Neurological worsening in Wilson disease - clinical classification and outcome.

BACKGROUND & AIMS: Prevention of neurological worsening (NW) under therapy is an unmet need in the management of Wilson disease (WD). In this study, we aimed to characterize the occurrence, associated outcomes and potential reversibility of NW in WD. METHODS: From a total cohort of 457 patients with WD, 128 patients with WD and neurological features at any time point (all Caucasian, 63 females, median age at diagnosis 22 years) were identified by chart review at University Hospital Heidelberg and grouped according to initial presentation. The timing and occurrence of NW was assessed following a structured clinical examination during clinical visits. RESULTS: Early NW (within the first 3 months of therapy) was observed in 30 out of 115 (26.1%) patients with neurological or mixed presentation and never in patients with a purely hepatic or asymptomatic presentation (0%). Late NW (after >12 months) was seen in a further 23 (20%) with neurological or mixed presentation and in 13 out of 294 (4.4%) patients with a hepatic or asymptomatic presentation. The median time from start of treatment to late NW was 20 months. Only three patients experienced NW between 3 and 12 months. NW was observed with D-penicillamine, trientine and zinc therapy and was reversible in 15/30 (50%) with early NW and in 29/36 (81%) with late NW. CONCLUSIONS: In this study, we identified two peaks in NW: an early (≤3 months) treatment-associated peak and a late (>12 months of treatment) adherence-associated peak. Early paradoxical NW was attributed to treatment initiation and pre-existing neurological damage, and was not observed in those with a hepatic or asymptomatic presentation. Late NW is likely to be associated with non-adherence. IMPACT AND IMPLICATIONS: In patients with Wilson disease, defined as an excess accumulation of copper which can damage the liver, brain and other vital organs, neurological worsening can occur despite chelation therapy. The study identifies different patterns of 'early' (<3 months) vs. 'late' (>12 months) neurological worsening in relation to initiation of chelation therapy and establishes possible causes and the potential for reversibility. These data should be useful for counseling patients and for guiding the optimal management of chelation therapy.

Oxidative stress and ER stress are related to severity of tubercular infection.

To report the markers of oxidative stress and endoplasmic reticulum (ER) stress in tuberculosis of differing severity. Ninety patients with tuberculosis, 30 each with pulmonary tuberculosis (PTB), Pott's spine (PS) and tuberculous meningitis (TBM) were included. The diagnosis and severity of the respective group was based on pre-defined criteria. Six-months outcome and complications (Hyponatremia, paradoxical worsening and Drug induced hepatitis(DIH)) were recorded. Serum Melanodehyde (MDA) , glutathione (GSH), total antioxidant capacity (TAC), ER stress markers ATF-4,GRP-78 and CHOP, were measured using spectrophotometry and real time PCR. The oxidative and ER stress markers were correlated with different subgroups, severity of TBM, complications and outcome. The severity of TBM correlated with alteration in oxidative and ER stress markers. MDA was related to hyponatremia (P = 0.045), paradoxical worsening (P = 0.035) and DIH (P = 0.038), TAC correlated with paradoxical worsening (P = 0.047) and DIH (P = 0.015). In PS, MDA correlated with paradoxical worsening (P = 0.032) and DIH (P = 0.032); and in PTB, MDA correlated with hyponatremia (P = 0.025) and DIH (P = 0.037). Changes in stress marker levels were more marked in TBM compared to PS and PTB. Outcome of TBM correlated with MDA (P = 0.002), PS to MDA(P = 0.004), TAC(P = 0.05) CHOP(P = 0.004), GRP78(P = 0.001), ATF4(P = 0.045) and PTB to MDA(P = 0.0450), TAC(P = 0.014), CHOP(P = 0.025) and GRP78(P = 0.035). Oxidative and ER stress markers seem to be related to severity of TB, its complications and outcome.

MRI findings in Pott's spine and correlating clinical progress with radiological findings.

PURPOSE: To document magnetic resonance imaging (MRI) changes in Pott's spine and to correlate these with clinical findings and outcome. METHODS: Patients with Pott's spine having more than one set of MRI were included in the study. Patients were grouped according to timing of their second MRI. The MRI findings included changes in bone, disc, spinal cord, and soft tissue. The MRI changes were categorized into improvement, no change, or worsening. "Paradoxical worsening" was defined as radiological worsening in setting of clinical improvement, as described by improvement of Nurick's grade. Outcome was defined by mRS scale at three, six, and 12 months. The MRI findings and outcome were correlated. RESULTS: The results are based on 36 patients. The MRI changes included vertebral changes in form of spondylodiscitis in 33 (92%), epidural abscess in 29 (81%), spinal cord changes including edema and granuloma in 17 (47%), paravertebral abscess in 29 (81%), and vertebral body collapse in 12 (33.3%) patients. At three months, clinical improvement occurred in eight out of 12 patients, deterioration in two, and no change in two. Spinal MRI revealed improvement in one patient only; whereas eight had deterioration and three had no change. At six months, all nine patients improved clinically, but MRI showed improvement in only four, while another four showed deterioration and one had no change. In the nine and 12 months group, while all patients clinically improved, MRI showed minimal worsening. CONCLUSION: In Pott's spine, the clinical improvement precedes the radiological improvement.

Clinical Worsening in an Adolescent With Pleural Tuberculosis.

A 17-year-old previously healthy female presented with unilateral chest pain and dyspnea. Chest radiographs demonstrated a unilateral pleural effusion and pneumonia. Pleural fluid bacterial cultures were negative; acid-fast cultures grew Mycobacterium tuberculosis. Two months after starting appropriate therapy, she had a recrudescence of symptoms and reaccumulation of the pleural fluid. Her tuberculosis antibiotic regimen was expanded, the effusion drained, and systemic corticosteroids initiated, resulting in rapid clinical improvement. Cultures of the second pleural fluid collection were negative. Her clinical deterioration was due to immune reconstitution inflammatory syndrome (IRIS). IRIS can be seen within the first several months of starting tuberculosis therapy and can result in paradoxical worsening of symptoms or radiographic findings in adolescents who are on the appropriate therapy. IRIS is a diagnosis of exclusion after drug resistance and medication malabsorption, intolerance, and nonadherence are excluded. Therapy includes nonsteroidal anti-inflammatory agents for milder reactions and systemic corticosteroids for more severe IRIS cases.

Successful treatment of tuberculous meningitis in an Indian female under hemodialysis therapy.

Hemodialysis is a well-known risk factor for severe infection by putting patients under an immunocompromised state. Such patients are prone to opportunistic pathogen and present with atypical manifestations during infection. Tuberculous meningitis is a central nervous system infection of Mycobacterium tuberculosis, accounting for the highest mortality of all forms of tuberculosis. In fact, the mortality rate of tuberculous meningitis in hemodialysis patients is extremely poor because early clinical diagnosis is difficult. Here, we report a case of tuberculous meningitis in a 61-year-old Indian hemodialysis patient, who presented with fever of unknown origin and was successfully treated with empiric treatment with standard four-drug regimen against tuberculosis. Comprehensive screening of the origin of fever revealed only the positive results of interferon-gamma release assay, which led us to initiate an empiric therapy for tuberculosis, before making a definitive diagnosis by cerebrospinal fluid nested PCR. Soon after the initiation of the treatment, the fever immediately abated. Although the patient experienced a single episode of paradoxical worsening and severe liver injury, she recovered well without any complications. This report provides a clinical course of the disease in a hemodialysis patient, highlighting the importance of early clinical diagnosis and rapid initiation of empirical tuberculosis treatment.

Treatment response and complications during management of Pott's spine.

The global incidence of TB in 2016 was 10.4 million and India accounts for a quarter of the global burden of TB. It is estimated that there are 2.79 million people with TB in India. About 10% of extra pulmonary TB involves bone and joints. Spinal TB accounts for half the cases of skeletal TB. The incidence of spinal TB is 1-4% of total TB cases, then it is estimated that only in India approximately 60,000 spinal TB cases exist. To report the pattern of recovery and predictors of outcome of Pott's spine. The intervention comprised of four drug antitubercular treatment, rest, immobilization, and ultrasonography or computerized tomography guided aspiration or biopsy as indicated outcome measures were six months Nurick grade, and mRS and complications like drug induced hepatitis (DIH) and paradoxical worsening. Seventy-three patients with Pott's spine, median age 36 (11-73) years, 32 (43.8%) females were included. The neurological signs were present in 44 (64.4%) patients. At six months, median Nurick grade improved from 4 to 2 and;and 70% patients had a good outcome as defined by mRS.The predictors of poor outcome were weight loss, non-ambulatory state on admission and paradoxical worsening. It is concluded that neurological involvement in Pott's spine was present in 64% patients, paradoxical worsening (deterioration in symptoms after one month of ATT) in 11% and DIH in 16%. Weight loss, non-ambulatory state on admission and paradoxical worsening predicted poor outcome.

Yellow Subretinal Lesions following Initiation of Antituberculosis Therapy in A Tubercular Choroidal Granuloma: A Sign of Paradoxical Worsening?

PURPOSE: To describe the presentation and management of atypical subretinal lesions following initiation of antitubercular therapy for a tubercular choroidal granuloma. CASE REPORT: An 18-year-old female was diagnosed with choroidal granuloma and shallow exudative retinal detachment in the left eye. Biopsy from a cervical lymph node was positive for tuberculosis. She was treated with antitubercular therapy (ATT) and oral steroids. After one week of therapy exudative detachment increased markedly and discrete yellowish-white subretinal lesions appeared first in the inferior periphery, then temporally and later involved the macula leading to a drop in visual acuity. A diagnosis of paradoxical worsening was considered and she was managed with a higher dose of oral corticosteroids, intravitreal methotrexate and intravitreal ranibizumab. The granuloma healed and the subretinal lesions as well as exudative detachment gradually resolved with improvement in visual acuity. CONCLUSION: Subretinal yellow-white lesions may develop as a paradoxical response to ATT.

Tubercular panophthalmitis in a patient with human immunodeficiency virus infection: Proven clinicopathologically and by molecular diagnostic tests.

Ocular tuberculosis (OTB) in patients with human immunodeficiency virus (HIV) commonly presents as choroidal tubercles or granuloma. We report a rare presentation of OTB with hypopyon granulomatous uveitis in a patient with HIV on highly active antiretroviral therapy (HAART). Aqueous humor polymerase chain reaction (PCR) was positive for Mycobacterium tuberculosis (MTB). Antitubercular therapy (ATT) was initiated despite which it progressed to scleral abscess and panophthalmitis. Enucleation with ball implantation was done. Histopathology revealed caseating granuloma with numerous acid-fast bacilli (AFB) and real-time PCR showed increased copies of MTB genome. After a full course of ATT, he had stable ocular and systemic condition at final follow-up.

Dual lesion margins on fundus autofluorescence associated with paradoxical worsening following treatment for tubercular serpiginous-like choroiditis.

A 31-year-old male presented with decreased vision in the right eye associated with an active plaque-like serpiginoid choroiditis. The lesion showed a unique feature of dual margins of hyperautofluorescence of the lesion on fundus autofluoresence (FAF) imaging. Systemic investigations suggested a tubercular etiology. He was started on antitubercular treatment and a conventional dose of oral corticosteroids (1mg/kg body weight). However, the lesions showed paradoxical worsening and required increased immunosuppression in the form of local steroids and oral immunomodulators. The presence of dual margins of hyperautofluorescence could suggest increased inflammatory activity leading to paradoxical worsening on treatment requiring increased immunosuppression.

Ultra-Wide Field Imaging in Paradoxical Worsening of Tubercular Multifocal Serpiginoid Choroiditis after the Initiation of Anti-Tubercular Therapy.

Purpose: To evaluate role of ultra-wide field (UWF) versus conventional imaging in the follow-up and paradoxical worsening (PW) of tubercular (TB) multifocal serpiginoid choroiditis (MSC). Methods: Prospective observational study of patients with TB MSC undergoing UWF imaging, autofluorescence and fluorescein angiography was performed. A circle simulating central 75° field representing conventional imaging was drawn on UWF images. The information yielded by the two modalities, progression of choroiditis lesions and PW was compared. Results: 44 eyes (29 patients, mean age: 30.7 ± 9 years; 23 males) were included. UWF imaging showed additional lesions in 39/44 eyes (88.6%). Overall, 16/44 eyes (36.4%) showed PW; 3/16 eyes (18.7%) showed only peripheral PW, while 10/16 eyes showed both central and peripheral PW. Management was altered in 11 patients (37.93%) based on UWF imaging. Conclusions: UWF is more useful than conventional imaging in identifying additional choroiditis lesions, PW and altering the course of therapy in TB MSC.

Paradoxical reactions in ocular tuberculosis.

Paradoxical reactions following initiation of anti-tubercular therapy have been documented most often in extrapulmonary tuberculosis. A combination of factors such as delayed hypersensitivity, decreased suppressor mechanisms, and an increased response to mycobacterial antigens mediated by the host's immune system have been implicated in the development of these reactions. Similar worsening in patients with ocular tuberculosis while on treatment has been described. It is therefore important for the clinician to be aware of this occurrence, as prompt recognition and timely institution of corticosteroids and immunosuppressants can lead to restoration of vision. In these patients, an alteration or discontinuation of anti-tubercular therapy may not be indicated.

Pneumoperitoneum during treatment of abdominal tuberculosis in a Non-HIV patient: Natural progression or paradoxical worsening?

Paradoxical reactions during tuberculosis (TB) treatment are well-described in the HIV seropositive population but less so in the HIV seronegative group. Abdominal TB rarely presents as spontaneous perforation; cases occurring during anti-TB therapy are even rarer. We describe the clinical progress of a case of an HIV-negative patient who developed acute peritonitis while on anti-TB treatment for peritoneal TB through a series of clinical, radiological and histological images. Visceral perforation can occur as a complication of TB treatment. A high index of suspicion with early surgical intervention is crucial in the management of such cases.

Paradoxical Worsening of Tubercular Serpiginous-Like Choroiditis after Initiation of Antitubercular Therapy.

In this study, a case with tubercular choroiditis showing severe macular edema and progression of choroidal lesions following initiation of antitubercular treatment is presented and the management of posterior uveitis associated with tuberculosis is evaluated. A 40-year-old female patient was admitted with decreased vision in her right eye and her fundoscopic examination revealed serpiginous choroiditis. It was learned from her medical history that she had taken antitubercular therapy 9 years ago. Mantoux tuberculin skin test showed an area of induration measuring 15 mm and a positive interferon-gamma release assay was documented. Additionally, sequelae lesions due to previous tubercular infection were remarkable on her chest imaging. By excluding other causes of uveitis, the patient was considered presumed ocular tuberculosis and a full standard course of 4-drug antitubercular therapy was initiated. On the seventh day of the treatment existing choroidal lesions showed progression, new foci of choroiditis appeared and severe macular edema occurred. After adding systemic corticosteroid to the treatment, the macular edema resolved and choroidal lesions began to inactivate. In patients with tubercular choroiditis, continued progression may develop after initiation of antitubercular therapy. This paradoxical worsening is thought to be a hyperacute immunologic reaction occurring against antigen load released after antitubercular therapy. This phenomenon may be suppressed by the addition of systemic corticosteroids to the treatment.

Optical Coherence Tomography Angiography Features of Paradoxical Worsening in Tubercular Multifocal Serpiginoid Choroiditis.

PURPOSE: To describe optical coherence tomography angiography (OCTA) features of lesions of tubercular multifocal serpiginoid choroiditis (TB MSC) that developed paradoxical worsening (PW). METHODS: In this prospective study, subjects with TB MSC who developed PW upon initiation of anti-tubercular therapy were included. Multimodal imaging was performed using OCTA, enhanced-depth imaging OCT, fluorescein angiography (FA), and indocyanine green angiography (ICGA). Morphologic changes in the retinochoroidal vasculature during progression of TB MSC were assessed on OCTA. RESULTS: Five subjects (4 males, 1 female) were included in the study. PW of the lesions was associated with increased areas of choriocapillaris flow void on en face OCTA in all eyes. The lesions showed partial healing in the center and continuous progression at the active edges. Two eyes showed development of vascular tufts on OCTA as the lesions progressed. CONCLUSIONS: OCTA provides high-resolution imaging of progressive choriocapillaris hypoperfusion among TB MSC patients developing PW of the disease.

Paradoxical worsening of tuberculous chorioretinitis in a Chinese gentleman.

We report a case of paradoxical worsening of tuberculous chorioretinitis after initiation of anti-tuberculous therapy (ATT). The patient had left panuveitis with tuberculous chorioretinitis and was started on systemic ATT and oral steroids a week later. However, he developed paradoxical worsening 2 months after initiation of therapy. He was continued on ATT, oral steroids and intravitreal amikacin with resolution of the chorioretinal lesion subsequently. Ocular tuberculosis often poses a diagnostic challenge, and clinicians should be aware of the possibility of paradoxical worsening despite appropriate ATT. Clinicians should strongly consider starting oral steroids concurrently with ATT when managing ocular tuberculosis.

Peoría paradójica en fístulas carótido-cavernosas durales: cuando el cuerpo se enferma más para curarse / Paradoxical worsening in carotid-cavemous ductal fistulas: when the body get more sick in order to cure

Las fístulas carótido-cavernosas son comunicaciones arteriovenosas patológicas entre la arteria carótida interna intravenosa y el seno venoso-cavernoso que la rodea. Un sistema de flujo y presión elevados irrumpe sobre otro de bajo flujo y velocidad. Ello origina los síntomas y signos. La gran mayoría, son resultantes de traumatismos craneales siendo de alto flujo y alta velocidad-fístulas traumáticas o directas; menos comunes son las llamadas fístulas espontáneas o durales localizadas en la duramadre y alimentadas por ramas menígeas provenientes de las arterías carótidas externa, interna o ambas y de las arterias vertebrales. Estas últimas raras veces tienen implicaciones graves para la vida, pero la pérdida visual constituye el mayor riesgo; no obstante, con elevada frecuencia, ocurre la oclusión espontánea, por lo que se impone la observación hasta que la sintomatología justifique el tratamiento. En el curso evolutivo puede ocurrir la trombosis aguda de la fístula y más propiamente de la totalidad de la vena oftálmica superior la que produce un distintivo cuadro de notable agravamiento de los síntomas que en forma contradictoria ocurre antes de la mejoría y reversión de los síntomas, el síndrome de empeoramiento o peoría paradójica. Para ilustrar el síndrome se presentan los casos clínicos de los pacientes

Caroid-cavernous fistulas are pathological arteriovenous communications between the intracavernous internal carotid artery and the cavernous sinus. A system of high flow and pressure bursts over another system of low flow and slow velocity. This causes the symptoms and signs. The vast majority are related with head trauma being high flow and high speed fistulas: traumatic or direct. Less common are the so-called spontaneous or dural fistulas located in the duramater and fed by meningeal branches from the external, internal, or both carotic arteries and the vertebral arteries. These latest rarely have serious implications for life, but visual loss is the greatest risk; however, with high frequency spontaneously occlusion occurs, and then observation imposes until symptoms justified the treatment. During its evolution acute thrombosis of the fistula itself can occur along the entire length of the ophthalmic vein which produces a distinctive and paradoxical worserning and reversal of symptoms, which is called the syndrome of paradoxical worserning. Clinical cases of two patients are presented to illustrate the syndrome