Brainstem auditory pathway maturation in term neonates with congenital cytomegalovirus infection: a cohort study.

Congenital cytomegalovirus infection (cCMVi) is a leading cause of sensorineural hearing loss (SNHL) and developmental delay. Brainstem auditory evoked potentials (BAEPs) recording allows assessment of central auditory pathway maturation in neonates. We aimed to characterize the effect of cCMVi on the maturation of the brainstem auditory pathway in term neonates. We retrospectively reviewed medical records of neonates born with cCMVi in 2010-2018 and characterized their auditory pathway maturation using brainstem auditory-evoked potentials (BAEPs). We compared inter-peak latency differences (IPLDs) of the main BAEP components (I-V, I-III, and III-V) in terms of cCMVi patients and healthy controls and described their changes in cCMVi patients throughout the first year of life. Of 101 cCMVi patients, 57 (56.4%) were considered symptomatic, 6 (5.9%) were small for gestational age, 6 (5.9%) had microcephaly, 4 (4%) had thrombocytopenia, 5 (6.6%) had hepatitis, 2 (2.1%) had retinitis, 47 (49.5%) had typical abnormalities on head ultrasound, 9 (8.9%) developed SNHL, and 34 (59.6%) received antiviral therapy. No significant difference was found between IPLDs of full-term cCMVi patients compared to controls throughout the entire auditory pathway (I-III, III-V, and I-V IPLDs), for both ears (p > 0.05). On serial BAEP examinations, cCMVi patients presented decreased IPLDs throughout the first year of life (p < 0.05 of compared 1st, 2nd, and 3rd BAEPs in both ears).   Conclusions: Intrauterine cytomegalovirus infection does not affect the auditory brainstem maturation process in term neonates. Our findings support previous studies noting the normal neurodevelopmental outcome of asymptomatic cCMVi patients, suggesting antiviral treatment is not warranted in these cases. What is Known: • cCMVi is a leading cause of developmental delay and hearing loss. Treatment is recommended for patients with symptomatic diseases who are at significant risk of long-term sequelae. • It is unknown whether cCMVi affects the central nervous system maturation process. What is New: • We performed a neurophysiological evaluation of brainstem conduction by recording the BAEPs. We found that cCMVi has no significant impact on central conduction times along the auditory pathways in the brainstem at birth nor changes the neuronal maturation process during the first year of life. • Our findings suggest that cCMVi does not universally affect central nervous system maturation, supporting a highly selective approach when considering the benefits of antiviral therapy.

Biallelic DMXL2 mutations impair autophagy and cause Ohtahara syndrome with progressive course.

Ohtahara syndrome, early infantile epileptic encephalopathy with a suppression burst EEG pattern, is an aetiologically heterogeneous condition starting in the first weeks or months of life with intractable seizures and profound developmental disability. Using whole exome sequencing, we identified biallelic DMXL2 mutations in three sibling pairs with Ohtahara syndrome, belonging to three unrelated families. Siblings in Family 1 were compound heterozygous for the c.5135C>T (p.Ala1712Val) missense substitution and the c.4478C>G (p.Ser1493*) nonsense substitution; in Family 2 were homozygous for the c.4478C>A (p.Ser1493*) nonsense substitution and in Family 3 were homozygous for the c.7518-1G>A (p.Trp2507Argfs*4) substitution. The severe developmental and epileptic encephalopathy manifested from the first day of life and was associated with deafness, mild peripheral polyneuropathy and dysmorphic features. Early brain MRI investigations in the first months of life revealed thin corpus callosum with brain hypomyelination in all. Follow-up MRI scans in three patients revealed progressive moderate brain shrinkage with leukoencephalopathy. Five patients died within the first 9 years of life and none achieved developmental, communicative or motor skills following birth. These clinical findings are consistent with a developmental brain disorder that begins in the prenatal brain, prevents neural connections from reaching the expected stages at birth, and follows a progressive course. DMXL2 is highly expressed in the brain and at synaptic terminals, regulates v-ATPase assembly and activity and participates in intracellular signalling pathways; however, its functional role is far from complete elucidation. Expression analysis in patient-derived skin fibroblasts demonstrated absence of the DMXL2 protein, revealing a loss of function phenotype. Patients' fibroblasts also exhibited an increased LysoTracker® signal associated with decreased endolysosomal markers and degradative processes. Defective endolysosomal homeostasis was accompanied by impaired autophagy, revealed by lower LC3II signal, accumulation of polyubiquitinated proteins, and autophagy receptor p62, with morphological alterations of the autolysosomal structures on electron microscopy. Altered lysosomal homeostasis and defective autophagy were recapitulated in Dmxl2-silenced mouse hippocampal neurons, which exhibited impaired neurite elongation and synaptic loss. Impaired lysosomal function and autophagy caused by biallelic DMXL2 mutations affect neuronal development and synapse formation and result in Ohtahara syndrome with profound developmental impairment and reduced life expectancy.

[Acute hemiplegia and hemianesthesia together with decreased tendon reflexes mimicking acute stroke representing a conversion disorder].

Acute hemiplegia and hemianesthesia is commonly caused by obstruction of major cortical arteries. Such a presentation secondary to a conversion reaction is very rare, especially in the pediatric age group. The authors report an adolescent presenting with acute complete left-sided hemiplegia and sensory loss together with decreased tendon reflexes mimicking an acute arterial stroke. Examination revealed Hoover's sign was present and the patient was oblivious to his stern neurological state. Movement of his paralytic limbs was observed during sleep. Cortical and spinal CT, cortical MRI, motor and somatosensory evoked potentials and a PET study were all normal. As such, the diagnosis of psychogenic hemiplegia was established, apparently within a period that the patient had experienced severe emotional stress while questioning his gender identity. After three days, the adolescent began to move the paralytic limbs along gradual resolution of sensory deficit, leading to complete clinical recovering within two months. Although extremely rare, a conversion reaction should be taken into account in children presenting with acute hemiplegia and anaesthesia, even accompanied with decreased tendon reflexes, when the patient is oblivious to his alleged grave state, and when clinical observations such as Hoover's sign remain intact, substantiated by normal extensive radiological and neurophysiological investigation. Intact motor evoked potentials serve as a key for the diagnosis of psychogenic hemiplegia and, should therefore be performed in suspected cases.

Evidence for cortical hyperexcitability of the affected limb representation area in CRPS: a psychophysical and transcranial magnetic stimulation study.

Functional alterations in noxious, sensory and motor circuits within the central nervous system may play an important role in the pathophysiology of complex regional pain syndrome (CRPS). The aim of the present study was to search for further evidence of hyperexcitability in the hemisphere contralateral to the affected limb in patients with CRPS by employing both psychophysical and transcranial magnetic stimulation (TMS) methods. Twelve patients with CRPS type I, confined to the distal part of a limb (six in an upper-limb and six in a lower-limb), were enrolled in the study. The quantitative thermal, mechanical and 'wind-up' like pain testing was performed at the most painful site in the affected limb and in the ipsilateral limb. Results were then compared to those found at mirror sites in the contralateral limbs. TMS was used to assess the inter-hemispheric difference in parameters of corticospinal excitability, intracortical inhibition, and intracortical facilitation. The quantitative thermal and mechanical testing showed significant differences in cold, heat and mechanical pain thresholds, as well as in the first and last 'wind-up' stimuli between the affected and the contralateral limbs of the CRPS patients. No significant differences between the ipsilateral unaffected limbs and their contralateral pair limbs were found. A significant reduction in the short intracortical inhibition associated with a significant increase of the I-wave facilitation was found in the hemisphere contralateral to the affected side in the upper-limb CRPS group. No significant inter-hemispheric asymmetry between the affected and the non-affected sides was revealed in the lower-limb CRPS group. Taken together, these results suggest that in patients with well-localized CRPS, there is evidence for sensory and motor CNS hyperexcitability, though it seems to involve only corresponding regions within the CNS rather than the entire hemisphere.

Effect of electroconvulsive therapy on cortical excitability in patients with major depression: a transcranial magnetic stimulation study.

OBJECTIVE: The antidepressant action of electro-convulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS) may be related to their ability to modulate cortical excitability. The aim of this study was to investigate changes in cortical excitability following ECT in patients with major depression (MD) and to compare therapeutic efficacy of ECT combined with rTMS to that of ECT alone. METHODS: Twenty-two patients with MD were assigned to receive ECT and right prefrontal 1 Hz rTMS (n=12) or ECT with sham rTMS (n=10). ECT was given twice weekly and rTMS was applied on the remaining 4 days, throughout 3 weeks. The resting motor threshold (rMT) and motor evoked potential (MEP)/M-wave area ratio were evaluated before and 6 h after the first, third and sixth ECT session. The active motor threshold (aMT), intra-cortical inhibition (ICI) and intra-cortical facilitation (ICF) were measured at baseline and 24 h after the last ECT. RESULTS: There were no significant differences in the degree of clinical improvement and measures of cortical excitability in the ECT+active rTMS group as compared to the ECT+sham rTMS group. Marked clinical improvement observed in 19 out of the 22 patients was associated with a significant increase of the MEP/M-wave area ratio, decrease of the aMT and reduction of the ICI in the left hemisphere. CONCLUSIONS: The antidepressant effect of ECT was associated with an enhancement of left hemispheric excitability. rTMS did not add to the beneficial effect of ECT. However, the small sample size and the robust effect of ECT might have obscured a potential therapeutic effect of rTMS. SIGNIFICANCE: Measures of cortical excitability may provide insight to our understanding of the mechanism of action of ECT and might be useful for the assessment of treatment response.

Sound localization in patients with cochlear implant--preliminary results.

OBJECTIVES: To evaluate sound localization ability in patients with unilateral cochlear implant, who do not wear a hearing aid on the contralateral ear, and to try to improve this ability by training. SETTING: Tertiary academic referral center. METHODS: In the initial test, patients were exposed to sound stimuli from different directions and were asked to localize them. Following a training period the patients were re-evaluated by the same test. For each test, the percentage of correct answers and the final test score were calculated. RESULTS: In the initial test, the mean score of the study group of four cochlear implant users was 42.8 (out of a maximal score of 100), the mean rate of correct responses was 27.5%. Following a training period (6.5 sessions on the average), on the final test the mean score of the group was 74.3, while the mean rate of correct responses was 66.5%. CONCLUSIONS: The results demonstrated that patients with unilateral cochlear implant have some ability to localize sound, and that this ability may be improved by regular training.

Diagnostic value of Hoover sign and motor-evoked potentials in acute somatoform unilateral weakness and sensory impairment mimicking vascular stroke.

Acute unilateral weakness along with sensory impairment is commonly caused by obstruction of major cortical arteries in either adults or children. A somatoform presentation mimicking acute vascular stroke is very rare, especially in the pediatric age group. Here we report three adolescents presenting with acute unilateral weakness and sensory impairment along with diminished tendon reflexes who were suspected to have an acute stroke but who had developed a somatoform psychogenic disorder. Two adolescents had complete hemiplegia and one had weakness of the left leg - two had moved the alleged paralytic limbs during sleep. A normal Hoover sign was suggestive of a somatoform psychogenic etiology rather than true vascular stroke. Cortical and spinal MRI, motor-evoked potentials (MEP) and somatosensory-evoked potentials were normal. All adolescents recovered completely. Therefore, a somatoform conversion reaction should be considered in children presenting with acute unilateral weakness and sensory alterations, which is corroborated by a normal Hoover sign and intact MEP.

Motor cortex disinhibition in normal-pressure hydrocephalus.

OBJECT: Previous studies have shown a close association between frontal lobe dysfunction and gait disturbance in idiopathic normal-pressure hydrocephalus (iNPH). A possible mechanism linking these impairments could be a modulation of corticospinal excitability. The aim of this study was 2-fold: 1) to determine whether iNPH affects corticospinal excitability; and 2) to evaluate changes in corticospinal excitability following ventricular shunt placement in relation to clinical outcome. METHODS: Twenty-three patients with iNPH were examined using single- and paired-pulse transcranial magnetic stimulation of the leg motor area before and 1 month after ventricular shunt surgery. The parameters of corticospinal excitability assessed were the resting motor threshold (rMT), motor evoked potential/M-wave area ratio, central motor conduction time, intracortical facilitation, and short intracortical inhibition (SICI). The results were compared with those obtained in 8 age-matched, healthy volunteers, 19 younger healthy volunteers, and 9 age-matched patients with peripheral neuropathy. RESULTS: Significant reduction of the SICI associated with a decrease of the rMT was observed in patients with iNPH at baseline evaluation. Ventricular shunt placement resulted in significant enhancement of the SICI and increase of the rMT in patients who markedly improved, but not in those who failed to improve. CONCLUSIONS: This study demonstrates that iNPH affects corticospinal excitability, causing disinhibition of the motor cortex. Recovery of corticospinal excitability following ventricular shunt placement is correlated with clinical improvement. These findings support the view that reduced control of motor output, rather than impairment of central motor conduction, is responsible for gait disturbances in patients with iNPH.

The value of motor and somatosensory evoked potentials in evaluation of cervical myelopathy in the presence of peripheral neuropathy.

STUDY DESIGN: Patterns and rates of motor-evoked potential (MEP) and somatosensory-evoked potential (SEP) abnormalities were evaluated in 9 patients with combined cervical cord compression and diabetic neuropathy and 15 patients with asymptomatic cervical cord compression. The results were compared with those of 8 patients with pure cervical myelopathy and 7 patients with pure diabetic neuropathy. OBJECTIVE: To assess the efficacy of MEPs and SEPs in the evaluation of cervical myelopathy in the presence of peripheral neuropathy. SUMMARY OF BACKGROUND DATA: Previous studies have demonstrated a high sensitivity of MEPs and SEPs in documenting a functional involvement of motor and somatosensory pathways in pure or preclinical cervical myelopathy. However, there have been no detailed reports on MEPs and SEPs in cervical cord compression associated with peripheral neuropathy. METHODS: Central somatosensory conduction was assessed by median and tibial SEPs using peak-to-peak and onset-to-onset methods. Central motor conduction was measured by MEPs and F-waves elicited from upper and lower limb muscles in response to transcranial magnetic stimulation, magnetic stimulation of cervical motor roots, and electrical stimulation of peripheral nerves. RESULTS: MEPs were more sensitive than SEPs in detecting central conduction impairments in patients with either pure or preclinical or combined forms of cervical myelopathy. The rate of MEP abnormalities suggesting the corticospinal tract involvement in the combined cervical cord compression-neuropathy group did not differ significantly from that in the asymptomatic cervical cord compression group but was lower than in the pure cervical myelopathy group. Combined MEP and SEP analysis improved the test sensitivity in detecting clinically "silent" cervical cord dysfunctions. CONCLUSIONS: MEPs associated with SEPs are a valuable tool for assessing the presence and severity of cervical cord involvement in combined cervical cord compression and peripheral neuropathy lesions.