Hypertrophic Pachymeningitis - Differential Diagnosis Framework Pachymeningitis is a rare condition that causes areas of a layer of tissue that surrounds the spinal cord and brain (dura mater) to thicken and become inflamed. This thickening can cause different symptoms based on its location. Some people may have vision changes, headaches, or hearing loss. Idiopathic Infective • Neurosyphilis • CNS tuberculosis: tuberculous pachymeningitis • CNS cryptococcosis • Bacterial meningitis Inflammatory • IgG4-related hypertrophic pachymeningitis • GPA • Neurosarcoidosis • Polyarteritis nodosa • Rheumatoid arthritis • Relapsing polychondritis • Behçet disease Other • Rosai-Dorfman disease • Hemodialysis • Mucopolysaccharidoses Tumors • Dural metastases CT Imaging: • Subdural collection • Acquired tonsillar ectopia • Dural venous sinus distention • Layer cake skull: diffuse layered calvarial hyperostosis seen in 14-32% of patients MRI Imaging: • The most common qualitative finding is pachymeningeal thickening and enhancement • dural venous engorgement • tonsillar herniation • Subdural collection Changes in Perfusion/Pressure • Intracranial hypotension - Primary: spontaneous intracranial hypotension - Secondary: iatrogenic (lumbar puncture or surgery) - Frontotemporal brain sagging syndrome (FBSS) - type 1: dural tear - type 2: lateral leak - type 3: CSF-venous fistula - type 4: distal nerve root sleeve leaks • Cerebral venous thrombosis CT • Subdural collection • Acquired tonsillar ectopia • Dural venous sinus distention • Layer cake skull: diffuse layered calvarial hyperostosis seen in 14-32% of patients MRI • The most common qualitative finding is pachymeningeal thickening and enhancement • dural venous engorgement • tonsillar herniation • Subdural collection #Hypertrophic #Pachymeningitis #HP #Neurology #differential #diagnosis

Acute Generalized Exanthematous Pustulosis (AGEP) AGEP is largely a clinical diagnosis based on classical skin findings in a patient who recently started taking one of the commonly implicated agents or had a recent infection. How? The mechanism of development is a T-cell-mediated inflammatory response. Who? Annual incidence of one to five cases per million people. Causes? In about 90% of patients, AGEP is caused by medications. Antibiotics: - cephalosporins - macrolides - aminopenicillins - antifungals - antimalarials - diltiazem Infections: - Parvovirus B19 - Cytomegalovirus - Coxsackievirus - Mycoplasma pneumoniae Diagnostic Criteria: - Fever onset (temperature above 38 degrees Celsius) and pustular rash shortly after starting a potentially triggering medication. - Multiple small pustules with underlying redness. - Elevated white blood cell count with increased neutrophil levels. - Skin biopsy revealing non-bacterial origin. - Rash improvement after stopping the triggering substance. Clinical Presentation? The rash can be associated with: - Facial edema - Purpura - Blisters - Vesicles The rash typically spares mucous membranes, can present with lesions on the lips. During the acute phase, patients often are febrile (temperature greater than 38°C or 100.4°F). Manifestations generally are limited to the skin. Labs? - Leukocytosis and neutrophilia - Elevated transaminases - Reduction in creatinine clearance can occur Typically, the rash resolves spontaneously after removal of the offending agent, with patients unlikely to have any major complications. - Desquamation of the rash typically begins 5 to 7 days after its onset, with full resolution of the rash within 1 to 2 weeks. - AGEP can recur with reexposure to the drug, so patients should be counseled to avoid the offending medication for life. #AGEP #Generalized #Exanthematous #Pustulosis #Dermatology #diagnosis

Hashitoxicosis ‘Leakage’ symptoms of active Hashimoto’s disease - Hashitoxicosis (Htx) can occur during the initial hyperthyroid stage in Hashimoto’s thyroiditis that causes thyroid swelling. - In the early stages of Hashimoto’s disease, the thyroid may make too much thyroid hormone (hyperthyroidism) before not making enough of it (hypothyroidism). 1. Diffuse infiltration of the thyroid by lymphocytes and plasma cells with subsequent follicular atrophy and scarring 2. ‘Leakage’ symptoms of active Hashimoto’s disease as thyroid is damaged due to thyroid cell inflammation and destruction 3. Eventually thyroid is depleted and hypothyroidism sets in ‘Leakage’ phenomenon can occur in several states: - Post-partum thyroiditis - Silent thyroiditis - Thyroiditis de Quervain/Subacute - Initial ‘active’ state of Hashimoto’s thyroiditis #Hashitoxicosis #Hashimotos #Endocrinology #Diagnosis #Pathophysiology

Hashitoxicosis - Autoimmune thyroid disease overlap syndrome of Graves' and Hashimoto's disease Autoimmune thyroid disease overlap syndrome of Graves' and Hashimoto's disease Hashimoto’s Disease → Hypothyroidism • Autoimmune disease leading to thyroid tissue destruction by cell and antibody-mediated immune processes • Thyroid peroxidase (TPO) antibodies (Anti-TPO) • Antithyroglobulin (anti-Tg) Grave’s Disease → Hypothyroidism • Thyroid stimulating immunoglobulin (TSI) antibodies • TSH-receptor antibodies Simultaneously having both Graves’ stimulating and Hashimoto’s blocking antibodies means that your balance of antibodies at any time determines your thyroid function. This state is sometimes called Hashitoxicosis. 15 to 20 percent of people with Graves' disease develop spontaneous hypothyroidism from Hashimoto's thyroiditis. Developing Graves’ disease after Hashimoto’s is quite rare, but it is possible. #Hashitoxicosis #Endocrinology #Pathophysiology #Diagnosis #Graves #Hashimotos

TAFRO TAFRO syndrome was first described in 2010, standing for: - Thrombocytopenia - Anasarca - Fever - Reticulin fibrosis - Organomegaly TAFRO syndrome is considered a variant of multicentric Castleman disease, which is a rare disorder involving an overgrowth of cells in the lymph nodes TAFRO syndrome as a distinct subtype of idiopathic MCD, and as such, iMCD was divided into 2 categories: iMCD with TAFRO (iMCD-TAFRO) and iMCD without TAFRO (iMCD-NOS). Idiopathic MCD without TAFRO typically presents with thrombocytosis, hypergammaglobulinemia, and less severe anasarca Epidemiology: - W > M - 30-40 years old DDX: - Malignancies, including lymphoma, myeloma, mesothelioma, etc - Autoimmune disorders, including systemic lupus erythematosus (SLE), Sjögren’s syndrome, ANCA-associated vasculitis - Infectious disorders, including acid fast bacterial infection, rickettsial disease, Lyme disease, severe fever with thrombocytopenia syndrome (SFTS) - POEMS syndrome - IGG4 - Hepatic cirrhosis - TTP/HUS - Angioimmunoblastic T cell lymphoma - Intravascular large B cell lymphoma Pathophysiology: Hypercytokinemia, with interleukin (IL)-6 along with (VEGF) vascular endothelial growth factor leads to histopathologic changes in LNs and the systemic symptoms Histopathological Diagnoses - The lymph node histopathology of TAFRO syndrome mimics that of MCD; thus, TAFRO syndrome is thought to be a variant of iMCD (iMCD-TAFRO) - Lymph nodes: Atrophic germinal centers with expansion of the interfollicular zone, highly dense endothelial venules, and few mature plasma cells Labs: - Leukocytosis - Thrombocytopenia - Elevated alkaline phosphatase - Normal immunoglobulin levels - Increased CRP/ESR - Hypoalbuminemia Treatment: - 1st line: Glucocorticoid, high dose - 2nd line: Rituximab, Tocilizumab, Cyclosporin A, Thrombopoietin receptor agonists #TAFRO #diagnosis #management #rheumatology #Thrombocytopenia

Inherited Non-hemolytic Disorders of Hyperbilirubinemia == Disorders of Conjugation == Gilbert Syndrome: • 5-10% of the population • Most common hereditary hyperbilirubinemia syndrome • An autosomal recessive syndrome • Has a UGT1A1 activity level of about 30% of normal • Patients typically present as mild, intermittent unconjugated hyperbilirubinemia in otherwise asymptomatic young adults without evidence of hemolysis or liver injury. • Associated with: breastfeeding jaundice and breastmilk jaundice • May manifest only as jaundice on clinical examination; nonspecific symptoms, such as abdominal cramps, fatigue, and malaise, are common Crigler-Najjar Syndromes: • Type I CN is a super rare, autosomal recessive disorder in which patients have no UGT1A1 activity • Presents shortly after birth with serum bilirubin levels greater than 20 to 50 mg/dL. Newborn: associated with bilirubin encephalopathy • Type II CN is an autosomal dominant disorder in which patients have some UGT1A1 activity • Unconjugated hyperbilirubinemia occurs in the first days of life • Bilirubin levels ranging from 7-20 mg/dL • CN syndrome type II rarely results in kernicterus. • Older children and adults, illness and stress may cause temporary increases in bilirubin levels. == Disorders of Reuptake == Rotor Syndrome: • Autosomal recessive disorder in which patients have an increase in conjugated bilirubin in the blood • Defect in hepatic uptake and storage. • Disorder is indistinguishable from DJS and presents with predominantly a mixed conjugated and unconjugated hyperbilirubinemia in otherwise asymptomatic individuals == Disorders of Excretion into Bile == Dubin-Johnson: • Autosomal recessive disorder • Increase in conjugated bilirubin • Defect in secretion of bilirubin glucuronides across the canalicular membrane • Patients are missing a canalicular protein that transports bilirubin glucuronides into bile #Hyperbilirubinemia #Inherited #Congenital #bilirubin #hepatology #diagnosis #gastroenterology

BEE Syndromes - Non-inflammatory Causes Immune-mediated conditions affecting the Brain, Eye, and Ear Visual or auditory symptoms in conjunction with symptoms attributable to central nervous system (CNS) involvement can be seen in several common and less common diseases. Prompt recognition of an underlying autoimmune basis to these conditions is important, as early diagnosis and treatment can prevent permanent disability. Non-inflammatory causes: • Infectious • Syphilis • Tuberculosis with pachymeningitis • HIV • Enteroviral infections • Herpes virus infections • Lyme disease • Malignant • Lymphoma • Infiltrating base of skull neoplasms (e.g., nasal squamous cell carcinoma) • Carcinomatous meningitis • Genetic • Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations due to three prime repair exonuclease 1 (TREX1) mutations • Autosomal dominant optic neuropathy and sensorineural hearing loss—wolfram (WFS1), optic atrophy-1 gene (OPA1) gene • Autosomal recessive—Usher syndrome • X-linked inheritance—Mohr-Tranebjaerg syndrome • Mitochondrial • Harding’s syndrome—Leber’s hereditary optic neuropathy (LHON) plus MRI lesions and clinical consistent with MS • Other • Syndromes of raised intracranial pressure for example, IIH • Migraine with aura #BEE #Syndromes #neurology #noninflammatory #differential #diagnosis

BEE Syndromes - Immune-mediated conditions affecting the brain, eye, and ear Visual or auditory symptoms in conjunction with symptoms attributable to central nervous system (CNS) involvement can be seen in several common and less common diseases. Prompt recognition of an underlying autoimmune basis to these conditions is important, as early diagnosis and treatment can prevent permanent disability. Inflammatory causes: • Susac syndrome • Vogt-Koyanagi-Harada (VKH) disease • Cogan syndrome • Acute disseminated encephalomyelitis • MOG antibody-associated demyelination • Antiphospholipid syndrome • Sjögren syndrome • Systemic lupus erythematosus • Relapsing polychondritis • Behcet disease • Multiple sclerosis • Neuromyelitis optica spectrum disorder • ANCA-associated vasculitides • Neurosarcoidosis #BEE #Syndromes #neurology #inflammatory #differential #diagnosis

Macrophage Activation Syndrome (MAS) Classified among the secondary or acquired forms of haemophagocytic lymphohistiocytosis (sHLH) What? A subset of hemophagocytic lymphohistiocytosis (HLH) that develops on the background of a highly inflammatory disease How? Excessive release of pro-inflammatory cytokines, such as IL-1 and IL-6, leading to widespread inflammation via hemophagocytosis and cytokine overproduction. Where? Seen in: • Systemic juvenile idiopathic arthritis (sJIA) • Adult-onset Still disease • Systemic lupus erythematosus • Kawasaki disease • Periodic fever syndromes Clinical Presentation: • Rapid development of multiorgan failure • Fever is the main clinical manifestation of MAS - Nonremitting fever • Hepatosplenomegaly and generalized lymphadenopathy • Central nervous system (CNS) dysfunction • Hemorrhagic manifestations: from easy bruising to purpura to mucosal bleeding (Petechial or purpuric rash) • Heart, lung, and kidney failure DDX: • Flare of underlying disease (eg, systemic juvenile idiopathic arthritis [SJIA], systemic lupus erythematosus [SLE], AOSD) • Infection (eg, visceral leishmaniasis, brucellosis) • Sepsis • Drug-induced hypersensitivity syndromes • HLH Labs: • Profound cytopenia with leukopenia, anemia, and thrombocytopenia • Liver function tests ↑ AST ↑ ALT ↑ bilirubin level • Hypoalbuminemia • Hypofibrinogenemia • ↑ PT ↑ PTT • ↑ Fibrin degradation products • ↑ D-dimers • ↑ Triglycerides • ↑ Lactate dehydrogenase • ↑ Ferritin > 5000 to 10,000 ng/mL • Hyponatremia • Increased soluble IL-2 receptor alpha (or soluble CD25) • Increased soluble CD163 • Histopathologic features • Macrophage hemophagocytosis in the bone marrow • Increased CD163 staining of bone marrow Histopathologic criteria: Evidence of macrophage hemophagocytosis is found in the bone marrow aspirate sample. Treatment: • Corticosteroids • IVIG • Cyclophosphamide • Plasma exchange #MAS #Macrophage #Activation #Syndrome #Diagnosis #Management #Hematology #Rheumatology

Idiopathic Inflammatory Myopathies (IIM's) RASH + MUSCLE WEAKNESS → Consider idiopathic inflammatory myopathies (IIM's) • Overlap Myositis Any inflammatory myopathy that occurs in association with features of another autoimmune connective tissue disease like antisynthetase syndrome • Inclusion body myositis Inflammatory myopathy affecting both the proximal and distal skeletal muscles • NAM or IMNM Severe proximal weakness, myofiber necrosis with minimal inflammatory cell infiltrate on muscle biopsy, and infrequent extra-muscular involvement. #Idiopathic #Inflammatory #Myopathies #IIMs #diagnosis #rheumatology #dermatology #Myopathy #Rash