A recent surge of nitrous oxide misuse around London which merits a public health warning.

BACKGROUND: Use of nitrous oxide (N2O) gas for recreational purposes by young people is increasingly recognized as a public health hazard in the UK. METHODS: We looked at the hospital records of patients admitted over the last 4 years to a single neurological centre in Essex to determine the demographics, presentation, and management of patients presenting with symptoms of N2O toxicity from its recreational use. RESULTS: Of the 17 patients (mean age = 22.9 ± 3 years) admitted between September 2018 and October 2022, 70% were admitted between January and October 2022. All patients reported limb paraesthesiae and 16/17 reported (95%) imbalance; 11/17 (65%) showed objective limb weakness. Serum B12 concentration was low in 9/17 (53%). Plasma methylmalonic acid (n = 7) and homocysteine (n = 8) levels were elevated in all patients tested. Spinal cord Magnetic Resonance Imaging (MRI) imaging was abnormal in 10/17 (59%) patients. Nerve conduction studies were abnormal in 10/13 (77%) patients, with evidence of a symmetric, length-dependent, large fibre neuropathy. CONCLUSIONS: There has been a recent surge of cases with neurological complications of recreational N2O abuse in the UK, with a relatively greater rate in 2022. Greater awareness of this condition amongst clinicians and health regulators is urgently required to prevent harm from N2O misuse in young people.

Anti-collapsin response mediator protein 5 encephalitis masquerading as a low-grade brain tumour.

A 71-year-old woman presented acutely with seizures; her MRI suggested a low-grade glioma of the right temporal lobe. Over the preceding 18 months, she had developed progressive limb chorea and orofacial dyskinesia. Examination showed a predominantly amnestic cognitive profile. Initial investigations were normal, but later she was found to have antibodies to collapsin response mediator protein 5 (also called CV2). Her symptoms and neuroimaging abnormalities gradually improved without treatment. Four months later, surveillance imaging with (18)F-fluorodeoxyglucose-positron-emission tomography revealed a lesion confirmed by biopsy as a TX, N2, M0 small-cell lung cancer. This case is unusual for the strikingly unilateral neuroimaging abnormalities, which led to an initial misdiagnosis, and the spontaneous symptomatic improvement without treatment. In retrospect, the co-occurrence of paraneoplastic chorea, limbic encephalitis and neuropathy in the presence of an occult lung tumour make this almost a 'full house' of symptoms associated with antibodies to collapsin response mediator protein 5. It underlines the importance in clinical reasoning of avoiding the cognitive errors of premature closure and anchoring.

Rheumatoid disease: an unusual cause of relapsing meningoencephalitis.

A 73-year-old man presented with three episodes of dysphasia and disinhibited behaviour, a single seizure and transient ischaemic attack-like events characterised by right arm and/or leg weakness. These episodes were separated by month-long asymptomatic intervals. Medical history included rheumatoid arthritis, which was clinically quiescent on leflunomide.Repeated cerebrospinal fluid examination showed a persistent lymphocytosis with mildly reduced glucose and elevated protein; oligoclonal bands and viral PCR were negative. MRI of the brain was initially normal, but 7 months after initial presentation revealed meningeal enhancement with bifrontal cortical hyperintensities on T2/fluid-attenuated inversion recovery. Brain biopsy demonstrated necrotising granulomatous meningitis with mixed T cell and B cell infiltrates and without evidence of vasculitis or infection. Serum anticyclic citrullinated peptide antibodies were strongly positive.The diagnosis of rheumatoid meningoencephalitis was made on the basis of brain biopsy findings and serological evidence of active rheumatoid disease. Steroids and rituximab therapy were started leading to clinical stabilisation.

Reduced brain functional reserve and altered functional connectivity in patients with multiple sclerosis.

Cognitive dysfunction (affecting particularly attention and working memory) occurs early in patients with multiple sclerosis. Previous studies have focused on identifying potentially adaptive functional reorganization through recruitment of new brain regions that could limit expression of these deficits. However, lesion studies remind us that functional specializations in the brain make certain brain regions necessary for a given task. We therefore have asked whether altered functional interactions between regions normally recruited provide an alternative adaptive mechanism with multiple sclerosis pathology. We used a version of the n-back task to probe working memory in patients with early multiple sclerosis. We applied a functional connectivity analysis to test whether relationships between relative activations in different brain regions change in potentially adaptive ways with multiple sclerosis. We studied 21 patients with relapsing-remitting multiple sclerosis and 16 age- and sex-matched healthy controls with 3T functional MRI. The two groups performed equally well on the task. Task-related activations were found in similar regions for patients and controls. However, patients showed relatively reduced activation in the superior frontal and anterior cingulate gyri (P > 0.01). Patients also showed a variable, but generally substantially smaller increase in activation than healthy controls with greater task complexity, depending on the specific brain region assessed (P < 0.001). Functional connectivity analysis defined further differences not apparent from the univariate contrast of the task-associated activation patterns. Control subjects showed significantly greater correlations between right dorsolateral prefrontal and superior frontal/anterior cingulate activations (P < 0.05). Patients showed correlations between activations in the right and left prefrontal cortices, although this relationship was not significant in healthy controls (P < 0.05). We interpret these results as showing that, while cognitive processing in the task appears to be performed using similar brain regions in patients and controls, the patients have reduced functional reserve for cognition relevant to memory. Functional connectivity analysis suggests that altered inter-hemispheric interactions between dorsal and lateral prefrontal regions may provide an adaptive mechanism that could limit clinical expression of the disease distinct from recruitment of novel processing regions. Together, these results suggest that therapeutic enhancement of the coherence of interactions between brain regions normally recruited (functional enhancement), as well as recruitment of alternative areas or use of complementary cognitive strategies (both forms of adaptive functional change), may limit expression of cognitive impairments in multiple sclerosis.

The role of working memory and verbal fluency in autobiographical memory in early Alzheimer's disease and matched controls.

Retrieval of autobiographical memories (AMs) is important for "sense of self". Previous research and theoretical accounts suggest that working memory (WM) and semantic and phonemic fluency abilities facilitate the hierarchical search for, and reliving of past, personal events in the mind's eye. However, there remains a lack of consensus as to the nature of the relationships between these cognitive functions and the truly episodic aspects of AM. The present study therefore aimed to explore the associations between these variables in a sample with a wide range of cognitive abilities. The study incorporated a between-groups component, and a correlational component with multiple regression. Participants with Alzheimer's disease (n=10) and matched healthy controls (n=10) were assessed on measures of semantic and episodic AM search and retrieval, auditory and spatial WM, and semantic and phonemic fluency. The AD group produced less episodic AM content compared to controls. Semantic fluency predicted episodic AM retrieval independent of age effects but there were no significant relationships between measures of phonemic fluency, WM and episodic AM. The results suggest that the ability to maintain hierarchical search of the semantic knowledge-base is important for truly episodic reliving, and interventions for people with AM impairment might therefore benefit from incorporating structured, individualised external memory-aids to facilitate AM search and retrieval.

The role of microembolisation in cerebral injury as defined by functional magnetic resonance imaging.

OBJECTIVE: Cerebral injury, in both overt and subtle forms, is common following cardiac surgery. Current methods of assessment, most commonly neuropsychological testing, have several limitations and do not accurately define the anatomical and functional injury that occurs. We have assessed the degree of cerebral injury following on-pump and off-pump cardiac surgery using functional magnetic resonance imaging and correlated this with the severity of microembolism as measured by transcranial Doppler ultrasound. METHODS: Sixteen patients undergoing cardiac surgery (8 off-pump coronary artery bypass grafting (CABG), 4 on-pump CABG and 4 open-heart surgery) underwent functional magnetic resonance imaging of the brain pre-operatively and 4 weeks post-operatively. The functional magnetic resonance images demonstrated brain activation during performance of a verbal working memory paradigm. Each patient had continuous transcranial Doppler monitoring intraoperatively using a recently validated technique (multirange, multifrequency Doppler) that allows rejection of artefacts and separation of gas and solid microemboli. Covariate analysis of pre- and post-operative functional magnetic resonance images was performed to correlate local mean signal intensity change with the extent of gas and solid microembolism. RESULTS: The median number of microemboli was 34 (range 10-176) in the off-pump group, 229 (range 127-314) in the on-pump CABG group, and 1220 (range 874-1261) in the open-heart group (P<0.05). The proportion of solid microemboli was significantly lower in the off-pump group in comparison to the on-pump CABG and open-heart groups (9 vs. 25 vs. 20%, respectively, P<0.01). Comparison of pre- and post-operative functional magnetic resonance images demonstrated an overall reduction in task-associated activation in the post-operative period. However, and paradoxically, in certain specific regions of interest there was an increase in the signal intensity which correlated with the total number of microemboli (r=0.9, P<0.01). CONCLUSIONS: Patients undergoing on-pump surgery have a higher degree of gas and solid microembolism which correlates with post-operative cerebral functional MRI activation. As activation with functional magnetic resonance imaging of the brain is known to be sensitive to a wide range of insults, it may prove to be a useful marker of perioperative cerebral injury that could help in the evaluation of potential cerebroprotective strategies.

"The mind is its own place": amelioration of claustrophobia in semantic dementia.

Phobias are among the few intensely fearful experiences we regularly have in our everyday lives, yet the brain basis of phobic responses remains incompletely understood. Here we describe the case of a 71-year-old patient with a typical clinicoanatomical syndrome of semantic dementia led by selective (predominantly right-sided) temporal lobe atrophy, who showed striking amelioration of previously disabling claustrophobia following onset of her cognitive syndrome. We interpret our patient's newfound fearlessness as an interaction of damaged limbic and autonomic responsivity with loss of the cognitive meaning of previously threatening situations. This case has implications for our understanding of brain network disintegration in semantic dementia and the neurocognitive basis of phobias more generally.

Agnosia for accents in primary progressive aphasia.

As an example of complex auditory signal processing, the analysis of accented speech is potentially vulnerable in the progressive aphasias. However, the brain basis of accent processing and the effects of neurodegenerative disease on this processing are not well understood. Here we undertook a detailed neuropsychological study of a patient, AA with progressive nonfluent aphasia, in whom agnosia for accents was a prominent clinical feature. We designed a battery to assess AA's ability to process accents in relation to other complex auditory signals. AA's performance was compared with a cohort of 12 healthy age and gender matched control participants and with a second patient, PA, who had semantic dementia with phonagnosia and prosopagnosia but no reported difficulties with accent processing. Relative to healthy controls, the patients showed distinct profiles of accent agnosia. AA showed markedly impaired ability to distinguish change in an individual's accent despite being able to discriminate phonemes and voices (apperceptive accent agnosia); and in addition, a severe deficit of accent identification. In contrast, PA was able to perceive changes in accents, phonemes and voices normally, but showed a relatively mild deficit of accent identification (associative accent agnosia). Both patients showed deficits of voice and environmental sound identification, however PA showed an additional deficit of face identification whereas AA was able to identify (though not name) faces normally. These profiles suggest that AA has conjoint (or interacting) deficits involving both apperceptive and semantic processing of accents, while PA has a primary semantic (associative) deficit affecting accents along with other kinds of auditory objects and extending beyond the auditory modality. Brain MRI revealed left peri-Sylvian atrophy in case AA and relatively focal asymmetric (predominantly right sided) temporal lobe atrophy in case PA. These cases provide further evidence for the fractionation of brain mechanisms for complex sound analysis, and for the stratification of progressive aphasia syndromes according to the signature of nonverbal auditory deficits they produce.

Thalamic neurodegeneration in multiple sclerosis.

Multiple sclerosis is still regarded primarily as a disease of the white matter. However, recent evidence suggests that there may be significant involvement of gray matter. Here, we have used magnetic resonance imaging and magnetic resonance spectroscopy in vivo and histopathology postmortem to estimate thalamic neuronal loss in patients with multiple sclerosis. Our results show that neuronal loss in multiple sclerosis can be substantial (30-35% reduction). We conclude that a neurodegenerative pathology may make a major contribution to the genesis of symptoms in multiple sclerosis.