Transverse myelitis following COVID-19: Insights from a multi-center study and systematic literature review.

INTRODUCTION: We aimed to provide insights into transverse myelitis (TM) following COVID-19 by analyzing cases treated at tertiary care neurology centers and a systemic review of the literature. METHODS: The retrospective observational multi-center study was conducted at the four university neurology departments in Croatia, Slovenia, Serbia, and Austria. We searched for acute myelitis cases that occurred during or after COVID-19. A systemic review of the literature on COVID-19 and transverse myelitis was performed. RESULTS: We identified 76 persons with TM associated with COVID-19, 13 from the multi-center study and 63 from the literature review. Most of the participants (55.6%) had an intermediate latency, 25.4% had short and 19% long latency from COVID-19 symptoms to TM. The clinical presentation consisted of the typical TM signs. More than half of the participants had inflammatory changes in the CSF, with rare patients having intrathecal OCB synthesis and positive serology for anti-MOG or anti-AQP4 antibodies. Persons with autonomic symptoms and CSF pleocytosis were significantly more common to have an intermediate latency of 8 to 21 days from COVID-19 to TM (p = 0.005 and p = 0.003; respectively). According to logistic regression analysis, only participants with lesions evident on spinal cord MRI compared to normal spinal cord MRI had reduced risks for poor recovery. >80% of participants were treated with a combination of corticosteroids and intravenous immunoglobulins or plasma exchange with 73% having incomplete recovery. CONCLUSION: Our study further characterizes clinical, laboratory, and MRI features, as well as treatment of TM associated with COVID-19.

Determinants and Clinical Significance of Musculoskeletal Symptoms in Patients With Chronic Graft-Versus-Host Disease.

Musculoskeletal symptoms in chronic graft-versus-host disease (cGVHD) are rare manifestations contributing to disease burden. This study assesses the frequency of muscle cramps, joint and muscle aches, and muscle weakness in a cohort of patients severely affected by cGVHD. Three hundred thirty-four patients participated in the NCI natural history study of cGVHD (NCT00092235) from October 2004 to March 2017. Five-point Lee cGVHD Symptom Scale was dichotomized (less symptom bother-0, 1, 2; severe symptom bother-3, 4) and tested for associations with: Short Form 36 (SF36), 2-minute walk test, grip strength, joint range of motion, and human activity profile, clinical and laboratory data. Seventy-five point four percent of patients reported joint and muscle aches (36.8% severe, Lee Symptom Scale score 3-4), 74.3% muscle cramps (33.5% severe), and 82.34% muscle weakness (45.51% severe), which were associated with reduced functional capacity (SF36 Physical Component Scale, P < 0.0001). Muscle cramps were associated with limited joint movement (P < 0.0001) and skin manifestations (skin thickening, P = 0.0008; itchy skin, P = 0.0003). Muscle cramps did not show association with potential causative agents, such as concomitant calcineurin inhibitors therapy, statins, or use of antidiabetic drugs. Joint and muscle aches showed associations with multiple variables (including strong associations with mood symptoms and fatigue, P < 0.0001). Muscle weakness was not associated with steroid dose, but was significantly associated with depression (P < 0.0001) and anxiety (P = 0.0009). This study documents a high frequency of musculoskeletal symptoms in a cohort of adult patients with cGVHD. The multivariable logistic regression models showed that a joint set of factors were moderately well associated with musculoskeletal symptoms in this study.

Toward a Better Understanding of the Atypical Features of Chronic Graft-Versus-Host Disease: A Report from the 2020 National Institutes of Health Consensus Project Task Force.

Alloreactive and autoimmune responses after allogeneic hematopoietic cell transplantation can occur in nonclassical chronic graft-versus-host disease (chronic GVHD) tissues and organ systems or manifest in atypical ways in classical organs commonly affected by chronic GVHD. The National Institutes of Health (NIH) consensus projects were developed to improve understanding and classification of the clinical features and diagnostic criteria for chronic GVHD. Although still speculative whether atypical manifestations are entirely due to chronic GVHD, these manifestations remain poorly captured by the current NIH consensus project criteria. Examples include chronic GVHD impacting the hematopoietic system as immune mediated cytopenias, endothelial dysfunction, or as atypical features in the musculoskeletal system, central and peripheral nervous system, kidneys, and serous membranes. These purported chronic GVHD features may contribute significantly to patient morbidity and mortality. Most of the atypical chronic GVHD features have received little study, particularly within multi-institutional and prospective studies, limiting our understanding of their frequency, pathogenesis, and relation to chronic GVHD. This NIH consensus project task force report provides an update on what is known and not known about the atypical manifestations of chronic GVHD while outlining a research framework for future studies to be undertaken within the next 3 to 7 years. We also provide provisional diagnostic criteria for each atypical manifestation, along with practical investigation strategies for clinicians managing patients with atypical chronic GVHD features.

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. The 2020 Highly morbid forms report.

Chronic graft-versus-host disease (GVHD) can be associated with significant morbidity, in part because of nonreversible fibrosis, which impacts physical functioning (eye, skin, lung manifestations) and mortality (lung, gastrointestinal manifestations). Progress in preventing severe morbidity and mortality associated with chronic GVHD is limited by a complex and incompletely understood disease biology and a lack of prognostic biomarkers. Likewise, treatment advances for highly morbid manifestations remain hindered by the absence of effective organ-specific approaches targeting "irreversible" fibrotic sequelae and difficulties in conducting clinical trials in a heterogeneous disease with small patient numbers. The purpose of this document is to identify current gaps, to outline a roadmap of research goals for highly morbid forms of chronic GVHD including advanced skin sclerosis, fasciitis, lung, ocular and gastrointestinal involvement, and to propose strategies for effective trial design. The working group made the following recommendations: (1) Phenotype chronic GVHD clinically and biologically in future cohorts, to describe the incidence, prognostic factors, mechanisms of organ damage, and clinical evolution of highly morbid conditions including long-term effects in children; (2) Conduct longitudinal multicenter studies with common definitions and research sample collections; (3) Develop new approaches for early identification and treatment of highly morbid forms of chronic GVHD, especially biologically targeted treatments, with a special focus on fibrotic changes; and (4) Establish primary endpoints for clinical trials addressing each highly morbid manifestation in relationship to the time point of intervention (early versus late). Alternative endpoints, such as lack of progression and improvement in physical functioning or quality of life, may be suitable for clinical trials in patients with highly morbid manifestations. Finally, new approaches for objective response assessment and exploration of novel trial designs for small populations are required.

Severe Demyelinating Polyneuropathy and Cranial Neuropathy During Avelumab Treatment of Metastatic Merkel Cell Carcinoma.

INTRODUCTION: Avelumab is a programmed death ligand 1-blocking monoclonal antibody used for the treatment of Merkel cell carcinoma (MCC), urothelial carcinoma, and other solid tumors. It acts as an immune checkpoint inhibitor and prolongs survival of MCC patients. Immune-mediated neurological adverse effects are rare and usually respond well to specific therapy. METHODS AND RESULTS: A case of a 70-year-old man with metastatic MCC is described in this study. The patient developed diplopia after the fourth dose of avelumab, which was then discontinued. Seven months later, therapy was reinitiated and followed by a new adverse neurological event: severe demyelinating polyneuropathy combined with ophthalmoplegia refractory to a plethora of immune suppressive/modulatory treatment regimes. DISCUSSION: This report of severe demyelinating polyneuropathy and cranial neuropathy associated with an anti-programmed death ligand 1 drug refractory to immune suppressive/modulatory treatments sheds a new light to evolving spectrum of immune checkpoint inhibitor immune-related neurological adverse events.

B regulatory cells and monocyte subpopulations in patients with chronic graft-vs-host disease.

AIM: To assess the correlations of B regulatory cells (Bregs) and monocyte subsets in peripheral blood with the National Institutes of Health (NIH)-consensus-defined clinical manifestations of chronic graft-vs-host disease (cGvHD), in an attempt to establish their role as cellular biomarkers. METHODS: This multidisciplinary prospective study enrolled adult cGVHD patients treated in the University Hospital Center Zagreb and University of Zagreb School of Medicine. Immunophenotypic subpopulations of CD24highCD38high Bregs (CD27-, CD27+, and total) and monocyte (classical, intermediate, and non-classical) counts were correlated with demographic, transplant, and cGVHD-related data. Bivariate correlation analysis was performed to evaluate the correlations between Bregs and monocytes subsets and cGVHD organ involvement, as well as cGVHD severity and immunosuppression intensity. RESULTS: Twenty-two adult patients (54.5% female) with cGVHD were enrolled. The median (range) age was 44.5 years (24-65). All patients were transplanted for hematologic malignancies and 40.9% had severe NIH cGVHD global score. The median time from cGVHD diagnosis to the analysis was 16.6 months (0-176). The organ most frequently affected with cGVHD were the eyes (68.2%), skin (45.5%), lungs (45.5%), and liver (40.9%). Lower total and CD27-Bregs counts were correlated with worse cGVHD severity, higher immunosuppression intensity, and lung cGVHD, in terms of cell count, but also with skin cGVHD, in terms of percentages. Patients with liver and joint/fascia cGVHD had a lower percentage of non-classical monocytes and patients with more severe global NIH score had a higher classical monocytes count. CONCLUSION: Different organs affected by cGVHD are differently associated with different subpopulations of Bregs and monocytes.

A rare case of parasagittal meningioma causing isolated foot drop: case report and review of the literature.

Foot drop represents a very common reason for a neurologist referral and is often first seen in emergency departments or by a general practitioner. This condition is defined as weakness of ankle dorsiflexion (mainly through tibialis anterior muscle weakness). The most common causes include lower motor neuron lesion, with L4-L5 radiculopathy and peroneal neuropathy being the most frequent ones. Classical diagnostic pathway includes a thorough medical history, detailed neurological examination, radiological studies (MRI of the lumbosacral spine), EMG and nerve conduction studies, and a battery of laboratory tests. The absence of abnormal radiological and neurophysiological findings when searching for the most common causes of foot drop, should raise a red flag and broaden the diagnostic yield for central nervous system pathology (upper motor neuron, UMN) as a possible cause of foot drop. Central causes of isolated foot drop are very rare, with less than 20 cases reported in literature so far, and seven of them being a meningioma. We present a case of a 79-year-old female patient with an isolated foot drop (with no UMN signs on the initial examination) and parasagittal meningioma. Central causes of foot drop should be suspected when foot drop is associated with UMN signs on examination (hyperreflexia of the patellar or ankle jerk and extensor plantar reflex) and when standard diagnostic work-up (MRI of the lumbar spine, EMG and NCS, standard laboratory screening for most common causes of foot drop) is negative or inconclusive. Although very rare, central lesions present a far more serious cause of foot drop and require a more urgent diagnostic work up and a potential neurosurgical referral and treatment. Keeping in mind the possible central causes of foot drop would eliminate unnecessary diagnostic work up and avoid delayed diagnosis and treatment.

Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses.

Despite wide genetic, environmental and clinical heterogeneity in amyotrophic lateral sclerosis, a rapidly fatal neurodegenerative disease targeting motoneurons, neuroinflammation is a common finding. It is marked by local glial activation, T cell infiltration and systemic immune system activation. The immune system has a prominent role in the pathogenesis of various chronic diseases, hence some of them, including some types of cancer, are successfully targeted by immunotherapeutic approaches. However, various anti-inflammatory or immunosuppressive therapies in amyotrophic lateral sclerosis have failed. This prompted increased scrutiny over the immune-mediated processes underlying amyotrophic lateral sclerosis. Perhaps the biggest conundrum is that amyotrophic lateral sclerosis pathogenesis exhibits features of three otherwise distinct immune dysfunctions-excessive inflammation, autoimmunity and inefficient immune responses. Epidemiological and genome-wide association studies show only minimal overlap between amyotrophic lateral sclerosis and autoimmune diseases, so excessive inflammation is usually thought to be secondary to protein aggregation, mitochondrial damage or other stresses. In contrast, several recently characterized amyotrophic lateral sclerosis-linked mutations, including those in TBK1, OPTN, CYLD and C9orf72, could lead to inefficient immune responses and/or damage pile-up, suggesting that an innate immunodeficiency may also be a trigger and/or modifier of this disease. In such cases, non-selective immunosuppression would further restrict neuroprotective immune responses. Here we discuss multiple layers of immune-mediated neuroprotection and neurotoxicity in amyotrophic lateral sclerosis. Particular focus is placed on individual patient mutations that directly or indirectly affect the immune system, and the mechanisms by which these mutations influence disease progression. The topic of immunity in amyotrophic lateral sclerosis is timely and relevant, because it is one of the few common and potentially malleable denominators in this heterogenous disease. Importantly, amyotrophic lateral sclerosis progression has recently been intricately linked to patient T cell and monocyte profiles, as well as polymorphisms in cytokine and chemokine receptors. For this reason, precise patient stratification based on immunophenotyping will be crucial for efficient therapies.

Lower number of plasma exchange sessions and glomerular filtration rate decline are associated with second relapses in patients with myasthenia gravis.

The aims were to determine the impact of dysphagia and glomerular filtration rate (GFR) in the prediction of myasthenia relapse and analyse whether different number of plasma exchange sessions could prolong the time before future relapse.This was a retrospective, longitudinal follow-up study with 60 enrolled patients. The patients were followed-up for a total of 50 months.Patients without relapses had significantly higher GFR and higher number of plasma exchange sessions when compared to patients with relapses. Mean time before next myasthenia relapse was significantly longer in patients with GFR ≥ 60 mL/min. Time before next and number of following myasthenia relapses were significantly higher in patients with symptoms of dysphagia.Decline in GFR levels is strongly associated with the presence of dysphagia and independently impacts the onset of myasthenia relapses. Timely initiation of plasmapheresis therapy and adequate hydration of patients with prolonged dysphagia should be one of the treatment goals for clinicians treating this disease.

Factors Contributing to the Reduction of Pain during Electromyography and Nerve Conduction Studies.

BACKGROUND: Electromyography (EMG) and nerve conduction studies (NCS) are an unpleasant and sometimes painful examinations. Pain can reduce patient's compliance and have a negative effect on the examination results. Different studies report that music affects pain perception by acting as a distractor, by inducing positive emotional valence or through the concept of convergence of different sensory modalities. The aim of this study was to explore the effect of music and different environmental and sociodemographic factors on pain perception during EMG and NCS. SUBJECTS AND METHODS: Sixty patients with suspected neuromuscular disease were randomized into music and control group. Specific questionnaire assessed sociodemographic characteristics, medical history, examination waiting time, examination extent and biometeorological forecast. The numerical rating scale was used for the evaluation of pain. The examiner evaluated patient's compliance after the examination. RESULTS: NCS was less painful for patients in the music group (p=0.03), as well as for more cooperative patients (p=0.011). For patients who previously underwent EMG/NCS, present NCS was more painful (p=0.001), regardless of the music intervention (p=0.019). EMG was more painful for older patients (p=0.041). Patients with lower level of education reported lower pain during NCS (p=0.026). Gender, financial satisfaction, biometeorological forecast, diabetes, depression or malignant disease, use and dosing of analgesics or antidepressants, symptoms, examination waiting time and the examination extent had no effect on pain perception. CONCLUSIONS: Music significantly decreased the perception of pain associated with NCS, but not the EMG portion of the examination. During EMG pain level was not significantly reduced, but the median of pain was still lower. Generally, the pain level during NCS, unlike the one during EMG, was affected by patients' compliance, level of education and painful predetermination. We propose using music during EMG/NCS because it can make the examination more comfortable for the patient and thus contribute to better quality of this examination.

High frequency of cutaneous manifestations including vitiligo and alopecia areata in a prospective cohort of patients with chronic graft-vs-host disease.

AIM: To determine the frequency and the characteristics of cutaneous manifestations, especially vitiligo and alopecia areata, in patients with chronic graft-vs-host disease (cGVHD). METHODS: 50 patients with cGVHD were prospectively enrolled in the observational study protocol and evaluated by an experienced dermatologist. The evaluation was focused on the clinical spectrum of skin and adnexal involvement, and the cutaneous GVHD score was determined according to National Institutes of Health (NIH) Consensus criteria. The presence of vitiligo, alopecia, xerosis, nail changes, and dyspigmentation was also assessed. RESULTS: Out of 50 cGVHD patients, 28 (56%) had skin involvement, and 27 of them (96%) had hypo and/or hyperpigmentations. 11 patients (39%) had a mild cutaneous NIH cGVHD score, 22% moderate, and 39% severe. 15 (30%) patients had nail changes and 10 (20%) had vitiligo or alopecia areata. Univariate analysis showed that patients with vitiligo/alopecia areata received more lines of prior systemic immunosuppressive therapy (P=0.043), had lower Karnofsky performance status (P=0.028), and had a higher B-cell number (P=0.005), platelet count (P=0.022), and total protein (P=0.024). Vitiligo and alopecia areata were associated with higher NIH skin score (P=0.001), higher intensity of immunosuppressive treatment (P=0.020), and total body irradiation conditioning (P=0.040). Multivariate regression model showed that patients with higher NIH skin scoring were 3.67 times more likely to have alopecia and/or vitiligo (odds ratio 3.67; 95% confidence interval 1.26-10.73), controlled for all other factors in the model (age at study entry, number of B-cells, platelet count, and global NIH score). CONCLUSION: These data indicate that vitiligo and alopecia areata occur more frequently in cGVHD than previously reported.

Complex regional pain syndrome type I after diphtheria-tetanus (Di-Te) vaccination.

Complex regional pain syndrome type I (CRPS I) is a disorder of one or more extremities characterized by pain, abnormal sensitivity (allodynia), swelling, limited range of motion, vasomotor instability, fatigue and emotional distress. The symptoms may be aggravated by even minor activity or weather change. It is usually provoked by injury, surgery or injection but in a small proportion of patients CRPS I develops without a clear causative event. There are several literature reports on CRPS after rubella and hepatitis B vaccination. We present a case of CRPS I affecting the left arm after diphtheria and tetanus (Di-Te) vaccination in the left deltoid muscle in a young girl having experienced profound emotional stress before the vaccination procedure. History data on previous minor trauma at the site of vaccination or emotional stress may necessitate temporary vaccination delay due to their proneness to impaired local or systemic immune response and CRPS as a complication of vaccination. If a child or an adult has prominent swelling and severe pain after vaccination, the diagnosis of CRPS I should be considered and if confirmed, the multidisciplinary treatment should start as soon as possible.

Paraneoplastic stiff person syndrome associated with colon cancer misdiagnosed as idiopathic Parkinson's disease worsened after capecitabine therapy.

OBJECTIVES: To refresh clinical diagnostic dilemmas in patients presenting with symptoms resembling to those of parkinsonism, to report rare association of colon cancer and paraneoplastic stiff person syndrome (SPS), and to draw attention on the possible correlation of capecitabine therapy with worsening of paraneoplastic SPS. METHODS: Case report of the patient with paraneoplastic SPS due to colon cancer that was misdiagnosed as idiopathic Parkinson's disease (iPD), whose symptoms worsened after beginning adjuvant capecitabine chemotherapy. RESULTS: We describe a 55-year-old woman with subacute onset of symmetrical stiffness and rigidity of the truncal and proximal lower limb muscles that caused lower body bradykinesia, gait difficulties, and postural instability. Diagnose of iPD was made and levodopa treatment was initiated but failed to provide beneficial effect. Six months later, colon cancer was discovered and the patient underwent surgical procedure and chemotherapy with capecitabine thereafter. Aggravation of stiffness, rigidity, and low back pain was observed after the first chemotherapy cycle and capecitabine was discontinued. Furthermore, levodopa was slowly discontinued and low dose of diazepam was administered which resulted in partial resolution of the patient's symptoms. CONCLUSION: Paraneoplastic SPS is rare disorder with clinical features resembling those of parkinsonian syndrome and making the correct diagnosis remains a challenge. The diagnosis of parkinsonian syndrome should be re-examined if subsequent examinations discover an associated malignant process. Although it remains unclear whether the patients with history of SPS are at the greater risk for symptoms deterioration after administration of capecitabine, clinicians should be aware of capecitabine side effects because recognition and appropriate management can prevent serious adverse outcomes.

[Stiff person syndrome (Moersch-Woltman)]. / Sindrom ukocene osobe (Moersch-Woltman).

The prime goal of this paper is to offer an overview of main scientific points in epidemiology, genetics, pathogenesis, clinical course and therapeutic strategies in stiff person syndrome (SPS). This syndrome is characterized by progressive muscle rigidity and painful muscle spasms. Three major forms of SPS are described, according to the pathophysiologic basis, autoimmune, paraneoplastic and idiopathic SPS. In autoimmune form of SPS the antibodies are specific for an enzyme (glutamic acid decarboxylase, GAD). If the paraneoplastic form takes place, the antibodies may be specific for presynaptic (amphyphysin) or the postsynaptic protein (gephyrin). The SPS diagnosis should be based on clinical, laboratory and electromyoneurographic criteria, according to Gordon and Lorish. The therapeutic approaches are focused on symptomatic therapy managing the muscle spasm and on possible immunomodulatory procedures to attenuate an autoimmune reaction. Two cases of SPS are reported in the Republic Croatia since 2005. Although it is a rare medical condition, SPS is of clinical importance, especially because it may be the first sign of an underlying undiagnosed malignant disease or if the anesthesia is necessary in SPS patient.

Myasthenia gravis patients with anti-MuSK antibodies.

In myasthenia gravis (MG) patients without detectable anti-acetylcholine receptor (anti-AChR) antibody, referred to as seronegative myasthenia gravis patients, there is a variable proportion of patients with antibodies against the muscle-specific kinase (MuSK). MuSK antibodies were found in 8 (29.6%) of our 27 patients with generalized MG without anti-AChR antibodies. All these patients were female. The age at the onset ranged from 22 to 38 years. All patients had ocular and bulbar symptoms, and two patients also had generalized limb weakness. Two patients had pure ocular symptoms for 7 or 8 years before the development of bulbar symptoms. All anti-MuSK positive patients were treated with immunosuppressive drugs, three received plasmapheresis and one patient required mechanical ventilation. Our results are consistent with other literature reports.