Cranial nerve involvement, visual complications and headache syndromes in Lyme disease.

PURPOSE OF REVIEW: To provide a summary of the visual manifestations and cranial neuropathies seen in Lyme disease. RECENT FINDINGS: Lyme facial palsy remains the most common manifestation of Lyme neuroborreliosis. Recent investigations show likely evidence of vagal involvement in Lyme disease. SUMMARY: The literature on Lyme neuroborreliosis continues to evolve. Lyme disease can affect nearly any cranial nerve in addition to causing various headache syndromes. The most common manifestation is Lyme disease facial palsy, occurring in up to 5-10% of patients with documented Lyme disease. Headache syndromes are common in the context of facial palsy but can occur in isolation, and more specific headache syndromes including trigeminal and geniculate neuralgias can occur rarely. Signs and symptoms indicative of vestibulocochlear nerve involvement are relatively common, although it could be that these represent other vestibular involvement rather than a specific cranial neuropathy. Optic neuritis is a controversial entity within Lyme disease and is likely overdiagnosed, but convincing cases do exist. Physicians who see any cranial neuropathy, including optic neuritis, in an endemic area can consider Lyme disease as a possible cause.

Epithelial sheath neuroma: A case report and literature review.

In this paper we report a case of the rare entity epithelial sheath neuroma (ESN). A 66-year-old white female presented with a 1-month history of pruritic, raised, erythematous skin lesion on her upper back. The clinical impression initially led to a differential diagnosis that included lymphoma or inflamed sebaceous cyst. The patient had past medical history significant for squamous cell carcinoma of skin of the left calf status post Mohs surgery 9 years prior to presentation and inflamed seborrheic keratosis of the shoulder 3 years prior to presentation. She had no history of surgery or trauma at the area of concern for this presentation. A punch biopsy obtained to characterize the lesion showed dermal fibrosis and proliferation of nerves throughout the dermis without significant atypia, consistent with the diagnosis of ESN. The histologic differential diagnosis of ESN is presented here, and we discuss its most likely pathogenesis. This diagnosis is important for the clinician to keep in mind as excision appears to be curative, and it can easily be mistaken for many other entities.

Impaired Arm Function and Finger Dexterity in a Nonhuman Primate Model of Stroke: Motor and Cognitive Assessments.

BACKGROUND AND PURPOSE: Ischemic stroke is the leading cause of upper extremity motor impairments. Although several well-characterized experimental stroke models exist, modeling of upper extremity motor impairments, which are unique to primates, is not well established. Cortical representation of dexterous movements in nonhuman primates is functionally and topographically similar to that in humans. In this study, we characterize the African green monkey model of focal ischemia reperfusion with a defined syndrome, impaired dexterous movements. METHODS: Cerebral ischemia was induced by transient occlusion of the M3 segment of the left middle cerebral artery. Motor and cognitive functions after stroke were evaluated using the object retrieval task with barrier-detour. Postmortem magnetic resonance imaging and histopathology were performed to map and characterize the infarct. RESULTS: The middle cerebral artery occlusion consistently produced a necrotic infarct localized in the sensorimotor cortex in the middle cerebral artery territory. The infarction was reproducible and resulted in significant loss of fine motor function characterized by impaired dexterity. No significant cognitive impairment was detected. Magnetic resonance imaging and histopathology demonstrated consistent and significant loss of tissue on the left parietal cortex by the central sulcus covering the sensorimotor area. The results suggest that this species has less collateralization, which closely resembles humans. CONCLUSIONS: The reported nonhuman primate model produces a defined and reproducible syndrome relevant to our understanding of ischemic stroke, cortical representation, and sensorimotor integration controlling dexterous movements. This model will be useful in basic and translational research addressing loss of arm function and dexterity.

Comparison of fetal mesencephalic grafts, AAV-delivered GDNF, and both combined in an MPTP-induced nonhuman primate Parkinson's model.

We combined viral vector delivery of human glial-derived neurotrophic factor (GDNF) with the grafting of dopamine (DA) precursor cells from fetal ventral mesencephalon (VM) to determine whether these strategies would improve the anti-Parkinson's effects in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys, an animal model for Parkinson's disease (PD). Both strategies have been reported as individually beneficial in animal models of PD, leading to clinical studies. GDNF delivery has also been reported to augment VM tissue implants, but no combined studies have been done in monkeys. Monkeys were treated with MPTP and placed into four balanced treatment groups receiving only recombinant adeno-associated virus serotype 5 (rAAV5)/hu-GDNF, only fetal DA precursor cells, both together, or a buffered saline solution (control). The combination of fetal precursors with rAAV5/hu-GDNF showed significantly higher striatal DA concentrations compared with the other treatments, but did not lead to greater functional improvement in this study. For the first time under identical conditions in primates, we show that all three treatments lead to improvement compared with control animals.

Symmetric leukoencephalopathy associated with systemic lupus erythematosus: A systematic review of a distinctive neurorheumatologic syndrome.

BACKGROUND: A symmetric leukoencephalopathy can occur in the context of systemic lupus erythematosus (SLE), often as a first manifestation of underlying rheumatologic disease. Recognition of this distinctive syndrome can prompt investigation for SLE when undiagnosed, or prompt treatment initiation when the diagnosis is already known. Earlier recognition of this syndrome could lead to more effective treatment of the disease. METHODS: Clinical, laboratory, and radiographic features of three patients were described from an academic medical center in the United States with treatment dates between 2015 and 2022. A systematic review of literature from 1991 to 2023 yielded data for an additional 23 patients. RESULTS: Twenty-six total patients with symmetric leukoencephalopathy were included in this study. The median age of the patients was 37 years (range 10-69), 22 patients (85 %) were female, and 4 (15 %) were male. Fourteen of 26 patients (54 %) had this as the first clinical manifestation of SLE. Contrast enhancement was present on MRI brain in 3/26 (88 %) patients. Twenty patients (77 %) were treated with pulse-dose steroids, and all but one patient received some immunomodulatory therapy. Seven patients (27 %) progressed to death. No meaningful predictive differences were found between patients who survived and those who did not. CONCLUSIONS: In this case series and literature review patients developed symmetric leukoencephalopathy in systemic lupus erythematosus most often as the first clinical manifestation of SLE. Clinicians should consider this syndrome in any patient with acute onset of symmetric leukoencephalopathy on brain magnetic resonance imaging.

Case Report and Clinical Reasoning: Fulminant Liver Failure and Invasive Aspergillosis Following Ocrelizumab Treatment in a 21 Year-Old Woman.

We present the case of a 21 year-old woman with newly diagnosed relapsing-remitting multiple sclerosis who is given a single dose of ocrelizumab and placed on moderate-dose steroids with subsequent development of hepatic failure who goes on to develop highly fulminant systemic and central nervous system (CNS) aspergillosis. Ocrelizumab has no documented association with aspergillus infection, and moderate-dose steroids less often lead to such fulminant disease, but liver failure is associated with often-fatal aspergillus infection. We emphasize that liver failure is an underrecognized immune dysregulated state that predisposes to bacterial and fungal infections and suggest changes in diagnostic reasoning that could be considered in patients with multiple modalities of immunosuppression.

Characteristics of Progressive Multifocal Leukoencephalopathy Associated With Sarcoidosis Without Therapeutic Immune Suppression.

Importance: Progressive multifocal leukoencephalopathy can occur in the context of systemic sarcoidosis (S-PML) in the absence of therapeutic immune suppression and can initially be mistaken for neurosarcoidosis or other complications of sarcoidosis. Earlier recognition of S-PML could lead to more effective treatment of the disease. Objective: To describe characteristics of patients with S-PML. Design, Setting, and Participants: For this case series, records from 8 academic medical centers in the United States were reviewed from 2004 to 2022. A systematic review of literature from 1955 to 2022 yielded data for additional patients. Included were patients with S-PML who were not receiving therapeutic immune suppression. The median follow-up time for patients who survived the acute range of illness was 19 months (range, 2-99). Data were analyzed in February 2023. Exposures: Sarcoidosis without active therapeutic immune suppression. Main Outcomes and Measures: Clinical, laboratory, and radiographic features of patients with S-PML. Results: Twenty-one patients with S-PML not receiving therapeutic immune suppression were included in this study, and data for 37 patients were collected from literature review. The median age of the 21 study patients was 56 years (range, 33-72), 4 patients (19%) were female, and 17 (81%) were male. The median age of the literature review patients was 49 years (range, 21-74); 12 of 34 patients (33%) with reported sex were female, and 22 (67%) were male. Nine of 21 study patients (43%) and 18 of 31 literature review patients (58%) had simultaneous presentation of systemic sarcoidosis and PML. Six of 14 study patients (43%) and 11 of 19 literature review patients (58%) had a CD4+ T-cell count greater than 200/µL. In 2 study patients, a systemic flare of sarcoidosis closely preceded S-PML development. Ten of 17 study patients (59%) and 21 of 35 literature review patients (60%) died during the acute phase of illness. No meaningful predictive differences were found between patients who survived S-PML and those who did not. Conclusions and Relevance: In this case series, patients with sarcoidosis developed PML in the absence of therapeutic immune suppression, and peripheral blood proxies of immune function were often only mildly abnormal. Systemic sarcoidosis flares may rarely herald the onset of S-PML. Clinicians should consider PML in any patient with sarcoidosis and new white matter lesions on brain magnetic resonance imaging.

Neuroinfectious Disease Emergencies.

Neuroinfectious diseases can affect immunocompetent and immunosuppressed individuals and cause a variety of emergencies including meningitis, encephalitis, and abscess. Neurologic infections are frequently complicated by secondary injuries that also present emergently such as cerebrovascular disease, acute obstructive hydrocephalus, and seizure. In most cases, timely recognition and early treatment of infection can improve the morbidity and mortality of infectious neurologic emergencies.

Acute Disseminated Encephalomyelitis and Acute Hemorrhagic Leukoencephalitis Following COVID-19: Systematic Review and Meta-synthesis.

BACKGROUND AND OBJECTIVES: Since the onset of the COVID-19 pandemic, a growing number of reports have described cases of acute disseminated encephalomyelitis (ADEM) and acute hemorrhagic leukoencephalitis (AHLE) following infection with COVID-19. Given their relatively rare occurrence, the primary objective of this systematic review was to synthesize their clinical features, response to treatments, and clinical outcomes to better understand the nature of this neurologic consequence of COVID-19 infection. METHODS: Patients with a history of COVID-19 infection were included if their reports provided adequate detail to confirm a diagnosis of ADEM or AHLE by virtue of clinical features, radiographic abnormalities, and histopathologic findings. Cases purported to be secondary to vaccination against COVID-19 or occurring in the context of a preexisting relapsing CNS demyelinating disease were excluded. Case reports and series were identified via PubMed on May 17, 2021, and 4 additional cases from the authors' hospital files supplemented the systematic review of the literature. Summary statistics were used to describe variables using a complete case analysis approach. RESULTS: Forty-six patients (28 men, median age 49.5 years, 1/3 >50 years old) were analyzed, derived from 26 case reports or series originating from 8 countries alongside 4 patient cases from the authors' hospital files. COVID-19 infection was laboratory confirmed in 91% of cases, and infection severity necessitated intensive care in 67%. ADEM occurred in 31 cases, whereas AHLE occurred in 15, with a median presenting nadir modified Rankin Scale score of 5 (bedridden). Anti-MOG seropositivity was rare (1/15 patients tested). Noninflammatory CSF was present in 30%. Hemorrhage on brain MRI was identified in 42%. Seventy percent received immunomodulatory treatments, most commonly steroids, IV immunoglobulins, or plasmapheresis. The final mRS score was ≥4 in 64% of patients with adequate follow-up information, including 32% who died. DISCUSSION: In contrast to ADEM cases from the prepandemic era, reported post-COVID-19 ADEM and AHLE cases were often advanced in age at onset, experienced severe antecedent infection, displayed an unusually high rate of hemorrhage on neuroimaging, and routinely had poor neurologic outcomes, including a high mortality rate. Findings are limited by nonstandardized reporting of cases, truncated follow-up information, and presumed publication bias.

Acute Myelopathy: Vascular and Infectious Diseases.

Vascular and infectious causes are rare but important causes of spinal cord injury. High suspicion for these processes is necessary, as symptoms may progress over hours to days, resulting in delayed presentation and diagnosis and worse outcomes. History and clinical examination findings can assist with localization of the affected vascular territory and spinal level, which will assist with focusing spinal imaging. Open and/or endovascular surgical management depends on the associated vascular abnormality. Infectious myelopathy treatment consists of targeted antimicrobial therapy when possible, infectious source control, and again, close monitoring for systemic complications.

Central nervous system disease with JC virus infection in adults with congenital HIV.

OBJECTIVE: The aim of this study was to describe the natural history of individuals with congenital HIV who develop JC virus (JCV) infection of the central nervous system (CNS). METHODS: We retrospectively evaluated individuals with congenital HIV who met criteria for progressive multifocal leukoencephalopathy (PML) or JCV granule cell neuronopathy (JCV GCN) at three major healthcare centres in the northeast USA. Data on adherence to combined antiretroviral therapy (cART), neurologic symptoms, serum markers of immunity and HIV infection, cerebrospinal fluid (CSF) analyses, radiographic features, modified Rankin Scale (mRS) scores and survival were collected from the electronic medical record up to a censoring date of 1 August 2020. RESULTS: Among 10 adults with congenitally acquired HIV, nine were diagnosed with definitive PML and one was diagnosed with probable JCV GCN. Individuals presented at the time of their PML or JCV GCN diagnosis with a mean mRS of 2.0 (standard deviation 1.0). A premorbid mRS was documented for six patients and was zero in all cases. The most common risk factor was confirmed cART nonadherence in nine individuals. Five individuals with PML and one with JCV GCN died, with a latency from symptom onset to death of approximately 3 months for three individuals, and approximately 2 years for the remaining two. CONCLUSION: Youth-adulthood transition is a high-risk point for dropping off from medical care. The study of this timepoint in people living with HIV could help inform effective care in these individuals.

Neurologic Manifestations of the World Health Organization's List of Pandemic and Epidemic Diseases.

The World Health Organization (WHO) monitors the spread of diseases globally and maintains a list of diseases with epidemic or pandemic potential. Currently listed diseases include Chikungunya, cholera, Crimean-Congo hemorrhagic fever, Ebola virus disease, Hendra virus infection, influenza, Lassa fever, Marburg virus disease, Neisseria meningitis, MERS-CoV, monkeypox, Nipah virus infection, novel coronavirus (COVID-19), plague, Rift Valley fever, SARS, smallpox, tularemia, yellow fever, and Zika virus disease. The associated pathogens are increasingly important on the global stage. The majority of these diseases have neurological manifestations. Those with less frequent neurological manifestations may also have important consequences. This is highlighted now in particular through the ongoing COVID-19 pandemic and reinforces that pathogens with the potential to spread rapidly and widely, in spite of concerted global efforts, may affect the nervous system. We searched the scientific literature, dating from 1934 to August 2020, to compile data on the cause, epidemiology, clinical presentation, neuroimaging features, and treatment of each of the diseases of epidemic or pandemic potential as viewed through a neurologist's lens. We included articles with an abstract or full text in English in this topical and scoping review. Diseases with epidemic and pandemic potential can be spread directly from human to human, animal to human, via mosquitoes or other insects, or via environmental contamination. Manifestations include central neurologic conditions (meningitis, encephalitis, intraparenchymal hemorrhage, seizures), peripheral and cranial nerve syndromes (sensory neuropathy, sensorineural hearing loss, ophthalmoplegia), post-infectious syndromes (acute inflammatory polyneuropathy), and congenital syndromes (fetal microcephaly), among others. Some diseases have not been well-characterized from a neurological standpoint, but all have at least scattered case reports of neurological features. Some of the diseases have curative treatments available while in other cases, supportive care remains the only management option. Regardless of the pathogen, prompt, and aggressive measures to control the spread of these agents are the most important factors in lowering the overall morbidity and mortality they can cause.

Neural Stem Cells Derived from Human Parthenogenetic Stem Cells Engraft and Promote Recovery in a Nonhuman Primate Model of Parkinson's Disease.

Cell therapy has attracted considerable interest as a promising therapeutic alternative for patients with Parkinson's disease (PD). Clinical studies have shown that grafted fetal neural tissue can achieve considerable biochemical and clinical improvements in PD. However, the source of fetal tissue grafts is limited and ethically controversial. Human parthenogenetic stem cells offer a good alternative because they are derived from unfertilized oocytes without destroying potentially viable human embryos and can be used to generate an unlimited supply of neural cells for transplantation. We have previously reported that human parthenogenetic stem cell-derived neural stem cells (hpNSCs) successfully engraft, survive long term, and increase brain dopamine (DA) levels in rodent and nonhuman primate models of PD. Here we report the results of a 12-month transplantation study of hpNSCs in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned African green monkeys with moderate to severe clinical parkinsonian symptoms. The hpNSCs manufactured under current good manufacturing practice (cGMP) conditions were injected bilaterally into the striatum and substantia nigra of immunosuppressed monkeys. Transplantation of hpNSCs was safe and well tolerated by the animals with no dyskinesia, tumors, ectopic tissue formation, or other test article-related serious adverse events. We observed that hpNSCs promoted behavioral recovery; increased striatal DA concentration, fiber innervation, and number of dopaminergic neurons; and induced the expression of genes and pathways downregulated in PD compared to vehicle control animals. These results provide further evidence for the clinical translation of hpNSCs and support the approval of the world's first pluripotent stem cell-based phase I/IIa study for the treatment of PD (Clinical Trial Identifier NCT02452723).

Primate adult brain cell autotransplantation produces behavioral and biological recovery in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonian St. Kitts monkeys.

The potential for "replacement cells" to restore function in Parkinson's disease has been widely reported over the past 3 decades, rejuvenating the central nervous system rather than just relieving symptoms. Most such experiments have used fetal or embryonic sources that may induce immunological rejection and generate ethical concerns. Autologous sources, in which the cells to be implanted are derived from recipients' own cells after reprogramming to stem cells, direct genetic modifications, or epigenetic modifications in culture, could eliminate many of these problems. In a previous study on autologous brain cell transplantation, we demonstrated that adult monkey brain cells, obtained from cortical biopsies and kept in culture for 7 weeks, exhibited potential as a method of brain repair after low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) caused dopaminergic cell death. The present study exposed monkeys to higher MPTP doses to produce significant parkinsonism and behavioral impairments. Cerebral cortical cells were biopsied from the animals, held in culture for 7 weeks to create an autologous neural cell "ecosystem" and reimplanted bilaterally into the striatum of the same six donor monkeys. These cells expressed neuroectodermal and progenitor markers such as nestin, doublecortin, GFAP, neurofilament, and vimentin. Five to six months after reimplantation, histological analysis with the dye PKH67 and unbiased stereology showed that reimplanted cells survived, migrated bilaterally throughout the striatum, and seemed to exert a neurorestorative effect. More tyrosine hydroxylase-immunoreactive neurons and significant behavioral improvement followed reimplantation of cultured autologous neural cells as a result of unknown trophic factors released by the grafts.