Brain functional connectome abnormalities in amyotrophic lateral sclerosis are associated with disability and cortical hyperexcitability.

BACKGROUND AND PURPOSE: The present study utilized a multimodal approach encompassing connectome networks combined with brain volume analysis, and assessment of cortical excitability to provide novel insights into amyotrophic lateral sclerosis (ALS) pathogenesis. METHODS: Magnetic resonance images were acquired using a 3.0-Tesla Signa HDx scanner (GE Healthcare, Milwaukee, WI, USA), using an eight-channel head coil. Magnetic resonance images for the resting-state scan were acquired using an echo-planar imaging magnetic resonance sequence, acquiring 40 contiguous axial/oblique slices. Structural magnetic resonance imaging three-dimensional T1-weighted images were acquired in the sagittal plane using three-dimensional spoiled gradient echo sequences. For structural imaging, a T1-weighted high-resolution (3.0-Tesla) magnetic resonance imaging scan was used. Cortical excitability was assessed by using the threshold-tracking transcranial magnetic stimulation paradigm. Network-based statistics and whole-brain functional topology (using graph theoretical approaches) assessed functional connectivity. RESULTS: Using a global network-based statistical analysis approach, functional connectivity was increased in 12 network edges connecting 14 nodes (P < 0.05) within the frontal, temporal, parietal and subcortical regions. Analysis of local connectedness disclosed dichotomous effects with reduced connectivity in frontal regions and increased connectivity in occipital regions in ALS. Cortical hyperexcitability was evident in patients with ALS, negatively correlated with functional connectivity changes in the pre-central gyrus (P < 0.01). Connectivity changes in the frontal regions were negatively associated with functional disability (P < 0.05). CONCLUSIONS: Multimodal assessment of cortical function in patients with ALS identified deficits in functional connectivity associated with cortical hyperexcitability that correlated with patient disability. Novel integration of functional brain assessment further contributes to the understanding of disease pathogenesis in ALS.

Cortical hyperexcitability and disease spread in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is characterized by focal disease onset with a predominantly contiguous pattern of disease spread. The pathophysiological mechanisms underlying disease progression in ALS have not been elucidated. Given that cortical hyperexcitability has been identified as an important pathogenic mechanism in ALS, the aim of the present study was to determine whether changes in cortical function could mediate disease spread in ALS. METHODS: Threshold-tracking transcranial magnetic stimulation was undertaken in 50 patients with sporadic ALS with recording of responses over both abductor pollicis brevis muscles, with results matched to clinical assessments and concurrent neurophysiological investigation of lower motor neuron function. Subsequently, patients were followed longitudinally to map patterns of clinical disease progression. RESULTS: Cortical dysfunction was evident over both motor cortices, with hyperexcitability more prominent over the dominant motor cortex, contralateral to the site of disease onset, with reduction of resting motor threshold (F = 3.83, P < 0.05), short-interval intracortical inhibition (F = 15.0, P < 0.0001) and cortical silent-period duration (F = 8.01, P < 0.01), along with an increase in motor evoked potential amplitude (F = 5.66, P < 0.01). In addition, patterns of cortical change were consistent with a contiguous pattern of disease progression. CONCLUSIONS: Cortical hyperexcitability appears to be more prominent over the dominant motor cortex, contralateral to the side of symptom onset, and contributes to a contiguous pattern of spread in sporadic ALS.

Cortical excitability changes distinguish the motor neuron disease phenotypes from hereditary spastic paraplegia.

BACKGROUND AND PURPOSE: Cortical hyperexcitability has been identified as an important pathogenic mechanism in motor neuron disease (MND). The issue as to whether cortical hyperexcitability is a common process across the MND phenotypes, including amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS), remains unresolved. Separately, the clinical distinction between PLS and 'mimic disorders' such as hereditary spastic paraparesis (HSP) may be difficult, potentially delaying diagnosis. Consequently, the aim of the present study was to determine the nature and spectrum of cortical excitability changes across the MND phenotypes, and to determine whether the presence of cortical dysfunction distinguishes PLS from HSP. METHODS: Cortical excitability studies were undertaken on a cohort of 14 PLS, 82 ALS and 13 HSP patients with mutations in the spastin gene. RESULTS: Cortical hyperexcitability, as heralded by reduction of short interval intracortical inhibition (PLS 0.26%, -3.8% to 1.4%; ALS -0.15%, -3.6% to 7.0%; P < 0.01) and cortical silent period duration (CSPPLS 172.2 ± 5.4 ms; CSPALS 178.1 ± 5.1 ms; P < 0.001), along with an increase in intracortical facilitation was evident in ALS and PLS phenotypes, although appeared more frequently in ALS. Inexcitability of the motor cortex was more frequent in PLS (PLS 71%, ALS 24%, P < 0.0001). Cortical excitability was preserved in HSP. CONCLUSIONS: Cortical dysfunction appears to be an intrinsic process across the MND phenotypes, with cortical inexcitability predominating in PLS and cortical hyperexcitability predominating in ALS. Importantly, cortical excitability was preserved in HSP, thereby suggesting that the presence of cortical dysfunction could help differentiate PLS from HSP in a clinical setting.

Diagnostic utility of cortical excitability studies in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: The diagnosis of amyotrophic lateral sclerosis (ALS) relies on identification of a combination of upper and lower motor neuron signs. In order to improve the diagnostic sensitivity for ALS, Awaji criteria were developed, in part to better incorporate neurophysiological measures, although assessment of upper motor neuron dysfunction remained clinically based. Given that cortical hyperexcitability appears to be an early feature in ALS, the present study assessed the diagnostic utility of a threshold tracking transcranial magnetic stimulation technique as an aid to the research-based Awaji criteria in establishing an earlier diagnosis of ALS. METHODS: Prospective studies were undertaken on a cohort of 82 patients with suspected ALS and results were compared with 34 healthy controls. RESULTS: Short-interval intracortical inhibition (SICI) was significantly reduced in ALS patients (P < 0.0001), with a comparable reduction evident in the Awaji groups (SICIAWAJI POSSIBLE 1.3% ± 1.3%; SICIAWAJI PROBABLE/DEFINITE 1.4% ±1.7%). Central motor conduction time was significantly prolonged (P < 0.001), whereas the motor evoked potential amplitude (P < 0.05) and intracortical facilitation (P < 0.05) were increased. The frequency of transcranial magnetic stimulation abnormalities was similar across Awaji subgroups, and addition of transcranial magnetic stimulation abnormalities as a diagnostic category enabled reclassification of 88% of Awaji possible patients to Awaji probable/definite. CONCLUSIONS: Cortical excitability studies potentially facilitate an earlier diagnosis of ALS when combined with clinical and conventional neurophysiological findings, albeit in a research setting.

Multifocal motor neuropathy and muscle hypertrophy.

Multifocal motor neuropathy is frequently an asymmetrical neuropathy predominantly affecting the upper limbs. Patients present with weakness, fasciculations and distal muscle wasting. Hypertrophy of muscles is very infrequently reported. We present two cases of multifocal motor neuropathy with upper limb muscle hypertrophy and discuss possible pathophysiological mechanisms. Botulinum toxin may be useful to alleviate cramp.

A retrospective review of X-linked Charcot-Marie-Tooth disease in childhood.

OBJECTIVE: X-linked Charcot-Marie-Tooth disease (CMTX) is infrequently diagnosed in childhood, and its clinical and neurophysiologic features are not well-described. We reviewed clinical, neurophysiologic, and pathologic findings in 17 children with CMTX. METHODS: This was a retrospective review of children with CMTX from 2 tertiary pediatric hospitals. The diagnosis of CMTX was based on an identifiable connexin 32 mutation (CMTX1) or a consistent pedigree and neurophysiologic features in children without a connexin 32 mutation (CMTX-other). RESULTS: Six boys and 2 girls from 8 kindreds had CMTX1, and 8 boys and 1 girl from 5 kindreds had other forms of CMTX (CMTX-other). Fifteen children, including males and carrier females, were symptomatic from infancy or early childhood (younger than 5 years). In addition to the typical Charcot-Marie-Tooth disease clinical phenotype, some patients had delayed motor development, sensorineural hearing loss, tremor, pathologic fractures, or transient CNS disturbances. Eleven children underwent nerve conduction studies. Median nerve motor nerve conduction velocities were in the intermediate to normal range (30-54 m/s) in all children older than 2 years. Axon loss, reflected by low-amplitude compound muscle action potentials, was present in all patients. A pattern of X-linked dominant inheritance, with carrier females showing an abnormal neurologic or neurophysiologic examination, correlated with the presence of a connexin 32 mutation in all but 2 pedigrees. CONCLUSIONS: The clinical phenotype of CMTX is broader than previously reported. Onset in males and carrier females is most often in early childhood. Families with an X-linked dominant inheritance pattern are likely to have CMTX1.

Histiocytosis and bone: experience from one major Sydney teaching hospital.

Langerhans cell histiocytosis (LCH) has diverse presentations which can bring it before all physicians regardless of specialty. A retrospective audit was undertaken at Westmead Hospital, Sydney, Australia, to ascertain the incidence, epidemiology and clinical features of patients with LCH over a 10-year period (1994-2004). A total of 12 patients was identified (six male, six female). Eleven patients had involvement of the skeletal system, three of the patients had pulmonary LCH and only one patient presented with soft tissue involvement (nose and antrum). Three patients had diabetes insipidus. Our results are consistent with that noted in the published literature and confirm the low incidence, diverse nature of presentation and the differing treatment strategies available for this rare and yet interesting condition.