Paraneoplastic/autoimmune myelopathies.

Paraneoplastic myelopathies are a rare but important category of myelopathy. They usually present with an insidious or subacute progressive neurologic syndrome. Risk factors include tobacco use and family history of cancer. Cerebrospinal fluid analysis usually shows lymphocytic pleocytosis with elevated protein. MRI findings suggest that paraneoplastic myelopathies include longitudinally extensive T2 hyperintensities that are tract-specific and accompanied by enhancement, but spinal MRIs can also be normal. The most commonly associated neural antibodies include amphiphysin and collapsin-response-mediator-protein-5 (CRMP5/anti-CV2) antibodies with lung and breast cancers being the most frequent oncologic accompaniments. The differential diagnosis of paraneoplastic myelopathies includes nutritional deficiency myelopathy (B12, copper) as well as autoimmune/inflammatory conditions such as primary progressive multiple sclerosis or spinal cord sarcoidosis. Patients treated with immune checkpoint inhibitors for cancer may develop myelitis, that can be considered along the spectrum of paraneoplastic myelopathies. Management of paraneoplastic myelopathy includes oncologic treatment and immunotherapy. Despite these treatments, the prognosis is poor and the majority of patients eventually become wheelchair-dependent.

Progressive multifocal leukoencephalopathy without overt immunosuppression.

Progressive multifocal leukoencephalopathy (PML) is a central nervous system disease caused by the human polyomavirus 2 that usually occurs in a setting of immunodeficiency. PML without overt immunosuppression is considered a rare occurrence but has been described in multiple previous case reports and series. Its prevalence, overall frequency, and prognosis are largely unknown. This is a single-center retrospective review of all University of Florida cases with the ICD10 PML diagnosis code (A81.2). PML without overt immunosuppression was defined as absence of human immunodeficiency virus (HIV) infection, hematological malignancy, immunomodulatory/-suppressive medications, autoimmune conditions with a propensity for PML (sarcoidosis, systemic lupus erythematosus). Cases that did not fulfill criteria for clinically or histologically definite PML were excluded. Of 52 patients with the ICD10 code A 81.2, 17 fulfilled definite diagnostic criteria for PML. Overt immunosuppression was identified in 15/17 (88.2%) cases (10/17 (58.8%): human immunodeficiency virus; 5/17 (29.4%): immunomodulatory/-suppressive medication). Two/seventeen (11.8%) cases were consistent with PML without overt immunosuppression. Possible contributing factors were a preceding dog bite and mild hypogammaglobulinemia M (39 mg/dL) in case 1 and significant alcohol use without evidence for liver disease in case 2. Both cases were fatal within 6 (case 1) and 2 (case 2) months. The results suggest that PML without overt immunosuppression may be more common than previously described. Therefore, PML should be considered even in the absence of overt immunosuppression if clinical and radiographic findings are suggestive of the diagnosis.

Detection of High-Risk Paraneoplastic Antibodies against TRIM9 and TRIM67 Proteins.

OBJECTIVE: Co-occurring anti-tripartite motif-containing protein 9 and 67 autoantibodies (TRIM9/67-IgG) have been reported in only a very few cases of paraneoplastic cerebellar syndrome. The value of these biomarkers and the most sensitive methods of TRIM9/67-IgG detection are not known. METHODS: We performed a retrospective, multicenter study to evaluate the cerebrospinal fluid and serum of candidate TRIM9/67-IgG cases by tissue-based immunofluorescence, peptide phage display immunoprecipitation sequencing, overexpression cell-based assay (CBA), and immunoblot. Cases in which TRIM9/67-IgG was detected by at least 2 assays were considered TRIM9/67-IgG positive. RESULTS: Among these cases (n = 13), CBA was the most sensitive (100%) and revealed that all cases had TRIM9 and TRIM67 autoantibodies. Of TRIM9/67-IgG cases with available clinical history, a subacute cerebellar syndrome was the most common presentation (n = 7/10), followed by encephalitis (n = 3/10). Of these 10 patients, 70% had comorbid cancer (7/10), 85% of whom (n = 6/7) had confirmed metastatic disease. All evaluable cancer biopsies expressed TRIM9 protein (n = 5/5), whose expression was elevated in the cancerous regions of the tissue in 4 of 5 cases. INTERPRETATION: TRIM9/67-IgG is a rare but likely high-risk paraneoplastic biomarker for which CBA appears to be the most sensitive diagnostic assay. ANN NEUROL 2023;94:1086-1101.

Cerebral Cortical Encephalitis in Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease.

Cerebral cortical encephalitis (CCE) is a recently described myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) phenotype. In this observational retrospective study, we characterized 19 CCE patients (6.7% of our MOGAD cohort). Headache (n = 15, 79%), seizures (n = 13, 68%), and encephalopathy (n = 12, 63%) were frequent. Magnetic resonance imaging revealed unilateral (n = 12, 63%) or bilateral (n = 7, 37%) cortical T2 hyperintensity and leptomeningeal enhancement (n = 17, 89%). N-Methyl-D-aspartate receptor autoantibodies coexisted in 2 of 15 tested (13%). CCE pathology (n = 2) showed extensive subpial cortical demyelination (n = 2), microglial reactivity (n = 2), and inflammatory infiltrates (perivascular, n = 1; meningeal, n = 1). Most received high-dose steroids (n = 17, 89%), and all improved, but 3 had CCE relapses. This study highlights the CCE spectrum and provides insight into its pathogenesis. ANN NEUROL 2023;93:297-302.

Acute symptomatic seizures secondary to myelin oligodendrocyte glycoprotein antibody-associated disease.

OBJECTIVE: To report the clinical presentations and outcomes of patients with seizure and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). METHODS: We retrospectively reviewed the electronic medical records for clinical and paraclinical features among patients with seizures and MOG-IgG (immunoglobulin G) seropositivity. RESULTS: We identified 213 patients with MOG-IgG seropositivity who fulfilled criteria for MOGAD. Seizures attributed to central nervous system (CNS) autoimmunity were observed in 10% of patients (n = 23: 19 children, 4 adults). The majority (n = 19, 83%) had pediatric disease onset. Focal motor seizures were the most common seizure semiology (16/23; 70%). Focal to bilateral tonic-clonic seizures were present in 12 patients (53%), and 3 patients (13%) developed status epilepticus. All patients had features of encephalitis at onset of seizures. Cerebral cortical encephalitis (CCE) was the most common radiological finding (10 unilateral and 5 bilateral cases). Eight of 23 patients (35%) had only CCE, six of 23 patients (26%) had only acute disseminated encephalomyelitis (ADEM), and seven of 23 patients (30%) had features of both. Fifteen patients (65%) had leptomeningeal enhancement. Three patients (13%) had coexistence of N-methyl-d-aspartate receptor (NMDAR) IgG. Only 3 of 23 patients (13%) developed drug- resistant epilepsy. Although the majority had MOGAD relapses (14/23, 60%) had only 5 of 23 patients had recurrence of episodes of encephalitis with associated seizures. Twenty-one of 23 patients (91%) had seizure freedom at last follow-up. SIGNIFICANCE: MOG-IgG evaluation should be considered in patients who present with encephalitis and focal motor and/or focal to bilateral tonic-clonic seizures, especially pediatric patients with magnetic resonance imaging (MRI) brain findings consistent with CCE, ADEM, or other MOGAD presentations. The majority of these seizures are self-limited and do not require maintenance/chronic antiseizure medications. Although seizure recurrence is uncommon, many patients have MOGAD relapses in the form of encephalitis and optic neuritis.

Septin-5 and -7-IgGs: Neurologic, Serologic, and Pathophysiologic Characteristics.

BACKGROUND AND OBJECTIVES: We sought to determine clinical significance of neuronal septin autoimmunity and evaluate for potential IgG effects. METHODS: Septin-IgGs were detected by indirect immunofluorescence assays (IFAs; mouse tissue and cell based) or Western blot. IgG binding to (and internalization of) extracellular septin epitopes were evaluated for by live rat hippocampal neuron assay. The impact of purified patient IgGs on murine cortical neuron function was determined by recording extracellular field potentials in a multielectrode array platform. RESULTS: Septin-IgGs were identified in 23 patients. All 8 patients with septin-5-IgG detected had cerebellar ataxia, and 7 had prominent eye movement disorders. One of 2 patients with co-existing septin-7-IgG had additional psychiatric phenotype (apathy, emotional blunting, and poor insight). Fifteen patients had septin-7 autoimmunity, without septin-5-IgG detected. Disorders included encephalopathy (11; 2 patients with accompanying myelopathy, and 2 were relapsing), myelopathy (3), and episodic ataxia (1). Psychiatric symptoms (≥1 of agitation, apathy, catatonia, disorganized thinking, and paranoia) were prominent in 6 of 11 patients with encephalopathic symptoms. Eight of 10 patients with data available (from 23 total) improved after immunotherapy, and a further 2 patients improved spontaneously. Staining of plasma membranes of live hippocampal neurons produced by patient IgGs (subclasses 1 and 2) colocalized with pre- and post-synaptic markers. Decreased spiking and bursting behavior in mixed cultures of murine glutamatergic and GABAergic cortical neurons produced by patient IgGs were attributable to neither antigenic crosslinking and internalization nor complement activation. INTERPRETATION: Septin-IgGs are predictive of distinct treatment-responsive autoimmune central nervous system (CNS) disorders. Live neuron binding and induced electrophysiologic effects by patient IgGs may support septin-specific pathophysiology. ANN NEUROL 2022;92:1090-1101.

Autoimmune gastrointestinal dysmotility following SARS-CoV-2 infection successfully treated with intravenous immunoglobulin.

BACKGROUND: Autoimmune gastrointestinal dysmotility (AGID) is a limited form of dysautonomia that can be paraneoplastic or idiopathic. Some presentations can be preceded by a viral infection. METHODS: We report a case of a 17-year-old girl that developed intractable nausea and early satiety after SARS-CoV-2 infection. KEY RESULTS: Over ten months, she required nasogastric and nasoduodenal tube feedings and finally was advanced to total parenteral nutrition to meet her caloric needs. Her α3 nicotinic ganglionic acetylcholine and anti-striational antibodies were mildly elevated. Gastrointestinal transit scintigraphy studies showed delayed gastric emptying and slowed small bowel transit. Thermoregulatory sweat test showed areas of anhidrosis consistent with autonomic sudomotor impairment. After IVIG treatment the patient's symptoms improved dramatically and she was able to tolerate full oral diet. This was reflected by improvement of her baseline transit studies and the thermoregulatory sweat test. CONCLUSIONS AND INFERENCES: This is the first report of AGID occurring after SARS-CoV-2 infection. The dramatic response to IVIG emphasizes the importance of early recognition and the reversible and treatable nature of this condition.

Diagnostic value of aquaporin-4-IgG live cell based assay in neuromyelitis optica spectrum disorders.

OBJECTIVE: Determine the utility of aquaporin 4 IgG (AQP4-IgG) testing (live cell-based assay) for Neuromyelitis Optica Spectrum Disorders (NMOSD). METHODS: We included Mayo Clinic patients (1/1/2018-12/31/2019) tested for serum AQP4-IgG by live cell-based flow-cytometric assay. Medical records were reviewed to assess if patients fulfilled 2015 NMOSD criteria. RESULTS: Of 1371 patients tested, 41 were positive (3%) and all fulfilled NMOSD criteria with AQP4-IgG (specificity = 100%). Only 10/1330 testing negative met NMOSD criteria without AQP4-IgG (sensitivity = 80%) and seven of these 10 were MOG-IgG positive. CONCLUSIONS: AQP4-IgG by live cell-based assay was highly specific and without false positives in a high throughput setting.

Eastern Equine Encephalitis: Case Series in Southern New England and Review of the Literature.

PURPOSE OF REVIEW: To describe the clinical presentation, diagnosis, management, and outcomes of 4 confirmed Eastern equine encephalitis (EEE) cases and a review of the literature. RECENT FINDINGS: There was a sharp rise in the number of EEE cases in the United States in 2019, with 38 confirmed cases and 15 deaths. Our institution cared for 10% of patients with neuroinvasive EEE nationwide. These were the first cases seen locally since 2010. SUMMARY: EEE virus causes one of the most lethal types of arboviral encephalitis in the United States with a mortality of 30%-40%. Manifestations of EEE infections can range from mild encephalopathy to coma. Common findings include CSF pleocytosis and involvement of the basal ganglia on MRI. Given the rarity of this disease and nonspecific findings, diagnosis can be challenging, and a high clinical suspicion is important. Management is mainly supportive, and the use of IV immunoglobulin remains controversial. Two of our 4 patients died; these patients had coma within 48 hours, hyponatremia, involvement of bilateral thalami and brainstem, status epilepticus, and severe brain dysfunction in EEG.

Paraneoplastic cochleovestibulopathy: clinical presentations, oncological and serological associations.

OBJECTIVE: Cochleovestibulopathy is a distinguishable paraneoplastic phenotype. In this study, we evaluate clinical presentation, serological/cancer associations and outcomes of paraneoplastic cochleovestibulopathy. METHODS: Retrospective chart review of patients with hearing impairment and/or vestibulopathy who underwent serological evaluations for paraneoplastic antibodies between January 2007 and February 2021 was performed. RESULTS: Twenty-six patients were identified (men, n=23; median age, 45 years, range: 28-70). Biomarkers detected included: KLHL11-IgG| |(n=20,| |77% (coexisting LUZP4-IgG, n=8)),| ||ANNA1-IgG| | |(n=3,| |12%),| |amphiphysin-IgG|| |(n=2,| |8%)| |and| |LUZP4-IgG|| |(n=1,| |4%). Most common neoplastic association was |testicular|/|extra-testicular| |seminoma| | (n=13,| |50%).|| Hearing| impairment (bilateral, 62%) was |present| |in| |all| |patients.| |Fifteen patients (58%) had cochleovestibular dysfunction as their initial presentation before rhombencephalitis/encephalomyelitis manifestations (hearing loss, four; acute vertigo, eight; both, three). |Brain| |MRI| |demonstrated| |internal| |auditory| |canal| |enhancement| |in| |four |patients.| Audiometry commonly revealed severe-profound bilateral sensorineural hearing loss. Most patients |had| a refractory course |despite| |immunotherapy| |and/or| |cancer| |treatment|. CONCLUSION: Cochleovestibulopathy commonly presents with rapidly progressive bilateral hearing loss and/or acute vertigo. However, in some patients, these symptoms present along with or following brainstem/cerebellar manifestations. KLHL11-IgG and seminoma are the most common serological and cancer associations, respectively. Recognition of this phenotype may aid in earlier diagnosis of paraneoplastic autoimmunity and associated cancer.

Predicting symptomatic intracranial haemorrhage after mechanical thrombectomy: the TAG score.

BACKGROUND: There is limited data on predictors of symptomatic intracranial haemorrhage (sICH) in patients who underwent mechanical thrombectomy. In this study, we aim to determine those predictors with external validation. METHODS: We evaluated mechanical thrombectomy in a derivation cohort of patients at a comprehensive stroke centre over a 30-month period. Clinical and radiographic data on these patients were obtained from the prospective quality improvement database. sICH was defined using the European Cooperative Acute Stroke Study III. We compared clinical and radiographic characteristics between patients with and without sICH using χ2 and t tests to identify independent predictors of sICH with p<0.1. Significant variables were then combined in a multivariate logistic regression model to derive an sICH prediction score. This score was then validated using data from the Blood Pressure After Endovascular Treatment multicentre prospective registry. RESULTS: We identified 578 patients with acute ischaemic stroke who received thrombectomy, 19 had sICH (3.3%). Predictive factors of sICH were: thrombolysis in cerebral ischaemia (TICI) score, Alberta stroke program early CT score (ASPECTS), and glucose level, and from these predictors, we derived the weighted TICI-ASPECTS-glucose (TAG) score, which was associated with sICH in the derivation (OR per unit increase 1.98, 95% CI 1.48 to 2.66, p<0.001, area under curve ((AUC)=0.79) and validation (OR per unit increase 1.48, 95% CI 1.22 to 1.79, p<0.001, AUC=0.69) cohorts. CONCLUSION: High TAG scores are associated with sICH in patients receiving mechanical thrombectomy. Larger studies are needed to validate this scoring system and test strategies to reduce sICH risk and make thrombectomy safer in patients with elevated TAG scores.

Infectious Myelopathies.

Infectious diseases are an important cause of spinal cord dysfunction. Infectious myelopathies are of growing concern given increasing global travel and migration and expanding prevention and treatment with vaccinations, antibiotics, and antiretrovirals. Clinicians must recognize these pathologies because outcomes can dramatically improve with prompt diagnosis and management. We provide a complete review of the most frequent infectious agents that can affect the spinal cord. For each pathogen we describe epidemiology, pathophysiology, anatomic location, characteristic clinical syndromes, diagnostic approach, treatment, and prognosis. The review includes spinal imaging from selected cases.

PR Interval Prolongation and Cryptogenic Stroke: A Multicenter Retrospective Study.

BACKGROUND: Atrial dysfunction or "cardiopathy" has been recently proposed as a mechanism in cryptogenic stroke. A prolonged PR interval may reflect impaired atrial conduction and thus may be a biomarker of atrial cardiopathy. We aim to compare the prevalence of PR interval prolongation in patients with cryptogenic stroke (CS) when compared with known non-cryptogenic non-cardioembolic stroke (NCNCS) subtypes. METHODS: We used prospective ischemic stroke databases of 3 comprehensive stroke centers to identify patients 18 years or older with a discharge diagnosis of ischemic non-cardioembolic stroke between December 1, 2013 and August 31, 2015. The main outcome was ischemic stroke subtype (CS versus NCNCS). We compared PR intervals as a continuous and categorical variable (<200 milliseconds; ≥200 milliseconds) and other clinical and demographic factors between the 2 groups and used multivariate regression analyses to determine the association between PR interval prolongation and CS. RESULTS: We identified 644 patients with ischemic non-cardioembolic stroke (224 CS and 420 NCNCS). Patients with CS were more likely to have a PR of 200 milliseconds or greater when compared with those with NCNCS (23.2% versus 13.8%, P = .009). After adjusting for factors that were significant in univariate analyses, a PR of 200 milliseconds or greater was independently associated with CS (odds ratio [OR] 1.70, 95% CI 1.08-2.70). The association was more pronounced when excluding patients on atrioventricular nodal blocking agents (OR 2.64, 95% CI 1.44-4.83). CONCLUSIONS: A PR of 200 milliseconds or greater is associated with CS and may be a biomarker of atrial cardiopathy in the absence of atrial fibrillation. Prospective studies are needed to confirm this association.

Long-term Arrhythmia Monitoring in Cryptogenic Stroke: Who, How, and for How Long?

Cryptogenic stroke and transient ischemic attack (TIA) account for approximately one-third of stroke patients [1]. Paroxys-mal atrial fibrillation (PAF) has been suggested as a major etiology of these cryptogenic strokes [2, 3]. PAF can be difficult to diagnose because it is intermittent, often brief, and asymptomatic. PAF might be more prevalent than persistent atrial fibrillation in stroke and TIA patients, especially in younger populations [4, 5]. In patients with atrial fibrillation, anticoagulation provides significant risk reduction [6]. A new generation of oral anticoagulants has been approved for non-valvular atrial fibrillation, providing a variety of therapeutic options for patients with atrial fibrillation and risk of stroke [7]. Prior practice included an admission electrocardiogram (ECG) and continuous telemetry monitoring while in hospital [8]. However, this approach can lead to under-detection of brief asymptomatic events, which can occur at variable intervals, often outside of the hospital setting. Technological advancements have led to devices that can monitor cardiac rhythms outside of the hospital for longer durations resulting in higher yield of detection of atrial fibrillation events. Moreover, recent studies show that the normal monitoring time for arrhythmias may be shorter than ideal in order to detect atrial fibrillation, and increasing this interval could significantly improve detection of atrial fibrillation in these patients [9, 10]. The aim of this study is to review the literature in order to define what subgroup of patients, with what methodologies, and for how long monitoring for atrial fibrillation should occur in patients presenting with cryptogenic stroke.

Clinicoradiological Correlation of Macropsia due to Acute Stroke: A Case Report and Review of the Literature.

Dysmetropsia (macropsia, micropsia, teleopsia, or pelopsia) most commonly results from retinal pathologies, epileptic seizure, neoplastic lesions, viral infection, or psychoactive drugs. Vascular lesions are an uncommon cause of dysmetropsia. Vascular hemimicropsia, although rare, has been more frequently described in the literature, whereas hemimacropsia from acute ischemic injury is exceedingly rare. We describe a patient presenting in the emergency room (ER) with visual perception disturbances characterized by a distorted perception of the size of objects, compatible with left hemimacropsia. Magnetic resonance imaging (MRI) of the brain showed an acute occipitotemporal ischemic injury corresponding to the posterior cerebral artery (PCA) territory. The location of the lesion is consistent with previous case reports that suggest that hemimacropsia is associated with the occipitotemporal projection, which plays a decisive role in the visual identification of objects by interconnecting the striate, prestriate, and inferior temporal areas. The difference of our case as compared to previous case reports is that the lesion in our patient spared Brodmann area 17 (calcarine cortex) and therefore did not present symptoms of quadrantanopsia. Instead, the patient presented isolated hemimacropsia, therefore suggesting that the anatomical lesion causing hemimacropsia is located in the ventral portion of the occipitotemporal projection, more specifically Brodmann areas 18 (parastriate) and 19 (peristriate).

Amyotrophic lateral sclerosis: analysis of ALS cases in a predominantly admixed population of Ecuador.

Recent studies suggest amyotrophic lateral sclerosis (ALS) prevalence, incidence, and age of onset are heterogeneous across populations. These include studies from South America (SA) where lower prevalence, earlier onset, and reduced survival time of ALS are reported. However, the scarcity of epidemiological and clinical data confounds effective comparison. To investigate ALS incidence in the predominantly admixed population of Ecuador, we analyzed patient data. We analyzed case data from two major hospitals. To confirm diagnosis, we evaluated clinical and EMG examinations in a cohort of patients. For 2000-2012, we found 116 patients with ALS diagnosis in the two hospitals. Crude incidence was 0.2-0.6 per 100,000. Median age of onset was 54.3 (+ 15.06 SD). Clinical re-evaluation found misdiagnosis in three cases in the cohort. In conclusion, ALS incidence in the Ecuadorian hospital population is in accord with rates reported in recent studies for other admixed populations, and lower than that in the United States and Europe. Our study found that appropriate EMG administration and interpretation for the purposes of supporting a diagnosis of ALS with current consensus guidelines prevent adequate use of this test as an essential tool in the evaluation and diagnosis of ALS. Training for required standardization in Ecuador is recommended.