Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS): contemporary advances and current controversies.

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory syndrome with characteristic clinical, radiological, and pathological features, and can be effectively treated with corticosteroid-based immunotherapies. The exact pathogenesis of CLIPPERS remains unclear, and specific diagnostic biomarkers are not available. According to the 2017 diagnostic criteria, probable CLIPPERS should be considered in middle-aged patients with subacute onset of pontocerebellar symptoms and typical punctuate and curvilinear gadolinium enhancement lesions ("salt-and-pepper" appearance) located in the hindbrain (especially pons) on magnetic resonance imaging. In addition, CLIPPERS-mimics, such as central nervous system (CNS) lymphoma, and several antibody-associated autoimmune CNS diseases (e.g., myelin oligodendrocyte glycoprotein antibody-associated disease, autoimmune glial fibrillary acidic protein astrocytopathy, and anti-N-methyl-D-aspartate receptor encephalitis), should be extensively excluded. The prerequisite for definite CLIPPERS is the perivascular T-cell-predominant inflammatory infiltration observed on pathological analysis. A biopsy is strongly suggested when clinical/radiological red flags are present. Most patients with CLIPPERS respond well to corticosteroids and have a good prognosis. Long-term low-dose corticosteroid maintenance therapy or corticosteroids coupled with immunosuppressants are recommended to prevent the recurrence of the syndrome. The potential progression of CLIPPERS to lymphoma has been suggested in some cases; therefore, at least 2-year clinical and radiological follow-up is essential. Here, we critically review the recent developments and provided an update on the clinical characteristics, diagnostic criteria, differential diagnoses, and therapeutic management of CLIPPERS. We also discuss the current controversies in this context that can be resolved in future research studies.

Keyhole Retrosigmoid Craniotomy for Lateral Pontine Cavernous Malformation.

With improvements in anesthesia, monitoring, and peroperative care, the surgical removal of intrinsic brainstem pathology has become a possibility.1 Although surgical removal of deep-seated lesions continues to have significant morbidity, at least temporarily, associated with it, removal of exophytic lesions can be accomplished with little disability for the patient. The key to a good outcome, when removing cerebral cavernous malformation, is preservation of adjacent neurovascular bundles, use of sharp dissection over blunt pulling, judicious use of cautery in and around the brainstem, and preservation of the developmental venous anomaly, when present. The authors present a case of a lateral pontine cerebral cavernous malformation that was exophytic at the lateral and peritrigeminal safe entry zones.2 Neuromonitoring was used an adjunct to ensure safety of the procedure. The lesion is accessed using a keyhole retrosigmoid craniotomy (Video 1). We do not routinely use lumbar drains for these procedures as careful arachnoid dissection can result in adequate cerebrospinal fluid release. The window of access to this area is between CN 5 and the CN 7/8 complex. The arachnoid over the nerves is preserved, but the layer between the nerves is exposed to gain access to the lateral pons. The lesion is sharply dissected from the lateral pons, taking care to save the developmental venous anomaly, from which this lesion arises.

The relationship between dysphagia and the localisation of brain lesion in stroke: is the involvement of the pons and medulla important?

OBJECTIVES: The presence of dysphagia in stroke is associated with mortality and morbidity. The aim of this retrospective study is to present the relationship between dysphagia and the demographic characteristics of the patient, and the type and localisation of brain lesion in the acute period in stroke patients with dysphagia. MATERIALS AND METHODS: The data of 284 patients who had stroke-related dysphagia, had a disease duration 1-3 months, had no history of swallowing dysfunction before the event, and had their brain MRI/CT reports in the hospital were included. RESULTS: The rate of tube-dependent oral areas was higher in the lesions located in the pons and the medulla than in the lesions located in the MCA cortex, the basal ganglia, and the cerebellum (p ˂ 0.001, p = 0.032 and p = 0.011, respectively) and the percentage of those fed with NG + TPN + PEG was statistically significantly higher (p = 0.002, p = 0.032 and p = 0.011, respectively). History of pneumonia was found to be statistically significantly higher in the lesions located in the pons and the medulla than in the lesions located in the MCA cortex, ACA cortex, PCA cortex, the basal ganglia, periventricular white matter, the thalamus, the cerebellum, and the midbrain (p ˂ 0.001, p = 0.005, p = 0.023, p ˂ 0.001, p = 0.023, p = 0.001, p = 0.011 and p = 0.023, respectively). CONCLUSION: In conclusion, although lesion localisation in the acute period in patients with dysphagia varied in terms of clinical swallowing evaluation findings, weight loss, pneumonia history, the rate of tube-dependent intake, were shown to be higher in patients who had lesions in the pons and the medulla, which is a finding that should be considered in the clinical follow-up of acute stroke patients with lesions in the pons and the medulla.

A woman with focal neurological deficit following treatment for cholera.

A 41-year old woman was treated for cholera at one of the health centers in Blantyre. Two days after discharge from the treatment unit, she developed weakness of all 4 limbs and difficulties with speech. She was referred to the Queen Elizabeth Central Hospital. A CT scan of the brain showed hypodense lesions in the pons. A diagnosis of central pontine myelinolysis was made. She recovered slowly and was discharged from hospital 17 days after admission.

Clinical outcomes of stereotactic biopsy on children with pontine diffuse midline glioma.

INTRODUCTION: Diffuse midline glioma (DMG) of the pons occurs in pediatric patients and carries a dismal prognosis. Biopsy is not necessary for diagnosis but provides information, particularly H3K27M status, with prognostic implications. Additionally, biopsy information may open therapeutic options such as clinical trials that require mutation status. Therefore, we sought to assess the safety of surgical biopsy in DMG patients as well as its potential impact on clinical course. METHODS: Retrospective analysis of patients who were radiographically and clinically diagnosed with pontine DMG in the last 5 years was performed. We assessed demographic, clinical, radiographic, surgical, and follow-up data. RESULTS: 25 patients were included; 18 (72%) underwent biopsy while 7 (28%) declined. 12 biopsies (67%) were performed with robotic arm and 5 (27%) with frameless stereotaxy. Three biopsied patients (17%) experienced new post-operative neurologic deficits (1 facial palsy, 1 VI nerve palsy and 1 ataxia) that all resolved at 2-week follow-up. All biopsies yielded diagnostic tissue. Fourteen patients (78%) had H3K27M mutation. Median OS for H3K27M patients was 10 months compared to 11 months in the wild-type patients (p = 0.30, log-rank test). Median OS for patients enrolled in clinical trials was 12 months compared to 8 months for non-trial patients (p = 0.076). CONCLUSION: In our series, stereotactic pontine DMG biopsies did not carry any permanent deficit or complication and yielded diagnostic tissue in all patients. Similar post-operative course was observed in both robot-assisted and frameless stereotactic approaches. There was no significant difference in survival based on mutation status or clinical trial enrollment.

Recurrent haemorrhagic pontine cavernoma resection via a retrosigmoid microsurgical approach.

BACKGROUND: Brainstem cavernomas occasionally require surgical treatment. Appropriate patient selection and thorough understanding of the anatomy and technical nuances involved in microsurgical resection is a pre-requisite in undertaking these challenging cases. CASE DESCRIPTION: We present a video case of a patient with a recurrent haemorrhagic pontine cavernoma. A step-by-step commentary of surgical footage is provided along with clinical, anatomical and technical learning points pertinent to the safe surgical management of these lesions.

Long-standing myoclonic hand tremor as an isolated symptom of hypertrophic olivary degeneration.

Hypertrophic olivary degeneration (HOD) is a rare condition caused by lesions of the dentato-rubro-olivary pathway, usually bilateral. We presented a case of a 64-year old male with HOD caused by a unilateral, posterior pontine cavernoma. The patient has not developed the typical palate myoclonus until recently. Isolated hand myoclonus with coexisting asterixis was present for years. This case shows unique HOD symptomatology and emphasizes the important role of MRI in the differential diagnosis of monomelic myoclonus.

Fifty years of DIPG: looking at the future with hope.

Diffuse intrinsic pontine glioma (DIPG) is a primary brainstem tumor of childhood that carries a dismal prognosis, with median survival of less than 1 year. Because of the brain stem location and pattern of growth within the pons, Dr. Harvey Cushing, the father of modern neurosurgery, urged surgical abandonment. Such a dismal prognosis remained unchanged for decades, coupled with a lack of understanding of tumor biology and an unchanging therapeutic panorama. Beyond palliative external beam radiation therapy, no therapeutic approach has been widely accepted. In the last one to two decades, however, increased tissue availability, an improving understanding of biology, genetics, and epigenetics have led to the development of novel therapeutic targets. In parallel with this biological revolution, new methods intended to enhance drug delivery into the brain stem are contributing to a surge of exciting experimental therapeutic strategies.

Deceptive Appearances - Spastic Paretic Hemifacial Contractures in Cases of Seventh Nerve Involvement 'Inside' and 'Outside' the Brainstem.

Spastic paretic hemifacial contracture (SPHC) is a rare clinical phenomenon characterized by facial weakness and simultaneous well-sustained contraction of the unilateral half of the face, mimicking a paresis of the normal contralateral side on casual inspection. We present three cases with such phenomenon and have postulated the underlying mechanisms. One patient had intrinsic brainstem glioma, and the others were operated for extra-axial lesions compressing the pons. The former presented with SPHC, whereas the latter two gradually developed this phenomenon following postoperative facial paresis. This condition is possibly due to denervation hyper-excitability of the facial supranuclear pathway or an aberrant regeneration secondary to nerve injury leading to functional facial-nerve nuclear reorganization. SPHC occurrence is not limited to intra-axial lesions but can also be seen after partial injury to the facial nerve beyond its exit from the brainstem.

Comparative examination of the pons and corpus callosum as reference regions for quantitative evaluation in positron emission tomography imaging for Alzheimer's disease using 11C-Pittsburgh Compound-B.

OBJECTIVES: Standardised uptake value ratio (SUVR) is usually obtained by dividing the SUV of the region of interest (ROI) by that of the cerebellar cortex. Cerebellar cortex is not a valid reference in cases where amyloid ß deposition or lesions are present. Only few studies have evaluated the use of other regions as references. We compared the validity of the pons and corpus callosum as reference regions for the quantitative evaluation of brain positron emission tomography (PET) using 11C-PiB compared to the cerebellar cortex. METHODS: We retrospectively evaluated data from 86 subjects with or without Alzheimer's disease (AD). All subjects underwent magnetic resonance imaging, PET imaging, and cognitive function testing. For the quantitative analysis, three-dimensional ROIs were automatically placed, and SUV and SUVR were obtained. We compared these values between AD and healthy control (HC) groups. RESULTS: SUVR data obtained using the pons and corpus callosum as reference regions strongly correlated with that using the cerebellar cortex. The sensitivity and specificity were high when either the pons or corpus callosum was used as the reference region. However, the SUV values of the corpus callosum were different between AD and HC (p < 0.01). CONCLUSIONS: Our data suggest that the pons and corpus callosum might be valid reference regions.

DIPG-like MYB-altered diffuse astrocytoma with durable response to intensive chemotherapy.

Pontine gliomas represent difficult to treat entity due to the location and heterogeneous biology varying from indolent low-grade gliomas to aggressive diffuse intrinsic pontine glioma (DIPG). Making the correct tumor diagnosis in the pontine location is thus critical. Here, we report a case study of a 14-month-old patient initially diagnosed as histone H3 wild-type DIPG. Due to the low age of the patient, the MRI appearance of DIPG, and anaplastic astrocytoma histology, intensive chemotherapy based on the HIT-SKK protocol with vinblastine maintenance chemotherapy was administered. Rapid clinical improvement and radiological regression of the tumor were observed with nearly complete remission with durable effect and excellent clinical condition more than 6.5 years after diagnosis. Based on this unexpected therapeutic outcome, genome-wide DNA methylation array was employed and the sample was classified into the methylation class "Low-grade glioma, MYB(L1) altered." Additionally, RT-PCR revealed the presence of MYB::QKI fusion. Taken together, the histopathological classification, molecular-genetic and epigenetic features, clinical behavior, and pontine location have led us to reclassify the tumor as a pontine MYB-altered glioma. Our case demonstrates that more intensive chemotherapy can achieve long-term clinical effect in the treatment of MYB-altered pontine gliomas compared to previously used LGG-based regimens or radiotherapy. It also emphasizes the importance of a biopsy and a thorough molecular investigation of pontine lesions.

[Reversible central pontine myelinolysis without hyponatremia in a child with acute lymphoblastic leukemia: a case report]. / Myélinolyse centropontine réversible sans hyponatrémie chez un enfant atteint de leucémie aigüe lymphoblastique: à propos d'un cas.

Central pontine myelinolysis is a demyelinating disorder mainly affecting the central pons. In some cases, it is associated with extrapontine myelinolysis. It is usually caused by rapid correction of hyponatremia and osmotic shock. We here report the case of a 3.5-year-old girl diagnosed with acute lymphoblastic leukemia admitted to our Oncology Unit with neutropenic fever and diarrhea. Laboratory tests showed mild neutropenia, normochromic normocytic anemia. Electrolyte tests were normal without hyponatremia. She received antibiotic therapy with Metronidazole. Five days later, she developed flaccid quadriparesis with mutism. Computerized tomography (CT) scan was normal, cerebrospinal fluid (CSF) examination was normal (there was no evidence of leukemic cells) and ophthalmological examination did not show any abnormalities. Brain MRI found hyperintense signal in the pons. The child improved without specific treatment, and clinical and complete neurological recovery was noted. This case highlights that myelinolysis can occur under some circumstances not related with hyponatremia such as malignancy, chemotherapy.

"Uncrossed Central Facial Paralysis" Caused by Pontine Infarction: A Case Report.

INTRODUCTION: We report a patient with extraordinary pontine infarction-induced contralateral central facial palsy and weakened limb strength. CASE REPORT: This is a 66-year-old man with left arm movement difficulty for 10 days and worsening over the last 1 day. His left nasolabial fold flattening and left arm strength and sensory were decreased. He could not complete the finger-nose test well with his right hand. Magnetic resonance and magnetic resonance angiography tests confirmed his right pontine acute infarction but without large vessel stenosis or occlusion. CONCLUSION: "Uncrossed paralysis" patients may present with contralateral face and body weakness with pontine infarcts, if the infarct occurs above the level of the facial nucleus head, and may be simmilar with the higher level pontine lesions or cerebrum semisphere infarction, which need particular attention during clinical practice.

The pathogenesis hypothesis and research progress of CLIPPERS: A literature review.

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is still a rare autoimmune disease in the world. In recent years, there are more and more reports about the clinical manifestations of CLIPPERS, but the specific etiology and pathogenesis are not clear. In this paper, by collating the literature reported in recent years, in the reported effective treatment cases, we found the current hypothesis about the pathogenesis of CLIPPERS. Three pathogenesis hypotheses: organ-specific autoimmunity; virus infection affects autoimmunity; and helper T lymphocyte 17 mediates autoimmunity. Although it is hypothetical, it is expected to further clarify the pathogenesis, evolution characteristics, and treatment of CLIPPERS, so as to provide a reference for further understanding of the disease. In the future, more observations and studies are needed to further verify the feasibility of the hypothesis. This article expands on atypical clinical manifestations and summarizes treatment options. Hope to provide a reference for clinical diagnosis and treatment of CLIPPERS.

Morphological predictors of neurological deterioration in patients with acute isolated pontine infarct.

OBJECTIVE: To investigate morphological predictors of neurological deterioration (ND) in patients with acute isolated pontine infarct. METHODS: Acute isolated pontine infarct patients within 7 days after onset of stroke symptoms were included retrospectively and classified into ND and non-ND groups. Morphological phenotypes (paramedian pontine infarct [PPI], atypical PPI, small deep infarct, and other types), topographical location, and lesion size were evaluated on axial diffusion-weighted imaging. RESULTS: There were 210 eligible patients, of whom 62 patients had ND (29.5%). The proportion of PPI was significantly higher in ND than that in non-ND (62.9% vs 39.6%). ND occurred more frequently in PPI patients than non-PPI patients (39.8% vs 20.5%). PPI located more frequently in lower pontine (20.4% vs 8.0%) and less in upper pontine (17.3% vs 30.4%, P = 0.028), and had larger ventro-dorsal length (13.8 ± 3.8 vs 9.9 ± 3.1) and width (8.3 ± 2.3 vs 6.2 ± 1.8) than non-PPI patients. The morphological phenotype of PPI was an independent risk factor for ND (OR 4.81, 95%CI 1.54-15.07, P = 0.007) in patients with isolated pontine infarct. The ventro-dorsal length of pontine infarct lesion was associated with ND (OR 1.18, 95%CI 1.01, 1.37, P = 0.034) in PPI patients. CONCLUSIONS: The morphological phenotype of PPI was a potential predictor for ND in patients with acute isolated pontine infarct. The ventro-dorsal length of pontine infarct lesion was possibly associated with ND in PPI patients.

Nonpainful Trigeminal Neuropathy Associated with a Solitary Pontine Lesion: A Case Series.

A solitary pontine lesion (SPL) is a single brainstem lesion on the trigeminal nerve pathway without any other central nervous system lesion. This research aimed to investigate the demographic and clinical features of nonpainful TNO patients with SPL and identify the most frequently affected anatomical areas using lesion mapping techniques. Demographic and clinical features were retrospectively reviewed from the patients' charts. Brain lesions were mapped using MRIcroGL software. The study included 6 patients (three females and three males) with an SPL. The median age of the patients was 57 (range: 46-68) years. Cranial MRI displayed lesions in the dorsolateral pons and the cerebellar peduncle. The lesion mapping revealed that the lesions were on the trigeminal nerve pathway. SPL is an uncommon cause of TNO. Nonpainful SPL patients have demographic, clinical, and radiological features similar to those of painful SPL patients. The lesion mapping showed that the same brainstem areas are affected in painful and nonpainful SPL patients.

Glutathione in the Pons Is Associated With Clinical Status Improvements in Subacute Spinal Cord Injury.

OBJECTIVES: In spinal cord injury (SCI), the primary mechanical injury is followed by secondary sequelae that develop over the subsequent months and manifests in biochemical, functional, and microstructural alterations, at the site of direct injury but also in the spinal cord tissue above and below the actual lesion site. Noninvasive magnetic resonance spectroscopy (MRS) can be used to assess biochemical modulation occurring in the secondary injury phase, in addition to and supporting conventional MRI, and might help predict and improve patient outcome. In this article, we aimed to examine the metabolic levels in the pons of subacute SCI by means of in vivo proton MRS at 3 T and explore the association to clinical scores. MATERIALS AND METHODS: In this prospective study, between November 2015 and February 2018, single-voxel short-echo MRS data were acquired in healthy controls and in SCI subjects in the pons once during rehabilitation. Besides the single-point MRS examination, in addition, in participants with SCI, the clinical status (ie, motor, light touch, and pinprick scores) was assessed twice: (1) around the MRS session (approximately 10 weeks postinjury) and (2) before discharge (at approximately 9 months postinjury). The group differences were assessed with Kruskal-Wallis test, the post hoc comparison was assessed with Wilcoxon rank sum test, and the clinical correlations were conducted with Spearman rank correlation test. Bayes factor calculations completed the statistical part providing relevant evidence values. RESULTS: Twenty healthy controls (median age, 50 years; interquartile range, 41-55 years; 18 men) and 18 subjects with traumatic SCI (median age, 50 years; interquartile range, 32-58 years; 16 men) are included. Group comparison showed an increase of total N -acetylaspartate and combined glutamate and glutamine levels in complete SCI and a reduction of total creatine in incomplete paraplegic SCI. The proton MRS-based glutathione levels at baseline correlate to the motor score improvement during rehabilitation in incomplete subacute SCI. CONCLUSIONS: This exploratory study showed an association of the metabolite concentration of glutathione in the pons assessed at approximately 10 weeks after injury with the improvements of the motor score during the rehabilitation. Pontine glutathione levels in subjects with traumatic subacute incomplete SCI acquired remote from the injury site correlate to clinical score and might therefore be beneficial in the rehabilitation assessments.

A rare case report of primary Sjögren's syndrome with clinical characteristics similar to those of CLIPPERS.

BACKGROUND: Primary Sjögren's syndrome (pSS) is an autoimmune inflammatory disease characterized by dryness of the eyes, mouth and other mucous membranes. Patients with pSS can also present with extraglandular manifestations, such as pulmonary, kidney and nervous system involvement. Central nervous system (CNS) manifestations have rarely been described in pSS. CASE PRESENTATION: A 33-year-old man was admitted with a one-month history of dizziness, speech disturbance, and walking instability. His brain enhanced magnetic resonance imaging (MRI) showed symmetrical, enhanced "salt-and-pepper-like" speckled lesions in the brainstem, basal ganglia, and subcortical regions, and his diagnosis was considered possible chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). Further examination revealed that anti-SSA antibody was positive, and the Schirmer test and labial salivary gland histopathology were abnormal, which supported the diagnosis of pSS. CONCLUSION: pSS is a chronic systemic autoimmune disease that involves neurological complications. This case suggests that CNS lesions of pSS can present with clinical and MRI findings similar to those of CLIPPERS.

Morphometric examination of trigeminal nerve and its adjacent structures in patients with trigeminal neuralgia: a case-control study.

BACKGROUND: Morphological differences that can lead the trigeminal nerve to neurovascular conflict and a new solitary pontine lesion are associated with the pathogenesis of trigeminal neuralgia (TN). In this case-control study, we aimed to contribute to the current discussions about the pathogenesis of TN by investigating the anatomical structures that may have an effect on the morphometric parameters of the trigeminal nerve. METHODS: This study included 25 patients with TN followed up for pain in the Department of Algology, Faculty of Medicine, and 25 age- and gender-matched controls. We performed morphometric measurements including the length and volume of the trigeminal nerve, cerebellopontine cistern, pons, and posterior fossa in the MRIs of these individuals. Comparative analyses were performed for the mean of the affected and unaffected sides of the TN patients and the right, left, and both sides of the control group. RESULTS: In patients with TN, on the affected side, length and volume of the trigeminal nerve and cerebellopontine cistern volume were found smaller than controls (p < 0.05). Pons volume was higher in patients with TN compared to controls (p < 0.05). The length of the affected nerve was significantly related to prepontine cistern length and cerebellopontine cistern volume (p < 0.05). DISCUSSION: The cerebellopontine cistern volume has a significant impact on the morphometric characteristics of the trigeminal nerve. Especially, whether the increase in the volume of pons causes a decrease in the volume of cerebellopontine cistern should be clarified with further research.