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.

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.

Reversible posterior leukoencephalopathy syndrome complicating cytotoxic chemotherapy for hematologic malignancies.

Reversible posterior leukoencephalopathy syndrome (RPLS) is an uncommon but distinctive clinicoradiological entity comprising of headache, seizures, visual disturbance, and altered mental function, in association with posterior cerebral white matter edema. With appropriate management, RPLS is reversible in the majority of cases. Previous reported associations of RPLS include hypertension, eclampsia, renal failure, and use of immunosuppressive drugs; reports in the adult hematology setting are rare. We report two cases of adults undergoing treatment for hematological malignancies who developed RPLS, and we emphasize the importance of early recognition and institution of appropriate management in reducing the risk of development of permanent neurological disability.

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.

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.

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.

HTLV-I associated myelopathy in a Seychellois immigrant.

OBJECTIVE: To describe the clinical and laboratory features of human T-lymphotropic virus type I (HTLV-I) associated myelopathy in an immigrant from the Seychelles. CLINICAL FEATURES: A slowly progressive myelopathy has been recently diagnosed in a 64-year-old woman who emigrated to Australia from the Seychelles in 1957. Sphincter disturbance and back pain were the first manifestations, followed by gait disturbance. Neurophysiological investigation supported the clinical diagnosis of a myelopathy and radiological investigations revealed no structural cause. Serum antibodies to HTLV-I were detected by enzyme-linked particle agglutination and the presence of antibodies to individual HTLV-I gene products in the serum was confirmed by western blot. The virus was detected in a culture of the patient's peripheral blood mononuclear cells by antigen capture assay and by sequencing a polymerase chain reaction product amplified from the env gene. INTERVENTION AND OUTCOME: The patient was advised of the nature and prognosis of her illness. Oral corticosteroids were tried without benefit. CONCLUSIONS: The prevalence of HTLV-I infection is low in Australia although it may be endemic in some Aboriginal communities. Most infections are asymptomatic but the chronic neurological disease associated with HTLV-I infection has now been shown to exist in this country. HTLV-I infection should be considered in the aetiology of myelopathy without another obvious cause.

Thrombolytic therapy in vertebrobasilar occlusion.

Since 1983 at the Alfred Hospital 4 patients with thrombotic or embolic vertebrobasilar occlusions have been treated with intra-arterial streptokinase (SK) infusions for the effects of persisting brainstem ischaemia despite anticoagulation with heparin. In 3 cases there was immediate and dramatic neurological improvement, in all cases associated with arteriographically demonstrated reperfusion of a blocked vessel. Two of these patients suffered further thromboembolic vertebral or basilar artery occlusions (3 days and 2 years later) but recovered fully without further thrombolytic therapy. The other patient was given intra-arterial SK 12 days after an apparently completed brainstem stroke: the therapy failed to cause reperfusion of a vertebral occlusion or produce any clinical improvement. Complications from the therapy were nausea requiring the termination of the SK infusion in one case, easily controlled bleeding from a recent surgical wound, and a clinically insignificant haemorrhagic transformation of cerebellar infarction in a third. The benefits of thrombolytic therapy in vertebrobasilar ischaemia and the dose of streptokinase required are discussed.

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.

Intraventricular infusion of Dopamine in Parkinson's disease.

A patient with severe end-stage Parkinson's disease and troublesome fluctuations in motor function was treated with a long-term intraventricular infusion of dopamine. There was modest improvement in speech and mentation and there was smoother control of motor symptoms that was superior to that achieved by conventional oral medications.

Cerebral deposits of carcinoid tumour.

This report details a most unusual case of cystic cerebral metastasis. The patient developed symptoms due to carcinoid deposits in the brain. The clinical course has been protracted and the primary source of the carcinoid tumour remains unknown.

Spinal subdural abscess.

Spinal subdural abscess is a rare condition that is clinically similar to spinal epidural abscess. A case of spinal subdural abscess is reported, and the characteristic clinical findings and specific myelographic features in this patient are noted. Urgent myelography and surgery are necessary to prevent the rapid deterioration that often occurs in this condition.

Paramedian thalamic and midbrain infarction: the 'mesencephalothalamic syndrome'.

Paramedian infarction in the region of the thalamus and upper midbrain may produce a wide range of neuro-ophthalmological, behavioural and motor abnormalities. The paramedian arteries arise from the first part of the posterior cerebral artery, also known as the basilar communicating artery. The particular arterial topography and its anatomical variation may result in unusual combinations of clinical signs, and infarction may be bilateral in some cases. Diagnosis is often aided by CT scanning and magnetic resonance imaging. Both atherosclerotic occlusion and embolism are thought to be responsible for these particular syndromes. We describe 3 cases that illustrate some of the various clinical features and underlying anatomical vascular arrangements which may be seen in this condition. Thalamic dementia was present in one case with evidence of bilateral thalamic infarction. A complex ophthalmoplegia and hemiparesis were seen in another case, and the third case had a combination of thalamic dementia and ophthalmoplegia.

Vincristine neurotoxicity enhanced in combination chemotherapy including both teniposide and vincristine.

A high incidence of severe peripheral neuropathy occurred during the pilot study of a new regimen for the treatment of non-Hodgkin's lymphoma. The clinically observed incidence and severity of vincristine-induced peripheral neuropathy was considerably enhanced by the sequential use of vincristine and teniposide in this combination chemotherapy.

Vincristine neurotoxicity in Charcot-Marie-Tooth syndrome.

The case of a patient with Charcot-Marie-Tooth syndrome and diffuse large-cell lymphoma, in whom a severe generalized weakness developed after the intravenous administration of vincristine (2 mg) during combination chemotherapy, is reported. Spontaneous resolution of the severe weakness occurred when teniposide was substituted for vincristine in the chemotherapy regimen.

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.

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.

Primary orthostatic cerebral ischaemia.

four patients with "primary orthostatic cerebral ischaemia" are described. They complained of dizziness, light-headedness or syncope on standing. None had a significant fall in his systemic blood pressure on assuming the erect posture. Each had bruits over the major neck vessels or absent pulses. Angiography showed widespread narrowing or occlusion of the cervical blood vessels which supply the brain. Carotid endarterectomy relieved the patients' symptoms and also reduced the fall in retinal artery pressures on standing noted preoperatively. The clinician who is not aware of the poorly documented syndrome of "primary orthostatic cerebral ischaemia" may fail to recognise that a patient's complaints are due to cerebrovascular disease for they are strikingly different from those of classical transient ischaemic attacks.