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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Clinical characteristics, management, and outcomes of CLIPPERS: A comprehensive systematic review of 140 patients from 100 studies.

INTRODUCTION: Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a rare inflammatory disorder of the central nervous system, characterized by symptoms referable to the brainstem and cerebellum such as, diplopia, gait ataxia and cerebellar dysarthria. The features and outcomes of CLIPPERS remains uncertain. we conducted this comprehensive systematic review to summarize all the existing studies that described CLIPPERS in the literature and to provide a quantitative assessment on the clinical characteristics, management, and outcomes of this rare syndrome. METHODS: A comprehensive search of PubMed and Web of Science databases was conducted from inception until January 15, 2022, was conducted. We only included the cases that clearly reported probable or definite diagnosis of CLIPPERS based on Taieb et al.'s criteria. The quality of the included studies was assessed using the JBI Critical Appraisal Tool. Descriptive statistics were performed to analyze the studies. Data were expressed as mean and standard deviation (SD) for continuous variables and proportions for categorical variables. RESULTS: We identified 100 case reports and series including a total of 140 patients with CLIPPERS (mean age: 46±18 years and males were 60%). The average follow-up duration was 32.27±57.8 months. Ataxia was the most common presenting symptom. Sixteen percent of the cases were associated with malignancy, mostly hematologic malignancies. The overall relapse rate was 59.2%, and the duration of steroid therapy was considerably shorter in the relapsed cases than in the non-relapsed (mean 6.19±7.9 vs. 10.14±12.1 days, respectively, P = 0.04). The overall mortality rate was 10%, but mortality in patients with malignancy was 30% and it was 12% in patients with relapses. In the case of steroid dosing (less than 20 mg/d versus greater than 20 mg/d) there was no significant modification in the risk of relapse. CONCLUSION: CLIPPERS is a rare clinical syndrome that affects mainly middle-aged males. Diagnosis of CLIPPERS is often challenging, and delays in diagnosis and treatment can lead to unfavorable outcomes. Therefore, neurologists should maintain a high index of suspicion for CLIPPERS in any patient presenting with symptoms and signs referrable to the brainstem. These patients should be screened for associated malignancies, especially hematological malignancies. The cases associated with malignancy tend to have worse outcomes. The relapse rate is relatively high. The relapse rate may be associated with worse mortality. Based on our findings, we recommend that CLIPPERS be treated with high-dose steroid therapy for at least ten days during the acute phase with a very slow taper. Prospective studies with a larger sample size are needed to validate our findings and guide the clinical care of these patients.

Isaac Syndrome with Intractable Neuropathic Pain Features: A Case Report.

Isaac syndrome (IS) is a peripheral nerve hyperexcitability state associated with voltage-gated potassium channel (VGKC) complex antibodies. Major manifestations are muscle twitching, stiffness, hypertrophy, and dysautonomic features such as hyperhidrosis [Ahmed and Simmons. Muscle Nerve. 2015;52(1):5-12]. Neuropathic pain is a rare manifestation. We describe a case of IS characterized by muscle twitching and intractable neuropathic pain. Diagnostic workup included elevated VGKC complex antibodies and EMG/NC that showed neuromyotonic discharges. Neuropathic pain was initially difficult to relieve even after using multiple medications, including opiates, benzodiazepines, anticonvulsants, and intravenous immunoglobulin (IVIg). Moderate pain control was eventually achieved with long-term use of carbamazepine and subcutaneous immunoglobulin (SCIg). Common manifestations of IS are muscle twitching, stiffness hypertrophy, and dysautonomia [Ahmed and Simmons. Muscle Nerve. 2015;52(1):5-12]. Sensory manifestations such as neuropathic pain are rare, but, as illustrated by our patient, can be the most distressing symptom. In our patient, not only was neuropathic pain disabling but it also showed the least response to IVIg. The use of 200 mg of long-acting carbamazepine twice daily with weekly SCIg demonstrated the best response. This case highlights an uncommon but potentially resistant symptom of IS.

Reactive Oxygen Species (ROS) and Antioxidants as Immunomodulators in Exercise: Implications for Heme Oxygenase and Bilirubin.

Exercise is commonly prescribed as a lifestyle treatment for chronic metabolic diseases as it functions as an insulin sensitizer, cardio-protectant, and essential lifestyle tool for effective weight maintenance. Exercise boosts the production of reactive oxygen species (ROS) and subsequent transient oxidative damage, which also upregulates counterbalancing endogenous antioxidants to protect from ROS-induced damage and inflammation. Exercise elevates heme oxygenase-1 (HO-1) and biliverdin reductase A (BVRA) expression as built-in protective mechanisms, which produce the most potent antioxidant, bilirubin. Together, these mitigate inflammation and adiposity. Moderately raising plasma bilirubin protects in two ways: (1) via its antioxidant capacity to reduce ROS and inflammation, and (2) its newly defined function as a hormone that activates the nuclear receptor transcription factor PPARα. It is now understood that increasing plasma bilirubin can also drive metabolic adaptions, which improve deleterious outcomes of weight gain and obesity, such as inflammation, type II diabetes, and cardiovascular diseases. The main objective of this review is to describe the function of bilirubin as an antioxidant and metabolic hormone and how the HO-1-BVRA-bilirubin-PPARα axis influences inflammation, metabolic function and interacts with exercise to improve outcomes of weight management.

Deletion of the creatine transporter gene in neonatal, but not adult, mice leads to cognitive deficits.

Creatine (Cr) is a guanidino compound that provides readily available phosphate pools for the regeneration of spent adenosine triphosphate (ATP). The lack of brain Cr causes moderate to severe intellectual disability, language impairment, and epilepsy. The most prevalent cause of Cr deficiency are mutations in the X-linked SLC6A8 (Creatine transporter; CrT) gene, known as CrT deficiency (CTD). One of the most critical areas that need to be addressed is whether Cr is necessary for brain development. To address this concern, the Slc6a8 gene was knocked out in either neonatal (postnatal day (P)5) or adult (P60) mice using a tamoxifen-inducible Cre recombinase driven by the human ubiquitin C (UBC) promoter. Mice were tested in the Morris water maze, novel, object recognition, and conditioned fear 60 days after Slc6a8 deletion. In addition, overnight locomotor activity was analyzed. Mice that had the gene deleted on P5 showed deficits in the Morris water maze and novel object recognition, while there were no deficits in P60 knockout mice. Interestingly, the P5 knockout mice showed hyperactivity during the dark phase; however, when examining control mice, the effect was due to the administration of tamoxifen from P5 to 10. Taken together, the results of this study show that Cr is necessary during periods of brain development involved in spatial and object learning. This study also highlights the continued importance of using proper control groups for behavioral testing.