Neurophysiological evaluation of motor corticospinal pathways by TMS in idiopathic early-onset Parkinson's disease.

OBJECTIVE: In a previous study we found altered motor corticospinal conduction in patients with early-onset Parkinson's disease (EOPD) and parkin gene mutations (PARK2). Aim of the present study was to evaluate central motor conduction in patients with EOPD, negative for parkin mutations to establish if prolonged CMCT is specific of PARK2 or it may be present in other EOPD patients. METHODS: Eleven patients with non-PARK2 EOPD underwent transcranial magnetic stimulation (TMS) to evaluate central motor conduction time (CMCT). Motor threshold (MT), motor evoked potential (MEP) amplitude, central silent period threshold (cSPT), and duration were also determined. RESULTS: All patients but one showed normal CMCT. CMCT and the other electrophysiological data did not differ significantly between patients and healthy controls, except for cSPT mean value which was higher in patients than in controls (p=0.008). No significant correlation was found between electrophysiological and clinical data in EOPD patients. CMCT was significantly prolonged in six PARK2 patients compared to non-PARK2 patients. CONCLUSIONS: We conclude that CMCT is usually normal in idiopathic EOPD: we suggest that in presence of a prolonged CMCT the diagnosis of PARK2 should be considered. SIGNIFICANCE: CMCT may represent a simple electrophysiological test that could be utilized in an early phase of diagnosis to differentiate PARK2 patients from those with idiopathic EOPD.

Motor cortex cholinergic dysfunction in CADASIL: a transcranial magnetic demonstration.

OBJECTIVE: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a hereditary small vessel disease responsible for an early onset cognitive impairment. Aim of our study was to test the cortical cholinergic innervation in CADASIL by short latency afferent inhibition (SAI) technique. METHODS: We applied SAI in ten CADASIL patients and in ten age-matched normal controls. SAI is a phenomenon observed on motor evoked potential when transcranial magnetic stimulation is delivered after a time ranging from 2 to 8 ms longer than the time needed by the peripheral nerve afferent input to reach the somatosensory cortex. RESULTS: The amount of short latency afferent inhibition was significantly smaller in CADASIL patients than in controls (79.5+/-21.7% Vs 42.7+/-14.1% of test size; p<0.001, two tailed Mann-Whitney test). The mean resting motor threshold (RMT) was significantly lower in CADASIL patients than in controls (49.4+/-14.4% Vs 65.6+/-15.4%; p=0.02). CONCLUSIONS: We demonstrated by SAI technique a central cholinergic impairment in CADASIL. SIGNIFICANCE: SAI could be used to evaluate the cholinergic dysfunction and potentially the efficacy of cholinomimetic therapy in CADASIL.

Small-fiber involvement in spinobulbar muscular atrophy (Kennedy's disease).

We assessed the involvement of cutaneous innervation in two subjects with a molecularly confirmed diagnosis of spinobulbar muscular atrophy (SBMA) using antidromic nerve conduction studies, quantitative sensory testing, and sweat tests, as well as immunohistochemical techniques and confocal microscopy of glabrous and hairy skin biopsy. Both patients showed a marked reduction in amplitude of sensory action potentials and moderate or severe abnormalities of tactile thresholds and mechanical pain perception. A severe reduction of sweat drops on the Silastic imprint test and a widespread loss of small myelinated and unmyelinated fibers in hairy skin were also observed. Fiber loss involved either somatic or autonomic fibers and did not show any distal-proximal gradient. These results, together with loss of Meissner corpuscles and their large myelinated afferent fibers in glabrous skin, confirmed the extensive involvement of sensory neurons of large and small size and revealed an autonomic skin denervation in SBMA.

Ross syndrome: a rare or a misknown disorder of thermoregulation? A skin innervation study on 12 subjects.

Ross syndrome is described as a rare disorder of sweating associated with areflexia and tonic pupil. Since Ross's first description in 1958, approximately 40 cases have been described. We assessed the involvement of cutaneous innervation in 12 subjects with Ross syndrome using quantitative sensory testing, sweating assessment and immunohistochemical study of anhidrotic and hyperhidrotic skin. This evaluation was repeated over time in 4 out of 12 subjects. In addition, we enrolled four subjects with Holmes-Adie syndrome (areflexia and tonic pupil) to investigate similarities between the two conditions. We found in Ross patients a complex and progressive involvement of cutaneous sensory and autonomic innervation underlying the impairment of heat production and heat dissipation through both loss of sweating and loss of cutaneous blood flow regulation. In Holmes-Adie subjects we found a mild impairment of sweating without thermoregulatory problems. The persistence of a sudomotor vasoactive intestinal peptide-immunoreactive (VIP-ir) innervation, although deranged and poor, definitely differentiated Holmes-Adie from Ross patients. Ross syndrome is a progressive and complex disorder of thermoregulation difficult to differentiate from the probably pathogenetically related Holmes-Adie syndrome. Sweating assessment and skin biopsy are suitable tools to define a boundary between them. Owing to the large number of Ross patients observed in only 5 years, and to the long and complex medical history of most of them, doubts arise on the effective rarity of this condition, and we warn family doctors and other specialists, besides neurologists, to become aware of this complex disorder.

Neurophysiological evidence of corticospinal tract abnormality in patients with Parkin mutations.

Mutations in the parkin gene (PARK2) are the most frequent cause of autosomal recessive early-onset Parkinson disease. We performed a transcranial magnetic stimulation study in four patients with parkin mutations. Two patients had a prolonged central motor conduction time at both upper and lower limb, one only at the arm and one only at the leg. The MEP threshold was increased in one patient for the arm and in two for the leg. The MEP amplitude was reduced in one and central silent period shortened in two. The findings demonstrate corticospinal dysfunction in these patients and suggest that the extent of central nervous system involvement in parkin disease may be wider that hitherto supposed.

Levetiracetam in patients with cortical myoclonus: a clinical and electrophysiological study.

Levetiracetam is a new antiepileptic agent that exerts antimyoclonic effects. We conducted an open-label trial to evaluate the effect of levetiracetam in chronic cortical myoclonus of diverse etiologies and to determine whether levetiracetam affects electrophysiological findings. Sixteen patients, aged between 19 and 72 years, with refractory, chronic, cortical myoclonus were recruited. We assessed myoclonus severity with the Unified Myoclonus Rating Scale (UMRS). The electrophysiological study comprised jerk-locked averaging, somatosensory evoked potentials (SEPs), and long loop reflex I. Levetiracetam was administered add-on at a starting dose of 500 mg twice per day up to the target dose of 50 mg/kg/day. Patients were reevaluated clinically and electrophysiologically 2 weeks after the titration phase. Fourteen patients completed the trial. Posttreatment UMRS scores showed an improvement of myoclonus in all cases. Pretreatment, 9 patients had "giant" SEPs. Posttreatment, the amplitude of these SEPs was reduced by more than 50% in 3 of 9 patients, and the mean N20-P25 amplitude was reduced significantly. Pre- and posttreatment SEP amplitude was not related to myoclonus severity or duration. Levetiracetam is a promising and a relatively easy-to-test antimyoclonic agent, which has the potential to improve significantly the patient's disability; however, its long-term efficacy should be verified in larger controlled studies.

Trigeminal stimulation elicits a peripheral vestibular imbalance in migraine patients.

OBJECTIVE: The study explored the hypothesis that spontaneous nystagmus (Ny) in migraine patients can be triggered or modulated by painful trigeminal stimulation, providing evidence of a functional connection between vestibular and trigeminal systems. BACKGROUND: Vertigo attacks are reported by subjects with migraine or a familiar history of migraine, also independently of headache episodes. Idiopathic vertigo is three times more frequent in migraine patients than in controls. Vestibular investigations in migraine patients have consistently demonstrated spontaneous Ny both of central and peripheral origin. DESIGN: In the first phase of the study 10 outpatients experiencing migraine without aura (MO) and 10 healthy volunteers were submitted to the registration of spontaneous primary-position Ny in the dark by Ulmer's video-ocular-nystagmographic equipment. Two electrodes for electrical stimulation were applied on the supraorbital point of one side of the head and the intensity of stimulation corresponding to pain threshold was calculated. Spontaneous ocular movements were recorded for 5 minutes at baseline and after a sequence of five electric pulses (square waves of .5 Hz frequency and 50 micros duration, at pain threshold intensity). Nystagmographic responses were expressed as latency after stimulation, direction of the quick phase, and duration. The second phase of the study explored, with the same procedure, the effects on Ny of supraorbital versus median nerve stimulation in other 10 MO patients. Responses to stimulation were considered the appearance of de novo Ny after stimulation in subjects without baseline Ny, or the change of the frequency (at last a 50% variation) or of the direction of Ny after stimulation in subjects with baseline Ny. The latency and the duration of responses to stimulation were also calculated. RESULTS: In the first series supraorbital painful electric stimulation was able to modify or to evoke Ny in 8 of 10 migraineurs and in none of 10 volunteers (Fisher's exact test, P<.01). Both the baseline and the induced Ny were second degree, stationary persistent, with a linear slow phase and were suppressed by visual fixation. In the second series, supraorbital nerve stimulation was able to induce or modify Ny in all of 10 patients but only in 1 patient Ny was induced by median nerve stimulation. Characters of Ny were the same as previously described. Statistical comparison of the responses at the two sites of stimulation was significant (Fisher's exact test, P<.01). In those 7 patients who presented de novo Ny after stimulation it was possible to calculate Ny latency and duration. The mean latency was 25 s (SD: 16, range: 14 to 60). The mean duration was 120 s (SD: 94, range: 20 to 290). CONCLUSION: The main result of our study is that in migraine patients painful trigeminal stimulation elicits de novo, or modifies pre-existing spontaneous Ny, generally increasing it. The finding was obtained after trigeminal stimulation, but not after median nerve stimulation. We suggest that painful trigeminal stimulation can induce an imbalance of the vestibular system in migraine patients and possibly explain their predisposition to vertigo. Our data require confirmation by other studies.

Study of multimodal evoked potentials in patients with type 1 Gaucher's disease.

To detect early subclinical nervous dysfunction in Gaucher's disease type 1, we carried out motor, brainstem auditory, visual, and somatosensory evoked potentials in 17 patients with Gaucher's disease type 1. Central motor evoked potential abnormalities were found in nine patients (69.2%), consisting of an increased motor threshold in all, with prolonged central motor conduction time in two patients. Brainstem auditory evoked potentials were abnormal in five patients (31.2%), and the most frequent abnormality was a bilateral increased I-III interpeak latency. Visual evoked potentials showed a delayed latency of the P100 wave in four patients (25%). Somatosensory evoked potential abnormalities were found in three patients (18.7%), consisting of an increased N13-N20 interval in two patients and a not reproducible N13 wave in one patient. Our findings suggest that the multimodal evoked potential approach provides information about nervous subclinical damage in Gaucher's disease type 1; transcranial magnetic stimulation proved to be the most sensitive tool. Early detection of subclinical neurologic dysfunction can be useful in view of more effective therapeutic strategies.

The R495W mutation in SPG3A causes spastic paraplegia associated with axonal neuropathy.

Mutations in the SPG3A gene cause a form of pure, early-onset autosomal dominant hereditary spastic paraplegia linked to chromosome 14q. The encoded protein, atlastin, is a putative member of the dynamin superfamily of large GTPases involved in cellular trafficking patterns. We report a new atlastin mutation causing spastic paraplegia in association with axonal neuropathy in an Italian family.

Autosomal recessive progressive myoclonus epilepsy with ataxia and mental retardation.

We describe two couples of sibs from a southern Italian family affected by epilepsy, myoclonus, mental retardation and slight ataxia. Onset was between 4 and 12 years and the course slowly progressive. The clinical picture suggested the diagnosis of Unverricht-Lundborg disease. Molecular study excluded linkage to EPM1. Other possible causes of progressive myoclonus epilepsy were also excluded.

Brain damage in glycogen storage disease type I.

OBJECTIVE: To investigate brain morphology and function in patients with glycogen storage disease type I (GSDI). STUDY DESIGN: Nineteen patients (13 females and 6 males, aged 0.9-22.6 years) and 38 sex- and age-matched controls entered the study. Neurological examinations, psychometric tests (IQ, tests of performance and verbal abilities), standard electroencephalogram (EEG), somatosensory (SEPs), visual (VEPs), and brain-stem auditory evoked potentials (BAEPs), and brain magnetic resonance imaging (MRI) were performed. RESULTS: The results of tests of performance ability were lower in patients than in controls (P <.05). The prevalence of abnormal EEG findings (26.3% versus 2.6%), VEPs (38.4% versus 7.7%), SEPs (23.0% versus 0%), and BAEPs abnormalities (15.7% versus 0%) was higher in patients than in controls (P <.05). MRI pattern was altered in 57.1% of patients and was normal in all controls (P <.05). Both results of tests of performance ability and BAEPs abnormalities significantly correlated with the frequency of admissions for hypoglycemia, whereas EEG abnormalities correlated with dietary compliance (P <.05). CONCLUSIONS: Brain damage, probably caused by recurrent severe hypoglycemia, may be present in patients with GSDI.

Postexercise facilitation of motor evoked potentials following transcranial magnetic stimulation: a study in normal subjects.

The size of the motor evoked potential (MEP) elicited by transcranial magnetic stimulation increases soon after a nonexhaustive voluntary contraction of the target muscle (postexercise facilitation). Our aim was to determine whether the duration or intensity of voluntary muscle contraction influenced postexercise facilitation in normal subjects. We recorded the MEP from the thenar muscles following contractions of different durations (5, 15, and 30 s) and intensities (10%, 25%, and 50% of maximal voluntary contraction). We found that every combination of the tested intensities and durations of physical effort could induce postexercise MEP facilitation. Although the degree of postexercise MEP facilitation was comparable across the different durations and intensities, the maximal facilitation was observed with the shortest and strongest muscle contraction. Our study thus defines the optimal setting to study postexercise facilitation for clinical purposes.