Mary Kay Floeter

Mutant dynactin in motor neuron disease.

Impaired axonal transport in motor neurons has been proposed as a mechanism for neuronal degeneration in motor neuron disease. Here we show linkage of a lower motor neuron disease to a region of 4 Mb at chromosome 2p13. Mutation analysis of a gene in this interval that encodes the largest subunit of the axonal transport protein dynactin showed a single base-pair change resulting in an amino-acid substitution that is predicted to distort the folding of dynactins microtubule-binding domain. Binding assays show decreased binding of the mutant protein to microtubules. Our results show that dysfunction of dynactin-mediated transport can lead to human motor neuron disease.

Acute Oxaliplatin-Induced Peripheral Nerve Hyperexcitability

PURPOSE Oxaliplatin is a novel platinum compound with clinical activity in several malignancies. Neurotoxicity is dose-limiting and occurs in two distinct forms, an acute neurologic symptom complex that occurs within hours or days of therapy and a chronic, cumulative sensory neuropathy. PATIENTS AND METHODS Patients were treated in a phase I study designed to establish the maximum-tolerated dose of capecitabine given with oxaliplatin. Because of the unusual neurosensory toxicity of oxaliplatin, detailed neurologic examination, needle electromyography (EMG), and nerve conduction studies (NCS) were performed before and the day after oxaliplatin in a subset of 13 patients. Carbamazepine therapy was tried in 12 additional patients to determine whether the neurologic effects might be relieved. RESULTS All patients experienced acute, reversible neurotoxicities with oxaliplatin. Symptoms included paresthesias, dysesthesias, cold hypersensitivity, jaw pain, eye pain, pain in the arm used for drug infusion, ptosis, leg cramps, and visual and voice changes. Serial EMG and NCS revealed striking signs of hyperexcitability in motor nerves after oxaliplatin. In patients who achieved therapeutic levels, carbamazepine did not alter the clinical or electromyographic abnormalities. CONCLUSION The acute neurotoxicity seen with oxaliplatin is characterized by peripheral-nerve hyperexcitability, and the findings are similar to the clinical manifestations of neuromyotonia. Carbamezepine, which provides symptomatic relief in acquired neuromytonia, did not seem to be beneficial. Efforts to identify a successful neuroprotectant strategy would have a major impact on improving patient quality of life and the ability to deliver full doses of oxaliplatin.

Inhibitory influence of the ipsilateral motor cortex on responses to stimulation of the human cortex and pyramidal tract

1 The ability of the primary motor cortex (M1) to modulate motor responses in ipsilateral hand muscles seems to be important for normal motor control and potentially also for recovery after brain lesions. It is not clear which pathways mediate this ipsilateral modulation. Transcallosal connections have been proposed, but are known to be sparse between cortical hand motor representations in primates. The present study was performed to determine whether descending ipsilateral modulation of motor responses might also be mediated below the cortical level in humans. 2 A paired‐pulse protocol was used, in which motor‐evoked potentials (MEPs) were produced by cortical transcranial magnetic stimulation (cTMS) or by electrical stimulation of the pyramidal tract at the level of the pyramidal decussation (pdTES), in both preactivated and relaxed hand muscles. Paired stimuli were applied at various interstimulus intervals (ISIs) between 2 and 100 ms. The conditioning stimulus (CS) was always magnetic, and delivered to the M1 ipsilateral to the target hand, prior to the test stimulus (TS). The magnetic TS was delivered to the M1 contralateral to the target hand; the electrical TS was applied through electrodes placed over the mastoid process bilaterally. Further experiments included cortical electrical stimulation and H‐reflexes. The MEP amplitudes were averaged separately for each ISI and the control condition (no CS), and expressed as a percentage of the unconditioned response. 3 Conditioning stimulation of the ipsilateral M1 resulted in significant inhibition of magnetically evoked MEPs, and also of MEPs produced by pdTES. Inhibition occurred at ISIs between 6 and 50 ms, and was observed in preactivated and relaxed muscles. Higher CS intensities caused greater inhibition of both cTMS‐ and pdTES‐evoked MEPs. 4 While the conditioning effects on magnetically evoked muscle responses could be explained by a transcallosal mechanism, the effects on pdTES‐evoked MEPs cannot, because they are elicited subcortically and are therefore not susceptible to inhibitory mechanisms transmitted at the cortico‐cortical level. 5 In conclusion, the present results provide novel evidence that the inhibitory influence of the human M1 on ipsilateral hand muscles is to a significant extent mediated below the cortical level, and not only through cortico‐cortical transcallosal connections. They point to a concept of inhibitory interaction between the two primary motor cortices that is relayed at multiple levels along the neuroaxis, thus perhaps providing a structurally redundant system which may become important in case of lesions.

Oxaliplatin‐induced neurotoxicity: Acute hyperexcitability and chronic neuropathy

Oxaliplatin, a platinum‐based chemotherapeutic agent, is effective in the treatment of solid tumors, particularly colorectal cancer. During and immediately following oxaliplatin infusion, patients may experience cold‐induced paresthesias, throat and jaw tightness, and occasionally focal weakness. We assessed nerve conduction studies and findings on needle electromyography of patients with metastatic colorectal cancer before and during treatment with oxaliplatin. Twenty‐two patients had follow‐up studies within 48 h following oxaliplatin infusions, and 14 patients had follow‐up studies after 3–9 treatment cycles. Repetitive compound muscle action potentials and neuromyotonic discharges were observed in the first 24–48 h following oxaliplatin infusion, but resolved by 3 weeks. After 8–9 treatment cycles, sensory nerve action potential amplitudes declined, without conduction velocity changes or neuromyotonic discharges. The acute neurological symptoms reflect a state of peripheral nerve hyperexcitability that likely represents a transient oxaliplatin‐induced channelopathy. Chronic treatment causes an axonal neuropathy similar to other platinum‐based chemotherapeutic agents. Muscle Nerve 29: 387–392, 2004

Enzyme replacement therapy improves peripheral nerve and sweat function in Fabry disease

Fabry disease is an X‐linked disorder caused by a deficiency of lysosomal α‐galactosidase A resulting in accumulation of α‐D‐galatosyl conjugated glycosphingolipids. Clinical manifestations include a small‐fiber neuropathy associated with debilitating pain and hypohidrosis. We report the effect of a 3‐year open‐label extension of a previously reported 6‐month placebo‐controlled enzyme replacement therapy (ERT) trial in which 26 hemizygous patients with Fabry disease received 0.2 mg/kg of α‐galactosidase A every 2 weeks. The effect of ERT on neuropathic pain scores while off pain medications, quantitative sensory testing, quantitative sudomotor axon reflex test (QSART), and thermoregulatory sweat test (TST) is reported. In the patients who crossed‐over from placebo to ERT (n = 10), mean pain‐at‐its‐worst scores on a 0–10 scale decreased (from 6.9 to 4.5). There was a significant reduction in the threshold for cold and warm sensation in the foot. At the 3‐year time‐point, pre‐ERT sweat excretion in 17 Fabry patients was 0.24 ± 0.33 μl/mm2 vs. 1.05 ± 0.81 in concurrent controls (n = 38). Sweat function improved 24–72 h post‐enzyme infusion (0.57 ± 0.71 μl/mm2) and normalized in four anhidrotic patients. TST confirmed the QSART results. We conclude that prolonged ERT in Fabry disease leads to a modest but significant improvement in the clinical manifestations of the small‐fiber neuropathy associated with this disorder. QSART may be useful to further optimize the dose and frequency of ERT. Muscle Nerve 28: 703–710, 2003

Distal spinal and bulbar muscular atrophy caused by dynactin mutation.

Impaired axonal transport has been postulated to play a role in the pathophysiology of multiple neurodegenerative disorders. In this report, we describe the results of clinical and neuropathological studies in a family with an inherited form of motor neuron disease caused by mutation in the p150Glued subunit of dynactin, a microtubule motor protein essential for retrograde axonal transport. Affected family members had a distinct clinical phenotype characterized by early bilateral vocal fold paralysis affecting the adductor and abductor laryngeal muscles. They later experienced weakness and atrophy in the face, hands, and distal legs. The extremity involvement was greater in the hands than in the legs, and it had a particular predilection for the thenar muscles. No clinical or electrophysiological sensory abnormality existed; however, skin biopsy results showed morphological abnormalities of epidermal nerve fibers. An autopsy study of one patient showed motor neuron degeneration and axonal loss in the ventral horn of the spinal cord and hypoglossal nucleus of the medulla. Immunohistochemistry showed abnormal inclusions of dynactin and dynein in motor neurons. This mutation of dynactin, a ubiquitously expressed protein, causes a unique pattern of motor neuron degeneration that is associated with the accumulation of dynein and dynactin in neuronal inclusions. Ann Neurol 2005;57:687–694

A high performance sensorimotor beta rhythm-based brain-computer interface associated with human natural motor behavior

UNLABELLED To explore the reliability of a high performance brain-computer interface (BCI) using non-invasive EEG signals associated with human natural motor behavior does not require extensive training. We propose a new BCI method, where users perform either sustaining or stopping a motor task with time locking to a predefined time window. Nine healthy volunteers, one stroke survivor with right-sided hemiparesis and one patient with amyotrophic lateral sclerosis (ALS) participated in this study. Subjects did not receive BCI training before participating in this study. We investigated tasks of both physical movement and motor imagery. The surface Laplacian derivation was used for enhancing EEG spatial resolution. A model-free threshold setting method was used for the classification of motor intentions. The performance of the proposed BCI was validated by an online sequential binary-cursor-control game for two-dimensional cursor movement. Event-related desynchronization and synchronization were observed when subjects sustained or stopped either motor execution or motor imagery. Feature analysis showed that EEG beta band activity over sensorimotor area provided the largest discrimination. With simple model-free classification of beta band EEG activity from a single electrode (with surface Laplacian derivation), the online classifications of the EEG activity with motor execution/motor imagery were: >90%/ approximately 80% for six healthy volunteers, >80%/ approximately 80% for the stroke patient and approximately 90%/ approximately 80% for the ALS patient. The EEG activities of the other three healthy volunteers were not classifiable. The sensorimotor beta rhythm of EEG associated with human natural motor behavior can be used for a reliable and high performance BCI for both healthy subjects and patients with neurological disorders. SIGNIFICANCE The proposed new non-invasive BCI method highlights a practical BCI for clinical applications, where the user does not require extensive training.

Patterned Sensory Stimulation Induces Plasticity in Reciprocal Ia Inhibition in Humans

Training of spinal cord circuits using sensorimotor stimulation has been proposed as a strategy to improve movement after spinal injury. How sensory stimulation may lead to long-lasting changes is not well understood. We studied whether sensory stimulation might induce changes in the strength of a specific spinal interneuronal circuit: spinally mediated reciprocal Ia inhibition. In healthy humans, the strength of reciprocal inhibition between ankle flexor and extensor muscles was assessed before and after 30 min of peroneal nerve stimulation at motor threshold intensity. Three stimulation protocols were assessed: patterned nerve stimulation (10 pulses at 100 Hz every 1.5 sec), uniform nerve stimulation (one pulse every 150 msec), and combined stimulation of the peroneal nerve and the motor cortex with transcranial magnetic stimulation. Short-latency reciprocal inhibition from ankle flexor to extensor muscles was measured by conditioning the soleus H-reflex with stimulation of the common peroneal nerve. The strength of the reciprocal inhibition was measured at baseline and for 20 min after each stimulation session. Patterned stimulation, with or without motor cortex stimulation, enhanced reciprocal inhibition for at least 5 min afterward. The uniform pattern of stimulation was ineffective. These results demonstrate the presence of short-term plasticity within spinal inhibitory circuits. We conclude that the pattern of sensory input is a crucial factor for inducing changes in the spinal circuit for reciprocal inhibition in humans. These findings may have implications for the use of repetitive patterned sensory stimulation in rehabilitative efforts to improve walking ability in patients with spinal injury.

Recommendations of the Neurolaryngology Study Group on laryngeal electromyography

The Neurolaryngology Study Group convened a multidisciplinary panel of experts in neuromuscular physiology, electromyography, physical medicine and rehabilitation, neurology, and laryngology to meet with interested members from the American Academy of Otolaryngology Head and Neck Surgery, the Neurolaryngology Subcommittee and the Neurolaryngology Study Group to address the use of laryngeal electromyography (LEMG) for electrodiagnosis of laryngeal disorders. The panel addressed the use of LEMG for: 1) diagnosis of vocal fold paresis, 2) best practice application of equipment and techniques for LEMG, 3) estimation of time of injury and prediction of recovery of neural injuries, 4) diagnosis of neuromuscular diseases of the laryngeal muscles, and, 5) differentiation between central nervous system and behaviorally based laryngeal disorders. The panel also addressed establishing standardized techniques and methods for future assessment of LEMG sensitivity, specificity and reliability for identification, assessment and prognosis of neurolaryngeal disorders. Previously an evidence-based review of the clinical utility of LEMG published in 2004 only found evidence supported that LEMG was possibly useful for guiding injections of botulinum toxin into the laryngeal muscles. An updated traditional/narrative literature review and expert opinions were used to direct discussion and format conclusions. In current clinical practice, LEMG is a qualitative and not a quantitative examination. Specific recommendations were made to standardize electrode types, muscles to be sampled, sampling techniques, and reporting requirements. Prospective studies are needed to determine the clinical utility of LEMG. Use of the standardized methods and reporting will support future studies correlating electro-diagnostic findings with voice and upper airway function.

Iron accumulation in deep cortical layers accounts for MRI signal abnormalities in ALS: Correlating 7 tesla MRI and pathology

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by cortical and spinal motor neuron dysfunction. Routine magnetic resonance imaging (MRI) studies have previously shown hypointense signal in the motor cortex on T2-weighted images in some ALS patients, however, the cause of this finding is unknown. To investigate the utility of this MR signal change as a marker of cortical motor neuron degeneration, signal abnormalities on 3T and 7T MR images of the brain were compared, and pathology was obtained in two ALS patients to determine the origin of the motor cortex hypointensity. Nineteen patients with clinically probable or definite ALS by El Escorial criteria and 19 healthy controls underwent 3T MRI. A 7T MRI scan was carried out on five ALS patients who had motor cortex hypointensity on the 3T FLAIR sequence and on three healthy controls. Postmortem 7T MRI of the brain was performed in one ALS patient and histological studies of the brains and spinal cords were obtained post-mortem in two patients. The motor cortex hypointensity on 3T FLAIR images was present in greater frequency in ALS patients. Increased hypointensity correlated with greater severity of upper motor neuron impairment. Analysis of 7T T2 *-weighted gradient echo imaging localized the signal alteration to the deeper layers of the motor cortex in both ALS patients. Pathological studies showed increased iron accumulation in microglial cells in areas corresponding to the location of the signal changes on the 3T and 7T MRI of the motor cortex. These findings indicate that the motor cortex hypointensity on 3T MRI FLAIR images in ALS is due to increased iron accumulation by microglia.