Opioid-Induced Leukoencephalopathies: A Report of Two Cases.

Acute toxic leukoencephalopathy (ATL) and delayed post-hypoxic leukoencephalopathy (DPHL) are two possible adverse entities related to opioid intoxication (OI), each having a distinct clinical course. While ATL shows a monophasic course with gradual neurological deterioration, DPHL has a distinct biphasic course. We report a case of ATL along with a case of DPHL happening in young male patients with OI, including their clinical courses as well as imaging characteristics with comparable time intervals. Initially, both leukoencephalopathies typically show magnetic resonance imaging findings with confluent and symmetric white matter (WM) abnormalities in the periventricular regions on T2 and fluid-attenuated inversion recovery images along with restricted diffusion on diffusion-weighted imaging. The DPHL patient however also presented with WM cystic substance loss in the deterioration phase, several weeks after hospital admission, which was previously described in a case of DPHL. Interestingly, similar WM changes have recently been observed in virus-associated necrotizing disseminated acute leukoencephalopathy in patients with coronavirus disease 2019 which may suggest a common pathophysiological mechanism. Knowing the distinct imaging features of ATL and DPHL along with their typical clinical courses can provide a faster and more reliable differentiation between these two entities.

Prophylactic Corticosteroid Use with Axicabtagene Ciloleucel (Axi-Cel) in Patients (Pts) with Relapsed/ Refractory Large B-Cell Lymphoma (R/R LBCL): 2-Year Follow-up of Zuma-1 Cohort 6

Background: The ZUMA-1 safety management Cohort 6 (N=40), which evaluated whether prophylactic corticosteroids and earlier corticosteroids and/or tocilizumab could improve safety outcomes, demonstrated an improved safety profile (no Grade >=3 cytokine release syndrome [CRS];15% Grade >=3 neurologic events [NEs]) vs pivotal Cohorts 1+2, without compromising response rate or durability (95% ORR, 80% CR rate, and 53% ongoing response rate with >=1 y of follow-up;Oluwole, et al. ASH 2021. 2832). Here, 2-y updated outcomes are reported. Method(s): Eligible pts with R/R LBCL underwent leukapheresis (followed by optional bridging therapy) and conditioning chemotherapy, then a single axi-cel infusion. Pts received corticosteroid prophylaxis (once-daily oral dexamethasone 10 mg on Days 0 [before axi-cel], 1, and 2) and earlier corticosteroids and/or tocilizumab for CRS and NE management vs Cohorts 1+2 (Oluwole, et al. Br J Haematol. 2021). The primary endpoints were incidence and severity of CRS and NEs. Secondary endpoints included ORR (investigator-assessed), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and chimeric antigen receptor (CAR) T-cell levels in blood. Result(s): As of December 16, 2021, the median follow-up time for the 40 treated pts was 26.9 mo. Since the 1-y analysis, no new CRS events were reported (no pts had Grade >=3 CRS to date). The incidence of Grade >=3 NEs increased from 15% to 18%between the 1-y and 2-y analyses. Two new NEs occurred in 2 pts: 1 pt had Grade 2 dementia (onset on Day 685 and ongoing at time of data cutoff;not related to axi-cel) and 1 had Grade 5 axi-cel-related leukoencephalopathy. Since the 1-y analysis, 6 new infections were reported (Grades 1, 2, and 5 COVID-19 [n=1 each], Grade 3 Pneumocystis jirovecii pneumonia [n=1], Grade 3 unknown infectious episode with inflammatory syndrome [n=1], and Grade 2 herpes zoster [n=1]). In total, 8 deaths occurred since the 1-y analysis (progressive disease [n=5], leukoencephalopathy [n=1], and COVID-19 [n=2]). The ORR was 95% (80% CR), which was unchanged from the 1-y analysis. Median DOR and PFS were since reached (25.9 mo [95% CI, 7.8-not estimable] and 26.8 mo [95% CI, 8.7-not estimable], respectively). Median OS was still not reached. Kaplan- Meier estimates of the 2-y DOR, PFS, and OS rates were 53%, 53%, and 62%, respectively. Of 18 pts (45%) in ongoing response at data cutoff, all achieved CR as the best response. By Month 24, 14/20 pts with evaluable samples (70%) had detectable CAR T cells (vs 23/36 pts [64%] in Cohorts 1+2). Conclusion(s): With 2 y of follow-up, the ZUMA-1 Cohort 6 toxicity management strategy continued to demonstrate an improved long-term safety profile of axi-cel in pts with R/R LBCL. Further, responses remained high, durable, and similar to those observed in Cohorts 1+2 (Locke, et al. Lancet Oncol. 2019).Copyright © 2023 American Society for Transplantation and Cellular Therapy

Evaluation of risk management in a natalizumab home infusion procedure.

Natalizumab is a well-established disease-modifying therapy used in active multiple sclerosis (MS). The most serious adverse event is progressive multifocal leukoencephalopathy. For safety reasons, hospital implementation is mandatory. The SARS-CoV-2 pandemic has deeply affected hospital practices leading French authorities to temporarily authorize to administer the treatment at home. The safety of natalizumab home administration should be assessed to allow ongoing home infusion. The aim of the study is to describe the procedure and assess the safety in a home infusion natalizumab model. Patients presenting relapsing-remitting MS treated by natalizumab for over two years, non-exposed to John Cunningham Virus (JCV) and living in the Lille area (France) were included from July 2020 to February 2021 to receive natalizumab infusion at home every four weeks for 12 months. Teleconsultation occurrence, infusion occurrence, infusion cancelling, JCV risk management, annual MRI completion were analyzed. The number of teleconsultations allowing infusion was 365 (37 patients included in the analysis), all home infusions were preceded by a teleconsultation. Nine patients did not complete the one-year home infusion follow-up. Two teleconsultations canceled infusions. Two teleconsultations led to a hospital visit to assess a potential relapse. No severe adverse event was reported. All 28 patients who have completed the follow-up benefited from biannual hospital examination and JCV serologies and annual MRI. Our results suggested that the established home natalizumab procedure was safe using the university hospital home-care department. However, the procedure should be evaluated using home-based services outside the university hospital.

Multiple Sclerosis and the Risk of Infection: A Consensus Guideline

Multiple sclerosis (MS) is an inflammatory condition affecting the central nervous system. Infection is a major consideration in the MS population due to its relevance to several stages of the disease process: (i) it has been suggested that infective processes may be 'triggering' or aetiological factors for MS, (ii) concurrent infection is known to exacerbate symptoms in MS, (iii) people with MS are at higher risk of infection when compared to the general population, and this risk is exaggerated in those receiving disease modifying therapies (DMTs). This guidance document was developed by specialists in the field of MS, Immunology, Infectious Disease and Pharmacy. A modified Delphi approach was used to develop clinically relevant, evidence-based consensus guidelines to help physicians navigate the complex interaction between DMTs and infectious diseases. We focus on specific risks predisposing people with MS to infection and how to manage these risks. We also provide recommendations on how to screen for, prevent, and manage infection in this population, in particular tuberculosis, progressive multifocal leukoencephalopathy, hepatitis B, human papillomavirus, herpetic and other opportunistic infections. We also discuss vaccination and the COVID-19 pandemic in people on DMTs.

Covid-19-associated diffuse posthypoxic leukoencephalopathy and microhemorrhages - A case report

Background: Delayed post-hypoxic leukoencephalopathy (DPHL) with associated microbleeds is a clinical entity presenting with cognitive impairment days or weeks after an episode of acute hypoxic brain injury. Case report: We describe a 68-year-old male with SARS-CoV2 infection who had cardiac arrest, required sedation and mechanical ventilation for 17 days, and after sedation was discontinued, he became unresponsive. Brain MRI showed diffuse confluent hyperintense signals in the subcortical white matter and multiple subcortical white matter microhemorrhages. EEG revealed diffuse attenuation of brain electrical activity with isolated polymorphic delta waves in the frontal region without epileptiform activity. Conclusion(s): Clinicians need to be aware that patients with Covid-19 can develop delayed post-hypoxic leukoencephalopathy.Copyright © 2022 The Authors

Multifactorial White Matter Damage in the Acute Phase and Pre-Existing Conditions May Drive Cognitive Dysfunction after SARS-CoV-2 Infection: Neuropathology-Based Evidence.

BACKGROUND: There is an urgent need to better understand the mechanisms underlying acute and long-term neurological symptoms after COVID-19. Neuropathological studies can contribute to a better understanding of some of these mechanisms. METHODS: We conducted a detailed postmortem neuropathological analysis of 32 patients who died due to COVID-19 during 2020 and 2021 in Austria. RESULTS: All cases showed diffuse white matter damage with a diffuse microglial activation of a variable severity, including one case of hemorrhagic leukoencephalopathy. Some cases revealed mild inflammatory changes, including olfactory neuritis (25%), nodular brainstem encephalitis (31%), and cranial nerve neuritis (6%), which were similar to those observed in non-COVID-19 severely ill patients. One previously immunosuppressed patient developed acute herpes simplex encephalitis. Acute vascular pathologies (acute infarcts 22%, vascular thrombosis 12%, diffuse hypoxic-ischemic brain damage 40%) and pre-existing small vessel diseases (34%) were frequent findings. Moreover, silent neurodegenerative pathologies in elderly persons were common (AD neuropathologic changes 32%, age-related neuronal and glial tau pathologies 22%, Lewy bodies 9%, argyrophilic grain disease 12.5%, TDP43 pathology 6%). CONCLUSIONS: Our results support some previous neuropathological findings of apparently multifactorial and most likely indirect brain damage in the context of SARS-CoV-2 infection rather than virus-specific damage, and they are in line with the recent experimental data on SARS-CoV-2-related diffuse white matter damage, microglial activation, and cytokine release.

The challenge of managing parkinson's disease patients during the COVID-19 pandemic

The 2019 novel coronavirus (nCoV) pandemic is rapidly developing across the globe and new information is emerging expeditiously and constantly, particularly in relation to neurological illnesses. Both central and peripheral nervous system involvement has been reported including headache, dizziness, hyposmia/anosmia, taste disturbances, seizures, stroke, alteration of the sensorium, and even acute hemorrhagic necrotizing leukoencephalopathy. Varying degrees of olfactory disturbances may pre-empt the diagnosis of COVID-19. Although no direct effect of 2019 nCoV has been reported yet on Parkinson's disease, there are enormous possible indirect effects and implications. We examine the potential effects and challenges posed by this pandemic to individuals with Parkinson's disease, particularly in the Indian context where telecommunication access or support group access may be lacking for these patients. Additionally, lockdown and social distancing may pose hurdles in the provision of optimum medical therapy, particularly if patients experience motor and non-motor deteriorations due to diverse reasons.

NUBE Abstract

The proceedings contain 14 papers. The topics discussed include: providing comprehensive services to treat patients and the inpatient psychiatric bed crisis;impact of COVID-19 pandemic on pediatric substance abuse related presentations to emergency services between July 2019 and March 2022;patient-specific characteristics that influence a psychiatrist' perception of a patient' risk for attempting suicide in the emergency department;racial disparities in emergency restraint use for agitated patients;emergency department use of a restraint chair is associated with shorter restraint periods and less medication use than the use of 4-point restraints;the utility of the Columbia-suicide severity rating scale in determining a patient' imminent risk for suicide in the emergency department;and rare disease masked behind common presentation: toxic leukoencephalopathy up close.

Progressive multifocal leukoencephalopathy, neuroradiology-neuropathology

Introduction: Progressive multifocal leukoencepha-lopathy (PmL) is an unfavorable demyelinating disease of the CNS caused by reactivation of JC virus (JCV). JCV is a double-stranded DNA human polyomavirus predominatingly acquired in childhood. Blood samples taken from healthy persons indicate that 50-90% of adults have been exposed to this virus. JCV is an opportunistic pathogen, with PmL manifesting primarily in patients with immunodefciency or taking immunomodulatory treatments or with lymphoproliferative diseases. We report a patient who developed PmL shortly after diagnosis of follicular lymphomma. Case presentation: A 70-year-old-woman admitted to the neurological departament with hemiparesis, psy-chomotor slowing down, balance problems, dizziness and in depressed mood. the patient underwent aorto-femoral transplant 12 years ago and for 10 years was under constant observation of a hematologist due to enlarged lymph nodes. Five years ago, the patient had planoepithelial cell carcinoma removed. the patient also sufered from COViD-19 infection and sufered from depression. elevated leukocytosis and D dimers, were the only abnormal results obtained in laboratory tests. However, pulmonary embolism was excluded in Ct angio. Cytometry of blood showed follicular lymphoma. Radiological fndings: mRi and Ct scans showed multiple asymmetrical pathological areas of hyperin-tense signal in t2-dependent images, hypointense in t1-dependent ones and Ct-hypodense regions which extended continuously in control examinations. they were located in the white matter of multiple lobes of both brain hemispheres subcortically and periventric-ullary. the subcortical U-fbers were involed. they did not show contrast enhancement and mass efect. they showed peripheral ring and patchy difusion restriction particularly at their leading edge. in spite of the used steroid therapy the patient's health deteriorated rapidly. the patient died of symptoms of cardio-respiratory failure 1 month after admission to hospital. Neuropathological features: the neuropathological examination revealed numerous foci of demyelination in the white matter of the frontal lobe, the parietal lobe in the pons and in the cerebellum. myelin losses were accompanied by damage to oligodendrocytes and proliferation of macrophages. the nuclei of the damaged oligodendrocytes were enlarged and hyperchromatic, and some had a "ground-glass" appearance typical of viral infection. the astrocytes were bizarre with lobulat-ed, hiperchromatic or hypochromatic nuclei and damage of cytoplasmic procesesses (clasmatodendrosis). Conclusion(s): the triad of neuropathological injuries: destruction of oligodendrocytes with intranuclear viral inclusions ("ground-glass" appearance), multifocal demyelination and bizarre astrocytes allowed for the diagnosis of late form of classical progressive multifo-cal leukoencephalopathy (cPmL), despite the short time since diagnosis of follicular lymphoma, but with many years of enlargement of the lymph nodes.

Posterior reversible encephalopathy syndrome in SARS-CoV-2 infection: A case report and review of literature.

Consider PRES in SARS-CoV-2 infected patients who develop encephalopathy, seizures or impaired vision; especially if the disease is complicated by respiratory distress and need for mechanical ventilation.

Post-Vaccination/Post-COVID Immune-Mediated Demyelination of the Brain and Spinal Cord: A Novel Neuroimaging Finding.

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which not only produces respiratory symptoms but is known to involve almost every system, and its neuroinvasive properties have been well demonstrated throughout the pandemic. Also, to combat the pandemic, there was rapid development and induction of various vaccination drives, following which many adverse events following immunization (AEFIs) have been reported, which include neurological complications as well. Method: We present a series of three cases, post vaccination, with and without a history of COVID illness that showed remarkably similar findings on magnetic resonance imaging (MRI). Result: A 38-year-old male presented with complaints of weakness of the bilateral lower limbs with sensory loss and bladder disturbance a day after receiving his first dose of ChadOx1 nCoV-19 (COVISHIELD) vaccine. A 50-year-old male with hypothyroidism characterized by autoimmune thyroiditis and impaired glucose tolerance experienced difficulty in walking 11.5 weeks after being administered with COVID vaccine (COVAXIN). A 38-year-old male presented with subacute onset progressive symmetric quadriparesis 2 months after their first dose of a COVID vaccine. The patient also had sensory ataxia, and his vibration sensation was impaired below C7. All three patients had typical pattern of involvement of the brain and spine on MRI with signal changes in bilateral corticospinal tracts, trigeminal tracts in the brain, and both lateral and posterior columns in the spine. Conclusion: This pattern of brain and spine involvement on MRI is a novel finding and is likely a result of post-vaccination/post-COVID immune-mediated demyelination.

Case report: Bilateral globus pallidus lesions and delayed progressive leukoencephalopathy in COVID-19: Effects of hypoxia alone or combination of hypoxia and inflammation?

Background: The globus pallidus is a highly mitochondria-rich metabolic structure that is particularly sensitive to metabolic disturbances and hypoxia. Symmetric lesions of globus pallidus and delayed diffuse leukoencephalopathy were documented in toxic-metabolic disorders, hypoxia, a neurodegenerative disorder, and mitochondrial encephalopathies. Similar changes are also reported in individuals with active COVID-19 infections with associated hypoxia or critical illness. Case information: We describe a patient with post-COVID-19 infection who presented with rapid cognitive and neurological decline associated with similar neuroimaging structural changes but without toxic-metabolic changes or hypoxia. Despite multiple non-inflammatory cerebrospinal fluid studies, mechanisms involving post-COVID-19 inflammation and immune dysregulation are suspected, given the unexplained continued decline in the neurological status, lack of concurrent hypoxia or antecedent respiratory difficulties, and after a reasonable exclusion of alternative etiologies. Hypermetabolism of both anteromedial temporal structures and diffuse hypometabolism predominantly in the frontal region on PET scan provided indirect support for possible inflammatory mechanisms after reasonable exclusion of alternative etiologies, such as direct CNS infection, among others. The patient's neurological impairment improved substantially after treatment with pulse steroids, plasmapheresis, and rituximab. Conclusion: To the best of our knowledge, this is the first report of post-COVID-19 with bilateral symmetric contrast-enhancing necrotic lesions of globus pallidus with delayed diffuse supratentorial leukoencephalopathy with microhemorrhages without concurrent hypoxia or reported preceding symptoms suggestive of hypoxia. We suspect that these inflammatory mechanisms might be triggered by prior COVID-19 exposure/infection. Furthermore, the role of the cross-talk between inflammation and clinically mild or silent hypoxia linked to prior COVID-19 infection cannot be excluded. Awareness of these post-COVID-19 neurological sequelae and their potential pathophysiology among those with no known antecedent significant hypoxia are important for early recognition and treatment.

X-linked Charcot-Marie-Tooth disease after SARS-CoV-2 vaccination mimicked stroke-like episodes: A case report.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccinations have been administered worldwide, with occasional reports of associated neurological complications. Specifically, the impact of vaccinations on individuals with X-linked Charcot-Marie-Tooth disease type 1 (CMTX1) is unclear. Patients with CMTX1 can have stroke-like episodes with posterior reversible encephalopathy syndrome on magnetic resonance imaging (MRI), although this is rare. CASE SUMMARY: A 39-year-old man was admitted with episodic aphasia and dysphagia for 2 d. He received SARS-CoV-2 vaccination 39 d before admission. Physical examination showed pes cavus and reduced tendon reflexes. Brain MRI showed bilateral, symmetrical, restricted diffusion with T2 hyperintensities in the cerebral hemispheres. Nerve conduction studies revealed peripheral nerve damage. He was diagnosed with Charcot-Marie-Tooth disease, and a hemizygous mutation in the GJB1 gene on the X chromosome, known to be pathogenic for CMTX1, was identified. Initially, we suspected transient ischemic attack or demyelinating leukoencephalopathy. We initiated treatment with antithrombotic therapy and immunotherapy. At 1.5 mo after discharge, brain MRI showed complete resolution of lesions, with no recurrence. CONCLUSION: SARS-CoV-2 vaccination could be a predisposing factor for CMTX1 and trigger a sudden presentation.

Brain autopsies of critically ill COVID-19 patients demonstrate heterogeneous profile of acute vascular injury, inflammation and age-linked chronic brain diseases.

BACKGROUND: This study examined neuropathological findings of patients who died following hospitalization in an intensive care unit with SARS-CoV-2. METHODS: Data originate from 20 decedents who underwent brain autopsy followed by ex-vivo imaging and dissection. Systematic neuropathologic examinations were performed to assess histopathologic changes including cerebrovascular disease and tissue injury, neurodegenerative diseases, and inflammatory response. Cerebrospinal fluid (CSF) and fixed tissues were evaluated for the presence of viral RNA and protein. RESULTS: The mean age-at-death was 66.2 years (range: 26-97 years) and 14 were male. The patient's medical history included cardiovascular risk factors or diseases (n = 11, 55%) and dementia (n = 5, 25%). Brain examination revealed a range of acute and chronic pathologies. Acute vascular pathologic changes were common in 16 (80%) subjects and included infarctions (n = 11, 55%) followed by acute hypoxic/ischemic injury (n = 9, 45%) and hemorrhages (n = 7, 35%). These acute pathologic changes were identified in both younger and older groups and those with and without vascular risk factors or diseases. Moderate-to-severe microglial activation were noted in 16 (80%) brains, while moderate-to-severe T lymphocyte accumulation was present in 5 (25%) brains. Encephalitis-like changes included lymphocytic cuffing (n = 6, 30%) and neuronophagia or microglial nodule (most prominent in the brainstem, n = 6, 30%) were also observed. A single brain showed vasculitis-like changes and one other exhibited foci of necrosis with ball-ring hemorrhages reminiscent of acute hemorrhagic leukoencephalopathy changes. Chronic pathologies were identified in only older decedents: 7 brains exhibited neurodegenerative diseases and 8 brains showed vascular disease pathologies. CSF and brain samples did not show evidence of viral RNA or protein. CONCLUSIONS: Acute tissue injuries and microglial activation were the most common abnormalities in COVID-19 brains. Focal evidence of encephalitis-like changes was noted despite the lack of detectable virus. The majority of older subjects showed age-related brain pathologies even in the absence of known neurologic disease. Findings of this study suggest that acute brain injury superimposed on common pre-existing brain disease may put older subjects at higher risk of post-COVID neurologic sequelae.

JC virus-induced progressive multifocal leukoencephalopathy in a presumably healthy patient.

BACKGROUND: JC virus (JCV) is common among healthy individuals and remains latent but may be reactivated under immunosuppressive conditions, resulting in progressive multifocal leukoencephalopathy (PML). Here, we present a rare case of PML caused by JC virus infection in a previously healthy and immunocompetent patient. CASE PRESENTATION: A 67-year-old female without any disease history was admitted after presenting with rapidly progressive dementia. The preoperative diagnosis was progressive multifocal leukoencephalopathy, and corticosteroid treatment did not improve the symptoms. Brain lesions were surgically sampled, and JCV infection was confirmed by high-throughput DNA gene detection. This patient received a combined treatment of mirtazapine, mefloquine, and traditional Chinese herbs, and had stabilization of the disease on followed-up. CONCLUSIONS: Although it is a rare, this case demonstrates that JC virus infection within the brain occurs in apparently healthy people. This case may increase our understanding of virus infection when facing the coronavirus epidemic in recent years, considering that similar medications were used.