Multisystem Involvement in Post-Acute Sequelae of Coronavirus Disease 19.

OBJECTIVE: The purpose of this study was to describe cerebrovascular, neuropathic, and autonomic features of post-acute sequelae of coronavirus disease 2019 ((COVID-19) PASC). METHODS: This retrospective study evaluated consecutive patients with chronic fatigue, brain fog, and orthostatic intolerance consistent with PASC. Controls included patients with postural tachycardia syndrome (POTS) and healthy participants. Analyzed data included surveys and autonomic (Valsalva maneuver, deep breathing, sudomotor, and tilt tests), cerebrovascular (cerebral blood flow velocity [CBFv] monitoring in middle cerebral artery), respiratory (capnography monitoring), and neuropathic (skin biopsies for assessment of small fiber neuropathy) testing and inflammatory/autoimmune markers. RESULTS: Nine patients with PASC were evaluated 0.8 ± 0.3 years after a mild COVID-19 infection, and were treated as home observations. Autonomic, pain, brain fog, fatigue, and dyspnea surveys were abnormal in PASC and POTS (n = 10), compared with controls (n = 15). Tilt table test reproduced the majority of PASC symptoms. Orthostatic CBFv declined in PASC (-20.0 ± 13.4%) and POTS (-20.3 ± 15.1%), compared with controls (-3.0 ± 7.5%, p = 0.001) and was independent of end-tidal carbon dioxide in PASC, but caused by hyperventilation in POTS. Reduced orthostatic CBFv in PASC included both subjects without (n = 6) and with (n = 3) orthostatic tachycardia. Dysautonomia was frequent (100% in both PASC and POTS) but was milder in PASC (p = 0.002). PASC and POTS cohorts diverged in frequency of small fiber neuropathy (89% vs 60%) but not in inflammatory markers (67% vs 70%). Supine and orthostatic hypocapnia was observed in PASC. INTERPRETATION: PASC following mild COVID-19 infection is associated with multisystem involvement including: (1) cerebrovascular dysregulation with persistent cerebral arteriolar vasoconstriction; (2) small fiber neuropathy and related dysautonomia; (3) respiratory dysregulation; and (4) chronic inflammation. ANN NEUROL 2022;91:367-379.

Network autonomic analysis of post-acute sequelae of COVID-19 and postural tachycardia syndrome.

BACKGROUND: The autonomic nervous system (ANS) is a complex network where sympathetic and parasympathetic domains interact inside and outside of the network. Correlation-based network analysis (NA) is a novel approach enabling the quantification of these interactions. The aim of this study is to assess the applicability of NA to assess relationships between autonomic, sensory, respiratory, cerebrovascular, and inflammatory markers on post-acute sequela of COVID-19 (PASC) and postural tachycardia syndrome (POTS). METHODS: In this retrospective study, datasets from PASC (n = 15), POTS (n = 15), and matched controls (n = 11) were analyzed. Networks were constructed from surveys (autonomic and sensory), autonomic tests (deep breathing, Valsalva maneuver, tilt, and sudomotor test) results using heart rate, blood pressure, cerebral blood flow velocity (CBFv), capnography, skin biopsies for assessment of small fiber neuropathy (SFN), and various inflammatory markers. Networks were characterized by clusters and centrality metrics. RESULTS: Standard analysis showed widespread abnormalities including reduced orthostatic CBFv in 100%/88% (PASC/POTS), SFN 77%/88%, mild-to-moderate dysautonomia 100%/100%, hypocapnia 87%/100%, and elevated inflammatory markers. NA showed different signatures for both disorders with centrality metrics of vascular and inflammatory variables playing prominent roles in differentiating PASC from POTS. CONCLUSIONS: NA is suitable for a relationship analysis between autonomic and nonautonomic components. Our preliminary analyses indicate that NA can expand the value of autonomic testing and provide new insight into the functioning of the ANS and related systems in complex disease processes such as PASC and POTS.

Lorlatinib After Alectinib-Induced Pneumonitis: A Case Report.

ALK gene rearrangements are detected in approximately 3% to 5% of NSCLC. ALK tyrosine kinase inhibitors, such as third-generation lorlatinib, have exhibited remarkable efficacy in ALK-rearranged NSCLC; however, they have been associated with a low incidence of treatment-limiting and potentially fatal drug-induced interstitial lung disease (ILD). There is concern that this may represent a class effect, a theory that is supported by a number of case reports. Because of clinical trial exclusion criteria, there are limited prospective data to guide decision-making after ALK tyrosine kinase inhibitors-induced ILD. A systematic review of the literature was conducted and only identified four reported cases of lorlatinib safety in this context. Here, we report the successful sequencing of lorlatinib in a patient who discontinued alectinib secondary to grade 3 drug-induced ILD.

Mismatch between subjective and objective dysautonomia.

Autonomic symptom questionnaires are frequently used to assess dysautonomia. It is unknown whether subjective dysautonomia obtained from autonomic questionnaires correlates with objective dysautonomia measured by quantitative autonomic testing. The objective of our study was to determine correlations between subjective and objective measures of dysautonomia. This was a retrospective cross-sectional study conducted at Brigham and Women's Faulkner Hospital Autonomic Laboratory between 2017 and 2023 evaluating the patients who completed autonomic testing. Analyses included validated autonomic questionnaires [Survey of Autonomic Symptoms (SAS), Composite Autonomic Symptom Score 31 (Compass-31)] and standardized autonomic tests (Valsalva maneuver, deep breathing, sudomotor, and tilt test). The autonomic testing results were graded by a Quantitative scale for grading of cardiovascular reflexes, sudomotor tests and skin biopsies (QASAT), and Composite Autonomic Severity Score (CASS). Autonomic testing, QASAT, CASS, and SAS were obtained in 2627 patients, and Compass-31 in 564 patients. The correlation was strong between subjective instruments (SAS vs. Compass-31, r = 0.74, p < 0.001) and between objective instruments (QASAT vs. CASS, r = 0.81, p < 0.001). There were no correlations between SAS and QASAT nor between Compass-31 and CASS. There continued to be no correlations between subjective and objective instruments for selected diagnoses (post-acute sequelae of COVID-19, n = 61; postural tachycardia syndrome, 211; peripheral autonomic neuropathy, 463; myalgic encephalomyelitis/chronic fatigue syndrome, 95; preload failure, 120; post-treatment Lyme disease syndrome, 163; hypermobile Ehlers-Danlos syndrome, 213; neurogenic orthostatic hypotension, 86; diabetes type II, 71, mast cell activation syndrome, 172; hereditary alpha tryptasemia, 45). The lack of correlation between subjective and objective instruments highlights the limitations of the commonly used questionnaires with some patients overestimating and some underestimating true autonomic deficit. The diagnosis-independent subjective-objective mismatch further signifies the unmet need for reliable screening surveys. Patients who overestimate the symptom burden may represent a population with idiosyncratic autonomic-like symptomatology, which needs further study. At this time, the use of autonomic questionnaires as a replacement of autonomic testing cannot be recommended.

The Neurologic Exam.

For most of human history, diseases preying upon the nervous system could only be identified indirectly through neurological signs-making the neurology clinician's examination the principal diagnostic tool. While advanced imaging and electrophysiology of today's practice provides greater diagnostic precision, the wide array of tools available and their applications emphasizes the accuracy that the neurological examination provides to localization, which in turn enables our technology's precision to effectively and efficiently aid one's diagnosis.

The prognostic value of the derived neutrophil-to-lymphocyte ratio (dNLR) in patients treated with immune checkpoint inhibitors.

BACKGROUND: The (derived) neutrophil-to-lymphocyte ratio (dNLR) is a potential predictive biomarker in the era of checkpoint inhibitors (CPI). An elevated dNLR is associated with worse outcomes across several malignancies. However, there is no clearly defined cut-off in the clinical setting. AIM: To compare outcomes in patients prescribed CPI with a baseline dNLR0 > 3 and dNLR0 ≤ 3. The dNLR6 was measured 6 weeks later to determine its impact on patient overall survival (OS). METHODS: Prospectively maintained pharmacy databases in a regional cancer centre were interrogated for patients who were prescribed CPI in the advanced setting between January 2017 and May 2020. RESULTS: There were 121 patients with advanced cancer and a median age of 68 (range 30 to 88) years. Forty-four percent (n = 53) received prior systemic therapy. Patients with an initial dNLR0 > 3 when compared with a dNLR0 ≤ 3 had significantly shorter median progression-free survival (PFS), 3 vs. 14 months (p = 0.001) and median OS, 6.4 vs. 30.2 months (p = 0.001). Patients with an initial dNLR0 > 3 and increased dNLR at 6 weeks (dNLR6) had significantly reduced median PFS (3.5 vs. 14.7 months, p = 0.03) and OS (5.7 vs. 16.3, p = 0.03) when compared with those whose dNLR decreased. In the dNLR0 ≤ 3 cohort, any increased dNLR when compared with decreased dNLR after 6 weeks of CPI had significantly reduced PFS (8.4 months vs. NR, p = 0.01) and OS (24.2 months vs. NR, p = 0.02). CONCLUSIONS: Lower pre-CPI treatment dNLR is associated with improved OS. A decrease in dNLR during treatment confers improved OS.

Lack of familiarity with genetic testing among patients in Ireland with Cancer.

BACKGROUND: Cancer gene panel testing is available in Ireland. The need for a clear strategy to deal with patient information generated from tumour genomic testing is recognised as a challenge in the National Cancer Strategy. However, the public's attitude and opinions regarding these results is not known in Ireland. AIMS: This prospective questionnaire study assessed the knowledge and opinions of patients in a national oncology centre, surrounding cancer gene panel testing. METHODS: An anonymised modified validated questionnaire was completed by volunteering patients in the medical oncology department. It comprised 14 questions which assessed patient's familiarity, intention, benefits and concerns associated with tumour genetic testing using a four-point Likert scale. Patients recorded their primary cancer diagnosis and family cancer history. RESULTS: Eighty-four patients completed the questionnaire with 77 (92%) patients declaring their primary cancer diagnosis. The median age was 56 (range 26 to 83) years. Overall, 42% (n = 35) of oncology patients were familiar/somewhat familiar with testing and 90% (n = 76) stated they would avail of genetic testing if available. Patients with breast cancer were no more likely to avail of genetic testing when compared with the non-breast cancer cohort (n = 21 vs. 56, p = 0.58) though they identified concerns with potential discrimination. CONCLUSION: This is the first prospective Irish study to assess opinions surrounding cancer gene results. Addressing patient's lack of information as regards genetic testing is the first step in establishing a national cancer genetics testing programme in Ireland.

Hypnic headache secondary to haemangioblastoma of the cerebellum.

We report a case of secondary hypnic headache in a patient with a haemangioblastoma of the cerebellum. The number of secondary cases is steadily increasing in the medical literature and magnetic resonance imaging of the brain should be considered mandatory after arriving at a presumptive diagnosis.

Pain Neurology.

Pain is often the initial complaint for which patients seek medical care, presenting both a diagnostic and therapeutic challenge to the primary care provider. The appreciation of pain is not merely the result of abnormal sensory stimulation causing an unpleasant sensation but rather a combination of the recognition of the somatic discomfort in association with an emotional response to that discomfort. The perception of pain and the extent of distress and disability can vary depending on previous experience, cultural background, situational factors, and comorbid psychiatric disease. Though acute pain is usually the result of tissue damage, this is not always the case, as evidenced by primary headache disorders. Chronic pain may be the result of an injury, irreversible underlying disease, or clinical conditions such as fibromyalgia for which the mechanism remains unclear. Treatment of the underlying cause will usually effect a resolution or improvement in the pain, but when the discomfort persists, a consultation with a neurologist or pain management specialist should be considered.

Headache.

Headache, an almost universal human experience, is one of the most common complaints encountered in medicine and neurology. Described and categorized since antiquity, with the first classification by Aretaeus of Cappadocia, other classifications followed. The evaluation of this condition may be straightforward or challenging, and, though often benign, headache may prove to be an ominous symptom. This review discusses the current diagnosis and classification of headache disorders and principles of management, with a focus on migraine, tension-type headache, trigeminal autonomic cephalgias, and various types of daily headache.

Value of Patient-Directed Brain Magnetic Resonance Imaging Scan with a Diagnosis of Migraine.

BACKGROUND: The objective of this study was to determine whether a brain magnetic resonance imaging (MRI) scan in patients with a diagnosis of migraine, who insist on the performance of imaging, is of more benefit in detecting clinically significant unsuspected structural abnormalities than would be expected by chance. METHODS: This prospective, observational, single-center study was performed from January 1, 2010 to December 31, 2012 and included 100 subjects with a diagnosis of migraine and normal results on neurologic examination. A brain MRI scan was performed on all patients, solely at their request, to detect an unsuspected clinically significant structural lesion. RESULTS: Of the 100 patients, 86 were female, and the average age was 31.5 years. Forty-five patients experienced migraine without aura, 41 chronic migraine, and 14 migraine with aura. All of the patients had normal results on neurologic examination. The duration of headaches ranged from 4 months to 40 years. In all, 82 of the MRI scans showed normal results, and 17 revealed clinically insignificant abnormalities. One MRI in a patient with chronic migraine without aura revealed a meningioma that subsequently required surgery and radiation therapy. The 1% prevalence of tumor in this study was then compared with 2 large cohorts of MRI abnormalities in the general asymptomatic population, in which tumor was found in 35 out of 3000. Fisher's exact test was used to compare the prevalence of tumor in the study population with the combined cohorts, and there was no statistical difference between these rates (P > .99). CONCLUSIONS: Brain MRI obtained at the specific request of patients with a diagnosis of migraine in the presence of normal neurologic examination results has a yield that is equivalent to that of the general asymptomatic population. Patients do not seem to have more insight than the examining clinician with regard to detecting underlying structural abnormalities, and brain MRI should not performed as part of the routine evaluation of migraine without a clear clinical indication.

Concussion.

Concussion has been recognized as a clinical entity for more than 1000 years. Throughout the 20th century it was studied extensively in boxers, but it did not pique the interest of the general population because it is the accepted goal of the boxer to inflict such an injury on their opponent. In 2002, however, the possibility that repetitive concussions could result in chronic brain damage and a progressive neurologic disorder was raised by a postmortem evaluation of a retired player in the most popular sports institution in the United States, the National Football League. Since that time concussion has been a frequent topic of conversation in homes, schools, and on television and has become a major focus of sports programs in communities and schools at all levels. Now all 50 states, the District of Columbia, and the National Collegiate Athletic Association have enacted laws and rules to protect the athlete.

Efficacy of biofeedback in the treatment of migraine and tension type headaches.

BACKGROUND: Biofeedback is an established non-pharmacologic technique commonly used in the treatment of migraine and tension type headaches. Multiple published studies have suggested that biofeedback is effective in reducing the frequency and severity of headaches, often allowing patients to decrease their dependence on medication. Studies have also suggested that biofeedback may effect a decrease in medical utilization. OBJECTIVE: Assess the efficacy of biofeedback in reducing the frequency and severity of migraine and tension type headaches. DESIGN: Randomized, prospective, single blind, single center controlled trial. METHODS: Sixty-four patients with migraine with or without aura and/or tension type headaches, by ICHD-1 criteria, age 18 to 55, who had suffered from headaches for more than one year, were entered into the study. Patients were randomly assigned to receive biofeedback in addition to the basic relaxation instruction or relaxation techniques alone. All patients received instruction in pain theory. Biofeedback training consisted of 10 50-minute sessions utilizing standard EMG feedback from the frontalis and trapezius muscles and temperature from the third finger of the dominant hand. Visual and auditory feedback was provided. Thirty-three patients were assigned to receive biofeedback plus the relaxation techniques and 31, the relaxation techniques alone. All patients were asked to respond to periodic questionnaires for 36 months. The primary analysis was an intention-to-treat (ITT) analysis. The subsidiary analyses were not and the 11 subjects (7 in the relaxation alone and 4 in the biofeedback group) who received no treatment at all were analyzed and the results were qualitatively the same. RESULTS: Patients who completed the program with education in pain theory and relaxation techniques showed a statistically significant decrease in the frequency and severity of the headaches in the first 12 months that continued to 36 months. Biofeedback provided no additional benefit, specifically no change in the frequency or severity of the headaches. After 3 months 48% of those in the relaxation group reported fewer severe headaches, while 35% of those in the biofeedback group reported fewer severe headaches; after 6 months, 52% of those in the relaxation group reported fewer severe headaches as compared with 57% reporting fewer severe headaches in the biofeedback group. The number of medications used by the patients and the utilization of medical care decreased in both groups over 36 months suggesting a regression to the mean. LIMITATIONS: Compliance was an issue throughout the study. Patients dropped out from the outset and that increased over time. Recovery of questionnaires was difficult and fewer were completed at each 3-month interval. Lack of a large control group who did not receive biofeedback or instruction in relaxation techniques. CONCLUSION: Biofeedback is an extremely costly and time-consuming treatment modality that, in our study, provided no additional benefit when compared to simple relaxation techniques alone, in the treatment of migraine and tension type headaches in adults.