Search Results (29)

Background: Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an uncommon inflammatory disorder of the central nervous system that is exceptionally rare during childhood. Although pontocerebellar punctate enhancement is considered its neuroradiological hallmark, the full spectrum of pediatric clinical and imaging manifestations remain poorly characterized because available evidence is limited to isolated case reports and small case series. We conducted a systematic review to characterize the clinical presentation, neuroimaging phenotype, diagnostic challenges, therapeutic strategies, and outcomes of pediatric CLIPPERS. Methods: A systematic literature search was conducted in PubMed/MEDLINE and Scopus from database inception to December 2025, following PRISMA guidelines. Studies reporting patients younger than 18 years with a diagnosis of CLIPPERS were eligible. Clinical, neuroradiological, laboratory, histopathological, therapeutic, and outcome data were extracted using a standardized form. Diagnostic certainty was assessed according to the Tobin criteria, and methodological quality was evaluated using the Joanna Briggs Institute (JBI) critical appraisal tools. Results: Ten studies comprising 13 pediatric patients fulfilled the inclusion criteria. Median age at presentation was 13 years (range 3–16 years), with a slight male predominance. Ataxia was the most common presenting manifestation (84.6%), followed by cranial nerve involvement (61.5%) and diplopia (46.2%). Magnetic Resonance Imaging (MRI) consistently demonstrated brainstem involvement, predominantly affecting the pons (84.6%) and cerebellum (76.9%), while supratentorial lesions (46.2%), midbrain involvement (46.2%), and spinal cord abnormalities (23.1%) suggest that the neuroradiological phenotype may extend beyond the classic pontocerebellar pattern, although these findings were observed in a limited number of patients. Cerebrospinal fluid (CSF) findings were nonspecific, typically showing normal results or mild lymphocytic pleocytosis. Histopathological examination, when available, demonstrated characteristic perivascular T-cell-predominant inflammatory infiltrates. All patients received high-dose corticosteroids with initial clinical improvement; however, relapses occurred in 61.5% of cases, frequently during corticosteroid tapering, often requiring steroid-sparing immunosuppressive therapy. Based on the available evidence, we suggest a practical clinic-radiological framework to facilitate the evaluation of children presenting with suspected CLIPPERS. Conclusions: Pediatric CLIPPERS represents a rare but increasingly recognized neuroinflammatory disorder characterized by marked corticosteroid responsiveness and a wide range of neuroradiological phenotypes. Although pontocerebellar involvement remains the defining imaging feature, supratentorial and spinal cord lesions are not uncommon and should not exclude the diagnosis after careful consideration of alternative inflammatory, autoimmune, infectious, and neoplastic disorders. Given the high relapse rate and the limited quality of available evidence, prolonged follow-up and collaborative multicenter studies are needed to refine pediatric diagnostic criteria and optimize long-term management. Full article

Background: Varicella-zoster virus (VZV) is a neurotropic alphaherpesvirus capable of causing a broad spectrum of neurologic complications beyond classic dermatomal herpes zoster. Although meningitis and encephalitis are well recognized manifestations of neuroinvasive VZV infection, associated autonomic dysfunction remains comparatively underreported, particularly in immunocompetent individuals. Case Presentation: We describe a 66-year-old immunocompetent man who developed VZV meningoencephalitis associated with sacral dermatomal herpes zoster, urinary retention, and bowel dysmotility. Initial symptoms included fever, severe headache, photophobia, and low back pain, with delayed recognition of the characteristic sacral vesicular eruption. The patient subsequently developed encephalopathy and meningeal signs requiring intensive care unit admission. Cerebrospinal fluid analysis demonstrated lymphocytic pleocytosis and markedly elevated protein concentration, and VZV DNA was detected by polymerase chain reaction testing. During hospitalization, the patient developed severe urinary retention and gastrointestinal dysmotility without evidence of mechanical obstruction, raising concern for concurrent autonomic nervous system involvement. Following intravenous acyclovir therapy and supportive management, the patient experienced gradual neurologic and autonomic recovery. Conclusions: This case highlights the potential for multifocal neuroinvasive VZV disease involving both central and autonomic nervous system structures in immunocompetent hosts. Clinicians should maintain awareness that urinary retention and bowel dysmotility may represent clinically significant autonomic manifestations of VZV reactivation, particularly in the setting of sacral dermatomal involvement. Full article

Post-transplant lymphoproliferative disorder (PTLD) involving the central nervous system (CNS) is a rare but serious life-threatening complication seen in recipients of solid organ transplant. Primary CNS encompasses 5–15% of all types of PTLD diagnoses, and heart transplant recipients represent 3–5% of those reported cases. Diagnosis is often delayed due to the highly variable presentation, with some cases remaining undiagnosed for years. Multidisciplinary collaboration is crucial for early diagnosis and management. A 53-year-old woman patient presented with altered mental status. MRI revealed nodular ventriculitis and bilateral periventricular hyperdense infiltrates. CSF studies demonstrated lymphocytic pleocytosis, elevated protein, and EBV-PCR-positive results. A stereotactic brain needle biopsy confirmed the presence of EBV-positive diffuse large B-cell lymphoma, consistent with primary CNS PTLD, 14 months after her heart transplant. Despite appropriate management, the patient experienced progressive neurological decline and ultimately suffered a fatal intracerebral hemorrhage. We demonstrate the importance of the early diagnosis and variable presentation of post-heart-transplant PTLD. The importance of surveillance regardless of EBV status and close monitoring of disease progression due to potential life-threatening complications, such as fatal hemorrhages. Therefore, primary CNS-PTLD remains a challenging disease and is being increasingly recognized with improved transplant recipient survival and prolonged exposure to chronic immunosuppression. Full article

Background: Acute transverse myelitis (ATM) is an inflammatory disorder of the spinal cord with heterogeneous etiologies, including autoimmune, infectious, paraneoplastic, and drug-induced causes. Tumor necrosis factor-alpha (TNF-α) inhibitors have been infrequently associated with inflammatory central nervous system events, including transverse myelitis. TNF-inhibitor-associated myelitis typically presents with short-segment lesions, a normal brain MRI, and partial responsiveness to corticosteroids. Longitudinally extensive transverse myelitis (LETM) and steroid-refractory cases are uncommon. Case Presentation: A 39-year-old woman with psoriatic arthritis treated with etanercept for two years presented with subacute progressive bilateral lower-extremity sensory loss and weakness. MRI revealed a T2 hyperintense spinal cord lesion extending from T11 to L1 with gadolinium enhancement, consistent with transverse myelitis, while brain MRI was normal. Cerebrospinal fluid analysis showed lymphocytic pleocytosis, elevated protein, oligoclonal bands, and increased kappa free light chains. Extensive infectious, metabolic, paraneoplastic, and autoimmune testing, including aquaporin-4 and MOG antibodies, was negative. Despite high-dose intravenous corticosteroids and the discontinuation of etanercept, the patient experienced clinical worsening with lesion expansion, meeting criteria for LETM, and developed urinary retention. She subsequently underwent plasma exchange, resulting in radiologic improvement and moderate clinical recovery. Conclusions: This case highlights an atypical presentation of TNF-inhibitor-associated myelitis characterized by a biphasic course, longitudinally extensive spinal cord involvement, steroid refractoriness, and responsiveness to plasma exchange. These features suggest either an unusually severe TNF-inhibitor-related inflammatory phenotype or a TNF-inhibitor-triggered antibody-mediated demyelinating process. Reports of TNF-inhibitor-associated myelitis evolving into longitudinally extensive, steroid-refractory disease remain limited, and this presentation may broaden the recognized clinical spectrum of TNF-α-related CNS inflammatory events. Close neurologic follow-up and heightened awareness of severe CNS complications associated with TNF-α inhibitors are warranted. Full article

Background: Tuberculous meningitis (TBM) is the most severe manifestation of tuberculosis in children, with high mortality rates and long-term neurological sequelae. Early diagnosis is challenging due to its nonspecific symptoms and insidious onset. Case Presentation: An 8-year-old previously healthy male, fully vaccinated, presented with a two-week history of fever, headache, vomiting, and abdominal pain. Cerebrospinal fluid (CSF) analysis revealed lymphocytic pleocytosis, elevated protein, and low glucose levels, while multiplex polymerase chain reaction (PCR) testing for bacteria and viruses yielded negative results. Brain computed tomography (CT) revealed mild ventricular dilation and pansinusitis. Empirical antibacterial and antiviral therapy were initiated; however, the patient subsequently experienced neurological deterioration, including cranial nerve deficits and hemiparesis. Brain magnetic resonance imaging (MRI) demonstrated acute infarctions of the basal ganglia, raising suspicion for TBM. Repeated CSF sampling and Xpert MTB/RIF assay confirmed infection with Mycobacterium tuberculosis. Anti-tuberculosis treatment was initiated in combination with adjunctive corticosteroids, anticonvulsant and anticoagulant therapies, and supportive care, including neurosurgical intervention for hydrocephalus. After 16 months of treatment, the patient showed clinical improvement but sustained left-sided hemiparesis, visual impairment, and cognitive deficits. Conclusions: This case highlights the diagnostic challenges of pediatric TBM in immunocompetent and Bacillus Calmette–Guérin (BCG)-vaccinated children, particularly in the presence of initially negative microbiological findings. It emphasizes the importance of maintaining a high index of clinical suspicion and the crucial supportive role of neuroimaging findings, as well as the earlier initiation of empirical TB therapy especially when epidemiological plausibility exists. Early recognition and intervention remain critical to reducing morbidity and mortality associated with this devastating disease. Full article

Central nervous system (CNS) cryptococcosis caused by Cryptococcus neoformans is a severe opportunistic infection that primarily affects individuals with impaired cellular immunity. Although the classic presentation includes headache, fever, and meningeal signs, chronically immunosuppressed patients may develop atypical neuropsychiatric manifestations, leading to diagnostic delays. We report the case of a 53-year-old man with rheumatoid arthritis (RA) receiving long-term prednisolone and etanercept therapy, who presented with a 7-day history of depressive mood, anhedonia, social withdrawal, irritability, and progressive confusion. Neurological examination revealed disorientation without focal deficits. Brain imaging showed only mild cortical atrophy, and cerebrospinal fluid (CSF) analysis revealed lymphocytic pleocytosis, low glucose, and elevated protein levels. Multiplex PCR (FilmArray^®) of CSF identified Cryptococcus neoformans, CSF positive to C. neoformans. The patient was treated with liposomal amphotericin B followed by fluconazole, resulting in gradual improvement of both neurological and psychiatric symptoms. This case highlights an unusual presentation of CNS cryptococcosis in a non-HIV immunosuppressed patient with RA, emphasizing that acute psychiatric or cognitive changes can be the predominant manifestation. Clinicians should consider fungal infections in the differential diagnosis of acute neuropsychiatric symptoms in patients receiving chronic corticosteroid and biologic therapy. Early recognition and molecular diagnosis can facilitate timely antifungal treatment, potentially improving prognosis and reducing morbidity associated with delayed therapy. This report underscores the importance of awareness of atypical presentations of opportunistic infections in immunosuppressed populations. Full article

A 47-year-old woman presented with a two-year history of progressive visual symptoms and headaches. Lumbar puncture revealed lymphocytic pleocytosis, elevated protein, low glucose, and a CSF CrAg titer of 1:256. She was treated empirically for cryptococcal meningitis with amphotericin B, flucytosine, and fluconazole for 15 months. Her symptoms persisted, and repeated CSF and serum CrAg, fungal cultures, and an extensive infectious workup were negative. CSF flow cytometry eventually demonstrated a monoclonal B-cell population suggestive of a lymphoproliferative process. Imaging, including MRI and PET scans, did not reveal systemic disease. A ventriculoperitoneal (VP) shunt was placed for symptom management. This case emphasizes the limitations of CrAg testing and the potential for false positives. It underscores the need for integrating clinical, laboratory, and imaging data when evaluating chronic meningitis. Full article

Bacillus Calmette–Guerin (BCG) central nervous system (CNS) infections are one of the rarest complications following BCG exposure. A 77-year-old male, with bladder cancer previously treated with BCG instillation, presented with fever, confusion, and brain magnetic resonance imaging (MRI) consistent with encephalitis one month after the last BCG instillation. Cerebrospinal fluid (CSF) showed marked hypoglycorrhachia, hyperproteinorrachia, and lymphocytic pleocytosis. Despite CSF culture negativity, the presentation was considered suggestive of BCG-related encephalitis, and the empirical standard antitubercular treatment (rifampin, isoniazid and ethambutol), plus dexamethasone, was initiated. Following initial improvement, gait ataxia and hemiplegia were observed at the 4-month follow-up. MRI revealed an excluded enlarged left lateral ventricle with signs of ventriculitis, requiring surgical drainage. CSF collected during neurosurgery resulted positive on PCR for M. tuberculosis complex. Adjunctive linezolid was initiated, replaced by levofloxacin due to adverse events after 2 weeks. The patient was discharged following a normal CSF analysis. Oral antitubercular therapy was prescribed for 14 months and there were no signs of relapse at the 24-month follow-up. Previously, 16 cases of CNS BCGitis have been reported, without any cases of clinical relapse during antitubercular treatment. Furthermore, our study reports the use of linezolid as a 4th antitubercular drug for CNS BCGitis. Full article

In tick-borne encephalitis (TBE), the central nervous system (CNS) is infiltrated by a mixed leukocyte population contributing both to the infection control and the immune-mediated pathology. To elucidate the roles of chemotactic cytokines in this process, we measured concentrations of 25 cytokines in serum and cerebrospinal fluid (CSF) simultaneously with total CSF leukocyte count (pleocytosis) and leukocyte subpopulation counts in 103 TBE patients. We created models describing the dependence of pleocytosis and clinical severity on cytokine concentrations. Ten polymorphisms in genes for cytokines or their receptors were studied with rtPCR in patients’ DNA samples. The strongest chemotactic gradients towards CSF were created by CXCL1, IL-8, CXCL10, CCL2, CCL3, CCL4, CCL7, CCL8, CCL19 and CCL20. Neutrophil counts in CSF correlated with concentrations of CXCL1 and IL-8 and lymphocyte counts with IL-16, CCL19, CCL20, CCL4, CXCL12, and CXCL13. The milder disease is associated with CCL11, CCL19, CXCL10 and CXCL13,-while the more severe with CXCL1 and CCL20. The polymorphisms in the genes CCR2, CCL5, CXCR3 and CX3CR1 are associated with the cytokine concentrations and pleocytosis, but not with clinical severity. Multiple chemotactic cytokines contribute to pleocytosis in TBE, with no straightforward relationship between their effects on pleocytosis and the clinical presentation. Full article

Background: Bickerstaff brainstem encephalitis (BBE) is a rare autoimmune disease and approximately 74 cases have been reported in the literature, mostly in childhood. Methods: We reported this case report according to the CARE guidelines. Results: A 13-year-old female presented with a 4-day history of persistent fever and hallucinations. She rapidly developed nystagmus associated with blurred vision with ataxic gait. She also developed altered mental status, blepharoptosis, diplopia and extrinsic ocular motility. An EEG showed asymmetric brain electrical activity with slow and spiky abnormalities in the left cerebral hemisphere. Lumbar puncture showed mild pleocytosis with lymphocytic predominance, elevated protein, with normal glucose. Anti-GM1 and anti-GM2 antibodies were positive. She was administered intravenous immunoglobulin therapy due to a suspicion of BBE, showing rapid improvement in mental status. Conclusions: BBE is a diagnosis of exclusion and should be considered especially in pediatric age. Full article

Neuroinvasive flaviviruses such as tick-borne encephalitis virus (TBEV) and West Nile virus (WNV) are widely distributed in continental Croatian regions. We analyzed clinical characteristics, laboratory parameters, and molecular epidemiology of neuroinvasive flavivirus infections in eastern Croatia. A total of 43 patients with confirmed flavivirus infection hospitalized from 2017 to 2023 were included in the study. Reverse-transcription polymerase chain reaction (RT-qPCR) was used to detect flavivirus RNA in clinical samples (cerebrospinal fluid; CSF, urine). ELISA was used for IgM and IgG antibody detection in serum and CSF with confirmation of cross-reactive samples by virus neutralization test. WNV was detected more frequently (74.4%) than TBEV (25.6%). A statistically significant age difference was found between WNV patients (median 65 years) and TBEV patients (median 36 years). Comorbidities were more frequently detected in WNV patients (hypertension 56.3 vs. 18.2%; diabetes 31.3 vs. 0%). Meningitis was the most common clinical presentation in both TBE and WNV neuroinvasive disease (WNND; 63.6 and 59.4%, respectively). In addition, some rare clinical presentations of WNND were also detected (cerebellitis, polyradiculoneuritis). No significant differences in the frequency of clinical symptoms were observed between WNV and TBEV-infected patients (fever 93.7 vs. 100%; malaise 78.1 vs. 100%; headache 75.0 vs. 100%; nausea 50.0 vs. 63.6%; vomiting 34.4 vs. 54.6%). Comparative analysis of total and differential leukocyte blood count showed similar results. However, CSF pleocytosis was higher in TBE patients, with a significant difference in the neutrophil and lymphocyte count (WNND median 48.5% and 51.5%; TBE median 10.0 and 90.0%, respectively). The length of hospital stay was 12 days for WNND and 9 days for TBE. Phylogenetic analysis of detected WNV strains revealed the presence of WNV lineage 2 in eastern Croatia. Full article

Background: Paraneoplastic neurological syndromes (PNSs) are rare conditions characterized by immune-mediated pathogenesis, frequently associated with the presence of a neoplasm. Although a single antineuronal antibody mediates a specific syndrome, atypical manifestations mediated by the same antibody have been described. Methods: The aim of this study was to report on an atypical case of PNS with dual positivity for anti-GAD65 and anti-CRMP5/CV2 antibodies, simultaneously characterized by cognitive decline associated with progressive ataxia and parkinsonism. We also reviewed the current literature for published cases of PNSs with parkinsonism associated with anti-GAD65 and anti- CRMP5/CV2 antibodies. Results: A 68-year-old man with an insidious onset of bradykinesia, cognitive decline, and gait instability that began the year before our evaluation had been diagnosed with parkinsonian syndrome. Analysis of the cerebrospinal fluid showed lymphocytic pleocytosis, and a panel for PNS tested positive for anti-GAD65 and anti- CRMP5/CV2 antibodies. After investigation, a microcitoma was found in the lung. Conclusions: In light of our findings, we suggest considering PNS as an alternative diagnosis to parkinsonism-plus syndromes, in particular if bradykinetic syndrome is accompanied by other clinical manifestations including cognitive decline or ataxia in rapidly deteriorating patients. Earlier detection of PNS would lead to timelier identification of any occult tumors, therein promising improvement in the patient’s prognosis. Full article

Background/Objectives: diagnosis of Lyme neuroborreliosis (LNB) relies on medical history, clinical findings, and detection of pathogen-specific antibodies in the blood and cerebrospinal fluid (CSF). The chemoattractant CXCL13 serves as an additional marker for LNB acuity. During the diagnostic workup, cytomorphological examination of immune cells in CSF provides early insights. Lympho-monocytic pleocytosis with plasma cells and activated lymphocytes is usually described as a typical feature of LNB. In contrast we frequently observe a cytological cell picture featuring neutrophilic granulocytes as well as activated mononuclear cells and plasma cells in patients with LNB, which we refer to as a mixed cell picture. We, hence, investigated the presence of granulocytes to determine their role as typical findings associated with LNB. Methods: we conducted a retrospective analysis of CSF cytology in patients diagnosed with definite LNB at the Department of Neurology, Christian Doppler Medical Centre, Salzburg between 2015 and 2021. CSF results of patients with more than 10 erythrocytes/µL were excluded to avoid the presence of granulocytes due to artificial blood contamination. Additionally, CXCL13 levels were recorded, where available. Results: a total of 75 patients (42 female; 56%) met the diagnostic criteria of definite LNB. Cytology revealed the presence of granulocytes in the CSF of 91% of the patients (68/75). CXCL13 elevation was found to be significantly associated with the presence of granulocytes in CSF (p = 0.0025, or 1.009 (95% CI: 1.003–1.016). Conclusions: we confirm a mixed cell picture with granulocytes, activated mononuclear cells and plasma cells being a typical finding in the CSF cytology of LNB. The association between granulocytes and elevated CXCL13 suggests that their presence is a specific feature of the acute, untreated phase of LNB. Full article

Introduction: Central nervous system (CNS) infection due to the varicella zoster virus (VZV) can complicate the primary infection or the reactivation, leading to significant mortality and morbidity. This study aimed to describe the clinical, laboratory, and radiological characteristics of patients with confirmed VZV CNS infection in a tertiary hospital in Greece. Methods: Data about patients hospitalized from January 2018 to September 2023 with CNS infection by VZV, confirmed by a syndromic polymerase chain reaction in the cerebrospinal fluid (CSF), were retrospectively collected and evaluated. Results: In total, 14 patients were recorded. The median age was 49 years, and 35.7% were male. Headache was present in 71.4%, a rash in 57.1%, and fevers, nausea or vomiting, and disorientation in 35.7%. The CSF showed lymphocytic pleocytosis in all patients. Brain magnetic resonance imaging was performed in 53.8%. Empirical antivirals were given in 69.2%, and intravenous acyclovir was given to all patients after identification of VZV in the CSF. Only 7.1% (1 patient) required intensive care unit admission, and 7.1% (1 patient) died. Patients presenting without a rash may be slightly younger, have a slightly lower Charlson comorbidity index, be more likely to present with photophobia or phonophobia, and have lower serum CRP. Conclusions: Patients presenting with VZV CNS infection have lymphocytic pleocytosis in the CSF and usually have a favorable outcome with antiviral treatment. Those presenting without a rash may have a different overall clinical phenotype from those with a rash; however, this must be evaluated in larger studies in the future. Full article

Mollaret’s meningitis is a rare neurological disorder characterized by recurrent episodes of aseptic lymphocytic meningitis, often associated with herpes simplex virus 2 (HSV-2) infection. We report the case of a 39 y.o. Italian woman who experienced four episodes of aseptic lymphocytic meningitis between 2004 and 2023, diagnosed as Mollaret’s meningitis. In each episode, the patient presented with fever, severe headache and photophobia. In two episodes cutaneous vesicles in the left gluteal area preceding meningitis symptoms were also reported. A diagnostic evaluation included a physical–chemical analysis and a real-time PCR of the cerebrospinal fluid (CSF). The CSF presented pleocytosis with lymphocytic predominance and a positive HSV-2 load, with a peak of 1234 copies/mL. The patient was treated successfully with acyclovir, and the symptoms resolved without neurological sequelae. This case highlights the importance of comprehensive diagnostic testing and vigilant monitoring to manage Mollaret’s syndrome effectively. Full article