[Neuronal plasticity and neuromodulation in pediatric neurology]. / Neuronale Plastizität und Neuromodulation in der Kinderneurologie.

BACKGROUND: Neuronal plasticity is a core mechanism for learning and memory. Abnormal neuronal plasticity has emerged as a key mechanism in many neurological and neuropediatric diseases. OBJECTIVE: Chances and perspectives of neuromodulation techniques in neurological and neuropediatric diseases with altered neuronal plasticity. MATERIAL AND METHODS: Presentation and discussion of own results of neuronal plasticity investigations in patients with neurodevelopmental disorders including RASopathies, autism spectrum disorders (ASD) and Gilles de la Tourette syndrome (GTS). RESULTS: The results of neuronal plasticity studies in patients with RASopathies, ASD and GTS underline the pathophysiological relevance of abnormal neuronal plasticity in these diseases. Transcranial magnetic stimulation (TMS) is a useful tool to examine and also induce neuronal plasticity in these patients. CONCLUSION: Neuronal plasticity appears to be an important pathophysiological factor in neuronal developmental disorders and can be investigated using TMS. New and innovative techniques may offer novel approaches for individualized TMS applications, particularly in children with neuropediatric conditions.

Striatal dysfunction in X-linked dystonia-parkinsonism is associated with disease progression.

BACKGROUND AND PURPOSE: X-linked dystonia-parkinsonism (XDP) is an inherited neurodegenerative adult-onset movement disorder associated with striatal atrophy. As the dopaminergic system has not yet been systemically studied in this basal ganglia model disease, it is unclear whether nigrostriatal dysfunction contributes to parkinsonism in XDP. METHODS: Pre- and post-synaptic dopaminergic function was assessed in XDP. A total of 10 123 jod-benzamide (IBZM) single-photon emission computed tomography (SPECT) images were obtained for nine patients aged 42.3 ± 9.5 years (SD; range 30-52) and one asymptomatic mutation carrier (38 years), and four ioflupane (FP-CIT) SPECT images were obtained for four patients, aged 41.5 ± 11.6 years (range 30-52 years). Structural magnetic resonance imaging was also performed for all mutation carriers and 10 matched healthy controls. RESULTS: All patients were men who suffered from severe, disabling segmental or generalized dystonia and had varying degrees of parkinsonism. IBZM SPECT images were pathological in 8/9 symptomatic patients with distinct reduced post-synaptic tracer uptake in the caudate nucleus and putamen, and unremarkable in the asymptomatic mutation carrier. Longer disease duration was correlated with lower IBZM binding ratios. All subjects exhibited slightly reduced FP-CIT uptake values compared to controls for each analyzed region (-37% to -41%) which may be linked to basal ganglia volume loss. Visual inspection revealed physiological FP-CIT uptake in 1/4 patients. CONCLUSIONS: This nuclear imaging study provides evidence that the functional decline of post-synaptic dopaminergic neurotransmission is related to disease duration and ongoing neurodegeneration. Given the severe striatal cell loss which could be verified with post-synaptic nuclear imaging, both parkinsonism and dystonia in XDP are probably mainly due to striatal dysfunction.

Effects of dopaminergic treatment on functional cortico-cortical connectivity in Parkinson's disease.

Interactions between dorsal premotor cortex (PMd) and primary motor cortex (M1) and interhemispheric inhibition (IHI) between M1 are impaired in Parkinson's disease (PD). We used dual-site transcranial magnetic stimulation to compare effects of first-time levodopa application with chronic dopaminergic therapy on these interactions in PD. Twelve untreated PD patients were studied before and after their first-ever intake of levodopa. The effects of chronic dopaminergic medication were evaluated in 11 patients who had received regular dopaminergic medication for approximately 3 years. Nine of these patients were also measured after overnight withdrawal of medication. For IHI, conditioning stimuli (CS) were applied to left M1 followed by test stimuli (TS) over right M1 and vice versa in separate blocks at interstimulus intervals (ISI) of 6-10 ms. Next, CS were applied to left PMd at subthreshold intensity followed by TS over left M1 at ISIs of 4 and 6 ms. Results were compared to 17 age- and gender-matched controls. In de novo PD patients, levodopa reduced left-to-right IHI, but did not alter PMd-M1 connectivity. In contrast, inhibitory PMd-M1 connectivity was present in early disease patients under chronic dopaminergic stimulation, but not in de novo PD patients at low stimulus intensities at an ISI of 4 ms. First-time exposure to levodopa exerts different effects on cortico-cortical pathways than chronic dopaminergic stimulation in PD, suggesting a change in the responsiveness of cortico-cortical circuits during the course of PD.

[B symptoms in unexplained mediastinal lymphadenopathy : Case report of a 72-year-old male patient with VEXAS syndrome]. / B-Symptomatik bei unklarer mediastinaler Lymphadenopathie : Fallbericht eines 72-jährigen Patienten mit VEXAS-Syndrom.

The case of a 72-year-old male patient who presented to our centre for rare diseases with recurrent fever, night sweats and weight loss with initially confirmed mediastinal lymphadenopathy is reported. Investigation of lymph node material was unrevealing. As an additional finding, the patient had a myelodysplastic syndrome. VEXAS syndrome (vacuoles, E1 enzyme, X­linked, autoinflammatory, somatic) could be confirmed on the basis of a bone marrow biopsy and genetic testing.

Altered modulation of intracortical excitability during movement preparation in Gilles de la Tourette syndrome.

Gilles de la Tourette syndrome is a neuropsychiatric disorder in which cortical disinhibition has been proposed as a pathophysiological mechanism involved in the generation of tics. Tics are typically reduced during task performance and concentration. How this task-dependent reduction of motor symptoms is represented in the brain is not yet understood. The aim of the current research was to study motorcortical excitability at rest and during the preparation of a simple motor task. Transcranial magnetic stimulation was used to examine corticospinal excitability, short-interval intracortical inhibition and intracortical facilitation in a group of 11 patients with Gilles de la Tourette syndrome and age-matched healthy controls. Parameters of cortical excitability were evaluated at rest and at six points in time during the preparation of a simple finger movement. Patients with Gilles de la Tourette syndrome displayed significantly reduced short-interval intracortical inhibition at rest, while no differences were apparent for unconditioned motor evoked potential or intracortical facilitation. During the premovement phase, significant differences between groups were seen for single pulse motor evoked potential amplitudes and short-interval intracortical inhibition. Short-interval intracortical inhibition was reduced in the early phase of movement preparation (similar to rest) followed by a transition towards more inhibition. Subsequently modulation of short-interval intracortical inhibition was comparable to controls, while corticospinal recruitment was reduced in later phases of movement preparation. The present data support the hypothesis of motorcortical disinhibition in Gilles de la Tourette syndrome at rest. During performance of a motor task, patients start from an abnormally disinhibited level of short-interval intracortical inhibition early during movement preparation with subsequent modulation of inhibitory activity similar to healthy controls. We hypothesize that while at rest, abnormal subcortical inputs from aberrant striato-thalamic afferents target the motor cortex, during motor performance, motor cortical excitability most likely underlies top-down control from higher motor areas and prefrontal cortex, which override these abnormal subcortical inputs to guarantee adequate behavioural performance.

European clinical guidelines for Tourette syndrome and other tic disorders. Part I: assessment.

A working group of the European Society for the Study of Tourette Syndrome (ESSTS) has developed the first European assessment guidelines of Tourette Syndrome (TS). The available literature including national guidelines was thoroughly screened and extensively discussed in the expert group of ESSTS members. Detailed clinical assessment guidelines of tic disorders and their comorbidities in both children and adults are presented. Screening methods that might be helpful and necessary for specialists' differential diagnosis process are suggested in order to further analyse cognitive abilities, emotional functions and motor skills. Besides clinical interviews and physical examination, additional specific tools (questionnaires, checklists and neuropsychological tests) are recommended.

Myoclonus-dystonia: significance of large SGCE deletions.

Myoclonus-dystonia (M-D) is an autosomal-dominant movement disorder caused by mutations in SGCE. We investigated the frequency and type of SGCE mutations with emphasis on gene dosage alterations and explored the associated phenotypes. We tested 35 M-D index patients by multiplex ligation-dependent probe amplification (MLPA) and genomic sequencing. Mutations were found in 26% (9/35) of the cases, all but three with definite M-D. Two heterozygous deletions of the entire SGCE gene and flanking DNA and a heterozygous deletion of exon 2 only were detected, accounting for 33% (3/9) of the mutations found. Both large deletions contained COL1A2 and were additionally associated with joint problems. Further, we discovered one novel small deletion (c.771_772delAT, p.C258X) and four recurrent point mutations (c.289C>T, p.R97X; c.304C>T, p.R102X; c.709C>T, p.R237X; c.1114C>T, p.R372X). A Medline search identified 22 articles on SGCE mutational screening. Sixty-four unrelated M-D patients were described with 41 different mutations. No genotype-phenotype association was found, except in patients with deletions encompassing additional genes. In conclusion, a rigorous clinical preselection of patients and careful accounting for non-motor signs should precede mutational tests. Gene dosage studies should be included in routine SGCE genetic testing.

Prospective evaluation of Globus pallidus internus deep brain stimulation in Huntington's disease.

INTRODUCTION: Pharmacological treatment of chorea in Huntington's disease (HD) is often limited by poor efficacy or side effects. Pallidal deep brain stimulation (DBS) has been considered in these patients but experience is so far limited. METHODS: We prospectively evaluated the effects of bilateral DBS of the Globus pallidus internus (GPi) over one year in six severely affected HD patients with treatment refractory chorea in an advanced stage of the disease. Primary endpoint of the study was improvement in chorea. Additionally, we evaluated the effects of GPi DBS on the motor part of the Unified Huntington's Disease Rating Scale (UHDRS), bradykinesia, dystonia, functional impairment, psychiatric and cognitive symptoms. Side effects were systematically assessed. RESULTS: The chorea subscore was significantly reduced postoperatively (-47% six months, -40% twelve months postoperatively). The UHDRS total motor score was significantly reduced at six months postoperatively (- 17%) but the effect was not sustained twelve months after the operation (- 5%). Pallidal DBS did not improve other motor symptoms or functional impairment. There was no effect on psychiatric symptoms or cognition. A number of side effects were noted, especially spasticity in three of the patients. CONCLUSIONS: Pallidal DBS is a treatment option for HD patients with severe pharmacologically refractory chorea. Further studies are needed to define optimal candidates for this procedure.

The basal ganglia are hyperactive during the discrimination of tactile stimuli in writer's cramp.

Writer's cramp is a focal hand dystonia that specifically affects handwriting. Though writer's cramp has been attributed to a dysfunction of the basal ganglia, the role of the basal ganglia in the pathogenesis of writer's cramp remains to be determined. Seventeen patients with writer's cramp (nine females; age range: 24-71 years) and 17 healthy individuals (six females; age range: 27-68 years) underwent functional MRI (fMRI) while they discriminated the orientation of gratings delivered to the tip of the right index finger. Statistical parametric mapping was used to analyse the fMRI data. The significance level was set at a corrected P-value of 0.05. Relative to healthy controls, patients with writer's cramp showed a widespread bilateral increase in task-related activity in the putamen, caudate nucleus, internal globus pallidus and lateral thalamus. In these areas, hyperactivity was more pronounced in patients who had recently developed writer's cramp. The enhanced response of the basal ganglia to tactile input from the affected hand is compatible with the concept of impaired centre-surround inhibition within the basal ganglia-thalamic circuit and may lead to an excessive activation of sensorimotor cortical areas during skilled movements affected by dystonia. Outside the basal ganglia, dystonic patients showed task-related overactivity in visual cortical areas, left anterior insula and right intraparietal sulcus, but not in the primary or secondary sensory cortex. In addition, task-related activity in the cerebellar nuclei, posterior vermis, right paramedian cerebellar hemisphere and dorsal pons was inversely related with the severity of hand dystonia. Regional activity in these areas may reflect secondary adaptive reorganization at the systems level to compensate for the dysfunction in the basal ganglia-thalamic loop.

Involvement of obliquus capitis inferior muscle in dystonic head tremor.

INTRODUCTION: Head tremor is a common feature in cervical dystonia (CD) and often less responsive to botulinum neurotoxin (BoNT) treatment than dystonic posturing. Ultrasound allows accurate targeting of deeper neck muscles. METHODS: In 35 CD patients with dystonic head tremor the depth and thickness of the splenius capitis (SPL), semispinalis capitis and obliquus capitis inferior muscles (OCI) were assessed using ultrasound. Ultrasound guided EMG recordings were performed from the SPL and OCI. RESULTS: Burst-like tremor activity was present in both OCI in 25 and in one in 10 patients. In 18 patients, tremor activity was present in one SPL and in 2 in both SPL. Depth and thickness of OCI, SPL and semispinalis capitis muscles were very variable. CONCLUSION: Muscular activity underlying tremulous CD is most commonly present in OCI. Due to the variability of muscle thickness, we suggest ultrasound guided BoNT injections into OCI.

Functional connectivity of human premotor and motor cortex explored with repetitive transcranial magnetic stimulation.

Connections between the premotor cortex and the primary motor cortex are dense and are important in the visual guidance of arm movements. We have shown previously that it is possible to engage these connections in humans and to measure the net amount of inhibition/facilitation from premotor to motor cortex using single-pulse transcranial magnetic stimulation (TMS). The aim of this study was to test whether premotor activation can affect the excitability of circuits within the primary motor cortex (M1) itself. Repetitive TMS (rTMS), which is known to produce effects that outlast the train at the site of stimulation, was given for 20 min at 1 Hz over premotor, primary motor, and sensory areas of cortex at an intensity of 80% of the active motor threshold for the motor hand area. The excitability of some corticocortical connections in M1 was probed by using paired-pulse testing of intracortical inhibition (ICI) and intracortical facilitation (ICF) with a coil placed over the motor cortex hand area. rTMS over the premotor cortex, but not other areas, changed the time course of the ICI/ICF for up to 1 hr afterward without affecting motor thresholds or motor-evoked potential recruitment. The cortical silent period was also shortened. The implication is that rTMS at a site distant from the motor cortex can change the excitability of circuits intrinsic to the motor cortex.

Motor cortex excitability after thalamic infarction.

OBJECTIVE: We examined 8 patients with hemihypesthesia due to an ischemic thalamic lesion to explore the effects of a central sensory dysfunction on motor cortex excitability. METHODS: Motor excitability was assessed using transcranial magnetic stimulation techniques and electrical peripheral nerve stimulation. Motor function was evaluated by the Nine-Hole-Peg Test and measurement of hand grip strength. The affected side was compared with the non-lesioned side and with an age-matched control group. RESULTS: Patients had a loss of inhibition and an increase of facilitation in the motor cortex of the affected side. The silent period was prolonged and motor function was impaired on the affected side. CONCLUSIONS: A thalamic lesion can modulate motor cortical excitability. SIGNIFICANCE: This study suggests that, under normal conditions, somatosensory afferents influence inhibitory and excitatory properties in the motor cortex.

Subthreshold rTMS over pre-motor cortex has no effect on tics in patients with Gilles de la Tourette syndrome.

OBJECTIVE: A previous study showed no effect of 1Hz repetitive transcranial magnetic stimulation (rTMS) on tics in Gilles de la Tourette Syndrome (GTS). We modified the rTMS protocol in order to investigate some of the possible methodological reasons for the negative outcome in that study. METHODS: In a single blinded placebo-controlled cross-over study in five GTS patients without obsessive compulsive disorder we probed whether longer trains (1800 stimuli) of 1 Hz pre-motor cortex rTMS at 80% of active motor threshold and application to both hemispheres can improve tics in GTS. This was measured with the Yale Global Tic severity rating scale, the MOVES self-rating scale and video analysis. RESULTS: We found no significant effect of either left pre-motor cortex stimulation alone, or left pre-motor followed by right pre-motor cortex stimulation. CONCLUSIONS: These results suggest that the rTMS protocol used in this study is not useful for the treatment of tics in GTS. SIGNIFICANCE: rTMS protocols need to be modified substantially in order to explore their potential for the treatment of tics in GTS.

Abnormal excitability of premotor-motor connections in de novo Parkinson's disease.

The dorsal premotor cortex (PMd) is abnormally active in patients with idiopathic Parkinson's disease. This has been interpreted as a functional correlate of adaptive plasticity within the motor system to compensate for deficient activation of striato-mesial-frontal projections in these patients. Whether abnormal PMd activity influences excitability in the primary motor cortex (M1) in untreated Parkinson's disease patients and how this premotor-motor interaction might be altered by l-dopa is unclear. To this end, we studied the effects of 1 Hz premotor repetitive transcranial magnetic stimulation (rTMS) on M1 excitability in 10 previously untreated non-tremulous Parkinson's disease patients before (day 1) and after (day 8) their first ever l-dopa treatment and compared the results with those of a group of nine age- and sex-matched healthy controls. In each rTMS session, 1200 pulses of 1 Hz rTMS were applied at an intensity of 80% active motor threshold (AMT) to the PMd contralateral to the clinically more affected side in Parkinson's disease patients and to the left PMd in healthy controls. Intracortical paired pulse excitability of ipsilateral M1 was probed using a TMS paired pulse paradigm where subthreshold conditioning pulses (80% of AMT) were given 2-15 ms prior to a suprathreshold test pulse. In Parkinson's disease patients, abnormal baseline intracortical excitability at an interstimulus interval (ISI) of 5 ms was normalized by premotor rTMS. In contrast, rTMS led to an increased excitability at an ISI of 5 ms in healthy controls. Premotor rTMS effects lasted longer (for at least a week) in patients. These results show that the modifiability of premotor-motor connections is abnormal in untreated Parkinson's disease. A single dose of l-dopa reversed, i.e. normalized, the direction of excitability changes in M1 following premotor rTMS in Parkinson's disease patients, suggesting that dopamine depletion directly or indirectly influences premotor-motor interactions in Parkinson's disease. The rTMS conditioning approach described here provides a promising tool to delineate further the excitability changes in frontal motor areas in response to progressive degeneration of nigrostriatal dopaminergic neurons and also to chronic l-dopa treatment in Parkinson's disease.

Normalization of sensorimotor integration by repetitive transcranial magnetic stimulation in cervical dystonia.

Previous studies indicated that sensorimotor integration and plasticity of the sensorimotor system are impaired in dystonia patients. We investigated motor evoked potential amplitudes and short latency afferent inhibition to examine corticospinal excitability and cortical sensorimotor integration, before and after inhibitory 1 Hz repetitive transcranial magnetic stimulation over primary sensory and primary motor cortex in patients with cervical dystonia (n = 12). Motor evoked potentials were recorded from the right first dorsal interosseous muscle after application of unconditioned transcranial magnetic test stimuli and after previous conditioning electrical stimulation of the right index finger at short interstimulus intervals of 25, 30 and 40 ms. Results were compared to a group of healthy age-matched controls. At baseline, motor evoked potential amplitudes did not differ between groups. Short latency afferent inhibition was reduced in cervical dystonia patients compared to healthy controls. Inhibitory 1 Hz sensory cortex repetitive transcranial magnetic stimulation but not motor cortex repetitive transcranial magnetic stimulation increased motor evoked potential amplitudes in cervical dystonia patients. Additionally, both 1 Hz repetitive transcranial magnetic stimulation over primary sensory and primary motor cortex normalized short latency afferent inhibition in these patients. In healthy subjects, sensory repetitive transcranial magnetic stimulation had no influence on motor evoked potential amplitudes and short latency afferent inhibition. Plasticity of sensorimotor circuits is altered in cervical dystonia patients.

Visual feedback of own tics increases tic frequency in patients with Tourette's syndrome.

Gilles de la Tourette syndrome (GTS) is characterized by motor and phonic tics. It is unknown how paying attention to one's own tics might modulate tic frequency. We determined tic frequency in freely ticcing GTS patients while they were being filmed. In Study 1, we investigated 12 patients (1) alone in a room (baseline); (2) alone in front of a mirror. In Study 2, we replicated these conditions in 16 patients and additionally examined how watching a video, in which the individual was shown not ticcing, affected their tic frequency. In both studies, tic frequency was significantly higher when patients watched themselves in a mirror compared to baseline. In contrast, tic frequency was significantly reduced in the video condition. Paying attention to one's own tics increases tic frequency when tics are not suppressed and appears to be specific for attention to tics, rather than attention to the self.

Biochemical mechanisms of pallidal deep brain stimulation in X-linked dystonia parkinsonism.

OBJECTIVE: Invasive techniques such as in-vivo microdialysis provide the opportunity to directly assess neurotransmitter levels in subcortical brain areas. METHODS: Five male Filipino patients (mean age 42.4, range 34-52 years) with severe X-linked dystonia-parkinsonism underwent bilateral implantation of deep brain leads into the internal part of the globus pallidus (GPi). Intraoperative microdialysis and measurement of gamma aminobutyric acid and glutamate was performed in the GPi in three patients and globus pallidus externus (GPe) in two patients at baseline for 25/30 min and during 25/30 min of high-frequency GPi stimulation. RESULTS: While the gamma-aminobutyric acid concentration increased in the GPi during high frequency stimulation (231 ± 102% in comparison to baseline values), a decrease was observed in the GPe (22 ± 10%). Extracellular glutamate levels largely remained unchanged. CONCLUSIONS: Pallidal microdialysis is a promising intraoperative monitoring tool to better understand pathophysiological implications in movement disorders and therapeutic mechanisms of high frequency stimulation. The increased inhibitory tone of GPi neurons and the subsequent thalamic inhibition could be one of the key mechanisms of GPi deep brain stimulation in dystonia. Such a mechanism may explain how competing (dystonic) movements can be suppressed in GPi/thalamic circuits in favour of desired motor programs.

Repetitive transcranial magnetic stimulation for Tourette syndrome.

In a single-blinded, placebo-controlled, crossover repetitive transcranial magnetic stimulation (rTMS) trial, 16 patients with Gilles de la Tourette syndrome (GTS) received in random sequence 1 Hz motor, premotor, and sham rTMS, which each consisted of two 20-minute rTMS sessions applied on 2 consecutive days. In the 12 patients who completed the trial, there was no significant improvement of symptoms after any of the rTMS conditions as assessed with the Motor tic, Obsessions and compulsions, Vocal tic Evaluation Survey.

Computed tomography characterization of renal cell tumors in correlation with histopathology.

RATIONALE AND OBJECTIVES: The authors distinguish the histomorphologic subtypes of renal cell tumors (RCTs) by computed tomography (CT). METHODS: In a consensus conference between radiologists, pathologists, and urologists, the CT criteria of the various subtypes of RCTs (clear cell, chromophilic cell, chromophobic cell renal carcinoma and oncocytoma) were established. Computed tomography scans of 65 resected RCTs were reevaluated independently by seven radiologists. Using a numerical scoring system, they first attempted to differentiate clear cell from nonclear cell RCTs. A further attempt then was made to classify each tumor into one of the four categories. RESULTS: The sensitivity for the diagnosis of clear cell RCT was 72.5% (213 of 294 true-positive findings) and 82% (132 of 161 true-positive findings) for the nonclear cell group. For tumors more than 3 cm in diameter the sensitivities were 80.25% for the clear cell group and 80.7% for the nonclear cell group. Specific differentiation into the four subtypes was not possible. Oncocytomas were classified correctly in only 6 of 49 observations (12.2%). CONCLUSIONS: Small clear cell tumors often fail to show the CT characteristics that would permit an accurate classification. In tumors measuring 3 cm or more, differentiation between clear cell and nonclear cell types by means of CT criteria is possible. Nevertheless, as RCTs show a great variation in appearance, a differentiation into subtypes of the nonclear cell RCTs cannot be accomplished by CT. Using a uniform examination protocol and spiral scanning technique, the sensitivity of CT in the diagnosis of the subtypes of RCTs may be able to be further increased. Some tumors, especially oncocytomas, undoubtedly will remain diagnostic dilemmas.