Homozygous deletion of an EGR2 enhancer in congenital amyelinating neuropathy.

The transcription factor EGR2 is expressed in Schwann cells, where it controls peripheral nerve myelination. Mutations of EGR2 have been found in patients with congenital hypomyelinating neuropathy or Charcot-Marie-Tooth disease type 1D. In a patient with congenital amyelinating neuropathy, we observed pathological abnormalities recapitulating the peripheral nervous system phenotype of homozygous Egr2-null mice. This patient, born from consanguineous parents, showed no EGR2 immunoreactivity in Schwann cells and harbored a homozygous 10.7-kilobase-long deletion encompassing a myelin-specific enhancer of EGR2. This regulatory mutation is the first genetic abnormality associated with congenital amyelinating neuropathy in humans.

Direct corticospinal control of force derivative.

During simultaneous generation of static and dynamic forces, motor cortical signals only predict the dynamic components, suggesting a key role in the coding of force changes. However, such a role is obscured by uncertainties regarding the representation of dynamic force signals in corticospinal outputs. We used transcranial magnetic stimulation (TMS) of the motor cortex in humans during a task that dissociated the direction of instantaneous net force and that of force derivative. The direction of TMS-evoked force outputs was closely associated with that of the force derivative, and had no relationship with that of the net force generated simultaneously, even though the magnitude of the instantaneous net force largely exceeded that of the force derivative. This observation supports the hypothesis that during dynamic force generation, the motor cortex and the corticospinal system assume a pivotal role in coding the direction of force changes, through selective recruitment of spinal motoneurons.

Targeted mutation of mouse skeletal muscle sodium channel produces myotonia and potassium-sensitive weakness.

Hyperkalemic periodic paralysis (HyperKPP) produces myotonia and attacks of muscle weakness triggered by rest after exercise or by K+ ingestion. We introduced a missense substitution corresponding to a human familial HyperKPP mutation (Met1592Val) into the mouse gene encoding the skeletal muscle voltage-gated Na+ channel NaV1.4. Mice heterozygous for this mutation exhibited prominent myotonia at rest and muscle fiber-type switching to a more oxidative phenotype compared with controls. Isolated mutant extensor digitorum longus muscles were abnormally sensitive to the Na+/K+ pump inhibitor ouabain and exhibited age-dependent changes, including delayed relaxation and altered generation of tetanic force. Moreover, rapid and sustained weakness of isolated mutant muscles was induced when the extracellular K+ concentration was increased from 4 mM to 10 mM, a level observed in the muscle interstitium of humans during exercise. Mutant muscle recovered from stimulation-induced fatigue more slowly than did control muscle, and the extent of recovery was decreased in the presence of high extracellular K+ levels. These findings demonstrate that expression of the Met1592ValNa+ channel in mouse muscle is sufficient to produce important features of HyperKPP, including myotonia, K+-sensitive paralysis, and susceptibility to delayed weakness during recovery from fatigue.

The clinical diagnostic utility of transcranial magnetic stimulation: report of an IFCN committee.

The review focuses on the clinical diagnostic utility of transcranial magnetic stimulation (TMS). The central motor conduction time (CMCT) is a sensitive method to detect myelopathy and abnormalities may be detected in the absence of radiological changes. CMCT may also detect upper motor neuron involvement in amyotrophic lateral sclerosis. The diagnostic sensitivity may be increased by using the triple stimulation technique (TST), by combining several parameters such as CMCT, motor threshold and silent period, or by studying multiple muscles. In peripheral facial nerve palsies, TMS may be used to localize the site of nerve dysfunction and clarify the etiology. TMS measures also have high sensitivity in detecting lesions in multiple sclerosis and abnormalities in CMCT or TST may correlate with motor impairment and disability. Cerebellar stimulation may detect lesions in the cerebellum or the cerebellar output pathway. TMS may detect upper motor neuron involvement in patients with atypical parkinsonism and equivocal signs. The ipsilateral silent period that measures transcallosal inhibition is a potential method to distinguish between different parkinsonian syndromes. Short latency afferent inhibition (SAI), which is related to central cholinergic transmission, is reduced in Alzheimer's disease. Changes in SAI following administration of cholinesterase inhibitor may be related to the long-term efficacy of this treatment. The results of MEP measurement in the first week after stroke correlate with functional outcome. We conclude that TMS measures have demonstrated diagnostic utility in myelopathy, amyotrophic lateral sclerosis and multiple sclerosis. TMS measures have potential clinical utility in cerebellar disease, dementia, facial nerve disorders, movement disorders, stroke, epilepsy, migraine and chronic pain.

Relapsing Guillain Barré Syndrome and nephrotic syndrome secondary to focal segmental glomerulosclerosis.

A 49-year-old man developed simultaneously a Guillain Barré Syndrome (GBS) and a nephrotic syndrome (NS). The patient relapsed twice, despite treatment with intravenous immunoglobulins (IVIg) after a full or partial recovery, and became resistant to IVIg. Renal biopsy revealed focal segmental glomerulosclerosis (FSGS). He responded to plasmapheresis and corticosteroids with simultaneous recovery of his GBS and NS, suggesting a common pathogenesis of the two conditions.

Neuregulin 1-erbB signaling is necessary for normal myelination and sensory function.

To investigate the role of erbB signaling in the interactions between peripheral axons and myelinating Schwann cells, we generated transgenic mice expressing a dominant-negative erbB receptor in these glial cells. Mutant mice have delayed onset of myelination, thinner myelin, shorter internodal length, and smaller axonal caliber in adulthood. Consistent with the morphological defects, transgenic mice also have slower nerve conduction velocity and defects in their responses to mechanical stimulation. Molecular analysis indicates that erbB signaling may contribute to myelin formation by regulating transcription of myelin genes. Analysis of sciatic nerves showed a reduction in the levels of expression of myelin genes in mutant mice. In vitro assays revealed that neuregulin-1 (NRG1) induces expression of myelin protein zero (P0). Furthermore, we found that the effects of NRG1 on P0 expression depend on the NRG1 isoform used. When NRG1 is presented to Schwann cells in the context of cell-cell contact, type III but not type I NRG1 regulates P0 gene expression. These results suggest that disruption of the NRG1-erbB signaling pathway could contribute to the pathogenesis of peripheral neuropathies with hypomyelination and neuropathic pain.

Transcranial magnetic stimulation during voluntary action: directional facilitation of outputs and relationships to force generation.

Single-pulse transcranial magnetic stimulation (TMS) of the human motor cortex evokes simple muscle jerks whose physiological significance is unclear. Indeed, in subjects performing a motor task, there is uncertainty as to whether TMS-evoked outputs reflect the ongoing behavior or, alternatively, a disrupted motor plan. Considering force direction and magnitude to reflect qualitative and quantitative features of the motor plan respectively, we studied the relationships between voluntary forces and those evoked by TMS. In five healthy adults, we recorded the isometric forces acting a hand joint and the electromyographic activity in the first dorsal interosseous (FDI) muscle. Responses obtained at rest were highly invariant. Evoked responses obtained while subjects generated static and dynamic contractions were highly codirectional with the voluntary forces. Such directional relationships were independent of stimulation intensity, stimulated cortical volume, or magnitude of voluntary force exerted. Dynamic force generation was associated with a marked increase in the magnitude of the evoked force that was linearly related to the rate of force generation. The timing of central conduction was different depending on functional role of the target muscle, as either agonist or joint fixator. These results indicate that the architecture of motor plans remain grossly undisrupted by cortical stimulation applied during voluntary motor behavior. The significant magnitude modulation of responses during dynamic force generation suggests an essential role of the corticospinal system in the specification of force changes. Finally, the corticospinal activation depends on the functional role assumed by the target muscle, either postural or agonist.

Multifocal motor neuropathy with conduction block: Distribution of demyelination and axonal degeneration.

OBJECTIVE: Multifocal motor neuropathy with conduction block (MMN) is an immune-mediated neuropathy, characterized by progressive muscle weakness. Although demyelination is regarded as the underlying pathophysiologic mechanism of MMN, recently, it was reported that different pathophysiologic mechanisms were responsible for disease in the upper and lower limbs. Specifically, demyelination in the upper limbs and axonal loss in the lower limbs. Consequently, the aim of the present study was to assess, through clinical neurophysiology studies, whether different pathophysiologic mechanisms were occurring in the upper and lower extremities. Furthermore, we wanted to investigate whether the presence of conduction block (CB) correlated with axonal degeneration (AD), and to determine the electrophysiological abnormalities that correlate with muscle weakness. METHODS: We reviewed medical records of 18 patients with MMN for clinical features (using the Medical Research Council score and Guys Neurology Disability Scale) and neurophysiologic abnormalities (CB, AD prolongation of distal motor and F-wave latencies, and reduction of conduction velocity in the demyelinating range). RESULTS: Electrophysiological abnormalities deemed specific of demyelination were non-significantly different in the upper and lower extremities. The presence of axonal degeneration correlated significantly with conduction block (odds ratio 10.4, 95% CI 4.2-25.6), and both parameters correlated with muscle weakness (P<0.01). CONCLUSION: Our study suggests that the same pathophysiologic process occurs in the upper and lower extremity nerves. Moreover, one pathophysiologic process may be responsible for the development of CB and AD, and therefore muscle weakness. SIGNIFICANCE: The present study has established that both AD and CB occur in MMN, irrespective of extremity, and both correlate with muscle weakness.

Cervical nerve root stimulation. Part II: findings in primary demyelinating neuropathies and motor neuron disease.

OBJECTIVE: Cervical nerve root stimulation (CRS) allows the assessment of conduction in the proximal segments of motor fibers destined to the upper extremities, which are not evaluated by routine nerve conduction studies (NCS). Since many primary demyelinating polyneuropathies (PDP) are multifocal lesions may be confined to the proximal nerve segments. CRS may therefore increase the yield of neurophysiologic studies in diagnosing PDP. METHODS: We reviewed clinical and neurophysiologic data from 38 PDP patients and compared them to 35 patients with motor neuron disease (MND), and 21 healthy controls (HC). RESULTS: Mean onset-latency was significantly prolonged in PDP patients. The optimal onset-latency cutoff necessary to distinguish PDP from MND and controls was 17.5 ms for the abductor pollicis brevis (APB) and abductor digiti minimi (ADM), and 7 ms for Biceps and Triceps. Mean reduction in proximal to distal CMAP amplitude to APB and ADM was significantly greater in PDP patients, with an optimal cutoff in proximal to distal CMAP amplitude reduction necessary to distinguish PDP from MND and HC being 45%. CONCLUSIONS: CRS is effective in distinguishing PDP from MND and HC based on prolonged onset latency and conduction block criteria. SIGNIFICANCE: CRS may increase the diagnostic yield in cases where demyelinating lesions are confined to the proximal peripheral neuraxis.

Cervical nerve root stimulation. Part I: technical aspects and normal data.

OBJECTIVE: Cervical nerve root stimulation (CRS) is a technique of assessing the proximal segments of motor axons destined to upper extremity muscles. Few studies report normal values. The objective was to determine CMAP onset-latencies and CMAP amplitude, area, and duration changes in healthy controls for the abductor pollicis brevis (APB), abductor digiti minimi (ADM), biceps, and riceps muscles. In addition, to determine the tolerability of CRS, as measured by the visual analog scale (VAS). METHODS: We studied 21 healthy volunteers prospectively with CRS using four target muscles (APB, ADM, biceps, and triceps) bilaterally. Collision studies were used in all APB recordings. VAS was obtained in all subjects. RESULTS: Mean CMAP onset-latencies were: APB 14 +/- 1.5 ms; ADM 14.2 +/- 1.5 ms; biceps 5.4 +/- 0.6 ms; triceps 5.4 +/- 1.0 ms. Onset-latency significantly correlated with height for all nerves. The mean change in CMAP amplitude and area (%) between most distal stimulation and CRS was: APB reduction of 15.1 +/- 11.6 and 4.9 +/- 3.6%; ADM reduction of 21.1 +/- 10.7 and 17.2 +/- 8.8; biceps reduction of 10 +/- 11.5 and reduction of 8.7 +/- 6.8; triceps increase of 3.3 +/- 5.2 and 11.0 +/- 9.9% respectively. Mean CMAP duration change between most distal stimulation and CRS was: APB, increase of 20.4 +/- 7.4%; ADM, increase of 14.4 +/- 8.5%; biceps, increase of 13.9 +/- 10.8%; triceps, increase of 7.7 +/- 6.7%. The mean VAS score was 3.8 +/- 1.2, and all subjects completed the study. CONCLUSIONS: The present study establishes normative data and indicates that CRS is a well-tolerated technique. SIGNIFICANCE: The normal values may be used as reference data for the needle CRS technique in the assessment of proximal conduction abnormalities.

Acute sensory neuronopathy as the presenting symptom of Sjögren's syndrome.

Sensory neuronopathy associated with Sjögren's syndrome (SS) usually has a subacute or chronic onset. We report the case of a 37-year-old woman who presented with an unusual hyperacute form of SS ganglionopathy. She initially developed paresthesias of her fingertips and rapidly became severely ataxic. Nerve conduction studies revealed abnormal sensory but normal motor functions. Lip biopsy showed findings consistent with SS. Sural nerve biopsy showed severe axonal loss. The patient showed modest improvement with immunosuppressive therapies.

IgG neuropathy: an immunoelectron microscopic study.

There are many potential mechanisms of peripheral nerve impairment by a monoclonal IgG dysglobulinemia. In this study, using electron microscopy, we observed widening of the myelin lamellae comparable to that commonly described in IgM neuropathies with antimyelin-associated glycoprotein activity. Such features have yet to be described in IgG neuropathies. In addition, we observed deposits of a granular material in the interstitial tissue of the nerve. By immunoelectron microscopy, we demonstrated the presence of the IgG in the lesions of myelin and the endoneurial space. A direct link between monoclonal dysglobulinemia (regardless of type) and polyneuropathy should be confirmed by nerve biopsy, because the result may influence treatment.

Neurophysiologic findings in early acute inflammatory demyelinating polyradiculoneuropathy.

BACKGROUND: Patients with early acute inflammatory demyelinating polyradiculoneuropathy (AIDP) may not meet the current neurophysiologic criteria. OBJECTIVE: To document neurophysiologic findings in early AIDP. METHODS: Clinical and neurophysiologic data from 38 AIDP patients, assessed within 10 days of symptom onset were reviewed. RESULTS: In addition to absent H reflexes and abnormal F-wave responses in the acute stage of AIDP, abnormalities of blink reflexes, upper limb sensory responses abnormalities with spared sural responses, presence of distal CMAP dispersion, and A-waves were frequently observed. Established demyelinating neurophysiologic parameters were infrequently seen. CONCLUSIONS: Abnormalities of H reflexes and F responses were most frequently noted in early AIDP. Additionally, distal temporal dispersion, prolonged or absent blink reflexes, and A-waves were often present in the acute stage of AIDP when classic diagnostic criteria of AIDP were not satisfied. SIGNIFICANCE: Neurophysiologic studies in early AIDP frequently reveal abnormalities that are not specific of primary demyelinating neuropathy.

Quantitative sensory testing.

Quantitative sensory testing is a reliable way of assessing large and small sensory nerve fiber function. Sensory deficits may be quantified and the data used in parametric statistical analysis in research studies and drug trials. It is an important addition to the neurophysiologic armamentarium, because conventional sensory nerve conduction tests only the large fibers. QST is a psychophysical test and lacks the objectivity of NCS. The results are subject to changes owing to distraction, boredom, mental fatigue, drowsiness, or confusion. When patients are consciously or unconsciously biased toward an abnormal QST result, no psychophysical testing can reliably distinguish these patients from those with organic disease. QST tests the integrity of the entire sensory neuraxis and is of no localizing value. Dysfunction of the peripheral nerves or central nervous system may give rise to abnormalities in QST. As is true for other neurophysiologic tests, QST results should always be interpreted in light of the patient's clinical presentation. Quantitative sensory testing has been shown to be reasonably reproducible over a period of days or weeks in normal subjects. Because longitudinal QST studies of patients in drug trials are usually performed over a period of several months to a few years, reproducibility studies on the placebo-control group should be included. For individual patients, more studies are needed to determine the maximum allowable difference between two QSTs that can be attributed to experimental error. The reproducibility of thermal thresholds may not be as good as that of vibration threshold. Different commercially available QST instruments have different specifications (thermode size, stimulus characteristics), testing protocols, algorithms, and normal values. Only QST instruments and their corresponding methodologies that have been shown to be reproducible should be used for research and patient care. The data in the literature do not allow conclusions regarding the superiority of any QST instruments. The future of QST is promising; however, many factors can affect QST results. As is true for other neurophysiologic tests, QST is susceptible to many extraneous factors and to misuse when not properly interpreted by the clinician.

FOSMN syndrome: novel insight into disease pathophysiology.

OBJECTIVE: To better define the pathophysiologic mechanisms underlying the development of the novel facial-onset sensory and motor neuronopathy (FOSMN) syndrome and, in particular, to determine whether neurodegenerative processes, mediated by excitotoxicity, or autoimmune mechanisms contribute to the development of FOSMN syndrome. METHODS: Clinical, laboratory, neurophysiologic, and pathologic assessments were undertaken for 5 patients with FOSMN syndrome (3 male and 2 female), the largest cohort of FOSMN syndrome reported to date. In addition to conventional neurophysiologic studies, novel threshold tracking transcranial magnetic stimulation (TMS) techniques were undertaken to assess for the presence of cortical excitability. RESULTS: Clinically, all patients exhibited the typical FOSMN syndrome phenotype, heralded by facial-onset sensory deficits with subsequent development of motor deficits evolving in a rostral-caudal direction. Pathologic studies, including an autopsy, disclosed widespread degeneration of sensory and motor neurons with no evidence of inflammation, amyloid deposition, or intraneuronal inclusions, such as TDP-43, Bunina bodies, or ubiquitin inclusions. Conventional neurophysiologic studies revealed abnormalities of blink reflexes, along with features of motor and sensory neuronopathy. Threshold tracking TMS disclosed normal cortical excitability in patients with FOSMN syndrome, with preserved short-interval intracortical inhibition, resting motor threshold, motor evoked potential amplitude, and cortical silent period duration. Patients with FOSMN syndrome failed to respond to immunomodulatory approaches. CONCLUSIONS: Findings from the present study suggest that FOSMN syndrome is a primary neurodegenerative disorder of sensory and motor neurons, with distinct pathophysiologic mechanisms.