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.

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.

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.

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.

Analysis of downbeat nystagmus. Otolithic vs semicircular canal influences.

The relative strengths of vertical canal and otolithic factors influencing downbeat nystagmus (DBN) were investigated in a patient whose nystagmus was of maximum intensity with the head in the upright position and abolished with the head in the supine position. The vestibuloocular reflex (VOR) was assessed by oscillating the patient about both the supine and upright positions. During oscillation about the supine position both the upward and downward VORs had equal gains in the dark (0.6) and unity gain in the light. In contrast, during oscillation about the upright, the upward VOR became hyperactive with a gain of 1.8 in the dark and 1.2 in the light, whereas the downward VOR became hypoactive with a maximum gain of 0.86 in the light. This degree of asymmetry of the VOR is greater than would be expected from a summation of spontaneous nystagmus with normal canal reflexes. We concluded that the DBN arose from an asymmetry of vertical canal function, which became manifest when the otoliths were tilted with respect to gravity. Contrasting findings are presented in a patient whose DBN was insensitive to tilt. It would seem that other cases of DBN lie on a continuum between these extreme examples.

Downbeating nystagmus. A review of 62 cases.

We reviewed the clinical and oculomotor findings in 62 patients with downbeating nystagmus (DBN). Only those patients whose DBN was enhanced in lateral gaze were included. Apart from gait ataxia, few patients had additional neurologic signs. The two most common causes of DBN were cerebellar ectopia (25%) and cerebellar degeneration (25%) with another 10% having a variety of conditions. In about 40% the cause remained undiagnosed. In some patients with idiopathic DBN and in others with DBN due to cerebellar ectopia, the disease progressed slowly, if at all. In DBN the slow-phase velocity is dependent on vertical head position and head velocity in pitch; vertical pursuit, particularly downward pursuit, is defective and vertical vestibulo-ocular reflexes are intact. We concluded that at least some cases of DBN were due to an imbalance in otolithocular reflexes. The lesion causing DBN appears to be in the vestibulocerebellum, perhaps the nodulus, a structure that normally inhibits otolith-ocular reflexes.

Convergence nystagmus associated with Arnold-Chiari malformation.

A case of convergence nystagmus associated with an Arnold-Chiari type I malformation is presented. The nystagmus appeared in the absence of fixation, was provoked during Valsalva's maneuver and neck flexion and extension, and attenuated on deep inspiration. Sagittal magnetic resonance images showed that the diameter of the cerebral aqueduct increased with the neck in full flexion and in full extension. Surgical foramen magnum decompression considerably reduced the nystagmus and abolished the postural variation of aqueduct diameter. It is postulated that this nystagmus was due to a combination of mechanical distortion and abnormal transmission of cerebrospinal fluid pressure to the aqueductal region.

Cyclosporine and multiple sclerosis: the cons.

Although the pathophysiologic cause of multiple sclerosis (MS) is unknown, there is a considerable body of evidence that immunologic factors play a part. As experimental allergic encephalomyelitis (EAE), particularly its relapsing and remitting forms, has some similarities to MS, and because EAE can be modified by immunosuppression, a large number of immunomodulating drugs have been given to patients with MS. None of these therapies has been dramatically successful, but immunosuppression with azathioprine, mercaptopurine, and cyclophosphamide have been of marginal benefit to the patients. The reason for this relative failure of such therapy in MS might be because these conventional immunosuppressants do not sufficiently modify the immunologic abnormalities in the patients. Cyclosporine A is the first of a new generation of immunosuppressants that appear to be more potent, at least in the field of transplantation. For this reason, it is logical to determine its efficacy in MS. Based on the hypothesis that MS is an immunopathologic disease, many immunosuppressive therapies have been tried for this condition. Cyclosporine is the newest such agent. Studies in animals with EAE indicate that the drug suppresses the disease, but when the drug is stopped the disease exacerbates. This may also happen in MS. Furthermore, our studies indicate that cyclosporine has a low therapeutic index, so that in doses that are well tolerated the drug is not effective and in doses that are effective there is significant toxicity. For these reasons, we reluctantly conclude that cyclosporine should not be used in MS.

Congenital-type nystagmus emerging in later life.

We describe six patients who, as teenagers or adults, developed florid nystagmus with consequent visual symptoms without any other manifestation of disease. In three patients, previous ophthalmologic examination had excluded nystagmus, and there was medically informed witness to its onset. The remainder may or may not have had a milder, unsuspected nystagmus before the development of symptoms. Ophthalmologic and neurologic investigations were negative, and follow-up of 2 to 15 years has been uneventful. Eye movement recordings showed the characteristics of the nystagmus to be indistinguishable from congenital nystagmus, which normally becomes manifest in early infancy. We conclude that a congenital-type nystagmus can emerge or enhance in later life without apparent provocation and is probably associated with a benign pathophysiology.

Effects of anti-CD4 antibody treatment on lymphocyte subsets and stimulated tumor necrosis factor alpha production: a study of 29 multiple sclerosis patients entered into a clinical trial of cM-T412.

T lymphocytes may play a central role in MS. The search for more targeted immunosuppression than is currently available has led to recent clinical trials of novel therapeutics. We studied 29 patients in a double-blind placebo-controlled trial of the chimeric monoclonal anti-CD4 antibody, cM-T412 (Centocor, Leiden, Holland) over a period of 18 months. Total and differential WBC counts; T, B, and natural killer lymphocytes; CD4+ and CD8+ T cells; CD4+ and CD4- naive cells; CD4+ and CD4- memory cells; interleukin-2 receptor- and major histocompatibility class II-positive T cells; serum tumor necrosis factor alpha (TNF-alpha); and PHA (phytohemagglutinin)/LPS (lipopolysaccharide)-stimulated whole blood TNF-alpha production were all examined serially in peripheral blood for the duration of the trial. In addition, for the first two treatment cycles, the above variables were tested 1 and 7 days after treatment. The results demonstrated significant long-term reductions, lasting up to 12 months after the last treatment cycle in all CD4+ subsets studied, but with a relative preservation of CD4+ memory cells as opposed to CD4+ naive cells. CD4- subsets also showed significant reductions after treatment but returned to baseline levels within 7 days. Monocyte counts were unaffected by cM-T412. Serum TNF-alpha and 2- and 18-hour PHA/LPS-stimulated TNF-alpha levels were also unchanged in the long term, although significant increases were observed in the 2- and 18-hour PHA/LPS-stimulated TNF-alpha levels the day immediately after treatment. There was no significant correlation between any of the immunologic markers studied and MRI measures of disease activity.

Quantitative brain MRI lesion load predicts the course of clinically isolated syndromes suggestive of multiple sclerosis.

We performed semiautomated quantitative measurement of brain magnetic resonance imaging (MRI) abnormalities seen at presentation and at 5-year follow-up in 84 patients presenting with an acute clinically isolated syndrome of the optic nerves, brainstem, or spinal cord suggestive of multiple sclerosis (MS). At follow-up, 34 (40%) had developed clinically definite and four (5%) clinically probable MS. Patients who developed MS during follow-up had a higher lesion load at presentation than those who did not. There was a strong correlation of the MRI lesion load at presentation with both the increase in lesion load over the next 5 years and disability at follow-up. Increasing initial lesion load correlated with a decreasing time to development of MS clinically (r = -0.328, p < 0.05). At follow-up, disability and brain lesion load were strongly correlated in patients who had developed MS. These results establish that MRI at presentation with clinically isolated syndromes suggestive of MS is useful in predicting the subsequent clinical course and the development of new MRI lesions. This suggests that quantitative brain MRI will be helpful in selecting patients with early clinical MS for treatment trials and for subsequent monitoring of their response to treatment.

Heterogeneity of blood-brain barrier changes in multiple sclerosis: an MRI study with gadolinium-DTPA enhancement.

We performed 15 dynamic gadolinium-DTPA (Gd-DTPA)-enhanced MRI studies in 8 patients with relapsing and remitting multiple sclerosis; 7 were follow-up studies. We measured the time course of enhancement in 102 enhancing lesions for up to 384 minutes, with rest breaks. Immediate postcontrast MRIs demonstrated many different patterns of enhancement. We observed both uniformly enhancing and ring enhancing lesions. The enhancing regions were often less extensive than the corresponding high signal on T2-weighted images. Three lesions were seen with Gd-DTPA but not on unenhanced scans; 1 was seen on unenhanced scans 10 days later, suggesting that blood-brain barrier disturbance may precede other MRI signs of MS lesions. Three months later, some high-signal areas on T2-weighted scans had decreased in size to resemble the areas previously outlined by Gd-DTPA. This technique provides useful information about the pathogenesis and behavior of MS lesions.

Treatment of multiple sclerosis with the monoclonal anti-CD4 antibody cM-T412: results of a randomized, double-blind, placebo-controlled, MR-monitored phase II trial.

We report the results of a randomized, double-blind, placebo-controlled exploratory trial of the chimeric monoclonal anti-CD4 antibody cM-T412 in 71 patients suffering from active relapsing-remitting and secondary progressive multiple sclerosis. Infusion of the antibody produced frequent but usually minor side effects and resulted in a long-lasting reduction of circulating CD4-positive T cells. There was no significant effect on the primary measure of efficacy, the number of active lesions on monthly gadolinium-enhanced MRI over 9 months. Further statistical evaluation provided evidence that the degree of depletion of CD4-positive cells was important with regard to treatment efficacy; using CD4 counts as a covariate there was a statistically significant effect on the number of active lesions over 18 months (p = 0.04). There was a statistically significant reduction of 41% in the number of clinical relapses (a secondary efficacy parameter) after 9 months (p = 0.02), which was still present after 18 months, but this finding may be partly due to physician unblinding. Other secondary efficacy parameters (Expanded Disability Status Scale progression, number of courses of methylprednisolone) were not influenced by anti-CD4 treatment. We conclude that intravenous treatment with the monoclonal antibody cM-T412 in the dosage we used results in a substantial and sustained reduction of the number of circulating CD4-positive cells, but is not able to reduce MS activity as measured by monthly gadolinium-enhanced MRI, and is therefore unlikely to have a beneficial effect on the clinical disease course. We found preliminary evidence suggesting that more aggressive depletion of CD4-positive cells might lead to a more substantial reduction in MRI activity.

Long-term retrograde amnesia...the crucial role of the hippocampus.

For patients with hippocampal pathology, disagreement exists in the literature over whether retrograde amnesia is temporally limited or very extensive depending on whether the anatomical damage is restricted to this structure or also involves additional temporal cortex. We report a comprehensive assessment of retrograde and anterograde memory functions of a severely global amnesic patient (VC). We found that he presented with a remarkably extensive and basically ungraded retrograde amnesia. This impairment profoundly affected four decades preceding the onset of his amnesia and encompassed both non personal and personal facts and events. VC also presented with a severe anterograde amnesia and a deficit in the acquisition of new semantic knowledge in the post-morbid period. Detailed MRI volumetric measurements revealed gross abnormalities in both hippocampi which were markedly shrunken. Of relevance to the debate on retrograde amnesia were the observations that the volumes of both entorhinal cortices and the remainder of both temporal lobes were normal. These data suggest that the hippocampus is critical not only for the efficient encoding and hence normal recall of new information but also for the recall of episodic information acquired before the onset of amnesia. Our results are compatible with the view that retrograde amnesia is both extensive and ungraded when the damage is limited to the hippocampus.

Quality of life in hypertensives treated with atenolol or captopril: a double-blind crossover trial.

AIM: To compare the effects of captopril and atenolol on quality of life of hypertensive patients. METHODS: In a randomly allocated double-blind crossover trial with two 6-week treatment periods captopril at 25 mg twice a day or atenolol at 50 mg once a day were administered to 265 hypertensive patients (mean age 56 years; 55% men). Of these, 65% were newly treated hypertensives and 35% were previously uncontrolled on a diuretic alone. A seated diastolic blood pressure of 95-115 mmHg was required after a 3-week placebo run-in period. Any previous diuretic therapy was changed to hydrochlorothiazide (25 mg once a day) and the dose was kept constant throughout the trial. Newly diagnosed patients did not take a diuretic at any time. Quality of life was assessed from self-completed questionnaires measuring psychological well-being, symptomatic side effects of treatment, and activity and perceived well-being (a health index). A relative's perception of the patients' mood was also obtained where possible. RESULTS: Twelve patients withdrew on atenolol and 10 on captopril. No differences between the drugs were observed in quality of life measures, and 95% confidence intervals suggested that important differences were excluded. CONCLUSION: We conclude that at the doses used in this trial there were no important differences between captopril and atenolol in their effects on quality of life.

Dendritic cells from patients with tropical spastic paraparesis are infected with HTLV-1 and stimulate autologous lymphocyte proliferation.

Dendritic cells (DC), important antigen-presenting cells for recruiting T cells into immune responses, are susceptible to infection with HIV-1 and this can cause either stimulatory or suppressive effects on T cells. We examined another human retrovirus, HTLV-1, to determine whether DC were infected and caused any changes in T-cell function. Patients infected with HTLV-1 who have tropical spastic paraparesis (TSP) show high 'spontaneous' lymphocyte proliferation. We studied the basis for this by analyzing the interactions in vitro between lymphocytes and antigen-presenting cells and compared cells taken from HTLV-1-positive TSP patients with those taken from HTLV-1-positive healthy carriers and HTLV-1-negative family members. In HTLV-1-positive individuals, 0.4-5.1% of the DC were infected with HTLV-1 as determined by in situ hybridisation. In TSP patients, depletion of DC and purification of T cells abolished 'spontaneous' lymphocyte proliferation. Reinstating the DC, but not B cells or macrophages, restored proliferation, an effect that was blocked by antibodies either to class II major histocompatibility antigens or to HTLV-1 itself. Thus, presentation of HTLV-1 antigens by infected DC to autologous T cells could result in the abnormal T-cell proliferation and cause the inflammatory reaction leading to tissue damage in TSP. We also speculate that persistent infection of DC with HTLV-1 and consequent continuous stimulation of T cells might be instrumental in the development of HTLV-1-mediated T-cell leukemia.

Neopterin concentrations in serum and cerebrospinal fluid in HTLV-I infected individuals.

The concentration of neopterin was measured in serum samples taken from individuals infected with HTLV-I: 5 from asymptomatic individuals, 1 from a patient with adult T-cell leukaemia and 30 from patients with tropical spastic paraparesis (TSP). In addition, cerebrospinal fluid (CSF) was available from 22 of the TSP patients and neopterin concentrations were determined in these. Elevated levels of neopterin were found in only 3 of the 36 HTLV-I-positive serum samples, all from TSP patients, but significantly elevated neopterin levels were observed in 12 of the 22 CSF samples. The localisation of the elevated neopterin concentrations to the CSF of patients with TSP suggests a marked degree of activation of the cell-mediated immune system intrathecally. This provides further evidence in favour of powerful immune mechanisms operating centrally in the pathogenesis of TSP.

Viral specific IgG and IgM antibodies in the CSF of patients with tropical spastic paraparesis.

The cerebrospinal fluid (CSF) from seven West Indian migrants to the United Kingdom with tropical spastic paraparesis were studied by antigen immunoblotting for specific anti-HTLV1 oligoclonal IgG and IgM. Eight CSFs from five patients were positive for specific IgG and negative for IgM; three CSFs from two patients were positive for IgM and negative for IgG. No patient had both IgG- and IgM-positive CSF. Those patients with IgM only had disease of the shortest duration. When looking for evidence that neurological damage is caused by HTLV1, both IgM and IgG should be examined.

Bilateral loss of vestibular function: clinical findings in 53 patients.

The clinical presentations and aetiologies of a series of 53 cases of bilateral vestibular failure (BVF) seen by the authors over a decade were evaluated by retrospective review of the medical records. Thirty-nine per cent of patients had associated neurological disease; 13% had a progressive cerebellar syndrome with disabling gait ataxia, abnormal eye movements and cerebellar atrophy on neuro-imaging. BVF was usually unsuspected. Nine per cent had cranial or peripheral neuropathies and in this group there was no abnormality of brain stem/cerebellar oculomotor function, but hearing loss was common. Eleven per cent revealed BVF and hearing loss secondary to meningitis, and 6% had other neurological disorders. Idiopathic BVF was found in 21% of cases, characterised by paroxysmal vertigo and/or oscillopsia, but no abnormal clinical signs. Gentamicin ototoxicity accounted for a further 17%, while autoimmune disease was present in 9% of patients. Otological or neoplastic disease was diagnosed in the remaining 13% of patients. It was concluded that neurological, audiological and ocular motor assessments allow the probable cause of BVF to be defined in approximately 80% of cases. A group of BVF related to autoimmune pathologies is reported for the first time, indicating the need for immunological screening. Idiopathic BVF may present with only minor visual or vestibular symptoms, while in patients with cerebellar degeneration, BVF may be unsuspected and, thus, underdiagnosed.