LAUSR

In this issue of Clinical Neurophysiology, Dr. Matamala and coauthors investigated membrane properties of peripheral sensory myelinated axons in amyotrophic lateral sclerosis (ALS) (Matamala et al., 2018). The study follows the path of a long-standing tradition of renowned Australian neurologists who approach clinical neurological problems by advanced physiological methods, the tradition being started by doctors Lance and McLeod, followed by Dr. Burke (who is one of the co-authors of the paper), and currently continued by Dr. Kiernan. The authors of this paper performed excitability tests in sensory axons of the median nerve at the wrist in 28 patients with sporadic ALS. Many of the patients had loss of motor axons in the median nerve since 50% had an MRC score for thumb abduction of 3 or less and mean MUNE value was reduced; furthermore, the tests were performed on the side where muscle weakness was most pronounced. The patients had no upper limb clinical sensory impairment of the upper limbs and had normal median nerve SNAPs, but eight patients had mild lower limb sensory deficits. The excitability tests comprised strength duration properties, threshold electrotonus, currentthreshold relation, and recovery cycle. Two extra tests were added. To better explore inward rectification sustained by hyperpolarization-activated nucleotide-gated cation (HCN) channels, the duration of hyperpolarizing currents in threshold electrotonus was increased to 300 ms. For better assessment of outward rectification by slow potassium channels, the recovery cycle after two closely spaced stimuli was recorded. Despite these extensive tests, no abnormalities were found. It is important to realize what these findings exactly mean. Excitability tests form an important translational link between basic and clinical neuroscience as they provide information on currents sustained by transient and persistent sodium channels, fast and slow potassium channels, and HCN channels. During excitability testing, electrical stimuli are repeatedly given at one site over a nerve in order to assess the threshold current for a compound potential (motor or sensory) of a predefined portion of its maximal amplitude, this portion being known as target response. Adding a conditioning stimulus to each test stimulus will result in a threshold change and it is this change that gives information on the above described ion-channels and resting membrane potential. Since the target SNAP in this study was 40% of the maximal SNAP, the authors investigated those myelinated sensory axons with an intermediate threshold value around 40% (to investigate higher threshold axons the target SNAP has to be higher and for lower threshold axons it has to be lower). It would be interesting to know how many axons have such an intermediate threshold value, but this is unknown. Although the results of this study seem modest (normal ion channel activity in intermediate threshold sensory axons at one site of the median nerve) it must be stressed that excitability studies of intermediate threshold motor axons in ALS at the same site showed prominent abnormalities. Excitability studies of median nerve motor axons at the wrist and in terminal motor axon branches in ALS showed specific abnormalities that have been repeatedly observed by different investigators. These consist of increased persistent sodium conductances in early stages and loss of fast and slow potassium conductances in later stages of the disease (Kanai et al., 2006; Nakata et al., 2006). A subsequent study showed similar findings in both sporadic and C9orf72 familial ALS suggesting that factors other than inheritance of genetic abnormalities are required to trigger ALS (Geevasinga et al., 2015). Each of these abnormalities decreases the threshold for ectopic impulse generation and may therefore give rise to fasciculations. Furthermore, the increase in inward persistent sodium current may induce reversal of the transmembrane calcium-sodium exchanger resulting in removal of accumulated sodium ions from the axon in exchange for influx of calcium ions into the axon, the latter of which gives rise to calcium-mediated axonal degeneration. The findings on excitability studies are supported by gene expression studies performed in spinal motor neuron cell bodies of ALS patients. These showed reduced mRNA expression for the potassium channels KCNA1, KCNA2, and KCNQ2, which generate fast juxtaparanodal and slow nodal potassium currents in myelinated axons (Jiang et al., 2005). In order to elucidate why motor symptoms and signs predominate in ALS, it would be interesting to know if similar mRNA reductions would, or would not, occur in sensory ganglion cells of ALS patients. The authors discuss the large body of evidence showing that ALS is a multisystem disorder, which not only affects peripheral and central motor neurons but also sensory, extrapyramidal, cerebellar, cognitive, and behavioral systems. About one third of patients with ALS were reported to have sensory symptoms and a large portion of these had decreased sural SNAPs (Hammad et al., 2007). Pathological studies of the sural nerve in selected patients with ALS showed loss of large myelinated axons, axonal atrophy, remyelination, and myelin irregularity. These abnormalities correlated with disease duration, making a relation with ALS