Peripherin is a biomarker of axonal damage in peripheral nervous system disease.

Valid, responsive blood biomarkers specific to peripheral nerve damage would improve management of peripheral nervous system (PNS) diseases. Neurofilament light chain (NfL) is sensitive for detecting axonal pathology but is not specific to PNS damage, as it is expressed throughout the PNS and CNS. Peripherin, another intermediate filament protein, is almost exclusively expressed in peripheral nerve axons. We postulated that peripherin would be a promising blood biomarker of PNS axonal damage. We demonstrated that peripherin is distributed in sciatic nerve, and to a lesser extent spinal cord tissue lysates, but not in brain or extra-neural tissues. In the spinal cord, anti-peripherin antibody bound only to the primary cells of the periphery (anterior horn cells, motor axons and primary afferent sensory axons). In vitro models of antibody-mediated axonal and demyelinating nerve injury showed marked elevation of peripherin levels only in axonal damage and only a minimal rise in demyelination. We developed an immunoassay using single molecule array technology for the detection of serum peripherin as a biomarker for PNS axonal damage. We examined longitudinal serum peripherin and NfL concentrations in individuals with Guillain-Barré syndrome (GBS, n = 45, 179 time points), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP, n = 35, 70 time points), multiple sclerosis (n = 30), dementia (as non-inflammatory CNS controls, n = 30) and healthy individuals (n = 24). Peak peripherin levels were higher in GBS than all other groups (median 18.75 pg/ml versus < 6.98 pg/ml, P < 0.0001). Peak NfL was highest in GBS (median 220.8 pg/ml) and lowest in healthy controls (median 5.6 pg/ml), but NfL did not distinguish between CIDP (17.3 pg/ml), multiple sclerosis (21.5 pg/ml) and dementia (29.9 pg/ml). While peak NfL levels were higher with older age (rho = +0.39, P < 0.0001), peak peripherin levels did not vary with age. In GBS, local regression analysis of serial peripherin in the majority of individuals with three or more time points of data (16/25) displayed a rise-and-fall pattern with the highest value within the first week of initial assessment. Similar analysis of serial NfL concentrations showed a later peak at 16 days. Group analysis of serum peripherin and NfL levels in GBS and CIDP patients were not significantly associated with clinical data, but in some individuals with GBS, peripherin levels appeared to better reflect clinical outcome measure improvement. Serum peripherin is a promising new, dynamic and specific biomarker of acute PNS axonal damage.

Toxic neuropathies: a practical approach.

Toxic neuropathies result from exogenous substances damaging the peripheral nerves. There are numerous causes, including prescribed and recreational drugs, heavy metals, industrial agents and biological toxins. Timely recognition of these neuropathies gives better outcomes, as they usually improve or stabilise once the toxin is removed. Most toxic neuropathies are axonal, length-dependent and sensory predominant, although some have significant motor involvement or can present acutely or subacutely. Here, we outline our clinical approach and discuss the major causes of toxic neuropathy, while emphasising the clinical and neurophysiological features and the neuropathy phenotype. We also include an update on newer medications that can cause neuropathy, including immune checkpoint inhibitors and BRAF/MEK inhibitors.

The endogenous calpain inhibitor calpastatin attenuates axon degeneration in murine Guillain-Barré syndrome.

Axon degeneration accounts for the poor clinical outcome in Guillain-Barré syndrome (GBS), yet no treatments target this key pathogenic stage. Animal models demonstrate anti-ganglioside antibodies (AGAb) induce axolemmal complement pore formation through which calcium flux activates the intra-axonal calcium-dependent proteases, calpains. We previously showed protection of axonal components using soluble calpain inhibitors in ex vivo GBS mouse models, and herein, we assess the potential of axonally-restricted calpain inhibition as a neuroprotective therapy operating in vivo. Using transgenic mice that over-express the endogenous human calpain inhibitor calpastatin (hCAST) neuronally, we assessed distal motor nerve integrity in our established GBS models. We induced immune-mediated injury with monoclonal AGAb plus a source of human complement. The calpain substrates neurofilament and AnkyrinG, nerve structural proteins, were assessed by immunolabelling and in the case of neurofilament, by single-molecule arrays (Simoa). As the distal intramuscular portion of the phrenic nerve is prominently targeted in our in vivo model, respiratory function was assessed by whole-body plethysmography as the functional output in the acute and extended models. hCAST expression protects distal nerve structural integrity both ex and in vivo, as shown by attenuation of neurofilament breakdown by immunolabelling and Simoa. In an extended in vivo model, while mice still initially undergo respiratory distress owing to acute conduction failure, the recovery phase was accelerated by hCAST expression. Axonal calpain inhibition can protect the axonal integrity of the nerve in an in vivo GBS paradigm and hasten recovery. These studies reinforce the strong justification for developing further animal and human clinical studies using exogenous calpain inhibitors.

Comprehensive Diagnosis and Management of POEMS Syndrome.

Polyneuropathy Organomegaly, Endocrinopathy, Monoclonal protein and Skin changes syndrome is a rare multisystem condition with a range of manifestations which are often overlooked as trivial comorbidities, until their whole triggers the possibility of the diagnosis. The diagnosis is typically delayed by 12-16 months, by which time patients can be severely disabled. There are no established consensus guidelines. We provide clinicians a comprehensive blueprint for managing POEMS from diagnostic suspicion through the work-up, selection of therapy, follow-up, and treatment of relapse based on published evidence and our large single-center experience. A multidisciplinary approach is essential including expert hematologists, neurologists, histopathologists, radiologists, and neurophysiologists. The aim of treatment is to eradicate the underlying plasma cell dyscrasia, but there are limited trial data to guide treatment decisions. Supportive care considerations include management of endocrinopathy, neuropathy, thrombosis, and infection. Response assessment is centered on clinical, neuropathy, hematological, vascular endothelial growth factor, and radiological criteria. Future clinical trials are welcomed in this setting where evidence is limited.

Daratumumab-bortezomib-dexamethasone use in relapsed POEMS syndrome.

POEMS syndrome is a rareparaneoplastic disorder driven by an underlying low level plasma cell dyscrasiaand associated with elevated serum vascular endothelial growth factor (VEGF). Dueto its rarity, there are no internationally agreed standards of care, with verylimited data to guide management in the relapse setting. Agents used in myelomaare rational choices and have been employed. Daratumumab has been reported intwo case studies with lenalidomide-dexamethasone, one in the upfront and one inthe relapsed setting. We are the first to report here three cases ofdaratumumab-bortezomib-dexamethasone (DVd) use in relapsed POEMS postautologous stem cell transplant with good VEGF and clinical responses. Our casesadd to the literature on efficacy of daratumumab and are the first to report onits safe use with bortezomib in relapsed POEMS. It should be considered as aclinical option, in patients not responding to conventional first linetherapies.

Vestibular migraine treatment: a comprehensive practical review.

Vestibular migraine is an underdiagnosed but increasingly recognized neurological condition that causes episodic vertigo associated with other features of migraine. It is now thought to be the most common cause of spontaneous (non-positional) episodic vertigo, affecting up to 1% of the population. A meta-analysis of preventative treatments for vestibular migraine was published in 2021, but the authors were unable to establish a preferred treatment strategy due to low quality of evidence and heterogeneity of study design and outcome reporting. Therefore, there remains a clinical need for pragmatic management guidelines specific to vestibular migraine using the available evidence. Here, we provide a practical review utilizing a systematic qualitative assessment of the evidence for abortive and preventative interventions in adults. The overall evidence base for vestibular migraine treatment is of low quality. Nevertheless, we provide practical treatment recommendations based on the available evidence and our experience to help guide clinicians treating patients with vestibular migraine. We also discuss how future clinical trials could be designed to improve the quality of evidence in this condition.

Bilateral Vestibular Failure May Improve With Treatment of the Underlying Condition: A Report of 2 Cases.

INTRODUCTION: Bilateral vestibular failure (BVF) is an uncommon condition with numerous etiologies. It causes chronic oscillopsia and imbalance and is usually irreversible. We report 2 cases of BVF due to unusual causes, both of which improved with treatment of the underlying condition. CASE REPORTS: The first patient was a 39-year-old female who developed profound BVF due to neurosarcoidosis. She was started on steroids and azathioprine and her vestibular function gradually improved, with essentially normal function 4.5 years after starting treatment. The second patient was a 54-year-old female who developed BVF in the context of glucagonoma. After treatment with octreotide, her vestibular function improved to almost normal, and she thus met the criteria for a probable paraneoplastic syndrome. CONCLUSIONS: While BVF is usually permanent, this report demonstrates that some cases are likely to be reversible with treatment of the underlying cause. It is therefore imperative for clinicians to ensure that patients with BVF are thoroughly investigated.

Fluid Biomarkers for Monitoring Structural Changes in Polyneuropathies: Their Use in Clinical Practice and Trials.

Reliable and responsive tools for monitoring disease activity and treatment outcomes in patients with neuropathies are lacking. With the emergence of ultrasensitive blood bioassays, proteins released with nerve damage are potentially useful response biomarkers for many neurological disorders, including polyneuropathies. In this review, we provide an overview of the existing literature focusing on potential applications in polyneuropathy clinical care and trials. Whilst several promising candidates have been identified, no studies have investigated if any of these proteins can serve as response biomarkers of longitudinal disease activity, except for neurofilament light (NfL). For NfL, limited evidence exists supporting a role as a response biomarker in Guillain-Barré syndrome, vasculitic neuropathy, and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Most evidence exists for NfL as a response biomarker in hereditary transthyretin-related amyloidosis (hATTR). At the present time, the role of NfL is therefore limited to a supporting clinical tool or exploratory endpoint in trials. Future developments will need to focus on the discovery of additional biomarkers for anatomically specific and other forms of nerve damage using high-throughput technologies and highly sensitive analytical platforms in adequality powered studies of appropriate design. For NfL, a better understanding of cut-off values, the relation to clinical symptoms and long-term disability as well as dynamics in serum on and off treatment is needed to further expand and proceed towards implementation.

Dietary nitrate reduces blood pressure and cerebral artery velocity fluctuations and improves cerebral autoregulation in transient ischemic attack patients.

Accentuated blood pressure (BP) fluctuation and low cerebral blood flow (CBF) response to CO2 increase the risk of transient ischemic attack (TIA) recurrence and stroke in TIA patients. Improving cardio- and cerebrovascular function may reduce stroke risk. We found dietary nitrate lowered dynamic blood pressure variability (BPV) in rats and improved cerebrovascular CO2 reactivity in healthy individuals. In 30 TIA patients, we examined the effects of a 7-day supplementation of dietary nitrate (0.1 mmol·kg-1·day-1) on cerebrovascular function using a randomized, single-blinded, placebo-controlled study design. We hypothesized that 7-day dietary nitrate supplementation would decrease variabilities in BP and CBF and improve CBF-CO2 slope and cerebral autoregulation (CA). We assessed beat-to-beat middle cerebral artery blood velocity (MCAv; index of CBF) and BP at rest and during CO2 breathing. Transfer function analysis was performed on beat-to-beat MCAv and BP to determine CA parameters (gain, phase, and coherence). Irrespective of treatment, high- and low-frequency BP-MCAv gain and MCAv-CO2 slope increased 7 days following TIA onset, while low-frequency BPV decreased (P < 0.05 vs. baseline). At follow-up, dietary nitrate elevated plasma nitrate concentration by ~547% (P < 0.001) and moderately lowered BPV (d = 0.6, P = 0.011), MCAv variability (d = 0.7, P = 0.018), and BP-MCAv coherence (d = 0.7, P = 0.008) in the very-low-frequency range (0.02-0.07 Hz), while MCAv-CO2 slope and arterial stiffness were unaffected (P > 0.05). Concurrent with standard treatment, dietary nitrate supplementation reduces BP and CBF fluctuation and improves cerebral autoregulation in TIA patients, without affecting cerebrovascular CO2 reactivity.NEW & NOTEWORTHY We found dietary nitrate supplementation reduced blood pressure and brain blood flow fluctuations and improved the relationship between blood pressure and brain blood flow in transient ischemic attack patients. Meanwhile, dietary nitrate had no effects on the brain blood vessels' response to CO2. We attribute the improved brain blood flow stability to the improved myogenic control of blood pressure with dietary nitrate. Our findings indicate that dietary nitrate could be an effective strategy for stabilizing blood pressure and brain blood flow following transient ischemic attack.

Safety and acceptability of clozapine and risperidone in progressive multiple sclerosis: a phase I, randomised, blinded, placebo-controlled trial.

OBJECTIVE: Because clozapine and risperidone have been shown to reduce neuroinflammation in humans and mice, the Clozapine and Risperidone in Progressive Multiple Sclerosis (CRISP) trial was conducted to determine whether clozapine and risperidone are suitable for progressive multiple sclerosis (pMS). METHODS: The CRISP trial (ACTRN12616000178448) was a blinded, randomised, placebo-controlled trial with three parallel arms (n=12/arm). Participants with pMS were randomised to clozapine (100-150 mg/day), risperidone (2.0-3.5 mg/day) or placebo for 6 months. The primary outcome measures were safety (adverse events (AEs)/serious adverse events (SAE)) and acceptability (Treatment Satisfaction Questionnaire for Medication-9). RESULTS: An interim analysis (n=9) revealed significant differences in the time-on-trial between treatment groups and placebo (p=0.030 and 0.025, clozapine and risperidone, respectively) with all participants receiving clozapine being withdrawn during the titration period (mean dose=35±15 mg/day). Participants receiving clozapine or risperidone reported a significantly higher rate of AEs than placebo (p=0.00001) but not SAEs. Specifically, low doses of clozapine appeared to cause an acute and dose-related intoxicant effect in patients with pMS who had fairly severe chronic spastic ataxic gait and worsening over all mobility, which resolved on drug cessation. INTERPRETATION: The CRISP trial results suggest that patients with pMS may experience increased sensitivity to clozapine and risperidone and indicate that the dose and/or titration schedule developed for schizophrenia may not be suitable for pMS. While these findings do not negate the potential of these drugs to reduce multiple sclerosis-associated neuroinflammation, they highlight the need for further research to understand the pharmacodynamic profile and effect of clozapine and risperidone in patients with pMS. TRIAL REGISTRATION NUMBER: ACTRN12616000178448.

Gentamicin vestibulotoxicity with modern systemic dosing regimens: a prospective study using video-oculography.

Objectives: To determine the incidence of gentamicin vestibulotoxicity with current dosing regimens, and to evaluate the feasibility of routine video-oculography on all patients given gentamicin. Materials and methods: In this prospective incidence study serial horizontal vestibulo-ocular reflex (HVOR) gain measurements were recorded using video-oculography on adult inpatients receiving intravenous gentamicin. The primary outcome was the proportion of patients developing impairment of their HVOR gain. Results: After exclusions, 42 patients were included in the analysis. Three patients (7.1%) developed asymptomatic vestibulotoxicity, exact 95% confidence interval 1.5-19.5%. In two of these patients the deficit resolved within several hours. No patients developed symptomatic vestibulotoxicity. There was no evidence for a generalised reduction in group HVOR gain with time. HVOR gain was not associated with total gentamicin dose, dynamic visual acuity or subjective imbalance. Conclusions and significance: Gentamicin may cause reversible, asymptomatic vestibulotoxicity. Video-oculography may be useful to monitor for vestibulotoxicity in patients treated with gentamcin; however, testing all patients routinely may be challenging.

Decompressive hemicraniectomy after malignant middle cerebral artery infarction: does hospital of origin matter?

Decompressive hemicraniectomy (DHC) has been shown to reduce mortality in malignant middle cerebral artery (MCA) infarction. Our primary objective was to compare 1-year mortality between patients receiving DHC for malignant MCA infarction at our institution based on hospital of origin. We retrospectively reviewed the medical records of all patients treated for malignant MCA infarction with DHC at our institution over a 3-year period. One-year mortality rates and time to surgery were comparable regardless of whether the patient first attended the tertiary referral centre or a peripheral centre.

A case of botulism in New Zealand.

We describe the first case of food-borne botulism seen in New Zealand for 30 years. Botulism is an important diagnosis to consider in a patient with rapidly progressive descending paralysis and normal sensorium. Early recognition, timely institution of intensive care support and administration of botulism antitoxin are the most important aspects of management.

Identification of factors associated with a need for rehabilitation for patients over 65 years following admission to a general and vascular surgical service.

AIM: To identify factors that predict admission to a rehabilitation hospital for patients over 65 years of age. METHODS: This study reviewed the destinations of all patients over 65 years admitted to a Department of General and Vascular Surgery over 1 year to analyse factors associated with subsequent admission to a rehabilitation hospital. Data recorded included demographic characteristics, type of admission, length of stay at the primary hospital, operation, speciality type, previous admission to rehabilitation hospital, diagnoses and procedures. RESULTS: Of the 2632 patients examined, 8.7% were subsequently admitted to a rehabilitation hospital. Multivariate analysis showed that previous admission to the rehabilitation hospital, increasing age, number of diagnoses and admission under vascular service were all independently associated with admission for rehabilitation. CONCLUSIONS: Factors associated with increased risk of requiring transfer to a rehabilitation hospital can be identified. This allows early recognition of at-risk patients.