To tell or not to tell? Revealing the diagnosis in multiple sclerosis.

We review briefly (1) the history of patient-physician relationship and its evolution from a physician-centered to patient-centered model; (2) the impact of the McDonald Criteria for Multiple Sclerosis (MS); (3) why it is important to tell patients of their diagnosis; (4) how physicians should disclose the diagnosis to patients; (5) dealing with suspected MS; and (6) prognosis and treatment. For the majority of clinically definite MS patients we advocate disclosure, identify steps for physicians to communicate the diagnosis and propose a framework to follow when revealing a diagnosis of MS.

MRI and visual-evoked potentials in partners of multiple sclerosis patients.

OBJECTIVE: Some epidemiological evidence, particularly concerning the role of Epstein Barr Virus implies that multiple sclerosis (MS) may be transmissible and if correct, this might be revealed by increased prevalence of MS in cohabiting partners. METHODS: We addressed this problem by neurological assessment, visual-evoked potentials (VEP) and magnetic resonance imaging (MRI) in 112 partners of patients with MS in comparison to a control group of 93 individuals with clinically non-significant head or neck pain and in comparison to UK prevalence. RESULTS: We found one instance of conjugal definite MS. Including this case, VEP were abnormal in five instances with either significant delay (n = 3) or increased interocular latency difference (IOLD) (n = 2) in partners of MS patients thus raising the possibility of subclinical optic nerve demyelination. The mean absolute value of IOLD in partners was greater than the value in controls (P = 0.033). There were no significant differences in MRI findings between the two groups. CONCLUSION: The finding of one conjugal pair and abnormal VEP in a further four MS partners could have several explanations. It is compatible with the concept of a transmissible agent, although our observations could be due to several biases as well as the play of chance alone.

A basic smell test is as sensitive as a dopamine transporter scan: comparison of olfaction, taste and DaTSCAN in the diagnosis of Parkinson's disease.

AIM: To evaluate relationship between odour identification, taste threshold, dopamine transporter scan (DaTSCAN) and motor function in early Parkinson's disease (PD) and their diagnostic accuracy. METHODS: Seventy-three patients with early parkinsonism were evaluated by the Unified Parkinson's Disease Rating Scale (UPDRS), DaTSCAN, electrogustometry (EGM) threshold and University of Pennsylvania Smell Identification Test (UPSIT). Olfactory Event-Related potentials (OERP) were performed on 49 patients. At follow-up (mean 15.3 months), patients were diagnosed as 'PD' or 'non-PD'. DaTSCAN images were assessed visually and semi-quantitatively by QuantiSPECT. RESULTS: The sensitivity of UPSIT (86%) was not significantly different from that of the DaTSCAN (92%). UPSIT correlated moderately with DaTSCAN uptake (r = 0.44; P < 0.005) and UPDRS score (r = 0.43; P < 0.05) and weakly with symptom duration (r = 0.25; P < 0.05). In the PD group, OERP showed increased latency but no change in amplitude and no correlation with DaTSCAN. EGM thresholds were impaired in 22% of the PD group but they did not correlate with any other test parameters. DaTSCAN-UPSIT discordance was found in nine patients with PD, but neither was diagnostically superior. CONCLUSION: Our patients with early PD have a frequent and severe olfactory deficit that correlates with disease severity, symptom duration and DaTSCAN but not EGM. The sensitivities of UPSIT and DaTSCAN are high at 86% and 92%, respectively. Although DaTSCAN is superior for 'localization', UPSIT is considerably 'cheaper', and neither is disease specific. EGM threshold impairment in PD is independent of the smell deficit, and probably signifies advanced disease.

Twin studies and the heritability of MS: a conclusion.

OBJECTIVE: The classical twin study has the potential to evaluate the relative contribution of genes and environment and guide further research strategies, provided the sampling and methods of analysis are correct. We wish to review all the more informative twin studies on multiple sclerosis (MS). METHODS: We examined six large population-based twin studies in MS and calculated indices of heritability (h(2)), which is the traditional method of assessing genetic contribution to disease and to allow comparison between studies. RESULTS: This index was found to vary widely from 0.25 to 0.76 with large confidence intervals that reflect small sample size and prevent robust interpretation. CONCLUSION: Overall the studies support a genetic contribution to disease; however, the imprecision of the heritability estimates and potential biases that they contain mean that very little inference can be drawn its exact size. Given that the magnitude of genetic effect cannot be measured because of the relative infrequency of MS; the consequent difficulty in collecting an informative sample; and in many countries, the lack of a comprehensive twin register, we suggest that further twin prevalence surveys should not be undertaken. Twin studies could be used more effectively in other ways, such as the co-twin case-control approach.

Parkinson's disease: a dual-hit hypothesis.

Accumulating evidence suggests that sporadic Parkinson's disease has a long prodromal period during which several non-motor features develop, in particular, impairment of olfaction, vagal dysfunction and sleep disorder. Early sites of Lewy pathology are the olfactory bulb and enteric plexus of the stomach. We propose that a neurotropic pathogen, probably viral, enters the brain via two routes: (i) nasal, with anterograde progression into the temporal lobe; and (ii) gastric, secondary to swallowing of nasal secretions in saliva. These secretions might contain a neurotropic pathogen that, after penetration of the epithelial lining, could enter axons of the Meissner's plexus and, via transsynaptic transmission, reach the preganglionic parasympathetic motor neurones of the vagus nerve. This would allow retrograde transport into the medulla and, from here, into the pons and midbrain until the substantia nigra is reached and typical aspects of disease commence. Evidence for this theory from the perspective of olfactory and autonomic dysfunction is reviewed, and the possible routes of pathogenic invasion are considered. It is concluded that the most parsimonious explanation for the initial events of sporadic Parkinson's disease is pathogenic access to the brain through the stomach and nose - hence the term 'dual-hit'.

Smoking is a risk factor for multiple sclerosis: a metanalysis.

Several case control studies have probed a link between cigarette smoking and subsequent multiple sclerosis (MS). Data collection and statistical methods have varied, and frequently, case numbers have been small. Publications relating to MS and smoking are reviewed and combined where comparable methods have been used. Metanalysis of six informative studies show significantly elevated odds or rate ratios, ranging from 1.22 to 1.51, depending on the method of analysis, confirming that the risk of MS is increased for those who smoke prior to disease onset, as measured by commencement of symptoms. A variety of direct causative mechanisms are discussed, but an indirect association through health adverse conduct is favoured.

Multiple sclerosis in Latter Day Saints (Mormons).

BACKGROUND: Compliant members of the Church of Jesus Christ of Latter Day Saints (LDS, Mormons) have a low incidence of heart and lung disease that may relate to their healthy life style. We wished to determine whether multiple sclerosis (MS) was less frequent in this religious body. METHODS: To ascertain this, diagnostic and treatment coding records were accessed from the Deseret Mutual Benefit Administrators (DMBA) for the 6 year period 1997-2002. DMBA is a medical insurance company that provides medical insurance to all employees of LDS Church in the US. This information was combined with prescribing records for disease modifying treatment, principally beta-interferon and Copaxone which are medications specific to MS. RESULTS: Using various search strategies we derived an approximate MS prevalence of 45-64/100,000. CONCLUSION: Comparison with MS rates from Utah and other states of comparable latitude suggest that strict LDS have an MS prevalence that is lower than expected and may reflect their healthy life style.

Seroprevalence of herpes simplex virus type 2 in multiple sclerosis.

BACKGROUND: It has been proposed that multiple sclerosis (MS) might be a sexually transmitted disorder. There is evidence that seropositivity to herpes simplex virus type 2 (HSV-2) correlates well with the number of sexual partners. Accordingly, a raised overall HSV-2 seroprevalence in MS would lend support to this theory. MATERIALS AND METHODS: Serum from 497 UK subjects with clinically definite MS was tested for antibodies to HSV-2 and compared with matched historical controls from within and outside London, blood donors and genito-urinary medicine (GUM) clinics. RESULTS: The unadjusted MS seropositivity rate was 14%. HSV-2 seroprevalence in MS patients aged 35-64 years was significantly higher overall compared with a non-London general population in an unadjusted comparison. HSV-2 seroprevalence in London MS patients compared with London blood donors was significantly greater irrespective of age, but the MS seropositive rate was lower than GUM clinic attenders. In a logistic regression analysis, increased age, female sex and MS diagnosis all independently increased the odds of seropositivity after adjustment for each other. CONCLUSION: It is concluded that there is increased likelihood of HSV-2 exposure in patients with MS and this may indicate a higher than average number of partners.

Are multiple sclerosis patients risk-takers?

Several factors appear to be associated with multiple sclerosis (MS), and each has a postulated immune or environmental explanation, but a common theme is lacking. This article suggests that a unifying premise could be risk-associated behaviour. Evidence is reviewed for associations with smoking, alcohol, recreational drug use, oral contraception, cholesterol intake, risk attitude and behaviour, ultraviolet light and vitamin D exposure, frequency of MS in healthy societies, and viral infection. The evidence associated with smoking, not taking vitamin D supplements and Epstein-Barr viral infection appears good. There may be a pattern of risk-associated behaviour that characterizes patients with MS and brings them into contact with one or more causative agents. Of the possible agents, viral infection seems the most likely.

Is multiple sclerosis a sexually transmitted infection?

It is proposed that multiple sclerosis may be transmitted chiefly by sexual contact. Arguments favouring this include: migration studies that suggest a transmissible agent in adolescence; clusters of multiple sclerosis which have occurred in low prevalence areas following entry of young males; the similarity of multiple sclerosis to tropical spastic paraplegia, a known sexually transmitted infection with resemblance to primary progressive multiple sclerosis; an increased rate in drug misusers; a similar age of onset and sex pattern to that found in sexually transmitted disease; increased incidence of multiple sclerosis in those using oral contraceptives; low multiple sclerosis rates in societies with a strict moral code; longitudinal shifts in sex prevalence that show an increase in women after the sexual revolution of the 1960s; and important exceptions to the worldwide distribution corresponding to countries with permissive attitudes to sex. Family, conjugal pair, twin, and adoption studies are compatible with an infectious cause of multiple sclerosis if this is sexually transmitted. It is not proposed that sexual transmission is the only cause but that inherited factors create a susceptibility to a sexually transmitted neurotropic agent. It is hoped this hypothesis might encourage a new direction of neurological research.

Is Parkinson's disease a primary olfactory disorder?

It has been known for over 30 years that olfactory function is disordered in idiopathic Parkinson's disease (IPD). The severity and partial specificity of anosmia was not realized until recently, with the advent of more detailed analysis and sophisticated measurement. The olfactory vector hypothesis suggests that the causative agent for IPD enters the brain via the nasal route, but the reason for olfactory dysfunction may be more subtle. Evidence for olfactory disturbance is reviewed from pathological, psychological, neurophysiological and genetic stand-points. It is proposed that the initial causative event in IPD may start in the rhinencephalon (olfactory brain) prior to damage in the basal ganglia.

Olfactory disorder in motor neuron disease.

In Parkinson's disease and Alzheimer's disease there is profound disorder of olfaction. The extent to which this modality is involved in motor neuron disease (MND) has been studied little. To address this further we assessed olfaction by three methods-a smell identification test ("UPSIT") in 58 patients and 135 controls; olfactory-evoked response (OEP) to H2S in 15 patients, and pathological examination of olfactory bulbs obtained from 8 cadavers. It was found that smell identification compared with the controls was slightly worse overall in the MND group as a whole, but only the bulbar patients scored significantly less on the UPSIT. Patients displayed a subtle defect in cheese odor recognition. OEPs were normal in 9 subjects and delayed in 1 subject. The remaining 5 OEPs were unsuccessful. Histopathological studies of olfactory bulbs showed excess lipofuscin deposition in all 8 cases examined, indicating subclinical neuronal damage. Olfactory neurons with a degree of antioxidant defect may be more susceptible to cellular damage than other neuronal groups because of their direct relationship to environmental agents. Overall we found the degree of olfactory dysfunction in MND to be mild and in contrast with the marked changes described by others.

Olfactory evoked responses and identification tests in neurological disease.

UNLABELLED: To assess the value of smell testing we used olfactory evoked potentials (OEP) and an identification test in multiple sclerosis, Parkinson's disease, motor neuron disease and Alzheimer's disease. METHODS: The OEP to H2S (20 ppm) was obtained using an olfactometer designed to stimulate olfactory nerve endings only. Odor recognition was assessed by the University of Pennsylvania Smell Identification Test (UPSIT). In all instances the disease was 'definite' based on standard diagnostic criteria. Controls were derived from 156 healthy people. RESULTS: 1) Multiple Sclerosis: 11/72 patients (15%) were abnormal on UPSIT. For OEP there was significant increase of latency and decrease in amplitude in 6/26 patients (23%). 2) Parkinson's Disease: 126/155 (81%) patients had an abnormal UPSIT score. 12/37 (32%) had prolonged latency with normal amplitude measurement on OEP, but 27 had absent or unclear readings. 4/10 with normal UPSIT displayed abnormality on OEP. 3) Motor Neuron Disease: 9/58 (16%) were abnormal on UPSIT. There was significant delay in 1/10 (10%) patients on OEP. 4) Alzheimer's Disease: UPSIT scores were abnormal in all 8 patients examined. OEP was normal in 4 of these who could be tested. CONCLUSION: Smell dysfunction was found in all 4 conditions but most severely in Parkinson's Disease (over 80%). The UPSIT in general showed abnormality more frequently than OEP. The olfactory defect probably involves peripheral structures in all diseases tested except Alzheimer's. A patient with normal olfaction is unlikely to have idiopathic Parkinson's disease.

Assessment of olfaction in multiple sclerosis: evidence of dysfunction by olfactory evoked response and identification tests.

OBJECTIVE: To resolve whether the olfactory pathways are affected in multiple sclerosis. METHODS: Olfaction was assessed by: (1) The University of Pennsylvania smell identification test (UPSIT, which uses microencapsulated odours that are released when scratched with a pencil) in 72 patients with multiple sclerosis and 96 controls, (2) olfactory evoked potentials (OEP) to 20 ppm H2S by volume, and 50% CO2 in air for 45 patients with multiple sclerosis and 47 controls. The abnormality rate in patients with multiple sclerosis for both tests (1) and (2) was compared with that for visual evoked potentials measured using a standard checquerboard technique. RESULTS: By comparison with controls, patients exhibited significantly low scores on the smell identification test with 15% of patients scoring outside the 95% confidence intervals for controls. The UPSIT was occasionally abnormal when the visual evoked potential (VEP) was normal. In general UPSIT scores correlated well with the H2S-evoked response in controls and patients. For H2S, there was a statistically significant increase of latency and decrease of amplitude for patients compared with controls. Increased H2S latency and reduced UPSIT score correlated with greater disability on conventional rating scales. Overall, H2S responses were abnormal in about one quarter of patients with multiple sclerosis. The sensitivity of UPSIT and OEP was similar although disorder on one test did not necessarily indicate abnormality in the other. The visual evoked potential was found to be a more sensitive indicator of disease than OEP or UPSIT. CONCLUSION: These findings confirm the existence of olfactory dysfunction in multiple sclerosis and validate a new evoked potential technique.