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Background Early diagnosis is of substantial benefit for patients with Pompe disease. Yet underdiagnosing and substantial diagnostic delay are still frequent and the determinants of this are unknown. This study is the first to systematically investigate the diagnostic odyssey in Pompe disease from patients', parents', and physicians' perspectives. Methods Patients with infantile or late onset Pompe disease, their parents as well as their metabolic experts were invited to fill in respective surveys. The survey addressed perceived disease symptoms at onset and during the course of the disease, specialties of involved physicians, activities of patient-initiated search for diagnosis and the perceived impact of time to diagnosis on outcome. Results of experts' and patients'/parents' surveys were compared and expressed by descriptive statistics. Results and Discussion We collected data on 15 males and 17 females including 9 infantile and 23 late onset Pompe patients. All received the correct diagnosis at a metabolic or musculoskeletal expert center. Patients with direct referral to the expert center had the lowest diagnostic delay, while patients who were seen by several physicians, received the correct diagnosis after 44%-200% longer delay. The proportion of direct referral varied strongly between pediatricians (57%) and other disciplines (18%-36%). Conclusion Our study highlights a substantially larger diagnostic delay in Pompe patients that are not directly referred to expert centers for diagnostic work. Our findings may be used to develop more successful strategies for early diagnosis. Synopsis Diagnostic delay in Pompe disease is substantial particularly in patients that are not directly referred to expert centers for diagnostic workup, so facilitating direct referral may be a new strategy for early diagnosis.

HYPOTHESIS A multielectrode probe in combination with an optimized stimulation protocol could provide sufficient sensitivity and specificity to act as an effective safety mechanism for preservation of the facial nerve in case of an unsafe drill distance during image-guided cochlear implantation. BACKGROUND A minimally invasive cochlear implantation is enabled by image-guided and robotic-assisted drilling of an access tunnel to the middle ear cavity. The approach requires the drill to pass at distances below 1 mm from the facial nerve and thus safety mechanisms for protecting this critical structure are required. Neuromonitoring is currently used to determine facial nerve proximity in mastoidectomy but lacks sensitivity and specificity necessaries to effectively distinguish the close distance ranges experienced in the minimally invasive approach, possibly because of current shunting of uninsulated stimulating drilling tools in the drill tunnel and because of nonoptimized stimulation parameters. To this end, we propose an advanced neuromonitoring approach using varying levels of stimulation parameters together with an integrated bipolar and monopolar stimulating probe. MATERIALS AND METHODS An in vivo study (sheep model) was conducted in which measurements at specifically planned and navigated lateral distances from the facial nerve were performed to determine if specific sets of stimulation parameters in combination with the proposed neuromonitoring system could reliably detect an imminent collision with the facial nerve. For the accurate positioning of the neuromonitoring probe, a dedicated robotic system for image-guided cochlear implantation was used and drilling accuracy was corrected on postoperative microcomputed tomographic images. RESULTS From 29 trajectories analyzed in five different subjects, a correlation between stimulus threshold and drill-to-facial nerve distance was found in trajectories colliding with the facial nerve (distance 95%) at distances to the facial nerve below 0.5 mm. However, reduction in stimulus threshold to 0.3 mA or lower resulted in a decrease of facial nerve distance detection range below 0.1 mm (>95% sensitivity). Subsequent histopathology follow-up of three representative cases where the neuromonitoring system could reliably detect a collision with the facial nerve (distance

Objective : To quantify temperature induced changes (=Uhthoff phenomenon) in central motor conduction and their relation to clinical motor deficits in 20 multiple sclerosis (MS) patients. Methods : Self-assessment of vulnerability to temperature and clinical examination were performed. We used motor evoked potentials to measure central motor conduction time (CMCT) and applied the triple stimulation technique (TST) to assess conduction failure. The TST allows an accurate quantification of the proportion of conducting central motor neurons, expressed by the TST amplitude ratio (TST-AR). Results : Temperature induced changes of TST-AR were significantly more marked in patients with prolonged CMCT ( P =0.037). There was a significant linear correlation between changes of TST-AR and walking velocity ( P =0.0002). Relationships were found between pronounced subjective vulnerability to temperature and (i) abnormal CMCT ( P =0.02), (ii) temperature induced changes in TST-AR ( P =0.04) and (iii) temperature induced changes in walking velocity ( P =0.04). CMCT remained virtually unchanged by temperature modification. Conclusions : Uhthoff phenomena in the motor system are due to varying degrees of conduction block and associated with prolonged CMCT. In contrast to conduction block, CMCT is not importantly affected by temperature. Significance : This is the first study quantifying the Uhthoff phenomenon in the pyramidal tract of MS patients. The results suggest that patients with central conduction slowing are particularly vulnerable to develop temperature-dependent central motor conduction blocks.

Glycogen storage disease type II is a rare multi-systemic disorder characterised by an intracellular accumulation of glycogen due a mutation in the acid alpha glucosidase (GAA) gene. The level of residual enzyme activity, the genotype and other yet unknown factors account for the broad variation of the clinical phenotype. The classical infantile form is characterised by severe muscle hypotonia and cardiomyopathy leading to early death. The late-onset form presents as a limb girdle myopathy with or without pulmonary dysfunction. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) in infants is life saving. In contrast, therapeutic efficacy of rhGAA in the late-onset form is modest. High expenses of rhGAA, on-going infusions and poor pharmacokinetic efficacy raised a discussion of the cost effectiveness of ERT in late-onset Pompe disease in Switzerland. This discussion was triggered by a Swiss federal court ruling which confirmed the reluctance of a health care insurer not to reimburse treatment costs in a 67-year-old female suffering from Pompe disease. As a consequence of this judgement ERT was stopped by all insurance companies in late-onset Pompe patients in Switzerland regardless of their clinical condition. Subsequent negotiations lead to the release of a national guideline of the management of late-onset Pompe disease. Initiation and limitation of ERT is outlined in a national Pompe registry. Reimbursement criteria are defined and individual efficacy of ERT with rhGAA is continuously monitored.

Transcranial magnetic stimulation allows to study the properties of the human corticospinal tract non-invasively. After a single transcranial magnetic stimulus, spinal motor neurons (MNs) sometimes fire not just once, but repetitively. The biological significance of such repetitive MN discharges (repMNDs) is unknown. To study the relation of repMNDs to other measures of cortico-muscular excitability and to physiological measures of the skill for finely tuned precision movements, we used a previously described quadruple stimulation (QuadS) technique (Z'Graggen et al. 2005) to quantify the amount of repMNDs in abductor digiti minimi muscles (ADMs) on both sides of 20 right-handed healthy subjects. Skillfulness for finger precision movements of both hands was assessed using a finger tapping task. In 16 subjects, a follow-up examination was performed after training of either precision movements (n = 8) or force (n = 8) of the left ADM. The size of the QuadS response (amplitude and area ratios) was greater in the dominant right hand than in the left hand (QuadS amplitude ratio: 47.1 +/- 18.1 versus 37.7 +/- 22.0%, Wilcoxon test: P0.05; QuadS area ratio: 49.7 +/- 16.2% versus 36.9 +/- 23.0%, Wilcoxon test: P0.05), pointing to a greater amount of repMNDs. Moreover, the QuadS amplitude and area increased significantly after finger precision training, but not after force training. This increase of repMNDs correlated significantly with the increase in performance in the finger tapping task. Our results demonstrate that repMNDs are related to handedness and therefore probably reflect supraspinal excitability differences. The increase of repMNDs after skills training but not after force training supports the hypothesis of a supraspinal origin of repMNDs.

The review focuses on the clinical diagnostic utility of transcranial magnetic stimulation (TMS). The central motor conduction time (CMCT) is a sensitive method to detect myelopathy and abnormalities may be detected in the absence of radiological changes. CMCT may also detect upper motor neuron involvement in amyotrophic lateral sclerosis. The diagnostic sensitivity may be increased by using the triple stimulation technique (TST), by combining several parameters such as CMCT, motor threshold and silent period, or by studying multiple muscles. In peripheral facial nerve palsies, TMS may be used to localize the site of nerve dysfunction and clarify the etiology. TMS measures also have high sensitivity in detecting lesions in multiple sclerosis and abnormalities in CMCT or TST may correlate with motor impairment and disability. Cerebellar stimulation may detect lesions in the cerebellum or the cerebellar output pathway. TMS may detect upper motor neuron involvement in patients with atypical parkinsonism and equivocal signs. The ipsilateral silent period that measures transcallosal inhibition is a potential method to distinguish between different parkinsonian syndromes. Short latency afferent inhibition (SAI), which is related to central cholinergic transmission, is reduced in Alzheimer's disease. Changes in SAI following administration of cholinesterase inhibitor may be related to the long-term efficacy of this treatment. The results of MEP measurement in the first week after stroke correlate with functional outcome. We conclude that TMS measures have demonstrated diagnostic utility in myelopathy, amyotrophic lateral sclerosis and multiple sclerosis. TMS measures have potential clinical utility in cerebellar disease, dementia, facial nerve disorders, movement disorders, stroke, epilepsy, migraine and chronic pain.

Three different stimulating coil designs were evaluated for magnetic motor cortex stimulation by comparing threshold stimulus intensities at different sites over the scalp for exciting upper and lower limb muscles. Little difference was found between stimulation characteristics of two circular coils of different size, the smaller coil delivering slightly more focal stimuli. A twin coil composed of two single circular coils in series arranged side-by-side, produced significantly more powerful and more focal stimuli. It proved to be superior for exciting the leg muscles, in that less output energy was needed. For all coils, the orientation of the inducing current over the presumed motor area was the most critical stimulation parameter, and a sagittal current in anterior direction or coronal towards the stimulated hemisphere was optimal for the upper limb or lower limb muscles, respectively.

During robotic cochlear implantation a drill trajectory often passes at submillimeter distances from the facial nerve due to close lying critical anatomy of the temporal bone. Additional intraoperative safety mechanisms are thus required to ensure preservation of this vital structure in case of unexpected navigation system error. Electromyography based nerve monitoring is widely used to aid surgeons in localizing vital nerve structures at risk of injury during surgery. However, state of the art neuromonitoring systems, are unable to discriminate facial nerve proximity within submillimeter ranges. Previous work demonstrated the feasibility of utilizing combinations of monopolar and bipolar stimulation threshold measurements to discretize facial nerve proximity with greater sensitivity and specificity, enabling discrimination between safe (>0.4 mm) and unsafe (0.4 mm) to the facial nerve in all cases.