William Huynh

Post-vaccination encephalomyelitis: Literature review and illustrative case

Abstract Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disease of the central nervous system that is usually considered a monophasic disease. ADEM forms one of several categories of primary inflammatory demyelinating disorders of the central nervous system including multiple sclerosis, optic neuropathy, acute transverse myelitis, and neuromyelitis optica (Devic’s disease). Post-infectious and post-immunisation encephalomyelitis make up about three-quarters of cases, where the timing of a febrile event is associated with the onset of neurological disease. Post-vaccination ADEM has been associated with several vaccines such as rabies, diphtheria–tetanus–polio, smallpox, measles, mumps, rubella, Japanese B encephalitis, pertussis, influenza, hepatitis B, and the Hog vaccine. We review ADEM with particular emphasis on vaccination as the precipitating factor. We performed a literature search using Medline (1976–2007) with search terms including “ADEM”, “acute disseminated encephalomyelitis”, “encephalomyelitis”, “vaccination”, and “immunisation”. A patient presenting with bilateral optic neuropathies within 3 weeks of “inactivated” influenza vaccination followed by delayed onset of ADEM 3 months post-vaccination is described.

Longitudinal Plasticity Across the Neural Axis in Acute Stroke

Background. With the advent of novel brain stimulation techniques aimed at improving functional outcome, understanding poststroke plasticity becomes critical for the appropriate selection of patients and optimal timing to introduce neuromodulatory interventions. Objective. To better define the temporal evolution of central and peripheral neuroplastic changes in the first 3 months after stroke and their clinical implications. Methods. Transcranial magnetic stimulation, peripheral nerve excitability, and clinical assessments were undertaken longitudinally in 31 acute stroke patients, comprising a total of 384 clinical studies. Results. During the hyperacute phase (<7 days), short-interval intracortical inhibition (SICI) was significantly reduced in lesioned (4.3% ± 1.3%) and contralesional hemispheres (3.6% ± 1.9%) compared with controls (11.4% ± 1.3%, P = .001). There were also significant alterations in accommodative properties of motor axons in the affected limb. At follow-up, SICI remained suppressed in both hemispheres in the context of significant clinical improvement. Conclusion. Simultaneous assessment of central and peripheral motor pathways has identified bilateral plastic changes that develop throughout the neural axis in acute stroke patients. It is proposed that these changes represent an adaptive response and that the persistent bihemispheric reduction in SICI may act to promote stroke recovery through cortical reorganization.

Assessment of the upper motor neuron in amyotrophic lateral sclerosis

Clinical signs of upper motor neuron (UMN) involvement are an important component in supporting the diagnosis of amyotrophic lateral sclerosis (ALS), but are often not easily appreciated in a limb that is concurrently affected by muscle wasting and lower motor neuron degeneration, particularly in the early symptomatic stages of ALS. Whilst recent criteria have been proposed to facilitate improved detection of lower motor neuron impairment through electrophysiological features that have improved diagnostic sensitivity, assessment of upper motor neuron involvement remains essentially clinical. As a result, there is often a significant diagnostic delay that in turn may impact institution of disease-modifying therapy and access to other optimal patient management. Biomarkers of pathological UMN involvement are also required to ensure patients with suspected ALS have timely access to appropriate therapeutic trials. The present review provides an analysis of current and recently developed assessment techniques, including novel imaging and electrophysiological approaches used to study corticomotoneuronal pathology in ALS.

Botulinum toxin modulates cortical maladaptation in post-stroke spasticity.

Introduction: Maladaptive plasticity involving the unaffected hemisphere (UH) in stroke patients may contribute to post‐stroke deficits, including spasticity. We investigated the central and peripheral effects of botulinum toxin in post‐stroke spasticity to determine whether there is modulation of cortical processes in the UH. Methods: Transcranial magnetic stimulation and peripheral nerve excitability studies were undertaken in 5 stroke patients with upper limb spasticity before (T1) and 6 weeks after (T2) botulinum injection. Results: Transcranial magnetic stimulation demonstrated inexcitable motor cortices of the affected hemisphere at T1 and T2, and short‐interval intracortical inhibition (SICI) in the UH was significantly reduced at T1. At T2, SICI in the UH increased significantly compared with T1, normalizing to controls, and was found to be associated with clinical improvements in spasticity. Peripheral excitability parameters were unchanged after injection. Conclusion: Cortical excitability changes were demonstrated in UH, suggesting that the clinical benefits of botulinum toxin relate to modulation of abnormal central reorganization (maladaptive plasticity) in post‐stroke spasticity. Muscle Nerve, 2013

Exploring the Evolution of Cortical Excitability Following Acute Stroke

Background. Evolution of changes in intracortical excitability following stroke, particularly in the contralesional hemisphere, is being increasingly recognized in relation to maximizing the potential for functional recovery. Objective. The present study utilized a prospective longitudinal design over a 12-month period from stroke onset, to investigate the evolution of intracortical excitability involving both motor cortices and their relationship to recovery, and whether such changes were influenced by baseline stroke characteristics. Methods. Thirty-one patients with acute unilateral ischemic stroke were recruited from a tertiary hospital stroke unit. Comprehensive clinical assessments and cortical excitability were undertaken at stroke onset using a novel threshold-tracking paired-pulse transcranial magnetic stimulation technique, and repeated at 3-, 6-, and 12-month follow-up in 17 patients who completed the longitudinal assessment. Results. Shortly following stroke, short-interval intracortical inhibition (SICI) was significantly reduced in both lesioned and contralesional hemispheres that correlated with degree of recovery over the subsequent 3 months. Over the follow-up period, ipsilesional SICI remained reduced in all patient groups, while SICI over the contralesional hemisphere remained reduced only in the groups with cortical stroke or more baseline functional impairment. Conclusions. The current study has demonstrated that evolution of intracortical excitability, particularly over the contralesional hemisphere, may vary between patients with differing baseline stroke and clinical characteristics, suggesting that ongoing contralesional network recruitment may be necessary for those patients who have significant disruptions to the integrity of ipsilesional motor pathways. Results from the present series have implications for the development of neuromodulatory brain stimulation protocols to harness and thereby facilitate stroke recovery.

Motor cortical function determines prognosis in sporadic ALS

Objective: To study the relationship between cortical function and survival in amyotrophic lateral sclerosis (ALS). Methods: A total of 216 referrals were screened, and participants with familial ALS or an inexcitable cortex were excluded. Clinical measures and phenotyping from 169 patients with sporadic ALS were combined with an assessment of cortical function using threshold tracking transcranial magnetic stimulation with indices including short interval intracortical inhibition (SICI). Peripheral nerve studies were collected, incorporating compound muscle action potential amplitude. Clinical prognostic factors were recorded longitudinally, including ALS Functional Rating Scale–Revised (ALSFRS-R). Results: Compared to 109 healthy controls, 169 patients had reduced SICI (p < 0.0001). In survival analysis, 105 patients progressed to death with an estimated median survival time of 37 months. In patients with less than 2 years disease duration (n = 140), those with bulbar onset (p = 0.017), rapid vital capacity (VC) decline (p < 0.0001), rapid ALSFRS-R decline (p < 0.0001), and reduced averaged SICI (p = 0.047) had a poorer prognosis. Multivariate analysis identified rapid VC decline (p < 0.0001), rapid ALSFRS-R decline (p = 0.0060), and reduced averaged SICI (p = 0.011) as factors independently associated with a shorter survival. Conclusions: Cortical dysfunction appears to be a prognostic marker in patients with ALS within 2 years of disease onset, such that patients with reduced averaged SICI, indicative of intracortical hyperexcitability, demonstrated a worse prognosis.

Safety and efficacy of ozanezumab in patients with amyotrophic lateral sclerosis : a randomised, double-blind, placebo-controlled, phase 2 trial

BACKGROUND Neurite outgrowth inhibitor A (Nogo-A) is thought to have a role in the pathophysiology of amyotrophic lateral sclerosis (ALS). A monoclonal antibody against Nogo-A showed a positive effect in the SOD1G93A mouse model of ALS, and a humanised form of this antibody (ozanezumab) was well tolerated in a first-in-human trial. Therefore, we aimed to assess the safety and efficacy of ozanezumab in patients with ALS. METHODS This randomised, double-blind, placebo-controlled, phase 2 trial was done in 34 centres in 11 countries. Patients aged 18-80 years with a diagnosis of familial or sporadic ALS were randomly assigned (1:1), centrally according to a computer-generated allocation schedule, to receive ozanezumab (15 mg/kg) or placebo as intravenous infusions over 1 h every 2 weeks for 46 weeks, followed by assessments at week 48 and week 60. Patients and study personnel were masked to treatment assignment. The primary outcome was a joint-rank analysis of function (ALS Functional Rating Scale-Revised) and overall survival, analysed at 48 weeks in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01753076, and with GSK-ClinicalStudyRegister.com, NOG112264, and is completed. FINDINGS Between Dec 20, 2012, and Nov 1, 2013, we recruited 307 patients, of whom 303 were randomly assigned to receive placebo (n=151) or ozanezumab (n=152). The adjusted mean of the joint-rank score was -14·9 (SE 13·5) for the ozanezumab group and 15·0 (13·6) for the placebo group, with a least squares mean difference of -30·0 (95% CI -67·9 to 7·9; p=0·12). Overall, reported adverse events, serious adverse events, and adverse events leading to permanent discontinuation of study drug or withdrawal from study were similar between the treatment groups, except for dyspepsia (ten [7%] in the ozanezumab group vs four [3%] in the placebo group), depression (11 [7%] vs five [3%]), and diarrhoea (25 [16%] vs 12 [8%]). Respiratory failure was the most common serious adverse event (12 [8%] vs seven [5%]). At week 60, the number of deaths was higher in the ozanezumab group (20 [13%]) than in the placebo group (16 [11%]), mainly as a result of respiratory failure (ten [7%] vs five [3%]). Two deaths were considered related to the study drug (bladder transitional cell carcinoma in the ozanezumab group and cerebrovascular accident in the placebo group). INTERPRETATION Ozanezumab did not show efficacy compared with placebo in patients with ALS. Therefore, Nogo-A does not seem to be an effective therapeutic target in ALS. FUNDING GlaxoSmithKline.

Differentiating lower motor neuron syndromes

Lower motor neuron (LMN) syndromes typically present with muscle wasting and weakness and may arise from pathology affecting the distal motor nerve up to the level of the anterior horn cell. A variety of hereditary causes are recognised, including spinal muscular atrophy, distal hereditary motor neuropathy and LMN variants of familial motor neuron disease. Recent genetic advances have resulted in the identification of a variety of disease-causing mutations. Immune-mediated disorders, including multifocal motor neuropathy and variants of chronic inflammatory demyelinating polyneuropathy, account for a proportion of LMN presentations and are important to recognise, as effective treatments are available. The present review will outline the spectrum of LMN syndromes that may develop in adulthood and provide a framework for the clinician assessing a patient presenting with predominantly LMN features.

Corticospinal tract dysfunction and development of amyotrophic lateral sclerosis following electrical injury

The causal relationship between electrical injury and development of amyotrophic lateral sclerosis (ALS) remains controversial. We describe the case of a 25‐year‐old man who developed ALS after a severe electrical injury. Cerebral magnetic resonance imaging (MRI) demonstrated hyperintensities involving the corticospinal tract. Functional testing with transcranial magnetic stimulation established that the motor cortex was relatively inexcitable. In addition, there were features of denervation on electromyography and muscle biopsy that supported concomitant lower motor neuron findings and the diagnosis of ALS. Muscle Nerve, 2010

Threshold tracking transcranial magnetic stimulation: Effects of age and gender on motor cortical function

OBJECTIVE Recently, the utility of threshold tracking paired-pulse transcranial magnetic stimulation (TTTMS), to measure changes in cortical excitabilitability, has been established for diagnostic purposes across a range of neurological diseases. However, the impact of healthy aging on the GABA-ergic intracortical inhibitory system remains unclear. To improve the clinical applicability, TTTMS was performed across an age spectrum. METHODS TTTMS, single-pulse TMS and nerve conduction studies (NCS) were performed in 113 healthy subjects aged between 20 and 83years (57 male and 56 female). RESULTS Prolonged motor evoked potential (MEP) latency, increased central motor conduction time, decreased compound muscle action potential (CMAP) amplitude, prolonged F-wave latency and decreased neurophysiological index (NI), calculated from CMAP amplitude, latency and F-wave frequency, were observed as subjects aged. In contrast, short interval intracortical inhibition (SICI) and facilitation did not change. Compared to females, males exhibited a reduced SICI and NI along with longer MEP, CMAP with prolonged F-wave latencies. Multivariate analyses revealed similar results. CONCLUSION Utilizing clinically applicable TTTMS protocols, findings suggest that GABA mediated intracortical inhibition may be greater in females but does not significantly change with age. SIGNIFICANCE These findings may better inform the interpretation of diagnostic TTTMS studies in the clinical setting.