Conduction block in immune-mediated neuropathy: paranodopathy versus axonopathy.

BACKGROUND AND PURPOSE: Conduction block is a pathognomonic feature of immune-mediated neuropathies. The aim of this study was to advance understanding of pathophysiology and conduction block in chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). METHODS: A multimodal approach was used, incorporating clinical phenotyping, neurophysiology, immunohistochemistry and structural assessments. RESULTS: Of 49 CIDP and 14 MMN patients, 25% and 79% had median nerve forearm block, respectively. Clinical scores were similar in CIDP patients with and without block. CIDP patients with median nerve block demonstrated markedly elevated thresholds and greater threshold changes in threshold electrotonus, whilst those without did not differ from healthy controls in electrotonus parameters. In contrast, MMN patients exhibited marked increases in superexcitability. Nerve size was similar in both CIDP groups at the site of axonal excitability. However, CIDP patients with block demonstrated more frequent paranodal serum binding to teased rat nerve fibres. In keeping with these findings, mathematical modelling of nerve excitability recordings in CIDP patients with block support the role of paranodal dysfunction and enhanced leakage of current between the node and internode. In contrast, changes in MMN probably resulted from a reduction in ion channel density along axons. CONCLUSIONS: The underlying pathologies in CIDP and MMN are distinct. Conduction block in CIDP is associated with paranodal dysfunction which may be antibody-mediated in a subset of patients. In contrast, MMN is characterized by channel dysfunction downstream from the site of block.

Cortical hyperexcitability and disease spread in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is characterized by focal disease onset with a predominantly contiguous pattern of disease spread. The pathophysiological mechanisms underlying disease progression in ALS have not been elucidated. Given that cortical hyperexcitability has been identified as an important pathogenic mechanism in ALS, the aim of the present study was to determine whether changes in cortical function could mediate disease spread in ALS. METHODS: Threshold-tracking transcranial magnetic stimulation was undertaken in 50 patients with sporadic ALS with recording of responses over both abductor pollicis brevis muscles, with results matched to clinical assessments and concurrent neurophysiological investigation of lower motor neuron function. Subsequently, patients were followed longitudinally to map patterns of clinical disease progression. RESULTS: Cortical dysfunction was evident over both motor cortices, with hyperexcitability more prominent over the dominant motor cortex, contralateral to the site of disease onset, with reduction of resting motor threshold (F = 3.83, P < 0.05), short-interval intracortical inhibition (F = 15.0, P < 0.0001) and cortical silent-period duration (F = 8.01, P < 0.01), along with an increase in motor evoked potential amplitude (F = 5.66, P < 0.01). In addition, patterns of cortical change were consistent with a contiguous pattern of disease progression. CONCLUSIONS: Cortical hyperexcitability appears to be more prominent over the dominant motor cortex, contralateral to the side of symptom onset, and contributes to a contiguous pattern of spread in sporadic ALS.

Progression of retinal ganglion cell loss in multiple sclerosis is associated with new lesions in the optic radiations.

BACKGROUND AND PURPOSE: The mechanism of retinal ganglion cell and retinal nerve fiber layer loss in multiple sclerosis (MS) remains unknown. This study aimed to investigate the association between temporal retinal nerve fiber layer (tRNFL) thinning and disease activity in the brain determined by T2 lesions on magnetic resonance imaging (MRI). METHODS: Fifty-five consecutive patients with relapsing-remitting MS and 25 controls were enrolled. All patients underwent annual optical coherence tomography and high-resolution MRI scans for tRNFL thickness and brain lesion volume analysis, respectively. RESULTS: Significant tRNFL thickness reduction was observed over the 3-year follow-up period at a relatively constant rate (1.02 µm/year). Thinning of tRNFL fibers was more prominent in younger patients (P = 0.01). The tRNFL loss was associated with new MRI lesions in the optic radiations (ORs). There was significantly greater tRNFL thinning in patients with new lesional activity in the ORs compared with patients with new lesions outside the ORs (P = 0.009). CONCLUSIONS: This study supports the notion that retrograde transneuronal degeneration caused by OR lesions might play a role in progressive retinal nerve fiber layer loss. In addition, the results of the study also indicate that the disease-related neurodegenerative changes in the retina start much earlier than the clinical diagnosis of MS.

Cortical excitability changes distinguish the motor neuron disease phenotypes from hereditary spastic paraplegia.

BACKGROUND AND PURPOSE: Cortical hyperexcitability has been identified as an important pathogenic mechanism in motor neuron disease (MND). The issue as to whether cortical hyperexcitability is a common process across the MND phenotypes, including amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS), remains unresolved. Separately, the clinical distinction between PLS and 'mimic disorders' such as hereditary spastic paraparesis (HSP) may be difficult, potentially delaying diagnosis. Consequently, the aim of the present study was to determine the nature and spectrum of cortical excitability changes across the MND phenotypes, and to determine whether the presence of cortical dysfunction distinguishes PLS from HSP. METHODS: Cortical excitability studies were undertaken on a cohort of 14 PLS, 82 ALS and 13 HSP patients with mutations in the spastin gene. RESULTS: Cortical hyperexcitability, as heralded by reduction of short interval intracortical inhibition (PLS 0.26%, -3.8% to 1.4%; ALS -0.15%, -3.6% to 7.0%; P < 0.01) and cortical silent period duration (CSPPLS 172.2 ± 5.4 ms; CSPALS 178.1 ± 5.1 ms; P < 0.001), along with an increase in intracortical facilitation was evident in ALS and PLS phenotypes, although appeared more frequently in ALS. Inexcitability of the motor cortex was more frequent in PLS (PLS 71%, ALS 24%, P < 0.0001). Cortical excitability was preserved in HSP. CONCLUSIONS: Cortical dysfunction appears to be an intrinsic process across the MND phenotypes, with cortical inexcitability predominating in PLS and cortical hyperexcitability predominating in ALS. Importantly, cortical excitability was preserved in HSP, thereby suggesting that the presence of cortical dysfunction could help differentiate PLS from HSP in a clinical setting.

Diagnostic utility of cortical excitability studies in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: The diagnosis of amyotrophic lateral sclerosis (ALS) relies on identification of a combination of upper and lower motor neuron signs. In order to improve the diagnostic sensitivity for ALS, Awaji criteria were developed, in part to better incorporate neurophysiological measures, although assessment of upper motor neuron dysfunction remained clinically based. Given that cortical hyperexcitability appears to be an early feature in ALS, the present study assessed the diagnostic utility of a threshold tracking transcranial magnetic stimulation technique as an aid to the research-based Awaji criteria in establishing an earlier diagnosis of ALS. METHODS: Prospective studies were undertaken on a cohort of 82 patients with suspected ALS and results were compared with 34 healthy controls. RESULTS: Short-interval intracortical inhibition (SICI) was significantly reduced in ALS patients (P < 0.0001), with a comparable reduction evident in the Awaji groups (SICIAWAJI POSSIBLE 1.3% ± 1.3%; SICIAWAJI PROBABLE/DEFINITE 1.4% ±1.7%). Central motor conduction time was significantly prolonged (P < 0.001), whereas the motor evoked potential amplitude (P < 0.05) and intracortical facilitation (P < 0.05) were increased. The frequency of transcranial magnetic stimulation abnormalities was similar across Awaji subgroups, and addition of transcranial magnetic stimulation abnormalities as a diagnostic category enabled reclassification of 88% of Awaji possible patients to Awaji probable/definite. CONCLUSIONS: Cortical excitability studies potentially facilitate an earlier diagnosis of ALS when combined with clinical and conventional neurophysiological findings, albeit in a research setting.

Relationship between chronic demyelination of the optic nerve and short term axonal loss.

BACKGROUND: Axonal loss is a major determinant of disability in multiple sclerosis (MS). While acute inflammatory demyelination is a principal cause of axonal transection and subsequent axonal degeneration in acute disease, the nature of chronic axonal loss is less well understood. In the current study, the relationship between degree of chronic demyelination and axonal degeneration was investigated using optic neuritis (ON) as a model. METHOD: 25 patients with a first episode of unilateral ON, good recovery of visual function and concurrent brain or spinal cord MRI lesions were enrolled. Axonal loss was assessed using change in retinal nerve fibre layer (RNFL) thickness between 1 and 3 years after ON. Optic nerve conduction was evaluated using latency of multifocal visual evoked potentials (mfVEP). The level of mfVEP latency delay at 12 and 36 months was considered indicative of the degree of permanent demyelination. Data from 25 age and gender matched normal controls were used for comparison. RESULTS: RNFL thickness was significantly reduced in ON eyes at 12 months compared with controls but remained unchanged in fellow eyes. Average RNFL thickness demonstrated a small but significant reduction between 12 and 36 months for both ON and fellow eyes. Change in RNFL thickness between 12 and 36 months, however, did not correlate with the degree of mfVEP latency delay. CONCLUSION: The results, therefore, show no association between the degree of permanent optic nerve demyelination (as measured by latency delay) and progressive axonal degeneration, at least in the early stages of the disease. The fact that fellow eyes demonstrated a similar degree of progressive axonal loss supports this suggestion.

Magnetisation transfer ratio in optic neuritis is associated with axonal loss, but not with demyelination.

BACKGROUND: Pathophysiological basis of Magnetisation Transfer Ratio (MTR) reduction in multiple sclerosis still remains a matter of controversy. Optic nerve represents an ideal model to study the consequences of axonal loss and demyelination on MTR since effects of disease on the optic nerve are clinically apparent and potentially quantifiable by objective means. By measuring the latency of multifocal visual evoked potentials (mfVEP) (measure of optic nerve conduction) and Retinal Nerve Fiber Layer (RNFL) thickness (measure of axonal damage) we investigated the effect of neurodegeneration and demyelination on MTR after an episode of optic neuritis (ON). METHODS: 23 patients with a single unilateral episode of ON and 10 healthy volunteers were enrolled. Orbital MRI including MTR protocol, Optical Coherence Tomography and Multifocal VEP were performed at post-acute stage of ON. RESULTS: Average MTR of affected eye was significantly reduced as compared to the fellow eye and normal controls. There was a highly significant correlation between MTR and measures of axonal loss (RNFL thickness and mfVEP amplitude), which was independent on the level of demyelination. While latency delay also correlated significantly with MTR, correlation became non-significant when adjusted for the degree of axonal loss. There was a significant reduction of MTR in a group of patients with extensive axonal damage, while MTR remained normal in a group of patients with extensive demyelination, but little or no axonal loss. CONCLUSION: Results of this study indicate that reduction of optic nerve MTR after an episode of ON has a strong association with the degree of axonal damage, but not with demyelination.

Antiphospholipid syndrome and rheumatic fever: a case spanning three decades of changing concepts and common immunological mechanisms.

We present a case of primary antiphospholipid syndrome (APS), initially diagnosed as acute rheumatic fever, resulting in severe mitral valve incompetence. This case raises questions of the specificity of the Jones diagnostic criteria for rheumatic fever in a population where it is infrequently encountered. There are similarities in clinical, pathological and echocardiographic presentations between rheumatic fever and APS, in addition to common immunological mechanisms. Our case highlights the possibility that rather than rheumatic fever being primarily responsible for her recurrent attacks of chorea and arthritis, the streptococcal infections in our patient occurred either in the setting of underlying antiphospholipid antibodies ('second hit' phenomenon), or may have triggered the development of pathogenic antibodies (molecular mimicry), subsequently leading to the clinical evolution of APS. During the three decades of our patient and her recurrent problems, there has been an evolving knowledge of the mechanisms of APS and rheumatic fever, allowing us to extend our understanding beyond symptoms and syndromes, to a better realization of the underlying immunological relationship between the two.

Multifocal VEP and OCT in optic neuritis: a topographical study of the structure-function relationship.

PURPOSE: To investigate topographical relationship between amplitude of multifocal visual evoked potentials (mfVEP) and retinal nerve fibre layer (RNFL) thickness following acute optic neuritis (ON). PATIENTS AND METHODS: Fifty patients with a clinical diagnosis of acute unilateral ON between 6 and 36 months prior to the study and 25 age-matched controls underwent mfVEP testing (Accumap V 2.1, ObjectiVision Pty Ltd, Sydney, Australia) and OCT imaging (fast RNFL protocol, Stratus, software version 3.0, Carl Zeiss Meditec, Inc., Dublin, CA). RNFL thickness and mfVEP amplitude were measured for upper, temporal and lower retinal sectors and corresponding areas of the visual field in affected eyes of ON patients and control eyes. Inter-eye asymmetry coefficients for both RNFL thickness and mfVEP amplitude were calculated for each zone, and corresponding coefficients were correlated between each other. RESULTS: There was highly significant reduction of RNFL thickness and mean mfVEP amplitude in all three retinal sectors of the affected eye. Largest reduction of RNFL thickness was noticed in temporal sector and of mfVEP amplitude in corresponding central part of the visual field. RNFL thickness correlated highly with amplitude of the mfVEP derived from corresponding areas of the visual field in all three zones. CONCLUSIONS: We demonstrated strong topographical associations between structural and functional measures of optic nerve integrity in patients with ON.

Autoantibody responses to nodal and paranodal antigens in chronic inflammatory neuropathies.

Autoantibodies to nodal/paranodal proteins have been reported in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). To determine the frequency of anti-paranodal antibodies in our cohort of CIDP patients and to validate the presence anti-nodal antibodies in MMN, sera were screened for IgG against human neurofascin 155, contactin-1, neurofascin 186 and gliomedin using ELISA. In CIDP patients, 7% were anti-NF155 IgG4 positive and 7% were anti-CNTN1 IgG4 positive. Positive results were confirmed using cell based assays and indirect immunofluorescence on teased nerve fibres. We did not detect IgG autoantibodies against these nodal/paranodal antigens in MMN patients.

Utility of magnetic resonance imaging in diagnosing ulnar neuropathy at the elbow.

OBJECTIVE: Magnetic resonance imaging (MRI) of the ulnar nerve is being increasingly employed in the diagnosis of ulnar neuropathy at the elbow (UNE). Our aims were to: (i) assess the sensitivity of MRI in diagnosing UNE, especially in cases where neurophysiologic studies were non-localizing, (ii) determine the spectrum of MRI abnormalities in patients presenting with symptoms and signs of ulnar neuropathy, (iii) assess whether MRI findings differ between grades of UNE severity, and (iv) to see if MRI findings give an input into the pathological mechanisms of UNE. METHODS: Clinical, neurophysiologic, and radiologic (MRI) records were reviewed in 52 patients with symptoms and signs of ulnar neuropathy. Ulnar nerve MRI studies were assessed by an unblinded observer. RESULTS: The sensitivity of MRI at diagnosing UNE was higher than conventional nerve conduction studies, 90 versus 65%, respectively. In patients with non-localizing neurophysiologic studies (n=19), MRI disclosed changes consistent with UNE in 16 (84%) cases. The most frequent MRI findings included a combination of high signal intensity and nerve enlargement (63%), followed by nerve compression (27%) and isolated high signal intensity (23%), and isolated nerve enlargement (2%). There was no significant difference between patients with localizing and non-localizing neurophysiologic testing. Lastly, there were no differences between different grades of UNE, suggesting that UNE may be a neurophysiologically heterogeneous disorder. CONCLUSIONS: MRI studies proved to be more sensitive than conventional nerve conduction studies at diagnosing UNE. In addition, the MRI studies were highly sensitive in patients with non-localizing UNE. SIGNIFICANCE: Our study shows that MRI of the ulnar nerve should be used in patients with clinical features of UNE especially in those with non-localizing neurophysiologic testing.

The relevance of contralateral recordings and patient disability to assessment of brain-stem auditory evoked potential abnormalities in multiple sclerosis.

Brain-stem auditory evoked responses (BAER) were recorded in a group of 83 patients with a diagnosis of clinically definite or probable multiple sclerosis to assess the relevance of recording contralateral responses simultaneously with ipsilateral responses and to correlate patients disability with the detection of abnormalities. The contralateral responses generally mirrored the ipsilateral responses, but in seven patients the responses differed, mainly involving the presence or absence of wave V. However, contralateral recordings did not contribute significantly to the sensitivity of lesion detection, and their main value was to aid in the recognition of waves when they were not clearly seen in the ipsilateral recordings. The BAER abnormality rates were found to be significantly correlated with disability, and it is suggested that this is an important variable to consider when undertaking or comparing results of BAER studies in patients with multiple sclerosis.

Multimodality evoked potentials in motor neuron disease.

We performed median and tibial nerve somatosensory evoked potentials (SEPs), pattern-shift visual evoked potentials (PSVEPs), and brain-stem auditory evoked potentials (BAEPs) on 27 patients with motor neuron disease (MND). Median and tibial nerve SEPs were abnormal in 8 (30%) of 27 and 3 (14%) of 21 patients tested, respectively. Central and peripheral abnormalities were recorded in the absence of spondylosis. As a group, patients with MND and no evidence of cervical spondylosis had normal conduction to Erb's point following median nerve stimulation, but conduction times beyond this point were prolonged. The PSVEPs and BAEPs were within normal limits in all patients, excluding abnormalities attributable to other disease, but the group P100 latency was significantly prolonged in the group with MND. The BAEPs were normal in the group with MND. This study provides neurophysiological evidence of sensory system involvement in MND.

Short-latency somatosensory-evoked potentials from radial, median, ulnar, and peroneal nerve stimulation in the assessment of cervical spondylosis. Comparison with conventional electromyography.

A study of data on 30 patients with cervical spondylosis was carried out to determine whether short-latency somatosensory-evoked responses (SEPs) to median, ulnar, radial, and peroneal nerve stimulation provided additional information to that obtained by electromyography (EMG), late responses, and peripheral conduction studies. Peripheral studies, EMG results and SEPs were within normal limits in ten patients with pain, but without objective neurological deficit. By contrast, of ten patients who had objective signs of root compression, conventional EMG results were normal in nine, but abnormalities of the SEPs from radial nerve stimulation were obtained in only five patients, and were normal from ulnar and median nerve stimulation. In ten patients with clinical features of myelopathy, seven had abnormal median SEPs and all had abnormal peroneal SEPs, whereas EMG results were abnormal in only five patients. It is suggested that SEPs and EMG are both of limited use in patients with only symptoms of root compression. In patients with signs of root compression, EMG is the most sensitive procedure; however, some additional information can be obtained from superficial radial SEPs. In patients with cervical myelopathy, SEP was the most useful procedure, especially when upper and lower limbs were studied.

Visual evoked potentials in the detection of subclinical optic toxic effects secondary to ethambutol.

In 14 patients with tuberculosis treated with ethambutol hydrochloride, pattern-reversal visual evoked potentials (VEPs) were recorded to monocular, whole-field stimulation before the commencement of treatment and one month and three months subsequently. In six subjects, the VEPs showed changes in the latency and amplitude of the P100 component at the one- or three-month interval. In three cases, the VEP changes reversed after cessation of treatment. In five of the six cases, changes were not associated with a change in visual function, as measured by clinical neuro-ophthalmologic examination. Our findings confirm the usefulness of VEPs in the detection of subclinical optic nerve disease and suggest their use in routine monitoring of ocular function in patients treated with ethambutol.

Peripheral neuropathy associated with polycythemia vera.

Nerve conduction studies were performed on 26 patients with polycythemia vera, 11 of whom had sensory symptoms in the extremities and 3 of whom had clinical signs of peripheral neuropathy. There was significant impairment of sensory conduction in the ulnar and sural nerves and mild slowing of motor conduction in the lateral popliteal nerve. Sural nerve biopsies were performed on three patients. The pathological findings, including teased fiber studies, were consistent with mild chronic axonal degeneration. There is an association between polycythemia vera and peripheral neuropathy.

A comparison of brainstem auditory evoked responses evoked by rarefaction and condensation stimulation in control subjects and in patients with Wernicke-Korsakoff syndrome and multiple sclerosis.

Brainstem auditory evoked responses (BAER) evoked by rarefaction and condensation stimulation were compared in patients with Wernicke-Korsakoff syndrome (WKS) and multiple sclerosis (MS) and click polarity-related differences in topodiagnosis were found in 24% of the WKS and 40% of the MS patients. These results suggest the need to record BAER routinely with both stimulus polarities separately if practicable. BAER from rarefaction and condensation stimulation were recorded from control subjects of both sexes to provide control data for the patient study and also to investigate the interaction between sex and click polarity. BAER latency and amplitude differences between males and females were found to be independent of click polarity. However, the study did show an interaction between female sex and click polarity-related BAER latency differences although differences in amplitude and waveform morphology were essentially independent of sex. This further emphasises the importance of taking into account the variables of sex and stimulus polarity in establishing BAER control values.

Postural tremor of Parkinson's disease.

Previous studies have reported the resting tremor (RT) of Parkinson's disease to occur at frequencies between 3-7 Hz and to be characterised by an alternating pattern of electromyographic (EMG) bursting activity between opposing muscles. A postural tremor (PT), of higher frequency (> 6 Hz) and with a synchronous pattern of EMG activity, has also been previously described in Parkinson's disease. We investigated the electrophysiological and pharmacological properties of both the RT and PT of 11 patients with Parkinson's disease and 10 patients with essential tremor in a double-blind, placebo-controlled study of L-Dopa/benserazide and propranolol. Tremor amplitude and frequency were assessed via bidirectional accelerometry, and the pattern of activation of the antagonist muscles of the forearm was determined with use of surface EMG. In the Parkinson's disease group studied, the frequency, EMG pattern of bursts, and response to L-Dopa were similar for the two tremors (median improvement of RT by 70% and PT by 61%). Despite some overlap between the Parkinson's disease and essential tremor groups in the electrophysiology of the tremor, there was no such dramatic pharmacological response in the latter group. These results suggest that the RT and PT of Parkinson's disease share a common pathophysiology and are distinct from essential tremor.

The relationship between quantified EEG and skin conductance level.

Electroencephalographic measures (EEG) and skin conductance level (SCL) respectively reflect cerebral cortical activity and sympathetic autonomic activity. Such central and autonomic activities associated with arousal generally have been studied separately, despite their potential to reflect complementary dimensions of reticular-thalamo-hypothalamo-cortical activating networks. In this study, we examined the relationship between cortical (19 EEG sites) and autonomic (SCL) activities recorded simultaneously in 10 normal adults. Two second pre-stimulus EEGs and SCLs were assessed from an habituation paradigm which presented 22 trains of 7 tones in an 'ignore' condition. The mean SCLs of the epochs across subjects showed an initial rise (sensitization) followed by an exponential decline (habituation). Although EEG associated with the tones did not demonstrate such a distinct profile, EEG total power and band powers (beta, alpha and theta) associated with the trains showed a systematic increasing response profile. In the group data the mean SCLs within trains showed a significant correlation with alpha and beta band powers. Finer EEG band analyses indicated that beta 3 at Fz and alpha 2 at Cz showed the strongest separate linear correlations with SCL. beta 3 and alpha 1 at Fz were found to jointly covary with SCL. The findings indicate a substantive relationship between measures of cerebral function and autonomic arousal.

Treatment of upper limb dystonia with botulinum toxin.

The use of botulinum toxin A (BTX A) in upper limb dystonia is gaining increasing acceptance and it has recently been suggested that it be considered as first line treatment.(1) We have reviewed our experience since 1991 of treating 20 cases of upper limb dystonia. 14 patients had task-specific dystonias (6 simple writer's cramp, 5 dystonic writer's cramp, 3 musician's cramp) and 6 had secondary focal or segmental dystonias (4 with early cortico-basal degeneration). All patients had electromyography to both determine and guide muscle selection. Pre- and post-treatment video as well as questionnaires formed the basis for outcome assessment. Botulinum toxin therapy was clearly beneficial in about two-thirds of those with primary upper limb dystonia, a condition affecting young adults (mean onset 32.9 years). In contrast, BTX A was far less effective in secondary upper limb dystonias which occurred in the elderly (mean onset 71.7 years). Optimal treatment strategies are discussed. In conclusion, botulinum toxin is an effective form of treatment for primary upper limb dystonia; its role in late onset secondary dystonia is mainly palliative.