Genome-wide association study of behavioural and psychiatric features in human prion disease.

Prion diseases are rare neurodegenerative conditions causing highly variable clinical syndromes, which often include prominent neuropsychiatric symptoms. We have recently carried out a clinical study of behavioural and psychiatric symptoms in a large prospective cohort of patients with prion disease in the United Kingdom, allowing us to operationalise specific behavioural/psychiatric phenotypes as traits in human prion disease. Here, we report exploratory genome-wide association analysis on 170 of these patients and 5200 UK controls, looking for single-nucleotide polymorphisms (SNPs) associated with three behavioural/psychiatric phenotypes in the context of prion disease. We also specifically examined a selection of candidate SNPs that have shown genome-wide association with psychiatric conditions in previously published studies, and the codon 129 polymorphism of the prion protein gene, which is known to modify various aspects of the phenotype of prion disease. No SNPs reached genome-wide significance, and there was no evidence of altered burden of known psychiatric risk alleles in relevant prion cases. SNPs showing suggestive evidence of association (P<10(-5)) included several lying near genes previously implicated in association studies of other psychiatric and neurodegenerative diseases. These include ANK3, SORL1 and a region of chromosome 6p containing several genes implicated in schizophrenia and bipolar disorder. We would encourage others to acquire phenotype data in independent cohorts of patients with prion disease as well as other neurodegenerative and neuropsychiatric conditions, to allow meta-analysis that may shed clearer light on the biological basis of these complex disease manifestations, and the diseases themselves.

Multiparameter MR imaging in the 6-OPRI variant of inherited prion disease.

BACKGROUND AND PURPOSE: Inherited prion diseases represent over 15% of human prion cases and are a frequent cause of early onset dementia. The purpose of this study was to define the distribution of changes in cerebral volumetric and microstructural parenchymal tissues in a specific inherited human prion disease mutation combining VBM with VBA of cerebral MTR and MD. MATERIALS AND METHODS: VBM and VBA of cerebral MTR and MD were performed in 16 healthy control participants and 9 patients with the 6-OPRI mutation. An analysis of covariance consisting of diagnostic grouping with age and total intracranial volume as covariates was performed. RESULTS: On VBM, there was a significant reduction in gray matter volume in patients compared with control participants in the basal ganglia, perisylvian cortex, lingual gyrus, and precuneus. Significant MTR reduction and MD increases were more anatomically extensive than volume differences on VBM in the same cortical areas, but MTR and MD changes were not seen in the basal ganglia. CONCLUSIONS: Gray matter and WM changes were seen in brain areas associated with motor and cognitive functions known to be impaired in patients with the 6-OPRI mutation. There were some differences in the anatomic distribution of MTR-VBA and MD-VBA changes compared with VBM, likely to reflect regional variations in the type and degree of the respective pathophysiologic substrates. Combined analysis of complementary multiparameter MR imaging data furthers our understanding of prion disease pathophysiology.

The Tullio phenomenon: a neurologically neglected presentation.

The Tullio phenomenon refers to sound-induced disequilibrium or oscillopsia. Patients with this condition frequently present to neurologists, many of whom are unfamiliar with the condition and its diagnostic criteria. Indeed, due to the unusual nature of the symptoms patients are often misdiagnosed as having psychiatric disturbances. Tullio patients describe disequilibrium, auditory and visual symptoms, which are recurrent, brief, and often triggered by loud noises or middle ear pressure changes, e.g. the Valsalva manoeuvre. Many cases are associated with superior semicircular canal dehiscence (SCCD). Early work suggested that the presence of sound-induced torsional eye movements and visual field tilts were consequent upon a utricular-mediated ocular tilt reaction. However, more recent evidence from imaging and oculographic research, as well as data from our patient series indicates that these ocular abnormalities are usually the result of superior semicircular canal stimulation. The clinical history and a focussed examination are often sufficient to make the diagnosis, which can be confirmed with high resolution CT imaging of the temporal bones. In some patients, surgical occlusion or resurfacing of the affected canal can ameliorate symptoms and signs. The aim of this paper is two-fold: Firstly, to review the clinical features of the Tullio phenomenon, and secondly, to highlight our own observations in three cases with a new clinical syndrome consisting of Tullio's phenomenon with bilateral vestibular failure, a pure horizontal nystagmus in response to sound, and no evidence of canal dehiscence.

Distinct neuropsychological profiles correspond to distribution of cortical thinning in inherited prion disease caused by insertional mutation.

BACKGROUND: The human prion diseases are a group of universally fatal neurodegenerative disorders associated with the auto-catalytic misfolding of the normal cell surface prion protein (PrP). Mutations causative of inherited human prion disease (IPD) include an insertion of six additional octapeptide repeats (6-OPRI) and a missense mutation (P102L) with large families segregating for each mutation residing in southern England. Here we report for the first time the neuropsychological and clinical assessments in these two groups. METHOD: The cognitive profiles addressing all major domains were obtained for 26 patients (18 6-OPRI, 8 P102L) and the cortical thickness determined using 1.5T MRI in a subset of 10 (six 6-OPRI, four P102L). RESULTS: The cognitive profiles were different in patients with the two mutations in the symptomatic phase of the disease. The 6-OPRI group had lower premorbid optimal levels of functioning (assessed on the NART) than the P102L group. In the symptomatic phase of the disease the 6-OPRI patients had significantly more executive dysfunction than the P102L group and were more impaired on tests of perception and nominal functions. There was anecdotal evidence of low premorbid social performance in the 6-OPRI but not P102L patients. Cortical thinning distribution correlated with the neuropsychological profile in the 6-OPRI group principally involving the parietal, occipital and posterior frontal regions. The small number of patients in the P102L group precluded statistical comparison between the groups. CONCLUSIONS: The 6-OPRI patients had more widespread and severe cognitive dysfunction than the P102L group and this correlated with cortical thinning distribution.

PRION-1 scales analysis supports use of functional outcome measures in prion disease.

OBJECTIVES: Human prion diseases are heterogeneous but invariably fatal neurodegenerative disorders with no known effective therapy. PRION-1, the largest clinical trial in prion disease to date, showed no effect of the potential therapeutic quinacrine on survival. Although there are several limitations to the usefulness of survival as an outcome measure, there have been no comprehensive studies of alternatives. METHODS: To address this we did comparative analyses of neurocognitive, psychiatric, global, clinician-rated, and functional scales, focusing on validity, variability, and impact on statistical power over 77 person-years follow-up in 101 symptomatic patients in PRION-1. RESULTS: Quinacrine had no demonstrable benefit on any of the 8 scales (p > 0.4). All scales had substantial numbers of patients with the worst possible score at enrollment (Glasgow Coma Scale score being least affected) and were impacted by missing data due to disease progression. These effects were more significant for cognitive/psychiatric scales than global, clinician-rated, or functional scales. The Barthel and Clinical Dementia Rating scales were the most valid and powerful in simulated clinical trials of an effective therapeutic. A combination of selected subcomponents from these 2 scales gave somewhat increased power, compared to use of survival, to detect clinically relevant effects in future clinical trials of feasible size. CONCLUSIONS: Our findings have implications for the choice of primary outcome measure in prion disease clinical trials. Prion disease presents the unusual opportunity to follow patients with a neurodegenerative disease through their entire clinical course, and this provides insights relevant to designing outcome measures in related conditions.

Lymphomatosis cerebri presenting as a rapidly progressive dementia with a high methylmalonic acid.

We report a case of a patient with a rapidly progressive dementing illness and gait disturbance, in whom initial screening demonstrated a high methylmalonic acid level only, suggestive of a functional vitamin B(12) deficiency. Despite B(12) replacement therapy, he continued to decline. Further investigations demonstrated extensive signal change on magnetic resonance imaging involving grey and white matter within the corpus callosum, deep grey matter, brainstem and cerebellar peduncles, and patchy post-contrast enhancement. Laboratory testing revealed a raised erythrocyte sedimentation rate, raised anti-nuclear, intrinsic factor and lupus anticoagulant antibody titres, and a IgG kappa paraprotein. Cerebrospinal fluid was unremarkable. Bone marrow trephine biopsy showed monoclonal gammopathy of unknown significance. The patient initially responded to steroids, and underwent a brain biopsy, which was uninformative. However, 3 weeks following admission, he died due to an aspiration pneumonia. Autopsy findings were consistent with a diffuse primary central nervous system small cell B-cell lymphoma. This has been rarely reported in the medical literature, but our case exhibits typical clinical features, although patchy enhancement on imaging and the high methylmalonic acid have not been previously described. We hypothesise that his functional B(12) deficiency may have resulted from rapid cell turnover, perhaps in conjunction with the presence of intrinsic factor antibodies.

High-b-value diffusion MR imaging and basal nuclei apparent diffusion coefficient measurements in variant and sporadic Creutzfeldt-Jakob disease.

BACKGROUND AND PURPOSE: DWI using a standard b-value of 1000 s/mm(2) has emerged as the most sensitive sequence for the diagnosis of CJD. The purpose of this study was to investigate whether DWI at a high b-value (b = 3000 s/mm(2)) and ADC measurements in the basal nuclei improve the diagnosis of vCJD and sCJD compared with visual assessment of DWI at a standard b-value (b = 1000 s/mm(2)). MATERIALS AND METHODS: Eight patients with vCJD, 9 patients with sCJD, and 5 healthy volunteers underwent DWI at b = 1000 s/mm(2), and 5 vCJD patients, 4 sCJD patients, and 1 growth hormone-related CJD patient underwent DWI at b = 3000 s/mm(2). Two consultant neuroradiologists performed a visual comparison of the b = 1000 and b = 3000 images. Mean MR SI and ADC values were determined for C, P, and DM thalamus ROIs bilaterally at each b-value. SI ratios for each ROI relative to white matter were calculated. RESULTS: In 9 out of 10 patients, the higher b-value images were more sensitive to SI change, particularly in cortex and thalamus, with higher SI ratios at b = 3000 in the DM thalamus. For sCJD at b = 1000, we found significantly lower ADC values in the C and P compared with controls (mean C ADC = 587.3 +/- 84.7 mm(2)/s in sCJD patients versus 722.7 +/- 16.6 mm(2)/s in controls; P = .007), and at b = 3000, the differences were more pronounced. In comparison, in vCJD at b = 1000, ADC values were elevated in the Pu (mean Pu ADC = 837.6 +/- 33.0 mm/s(2) in vCJD patients versus 748.0 +/- 17.3 mm/s(2) in controls; P < .001) but failed to reach significance at b = 3000. CONCLUSIONS: Our results demonstrate that b = 3000 DWI, being more sensitive to slowly diffusing tissue water, is more sensitive to pathology in sCJD than is conventional DWI. High-b-value DWI increases confidence in the radiologic diagnosis of human prion disease.

Neutralizing anti-interferon beta antibodies are associated with reduced side effects and delayed impact on efficacy of Interferon-beta.

UNLABELLED: Interferon-beta (IFNbeta) is a biological therapy which is immunogenic, inducing anti-IFN-beta neutralizing antibodies (Nabs) in some subjects. The frequency of Nabs varies depending on IFN-beta product and the Nab assay used. OBJECTIVE: Assess frequency of Nabs using novel Luciferase assay, evaluate association with relapses, frequency of side effects and to compare results with published data. METHODS: Serum samples at 12 and 24 months and a follow up sample were tested for binding and Nabs. Titre >20 NU was considered positive. Charts were reviewed retrospectively for clinical data. RESULTS: Out of 327 subjects included, 130 subjects (40%) were binding antibody positive, 89 (27%) were Nab +ve at anytime. Risk at 12 months for being Nab +ve: Avonex 8%, Betaferon 39%, Rebif 33%, P < 10(-5); at 24 months 8, 31 and 27% respectively, P = 0.002. Nab titres were highest in Rebif Nab +ve subjects - 50% >320 NU. Annualized relapse rate was 1.53 pre-treatment, after treatment relapse rate was higher in Nab +ve group 0.67 (95% CI 0.38-0.97) versus 0.5 (0.38-0.61) Nab -ve P = 0.04. Nab status at 12 and 24 months was significantly associated with risk of subsequent relapse, risk being greatest in those with highest titres. Side effects were also significantly associated with Nab -ve status.

Syncope associated with pain as the presenting feature of neck malignancy: failure of cardiac pacemaker to prevent attacks in two cases.

Two patients are described in whom syncope was the presenting clinical feature of an undiagnosed neck malignancy. Both patients also had attacks associated with paroxysms of severe neck pain. Neither patient responded to cardiac pacing.

Brain biopsy in dementia.

Brain biopsy has an uncertain role in the diagnosis of dementia. Here we report a retrospective analysis of 90 consecutive cerebral biopsies undertaken for the investigation of dementia in adults at a tertiary referral centre between 1989 and 2003. In most cases (90%), biopsy consisted of a right frontal full thickness resection of cortex, white matter and overlying leptomeninges. Fifty-seven per cent of biopsies were diagnostic: the most frequent diagnoses were Alzheimer's disease (18%), Creutzfeldt-Jakob disease (12%) and inflammatory disorders (9%). Other diagnoses in individual patients included Pick's disease, corticobasal degeneration and other tauopathies, Lewy body dementia, multiple sclerosis, Whipple's disease, progressive multifocal leucoencephalopathy, cerebral autosomal dominant arteriopathy with subcortical ischaemic leucoencephalopathy, vasculopathies and paraneoplastic encephalopathy. The most frequent biopsy finding in the non-diagnostic group and for the series as a whole (37%) was non-specific gliosis variably affecting both cortex and white matter. Complications (11%) included seizures, intracranial and wound infections, and intracranial haemorrhage; there were no deaths or lasting neurological sequelae attributable to the procedure. No trends in diagnostic yield or complication rate over the course of the series were identified. Information obtained at biopsy determined treatment in 11%. A raised cerebrospinal fluid cell count was the only robust predictor of a potentially treatable (inflammatory) process at biopsy. The constellation of behavioural change, raised CSF protein and matched oligoclonal bands in CSF and serum was associated with non-specific gliosis at biopsy. This series underlines the value of cerebral biopsy in the diagnosis of dementia, and suggests that certain clinical and laboratory features may be useful in guiding the decision to proceed to brain biopsy where a treatable disease cannot be excluded by other means.

Cognitive and social impairments in patients with superficial siderosis.

Superficial siderosis of the CNS is a rare condition, caused by deposition of haemosiderin in the superficial layers of the CNS due to repeated chronic subarachnoid or intraventricular haemorrhage. Typically, the hindbrain structures, especially the cerebellum, are most affected. There is a surprising lack of studies investigating in detail the behavioural functioning of patients with such a condition. In this study, we document for the first time the cognitive, social and emotional processing of six patients with a confirmed clinical diagnosis of superficial siderosis. They were aged between 40 and 62 years, with a mean age of 50.2 years; four were male. We administered a comprehensive battery of general cognitive ability and social cognitive tasks. A review of MRI was also undertaken. The findings indicate selective cognitive impairments affecting speech production, visual recall memory and executive functions. In addition, a selective pattern of social dysfunction, affecting the ability to represent other people's mental states, was found. These behavioural dysfunctions are reported in the context of MRI-documented lesions maximally involving the cerebellum, in particular the superior vermis, as well as the medial and inferior frontal cortex. These results suggest that superficial siderosis is associated with a distinct pattern of cognitive and social impairments. They are consistent with the recently proposed role of the cerebellum as a modulator of cognitive, social and emotional functions.

Late recurrences of Sydenham's chorea are not associated with anti-basal ganglia antibodies.

Anti-basal ganglia antibodies (ABGA) have been associated with 100% of acute cases and 69% of persistent cases of Sydenham's chorea. We describe two cases of late recurrences of Sydenham's chorea with absence of ABGA. Both patients had several childhood episodes of Sydenham's chorea. MRI imaging of the basal ganglia and exhaustive investigations for other causes of chorea were normal or negative. The absence of ABGA may be evidence against an autoimmune pathology in late and some persistent recurrences. We suggest the likely pathophysiology to be dopamine hypersensitivity of chronically damaged basal ganglia neurones possibly following induction of an autoimmune antibody response in childhood.

Dissociation of visual and haptic vertical in two patients with vestibular nuclear lesions.

The somatosensory (haptic) vertical (HV) and visual vertical (VV) were assessed in two patients with vestibular nuclear lesions. Patient 1 had paroxysmal nystagmus, and was tested "on" and "off." The HV was normal "on" and "off" but the VV was severely tilted during vestibular paroxysms. Patient 2, with a brainstem stroke, was tested at months 1 and 6. The VV was severely tilted on both occasions (>12 degrees) but the HV was marginally tilted (4 degrees) in the acute stage only. These VV-HV dissociations suggest that vestibular nuclear lesions influence gravity perception mostly via ocular torsional effects rather than by disrupting a single, internal representation of verticality.

Interferon beta in multiple sclerosis: experience in a British specialist multiple sclerosis centre.

BACKGROUND: The efficacy of interferon beta (IFN beta) is well established in relapsing-remitting multiple sclerosis (MS). However, the use of this drug in clinical practice is complex, especially because it is only partially effective, its long term efficacy and side effects are unknown, its efficacy may be abrogated by the development of neutralising antibodies, compliance is variable, and its cost effectiveness is controversial. OBJECTIVES AND METHODS: Analysis of a prospectively followed up series of 101 MS patients treated with IFN beta was undertaken to: (1) monitor the outcome of IFN beta treatment in clinical practice; (2) compare the immunogenicity of the three commercial IFN beta preparations available; (3) assess the proportion of patients fulfilling the current guidelines of the Association of British Neurologists for stopping IFN beta therapy. RESULTS: During a median treatment period of 26 months (range 2-85), the relapse rate decreased by 41%. Although the reduction in the relapse rate was similar for all three commercial products, none of the Avonex treated patients were relapse free, compared with 19% of the Betaferon treated and 27% of the Rebif treated patients (p=0.02). Neutralising antibodies were not detected in Avonex treated patients (0 of 18), compared with 12 of 32 (38%) Betaferon treated and 10 of 23 (44%) Rebif treated patients (p=0.02). Forty of 101 (40%) patients satisfied the current (2001) Association of British Neurologists criteria for stopping IFN beta treatment at some stage during their treatment. CONCLUSION: IFN beta is effective in reducing the relapse rate in patients with relapsing-remitting MS in routine clinical practice. However, after a median treatment duration of 26 months, 40% of initially relapsing-remitting MS patients seem to have ongoing disease activity, presenting as disabling relapses or insidious progression.

One-and-a-half syndrome resulting from spontaneous vertebral artery dissection.

A patient with one-and-a-half syndrome due to brainstem ischaemia is presented. The case emphasises the importance of attempting to establish the aetiology of this syndrome--in this case infarction secondary to spontaneous vertebralartery dissection--when making therapeutic decisions.

Positional down beating nystagmus in 50 patients: cerebellar disorders and possible anterior semicircular canalithiasis.

OBJECTIVES: To clarify the clinical significance of positional down beat nystagmus (pDBN). METHODS: A discussion of the neuro-otological findings in 50 consecutive patients with pDBN. RESULTS: In 38 patients there was evidence of CNS disease (central group) but in 12 there was not (idiopathic group). In the CNS group, presenting symptoms were gait, speech, and autonomic dysfunction whereas in the idiopathic group patients mostly reported positional vertigo. The main neurological and oculomotor signs in the CNS group were explained by cerebellar dysfunction, including 13 patients with multiple system atrophy. In patients with multiple system atrophy with a prominent extrapyramidal component, the presence of pDBN was helpful in the differential diagnosis of atypical parkinsonism. No patient with pDBN had the Arnold-Chiari malformation, a common cause of constant down beat nystagmus (DBN). In the idiopathic group, the pDBN had characteristics which suggested a peripheral labyrinthine disorder: vertigo, adaptation, and habituation. In six patients an additional torsional component was found (concurrently with the pDBN in three). Features unusual for peripheral disorder were: bilateral positive Dix-Hallpike manoeuvre in nine of 12 patients and selective provocation by the straight head-hanging manoeuvre in two. CONCLUSION: It is argued that some patients with idiopathic pDBN have benign paroxysmal positional vertigo (BPPV) with lithiasis of the anterior canal. The torsional component may be weak, because of the predominantly sagittal orientation of the anterior canal, and may not be readily seen clinically. Nystagmus provocation by bilateral Dix-Hallpike and straight head-hanging may be explained by the vertical upwards orientation of the ampullary segment of the anterior canal in the normal upright head position. Such orientation makes right-left specificity with the Dix-Hallpike manoeuvre less important than for posterior canal BPPV. This orientation requires a further downwards movement of the head, often achieved with the straight head-hanging position, to provoke migration of the canaliths. The straight head-hanging manoeuvre should be carried out in all patients with a history of positional vertigo and a negative Dix-Hallpike manoeuvre.