Electrodiagnostic studies and new diagnostic modalities for evaluation of peripheral nerve disorders.

Electrodiagnostic studies (EDx) are frequently performed in the diagnostic evaluation of peripheral nerve disorders. There is increasing interest in the use of newer, alternative diagnostic modalities, in particular imaging, either to complement or replace established EDx protocols. However, the evidence to support this approach has not been expansively reviewed. In this paper, diagnostic performance data from studies of EDx and other diagnostic modalities in common peripheral nerve disorders have been analyzed and described, with a focus on radiculopathy, plexopathy, compressive neuropathies, and the important neuropathy subtypes of Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), vasculitic neuropathy and diabetic neuropathy. Overall EDx retains its place as a primary diagnostic modality in the evaluated peripheral nerve disorders. Magnetic resonance imaging and ultrasound have developed important complementary diagnostic roles in compressive and traumatic neuropathies and atypical CIDP, but their value is more limited in other neuropathy subtypes. Identification of hourglass constriction in nerves of patients with neuralgic amyotrophy may have therapeutic implications. Investigation of radiculopathy is confounded by poor correlation between clinical features and imaging findings and the lack of a diagnostic gold standard. There is a need to enhance the literature on the utility of these newer diagnostic modalities.

Upper and lower limb tremor in inflammatory neuropathies.

OBJECTIVE: The mechanisms underlying neuropathic tremor remain incompletely understood and a distinction has not been drawn between proximal and distal neuropathies. Lower limb tremor contributes to imbalance in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), but this is unexplored in other neuropathies. We characterized upper and lower limb tremor in chronic immune sensory polyradiculopathy (CISP) and distal acquired demyelinating neuropathy with anti-MAG antibodies (DADS-MAG), contrasted to CIDP. METHODS: This was a cross-sectional study of 38 patients (CIDP [n = 25], CISP [n = 7], DADS-MAG [n = 6]). Clinical assessment, tremor study recordings, nerve conduction studies, and somatosensory evoked potentials were performed. Balance was measured by force platform. RESULTS: Upper limb tremor was prevalent (CIDP 66%, CISP 70%, DADS-MAG 100%). Peak frequencies followed a gradient along the upper limb, unchanged by weight-loading. Lower limb tremor was also present (CIDP 32%, CISP 29%, DADS-MAG 66%) and associated with imbalance. Nerve conduction parameters correlated with upper limb tremor in DADS-MAG and CISP, and imbalance in CISP. CONCLUSIONS: Upper limb tremor is mediated by peripheral and central mechanisms regardless of distal or proximal pathology. Lower limb tremor correlates with peripheral nerve function and contributes to imbalance. SIGNIFICANCE: This study contributes to the understanding of neuropathic tremor. Addressing lower limb tremor may be of therapeutic importance for neuropathy-associated imbalance.

Upper and lower limb tremor in Charcot-Marie-Tooth neuropathy type 1A and the implications for standing balance.

BACKGROUND: Neuropathic tremor occurs in Charcot-Marie-Tooth neuropathy type 1A (CMT1A; hereditary motor and sensory neuropathy, HMSN), although the pathophysiological mechanisms remain to be elucidated. Separately, lower limb tremor has not been explored in CMT1A and could be associated with imbalance as in other neuropathies. The present study aimed to determine tremor characteristics in the upper and lower limbs in CMT1A and relate these findings to clinical disability, particularly imbalance. METHODS: Tremor and posturography studies were undertaken in phenotyped and genotyped CMT1A patients. Participants underwent detailed clinical assessment, tremor study recordings, and nerve conduction studies. Tremor stability index was calculated for upper limb tremor and compared to essential tremor. RESULTS: Seventeen patients were enrolled. Postural and kinetic upper limb tremors were evident in 65%, while postural and orthostatic lower limb tremors were seen in 35% of CMT1A patients. Peak upper limb frequencies were lower distally (~ 6 Hz) and higher proximally (~ 9 Hz), were unchanged by weight-loading, and not impacted by fatigue. The tremor stability index was significantly higher in CMT1A than in essential tremor. A 5-6 Hz lower limb tremor was recorded which did not vary along the limb and was unaffected by fatigue. Balance was impaired in patients with postural lower limb tremor. A high frequency peak on posturography was associated with 'good' balance. CONCLUSIONS: Tremor is a common clinical feature in CMT1A, distinct from essential tremor, mediated by a complex interaction between peripheral and central mechanisms. Postural lower limb tremor is associated with imbalance; strategies aimed at tremor modulation could be of therapeutic utility.

Imbalance and lower limb tremor in chronic inflammatory demyelinating polyradiculoneuropathy.

BACKGROUND AND AIMS: Imbalance is a prominent symptom of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Although upper limb tremor in CIDP is described, lower limb tremor has not been assessed. The aim of this study was to determine whether lower limb tremor was present in CIDP and assess potential relationships with imbalance. METHODS: This was a cross-sectional observational study of prospectively recruited consecutive patients with typical CIDP (N = 25). Clinical phenotyping, lower limb nerve conduction and tremor studies, and posturography analyses were performed. The Berg Balance Scale (BBS) divided CIDP patients into those with "good" and "poor" balance. RESULTS: Lower limb tremor was evident in 32% of CIDP patients and associated with poor balance (BBSTremor 35 [23-46], BBSNo Tremor 52 [44-55], p = .035). Tremor frequency was 10.2-12.5 Hz with legs outstretched and on standing, apart from four patients with a lower frequency tremor (3.8-4.6 Hz) while standing. Posturography analysis revealed a high-frequency spectral peak in the vertical axis in 44% of CIDP patients (16.0 ± 0.4 Hz). This was more likely in those with "good" balance (40% vs. 4%, p = .013). INTERPRETATION: Lower limb tremor is present in one third of CIDP patients and is associated with poor balance. A high-frequency peak on posturography is associated with better balance in CIDP. Lower limb tremor and posturography assessments could serve as important biomarkers of balance in a clinical setting.

Advances in diagnosis and management of distal sensory polyneuropathies.

Distal sensory polyneuropathy (DSP) is characterised by length-dependent, sensory-predominant symptoms and signs, including potentially disabling symmetric chronic pain, tingling and poor balance. Some patients also have or develop dysautonomia or motor involvement depending on whether large myelinated or small fibres are predominantly affected. Although highly prevalent, diagnosis and management can be challenging. While classic diabetes and toxic causes are well-recognised, there are increasingly diverse associations, including with dysimmune, rheumatological and neurodegenerative conditions. Approximately half of cases are initially considered idiopathic despite thorough evaluation, but often, the causes emerge later as new symptoms develop or testing advances, for instance with genetic approaches. Improving and standardising DSP metrics, as already accomplished for motor neuropathies, would permit in-clinic longitudinal tracking of natural history and treatment responses. Standardising phenotyping could advance research and facilitate trials of potential therapies, which lag so far. This review updates on recent advances and summarises current evidence for specific treatments.

Chronic inflammatory demyelinating polyradiculoneuropathy-associated tremor: Phenotype and pathogenesis.

BACKGROUND AND PURPOSE: Tremor in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is underrecognized, and the pathophysiology remains incompletely understood. This study evaluated tremor in CIDP and tested the hypothesis, established in other demyelinating neuropathies, that tremor occurs due to mistimed peripheral inputs affecting central motor processing. Additionally, the tremor stability index (TSI) was calculated with the hypothesis that CIDP-related tremor is more variable than other tremor disorders. METHODS: Consecutive patients with typical CIDP were prospectively recruited from neuromuscular clinics. Alternative causes of neuropathy and tremor were excluded. Cross-sectional clinical assessment and extensive tremor study recordings were undertaken. Pearson correlation coefficient was used to compare nerve conduction studies and tremor characteristics, and t-test was used for comparisons between groups. RESULTS: Twenty-four patients with CIDP were included. Upper limb postural and action tremor was present in 66% and was mild according to the Essential Tremor Rating Assessment Scale. Tremor did not significantly impact disability. Surface electromyography (EMG) found high-frequency spectral peaks in deltoid (13.73 ± 0.66 Hz), biceps brachii (11.82 ± 0.91 Hz), and extensor carpi radialis (11.87 ± 0.91 Hz) muscles, with lower peaks in abductor pollicis brevis EMG (6.07 ± 0.45 Hz) and index finger accelerometry (6.53 ± 0.42 Hz). Tremor was unchanged by weight loading but correlated with ulnar nerve F-wave latency and median nerve sensory amplitude. TSI (2.3 ± 0.1) was significantly higher than essential tremor. CONCLUSIONS: Postural tremor is a common feature in CIDP. Tremor was unaffected by weight loading, typical of centrally generated tremors, although there was a correlation with peripheral nerve abnormalities. The high beat-to-beat variability on TSI and gradation of peak frequencies further suggest a complex pathophysiology. These findings may assist clinicians with the diagnosis of neuropathic tremor.

Electrodiagnostic findings in facial onset sensory motor neuronopathy (FOSMN).

OBJECTIVE: To determine the electrodiagnostic characteristics of facial onset sensory and motor neuronopathy (FOSMN). METHODS: Electrophysiological data from 10 FOSMN patients in Newcastle-upon-Tyne and Sydney were reviewed. Relevant literature was reviewed. RESULTS: Findings on standard electrophysiological assessment were in broad agreement with those published: blink reflexes were abnormal in all but one patient; sensory nerve action potentials were reduced but compound muscle action potentials preserved; mixed acute and chronic neurogenic change was identified on needle electromyography in bulbar and cervico-thoracic muscles in approximately 50% of patients. Upper limb somatosensory evoked potential (SEP) central conduction times were increased (n = 4) and progressed on repeat testing (n = 3). Upper motor neuron dysfunction was revealed by several measures [ipsilateral motor evoked potentials (MEPs) (n = 1); reduced short interval intra-cortical inhibition on threshold-tracking transcranial magnetic stimulation (n = 2); absent beta-band intermuscular coherence (n = 3)]. CONCLUSIONS: Electrodiagnostic investigation of FOSMN should include blink reflex testing, SEPs and tests of upper motor neuron function. The combination of progressive lower motor neuron disease and upper motor neuron disease on neurophysiological investigation provides further support for the contention that FOSMN is a rare variant of motor neurone disease. SIGNIFICANCE: These findings will aid the neurologist and neurophysiologist in making a confident diagnosis of FOSMN, thus expediting appropriate care.

Posturography as a biomarker of intravenous immunoglobulin efficacy in chronic inflammatory demyelinating polyradiculoneuropathy.

INTRODUCTION/AIMS: Imbalance is a common feature of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Intravenous immunoglobulin (IVIg) exerts clinical benefit in CIDP, including improving balance, although objective markers of efficacy are lacking. Posturography is an established objective marker of balance; therefore, this study aimed to determine the utility of posturography as an objective marker of treatment efficacy in CIDP. METHODS: Posturography was performed on 18 CIDP patients, established on IVIg infusions, and results were compared to age-matched healthy controls. CIDP patients were assessed just prior to IVIg infusion and at the mid-point of the cycle. Center of pressure (CoP) was measured and the total path traveled by CoP (Sway Path, SP) was calculated for five different conditions: feet placed in parallel 16 cm apart at the medial border with eyes open (16cmEO) and eyes closed (16cmEC); medial borders of the feet touching with eyes open (0cmEO) and eyes closed (0cmEC); and tandem stance. RESULTS: The sway path (SP) was significantly increased in CIDP patients (mean SP 1191 ± 104 mm) when compared to healthy controls (mean SP 724 ± 26 mm, P < .001). The increase was most prominent during eyes closed and tandem stance conditions. Treatment with IVIg significantly reduced SP when assessing 0cmEC (1759 ± 324 mm vs. 1081 ± 134 mm, P = .019) and tandem stance (1775 ± 290 mm vs. 1152 ± 113 mm, P = .027). DISCUSSION: Posturography detected significant improvements in balance following IVIg in CIDP patients established on maintenance therapy. As such, posturography may be considered an objective marker of treatment response in clinical management and therapeutic trials.

New onset headache caused by histiocytic sarcoma of the spinal cord and leptomeninges: a case report.

BACKGROUND: Headache due to raised intracranial pressure is rarely caused by spinal lesions. We describe a patient with primary histiocytic sarcoma who presented with a new onset headache with features of raised intracranial pressure and subtle signs of cauda equina syndrome due to predominant lower spinal cord infiltration and minimal intracranial involvement. CASE: A previously well 54-year-old man presented with a 2-month history of new onset headache with features of raised intracranial pressure. Progression of lower limb weakness was delayed and mild with diagnostic delay resulting from the primary presentation with headache leading to an initial focus on cerebral pathology. Subsequent investigations revealed a previously unreported presentation of primary histiocytic sarcoma infiltrating the cauda equina causing raised intracranial pressure headache. CONCLUSION: This case highlights the importance of a broad search in the investigation of new onset raised intracranial pressure headache, including imaging of the lower spinal cord. Primary histiocytic sarcoma should be considered in the differential diagnosis of this rare syndrome.

Proximal Median Neuropathy Following Anterior Shoulder Dislocation: The Use of Magnetic Resonance Neurography.

Proximal median nerve injury is an uncommon consequence of anterior shoulder dislocation, especially occurring in isolation of other upper limb peripheral nerve injury. We report the case of an 82-year-old woman with a median nerve injury as detected by clinical and neurophysiological examination following a fall and anterior shoulder dislocation. Magnetic resonance neurography confirmed the diagnosis, but also detected asymptomatic brachial plexus and ulnar nerve involvement. Management was non-operative and there has been some improvement over several months. Our case expands the differential diagnosis for proximal median neuropathy and discusses the utility of neurography in cases of neural injury.

TDP-43 proteinopathies: a new wave of neurodegenerative diseases.

Inclusions of pathogenic deposits containing TAR DNA-binding protein 43 (TDP-43) are evident in the brain and spinal cord of patients that present across a spectrum of neurodegenerative diseases. For instance, the majority of patients with sporadic amyotrophic lateral sclerosis (up to 97%) and a substantial proportion of patients with frontotemporal lobar degeneration (~45%) exhibit TDP-43 positive neuronal inclusions, suggesting a role for this protein in disease pathogenesis. In addition, TDP-43 inclusions are evident in familial ALS phenotypes linked to multiple gene mutations including the TDP-43 gene coding (TARDBP) and unrelated genes (eg, C9orf72). While TDP-43 is an essential RNA/DNA binding protein critical for RNA-related metabolism, determining the pathophysiological mechanisms through which TDP-43 mediates neurodegeneration appears complex, and unravelling these molecular processes seems critical for the development of effective therapies. This review highlights the key physiological functions of the TDP-43 protein, while considering an expanding spectrum of neurodegenerative diseases associated with pathogenic TDP-43 deposition, and dissecting key molecular pathways through which TDP-43 may mediate neurodegeneration.

Investigation of tumefactive demyelination is associated with higher economic burden and more adverse events compared with conventional multiple sclerosis.

BACKGROUND: Tumefactive demyelinating lesions occur as part of the spectrum of multiple sclerosis (MS), but can be difficult to distinguish from other large cerebral lesions such as neoplasm or abscess. OBJECTIVES: To estimate the cost associated with diagnostic investigation of patients with tumefactive demyelination (TD), including associated morbidity, and compare this to more typical relapsing-remitting MS. METHODS: Retrospective review of medical records of patients seen between 2013 and 2018 in clinics at the Brain and Mind Centre, Sydney, Australia; a center with tertiary referral expertise in MS. RESULTS: Thirty-one patients with TD and 31 patients with MS were compared. The cost of investigating TD was more than 7.5 times higher per patient than MS ($18,300 vs $2418, p < 0.01). More patients in the TD group were admitted to hospital (22/31 versus 10/31) and ICU admissions only occurred in the TD group (10/22 versus 0/10). Brain biopsy was performed only in the TD group (7 patients), which contributed to cost differences and also accounted for differences in adverse outcomes. CONCLUSION: The cost and morbidity related to investigating TD is higher than in typical MS. Improvements in the diagnosis of TD have the potential to improve health and economic outcomes.

Time to acute stroke treatment in-hours was more than halved after the introduction of the Helsinki Model at Westmead Hospital.

BACKGROUND: Management of acute ischaemic stroke is time critical. Reducing time to treatment with thrombolysis is strongly associated with improved outcomes in properly selected patients. However, there are barriers to ensuring timely treatment in the hospital setting. AIM: To determine if simple, no-cost protocol changes could improve time to treatment for acute ischaemic stroke at a busy tertiary hospital. METHODS: Prospectively collected routine clinical data were compared retrospectively before and after a protocol change designed to mirror the successful model from Helsinki University Central Hospital. Consecutive patients who activated a 'code stroke' (presentation consistent with acute stroke, eligible for acute stroke therapy) during working hours were included. RESULTS: Prior to the protocol change, 143 patients activated a code stroke, and 30 patients received thrombolysis. Following the protocol change, 134 patients activated a code stroke, and 14 patients received thrombolysis. The median time to administer thrombolysis was reduced from 76 min (interquartile range 54-91) to 33 min (27-44), P < 0.01. The median time to perform diagnostic computed tomography was unchanged between the two groups, 23 (14-54) min versus 22 (9-49) min, P = 0.12. However, this was reduced on subgroup analysis of patients whose arrival was pre-notified by the ambulance service, 16 (9-22) min versus 8 (4-14) min, P < 0.01. CONCLUSION: Time to treatment in acute stroke was dramatically improved with a simple intervention. This was achieved without a large stroke team or additional funding, making it highly accessible to other health services also seeking to improve their stroke service.

Novel Surrogate Markers of CNS Inflammation in CSF in the Diagnosis of Autoimmune Encephalitis.

Background: Autoimmune encephalitis (AE) is an important cause of refractory epilepsy, rapidly progressive cognitive decline, and unexplained movement disorders in adults. Whilst there is identification of an increasing number of associated autoantibodies, patients remain with a high clinical probability of autoimmune encephalitis but no associated characterized autoantibody. These patients represent a diagnostic and treatment dilemma. Objective: To evaluate routine and novel diagnostic tests of cerebrospinal fluid (CSF) in patients with a high probability of AE to attempt to identify better biomarkers of neuroinflammation. Methods: Over 18 months (2016-2018), adult patients with a high clinical probability of AE were recruited for a pilot cross-sectional explorative study. We also included viral polymerase-chain-reaction (PCR) positive CSF samples and CSF from neurology patients with "non-inflammatory" (NI) diagnoses for comparison. CSF was examined with standard investigations for encephalitis and novel markers (CSF light chains, and cytokines). Results and Conclusions: Thirty-two AE patients were recruited over 18 months. Twenty-one viral controls, 10 NI controls, and five other autoimmune neurological disease controls (AOND) were also included in the analysis. Our study found that conventional markers: presence of CSF monocytosis, oligoclonal bands, anti-neuronal immunofluorescence, and magnetic resonance imaging (MRI) changes could be suggestive of AE, but these investigations were neither sensitive nor specific. Promising novel makers of autoimmune encephalitis were the CSF cytokines IL-21 and IP10 which may provide better delineation between viral infections and autoimmune encephalitis than conventional markers, potentially leading to more immediate diagnosis and management of these patients.

Miller Fisher Syndrome Associated With Immunotherapy for Metastatic Melanoma.

Immunotherapy is a treatment strategy that has demonstrated survival benefit for metastatic melanoma. Ipilimumab and nivolumab are examples of immunotherapy, in which monoclonal antibodies antagonize cytotoxic T-lymphocyte-associated protein 4 and programmed death-ligand 1 receptors, respectively, resulting in upregulation of the host immune response to cancer cells. There is increasing recognition of immune-mediated adverse events associated with immune therapies in patients with cancer. We present a case report of a patient who developed Miller Fisher syndrome associated with these therapies for metastatic melanoma along with a discussion of its management.