerve stimulation. We investigated the effect of noxious and non-noxious conditioning stimuli applied to right and left digit II and right digit V on motor evoked potentials (MEPs) recorded from right thenar eminence, abductor digiti minimi, biceps and triceps brachii muscles in twelve healthy subjects. Transcranial magnetic stimulation (TMS) was applied at interstimulus intervals (ISI) ranging from 40 to 160 ms following conditioning distal digital stimulation. TMS and transcranial electrical stimulation (TES) were compared at ISI 80 ms. Painful digital stimulation caused differential MEP amplitude modulation with an early maximum inhibition in hand muscles and triceps brachii followed by a maximum facilitation in arm muscles. Stimulation of different digits elicited a similar pattern of MEP modulation, which largely paralleled the behavior of cutaneous silent periods in the same muscles. Contralateral digital stimulation was less effective. MEPs following TMS and TES did not differ in their response to noxious digital stimulation. MEP latencies were shortened by cutaneous stimuli. The observed effects were stimulus intensity dependent. We conclude that activation of A-alpha and A-delta fibers gives rise to complex modulatory effects on upper limb motoneuron pools. A-delta fibers initiate a spinal reflex resulting in MEP amplitude reduction in muscles involved in reaching and grasping, and MEP amplitude facilitation in muscles involved in withdrawal. These findings suggest a protective reflex mediated by A-delta fibers that protects the hand from harm. A-alpha fibers induce MEP latency shortening possibly via a transcortical excitatory loop.

Cutaneous and mixed nerve silent periods in syringomyelia.

OBJECTIVES AND METHODS: We studied cutaneous and mixed nerve silent periods (CSP, MNSP) in 4 patients with cervical syringomyelia documented by magnetic resonance imaging who on clinical examination presented with unilateral hypalgesia and hypothermesthesia. In addition, we recorded upper and lower extremity somatosensory and motor evoked potentials (SEP, MEP), and cortical silent periods. RESULTS: In all patients, CSP and the later portion of MNSP were absent or shortened on their affected side, while both were normal on their unaffected side. In all patients, SEP latencies were normal following both median and tibial nerve stimulation. In two patients, the amplitude N13 (median nerve SEP), and in one patient each the amplitudes N20 (median nerve SEP) and P37 (tibial nerve SEP) were reduced. Central motor conduction time was prolonged to abductor digiti minimi muscle in one patient on the affected side, but was normal to tibialis anterior muscle in all patients. Cortical silent periods where present bilaterally in spite of unilateral complete absence of CSP and MNSP in two subjects tested. Loss of CSP and MNSP were a sensitive parameter of spinal cord dysfunction in syringomyelia. The cervical median nerve SEP response N13 reflected gray matter involvement, while corticospinal tract dysfunction was less frequently observed. CONCLUSION: Our data suggest that CSP and later portion of MNSP are generated at the spinal level by the same small myelinated A-delta fibers, and that their central network is distinct from large diameter fiber afferents and efferents.

Nociceptive fingertip stimulation inhibits synergistic motoneuron pools in the human upper limb.

BACKGROUND: Activation of distinct muscle groups organized in a stereotyped manner ("muscle synergies") is thought to underlie the production of movement by the vertebrate spinal cord. This results in movement with minimum effort and maximum efficiency. The question of how the vertebrate nervous system inhibits ongoing muscle activity is central to the study of the neural control of movement. OBJECTIVE: To investigate the strategy used by the human spinal cord to rapidly inhibit muscle activation in the upper limb. METHODS: The authors performed a series of experiments in 10 healthy subjects to assess the effect of nociceptive cutaneous stimulation on voluntarily contracting upper limb muscles. They recorded the electromyogram (EMG) with surface electrodes placed over various upper limb muscles. RESULTS: The authors found evidence of a simple inhibitory strategy that 1) was dependent on the intensity of the stimulus, 2) was maximally evoked when stimulation was applied to the fingertips, 3) preceded the earliest onset of voluntary muscle relaxation, and 4) produced inhibition of EMG activity in specific upper limb muscle groups. Nociceptive fingertip stimulation preferentially inhibited contraction of synergistic muscles involved in reaching and grasping (intrinsic hand muscles, forearm flexors, triceps) while having little effect on biceps or deltoid. CONCLUSIONS: Neural circuitry within the human spinal cord is organized to inhibit movement by rapidly deactivating muscles that constitute distinct muscle synergies. This strategy of selective and concurrent deactivation of the same basic elements that produce synergistic movement greatly simplifies motor control.

Anodal block: can this occur during routine nerve conduction studies?

The median nerves of five normal subjects were electrically excited at the wrist with fine-tipped stimulating electrodes in a bipolar fashion. Compound sensory nerve action potentials (CSNAPs) were recorded from the index finger and compound muscle action potentials (CMAPs) from the thenar muscles. Both the cathode and the anode were positioned over the length of the nerve. Recordings were performed with different cathode-to-anode distances of 5, 10, 20, and in some cases, 30 mm. Just supramaximal CSNAPs and CMAPs were obtained initially with the cathode situated distal to the anode and then with the stimulus polarity reversed. There were no significant differences in the amplitude, duration, and morphology of the CSNAPs or CMAPs that were recorded by using different stimulus polarities. There was a consistent increase in the onset latency of the responses when the stimulus polarity was reversed (cathode located proximal to anode). This increase in latency was proportionate to the increase in distance from the cathode to the recording electrode. The effect of anodal block could not be observed from the above experiment.

Myasthenia gravis, thymoma, intestinal pseudo-obstruction, and neuronal nicotinic acetylcholine receptor antibody.

Intestinal pseudo-obstruction occurs rarely in patients with myasthenia gravis (MG) and thymoma. The etiology of the intestinal pseudo-obstruction remains to be elucidated, although an autoimmune mechanism is postulated. We present the first report of neuronal nicotinic acetylcholine receptor (AChR)-specific antibody in a patient with seropositive MG, malignant thymoma, and intestinal pseudo-obstruction. This finding provides evidence that intestinal pseudo-obstruction associated with thymoma and possibly other neoplasms may be related to antibodies against the neuronal nicotinic receptors at autonomic ganglia.

Modulation of upper extremity motoneurone excitability following noxious finger tip stimulation in man: a study with transcranial magnetic stimulation.

Little is known about nociceptive reflex mechanisms in the upper limb in humans. To investigate nociceptive effects on spinal motoneurone excitability, a conditioning noxious stimulus was applied to the index finger of five healthy subjects. Motor evoked potentials (MEPs) following contralateral transcranial magnetic stimulation (TMS) were recorded from thenar eminence (TE) and biceps brachii (BB) muscles ipsilateral to finger stimulation. TMS was randomly applied alone or combined with preceding finger stimulation at an interstimulus interval of 100 ms. MEP amplitudes were profoundly suppressed in TE and augmented in BB. We conclude that nociception produces a differential effect on different spinal motoneurone pools, which may be part of a complex protective reflex mechanism in the upper limb of humans.

Chondrosarcoma of the spine and thyroid carcinoma following radiation therapy for Hodgkin's lymphoma.

Second malignant neoplasms are an infrequent but well-documented sequelae of radiation therapy for childhood cancer. We report a 34-year-old man with chondrosarcoma of the spine and thyroid carcinoma diagnosed 24 years after radiation therapy for Hodgkin's lymphoma. Both tumors arose in the previously irradiated field and were not detected until the patient presented with paraplegia. The propensity of these neoplasms to arise in the previously irradiated field warrants physicians to be alert to any manifestations arising in this anatomic area.

Spinal cord motoneuron excitability during isoflurane and nitrous oxide anesthesia.

BACKGROUND: Recent evidence suggests that the spinal cord is an important site of anesthesia that is necessary for surgical immobility, but the specific effect of anesthetics within the spinal cord is unclear. This study assessed the effect of isoflurane and nitrous oxide on spinal motoneuron excitability by monitoring the H-reflex and the F wave. METHODS: Eight adult patients, categorized as American Society of Anesthesiologists physical status 1 or 2, who were undergoing elective orthopaedic surgery were anesthetized with 0.6, 0.8, 1.0, and 1.2 times the estimated minimum alveolar concentration (MAC) of isoflurane. Nitrous oxide was added in graded concentrations of 30%, 50%, and 70%, whereas the isoflurane concentration was decreased to maintain a total MAC of 1. The H-reflex of the soleus muscle and the F wave of the abductor hallucis muscle were measured before anesthesia and 15 min after each change of anesthetic concentration. Four or more trials of the H-reflex and 18 trials of the F wave were recorded at each concentration of anesthesia. The effect of the anesthetics on the H-reflex and F wave was analyzed using. Dunnett's test. RESULTS: H-reflex amplitude was decreased to 48.4 +/- 18.6% of preanesthesia level at 0.6 MAC isoflurane and to 33.8 +/- 19.1% when isoflurane concentration increased from 0.6 MAC to 1.2 MAC. F wave amplitude and persistence decreased to 52.2 +/- 33.6% and 44.4 +/- 26% of baseline at 0.6 MAC isoflurane, and to 33.8 +/- 26% and 21.7 +/- 22.8% at 1.2 MAC isoflurane. Isoflurane plus nitrous oxide (total 1 MAC) decreased H-reflex amplitude to 30.4-33.3% and decreased F wave persistence to 42.8-56.3% of baseline. CONCLUSIONS: Both isoflurane alone and isoflurane plus nitrous oxide decrease H-reflex and F-wave amplitude and F-wave persistence. These effects suggest that isoflurane and nitrous oxide decrease motoneuronal excitability in the human spinal cord. This may play an important role in producing surgical immobility.

Behavior of the H-reflex in humans following mechanical perturbation or injury to rostral spinal cord.

In humans H-reflexes are suppressed during early spinal shock. In animals rostral cord injury results in loss of segmental reflexes within seconds. If H-reflexes persist under general anesthesia, can they be used to monitor the integrity of the rostral cord? In part I of this study, we recorded H-reflexes intraoperatively in 25 patients to elucidate general anesthesia effect. In 23 subjects, H-reflexes were consistently elicited, and within +/- 13% of the normalized group mean amplitude. In part II, we recorded H-reflexes in 31 patients during spinal cord surgery to elucidate H-reflex behavior immediately following rostral spinal cord injury. In 6, abrupt suppression of the H-reflex coincided with cord injury. In 4 of 6, suppression was transient and less than 50% of baseline; none of these patients developed neurological deficits. In 2, suppression exceeded 90% and persisted throughout surgery; both patients developed profound deficits. We conclude that (1) the H-reflex can be consistently elicited under general anesthesia in most patients, (2) rostral cord injury rapidly suppresses the H-reflex, and (3) the degree and duration of H-reflex suppression reflects the severity of the injury.