Srikanth Muppidi

MG-ADL: still a relevant outcome measure.

The aim of this analysis was to examine the performance of the Myasthenia Gravis–specific Activities of Daily Living scale (MG‐ADL) during a multicenter scale validation study.

The Myasthenia Gravis-Specific Activities of Daily Living Profile

The myasthenia gravis activities of daily living (MG‐ADL) profile is an eight‐item patient‐reported scale developed to assess MG symptoms and their effects on daily activities. The MG‐ADL profile correlated well with the Quantitative MG (QMG) score (r= 0.58, P < 0.001) in 254 consecutive patient visits. Further analysis during clinical trials confirmed the excellent correlation with the QMG test and provided additional evidence that the MG‐ADL profile is responsive to clinical improvement. MG‐ADL performance was further analyzed during a recent multicenter, prospective scale validation study for two new outcome measures. At the first visit, there was a strong positive correlation between the MG‐ADL and the MG Composite (r= 0.85, P < 0.0001) and between the MG‐ADL and the MG‐Quality of life15 (MG‐QOL15) (r= 0.76, P < 0.0001). Test–retest analysis demonstrated a high reliability coefficient. Sensitivity/specificity analysis revealed that a 2‐point improvement has the best trade‐off attributes to predict clinical improvement. The MG‐ADL profile also performed well on Rasch analysis. The MG‐ADL scoring system is useful as a secondary outcome measure and in routine clinical management.

Autoimmune autonomic failure

Autoimmune autonomic ganglionopathy is a syndrome of panautonomic failure caused by antibodies to ganglionic acetylcholine receptors. The clinical syndrome is characterized by significant postural hypotension, diffuse cholinergic and adrenergic impairment, gastrointestinal dysmotility, urinary retention, and pupillary dysfunction. While acute to subacute onset of disease is commonly seen, chronic, slowly progressive variants have been described. Serological testing for ganglionic acetylcholine receptor antibodies helps confirm the diagnosis. These antibodies cause a similar phenotype of autonomic failure in animal models indicating that an antibody-mediated functional impairment of ganglionic transmission is the underlying etiology. Decrease in antibody levels correlates with clinical improvement. Patients may respond to immunomodulatory therapies such as prednisone, intravenous immunoglobulin, plasma exchange, and oral immunosuppressants. A combination treatment is often required as well as symptomatic therapy.

Muscle-specific receptor tyrosine kinase antibody-positive and seronegative myasthenia gravis.

BACKGROUND/AIMS To summarize current understanding of muscle-specific receptor tyrosine kinase antibody (MuSKAb)-positive and seronegative myasthenia gravis (MG). METHODS We reviewed the current literature on MuSK and seronegative MG, and placed lighter emphasis on seronegative MG studies published prior to the discovery of MuSKAb. RESULTS MuSKAb are detected in approximately 40% of generalized acetylcholine receptor antibody (AChRAb)-negative MG, but the rate of sero-positivity differs across the globe. MuSK MG patients are predominantly female, have prominent cranial and bulbar involvement, and tend to have a higher rate of crises than those with other forms of MG. Disease onset tends to be earlier, with most patients presenting by the third or fourth decade. The yield of repetitive nerve stimulation on conventional limb muscles is lower in both MuSK MG and seronegative ocular MG. Including cranial muscles increases the yield. Single-fiber electromyography of distal limb muscles tends to have a lower rate of abnormality in MuSK MG than in either AChRAb-positive or seronegative MG. MuSK MG patients are more likely to display poor tolerance ofor a lack of improvement with anticholinesterase agents; this is not a feature of seronegative myasthenia. Both MuSK and seronegative MG patients are managed successfully with immunomodulatory therapies, but a higher proportion of MuSK MG patients have a refractory course. Evidence for a favorable response to thymectomy in both MuSK and seronegative MG is limited. CONCLUSION MuSK and seronegative MG are distinct entities. Clinical characteristics and response to symptomatic andimmunomodulatory treatments show meaningful differences for these two populations when compared to AChRAb-positive MG.

Isolated neck extensor myopathy: Is it responsive to immunotherapy?

Objective: To determine if isolated neck extensor myopathy (INEM) is responsive to immunosuppressive treatment. Methods: We retrospectively reviewed charts of patients with INEM from 2002 to 2008 to identify patients and determine the response to immunomodulatory therapy. Clinical, electrodiagnostic, histologic, and radiographic data were reviewed. Results: Four patients were identified during the study period. Three were women. The age of onset of neck extensor weakness ranged from 58 to 78 years. Serum creatine kinase levels were within normal limits in all patients. None had clinical, laboratory, or electrophysiological findings to suggest a generalized neuromuscular disorder. On electrodiagnostic studies, all patients had myopathic changes with or without irritative features in cervical paraspinal muscles. No inflammation was present on muscle biopsy from three of the patients. All patients received one or more immunosuppressive agents. Neck strength improved by 1 point or greater on the Medical Research Council scale in all subjects with a peak response observed between 3 and 6 months after treatment initiation. Conclusions: A trial of immunosuppressive agents should be offered to patients with INEM because a subset will improve. Rigorously defined, INEM is a noninflammatory myopathy. However, a focal myositis could be missed on muscle biopsy and may explain the favorable response to treatment.

Is pure autonomic failure an early marker for Parkinson disease, dementia with Lewy bodies, and multiple system atrophy? And other updates on recent autonomic research

Pure autonomic failure (PAF) is a disorder of a-synuclein deposition that results in neurogenic orthostatic hypotension (OH) and other features of autonomic failure, without signs of central nervous system (CNS) involvement. If patients are followed for a sufficient period, some may eventually develop Parkinson disease (PD), multiple system atrophy (MSA), or dementia with Lewy bodies (DLB). Determining which patients will go on to convert to a CNS synucleinopathy and which will remain as PAF has been, so far, a prognostic dilemma for medical providers. Is PAF purely peripheral and restricted to the autonomic nerves, or does it presage a more widespread CNS disorder? A recent pivotal paper published in the Annals of Neurology by members of the U.S. Autonomic Disorders Consortium reports the results of the natural history of pure autonomic failure, enrolling patients with PAF and followed annually for a 4-year period [3]. All subjects underwent extensive clinical and autonomic testing, including cognitive screening, olfaction, and supine, and upright serum norepinephrine levels. This multi-center study performed at five U.S. sites enrolled 75 patients with PAF, the largest cohort reported to date. The majority of them were male (70%), and the mean duration of disease since onset of autonomic symptoms was 5 years. Ninety-five percent of patients reported orthostatic intolerance, 58% constipation, 50% urinary symptoms, 44% abnormalities of sweating, and 65% of men reported erectile dysfunction. All patients had evidence of OH on tilt testing, and all patients had an absent phase IV overshoot on Valsalva maneuver, indicative of neurogenic OH (nOH). Seventy-one percent had reduced heart rate variability with deep breathing and 54% had reduced serum norepinephrine levels on upright tilt. The prevalence of probable rapid eye movement (REM) sleep behavior disorder (RBD) by questionnaires was 72%, raising the possibility of brainstem involvement. Interestingly, a similar prevalence of polysomnography-confirmed RBD (63%) was documented in a small cohort of PAF patients [4]. Olfactory function was significantly impaired in 73% of the natural history cohort, further indicating CNS involvement. At 1-year follow up, 15% of patients converted to a CNS synucleinopathy (two PD, four DLB, and five MSA). The conversion rates of the remaining patients at years two, three, and four were 13, 13, and 27%, respectively. Predictors of phenoconversion to PD/DLB included impaired olfactory function with probable RBD, and phenoconverstion to MSA included preserved olfaction with probable RBD. Subtle motor deficits were noted in 88% of patients that converted to a CNS synucleinopathy. This study supports the notion that a-synuclein spreads in a prion-like fashion through adjacent cells. However, not all patients with a PAF phenotype may be associated with a-synuclein spread, as described in a case-report in this issue of Clinical Autonomic Research [2]. The Natural History Study of Synucleinopathies continues on its second iteration, as a multi-center, National Institutes of Health (NIH)-sponsored study hoping to expand these results. Several sites in North America, South America, Europe, and Asia participating in this study are currently enrolling patients with PAF, MSA and idiopathic RBD in order to document the natural history of these & Srikanth Muppidi muppidis@stanford.edu

Multiple intracerebral hemorrhages after cervical epidural injections

Epidural steroid injections are commonly used to treat chronic pain secondary to radiculopathy. Complications of epidural injections include unintentional dural puncture, vasovagal syncope, apnea, and hypotension. Cervical epidural injections are associated with higher rates of complications than lumbar or caudal epidural injections.1 Recent American Academy of Neurology guidelines do not recommend epidural injections for radicular pain.2 We report a rare complication of low CSF pressure headache and multiple simultaneous intraparenchymal hemorrhages, occurring 7 days after cervical epidural injection. ### Case report. A 36-year-old left-handed woman with a history of a motor vehicle accident 1 year prior to admission presented with left-sided weakness and paresthesias of her right hand. She had chronic cervical neck pain since her motor vehicle accident, and was treated with a series of four cervical epidural anesthetic injections. She had no complications following the first three injections. The patient then had a fourth cervical epidural injection with no indication of dural puncture. However, approximately 4 days after this epidural injection she developed a positional, holoacranial, throbbing headache. The headache became severe when she was in the upright or sitting position and dramatically decreased with …

Reversible right vagal neuropathy.

Vagus nerve efferent fibers carry the parasympathetic innervation to the heart. The right and left vagal nerve innervation to the heart is believed to be asymmetric, with the right vagal nerve providing most of the parasympathetic innervation to the atria and sinoatrial (SA) node. The left vagal nerve carries parasympathetic innervation to the ventricles. This anatomic and physiologic asymmetry has been studied in animals1 but not as extensively in humans. Cardiovascular parasympathetic function can be assessed noninvasively by measuring the heart rate variability in response to deep breathing (heart rate deep breathing range [HRDB]) or heart rate changes during the Valsalva maneuver (Valsalva ratio [VR]).2

Autonomic dysfunction predicts poor outcome in stroke: Updates on recent autonomic research

Inpatient neurologists are well aware of how common autonomic dysfunction is in patients with acute stroke. For those of us who no longer practice inpatient medicine, we can still remember the many stroke patients we cared for during our neurology training: labile blood pressures, refractory hypertension, fevers, and cardiac arrhythmias were not uncommon, despite aggressive treatments. Research has demonstrated that impaired heart rate variability correlates with both post-stroke disability [4] and all-cause mortality [5]. What is less clear is the how the magnitude of autonomic dysfunction in the acute stroke period influences stroke recovery. Xiong and colleagues have attempted to help answer this question in their recent paper published in the December 4, 2017 issue of Stroke [6]. The authors recruited 150 adult patients who were admitted for mild acute ischemic stroke (NIHSS 4–10). Stroke was confirmed on imaging, and patients were recruited within 7 days of stroke symptom onset. Patients with arrhythmias such as atrial fibrillation were excluded, as were those with hemodynamic instability or major concurrent illness (ex. chronic obstructive pulmonary disease, renal failure, active malignancy), as these variables may have altered autonomic testing results. Autonomic cardiovascular testing was performed with a portable system (Task Force Monitoring, CNSystems) capable of measuring beat-to-beat BP and HR. All patients underwent measures of HR variability with deep breathing, Valsalva maneuver, sustained handgrip testing, and active standing to calculate BP responses and the 30:15 ratio. Patients were grouped according to the Ewing classification [7]: Normal: all tests normal or one borderline; early involvement: one of the three HR tests abnormal or two borderline; definite involvement: two or more of the HR tests abnormal; severe involvement: two or more of the HR tests abnormal plus one or both of the BP pressure tests abnormal, or both borderline; atypical pattern: any other combination of abnormal tests. Patients with normal or early impairment were classified as “minor autonomic function impairment” by the authors, whereas the remaining patients in the definite, severe, or atypical groups were classified as “significant autonomic function impairment.” Patients were reassessed at 3 months, and their outcome was dichotomized based on their Rankin score: good (modified Rankin Scale score 0–2) or poor (modified Rankin Scale score 3–6). The authors then calculated odds ratios of the magnitude of autonomic dysfunction related to poor functional outcome. Most patients were men (71%), with a mean age of 66.4 ± 9.9 years. The majority (76.0%) of patients were classified as having significant autonomic dysfunction. After adjusting for statistically significant confounding variables, such as gender and NIHSS on admission, the magnitude of autonomic dysfunction independently predicted an unfavorable outcome, with an odds ratio of 3.263 (95% confidence interval, 1.141–9.335; p = 0.027). A poor functional outcome was seen in 32.5% of patients with significant autonomic impairment, compared to 13.9% of patients with minor autonomic impairment (p = 0.031). Patients in the poor outcome group were more likely to be women, have a higher NIHSS score on admission, and have more significant autonomic dysfunction. The authors suggest several possible explanations for the greater risk of poor outcome in those with significant * Srikanth Muppidi muppidis@stanford.edu

Postural tachycardia in hypermobile Ehlers-Danlos syndrome: A distinct subtype?

INTRODUCTION It is not clear if patients with postural tachycardia syndrome (POTS) and Ehlers-Danlos syndrome (hEDS) differ from patients with POTS due to other etiologies. We compared the results of autonomic testing and healthcare utilization in POTS patients with and without hEDS. METHODS Patients with POTS+hEDS (n=20) and POTS controls without hypermobility (n=20) were included in the study. All patients underwent autonomic testing, and the electronic medical records were reviewed to determine the number and types of medications patients were taking, as well as the number of outpatient, emergency department, and inpatient visits over the prior year. RESULTS Patients with hEDS had twice as many outpatient visits (21 v. 10, p=0.012), were taking more prescription medications (8 vs. 5.5, p=0.030), and were more likely to see a pain physician (70% vs 25%, p=0.005). Autonomic testing demonstrated a slight reduction in heart rate variability and slightly lower blood pressures on tilt table testing in hEDS patients, however for most patients these variables remained within the range of normal. Orthostatic tachycardia on tilt table testing was greater in POTS controls (46bpm vs 39bpm, p=0.018). Abnormal QSweat responses were common in both groups (38% of POTS+hEDS and 36% of POTS controls). CONCLUSIONS While autonomic testing results were not significantly different between groups, patients with POTS+hEDS took more medications and had greater markers of healthcare utilization, with chronic pain likely playing a prominent role.