Emotional experience in patients with clinically isolated syndrome and early multiple sclerosis.

BACKGROUND AND PURPOSE: Evidence suggests that there are changes in the processing of emotional information (EP) in people with multiple sclerosis (MS). It is unclear which functional domains of EP are affected, whether these changes are secondary to other MS-related neuropsychological or psychiatric symptoms and if EP changes are present in early MS. The aim of the study was to investigate EP in patients with early MS (clinically isolated syndrome and early relapsing/remitting MS) and healthy controls (HCs). METHODS: A total of 29 patients without neuropsychological or psychiatric deficits and 29 matched HCs were presented with pictures from the International Affective Picture System with negative, positive or neutral content. Participants rated the induced emotion regarding valence and arousal using nine-level Likert scales. A speeded recognition test assessed memory for the emotional stimuli and for the emotional modulation of response time. A subgroup of participants was tested during a magnetic resonance imaging (MRI) session. RESULTS: Patients in the MRI subgroup rated the experience induced by pictures with positive or negative emotional content significantly more weakly than HCs. Further, these patients were significantly less aroused when watching the pictures from the International Affective Picture System. There were no effects in the non-MRI subgroup or effects on emotional memory or response times. CONCLUSIONS: Emotional processing changes may be present in early MS in the form of flattened emotional experience on both the valence and arousal dimensions. These changes do not appear to be secondary to neuropsychological or psychiatric deficits. The fact that emotional flattening was only found in the MRI setting suggests that EP changes may be unmasked within stressful environments and points to the potential yet underestimated impact of the MRI setting on behavioral outcomes.

Progressive sudomotor dysfunction in amyotrophic lateral sclerosis.

Autonomic dysregulation is part of the complex degenerative process in amyotrophic lateral sclerosis (ALS). To investigate this, sweating was examined at rest in 39 patients with ALS in comparison with a control group. Sweat was collected over a 30 second period over the thenar and hypothenar eminences and on the sole of the foot, using a commercial device based on vapour pressure gradient. The measurements were repeated after three and six months in 10 patients for longitudinal analysis. In early ALS, patients had significantly higher skin water loss than control subjects over the thenar and the hypothenar eminences. In advanced disease stages, sweating was decreased at all sites compared with controls. A significant decline in sweat secretion of about 40% was found over a six month period. The findings suggest an abnormal sympathetic activity with hyperhidrosis in early ALS and a reduction in sweat production as the disease progresses.

Disease progression in amyotrophic lateral sclerosis: predictors of survival.

Predicting the rate of disease progression has become important as trials of new medical treatments for amyotrophic lateral sclerosis (ALS) are planned. Bulbar onset, early impairment of forced vital capacity, and older age have all been associated with shorter survival. We performed a retrospective study to compare survival factors with disease progression in a German ALS population. We analyzed disease progression in 155 patients at intervals of 4 months over a period of 3 years. To evaluate disease progression, the ALS functional rating scale (ALS-FRS), forced vital capacity (FVC%), and a Medical Research Council (MRC) compound score based on a nine-step modified MRC scale were used. We compared age (< 55 years vs. > or =55 years), different sites of disease onset (bulbar vs. limb), and gender to the rate of disease progression and performed survival analyses. No overall significant difference could be detected when analyzing these subgroups with regard to disease progression. By contrast, significantly longer survival was observed in the younger age group (56 months vs. 38 months, P < 0.0001) and in patients with limb-onset disease (51 months vs. 37 months, P = 0.0002). Using Cox analyses values we found that the declines of ALS-FRS, FVC%, and MRC compound score were predictive of survival (P < 0.0001, P = 0.002, and P = 0.003, respectively). Future studies are needed to clarify whether nonspecific factors including muscle atrophy, dysphagia, and coexisting diseases influence prediction of survival in ALS patients. A more precise set of predictors may help to better stratify patient subgroups for future treatment trials.

[Ciguatera: clinical relevance of a marine neurotoxin]. / Ciguatera: Klinische Bedeutung eines marinen Neurotoxins.

HISTORY AND CLINICAL FINDINGS: A 45-year-old woman complained of gastrointestinal symptoms followed by paraesthesiae of the mouth, face, hands, feet, and trunk after she had eaten fish while she was on a journey to the red sea. Additionally, she suffered from headaches and muscle aches, weakness of the arms and legs, instability of gait as well as troubles of vision, taste, speech, and swallowing. Neurological examination revealed a cerebellar syndromE with mild dysarthria, multifocal dysaesthesiae, paresis of the arms and legs, generalized hyporeflexia, bilaterally reduced vision, and ataxic gait. INVESTIGATIONS: Laboratory work-up provided no diagnostic clues. Cranial and spinal magnetic resonance imaging were normal. The cerebrospinal fluid showed a normal cell count and a moderately impaired barrier function. Electrophysiological evaluation suggested a sensory and motor axonal neuropathy. DIAGNOSIS, TREATMENT AND COURSE: Based on the history and the characteristic clinical findings we made a diagnosis of ciguatera, a marine food poisoning caused by the ingestion of fish contaminated with ciguatoxin. Symptomatic treatment with mannitol, amitriptyline, carbamazepine, and corticosteroids started 3 weeks after the onset of symptoms proved inefficient, however, during the 21 months of follow-up there was a marked spontaneous clinical and electrophysiological reversal of symptoms. CONCLUSIONS: In the age of growing foreign tourism marine food intoxications have to be considered in the differential diagnosis of the frequently occurring travellers-diarrhea. The diagnosis of ciguatera is based on the typical history of a fishmeal followed by characteristic clinical findings with predominant neurological symptoms, often including dysaesthesiae, besides gastrointestinal disturbances. In the early phase of the disease intravenous therapy with mannitol has emerged as an efficient treatment.

Injections of botulinum toxin A into the salivary glands improve sialorrhoea in amyotrophic lateral sclerosis.

Sialorrhoea is a socially disabling problem in bulbar amyotrophic lateral sclerosis (ALS). Botulinum toxin A (BoNT/A) was injected into the salivary glands in five patients with bulbar ALS and sialorrhoea. The effect of BoNT/A was measured by the number of paper handkerchiefs used each day and by salivary gland scintigraphy. BoNT/A ameliorated sialorrhoea and quality of life without major adverse effects. BoNT/A may be a relatively safe and effective treatment for sialorrhoea in selected patients.

Potential role of LIF as a modifier gene in the pathogenesis of amyotrophic lateral sclerosis.

Leukemia inhibitory factor (lif) is a potent survival factor for motoneurons in cell culture and in vivo. The authors screened 104 patients with ALS and 338 control subjects for mutations in the LIF gene. In four ALS patients, but in no control subject, a G-to-A point mutation at position 3400 was identified, which leads to an amino acid exchange of valine to methionine at position 64 of the mature lif protein. This region of the lif protein (AB loop) interacts with the lif receptor. The authors suggest that LIF could act as a modifier gene which, in combination with other genetic predispositions, might lead to motoneuron disease.

Genetic variation at position -1082 of the interleukin 10 (IL10) promotor and the outcome of multiple sclerosis.

Interleukin-10 is a potent immunomodulatory cytokine with possible implications for the pathogenesis of multiple sclerosis. Increased IL10 mRNA expression is associated with stable disease. The interleukin 10 gene is highly polymorphic and certain haplotypes result in differential interleukin-10 expression. The presence of guanine instead of adenine at position -1082 in the IL10 promotor was shown to result in a higher IL10 production. We analysed this diallelic polymorphism in patients with multiple sclerosis but did not find any association between a certain -1082 IL10 genotype and susceptibility to or severity of multiple sclerosis.

A phase I/II trial of recombinant methionyl human brain derived neurotrophic factor administered by intrathecal infusion to patients with amyotrophic lateral sclerosis.

BACKGROUND: Brain derived neurotrophic factor (BDNF) is a potent survival factor for motoneurons. This study investigated the safety and tolerability of recombinant methionyl human BDNF (r-metHuBDNF) infused intrathecally by means of an implanted pump in patients with ALS. METHODS: Twenty-five patients with probable or definite ALS were treated with either r-metHuBDNF (25, 60, 150, 400 or 1000 microg/day) or placebo in a 12-week, randomized, double-blinded, sequential, dose-escalation study. Test treatment was interrupted by a washout period from days 11 to 25 to allow the evaluation of laboratory safety measures. In each dose cohort four patients received r-metHuBDNF and one received placebo. On completion of the double-blind period of the study all patients continued to receive r-metHuBDNF in an open-label extension for up to 60 weeks. Lumbar cerebrospinal fluid (CSF) samples were taken periodically from all patients for the measurement of r-metHuBDNF levels and in a minority of patients these were supplemented by cistemal samples. RESULTS: Within days after the initiation of infusion the majority of patients receiving r-metHuBDNF reported mild sensory symptoms, including paraesthesias or a sense of warmth, which were usually confined to the lower limbs and were frequently exacerbated by neck flexion. In most instances these symptoms decreased or even disappeared over several weeks. Sleep disturbance, dry mouth, agitation and other behavioural effects were encountered at higher doses (>150 microg/day) and necessitated dose reductions. The spinal CSF levels of r-metHuBDNF were directly related to dose, with a lumbar to cervical ratio of approximately 4:1. CONCLUSIONS: The intrathecal delivery of r-metHuBDNF in doses of up to 150 microg/day was well tolerated and appears feasible. The reversible CNS effects with higher dose indicate that BDNF can be delivered cranially against CSF flow. The small number of patients and the design of the study did not permit conclusions to be drawn about the efficacy of the treatment.

Gene polymorphism at position -308 of the tumor necrosis factor alpha promotor is not associated with disease progression in multiple sclerosis patients.

Tumor necrosis factor-alpha (TNFalpha) is a pluripotent proinflammatory cytokine and is thought to play an important role in the inflammatory process of multiple sclerosis (MS). A G-->A transition in the TNFalpha promotor at position -308 (TNF2 allele) has been shown to be associated with increased TNFalpha production. This study was designed to detect wether the TNF2 allele is associated with disease progression in MS. We examined the TNFalpha -308 polymorphism with an allelic discrimination PCR to detect the G-->A transition in the genomic DNA of 283 MS patients from Germany and in 72 patients with amyotrophic lateral sclerosis (ALS) and 66 with stroke from the same genetic background who served as controls. Disease severity was defined by the progression index (PI) and by progression to the important clinical landmarks of Extended Disability Status Score (EDSS) 3.5 and 6. In addition, we evaluated the TNFalpha mRNA expression in whole blood with quantitative PCR. No differences were found between the presence of the TNF2 allele in MS, ALS, or stroke patients. Among the MS patients the TNF2 allele was not associated with a certain disease course. No association was found between the accumulation of neurological deficits and progression to clinical landmarks. Although MS patients with the TNF2 allele tended to progress more rapidly from EDSS 3.5 to EDSS 6 this difference was nonsignificant (P = 0.2). Nevertheless, we observed significantly higher TNFalpha mRNA expression in blood cells of stable patients carrying the TNF2-allele in comparison to the group with the wild type (P = 0.024). To examine the effect of genetic background we examined the DNA of 60 MS patients and 20 healthy controls in a Cypriot population of Greek origin. There was a significantly lower frequency of the TNF2 allele in the Cyprus population than in Germans (P = 0.01). No significant differences were found between the frequencies of the TNF2 allele in Cypriot MS patients and controls. Although the TNF2 allele is associated with higher TNFalpha mRNA baseline levels, our data indicate that this allele appears not to contribute to MS susceptibility or severity. In addition our data demonstrate that the TNFalpha -308 polymorphism is segregated differentially in two European populations of different genetic origin.

Epi-arachnoidal drug deposit: a rare complication of intrathecal drug therapy.

Intrathecal (i.t.) drug application is accepted as a highly effective treatment option for various neurological conditions. Technical risks and potentially dangerous complications require appreciation. We present the case of a patient treated with i.t. recombinant, human brain-derived neurotrophic factor (rhBDNF) as an experimental therapy for amyotrophic lateral sclerosis (ALS). Five days after starting the i.t. drug infusion, she complained of severe headache and nausea. Radiological studies suggested the catheter was located within the epi-arachnoidal space. A deposit of more than 10 ml secluded from the subarachnoidal space was found within this space. I.t. contained a high concentration of the applied drug. Revision of the catheter resulted in complete recovery from symptoms and i.t. infusion could be continued. The epi-arachnoidal positioning of a spinal catheter is a potential cause for treatment failure. If the membrane around the fluid deposit ruptures, the drug could be released into the subarachnoidal space, with the consequence of a potentially life-threatening complication.

Comparison of maximal voluntary isometric contraction and Drachman's hand-held dynamometry in evaluating patients with amyotrophic lateral sclerosis.

Maximal voluntary isometric contraction (MVIC) is a standard tool for assessment of muscle strength in treatment trials for amyotrophic lateral sclerosis (ALS). There is need for more practical bedside techniques especially for severely disabled patients. Hand-held dynamometry (HH-Dyn) is an inexpensive and easy-to-handle device. MVIC was measured in five proximal muscle groups bilaterally and compared with HH-Dyn in 43 ALS patients. After a training period we found good intrarater correlation for HH-Dyn (r = 0.99), with a low coefficient of variation. Measurements tended to become more accurate after repeated testing due to practice effects in examiners and patients. Overall correlation between HH-Dyn and MVIC was good [r = 0.85 (P < 0.01)]. Strength-range-specific analysis showed a significant linear correlation up to 20 kg (44 lbs.) [r = 0.57 (P < 0.01)]. However, we found a tendency to underestimate muscle strength above 10 kg by HH-Dyn as compared with MVIC, but this became meaningful only above a force of 20 kg. HH-Dyn provides a strength estimate with a precision close to MVIC in weak muscle groups (MRC grade 4). With standardization and appropriate training, HH-Dyn is a useful bedside test, providing an alternative to MVIC for follow-up assessment in ALS.

Leukaemia inhibitory factor gene mutations in infertile women.

The glycoprotein leukaemia inhibitory factor (LIF) is produced by the endometrium and is involved in the control of implantation. In women with unexplained infertility reduced uterine concentrations of LIF have been reported. Studies with mice lacking a functional LIF gene have shown that the LIF protein is essential for implantation of the embryo. We have developed a method for screening of gene mutations in the coding region and critical regulatory regions of the LIF gene. Thus we could screen nulligravid infertile women (n = 74), fertile controls (n = 75) and as a second unrelated control group, neurological patients (n = 131) for LIF gene mutations. In infertile women, three heterozygous point mutations have been identified: one in close proximity to the start codon of exon 1 and two mutations in exon 3. These correspond to regions of the LIF protein which are thought to be highly important for interaction with the LIF receptor and thus lead to reduced biological activity of the LIF protein. Only one point mutation/polymorphism in the non-coding region between exon 2 and 3 was found in the control groups. Our results suggest that heterozygosity for a LIF gene mutation could give rise to decreased availability or biological activity of LIF in the uterus and cause implantation failure. Thus the mutations identified in our study could be responsible for infertility in a subgroup of nulligravid women.

[Clenbuterol in amyotrophic lateral sclerosis. No indication for a positive effect]. / Clenbuterol bei der Amyotrophen Lateralsklerose. Kein Hinweis für einen positiven Effekt.

The anabolic effects of clenbuterol have been recognized for a long time. Clenbuterol augments the expression of specific muscle proteins with a differential effect on type I and type II fibres. Furthermore, clenbuterol induces the synthesis of endogenous nerve growth factor (NGF) and may itself be a myotrophic factor released by neuron endings. Side effects include tremor and headache and dose dependent abnormalities of laboratory values (hypokalemia, hypoglycemia). After long-term medication increasing fatigue of muscles has been observed. Decreased expression of beta 2-adrenergic receptors may limit the expected functional improvement. The efficacy of clenbuterol as symptomatic treatment of amyotrophic lateral sclerosis has not been proved. Controlled treatment trials are warranted to assess this question.

[Juvenile cerebral ischaemia caused by designer drugs]. / Juvenile zerebrale Ischämien durch Designerdrogen.

HISTORY AND CLINICAL FINDINGS: A 29-year-old man reported two episodes, 3 months apart, of dysarthria, each lasting for several hours. It was associated with hypaesthesia over the cheeks. Neurological examination several hours later was unremarkable. On direct questioning the patient reported that he had been taking marihuana and cocaine immediately before each episode. There was also a history of regular abuse of various drugs over several years by this socially well integrated young man. INVESTIGATIONS: Cranial computed tomography, cranial magnetic resonance imaging and cerebral scintigraphy indicated multiple cortical and subcortical ischaemic lesions of different sizes and ages. ECG, long-term ECG monitoring, transoesophageal echocardiography and upper abdominal sonography were normal. Cerebrospinal fluid revealed a slightly abnormal blood-brain barrier (5.3 g/l protein, albumin ratio of 7.3). Auto-antibody titres and coagulation and serological tests for neurotropic bacteria and viruses were normal. Urinary drug screening was positive for cannabinoids. DIAGNOSIS, TREATMENT AND COURSE: We assume that the patient had transitory cocaine-induced ischaemic attacks (TIA) and clinically silent cerebrovascular accidents (CVA). He was discharged without specific treatment after being informed of the severe neurological sequelae of his drug abuse. CONCLUSIONS: The rising abuse of "designer drugs" is of increasing diagnostic significance in TIA-like symptoms and CVAs in young adults, which may be of haemorrhagic or ischaemic aetiology. Thromboembolic, vasospastic or vasculitic factors play a pathogenetic role. Early performance of appropriate blood and urine tests is of great diagnostic importance.

Potential implications of a ciliary neurotrophic factor gene mutation in a German population of patients with motor neuron disease.

The frequency of a recently described point mutation of the ciliary neurotrophic factor (CNTF) gene was investigated in a population of 154 German patients with motor neuron disease (MND). Twenty-two percent of the patients were heterozygous, 2% homozygous for the CNTF mutation. Since the gene defect is per se not linked to MND, the identification of additional gene defects occurring simultaneously with this mutation could be informative for the understanding of pathogenic mechanisms of MND.

Localisation and association of pathomorphological changes at the brainstem in Alzheimer's disease.

The brainstems of ten patients with Alzheimer's disease were examined with specific silver impregnations for beta-amyloid deposits, neurofibrillary tangles, neuropil threads and neuritic plaques. The results show a selective and focal involvement of brainstem nuclei, which are diffusely connected to the cortex or are neuronally connected with other damaged subcortical and cortical regions. Therefore, it is concluded that neuronal connectivity plays an important role in the pathogenesis of Alzheimer's disease lesions. This may be due to the intraneuronal transport of beta-amyloid precursor protein. There was a local association between neurofibrillary tangles and neuropil threads, but not between beta-amyloid structures on the one hand and neurofibrillary structures on the other hand. Neuritic plaques were rarely found.