Tadashi Kanouchi

Can regional spreading of amyotrophic lateral sclerosis motor symptoms be explained by prion-like propagation?

Progressive accumulation of specific misfolded protein is a defining feature of amyotrophic lateral sclerosis (ALS), similarly seen in Alzheimer disease, Parkinson disease, Huntington disease and Creutzfeldt–Jakob disease. The intercellular transfer of inclusions made of tau, α-synuclein and huntingtin has been demonstrated, revealing the existence of mechanisms reminiscent of those by which prions spread through the nervous system. Evidence for such a prion-like propagation mechanism has now spread to the major misfolded proteins, superoxide dismutase 1 (SOD1) and the 43 kDa transactive response DNA binding protein (TDP-43), implicated in ALS. The focus in this review is on what is known about ALS progression in terms of clinical as well as molecular aspects. Furthermore, the concept of ‘propagation’ is dissected into contiguous and non-contiguous types, and this concept is expanded to the severity of the focal symptom as well as its regional spread which can be explained by cell to cell propagation in the local neuron pool.

Spreading of amyotrophic lateral sclerosis lesions—multifocal hits and local propagation?

Objective To investigate whether or not the lesions in sporadic amyotrophic lateral sclerosis (ALS) originate from a single focal onset site and spread contiguously by prion-like cell-to-cell propagation in the rostrocaudal direction along the spinal cord, as has been hypothesised (the ‘single seed and simple propagation’ hypothesis). Methods Subjects included 36 patients with sporadic ALS and initial symptoms in the bulbar, respiratory or upper limb regions. Abnormal spontaneous activities in needle electromyography (nEMG)—that is, fibrillation potentials, positive sharp waves (Fib/PSWs) or fasciculation potentials (FPs)—were compared among the unilateral muscles innervated by different spinal segments, especially between the T10 and L5 paraspinal muscles, and between the vastus medialis and biceps femoris. Axon length and the proportion of muscle fibre types, which are both related to motoneuronal vulnerability in ALS, are similar in the paired muscles. Results Fourteen of 36 patients showed a non-contiguous distribution of nEMG abnormalities from the onset site, with skipping of intermediate segments. In eight of them, the non-contiguous pattern was evident between paired muscles with the same motoneuronal vulnerability. The non-contiguously affected lumbosacral lesions involved motoneuron columns horizontally or radially proximate to one another, appearing to form a cluster in four of the eight patients. FPs, known to precede Fib/PSWs, were shown more frequently than Fib/PSWs in all the lumbosacral segments but L5, suggesting that 2nd hits occur at L5 and then spread to other lumbosacral segments. Conclusions In sporadic ALS, the distribution of lower motoneuron involvement cannot be explained by the ‘single seed and simple propagation’ hypothesis alone. We propose a ‘multifocal hits and local propagation’ hypothesis instead.

Role of the ipsilateral motor cortex in mirror movements.

The mechanism of mirror movements in two patients was investigated; one with congenital mirror movement, the other with schizencephaly. Transcranial magnetic stimulation on one side elicited motor evoked potentials (MEPs) in their thenar muscles on both sides with almost the same latencies, minimal thresholds, and cortical topographies. During voluntary contraction of the thenar muscle on one side, contralateral transcranial magnetic stimulation induced a silent period not only on the voluntary contraction side but on the mirror movement side and of the same duration. By contrast, ipsilateral transcranial magnetic stimulation elicited MEPs without silent periods in both muscles. With intended unilateral finger movements, an H2(15)O-PET activation study showed that the regional cerebral blood flow increased predominantly in the contralateral sensorimotor cortex, as seen in normal subjects, although mirror movements occurred. It is considered that the ipsilateral motor cortex plays a major part in the generation of mirror movements, which may be induced through the ipsilateral uncrossed corticospinal tract.

Motor nerve conduction study in cauda equina with high-voltage electrical stimulation in multifocal motor neuropathy and amyotrophic lateral sclerosis

In this study we aim to establish a motor nerve conduction study (NCS) for the cauda equina and examine its usefulness in multifocal motor neuropathy (MMN) and amyotrophic lateral sclerosis (ALS). NCS of the tibial nerve proximal to the knee was performed with an optimized high‐voltage electrical stimulation (HV‐ES) method in 21 normal subjects, 5 with MMN, and 11 with ALS. HV‐ES, but not magnetic stimulation, could supramaximally stimulate the cauda equina. Cauda equina motor conduction time determined by HV‐ES, but not that with F‐waves, correlated well with cauda equina length on magnetic resonance imaging. HV‐ES revealed proximal lesions in 4 MMN patients but in none of the ALS patients. Importantly, 1 patient with “MMN without conduction block (CB)” had a CB in the cauda equina. Cauda equina motor conduction is better evaluated by HV‐ES than with F‐wave study or magnetic stimulation. HV‐ES can help to distinguish MMN and “MMN without CB” from ALS. Muscle Nerve 43: 274–282, 2011

Chiasmal optic neuritis following mumps parotitis.

JO N 2810 became aware of bitemporal hemianopsia. On ophthalmological examination, the best corrected visual acuity was 20/16 left eye and 20/20 right eye. There was a right relative afferent pupillary defect. Funduscopic examination was normal, and the Goldmann perimetry test revealed bitemporal hemianopsia (Fig. 1A). Pattern-reversal visual evoked potentials by monocular stimulation showed a delayed P100 response from the left eye (latency 118 ms), and barely detectable responses from the right eye. Physical, neurological, and routine laboratory examinations were normal. Cerebrospinal fluid (CSF) analysis was normal (3 cells/mm3, protein 25 mg/dl), and there were no oligoclonal bands. Anti-mumps virus antibodies were elevated in the serum (enzyme-linked immunosorbent assay: IgM = 7.71, normally < 0.8, IgG = 19.9, normally < 2.0), but not in the CSF, on the 16th day of neurological illness. Reverse-transcription polymerase chain reaction detected no mumps genomic RNA in the CSF. Antinuclear antibody, anticardiolipin antibodies, lupus anticoagulant activity, and anti-SS-A/-B antibodies were absent. Serum angiotensin-converting enzyme and lysozyme were within normal ranges. Blood mitochondrial DNA analysis revealed no point mutations responsible for Leber’s hereditary optic neuropathy (LHON). Chest X-ray showed no hilar lymphadenopathy. Brain magnetic resonance imaging (MRI) was normal. However, MRI of the optic nerves revealed an enlarged optic chiasma, with an increased signal intensity on a T2-weighted image, and gadolinium enhancement on a T1weighted image (Fig. 1B, C). We treated the patient with corticosteroids (intravenous methylprednisolone, 1 g daily for 3 days, and then for another 3 days; plus oral prednisolone 60 mg daily followed by Takashi Irioka Miho Akaza Keisuke Nakao Tadashi Kanouchi Takanori Yokota Hidehiro Mizusawa

The F wave disappears due to impaired excitability of motor neurons or proximal axons in inflammatory demyelinating neuropathies.

OBJECTIVES--Investigation of pathophysiology of F wave disappearance in demyelinating neuropathies. METHODS--The peripheral motor nerve conduction was studied by motor evoked potential (MEP) on transcranial magnetic stimulation as well as conventional nerve conduction studies before and after the treatment in 26 patients with inflammatory demyelinating neuropathies. In addition, serum antiganglioside antibodies in the acute or active stage were examined. RESULTS--The F wave was abolished in 10 patients. Seven of the 10 patients showed motor evoked potentials (MEPs) on transcranial magnetic stimulation that ranged from 1-4 mV. In six of them the F wave reappeared in the recovery stage, but the MEP size did not change. This may be caused by humoral factors, because the F wave reappeared immediately after plasma exchange or intravenous immunoglobulin treatment. A correlation of F wave disappearance with the presence of serum antiganglioside antibodies was found. CONCLUSIONS--The major pathophysiology of F wave disappearance in demyelinating neuropathies is impairment of motor neuron excitability or prolonged refractoriness of the most proximal axon for backfiring. The conventional interpretation that absent F waves suggest a conduction block at the proximal site is often inadequate.

Safety and efficacy of eculizumab in Guillain-Barré syndrome: a multicentre, double-blind, randomised phase 2 trial

BACKGROUND Despite the introduction of plasmapheresis and immunoglobulin therapy, many patients with Guillain-Barré syndrome still have an incomplete recovery. Evidence from pathogenesis studies suggests the involvement of complement-mediated peripheral nerve damage. We aimed to investigate the safety and efficacy of eculizumab, a humanised monoclonal antibody against the complement protein C5, in patients with severe Guillain-Barré syndrome. METHODS This study was a 24 week, multicentre, double-blind, placebo-controlled, randomised phase 2 trial done at 13 hospitals in Japan. Eligible patients with Guillain-Barré syndrome were aged 18 years or older and could not walk independently (Guillain-Barré syndrome functional grade 3-5). Patients were randomly assigned (2:1) to receive 4 weeks of intravenous immunoglobulin plus either eculizumab (900 mg) or placebo; randomisation was done via a computer-generated process and web response system with minimisation for functional grade and age. The study had a parallel non-comparative single-arm outcome measure. The primary outcomes were efficacy (the proportion of patients with restored ability to walk independently [functional grade ≤2] at week 4) in the eculizumab group and safety in the full analysis set. For the efficacy endpoint, we predefined a response rate threshold of the lower 90% CI boundary exceeding 50%. This trial is registered with ClinicalTrials.gov, number, NCT02493725. FINDINGS Between Aug 10, 2015, and April 21, 2016, 34 patients were assigned to receive either eculizumab (n=23) or placebo (n=11). At week 4, the proportion of the patients able to walk independently (functional grade ≤2) was 61% (90% CI 42-78; n=14) in the eculizumab group, and 45% (20-73; n=5) in the placebo group. Adverse events occurred in all 34 patients. Three patients had serious adverse events: two in the eculizumab group (anaphylaxis in one patient and intracranial haemorrhage and abscess in another patient) and one in the placebo group (depression). The possibility that anaphylaxis and intracranial abscess were related to eculizumab could not be excluded. No deaths or meningococcal infections occurred. INTERPRETATION The primary outcome measure did not reach the predefined response rate. However, because this is a small study without statistical comparison with the placebo group, the efficacy and safety of eculizumab could be investigated in larger, randomised controlled trials. FUNDING The Japan Agency for Medical Research and Development, Ministry of Health, Labor and Welfare, and Alexion Pharmaceuticals.

Somatosensory-evoked cortical potential during attacks of paroxysmal dysesthesia in multiple sclerosis

Paroxysmal dysesthesia is considered to be one of the characteristic symptoms of multiple sclerosis (MS), but the lesion responsible and the pathophysiology of this dysesthesia are not known. We report the interesting finding of somatosensory-evoked potentials (SEPs) in a patient with MS during a paroxysmal dysesthesia attack.

Utility of Autonomic Function Tests to Differentiate Dementia with Lewy Bodies and Parkinson Disease with Dementia from Alzheimer Disease

Objective: We studied autonomic disturbance in patients with dementia with Lewy bodies (DLB), Parkinson disease with dementia (PDD), Alzheimer disease (AD), to determine whether autonomic function tests can be used to distinguish these disorders. Methods: Autonomic function was tested in 56 patients with DLB, 37 patients with PDD, and 59 patients with AD by using the sympathetic skin response, coefficient of variation in R-R interval, the head-up tilt test, serum norepinephrine concentration, and 123I-meta-iodobenzylguanidine cardiac scintigraphy. Symptoms of autonomic dysfunction, such as constipation, urinary symptoms, and orthostatic hypotension, were also noted. Results: The groups did not differ on baseline characteristics other than those associated with Parkinsonism and dementia. All patients with DLB and PDD had some dysautonomia, whereas rates were much lower for patients with AD (19%). Significantly more DLB and PDD patients than AD patients showed abnormalities on autonomic function tests. Conclusions: Autonomic function tests might be quite useful to distinguish DLB and PDD from AD.

High voltage electrical stimulation of the proximal hypoglossal nerve in normal subjects

OBJECTIVES It is often difficult to stimulate the proximal hypoglossal nerve by magnetic occipital stimulation, even in normal subjects. Therefore, we tested an improved method of stimulating the proximal hypoglossal nerve, using high voltage electrical stimulation. METHODS The proximal hypoglossal nerve was activated by high voltage electrical stimulation using surface electrodes over the occipital skull. The compound muscle action potential (CMAP) was recorded from the lingual muscles using surface electrodes in 10 normal subjects. CMAP and F waves produced by distal hypoglossal nerve stimulation and motor evoked potentials produced by transcranial magnetic stimulation were also recorded. RESULTS When the anode electrode was placed at the mastoid process and the cathode below the inion, the unilateral proximal hypoglossal nerve was readily stimulated supramaximally in all the subjects. The CMAP latency was the same as that obtained with magnetic occipital stimulation. The central motor conduction time (CMCT) calculated from the proximal CMAP was 4.1+/-0.4 ms in the contralateral corticobulbar tract and 4.4+/-0.4 ms in the ipsilateral. The CMCT calculated from the minimal F wave latency was 3.3+/-0.2 ms. CONCLUSIONS The high voltage electrical stimulation is a useful method for stimulating the proximal hypoglossal nerve to estimate the CMCT of the corticobulbar tract.