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To contrast the relationships of hormonal eating peptides and hypothalamic volumes to eating behavior and metabolic changes (body mass index [BMI]) in behavioral variant frontotemporal dementia (bvFTD) and semantic variant primary progressive aphasia (svPPA).Seventy-five patients with dementia (19 bvFTD, 26 svPPA, and 30 Alzheimer disease dementia) and 23 controls underwent fasting blood analyses of leptin, ghrelin, cholecystokinin, peptide tyrosine tyrosine (PYY), and agouti-related peptide (AgRP) levels. On brain MRI anterior, posterior, and total hypothalamic volumes were measured. Relationships between endocrine measures, hypothalamic volumes, eating behaviors, and BMI were investigated.Levels of AgRP were higher in patients with bvFTD (69 ± 89 pg/mL) and svPPA (62 ± 81 pg/mL) compared with controls (23 ± 19 pg/mL, p0.01). No differences were found for leptin, oxytocin, cholecystokinin, ghrelin, and PYY levels. Patients with bvFTD and svPPA had higher scores on questionnaires measuring eating behaviors. Atrophy of the posterior and total hypothalamus was observed in the bvFTD group only. Linear regression modeling revealed that leptin and AgRP levels predicted BMI.Eating abnormalities are multifactorial in FTD. In bvFTD, they are in part related to hypothalamic degeneration, with potential disintegration of the network connections between the hypothalamus and orbitofrontal cortex/reward pathways. In svPPA, although hypothalamic volumes are preserved, this group experiences elevated AgRP levels similar to bvFTD, which predicts BMI in both groups. This finding highlights the potential key role of AgRP in eating and metabolic changes and provides a potential target for treatment to modify disease progression.

1. Glyceryl trinitrate (GTN) is frequently infused intravenously as a component of the management of acute coronary syndromes (ACS). Abrupt cessation of GTN infusion after periods of more than 24 h administration often induces rebound vasoconstriction reflecting 'pseudotolerance'; this is also the basis of the 'zero hour phenomenon' during chronic nitrate therapy. The efficacy of oral nitrate regimens to prevent vasoconstriction following cessation of intravenous GTN has not been previously examined. Therefore, we investigated the effects of transition from intravenous GTN to oral isosorbide dinitrate (ISDN) on a parameter of apparent arterial stiffness in patients with ACS. 2. The effects of GTN infusion at 5 microg/min on augmentation index (AIx) were quantified in patients (n = 10) with stable angina pectoris in order to establish the magnitude of effect on apparent arterial stiffness. 3. This infusion rate of GTN reduced AIx from 23 +/- 10% (SD) to 3 +/- 14% (SD) (P < 0.01). The effect of transition from GTN infusion of greater than 24 h duration to ISDN (10 mg tds) were examined in patients (n = 16) with ACS (unstable angina/non-Q-wave myocardial infarction). No patient developed recurrent angina during the 24 h following cessation of GTN infusion. The level of AIx was 8 +/- 4% (SD) prior to GTN cessation and fell to 5 +/- 6% (SD) on ISDN (P = 0.05). 4. Thus, in patients treated for ACS, transition from intravenous GTN to low dose oral ISDN is associated with an incremental vasodilatation and no evidence of 'rebound' ischaemia.

Importance Presence of eating abnormalities is one of the core criteria for the diagnosis of behavioral variant frontotemporal dementia (bvFTD), yet their occurrence in other subtypes of frontotemporal dementia (FTD) and effect on metabolic health is not known. Objective To define and quantify patterns of eating behavior and energy, sugar, carbohydrate, protein, and fat intake, as well as indices of metabolic health in patients with bvFTD and semantic dementia (SD) compared with patients with Alzheimer disease (AD) and healthy control participants. Design, Setting, and Participants Prospective case-controlled study involving patient and caregiver completion of surveys. Seventy-five participants with dementia (21 with bvFTD, 26 with SD, and 28 with AD) and 18 age- and education-matched healthy controls were recruited from FRONTIER, the FTD research clinic at Neuroscience Research Australia in Sydney. Main Outcomes and Measures Caregivers of patients with FTD and AD completed validated questionnaires on appetite, eating behaviors, energy consumption, and dietary macronutrient composition. All participants completed surveys on hunger and satiety. Body mass index and weight measurements were prospectively collected. Results The bvFTD group had significant abnormalities in the domains of appetite ( U = 111.0, z = 2.7, P = .007), eating habits ( U = 69.5, z = 3.8, P = .001), food preferences ( U = 57.0, z = 4.1, P = .001), swallowing ( U = 109.0, z = 3.0, P = .003), and other oral behaviors ( U = 141.0, z = 2.6, P = .009) compared with the AD group. The bvFTD and SD groups tended to have increased energy consumption. Compared with controls, the bvFTD group had significantly increased carbohydrate intake (251 vs 170 g/d; P = .05) and the SD group had significantly increased sugar intake (114 vs 76 g/d; P = .049). No significant differences in total fat or protein intake between the groups were found. Despite similar energy intake, the SD group had lower hunger and satiety scores compared with the bvFTD group. In contrast, hunger and satiety scores did not differ between the bvFTD group and controls. The abnormal eating behavior was found in the 2 groups (bvFTD and SD) with the highest body mass index ( F = 4.2, P = .008) and waist circumference ( F = 6.4, P = .001). Conclusions and Relevance Abnormal eating behaviors are prominent in patients with bvFTD and those with SD and are not limited to increased appetite. The observed higher intake of sugar and carbohydrates was found in patients with the FTD subtypes and those with higher body mass index and waist circumference and was not explained simply by increased hunger or lower satiety.

Objective: To document the metabolic changes in frontotemporal dementia, including serum cholesterol and insulin levels, and compare and contrast these changes to motor neuron disease, where metabolism is proposed to affect disease progression. Methods: A cohort of 90 patients with dementia (31 behavioral-variant frontotemporal dementia [bvFTD], 30 semantic dementia [SD], and 29 Alzheimer disease [AD]) underwent fasting blood cholesterol, glucose, and peripheral insulin level analysis. Insulin resistance was calculated using the homeostasis model assessment of insulin resistance (HOMA-IR). These results were compared with a cohort of 19 control subjects. Results: The bvFTD cohort had lower high-density lipoprotein (HDL) cholesterol levels compared with control and AD groups, and increased total cholesterol/HDL ratio and triglyceride levels compared with the control group. The SD cohort had increased triglyceride levels compared with control subjects. Both FTD groups had increased fasting insulin levels and HOMA-IR index compared with the control group, and this remained increased in the subjects with bvFTD compared to subjects with AD. Conclusion: Both patients with bvFTD and those with SD have increased triglyceride and insulin levels and lower HDL cholesterol levels compared with controls, suggesting a state of peripheral insulin resistance. These factors have been found to affect prognosis in motor neuron disease favorably, although insulin resistance has been proposed as a mechanism promoting neurodegeneration. We discuss the potential role of metabolism in FTD pathophysiology and progression.

Weight loss and catabolic changes are increasingly recognized as factors that influence outcomes in patients with amyotrophic lateral sclerosis (ALS). An association between disease progression and low BMI has been reported in ALS; however, it remains unknown whether low BMI occurs across all forms of ALS and whether BMI changes with the development of cognitive impairment across the spectrum between ALS and frontotemporal dementia (FTD). One hundred and three ALS patients (56 limb predominant, 18 bulbar predominant, 13 ALS plus, 16 ALSFTD) were recruited and compared to 19 behavioral variant FTD (bvFTD) patients and a group of age-matched healthy controls. BMI was measured at the initial clinical visit. Patients were characterized as underweight, normal, overweight or obese, based on the current World Health Organization (WHO) guidelines. Limb and bulbar ALS patients had significantly lower BMI than ALS plus, ALSFTD, and bvFTD patient groups. When BMI was categorized using WHO guidelines the majority of the limb and bulbar ALS patients were either underweight or normal weight, whilst the majority of the ALS plus, ALSFTD and bvFTD patients were either overweight or obese. On follow-up BMI assessment the limb and bulbar groups tended to decline whilst ALS plus, ALSFTD and bvFTD groups remained stable or increased. BMI is significantly higher in ALS individuals with cognitive deficits. The present findings have prognostic implications for disease progression and may help delineate the metabolic profile across the ALSFTD spectrum.

Malignant leptomeningitis can present as the clinical syndrome of pseudotumor cerebri due to infiltration of arachnoid villi in the superior sagittal sinus. We show that malignant pachymeningitis can also present with pseudotumor cerebri, likely due to cerebral venous hypertension from transverse sinus compression. We present 3 cases of pseudotumor cerebri due to pachymeningeal or leptomeningeal metastases and discuss the mechanism of intracranial hypertension in such cases, its diagnosis and treatment.

A 56-year-old man gave a 6-month history of progressive dyspnoea and orthopnoea. During breathing, his abdominal muscles showed paradoxical movement and he rapidly and reproducibly developed difficulty breathing when lying supine. The most likely explanation was severe weakness or paralysis of both hemidiaphragms. This was confirmed with electrophysiology and ultrasonography. Extensive investigation identified no underlying cause, suggesting this is a case of bilateral isolated phrenic neuropathy. We present a video showing how easily bilateral diaphragmatic palsy can be detected clinically through identifying paradoxical abdominal wall movement.

OBJECTIVE To review patients with severe bilateral vestibular loss associated with gentamicin treatment in hospital. DESIGN AND SETTING A retrospective case series of presentations to a balance disorders clinic between 1988 and 2010. MAIN OUTCOME MEASURES Relationship between vestibulotoxicity and gentamicin dose or dosing profile; indications for prescribing gentamicin. RESULTS 103 patients (age, 18-84 years; mean, 64 years) presented with imbalance, oscillopsia or both, but none had vertigo. Only three noted some hearing impairment after having gentamicin, but audiometric thresholds for all patients were consistent with their age. In all patients, the following tests gave positive results: a bilateral clinical head-impulse test, a vertical head-shaking test for vertical oscillopsia, and a foam Romberg test. In 21 patients, imbalance occurred during gentamicin treatment (ignored or dismissed by prescribers in 20) and in 66 after treatment; the remaining 16 could not recall when symptoms were first noticed, except that it was after gentamicin treatment in hospital. Total gentamicin dose range was 2-318 mg/kg (mean, 52 mg/kg), daily dose range was 1.5-5.6 mg/kg (mean, 3.5mg/kg), and duration was 1-80 days (mean, 17 days). Six patients had only a single dose; 26 had five or fewer doses. Serum gentamicin levels, measured in 82 patients, were in the recommended range in 59. Time to diagnosis ranged from 4 days to 15 years. Nephrotoxicity developed in 43 patients. Gentamicin dosage complied with contemporary or current Australian antibiotic guidelines in under half the patients. CONCLUSIONS Gentamicin ototoxicity is vestibular, not cochlear, producing permanent loss of balance, but not of hearing. Gentamicin can be vestibulotoxic in any dose, in any regimen, at any serum level.

To report the little known fact that systemically administered gentamicin can cause severe unilateral, rather than only bilateral vestibular loss.This is a retrospective review of patients presenting with imbalance and oscillopsia due to a compensated, selective unilateral vestibular loss, who denied ever experiencing vertigo, but who had been administered systemic gentamicin during a hospital admission just before their symptoms began.From 1993 to 2011, 18 such patients were identified from the records of our tertiary referral Balance Disorders Clinic. The fact that they had been administered gentamicin was confirmed only when the hospital charts were examined. Only 4 of 18 patients knew or suspected that they had been administered gentamicin; none had been administered gentamicin at the authors' hospital.These results mean that any patient presenting with imbalance due to a compensated, selective unilateral vestibular loss, who has never experienced vertigo, should be closely questioned about any hospital admission just before symptoms started and the hospital records for that admission requisitioned and scrutinized for possible gentamicin therapy.

We describe a fatal case of proven enterovirus 71 meningoencephalitis complicating monoclonal anti-CD20 antibody therapy for non-Hodgkin's lymphoma. B-cell depletion, an effective treatment strategy in an expanding spectrum of hematological and inflammatory disorders, impairs neutralising antibody-mediated clearance of enterovirus. The global threat of emerging neurotropic viruses such as enterovirus 71 is heightened by an increasing pool of susceptible individuals in non-endemic regions.

Autonomic symptoms are associated with a number of neurodegenerative conditions.1 Cerebral structures mediating these symptoms include the anterior cingulate cortex, insular, amygdala, hypothalamus and brainstem.1 ,2 Of the cerebral structures implicated in autonomic control, the hypothalamus3 and insula4 undergo pathological changes in frontotemporal dementia (FTD). Given the locus of the pathology, it is likely that other hypothalamic functions such as blood pressure control, thermoregulation and urinary control may be affected in FTD through the process of autonomic dysfunction. Cardiac dysfunction,5 urinary dysfunction6 and thermoregulatory dysfunction7 have been previously reported in FTD; features which were included in the original 1998 diagnostic criteria.8 Despite these reports, investigations into the integrity of the autonomic system and whether dysfunction results in clinically significant symptoms have been limited. Carers of 69 patients with dementia: 28 behavioural-variant FTD (bvFTD; 10 female (F), 18 male (M)), 20 semantic dementia (SD; 9 F, 11 M), 21 Alzheimer's disease (AD; 10 F, 11 M) from the FTD clinic at Neuroscience Research Australia, completed the Autonomic Symptoms Questionnaire (ASQ), which comprises 44 questions that examine physical symptoms related to autonomic functions including blood pressure/cardiovascular function, gastrointestinal, temperature regulation and sweating, urinary symptoms and sleep. The survey was validated in the Autonomic unit at the National Hospital for Neurology and Neurosurgery, London (see online supplementary file S1). Carers were asked to rate the frequency of …

Abnormal eating behavior is a core diagnostic feature for behavioral frontotemporal dementia (bvFTD). We aimed to define the patterns of eating behavior and intake in bvFTD and semantic dementia (SD) compared to Alzheimer’s disease (AD) and controls. We hypothesized that these changes are not the result of increased hunger/decreased satiety, but may relate to disinhibition and dysfunction of hypothalamic pathways that control appetite. We examined the association between eating behaviors and metabolic health of FTD compared with motor neuron disease (MND), which shares a common pathology with FTD, and where the metabolic profile has been hypothesized to affect disease progression. Carers of 75 dementia patients (21 bvFTD, 26 SD, 28 AD) and 18 healthy control subjects completed validated questionnaires on appetite and eating behavior. All participants completed surveys on their hunger and satiety. Body mass index (BMI), and blood samples measuring cholesterol and insulin levels were prospectively collected. BMI measurements were compared to a cohort of 100 MND (bulbar and limb) and FTD/ MND patients. bvFTD patients displayed significant abnormalities in all domains of eating compared to AD patients. bvFTD patients had significantly increased carbohydrate intake and SD patients significantly increased sugar intake. Despite increased intake in the FTD groups, their hunger/satiety scores did not differ from the control group. BMI measurements were significantly higher in the FTD and FTD/MND groups than in the MND (bulbar and limb) and control groups. Increased BMI in the bvFTD and SD groups was also significantly associated with abnormal eating behavior. BvFTD patients had significantly increased insulin levels, triglyceride, cholesterol ratios, and lower high-density lipoprotein cholesterol levels compared to controls. Abnormal eating behavior is prominent in bvFTD and SD patients, and is associated with increased sugar and carbohydrate intake, and is not the result of increased hunger and lower satiety. Similar findings have been shown in obese patients, attributed to disinhibition, orbitofrontal pathology and dysfunction of hypothalamic pathways that control appetite, suggesting similar pathways may be affected in FTD. Abnormal eating behavior in FTD is associated with changes in BMI, and a blood metabolic profile similar to that seen in MND. Despite similar pathology however, BMI in all forms of MND appears lower than in FTD.

Objective Carotid endarterectomy (CEA) guidelines in symptomatic carotid stenosis are based on NASCET and ECST criteria with 70% or greater carotid stenosis as estimated from a catheter angiogram the major indication. This has several problems: (1) lack of reliable correlation between non-invasive imaging and catheter angiography, which has been largely superseded by non-invasive imaging in investigating carotid stenosis; (2) errors inherent in estimating the degree of stenosis from catheter angiography; (3) disregard for the fact that stroke risk also depends on plaque stability, and number of ischaemic events. Methods A retrospective review of ischaemic events, imaging results, operative findings, surgical complications and stroke-free follow-up in 31 patients presenting over a 23 year period with TIA/stroke (symptoms lasting > 24 h and/or imaging evidence of infarction) who had 70% or less carotid stenosis (on non-invasive imaging), but nonetheless underwent CEA. Results Nineteen patients had small strokes, 7 had TIAs and 5 had ocular events; 28 patients had features of unstable plaque on imaging; 19 patients experienced multiple events before CEA. All had haemorrhagic, ruptured plaque at CEA. One patient suffered an intra-operative stroke, only 1 patient suffered a further stroke/TIA (mean follow-up 4.2 years). Conclusion To predict the likelihood of major stroke in symptomatic carotid stenosis and the benefit of CEA, plaque stability and the number of ischaemic events might be as important as an estimate of the degree of stenosis.

Objective: To determine if there is any relationship between gentamicin vestibulotoxicity and gentamicin dose or dosing profile, and if there are ways of detecting early vestibulotoxicity. Background Gentamicin ototoxicity is exclusively vestibular, not cochlear and is almost always missed by prescribers; patients are referred to neurologists, sometimes years later, with undiagnosed imbalance, and oscillopsia. Design/Methods: We reviewed 103 patients with bilateral, and 24 with unilateral gentamicin vestibulotoxicity, seen between 1988-2010, to determine if there is any relationship between vestibulotoxicity and gentamicin dose, and ways of detecting early vestibulotoxicity. Results: Patients9 were aged 18-84 years (mean= 65). Presentation was with imbalance (50), oscillopsia (4), or both (61) and indeterminate (12). Only 3 might have developed symptomatic hearing loss, none developed vertigo. All had positive horizontal and vertical clinical Head Impulse Tests to one or to both sides. Total dose of gentamicin was 2 to 318mg/kg (mean= 47); daily dose 1.5 to 5.6mg/kg (mean=3.5); Seven patients had only one dose, 34 patients had fewer than 5 doses. Delay to diagnosis: 4 days to 15 years. Gentamicin was given appropriately in only 50% of patients, according to the Australian Antibiotics Guidelines (a PDR equivalent). Six patients with bilateral vestibulotoxicity and 3 with unilateral vestibulotoxicity had video-oculographic measurement of the Head Impulse Test which in each case confirmed the vestibular loss. Conclusions: Gentamicin vestibulotoxicity produces imbalance and oscillopsia but not vertigo or hearing loss, and develops regardless of how much gentamicin is given and can develop after one dose. In any patient with imbalance or oscillopsia due to unilateral or bilateral vestibular loss presenting after a hospital admission it is important to examine the treatment charts for evidence of gentamicin therapy. In a patient having gentamicin the diagnosis of vestibulotoxicity can be made by video-oculography, perhaps even at a stage when drug withdrawal might allow recovery from vestibular damage. Disclosure: Dr. Ahmed has nothing to disclose. Dr. Hannigan has nothing to disclose. Dr. MacDougall has nothing to disclose. Dr. Halmagyi has nothing to disclose.

The acid metabolites of dopamine and 5-hydroxytryptamine were estimated in the lumbar cerebrospinal fluid (CSF) of Parkinsonian patients both before and during treatment with l-dopa, the amino acid precursor of dopamine. An attempt was made to relate clinical improvement to the biochemical results. The dopamine metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, showed increases related to the dose of l-dopa, the increase in homovanillic acid concentration being proportionately greater than that of 3,4-dihydroxyphenylacetic acid. The concentration of the 5-hydroxytryptamine metabolite, 5-hydroxyindol-3ylacetic acid, was unaltered by the drug. Clinical improvement, which in the early stages was evident particularly in the bradykinesia, was found to occur at doses of l-dopa greater than 1·5 g/day. Effective doses of l-dopa gave rise to concentrations of dopamine metabolites in the CSF which were greater than normal. Possible implications of these findings are discussed.

Abnormal eating behaviour and metabolic parameters including insulin resistance dyslipidaemia and body mass index are increasingly recognized as important components of neurodegenerative disease and may contribute to survival. It has previously been established that behavioural variant frontotemporal dementia is associated with abnormal eating behaviour characterized by increased sweet preference. In this study it was hypothesized that behavioural variant frontotemporal dementia might also be associated with altered energy expenditure. A cohort of 19 patients with behavioural variant frontotemporal dementia 13 with Alzheimer{\textquoteright}s disease and 16 (age and sex matched) healthy control subjects were studied using Actiheart devices (CamNtech) to assess resting and stressed heart rate. Actiheart devices were fitted for 7 days to measure sleeping heart rate activity levels and resting active and total energy expenditure. Using high resolution structural magnetic resonance imaging the neural correlates of increased resting heart rate were investigated including cortical thickness and region of interest analyses. In behavioural variant frontotemporal dementia resting (P = 0.001) stressed (P = 0.037) and sleeping heart rate (P = 0.038) were increased compared to control subjects and resting heart rate (P = 0.020) compared to Alzheimer disease patients. Behavioural variant frontotemporal dementia was associated with decreased activity levels compared to controls (P = 0.002) and increased resting energy expenditure (P = 0.045) and total energy expenditure (P = 0.035). Increased resting heart rate correlated with behavioural (Cambridge Behavioural Inventory) and cognitive measures (Addenbrooke{\textquoteright}s Cognitive Examination). Increased resting heart rate in behavioural variant frontotemporal dementia correlated with atrophy involving the mesial temporal cortex insula and amygdala regions previously suggested to be involved exclusively in social and emotion processing in frontotemporal dementia. These neural correlates overlap the network involved in eating behaviour in frontotemporal dementia suggesting a complex interaction between eating behaviour autonomic function and energy homeostasis. As such the present study suggests that increased heart rate and autonomic changes are prevalent in behavioural variant frontotemporal dementia and are associated with changes in energy expenditure. An understanding of these changes and neural correlates may have potential relevance to disease progression and prognosis.AbbreviationsALSamyotrophic lateral sclerosisBMIbody mass indexbvFTDbehavioural variant frontotemporal dementiaFTDfrontotemporal dementiaRMSSDroot mean squared of successive differences