Darren R. Fuerst

Reliability and validity of the CMT neuropathy score as a measure of disability

Objective: To determine the validity and reliability of the Charcot-Marie-Tooth disease (CMT) neuropathy score (CMTNS) in patients with inherited neuropathy. Background: Natural history studies and potential treatment trials for patients with various forms of CMT are limited by the lack of quantitative methodologies to monitor disease progression. Most cases of CMT can be considered length-dependent axonal neuropathies because disability for even the demyelinating forms correlates with length-dependent axonal degeneration. The total neuropathy score (TNS) is a validated composite measure of disability in length-dependent axonal neuropathies but is weighted toward predominantly sensory neuropathies. Thus, the authors have devised a CMTNS, modified from the TNS, to provide a single measure to quantify CMT disability. Methods: The authors measured inter- and intrainvestigator reliability of the CMTNS and performed a validation of the score with the Neuropathy Impairment Score (NIS), patient self-assessment scores, an ambulation index, and other measures of disability. Results: Inter- and intrainvestigator reliability was more than 95% in the 60 patients evaluated. Patients could be divided into mild (CMTNS, ≤10), moderate (CMTNS, 11 to 20), and severe (CMTNS, ≥21) categories and demonstrated excellent correlations among all measures of disability. Conclusion: The Charcot-Marie-Tooth disease (CMT) neuropathy score is a validated measure of length-dependent axonal and demyelinating CMT disability and can be investigated as an end point for longitudinal studies and clinical trials of CMT.

Hippocampal sclerosis is a progressive disorder: a longitudinal volumetric MRI study.

Twelve patients with refractory temporal lobe epilepsy and unilateral hippocampal sclerosis had repeat volumetric magnetic resonance imaging scans after a mean of 3.4 years to determine whether progressive hippocampal volume loss occurred. Seizure‐free patients showed no change in hippocampal volume. Patients with continuing seizures had a decline in ipsilateral hippocampal volume that correlated with seizure frequency. Patients with medically refractory temporal lobe epilepsy and unilateral hippocampal sclerosis have progressive hippocampal atrophy. Ann Neurol 2003;53:413–416

CMT1X phenotypes represent loss of GJB1 gene function

Objective: To investigate possible genotype–phenotype correlations and to evaluate the natural history of patients with Charcot–Marie–Tooth disease type 1X (CMT1X). Background: CMT1X is caused by over 260 distinct mutations in the gap junction beta 1 (GJB1) gene, located on the X chromosome, which encodes the gap junction protein connexin 32 (Cx32). The natural history of CMT1X is poorly understood, and it remains unknown whether particular mutations cause more severe neuropathies through abnormal gain-of-function mechanisms. Methods: We evaluated 73 male patients with CMT1X, who each have 1 of 28 different GJB1 mutations predicted to affect nearly all domains of Cx32. Disability was evaluated quantitatively by the CMT Neuropathy Score (CMTNS) as well as by the CMT Symptom Score (CMTSS) and the CMT Examination Score (CMTES), which are both based on the CMTNS. Patients were also evaluated by neurophysiology. Results: In all patients, disability increased with age, and the degree of disability was comparable with that observed in patients with a documented GJB1 deletion. Disability correlated with a loss of motor units as assessed by motor unit number estimates. Conclusions: Taken together, these data suggest that most GJB1 mutations cause neuropathy by a loss of normal connexin 32 function. Therefore, treatment of male patients with Charcot–Marie–Tooth disease type 1X may prove amenable to gene replacement strategies.

Volumetric MRI, pathological, and neuropsychological progression in hippocampal sclerosis

Objective: To examine the relationships between age at onset and duration of seizure disorder with severity of hippocampal sclerosis (HS) and cognitive functioning in patients with HS and unilateral temporal lobe epilepsy. Methods: Twenty-six subjects had left temporal lobe seizure onset; 20 had right temporal onset. Measures were age at seizure onset, duration of seizure disorder divided by age (seizure duration), history of febrile convulsion (FC), ratio of the smaller hippocampal volume to the larger (HF) as determined by volumetric MRI, and pathologic HS grade. Results: Results showed that pathologic HS grade and HF were positively related to seizure duration, and negatively related to seizure onset. When subjects were divided into onset prior to age 10 versus later, subjects with earlier onset had higher mean pathologic HS grade and smaller (more asymmetric) mean HF. When subjects were divided into seizure duration <0.5 (i.e., less than half current lifetime) vs greater, subjects with seizure duration ≥0.5 had higher mean pathologic HS grade and lower mean HF. There was also evidence for earlier age at seizure onset and longer seizure duration being associated with worse performance on neuropsychological measures. FC was not related to either seizure duration or age at seizure onset, but patients with a history of FC showed higher pathologic HS grade and lower HF. A history of FC was not related to cognitive functioning. Conclusions: Unilateral HS patients with earlier seizure onset and longer duration of epilepsy have more severe HS and greater hippocampal volume asymmetry. This suggests that HS may be a progressive disorder with risk for cognitive dysfunction.

[15O]-water PET and intraoperative brain mapping: A comparison in the localization of eloquent cortex

Abstract[15O]-water PET was performed on 12 patients with structural lesions for localization of the motor (n=5), language (receptive and expressive; n=6), and visual cortex (n=1). All these patients undeiwent interactive image-guided surgery using an infrared digitizer and intraoperative electrical stimulation mapping for motor, sensory, language, and visual cortex location. MRI-PET coregistration was performed using a surface matching approach t~at integrated functional information with interactive image guidance during the surgical procedure. An awake craniotomy with motor and sensory intraoperative stimulation was performed using a registered bipolar electrode that was tracked on real-time during the surgical procedure. Intraoperative functional findings were displayed and saved on the registered MRI images. The sites of functional PET activation during the performance of motor, visual and language tasks were then compared to the results of intraoperative cortical stimulation in 11 patients and visual...

Gamma-oscillations modulated by picture naming and word reading: Intracranial recording in epileptic patients

OBJECTIVE We measured cortical gamma-oscillations in response to visual-language tasks consisting of picture naming and word reading in an effort to better understand human visual-language pathways. METHODS We studied six patients with focal epilepsy who underwent extraoperative electrocorticography (ECoG) recording. Patients were asked to overtly name images presented sequentially in the picture naming task and to overtly read written words in the reading task. RESULTS Both tasks commonly elicited gamma-augmentation (maximally at 80-100 Hz) on ECoG in the occipital, inferior-occipital-temporal and inferior-Rolandic areas, bilaterally. Picture naming, compared to reading task, elicited greater gamma-augmentation in portions of pre-motor areas as well as occipital and inferior-occipital-temporal areas, bilaterally. In contrast, word reading elicited greater gamma-augmentation in portions of bilateral occipital, left occipital-temporal and left superior-posterior-parietal areas. Gamma-attenuation was elicited by both tasks in portions of posterior cingulate and ventral premotor-prefrontal areas bilaterally. The number of letters in a presented word was positively correlated to the degree of gamma-augmentation in the medial occipital areas. CONCLUSIONS Gamma-augmentation measured on ECoG identified cortical areas commonly and differentially involved in picture naming and reading tasks. Longer words may activate the primary visual cortex for the more peripheral field. SIGNIFICANCE The present study increases our understanding of the visual-language pathways.

Psychosocial Functioning of Learning-Disabled Children: Replicability of Statistically Derived Subtypes.

The PIC scores of 132 learning-disabled children between the ages of 6 and 12 years were investigated using Q-factor analysis, four hierarchical-agglomerative clustering techniques, and one iterative partitioning clustering technique. Results revealed excellent correspondence between the subtypes derived by all grouping methods in terms of both misclassifications and mean PIC profile similarity of the subtypes across techniques. The mean PIC profile of one subtype indicated normal psychosocial adjustment; a second subtype exhibited evidence of significant internalized psychopathology; a third subtype had a mean PIC profile suggestive of externalized psychosocial maladjustment. These subtypes were virtually identical to three subtypes reported by Porter and Rourke (1985) in another study of learning-disabled children. The results indicate that learning-disabled children comprise a heterogeneous population in terms of psychosocial functioning and that subtypes of learning-disabled children with similar patterns of socioemotional adjustment can be recovered reliably from this population across samples and statistical grouping techniques.

Motor unit number estimate of distal and proximal muscles in Charcot–Marie–Tooth disease

In order to determine the utility of motor unit number estimation (MUNE) in assessing axonal loss in chronic inherited neuropathies, we determined MUNEs in 54 patients with Charcot–Marie–Tooth (CMT) disease (29 patients with CMT‐1A, 13 with CMT‐X, and 12 with CMT‐2) by using spike‐triggered averaging (STA) of the ulnar‐innervated abductor digiti minimi/hypothenar muscles (ADM) and the musculo‐cutaneous innervated biceps/brachialis (BB) muscles. MUNEs were analyzed in relationship to the corresponding compound muscle action potential (CMAP) amplitudes as well as to clinical strength. Proximal muscles, which appeared strong clinically, had evidence of chronic denervation/reinnervation, although to a lesser extent than weak distal hand muscles, supporting the concept that axonal loss in CMT occurs in a length‐dependent fashion. The reduction in ADM‐MUNE strongly correlated with clinical weakness in the hand. Both the ADM‐MUNE and BB‐MUNE were abnormal more often than CMAP amplitude, probably reflecting extensive motor unit reconfiguration and enlargement that maintains CMAP amplitude despite severe motor unit loss. This study suggests that MUNE can assess motor unit loss in CMT and may better reflect axonal loss than CMAP amplitude. The STA technique of MUNE may be useful in longitudinal studies of proximal and distal motor unit changes in CMT. Muscle Nerve 28: 161–167, 2003

Multimodality language mapping in patients with left-hemispheric language dominance on Wada test

OBJECTIVE We determined the utility of electrocorticography (ECoG) and stimulation for detecting language-related sites in patients with left-hemispheric language-dominance on Wada test. METHODS We studied 13 epileptic patients who underwent language mapping using event-related gamma-oscillations on ECoG and stimulation via subdural electrodes. Sites showing significant gamma-augmentation during an auditory-naming task were defined as language-related ECoG sites. Sites at which stimulation resulted in auditory perceptual changes, failure to verbalize a correct answer, or sensorimotor symptoms involving the mouth were defined as language-related stimulation sites. We determined how frequently these methods revealed language-related sites in the superior-temporal, inferior-frontal, dorsolateral-premotor, and inferior-Rolandic regions. RESULTS Language-related sites in the superior-temporal and inferior-frontal gyri were detected by ECoG more frequently than stimulation (p < 0.05), while those in the dorsolateral-premotor and inferior-Rolandic regions were detected by both methods equally. Stimulation of language-related ECoG sites, compared to the others, more frequently elicited language symptoms (p < 0.00001). One patient developed dysphasia requiring in-patient speech therapy following resection of the dorsolateral-premotor and inferior-Rolandic regions containing language-related ECoG sites not otherwise detected by stimulation. CONCLUSIONS Language-related gamma-oscillations may serve as an alternative biomarker of underlying language function in patients with left-hemispheric language-dominance. SIGNIFICANCE Measurement of language-related gamma-oscillations is warranted in presurgical evaluation of epileptic patients.

Psychosocial Dimensions of Learning Disabilities External Validation and Relationship with Age and Academic Functioning

This study was designed to assess the following in a group of 152 children with learning disabilities between the ages of 7 and 13 years: (a) the relationships between age and psychosocial functioning; (b) the relationships among psychosocial functioning, cognitive abilities, and academic achievement; and (c) the external validity of statistically derived psychosocial subtypes. Participants were assigned to one of seven psychosocial subtypes on the basis of a profile-matching algorithm. Overall, the findings suggested no increase in psychopathology with advancing age. In addition, clear relationships were found between academic achievement patterns and personality subtypes. Finally, the subtypes could be distinguished on the basis of a behavior problem checklist not used for the construction of the subtypes.