Spectrum of delayed post-hypoxic leukoencephalopathy syndrome:A systematic review

BACKGROUND Delayed post hypoxic leukoencephalopathy syndrome(DPHLS),also known as Grinker’s myelinopathy,is a rare but significant neurological condition that manifests days to weeks after a hypoxic event.Characterized by delayed onset of neurological and cognitive deficits,DPHLS presents substantial diagnostic and therapeutic challenges.AIM To consolidate current knowledge on pathophysiology,clinical features,diagnostic approaches,and management strategies for DPHLS,providing a comprehensive overview and highlighting gaps for future research.METHODS Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes guidelines,we systematically searched PubMed,ScienceDirect and Hinari databases using terms related to delayed post-hypoxic leukoencephalopathy.Inclusion criteria were original research articles,case reports,and case series involving human subjects with detailed clinical,neuroimaging,or pathological data on DPHLS.Data were extracted on study characteristics,participant demographics,clinical features,neuroimaging findings,pathological findings,treatment,and outcomes.The quality assessment was performed using the Joanna Briggs Institute critical appraisal checklist.RESULTS A total of 73 cases were reviewed.Common comorbidities included schizoaffective disorder,bipolar disorder,hypertension,and substance use disorder.The primary causes of hypoxia were benzodiazepine overdose,opioid overdose,polysubstance overdose,and carbon monoxide(CO)poisoning.Symptoms frequently include decreased level of consciousness,psychomotor agitation,cognitive decline,parkinsonism,and encephalopathy.Neuroimaging commonly revealed diffuse T2 hyperintensities in cerebral white matter,sometimes involving the basal ganglia and the globus pallidus.Magnetic resonance spectroscopy often showed decreased N-acetylaspartate,elevated choline,choline-to-creatinine ratio,and normal or elevated lactate.Treatment is often supportive,including amantadine,an antioxidant cocktail,and steroids.Hyperbaric oxygen therapy may be beneficial in those with CO poisoning.Parkinsonism was often treated with levodopa.Most of the patients had substantial recovery over the course of months and many cases had some residual neurocognitive deficits.CONCLUSION DPHLS remains a complex and multifaceted condition with various etiologies and clinical manifestations.Early recognition and appropriate management are crucial to improving patient outcomes.Future research should focus on standardizing diagnostic criteria,using advanced imaging techniques,and exploring therapeutic interventions to improve understanding and treatment of DPHLS.Conducting prospective cohort studies and developing biomarkers for early diagnosis and monitoring will be essential to advance patient care.

Effects of Comprehensive Rehabilitation on Patients with Progressive Multifocal Leukoencephalopathy Due to Systemic Lupus Erythematosus: A Case Report

Introduction: Little is known about the feasibility and effectiveness of rehabilitative treatment for systemic lupus erythematosus (SLE) in individuals with progressive multifocal leukoencephalopathy (PML). We describe a patient with SLE complicated by PML and ameliorated by comprehensive rehabilitation. We also review the epidemiology, pathology, imaging characteristics, and treatment of PML. Patient Concerns: We found a patient with SLE with PML improved by multidisciplinary rehabilitation techniques. Diagnoses, Interventions, and Outcomes: We diagnosed a PML with a 13-year history of SLE and lupus nephritis after longtime immunosuppressive therapy. The patient underwent a comprehensive, multifaceted rehabilitation program, including drug therapy, integrated physical therapy, occupational therapy, acupuncture, music therapy, computer-aided cognitive rehabilitation training, and behavioral management training. This rehabilitation program improved her motor function and activities of daily living. Conclusions: Her condition improved in the short term through comprehensive rehabilitation, including physical, speech, and cognitive therapy. Therefore, we recommend comprehensive rehabilitation to improve the function and activities of daily living in patients with PML.

Pontocerebellar Progressive Multifocal Leukoencephalopathy. Radiological, Clinical, Histological and Immunohistochemical Findings in a Hematological Patient

Objective: To describe the radiological, histological and immunohistochemical findings in a case of Progressive Multifocal Leukoencephalopathy (PML) affecting the cerebellar peduncles in a patient with chronic lymphocytic leukemia. Patient and Methods: Magnetic Resonance Imaging (MRI), histological picture (H.E., Kluver-Barrera) and immunohistochemical picture (GFAP, neurofilaments, CD68, JC virus) were obtained. Results: 1) Magnetic resonance imaging: Asymmetric and progressive lesions on middle cerebellar peduncles, that were hyperintense in T2/FLAIR, extended towards the pons, had no mass effect and were unmodified after intravenous contrast. 2) Histology: Marked reactive gliosis with cytopathic changes suggesting viral infection, plus demyelination areas with axonal preservation. 3) Immunohistochemistry: Marked positivity for viral (polyoma and JC virus) markers in glial cells showing cytopathic changes. Conclusions: The importance of histological and immunohistochemical diagnosis in everyday assistance;of the collaboration between clinicians, radiologists and pathologists;and the validity of postmortem studies as a key element for research and clinical quality assessment must be stressed.

The Gene of Megalencephalic Leukoencephalopathy with Subcortical Cysts is Mapped on Chromosome 22q13.3 with 250 kb Interval

Objective: Vacuolating megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a recently described syndrome with autosomal recessive mode of inheritance. Its possible gene was located on chromosomal 22q tel with 3-cM. The purpose of this study was to narrow down the genetical distance on chromosomal 22q tel with MLC. Methods: Thirty-nine MLC patients in 33 families were collected,and the linkage analysis and haplotype analysis of twelve informative families were done, using seven microsatellite markers and four SNP markers. Results: The maximum tow-point LOD score for marker 355c18 was 6.65 at recombination fraction 0.02. The haplotype analysis narrowed down the critical region of MLC to 250 kb on chromosomal 22q tel. Conclusion: One of the causing genes of MLC was located on chromosomal 22q tel with 250 kb. Four candidate genes were considered. The heterogeneity of one informative family indicated possible existence of a second locus for MLC.

Megalencephalic Leukoencephalopathy with Subcortical Cysts-a New Child Leukoencephalopathy

Here we review a new variety of leukoencephalopathy with infantile megalencephaly and discrepant clinical course (MLC, MIM: 604004). These children had megalencephaly in the first year of life, with or without mild delay of motor function and/or seizures. After a few years, motor handicap was slowly progressive with unsteady gait, serious cerebellar ataxia and mild plasticity. Eventually most of patients were confined to a wheelchair. Meanwhile mental development was relatively preserved, although the learning problems was increased from the midway of elementary school. Most of patients had tonic-clonic seizure and some might advance to status epilepticus. Antiepileptic drugs may effectively control seizure. The disorders of known metabolic defects were excluded. Neurophysiological examination showed that EEG had interictal epileptic discharges on the generalized slow wave background in most patients. The cerebral white matter had diffuse abnormality, with swelling of white matter, and cysts in the frontoparietal and anterior-temporal lobes on MRI examination. Some central white matter structures were spared, such as corpus callosum. The severity of lesions on MRI is inconsistent with the clinical signs. Pathogenesis of this disease was unknown. The pathological findings found a spongiform leukoencephalopathy due to myelin splitting and intramyelinic vacuole formation but without myelin loss. This disease had probably an autosomal recessive inheritance. The gene KIAA027 on 22qtel was responsible for MLC.

Reversible posterior leukoencephalopathy syndrome induced by bevacizumab plus chemotherapy in colorectal cancer

Reversible posterior leukoencephalopathy syndrome(RPLS)is a rare brain-capillary leak syndrome,characterized by clinical symptoms of headache,visual loss,seizures and altered mental functioning.This syndrome is usually reversible and is associated with hypertension,nephropathy,and use of immunosuppressive medication and cytotoxic agents.We describe two rare cases of RPLS occurring in colorectal cancer,both of which presented with coma,that we believe can be directly attributed to bevacizumab,a monoclonal antibody that inhibits the angiogenesis of tumours by specifically blocking vascular endothelial growth factor.We analysed the clinical features,risk factors and outcomes of RPLS in these two patients,and although no typical finding was identified on imaging examination,we found that inadequate blood pressure control was one of the risk factors leading to RPLS and that supportive treatment including intensive blood pressure control improved outcomes.Due to the increasing use of bevacizumab in colorectal cancer,clinicians should be aware of this potential complication.

Reversible Posterior Leukoencephalopathy Syndrome in Children with Nephrotic Syndrome:a Case Report

REVERSIBLE posterior leukoencephalopathy syn- drome （RPLS） is a rare neurological syndrome charac- terized by headache, altered mental status, seizures, and visual disturbance,associated with reversible white matter cnanges,- n been commonly reported in patients with severe hypertension and pre-eclampsia. Here we report a case with nephrotic syndrome complicated by RPLS.

Unexpected Occurrence of Fetal Hemophagocytic Syndrome in a Patient with Hereditary Diffuse Leukoencephalopathy with Spheroids

Colony stimulating factor-1 receptor (CSF1R) plays important roles in the differentiation and proliferation of macrophage and microglia in systemic organs and the brain. A genetic defect in CSF1R causes hereditary diffuse leukoencephalopathy with spheroids (HDLS). HDLS mainly affects the cerebral white matter and shows pre-senile cognitive decline, motor disturbance, and epilepsy. However, systemic manifestations outside the brain have not yet been described in patients with HDLS. Here, we report the case of a 41-year-old man with HDLS carrying the p. K793T mutation in CSF1R, who unexpectedly died of sepsis and hemophagocytic syndrome shortly after the onset of HDLS. The fetal sequence of sepsis and hemophagocytic syndrome was triggered by enterocolitis. An autopsy revealed that focal inflammation in the intestine had almost resolved. Most strikingly, massive infiltration of cluster of differentiation (CD) 68- and CD163-immunopositive macrophages with hemophagocytosis was observed in the bone marrow, spleen, and liver. Less abundant infiltration of CD68- and CD204-immunopositive macrophages without hemophagocytosis was also seen in the lung and intestine. At present, the pathogenetic link between CSF1R mutation and hemophagocytic syndrome in this patient is unclear. Our case, however, clearly shows that even in patients with HDLS, aberrant activation of functional macrophages can be induced under certain conditions in visceral organs.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy in a Chinese pedigree A case report using brain magnetic resonance imaging and biospy

The present study enrolled a Chinese family that comprised 34 members and spanned three generations. Eight members were diagnosed with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, and disease diagnoses corresponded with autosomal incomplete dominance inheritance. The primary clinical manifestations included paralysis, dysarthria, and mild cognitive deficits. Magnetic resonance imaging revealed diffuse leukoencephalopathy with involvement of bilateral anterior temporal lobes, in particular the pons. In addition, multiple cerebral infarction was identified in the proband. Sural nerve biopsy findings of the proband revealed granular osmophilic material deposits in the extracellular matrix, which were adjacent to smooth muscle cells of dermal arterioles. Screening exons 2-4 for NOTCH 3 mutations by direct sequencing did not reveal any abnormalities.

Functional outcomes after home-based rehabilitation for heroin-induced spongiform leukoencephalopathy

A 22-year-old man with a 2-year history of heroin vapor inhalation developed spongiform leukoencephalopathy and underwent clinical and home-based rehabilitative treatments. Activities of daily living were measured using the Functional Independence Measure at discharge and at 6, 12, and 24 months after discharge. His neurological symptoms gradually disappeared with rehabilitative treatment, and the functional scale scores increased from 55 on admission to 105 at 24 months after discharge. These results suggest that home-based rehabilitation was effective in ameliorating the pathology and improving activities of daily living in this patient with heroin-induced spongiform leukoencephalopathy.

CADASIL syndrome(cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy)presenting as psychosis

Cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy(CADASIL) is the most common monogenic form of cerebral small-vessel disease characterised by recurrent strokes. Behavioural disturbance also presents in a significant proportion of subjects as neurotic spectrum disorders and psychotic features are rarely reported. In this case report, we highlight a 32-year-old man with CADASIL syndrome, who had overt psychotic symptoms with neurological signs later on.

Delayed post-hypoxic leukoencephalopathy following barbiturate overdose: A case report

Rationale:Delayed post-hypoxic leukoencephalopathy(DPHL)is usually an overlooked condition,which arises as a result of a multitude of reversible and irreversible conditions.Patient’s Concern:A 50-year-old female with a history of epilepsy,who developed DPHL 12 days after respiratory failure secondary to barbiturate toxicity.Diagnosis:DPHL on magnetic resonance imaging of the brain.Interventions:Mechanical ventilation was initiated for respiratory failure and hemodialysis for barbiturate toxicity.Outcomes:The patient developed akinetic mutism due to infirmity and had a residual disability,which led to permanent dependency.Lessons:The diagnosis of DPHL is often delayed or missed,given the rarity of this condition and its inconsistent clinical symptomatology.Diagnostic delay can be avoided by early recognition of the classical“delayed onset”symptoms.

CT and MR imaging of Spongiform leukoencephalopathy after heroin vapor inhalation: analysis of 13 cases

Objective: To study the CT and MR imaging features of spongiform leukoencephalopathy after heroin vapor inhalation. Method,: The CT and MR imaging features and pathologic findings of 13 patients with heroin-induced spongiform leukoencephalopathy were analyzed. Results: CT scanning and MRI of all the patients showed diffuse, symmetric lesion in the cerebellar and cerebral white matter, and the cerebellum was invariably involved in all cases. Symmetric round or butterfly-like lesions lateral to the midline of the cerebellum with clear border was the most distinct feature in CT and MRI examination. The lesions were not found in the anterior limbs of the internal capsules. CT scanning showed low-density changes while MRI TIWI imaging presented low-signal and T2WI high-signal lesions without space-occupying mass. The pathologic findings showed spongiform degeneration of the white matter in the central nervous system, but necrotic lesions were not observed. Conclusions: Spongiform leukoencephalopathy should be considered when acute. cerebellar signs are present in patients who admitted a history of heroin inhalation. The CT and MRI manifestation of this disease is typical and the diagnosis can thus be made.

Neuropathology of JC virus infection in progressive multifocal leukoencephalopathy in remission

AIM: To investigate the neuropathology of the brain in a rare case of remission following diagnosis of progressive multifocal leukoencephalopathy(PML).METHODS: Consent from the family for an autopsy was obtained, clinical records and radiograms were retrieved. A complete autopsy was performed, with brain examination after fixation and coronal sectioning at 1 cm intervals. Fourteen regions were collected for paraffin embedding and staining for microscopic analysis. Histologic sections were stained with Luxol blue, hematoxylin/eosin, and immunostained for myelin basic protein, neurofilament, SV40 T antigen and p53. The biopsy material was also retrieved and sections were stained with hematoxylin/eosin and immunostained for SV40 and p53. Sections were examined by American Board of Pathology certified pathologists and images captured digitally.RESULTS: Review of the clinical records was notable for a history of ulcerative colitis resulting in total colectomy in 1977 and a liver transplant in 1998 followed by immune-suppressive therapy. Neurological symptoms presented immediately, therefore a biopsy was obtained which was diagnosed as PML. Immunotherapy was adjusted and clinical improvement was noted. No subsequent progression was reported. Review of the biopsy demonstrated atypical astrocytes and enlarged hyperchromatic oligodendroglial cells consistent with JC virus infection. Strong SV40 and p53 staining was found in glial cells and regions of dense macrophage infiltration were present. On gross examination of the post-mortem brain, a lesion in the same site as the original biopsy in the cerebellum was identified but no other lesions in the brain were found. Microscopic analysis of this cerebellar lesion revealed a loss of myelin and axons, and evidence of axonal damage. This single burned-out lesion was equivocally positive for SV40 antigen with little p53 staining. Examination of thirteen other brain regions found no other occult sites.CONCLUSION: Our study reveals residual damage, rare macrophages or other inflammation and minimal evidence of persistent virus. This case demonstrates the possibility of complete remission of PML.

Bevacizumab Related Hypertension and Reversible Posterior Leukoencephalopathy Syndrome in Gynecologic Malignancies: A case Control Study

Background: Bevacizumab is increasingly being used in the treatment of gynecologic malignancies, but has significant side-effects including hypertension and reversible posterior leukoencephalopathy (RPLS), which must be recognized by the gynecologic oncologist. Methods: A 26-month institutional retrospective review of bevacizumab in the treatment of gynecologic malignancies. Patients were grouped according to whether they had bevacizumab-related hypertension (defined as at least a grade one hypertensive toxicity) or not. There were no differences in patient demographics between the groups. Risk factors for developing bevacizumab-related hypertension were assessed using t-tests, Wilcoxon rank sum test and Fisher’s exact test. Results: Our group has treated 45 patients with bevacizumab. Fifteen (33%) patients had a pre-existing diagnosis of hypertension, 12 (80%) of whom had at least one elevated blood pressure during treatment. The 30 (67%) patients who did not have a pre-existing diagnosis of hypertension still had a high incidence of bevacizumab-related elevated blood pressure (14, 47%). The majority of patients (26, 58%) had at least one therapy cycle complicated by hypertension. Patients who experienced bevacizumab-related hypertension were significantly more likely than not to have a history of hypertension (odds ratio of 4.6, 95% CI 1.1-19.6). There was a 4.4% incidence of reversible posterior leukoencephalopathy. Patients with age equal to or greater than 75 years, stage IV disease, and creatinine elevations greater than or equal to 1.4 mg/dL were significantly more likely to develop bevacizumab-related hypertension. Other factors such as numbers of prior chemotherapies, cycles of bevacizumab, BMI, cancer site, and histology were not significantly associated with bevacizumab-related hypertension. Conclusions: Hypertension is a problem for patients on bevacizumab whether or not they have a pre-existing diagnosis. However, those with a history of hypertension were significantly more likely to have bevacizumab-related hypertension.

Cerebral Localization of Chronic Lymphocytic Leukemia Simulating Progressive Multifocal Leukoencephalopathy: The Lessons from a Case

Background: Central neurological involvement is the most frequent extra hematological manifestation of chronic lymphocytic leukemia;it is multifactorial and rarely due to a cerebral localization of the disease. We report a case of cerebral localization of chronic lymphoid leukemia whose clinical and radiological aspects were very suggestive of progressive multifocal leukoencephalopathy. Case Presentation: A 65-year-old patient who was HIV-negative (human immunodeficiency virus), had consulted for bilateral axillary, cervical and inguinal lymphadenopathy associated with major asthenia and hyper lymphocytosis (lymphocyte count was 11 giga/l). Chronic lymphocyticleukemia with TP53 mutation was diagnosed and treatment with Ibrutinib 420 mg/day was initiated. After 2 months of treatment, the evolution was marked by the onset of neurological disorders whose clinical-radiological presentation and temporal evolution had led to the diagnosis of progressive multifocal leukoencephalopathy. In the absence of virological evidence in the cerebrospinal fluid analysis, a stereotactic biopsy of the brain lesions had been performed, making it possible to formally rule out this infectious hypothesis and to demonstrate cerebral invasion by tumour cells. Immuno-chemotherapy combining Rituximab-Cyclophosphamide-Doxorubicin-Vincristine-Prednisone-Ibrutinib (RCHOP-Ibrutinib) with intrathecal chemotherapy resulted in a very good clinical-radiological response. Conclusion: The appearance of neurological manifestations in the context of chronic lymphocytic leukemia must systematically lead to a search for a cerebral localization of the disease. In the absence of virological evidence in the cerebrospinal fluid, any suspicion of progressive multifocal leukoencephalopathy in this context should lead to the histological study of brain lesions.

Heroin-Induced Toxic Leukoencephalopathy

Toxic leukoencephalopathy is an important complication of heroin abuse and has mostly been described after inhaling heroin vapor, known as “chasing the dragon syndrome” or heroin inhalation leukoencephalopathy (HIL). We present a 51 year-old male patient with toxic leukoencephalopathy following intranasal administration of heroin.

Unusual MR Feature Presenting Discrete Involvement of Pyramidal Tract in Progressive Multifocal Leukoencephalopathy: A Case Report

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease caused by reactivation of JC virus in immunocompromised patients. To date, PML with discrete involvement of the pyramidal tract has been described in only two patients. This report describes an additional case with PML showing discrete involvement of the pyramidal tract on T2-weighted images and FLAIR images.

Progressive Multifocal Leukoencephalopathy—A Case Report in an Immunocompetent Patient

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system due to the reactivation of the JC virus, which usually occurs in immunocompromised patients and is a major opportunistic infection associated with HIV infection. We report a case of a previously healthy patient who was diagnosed with PML.

Stroke-like presentation of acute toxic leukoencephalopathy due to capecitabine treatment with extensive intramyelinic edema

1|INTRODUCTION Capecitabine is an oral prodrug of 5-fluorouracil(5-FU),which is widely used for adjuvant and neoadjuvant chemotherapy of different solid tumors,particularly breast and colorectal cancers.1 Neurotoxicity of capecitabine has been consistently reported as capecitabine-induced toxic leukoencephalopathy,which includes bilateral lesions in the corpus callosum and corticospinal tract presenting as acute or delayed central nervous system toxicity.2 This side effect requires discontinuation of chemotherapy3;however,neurological symptoms due to capecitabine are reported to be usually reversible upon drug withdrawal.