Aisling M. Ryan

The phenomenon of disproportionate antecollis in Parkinson's disease and multiple system atrophy

We sought to explore the phenomenon of disproportionate antecollis in multiple system atrophy (MSA) and Parkinsons disease (PD). The etiology is much debated and the main issue is whether it represents a primary myopathy or is secondary to the underlying motor disorder. The clinical, electrophysiological, and biopsy data of MSA or PD patients with antecollis were reviewed. We reviewed 16 patients (7 MSA and 9 PD) who developed antecollis during the course of their disease. The interval between onset of motor symptoms and of antecollis was shorter in the MSA group (4.6 ± 1.7 years vs. 10.5 ± 7.0 years). In 6 patients, the antecollis developed subacutely, and in 2 the abnormal neck flexion was initially an off‐period phenomenon. Two additional patients also showed some dopa‐responsiveness. Clinically, the antecollis was characterized by a forward flexion and anterior shift of the neck, with prominent cervical paraspinal and levator scapulae muscles, usually without weakness of residual neck extension. Electromyography of cervical paraspinal muscles showed mixed myopathic, normal, and neurogenic units, without early recruitment. Cervical paraspinal muscle biopsy in 2 patients disclosed fibrosis and nonspecific myopathic changes. We suggest that, in the context of MSA or PD, the initiating event in antecollis could be a disproportionately increased tone in anterior neck muscles that leads to secondary fibrotic and myopathic changes. However, a primary but yet unexplained neck extensor myopathy still remains the alternative possibility and longitudinal studies are necessary to settle this issue.

Atypical presentation of macrophagic myofasciitis 10 years post vaccination.

Macrophagic myofasciitis (MMF) is an uncommon inflammatory disorder of muscle believed to be due to persistence of vaccine-derived aluminium hydroxide at the site of injection. The condition is characterised by diffuse myalgias, arthralgia and fatigue. We describe a patient with histologically confirmed MMF whose presentation was atypical with left chest and upper limb pain beginning more than 10 years post vaccination. Treatment with steroids led to symptomatic improvement. Although rare, clinicians should consider MMF in cases of atypical myalgia.

Skeletal-muscle channelopathies : periodic paralysis and nondystrophic myotonias

Purpose of reviewTo provide a current review of clinical phenotypes, genetics, molecular pathophysiology, and electro-diagnostic testing strategies of periodic paralysis and nondystrophic myotonias. Recent findingsThe number of pathogenic mutations causing periodic paralysis and nondystrophic myotonias continues to increase. Important insight into the molecular pathogenesis of muscle sodium channelopathies has been revealed by the finding of ‘leaky’ closed sodium channels. Previously, alterations in sodium-channel activation or inactivation have been identified as important disease mechanisms. The recent discovery that substitutions of key arginine residues in the voltage-sensing segment of the channel may lead to a ‘pore leak’ when the channel is closed suggests a new mechanism. Since similar mutations exist in corresponding positions of other channels, this mechanism may apply to other channel diseases. The recognition of different electrophysiological patterns that are specific to muscle ion-channel genotypes will be useful in diagnosis and in guiding genetic testing. Recent studies demonstrate that magnetic resonance imaging may be used to detect intramuscular accumulation of sodium during episodes of weakness. SummaryRecent advances have refined our ability to make a precise molecular diagnosis in muscle channelopathies. The description of a pore leak with voltage-sensor mutations may represent a new disease mechanism.

A novel alteration of muscle chloride channel gating in myotonia levior

Mutations in the voltage‐dependent skeletal muscle chloride channel, ClC‐1, result in dominant or recessive myotonia congenita. The Q552R mutation causes a variant of dominant myotonia with a milder phenotype, myotonia levior. To characterise the functional properties of this mutation, homodimeric mutant and heterodimeric wild‐type (WT) mutant channels were expressed in tsA201 cells and studied using the whole‐cell recording technique. Q552R ClC‐1 mutants formed functional channels with normal ion conduction but altered gating properties. Mutant channels were activated by membrane depolarisation, with a voltage dependence of activation that was shifted by more than +90 mV compared to WT channels. Q552R channels were also activated by hyperpolarisation, and this process was dependent upon the intracellular chloride concentration ([Cl−]i). Together, these alterations resulted in a substantial reduction in the open probability at −85 mV at a physiological [Cl−]i. Heterodimeric WT‐Q552R channels did not exhibit hyperpolarisation‐activated gating transitions. As was the case for WT channels, activation occurred upon depolarisation, but the activation curve was shifted by 28 mV to more positive potentials. The functional properties of heterodimeric channels suggest a weakly dominant effect, a finding that correlates with the inheritance pattern and symptom profile of myotonia levior.

A population-based epidemiologic study of adult neuromuscular disease in the Republic of Ireland

Objective: To estimate the prevalence rates (PRs) of acquired and inherited neuromuscular diseases (NMD) in the adult Irish population, reflecting the burden of these conditions in a single country. Methods: This population-based study was performed in the Republic of Ireland (RoI), with a PR estimated for December 2013. Multiple case ascertainment sources were utilized. Demographic and clinical information and relevant diagnostic results were registered. Results: A total of 2,641 adults were identified, giving a PR of 62.6/100,000 (95% confidence interval [CI] 59.95–65.24) for all NMD in RoI. Disease-specific PR include chronic inflammatory demyelinating polyradiculoneuropathy 5.87/100,000 (95% CI 5.06–6.68), Charcot-Marie-Tooth 10.52/100,000 (95% CI 9.44–11.61), hereditary neuropathy with liability to pressure palsies 0.84/100,000 (95% CI 0.54–1.15), myotonic dystrophy type I 6.75/100,000 (95% CI 5.88–7.61), Duchenne muscular dystrophy 3.0/100,000 (95% CI 2.33–3.70), Becker muscular dystrophy 2.2/100,000 (95% CI 1.64–2.88), facioscapulohumeral dystrophy 2.59/100,000 (95% CI 2.05–3.13), limb-girdle muscular dystrophy 2.88/100,000 (95% CI 2.31–3.45), periodic paralysis 1.72/100,000 (95% CI 1.28–2.15), myotonia congenita 0.32/100,000 (95% CI 0.18–0.56), paramyotonia congenita 0.15/100,000 (95% CI 0.06–0.34), Kennedy disease 0.83/100,000 (95% CI 0.40–1.27), Lambert-Eaton myasthenic syndrome 0.29/100,000 (95% CI 0.11–0.47), myasthenia gravis 15.12/100,000 (95% CI 13.82–16.42), and sporadic inclusion body myositis 11.7/100,000 (95% CI 9.82–13.58). PR for amyotrophic lateral sclerosis was established from an existing Register as 7.20/100,000 (95% CI 6.34–8.15). Conclusions: The PR of all adult NMD in RoI is relatively high when compared with other chronic neurologic disorders, although some figures may be an underestimate of the true prevalence. The data provide a framework for international comparison and service planning.

Vascular dysplasia in neurofibromatosis type 2

Neurofibromatosis type 1 (NF1) and 2 (NF2) are autosomal dominant disorders characterized by dysplasia in tissues of mesodermal and neuro-ectodermal origin. NF1 is associated with pigmented cutaneous lesions, neurofibromas, and other systemic features including pheochromocytoma, scoliosis, and epilepsy.1 An important cause of morbidity and mortality is an associated vasculopathy causing stenosis, occlusion, aneurysm, or arteriovenous fistula formation.2 Patients with NF2 have few cutaneous lesions but a strong propensity to develop multiple tumors of the CNS, particularly bilateral vestibular schwannomas (VS).3 Systemic features are rare and vasculopathy is not known to be a manifestation of NF2. We report a case of intracerebral vascular dysplasia leading to left middle cerebral artery (MCA) infarction in a patient with molecularly confirmed NF2. An 18-year-old right-handed woman was diagnosed clinically with NF2 in another institution. On presentation at age 11, she had a right trigeminal neuropathy, right eye proptosis, bilateral papilledema, and partial right third nerve palsy. …

The use of cytokine signature patterns: separating drug naïve, interferon and natalizumab-treated multiple sclerosis patients

Abstract Multiple sclerosis (MS) is an inflammatory illness characterized by demyelination and axonal neurodegeneration. Here, we used serum samples from MS patients to demonstrate if “cytokine signature” patterns can separate different patient groups better than using single cytokines. In this case, we used cytokine profiling to demonstrate if “cytokine signature” patterns can separate MS patients treated with interferon or natalizumab from drug naïve patients. Serum levels of eight individual cytokines (TNFα, IFNγ, S100B, IL-1β, IL-6, IL-8, IL-17 and IL-23) in MS patients treated with interferons (n = 11) and natalizumab (n = 14) were measured and, in general, showed reduced levels compared to drug naïve MS patients (n = 12). More evident changes were seen when analyzing “cytokine signatures” (i.e. summed value of all eight cytokines), which showed that patients treated with natalizumab and interferons showed significantly reduced cytokine signature levels than drug naïve MS patients. Moreover, patients treated with natalizumab were separated from drug naïve patients by almost 100% fidelity and that patients treated with natalizumab also had reduced levels of pro-inflammatory cytokines compared to patients treated with interferon. Overall, this study provides an example showing that the use of “cytokine signatures” may provide benefits over the analysis of single cytokines for the development of potential biomarkers.

Impact of Exercise on Innate Immunity in Multiple Sclerosis Progression and Symptomatology.

Multiple Sclerosis (MS), an idiopathic progressive immune-mediated neurological disorder of the central nervous system (CNS), is characterized by recurrent episodes of inflammatory demyelination and consequent axonal deterioration. It accounts for functional deterioration and lasting disability among young adults. A body of literature demonstrates that physical activity counteracts fatigue and depression and may improve overall quality of life in MS patients. Furthermore, much data indicates that exercise ameliorates chronic neuroinflammation and its related pathologies by tipping cytokine profiles toward an anti-inflammatory signature. Recent data has focused on the direct impact of exercise training on the innate immune system by targeting toll-like receptors (TLRs), signaling pattern recognition receptors that govern the innate immune response, shedding light on the physiological role of TLRs in health and disease. Indeed, TLRs continue to emerge as players in the neuroinflammatory processes underpinning MS. This review will highlight evidence that physical activity and exercise are potential immunomodulatory therapies, targeting innate signaling mechanism(s) to modulate MS symptom development and progression.

Simultaneous transverse myelitis and acute motor axonal neuropathy in an adult.

Transverse myelitis (TM), which is characterised by focal spinal-cord inflammation, may be idiopathic, parainfectious or disease associated. Diseases associated with TM include demyelinating conditions and connective tissue disorders. Apart from TM due to direct spinal-cord infection, TM is autoimmune.1 Acute motor axonal neuropathy (AMAN), a subtype of Guillain–Barre syndrome (GBS), is characterised by peripheral motor axonal neuropathy, is autoimmune and usually post-infectious. To our knowledge, there are no adult reports of simultaneous TM and AMAN. We report a case of concomitant TM and AMAN in an adult and describe the response to immune modulation. A 19-year-old male presented to the neurology services with a 2-day history of progressive bilateral lower limb weakness, urinary retention and a band of numbness around the waist extending into the feet. Two weeks previously, he had a diarrhoeal illness lasting 3 days. Muscle strength testing revealed weakness of right hip flexion (MRC grade 4), bilateral knee flexion (grade 3), …

VGKC positive autoimmune encephalopathy mimicking dementia.

Voltage gated potassium channel antibodies (VGKC Abs) are known to cause three rare neurological syndromes- neuromyotonia, Morvan’s syndrome and limbic encephalitis although an increasing array of other associated neurological symptoms are becoming recognised. The authors describe the case of a 60-year-old female who presented to the neurology clinic with an apparent early onset dementing process. She was noted to have both extrapyramidal and frontal release signs on examination and was admitted for further evaluation. Her dementia investigation including a neoplastic screen was negative except for VGKC antibody positivity. Her symptoms dramatically improved with commencement of immunosuppression. A non-paraneoplastic VGKC antibody associated dementia-like syndrome has rarely been described. The authors add to the few existing reports of what represents an important reversible cause of cognitive impairment.