Progressive leukoencephalopathy as a manifestation of primary angiitis of the central nervous system: case report and review of the literature.

BACKGROUND AND OBJECTIVE: Primary angiitis of the central nervous system (PACNS) is a rare form of vasculitis solely affecting the vessels of the brain, spinal cord, and leptomeninges. A range of magnetic resonance imaging (MRI) features have been associated with PACNS, including cerebral infarction, hemorrhage, and parenchymal or leptomeningeal contrast enhancement. METHODS AND RESULTS: We describe a 51-year-old man with a case of PACNS manifesting as akinetic mutism with progressive leukoencephalopathy. DISCUSSION: Progressive leukoencephalopathy has not been well defined as a manifestation of PACNS. We review a small number of cases with comparable features, providing additional context on this PACNS manifestation with consideration of clinical subtypes.

Intracranial Hypertension Associated With Poly-Cranio-Radicular-Neuropathies: A Case Report and Review of the Literature.

INTRODUCTION: We present the case of a gentleman who developed rapidly progressive vision loss, ophthalmo-paresis, and flaccid quadriparesis in the context of severe intracranial hypertension. We reviewed the available cases in the literature to increase awareness of this rare clinical entity.Case Report:A 36-year-old man developed rapidly progressive vision loss, ophthalmo-paresis, and flaccid quadriparesis. He had an extensive workup, only notable for severe intracranial hypertension, >55 cm of H 2 O. No inflammatory features were present, and the patient responded to CSF diversion. Few similar cases are available in the literature, but all show markedly elevated intracranial pressure associated with extensive neuroaxis dysfunction. Similarly, these patients improved with CSF diversion but did not appear to respond to immune-based therapies. CONCLUSIONS: We term this extensive neuroaxis dysfunction intracranial hypertension associated with poly-cranio-radicular-neuropathy (IHP) and distinguish it from similar immune-mediated clinical presentations. Clinicians should be aware of the different etiologies of this potentially devastating clinical presentation to inform appropriate and timely treatment.

Intrathecal methotrexate - Another tool for the treatment of refractory autoimmune encephalitis - Single institution cohort and literature review.

BACKGROUND: Autoimmune encephalitis (AIE) encompasses a range of inflammatory disorders manifesting with some combination of encephalopathy, seizures, behavioral changes, movement disorders, dysautonomia or other neurologic symptoms. Anti-N-methyl-d-aspartate receptor encephalitis (NMDARE) is the most common AIE and is an autoantibody mediated disorder, often paraneoplastic. Untreated or undertreated AIE has a high degree of morbidity and mortality. Immunosuppressive treatment regimens including glucocorticoids, plasma exchange (PLEX), intravenous immunoglobulin (IVIG) and rituximab used alone or in combination for such patients. Patients' refractory to such treatments requires more aggressive and potentially toxic therapies. We report favorable outcomes in patients with refractory AIE who received intrathecal methotrexate (IT-MTX) as part of treatment. METHODS: Cases at our institution seen between 2010 and 2020 were reviewed. We identified 5 patients in our clinical practice whose clinical presentation was compatible with NMDARE. Three patients met criteria for definite NMDARE. An additional two patients met criteria for probable NMDARE in the acute setting but were ultimately seronegative autoimmune encephalitis. All patients received at least one dose of IT-MTX after failing conventional therapies. At the time of IT-MTX administration patients were catatonic, comatose, or severely encephalopathic despite initial treatments. RESULTS: All patients were treated with methylprednisolone; 3 received a course of IVIG, 4 underwent PLEX, and 4 received rituximab. At the time IT-MTX was given, three patients required mechanical ventilation and 1 had a pacemaker placed for autonomic failure. Two patients were under consideration for transition to palliative care. All patients improved and were at or near their premorbid baseline at last follow-up. All patients tolerated IT-MTX well. CONCLUSIONS: This retrospective review demonstrates the efficacy of intrathecal methotrexate in the treatment of severe AIE who had failed other immunosuppressive regimens.

Expanded Clinical Phenotype, Oncological Associations, and Immunopathologic Insights of Paraneoplastic Kelch-like Protein-11 Encephalitis.

Importance: Recognizing the presenting and immunopathological features of Kelch-like protein-11 immunoglobulin G seropositive (KLHL11 IgG+) patients may aid in early diagnosis and management. Objective: To describe expanding neurologic phenotype, cancer associations, outcomes, and immunopathologic features of KLHL11 encephalitis. Design, Setting, and Participants: This retrospective tertiary care center study, conducted from October 15, 1998, to November 1, 2019, prospectively identified 31 KLHL11 IgG+ cases in the neuroimmunology laboratory. Eight were identified by retrospective testing of patients with rhomboencephalitis (confirmed by tissue-based-immunofluorescence and transfected-cell-based assays). Main Outcomes and Measures: Outcome variables included modified Rankin score and gait aid use. Results: All 39 KLHL11 IgG+ patients were men (median age, 46 years; range, 28-73 years). Initial clinical presentations were ataxia (n = 32; 82%), diplopia (n = 22; 56%), vertigo (n = 21; 54%), hearing loss (n = 15; 39%), tinnitus (n = 14; 36%), dysarthria (n = 11; 28%), and seizures (n = 9; 23%). Atypical neurologic presentations included neuropsychiatric dysfunction, myeloneuropathy, and cervical amyotrophy. Hearing loss or tinnitus preceded other neurologic deficits by 1 to 8 months in 10 patients (26%). Among patients screened for malignancy (n = 36), testicular germ-cell tumors (n = 23; 64%) or testicular microlithiasis and fibrosis concerning for regressed germ cell tumor (n = 7; 19%) were found in 83% of the patients (n = 30). In 2 patients, lymph node biopsy diagnosed metastatic lung adenocarcinoma in one and chronic lymphocytic leukemia in the other. Initial brain magnetic resonance imaging revealed T2 hyperintensities in the temporal lobe (n = 12), cerebellum (n = 9), brainstem (n = 3), or diencephalon (n = 3). Among KLHL11 IgG+ patients who underwent HLA class I and class II genotyping (n = 10), most were found to have HLA-DQB1*02:01 (n = 7; 70%) and HLA-DRB1*03:01 (n = 6; 60%) associations. A biopsied gadolinium-enhancing temporal lobe lesion demonstrated T cell-predominant inflammation and nonnecrotizing granulomas. Cerebellar biopsy (patient with chronic ataxia) and 2 autopsied brains demonstrated Purkinje neuronal loss and Bergmann gliosis, supporting early active inflammation and later extensive neuronal loss. Compared with nonautoimmune control peripheral blood mononuclear cells, cluster of differentiation (CD) 8+ and CD4+ T cells were significantly activated when patient peripheral blood mononuclear cells were cultured with KLHL11 protein. Most patients (58%) benefitted from immunotherapy and/or cancer treatment (neurological disability stabilized [n = 10] or improved [n = 9]). Kaplan-Meier curve demonstrated significantly higher probability of wheelchair dependence among patients without detectable testicular cancer. Long-term outcomes in KLHL11-IgG+ patients were similar to Ma2 encephalitis. Conclusions and Relevance: Kelch-like protein-11 IgG is a biomarker of testicular germ-cell tumor and paraneoplastic neurologic syndrome, often refractory to treatment. Described expanded neurologic phenotype and paraclinical findings may aid in its early diagnosis and treatment.

Avoiding anaesthetics after multiple failed drug-induced comas: an unorthodox approach to management of new-onset refractory status epilepticus (NORSE).

New-onset refractory status epilepticus (NORSE) is a rare, poorly understood and often catastrophic condition. There is little guidance available for management. Here, we describe the course of a 19-year-old man with NORSE who was treated successfully with a new approach. Our patient was initially treated with first-, second- and third-line agents including a total of seven failed drug-induced coma courses until the 30th day of hospitalization. When withdrawal of care was contemplated, management was then assumed by dedicated epileptologists and treatment course was changed. An unorthodox decision was made to avoid IV anaesthetics unless there were generalized bisynchronous tonic-clonic or generalized non-convulsive (electrographic) seizures. This approach allowed real-time assessment of treatment response to aggressive non-sedating AED therapy while the multifocal convulsive and non-convulsive seizures were ongoing. It also eliminated potentially fatal IV anaesthetic-induced complications and prevented anaesthetic withdrawal seizures. This was effective in achieving full recovery in our patient. The patient's awakening also changed the perspective of family members and care providers, avoiding premature withdrawal of care, which is often the cause of death in similar patients.

The application of (Z)-3-aryl-3-haloenoic acids to the synthesis of (Z)-5-benzylidene-4-arylpyrrol-2(5H)-ones.

Studies directed at the synthesis of (Z)-5-benzylidene-4-arylpyrrol-2(5H)-ones from (Z)-3-aryl-3-haloenoic acids are described. The successful strategy relies on the preparation of (Z)-3-aryl-3-haloenoic acids from acetophenones through the corresponding (Z)-3-aryl-3-haloenals and the conversion of the (Z)-3-aryl-3-haloenoic acids to (Z)-5-benzylidene-4-aryl-5H-furan-2-ones. The furanones were subsequently treated with primary amines and dehydrated to the corresponding (Z)-5-benzylidene-4-arylpyrrol-2(5H)-ones.

Further studies on vinamidinium salt amine exchange reactions, borohydride reductions and subsequent transformations.

Studies directed at the amine exchange reaction of vinamidinium salts followed by sodium borohydride reduction to secondary and tertiary allylic amines are described. The tertiary allylic amines were alkylated and subjected to base mediated rearrangement to yield a variety of highly functionalized tertiary homoallylic amines.

The application of vinylogous iminium salt derivatives to efficient formal syntheses of the marine akaloids lamellarin G trimethyl ether and ningalin B.

Studies directed at the synthesis of lamellarin G trimethyl ether and ningalin B via vinylogous iminium salt derivatives are described. The successful strategy relies on the formation of a 2,4-disubstituted pyrrole or a 1,2,3,4-tetrasubstituted pyrrole from a vinylogous iminium salt or vinylogous iminium salt derivative. Subsequent transformations of these highly substituted pyrroles lead to efficient and regiocontrolled formal syntheses of the respective pyrrole containing natural products.