Global uncertainty in the diagnosis of neurological complications of SARS-CoV-2 infection by both neurologists and non-neurologists: An international inter-observer variability study.

INTRODUCTION: Uniform case definitions are required to ensure harmonised reporting of neurological syndromes associated with SARS-CoV-2. Moreover, it is unclear how clinicians perceive the relative importance of SARS-CoV-2 in neurological syndromes, which risks under- or over-reporting. METHODS: We invited clinicians through global networks, including the World Federation of Neurology, to assess ten anonymised vignettes of SARS-CoV-2 neurological syndromes. Using standardised case definitions, clinicians assigned a diagnosis and ranked association with SARS-CoV-2. We compared diagnostic accuracy and assigned association ranks between different settings and specialties and calculated inter-rater agreement for case definitions as "poor" (κ ≤ 0.4), "moderate" or "good" (κ > 0.6). RESULTS: 1265 diagnoses were assigned by 146 participants from 45 countries on six continents. The highest correct proportion were cerebral venous sinus thrombosis (CVST, 95.8%), Guillain-Barré syndrome (GBS, 92.4%) and headache (91.6%) and the lowest encephalitis (72.8%), psychosis (53.8%) and encephalopathy (43.2%). Diagnostic accuracy was similar between neurologists and non-neurologists (median score 8 vs. 7/10, p = 0.1). Good inter-rater agreement was observed for five diagnoses: cranial neuropathy, headache, myelitis, CVST, and GBS and poor agreement for encephalopathy. In 13% of vignettes, clinicians incorrectly assigned lowest association ranks, regardless of setting and specialty. CONCLUSION: The case definitions can help with reporting of neurological complications of SARS-CoV-2, also in settings with few neurologists. However, encephalopathy, encephalitis, and psychosis were often misdiagnosed, and clinicians underestimated the association with SARS-CoV-2. Future work should refine the case definitions and provide training if global reporting of neurological syndromes associated with SARS-CoV-2 is to be robust.

Calcium regulation during stimulus-secretion coupling: continuous measurement of intracellular calcium activities.

Accurate measurements of intracellular calcium activities in salivary gland epithelial cells of the insect Phormia regina were obtained with microelectrodes in which N,N'-di(11-ethoxycarbonyl)undecyl-N,N'-4,5-tetramethyl-3,6-dioxaoctane diacid diamide wsa incorporated in a liquid membrane system. When calibrated in solutions approximating the ionic concentration of the cell interior, these microelectrodes gave rapid stable responses that were linear functions of the logarithm of calcium activities and were not affected by potassium, sodium and magnesium. Continuous monitoring of calcium activities during serotonin-induced saliva release provided direct evidence of hormonal influence on transmembrane calcium movement and spontaneous regulation of intracellular calcium by stimulated cells.

Insulin does not act by causing a change in membrane potential or intracellular free sodium and potassium concentration of adipocytes.

The influence of insulin on the intracellular free sodium and potassium ion concentrations ([Na+]i, [K+]i) and resting membrane potential of rat epididymal adipocytes was examined to determine its potential for mediating insulin's action on other cellular processes. Direct intracellular measurements of [Na+]i, [K+]i, and the resting membrane potential were made using ion-selective and conventional microelectrodes. The use of these microelectrodes enabled us to continuously monitor these parameters in the same cell before, during, and after periods of insulin stimulation of up to 20-min duration. The electrical potentials measured in these experiments remained unchanged when the cells were stimulated with insulin (0.01, 0.1, or 1.0 mU/ml). Varying the extracellular glucose concentration had no effect on these results. Our results provide the first direct measurement of [Na+]i and [K+]i in adipose tissue and clearly demonstrate that the response to insulin's association with its receptors on the cell surface and subsequent action on hexose transport and cellular metabolism does not involve a change in membrane potential or intracellular sodium and potassium ions.

Eosinophilc polymyositis.

A case of eosinophilic polymyositis is reported. Tender muscle swelling was followed by proximal weakness, creatinine kinase elevation, and electromyographic features typical of polymyositis. Severe myocarditis, pericarditis and heart failure were present. Muscle biopsy specimen showed active myositis with eosinophil infiltrate. Unlike previous cases, blood eosinophils count was normal. The clinical response to corticosteroids was excellent, and a relapse occurring as steroid dose was lowered responded rapidly to an increased dose of prednisolone. Eosinophilic polymyositis may be a component of a general systemic illness with prominent cardiac involvement.

Tonic contraversive ocular tilt reaction due to unilateral meso-diencephalic lesion.

We studied 4 patients with tonic contraversive ocular tilt reactions due to unilateral, paramedian, mesodiencephalic lesions. This is in contrast to the only 2 previously reported patients with ocular tilt reactions due to unilateral mesodiencephalic lesions, each of whom had a paroxysmal ipsiversive ocular tilt reaction. This new finding is considered in the context of previous clinical and experimental data on the various types of ocular tilt reactions that follow stimulation or destruction of the peripheral and central vestibular system. Otolithic inputs to the interstitial nucleus of Cajal from the contralateral vestibular nucleus and motor outputs from the interstitial nucleus of Cajal to cervical and ocular motoneurons could be involved in the ocular tilt reaction. We propose that in patients with unilateral meso-diencephalic lesions, a tonic contraversive ocular tilt reaction could be due to persistently decreased resting activity of ipsilateral interstitial nucleus neurons, whereas a paroxysmal ipsiversive ocular tilt reaction could be due to transiently increased activity of the same interstitial nucleus neurons. Cases of ocular tilt reaction due to unilateral meso-diencephalic lesion point to the existence of a crossed graviceptive pathway between the vestibular nucleus and the contralateral interstitial nucleus of Cajal.

Supranuclear ophthalmoplegia with basilar artery aneurysms.

In two patients, large aneurysms of the basilar artery produced a supranuclear gaze paresis, involving horizontal gaze in one case and vertical gaze in the other. In both cases the diagnosis was suggested by computed tomography and confirmed by vertebral angiography. Autopsy findings in one case confirmed the diagnosis. Although supranuclear gaze palsies must reflect damage to structures deep within the brain stem, these cases illustrate that an extrinsic lesion may produce such damage indirectly. Basilar artery aneurysm should be considered in patients presenting with supranuclear gaze paresis and long tract signs.

Hunter syndrome complicated by hydrocephalus and an endogenous anticoagulant.

This case illustrates the features of Hunter syndrome (mucopolysaccharidosis type 2) complicated by hydrocephalus and a prolonged activated partial thromboplastin time (APTT). Ventriculo-peritoneal shunt insertion was performed but was complicated by an extradural haematoma which was successfully drained. Other neurological complications of Hunter syndrome include compressive cervical myelopathy, diffuse cerebral white matter changes and punctate lesions in the basal ganglia. This case is the first report of a coagulation defect in a patient with Hunter syndrome.

Mechanical properties of the equine superficial digital flexor tendon relate to specific collagen cross-link levels.

REASONS FOR PERFORMING STUDY: Damage to the flexor tendons, particularly the superficial digital flexor tendon (SDFT), is one of the most common musculoskeletal injuries sustained by horses competing in all disciplines. Our previous work has shown that SDFTs from different individuals show a wide variation in mechanical strengths; this is important clinically as it may relate to predisposition to injury. The high mechanical strength of tendon relies on the correct orientation of collagen molecules within fibrils and stabilisation by the formation of chemical cross-links between collagen molecules. It is not known whether the variation in SDFT mechanical properties between individuals relates to differences in collagen cross-link levels. HYPOTHESIS: Enzyme-derived, intermolecular cross-linking of tendon collagen correlates with mechanical properties of the SDFT. METHODS: SDFTs were collected from 38 horses and mechanically tested to failure. Structural and material properties were calculated from the load/deformation plot and cross-sectional area for each tendon. Following mechanical testing, pyrrolic cross-link levels were measured using a spectrophotometric assay for Ehrlich's reactivity and pyridinoline levels were quantified by HPLC. Cross-link levels were correlated with mechanical properties and statistical significance tested using a Pearson's correlation test. RESULTS: Pyrrole cross-link levels showed a significant positive correlation with ultimate stress (P = 0.004), yield stress (P = 0.003) and elastic modulus (P = 0.018) of the tendons, despite being a minor cross-link in these tendons. There was no significant correlation of mechanical properties with either hydroxylysyl- or lysyl-pyridinoline levels. CONCLUSIONS: Given the low absolute levels of pyrrole, we suggest that the correlation with high mechanical strength is through an indirect mechanism. Understanding the nature of the relationships between pyrrole cross-links, other matrix characteristics and tendon material properties may allow development of strategies to identify horses at risk from tendon injury and be of value in informing training practices.

Polymyositis presenting with severe weakness involving only one arm.

A woman presented with severe weakness and wasting involving only one arm. A definite diagnosis was not made until almost six years later when she developed proximal weakness in the legs as well, and a muscle biopsy showed changes of polymyositis. Asymmetry of weakness in polymyositis has been noted previously in the literature, but is rare. In previous reports asymmetry as marked as in the present case has not been noted.

Spasticity due to phenytoin toxicity.

A young epileptic presented with spasticity as well as ataxia, diplopia and nystagmus; his serum phenytoin level was very high. All the abnormal signs disappeared after withdrawal of phenytoin. Spasticity, hyperreflexia, and clonus are features of phenytoin intoxication, present in this case, which are not commonly seen, and which have rarely been mentioned previously in the literature.

Intravenous lignocaine (lidocaine) infusion for the treatment of chronic daily headache with substantial medication overuse.

Patients with chronic daily headache with medication overuse are difficult to treat, especially when the doses of analgesia are substantial. We have previously shown that intravenous lignocaine (lidocaine) infusion is useful in maintaining pain control while the offending analgesic agent is withdrawn in these patients. The published data on long-term efficacy of this treatment is limited. We undertook a retrospective survey of 71 consecutive patients admitted for lignocaine infusion (mean 8.7 days) for treatment of chronic daily headache, with substantial analgesic abuse. Ninety percent of patients had a history of migraine headaches. In 80% of patients codeine was the predominant agent implicated in the analgesic rebound headaches (mean 1053 mg/week) and 24% used ergotamine-containing medications (mean 16 mg/week). Thirty-one percent frequently used injected narcotics. At completion 90% reported that their daily headache was absent or improved, and the analgesic agent was withdrawn successfully in 97%. At six month follow-up, 70% of patients reported that their daily headache was absent or improved and 72% of patients remained free of the offending analgesic agent. Intravenous lignocaine is a useful treatment in the management of chronic daily headache with substantial medication overuse. The benefits of the program last for at least six months.

A transcellular route for Na-coupled Cl transport in secreting pancreatic acinar cells.

Ion-selective microelectrodes were employed to determine the electrochemical driving forces involved in the transepithelial transport of Na+ and Cl- during acetylcholine (ACh) stimulation of pancreatic acinar cells. In HCO-3-free Ringer solution, the mean values of intracellular Cl and Na activities (aiCl and aiNa) were 68.9 +/- 1.1 and 8.3 +/- 0.3 mM, respectively. The mean value of aiCl is above the calculated equilibrium value, indicating that Cl entry into the cell is an energy-requiring process. Continuous measurement of intracellular electrode potentials during stimulation of the cells with concentrations of ACh ranging from 10(-7) to 10(-5) M demonstrated the neurotransmitter's influence on transmembrane Na+ and Cl- movement in secreting cells. The mean values of the induced changes in aiCl and aiNa at every concentration of ACh measured were not significantly different (P greater than 0.5), although the mean changes in either aiNa or aiCl determined with every decade change in ACh concentration were significant (P less than 0.05). The transmembrane Na+ electrochemical gradient dissipated with the induced increases in aiCl. These results suggest that, during stimulus-secretion coupling of pancreatic acinar cells, there is a transcellular route for NaCl secretion, and the energy for NaCl entry into the cell may be derived from the Na+ electrochemical gradient that exists across the basolateral epithelial membrane. They also suggest that the ACh-induced changes in ionic permeability of the plasma membrane may be the coupling mechanism by which the simultaneous events enzyme release and electrolyte secretion are controlled in stimulated cells.

Peripheral neuropathy with gammopathy responding to plasmapheresis.

Two patients with subacute sensorimotor peripheral neuropathy were found to have benign gammopathies. They both responded to treatment by plasmapheresis. We suggest that a vigorous search for a paraprotein should be made in all undiagnosed patients presenting with peripheral neuropathy, including electrophoresis with isoelectric focusing. Plasmapheresis may be a treatment modality that should be explored in such cases.

Cerebral compression by myeloma.

A patient presented with right hemiparesis, dysphasia and a large, palpable, left frontoparietal mass arising from the calvarial diploe. A diagnosis of multiple myeloma was made on radiological and biochemical grounds, together with bone marrow examination. Few cases of cerebral compression by a massive plasmacytoma have been reported, but in some surgical management produced clinical deterioration. The present case was treated with radiotherapy and chemotherapy, with satisfactory results.

Transmembrane and transepithelial movement of calcium during stimulus-secretion coupling.

Electrophysiological studies were undertaken to determine the transmembrane and transepithelial changes in free Ca2+ concentration that occur during serotonin-induced secretion in the salivary glands of the blowfly, Phormia regina. Ca-selective and conventional microelectrodes were used to measure intracellular and luminal Ca2+ concentrations ([Ca]L), serosal membrane and transepithelial potentials (Em, Etr), and their changes during serotonin (5-hydroxytryptamine, 5HT)-induced salivary secretion. The effect of stimulus concentration on these parameters and enzyme release was also determined. Previous studies provided evidence that serosal stimulation with 10(-8) M 5HT caused a hyperpolarization of Em and short phasic two- to threefold increases in [Ca]i. In these studies, higher concentrations of 5HT (10(-7) M) resulted in depolarization of Em by 13 +/- 1.2 mV and of ECa by 64 +/- 2.1 mV, a dramatic increase in [Ca]i, and a decrease in enzyme release. In addition, serotonin (10(-8) M) reduced the normal spontaneous Etr (+19.6 +/- 1 mV) to near zero while causing an increase in [Ca]L from 1.3 +/- 0.3 X 10(-5) mM to 2.0 +/- 0.1 X 10(-3) mM, a concentration isomolar with that of the bathing medium. These results provide direct electrochemical evidence that, during stimulus-secretion coupling of the salivary epithelial cells, the neurohormone serotonin controls the secretory response by the regulation of intracellular Ca2+ and induces transepithelial transport of Ca2+, thereby suggesting that, during secretion, the neurohormone causes the salivary gland to behave as a "leaky epithelium" by activating the paracellular shunt pathways.

Ionophore A23187 can mimick the changes in membrane permeability that occur during acetylcholine-stimulation of pancreatic acinar secretion.

Acetylcholine (ACh) released from vagal terminals increases the permeability of the pancreatic acinar membrane to Na+ and Ca2+ ions. In this report, we compare the induced changes in intracellular Na+ and Ca2+ electrode potentials (ENa and ECa) due to ACh-stimulation of acini with those observed during stimulation with the calcium ionophore, A23187, which mimicks the action of ACh on pancreatic secretion. Stimulation with ACh concentrations varying from 10(-8) to 10(-5) M and with A23187 concentrations of 10(-6) and 10(-5) M caused parallel increases in cytosolic Ca2+ and Na+ ([Ca]i, [Na]i). The magnitude of the increases in [Ca]i and [Na]i due to A23187-stimulation further indicate that when presented with a calcium challenge the acinar cells continue to regulate [Ca]i close to physiological levels and suggest that the observed increases in ionized calcium could reflect much larger increases in complexed Ca2+. ACh-stimulation following removal of either extracellular Na+ or Ca2+ ions, eliminated the intracellular increases found when the removed ions is present, but did not affect the increases usually found with the other ion. The independence of the permeability changes to either the presence of Ca2+ or Na+ indicates the ACh-induced currents carried by Na+ and Ca2+ are also independent. The selective translocation of Na+ and Ca2+ during acetylcholine-stimulation in a manner analogous to the changes observed when ionophore A23187 was used as stimulus, indicates the ability of the activated acinar membrane to function as an ionophore.

Stimulation of pancreatic acinar secretion: increases in cytosolic calcium and sodium.

Na+-selective and Ca2+-selective microelectrodes were used to examine the ionic mechanisms regulating acetylcholine (ACh) stimulation of pancreatic secretion. The cytosolic concentrations of free ionized Na+ and Ca2+ ([Na]i, [Ca]i) were determined in unstimulated acinar cells to be 10.5 +/- 0.4 mM and 0.43 +/- 0.03 microM, respectively. By measuring the induced changes in intracellular Ca2+, Na+, and membrane potentials (ECa, ENa, Em), we were able to demonstrate that 5 X 10(-8) M ACh depolarized Em by 4.3 +/- 0.2 mV and increased [Na]i and [ca]i to 12.2 +/- 0.3 mM and 0.58 +/- 0.02 microM, respectively. Stimulation with ACh at concentrations ranging from 10(-8) to 10(-5) M increased [Ca]i from 0.4 microM to between 0.5 and 1.0 microM. Amylase release reached a maximum at 10(-7) M ACh stimulation and progressively decreased at higher concentrations of stimulus. Increasing the stimulus above an optimal concentration appears to reduce or inhibit enzyme release. These experiments provide direct evidence supporting the concept that acinar cell secretion is triggered by increases in [Ca]i and of calcium's ability to act as primary intracellular mediator. Stimulation after removal of extracellular Ca2+ eliminated the increase in [ca]i that is usually observed in secreting cells, while producing the normal depolarization of Em and increase in [Na]i. These studies demonstrate the increases in [Ca]i are derived from an increase in membrane permeability to Ca2+ and the ability of ACh to depolarize the Em by a transmembrane movement of Na+ that is independent of the change in intracellular Ca2+.

Intravenous lignocaine infusions for severe chronic daily headache.

OBJECTIVES: To determine the safety and efficacy of intravenous lignocaine infusion in patients with severe chronic daily headache (CDH). DESIGN: Retrospective survey of consecutive patients. PARTICIPANTS: 19 patients, 18 with rebound headache and three with status migrainosus. Two patients had both conditions at different times. SETTING: Neurology unit in a major metropolitan teaching hospital, 1994-1998. MAIN OUTCOME MEASURES: Adverse events; headache resolution; long term efficacy. RESULTS: The 19 patients (16 women) received 27 lignocaine infusions. Seven minor adverse events were noted during four infusions. Twenty-two infusions were given for analgesic rebound headache in 18 patients, with headache resolution in 82% of infusions (17 of the 18 patients responded at least once). Four patients obtained lasting relief, six returned to their regular manageable pattern of migraine (in two of these patients CDH recurred after six months), four were lost to follow-up, and in four there was no long term benefit. Five infusions were given for status migrainosus in three patients, with four of these infusions successfully relieving the headache. CONCLUSIONS: Intravenous lignocaine appears to be useful in the management of severe intractable CDH and status migrainosus.