Cognitive decline in multiple sclerosis: impact of topographic lesion distribution on differential cognitive deficit patterns.

BACKGROUND: Multiple sclerosis (MS) is often accompanied by cognitive dysfunction. A negative correlation between cerebral lesion load and atrophy and cognitive performance has been pointed out almost consistently. Further, the distribution of lesions might be critical for the emergence of specific patterns of cognitive deficits. OBJECTIVE: The current study evaluated the significance of total lesion area (TLA) and central atrophy for the prediction of general cognitive dysfunction and tested for a correspondence between lesion topography and specific cognitive deficit patterns. METHODS: Thirty-seven patients with MS underwent neuropsychological assessment and magnetic resonance imaging. Lesion burden and central atrophy were quantified. Patients were classified into three groups by means of individual lesion topography (punctiform lesions/periventricular lesions/confluencing lesions in both periventricular and extra-periventricular regions). RESULTS: TLA was significantly related to 7 cognitive variables, whereas third ventricle width was significantly associated with 20 cognitive parameters. The three groups differed significantly in their performances on tasks concerning alertness, mental speed, and memory function. CONCLUSION: Third ventricle width as a straight-forward measure of central atrophy proved to be of substantial predictive value for cognitive dysfunction, whereas total lesion load played only a minor role. Periventricular located lesions were significantly related to decreased psychomotor speed, whereas equally distributed cerebral lesion load did not. These findings support the idea that periventricular lesions have a determinant impact on cognition in patients with MS.

[Therapy of pain syndromes in multiple sclerosis -- an overview with evidence-based recommendations]. / Therapie von Schmerzen bei MS -- eine Ubersicht mit evidenzbasierten Therapieempfehlungen.

While pain is a common problem in multiple sclerosis (MS) patients, it is frequently overlooked and has to be asked for actively. Pain can be classified into 4 diagnostically and therapeutically relevant categories. 1. PAIN DIRECTLY RELATED TO MS: Painful paroxysmal symptoms like trigeminal neuralgia or painful tonic spasms are treated with carbamazepine as first choice, or lamotrigine, gabapentin, oxcarbazepine and other anticonvulsants. Painful "burning" dysaesthesia, the most frequent chronic pain syndrome, are treated with tricyclic antidepressants or carbamazepine, further options include gabapentin or lamotrigine. While escalation therapy may require opioids, the role of cannabinoids in the treatment of pain still has to be determined. 2. PAIN INDIRECTLY RELATED TO MS: Pain related to spasticity often improves with adequate physiotherapy. Drug treatment includes antispastic agents like baclofen or tizanidine, alternatively gabapentin. In severe cases botulinum toxin injections or intrathecal baclofen merit consideration. Physiotherapy and physical therapy may ameliorate malposition-induced joint and muscle pain. Moreover, painful pressure lesions should be avoided using optimally adjusted aids. 3. Treatment-related pain can occur with subcutaneous injections of beta interferons or glatiramer acetate and may be reduced by optimizing the injection technique and by local cooling. Systemic side effects of interferons like myalgias can be reduced by paracetamol or ibuprofen. 4. Pain unrelated to MS such as back pain or headache are frequent in MS patients and may be worsened by the disease. Treatment should be follow established guidelines. In summary, a careful analysis of the pain syndrome will allow the design of the appropriate treatment plan using various medical and non-medical options and thus will help to ameliorate the patients' quality of life.

Transcranial magnetic stimulation as a provocation for epileptic seizures in multiple sclerosis.

Epileptic seizures may be of a provoked origin in acute phases of multiple sclerosis (MS), while chronic epilepsy typically occurs in advanced stages of the disease. A case of seizure provocation during diagnostic transcranial magnetic stimulation (TMS) is described here with a corresponding central nervous system (CNS) lesion in cranial magnetic resonance imaging. A subsequent chronic epileptogenesis originating from the opposite cerebral hemisphere was observed without further TMS influence after several years. The case in its clinical rarity demonstrates that standard single pulse TMS may trigger epileptic seizures only under limited conditions. Single pulse TMS is still regarded a safe procedure in MS.

Cognitive, but not mood dysfunction develops in multiple sclerosis during 7 years of follow-up.

Long-term development of psychological deficits in disability-free early multiple sclerosis (MS) was evaluated in 27 female patients over a period of 7 years and compared with healthy controls. Physical and cognitive parameters deteriorated significantly but not depression scores. In particular, the self-assessed somatic complaints remained non-similar between patients and controls. This indicates that although depression is clinically relevant and frequent in MS, in contrast to cognition it is not related to physical disease progression.

Diagnosis of multiple sclerosis: comparison of the Poser criteria and the new McDonald criteria.

OBJECTIVES: A confident and accurate diagnosis of multiple sclerosis (MS) is important, but a specific diagnostic test for the disease does not exist. The traditional diagnostic criteria of Poser et al. were published in 1983, and recently, McDonald et al. recommended new criteria for the diagnosis of MS. PATIENTS AND METHODS: In this study these two diagnostic schemes were compared by prospectively applying both of them to 76 patients with clinical features suggesting a new diagnosis of MS. RESULTS: Using the Poser criteria, 29 patients (38%) were classified as clinically definite and 35 patients (46%) as laboratory definite MS. According to the new McDonald criteria, MS was diagnosed in 39 (52%) patients, 37 patients (48%) had 'possible MS'. All patients with a clinically definite MS with the Poser criteria were also given the diagnosis of MS as recommended by McDonald et al. Of those 35 patients with laboratory definite MS according to Poser et al., four patients could be classified as having MS with the McDonald criteria, 89% of them had 'possible MS'. Conversely, 75% of the 39 patients, who fulfilled the new McDonald criteria for MS were assigned to the category of clinically definite MS according to the Poser criteria, and 83% of the patients with a 'possible MS' using the McDonald criteria, had a laboratory definite MS with the Poser criteria. CONCLUSION: MS according to the McDonald criteria was diagnosed more often than 'clinically definite MS' according to Poser et al., but combining the categories of clinically and laboratory definite MS, the diagnosis of MS could clearly be established more frequently using the Poser criteria.

[Quality of life in patients with remitting-relapsing multiple sclerosis in Germany]. / Lebensqualität bei Patienten mit schubförmiger MS in Deutschland.

The concept of health-related quality of life (QoL) includes physical, psychological,and social aspects. This pertains to consequences of chronic diseases and their therapies beyond biological or pharmacological relations. A considerable amount of literature concerning QoL has been published with regard to neurological and non-neurological entities. This study summarizes data from a study in 717 persons with remitting-relapsing multiple sclerosis (MS). Of them,576 could be reevaluated longitudinally after 1 year of treatment with interferon-beta 1a (44 microg subcutaneous Rebif once weekly). Compared to populations of healthy controls or other patients, considerable reductions in the eight subscales and both physical and emotional sum scales of the German version of the short form of the Rand Health Questionnaire (SF-36) questionnaire were assessed. These reductions were even more pronounced in persons with gait impairments. Most SF-36 scales only modestly correlated to physical disability. This indicates that QoL as reported by patients does not depend solely on the physical symptoms of MS. Most findings remained stable for the study population as a whole during 1 year of therapy, while statistically significant improvements were found in clinical responders as defined in this study (relapse-free, physically stable, stable or improved in physician's judgement). Side effects of therapy were not reflected in lower QoL scale values. Implications of findings for future concepts in MS therapy are discussed.

Inhibitors in the NFkappaB cascade comprise prime candidate genes predisposing to multiple sclerosis, especially in selected combinations.

Multiple sclerosis (MS) is an autoimmune disease displaying different clinical courses. In this multifactorial disease complex environmental as well as genetic predisposition factors contribute to the disease manifestation. Following the candidate gene approach we analysed several genes of the NFkappaB cascade, which are prime candidates for MS because of their involvement in almost all immunological reactions. MS association was excluded for the NFKB1 and NFKB3 genes, which show remarkably low degrees of polymorphism. The genes of NFkappaB inhibitors exhibit more sequence variations. In the IKBL gene a predisposing allele was identified (13.1% vs 7.5% in the control group, P < 0.001). This difference in the allelic distribution was even increased in the group of MS patients with a relapsing remitting course of the disease (14.9%, P < 0.0001). A protecting allele was found in the NFKBIA promotor for the patients with primary progressive MS (15.4% vs 28.4% in the control group, P < 0.01). Given predisposing alleles increase MS risk dramatically in certain combinations.

[Interferon beta-1b (Betaferon)therapy in patients with relapsing-remitting multiple sclerosis: findings of a prospective, multi-center study of disease progression]. / Interferon beta-1b (Betaferon) bei Patienten mit schubförmig-remittierender Multipler Sklerose. Ergebnisse einer prospektiven, multizentrischen Verlaufsbeobachtung.

In a survey of disease course, the efficacy and tolerability of 24-month interferon beta-1b therapy for relapsing remitting multiple sclerosis (RRMS) were evaluated in 410 patients. The investigation aimed at obtaining data from general practice and of possibly unknown, unexpected adverse reactions. In the 241 patients still on therapy, efficacy was rated after 24 months as "good" or "very good" in 75% of cases. After 24 months, 36.9% of the patients had no exacerbation (baseline 0.3%). Annual exacerbation rates dropped from 1.5 before treatment to 0.7 in the second treatment year. In the 2 years before treatment, 66.2% had worsened by at least 0.5 points on the extended disability status scale (EDSS). This proportion was reduced to 41.2% after 2 years of treatment. The safety profile corresponded to results from controlled trials. This postmarketing survey supports data from the published controlled interferon beta-1b studies and confirms the main effects of this therapy under routine conditions in general practice.

[Quantification of postoperative vigilance by evoked potentials]. / Quantifizierung der postoperativen Vigilanz mittels evozierter Potentiale.

OBJECTIVE: Patients will be discharged from the postoperative recovery room mostly on subjective clinical assessment. In this study an approach to a more quantitative judgment of postoperative vigilance is made by recording the P300-latency and neuropsychological tests. METHODS: 22 adult patients undergoing a disc operation were examined. For induction of anesthesia thiopental (4-5 mg/kg), fentanyl (0.1 mg) and a musclerelaxant (atracurium 0.4 mg/kg or succinylcholine 1-2 mg/kg after precurarisation with atracurium 5 mg) were given. Anesthesia was then continued with enflurance (1.0-1.2 MAC) in a mixture of 67% nitrous oxide in oxygen. If postoperative analgesia was needed, piritramid was injected in boli à 3-6 mg. The P300 was acoustically stimulated with an oddball-paradigm and recorded at Fz and Cz. Afterwards the latencies were measured and compared with a vigilance score composed of clinical parameters and neuropsychological tests. Recordings were done preoperatively and every 30 minutes up to 2 hours postoperatively. A correlation between P300-latencies and vigilance score was made with the coefficient of Spearman. Comparison of pre- and postoperative values was managed by using Wilcoxon test for matched pairs with Bonferroni-correction. RESULTS: Immediately after operation, P300 was obtained only in 8 patients (36%). The latencies were delayed (394 +/- 35 ms versus 326 +/- 12 ms preoperatively). During follow-up patients recovered and 2 hours postoperatively only one patient had no P300. At the end of the examination period P300-latencies of most patients had not yet reached the preoperative levels. The vigilance score in parallel showed decreases immediately after the operation and increases later on. However there were discrepancies between P300 latencies and neuropsychological findings, in some cases possibly due to the sedative effects of postoperative analgetics. CONCLUSION: Recording of P300-latencies showed remarkable cognitive deficits because of subclinical anesthesia hangover even 2 hours after a routine inhalational anesthesia. It is a good quantifiable method for assessment of postoperative vigilance. In some cases P300-latency is a more sensitive parameter for vigilance phenomena than clinical and neuropsychological scores.

Genetic predisposition to multiple sclerosis as revealed by immunoprinting.

This study was designed to examine the immunogenetic background predisposing to multiple sclerosis (MS). Three hundred fifty-eight clinically well-characterized MS patients from Germany were investigated and compared to 395 healthy control subjects. Each individual was genotyped for 22 polymorphic markers located within or close to immunorelevant candidate genes including HLA-DRB1*, T-cell receptor (TCR), cell interaction molecules, cytokines, and cytokine receptor genes. Altogether, approximately 17,000 genetic analyses were performed. Patients were grouped according to the course of MS-relapsing-remitting or chronic progressive. Most of the genetic markers were not associated with increased risk or their exact contribution was not clear (e.g., tumor necrosis factor). The relative risks for HLA-DRB1*15+ and DRB1*03+ individuals were 3.64 and 1.42, respectively. In both groups of patients, certain TCRB gene polymorphisms were risk factors. In DRB1*03+ individuals the relative risk was increased (> 22) when a specific TCRBV6S3 allele was also inherited. Furthermore, distinct linkage disequilibria of TCRBV6S1/TCRBV6S3 elements in patients and control subjects strongly suggested an additional risk factor in the TCRBV region for DRB1*15+ individuals. These findings are discussed with respect to the pathogenesis and rational approaches to the therapy of MS.

Right temporofrontal cortex as critical locus for the ecphory of old episodic memories.

A 54 year old patient of average intelligence with a severe and enduring loss of old autobiographical memories after herpes simplex type 1 infection is described. She was tested with a comprehensive neuropsychological battery two years after the infection. Special emphasis was laid on examining different aspects of retrograde memory. The neurological examination involved MRI and SPECT. Brain damage was found mainly in the right temporofrontal region, but minor left sided damage to this region seems possible. The patient was in the normal or slightly subnormal range for all tested anterograde memory functions, but manifested severe retrograde memory deficits with respect to episodic old memories and more moderate deficits in tests of general knowledge (semantic old memories). It is concluded that the ecphory of old autobiographical memories relies heavily on an activation of the right lateral temporofrontal junction area, but that probably only some complementary left hemispheric damage to these regions will lead to major and persistent retrograde amnesia. Alternatively, the disconnection between major prefrontal and posterior cortical regions may provide a basis for retrograde amnesia.

Left hemispheric neuronal heterotopia: a PET, MRI, EEG, and neuropsychological investigation of a university student.

A 21-year-old left-handed medical student had a prominent unilateral cerebral cortical malformation due to an ontogenetic migration disorder. We performed neuropsychological studies, EEG, T1- and T2-weighted and proton-density MRI, and positron emission tomography (PET) (under both the resting condition and neuropsychological activation). Neuropsychological testing revealed normal intelligence and generally normal memory functioning but selective deficits in tests of verbal fluency and spatial-figural relationships. Proton-density and T2-weighted MRI revealed extensive left cortical heterotopia that included parts of the Wernicke area. PET under the resting condition revealed a small interhemispheric difference with slightly reduced glucose metabolism in the left temporoparietal cortical zone. An activation PET (with the patient performing a verbal fluency test) resulted in a normal overall increase in metabolism but marked deviations in cortical areas. The highest activity changes were in the Broca and Wernicke areas of the right hemisphere, and there was very little activation in those regions of the left hemisphere that were expected to respond well to the activation--the temporal, parietal, and temporo-occipital cortical zones. We conclude that there can be large compensations for unilateral heterotopia.