Showing papers in "Journal of Neurology in 2004"

The role of oxidative stress in the pathogenesis of multiple sclerosis: the need for effective antioxidant therapy.

Abstract: Accumulating data indicate that oxidative stress (OS) plays a major role in the pathogenesis of multiple sclerosis (MS). Reactive oxygen species (ROS), leading to OS, generated in excess primarily by macrophages, have been implicated as mediators of demyelination and axonal damage in both MS and experimental autoimmune encephalomyelitis (EAE), its animal model. ROS cause damage to cardinal cellular components such as lipids, proteins and nucleic acids (e. g., RNA, DNA), resulting in cell death by necrosis or apoptosis. In addition, weakened cellular antioxidant defense systems in the central nervous system (CNS) in MS, and its vulnerability to ROS effects may increase damage. Thus, treatment with antioxidants might theoretically prevent propagation of tissue damage and improve both survival and neurological outcome. Indeed, several experimental studies have been performed to see whether dietary intake of several antioxidants prevents or reduces the progression of EAE. Although a few antioxidants showed some efficacy in these studies, little information is available on the effect of treatments with such compounds in patients with MS. Well-designed clinical studies using antioxidant intake, as well as investigations based on larger cohorts studied over a longer periods of time, are needed in order to assess whether antioxidant intake together with other conventional treatments, might be beneficial in treating MS.

Water content and myelin water fraction in multiple sclerosis. A T2 relaxation study.

Abstract: Measurements of the T2 decay curve provide estimates of total water content and myelin water fraction in white matter in-vivo, which may help in understanding the pathological progression of multiple sclerosis (MS). Thirty-three MS patients (24 relapsing remitting, 8 secondary progressive, 1 primary progressive) and 18 controls underwent MR examinations. T2 relaxation data were acquired using a 32-echo measurement. All controls and 18 of the 33 MS patients were scanned in the transverse plane through the genu and splenium of the corpus callosum. Five white matter and 6 grey matter structures were outlined in each of these subjects. The remaining 15 MS patients were scanned in other transverse planes. A total of 189 lesions were outlined in the MS patients. Water content and myelin water fraction were calculated for all regions of interest and all lesions. The normal appearing white matter (NAWM) water content was, on average, 2.2% greater than that from controls, with significant differences occurring in the posterior internal capsules, genu and splenium of the corpus callosum, minor forceps and major forceps (p < 0.0006). On average, MS lesions had 6.3% higher water content than contralateral NAWM (p < 0.0001). Myelin water fraction was 16% lower in NAWM than for controls, with significant differences in the major and minor forceps, internal capsules, and splenium (p < 0.05). The myelin water fraction of MS lesions averaged 52 % that of NAWM. NAWM in MS has a higher water content and lower myelin water fraction than control white matter. The cause of the myelin water fraction decrease in NAWM could potentially be due to either diffuse edema, inflammation, demyelination or any combination of these features. We present a simple model which suggests that myelin loss is the dominant feature of NAWM pathology.

Falls in frequent neurological diseases--prevalence, risk factors and aetiology.

Abstract: The prevalence of falls among neurological patients is unknown, although disturbances of gait and posture are common. Falls may lead to burdens for the patient, the caregivers and the health system. We designed a prospective study and investigated all patients for a history of falls admitted to a neurological hospital during a 100-day period. Clinical investigation was carried out and several disease specific rating scales were applied. A total of 548 patients were investigated. Of all patients 34% had fallen once or more often during the last twelve months. A disturbance of gait was blamed for the fall in 55%, epileptic seizures in 12%, syncope in 10 % and stroke in 7%. Intrinsic risk factors for falls were high age, disturbed gait, poor balance and a fear of falling. As extrinsic factors we identified the treatment with antidepressants, neuroleptics and different cardiovascular medications, adverse environmental factors in the patients' home and the use of walking aids. Within the diagnoses, falls were most frequent in Parkinson's disease (62 %), syncope (57%) and polyneuropathy (48 %). According to these findings falls in neurological in-patients are twice as frequent as in an age-matched population living in the community. Falls in neurological patients are particularly linked to medication and disorders affecting gait and balance.

Cerebral venous and sinus thrombosis.

Abstract: Cerebral venous and sinus thrombosis (CVST) can present with a variety of clinical symptoms ranging from isolated headache to deep coma. Prognosis is better than previously thought and prospective studies have reported an independent survival of more than 80% of patients. Although it may be difficult to predict recovery in an individual patient, clinical presentation on hospital admission and the results of neuroimaging investigations are--apart from the underlying condition--the most important prognostic factors. Comatose patients with intracranial haemorrhage (ICH) on admission brain scan carry the highest risk of a fatal outcome. Available treatment data from controlled trials favour the use of anticoagulation (AC) as the first-line therapy of CVST because it may reduce the risk of a fatal outcome and severe disability and does not promote ICH. A few patients deteriorate despise adequate AC which may warrant the use of more aggressive treatment modalities such as local thrombolysis. The risk of recurrence is low (< 10%) and most relapses occur within the first 12 months. Analogous to patients with extracerebral venous thrombosis, oral AC is usually continued for 3 months after idiopathic CVST and for 6-12 months in patients with inherited or acquired thrombophilia but controlled data proving the benefit of long-term AC in patients with CVST are not available.

Topiramate in migraine prophylaxis--results from a placebo-controlled trial with propranolol as an active control.

Abstract: Topiramate (TPM) has shown efficacy in migraine prophylaxis in two large placebo-controlled, dose-ranging trials. We conducted a randomised, double-blind, multicentre trial to evaluate the efficacy and safety of two doses of topiramate vs placebo for migraine prophylaxis, with propranolol (PROP) as an active control. Subjects with episodic migraine with and without aura were randomised to TPM 100 mg/d, TPM 200 mg/d, PROP 160 mg/d (active control), or placebo. The primary efficacy measure was the change in mean monthly migraine frequency from the baseline phase relative to the double-blind treatment phase. Five hundred and seventy-five subjects were enrolled from 61 centres in 13 countries. TPM 100 mg/d was superior to placebo as measured by reduction in monthly migraine frequency, overall 50% responder rate, reduction in monthly migraine days, and reduction in the rate of daily rescue medication use. The TPM 100 mg/d and PROP groups were similar with respect to reductions in migraine frequency, responder rate, migraine days, and daily rescue medication usage. TPM 100 mg/d was better tolerated than TPM 200 mg/d, and was generally comparable to PROP. No unusual or unexpected safety risks emerged. These findings demonstrate that TPM 100 mg/d is effective in migraine prophylaxis. TPM 100 mg/d and PROP 160 mg/d exhibited similar efficacy profiles.

Clinical characteristics, course and prognosis of relapsing Devic's Neuromyelitis Optica.

Abstract: To evaluate the clinical characteristics, course and prognosis of Devic’s neuromyelitis optica (DNO), to evaluate the prognostic role of demographic and clinical features, to evaluate the current DNO diagnostic criteria. Demographic, clinical, CSF and MRI data of patients affected by DNO were collected from fifteen Italian MS centres. Inclusion criteria were: 1) two or more acute episodes of neurological dysfunction indicating involvement of the optic nerve and spinal cord, in a simultaneous or subsequent temporal relationship; 2) no evidence of lesions beyond the optic nerve or the spinal cord; 3) brain MRI at onset negative or non-specific for multiple sclerosis (MS) (white matter lesions ≤ 2). Disability was scored by means of Kurtzke’s Expanded Disability Status Scale (EDSS). 46 patients with relapsing DNO were included, 37 females and 9 males, with mean age at onset of 40.1 ± 16.3 years (range 12–77 years). The follow up duration was 8.8 ± 3.5 years, the mean annualised relapse rate was 1.3 ± 1.2. After 5, 10 and 15 years EDSS 3.0 was reached respectively by 65%, 82 % and 86% of cases, EDSS 6.0 respectively by 42%, 53 % and 69% of cases, EDSS 10 respectively by 8%, 12% and 23% of cases. The probability of reaching EDSS 3 was statistically correlated with age at onset, interval between the first and 2nd attack, and relapse rate. The probability of reaching EDSS 6.0 was correlated with the residual EDSS at onset and to relapse rate.During the follow up, brain white matter lesions appeared in 8 subjects. Spinal cord MRI showed lesions extending across 3 or more segments in 39 subjects, only 1 lesion involving 1 segment in 4 subjects, and was normal in 3 subjects. One or more CSF abnormalities were found at least once in 29/44 patients (65.9 %), the most frequent findings being pleocytosis (38.6 %), oligoclonal bands (34.1 %), high protein level (25 %), and high albumin ratio (20.5 %). DNO has a poor prognosis in most cases. Compared with MS, DNO patients have a higher age at onset, females are more frequently affected, the course is more severe. Brain and spinal cord MRI permit the differentiation of DNO from MS. CSF supports the probability of DNO if it shows increased cells and proteins.

Cognitive changes in patients with Huntington's disease (HD) and asymptomatic carriers of the HD mutation: A longitudinal follow-up study

Abstract: Objective information about the onset and progression of cognitive impairment in Huntington’s disease (HD) is very important in the light of appropriate outcome measures when conducting clinical trials. Therefore, we evaluated the progression of cognitive functions in HD patients and asymptomatic carriers of the HD mutation (AC) over a 2.5–year period.We also sought to detect the earliest markers of cognitive impairment in AC. A prospective study comparing HD patients, clinically asymptomatic HD mutation–carriers (AC) and non–carriers (NC). These groups were examined three times during a period of 2.5 years. At baseline the study sample consisted of 49 subjects. Forty–two subjects (19 HD patients, 12 AC and 11 NC) completed three assessments. A battery of neuropsychological tests measuring intelligence, attention, memory, language, visuospatial perception, and executive functions was performed. The performance of HD patients deteriorated on the following cognitive tests: Symbol Digit Modalities Test (SDMT), Stroop Colour and Word, Boston Naming Test (BNT), Object and Space Perception and Trail Making Test–B. Longitudinal comparison of AC and NC revealed that performances on SDMT, Block Span, Digit Span Backwards, Hopkins Verbal Learning Test (learning and delayed recall) and Conditional Associative Learning Test are impaired in AC. Tasks measuring mainly attention, object and space perception and executive functions adequately assess the progression of HD disease. Other cognitive functions do not significantly deteriorate. Furthermore, problems in attention, working memory, verbal learning, verbal long–term memory and learning of random associations are the earliest cognitive manifestations in AC.

Long-term prognosis of ischemic stroke in young adults. Study of 272 cases

Abstract: There have been few studies of the long-term prognosis of young adults with ischemic stroke. The present study aimed to evaluate the long-term clinical outcome in a large series of young adults with ischemic stroke admitted to a tertiary medical center over the last 27 years, and to identify possible predictors for mortality, stroke recurrence and poor functional recovery. We retrospectively reviewed 272 young adults (15–45 years) with a first-ever ischemic stroke admitted to the Neurology Department of University Hospital “12 de Octubre” between 1974 and 2001. Follow-up assessments were performed by review of medical records and telephone interviews. Nine patients (3 %) died as the result of their initial stroke and follow-up information about the status of 23 (8%) patients was not available. The remaining 240 patients (89%) were followed. Two hundred and ten of them (88%) were alive with a mean follow-up of 12.3 years and 30 (12%) died during follow-up. The average annual mortality rate was 1.4%, being notably higher during the first (4.9%) than in the subsequent years (0.9 %) after the initial stroke. Ninety per cent of the followed patients were independent and 53% returned to work, although adjustments were necessary for 23% of them. The annual stroke recurrence rate during the first year was 3.6% dropping to 1.7 % in subsequent years. Age over 35 years, male gender, the presence of cardiovascular risk factors and large-artery atherosclerosis in the carotid territory were predictors of negative long-term outcome after the initial stroke. The long-term prognosis for the ischemic stroke in the young is better than in the elderly, but the risk of mortality in young adults with ischemic stroke is much higher than in the general population of the same age. A bad prognosis is associated with an atherosclerotic risk profile, with a higher mortality and recurrent stroke rates and poorer functional recovery. The main functional limitation in the young survivors of their initial ischemic stroke occurs in work activity, since most patients are independent but almost half of them do not return to work.

Large artery ischaemic stroke in severe acute respiratory syndrome (SARS).

Abstract: Of the 206 patients who contracted Severe Acute Respiratory Syndrome (SARS) in Singapore five developed large artery cerebral infarctions. Four patients were critically-ill and three died. Intravenous immunoglobulin was given to three patients. An increased incidence of deep venous thrombosis and pulmonary embolism was also observed among the critically-ill patients. We believe our experience warrants an increased vigilance against stroke and other thrombotic complications among critically-ill SARS patients in future outbreaks, especially if treatment such as intravenous immunoglobulin, that increases pro-thrombotic tendency, is contemplated.

Autosomal dominant nocturnal frontal lobe epilepsy--a critical overview.

Abstract: Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is an idiopathic epilepsy, with a spectrum of clinical manifestations, ranging from brief, stereotyped, sudden arousals to more complex dystonic–dyskinetic seizures. Video–polysomnography allows a correct differential diagnosis. There is no difference between sporadic nocturnal frontal lobe epilepsy (NFLE) and ADNFLE in the clinical and neurophysiological findings. ADNFLE is the first idiopathic epilepsy for which a genetic basis has been identified. Mutations have been found in two genes (CHRNA4 and CHRNB2) coding for neuronal nicotinic receptor subunits (α4 and β2, respectively). Contrasting data have been reported on the effect of these mutations on the functionality of the receptor.Moreover, the incomplete data on the neuronal network/s in which this receptor is involved, make difficult the understanding of the genotype–phenotype correlation. This is an overview on the clinical and genetic aspects of ADNFLE including a discussion of some open questions on the role of the neuronal nicotinic receptor subunit mutations in the pathogenesis of this form of epilepsy.

Trigeminocardiac reflex. A clinical phenomenon or a new physiological entity

Abstract: The trigemino-cardiac reflex (TCR) is defined as the sudden onset of parasympathetic dysrhythmia, sympathetic hypotension, apnea or gastric hypermotility during stimulation of any of the sensory branches of the trigeminal nerve. The sensory nerve endings of the trigeminal nerve send neuronal signals via the Gasserian ganglion to the sensory nucleus of the trigeminal nerve, forming the afferent pathway of the reflex arc. This afferent pathway continues along the short internuncial nerve fibers in the reticular formatio to connect with the efferent pathway in the motor nucleus of the vagus nerve. Clinically, the trigemino-cardiac reflex has been reported to occur during craniofacial surgery, balloon-compression rhizolysis of the trigeminal ganglion, and tumor resection in the cerebellopontine angle. Apart from the few clinical reports, the physiological function of this brainstem-reflex has not yet been fully explored. From experimental findings, it may be suggested that the trigemino-cardiac reflex represents an expression of a central neurogenic reflex leading to rapid cerebrovascular vasodilatation generated from excitation of oxygen-sensitive neurons in the rostral ventrolateral medulla oblongata. By this physiological response, the adjustments of the systemic and cerebral circulations are initiated to divert blood to the brain or to increase blood flow within it. As it is generally accepted that the diving reflex and ischemic tolerance appear to involve at least partially similar physiological mechanisms, the existence of such endogenous neuroprotective strategies may extend the actually known clinical appearance of the TCR and include the prevention of other potentially brain injury states as well. This may be in line with the suggestion that the TCR is a physiological, but not a pathophysiological entity.

Effect of intravenous immunoglobulin treatment on pregnancy and postpartum-related relapses in multiple sclerosis.

Abstract: Acute exacerbations may complicate the course of pregnancy and the postpartum period in patients with relapsing-remitting multiple sclerosis (RRMS). To evaluate relapse rate and the effect of immunomodulatory treatment with intravenous immunoglobulin (IVIg) during pregnancy and the postpartum period we retrospectively analysed the data of 108 pregnant RRMS patients. Group I patients were not treated, Group II patients were treated with IVIg 0.4 g/kg body weight/day for 5 consecutive days within the first week after delivery with additional booster doses of 0.4 g/kg body weight/day at 6 and 12 weeks postpartum (defined as 12 weeks after labor), and Group III patients were treated continuously with IVIg during gestation and the postpartum period (0.4 g/kg body weight/day for 5 consecutive days within the 6-8 weeks of gestation with additional booster doses of 0.4 g/kg body weight/day once every 6 weeks until 12 weeks postpartum). All patients underwent antenatal care and fetal ultrasonographic surveillance examinations. Relapse rate per woman per year during the pregnancy and the postpartum period as well as neonatal outcome data and IVIg related adverse events were analysed. Relapse rate per woman per year for patients treated with IVIg for the whole pregnancy and postpartum period (Group III, N = 28) compared with the untreated Group I patients (N = 39) were as follows: first trimester 0.43 vs. 0.72, second trimester 0.15 vs. 0.61, third trimester 0.0 vs. 0.41, and postpartum period 0.28 vs.1.33 (p < 0.05). Patients treated with IVIg only during the postpartum period (Group II, N = 41) also showed a decrease in relapse rate compared with untreated Group I patients, 0.58 vs. 1.33 (p = 0.012). The mean maternal age, disease duration, gestational age at delivery and fetal delivery weight did not significantly differ between the three groups. Mode of delivery, obstetrical complications, the use of epidural analgesia and breast-feeding, did not affect postpartum relapse rate. No severe adverse events were associated with IVIg treatment either during the pregnancy or postpartum period for the patients and newborns.We conclude that in RRMS patients IVIg treatment could be considered as an optional treatment to reduce the incidence of pregnancy and postpartum-related relapses. Further randomized double-blind studies are needed to confirm our findings.

Psychiatric aspects of Parkinson's disease--an update.

Abstract: In patients with Parkinson's disease (PD) disturbances of mental state constitute some of the most difficult treatment challenges of advanced disease, often limiting effective treatment of motor symptoms and leading to increased disability and poor quality of life. This article provides an update on the current knowledge of these complications and the use of old and new drugs in their management. Mental state alterations in PD include depression, anxiety, cognitive impairment, apathy, and treatment-related psychiatric symptoms. The latter range from vivid dreams and hallucinations to delusions, manic symptoms, hypersexuality, dopamine dysregulation syndrome and delirium. While some of these symptoms may be alleviated by anti-parkinsonian medication, especially if they are off-period related, treatment-related phenomena are usually exacerbated by increasing the number or dosage of antiparkinsonian drugs. Elimination of exacerbating factors and simplification of drug regimes are the first and most important steps in improvement of such symptoms. However, the advent of atypical antipsychotics such as clozapine has dramatically helped the management of treatment-related psychiatric complications in PD. In patients with dementia associated with PD cognitive functioning and behavioural problems appear to respond to cholinesterase inhibitors, such as rivastigmine or donepezil. Depression is a common problem in early as well as advanced PD, and selective serotonin reuptake inhibitors, reboxetine, and tricyclic antidepressants have been reported to be effective and well tolerated antidepressants. Randomised, controlled studies are required to assess the differential efficacy and tolerability of antidepressants in patients with PD, including the newer antidepressants with serotonergic and noradrenergic properties.

Memory complaints in patients with normal cognition are associated with smaller hippocampal volumes.

Abstract: We aimed to investigate volumetry of the medial temporal lobe in patients with subjective memory complaints without any cognitive impairment. This study included 20 patients with subjective memory complaints and normal cognitive function and 28 controls without memory complaints. Volumes of the hippocampus and parahippocampal gyrus (PHG) were measured using coronal T1-weighted MR images. Cognitive functions were assessed using the Cambridge Cognitive Examination. Depressive symptoms were assessed using the Geriatric Depression Scale. Differences between groups were analysed using t-tests. Patients with subjective memory complaints had a higher education and more depressive symptoms than controls (p < 0.01). Moreover, they had smaller left hippocampal volumes than controls (p < 0.01). There were no differences between groups in the volume of the right hippocampus or PHG. There was a moderate association between the volume of left hippocampus and left PHG and memory-score (r = 0.32, p = 0.03; r = 0.34, p = 0.02). We concluded that memory complaints in patients without any cognitive impairment were associated with smaller left hippocampal volumes and more depressive symptoms. These preliminary results suggest that memory complaints may reflect minimal brain deficits associated with impending dementia, depression or a combination of both disorders.

Depression and Parkinson’s disease

Abstract: Depression occurs in approximately 45% of all patients with Parkinson’s disease (PD), reduces quality of life independent of motor symptoms and seems to be underrated and undertreated. Characteristics of symptoms differ from major depression. Because of overlapping clinical symptoms, diagnosis is based on subjectively experienced anhedonia and feeling of emptiness. Available rating scales for major depression may not be adequate to correctly measure severity of depression in PD. Anxiety and depression may manifest as first symptoms of PD many years before motor symptoms. Serotonergic, noradrenergic and dopaminergic mechanisms play key roles in the etiology of depression in PD. Tricyclic and newer, selective antidepressants including serotonin and noradrenaline reuptake inhibitors (SSRI, SNRI) appear to be effective in treating depression in PD. Selective reuptake inhibitors seem to have a favorable side effect profile. Recent controlled studies show antidepressant effects of pramipexole in bipolar II depression. New dopamine agonists pramipexole and ropinirole appear to ameliorate depressive symptoms in PD in addition to effects on motor symptoms. There is a lack of appropriate rating scales and controlled studies regarding depression in PD.

A placebo-controlled trial of gabapentin for painful HIV-associated sensory neuropathies

Abstract: Painful HIV-associated sensory neuropathies (HIV-SN) are a common complication of HIV infection. The pathogenesis is unknown and the treatment very limited. Gabapentin (GBP) is effective in painful diabetic neuropathy and postherpetic neuralgia and its effectiveness on painful HIV-SN has been reported anecdotally. Multicenter, prospective, randomised, double-blind, placebo-controlled study. Patients were followed for a 1-week screening, a 4-week double-blind and a 2-week open treatment phase. GBP was initiated at 400 mg/d, titrated over 2 weeks to 1200 mg/d, and then either maintained at this level or—if not beneficial—titrated to 2400 mg/d. After 4 weeks the medication was unblinded and the patient had the choice to begin, to maintain or to increase GBP to 3600 mg/d. The primary outcome measure was an improvement in median pain on the Visual Analogue Scale (VAS) from the screening week compared to the 4th treatment week. A secondary efficacy measure was the median sleep score (VAS). 15 patients received GBP and 11 placebo. In each group one patient dropped out during the doubleblind phase. Median pain (GBP 5.1; placebo 4.7) and sleep score (GBP 4.5; placebo 5.6) did not differ between both groups at baseline. In the GBP-group there was a significant decrease of the pain to 2.85 (–44.1 %) as well as of the sleep VAS to 2.3 (–48.9 %). No significant decrease in the pain (median VAS=3.3, –29.8 %) as well as in the sleep score (median VAS=4.95, –11.6 %) was observed in the placebo-group. GBP was generally well tolerated. The most frequent side effect was somnolence reported in 80% of GBP-treated patients. GBP was more effective than placebo in reducing pain and sleep interference in patients with HIV-SN.

Incidence rates and determinants in meralgia paresthetica in general practice.

Abstract: To determine incidence rates for meralgia paresthetica (MP) in the primary care setting and establish determinants for MP in a case-control study in general practices. Using a cohort (in total 173,375 patient years) of registered persons in primary care from a computerized registration network for general practitioners (GPs) in the Rotterdam area from 1990 to 1998, persons with the diagnosis MP were included. In a nested case-control study we studied the relationship between comorbidity (e. g. carpal tunnel syndrome, pregnancy, osteoarthritis of the hip, overweight, symptoms of the pubic bone, thrombosis of the leg, diabetes mellitus and the use of corticosteroids) and the occurrence of MP. The incidence rate of MP is 4.3 per 10,000 person years. MP is more often present in patients suffering from carpal tunnel syndrome OR 7.7 (95 % CI 1.9–31.1) and is related to pregnancy OR 12.0 (95 % CI 1.2–118.0). This is the first report on incidence rates of MP and on suspected determinants studied in a case-control setting in general practice. Carpal tunnel syndrome and pregnancy are significantly related to MP. Calculating the Population Attributable Risk in this study leaves 79% of all MP unexplained. Our results suggest that MP is caused by a combined susceptibility for entrapment and a trigger causing entrapment. More research on determinants is needed. Because MP occurs in every GP practice at least once a year more studies are needed on prognosis and treatment.

Simulator based rehabilitation in refractory dizziness.

Abstract: Patients with chronic vestibular symptoms are common in neurological practice but the most effective treatment remains an open question The purpose of our study was to conduct a controlled, between–group comparison of patients’ responses to a customised exercise regime (Group C, for customised) versus treatment additionally incorporating simulator based desensitisation exposure (Group S, for simulator) integrating whole–body or visual environment rotators Forty chronic peripheral vestibular patients who had previously undergone conventional vestibular rehabilitation without notable improvement were randomly assigned into Group C or S Individuals attended therapy sessions twice weekly for eight weeks and were provided with a customised home programme Response to treatment was assessed at four–week intervals with dynamic posturography, vestibular time constants, and questionnaires concerning symptoms, symptom–triggers and emotional status At final assessment posturography and subjective scores had significantly improved for both groups, although Group S showed greater improvement A statistically significant improvement for visual vertigo symptom scores was noted only for Group S (p < 001; total improvement 535 %) Anxiety and depression levels significantly decreased for both groups; improvements were significantly correlated particularly to improvements in visual vertigo (SCQ) (p < 001; r = 053 and r = 057, respectively) Significant differences were noted between groups (p = 002) for posturography scores Vestibular time constants showed no notable change in either group Conclusions: Both groups improved but exposure to simulator motion gave overall better results These effects were also observed in psychological symptoms and partly relate to simulator effects on visual vertigo symptoms Visual motion and visuo–vestibular conflict situations should be incorporated in the rehabilitation of patients with refractory dizziness

The neuroprotective role of inflammation in nervous system injuries.

Abstract: The contribution of inflammation to the pathogenesis of several nervous system disorders has long been established. Other observations, however, indicate that both inflammatory cells and mediators may also have beneficial functions, assisting in repair and recovery processes. There is compelling evidence to indicate that in the injured nervous system, as in other tissues, macrophages are needed at an early stage after injury in order for healing to take place. Likewise, activated T cells of a particular specificity can reduce the spread of damage. This neuroprotective effect of T cells may be caused, at least in part, by the production of neurotrophic factors such as neurotrophin-3 or brain-derived neurotrophic factor. Interestingly, recent findings indicate that immune cells are able to produce a variety of neurotrophic factors which promote neuronal survival and may also mediate anti-inflammatory effects. Numerous cytokines are induced after nervous system injuries. Some cytokines, such as TNF-alpha, IL-1 and IFN-gamma, are well known for their promotion of inflammatory responses. However, these cytokines also have immunosuppressive functions and their subsequent expression also assists in repair or recovery processes, suggesting a dual role for some pro-inflammatory cytokines. This should be clarified, as it may be crucial in the design of therapeutic strategies to target specific cytokine(s). Finally, there is a growing body of evidence to show that autoreactive IgM antibodies may constitute an endogenous system of tissue repair, and therefore prove of value as a therapeutic strategy. Available evidence would appear to indicate that the inflammatory response observed in several neurological conditions is more complex than previously thought. Therefore, the design of more effective therapies depends on a clear delineation of the beneficial and detrimental effects of inflammation.

Escalating immunotherapy of multiple sclerosis--new aspects and practical application.

Abstract: Recent clinical studies in multiple sclerosis (MS) provide new data on the treatment of clinically isolated syndromes, on secondary progression, on direct comparison of immunomodulatory treatments and on dosing issues. All these studies have important implications for the optimized care of MS patients. The multiple sclerosis therapy consensus group (MSTCG) critically evaluated the available data and provides recommendations for the application of immunoprophylactic therapies. Initiation of treatment after the first relapse may be indicated if there is clear evidence on MRI for subclinical dissemination of disease. Recent trials show that the efficacy of interferon beta treatment is more likely if patients in the secondary progressive phase of the disease still have superimposed bouts or other indicators of inflammatory disease activity than without having them. There are now data available, which suggest a possible dose-effect relation for recombinant beta-interferons. These studies have to be interpreted with caution, as some potentially important issues in the design of these studies (e. g. maintenance of blinding in the clinical part of the study) were not adequately addressed. A meta-analysis of selected interferon trials has been published challenging the value of recombinant IFN beta in MS. The pitfalls of that report are discussed in the present review as are other issues relevant to treatment including the new definition of MS, the problem of treatment failure and the impact of cost-effectiveness analyses. The MSTCG panel recommends that the new diagnostic criteria proposed by McDonald et al. should be applied if immunoprophylactic treatment is being considered. The use of standardized clinical documentation is now generally proposed to facilitate the systematic evaluation of individual patients over time and to allow retrospective evaluations in different patient cohorts. This in turn may help in formulating recommendations for the application of innovative products to patients and to health care providers. Moreover, in long-term treated patients, secondary treatment failure should be identified by pre-planned follow-up examinations, and other treatment options should then be considered.

Life style risks of Parkinson's disease: association between decreased water intake and constipation.

Abstract: Gastrointestinal dysfunction, especially constipation, is one of the major problems in the daily life of patients with Parkinson’s disease (PD). About 60 to 80% of PD patients suffer from constipation. Several studies have proven that constipation appears about 10 to 20 years prior to motor symptoms. More recently, Abbott et al. have found from a large scale prospective study that lower frequency bowel movements predict the future risk of PD. Furthermore, Braak et al. have found that Lewy neuritis and Lewy bodies, the hallmarks of PD pathology, appear in the dorsal nucleus of vagus in the earliest stage of the disease and then extend upward through the brain stem to reach the substantia nigra in the third stage. They also hypothesize that some yet undefined toxins break through the mucosal barrier of the intestine and are incorporated into the axon terminal of the vagus nerve and transported in a retrograde manner to the vagus nucleus. In this study, we assessed bowel movements and nutritional status in Japanese patients with PD. We found that intake of water was significantly decreased in PD patients from early life and associated with their constipation. Ninety four patients with PD (M 50, F 44) were enrolled. Nutritional status was assessed using the Self-administered Diet History Questionnaire (DHQ). Total water intake was calculated from the consumption of coffee, green tea, and tea. We also questioned the behavior of water drinking from the early stage of life. The questionnaire for bowel movements concerned the frequency of defecation, age of onset of constipation, and age of onset of motor dysfunction. Less than one bowel movement in 3 days was defined as constipation. The nutritional status of PD patients did not differ significantly from those of controls though several studies have shown excess intake of animal fats or reduced consumption of coffee are risks in PD. In contrast, water intake was significantly lower in PD patients than controls (604.0±377.2 ml/d vs 909.5±531.6 ml/d; P<0.0001). Interestingly, PD patients tended not to feel thirsty and thus they had no desire to drink water throughout their life. Seventy four patients out of 94 (78.7 %) complained of constipation. Mean bowel frequency was once per 3.3±1.1 days and 71.1% of patients were defined as having constipation. Women suffered from constipation more frequently than men (82.4% vs 61.9 %). In 33 patients out of 74 (44.6 %), onset of constipation preceded motor disturbance by an average time of 18.1±18.8 years. Furthermore, the amount of water intake correlated inversely with the severity of constipation and the depletion of water intake preceded constipation in most cases. The present results support previous findings that constipation precedes the onset of motor dysfunction in PD. To our knowledge, this is the first report to point out latent water depletion in PD patients. It is not certain at present whether coffee or caffeine themselves are the protective factor for PD or alternatively the amount of water in coffee drinking is more essential. Prospective studies on a large scale are necessary to elucidate the real meaning of water depletion in PD.

Clinicoradiologic subtypes of Marchiafava-Bignami disease.

Abstract: The clinical diagnosis of Marchiafava-Bignami disease (MBD) has considerably changed during recent decades with brain MRI providing the opportunity of a reliable in-vivo diagnosis. However, semiologic and neuroimaging characteristics of the currently known spectrum of MBD have not been investigated systematically, and knowledge of clinicoradiologic associations is sketchy. We report an illustrative case with limited callosal involvement on MRI and a favorable outcome and have reviewed literature on clinical and radiologic features in 50 cases of MBD diagnosed in vivo since 1985. Our reviewed data suggest the differentiation of two clinicoradiologic subtypes: Type A is characterized by major impairment of consciousness, T2-hyperintense swelling of the entire corpus callosum on early MRI and poor outcome. Type B shows at most slight impairment of consciousness, partial callosal lesions on MRI and a favorable outcome. Differentiation of these clinicoradiologic subtypes may help resolve inconsistencies of the established clinical classification resulting from new insights into the clinical course and prognosis of MBD by structural neuroimaging.

Immunogenicity of recombinant human proteins: causes and consequences.

Abstract: Antibodies develop to varying degrees during treatment with human proteins, including insulin, growth hormone, granulocyte-macrophage colony-stimulating factor, factor VIII, erythropoietin, and interferons. These antibodies may reduce the clinical efficacy of these agents by blocking or neutralizing their biologic activity and may have other biologic effects. For example, antibodies develop in 20 % to 40% of patients with severe hemophilia treated with human factor VIII; the presence of these antibodies can result in tolerance to the clotting effects of this agent. Similarly, a proportion of patients treated with interferon alpha develop antibodies, which inhibit its therapeutic effects. Therefore, it is important to test for neutralizing antibodies during treatment with these agents, particularly in patients who are unresponsive to treatment or have breakthrough disease. This article reviews the incidence and clinical impact of antibodies that develop in response to some of the commonly used protein therapeutic agents.

Neurobiological basis for the use of botulinum toxin in pain therapy.

Abstract: The various serotypes of botulinum toxin (BoNT) exert their action by inhibiting the exocytosis of acetylcholine (ACh) in cholinergic nerve endings. BoNT cleaves proteins (e. g. SNAP-25 or VAMP) that are necessary for the docking of the ACh vesicle to the presynaptic membrane. Without docking, no ACh can be released into the synaptic cleft and the innervated structure is paralyzed. This article focusses on the neuromuscular endplate. The main targets of BoNT therapy are states of muscle hyperactivity such as contractures (in the physiological sense), or spasm and focal dystonias. The “integrated hypothesis” of the formation of myofascial trigger points suggests that a lesion of a muscle damages the endplate so that excessive ACh is released. This causes a local contracture (partial contraction of a muscle fiber) underneath the endplate. The contracture compresses small blood vessels, and the tissue becomes ischemic. Ischemia leads to the release of bradykinin (BKN) and sensitization or excitation of nociceptors. BoNT is a causal therapy in these cases, because it stops the excessive ACh release. Reflex spasm in a given muscle can be induced by nociceptive input from neighboring joints or muscles. If the force generated by a spasm is relatively high, it will compress the large blood vessels supplying the muscle. The final effect again is ischemia. In this case a drop in pH may accompany the ischemia and BKN release. Protons and BKN are known to be effective stimulants for muscle nociceptors. In cases of weak dystonias, a compression of blood vessels is unlikely. However, the tonic contraction will cause a lowering of pH and a release of ATP. Muscle cells contain ATP at concentrations sufficient to excite muscle nociceptors. In cases of spasm and dystonia, BoNT can abolish the pain by relaxing the muscle. Since many patients report alleviation of their pain before the muscle relaxing effect of BoNT has set in, a direct analgesic action of BoNT is being discussed. Most hypotheses rest on the assumption that BoNT inhibits not only the exocytosis of ACh but also of other neurotransmitters. Such an action could be analgesic if the release of neuropeptides from nociceptive nerve endings is prevented. This way, BoNT could alleviate the pain of neuropathies and various types of headache where neurogenic inflammation plays a role. Another site of an analgesic action could be the postganglionic sympathetic nerve ending that uses norepinephrine and ATP as transmitters. Norepinephrine is known to increase cases of chronic pain, and ATP is a stimulant of muscle nociceptors. If BoNT inhibits the release of these transmitters, it could be analgesic in cases of sympathetically maintained pain including the complex regional pain syndrome.

Vision and vertigo: some visual aspects of vestibular disorders.

Abstract: This review deals with two syndromes, oscillopsia and visual vertigo. Oscillopsia is the illusion of oscillation of the visual surroundings. For diagnosis purposes one should ask, when does the oscillopsia occur? If oscillopsia is only present during head (or whole body) movements, the likely underlying cause is a bilateral defect in the vestibulo-ocular reflex (VOR). The more common causes are post meningitic vestibular damage, gentamicin ototoxicity or bilateral idiopathic vestibular failure. When oscillopsia develops after specific head positions, it is usually due to a positional nystagmus, usually the result of brainstem-cerebellar disease. When the oscillopsia is largely unrelated to head movements, one should ask, is it fairly constant or is it in attacks (paroxysmal)? If the oscillopsia is constant it is usually due to the presence of a clinically observable nystagmus; the most common is downbeat nystagmus but the most visually disabling is pendular nystagmus. If the oscillopsia comes in brief attacks it is usually due to a paroxysmal nystagmus as observed in irritative VIII nerve and brainstem lesions. However, the most common cause of paroxysmal oscillopsia is a non organic condition called voluntary nystagmus. Treatment of oscillopsia is often pharmacological but disappointing; the best chance of success is carbamazepine for paroxysmal disorders secondary to structural vestibular nerve/nuclear lesions.Visual vertigo should not be confused with oscillopsia. It can be defined as dizziness provoked by visual environments with large size (full field) repetitive or moving visual patterns. Patients with visual vertigo report discomfort in supermarkets and when viewing movement of large visual objects, eg crowds, traffic, clouds or foliage. Visual vertigo is present in many patients with a history of a peripheral vestibular disorder, particularly those who are visually dependent (ie subjects who use vision preferentially for postural and space orientation control). Patients with visual vertigo benefit from the addition to their standard vestibular rehabilitation of optic flow (optokinetic) stimuli and exercises involving visuo-vestibular conflict.

Gender-related effect of clinical and genetic variables on the cognitive impairment in multiple sclerosis

Abstract: Cognitive impairment may occur at any time during the course of multiple sclerosis (MS), and it is often a major cause of disability in patients with the disease. The APOE-epsilon4 allele is the major known genetic risk factor for late onset familial and sporadic Alzheimer's Disease (AD), and it seems to be implicated in cognitive decline in normal elderly persons.

Hemichorea after stroke: Clinical-radiological correlation

Abstract: Post-stroke hemichorea is an uncommon involuntary hyperkinetic disorder involving unilateral body parts. The incidence and precise lesion location of post-stroke hemichorea remain unclear. The authors describe 27 consecutive patients with hemichorea after stroke. The incidence of post-stroke hemichorea was 0.54 % (27 out of 5,009 patients). The lesions were located in the caudate and putamen (n = 6), cortex (n = 6), thalamus and subthalamic area (n = 4), subthalamus (n = 4), putamen (n = 3), caudate (n = 2), and the globus pallidus (n = 2). Over the mean follow-up period of 22 months, the hemichorea disappeared in 56% of the patients, while it persisted in others. The rate of disappearance of hemichorea was significantly higher in patients with cortical strokes than in those with subthalamic lesions (P < 0.05).We conclude that hemichorea is a rare manifestation of stroke and most often produced by lenticular lesions followed by subthalamic and cortical lesions. The functional prognosis is better in patients with cortical lesions than those with subthalamic strokes.

Marked increase of β-amyloid (1–42) and amyloid precursor protein in ventricular cerebrospinal fluid after severe traumatic brain injury

Abstract: Severe traumatic brain injury (TBI) may result in widespread damage to axons, termed diffuse axonal injury. Alzheimer’s disease (AD) is characterised by synaptic and axonal degeneration together with senile plaques (SP). SP are mainly composed of aggregated β-amyloid (Aβ), which are peptides derived from the amyloid precursor protein (APP). Apart from TBI in itself being considered a risk factor for AD, severe head injury seems to initiate a cascade of molecular events that are also associated with AD. We have therefore analysed the 42 amino acid forms of Aβ (Aβ(1–42)) and two soluble forms of APP (α-sAPP and ssAPP) in ventricular cerebrospinal fluid (VCSF) and Aβ(1–42) in plasma from 28 patients in a serial samples 0–11 days after TBI. The levels of α-sAPP, s-sAPP and Aβ(1–42) were determined using ELISA assays. After TBI, there was a significant stepwise increase in VCSF-Aβ(1–42) up to 1173 % from day 0–1 to day 5–6 and in VCSF-β-sAPP up to 2033 % increase from day 0–1 to day 7–11. There was also a slight but significant increase of VCSF-β-sAPP from day 0–1 to day 5–6 and day 7–11. By contrast, the plasma- Aβ(1–42) level is unchanged after injury. The marked increase in VCSFAβ( 1–42) implies that increased Aβ expression may occur as a secondary phenomenon after TBI with axonal damage. The unchanged level of plasma-Aβ(1–42) in contrast to the marked increase in VCSF-Aβ(1–42) after severe TBI, supports the suggestion that plasma Aβ(1–42) does not reflect Aβ metabolism in the central nervous system (CNS).

Delirium in the first days of acute stroke.

Abstract: Delirium is an acute, transient disorder of cognition and consciousness with fluctuating intensity The aim of this study was to investigate the presence and the risk factors for delirium in the first days after stroke onset We assessed delirium prospectively in a sample of 218 consecutive patients (mean age 57 years) with an acute (≤ 4 days) stroke (28 subarachnoid haemorrhages, 48 intracerebral haemorrhages, 142 cerebral infarcts) and in a control group of 50 patients with acute coronary syndromes with the Delirium Rating Scale (DRS) (cut-off score ≥ 10) 29 (13%) acute stroke patients (mean DRS score = 132, SD = 23) and only one (2 %) acute coronary patient had delirium (χ2 = 52, p = 002) In nine patients delirium was secondary to stroke without any additional cause, in 10 patients there were also medical complications and in the remaining 10 there were multiple potential causes for delirium Delirium was more frequent after hemispherical than after brainstem/cerebellum strokes (p = 002) No other statistically significant associations with stroke locations were found Medical complications (OR = 43; 95% CI = 18 to 102), neglect (OR = 35; 95% CI = 13 to 92), intracerebral haemorrhage (OR = 31; 95% CI = 13 to 75) and age ≥ 65 (OR = 24; 95% CI = 10 to 58) were independent factors to the development of delirium in stroke patients Delirium was more frequent in stroke than in coronary acute patients Among stroke patients, delirium was most frequent in older patients, in those with neglect, with medical complications and with intracerebral haemorrhages These findings indicated that delirium in acute stroke patients 1) is not a non-specific consequence of acute disease and hospitalisation and 2) is secondary to hemisphere brain damage and to metabolic disturbances due to medical complications

Effect of natalizumab on conversion of gadolinium enhancing lesions to T1 hypointense lesions in relapsing multiple sclerosis.

Abstract: Natalizumab, a humanized monoclonal anti-adhesion molecule antibody, reduces the frequency of new gadolinium (Gd) enhancing lesions and relapses in multiple sclerosis (MS). Its effect on evolution of new Gd enhancing lesions to T1 hypointense lesions is unknown. 213 patients were randomized to receive 3 mg/kg or 6 mg/kg natalizumab or placebo monthly for 6 months and then followed for a further 6 months. A subset of patients who had one or more new gadolinium enhancing lesions from Month 0 to Month 6 and available electronic data were analysed. Each new Gd enhancing lesion that developed during treatment (months 1–6) was investigated for conversion to a new T1 hypointense lesion at month 12. Lesions were classified as large or small if their cross-sectional area was greater or less than 20mm2. Because of the similarity of both doses of natalizumab on the frequency of new Gd enhancing lesions, the two natalizumab arms were combined in all analyses. Compared with the placebo group, the natalizumab group exhibited significant decreases in: (i) the proportion of patients with new Gd enhancing lesions that evolved to T1-hypointense lesions (10/38 [26 %] versus 27/40 [68 %]; p < 0.01); (ii) the proportion of patients who developed large T1 hypointense lesions (2/38 [5 %] versus 16/40 [40 %]; p < 0.01); (iii) the proportion of new Gd enhancing lesions that became T1 hypointense (11/75 [15 %] versus 118/466 [25 %]; p = 0.045); (iv) the mean proportion per patient of new Gd enhancing lesions that converted to T1-hypointense lesions (0.15 versus 0.28; p = 0.005), and (v) the odds ratio (OR) of converting from Gd enhancing to T1-hypointense lesions (OR = 0.48; 95% CI = 0.24, 0.94, p = 0.031)). Natalizumab significantly suppresses the evolution of new Gd enhancing to T1-hypointense lesions. This may reflect several mechanisms including reduced cell migration across the blood brain barrier, reduced T cell activation within lesions, an inhibitory effect on subsequent axonal damage within the new central nervous system lesion, and a reduced likelihood of recurrent lesion inflammation.