Michael Haupts

Retrograde amnesia after traumatic injury of the fronto-temporal cortex.

An industrial manager had severe retrograde and variable but usually mild anterograde amnesia four years after a head injury. MRI showed damage of both temporal poles and the lateral portion of the right prefrontal cortex. The prefrontal and temporal cortical damage on the right side extended deeply into the white matter while the temporal cortical damage on the left side was much smaller. There was an additional left temporo-parietal lesion. The patient was of average intelligence. His attention, short term memory and learning ability were average or somewhat below average. His old memories were severely affected for the personal-episodic domain and less so for semantic remote memory abilities. Therefore an anatomical dissociation between anterograde and retrograde amnesia is possible at the anterior temporal regions, possibly interacting with the prefrontal cortex; these regions seem necessary for the retrieval of old episodic memories.

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.

Searching for the anatomical basis of retrograde amnesia

Abstract The case of a patient with profound retrograde and minor anterograde amnesia is described and used to discuss the kind of brain damage which will most likely result in persistent retrograde amnesia as the principal symptom. The patient was an industrial manager who had fallen off a horse four years prior to the present neuropsychological and neuroradiological investigation. MRI examination revealed an injury to both temporal poles and to the latero-ventral portion of the right prefrontal cortex. The prefrontal and temporal cortical damage on the right side deeply invaded the white matter while the temporal cortical damage on the left side was much smaller; here, however, portions of the temporo-parietal transition zone were affected as well. The patient was of average intelligence. His attention, short-term memory, and learning ability were average or somewhat below average. His old memories were severely affected in the personal-episodic domain, and much less so in that of semantic remote memory...

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.

A genome screen for linkage disequilibrium in HLA-DRB1*15-positive Germans with multiple sclerosis based on 4666 microsatellite markers

Abstract. Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system with putative autoimmune aetiology and complex genetic background. Here, we report the results of a genome screen for linkage disequilibrium (LD) by using 6000 microsatellite markers in 198 HLA-DRB1*15-positive MS patients and 198 unrelated controls (pooled DNA); 4666 analysed markers could be included in the resulting association map, from which 87 revealed significant differences between MS cases and controls.

Intracranial venous pressure is normal in patients with multiple sclerosis

Chronic cerebrospinal venous insufficiency (CCSVI) has been postulated as a cause for multiple sclerosis (MS). Venous pressure assessments have not been made. Intracranial venous pressure was assessed using ophthalmodynamometry in 29 MS patients and compared with 28 healthy controls and 19 cases with elevated intracranial pressure (ICP). MS and control subjects had normal venous pressures (mean 15.5 resp. 15.1 cmHg). Only cases with intracranial pressure pathology had elevated venous pressures (mean 28.8 cmHg). There is no evidence of an increased intracranial venous pressure in MS patients.

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.

Association of the HLA region with multiple sclerosis as confirmed by a genome screen using >10,000 SNPs on DNA chips

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system, with a complex genetic background. Here, we present a genome screen for association in small scale, employing 11,555 single nucleotide polymorphisms (SNPs) on DNA chips for genotyping 100 MS patients stratified for HLA-DR2+ and 100 controls. More than 500 SNPs revealed significant differences between cases and controls before Bonferroni correction. A fraction of these SNPs was reanalysed in two additional cohorts of patients and controls, using high-throughput genotyping methods. A marker on chromosome 6p21.32 (rs2395182) yielded the highest significance level, validating the established HLA-DR association.

PTPRC (CD45) is not associated with multiple sclerosis in a large cohort of German patients

BackgroundSince contradictory results have been reported, we reanalysed the 77C→G transition in exon 4 of the protein-tyrosine phosphatase receptor-type C (PTPRC also known as CD45) in a large cohort of German MS patients and controls. Different isoforms of the protein are expressed, depending on alternative splicing of exons 4 (CD45RA), 5 (CD45RB) and 6 (CD45RC) (CD45RO, exons 4–6 spliced out). The 77C→G transition does not change the amino acid sequence, but it is probably part of a motif necessary for splicing leading to the isoform CD45RA. The expression of CD45RA is increased in 77C/G heterozygous individuals. The aim of the study was to clarify the importance of the PTPRC 77C→G transition in our German cohort of MS patients.MethodsPCR products of exon 4 were digested using endonuclease MspI. The resulting restriction fragments of the wildtype C allele are 198 and 62 bp in length. In the G allele an additional restriction site is present yielding fragments of 114 and 84 bp.ResultsThe G allele was identified in 10 of the 347 controls (1.4%) and in 7 of 454 MS patients (0.8%; Table 1). No homozygous individuals were found either in the control or in the patient group. Genetic association between the PTPRC 77C→G transition and MS susceptibility was excluded in the MS cohort. In addition, subgrouping patients according to differences in the clinical course of MS or according to HLA-DRB1*15 status did not yield significant differences.ConclusionsThe 77C→G transition in exon 4 of the PTPRC gene may contribute to MS susceptibility only in very few families, if at all, but it is not relevant for the majority of MS cases, including virtually all German patients.

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.