Role and Relevance of Cerebrospinal Fluid Cells in Diagnostics and Research: State-of-the-Art and Underutilized Opportunities

Cerebrospinal fluid (CSF) has recently experienced a revival in diagnostics and research. However, little progress has been made regarding CSF cell analysis. For almost a century, CSF cell count and cytomorphological examination have been central diagnostic parameters, with CSF pleocytosis as a hallmark finding of neuroinflammation and cytology offering valuable clues regarding infectious, autoimmune, and malignant aetiologies. A great deal of information, however, remains unattended as modern immune phenotyping technologies have not yet been broadly incorporated into routine CSF analysis. This is a serious deficit considering the central role of CSF cells as effectors in central nervous system (CNS) immune defence and autoimmune CNS processes, and the diagnostic challenges posed by clinically overlapping infectious and immune-mediated CNS diseases. Here, we summarize historical, specimen-intrinsic, methodological, and technical issues determining the state-of-the-art diagnostics of CSF cells and outline future perspectives for this underutilized window into meningeal and CNS immunity.

Evaluation of an Algorithm for the Diagnosis and Therapy of Lyme Neuroborreliosis: A Follow-up Study

Background: Although Lyme Neuroborreliosis (LNB) is often seen in paediatric practice, diagnostic criteria for LNB in children are not clearly defined. The guidelines for LNB in adults are based on a combination of clinical picture, CSF pleocytosis and the detection of specific antibodies against Borrelia burgdorferi in CSF and serum. Diagnostic procedure takes several days, thus it isn´t useful in deciding for the need of prompt antibiotic treatment. Aim of study was a retrospective evaluation of an algorithm for the diagnosis and therapy of lyme’s disease, which is used since 2005 at the paediatric department of Innsbruck. Patients and Methods: All patients presenting with acute peripheral facial palsy from January 2006 to December 2014 were reviewed. The patients were diagnosed according to the algorithm, based on the criteria of the German Society of Neurology. The focus lay on evaluation of diagnosis and therapy according to the algorithm and whether overtreatment and underdiagnosis could therefore be avoided. Results: 120 patients were enrolled with peripheral facial palsy. 65 (54%) were handled as bell´s palsy and 55 (46 %) as B. burgdorferi s.l. infection. 19 cases were classified as confirmed LNB, 10 as probable and 26 as possible LNB. A total of 69 patients (58 %) were treated correctly according to the algorithm, 16 (13%) were over treated and 14 (11%) under treated with antibiotics. 21 (18%) could not be classified, according to the algorithm, due to the lack of CSF results. Although receiving proper treatment, 3 cases had a persistent defect after recovery. Conclusions: The algorithm is an appropriate diagnostic tool for the diagnosis and therapy of LNB, particularly with regard to the necessity of a prompt antibiotic treatment, and therefore helpful to avoid underdiagnosis and overtreatment.

Subacute Cognitive Impairment in Individuals With Mild and Moderate COVID-19: A Case Series

Background: Previous reported neurologic sequelae associated with SARS-CoV-2 infection have mainly been confined to hospital-based patients in which viral detection was restricted to nasal/throat swabs or to IgM/IgG peripheral blood serology. Here we describe seven cases from Brazil of outpatients with previous mild or moderate COVID-19 who developed subacute cognitive disturbances.Methods: From June 1 to August 15, 2020, seven individuals 18 to 60 years old, with confirmed mild/moderate COVID-19 and findings consistent with encephalopathy who were observed >7 days after respiratory symptom initiation, were screened for cognitive dysfunction. Paired sera and CSF were tested for SARS-CoV-2 (IgA, IgG ELISA, and RT-PCR). Serum and intrathecal antibody dynamics were evaluated with oligoclonal bands and IgG index. Cognitive dysfunction was assessed by the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and the Clock Drawing Test (CDT).Results: All but one of our patients were female, and the mean age was 42.6 years. Neurologic symptoms were first reported a median of 16 days (IQR 15–33) after initial COVID-19 symptoms. All patients had headache and altered behavior. Cognitive dysfunction was observed mainly in phonemic verbal fluency (MoCA) with a median of six words/min (IQR 5.25–10.75) and altered visuospatial construction with a median of four points (IQR 4–9) (CDT). CSF pleocytosis was not detected, and only one patient was positive for SARS-CoConclusions: A subacute cognitive syndrome suggestive of SARS-CoV-2-initiated damage to cortico-subcortical associative pathways that could not be attributed solely to inflammation and hypoxia was present in seven individuals with mild/moderate COVID-19.

Autoimmune Encephalitis Resembling Dementia Syndromes

ObjectiveAs autoimmune encephalitis (AIE) can resemble neurodegenerative dementia syndromes, and patients do not always present as encephalitis, this study evaluates how frequently AIE mimics dementia and provides red flags for AIE in middle-aged and older patients.MethodsIn this nationwide observational cohort study, patients with anti–leucine-rich glioma-inactivated 1 (LGI1), anti–NMDA receptor (NMDAR), anti–gamma-aminobutyric acid B receptor (GABABR), or anti–contactin-associated protein-like 2 (CASPR2) encephalitis were included. They had to meet 3 additional criteria: age ≥45 years, fulfillment of dementia criteria, and no prominent seizures early in the disease course (≤4 weeks).ResultsTwo-hundred ninety patients had AIE, of whom 175 were 45 years or older. Sixty-seven patients (38%) fulfilled criteria for dementia without prominent seizures early in the disease course. Of them, 42 had anti-LGI1 (48%), 13 anti-NMDAR (52%), 8 anti-GABABR (22%), and 4 anti-CASPR2 (15%) encephalitis. Rapidly progressive cognitive deterioration was seen in 48 patients (76%), whereas a neurodegenerative dementia syndrome was suspected in half (n = 33). In 17 patients (27%; 16/17 anti-LGI1), subtle seizures had been overlooked. Sixteen patients (25%) had neither inflammatory changes on brain MRI nor CSF pleocytosis. At least 1 CSF biomarker, often requested when dementia was suspected, was abnormal in 27 of 44 tested patients (61%), whereas 8 had positive 14-3-3 results (19%). Most patients (84%) improved after immunotherapy.ConclusionsRed flags for AIE in patients with suspected dementia are: (1) rapidly progressive cognitive decline, (2) subtle seizures, and (3) abnormalities in ancillary testing atypical for neurodegeneration. Physicians should be aware that inflammatory changes are not always present in AIE, and that biomarkers often requested when dementia was suspected (including 14-3-3) can show abnormal results. Diagnosis is essential as most patients profit from immunotherapy.

Cognitive impairment in syphilis: Does treatment based on cerebrospinal fluid analysis improve outcome?

Background Individuals with previous syphilis may experience cognitive impairment. The goal of this study was to determine if those at high risk for laboratory-defined neurosyphilis are cognitively impaired, and whether treatment based on cerebrospinal fluid (CSF) findings results in better outcomes. Methods Participants had a new syphilis diagnosis, serum RPR titer ≥ 1:32 or peripheral blood CD4+ T cells ≤ 350/ul (in persons living with HIV) and did not endorse neurological symptoms. They underwent computerized cognitive assessment with the CogState. Thirty-two were randomized to either undergo lumbar puncture (LP) or to not undergo LP and 14 underwent LP; 64 were not randomized and 48 opted to undergo LP. Results Demographics, cognitive complaints and cognitive impairment did not differ between randomized and nonrandomized participants. Two-thirds were cognitively impaired, and impairment was not more common in those with cognitive complaints. The adjusted odds of increased severity of impairment were 3.8 times greater in those with CSF pleocytosis compared to those without. Time to cognitive normalization, improvement or decline did not differ between those who did not undergo LP and those who underwent LP and whose treatment was based on CSF analysis. Taking into account pre-treatment cognitive impairment, the risk of cognitive decline was lower in those with CSF pleocytosis treated for neurosyphilis compared to those without CSF pleocytosis not treated for neurosyphilis, (HR 0.24 (95% CI 0.07–0.88], p = 0.03). Conclusion In individuals at high risk for laboratory-defined neurosyphilis, cognitive complaints are not a good indicator of cognitive impairment. Severity of cognitive impairment was greater in those with CSF pleocytosis. Identification and treatment of those with neurosyphilis may mitigate subsequent cognitive decline.

Cerebrospinal Fluid Findings in 541 Patients With Clinically Isolated Syndrome and Multiple Sclerosis: A Monocentric Study

BackgroundReports on typical routine cerebrospinal fluid (CSF) findings are outdated owing to novel reference limits (RL) and revised diagnostic criteria of Multiple Sclerosis (MS).ObjectiveTo assess routine CSF parameters in MS patients and the frequency of pathologic findings by applying novel RL.MethodsCSF white blood cells (WBC), CSF total protein (CSF-TP), CSF/serum albumin quotient (Qalb), intrathecal synthesis of immunoglobulins (Ig) A, M and G, oligoclonal IgG bands (OCB) were determined in patients with clinically isolated syndrome (CIS) and MS.ResultsOf 541 patients 54% showed CSF pleocytosis with a WBC count up to 40/μl. CSF cytology revealed lymphocytes, monocytes and neutrophils in 99%, 41% and 9% of patients. CSF-TP and Qalb were increased in 19% and 7% applying age-corrected RL as opposed to 34% and 26% with conventional RL. Quantitative intrathecal IgG, IgA and IgM synthesis were present in 65%, 14% and 21%; OCB in 95% of patients. WBC were higher in relapsing than progressive MS and predicted, together with monocytes, the conversion from CIS to clinically definite MS. Intrathecal IgG fraction was highest in secondary progressive MS.ConclusionsCSF profile in MS varies across disease courses. Blood-CSF-barrier dysfunction and intrathecal IgA/IgM synthesis are less frequent when the novel RL are applied.

Clinical, Neuroimmunologic, and CSF Investigations in First Episode Psychosis

Objectives:To report the neuropsychiatric features and frequency of N-methyl-d-aspartate receptor (NMDAR) and other neuronal IgG antibodies in patients with first episode psychosis (FEP), and assess the performance of reported warning signs and criteria for autoimmune psychosis (AP).Methods:Prospective observational study of patients with FEP assessed for neuropsychiatric symptoms, serum and CSF neuronal antibodies (brain immunohistochemistry, cell-based assays, live neurons), and warning signs and criteria of AP. Previous autoimmune FEP series were reviewed.Findings:105 patients were included; median age 30 years (range 14-75), 44 (42%) female. None had neuronal antibodies. Two/105 (2%) had CSF pleocytosis, 4/100 (4%) brain MRI abnormalities, and 3/73 (4%) EEG alterations. Thirty-four (32%) and 39 (37%) patients fulfilled two sets of warning signs of AP, and 21 (20%) fulfilled criteria of possible or probable AP, yet none developed AP. The cause of FEP was psychiatric in 101 (96%) and non-psychiatric in 4 (4%). During this study, 3 patients with psychosis caused by anti-NMDAR encephalitis were transferred to our center; 2 did not meet criteria for possible AP. Of 1159 reported FEP patients, only 7 (1%) had CSF studies; 36 (3%) had serum NMDAR-antibodies (without definite diagnosis of AP), and 4 had CSF NMDAR-antibodies (3 classic anti-NMDAR encephalitis and 1 with isolated psychiatric features).Conclusions:NMDAR-antibodies were not found in patients with FEP unless they had anti-NMDAR encephalitis. Warning signs and criteria for AP have limited utility when neurological symptoms are absent or paraclinical tests are normal. A diagnostic algorithm for autoimmune FEP is provided.

The consequences of the edge-effect in a commercial enzyme-linked immunosorbent assay (ELISA) for the diagnosis of Lyme neuroborreliosis

The diagnosis of Lyme neuroborreliosis (LNB) is based on neurological symptoms, cerebrospinal fluid (CSF) pleocytosis, and intrathecally produced Borrelia-specific antibodies. In most cases, the presence of intrathecally produced Borrelia-specific antibodies is determined by using an enzyme-linked immunosorbent assay (ELISA). The edge-effect is a known phenomenon in ELISAs and can negatively influence the assay reproducibility, repeatability, as well as index calculations of sample pairs which are tested in the same run.

Eastern Equine Encephalitis: Case Series in Southern New England and Review of the Literature

ABSTRACTPurposeof review: To describe the clinical presentation, diagnosis, management and outcomes of four confirmed Eastern Equine Encephalitis (EEE) cases and a review of the literatureRecent findings:There was a sharp rise in the number of EEE cases in the US in 2019, with 38 confirmed cases and 15 deaths. Our institution cared for 10% of patients with neuro-invasive EEE nationwide. These were the first cases seen locally since 2010.Summary:EEE virus causes one of the most lethal types of arboviral encephalitis in the US with a mortality of 30-40%. Manifestations of EEE infections can range from mild encephalopathy to coma. Common findings include CSF pleocytosis and involvement of the basal ganglia on MRI. Given the rarity of this disease and nonspecific findings, diagnosis can be challenging and a high clinical suspicion is important. Management is mainly supportive and the use of IVIg remains controversial. Two of our four patients died; these patients had coma within 48 hours, hyponatremia, involvement of bilateral thalami and brainstem, status epilepticus, and severe brain dysfunction in EEG.

Multicystic Encephalomalacia: The Neuropathology of Systemic Neonatal Parechovirus Infection

The Neuropathology of Human Parechovirus (HPeV) is not widely described due to the relatively recent discovery of the virus combined with a limited number of autopsy case reports. We report the case of an infant boy born at 38 weeks who, six days after birth, presented with fever and severe neurological dysfunction. Human Parechovirus Type 3 (HPeV3) RNA was detected in his cerebrospinal fluid (CSF) and blood. He died five days after his initial presentation. Neuropathologic examination demonstrated multicystic encephalomalacia (ME). This case report confirms that white matter pathology is dominant in HPeV3 infection. A unique feature, of HPeV encephalomalacia is absence of CSF pleocytosis and minimal inflammation in the meninges. The findings permit comment on the pathogenesis of brain injury by this virus.