Seropositive Neuromyelitis Optica in a Case of Undiagnosed Ankylosing Spondylitis: A Neuro-Rheumatological Conundrum.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy against foot processes of aquaporin-4 (AQP4) water channels. Patients with NMOSD tend to have other coexisting autoimmune/connective tissue diseases. However, AQP-4-antibody-positive NMOSD coexisting with ankylosing spondylitis (AS) is rare. AS is an immune-mediated disorder, a subset of axial spondyloarthropathies, which commonly manifests as chronic inflammatory back pain in young people, and it has a strong association with HLA-B27. In this study, a 35-year-old Indian man with an undiagnosed progressive axial spondyloarthropathy (i.e., AS) is reported presenting with acute-onset longitudinally extensive transverse myelitis, a clinical subset of NMOSD. Neuromyelitis optica spectrum disorder (NMOSD), a primary demyelinating disorder of the central nervous system (CNS), is an autoimmune astrocytopathy against foot processes of aquaporin-4 (AQP4) water channels, which manifests with optic neuritis, longitudinally extensive transverse myelitis (LETM), area-postrema syndrome, brainstem syndrome diencephalic syndrome, and cerebral syndrome.1-4 Ankylosing spondylitis (AS) is an immune-mediated disorder, a subset of axial spondyloarthropathies, which commonly manifests as chronic inflammatory back pain in young people, and it has a strong association with HLA-B27.5,6 AS characteristically targets the axial skeleton, peripheral joints, entheses (connective tissues between tendons/ligaments and bones), and gut.5,6 Patients with NMOSD tend to have other coexisting autoimmune/connective tissue diseases.7 For example, cases with NMOSD and multiple sclerosis, which are other autoimmune primary demyelinating disorders of the CNS, have been reported.8,9 However, concurrent existence of AS and NMOSD in the same patient even over years of disease course is rare.10,11 In addition, studies describing neurological manifestations of AS are limited,12 and they focus on joint inflammation and long-standing bony pathology (ankylosis) related to compressive myelopathy, myelo-radiculopathy, and cauda equina syndromes.12,13 The authors present a case of a young Indian man with an undiagnosed progressive AS (misdiagnosed and mismanaged by an indigenous medical practitioner) presenting with acute-onset LETM variant of AQP4-positive NMOSD. A 35-year-old healthy, non-comorbid man from rural India came to the outpatient department with complaints of persistent tingling, numbness, and weakness of both lower limbs (right more than left) for 10 days. The clinical picture showed acute-onset urinary retention, which was relieved by urinary catheterization. An indigenous medical practitioner had prescribed drugs to treat a urinary tract infection. His weakness gradually progressed over the following week, causing him to become bedridden. During the removal of the catheter, he felt urgency, increased frequency of micturition, and overt urinary incontinence. He gave no history suggestive of any girdle-like sensations, root/radicular/tract pain, vertebral pain, trauma, recent vaccination, and diarrheal or febrile illness. For the last 8 months, he had a complaint of an insidious-onset, persistent, bilateral, dull aching pain in the gluteal region accompanied by low-back pain and morning stiffness up to 1 h, which markedly improved with activity and reoccurred following long periods of inactivity. He sometimes had to rise in the middle of the night because of excruciating pain, which could be relieved after moving around the room and corridors for half an hour. He was taking over-the-counter diclofenac tablets for pain relief prescribed by some indigenous medical practitioners who told him that it was due to overwork in agricultural fields, that is, mechanical back pain. He also had a normal X-ray of the lumbosacral spine. He had no addiction liabilities, and none of the family members had ever suffered from a similar kind of illness. He had never consulted any trained medical practitioner, as his previous back-pain-related symptoms responded well to the tablets prescribed by the indigenous medical practitioner(s). During examination, he was found to have recent-onset, asymmetric spastic paraparesis (right more than left) with upper motor neuron-type urinary bladder symptoms. Cognitive assessment (assessed by the Montreal cognitive assessment test) was normal, and posterior column sensations were preserved. Sensory system examination revealed no definite sensory level. Except for the paretic lower limbs, cerebellar functions were normal in other regions. Neuro-ophthalmological examinations were also normal, and no signs of meningeal irritation were observed. The history and course of the disease and clinical examinations were analyzed. Selective tractopathy (early and predominant motor and autonomic tract affection) was suggested for an intramedullary demyelinating pathology affecting the anterior central cord. This case was initially classified as acute-onset non-compressive myelopathy at the lower cervical/upper dorsal region level in a patient with a pre-existing axial spondyloarthropathy. Complete blood cell count; liver, kidney, and thyroid function tests; and plasma glucose and electrolytes were normal, except for an increased erythrocyte sedimentation rate (66 mm in the first hour). Magnetic resonance imaging (MRI) of the spinal cord revealed a demyelinating LETM from C5 to D4 level (Figure 1). Meanwhile, an MRI of the sacroiliac joints revealed bilateral sacroiliitis. Brain and orbital MRIs were devoid of any lesions. Anti-aquaporin 4 (AQP-4) antibodies were tested by cell-based assay in serum and cerebrospinal fluid (CSF), and both were positive. CSF further revealed lymphocytic pleocytosis and increased intrathecal protein production. Visually evoked potential recordings were also normal. In addition, anti-myelin oligodendrocyte glycoprotein antibodies were negative. Anti-nuclear antibody (ANA), ANA-profile, autoimmune vasculitis profile (c-ANCA, p-ANCA), neurovirus panel (i.e., polymerase chain reaction for adenovirus, Epstein-Barr virus, herpes simplex viruses 1 and 2, human herpesviruses 6 and 7, cytomegalovirus, enteroviruses, varicella-zoster virus, Japanese encephalitis, and dengue virus), CSF-polymerase chain reaction for Mycobacterium tuberculosis, angiotensin-converting enzyme, anti-phospholipid, and anti-thyroid antibodies were negative. Anti-CCP-antibody and rheumatoid factor were also negative, including creatine phosphokinase level and serum vitamin B12. Moreover, serologies for hepatitis B, C, human immunodeficiency virus, and scrub typhus were negative. However, HLA-B27 assay was positive. The final diagnosis was AQP4-positive NMOSD associated with AS. He was placed on pulse intravenous methylprednisolone (1 g/day for 5 days). Consequently, his lower limb power improved remarkably. Cyclical rituximab therapy was initiated to prevent relapses. At 3-month follow-up, he had no residual neurological deficit except for persistence of paresthesias. Neuroimaging and visually evoked potential studies revealed no active or new lesions. After 6 months of therapy, a subjective and objective improvement was observed in disease severity based on the Ankylosing Spondylitis Disease Activity Score. Our patient satisfied the new Assessment of SpondyloArthritis International Society diagnostic/classification criteria for AS and the Wingerchuk criteria for NMOSD,4,14 an association that has been rarely reported.10,11 Amid the extra-articular complications of long-standing AS, neurological manifestations are considered infrequent.15 However, subclinical neurological complications may be frequent in AS.12 Common neurological manifestations result from bony (vertebral) ankylosis, subluxation of joints, ossification of anterior and posterior longitudinal ligaments, secondary spinal canal stenosis, bony (vertebral) fractures, and subsequent compressions over nerve radicles/roots/cauda equina, and inflammation-related (entrapment) peripheral neuropathies.12,16,17 Acute transverse myelitis can occur as a subset of several primary demyelinating disorders of the CNS (i.e., multiple sclerosis, NMOSD, myelin oligodendrocyte glycoprotein antibody disease, and acute disseminated encephalomyelitis) and various systemic autoimmune connective tissue disorders (i.e., systemic lupus erythematosus, mixed connective tissue disease, Sjögren syndrome, inflammatory bowel disease, and neurosarcoidosis).18 Acute transverse myelitis (short or long segment) is an infrequent extra-articular complication of AS.18 It has been reported to evolve either as a distinct neurological complication of AS, or it may develop secondary to TNF-alpha-inhibitor therapy for the treatment of AS.18,19 AS is a heritable inflammatory spondyloarthropathy that primarily affects the axial skeleton, which is mediated by T-cells; B-cells only play a minor role.5 On the contrary, the key for the pathogenesis of NMOSD is the production of autoantibodies against AQP-4 channels expressed on astrocytes, leading to complement-mediated damage, with ensuing demyelination. Myelitis usually shows high signal intensity on the tbl2-weighted image and contrast enhancement in the spinal cord.1-4 Despite the difference in molecular mechanisms, the diagnosis of these diseases in the same individual may not be coincidental. Recent evidence has shown T-cell-mediated inflammatory responses in cases of NMOSD.20 In particular, Th17 and Th2-related cytokines are elevated in the CSF of NMO patients.20 Environmental factors such as Escherichia coli have also been proven to aggravate autoimmunity in AS and NMOSD (however, body fluid cultures for Escherichia coli, performed in our patient, showed similar association, and they were found negative two times).21,22 Although large-scale epidemiological studies investigating the underlying pathogenesis related to these diseases are lacking, studies have demonstrated anincreased incidence of optic neuritis among patients with AS.23 Systemic sclerosis and mixed and undifferentiated connective tissue diseases were excluded after expert opinions (from two board-certified rheumatologists and two dermatologists) because of the lack of suggestive clinical findings (e.g., absence of skin thickening, salt-and-pepper appearance, nail changes, Mauskopf facies, sclerodactyly, calcinosis cutis, Raynaud's phenomenon, other cutaneous manifestations, pulmonary arterial hypertension/interstitial lung disease, dysphagia, muscular pain/weakness renal impairments, absence of ANA, anti-centromere antibodies, anti-Scl-70, PM-Scl antibodies, anti-ds DNA, PCNA, CENP-B, anti-nucleosomes, anti-Smith, anti-U1-RNP, anti-Jo1, anti-Mi2, anti-Ro52, anti-La antibodies, and normal C3 and C4 complement levels) (The European League Against Rheumatism and the American College of Rheumatology classification criteria 2019).24 Finally, our patient was treated with intravenous steroids followed by rituximab infusions, a monoclonal anti-CD20 antibody directed against B-cells. In particular, this patient clinically and radiologically responded to immunomodulatory drugs, which might support a possible common pathogenic basis of the two processes. TNF-alpha inhibitors are commonly used as novel therapeutics in AS; however, they can potentially result in serious complications, that is, secondary demyelinating disorders.25 However, such inhibitors in this patient were not used. When used in cases of AS, they show satisfactory results.25,26 Therefore, it was decided to treat him with rituximab only without adding any second immunomodulatory. Other possible therapeutic options include cyclophosphamide and mycophenolate mofetil, but they were not used because of their low efficacy-safety balance. Moreover, plasmapheresis was not available in our specific setting, despite solid evidence that early treatment with therapeutic strategy (5-7 courses) provides good long-term outcomes in patients with NMOSD.27 Therefore, when dealing with a case of acute non-compressive myelopathy, history and clinical examination are important to determine the potential underlying etiology and identify an undermined systemic disorder with apparently unrelated non-specific features. Connective tissue disorders should always be considered as a differential diagnosis and be ruled out in all cases of either seropositive or seronegative NMOSD. A diagnosis of AS should be considered in relevant circumstances when dealing with a case of isolated seronegative LETM. Moreover, early diagnosis and treatment of AS are quintessential to prevent lifelong distressing disabilities. However, whether patients with AS have any extra predilection to develop NMOSD throughout their life requires further studies.

Primary angiitis of central nervous system - A challenging diagnosis.

Primary angiitis of the central nervous system is a rare disease characterized by vasculitis of the central nervous system without any systemic involvement. This review aims to provide an insight into the existing stagnancies in the diagnostic approach and management of this disease. The clinical presentation is typically nonspecific, ranging from headaches, altered sensorium, and seizures to recurrent ischemic strokes. The definitive diagnosis can only be ascertained by histopathological studies of tissue obtained from a brain biopsy. While angiography can provide clues to diagnosis, it has often been normal, even in biopsy-proven cases. Primary angiitis of the central nervous system continues to be a diagnostic challenge as little progress has been made over the years in the diagnosis and management strategies. Considering the vast list of mimickers of primary angiitis of the central nervous system and the existence of a significant proportion of imaging-negative and biopsy-negative cases, it becomes imperative to devise universally accepted diagnostic criteria for this disease. Steroids in combination with cyclophosphamide are the agents used to achieve remission. Rituximab can be an alternative. The treatment-related toxicity of cyclophosphamide warrants larger trials for alternative drugs to be studied.

Nature and Dimensions of Systemic Hyperinflammation and its Attenuation by Convalescent Plasma in Severe COVID-19.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing coronavirus disease 2019 (COVID-19), has led to significant morbidity and mortality. While most suffer from mild symptoms, some patients progress to severe disease with acute respiratory distress syndrome (ARDS) and associated systemic hyperinflammation. METHODS: First, to characterize key cytokines and their dynamics in this hyperinflammatory condition, we assessed abundance and correlative expression of a panel of 48 cytokines in patients progressing to ARDS as compared to patients with mild disease. Then, in an ongoing randomized controlled trial of convalescent plasma therapy (CPT), we analyzed rapid effects of CPT on the systemic cytokine dynamics as a correlate for the level of hypoxia experienced by the patients. RESULTS: We identified an anti-inflammatory role of CPT independent of its neutralizing antibody content. CONCLUSIONS: Neutralizing antibodies, as well as reductions in circulating interleukin-6 and interferon-γ-inducible protein 10, contributed to marked rapid reductions in hypoxia in response to CPT. CLINICAL TRIAL REGISTRY OF INDIA: CTRI/2020/05/025209. http://www.ctri.nic.in/.

Panhypopituitarism in acute myocardial infarction.

While hypopituitarism is known to be associated with increased cardiovascular morbidity and mortality, panhypopituitarism as a complication of myocardial infarction (MI) is very rare. Here, we report a case of rapidly developing empty sella syndrome with florid manifestations of panhypopituitarism after MI (due to critical stenosis in the left anterior descending artery) complicated by cardiogenic shock in a 65-year-old man. The patient was initially stabilized with conservative management of non-ST-elevated MI and cardiogenic shock, but after initial improvement, he again deteriorated with refractory shock (not adequately responding to vasopressors), seizures, hypoglycemia, hyponatremia, hyperkalemia, and metabolic acidosis. After ruling out recurrent cardiogenic shock or other causes of refractory hypotension, panhypopituitarism was diagnosed with the help of hormonal assays and imaging. With no prior evidence of hypopituitarism, we suspect that panhypopituitarism developed due to acute pituitary apoplexy secondary to initial cardiogenic shock. The patient was successfully survived by the emergency endocrine management followed by secondary coronary angioplasty.

Résumé Bien que l'hypopituitarisme soit associé à une augmentation de la morbidité et de la mortalité cardiovasculaires, le panhypopituitarisme en tant que complication de l'infarctus du myocarde (IM) est très rare. Ici, nous rapportons un cas de développement rapide du syndrome de la selle vide avec des manifestations florales de panhypopituitarisme après IM (en raison d'une sténose critique dans l'artère descendante antérieure gauche) compliquée par un choc cardiogénique chez un homme de 65 ans. Le patient a été initialement stabilisé avec une gestion conservatrice de l'IM non élevé ST et du choc cardiogénique, mais après une amélioration initiale, il s'est à nouveau détérioré avec un choc réfractaire (ne répondant pas adéquatement aux vasopresseurs), des convulsions, une hypoglycémie, une hyponatrémie, une hyperkaliémie et une acidose métabolique. Après avoir écarté le choc cardiogénique récurrent ou d'autres causes d'hypotension réfractaire, le panhypopituitarisme a été diagnostiqué à l'aide de tests hormonaux et d'imagerie. En l'absence de preuve antérieure d'hypopituitarisme, nous soupçonnons que le panhypopituitarisme s'est développé en raison d'une apoplexie hypophysaire aiguë secondaire au choc cardiogénique initial. Le patient a été survécu avec succès par la prise en charge endocrinienne d'urgence suivie d'une angioplastie coronaire secondaire.

Seizure as a presenting manifestation of Wernicke's encephalopathy induced by hyperemesis gravidarum.

Wernicke's encephalopathy (WE) is an acute neurological condition characterized by the triad of ophthalmoparesis with nystagmus, ataxia, and global confusion. WE is a life-threatening illness caused by thiamine deficiency, primarily affecting the peripheral and central nervous systems. Thiamine deficiency is predominantly associated with chronic alcoholism, but various other causes have also been reported, including severe malnutrition, prolonged parenteral nutrition, malignancies, immunodeficiency syndromes, liver disease, hyperthyroidism and severe anorexia nervosa, and hyperemesis gravidarum. We, hereby, report a unique case of WE induced by hyperemesis gravidarum that presented in mid-trimester of pregnancy in a rather extremely unusual way with focal seizures and secondary generalization but fortunately ended up with a good feto-maternal outcome.

A Rare Case of SARS-CoV-2 Infection Associated With Pituitary Apoplexy Without Comorbidities.

Pituitary apoplexy is a medical and surgical emergency caused by hemorrhage or infarction of the hypophysis, which typically occurs within a pituitary adenoma. It is usually characterized by severe (often thunderclap) headache, visual disturbances, cranial nerve impairments, and hormonal deficiencies. We herein report a case of a previously healthy woman with severe acute respiratory syndrome coronavirus 2 infection associated with pituitary apoplexy. The plausible pathophysiological mechanisms of pituitary apoplexy in infectious coronavirus disease 2019 are discussed.

Neurological and Neuropsychiatric Impacts of COVID-19 Pandemic.

BACKGROUND: Albeit primarily a disease of respiratory tract, the 2019 coronavirus infectious disease (COVID-19) has been found to have causal association with a plethora of neurological, neuropsychiatric and psychological effects. This review aims to analyze them with a discussion of evolving therapeutic recommendations. METHODS: PubMed and Google Scholar were searched from 1 January 2020 to 30 May 2020 with the following key terms: "COVID-19", "SARS-CoV-2", "pandemic", "neuro-COVID", "stroke-COVID", "epilepsy-COVID", "COVID-encephalopathy", "SARS-CoV-2-encephalitis", "SARS-CoV-2-rhabdomyolysis", "COVID-demyelinating disease", "neurological manifestations", "psychosocial manifestations", "treatment recommendations", "COVID-19 and therapeutic changes", "psychiatry", "marginalised", "telemedicine", "mental health", "quarantine", "infodemic" and "social media". A few newspaper reports related to COVID-19 and psychosocial impacts have also been added as per context. RESULTS: Neurological and neuropsychiatric manifestations of COVID-19 are abundant. Clinical features of both central and peripheral nervous system involvement are evident. These have been categorically analyzed briefly with literature support. Most of the psychological effects are secondary to pandemic-associated regulatory, socioeconomic and psychosocial changes. CONCLUSION: Neurological and neuropsychiatric manifestations of this disease are only beginning to unravel. This demands a wide index of suspicion for prompt diagnosis of SARS-CoV-2 to prevent further complications and mortality.

Les impacts neurologiques et neuropsychiatriques d'une infection à la COVID-19. CONTEXTE: Bien qu'il s'agisse principalement d'une maladie des voies respiratoires, la maladie infectieuse à coronavirus apparue en 2019 (COVID-19) s'est avérée avoir un lien de causalité avec une pléthore d'impacts d'ordre neurologique, neuropsychiatrique et psychologique. Cette étude entend donc analyser ces impacts tout en discutant l'évolution des recommandations thérapeutiques se rapportant à cette maladie. MÉTHODES: Les bases de données PubMed et Google Scholar ont été interrogées entre les 1er janvier et 30 mai 2020. Les termes clés suivants ont été utilisés : « COVID-19 ¼, « SRAS ­ CoV-2 ¼, « Pandémie ¼, « Neuro ­ COVID ¼, « AVC ­ COVID ¼, « Épilepsie ­ COVID ¼, « COVID ­ encéphalopathie ¼, « SRAS ­ CoV-2 ­ encéphalite ¼, « SRAS ­ CoV-2 ­ rhabdomyolyse ¼, « COVID ­ maladie démyélinisante ¼, « Manifestations neurologiques ¼, « Manifestations psychosociales ¼, « Recommandations thérapeutiques ¼, « COVID-19 et changement thérapeutiques ¼, « Psychiatrie ¼, « Marginalisés ¼, « Télémédecine ¼, « Santé mentale ¼, « Quarantaine ¼, « Infodémique ¼ et « Médias sociaux ¼. De plus, quelques articles de journaux relatifs à la pandémie de COVID-19 et à ses impacts psychosociaux ont également été ajoutés en fonction du contexte. RÉSULTATS: Il appert que les manifestations neurologiques et neuropsychiatriques des infections à la COVID-19 sont nombreuses. Les caractéristiques cliniques d'une implication des systèmes nerveux central et périphérique sautent désormais aux yeux. Ces caractéristiques ont fait l'objet d'une brève analyse systématique à l'aide de publications scientifiques. En outre, la plupart des impacts d'ordre psychologique de cette pandémie se sont révélés moins apparents que les changements réglementaires, socioéconomiques et psychosociaux. CONCLUSION: Les manifestations neurologiques et neuropsychiatriques de cette maladie ne font que commencer à être élucidées. Cela exige donc une capacité accrue de vigilance en vue d'un diagnostic rapide, et ce, afin de prévenir des complications additionnelles et une mortalité accrue.

A case of area postrema variant of neuromyelitis optica spectrum disorder following SARS-CoV-2 infection.

Neuromyelitis optica spectrum disorder (NMOSD) is a disabling autoimmune astrocytopathic channelopathy, characterized by the presence of pathogenic antibodies to aquaporin-4 (AQP-4) water channels. Several viral infections including HIV, influenza virus, varicella zoster virus, and Epstein Barr virus, among others, have been alleged to trigger NMOSD in both immunocompetent and immunocompromised individuals. Neurological manifestations of coronavirus infectious disease of 2019 (COVID-19) have been ever evolving and the spectrum of neuraxial involvement is broadening. Albeit it may affect any area of the neural axis, the involvement of the spinal cord is rare compared to that of the brain and of the peripheral nervous system. Cases with acute longitudinally extensive transverse myelitis (LETM) have been recently reported in SARS-CoV-2 infection but did not fulfill the international consensus diagnostic criteria for NMOSD. AQP-4-antibody-seropositive NMOSD following SARS-CoV-2 infection had not yet been reported. We herein report a novel case of a previously healthy man who presented with a clinical picture of bouts of vomiting and hiccoughs (area postrema syndrome), which rapidly evolved to acute LETM, all following SARS-CoV-2 infection. He was finally diagnosed to be a case of seropositive NMOSD which presented as area postrema syndrome. The response to immunomodulatory drugs was excellent.

Hashimoto's encephalopathy in association with retinitis pigmentosa - First reported case.

Hashimoto's Encephalopathy (HE), also known as steroid responsive encephalopathy associated with autoimmune thyroiditis (SREAT), is a proteiform disorder known for its wide spectrum of presentations from subtle neuropsychiatric manifestations, movement disorders, seizures, stroke-like episodes to coma. Here, we report a case of HE which initially masqueraded as bipolar affective disorder (BPAD) and ultimately progressed to generalized tonic clonic seizures and coma. Although SREAT is characterized by exquisite responsive to steroid, in our case it was unresponsive to pulse methylprednisolone therapy. Rapid recovery was noted with intravenous immunoglobulin (IVIG) therapy. This case was also peculiar for its association with non-sydnromic retinitis pigmetosa (RP). To the best of our knowledge, this was the first reported case of HE which was associated with RP.

Juvenile dermatomyositis presenting as complete heart block in a 10-year-old girl.

Juvenile dermatomyositis (JDM) is an auto-immune inflammatory condition associated with cardiac disorders including conduction abnormalities and myocardial dysfunction. The time of presentation of cardiac abnormalities can range from disease onset to after long-term follow-up, emphasising the importance of screening for cardiac involvement in JDM. A previously healthy 10-year-old girl presented with syncope, fatigue and weakness associated with a heliotrope rash. JDM was diagnosed based on the clinical, laboratory and imaging findings. An ECG demonstrated complete heart block (CHB). All symptoms resolved following treatment with parenteral corticosteroids. In JDM, it is important to investigate for cardiac manifestations and in CHB to consider administering corticosteroids.

Jaw clonus in neuromyelitis optica spectrum disorder with subsequent osmotic demyelination syndrome.

Jaw clonus, a fascinating, yet uncommon clinical sign, is suggestive of supranuclear lesions of the trigeminal nerve. It has previously been reported in association with amyotrophic lateral sclerosis. Hereby, we report an index case of jaw clonus in a patient of neuromyelitis optica spectrum disorder with subsequent osmotic demyelination syndrome with pseudobulbar palsy due to the involvement of pontine corticobulbar fibres.

Test anxiety effects, predictors, and correlates: A 30-year meta-analytic review.

BACKGROUND AND OBJECTIVES: Since the 1988 publication of Hembree's seminal meta-analysis on test anxiety, much has changed in the theoretical conceptualization of test anxiety, as well as the influences on test performance. The present study examined the influence of test anxiety on a variety of educational outcomes, in addition to demographic and intrapersonal correlates. DESIGN AND METHODS: Results of 238 studies from 1988 to the present, were synthesized via a meta-analytic framework to explicate predictors, correlates, and relationships with the test anxiety construct. Pooled effect sizes were calculated. RESULTS: Results indicated that test anxiety was significantly and negatively related to a wide range of educational performance outcomes, including standardized tests, university entrance exams, and grade point average. Results were most pronounced at the middle grades level. Self-esteem was a significant and strong predictor of test anxiety. Perceived difficulty of the test and the high-stakes nature or consequences of the test was also related to higher test anxiety. CONCLUSIONS: The magnitude of the relationship of test anxiety across a number of variables was in the small to moderate range. Implications for researchers and educators are discussed including the use of evidence-based assessment and interventions when warranted.