[Show abstract][Hide abstract] ABSTRACT: Recessive mutations in GJC2, the gene-encoding connexin 47 (Cx47), cause Pelizaeus–Merzbacher-like disease type 1, a severe dysmyelinating disorder. One recessive mutation (p.Ile33Met) has been associated with a much milder phenotype––hereditary spastic paraplegia type 44. Here, we present evidence that a novel Arg98Leu mutation causes an even milder phenotype––a subclinical leukodystrophy. The Arg98Leu mutant forms gap junction plaques in HeLa cells comparable to wild-type Cx47, but electrical coupling was 20-fold lower in cell pairs expressing Arg98Leu than for cell pairs expressing wild-type Cx47. On the other hand, coupling between Cx47Arg98Leu and Cx43WT expressing cells did not show such reductions. Single channel conductance and normalized steady-state junctional conductance–junctional voltage (G
j) relations differed only slightly from those for wild-type Cx47. Our data suggest that the minimal phenotype in this patient results from a reduced efficiency of opening of Cx47 channels between oligodendrocyte and oligodendrocyte with preserved coupling between oligodendrocyte and astrocyte, and support a partial loss of function model for the mild Cx47 associated disease phenotypes.
Full-text · Article · Jul 2014 · Journal of Neurology
[Show abstract][Hide abstract] ABSTRACT: Objective
The aim of this study was to verify the value of multiple neurophysiological tests in classifying disorders of consciousness (DOCs) in patients in a chronic vegetative or minimal consciousness state categorised on the basis of the Coma Recovery Scale (CRS).
The study included 142 patients, all of whom underwent long (18-hour) EEG-polygraphic recordings including one night. The EEG was scored using the Synek scale and sleep patterns using an arbitrary scale. Absolute total power and relative EEG power were evaluated in different frequency bands. Multimodal evoked potentials (EPs), including auditory event-related potentials, were also evaluated and scored.
The most information came from the combined multimodal EPs and sleep EEG scores. A two-step cluster analysis based on the collected information allowed a satisfactory evaluation of DOC severity. Spectral EEG properties seemed to be significantly related to DOC classes and CRS scores, but did not seem to make any significant additional contribution to DOC classification.
Multiple electrophysiological evaluations based on EEG, sleep polygraphic recordings and multimodal EPs are helpful in assessing DOC severity and residual functioning in patients with chronic DOCs.
Simple electrophysiological measures that can be easily applied at patients’ bedsides can significantly contribute to the recognition of DOC severity in chronic patients surviving a severe brain injury.
[Show abstract][Hide abstract] ABSTRACT: We detail the phenotype of a novel form of neuronal ceroid lipofuscinosis due to a homozygous progranulin gene mutation (c.813_816del; CLN11 MIM #614706). The symptoms appeared in two young adult siblings, and included progressive retinopathy, recurrent generalized seizures, moderate ataxia, and subtle cognitive dysfunction. Long-lasting episodes of palinopsia were a recurring symptom and associated with polyphasic visual-evoked potential waveform that suggested hyperexcitability of the occipital cortex. Electroencephalography showed rare spike-wave paroxysms, and magnetic resonance imaging revealed selective cerebellar atrophy. Skin biopsy revealed fingerprint storage and the absence of progranulin protein. Electron microscopy of peripheral blood leukocytes showed fingerprint profiles in 1/100 lymphocytes. These findings define a novel phenotype and provide clues for better understanding of progranulin function.A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: To evaluate the relationship between sensory hyperexcitability as revealed by giant SEPs and the SEP recovery function (SEP-R) in a series of patient with progressive myoclonic epilepsy of Unverricht-Lundborg type, identified as epilepsy, progressive myoclonic 1A (EPM1A), MIM #254800. METHODS: We evaluated SEPs by applying median nerve stimuli and SEP-R using paired stimuli at inter-stimulus intervals (ISIs) of between 20 and 600ms in 25 patients and 20 controls. The SEPs were considered "giant" if the N20P25 and P25N33 amplitudes exceeded normal mean values by +3SD. RESULTS: During the paired-stimulus protocol, the SEPs elicited by the second stimulus (S2) were detectable at all ISIs but consistently suppressed in the 13 patients with giant SEPs reflecting a significantly delayed SEP-R. Maximal suppression roughly corresponded to the plateau of a broad middle latency (>100ms) wave pertaining to the S1 response. CONCLUSIONS: The cortical processing dysfunction generating giant SEPs in EPM1A patients consistently combines with a long-lasting suppression of hyperexcitability that leads to a delayed giant SEP-R without obstructing the response to incoming stimuli. SIGNIFICANCE: The delayed SEP-R is not due to true inhibition but the suppression of aberrant hyper-synchronisation sustaining giant SEPs. A broad middle latency SEP component adds a significantly suppressive effect. This suggests that cortico-subcortical circuitries contribute to both the gigantism and the delayed SEP-R.
No preview · Article · Dec 2012 · Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology
[Show abstract][Hide abstract] ABSTRACT: The surgical results of this series of occult spina bifida seem better than the natural history registered in the long pre-operative period in terms of neurological deterioration. The major contribution to this result is attributed to neurophysiological monitoring that lowers the risks of permanent damage and increases the percentage of effective detethering. The present series of TCS, due to conus and filar lipoma, documents that CM1 is a really rare association occurring in less than 6% of the patients, despite the low position of conus. The detethering procedure did not influence the tonsillar position, thus excluding the correlation between the tethering and the tonsillar descent. The genetic alteration documented in a girl reinforces the hypothesis of a rare complex polymaformative picture deserving multiple procedures according to the prevailing clinical symptoms.
[Show abstract][Hide abstract] ABSTRACT: Gerstmann-Sträussler-Scheinker disease Pro102Leu (GSS102) is a rare autosomal dominant inherited prion disease due to a substitution of proline for leucine at codon 102 in the Prion Protein gene, and characterized by early walking difficulties and much later occurring dementia. We report clinical, electrophysiological and neuroradiological features of seven novel Italian cases of GSS102. The findings in our series support the thesis that early signs of GSS102 (including areflexia, ataxia, lower limb weakness, and painful dysesthesias) are likely due to a caudal myelopathic process, and suggest that GSS102 should be included among the causes of ataxia with areflexia. Moreover, our observations show that in patients with GSS102, as opposed to Friedreich's ataxia and other forms of ataxia with areflexia, nerve conduction studies and somato-sensory evoked potentials are normal, despite the presence of lower limb areflexia. Hence, in subjects with walking difficulties, the presence of lower limb areflexia without central and peripheral conduction abnormalities is highly suggestive or possibly pathognomonic of GSS102, and can easily guide the clinicians to make the diagnosis of this rare neurodegenerative disease.
No preview · Article · Mar 2011 · Journal of the neurological sciences
[Show abstract][Hide abstract] ABSTRACT: To asses the characteristics of severe action myoclonus in three patients with progressive myoclonus epilepsy (PME) due to sialidosis. We assessed EEG-EMG coherence, relative power (RP) and bandwidth (BW) of the EMG-peak associated with myoclonus; we also evaluated somatosensory evoked potentials and long-loop reflexes (LLRs). We compared the findings with those obtained in ten Unverricht-Lundborg (UL) patients. The presentation of sialidosis included macular cherry-red spot, skeletal malformation and polyneuropathy in the infantile form and optic atrophy in the juvenile form. From its onset in adolescence myoclonus rapidly worsened, quickly leading to severe disability. In sialidosis patients, the EMG-peak was characterised by higher RP (p<0.01) and narrower BW (p<0.02) than in UL. EEG-EMG coherence values were higher (p<0.05) than in UL patients. Taking into account both sialidosis and UL patients, the coherence values and the RP of the EMG-peak were directly correlated with the severity of the myoclonus; while BW values were inversely correlated. All these measures showed extreme values in sialidosis patients. In the sialidosis patients, the strongly rhythmic recurrence of the jerks reflected on LLR, which included multiple components. Subtle differences indicate an especially high level of cortical motor synchronization in the sialidosis patients, which may account for their particularly severe motor impairment. Neurophysiological indexes indicating high EEG-EMG synchronization parallels the severity of the myoclonus.
No preview · Article · Feb 2011 · Epilepsy research
[Show abstract][Hide abstract] ABSTRACT: We used electroencephalography (EEG)-polygraphic recordings to classify myoclonus in 109 patients with Creutzfeldt-Jakob disease (CJD) on the basis of its electromyography (EMG) pattern, time course, distribution, and EEG correlates. We recorded myoclonic jerks in 55 patients (50.4%), and we classified them as periodic myoclonus in 28, rhythmic in 13, and irregular in 20 (6 patients showed two types of myoclonus). Myoclonus occurred as a prominently negative event (interrupting the EMG discharge) in 10. Periodic sharp-wave complexes (PSWCs) were present in all but one patient with myoclonic jerks but were time-locked with EMG-bursts only in case of periodic myoclonus. Jerk-locked back averaging revealed a variable EEG-EMG transfer-time commonly exceeding that characterizing cortical myoclonus. Myoclonus was frequently associated with Met/Met polymorphism at codon 129 of the prion protein gene, but it was also observed in association with Met/Val or Val/Val polymorphisms provided that the EEG showed the presence of the PSWC pattern. The presence of enlarged somatosensory evoked potentials significantly correlated with the myoclonic presentation, as did MR signal hyperintensity involving the cortical mantle. Our observations on the basis of standard polygraphic criteria suggest that CJD associates with a remarkable variety of myoclonic jerks, and therefore different brain structures are probably involved as generators. The significant association between the presence of all myoclonus types with PSWCs suggests that hyperexcitable corticosubcortical loops are always required to generate (or allow) both myoclonus and the EEG complexes, either they are time locked or not.
No preview · Article · Dec 2010 · Movement Disorders
[Show abstract][Hide abstract] ABSTRACT: To report 4 cases of autosomal recessive hereditary neuropathy associated with novel mutations in the periaxin gene (PRX) with a review of the literature. Periaxin protein is required for the maintenance of peripheral nerve myelin. Patients with PRX mutations have early-onset autosomal recessive demyelinating Charcot-Marie-Tooth disease (CMT4F) or Déjèrine-Sottas neuropathy (DSN). Only 12 different mutations have been described thus far.
Case reports and literature review.
Four patients from 3 unrelated families (2 siblings and 2 unrelated patients) were affected by an early-onset, slowly progressive demyelinating neuropathy with relevant sensory involvement. All carried novel frameshift or nonsense mutations in the PRX gene. The 2 siblings were compound heterozygotes for 2 PRX null mutations (p.Q547X and p.K808SfsX2), the third patient harbored a homozygous nonsense mutation (p.E682X), and the last patient had a homozygous 2-nt insertion predicting a premature protein truncation (p.S259PfsX55). Electrophysiologic analysis showed a severe slowing of motor nerve conduction velocities (MNCVs, between 3 and 15.3 m/s) with undetectable sensory nerve action potentials (SNAPs). Sural nerve biopsy, performed in 2 patients, demonstrated a severe demyelinating neuropathy and onion bulb formations. Interestingly, we observed some variability of disease severity within the same family.
These cases and review of the literature indicate that PRX-related neuropathies have early onset but overall slow progression. Typical features are prominent sensory involvement, often with sensory ataxia; a moderate-to-dramatic reduction of MNCVs and almost invariable absence of SNAPs; and pathologic demyelination with classic onion bulbs, and less commonly myelin folding and basal lamina onion bulbs.
[Show abstract][Hide abstract] ABSTRACT: Previous studies have demonstrated that the event-related potential (ERP) evoked by a note shows substantial differences depending on whether the note is part of a melodic context or presented in an unstructured repetition. In particular, the N2 component has been found to have considerably increased latency and a more frontal topography for notes presented in a melody. An open question is whether such effect is related to the 'meaningfulness' of a note sequence, that is due to the formation of abstract melodic entities, rather than more simply an indicator of cognitive load associated with processing a structurally-complex sequence as opposed to an unstructured repetition. In this study, we addressed this issue by recording ERPs from 10 healthy non-musicians listening to eight one-part unfamiliar tonal melodies and eight sequences of random notes. The two stimuli were matched for distribution of pitch, intervals and note duration as well as for entropy of the time-series of pitch and duration. While tonal melodies were rated more meaningful (p<0.001) and pleasant (p<0.001) by all participants, no effects were found for the N2 component amplitude (p> or =0.8) and latency (p=0.2). Combined with previous findings, this indicates that the N2 evoked by each individual note responds to the structural complexity of the note sequence, i.e., to the presence of pitch and duration changes, but not to higher-level processing related to the formation of abstract melodic entities. In contrast, we found that the amplitude of the P2 component was marginally (p=0.04) elevated for random notes as compared to tonal melodies. This may be related to attentional modulation, or more specifically to associative components of auditory processing.
No preview · Article · Aug 2010 · Brain research bulletin
[Show abstract][Hide abstract] ABSTRACT: The clinical use of cisplatin chemotherapy is limited by severe peripheral neurotoxicity reported in up to 90% of patients receiving a cumulative dose higher than 300 mg/m(2). The present study evaluates the neuroprotective effect of antioxidant supplementation (vitamin E) in patients treated with cisplatin chemotherapy.
A total of 108 patients treated with cisplatin chemotherapy were randomly assigned to receive vitamin E supplementation (alpha-tocopherol 400 mg/day) or placebo. Treatment was started orally before chemotherapy and continued for 3 months after the suspension of cisplatin.
Of 108 randomized patients, 68 received at least one clinical and neurophysiologic examination after cisplatin CT; 41 patients received a cumulative dose of cisplatin higher than 300 mg/m(2) and were eligible for statistical analysis: 17 in the vitamin E group (group 1) and 24 in the placebo group (group 2). The incidence of neurotoxicity was significantly lower in group 1 (5.9%) than in group 2 (41.7%) (p < 0.01). The severity of neurotoxicity, measured with a validated neurotoxicity score (Total Neuropathy Score [TNS]), was significantly lower in patients receiving vitamin E than those receiving placebo (mean TNS 1.4 vs 4.1; p < 0.01).
This phase III study confirms the neuroprotective role of vitamin E against cisplatin peripheral neurotoxicity. Vitamin E supplementation should be adopted in patients receiving cisplatin-based chemotherapy. Classification of evidence: This study provides Class II evidence that vitamin E supplementation significantly reduces the relative risk of developing signs or symptoms of neurotoxicity (relative risk = 0.14) (95% confidence interval = 0.02-1.00, p < 0.05).