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

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.

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.

Non-convulsive status epilepticus in two patients receiving tiagabine add-on treatment.

We report two patients with epileptic syndromes who developed non-convulsive status epilepticus under adjunctive antiepileptic therapy with tiagabine. The paradoxical effect may be the result of a difference in effects between GABAA and GABAB receptors, or between GABA receptors in different regions of the brain.

[Word generation in bilinguals--fMRI study with implications for language and memory processes]. / Wortgenerierung bei Bilingualen--eine fMRT-Studie mit Implikationen für Sprach- und Gedächtnisprozesse.

For over a century the cerebral representation of language functions is a matter of debate. In Neuroscience language is regarded as one of the most lateralized cognitive functions. Thus, while the language which is acquired first in most cases is processed by the left hemisphere some studies in brain damaged but also experimental investigations propose a pivotal role of the right hemisphere in second language processing. By the advent of modern neuroimaging it is now possible to study language lateralization and bilinguality also in healthy subjects. We studied first and second language abilities in a group of bilingual, healthy individuals by means of functional magnetic resonance imaging (fMRI) with a word-fluency paradigm. While we found a predominantly left prefrontal activity during both first and also second language processing an additional right prefrontal activation was registered during the use of second language. Our findings are discussed on the basis of an interaction between language and memory processes.

Quantitative assessment of the ischemic brain by means of perfusion-related parameters derived from perfusion CT.

BACKGROUND AND PURPOSE: Besides the delineation of hypoperfused brain tissue, the characterization of ischemia with respect to severity is of major clinical relevance, because the degree of hypoperfusion is the most critical factor in determining whether an ischemic lesion becomes an infarct or represents viable brain tissue. CT perfusion imaging yields a set of perfusion related parameters which might be useful to describe the hemodynamic status of the ischemic brain. Our objective was to determine whether measurements of the relative cerebral blood flow (rCBF), relative cerebral blood volume (rCBV), and relative time to peak (rTP) can be used to differentiate areas undergoing infarction from reversible ischemic tissue. METHODS: In 34 patients with acute hemispheric ischemic stroke <6 hours after onset, perfusion CT was used to calculate rCBF, rCBV, and rTP values from areas of ischemic cortical and subcortical gray matter. Results were obtained separately from areas of infarction and noninfarction, according to the findings on follow-up imaging studies. The efficiency of each parameter to predict tissue outcome was tested. RESULTS: There was a significant difference between infarct and peri-infarct tissue for both rCBF and rCBV but not for rTP. Threshold values of 0.48 and 0.60 for rCBF and rCBV, respectively, were found to discriminate best between areas of infarction and noninfarction, with the efficiency of the rCBV being slightly superior to that of rCBF. The prediction of tissue outcome could not be increased by using a combination of various perfusion parameters. CONCLUSIONS: The assessment of cerebral ischemia by means of perfusion parameters derived from perfusion CT provides valuable information to predict tissue outcome. Quantitative analyses of the severity of ischemic lesions should be implemented into the diagnostic management of stroke patients.

Phenomenological diversity of spinal reflexes in brain death.

In brain death, spinal reflexes and automatisms are observed which may cause irritation and even doubt in the diagnosis. In the literature there are no dedicated descriptions of the diversity and of neuroanatomical considerations. In 278 examinations of 235 patients for the determination of brain death, on 42 occasions obvious spinal reflexes and/or spinal automatisms were observed in 27 brain dead bodies. Because they were not systematically searched for, minute forms have probably been missed. The reflexes (R) and automatisms (A) are described according to the time of observation in relation to the development of brain death, the presumable spinal localization and the possible phylogenetical interpretation. Especially disquieting examples are discussed in more detail, e.g. monophasic EndotrachealSuction-ThoracicContraction-R supposedly switched in segments C2-6 or TrapeziusPinch-ShoulderProtrusion-R conveyed by the accessory nerve (terminology according to the scheme: for the reflexes, Trigger-Response-R: for the automatisms, Movement-A). After these experiences a more thorough examination showed frequent observations of rather minute forms of spinal reflexes, as well as automatisms and even the Lazarus sign (in possibly more than two thirds of the examinations). An estimation of the factual frequency would necessitate special attention to those much more frequent but less obvious minute spinal reflexes and automatisms.

[CT perfusion imaging in acute ischemic cerebral infarct: comparison of cerebral perfusion maps and conventional CT findings]. / CT-Perfusionsbildgebung beim akuten ischämischen Hirninfarkt: Vergleich von Parameterbildern der zerebralen Perfusion und Nativ-CT-Befunden.

PURPOSE: To evaluate the findings of acute brain ischemia on different functional maps of cerebral perfusion CT in stroke patients and to compare the results with early ischemic changes on conventional CT. METHODS: The baseline CT scans of 45 acute stroke patients were retrospectively evaluated with respect to early CT findings. For each patient the extent of cerebral ischemia as shown on the maps of cerebral blood flow (CBF), cerebral blood volume (CBV), and "time to peak" (TP) was compared and the severity of ischemia was assigned to one of three levels based on the findings of the CBF image. RESULTS: In 75% of all patients conventional CT was performed within 2 hours from symptom onset. 29 of 45 patients showed early signs of ischemia on conventional CT, whereas perfusion CT revealed cerebral ischemia in all patients. Severe ischemia was found in approximately the same rate of incidence in patients with early CT changes (55.2%) and in those with normal findings (43.8%). If the perfusion impairment was judged as mild or moderate the extent of the hypoperfused area was significantly larger on the CBF and TP images than on the CBV map. This was significantly different in patients with severe hypoperfusion where a complete correspondence of the affected area between the three functional maps was found. DISCUSSION: The use of conventional CT for the assessment of stroke in the hyperacute phase is limited. Perfusion CT yields excellent information regarding the severity and extent of ischemia. The use of various perfusion maps helps to differentiate the core of infarction from the ischemic penumbra zone.

[CADASIL. Clinical aspects, neuroradiology, genetics and diagnosis]. / CADASIL. Klinik, Neuroradiologie, Genetik und Diagnose.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebral vasculopathy progressing to subcortical dementia, caused by multiple lacunar infarcts and ischemic white matter degeneration. Migraine with aura, epileptic seizures and affective disorders are frequent additional symptoms of CADASIL. The causative mutations of the Notch3 gene are located on chromosome 19p13.1. There is complete penetrance of this disorder, although individual expression of symptoms may vary. Manifestation of CADASIL is usually in the 3rd decade, but some individuals remain asymptomatic close to the age of 60. MRI displays a marked leukoencephalopathy in affected individuals as early as in the age of 20. Frontal and subcortical hypoperfusion in demented individuals was demonstrated by SPECT-studies. The prevalence of CADASIL is still not known. To date there is no causative therapy.

Retrograde amnesia for world knowledge and preserved memory for autobiographic events. A case report.

A patient (PC) with severe and chronic retrograde amnesia for world knowledge (tested with famous events and famous faces), but unimpaired autobiographical memory is described. The 64-year-old man had traumatic brain injury four years prior to the present evaluation. Current brain imaging showed principally damage involving the infero-lateral prefrontal and the lateral temporal regions of the left-hemisphere. PC was of average intelligence, had no depression and only minor language problems, but manifested some additional anterograde memory deficits and performed subaverage in various frontal lobe-sensitive tests. Patient PC represents one of the very few cases with a preserved retrograde episodic and an impaired retrograde knowledge system, showing a dissociation between preserved retrieval of autobiographical events and amnesia for nonpersonal famous events. It is hypothesized that the sparing of autobiographical memories can be linked to the integrity of the right frontal and temporo-polar cortices.

Impaired episodic memory retrieval in a case of probable psychogenic amnesia.

A patient with severe, selective retrograde amnesia for personal material diagnosed as probable psychogenic amnesia, was investigated intensively neuropsychologically with cranial computed tomography (CCT), magnetic resonance imaging (MRI), and single photon emission tomography (SPECT). The patient was of average intelligence and memory with no anterograde amnesia. No evidence for structural brain damage was detected in CCT and MRI. SPECT, performed about 3 weeks after the onset of symptoms, demonstrated reduced perfusion in right temporal and frontal areas, that is, in areas which have been suggested as critical for episodic memory retrieval. To study episodic memory retrieval, positron-emission-tomography (PET) blood flow (rCBF) measurements were performed 6 months after the onset of symptoms. During episodic memory retrieval bilateral neuronal activations were observed in the precuneus, the lateral parietal and the right dorsolateral and polar prefrontal cortex. Compared to the results of previous functional imaging studies on episodic memory retrieval, our findings suggest an underlying functional disturbance of brain areas previously demonstrated to be involved in episodic memory retrieval.

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.

Fornix damage and memory. A case report.

The role of the fornix for episodic memory processing is still a matter of controversy. A juvenile patient of average post-surgical intelligence with fornical damage due to tumor removal is described. The fornix was damaged bilaterally at the level of the fornical columns. The patient thereafter suffered major anterograde amnesia which was most pronounced in tests using long delays (e.g., in the delayed recall index of the revised Wechsler Memory Scale). Amnesia was a prominent on the verbal as on the nonverbal level. Attention, concentration and short term memory abilities were preserved. Cognitive flexibility, procedural memory and priming were principally unimpaired. There was no evidence of retrograde amnesia. It is concluded that the fornix constitutes a major link between the three memory interfaces (medial diencephalon, medial temporal lobe, basal forebrain) and that its bilateral rupture anterior to the thalamic level may lead to lasting anterograde amnesia.

[Neuropsychological aspects in idiopathic Parkinson disease]. / Neuropsychologische Aspekte bei idiopathischem Morbus Parkinson.

Patients with Parkinson's disease can suffer from neuropsychological deficits which, in most cases, are already demonstrated at the very beginning (53). Primarily, they are characterized by impairments associated with frontal lobe function affecting psychomotor speed and mental flexibility. Furthermore they show circumscribed impairment of memory functions as well as deficits of visuospatial information processing. Sets of neuropsychological dysfunction of that kind are called subcortical dementia in the American literature. In addition, Parkinson's disease is quite often associated with depressive states which are independent of the neuropsychological deficits. Application of L-Dopa helps to improve the cognitive impairment.

The amygdala's contribution to memory--a study on two patients with Urbach-Wiethe disease.

The consequences of primary amygdaloid damage on memory performance are described in terms of neuropsychological, CT, MRI and PET results of two patients, a brother and a sister. Both had circumscribed, bilaterally symmetrical damage confined to the amygdaloid region, while the hippocampal formation and other brain structures were intact. PET-imaging furthermore revealed an overall decrease in glucose metabolism which was particularly apparent at the cingular and thalamic levels. Although neither patient was amnesic, both showed memory impairments in selective tests. In one patient these impairments were more pronounced and they were accompanied by marked affective-emotional fluctuations. Our results suggest that the amygdaloid region is a bottle-neck structure that confers an affective flavour to memories, thereby enhancing the probability of their long term storage.

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.

[The structure of mnestic problems in multiple sclerosis: everyday memory performance and neuroradiologic findings]. / Zur Struktur mnestischer Probleme bei Multipler Sklerose--Alltagsgedächtnisleistungen und neuroradiologische Befunde.

35 multiple sclerosis patients and 30 matched healthy controls were investigated for mnestic problems using a German everyday memory test. The objects were both the description of structural characteristics of disturbances and "ecological validity" to meet rehabilitative issues prospectively. In the MS group, impairments were found mainly in the memory domain under delayed recall conditions of complex material. The processing of these tasks may be especially sensitive against fiber tract lesions. While discrete lesions, mostly found in patients with relapsing-remitting courses, inconsistently lead to partial memory disturbances, global mnestic deficits are to be expected in confluent lesion patterns exceeding a critical "threshold of cerebral tolerance." The latter characterises mostly patients with chronic progressive disease courses.