Paraneoplastic Syndrome. Clinical Case

Pseudo-Foster Kennedy syndrome due to idiopathic intracranial hypertension

Methanol poisoning is a serious problem due to its high mortality and revalence of health sequelae among survivors. Death from methanol poisoning has been reported in 8-36% and permanent vision loss has been observed in 20- 0% of acute trauma survivors. Formic acid that builds up in the optic nerve can disrupt the visual system and cause optic neuropathy. Vision loss is painless and usually occurs in both eyes within one to three days. This Systematic Review based on Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) protocol. This protocol has administered in The International Prospective Register of Systematic Reviews (PROSPERO) database. The literature showed visual acuity and funduscopic examinations of methanol induced optic toxic neuropathy and high-dose steroid, erythropoietin and antioxidant as the therapy. Methanol poisoning is a serious problem due to its high mortality and prevalence of health sequelae among survivors. Pericapillary retinal edema and optic disc edema after blurred vision or "snowfield" vision, visual hallucinations, dense central fibroids, photophobia, peripheral constriction of the visual field, and decreased visual acuity even total blindness as a symptom can be found. Prevention of formic acid formation is the main steps of treatment. Keywords:Methanol, Literature Review, ManagementABSTRACT Methanol poisoning is a serious problem due to its high mortality and revalence of health sequelae among survivors. Death from methanol poisoning has been reported in 8-36% and permanent vision loss has been observed in 20- 0% of acute trauma survivors. Formic acid that builds up in the optic nerve can disrupt the visual system and cause optic neuropathy. Vision loss is painless and usually occurs in both eyes within one to three days. This Systematic Review based on Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) protocol. This protocol has administered in The International Prospective Register of Systematic Reviews (PROSPERO) database. The literature showed visual acuity and funduscopic examinations of methanol induced optic toxic neuropathy and high-dose steroid, erythropoietin and antioxidant as the therapy. Methanol poisoning is a serious problem due to its high mortality and prevalence of health sequelae among survivors. Pericapillary retinal edema and optic disc edema after blurred vision or "snowfield" vision, visual hallucinations, dense central fibroids, photophobia, peripheral constriction of the visual field, and decreased visual acuity even total blindness as a symptom can be found. Prevention of formic acid formation is the main steps of treatment. Keywords: Methanol, Literature Review, Management

Neurological complications of paediatric cancers are a substantial problem. Complications can be primary from central nervous system (CNS) spread or secondary from indirect or remote effects of cancer, as well as cancer treatments such as chemotherapy and radiation therapy. In this review, we present the clinical and imaging findings of rare but important neurological complications in paediatric patients with cancer. Neurological complications are classified into three phases: pre-treatment, treatment and post-remission. Paraneoplastic neurological syndromes, hyperviscosity syndrome, haemophagocytic lymphohistiocytosis and infection are found in the pre-treatment phase, while Trousseau’s syndrome, posterior reversible encephalopathy syndrome and methotrexate neurotoxicity are found in the treatment phase; though some complications overlap between the pre-treatment and treatment phases. Hippocampal sclerosis, radiation induced tumour, radiation induced focal haemosiderin deposition and radiation-induced white matter injury are found in the post-remission phase. With increasingly long survival after treatment, CNS complications have become more common. It is critical for radiologists to recognise neurological complications related to paediatric cancer or treatment. Magnetic resonance imaging (MRI) plays a significant role in the recognition and proper management of the neurological complications of paediatric cancer.Teaching Points• Neurological complications of paediatric cancer include various entities.• Neurological complications are classified into three phases: pre-treatment, treatment and post-remission.• Radiologists should be familiar with clinical and imaging findings of neurological complications.• MRI features may be characteristic and lead to early diagnosis and proper treatments.

Postoperative Ischemic Optic Neuropathy

Tumors that compress the retrobulbar optic nerve at a position posterior to the exit of the central retinal vein (CRV) from the optic nerve sheath typically produce progressive optic atrophy without optic disc edema, whereas those anterior to the CRV exit often result in optic disc edema, presumably due to compromised venous outflow with resultant optic disc congestion. There is evidence, however, that more posterior optic nerve compressive tumors may be associated with dilation of the perioptic subarachnoid space (SAS) anterior to the lesion, and chronic optic disc edema may be present. Our report demonstrates long-term clinical and radiographic follow-up of a patient with dilated perioptic SAS and chronic optic disc edema secondary to a presumed optic nerve sheath meningioma. A 54-year-old woman was noted to have optic disc edema in the right eye on routine examination. She reported vague intermittent visual blurring, but the visual acuity and automated perimetry were normal. Over the next 2 months, she developed transient visual obscurations with blackout of vision in the right eye lasting seconds, associated with orthostatic change or rapid head movements. The past medical, surgical, family, allergic, and medication histories were noncontributory. Examination revealed visual acuity of 20/20 in each eye with normal color vision and pupillary responses. The right optic disc showed 1+ edema, without optic atrophy or retinochoroidal venous collateral vessels (Fig. 1). The remainder of the examination was normal. Perimetry was normal. MRI of the orbits revealed thickening and enhancement of the right optic nerve sheath in the posterior orbit and optic canal, consistent with optic nerve sheath meningioma. The perioptic SAS anterior to the tumor was dilated, with increased T2 weighted hyperintensity consistent with cerebrospinal fluid (CSF), with a sharp demarcation at the anterior tumor margin, 12 mm posterior to the globe (Fig. 2).FIG. 1.: Color fundus photographs. Initial evaluation. Right eye (top left) showing optic disc edema without retinochoroidal collateral vessels. Left eye (top right) showing normal optic disc. Follow-up evaluation 4 years later. Right eye (bottom left) continues to show optic disc edema without retinochoroidal collateral vessels. Left eye (bottom right), optic disc remains normal.FIG. 2.: MRI of the orbits. Axial orbital views. T1-weighted image (top left) with fat-suppression and gadolinium administration: The right optic nerve sheath is thickened and enhancing from the optic canal to mid-orbit. A sharp demarcation is present at mid-orbit, anterior to which the perioptic subarachnoid space is dilated to the globe. Axial T2-weighted image (top right) confirms dilation of the subarachnoid space anteriorly on the right with no space visible posteriorly. Coronal orbital views. T1-weighted image through mid-posterior orbit (bottom left) shows thickened and enhancing right optic nerve sheath. T2-weighted image through anterior orbit (bottom right) shows dilated perioptic subarachnoid space on the right.Conservative management with observation was recommended, and the symptoms decreased without visual loss. Two years later, transient visual obscurations in the right eye recurred with increased frequency. Examination again revealed visual acuities of 20/20, with normal pupillary reactions, mild optic disc edema right eye, and otherwise normal findings. Automated perimetry demonstrated mild blind spot enlargement. MRI showed no significant change in the lesion. The patient preferred to defer treatment, with continuing mild transient visual obscurations in the right eye but no persistent visual loss or other symptoms. Two years later, she again reported increasing visual symptoms and was re-evaluated. Visual acuities remained 20/20 with normal color vision, pupillary reactions, and mildly increased optic disc edema (Fig. 1). MRI, however, remained unchanged, with evidence of perioptic SAS distention and increased CSF collection anterior to the lesion. McNab and Wright (1) described cystic enlargement of the optic nerve sheath in 3 cases of intraorbital meningioma. In one of the cases, optic disc edema was present; at exploratory surgery, the dilated perineural optic nerve space was incised, with emergence of a gush of fluid suggesting high pressure within the perioptic SAS. Lindblom et al. (2) reported 7 cases of focally dilated perioptic SAS anterior to optic nerve sheath meningiomas; 3 of the 7 had chronic optic disc edema, although no other details of the clinical examination were described. Imaging in the 3 cases shown demonstrated posterior orbital tumors with varying anterior extent, all with the sharp demarcation of the tumor from anterior dilated perioptic SAS, as seen in our case. The anterior border of the tumors ranged from 6 to 10 mm posterior to the globe. Killer et al. (4) also described unilateral disc edema secondary to an orbital apex meningioma, anterior to which the perioptic SAS was distended. The mechanism by which the perioptic SAS becomes dilated and its relation to optic disc edema remains unclear. Killer et al. (3) postulated that even in the absence of mechanical tumor blockage of flow around the optic nerve, the perioptic SAS is trabeculated and may be compartmentalized and separate from the remainder of the space in the central nervous system. Decrease of the venous and lymphatic outflow may result in increased pressure and possibly collection of toxins, both contributing to optic disc edema in the absence of elevated intracranial pressure elsewhere. Mader et al. (4) have recently reported on unilateral and asymmetric optic disc edema developing in space travel, again raising the issue of compartmentalization within the perioptic SAS, impaired venous and lymphatic (glymphatic) outflow, at least partially the result of the low-gravity environment. Our case suggests that chronic unilateral optic disc edema may result from dilation of the perioptic SAS anterior to a posterior optic nerve sheath meningioma that does not directly compress the central retinal vein as it traverses the space. Whether the optic disc edema results from locally increased SAS pressure, collection of toxins, or both, remains unproven. Although dilation of the perioptic SAS (with increased T2 weighted MRI CSF signal) is a typical radiographic feature of increased intracranial pressure, any compressive lesion in the orbit may reduce CSF egress from the perioptic SAS and produce dilation. The dilated SAS, especially if unilateral, should prompt detailed orbital imaging with gadolinium administration and fat suppression to detect an occult compressive lesion.

This article discusses the diagnosis and treatment of cancer-related neurologic complications including (1) diagnosis and management of brain, spinal, and leptomeningeal metastases; (2) toxicities of conventional cytotoxic, biologic, and targeted therapies with a focus on immunotherapies (immune checkpoint inhibitors and chimeric antigen receptor [CAR] T-cell therapy); (3) paraneoplastic syndromes; and (4) acute and long-term sequelae, including seizures, stroke, neuropathy, and long-term effects of young adult and childhood cancer treatment. Brain metastases can differ genetically from the primary neoplasm, with some responding to systemic rather than local therapies. Increasing use of immune checkpoint inhibitors has increased the incidence of immune-mediated neurologic complications, including paraneoplastic neurologic syndromes. CAR T-cell therapy, initially developed for leukemia and lymphoma, is being applied to an increasing range of cancers and can cause complications such as cytokine release syndrome and immune effector cell-associated neurologic syndrome, for which specific therapeutic protocols are available. Prompt recognition of direct and indirect neurologic complications of systemic cancers and their evolving treatments is essential to maximize favorable outcomes. Neurologists should be familiar with common and rare neurologic toxicities of conventional chemotherapy, immune checkpoint inhibitors, and CAR T-cell therapy.

Bilateral disc edema in hypertensive emergency

Optic disc morphology after AAION: author reply

BackgroundSudden visual loss and optic disc edema caused by optic neuritis (ON) is usually followed by significant visual recovery. However, little or no recovery occurs when the loss is caused by atypical ON, especially in patients with neuromyelitis optica (NMO). Optic disc drusen (ODD) is a cause of pseudo optic disc edema and may be a predisposing factor for non-arteritic anterior ischemic optic neuropathy (NAION), thereby mimicking atypical ON. In such cases, if globular concretions are seen protruding from the disc substance, ODD may be suspected. The purpose of this paper is to describe two patients with acute visual loss followed by optic disc atrophy initially labeled as atypical ON. Though not suspected on clinical examination, optical coherence tomography (OCT) revealed deeply buried ODD as a predisposing factor for NAION.Case presentationsCase 1: A 48-year-old woman had bilateral sequential visual loss associated with optic disc edema. Despite treatment, vision did not improve and severe disc pallor ensued. Atypical ON was suspected. Eventually, she was started on immunosuppressant therapy based on a tentative diagnosis of NMO-spectrum disorder. On examination 5 years later, only severe optic disc pallor was observed, but OCT radial B-scans showed ovoid hyporeflective areas in the retrolaminar region of both eyes, compatible with ODD; this led to a diagnosis of NAION and deeply buried ODD. Case 2. A 35-year-old woman with suspicion of ON in the left eye and a history of previous atypical ON in the right eye was referred for neuro-ophthalmic examination which revealed diffuse optic disc pallor and a dense arcuate visual field defect in the right eye. OCT B-scans passing through the disc showed large ovoid areas of reduced reflectivity in the retrolaminar region of the optic disc in the right eye. These findings helped confirm the diagnosis of NAION in one eye, with deeply buried ODD as predisposing factor.ConclusionsDeeply buried ODD may be associated with NAION causing irreversible visual loss and optic disc pallor, a condition easily mistaken for atypical ON. Awareness of such occurrence is important to avoid unnecessary testing and minimize the risk of mismanagement.

Alpha-interferon (alpha-IFN) is widely used in the treatment of chronic viral hepatitis, either alone or combined with other antiviral therapies such as ribavirin (1). It can induce various side effects, particularly systemic effects such as fever, influenza-like symptoms, thrombocytopenia and neutropenia (2). Ocular toxicity, including retinopathy, optic neuropathy and ocular vision loss, has been infrequently (<1%) reported as a potentially serious adverse event associated with alpha-IFN. Anterior ischemic optic neuropathy (AION) is presumed to be a small infarct within the optic nerve head. Many patients have arteriosclerotic risk factors (3). We report a patient in whom bilateral AION occurred shortly after onset of treatment with alpha-IFN for chronic hepatitis C (CHC). A 28-year-old man has been followed up with chronic renal failure and CHC infection probably as a result of hemodialysis treatment. Pegylated-IFN-α 135 µgr/week was started. Two months after treatment, suden onset, painless left visual field defect happened. Visual acuity was 20/30 OD ( right ), 20/80 OS ( left ). Fundus examination of the OD revealed pallid edema of the optic nerve head with cotton wool spots. In the OS disc, there was optic disc edema, more elevated than in the right, with splinter hemorrhages on the nasal side, and a few cotton wool spots at the edge of the edema. Visual field examination demonstrated defects suggestive of inferior nerve fiber bundle defects in both eyes, worse in the OS. Neurologic assessment was otherwise normal. Standard blood study results were normal, including erythrocyte sedimentation rate, white blood cell count, hemoglobin, prothrombin time, partial thromboplastin time, protein S, protein C, antithrombin III, antiphospholipid Ab, antinuclear antibody, venereal disease research laboratory titer. Thyroid-stimulating hormone was on the lower edge of normal values, other thyroid function test results were normal. Cranial and orbital computed tomography findings were normal. Pegylated-IFN-α was discontinued, The patient was treated with orally methylprednisolone 32 mg/d for 14 days, with tapering of the next two months. After this treatment visual disturbances resolved and the parameters of neurophysiologic testing returned to normal . We describe a patient undergoing treatment with pegylated-IFN-α who developed optic neuropathy within two months of starting this medication. The patient had established risk factors for conventional AION, including hypertension, chronic renal failure and we doubt that the HCV also precipitated. Because our patient did not have systemic symptoms of vasculitis and cryoglobulins Ab were negative, we had ruled out essential mixed cryoglobulinemia. We conclude that clinically evident optic tract neuropathy may complicate pegylated-IFN-α administration. Candidates for pegylated-IFN-α treatment may need routine examination of optic fields and visual evoked potentials, before and during administration of the drug to avoid possibly permanent visual sequelae References EASL International Consensus Conference on Hepatitis C. Paris, 26-28, February 1999 Consensus Statement. European Association for the Study of the Liver. J Hepatol 1999;30:956-961. Fattovich G, Giustina G, Favarato S, Ruol A. A survey of adverse events in 11,241 patients with chronic viral hepatitis treated with alfa interferon. J Hepatol 1996;24:38–47. Jacobson DM, Vierkant RA, Belongia EA. Nonarteritic anterior ischemic optic neuropathy: a case control study of potential risk factors. Arch Ophthalmol 1997;115:1403–7. Morrissey SP, Borraut FX, Miller DH, et al. Bilateral simultaneousoptic neuropathy in adults: clinical, imaging, serological, and genetic studies. J Neurol Neurosurg Psychiatry 1995;58:70–4. Guyer DR, Tiedeman J, Yannuzzi LA, et al. Interferon associated retinopathy. Arch Ophthalmol 1993;111:350–6.

Collapsin response mediator protein 5-associated optic neuropathy (CRMP5-ON) is a rare entity of autoimmune optic neuropathy. This study aimed to review the neuro-ophthalmic findings and outcomes in a series of patients with CRMP5-ON to further characterize its clinical phenotype, radiologic clues, and outcomes. This was a retrospective case series and a single-center medical chart review of all patients with CRPM5-seropositive ON at the Department of Neurology, Beijing Tongren Hospital, from December 1, 2020, to March 31, 2023. The main outcome measures were neuro-ophthalmic manifestations, radiologic characteristics, and clinical outcomes of CRMP5-ON; coexisting neural autoantibody, paraneoplastic associations, and the impact of immunosuppressant therapy. Five patients were identified. Four (80%) were female, and the average age at onset was 59.4 years (range 53-69 years), with an average follow-up of 15.3 months (range 1.4-28.7 months). The average best-corrected visual acuity (BCVA) at nadir was 20/120 (range 20/20 to count fingers). Seven of ten affected eyes (70%) showed diffuse defects of the central field. Painless bilateral involvement and optic disk edema occurred in 100% of patients, combined with vitritis, uveitis, or retinitis in four (80%). Four patients (80%) had MRI abnormalities along the optic nerve (one patient with optic nerve enhancement and three patients had optic nerve sheath enhancement or peribulbar fat enhancement). Three patients (60%) had optic neuropathy with other neurologic symptoms. Four patients (80%) had confirmed cancer (two were small-cell lung carcinoma, one was papillary thyroid carcinoma and another was thymoma and invasive pulmonary adenocarcinoma). All cancers were identified after the presentation of the optic neuropathy. The intervention included IVIG, IVMP, surgery and chemotherapy. The average BCVA at the last follow-up was 20/50 (range 20/20 to count fingers). Three patients had surgery during the initial hospitalization, and were stable during the follow-up. Among two patients who received IVMP, both had improvement after treatment, although one patient had worsening non-ocular neurologic symptoms during the steroid taper. CRMP5-ON presented with optic disc edema, often bilateral involved and combined with vitreitis, retinitis, or uveitis. CRMP5-ON can present with MRI optic nerve or perineural optic nerve enhancement, especially in the optic nerve sheath. CRMP5-ON is closely related to paraneoplastic neurologic syndrome. Cancer screening and intervention are crucial to prognosis.

Optical coherence tomography angiography (OCTA) is a new noninvasive imaging modality that provides high resolution images of the optic nerve head and peripapillary retinal capillary vasculature which can be affected by optic nerve or retinal pathologies. High repeatability of peripapillary capillary density measurement using OCTA has been demonstrated in normal eyes and eyes with glaucoma. The purpose of our study was to quantify the repeatability of peripapillary capillary density measurement using OCTA in both normal eyes and eyes with optic atrophy, optic disc edema, and retinal vasculopathy. This prospective cross-sectional study enrolled 31 patients (59 eyes) including 16 eyes with optic nerve pathology (7 with disc edema from papilledema and 9 with optic atrophy), 35 eyes with retinal vascular disease, and 8 normal eyes. All eyes were imaged twice (30 minutes apart) with the Optovue AngioVue OCTA instrument to obtain 4.5 × 4.5 mm peripapillary scans. Scans were considered good quality if signal strength was 6 or greater. The OCTA parameters obtained include the radial peripapillary capillary (RPC) density of the whole disc, inside the disc, peripapillary region, and the 4 quadrants of the disc (superior, nasal, inferior, and temporal). A Student's t test was used to compare means. Intraclass correlation coefficient (ICC) was calculated to measure repeatability. Repeatability of RPC density measurements for all regions analyzed demonstrated good to excellent repeatability for the whole cohort {ICC for the whole image was 0.915 (95% confidence interval [CI] = 0.855-0.951)}; ICC for the peripapillary region was 0.945 (95% CI = 0.905-0.969). In the subset of eyes with good image quality (i.e., signal strength ≥ 6), ICC was slightly higher for all regions, with excellent repeatability of the peripapillary region (ICC was 0.971 [95% CI = 0.943-0.986]). Conversely, for eyes with poor image quality scans (i.e., signal strength < 6), ICC was lower, corresponding to moderate to good repeatability for most parameters. For the subset of eyes with optic atrophy, disc edema from papilledema or retinal vasculopathy, all had good to excellent repeatability of the vessel density of the entire disc (ICC values were 0.954 [95% CI = 0.804-0.990], 0.921 [95% CI = 0.711-0.982], and 0.895 [95% CI = 0.788-0.951, respectively]) and of the peripapillary region (ICC values were 0.980 [95% CI = 0.904-0.996], 0.966 [95% CI = 0.854-0.993], and 0.916 [95% CI = 0.827-0.961], respectively). The peripapillary capillary density measurement obtained using a commercial OCTA instrument is highly repeatable in eyes with optic nerve atrophy, disc edema from papilledema, or retinal vasculopathy.

1. Schiller M, Bohm M, Hensen P, Riemann H, Luger TA, Nashan D. Dermatomyositis associated with malignant melanoma –A marker of poor prognosis? J Am Acad Dermatol, 2006; 54(2): 221–226. CrossRef Google Scholar

IntroductionMedullary thyroid carcinoma (MTC) accounts for 5-10% of all thyroid cancers and up to 30% of MTCs are hereditary. Only 0.6% of MTCs are associated with a paraneoplastic ACTH-dependent Cushing's syndrome (CS) (PMID: 16029131). Even rarer are MTCs without a primary intra-thyroidal tumor. Here we describe a patient with metastatic MTC without a known primary intrathyroidal tumor presenting with paraneoplastic ACTH-dependent CS.Clinical CaseA 47-year-old Ukrainian man was referred to our center for management of metastatic MTC. During evaluation of refractory diarrhea two years earlier, an elevated serum calcitonin (1758 pg/mL, normal: <11.5) led to the diagnosis. Thyroid ultrasound revealed a normal thyroid with bulky cervical lymphadenopathy. Cervical lymph node biopsy revealed metastatic MTC with positive calcitonin, synaptophysin, and chromogranin-A on immunohistochemistry (IHC) and RET protooncogene M918T pathogenic variant on molecular testing. Germline testing for RET pathogenic variants was negative. Prior to referral, the patient was on octreotide to control diarrhea and vandetanib for a few months, but they were discontinued due to financial stress. At our center, patient complained of 4-6 watery bowel movements daily. Physical examination revealed facial plethora, dorsocervical fat pad, central adiposity, wide purple striae, and pustular acne on the chest wall and proximal muscle weakness.Biochemical testing revealed elevated serum calcitonin (158,535 pg/mL, normal: <14.3), carcinoembryonic antigen (3,634 ng/mL, normal: 0.8–6.2), and chromogranin-A (5504 ng/mL, normal<93) levels. Morning serum cortisol (40.4 mcg/dL, normal: 3.7–19.4), and plasma ACTH (116.0 pg/mL, normal: 5.0-46.0) levels were elevated, along with markedly elevated 24-hour urine free cortisol levels (12,460.8 mcg/24-hour, normal: 35-45.0), consistent with ACTH-dependent Cushing's syndrome. Further IHC testing of the tumor biopsy sample revealed mild ACTH positivity. A pituitary MRI was normal. Stool osmolality studies showed a secretory diarrhea pattern. Computed tomography (CT) of neck and torso demonstrated bulky cervical, retroperitoneal, and inguinal lymphadenopathy, and extensive liver metastasis, all of which were strongly avid on an 18-fluorodeoxyglucose positron emission tomography CT scan, but poorly avid on a gallium-68 DOTATATE scan. Sodium fluoride bone scan revealed multiple osseous metastases in the spine, ribs, pelvis, and in the right femoral shaft. An adrenal CT scan revealed bilateral adrenal hyperplasia.The patient was unfortunately not eligible for any ongoing local clinical trials on RET-mutated cancer therapies. After extensive discussion with the patient, a palliative approach was pursued. The cervical lymphadenopathy and right femoral shaft metastasis were treated with external beam radiation. Diarrhea was controlled with loperamide. Cushing's syndrome was initially managed with metyrapone and ketoconazole, followed by bilateral adrenalectomy and hydrocortisone and fludrocortisone replacement.ConclusionSporadic metastatic MTC can rarely present without an intrathyroidal primary tumor and may originate from ectopic C-cells. Paraneoplastic syndromes such as Cushing's syndrome can be observed in MTC due to ectopic-ACTH production.Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

The present study demonstrates a clear inverse correlation between age and the severity of acute hydrops, as well as the likelihood of developing neovascularisation after its resolution.This correlation could be...