A. Arturo Leis

N-acetylcysteine inhibits muscle fatigue in humans.

N-acetylcysteine (NAC) is a nonspecific antioxidant that selectively inhibits acute fatigue of rodent skeletal muscle stimulated at low (but not high) tetanic frequencies and that decreases contractile function of unfatigued muscle in a dose-dependent manner. The present experiments test the hypothesis that NAC pretreatment can inhibit acute muscular fatigue in humans. Healthy volunteers were studied on two occasions each. Subjects were pretreated with NAC 150 mg/kg or 5% dextrose in water by intravenous infusion. The subject then sat in a chair with surface electrodes positioned over the motor point of tibialis anterior, an ankle dorsiflexor of mixed-fiber composition. The muscle was stimulated to contract electrically (40-55 mA, 0.2-ms pulses) and force production was measured. Function of the unfatigued muscle was assessed by measuring the forces produced during maximal voluntary contractions (MVC) of ankle dorsiflexor muscle groups and during electrical stimulation of tibialis anterior at 1, 10, 20, 40, 80, and 120 Hz (protocol 1). Fatigue was produced using repetitive tetanic stimulations at 10 Hz (protocol 1) or 40 Hz (protocol 2); intermittent stimulations subsequently were used to monitor recovery from fatigue. The contralateral leg then was studied using the same protocol. Pretreatment with NAC did not alter the function of unfatigued muscle; MVC performance and the force-frequency relationship of tibialis anterior were unchanged. During fatiguing contractions stimulated at 10 Hz, NAC increased force output by approximately 15% (P < 0.0001), an effect that was evident after 3 min of repetitive contraction (P < 0.0125) and persisted throughout the 30-min protocol. NAC had no effect on fatigue induced using 40 Hz stimuli or on recovery from fatigue. N-acetylcysteine pretreatment can improve performance of human limb muscle during fatiguing exercise, suggesting that oxidative stress plays a causal role in the fatigue process and identifying antioxidant therapy as a novel intervention that may be useful clinically.

Psychogenic seizures Ictal characteristics and diagnostic pitfalls

We analyzed ictal features of psychogenic seizures using video-EEG recordings in 47 patients and reviewed the medical records to determine if patients received antiepileptic drug therapy and whether they were treated pharmacologically for status epilepticus. Unresponsive behavior in the absence of motor manifestations was the single most common ictal presentation. Motor characteristics previously considered to distinguish psychogenic seizures (out-of-phase limb movements, side-to-side head movements, pelvic thrusting) were infrequent. Most patients (74%) received anticonvulsants, and six were treated as status epilepticus. Slow, subtle writhing or in-phase limb movements were most likely to be mistaken for status epilepticus. Physicians, assuming that the spells constituted a neurologic emergency, omitted the neurologic examination and chart review and proceeded with aggressive pharmacotherapy based merely on observation.

Acute Flaccid Paralysis and West Nile Virus Infection

Acute weakness associated with West Nile virus (WNV) infection has previously been attributed to a peripheral demyelinating process (Guillain-Barré syndrome); however, the exact etiology of this acute flaccid paralysis has not been systematically assessed. To thoroughly describe the clinical, laboratory, and electrodiagnostic features of this paralysis syndrome, we evaluated acute flaccid paralysis that developed in seven patients in the setting of acute WNV infection, consecutively identified in four hospitals in St. Tammany Parish and New Orleans, Louisiana, and Jackson, Mississippi. All patients had acute onset of asymmetric weakness and areflexia but no sensory abnormalities. Clinical and electrodiagnostic data suggested the involvement of spinal anterior horn cells, resulting in a poliomyelitis-like syndrome. In areas in which transmission is occurring, WNV infection should be considered in patients with acute flaccid paralysis. Recognition that such weakness may be of spinal origin may prevent inappropriate treatment and diagnostic testing.

Modification of cervical dystonia by selective sensory stimulation

Cervical dystonia is often refractory to all forms of therapy. Many patients, however, are able to transiently abolish their spasms following a specific gesture that presumably enhances sensory input. Such observations prompted us to develop a protocol to determine if various forms of sensory stimulation could modify the motor control patterns in cervical dystonia. Surface EMG recordings of multiple neck and trunk muscles were obtained in 11 consecutive cervical dystonia patients. Baseline patterns of voluntary and involuntary muscle activation were established during a series of motor and non-motor tasks. The tasks were repeated during the application of vibratory or electrical stimulation to select muscle groups or to cutaneous and mixed nerves. Analysis of the results was made on the basis of paper and computer recordings of the data. Sensory stimulation decreased involuntary muscle activity and reduced spasms in 5 subjects. However, objective or subjective improvement usually occurred only after specific stimuli were applied to specific anatomical sites. In these cases, the protocol identified the site at which a specific sensory stimulus could be applied to control the dystonia. We conclude that selective sensory stimulation can beneficially modify cervical dystonia in some patients. Such findings warrant further investigation of the use of sensory stimulation for control of cervical dystonia.

Clinical spectrum of muscle weakness in human west nile virus infection

Poliomyelitis has recently been identified as a cause of muscle weakness in patients with West Nile virus (WNV) infection. However, the clinical spectrum of WNV‐associated weakness has not been described. We reviewed data on 13 patients with WNV infection. Patients with muscle weakness were classified into one of three distinct groups based on clinical features. Group 1 comprised five patients who developed acute flaccid paralysis, four with meningoencephalitis and one without fever or other signs of infection. Paralysis was asymmetric, and involved from one to four limbs in individual patients. Electrodiagnostic studies confirmed involvement of anterior horn cells or motor axons. Group 2 involved two patients without meningoencephalitis who developed severe but reversible muscle weakness that recovered completely within weeks. Muscle weakness involved both lower limbs in one patient and one upper limb in the other. Group 3 consisted of two patients who experienced subjective weakness and disabling fatigue, but had no objective muscle weakness on examination. In addition to the three distinct groups, two other patients developed exaggerated weakness in the distribution of preexisting lower motor neuron dysfunction. We conclude that the clinical spectrum of WNV‐associated muscle weakness ranges from acute flaccid paralysis, with or without fever or meningoencephalitis, to disabling fatigue. Also, preexisting dysfunction may predispose anterior horn cells to additional injury from WNV. Awareness of this spectrum will help to avoid erroneous diagnoses and inappropriate treatment. Muscle Nerve 28: 302–308, 2003

Spinal motoneuron excitability after acute spinal cord injury in humans

Background: Few studies in humans have assessed the ability of Ia afferent and antidromic motor volleys to activate motoneurons during spinal shock. Hence, little is known about the excitability state of the spinal motoneuron pool after acute spinal cord injury (SCI) in humans. Methods: In 14 patients with acute SCI involving anatomic levels T10 and above, we performed clinical and electrophysiologic studies early after injury (within 24 hours in seven subjects) and on day 10, 20, and 30 postinjury. Maximal H:M ratios, F-wave persistence, and tendon tap T-reflexes were recorded. Sixteen normal subjects and eight chronic SCI patients served as control subjects. Results: Ten of 14 patients had spinal shock (complete paralysis, loss of sensation, absent reflexes, and muscle hypotonia below the injury) at the time of initial evaluation. F-waves were absent in patients with spinal shock, reduced in persistence in patients with acute SCI without spinal shock, and normal in persistence in patients with chronic SCI. H-reflexes were absent or markedly suppressed in patients with spinal shock within 24 hours of injury but recovered to normal amplitudes within several days postinjury. This recovery occurred despite absence of F-waves that persisted for several weeks postinjury. Deep tendon reflexes were proportionally more depressed in spinal shock than were H-reflexes. All patients had elicitable H-reflexes for days or weeks before the development of clinical reflexes. Conclusions: Rostral cord injury causes postsynaptic changes (hyperpolarization) in caudal motoneurons. This hyperpolarization is a major physiologic derangement in spinal shock. The rise in H-reflex amplitude despite evidence of persistent hyperpolarization is due to enhanced transmission at Ia fiber-motoneuron connections below the SCI. Finally, the observation that the stretch reflex is proportionally more depressed than the H-reflex is consistent with fusimotor drive also being depressed after SCI. NEUROLOGY 1996;47: 231-237

Neuromuscular Manifestations of West Nile Virus Infection

The most common neuromuscular manifestation of West Nile virus (WNV) infection is a poliomyelitis syndrome with asymmetric paralysis variably involving one (monoparesis) to four limbs (quadriparesis), with or without brainstem involvement and respiratory failure. This syndrome of acute flaccid paralysis may occur without overt fever or meningoencephalitis. Although involvement of anterior horn cells in the spinal cord and motor neurons in the brainstem are the major sites of pathology responsible for neuromuscular signs, inflammation also may involve skeletal or cardiac muscle (myositis, myocarditis), motor axons (polyradiculitis), and peripheral nerves [Guillain–Barré syndrome (GBS), brachial plexopathy]. In addition, involvement of spinal sympathetic neurons and ganglia provides an explanation for autonomic instability seen in some patients. Many patients also experience prolonged subjective generalized weakness and disabling fatigue. Despite recent evidence that WNV may persist long-term in the central nervous system or periphery in animals, the evidence in humans is controversial. WNV persistence would be of great concern in immunosuppressed patients or in those with prolonged or recurrent symptoms. Support for the contention that WNV can lead to autoimmune disease arises from reports of patients presenting with various neuromuscular diseases that presumably involve autoimmune mechanisms (GBS, other demyelinating neuropathies, myasthenia gravis, brachial plexopathies, stiff-person syndrome, and delayed or recurrent symptoms). Although there is no specific treatment or vaccine currently approved in humans, and the standard remains supportive care, drugs that can alter the cascade of immunobiochemical events leading to neuronal death may be potentially useful (high-dose corticosteroids, interferon preparations, and intravenous immune globulin containing WNV-specific antibodies). Human experience with these agents seems promising based on anecdotal reports.

West Nile poliomyelitis.

gen, and alpha fetoprotein, were negative. The x-ray films of the chest and computed tomography scan of the thorax and abdomen were normal. The patient was treated with subcutaneous heparin and diclophenac, and fever and migratory thrombophlebitis subsided. Because the patient had been working with manure several days before his initial symptoms, Q fever serologic testing was requested. The antibody levels measured by complement fixation (CF) against phase II Coxiella burnetii antigen was 1:512. By indirect immunofluorescence, the titers of IgM and IgG against phase I and II were 1:64 and 1:512 and 1:256 and >2,048, respectively. Antibody titers against Mycoplasma, Chlamydia, Legionella, enterovirus, and influenza were negative. Recovery was uneventful and the patient was asymptomatic during a follow-up visit 3 weeks later. Antiphospholipid antibodies were negative. Three months after the acute phase of the infection, new titers of antibodies (CF) against C. burnetii were 1:128. Two years after the episode the patient was asymptomatic. This patient is unique in that he had acute Q fever with migratory thrombophlebitis. A diagnosis of Trousseau’s syndrome associated with an occult malignancy was considered on admission, but it was excluded soon. The recent history of exposure to manure was the key for the clinical diagnosis. Although specific anti-coxiella treatment was not given, the patient followed a self-limited course, and both clinical and laboratory abnormalities promptly subsided. Microscopic vasculitis and thrombosis are commonly found in patients with other rickettsial infections (5), but vascular phenomena must be considered an exceptional event in patients with Q fever. However, thrombophlebitis and pulmonary embolisms have been occasionally reported (6–8). These unusual manifestations have been associated with aPL during the course of acute Q fever (7,8). Antibodies to phospholipids have been found in 80% of patients in a large series of acute Q fever (9). None of the patients in the study showed thrombotic events or cardiac valve involvement in contrast to patients with lupus or primary aPL syndrome in whom clinical manifestations attributed to aPL developed (9). This observation could be explained by the fact that aPL found in patients with lupus and primary aPL syndrome are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation, which has been characterized as a β2-glycoprotein I (apolipoprotein H). This glycoprotein seems to inhibit the activation of the contact phase system of the intrinsic pathway of blood coagulation (10). On the other hand, apolipoprotein H is not necessary for the aPL activity observed in patients with Q fever and other infectious diseases (10). According to these studies, the observation of low titers of aPL in the serum of our patient during the acute phase of Q fever must be seen as a finding of uncertain importance not necessarily associated with migratory thrombophlebitis. In short, migratory thrombophlebitis (Trousseau’s syndrome) should be added to the evergrowing list of unusual manifestations of Q fever.

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.

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.