[Requirements of neurologists for autopsies]. / Anforderungen des Neurologen an Obduktionen.

BACKGROUND: In assuring the quality of the healthcare system, it is the intention of healthcare politics to raise the number of clinical autopsies. OBJECTIVE: What are the requirements of clinical neurologists for neuroautopsies and how can the post-mortem examiner cope with these requests? METHODS: Discussion on how the questions that arise with the most relevant neurological disease groups can be solved by post-mortem examination. RESULTS: The diagnostics of inflammatory, inflammatory demyelinating and demyelinating brain diseases, neurodegenerative diseases and neuromuscular diseases as well as central nervous system tumors necessitate the removal of specific brain regions, specific examination techniques, immunohistochemical investigations or specific samples taken for biochemical, molecular pathological or genetic investigations according to international published consensus criteria. It is the first priority in post-mortem examinations to use all possible options and appraisals to identify patients with the aforementioned neurological diseases or suspected diseases early enough during the autopsy process that the tissue sampling, necessary for diagnosing the assumed diseases, will take place. CONCLUSION: Demands made on neuropathological investigations have increased tremendously, because of rapid progress in understanding chronic neurological diseases and the requirements of consensus criteria. To cope with expectations on neuropathological post-mortem investigations, a close collaboration should be established between clinical neurologists, post-mortem examiners and neuropathologists.

Nicotinic α4ß2 acetylcholine receptors and cognitive function in Parkinson's disease.

BACKGROUND: Idiopathic Parkinson's disease (IPD) is characterized by the clinical motor symptoms of hypokinesia, rigidity, and tremor. Apart from these motor symptoms, cognitive deficits often occur in IPD. The positive effect of cholinesterase inhibitors on cognitive deficits in IPD and findings of earlier molecular imaging studies suggest that the cholinergic system plays an important role in the origin of cognitive decline in IPD. METHODS: Twenty-five non-demented patients with IPD underwent a 5-[123I]iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-I-A-85380) SPECT to visualize α4ß2 nicotinic acetylcholine receptors (nAchR) and cognitive testing with the CERAD (Consortium to Establish a Registry for Alzheimer's Disease) battery to identify domains of cognitive dysfunction. RESULTS: In the CERAD, the IPD patients exhibited deficits in non-verbal memory, attention, psychomotor velocity, visuoconstructive ability, and executive functions. After Bonferroni correction for multiple comparisons, we found significant correlations between performance of the CERAD subtests Boston Naming Test (a specific test for visual perception and for detection of word-finding difficulties) and Word List Intrusions (a specific test for learning capacity and memory for language information) vs binding of α4ß2 nAchR in cortical (the right superior parietal lobule) and subcortical areas (the left thalamus, the left posterior subcortical region, and the right posterior subcortical region). CONCLUSIONS: These significant correlations between the results of the CERAD subtests and the cerebral α4ß2 nAchR density, as assessed by 5-I-A-85380 SPECT, indicate that cerebral cholinergic pathways are relevant to cognitive processing in IPD.

[Neurological manifestations of AGel amyloidosis (Meretoja's syndrome) in a German family]. / Neurologische Manifestationen der AGel-Amyloidose (Meretoja-Syndrom) bei einer deutschen Familie.

AGel amyloidosis is an autosomal dominantly inherited systemic amyloidosis which is most commonly observed in Finland. The clinical manifestation is characterised by lattice corneal dystrophy, bilateral facial palsy with myokymias, and cutis laxa. We report on a German family with an AGel amyloidosis due to a gelsolin p.Asp214Asn/D187N mutation encoded by exon 4 of the GSN gene on chromosome 9q34.

[Early deep brain stimulation for Parkinson's disease]. / Brauchen wir die frühzeitige tiefe Hirnstimulation beim Morbus Parkinson?

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a powerful treatment for advanced Parkinson's disease with levodopa-induced motor complications. Randomized controlled studies have shown that motor fluctuations and quality of life are significantly more improved by STN-DBS than by best medical treatment. The main delay before neurosurgery is currently 14 years after diagnosis. Clinical pilot data suggest that neurosurgery performed already with beginning motor fluctuations and an average disease duration of 7 years may lead to earlier improvement of motor deficits and quality of life, thus preventing disease-related psycho-social decline, and extending the period of beneficial effects of STN-DBS. Results of an ongoing multicenter trial (EARLYSTIM) comparing the effects of STN-DBS and best medical treatment on motor symptoms, quality of life, and psycho-social adaptation will be available in 2 years time and will clarify whether or not early STN-DBS is superior to best medical treatment.

Hyperechogenicity of the substantia nigra in healthy controls is related to MRI changes and to neuronal loss as determined by F-Dopa PET.

Transcranial ultrasound (TCS) has been shown to reveal hyperechogenicity of the substantia nigra (SN) in Parkinsonian patients and in about 10% of healthy controls. It is hypothesized that SN hyperechogenicity in healthy subjects is a vulnerability marker for idiopathic Parkinson's disease (IPD). Although there is strong evidence that the echomarker results from increased local iron content, the exact pathophysiological mechanisms remain incompletely understood. Thus, prognostic impact can only be estimated. We examined 14 subjects with SN hyperechogenicity (SN+) (7 IPD patients and 7 controls) and 7 healthy controls without the echomarker (SN-) by a magnetic resonance imaging method (MRI; T2 relaxation times) known to reveal tissue inhomogeneity following abnormal iron content and by F-Dopa PET to assess nigrostriatal function.

A novel mitochondrial ATP8 gene mutation in a patient with apical hypertrophic cardiomyopathy and neuropathy.

PURPOSE: To identify the biochemical and molecular genetic defect in a 16-year-old patient presenting with apical hypertrophic cardiomyopathy and neuropathy suspected for a mitochondrial disorder. METHODS: Measurement of the mitochondrial energy-generating system (MEGS) capacity in muscle and enzyme analysis in muscle and fibroblasts were performed. Relevant parts of the mitochondrial DNA were analysed by sequencing. Transmitochondrial cybrids were obtained by fusion of 143B206 TK(-) rho zero cells with patient-derived enucleated fibroblasts. Immunoblotting techniques were applied to study the complex V assembly. RESULTS: A homoplasmic nonsense mutation m.8529G-->A (p.Trp55X) was found in the mitochondrial ATP8 gene in the patient's fibroblasts and muscle tissue. Reduced complex V activity was measured in the patient's fibroblasts and muscle tissue, and was confirmed in cybrid clones containing patient-derived mitochondrial DNA. Immunoblotting after blue native polyacrylamide gel electrophoresis showed a lack of holocomplex V and increased amounts of mitochondrial ATP synthase subcomplexes. An in-gel activity assay of ATP hydrolysis showed activity of free F(1)-ATPase in the patient's muscle tissue and in the cybrid clones. CONCLUSION: We describe the first pathogenic mutation in the mitochondrial ATP8 gene, resulting in an improper assembly and reduced activity of the complex V holoenzyme.

Facial emotion recognition in Parkinson's disease: Association with age and olfaction.

OBJECTIVE: The ability to recognize facial emotion expressions has been reported to be impaired in Parkinson's disease (PD), yet previous studies showed inconsistent findings. The aim of this study was to further investigate facial emotion recognition (FER) in PD patients and its association with demographic and clinical parameters (including motor and nonmotor symptoms). METHOD: Thirty-four nondemented PD patients and 24 age- and sex-matched healthy controls (HC) underwent clinical neurological and neuropsychological assessment, standardized olfactory testing with Sniffin' Sticks, and the Ekman 60 Faces Emotion Recognition Test. RESULTS: PD patients had a significantly lower score on the total FER task than HC (p = .006), even after controlling for the potential confounding factors depression and apathy. The PD group had a specific impairment in the recognition of surprise (p = .007). The recognition of anger approached statistical significance (p = .07). Increasing chronological age and age at disease onset were associated with worse performance on the FER task in PD patients. Olfactory function along with PD diagnosis predicted worse FER performance within all study participants. CONCLUSION: Facial emotion recognition and especially the recognition of surprise are significantly impaired in PD patients compared with age- and sex-matched HC. The association of FER with age and olfactory function is endorsed by common structures that undergo neurodegeneration in PD. The relevance of FER in social interaction stresses the clinical relevance and the need for further investigation in this field. Future studies should also determine whether impaired FER is already present in premotor stages of PD.

End-plate dysfunction in acute organophosphate intoxication.

Acute organophosphate intoxication resulting from suicide attempts in 14 patients produced a series of electrophysiologic abnormalities that correlated with the clinical course. Spontaneous repetitive firing of single evoked compound muscle action potentials (CMAP) was the earliest and most sensitive indicator of the acetylcholinesterase inhibition. A decrement of evoked CMAP following repetitive nerve stimulation was the most severe abnormality. At the height of the intoxication no CMAP was evoked after the first few stimuli. The decrement-increment phenomenon occurred only at milder stages of intoxication and its features are characteristic of acetylcholinesterase inhibition. These electrophysiologic features proved to be the most useful for determining initial severity and clinical course of the acute organophosphate intoxication and differentiated this syndrome from those of myasthenia gravis, Eaton-Lambert syndrome, and botulism.

Hereditary motor and sensory neuropathy with spastic paraplegia and optic atrophy: report on a family.

We describe two siblings affected by a motor and sensory neuropathy starting in childhood. Already in infancy, a spastic gait disturbance had become obvious, leading later to multiple surgical interventions. In adolescence, progressive loss of vision developed. At the time of our examination, both siblings showed severe weakness and atrophy of the distal muscles of legs and arms. Tendon jerks were brisk in proximal muscles; in the lower extremities, muscle tone was increased. Visual acuity was severely decreased. Nerve conduction studies revealed an axonal degeneration. This finding was confirmed by evaluation of a sural biopsy specimen in one patient, showing only few remaining myelinated fibres without signs of demyelination. This combination of hereditary motor and sensory neuropathy with spastic paraplegia and optic atrophy shows features of both hereditary motor and sensory neuropathy V and VI according to the classification of Dyck, indicating that these subtypes may not represent distinct entities.

Impact of different stimulation types on orthostatic tremor.

OBJECTIVE: Primary orthostatic tremor (OT) is thought to be generated by a unique supraspinal tremor generator. Here we studied the effect of ipsi- and contralateral stimulation of the central and peripheral nervous system on OT. METHODS: In 7 patients with primary OT, surface EMG was recorded from both tibialis anterior muscles. We performed transcranial magnetic stimulation (TMS) over the vertex, and lumbar magnetic stimulation (LMS) over the lumbar spine. Supramaximal electrical nerve stimuli were applied to the tibial or peroneal nerve at the knee. Proprioceptive input was evoked by rhythmical submaximal stimulation of the tibial, peroneal or sural nerve at the ankle. RESULTS: TMS reset OT significantly in the contralateral as well as the ipsilateral tibialis anterior muscle. The resetting in both muscles was identical. In contrast, peripheral input by means of LMS, supra- or submaximal nerve stimulation had no impact on OT. CONCLUSIONS: Transcranial magnetic stimulation of one cortical leg area resets OT in both legs whereas OT is not modified by any peripheral stimuli applied in this study. SIGNIFICANCE: Our results support the hypothesis of n unique supraspinal OT generator. This generator receives a modulating input from the motor cortex.

A novel mitochondrial ATP8 gene mutation in a patient with apical hypertrophic cardiomyopathy and neuropathy.

To identify the biochemical and molecular genetic defect in a 16-year-old patient presenting with apical hypertrophic cardiomyopathy and neuropathy suspected for a mitochondrial disorder.Measurement of the mitochondrial energy-generating system (MEGS) capacity in muscle and enzyme analysis in muscle and fibroblasts were performed. Relevant parts of the mitochondrial DNA were analysed by sequencing.A homoplasmic nonsense mutation m.8529G→A (p.Trp55X) was found in the mitochondrial ATP8 gene in the patient's fibroblasts and muscle tissue. Reduced complex V activity was measured in the patient's fibroblasts and muscle tissue, and was confirmed in cybrid clones containing patient-derived mitochondrial DNAWe describe the first pathogenic mutation in the mitochondrial ATP8 gene, resulting in an improper assembly and reduced activity of the complex V holoenzyme.

Quantification of temporal and spatial accuracy of alternating arm movements in multiple sclerosis patients treated with deep brain stimulation of the thalamic ventralis intermedius nucleus (VIM).

OBJECTIVE: In patients with multiple sclerosis (MS) ataxia is a common symptom, which is barely influenced by pharmacological treatment. We studied whether stimulation of the thalamic ventralis intermedius nucleus (VIM) improves the performance of alternating forearm movements in MS patients. METHODS: We investigated 6 patients with primary (n=1) or secondary (n=5) chronic progressive MS (age 36-66 years, median 41.5 years, median EDSS [expanded disability status scale] 6.5). Patients were seated in a chair with one arm abduced at right angles to the body. This arm was strapped into a splint with one fixed section for the upper arm and one movable section for the forearm. The latter allowed horizontal movements in the elbow joint. The patients had to perform rhythmic alternating flexion and extension movements in the elbow joint. The rhythm and spatial extent of movements were indicated acoustically by a click tone stimulator and by marks respectively. Six manoeuvres (spatial extents of 48 degrees , 83 degrees at frequencies of 0.9 Hz, 1.5 Hz, and 2.5 Hz each) had to be performed. A potentiometer converted the horizontal movements of the forearm into a variable voltage. Forearm movements were measured with and without contralateral VIM stimulation. RESULTS: In all patients, spatial accuracy of the alternating forearm movements improved significantly after the stimulation had been switched on. Temporal accuracy increased during VIM stimulation in 5 of 6 patients. In 1 of 6 patients the spatial but not the temporal movement accuracy improved during stimulation. CONCLUSIONS: During VIM stimulation, performance of alternating forearm movements improved significantly. This might indicate that VIM stimulation could be a therapeutic alternative in the treatment of upper limb ataxia in MS.

Striatal FP-CIT uptake differs in the subtypes of early Parkinson's disease.

In idiopathic Parkinson's disease (PD), a tremor-dominant type (TDT), an akinetic-rigid type (ART), and a mixed type (MT) are distinguished. We compared cerebral [I-123]FP-CIT SPECT in the PD subtypes (67 patients Hoehn and Yahr stage 1:26 with ART, 19 with MT, 22 with TDT). We measured the ratios putamen/occipital lobe binding and caudate nucleus/occipital lobe binding. Parkinsonian motor symptoms were quantified by UPDRS motor scale. In both putamen and caudate nucleus contralateral to the clinically affected body side TDT patients showed a significantly higher FP-CIT uptake than ART or MT patients (ANOVA; p<0.01). Contralateral putamen and caudate nucleus FP-CIT uptake correlated significantly with severity of rigidity (p<0.01) and hypokinesia (p<0.01) but not with severity of resting or postural tremor (p>0.05). The missing correlation between striatal FP-CIT uptake and tremor suggests, that further systems besides the nigrostriatal dopaminergic system may contribute to generation of parkinsonian tremor.

Mutations in the gene encoding peroxisomal sterol carrier protein X (SCPx) cause leukencephalopathy with dystonia and motor neuropathy.

In this report, we describe the first known patient with a deficiency of sterol carrier protein X (SCPx), a peroxisomal enzyme with thiolase activity, which is required for the breakdown of branched-chain fatty acids. The patient presented with torticollis and dystonic head tremor as well as slight cerebellar signs with intention tremor, nystagmus, hyposmia, and azoospermia. Magnetic resonance imaging showed leukencephalopathy and involvement of the thalamus and pons. Metabolite analyses of plasma revealed an accumulation of the branched-chain fatty acid pristanic acid, and abnormal bile alcohol glucuronides were excreted in urine. In cultured skin fibroblasts, the thiolytic activity of SCPx was deficient, and no SCPx protein could be detected by western blotting. Mutation analysis revealed a homozygous 1-nucleotide insertion, 545_546insA, leading to a frameshift and premature stop codon (I184fsX7).

Echogenic substantia nigra in patients with orthostatic tremor.

OBJECTIVES: Previous studies suggest that the nigrostriatal dopaminergic transmission is impaired in patients with primary orthostatic tremor. METHODS: We used transcranial sonography (TCS) to examine the morphology of the substantia nigra (SN) in four patients with primary orthostatic tremor (OT). RESULTS: TCS revealed an SN echogenicity in all patients, in three patients unilaterally, in one patient bilaterally. CONCLUSIONS: Our data suggest nigrostriatal dopaminergic deficits in OT patients. The exact impact of these dopaminergic deficits on OT generation is unclear.

[Gustatory rhinorrhea after hemiresection of the maxilla]. / Gustatorische Rhinorrhoe nach Halbseitenresektion des Oberkiefers.

A case of gustatory rhinorrhea after maxillary resection is reported about. The symptoms can be explained as defective regeneration of secretory nerves, especially of the nasopalatinal nerve.

[Visual evoked potentials in Creutzfeldt-Jakob disease]. / Visuell evozierte Potenziale bei der Creutzfeldt-Jakob-Erkrankung.

Neuropathological studies show frequent and extensive effects on the visual system in Creutzfeldt-Jakob disease (CJD), but deterioration of vision is not reported by all patients. We examined the function of the visual system by means of visual evoked potentials (VEP). We recorded monocular pattern-reversal VEP in six patients with sporadic CJD 1-13 months after first symptoms occurred. Three patients had normal vision, and in a further three, vision was impaired. All patients had pathological VEP with a delayed P100 component (six eyes) or loss of cortical response (five eyes). The patients with visual impairment vs those without were not different concerning VEP findings. The VEP are already pathological in initial CJD stages and point to an early effect on the visual system in CJD, irrespective of clinical visual deficits.

[The effect of a reference electrode on the configuration of somatosensory evoked potentials]. / Der Einfluss der Referenzelektrode auf die Konfiguration der somatosensorisch evozierten Potentiale.

Early somatosensory evoked potentials to median nerve stimulation were recorded in 6 normal adults from the scalp and the neck. Simultaneous derivations consisted of a recording with a cephalic reference, recordings of both electrodes with a noncephalic reference and an arithmetically subtraction of these potentials. The electrodes were placed over the scalp (P4'), the lower and the upper neck and the reference electrodes over the midfrontal region (Fz), both ears (M1/2) and the contralateral hand. P15/P16 in the P4'-Fz derivation had no identity to the far field potentials (FFP) P13/P14 recorded from the scalp with hand reference. FFP P9 and P11 from the ear lobes was abolished in the P4'-M1/2 derivation and the residual positive waves corresponded to P13 and P14. None of the electrodes picked up a wave equivalent to P15 regardless of the reference electrode. In the neck (CV 7) - scalp derivation NSEP9, 13 and 14 corresponded to the FFP P9, 13 and 14. NSEP11 differed in latency from P11 and N11. There was no latency shift from the lower (CV 7) to the upper (CV 2) neck. NSEP9 and 11 was enhanced in amplitude from CV 7, which resulted from different polarities (N11/P11) over CV 7 and CV 2. These results indicate the necessarity of potential analysis with respect to the activity of the recording electrodes.