Cerebrospinal Fluid Lymphocytosis Research Articles

Nucleotide metabolism, leukodystrophies, and CNS pathology.

The balance between a protective and a destructive immune response can be precarious, as exemplified by inborn errors in nucleotide metabolism. This class of inherited disorders, which mimics infection, can result in systemic injury and severe neurologic outcomes. The most common of these disorders is Aicardi Goutières syndrome (AGS). AGS results in a phenotype similar to "TORCH" infections (Toxoplasma gondii, Other [Zika virus (ZIKV), human immunodeficiency virus (HIV)], Rubella virus, human Cytomegalovirus [HCMV], and Herpesviruses), but with sustained inflammation and ongoing potential for complications. AGS was first described in the early 1980s as familial clusters of "TORCH" infections, with severe neurology impairment, microcephaly, and basal ganglia calcifications (Aicardi & Goutières, Ann Neurol, 1984;15:49-54) and was associated with chronic cerebrospinal fluid (CSF) lymphocytosis and elevated type I interferon levels (Goutières et al., Ann Neurol, 1998;44:900-907). Since its first description, the clinical spectrum of AGS has dramatically expanded from the initial cohorts of children with severe impairment to including individuals with average intelligence and mild spastic paraparesis. This broad spectrum of potential clinical manifestations can result in a delayed diagnosis, which families cite as a major stressor. Additionally, a timely diagnosis is increasingly critical with emerging therapies targeting the interferon signaling pathway. Despite the many gains in understanding about AGS, there are still many gaps in our understanding of the cell-type drivers of pathology and characterization of modifying variables that influence clinical outcomes and achievement of timely diagnosis.

Transient Headache and Neurological Deficits with cerebrospinal fluid Lymphocytosis (HaNDL) following COVID-19.

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Neurologic Deficits and cerebrospinal fluid (CSF) lymphocytosis (HaNDL): a comprehensive systematic review of 93 patients from 57 studies (P3-12.003)

<h3>Objective:</h3> N/A <h3>Background:</h3> Headache with Neurologic Deficits and cerebrospinal fluid (CSF) lymphocytosis (HaNDL) is a self-limiting syndrome characterized by moderate to severe headache associated with focal neurological deficits such as, motor or sensory deficits, or speech disturbances, occurring in the context of lymphocytosis in the cerebrospinal fluid. Due to being a rare condition, data regarding HaNDL is sparse. Therefore, we conducted this review to analyze data related to 93 patients of HaNDL, to characterize their demographics, wide range of presenting symptoms, treatment options in the acute and chronic phases, EEG, brain imaging and CSF findings. <h3>Design/Methods:</h3> We performed a systematic review of cases reported through PubMed and Google scholar database, using Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol. <h3>Results:</h3> The mean age was 28.8 years at onset. 70 patients (75.2%) were adults, while 23 (24.7%) were pediatrics. 30% of patients experienced relapsing episodes of HaNDL symptoms. The most common type of headache reported was unilateral severe throbbing episodic headache. Other associated symptoms included sensory deficit (60%) and motor deficits (54.8%). The least common symptoms were nystagmus and agraphia. Antiviral agents were a common treatment option in the acute phase [n=23 patients (23.6%)], while Flunarizine was the most commonly used agent in the chronic setting [n= 3 patients (3.2%)]. The most common brain MRI findings included nonspecific white matter lesions and meningeal enhancement, whereas the most common EEG findings include diffuse and focal slowing. The mean CSF opening pressure was 240.5 mmH2O. CSF protein was elevated in 59 patients , with a mean value of 114mg/dL. <h3>Conclusions:</h3> HaNDL tends to affect young individuals with a slight male predominance. Unilateral severe throbbing episodic headache with associated hemi-paresthesia and hemiparesis were the most common presenting symptoms based on our review. Early recognition of this syndrome is critical in order to prevent unnecessary treatments such as, antimicrobials. <b>Disclosure:</b> Mr. Asghar has nothing to disclose. Mr. Asghar has nothing to disclose. Mr. Hegde has nothing to disclose. Mr. Delcimmuto has nothing to disclose. Dr. Gharaibeh has nothing to disclose. Dr. Aladamat has nothing to disclose. Dr. Esengul has nothing to disclose. Mohammad Mahmoud Samara, MD has nothing to disclose. Dr. Sheikh has nothing to disclose.

Syndrome of Transient Headache and Neurologic Deficits with Cerebrospinal Fluid Lymphocytosis (HaNDL): HHV-7 Finding in Cerebrospinal Fluid Challenges Diagnostic Criteria

The syndrome of transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis (HaNDL) is a rare, self-limiting condition with severe headaches combined with neurological symptoms. However, evidence-based recommendations on diagnostics and treatments are unavailable due to the condition's rarity and unknown pathophysiology. A young man experiencing severe headache attacks fulfilled the HaNDL diagnostic criteria according to the third edition of the International Classification of Headache Disorders (ICHD-3). We present the dynamics of cerebrospinal fluid (CSF) biomarkers related to low human herpesvirus 7 (HHV-7) load and anti-inflammatory treatment outcomes. Low HHV-7 load may be an immunological trigger of HaNDL, such that elevated levels of CSF- chemokine (C-X-C motif) ligand 13 open a new way to interpret the role of B cells in HaNDL pathogenesis. We discuss the diagnostic challenge of HaNDL, according to the ICHD-3, in the case of pathogen presence at low load in CSF.

Transient headache and neurological deficits with cerebrospinal fluid lymphocytosis syndrome: A comprehensive systematic review of 93 patients from 57 studies.

Headache with neurologic deficits and cerebrospinal fluid lymphocytosis, previously also termed pseudomigraine with temporary neurologic symptoms and lymphocytic pleocytosis, is a self-limiting syndrome characterized by moderate to severe headache associated with focal neurological deficits occurring in the context of lymphocytosis in the cerebrospinal fluid. As a consequence of its rarity, data regarding headache with neurologic deficits and cerebrospinal fluid lymphocytosis is sparse. Therefore, we conducted this review to analyze data related to 93 patients of headache with neurologic deficits and cerebrospinal fluid lymphocytosis, to characterize their demographics, clinical manifestations, investigations and treatment options. We performed a systematic review of cases reported through PubMed and Google scholar database, using Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol. Keywords used were 'Headache with Neurologic Deficits and cerebrospinal fluid lymphocytosis', 'Headache with neurologic deficits and cerebrospinal fluid lymphocytosis syndrome'. The quality of the included studies was assessed using the Joanna Briggs Institute Critical Appraisal Tool. We analyzed a total of 93 cases of headache with neurologic deficits and cerebrospinal fluid lymphocytosis with a mean age of 28.8 years at onset. Seventy patients (75.2%) were adults, while 23 (24.7%) belonged to the pediatric age group. Comparing these groups, mean age at onset was 32.5 years and 14.3 years, respectively. The average duration of follow-up was 11.08 months. Thirty percent of patients experienced relapsing episodes of headache with neurologic deficits and cerebrospinal fluid lymphocytosis symptoms. The most common type of headache reported was unilateral severe throbbing episodic headache. Other associated symptoms included sensory deficit (60%) and motor deficits (54.8%). The least common symptoms were nystagmus and agraphia, which were reported in one patient each. Antiviral agents were a common treatment option in the acute phase (n = 23 patients [23.6%]), while Flunarizine was the most commonly used agent in the chronic setting (n = 3 patients [3.2%]). While most of the patients had normal brain magnetic resonance imaging, 20 patients had magnetic resonance imaging abnormalities, including (but not limited to) non-specific white matter lesions (eight patients) and meningeal enhancement (six patients). The most common electroencephalographic findings included diffuse and focal slowing. The mean cerebrospinal fluid opening-pressure was 240.5 mmH2O. Cerebrospinal fluid protein was elevated in 59 (63.4%) patients, with a mean value of 114 mg/dL. Two patients in our cohort were found to have cerebrospinal fluid oligoclonal bands. Headache with neurologic deficits and cerebrospinal fluid lymphocytosis tends to affect young individuals with a slight male predominance. Unilateral severe throbbing episodic headache with associated hemi-paresthesia and hemiparesis were the most common symptoms based on our review. Elevated cerebrospinal fluid opening-pressure can be seen in headache with neurologic deficits and cerebrospinal fluid lymphocytosis syndrome. Early recognition of the syndrome is paramount. Antivirals were found to be among the most widely used treatments in the acute setting. Magnetic resonance imaging of the brain is mostly normal. Diffuse and focal slowing were among the most common electroencephalographic findings. Cerebral flow abnormalities on perfusion scans are not uncommon in headache with neurologic deficits and cerebrospinal fluid lymphocytosis. Prospective studies with a larger sample size are needed to validate our findings and guide the clinical care of these patients.

Syndrome of Transient Headache and Neurological Deficits with Cerebrospinal Fluid Lymphocytosis (HaNDL): A Case Report - Is there an Association with the COVID-19 Vaccine?

Syndrome of Transient Headache and Neurological Deficits with Cerebrospinal Fluid Lymphocytosis (HaNDL): A Case Report - Is there an Association with the COVID-19 Vaccine?

Aicardi-Goutières syndrome with SAMHD1 deficiency can be diagnosed by unscheduled DNA synthesis test.

Aicardi-Goutières syndrome (AGS) is a rare genetic disorder characterised by progressive encephalopathy, involving microcephaly, intracranial calcification, and cerebrospinal fluid lymphocytosis with increased interferon-α concentrations. The clinical features of AGS overlap with fetal cerebral anomalies caused by congenital infections, such as TORCH (toxoplasmosis, other, rubella, cytomegalovirus, and herpes), or with those of other genetic disorders showing neonatal microcephaly, including Cockayne syndrome (CS) with transcription-coupled DNA repair deficiency, and Seckel syndrome (SS) showing aberrant cell-cycle checkpoint signaling. Therefore, a differential diagnosis to confirm the genetic cause or a proof of infection should be considered. In this report, we describe an individual who showed primordial dwarfism and encephalopathy, and whose initial diagnosis was CS. First, we conducted conventional DNA repair proficiency tests for the patient derived fibroblast cells. Transcription-coupled nucleotide excision repair (TC-NER) activity, which is mostly compromised in CS cases, was slightly reduced in the patient's cells. However, unscheduled DNA synthesis (UDS) was significantly diminished. These cellular traits were inconsistent with the diagnosis of CS. We further performed whole exome sequencing for the case and identified a compound heterozygous loss-of-function variants in the SAMHD1 gene, mutations in which are known to cause AGS. As SAMHD1 encodes deoxyribonucleoside triphosphate triphosphohydrolase, we reasoned that the deoxyribonucleoside triphosphate (dNTP) pool size in the patient's cells was elevated, and the labeling efficiency of UDS-test was hindered due to the reduced concentration of phosphorylated ethynyl deoxyuridine (EdU), a nucleoside analogue used for the assay. In conclusion, UDS assay may be a useful diagnostic tool to distinguish between AGS with SAMHD1 mutations and other related diseases.

Case series of HaNDL syndrome responding to valproic acid

Objective: We report a case series of patients diagnosed with the syndrome of transient headache and neurological deficits with cerebrospinal fluid lymphocytosis (HaNDL) responding to high dose Valproic acid. Background: HaNDL syndrome is an infrequent entity, presenting with neurological impairment episodes and severe headache. A treatment to prevent the attacks has not been proposed yet. Results: We describe 6 patients with a definite diagnosis of HaNDL, responding to Valproic acid 1000–1500 mg/day. Conclusion: Although HaNDL’s self-limiting nature, episodes may cause important disability and can last up to 3 months. Valproic acid may be a good choice to prevent attacks due to its effect on cortical depression and fast titration.

La sindrome “Cefalea e deficit neurologici transitori con linfocitosi liquorale”: un’altra encefalopatia autoimmune?

Headache and neurologic deficits with cerebrospinal fluid lymphocytosis syndrome (HaNDL) is a rare nosographic entity, which mainly affects adults but can also occur in the paediatric age. In the literature, 31 cases in this age group are described. Symptomatology typically lasts about three months with episodes that tend to relapse. An autoimmune pathogenesis has been hypothesized. The paper describes the case of an adolescent who presented with three acute and transient episodes of migraine headache in three days associated with impaired consciousness, focal neurological deficits and CSF lymphocytosis. After treatment with steroidal and non-steroidal anti-inflammatory drugs, the patient did not relapse in the following four months. The treatment indicated in the literature is only supportive (analgesics, antiemetics), however in this case the anti-inflammatory therapy reduced the duration of the episode and the recurrence of further episodes.

A case report on Syndrome of transient Headache and Neurological Deficits with cerebrospinal fluid Lymphocytosis (HaNDL)

HaNDL syndrome (transient headache and neurological deficits with cerebrospinal fluid lymphocytosis) is a rare headache disorder previously known as Migraine with cerebrospinal fluid pleocytosis. The disease is characterized by one or more episodes of headache and transient neurological deficits associated with cerebrospinal fluid lymphocytosis. It is a benign disorder and a stroke mimicker. We describe a case of 50 years old lady presented with acute onset headache, right hemi sensory tingling and bilateral papilloedema. Her blood test, MRI of brain and MRV was normal. CSF study revealed lymphocytic pleocytosis. The patient was discharged with full recovery. HaNDL syndrome is a diagnosis of exclusion. High degree of suspicion and characteristic clinical and laboratory findings are important to recognize.&#x0D; J Dhaka Medical College, Vol. 29, No.1, April, 2020, Page 89-91

Scrub typhus meningoencephalitis in children: A single centre, observational study from Eastern India

Background: Scrub typhus is being reported from different parts of India. Meningitis or meningoencephalitis among various neurological complication seen in scrub typhus is not uncommon. Delay in diagnosis may cause higher mortality without prompt treatment. The aim of the study was to describe the various manifestations of scrub typhus meningoencephalitis and their outcome from eastern part of India. Subjects and Methods: A prospective observational study of scrub meningoencephalitis was carried out at Kalinga Institute of Medical Sciences, between October 2018 and August 2020.The diagnosis was made based on the compatible clinical features, positive Scrub Ig M by ELISA and cerebrospinal fluid lymphocytosis (>5 cell/cmm), after excluding other causes of meningoencephalitis. Results: Twenty-seven (12.38%) cases of scrub meningoencephalitis were included in the study with male (66.6%) predominance. All had presented with fever of mean duration of 8.5 days of illness. Altered sensorium and seizure was observed in 70.5% and 62.9% of our patients along with two patients who had sixth cranial nerve palsy. Eschar was found in 25.9% of our children. The mean CSF cell count, protein and glucose were 25 cells/cmm,84.2 mg/dL and 62.9 mg/dL respectively with lymphocytosis in all cases. There was no mortality in this study. Conclusion: Meningoencephalitis is an important complication of scrub typhus in children. Unlike most viral encephalitis cases, it has a definite treatment with good outcome, if treated early.

Headache, confusion, and behavioral changes - a HaNDL case report

Background: The clinical syndrome of headache and neurological deficits and cerebrospinal fluid lymphocytosis (HaNDL) is recognized as a self-limiting condition consisting of discrete episodes of neurological deficit associated with moderate to severe headache. The spectrum of neurological features most commonly include aphasia, sensory, and motor disturbances. However, confusion and agitation has also been described. Case Presentation: We present an unusual case of a 28-year-old male with recurrent hospital presentations for headache, confusion, and other neurological stigmata over a period of 15 days, culminating in a diagnosis of HaNDL following extensive investigations. He was treated empirically for viral encephalitis initially; however, there were no positive results on virology screening. In addition, autoimmune screens were also negative. He was then managed symptomatically and discharged from hospital with resolution of symptoms thereafter. Conclusion: The differential diagnoses for transient acute confusional disorders remain expansive, with HaNDL being one of the many rare causes. Rigorous testing is required to exclude infective, inflammatory, ischemic, structural, or iatrogenic pathology, whil HaNDL primarily remains a diagnosis of exclusion.

Generalized Convulsions- a rare Presentation of HaNDL Syndrome

Headache with Neurologic Deficits and cerebrospinal fluid Lymphocytosis (HaNDL) syndrome is a rare entity related to migrainous headaches. It is a benign, self-limited disorder, which is characterized by transient neurological symptoms and cerebrospinal fluid lymphocytosis. The International Headache Society criteria requires, episodes involve migraine-like headache along with weakness, sensory changes, and/or aphasia lasting at least 4 hours. The cerebrospinal fluid is notably abnormal, with an elevated protein and lymphocyte count greater than 15 cells/μL. Episodes typically recur but resolve without long-term sequalae. The most frequent neurologic signs are hemiparesis, hemisensory disturbances, and aphasia. Electroencephalogram (EEG) studies have shown that patients with HaNDL may have non-specific non-epileptiform changes such as asymmetrical generalized slowing, intermittent rhythmic delta activity and triphasic waves on their EEG. On our literature review, there are no reports of convulsive seizures that have been reported as a symptom of HaNDL. Our patient met the diagnostic criteria of HaNDL but had a unique neurological symptom of convulsive seizures.

The syndrome of transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis (HaNDL): a description of three patients

Three clinical cases of the syndrome of transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis (HaNDL) are first described in Russian literature. The patients were young (aged 30–35 years), had symptoms characteristic of the prodromal period of infections. In all the patients, the disease started with intense headache, followed by focal neurological symptoms: aphasia and hemihypesthesia in all cases and confusion with psychomotor agitation in two cases. All the three patients showed spontaneous recovery within 2–3 days. Perfusion computed tomography, magnetic resonance imaging, and electroencephalography are compared in one of the cases. The differential diagnosis of HaNDL with acute cerebrovascular accident, herpetic encephalitis, epilepsy, and migraine is discussed.

An adult woman with transient headache, neurological deficits, and lymphocytic pleocytosis (HaNDL syndrome) with intracerebral melanosis: case report

Headache with a neurological deficit and cerebrospinal fluid (CSF) lymphocytosis (HaNDL) is usually under-recognized and under-reported. HaNDL is a self-limiting condition, but the grave symptoms require a large-scale differential diagnosis. We report a case of a 24-year-old female who developed dysarthria for several hours and decreased use of the right arm with right-sided facial weakness. After extensive investigation of blood, CSF, and neuroimaging, we excluded central nervous system infections and autoimmune and vascular diseases. A diagnosis of HaNDL was made according to clinical symptoms and CSF analysis. The prognosis was good, and the symptoms resolved. Repeated physical examination after 48 h was unremarkable. HaNDL is probably not as rare as commonly thought; awareness of its existence can avoid unnecessary and potentially harmful investigations and therapies. The clinical challenge relies on the fact that it remains a diagnosis of exclusion.

HaNDL with bilateral central venous occlusions.

BackgroundThe syndrome of Headache and focal Neurological Deficits with cerebrospinal fluid Lymphocytosis (HaNDL) is considered a rare, idiopathic and self-limited condition.MethodsWe present a patient with HaNDL who had unique findings of florid optic disc haemorrhages from bilateral central retinal vein occlusions.ResultsOur patient made a full recovery with conservative management.ConclusionIt is important for medical attendants to recognise that HaNDL syndrome can be associated with neuro-ophthalmic complications.

2652. Cytomegalovirus Meningoencephalitis: A Comparison to Other Viral CNS Infections

BackgroundCytomegalovirus (CMV) is a rare cause of meningoencephalitis (ME) with clinical data limited to case reports.MethodsRetrospective observational study of all viral central nervous system (CNS) infections identified in 17 hospitals in the Greater Houston area from 2000 to 2017. CMV, herpes simplex virus (HSV), varicella zoster virus (VZV), and enterovirus were all identified by a positive cerebrospinal fluid (CSF) polymerase chain reaction (PCR) and all arboviruses were identified by serology.ResultsA total of 361 patients with viral CNS infections were identified: CMV (n = 33), enterovirus (n = 147), herpes simplex virus (n = 83), varicella zoster virus (n = 28), and arbovirus (n = 70). CMV ME occurred more frequently in immunosuppressed patients [e.g., Acquired Immune Deficiency Syndrome (AIDS)], had more hypoglycorrhachia (59%), and had worse clinical outcomes (61%) as compared with those with HSV, enterovirus, VZV and arboviruses. Furthermore, CMV ME had more altered mental status than enterovirus and HSV and had lower CSF pleocytosis compared with HSV. Additionally, CMV ME had higher CSF protein levels than enteroviral infections and had less CSF lymphocytosis than HSV and VZV.ConclusionCMV meningoencephalitis is seen more frequently in immunosuppressed patients (e.g., AIDS), is associated with more hypoglycorrhachia and have worse clinical outcomes compared with other viral CNS pathogens.Disclosures All authors: No reported disclosures.

Generation of three isogenic induced Pluripotent Stem Cell lines (iPSCs) from fibroblasts of a patient with Aicardi Goutières Syndrome carrying a c.2471G>A dominant mutation in IFIH1 gene.

Aicardi-Goutières syndrome (AGS) is an early-onset monogenic encephalopathy characterized by intracranial calcification, leukodystrophy and cerebrospinal fluid lymphocytosis. To date, seven genes have been related to AGS. Among these, IFIH1 encodes for MDA5, a cytosolic double-stranded RNA receptor, and is responsible for AGS type 7. We generated three isogenic iPSC clones, using a Sendai virus-based vector, starting from fibroblasts of a patient carrying a dominant mutation in IFIH1. All lines were characterized for genomic integrity, genetic uniqueness, pluripotency, and differentiation capability. Our clones might offer a good model to investigate AGS7 pathophysiological mechanism and to discover new biomarkers for this condition treatment.

Chorea and the effectiveness of steroids in a patient with the syndrome of transient headache with neurologic deficits and cerebrospinal fluid lymphocytosis: a case report.

BackgroundThe clinical manifestations of the transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis (HaNDL) syndrome are variable, and involuntary movements have not been reported. The etiology and treatment of the syndrome are not entirely clarified.CaseA 25-year-old female presented with recurrent transient headache, involuntary movements (left upper extremity chorea) and paralysis. Lumbar punctures showed intracranial hypertension and cerebrospinal fluid pleocytosis. Symptoms and intracranial hypertension were relieved after administration of steroids.Discussion/conclusionChorea may also present in the HaNDL syndrome. Steroids might relieve the symptoms of the HaNDL syndrome, which indicates the possible treatment strategy for HaNDL and supports the infectious or postinfectious autoimmune etiology hypothesis.

Syndrome of Transient Headache and Neurological Deficits with Cerebrospinal Fluid Lymphocytosis (HaNDL): A Case Report with Newly Described Electroencephalography (EEG) findings, Symptomatic Treatment Strategies, and Literature Review (P5.10-008)

Syndrome of Transient Headache and Neurological Deficits with Cerebrospinal Fluid Lymphocytosis (HaNDL): A Case Report with Newly Described Electroencephalography (EEG) findings, Symptomatic Treatment Strategies, and Literature Review (P5.10-008)