Longitudinal study of prevalence and spatio-temporal distribution of Borrelia burgdorferi sensu lato in ticks from three defined habitats in Latvia, 1999-2010.

Members of the Borrelia burgdorferi sensu lato (s.l.) species complex are known to cause human Lyme borreliosis. Because of longevity of some reservoir hosts and the Ixodes tick vectors' life cycle, long-term studies are required to better understand species and population dynamics of these bacteria in their natural habitats. Ticks were collected between 1999 and 2010 in three ecologically different habitats in Latvia. We used multilocus sequence typing utilizing eight chromosomally located housekeeping genes to obtain information about species and population fluctuations and/or stability of B. burgdorferi s.l. in these habitats. The average prevalence over all years was 18.9%. From initial high-infection prevalences of 25.5%, 33.1% and 31.8%, from 2002 onwards the infection rates steadily decreased to 7.3%. Borrelia afzelii and Borrelia garinii were the most commonly found genospecies but striking local differences were obvious. In one habitat, a significant shift from rodent-associated to bird-associated Borrelia species was noted whilst in the other habitats, Borrelia species composition was relatively stable over time. Sequence types (STs) showed a random spatial and temporal distribution. These results demonstrated that there are temporal regional changes and extrapolations from one habitat to the next are not possible.

Grey matter abnormalities in methcathinone abusers with a Parkinsonian syndrome.

BACKGROUND: A permanent Parkinsonian syndrome occurs in intravenous abusers of the designer psychostimulant methcathinone (ephedrone). It is attributed to deposition of contaminant manganese, as reflected by characteristic globus pallidus hyperintensity on T1-weighted MRI. METHODS: We have investigated brain structure and function in methcathinone abusers (n = 12) compared to matched control subjects (n = 12) using T1-weighted structural and resting-state functional MRI. RESULTS: Segmentation analysis revealed significant (p < .05) subcortical grey matter atrophy in methcathinone abusers within putamen and thalamus bilaterally, and the left caudate nucleus. The volume of the caudate nuclei correlated inversely with duration of methcathinone abuse. Voxel-based morphometry showed patients to have significant grey matter loss (p < .05) bilaterally in the putamina and caudate nucleus. Surface-based analysis demonstrated nine clusters of cerebral cortical thinning in methcathinone abusers, with relative sparing of prefrontal, parieto-occipital, and temporal regions. Resting-state functional MRI analysis showed increased functional connectivity within the motor network of patients (p < .05), particularly within the right primary motor cortex. CONCLUSION: Taken together, these results suggest that the manganese exposure associated with prolonged methcathinone abuse results in widespread structural and functional changes affecting both subcortical and cortical grey matter and their connections. Underlying the distinctive movement disorder caused by methcathinone abuse, there is a more widespread pattern of brain involvement than is evident from the hyperintensity restricted to the basal ganglia as shown by T1-weighted structural MRI.

Novel HSAN1 mutation in serine palmitoyltransferase resides at a putative phosphorylation site that is involved in regulating substrate specificity.

1-Deoxysphingolipids (1-deoxySL) are atypical sphingolipids that are formed by the enzyme serine palmitoyltransferase (SPT) due to a promiscuous use of L-alanine over its canonical substrate L-serine. Several mutations in SPT are associated with the hereditary sensory and autonomic neuropathy type I (HSAN1). The current hypothesis is that these mutations induce a permanent shift in the affinity from L-serine toward L-alanine which results in a pathologically increased 1-deoxySL formation in HSAN1 patients. Also, wild-type SPT forms 1-deoxySL under certain conditions, and elevated levels were found in individuals with the metabolic syndrome and diabetes. However, the molecular mechanisms which control the substrate shift of the wild-type enzyme are not understood. Here, we report a novel SPTLC2-S384F variant in two unrelated HSAN1 families. Affected patients showed elevated plasma 1-deoxySL levels and expression of the S384F mutant in HEK293 cells increased 1-deoxySL formation. Previously, S384 has been reported as one of the two (S384 and Y387) putative phosphorylation sites in SPTLC2. The phosphorylation of wild-type SPTLC2 was confirmed by isoelectric focusing. The impact of an S384 phosphorylation on SPT activity was tested by creating mutants mimicking either a constitutively phosphorylated (S384D, S384E) or non-phosphorylated (S384A, Y387F, Y387F+S384A) protein. The S384D but not the S384E variant was associated with increased 1-deoxySL formation. The other mutations had no influence on activity and substrate affinity. In summary, our data show that S384F is a novel mutation in HSAN1 and that the substrate specificity of wild-type SPT might by dynamically regulated by a phosphorylation at this position.

Multilocus sequence typing using mitochondrial genes (mtMLST) reveals geographic population structure of Ixodes ricinus ticks.

The hard tick Ixodes ricinus is the principal vector of Lyme borreliosis (LB) group spirochaetes in Europe, but it also transmits a large number of other microbial pathogens that are of importance to animal and human health. Here, we characterise geographically distinct populations of this important ectoparasite based on multilocus sequence typing (MLST) of multiple mitochondrial (mt) genes (mtMLST). Internal fragments of approximately 500 bp were amplified and sequenced for 6 protein-encoding and ribosomal genes (atp6, coi, coii, coiii, cytB, and 12s). The samples analysed consisted of 506 questing nymphs collected in Britain and Latvia in 2006-2008 and in Latvia in 2002. Although little genetic structure has previously been observed in I. ricinus ticks among Europe, our data could clearly differentiate these 2 populations. Here, we argue that this novel scheme provides additional phylogenetic resolution which is important for understanding the genetic and geographic structure of I. ricinus populations. This in turn will benefit monitoring and management of tick-borne diseases.

Host migration impacts on the phylogeography of Lyme Borreliosis spirochaete species in Europe.

The geographic patterns of transmission opportunities of vector-borne zoonoses are determined by a complex interplay between the migration patterns of the host and the vector. Here we examine the impact of host migration on the spread of a tick-borne zoonotic disease, using Lyme Borreliosis (LB) spirochaetal species in Europe. We demonstrate that the migration of the LB species is dependent on and limited by the migration of their respective hosts. We note that populations of Borrelia spp. associated with birds (Borrelia garinii and B. valaisiana) show limited geographic structuring between countries compared with those associated with small mammals (Borrelia afzelii), and we argue that this can be explained by higher rates of migration in avian hosts. We also show the presence of B. afzelii strains in England and, through the use of the multi-locus sequence analysis scheme, reveal that the strains are highly structured. This pattern in English sites is very different from that observed at the continental sites, and we propose that these may be recent introductions.

White matter abnormalities in methcathinone abusers with an extrapyramidal syndrome.

We examined white matter abnormalities in patients with a distinctive extrapyramidal syndrome due to intravenous methcathinone (ephedrone) abuse. We performed diffusion tensor imaging in 10 patients and 15 age-matched controls to assess white matter structure across the whole brain. Diffuse significant decreases in white matter fractional anisotropy, a diffusion tensor imaging metric reflecting microstructural integrity, occurred in patients compared with controls. In addition, we identified two foci of severe white matter abnormality underlying the right ventral premotor cortex and the medial frontal cortex, two cortical regions involved in higher-level executive control of motor function. Paths connecting different cortical regions with the globus pallidus, the nucleus previously shown to be abnormal on structural imaging in these patients, were generated using probabilistic tractography. The fractional anisotropy within all these tracts was lower in the patient group than in controls. Finally, we tested for a relationship between white matter integrity and clinical outcome. We identified a region within the left corticospinal tract in which lower fractional anisotropy was associated with greater functional deficit, but this region did not show reduced fractional anisotropy in the overall patient group compared to controls. These patients have widespread white matter damage with greatest severity of damage underlying executive motor areas.

MLST of housekeeping genes captures geographic population structure and suggests a European origin of Borrelia burgdorferi.

Lyme borreliosis, caused by the tick-borne bacterium Borrelia burgdorferi, has become the most common vector-borne disease in North America over the last three decades. To understand the dynamics of the epizootic spread and to predict the evolutionary trajectories of B. burgdorferi, accurate information on the population structure and the evolutionary relationships of the pathogen is crucial. We, therefore, developed a multilocus sequence typing (MLST) scheme for B. burgdorferi based on eight chromosomal housekeeping genes. We validated the MLST scheme on B. burgdorferi specimens from North America and Europe, comprising both cultured isolates and infected ticks. These data were compared with sequences for the commonly used genetic markers rrs-rrlA intergenic spacer (IGS) and the gene encoding the outer surface protein C (ospC). The study demonstrates that the concatenated sequences of the housekeeping genes of B. burgdorferi provide highly resolved phylogenetic signals and that the housekeeping genes evolve differently compared with the IGS locus and ospC. Using sequence data, the study reveals that North American and European populations of B. burgdorferi correspond to genetically distinct populations. Importantly, the MLST data suggest that B. burgdorferi originated in Europe rather than in North America as proposed previously.

A Parkinsonian syndrome in methcathinone users and the role of manganese.

BACKGROUND: A distinctive extrapyramidal syndrome has been observed in intravenous methcathinone (ephedrone) users in Eastern Europe and Russia. METHODS: We studied 23 adults in Latvia who had extrapyramidal symptoms and who had injected methcathinone for a mean (+/-SD) of 6.7+/-5.1 years. The methcathinone was manufactured under home conditions by potassium permanganate oxidation of ephedrine or pseudoephedrine. All patients were positive for hepatitis C virus, and 20 were also positive for the human immunodeficiency virus (HIV). RESULTS: The patients reported that the onset of their first neurologic symptoms (gait disturbance in 20 and hypophonia in 3) occurred after a mean of 5.8+/-4.5 years of methcathinone use. At the time of neurologic evaluation, all 23 patients had gait disturbance and difficulty walking backward; 11 patients were falling daily, and 1 of these patients used a wheelchair. Twenty-one patients had hypophonic speech in addition to gait disturbance, and one of these patients was mute. No patient reported decline in cognitive function. T(1)-weighted magnetic resonance imaging (MRI) showed symmetric hyperintensity in the globus pallidus and in the substantia nigra and innominata in all 10 active methcathinone users. Among the 13 former users (2 to 6 years had passed since the last use), lesser degrees of change in the MRI signal were noted. Whole-blood manganese levels (normal level, <209 nmol per liter) averaged 831 nmol per liter (range, 201 to 2102) in the active methcathinone users and 346 nmol per liter (range, 114 to 727) in former users. The neurologic deficits did not resolve after patients discontinued methcathinone use. CONCLUSIONS: Our observation of a distinctive extrapyramidal syndrome, changes in the MRI signal in the basal ganglia, and elevated blood manganese levels in methcathinone users suggests that manganese in the methcathinone solution causes a persistent neurologic disorder.

Multifocal motor neuropathy: the diagnostic spectrum and response to treatment.

OBJECTIVE: To define the clinical spectrum in a large cohort of patients with multifocal motor neuropathy (MMN) and the effectiveness of IVIg treatment. We also test two neurophysiologic criteria for conduction block (CB) for relevance to treatment responsiveness. METHODS: Retrospective case cohort analysis of 47 patients with MMN followed for up to 12 years. RESULTS: A total of 32 (70%) had an upper-limb onset with most showing clinical features of conduction block: weakened but non-wasted muscles (67%) and differential weakness across muscles supplied by a common terminal motor nerve (54%). Differential weakness of finger extension was a characteristic early sign. Application of consensus criteria for definite CB would have denied a trial of treatment to 6 patients with a typical phenotype compared with new criteria. No association was found between CB and presence of anti-GM1 ganglioside antibody. A total of 24 (51%) patients were treated with IVIg, which was associated with a marked initial improvement in self-reported disability in most patients. The magnitude of initial disability improvement was not sustained in all patients over time. However, the majority of treated patients reported significantly less disability at last follow-up than prior to treatment. Patients converted to a domiciliary IVIg program maintained function at least as well as hospital treated patients. CONCLUSION: The importance of the clinical phenotype of multifocal motor neuropathy (MMN) is emphasized. Neither conduction block (CB) nor antibody status is a reliable predictor of treatment responsiveness. Over-reliance upon consensus CB criteria can deny IVIg to patients with MMN who are treatment responsive.

Neurologists and the threat of bioterrorism.

Neurologists are most likely to become involved in primarily diagnosing those bioterrorist attacks utilising botulinum toxin. Oral ingestion, or possibly inhalation, are likely routes of delivery. The characteristic descending paralysis starts in the extraocular and bulbar muscles, with associated autonomic features. Repetitive nerve stimulation usually shows an incremental muscle response. Treatment is supportive. The differential diagnosis is from naturally occurring paralysing illnesses such as Guillain-Barré syndrome, myasthenic crisis or diphtheria, from paralysing seafood neurotoxins (tetrodotoxin, saxitoxin), snake envenomation, and from chemical warfare poisoning by organophosphates. Primary neurological infections are less feasible for use as bioweapons. There are theoretical possibilities of Venezuelan equine encephalitis transmission by inhalation and secondary zoonotic transmission cycles sustained by horses and mosquitoes. Severe haemorrhagic meningitis regularly occurs in anthrax, usually in the aftermath of severe systemic disease likely to have been transmitted by spore inhalation. Panic and psychologically determined 'me-too' symptomatology are likely to pose the biggest diagnostic and management burden on neurologists handling bioterrorist attack on an institution or a random civilian population. Indeed civilian panic and disablement of institutional operations are likely to be prominent intentions of any bioterrorist attack.

Clinical relevance of low serum vitamin B12 concentrations in older people: the Banbury B12 study.

BACKGROUND: low vitamin B12 concentrations are common in older people, but the clinical relevance of biochemical evidence of vitamin B12 deficiency in the absence of anaemia is uncertain. OBJECTIVE: to examine associations of cognitive impairment, depression and neuropathy with blood measurements of vitamin B12 and folate status in older people. DESIGN: cross-sectional study in general practice in Banbury, England. PARTICIPANTS: a total of 1,000 individuals aged 75 years or older living in the community. RESULTS: low vitamin B12 concentrations were identified in 13% of older people and were associated with memory impairment and depression. After adjustment for age, sex and smoking, individuals with vitamin B12 or holotranscobalamin (holoTC) in the bottom compared with top quartiles had a 2-fold risk (OR = 2.17; 95% CI 1.11-4.27) and a 3-fold risk (OR = 3.02; 95% CI 1.31-6.98) of cognitive impairment, respectively. Low vitamin B12 status was also associated with missing ankle tendon jerks but not with depression. Treatment with vitamin B12 for 3 months corrected the biochemical abnormalities but had no effect on any of the clinical measurements. CONCLUSIONS: low vitamin B12 concentrations are associated with cognitive impairment and missing ankle tendon jerks in older people in the absence of anaemia. Large-scale trials of vitamin B12 supplementation are required to assess the clinical significance of these associations.

Confirmation of a hereditary motor and sensory neuropathy IIC locus at chromosome 12q23-q24.

Hereditary motor and sensory neuropathy type IIC (HMSN IIC) is an autosomal dominant axonal neuropathy. The cardinal features include distal muscle wasting and weakness, vocal cord paralysis, and mild sensory impairment. Recently, HMSN IIC locus was mapped to chromosome 12q23-24. Two families affected by HMSN IIC were identified and evaluated for linkage to this region. Segregation analysis in both families was consistent with linkage to chromosome 12q23-24. Combined analysis generated a multipoint LOD score of 2.1 at marker D12S1583 and refined the HMSN IIC gene interval to The clinical and molecular findings are discussed.

The clinical syndrome associated with lumbar spinal stenosis.

Lumbar spinal stenosis is well defined in patho-anatomical terms but its clinical features are heterogeneous. We carried out a comprehensive retrospective review of the clinical features, radiological changes and outcome of 75 patients with radiologically diagnosed lumbar spinal stenosis in order to define its clinical spectrum. The presenting complaints were of weakness, numbness/tingling, radicular pain and neurogenic claudication in almost equal proportions. The commonest symptom was numbness or tingling of the legs. Neurogenic claudication eventually occurred in only 61%. Ninety-three per cent showed abnormalities on neurological examination, but these were generally mild with reduced ankle jerks being commonest. Imaging of the lumbar spine showed that moderate to severe central spinal stenosis correlated with complaints of weakness and abnormal motor power on clinical examination. Patients were reviewed at a mean of 4 years after diagnosis and 65% had undergone surgical decompression; this was not a prospective comparison of different treatment modalities. Overall, a third of patients felt that their symptoms had improved while a quarter felt that they had worsened. More than half had satisfactory neurological function at the time of review. Thirty-nine per cent of those treated surgically, and 25% of those managed conservatively, reported improved symptoms. A poorer functional status at review correlated with complaints of motor weakness and associated comorbid disease. Degenerative lumbar stenosis is a clinically heterogeneous neurological disorder of the lower limbs in the elderly with variable longer-term outcome. A high index of suspicion is required and neuroimaging should be obtained to confirm the diagnosis.

Symptoms and the perception of disease.

Any symptom represents a perception of an abnormal internal body state. The threshold for perceiving the internal body state as abnormal varies and depends particularly on psychological influences. As a result, a symptom can either reflect pathology, whether serious or not, or be generated wholly psychologically. Intuition allowing discrimination between these possibilities is central to the physician's art. Particular difficulty arises in differentiating between those psychologically generated symptoms which are produced unconsciously, often as a result of anxiety or depression, and those that constitute deliberate deception. Such malingering has the unstated intent of accessing a secondary gain, such as welfare benefit. The art of diagnosis includes estimation of whether symptoms resonate with known pathophysiological processes, using history-taking as a story which unfolds logically towards a diagnosis, assessing how a patient reacts to their symptoms compared to neutral matters, detecting exaggeration or falsification, and documenting evidence of psychologically generated abnormalities during examination. Scientific ability is only one of the attributes of a good diagnostician; equally important are abilities to notice things, to weigh up human nature and to recognise dilemmas. Our procedures for selecting medical students and physicians need to assess these skills as well as scientific qualifications.

Chronic dysimmune neuropathy. A subclassification based upon the clinical features of 102 patients.

The Chronic Dysimmune neuropathies (CDN) are a clinically heterogeneous group of polyneuropathies united by their presumed immune mediated aetiology. At present such neuropathies are classified as Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Multifocal Motor Neuropathy (MMN) and the Neuropathies in association with serum Paraproteins (Paraproteinaemic Neuropathies). This classification fails to recognise other distinctive syndromes and is limited by heterogeneity within, and overlap between, subgroups. We have refined this clinical subclassification by a review of a consecutive series of 102 unselected patients with CDN referred to a single neurologist. We recognise 6 clinical subtypes of CDN: one sensory ataxic group; three motor-sensory subgroups (chronic motor sensory demyelinating neuropathy, subacute motor sensory demyelinating neuropathy and a multifocal motor sensory neuropathy); and two pure motor subgroups (symmetric pure motor demyelinating neuropathy and multifocal motor neuropathy). This subclassification allows distinct syndromes to be recognised and helps resolve problems of heterogeneity and overlap. Distinction between these subgroups is of immediate practical relevance to patient management. Although steroids are beneficial for most of the subgroups, this is not so for both of the pure motor syndromes which should be treated with intravenous immunoglobulin. Patients with chronic development of Motor Sensory Demyelinating Neuropathy respond less well to steroids than those with a subacute onset. An association was found between elderly patients with Subacute Motor Sensory Demyelinating Neuropathy and carcinomas. Within any clinical subgroup patients behave similarly regardless of the presence of associated paraproteins or nerve specific antibodies.

Habitat-specific diversity of Borrelia burgdorferi sensu lato in Europe, exemplified by data from Latvia.

The distribution of Borrelia burgdorferi sensu lato genospecies in questing Ixodes ricinus ticks from ecologically distinct habitats in Latvia was analyzed. A significant variation in the frequency of the genospecies across sites was observed, pointing to the importance of the host community in the ecology of Lyme borreliosis.

The key roles of selection and migration in the ecology of Lyme borreliosis.

The roles of selection and migration of B. burgdorferi s. l. were studied. Questing adult Ixodes ricinus ticks were collected across Europe and analysed for infection with B. burgdorferi s. l. Analysis of the genospecies in individual ticks showed that B. garinii and B. valaisiana segregate from B. afzelii. Segregation of bird- and rodent-associated Borrelia genotypes can be explained by the operation of complement-mediated selection in the midgut of the feeding tick. Phylogenetic analyses of B. burgdorferi s. l. indicate high rates of migration for bird-associated genotypes. Altogether, it is emerging that the ecology of Lyme borreliosis is largely host-driven and that selection and migration are major forces shaping the population structures of B. burgdorferi s. l.