Differentiation of progressive supranuclear palsy: clinical, imaging and laboratory tools.

Progressive supranuclear palsy (PSP) is the most common atypical parkinsonian syndrome comprising two main clinical subtypes: Richardson's syndrome (RS), characterized by prominent postural instability, supranuclear vertical gaze palsy and frontal dysfunction; and PSP-parkinsonism (PSP-P) which is characterized by an asymmetric onset, tremor and moderate initial therapeutic response to levodopa. The early clinical features of PSP-P are often difficult to discern from idiopathic Parkinson's disease (PD), and other atypical parkinsonian disorders, including multiple system atrophy (MSA) and corticobasal syndrome (CBS). In addition, rare PSP subtypes may be overlooked or misdiagnosed if there are atypical features present. The differentiation between atypical parkinsonian disorders and PD is important because the prognoses are different, and there are different responses to therapy. Structural and functional imaging, although currently of limited diagnostic value for individual use in early disease, may contribute valuable information in the differential diagnosis of PSP. A growing body of evidence shows the importance of CSF biomarkers in distinguishing between atypical parkinsonian disorders particularly early in their course when disease-modifying therapies are becoming available. However, specific diagnostic CSF biomarkers have yet to be identified. In the absence of reliable disease-specific markers, we provide an update of the recent literature on the assessment of clinical symptoms, pathology, neuroimaging and biofluid markers that might help to distinguish between these overlapping conditions early in the course of the disease.

ALS and FTLD: two faces of TDP-43 proteinopathy.

Major discoveries have been made in the recent past in the genetics, biochemistry and neuropathology of frontotemporal lobar degeneration (FTLD). TAR DNA-binding protein 43 (TDP-43), encoded by the TARDBP gene, has been identified as the major pathological protein of FTLD with ubiquitin-immunoreactive (ub-ir) inclusions (FTLD-U) with or without amyotrophic lateral sclerosis (ALS) and sporadic ALS. Recently, mutations in the TARDBP gene in familial and sporadic ALS have been reported which demonstrate that abnormal TDP-43 alone is sufficient to cause neurodegeneration. Several familial cases of FTLD-U, however, are now known to have mutations in the progranulin (GRN) gene, but granulin is not a component of the TDP-43- and ub-ir inclusions. Further, TDP-43 is found to be a component of the inclusions of an increasing number of neurodegenerative diseases. Other FTLD-U entities with TDP-43 proteinopathy include: FTLD-U with valosin-containing protein (VCP) gene mutation and FTLD with ALS linked to chromosome 9p. In contrast, chromosome 3-linked dementia, FTLD-U with chromatin modifying protein 2B (CHMP2B) mutation, has ub-ir, TDP-43-negative inclusions. In summary, recent discoveries have generated new insights into the pathogenesis of a spectrum of disorders called TDP-43 proteinopathies including: FTLD-U, FTLD-U with ALS, ALS, and a broadening spectrum of other disorders. It is anticipated that these discoveries and a revised nosology of FTLD will contribute toward an accurate diagnosis, and facilitate the development of new diagnostic tests and therapeutics.

Functional organisation of the facial motor system in man.

To investigate human corticobulbar projections, electromyographic responses from orbicularis oculi and orbicularis oris muscles were recorded in 11 healthy subjects after transcranial magnetic stimulation. Selective activation of lower facial motoneurones of one hemisphere was reached with the round coil 4 cm lateral to the vertex on a line to the external auditory meatus with stimulus intensities from 45 to 55% (100% = 1.5 T). The mean latency of the OR muscle was 11.5 +/- 1.77 ms contralaterally. Ipsilateral cortical responses were observed in 5 subjects (45%) at a mean latency of 13.88 +/- 2.17 ms. Corticobulbar innervation may have affected bilateral responses in the lower facial muscles as those persisted even after lidocaine blockade of both supraorbital nerves. The functional importance of ipsilateral projections to the lower facial muscles in man is lower than that of the contralateral projections, as evidenced by the fact that they cannot be observed in all subjects or in all motor units. The influence of the trigeminal sensory afferents was excluded from the study after blockade of both supraorbital nerves.

Event-related potentials in medical workers with long-term exposure to xylene.

The effects of chronic exposure to xylene on cognitive ability were studied in a group of 35 medical workers occupationally exposed to low-level concentrations of xylene for at least five years by using event-related potentials (ERPs), and compared with a control group of 21 subjects. The exposure to xylene was confirmed through determination of m-methylhippuric acid, a reliable biological indicator of xylene exposure, in pre- and post-shift urine. A dose-effect relationship between log m-methylhippuric acid and ERP log latency (p = 0.032), and the ERP amplitude (p = 0.047) was statistically significant. The group of medical workers showed significantly longer ERP log latency (p < 0.001) than did the control group with respect to factors of exposure to smoking, education and age as covariates. For the ERP amplitude the difference was found not to be significant (p = 0.263), probably due to high between subject variability. The cognitive impairment may occur in workers chronically exposed to xylene.

Creutzfeldt-Jakob disease in a patient with a lyophilized dura mater graft.

A 37-year-old patient with Creutzfeldt-Jakob disease (CJD) is presented, who had received a cadaveric dura matter graft 12 year before the onset of neurologic symptoms. Initial clinical presentation included cerebellar symptoms, with dementia and myoclonus developing in later stages of the disease. EEG showed diffuse slowing with sporadic triphasic periodic activity. CT was normal in the early stage but pronounced cerebral and cerebellar atrophy with widened sulci were seen on MRI in the late stage of the disease. The prion protein (PrP) gene was homozygous for valin at the polymorphic codon 129. Cerebrospinal fluid analysis for 14-3-3 protein was positive. We believe that this patient is the first Croatian to acquire CJD by dural implant. Based on this case and a review of 66 cases from the literature, it is manifest that the awareness of iatrogenic transmission of CJD and adoption of preventive measures are the only effective way to stop the spread of CJD among surgically treated patients.

A custom designed system to measure corticospinal tract jitter.

Typical latency of an individual limb muscle response to magnetic or electric stimulation of the human cortex is in the range of 10-50 ms. For the latency variability, i.e., jitter studies, a resolution of at least 20 micros is needed. Commercially available EMG equipment needs custom-designed upgrading to allow for such studies. Two solutions were designed: (i) a hardware unit allowing an adjustable delay of data acquisition after the delivered stimuli; and (ii) diverting of the amplified biological signal and the EMG equipment trigger to an external computer equipped with an analogue-to-digital conversion (ADC) module. Custom-designed software made fast ADC possible during the whole period of data acquisition. Both concepts were applied to a Vickers Medical Mystro electromyograph, and have been successfully used in the Ljubljana (Slovenia) Institute of Clinical Neurophysiology for the last 2 years.

Evidence of direct connection of corticobulbar fibers to orofacial muscles in man: electromyographic study of individual motor unit responses.

We studied corticobulbar influence on the orbicularis oris (OR) muscles by anodal and magnetic transcranial stimulation and compared it to the corticospinal influence on first dorsal interosseous muscles of healthy human volunteers. We recorded single motor unit (MU) responses and applied peristimulus time histogram (PSTH) technique to determine their properties. Peaks in the PSTHs are assumed to coincide with multiple excitatory postsynaptic potentials (EPSPs) induced at the motoneurons by corticospinal input. We found relatively small latency variation of consecutive single MU responses for both muscles. Additionally, we found a narrow initial peak in five OR MUs after anodal stimulation. This short duration indicates the presence of monosynaptic cortical projection in the lower facial motoneurons. The EPSP amplitudes, estimated on the basis of initial peak, were used as a measure of the synaptic transmission efficiency. Our results support the concept of predominantly monosynaptic transmission at the spinal level.

Intramedullar stimulation of the facial and hypoglossal nerves: estimation of the stimulated site.

AIM: To determine the stimulation site of both facial and hypoglossal nerves after transcranial magnetic stimulation. METHODS: After surgical exposure of the brainstem in 22 patients with intrinsic pontine (n=9) or medullary (n=13) tumors, the facial colliculus and the hypoglossal triangle were electrically stimulated. The EMG responses were recorded with flexible wire electrodes from the orbicularis oculi/orbicularis oris muscles, and genioglossal muscles. Patients had no preoperative deficit of the nerves. RESULTS: The EMG mean latencies of the unaffected facial nerve were 5.2+/-0.6 ms for the orbicularis oculi, and 5.2+/-0.5 ms for the orbicularis oris muscle. After the stimulation of 18 possibly affected facial nerves, the EMG mean latencies were 5.3+/-0.3 ms for the orbicularis oculi (p=0.539, unpaired Student's t-test), and 5.4+/-0.2 ms for the orbicularis oris (p=0.122). The EMG mean latency of the unaffected hypoglossal nerve was 4.1+/-0.6 ms for the genioglossal muscle. After the stimulation of 26 possibly affected hypoglossal nerves, the EMG mean latency for the genioglossal muscle was 5.3+/-0.3 ms. There was a significant difference (p<0.001) in latency for genioglossal EMG responses between the patients with pontine and those with medullary tumors. CONCLUSION: Shorter EMG mean latencies of unaffected facial nerves obtained after direct stimulation of the facial colliculi confirm that magnetic stimulation is most likely to occur closer to the nerve's exit from the brainstem than to its entrance into the internal auditory meatus. The hypoglossal nerve seems to have the site of excitation at the axon hillock of the hypoglossal motor neurons.