Idiopathic hypertrophic pachymeningitis with anticardiolipin antibody: A case report.

RATIONALE: Idiopathic hypertrophic pachymeningitis (IHP) is a rare neurological disorder without a definite etiology. Diagnosis is mainly based on exclusion of other etiologies. PATIENT CONCERNS: A 41-year-old male patient presented with insidious onset headache of 3-month duration. DIAGNOSES: Contrast-enhanced brain magnetic resonance imaging (MRI) revealed diffuse pachymeningeal enhancement over bilateral cerebral hemispheres and the tentorium cerebelli. Lumbar puncture showed increased pressure, lymphocytic pleocytosis, and elevated protein level with normal glucose concentration. Blood tests detected elevated erythrocyte sedimentation rate (ESR) and C-reactive protein. Pathological examination of the dura mater from the right frontal convexity disclosed coarse collagenous deposition with focal lymphoid aggregation. After malignancy and infectious etiologies were excluded, a diagnosis of IHP was made. INTERVENTIONS: Oral prednisolone and azathioprine followed by methotrexate were administered. OUTCOMES: During the 7-year follow-up period, although the patient was not totally headache-free, medical therapy significantly reduced the severity of headache. Follow-up MRI studies showed a reduction in meningeal enhancement and serial ESR measurements revealed a trend of improvement. LESSONS: Methotrexate therapy may be considered in cases of steroid-resistant IHP. In addition to clinical evaluation, serial ESR testing may be considered to guide the treatment strategy and assess the response to therapy.

Herpes simplex virus type 2 meningitis as a manifestation of Good's syndrome.

Good's syndrome is a primary immunodeficiency phenocopy characterized for thymoma and immunodeficiency. The most frequent clinical presentation is recurrent or opportunistic infections, hematological alterations, and chronic diarrhea. We treated a 66-year-old man who consulted for 5 days of headache and diplopia with right sixth cranial nerve palsy at examination. Patient reported chronic diarrhea and prolonged febrile syndrome accompanied by weight loss of 23 kg in the last year. Exhaustive evaluation revealed Herpes simplex virus (HSV) type 2 meningitis, eosinophilic colitis, and type A thymoma. Severe antibody deficiency (hypogammaglobulinemia) associated with thymoma confirmed the diagnosis of Good's syndrome.

Neurologic Deficits in Patients With Newly Diagnosed Celiac Disease Are Frequent and Linked With Autoimmunity to Transglutaminase 6.

BACKGROUND & AIMS: Celiac disease is an autoimmune disorder induced by ingestion of gluten that affects 1% of the population and is characterized by gastrointestinal symptoms, weight loss, and anemia. We evaluated the presence of neurologic deficits and investigated whether the presence of antibodies to Transglutaminase 6 (TG6) increases the risk of neurologic defects in patients with a new diagnosis of celiac disease. METHODS: We performed a prospective cohort study at a secondary-care gastroenterology center of 100 consecutive patients who received a new diagnosis of celiac disease based on gastroscopy and duodenal biopsy. We collected data on neurologic history, and patients were evaluated in a clinical examination along with magnetic resonance imaging of the brain, magnetic resonance (MR) spectroscopy of the cerebellum, and measurements of antibodies against TG6 in serum samples. The first 52 patients recruited underwent repeat MR spectroscopy at 1 year after a gluten-free diet (GFD). The primary aim was to establish if detection of antibodies against TG6 can be used to identify patients with celiac disease and neurologic dysfunction. RESULTS: Gait instability was reported in 24% of the patients, persisting sensory symptoms in 12%, and frequent headaches in 42%. Gait ataxia was found in 29% of patients, nystagmus in 11%, and distal sensory loss in 10%. Sixty percent of patients had abnormal results from magnetic resonance imaging, 47% had abnormal results from MR spectroscopy of the cerebellum, and 25% had brain white matter lesions beyond that expected for their age group. Antibodies against TG6 were detected in serum samples from 40% of patients-these patients had significant atrophy of subcortical brain regions compared with patients without TG6 autoantibodies. In patients with abnormal results from MR spectroscopy of the cerebellum, those on the GFD had improvements detected in the repeat MR spectroscopy 1 year later. CONCLUSIONS: In a prospective cohort study of patients with a new diagnosis of celiac disease at a gastroenterology clinic, neurologic deficits were common and 40% had circulating antibodies against TG6. We observed a significant reduction in volume of specific brain regions in patients with TG6 autoantibodies, providing evidence for a link between autoimmunity to TG6 and brain atrophy in patients with celiac disease. There is a need for early diagnosis, increased awareness of the neurologic manifestations among clinicians, and reinforcement of adherence to a strict GFD by patients to avoid permanent neurologic disability.

CGRP, Amylin, Immunology, and Headache Medicine.

BACKGROUND: Calcitonin gene-related peptide (CGRP) therapeutics introduce new excitement and possibly yet to be determined distressing discords in the field of Headache Medicine. Growth in knowledge of CGRP in the pathophysiology of migraine introduced CGRP antagonism to headache treatment. Potential adverse effects on the other circulatory and neurovascular diseases have been foremost concerns. Failures in development of gepants and growth in knowledge of monoclonal antibody therapeutics combined to deliver the anti-CGRP monoclonal antibodies (mAbs). CURRENT SITUATION AS OF JULY 2018: Erenumab, eptinezumab, fremanezumab, and galcanezumab are approved, submitted to, or preparing for submission at both the European Medicines Agency and the US Food and Drug Administration (FDA). METHODS: This Headache Currents update emanates from a symposium on CGRP and immunology in Headache Medicine, and reviews both. RESULTS AND CONCLUSION: Understanding CGRP in Headache Medicine requires information on aspects of the CGRP ligand, cell surface G protein receptor, CGRP receptor specifics, and antagonism by CGRP small and large molecules. Recent reports of CGRP's high affinity for amylin receptors dictate some attention to this family-related peptide. To better understand potential immunogenic risks and off-target toxicities of the anti-CGRP monoclonal antibodies, this review discusses immunology and CGRP and reviews IgG structure and function, monoclonal antibody production, ligand-antigen-antibody relationships, and clinical CGRP mAb specifics. Upon completion, the reader should better summarize CGRP antagonist fundamentals, recall antibody structure and function, restate therapeutic mAbs attributes, and appraise immunogenic risks.

Central nervous system involvement in patients with granulomatosis with polyangiitis: a single-center retrospective study.

The aims of this study were to estimate the frequency of central nervous system (CNS) involvement in Greek patients with granulomatosis with polyangiitis (GPA) and describe the related clinical characteristics and long-term outcomes of these patients. Medical charts of all ANCA-associated vasculitis patients were retrospectively reviewed, and GPA patients with CNS involvement were identified. Demographics, serological, and clinical features throughout the disease course were recorded. Comparisons of disease characteristics and long-term outcomes were performed between GPA patients with and without CNS involvement. Seventy-seven GPA patients were studied. Of these, 9 (11.7%) developed CNS manifestations. At the time of CNS involvement, all patients had increased acute phase reactants, and all but one had vasculitic manifestations in multiple systems and increased ANCA titers. CNS manifestations included the following: sensor/sensorimotor symptomatology (33.3%), severe headache and hearing loss (33.3%), delirium/seizures (22.2%), diplopia (11.1%), and cerebellar symptoms (11.1%). At initial GPA diagnosis, patients with CNS involvement, compared to those without, had ENT involvement more frequently (77.8 versus 25.4%, p = 0.004) along with a lower disease activity (BVAS) while during the overall disease course, they experienced lung vasculitis less frequently (44.4 vs. 79.4%, p = 0.02). Comparisons between the two groups did not reveal any differences regarding the long-term outcomes, including relapse rate, treatment-related adverse events, and patient survival. CNS involvement was recorded in 11.7% of our GPA patients. At disease onset, ENT involvement and lower BVAS scores were more common in GPA patients with CNS manifestations. Based on our results, CNS involvement did not affect the long-term outcomes of GPA patients.

Diagnosis and classification of central nervous system vasculitis.

Central nervous system vasculitis is one of the foremost diagnostic challenges in rheumatology. It results in inflammation and destruction of the vasculature within the CNS. When vasculitis is confined to brain, meninges or spinal cord, it is referred to as primary angiitis of the CNS. Secondary CNS vasculitis occurs in the setting of a systemic vasculitis, auto-inflammatory or infectious disease. Prompt and accurate diagnosis of CNS vasculitis is essential to prevent irreversible brain damage, and to secure precise treatment decisions. Progressive debilitating and unexplained neurological deficits, associated with abnormal cerebrospinal fluid is the typical picture of the disease. Biopsy of the brain remains the gold standard diagnostic test. The differential diagnosis of CNS vasculitis is highly diverse with a broad array of mimics at the clinical, radiographic and angiographic levels.

Relationship between headache and mucosal mast cells in pediatric Helicobacter pylori-negative functional dyspepsia.

BACKGROUND: Although many patients with functional dyspepsia experience headache concurrently with dyspeptic symptoms, studies suggesting mechanisms underlying this phenomenon are limited. Herein, we explore the relationship between gastrointestinal inflammatory cells and presence of headache associated with dyspeptic symptoms in children with HELICOBACTER PYLORI -negative functional dyspepsia. METHODS: Fifty-six patients with H. PYLORI -negative functional dyspepsia underwent upper endoscopy with biopsy to investigate recurrent epigastric pain or discomfort. Patients were divided into two groups according to self-reported presence of headache associated with dyspeptic symptoms. Inflammatory cells including mast cells, and enteroendocrine cells in the gastroduodenal mucosa were evaluated. Associations between headache presence and cellular changes in the gastroduodenal mucosa were examined. RESULTS: Headache was not associated with the grade of lymphocytes, neutrophil infiltration, or enteroendocrine cell density in the gastroduedenal mucosa. However, headache was significantly associated with high mast cell density in the body (27.81 ± 8.71 vs. 20.30 ± 8.16, P < 0.01) and duodenum (23.16 ± 10.40 vs. 14.84 ± 5.88, P < 0.01). CONCLUSIONS: Presence of headache associated with dyspeptic symptoms is strongly related to mucosal mast cell density in pediatric patients with H. PYLORI -negative functional dyspepsia. Thus, our results may help clinicians understand and treat headache during dyspeptic symptoms in such pediatric patients.

Presentation of opsoclonus myoclonus ataxia syndrome with glutamic acid decarboxylase antibodies.

In this rare case, the patient presented with opsoclonus, myoclonus and ataxia. Serological and imaging studies revealed high glutamic acid decarboxylase antibody (GAD-Ab) levels. High-dose corticosteroids were of no benefit and subsequent intravenous immunoglobulin (IVIg) administration proved resolution of the condition. Levetiracetam proved useful in symptomatically controlling the myoclonus. Follow-up GAD-Ab levels were within normal limits.

Atypical presentation of Behçet's disease with central nervous system involvement successfully treated with infliximab.

Central nervous system involvement is a rare and serious complication of Behçet's disease (BD). Herein, we describe a patient with an atypical central lesion, who experienced progressive hypesthesia of the right arm and sensory loss of the trigeminal nerve together with intense headache. A repeated biopsy was necessary to conclusively establish the diagnosis of BD. Therapy with infusions of infliximab led to a remarkable full remission. TNFα-blocking therapy was successfully replaced by azathioprine. The present well-illustrated case demonstrates the difficulty of establishing the diagnosis of BD with central nervous system involvement, the dramatic benefit of short given TNF-α-blocking agent, and the long-term remission with azathioprin.

IgG4-related hypophysitis: a new addition to the hypophysitis spectrum.

CONTEXT: Hypophysitis is a chronic inflammation of the pituitary gland that comprises an increasingly complex clinicopathological spectrum. Within this spectrum, lymphocytic and granulomatous hypophysitis are the most common forms, but newer variants have recently been reported. OBJECTIVE: The aims of the study were to describe a new patient with IgG4-related hypophysitis, review the published literature, and provide diagnostic criteria. SETTING: A 75-yr-old man presented with a 1-yr history of frontal headache. Initial studies revealed panhypopituitarism and a mass in both the sella turcica and the sphenoidal sinus. The patient underwent transphenoidal surgery, initiated high-dose prednisone followed by hormone replacement therapy, and was closely monitored for 3 yr. RESULTS: Symptoms improved after prednisone, along with shrinkage of the pituitary and sphenoidal masses, but recurred when prednisone dose was lowered. Histopathology showed a marked mononuclear infiltrate in both the pituitary and sphenoidal specimens, mainly characterized by increased numbers of plasma cells. Many of the infiltrating plasma cells (>10 per high-power field) were IgG4-positive. Review of the literature identified 11 cases of IgG4-related hypophysitis (two diagnosed based on pituitary histopathology). CONCLUSIONS: We describe the first Caucasian patient with biopsy-proven IgG4-related hypophysitis and provide classification criteria for this disease.

Sjogren's syndrome-associated meningoencephalomyelitis: cerebrospinal fluid cytokine levels and therapeutic utility of tacrolimus.

Serial changes in the circulating and cerebrospinal fluid (CSF) cytokine levels were assessed in a patient with Sjogren's syndrome (SS)-associated meningoencephalomyelitis. A 16-yr-old girl diagnosed as having primary SS at 8 yr of age presented headache and vomiting. CSF studies revealed lymphocyte-dominant pleocytosis and high IgM index, but no evidence of infection. Disturbed consciousness and diffuse slow waves on electroencephalogram led to the diagnosis of SS-meningoencephalitis. The clinical condition subsided after a cycle of dexamethasone therapy, however, 2 months later urinary retention and paresthesia of the lower body developed. Craniospinal magnetic resonance imaging (MRI) showed extensive intraparenchymal lesions with high T2-weighted signal intensity adjacent to the posterior left horn of lateral ventricle of the brain and the longitudinal lesion from C5 to T10 of the spinal cord. High-dose methyl-prednisolone and subsequent tacrolimus therapy has effectively controlled the activity of SS-meningoencephalomyelitis. Monitoring of systemic and CSF cytokine levels during the course of illness revealed that CSF interleukin-6, but not interferon-gamma or tumor necrosis factor-alpha levels were the sensitive indicator of disease activity. The unique cytokine profile, differing from those of infectious meningitis may be useful for predicting the central nervous system involvement in autoimmune disease.

Effects of alcohol hangover on cytokine production in healthy subjects.

A hangover is the syndrome of physical and mental symptoms that occurs 8 to 16 h after alcohol consumption with a zero level of alcohol. The aim of the current study was to investigate the effects of the alcohol hangover on cytokine production in healthy subjects. The hangover state was defined as 13 h after drinking 1.5 g/kg of alcohol (blood alcohol level=0). A venous blood sample was taken from 20 healthy adult men before consumption of alcohol and during the hangover state. Peripheral blood mononuclear cells were separated and stimulated with phytohemagglutinin. An enzyme-linked immunosorbent assay was used to measure the production of the following cytokines: interleukin (IL)-1beta, IL-4, IL-6, IL-10, IL-12, interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha). We found that the concentrations of IL-10, IL-12, and IFN-gamma were significantly increased during the hangover state compared with the concentrations in normal conditions. These results support the suggestion that the dysregulated cytokine pathway (IL-10, IL-12, and IFN-gamma) is associated with the symptoms of hangovers.

Successful treatment of headache related to intravenous immunoglobulin with antimigraine medications.

In order to investigate headache related to intravenous immunoglobulin, we studied a 36-year-old woman with a history of migraine receiving weekly intravenous immunoglobulin for refractory myasthenia gravis who experienced severe headaches with each treatment. Neurological examination, CT scan of the head, and a lumber puncture after the first headache were normal. Significant therapeutic response was based upon 50% reduction in pain and associated features. Headache features included throbbing pain which worsened with head movement and was associated with severe photophobia and nausea. Sumatriptan, 6 mg subcutaneous, reduced headache significantly with resolution of associated complaints. Treatment prior to intravenous immunoglobulin with dihydroergotamine mesylate resulted in development of only a mild dull ache without further development of severe head pain. Dihydroergotamine mesylate was also abortive in the few instances when the headache worsened. Headaches associated with intravenous immunoglobulin may have features of migraine and may be successfully prevented and/or treated with 5-HT1D receptor agonists.

Antinuclear antibodies in children with chronic nonspecific complaints.

Children who are chronically complaining nonspecific symptoms such as headache, fatigue, abdominal pain, and low grade fever are commonly seen in daily pediatric outpatient clinics. Some of them are unable to go to school and are diagnosed as school refusal by physicians or educational staff. On the other hand, there are children who do not fulfill any criteria of collagen diseases and whose anti-nuclear antibodies (ANA) are found to be positive. Some of these children have chronic nonspecific complaints. We prospectively studied the prevalence of ANA in children who visited a pediatric outpatient clinic because of chronic nonspecific complaints. Surprisingly, 74 out of 140 symptomatic children (52.4%) were positive for ANA, while only 5 out of 82 healthy control children (6.1%) were positive (p < 0.0001). 39 of 74 ANA positive patients (52.1%) have low ANA titers < or = 1:80, nevertheless 36 patients (47.9%) have high ANA titers > or = 1:160. ANA fluorescent patterns were homogeneous and speckled in 75.3%, speckled in 17.6% and others in 6.8%. ANA positive patients tended to have general fatigue and low grade fever, while gastrointestinal problems such as abdominal pain and diarrhea and orthostatic dysregulation symptoms were commonly seen in ANA negative patients. Children who were unable to go to school more than 1 day a week were seen significantly more in ANA positive patients than in negative patients. Autoantibody analysis using Western immunoblot revealed that 26 out of 63 ANA positive sera (41.3%) had antibodies to the 62 kD protein which had not been previously noticed. These data suggest that autoimmune mechanism may play a role in childhood chronic nonspecific symptoms. We therefore propose a new disease entity of the autoimmune fatigue syndrome in children. When chronically complaining children visit a pediatric out-patient clinic, immunological approaches should be considered before they are discriminated as school refusal or having psychogenic disorders.

The cytokine theory of headache.

Immune cell cytokines are proposed as the common mediators of headache. This unifying concept can not only account for headache, but also the prostaglandins, leukotrienes, platelet activating and vasoactive substances linked with headache, the varied symptoms associated with headache and the high incidence of headache with depression, infectious disease, trauma and in premenopausal women. The immune system as the central mediator of headache is consistent with the promoting effect of estrogen, the abortive activity of cortisol and the prophylactic properties of fish oil and evening primrose oil. This hypothesis provides a unified mechanism to explain headache triggered by food, infectious disease or trauma.